Metal- and Base-Free Three-Component Reaction of Ynones, Sodium Azide, and Alkyl Halides: Highly Regioselective Synthesis of 2,4,5-Trisubstituted 1,2,3-NH-Triazoles

Abstract

A base- and metal-free three-component reaction of ynones, sodium azide, and alkyl halides is developed for the ­regioselective synthesis of 2,4,5-trisubstituted-1,2,3-triazoles. The method is general, convenient, environmentally benign, atom-­economical, and high-yielding.

2,4,5-trisubstituted 1,2,3-NH-triazole - three-component reaction - green chemistry - click chemistry

References

1a Al-Masoudim NA. Al-SoudY A. Tetrahedron Lett.  2002,  43:  4021 

1b Alvarez R. Velazquez S. Aquaro A. San-Felix S. Clercq ED. Perno C. Karlsson A. Balzarini J. Camarasa MJ. J. Med. Chem.  1994,  37:  4185 

1c Wamhoff H. In Comprehensive Heterocyclic Chemistry   Vol. 5:  Katritzky AR. Rees CW. Pergamon; Oxford: 1984.  p.669 

1d Buckle DR. Rockell CJM. Smith H. Spicer BA. J. Med.Chem.  1986,  29:  2262 

1e Buckel DR. Outred DJ. Rockell CJM. Smith H. Spicer BA. J. Med. Chem.  1983,  26:  251 

1f Holla BS. Mahalinga M. Karthikeyan MS. Poojary B. Akberali PM. Kumari NS. Eur. J. Med. Chem.  2005,  40:  1173 

1g Olesen PH. Sørensen AR. Ursø B. Kurtzhals P. Bowler AN. Ehrbar U. Hansen BF. J. Med. Chem.  2003,  46:  3333 

2a Wacharasindhu S. Bardhan S. Wan Z.-K. Tabei K. Mansour TS. J. Am. Chem. Soc.  2009,  131:  4174 

2b Bock VD. Speijer D. Hiemstra H. Maarseveen JHV. Org. Biomol. Chem.  2007,  5:  971 

2c Costa MS. Boechat N. Rangel EA. Silva FDD. Souza AMTD. Rodrigues CR. Castro HC. Junior IN. Lourenco MCS. Wardell S. Ferreira VF. Bioorg. Med. Chem.  2006,  14:  8644 

2d Sivakumar K. Xie F. Cash BM. Long S. Barnhill HN. Wang Q. Org. Lett.  2004,  6:  4603 

2e Kolb HC. Sharpless KB. Drug Discovery Today  2003,  8:  1128 

2f Manetsch R. Krasiski A. Radi Z. Raushel J. Taylor PK. Sharpless B. Kolb HC.
J. Am. Chem. Soc.  2004,  126:  12809 

Selected examples of methods of synthesizing 1,2,3 triazoles:

3a Rostovtsev VV. Green LG. Fokin VV. Sharpless KB. Angew. Chem. Int. Ed.  2002,  41:  2596 

3b Zhang L. Chen X. Xue P. Sun HHY. Williams ID. Sharpless KB. Fokin VV. Jia G. J. Am. Chem. Soc.  2005,  127:  15998 

3c Yang D. Fu N. Liu Z. Li Y. Chen B. Synlett  2007,  278 

3d Tornøe CW. Christensen C. Meldal M. J. Org. Chem.  2002,  67:  3057 

3e Chen Z.-Y. Wu M.-J. Org. Lett.  2005,  7:  475 

3f Sreedhar B. Reddy PS. Krishna VR. Tetrahedron Lett.  2007,  48:  5831 

3g Coats SJ. Link JS. Gauthier D. Hlasta DJ. Org. Lett.  2005,  7:  1469 

4a Hlasta DJ. Ackerman JH. J. Org. Chem.  1994,  59:  6184 

4b Sasaki T. Eguchi S. Yamaguchi M. Esaki T.
J. Org. Chem.  1981,  46:  1800 

4c Howell SJ. Spencer N. Philp D. Tetrahedron  2001,  57:  4945 

4d Scriven EFV. Turnbull K. Chem. Rev.  1988,  88:  297 

Recent developed methods of synthesizing N2-substitued 1,2,3 triazoles:

5a Kamijo S. Jin T. Huo Z. Yamamoto Y. J. Am. Chem. Soc.  2003,  125:  7786 

5b Chen Y. Liu Y. Petersena JL. Shi X. Chem. Commun.  2008,  3254 

5c Liu Y. Yan W. Chen Y. Petersen JL. Shi X. Org. Lett.  2008,  10:  5389 

5d Wang X. Zhang L. Lee H. Haddad N. Krishnamurthy D. Senanayake CH. Org. Lett.  2009,  11:  5026 

5e Kalisiak J. Sharpless KB. Fokin VV. Org. Lett.  2008,  10:  3171 

6 Li J. Wang D. Zhang Y. Li J. Chen B. Org. Lett.  2009,  11:  3024 

7

Three isomers can be readily isolated by column chroma-tography. According to the ref. 5b, N2-alkylation of 4,5-disubstituted 1,2,3-triazoles is the most favorable and the polarity of N2 product is the lowest. Additionally, N1-alkylation was the least favored in almost all cases due to the conformation of 1,4,5-trisubstituted 1,2,3-triazoles. Therefore, we can distinguish the N-1, N-2, and N-3 products easily.

8

The CCDC number of 4f (C₂₁H₁₃FN₄O₃): 752728, the CCDC number of 9e (C₂₁H₁₃ClN₄O₃): 752729.

9

Regioselective Synthesis of 2,4,5-Trisubstituted 1,2,3-Triazoles - General Procedure for the Reaction between Ynones, Sodium Azide, and Aliphatic Alkyl Halides, Regioselective Sythesis of (2-Benzyl-5-phenyl-2 H -1,2,3-triazol-4-yl)(phenyl)methanone (1a)
All reactions were performed on a 0.25 mmol scale relative to ynones. 1,3-Diphenylprop-2-yn-1-one (0.25 mmol), NaN₃ (0.275 mmol) and DMSO (1.5 mL) were successively added to a round-bottom sidearm flask (10 mL) reacted at r.t. until ynones disappeared by TLC test (about 20 min), then benzyl bromide (0.375 mmol) was added to the mixture and the reaction continued at r.t. for 160 min. Following, to the reaction mixture was added H₂O (2 mL), 20% HCl solution (1 mL), and extracted with ester (3 × 10 mL). The combined organic phases were washed with brine (2 × 3 mL), dried over anhyd MgSO₄, and concentrated in vacuo. The residue was subjected to flash column chromatography with hexanes-EtOAc (40:1, 20:1, 5:1) as eluent to obtain the desired isomers 1a (1a: 63mg), 2a (6 mg), 3a (12 mg), 98% yield.
(2-Benzyl-5-phenyl-2 H -1,2,3-triazol-4-yl)(phenyl)-methanone (1a)
Mp 93-95 ˚C. IR: 3063.48, 1661.58, 1597.39 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 8.03-8.06 (m, 2 H), 7.79-7.82 (m, 2 H), 7.56-7.61 (m, 1 H), 7.35-7.48 (m, 10 H), 5.68 (s, 2 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 187.84, 150.01, 142.24, 137.25, 134.47, 133.30, 130.44, 129.61, 129.07, 128.86, 128.71, 128.60, 128.32, 128.27, 128.17, 59.24. HRMS: m/z calcd for C₂₂H₁₈N₃O [M + H]⁺: 340.14444; found: 340.14426.^5b
General Procedure of the Reaction between Ynones, Sodium Azide, and Aryl Halides: Regioselective Synthesis of [2-(4-Nitrophenyl)-5-phenyl-2 H -1,2,3-triazol-4-yl](phenyl) Methanone (2a)
All reactions were performed on a 0.25 mmol scale relative to ynones. 1,3-Diphenylprop-2-yn-1-one (0.25 mmol), NaN₃ (0.25 mmol), 4-O₂NC₆H₄Cl (0.375 mmol), and DMSO (1.5 mL) were successively added to a round-bottom sidearm flask (10 mL) and reacted at 120 ˚C for 48 h, then H₂O (2 mL), 20% HCl solution (1 mL) were added to the reaction mixture after cooled and extracted with ester (3 × 10 mL). The combined organic phases were washed with brine (2 × 3 mL), dried over anhyd MgSO₄, and concentrated in vacuo. The residue was subjected to flash column chromatography with hexanes-EtOAc (20:1) as eluent to obtain the desired 4a (79 mg, yield 85%); mp 145-147 ˚C. IR: 3074.59, 2918.34, 1652.74, 1593.64 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.33-8.35 (m, 4 H), 8.11-8.13 (m, 2 H), 7.87-7.90 (m, 2 H), 7.64-7.67 (m, 1 H), 7.44-7.54 (m, 5 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 187.45, 151.34, 146.89, 144.36, 143.09, 136.65, 133.90, 130.44, 129.82, 128.69, 128.58, 128.56, 128.52, 125.20, 119.50. MS (EI): m/z = 370 [M]⁺. Anal. Calcd for C₂₁H₁₄N₄O₃: C, 68.10; H, 3.81; N, 15.13. Found: C, 68.14; H, 3.79; N, 15.15.⁶ Copies of NMR spectroscopic, ESI-HRMS analysis, MS (EI) element analysis, and X-ray crystallography are found in the Supporting Information.