Cycloadditions of Ketenes with Imines

The three most important reactions for generating ketenes are the base-mediated dehydrochlorination of acyl chlorides, the dehalogenation of a-chloroacyl chlorides, and the transformation of a-diazoketones. These three methods have been explored under microwave conditions. 

The Bose research group has developed a large variety of [2+2] cycloaddition reactions of ketenes with imines to form yS-lactams [16, 112, 113]. In 1991, Bose et al. described the synthesis of a-vinyl yS-lactams by [2-p2] cydoaddition of a,p-unsaturated acyl chlorides with a SchifF base in chlorobenzene. Reaction times were reduced from several hours with conventional methods to 5 min under the action of microwaves [112], and yields of the desired adducts were improved from very low to approximately 70% when compared with classical methods. 

An efficient and rapid method for synthesis of jS-lactams under solvent-free conditions in the presence of a phase-transfer agent (18-crown-6) in a closed Teflon vessel has also been developed by Hamelin et al. [46a]. The same solvent-free approach has also been successfully used by Kidwai et al. for synthesis of N-(4-hydroxycyclohexyl)-3-mercapto-3-cyano-4-arylazetidine-2-ones [40]. The adducts 

These results indicate that the zwitterionic azabutadiene intermediates generated from imines 227 or 228 and ketenes undergo a conrotatory ring closure only to produce j5-lactams 229 or 230. This reveals the inapplicability of the Woodward-HofFmann rules to the photoirradiation-induced Staudinger reaction. Second, when acyclic imines 227 were employed, to Z isomerization of the imine moiety in the zwitterionic intermediates occurs, induced by microwave or ultraviolet irradiation. The results also provide direct experimental evidence for the proposed stereochemical process of the microwave and photoirradiation-induced Staudinger reactions, which, in conjunction with the results of Podlech 

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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],... 

The synthesis of 1,3-disubstituted-4-trichloromethyl azetidin-2-ones by the Staudinger cycloaddition of ketenes with imines derived from chloral has been described to occur with high stereoselectivity [91], The civ-isomer was obtained almost always as the major or the single product. 

Lower levels of asymmetric induction are typically seen in the cycloadditions of ketenes with imines bearing chiral substituents on the nitrogen, although in exceptional cases excellent results are obtained. Cycloaddition of imine 23 (X = F), obtained from fluoroacetaldehyde and 1-phenylethylamine with phthalimidoketene, gives a 59% yield of m-/Mactam 24 in 81 19 d.r.68. Imine 23 (X = Cl) gives a 74% yield of cw-/f-lactam 24 in 90 10 d.r.69. 

By forming adducts with azolecarbenes, cycloaddition of ketenes with imines to form P-lactams is facilitated. Azolecarhenes such as 133 and 134 induce chirahty because in the enolates (initial adducts) the elements of asymmetry can dictate the approach of the reactants. Of particular interest is the reaction between enals and conjugated imines that leads to bicylic structures. 

The [2H-2]-cycloaddition of ketenes with imines is an excellent method for the generation of azetidinones, generally providing good yields and allowing a wide latitude in substitution pattern on the product. The major advances in this field during the period covered by this review have been in the synthesis of optically active compounds by asymmetric induction in the cycloaddition step. Chiral auxiliaries have been employed at all four positions of the azetidinone ring. 

The [2+2] cycloaddition of ketenes with imines to form P-lactams is perhaps the most studied of ketene reactions, and because of the continued search for new drugs continues to attract close attention. The reaction of methylketene with the bis-imine forms the dx-monoadduct as the only observed mono-addition product (Scheme 7.54). 

Even though aza-p-lactams have attracted interest because of their biological activities, only limited progress has been reported with regard to the enantio-selective synthesis of this family of heterocycles. The Staudinger [2-1-2] cycloaddition of ketenes with imines is a versatile and efficient route to... 

The 2 + 2-cycloaddition reaction of a-alkoxyketene-derived imines yields /l-lactams with quaternary stereogenic centres at C(4).33 The 2 + 2-cycloaddition of chiral aminoketenes with chiral imines yields cis-fi-lactams with the absolute stereochemistry of file C(3) and C(4) positions being controlled by the ketene partner only.34 The 2 + 2-cycloaddition of ketenes with (W)-2-/-butyldihydrooxazole (19) yields predominately the regioisomer (20) from steric control rather than the expected electronic control (Scheme 7).35 The double 2 + 2-cycloaddition reaction between ketenylidenetriphe-nylphosphorane (21) and carbon suboxide (22) produces the bis(ylidic) spirocyclobut-anedione (23) (Scheme 8).36 Semiempirical and ab initio calculations have been used to investigate the Lewis acid-promoted 2 + 2-cycloaddition leading to the formation of jS-lactones.37... 

Ab initio calculations indicate that in the gas phase the reaction of ketene inline and formaldehyde is concerted but asynchronous whereas in dichloromethane it is a two-step zwitterionic reaction.38 The 2 + 2-cycloadditions of keteniminium triflates with imines yields 2-azetidiniminium salts with cis stereoselectivity.39 The intramolecular 2 + 2-cycloaddition of ketenimines with imines (24) provides a novel synthesis of azeto[2,l-Z>]quinazolines (25) (Scheme 9).40... 

The thermal [2-1-2] cycloaddition of cumulenes with alkenes, imines or carbonyl compounds is one of the most useful methods of four-membered ring formation. The cycloaddition of ketenes with alkenes to give cyclobutanones represents a reaction of general importance. According to Woodward and Hoffmann, these reactions proceed via a [ttIs+ttIi,] pathway [24]. Dihaloketenes are more reactive than simple ketenes and readily react with electron-rich olefins [25]. 

Reactions of ketenes with imines open a useful route to (3-lactams [27]. The stereospecificity of these reactions has been extensively investigated given the practical importance of 3-lactam antibiotics [28]. The generally accepted mechanism of this cycloaddition is outlined below (Scheme 10.7). 

The [2 -I- 2] cycloaddition of ketenes and imines is an important route to the P-lactam ring (azetidinone), which is a crucial structural feature of the penicillin class of antibiotics. A number of theoretical treatments of this reaction indicate that in solution phase this is a two-step reaction, with the second step being rate determining. The stepwise nature of the reaction is accommodated by the relative stability of both charged moieties, an iminium cation and an enolate anion. 

In 2008, Ye and coworkers reported that chiral NHCs prepared from l-pyroglutamic acid were efficient catalysts for the enantioselective Staudinger reaction of ketenes with imines. The corresponding c/s-p-lactams 158 were obtained in good yields with good diastereoselectivities and excellent enantioselectivities (up to 99% ee) (Scheme 20.66). In the same year. Smith and coworkers independently reported the NHC-catalysed [2 + 2] cycloaddition of disubstituted ketenes and N-tosylimines. ... 

In the same area, enantiopure imidazolinium-dithiocarboxylates have been found to be efficient organocatalysts for the [2 + 2] cycloaddition of ketenes with N-para-a.osy imines. The corresponding cis-N-para-nosy p-lactams were obtained as major diastereomers in excellent yields (96 99%) and moderate to good diastereoselectivities (<78% de) combined with good enantio-selectivities of up to 96% ee, as shown in Scheme 6.21. 

Sometimes, different stereoisomers are obtained in the [2+2] cycloaddition reaction of ketenes with imines depending on the structure of the imine. As an example, ethylketene reacts with alkylarylimines to give cm--lactams, while diarylimines give the trans-fi-lactams. Whenphenoxyketenes are reacted with diarylimines, the CM-]3-lactams are formed. 

Cycloaddition reactions are important in the synthesis of /3-lactams, since these compounds make up the penicillin and cephalosporin antibiotics. Amongst the many computational studies on these synthetic processes, a number have involved comprehensive calculations on the Staudinger reaction, the cycloaddition of ketenes and imines." Once again the solvent effect is found to be important and, although the reaction is shown to be a concerted cycloaddition in the gas phase, in solution the reaction is predicted to be a stepwise process (Figure 2). For substituted systems, the calculations predict that ring-closure in the second step occurs with conrotatory motion, in accordance with experimental observations. 

Scheme 7.28 Formal [2+2] cycloaddition of ketenes with aldehydes and imines.

The cycloaddition of nitrones with ketenes produced 5-isoxazolidinones as well as oxazolones, as shown in Scheme 162 (78H(9)457, 79JOC2961). In a similar fashion, nitrones also react with ketenimines to generate the 5-isoxazolidinone imines (75JHC175, 68JHC881). 

Condensation with imines to afford jS-lactams. These latter ones can also be obtained by cycloaddition of the same imines with the keten stemming from fluoroacetyl chloride. ... 

Gonzalez et al. [105] have further investigated the diastereoselective [2+2] cycloaddition reaction of unsymmetrical cyclic ketenes with imines for the synthesis of a variety of spiro-(3-lactams (Scheme 34). 

Spiro-p-lactams have been synthesized via [2+2] cycloaddition of cyclic ketenes with imines [100]. Opposite trans or cis diastereoselectivity was obtained using different imines with electron-donating or electron-withdrawing (R1) substituents at the N-atom, (Scheme 33). 

Gallop et al. [80] reported the preparation of p-lactams via a [2+2] cycloaddition reaction of ketenes with resin-bound imines derived from amino acids (Scheme 9). This is another solid-phase adaptation of the Staudinger reaction, which could lead to the synthesis of structurally diverse 3,4-bis-substituted 2-azetidinones [81]. In addition, a novel approach to the synthesis of A-unsubstituted-p-lactams, important building blocks for the preparation of p-lactam antibiotics, and useful precursors of chiral p-amino acids was described [82]. 

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