Nitrogen ketene formation

SCHEME 12.1 Photochemical reactions of diazonaphtoquinone derivatives elimination of molecular nitrogen with formation of a carbene, followed by Wolff rearrangement to give a ketene that reacts with water traces to form a carboxylic acid. 

A ketene intermediate is not required in order to generate the P-lactam. In the case of 2.111, ketene formation is not possible. Reaction of the acid chloride with the imine, however, generates an intermediate where the nitrogen can displace the bromine moiety to give the lactam. The reaction of 2.111 and 2.115 proceeded, in the presence of pyridine, to give 2.772.55 Reaction with HCl gave 2,2-diethyl-3-aminopropanoic acid, 2.113. Similarly, 2,2-dipropyl and 2,2-dibutyl-3-aminopro-panoic acids were prepared from the appropriate acid chloride and 2.110. ... 

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. 

Excellent /(-methyl selectivity is observed in the zinc chloride mediated condensation with 0-silyl enol ethers of 2-pyridinylmethyl thiopropionates109. Supposedly, chelate formation of zinc(II) with the sulfur and the nitrogen atom of the pyridinylmethyl thioester is essential for the high /(-selectivity. The geometry of the ketene acetal also seems to have some influence. 

The results of low-temperature matrix-isolation studies with 6 [41a] are quite consistent with the photochemical formation of cyclo-Cif, via 1,2-diketene intermediates [59] and subsequent loss of six CO molecules. When 6 was irradiated at A > 338 nm in a glass of 1,2-dichloroethane at 15 K, the strong cyclobut-3-ene-1,2-dione C=0 band at 1792 cm in the FT-IR spectrum disappeared quickly and a strong new band at 2115 cm appeared, which was assigned to 1,2-diketene substructures. Irradiation at A > 280 nm led to a gradual decrease in the intensity of the ketene absorption at 2115 cm and to the appearance of a weak new band at 2138 cm which was assigned to the CO molecules extruded photo-chemically from the 1,2-diketene intermediates. Attempts to isolate cyclo-Cig preparatively by flash vacuum pyrolysis of 6 or low-temperature photolysis of 6 in 2-methyltetrahydrofuran in NMR tubes at liquid-nitrogen temperature have not been successful. 

Photolysis or thermolysis of heteroatom-substituted chromium carbene complexes can lead to the formation of ketene-like intermediates (cf. Sections 2.2.3 and 2.2.5). The reaction of these intermediates with tertiary amines can yield ammonium ylides, which can undergo Stevens rearrangement [294,365,366] (see also Entry 6, Table 2.14 and Experimental Procedure 2.2.1). This reaction sequence has been used to prepare pyrrolidones and other nitrogen-containing heterocycles. Examples of such reactions are given in Figure 2.31 and Table 2.21. 

Ketenes rarely produce [3+ 2]-cycloaddition products with diazo compounds. The reaction possibilities are complex, and nitrogen-free products are often obtained (5). Formation of a cyclopropanone represents one possibihty. Along these lines, the synthesis of (Z)-2,3-bis(trialkylsilyl)cyclopropanones and (Z)-2-trialkylsilyl-3-(triethylgermyl)cyclopropanones from diazo(trialkylsilyl)methanes and appropriate silyl- or germylketenes has been reported (256,257). It was found that subsequent reaction of the cyclopropanone with the diazoalkane was not a problem, in contrast to the reaction of diazomethane with the same ketenes. The high cycloaddition reactivity of diazomethylenephosphoranes also extends to heterocumulenes. The compound R2P(C1)=C=N2 (R = N(/-Pr)2) reacts with CS2, PhNCO and PhNCS to give the corresponding 1,2,3-triazole derivative (60). 

Heterocyclic derivatives can be prepared by this route when one of the tether atoms is a nitrogen or an oxygen. Again this route is more efficient than the corresponding intramolecular ketene cycloaddition method for monosubstituted ketenes. Examples are the formation of 17,17 18,18 19 and 20,19 21,19 and 22.19... 

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. 

Thus, nucleophilic attack of the nitrogen of the a, 3-unsaturated imine (21) (Scheme 6) on the electrophilic carbon atom of ketenes (2) leads to the formation of zwitterionic intermediates (22) in the (3 and 8 conformations. The thermally allowed [n4c] reaction (22(3) leads to the formation of (3-lactams (23), whereas the [n6d] electrocyclization of (228) leads to the formation of the corresponding 8-lactams (24) (Scheme 6). 

It should be possible to see the chemical products in the infrared spectra of the thin film. In order to look at the small quantities of material involved, it was necessary to do in situ exposures of the resist coatings on silicon wafers in a Fourier transform infrared spectrophotometer. The technique was capcUsle of following the loss of quinone and the formation of ketene with considerable success. By purging the wafer in the chamber for some time in the presence of dry nitrogen, it was possible to observe a stable ketene signal even hours after the exposure. While these experiments were not quantitative, they did give two pieces of... 

The loss of molecular nitrogen and the migration of the annulated residue proceed in one concerted step, avoiding the formation of the highly reactive carbene intermediate 16. The resulting ketene 17 is attacked by methanol, yielding the diastereomeric mixture of esters endo-1 and exo-18, immediately. 

---