The aza Wtitig-type reaction of iminophosphorane 3, ethyl a-[(triphenylphosphoranylldane) amino]-p-[3-(g-methyl)catbazolyI)acryiafe with Isocyanates leads to the corresponding pyrido[4,3-c]carbazoles 5. Slmilariy. iminophosphorane 8 Undergoes pyrido annelahon by reaction with isocyanales to give the isomeric lgH-pyrido (3,cblcarbazoles (isoellipticines) 10 Ellipticine, 9-methoxyellipticine, olivactne and other GH-pyrido[4,3-blcarbazoles have received much attention because they exhibit broad spectrum antitumor activity in a variety of experimental model both in vitro and in viva'. The size and the shape of the GH-pyridocarbazole ring lead to an almost perfect overlapping of the aromatic ring with that of a DNA base paiP. As a consequence synthetic activity involving this ring system has been vigorous and unabated 3fi. However, in contrast to synthetic and structure-activity studies focused on GH-pyridocarbazoles very little attention has been directed towards the isometic pyridocarbazoles. P. MOLINA et al. In the course of our studies directed toward the synthesis of fused heterocycles based on heterocyclization reaction of carbodiimides we have developed the so-called tandem aza-Wittig/electrocyclization strategy for the synthesis of pyrtdines" and isoquinoline derivatives'*. As a further extension of the above methodology we would like now to report a fundamentally new approach to the synthesis of 7Hpyrido[4,3-c] and 1 OH-pyrido[3,4-b]carbazoles by thermally induced 6x-electrocyclization of conjugated catbodiimides. Our approach is centered on the aza-Wittig type reaction of vinyl iminophosphoranes with isocyanates or isothiocyanates to give a P-aza-1,3,5hexatnene moiety containing a carbodiimide function at one end. Pyrido annelation is achieved by electrocyclic ring closure followed by [1,3] proton shift. In thiscontext, it is worth noticing that various pyrido annelations involving 3substituted carbazoles have been reported, but no clear pattern emerges from an examination of the direction of closure in whrch there are alternatives. Thus, 9-ethyl-3-aminocarbazole underwent the Skraup13 and Conrad-Limpach'4 reaction, closure occurring at C-4 giving the angular isomer; similarly this compound reacted with formaldehyde and a-or j3-naphthol by C-C bonding at carbazole C-4 producing the angular isomer15. On the other hand, Combes reaction of 9-ethyl-3-aminocarbazole with pentan-2,4-dione led to the linear isomer13, and Bischler-Napieralski cyclization of amides derived from carbazole with the side chain at C-3 apparently occurred at C-2 to give the linear isomer lo. The acid catalyzed cyclization of aldimines derived from 3-formylcarbazoles and 2,2-diethoxyethylamine has been much used for the preparation of pyridocarbazoles (Cranwell-Saxton reaction) and in only two examples a small amount of the angular isomer in addition to the lmear pyridocarbazole was isolated'7. R R = H, El R' = NH2; CHO, -(CH2)rNHCOR' skraup Conrad-Limpach qeombes Cramvell-Saxton ri Btschler-Napieralskl Results.-The 3-formyl-9-methylcarbazole 1 was condensed with ethyl azidoacetate in the presence of sodium ethoxide at -30Β°C to give the ethyl a-azido-b-(3-carbazolyl) acrylate 2 as crystalline solid in 75% yield. The preparation of the key intermediate rminophosphorane 3 was accomplished easily by Staudinger's reaction of 2 with tnphenylphosphine in dichloromethane at room temperature. The IR spectrum of 3 shows a carbonyl absorption band at 1681 cm ', and the'H-NMR spectrum displays among It is worth nothing that electrocyclization of carbodiimides 9 requires thermal conditions stronger than electrocyclization of carbodiimides 4. In other words, carbazole derivatives bearing in the 3-position a C=C conjugated carbodiimide moiety as side chain undergo ring-closure onto 4position (angular isomer) much easier than 2position (linear isomer). This fact could explain the regioselectivity observed In the nng closure of 4 to give 5. The identity of compounds 10 was accomplished by 2D-NMR, HCCOR, and DEPT experiments. In the 'H-NMR spectrum the 4-H proton appears as a singlet at &8.07-8.32 ppm.
Salient features of the YZ-NMR spectra are given in table .
The present study demostrated that tandem aza Wittig/electrocyclic ring-closure strategy afford a new entryto avariety of substituted fused catbazoles. Our approach is simple and direct and leds from readily available carbazoles to the key intermediates 3 and 8 in a few steps in an overall yields of 61% and 64%
respectively. The subsequent cyclization and aromatization which have been described previously, take place in good yields (68-80%). Further, the approach offers an entry to a numberof substituted deri vatives of isoellipticine with a high degree of functionality and a opportunity exists to exploit the amino and the ethoxycarbonyl functions to manipulate the pyrtdocarbazoles at a later stage. Table I. W Chemical Shifts (ppm) for Carbon Atoms in the Heteroaromatic Ring of Several
7H-Pyrido [4,3-c] carbazoles (5) and lOH-Pyrido [3,4-b] carbazoles (10). Carbon Atoms 5 10 Compound 5a SC lob 1oc Cl C, C, c4m 153.65 (d) J=O.5 137.61 (s) 114.62 (dt) J=166.2, J=4.5 131.94 (dt) Ja7.2, J-2.5 150.0 (s) 137.0 (s) 116.7 (dt) J1162.0, J=4.3 132.3 (m) 154.95 (d) J=l.2 135.43 (m) 111.0 (d) J=165 130.28 (m) 151.97 (m) 135.1 (m) 113.80 (d)