A-Methylene-/ -lactam

In Entry 11 the dienophile is an a-methylene lactam. As noted for this class of dienophiles, the stereoselectivity results from preferred exo addition (see p. 471). The reaction in Entry 12 was used in an enantiospecific synthesis of estrone. The dienophile was used in enantiomerically pure form and the dioxolane ring imparts a high facial selectivity to the dienophile. The reaction occurs through an endo TS. 

In order to obtain stereoselective formation of the chiral centers C-3, C-7, and C-14, we explored the use of chiral derivatives of our indoloaze-pine 153. Earlier, we had already found that the A(-benzylindoloazepine ester 215 rearranged on heating to an a-methylene lactam 216, indicating the possibility of thermal generation of an intermediate secondary amine indoloacrylate 217. It was also found that this intermediate could be trapped with a variety of aldehydes. Thus, D-seco D-E-trans vincadiffor-mine congeners (218) could be obtained by condensation of the indoloaze-pine 215 with aldehydes at 100°C (Scheme 54) (132). Consequently, introduction of a chiral substituent onto N of the indoloazepine 153 prior to condensation with our 4-ethyl-4,5-dihydroxypentanal acetonides 186 and 187 appeared to be an option for chiral induction in the formation of cen-... 

Fletcher and Kay83 have obtained a-methylene-/ -lactams in good yield from 3-bromo-2-bromomethylpropionamides by an internal N-alkylation of the amide, followed by elimination. 

Pd(OAc)2] in the presence of PPh3 was used as catalyst. The use of vinyl bromides in lactam formation has also been reported.498 Imides were obtained from aryl bromides. The method has further been applied to the synthesis of diazepam and 1,4-benzodiazepines499 and to a-methylene lactams and lactones.S00 501 In connection with the synthesis of natural products, the reaction has been employed in the preparation of hexadehydrohimbane,502 anthramycin503 and berbine derivatives.504 The catalyst was prepared in situ from [Pd(OAc)2] (106) and PPh3 in all cases. The mechanism of lactam formation is analogous to that for amides (Scheme 42). 

P-Lactams. Carbon monoxide inserts into 2-bromo-3-aminopropene derivatives in the presence of a catalytic amount of Pd(OAc)2 and triphenylphosphine to give a-methylene- -lactams in 38-89% yield. Pd(acac)j can be used instead of Pd(OAc)2 with similar results. ... 

Although armed with a wealth of experience in the field,68 several stereochemical problems proved unavoidable, and Rapoport finally resorted to interception of Evans route, thus doubly formalizing his synthesis. However, the construction of the key intermediate, via an effective a-methylene lactam rearrangement, is markedly different. 

Romo and coworkers have utilized an enantioselective Cu(II)-catalyzed Diels-Alder cycloaddition to set the key all-carbon quaternary stereocenter in the spiro-cyclic imine core of the marine toxin immunogen (—)-Gymnodimine (251) [76]. Cu(SbF6)2/t-Bu-BOX (13)-catalyzed cycloaddition of diene (248) to a-methylene lactam (247) provides spirolactam (249) in high yield with high stereoselectivity (Scheme 17.55). Subsequent synthetic efforts resulted in an efficient synthesis of the spirocyclic imine portion of (251). 

Cyclic 8-amino acids rearrange to a-methylene lactams upon treatment with acetic anhydride, as shown in eq 11. ... 

In 2014, Lei and You demonstrated the -lactam scaffold synthesis through the oxidative carbonylation of iV-allylamines in the presence of palladium catalyst, thus a series of (19 examples) a-methylene- -lactams was produced smoothly (Table 15.11) [16]. DFT calculations indicated that a four-membered-ring... 

Table 15.11 Selected products of a-methylene- -lactam formation through the carbonylation of A/-allylamines . ...

Carbonylation of halides in the presence of primary and secondary amines at I atm affords amides[351j. The intramolecular carbonylation of an aryl bromide which has amino group affords a lactam and has been used for the synthesis of the isoquinoline alkaloid 498(352], The naturally occurring seven-membered lactam 499 (tomaymycin, neothramycin) is prepared by this method(353]. The a-methylene-d-lactam 500 is formed by the intramolecular carbonylation of 2-bromo-3-alkylamino-l-propene(354]. 

The reaction can be applied to allyl malonates. Alkylation of diallyl mal-onate (734) with bromoacetate and acetoxymethylation afford the mixed triester 735. Treatment of the tricster 735 with Pd catalyst affords allyl ethyl itaconate (736). In a similar way, a-methylene lactone and the lactam 737 can be prepared[462]. 

The a-methylene-/3-lactam 103 is obtained by the carbonylation of the inethyleneaziridine 102 under mild conditions[91]. The azirine 104 undergoes an interesting dimerization-carbonylation to form the fused )3-lactam 105[92]. 

N-(n-Butyl)>a-methylene-3-lactam (2). CO was bubbled through Pd(OAc)2 or Pd(Ph3P)4 (0.136 mmol) in CH2CI2 (4 mL) After 2 rmn PhsP (0 54 mmol) n CH2CI2 (2 mL) is added followed by aziridine 1 In CH2CI2 After 40 h, the solvent was removed in vacuum and the residue purified by prep tic (silica gel, hexane ElOAc 8 1) to yield 2 (79%)... 

Scheme 6.177 a-Methylenation of ketones [335], lactam formation from lactones [336], urea formation [337], and Knoevenagel condensation [338, 478]. 

Lactams. a-Methylene-0-lactams can be prepared by carbonylation of 2-bromoallylamines catalyzed by Pd(OAc)2 or Pd(acac)2 and P(C6H5)3.1 Example ... 

Optically active a-methylene-(3-lactam 10 was synthesized and submitted to 1,3-dipolar cycloadditions with diazomethane, 4-methoxybenzonitrile oxide, and diphenylnitrone [51]. All cycloadditions proceed with complete regioselectivity giving products 11-13 in an anhfashion with respect to the substituent at the... 

In continuation to this, they used ot,(3-unsaturated (3-lactams 79 for the construction of spirocyclic compounds 80-82 (Scheme 21) by the addition of a methylene... 

Electron-poor a-methylene-(3-lactams were reported to undergo cross-metathesis more rapidly and efficiently than more electron-rich analogs. Significantly, tetrasubstituted alkenes have for the first time been accessed by cross-metathesis reactions (III, Fig. 27), [308]. 

The methylene group adjacent to the carbonyl group in a /3-lactam is weakly acidic and compound 164 was alkylated to give 165 by the action of lithium diisopropylamide (LDA) and acetyl trimethylsilane (Equation 18) <1996TL2467>. 

Ozonolysis has also been demonstrated to play a role in the production of another important intermediate in (3-lactam synthesis, hydroxyl-cepham sulfoxide esters 92.84 Ozonolysis plays a role in the conversion of a methylene group in compound 93 into the required hydroxy group in compound 92 (Scheme 11.25). 

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