Reissert analog, pyridine

A novel method for the synthesis of 2-alkylpyridines and 2-pyridine-carbinols starts from pyridine and involves the pyridine Reissert analog 175. Anion formation with sodium hydride and alkylation with alkyl halides afford the 2-alkyl-l-ethoxycarbonyl-2-cyano-1,2-dihydropyridines 176, which on heating with HMPT/Nal (HMPT = hexamethylphosphorous triamide) give 2-alkylpyridines 177. Condensation of the anion with benzaldehyde or o-tolualdehyde leads to 2-pyridinecarbinols (85CI(L)125). The reaction of 1,4-bis(trimethylsilyl)-1,4-dihydropyridine (178) with aldehydes (and ketones) in... 

Analogously, although the enhanced reactivity of quinoline derivatives (relative to pyridine counterparts) in nucleophilic additions such as the formation of pseudobases and Reissert compounds probably relates to the relatively lower energy of the LUMO in the quinoline derivatives, the radicals from these heterocycles, in which the corresponding orbitals are singly occupied, are anionic thus, reactivity toward nucleophiles is also unlikely to be important. 

Alternative reaction pathways exploring different synthetic possibilities have been studied. For instance, electron-rich dihydroazines also react with isocyanides in the presence of an electrophile, generating reactive iminium species that can then be trapped by the isocyanide. In this case, coordination of the electrophile with the isocyanide must be kinetically bypassed or reversible, to enable productive processes. Examples of this chemistry include the hydro-, halo- and seleno-carba-moylation of the DHPs 270, as well as analogous reactions of cyclic enol ethers (Scheme 42a) [223, 224]. p-Toluenesulfonic acid (as proton source), bromine and phenylselenyl chloride have reacted as electrophilic inputs, with DHPs and isocyanides to prepare the corresponding a-carbamoyl-(3-substituted tetrahydro-pyridines 272-274 (Scheme 42b). Wanner has recently, implemented a related and useful process that exploits M-silyl DHPs (275) to promote interesting MCRs. These substrates are reacted with a carboxylic acid and an isocyanide in an Ugi-Reissert-type reaction, that forms the polysubstituted tetrahydropyridines 276 with good diasteroselectivity (Scheme 42c) [225]. The mechanism involves initial protiodesilylation to form the dihydropyridinum salt S, which is then attacked by the isocyanide, en route to the final adducts. 

The failure of pyridine and acridine to yield Reissert compounds has already been discussed. Although many of the arguments advanced for the failure of pyridine to yield a Reissert compound suffer from the fact that analogous compounds have been prepared from pyridine, no one yet appears to have found the proper conditions for formation of a pyridine Reissert compound. 

The hydrochlorides of 64, 65, and 66 were obtained by reaction of iV-phenylbenzimidyl chloride and hydrogen cyanide with the appropriate heterocyclic base. As is typical of the Reissert compounds, these three compounds lack absorption peaks in the region 2200-2400 cm h To further the analogy to Reissert compounds, acid-catalyzed hydrolysis of 64, 65, and 66 gave benzaldehyde. Picolinio acid, quinaldic acid, and isoquinaldic acid, respectively, as well as aniline, are also obtained from the hydrolysis. Nitrobenzene oxidation of the three compounds gave pyridine-2-carboxamide, quinaldonitrile, and isoquinaldonitrile, respectively. ... 

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