Acyl Cyanides Research Articles

Efficient Synthesis of Cyanohydrin Esters: P(NMe2)3 Mediated Direct Deoxygenation of Acyl Cyanides with Carboxylic Acids.

An efficient synthesis of cyanohydrin esters via a P(NMe2)3 mediated direct deoxygenation process has been exploited, circumventing the release or transformation of the CN─ anion during the reaction. This approach possesses a broad scope and acts as a powerful supplement for the construction of diverse cyanohydrin esters. It offers advantages such as mild conditions, straightforward operations, and excellent scalability, affirming the feasibility and versatility of this approach and highlighting its potential in practical synthesis.

High anti Diastereoselectivity in a Tandem Oxyhomologation-Coupling Protocol for the Preparation of Amides and Peptides Incorporating α-Hydroxy β-Amino Acids.

The one-pot MAC (Masked Acyl Cyanide) reaction is used to perform the tandem oxyhomologation reaction of N,N-dibenzyl-l-phenylalaninal and coupling with nitrogen nucleophiles to provide a wide selection of amide and peptide derivatives of (2S,3S)-allophenylnorstatin in generally good yields and with high anti selectivity, often with dr >98:2. The procedure works equally well with other selected N,N-dibenzyl α-amino aldehydes, and is used to achieve a very short synthesis of (2S,3S,S)-epibestatin.

Squaramide Organocatalyzed Addition of a Masked Acyl Cyanide to β-Nitrostyrenes.

A method for the squaramide-organocatalyzed enantioselective addition of a silyl-protected masked acyl cyanide (MAC) reagent to various β-nitrostyrenes is described. Reactions are carried out in a freezer and provide products cleanly and in high enantioselectivities at very low catalyst loadings. Adducts are then unmasked, providing various oxidation state 3 functional groups, thereby highlighting the utility of these MAC reagents and a new strategy for the preparation of β-amino acids.

Scalable Preparation of the Masked Acyl Cyanide TBS-MAC.

This paper describes the three-step synthesis of TBS-MAC, a masked acyl cyanide (MAC) and a versatile one-carbon oxidation state three synthon. We have developed a scalable and detailed synthesis that involves: (1) acetylation of malononitrile to form the sodium enolate, (2) protonation of the enolate to form acetylmalononitrile, and (3) epoxidation of the enol, rearrangement to an unstable alcohol, and TBS-protection to form the title compound. Both the sodium enolate and acetylmalononitrile are bench-stable precursors to the intermediate hydroxymalononitrile, which can be converted to other MAC reagents beyond TBS by varying the protecting group (Ac, MOM, EE, etc.).

Synthesis of (2-Nitro-1-AfAlemphenylethyl)malononitriles by Michael Addition of Masked Acyl Cyanides to Nitroalkenes

AbstractA highly efficient method has been developed for the synthesis of (2-nitro-1-phenylethyl)malononitriles through a Michael addition reaction between substituted nitroolefins and masked acyl cyanide reagents, serving as carbon monoxide equivalents. Under mild conditions, the reaction took place with excellent yields (90–98%), providing a short entry into a series of the title compounds in a scalable fashion. An asymmetric version of this reaction has also been briefly explored.

A facile one-pot synthesis of N-acyl-1-cyano-1,2,3,4-tetrahydroisoquinoline via a photoredox and Reissert-type reaction from 1,2,3,4-tetrahydroisoquinolines

This work reports a protocol for the direct α-cyanation/N-acylation of 1,2,3,4-tetrahydroisoquinolines via a one-pot photoredox and Reissert-type reaction using air as the oxidant and acyl cyanide as acyl and cyano source at ambient temperature.

Studies towards the Total Synthesis of Amycolamicin: A Chiral Auxiliary‐Based Diels‐Alder Approach towards the Decalin Core

AbstractThe stereoselective synthesis of (1S,2S,5R)‐5‐((4‐methoxybenzyl)oxy)‐2‐methyl‐8‐methylene‐1,2,4a,5,6,7,8,8a‐octahy‐dronaphthalene‐1‐carboxylic acid (2) is described, which comprises the bicyclic core structure of the natural product amycolamicin (1). The bicyclic ring‐system was established via an intramolecular Diels‐Alder reaction of a triene carrying a SuperQuat chiral auxiliary. The latter could be readily removed by methanolysis in excellent yield, which allowed for effective conversion of a hydroxy group at C(1) into the methylene group present in the natural product. The intramolecular Diels‐Alder reaction could also be performed with a triene incorporating a classical, phenylalanine‐derived Evans auxiliary, but the removal of the latter from the initial Diels‐Alder product was hampered by competing attack of nucleophiles on the endocyclic carbonyl group in the oxazolidinone ring. Acid 2 could be converted into an acyl cyanide that features as a key advanced intermediate in one of the three total syntheses of amycolamicin reported to date.

Synthesis of N-Heteroarenemethyl Esters via C-C Bond Cleavage of Acyl Cyanides Under Transition Metal-Free Conditions.

A practical method to synthesize N-heteroaryl esters from N-heteroaryl methanols with acyl cyanides via C–C bond cleavage without using any transition metal is demonstrated here. The use of Na2CO3/15-crown-5 couple enables access to a series of N-heteroaryl esters in high efficiency. This protocol is operationally simple and highly environmentally benign producing only cyanides as byproducts.

A case study of the MAC (masked acyl cyanide) oxyhomologation of N,N-dibenzyl-L-phenylalaninal with anti diastereoselectivity: preparation of (2S,3S)-allophenylnorstatin esters.

The three-component reaction between a protected α-amino aldehyde, an alcohol and an α-silyloxymalononitrile provides an expedient access to protected α-hydroxy-β-amino acid derivatives. The prototypical process, performed on N-Cbz-phenylalaninal, is known to proceed with syn diastereoselectivity. The present study demonstrates that the diastereoselectivity of the reaction can be inverted, using the rationale of a Felkin-Anh interaction model. Reactions performed on N,N-dibenzyl-L-phenylalaninal proceed with a high anti diastereoselectivity, providing a panel of synthetically useful ester derivatives of (2S,3S)-allophenylnorstatin. The procedure is exploited to accomplish one of the most efficient syntheses of the title compound to date, in 3 steps (66% yield) from N,N-dibenzyl-L-phenylalaninal.

Synthetic Approaches to N‐Methoxy‐N‐methylamides

N‐Methoxy‐N‐methylamides were prepared by the acylation of acid halides, acyl cyanides, esters, lactones, activated amides, and mesyl carboxylates with N,O‐dimethylhydroxylamine hydrochloride. The reaction of carboxylic acids with alkyl chloroformates, phosphonate reagents, or coupling agents afforded the activated esters, which were converted to N‐methoxy‐N‐methylamides by (CH3O)NHCH3. N‐Methoxy‐N‐methylamides were also prepared by the oxidative amidation of benzyl alcohols and palladium‐catalyzed aminocarbonylation of organoboronic acids or aryl halides with (CH3O)NHCH3 under CO equivalents. Furthermore, N‐methoxy‐N‐methylamides were produced by the selective substitution of N,O‐dimethylcarbamoylation agents with organometallic reagents.

Acyl Cyanides as Bifunctional Reagent: Application in Copper-Catalyzed Cyanoamidation and Cyanoesterification Reaction.

Cu-catalyzed domino decyanation and cyanation reaction of acyl cyanides with amines or alcohols have been developed. The cyano sources were generated in situ via C-CN cleavage yielding the corresponding cyano substituted amides or esters in moderate to excellent yields. This approach features a cheap copper catalyst, domino decyanation and cyanation reaction, readily available starting materials, broad substrate scope, operational simplicity, and the potential for further transformation of the cyano group.

Reversal of Diastereoselectivity in a Masked Acyl Cyanide (MAC) Reaction: Synthesis of Protected erythro-β-Hydroxyaspartate Derivatives.

Using Garner's aldehyde as a substrate, one-pot MAC hydroxyhomologation reactions proceeded in good yields and with anti selectivity for the first time (dr up to 9:1). The products were used to prepare a panel of protected derivatives of erythro-β-hydroxyaspartic acid and erythro-β-hydroxyasparagine as single enantiomers in a few steps.

Aroyl and acyl cyanides as orthogonal protecting groups or as building blocks for the synthesis of heterocycles.

α-Cyanoketones represent a synthetically attractive scaffold possessing bifunctional reactivity which enabled synthesis of a diversity of products. This involves reaction of nucleophiles with electrophilic carbonyl carbon performing an efficient and regioselective way to acylation reaction, cycloaddition of activated cyano function with dipolarophiles, metal-catalyzed cross-dehydrogenative coupling carbocyanation across C-C multiple bonds as well as hydrocyanation. This review provides the recent developments in the chemistry of α-cyanoketones which will be beneficial for researchers and scientists in such field.

Rhodium-Catalyzed Asymmetric Allylation of Malononitriles as Masked Acyl Cyanide with Allenes: Efficient Access to β,γ-Unsaturated Carbonyls.

A rhodium-catalyzed regio- and enantioselective intermolecular allylation of malononitriles as masked acyl cyanides (MAC) with terminal and symmetrical internal allenes is reported. A RhI /Josiphos catalytic system combined with subsequent oxidative degradation of the primary adducts enables a straightforward access to α-branched, β,γ-unsaturated carbonyl compounds. The present protocol exhibits perfect atom economy in the allylation step and is characterized by a great functional group compatibility. Furthermore, the use of α-substituted malononitriles allowed for the construction of all-carbon quaternary centers.

Electrophile-Dependent Alkylations of Lithiated 4-Alkoxyalk-4-enenitriles.

Alkylations of acyclic, lithiated 4-alkoxyalk-4-enenitriles are highly diastereoselective with an unusual electrophile-dependent preference. Alkyl halides, sulfur, chlorine, and acyl cyanide electrophiles intercept a series of lithiated 4-alkoxyalk-4-enenitriles to install contiguous tertiary-quaternary stereocenters with high diastereoselectivity, whereas acylations with ester and carbonate electrophiles are modestly selective. The diastereoselectivity is consistent with electrophilic attack on the most accessible face of the lithated nitrile for most electrophiles except ester and carbonate electrophiles, which likely precoordinate the lithiated nitrile before acylation. Intercepting the lithiated 4-alkoxyalk-4-enenitriles with a range of electrophiles provide insight into the criteria for otherwise challenging diastereoselective alkylations and acylations of acyclic nitriles.

Chemoselective phosphine-catalyzed cyanoacylation of α-dicarbonyl compounds: a general method for the synthesis of cyanohydrin esters with one quaternary stereocenter

A chemoselective phosphine-catalyzed cyanoacylation of α-dicarbonyl compounds with acyl cyanides is reported.

MAC反応剤を用いた触媒的不斉炭素-炭素結合形成反応

MAC反応剤を用いた触媒的不斉炭素-炭素結合形成反応

Synthesis of Malononitrile-Substituted Diarylmethines via 1,6-Addition of Masked Acyl Cyanides to para-Quinone Methides

An efficient method for the synthesis of malononitrile-substituted­ diarylmethines through 1,6-conjugate addition of para-quinone­ methides with masked acyl cyanide (MAC) reagents has been developed. Under mild conditions, the scalable reaction occurs in good to excellent yields providing a straightforward access to a series of malononitrile-substituted diarylmethines. The synthetic utility of this protocol has been demonstrated in the synthesis of bioactive compounds.

Acceptorless and Base‐free Dehydrogenation of Cyanohydrin with (η6‐Arene)halide(Bidentate Phosphine)ruthenium(II) Complex

AbstractRuthenium‐catalyzed dehydrogenation of cyanohydrins under acceptorless and base‐free conditions was demonstrated for the first time in the synthesis of acyl cyanide. As opposed to the thermodynamically preferred elimination of hydrogen cyanide, the dehydrogenation of cyanohydrins could be kinetically controlled with ruthenium (II) bidentate phosphine complexes. The effects of the arene, phosphine ligands and counter anions were investigated in regard to catalytic activity and selectivity. Selective dehydrogenation can occur via β‐hydride elimination with the experimentally observed [(alkoxide)Ru] complex.magnified image

Enantioselective Synthesis of Acyclic α‐Quaternary Carboxylic Acid Derivatives through Iridium‐Catalyzed Allylic Alkylation

AbstractThe first highly enantioselective iridium‐catalyzed allylic alkylation that provides access to products bearing an allylic all‐carbon quaternary stereogenic center has been developed. The reaction utilizes a masked acyl cyanide (MAC) reagent, which enables the one‐pot preparation of α‐quaternary carboxylic acids, esters, and amides with a high degree of enantioselectivity. The utility of these products is further explored through a series of diverse product transformations.