Ketenes to imines

Addition of ketenes to imines addition of enamines to isocyanates... 

An important point, however, is that although the configurations of the reactants are preserved in the products (i.e. the additions are stereoselective), some cycloadditions, including those of ketenes to imines, occur more rapidly in polar rather than in non-polar solvents (Scheme 8.9). For such examples it may well be that the addition proceeds in a stepwise manner (non-concerted), and the collapse of a dipolar intermediate is so quick that the stereochemistry of the reacting species is not compromised. 

Addition of ketenes to imines addition of enamines to isocyanates 8-17 Reaction between cyclic ketones and hydrazoic acid (Schmidt)... 

Other 1,2-cycloadditions have been accomplishedphotochemically. The photolytic decomposition of diazoketones in the presence of imines to give azetidinones [see, for example, Eq. (80)] is sometimes preferable310 to the direct chemical addition of ketene to imine. Diazetidinones of general structure (291) can be prepared311 either by thermal or photochemical addition of ketenes to azobenzenes, or by photolysis of diazoketones in azobenzene. 

Cossio, F. P., Lecea, B., Cuevas, C., Mielgo, A., Palomo, C. A novel entry for the asymmetric Staudinger reaction experimental and computational studies on the formation of P-lactams through [2+2] cycloaddition reaction of ketenes to imines. An. Quim. 1993, 89, 119-122. 

Lewis Acid Assisted Nucleophilic Addition of Ketenes to Imines ... 

Over the last 12 years direct formation of a four-membered /8-lactam ring via [2 + 2 jcyclo addition of ketenes to imines and of isocyanates to olefins dominated over other methods. Because of the well-defined transition states, both cycloadditions usually offer an excellent stereoselectivity. In the case of cycloaddition of ketenes or their equivalents to imines, the cycloadducts were used not only for the synthesis of /8-lactam antibiotics, but also as intermediates for the preparation of other biologically active compounds. 

Owing to the importance of p-lactam antibiotics, the [2+2]cycloadditions of ketenes to imines and isocyanates to olefins play a special role because both reactions lead to direct formation of a four-membered azetidinone-2 ring. The first one can be performed using a large variety of ketenes and ketene equivalents, whereas the second one leads to useful compounds only in the case of chlorosulfonyl isocyanate and vinyl acetates, vinyl silyl ethers, and dienes. One example of the addition of an isocyanate to a vinyl ether has been reported (Scheme 1). ... 

Cycloaddition reactions of ketenes to imines derived from glycosylamine and aldehydes provide access to P-lactams, although the level of selectivity observed with these N-linked auxiliaries is modest. The alkenyl moiety of glycoside 212 undergoes diastereoselective epoxidation using peracid in 80 %d.e. Simmons-Smith cyclopropanation of 212 was reported earlier (Vol. 25, p.335). 

Monocyclic /3-lactams undergo thermolysis or photolysis to give alkenes and isocyanates or ketenes and imines depending on the substitution pattern (75S547 p. 586). Apparently, thermolysis favours the former pathway while photolysis favours the latter (68CB2669). 

The first /3 -lactam was produced by addition of a ketene to an imine and there are now many examples of this type of approach. The ketenes are most frequently generated in situ from acid chlorides by dehydrohalogenation, but have also been produced from diazo ketones, by heating of alkoxyacetylenes and in the case of certain cyanoketenes by thermolysis of the cyclic precursors (162) and (163). 

Two extreme mechanisms can be envisaged (Scheme 12), concerted [2 + 2] cycloaddition or the more generally accepted formation of a dipolar intermediate (164) which closes to a /3-lactam or which can interact with a second molecule of ketene to give 2 1 adducts (165) and (166) which are sometimes found as side products. In some cases 2 1 adducts result from reaction of the imine with ketene dimer. 

Ketenes also add to imines in 2 + 2 cycloadditions giving the important g-lactams (20). The reglochemistry is predictable as the nitrogen is the nucleophilic atom in the imine. This is true even in conjugated imine (21) which gives (22) with azidoketene. The azido group can... 

Recently, N-aryl sulphimides were found to react with diphenyl cyclopropenone and its thione226 giving rise to imines 331 and 332. Apparently attack of the sulph-imide at cyclopropenone C3 gives rise to intermediacy of a ketene 330, which is consumed by an excess of the sulphimide (to give 331 after hydrolysis) or by its Somme-let-Hauser rearrangement (to give 332) ... 

Cycloadditions give rise to four-membered rings. Thermal concerted [2+2] cycloadditions have to be antarafacial on one component and the geometrical and orbital constraints thus imposed ensure that this process is encountered only in special circumstances. Most thermal [2+2] cycloadditions of alkenes take place by a stepwise pathway involving diradical or zwitterionic intermediates [la]. Considerably fewer studies have been performed regarding the application of microwave irradiation in [2+2] cydoadditions than for other kinds of cydoaddition (vide supra). Such reactions have been commonly used to obtain /1-lactam derivatives by cycloaddition of ketenes with imines [18-20,117,118],... 

Although four-membered rings are highly strained and not very stable heterocycles, there are some examples (Fig. 3.5) for the preparation of heterocycles of this type on solid supports. Different /9-lactams (229-230) have been synthesized employing different synthetic pathways [133, 275, 306-309] such as the addition of ketenes (Scheme 3.34) [306], or ester enolates to imines [133]. Also the synthesis of four-membered rings with two heteroatoms has been reported [310]. 

Cycloaddition of ketene and imine to form 3-lactam. Other coupling partners for ketene also include olefin to give cyclobutanone and carbonyl to give 13-lactone. 

In an analogous late-stage arylation approach, terminal alkyne 31 was envisioned as a versatile intermediate. Slow addition of 4-pentynoyl chloride to imine 3 and (n-Bu)3N at reflux (efficient condenser, 100°C, 12 h, 1 1 toluene heptane) afforded only trace amounts of 31. Reaction of 4-pentynoyl chloride with triethylamine in methylene chloride under preformed ketene conditions ( 78°C, 1 h), followed by addition of 3 and warming to — 10°C over 4 h, afforded a complex mixture of products. Since high-yield preparation of 31 remained elusive, access to internal alkynyl analogs (type 33) was accomplished by preassembly of the appropriate arylalkynyl acid substrate for the ketene-imine cycloaddition reaction (Scheme 13.9). 

Photocyclization of a,/3-unsaturated amides (152) also gives /3-lactams. This proceeds by cleavage of the intermediate biradical (153) to give ketene and imine which recombine. A small amount of amide (154) results from reaction of the ketene with amine that is produced by hydrolysis of the imine. This type of photodealkylation detracts from the generality of the process (79JCS(P1)263, 77T485). 

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