Alicyclic lactams

The hydroxamic acid function in most alicyclic and aromatic compounds is stable to hot dilute acid or alkali, and derivatives cannot undergo normal base-catalyzed Lessen rearrangement. Di Maio and Tardella," however, have shown that some alicyclic hydroxamic acids when treated with polyphosphoric acid (PPA) at 176°-195° undergo loss of CO, CO.2, or H2O, in a series of reactions which must involve earlj fission of the N—0 bond, presumably in a phosphoryl-ated intermediate. Thus, l-hydroxy-2- piperidone(108) gave carbon monoxide, 1-pyrroline (119), and the lactams (120 and 121). The saturated lactam is believed to be derived from disproportionation of the unsaturated lactam. 

In 1979, Olah [47] reported a one step conversion of alicyclic ketones into lactams by means of hydroxylamine O-sulfonic acid and formic acid under reflux for a few hours. More recently this reaction has been realized under solvent-free conditions with Si02 as inorganic support and focused irradiation, as exemplified in Scheme 8.29 for caprolactam synthesis. 

There have been a number of reports where alicyclic-bridged precursors underwent an IAAC reaction. Thus, the dioxolane (203b), formed from triflate (203a), cyclized in situ to a tricyclic triazoline (Scheme 63).113 Treatment of this triazoline with sodium ethoxide converted it to a diazopyrrolidine in 86% yield, which underwent smooth catalytic hydrogenation in 89% yield. The (Z)-azidoalkene (204), bridged by a (3-lactam, cyclized at 20 °C to triazoline (205).114 The triazoline (205) extruded nitrogen at 80 C providing a tricyclic aziridine. The ( )-isomer of (204) did not cyclize to a triazoline but instead produced an azirine, presumably via a nitrene intermediate. 

Scheme 91 Liquid-phase synthesis of alicyclic P-lactams via Ugi three-component reaction...

Figure 56 lipase-catalyzed enantioselective ring opening of unactivated alicyclic /J-lactams. 

Forro, E. Fulop, F. Lipase-catalyzed enantioselective ring opening of unactivated alicyclic-fused / lactams in an organic solvent. Organic Letters 2003, 5(8), 1209-1212. 

Gyarmati, Z. Cs. Liljeblad, A. Rintola, M. Bemath, G. Kanerva, T. L. Lipase- catalyzed kinetic resolution of 7-, 8- and 12-membered alicyclic fi-amino esters and N-hydroxymethyl-/ -lactam enantiomers. Tetrahedron Asymmetry 2003, 14, 3805-3814. 

A more direct method for the enantioselective ring opening of unactivated bicyclic /3-lactams has been reported. When lipolase (modified lipase B from Candida antarctica adsorbed on a macroporous resin) was allowed to interact with racemates 126 (n 1 or 2) and 127 (n= 1 or 2) in aqueous diisopropyl ether at 70 °C for 4.5-7 h, the products were the enantiomerically pure ring-opened unsaturated alicyclic /3-amino acids 128 (n = 1 or 2) and 129 (n 1 or 2), and the bicyclic /3-lactams 130 ( = 1 or 2) and 131 (n = 1 or 2) in 45 48% yield with ee 95-99% (Equations 13 and 14) <2004TA2875>. 

The synthesis of fused alicyclic ft-lactams by the four-center three-component Ugi reaction (U-4C-3CR) on a solid support has been reported. Also, resins have been used as scavengers in the purification of fused /3-lactams prepared in the solution phase <2004MI215>. 

Alicyclic P-lactams 28 were successfully synthesized via a parallel liquid-phase Ugi four-center three-component reaction, starting from alicyclic P-amino acids such as cis-2-aminocyclohexanecarboxylic acid, c/.s-2-aminocyclopentanecarboxylic acid, 2,3-diexo-3-aminobicyclo-[2.2.1]heptane-2-carboxylic acid and some of their partially unsaturated analogues <02OL1967>. 

Alicyclic tertiary amines often generate lactam metabolites by or-carbon hydroxylation reactions. For example, the tolmcco alkaloid nicotine is hydroxylated initially at the ring carbon atom a to the nitrogen to yield a carbinolamine intermediate. Furthermore, en/.ymatic oxidation of this cyclic carbinolaminc generates the lactam metabolite coti-ninc." ... 

The 1,2-dipolar cycloaddition of chlorosulfonyl isocyanate to different cycloalkenes has become a well-known route for the synthesis of cycloalkane-fused p-lactams, and for alicyclic P-amino acids, after hydrochloric acid treatment. The addition takes places regio- and stereospecifically, in accordance with the Markovnikov orientation rule [51-55]. In this manner, a number of homologue and analogue alicyclic P amino acids have been prepared, such as czs-2-amino-2-methylcyclopentanecarboxylic acid [56], m-2-amino-2-methylcyclo-hexanecarboxylic acid [56], (l/ , 2S, 4S )2-amino-4-terMnitylcyclopenta-necarboxylic acid [55, 58], 3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid [59, 60] and 3-exo-aminobicyclo[2.2.1]hept-5-ene-2-exo-carboxylic acid [61]. 

An improved one-step conversion of alicyclic ketones (30) into lactams (31 n = 3-10) involves the use of hydroxylamine-O-sulphonic acid and methanoic acid at reflux temperature. Treatment of 1-chloro-l-nitroso- and 1-chloro-l-nitro-cycloalkanes (32) with PhaP and then hydrolysis of the intermediate chloro-imine provides a new route to (31 n — 3-6, or 10)." ... 

Formation of lactams 431 was achieved in good yields (60-86%) by allowing a mixture of alicyclic-ketones 429 and hydroxylamine-(9-sulfonic acid adsorbed on Si02 to be irradiated in a focused MW oven for 10-20 min (Scheme 85). The reaction proceeded by forming the oxime 430 and sulfuric acid, which promoted a Beckmann rearrangement of 430 to give lactams 431 (95JCS(CC)1101). 

With alicyclic heteroring compounds With lactams and derivatives [Co(C4H,NO),](C104)3 297 10831 c. 5.11 Farad probably octahedral 67M6... 

Isomerizations also occur during the carbonylation of unsaturated alicyclic amines for example, the carbonylation of (3-cyclohexenyl-methyl) amine leads, besides the expected bicyclic six-membered lactam, also to a five-membered lactam. 

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