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DOI: 10.1055/s-0030-1258561
A Metal-Free, Three-Component Manifold for the C2-Functionalization of 1-Substituted Imidazoles Operating ‘On Water’
Publikationsverlauf
Publikationsdatum:
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
- Supporting Information for this article is available online:
- Supporting Information
- 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
References and Notes
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.