Regioselective and Regiospecific Cycloaddition of Acetylenes to 2,4,6-Triazidopyridine

The cycloaddition of tert-butylacetylene to 2,4,6-triazido-3,5-dicyanopyridine and 2,4,6-triazido-3-chloro-5-cyanopyridine occurs regioselectively and regiospecifically at the azide group in position 4 of the pyridine ring leading to the formation of the corresponding 4-(4'-tert-butyl-1H-1,2,3-triazolyl)pyridines as the sole products. Analogous reactions with the less sterically hindered n-butylacetylene are characterized by less regiospecificity and give a mixture of the isomeric 4'- and 5'-n-butyl-substituted triazoles at ratios of 96 : 4 and 91 : 9 respectively for the two different triazides. The interaction energies of the pyridine - and -azide groups with the acetylene molecules, and the energies of the transition states for these reactions have been calculated by the PM3 method. It was established that the high reactivity of the -azide group of the triazidopyridines in relation to the! ace tylenes is caused by the anomalously low distribution of bonding orbital density on these groups, leading to substantially lower activation energies in 1,3-dipolar cycloaddition reactions.     

Regioselective Cycloaddition of the Dimethyl Ester of Acetylenedicarboxylic Acid to 2,4,6-Triazidopyridines

2,4,6-Triazido-3,5-dichloropyridine was obtained in the reaction of pentachloropyridine with sodium azide. At room temperature, this azide reacts regioslectively with norbornene at the -azide group to give the corresponding 4-(3-azatricyclo[3.2.1.0]octanyl)-2,6-diazidopyridine in 88% yield. The cycloaddition of the dimethyl ester of acetylenedicarboxylic acid to this triazide proceeds at the azide groups at C₍₂₎ and C₍₆₎ in the pyridine ring to give 4-azido-2,6-di(4',5'-dimethoxycarbonyl)-1H-1,2,3-triazolopyridine. The analogous reaction of 2,4,6-triazido-3,5-dicyanopyridine with the dimethyl ester of acetylenedicarboxylic acid stops at the formation of 2,4-diazido-6-(4',5'-dimethoxycarbonyl)-1H-1,2,3-triazolopyridine. In contrast to reactions with electron-rich dipolarophiles, the cycloaddition of electron-deficient dipolarophiles to 2,4,6-triazidopyridines proceeds with thermodynamic control primarily a! t the azide groups bearing the highest orbital density in the HOMO.     

Regioselective synthesis of 2,4-disubstituted thiophenes

A highly regioselective route was established to 2-aryl-, 2-cyclohexyl-, and 2-(2-arylethyl)4-alkylthiophenes, which are potential candidates as liquid crystalline compounds of low viscosity. The key synthetic intermediates, 2-substituted-4-(chloromethyl)thiophenes 6, 14, and 20 were prepared respectively from the reactions of β, γ-epoxycarbonyl compounds 5, 13, and 19 with Lawesson's reagent in the presence of a catalytic amount of p -toluenesulfonic acid. The epoxycarbonyl compounds were obtained from the TiCl₄-mediated reactions of 2-(chloromethyl)-3-(trimethylsliyl)propene (10) with acid chlorides followed by epoxidation with m-chloroperoxybenzoic acid, or from prior epoxidation followed by oxidation with pyridinium dichromate of homoallylic alcohols 3. The homoallylic alcohols 3 were synthesized from the reactions of 2-(chloromethyl)-3-(trichlorosilyl)propene (2) with aldehydes in N, N-dimethylformamide. Copper (I) catalysed cross-coupling reactions of 2-substituted-4-(bromomethyl)thiophenes (which were prepared by transhalogenation of 2-substituted-4- (chloromethyl)thiophenes with NaBr in acetone) with Grignard reagents afforded 2,4-disubstituted thiophenes. Using this method, eleven 2,4-disubstituted thiophenes were synthesized and their potentials as liquid crystalline compound of low viscosity were examined. The synthesized 2-(4-cyanophenyl)-4-pentylthiophene was observed to have a lower melting point than the corresponding 2,5-disubstituted thiophene. This observation is consistent with the expectation from the basis of molecular linearity which can affect the viscosity and/or melting point of crystalline compounds.     

Regioselective synthesis of multiply halogenated azaxanthones

Four multiply halogenated azaxanthones 3, 4b, 5, and 6 were synthesized as novel core building blocks of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors. Each of these heterocycles requires a specific synthetic strategy to control not only the aza-positions, but also the regiochemistry of the fully differentiated and highly reactive halogen substituents.     

Regioselective synthesis of 1,4-disubstituted imidazoles

A short and efficient synthesis of 1,4-disubstituted imidazoles has been developed which provides the desired products with complete regioselectivity. This protocol allows preparation of compounds which are challenging to prepare by current literature methods in a regioselective fashion, a sterically and electronically diverse range of N-substituents being accessible. The sequence involves an unusual double aminomethylenation of a glycine derivative, to yield a 2-azabuta-1,3-diene, onto which addition of an amine nucleophile results in a transamination/cyclization to prepare the substituted imidazole. The cyclization event is surprisingly insensitive to steric and electronic variations on the amine component, enabling a diverse range of imidazoles to be prepared.     

Regioselective synthesis of 2,8-disubstituted 1,5-diphenylglycolurils

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Regioselective synthesis of 2-chloro-3-pyridinecarboxylates

2-Chlorocyanoacetate was found to undergo base-catalyzed Michael addition to ,β-unsaturated ketones or aldehydes to afford 5-oxopentenenitrile derivatives. In the presence of anhydrous HCl, these compounds cyclize to yield 2-chloro-3-pyridinecarboxylates. The process is highly regiospecific and useful in the synthesis of 2,3-disubstituted pyridines.     

Regioselective single-step synthesis of 2-aminoimidazole derivatives

A convenient single-step strategy for the regioselective assembly of 2-aminoimidazole derivatives is herein described. Through a transition metal-free domino addition/cyclization process, the reactions of unsymmetrical carbodiimides with propargylic amines mediated by Cs₂CO₃ selectively afforded the corresponding polysubstituted 2-aminoimidazoles in moderate to good yields under very mild conditions. The regioselectivity was reversed in the presence of TEA at a higher temperature. The obtained 2-(o-iodoaryl)amino imidazoles could be easily converted to 2-(2-biphenyl)amino imidazole, 2-(o-alkynylphenyl)amino imidazole, benzoimidazo[1,2-a]imidazole and N-(imidazol-2-yl)indole derivatives.     

Regioselective synthesis of 6-alkylated lumazine derivatives

The regiospecific synthesis of alkylated lumazines is achieved by hetero Diels-Alder addition between an oxadiazinone 2 and enamine. The reactions proceed stepwise by cycloaddition, decarboxylation and deamination to produce the 6-alkylated lumazines.     

Regioselective synthesis of 2-substituted 3-diarylmethylenylpiperidines

A simple three-step synthetic routes toward 2-substituted 3-diarylmethylenylpiperidines 7 (Y = CN) and 8 (Y = allyl) starting with 3-diarylmethylenylpiperidines 9 is described. The process was carried out by the bromomethoxylation of skeleton 9 with NBS in MeOH at reflux for 2 h, regioselective α-dehydrobromination with DBU in THF at reflux for 10 h, and BF₃·OEt₂-catalyzed cross-coupling of the corresponding enamine with trimethylsilyl-based nucleophiles (TMS-Y) in DCM at rt for 2 h. α-Amino ester 18 and β-amino acid 19 are also synthesized via the simple three-step synthetic protocol.     

Regioselective synthesis of polysubstituted pyrazoles and isoxazoles

A regioselective synthesis has been developed for the preparation of unsymmetrical 1,3,5-triaryl-4-alkylpyrazolines and -pyrazoles by treatment of alpha-benzotriazolyl-alpha,beta-unsaturated ketones with monosubstituted hydrazines followed by alkylation at the 4-position of the pyrazoline ring. Reaction of alpha-benzotriazolyl-alpha,beta-unsaturated ketones with hydroxylamine gives 3,5-disubstituted isoxazoles regioselectively.     

Regioselective synthesis of the tricyclic core of lateriflorone

An efficient synthetic approach to the tricyclic core 8 of lateriflorone is described. Essential to the synthesis was the implementation of a biomimetic tandem Claisen/Diels-Alder reaction that produced the desired tricyclic scaffold as a single isomer. A rationalization of the excellent regio and stereoselectivity of this transformation is also proposed. [reaction: see text]     

Regioselective synthesis of gentisyl alcohol-type marine natural products

Gentisyl alcohol-type natural products, possessing various important biological properties, have been synthesized from 4-methoxyphenol by using a selective phenol monohydroxymethylation/monochlorination, a CAN oxidation and a sodium dithionite reduction as the key steps. The natural product synthesis is efficient, atom- and step-economical, and requires no protecting groups.     

Regioselective synthesis of (±)-gabaculine hydrochloride

3- Cyclohexenecarboxylic acid (2) has been functionalized to the protected amino acid 5 in a novel reaction sequence, the crucial step being the acid catalysed cyclization of the γ, δ-unsaturated isocyanate 3 to the bicyclic lactam 4. 5 was converted into gabaculine hydrochloride (1 · HCl).     

Regioselective synthesis of 1,2- vs 1,3-squaraines

Squaraines have been known for many decades as very stable and versatile vis-NIR absorbing dyes. They have found applications for example as sensitizers in organic photovoltaics and photodetectors. The most common squaraine structure is the 1,3-regioisomer. Their 1,2-regioisomers are seldom mentioned and unanimously regarded as side products. A facile direct synthesis of 1,2-squaraines, highlighting the role played by reaction conditions and electronic factors, is described. The first electrochemical characterization of these dyes is also shown.     

Regioselective synthesis of new functionally substituted tetrazolium salts

The 1,4-, 1,3-di- and 1,3,5-trisubstituted tetrazolium salts were obtained regioselectively and with high yields by the quaternization of 1- and 2-monosubstituted and 1,5-disubstituted tetrazoles with diacetone alcohol in perchloric acid. An X-ray crystallographic analysis of 1-(2-methylpentan-4-on-2-yl)-4-methyltetrazolium perchlorate was undertaken.Scientific-Research Institute of Physicochemical Problems, Belorus State University, Minsk; e-mail: fhp@fhp.bsu.unibel.by. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1222–1229, September, 1999.     

Regioselective and diastereoselective synthesis of highly substituted cyclopentanes

Highly substituted cyclopentane rings are present in a wide range of targets, and the efficient synthesis of such compounds constitutes a continuing challenge to organic synthesis. We present two complementary approaches to the regio- and diastereoselective synthesis of highly substituted cyclopentane structures. In both cases, a non-symmetrically disposed norbornene is employed as a common intermediate. One strategy relies on the Lewis acid-catalyzed ring opening of an anhydride, while the other employs production of a bicyclic lactone followed by its selective functionalization.