Synthesis of polysubstituted pyridine from oxime and α, β - unsaturated imine catalyzed by copper

Pyridine ring is the core structure of many natural products and synthetic drugs, and plays a key role in coordination chemistry, catalysis and materials science Therefore, how to synthesize regioselective substituted pyridine efficiently is an important research content in Heterocyclic Chemistry There are many classical methods of pyridine ring synthesis, such as Chichibabin pyridine synthesis with aldehydes, ketones or unsaturated carbonyl compounds and ammonia as raw materials, Hantzsch pyridine synthesis with β - ketoacids (esters), aldehydes and ammonia or ammonium salts as raw materials, etc Professor naohiko yoshikai, from the Department of chemistry and biochemistry, Nanyang University of technology, Singapore, recently published an article on angew Chem Int ed., reporting the condensation of oxime acetate and α, β - unsaturated ketimine to form pyridine compounds under the catalysis of copper The presence of oxime group can activate the ortho C-H bond, and the N-O bond in oxime compound is easy to break Therefore, under the catalysis of transition metal, oxime can be used to synthesize pyridine and other nitrogen-containing heterocycles Before the catalytic synthesis of pyridine compounds with oxime acetate as c2n1 unit, there were many reports (Fig 1-A) Different methods have their own characteristics and scope of application The new method developed by Professor naohiko yoshikai has mild reaction conditions, high regioselectivity, and can prepare some polysubstituted pyridines that are difficult to be obtained by traditional methods (Fig 1-C) Figure 1 oxime as a c2n1 unit to synthesize pyridine: angelw Chem Int ed according to the literature and previous experiments, the author determined the standard reaction conditions: phenylacetoxime acetate (1a, 0.24 mmol) and chalcone n-tosyl imine (2a, The yield of 2,4,6-triphenyl-3-methylpyridine (3AA) can be as high as 99% Then, on the basis of standard conditions, the author studies the influence of various variables in the reaction The experimental results show that the yield of the reaction will decrease when using other copper catalysts, no NaHSO 3, DMSO to DMF, nts to npmp (p-methoxyphenyl) or chalcone directly Fig 2 source of influence of reaction conditions: angelw Chem Int ed next, the author investigated the universality of reaction substrate As shown in Fig 3, 1A reacts with different α, β - unsaturated KETIMINES Chalcone imines with different substituents, heterocycles and alkyl substituted α, β - unsaturated KETIMINES on benzene ring can obtain ideal yield (3AB - 3aq), and all substituted pyridines can also be synthesized by this method (3ar, 3As) Fig 3 reaction substrate investigation (α, β - unsaturated ketimine) source: angelw Chem Int ed different oximes react with 2A as shown in Fig 4 The yield of 2,3,4,6-tetrasubstituted pyridine is very high (3oa-3qa, 3VA, 3wa), but the yield of 2,4,6-trisubstituted pyridine is not satisfactory Therefore, on the basis of the optimum conditions, the author raised the oxime equivalent to 1.6 and the reaction temperature to 90 ℃ Most of 2,4,6-triarylpyridine (3ba-3na) can be obtained with high yield when the conditions are changed, but the yield of 2-alkyl-4,6-diphenylpyridine obtained with this condition is slightly lower (3sa-3ua) The yields of 3ra, a 3,4-dihydropyridine derivative, and 3xa, a double condensation product, are relatively low Fig 4 reaction substrate investigation (oxime acetate) source: angelw Chem Int ed The author further studied asymmetric oxime acetate that can be alkenolized at both α positions As shown in Fig 5, when methyl and methylene exist at the same time, methylene is the only reaction site; when α positions are methyl and cyclopropyl, C-C bond is formed on methyl The results show that the reaction is regioselective Fig 5 source of regioselectively generated pyridine derivatives: angelw Chem Int ed in order to explore the reaction mechanism, the author designed a series of competition and control experiments, and the proposed mechanism is shown in Fig 6 Firstly, the oxime acetate was reduced by Cu I single electron After the C-N bond was broken, the imine radical a was formed Then, the imine copper (II) B was formed by Cu I and B, and the copper (II) enamine C was formed by mutual variation Then, C and n-ts imine 2 were conjugated to form D, and then the intramolecular cyclization was carried out to form dihydropyridine F after the oxidation of F by Cu II, pyridine product 3 was obtained Fig 6 possible reaction mechanism source: angelw Chem Int ed summary: Professor yohiko yoshikai has developed a method for the condensation of copper catalyzed oxime and α, β - unsaturated ketimine to generate regioselective polysubstituted pyridine The reaction covers a wide range of substrates, which can be used to synthesize polysubstituted pyridine that is difficult to be synthesized by traditional methods, opening a new way for pyridine synthesis.