Pyridine-3-carbaldehyd

An interesting intermediate 30 was proposed to result from the sequential addition of pyridine to tetrachlorocyclopropene (31). Compound 30 represents an alkyl nitrogen ylide with two 1-chloroalkyl pyridinium moieties in the same molecule. Pyridines with electron-withdrawing groups and heterocycles with an electron-deficient nitrogen, for example, pyridine-3-carbaldehyde or quinoline, react with 31 to yield the corresponding mono-substituted products 32a and 32b (83JOC2629) (Scheme 8). 

Pyridyl alkanol [41], diol [42], and ferrocenyl alcohol [43] were the first asymmetric autocatalysts found by Soai and co-workers in the enantioselective alkylation of pyridine-3-carbaldehyde, dialdehyde, and ferrocenecarbaldehyde, respectively, with dialkylzincs. 

In the course of the continuing study [9a,b] on the enantioselective addition of dialkylzincs to aldehydes by using chiral amino alcohols such as diphenyl(l-methyl-2-pyrrolidinyl)methanol (45) (DPMPM) [48] A. A -dibutylnorephedrine 46 (DBNE) [49], and 2-pyrrolidinyl-l-phenyl-1-propanol (47) [50] as chiral catalysts, Soai et al. reacted pyridine-3-carbaldehyde (48) with dialkylzincs using (lS,2/ )-DBNE 46, which gave the corresponding chiral pyridyl alkanols 49 with 74-86% ee (Scheme 9.24) [51]. The reaction with aldehyde 48 proceeded more rapidly (1 h) than that with benzaldehyde (16 h), which indicates that the product (zinc alkoxide of pyridyl alkanol) also catalyzes the reaction to produce itself. This observation led them to search for an asymmetric autocatalysis by using chiral pyridyl alkanol. 

Knowledge on these kinds of reactions is being accumulated for thermal reactions, which is also relevant for photoreactions. The topic is thoroughly discussed by Todd [132]. Soai and his group have presented a very efficient amplification system, the addition of dialkyl zinc to pyridine-3-carbaldehyde 49 [16,133], in which the chiral alcohol produced catalyzes the addition. 

Decarboxylative condensation of N-unsubstituted tx-amino acids with benzaldehyde as an aromatic aldehyde requires somewhat harsher conditions. Benzaldehyde and oc-amino acids are heated under reflux in DMF together with N-phenylmaleimide. The azomethine ylides 108 generated can be captured as mixtures of several stereoisomeric cycloadducts (84CC180). 1-Aminocyclopentane-l-carboxylic acid undergoes a similar reaction with pyridine-3-carbaldehyde in the presence of N-phenylmaleimide to afford a spirocyclic cycloadduct, the maleimide cycloadduct of azomethine ylide 109 (84CC182). 

Several scientists had pointed out the importance of asymmetric autocatalysis but it remained a theoretical system until Soai found an asymmetric alkylation of pyridine-3-carbaldehyde the 3-pyridylalkanol functions as an asymmetric autocatalyst in an enantioselective alkylation of pyridine-3-carbaldehyde us-... 

The dienamines (66) and (67) afford the corresponding iminium salts (68) and (69) resulting from disubstitution. Hydrolysis of these salts gives the dialdehyde derivatives (70 35%) and (71 36%) respectively. Salt (68) forms pyridine-3-carbaldehyde (97%) when treated with aqueous ammonium chloride solution. 

Several enamides, for example compound (72 Scheme 5), have been used as precursors to 1 -sub-stituted-2-pyridone derivatives (73) and pyridine-3-carbaldehyde derivatives (74 14-69%). Salt (1) promotes dehydration of tautomers (75b) of 2-acetylbenzamide derivatives (75a) to give enamides (76), which are converted by further reaction with salt U) into iminium salts (77). Hydrolysis of these salts yields aldehydes (78 81-99% Scheme 5). Enecarbamates, such as (79), give formylation products (80 26-94%) in the Vilsmeier-Haack reaction (Scheme 5). ... 

When 3-cyano-l-methylpyridinium iodide (X) is heated in 2 N aqueous NaOH together with methylamine hydrochloride, 2-(methylamino)pyridine-3-carbaldehyde (A) is formed in 60% yield. 

Aminocyclopentane-l-carboxylic acid undergoes a similar reaction with pyridine-3-carbaldehyde in the presence of N-phenylmaleimide to afford a spirocyclic cycloadduct, the maleimide cycloadduct of azomethine ylide 109 (84CC182). 

Soai K, Niwa S, Hori H Asymmetric self-catalytic reaction — Self-production of chiral l-(3-pyridyl)alkanols as chiral self-catalysts in the enantioselective addition of dialkylzinc reagents to pyridine-3-carbaldehyde. J Chem Soc Chem Common 1990, (l4) 982-983. 

Scheme 5 Faster reaction with pyridine-3-carbaldehyde than benzaldehyde...

As described in the preceding sections, we already had experience on the enantioselective alkylation of aldehydes with dialkylzincs and the enantioselective synthesis of 3-pyridyl alkanol. In 1990, we found the first asymmetric autocatalysis of (5)-3-pyridyl alkanol 6 in the enantioselective addition of i-Pr2Zn to pyridine-3-carbaldehyde 7 to produce more of itself of 35% ee with the same S configuration (Scheme 6) [24]. Although the ee of product 6 decreased compared to that of the initial catalyst, the newly formed predominant enantiomer of the product is the same with that of asymmetric autocatalyst 6. We claim that this is the first asymmetric autocatalysis, that is, catalytic replication of chiral compound with the generation of new stereogenic centers. 

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