Transition metal- and catalyst-free one-pot green method for the synthesis of N-sulfonyl amidines via direct reaction of sulfonyl azides with amines

In this report, a green synthesis of N-sulfonyl amidines via the direct reaction of tertiary or secondary amines with sulfonyl azides is described. Transition metal- and catalyst-free conditions were used for the synthesis of biologically important N-sulfonyl amidines. Further studies showed that the reaction proceeded via in situ aerobic oxidation of amines under reflux conditions.

A green synthesis of N-sulfonyl amidines via the direct reaction of tertiary or secondary amines with sulfonyl azides.     

TBAI-assisted direct C–H activation of indoles with β-E-styrene sulfonyl hydrazides: a stereoselective access to 3-styryl thioindoles

The current work describes the challenging introduction of a vinyl sulfide group by simple C–H activation on a variety of substrates. The direct C–H activation of indoles with β-(E)-styrene sulfonyl hydrazides under the sulfenylation conditions, assisted by the iodic catalyst tert-butyl ammonium iodide (TBAI), afforded a series of (E)-styrylthioindoles. Accordingly, β-(E)-styrene sulfonyl hydrazides undergo radical cross-coupling reactions with a variety of substituted indoles to afford structurally diverse indole vinyl thioethers in moderate to high yields with E-stereoselectivity. This method is metal-catalyst-free and is valuable not only because of its novelty, but also for providing a convenient synthetic pathway to a variety of (E)-styrylthioindoles with retention of the configuration. The current study paves the way for the use of β-(E)-styrene sulfonyl hydrazides as a unique styryl mercaptan source in chemical synthesis.

Direct C–H activation of indoles with beta-(E)-styrene sulfonyl hydrazides assisted by TBAI afforded structurally diverse indole vinyl thioethers in moderate to high yields with E-stereoselectivity.     

Conversion of N-acyl amidines to amidoximes: a convenient synthetic approach to molnupiravir (EIDD-2801) from ribose

An efficient method is described for the preparation of molnupiravir (EIDD-2801) an antiviral agent via regioselective conversion of an N-acyl-nucleoside intermediate, generated through stereo and regioselective glycosylation of protected ribose and N⁴-acetyl cytosine, to an amidoxime. This method avoids use of expensive starting materials, enzymes, complex reagents, and cumbersome purification procedures.

A method for the preparation of molnupiravir (EIDD-2801) via regioselective conversion of an N-acyl-nucleoside intermediate, generated through stereoselective glycosylation of protected ribose and N⁴-acetyl cytosine, to an amidoxime.     

Pd-catalyzed [3 + 2] cycloaddition of cyclic ketimines and trimethylenemethanes toward N-fused pyrrolidines bearing a quaternary carbon

A Pd-catalyzed [3 + 2] cycloaddition of N-sulfonyl cyclic ketimines and trimethylenemethanes (TMM) was developed that afforded N-fused pyrrolidines bearing a quaternary carbon. Under mild reaction conditions, structurally diverse N-sulfonyl cyclic imines, including sulfamate-fused aldimines, aryl- or styryl-substituted sulfamate-derived ketimines, and N-sulfonyl cyclic ketimines, were tolerated as reactants, affording N-fused pyrrolidines with high efficiency.

A facile route to access N-fused pyrrolidines bearing a quaternary carbon from N-sulfonyl ketimines and commercially available trimethylenemethanes has been developed.     

Preparation of 1,2-substituted benzimidazoles via a copper-catalyzed three component coupling reaction

1,2-Substituted benzimidazoles were prepared by simply stirring a mixture of copper catalysts, N-substituted o-phenylenediamines, sulfonyl azides and terminal alkynes. Particularly, the intermediate N-sulfonylketenimine occurred with two nucleophilic addition and the sulfonyl group was eliminated via cyclization. In a way, sulfonyl azides and copper catalysts activated the terminal alkynes to synthesize benzimidazoles.

The intermediate N-sulfonylketenimine occurred with two nucleophilic addition, and the sulfonyl group was easily eliminated through cyclization.     

A regioselective C7 bromination and C7 palladium-catalyzed Suzuki–Miyaura cross-coupling arylation of 4-substituted NH-free indazoles

A direct and efficient regioselective C7-bromination of 4-substituted 1H-indazole has been achieved. Subsequently, a successful palladium-mediated Suzuki–Miyaura reaction of C7-bromo-4-substituted-1H-indazoles with boronic acids has been performed under optimized reaction conditions. A series of new C7 arylated 4-substituted 1H-indazoles was obtained in moderate to good yields.

A regioselective C7-bromination of 4-substituted 1H-indazoles followed by a palladium-catalyzed Suzuki–Miyaura reaction with boronic acids is described.     

Iridium-catalyzed regioselective C–H sulfonamidation of 1,2,4-thiadiazoles with sulfonyl azides in water

We have developed a regioselective C–N cross-coupling of 1,2,4-thiadiazoles with sulfonyl azides through iridium catalysis in water. This method tactically linked the 1,2,4-thiadiazoles and sulfonamides together, and the novel molecules increased the diversity of 1,2,4-thiadiazoles which may have potential applications.

We have developed a regioselective C–N cross-coupling of 1,2,4-thiadiazoles with sulfonyl azides through iridium catalysis in water.     

Modular synthesis and transition metal-free alkynylation/alkenylation of Castagnoli–Cushman-derived N,O- and N,S-heterocyclic vinyl chlorides

A modular and functional group-tolerant protocol for the transition metal-free coupling of novel N,O- and N,S-heterocyclic vinyl chlorides with terminal acetylenes and styrenes has been developed, leading to the epimerization-free synthesis of fully carbofunctionalized dihydro-1,4-oxazines/thiazines. Bicyclic morpholines have also been prepared through the interrogation of newly synthesized cross-conjugated dienes in Diels–Alder reactions. The use of environmentally benign reaction media endows the current strategy with a practical advantage.

A functional group-tolerant and transition metal-free coupling of novel N,O- and N,S-heterocyclic vinyl chlorides, which affords fully carbosubstituted dihydro-1,4-oxazines/thiazines as well as bicyclic morpholines, is described.     

A new approach to the synthesis of legionaminic acid analogues

Legionaminic acid is a member of the nonulosonic acids, which are a class of sugars considered to be a virulence factor within a wide variety of pathogenic bacteria. We have developed a synthetic pathway towards C-7 analogues of legionaminic acid starting from Neu5Ac, resulting in the complete synthesis of both legionaminic acid, and its C-7 epimer, from a common precurser. Our approach involves the late-stage introduction of the requisite C-7 nitrogen functionality, thus making our strategy amenable to the introduction of a range of different amide groups at C-7 of legionaminic acid.

We report the synthesis of the bacterial nonulosonic acid legionaminic acid, together with its C-7 epimer, from a common precursor derived from N-acetylneuraminic acid.     

Substrate controlled,regioselective carbopalladation for the one-pot synthesis of C4-substituted tetrahydroisoquinoline analogues

6-Exo-trig cyclization reaction through regioselective carbopalladation was demonstrated with N-(2-halobenzyl)-N-allylamines to furnish the corresponding C4-substituted tetrahydroisoquinoline derivatives. The scope of the reaction was extended to the synthesis of C4-quaternary tetrahydroisoquinoline derivatives also. The nature of the substituent on the olefin moiety dictates the course of the carbopalladation sequence. Regioselective carbopalladation is substantiated by performing the reaction with unsymmetrical diallylated amine substrates.

6-Exo-trig cyclization reaction through regioselective carbopalladation was demonstrated with N-(2-halobenzyl)-N-allylamines to furnish the corresponding C4-substituted tetrahydroisoquinoline derivatives.     

Three successive and regiocontroled palladium cross-coupling reactions to easily synthesize novel series of 2,4,6-tris(het)aryl pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidines

The first access to tris(het)arylated pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine derivatives is reported. The series were generated from 4-chloroaminopyridinium, which afforded the key intermediate bearing three leaving groups, i.e. a C-2 methylsulfanyl, a lactame carbonyl group in C-4 and a chlorine atom in C-6. The regioselective reactions led to the tris(het)aryl derivatives with satisfying to high yields. The three successive cross-coupling reactions occurred first in C-6 by the displacement of chlorine, next in C-4 position by a sequential Pd-catalyzed phosphonium coupling and finally in C-2 under a Pd/Cu-catalyzed desulfitative cross-coupling reaction. The optimization and scope of each reaction are discussed and the original compounds characterized.

The first access to tris(het)arylated pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine derivatives is reported.     

Catalyst-free one-pot,four-component approach for the synthesis of di- and tri-substituted N-sulfonyl formamidines

A straightforward one-pot, multicomponent approach was developed to synthesize di- and tri-substituted N-sulfonyl formamidines from sulfonyl chlorides, NaN₃, ethyl propiolate, and primary/secondary amines under mild conditions without catalysts or additives. Structural analysis of the di-substituted sulfonyl formamidines indicated formation of the E-syn/anti isomeric form. Tri-substituted analogues only formed E-isomers.

We report a one-pot, four-component catalyst-free strategy for the synthesis of di- and tri-substituted N-sulfonylformamidines, from simple, widely-available precursors.

Amidines are important nitrogen-containing organic compounds owing to their unique structural and chemical properties.¹N-Sulfonyl amidines are a special class of amidines, which serve as essential intermediates in numerous important organic reactions,² and can be useful building blocks for synthesizing heterocyclic compounds³ or chelating ligands for transition metals.⁴ In addition, sulfonyl amidines have wide applications in biopharmaceutical molecular design and the exploration of lead compounds in drug discovery.⁵ Over the past decade, research regarding the formation of N-sulfonyl amidines has led to remarkable progress.⁶Recently, multicomponent reaction (MCR) methods have attracted considerable attention for their potential ability to access biologically active compounds⁷ and molecules relevant to drug discovery.⁸N-Sulfonylamidines fit these criteria because they are found in numerous biologically active natural products and important biopharmaceuticals.⁵ Various elegant MCR methods involving the formation of N-sulfonylamidines have already been developed. For example, a Cu-catalyzed three-component tandem reaction between (i) sulfonyl azides⁹/amides,¹⁰ (ii) alkynes, and (iii) primary, secondary, or tertiary amines or ammonium salts has been described (Scheme 1a). Another recently reported Cu-catalyzed three-component approach employed sulfonyl chlorides, sodium azides, and amines (Scheme 1b).¹¹ Additionally, Bi and co-workers¹² described a silver-catalyzed, one-pot, four-component reaction involving terminal alkynes reacting directly with trimethylsilyl azide (TMSN₃), sodium sulfinate, and sulfonyl azide (Scheme 1c). Phukan et al.¹³ described a metal-free strategy for the synthesis of di-substituted sulfonyl amidines via a one-pot reaction between tert-butylisonitrile and N,N-dibromoaryl sulfonamides in the presence of a nitrile compound in aqueous media (Scheme 1d), and other groups have applied similar methods.¹⁴ However, most protocols still typically require special reagents, including transition metal catalysts or expensive and potentially explosive sulfonyl azides, and they often proceed at elevated temperatures. Therefore, the development of an efficient and practical method for the synthesis of N-sulfonylamidine derivatives is critical. Although tri-substituted sulfonyl(form)amidines have been widely explored,^6a–r the synthesis of di-substituted N-sulfonyl formamidines is rare in the literature; to our knowledge, only one research paper (from Jacobson and co-workers, 1977)¹⁵ has described the synthesis of N,N′-di-substituted sulfonyl formamidines using sulfonamide and isocyanides in the presence of a copper catalyst.Open in a separate windowScheme 1Multicomponent reactions for the synthesis of N-sulfonylamidines.In recent years, the reaction of enamines and azides has received increasing interest due to their diversified chemical reactions.¹⁶ More recently, Wan and co-workers developed methods for the direct synthesis of tri-substituted,^6o and NH₂-featured^6t sulfonyl (form)amidines by using N,N-disubstituted enaminoesters and NH₂-functionalized enaminone with sulfonylazide. However, NH-functionalized enaminone did not undergo this reaction. In addition these reactions require 5.0 and 2.5 equiv. of sulfonyl azides, respectively, and the desired tri-substituted N-sulfonyl formamidine was obtained in a lower yield. We hypothesized that sulfonyl chlorides, NaN₃, primary (secondary) amine, and ethyl propiolate might react under same conditions to generate N-sulfonyl formamidines via in situ formation of corresponding NH-mono and N,N-disubstituted enaminoesters¹⁷ and sulfonyl azides.¹⁸ On the basis of our previous work regarding the synthesis of N-sulfonyl formamidine,¹⁹ we herein describe a mild and simple one-pot multicomponent method for the synthesis of di- and tri-substituted N-sulfonyl formamidines (Scheme 1e). This catalyst-free cascade approach avoids any metals and additives, all of the substrates are commercially available, inexpensive and easily handled. In addition these reactions can be carried out in an open atmosphere at room temperature.To evaluate the feasibility of this hypothesis, we initially considered the formation of di-substituted sulfonyl formamidines, and tosyl chloride (TsCl; 1a), NaN₃ (2), ethyl propiolate (3), and butylamine (4a) were chosen as model substrates to optimize the reaction conditions (12 Therefore we thought to increase the substrate loading of 1a and 2 under the same reaction conditions, when both the 1a and 2 dosages were increased to 1.5 equiv. the highest yield (67%) of desired 5a and 24% of N-butyltosyl amide (by-product) were obtained, respectively (entry 10). With addition of more 1a and 2, the yield did not improve further (entry 11). When the reaction temperature was increased to 40 °C or decreased to 0 °C, the yield was reduced to 60% or 30%, respectively (entries 12 and 13). When, 3-butyn-2-one was used in place of ethyl propiolate (3), and the same product was isolated in 30% yield (entry 14). Whereas, under O₂ or N₂ atmosphere, the yields were no longer improved, and afforded 65% and 68% yields of desired product, respectively (entries 15 and 16). Therefore, the optimal reaction conditions (entry 11) were set as follows: TsCl (1.5 equiv.), NaN₃ (1.5 equiv.), ethyl propiolate (1.0 equiv.), and BuNH₂ (1.0 equiv.) in MeCN at room temperature.Optimization of reaction conditions^a

Total synthesis of kealiiquinone: the regio-controlled strategy for accessing its 1-methyl-4-arylbenzimidazolone core

A practical, concise and straightforward total synthesis of kealiiquinone 1, a naphtho[2,3-d]imidazole alkaloid obtained from the Micronesian marine sponge Leucetta sp. was accomplished. The squaric acid chemistry to construct the 1,4-quinoid ring and the regioselective N-methylation through a benzo[c][1,2,5]selenadiazolium heterocycle are the key features in this report. The full details of the representative approaches involving the different attempted synthetic strategies are also presented. Finally a successful total synthesis of this complex secondary metabolite is described.

A practical, concise and straightforward total synthesis of kealiiquinone 1, a naphtho[2,3-d]imidazole alkaloid obtained from the Micronesian marine sponge Leucetta sp. was accomplished.     

Chemical synthesis of the organoarsenical antibiotic arsinothricin

We report two routes of chemical synthesis of arsinothricin (AST), the novel organoarsenical antibiotic. One is by condensation of the 2-chloroethyl(methyl)arsinic acid with acetamidomalonate, and the second involves reduction of the N-acetyl protected derivative of hydroxyarsinothricin (AST-OH) and subsequent methylation of a trivalent arsenic intermediate with methyl iodide. The enzyme AST N-acetyltransferase (ArsN1) was utilized to purify l-AST from racemic AST. This chemical synthesis provides a source of this novel antibiotic for future drug development.

Arsinothricin is prepared from 2-chloroethyl(methyl)arsinic acid or by reduction of N-acetyl protected derivative of hydroxyarsinothricin and methylation with methyl iodide.     

Novel synthesis of benzotriazolyl alkyl esters: an unprecedented CH2 insertion

We have developed a novel method for the synthesis of benzotriazolyl alkyl esters (BAEs) from N-acylbenzotriazoles and dichloromethane (DCM) under mild conditions. This reaction is one of few examples to show the use of DCM as a C-1 surrogate in carbon–heteroatom bond formation and to highlight the versatility of using DCM as a methylene building block.

Versatile synthesis of benzotriazolyl alkyl esters (BAEs) from N-acylbenzotriazoles using DCM as a methylene building block.     

Direct oxidation of N-ynylsulfonamides into N-sulfonyloxoacetamides with DMSO as a nucleophilic oxidant

N-Arylethynylsulfonamides are oxidized into N-sulfonyl-2-aryloxoacetamides directly and efficiently with dimethyl sulfoxide (DMSO) as both an oxidant and solvent with microwave assistance. DFT calculations indicate that DMSO nucleophilically attacks the ethylic triple bond and transfers its oxygen atom to the triple bond to form zwitterionic anionic N-sulfonyliminiums to trigger the reaction. Then it nucleophilically attacks the generated iminium intermediates to accomplish the oxidation via the second oxygen atom transfer. The current method provides a straightforward and efficient strategy to transform various N-arylethynylsulfonamides into N-sulfonyl-2-aryloxoacetamides, sulfonyl oxoacetimides, without any other electrophilic activators or oxidants.

Microwave-assisted direct oxidation of N-arylethynylsulfonamides with DMSO as a nucleophilic oxidant and solvent affords N-sulfonyl-2-aryloxoacetamides without any other additional electrophilic activators or oxidants.     

Regio- and stereoselective synthesis of spiropyrrolidine-oxindole and bis-spiropyrrolizidine-oxindole grafted macrocycles through [3 + 2] cycloaddition of azomethine ylides

A convenient and efficient method for the regioselective macrocyclization of triazole bridged spiropyrrolidine-oxindole, and bis-spiropyrrolizidine-oxindole derivatives was accomplished through intra and self-intermolecular [3 + 2] cycloaddition of azomethine ylides. The chalcone isatin precursors 9a–i required for the click reaction were obtained from the reaction of N-alkylazidoisatin 4 and propargyloxy chalcone 8a–i which in turn were obtained by the aldol condensation of propargyloxy salicylaldehyde 6 and substituted methyl ketones 7a–i. The regio- and stereochemical outcome of the cycloadducts were assigned based on 2D NMR and confirmed by single crystal XRD analysis. High efficiency, mild reaction conditions, high regio- and stereoselectivity, atom economy and operational simplicity are the exemplary advantages of the employed macrocyclization procedure.

Spiropyrrolidine-oxindole grafted and bis-spiropyrrolizidine-oxindole grafted macrocyles with triazole as a spacer unit have been achieved via regioselective and stereoselective intra and self-intermolecular [3 + 2] cycloaddition of azomethine ylides (click reaction).     

Domino C–C/C–O bond formation: palladium-catalyzed regioselective synthesis of 7-iodobenzo[b]furans using 1,2,3-triiodobenzenes and benzylketones

A facile and efficient synthesis of 7-iodobenzo[b]furan derivatives via a highly regioselective tandem α-arylation/intramolecular O-arylation of 5-substituted-1,2,3-triiodobenzenes and benzylketones is described. Remarkably, the α-arylation coupling reactions initiate exclusively at the least sterically-hindered position of the triiodoarene, which results in a highly chemoselective transformation. The highest yields were observed in reactions between electron-poor 1,2,3-triiodoarenes and electron-rich benzylketones, yet the optimized reaction conditions were found to be tolerant to a wide range of different functional groups. This unprecedent synthesis of 7-iodobenzo[b]furans from 1,2,3-triiodobenzenes is scalable, general in scope, and provides easy access to valuable precursors for other chemical transformations.

A facile and unprecedented synthesis of 7-iodobenzo[b]furans via a highly regioselective tandem α-arylation/intramolecular O-arylation is reported that is efficient, scalable and creates versatile precursors for further chemical manipulation.     

In(OTf)3-catalyzed intramolecular hydroarylation of α-phenylallyl β-ketosulfones – synthesis of sulfonyl 1-benzosuberones and 1-tetralones

In(OTf)₃-catalyzed intramolecular hydroarylation of α-phenylallyl β-ketosulfones provides sulfonyl 1-benzosuberones and 1-tetralones in moderate to good yields in refluxing (CH₂Cl)₂ under open-vessel and easy-operation reaction conditions. A plausible mechanism is proposed and discussed. This highly regioselective protocol provides an atom-economic ring-closure route.

In(OTf)₃-catalyzed intramolecular hydroarylation of α-phenylallyl β-ketosulfones provides sulfonyl 1-benzosuberones and 1-tetralones in moderate to good yields in refluxing (CH₂Cl)₂ under open-vessel and easy-operation reaction conditions.     

Synthesis and biological evaluation of potent benzoselenophene and heteroaromatic analogues of (S)-1-(chloromethyl)-8-methoxy-2,3-dihydro-1H-benzo[e]indol-5-ol (seco-MCBI)

A diverse series of compounds (18a–x) were synthesized from (S)-1-(chloromethyl)-8-methoxy-2,3-dihydro-1H-benzo[e]indol-5-ol (seco-MCBI) and benzoselenophene or heteroaromatic acids. These new compounds were evaluated for their cytotoxicity against the human gastric NCI-N87 and human ovarian SK-OV3 cancer cell lines. The incorporation of a methoxy substituent at the C-7 position of the seco-CBI unit enhances the cytotoxicity through its additional van der Waals interaction and gave a much higher potency than the corresponding seco-CBI-based analogues. Similarly, the seco-MCBI-benzoselenophene conjugates (18h–x) exhibited substitution effects on biological activity, and the N-butyramido and N-methylthiopropanamido analogues are highly potent, possessing >77- and >24-fold better activity than seco-MCBI-TMI for the SK-OV3 and NCI-N87 cell lines, respectively.

Incorporation of a methoxy substituent at the C-7 position of CBI and N-amido substitution at the C-5 position of benzoselenophene significantly enhances the anticancer activity of duocarmycin analogs.