Efficient synthesis of 5′-O(N)-carbamyl and -polycarbamyl nucleosides

A simple and efficient method for the preparation of 5′-O(N)-carbamyl and 5′-O(N)-polycarbamyl nucleoside derivatives is reported. The method consisted of treatment of 2′,3′-O-protected purine (Ado, Ino) or pyrimidine nucleosides (Thd, Urd) with trichloroacetylisocyanate, followed by cleavage of the trichloroacetyl moiety by silica-gel promoted methanolysis during column chromatography. Iterative application of this method gave mono, di, and tricarbamyl derivatives in good to excellent yields (ave = 80%).     

PTSA catalyzed straightforward protocol for the synthesis of 2-(N-acyl)aminobenzimidazoles and 2-(N-acyl)aminobenzothiazoles in PEG

An efficient PTSA catalyzed synthesis of 2-(N-acyl)aminobenzimidazoles and 2-(N-acyl)aminobenzothiazoles has been described using S-ethylated-N-acylthioureas as substrates and polyethylene glycol as solvent.     

New approach to preparation of N-acylphosphoramido(thio)(seleno)ates

N-[2-(X)-1,3,2-Oxathiaphospholane] derivatives (X = S, Se, O) of carboxamides were prepared and their DBU-assisted reaction with alcohols led to the corresponding O-alkyl-N-acylphosphoramido(thio)(seleno)ates. Their structures were confirmed by MS analysis and ¹H and ³¹P NMR spectroscopy. Independently N-acylphosphoramidoselenoates were converted to N-acylphosphoramidates by treatment with tert-butylperoxytrimethylsilane. The oxathiaphospholane approach was also applied to the synthesis of derivatives having N-prolylphosphoramido(thio)(seleno)ate linkages on the 5′-OH group of AMP.     

Vinylogous N,N-dimethylaminomethylenation of 3-[(1-substituted)ethylidene]-oxindoles with N,N-dimethylformamide dimethylacetal

An efficient stereoselective synthesis of various 3-(3-dimethylaminoprop-2-enylidene)oxindoles has been disclosed. The compounds were synthesized via a vinylogous N,N-dimethylaminomethylenation at the γ-position of 3-[(1-substituted)ethylidene]oxindoles with DMF-DMA.     

Dibutylphosphate (DBP) mediated synthesis of cyclic N,N′-disubstituted urea derivatives from amino esters: a comparative study

The N,N′-disubstituted urea derivatives such as amino acid hydantoins and dihydrouracil derivatives were prepared starting from natural and unnatural amino acid esters using dibutylphosphate (DBP). During the attempted synthesis of N-heterocycles with larger than six-membered rings containing the N,N′-disubstituted urea functionalities, three unexpected products namely squamolone, N-methyl pyrrolidine-2-one, and diketopiperazine were isolated.     

N-Polyfluoro(trimethylsilyl)ethyl azole derivatives

A facile synthetic route to N-polyfluoro(trimethylsilyl)ethyl azole derivatives was developed starting from N-bromo(chloro)polyfluoroethyl-substituted azoles. The silanes thus obtained were reacted with various electrophiles in the presence of the fluoride ion to yield the corresponding fluorinated carbinols, ketones, carboxylic acids, and methyl dithiocarboxylates as well as N-pentafluoroethylbenzimidazole.     

Acylation of α-(N-carbamoyl)alkylcuprates and alkyl- or aryl(halo)cuprates

α-(N-Carbamoyl)alkylcuprates [R₂CuLi·LiX or RCuXLi (X=CN, Cl)] when prepared from THF soluble CuX·2LiCl (X=Cl, CN) undergo a reliable and generally high yield reaction with aroyl, alkanoyl, and alkenoyl chlorides to provide a rapid and efficient synthesis of α-carbamoyl ketones. Cuprates prepared from acyclic, cyclic, and a functionalized carbamate can be utilized. Although yields are a function of cuprate reagent and substrate structure, nearly quantitative yields can be obtained with reagents generated from 2RLi+CuCN·2LiCl. The use of reagents generated from CuCl·2LiCl are more efficient in the α-(N-carbamoyl)alkyl ligand, although yields are slightly lower. Acylation of alkyl(chloro)cuprates generated from one equivalent of CuCl·2LiCl and organolithium or Grignard reagents provides an efficient and high yield procedure for ketone synthesis.     

N-Polyfluoroethyl and N-2-chlorodifluorovinyl derivatives of azoles

Reactions of tetrafluoroethylene, chlorotrifluoroethylene and 1,2-dichlorodifluoroethylene with N-potassium salts of imidazole, 2-methylbenzimidazole, 3,5-dimethylpyrazole, 1,2,4-triazole, and benzotriazole lead to the formation of the corresponding N-(1,1,2,2-tetrafluoroethyl), N-(2-chloro-1,1,2-trifluoroethyl), and N-(2-chloro-1,2-difluorovinyl) azoles. Treatment of N-(2-chloro-1,2-difluorovinyl) and N-(2-chloro-1,1,2-trifluoroethyl) derivatives of azoles with tetramethylammonium fluoride is a useful synthetic method for the preparation of heterocycles with 1,2,2,2-tetrafluoroethyl group attached to nitrogen.     

Efficient preparation of (Z)-alkenyl derivatives from (Z)-vinyl (N,N-diisopropyl)carbamate via Ni-catalysed coupling reactions

A (Z)-vinyl (N,N-diisopropyl)carbamate treated with Grignard reagents, under Wenkert Nickel-catalysed conditions, gave access to several substituted (Z)-alkenyl derivatives. These Nickel-catalysed reactions, carried out with vinyl-, phenyl-, p-methoxyphenyl-, trimethylsilylmethylmagnesium bromide and benzylmagnesium chloride, led to the corresponding (Z)-alkenyl derivatives in good yields and high stereoselectivities.     

N,N′,N″-Tri-Boc-guanidine (TBG): a common starting material for both N-alkyl guanidines and amidinoureas

In this Letter, we describe the unexpected reaction pattern of N,N′N″-tri-Boc-guanidine (TBG) with amines at room temperature and under reflux conditions affording N-substituted guanidines and amidinoureas, potentially important compounds with extensive applications in medicinal chemistry. This investigation shows that TBG is an excellent, readily available common starting material for the synthesis of various N-alkyl guanidines as well as N-alkyl-N′-substituted amidinoureas by simply manipulating the reaction conditions.     

Easy access to N-alkylation of N-unsubstituted [60]fulleropyrrolidines: reductive amination using sodium triacetoxyborohydride

[60]Fulleropyrrolidines were used as secondary amines to react with aldehydes through reductive aminations to afford N-alkylated derivatives. In spite of the very weak base activity of the nitrogen atom of N-unsubstituted [60]fulleropyrrolidines, this method was found to be efficient at the aid of sodium triacetoxyborohydride. Several N-alkylated derivatives were synthesized and fully characterized.     

Facile Cu(OTf)2-catalyzed preparation of 9-tosylaminofluorene derivatives from o-arylated N-tosylbenzaldimines

The 9-tosylaminofluorene derivatives were synthesized conveniently by Cu(OTf)₂-catalyzed aza-Friedel-Crafts reaction of o-arylated N-tosylbenzaldimines in high yields. This is an efficient, atom-economic, and green method.     

Palladium-catalyzed arylation of N,N-dialkylhydrazines and the subsequent conversion to anilines

Palladium-catalyzed aminations of different ArBr with N,N-dialkylhydrazines are described. The reaction proceeded in moderate to excellent yield (up to 90%) with good functional groups compatibilities as cyano, ester, ketone and Boc-amine groups are all well tolerated. Several hydrazines were proved to be good coupling partners and this process provided a general method for the isosteric replacement of benzyl amines with arylhydrazines. Moreover, a method for the N-N bond cleavage of arylhydrazines was discovered, and this two-step sequence could be employed as an alternative synthesis of aniline derivatives.     

N-(Diethoxyphosphoryl)-O-benzylhydroxylamine—a convenient substrate for the synthesis of N-substituted O-benzylhydroxylamines

Easily available N-(diethoxyphosphoryl)-O-benzylhydroxylamine was shown to be convenient, orthogonally protected substrate for regioselective N-alkylation by means of diverse halides under basic conditions (sodium hydride/tetrabutylammonium bromide). An efficient procedure for dephosphorylation of N-substituted N-(diethoxyphosphoryl)-O-benzylhydroxylamine to provide N-substituted O-benzylhydroxylamines was also established.     

N,N,N′-Trialkyl-1,8-diaminonaphthalenes: convenient method of preparation from protonated proton sponges and the first X-ray information

A simple procedure for the synthesis of N,N,N′-trialkyl-1,8-diaminonaphthalenes is described. It consists in partial demethylation (dealkylation) of commercially available proton sponge [1,8-bis(dimethylamino)naphthalene] and some of its derivatives at heating with HBr-KI-DMF system. Limitation, scope and a possible mechanistic pathway for the reaction are discussed. For isomeric 8-dimethylamino-1-methylamino- and 1-dimethylamino-8-methylamino-4-nitronaphthalenes, X-ray measurements have been conducted. The first examples of complete realkylation reactions in the naphthalene proton sponges are reported.     

A practical synthesis of 2-(N-substituted)-aminobenzimidazoles utilizing CuCl-promoted intramolecular cyclization of N-(2-aminoaryl)thioureas

A practical protocol for synthesis of 2-(N-substituted)-aminobenzimidazoles was developed. N-(2-Aminoaryl)thioureas undergo a CuCl-promoted intramolecular cyclization to give the corresponding 2-(N-substituted amino)benzimidazoles in good to excellent isolated yields.     

A facile procedure for synthesis of 3-[2-(N,N-dialkylamino)ethyl]-3-fluorooxindoles by direct fluorination of N,N-dialkyltryptamines

A practical procedure for the synthesis of 3-fluorooxindole derivatives having basic amine moieties was developed, which involves Selectfluor™-mediated oxidative fluorination of N,N-dialkyltryptamines in the presence of Lewis acid. This procedure was applied to an antimigraine drug, rizatriptan, to afford the corresponding 3-fluorooxindole, which is a potential fluorine-containing drug candidate.     

Oxidative entry to α-oxy N-acyl aminals and hemiaminals: efficient formation of 2-(N-acylaminal) substituted tetrahydropyrans

An efficient new method to synthesize α-oxy N-acyl aminals and hemiaminals in a single step from readily synthesized N-acyl enamines has been developed using PhI(OAc)₂ as the oxidant. The reaction conditions are very mild and the products are obtained in good yields (65-92%). A possible mechanistic pathway is laid out.     

Catalytic photocarboxylation of 1,1-diphenylethylene with N,N,N′,N′-tetramethylbenzidine and carbon dioxide

Photocarboxylation of 1,1-diphenylethylene with N,N,N′,N′-tetramethylbenzidine (TMB) in MeCN under bubbling of CO₂ proceeded with high catalytic efficiency, giving 3,3-diphenylacrylic acid (DPA) and 3-hydroxy-3,3-diphenylpropionic acid (20). The turnover number (TON=(DPA+20)/TMB) reached 17. Similarly, 1-phenyl-1-cyclohexene yielded cis-2-acetamido-2-phenylcyclohexanecarboxylic acid with TON 5.9. As compared with related N,N-dimethylaniline derivatives, TMB is more resistant to photodecomposition, has the much larger absorbance in the S₀→S₁ transition, and has the lower quenching efficiency by CO₂. Probably these factors are partly responsible for the high TON observed for TMB.     

Gold(I)-catalyzed [4+2] cycloaddition of N-(hex-5-enynyl) tert-butyloxycarbamates

A study concerning the gold(I)-catalyzed transformation of N-(hex-5-enynyl) tert-butyloxycarbamates is described. The mild conditions employed allow the moderately efficient but stereoselective synthesis of a range of bicyclic carbamates following a formal [4+2] cycloaddition process.