Metalated nitriles: internal 1,2-asymmetric induction

Alkylations of conformationally constrained acyclic nitriles containing vicinal dimethyl groups and an adjacent phenyl group or trisubstituted alkene are exceptionally diastereoselective. Probing the alkylation stereoselectivity with a series of C- and N-metalated nitriles implicates a reactive conformation in which an sp2-hybridized substituent projects over the metalated nitrile to avoid allylic strain. Steric screening thereby directs the electrophilic attack to the face of the metalated nitrile opposite the projecting substituent. Excellent stereoselectively is maintained in a diverse range of alkylations that efficiently install quaternary centers, even with isopropyliodide in which a contiguous array of tertiary-quaternary-tertiary stereocenters is created! Screening the conformational requirements with a series of acyclic nitriles and esters reveals the key structural requirements for high selectivity while providing a robust, predictive model that accounts for comparable ester alkylations affording the opposite diastereomer! The intensive survey of metalated nitrile alkylations identifies the key structural features required for high 1,2-asymmetric induction, addresses the long-standing challenge of asymmetric alkylations with acylic metalated nitriles, and provides a versatile method for installing hindered quaternary centers with excellent stereocontrol.     

Metalated nitriles: chelation-controlled cyclizations to cis and trans hydrindanes and decalins

Chelation provides a powerful means of stereocontrol in alkylations of metalated nitriles. Doubly deprotonating a series of cyclic beta-hydroxynitriles triggers cyclizations that implicate metalated nitrile intermediates having configurations imposed by chelation with an adjacent, chiral lithium alkoxide. Identifying chelation as a general stereocontrol element explains several previously anomalous alkylations of metalated nitriles and provides a potential solution to the long-standing difficulty of synthesizing trans-hydrindanes. Employing chelation to control the metalated nitrile geometry permits selective cyclizations to cis and trans hydrindanes and decalins and provides key insight into the geometrical requirements of these demanding cyclizations.     

Sulfinylnitriles: Sulfinyl–Metal Exchange–Alkylation Strategies

Adding organolithiums, Grignard reagents, or zincates to sulfinylnitriles triggers a facile sulfinyl–metal exchange to afford N‐ or C‐metalated nitriles. Sulfinyl–magnesium exchange–alkylations efficiently install quaternary and tertiary centers, even in the case of tertiary sulfinylnitriles that contain a highly acidic methine proton. α‐Sulfinylalkenenitriles afford moderately nucleophilic magnesiated nitriles, and the reactivity can be dramatically increased by conversion to the corresponding magnesiates. The sulfinyl‐metal exchange is extremely fast, proceeds efficiently with quaternary, tertiary, and vinylic α‐sulfinylnitriles, and exhibits an exceptional functional group tolerance in nitrile alkylations.     

Sulfone–Metal Exchange and Alkylation of Sulfonylnitriles

The first general sulfone–metal exchange is described. Treating substituted 2-pyridylsulfonylacetonitriles with either BuLi or Bu₃MgLi generates metalated nitriles that efficiently intercept a variety of electrophiles to afford quaternary nitriles. The 2-pyridylsulfone is critical for the sulfone–metal exchange because chelation anchors the organometallic proximal to the electrophilic, tetrasubstituted sulfone to override complex-induced deprotonation. Alkylating commercial 2-pyridinesulfonylacetonitrile with mild bases, either K₂CO₃ or DBU, and subsequent sulfone–metal exchange and alkylation rapidly assembles quaternary nitriles by three alkylations, only one of which requires an organometallic reagent.     

Sulfone–Metal Exchange and Alkylation of Sulfonylnitriles

The first general sulfone–metal exchange is described. Treating substituted 2‐pyridylsulfonylacetonitriles with either BuLi or Bu₃MgLi generates metalated nitriles that efficiently intercept a variety of electrophiles to afford quaternary nitriles. The 2‐pyridylsulfone is critical for the sulfone–metal exchange because chelation anchors the organometallic proximal to the electrophilic, tetrasubstituted sulfone to override complex‐induced deprotonation. Alkylating commercial 2‐pyridinesulfonylacetonitrile with mild bases, either K₂CO₃ or DBU, and subsequent sulfone–metal exchange and alkylation rapidly assembles quaternary nitriles by three alkylations, only one of which requires an organometallic reagent.     

Omega-halonitriles: domino cyclizations to oxa- and carbocyclic nitriles

t-BuOK-induced deprotonation of omega-haloalkylnitriles generates remarkably stable potassiated nitriles. In situ deprotonation and alkylation of omega-chloroalkylnitriles with aldehyde electrophiles trigger sequential nucleophilic-electrophilic alkylations generating substituted tetrahydrofuranyl and tetrahydropyranyl nitriles. Redirecting the cyclization manifold with 5-iodopentanenitrile and a ketone causes a complementary electrophilic-nucleophilic cyclization to the corresponding carbonitrile. Collectively these cyclizations provide rapid assembly of five- and six-membered oxa- and carbocyclic nitriles demonstrating the utility of omega-halonitriles in domino alkylations.     

Metalated nitriles: organolithium, -magnesium, and -copper exchange of alpha-halonitriles

[reaction: see text] alpha-Halonitriles react with alkyllithium, organomagnesium, and lithium dimethylcuprate reagents generating reactive, metalated nitriles. The rapid halogen-metal exchange with alkyllithium and Grignard reagents allows selective exchange in the presence of reactive carbonyl electrophiles, including aldehydes, providing a high-yielding alkylation protocol. Lithiated and magnesiated nitriles react with propargyl bromide by S(N)2 displacement whereas organocopper nitriles react by S(N)2' displacement, correlating with the formation of a C-metalated nitrile.     

Metalated nitriles: cation-controlled cyclizations

Judicious choice of cation allows the selective cyclization of substituted gamma-hydroxynitriles to trans- or cis-decalins and trans- or cis-bicyclo[5.4.0]undecanes. The stereoselectivities are consistent with deprotonations generating two distinctly different metalated nitriles: an internally coordinated nitrile anion with BuLi, and a C-magnesiated nitrile with i-PrMgCl. Employing cations to control the geometry of metalated nitriles permits stereodivergent cyclizations with complete control over the stereochemistry of the quaternary, nitrile-bearing carbon.     

A diastereomerically enriched, dimeric organolithium compound and the stereochemical course of its transformations

A dimeric α-silylated ethyllithium compound is presented featuring stereogenic metalated carbon centres with defined configurations. It can be generated by diastereoselective deprotonation of the corresponding ethylsilane. Reaction with Me(3)SnCl proceeds under inversion and the transfer of the stereoinformation is possible with dr's of up to 97:3.     

C-metalated nitriles: electrophile-dependent alkylations and acylations

Sequential carbonyl addition-conjugate addition of Grignard reagents to 3-oxocyclohex-1-ene-1-carbonitrile generates C-magnesiated nitriles whose alkylation stereoselectivities intimately depend on the nature of the electrophile. The alkylation of these C-magnesiated nitriles with alkyl halides, sulfonates, and unstrained ketones occurs with the retention of the C-Mg configuration, whereas aldehyde and acyl cyanide acylations proceed with inversion of the stereochemistry. Mechanistic probes indicate that the stereoselectivity is controlled by stereoelectronic effects for most electrophiles, except allylic, benzylic, and cyclopropyl halides where single-electron-transfer processes intervene. Screening numerous alkylations of C-magnesiated nitriles with a diverse range of electrophiles reveals the reaction scope and delineates the fundamental stereoelectronic effects responsible for the highly unusual electrophile-dependent alkylations.     

Preparation of 1H-2,3,4,5-Tetraarylpyrroles by oxidation of heterocyclic imine-enamines

Heterocyclic imine-enamines 1 were prepared from metalated methyl substituted heterocycles and aromatic nitriles and then oxidized with lead tetracetate to give various tetraarylpyrroles 2.     

Metalated nitriles: halogen-metal exchange with alpha-halonitriles

[reaction: see text] Alpha-halonitriles react with organometallic reagents in a facile halogen-metal exchange. The halogen-metal exchange is extremely fast with Grignard and alkyllithium reagents, generating metalated nitriles in situ with aldehyde, ketone, acid chloride, and acyl cyanide electrophiles. Sequential halogen-metal exchange and methylation of conformationally constrained nitriles is highly stereoselective and consistent with a retentive alkylation of a C-magnesiated nitrile.     

Cyclic oxonitriles: stereodivergent grignard addition-alkylations

Sequential carbonyl addition-conjugate addition of Grignard reagents to cyclic 5-7-membered oxoalkenenitriles efficiently generates cyclic magnesiated nitriles. Alkylations of these magnesiated nitriles exhibit diastereoselectivities that depend intimately on the size of the carbocyclic ring: 5-membered oxonitriles generate magnesiated nitriles whose alkylations are controlled by steric constraints whereas 6- and 7-membered oxonitriles generate internally coordinated, C-magnesiated nitriles whose alkylations are controlled by stereoelectronic effects. Reversing the alkylation selectivity of 6-membered C-magnesiated nitriles is achieved by conversion to an N-metalated nitrile in which steric, rather than electronic, effects direct the electrophile trajectory. Collectively, the conjugate addition-alkylation generates highly substituted, cyclic 5-7-membered nitriles containing three new stereocenters with selective access to diastereomers at the quaternary nitrile-bearing carbon.     

Stereoselective alkylation–reduction of β-keto nitriles by the fungus Curvularia lunata

The alkylation–reduction (AR) reaction of β-keto nitriles by growing cells of Curvularia lunata CECT 2130 has been explored. The reaction conditions for the ethylation of benzoylacetonitrile have been optimized in terms of both yield and stereoselectivity and the mechanism of this biotransformation was studied. The scope of this reaction has been extended to other alkylations (R=Et, Pr, Bu, iso-Bu) and to a series of aromatic and heteroaromatic substrates, yielding the corresponding optically active α-alkyl β-hydroxy nitriles. The yield (directly related to competing carbonyl reduction reaction) depends on the substrate bulk, whereas the enantiomeric and diastereomeric excesses (both up to 98%) seem to be dependent on several factors.     

Diastereoselective alkylations of β-tetrazolyl propionic acids

A new procedure for the diastereoselective alkylations of β-tetrazolyl propionic acids is described. A seven-membered chelation model is proposed to rationalize the observed high level of syn selectivity.     

First asymmetric synthesis of (un)substituted bridged tetrahydro-2-benzazepines

A new and flexible route for the asymmetric synthesis of a variety of alkylated bridged tetrahydro-2-benzazepines has been developed. The key steps are the highly diastereoselective Michael addition of metalated SAMP-hydrazones to α,β-unsaturated esters combined with cyclomethylenation/Mitsunobu coupling reactions to secure the formation of the seven-membered azaheterocycle and of the bridged unit, respectively.     

LiClO4 Accelerated Michael addition of amines to α,β-unsaturated olefins under solvent-free conditions

Several primary and secondary amines were added to α,β-unsaturated esters, nitriles, amides, and ketones to give the corresponding saturated amines mediated by solid lithium perchlorate under solvent-free and environmentally friendly conditions at room temperature.     

Fluoroalkyl alpha,beta-unsaturated imines. Valuable synthetic intermediates from primary fluorinated enamine phosphonates

[reaction: see text] A simple method for the preparation of fluoroalkyl allylamines or alpha,beta-unsaturated ketones by an olefination reaction of primary enamine phosphonates and aldehydes, followed by selective reduction with hydrides or hydrolysis, is reported. Fluorinated beta-amino nitriles are also obtained by an olefination reaction of primary enamine phosphonates with aldehydes and subsequent addition of metalated acetonitrile.     

An efficient,asymmetric synthesis of pipecolic acid and 2-alkyl pipecolic acids

Both (R)- and (S)-pipecolic acids and their 2-alkyl derivatives have been synthesized via diastereoselective alkylations of (R)-5-phenylmorpholin-2-one 5.     

Highly diastereoselective aminoalkylation of naphthols with chiral amines mediated by lithium perchlorate solution in diethyl ether

One-pot, three-component, Mannich reaction of naphthols with in situ prepared imines in 5 M ethereal lithium perchlorate at room temperature affords the corresponding aminoalkylated products in high yields with high diastereoselectivities. The process is exemplified by the reaction of 2-naphthol with (R)-1-phenylethylamine and an aromatic aldehyde in concentrated ethereal lithium perchlorate solution, which affords a highly diastereoselective access to the requisite 2-aminoalkylated product.