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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

    References and Notes

  • 1 Bourne Y. Kolb HC. Radić Z. Sharpless KB. Taylor P. Marchot P. Proc. Natl. Acad. Sci. U. S. A.  2004,  101:  1449 
    CrossrefGoogle Scholar
  • 2 Lewis WG. Green LG. Grynszpan F. Radić Z. Carlier PR. Taylor P. Finn MG. Sharpless KB. Angew. Chem. Int. Ed.  2002,  41:  1053 
    Google Scholar
  • 3a Kawamoto H, Ito S, Satoh A, Nagatomi Y, Hirata Y, Kimura T, Suzuki G, Sato A, and Ohta H. inventors; WO  2005085214. 
    Crossref
  • 3b Kawamoto H, Ito S, Satoh A, Nagatomi Y, Hirata Y, Kimura T, Suzuki G, Sato A, and Ohta H. inventors; WO  2006004142. 
    Crossref
  • 3c Timpe C, Borghese A, Coffey DS, Footman PK, Pedersen SW, Reutzel-Edens SM, Tameze SL, and Weber C. inventors; WO  2005042515. 
    Crossref
  • 3d Amegadzie AK, Gardinier KM, Hembre EJ, Hong JE, Jungheim LN, Muehl BS, Remick DM, Robertson MA, and Savin KA. inventors; WO  2003091226. 
    Crossref
  • 3e Tullis JS. Van Rens JC. Natchus MG. Clark MP. De B. Hsieh LC. Janusz MJ. Bioorg. Med. Chem. Lett.  2003,  13:  1665 
    CrossrefGoogle Scholar
  • 3f Tullis JS, Van Rens JC, Clark MP, Blass BE, Natchus MG, and De B. inventors; WO  2002088113. 
    Crossref
  • 3g Tullis JS, Van Rens JC, Clark MP, Blass BE, Natchus MG, and De B. inventors; WO  2002088108. 
    Crossref
  • 4 Gold H. Justus Liebigs Ann. Chem.  1965,  688:  205 
    Google Scholar
  • 5a Huisgen R. In 1,3-Dipolar Cycloaddition Chemistry   Padwa A. Wiley; New York: 1984.  p.1-176  
    Google Scholar
  • 5b Padwa A. In Comprehensive Organic Synthesis   Vol. 4:  Trost BM. Pergamon; Oxford: 1991.  p.1069-1109  
    Google Scholar
  • 5c Fan W.-Q. Katritzky AR. In Comprehensive Heterocyclic Chemistry II   Vol. 4:  Katritzky AR. Rees CW. Scriven EFV. Pergamon; Oxford: 1996.  p.101-126  
    Google Scholar
  • 5d Himbert G. Frank D. Regitz M. Chem. Ber.  1976,  109:  370 
    Google Scholar
  • 5e Fridman SG. Lisovska NM. Zap. Inst. Khim., Akad. Nauk Ukr. R.S.R., Inst. Khim.  1940,  6:  353 
    Google Scholar
  • 5f Boyer NM. Mack CH. Goebel N. Morgan LR. J. Org. Chem.  1958,  23:  1051 
    Google Scholar
  • 5g Akimova GS. Chistokletov VN. Petrov AA. Zh. Org. Khim.  1965,  1:  2077 
    Google Scholar
  • 6 Krasiński A. Fokin VV. Sharpless KB. Org. Lett.  2004,  6:  1237 
    CrossrefGoogle Scholar
  • 7a Deng J. Wu Y.-M. Chen Q.-Y. Synthesis  2005,  2730 
    Article in Thieme ConnectGoogle Scholar
  • 7b Wu Y.-M. Deng J. Li Y. Chen Q.-Y. Synthesis  2005,  1314 
    Article in Thieme ConnectGoogle Scholar
  • 8 Zhang L. Chen X. Xue P. Sun HHY. Williams ID. Sharpless KB. Fokin VV. Jia G. J. Am. Chem. Soc.  2005,  127:  15998 
    CrossrefPubMedGoogle Scholar
  • 9 Majireck MM. Weinreb SM. J. Org. Chem.  2006,  71:  8680 
    Google Scholar
  • 10 Kamijo S. Jin T. Yamamoto Y. Tetrahedron Lett.  2004,  45:  689 
    CrossrefGoogle Scholar
  • 11a Akimova GS. Chistokletov VN. Petrov AA. Zh. Org. Khim.  1967,  3:  968 
    Google Scholar
  • 11b Akimova GS. Chistokletov VN. Petrov AA. Zh. Org. Khim.  1967,  3:  2241 
    Google Scholar
  • 11c Akimova GS. Chistokletov VN. Petrov AA. Zh. Org. Khim.  1968,  4:  389 
    Google Scholar
  • 12a Tsuji J. In Palladium Reagents and Catalysts: New Perspectives for the 21st Century   Tsuiji J. Wiley; Chichester: 2004.  p.327-351  
    CrossrefGoogle Scholar
  • 12b Knochel P. Perea JJA. Jones P. Tetrahedron  1998,  54:  8275 
    CrossrefGoogle Scholar
  • 13 Dai C. Fu GC. J. Am. Chem. Soc.  2001,  123:  2719 
    CrossrefPubMedGoogle Scholar
  • 14 Huang X. Anderson KW. Zim D. Jiang L. Klapars A. Buchwald SL. J. Am. Chem. Soc.  2003,  125:  6653 
    CrossrefPubMedGoogle Scholar
  • 15a Hadei N. Kantchev EAB. O’Brien CJ. Organ MG. Org. Lett.  2005,  7:  3805 
    Google Scholar
  • 15b Hadei N. Kantchev EAB. O’Brien CJ. Organ MG. J. Org. Chem.  2005,  70:  8503 
    Google Scholar
  • 16 Bite angle as a cis-coordinating ligand: Mann G. Shelby Q. Roy AH. Hartwig JF. Organometallics  2003,  22:  2775 
    CrossrefGoogle Scholar
  • 17 Ogasawara M. Yoshida K. Hayashi T. Organometallics  2000,  19:  1567 
    CrossrefGoogle Scholar
  • 18 Hamman BC. Hartwig JF. J. Am. Chem. Soc.  1998,  120:  7369 
    CrossrefGoogle Scholar
  • It is known that DPPF generally behaves as a cis-coordinat-ing ligand. However, DtBPF has been reported to behave as a trans-coordinating ligand; this may be the reason for the shut-down of our Negishi reaction. See:
  • 19a Dekker GPCM. Elsevier CJ. Vrieze K. van Leeuwen PWNM. Organometallics  1991,  11:  1598 
    CrossrefGoogle Scholar
  • 19b Zuideveld MA. Swennenhuis BHG. Boele MDK. Guari Y. van Strijdonck GPF. Reek JNH. Kamer PCJ. Goubitz K. Fraanje J. Lutz M. Spek AL. van Leeuwen PWNM. J. Chem. Soc., Dalton Trans.  2002,  2308 
    CrossrefGoogle Scholar
  • 20a Shi J.-C. Zeng X. Negishi E. Org. Lett.  2003,  5:  1825 
    CrossrefGoogle Scholar
  • 20b Schöpfer U. Schlapbach A. Tetrahedron  2001,  57:  3069 
    CrossrefGoogle Scholar
  • 20c Zeng X. Hu Q. Qian M. Negishi E. J. Am. Chem. Soc.  2003,  125:  13636 
    CrossrefGoogle Scholar
  • 20d Shi J.-C. Negishi E. J. Organomet. Chem.  2003,  687:  518 
    CrossrefGoogle Scholar
  • 20e Qian M. Negishi E. Tetrahedron Lett.  2005,  46:  2927 
    CrossrefGoogle Scholar
  • 20f Qian M. Negishi E. Synlett  2005,  1789 
    CrossrefGoogle Scholar
  • 20g Negishi E. Shi J.-C. Zeng X. Tetrahedron  2005,  61:  9886 
    CrossrefGoogle Scholar
  • 20h Tan Z. Negishi E. Angew. Chem. Int. Ed.  2006,  45:  762 
    CrossrefGoogle Scholar
  • 21a Itoh T. Mase T. Org. Lett.  2004,  6:  4587 
    CrossrefGoogle Scholar
  • 21b Wu L. Hartwig JF. J. Am. Chem. Soc.  2005,  127:  15824 
    CrossrefGoogle Scholar
  • 21c Willis MC. Brace GN. Holmes IP. Angew. Chem. Int. Ed.  2005,  44:  403 
    CrossrefGoogle Scholar
  • 21d Cacchi S. Fabrizi G. Goggiamani A. Parisi LM. Bernini R. J. Org. Chem.  2004,  69:  5608 
    CrossrefGoogle Scholar
  • 21e Anderson KW. Mendez-Perez M. Priego J. Buchwald SL. J. Org. Chem.  2003,  68:  9563 
    CrossrefGoogle Scholar
  • 21f Karnenburg M. van der Burgt YEM. Kamer PCJ. van Leeuwen PWNM. Organometallics  1995,  14:  3081 
    CrossrefGoogle Scholar
  • 21g Guari Y. van Es DS. Reek JNH. Kamer PCJ. van Leeuwen PWNM. Tetrahedron Lett.  1999,  40:  3789 
    CrossrefGoogle Scholar
  • 21h Wagaw S. Yang BH. Buchwald SL. J. Am. Chem. Soc.  1999,  121:  10251 
    CrossrefGoogle Scholar
  • 21i Harris MC. Geis O. Buchwald SL. J. Org. Chem.  1999,  64:  6019 
    CrossrefGoogle Scholar
  • 21j Yin J. Buchwald SL. Org. Lett.  2000,  2:  1101 
    CrossrefGoogle Scholar
  • 21k Yin J. Buchwald SL. J. Am. Chem. Soc.  2002,  124:  6043 
    CrossrefGoogle Scholar
  • 21l Ali MH. Buchwald SL. J. Org. Chem.  2001,  66:  2560 
    CrossrefGoogle Scholar
  • 21m Mispelaere-Canivet C. Spindler J.-F. Perrio S. Beslin P. Tetrahedron  2005,  61:  5253 
    CrossrefGoogle Scholar
  • 24 Hayashi T. Konishi M. Kobori Y. Kumada M. Higuchi T. Hirotsu K. J. Am. Chem. Soc.  1984,  106:  158 
    CrossrefGoogle Scholar
  • 25 Van Leeuwen PWNM. Kamer PCJ. Reek JNH. Dierkes P. Chem. Rev.  2000,  100:  2741 
    CrossrefGoogle Scholar
  • 26 Ogasawara M. Yoshida K. Hayashi T. Organometallics  2000,  19:  1567 
    CrossrefGoogle Scholar
22

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.

23

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.

27

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).

28

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.