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

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.

nitrogen heterocycles - carbenes - ylides - multicomponent reactions - water

References and Notes

1 Trofimov BA. Andriyankova LV. Belyaeva KV. Mal’kina AG. Eur. J. Org. Chem.  2010,  1772 

2 On water refers to the reactions performed with sparingly soluble or insoluble reactants in water. See: Narayan S. Muldoon J. Finn MG. Fokin VV. Kolb HC. Sharpless KB. Angew. Chem. Int. Ed.  2005,  44:  3275 

For selected contributions of our work on this field, see:

3a Tejedor D. López-Tosco S. Cruz-Acosta F. Méndez-Abt G. García-Tellado F. Angew. Chem. Int. Ed.  2009,  48:  2090 

3b Tejedor D. López-Tosco S. González-Platas J. García-Tellado F. J. Org. Chem.  2007,  72:  54545 

3c Tejedor D. Santos-Expósito A. García-Tellado F. Chem. Eur. J.  2007,  13:  1201 

3d Tejedor D. González-Cruz D. Santos-Expósito A. Marrero-Tellado JJ. de Armas P. García-Tellado F. Chem. Eur. J.  2005,  11:  3502 

3e Tejedor D. García-Tellado F. Marrero-Tellado JJ. de Armas P. Chem. Eur. J.  2003,  9:  3122 

4 González-Cruz D. Tejedor D. de Armas P. García-Tellado F. Chem. Eur. J.  2007,  13:  4823 

5 Chemo-differentiating ABB′ 3CRs refer to three-component reactions that utilize two different components (A and B) to give a product which incorporates into its structure one unit of component A and two chemo-differentiated units of component B (B and B′). For full details and more examples of this type of multicomponent reactions, see: Tejedor D. García-Tellado F. Chem. Soc. Rev.  2007,  36:  484 

6a Grimmett MR. In Comprehensive Heterocyclic Chemistry II   Vol. 3:  Katrizky AR. Rees CW. Scriven EFV. Pergamon; Oxford: 1996.  p.77-220  

6b Grimmett MR. In Imidazole and Benzimidazole Synthesis   Academic Press; New York: 1997.  p.1-143  

6c Bellina F. Cauteruccio S. Rossi R. Tetrahedron  2007,  63:  4571 

For previous examples of metal-free C2-substitution of N-substituted imidazoles via nucleophilic carbenes, see:

7a Zificsak C. Hlasta DJ. Tetrahedron Lett.  2005,  46:  4789 

7b Deng Y. Hlasta DJ. Org. Lett.  2002,  4:  4017 

7c Deng Y. Hlasta DJ. Tetrahedron Lett.  2002,  43:  189 

7d Hlasta DJ. Org. Lett.  2001,  3:  157 

8a Bellina F. Rossia R. Adv. Synth. Catal.  2010,  352:  1223 

8b Zificsak CA. Hlasta DJ. Tetrahedron  2004,  60:  8991 

9 In addition to this cause, chemical and physical factors such as differences in viscosity between H₂O and D₂O may affect droplet size and consequently the efficiency of the reaction. For a discussion, see: Jing Y. Marcus MRA. J. Am. Chem. Soc.  2007,  129:  5492 

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.