Lactams reaction with Grignard reagents

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. 

Cyclic enamines with an isomeric position of the double bond have been obtained by the addition of Grignard reagents to five- (78-81), six- (82-86), seven- (87-90), and thirteen- (89-91) membered lactams, whereas other medium-sized (92,93) lactams furnished amino ketones. The reaction has been extended to substituted lactams (94-98), and iminoethers (99,100). 

The intramolecular cyclization route to p-lactams still provides interest. P-Amino esters (obtained by a Reformatsky-type reaction of an imine and bromoacetates derived from chiral alcohols) are cyclized by the action Grignard reagents to 4-substituted P-lactams with impressive e.e. <96TL4095>. A similar approach through a Reformatsky-type reaction uses tricarbonyl(Ti -benzaldimine)chromium complexes and ultrasound <96T4849>. 3-Methyl-azetidin-2-ones (obtained from 3-amino-2-methylpropionates) have been resolved and their... 

Methyl l,3-indandione-2-carboxylate, 299 N-Methyl lactams, reaction with Grignard reagents, 93... 

Other carbon nucleophiles may also be employed in such a coupling reaction that provides (3-amino ketones and polyol intermediates. As shown in Scheme 32, aryl-Grignard reagents react at low temperature with the Ai-Boc p-lactam 96 to afford p-aminoketones 97 in 90-96% yields as the exclusive products. In no case over-addition is observed, even when an excess of the Grignard reagent is present in the reaction medium. On the other hand, when the reaction is performed at room temperature, only tertiary carbinols 98 are produced. 

Further, Taylor and co-workers carried out reactions to attach a suitable side chain at nitrogen, which subsequently could be cyclized to give aza analogues of ft-lactam antibiotics. Thus, the readily available inner salt 1,1-disubsti-tuted-3-oxo-l,2-diazetidinium tosylate 209 was selectively reduced at the side chain attached to N-l of 210 by sodium borohydride, or was alkylated selectively at the side chain by the reaction of 210 with a Grignard reagent (Scheme 30) <1984JOC4415>. 

The amide and lactam groups in 136 and 137 are inactive when boiled with concentrated HC1 on reaction with Grignard reagents they yield trialkylgermyl derivatives (equation 35). According to the IR spectra, there is no intramolecular O — Ge interaction in compounds of type 141480. 

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-... 

Enantiomerically enriched or pure benzaldehydeimine complexes react with nucleophiles such as Grignard see Grignard Reagents) and organozinc reagents, and they participate in a number of cycloaddition reactions. Enantiopure tricyclic /3-lactams can be obtained from stereoselective [2 - - 2]cycloaddition between a complexed chiral benzaldehyde imine and a ketene (Scheme 85). For example, reaction of (44) with acetoxyketene gives (45). 

Lukes and coworkers " developed a very simple and useful method for the preparation of heterocyclic enamines. A-M ethyl lactams with five- and six-membered rings (104, n = 1,2) give, with Grignard reagents, l-methyl-2-alkyI(aryl)-2-pyrrolines (105, n = 1) and l-methyl-2-alkyl(aryl)-2-piperideines (105, n = 2), respectively. 2,2-Dialky-lated bases (106, n = 1,2) are by-products of this reaction. Aromatic Grignard reagents afford only the unsaturated bases, probably because of steric factors " ". Some authors who repeated the reactions isolated only pyrrolines or, in other cases, 2,2-dialkylated bases . This can be ascribed to the use of unsuitable isolation technique by the authors. The reaction was also carried out with various substituted and non-methylated lactams . ... 

Imino aldol reaction of ketene silyl acetals with the chiral imine derived from tartaric acid 83 in the presence of a cation-exchange resin provided the corresponding /i-amino esters 84 in a good yield and high diastereose-lectivity [68]. The esters 84, thus obtained, were subjected to the Grignard reagent which promoted S-lactam formation. After a sequence of reactions compound 84 was transformed into the ester 85 [68] which in the past was... 

---