Pyridines from enamides

Scheme 3.55 Ru-catalyzed synthesis of pyridines from enamides and alkynes.

Recently, the group of Boruah achieved the synthesis of annelated pyridines from yfi-formyl enamides via a Henry reaction in a one-pot process [186]. Under the action of microwave irradiation, in the presence of a base, for example pyrrolidine, morpholine or piperidine, yields from 80 to 90% were obtained after 8 to 10 min (Scheme 10.96). 

A novel strategy for the synthesis of pyridines from aldehyde, enam-ide, and isonitrile was described by Wang and coworkers in 2013 [122], The reaction works under mild reaction conditions and good to excellent yields can be achieved. Mechanistically, this cascade reaction consisted by Zn(OTf)2-promoted [1 + 5] cycloaddition of isonitrile with A-formylmethyl-substituted enamide, facile aerobic oxidative aromatization and intermolecular acyl transfer from the pyridinium nitrogen to the 5-hydroxy oxygen, and finally acylation of the 4-amino group by an external acyl chloride efficiently afforded 2-substituted 4-acylamino-5-acyloxypyridines. 

Steroidal, alicyclic or aromatic annulated pyridines were prepared via a microwave-assisted, base-catalyzed Henry reaction of /1-formyl enamides and nitromethane on an alumina support [97]. Highly substituted tri- and tetrasubstituted pyridines were synthesized in a Bohlmann-Rahtz reaction from ethyl /3-amino crotonate and various alkynones. The reaction involved a Michael addition-cyclodehydration sequence and was effected in a single synthetic step under microwave heating conditions [98]. An alternative approach towards polysubstituted pyridines was based on a reaction sequence involving an inverse electron-demand Diels-Alder reaction between various enamines 45 and 1,2,4-triazines 44 (Sect. 3.6), followed by loss of nitrogen and subsequent elimination-aromatization. Enamines 45 were formed in situ from various ketones and piperidine under one-pot microwave dielectric heating conditions [99]. Furthermore, a remarkable acceleration of the reaction speed (from hours and days to minutes) was observed in a microwave-assisted cycloaddition. Unsymmetrically substituted enamines 45 afforded mixtures of regioisomers (Scheme 35). 

Oximes, Tosylhydrazones, and Related Derivatives.—Ketoximes afford enimides in refluxing acetic anhydride-pyridine.181 Theproduct (207) from 5a-cholestan-3-one oxime (206), for example, gave 3-acetylamino-5a-cholest-2-ene (208) in 93% yield after chromatography on alumina. Use of succinic instead of acetic anhydride, with pyridine, gave the enimide (209) which was stable to chromatography. A radical mechanism is proposed. Reduction of ketoximes by Cr11, V11, or Tiin salts in acetic anhydride affords the same enamides, by acetylation of the intermediate imines. The... 

As a further extension of photocyclization of the enamides prepared from 1-methylisoquinolines, Naito and Ninomiya (67) and Lenz (48) synthesized aza analogs of berbine, azaberbines, by irradiation of pyridine analogs of the parent enamides (27) (Scheme 57). 

Amythiamicin D was the first in the family to be synthesized. The 2,3,6-trisubstituted pyridine core was synthesized from serine-derived l-alkoxy-2-azadienes and thiazoyl enamide dienophiles ultilizing a biosynthesis-inspired hetero-Diels-Alder route under MW irradiation. After successive incorporation of glycine and bis-thiazole fragments, amythismicin D was obtained by macrocyclization <2005JA15644, 2004CC946>. 

A simple synthesis of enamides from ketoximes has been described and demonstrated with various steroidal derivatives. Thus, 5a-cholestan-3-one oxime (54a) and its derivatives (54b—e) when refluxing in acetic anhydride and pyridine afforded (55) with 10% of its A-3 isomer. From crude reaction mixture, the enimide (56) could be isolated by crystallization or silica gel chromatography. Compound (55) was obtained by alumina chromatography and led to (56) with acetic anhydride-... 

In addition to several general reviews on enamine chemistry, all of which include heterocyclic syntheses, there is an extensive survey by Hickmott which is entirely concerned with the formation of heterocycles. More specialized reviews deal with heterocyclic enamines, enaminones, the photochemistry of enamides , heterocyclic jS-enamino esters , enamino thiones , the synthesis of indole alkaloids via enamines , formation of pyrimidines, pyridopyrimidines, pyridines and pyrrolizines from enamines , synthesis of lactams , formation of heterocycles from cyclic enamino ketones and 2-acetylcyclohexen-l-ones, the synthesis of 3-cyano-2(l -pyrimidine-thiones and -selenones from jS-enamino ketones and the chemistry of cyclic en-aminonitriles. ... 

Boruah et al. reported a facile and convenient synthesis of pyridines 16 from P-formyl enamides 17 under microwave irradiation employing a Henry reaction <04SL1309>. The author postulates that nitromethane reacts with the formyl group, followed by dehydration and subsequent cyclization and aromatization to yield the nitro-pyridine 16. 

A facile one-pot synthesis of trifluoromethyl-substituted pyridine derivatives has been reported (93JHC71). The procedure depends on the high reactivity of trifluroacetoacetyl chloride, which is generated in situ from trifluoroacetyl chloride and ketene. Thus, the enaminone 391 gives the intermediate enamide 392, which is refluxed in triethylamine to give the... 

Shortly later, within 2 months, a similar reaction, the enantioselective cascade aza-ene-type cyclization reactions of a,p-unsaturated aldehydes 28 and enamide 154, was also reported by Wang et al. In addition, the reaction product hemiaminal 157 was converted to ketoaldehyde 158, pyridine 159 and enamide 160, Scheme 3.51 [67]. Similarity, the reaction mechanism started from a nucleophilic attack of enamide (an aza-ene-type reaction), followed by reversible enamine-iminium transformation and hydrolysis to provide the hemiaminal. 

In 2013, Yoshikai and Wei developed a copper-catalyzed pyridines synthesis from oximes and enals [65]. Under redox-neutral reaction conditions, with 0-acetyl ketoximes and 0 ,/3-unsaturated aldehydes as the substrates and using copper(I) salt and a secondary ammonium salt (or amine) as the catalyst system, a variety of substituted pyridines were prepared with a broad range of functional groups tolerance (Scheme 3.29). By merging iminium catalysis and copper catalyst, imder the redox activity of the copper catalyst, the reaction started to reduce the oxime N—O bond to generate a nucleophilic copper(II) enamide and later oxidize a dihydropyridine intermediates to the final products. 

A [3+3]-type condensation of O-acetyl ketoximes and a, -unsaturated aldehydes yields pyridines " for example, Ph-(Me)C=N-OAc and trans-cinnamaldehyde (trans-Ph-CH=CH-CHO) give 2,4-diphenylpyridine (54) using copper(I) iodide as catalyst and a salt of a secondary amine only a trace of the 2,6-product is observed. A synergistic copper/iminium catalysis is proposed the oxime reacts with the copper iodide to give an iminyl copper species, Ph-(Me)C=N-Cu-X (i.e., N-O reduction), which tautomerizes to a copper(II) enamide, Ph-C(=CH2)-NH-CuX, which then acts as a nucleophile towards the iminium ion (formed from the aldehyde and 2° amine). 

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