3832 J. Org. Chem. 1985,50,3832-3838 An Improved Approach to 5'-Unsubstituted 5-Formyldipyrromethanes Tilak P. Wijesekera, John B. Paine, III, and David Dolphin* Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada V6T lY6 Received June 29, 1984 A general synthesis of 5'-unsubstituted 5-formyl-2,2'-dipyrromethanes, precursors to centrosymmetric porphyrins, is described. Cyanovinyl groups are used to protect the aldehydes and stabilize the dipyrromethanes. 5- (Chloromethyl)-2-(2,2-dicyanovinyl)pyrroles were condensed with 5-unsubstituted pyrrole-2-carboxylate ethyl esters in warm glacial acetic acid to give a series of 5'-(ethoxycarbonyl)-5-(2,2-dicyanovinyl)-2,2'-dipyrromethanes in high yield. Aqueous alkali was used to deprotect the dicyanovinyl substituent to regenerate the aldehyde and saponify the ethyl ester in a single step. The acid group was subsequently de carboxylated thermally to give the 5'-unsubstituted 5-formyl-2,2'-dipyrromethane. An alternative route was also designed by substitution of a benzyl for an ethyl ester. Hydrogenolysis released the carboxylic acid without affecting the cyanovinyl group, and the subsequent decarboxylation in neat trifluoroacetic acid occurred without rearrangement. Deprotection using aqueous alkali produced crystalline 5'-unsubstituted 5-formyldipyrromethane. The complete lack of rearrangement during the synthesis and manipulation of the dipyrromethanes was confirmed by laC NMR spectroscopy. Among the various syntheses of porphyrins that have been devised since the 1950s, one of the more useful has been that developed independently by Woodward 1 and MacDonald 2 which involves the use of the well-known reactionS whereby 2-formylpyrroles condense with acid and 2-unsubstituted pyrroles to afford efficiently the stable 2,2'-dipyrromethenium salts. The extension of this reac- tion to porphyrin synthesis (Scheme 1) entails the coupling of a 5,5'-diformyldipyrromethane (1) with a 5,5'-diunsub- stituted dipyrromethane (2) to produce an intermediary porphodimethene (3), which upon air oxidation is con- verted to the final porphyrin (4a or 4b). The MacDonald synthesis requires that at least one of the two components be symmetrical in order to obtain a single product. The MacDonald synthesis has been employed to produce uro_,2,3 copro-,4 and aetioporphyrins of symmetry types II, III, and IV. 3 Somewhat later,5 it was appreciated that 5'-unsubsti- tuted 5-formyldipyrromethane 5 could also condense and lead to porphyrins via similar porphodimethenes (Scheme I), In order to obtain a single product, such pyrromethanes must be allowed to react only with themselves, to produce porphyrins of twofold axial symmetry (which includes porphyrins of type I or lI). Recently, Chakrabarty et aI.a have employed mixed condensations using two such di- pyrromethanes. By arranging to have substituents of differing polarity and number on the three possible products, the resulting porphyrins proved separable by HPLC. It occurred to us, that under conditions of sufficiently high dilution, covalently linked bis(dipyrromethanes) of this type could be made to condense intramolecularly, to lead, after oxidation, to porphyrins variously strapped at diametrically opposed ,a-positions. This paper presents the studies that were made to optimize the synthesis of such dipyrromethanes employing the (cyanovinyl)pyrrole aldehyde protecting groups, a strategy that we have found to be extremely efficient and especially suited to extension to dimeric homologues (as briefly reported elsewhere 7 ). (1) Woodward, R. B. Angew. Chem. 1960, 72,651-662. (2) Arsenault, G. P.; Bullock, E.; MacDonald, S. F. J. Am. Chern. Soc. 1960,82,4384-4389. (3) Tarlton, E. J.; MacDonald, S. F.; Baltazzi, E. J. Am. Chern. Soc. 1960,82,4389-4395. (4) (a) Jackson, A. H.; Kenner, G. W.; Wass, J. J. Chern. Soc., Perkin Trans. 1 1972,1475-1483. (b) Inhoffen, H. H.; Buchler, J. W.; Jager. P. Fortschr. Chem. Org. Naturst. 1968,26,284-355. (5) Markovac, A.; MacDonald, S. F. Can. J. Chern. 1965, 43, 3364-3371. (See also ref 4b, 13.) (6) Chakrabarty, M.; Ali, S. A.; Philipe, G.; Jackson, A. H. Heterocy· cles 1981, 15, 1199-1204. 0022-3263/85/1950-3832$01.50/0 Scheme I H H 3 4a 4b (Cyanovinyl)pyrroles 8 have been employed since Hans Fischer's time for the synthesis of dipyrromethanes,9 but their first deliberate use for synthesis of 5-formyldi- pyrromethanes was made by Woodward 1 in his classical assault on chlorophyll a. Woodward showed that (di- cyanovinyl)cryptopyrrole (17) could be oxidized with sulfuryl chloride in glacial acetic acid 10 at the 5-methyl substituent without significant destruction of the di- cyanovinyl group. The resulting monochloromethylpyrrole 19 was condensed with 3-(ethoxycarbonyl)-4-methylpyrrole in ethanolic hydrochloric acid. This substrate bore two unsubstituted a-positions, and although the 3-carbonyl substituent strongly discouraged reaction at the adjacent 2-position, it did not prevent it entirely, with the result that the product required a complex workup (fractional crystallization) to remove the byproduct tripyrrane, ethyl 2,5· bis [ (5- (2 ,2-dicyanoviny l) - 3-ethyl-4-methy I pyrrol- 2- yl)methyl]-4-methylpyrrole-3-carboxylateY By use of the appropriate 2:1 stoichiometry, such tripyrranes could be obtained in up to 87% yield,12 Subsequently, Davies 13 and Flaugh and Rapoport 14 have made similar use of this synthon. We have earlier 15 re- (7) Wijesekera, T. P.; Paine, J. B., III; Dolphin, D.; Einstein, F. W. B.; Jones, T. J. Am. Chern. Soc. 1983, 105,6747-6749. (8) Fischer, H.; Neber, H. Justus Liebigs Ann. Chern. 1932,496, 1-26. (9) Fischer, H.; Wasenegger, H. Justus Liebigs Ann. Chern. 1928, 461, 277-295. (10) Corwin, A. H.; Bailey, W. A. Jr.; Viohl, P. J. Am. Chern. Soc. 1942, 64, 1267-1273. (11) Woodward, R. B., personal communication (1972). (12) Paine, J. B., III. Ph.D. Thesis, Harvard University, 1973. (13) Davies, J. L. J. Chern. Soc. C 1969, 1392-1396. (14) Flaugh, M. E.; Rapoport, H. J. Am. Chern. Soc. 1969, 90, 6877-6879. © 1985 American Chemical Society