1 Carbon dioxide lactam rings

The reductive ring opening of six-membered nitrogen-containing heterocycles was studied with A-phenyltetrahydroisoquinoline (391). Its lithiation with lithium and a catalytic amount of DTBB (4.5%) afforded the benzylic intermediate 392, which was allowed to react with electrophiles giving, after hydrolysis, functionalized amines 393 (Scheme 110) . It is noteworthy that in the reaction with carbon dioxide, instead of the corresponding lactam, amino acid 393 with X = CO2H was exclusively isolated. 

The characteristic SO2 stretch of thiadiazetidine dioxides occurs at 1160 and 1330 cm-1 (70BCJ3543, 62HCA717). Carbonyls in the 3-position absorb at 1750 cm-1, which is approximately the same place as (3 -lactams (62HCA717,79CB1012). Sulfur, unlike oxygen or nitrogen, does not raise the frequency of absorption when substituted for carbon in the /3 -lactam ring. 

An unusual reaction of a diazolium salt was reported during an attempt to form copper complexes of the NHC.100 The isolated products showed ring expansion of the carbene to form six-membered lactams. The authors verified the product by X-ray crystallography and independent synthesis. It is not clear where the extra carbon comes from. The authors consider a possible mechanism involving a carbene dimer formation, but point out that the carbenes are very hindered. Possible reaction with atmospheric carbon dioxide was not considered. Direct oxidation of the carbene to give a urea is also noted. 

A fourth type of product, a carbamate RNHCOOR , can be obtained from primary or secondary amines, if these are treated with CO, O2, and an alcohol R OH in the presence of a catalyst. " Primary amines react with dimethyl carbonate in supercritical CO2 (see p. 414) to give a carbamate. " Carbamates can also be obtained from nitroso compounds, by treatment with CO, R OH, Pd(OAc)2, and Cu(OAc)2, " and from nitro compounds. " When allylic amines (R2C=CHRCHRNR 2) are treated with CO and a palladium-phosphine catalyst, the CO inserts to produce the p,y-unsa-turated amides (R2C=CHRCHRCONR 2) in good yields. " Ring-expanded lactams are obtained from cyclic amines via a similar reaction (see also, 16-22). Silyloxy carbamates (RNHC02SiR 3) can be prepared by the reaction of a primary amine with carbon dioxide and triethylamine, followed by reaction with triisopropylsilyl triflate and tetrabutylammonium fluoride. ... 

The spectrum of the free acid showed no molecular ion. Ions of highest mass, m/e 30 + and 292, probably arose from the free acid by the hydrolytic elimination of acetic acid and sulfur, and acetic acid and carbon dioxide respectively. An intense peak at m/e + + (CO ) supported this conclusion. Peaks at m/e 216 and 215, expected from the fission across the p-lactam ring, were not observed. Three peaks which may be assigned to the side chain and part of the p-lactam ring were m/e 97 (CsD -CH +), m/e 12 + ( -CH-C=0+), and m/e l8l ( -CH -C0-NH-CH=G=0+). Occolowitz concluded that the spectrum arose by ionization of hydrolysis products of the free acid. 

Recent work has cast doubt on the previous conclusions that ring E of strychnine is a five-membered ring. The a-ketoamide of dihydrostrych-ninone (Ci9His08N2) has been oxidized by barium hydroxide-hydrogen peroxide to carbon dioxide and an amino acid, cuninecarboxylic acid (C18H20O3N2) (232). The carboxyl of this j3-amino acid (on formula XV for strychnine) should be lost by pyrolysis, but on the contrary lactamiza-tion occurred. This unexpected lactamization is explained most satisfactorily by the assumption of a piperidine nucleus for ring E (LXXXIX). 

Across C=0 bonds The [2+2] cycloaddition of ketenes across C=0 bonds to give fi-lactones was extensively investigated by Staudinger and his coworkers. The reaction often proceeds without a catalyst, but added catalysts sometimes alter the course of the reaction. The reaction involves the C=C bond of the ketene, which adds across the C=0 bond of the carbonyl compound. At elevated temperatures, the cycloadducts eliminate carbon dioxide to give olefins. Trihaloaldehydes react especially well to produce the four-membered ring cycloadducts The thus obtained /3-lactones can be converted in a one-pot (two steps) reaction into /3-lactames . 

Hydrolysis of the labeled compound with 2 N sulfuric acid furnished 3-amino-4-methyl-2-hexanone which, on treatment with iodine in the presence of sodium hydroxide, furnished isoleucine and iodoform. The iodoform was oxidized to carbon dioxide, while treatment of isoleucine with ninhydrin furnished 2-methylbutanal, isolated as its 2,4-dinitrophenylhydrazone. Kuhn-Roth oxidation of the aldehyde gave acetic acid which was degraded by the Schmidt procedure to carbon dioxide and methylamine. The 2-methylbutanal was also degraded stepwise by the method of Strassman. Determination of the radioactivity of the various degradation products showed that 94% of the activity was equally shared between the lactam C(2) and side-chain C(10) carbonyl atoms. The remaining activity was shared between C(4) of the lactam ring and the a> carbon atom of the ec-butyl side chain. The results are consistent with derivation of tenuazonic acid from isoleucine and two molecules of acetic acid. However, the direct incorporation of isoleucine into tenuazonic acid was not investigated. 

---