N-[1-(Benzotriazol-1-yl)alkyl]amides from N-acyl-α-amino acids or N-alkylamides

A variety of N-(1-methoxyalkyl)amides react with benzotriazole in the presence of PPh₃·HBF₄ and organic bases (Hünig's base, DBU or DABCO) or solid-state-supported bases (SiO₂-Pip or IRA-67) in CHCl₃ to give N-[1-(benzotriazol-1-yl)alkyl]amides in good yields. The most convenient and efficient procedure for obtaining N-[1-(benzotriazol-1-yl)alkyl]amides consists, however, of the addition of benzotriazole sodium salt to a solution of crude 1-(N-acylamino)alkyltriphenylphosphonium salt, obtained in situ from N-(1-methoxyalkyl)amides and PPh₃·HBF₄. A combination of these reactions with the recently described electrochemical decarboxylative α-methoxylation of N-acyl-α-amino acids in the presence of SiO₂-Pip enables an effective two-pot transformation of N-acyl-α-amino acids to N-[1-(benzotriazol-1-yl)alkyl]amides.     

A novel strategy toward the synthesis of N-(β-glycosyl)asparagines based on the alkylation of ethyl nitroacetate using N-(β-glycosyl)iodoacetamides

A conceptually novel strategy has been developed for the synthesis of N-(β-glycosyl)asparagine precursors in good yield by the alkylation of ethyl nitroacetate using six per-O-acetylated N-(β-glycosyl)iodoacetamides derived from mono- and disaccharides. The use of a chiral organocatalyst, N-(9-anthracenylmethyl)cinchoninium chloride (10 mol %), resulted in diastereoselective alkylation up to 64% de. Single crystal structure analysis of the purified major diastereomer of the Glc derivative revealed an absolute configuration of S at the α-carbon of the monosubstituted ethyl nitroacetate which is a precursor of the l-asparagine conjugate.     

Regioselective halogenation of pyridinium N-(benzoazynyl) aminides as a way to produce N-benzyl-α-aminobenzoazines

The halogenation of pyridinium N-(benzoazynyl) aminides with N-halosuccinimides provides a mild and regioselective method to functionalize the negatively charged diazine moiety in most cases. In some examples, however, formation of other products is explained. Finally, alkylation of the exocyclic nitrogen and reduction of the N–N bond provides a simple and straightforward strategy to obtain functionalized N-benzyl-benzoazynyl-α-amines.     

DABCO/AgOAc cooperatively catalyzed α-sulfenylation of isocyanoacetates with N-(sulfanyl)succinimides

The first organo/metal cooperatively catalyzed α-sulfenylation of isocyanoacetates with N-(sulfanyl)succinimides has been developed. The reaction condition was suitable to α-aryl and alkyl-substituted isocyanoactates as well as N-(arylthio)succinimides, affording the corresponding products with high yields (90–96%). Preliminary asymmetric organocatalysis has also been evaluated.     

Diastereocontrolled addition of organometallic reagents to S-chiral N-(tert-butanesulfinyl)-α-fluoroenimines

Grignard and organolithium reagents efficiently react with (S)-N-(tert-butanesulfinyl)-α-fluoroenimines to provide chiral allylamines in excellent yields and with diastereomeric ratios of up to 96:4. Acidic removal of the sulfinyl group and simple functional group transformations allow to get enantiopure fluoroolefin dipeptide mimics.     

Synthesis of novel glycolipids derived from glycopyranosyl azides and N-(β-glycopyranosyl)azidoacetamides

A general and expedient method based on a click reaction has been developed for the synthesis of novel glycolipids. The Cu(I) catalyzed [3+2] cycloaddition of several fully acetylated β- as well as α-d-glycopyranosyl azides, including the 1,6-diazide derived from d-glucose, with long chain alkyl propargyl ethers gave the respective 1,4-substituted 1,2,3-triazole derivatives in good yields. Treatment of fully acetylated N-(β-glycopyranosyl)azidoacetamides under similar conditions with alkyl propargyl ethers afforded the 1,2,3-triazolylacetamido derivatives in fairly good yields. Zemplen de-O-acetylation of all the fully acetylated derivatives furnished the free glycolipids in quantitative yields.     

Highly enantioselective α-sulfenylation of 5H-oxazol-4-ones to N-(sulfanyl)succinimides

An unprecedented asymmetric α-sulfenylation of 5H-oxazol-4-ones to N-(sulfanyl)succinimides has been established, to access various α-sulfenylated adducts with good to excellent enantioselectivities (86–95% ee) by utilizing a cinchona alkaloid-derived squaramide as catalyst. The conditions of this α-sulfenylation protocol simultaneously satisfy N-(arylthio)succinimides, N-(benzylthio)succinimides, and N-(alkylthio)succinimides by tuning the substituted groups of 5H-oxazol-4-ones on the 2-position as well as additives.     

Orthoamides by selective borohydride reduction of N,N′,N″-triacyl- and N,N′,N″-tri(alkoxycarbonyl)-guanidines

N,N′,N″-Triacylguanidines and N,N′,N″-tri(alkoxycarbonyl)guanidines were prepared and reduced with borohydride salts in a mixture of tetrahydrofuran and acetic acid to give triacyl and tri(alkoxycarbonyl) orthoamides in yields of 40–85%. However, similar reduction of N,N′,N″-tri(t-butoxycarbonyl)guanidine did not give orthoamide but the aminal di(t-butyl) methylenedicarbamate.     

Synthesis of novel α-CF3-trifluoroalanine derivatives containing N-(diethoxyphosphoryl)difluoroacetyl group

An efficient synthesis of biologically interesting α-CF₃-trifluoroalanine derivatives bearing N-(diethoxyphosphoryl)difluoroacetyl moiety in good yields has been elaborated. The key substrate, α-TFM-imino ester, prepared from methyl trifluoropyruvate and (diethoxyphosphoryl)difluoroacetamide, followed by dehydration, was subjected to regiospecific reactions with various nucleophiles, including organometallic, π-donor compounds and sodium borohydride. These novel products may find a viable application in the modification of peptides or serve as potential drug candidates.     

Synthesis of 2-(N-arylimino-κN-methyl)pyrrolide-κN complexes of nickel

2-(N-aryliminomethyl)pyrrole precursors (2,6-R₂-C₆H₃-NCH-2-C₄H₃NH) (R = Me, IH; R = ⁱPr, IIH) were prepared and transformed into their corresponding sodium salts (Na⁺I⁻ and Na⁺II⁻) by treatment with NaH. Both salts readily react with [NiBr₂(DME)] (DME = 1,2-dimethoxyethane) to give the respective bis{2-(N-arylimino-κN-methyl)pyrrolide-κN}nickel(II) complexes (1, 2) in almost quantitative yields. The oxidative addition of IH to [Ni(COD)₂] (COD = 1,5-cyclooctadiene) results in the formation of 3, which is a mono(iminomethylpyrrolide)-η³-(cyclic-allyl)-type organonickel(II) complex. The crystal structure of compound 1 has been established by X-ray diffraction studies.     

N-(α-Amidoalkyl)benzotriazole-mediated synthesis of β′-amido β-diketones: a general synthetic protocol for N-[β-(3,5-di and 1,3,5-trisubstituted pyrazol-4-yl)alkyl] amides

Various β′-amido-β-diketones were first synthesized with N-(α-amidoalkyl)benzotriazole-mediated amidoalkylation of 1,3-diketones in moderate yields. These intermediates undergo rapid condensation with hydrazines to give the corresponding N-[β-(3,5-di and 1,3,5-trisubstituted pyrazol-4-yl)alkyl]amides.     

A simple one-pot 2-step N-1-alkylation of indoles with α-iminoketones toward the expeditious 3-step synthesis of N-1-quinoxaline-indoles

A straightforward procedure for the preparation of N-quinoxaline-indoles is presented. A base-catalyzed one-pot addition of indoles to a preformed α-iminoketone proceeds on the N-1 indole and the subsequent adduct undergoes an acid-mediated deprotection of an internal amino nucleophile, intramolecular cyclization, and final oxidation generating N-1-quinoxaline-indoles in good yield.     

Stereoselective tribromomethylation of N-(tert-butanesulfinyl)imines with bromoform: practical synthesis of α-tribromomethyl amines

The unprecedented nucleophilic tribromomethylation of N-(tert-butanesulfinyl)imines with bromoform has been shown to be a highly stereoselective and practical method for the synthesis of enantiomerically pure α-tribromomethyl amines. THF has proven to be the best solvent in this addition reaction. By changing the reaction solvent from THF to DMF, 2,2-dibromoaziridines can also be synthesized directly from bromoform and N-(tert-butanesulfinyl)imines under similar reaction conditions.     

Conjugate addition of lithium N-tert-butyldimethylsilyloxy-N-(α-methylbenzyl)amide: asymmetric synthesis of β-trisubstituted amino acids

Conjugate addition of the homochiral ammonia equivalent lithium N-tert-butyldimethylsilyloxy-N-(α-methylbenzyl)amide to a range of α,β-unsaturated esters gives the corresponding β-amino esters in moderate to good levels of diastereoselectivity. O-Desilylation and cyclisation furnishes homochiral isoxazolidin-5-ones in >99:1 dr after purification. Sequential alkylation of these templates proceeds to give the corresponding 3,4-anti-disubstituted and 3,4,4-trisubstituted derivatives as single diastereoisomers after purification. The first alkylation occurs with high levels of diastereoselectivity on the face of the enolate anti to the C(3)-substituent, whereas the facial selectivity of the second alkylation is governed by a chiral relay effect, which depends upon the relative steric bulk of both the C(3)- and C(4)-substituents. Subsequent hydrogenolysis promotes cleavage of both the N-α-methylbenzyl group and the N-O bond within the isoxazolidin-5-one ring in one pot to give the corresponding β^2,2,3-trisubstituted amino acids directly.     

Oxidative ring opening of 3-hydroxyquinoline-2,4(1H,3H)-diones into N-(α-ketoacyl)anthranilic acids

N-(α-Ketoacyl)anthranilic acids were prepared by oxidative ring opening of 3-hydroxyquinoline-2,4(1H,3H)-diones by using paraperiodic acid (H₅IO₆) or sodium periodate (NaIO₄). The optimisation of the reaction conditions is described as well as the utilisation of N-(α-ketoacyl)anthranilic acids in the preparation of anthranilic acid hydrochlorides.     

Selective C-N bond oxidation: demethylation of N-methyl group in N-arylmethyl-N-methyl-α-amino esters utilizing N-iodosuccinimide (NIS)

Demethylation of N-methyl group in N-methyl-N-arylmethyl-α-amino esters was accomplished by the oxidation of the amino group using the N-iodosuccinimide (NIS)/acetonitrile system followed by treatment with O-methylhydroxylamine hydrochloride. This combination of reagents could provide a complementary method to catalytic hydrogenolysis, which certainly cleaves N-arylmethyl groups, in organic synthesis.     

Aminolithiation–arylation consecutive cyclization of N-(2-fluorophenyl)methylaminoalkylstyryls giving aryl-substituted pyrido[1,2-b]isoquinolines

Aminolithiation–arylation tandem cyclization of N-(2-fluorophenyl)methylaminoalkylstyryls proceeded smoothly to give hexahydro-2H-pyrido[1,2-b]isoquinoline using a stoichiometric amount of n-BuLi with high trans selectivity. The arylation reaction was highly accelerated by the addition of HMPA. Both pyrido- and pyrrolo-[1,2-b]isoquinoline were successfully constructed by this tandem reaction.     

Bromophilic substitution/carbophilic substitution cascade reactions of α,α-dibromo-2-methoxyacetophenone with C-, N- and O-nucleophiles

α,α-Dibromo-2-methoxyacetophenone reacts, under mild reaction conditions, with C-, N- and O-nucleophiles via a bromophilic substitution/protonation/carbophilic substitution cascade process to afford α-monosubstituted-2-methoxyacetophenones in moderate to good yield. The only exception from this reaction pathway is the reaction with the anion derived from malononitrile in which 2-aroyl-1,1,3,3-tetracyanopropene is obtained.     

Versatile synthesis of 4-spiro-β-lactam-3-carbonitriles via the intramolecular nucleophilic cyclization of N-(p-hydroxyphenyl)cyanoacetamides

A series of 4-spiro-cyclohexadienonyl-β-lactam-3-carbonitriles, 2,7-dioxo-1-azaspiro[3.5]nona-5,8-diene-3-carbonitriles, was synthesized in satisfactory to excellent yields via the intramolecular nucleophilic cyclization of N-(p-hydroxyphenyl)cyanoacetamides with iodobenzene diacetate (IBD) as oxidant and potassium hydroxide as base. Acetic 4-spiro-cyclohexadienonyl-β-lactam-3-carbimidic anhydrides were obtained when organic base triethylamine was applied instead of potassium hydroxide. The mechanisms of the intramolecular nucleophilic cyclization and formation of acetic β-lactam-3-carbimidic anhydrides were proposed. The cyclization is a sequence of nucleophilic ipso addition and oxidative dearomatization. The formation of acetic carbimidic anhydrides is an acid-catalyzed acetate addition to the nitriles.