Palladium-catalyzed C-H arylation of 2,5-substituted pyrroles

Article abstract of DOI:10.1021/ol102734g

The palladium-catalyzed direct arylation of 2,5-substituted pyrrole derivatives with diaryliodonium salts to generate tri-, tetra-, and penta-substituted pyrrole products is described. The scope and limitations of these transformations are also reported.

Full text of DOI:10.1021/ol102734g

ORGANIC
LETTERS
2011
Vol. 13, No. 2
288-291
Palladium-Catalyzed C-H Arylation of
2,5-Substituted Pyrroles
Anna M. Wagner and Melanie S. Sanford*
UniVersity of Michigan, Department of Chemistry, 930 North UniVersity AVenue,
Ann Arbor, Michigan 48019, United States
mssanfor@umich.edu
Received November 11, 2010
ABSTRACT
The palladium-catalyzed direct arylation of 2,5-substituted pyrrole derivatives with diaryliodonium salts to generate tri-, tetra-, and penta-
substituted pyrrole products is described. The scope and limitations of these transformations are also reported.
Densely substituted pyrroles are an important class of
heterocyclic compounds with useful biological and physical
Scheme 1. Complementary Strategies for Pyrrole Synthesis
properties.1 For example, tetra- and penta-substituted pyrroles
feature prominently in natural products (e.g., the lamellarin,
lukianol, ningalin, polycitone, and storniamide classes of
natural products),2 pharmaceuticals (e.g., Lipitor), agro-
chemicals (e.g., chlorfenapyr), fluorescent dyes (e.g., BO-
DIPY derivatives),3 and conducting polymers (e.g., poly-
pyrroles).4 The most common route to pyrrole derivatives
involves cyclization reactions, such as the Knorr, Paal-Knorr,
and Hantzsch reactions (for example, see Scheme 1a).5 While
these are all robust and versatile transformations, they require
preassembly of appropriately substituted carbonyl precur-
sors.5
sification of the pyrrole core into a wide variety of func-
tionalized structures.6
Over the past 5 years, a variety of elegant methods have
been developed for the intermolecular C-H arylation,6,7
olefination,8 alkynylation,9 and borylation10 of pyrrole
derivatives. The vast majority of these transformations
The direct C-H functionalization of preformed pyrroles
(Scheme 1b) offers a highly complementary strategy for the
synthesis and derivatization of these important heterocycles.
In particular, this approach facilitates the late-stage diver-
(6) (a) Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173.
(b) Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269. (c) Ackermann, L.;
Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (d) Yu,
J. Q.; Shi, Z. Top. Curr. Chem. 2010, 292. (e) Guchhait, S. K.; Kashyap,
M.; Saraf, S. Synthesis 2010, 7, 1166.
(1) Taylor, E. C.; Jones, R. A. Pyrroles; Wiley: New York, 1990. (b)
Sundberg, R. J. In ComprehensiVe Heterocyclic Chemistry II; Kartritzky,
A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1996; Vol. 4, p 380-382.
(2) Gupton, J. T. Top. Heterocycl. Chem. 2006, 2, 53.
(7) For select recent examples of the C2 or C5 arylation of pyrroles,
see: (a) Rieth, R. D.; Mankad, N. P.; Calimano, E.; Sadighi, J. P. Org.
Lett. 2004, 6, 3981. (b) Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem.
2007, 72, 1476. (c) Roger, J.; Doucet, H. AdV. Synth. Catal. 2009, 351,
1977. (d) Roy, D.; Mom, S.; Beauperin, M.; Doucet, H.; Hierso, J.-C. Angew.
Chem., Int. Ed. 2010, 49, 6650. (e) Jafarpour, F.; Rahiminejadan, S.; Hazrati,
(3) Loudet, A.; Burgess, K. Chem. ReV. 2007, 107, 4891.
(4) (a) Nalwa, H. S. AdVanced Functional Molecules and Polymers:
Electronic and Photonic Properties; CRC Press: New York, 2001.
(5) Schmuck, C.; Rupprecht, D. Synthesis 2007, 3095.
H. J. Org. Chem. 2010, 75, 3109
.
10.1021/ol102734g  2011 American Chemical Society
Published on Web 12/08/2010

involve functionalization at the 2- and/or 5-positions of
pyrroles due to the inherent reactivity of these sites. In
marked contrast, very little work has addressed the C-H
functionalization of 2,5-disubstituted pyrroles.8c,9b,11-13 Most
relevant to the current studies, Doucet and Santelli have
reported the Pd(OAc)2-catalyzed 3-arylation of several 1,2,5-
trisubstituted pyrroles with aryl bromides (Scheme 2).12
ined Pd(OAc)2 as the catalyst in AcOH at room temperature,
since these were effective conditions for the C2-arylation of
1-methylpyrrole.14 Gratifyingly, traces (3%) of the desired
product 1 were obtained (Table 1, entry 1). A screen of other
Table 1. Optimization of the Pd-Catalyzed C-H Phenylation of
a
1,2-Dimethyl-5-Phenylpyrrole with Ph2IBF4
Scheme 2. Previous Example of C3 Arylation of Pyrroles
entry
[Pd]
solvent
temp (°C)
yieldb
1
2
3
4
5
6
Pd(OAc)2
AcOH
AcOH
DCE
DCE
DCE
DCE
25c
25c
25c
40c
60d
80e
3%
7%
11%
42%
60%
84%
(MeCN)2PdCl2
(MeCN)2PdCl2
(MeCN)2PdCl2
(MeCN)2PdCl2
(MeCN)2PdCl2
While this was an important advance, the reaction suffers
from several key limitations, including (i) a modest scope
of pyrrole substrates, (ii) the requirement for electron-
deficient aryl bromides, (iii) high reaction temperatures (130
°C), and (iv) moderate yields (typically <65%).
a 1 equiv (0.5 mmol) of pyrrole, 1 equiv (0.5 mmol) of Ph2IBF4, 2.5
mL of solvent, 2.5 mol % of [Pd]. b Isolated yields (average of two or three
runs). c 15 h. d 5 h. e 2 h.
Previous studies from our group have shown that PdII
catalysts promote the 2-arylation of indoles and pyrroles with
diaryliodonium salts.14,15 These reactions proceed with high
functional group tolerance and under extremely mild condi-
tions (typically at room temperature). In contrast, most other
Pd-catalyzed indole/pyrrole arylation methods require tem-
peratures in excess of 100 °C.16 On the basis of our prior
work, we hypothesized that the combination of a PdII catalyst
and Ar2IBF4 might also promote the C-H arylation of 2,5-
substituted pyrrole derivatives. We report herein that this is
an effective strategy for the synthesis of tri-, tetra-, and even
penta-substituted pyrrole products.
17
PdII catalysts revealed that (MeCN)2PdCl2 provided a
significantly higher yield (7%, entry 2). Moving from AcOH
to DCE as the solvent and increasing the reaction temperature
from 25 to 84 °C further enhanced the yield to 84% (entry
6). Notably, the optimal conditions (2.5 mol % of [Pd], 84
°C, 2 h in DCE) are mild compared to most other Pd-
catalyzed pyrrole arylation reactions reported in the litera-
ture.6,7,12,13 In addition, this transformation was highly site
selective, providing 1,2-dimethyl-3,5-diphenylpyrrole as the
only regioisomer detected by GC and GCMS analysis.
As shown in Table 2, a variety of 1,2-dimethyl-5-aryl
pyrrole derivatives were effective substrates for this trans-
formation.18 Electron-withdrawing and -donating substituents
as well as ortho-substitution on the aryl ring were all well-
tolerated (Table 2, entries 2-6). With all of these substrates,
excellent (>50:1) selectivity was observed for C-H func-
tionalization adjacent to the CH3 substituent. The only case
in which another isomer was even detected was with the
electron-rich p-MeOC6H4-substituted pyrrole (entry 2). Prod-
uct 2 was formed along with traces (∼0.3%) of a minor
isomer. Interestingly, 2-methyl-5-phenylpyrrole also showed
modest reactivity to form 7 under these conditions (entry
7).
Our initial investigations focused on the phenylation of
1,2-dimethyl-5-phenylpyrrole with Ph2IBF4. We first exam-
(8) For examples of pyrrole C-H olefination, see: (a) Beck, E. M.;
Grimster, N. P.; Hatley, R.; Gaunt, M. J. J. Am. Chem. Soc. 2006, 128,
2528. (b) Beck, E. M.; Hatley, R.; Gaunt, M. J. Angew. Chem., Int. Ed.
2008, 47, 3004. (c) Garcia-Rubia, A.; Urones, B.; Arrayas, R. G.; Carretero,
J. C. Chem.sEur. J. 2010, 16, 9676
.
(9) For examples of pyrrole C-H alkynylation, see: (a) Trofimov, B. A.;
Sobenina, L. N.; Stepanova, Z. V.; Vakul’skaya, T. I.; Kazheva, O. N.;
Alexsandrov, G. G.; Dyachenko, O. A.; Mikhaleva, A. I. Tetrahedron 2008,
64, 5541. (b) Brand, J. P.; Charpentier, J.; Waser, J. Angew. Chem., Int.
Ed. 2009, 48, 9346
.
(10) For examples of pyrrole C-H borylation, see: (a) Tse, M. K.; Cho,
J. Y.; Smith, M. R., III. Org. Lett. 2001, 3, 2831. (b) Takagi, J.; Sato, K.;
Hartwig, J. F.; Ishiyama, T.; Miyaura, N. Tetrahedron Lett. 2002, 43, 5649.
(c) Ishiyama, T.; Takagi, J.; Yonekawa, Y.; Hartwig, J. F.; Miyaura, N.
AdV. Synth. Catal. 2003, 345, 1103. (d) Harrisson, P.; Morris, J.; Marder,
T. B.; Steel, P. G. Org. Lett. 2009, 11, 3586. (e) Kallepalli, V. A.; Shi, F.;
Paul, S.; Onyeozili, E. N., Jr.; Smith, M. R., III. J. Org. Chem. 2009, 74,
9199. (f) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.;
2,5-Methyl/alkyl substituted pyrroles also underwent ef-
ficient C-H arylation with diphenyliodonium tetrafluorobo-
rate (Table 2, entries 8-11). In all cases examined, arylation
adjacent to the CH3 substituent was favored. The selectivity
was modest (2.0:1) with R1 ) ethyl but was very good (29:
1) with R1 ) cyclohexyl (entries 9 and 10, respectively).
Hartwig, J. F. Chem. ReV. 2010, 110, 890
.
(11) Ban, I.; Sudo, T.; Taniguchi, T.; Itami, K. Org. Lett. 2008, 10,
3607
.
(12) Fall, Y.; Doucet, H.; Santelli, M. ChemSusChem 2009, 2, 153
(13) Roger, J.; Gottumukkala, A. L.; Doucet, H. ChemCatChem 2010,
2, 20
.
(17) Abrunhosa, I.; Delain-Bioton, L.; Gaumont, A. C.; Gulea, M.;
Masson, S. Tetrahedron 2004, 60, 9263.
.
(14) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem.
(18) Pyrrole substrates were prepared according to the following: (a)
Biava, M.; Porretta, G. C.; Poce, G.; De Logu, A.; Meleddu, R.; De Rossi,
E.; Manetti, F.; Botta, M. Eur. J. Med. Chem. 2009, 44, 4734. (b) De, S.
Synth. Commun. 2008, 38, 803.
Soc. 2006, 128, 4972
.
(15) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052
.
(16) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608.
Org. Lett., Vol. 13, No. 2, 2011
289

Table 2. Scope of Pyrrole Substratesa
Table 3. Scope of Arylating Reagentsa
a 1 equiv (1.0 mmol) of pyrrole, 1 equiv (1.0 mmol) of Ph2IBF4, 2.5
mol % of (MeCN)2PdCl2 in 5 mL of DCE at 84 °C for 2 h. All yields
represent an average of at least two runs. Mass balance in reactions with
moderate yields was generally pyrrole decomposition products (oligomers).
Excess hypervalent iodine reagent did not enhance yields.
a 1 equiv (1.0 mmol) of pyrrole, 1 equiv (1.0 mmol) of Ph2IBF4, 2.5
mol % (MeCN)2PdCl2 in 5 mL of DCE at 84 °C for 2 h. All yields rep-
resent an average of at least two runs. Mass balance in reactions with
moderate yields was generally pyrrole decomposition products (oligomers).
Excess hypervalent iodine reagent did not enhance yields. b Isomer ratio )
29:1 as determined by 1H NMR spectroscopy. c Isomer ratio ) 2.0:1 as
determined by 1H NMR spectroscopy. All results are an average of two
runs.
rolecarboxaldehyde) exhibited low reactivity. Under our
standard reaction conditions, <5% yields of C-H arylation
products were detected, and the mass balance was largely
unreacted starting material. As such, the current method is
highly complementary to the Doucet/Santelli chemistry
(Scheme 2),12 which works particularly well with 1,5-
dimethyl-2-pyrrolecarbonitrile.19
We next evaluated the scope of this transformation with
respect to the hypervalent iodine coupling partner. A series
of diverse reagents of general structure Ar2IBF4 were
These results suggest that steric factors are a major contribu-
tor to site selectivity in this system.
In contrast to the alkyl and aryl substituted derivatives in
Table 2, pyrroles containing highly electron-withdrawing
substituents (e.g., 1,5-dimethyl-2-pyrrolecarbonitrile, 1,2-
dimethyl-5-pyrrolecarboxylic acid, and 1,5-dimethyl-2-pyr-
290
Org. Lett., Vol. 13, No. 2, 2011

prepared from the corresponding ArI and ArB(OH)2 using a
versatile one-pot procedure developed by Olofsson and co-
workers.20 As summarized in Table 3, these reagents were
effective for the 3-arylation of 1,2-dimethyl-5-phenyl pyrrole,
1,2,5-trimethylpyrrole, and 2,5-dimethylpyrrole. Remarkably,
chloride, bromide, and iodide substituents were all well-
tolerated on the oxidant (entries 1, 2, and 7). These serve as
valuable synthetic handles for further manipulation of the
products. In addition, good to excellent yields of C-H
arylation products were obtained with Ar2IBF4 containing
electron-donating methyl and methoxy substituents (entries
4 and 5). This is in marked contrast to the Doucet/Santelli
system,12 which requires electron-deficient aryl bromide
electrophiles. Finally, even the sterically congested ortho-
methyl substituted iodine(III) reagent provided a modest yield
of C-H arylated product 17 (entry 6).
Figure 1. Sequential diarylation to form penta-substituted pyrroles.
In conclusion, this paper demonstrates the Pd-catalyzed
monoarylation and sequential diarylation of 2,5-substituted
pyrrole derivatives with Ar2IBF4. These reactions provide
an attractive and selective method for synthesizing polysub-
stituted pyrroles under mild conditions. Efforts to expand
the scope of this reaction with respect to a pyrrole substrate
as well as to develop improved catalysts for accessing penta-
substituted pyrroles are underway and will be reported in
due course.
A final set of investigations focused on further function-
alization of the 3-arylated pyrrole products. Specifically, we
sought to examine whether these species underwent Pd-
catalyzed C4-arylation with Ar2IBF4 to generate 1,2,3,4,5-
substituted pyrrole derivatives. We were pleased to find that
the reaction of 14 and 21 with Ar2IBF4 in the presence of 5
mol % of (MeCN)2PdCl2 at 84 °C in DCE provided penta-
substituted pyrroles 20 and 22 in 44% and 32% yield,
respectively (Figure 1). Despite the relatively modest yields,
this type of reaction is quite valuable because it provides
access to pyrroles with different aryl groups at the 3- and
4-positions, a difficult substitution pattern to achieve using
the Paal-Knorr synthesis.
Acknowledgment. This material is based upon work
supported by U.S. Department of Energy [Office of Basic
Energy Sciences] DE-FG02-08ER 15997. A.M.W. thanks
Rackham graduate school for a predoctoral fellowship.
(19) Differences in substrate scope and reactivity between the current
reaction and the Doucet/Santelli system may be due to a change in
mechanism from a Pd0/II to a PdII/IV catalytic cycle. Studies to more fully
understand electronic effects and the mechanism in this system are
underway.
Supporting Information Available: Experimental details
and spectroscopic data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) Bielawski, M.; Aili, D.; Olofsson, B. J. Org. Chem. 2008, 73, 4602.
OL102734G
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