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Fraser F Fleming

Publications and source records attributed to Fraser F Fleming.

18 recordsLinked to original sources
PubMed2006

Oxonitriles: a grignard addition-acylation route to enamides.

[reaction: see text] Sequential addition of three different Grignard reagents and pivaloyl chloride to 3-oxo-1-cyclohexene-1-carbonitrile installs four new bonds to generate a diverse array of cyclic enamides. Remarkably, formation of the C-magnesiated nitrile intermediate is followed by preferential acylation by pivaloyl chloride rather than consumption by an in situ Grignard reagent. Rapid N-acylation of the C-magnesiated nitrile generates an acyl ketenimine that reacts readily with Grignard reagents or a trialkylzincate, effectively assembling highly substituted, cyclic enamides.

Acylation↗
PubMed2006

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.

Journal Article↗
PubMed2006

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.

Acylation↗
PubMed2005

Cyclic nitriles: diastereoselective alkylations.

[reaction: see text] Diastereoselective alkylations of metalated conformationally locked 4-tert-butylcyclohexanecarbonitrile are highly diastereoselective with magnesium and copper counterions but only modestly diastereoselective with lithium as the counterion. Selective generation of diverse metalated nitriles is readily achieved through bromine-magnesium, -copper, and -lithium exchange reactions of the corresponding bromonitrile or, for lithium, by deprotonating the parent nitrile with lithium diethylamide. Collectively, high alkylation stereoselectivities correlate with the retentive alkylations of C-metalated nitriles, whereas N-lithiated nitriles alkylate with modest selectivity, reflecting minimal steric differences in the corresponding axial and equatorial electrophile trajectories.

Journal Article↗
PubMed2005

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.

Copper↗
PubMed2005

Metalated nitriles: electrophile-dependent alkylations.

[reaction: see text] Sequential carbonyl addition-conjugate addition to oxonitriles generates a C-magnesiated nitrile exhibiting electrophile-dependent alkylation stereoselectivities. Alkylations with alkyl halides, sulfonates, and ketones proceed with retention of stereochemistry, whereas aldehyde and acyl cyanide acylations proceed with inversion of stereochemistry. BuLi-initiated conversion of the C-magnesiated nitrile to the corresponding N-lithiated nitrile reverses the alkylation stereoselectivity, providing a facile route to diastereomeric nitriles that vary at a single, quaternary stereocenter.

Aldehydes↗
PubMed2004

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.

Journal Article↗
PubMed2003

Cyclic alkenenitriles: synthesis, conjugate addition, and stereoselective annulation.

O-Alkylation of unsaturated silyl cyanohydrins with DMSO-Ac2O triggers a rearrangement to methylthiomethyl-protected hydroxyalkenenitriles that are easily hydrolyzed for subsequent annulations with omega-chloroalkyl Grignard reagents. Deprotonating the gamma-hydroxyalkenenitriles with t-BuMgCl followed by addition of omega-chloroalkyl Grignard reagents triggers a conjugate addition-alkylation sequence leading exclusively to cis-octalins, hydrindanes, and decalins. Stereoelectronic control favors an axial conjugate addition leading to a particularly reactive conformer that rapidly cyclizes to cis-fused bicyclic nitriles, whereas generating the ring-flipped conformer, through a stepwise sequence, allows access to the diastereomeric trans-decalin. Collectively, the rearrangement-annulation sequence represents the first general annulation of alkenenitriles to assemble diverse bicyclic nitriles with complete control over the two newly installed stereocenters.

Alkenes↗
PubMed2003

Hydroxy alkenenitriles: diastereoselective conjugate addition-alkylations.

Chelation-controlled conjugate addition of Grignard reagents to cyclic and acyclic gamma-hydroxyalkenenitriles stereoselectively generates beta-substituted hydroxynitriles. t-BuMgCl-induced deprotonation of gamma-hydroxyalkenenitriles followed by chloride-alkyl exchange from a second Grignard reagent, generates an alkylmagnesium alkoxide that triggers conjugate addition. Alkylation of the resulting magnesiated nitrile with alkyl halide and carbonyl electrophiles efficiently installs two new bonds and up to three stereocenters in a single synthetic operation.

Alkenes↗
PubMed2003

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.

Alkylation↗
PubMed2002

Cyclic alkenenitriles: chemoselective oxonitrile cyclizations.

Potassium tert-butoxide triggers the chemoselective cyclization between nitrile anions and remote, enolizable carbonyl groups, despite the acidity difference favoring enolate formation and addition to the nitrile group. Domino deprotonation, cyclization, and dehydration efficiently transform a diverse array of omega-oxonitriles into carbocyclic and heterocyclic five- and six-membered alkenenitriles in a single synthetic operation.

Journal Article↗
PubMed2002

Gamma-hydroxy-alpha,beta-alkenenitriles: chelation-controlled conjugate additions.

Temporarily anchoring Grignard and organolithium reagents to gamma-hydroxy-alpha,beta-alkenenitriles promotes efficient conjugate additions to what are otherwise recalcitrant Michael acceptors. Sequential deprotonation and addition of a modest excess of a second Grignard reagent allows effective conjugate delivery of alkyl groups to cyclic and acyclic alkenenitriles. Mechanistically, conjugate additions proceed through alkylmagnesium alkoxide complexes for all but the more substituted alkenenitriles that require alkyl transfers from the more reactive ate complexes. Synthetically, chelation-controlled conjugate additions rapidly, and stereoselectively, assemble substituted nitriles, installing up to two new stereocenters in a single synthetic operation.

Alkenes↗
PubMed2002

Alkenenitriles: annulations with omega-chloro Grignard reagents.

[reaction: see text] omega-Chloro Grignard reagents chelate with cyclic gamma-hydroxy-alpha,beta-alkenenitriles to trigger a conjugate addition-alkylation annulation. The chelation-controlled conjugate addition-alkylation is the first anionic annulation with alpha, beta-alkenenitriles, providing cis bicyclo[3.3.0]octane, hydrindane, and decalin ring systems in a single synthetic operation.

Alkenes↗
PubMed2002

Unsaturated nitriles: stereoselective MgO eliminations.

Alpha,beta-unsaturated nitriles are readily synthesized by eliminating MgO from beta-hydroxynitriles. Deprotonating acyclic, and cyclic, beta-hydroxynitriles with excess MeMgCl smoothly generates dianion intermediates that eject MgO with concurrent formation of alpha,beta-unsaturated nitriles. Alternatively, sequential addition of lithioacetonitrile and MgBr(2) to aldehydes and ketones generates magnesium alkoxides in situ that eliminate MgO upon addition of MeMgCl. The MeMgCl-induced MgO eliminations smoothly generate alpha,beta-unsaturated nitriles from hindered ketones that are otherwise difficult to synthesize.

Aldehydes↗
PubMed2002

Nitrile anions: solvent-dependent cyclizations.

Extensive cyclizations in hydrocarbon and polar solvents demonstrate a profound solvent sensitivity for intramolecular nitrile anion alkylations. S(N)i cyclizations enforce very precise steric constraints in the transition state, allowing correlation of the cyclization stereochemistry with the orbital orientation of the nitrile anion. Collectively the cyclizations suggest a continuum of nitrile anion transition states, varying from planar to fully pyramidal, that selectively cyclize to cis- and trans-decalins, respectively.

Anions↗
PubMed2002

Alkynenitriles: chelation-controlled conjugate additions.

[reaction: see text] Chelation between gamma-hydroxybutynenitrile and Grignard reagents triggers a particularly facile anionic conjugate addition reaction. Structurally diverse Grignard reagents add with equal efficiency, providing an intermediate anion that stereoselectively alkylates benzaldehyde in an overall addition-alkylation reaction.

Alkynes↗