Amines from lactams

Sodium tetrahydridoborate I alcohols Cyclic amines from lactams s. 44, 72... 

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. 

As in 10-55 hydrazides and hydroxamic acids can be prepared from carboxylic esters, with hydrazine and hydroxylamine, respectively. Both hydrazine and hydroxylamine react more rapidly than ammonia or primary amines (the alpha effect, p. 445). Imidates, RC(=NH)OR, give amidines, RC(=NH)NH2. Lactones, when treated with ammonia or primary amines, give lactams. Lactams are also produced from y- and 5-amino esters in an internal example of this reaction. 

When the 2H-1,3-thiazine derivatives (236) were allowed to react with diphenylketene or with chloroacetyl chloride and a tertiary amine, /3-lactam systems 237 and 238 were obtained (Scheme 96) (85BSB149). Instead of 3,4-cyclocondensation, as in the previous case, 2,3-cyclocondensation may be obtained by starting from 6//-l,3-thiazines (239) (Scheme 97)... 

Using LiAlH4 is a widespread method to generate piperidine rings from lactams. Mechanistically the tetrahedral intermediate 46 is formed first, and this then collapses to the iminium ion 47. The iminium ion is of course more electrophilic than the carbonyl group. Thus after a hydride transfer to the iminium ion and repetition of the reaction sequence again, the tertiary amine 49 is formed. As a matter of principle parallel to this reduction sequence the ketone in ring B is reduced to form 50. 

A practical method for the synthesis of gem-2,2-disubstituted tertiary amines from the corresponding lactams (or amides) has been reported. It is based on the reaction of thioiminium ions, easily prepared from lactams and amides with primary alkylcerium reagents.40... 

Chiral enolates in which the auxiliary is in the ester portion provide still another route to optically active lactams. Early results indicated that little asymmetric induction was obtained with menthyl enolates. Use of the enolate obtained from 24 did lead to high levels of asymmetric induction. Treatment of 24 with lithium diisopropylamide in tetrahydrofuran, followed by addition of imine 25, gives cf -/(-lactam 26 in 79% yield and 91%ee98. Optically active /3-lactams can be prepared by addition of chiral iron enolates (see Section D.l. 1.1.3.2.) to imines99-101. Addition of aluminum enolate 27 to imine 28, followed by oxidative cyclization with iodine and an amine, affords /(-lactam 29 in 54% yield and >95% ee. 

Aziridines (351) and oxiranes (353) derived from ) -lactam compounds react with aromatic amines in a boron trifluoride-diethylether catalyzed reaction to give enaminopyrrolo[2,l-fc]thiazoles (352) and the pyrrolothiazole (354) respectively (Scheme 64) <86JCS(p1)2195>. 

Schiff bases s. Azomethines Schlotterbeck s. Buchner Schmidt reaction 17, 524 —, amines from carboxylic acids 19, 305 20, 366 —, lactams from ketones, cyclic, ring expansion... 

In a model study, the saturated 14-membered D ring of madangamine D was assembled by two alternative methodologies, lactamization and reductive amination, from the 3,3-disubstituted piperidine derivatives 78 and 79, which incorporate the required 11 -carbon chain, ending with either a car-boxy or a formyl functionality. These precursors were prepared by controlled oxidation of alcohol 77, which in turn was obtained from 2-piperidone 76, as outlined in Scheme 18. Operating under high-dilution conditions, acid 78 was converted to macrocychc lactam 80, whereas aldehyde 79 afforded macrocychc amine 81." ... 

Pingen D, Vogt D (2014) Amino-alcohol cyclization selective synthesis of lactams and cyclic amines from amino-alcohols. Catal Sci Technol 4(l) 47-52... 

The cyclic carbonate of benzoin (4,5-diphenyl-l,3-dioxol-2-one, prepared from benzoin and phosgene) blocks both hydrogen atoms of primary amines after dehydration acid stable, easily crystallizable Sheehan oxazolinones are formed, which are also called Ox derivatives. The amine is quantitatively deblocked by catalytic hydrogenation in the presence of 1 equiv. of aqueous acid (J.C Sheehan, 1972, 1973 M.J. Miller, 1983). An intelligent application to syntheses of acid labile -lactams is given in the previous section (p. 161). 

Allylic phosphates are used for carbonylation in the presence of amines under pressure. Carbonylation of diethyl neryl phosphate (389) affords ethyl homonerate (390), maintaining the geometric integrity of the double bond[244]. The carbonylation of allyl phosphate in the presence of the imine 392 affords the /3-lactam 393. The reaction may be explained by the formation of the ketene 391 from the acyl phosphate, and its stereoselective (2 + 2] cycloaddition to the imine 392 to give the /3-lactam 393(247],... 

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