Enantioselective conjugate hydrosilylation of α,β-unsaturated ketones

Enantioselective conjugate hydrosilylation of β,β-disubstituted α,β-unsaturated ketones was realized. In the presence of a chiral picolinamide–sulfonate Lewis base catalyst, the reactions provided various chiral ketones bearing a chiral center at the β-position in up to quantitative yields with moderate enantioselectivities.

Enantioselective conjugate hydrosilylation of β,β-disubstituted α,β-unsaturated ketones was realized.

Chiral ketones are important intermediates for the synthesis of natural products or chiral drugs, and some themselves are useful chiral drugs.¹ Asymmetric conjugate reduction of α,β-unsaturated carbonyl compounds is an attractive and challenging transformation for the construction of chiral ketones. During the past few decades, many groups have devoted considerable efforts to this area and made great improvement, for instance, transition metal catalyzed asymmetric hydrogenation of α,β-unsaturated carbonyl compounds, including palladium,² iridium,³ copper,⁴ ruthenium,⁵ rhodium⁶ and cobalt.⁷ Besides, some organocatalyzed asymmetric conjugate transfer hydrogenations using Hantzsch ester⁸ or pinacolborane⁹ as the hydride source have also been reported. However, very few examples about chiral Lewis base catalyzed conjugate hydrosilylation of α,β-unsaturated carbonyl compounds have been reported and only chiral phosphine oxide Lewis base catalysts were used in these reactions (Scheme 1).¹⁰ Therefore, exploration of the application of other kinds of chiral Lewis base catalysts in this reaction is still highly desirable.Open in a separate windowScheme 1Enantioselective conjugate hydrosilylation of α,β-unsaturated ketones by chiral Lewis base catalysts.Recently, we developed a kind of easily accessible chiral picolinamide–sulfonate Lewis base catalysts and used them in asymmetric hydrosilylation of α-acyloxy-β-enamino esters,¹¹ one of them exhibiting excellent reactivity, diastereoselectivity and enantioselectivity. Herein we present the enantioselective conjugate hydrosilylation of β,β-disubstituted α,β-unsaturated ketones using this kind of Lewis base as catalysts, leading to various chiral ketones bearing a chiral center at β-position (Fig. 1).Open in a separate windowFig. 1Three typical chiral drugs containing chiral ketone moiety.First, various chiral Lewis base catalysts 2 were screened in the enantioselective hydrosilylation of (E)-1,3-diphenylbut-2-en-1-one 1a in acetonitrile at 0 °C. As shown in Fig. 2, l-piperazine-2-carboxylic acid derived N-formamide 2a,^12aR-(+)-tert-butylsulfinamide derived catalyst 2b^12b and picolinamide 2c^12c were found to be totally inactive for the reaction. Meanwhile picolinamide–tosylate catalyst 2d was highly active to afford the product with excellent yield in moderate ee value. Afterwards, several picolinamide–tosylate catalysts 2f–2h bearing electron-withdrawing group in 4-position of pyridine were employed in the reaction and 4-bromo picolinamide 2f delivered a slightly higher ee value. 5-Methoxy picolinamide 2i gave the product with the same ee value as that of 2d but in much lower yield. Lower enantioselectivities were observed with 4-phenyl picolinamide 2j and 3-methyl picolinamide 2k. When (R)-1-(2-aminonaphthalen-1-yl)naphthalen-2-ol derived catalyst 2l was used, no product was observed. When (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol derived catalyst 2m gave the product in both poor yield and ee value. Moreover, two picolinamide–sulfonamide catalysts 2n and 2o were also used in the reaction and almost racemic products were obtained. Hence, 2f was determined as the optimal catalyst and was used through out our study.Open in a separate windowFig. 2Evaluation of the chiral Lewis base catalysts 2 in conjugate hydrosilylation of (E)-1,3-diphenylbut-2-en-1-one 1a. Unless otherwise specified, the reactions were carried out with 1a (0.1 mmol), trichlorosilane (0.2 mmol) and catalyst 2 (0.02 mmol) in 1 mL of acetonitrile at 0 °C for 24 hours. Isolated yield based on 1a. The ee values were determined by using chiral HPLC.Subsequently, the other reaction conditions were optimized. The results are summarized in

Enantioselective Michael addition of malonates to α,β-unsaturated ketones catalyzed by 1,2-diphenylethanediamine

A general and highly enantioselective Michael addition of malonates to cinnamones and chalcones has been developed. The commercially available 1,2-diphenylethanediamine could be directly utilized as the organocatalyst to furnish the desired adducts in satisfactory yield (61–99%) and moderate to excellent enantiopurity (65 to >99% ee). β-Ketoester was also a competent donor and was employed to construct densely functionalized cyclohexenones via a tandem Michael-aldol condensation process.

1,2-Diphenylethanediamine could be directly utilized to promote the Michael addition of malonates and β-ketoesters to various α,β-unsaturated ketones.     

Metal-free hydrosulfonylation of α,β-unsaturated ketones: synthesis and application of γ-keto sulfones

γ-Keto sulfones are versatile building blocks and valuable intermediates in organic synthesis and pharmaceutical chemistry. Motivated by their excellent properties, we herein report a green, convenient, metal-free hydrosulfonylation method for a variety of ynones, vinyl ketones, and sodium sulfinates in the absence of stoichiometric oxidants. This operationally simple protocol provides straightforward and practical access to a wide range of γ-keto sulfones with broad functional group tolerance from easily available starting materials. Moreover, the β,γ-unsaturated keto sulfones could further react with 2,3-butadienoate to generate cyclopentenes in phosphine-mediated [3 + 2] cycloaddition.

The methodology features a convenient, mild, efficient, C–S sulfonylation approach without the use of any metal catalysts and stoichiometric oxidants.

As a useful common structural fragment in a broad number of pharmaceuticals¹ and functional materials,² keto sulfones are usually present in promising biologically active molecules such as Casodex,³VCAM-1 (ref. 4) and anti-HIV-1 (ref. 5) (Fig. 1). Furthermore, a valuable synthetic impression is associated with the role of reactive intermediates in various high-demand synthetic transformations,⁶ including total synthesis.⁷ Owing to their excellent properties, and efficient and practical synthesis methods keto sulfones are in high demand.Open in a separate windowFig. 1Representative biologically active γ-keto sulfones.In the past decades, a variety of protocols have been developed to construct β-keto sulfones.⁸ Whereas succinct synthetic routes toward structurally related γ-keto sulfones are scarce,⁹ traditionally, γ-keto sulfones were synthesized via the nucleophilic substitution of sodium sulfinates by 2-chlorovinyl ketones,¹⁰ the elimination of the bromo derivatives of saturated keto sulfones¹¹ and the oxidation of the corresponding sulfides or sulfoxides.¹² However, the principal drawback is that these procedures were strongly limited by multiple steps, narrow substrate scope, or poor stereoselectivity.Indeed, several streamlined strategies for the preparation of γ-keto sulfones involves addition reaction of alkenes or alkynes have been developed.¹³ Li''s group¹⁴ reported the synthesis of (E)-vinyl sulfones through Pd-catalyzed conjugate additions of alkynes with 1,2-bis(phenylsulfonyl)ethane. In 2013 Jiang and co-workers¹⁵ showed that a Pd-catalyzed sulfonylation of alkynoates with sodium sulfinates affords γ-keto sulfones (Scheme 1a). Li and coworkers¹⁶ reported that BPO triggered the hydrosulfonylation of chalcones with arylsulfonyl hydrazides producing γ-keto sulfones. Subsequently, Bi''s group¹⁷ developed a Ag₂CO₃-promoted sulfonylation of allyl/propargyl alcohols with sodium sulfinates for the preparation of γ-keto sulfones (Scheme 1b). Nevertheless, most cases still have to use large excess oxidants, noble metal catalysts, or require high temperatures. Accordingly, an efficient, mild and practical method to furnish γ-keto sulfones is worthwhile studying.Open in a separate windowScheme 1Methods for the synthesis of γ-keto sulfones.With growing demand for sustainable chemistry, an “ideal” reaction system for such transformations would be “metal-free” due to cost efficiency and possible advantages regarding toxicity, as well as selectivity. With this intent, we herein describe a simple and efficient acid-mediated sulfonylation of sodium sulfinates and α,β-unsaturated ketones for the selective synthesis of γ-keto sulfones (Scheme 1c). The significant advantages of this method are high efficiency, metal-free and mild reaction conditions, thus providing a potential application in natural product synthesis and medicinal chemistry.Further studies were commenced with the optimization of the conditions for the hydrosulfonylation of the ynone 1f with sodium benzosulfonate 2a (13e and acetyl chloride/H₂O,¹⁹ as used in the previous study, were completely ineffective due to several unknown complex products being formed (entry 1). Gratifyingly, the desired γ-keto sulfone 3fa was isolated in a 49% yield (E/Z = 90 : 10) as the major product for the reaction mediated by AcOH (entry 3). Encouraged by this initial result, we screened an array of acids. The results showed that 4-chlorobenzoic acid (PCBA) gave the best result, leading to the isolation of γ-keto sulfone 3fa in a yield of 80% (E/Z = 98 : 02) (entries 4–15). Solvent screening indicated that mesitylene could improve the yield to 85% (E/Z = 95 : 05) (entry 21). Further investigations on the reduced usage of PCBA to 2.0 equivalents, the yield of 3fa was slightly reduced (entry 22, 83% yield, E/Z = 95 : 05). The amounts of sodium benzosulfonate 2a and the reaction temperature have deleterious effects on the reaction yields (entries 23–27). Thus, the optimized reaction conditions were successfully established as 1f (1.0 equiv.), 2a (2.5 equiv.), PCBA (2.0 equiv.), and mesitylene (2.0 mL) at 30 °C in this process.Optimization of the reaction conditions^a

Asymmetric vinylogous aldol addition of alkylidene oxindoles on trifluoromethyl-α,β-unsaturated ketones

A novel vinylogous aldol addition of alkylidene oxindole with 1-trifluoromethyl-3-alkylidene-propan-2-ones is presented. The reaction, catalyzed by a bifunctional tertiary amine, provides an efficient application of the vinylogous reactivity of oxindoles for the preparation of enantioenriched trifluoromethylated allylic alcohols.

The vinylogous aldol addition of alkylidene oxindole with 1-trifluoromethyl-3-alkylidene-propan-2-ones was developed. The reaction, provides straightforward access to enantioenriched trifluoromethylated allylic alcohols.     

Photoinduced metal-free α-selenylation of ketones

Herein, we report an efficient photoinduced α-selenylation of ketones without metal, additives or under photosensitizer-free conditions, providing a green protocol using light energy to synthesize a variety of α-selenoketones. This new methodology proved to be a mild, simple and eco-friendly tool for the efficient synthesis of the desired products.

Herein, we report an efficient photoinduced α-selenylation of ketones without metal, additives or under photosensitizer-free conditions, providing a green protocol using light energy to synthesize a variety of α-selenoketones.     

Catalyst-free chemoselective α-sulfenylation/β-thiolation for α,β-unsaturated carbonyl compounds

A novel, efficient, catalyst-free and product-controllable strategy has been developed for the chemoselective α-sulfenylation/β-thiolation of α,β-unsaturated carbonyl compounds. An aromatic sulfur group could be chemoselectively introduced at α- or β-position of carbonyls with different sulfur reagents under slightly changed reaction conditions. A series of desired products were obtained in moderate to excellent yields. Mechanistic studies revealed that B₂pin₂ played the key role in activating the transformation towards the β-thiolation of α,β-unsaturated carbonyl compounds. This transition-metal-catalyst-free method provides a convenient and efficient tool for the highly chemoselective preparation of α-thiolation or β-sulfenylation products of α,β-unsaturated carbonyl compounds.

This catalyst-free method provides a useful and efficient tool for the highly chemoselective preparation of α-thiolation or β-sulfenylation products of α,β-unsaturated carbonyl compounds.     

Iodine/water-mediated deprotective oxidation of allylic ethers to access α,β-unsaturated ketones and aldehydes

The first iodine/water-mediated deprotective oxidation of allylic ethers to access α,β-unsaturated ketones and aldehydes was achieved. The reaction tolerates a wide range of functionalities. Furthermore, this protocol was found to be applicable to the oxidative transformation of allylic acetates. The proposed mechanism involves an oxygen transfer from solvent water to the carbonyl products.

The first iodine/water-mediated deprotective oxidation of allylic ethers to access α,β-unsaturated ketones and aldehydes was effectively achieved.     

Cationic palladium(ii)-catalyzed synthesis of substituted pyridines from α,β-unsaturated oxime ethers

An efficient method for the synthesis of multi-substituted pyridines from β-aryl-substituted α,β-unsaturated oxime ethers and alkenes via Pd-catalyzed C–H activation has been developed. The method, using Pd(OAc)₂ and a sterically hindered pyridine ligand, provides access to various multi-substituted pyridines with complete regioselectivity. Mechanistic studies suggest that the pyridine products are formed by Pd-catalyzed electrophilic C–H alkenylation of α,β-unsaturated oxime followed by aza-6π-electrocyclization. The utility of this method is showcased by the synthesis of 4-aryl-substituted pyridine derivatives, which are difficult to synthesize efficiently using previously reported Rh-catalyzed strategies with alkenes.

An efficient method for the synthesis of multi-substituted pyridines from α,β-unsaturated oxime ethers via cationic Pd(ii)-catalyzed C–H activation has been developed.     

Chemoselective and one-pot synthesis of novel coumarin-based cyclopenta[c]pyrans via base-mediated reaction of α,β-unsaturated coumarins and β-ketodinitriles

In this paper, the base-mediated cascade reactions of 4-chloro-3-vinyl coumarins with β-ketodinitriles were demonstrated, allowing the efficient synthesis of coumarin-based cyclopenta[c]pyran-7-carbonitriles with interesting chemoselectivity. These transformations include the domino-style formation of C–C/C–C/C–O bonds through a base-mediated nucleophilic substitution, Michael addition, tautomerization, O-cyclization, elimination, and aromatization. The presented synthetic strategy has many advantages such as simple and readily available starting materials, green solvent, highly chemoselective route, synthetically useful yields, and easy purification of products by washing them with EtOH (96%), described as GAP (Group-Assistant-Purification) chemistry.

In this paper, the base-mediated cascade reactions of 4-chloro-3-vinyl coumarins with β-ketodinitriles were demonstrated, allowing the efficient synthesis of coumarin-based cyclopenta[c]pyran-7-carbonitriles with interesting chemoselectivity.     

Correction: Chemoselective and one-pot synthesis of novel coumarin-based cyclopenta[c]pyrans via base-mediated reaction of α,β-unsaturated coumarins and β-ketodinitriles

Correction for ‘Chemoselective and one-pot synthesis of novel coumarin-based cyclopenta[c]pyrans via base-mediated reaction of α,β-unsaturated coumarins and β-ketodinitriles’ by Behnaz Farajpour et al., RSC Adv., 2022, 12, 7262–7267, DOI: 10.1039/D2RA00594H.

The authors regret that an incorrect version of Fig. 4 was included in the original article. The correct version of Fig. 4 is presented below. The CCDC number was also incorrectly cited for this same compound (compound 3d) and should instead be cited as 1970237.Open in a separate windowFig. 1ORTEP diagram of 3d (CCDC 1970237).The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

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

Lanthanide complexes combined with chiral salen ligands: application in the enantioselective epoxidation reaction of α,β-unsaturated ketones

Readily available lanthanide amides Ln[N(SiMe₃)₂]₃ (Ln = Nd (1), Sm (2), Eu (3), Yb (4), La (5)), combined with chiral salen ligands H₂L^a ((S,S)-N,N′-di-(3,5-disubstituted-salicylidene)-1,2-cyclohexanediamine) and H₂L^b ((S,S)-N,N′-di-(3,5-disubstituted-salicylidene)-1,2-diphenyl-1,2-ethanediamine) were employed in the enantioselective epoxidation of α,β-unsaturated ketones. It was found that the salen–La complex shows the highest efficiency and enantioselectivity. A relatively broad scope of α,β-unsaturated ketones was investigated, and excellent yields (up to 99%) and moderate to good enantioselectivities (37–87%) of the target molecules were achieved.

The enantioselective epoxidation of α,β-unsaturated ketones was catalysed by readily available lanthanide amides La[N(SiMe₃)₂]₃ combined with chiral salen ligands.     

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.     

Direct access to multi-functionalized benzenes via [4 + 2] annulation of α-cyano-β-methylenones and α,β-unsaturated aldehydes

An efficient [4 + 2] benzannulation of α-cyano-β-methylenones and α,β-unsaturated aldehydes was achieved under metal-free reaction conditions selectively delivering a wide range of polyfunctional benzenes in high yields respectively (up to 94% yield).

An efficient [4 + 2] benzannulation of α-cyano-β-methylenones and α,β-unsaturated aldehydes was achieved under metal-free reaction conditions selectively delivering a wide range of polyfunctional benzenes in high yields respectively (up to 94% yield).

Multi-substituted benzenes are privileged structural units ubiquitous in pharmaceuticals,¹ natural products² and advanced functional materials.³ Various excellent methodologies have been investigated for the construction of functionalized aromatics including nucleophilic or electrophilic substitution,⁴ transition metal-catalyzed coupling reactions⁵ and directed metalation.⁶ However, the widespread application of these strategies established thus far suffer from the limitations of functional groups introduced on the pre-existing benzene and regioselectivity issues. Among various synthetic methods, tandem benzannulation reactions arguably represent an attractive alternative to classical methods for rapid construction of polysubstituted benzenes in an atom-economical fashion.⁷ This protocol featuring an efficient transformation of acyclic building blocks into structurally valuable benzene skeletons. In this context, α-cyano-β-methylenones has been employed as substrates to format six-membered ring in tandem cyclization reactions due to the activation of the pronucleophile methyl group. In 2015, Tong and co-workers developed a phosphine-catalyzed addition/cycloaddition domino reactions of β′-acetoxy allenoate with 2-acyl-3-methyl-acrylonitriles to give 2-oxabicyclo[3.3.1]nonanes (Scheme 1a).⁸ Soon after that, the construction of benzonitrile derivatives and 1,3,5-trisubstituted benzenes via N-heterocyclic carbene catalysis has been reported by the groups of Wang and Ye independently (Scheme 1b).⁹ Then the synthesis of 1,3,5-trisubstituted benzenes by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-mediated annulation of α-cyano-β-methylenones and α,β-unsaturated carboxylic acids was also developed by Ye and co-workers (Scheme 1c).¹⁰ Shi et al. reported a base-promoted tandem cyclization reaction of α-cyano-β-methylenones and α,β-unsaturated enones, which have electron-withdrawing group (EWG), accessing to a wide range of benzonitriles in a different C–C bond formation process (Scheme 1d).¹¹ As part of our ongoing interest in harnessing enones for developing new methodologies for the construction of functionalized benzenes, we have recently demonstrated NHC-catalyzed convenient benzonitrile assembly in the presence of oxidant.^9a While the same reaction of enals and α-cyano-β-methylenones was conducted in the basic condition without NHC, a novel polyfunctionalized benzene product was obtained (Scheme 1e). The result inspired us to extend the synthetic potential of benzannulation strategy to access diverse benzonitriles, particularly from simpler, abundantly available starting materials.Open in a separate windowScheme 1α-Cyano-β-methylenones in cycloaddition domino reactions.At the outset, model reaction of 2-benzoyl-3-phenylbut-2-enenitrile 1a and cinnamaldehyde 2a was used to evaluate reaction parameters. Key results of condition optimization are summarized in 12 The configuration of products were assigned unambiguously by X-ray analysis of the product 3a. A quick solvent screening demonstrated that chloroform is the best choice to produce the benzannulation product 3a in a desirable yield (entries 10–13, †). Reducing the loading of the cinnamaldehyde or NaOH to 1.2 equivalence led to dramatical loss of the yield (entries 14 &15, EntryBaseSolventTime (h)Yield^b (%)1Cs₂CO₃Toluene24702Na₂CO₃Toluene24423K₂CO₃Toluene24384NaOHToluene12785NaOAcToluene24526KOHToluene12747K₃PO₄Toluene24588DBUToluene24339Et₃NToluene484610NaOHDCM1288 11 NaOH CHCI ₃ 12 94 12NaOHDCE128413NaOHH₂O48014^cNaOHCHCI₃128515^dNaOHCHCI₃128416^eNaOHCHCI₃1280Open in a separate window^aReaction conditions: 1a (0.1 mmol, 1.0 equiv.), 2a (0.15 mmol, 1.5 equiv.), base (0.2 mmol, 2.0 equiv.), and solvent (1 mL) for 12 h.^bIsolated yields.^c1a : 2a = 1 : 1.2.^dNaOH used 1.2 equiv.^e50 °C.Finally, the standard reaction conditions for the base-promoted synthesis of the multi-functionalized benzene derivatives identified as follows: 1.5 equivalence of NaOH and CHCl₃ as the solvent under an atmosphere of air for 12 hours at room temperature.With the optimized reaction conditions in hand, we explored the scope of the reaction. A series of enones were examined, variation of the electronic nature of the aromatic ring (R¹, including the substituted phenyl or thienyl) has little influence on the reaction efficiency (3b–f, 86–93% yields, Open in a separate window^aReaction conditions: 1a (0.1 mmol, 1.0 equiv.), 2a (0.15 mmol, 1.5 equiv.), NaOH (0.2 mmol, 2.0 equiv.), and CHCl₃ (1 mL) for 12 h.We next turned our attention to examine the scope of enals. Different substituents on the phenyl ring of cinnamaldehydes were tolerated even disregarding the position and properties, giving 4a–g in satisfying yields (82–92% yields, Open in a separate window^aReaction conditions: 1a (0.1 mmol, 1.0 equiv.), 2a (0.15 mmol, 1.5 equiv.), NaOH (0.2 mmol, 2.0 equiv.), and CHCl₃ (1 mL) for 12 h.To highlight the practicality of this mild and efficient method, the reaction of 2-benzoyl-3-phenylbut-2-enenitrile 1a at 4.0 mmol scale proceed well under the standard conditions to generate the desired product in 88% yield (Scheme 2).Open in a separate windowScheme 2Gram-Scale Synthesis of 3a.The formyl group could be easily reduced by using LiAlH₄ in THF at reflux, leading to the formation of the benzyl alcohol product 5 in 95% yield while keeping the CN group intact. Suzuki coupling of 3o with phenylboronic acid furnished derivative 6 in 90% yield¹³ (Scheme 3).Open in a separate windowScheme 3Synthetic transformation.To gain insight into the role of air in this reaction, a control experiment was designed and investigated (Scheme 4). When the reaction of 1a and 2a was carried out under an argon atmosphere, the desired product 3a was obtained in 10% yield and product 7 could be isolated in 82% yield. The results indicate that oxygen is necessary for the oxidation process and played a key role in this reaction.Open in a separate windowScheme 4Control experiment.A postulated reaction course is illustrated in Scheme 5. Briefly, α-deprotonation of enone 1a in the presence of bases, subsequent 1,4-addition of deprotonated enone I to enal 2a generates intermediate II, which undergoes an intramolecular aldol reaction to yield the adduct 7.¹⁴ Lastly, dehydration of 7 followed by spontaneous oxidative aromatization affords the polysubstituted benzonitrile 3a.Open in a separate windowScheme 5The proposed mechanism.     

Synthesis of α,β-unsaturated esters of perfluoropolyalkylethers (PFPAEs) based on hexafluoropropylene oxide units for photopolymerization

α,β-unsaturated esters are usually synthesized for polymer applications. However, the addition of maleate (cis-configuration) to a fluorinated moiety is challenging due to its potential isomerization during esterification. Various synthetic routes were attempted and led to very low conversion or side-products. The immiscibility of both reagents combined with an easy isomerization or attack on the double bond were potential explanations. In this paper, the synthesis of maleates oligo(hexafluoropropylene oxide) is reported by Steglich esterification and the reaction conditions are discussed depending on the molecular weight of the fluorinated moieties. After UV-curing, hydrophobic polymers were obtained by copolymerization with vinyl ethers by electron acceptor–donor systems.

Hydrophobic macromonomers synthesized by Steglich esterification to generate UV-curable materials.     

Cs2CO3 catalyzed direct aza-Michael addition of azoles to α,β-unsaturated malonates

A highly efficient method for the synthesis of azole derivatives via a direct aza-Michael addition of azoles to α,β-unsaturated malonates using Cs₂CO₃ as a catalyst, has been successfully developed. A series of azole derivatives have been obtained in up to 94% yield and the reaction could be amplified to gram scale in excellent yield in the presence of 10 mol% of Cs₂CO₃.

A highly efficient method for the synthesis of azole derivatives via a direct aza-Michael addition of azoles to α,β-unsaturated malonates has been successfully developed. A series of azole derivatives have been obtained in up to 94% yield.     

Hydrophilic and organophilic pervaporation of industrially important α,β and α,ω-diols

The distillation-based purification of α,β and α,ω-diols is energy and resource intensive, as well as time consuming. Pervaporation separation is considered to be a remarkable energy efficient membrane technology for purification of diols. Thus, as a core pervaporation process, hydrophilic polyvinyl alcohol (PVA) membranes for the removal of water from 1,2-hexanediol (1,2-HDO) and organophilic polydimethylsiloxane–polysulfone (PDMS–PSF) membranes for the removal of isopropanol from 1,5 pentanediol (1,5-PDO) were employed. For 1,2-HDO/water separation using a feed having a 1 : 4 weight ratio of 1,2-HDO/water, the membrane prepared using 4 vol% glutaraldehyde (GA4) showed the best performance, yielding a flux of 0.59 kg m⁻² h⁻¹ and a separation factor of 175 at 40 °C. In the organophilic pervaporation separation of the 1,5-PDO/IPA feed having a 9 : 1 weight ratio of components, the PDMS membrane prepared with a molar ratio of TEOS alkoxy groups to PDMS hydroxyl groups of 70 yielded a flux of 0.12 kg m⁻² h⁻¹ and separation factor of 17 638 at 40 °C. Long term stability analysis found that both hydrophilic (PVA) and organophilic (PDMS) membranes retained excellent pervaporation output over 18 days'' continuous exposure to the feed. Both the hydrophilic and organophilic membranes exhibited promising separation performance at elevated operating conditions, showing their great potential for purification of α,β and α,ω-diols.

The distillation-based purification of α,β and α,ω-diols is energy and resource intensive, as well as time consuming.     

Kinetics and thermodynamics of enzymatic decarboxylation of α,β-unsaturated acid: a theoretical study

Enzymatic decarboxylation of α,β-unsaturated acid through ferulic acid decarboxylase (FDC1) has been of interest because this reaction has been anticipated to be a promising, environmentally friendly industrial process for producing styrene and its derivatives from natural resources. Because the local dielectric constant at the active site is not exactly known, enzymatic decarboxylation to generate β-methylstyrene (β-MeSt) was studied under two extreme conditions (ε = 1 and 78 in the gas phase and aqueous solution, respectively) using the B3LYP/DZP method and transition state theory (TST). The model molecular clusters consisted of an α-methylcinnamate (Cin) substrate, a prenylated flavin mononucleotide (PrFMN) cofactor and all relevant residues of FDC1. Analysis of the equilibrium structures showed that the FDC1 backbone does not play the most important role in the decarboxylation process. The potential energy profiles confirmed that the increase in the polarity of the solvent could lead to significant changes in the energy barriers, especially for the transition states that involve proton transfer. Analysis of the rate constants confirmed the low/no quantum mechanical tunneling effect in the studied temperature range and that inclusion of the fluctuation of the local dielectric environment in the mechanistic model was essential. Because the computed rate constants are not compatible with the time resolution of the stopped-flow spectrophotometric experiment, the direct route for generating β-MeSt after CO₂ elimination (acid catalyst (2)) is unlikely to be utilized, thereby confirming that indirect cycloelimination in a low local dielectric environment is the rate determining step. The thermodynamic results showed that the elementary reactions that involve charge (proton) transfer are affected by solvent polarity, thereby leading to the conclusion that overall, the enzymatic decarboxylation of α,β-unsaturated acid is thermodynamically controlled at high ε. The entropy changes due to the generation of molecules in the active site appeared more pronounced than that due to only covalent bond breaking/formation or structural reorientation. This work examined in detail for the first time the scenarios in each elementary reaction and provided insight into the effect of the fluctuations in the local dielectric environment on the enzymatic decarboxylation of α,β-unsaturated acids. These results could be used as guidelines for further theoretical and experimental studies on the same and similar systems.

The kinetically controlled path for enzymatic decarboxylation of α,β-unsaturated acid is proposed based on DFT and TST methods. The mechanism involves fluctuation of the local dielectric environment in the active site of the FDC1 enzyme.     

Copper(i) pyrimidine-2-thiolate cluster-based polymers as bifunctional visible-light-photocatalysts for chemoselective transfer hydrogenation of α,β-unsaturated carbonyls

The photoinduced chemoselective transfer hydrogenation of unsaturated carbonyls to allylic alcohols has been accomplished using cluster-based MOFs as bifunctional visible photocatalysts. Assemblies of hexanuclear clusters [Cu₆(dmpymt)₆] (1, Hdmpymt = 4,6-dimethylpyrimidine-2-thione) as metalloligands with CuI or (Ph₃P)CuI yielded cluster-based metal organic frameworks (MOFs) {[Cu₆(dmpymt)₆]₂[Cu₂(μ-I)₂]₄(CuI)₂}_n (2), {[Cu₆(dmpymt)₆]₂[Cu₂(μ-I)₂]₄}_n (3), respectively. Nanoparticles (NPs) of 2 and 3 served both as photosensitizers and photocatalysts for the highly chemoselective reduction of unsaturated carbonyl compounds to unsaturated alcohols with high catalytic activity under blue LED irradiation. The photocatalytic system could be reused for several cycles without any obvious loss of efficiency.

The photoinduced chemoselective transfer hydrogenation of unsaturated carbonyls to allylic alcohols has been accomplished using cluster-based MOFs as bifunctional visible photocatalysts.