SPECIAL TOPIC
Direct 5-Arylation of 1-Methylpyrazole
5-(2-Methylpyrazol-3-yl)pyrimidine (20a)
From 5-bromopyrimidine (0.159 g, 1 mmol), 1-methylpyrazole
(0.328 g, 4 mmol), KOAc (0.196 g, 2 mmol) and Pd(OAc)2 (2.2 mg,
0.01 mmol), 20a was obtained.
2559
Anal. Calcd for C14H12N2: C, 80.74; H, 5.81. Found: C, 80.59; H,
5.97.
Traces of product 16b were also isolated:
1H NMR (300 MHz): d = 8.20–8.10 (m, 1 H), 8.00–7.80 (m, 2 H),
7.73 (s, 1 H), 7.60 (s, 1 H), 7.55–7.35 (m, 4 H), 3.97 (s, 3 H).
Yield: 95 mg (59%).
1H NMR (300 MHz): d = 9.26 (s, 1 H), 8.85 (s, 2 H), 7.59 (d,
J = 1.8 Hz, 1 H), 6.45 (d, J = 1.8 Hz, 1 H), 3.95 (s, 3 H).
5-Anthracen-9-yl-1-methylpyrazole (16a)
From 9-bromoanthracene (0.257 g, 1 mmol), 1-methylpyrazole
(0.328 g, 4 mmol), KOAc (0.196 g, 2 mmol) and Pd(OAc)2 (2.2 mg,
0.01 mmol), 16a was obtained.
13C NMR (75 MHz): d = 158.6, 156.4, 139.6, 136.9, 125.7, 107.8,
38.1.
Anal. Calcd for C8H8N4: C, 59.99; H, 5.03. Found: C, 60.14; H,
5.20.
Yield: 98 mg (38%).
1H NMR (300 MHz): d = 8.52 (s, 1 H), 8.08 (d, J = 8.2 Hz, 2 H),
7.82 (d, J = 1.7 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 2 H), 7.60–7.40 (m,
4 H), 6.52 (d, J = 1.7 Hz, 1 H), 3.52 (s, 3 H).
References
13C NMR (75 MHz): d = 139.7, 139.3, 131.7, 131.6, 129.1, 129.0,
(1) For examples of palladium-catalysed cross-coupling with
heteroaromatic compounds, see: (a) Li, J. J.; Gribble, G. W.
Palladium in Heterocyclic Chemistry; Pergamon:
Amsterdam, 2000. (b) Doucet, H.; Santelli, M. Synlett 2006,
2001.
(2) For the synthesis of 5-arylpyrazoles using Suzuki reaction,
see: (a) Gerard, A.-L.; Bouillon, A.; Mahatsekake, C.;
Collot, V.; Rault, S. Tetrahedron Lett. 2006, 47, 4665.
(b) Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem. Int.
Ed. 2006, 45, 1282. (c) Gerard, A.-L.; Mahatsekake, C.;
Collot, V.; Rault, S. Tetrahedron Lett. 2007, 48, 4123.
(d) McLaughlin, M.; Marcantonio, K.; Chen, C.-y.; Davies,
I. W. J. Org. Chem. 2008, 73, 4309.
(3) For the synthesis of 5-arylpyrazoles using the Negishi
reaction, see: (a) Yagi, K.; Ogura, T.; Numata, A.; Ishii, S.;
Arai, K. Heterocycles 1997, 45, 1463. (b) Kristensen, J.;
Begtrup, M.; Vedso, P. Synthesis 1998, 1604. (c)Pawlas,J.;
Vedso, P.; Jakobsen, P.; Huusfeldt, P. O.; Begtrup, M.
J. Org. Chem. 2000, 65, 9001. (d) Fray, M. J.; Allen, P.;
Bradley, P. R.; Challenger, C. E.; Closier, M.; Evans, T. J.;
Lewis, M. L.; Mathias, J. P.; Nichols, C. L.; Po-Ba, Y. M.;
Snow, H.; Stefaniak, M. H.; Vuong, H. V. Heterocycles
2006, 67, 489.
(4) For the synthesis of 5-arylpyrazoles using the Stille reaction,
see: Whitlock, G. A.; Conlon, K.; McMurray, G.; Roberts, L.
R.; Stobie, A.; Thurlow, R. J. Bioorg. Med. Chem. Lett.
2008, 18, 2930.
127.0, 126.1, 125.9, 125.0, 109.4, 37.2.
Product 16b was also isolated:
1H NMR (300 MHz): d = 8.49 (s, 1 H), 8.05 (d, J = 8.2 Hz, 2 H),
8.00 (d, J = 8.2 Hz, 2 H), 7.71 (s, 1 H), 7.58 (s, 1 H), 7.55–7.35 (m,
4 H), 4.14 (s, 3 H).
13C NMR (75 MHz): d = 140.2, 130.3, 130.2, 130.0, 127.4, 125.7,
125.6, 124.5, 124.1, 116.7, 38.2.
3-(2-Methylpyrazol-3-yl)pyridine (17a)
From 3-bromopyridine (0.158 g, 1 mmol), 1-methylpyrazole (0.328
g, 4 mmol), KOAc (0.196 g, 2 mmol) and Pd(OAc)2 (2.2 mg, 0.01
mmol), 17a was obtained.
Yield: 100 mg (63%).
1H NMR (300 MHz): d = 8.78 (s, 1 H), 8.72 (d, J = 4.4 Hz, 1 H),
7.76 (d, J = 7.9 Hz, 1 H), 7.56 (d, J = 1.8 Hz, 1 H), 7.43 (dd,
J = 7.9, 4.4 Hz, 1 H), 6.39 (d, J = 1.8 Hz, 1 H), 3.92 (s, 3 H).
13C NMR (75 MHz): d = 149.9, 149.7, 140.5, 139.3, 136.3, 127.4,
124.0, 107.2, 38.0.
Anal. Calcd for C9H9N3: C, 67.90; H, 5.70. Found: C, 67.68; H,
5.84.
3-(2-Methylpyrazol-3-yl)quinoline (18a)
From 3-bromoquinoline (0.208 g, 1 mmol), 1-methylpyrazole
(0.328 g, 4 mmol), KOAc (0.196 g, 2 mmol) and Pd(OAc)2 (2.2 mg,
0.01 mmol), 18a was obtained.
(5) For examples of 5-arylations of pyrazoles using magnesium
derivatives, see: Despotopoulou, C.; Klier, L.; Knochel, P.
Org. Lett. 2009, 11, 3326.
Yield: 107 mg (51%).
(6) Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.;
Miyafuji, A.; Nakata, T.; Tani, N.; Aoyagi, Y. Heterocycles
1990, 31, 1951.
1H NMR (300 MHz): d = 8.93 (s, 1 H), 8.15–8.05 (m, 2 H), 7.81 (d,
J = 7.9 Hz, 1 H), 7.72 (t, J = 7.5 Hz, 1 H), 7.68 (d, J = 7.9 Hz, 1 H),
7.54 (d, J = 1.6 Hz, 1 H), 6.41 (d, J = 1.6 Hz, 1 H), 3.91 (s, 3 H).
(7) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007,
107, 174. (b) Satoh, T.; Miura, M. Chem. Lett. 2007, 36,
200. (c) Campeau, L.-C.; Stuart, D. R.; Fagnou, K.
Aldrichimica Acta 2007, 40, 35. (d) Seregin, I. V.;
Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173. (e) Li, B.-
J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949. (f)Ackermann,
L.; Vicente, R.; Kapdi, A. Angew. Chem. Int. Ed. 2009, 48,
9792. (g) Bellina, F.; Rossi, R. Tetrahedron 2009, 65,
10269. (h) Roger, J.; Gottumukkala, A. L.; Doucet, H.
ChemCatChem 2010, 2, 20.
13C NMR (75 MHz): d = 150.1, 147.6, 140.2, 138.9, 135.2, 130.3,
129.5, 128.0, 127.5, 127.4, 124.0, 107.1, 37.7.
Anal. Calcd for C13H11N3: C, 74.62; H, 5.30. Found: C, 74.60; H,
5.21.
4-(2-Methylpyrazol-3-yl)isoquinoline (19a)
From 4-bromoisoquinoline (0.208 g, 1 mmol), 1-methylpyrazole
(0.328 g, 4 mmol), KOAc (0.196 g, 2 mmol) and Pd(OAc)2 (2.2 mg,
0.01 mmol), 19a was obtained.
(8) For recent examples of palladium-catalysed direct arylations
of thiophenes, see: (a) David, E.; Pellet-Rostaing, S.;
Lemaire, M. Tetrahedron 2007, 63, 8999. (b) Chiong, H.
A.; Daugulis, O. Org. Lett. 2007, 9, 1449. (c) Amaladass,
P.; Clement, J. A.; Mohanakrishnan, A. K. Tetrahedron
2007, 63, 10363. (d) Derridj, F.; Gottumukkala, A. L.;
Djebbar, S.; Doucet, H. Eur. J. Inorg. Chem. 2008, 2550.
(e) Nakano, M.; Tsurugi, H.; Satoh, T.; Miura, M. Org. Lett.
Yield: 94 mg (45%).
1H NMR (300 MHz): d = 9.33 (s, 1 H), 8.50 (s, 1 H), 8.06 (d,
J = 7.3 Hz, 1 H), 7.75–7.60 (m, 4 H), 6.42 (s, 1 H), 3.67 (s, 3 H).
13C NMR (75 MHz): d = 154.0, 144.4, 139.3, 138.5, 135.1, 131.8,
128.5, 128.2, 125.9, 124.7, 122.7, 108.9, 37.6.
Anal. Calcd for C13H11N3: C, 74.62; H, 5.30. Found: C, 74.41; H,
5.22.
Synthesis 2011, No. 16, 2553–2560 © Thieme Stuttgart · New York