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Synlett 2007(1): 0031-0036  
DOI: 10.1055/s-2006-958435
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Versatile One-Pot Synthesis of 4-Aryl-1,5-disubstituted 1,2,3-Triazoles via 1,3-Dipolar Cycloaddition Followed by Negishi Reaction under New Conditions

Atsushi Akao*a, Takayuki Tsuritania, Satoshi Kiia, Kimihiko Satoa, Nobuaki Nonoyamaa, Toshiaki Masea, Nobuyoshi Yasudab
a Process Research, Preclinical Development, Merck Research Laboratories, 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan
Fax: +81(29)8772024; e-Mail: atsushi_akao@merck.com;
b Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA
Further Information

Publication History

Received 2 August 2006
Publication Date:
21 December 2006 (online)

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Abstract

Several derivatives of 4-aryl-1,5-disubstituted 1,2,3-tri­azole were synthesized in good yields via 1,3-dipolar cycloaddition followed by Negishi reaction under new conditions.

Key words

triazole - Negishi reaction - 1,3-dipolar cycloaddition - XANTPHOS - zinc - cross-coupling

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The results of the Negishi reaction under new conditions using simple substrates are as follows. Negishi reactions were conducted using 1 mol% of Pd2(dba)3 and 2 mol% XANTPHOS in THF-NMP (2:1) at 70 °C for 12-19 h. Zinc reagents were prepared by transmetalation from the corresponding Grignard reagents. Negishi reactions of bromobenzene with phenyl-, vinyl- and propynylzinc chloride produced coupling products in almost quantitative yields. A Negishi reaction of chlorobenzene and phenylzinc chloride produced biphenyl in 78% yield. Further results from reactions using a variety of zinc reagents and halides will be reported.

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The reaction was conducted with magnesium species 4a and bromobenzene(6) in the presence of 1 mol% of Pd2(dba)3 and 2 mol% XANTPHOS at 65 °C for 12 h.

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Typical Procedure for 1,3-Dipolar Cycloaddition Followed by Negishi Reaction.
To a stirred solution of 8.4 wt% propynylmagnesium bromide(1a) in THF (d = 0.9339 g/cm-3, 1.35 mL, 0.742 mmol) was added azide 2a (95 mg, 0.693 mmol) in THF (0.1 mL), and the flask was washed with THF (2 × 0.1 mL). After stirring for 2 h at r.t., 1.41 M ZnCl2 in THF solution (0.54 mL, 0.762 mmol) was added to the resulting yellow slurry. The resulting red solution was stirred for 1 h, and then bromobenzene (6; 73 µL, 0.693 mmol) and an active palladium catalyst solution prepared by mixing Pd2(dba)3 (6.3 mg, 0.00693 mmol) and XANTPHOS (8.0 mg, 0.0138 mmol) in THF (0.38 mL) for 2 h (this pre-mixing step is important in ensuring that the Negishi reaction proceeds smoothly) were added. After degassing, the mixture was stirred at 60-65 °C for 12 h. The mixture was then cooled to r.t., and the reaction mixture was added to 15% aq NH4Cl (5 mL), stirred for 10 min, and extracted with THF (10 mL and 5 mL); the volume was then adjusted to 25 mL using THF. HPLC analysis showed that product 5a (158 mg assay) was obtained in 90% overall yield from 2a, and protonated triazole 3a was also recovered (12 mg assay, 10% recovery).

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Spectroscopic Data for Products (Figure 2).
Compound 5a: IR (KBr): 3055, 2926, 1605, 1580, 1562, 1519, 1464, 1444, 1415, 1383, 1367, 1297, 1237, 1157, 1117, 1092, 1072, 1041, 1010 cm-1. 1H NMR (500 MHz, CDCl3): δ = 7.77 (br d, J = 8.0 Hz, 2 H), 7.52-7.47 (m, 4 H), 7.39 (br t, J = 7.5 Hz, 1 H), 7.29-7.25 (m, 2 H), 2.47 (s, 3 H). HRMS (ESI): m/z calcd for C15H13N3F [M + H]+: 254.1094; found: 254.1091.
Compound 5b: IR (KBr): 3052, 1610, 1526, 1495, 1460, 1442, 1278, 1260, 1151, 1110, 1006 cm-1. 1H NMR (500 MHz, CDCl3): δ = 7.80-7.77 (m, 2 H), 7.55 (m, 1 H), 7.49-7.46 (m, 2 H), 7.37 (m, 1 H), 7.11-7.04 (m, 2 H), 2.39 (d, J = 1.6 Hz, 3 H). HRMS (ESI): m/z calcd for C15H12N3F2 [M + H]+: 272.0999; found: 272.1001.
Compound 5c: IR (KBr): 3083, 1685, 1609, 1574, 1509, 1466, 1435, 1406, 1362, 1295, 1261, 1183, 1157, 1113, 1092, 1009 cm-1. 1H NMR (500 MHz, CDCl3): δ = 8.07 (br d, J = 8.3 Hz, 2 H), 7.90 (br d, J = 8.3 Hz, 2 H), 7.51-7.48 (m, 2 H), 7.29-7.26 (m, 2 H), 2.65 (s, 3 H), 2.51 (s, 3 H). HRMS (ESI): m/z calcd for C17H15N3OF [M + H]+: 296.1199; found: 296.1202.
Compound 5d: IR (KBr): 3087, 2986, 2944, 2904, 1696, 1657, 1611, 1563, 1518, 1474, 1448, 1432, 1410, 1390, 1365, 1312, 1279, 1222, 1176, 1160, 1106, 1011 cm-1. 1H NMR (500 MHz, CDCl3): δ = 8.16 (br d, J = 8.0 Hz, 2 H), 7.87 (br d, J = 8.0 Hz, 2 H), 7.51-7.49 (m, 2 H), 7.29-7.26 (m, 2 H), 4.41 (q, J = 7.0 Hz, 2 H), 2.50 (s, 3 H), 1.42 (t, J = 7.0 Hz, 3 H). HRMS (ESI): m/z calcd for C18H17N3O2F [M + H]+: 326.1305; found: 326.1306.
Compound 5e: IR (KBr): 3060, 2977, 1749, 1617, 1523, 1444, 1347, 1271, 1227, 1152, 1109, 1054, 1029, 1013 cm-1. 1H NMR (500 MHz, CDCl3): δ = 8.00 (br s, 1 H), 8.00 (d, J = 7.5 Hz, 1 H), 7.92 (br d, J = 7.5 Hz, 1 H), 7.57 (m, 1 H), 7.15-7.09 (m, 2 H), 5.39 (s, 2 H), 2.47 (d, J = 1.6 Hz, 3 H). HRMS (ESI): m/z calcd for C17H12N3O2F2 [M + H]+: 328.0898; found: 328.0896.
Compound 5f: IR (KBr): 2984, 2928, 1606, 1518, 1495 1466, 1443, 1415, 1383, 1351, 1294, 1257, 1235, 1156, 1116, 1091, 1007 cm-1. 1H NMR (500 MHz, CDCl3): δ = 8.85 (br s, 1 H), 8.10 (br d, J = 7.8 Hz, 1 H), 7.52-7.49 (m, 2 H), 7.33-7.26 (m, 3 H), 2.65 (br s, 3 H), 2.48 (s, 3 H). HRMS (ESI): m/z calcd for C15H14N4F [M + H]+: 269.1202; found: 269.1205.