Polymer support assisted selective functionalization of Azoles using a palladium-catalyzed coupling reaction

Article abstract of DOI:10.1021/ol000183u

(matrix presented) Regioselective palladium-catalyzed monoarylation of azoles was achieved using iodobenzoate immobilized on an insoluble polymer support. The positional selectivity for the coupling reaction was dramatically influenced by the presence of Cul. No diarylation was observed in either case. Unsymmetrical diarylation was also obtained with the polymer support using sequential coupling reactions.

Full text of DOI:10.1021/ol000183u

ORGANIC
LETTERS
2000
Vol. 2, No. 20
3111-3113
Polymer Support Assisted Selective
Functionalization of Azoles Using a
Palladium-Catalyzed Coupling Reaction
Yoshinori Kondo,* Takashi Komine, and Takao Sakamoto
Graduate School of Pharmaceutical Sciences, Tohoku UniVersity, Aobayama, Aoba-ku,
Sendai 980-8578, Japan
ykondo@mail.pharm.tohoku.ac.jp.
Received July 11, 2000
ABSTRACT
Regioselective palladium-catalyzed monoarylation of azoles was achieved using iodobenzoate immobilized on an insoluble polymer support.
The positional selectivity for the coupling reaction was dramatically influenced by the presence of CuI. No diarylation was observed in either
case. Unsymmetrical diarylation was also obtained with the polymer support using sequential coupling reactions.
Recently, solid-phase organic chemistry has been regarded
as one of the important new fields in synthetic organic
chemistry.1 Solid-phase organic synthesis has drawn the
attention of many chemists, as it is a powerful method for
accelerating the process of drug discovery, owing to a faster
and increased production of compounds than allowed by
conventional solution-phase synthesis. The products of solid-
phase synthesis can be easily purified with a simple wash
of the insoluble resin, making this method interesting in both
technical and practical terms.2 In 1970, H. Rapoport intro-
duced the concept of high dilution effect in solid-supported
chemistry.3 There are also a number of reports on this effect
in the literature.4 However, more examples should be
Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gordon, E.
M. J. Med. Chem. 1994, 37, 1233-1251, 1385-1401. (l) Terrett, N. K.;
Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J. Tetrahedron 1995,
51, 8135-8173. (m) Lowe, G. Chem. Soc. ReV. 1995, 309-317. (n)
Balkenhohl, F.; von dem Bussche-Hunnefeld, C.; Lansky, A.; Zechel, C.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2288-2337. (o) Fruchtel, J. S.;
Jung, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 17-42. (p) Thompson, L.
A.; Ellman, J. A. Chem. ReV. 1996, 96, 555-600. (q) DeWitt, S. H.; Czarnik,
A. W. Acc. Chem. Res. 1996, 29, 114-122. (r) Armstrong, R. W.; Combs,
A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996,
29, 123-131. (s) Ellman, J. A. Acc. Chem. Res. 1996, 29, 132-143. (t)
Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29,
144-154. (u) Still, W. C. Acc. Chem. Res. 1996, 29, 155-163. (v) Hsieh-
Wilson, L. C.; Xiang, X.-D.; Schultz, P. G. Acc. Chem. Res. 1996, 29, 164-
170. (w) Floyd, C. D.; Lewis, C. N.; Whittaker, M. Chem. Br. 1996, 31-
35. (x) Czarnik, A. W.; DeWitt, S. H. Chem. Br. 1996, 43-45. (y)
Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1996, 52,
4527-4554. Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron
1997, 53, 5643-5678.
(1) (a) Combinatorial Chemistry; Jung, G., Ed.; Wiley-VCH: Weinheim,
1999. (b) Obrecht, D.; Villalgordo, J. M. Solid-Supported Combinatorial
and Parallel Synthesis of Small-Molecular-Weight Compound Libraries;
Pergamon: Oxford, 1998. (c) Terrett, N. K. Combinatorial Chemistry;
Oxford University Press: Oxford, 1998. (d) Bunin, B. A. The Combinatorial
Index; Academic Press: San Diego, 1998. (e) Combinatorial Chemistry
and Molecular DiVersity in Drug DiscoVery; Gordon, E. M., Kerwin, J. F.,
Jr., Eds.; Wiley-Liss: New York, 1998. (f) A Practical Guide to Combi-
natorial Chemistry; Czarnik, A. W., DeWitt, S. H., Eds.; American Chemical
Society: Washington, DC, 1997. (g) Annual Reports in Combinatorial
Chemistry and Molecular DiVersity; Moos, W. H., Pavia, M. R., Ellington,
A. D., Kay, B. K., Eds.; ESCOM: Leiden, 1997; Vol. 1. (h) Combinatorial
Chemistry; Wilson, S. R., Czarnik, A. W., Eds.; John Wiley & Sons: New
York, 1997. (i) Combinatorial libraries, Synthesis, Screening, and Applica-
tion Potential; Cortese, R., Ed.; Walter de Gruyter; Berlin, 1996. (j)
Molecular DiVersity and Combinatorial Chemistry; Chaiken, I. M., Janda,
K. D., Eds.; American Chemical Society: Washington, DC, 1996. (k)
(2) Solid-Phase Synthesis; Blossey, E. C.; Neckers, D. C., Eds.; Dowden,
Hutchinson & Ross, Inc.: Stroudsburg, 1975.
(3) Crowly, J. I.; Rapoport, H. Acc. Chem. Res. 1976, 9, 135-145.
10.1021/ol000183u CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/07/2000

provided to further support the advantages of the particular
environment in polymer matrix-based reactions. In connec-
tion with our recent studies on polymer-supported organo-
metallic chemistry,5 we initiated the investigation on the
regioselective arylation of azoles catalyzed by palladium, in
a media for polymer matrix-assisted reaction. Many biologi-
cally active compounds contain azole moieties, and some
examples of solid-phase azole synthesis have been reported.6
Still, the selective functionalization of azoles at the desired
position is one of the many important subjects in azole
chemistry.
Direct arylation of azoles employing palladium-catalyzed
solution-phase chemistry has been reported by Miura et al.7
However, the selectivity for monoarylation is not satisfactory,
leading to the formation of 2,5-diarylated products as well
(Scheme 1). In this study, we focused our interest in applying
Scheme 2
On the other hand, in the presence of CuI as an additive,
the cross coupling reaction was found to proceed exclusively
at position 2, as it is the case for the reaction in solution-
phase chemistry. The 2-arylated N-methylimidazole and the
2-arylated thiazole were obtained with respective yields of
49% and 65% after cleavage (Scheme 3).9
Scheme 1
Scheme 3
solid-phase chemistry to the arylation of azoles, expecting
that the pseudodilution effect provided by the polymer matrix
would improve the selectivity of monoarylation.
We first examined the palladium-catalyzed coupling reac-
tion of immobilized iodobenzoate with N-methylimidazole
and thiazole. The immobilized iodobenzoate was prepared
using conventional methods, i.e., by the reaction in DMF of
chloromethylated polystyrene with iodobenzoic acid, Cs2CO3,
and KI. The loading was estimated from the yield of methyl
iodobenzoate after cleavage of the resin with NaOMe in
THF-MeOH.5a The cross coupling reaction of N-methyl-
imidazole with the immobilized iodobenzoate was carried
out in the presence of Pd(OAc)2, PPh3, and Cs2CO3 in DMF
at 120 °C for 16 h. After cleavage with NaOMe in THF-
MeOH, the 5-arylated N-methylimidazole was obtained with
a yield of 67%. The suitable amount of Pd(OAc)2 was found
to be 10 mmol %. The coupling reaction of thiazole with
the immobilized iodobenzoate under the same reaction
conditions also produced the 5-arylated thiazole, with a yield
Synthesis of the unsymmetrical 2,5-diarylated azoles was
also investigated using sequential palladium-catalyzed cou-
pling reactions. The immobilized 5-arylated azoles described
in Scheme 2 were reacted with iodobenzene in the presence
of Pd(OAc)2, PPh3, Cs2CO3, and CuI as an additive, in DMF
at 120 °C for 16 h. After cleavage of the azoles from the
polymer support, the desired unsymmetrical 2,5-diarylated
azoles were obtained (Scheme 4).
Scheme 4
8
of 54% after cleavage (Scheme 2).
(4) (a) Leznoff, C. C. Chem. Soc. ReV. 1974, 3, 65-85. (b) Leznoff, C.
C. Acc. Chem. Res. 1978, 11, 327-333. (c) Akelah, A. Synthesis 1981,
413-438. (d) Frechet, J. M. J. Tetrahedron 1981, 37, 663-683. (e) Frechet,
J. M. J. Pure Appl. Chem. 1988, 60, 353-364. (f) Hodge, P. Chem. Soc.
ReV. 1997, 26, 417-424.
(5) (a) Kondo, Y.; Komine, T.; Sakamoto, T. J. Comb. Chem. 1999, 1,
123-126. (b) Kondo, Y.; Inamoto, K.; Sakamoto, T. J. Comb. Chem. 2000,
2, 232-233.
The present study indicates that the palladium-catalyzed
coupling reaction of azoles proceeds more selectively when
employed in solid-phase synthesis than in solution-phase
synthesis. The pseudodilution effect of the polymer matrix
(6) (a) Tortolani, D. R.; Biller, S. A. Tetrahedron Lett. 1996, 37, 5687-
5690. (b) Zhang, C.; Moran, E. J.; Woiwode, T. F.; Short, K. M.; Mjalli,
A. M. M. Tetrahedron Lett. 1996, 37, 751-754. (c) Sarshar, S.; Siev. D.;
Mjalli, A. M. M. Tetrahedron Lett. 1996, 37, 835-838. (d) Stadlwieser,
J.; Ellmerer-Muller, E. P.; Tako, A.; Maslouh, N.; Bannwarth, W. Angew.
Chem., Int. Ed. 1998, 37, 1402-1404. (e) Kearney, P. C.; Fernandez, M.;
Flygare, J. A. J. Org. Chem. 1998, 63, 196-200. (f) Goff, D.; Fernandez,
J. Tetrahedron Lett. 1999, 40, 423-426. (g) Pons, J.-F.; Mishir, Q.; Nouvet,
A.; Brookfield, F. Tetrahedron Lett. 2000, 41, 4965-4968.
(7) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull.
Chem. Soc. Jpn. 1998, 71, 467-473.
(8) Typical procedure for Scheme 2: Immobilized iodobenzoate (1.0
g, 0.33 mmol), Pd(OAc)2 (7.41 mg, 0.033 mmol), PPh3 (17.2 mg, 0.066
mmol), and Cs2CO3 (107.1 mg, 0.33 mmol) were placed in a 50 mL round-
bottom flask and then dried in vacuo for 1 h. N-Methylimidazole (0.13
mL, 1.63 mmol) and DMF (4 mL) were then added, and the resulting
mixture was stirred under argon at 120 °C for 16 h. After cooling, the
mixture was filtered and washed with THF and MeOH for several cycles.
The resin was treated with NaOMe in MeOH (0.4 mL, 2.0 mmol) and THF-
MeOH (2:1, 12 mL), and the mixture was stirred at room temperature for
6 h. Methyl 4-(1-methyl-1H-imidazol-5-yl)benzoate (47.9 mg, 67%) was
then obtained.
3112
Org. Lett., Vol. 2, No. 20, 2000

monoarylation of azoles was achieved using iodobenzoate
immobilized on an insoluble polymer support. The positional
selectivity for the coupling reaction was dramatically influ-
enced by the presence of CuI, and no diarylation was
observed in both cases. Further application of the selective
coupling reaction in solid-phase synthesis is underway.
Acknowledgment. This work was partly supported by
the Grant-in-Aid for Scientific Research (No. 12557198)
from the Ministry of Education, Science, Sports and Culture
of Japan and by Tokuyama Science Foundation.
OL000183U
(9) Typical procedure for Scheme 3: Immobilized iodobenzoate (1.0
g, 0.53 mmol), Pd(OAc)2 (11.6 mg, 0.053 mmol), PPh3 (27.7 mg, 0.106
mmol), Cs2CO3 (172.8 mg, 0.53 mmol), and CuI (609.7 mg, 3.2 mmol)
were placed in a 50 mL round-bottom flask and then dried in vacuo for 1
h. N-Methylimidazole (0.13 mL, 1.63 mmol) and DMF (6 mL) were then
added, and the resulting mixture was stirred under argon at 120 °C for 16
h. After cooling, the mixture was filtered and washed with THF and MeOH
for several cycles. The resin was treated with NaOMe in MeOH (0.4 mL,
2.0 mmol) and THF-MeOH (2:1, 12 mL), and the mixture was stirred at
room temperature for 6 h. Methyl 4-(1-methyl-1H-imidazol-2-yl)benzoate
(56.3 mg, 49%) was then obtained.
Figure 1. Dilution Effect for Selective Monoarylation.
is considered to work advantageously to selectively mono-
functionalize the substrate, providing an ideal reaction
environment to minimize undesired diarylation (Figure 1).
In summary, positionally selective palladium-catalyzed
Org. Lett., Vol. 2, No. 20, 2000
3113