A direct, one step synthesis of imidazoles from imines and acid chlorides: A palladium catalyzed multicomponent coupling approach

Article abstract of DOI:10.1021/ja060705m

A palladium-catalyzed one-step synthesis of imidazoles from imines and acid chlorides is described. A plausible mechanism for this multicomponent reaction is provided, which explains the selective incorporation of two different imines into the final product with perfect regiocontrol. Overall, this catalytic process provides a modular method to prepare imidazoles directly from building blocks that are all either commercially available or readily generated. Copyright

Full text of DOI:10.1021/ja060705m

Published on Web 04/14/2006
A Direct, One Step Synthesis of Imidazoles from Imines and Acid Chlorides:
A Palladium Catalyzed Multicomponent Coupling Approach
Ali R. Siamaki and Bruce A. Arndtsen*
Department of Chemistry, McGill UniVersity, 801 Sherbrooke Street West, Montreal, Quebec H3A 2K6, Canada
Received January 30, 2006; E-mail: bruce.arndtsen@mcgill.ca
1
Imidazoles have found utility in a diverse range of areas, with
Scheme 1. Postulated Mechanism for Imidazole Synthesis
2a
examples including drug cores (e.g., angiotensin II inhibitors, anti-
2b
2c
inflammatory, and anticancer agents), conjugated and functional
polymers,3 natural products,
a
3b,c
and coordination complexes.
3d
4
Imidazoles are also important as ligands in metalloenzymes and,
more recently, have been found to serve as precursors to environ-
5
6
mentally friendly ionic solvents and carbene ligands. In light of
their wide use, many synthetic approaches have been developed to
generate these heterocycles. This includes traditional cycloconden-
1
7a
sation methods (e.g., with presynthesized 1,2-diketones, R-sulfonyl-
isocyanides,7b or R-ketoamides ) and a number of efficient recent
7c
8
cyclization routes. In addition, imidazoles can be prepared via
stepwise substitution reactions on simple imidazoles, including
9
10
catalytic C-H activation, cross coupling, or aromatic substitution
reactions.1
,11
Closer examination of the reaction products shows the low
imidazole yield is due to two competing processes, leading to the
formation an R-sulfonylamide 4 (25%) and amide 5 (46%) (Scheme
1). These presumably arise from the in situ generated iminium salt
6, via either attack of the sulfonyl anion released by cycloaddition
or decomposition, respectively.17 On the basis of this postulate, the
efficiency of this reaction can be improved by inhibiting these steps.
First, since iminium salt decomposition to 5 is a thermal process
competing with catalysis, its role can be limited by lowering the
temperature and accelerating the reaction with CO pressure (entry
3). The addition of phosphine ligands can further accelerate
While all effective, these methods often require multiple steps
to prepare diversely substituted imidazoles. An intriguing alternative
approach to imidazoles could involve considering their structure
as made up of multiple, simple, and easily diversified reagents,
put together all at once by metal catalysis. This can provide an
attractive method to both easily generate products and, at the same
time, independently vary substituents, in a single step, as illustrated
in the Pauson-Khand, alkyne trimerization, amidocarbonyla-
tion,14 and a range of more recent catalytic multicomponent
syntheses.15 We report herein the design of such a direct metal-
catalyzed synthesis of imidazoles, providing overall a highly
modular, one-step route to these heterocycles.
12
13
catalysis, with the bulky P(oTol) allowing imidazole formation in
3
60% yield. The inhibition of sulfonylamide 4 proved more
challenging since sulfonyl anion formation is part of the catalytic
mechanism and its attack on 6 is rapid.17 However, experiments
with an independently synthesized 4 demonstrate that the addition
of LiCl can lead to the equilibrium regeneration of 6. Similarly,
while several salts inhibit the reaction,17 LiCl completely suppresses
Figure 1. A multicomponent approach to imidazole synthesis.
Table 1. A One-Step Catalytic Synthesis of Imidazole 3a
Our approach to this synthesis involves considering the imidazole
core as the product of two imines and an acid chloride (Figure 1),
each of which is readily available in many forms. This is based
upon our recently observed palladium-catalyzed coupling of imine,
acid chloride, and carbon monoxide to generate 1,3-oxazolium-5-
olates (M u¨ nchnones, 1).16 As such, we considered the possibility
that performing this catalytic reaction in the presence of N-tosyl-
substituted imines, which can undergo in situ 1,3-dipolar cycload-
dition with M u¨ nchnones,8 could provide a route to construct
imidazoles. While mechanistically plausible (Scheme 1), this
reaction would require the selective coupling of two similar imine
substrates in a single reaction; a feature that has proven challenging
for multicomponent reactions.13 Nevertheless, our initial attempt
toward this direct synthesis was encouraging. The reaction of (p-
[CO]a
Lb
additivec
%d
no.
temp (
°
C)
Pd cat
1
2
3
4
5
6
7
8
9
65
45
45
45
45
45
45
45
45
45
45
45
45
45
1
1
4
20
4
4
4
4
4
4
4
4
4
4
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
Pd
Bu
Bu
Bu
Bu
4
NBr
4
NBr
4
NBr
4
NBr
28
28
43
48
0
e
PPh
3
t
P Bu
3
58
60
25
20
54
76
68
0
P(oTol)
P(oTol)
P(oTol)3
P(oTol)3
P(oTol)
P(oTol)
P(oTol)
P(oTol)
3
3
Bu
4
NCl
LiOTf
LiBr
LiCl
LiCl
LiCl
LiCl
10
1
1
1
2
3
3
3
3
2 3 3
dba ‚CHCl
Pd(PPh )
3 4
tolyl)HCdNEt, (Ph)HCdNTs, PhCOCl, and CO in the presence
of the previously developed catalyst 2a16 led to the consumption
13
14
e
2a
79
of starting materials over the course of 24 h and did form imidazole
a
Measured in atm. b With 15 mol %. c With 3 equiv. d NMR yield.
e
3a, though in low yield (28%, Table 1).
With Ph(H)CdN(SO2C6H4Cl).
6050
9
J. AM. CHEM. SOC. 2006, 128, 6050-6051
10.1021/ja060705m CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. A Modular Catalytic Synthesis of Imidazolesa
this provides complete regiochemical control of all the substituents
about the ring, where each unit can be independently varied by
choice of imine(s) and acid chloride reagents.
We have begun to probe the utility of this reaction to provide
access to imidazole targets. 3j has been demonstrated to be a potent
p38 MAP kinase inhibitor and lead in the design of new anti-
inflammatory agents.2b While the previously reported route to 3j
is a multistep process via 1,2-diketones, this catalytic coupling can
allow the one-pot, regioselective assembly of 3j directly from
available imine and acid chloride substrates, after deprotection.
In conclusion, the palladium-catalyzed coupling of imines and
acid chloride can be used to provide a new, one-step method to
synthesize imidazoles. Considering the efficiency of this reaction,
and availability of the building blocks, this provides a very
straightforward method to assemble these products. Experiments
directed toward its application to other targets are underway.
Acknowledgment. We thank NSERC, FQRNT, and CFI for
their financial support of this research.
Supporting Information Available: Synthesis and characterization
of 3a-j; experiments in ref 17. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(
1) Grimmett, M. R. In ComprehensiVe Heterocyclic Chemistry II: Katritzky,
A. R., Ress, C. W., Schriven, E. F., Eds.; Pergamon Press: Oxford, 1996.
2) (a) Carini, D. J.; Duncia, J. V.; Johnson, A. L.; Chiu, A. T.; Price, W. A.;
Wong, P. C.; Timmermans, P. J. Med. Chem. 1990, 33, 1330. (b) Lee, J.
C.; Laydon, J. T.; McDonnell, P. C.; Gallagher, T. F.; Kumar, S.; McNully,
D.; Blumenthal, M.; Heys, J. R. Nature 1994, 372, 739. (c) Atwell, G.
A.; Fan, J.-Y.; Tan, K.; Denny, W. A. J. Med. Chem. 1998, 41, 4744.
3) (a) Yamamoto, T.; Uremura, T.; Tanimoto, A.; Sasaki, S. Macromolecules
(
a
Conditions: 0.68 mmol imine, 0.82 mmol tosyl imine, 0.95 mmol acid
(
chloride, 5 mol % of 2, 15 mol % of P(oTol)3, 3 equiv of NEtiPr2/LiCl, 4
atm CO, 45 °C, 18 h.
2003, 36, 1047 and references therein. (b) Iinuma, Y.; Kozawa, S.;
Ishiyama H.; Tsuda, M.; Fukushi, E.; Kawabata, J.; Fromont, J.;
Kobayashi, J. J. Nat. Prod. 2005, 68, 1109. (c) Fresneda, P. M.; Molina,
P.; Sanz, M. A. Tetrahedron Lett. 2001, 42, 851. (d) Cotton, F. A.;
Wilkinson, G.; Murillo, C. A.; Bochmann, M. AdVanced Inorganic
Chemistry; Wiley: New York, 1999.
4) Holm, R. H.; Kennepohl, P.; Solomon, E. I. Chem. ReV. 1996, 96, 2239.
5) Dupont, J.; de Souza, R. F.; Suarez, P. A. Z. Chem. ReV. 2002, 102, 3667.
6) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290.
4
and provides, overall, a very selective method to catalytically
couple these three reagents directly into an imidazole (entry 11).
Notably, commercially available Pd dba is also an effective catalyst
for this reaction.
(
(
(
2
3
As shown in Table 2, since the building blocks employed are
all commercially available or readily prepared, this reaction can
be directly applied to the one-step synthesis of diversely substituted
imidazoles. N-alkyl and N-aryl imines can be used in this coupling,
as can imines of aromatic and even nonenolizable alkyl (3c)
aldehydes. Similarly, aryl, heteroaryl, and alkyl acid chlorides can
all be employed. Even greater diversity can be achieved with the
N-tosylimines, including aryl, alkyl, heterocyclic, and R,â-unsatur-
ated substituents. While enolizable imines cannot be employed with
N-alkyl-substituted imines, they can be added via the N-tosylimine
(7) (a) Krieg, B.; Manecke, G. Z. Naturforsch. 1967, 22b, 132. (b) van Leusen,
A. M.; Wildeman, J.; Oldenziel, O. H. J. Org. Chem. 1977, 42, 1153. (c)
Lee, H. B.; Balasubramanian, S. Org. Lett. 2000, 2, 323.
(8) For examples, see: (a) Zaman, S.; Mitsuru, K.; Abell, A. D. Org. Lett.
2005, 7, 609. (b) Frantz, D. F.; Morency, L.; Soheili, A.; Murry, J. A.;
Grabowski, E. J. J.; Tillyer, R. D. Org. Lett. 2004, 6, 843. (c) Illgen, K.;
Nerdinger, S.; Behnke, D.; Friedrich, C. Org. Lett. 2005, 7, 39. (d)
Bilodeau, M. T.; Cunningham, A. M. J. Org. Chem. 1998, 63, 2800. (e)
Croce, P. D.; Rerraccioli, R.; La Rosa, C. Tetrahedron 1999, 55, 201.
(9) (a) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001,
1
23, 2685. (b) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 10580.
(
c) Fukumoto, Y.; Sawada, K.; Hagaihara, M.; Chatani, N.; Murai, S.
Angew. Chem., Int. Ed. 2002, 41, 2779.
10) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry; Perga-
mon: Oxford, 2000.
(
(3h,i). This reaction also displays good functional group compat-
(11) For example, see: Langhammer, I.; Erker, T. Heterocycles 2005, 65, 2721.
(
(
(
(
12) Gibson, S. E.; Stevenazzi, A. Angew. Chem., Int. Ed. 2003, 42, 1800.
ibility and even proceeds in the presence of coordinating function-
alities (3d,f), all generating substituted imidazoles in good yield.
Interestingly, while this reaction involves the simultaneous
coupling of different imines, no products incorporating two of the
same imine are observed. This selectivity is believed to result from
the catalytic mechanism (Scheme 1).16 In particular, the N-
tosylimine is not sufficiently nucleophilic to interact with the acid
chloride, thus it is only imine 7 that is incorporated into iminium
salt 6 and ultimately forms M u¨ nchnone 1. However, once 1 is
generated, it reacts exclusively with the more electron-poor imine
via cycloaddition. Consistent with this mechanism, the more
electron-deficient p-chlorosulfonylimine leads to higher imidazole
yield (Table 1, no. 14).18 Important from a synthetic perspective,
13) Shore, N. E. Chem. ReV. 1988, 88, 1081.
14) Beller, M.; Eckert, M. Angew. Chem., Int. Ed. 2000, 39, 1010.
15) Representative examples: (a) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto,
Y. J. Am. Chem. Soc. 2003, 125, 7786. (b) Dhawan, R.; Arndtsen, B. A.
J. Am. Chem. Soc. 2004, 126, 468. (c) Cao, C.; Shi, Y.; Odom, A. L. J.
Am. Chem. Soc. 2003, 125, 2880. (d) Trost, B. M.; Pinkerton, A. B. J.
Am. Chem. Soc. 2000, 122, 8081. (e) Montgomery, J. Acc. Chem. Res.
2
000, 33, 467. (f) Wie, C.; Li, Z.; Li, C.-J. Synth. Lett. 2004, 1472. (g)
Ng, S. S.; Jamison, T. F. J. Am. Chem. Soc. 2005, 127, 14194. (h) Wie,
C.; Li, Z.; Li, C.-J. Synth. Lett. 2004, 1472.
(
16) Dhawan, R.; Dghaym, R. D.; Arndtsen, B. A. J. Am. Chem. Soc. 2003,
125, 1474.
(
17) Warming 6 to 65 °C with NEtiPr
2
leads to 5 (63%, 12 h). 6 reacts with
Tol form 4 in 5 min at rt. The addition of LiCl (3 equiv) to 4
LiSO
2
regenerates 6 in 1/2 h (79%). Other salts in Table 1 do not react with 4.
18) M u¨ nchnone 1 also decomposes under the catalytic conditions (ref 16).
(
JA060705M
J. AM. CHEM. SOC.
9
VOL. 128, NO. 18, 2006 6051