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Synlett 2010(16): 2421-2424  
DOI: 10.1055/s-0030-1258561
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Metal-Free, Three-Component Manifold for the C2-Functionalization of 1-Substituted Imidazoles Operating ‘On Water’

Fabio Cruz-Acostaa,b, Pedro de Armas*a,b, Fernando García-Tellado*a,b
a Departamento de Química Biológica y Biotecnología, Instituto de Productos Naturales y Agrobiología Consejo Superior de Investigaciones Científicas Astrofísico Francisco Sánchez 3, 38206 La Laguna, Tenerife, Spain
Fax: +34(922)260135; e-Mail: fgarcia@ipna.csic.es; e-Mail: parmas@ipna.csic.es;
b Instituto Canario de Investigación del Cáncer, Canary Islands, Spain
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Publication History

Received 20 July 2010
Publication Date:
03 September 2010 (online)

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Abstract

A metal-free, three-component process for the C2-functionalization of N-alkylated imidazoles is reported The multicomponent manifold operates under ‘on water’ conditions through the formation of a water-stable (permanent) nucleophilic imidazole carbene (imidazolium ylide). Whereas the incorporated vinyl ether functionality is a convenient handle for further chemical manipulation of the functionalized heterocycle (complexity generation), the use of water as the reaction media gives it a bonus of added benefits in terms of safety, bench-friendly processing and environmental care.

Key words

nitrogen heterocycles - carbenes - ylides - multicomponent reactions - water

    References and Notes

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10

General Procedure for the Multicomponent Functionalization of N -Alkyl Imidazoles ‘on Water’ - Preparation of Compound 2c
To a 250 rpm stirred round-bottomed flask charged with H2O (5 mL) were sequentially added (order is important) methyl propiolate (0.3 mmol), N-methylimidazole (0.2 mmol) and n-heptanal (0.1 mmol). An aqueous suspension was inmediately formed which was further stirred at 1000 rpm during 16 h at r.t. The resulting heteroegeneous mixture was extracted with CH2Cl2 (3×), and the collected organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Flash chromatography (EtOAc-hexanes, 40:60) gave pure derivative 2c (70%) as yellow oil.
(E)-2c/(Z)-2c = 3:2. IR (CHCl3): ν = 1714, 1643, 1445, 1172 cm-¹.
(E)-2c: ¹H NMR (500 MHz, CDCl3): δ = 7.49 (d, ³ J H,H = 12.4 Hz, 1 H), 6.93 (br d, ³ J H,H = 1.2 Hz, 1 H), 6.80 (br d, ³ J H,H = 1.2 Hz, 1 H), 5.32 (d, ³ J H,H = 12.4 Hz, 1 H), 5.05 (dd, ³ J H,H = 7.8 and 6.6 Hz, 1 H), 3.62 (s, 3 H), 3.61 (s, 3 H), 2.10-1.95 (m, 2 H), 1.43-1.36 (m, 1 H), 1.32-1.18 (m, 7 H), 0.83 (t, ³ J H,H = 7.0 Hz, 3 H) ppm. ¹³C NMR (125 MHz, CDCl3): δ = 167.8, 160.2, 144.6, 127.6, 122.6, 98.8, 77.9, 50.9, 33.2, 33.0, 31.4, 28.7, 25.3, 22.4, 13.9 ppm.
(Z)-2c: ¹H NMR (500 MHz, CDCl3): δ = 6.94 (s, 1 H), 6.85 (s, 1 H), 6.58 (d, ³ J H,H = 7.0 Hz, 1 H), 5.15 (t, ³ J H,H = 7.3 Hz, 1 H), 4.83 (d, ³ J H,H = 7.0 Hz, 1 H), 3.77 (s, 3 H), 3.64 (s, 3 H), 2.18-2.10 (m, 1 H), 2.07-1.98 (m, 1 H), 1.36-1.21 (m, 8 H), 0.84 (t, ³ J H,H = 7.0 Hz, 3 H) ppm. ¹³C NMR (125 MHz, CDCl3): δ = 165.1, 156.6, 144.5, 123.6, 120.7, 98.5, 78.1, 50.9, 35.3, 33.8, 31.4, 28.7, 24.9, 22.9, 13.9 ppm. MS (70 eV): m/z (%): = 281 (0.7) [M + 1]+, 280 (2) [M]+, 179 (100), 213 (16), 195 (17), 180 (63), 135 (34), 125 (10), 122 (11), 121 (24), 110 (10), 109 (53), 108 (15), 107 (41), 96 (84), 95 (65), 81 (11), 55 (12), 54 (15). Anal. Calcd (%) for C14H22N2O3: C, 64.26; H, 8.63; N, 9.99. Found: C, 64.29; H, 8.76; N, 10.12.