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

N-Heterocyclic carbene (NHC)-catalyzed oxidation of unactivated aldimines to amides via imine umpolung under aerobic conditions

Herein, we disclose an NHC-catalyzed aerobic oxidation of unactivated aldimines for the synthesis of amides via umpolung of imines proceeding through an aza-Breslow intermediate. We have developed an eco-friendly method for the conversion of imines to amides by using molecular oxygen in air as the sole oxidant and dimethyl carbonate (DMC) as a green solvent under mild reaction conditions. Broad substrate scope, high yields and gram scale syntheses expand the practicality of the developed method.

A general NHC-catalyzed conversion of imines to amides proceeding through umpolung–oxidation under aerobic conditions in green solvent is reported.

NHCs have emerged as an important class of organocatalysts for unconventional organic transformations due to their unique property of umpolung i.e. essentially reversing the polarity of electrophilic carbon centers. NHC-catalyzed umpolung reactivity has been extensively exploited over the past two decades for the construction of carbon–carbon and carbon–heteroatom bonds.¹ NHC-catalytic transformations proceeding through umpolung reactivity, via Breslow intermediate, have been well established using aldehydes.^1,2 Despite imines being considered to be potentially important building blocks, the obvious use of imines as reactants for the same is still an under developed area, probably due their lower reactivity. The umpolung of imine came into existence after the isolation of a nitrogen containing Breslow intermediate (known as aza-Breslow intermediate) by the Douthwaite and Rovis groups from the reaction of stoichiometric amounts of NHC and imine or iminium salt, respectively.³ For the first time, our group⁴ and the Biju group,⁵ independently, reported the NHC-catalyzed imine umpolung transformations. Recently, a few other groups including our group,⁶ the Wei–Fu–Huang,⁷ Biju,⁸ Lupton⁹ and Tian–Zhang–Chi¹⁰ groups reported NHC-catalyzed imine C–H functionalization or oxidation of imines. In continuation of our ongoing research on NHC-catalyzed umpolung transformations,^4,6,11 herein, we present the development of NHC-catalyzed aerobic oxidation of aldimines to amides, via imine umpolung without using any additive. We became interested to access the amide functionality because amide is a very crucial functional group due its ubiquitous presence in life-processes in the form of peptide bond in protein molecules as well as its appearance in several of the drug molecules.¹² For example, imatinib^13a and ponatinib^13a are used in the chemotherapy treatment of chronic myelogenous leukemia (CML) in cancer disease (Fig. 1). Betrixaban containing two amide functional groups is an oral anticoagulant drug (Fig. 1).^13bOpen in a separate windowFig. 1Selected amide containing therapeutic molecules.The scientific community has been showing great interest to develop new and efficient methods for the construction of amide bond. Coupling of carboxylic acid with amine is one of the most common methods used for the construction of amide molecule.¹⁴ However, this method requires stoichiometric amounts of peptide coupling reagents such as carbodiimides and 1-hydroxy benzotriazoles or activated carboxylic acid derivatives.¹⁵ The Schmidt reaction¹⁶ and Beckmann rearrangement¹⁷ are classical examples for the synthesis of amides. However, there are considerably a few reports available for the oxidation of imine to amide. Palladium-catalyzed oxidation of imines to amides was reported by using excess tert-butyl hydroperoxide (TBHP) as an oxidant.¹⁸ Methods for the oxidation of imines to amides were reported by using peroxy acids in the presence of strong Lewis acid and Brønsted acid, which generate stoichiometric amount of by-products.¹⁹ Cheon and co-workers reported the oxidation of imines to amides by using sodium cyanide (NaCN) in stoichiometric amounts. High toxic nature of NaCN is the limitation of this methodology (Scheme 1a).^20a Recently, Fu and Huang group reported the oxidation of imines, limited to the imines derived from heteroaryl amines, to amides by using NHC catalysis with the assistance of excess lithium chloride as Lewis acid (Scheme 1b).^7a Recently, we reported an NHC-catalyzed tandem aza-Michael oxidation of β-carboline cyclic imines in the presence of external Michael acceptors (Scheme 1c).⁶ Besides the limitations associated with the above transformations, those were performed in non-green solvent media. However, to the best of our knowledge, there are no reports for the conversion of imines to amides under NHC-catalysis without using an external additive/assistance.²¹ On the other hand, the development of new methods to access amide functionality inclusive of green chemistry principles such as organocatalysis, air as the sole oxidant and use of green solvent medium under ambient conditions is highly desirable. Herein, we report an NHC-catalyzed conversion of aldimines to amides, proceeding through imine umpolung–oxidation, in the presence of air in a green solvent such as DMC²² under mild conditions.Open in a separate windowScheme 1Prior work and this work.Initially, we began our investigation with the reaction of aldimine 3a, derived from benzaldehyde 1a and aniline 2a, in the presence of NHC A1 catalyst under open air conditions at room temperature in a green solvent such as DMC. Gratifyingly, we observed the formation of the corresponding amide 4a in 53% yield († for an extensive optimization survey). We conducted an experiment in presence of LiCl (1.2 equiv.), and it did not help to improve the yield of the product.Optimization study

Concise synthesis of α-cyano tetrahydroisoquinolines with a quaternary center via Strecker reaction

A concise synthesis of α-cyano tetrahydroisoquinolines with a quaternary center via the Strecker reaction was successfully realized by employing TMSCN as cyano source and KF as fluoride source, furnishing the products with up to 99% yield. An isomerization of α-cyano tetrahydroisoquinoline was observed under alkaline conditions to give the isomer via [1,3]-H shift.

Concise synthesis of α-cyano tetrahydroisoquinolines with a quaternary center was successfully realized, furnishing products with up to 99% yield and an isomerization was observed under alkaline conditions, giving the isomer via [1,3]-H shift.

Tetrahydroisoquinoline is an important molecular skeleton widely distributed in natural alkaloids.¹ The abundant biological activity of tetrahydroisoquinoline alkaloids, such as anti-tumor, anti-inflammatory, anti-convulsant and anti-epileptic activity, promotes its potential application in pharmaceutical chemistry and clinical medicine.² Besides, tetrahydroisoquinolines with a quaternary center at the C-1 position also have diverse biological activities (Scheme 1). For example, MK801, also known as dizocilpine, was an effective and highly selective NMDA receptor (N-methyl-d-aspartic acid receptor).³ As a kind of central nervous system drug, MK801 has anaesthetic, anticonvulsant and antiepileptic effects. In addition, quaternary substituted tetrahydroisoquinoline carboxylic acids DNLCA and NLCA are potent noncompetitive dopamine hydroxylase inhibitors, which play an important role in the control of adrenaline synthesis.⁴ Therefore, the development of synthetic methodology for α-substituted tetrahydroisoquinolines with a quaternary center is important and desirable in organic synthesis.Open in a separate windowScheme 1Representative biologically active molecules of tetrahydroisoquinolines with a quaternary center.Although the synthesis of tetrahydroisoquinolines have been widely developed,⁵ the research on quaternary substituted tetrahydroisoquinolines synthesis was rarely explored in the past decades. It still remains a great challenge for the construction of quaternary carbon center attributed to steric hindrance and poor reactivity of substrates.⁶ Only a few researches focused on the study of tetrahydroisoquinolines with quaternary center. Currently, the most frequently used two strategies for the diverse synthesis were as follows: (1) the Lewis acid or enzyme catalysed classical Pictet–Spengler cyclization which provides a concise and straightforward methodology towards tetrahydroisoquinolines;⁷ (2) nucleophilic addition and electrophilic addition/substitution reaction of isoquinoline type substrates. The direct addition of nucleophiles to isoquinolines/isoquinoline type imines was restricted due to the poor reactivity of substrates. With acylating reagents as activator, the reactivity would be effectively enhanced.^5e,h,8 With regard to isoquinoline type amines which was activated by acylating reagents to enhance the acidity of C-1 position proton of substrate, base is also essential for the electrophilic addition/substitution to the synthesis of quaternary substituted tetrahydroisoquinolines.⁹ Furthermore, Streuff group reported a concise and direct synthesis via titanium(iii)-catalyzed reductive umpolung reaction of isoquinoline type imines with nitriles act as effective acylation agents without substrate activation.¹⁰The Strecker reaction was an efficient and convenient strategy for the synthesis of quaternary amino nitrile adduct with a tetrahydroisoquinoline core via the cyanation of prochiral imine or iminium, which could be easily transformed into the corresponding carboxylic acid (Scheme 2).¹¹ In 2001, Shibasaki and co-workers initially reported the bifunctional Al catalysed nucleophilic addition of isoquinolines using an acylating reagent as substrate activator via Strecker reaction.⁸ And then Maruoka group^9b & Zhang group^9c employed α-cyano tetrahydroisoquinolines possessing an N-acyl group as substrate in the base conditions, giving the products via electrophilic substitution/addition, respectively. And very recently, the Sbei group reported an electrosynthesis of 1,2,3,4-tetrahydroisoquinoline-1-carbonitriles via the electrogenerated cyanide anions from acetonitrile.¹² Herein, we present a concise synthesis of α-cyano tetrahydroisoquinolines with a quaternary center via Strecker reaction, providing the quaternary α-aminonitriles with up to 99% yield.Open in a separate windowScheme 2Selected strategies for α-cyano tetrahydroiso-quinolines with a quaternary center.At the outset of our study, 2-methyl-1-phenyl-3,4-dihydro-isoquinolin-2-ium iodide 1a, was selected as the model substrate for investigation ( EntrySolventBase (mol%) T (°C)Yield^b (%)1CH₂Cl₂Na₂CO₃ (50 mol%)60802TolueneNa₂CO₃ (50 mol%)605431,4-DioxaneNa₂CO₃ (50 mol%)60814MeOHNa₂CO₃ (50 mol%)60Mixture5ClCH₂CH₂ClNa₂CO₃ (50 mol%)60866ClCH₂CH₂ClK₂CO₃ (50 mol%)60727ClCH₂CH₂ClLi₂CO₃ (50 mol%)60798ClCH₂CH₂ClK₃PO₄ (34 mol%)60679ClCH₂CH₂ClEt₃N (100 mol%)608310ClCH₂CH₂ClNa₂CO₃ (50 mol%)308311^cClCH₂CH₂ClNa₂CO₃ (50 mol%)3092Open in a separate window^aReaction conditions: 1a (0.5 mmol), TMSCN (1.0 mol), 3 mL of solvents, 24 h.^bIsolated yield.^cKF (1.0 mol) was added as additive.With the optimized condition established, we then set out to demonstrate the generality and practicality of this Strecker reaction of iminiums with a tetrahydroisoquinoline core. A variety of 1-substituted 2-alkyl 3,4-dihydroisoquinolin-2-ium salts were examined under the standard condition, and the results were summarized in EntryR¹/R²R³/XRYield^b (%)1H/HCH₃/IC₆H₅93 (2a)2H/HCH₃/I2-CH₃C₆H₄85 (2b)3H/HCH₃/I3-CH₃C₆H₄99 (2c)4H/HCH₃/I4-CH₃C₆H₄94 (2d)5H/HCH₃/I4-FC₆H₄88 (2e)6H/HCH₃/I4-ClC₆H₄94 (2f)7H/HCH₃/I4-CH₃OC₆H₄92 (2g)8H/CH₃CH₃/IC₆H₅95 (2h)9CH₃/CH₃CH₃/IC₆H₅93 (2i)10H/CH₃OCH₃/IC₆H₅86 (2j)11H/HCH₃/ICH₃87 (2k)12H/HEt/IC₆H₅85 (2l)13H/HCH₃(CH₂)₉/IC₆H₅80 (2m)14H/HBn/BrC₆H₅85 (2n)Open in a separate window^aReaction conditions: 1 (0.5 mmol), TMSCN (1.0 mol), KF (1.0 mol), Na₂CO₃ (0.25 mmol), 3 mL of ClCH₂CH₂Cl, 48 h.^bIsolated yield.In order to further estimate the application possibility, iminium salt with a β-carboline core (3) was subjected to the standard condition (Scheme 3). To our satisfaction, the desired product (4) was obtained in 73% yield. It also provided a concise and efficient methodology for the synthesis of α-cyano tetrahydro-β-carboline with a quaternary center.Open in a separate windowScheme 3Synthesis of α-cyano tetrahydro-β-carboline.To demonstrate the practical utility, the gram scale reactions were conducted under the optimal condition, providing the corresponding products 2-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile (2a, 98% yield) and 2-benzyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile (2n, 81% yield), respectively (Scheme 4).Open in a separate windowScheme 4Gram scales.With 1-phenyl-3,4-dihydroisoquinoline as substrate, the cascade reaction for the synthesis of 2-methyl-1-phenyl-tetrahydroisoquinoline-1-carbonitrile (2a) via an iminium intermediate generated in situ was subsequently investigated (Scheme 5). The reaction was performed well, giving the product in 88% yield.Open in a separate windowScheme 5Cascade reaction for the synthesis of α-cyano tetrahydroisoquinoline.To further highlight the practical utility of the addition product α-cyano tetrahydroisoquinolines, the hydrolysis of 2-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile (2a) was conducted under alkaline conditions in the presence of potassium hydroxide (Scheme 6). To our surprise, the reaction performed smoothly to provide the isomerization product 2-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carbonitrile (5a) in good yield instead of hydrolysis product.¹³Open in a separate windowScheme 6Isomerization of α-cyano tetrahydroisoquinolines under alkaline condition.Then, to gain insight to the isomerization reaction mechanism, an isotopic labelling experiment was conducted with EtOD/D₂O as solvent (Scheme 7). The product was obtained in 61% yield and with 70% deuterium incorporation in C-1 and C-3 positions and 75% deuterium incorporation on the methyl group.Open in a separate windowScheme 7Mechanistic investigation.Based on the experimental results and structure of the product, the mechanism was proposed that the reaction experienced the process of base promoted tautomerization of iminium isomers and the [1,3]-H shift via a six-membered cyclic transition state under alkaline condition as depicted in Scheme 8. Considering the steric hindrance effect and stability of the iminium intermediate, the reaction was then followed by a nucleophilic addition of CN at C-3 position toward the isomerized product.Open in a separate windowScheme 8Proposed reaction pathways.     

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.     

Iodine-catalyzed sulfonylation of sulfonyl hydrazides with tert-amines: a green and efficient protocol for the synthesis of sulfonamides

This study provides a direct, sustainable and eco-friendly method for the synthesis of various sulfonamides via the sulfonylation of sulfonyl hydrazides with tert-amines. The method utilizes sulfonyl hydrazides to oxidize and couple with tertiary amines through selective cleavage of C–N bonds. In this reaction, molecular iodine was used as the catalyst and t-butyl hydroperoxide was used as the oxidant.

Sustainable and eco-friendly method for the synthesis of various sulfonamides.

Sulfonamides commonly serve as synthetic intermediates to produce various drugs and industrial compounds (Scheme 1).¹ They also commonly act as a N-sulfonyl protecting group for easy removal under mild conditions.² There have been many efforts devoted to synthesizing these compounds. Among the methods developed, nucleophilic substitution of an amine with a sulfonyl chloride or sulfonamides with organic halides in the presence of a base is frequently utilized.³ Over the past few years, transition metal catalysis has been proved a powerful tool to synthesize sulfonamides. For example, a cross-coupling reaction of primary sulfonamides with aryl halide or boronic acids,⁴ a Chan-Lam type coupling reaction of sulfonyl azides with boronic acids,⁵ or an oxidative coupling reaction of sulfinate salts with amines were developed.⁶ However, the use of non-stable, hazardous and mutagenic starting materials and toxic high boiling polar solvents in these reactions resulted in a larger amount of toxic waste. Furthermore, the use of stoichiometric amounts of bases or transition metals makes reactions with a slow reactivity and poor functional group tolerability. Therefore, a novel, sustainable, efficient, and eco-friendly method is desired to synthesize sulfonamides.Open in a separate windowScheme 1Examples of important sulfonamide drugs in top 200 pharmaceuticals of 2018.Iodine and its salts have been reported as very efficient catalysts in CDC reactions in which transition metals are used as catalysts.⁷ In recent years, many methods have been reported for synthesis of sulfonamides under metal-free conditions.⁸ As a source of sulfonyl groups, sulfonyl hydrazides are readily accessible solid. They are stable in air and under moisture conditions, and can be easily prepared and stored. Most importantly, only water and nitrogen were obtained as by-products during the reactions using sulfonyl hydrazides as starting materials. Iodine catalyzed oxidative coupling of sulfonyl hydrazides with secondary amines have been developed (Scheme 2(a)).⁹Tert-amines can donate an amine group via a C–N cleavage in place of primary or secondary amines. Compared to the high reactivity of primary or secondary amines, tert-amines are less nucleophilic and non-destructive for some amine-sensitive functional groups. Recently, Yuan et al. and Gui''s have developed a new method to sulfonamides using I₂-mediated or catalyzed C–N bond cleavage of tert-amines (Scheme 2(b)).¹⁰ Meanwhile, Sheykhan et al. reported a novel electrochemical oxidative sulfonylation¹¹ of tert-amines (Scheme 2(c)).¹² Moreover, catalytic reactions in the aqueous phase have also been recently developed,¹³ and sulfonylation of sulfonyl hydrazides has caused wide interest recently.¹⁴ In this study, we will report a new method to synthesize sulfonamides using iodine-catalyzed oxidative coupling of sulfonyl hydrazides with tert-amines (Scheme 2(d)). This approach avoids use of metal catalysts and hazardous regents; the materials, sulfonyl hydrazides and tert-amines, are versatile intermediates in commercial.Open in a separate windowScheme 2Methods for the synthesis of sulfonamides.Commercially available sulfonyl hydrazide 1a was selected as a sulfonyl source to synthesize sulfonamides. When 1a was mixed with 1 equiv. of N-ethyl pyrrolidine under various solvents at 80 °C, an 80% yield of the corresponding sulfonamide 3a was obtained after 4 hours in the aqueous phase (Scheme 3).Optimization of the reaction conditions^a

Photoinduced successive oxidative ring-opening and borylation of indolizines with NHC–boranes

A facile photoinduced successive oxidative ring-opening and borylation of indolizines with NHC–boranes via a one-pot method has been unveiled. This photo-promoted strategy enables the formation of unsaturated NHC–boryl carboxylates under transition metal-free and radical initiator-free conditions. A wide array of pyridine-containing NHC–boryl carboxylates were directly prepared in moderate to good yields. This work contributes to a better understanding of the reactivity and photo-behavior of both indolizines and NHC–boranes.

A facile photoinduced successive oxidative ring-opening and borylation of indolizines with NHC–boranes via a one-pot method has been unveiled. This photo-promoted strategy enables the formation of unsaturated NHC–boryl carboxylates under transition metal-free conditions.

Organoboron compounds are of vital significance in modern organic synthesis, and they also show great promise in luminescent materials, covalent organic frameworks, and pharmaceutical industries.^1–3N-Heterocyclic carbene (NHC)–boranes have recently gathered a lot of attention in building various C–B bonds.⁴ In fact, as an increasingly popular and reliable boron source, NHC–boranes have the typical characteristics of being: (1) weaker B–H bonds compared to other LB·BH₃; (2) stable solids under ambient conditions; (3) easily prepared on the gram scale. Owing to these advantages, many borylation methods via NHC–boryl radicals have been extensively exploited.⁵ Among them, photochemical borylations with high efficiency have become a powerful, practical, and economic strategy.⁶ For example, Xie and Zhu reported a photoinduced inverse hydroboration of imines and alkenes with NHC–boranes.⁷ Visible-light-induced selective defluoroborylation of fluorinated alkenes have been well established by Wu, Wang, Yang, and co-workers (Scheme 1a).⁸ Recently, Curran reported an Ir-catalyzed 1,4-hydroboration of electron-deficient arenes with NHC–BH₃ under CFL irradiation (Scheme 1b).⁹ Very recently, Wang, Liang, and Zhu disclosed a photoinduced regio- and stereoselective fluorocarboborylation of alkenes.¹⁰ However, direct C–H borylation of N-heterocycles especially for indolizines utilizing NHC–boranes have not been successfully developed.Open in a separate windowScheme 1Visible light-induced borylation with NHC–BH₃.Indolizines, which contain 10 π-electrons, are isoelectronic with indole. So, they represent an important class of N-heterocycles and are widely applied in the field of material science.¹¹ We have long been committed to developing green and sustainable new methods for C–H bond functionalization of indolizines to synthesize indolizines derivatives.¹² In 2019, we disclosed visible-light-induced intermolecular [3 + 2] alkenylation–cyclization of indolizines to obtain pyrrolo[2,1,5-cd]indolizines.¹³ Very recently, we successfully constructed pyrrolo[2,1,5-cd]indolizine rings via visible-light-induced intermolecular [3 + 2] cycloaddition of indolizines and alkynes.¹⁴ Considering the great value of organoboron compounds, we expected that direct C–H borylation of indolizines with NHC–boranes would be realized via a clean photoredox system (Scheme 1c). However, the desired borylated indolizines were not observed via photoinduced C(sp²)–H borylation of indolizines and NHC–boranes. It turned out that sequence photooxygenation–borylation of indolizines occurred, delivering the deconstructive NHC–boryl carboxylates, and this type of borane compound is rarely reported.¹⁵ Herein, we disclose our unexpected findings that successive oxidative ring-opening and borylation of indolizines with NHC–boranes was accomplished under the irradiation of visible light. A variety of NHC–boryl carboxylates could be afforded through this manner (Scheme 1c).To optimize the conditions, we employed 2-phenylindolizine 1a and NHC–borane 2a as the model substrates for reaction development ( EntryPhotocatalystAdditiveSolventYield^b (%)1Rose bengal—CH₃CN362Eosin Y—CH₃CN183Rhodamine 6G—CH₃CNn. d.4Fluorescein—CH₃CNn. d.5Ir(ppy)₃—CH₃CN236Rose bengalCs₂CO₃CH₃CN517Rose bengalK₂CO₃CH₃CN388Rose bengalDBUCH₃CN219Rose bengalDABCOCH₃CN14 10 Rose bengal NaOAc CH ₃ CN 72 11Rose bengalNaOAcTHF6812Rose bengalNaOAcDCE6013Rose bengalNaOAcToluene4514Rose bengalNaOAcDMSO5115—NaOAcCH₃CNn. d.16^cRose bengalNaOAcCH₃CNn. d.17^dRose bengalNaOAcCH₃CN7018^eRose bengalNaOAcCH₃CNn. d.19^fRose bengalNaOAcCH₃CNn. d.20^gRose bengalNaOAcCH₃CNn. d.Open in a separate window^aStandard conditions: 1a (0.2 mmol), 2a (0.4 mmol), photocatalyst (5 mol%), additive (0.4 mmol), solvent (2 mL), and irradiation with a 20 W blue LED for 12 h, air, n. d. = not detected.^bIsolated yields.^cWithout light.^dUnder O₂.^eUnder N₂.^fCuI (5 mol%).^gCu(OAc)₂ (5 mol%).Then, we turned our attention to examining the effect of different additives, such as Cs₂CO₃, K₂CO₃, DBU, DABCO, and NaOAc (i) or Cu(ii) salts (Scheme 2). The reaction proceeded well under the standard reaction conditions and afforded the corresponding NHC–boryl carboxylates 3a–3aa in 56–75% yields. For example, alkyl substituents (–Me or –Et) and electron-donating substituents (–OMe), electron-withdrawing substituents (–Br) substituted on the indolizine ring did not affect the reactivity, and they were effective to afford NHC–boryl carboxylates under the optimized conditions (3b–3g). A series of various functional groups substituted on the ortho, para and meta position of benzene ring were compatible too (3h–3r). We next tested the reactivity of the substrates that are dichlorosubstituted on benzene rings, and the desired products 3s and 3t were obtained in 70% and 72% yields. Furthermore, when the model substrate 1a was replaced by 2-(4-fluorophenyl)-8-methylindolizine 1u, 2-(4-chlorophenyl)-8-methylindolizine 1v, and their analogues(1w–1z), respectively, the corresponding products (3u–3z) were obtained in good yields as well. The molecular structure of the product 3w was determined by X-ray crystallography (CCDC number: 2116778) (Scheme 3). In addition, the reaction of 2-(naphthalen-2-yl)indolizine 1aa with 2a was also performed to give the desired NHC–boryl carboxylate 3aa in 70% yield.Open in a separate windowScheme 2Substrate scope of 2-phenylindolizine^a. ^aReaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), RB (5 mol%), NaOAc (0.4 mmol), MeCN = 2 mL, irradiation with a 20 W blue LED for 12 h, air, isolated yield.Open in a separate windowScheme 3Crystal structure of compound 3w.Next, we further turned our attention to exploring the NHC–borane of this photoinduced successive oxidative ring-opening and borylation reaction. We employed (1-isopropyl-3-methyl-1H-imidazol-3-ium-2-yl) trihydroborate 2b instead of 2a to participate in photoinduced transformation (Scheme 4). It was pleased to find that the desired NHC–boryl carboxylate 4a was obtained in 71% yield under the standard reaction conditions.Open in a separate windowScheme 4Substrate scope of NHC–borane^a. ^aReaction conditions: 1a (0.2 mmol), 2b (0.4 mmol), RB (5 mol%), NaOAc (0.4 mmol), MeCN (2 mL), and irradiation with a 20 W blue LED for 12 h. Isolated yield.After the substrate scope exploration of this transformation, the scale-up experiment was studied. We enlarged the model substrate 1a to 1.0 mmol with 2a (2 mmol) under the irradiation with a 20 W blue LED for 12 h, and we found that boryl carboxylate product 3a was still produced though the yield has a small decrease (49%) (Scheme 5).Open in a separate windowScheme 5Scale-up experiment^a. ^aReaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), RB (5 mol%), NaOAC (2 mmol), MeCN (10 mL), and irradiation with a 20 W blue LED for 12 h.To gain some insight into the mechanism of this transformation, several controlled experiments were designed and carried out (Scheme 6). The yield of 3a dropped sharply when the reaction of 1a with 2a was conducted in the presence of a radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT).Open in a separate windowScheme 6Control experiment.Based on our experimental results and literature reports,^13,16 the possible mechanisms for this reaction of the ring-opening and borylation of indolizines have been depicted in Scheme 7. Under visible-light irradiation, the ground state of RB is converted to the excited RB* via the energy transfer, which interacts with ³O₂ to give the ¹O₂ and RB to realize the photoredox cycle. In the presence of singlet oxygen, 1a readily forms the perepoxide exciplex A which is easily transferred to peroxidic zwitterion intermediate B. Subsequently, the intermediate B produced the intermediate C by intramolecular electron transfer. Then the trace amount of water in the solvent attack at C3 of intermediate C and cleavage the C–N bond to give the intermediate D, which would get rid of a molecule of water to generate acrylic acid intermediate E. Finally, the intermolecular reaction of acrylic acid intermediate E to NHC–borane 2a furnishes the target product 3a.Open in a separate windowScheme 7Plausible mechanistic pathway.     

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.     

I2-mediated Csp2–P bond formation via tandem cyclization of o-alkynylphenyl isothiocyanates with organophosphorus esters

A novel, I₂-mediated tandem cyclization of o-alkynylphenyl isothiocyanates with organophosphorus esters has been developed under mild conditions. Different kinds of 4H-benzo[d][1,3]thiazin-2-ylphosphonate could be synthesized in moderate to excellent yields. This method has the advantages of easy access to raw materials, free-metal catalyst, simple operation, high yield and high functional group tolerance.

A highly efficient molecular-iodine-catalyzed cascade cyclization reaction has been developed, creating a series of 4H-benzo[d][1,3]thiazin-2-yl phosphonates in moderate to excellent yields. This approach benefits from metal-free catalysts and available raw materials.

As an important class of organic products, organophosphorus compounds have received considerable attention because they have broad application in the field of materials science,¹ medicinal chemistry,² organic synthesis,³ natural products,⁴ and ligand chemistry.⁵ Phosphorus-containing compounds are valuable precursors of many biologically active molecules which can act as antibiotics,⁶ anti-tumor agents⁷ and enzyme inhibitors.⁸ Traditionally, the preparation of organophosphorus compounds relies on a transition-metal-catalyzed cross-coupling of phosphine reagents with electrophilic aryl halides (Ar-X),⁹ aryl boronic acids (Ar-B),¹⁰ aryl diazonium salts (Ar-N),¹¹ and so on.¹² Recently, the construction of a Csp²–P bond on heterocycles is another powerful method to synthesize the organophosphorus compounds.¹³ For instance, the Duan group and the Ackermann group reported a Ag-mediated C–H/P–H functionalization method to construct a Csp²–P bond by using arylphosphine oxides and internal alkynes as the substrates^13a,b (Scheme 1a). In 2014, Studer and co-workers reported a pioneering radical cascade reaction for the synthesis of 6-phosphorylated phenanthridines from 2-isocyanobiphenyls and diphenylphosphine oxides (Scheme 1b).^13c Before long, Ji and Lu''s group described two similar radical process with excess of PhI(OAc)₂ or K₂S₂O₈ as the oxidant (Scheme 1c).^13d,e Recently, Liang and co-works developed two cases of cascade functionalization to construct phosphorylated heterocycles via the ionic pathway (Scheme 1d and 1e).^13f,g Meanwhile, Li and coworkers reported a Mn(ii)-promoted tandem cyclization reaction of 2-biaryl isothiocyanates with phosphine oxides which went through the same mechanism(Scheme 1f).^13h Despite the usefulness of the above methods, common problems, such as complex reaction substrates, relatively high temperature, excess amounts of oxidants, limited their applications. Furthermore, transition metals are required in these reactions, thereby resulting in limitations in reactants. Therefore, the development of a simple and transition-metal-free method for the formation of the Csp²–P bond from easily prepared starting materials is highly desirable.Open in a separate windowScheme 1Synthesis of P-containing heterocycles through Csp²–P bond formation. o-Alkynylphenyl isothiocyanates are easily prepared organic synthons with versatile chemical reactivity,¹⁴ and they could be used as electrophiles,¹⁵ nucleophiles,¹⁶ and radical receptors¹⁷ due to the N C S moiety in the structure. Recently, the rapid development of the transition-metal-catalyzed cascade cycloaddition of o-alkynylphenyl isothiocyanates with various nucleophiles provides a new and powerful synthetic strategy to synthesize different heterocycles. Very recently, we have developed a tandem cyclization process for the synthesis of 4H-benzo[d][1,3]thiazin-2-yl)phosphonates by using this strategy.¹⁸ As part of our continuing interest in the transformation of o-alkynylphenyl isothiocyanates,¹⁹ we describe herein a novel I₂-promotedtandem reaction to construct Csp²–P bond from o-alkynylphenyl isothiocyanates and phosphine oxides(Scheme 1g).The starting o-alkynylphenyl isothiocyanates were prepared via the Sonogashira coupling of 2-iodoanilines with terminal alkynes,²⁰ followed by the treatment with thiophosgene according to the literature procedure.²¹ We commenced our studies with the reaction of o-phenylethynylphenyl isothiocyanate (1a, 0.2 mmol) and diethyl phosphonate (2a, 0.6 mmol) in the presence of I₂ (0.5 equiv.) as the catalyst, 8-diazabicyclo[5,4,0]undec-7-ene (DBU, 3.0 equiv.) as the base, in dichloromethane (DCM, 2 mL) at 0 °C for 12 h in air atmosphere. Gratifyingly, the desired product diethyl (Z)-(4-benzylidene-4H-benzo[d][1,3] thiazin-2-yl)phosphonate 3a was obtained in 75% yield (Schemes 1–4)Optimization of the reaction conditions^a

Synthesis of selenated isochromenones by AgNO3-catalyzed three-component reaction of alkynylaryl esters,selenium powder and ArB(OH)2

Reported is the AgNO₃-catalyzed three-component reaction of alkynylaryl esters, selenium powder and ArB(OH)₂, providing a facile entry to selenated isochromenones. This work highlights the use of selenium powder as a selenium reagent in the synthesis of selenated isochromenones for the first time.

We reported AgNO₃-catalyzed three-component reaction of alkynylaryl esters, selenium powder and ArB(OH)₂, providing an efficient synthetic route to selenated isochromenones.

Organoselenium compounds are of increasing importance as synthetic targets, largely owing to their applications in drugs,¹ agriculture chemistry,² catalysis,³ synthetic intermediates⁴ and materials.⁵ In light of their importance, the incorporation of an organoselenium group into organic heterocyclic skeletons has drawn growing attention in organic synthesis. In this context, the installation of a selenium moiety onto isochromenones which exhibit a range of biological activities would be meaningful, because the resultant selenated isochromenones can serve as potential lead candidates that may bring about a vast improvement in enhanced physical and biological properties. Despite the attractive properties provided by the introduction of a selenium moiety, the development of the methods for the synthesis of selenated isochromenones have been less reported. One of the most commonly used strategies for the preparation of selenated isochromenones relied on the intramolecular electrophilic addition of PhSeCl/R_FCl to alkynylaryl esters.⁶ Nevertheless, selenenyl chlorides used as selenium reagents are usually unstable, costly and not easily available, eroding their overall appeal (Scheme 1a). Another access to selenated isochromenones via FeCl₃-promoted electrophilic cyclization of alkynylaryl esters with ArSeSeAr was reported by Zeni''s group (Scheme 1b).⁷ Recently, Du''s group disclosed an efficient approach to in situ generate selenenyl chlorides from the reaction between diselenides and PhICl₂, which enabled electrophilic intramolecular of alkynes to deliver selenated isochromenones (Scheme 1c).⁸ As far as we know, there have been no reports on the use of selenium powder as selenium reagent in the synthesis of selenated isochromenones.Open in a separate windowScheme 1The synthetic approaches to access selenated isochromenones.The utilization of element selenium as selenium source in the synthesis of organoselenium compounds is undoubtedly attractive due to its easy availability and stability. As part of our ongoing interests in the construction of C–Se bond,⁹ we report the preparation of selenated isochromenones via radical cascade cyclization of 2-alkynylaryl esters, selenium powder and arylboronic acids (Scheme 1d). Our synthetic strategy provides an efficient method for the installation of selenium moiety onto the isochromenones scaffold. In addition, this methodology can construct a pyrone ring, two C–Se bonds and a C–O bond in a single step from cheap and accessible raw materials.Our investigation began by selecting methyl 2-(phenylethynyl)benzoate (1a), selenium powder, and PhB(OH)₂ as model substrates for optimization of reaction conditions ( EntryCatalystSolventTemp (°C)Yield (%)1AgNO₂Dioxane120892AgNO₃Dioxane120923AgSbF₆Dioxane120464Ag₂SO₄Dioxane120225AgNO₃CH₃CN120236AgNO₃Toluene120497AgNO₃THF120658AgNO₃CH₃OH12009AgNO₃DMF1203010AgNO₃Dioxane1309011AgNO₃Dioxane1108512AgNO₃Dioxane1007713^bAgNO₃Dioxane1207114^cAgNO₃Dioxane1209115^dAgNO₃Dioxane1204616—Dioxane1200Open in a separate window^aReaction conditions: 1a (0.3 mmol), selenium powder (0.6 mmol), 2a (0.6 mmol), catalyst (0.06 mmol), K₂S₂O₈ (0.45 mmol), solvent (2.0 mL), under air atmosphere, isolated yield.^bAgNO₃ (15 mol%).^cUnder the O₂ atmosphere.^dUnder the N₂ atmosphere.With the optimal reaction conditions in hand, we turned our attention to exploring the generality of our method ( Open in a separate window^aReaction conditions: 1 (0.3 mmol), selenium powder (0.6 mmol), 2 (0.6 mmol), AgNO₃ (0.06 mmol), K₂S₂O₈ (0.45 mmol), dioxane (2.0 mL), 120 °C, under the air atmosphere, isolated yields.To further investigate the substituents on oxygen atom on the reaction efficiency, the methyl group in 1a was replaced by other substituents. It was found that the replacement of the methyl group by other groups such as ethyl, isopropyl, benzyl or phenyl respectively led to inferior yields (Scheme 2a). When the substituent on oxygen atom was changed into 4-PhC₆H₄, the reaction delivered a byproduct biphenyl in 35% yield aside from the desired product 3a. The presence of TEMPO could completely inhibit this reaction, supporting a radical way (Scheme 2b). The addition of ethene-1,1-diyldibenzene to the model reaction resulted in 23% yield of product 3a, as well as 3% yield of product 4a that was detected by GC-MS, suggesting that the reaction involved a PhSe radical intermediate (Scheme 2c).Open in a separate windowScheme 2The control experiments.Based on our experimental observations and previous studies,^9,10 a plausible mechanism for the three-component reaction is proposed in Scheme 3. At the beginning, phenylboronic acid produces a phenyl radical (I) in the presence of AgNO₃. The trapping of the phenyl radical by selenium powder provides a selenium-centred radical, followed by radical addition with 1a to generate intermediate III. The intermediate III undergoes intramolecular radical cyclization to afford the final product 3a as well as methyl radical which goes through H-abstraction to give methane.Open in a separate windowScheme 3The plausible mechanism.     

Base-promoted highly efficient synthesis of nitrile-substituted cyclopropanes via Michael-initiated ring closure

A convenient and efficient annulation reaction has been developed for the general synthesis of dinitrile-substituted cyclopropanes in moderate to excellent yields. A variety of 2-arylacetonitriles and α-bromoennitriles were compatible under the standard conditions. The reaction was achieved through tandem Michael-type addition followed by intramolecular cyclization. The preliminary application of this method was confirmed by the synthesis of the 2,4-dioxo-3-azabicyclo[3.1.0]hexane scaffold.

An efficient base-promoted synthesis of nitrile-substituted cyclopropanes from 2-arylacetonitriles and α-bromoennitriles under mild conditions via Michael-initiated ring closure.

Substituted cyclopropanes, as attractive structural units, are commonly found in a variety of natural products and biologically active compounds.¹ The strained structure, interesting bonding characteristics, and value as an internal mechanistic probe of the cyclopropane subunit have attracted the attention of the physical organic community.² As a consequence, considerable efforts have been made to develop new and effective approaches toward cyclopropane derivatives.³ Classical approaches to cyclopropane synthesis are the Simmons–Smith cyclopropanation.⁴ Transition-metal-catalyzed cyclopropanation of alkenes with diazo compounds represents a direct protocol for their preparation.⁵ Furthermore, the new types of cyclopropanation reactions based on nucleophilic addition-ring closure sequence were well documented (Scheme 1a and b).⁶ Nitrile-substituted cyclopropanes are of great interest as they are versatile templates for the rapid formation of biologically active and synthetically useful functionalized cyclopropane derivatives.⁷ Recently, nitrile-substituted cyclopropanes were synthesized via transition-metal-catalyzed olefin functionalization with diazoacetonitriles.⁸ Despite the significant advancement, the development of complementary strategy toward functionalized cyclopropanes by using readily available substrates and cheap agents with high efficiency would be highly desirable.Open in a separate windowScheme 1Methods for synthesis of cyclopropane derivatives.α-Bromoennitrile is a class of readily available intermediate in organic synthesis.⁹ However, this intermediate is rarely used in organic synthesis compared to its analog α-bromoenal.¹⁰ Recently, our group has reported a series of functionalization of 2-arylacetonitriles and their derivatives.¹¹ We hypothesized five-membered nitrogen containing heterocycles could be formed from 2-pyridylacetonitrile and α-bromoennitriles via [3 + 2] annulation. However, dinitrile-substituted cyclopropanes were afforded through a novel Michael-initiated ring closure procedure (Scheme 1c). Herein, we present a base-promoted synthesis of dinitrile-substituted cyclopropanes from 2-arylacetonitriles and α-bromoennitriles under mild conditions via Michael-initiated ring closure (Scheme 1d).Initially, (Z)-2-bromo-3-phenylacrylonitrile 1a and 2-pyridylacetonitrile 2a were selected as the model substrates for the condition optimization. As illustrated in EntryBaseSolventTemp.Yield^b (%)1DABCOMeCNrtTrace2DBUMeCNrt383TEAMeCNrtnp4DMAPMeCNrtnp5Cs₂CO₃MeCNrt956K₂CO₃MeCNrt677NaOAcMeCNrt428K₃PO₄MeCNrt899KO^tBuMeCNrt8410—MeCNrtnp11Cs₂CO₃DMFrt8712Cs₂CO₃DMSOrt3613Cs₂CO₃H₂Ortnp14Cs₂CO₃DCErt6715Cs₂CO₃THFrtnp16Cs₂CO₃Dioxanert5317Cs₂CO₃MeCN06218Cs₂CO₃MeCN50npOpen in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (0.2 mmol) and base (1.5 equiv.) in solvent (1.0 mL) for 12 h.^bYields of isolated cis-3a and trans-3a are given. Cis refers the two nitriles positioned on the same face of the cyclopropane; trans refers the two nitriles positioned on the opposite face of the cyclopropane.Having the developed optimal conditions for the Michael-initiated ring closure reaction, the substrate scope was investigated. As illustrated in Scheme 2, a wide range of 2-arylacetonitriles were tolerated with (Z)-2-bromo-3-phenylacrylonitrile 1a to render dinitrile-substituted cyclopropanes in moderate to excellent yields (3a–3u). Except for 2-pyridylacetonitrile, 3-pyridyl and 4-pyridyl derivatives also reacted smoothly to generate the products in good yields (3a–3c). The annulation with 2-pyridylacetonitrils bearing electron-donating groups and withdrawing groups in the pyridine ring worked well to deliver the products in satisfactory yields (3d–3h). Thienyl derivatives were reactive to afford the corresponding products, but exhibited lower reactivity compared with pyridyl (3i–3j). In addition to heteroaryl-substituted substrates, various 2-arylacetonitriles were further tested. The reaction conditions were compatible with an array of substituents, such as alkyl, methoxy, phenyl, chloro, bromo, trifluoromethyl, fluoro, and cyano groups (3k–3u). In particular, the aryl bromide could be further functionalized in metal-catalyzed cross-coupling reactions and hold the enormous potential application in pharmaceutical and materials science (3p–3q). To our delight, nitrile-containing substrate could provide the product 3u in 86% yield. Significantly, the annulation reaction could be carried out on large-scale synthesis and formed the product 3a in 87% yield. The structure of cis-3a was verified by X-ray crystal analysis (CCDC: 2141258^†).Open in a separate windowScheme 2Substrate scope of 2-arylacetonitriles^a. ^aReaction conditions: 1a (0.2 mmol), 2 (0.2 mmol), Cs₂CO₃ (1.5 equiv.) and CH₃CN (1.0 mL) at room temperature for 12 h; isolated yields are given unless otherwise noted. Cis refers the two nitriles positioned on the same face of the cyclopropane; trans refers the two nitriles positioned on the opposite face of the cyclopropane. ^b2 mmol scale.Continuing to examine the generality and scope of the annulation reaction, we explored various α-bromoennitriles under the standard conditions (Scheme 3). α-Bromoennitriles bearing electron-rich or electron-deficient groups on the benzene ring reacted successfully with 2-pyridylacetonitrile to achieve the desired products in good yields (4a–4h). The substrates bearing a methyl at the ortho- and meta-positions of the benzene ring were suitable substrates for the transformation, thus indicating the steric hindrance is negligible (4a–4b). The bulky tert-butyl group was accommodated in this transformation (4c and 4j). The disubstituted α-bromoennitrile proved to be good substrate under the same reaction conditions (4d). The reaction of the fused ring system also yielded the products in satisfactory yields (4f). Finally, phenylacetonitriles also worked well with α-bromoennitriles to obtain the corresponding product in good yields (4i–4m). The structure of trans-4b was further confirmed by X-ray crystal diffraction measurements (CCDC: 2142244^†). It implied that this Michael-initiated ring closure reaction can be effective for the construction of dinitrile-substituted cyclopropane library.Open in a separate windowScheme 3Synthesis of nitrile-substituted cyclopropanes^a. ^aReaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), Cs₂CO₃ (1.5 equiv.) and CH₃CN (1.0 mL) at room temperature for 12 h; isolated yields are given unless otherwise noted. Cis refers the two nitriles positioned on the same face of the cyclopropane; trans refers the two nitriles positioned on the opposite face of the cyclopropane. ^bThe cis/trans (isomer) ratio was determined by crude ¹H NMR.To illustrate the applicability of this reaction, further transformation of product cis-3a was carried out as depicted in Scheme 4. 2,4-Dioxo-3-azabicyclo[3.1.0]hexane scaffold is known to be an important pharmacology agent and synthons for synthesis of functionally substituted cyclopropanes and various spirocompounds.¹² The target compound 5a can be readily accessible in excellent yield via a simple hydrolysis reaction. It is worth noting that similar result was obtained for trans-3a.Open in a separate windowScheme 4Synthetic application.A tentative mechanism for cyclopropane formation was proposed and outlined in Scheme 5 on the basis of aforementioned results as well as our experimental observations. Initially, carbanion intermediate B was produced via the sequential extraction of hydrogen proton and Michael-type addition process. Then the intermediate B was converted into intermediate C through 1,3-hydride transfer. Finally, the dinitrile-substituted cyclopropane 3a was formed through intramolecular nucleophilic substitution. The diastereomer 3a is the favored product due to steric effects, in which the two aryl groups are located on the opposite face of the plane of the cyclopropane moiety.Open in a separate windowScheme 5Possible reaction mechanism.In summary, we have explored a convenient and highly efficient annulation reaction of 2-arylacetonitriles and α-bromoennitriles. A wide range of dinitrile-substituted cyclopropanes were obtained in moderate to excellent yields through a novel Michael-initiated ring closure procedure. The advantages of this transformation include readily accessible substrates, transition-metal-free conditions, good functional group tolerance, simple operation, etc. In addition, nitrile-substituted products have potential applications in synthetic and pharmaceutical chemistry. Further synthetic utilization and asymmetric transformations are currently ongoing in our laboratory.     

Sequential cycloaddition and ring expansion reaction of arynes and methylenebenzothiopheneones: synthesis of a benzo-fused eight-membered ring via sulfonium ylides

A sequential cycloaddition and ring expansion of arynes and methylenebenzothiopheneones has been disclosed. This strategy proceeds through a sulfonium ylides intermediate and allows for the efficient synthesis of a sulfur-containing benzo-fused eight-membered ring.

Efficient construction of benzo-fused eight-membered ring containing sulfur. New reaction profile with sulfonium ylides.

As leading biologically relevant structural components, organosulfur compounds are widely present in many pharmaceuticals and bioactive compounds.¹ Accordingly, sulfur-containing compounds have found their medical applications including as antibacterials, anti-inflammatories, dermatologics, and cancer treatments. A survey of the structures of compounds among the top 200 brand name drugs by U.S. retail sales (RS) in 2011 revealed that 24.8% of the drugs contain sulfur. The list included the famous Plavix (blood thinner, no. 2) and Seroquel (antipsychotic drug, no. 6).² In addition, the benzothiazepine-containing drug diltiazem (calcium channel blocker) is used in the treatment of hypertension and angina (Scheme 1).³ On the other hand, Et743 as a sulfur-containing marine natural product was also used as an effective drug for the treatment of advanced soft tissue sarcoma.⁴ As a consequence, many efforts have been devoted to the synthesis of such skeletons.Open in a separate windowScheme 1Representative natural products and bioactive molecules with sulfur-containing ring.Arynes are recognized as one of the most reactive intermediates in organic synthesis. The past years have witnessed a great progress with respect to the carbon–carbon and carbon-heteroatom bond-forming reactions involving arynes.^5,6 A careful literature screening revealed that reactions involving the insertion of aryne into C–C, C–N, C–O, C–S, and other bonds have been well documented.^7–9 Furthermore, the aryne-based Diels–Alder reaction, [2 + 5], nucleophilic addition and annulation reactions.^8,9 Among [2 + 8] and many other pericyclic reactions have been intensively investigated for the construction of various benzo-fused frameworks.¹⁰ Remarkably, the reactions between arynes and organosulfur compounds have been widely investigated. As such, arynes can react with a variety of organosulfur compounds including S(ii), S(iv), and S(iv) valence state, thus allows for the diversity-oriented synthesis of aromatic organosulfurs that are difficult to access by conventional methods.^11,12 Among them, we are particularly interested in those reactions involves sulfonium ylides, a neutral 1,2-dipolar species consisting of electron-rich carbon atom and an adjacent electro-positive sulfur atom. For example, nucleophilic attack of alkyl thioether towards aryne followed by intramolecular 1,4-proton shift contribute an elegant strategy for the formation of sulfonium ylides (Scheme 2a), which can be further applied to various conversions.¹³ Remarkably, this strategy has been established from various modes of trapping of HDDA-generated benzynes with sulfides by Hoye and co-workers.¹⁴ Recently, Studer and co-workers have disclosed that vinyl thioethers lacking α-CH protons reacted with benzyne through direct [3 + 2] cycloaddition to give cyclic sulfonium ylides. This methods eventually enables the preparation of corresponding tetrasubstituted alkenes with high stereoselectivity (Scheme 2b).¹⁵ In the past years, we have paid much attention to the aryne chemistry and the heterocycle synthesis.^16,17 As a continuation, herein we report that the unprecedented reaction of arynes and methylenebenzothiopheneones enables the synthesis of structurally unusual benzo-fused eight-membered ring.Open in a separate windowScheme 2Representative examples involving sulfonium ylide.We commenced our investigation using benzyne precursor 1 and 2-methylenebenzothiophene-3-ones 4a as the model substrates. As shown in EntryF sourceEquiv. of 1SolventTemp. (°C)Yield^b (%)1CsF1.5CH₃CN40482CsF1.5THF40633CsF1.5Toluene40624CsF1.5Dioxane40595CsF1.5DCMReflux^c876CsF1.5DCMrt657CsF1.5DCM60^d798CsF2.0DCMReflux829CsF1.0DCMReflux7510TBAF1.5DCMReflux4711KF/18-c-61.5DCMReflux6712KF/18-c-61.5THFReflux71Open in a separate window^aUnless otherwise noted, all reactions were carried out with 1.0 mmol 2-methylenebenzothiophene-3-one 4a, fluorine source, in 3 mL solvent.^bIsolated yield.^cBp of DCM: 39.8 °C.^dSealing reaction temperature.After the best conditions were obtained in hand, the feasibility of substituted 2-methylenebenzothiophene-3-ones 4 was next evaluated. As shown in Scheme 3, a variety of 2-methylenebenzothiophene-3-ones 4 having substituents including methyl, tert-butyl, halo, and methoxyl groups at the position 7, 6, 5 of the aromatic ring were used to react with benzyne precursor 1. All reactions worked well to produce the desired products (5a–5h). Additionally, when the ester moiety in substrate 4 was changed from OEt to OMe, OBn, or O^tBu, the corresponding products 5i–5k were afforded in high performance. It was also worthy to note that when the electron-withdrawing groups such as cyano, and substituted carbonyl groups were employed instead of ester unit, the corresponding products 5l–5s were isolated in satisfactory yields. Furthermore, the structure of compounds 5j and 5n was unambiguously characterized by single-crystal X-ray analysis.¹⁸Open in a separate windowScheme 3Substrate scope of the reaction with respect to the methylenebenzothiopheneone. Reaction condition: 1.5 mmol benzyne precursor 1, 1.0 mmol 2-methylenebenzothiophene-3-one 4, CsF (3.0 mmol), in 3 mL DCM. Isolated yields are reported.After a broad substrate scope with benzyne precursor was established, reactions of naphthyne precursor 6 and substituted 2-methylenebenzothiophene-3-ones were subsequently tested. As shown in Scheme 4, reactions with 2-methylenebenzothiophene-3-ones 4 bearing different electron-withdrawing groups proceeded smoothly to produce products 9a–9e in satisfactory yield.Open in a separate windowScheme 4Reaction conditions: 1.5 mmol naphthyne precursor 6, 1.0 mmol 2-methylenebenzothiophene-3-one 4, CsF (3.0 mmol), in 3 mL DCM. Isolated yields are reported.To gain more insight into the present reaction, several control experiments and preliminary mechanistic experiments were next conducted. As shown in Scheme 5, benzyne precursor ortho-(trimethylsilyl)aryltriflate 10a and 10b were proven to be compatible reaction partners to react with 2-methylenebenzothiophene-3-ones 4 (Scheme 5, eqn (1) and (2)). After that, reactions with unsymmetrical benzyne precursor 10c and 10d were also examined (Scheme 5, eqn (3) and (4)). Pleasingly, only one isomer was detected when 3-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate 10c was used. The isotope-labelling experiment with 10a and 4i also revealed that deuterium was incorporated in the product to produce [D]-11e (Scheme 5, eqn (5)). This result suggested that water was also involved in present transformation.Open in a separate windowScheme 5Control experiments and preliminary mechanistic studies.Based on the aforementioned results and previous reports, a plausible reaction mechanism is described in Scheme 6. Firstly, the [3 + 2] cycloaddition between 2-methylenebenzothiophene-3-ones 4 and aryne yields a sulfonium ylide intermediate B. In the presence of water, B is further protonated to deliver sulfonium salt C. After that, the in situ generated hydroxide ion serves as a base to facilitate the following intramolecular β-elimination, thus providing a quick access to the product.Open in a separate windowScheme 6Possible mechanism.To further explore the application of present reaction, an oxidation reaction of the products was also attempted. In the presence of H₂O₂,¹⁹ the resultant sulfide products 5k and 5s experienced oxidation to corresponding functionalized sulfones 12a and 12b in an efficient and environmentally friendly manner (Scheme 7, eqn (1) and (2)).Open in a separate windowScheme 7Further application of the products.In conclusion, we have described an unprecedented reaction from in situ generated aryne and 2-methylenebenzothiophene-3-ones. This strategy allows for a new approach to benzo-fused eight-membered ring containing sulfur, which was difficult to be synthesized by traditional methods. Mechanistically, this reaction proceeds through cycloaddition, proton shift, intramolecular β-elimination, and the formation of sulfonium ylide. Further study and application of the present reaction including the biological detection are still underway in our laboratory.     

[3 + 2] cycloaddition of nonstabilized azomethine ylides and 2-benzothiazolamines to access imidazolidine derivatives

A simple and practical method for the construction of 1,3,5-trisubstituted imidazolidine derivatives via [3 + 2] cycloaddition reaction has been developed. This reaction could smoothly proceed between nonstabilized azomethine ylides generated in situ and 2-benzothiazolamines to deliver a wide scope of differently substituted imidazolidines in high yields (up to 98%). The structure of one example was confirmed by X-ray single-crystal structure analysis.

An effective method for the synthesis of functionalized imidazolidine derivatives via a [3 + 2] cycloaddition reaction from nonstabilized azomethine ylides generated in situ from 2-benzothiazolamines in high yields (up to 98%) has been developed.

Heterocyclic compounds are important structural motifs that are frequently discovered in natural products and biologically active molecules, with wide applications and potency in the field of medicinal chemistry.¹ Among them, the 2-aminobenzothiazole scaffolds, which contain a core of isothiourea motifs as a privileged scaffold, are ubiquitous in natural products, drugs and bioactive compounds.² Some examples of biologically active molecules and pharmaceuticals containing benzothiazoles are shown in Fig. 1. These compounds display a variety of important biological activities, such as anti-HIV, anticancer, antineoplastic and anticonvulsant activity, and so on.³Open in a separate windowFig. 1Selected examples of biologically active compounds containing a 2-aminobenzothiazole scaffolds.Due to their momentous and potent biological activities and structural diversifications, more organic and medicinal chemists have been significantly attracted to developing effective and advanced methodologies for the construction of benzazole scaffolds.⁴ The 2-benzothiazolamines could serve as alternative C4 synthons with various reaction partners in [4 + 2] cycloadditions for the straightforward and convenient access to 2-aminobenzothiazole scaffolds, and this type of reaction has been well established (Scheme 1a).⁵ By contrast, the 2-benzothiazolamines which acted as C2 synthons in cycloaddition reactions have been very limited.⁶ Therefore, the development of efficient cycloaddition between the 2-benzothiazolamines as C2 synthons and suitable reaction partners to provide diverse functionalized heteroarenes molecules is always in great demand.Open in a separate windowScheme 1Previous reports and our protocol.On the other hand, the 1,3-dipole cycloaddition is recognized one of the most efficient and powerful methods for building five membered heterocyclic rings from simple starting materials.⁷ In particular, the nonstabilized azomethine ylides generated in situ from N-benzyl-substituted compounds were a highly reactive intermediate with unsaturated compounds, such as activated alkenes,⁸ aromatic ketones,⁹ aromatic aldehydes,¹⁰ phthalic anhydrides,¹¹ imines,¹² cyano compounds¹³ or stable dipoles,¹⁴ to build various N-containing heterocycles via [3 + 2] or [3 + 3] cycloaddition reactions (Scheme 1b). Despite the progress were well developed via 1,3-dipolar cycloadditions employing nonstabilized azomethine ylides as the substrates, challenges still remain. Herein, we would like to present an effective process to furnish functionalized 1,3,5-trisubstituted imidazolidine derivatives via [3 + 2] cycloaddition strategy from 2-benzothiazolamines with nonstabilized azomethine ylides generated in situ (Scheme 1c). In contrast, the desired product was not obtained via [4 + 3] cycloaddition reaction.Initially, we used 2-benzothiazolimine 1a and N-(methoxymethyl)-N-(trimethylsilyl-methyl)-benzyl amine 2a which could in situ form azomethine ylide in the presence of acid as model substrates to optimize the reaction conditions. The results were shown in EntryAdditiveSolventTimeYield of 3a^b (%)1AcOHCHCl₃12482TfOHCHCl₃12513TFACHCl₃3904HClCHCl₃12205TFACH₂Cl₂1986TFADCE3827TFAEtOAc6758TFAToluene12709TFAMeOH123110TFACH₃CN37111TFADioxane125912TFAEt₂O124613TFATHF1262Open in a separate window^aReaction conditions: 2-benzothiazolimine 1a (0.1 mmol, 1.0 equiv.), N-(methoxymethyl)-N-(trimethylsilyl-methyl)-benzyl-amine 2a (0.12 mmol, 1.2 equiv.), addition (0.01 mmol, 0.1 equiv.) and solvent (1.0 mL) in a test tube at room temperature.^bYield of the isolated product.After establishing the optimal reaction conditions, the scope and limitations of this [3 + 2] cycloaddition reaction for formation of 1,3,5-trisubstituted imidazolidines were examined. The results were shown in †)¹⁵ was unequivocally confirmed by X-ray crystallographic analysis (see ESI^†). On the other hand, when the R² groups were heteroaromatic substituted group, such as 2-furanyl, 3-thienyl, 1-naphthyl and 2-naphthyl, the cycloaddition reaction were well tolerated and could also proceed smoothly without obvious interference to produce corresponding pyrazoles 3k–3n in 92–96% yields. Meanwhile, substituted substrates at the C4 or C6-position of the 2-aminobenzothiazole, such as Me and Cl were also reacting smoothly to afford the corresponding products in 95%, 96% yields (3o–3p), respectively. Notably, the 2-benzoxazolimine as substrate also reacted smoothly with azomethine ylides 2a to deliver the corresponding product 3q in high yield (94%). Especially, when using (R)-nonstabilized azomethine ylide as the chiral substrate in the cycloaddition reaction, the reaction could proceed smoothly under the standard conditions to afford the corresponding chiral product 3r in 95% yield as single diastereomer only. The chiral center was determined by NOESY analysis (see ESI^†). Nevertheless, as for the R² group, when it was changed from an aryl group to an alkyl group, the reaction did not take place (3s). The possible reason may be due to the low activity of alkyl substituted substrate.Substrate scopes for the formation of 1,3,5-trisubstituted imidazolidine derivatives 3^a

Microwave-assisted iodine-catalyzed oxidative coupling of dibenzyl(difurfuryl)disulfides with amines: a rapid and efficient protocol for thioamides

An efficient protocol for synthesis of thioamides was developed via the microwave-assisted iodine-catalyzed oxidative coupling of dibenzyl(difurfuryl)disulfides with amines. This process is scalable and tolerates a wide spectrum of amines to deliver the corresponding products in moderate to excellent yields in 10 minutes, providing a cheap and rapid approach to thioamides.

Rapid and efficient protocol for thioamides via microwave-assisted iodine-catalyzed oxidative coupling of dibenzyl(difurfuryl)disulfides with amines.

Thioamides have become an attractive synthetic goal in organic chemistry,¹ because thioamide skeletons are widely present in drugs and natural products,² such as cycasthioamide,³ 6-thioyuanine,⁴ 2-thiocytidine⁵ and closthioamide^2a (Scheme 1), and their application as useful precursors and versatile building blocks for construction of a range of heterocyclic compounds has also been studied.^1a,6 In addition, thioamides also can be used as a synthetic isostere for amides in peptide backbones,⁷ and their application as directing groups has also been reported.^8,1c Furthermore, the application of thioamides in developing novel a fluorophore/quencher pair for monitoring the unfolding of a small protein was also explored.⁹Open in a separate windowScheme 1Structures of natural products bearing thiocarbonyl group.Because of their wide application, efforts are devoted toward their generation.¹⁰ The Willgerodt–Kindler reaction is a well-known method for construction of thioamides by using aldehydes and secondary amines as starting materials.¹¹ However, this thioamidation always suffers from the problems of low conversions and harsh conditions. Though, modified variations in Willgerodt–Kindler reaction were also reported,^1a,12 the use of excessive amounts of elemental sulphur makes it a less economical method. Lawesson''s reagent was also used as common sulfur reagent for synthesis of thioamides,¹³ however, this reaction was also occur under harsh conditions. Another thioamidation, where elemental sulfur was used as sulfur reagent, was also reported by Savateev''s groups via a photoinitiated reaction (Scheme 2a).^11a However, this transformation was only suitable for special thioamides with the same structure of amines. Thiols can also be used as sulfur reagent for construction of thioamides,^13b,c but its pungent smell makes this reaction difficult to carry out (Scheme 2b). Recently, Nguyen''s group described a novel process to thioamides by using sulfur as catalyst.¹⁴ This method was suitable for a large range of amines for giving the corresponding products in good to excellent yields at 80 °C for a long time of 16 h.Open in a separate windowScheme 2General methods for synthesis of thioamides.Other methods for thioamides were also reported,¹⁵ but challenges still exist in developing more convenient and efficient ways to these important scaffolds. In our previous work, thioamides were synthesized via the iodine-promoted thioamidation of several of amines.¹⁶ However, this reaction must be performed under high temperature, for a long time (100 °C, 8.0 h), and 0.5 equiv. of I₂ must to be used to promote the thioamidation effectively (Scheme 2c).As one of the efficient and clean procedures in modern synthetic organic chemistry, microwave-assisted organic synthesis (MAOS) has aroused wide interest among scientists, which are suited to the increased demands in industry with the advantages of short reaction times and expanded reaction range.¹⁷ Herein, we reported an efficient method for synthesis of thioamides via the microwave-assisted iodine-catalyzed oxidative coupling of dibenzyl(furan-2-ylmethyl) disulfides with amines (Scheme 2d).We initiated our studies with the reaction of dibenzyldisulfide (1a) with N-methylpiperazine (2a) catalyzed by 10 mol% of I₂ in DMSO under microwave radiation (100 °C) for 10 minutes, and the desired product (3a) was obtained in the yield of 36% ( EntryI₂ (mol%)SolventTemp. (°C)Time (min)Yield^b (%)1I₂ (10 mol%)DMSO1001036%2I₂ (10 mol%)DMSO1101048%3I₂ (10 mol%)DMSO1201065%4I₂ (10 mol%)DMSO1301088%5I₂ (10 mol%)DMSO1401088%6I₂ (10 mol%)DMSO1301588%7I₂ (10 mol%)DMF1301074%8I₂ (10 mol%)1,4-Dioxane1301067%9I₂ (10 mol%)THF1301065%10I₂ (10 mol%)CH₃CN1301070%11I₂ (10 mol%)HOAc1301062%12I₂ (10 mol%)Chlorobenzene1301074%13I₂ (10 mol%)Toluene1301063%14I₂ (10 mol%)Solvent-free1301021% 15 I ₂ (5 mol%) DMSO 130 10 88% (86%) ^c 16I₂ (3 mol%)DMSO1301073%17I₂ (3 mol%)DMSO1301578%18^dI₂ (5 mol%)DMSO1301088%19^eI₂ (5 mol%)DMSO1301018%Open in a separate window^aReaction conditions: dibenzyldisulfide 1a (0.2 mmol), N-methylpiperazine 2a (0.4 mmol), I₂, solvent (2.0 mL).^bGC yields based on dibenzyldisulfide 1a.^cIsolated yields based on dibenzyldisulfide 1a.^d0.6 mmol of N-methylpiperazine 2a was used.^eWithout microwave radiation.With the optimal conditions in hand, the scope of the amines and disulfides were investigated, and results were summarized in Open in a separate window^aReaction conditions: dibenzyldisulfide 1a (0.5 mmol), amines 2 (1.0 mmol), I₂ (0.025 mmol), DMSO (2.0 mL), 130 °C, 10 min.^bIsolated yields based on dibenzyldisulfide 1a.In subsequent studies, we examined the reaction of various amines with difurfuryl disulfide under the optimal conditions, and the results were summarized in Open in a separate window^aReaction conditions: difurfuryldisulfide (1b) (0.5 mmol), amines 2 (1.0 mmol), I₂ (0.025 mmol), DMSO (2.0 mL), 130 °C, 10 min.^bIsolated yields based on difurfuryldisulfide (1b).The thioamidation can also be carried out on a larger scale reaction, and the desired product (3a) were obtained in the yields of 87%, when 5 mmol of dibenzyldisulfide (1a) was treated with 10 mmol of N-methylpiperazine (2a) under the standard conditions (Scheme 3a). To shed light on the mechanism of the reaction, dibenzyldisulfide (1a) was treated with N-methylpiperazine (2a) under standard conditions by using 2.0 equiv. of TEMPO or BHT as radical scavengers (Scheme 3b), and desired product 3a was obtained in the yields of 86% and 80% respectively, suggesting that no single-electron transfer process was involved through the whole reaction. In addition, thioamides have been used as important intermediates for the construction of heterocycles and other compounds containing both nitrogen and sulfur in their backbones (Scheme 3c).¹⁸Open in a separate windowScheme 3(a) Larger-scale synthesis of 3a. (b) Control experimental for mechanism study. (c) Selected transformation of thioamides.On the basis of the above experimental results and previous works,^16,19 a possible mechanism has been depicted in Scheme 4. The first step of the thioamidation is the generation of the intermediate A by the reaction of dibenzyldisulfide (1a) with I₂, with concomitant loss of HI and BnS⁻. Then intermediate A react with N-methylpiperazine (2a) to yield intermediate B, which was converted to species Cvia coupling with BnS⁻ in the presence of DMSO. Finally, species C decomposed to desired product (3a) and BnSH, which was then converted to dibenzyldisulfide (1a) via oxidation reaction. During the whole reaction, the catalyst (I₂) was regenerated by the cycle of HI in the presence of DMSO, which catalyzed the thioamidation effectively.Open in a separate windowScheme 4Proposed mechanism of the thioamidation.     

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.     

Highly efficient construction of an oxa-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton and ring-opening of the bridged ring via C–O bond cleavage

We report herein a highly efficient strategy for construction of a bridged oxa-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton through [3 + 2] IMCC (intramolecular [3 + 2] cross-cycloaddition), and the substituents and/or stereochemistries on C-4, C-6, C-7 and C-10 fully match those in the rhamnofolane, tigliane and daphnane diterpenoids. Furthermore, ring-opening of the bridged oxa-[3.2.1]octane via C–O bond cleavage was also successfully achieved.

We reported a highly efficient construction of an oxa-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton with a full match of the substituents and stereochemistries on C-4/-6/-7/-10 with those in the rhamnofolane/tigliane/daphnane diterpenoids.

Rhamnofolane, tigliane, and daphnane are three families of diterpenoids displaying a broad range of biological activities such as antiviral, anticancer, anti-HIV, immunomodulatory and neurotrophic activities.¹ Three representative members are neoglabrescin A² and curcusones I/J.³ The unique structural features of these three compounds include a 5–7–6 tricyclic carbon skeleton with a trans-fused 5–7 bicyclic skeleton, a 4,7-bridged oxa-[3.2.1]octane skeleton and a methylene (methyl) group at C-6 (Fig. 1). Some other related natural products include crotophorbolone,⁴ phorbol,⁵ prostratin,⁶ resiniferatoxin⁷ and curcusone A.⁸Open in a separate windowFig. 1Representative rhamnofolane/tigliane/daphnane diterpenes with a trans-fused 5–7 bicyclic skeleton, a 4,7-bridged oxa-[3.2.1]octane skeleton (corresponding structures with a ring-opening of the oxa-[3.2.1]octane via C–O cleavage) and a methylene (methyl) group at C-6.Due to their remarkable biological activities and unique and complex structures, these types of diterpenoids have drawn considerable attention from organic chemists, and many creative strategies have been developed for construction of the 5–7–6 tricycles with desirable substituents and stereochemistries on C-4, C-6, C-7 and C-10.⁹ Dai et al. reported the total syntheses of curcusones I and J by using an intramolecular Au-catalysed [4 + 3] cycloaddition for construction of the oxa-[3.2.1]octane-embedded 5–7-fused carbon skeleton and Diels–Alder [4 + 2] cycloaddition for construction of the additional 6-membered carbocycle (Scheme 1).^10a Some other natural products have been reported by the groups of Wender (phorbol, resiniferatoxin and prostratin),¹¹ Cha (phorbol),¹² Baran (phorbol),¹³ Xu/Li (prostratin),¹⁴ Liu (crotophorbolone),¹⁵ Inoue (crotophorbolone, resiniferatoxin, prostratin and related molecules)¹⁶ and Dai/Adibekian (curcusones A–D).^10b The groups of West^9c and Maimone^9h have reported attempts toward the total syntheses of related molecules through construction of a 4,7-bridged oxa-[3.2.1]octane skeleton respectively (Scheme 2).Open in a separate windowScheme 1Representative total syntheses of rhamnofolane/tigliane/daphnane diterpenes containing a 5–7–6 tricyclic carbon skeleton with a trans-fused 5–7 bicyclic skeleton and a 4,7-bridged oxa-[3.2.1]octane skeleton.Open in a separate windowScheme 2Representative synthetic strategies for construction of a bridged oxa-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton with desirable substituents and stereochemistries.We have previously reported a highly efficient construction of 5–7–6 tricyclic carbon skeleton with an intramolecular [4 + 3] IMPC (intramolecular [4 + 3] parallel-cycloaddition) of cyclopropane with dendralene/Diels–Alder [4 + 2] cycloaddition strategy.¹⁷ With this strategy, the fused 5–7 bicycle was efficiently constructed which matched the trans-stereochemisty, however a C-4 oxygen atom was not be direct. Following our previously developed [3 + 2] IMCC strategy,^18a–h we have recently reported a novel and efficient construction of a bridged aza-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton with desirable substituents and stereochemistries toward total syntheses of calyciphylline D-type Daphniphyllum alkaloids (Scheme 3).¹⁸ⁱ Herein, we report the application of the [3 + 2] IMCC strategy for efficient construction of the bridged oxa-[3.2.1]octane-embedded 5–7–6 tricycle with stereochemistries on C-4, C-7 and C-10, as well as a methylene (methyl) group at C-6 matching those in neoglabrescin A, curcusones I/J and related rhamnofolane/tigliane/daphnane diterpenes.Open in a separate windowScheme 3Proposed [3 + 2] IMCC strategy for construction of the bridged oxa-[3.2.1]octane-embedded 5–7–6 tricycle with suitable substituents and stereochemistries on C-4, C-6, C-7 and C-10.We started the research from benzyl bromide 2 which was prepared from a known compound 1 according to our recently reported method (Scheme 4).¹⁸ⁱ Compound 2 was then oxidized with NMO to afford aldehyde 3 which was used directly in the next step without further purification. Under catalysis of Sc(OTf)₃ (0.2 equiv.), the [3 + 2] IMCC of aldehyde 3 was successfully carried out to afford compound 4 in 82% yield over two steps. The structure of 4 was confirmed by X-ray crystal structure analysis.¹⁹ Hereto, the bridged oxa-[3.2.1]octane-embedded 5–7–6 tricycle have been successfully constructed, the substituents and stereochemistries on C-4, C-6, C-7 and C-10 fully match those in the corresponding natural products.Open in a separate windowScheme 4Construction of the bridged oxa-[3.2.1]octane-embedded 5–7–6 tricycle.With compound 4 in hand, we started to investigate the ring-opening of the bridged oxa-[3.2.1]octane via C–O bond cleavage (Scheme 5). Krapcho decarboxylation of 4 afforded monoester 5 in 88% yield as a mixture of two diastereoisomers in a ratio of nearly 1 : 1. Reduction of 5 with DIBAL-H at −78 °C afforded aldehyde 6 in 85% yield. To our delight, the oxa-bridge was opened under catalysis of TMSOTf²⁰ at −5 °C and a dehydration product 7 was obtained in 16% yield (brsm 53%) (21 conditions (Open in a separate windowScheme 5Ring-opening of the oxa-[3.2.1]octane via C–O bond cleavage.Ring-opening of the compound 6

Synthesis of N-alkoxyphthalimide derivatives via PIDA-promoted cross dehydrogenative coupling reaction

A PIDA-promoted cross-dehydrogenative coupling reaction between N-hydroxyphthalimide (NHPI) and aryl ketones for efficient synthesis of N-alkoxyphthalimide products in moderate to good yields has been described. This methodology is distinguished by catalyst-free conditions, readily available starting materials, wide substrate scope and operational simplicity. In addition, a gram-scale reaction and synthetic transformation of the product into synthetically useful intermediates has been demonstrated.

A cross dehydrogenative coupling reaction of aryl ketones with N-hydroxyphthalimide was realized. The reactions afforded a clean and facile access to diverse N-alkoxyphthalimide derivatives in high yields (up to 99%).

N-Alkoxyphthalimide derivatives are one of the privileged core structural frameworks in the synthesis of pharmaceuticals and functional materials.¹ Consequently, the development of highly efficient methods for the synthesis of N-alkoxyphthalimides has emerged as a research topic.² Traditionally, the method to generate N-alkoxyphthalimides mainly involved the modified Gabriel reaction of N-hydroxyphthalimide (NHPI) with alcohol.³ Recently, the direct dioxygenation of alkenes with NHPI has been developed to produce β-keto-N-alkoxyphthalimides, which was realized by copper,⁴ iron⁵ and manganese catalyst,⁶ separately. In 2016, the group of Adimurthy has developed an efficient method for the synthesis of α-oxygenated ketones through PIDA (phenyliodine diacetate)-mediated oxidative functionalization of styrenes with NHPI and molecular oxygen (Scheme 1a).⁷Open in a separate windowScheme 1Strategies for the synthesis of N-alkoxyphthalimide products.In addition, due to its versatility and atom-economy potential, direct and selective C(sp³)–H bond functionalization has become one of the most powerful and efficient tool in organic synthesis in recent years, which allow direct conversion of C–H bonds to C–C and C–X bonds from simple precursors.⁸ Transition-metal-catalyzed C(sp³)–H functionalization has been extensively utilized for the construction of various chemical bonds. Considering the fact that these strategies are not environmentally friendly,⁹ therefore, great efforts have been devoted to develop metal-free free oxidative functionalization of C(sp³)–H bond. Tetrabutylammonium iodide (TBAI)/tert-butyl hydroperoxide (TBHP) has been proved as an efficient transition-metal-free system to apply in C(sp³)–H bond functionalization,¹⁰ especially through cross dehydrogenative coupling (CDC), which could assemble complicated molecules from the widely available and simple materials.¹¹ For example, Prabhu reported a TBAI-catalyzed α-aminoxylation of ketones using TBHP as oxidant to directly construct corresponding N-alkoxyphthalimide products (Scheme 1b).¹² Although many notable advances toward the synthesis of N-alkoxyphthalimide derivatives have been reported, the development of more simple, concise and efficient synthetic routes remains highly attractive. As a continuation of our previous work focused on free radical chemistry without transition metal catalyst,¹³ in this context, herein we disclose a novel and efficient method towards N-alkoxyphthalimides via direct cross dehydrogenative coupling of aryl ketones with NHPI without transition metal catalyst via a radical process (Scheme 1c).As a cheap and readily available reagent, PIDA has been widely used in organic synthesis.¹⁴ For example, Zhao and co-workers described a PIDA-mediated oxygenation reaction of N,N-diaryl tertiary amines.¹⁵ Recently, a PIDA-mediated radical cyclization of o-(allyloxy)arylaldehydes with NHPI has been realized by Wang''s group.¹⁶ At the outset of this investigation, we chose 1,2-diphenylethanone 1a and N-hydroxyphthalimide 2a as the model substrates to optimize the reaction conditions ( EntrySolventOxidantYield^b (%)1CH₂Cl₂PhI(OAc)₂922CHCl₃PhI(OAc)₂743DCEPhI(OAc)₂774ToluenePhI(OAc)₂<105THFPhI(OAc)₂<56CH₃CNPhI(OAc)₂777DMSOPhI(OAc)₂138AcetonePhI(OAc)₂539EtOAcPhI(OAc)₂5210CH₂Cl₂TBHPn.d.11CH₂Cl₂DTBPn.d.12CH₂Cl₂K₂S₂O₈n.d.13CH₂Cl₂BQn.d.14CH₂Cl₂H₂O₂n.d.15CH₂Cl₂I₂<516CH₂Cl₂NIS6117^cCH₂Cl₂PhI(OAc)₂9318^dCH₂Cl₂PhI(OAc)₂9319^eCH₂Cl₂PhI(OAc)₂6420^eCH₂Cl₂n.d.Open in a separate window^aReaction conditions: 1a (0.3 mmol), 2a (0.36 mmol, 1.2 equiv.), oxidant (0.36 mmol, 1.2 equiv.), and solvent (2.0 mL) in a test tube at room temperature for 10 h.^bIsolated yields.^cAt 60 °C.^d1 h.^e4 h. n.d. = not detected. TBHP = tert-butyl hydroperoxide (70% in water). DTBP = di-tert-butyl peroxide. BQ = 1,4-benzoquinone. NIS = N-iodosuccinimide.With the optimized reaction conditions in hand, the generality and limitation of the protocol were examined in †).¹⁷ 1-(Naphthalen-2-yl)-2-phenylethanone and 1-(2-methoxyphenyl)-2-phenylethanone also exhibited excellent reactivity, in which the corresponding products 3i and 3j were isolated in 92% and 95% yield, respectively. Meanwhile, 2-aryl substituted acetophenones have also been shown to be suitable substrates to furnish the corresponding products 3k–3l in moderate to good yields. The efficiency of the reaction was not affected by the substituents on both benzene rings (3m). To our delight, 1,2-diphenylbutan-1-one and 2-phenoxy-1-phenylethanone were compatible with reaction conditions, which reacted smoothly with 2a to furnish the corresponding products in good yields (3n–3o).Scope of the linear-chain aryl ketones^a

Catalyzed ring transformation of cyclic N-aryl-azadiperoxides with participation of α,ω-dithiols

Co(OAc)₂-catalyzed ring transformation reaction of 10-aryl-7,8,12,13-tetraoxa-10-azaspiro[5.7]tridecanes with α,ω-dithiols (ethane-1,2-, propane-1,3-, butane-1,4-, pentane-1,5-, and hexane-1,6-dithiols, 3,6-dioxaoctane-1,8-dithiol) giving 3-aryl-1,5,3-dithiazacyclanes was studied.

Co(OAc)₂-catalyzed ring transformation reaction of 10-aryl-7,8,12,13-tetraoxa-10-azaspiro[5.7]tridecanes with α,ω-dithiols giving 3-aryl-1,5,3-dithiazacyclanes was studied.

Cyclic peroxides attract attention for their antimalarial,¹ antibacterial,² and antitumor³ activities. Among numerous cyclic peroxides, heteroatomic cyclic peroxides occupy a special place owing to their high biological activities.⁴ The methods of synthesis of heteroatom-containing cyclic peroxides are limited. Recently,^5–10 nitrogen- and sulfur-containing cyclic di- and triperoxides with antitumor activity have been synthesized.^5–9 The development of efficient methods for the preparation of new cyclic hetero-di(tri)peroxides^5–10 promotes active investigation of their transformations. It was shown that the reduction of silatriperoxycycloalkanes with PPh₃ affords siladiperoxycycloalkanes;¹¹ the reaction of spiro{adamantane-[2,3′]-(pentaoxacane)} with o-phenylenediamine results in the synthesis of benzodioxazocine.⁵ The implemented conversion of pentaoxacane with o-phenylenediamine to benzodioxazocine⁵ suggests that cyclic N-containing peroxides can be involved in reactions with binucleophilic reagents, in particular α,ω-dithiols, to give new heterocycles. In contrast to the previously described methods of synthesis^5–10 and transformation of the peroxide ring,^5,11 this work for the first time discusses the method of catalytic conversion of tetraoxazaspirotridecane to dithiazacycloalkanes.It was shown by preliminary experiments that the reaction of 10-phenyl-7,8,12,13-tetraoxa-10-azaspiro[5.7]tridecane 1 with ethane-1,2-dithiol 2 does not proceed without a catalyst. The reaction of azadiperoxide 1 with ethane-1,2-dithiol 2 catalyzed by Sm(NO₃)₃·6H₂O, H₂SO₄ or BF₃·Et₂O in THF as a solvent affords 3-phenyl-1,5,3-dithiazepane 8 in 10–15% yield (Scheme 1, 12 is affected by the nature of the catalyst. When the reaction is carried out in a polar solvent (MeOH) in the presence of catalytic amounts of Sm(NO₃)₃·6H₂O, H₂SO₄ or BF₃·Et₂O, the yield of the target product 8 increases to 30%. In the presence of the Co(OAc)₂ catalyst, the yield of heterocycle 8 is 85%. When AlCl₃ or CuCl catalysts are used, the yields of heterocycle 8 are 55% and 75%, respectively (Scheme 1). All reactions were carried out at room temperature for 20 h.Open in a separate windowScheme 1Ring transformation reaction of 10-phenyl-7,8,12,13-tetraoxa-10-azaspiro[5.7]tridecane with α,ω-dithiols.Effect of the catalyst and solvent nature on the yield of 3-phenyl-1,5,3-dithiazacyclanes (∼20 °C, 20 h)

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.     

Electrosynthesis of polycyclic quinazolinones and rutaecarpine from isatoic anhydrides and cyclic amines

A direct decarboxylative cyclization between readily available isatoic anhydrides and cyclic amines was established to construct polycyclic fused quinazolinones employing electrochemical methods. This procedure was performed in an undivided cell without the use of a transition-metal-catalyst and external oxidant. A broad scope of polycyclic fused quinazolinones were obtained in moderate to good yields. Additionally, rutaecarpine was also prepared through our method in one step in good yield.

Polycyclic quinazolinones and rutaecarpine were synthesized from isatoic anhydrides and cyclic amines through an electrochemical method without an external oxidant and transition-metal-catalyst.

Quinazolinones represent a class of important nitrogen containing heterocyclic compounds which are widely distributed in natural products and synthetic materials. Over the last few decades, hundreds of quinazolinone alkaloids with a polycyclic structural motif have been discovered and studied for various purposes.¹ Representatively, rutaecarpine and its derivatives attracted considerable attention of pharmaceutical scientists due to their broad biological activities including antiobesity,² anti-tumor,³ and cardiovascular protection.⁴ Owing to their wide applications, tremendous efforts have been devoted to the construction of this privileged skeleton. The classical synthetic approaches⁵ to quinazolinones depend on the condensation between 2-aminobenzoic acid derivatives and other synthons, which suffered from tedious steps, hash conditions, limited scope and poor yields. To overcome these shortcomings, a number of methodologies were established to synthesis polycyclic quinazolinones. Thanks to the rapid development of transition-metal catalyzed C–H activation reactions, Pd,⁶ Ru,⁷ and Rh⁸ catalyzed intermolecular cyclization reactions between pre-synthesized quinazolinones and alkynes, vinyl/allyl acetates, sulfoxonium ylides were developed successively to prepare poly-cyclic quinazolinones (Scheme 2a). Alternatively, Zheng and co-workers explored light⁹ or (NH₄)₂S₂O₈ (ref. 10) induced intramolecular cyclization of 2-aminobenzamide and 2-nitrobenzamide derivatives, the products were synthesized under metal-free conditions (Scheme 2b). These brilliant works provide us efficient routes to polycyclic quinazolinones, however, the highly-functionalized substrates they used need to be synthesized in advance in several steps. More convenient and straightforward synthetic methods to produce polycyclic quinazolinones from readily available materials are still in need. Intermolecular oxidative annulation reaction using cyclic amines were reported by Zhang¹¹ and Li¹² to offer polycyclic fused quinazolinones employing oxygen as oxidant (Scheme 2c). Very recently, TBHP (t-butyl hydroperoxide) mediated reaction between isatins and tetrahydroisoquinolines via cascade Baeyer–Villiger oxidation rearrangement and cyclization were achieved by us¹³ and Hu¹⁴ respectively. In the last few years, the prosperity of electrochemistry provided us green and economy instrument for organic synthesis.¹⁵ Isatoic anhydrides are versatile bulk chemical materials which have been used to synthesis a large variety of compound especially N-heterocycles.¹⁶ Herein, as our continuous interests in the construction of bioactive heterocycles,¹⁷ we reported a direct electrochemical intermolecular [4 + 2] cycloaddition between readily available isatoic anhydrides and cyclic amines leading to polycyclic quinazolinones and rutaecarpine (Scheme 2d). This protocol exhibited mild conditions, excellent yield and good functional group tolerance. No additional oxidant and transition-metal-catalyst was need in the overall process (Scheme 1).Open in a separate windowScheme 1Bioactive polycyclic quinazolinones.Open in a separate windowScheme 2Synthesis of polycyclic quinazolinones.We start our investigation with isatoic anhydride (1a) and tetrahydroisoquinoline (2a) as the model substrates. The reaction was conducted in an undivided cell equipped with two graphite electrodes. At first, a series of commonly used electrolytes including perchlorate and ammonium were evaluated. There was no de-sired product generated until potassium iodide was employed as electrolyte (entries 1–5). When potassium iodide was replaced with tetra-butyl ammonium iodide (TBAI), a moderate yield of 66% was obtained (entry 6). Later, DMF was examined to maintain the yield to 72% (entry 7). The yield was promoted to over 80% when protic solvent such as MeOH, EtOH, TFE and HFIP were used (entries 8–11). It was worth mentioning that an excellent yield of 88% was obtained when the reaction was performed in EtOH (entry 9). Only 32% product was generated in H₂O may be attributed to the poor solubility of the reactant (entry 12). The yield was obviously decreased to 45% with the reduction of the temperature to 50 °C (entry 13). The reaction did not occur at room temperature (entry 14) ( EntrySolventElectrolyteTemperatureYield (3a)^b1EtOHNaClO₄75 °C0%2CH₃CNLiClO₄75 °C0%3CH₃CN nBn₄NBF₄75 °C0%4CH₃CN nBn₄NPF₆75 °C0%5CH₃CNKI75 °C33%6CH₃CNTBAI75 °C66%7DMFTBAI75 °C72%8MeOHTBAI75 °C80%9EtOHTBAI75 °C88%10TFETBAI75 °C85%11HFIPTBAI75 °C82%12H₂OTBAI75 °C32%13EtOHTBAI50 °C45%14EtOHTBAI25 °C0%Open in a separate window^aReaction conditions: 1a (1.2 mmol, 1.2 equiv.), 2a (1.0 mmol, 1.0 equiv.), electrolyte (1.0 M), solvent (10 mL), in an undivided cell equipped with two graphite electrodes, constant voltage (6.0 V) for 6 hours under air atmosphere.^bIsolated yields.Based on the optimized conditions, we turned to explore the scope of the reaction. We are pleased to find that this procedure exhibited excellent functional group tolerance, as shown in Open in a separate window^aReaction conditions: 1a (1.2 mmol, 1.2 equiv.), 2a (1.0 mmol, 1.0 equiv.), TBAI (1.0 M), EtOH (10 mL), in an undivided cell equipped with two graphite electrodes, constant voltage (6.0 V) for 6 hours under air atmosphere.^bIsolated yields.After the substrates scope exploration, the reaction was amplified to 10 mmol scales to illustrate the synthetic applications of the process. To our delight, this electrochemical procedure performed smoothly at gram scale to afford the product in 69% yield (Scheme 3a). Rutaecarpine is an interesting natural product with polycyclic quinazolinone skeleton. The convenient and environmental benign synthetic method for bioactive natural products is one of the most pursued issues for chemists. Herein, rutaecarpine was synthesised through our method from commercially available starting materials in the yield of 80% (Scheme 3b).Open in a separate windowScheme 3Synthetic application of the reaction.In the course of condition screening we found that only iodine anion electrolyte could generate the desired product. Molecular iodine and iodine reagents-mediated reactions have been well explored as powerful instruments for organic synthesis due to their characters of cheap, green, and easily available.¹⁸ When we replaced the electrochemical conditions with iodine, 80% yield was also obtained (Scheme 4). When radical scavengers such as TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) and BHT (butylated hydroxytoluene) (Scheme 4) were loaded to the reaction system, the yield were reduced to less than 30%. When 2a was treated with the standard conditions for two hours, 3,4-dihydroisoquinoline (4) was obtained in the yield of 81%. The combination of 1a and 4 offer 3a in the yield of 98% under standard conditions. When 1a and 2a were heated at 75 °C for 12 hours, 5 was generated in 95% yield. We treated 5 under standard conditions for 12 hours, 27% 3a was obtained with 70% starting material recovered.Open in a separate windowScheme 4Mechanism study.The cyclic voltammetry experiments have been conducted to determine the redox potential of the starting material (for details see ESI^†). Based on these results and previous reports, we proposed the plausible reaction pathway as shown in Scheme 5. The reaction could be accomplished in two paths. Firstly, the iodine anion was oxidized at anode to generate iodine radical which subsequently offered iodine. Next, intermediate 4 produced via the oxidation of 2a by iodine with the elimination of HI or direct anodic oxidation. The condensation of 1a and 4 led to intermediate 6. Finally, the oxidation of compound 6 under the function of iodine¹⁹ or anode offered the desired products 3a. Alternatively, the desired product could also be generated through another pathway. At first, the reactions between 1a and 2a yielded intermediate 5, which could be transformed to cation radical intermediate 5′ and 7 through successive anodic oxidation processes. The following intermolecular nucleophilic cyclization afforded 6. Then 3a was produced through the oxidation of 6 as same as path A.Open in a separate windowScheme 5Proposed reaction pathway.