5706
J . Org. Chem. 1998, 63, 5706-5707
Sch em e 1
A Str a igh tfor w a r d Syn th esis of
3,4-Diflu or op yr r ole
Eric K. Woller, Valeriy V. Smirnov, and
Stephen G. DiMagno*
Department of Chemistry, University of NebraskasLincoln,
Lincoln, Nebraska 68588-0304
Received March 30, 1998
Halogenated pyrroles have been synthetic targets for
over a century. 2,3,4,5-Tetrahalopyrroles were first
reported in the 1880s;1-3 by 1934 Fischer had catalogued
more than 60 simple ring-halogenated derivatives in Die
Chemie des Pyrrols.4 The first definitive preparation of
an otherwise unsubstituted 3,4-dihalopyrrole was due to
Fischer, who synthesized 3,4-dichloropyrrole by saponi-
fication and double decarboxylation of 3,4-dichloro-2,5-
dicarbethoxypyrrole.5 3,4-Dibromopyrrole has been pre-
pared by two routes: bromination and decarboxylation
of 2-pyrrole carboxylic acid6 and bromination and depro-
tection of N-(triisopropylsilyl)pyrrole.7 3,4-Diiodopyrrole
has been obtained from the N-(triisopropylsilyl)pyrrole
method and by a dissolving metal reduction (Zn, HOAc)
of 2,3,4,5-tetraiiodopyrrole8
3,4-Dihalopyrroles have been employed as Diels-Alder
dienes,9-11 and as precursors for poly(3,4-dihalopyr-
roles).6,12,13 In addition, these compounds have been
recognized as potential starting materials for selectively
or heavily halogenated azamacrocycles.14 The recently
reported class of highly electron deficient â-octachloro-
and â-octabromoporphyrins could, in principle, be pre-
pared from the corresponding 3,4-dihalopyrroles, but this
approach has been supplanted by the development of
efficient methods to chlorinate and brominate the mac-
rocycle periphery.15-22 In contrast, 2,3,7,8,12,13,17,18-
octafluoro-5,10,15,20-tetraarylporphyrins have only been
successfully synthesized from the condensation of 3,4-
difluoropyrrole, 1, with aryl aldehydes.23,24 Direct fluo-
rination of tetraarylporphyrins gave pigments of a still
undetermined structure.25 Despite the long-standing
interest in halogenated pyrroles, the diverse potential
synthetic routes into the 3,4-dihalogenated derivatives,
and the foreseeable and demonstrated synthetic utility
of 3,4-difluoropyrrole, 1, remains a remarkably uncom-
mon halogenated heterocycle.
The only reported preparation of 1 is outlined in
Scheme 1.26 The relatively elaborate isolation and pu-
rification protocol required after the final copper-cata-
lyzed decarboxylation is a severe obstacle to scaling up
this procedure; the initial report described the prepara-
tion of 35 mg of 1. Since small quantities of 1 are clearly
inadequate to explore the utility of this building block
in materials or macrocycle chemistry, an efficient, scal-
able preparation providing gram quantities from rela-
tively inexpensive precursors is highly desirable.
After variants of traditional 3,4-dihalopyrrole synthe-
ses proved fruitless, the double H-X elimination route
originally employed by Leroy and Wakselman (Scheme
1) was revisited. Modifications of this strategy that
(1) Ciamician, G. L.; Dennstedt, M. Chem. Ber. 1882, 15, 2579-
2585.
(2) Ciamician, G. L.; Silber, P. Chem. Ber. 1883, 16, 2388-2399.
(3) Kalle & Co. Chem. Ber. (Suppl.) 1887, 20, 123P-124P.
(4) Fischer, H.; Orth, H. Die Chemie des Pyrrols, Vol. 1; Akademische
Verlagsgesellschaft: Leipzig, 1934.
(5) Fischer, H.; Gangle, K. Z. Phys. Chem. 1941, 267, 188-200.
(6) Audebert, P.; Bidan, G. Synth. Met. 1986, 15, 9-22.
(7) Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.; Tidwell, T. T.;
Artis, D. R.; Muchowski, J . M. J . Org. Chem. 1990, 55, 6317-6328.
(8) Farnier, M.; Fournari, P. J . Heterocycl. Chem. 1975, 12, 373-
374.
(9) Anderson, P. S.; Christy, M. E.; Engelhardt, E. L.; Lundell, G.
F.; Ponticello, G. S. J . Heterocycl. Chem. 1977, 14, 213-218.
(10) Prinzbach, H.; Babsch, H.; Fritz, H.; Hug, P. Tetrahedron Lett.
1977, 1355-1358.
(11) Prinzbach, H.; Bingmann, H.; Fritz, H.; Markert, J .; Knothe,
L.; Eberbach, W.; Brokatzky-Geiger, J .; Sekutowski, J . C.; Kru¨ger, C.
Chem. Ber. 1986, 119, 616-644.
(12) Audebert, P.; Bidan, G. J . Electroanal. Chem. 1985, 190, 129-
(20) Hoffman, P.; Robert, A.; Meunier, B. Bull. Soc. Chim. Fr. 1992,
129, 85-97.
39.
(13) Audebert, P.; Bidan, G. Synth. Met. 1986, 14, 71-80.
(14) Motekaitis, R. J .; Heinert, D. H.; Martell, A. E. J . Org. Chem.
1970, 35, 2504-2511.
(15) Traylor, T. G.; Tsuchiya, S. Inorg. Chem. 1987, 26, 1338-1339.
(16) Wijeskera, T.; Matsumoto, A.; Dolphin, D.; Lexa, D. Angew.
Chem., Int. Ed. Engl. 1990, 29, 1028-1030.
(21) Battioni, P.; Brigaud, O.; Desvaux, H.; Mansuy, D.; Traylor, T.
G. Tetrahedron Lett. 1991, 32, 2893-2896.
(22) Bhyrappa, P.; Krishnan, V. Inorg. Chem. 1991, 30, 239-245.
(23) Woller, E. K.; DiMagno, S. G. J . Org. Chem. 1997, 62, 1588-
93.
(24) Leroy, J .; Bondon, A.; Toupet, L.; Rolando, C. Chem. Eur. J .
1997, 3, 1890-1893.
(25) Tsuchiya, S.; Seno, M. Chem. Lett. 1989, 263-266. These
compounds were proposed to be â-octafluoroporphyrins, but comparison
of their analytical data with those in refs 23 and 24 show that the
initial report was incorrect.
(17) Gonsalves, A. M. d. A. R.; J ohnstone, R. W. W.; Pereira, M. M.;
Shaw, J .; Sobral, A. J . F. d. N. Tetrahedron Lett. 1991, 32, 1355-1358.
(18) Mandon, D.; Ochsenbein, P.; Fischer, J .; Weiss, R.; J ayaraj, K.;
Austin, R. N.; Gold, A.; White, P. S.; Brigaud, O.; Battioni, P.; Mansuy,
D. Inorg. Chem. 1992, 31, 2044-2049.
(19) Hoffman, P.; Labat, G.; Robert, A.; Meunier, B. Tetrahedron
Lett. 1990, 31, 1991-1994.
(26) Leroy, J .; Wakselman, C. Tetrahedron Lett. 1994, 35, 8605-
8608.
S0022-3263(98)00579-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/17/1998