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.

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 

1c Gil MV. Arévalo MJ. López . Synthesis  2007,  1589 

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 

3b Appukkuttan P. Dehaen W. Fokin VV. Van der Eycken E. Org. Lett  2004,  6:  4223 

3c Molander GA. Ham J. Org. Lett  2006,  8:  2767 

3d Kacprzak K. Synlett  2005,  943 

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 

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.

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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9d Reddy KR. Rajgopal K. Kantam ML. Synlett  2006,  957 

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 

For a click reaction with allylic acetates, see:

12a Chandrasekhar S. Basu D. Rambabu C. Tetrahedron Lett.  2006,  47:  3059 

12b Sreedhar B. Reddy PS. Kumar NS. Tetrahedron Lett.  2006,  47:  3055