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Intramolecular [2 + 2] cycloaddition imine-ketenimine

Mateo Alajarin and Angel Vidal

Departamento Quimica Organica, Facultad de Quimica, Universidad de Murcia, 30500 Murcia, Spain


The reactivity of ketenimines (R1-N=C=CR2R3) has been extensively studied since their original preparation by Staudinger in 1921.1 The addition of different nucleophiles to the central sp carbon and the cycloaddition reactions to produce heterocyclic compounds have received considerable attention in the literature dealing with ketenimines.2 Concerning their cycloaddition reactions, just two papers describing briefly the intermolecular cycloaddition of ketenimines with imines have been reported.3

In this poster we describe representative examples of the previously unreported intramolecular [2 + 2] cycloaddition imine-ketenimine.

For this purpose we have prepared N-[2-(alkylideneaminomethyl)phenyl] diphenyl, trimethylsilyl and methylphenylketenimines. For the preparation of the imine fragment aromatic or aliphatic aldehydes and acetophenones have been used. The ketenimine fragment was furtherly generated by reaction of iminophosphoranes with ketenes.

Results and discussion

The reaction of o-azidobenzylamine 1 with several carbonyl compounds gave the corresponding imines 2. Then, the thus obtained azido-imines were treated with trimethylphosphine to generate the trimethyliminophosphoranes 3 which were not isolated but when treated with diphenylketene, yielded the corresponding derivatives of the new heterocyclic system azeto[2,1-b]quinazoline 4

The use of different carbonyl compounds (aldehydes, ketones) allowed us to introduce a variety of substituents at the stereogenic centre in the chiral 1,1-diphenylazetoquinazolines 4

Azeto[2,1-b]quinazolines 4.

Two mechanistic pathways can be proposed to explain the formation of compounds 4. The first one involves an initial aza-Wittig reaction between the iminophosphorane function and the ketene to give a imino-ketenimine intermediate 5 that undergoes intramolecular [2 + 2] cycloaddition. It is well known that ketenes reacts with imines to produce 2-azetidinones by a [2 + 2] cycloaddition. Taking this into account, a second mechanism may be envisaged: the ketene reacts in a [2 + 2] intermolecular cycloaddition with the imine fragment of the compound 3 to give a 2-azetidinone 6 which further experiences an intramolecular aza-Wittig reaction between the iminophosphorane function and the carbonyl group of the 2-azetidinone ring to give the azetoquinazoline 4.

We have prepared the 2-azetidinone-iminophosphorane 6 by an unequivocal route and proved that this compound did not undergo intramolecular aza-Wittig reaction to produce the azetoquinazoline 4, even at high temperatures, and so the second mechanism mentioned above for the formation of 4 can be disregarded.

Although ketenimines show a very strong absorption at ca. 2000 cm-1 in their IR spectra,we could not observe any absorption in this region when a IR spectrum of the reaction mixture was registered inmediately after the addition of diphenylketene to the solution of iminophosphorane 3;it seemed that the intramolecular [2 + 2] cycloaddition imine-ketenimine took place immediately following the formation of the imino-ketenimine.

In contrast, the reaction of trimethyliminophosphoranes 3 with trimethylsilylketene led to a ketenimine intermediate that could be evidenced by IR spectroscopy (strong absorption at 2004 cm-1) and which was persistent at room temperature for several hours. The intramolecular cycloaddition was notably accelerated by heating, and we could not isolate from the reaction mixture the expected C1-trimethylsilyl azetoquinazoline 8, but instead, after purification by silica gel column chromatography, we obtained directly the C1 unsubstituted azetoquinazoline 9

Finally, the sequential treatment of imines 2 (those prepared by reaction of o-azidobenzylamine 1 and aromatic aldehydes) with trimethylphosphine and methylphenylketene led to the azetoquinazolines 10.

300 MHz 1H NMR spectra of crystallized compounds 10a and 10b revealed that, in both cases, only one diastereoisomer was obtained. Similar analyses of the crude products also showed the same degree of diastereoselectivity. The relative configuration between the two stereogenic carbon atoms was ascertained by NOE difference experiments. Thus, irradiation of the CH3-C1 signal induced enhancement of the H-C2 proton signal and vice versa, thus showing that the methyl group at C1 and the hydrogen at C2 are cis.

The high diastereoselectivity observed in the formation of the azetoquinazolines 10 could be rationalized by assuming that the reactive conformation of the imine-ketenimine is the one stabilized by pi-stacking of the two aryl rings, that on the imine carbon atom and that on the carbon atom of the ketenimine fragment.

This assumption was suported by the following result: when the imine derived from o-azidobenzylamine and isobutyraldehyde was used as starting materials in a similar sequential treatment with trimethylphosphine and methylphenylketene, a 1:1 mixture of two diastereoisomers 11 and 12 was obtained.

Experimental details.

General Procedure for the Preparation of the Azetoquinazolines 4 and 10

To a solution of the azido-imine 2 (3 mmol) in dry toluene (15 mL) trimethylphosphine (3 mmol, 3 mL of a 1 M solution) was added. After stirring at room temp. for 1 h the solvent was removed under reduced pressure and the resulting material was chromatographed on a silica gel column.
Compound 10 b: 73 %, mp 159-161 oC (yellow prisms from diethyl ether); IR (Nujol): 1679 (vs), 1599 (s), 1520 (vs) and 1346 (vs) cm-1; 1H NMR (CDCl3) d: 2.01 (s, 3 H), 4.48 (d, 1 H, J = 12.76 Hz), 4.52 (d, 1 H, J = 12.76 Hz), 4.87 (s, 1 H), 6.93 (d, 1 H, J = 7.78 Hz), 7.02-7.10 (m, 6 H), 7.19 (d, 2 H, J = 8.72 Hz), 7.26-7.29 (m, 2 H), 7.97 (d, 2 H, J = 8.72 Hz); 13C NMR (CDCl3) d: 24.01, 45.13, 63.49 (s), 74.89, 121.12 (s), 123.37, 125.02, 125.49, 126.97, 127.17, 127.26, 127.92, 128.24, 128.90, 137.33 (s), 142.15 (s), 143.34 (s), 147.49 (s), 166.20 (s); MS m/z (%): 369 (M+, 79), 77 (100).


1. Staudinger, H.; Hauser, E. Helv. Chim. Acta 1921, 4, 887

2. Krow, G. R. Angew. Chem. Int. Ed. Engl. 1971, 10, 435; Gambaryan, N. P. Russ. Chem. Rev. 1976, 45, 1251; Perst, H. Methoden Org. Chem. (Houben-Weyl) 4th ed., 1993, vol. E15, part 3, p. 2531-2710

3. Bernhard, A; Manfred, R. Angew. Chem. Int. Ed. Engl. 1979, 18, 320; Barbaro, G.; Battaglia, A.; Giorgianni, P. J. Org. Chem. 1987, 52, 3289


We thank the Direccion General de Investigacion Cientifica y Tecnica (DGICYT) for financial support.