A metal-free, three-component manifold for the C2-functionalization of 1-substituted imidazoles operating on water

Article abstract of DOI:10.1055/s-0030-1258561

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. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258561

LETTER
2421
A Metal-Free, Three-Component Manifold for the C2-Functionalization of
1-Substituted Imidazoles Operating ‘On Water’
C
2-Functional
a
ization of
1
b
-
Substituted
i
Imidaz
o
oles
O
perating ‘O
n
C
W
ater’ ruz-Acosta,a,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
Received 20 July 2010
It was expected that the N-substituted imidazole triggered
the multicomponent process by the nucleophilic addition
on the terminal alkynoate to generate the corresponding
imidazolium allenolate A, which would be basic enough
Abstract: A metal-free, three-component process for the C2-func-
tionalization of N-alkylated imidazoles is reported The multicom-
ponent manifold operates under ‘on water’ conditions through the
formation of a water-stable (permanent) nucleophilic imidazole car-
bene (imidazolium ylide). Whereas the incorporated vinyl ether to transfer the reactivity from the chain (allenolate) to the
functionality is a convenient handle for further chemical manipula-
ring (C2-ylide) via a 1,5-prototropic rearrangement. In the
tion of the functionalized heterocycle (complexity generation), the
presence of an aldehyde, the imidazolinium ylide (imida-
use of water as the reaction media gives it a bonus of added benefits
zole carbene)7 intermediate B would generate the corre-
in terms of safety, bench-friendly processing and environmental
sponding zwitterionic alkoxide adduct C, which in turn
care.
would rearrange to the final product 2, restoring the aro-
Key words: nitrogen heterocycles, carbenes, ylides, multicompo-
maticity at the heterocyclic ring. Overall, this three-com-
nent reactions, water
ponent reaction would constitute a convenient and metal-
free manifold to the C2-functionalization of N-substituted
imidazoles8 ‘on water’. To the best of our knowledge,
A recent contribution from the Trofimov’s group1 de-
there are no precedents for such a multicomponent mani-
scribing a novel three-component C2-functionalization of
fold operating under ‘on water’ conditions.
1-substituted imidazoles under solvent-free conditions
prompted us to report our own results with the ‘on water’2
O–
CO2R2
CO2R2
version of such multicomponent reaction. Some years
ago, we started a wide research program aimed to the de-
sign and development of efficient domino synthetic man-
ifolds based on the catalytic generation of allenolate ions
by the reaction of a good nucleophile (tertiary amine or
phosphine) and a terminal conjugated alkyne.3 We have
described elsewhere4 that when these allenolate ions are
generated under ‘on water’ conditions and in the presence
of an aldehyde, they afford propargyl enol ethers 1 via a
chemo-differentiating ABB¢ 3CR5 manifold (Equation 1),
which operates with higher efficiency than the corre-
sponding organic homologues. Based on these results, we
explored the possibility to functionalize 1-substituted
imidazoles6 via the allenolate-driven multicomponent
manifold outlined in Scheme 1.
R3CHO
OR2
•
N
H2O
CO2R2
••
N+
N
••
N
N
R1
N
N+
R1
A
imidazolium
allenolate
R1
N
R1
B
imidazolium
ylide
imidazole
carbene
ABC 3CRs
R3CHO
N+
R1
R3
N
rearrangement
CO2R2
N
R1
N
O
CO2R2
O–
2
R3
C
Scheme 1 Three-component C2-functionalization of N-substituted
imidazoles ‘on water’
ABB' 3CR
R
O
CO2Me
CO2Me
O
quinine (10 mol%)
+
1
6 M LiCl, r.t., 12 h
70–97%
In this communication we report our results on the devel-
opment of this multicomponent manifold, which parallel
those reported by Trofimov et al. in the absence of sol-
vent.1 Importantly, our results show that nucleophilic
imidazole carbenes (imidazolium ylides) can be conve-
niently formed and handled under ‘on water’ conditions to
functionalize the parent heterocyclic ring at the C2-posi-
tion. The use of water as the supporting media ensures a
bonus of practicability and safety to these highly exother-
R
CO2Me
Equation 1
SYNLETT 2010, No. 16, pp 2421–2424
Advanced online publication: 03.09.2010
x
x
.x
x
.2
0
1
0
DOI: 10.1055/s-0030-1258561; Art ID: D19610ST
© Georg Thieme Verlag Stuttgart · New York

2422
F. Cruz-Acosta et al.
LETTER
N
CO2Me
mic processes in relation to their solvent-free counter-
parts.
N
O
H2O (5 mL)
r.t., 16 h
CO2Me
O
+
+
N
N
R2
R2
R1
We undertook this study with the implementation of the
reaction of N-methylimidazole, methyl propiolate, and
butyraldehyde under ‘on water’ conditions (Equation 2,
Table 1). Among the different stoichiometries assayed for
this multicomponent reaction, that one shown in entry 5
proved to be the most effective in terms of chemical effi-
ciency (61%) and atom economy (2:3:1 ratio). Tempera-
ture was an important reaction factor with a detriment
effect on the reaction yield (compare entries 2 and 3). Fi-
nally and not less important, the order of addition of the
reagents proved also to be significant. The addition order:
alkynoate, N-alkylated imidazole and aldehyde showed to
be the best and it was used in further experiments.
R1
2 R1 = Me
3 R1 = Bu
Equation 3
Table 2 Multicomponent C2-Functionalization of N-Substituted
Imidazoles
Entry
1
R1
R2
Product
2a
Yield (%)a E/Z
Me
Bu
Me
Bu
Me
Bu
Me
Bu
Me
Bu
Me
Bu
Bu
n-Pr
n-Pr
Et
63
30
28
61
70
53
30
66
50
90
74
55
75
3:2
3:2
3:2
3:2
3:2
3:2
3:2
3:2
3:2
3:2
3:2
3:2
3:2
2
3a
3
2b
3b
2c
O
N
CO2Me
N
H2O (5 mL)
r.t., 16 h
4
Et
CO2Me
O
+
+
N
N
n-Pr
5
n-Hex
n-Hex
i-Pr
n-Pr
Me
Me
2a
6
3c
Equation 2
7
2d
3d
2e
8
i-Pr
Table 1 Multicomponent C2-Functionalization of N-Methylimida-
zole
9
c-Hex
c-Hex
Ph
Entry
NMIa
(equiv)
HCCCO2Me n-PrCHO Temp (°C) Yield
10
11
12
13
3e
(equiv)
(equiv)
(%)b
17
6
2f
1
2
3
4
5
2
2
2
1
2
1
1
1
2
3
1
3
3
1
1
r.t.
r.t.
40
r.t.
r.t.
Ph
3f
4-O2NC6H4
3g
3
a Isolated and pure compound.
40
61
acrylates and alkoxide ions, which used to be stereoselec-
tive (E-isomer).
a NMI = N-methylimidazole.
b Isolated and pure compound.
Trofimov et al. also reported low stereoselectivities in
their solvent-free reaction of N-methylimidazole and dif-
ferent aldehydes when methyl propiolate was used as the
alkyne source.1 This low stereoselectivity seemed to us to
be related with a bimolecular route from the alkoxide C to
the final product 2 (3), via the zwitterionic intermediate D
(Scheme 2). The alternative intramolecular version for
this rearrangement (alkoxide addition–imidazole elimina-
tion) was expected to be stereoselective, mainly affording
the E-isomer. A piece of evidence for this bimolecular
mechanism came from the reaction of heptanal, methyl
propiolate, and N-methylimidazole in D2O (Scheme 2).
The reaction afforded derivative 2c-d2 in low yield (15%)
and stereoselectivity (E/Z = 3:2), with deuterium incorpo-
rated at both positions of the enol double bond (see Sup-
porting Information). Whereas this pattern for deuterium
incorporation was difficult to explain from an intramolec-
ular rearrangement from C to 2 (3), it was the expected re-
sult from the mechanistic picture outlined in Scheme 2, if
the reversible addition of N-methylimidazole on the
alkynoate is slow enough to allow a fast H–D alkynoate
exchange. If this was the case, deuterated alkynoate
Once a practical set of reaction conditions was found for
this multicomponent reaction, we began to explore its
scope and generality, using N-methyl and N-butylimida-
zoles as representative examples of N-alkylated imida-
zoles featuring different lipophilicity. We select a set of
aldehydes spanning a convenient spectrum of lipophicity
and reactivity and methyl propiolate as the only source of
the required alkynote (Equation 3, Table 2).10 In general,
the reaction was general for both aliphatic and aromatic
aldehydes, with a general better efficiency for the more li-
pophilic aldehydes (compare entries 9–13 with entries 1–
4, 7, and 8). An unexpected subtle influence of the lipo-
philicity of the N-alkylated imidazole was observed. We
found an erratic relationship between the aldehyde and
imidazole lipophilicities and the reaction efficiency (com-
pare entries 1, 2 with 3, 4 and 7,8). The low stereoselec-
tivity of this three-component reaction was something
more than surprising and unexpected from our own expe-
rience on multicomponent processes involving b-onium
Synlett 2010, No. 16, 2421–2424 © Thieme Stuttgart · New York

LETTER
C2-Functionalization of 1-Substituted Imidazoles Operating ‘On Water’
2423
should be incorporated into intermediate D, placing a deu- media gives to this manifold a bonus of added benefits in
terium atom at the b-position of the acrylate unit in the fi- terms of safety, bench-friendly processing, and environ-
nal product 2c. Deuteration of this intermediate D with mental care.
D2O should account for the second incorporation of deu-
terium in 2c. The low efficiency of this reaction in D2O
Supporting Information for this article is available online at
could be related with major isotopic effects operating at
http://www.thieme-connect.com/ejournals/toc/synlett.
this step (a net O–D bond is broken in this step).9
O–
Acknowledgment
CO2Me
CO2Me
OMe
This research was supported by the Spanish Ministerio de Ciencia e
Innovación, the European Regional Development Fund (CTQ2008-
06806-C02-02), the Spanish MSC ISCIII (RETICS RD06/0020/
1046), FUNCIS (REDESFAC PI01/06). F.C.-A thanks CSIC for a
predoctoral JAE grant.
•
N+
N
N
–
N+
N
R1
N
R1
R1
B
A
imidazolium
imidazolium
allenolate
References and Notes
ylide
(1) Trofimov, B. A.; Andriyankova, L. V.; Belyaeva, K. V.;
Mal’kina, A. G. Eur. J. Org. Chem. 2010, 1772.
R2CHO
(2) On water refers to the reactions performed with sparingly
soluble or insoluble reactants in water. See: Narayan, S.;
Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.;
Sharpless, K. B. Angew. Chem. Int. Ed. 2005, 44, 3275.
(3) For selected contributions of our work on this field, see:
(a) Tejedor, D.; López-Tosco, S.; Cruz-Acosta, F.; Méndez-
Abt, G.; García-Tellado, F. Angew. Chem. Int. Ed. 2009, 48,
2090. (b) Tejedor, D.; López-Tosco, S.; González-Platas, J.;
García-Tellado, F. J. Org. Chem. 2007, 72, 54545.
(c) Tejedor, D.; Santos-Expósito, A.; García-Tellado, F.
Chem. Eur. J. 2007, 13, 1201. (d) Tejedor, D.; González-
Cruz, D.; Santos-Expósito, A.; Marrero-Tellado, J. J.;
de Armas, P.; García-Tellado, F. Chem. Eur. J. 2005, 11,
3502. (e) Tejedor, D.; García-Tellado, F.; Marrero-Tellado,
J. J.; de Armas, P. Chem. Eur. J. 2003, 9, 3122.
N+
CO2Me
CO2Me
N
R1
O–
R2
C
H
N+
CO2Me
CO2Me
N
R1
O
O
R2
N
–
R2
CO2Me
N
D
R1
2 (3)
(4) González-Cruz, D.; Tejedor, D.; de Armas, P.; García-
Tellado, F. Chem. Eur. J. 2007, 13, 4823.
H2O
(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.
(6) (a) Grimmett, M. R. In Comprehensive Heterocyclic
Chemistry II, Vol. 3; Katrizky, A. R.; Rees, C. W.; Scriven,
E. F. V., Eds.; Pergamon: Oxford, 1996, 77–220.
(b) Grimmett, M. R. In Imidazole and Benzimidazole
Synthesis; Academic Press: New York, 1997, 1–143.
(c) Bellina, F.; Cauteruccio, S.; Rossi, R. Tetrahedron 2007,
63, 4571.
OHCCH2CO2Me
CO2Me
D
D
CO2Me
N
D2O
CHO
O
+
+
n-Hex
n-Hex
N
N
Me
N
Me
2c-d2
Scheme 2 A mechanistic proposal for the multicomponent C2-
functionalization of N-alkylated imidazoles with aldehydes and alky-
nolates
(7) For previous examples of metal-free C2-substitution of
N-substituted imidazoles via nucleophilic carbenes, see:
(a) Zificsak, C.; Hlasta, D. J. Tetrahedron Lett. 2005, 46,
4789. (b) Deng, Y.; Hlasta, D. J. Org. Lett. 2002, 4, 4017.
(c) Deng, Y.; Hlasta, D. J. Tetrahedron Lett. 2002, 43, 189.
(d) Hlasta, D. J. Org. Lett. 2001, 3, 157.
(8) (a) Bellina, F.; Rossia, R. Adv. Synth. Catal. 2010, 352,
1223. (b) Zificsak, C. A.; Hlasta, D. J. 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, M. R. A. J. Am.
Chem. Soc. 2007, 129, 5492.
In summary, we have reported a metal-free, three-compo-
nent process for the C2-functionalization of N-alkylated
imidazoles. The multicomponent manifold operates under
‘on water’ conditions through the formation of a water
stable (permanent) nucleophilic imidazole carbene (im-
idazolium ylide). This carbene is alkylated by a cascade
process involving an efficient carbene–aldehyde addition,
alkoxide–alkynoate addition, and protonation and hydrol-
ysis set of consecutive reactions. 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
Synlett 2010, No. 16, 2421–2424 © Thieme Stuttgart · New York

2424
F. Cruz-Acosta et al.
LETTER
(10) General Procedure for the Multicomponent
Functionalization of N-Alkyl Imidazoles ‘on Water’ –
Preparation of Compound 2c
5.05 (dd, 3JH,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, 3JH,H = 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): d = 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.
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): n = 1714, 1643, 1445, 1172
cm–1.
(Z)-2c: 1H NMR (500 MHz, CDCl3): d = 6.94 (s, 1 H), 6.85
(s, 1 H), 6.58 (d, 3JH,H = 7.0 Hz, 1 H), 5.15 (t, 3JH,H = 7.3 Hz,
1 H), 4.83 (d, 3JH,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, 3JH,H = 7.0 Hz, 3 H) ppm. 13C NMR (125 MHz,
CDCl3): d = 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.
(E)-2c: 1H NMR (500 MHz, CDCl3): d = 7.49 (d,
3JH,H = 12.4 Hz, 1 H), 6.93 (br d, 3JH,H = 1.2 Hz, 1 H), 6.80
(br d, 3JH,H = 1.2 Hz, 1 H), 5.32 (d, 3JH,H = 12.4 Hz, 1 H),
Synlett 2010, No. 16, 2421–2424 © Thieme Stuttgart · New York