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Synlett 2007(19): 3037-3041  
DOI: 10.1055/s-2007-990877
LETTER
© Georg Thieme Verlag Stuttgart · New York

Sequential Seyferth-Gilbert/CuAAC Reactions: Application to the One-Pot Synthesis of Triazoles from Aldehydes

Delphine Luvino, Camille Amalric, Michael Smietana*, Jean-Jacques Vasseur*
Institut des Biomolécules Max Mousseron, UMR 5247 CNRS-UMI-UMII, Université Montpellier II, Place Eugène Bataillon, 34095 Montpellier, France
Fax: +33(46)7042029; e-Mail: msmietana@univ-montp2.fr; e-Mail: vasseur@univ-montp2.fr;
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Publikationsverlauf

Received 13 September 2007
Publikationsdatum:
08. November 2007 (online)

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Abstract

A reliable and operationally simple one-pot reaction for a one-carbon homologation of various aldehydes followed by a Cu-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) is reported. 1,4-Disubstituted 1,2,3-triazoles are obtained in good to excellent yields from a variety of readily available aldehydes without the need for isolation of the alkyne intermediates. The reaction has a broad scope, allows the formation of new bioconjugates and is applied for the synthesis of new boronic acid based fluorescent sensors.

Key words

click chemistry - 1,2,3-triazole - Bestmann-Ohira reagent - bioconjugation - boronic acids

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A quick search in the Aldrich catalogue (sigma-aldrich.com) found 269 commercial alkynes vs. 870 aldehydes.

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General Experimental Procedure: The aldehyde (2 mmol), 2-oxopropyldiazodimethyl phosphonate (4 mmol) and K2CO3 (6 mmol) were suspended in MeOH-THF (1:1; 4 mL) under an argon atmosphere. The reaction mixture was stirred at r.t. until TLC showed the reaction to be complete (2-24 h, in some cases another 0.5 equiv of the reagent was needed to reach completion). When the starting aldehyde was completely converted into the intermediate alkyne, CuI (0.4 mmol) and the azide (2 mmol) were added, and the reaction mixture was stirred at r.t. The progress of the reaction was followed by TLC (2-12 h). The solvents were removed in vacuo and the residue was dissolved in EtOAc (20 mL) and H2O (20 mL). The aqueous layer was washed with EtOAc (2 × 20 mL). The organic phase was washed with a sat. solution of NH4Cl (20 mL), brine (20 mL) and dried over anhyd Na2SO4. The solvent was removed in vacuo and the crude product was further purified by column chromatography (n-hexane-EtOAc).
Characterization Data for Selected Compounds: 1-{2′-Deoxy-4′-[1-(pyren-1-ylmethyl)-1,2,3-triazol-4-yl]-3′- O - tert -butyldimethylsilyl-β-d -erythrofurano-syl}thymine (Table 1, entry 6): yield: 73%; mp 125-126 °C; R f 0.53 (n-hexane-EtOAc, 5:5). 1H NMR (300 MHz, CDCl3): δ = 0.03 (s, 3 H), 0.13 (s, 3 H), 0.75 (s, 9 H), 1.69 (s, 3 H), 2.20-2.29 (m, 1 H), 2.48-2.57 (m, 1 H), 4.66-4.68 (m, 1 H), 4.79 (d, J = 2.6 Hz, 1 H), 6.29 (s, 2 H), 6.44 (t, J = 5.9 Hz, 1 H), 7.31 (s, 1 H), 7.64 (s, 1 H), 7.99-8.16 (m, 9 H).13C NMR (75 MHz, CDCl3): δ = 4.8, 4.9, 12.4, 25.6, 40.4, 52.5, 75.8, 80.8, 85.7, 111.1, 121.7, 122.4, 124.5, 125.0, 125.2, 125.9, 126.1, 126.2, 126.5, 127.2, 127.8, 128.5, 129.3, 129.4, 130.5, 131.2, 132.3, 136.3, 140.0, 150.2, 163.4. MS (ESI+): m/z (%) = 608 (100) [M + H]+. HRMS (FAB+, NBA): m/z calcd for C34H38N5O4Si (M + H+): 608.2693; found: 608.2712.
(2 S ,3 R )- tert -Butyl-2-(benzyloxycarbonylamino)-3-[4-(pyren-1-yl)-1,2,3-triazol-1-yl]butanoate (Table 1, entry 10): yield: 75%; mp 81-83 °C; [α]20 +12° (c = 1, CHCl3); R f 0.10 (n-hexane-EtOAc, 8:2). 1H NMR (300 MHz, CDCl3): δ = 1.49 (s, 9 H), 1.83 (d, J = 6.8 Hz, 3 H), 4.85-4.89 (dd, J = 4.8, 8.5 Hz, 1 H), 5.11 (m, 1 H), 5.17 (s, 2 H), 5.90 (d, J = 8.3 Hz, 1 H), 7.18-7.31 (m, 3 H), 7.76-7.78 (m, 2 H), 8.00-8.14 (m, 9 H), 8.67 (d, J = 9.3 Hz, 1 H).13C NMR (75 MHz, CDCl3): δ = 21.4, 27.9, 58.3, 58.8, 84.0, 122.0, 124.7, 124.8, 125.2, 125.4, 126.1, 126.3, 127.2, 127.4, 127.8, 128.1, 128.2, 128.3, 128.5, 128.6, 129.6, 130.9, 131.3, 131.4, 139.3, 143.3, 147.2, 155.9, 167.9. MS (ESI+): m/z (%) = 561 (100) [M + H]+. HRMS (ESI+): m/z calcd for C34H33N4O4 (M + H+): 561.2502; found: 561.2480.
1-{2′-Deoxy-4′-[1-(2′,3′,4′,6′-tetra- O -benzyl-β-d -gluco-pyranosyl)[1,2,3]triazol-4-yl]-3′- O - tert -butyldimethyl-silyl-β-d -erythrofuranosyl}thymine (Table 1, entry 11): yield: 80%; mp 80-83 °C; R f 0.51 (n-hexane-EtOAc, 5:5). 1H NMR (300 MHz, CDCl3): δ = 0.00 (s, 3 H), 0.05 (s, 3 H), 0.88 (s, 9 H), 1.84 (s, 3 H), 2.34-2.63 (m, 2 H), 3.78-3.89 (m, 2 H), 4.05-4.18 (m, 2 H), 4.47-4.96 (m, 10 H), 5.61 (d, J = 9.0 Hz, 1 H), 6.53 (t, J = 6.80 Hz, 1 H), 6.92-6.96 (m, 2 H), 7.16-7.33 (m, 20 H), 7.64 (s, 1 H), 7.82 (s, 1 H), 9.10 (br s, 1 H). 13C NMR (75 MHz, CDCl3): δ = -4.79, -4.76, 12.5, 17.9, 25.6, 40.4, 68.3, 73.6, 74.8, 75.2, 75.8, 77.2, 77.5, 78.1, 80.2, 80.9, 85.5, 85.8, 87.6, 111.2, 122.1, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.4, 128.5, 136.6, 136.8, 137.6, 138.0, 146.1, 150.6, 163.9. MS (ESI+): m/z (%) = 916.3 (100) [M + H]+. HRMS (ESI+): m/z calcd for C51H62N5O9Si (M + H+): 916.4317; found: 916.4327.
3′-[4-(2′-Deoxy-3′- O - tert -butyldimethylsilyl-1′-thyminyl-β-d -erythrofuranos-4′-yl)-1,2,3-triazol-1-yl]thymidine (Table 1, entry 13): yield: 85%; mp 139-140 °C; R f 0.09 (CH2Cl2-EtOAc, 5:5). 1H NMR (300 MHz, CDCl3): δ = 0.06 (2 × s, 6 H), 0.87 (s, 9 H), 1.92 (s, 3 H), 1.95 (s, 3 H), 2.33-2.71 (m, 2 H), 2.94-3.09 (m, 2 H), 3.82-4.12 (m, 2 H), 4.44-4.46 (m, 1 H), 4.71-4.74 (m, 1 H), 4.97 (d, J = 3.01 Hz, 1 H), 5.43-5.49 (m, 1 H), 6.21 (t, J = 6.55 Hz, 1 H), 6.36 (t, J = 6.4 Hz, 1 H), 7.41 (s, 1 H), 7.65 (s, 1 H), 7.80 (s, 1 H), 8.61 (br s, 1 H), 8.64 (br s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 4.83, 12.4, 12.5, 14.2, 25.7, 36.5, 39.8, 59.1, 60.6, 61.2, 76.2, 81.0, 85.3, 87.5, 88.4, 111.2, 122.3, 137.6, 137.7, 146.0, 150.6, 150.8, 164.1, 164.2. MS (ESI+): m/z (%) = 618 (100) [M + H]+. HRMS (FAB+, NBA): m/z calcd for C27H39N7O8Si (M + H+): 618.2708; found: 618.2682.

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Characterization Data for Selected Compounds: 1-Benzyl-4-[3-(4,4,5,5-tetramethyl-1,3-dioxa-2-borolan-2-yl)phenyl]-1,2,3-triazole (Table 2, entry 1): yield: 30%; white solid; mp 172-173 °C; R f 0.24 (n-hexane-EtOAc, 8:2). 1H NMR (300 MHz, CDCl3): δ = 1.22 (s, 12 H), 5.44 (s, 2 H), 7.14-7.33 (m, 5 H), 7.25 (s, 1 H), 7.59 (s, 1 H), 7.64 (m, 1 H), 7.92 (m, 1 H), 7.97 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ = 22.6, 52.0, 81.7, 117.4, 125.8, 126.1, 126.4, 126.5, 126.9, 127.8, 129.7, 132.3, 132.5, 146.0. MS (ESI+): m/z (%) = 362.2 (100) [M + H]+. HRMS (ESI+): m/z calcd for C21H25BN3O2 (M + H+): 362.2040; found: 362.2037.
1-(Pyren-1-ylmethyl)-4-[4-(4,4,5,5-tetramethyl-1,3-dioxa-2-borolan-2-yl)phenyl]-1,2,3-triazole (Table 2, entry 4): yield: 55%; mp 168-170 °C; R f 0.14 (n-hexane-EtOAc, 8:2). 1H NMR (400 MHz, CDCl3): δ = 1.23 (s, 12 H), 6.21 (s, 2 H), 7.22 (d, J = 7.9 Hz, 2 H), 7.44-7.74 (m, 3 H), 7.92-8.19 (m, 8 H), 8.17 (s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 24.8, 55.3, 83.8, 119.9, 121.9, 124.8, 125.9, 126.0, 126.5, 127.2, 127.8, 128.4, 128.7, 129.2, 129.4, 130.6, 131.2, 132.3, 132.9, 135.2, 139.1, 143.6, 147.9. MS (ESI+): m/z (%) = 486 (100) [M + H]+. HRMS (ESI+): m/z calcd for C31H29BN3O2 (M + H+): 486.2353; found: 486.2378.