Five-membered rings Grignard reagents

The ketocarbene is formed from 3-phenylpropanoyl chloride (dihydrocinnamic acid chloride) and diazomethane ring substituted dihydrocinnamic acids provide a route to substituted azulenes. Alternatively the keto group in (25) may be treated with a Grignard reagent for the introduction of alkyl substituents into the five-membered ring. 

Richey and Veale have also reported a study of the effect of phenyl substitution on the rate of Grignard cyclizations to yield three- and five-membered rings (56). The phenyl substitution in Grignard reagents 5 and 6 led to rates of deuterium label equilibration [analogous to Eq. (6)]... 

This method of preparation has been developed primarily by Lukes (103,104). N-Methyl lactams (117) with five- and six-membered rings plus Grignard reagents yield the l-methyl-2-alkyl pyrroUnes (118, = 1) and l-methyl-2-alkylpiperideines(118, n = 2), respectively, plus 2,2-dialkylated bases (119) as by-products (103). For example, l,3-dimethyl-2-piperidone... 

Lukes studied the reaction of N-methyl lactams with Grignard reagents. With the five- (39-42) and six-membered (43-47) rings, 2,2-dialkylated bases (16, = 1,2) are formed as by-products in addition to the l-methyl-2-alkyl pyrrolines (15, = 1) or l-methyl-2-alkyl piperideines (15, =2). Aromatic Grignard reagents afford only the unsaturated bases, probably because of steric factors (48,49). Separation of enamines and 2,2-dialkylated amines from each other can be easily achieved since the perchlorates of the enamines and the picrates of 2,2-dialkylated bases crystallize readily. Therefore enamines can be isolated as crystalline perchlorates and the 2,2-dialkylated bases as crystalline picrates. Some authors who repeated the reactions isolated only pyrrolines (50,57) or, by contrast, 2,2-dialkylated bases (52). This can be explained by use of unsuitable isolation techniques by the authors. 

N-Methyl-2-phenyl-A2-tetraJiydropyridine and similar compounds have previously been prepared by the hydrolysis and decarboxylation of a-benzoyl-N-methyl-2-piperidone3 and by the addition of phenyl Grignard reagents to N-methyl-2-piperidone followed by dehydration.4 Both of these methods require that a heterocyclic ring already be present in the system. In contrast, this procedure offers a new flexible route to the construction of five- or six-membered heterocyclic rings which may easily be incorporated into a larger polycyclic product. Several examples of this process that can be cited to demonstrate this utility are... 

The reaction of Grignard reagents with -methyl lactams has been studied by Luke ef al. With the five- and six-membered rings, 2,2-dialkylated bases (20) are formed as by-products in addition to the expected l-methyl-2-alkylpyrrolines125-128 and l-methyl-2-alkyl-... 

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