Lactams, from carbenes

The usefulness of this reaction for the preparation of heterocycles under mild conditions became apparent in 1978, when chemists from Merck, Sharp Dohme reported the synthesis of bicyclic 3-lactams by intramolecular carbene N-H insertion [1179]. Intramolecular N-alkylation of P-lactams by carbene complexes is one of the best methods for preparation of this important class of antibiotic and many P-lactam derivatives have been prepared using this methodology [1180 -1186] (Table 4.11). Intramolecular N-H insertion can also be used to alkylate amines [1187-1189], y-lactams [1190], and carbamates [1191-1193] (Table 4.11). 

Scheme 24. Photoassisted formation of p-lactams from chromium carbene complexes.

Extension of this work to the diastereoselective synthesis of y-lactams from N-sulfonyl aldimines [93] and ketimines [94] was subsequently reported. Scheldt and coworkers disclosed an enantioselective version (up to 98% ee) from reactive hydrazones in the initial demonstration of cooperative NHC/Lewis acid catalysis using a bulky, chiral triazolium salt and catalytic Mg(OBu )2 [95]. Rovis and coworkers synthesized y-lactams 109 enantioselectively using a chiral N-C Fs triazolium salt (Scheme 18.19). A weak carboxylate base was sufficient to partially deprotonate the precatalyst 108 in situ, and the carboxylic acid formed could activate the N-Ar imine acceptor 107 via protonation [lib]. In all these cases, a fine balance must exist between sufficient electrophilicity vis-a-vis the competing enal and reversible addition of the carbene to the imine/hydrazone/iminium or to the Lewis acid. 

A final method of /3-lactam 3,4-bond formation which has found fairly wide application is based on carbenlc insertion (78T1731 p. 1739). The carbenic centre can be generated by photolysis of a diazo compound as in the case of (158) (72JA1629, 79CC846) or from organometalllc precursors, for example (159) (71ACS1927). 

Other miscellaneous imines that underwent photoreaction with chromium alkoxycarbenes include iminodithiocarbonates [33],the mono-N-phenylimine of benzil and the bis-JV-phenyl imine of acetoin [20]. By preparing the chromium carbene complex from 13CO-labeled chromium hexacarbonyl, /J-lactams with two adjacent 13C labels were synthesized [34]. 

Chromium aminocarbenes [39] are readily available from the reaction of K2Cr(CO)5 with iminium chlorides [40] or amides and trimethylsilyl chloride [41]. Those from formamides (H on carbene carbon) readily underwent photoreaction with a variety of imines to produce /J-lactams, while those having R-groups (e.g.,Me) on the carbene carbon produced little or no /J-lactam products [13]. The dibenzylaminocarbene complex underwent reaction with high diastereoselectivity (Table 4). As previously observed, cyclic, optically active imines produced /J-lactams with high enantioselectivity, while acyclic, optically active imines induced little asymmetry. An intramolecular version produced an unusual anti-Bredt lactam rather than the expected /J-lactam (Eq. 8) [44]. 

Rh2(OAc)4 has become the catalyst of choice for insertion of carbene moieties into the N—H bond of (3-lactams. Two cases of intermolecular reaction have been reported. The carbene unit derived from alkyl aryldiazoacetates 322 seems to be inserted only into the ring N—H bond of 323 246). Similarly, N-malonyl- 3-lactams 327 are available from diazomalonic esters 325 and (3-lactams 326 297). If, however, the acetate function in 326 is replaced by an alkylthio or arylthio group, C/S insertion rather than N/H insertion takes place (see Sect. 7.2). Reaction of ethyl diazoacetoacetate 57b with 328 also yields an N/H insertion product (329) 298>, rather than ethyl l-aza-4-oxa-3-methyl-7-oxabicyclo[3.2.0]hex-2-ene-2-earboxylate, as had been claimed before 299). 

Reactions of carbenoids with 4-thio-substituted 2-azetidinones have attracted much interest recently. Insertion of the carbene unit derived from diazomalonic esters 297-34°> or ethyl diazo(diethoxyphosphoryl)acetate 340 into the C4—S bond of simple P-lactams 353 and 354 took place irrespective of whether a N—H or a N—R... 

The photoelimination of nitrogen from diazo compounds provides a simple and versatile route for the generation of carbenes, and in certain instances, insertion reactions of carbenes can be employed in the synthesis of heterocycles. Carbenes are believed to be involved at least in part in the photochemically induced conversion of N,N-diethyldiazoacetamide (439) into the y-lactam 440 and the /Mactam 441,365 and a similar approach has been successfully employed in the synthesis of a carbapen-2-em366 and of 7-methylcephalosporin analogues.367 Carbene insertion of a different type has been observed on irradiation of the 6-anilino-5-diazouracils 442 to give the indolo[2,3-d]pyrimidines 443.368 Ring contractions in heterocycles... 

Stang etal. (94JA93) have developed another alkynyliodonium salt mediated approach for the synthesis of y-lactams including bicyclic systems containing the pyrrole moiety. This method is based on the formation of 2-cyclopentenones 114 via intramolecular 1,5-carbon-hydrogen insertion reactions of [/3-(p-toluenesulfonyl)alkylidene]carbenes 113 derived from Michael addition of sodium p-toluenesulfinate to /3-ketoethynyl(phenyl) iodonium triflates 112 (Scheme 32). Replacing 112 by j8-amidoethynyl (phenyl)iodonium triflates 115-119 provides various y-lactams as outlined in Eqs. (26)-(30). 

The diverse chemistry of carbenes is beyond the scope of this account, but a few typical reactions are shown here to illustrate the usefulness of the photochemical generation of these reactive species. A carbene can insert into a C—H bond, and this finds application in the reaction of an a-diazoamide to produce a P-lactam (5.29). Carbenes derived from o-diazoketones can rearrange to ketenes, and thus a route is opened up to ring-contraction for making more highly strained systems <5.301. Carbenes also react with alkenes, often by cycloaddition to yield cyclopropanes in a process that can be very efficient (5.31) and highly stereoselective (5.321. 

Scheme 61, yielded thiazole 200 as the major product, along with minor amounts of carbinol 201 [152]. On the other hand, treatment of the imine formed from 199 and p-methoxyphenylamine with catalytic tetrabutylammonium cyanide, produced suc-cinimide derivative 202. In both cases, the process is initiated by nucleophilic attack to the carbaldehyde C=0 (or azomethine s C=N) group, which is followed up by an anionic rearrangement. A variation of the above process using as catalysts /V-heterocyclic carbenes (NHC) derived from base treatment of azolium, imidazo-lium, or triazolium salts, has also been developed to access gem-disubstituted succinimides [153, 154]. Unfortunately, an attempt of kinetic resolution of racemic 4-formyl (3-lactams by using chiral NHC resulted in moderate selectivities only [154]. 

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. 

Cycloaddition of a ketene complex with unsaturated bonds other than alkenes and alkynes is also possible. The ketene 312, formed from 311, adds to imine 313 to give the /1-lactam 314 under sunlight photolysis. The optically active /1-lactam 314 was prepared from the optically active carbene complex 311 with 99% ee, and converted to 315 [95]. Irradiation of carbene complex 316 generates ketene 317, which cyclizes to the o-hydroquinone derivative 318 [96],... 

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