Regioselective synthesis of 1,2,4,5-tetrasubstituted pyridines from Baylis-Hillman adducts via consecutive [3+2+1] annulation protocol

An efficient synthetic method of poly-substituted pyridines was developed. Various poly-substituted pyridines were prepared from the combination of Baylis-Hillman adducts (3 carbons), activated methylene compounds (2 carbons) and ammonium acetate (1 nitrogen) via [3+2+1] annulation protocol in good yields, regioselectively.     

Kinetics and mechanism of the pyridinolysis of phenacyl bromides in acetonitrile

Kinetic studies of the reactions of substituted phenacyl bromides (YC6H4COCH2Br) with pyridines (XC5H4N) are carried out in acetonitrile at 45.0 degrees C. A biphasic Bronsted plot is obtained with a change in slope from a large (betaX approximately equals 0.65-0.80) to a small (betaX approximately 0.36-0.40) value at pKa = 3.2-3.6, which can be attributed to a change in the rate-determining step from breakdown to formation of a tetrahedral intermediate in the reaction path as the basicity of the pyridine nucleophile increases. This mechanism is supported by the faster rates with pyridines than with anilines and the change of cross-interaction constant rhoXY from a large positive (rhoXY = +1.4) to a small positive (rhoXY approximately +0.1) value. The large magnitude of Hammett rhoX (= -5.5 to -6.9) values for the pyridines with electron-withdrawing substituents and positive deviations of the pi-acceptors, p-CH3CO and p-CN, are quite similar to those for the pyridinium ion formation equilibria. The activation parameters are also in line with the proposed mechanism.     

Scope of Ru(II)-catalyzed synthesis of pyridines from alkynes and nitriles

Pyridines can be efficiently synthesized by Ru(II)-catalyzed [2 + 2 + 2] cycloaddition of 1,6-diynes to alpha,omega-dinitriles or electron-deficient nitriles or by Ru(II)-catalyzed [2 + 2 + 2] cocyclization of electron-deficient alkynes and electron-deficient nitriles. The reactions with dinitriles seem likely to proceed via ruthenacyclopentadiene intermediates and the reactions with electron-poor nitriles via azaruthenacyclopentadienes. The reaction with asymmetric electron-deficient alkynes affords 2,3,6-trisubstituted pyridines in good yield.     

One-pot synthesis of metalated pyridines from two acetylenes, a nitrile, and a titanium(II) alkoxide

Four-component coupling process involving two acetylenes, a nitrile, and a divalent titanium alkoxide reagent, Ti(O-i-Pr)(4)/2i-PrMgCl, directly yielded titanated pyridines in a highly selective manner. The reaction can be classified into four categories: (i) a combination of an internal acetylene, a terminal acetylene, sulfonylnitrile, and the titanium reagent to yield alpha-titanated pyridines, (ii) a combination of an internal acetylene, a (sulfonylamino)acetylene, a nitrile, and the titanium reagent to yield alternative alpha-titanated pyridines, (iii) a combination of an internal acetylene, a (sulfonylamino)acetylene, a nitrile, and the titanium reagent to yield titanated aminopyridines, and (iv) a combination of an acetylenic amide, a terminal acetylene, a nitrile, and the titanium reagent to yield pyridineamides with their side chain titanated. Some of these reactions enabled virtually completely regioselective coupling of two different, unsymmetrical acetylenes and a nitrile to form a single pyridine. Synthetic applications of these reactions have been illustrated in the preparation of optically active pyridines and medicinally useful compounds.     

Microwave-assisted synthesis and transformations of sterically hindered 3-(5-tetrazolyl)pyridines

Sterically hindered 2,4-disubstituted 3-(5-tetrazolyl)pyridines were synthesized from corresponding nicotinonitriles using microwave technology. 2-Methylnicotinonitriles were converted into the 2-azidomethyl-3-cyanopyridines via 2-hydroxymethyl and 2-chloromethyl derivatives. Intramolecular [3+2] cycloaddition of an heteroaromatic cyano group to side azido group was carried out to form a novel heterocyclic system containing a (tetrazolo)azaisoindole unit. Condensation of the 2-methylnicotinonitriles and aldehydes gave rise to the corresponding 2-vinyl derivatives, which were then transformed into novel heterocyclic system (5,6-dihydrotetrazolo[5,1-f]-1,6-naphthyridine) by intramolecular N-alkylation reaction of tetrazole ring with olefinic fragment. The 3-(5-tetrazolyl)pyridines obtained were alkylated to give the various N- and C-benzyl derivatives as well as acylated to afford the 3-(1,3,4-oxadiazol-2-yl)pyridines in good yields. A majority of above-mentioned reactions was carried out under microwave irradiation.     

Selective syntheses of metalated pyridines from two different unsymmetrical acetylenes, a nitrile, and a titanium(II) alkoxide

Cyclotrimerization of two different, unsymmetrical acetylenes and p-toluenesulfonylnitrile with a divalent titanium alkoxide reagent, Ti(O-i-Pr)4/2 i-PrMgCl, yielded single pyridyltitanium compounds in a highly selective manner. These metalated pyridines were confirmed by deuteriolysis to give the corresponding deuterated pyridines and underwent iodinolysis and copper-catalyzed alkylation to demonstrate their synthetic utility. Alternatively, a different type of cyclotrimerization of an alkynamide, terminal acetylenes, and alpha-alkoxynitriles mediated by the same titanium(II) alkoxide again proceeded in a highly selective manner to give single pyridines having a titanated side chain.     

Thiacalix[3]pyridine produces a stable mononuclear rhodium(II) complex with mutual Jahn-Teller effect

Thiacalix[3]pyridine (Py3S3) consists of pyridines and bridging sulfur atoms producing a stable octahedral mononuclear Rh(II) complex [Rh(II)(Py3S3)2]2+ showing mutual Jahn-Teller effect, a metal based reversible redox couple of Rh(III/II) at 0.02 V vs. SCE and a g(perpendicular) > g(||) relationship in EPR measurements.     

Terminal Alkynes as One-Carbon Donors in [5+1] Heteroannulation: Synthesis of Pyridines via Ynimine Intermediates and Application in the Total Synthesis of Anibamine B

Transition-metal-catalyzed [4+2] heteroannulation of α,β-unsaturated oximes and their derivatives with alkynes has been developed into a powerful strategy for the synthesis of pyridines. It nevertheless lacks regioselectivity when unsymmetrically substituted alkynes are used. We report herein the unprecedented synthesis of polysubstituted pyridines by a formal [5+1] heteroannulation of two readily accessible building blocks. A copper-catalyzed aza-Sonogashira cross-coupling between β,γ-unsaturated oxime esters and terminal alkynes affords ynimines, which, without isolation, undergo an acid-catalyzed domino reaction involving ketenimine formation, 6π-electrocyclization and aromatization to afford pyridines. Terminal alkynes served as a one-carbon donor to the pyridine core in this transformation. Di- through pentasubstituted pyridines are accessible with complete regioselectivity and excellent functional-group compatibility. The first total synthesis of anibamine B, an indolizinium alkaloid with potent antiplasmodial activity, was accomplished featuring this reaction as a key step.     

1-Alkynyl- and 1-alkenyl-3-arylimidazo[1,5-a]pyridines: synthesis, photophysical properties, and observation of a linear correlation between the fluorescent wavelength and Hammett substituent constants

1-Alkynyl- and 1-alkenyl-3-arylimidazo[1,5-a]pyridines were synthesized. The Sonogashira coupling of 3-aryl-1-iodoimidazo[1,5-a]pyridines and various terminal alkynes with Pd(PPh(3))(2)Cl(2) (10 mol %) and CuI (10 mol %) in triethylamine at 80 °C for 12 h afforded the corresponding 1-alkenyl-3-arylimidazo[1,5-a]pyridines in good to excellent yields. The Mizoroki-Heck reaction of 3-aryl-1-iodoimidazo[1,5-a]pyridines and various styrene derivatives proceeded smoothly with Pd(OAc)(2) (5 mol %), IMes·HCl (10 mol %), and Cs(2)CO(3) (2 equiv) in DMA at 130 °C for 20 h to give the alkenylated imidazo[1,5-a]pyridines in moderate to high yields. The fluorescence maxima and fluorescence quantum yields of the alkynylated products were 458-560 nm and Φ(F) = 0.08-0.26 in chloroform solution, and those of the alkenylated imidazopyridines were 479-537 nm and Φ(F) = 0.03-0.13. The absorption behaviors of the obtained alkynylated and alkenylated imidazo[1,5-a]pyridines showed a good fit to the values predicted by TDDFT calculations at the B3LYP/6-311++G(d,p) level. In addition, the alkynylated imidazo[1,5-a]pyridines obtained showed linear correlations between the Hammett substituent constants of the substituents on the arylalkynyl group and their fluorescence wavelengths.     

Synthesis of perfluoroalkylated benzenes and pyridines through cationic Rh(I)/modified BINAP-catalyzed chemo- and regioselective [2 + 2 + 2] cycloaddition

A convenient synthesis of perfluoroalkylated benzenes and pyridines has been achieved by a cationic Rh(I)/modified BINAP-complex-catalyzed chemo- and regioselective [2 + 2 + 2] cycloaddition of alkynes with a perfluoroalkylacetylene and a perfluoroalkylnitrile.     

Regio- and stereoselective oxetane formation via paterno-buchi photocycloaddition

Carbonyl 2 + 2 photoaddition occurs selectively to the alkene moiety of 3-(4-methyl-3-pentenoxy)pyridine. Photolysis of alkene containing pyridines in acetophenone gives rise to an oxetane which is obtained with extremely high diastereoselectivity as shown by analysis of the major 2 + 2 photoproduct. A second photoproduct, 2,3-dihydroxy-2,3-diphenylbutane, is obtained as a result of acetophenone coupling.     

Synthesis of functionalized arylpyridines and -pyrimidines by domino [4+2]/retro [4+2] cycloadditions of electron-rich dienes with alkynylpyridines and -pyrimidines

Aryl-substituted pyridines and pyrimidines were prepared by [4+2] cycloadditions of alkynyl-substituted pyridines and -pyrimidines with electron-rich dienes. The reactions proceed by formation of a bridged cycloadduct and subsequent thermal extrusion of ethylene. The pyridine moiety plays a crucial role for the success of the reaction.     

Photogeneration of Benzhydryl Cations by Near-UV Laser Flash Photolysis of Pyridinium Salts

Laser flash irradiation of substituted N-benzhydryl pyridinium salts yields benzhydryl cations (diarylcarbenium ions) and/or benzhydryl radicals (diarylmethyl radicals). The use of 3,4,5-triamino-substituted pyridines as photoleaving groups allowed us to employ the third harmonic of a Nd/YAG laser (355 nm) for the photogeneration of benzhydryl cations. In this way, benzhydryl cations can also be photogenerated in the presence of aromatic compounds and in solvents which are opaque at the wavelength of the quadrupled Nd/YAG laser (266 nm). To demonstrate the scope and limitations of this method, the rate constants for the bimolecular reactions of benzhydryl cations with several substituted pyridines were determined in acetonitrile and with water in acetone. The obtained data agree with results obtained by stopped-flow UV-vis spectroscopic measurements. The rate constants for the reaction of the 4,4'-bis[methyl(2,2,2-trifluoroethyl)amino]benzhydrylium ion with 4-(dimethylamino)pyridine were also determined in dimethyl sulfoxide, N,N-dimethylformamide, and acetone. From the second-order rate constants, we derived the nucleophilicity parameters N and s(N) for the substituted pyridines, as defined by the linear free energy relationship, log k(2) = s(N)(N + E).     

过渡金属催化[2 + 2 + 2]环加成反应合成吡啶衍生物

环加成反应可以一步同时构建多个化学键,是目前国内外研究最为活跃的领域之一。相比于传统方法,过渡金属催化的[2+2+2]环加成反应是合成吡啶衍生物的有效手段。本文从反应机理、非手性吡啶化合物合成和手性吡啶化合物合成三个方面阐述了近年来吡啶衍生物的研究情况,涉及Co、Rh、Ru、Fe、Ni、Ti等金属催化体系。     

2-,3-和4-溴甲基吡啶的水解反应的动力学研究

用HPLC测定了2-、3-和4-溴甲基吡啶在60℃、离子强度μ为0.15、pH 0.9～9.9的缓冲溶液中水解成相应的羟甲基吡啶的反应速度.通过数学处理,求得溴甲基吡啶的一级和二级反应速度常数以及溴甲基吡啶共轭酸的一级反应速度常数.水解反应的可能机理是S_N1和S_N2.     

A comparison of nucleophilicity and lability of thiazoles and pyridines in substitution reactions at platinum(II) complexes

The second order rate constants, k2, for the displacement of chloride by nitrogen donors L (L = thiazoles, pyridines, amines) from [Pt(S-S)Cl2] [S-S = 1, 2-bis-(phenylsulfanyl) ethane] and [Pt(SNS)Cl]+ [SNS=2, 6-bis- (methylsulfanylmethyl)pyridine] are linearly related to their proton basicity according to a free-energy relationship of the type logk2 = (pKa) + . In the reverse reactions, i.e. the displacement by chloride of the coordinated nitrogen donors, the lability depends not only upon ligand basicity but also upon the nature of the group to be displaced in the order thiazoles < pyridines. This behaviour, attributed to different interactions in the ground state, is confirmed in the solvolytic displacement of the organic bases from complexes of the type trans-[Pt(dmso)(L)Cl2]. Steric retardation, owing to the presence of a methyl group ortho to the nitrogen in the aromatic rings, is considerably less for entering thiazoles as compared to pyridines.     

Nickel-catalyzed dehydrogenative [4 + 2] cycloaddition of 1,3-dienes with nitriles

Pyridines, which comprise one of the most important classes of the six-membered heterocyclic compounds, are widely distributed in nature, and the transition-metal-catalyzed [2 + 2 + 2] cycloaddition reaction of two alkynes and a nitrile is one of the most powerful methods for preparing versatile, highly substituted pyridine derivatives. However, the lack of chemo- and regioselectivity is still a crucial issue associated with fully intermolecular [2 + 2 + 2] cycloaddition. The present study developed the Ni(0)-catalyzed intermolecular dehydrogenative [4 + 2] cycloaddition reaction of 1,3-butadienes with nitriles to give a variety of pyridines regioselectively.     

On the [2+2] cycloaddition of 2-aminothiazoles and dimethyl acetylenedicarboxylate. Experimental and computational evidence of a thermal disrotatory ring opening of fused cyclobutenes

The reaction of 2-(phenylamino)- and 2-(dimethylamino)thiazoles with dimethyl acetylenedicarboxylate led unexpectedly to dimethyl 6-(phenylamino)- and 6-(dimethylamino)-3,4-pyridinedicarboxylates. Those compounds reasonably result from a sequence of reactions initiated by a [2 + 2] cycloaddition of the alkyne to the formal C=C of the thiazole ring. These pyridines were obtained in nearly all the cases assayed as the exclusive reaction products under rather mild conditions and in fair to good yields. In contrast, the regioisomeric 2-amino-3,4-pyridinedicarboxylates, which would result from a [4 + 2] cycloaddition followed by sulfur extrusion, were only obtained in one particular case. The two reaction paths leading alternatively to both regioisomers were investigated computationally. The respective [2 + 2] and [4 + 2] cycloadducts were found to be formed stepwise from a common dipolar intermediate. Notably, the step following the [2 + 2] cycloaddition (i.e., the ring opening of the fused cyclobutene intermediate to give an all-cis 1,3-thiazepine) was found to take place in a disrotatory mode. Although geometric constraints and electronic factors may reduce the energy for the disrotation, the implication of the fused five-membered ring in the electronic reorganization leading to the 1,3-thiazepine is determinant. In this sense, this step could be regarded also as a thermally allowed six-electron five-center disrotatory electrocyclic ring opening. The proposed mechanism was experimentally supported by the isolation of several intermediates and other experimental facts.     

Pyridines via solid-supported [2 + 2 + 2] cyclotrimerization

The formation of pyridines via a crossed [2 + 2 + 2] cycloaddition has been achieved on a solid-support for the first time.