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Synlett 2008(14): 2089-2092  
DOI: 10.1055/s-2008-1078019
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Microwave Enhancement of a ‘One-Pot’ Tandem Azidation-‘Click’ Cycloaddition of Anilines

Adam D. Moorhouse, John. E. Moses*
School of Chemistry, University of Nottingham, University Park, Nottingham, UK
Fax: +44(115)9513564; e-Mail: john.moses@nottingham.ac.uk;
Further Information

Publication History

Received 21 May 2008
Publication Date:
31 July 2008 (online)

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Abstract

The practical and efficient one-pot azidation of anilines with the reagent combination t-BuONO and TMSN3 has become a useful addition to the click-chemistry toolbox. Herein we report a modification of this methodology, using microwave radiation to significantly enhance the rate of formation of 1,4-triazoles from in situ generated azides.

Key words

click chemistry - aromatic azides - Huisgen cycloaddition - chemoselectivity - 1,4-triazoles

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Typical Procedure - Synthesis of 4-{4-(4-Methoxyphen-yl)-[1,2,3]triazol-1-yl}benzonitrile (1) To a stirred solution of 4-aminobenzonitrile (200 mg, 1.69 mmol) in MeCN (2 mL) was added t-BuONO (0.22 mL, 1.69 mmol) at 0 ˚C in a 2-5 mL microwave reaction vial. To this solution was added TMSN3 (0.20 mL, 1.69 mmol) dropwise at 0 ˚C. The solution was stirred for 2 min at r.t., before completion of transformation to azide (monitored by TLC). At this point, 1-ethynyl 4-methoxybenzene (0.33 mL, 2.54 mmol) was added to the reaction mixture, followed by the addition of CuSO4˙5H2O (42 mg, 0.169 mmol) and sodium ascorbate (167 mg, 0.845 mmol) in H2O (1 mL). The vial was capped, then placed in a microwave reactor, and heated to 80 ˚C (125 W max) (Biotage® Initiator 2.0, 400 W). The reaction mixture was stirred at this temperature for 10 min before completion of reaction was observed by TLC analysis. The product was then precipitated by the addition of H2O (25 mL). The product was isolated by filtration then washed with H2O (2 × 10 mL), then PE (40-60, 2 × 10 mL). This gave the product as an orange powder (423 mg, 91%). IR (CHCl3): 3010.24 (CH), 2234.19 (CºN) cm-¹. ¹H NMR (400 MHz, DMSO): δ = 3.81 (s, 3 H, CH3), 7.07 (d, J = 8.9 Hz, 2 H, 2 × CH), 7.86 (d, J = 8.9 Hz, 2 H, 2 × CH), 8.11 (d, J = 9.0 Hz, 2 H, 2 × CH), 8.17 (d, J = 9.0 Hz, 2 H, 2 × CH), 9.32 (s, 1 H, CH). ¹³C NMR (100 MHz, DMSO): δ = 55.1, 110.8, 114.4, 118.0, 118.6, 120.1, 122.2, 128.7, 134.2, 139.4, 147.6, 159.4. HRMS: m/z calcd for C16H13N4O: 277.1084; found: 277.1076. Anal. Calcd for C16H12N4O: C, 69.55; H, 4.38; N, 20.28; Found: C, 69.32; H, 4.32; N, 20.11.