Copper(II) Triflate as a Double Catalyst for the One-Pot Click Synthesis of 1,4-Disubstituted 1,2,3-Triazoles from Benzylic Acetates

Abstract

Copper(II) triflate doubly catalyzed the substitution of benzylic acetates by TMSN₃ and the subsequent 1,3-dipolar addition with an alkyne in one pot. This procedure afforded the preparation of 1,4-disubstituted 1,2,3-triazoles in good yields starting from the easily accessible acetates without isolating an organic azide ­using a single catalyst.

Key words

triazole - copper(II) triflate - click reaction

References and Notes

• For reviews, see:
• 1a Kolb HC. Finn MG. Sharpless KB. Angew. Chem. Int. Ed.  2001,  40:  2004 
• 1b Bock VD. Hiemstra H. van Maarseveen JH. Eur. J. Org. Chem.  2006,  51 
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• 2 Rostovsev VV. Green LG. Fokin VV. Sharpless KB. Angew. Chem. Int. Ed.  2002,  41:  2596 
• For examples of one-pot reactions, see:
• 3a Feldman AK. Colasson B. Fokin VV. Org. Lett  2004,  6:  3897 
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• 3c Molander GA. Ham J. Org. Lett  2006,  8:  2767 
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• 3e Beckmann HSG. Wittmann V. Org. Lett  2007,  9:  1 
• 4 Chittaboina S. Xie F. Wang Q. Tetrahedron Lett.  2005,  46:  2331 
• 5 Fukuzawa S.-i. Suzuki T. Eur. J. Org. Chem.  2006,  1012 
• Azidotrimethylsilane has been used as a nitrogen source in the palladium-catalyzed 1,2,3-triazole synthesis. See:
• 8a Kamijo S. Jin T. Huo Z. Yamamoto Y. Tetrahedron Lett.  2002,  43:  9707 
• 8b Kamijo S. Jin T. Huo Z. Yamamoto Y. J. Am. Chem. Soc.  2003,  125:  7786 
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• It has been reported that the addition of DIPEA often improves the yield of 1,2,3-triazole by the Cu(I)-catalyzed click reaction. For examples, see:
• 9a Tornø CW. Christensen C. Meldal M. J. Org. Chem.  2002,  67:  3057 
• 9b Horne WS. Stout CD. Ghadiri MR. J. Am. Chem. Soc.  2003,  125:  9372 
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• 9e

  See also ref. 2.

• 10 Yoo EJ. Ahlquist M. Kim SH. Bae I. Fokin VV. Sharpless KB. Chang S. Angew. Chem. Int. Ed.  2007,  46:  1730 
• 11 Small amounts of 1,4,5-trisubstituted triazoles were detected by GC-MS analyses (ca. 5%), but these were not isolated. For the synthesis of the 1,4,5-trisubstituted triazoles, see: Gerard B. Ryan J. Beeler AB. Porco JA. Tetrahedron  2006,  62:  66405 
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6

The Cu(OTf)₂-catalyzed reaction of (R)-1-phenylethyl acetate (95% ee) with TMSN₃ under the conditions gave the racemate 1-phenylethyl azide. This result suggests that the substitution reaction proceeds with S_N1-type reaction.

7

The reaction must be carried out in two steps. Mixing of three components, i.e., compound 1, phenylacetylene, and TMSN₃, in the presence of the Cu catalyst and additive (DIPEA) in CH₂Cl₂ (1 mL) did not afford 2, along with recovering the starting compounds. A typical experimental procedure is as follows: In a 20 mL Schlenk tube containing a magnetic stirring bar were charged Cu(OTf)₂ (18 mg, 0.05 mmol) and dry CH₂Cl₂ (1 mL) under a slight pressure of nitrogen. A mixture of 1-phenylethyl acetate (1, 82 mg, 0.5 mmol) and TMSN₃ (86 mg, 1.5 mmol) was then added using a syringe through the septum with stirring at r.t. The reaction was monitored by TLC and after the starting acetate had almost disappeared (12 h), phenylacetylene 2 (62 mg, 0.6 mmol) was then added to the mixture followed by DIPEA (95 µL, 0.55 mmol). The mixture was stirred at r.t. for an additional 1 h. The reaction was quenched with H₂O, and extracted with EtOAc (3 × 15 mL). The combined extracts were washed with brine, dried over MgSO₄, filtered, and the solvent was removed using a rotary evaporator that left a yellow residue. The GC-MS analysis revealed the presence of 2 of which the yield was determined by GC using biphenyl as the internal standard. The product 2 was isolated by preparative TLC (hexane-EtOAc, 4:1); yield, 89 mg, 71%. ¹H NMR (300 MHz, CDCl₃): δ = 2.00 (d, 3 H, J = 7.1 Hz), 5.86 (q, 1 H, J = 7.1 Hz), 7.30-7.50 (m, 8 H), 7.63 (s, 1 H), 7.80 (d, 2 H, J = 7.3 Hz). ¹³C NMR (CDCl₃): δ = 21.2, 60.1, 118.4, 125.6, 126.4, 128.0, 128.5, 128.7, 128.9, 130.6, 139.8, 147.6. IR (KBr): ν = 3092, 1483, 1459, 1421, 1373, 1349, 1304, 1218, 1175, 1155, 1074, 1038, 1025, 993, 973, 913 cm^-1. Anal. Calcd for C₁₆H₁₅N₃: C, 77.08; H, 6.06; N, 16.85. Found: C, 76.86; H, 6.14; N, 17.01.