Palladium-catalyzed cross-coupling of pyrrole anions with aryl chlorides, bromides, and iodides

Article abstract of DOI:10.1021/ol048367m

(Chemical Equation Presented) A general method for the conversion of pyrrole anions to 2-arylpyrroles has been developed. Using a palladium precatalyst and sterically demanding 2-(dialkylphosphino)biphenyl ligands, (pyrrolyl)zinc chloride may be cross-coupled with a wide range of aryl halides, including aryl chlorides and aryl bromides, at low catalyst loadings and under mild conditions. A high degree of steric hindrance is tolerated. Certain ring-substituted pyrrole anions have also been arylated with aryl bromide substrates.

Full text of DOI:10.1021/ol048367m

ORGANIC
LETTERS
2004
Vol. 6, No. 22
3981-3983
Palladium-Catalyzed Cross-Coupling of
Pyrrole Anions with Aryl Chlorides,
Bromides, and Iodides
Ryan D. Rieth, Neal P. Mankad, Elisa Calimano, and Joseph P. Sadighi*
Department of Chemistry, Massachusetts Institute of Technology,
77 Massachusetts AVenue, Cambridge, Massachusetts 02139
jsadighi@mit.edu
Received August 16, 2004
ABSTRACT
A general method for the conversion of pyrrole anions to 2-arylpyrroles has been developed. Using a palladium precatalyst and sterically
demanding 2-(dialkylphosphino)biphenyl ligands, (pyrrolyl)zinc chloride may be cross-coupled with a wide range of aryl halides, including aryl
chlorides and aryl bromides, at low catalyst loadings and under mild conditions. A high degree of steric hindrance is tolerated. Certain
ring-substituted pyrrole anions have also been arylated with aryl bromide substrates.
In the pursuit of new low-coordinate complexes of late
transition metals, we became interested in pyrrole-derived
chelate ligands1 and in the incorporation of sterically
demanding aryl groups in the positions flanking the nitrogen
atoms. In several cases of interest, the precursor 2-aryl-
pyrroles had not been reported.2,3 Because 2-arylpyrroles are
also of interest in the synthesis of fluorescent dyes,4a
pharmaceuticals,4b and insecticides,4c a general method for
the arylation of pyrroles could be widely useful.
The great versatility of Pd-catalyzed cross-coupling in
C-C bond formation includes some noteworthy routes to
2-arylpyrroles. Polysubstituted pyrroles have been prepared
by elegant multicomponent coupling reactions;5 less substi-
tuted 2-arylpyrroles have been obtained by Suzuki cross-
coupling of N-protected pyrrole derivatives.6,7 The pyrrole
anion, as its (chloro)zinc derivative, couples with iodoben-
(1) Selected recent examples: (a) Halper, S. R.; Cohen, S. M. Angew.
Chem., Int. Ed. 2004, 43, 2385-2388. (b) Gao, G.; Korobkov, I.;
Gambarotta, S. Inorg. Chem. 2004, 43, 1108-1115. (c) Love, J. B.; Salyer,
P. A.; Bailey, A. S.; Wilson, C.; Blake, A. J.; Davies, E. S.; Evans, D. J.
Chem. Commun. 2003, 1390-1391. (d) Li, Y.; Turnas, A.; Ciszewski, J.
T.; Odom, A. L. Inorg. Chem. 2002, 41, 6298-6306. (e) Chen, Q.; Dolphin,
D. Can. J. Chem. 2002, 80, 1668-1675.
(2) Methods for 2-arylpyrrole synthesis include: (a) Guizzardi, B.; Mella,
M.; Fagnoni, M.; Albini, A. Tetrahedron 2000, 56, 9383-9389. (b)
Trofimov, B. A.; Mikhaleva, A. I.; Vasil’tsov, A. M.; Schmidt, E. Y.;
Tarasova, O. A.; Morozova, L. V.; Sobenina, L. N.; Preiss, T.; Henkelmann,
J. Synthesis 2000, 1125-1132. (c) Xu, Z.; Lu, X. J. Org. Chem. 1998, 63,
5031-5041. (d) Katritzky, A. R.; Li, J.; Gordeev, M. F. Synthesis 1994,
93-96. (e) Oda, K.; Machida, M. J. Chem. Soc., Chem. Commun. 1993,
437-438. (f) Ohkura, K.-i.; Seki, K.; Terashima, M.; Kanaoka, Y.
Heterocycles 1990, 30, 957-962. (g) Kruse, C. G.; Bouw, J. P.; Van Hes,
R.; Van de Kuilen, A.; Den Hartog, J. A. J. Heterocycles 1987, 26, 3141-
3151. (h) Buhr, G. Chem. Ber. 1973, 106, 3544-3558. (i) Rapoport, H.;
Look, M. J. Am. Chem. Soc. 1953, 75, 4605-4607. See also refs 4-8.
(3) Our attempt to synthesize 2-mesitylpyrrole, for example, by adaptation
of an existing route (ref 2g) afforded the desired compound in 1% yield.
More heavily substituted 2-mesitylpyrroles have been obtained indirectly
from azidocyclobutenes; see ref 2h.
(4) Selected references: (a) Burghart, A.; Thoresen, L. H.; Chen, J.;
Burgess, K.; Bergstro¨m, F.; Johansson, L. B.-A° . Chem. Commun. 2000,
2203-2204. (b) Pinna, G. A.; Loriga, G.; Murineddu, G.; Grella, G.; Mura,
M.; Vargiu, L.; Murgioni, C.; La Colla, P. Chem. Pharm. Bull. 2001, 49,
1406-1411. (c) Hunt, D. A. Pest. Sci. 1996, 47, 201-202.
(5) Dhawan, R.; Arndtsen, B. A. J. Am. Chem. Soc. 2004, 126, 468-
469.
(6) (a) Knight, L. W.; Huffman, J. W.; Isherwood, M. L. Synlett 2003,
1993-1996. (b) Thoresen, L. H.; Kim, H.; Welch, M. B.; Burghart, A.;
Burgess, K. Synlett 1998, 1276-1278. (c) Johnson, C. N.; Stemp, G.; Anand,
N.; Stephen, S. C.; Gallagher, T. Synlett 1998, 1025-1027.
10.1021/ol048367m CCC: $27.50
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Published on Web 09/30/2004

ligands,10 developed by Buchwald and co-workers, support
the Pd-catalyzed 2-arylation of pyrrolylzinc chloride with a
variety of aryl halide substrates, including aryl chlorides and
very sterically hindered bromides. These reactions require
far lower temperatures and, in most cases, catalyst loadings
than the pyrrole arylations reported to date. This method also
allows the coupling of certain ring-substituted pyrrolyl anions
with aryl bromides.
Table 1. Pd-Catalyzed Arylation of (Pyrrolyl)zinc Chloridesa
The results for the arylation of pyrrolylzinc chloride,
generated in situ from pyrrolylsodium and zinc chloride,11
are summarized in Table 1. These reactions proceed with
generally high (g19:1) selectivity for the 2-aryl isomer over
the easily separated 3-isomer. Aryl chloride substrates (entries
7-9), interestingly, react at a lower temperature than do
iodobenzene (entry 1) or aryl bromides. Both electron-rich
(entry 4)12 and electron-poor (Entry 6) aryl bromide sub-
strates may be used. A high degree of steric hindrance is
tolerated, as illustrated by the use of aryl bromides bearing
methyl or isopropyl groups in both ortho positions (entries
2 and 3), although in the latter case a higher catalyst loading
(4 mol % Pd) is required. In the case of the heterocyclic
substrate 3-bromoquinoline (entry 5), either 2-arylation or
N-arylation may be achieved efficiently, depending on the
supporting ligand used.13
The N-(chlorozinc) derivatives of certain ring-substituted
pyrroles, bearing methyl (Table 2) or aryl (Table 3) groups,
Table 2. Pd-Catalyzed Arylation of C-Methylated Pyrrole
Anions
a Unless noted otherwise: 1.0 equiv of ArX, 1.0 M in THF; 1.6 equiv
of [Na+ (C4H4N-)]/ZnCl2; 0.5 mol % Pd(OAc)2 and ligand (R ) t-Bu);
16-25 h. b With 3.0 equiv of [Na+ (C4H4N-)]/ZnCl2. c With 8.2 mmol of
ArBr in 20 mL of THF and 0.25 mol % Pd2(dba)3; 44 h. d With 2.0 mol %
Pd2(dba)3, 4.0 mol % phosphine, and 4.0 equiv of [Na+ (C4H4N-)]/ZnCl2;
41 h. e Ligand with R ) cyclohexyl was used. f When R ) Cy, reaction at
60 °C for 16 h gave 72% yield of N-arylpyrrole.
zene at relatively high temperatures and catalyst loadings,
giving a 4:1 mixture of 2- and 3-phenylpyrrole in moderate
yield.8 This method served as our starting point. An impres-
sively versatile and convenient method for the catalytic
C-arylation of free azoles, reported subsequently, works well
for the reaction of pyrrole itself with iodobenzene.9
Despite these important advances, a general protocol for
the 2-arylation of N-deprotonated pyrroles under mild
conditions had not been reported. We report here that
sterically demanding, electron-rich dialkylphosphinobiphenyl
a 0.5 M ArBr in THF; 1.6 equiv of [Na+ Pyr-]/ZnCl2; with 2.5 mol %
Pd2(dba)3. b 0.4 M ArBr in THF. c 1.3 M ArBr in 1,4-dioxane. d With
Pd(OAc)2; 2.0 equiv of [Na+ Pyr-]/ZnCl2. e L ) 2-(di-tert-butylphos-
phino)biphenyl. f L ) 2-(dicyclohexylphosphino)biphenyl. g L ) 2-(dicy-
clohexylphosphino)-2′,6′-dimethoxybiphenyl.
(7) Negishi coupling of (1-dimethylaminopyrrol-2-yl)zinc chloride,
prepared indirectly via directed lithiation, with C6H5Br and 1,4-Br2C6H4
has also been reported: Soloducho, J. Synth. Met. 1999, 99, 181-189.
(8) Filippini, L.; Gusmeroli, M.; Riva, R. Tetrahedron Lett. 1992, 33,
1755-1758.
(9) Bromobenzene was also reported to react, albeit in lower yield: Sezen,
B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 5274-5275.
may also be arylated by this method. Both electron-rich and
electron-poor aryl bromides are effective coupling partners
in these reactions.14,15 Compared to similar reactions of the
parent pyrrolylzinc chloride, higher catalyst loadings (5
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Org. Lett., Vol. 6, No. 22, 2004

of substrates including aryl chlorides and bromides, and we
have demonstrated the C-arylation of ring-substituted pyr-
roles. This method affords many previously unknown
2-arylpyrroles.
Table 3. Synthesis of 5-Aryl-2-(2′-methoxyphenyl)pyrrolesa
Acknowledgment. We thank the MIT Department of
Chemistry and UROP office for funding. We are grateful to
Ms. Anna B. Folinsky for early contributions to the reaction
protocol and to Professor Stephen L. Buchwald for helpful
discussions.
Supporting Information Available: Experimental pro-
cedures and characterization data for all products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL048367M
(11) Because of the air and moisture sensitivity of pyrrolyl anions, and
the ready hydration of zinc chloride, these reagents were normally handled
in a glovebox under nitrogen. A Schlenk-only variation, in which the pyrrole
is deprotonated in situ by sodium hydride (weighed in air as its 60%
dispersion in mineral oil), and the zinc chloride is added via syringe as a
solution in THF, works well for some substrate combinations (Table 1,
entries 4 and 6; see the Supporting Information for details). However, several
other cases gave slow and/or incomplete reactions under these conditions.
Further optimization will be needed to obviate in all cases the need for a
glovebox.
a [ArBr] ) 0.34 M; 1.5 equiv of [Na+ Pyr-]/ZnCl2. b [ArBr] ) 0.5 M;
2.0 equiv of [Na+ Pyr-]/ZnCl2. c L ) 2-(di-tert-butylphosphino)biphenyl.
d L ) 2-(di-tert-butylphosphino)-2′-dimethylaminobiphenyl. e L ) 2-(di-
cyclohexylphosphino)biphenyl.
mol % Pd) are needed for efficient conversion, and further
optimization will be needed before a general method is
achieved. These examples, however, represent a short route
to substituent patterns that would otherwise be difficult to
obtain.
(12) For convenience, the slightly air-sensitive product was not protected
against air-oxidation during workup; the oxidation products are readily
removed during the purification.
(13) The other ArX substrates gave only traces of N-arylpyrrole, if any.
Other examples of catalytic pyrrole N-arylation: (a) Klapars, A.; Antilla,
J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727-
7729. (b) Watanabe, M.; Nishiyama, M.; Yamamoto, T.; Koie, Y.
Tetrahedron Lett. 2000, 41, 481-483. (c) Mann, G.; Hartwig, J. F.; Driver,
M. S.; Ferna´ndez-Rivas, C. J. Am. Chem. Soc. 1998, 120, 827-828.
(14) One exception is 3-bromoquinoline, which under the conditions
examined did not react at all with (2,4-dimethylpyrrolyl)zinc chloride.
(15) Aryl chlorides have so far given incomplete reactions. Examples
include the cross-coupling of (3-methylpyrrolyl)zinc chloride with 2-chlo-
roanisole and of [2-(2′-methoxyphenyl)pyrrolyl]zinc chloride with 1-chloro-
4-n-butylbenzene.
In summary, we have greatly expanded the scope of the
palladium-catalyzed C-arylation of pyrrole, with a wide range
(10) (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871-1876. (b) Tomori, H.; Fox, J. M.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 5334-5341. (c) Wolfe, J. P.;
Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1999, 38, 2413-2416.
Org. Lett., Vol. 6, No. 22, 2004
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