Synthesis of 1H-Benzotriazoles via Reductive Amination on Solid Supports

Abstract

An efficient synthesis of N-benzyl-1H-benzotriazoles utilizing a two-step reductive amination reaction on solid supports has been achieved. The method is suitable for combinatorial synthesis.

Key words

solid-phase synthesis - nitrogen heterocycles - imines - benzotriazoles - reductive amination reaction

References and Notes

• 1 Katritzky AR. Lan X. Yang JZ. Denisko OV. Chem. Rev.  1998,  98:  409 
• 2a Lormann MEP. Walker CH. Es-Sayed M. Bräse S. Chem. Commun.  2002,  1296 
• 2b Bräse S. Acc. Chem. Res.  2004,  37:  805 
• 3 Zimmermann V. Bräse S. J. Comb. Chem.  2007,  9:  1114 
• 4 Avemaria F. Zimmermann V. Bräse S. Synlett  2004,  1163 
• 6 Dahmen S. Bräse S. In Handbook of Combinatorial Chemistry   Nicolaou KC. Hanko R. Hartwig W. Wiley-VCH; Weinheim: 2002.  Chap. 4.
• 7 Zimmermann V. Avemaria F. Bräse S. J. Comb. Chem.  2007,  9:  200 
• For leading references, see:
• 9a Review: Baxter EW. Reitz AB. Org. React. (N. Y.)  2002,  59:  1 
• For recent examples, see:
• 9b Rodriguez Loaiza P. Löber S. Hübner H. Gmeiner P. J. Comb. Chem.  2006,  8:  252 
• 9c DiCesare JC. White CE. Rasmussen WE. White BM. McComas CB. Craft LE. Synth. Commun.  2005,  35:  663 
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5

Merrifield resin (0.93 mmol/g) was obtained from Polymer Laboratories.

8

Representative Experimental Procedure:¹⁰
Resin: Resin 6 (0.600 g, 0.384 mmol, 1.0 equiv), 4-methoxybenzaldehyde (7i; 0.523 g, 3.84 mmol, 10 equiv) and molecular sieve (2 g) were suspended in anhyd toluene (15 mL) in a 20-mL glass vial and the vessel was sealed with a PTFE-coated cap. The mixture was heated at 80 °C for 3 d and occasionally shaken through. After cooling, the resin was separated from the molecular sieve, filtered on a polypropylene plastic frit, subsequently roughly washed with anhyd acetone, CH₂Cl₂ and pentane and dried in air stream for 5 min. The molecular sieve was disposed and the glass vial was briefly rinsed with anhyd toluene. The resin was then immediately placed back into the glass vial, NaBH₃CN (0.145 g, 3.84 mmol, 10 equiv) and anhyd toluene (15 mL) were added and the vessel was sealed. The mixture was heated at 80 °C for another 3 d and occasionally shaken through. After cooling, the resin was filtered on a polypropylene plastic frit, subsequently washed with MeOH, 2 × [THF, pentane (2 ×)], 3 × [CH₂Cl₂, pentane (2 ×)], and dried in vacuo for 12 h, to give the resin 10i.
Cleavage: The resin 10i (0.400 g) was placed into a glass vial and a solution of trifluoroacetic acid (0.100 mL) in CH₂Cl₂ (10 mL) was added. After 5 min, the mixture was filtered on a glass frit (polypropylene plastic frits are not suitable) and washed with CH₂Cl₂ (8 mL). The combined filtrates were washed with H₂O (2 × 10 mL), the solvent was removed by distillation, and the product was dried in vacuo to yield the benzotriazole 12k with 95% purity (¹H NMR).

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Spectroscopic data for 12c: ¹H NMR (300 MHz, CDCl₃): δ = 3.02 (s, 6 H, NMe₂), 5.79 (s, 2 H, CH₂), 7.12 (br d, ³ J = 8.67 Hz, 2 H, 3′-H, 5′-H), 7.30 (br d, ³ J = 8.67 Hz, 2 H, 2′-H, 6′-H), 7.32-7.45 (m, 3 H, 5-H, 6-H, 7-H), 8.05 (ddd, ³ J = 8.10 Hz, ⁴ J = 1.13 Hz, ⁵ J = 0.94 Hz, 1 H, 4-H). ¹³C NMR (75 MHz, CDCl₃): δ = 43.5 (+, NMe), 51.7 (-, CH₂), 109.6 (+, CAr), 117.3 (+, 2 × C, CAr′), 119.9 (+, CAr), 124.3 (+, CAr), 127.7 (+, CAr), 129.3 (+, 2 × C, CAr′), 129.9 (quart, C-7a), 132.7 (quart, C-1′), 145.9 (quart, C-4′), 146.8 (quart, C-3a).