Microwave-Assisted Stille Reactions as a Powerful Tool for Building Polyheteroaryl Systems Bearing a (1H)-1,2,4-Triazole Moiety

Abstract

Stille couplings and the combination of Stille/Heck cross-coupling reactions provide useful access to tricyclic systems with valuable material properties from 3,5-dibromo-1,2,4-triazoles. The reactions can all be dramatically improved under microwave irradiation.

Stille reaction - microwave - (1H)-1,2,4-triazole - 1,2,3-triazole - electropolymerization

References and Notes

1a Skotheim TA. Reynolds JR. In Conjugated Polymers. Theory, Synthesis, Properties, and Characterization   3rd ed.:  CRC Press; Boca Raton: 2006.  Chap. 13 and 18.

1b Heinze J. In Organic Electrochemistry   Lund H. Hammerich O. Marcel Dekker; New York: 2000. 

2 Diaz AF. Logan JA. J. Electroanal. Chem.  1980,  111:  111 

3 Diaz AF. Kanazawa KK. Gardini GP. J. Chem. Soc., Chem. Commun.  1979,  635 

4 Tourillon G. Garnier F. J. Electroanal. Chem.  1982,  135:  173 

5a Groenendaal L. Zotti G. Aubert P.-H. Waybright SM. Reynolds JR. Adv. Mater.  2003,  15:  855 

5b Reeves BD. Grenier CRG. Argun AA. Cirpan A. McCarley TD. Reynolds JR. Macromolecules  2004,  37:  7559 

5c Zotti G. Zecchin S. Schiavon G. Verdelli B. Berlin A. Grimoldi S. Macromol. Chem. Phys.  2004,  205:  2026 

6 Wu PL. Feng XJ. Tam HL. Wong MS. Cheah KW. J. Am. Chem. Soc.  2009,  131:  886 

7a Hanna NB. Dimitrijevich SD. Larson SB. Robins RK. Revankar GR. J. Heterocycl. Chem.  1988,  25:  1857 

7b Baldwin JJ, and Novello FC. inventors; US Patent 3 892  762. 

8 Kitchem JA. Noble A. Brandt CD. Moubaraki B. Murray KS. Brooker S. Inorg. Chem.  2008,  47:  9450 

9 Nicolaou KC. Bulger PG. Sarlah D. Angew. Chem. Int. Ed.  2005,  44:  4442 

10a de la Hoz A. Díaz-Ortiz A. Moreno A. Langa F. Eur. J. Org. Chem.  2000,  3659 

10b Microwaves in Organic Synthesis   2nd ed.:  Loupy A. Wiley-VCH; Weinheim: 2006. 

10c Microwave-Assisted Organic Synthesis   Lidström P. Tierney JP. Blackwell Scientific; Oxford: 2004.  p.320 

10d Kappe CO. Stadler A. Microwaves in Organic and Medicinal Chemistry   Wiley-VCH; Weinheim: 2005. 

10e de la Hoz A. Díaz-Ortiz A. Moreno A. Chem. Soc. Rev.  2005,  34:  164 

10f Bogdal D. Loupy A. Org. Process Res. Dev.  2008,  12:  710 

10g Kappe CO. Chem. Soc. Rev.  2008,  37:  1127 

10h Polshettiear V. Varma R. Chem. Soc. Rev.  2008,  37:  1546 

11a Lahred M. Moberg C. Hallberg A. Acc. Chem. Res.  2002,  35:  717 

11b Kappe CO. Curr. Opin. Chem. Biol.  2002,  4:  314 

11c Hayes BL. Aldrichimica Acta  2004,  37:  66 

11d Nilsson K. Olofsson M. Lahred M. Top. Curr. Chem.  2006,  266:  103 

11e Appunnutah P. Van der Eycken E. Eur. J. Org. Chem.  2008,  1133 ; and references therein

12a Kotha S. Lahiri K. Kashinath D. Tetrahedron  2002,  58:  9633 ; and references therein

12b Suenneman HW. de Meijere A. Angew. Chem. Int. Ed.  2004,  43:  895 

12c Kappe CO. Dallinger D. Nat. Rev. Drug Discovery  2006,  5:  51 ; and references therein

13 Pereyre M. Quintard JP. Rahm A. Tin in Organic Synthesis   Butterworths; London: 1987. 

14a Nicolaou KC. Sorensen EJ. Classics in Total Synthesis   VCH; Weinheim: 1996. 

14b Nicolaou KC. Snyder SA. Classics in Total Synthesis II   Wiley-VCH; Weinheim: 2003. 

15a Schnürch M. Flasik R. Khan A. Spina M. Milhovilovix M. Stannetty P. Eur. J. Org. Chem.  2006,  3286 

15b Schöter S. Stock C. Bach T. Tetrahedron  2005,  61:  2245 

15c Deng J. Wu Y. Chen Q. Synthesis  2005,  2730 

15d Maes W. Verstappen B. Dehaen W. Tetrahedron  2006,  62:  2677 

15e Chuprakov S. Chernyak N. Dudnik A. Gevrogyan V. Org. Lett.  2007,  9:  2333 

15f Chiong HA. Daugulis O. Org. Lett.  2007,  9:  1449 

15g Díaz-Ortiz A. Prieto P. de Cózar A. Cebrián C. Moreno A. de la Hoz A. Aus. J. Chem.  2009,  in press

15h Huang J. Macdonald SJF. Harrity JPA. Chem. Commun.  2009,  436 

15i Huang J. Macdonald SJF. Cooper AWJ. Fisher G. Harrity JPA. Tetrahedron Lett.  2009,  50:  5539 

16 Olofsson K. Kim SY. Lahred M. Curran DP. Hallberg A. J. Org. Chem.  1999,  64:  4539 

17 Heguaburu V. Sá MM. Scharpiro V. Pandolfi E. Tetrahedron Lett.  2008,  49:  6787 

18

General Procedure: A mixture of 3,5-dibromo-1-methyl-1H-1,2,4-triazole (1; 200 mg, 0.83 mmol), stannyl derivative (2; 1.08 mmol), PdCl₂(PPh₃)₂ (12 mg, 0.017 mmol) and LiCl (106 mg, 2.49 mmol) or CuI (15.8 mg, 0.083 mmol) was irradiated under argon in a Discover™ (CEM) focused microwave reactor at 110 ˚C for 15 min. The crude products 3a and 4a-g were purified by flash chromatography on silica gel (hexane-EtOAc).
5-Bromo-1-methyl-3-(thiophen-2-yl)-1 H -1,2,4-triazole (3a): Mp 54-55 ˚C; ^¹H NMR (CDCl₃): δ = 7.58 (dd, J = 3.7, 1.2 Hz, 1 H, H-3′), 7.28 (dd, J = 5.1, 1.2 Hz, 1 H, H-5′), 7.02 (dd, J = 5.1, 3.7 Hz, 1 H, H-4′), 3.84 (s, 3 H, CH₃); ^¹³C NMR (CDCl₃): δ = 159.0, 132.8, 129.7, 127.7, 126.8, 126.5, 36.5 (CH₃).
3-Bromo-1-methyl-5-(thiophen-2-yl)-1 H -1,2,4-triazole (4a): Mp 67-68 ˚C; ^¹H NMR (CDCl₃): δ = 7.54-7.62 (m, 2 H, H-3′′, H-5′′), 7.19 (dd, J = 5.1, 3.7 Hz, 1 H, H-4′′), 4.06 (s, 3 H, CH₃); ^¹³C NMR (CDCl₃): δ = 151.1, 138.7, 129.4, 129.0, 128.0, 127.9, 37.4 (CH₃).
3-Bromo-1-methyl-5-(1-methyl-1 H -pyrrol-2-yl)-1 H -1,2,4-triazole (4b): Mp 41-42 ˚C; ^¹H NMR (CDCl₃): δ = 6.74 (t, J = 1.8 Hz, 1 H, H-5′′), 6.41 (dd, J = 4.0, 1.5 Hz, 1 H, H-3′′), 6.14 (dd, J = 3.7, 2.6 Hz, 1 H, H-4′′), 4.06 (s, 3 H, CH₃); ^¹³C NMR (CDCl₃): δ = 149.9, 138.3, 126.8, 118.3, 113.1, 108.2, 37.1 (CH₃), 36.0 (CH₃).
5-(2,2′-Bithiophen-5-yl)-3-bromo-1-methyl-1 H -1,2,4-triazole (4c): Mp 152-154 ˚C; ^¹H NMR (CDCl₃): δ = 7.61 (d, J = 3.9 Hz, 1 H, H-3), 7.31 (dd, J = 5.1, 1.1 Hz, 1 H, H-3′), 7.27 (dd, J = 3.8, 1.1 Hz, 1 H, H-5′), 7.20 (d, J = 3.9 Hz, 1 H, H-4), 7.05 (dd, J = 5.1, 3.8 Hz, 1 H, H-4′); ^¹³C NMR (CDCl₃): δ = 150.7, 141.7, 138.7, 135.7, 129.5, 128.1, 125.9, 125.9, 125.0, 124.1, 35.5 (CH₃).
3-Bromo-1-methyl-5-phenyl-1 H -1,2,4-triazole (4d): Mp 120-121 ˚C; ^¹H NMR (CDCl₃): δ = 7.59-7.61 (m, 2 H, o-PhH), 7.44-7.46 (m, 3 H, m-PhH, p-PhH), 3.91 (s, 3 H, CH₃); ^¹³C NMR (CDCl₃): δ = 156.6, 139.1, 130.7, 129.0, 128.7, 126.7, 37.3 (CH₃).
3-Bromo-1-methyl-5-(phenylethynyl)-1 H -1,2,4-triazole (4e): Mp 119-120 ˚C; ^¹H NMR (CDCl₃): δ = 7.52-7.55 (m, 2 H, o-PhH), 7.28-7.94 (m, 3 H, m-PhH, p-PhH), 3.97 (s, 3 H, CH₃); ^¹³C NMR (CDCl₃): δ = 147.7, 140.3, 132.1, 132.0, 129.2, 128.7, 128.4, 121.7, 97.4, 89.5, 36.5 (CH₃). 2-(3-Bromo-1-methyl-1 H -1,2,4-triazol-5-yl)pyridine (4f): Mp 78-80 ˚C; ^¹H NMR (CDCl₃): δ = 8.68 (dd, J = 4.8, 1.8 Hz, 1 H, H-6), 8.20 (dd, J = 7.7, 1.1 Hz, 1 H, H-3), 7.85 (td, J = 7.7, 1.8 Hz, 1 H, H-4), 7.37 (ddd, J = 7.7, 4.8, 1.1 Hz, 1 H, H-5), 4.36 (s, 3 H, CH₃); ^¹³C NMR (CDCl₃): δ = 153.4, 148.9, 146.8, 138.3, 137.1, 124.5, 124.0, 39.3 (CH₃).
2-(3-Bromo-1-methyl-1 H -1,2,4-triazol-5-yl)pyrazine (4g): Mp 131-133 ˚C; ^¹H NMR (CDCl₃): δ = 9.45 (s, 1 H, H-3), 8.67, 8.64 (2 × s, 2 H, H-5 and H-6), 4.34 (s, 3 H, CH₃); ^¹³C NMR (CDCl₃): δ = 151.1, 145.2, 154.1, 143.1, 142.5, 138.8, 39.3 (CH₃).

19

General Procedure: A mixture of 3,5-dibromo-1-methyl-1H-1,2,4-triazole (1; 200 mg, 0.83 mmol), stannyl derivative (2; 2.16 mmol, 2.6 equiv), PdCl_{2 (}PPh₃)₂ (24 mg, 0.033 mmol) and LiCl (106 mg, 2.49 mmol) was irradiated under argon in a Discover™ (CEM) focused microwave reactor at 130 ˚C for the appropriate time. The crude products 5a-c were purified by flash chromatography on silica gel (hexane-EtOAc).
1-Methyl-3,5-di(thiophen-2-yl)-1 H -1,2,4-triazole (5a): Mp 107-108 ˚C; ^¹H NMR (CDCl₃): δ = 7.71 (dd, J = 3.7, 1.1 Hz, 1 H, H-3′), 7,54 (dd, J = 3.7, 1.1 Hz, 1 H, H-3′′), 7.53 (dd, J = 5.1, 1.1 Hz, 1 H, H-5′′), 7.34 (dd, J = 4.8, 1.1 Hz, 1 H, H-5′), 7.18 (dd, J = 5.1, 3.7 Hz, 1 H, H-4′′), 7.10 (dd, J = 5.1, 3.7 Hz, 1 H, H-4′), 4.07 (s, 3 H, CH₃); ^¹³C NMR (CDCl₃): δ = 157.3, 150.0, 133.5, 128.9, 128.7, 128.6, 127.9, 127.6, 126.3, 126.2, 37.1 (CH₃).
1-Methyl-3,5-bis(1-methyl-1 H -pyrrol-2-yl)-1 H -1,2,4-triazole (5b): Mp 78-79 ˚C; ^¹H NMR (CDCl₃): δ = 6.74 (t, J = 2.0 Hz, 1 H, H-5′′), 6.73 (dd, J = 2.0, 1.0 Hz, 1 H, H-5′), 6.62 (t, J = 2.0 Hz, 1 H, H-3′), 6.43 (dd, J = 4.4, 2.4 Hz, 1 H, H-3′′), 6.17 (dd, J = 4.0, 2.4 Hz, 1 H, H-4′′), 6.10 (dd, J = 3.4, 2.9 Hz, 1 H, H-4′), 3.94 (s, 3 H, CH₃), 3.91 (s, 3 H, CH₃), 3.85 (s, 3 H, CH₃); ^¹³C NMR (CDCl₃): δ = 155.9, 148.0, 126.1, 125.0, 124.8, 119.8, 112.3, 110.3, 108.0, 107.7, 36.7 (CH₃), 36.6 (CH₃), 36.1 (CH₃).
3,5-Di(2,2′-bithiophen-5-yl)-1-methyl-1 H -1,2,4-triazole (5c): Mp 146-148 ˚C; ^¹H NMR (CDCl₃): δ = 7.61 (d, J = 3.8 Hz, 1 H, H-3′′), 7.45 (d, J = 3.8 Hz, 1 H, H-3), 7.22-7.31 (m, 5 H, H-4, H-3′, H-5′, H-3′′′, H-5′′′), 7.17 (d, J = 3.8 Hz, 1 H, H-4′′), 7.07 (dd, J = 4.9, 3.8 Hz, 1 H), 7.03 (t, J = 4.3 Hz, 1 H, H-4′ and H-4′′′); ^¹³C NMR (CDCl₃): δ = 156.9, 149.7, 140.8, 138.2, 137.2, 136.1, 131.9, 129.0, 128.1, 127.9, 127.2, 126.9, 125.6, 124.8, 124.7, 124.2, 124.1, 124.0, 37.3 (CH₃).

20

General Procedure: A mixture of 5-monosubstituted triazole 4 (1 equiv), stannyl derivative (2; 1.3 equiv),
PdCl₂ (PPh₃)₂ (0.02 equiv) and LiCl (3 equiv) or CuI (0.1 equiv) was irradiated at the appropriate temperature and for the appropriate time under argon in a Discover™ (CEM) focused microwave reactor. The crude products 6a-c were purified by flash chromatography on silica gel (hexane-EtOAc).
1-Methyl-3-(1-methyl-1 H -pyrrol-2-yl)-5-(thiophen-2-yl)-1 H -1,2,4-triazole (6a): Mp 88-89 ˚C; ^¹H NMR (CDCl₃): δ = 7.53 (dd, J = 3.7, 1.5 Hz, 1 H, H-3′′), 7.52 (dd, J = 5.1, 1.1 Hz, 1 H, H-5′′), 7.18 (dd, J = 5.1, 3.7 Hz, 1 H, H-4′′), 6.81 (dd, J = 3.7, 1.8 Hz, 1 H, H-5′), 6.70 (t, J = 2.2 Hz, 1 H, H-3′), 6.17 (dd, J = 3.7, 2.6 Hz, 1 H, H-4′), 4.08 (s, 3 H, CH₃), 4.00 (s, 3 H, CH₃); ^¹³C NMR (CDCl₃): δ = 156.3, 149.1, 129.5, 128.5, 128.2, 127.8, 125.2, 124.4, 110.8, 107.8, 37.0 (CH₃), 36.5 (CH₃).
3-(2,2′-Bithiophen-5-yl)-1-methyl-5-(thiophen-2-yl)-1 H -1,2,4-triazole (6b): Mp 124-126 ˚C; ^¹H NMR (CDCl₃): δ = 7.62 (d, J = 3.8 Hz, 1 H, H-4′′), 7.57 (dd, J = 3.7, 1.1 Hz, 1 H, H-3′′′), 7.55 (dd, J = 5.1, 1.1 Hz, 1 H, H-5′′′), 7.24-7.23 (m, 2 H, H-3′, H-5′), 7.20 (dd, J = 5.1, 3.7 Hz, 1 H, H-4′′′), 7.07 (dd, J = 3.8 Hz, 1 H, H-3′′), 7.03 (dd, J = 3.8, 4.9 Hz, 1 H, H-4′), 4.09 (s, 3 H, CH₃); ^¹³C NMR (CDCl₃): δ = 156.9, 150.1, 138.2, 137.2, 131.9, 128.9, 128.8, 128.7, 127.9, 126.9, 124.7, 124.4, 124.0, 37.2 (CH₃).
2-[1-Methyl-3-(thiophen-2-yl)-1 H -1,2,4-triazol-5-yl]pyrazine (6c): Mp 139-140 ˚C; ^¹H NMR (CDCl₃): δ = 9.55 (d, J = 1.7 Hz, 1 H, H-3 Py), 8.64-8.67 (m, 2 H, H-5, H-6 Py), 7.75 (dd, J = 3.7, 1.1 Hz, H-3 thioph), 7.37 (dd, J = 5.1, 1.1 Hz, 1 H, H-5 thioph), 7.13 (dd, J = 5.1, 3.7 Hz, 1 H, H-4 thioph), 4.37 (s, 3 H, CH₃); ^¹³C NMR (CDCl₃): δ = 157.5, 150.1, 145.4, 144.7, 143.5, 143.0, 133.5, 127.7, 126.5, 126.3.

21

General Procedure: A mixture of 1-phenyl-4-(tributyl-stannyl)-1H-1,2,3-triazole (11; 100 mg, 0.23 mmol), halogenated derivative 12 (0.25 mmol), PdCl₂(PPh₃)₂ (3 mg, 0.004 mmol) and LiCl (29.3 mg, 0.69 mmol) was irradiated at the appropriate temperature and for the appropriate time under argon in a Discover™ (CEM) focused microwave reactor. The crude products 13a-g were purified by flash chromatography (hexane-EtOAc).
4-(3,5-Dimethylphenyl)-1-phenyl-1 H -1,2,3-triazole (13a): Mp 115-116 ˚C; ^¹H NMR (CDCl₃): δ = 8.1 (s, 1 H, H-5), 7.8 (d, J = 7.3 Hz, 2 H, o-PhH), 7.5 (m, 4 H, Ph′H), 7.4 (t, J = 7.3 Hz, 1 H, p-Ph′H), 7.0 (s, 1 H, p-PhH), 2.2 (s, 6 H, 2 × CH₃); ^¹³C NMR (CDCl₃): δ = 148.6, 138.5, 137.1, 130.1, 129.9, 128.7, 123.6, 120.5, 117.5, 21.3 (CH₃).
4-(2,6-Dimethylphenyl)-1-phenyl-1 H -1,2,3-triazole (13b): Colorless oil; ^¹H NMR (CDCl₃): δ = 7.9 (s, 1 H, H-5), 7.8 (d, J = 7.1 Hz, 2 H, o-PhH), 7.5 (t, J = 6.9 Hz, 2 H,
m-PhH), 7.4 (t, J = 7.3 Hz, 1 H, p-PhH), 7.2-7.1 (m, 3 H, PhH′), 2.3 (s, 6 H, 2 × CH₃); ^¹³C NMR (CDCl₃): δ = 146.2, 137.9, 137.1, 129.8, 129.6, 123.6, 120.3, 117.5, 20.8 (CH₃).
4-(3-Bromophenyl)-1-phenyl-1 H -1,2,3-triazole (13c): Yellow oil; ^¹H NMR (CDCl₃): δ = 8.2 (s, 1 H), 8.0 (m, 1 H), 7.8-7.7 (m, 3 H), 7.6-7.5 (m, 4 H), 7.3 (t, J = 7.3 Hz, 1 H, p-PhH); ^¹³C NMR (CDCl₃): δ = 147.0, 136.9, 132.3, 131.3, 130.5, 129.8, 128.9, 128.8, 124.4, 123.0, 120.6, 117.9.
4-(Naphthalen-1-yl)-1-phenyl-1 H -1,2,3-triazole (13d): Mp 106-107 ˚C; ^¹H NMR (CDCl₃): δ = 8.5-8.4 (m, 1 H, H-Naph), 8.2 (s, 1 H, H-5), 7.9-7.8 (m, 5 H), 7.6-7.4 (m, 6 H); ^¹³C NMR (CDCl₃): δ = 147.6, 137.1, 133.9, 131.2, 129.9, 129.8, 129.2, 128.8, 128.5, 127.7, 127.4, 126.7, 126.1, 125.4, 120.6.
2-(1-Phenyl-1 H -1,2,3-triazol-4-yl)pyrazine (13e): Colorless oil; ^¹H NMR (CDCl₃): δ = 9.5 (s, 1 H, H-Py), 8.6 (s, 1 H, H-5), 8.6-8.5 (m, 2 H, H-Py), 7.8 (d, J = 7.3 Hz, 2 H, o-PhH), 7.5 (t, J = 7.3 Hz, 2 H, m-PhH), 7.4 (t, J = 7.3 Hz, 1 H, p-PhH); ^¹³C NMR (CDCl₃): δ = 146.6, 145.7, 144.1, 143.9, 142.3, 136.7, 129.9, 129.2, 120.9, 120.6.
1,1′-Diphenyl-1 H ,1′ H -4,4′-bi(1,2,3-triazole) (13f): Mp 118-119 ˚C; ^¹H NMR (CDCl₃): δ = 8.6 (s, 1 H), 8.0 (s, 1 H), 7.7 (d, J = 7.3 Hz, 4 H, o-PhH), 7.5 (t, J = 7.3 Hz, 4 H,
m-PhH), 7.4 (d, J = 7.3 Hz, 2 H, p-PhH). ^¹³C NMR (CDCl₃): δ = 137.0, 134.4, 129.7, 128.7, 121.6, 120.6.
4-(3-Bromo-1-methyl-1 H -1,2,4-triazol-5-yl)-1-phenyl-1 H -1,2,3-triazole (13g): Mp 104-105 ˚C; ^¹H NMR (CDCl₃): δ = 8.5 (s, 1 H, H-5), 7.7 (d, J = 7.3 Hz, 2 H, o-PhH), 7.5 (t, J = 8 Hz, 2 H, m-PhH), 7.4 (d, J = 7.1 Hz, 1 H, p-PhH), 4.3 (s, 3 H, CH₃); ^¹³C NMR (CDCl₃): δ = 147.5, 138.9, 137.7, 136.3, 130.1, 129.6, 122.6, 120.6, 38.3 (CH₃).