Palladium-catalyzed 2-arylation of pyrroles

Article abstract of DOI:10.1021/jo902124c

(Chemical Equation Presented) A methodology that affords N-alkyl-2-arylpyrroles and N-aryl-2-arylpyrroles via direct coupling from aryl iodides has been developed. After examining various reaction parameters: solvent, ratio of reagents, catalyst, base and

Full text of DOI:10.1021/jo902124c

pubs.acs.org/joc
syntheses.3 They are also crucial building blocks in the
Palladium-Catalyzed 2-Arylation of Pyrroles
synthesis of cyclic π-conjugated oligopyrrolic systems such
as porphyrins4 and other porphyrinoids.5-9 Thus, many
synthetic methods are known for the construction10 and
derivatization of pyrrole ring.11
Daniel T. Gryko,* Olena Vakuliuk, Dorota Gryko, and
Beata Koszarna
Institute of Organic Chemistry of the Polish Academy of
Sciences, Warsaw, Poland
Aryl-substituted pyrrole derivatives can be prepared via
Suzuki coupling of N-substituted 2-bromopyrroles with
boronic acids12 or from N-protected pyrroleboronic acids
esters and aryl bromides.13 These strategies, however, cannot
be applied to N-alkylpyrroles since bromo derivatives of
these compounds lack an N-electron-withdrawing protecting
group and hence are not stable. Such N-alkyl-2-arylpyrroles
could be prepared via direct coupling as increased popularity
of this method has been observed during the past few years.14
In comparison to indole, only a few methods for direct
arylation of pyrrole derivatives have been published. Inter-
molecular arylation of pyrrole reported by Filippini15 (later
optimized by Sadighi et al.16) requires the formation of an
daniel@icho.edu.pl
Received October 2, 2009
(4) Ito, S.; Murashima, T.; Uno, H.; Ono, N. Chem. Commun. 1998, 1661–
1662.
(5) Gryko, D. T.; Fox, J. P.; Goldberg, D. P. J. Porphyrins Phthalocya-
nines 2004, 8, 1091–1105.
(6) Hannach, S.; Lynch, V. M.; Gerasimchuk, N.; Magda, D.; Sessler, J.
L. Org. Lett. 2001, 3, 3911.
(7) Sessler, J. L.; Seidel, D. Angew. Chem., Int. Ed. 2003, 42, 5134–5175.
(8) Gaze-zowski, M.; Gryko, D. T. Curr. Org. Chem. 2007, 11, 1310–1338.
(9) The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R.,
Eds.; Academic Press: New York, 2000; Vols. 1-10.
(10) (a) Black, D. St. C. In Science of Synthesis; Maas, G., Ed; Thieme:
Stuttgart, 2000; Vol. 9, p 441. (b) Ferreira, V. F.; de Souza, M. C. B. V.; Cunha,
A. C.; Pereira, L. O. R.; Ferreira, M. L. G. Org. Prep. Proced. Int. 2001, 33, 411–
445. (c) Schmuck, C.; Rupprecht, D. Synthesis 2007, 3095–3110. (d) Knorr, L.;
Lange, H. Chem. Ber. 1902, 35, 2998–3008. (e) Banik, B. K.; Samajdar, S.;
Banik, I. J. Org. Chem. 2004, 69, 213–216. (f) Chen, J.; Wu, H.; Zheng, Z.; Jin,
C.; Zhang, X.; Su, W. Tetrahedron Lett. 2006, 47, 5383–5387. (g) Cyr, D. J. S.;
Martin, N.; Arndtsen, B. A. Org. Lett. 2007, 9, 449–452. (h) Kel'in, A. V.;
Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074.
(i) Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6, 2465. (j) Larionov,
O. V.; de Meijere, A. Angew. Chem., Int. Ed. 2005, 44, 5644–5667. (k) Milgram,
B. C.; Eskildsen, K.; Richter, S. M.; Scheidt, W. R.; Scheidt, K. A. J. Org. Chem.
2007, 72, 3941–3944. (l) Wang, Y.-F.; Toh, K. K.; Chiba, S.; Narasaka, K. Org.
Lett. 2008, 10, 5019–5022.
A methodology that affords N-alkyl-2-arylpyrroles and
N-aryl-2-arylpyrroles via direct coupling from aryl io-
dides has been developed. After examining various reac-
tion parameters: solvent, ratio of reagents, catalyst, base
and additives the optimal conditions for the condensation
were identified. Two crucial factors, (a) anhydrous
DMSO as solvent and (b) 5 M excess of pyrrole counter-
part, were found to strongly influence the reaction out-
come. The conditions identified (PdCl2(PPh3)2, AgOAc,
anhyd DMSO, KF, 100 °C, 5 h) resulted in the formation
of 2-arylpyrroles in 14-80% yield. Furthermore, the
synthesis is compatible with electron-withdrawing and
electron-donating groups on the aryl moiety.
(11) (a) Miller, R.; Olsson, K. Acta Chem. Scand. B 1981, 35, 303–310.
(b) Song, C.; Knight, D. W.; Whatton, M. A. Tetrahedron Lett. 2004, 45,
9573–9576. (c) Zhuang, W.; Jørgensen, K. A. Chem. Commun. 2002, 1336–
1337. (d) Jenner, G.; Papadopoulos, M.; Jurczak, J.; Kozluk, T. Tetrahedron
Lett. 1984, 50, 5747–5750. (e) Freitas, J. M.; Abrantes, L. M.; Darbre, T.
Helv. Chim. Acta 2005, 88, 2470–2478. (f) Beshara, C. S.; Thompson, A.
J. Org. Chem. 2005, 70, 10607–10610. (g) Gryko, D. T.; Voloshchuk, R.
J. Porphyrins Phthalocyanines 2009, 13, 390–395. (h) Lee, C.-H.; Lindsey, J.
S. Tetrahedron 1994, 50, 11427–11440. (i) Knight, L. W.; Huffman, J. W.;
Isherwood, M. L. Synlett 2003, 1993–1996.
(12) (a) Thoresen, L. H.; Kim, H.; Welch, M. B.; Burghart, A.; Burgess,
K. Synlett 1998, 1276–1278. (b) Thoresen, L. H.; Reibenspies, J.; Burgess, K.;
Bergstroem, F.; Johansson, L. B.-A. J. Org. Chem. 1999, 64, 7813–7819.
(c) Toyota, T.; Tsuha, H.; Yamada, K.; Takakura, K.; Ikegami, T.;
Sugawara, T. Chem. Lett. 2006, 35, 708–709. (d) Ikeda, C.; Sakamoto, N.;
Nabeshima, T. Org. Lett. 2008, 10, 4601–4604.
(13) (a) Pinkerton, D. M.; Banwell, M. G.; Willis, A. C. Org. Lett. 2007, 9,
5127–5130. (b) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura, N.
Tetrahedron Lett. 2002, 43, 5649–5652. (c) Deng, J. Z.; Paone, D. V.;
Ginnetti, A. T.; Stauffer, S. R.; Burgey, C. S.; Kurihara, H.; Dreher, S. D.;
Weissman, S. A. Org. Lett. 2009, 11, 345–347.
(14) (a) Alberico, D.; Scot, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174–
238. (b) Joucla, L.; Djakovitch, L. Adv. Synth. Cat. 2009, 351, 673–714.
(c) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed.
2009, 48, 5094–5115. (d) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200–205.
(15) Filippini, L.; Gusmeroli, M.; Riva, R. Tetrahedron Lett. 1992, 33,
1755.
Pyrroles are abundant in natural products1 and medicinal
agents2 and serve as a number of intermediates in multistep
(1) (a) Larionov, O. V.; de Meijere, A. Angew. Chem., Int. Ed. 2005, 44,
5664–5667. (b) Garg, N. K.; Caspi, D. D.; Stoltz, B. M. J. Am. Chem. Soc.
2005, 127, 5970–5978. (c) Dhawan, R.; Arndtsen, B. A. J. Am. Chem. Soc.
2004, 126, 468–469. (d) Donohoe, T. J.; Sintim, H.; Sisangia, L.; Harling, J.
€
D. Angew. Chem., Int. Ed. 2004, 43, 2293–2296. (e) Furstner, A. Angew.
Chem., Int. Ed. 2003, 42, 3582–3603. (f) Hoffmann, H.; Lindel, T. Synthesis
2003, 1753–1783. (g) Handy, S. T.; Zhang, Y. Org. Prep. Proced. Int. 2005,
37, 411–445. (h) Walsh, C. T.; Garneau-Tsodikova, S.; Howard-Jones, A. R.
Nat. Prod. Rep. 2006, 23, 517–531. (i) Rossi, R.; Bellina, F. Tetrahedron 2006,
62, 7213–7256.
(2) (a) Baran, P. S.; Richter, J. M.; Lin, D. W. Angew. Chem., Int. Ed.
2005, 44, 609–612. (b) Naumovski, L.; Ramos, J.; Sirisawad, M.; Chen, J.;
Thieman, P.; Lecane, P.; Magda, D.; Wang, Z.; Cortez, C.; Boswell, G.; Cho,
D. G.; Sessler, J. L.; Miller, R. A. Mol. Cancer Ther. 2005, 4, 968–976.
(c) Hall, A.; Atkinson, S.; Brown, S. H.; Chesell, I. P.; Chowdhury, A.; Gibin,
G. M. P.; Goldsmith, P.; Healy, M. P.; Jandu, K. S.; Johnson, M. R.; Michel,
A. D.; Naylor, A.; Sweeting, J. A. Bioorg. Med. Chem. Lett. 2007, 17, 1200–
1205.
(3) (a) For examples in synthesis, see: F€urstner, A.; Radkowski, K.; Peters, H.
Angew. Chem., Int. Ed. 2005, 44, 2777-2781. (b) F€urstner, A. Angew. Chem.,
Int. Ed. 2003, 42, 3582–3603. (c) Johnson, J. A.; Ning, L.; Sames, D. J. Am.
Chem. Soc. 2002, 124, 6900–6903.
(16) Rieth, R. D.; Mankad, N. P.; Calimano, E.; Sadighi, J. P. Org. Lett.
2004, 6, 398.
DOI: 10.1021/jo902124c
r
Published on Web 11/11/2009
J. Org. Chem. 2009, 74, 9517–9520 9517
2009 American Chemical Society

Gryko et al.
JOCNote
anion and subsequent transmetalation. Two other procedures
(Sames’17,18 and Fagnou’s19) use complex rhodium and pal-
ladiumcatalysts and workonlyfor limited rangeof substrates.
Another method, recently developed by Sanford and co-
workers, implies the use of noncommercially available IIII
arylation agents.20 Finally, Forgione, Bilodeau, and co-work-
ers reported decarboxylative cross-coupling reaction between
N-methylpyrrole-2-carboxylic acid and aryl bromides.21
Since the existing procedures are either expensive or
noncomprehensive there is a need for the development of
more general approach.22 This prompted us to initiate the
study aimed at developing conditions for direct coupling of
N-alkylpyrroles with aryl halides.
SCHEME 1
Reactivity of pyrrole is similar to that of its benzo analo-
gues indole and indolizine. Therefore, reaction conditions
developed for indole served as a starting point of our study.
The reaction of N-methylpyrrole (1) and 4-iodobenzonitrile
(2) was chosen as a model system for the optimization studies
(Scheme 1). Submitting these reagents to the conditions
which work very well for arylation of indole23,24 led to
formation of N-methyl-2-(4-cyanophenyl)pyrrole (3) in poor
yields. Another palladium-based system (Pd(OAc)2, KOAc,
PPh3 in NMP) used for indolizine arylation employed by
Gevorgyan25 was also investigated without success.
Therefore, we investigated conditions developed for direct
coupling of thiophene, reported by Lemaire and co-workers
(Pd(OAc)2, K2CO3, Bu4NBr in CH3CN).26 However, the
reaction gave only a small amount of product 3. Finally,
following Mori’s procedure,27 the mixture of N-methylpyr-
role (1) and 4-iodobenzonitrile (2) was treated with PdCl2-
(PPh3)2, AgNO3, and KF in DMSO resulting in the
formation of product 3 in 10% yield (Scheme 1, Table 1,
entry 1). This initial success quickly led to the systematic
study of the reaction conditions. The first set of experiments
was carried out with PdCl2(PPh3)2 to allow optimization of
various parameters. In an effort to improve the yield of
compound 3, the solvent, ratio of reagents, silver salts, time,
as well as other factors were altered. The results of this study
are presented in Table 1.
TABLE 1. Influence of the Reaction Conditions for the Coupling of
N-Methylpyrrole (1) with 4-Iodobenzonitrile (2)a
silver
source
yield of
3b (%)
entry
ratio 1:2
solvent
1
2
3
4
5
6
7
8
AgNO3
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Ag2CO3
AgOTf
AgOAc
AgOAc
AgOAcd
AgOAc
AgOAc
AgOAc
1.2:1
1.2:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
2.5:1
3.5:1
5:1
DMSO wet
DMSO wet
MeCN
DMF
NMP
DMSO/dioxane
THF
AcOH
DMSO wet
DMSO wet
DMSO wet
DMSO anhyd
DMSO anhyd
DMSO anhyd
DMSO anhyd
DMSO anhyd
10
20
9
1
11
16
0
10
0
9
10
11c
12
13
14
15
16
0
11
32
16
42
66
82
The replacement of silver nitrate with silver acetate re-
sulted in an increase in the yield to 20% (Table 1, entry 2). In
contrast to DMSO, reactions in other solvents were sluggish
aAll reactions were performed under following constant conditions:
PdCl2(PPh3)2 (5 mol %), KF (2 equiv), 5 h, addition of silver salt
(altogether 1 equiv) in five equal portions every 1 h, 100 °C. bYields were
determined by HPLC. cReaction was performed at 150 °C. dAgOAc was
added in one portion.
(17) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127, 4996.
ꢀ
(18) Toure, B. B.; Lane, B. S.; Sames, D. Org. Lett. 2006, 8, 1979.
(19) Liegault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K.
J. Org. Chem. 2009, 74, 1826–1834.
(20) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem.
Soc. 2006, 128, 4972.
(21) Forgione, P.; Brochu, M.-C.; St-Ogne, M.; Thesen, K. H.; Bailey, M.
D.; Bilodeau, F. J. Am. Chem. Soc. 2006, 128, 11350–11351.
(22) During the preparation of this manuscript two reports were pub-
lished on palladium-catalyzed direct arylation of N-alkylpyrroles: (a) Gracia,
and low yielding (Table 1, entries 3-8). The counterion of
the silver salt was found to be crucial: AgOAc provided
better yield of 3 in comparison to other salts (entries 9-10).
Increasing the reaction temperature also did not improve the
yield (entry 11). Replacement of DMSO with anhydrous
DMSO increased the yield to 32% (entry 12). Mori et al.
reported that the addition of silver nitrate in portions is
crucial, presumably due to low stability of AgF. Our experi-
ments confirmed this observation since the addition of
AgOAc in one portion caused sudden decrease in the yield
of product 3 (entry 13).
ꢀ
S.; Cazorla, C.; Metay, E.; Pellet-Rostaing, S.; Lemaire, M. J. Org. Chem.
2009, 74, 3160–3163. (b) Fall, Y.; Doucet, H.; Santelli, M. ChemSusChem
2009, 2, 153–157.
(23) Lane, B. S; Sames, D. Org. Lett. 2004, 6, 2897–2900.
(24) Bellina, F.; Cauteruccio, S.; Renzo, R. Eur. J. Org. Chem. 2006,
1379–1382.
(25) Park, C.-H; Ryabova, V.; Seregin, I.; Gevorgyan, V. Org. Lett. 2004,
6, 1159–1162.
(26) (a) Gozzi, C.; Lavenot, L.; Ilg, K.; Lemaire, M. Tetrahedron Lett.
1997, 8867–8870.
(27) (a) Kobayashi, K.; Sugie, A.; Takahashi, M.; Masui, K.; Mori, A.
Org. Lett. 2005, 7, 5083–5085. (b) Masui, K.; Ikegami, H.; Mori, A. J. Am.
Chem. Soc. 2004, 126, 5074–5075. (c) Takahashi, M.; Masui, K.; Sekiguchi,
H.; Kobayashi, N.; Mori, A.; Funahashi, M.; Tamaoki, N. J. Am. Chem. Soc.
2006, 128, 10930–10933.
During the course of the reaction, 4,40-dicyanobiphenyl
(4) and bisarylated product 5 were formed in variable, albeit
low yield depending on the specific conditions (Scheme 1);
however, no 3-arylated product was found.
9518 J. Org. Chem. Vol. 74, No. 24, 2009

Gryko et al.
JOCNote
TABLE 2. Scope and Limitation Studies for Direct Arylation of Pyrrole
Derivatives with Iodoarenes
withdrawing substituent is present on aryl iodide. When
more complex aryl iodide 12 was used in the reaction with
N-methylpyrrole (1), the desired product 18 bearing an
ethynylphenyl moiety was obtained in moderate yield. In
addition, 2-(pyrrol-1-ylmethyl)pyridine (8) subjected to re-
action conditions led smoothly to product 24 (Table 2). Aryl
bromides do not react under these conditions. The use of
N-trimethysilylpyrrole did not lead to the desired arylation
product (neither protected not unprotected). Surprisingly,
the reaction also does not work for N-unsubstituted pyrrole.
It is reasonable to assume that the mechanism analogous to
that suggested previously,28 i.e., oxidative addition of the
palladium into the aryl iodide followed by electrophilic
substitution, accounts for the formation of arylated pyrroles
(however, other mechanisms also have to be taken into
account).
In summary, direct coupling of aryl iodides with pyrrole
derivatives provides a valuable method for the synthesis
of N-alkyl-2-arylpyrrole and N-aryl-2-arylpyrrole deriva-
tives. The relatively mild conditions and short reaction
times are especially noteworthy compared to other related
direct arylation of pyrrole.21 Considering that starting ma-
terials are readily available the reaction may be deemed
valuable. This approach should prove useful for the prepara-
tion of variety of derivatives and may open the door to
exciting applications of these compounds. Further studies
aimed at extending the scope of this method and gaining
insight into spectroscopic properties of these products are in
progress.
Experimental Section
General Procedure for Arylation of Pyrrole Derivatives.
N-Substituted pyrrole (10 mmol, 5 equiv) was dissolved in a
mixture of Pd(PPh3)2Cl2 (0.1 mmol, 5 mol %), KF (4 mmol,
2 equiv), and iodoarene (2 mmol, 1 equiv) in dry DMSO (2 mL).
Subsequently, AgOAc (2 mmol, 1 equiv) was added in five
portions every hour. The resulting suspension was stirred
at 100 °C under Ar for 5 h. The reaction mixture was cooled
to room temperature and poured into 50 mL of water.
The precipitation was filtered through Celite and washed
with dichloromethane. The organic layer was washed with
water, and all water fractions were combined and
extracted with toluene. Combined organic layers were dried
(Na2SO4), filtered, and evaporated with silica under reduced
pressure. The purification details are described for each case
as follows.
The ratio of compounds 1 and 2 was found to be the most
important factor that influenced the yield of the formation
of 3 (entries 14-16). Doubling the amount of compound 1
increased the yield by 10%. An additional increase of
that ratio (to 5:1) led to 82% yield. Further attempts to
improve the yield of 3 by changing the fluoride and the
palladium source and incorporating a phosphine with a
broad range of electron-donating abilities and steric effects
did not lead to any improvement (see the table in the
Supporting Information).
After establishing the optimum conditions (entry 16) for
the desired transformation, the scope and limitations of this
approach to synthesize broad range of 2-arylpyrroles was
analyzed by testing a variety of iodoarenes with N-substi-
tuted pyrroles (Table 2). Aryl iodides with various substitu-
ents were reacted with N-methyl-, N-benzyl-, and N-phenyl-
pyrrole leading to products 13-24 in yields ranging from
14% to 80%. Reaction with ortho-substituted aryl iodides 13
and 14 led to the desired products 19 and 20 albeit in lower
yields (Table 2). In all cases, complete regioselectivity was
observed. The reaction is more effective when an electron-
N-Methyl-2-(4-cyanophenyl)pyrrole (3). Following the gener-
al procedure, treatment of N-methylpyrrole (888 μL, 10 mmol)
and 4-iodobenzonitrile (458 mg, 2 mmol) and further purifica-
tion by dry column vacuum chromatography (DCVC) (EtOAc/
hexanes, 0.5:99.5) afforded 289 mg (80%) of 3 (crystallized from
Et2O/pentane) as fine white crystals: Rf = 0.5 (silica, EtOAc/
1
hexanes, 1:4); mp 102-103 °C; H NMR (500 MHz, CDCl3)
δ 3.71 (s, 3H), 6.23 (t, 1H, J = 3.3 Hz), 6.34 (dd, 1H, J1 = 3.6 Hz,
J2 = 1.7 Hz), 6.77 (t, 1H, J = 2.1 Hz), 7.49, 7.66 (AA0BB0, 2 ꢀ
2H, J = 8.4 Hz); 13C NMR (500 MHz, CDCl3) δ 35.4, 108.5,
109.7, 110.7, 118.9, 125.8, 128.3, 132.2, 132.6, 137.7; EI-MS HR
obsd 182.0833 [Mþ], calcd exact mass 182.0844 (C12H10N2).
Anal. Calcd for C12H10N2: C, 79.10; H, 5.53; N, 15.37. Found:
C, 79.03; H, 5.51; N, 15.33.
(28) (a) Catellani, M.; Chiusoli, G. P. J. Organomet. Chem. 1992, 425,
151. (b) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127,
8050.
J. Org. Chem. Vol. 74, No. 24, 2009 9519

Gryko et al.
JOCNote
N-Phenyl-2-(4-nitrophenyl)pyrrole (22). Following the gener-
al procedure, treatment of N-phenylpyrrole (1.43 g, 10 mmol)
C16H12N2O2: C, 72.72; H, 4.58, N, 10.60. Found: C, 72.74; H,
4.54; N, 10.67.
and 4-iodonitrobenzene (498 mg,
2 mmol) and further
purification by DCVC (hexanes) afforded 314 mg (59%) of 22
(crystallized from CH2Cl2) as fine yellow crystals: Rf = 0.64
(silica, EtOAc/hexanes, 1:4); mp 130-131 °C; H NMR (500
MHz, CDCl3) δ 6.41 (dd, 1H, J1 = 3.7 Hz, J2 = 2.8 Hz), 6.63
(dd, 1H, J1 = 3.7 Hz, J2 = 1.7 Hz), 7.02 (dd, 1H, J1 = 2.8 Hz,
J2 = 1.7 Hz), 7.18 (dt, 2H, J1 = 6.8 Hz, J2 = 1.6 Hz), 7.22, 8.04
(AA0BB0, 4H, J = 9.1 Hz), 7.37 (m, 3H); 13C NMR (500 MHz,
CDCl3) δ 110.1, 113.3, 126.6, 125.7 126.9, 127.4, 127.8, 129.4,
131.4, 139.2, 139.9, 145.6; EI-MS obsd 264.0890 [Mþ],
calcd exact mass 264.0899 (C16H12N2O2). Anal. Calcd for
Acknowledgment. We thank Marie Curie Research Train-
ing Network ‘REVCAT’ for financial support and Agnieszka
Ludwig-Gaze-zowska for amending the manuscript.
1
Supporting Information Available: Full description of ex-
1
perimental procedures and analyses of compounds 15-24. H
NMR and 13C NMR spectra for compounds 3-5 and 15-24.
This material is available free of charge via Internet at http://
pubs.acs.org.
9520 J. Org. Chem. Vol. 74, No. 24, 2009