Catalytic additions of acylsilanes to imines: an acyl anion strategy for the direct synthesis of alpha-amino ketones

The addition of acylsilanes to imines catalyzed by neutral carbenes (or zwitterions) generated in situ from readily available thiazolium salts is described. The general reaction successfully utilizes acylsilanes as carbonyl anion precursors and is tolerant of a range of structural diversity on the acylsilane or imine electrophile. The overall reaction utilizes easily available precursors and directly accesses protected alpha-amino ketones in the correct oxidation state.     

The thiazolium-catalyzed Sila-Stetter reaction: conjugate addition of acylsilanes to unsaturated esters and ketones

A new acyl anion addition reaction between acylsilanes and alpha,beta-unsaturated conjugate acceptors promoted by a nucleophilic organic catalyst has been disclosed. The 1,4-dicarbonyl products produced in this reaction are highly useful synthons. Neutral carbenes (or zwitterions) generated in situ from commercial thiazolium salts are used as effective catalysts for the reaction which is in contrast to established anionic catalysts typically employed to promote the required Brook rearrangement (1,2-silyl shift from carbon to oxygen) involved in the reported reaction. This process successfully utilizes acylsilanes as tunable acyl anion progenitors and is tolerant of a wide range of structural diversity on the acylsilane or the conjugate acceptor.     

Catalytic multicomponent synthesis of highly substituted pyrroles utilizing a one-pot sila-Stetter/Paal-Knorr strategy

[reaction: see text] A multicomponent synthesis of highly substituted pyrroles catalyzed by thiazolium salts has been disclosed. The reaction employs an acyl anion conjugate addition reaction of acylsilanes (sila-Stetter) and unsaturated ketones to generate 1,4-dicarbonyl compounds in situ. The subsequent addition of various amines promotes a Paal-Knorr reaction, affording the desired pyrrole nucleus in an efficient one-pot process.     

Direct nucleophilic acylation of nitroalkenes promoted by a fluoride anion/thiourea combination

The direct nucleophilic acylation of nitroalkenes is reported utilizing a fluoride-initiated rearrangement of protected thiazolium carbinols. The key combination of fluoride anion and thiourea accesses carbonyl anion reactivity without the use of amine or amide bases typically employed in the generation of these Umpolung nucleophiles. The mild reaction conditions used to generate the reactive carbonyl anion species in situ allow for conjugate additions in good yield to sensitive nitroalkene electrophiles. The process is tolerant of a variety of thiazolium carbinols and nitroalkene substrates and can be rendered enantioselective and diastereoselective by the addition of a chiral thiourea derived from quinine.     

Intermolecular Cross-Acyloin Reactions by Fluoride-Promoted Additions of O-Silyl Thiazolium Carbinols

The addition of acyl anion equivalents to aliphatic aldehydes (crossed-acyloin reaction) has been developed. Cesium fluoride with isopropanol as solvent promotes the addition of O-silyl thiazolium carbinols to various aliphatic aldehydes in moderate to good yields. These reactions represent a general procedure for the selective coupling of aliphatic aldehydes by an acyl anion reaction which have been problematic until now.     

Catalytic conjugate additions of carbonyl anions under neutral aqueous conditions

The conjugate addition of carbonyl anions catalyzed by thiazolium salts that is fully operative under neutral aqueous conditions has been accomplished. The combination of alpha-keto carboxylates and thiazolium-derived zwitterions produces reactive carbonyl anions in a buffered protic environment that readily undergo conjugate additions to substituted alpha,beta-unsaturated 2-acyl imidazoles. The scope of the reaction has been examined and found to accommodate various alpha-keto carboxylates and beta-aryl substituted unsaturated 2-acyl imidazoles. The optimal precatalyst for this process is the commercially available thiazolium salt 5, a simple analogue of thiamin diphosphate. In this process, no benzoin products from carbonyl anion dimerization are observed. The corresponding 1,4-dicarbonyl compounds can be efficiently converted into esters and amides by way of activation of the N-methylimidazole ring via alkylation.     

Diastereoselective alkylation and reduction of β-alkoxyacylsilanes: stereoselective construction of three contiguous stereogenic centers

The nucleophilic addition reaction to acylsilanes, having stereogenic centers at the α and β positions, derived from the aldol reaction of dimethyl acetals and acylsilane silyl enol ethers gives the corresponding α-silylalcohols in high yields with excellent diastereoselectivity. The protiodesilylation of α-silylalcohols proceeds with complete retention of the configuration. In addition, the reduction of acylsilanes having stereogenic centers at the α and β positions affords the corresponding α-silylalcohols in good yields with high diastereoselectivity similarly to the nucleophilic addition. And the treatment of acylsilanes having a phenyl group on silicon atom with fluoride ion results in the formation of phenyl carbinol derivatives via migration of the phenyl group with high diastereoselectivity.     

Synthesis of tertiary beta-hydroxy amides by enolate additions to acylsilanes

The synthesis of tertiary beta-hydroxy amides from acylsilanes, acetamides, and electrophiles is described. The addition of amide enolates to acylsilanes generates beta-silyloxy homoenolate reactivity by undergoing a 1,2-Brook rearrangement. These unique nucleophiles formed in situ can then undergo smooth addition to alkyl halides, aldehydes, and ketones. Enolates derived from amides are crucial for the success of this process since ketone enolates suffer from internal return of the beta-carbanion onto the carbonyl carbon. The use of optically active amide enolates delivers beta-hydroxy amide products with good levels of diastereoselectivity (>/=10:1).     

N-Heterocyclic carbene catalyzed intramolecular crossed aldehyde-ketone benzoin condensation in the chalcone of o-phthalaldehyde: a facile synthesis of naphthalenones

The intramolecular crossed aldehyde-ketone benzoin condensation in the chalcone of o-phthalaldehyde (OPA) catalyzed by N-heterocyclic carbene (NHCs) generated in situ from readily available imidazolium and thiazolium salts is described. In this reaction, bicyclic α-hydroxyl ketones (naphthalenone type tertiary alcohol) were selectively produced in good yields (75-94%) in shorter reaction times (20 min) through nucleophilic addition of acyl anion generated by umpolung in OPA-chalcone (regio controlled).     

Evaluation of C-trialkylsilyl enol and thioenol ethers as intermediates in the synthesis of acylsilanes

C-silyl enol ethers or thioenol ethers have been prepared by a Peterson reaction, as intermediates for acylsilane synthesis. Bis(trialkylsilyl)(methoxy)- or -(methylsulfanyl)methanes bearing identical or different trialkylsilyl groups were used as starting materials in order to assess the selectivity of the Peterson elimination step. A good selectivity was observed only with ethers bearing the TMS and TBDMS groups. However, there is no practical interest to use such reagents owing to the difficulty to obtain them in correct yields. Bis(trimethylsilyl)(methylsulfanyl)methane proved to be a good reagent for the preparation of C-silyl thioenol ethers, which are hydrolyzed under classical acid conditions to give acylsilanes in fair overall yields. This convenient procedure was extended to the synthesis of bis(acylsilanes).     

Pyrrole studies. : Part 36 The synthesis of 2,2'-bipyrroles and related compounds

Nucleophilic addition to but-1-en-3-one by the acyl anion equivalent of 2-formylpyrroles, generated by reaction with thiazolium salts, yields 1-(2-pyrrolyl)pent-1,4-diones, which undergo the Paal-Knorr reaction with ammonia and primary amines to give the 2,2'-bipyrroles. Alternatively, the 2,2'-bipyrrole system can be obtained by pyrolysis of 2-azido-5-(2-pyrrolyl)penta-2,4-dienoic esters.     

Lewis acid-catalyzed conjugate additions of silyloxyallenes: a selective solution to the intermolecular Rauhut-Currier problem

Silyloxyallenes serve as highly useful alpha-acylvinyl anion equivalents. These latent allenolates undergo conjugate additions to alkylidene malonates in the presence of 10 mol % Sc(OTf) 3. The reaction delivers intermolecular Rauhut-Currier products in excellent yields and regioselectivities for a wide scope of substrates. Notably, the formal cross-coupling of two different alpha,beta-unsaturated carbonyl compounds (a cross Rauhut-Currier reaction) is achieved. Preliminary investigations have demonstrated good levels of enantioselectivity for the addition of a racemic silyloxyallene with a chiral Lewis acid.     

Reaction of silyldihalomethyllithiums with nitriles: formation of alpha-keto acylsilanes via azirines and 1,3-rearrangement of silyl group from C to N

A synthesis of alpha-keto acylsilanes, where 2-bromo-2H-azirine participates as a key intermediate, is reported. The reaction of silyldibromomethyllithium with aryl nitriles provides alpha-keto acylsilanes in good yields. Interestingly, silyldichloromethyllithium induces aza-1,3-Brook rearrangement of the silyl group in th reaction with nitriles. The rearrangement enables a three-component coupling reaction in a one-pot operation.     

Efficient synthesis of acylsilanes using morpholine amides

[reaction: see text] A general synthesis of acylsilanes from the corresponding morpholine amides and silyllithium species is described. The use of morpholine amides is economical and prevents over-addition by the silyl nucleophile. The procedure cleanly affords acylsilanes in good yields and circumvents the use of stoichiometric copper(I) cyanide typically employed to synthesize these compounds from acid chlorides.     

Facile synthesis of highly substituted 3-aminofurans from thiazolium salts, aldehydes, and dimethyl acetylenedicarboxylate

[reaction: see text] A facile preparation of 3-aminofuran derivatives via multicomponent reactions of thiazole carbenes, aldehydes, and dimethyl acetylenedicarboxylate (DMAD) is reported. In this process, the thiazole carbenes, generated in situ from thiazolium salts, reacted with aldehydes and DMAD at -78 to 0 degree C in CH(2)Cl(2) to afford the substituted furans in moderate to good yields. Eight substituted thiazolium salts were employed as carbene precursors in the reaction. Besides aryl aldehydes, alpha,beta-unsaturated aldehydes, aliphatic aldehydes, and arenedial were also investigated and found to be applicable to this reaction.     

Asymmetric synthesis of cis-2-aminocyclopropanols by intramolecular Mannich addition of silyloxy benzyl carbanions

An efficient, highly diastereoselective method for the preparation of protected cis-2-aminocyclopropanols from N-tert-butanesulfinyl ketimines and various aryl acylsilanes is described. A tandem process for carbon-carbon bond formation via nucleophilic addition to acylsilanes, Brook rearrangement, and intramolecular Mannich reaction has been developed.     

An electrolytic system based on the anion exchange reaction between KCl and an anion exchange resin

We have developed a novel electrolytic system based on the anion exchange reaction between KCl and Amberlyst A26. It was demonstrated by preparative electrolysis experiments as well as cyclic voltammetry that the anion exchange reaction offers a unique electrolytic system for electroreduction of organic compounds. On the basis of the electrolytic system, electroreduction of aromatic carbonyl compounds was successfully achieved by using an undivided cell to provide the corresponding coupling products as pinacols in good to high yields with high diastereoselectivity.     

N-Heterocyclic carbene catalyzed intramolecular nucleophilic addition of carbonyl anion equivalents to enol ethers

The intramolecular nucleophilic addition reaction of acyl anion equivalents to enol ethers is described, which was catalyzed by N-heterocyclic carbenes generated in situ from readily available thiazolium salt. In this transformation, benzofuranones were obtained in excellent yield. In combination with our previous work, the precise mechanistic elucidation for the formation of benzofuranones has been further investigated. A labeling experiment implied that the transformation proceeds through a nucleophilic addition mechanism.     

Photochemically promoted transition metal-free cross-coupling of acylsilanes with organoboronic esters

Intermolecular carbon-carbon bond formation between acylsilanes and organoboronic esters was achieved by photoirradiation under almost neutral, transition metal-free conditions. In this reaction, siloxycarbenes generated by photoisomerization of acylsilanes reacted with boronic esters to give the formal B-C bond insertion intermediates, which underwent unique rearrangement to afford the cyclic α-alkoxyboronic esters. Acidic treatment of the resulting crude products under air furnished the cross-coupled ketones in good yields.     

Intermolecular Stetter reaction of aromatic aldehydes with (E)-(2-nitrovinyl)cyclohexane induced by N-heterocyclic carbene and thiourea

Intermolecular Stetter reaction of aromatic aldehydes with (E)-(2-nitrovinyl)cyclohexane catalyzed by thiazolium A has been developed. The reaction rate and efficiency are profoundly impacted by the presence of thiourea B. The reaction affords moderate to good yields of the Stetter product. Some factors influencing yield were discussed.