Asymmetric synthesis of polysubstituted chiral chromans via an organocatalytic oxa-Michael-nitro-Michael domino reaction

A catalytic asymmetric method for the synthesis of polysubstituted chromans via an oxa-Michael-nitro-Michael reaction has been developed. The squaramide-catalyzed domino reaction of 2-hydroxynitrostyrenes with trans-β-nitroolefins produced chiral chromans with excellent enantioselectivities (up to 99% ee), diastereoselectivities (up to >20 : 1 dr), and moderate to good yields (up to 82%).

A catalytic asymmetric method for the synthesis of polysubstituted chromans via an oxa-Michael-nitro-Michael domino reaction of 2-hydroxynitrostyrenes with trans-β-nitroolefins has been accomplished.

Chromans play an essential role in natural products and pharmaceutical molecules (Fig. 1).¹ Given the biological relevance and diverse applications of this indispensable structural motif, numerous valuable methods for building chiral chromans have been developed.² Rapid, direct, and highly atom-economical asymmetric strategies to construct optically active chromans are the first choice.Open in a separate windowFig. 1Selected biologically active compounds.In the past several years, considerable effort has been made to build chiral chroman derivatives with multichiral centers via asymmetric domino reactions³ catalyzed by aminocatalysts,⁴ thiourea organocatalysts⁵ squaramide organocatalysts,⁶ and other organocatalysts.⁷ Among these approaches, the addition to nitroolefins is a simple but highly efficient route to obtain chiral chromans containing nitro-group, and the nitro group can often lead to changes in chemical and physical properties.^{4d–h,4j,5b–d} In 2013, Zhu et al. reported the organocatalytic oxa-Michael-Michael cascade strategy for the construction of spiro [chroman/tetrahydroquinoline-3,3′-oxindole] scaffolds from 2-hydroxynitrostyrenes and N-Boc-protected methyleneindolinones using a squaramide-cinchona bifunctional catalyst.^6a Peng et al. disclosed the highly efficient synthesis of polysubstituted 4-amino-3-nitrobenzopyrans from 2-hydroxyaryl-substituted α-amido sulfones and nitroolefins mediated by chiral squaramides.^6b Furthermore, Yan and Wang''s group developed the squaramide-catalyzed cascade reaction of 2-hydroxychalcones with β-CF₃-nitroolefins to yield CF₃-containing heterocyclic compounds with a quaternary stereocenter.^6c Notably, a general strategy for the synthesis of chiral chromans bearing two nitro moieties was never reported, especially for 2-alkyl-substituted chromans. In 2003, an easy and efficient method for the synthesis of 3-nitrochromans via the reaction of 2-hydroxynitrostyrenes and trans-β-nitroolefins in the presence of DABCO was reported.⁸ Motivated by our previous work concerning the asymmetric synthesis of chromans,^4i,9 this paper presents a highly efficient asymmetric method for the synthesis of polysubstituted chiral chroman derivatives, especially 2-alkyl-substituted chiral types, from 2-hydroxynitrostyrenes and trans-β-nitroolefins using a chiral bifunctional squaramide organocatalyst.^10,11Given these considerations and previous work, the organocatalytic oxa-Michael-nitro-Michael reaction was performed with 2-hydroxynitrostyrene 1a and aliphatic trans-β-nitroolefin 2a as model substrates to examine the feasibility of our approach. Different parameters (5c,d An appropriate basic/nucleophilic moiety is critical to this kind of reaction. Under this consideration, chiral 1,2-diphenylethylenediamine, cyclohexanediamine, and quinine were selected as scaffolds. After a preliminary study, the quinine scaffold revealed excellent stereoinduction for the asymmetric synthesis of the chiral chroman 4a when paired with the squaramide unit (

Catalytic enantioselective bromohydroxylation of cinnamyl alcohols

This work describes an effective enantioselective bromohydroxylation of cinnamyl alcohols with (DHQD)₂PHAL as the catalyst and H₂O as the nucleophile, providing a variety of corresponding optically active bromohydrins with up to 95% ee.

Optically active bromohydrins are obtained with up to 95% ee via asymmetric bromohydroxylation of cinnamyl alcohols with H₂O as nucleophile.

Electrophilic halogenation of olefins allows installation of two stereogenic centers onto the C–C double bond and is one of the most important transformations in organic chemistry.¹ Optically active halogen containing products resulting from asymmetric halogenation would serve as versatile chiral building blocks for organic synthesis. As a result, extensive efforts have been devoted to the development of asymmetric halogenation process. In recent years, great progress has been made in both intramolecular^2,3 and intermolecular^4,5 reaction processes with various types of olefins and nucleophiles. However, there are still challenges remaining to be addressed. In many cases, the developed catalytic systems often only apply to certain ranges of substrates and the reaction reactivity as well as selectivity can''t be rationally adjusted. The substrate scope is also often difficult to be logically extended and requires much experimentation, largely due to the complexity of the reaction systems and the lack of clear understanding of the reaction mechanisms.Halohydroxylation of olefins simply with H₂O as nucleophile is a classic electrophilic addition reaction in organic chemistry and produces synthetically useful halohydrins (Scheme 1). Asymmetric version of such process has been challenging with only a few reports.^6,7 As part of our general intertest in asymmetric halogenation,⁸ recently we have been investigating the intermolecular asymmetric reaction processes, particularly with unfunctionalized olefins, which has been a long standing challenging problem. During such studies, we have found that up to 92% ee could be achieved for the bromoesterification of unfunctionalized olefins with (DHQD)₂PHAL (Scheme 2, eqn (a)).⁹ This work represents an early example of asymmetric halogenation for unfunctionalized olefins with high enantioselectivity. To our delight, high enantioselectivity can also be achieved for bromohydroxylation with H₂O upon further investigation, giving optically active bromohydrins with up to 98% ee (Scheme 2, eqn (b)).¹⁰ In our efforts to expand the reaction scope of the asymmetric bromohydroxylation, we have found that cinnamyl alcohols are effective substrates, giving the corresponding bromohydrins with up to 95% ee. Herein, we report our preliminary studies on this subject.Open in a separate windowScheme 1Asymmetric halohydroxylation of olefins.Open in a separate windowScheme 2Asymmetric oxybromination of olefins.Initial studies were carried out with (E)-3-(4-bromophenyl)prop-2-en-1-ol (1a) as substrate. Several bromine reagents were examined with 10 mol% (DHQD)₂PHAL (3a) (Fig. 1) as the catalyst and 10 mol% (−)-camphorsulfonic acid (CSA) as additive in acetone/H₂O (10 : 1) at −30 °C (Open in a separate windowFig. 1Selected examples of catalyst examined.Studies on reaction conditions^a

Direct β-selectivity of α,β-unsaturated γ-butyrolactam for asymmetric conjugate additions in an organocatalytic manner

The β-selective asymmetric addition of γ-butyrolactam with cyclic imino esters catalyzed by a bifunctional chiral tertiary amine has been developed, which provides an efficient access to optically active β-position functionalized pyrrolidin-2-one derivatives in both high yield and enantioselectivity (up to 78% yield and 95 : 5 er). This is the first catalytic method to access chiral β-functionalized pyrrolidin-2-one via a direct organocatalytic approach.

The asymmetric addition of γ-butyrolactam with cyclic imino esters catalyzed by (DHQD)₂AQN has been developed, which provides an access to β-position functionalized pyrrolidin-2-one derivatives in high levels yield and enantioselectivity.

Metal-free organocatalytic asymmetric transformations have successfully captured considerable enthusiasm of chemists as powerful methods for the synthesis of various kinds of useful chiral compounds ranging from the preparation of biologically important molecules through to novel materials.¹ Chiral pyrrolidin-2-ones have been recognized as important structural motifs that are frequently encountered in a variety of biologically active natural and synthetic compounds.² In particular, the β-position functionalized pyrrolidin-2-one backbones, which can serve as key synthetic precursors for inhibitory neurotransmitters γ-aminobutyric acids (GABA),³ selective GABA_B receptor agonists⁴ as well as antidepressant rolipram analogues,⁵ have attracted a great deal of attention. Therefore, the development of highly efficient, environmentally friendly and convenient asymmetric synthetic methods to access these versatile frameworks is particularly appealing.As a direct precursor to pyrrolidin-2-one derivatives, recently, α,β-unsaturated γ-butyrolactam has emerged as the most attractive reactant in asymmetric organometallic or organocatalytic reactions for the synthesis of chiral γ-position functionalized pyrrolidin-2-ones (Scheme 1). These elegant developments have been achieved in the research area of catalytic asymmetric vinylogous aldol,⁶ Mannich,⁷ Michael⁸ and annulation reactions⁹ in the presence of either metal catalysts or organocatalysts (a, Scheme 1). These well-developed catalytic asymmetric methods have been related to the γ-functionalized α,β-unsaturated γ-butyrolactam to date. However, in sharp contrast, the approaches toward introducing C-3 chirality at the β-position of butyrolactam through a direct catalytic manner are underdeveloped (b, Scheme 1)¹⁰ in spite of the fact that β-selective chiral functionalization of butyrolactam can directly build up α,β-functionalized pyrrolidin-2-one frameworks.Open in a separate windowScheme 1Different reactive position of α,β-unsaturated γ-butyrolactam in catalytic asymmetric reactions.So far, only a few metal-catalytic enantioselective β-selective functionalized reactions have been reported. For examples, a rhodium/diene complex catalyzed efficient asymmetric β-selective arylation^10a and alkenylation^10b have been reported by Lin group (a, Scheme 2). Procter and co-workers reported an efficient Cu(i)–NHC-catalyzed asymmetric silylation of unsaturated lactams (b, Scheme 2).^10c Despite these creative works, considerable challenges still exist in the catalytic asymmetric β-selective functionalization of γ-butyrolactam. First, the scope of nucleophiles is limited to arylboronic acids, potassium alkenyltrifluoroborates and PhMe₂SiBpin reagents. Second, the catalytic system and activation mode is restricted to metal/chiral ligands. To our knowledge, an efficient catalytic method to access chiral β-functionalized pyrrolidin-2-one via a direct organocatalytic approach has not yet been established. Therefore, the development of organocatalytic asymmetric β-selective functionalization of γ-butyrolactam are highly desirable. In conjunction with our continuing efforts in building upon chiral precedents by using chiral tertiary amine catalytic system,¹¹ we rationalized that the activated α,β-unsaturated γ-butyrolactam might serve as a β-position electron-deficient electrophile. This γ-butyrolactam may react with a properly designed electron-rich nucleophile to conduct an expected β-selective functionalized reaction of γ-butyrolactam under a bifunctional organocatalytic fashion, while avoiding the direct γ-selective vinylogous addition reaction or β,γ-selective annulation as outlined in Scheme 2. Herein we report the β-selective asymmetric addition of γ-butyrolactam with cyclic imino esters¹² catalyzed by a bifunctional chiral tertiary amine, which provides an efficient and facile access to optically active β-position functionalized pyrrolidin-2-one derivatives with both high diastereoselectivity and enantioselectivity.Open in a separate windowScheme 2β-Selective functionalization of γ-butyrolactam via metal- (previous work) or organo- (this work) catalytic approach.To begin our initial investigation, several bifunctional organocatalysts¹³ were firstly screened to evaluate their ability to promote the β-selective asymmetric addition of γ-butyrolactam 2a with cyclic imino ester 3a in the presence of 15 mol% of catalyst loading at room temperature in CH₂Cl₂ (entries 1–6, EntryCat.SolventYield^eer^f11aCH₂Cl₂70%40 : 6021bCH₂Cl₂<5%57 : 4331cCH₂Cl₂70%65 : 3541dCH₂Cl₂68%70 : 3051eCH₂Cl₂58%63 : 4761fCH₂Cl₂71%77 : 2371fDCE72%80 : 2081fCHCl₃70%80 : 2091fMTBE68%79 : 21101fToluene63%78 : 22111fTHF45%76 : 24121fMeOH32%62 : 3813^b1fDCE : MTBE75%87 : 1314^c1fDCE : MTBE72%87 : 1315^d1fDCE : MTBE70%85 : 15Open in a separate window^aReaction conditions: unless specified, a mixture of 2a (0.2 mmol), 3a (0.3 mmol) and a catalyst (15 mmol%) in a solvent (2.0 mL) was stirred at rt. for 48 h.^bThe reaction was carried out in 2.2 mL a mixture of dichloroethane and methyl tert-butyl ether (volume ratio = 10 : 1).^cThe reaction was carried out in 2.2 mL a mixture of dichloroethane and methyl tert-butyl ether (volume ratio = 10 : 1) for 24 h.^dThe reaction was carried out in 2.2 mL a mixture of dichloroethane and methyl tert-butyl ether (volume ratio = 10 : 1) and 10 mol% of catalyst was used.^eIsolated yields.^fDetermined by chiral HPLC, the product was observed with >99 : 1 dr by ¹H NMR and HPLC. Configuration was assigned by X-ray crystal data of 4a.The results of experiments under the optimized conditions that probed the scope of the reaction are summarized in Scheme 3. The catalytic β-selective asymmetric addition of γ-butyrolactam 2a with cyclic imino esters 3a in the presence of 15 mol% (DHQD)₂AQN 1f was performed. A variety of phenyl-substituted cyclic imino esters including those bearing electron-withdrawing and electron-donating substituents on the aryl ring, heterocyclic were also examined. The electron-neutral, electron-rich, or electron-deficient groups on the para-position of phenyl ring of the cyclic imino esters afforded the products 4a–4m in 57–75% yields and 82 : 18 to 95 : 5 er values. It appears that either an electron-withdrawing or an electron-donating at the meta- or ortho-position of the aromatic ring had little influence on the yield and stereoselectivity. Similar results on the yield and enantioselectivities were obtained with 3,5-dimethoxyl substituted cyclic imino ester (71% yield and 91 : 9 er). It was notable that the system also demonstrated a good tolerance to naphthyl substituted imino ester (78% yield and 92 : 8 er value). The 2-thienyl substituted cyclic imino ester proceeded smoothly under standard conditions as well, which gave the desired product 4p in good enantioselectivity (88 : 12 er), although yield was slightly lower. However, attempts to extend this methodology to aliphatic-substituted product proved unsuccessful due to the low reactivity of the substrate 3q. It is worth noting that the replacement of Boc group with 9-fluorenylmethyl, tosyl or benzyl group as the protection, no reaction occurred. The absolute and relative configurations of the products were unambiguously determined by X-ray crystallography (4a, see the ESI^†).Open in a separate windowScheme 3Substrate scope of the asymmetric reaction of α,β-unsaturated γ-butyrolactam 2 to cyclic imino esters 3.^{a a}Reaction conditions: unless specified, a mixture of 2 (0.2 mmol), 3 (0.3 mmol) and 1f (15.0 mmol%) in 2.2 mL a mixture of dichloroethane and methyl tert-butyl ether (volume ratio = 10 : 1) was stirred at rt. ^bIsolated yields. ^cDetermined by chiral HPLC, all products were observed with >99 : 1 dr by ¹H NMR and HPLC. Configuration was assigned by comparison of HPLC data and X-ray crystal data of 4a.We then examined the substrate scope of the imide derivatives (Scheme 4). Investigations with maleimides 4r–4u gave 48–61% yield of corresponding products as lower er and dr values than most of γ-butyrolactams. As for methyl substituted maleimides, the reaction failed to give any product.Open in a separate windowScheme 4Substrate scope of the asymmetric reaction of maleimides to cyclic imino esters.^{a a}Reaction conditions: unless specified, a mixture of 2 (0.2 mmol), 3 (0.3 mmol) and 1f (15.0 mmol%) in 2.2 mL a mixture of dichloroethane and methyl tert-butyl ether (volume ratio = 10 : 1) was stirred at rt. ^bIsolated yields. ^cDetermined by ¹H NMR and chiral HPLC.The chloride product 4a ((R)-tert-butyl 4-((R)-3-((E)-(4-chlorobenzylidene)amino)-2-oxotetra hydrofuran-3-yl)-2-oxopyrrolidine-1-carboxylate) was recrystallized and the corresponding single crystal was subjected to X-ray analysis to determine the absolute structure. Based on this result and our previous work, a plausible catalytic mechanism involving multisite interactions was assumed to explain the high stereoselectivity of this process (Fig. 1). Similar to the conformation reported for the dihydroxylation and the asymmetric direct aldol reaction, the transition state structure of the substrate/catalyst complexes might be presumably in the open conformation. The acidic α-carbon atom of cyclic imino ester 3a could be activated by interaction between the tertiary amine moiety of the catalyst and the enol of 3avia a hydrogen bonding. Moreover, the enolate of 3a in the transition state might be in part stabilized through the π–π stacking between the phenyl ring of 3a and the quinoline moiety. Consequently, the Re-face of the enolate is blocked by the left half of the quinidine moiety. The steric hindrance between the Boc group of 2a and the right half of the quinidine moiety make the Re-face of 2a face to the enolate of 3a. Subsequently, the attack of the incoming nucleophiles forms the Si-face of enolate of 3a to Re-face of 2a takes place, which is consistent with the experimental results.Open in a separate windowFig. 1Proposed transition state for the reaction.In conclusion, we have disclosed the β-selective asymmetric addition of γ-butyrolactam with cyclic imino esters catalyzed by a bifunctional chiral tertiary amine, which provides an efficient and facile access to optically active β-position functionalized pyrrolidin-2-one derivatives with high diastereoselectivity and enantioselectivity. To our knowledge, this is the first catalytic method to access chiral β-functionalized pyrrolidin-2-one via a direct organocatalytic approach. Current efforts are in progress to apply this new methodology to synthesize biologically active products.     

Iron-catalyzed tandem reaction of C–Se bond coupling/selenosulfonation of indols with benzeneselenols

An iron-catalyzed tandem reaction of C–Se bond coupling/selenosulfonation was developed. Starting from sample indols and benzeneselenols versatile biologically active 2-benzeneselenonyl-1H-indoles derivatives were efficiently synthesized. The reaction mechanism was studied by the deuterium isotope study and in situ ESI-MS experiments. This protocol features mild reaction conditions, wider substrate scope and provides an economical approach toward C(sp²)–Se bond formation.

Iron-catalyzed tandem reaction of C–Se bond coupling/selenosulfonation.

Due to the important applications in the preparation of synthetic materials,¹ pharmaceutical agents,² fluorescent probes,³ and functional organic materials,⁴ organoselenium compounds synthesis has attracted extensive attention from synthetic chemists. It is known that transition-metal catalyzed cross coupling reaction is the mostly used methodology for the incorporation of a Se atom into aromatic frameworks.⁵ However, prefunctionalization of the substrate is generally requested. Similar methods of C(sp²)–Se bonds formation have been scarcely described.^6–8Comparative to the C(sp)–H, the C(sp²)–H bond activation need more harsh conditions and activated reaction systems.⁹ Considering the significance of diversifying synthetic strategies, our group focuses on tradition-metal catalyzed C–H bond functionalizations.¹⁰ Herein, we report a novel iron-catalyzed direct C(sp²)–H bond activation/C–Se cross coupling reaction of indols with benzeneselenols. Versatile biologically active compounds 2-benzeneselenonyl-1H-indoles were efficiently synthesized in good to high yields. In this reaction, the inactive C(sp²)–H bonds were smoothly direct selenosulfonation under a moderate condition. At last, the reaction mechanism was studied by the deuterium isotope study and the in situ ESI-MS experiments.At first, as shown in EntryFe catalystBaseAdditive1a : 2aYield^b (%)1FeCl₂DBUO₂1 : 102FeBr₂DBUO₂1 : 103Fe(OAc)₂DBUO₂1 : 1194Fe₂(SO₄)₃DBUO₂1 : 1235FeCl₃DBUO₂1 : 1676FeCl₃ImidazoleO₂1 : 1367FeCl₃PiperidineO₂1 : 1498FeCl₃ N, N-DimethylanilineO₂1 : 1469FeCl₃Tri-n-propylamineO₂1 : 13810FeCl3DABCOO₂1 : 15711FeCl₃DBUAgO1 : 1012FeCl₃DBUH₂O₂1 : 13813FeCl₃DBUCH₃COOOH1 : 14214FeCl₃DBUO₂1 : 1.58315FeCl₃DBUO₂1 : 1.565^c16FeCl₃DBUO₂1 : 1.582^d17FeCl₃DBUO₂1 : 1.564^e18FeCl₃DBUO₂1 : 1.577^f19FeCl₃DBUO₂1 : 1.523^gOpen in a separate window^aUnless otherwise noted, reactions conditions were 1a (0.5 mmol), 2a (0.5 mmol), Fe catalyst (5 mol%), base (2 equiv.), additive (2 equiv or under atmosphere), 1,4-dioxane (4 mL), 80 °C for 10 h.^bIsolated yield.^c70 °C.^d90 °C.^eIn CHCl₃.^fIn DMF.^gSolvents not been dried.Next, the reaction scope was been screened, a wide array of indols 1 with benzeneselenols 2 were subjected to this reaction and given the products 3 in good to excellent yields ( EntryRR¹3Yield^b1HH 832H4-Me 843H4-tBu 874H4-OMe 925H4-F 786H4-Cl 817H4-Br 838H4-CF₃ 759H4-NO₂ 6910HNaphthyl 79115-Me4-Me 75127-Me4-Me 76134-OMe4-Me 74145-OMe4-Me 72157-OMe4-Me 67164-OCH₂Ph4-Me 66176-Cl4-Me 90187-Cl4-Me 91193-Me4-Me 65Open in a separate window^aUnless otherwise noted, reaction conditions were 1 (0.5 mmol), 2 (0.75 mmol), FeCl₃ (5 mol%), DBU (2 equiv.), under a O₂ atmosphere, 1,4-dioxane (5 mL), 80 °C for 10 h.^bIsolated yield.Furthermore, we next focused on evaluating the generality of tandem reaction of C–Se bond coupling/selenosulfonation by using a series of pyrroles. To our delight, N-methylpyrrole 4 with benzeneselenols 2 successfully provided the corresponding products 5 ( EntryR³R¹5Yield^b1HH 762H4-Me 793H4-tBu 784H4-F 695H4-Cl 656H4-Br 667H3-Br 688H4-CF₃ 599HNaphthyl 70Open in a separate window^aUnless otherwise noted, reaction conditions were 4 (0.5 mmol), 2 (0.75 mmol), FeCl₃ (5 mol%), DBU (2 equiv.), under a O₂ atmosphere, 1,4-dioxane (5 mL), 80 °C for 10 h.^bIsolated yield.To obtain the preliminary data of the mechanism, some addition reactions were been done (Scheme 1). At first, the model reaction (Scheme 1I) was conducted in two separate steps: the C–Se cross coupling reaction of 6 with 2a given a product 7 (Scheme 1II, 85% yield).¹¹ Next, 7 was reacted under our standard conditions, the reaction successfully obtained the target product 3a (Scheme 1III 79% yield), indicating that the intermediate 7 was involved in the reaction mechanism.Open in a separate windowScheme 1Preliminary data of the reaction mechanism.Next, we used isotope experiments to further study the reaction mechanism, as shown in Scheme 2. The kinetic deuterium isotope effects¹² observed in the control experiments were indicated that the C(sp²)–H cleavage being the rate-limiting step (k_H/k_D = 1.3, for detail information please see ESI^†).Open in a separate windowScheme 2The kinetic deuterium isotope effects.Additionally, the model reaction mixture¹³ was subjected to the in situ ESI-MS analysis which the detection temperature was enacted at 120 °C (Scheme 3). The positive-ion mode ESI-MS showed a peak at 296.0 (m/z) which corresponding to [C₁₄H₁₁NNaSe]⁺. The peak at 328.0 was assigned to [C₁₄H₁₁NNaO₂Se]⁺ (Scheme 3a). Meanwhile, using the ¹⁸O₂ deuterium labeling study gave a peak at 331.9 was assigned to [C₁₄H₁₁NNa¹⁸O₂Se]⁺ (Scheme 3b), also further validated the intermediate components hypothesis (For ESI HR-MS, please see ESI^†).¹⁴Open in a separate windowScheme 3The in situ ESI-MS spectras of iron-catalyzed direct C(sp²)–H bond activation/C–Se cross coupling ((a) for the mode reaction, (b) for the ¹⁸O₂ deuterium labeling reaction).Based on these results, we proposed a possible reaction mechanism (Scheme 4). At the beginning of the reaction, the coordination process of Fe^III and reactant 2 generated a intermediate 10. Then, reactant 1 was converted to intermediate 11 by reacted with DBU. Next, intermediate 12 was provided from intermediate 10 with 11via C–Se bond cross coupling. At last, through the oxidation reaction by O₂, intermediate 12 generated the desired products 3 and concomitantly formed a Fe^III intermediate, which re-entered the catalytic cycle.Open in a separate windowScheme 4Proposed mechanism.     

Construction of cyclopentane-fused coumarins via DBU-catalyzed [3+2] cycloaddition of 3-homoacyl coumarins with cyclic 1-azadienes

The metal-free DBU catalyzed [3+2] cycloaddition of 3-homoacyl coumarins with cyclic 1-azadienes proceeded smoothly to furnish the corresponding highly functionalized cyclopentane-fused coumarins with excellent diastereoselectivity and complete chemoselectivity and in good yields under mild conditions.

A metal-free DBU catalyzed [3+2] cycloaddition of 3-homoacyl coumarins with cyclic 1-azadienes has been developed for the synthesis of cyclopentane-fused coumarins with excellent diastereoselectivity and complete chemoselectivity.

Coumarins¹ and cyclopentane scaffolds² are widely distributed in natural products and display a wide range of biological and pharmacological activities. When combining coumarin skeletons with cyclopentane moieties, the cyclopentane-fused coumarins show interesting biological activities. For example, aflatoxins, which occur naturally, exhibit acute toxicity, teratogenicity, mutagenicity and carcinogenicity (Fig. 1).³ Herbertenolide, which belongs to the family of sesquiterpenoids, was first isolated from the leafy liverwort Herberta adunca, the extract of which showed significant inhibition against the growth of certain plant pathogenic fungi (Fig. 1).⁴ Not surprisingly, the strategies for synthesis of cyclopentane-fused coumarins have attracted much attention.⁵Open in a separate windowFig. 1Bioactive molecule bearing cyclopentane-fused coumarin.Recently, the group of Lin developed a 1,3-dipolar precursor 3-homoacyl coumarin, which is an efficient synthon for the construction of cyclopentane-fused coumarins under the catalysis of bases (Scheme 1a and b).⁶ However, the partners reacted with 3-homoacyl coumarins were focus on α,β-unsaturated carbonyl compounds and conjugated dienes. The other dipolarophiles, such as aza-dienes, might also be potential candidates for the [3+n] cycloadditions with 3-homoacyl coumarins but never been developed.Open in a separate windowScheme 1The reaction of 3-homoacyl coumarins with dipolarophiles catalyzed by Brønsted base.The cyclic 1-azadienes are extensive used dipolarophiles and have been widely involved in a series of cyclization reactions as two-,⁷ three-⁸ or four⁹ member synthons. While the organocatalytic [3+2] cycloaddition of cyclic 1-azadiene as two synthons has rarely been investigated.^7b,c In 2016, Chen''s^7b and Guo''s^7c group respectively developed a asymmetric [3+2] annulation reaction of Morita–Baylis–Hillman carbonates with cyclic 1-azadienes catalyzed by Lewis base. Encouraged by these works above and as our continuing efforts on cycloadditions,¹⁰ herein we expected to achieve the first [3+2] cycloaddition reaction of 3-homoacyl coumarins with cyclic 1-azadienes catalyzed by Brønsted base for synthesis of various functionalized cyclopentane-fused coumarins derivatives efficiently (Scheme 1d). However, Huang''s group reported a enantioselective 1,4-addition reaction of benzofuran azadiene with 3-homoacyl coumarin, instead of cycloaddition (Scheme 1c).¹¹ To achieve our assumption in high chemoselectivity would be a challenging work.In an initial experiment, cyclic 1-azadiene 1a and 6-bromo-3-(2-oxo-2-phenylethyl)-2H-chromen-2-one 2a were employed as the model substrates to carry out the reaction in CH₂Cl₂ at room temperature in the presence of DABCO. To our delight, the desired [3+2] cycloadduct 3aa was obtained in 56% yield ( EntryBaseSolventTime (h)Yield^b (%)dr^c1DABCOCH₂Cl₂2456>20 : 12DMAPCH₂Cl₂2460>20 : 13DBUCH₂Cl₂1278>20 : 14Et₃NCH₂Cl₂2467>20 : 15DBUTHF1286>20 : 16DBUToluene1231>20 : 17DBUDCE1276>20 : 18DBUCH₃CN1273>20 : 1Open in a separate window^aReactions were carried out with 1a (0.1 mmol), 2a (0.12 mmol), and base (20 mol%) in 2 mL of solvent at rt.^bIsolated yields.^cDetermined by ¹H NMR.Under optimal reaction conditions, the substrate scope of the cyclic 1-azadienes 1 was investigated and the results were summarized in EntryR¹ in 13Yield^b (%)dr^c12-FC₆H₄ (1b)3ba85>20 : 123-FC₆H₄ (1c)3ca90>20 : 134-FC₆H₄ (1d)3da85>20 : 143-ClC₆H₄ (1e)3ea86>20 : 154-ClC₆H₄ (1f)3fa80>20 : 163-BrC₆H₄ (1g)3ga79>20 : 174-BrC₆H₄ (1h)3ha80>20 : 184-CNC₆H₄ (1i)3ia75>20 : 192-MeC₆H₄ (1j)3ja79>20 : 1103-MeC₆H₄ (1k)3ka76>20 : 1114-MeC₆H₄ (1l)3la73>20 : 1122-OMeC₆H₄ (1m)3ma67>20 : 1133-OMeC₆H₄ (1n)3na75>20 : 1144-OMeC₆H₄ (1o)3oa77>20 : 1152-Naphthyl (1p)3pa72>20 : 1162-Thienyl (1q)3qa74>20 : 1Open in a separate window^aReactions were carried out with 1 (0.1 mmol), 2a (0.12 mmol), and DBU (20 mol%) in 2 mL of THF at rt for 12–48 h.^bIsolated yields.^cDetermined by ¹H NMR.Subsequently, we performed the application of cyclic 1-azadiene 1a in DBU-catalyzed [3+2] cycloaddition with a variety of 3-homoacyl coumarins 2 under the optimal conditions (12Substrate scope of 3-homoacyl coumarins 2^a

Synthesis of CHF2-substituted 3-azabicyclo[3.1.0]hexanes by photochemical decomposition of CHF2-pyrazolines

A practical synthesis of CHF₂-substituted 3-azabicyclo[3.1.0]hexanes was developed for the first time. The key step was photochemical decomposition of CHF₂-substituted pyrazolines. This protocol has the advantages of simple operation, and mild conditions, as well as excellent functional group tolerance, giving the desired products in moderate to excellent yields.

A general and efficient method has been developed to synthesize CHF₂-substituted 3-azabicyclo[3.1.0]hexane derivatives via photochemical decomposition of CHF₂-pyrazolines.

The 3-azabicyclo[3.1.0]hexyl ring system as a conformationally constrained bicyclic isostere for the piperidine motif displays diverse biological activities and great potential in the pharmaceutical industry.¹ Representative examples of this type of application are potent μ opioid receptor antagonist 1 for the treatment of pruritus,² the ketohexokinase (KHK) inhibitor 2 for the treatment of non-alcoholic fatty liver disease (NAFLD),³ muscarinic receptor antagonist 3 (ref. 4) and T-type calcium channel inhibitor 4 (ref. 5) (Fig. 1). In this context, considerable effort has been devoted to developing general and efficient methods for the synthesis of the 3-azabicyclo[3.1.0]hexane scaffolds (Scheme 1). The elegant early studies focused on the intramolecular cyclopropanation, such as metal-catalyzed oxidative cyclization of 1,6-enynes⁶ and cyclopropanation of N-allylamino acid dimethylamides using Ti(ii) reagents.⁷ Furthermore, the intermolecular cyclization of 3-pyrrolines and metal carbenoids was also a useful tool to construct this core structure.⁸ Although these known procedures had their merits, they were also associated with some drawbacks. For example, requiring long routes for the starting materials preparation and/or using expensive metal catalytic systems. In the last few years, [3 + 2] cycloaddition process has been the most popular method to construct this cyclopropane ring of 3-azabicyclo[3.1.0]hexanes. The coupling of maleimides and hydrazines has been reported by Lunn''s group.⁹ And Jiang and co-workers have disclosed a method of palladium-catalyzed cyclopropanation of maleimides and N-tosylhydrazones.¹⁰ To match the increasing scientific and practical demands, it is still of continued interest and great importance to explore new and straightforward methods to access these highly rigid cyclopropanes with more simple operation.Open in a separate windowFig. 1Representative bioactive compounds with a 3-azabicyclo[3.1.0]hexane core structure.Open in a separate windowScheme 1Construction of 3-azabicyclo[3.1.0]hexane scaffolds.On the other hand, decoration of organic molecules with fluorinated groups often affects their physicochemical and biological properties such as metabolic stability and lipophilicity,¹¹ so organofluorine compounds are widespread in pharmaceuticals, agrochemicals, and advanced functional materials. Among all fluorine-containing groups, difluoromethyl group can develop special effects on molecules: it can be used as a bioisostere of a carbinol moiety and as a more lipophilic hydrogen bond donor.¹² However, protocols for the synthesis of difluoromethylated azabicyclo[3.1.0]hexanes remain to be underexplored. In line with previous work from our group dealing with the preparation of difluoromethyl-substituted pyrazolines using in situ generated difluoromethyl diazomethane,¹³ we report herein the development of a simple and efficient method to synthesize CHF₂-substituted 3-azabicyclo[3.1.0]hexane derivatives from commercially available maleimides.Following our previously established protocol,¹⁴ we initially examined the thermal decomposition of pyrazoline A′, and the desired 3′a was observed in 51% yield, but 3′a was obtained only in 27% yield based on 1-benzyl-1H-pyrrole-2,5-dione 2a (see Scheme S1 and S2^†). Considering the low yield and the tedious operation, we tried to develop a one-pot cascade approach (see Table S1^†). Accidentally, we discovered that photochemical process was more effective than thermal decomposition. As we all know, photochemistry is considered as one of the simplest manifolds of chemical reactivity and photochemical reactions are the key for the synthesis of many reactive intermediates.¹⁵ Accordingly, this phenomenon attracted our attention. On the other hand, considering the quantitative formation of the isomeric Δ²-pyrazoline B′ in the [3 + 2] cycloaddition process, we decided to prevent the formation of the byproduct B′ by taking the simplest higher homologue – CF₂H(CH₃)CNH₂ (Scheme 2).Open in a separate windowScheme 2Synthesis of 3-benzyl-6-difluoromethyl-3-azabicyclo[3.1.0]hexane-2,4-dione.Initial tests were done on CF₂H(CH₃)CHN₂I generated in situ and 1-benzyl-1H-pyrrole-2,5-dione 2a as the model substrates.¹⁶ To our delight, both trans (3a₁) and cis (3a₂) products were isolated separately and the yields of 3a₁ and 3a₂ were 39% and 12%, respectively (†), and an example of which was shown for 3a₁ in Fig. 2. The bridgehead protons were correlated through space to the nearby difluromethyl protons, indicating they were on the same convex side of the bicyclic system. Encouraged by this result, we further optimized the reaction conditions, and the results were showed in Entry1 (equiv.) t-BuONO (equiv.)AcOH (equiv.)SolventLamp power (W)Time (h)Yield^b (%)dr^c3a₁3a₂12.02.40.4Toluene50024391278 : 2223.03.60.6Toluene50024511478 : 2234.04.80.8Toluene50024441476 : 2443.03.60.6THF50024291369 : 3153.03.60.6DMSO50024n.d.n.d.—63.03.60.6Et₂O50024521479 : 2173.03.60.6(i-Pr)₂O50024361275 : 2583.03.60.6i-PrOMe50024511478 : 2293.03.60.6MeCN50024561480 : 20103.03.60.6MeCN40024501676 : 24113.03.60.6MeCN60024581579 : 21123.03.60.6MeCN80024611679 : 21133.03.60.6MeCN1000^d24641680 : 20143.03.60.6MeCN100020631680 : 20153.03.60.6MeCN100028661680 : 20163.03.60.6MeCN100032641779 : 21Open in a separate window^aReaction conditions: a solution of 1-methyl-2,2-difluoroethanamine 1 in CHCl₃ and t-BuONO and HOAc were added in turn. After 10 min heating, the obtained yellow solution was cooled down to a room temperature by external water bath. Then 2a was added into the reaction mixture and stirred at 45 °C. After removing CHCl₃, the residue was dissolved in 5 mL solvent and transferred into a quartz tube which was irradiated with a high-pressure mercury lamp (250–720 nm).^bIsolated yield by chromatography on silicagel.^cDiastereomeric ratio of 3a₁ and 3a₂ was based on column chromatography.^dThis is the maximum power of this lamp.Open in a separate windowFig. 2NOESY of 3a₁ (irradiate hydrogen nuclei of 6-difluoromethyl).With the optimized reaction conditions in hand, the generality of maleimides in this cyclopropanation reaction was examined, and the results were summarized in Open in a separate window^aReaction conditions: a solution of 1-methyl-2,2-difluoroethanamine 1 (0.1 M, 3.0 eq.) in CHCl₃ and t-BuONO (3.6 eq.) and HOAc (0.6 eq.) were added in turn. After 10 min heating, the obtained yellow solution was cooled down to a room temperature by external water bath, and 2 (1.0 eq.) was added immediately. The reaction mixture was stirred at 45 °C for 12 h. After removing CHCl₃, the residue was dissolved by acetonitrile (5 mL) and transferred into a quartz tube which was irradiated with a 1000 W high-pressure mercury lamp for 28 h.^bIsolated yield.^cDiastereomeric ratio of trans and cis products was based on column chromatography.^dIsolated yield combined trans and cis products.^eDiastereomeric ratio was based on ¹H NMR.We further explored its application for the synthesis of the 3-azabicyclo[3.1.0]hexane scaffold. To our satisfaction, the representative reduction of the carbonyl groups in 3a₁ with LiAlH₄ in diethyl ether smoothly gave the pyrrolidine 4a₁ in nearly quantitative yield (Scheme 3).¹⁴ It is worth mentioning that no cyclopropane ring cleavage was observed during this reaction.Open in a separate windowScheme 3Synthesis of 3-azabicyclo[3.1.0]hexane 4a₁.Based on the experimental results and the previous literature,¹⁷ a plausible mechanistic pathway is depicted in Scheme 4 with 2a as a model substrate. Mechanistically, [3 + 2] cycloaddition is carried out with CF₂H(CH₃)CHN₂ and 2a to generate pyrazoline A. Subsequently the photodenitrogenation of pyrazoline occurs by the stepwise cleavage of the two C–N N–C bonds to give a 1,3-biradical. Finally, the 1,3-biradical recombines to give cyclopropane diastereoisomers 3a₁ and 3a₂.Open in a separate windowScheme 4Proposed mechanism.In summary, we have developed a general and efficient method for the synthesis of CHF₂-substituted 3-azabicyclo[3.1.0]hexane derivatives via photochemical process of commercially available maleimides and in situ generated CF₂H(CH₃)CHN₂. It is worth mentioning that both of the diastereoisomers could be easily isolated by silica gel chromatography. This protocol has the advantages of simple operation, mild conditions as well as excellent functional group tolerance. We believe that this method will expand the synthetic arsenal in the field of medicinal chemistry, agrochemistry and organic synthesis.     

Diastereoselective synthesis of new zwitterionic bicyclic lactams,scaffolds for construction of 2-substituted-4-hydroxy piperidine and its pipecolic acid derivatives

The synthesis of new chiral highly functionalized zwitterionic bicyclic lactams starting from acyclic β-enaminoesters derived from (R)-(−)-2-phenylglycinol is described. The key step involved an intramolecular non-classical Corey–Chaykovsky ring-closing reaction of the corresponding sulfonium salts derived from β-enaminoesters. This methodology permits the generation of two or three new stereogenic centers with high diastereoselectivity. The utility of these intermediates was demonstrated by the stereocontrolled total synthesis of cis-4-hydroxy-2-methyl piperidine and its corresponding pipecolic acid derivative.

The synthesis of new chiral highly functionalized zwitterionic bicyclic lactams starting from acyclic β-enaminoesters derived from (R)-(−)-2-phenylglycinol is described.

Stereocontrolled synthesis of polysubstituted piperidines is a very important field in organic synthesis due to the great variety of piperidine-moiety-containing drugs, making it the most prevalent nitrogen heterocycle in approved drugs;¹ therefore, their synthesis has been the focus of considerable attention.In this sense, chiral non-racemic bicyclic lactams derived from β-amino alcohols are commonly considered useful starting materials for preparing these substituted piperidine drugs.² One of the most effective methodologies for the synthesis of these bicyclic lactams is via an aza-annulation of β-enaminoesters³ derived from suitable β-amino alcohols.⁴We recently reported the preparation of new cyclic zwitterionic intermediates via an intramolecular non-classical Corey–Chaykovsky ring-closing reaction. Their utility was demonstrated by the synthesis of stereoisomers of σ¹-receptor agonists trozamicol⁵ or the synthesis of (+)- and (−)-Geissman–Waiss lactone (Scheme 1).⁶Open in a separate windowScheme 1Previous reports in the synthesis and utility of chiral cyclic zwitterionic intermediates.Considering this precedent and highlighting the utility of cyclic zwitterionic intermediates, we present a new versatile methodology to access new chiral zwitterionic non-racemic bicyclic lactams starting from acyclic β-aminoesters derived from (R)-(−)-2-phenylglycinol and its utility in the diastereoselective synthesis of 2-substituted-4-hydroxy piperidines.We commence our finding by synthesizing of a set of β-enaminoesters coming from (R)-(−)-2-phenylglycinol, which were prepared following the traditional methodologies, directly condensation of chiral amine with β-dicarbonyl compound⁷ or by addition to a corresponding alkyne.⁸ All enamino esters were obtained as an inseparable E : Z isomeric mixture and, these results are summarized below (Fig. 1).Open in a separate windowFig. 1β-Enamino esters derived from (R)-(−)-2-phenylglycinol.With a set of chiral β-enaminoesters in hand, next these compounds were condensed with bromo acetyl bromide,⁹ affording the desirable N-acyl oxazolidine with the formation of a new stereogenic center at the hemiaminal position in good to excellent diastereomeric ratio. The stereochemistry at the new stereogenic center of the major diastereoisomer was determined from its X-ray diffraction analysis of N-acyl oxazolidine 10 as (2R),¹⁰ therefore we assumed that this is the stereochemistry of the major diastereoisomer of each N-acyl oxazolidine (Scheme 2).Open in a separate windowScheme 2Synthesis of N-acyl oxazolidines. ^a Only the major diastereoisomer is shown. ^bN-acyl oxazolidines 12 and 14 were probed to be unstable therefore were employed without purification for the next reaction.Then, the diastereomeric mixture of 8 was selected as a model for preparing the desired zwitterionic chiral bicyclic lactam. To this end, 8 was treated with dimethyl sulfide in DCM,¹¹ delivering the corresponding sulfonium salt which was immediately subjected to the intramolecular non-classical Corey–Chaykovsky ring-closing reaction to avoid its conversion to the undesired thioether derivative.Firstly, sulfonium salt was treated with KOH (2 equiv.) in a mixture of CH₃CN : MeOH (9 : 1).⁶ Unfortunately, a mixture of expected zwitterion 22(a+b) and undesired pyridine-2-one 22c, was obtained. Therefore, screening experiments were performed. Gratifyingly, when the base was changed by K₂CO₃, the diastereomeric mixture of zwitterionic bicyclic lactams was exclusively obtained. ¹H-NMR analysis of the crude reaction revealed the presence of a diastereomeric mixture of bicyclic zwitterionic intermediates in a 73 : 27 dr. Two hemiaminal protons were assigned as a doublet of doublets at 5.40 ppm and 5.12 ppm with coupling constants J = 9.8, 5.3 Hz for the minor diastereoisomer and J = 11.4, 4.2 Hz for the major diastereoisomer. The assignment was confirmed by a ¹H–¹H COSY experiment ( EntryBaseGlobal yield [ratio 22(a+b)^b : 22c]1KOH (2.0 equiv.)95% [76 : 24]2KOH (1.0 equiv.)83% [82 : 18]3K₂CO₃ (1.2 equiv.)97% [100 : 0]Open in a separate window^aAll reactions were performed in CH₃CN : MeOH (9 : 1), for 4 hours at room temperature.^b22(a+b) was obtained in a 73 : 27 dr.The absolute configuration at the hemiaminal position of the zwitterionic bicyclic diastereomeric mixture was determined by its X-ray diffraction analysis. A single crystal was found to include two independent molecules in the asymmetric unit of a triclinic cell (space group P1 with Z′ = 2), one of which presenting a disorder on the chiral center C8a. Combining these features results in a mixture of disatereoisomers with a ratio refined to 77.5/22.5%,¹² close to that determined by NMR in solution, 73/27%. The determination of the absolute configuration in this crystal structure allowed the assignment for the major diastereoisomer 22a as (8aR) and the minor diastereoisomer 22b as (8aS) (Fig. 2).Open in a separate windowFig. 2X-ray structure of the diastereomeric mixture of chiral zwitterionic bicyclic intermediates 22(a+b).Once the optimal reaction conditions were established, the scope of our synthetic proposal was investigated. Chiral zwitterionic bicyclic intermediates containing alkyl or aryl substituents at the hemiaminal position were obtained in excellent chemical and stereochemical yields. Furthermore, the absolute configuration at the hemiaminal position was determined as (8aR) for the major diastereoisomer from the X-ray diffraction analysis of zwitterions 23a and 24a (Scheme 3).¹² In the case of 24a, orthorhombic single crystals feature three independent molecules in the asymmetric unit (space group P2₁2₁2₁, Z′ = 3), however, all display the same conformation and stereochemistry.Open in a separate windowScheme 3Intramolecular non-classical Corey–Chaykovsky ring-closing reaction for the synthesis of chiral zwitterionic bicyclic intermediates.To demonstrate the utility of these new chiral zwitterionic bicyclic compounds, the diastereoselective synthesis of 4-hydroxy piperidines was developed and 23a was selected as a model, therefore this compound was subjected to a desulfurization process to access the corresponding oxazolo[3,2-a]pyridine-5,7(6H)-dione 29. Catalytic hydrogenation was first attempted under various heterogeneous hydrogenation conditions. The use of Pd–C or RANEY®-Ni as a catalyst in acidic or neutral conditions led the oxazolo[3,2-a]pyridine-5,7(6H)-dione 29 in low chemical yield. The best result was obtained when reductive desulfurization was conducted using Zn (15 equiv.) in acetic acid, affording the compound 29 in 98% chemical yield (12 as in the starting material 23a.Screening experiments for desulfurization of zwitterion 23a^a

Palladium catalysed carbonylation of 2-iodoglycals for the synthesis of C-2 carboxylic acids and aldehydes taking formic acid as a carbonyl source

Pd catalyzed carbonylative reaction of 2-iodo-glycals has been developed taking formic acid as a carbonyl source for the synthesis of 2-carboxylic acids of sugars by the hydroxycarbonylation strategy. The methodology was successfully extended to the synthesis of 2-formyl glycals by using a reductive carbonylation approach. Both ester and ether protected glycals undergo the reaction and furnished sugar acids in good yield which is otherwise not possible by literature methods. The C-2 sugar acids were successfully utilized for the construction of 2-amido glycals, 2-dipeptido-glycal by Ugi reaction and C-1 and C-2 branched glycosyl esters.

Pd catalyzed carbonylative reaction of 2-iodo-glycals has been developed taking formic acid as a carbonyl source for the synthesis of 2-carboxylic acids of sugars by the hydroxycarbonylation strategy.

Sugar acids constitute a diverse family of carbohydrates¹ which play a crucial role in cell–cell recognition, cellular adhesion, and virus–host recognition processes, for protection of cells from pathogen attachment, and in the synthesis of biologically active natural products.² α,β-Unsaturated sugar acids such as zanamivir and ianinamivir (Fig. 1) are subjects of particular interest because of their application as inhibitors of different glycoproteins such as hemagglutinin (HA) and neuraminidase (NA),³ the major glycoproteins expressed by influenza viruses. While several reports dealing with the synthesis of carboxylic acids at C-6 and C-1 positions of sugars exist,^4a,b there is no established procedure for the synthesis of C-2 carboxylic acids. In glycals accessing carboxylic group at C-1 position required t-butyl lithium and carbon dioxide treatment at −78 °C.^4c There is only one report available in the literature in which carboxylic group was introduced to the C-2 position of glycals by Furstner et al.^4c,d where the C-2 carboxylic acid was derived from the Pinnick oxidation of 2-formyl glycal obtained by classical Vilsmeier–Haack reaction⁵ and thereafter utilized in the total synthesis of bioactive natural orevactaene (exhibits HIV-1 inhibitory property). This strategy has certain drawbacks like long reaction times with cocktails of oxidants and limited substrate specificity. For example, it works only with ether protected sugars like tri-O-benzyl-d-glycal and fails with other base labile and silyl protecting groups. Further, recovery of 2-formyl glycals after base workup is rather low in our hand. Our experience with glycals^6a–f encouraged us to formulate an attractive way to launch carboxylic acid at C-2 position of glycals as shown in Scheme 1 and apply them in the synthesis of C-2 glycoconjugates.Open in a separate windowFig. 1Glycal based acids in drugs.Open in a separate windowScheme 1Art of launching carboxyl group in sugars.This is pertinent to mention that carbonylation reactions of C-2 glycals have been successfully carried out by using metal carbonyl for the synthesis of C-2 branched glycoconjugates.^7a,b In these reaction stoichiometric amount of costly Mo(CO)₆ is required for such transformation that too ends up with some non-carbonylative side products. CO surrogates^8,9 such as formic acid, formamide, chloroform and anhydride have been explored in recent times obviating metal carbonyls and CO gas. Among all formic acid is an attractive candidate for insertion of CO in an organic molecule,¹⁰ because it liberates one water molecule after releasing one CO molecule thereby making the process environmentally benign. We felt that palladium catalyzed hydroxycarbonylation of stable glycal halides, which are conveniently accessed from glycals in good yield, may prove to be the most effective and environmentally benign method to prepare such molecules. With our continuous interest in synthesis of C-2 branched sugars,¹¹ this time we developed a reagent system for the direct synthesis of C-2 sugar carboxylic acids from 2-iodo glycals using formic acid as carbonyl source. Further, we transformed the synthesized acid for the synthesis of different C-2 branched glycoconjugates.Preliminary experiments were conducted by using 2-iodoglycal 1a, HCOOH as carbonyl source, N,N′-dicyclohexylcarbodiimide, (DCC) as an activator and xantphos as a ligand. When 1a was reacted with 5 mol% Pd(OAc)₂, 10 mol% of xantphos, 1 equiv. of DCC, 2 equiv. of formic acid and 2 equiv. of triethyl amine as base in DMF at 90 °C for 16 h the desired product 3a was obtained along with 3a′ in 60 : 40 ratio with overall 63% yield ( EntryPd sourceLigandTime (h)Conversion (%)(3a : 3a′)Yield^b (overall)%1Pd(OAc)₂L1169060 : 40632Pd(OAc)₂L21699>99 : 1723Pd(OAc)₂L2699>99 : 180 4 Pd(OAc) ₂ L2 1.5 99 >99 : 1 81 5Pd(OAc)₂L2190>99 : 1736Pd(OAc)₂L3164045 : 55237Pd(OAc)₂L4163030 : 70158Pd(OAc)₂L51610—Traces9Pd(OAc)₂L61610—Traces10Pd(PPh)₃L2275>99 : 12111Pd(TFA)₂L2235>99 : 12712PdCl₂L2223>99 : 111Open in a separate window^aReaction conditions: 1a (0.18 mmol), 2a (0.36 mmol), Pd(OAc)₂ (0.009 mmol), L2 (0.018 mmol), N,N′-dicyclohexylcarbodiimide (DCC) (0.18 mmol), triethylamine (0.36 mmol) at 90 °C for 2 h.^bYield of isolated product. Pd 5 mol% and ligand 10 mol% were used. Ratio of 3a and 3a′ and conversion were determined through ¹H NMR.Utilising the optimised reaction condition (l-rhamnal 1b was tested to get a better yield of the product 3b, (85%). The galactal substrate also furnished the desired 2-carboxyl galactal 3c in good yield (76%). In order to broaden the substrate scope the reactivity of glycals protected with different protecting groups was next investigated. Gratifyingly, 2, 3-acetonide protected 2-iodo-d-galactal 1d survived under the reaction condition and yielded the product 3d in good yield (75%). Tri-O-ethyl-2-iodoglucal 1e also reacted well and formed the respective acid derivative 3e in (76%) yield. Next we utilized different glycals having silicon based protection or ester protection. Tri-O-acetyl-2-iodoglucal 1f and di-O-acetyl-2-iodoxylal 1g were also well tolerated under the reaction condition and gave the desired products 3f–3g in reasonable yields (73–75%). 2-Bromo-glucal was next tested under the optimized reaction condition and the desired compound 3a was obtained in good yield although it takes 3 h to complete the reaction.Substrate scope^a

Entry	Substrate	Product	Time (h)	Yieldb (%)
1			1.5	81
2			1.5	85
3			1.5	76
4			1.5	75
5			2	76
6			2.5	73
7			2.5	75

Open in a separate window^aReaction conditions: 1 (1 equiv.), 2a (2 equiv.), Pd(OAc)₂ (5 mol%), L2 (10 mol%), DCC (1 equiv.), triethylamine (2 equiv.) at 90 °C for 1.5 to 2.5 h in 3 mL of DMF.^bYield of isolated product.TBS protected sugars acids are used in the total synthesis of various bioactive natural products by activating the anomeric carbon which is otherwise not possible with other protecting groups. In the literature in order to get such types of acids multiple steps are required along with poor overall yield. By utilizing carbonylation strategy under Pd catalysis we were able to synthesis the TBS protected acids in just 2 h when substrate 1h was reacted with HCOOH under Pd catalysis to generate product 3h in good yield.After successful execution of our strategy for hydroxycarbonylation of 2-iodoglycals, we became interested to apply the same carbonylative approach for the synthesis of 2-formyl glycals. In the literature formylation at C-2 of glycals has been carried out either by Vilsmeier–Haack or XtalFluor-E catalyzed reactions (Scheme 3).^5,12 We utilized the reductive carbonylation approach employing triethylsilyl hydride (1.2 equiv.) as a hydride source keeping other reagents same as for acid synthesis. To our delight, the required 2-formyl glycals were obtained in good to excellent yields (Scheme 3, 3aa–3ae).Open in a separate windowScheme 3Synthesis of 2-formyl glycals.Open in a separate windowScheme 2Synthesis of silyl protected C-2 carboxylic acid.To test the utility of sugar acids in the synthesis of C-2 glycoconjugates, sugar acid 3a was successfully utilized for the synthesis of C-2 linked dipeptides via Ugi reaction (Scheme 4, 5a). The simple amide 5b was also synthesised from 3a using thionyl chloride and ammonium hydroxide; the product is otherwise difficult to synthesize via the existing methods. Where substituted amides are synthesized. The acid chloride of 3a could be successfully coupled with 8-aminoquinoline, leading to the amide 5c in good yield. In order to test the reactivity of the acid 3a, we used it as a glycosyl acceptor in glycosylation reaction by treating with a suitable glycosyl donor like 6, when the pseudodisaccharide 7 was isolated in good yield (63%) with a mixture of anomers. On the other hand, treatment with aryne precursor 8 resulted in the formation of compound 9 in excellent yield (84%) via coupling of aryne with the sugar acid. When sugar acid 3a was treated with thiophenol thioester 11 was isolated in excellent yield (Scheme 5).Open in a separate windowScheme 4Synthesis of amides using 3a. Reaction conditions: (a) 3a (1.5 equiv.), aniline (1 equiv.), anisaldehyde (1 equiv.), cyclohexyl isocyanate (1 equiv.) in ethanol at rt for 48 h; (b) 3a (1.0 equiv.), SOCl₂ (1.5 equiv.), NH₄OH (37%, 2 mL) in THF for 2 h; (c) 3a (1.0 equiv.), PCl₅ (1.2 equiv.), pyridine (6 equiv.), 8-aminoquinoline (1.2 equiv.) in DCM for 5 h.Open in a separate windowScheme 5Utilization of 3a for establishing ester linkages.A plausible reaction mechanism has been proposed for hydroxycarbonylation of 2-iodoglycals (Scheme 6). Initially Pd(0) is generated in situ in the presence of ligand Ln. The catalytic cycle then starts with oxidative addition of Pd(0) to 2-iodoglycal A which produces the pallado complex B.Open in a separate windowScheme 6Plausible mechanism of hydroxycarbonylation reaction.Coordination and insertion of carbon monoxide generated in situ by the combination of DCC and formic acid leads to the formation of acyl Pd(ii) complex C. Formic acid attack on complex Cvia transmetallation affords the intermediate D with release of HI. Pd(0) could be regenerated for the next catalytic cycle after reductive elimination from complex D with formation of anhydride E. Decomposition of the anhydride with release of one molecule of CO generates the desired sugar acid F.In conclusion we have developed an efficient and mild Pd catalysed synthetic strategy for hydroxycarbonylation of 2-iodoglycals using the cheap reagent formic acid as CO source and 1 equiv. of DCC as an activator. The methodology was successfully extended to various glycals with different protecting groups like acetonide, ether, ester and silicon based ones. 2-Formyl glycals were also synthesised by using reductive carbonylation approach. The synthesised sugar acid could be used in the synthesis of glycoconjugates, pseudodisaccharides, for aryl ester and thioester.     

The selective synthesis of N-arylbenzene-1,2-diamines or 1-arylbenzimidazoles by irradiating 4-methoxy-4′-substituted-azobenzenes in different solvents

The solvent-controllable photoreaction of 4-methoxyazobenzenes to afford 1-aryl-1H-benzimidazoles or N-arylbenzene-1,2-diamines has been studied. The irradiation of 4-methoxyazobenzenes in DMF containing 0.5 M hydrochloric acid provided N²-aryl-4-methoxybenzene-1,2-diamines as the major product, while irradiation in acetal containing 0.16 M hydrochloric acid led to 1-aryl-6-methoxy-2-methyl-1H-benzimidazoles as the major product. A possible reaction mechanism explaining the selectivity was also discussed.

A solvent-controllable photoreaction involving 4-methoxyazobenzenes has been developed to synthesize 1-aryl-1H-benzimidazoles or N-arylbenzene-1,2-diamines in moderate to good yields.

Compounds with 1-phenyl-1H-benzimidazole skeleton¹ have gained attention for a long time and been studied for the applications of platelet-derived growth factor receptor (PDGFR),² cyclooxygenase (COX),³ and phosphodiesterase 10A⁴ inhibitors, as well as for many optoelectronic materials.⁵N-Aryl-1,2-phenylenediamines are also important for synthesizing various benzimidazole derivatives, and 1,3,5-tris(N-phenyl-benzimidazol-2-yl)benzene (TBPI) is an important electronic material for OLED applications that is still widely used nowadays.⁶The synthesis of 1-aryl-1H-benzimidazoles can be achieved via many synthetic strategies, including single and multiple molecular reactions. Single-molecule synthetic methods include the intramolecular cyclization of arylamino and oxime groups,⁷ the coupling of amidine and halogen (or hydrogen) groups,⁸ and the condensation of amide and amino groups.⁹ Methods involving bimolecular reactions include intermolecular coupling reactions of benzimidazoles,¹⁰ the cyclocondensation of o-diaminoarenes and aldehydes obtained from the oxidation of alcohols,¹¹ and the catalytic cyclization of aryl halides/amidines¹² or anilines/oxime acetates.¹³ Methods involving trimolecular reactions include one-pot reactions of arenediazonium salts, anilines, and nitriles,¹⁴ and the catalytic cascade cyclization of aryl halides, anilines, and amides.¹⁵ These synthetic methods provide solutions for the preparation of 1-phenyl-1H-benzimidazoles but they still present some difficulties, such as the use of transition metal catalysts and unsymmetrical starting materials.Using azobenzenes as reactants to afford 1-phenyl-1H-benzimidazoles¹⁶ and N-phenylbenzene-1,2-diamines¹⁷ was reported three decades ago. Compared to the above-mentioned synthetic methods, synthesis from azobenzenes showed the benefits of a simple preparation procedure and the good stability of symmetrical azobenzenes as starting materials (Scheme 1). The synthesis of a 1-phenyl-1H-benzimidazole¹⁶ from an azobenzene started from α-metallation with ruthenium trichloride, triggering the o-semidine rearrangement to produce the intermediate; this was then further transformed to a 1-phenyl-1H-benzimidazole upon reacting with an aldehyde that was produced via oxidizing an alcohol with ruthenium trichloride. However, the reaction needs high temperature, high pressure, transition-metal catalysts, and dangerous carbon monoxide, making it risky and environmentally unfriendly. Moreover, N-phenylbenzene-1,2-diamines¹⁷ could be obtained via the o-semidine rearrangement of hydrazobenzenes, which are the reductive products of azobenzenes. However, tributyltin hydride, which is used for the reduction of azobenzenes, is toxic, and the hydrazobenzenes were unstable in the presence of air because they were easily oxidized back to azobenzenes. Considering the previously discovered reactions involving azobenzenes and hydrazobenzenes, it would be worth developing a modified synthetic method that could be used to synthesize N-phenylbenzene-1,2-diamines and 1-phenyl-1H-benzimidazoles from azobenzenes more safely and easily.Open in a separate windowScheme 1The synthesis of 1-phenyl-1H-benzimidazoles and N-phenylbenzene-1,2-diamines from azobenzenes and hydrazo-benzenes.Inspired by research reporting the photoreduction of imine-containing compounds to amines in the presence of alcohols,¹⁸ a possible idea was suggested: the photoreduction of azobenzenes to hydrazobenzenes with ethanol followed by the instant transformation of hydrazobenzenes to N-phenylbenzene-1,2-diamines in acidic media. To investigate this synthetic idea, the irradiation of 4-methoxyazobenzene in ethanol containing 0.5 M hydrochloric acid with UV light at 365 nm was performed (Scheme 1). Surprisingly, this irradiation afforded both 4-methoxy-N²-phenylbenzene-1,2-diamine and 6-methoxy-2-methyl-1-phenyl-1H-benzimidazole as the two major products. This synthetic method seemed to have many advantages, including the use of stable and symmetrical azobenzenes as starting materials, the transition-metal-free synthesis, and the obtaining of two products in a one-pot synthesis process. Therefore, we report the study of the irradiation of 4-methoxy-4′-substitutedazobenzenes (2a–2g) to afford 4-methoxy-N²-(substitutedphenyl)benzene-1,2-diamines (3a–3g) and 6-methoxy-2-methyl-1-(4-substitutedphenyl)-1H-benzimidazoles (4a–4g).A series of 4-methoxy-4′-substituted azobenzenes (2a–2g) was synthesized via a two-step synthesis process (Scheme 2). The first step¹⁹ was an azo coupling reaction between phenol and the corresponding aryl diazonizum salt, which was prepared via a diazotization reaction between 4′-substituted aniline and sodium nitrite, to afford the 4-hydroxy-4′-substituted azobenzene (1a–1g) with a yield of 89–93%. The second step²⁰ was the methylation of the hydroxyl group of 1a–1g using potassium carbonate and dimethyl sulfate, with yields of 94–99%. The total yields from these two steps are ca. 85–92%.Open in a separate windowScheme 2The synthesis of the 4-methoxy-4′-substituted azobenzenes 2a–2g.In order to investigate suitable reaction conditions for the formation of N-arylbenzene-1,2-diamines and 1-aryl-1H-benzimidazoles, a series of test reactions involving 4-methoxy-azobenzene (2a) under different reaction conditions was performed (Scheme 3). The detailed experimental procedure for entry 10 in Open in a separate windowScheme 3The irradiation of 4-methoxyazobenzene (2a).The reaction conditions and results for the irradiation of 4-methoxyazobenzene (2a)

DMSO-mediated palladium-catalyzed cyclization of two isothiocyanates via C–H sulfurization: a new route to 2-aminobenzothiazoles

DMSO was found to activate arylisothiocyanates for self-nucleophilic addition. A subsequent intramolecular C–H sulfurization catalyzed by PdBr₂ enables access to a wide range of 2-aminobenzothiazole derivatives in moderate to good yields. This is the first example of a DMSO-mediated Pd-catalyzed synthesis of 2-aminobenzothiazoles through cyclization/C–H sulfurization of two isothiocyanates.

DMSO-initiated coupling of two isothiocyanates; Pd-catalyzed C–H sulfurization.

2-Aminobenzothiazole derivatives are privileged scaffolds which have been widely used in medicine and agricultural chemicals (Scheme 1a).¹ Significant effort has been devoted to the development of synthetic methodologies for the preparation of such species.² Thioureas,^3,4 isothiocyanates,^5,6 and benzothiazoles⁷ are effective reaction partners for the synthesis of 2-aminobenzothiazole derivatives via cross-coupling reactions or C–H functionalization. Intramolecular C–H sulfurization of N-arylthioureas is an effective strategy for the synthesis of 2-aminobenzothiazoles. Such a transformation can be achieved through metal-catalyzed C–H activation³ or via radical reactions.⁶ For example, Doi and coworkers reported a Pd-catalyzed intramolecular C–H sulfurization of arylthiourea using O₂ as an oxidant.^3c Metal-free iodine-catalyzed intramolecular C–H sulfurization also provides an effective pathway to 2-aminobenzothiazoles.^6e Zhu et al. developed an efficient oxidative radical strategy for the synthesis of 2-aminobenzothiazoles via an aminyl radical addition to aryl isothiocyanates followed by C–H sulfurization in the presence of n-Bu₄NI and TBHP.^6c Interestingly, Lei et al. reported a “green” synthesis of 2-aminobenzothiazoles by employing electro-catalysis technology for an external oxidant-free intramolecular C–H sulfurization.^6d In terms of metal-catalyzed C–H sulfurization,⁸ palladium-catalyzed C–H sulfurization has not been widely reported because thioureas are often strong metal-chelating species that may lead to poisoning of palladium catalysts. Thus, only a few examples of Pd-catalyzed protocols have been reported (Scheme 1b).^3b,c,e Therefore, the development of novel palladium-catalyzed C–H sulfurization reaction is of great interest. As a continuation of our interest in sulfur chemistry and C–H sulfurization,⁹ we attempted to transform isothiocyanates into sulfur-containing compounds.¹⁰ Unexpectedly, a newly formed 2-aminobenzothiazole was observed for the reaction of a phenylisothiocyanate. Encouraged by this discovery, we developed a new, facile and efficient DMSO-mediated palladium-catalyzed C–H sulfurization/cyclization of two isothiocyanates for the synthesis of 2-aminobenzothiazoles (Scheme 1c).Open in a separate windowScheme 1Biological application and synthetic methods for the preparation of 2-aminobenzothiazoles.Our study began with the reaction of phenyl isothiocyanate (1a) with PdCl₂ in different solvents ( EntryCatalystSolventYield^b (%)1PdCl₂Toluene02PdCl₂Chlorobenzene03PdCl₂DCE04PdCl₂CH₃CN05PdCl₂DMF126PdCl₂NMP167PdCl₂DMSO728^cPdCl₂DMSO329^dPdCl₂DMSO5810PdBr₂DMSO8211Pd(OAc)₂DMSOTrace12Pd(PPh₃)₂Cl₂DMSOTrace13^ePdBr₂DMSO7014—DMSO015^fPdBr₂DMSO/CH₃CN5516^gPdBr₂DMSO/CH₃CN2317^hPdBr₂DMSO/H₂O6118ⁱPdBr₂DMSO/H₂O75Open in a separate window^aReaction conditions: 1a (0.4 mmol), [Pd] (10 mol%), stirred at 80 °C in solvent (2 mL) for 24 h.^bIsolated yield.^cAt 100 °C.^dAt 60 °C.^ePdBr₂ (5 mol%).^fDMSO/CH₃CN = 1 : 1.^gDMSO/CH₃CN = 1 : 4.^hDMSO/H₂O = 10 : 1.ⁱDMSO/H₂O = 20 : 1.With the optimized reaction conditions in hand, the reaction scope was investigated ( Open in a separate window^aReaction conditions: 1 (0.4 mmol), PdBr₂ (10 mol%), stirred at 80 °C in DMSO (2 mL) for 24 h. Ortho-substituents, such as methyl, methoxy, methylthio, and phenyl, which increase steric hindrance, still performed well to give their corresponding products in moderate to good yields (products 12–20). For reactions involving ortho-substituted substrates, a small amount of brominated by-product similar to compound 19 was observed; however, the majority of these by-products were obtained in far lower yield than 19. To our delight, a naphthyl isothiocyanate also underwent reaction smoothly to give product 22 in 77% yield. 3-Isothiocyanatopyridine was also subjected to the reaction conditions. However, no cyclization/C–H sulfurization occurred; the electron-deficient pyridine ring is not reactive enough for C–H sulfurization. The reaction of meta-substituted methyl phenylisothiocyanates provided two isomers which could not be easily purified.To prove the feasibility of the cyclization of two different aryl isothiocyanates, a cross-reaction between 4-methyl-phenylisothiocyanate and 4-nitro-phenyliso-thiocyanate was conducted. The cross-reaction product 23, was obtained in 27% yield with compound 3 being formed as the main product in 52% yield (Scheme 2). The strong electron-withdrawing nitro group greatly reduces the electron density of the benzene ring, thus C–H sulfurization is disfavored; C–H sulfurization only occurred on the methyl-substituted benzene ring.Open in a separate windowScheme 2PdBr₂-catalyzed cross-reaction of two different isothiocyanates.To gain insight into the reaction mechanism, control experiments were conducted, as shown in Scheme 3. In the absence of PdBr₂, thiourea 24 was obtained in 35% yield for the reaction of 4-methyl phenylisothiocyanate in DMSO at 80 °C over 24 hours (Scheme 3, eqn (1)). This suggested that the thiourea may be the reaction intermediate; however, when thiourea 24 was subjected to reaction with PdBr₂, product 3 was obtained in only 16% yield (Scheme 3, eqn (2)). Aryl isothiocyanate may decompose to aniline, and react with isothiocyanate for C–H sulfurization. However, only a trace amount of product 25 was observed in the reaction between 4-methylphenyl isothiocyanate and aniline (Scheme 3, eqn (3)). None of the target product 26 was observed for the reaction of benzothiazole with 4-methyl phenylisothiocyanate, suggesting that benzothiazole is not a reaction intermediate (Scheme 3, eqn (4)). To our delight, a mass peak corresponding to intermediate 27 was observed with real-time ESI-MS when phenylisothiocyanate was stirred in DMSO at 60 °C (Scheme 3, eqn (5)) (see the ESI, Fig. S1^†). Based on theoretical calculations,¹¹ the dipole moment of the DMSO molecule is 3.9274 debye (gas) or 5.1281 debye in solvent form. Natural bond orbital analysis shows the differences in the charge distribution on the O and S atoms. Obviously, the polarity of the S–O bond increases and a greater distribution of the negative charge on the O atom leads to an improvement in its nucleophilic character. The oxygen atom attacks the carbon atom with the most positive NBO charge in PhNCS (see the ESI, Fig. S2 and S3^†). These results indicate that DMSO acts as a nucleophilic agent for the activation of arylisothiocyanates for C–H sulfurization.Open in a separate windowScheme 3Control experiments.Based on the above results and previous work,³ a possible reaction mechanism has been proposed and is shown in Scheme 4. Firstly, the polarized DMSO undergoes a nucleophilic addition with phenylisothiocyanate to afford the active intermediate A, which then reacts with another equivalent of phenylisothiocyanate to produce an intermediate B. Intermediate B chelates with PdBr₂ to form an intermediate C. Subsequent elimination of HBr leads to the formation of intermediate D, which undergoes reductive elimination to afford the desired product 2. The Pd(0) is oxidized by DMSO to PdBr₂ for the next catalytic cycle.Open in a separate windowScheme 4A possible mechanism.     

Phosphine-mediated enantioselective [1 + 4]-annulation of Morita–Baylis–Hillman carbonates with 2-enoylpyridines

This work describes a phosphine-catalyzed asymmetric [1 + 4] annulation of Morita–Baylis–Hillman carbonates with 2-enoylpyridines for constructing the enantiomerically enriched 2,3-dihydrofuran motif. In the presence of (−)-1,2-bis[(2R,5R)-2,5-dimethylphospholano]benzene, a series of Morita–Baylis–Hillman carbonates reacted with 2-enoylpyridines smoothly to afford a wide range of optically active 2,3-dihydrofurans featuring pyridine motifs in high yields with excellent asymmetric induction.

This work describes a phosphine-catalyzed asymmetric [1 + 4] annulation of Morita–Baylis–Hillman carbonates with 2-enoylpyridines for constructing the enantiomerically enriched 2,3-dihydrofuran motif.

Recently Morita–Baylis–Hillman (MBH) carbonates have been proved to be diverse reaction partners for the synthesis of a wide variety of carbo- and heterocyclic compounds.¹ In particular, MBH carbonates have been successfully employed as C1 synthons in many cyclization reactions for the construction of diverse heterocycles.² In terms of [1 + 4] annulations between MBH carbonates and α,β-unsaturated carbonyl compounds, Zhang et al. firstly reported a PPh₃ catalyzed [1 + 4] annulation of MBH carbonates with activated α,β-unsaturated ketones (enones) to furnish a series of racemic 2,3-dihydrofurans.³ The substituent (e.g., alkyne moiety) at the α-position of the enone was necessary to improve the reactivity of the enone by lowering the energy of the LUMO, which was critical for obtaining a high yield. Two years later, Huang et al. realized the catalyst dosage controlling the product distribution between 2,3-dihydrofurans and biaryls from the phosphine mediated [1 + 4] annulation of MBH carbonates and β,γ-unsaturated α-keto esters.⁴ In 2014, Shi et al. reported a tunable phosphine-triggered cascade reaction of MBH carbonates and 3-acyl-2H-chromen-2-ones for the synthesis of diverse chromenones.⁵ Different from [1 + 4] annulation, He et al. disclosed that the PBu₃-mediated reactions between MBH carbonates and chalcones underwent either [3 + 2] or [2 + 2 + 1] annulations depending on the substituent variation of both reactants.⁶ However, in sharp contrast, the reports on enantioselective catalytic annulation of MBH carbonate as C1-synthon are very limited.⁷ The landmark study reported by Shi and co-workers presented thiourea-phosphines that were efficient catalysts for the asymmetric [1 + 4] annulation of MBH carbonates with activated α,β-unsaturated ketones, although the reaction of MBH carbonates bearing an electron-donating substituent on their aromatic group remained a challenge (Scheme 1A).⁸ In 2016, Ouyang and Chen et al. remarkably disclosed the first highly enantio- and diastereoselective [1 + 2] annulation reactions of MBH carbonates and 2-alkylidene-1H-indene-1,3(2H)-diones (Scheme 1B).⁹ Despite their elegant examples, the organocatalytic asymmetric annulations of MBH carbonates as C1-synthons are still far from well-developed.¹⁰Open in a separate windowScheme 1Limited examples of enantioselective annulation of MBH carbonates with α,β-unsaturated ketones.Very recently, we overcame the restriction to successfully develop a chiral phosphine catalysed [1 + 4] annulation of MBH carbonates with electron-deficient olefins for constructing optitally active 2,3-dihydrofurans (Scheme 1C).¹¹ Furthermore, several cases of 2-enoylpyridines furnished the corresponding products in 60–90% yield with 94–98% ee and >20 : 1 dr. Although the ubiquitous nature of 2-enoylpyridines in enantioselective reactions,¹² the systematic study on asymmetric [1 + 4] annulation of MBH carbonates with 2-enoylpyridines has not been reported so far. Therefore, developing efficient strategy for the asymmetric [1 + 4] annulation of MBH carbonates with 2-enoylpyridines is highly desirable. Herein, we report comprehensive results from the phosphine-catalyzed asymmetric [1 + 4] annulation of MBH carbonates with 2-enoylpyridines (Scheme 1D).To achieve better yields without compromising the asymmetric induction of the [1 + 4] annulation of MBH carbonates and 2-enoylpyridines, we revisited the prototypical catalyst system (13 It was found that (−)-1,2-bis[(2R,5R)-2,5-dimethylphospholano]benzene P-I mediated reaction generated the better results, furnishing the desired product 3aa in 79% yield with 91% ee and >19 : 1 dr ( EntryCat.Solvent t (h)Yield^b (%)dr^cee^d (%)1P-ICH₂Cl₂2479>19 : 1912P-IICH₂Cl₂2455>19 : 1−783P-IIICH₂Cl₂2428>19 : 1−484P-IVCH₂Cl₂2440>19 : 1935P-ICHCl₃2456>19 : 1906P-ITHF2438>19 : 1847P-IToluene2465>19 : 1858P-IEtOAc2451>19 : 1909P-I(CH₂Cl)₂2471>19 : 19110P-IMeCN2477>19 : 19411^eP-IMeCN2469>19 : 19312^fP-IMeCN2457>19 : 19413^gP-IMeCN2469>19 : 19314P-IMeCN4881>19 : 195Open in a separate window^aReaction conditions: unless noted, a mixture of 1a (0.2 mmol), 2a (0.24 mmol), and catalyst (10 mol%) in the solvent (1.0 mL) was stirred at 30 °C for the time given.^bIsolated yield.^cdr = diastereomeric ratio, determined by ¹H NMR.^dEnantiomeric excess (ee) of major enantiomer, determined by chiral HPLC analysis.^ePerformed at 40 °C.^fPerformed at 0 °C.^g2a (0.3 mmol) was used.With the optimal reaction conditions determined, we then investigated the substrate scope of this asymmetric [1 + 4] annulation and the results were summarized in Entry R ¹ R ² 3Yield^b (%)dr^cee^d (%)1PhMe3aa81>19 : 1952PhEt3ab72>19 : 1943PhBn3ac54>19 : 19442-BrC₆H₄Me3ba76>19 : 19152-MeOC₆H₄Me3ca75>19 : 19463-ClC₆H₄Me3da82>19 : 19173-BrC₆H₄Me3ea79>19 : 19283-MeOC₆H₄Me3fa79>19 : 19494-FC₆H₄Me3ga79>19 : 193104-ClC₆H₄Me3ha80>19 : 193114-BrC₆H₄Me3ia78>19 : 192124-CF₃C₆H₄Me3ja85>19 : 191134-NO₂C₆H₄Me3ka30>19 : 191144-MeC₆H₄Me3la52>19 : 192152-NaphthylMe3ma85>19 : 183162-ThienylMe3na63>19 : 194172-PyridinylMe3oa60>19 : 19418PhCH CHMe3pa64>19 : 19219MeMe3qa61>19 : 19220^ePhMe3ad———Open in a separate window^aReaction conditions: unless noted, a mixture of 1 (0.2 mmol), 2 (0.24 mmol), and P-I (10 mol%) in MeCN (1.0 mL) was stirred at 30 °C for 48 h.^bIsolated yield.^cdr = diastereomeric ratio, determined by ¹H NMR.^dEnantiomeric excess (ee) of major enantiomer, determined by chiral HPLC analysis.^eInstead of 2a, 2-(methoxycarbonyl)-1-phenylallyl tert-butyl carbonate was used.In order to further explore the scope of the [1 + 4] annulation, other α,β-unsaturated pyridinyl ketones were also surveyed (Scheme 2). Under the standard conditions, 3-phenyl-1-(pyridin-3-yl)prop-2-en-1-one 4 reacted with MBH carbonate 2a smoothly to afford the product 5a in 75% yield with 94% ee and >19 : 1 dr (Scheme 2A). The P-I mediated [1 + 4] annulation of MBH carbonate 2a with 3-phenyl-1-(pyridin-4-yl)prop-2-en-1-one 6 also furnished the desired 7a in 84% yield with 92% ee and >19 : 1 dr (Scheme 2B). Notably, these results indicated that the pyridinyl group of α,β-unsaturated ketones has no effect on the stereoselectivity of the reaction. To highlight the synthetic potential of the catalytic system, we also evaluated the gram-scale synthesis of 3aa. In the presence of P-I with a loading of 2.5 mol% in MeCN of 25 mL at 30 °C for 48 h, 5.0 mmol of 1a (1.045 g) reacted smoothly with 6.0 mmol of 2a (1.296 g), affording 3aa in 60% yield (0.920 g) with 94% ee and >19 : 1 dr (Scheme 2C). As mentioned in our previous work,¹⁰ the product 3ma could be hydrogenated and tetrahydrofuran 8ma was obtained in 32% yield with 95% ee (Scheme 2D).Open in a separate windowScheme 2Further investigations of [1 + 4] annulation.The absolute configurations of chiral 2,3-dihydrofurans 3 were confirmed according to the products from the [1 + 4] annulation between MBH carbonates and α,β-unsaturated ketones under the same conditions.¹⁰ Accordingly, two proposed reaction pathways were shown in Scheme 3. An initial S_N2 attack of nucleophilic chiral phosphine catalyst P-I on the MBH carbonate 2 triggered the elimination of the leaving group (BocO⁻) delivering the chiral phosphonium salt intermediate M-1, which was then deprotonated by an in situ-generated base (BocO⁻ = CO₂ + t-BuO⁻) to give chiral allylic phosphorus ylide M-2. The β-selective reaction of M-2 with 2-enoylpyridine 1 furnished intermediate M-3, followed by cyclization to generate the desired product 3.⁹ Alternatively, the ylide M-2 reacted with 1via γ-selectivity to afford intermediate M-4, which interconverts with intermediate M-5.^2b,2d,7b Then an intramolecular Michael addition of M-5 afforded intermediate M-6. Finally, M-6 engaged in elimination of the chiral phosphine P-I to give the annulation product 3.Open in a separate windowScheme 3Proposed reaction mechanism.In conclusion, we have successfully developed an efficient organocatalytic asymmetric [1 + 4] annulation of MBH carbonates and 2-enoylpyridines. With (−)-1,2-bis[(2R,5R)-2,5-dimethylphospholano]benzene as catalyst, the reactions proceed well to furnish a series of chiral 2,3-dihydrofurans featuring pyridine motifs in high yields and excellent stereoselectivities. Importantly, the reaction was successfully extended to other α,β-unsaturated pyridinyl ketones without compromising the yields and asymmetric induction.     

Phosphine-catalyzed [3 + 2] annulation of β-sulfonamido-substituted enones with trans-α-cyano-α,β-unsaturated ketones for the synthesis of highly substituted pyrrolidines

To synthesize highly substituted pyrrolidines, we developed a phosphine-catalyzed [3 + 2] annulation of β-sulfonamido-substituted enones with trans-α-cyano-α,β-unsaturated ketones. We prepared a series of pyrrolidines under mild conditions with high yields and moderate-to-good diastereoselectivities. A catalytic mechanism for this reaction is suggested.

To synthesize highly substituted pyrrolidines, we developed a phosphine-catalyzed [3 + 2] annulation of β-sulfonamido-substituted enones with trans-α-cyano-α,β-unsaturated ketones.

Nucleophilic phosphine catalysis is a practical and powerful synthetic approach to obtain heterocyclic compounds using various annulation reactions, the advantages of which are it being mild and metal-free, ecologically friendly, and inexpensive.¹ Phosphine-catalyzed intermolecular [3 + 2],² [4 + 1],³ [2 + 2 + 1]⁴ and intramolecular annulations are often used to obtain pyrrole derivatives. Intermolecular [3 + 2] annulations of imines and phosphorus ylides formed in situ from allenoates, alkynes, or Morita–Baylis–Hillman carbonates under the presence of phosphine catalysts are especially the most widely used approach to synthesize pyrrolidine derivates. In these reactions, phosphorus ylides act as C–C–C synthons for the [3 + 2] annulations with a C N bond converting to a pyrrolidine ring (Scheme 1). However, literature reports on exploring new activation modes, namely, phosphorus ylides acting as C–C–N synthons for the [3 + 2] annulations, are rare.Open in a separate windowScheme 1Pyrrolidine ring formation through reaction of phosphorus ylides act as C–C–C and C–C–N synthons.β-Sulfonamido-substituted enones could be used as C–C–N synthons to form various N-based heterocycles. Catalytically activated (by amines) β-sulfonamido-substituted enones act as nucleophiles towards electron-deficient olefins or imines during [3 + 2] annulation reactions. Du''s⁵ and Pan''s groups⁶ have made outstanding contributions to this field.⁷ In 2018, Guo''s group developed a Bu₃P-catalyzed [5 + 1] annulation of γ-sulfonamido-substituted enones with N-sulfonyl-imines to obtain chiral 2,4-di-substituted imidazolidines. They also synthesized γ-sulfonamido-substituted enones attacked by phosphine catalyst and acting as C–C–C–C–N synthon (see Scheme 2).⁸ Recently, Guo et al.⁹ used β-sulfonamido-substituted enone as a phosphine acceptor as well as a C–C–N synthon for the [3 + 2] annulation with sulfamate-derived cyclic imines (see Scheme 2). Using of β-sulfonamido-substituted enone as a novel phosphine acceptor is very promising for phosphine-catalyzed reactions. Inspired by Guo''s work, we further extended the substrate scope of this reaction from sulfamate-derived cyclic imines to unsaturated ketones for the construction of pyrrolidine rings. Therefore, in this work, we report phosphine-catalyzed [3 + 2] annulation of β-sulfonamido-substituted enones and trans-α-cyano-α,β-unsaturated ketones, to synthesize highly substituted pyrrolidines (see Scheme 2), which are among the primary building blocks and the core structures of natural and bioactive compounds.¹⁰Open in a separate windowScheme 2Phosphine-catalyzed annulation of γ-sulfonamido-substituted enones and β-sulfonamido-substituted enones.We first used trans-α-cyano-α,β-unsaturated ketone 1a and β-sulfonamido-substituted enone 2a as model substrates to obtain optimum reaction conditions. Tertiary phosphine catalysts were screened with 1,2-dichloroethane (DCE) as solvent at room temperature (see † Thus, the optimum reaction conditions were determined as follows: using 20 mol% of PMe₃ as catalyst, CHCl₃ as solvent at room temperature.Optimization of reaction conditions^a

Enantioselective bromination of axially chiral cyanoarenes in the presence of bifunctional organocatalysts

Enantioselective bromination of axially chiral cyanoarenes bearing high intrinsic rotational barriers via dynamic kinetic resolution using bifunctional organocatalysts is reported. Sequential addition of a brominating reagent in several portions at an optimized temperature was effective in accomplishing high enantioselectivities.

Enantioselective bromination of axially chiral cyanoarenes bearing high intrinsic rotational barriers via dynamic kinetic resolution using bifunctional organocatalysts is reported.

Axially chiral biaryls are privileged structures in pharmaceuticals,¹ asymmetric catalysts,² functional materials,³etc. Thus, the development of efficient methods for their synthesis is desirable to advance research in these scientific fields. Among recent accomplishments on catalytic atroposelective transformations⁴ toward the synthesis of densely substituted axially chiral biaryls, powerful strategies include organocatalytic dynamic kinetic resolution involving ortho-functionalization of existing biaryls via the introduction of additional rotational barriers.⁵ In this method, substrates should in principle have rotational barriers low enough to enable fast rotation about the biaryl axis, leading to their rapid racemization. Therefore, it is difficult to employ biaryl substrates bearing intrinsic rotational barriers, which impede their racemization. In 2015, the Miller group reported an elegant example of this type of dynamic kinetic resolution via bromination of 3-arylquinazolin-4(3H)-ones, the rotational barrier of which is ∼19 kcal mol⁻¹, by slow addition of a brominating agent.^5e Here, we present enantioselective bromination of axially chiral cyanoarenes bearing intrinsic rotational barriers exceeding 18 kcal mol⁻¹ (Scheme 1). To the best of our knowledge, there has been no report of a catalytic asymmetric reaction affording axially chiral cyanoarenes,⁶ despite their prevalence in bioactive agents⁷ and the rich chemistry of cyano compounds as synthetic intermediates.⁸Open in a separate windowScheme 1Enantioselective bromination of axially chiral cyanoarenes using bifunctional organocatalysts. 9 Other catalysts 3d and 3e, bearing a cyclohexanediamine framework, and 3f, bearing a binaphthyl framework, resulted in poor enantioselectivities (10 Using 3a and 3c, lower reaction temperatures were investigated (Fig. 1) were also investigated; NBA (4a) still afforded the best enantioselectivities ( EntryCatalystBrominating reagentSolventTemp. (°C)Yield^b (%)ee (%)13aNBA (4a)CH₂Cl₂25812623bNBA (4a)CH₂Cl₂2587633cNBA (4a)CH₂Cl₂25891843dNBA (4a)CH₂Cl₂2583653eNBA (4a)CH₂Cl₂2585363fNBA (4a)CH₂Cl₂2579373aNBA (4a)CH₂Cl₂−40822083aNBA (4a)CH₂Cl₂−60<1—93cNBA (4a)CH₂Cl₂−408341103cNBA (4a)CH₂Cl₂−60<1—113cNBA (4a)CHCl₃−402154123cNBA (4a)Toluene−4018−10133cNBA (4a)THF−4013−2143cNBA (4a)Et₂O−4046−20153cNBA (4a)EtOAc−4068−4163cNBA (4a)EtOH−40<5—173cDBH (4b)CH₂Cl₂−40791183cNBS (4c)CH₂Cl₂−408220193cNBP (4d)CH₂Cl₂−4079−520^c,d3cNBA (4a)CH₂Cl₂−40854921^c,e3cNBA (4a)CH₂Cl₂−40515922^c,f3cNBA (4a)CH₂Cl₂−40336623^c,g3cNBA (4a)CH₂Cl₂−401771 Open in a separate window^aReactions were run using 1a (0.10 mmol), the brominating reagent (0.30 mmol), and the catalyst (0.010 mmol) in the solvent (10 mL).^bIsolated yields.^cReactions were run using 3c (0.0050 mmol).^dReaction was run for 48 h.^eReaction was run for 24 h.^fReaction was run for 12 h.^gReaction was run for 6 h.Open in a separate windowFig. 1Brominating reagents.Subsequently, to improve the efficiency of dynamic kinetic resolution by retarding the enantiodetermining bromination,^5e4a was added sequentially in five portions (Fig. 2).¹¹ Although the procedure hardly affected the results at −40 °C, the enantioselectivity was greatly improved for reactions carried out at −20 °C and −30 °C. Such effects were smaller at temperatures above −10 °C.Open in a separate windowFig. 2Investigations of temperatures and procedures. Blue bar: reactions were run with 4a added in 1 portion. Red bar: reactions were run with 4a added in 5 portions. Green values represent yields of 2a isolated after silica gel column chromatography. At 0, −10, −20, and −30 °C, reactions were run for 24 h; at −40 °C, reactions were run for 72 h.Next, at −30 °C and −40 °C, respectively, the relationships between enantioselectivity and yield were investigated (Fig. 3). Reactions were carried out using various amounts of 4a. At both temperatures, the enantioselectivity decreased as the yield increased; however, the quantitative reactions also exhibited some enantioselectivity (−30 °C: 99% yield, 50% ee; −40 °C: 99% yield, 47% ee), implying the presence of the characteristics of dynamic kinetic resolution. In addition, although the enantioselectivity was better at −40 °C than −30 °C when the yield was low, the relationship became reversed as the yield increased; hence, the efficiency of dynamic kinetic resolution was revealed to be better at −30 °C than at −40 °C. Furthermore, when 1.5 equiv. of 4a were used at −30 °C affording 2a in 22% yield with 65% ee, the ortho-monobrominated product 1a-Br (Fig. 4) was also obtained with 75% ee (see Scheme S1 in the ESI^† for details). It shows that the bromination at one of the ortho-positions introduces a rotational barrier high enough to set the chiral axis, which is consistent with the rotational barriers calculated at the M06-2X/6-311++G(2d,3p)//B3LYP/6-31+G(d,p) level of theory (Fig. 4).Open in a separate windowFig. 3Relationships between ee and yield. Red line: reactions were run at −30 °C for 24 h with 4a added in 5 portions. Blue line: reactions were run at −40 °C for 72 h with 4a added in 5 portions. Red and blue values represent amounts of 4a used for each reaction.Open in a separate windowFig. 4Rotational barriers of substrate, intermediate, and product calculated at the M06-2X/6-311++G(2d,3p)//B3LYP/6-31+G(d,p) level of theory.Under the conditions of using 3c as the catalyst at −30 °C with 3 equiv. of 4a added sequentially in five portions, other substrates bearing substituted phenols were also investigated (Scheme 2).¹² First, substrates 1b–1e bearing a substituent at the meta-position were investigated. While the electron-deficient substrate 1b resulted in poor enantioselectivity, 1c and 1d bearing aliphatic substituents gave improved enantioselectivities; however, substrate 1e with a methoxy group resulted in low enantioselectivity. In addition, substrates 1f–1i bearing substituents at the para-positions of the biaryl axis were then examined; phenol 2h bearing a methyl group resulted in higher enantioselectivities than phenols 2f and 2g bearing electron-withdrawing groups and 2i bearing a methoxy group. These results suggest that aliphatic substituents might efficiently facilitate the racemization of 1 during bromination, leading to dynamic kinetic resolution with greater enantioselectivity. Utilizing this methodology with the characteristics of dynamic kinetic resolution, the reactions of 1c and 1g were also carried out using a sub-stoichiometric amount of 4a (Scheme 3); higher enantioselectivities were accomplished albeit with lower yields.¹³ The absolute configuration of 2c was determined by X-ray crystallography (see the ESI^† for details), and the configurations of all other products were assigned analogously.Open in a separate windowScheme 2Reactions of substrates with substituted phenols. ^aReaction was run for 72 h.Open in a separate windowScheme 3Reactions with a substoichiometric amount of 4a.In summary, we present enantioselective bromination of axially chiral cyanoarenes bearing high intrinsic rotational barriers via dynamic kinetic resolution using bifunctional organocatalysts. The sequential addition of 4a in several portions at the optimized temperature was effective in improving the enantioselectivity. Although the enantioselectivities are still moderate using the current catalytic system, the guidelines for designing catalytic asymmetric syntheses of axially chiral cyanoarenes were established. Further studies on the additional optimization and application of this methodology to the construction of densely substituted axially chiral biaryls are currently underway.     

Ligand-free Pd/Ag-mediated dehydrogenative alkynylation of imidazole derivatives

A variety of 2-alkynyl(benzo)imidazoles have been synthesized by dehydrogenative alkynylation of (benzo)imidazoles with terminal alkyne in NMP under air in the presence of Ag₂CO₃ as the oxidant and Pd(OAc)₂ as the catalyst precursor. The data obtained in this study support a reaction mechanism involving a non-concerted metalation deprotonation (n-CMD) pathway.

The regioselective synthesis of 2-alkynyl(benz)imidazoles was successfully achieved by Pd(ii)/Ag(i)-mediated dehydrogenative alkynylation of the corresponding (benz)imidazoles with terminal alkynes in an open vessel.

The development of synthetic protocols that enable the direct and selective functionalization of C_sp²–H bonds are of primary importance in the decoration of the imidazole scaffold.^1–10 The presence of two nitrogen atoms in the pentatomic structure of this important azole in fact introduces a differentiation in the chemical behaviour of the three C–H bonds, allowing their selective involvement in carbon–carbon bond-forming reactions as long as appropriate experimental conditions are identified.During our studies dedicated to the synthesis and investigation of azole-based fluorophores featuring a π-conjugated backbone end-capped with electron-donating (EDG) and electron-acceptor (EWG) groups (the so-called “push–pull” systems),^11–15 taking into account the structural characteristics and synthetic versatility of a triple carbon–carbon bond^16–23 that make it an excellent π-spacer, we recently decided to evaluate the possibility of obtaining alkynyl-substituted imidazoles by transition metal-catalyzed C_sp²–C_sp bond-forming reactions. Among the synthetic procedures that allow the selective alkynylation of imidazoles and other five-membered heteroarenes,^5,24 there is no doubt that the possibility of forming the new σ carbon–carbon bond through the double activation of two distinct carbon–hydrogen bonds through a cross-dehydrogenative alkynylation (CDA) represents the best synthetic approach in terms of atom economy and functional group tolerance (eqn (1), Scheme 1).^25–34 In fact, when compared with the transition metal-catalyzed direct C_sp²–H alkynylation protocols involving 1-haloalkynes (the so-called “inverse Sonogashira coupling”) (eqn (2), Scheme 1),^35–45 hypervalent iodine reagents (eqn (3), Scheme 1),^46–48 or α,β-ynoic acids (decarboxylative direct arylation) (eqn (4), Scheme 1),^26,49,50 the CDA methodology makes it possible to use terminal alkynes without the need for preliminary activation.^5,24Open in a separate windowScheme 1Synthetic protocols for the transition metal-catalyzed C_sp²–H alkynylation of heteroarenes.Despite several papers having been dedicated to the dehydrogenative alkynylation of pyrroles,²⁷ indoles,^27,31 oxazoles,^{27,30,32–34} benzoxazoles,^{26,29,30,32,34} thiazoles,^27,30 benzothiazoles,^{26,29,31,32,34} pyrazoles,^25,27 1,3,4-oxadiazoles,³³ imidazopyridines,^27,34 and N-substituted sydnones,²⁸ to the best of our knowledge a study specifically devoted to the dehydrogenative alkynylation of imidazoles has never been reported. However, careful reading the literature where alkynylation reactions involving azoles other than imidazole were described, it emerged that two papers reported the C-2 alkynylation of N-benzylimidazole and N-benzylbenzimidazole with phenylacetylene. In a study mainly devoted to the dehydrogenative alkynylation of imidazo[1,5-a]pyridine, Shihabara, Dohke and Murai employed the commercially unavailable Pd(ii) complex bi(4-nitropyridinyl)Pd(OAc)₂, Ag₂CO₃ as the oxidant and AcOH as additive, in a 95 : 5 mixture of DMF and DMSO for 2 h at 120 °C under argon.³⁴ Due to the propensity of alkynes to give Glaser-type homocoupling side-products in the presence of silver(i) salts,⁵¹ phenylacetylene was slowly added over 90 min to the reaction mixture. In 2015, Likhar, Kantam and co-workers used a synthetic Pd(ii) carbene complex. In this case Ag₂O was used as the oxidant, Cs₂CO₃ base, performing the coupling in DMF at 85 °C under air.²⁶Encouraged by these results but with the intention of developing a simplified procedure that would allow the use of a commercial Pd(ii) pre-catalyst in the absence of any palladium ligands, we decided to review the conditions of reaction and, in this work, we are pleased to summarize the results obtained in the synthesis of 2-alkynylimidazole derivatives by dehydrogenative alkynylation with terminal alkynes (Scheme 2). In particular, a careful screening allowed us to show how the reactivity of C_sp²–H bond of imidazole derivatives and other azoles can be enhanced simply by performing the alkynylation using NMP as the reaction solvent, under air in non-anhydrous conditions, and without the need for palladium ligands.Open in a separate windowScheme 2Pd/Ag-Promoted dehydrogenative alkynylation of imidazole derivatives.We decided to start our synthetic investigations by trying a cross-dehydrogenative coupling between N-methylbenzimidazole (1) and phenylacetylene (2a), chosen as typical coupling partners, under conditions very similar to those proposed by Murai and co-workers for the regioselective C-3 dehydrogenative alkynylation of 1-alkynyl-3-arylimidazo[1,5-a]-pyridines.³⁴Hence, to a mixture of 1.0 mmol 1, 5 mol% Pd(OAc)₂, 1.5 equiv. Ag₂CO₃, and 1.0 equiv. AcOH in a 95 : 5 (v/v) mixture of DMF and DMSO under argon 3.0 equiv. of 2a were added dropwise over 90 min. However, after 2 h at 120 °C a 56% GLC conversion of 1 was recorded, and the required 2-phenylethynyl-N-methylbenzimidazole (3a) was obtained in only 34% GLC yield (entry 1, EntryPd cat. (mol%)Ag(i) salt (equiv.)RCOOHSolventTemp./react. time^b (°C/h)1 GLC conversion^c (%)3a GLC yield^d (%)3a:4 AP%1^ePd(OAc)₂ (5)Ag₂CO₃ (1.5)AcOHDMF/DMSO (95 : 5)120/2563457 : 432Pd(OAc)₂ (5)Ag₂CO₃ (1.5)AcOHDMF/DMSO (95 : 5)100/5.5676632 : 683Pd(OAc)₂ (5)Ag₂CO₃ (2.0)AcOHDMF/DMSO (95 : 5)100/2737034 : 664Pd(OAc)₂ (5)—AcOHDMF/DMSO (95 : 5)100/3.5NR——5Pd₂(dba)₃ (2.5)Ag₂CO₃ (2.0)AcOHDMF/DMSO (95 : 5)100/3.5736930 : 706Pd(acac)₂ (5)Ag₂CO₃ (2.0)AcOHDMF/DMSO (95 : 5)100/3.5676327 : 737PdCl₂ (5)Ag₂CO₃ (2.0)AcOHDMF/DMSO (95 : 5)100/3.5726835 : 658Pd(OAc)₂ (5)Ag₂CO₃ (2.0)—DMF/DMSO (95 : 5)100/3.5532372 : 289Pd(OAc)₂ (5)Ag₂CO₃ (2.0)—AcOH100/3.50—0 : 10010Pd(OAc)₂ (2.5)Ag₂CO₃ (2.0)AcOHDMF/DMSO (95 : 5)100/3.5766930 : 7011Pd(OAc)₂ (2.5)AgOAc (2.0)AcOHDMF/DMSO (95 : 5)100/3.5554825 : 7512Pd(OAc)₂ (2.5)Ag₂O (2.0)AcOHDMF/DMSO (95 : 5)100/3.5666228 : 7213Pd(OAc)₂ (2.5)Ag₂CO₃ (2.0)EtCOOHDMF/DMSO (95 : 5)100/3.5807135 : 6514Pd(OAc)₂ (2.5)Ag₂CO₃ (2.0)PivOHDMF/DMSO (95 : 5)100/3.5454522 : 7815Pd(OAc)₂ (2.5)Ag₂CO₃ (2.0)AcOHDMF/DMSO (95 : 5)80/3.5434017 : 8316Pd(OAc)₂ (2.5)Ag₂CO₃ (2.0)AcOHDMF100/3.5757034 : 6617Pd(OAc)₂ (2.5)Ag₂CO₃ (2.0)AcOHDMA100/3.58175(68)33 : 67 18 Pd(OAc) ₂ (2.5) Ag ₂ CO ₃ (2.0) AcOH NMP 100/3.5 85 81(69) 36 : 64 19^fPd(OAc)₂ (2.5)Ag₂CO₃ (2.0)AcOHNMP100/3.58266(51)40 : 6020^gPd(OAc)₂ (2.5)Ag₂CO₃ (2.0)AcOHNMP100/3.5838036 : 64Open in a separate window^aReaction conditions: 2a (3.0 mmol) in the selected solvent (2.0 mL) was added dropwise over 45 min to a mixture of 1 (1.0 mmol), Pd cat., Ag(i) salt, RCOOH (1.0 mmol) in the selected solvent (2.0 mL) under air, unless otherwise reported.^bAfter the reported reaction time the GLC conversion of 2a was quantitative.^cGLC conversion of 1vs. biphenyl.^dGLC yield vs. biphenyl. In parentheses isolated yield.^eThis reaction was carried out under an argon atmosphere.^fThis reaction was carried out on a 10 mmol scale.^gThis reaction was carried out in the presence of TEMPO (1.0 equiv.) as radical scavenger.Taking note of this unexpected negative result, we decided to re-examine the reaction conditions, starting from the consideration that even if Ag₂CO₃ can theoretically serve as the oxidant, run the reaction in air (open flask) may be critical.²⁸ Gratifyingly, when the coupling was performed under air there was a marked increase in GLC yield, which went from 34% to 66% (entry 2, i) salts different from Ag₂CO₃ gave slightly worse results (entries 11 and 12, 31 the use of the right buffer system may be crucial for the deprotonation of the terminal alkyne, and also for the reoxidation of Pd(0) to Pd(ii).With our delight the chemical yield went up to 69% when the DMF/DMSO mixture was replaced by NMP (entry 18, 34 it should be highlighted that the slow addition of phenylacetylene never avoided in our hands the formation of Glaser side-product 4.Finally, when the reaction was performed in the presence of 1.0 equiv. of TEMPO (2,2,6,6-tetramethylpiperidin-1-yl)oxyl as radical scavenger, it still proceeded smoothly to afford 2-alkynylazole 3a in 80% GLC yield (entry 20, Scheme 3).Open in a separate windowScheme 3Ligandless Pd/Ag-promoted dehydrogenative alkynylation of 1-methylimidazole 5 or 1-methylbenzimidazole 1 with terminal alkynes 2a–h.Noteworthy, the reaction outcome was not influenced by the electronic nature of the aromatic moiety on the terminal alkyne. More importantly, several functional groups on the phenyl ring resulted well tolerated, including formyl and hydroxy groups that are potentially sensitive to the oxidative conditions required by dehydrogenative couplings.While good results were obtained when arylacetylenes were used as coupling partners, worse results were observed when TIPS-acetylene 2i or 1-octyne (2j) were reacted with 5. In fact, the expected 2-alkynyl substituted imidazoles 6i and 6j were isolated in 30% and 11% yields, respectively (Scheme 4).^25,31 The low reactivity of these two terminal alkynes in respect to their aryl analogues could be attributed, as already noted,³¹ to the decreased electrophilic nature of the corresponding alkynyl-palladium(ii) intermediates being generated during the reaction. As a further proof of their lower reactivity, the slow addition of 2i and 2j was found to be unnecessary.Open in a separate windowScheme 4Ligandless Pd/Ag-promoted dehydrogenative alkynylation of 1-methylimidazole 5 with terminal alkynes 2i and 2j.Gratifyingly, the optimized Pd(OAc)₂/Ag₂CO₃-promoted coupling conditions proved to be useful also for the C-2 dehydrogenative alkynylation of 4,5-diphenyl-1-methylimidazole 7. In fact, this disubstituted azole gave the expected C-2 alkynylation product 8 in 70% isolated yield when reacted with phenylacetylene (2a) (Scheme 5).Open in a separate windowScheme 5Ligandless Pd/Ag-promoted dehydrogenative alkynylation of 4,5-disubstituted 1-methylimidazole 7 or 9 with terminal alkynes 2a or 2d.One of the main advantages of dehydrogenative cross-coupling reactions is the tolerance, among others, of carbon–halogen bonds that, hence, are available for subsequent transformations. We were please to confirm this tolerance; in fact, 4,5-dibromo-1-methyl-1H-imidazole 9 was efficiently reacted with alkynes 2a and 2d, giving rise to the required 2-alkynyl-4,5-dibromoimidazoles 10a,b in 68 and 75% isolated yields, respectively (Scheme 5). Notably, no conventional Sonogashira-type coupling side-products were observed.Similar satisfactory yields were obtained when 1-benzyl- and 1-phenyl-1H-imidazoles 11 and 12 when reacted with 2a. The corresponding 2-phenylethynylimidazoles 13 and 14 were recovered in 68% and 52% isolated yields, respectively (Scheme 6). In contrast, the C-2 alkynylation of thiazole (15) and oxazole (16) with 2a gave the required products 17 and 18 in somewhat lower yields (48 and 42%, respectively). It is noteworthy, however, that the observed reactivity of 1-substituted imidazole 6, 11 and 12, i.e. 1-methyl > 1-benzyl > 1-phenyl, and that found for the three 1,3-azoles 6, 13 and 14, i.e. 1-methylimidazole > thiazole > oxazole, parallels that reported in the literature for classical SEAr.^52,53 As regards the regioselectivity, when the reaction involved 1-substituted imidazoles 5, 11, and 12, thiazole 15 and oxazole 16 a clean C-2 alkynylation was observed, while the corresponding C-5 or even the less probable C-4 alkynyl-substituted regioisomers were never detected in the crude reaction mixtures.⁵⁴ However, it is worth mentioning that when the alkynylation was tempted on 1,2-dimethyl-1H-imidazole 19, the C-5 alkynylated product 20 was obtained in 42% isolated yield (eqn (1)).1Open in a separate windowScheme 6Ligandless Pd/Ag-promoted dehydrogenative alkynylation of 1-substituted imidazoles 5, 11, 12, thiazole (15), and oxazole (16) with phenylacetylene (2a).Based on earlier reports and our observations, a possible reaction mechanism for this Pd/Ag-promoted dehydrogenative alkynylation of imidazoles is summarized in Fig. 1, using 1-methylimidazole 5 as an example. Initial transmetallation involving a Pd(ii) complex and a (presumed) silver(i) acetylide generates the alkynyl Pd(ii) species A, which then affords the imidazole–Pd–alkyne complex E through a sequence of base-assisted carbanion generation from an azole–Pd complex (B → C), followed by a C-palladation step via carbene D. This particular C–H palladation mechanism, known as non-concerted metalation-deprotonation (n-CMD) pathway, was initially proposed by Hoarau and co-workers to justify the observed C-2 regioselectivity in the copper-free Pd-catalyzed direct arylation of oxa(thia)zoles-4-carboxylate with aryl bromides.^55–57Open in a separate windowFig. 1Proposed n-CMD mechanistic pathway for the Pd(OAc)₂/Ag₂CO₃-promoted dehydrogenative alkynylation of 1-methylimidazole 5.Although the comparison of the reactivity of 1-methylimidazole 5 with both the other two 1-substituted imidazoles 11 and 12, and with thiazole (15) and oxazole (16) suggested a SEAr mechanism (hence via a classic Wheland intermediate),^58–60 it should be noted that the most reactive position should have been C-5, and not the position C-2 that instead has the most acidic C–H bond. Similarly, a pure concerted metalation–deprotonation (CMD) pathway can reasonably be excluded considering that DFT calculations have shown that in the case of 1,3-azoles position C-5 is, again, the most reactive.⁶¹ The n-CMD mechanism hypothesizes that the deprotonation occurs through the formation of an azole–Pd(ii) complex and, therefore, justifies the observed reactivity by the most acidic C–H bond, i.e. the one in position 2 on the azole nucleus. On the other hand, one key step of this mechanism is the formation of N3–Pd complex C, which is the more effective the more the terminal alkyne is electron-poor (hence having the C_sp–H bond more acid). That the steps of the mechanism from A to E are certainly critical for the success of the reaction is also proved by the beneficial effect resulting from the slow addition of the terminal alkyne 2 to the reaction mixture. Finally, reductive elimination involving complex E gave the coupling product 6, and reoxidation of Pd(0) to Pd(ii) by Ag(i) or air closed the catalytic cycle.     

Visible light-induced photocatalytic C–H ethoxycarbonylmethylation of imidazoheterocycles with ethyl diazoacetate

A visible light-mediated regioselective C3-ethoxycarbonylmethylation of imidazopyridines with ethyl diazoacetate (EDA) was achieved under mild reaction conditions. In contrast to the carbene precursors from α-diazoester a first C3-ethoxycarbonylmethylation of imidazopyridines via a radical intermediate has been established. The present methodology provides a concise route to access pharmacologically useful esters with wide functional group tolerance in high yields.

A visible-light-promoted regioselective ethoxycarbonylmethylation of imidazoheterocycles has been developed using an α-diazoester via a radical pathway.

Ester groups are a most powerful and versatile synthetic building block in natural products as well as in organic synthesis since they can be derivatized to diverse functional groups such as carbonyl, hydroxymethyl, and amide, etc.¹ Beside the traditional methods of using xanthates for ethoxycarbonylmethylation,² the introduction of diazoesters represents a very important strategy for the synthesis of acetate derivatives.³ Generally, thermal,^4a photoinduced,^4b or metal catalyzed^4c reactions of diazo compounds produce reactive carbene precursors which further undergo an addition reaction, insertion reaction, cyclopropanation, Wolff rearrangement, etc. (Scheme 1a).⁴ In contrast to the carbene precursors from α-diazoester, a new methodology is always highly desirable especially with a significantly different mode of activation under a distinct mechanism.⁵ In this context, a new strategy for installation of alkyl radicals from diazo compounds under photoredox-catalysis is very important.⁶ Recently, visible light-mediated photoredox catalyzed direct C–H bond functionalization reactions have come to the forefront in synthetic organic chemistry⁷ where Ru(ii)-polypyridyl complexes have been extensively used as photoredox-catalysts due to their unique photo-physical properties.⁸Open in a separate windowScheme 1Visible light-mediated ethoxycarbonylmethylation. (a) Previous reports through carbene pathway. (b) This work: visible-light mediated radical reaction of diazoacetate with imidazopyridine.Imidazo[1,2-a]pyridines, an important class of nitrogen-based privileged structural motifs widely found in a variety of natural products and alkaloids.⁹ In pharmaceutical chemistry, it possesses large number of biological activities like antitumor, antibacterial, antifungal, antipyretic, analgesic, antiinflammatory, etc.^10a It is also important in material sciences due to its unique excited state intramolecular proton transfer phenomena (ESIPT).^10b In particular, ethoxycarbonylmethylated imidazopyridines are the core structure of several marketed drugs such as alpidem, zolpidem, saripidem, etc.¹¹ Therefore, practical methodologies for the synthesis of alkylated ester substituted imidazoheterocycles are highly desirable and will be of great interest to the synthetic chemists.¹¹ However, to the best of our knowledge there is no such method for the direct photo-initiated ethoxycarbonylmethylation reaction of imidazoheterocycles with diazo compounds through distinct radical pathway.^11–13 As part of our ongoing research on photoredox-catalyzed C–H functionalization reactions,¹³ herein we describe an environmentally benign visible light-promoted ethoxycarbonylmethylation for the synthesis of alkyl substituted imidazopyridines by the coupling between imidazopyridines and ethyl diazoacetate using Ru(bpy)₃Cl₂ as photoredox-catalyst under argon atmosphere at room temperature (Scheme 1b).To begin, the reaction was carried out using 2-phenylimidazo[1,2-a]pyridine (1a) and ethyl diazoacetate (EDA) (2) (2.0 equiv.) in presence of 0.2 mol% of Ru(bpy)₃Cl₂ as a photoredox-catalyst under the irradiation of 34 W blue LED lamp in methanol at room temperature. To our delight, 49% yield of the ethyl 2-(2-phenylimidazo[1,2-a]pyridin-3-yl)acetate (3a) was obtained after 36 h under argon atmosphere. However, no desired product was formed in aerobic conditions ( EntryPhotocatalyst (0.2 mol%)SolventYield (%)1Ru(bpy)₃Cl₂MeOH49, NR^b2Ru(bpy)₃Cl₂EtOH213Ru(bpy)₃Cl₂DCM434Ru(bpy)₃Cl₂MeCN475Ru(bpy)₃Cl₂TolueneNR6Ru(bpy)₃Cl₂MeOH : H₂O (1 : 1)767Ru(bpy)₃Cl₂MeOH : H₂O (2 : 1)898Ru(bpy)₃Cl₂MeOH : H₂O (1 : 2)Trace9Ru(bpy)₃Cl₂H₂ONR10Ru(bpy)₃Cl₂EtOH : H₂O (2 : 1)6811Ir(ppy)₃MeOH : H₂O (2 : 1)Trace12Rose bengalMeOH : H₂O (2 : 1)NR13Eosin YMeOH : H₂O (2 : 1)NR14Eosin BMeOH : H₂O (2 : 1)NR15Rhodamine BMeOH : H₂O (2 : 1)NR16—MeOH : H₂O (2 : 1)NR^c17Ru(bpy)₃Cl₂MeOH : H₂O (2 : 1)NR^d18Ru(bpy)₃Cl₂MeOH : H₂O (2 : 1)NR^e19Ru(bpy)₃Cl₂MeOH : H₂O (2 : 1)45^f, 84^g20Ru(bpy)₃Cl₂MeOH : H₂O (2 : 1)56^h, NRⁱOpen in a separate window^aReaction conditions: all reactions were carried out with 0.25 mmol of 1a, 0.5 mmol of 2, and 0.2 mol% of photocatalyst in 2.0 mL of solvent for 36 h at room temperature under argon atmosphere and irradiation with 34 W blue LED. NR = no reaction.^bIn aerobic condition.^cAbsence of Ru(bpy)₃Cl₂.^dWithout light source at rt.^eReaction at 60 °C without light scource.^f1.5 equiv. EDA.^g2.5 equiv. EDA.^hIrradiation with 20 W blue LED.ⁱ30 W white LED.With the optimized reaction conditions in hand we explored the substrate scope of this methodology with various substituted imidazopyridines. At first we checked the effect of various substituents on the pyridine ring of imidazopyridine derivatives and the results are summarized in Scheme 2. Imidazopyridine containing various electron-donating groups (8-Me and 7-OMe) efficiently reacted with ethyl diazoacetate to provide the desired products in good yields (3b and 3c). It is important to note that substrates bearing electron-withdrawing groups did not afford alkylated products under the optimized reaction condition. However, addition of 10 mol% N,N-dimethyl-m-toluidine as a redox-active additive gave a satisfactory yield of the desired products (see ESI^†). Therefore in modified reaction conditions, halogens containing imidazopyridines like –F, –Br, –I and strong electron-withdrawing group such as –CF₃, –CN containing substrates were successfully afforded the desired products in 67–90% yields (3d–3h). Next, we examined the substrate scope with various substitutions in phenyl part of imidazo[1,2-a]pyridine. Imidazopyridine with electron-releasing (4-Me, and 4-OMe), halogens (4-F, 4-Cl, and 3-Br) and strong electron-withdrawing group (4-CF₃, and 4-CN) containing substrates produced the desired products with good to excellent yields (3i–3p). 2-Hydroxy substituted imidazo[1,2-a]pyridine was also worked well in this transformation (3k). In addition, disubstituted imdazopyridines with different substituents at both the phenyl and pyridine ring underwent the reaction very smoothly (3q, and 3r). Heteroaryl and naphthyl substituted imidazopyridines produced the desired products without any difficulties (3s–3u). However, unsubstituted imidazo[1,2-a]pyridine did not produce the desired product in this protocol. To highlight the applicability of the present protocol a gram-scale reaction was carried out taking 1a in 6.0 mmol scale under normal laboratory setup. The yield of ethyl 2-(2-phenylimidazo[1,2-a]pyridin-3-yl)acetate (3a) was slightly diminished to 70% after 36 h along with the recovery of excess starting material.Open in a separate windowScheme 2Substrate scope of imidazopyridines.^a aReaction conditions: 0.25 mmol of 1, 0.5 mmol of 2 in presence of 0.2 mol% of Ru(bpy)₃Cl₂ in 2.0 mL of MeOH : H₂O (2 : 1) at room temperature under 34 W blue LED and argon atmosphere for 36 h. ^b10 mol% N,N-dimethyl-m-toluidine was added as an additive. ^c6.0 mmol scale.Next, to show the generality of this present methodology, we investigated the reaction taking other imidazoheterocycles like imidazo[2,1-b]thiazole and benzo[d]imidazo[2,1-b]thiazoles (Scheme 3). 6-Phenylimidazo-[2,1-b]thiazole reacted smoothly to afford 5a in 66% yield. Benzo[d]imidazo[2,1-b]thiazole containing –Me, –OMe, and –Cl substituted derivatives were well tolerable under the present reaction conditions (5b–5e). The structure of ethyl 2-(7-methoxy-2-phenylbenzo[d]imidazo[2,1-b]thiazol-3-yl)acetate (5c) was confirmed by X-ray crystallography.¹⁴ In addition, thiophene substituted benzo[d]imidazo[2,1-b]thiazole furnished the corresponding alkylated product in good yield (5f).Open in a separate windowScheme 3Substrate scope.^a aReaction conditions: 0.25 mmol of 4, 0.5 mmol of 2 in presence of 0.2 mol% of Ru(bpy)₃Cl₂ in 2.0 mL of MeOH : H₂O (2 : 1) at room temperature under 34 W blue LED and argon atmosphere for 36 h. ^b10 mol% N,N-dimethyl-m-toluidine was added as an additive.After that, we have directly modified the synthesized ethoxycarbonylmethylated product (3q) to amide derivative (6q) in 56% yield using benzylamine in the presence of La(OTf)₃ as a catalyst under ambient air at rt to 70 °C as shown in Fig. 1.Open in a separate windowFig. 1Modification of ester group via direct amidation process.A few control experiments were performed to understand the mechanistic insights of the present protocol (Scheme 4). The alkylation reaction did not proceed in the presence of 3.0 equiv. radical scavengers like 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), 2,6-di-tert-butyl-4-methyl phenol (BHT), 1,1-diphenylethylene (DPE), and p-benzoquinone (BQ) which suggest the reaction probably proceeds through radical pathway (Scheme 4, eqn (A)). Moreover, 3-phenylimidazo[1,2-a]pyridine (1v) did not produce the C-2 alkylated product that signifies the regioselectivity of the present protocol (Scheme 4, eqn (B)). Taking 2-(2-(vinyloxy)phenyl)imidazo[1,2-a]pyridine we also performed this reaction with ethyl diazoacetate under this standard reaction conditions. Desired C-3 alkylated product (8a) was formed in 35% yield (Scheme 4, eqn (C)). But cyclopropanation product was not formed in the alkene part of the allyl group via carbene pathway. From this experimental result strongly imply that the present strategy only proceeds through radical mechanistic pathway.Open in a separate windowScheme 4Control experiments.Based on the above mechanistic studies and previous literature reports,^7,8,13 a possible radical mechanism was proposed for the formation of ethyl 2-(2-phenylimidazo[1,2-a]pyridin-3-yl)acetate (3a) as presented in Scheme 5. Initially, photo-catalyst Ru(bpy)₃²⁺ is transformed to its excited-state *Ru(bpy)₃²⁺ under blue LED irradiation. In the presence of MeOH/H₂O, diazo compounds are in equilibrium with their protonated form (A). Then cationic diazoester involves single-electron transfer (SET) process with excited photocatalyst *Ru(bpy)₃²⁺ leading to the formation of alkyl radical intermediate (B) and Ru(bpy)₃³⁺.^6b,c Next, alkyl radical intermediate (B) effectively reacts with imidazopyridine (1a) to produce imidazole radical intermediate (C) which is successively transformed to imidazolium radical cation intermediate (D) along with the generation of ground state photocatalyst. Finally, C-3 alkylated imidazopyridine (3a) is obtained through deprotonation of intermediate D. It is worthy to mention that Meggers et al.^7h did not observe quenching of *Ru(bpy)₃²⁺ whereas Gryko et al.^6c did observe the quenching of *Ru(bpy)₃²⁺ by ethyl diazoacetate that was accelerated in the presence of protic sources.Open in a separate windowScheme 5Proposed mechanistic pathway.In case of halogen or electron-withdrawing substituted imidazoheterocycles a possible mechanism for the radical alkylation reaction is illustrated in Scheme 6.^6b,c Reductive quenching of *Ru(bpy)₃²⁺ by SET oxidation of aniline derivatives affords radical cation E and Ru(bpy)₃⁺. Then reduced photocatalyst Ru(bpy)₃⁺ comes back to ground state with the generation of radical intermediate Bvia the elimination of N₂. Subsequently, radical intermediate B reacts with imidazopyridine 1 to produce radical intermediate C′. Finally, the desired product 3′ is produced through the hydrogen atom transfer (HAT) process between radical cation E and radical intermediate C′.Open in a separate windowScheme 6Mechanistic pathway for electon-deficient substrates.     

Concise synthesis of N-thiomethyl benzoimidazoles through base-promoted sequential multicomponent assembly

An efficient method for the synthesis of N-thiomethyl benzimidazoles from o-phenylenediamines, thiophenols, and aldehydes via C–N/C–S bond formation under metal-free conditions is described. A broad range of functional groups attached to the substrates were well tolerated in this reaction system. Stable and low-toxicity paraformaldehyde was used as the carbon source.

An efficient method for the synthesis of N-thiomethyl benzimidazoles from o-phenylenediamines, thiophenols, and aldehydes via C–N/C–S bond formation under metal-free conditions is described.

Benzimidazole and its derivatives are extremely important in pharmaceuticals and bioactive natural products because they have found applications in diverse therapeutic areas, such as anticancer agents, antimicrobials, antivirals, antifungals and so on.¹ Furthermore, benzimidazoles are very important intermediates in organic synthesis and widely used as organocatalysts, ionic liquids and N-heterocyclic carbenes.² In particular, the broad spectrum of biological activities of compounds with the 1,2-disubstituted benzimidazole moiety make them highly sought as synthetic targets.³ Therefore, several efficient protocols have been developed to synthesize substituted benzimidazoles over the past several decades.⁴ Three general methods for the construction of 1,2-disubstituted benzimidazole are as follows: (1) oxidative cyclocondensation,⁵ (2) C-1 or N-2 alkylation/arylation,⁶ and (3) inter/intramolecular N-arylation.⁷ To date, most of these methods are reported for 1-phenyl-2-benzyl benzimidazoles synthesis. However, few examples of multicomponent reactions led to the development of N-thiomethyl benzimidazoles from simple starting materials under mild conditions.⁸Paraformaldehyde has been receiving more and more attention among molecule synthesis because of the advantages of low-cost, stability and low toxicity.⁹ It has been used as one-carbon homologation reagents for the synthesis of an incredible variety of complicated skeletons.¹⁰ In recent years, various methods have been developed to use paraformaldehyde to install a methylene,¹¹ carbonyl¹² and hydroxymethyl group¹³ into desired products. With respect to our recent studies on paraformaldehyde insertion to construct heterocycles, we reported synthetic methods for phthalazinones, 2-aroylbenzofurans and quinazolines formation.¹⁴ Very recently, we reported on an ethylenediamine-promoted three-component synthesis of 3-(thiomethyl)indoles from indoles, thiophenols, and paraformaldehyde.¹⁵ As part of our continuing efforts on using paraformaldehyde as the carbon source, herein, we describe a new and efficient multicomponent reaction for N-thiomethyl benzimidazoles formation from readily available starting materials. The reaction is successfully achieved in one-pot fashion under simple and facile reaction conditions (Scheme 1).Open in a separate windowScheme 1New strategy for the synthesis of N-thiomethyl benzimidazoles.For the optimization of reaction conditions, o-phenylenediamine (1a), p-toluenethiol (2a) and paraformaldehyde were chosen as model substrates ( EntryBaseSolvent (v/v)Yield^b (%)1K₂CO₃TCE : H₂O = 7 : 2382NaOHTCE : H₂O = 7 : 2373KO^tBuTCE : H₂O = 7 : 2314PiperidineTCE : H₂O = 7 : 2575DMAPTCE : H₂O = 7 : 2406MorpholineTCE : H₂O = 7 : 2357PDATCE : H₂O = 7 : 25884-ADPATCE : H₂O = 7 : 2759TCE : H₂O = 7 : 230104-ADPATCE : H₂O = 5 : 448114-ADPATCE : H₂O = 2 : 735124-ADPADMSO : H₂O = 7 : 222134-ADPAAnisole : H₂O = 7 : 243144-ADPAPhCl : H₂O = 7 : 22915^c4-ADPATCE : H₂O = 7 : 26116^d4-ADPATCE : H₂O = 7 : 252Open in a separate window^aConditions: 1a (0.2 mmol), 2a (0.5 mmol), base (0.2 mmol), paraformaldehyde (0.8 mmol), solvent (0.9 mL), 130 °C, 3 h, air. PDA = 1,4-benzenediamine, 4-ADPA = 4-aminodiphenylamine, TCE = 1,1,1,2-tetrachloroethane.^bGC yields.^c110 °C.^d4-ADPA (0.1 mmol).With the optimized reaction conditions established, the scope of thiophenols was probed for the three-component reaction ( Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2 (0.5 mmol), 4-ADPA (0.2 mmol), paraformaldehyde (0.8 mmol), TCE (0.7 mL), H₂O (0.2 mL), 130 °C, 3 h, air. Isolated yield based on 1a.To further evaluate the scope and limitations of the reaction, various o-phenylenediamines were treated with p-toluenethiol (2a) and the results are presented in Open in a separate window^aReaction conditions: 1 (0.2 mmol), 2a (0.5 mmol), 4-ADPA (0.2 mmol), paraformaldehyde (0.8 mmol), TCE (0.7 mL), H₂O (0.2 mL), 130 °C, 3 h, air. Isolated yield.The reaction of o-phenylenediamine (1a), p-toluenethiol (2a) and paraformaldehyde with other different aldehydes was investigated ( Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (0.5 mmol), 4 (0.4 mmol), 4-ADPA (0.2 mmol), paraformaldehyde (0.5 mmol), TCE (0.7 mL), H₂O (0.2 mL), 100 °C, 3 h, air. Isolated yield.We evaluated the late-stage transformation of 3aa (Scheme 2). When 3aa was treated with m-chlorope-roxybenzoic acid (m-CPBA) in CH₂Cl₂ at 50 °C, the oxidized sulfone product 6aa was obtained in 62% yield. The disulfonyl product 7aa and 8aa were obtained when p-toluenethiol (2a) or DMSO were used as the substrate with 3aa, although giving the corresponding products in lower yields.Open in a separate windowScheme 2Application of present work. Reaction conditions: (a) 3aa (0.1 mmol), m-CPBA (0.2 mmol), CH₂Cl₂ (0.5 mL), 50 °C, 12 h; (b) 3aa (0.1 mmol), p-toluenethiol (0.2 mmol), AgNO₃ (20 mol%), Cu(OAc)₂ (0.2 mmol), DMF (1 mL), 120 °C, 12 h; (c) 3aa (0.1 mmol), AgNO₃ (20 mol%), Cu(OAc)₂ (0.2 mmol), DMSO (1 mL), 140 °C, 15 h.To understand the mechanism of the reaction, we performed some control experiments under modified conditions. No desired product was observed when benzimidazole (1a′) was treated with p-toluenethiol (2a) and paraformaldehyde under standard conditions (Scheme 3a). No reaction occurred upon the treatment of o-phenylenediamine (1a) with 1,2-di-p-tolyldisulfane (2a′) and paraformaldehyde under the optimized reaction conditions (Scheme 3b). The reaction of 3aa with benzaldehyde (4a) could not give the corresponding product 5aa under standard conditions (Scheme 3c). According to above control experiments, a possible mechanism is illustrated in Scheme 4. Initially, condensation of o-phenylenediamine (1a) with formaldehyde generates an imine intermediate A. Then, intermediate A reacts with thiophenol anion to afford an intermediate B, which proceeds through intramolecular nucleophilic annulation to form intermediate C. Finally, dehydrogenative aromatization of intermediate C occurs to give desired product (3aa). On the other hand, the reaction mechanism of compound 5aa is similar to that of compound 3aa. Condensation of o-phenylenediamine (1a) with formaldehyde and benzaldehyde (4a) generates a non-symmetrical imine intermediate, which proceeds through nucleophilic addition/annulation/dehydrogenative aromatization sequence to give desired product (5aa).Open in a separate windowScheme 3Control experiments.Open in a separate windowScheme 4Proposed mechanism.In summary, we have developed a simple and efficient method for the synthesis of N-thiomethyl benzoimidazoles from o-phenylenediamines, thiophenols, and aldehydes under metal-free conditions. In this system, three carbon–nitrogen bonds and one carbon–sulfur bond were formed with high levels of chemo-selectivity. Various functional groups were well tolerated under the optimized reaction conditions. This method affords an efficient and general approach for the synthesis of biologically important 1,2-disubstituted benzimidazole from readily available starting materials.     

Transition-metal-free regioselective C–H halogenation of imidazo[1,2-a]pyridines: sodium chlorite/bromite as the halogen source

A facile transition-metal-free regioselective halogenation of imidazo[1,2-a]pyridines using sodium chlorite/bromite as the halogen source is presented. The reaction has provided an efficient method for the formation of C–Cl or C–Br bonds to synthesize 3-chloro or 3-bromo-imidazo[1,2-a]pyridines which were then efficiently transformed into imidazo[1,2-a]pyridine core π-systems by Suzuki–Miyaura reactions.

We report highly efficient strategies for the synthesis of 3-Cl or 3-Br-imidazo[1,2-a]pyridines using sodium chlorite/bromite as the halogenic source.

Aryl halides as a structural skeleton are present in a large number of natural products, pharmaceuticals, and biologically active compounds.¹ Significant drugs such as Aripiprazole, Chlortrimeton, Plavix and Zoloft all included the aryl chlorides motif (Scheme 1). Apart from this, aryl bromides have always been extremely important synthetic intermediates and building blocks in organic chemistry² for the construction of diverse and highly functionalized compounds. In the past few years, aryl halides have been used as substrates to form carbon–carbon and carbon–heteroatom bonds via transition-metal-catalyzed cross-coupling reactions. There are some classical methods: Heck, Suzuki, Negishi, Stille, Sonogashira, Ullmann, Buchwald–Hartwig, Kumada, etc.^3–10 Consequently, the development of a new route for the construction of these scaffolds is highly desirable, especially those based on assembling structures directly from readily available raw materials. In the last few years, several transition-metal-catalyzed halogenation transformations^11,12 have been developed, employing Pd, Rh or Cu as the catalysts and carboxylic acid, amide, nitrile, or pyridine as the directing groups (Scheme 1a). Recently, NH₄X, NaX and HX have been also employed as the halogen sources¹³ in transition-metal-free conditions for the halogenation of several arenes and heteroarenes (Scheme 1b). Nevertheless, directing groups and additional oxidants were usually needed in these transformations and the halogen sources were very limited.Open in a separate windowScheme 1Chlorine containing drugs.In order to expand the richness of green synthetic methods, we tried to hunt for other atom-economical and easy-to-obtain halogen sources. As we know, sodium chlorite or bromite are commodity chemicals that are widely used as main effective components of bleaches or desizing agents.¹⁴ On the other hand, imidazo[1,2-a]pyridines represent an important class of molecules and show unique bioactivities and chemical properties¹⁵ that lead them to broad applications in organic synthesis and pharmaceutical chemistry.¹⁶ Recent significant advances¹⁷ have been achieved in this field. We have also developed novel strategies for the construction of imidazo[1,2-a]pyridines.¹⁸ Herein, our current interest is focused on developing an efficient transition-metal-free selective halogenation of imidazo[1,2-a]pyridines without direct group, in which process sodium chlorite or bromite were used as both halogen sources and oxidants (Scheme 2c).Open in a separate windowScheme 2Selective halogenation reactions.Our initial investigation focused on the halogenation of imidazo[1,2-a]pyridine 1a. The results of the optimized reaction conditions are summarized in EntryNaClO₂ (equiv.)AdditiveSolventTemp (°C)Yield^b (%)12AcOHToluene606423AcOHToluene606231AcOHToluene604342CF₃COOHToluene604052PivOHToluene602962TsOHToluene603172—Toluene60Trace82AcOHDioxane606992AcOHNMP6045102AcOHCH₃CN6037112AcOHDMSO6063 12 2 AcOH DMF 60 87 132AcOHDCE6014142AcOHDMF4074152AcOHDMF808516^c2AcOHDMF60n.r.Open in a separate window^aReaction conditions: 1a (0.5 mmol), NaClO₂ (1–3 mmol), AcOH (2 mmol), solvent (2 mL), 40–80 °C for 10 h.^bDetermined by GC analysis.^cWithout NaClO₂.With the establishment of the optimal conditions, the scope of this transition-metal-free chlorination reaction was next investigated. And the results have been described in Scheme 3. A variety of 2-unsubstituted imidazo[1,2-a]pyridines were first employed under the optimized conditions. Different position substituted groups on the pyridine ring of imidazo[1,2-a]pyridine, having 6-CH₃, 6-Cl, 6-I, 7-CH₃, 8-CH₃ substitution, were well-tolerated under the optimized conditions. The results indicated that selective C-3 chlorination products 2a–2f were formed in good to excellent yields. This catalytic system was further found to be successfully applied to catalyze the chlorination of 2-CH₃, 2-C(CH₃)₃, and 2-Ph substituted imidazo[1,2-a]pyridines, generating the desired products in moderate to good yields (2g–2p). It was worth noting that when imidazo[1,2-a]pyridines substituted with sterically hindered 2-C(CH₃)₃ were employed as substrates, the transformation worked well and led to a beneficial effect on the reaction outcome.Open in a separate windowScheme 3Chlorination of imidazo[1,2-a]pyridines.We next examined the bromination of imidazo[1,2-a]pyridines derivatives in the presence of NaBrO₂ and AcOH in DMF at 60 °C for 10 h. The results were summarized in Scheme 4. As we expected, the optimal conditions could also be applied to bromination of imidazo[1,2-a]pyridines and afforded the brominated products 3a–3f in 70–88% yields. It was found that the reaction was also with great regioselective in the case of 2-unsubstituted imidazo[1,2-a]pyridines.Open in a separate windowScheme 4Bromination of imidazo[1,2-a]pyridines.The reactions of 2a or 3d with phenylboronic acid were conducted in the presence of Pd-catalyst (Scheme 5). The Suzuki–Miyaura reactions were performed very well, affording the product 5a or 6a in 74% or 79% yields, respectively.Open in a separate windowScheme 5Suzuki–Miyaura reactions of 2a or 3d with phenylboronic acid.In order to text whether this method is compatible with other aromatic species or not, we have tried to use indoles, 1-methyl-1H-indoles, benzofurans, N,N-dimethylaniline, N-phenylacetamide and 1,3,5-trimethoxybenzene to perform under the present reaction conditions, while no target products were obtained. We supposed that the specificity of this reported method is because of the rich electronic ethene-1,2-diamine moiety of imidazo[1,2-a]pyridine (Scheme 6).Open in a separate windowScheme 6Applications for other aromatic species.Gaining insight into the mechanism, control experiments were carried out for this transition-metal-free halogenation reaction. To prove a radical species involved in transformation, the reactions were conducted by adding radical-trapping reagent (TEMPO) or radical inhibitor (BHT) (Scheme 7, eqn (1)) in the reaction, and only trace amount of product 2a was observed. The result clearly showed that this reaction had been inhibited and a radical process was involved for this transformation, which was consistent with previous reported.¹⁷ To further investigated the chlorine source, NaClO and NaClO₃ were employed to react with imidazo[1,2-a]pyridine 2a under the standard conditions. The results showed that the chlorination products were obtained in yields of 47% or 63% respectively, which means chlorine ions having a charge of 1+ or 5+ can also proceed this transformation, albeit with low yields (Scheme 7, eqn (2)).Open in a separate windowScheme 7Control experiments for investigation of the mechanism.Base on the above results and previous works,¹⁹ a possible mechanism was proposed to account for this transition-metal-free regioselective halogenation reaction (Scheme 8). Firstly, oxidation–reduction reaction of sodium chlorite happened in the presence of AcOH to produce chlorine, NaOAc and H₂O. Subsequently, the chlorine radical was easily formed via homolysis of chlorine, which then attack the double bond between C2 and C3 of imidazo[1,2-a]pyridine, resulting in free radical intermediate I (more stable than II because of the p–π conjugation). Finally, the free radical intermediate I underwent an aromatization with chlorine free radical to give the target product 2a.Open in a separate windowScheme 8Possible mechanism.     

Enantioselective synthesis of anti-3-alkenyl-2-amido-3-hydroxy esters: application to the total synthesis of (+)-alexine

A straightforward synthesis of anti-3-alkenyl-2-amido-3-hydroxy esters from the corresponding racemic α-amino-β-keto esters by using a ATH/DKR protocol has been developed. This method gives moderate to excellent yields with high chemo-, diastereo- and enantioselectivities for a broad range of substrates. In order to highlight the versatility of the methodology it was applied in an efficient asymmetric synthesis of the polyhydroxylated pyrrolizidine alkaloid (+)-alexine.

A straightforward synthesis of anti-3-alkenyl-2-amido-3-hydroxy esters from the corresponding racemic α-amino-β-keto esters by using a ATH/DKR protocol has been developed.

β-Hydroxy-α-amino esters and their derivatives are important structural motif in a number of biologically relevant compounds.¹ As a consequence, several elegant methods have been developed for the stereoselective² and asymmetric³ synthesis of such compounds. We speculated that the versatility of this scaffold could be expanded by the incorporation of a vinyl moiety in 3-position (e.g.2, Scheme 1), thus allowing for additional stereoselective manipulation. For example, stereoselective epoxidation⁴ or dihydroxylation⁵ of the carbon–carbon double bond in compound 2, or cross metathesis, could furnish advanced such intermediates for the synthesis of polyhydroxylated alkaloids (Scheme 1), compounds with diverse biological activities.⁶ Compound 2, in turn, was excepted to be derived through a chemoselective asymmetric transfer hydrogenation (ATH) of α-amido-β-keto ester 1. Herein we detail our efforts towards realizing this methodology and its application to the synthesis of (+)-alexine (3).Open in a separate windowScheme 1Proposed route from α-amido- β-keto ester 1 to polyhydroxylated pyrrolizidine and indolizidine alkaloids.ATH coupled with a dynamic kinetic resolution (DKR) of configurationally labile α-amido-β-keto ester has been proven to be a powerful method for the synthesis of syn- or anti β-hydroxy-α-amino esters.⁷ In such transformation two contiguous stereocenters can be constructed in high er and dr in a single operation from a racemic starting material. We have previously developed a ATH process coupled with DKR for preparation aryl, alkyl or heterocyclic anti-β-hydroxy-α-amido ester in organic solvents, emulsions or water system.⁸ For the present investigation it was of interest to expand the substrate scope to encompass substrates having an vinylic group in 3-position, e.g. compound 1, and to investigate the possibility of developing a chemoselective 1,2-reduction of the carbonyl group in preference of a 1,4-reduction of the enone moiety.The investigation was initiated by examining the ATH of ester 1a using our previously optimized conditions ([RuCl₂(benzene)]₂/(S,S)-BnDPAE), yielding a mixture of the desired anti-amino alcohol 2a, having low dr and er, and the over-reduced compound 4 in poor selectivity (ii) dichloride dimer catalyst incorporating a substituted arene moiety resulted in an improved chemoselectivity with only traces of the over reduced compound 4 being observed, the best result being obtained with [RuCl₂(mesitylene)]₂ (entry 6). Encouraged by this result, other reaction parameters (solvent and catalyst loading) were screened in order to improve the reaction outcome. Performing the reaction in MeOH or CH₃CN did not improve the outcome (entries 8–9), while the use of dioxane or CHCl₃ afforded similar results in terms of yields and stereoselectivities as CH₂Cl₂ (entries 8–11). Since the reaction run in dioxane gave the best result this solvent was selected for the final screening of catalyst loading (entries 12–14). It was observed that similar yields but with improved diastereoselectivity could be achieved when lowering the amount of catalyst from 20 mol% to 5 mol%. The best result, 72% yield of 2a with 95 : 5 dr and 96.5 : 3.5 er, was obtained when using 2.5 mol% of [RuCl₂(mesitylene)]₂ and 5 mol% (S,S)-DPAE (entry 14).Optimization of the ATH Reaction of 1a^a

Entry	Ru dimer	Ligand	Solvent	1a/2a/4 (%)b	dr (anti : syn)c	er (anti)d
1	Benzene	L1	CH2Cl2	5/50/20	55 : 45	88.5 : 11.5
2	Benzene	L2	CH2Cl2	21/41/16	89 : 11	7 : 93
3	Benzene	L3	CH2Cl2	35/15/5	87 : 13	12.5 : 87.5
4	Benzene	L4	CH2Cl2	<5/52/20	80 : 20	95 : 5
5	p-Cymene	L4	CH2Cl2	33/47/<5	85 : 15	90.5 : 9.5
6	Mesitylene	L4	CH2Cl2	20/65/<5	91.5 : 8.5	93 : 7
7	Hexamethylbenzene	L4	CH2Cl2	34/28/<5	83 : 17	58 : 42
8	Mesitylene	L4	MeOH	49/24/<5	86 : 14	89.5 : 10.5
9	Mesitylene	L4	CH3CN	26/37/<5	85 : 15	85 : 15
10	Mesitylene	L4	Dioxane	8/68/<5	93 : 7	95.5 : 4.5
11	Mesitylene	L4	CHCl3	13/57/<5	94.5 : 5.5	96 : 4
12e	Mesitylene	L4	Dioxane	11/68/<5	93 : 7	96 : 4
13f	Mesitylene	L4	Dioxane	15/60/<5	94 : 6	96 : 4
14g	Mesitylene	L4	Dioxane	12/72/<5	95 : 5	96.5 : 3.5

Open in a separate window^aReactions preformed with [RuCl₂(arene)]₂ (0.1 eq.) and ligand (0.2 eq.) heated in 2-propanol (0.3 mL) at 80 °C for 1 h. After cooling to room temperature, the catalyst was then added to a solution of 1a (0.2 mmol, 1 eq.) and HCO₂H/Et₃N (1.5 : 3, 1.5 eq.) in solvent (1 mL).^bIsolated yields.^cDetermined by NMR analysis of the crude reaction mixture.^dDetermined by chiral HPLC.^eReaction run with 0.075 eq. of [RuCl₂(mesitylene)]₂ and 0.15 eq. of (S,S)-DPAE.^fReaction run with 0.05 eq. of [RuCl₂(mesitylene)]₂ and 0.1 eq. of (S,S)-DPAE.^gReaction run with 0.025 eq. of [RuCl₂(mesitylene)]₂ and 0.05 eq. of (S,S)-DPAE.Next the scope of the ATH reaction was investigated by screening a variety of γ-alkenyl-β-keto-α-amido esters 1 and the results are summarized in Open in a separate window^aReaction preformed with [RuCl₂(mesitylene)]₂ (0.025 eq.) and (S,S)-DPAE (0.05 eq.) heated in 2-propanol (0.3 mL) at 80 °C for 1 h. After cooling to room temperature, the catalyst was then added to the β-keto ester 1 (0.2 mmol, 1 eq.) and HCO₂H/EtN₃ (1.5 : 3, 1.5 eq.) in dioxane (1 mL).^bIsolated yields.^cdr determined by ¹H NMR analysis of the crude reaction mixture.^der determined by chiral HPLC.^eIsolated yields based on recovered start material.^fNo reaction.^gThe reaction gave a complicated mixture of product.To demonstrate the applicability of the developed methodology it was decided to apply it to the total synthesis of the polyhydroxylated pyrrolizidine alkaloid (+)-alexine.⁹ Previous syntheses of this natural product has relied on carbohydrate derived strategies and relatively high steps strategies, while the present approach relies on an efficient and non-carbohydrate entry into this class of compounds. Our retrosynthetic analysis is summarized in Scheme 2 and relies on the known cyclization of amino epoxides 10 into (+)-alexine.¹⁰ Compound 10, in turn is derived from alkene 8, which can be derived from 2b using standard transformations (Scheme 2).Open in a separate windowScheme 2Retrosynthetic analysis of (+)-alexine.Subjecting ester 1b (4 g) to the ATH reaction, using the optimized conditions, furnished anti-α-amido-β-hydroxy ester 2b (87% brsm) in high diastereo- and enantioselectivity (anti/syn 96 : 4, er 97 : 3), which also indicate that the ATH/DKR protocol is scalable. Reduction of 2b with NaBH₄, followed by protection of the resulting 1,3-diol as the bis-BOM ether provided 5 (78%, two steps). Ozonolysis of this material followed by a chelation controlled addition of vinylmagnesium bromide afforded compound 7 (58%, dr 75 : 25).¹¹ Attempts to improve the dr of this step involved screening different solvents, Lewis acids, temperatures and hydroxyl protecting groups, but did not improve the situation.¹² The cross metathesis reaction of mixture 7 with 4-butenol p-tolyl-sulfonate in the presence of Grubbs'' 2nd generation catalyst provided the trans olefin (64% brsm). After the deprotection of benzyloxymethyl group, an undesired diastereomer of compound 8 could be separated by column chromatography, and compound 8 was obtained (67%, dr > 95 : 5) as a pure form. Next the stage was set for the neighbouring group directed epoxidation of 8, which was accomplished using Ti(OiPr)₄ and β-hydroperoxy alcohol 9, yielding anti epoxide 10 (78%) as the only detectable isomer.¹³ Deprotection of 10 (Pd/C, H₂, MeOH) followed by purification on silica gel afforded (+)-alexine (3) in 76% yield as a white solid. The ¹H-NMR, ¹³C-NMR data, melting point and the optical rotation (mp 160–162 °C, [α]²⁰_D = +42.1 (c 0.3H₂O)) were in good agreement with the published data for (+)-alexine⁹ (mp 162–163 °C, [α]²⁰_D = +40 (c 0.25 in H₂O)) (Scheme 3).Open in a separate windowScheme 3Total synthesis of (+)-alexine.In summary, we have developed an operationally straightforward synthesis of anti-3-alkenyl-2-amido-3-hydroxy esters from the corresponding racemic α-amino-β-keto esters by using a ATH/DKR protocol. This method gives moderate to excellent yields, diastereoselective and enantioselectivities for a broad range of substrates. In order to highlight the versatility of the methodology it was applied in an asymmetric synthesis of the polyhydroxylated pyrrolizidine alkaloid (+)-alexine (3, 8 steps and 11.5% overall yield from 2b).     

Merging catalyst-free synthesis and iodine catalysis: one-pot synthesis of dihydrofuropyrimidines and spirodihydrofuropyrimidine pyrazolones

A new and efficient one-pot strategy combining catalyst-free synthesis and iodine catalysis has been developed for the synthesis of dihydrofuropyrimidines and spirodihydrofuropyrimidine pyrazolones. This approach affords products in moderate to high yields (up to 96%) with excellent diastereoselectivities (up to >25 : 1 dr). The reaction is simple to carry out and is metal-free.

A new and efficient one-pot strategy combining catalyst-free synthesis and iodine catalysis has been developed for the synthesis of dihydrofuropyrimidines and spirodihydrofuropyrimidine pyrazolones.

Furo fused pyrimidines¹ and dihydrofuro fused pyrimidines,² derivatives of the pyrimidine species,³ are prevalent heteroaromatic core structures found in a broad variety of natural products, pharmaceuticals, and other biologically active molecules (Scheme 1). In particular, dihydrofuropyrimidine derivatives have shown a diverse range of useful biological and pharmacological activities such as anticancer, anti-inflammatory, antiproliferative, and antirheumatic activities. The substituent group on the dihydrofuran moiety significantly influences the biological activity. However, efficient procedures for the synthesis of dihydrofuropyrimidines are not well developed. In 1987, Taylor et al. reported intramolecular Diels–Alder reactions of 1,2,4-triazines to synthesize dihydrofuro fused pyrimidines under very high temperature condition (Scheme 2A).⁴ Alternatively, dihydrofuropyrimidine derivatives can be prepared in relatively low yields from pre-synthesized 2,4-dichloro-dihydrofuropyrimidines via further substitution reactions and coupling reactions (Scheme 2B). However, several steps are required to prepare highly functionalized starting materials with different furan groups.^2a,5 Both of these methods have some well-known drawbacks: (a) harsh reaction conditions and the requirement of multistep synthetic sequences; (b) the use of poisonous or expensive reagents such as COCl₂, POCl₃, and transition metal Pd; and (c) low yields and limited substrate scope. Therefore, it is highly desirable to find an efficient and general synthetic methodology for the construction of various substituted dihydrofuropyrimidines, from easily accessible raw materials, under simple and mild reaction conditions, and without the use of potentially toxic transition metals.Open in a separate windowScheme 1Selected important biologically active heterocycles containing fused pyrimidine moieties.Open in a separate windowScheme 2General methods for the synthesis of dihydrofuropyrimidine derivatives.In past decades, catalyst-free synthesis has been extensively studied and applied to the construction of complex molecules, as it tends to be inexpensive and environmentally friendly.^6a,b,c For example, Deb, Baruah, and co-workers described two procedures for the synthesis of 1,3-oxazines^6d and pyrimidine ring compounds^6f under the catalyst-free conditions. In 2017, the group of Brahmachari presented a catalyst-free protocol for the construction of functionalized pyridodipyrimidines.^6e In recent years, iodine catalysis has also emerged as an efficient, metal-free methodology for chemical bond construction which has low toxicity, is environmentally benign, and is readily available.⁷ Very recently, we presented a new and efficient catalytic strategy that combined organocatalysis and iodine catalysis for the one-pot sequential catalytic synthesis of spirodihydrobenzofurans.⁸ The success of that approach suggested that it might be possible to prepare the biologically important dihydrofuro fused pyrimidines using a new strategy that combines catalyst-free synthesis and iodine catalysis. Herein, we report a facile and efficient methodology for the synthesis of dihydrofuro fused pyrimidine derivatives using 2,6-diaminopyrimidin-4(3H)-ones,⁹ versatile building blocks in organic synthesis which can be easily prepared,¹⁰ nitroolefins, and unsaturated pyrazolones (Scheme 2C), in which the intermolecular reaction can be easily induced under very mild and catalyst free conditions, and the subsequent step of intramolecular cyclization can then be easily realized via iodine catalysis.The one-pot reaction was initially performed with 2,6-diaminopyrimidin-4(3H)-one 1a and nitroolefin 2a as model substrates to demonstrate the feasibility of the designed approach. The overall synthesis proceeded smoothly, when the catalyst-free synthesis was conducted at 50 °C and the intramolecular cyclization was performed in the presence of I₂ and tert-butyl hydroperoxide in CH₃CN at room temperature, the reaction proceeded smoothly, affording the desired product 3a in 82% isolated yield ( EntryIodine sourceOxidantSolventYield^b (%)1I₂TBHPCH₃CN822^cNaITBHPCH₃CN84 3 ^c KI TBHP CH ₃ CN 86 4^cNH₄ITBHPCH₃CN725^c nBu₄NITBHPCH₃CN806^cNISTBHPCH₃CN837^cKITBPBCH₃CN548^cKIDTBPCH₃CN239^cKINaClO₂CH₃CN2810^cKIK₂S₂O₈CH₃CN3211^cKIH₂O₂CH₃CN7612^cKITBHPDMFTrace13^cKITBHPTHF8214^cKITBHP1,4-DioxaneTrace15^cKITBHPMeOH6816^cKITBHPH₂O6317^c,dKITBHPCH₃CN5518^c,eKITBHPCH₃CN7319^c,fKITBHPMeOH6520^c,fNH₄ITBHPMeOH5021^c,f nBu₄NITBHPMeOH7022^c,fNISTBHPMeOH52 23 ^{c , f} nBu ₄ NI H ₂ O ₂ MeOH 77 Open in a separate window^aUnless otherwise stated, all the reactions were conducted in solvent (1 mL) using 1a (0.1 mmol) and 2a (0.1 mmol) with stirring for 24 h at 50 °C, this was followed by the addition of iodine source (0.01 mmol) and oxidant (0.2 mmol), and the solution was then stirred for 24 h at room temperature.^bIsolated yield.^cThe reaction was conducted in the presence of 20 mol% iodine source.^dFirst step was conducted at 40 °C for 24 h.^eFirst step was conducted at 60 °C for 24 h.^fFirst step was conducted at room temperature for 24 h.^gThe dr value is >25 : 1 for all the isolated products.With the optimized conditions in hand, the substrate scope was then investigated (11 The reaction was found to be compatible with nitroolefins bearing both electron-withdrawing and electron-donating groups. Substrates with electron-withdrawing substituent groups, such as F, Cl, Br, NO₂, or CF₃ on the phenyl ring, afforded moderate to high yields, ranging from 54% to 88% (3b–m). It was worth noting that, at room temperature, nitroalkenes bearing electron-rich motifs such as MeO, or Me on the phenyl core, heterocyclic nitroolefins, an aliphatic nitroolefin and α-methyl-substituted nitroolefin all tolerated this transformation, producing the desired dihydrofuropyrimidines in 25% to 82% yields (3n–v). For example, by using heterocyclic nitroolefins, products 3s and 3t were obtained in 57% and 75% yields, respectively. Aliphatic nitroolefin bearing a butyl group provided 3u in 25% yield. Furthermore, the α-methyl-substituted nitroolefin was also able to participate in this transformation to afford product 3v with 54% yield.Substrate scope for nitroolefins^c,d

Access to 1-amino-3,4-dihydroisoquinolines via palladium-catalyzed C–H bond aminoimidoylation reaction from functionalized isocyanides

Efficient access to 1-amino-3,4-dihydroisoquinolines, through palladium-catalyzed intramolecular C–H bond aminoimidoylation of α-benzyl-α-isocyanoacetates, has been developed. Consecutive isocyanide insertion and C–H bond activation were realized with C–N and C–C bonds formation in one step under redox neutral conditions, employing O-benzoyl hydroxylamines as electrophilic amino sources.

Efficient and practice access to 1-amino-3,4-dihydroisoquinolines, through palladium-catalyzed intramolecular C–H bond aminoimidoylation of α-benzyl-α-isocyanoacetates, has been developed.

As a class of cyclic amidine compounds, 1-amino-3,4-dihydroisoquinolines are essential six-membered heterocycles which can be found in numerous natural products, functional chemicals and pharmaceutical agents (Scheme 1).¹ For example, piperazine tethered dihydroisoquinoline and benzocyclic amide I was found to be an efficient cardiovascular agent.^1a Phenylalanine-derived and arylamine or cyclic aliphatic-amine-containing 1-amino-3,4-dihydroisoquinolines (II–V) show outstanding BACE-1 inhibition, kinase VEGFR-2 inhibition, phosphodiesterase IV inhibition and hydrogen ion-sodium exchanger NHE-3 inhibition activities, respectively.^1b–e Traditional preparation of such 1-amino-3,4-dihydroisoquinoline scaffolds is mainly based on nucleophilic substitution of readily prepared 3,4-dihydroisoquinolines² and Bischler-Napieralski reaction starting from urea.³ Most of these methods suffer from multiple-step synthesis, harsh conditions or the use of toxic reagents. Thus, developing an efficient and practical method for the construction of 1-amino-3,4-dihydroisoquinoline derivatives remain an attractive synthetic task.Open in a separate windowScheme 1(a) Representative bioactive molecules containing the 1-amino-3,4-dihydroisoquinoline moiety. (b) Traditional synthetic methods.In recent decades, isocyanides have been extensively studied in multicomponent reactions,⁴ imidoyl radical-involved transformations⁵ and transition-metal-catalyzed insertion reactions⁶ due to their diverse and unique reactivities. A variety of acyclic imine derivatives were synthesized via palladium-catalyzed imidoylation reactions.⁷ For the construction of biorelevant nitrogen-containing heterocycles via Pd-catalyzed non-functionalized isocyanide insertion reactions, a nucleophilic group is usually preinstalled to the substrates containing C–X (C–H) bonds, followed by Pd-catalyzed oxidative addition (C–H bond activation)/isocyanide insertion/ligand substitution/reductive elimination sequence.⁸ For example, Maes and coworkers developed an efficient palladium-catalyzed synthesis of 4-aminoquinazolines from N-(2-bromoaryl)amidines using amidine as an internal nucleophile.^8a Access to the same scaffold through palladium-catalyzed amidine-directed C–H bond imidoylation/cyclization reaction was reported by Zhu group.^8c Isocyanide acted as a C1 synthon in these cyclization reactions, with the terminal carbon of isocyanide being used in the ring formation.⁹ Considering the diversity of R group on the nitrogen atom of isocyanide, the so-called functionalized isocyanide strategy was widely developed as well, with various N-heterocycles such as oxazoles,¹⁰ indoles,¹¹ phenanthridines,¹² 9H-pyrido[3,4-b]indoles¹³ and nonaromatic azepines¹⁴ being synthesized efficiently. Zhu and coworkers developed the first asymmetric C–H bond imidoylation reaction from easily accessible α,α-dibenzyl-α-isocyanoacetates with chiral quaternary-carbon-containing 3,4-dihydroisoquinolines being generated (Scheme 2a).¹⁵ Recently, a catalytic system controlled regioselective C–H bond imidoylation was realized for the selective synthesis of 5 or 6-membered cyclic imines (Scheme 2b).¹⁶ Aryl halides were mostly used in these transformations while N–O compounds were rarely reported as electrophiles in Pd-catalyzed isocyanide insertion reactions.¹⁷ Zhu group reported the synthesis of phenanthridin-6-amine derivatives from O-benzoyl hydroxylamines and commonly used biaryl isocyanides.^17c However, a methyl or methoxyl carbonyl group was needed at the ortho position of isocyano group, which critically limited the application of the reaction. Herein, we developed an efficient and practical synthesis of 1-amino-3,4-dihydroisoquinolines, through palladium-catalyzed intramolecular C–H bond aminoimidoylation reaction of α-benzyl-α-isocyanoacetates. Consecutive isocyanide insertion and C–H bond activation were realized with C–N and C–C bonds being constructed in one step, employing O-benzoyl hydroxylamines as electrophilic amino sources.Open in a separate windowScheme 2Palladium-catalyzed imidoylative cyclization of α-benzyl-ethylacetates.The reaction conditions were optimized with ethyl 2-benzyl-2-isocyano-3-phenylpropanoate (1a) and morpholino benzoate (2a) as model substrates, and ethyl 3-benzyl-1-morpholino-3,4-dihydroisoquinoline-3-carboxylate (3a) was obtained in 34% yield in the presence of Pd(OAc)₂ (1.5 equiv.), PPh₃ (20 mol%), Cs₂CO₃ (1.0 equiv.) and PivOH (0.6 equiv.) in toluene at 80 °C (entry 1, EntryCatalystLigandSolventYield^b1Pd(OAc)₂PPh₃Toluene342Pd(OAc)₂PPh₃THFTrace3Pd(OAc)₂PPh₃DCE294Pd(OAc)₂PPh₃Dioxane765Pd(OAc)₂PPh₃MeCNTrace6Pd(OAc)₂PPh₃DMSOTrace7Pd(OPiv)₂PPh₃Dioxane318Pd(TFA)₂PPh₃Dioxane269PdCl₂(MeCN)₂PPh₃Dioxane3811Pd(PPh₃)₄Dioxane5612Pd(OAc)₂BINAPDioxane3013Pd(OAc)₂dppbDioxane2614Pd(OAc)₂dpppDioxane2815Pd(OAc)₂XantPhosDioxane4216Pd(OAc)₂SPhosDioxane3417Pd(OAc)₂XPhosDioxane2418^cPd(OAc)₂PPh₃Dioxane84 (80)^d19^cNonePPh₃Dioxane020^cPd(OAc)₂NoneDioxane5621^c,ePd(OAc)₂PPh₃Dioxane022^c,fPd(OAc)₂PPh₃Dioxane4123^c,gPd(OAc)₂PPh₃Dioxane2424^c,hPd(OAc)₂PPh₃Dioxane3125^c,iPd(OAc)₂PPh₃Dioxane61Open in a separate window^aReaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), Pd-catalyst (0.01 mmol, 10 mol%), ligand (0.02 mmol, 20 mol%), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), PivOH (0.06 mmol, 0.6 equiv.), 80 °C, Ar. A solution of 1a was added via a syringe pump within 1 h.^bNMR yield with 1-iodo-4-methoxybenzene as an internal standard.^c T = 110 °C.^dIsolated yield.^eWithout Cs₂CO₃ and PivOH.^fCsOPiv was used as the base.^gK₂CO₃ was used as the base.^hNa₂CO₃ was used as the base.ⁱ5 mol% of catalyst was used.With the optimized conditions in hand, the scope of functionalized isocyanide was investigated first, using morpholino benzoate 2a as the coupling partner (Scheme 3). Both electron rich and withdrawing substituents such as Me, t-Bu, F, Cl, CF₃, CO₂Me and NO₂ at the para position of aromatic ring can tolerate the reaction conditions, and generate the corresponding products in good to excellent yields (3a–3h). Isocyanides bearing ortho substituents on the phenyl ring underwent the reaction smoothly, generating the products 3i and 3j in 58% and 82% yields respectively. Even substrates bearing two substituents were well suited to the reaction conditions, affording the aminoimidoylation products without loss of efficiency (3k–3l). Compound 3m was delivered with excellent regioselectivity in 63% yield when m-Cl substituted starting material was employed in the reaction, which indicated the hindrance sensitivity of this reaction. Modifying the ester moiety in 1 to a methyl ester or an amide did not impede the reaction, giving 3n and 3o with excellent yields. Changing one of the benzyl groups to alkyl substituents didn''t decrease the reaction efficiency, generating products 3p and 3q in moderate yields.Open in a separate windowScheme 3Scope of isocyanides. Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), Pd(OAc)₂ (0.01 mmol, 10 mol%), PPh₃ (0.02 mmol, 20 mol%), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), PivOH (0.06 mmol, 0.6 equiv.), 110 °C, Ar. A solution of 1 was added via a syringe pump within 1 h. Isolated yields.Then we moved our attention to the investigation of substrate scope of aminating partners (Scheme 4). It was found that various O-benzoyl hydroxylamines derived from piperidines could be smoothly employed in the reaction (4a–4e). Substituents such as Me, CO₂Et, OMe and ketal group on the piperidines were well tolerated (4b–4e). Aminating reagent derived from Boc-protected piperazine was also compatible with this reaction, generating the product 4f in 99% yield. Fortunately, acyclic aminated product 4g was obtained as well in moderate yield.Open in a separate windowScheme 4Substrate scope of aminating agents. Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), Pd(OAc)₂ (0.01 mmol, 10 mol%), PPh₃ (0.02 mmol, 20 mol%), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), PivOH (0.06 mmol, 0.6 equiv.), 110 °C, Ar. A solution of 1a was added via a syringe pump within 1 h. Isolated yields.When ethyl 2-isocyano-2,3-diphenylpropanoate was conducted in the reaction with 2a, the 3,4-dihydroisoquinoline product 6 was generated exclusively, albeit in only 37% yield (Scheme 5a). To examine if isoindoline could be afforded by this aminoimidoylation reaction, ethyl 2-isocyano-4-methyl-2-phenylpentanoate (7) was selected as the substrate with 2a (Scheme 5b). However, no desired product was generated under the standard conditions, showing different site-selectivity with the previous imidoylation reaction developed by Zhu and coworkers.¹⁶Open in a separate windowScheme 5Reaction conditions: 5(7) (0.1 mmol), 2a (0.15 mmol), Pd(OAc)₂ (0.01 mmol, 10 mol%), PPh₃ (0.02 mmol, 20 mol%), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), PivOH (0.06 mmol, 0.6 equiv.), 110 °C, Ar. A solution of 5(7) was added via a syringe pump within 1 h. Isolated yields.Gram-scale preparation of 3a was carried out smoothly under standard conditions (Scheme 6a). The reduction reaction of 3a was carried out using LiAlH₄ and the corresponding product 8 was generated in 70% yield (Scheme 6b). The ester group was successfully transformed to tertiary alcohol (9) in moderate yield with Grignard reagent.Open in a separate windowScheme 6Gram-scale preparation and diversifications of 3a.In order to get further insight into the reaction mechanism, a radical trapping reaction with 0.1 equivalents of TEMPO was carried out (Scheme 7a). The product 3a was generated without loss of efficiency, which indicated that the radical-involved pathway could be ruled out. A plausible mechanism was then proposed in Scheme 7b. The reaction was initiated with oxidative addition of O-benzoyl hydroxylamine 2a to the in situ generated Pd(0) species. Migratory isocyanide insertion to intermediate B afforded aminoimidoyl Pd(ii) intermediate C. The following intramolecular C–H bond activation and reductive elimination viaE yielded the final product 3a and regenerated Pd(0) to complete the catalytic cycle.Open in a separate windowScheme 7Proposed mechanism.In conclusion, we have developed an efficient and practical method to prepare 1-amino-3,4-dihydroisoquinolines via palladium-catalyzed intramolecular C–H bond aminoimidoylation of α-benzyl-α-isocyanoacetates under redox-neutral conditions. Consecutive isocyanide insertion and C–H bond activation were realized with C–N and C–C bonds formation in one step, employing O-benzoyl hydroxylamines as electrophilic amino sources. A broad range of substrates were applicable to the reaction in good to excellent yields.