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.     

Novel domino cyclization of tryptophan-derived amino nitriles: scope and stereoselectivity

[reaction: see text] The scope and stereoselectivity of the acid-promoted cyclization of new tryptophan-based alpha-amino nitriles derived from either ketones or aldehydes to novel hexahydropyrrolo[1',2',3':1,9a,9]imidazo[1,2-a]indoles is described. This cyclization involves the generation of two or three stereogenic centers. The time and stereoselectivity of this reaction mostly depended on both the steric volume of the substituents at the amino nitrile and its stereochemistry. Unhindered amino nitriles gave exclusively 2-exo-isomers, while hindered amino nitriles, which required higher reaction times, provided also these isomers under kinetic control. Under thermodynamic control, the 2-endo-isomer was the main reaction product, except for the benzaldehyde-derived alpha-amino nitriles, where a favorable electronic interaction between the phenyl and methoxycarbonyl groups in a relative cis-disposition might be responsible of the formation of the 2-exo-isomer as the only cyclization product.     

One-pot cyclization of dilithiated nitriles with isothiocyanates and epibromohydrin. Synthesis of 2-cyano-1-(hydroxymethyl)cyclopropanes and 2-cyanomethylidene-4-(hydroxymethyl)thiazolidines

The cyclization of dilithiated nitriles with epibromohydrin afforded 2-cyano-1-(hydroxymethyl)cyclopropanes. 2-Cyanomethylidene-(4-hydroxymethyl)thiazolidines were prepared by one-pot cyclization of dilithiated nitriles with isothiocyanates and epibromohydrin.     

Cyclic nitriles: stereodivergent addition-alkylation-cyclization to cis- and trans-abietanes

Diverse cyclic hydroxy nitriles are readily synthesized through sequential 1,2-1,4-Grignard addition-methylations to 3-oxo-1-cyclohexene-1-carbonitrile. Acid-catalyzed intramolecular cyclizations of the cyclic hydroxy nitriles reveal fundamental stereoselectivity trends in Friedel-Crafts cyclizations to cis- and trans-abietanes. In contrast to previous assumptions, comparative cationic cyclizations with electron-rich and electron-poor aromatic nucleophiles exhibit similar preferences for cyclization to cis-abietanes. Optimizing the cyclizations for trans-abietanes has identified ZrCl 4 as an exceptional Lewis acid which, for cyclizations of iminolactones, favors trans-abietanes as the only observable diastereomer. The sequential oxonitrile addition-Friedel-Crafts cyclization strategy provides a rapid, stereodivergent synthesis of cis- or trans-abietanes, demonstrates the dramatic influence of ZrCl 4 in promoting cationic cyclizations, and in contrast to previous assumptions suggests that the cyclization stereoselectivity is not correlated with the electronic nature of the aromatic nucleus.     

Synthesis and reactions of (E)-1,1,1-trifluoro-2-methyl-2-penten-4-ylidene-malonodinitrile

Condensation of (E)-1,1,1-trifluoro-2-methyl-2-penten-4-one with malonodinitrile affords mixtures of unsaturated nitriles. Attempted cyclization of these nitriles in concentrated sulfuric acid furnishes derivatives of alkylidenecyanoacetamides and alkylidenemalonodiamide.     

Metalated nitriles: stereodivergent cation-controlled cyclizations

Stereodivergent cyclizations of γ-hydroxy cyclohexanecarbonitriles are controlled simply through judicious choice of cation in the alkylmetal base. Deprotonating a series of cyclic γ-hydroxy nitriles with i-PrMgBr generates C-magnesiated nitriles that cyclize under stereoelectronic control to cis-fused hydrindanes, decalins, and bicyclo[5.4.0]undecanes. An analogous deprotonation with BuLi triggers cyclization to trans-fused hydrindanes, decalins, and bicyclo[5.4.0]undecanes consistent with a sterically controlled electrophilic attack on an equatorial nitrile anion. Using cations to control the geometry of metalated nitriles provides a versatile, stereodivergent cyclization to cis- and trans-hydrindanes, decalins, and [5.4.0]undecanes, and reveals the key geometric requirements for intramolecular S_N2 and S_N2′ displacements.     

Alkenenitriles: Zn-Cu promoted conjugate additions of alkyl iodides in water

[reaction: see text] A new silica-supported zinc-copper matrix dramatically promotes conjugate additions of alkyl iodides to alkenenitriles in water. Acyclic and cyclic nitriles react with functionalized alkyl iodides, overcoming the previous difficulty of performing conjugate additions to disubstituted alkenenitriles with nonstabilized carbon nucleophiles. Conjugate additions with omega-chloroalkyl iodides generate cyclic nitriles primed for cyclization, collectively providing one of the few annulation methods for cyclic alkenenitriles.     

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.     

Tandem addition-rearrangement of nitrile anions to benzyne. A convenient synthesis of 3-cyano-2-alkyl benzoic acids and benzaldehydes.

Benzynes derived from aryloxazolines react with lithio-alkyl nitriles to give addition followed by cyclization to benzocyclobutanone imines which fragment to the title products.     

Reaction of nitriles of enyne acids with hydrazines. synthesis of cyano derivatives of 2-pyrazolines

The reaction of nitriles of enyne acids with hydrazine, alkylhydrazines, and phenylhydrazine gives 5-cyanomethyl-2-pyrazolines. The possible mechanism of the cyclization is examined.     

Cyclization via carbolithiation of alpha-amino alkyllithium reagents

We report a new route to tertiary alpha-amino stereocenters by sequential alkylation of alpha-amino nitriles followed by reductive lithiation of the nitrile and cyclization onto an alkene. Reductive lithiation of alpha-amino nitriles using lithium 4,4'-di-tert-butylbiphenylide (LiDBB) and subsequent intramolecular carbolithiation proceeded with modest to high diastereoselectivity to deliver cyclic or spirocyclic ring systems. The stereoselectivity of these intramolecular carbolithiations was examined using density function calculations to evaluate plausible transition state models.     

Three-component synthesis of 3,4-dihydroisoquinoline derivatives

A simple and convenient method for the synthesis of 1-substituted 3,3-dimethyl-3,4-dihydroisoquinolines was developed. The method is based on the [2+2+2] cyclization of alkyl- or alkoxybenzenes with isobutyraldehyde and nitriles.     

Reductive cyclization of delta-hydroxy nitriles: a new synthesis of glycosylamines

[reaction: see text] The stereoselective cyclization of delta-hydroxy nitriles to afford N,O-acetals and the application of this reaction toward the synthesis of glycosylamines is described.     

Synthesis of 2-substituted benzothiazoles via the Brønsted acid catalyzed cyclization of 2-amino thiophenols with nitriles

A convenient and efficient method for the synthesis of 2-substituted benzothiazoles from simple and readily available 2-amino thiophenols and nitriles is described. The Brønsted acid-catalyzed cyclization reaction was performed under metal and solvent-free conditions.     

o-Benzenedisulfonimide as a Recyclable Homogeneous Organocatalyst for an Efficient and Facile Synthesis of 4-Amidotetrahydropyran Derivatives Through Prins–Ritter Reaction

A highly diastereoselective synthesis of 4-amidotetrahydropyran derivatives has been achieved using a catalytic amount of o-benzenedisulfonimide under mild conditions involving sequential allylation and Prins–Ritter amidation. The oxo-carbenium ion formed in Prins cyclization could be successfully trapped with nitriles through Ritter amidation. The catalyst is highly efficient in promoting both allylation and Prins cyclization with a net addition of nitrile. The catalyst can be easily recovered and reused in subsequent reactions.     

Parallel synthesis enablement of 2-pyridyl-5-cyano-pyrimidine-6-ones—a novel class of HIF-hydroxylase inhibitors

The synthesis of various substituted 2-pyridyl-5-cyano-pyrimidine-6-ones was accomplished via a three-step protocol. The key aspects of this parallel protocol was the preparation of amidines from nitriles under mild conditions followed by cyclization with ethyl (ethoxymethylene)cyanoacetate.     

Palladium- and nickel-catalyzed intramolecular cyanoboration of alkynes

Intramolecular addition of a boron-cyano bond across a carbon-carbon triple bond was achieved using palladium and nickel catalysts. Cyano(diisopropylamino)boryl homopropargyl ethers underwent regio- and stereoselective 5-exo cyclization, forming five-membered cyclic boryl ethers in high yields. The cyanoboration products thus obtained served as new precursors for the synthesis of highly substituted alpha,beta-unsaturated nitriles via transition-metal-catalyzed transformations.     

A novel modification of the Ritter reaction: stereoselective synthesis of bridgehead-fused Δ2-norbornanethiazolines from thiocamphor and thiofenchone

An easy two-step route for the stereoselective synthesis of novel bridgehead-fused norbornanethiazolines from readily available natural camphor and fenchone is described. The key step of the synthetic route is the highly stereoselective trapping of 1-(trifluoromethylsulfonylthio)-2-norbornyl cations by nitriles followed by intramolecular cyclization, which constitutes a new modification of the Ritter reaction.     

Carbopalladation of nitriles: synthesis of benzocyclic ketones and cyclopentenones via Pd-catalyzed cyclization of omega-(2-iodoaryl)alkanenitriles and related compounds

An efficient procedure for the synthesis of 2,2-disubstituted benzocyclic ketones by intramolecular carbopalladation of nitriles has been developed. The cyclization of substituted 3-(2-iodoaryl)propanenitriles affords indanones in high yields. The reaction is compatible with a wide variety of functional groups. This methodology has been extended to the synthesis of tetralones and cyclopentenones.     

Total synthesis of lepadiformine alkaloids using N-Boc α-amino nitriles as trianion synthons

Lepadiformine A, B, and C were synthesized in an enantiomerically pure form using a reductive cyclization strategy. N-Boc α-amino nitriles were deprotonated and alkylated with enantiomerically pure dibromides to afford the first ring. The products were manipulated to introduce phosphate leaving groups, and subsequent reductive lithiation followed by intramolecular alkylation formed the second ring with high stereoselectivity. The third ring was formed by intramolecular displacement of a mesylate by the deprotected amine. Lepadiformine A and B contain a hydroxymethyl group adjacent to the amine. This appendage was introduced in a sequence using a Polonovski-Potier reaction as the key step. The synthetic strategy is stereoselective and convergent and demonstrates the utility of N-Boc α-amino nitriles as linchpins for alkaloid synthesis.