Mechanisms ketene-imine cycloaddition

Sordo, J. A., Gonzalez, J., Sordo, T. L. An ab initio study on the mechanism of the ketene-imine cycloaddition reaction. J. Am. Chem. Soc. 

The mechanism of the Staudinger ketene imine cycloaddition reaction has been the subject of much debate and has recently been reviewed. The mechanism has been studied both computationally and experimentally. Experimental evidence gathered on solution phase reactions supports a two-step mechanism, in which addition of the imine nitrogen to the ketene carbonyl group occurs to generate an intermediate zwitterion. Subsequent cyclization of the zwitterion results in formation of the key C3-C4 a-bond. 

The imines derived from vicinal dicarbonyl substances afford cis-lactams (Scheme 2), whereas the imines prepared from aryl and alkenyl aldehydes yield trans-lactams (Schemes 3 and 4). The different basis for the stereoselection in the carbonylative cycloaddition from that of the usual base-induced process is worthy of anphasis. The mechanism of this carbonylative formal [2 + 2] cycloaddition is discussed in comparison with the results of the base-induced ketene-imine cycloaddition,... 

Scheme 29 describes a plausible mechanism for the formation of the products which fit the observed coulometric (n 0.45 F/mol) and preparative results. The intramolecular cyclization process involves a dimerization between a radical cation 52a and the ketene imine 52 to form the intermediate radical cation 52b which then cyclizes to the radical 52c which can abstract a hydrogen atom leading to 54 or can be further oxidized and transformed through a cyclization and deprotonation reaction to 53 which involves 1 F/mol. However, it seems that the [2 -1- 3]-cycloaddition between the parent compound 52 and the cation 52d giving rise to 55 is the fastest reaction as compared with the intramolecular cyclization of 52d to 53. This can also explain the low consumption of electricity. 

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). 

Cycloaddition is a member of pericyclic reactions in which reactive components possessing conjugated jr-electrons (e.g., diene/dienophile, 1,3-dipole/dipolarophile, and ketene/imine) transform into cyclic molecules. These reactions proceed in a concerted mechanism with a high degree of regio- and stereoselectivity. Thus, they have been widely used for the construction of cyclic skeletons of numerous natural products and pharmacologically active molecules. Based on the jr-electron systems of reactants, they can be further classihed into [4 + 2], [3 + 2], and [2 + 2] cycloadditions that produce six-, five-, and four-membered rings, respectively. ... 

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. 

The interaction of acid chlorides (167 X = Cl) with imines in the presence of bases such as triethylamine may involve prior formation of a ketene followed by cycloaddition to the imine, but in many cases it is considered to involve interaction of the imine with the acid chloride to give an immonium ion (168). This is then cyclized by deprotonation under the influence of the base. Clearly, the distinction between these routes is a rather fine one and the mechanism involved in a particular case may well depend on the reactants and the timing of mixing. Particularly important acid chlorides are azidoacetyl chloride and phthalimidoacetyl chloride, which provide access to /3-lactams with a nitrogen substituent in the 3-position as found in the penicillins and cephalosporins. 

Abstract The main computational studies on the formation of (3-lactams through [2+2] cycloadditions published during 1992-2008 are reported with special emphasis on the mechanistic and selectivity aspects of these reactions. Disconnection of the N1-C2 and C3-C4 bonds of the azetidin-2-one ring leads to the reaction between ketenes and imines. Computational and experimental results point to a stepwise mechanism for this reaction. The first step consists of a nucleophilic attack of the iminic nitrogen on the sp-hybridized carbon atom of the ketene. The zwitterionic intermediate thus formed yields the corresponding (3-1 actant by means of a four-electron conrotatoty electrocyclization. The steroecontrol and the periselectivity of the reaction support this two-step mechanism. The [2+2] cycloaddition between isocyanates and alkenes takes place via a concerted (but asynchronous) mechanism that can be interpreted in terms of a [n2s + (n2s + n2s)] interaction between both reactants. Both the regio and the stereochemistry observed are compatible with this computational model. However, the combination of solvent and substituent effects can result in a stepwise mechanism. 

When imines derived from a,(3-unsaturated aldehydes react with ketenes, formal [2+2] and [4+2] cycloadditions are possible [11, 41] (Scheme 5). Although a [ji2s+ji4s] concerted (but not necessarily synchronous) mechanism is conceivable,... 

As in the case of the reaction between ketenes and imines, the [2+2] cycloaddition between isocyanates and alkenes [106, 107] can take place via concerted and stepwise mechanisms. However, with the exception of highly nucleophilic alkenes (vide infra), concerted mechanisms were postulated, since isocyanates are suitable candidates to act as antarafacial partners in thermal [2+2] cycloadditions (Fig. 1). Aside from the [n2s + n2J mechanism, in principle [n2s + (A + A) [108] and [A + (A + A s)] [109] mechanisms can be envisaged (Fig. 5). 

Sordo et al. [144] explained the stereoselectivity on the basis of torquoelectronic effects. Low-temperature infrared spectroscopy was also used to identify the reactive intermediates [145]. Two mechanisms were proposed to explain the product distribution in the (3-lactam formation reaction. The ketene mechanism was observed in a low temperature infrared spectroscopy study [145], while the acylation of imine mechanism was believed to be involved in some [122]. Both mechanisms were supported by evidences. It had been hypothesized that cycloaddition of the imine occurs from the least hindered side of the ketene, and this process generates zwitterionic intermediates conrotatory cyclization of these intermediates then produce cis- and //Y/ .v-[S-lactanis. Acylation of the imine by the acid chloride to form /V-acyliminium chloride also produced zwitterionic intermediates (Scheme 10). 

There is ample evidence that these cycloadditions involve the initial formation of a dipolar intermediate (5 Scheme 6). Conrotatory cyclization of (5) leads to the 3-lactam. Intermediates of type (5) can be trapped by another molecule of ketene to yield (d) or by sulfur dioxide to yield sulfone (7). This mechanism also explains the formation of [4 -I- 2] adducts (8) which are sometimes observed with conjugated imines. ... 

SCHEME 10.7 Mechanism of the formation of p-lactams via the [2+2] cycloaddition of imines with ketenes. 

Macias, A., Alonso, E., Del Pozo, C., Venturini, A., Gonzalez, J. Diastereoselective [2+2]-Cycloaddition Reactions of Unsymmetrical Cyclic Ketenes with Imines Synthesis of Modified Prolines and Theoretical Study of the Reaction Mechanism. J. Org. Chem. 2004, 69, 7004-7012. 

Benzo[c]cinnoline N-acylimines and JV-alkylimines show interesting reactivities toward dimethyl acetylenedicarboxylate and some ketenes as summarized in Scheme 6.196-199 A multistep mechanism for the formation of 77 has been proposed. In contrast, the JV-(JV-phenylbenzimidoyl)imines undergo [2 + 2]-cycloaddition with ketenes to the C=N bond to give / -lactams, e.g., 78.200 201... 

G(d,p) level the reaction of ketene (125) with imines (126a,b) in the presence of BF3 (Scheme 32). These authors found that the most likely mechanism involves the coordination of the Lewis acid with the ketene to yield a stepwise mechanism, which is led by the endo and exo attacks to the formation of trans- and cis-cycloadducts (129a,b) via intermediates (127a,b) and (128a,b), respectively. A factor that complicates the efficiency of the reaction is the interaction between the Lewis acid and the imine, thus resulting in stable intermediates that make difficult the completion of the cycloaddition and the catalytic cycle. 

The mechanisms of the cascade cyclizations of homoallenyl aldazines and analogues to afford tetracyclic compounds have been computed and double sequential crisscross 1,3-dipolar cycloaddition through azomethine imine intermediates has been characterized both for the homoallenyl aldazine and for its ketene analogue (Scheme 23). ... 

Allyl phosphates also react with imines under similar carbonylative conditions to yield lactams, but the reaction mechanism involves a [2 + 2] cycloaddition of the imine and a ketene generated by decomposition of an acylpaUadation intermediate (for this type of reaction, vide infra, Sect. 

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