Thermal reactions of N‐alkyl‐2‐benzylaniline and N‐alkyl‐N′‐phenyl‐o‐phenylenediamine: An unusual route to 2‐phenylindole and 2‐phenylbenzimidazole

Thermal cyclization reactions of N‐alkyl‐2‐benzylaniline 1a‐d and N‐alkyl‐N′‐phenyl‐o‐phenylenediamine 2a‐b were carried out expecting to get seven‐membered heterocyclic compounds. However, the results show that aside from the formation of the normally expected six‐membered ring products of acridine 5 , anthracene 6 , and phenazine 8 , thermal cyclization of N‐alkyl‐2‐benzylaniline and N‐alkyl‐N′‐phenyl‐o‐phenylenediamine also resulted to the unexpected formation of 2‐phenylindole 3 and 2,3‐diphenylindole 4 , and 2‐phenylbenzimidazole 7 , respectively.     

Base‐Catalyzed Highly Stereoselective Conversion of γ‐Hydroxy‐α,β‐acetylenic Esters to γ‐Acetoxy Dienoates

A convenient route with high stereo control to γ‐acetoxy dienoates is provided by the reaction of methyl propiolate with aldehydes in the presence of ZnEt₂ and N‐methylimidazole at room temperature, followed by the catalytic conversion of the resulting γ‐hydroxy‐α,β‐acetylenic esters with p‐N,N‐dimethylaminopyridine (DMAP) in acetic anhydride (see scheme).

     

An interesting cyclization of N‐methyl‐3‐phenyl‐N‐(2‐(Z)‐phenylethenyl)‐cis‐oxiranecarboxamide

Under Lewis acid condition, N‐methyl‐3‐phenyl‐N‐(2‐(Z)‐phenylethenyl)‐cis‐oxiranecarboxamide undergoes elegant double cyclizations to give interesting products.     

Facile synthesis of N‐α‐boc‐1,2‐dialkyl‐l‐histidines: Utility in the synthesis of thyrotropin‐releasing hormone (trh) analogs and evaluation of the cns activity

A facile synthesis of N‐α‐Boc‐1,2‐dialkyl‐L‐histidines starting from N‐α‐trifluoroacetyl‐L‐histidine methyl ester is reported. The key steps involve direct and regiospecific N‐1(τ) ring‐alkylation of the N‐α‐trifluoroacetyl‐L‐histidine‐methyl ester by suitable alkyl iodide in the presence of NaH in DMF at ?15 °C followed by homolytic free radical C‐2 alkylation via a silver catalyzed oxidative decarboxylation of alkylcarboxylic acid in the presence of ammonium persulfate under acidic conditions. The application of newly synthesized bioimidazoles was illustrated by their incorporation into thyrotropin‐releasing hormone (TRH). The synthesized TRH analogs were evaluated in vivo for analeptic activity. We report discovery of a TRH analog, which was found to potentiate the pentobarbital‐induced sleep in vivo.     

N‐[(Diphenoxyphosphoryl)oxy]‐2‐phenyl‐1H‐benzimidazole as a versatile reagent for synthesis O‐alkylhydroxamic acids

Highly efficient reagent, N‐[(diphenoxyphosphoryl)oxy]‐2‐phenyl‐1H‐benzimidazole was synthesized and its applicability was demonstrated for the synthesis of O‐alkyl hydroxamic acids. The efficiency of the reagent was evaluated through the synthesis of range of O‐alkyl hydroxamic acids from aromatic carboxylic acids as well as N‐protected amino acids. The enatiomeric purity of synthesized compounds was measured using chiral HPLC and the degree of racemization that occurred was found to be negligible.     

N‐alkyl‐4‐chloro‐1H‐benzo[c][1,2]thiazine‐3‐carbaldehyde‐2,2‐dioxides—New functional benzothiazine derivatives

A synthesis of N‐alkyl‐4‐chloro‐1H‐benzo[c][1,2]thiazine‐3‐carbaldehyde‐2,2‐dioxides is described. Reactivity of new β‐chloroaldehydes is investigated, a number of novel benzo[c][1,2]thiazine derivatives are synthesized and characterized using ¹H, ¹³C‐NMR, MS and elemental analysis.     

Claisen Condensation of N‐Methylpyrrolidinone and α‐Chloronicotinic esters

Reaction between α‐halo‐nicotinic esters and a nucleophilic source such as the N‐methylpyrrolidin‐2‐one (NMP) gave unexpected results. The presence of the halide on the pyridine gave a very interesting migration reaction. Extension to 6‐methylnicotinic ester derivatives lead to an unexpected carbanion condensation.     

Asymmetric alkylation of N‐acylisoindolin‐1‐ones via α‐bromoimides: A novel route to 1‐substituted isoindolines

Key intermediate in the synthesis of the title compounds 9a‐c and 10a‐c was the chiral α‐bromoimide 1 which has been prepared by radical bromination of the corresponding N‐acylisoindolin‐1‐one 13. 1 was alkylated with silyl enol ethers under Lewis acid catalysis using α‐amidoalkylation methodology. N,N‐diacyliminium ion 14 is presumably the intermediate in this reaction. Further transformations of the alkylated compounds yielded 1‐substituted isoindolines as target compounds.     

N‐Heterocyclic Carbene Gold(I) Catalyzed Transformation of N‐Tethered 1,5‐Bisallenes to 6,7‐Dimethylene‐3‐azabicyclo[3.1.1]heptanes

Tying up loose ends : The reaction of bisallenes tethered with N‐(p‐tolylsulfonamide) in the presence of a cationic gold N‐heterocyclic carbene catalyst gave new cycloisomerization products, 6,7‐dimethyleneazabicyclo[3.1.1]heptanes, in high yields (see scheme; IPr=N,N′‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene).

     

Supramolecular Complexation of N‐Alkyl‐ and N,N′‐Dialkylpiperazines with Cucurbit[6]uril in Aqueous Solution and in the Solid State

Water seeds : Complex stoichiometry/composition and degree of oligomerization (oligomeric supramolecular complex formation) of cucurbit[6]uril (CB[6]) with N‐alkyl‐ and N,N′‐dialkylpiperazine were investigated in aqueous solutions by means of isothermal titration calorimetry (ITC), ESI‐MS, NMR and light scattering measurements.

     

Towards the syntheses of N‐H and N‐alkylated derivatives of meridianins

Novel N‐H and N‐alkylated derivatives of meridianins have been synthesized as potential antitumor agents by a two‐step conversion of N‐tosyl‐3‐acetylindoles or N‐alkyl‐3‐acetylindoles to the corresponding enaminones using DMF‐DMA, with or without added pyrrolidine. Further cyclization with guanidine gave the corresponding 2‐aminopyrimidines. The structures of the compounds, thus obtained, were proved by ¹H and ¹³C NMR spectroscopy, NOE experiments and X‐ray analysis.     

Preparation of 2‐(1H‐pyrazol‐5‐yl)benzenesulfonamides from polylithiated C(α),N‐carbo‐tert‐butoxyhydrazones and methyl 2‐(aminosulfonyl)benzoate

Select C(α), N‐carbo‐tert‐butoxyhydrazones were dilithiated with excess lithium diisopropylamide followed by condensation with methyl 2‐(aminosulfonyl)benzoate, acid cyclization, hydrolysis, and decarboxylation to afford new 2‐(1H‐pyrazol‐5‐yl)benzenesulfonamides, [NH‐pyrazolyl‐ortho‐benzene‐sulfonamides].     

(±)‐2,3‐dialkyl‐1,2,3,4‐tetrahydroquinoline‐3‐carboxylic esters by a tandem reduction‐reductive amination reaction

A series of 2‐methyl‐2‐(2‐nitrobenzyl)‐substituted β‐keto ester derivatives has been subjected to reductive cyclization under hydrogenation conditions to assess the importance of the ester group position on the diastereoselectivity of the process. Hydrogenation over 5% palladium‐on‐carbon at 4 atmospheres pressure resulted in formation of (±)‐2,3‐dialkyl‐1,2,3,4‐tetrahydroquinoline‐3‐carboxylic esters with a preference for the product isomer having the C2 alkyl cis to the C3 ester. The product ratios were synthetically useful (6‐16:1), but less than that observed in cyclizations to prepare (±)‐2‐alkyl‐1,2,3,4‐tetrahydroquinoline‐4‐carboxylic esters. The reduced selectivity in the current reactions has been rationalized in terms of the greater conformational mobility around the ester bearing carbon, which decreases the ability of the ester to sterically influence the addition of hydrogen to the final imine intermediate.     

Cyclization of dialkylpropyn‐1‐yl(allyl)(3‐isopropenylpropyn‐2‐yl)ammonium bromides and water‐base cleavage of 2,2‐dialkyl‐5‐methyl‐2,6,7,7a‐tetrahydro‐1h‐isoindolium and 2,2‐dialkyl‐5‐methylisoindolinium bromides

Dialkylpropyn‐1‐yl(or allyl)(3‐isopropenylpropyn‐2‐yl)ammonium bromides under base‐catalyzed condition instantly undergo intramolecular cyclization. The cyclization of dialkylpropyn‐1‐yl(3‐isopropenylpropyn‐2‐yl)ammonium bromides leads to the formation of 2,2‐dialkyl‐5‐methylisoindolinium salts. In case of allyl analogs, instead of the expected 2,2‐dialkyl‐6‐methyl‐3a,4‐dihydroisoindolinium salts their isomeric forms ‐ 2,2‐dialkyl‐5‐methyl‐2,6,7,7a‐tetrahydro‐1H‐isoindolium bromides are obtained. In alkaline medium they are transform into the dihydroisoindolinium salts, the cleavage of which in two directions ‐ 1,2 and 1,6 leads to the mixture of isomeric dialkyl‐1,4‐dimethyl‐ and 2,4‐dimethylbenzyl‐amines. Study of the behavior of 2,2‐dialkyl‐5‐methylisoindolinium salts under conditions of water‐base cleavage showed, that only spiro[5‐methylisoindolyn]morpholinium bromide undergoes 1,2‐elimination, forming 5‐methylisoindoline 2‐vinyl ethyl ester.     

Synthesis and characterization of a novel heterocycle: 1‐Substituted‐4‐arylazamethylene‐6‐arylpyrazolo[5,4‐d]‐1,3‐oxazine

A series of novel heterocycles 1‐aryl‐ or alkyl‐substituted‐4‐arylazamethylene‐6‐arylpyrazolo[5,4‐d]‐1,3‐oxazines were synthesized from the acylation of (5‐amino‐1‐substituted‐pyrazol‐4‐yl)‐N‐carboxamide in 63‐89% isolated yields at room temperature within 12 hours. The structure was confirmed by X‐ray crystal analysis.     

Novel azaandrostane derivatives for the synthesis of 17β‐(N‐tert‐butyl carbamoyl)‐4‐aza‐5α‐androst‐1‐ene‐3‐one

A new industrially viable process for the preparation of 1β‐(N‐tert‐butyl carbamoyl)‐4‐aza‐5α‐androst‐1‐ene‐3‐one, also known by the generic name finasteride ( 6 ) from the new azaandrostane derivatives such as 1β‐(N‐tert‐butyl carbamoyl)‐4‐benzoyl‐4‐aza‐5α‐androstane‐3‐one ( 4 ), 1β‐(N‐tert‐butyl carbamoyl)‐4‐benzoyl‐4‐aza‐5α‐androst‐1‐ene‐3‐one ( 5 ) is reported. In this process, benzoyl group is demonstrated as a novel protecting group for lactamic NH group. The structures of newly prepared compounds were established on the basis of spectral data (IR, ¹H‐NMR, and MS).     

Synthesis of α‐diaminomethylenebutyrolactams by the reaction of α‐cyanobutyrolactams with n‐trimethylsilylamines

Successive treatment of α‐cyanobutyrolactams 1 with N‐trimethylsilylamines and water gave the corresponding α‐diaminomethylenebutyrolacatms 2 in good yields. In the NOESY spectra of 2 , the E isomer, the NOE observed between β‐CH₂ (butyrolactam) and N‐CH₂ (morpholine, pyrrolidine) or N‐CH₃ (dimethylamine) indicated a cis configuration of these groups.     

Synthesis and characterization of some novel 2‐{2‐[1‐(3‐substituted‐phenyl)‐1H‐1,2,3‐triazol‐4‐yl‐] ethyl}‐1‐substituted‐1H‐benzo [d] imidazole derivatives

Synthesis of some novel 2‐{2‐[1‐(3‐substitutedphenyl)‐1H‐1,2, 3‐triazol‐4‐yl‐]ethyl)‐1H‐benzo[d]‐imidazole derivatives, by the condensation of o‐phenylenediamine with 3‐(1‐(3‐substituted‐phenyl)‐1H‐1,2,3‐triazol‐4‐yl) propanoic acid and then subsequent reactions with different substituted alkyl halides as electrophiles are mentioned. The synthesized compounds were characterized by ¹H NMR, EI‐MS and IR spectroscopic techniques.     

Synthesis of 5,6,7,8‐tetrahydroindolizines via a domino‐type transformation based on the rhodium catalyzed hydroformylation of N‐(β‐methallyl)pyrroles

Variously substituted 5,6,7,8‐tetrahydroindolizines can be easily synthesized via a domino reactions sequence under rhodium catalyzed hydroformylation of N‐(β‐methallyl)pyrroles. The later are readily prepared from properly functionalized pyrroles via phase‐transfer N‐allylation in the presence of 18‐crown‐6 and potassium tert‐butoxide.     

Synthesis of new 1‐[4‐methane(amino)sulfonylphenyl)]‐5‐[4‐(aminophenyl)]‐3‐trifluoromethyl‐1H‐pyrazoles

A regiospecific cyclization‐dehydration reaction of a 1‐[(4‐(N‐alkyl‐N‐(tert‐butyloxycarbony)amino)‐phenyl]‐4,4,4‐trifluorobutane‐1,3‐done with a 4‐aminosulfonyl‐, or 4‐methylsulfonyl‐, phenylhydrazine hydrochloride in refluxing ethanol proceeded with simultaneous loss of the N‐tert‐butyloxycarbonyl protecting group to afford a group of 1‐(4‐methanesulfonylphenyl or 4‐aminosulfonylphenyl)‐5‐[4‐(N‐alkylaminophenyl)]‐3‐(trifluoromethyl)‐11H‐pyrazoles(6). Subsequent reaction of the pyrazole 6 (R¹ = R² = Me) with nitric oxide (40 psi) proceeded via a N‐methylamino‐N‐diazen‐1‐ium‐1,2‐diolate intermediate that undergoes protonation of the more basic diazen‐1‐ium‐1,2‐diolate N²‐nitrogen and then loss of a nitroxyl (HNO) species to furnish the N‐nitroso product 7.