Chemoselective arylamidine cyclizations: Mild formation of 2-arylimidazole-4-carboxylic acids

Article abstract of DOI:10.1021/ol0514855

(Chemical Equation Presented) A versatile, one-pot synthesis of 2-arylimidazole-4-carboxylic acids from arylamidines and methyl-2- chloroacetoacetate is described. The transformation is chemoselective, and reaction conditions are mild. Moreover, the flexibility of the strategy offers rapid access to two important classes of biaryl compounds, both 2-arylimidazoles and 2-arylpyrimidmes, depending simply upon solvent and base selection.

Full text of DOI:10.1021/ol0514855

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3801-3803
Chemoselective Arylamidine
Cyclizations: Mild Formation of
2-Arylimidazole-4-carboxylic Acids
Joshua C. Yoburn* and Subramanian Baskaran
Sunesis Pharmaceuticals, 341 Oyster Point BouleVard, South San Francisco,
California 94080
jyoburn@sunesis.com
Received June 24, 2005
ABSTRACT
A versatile, one-pot synthesis of 2-arylimidazole-4-carboxylic acids from arylamidines and methyl-2-chloroacetoacetate is described. The
transformation is chemoselective, and reaction conditions are mild. Moreover, the flexibility of the strategy offers rapid access to two important
classes of biaryl compounds, both 2-arylimidazoles and 2-arylpyrimidines, depending simply upon solvent and base selection.
The importance of heterocycle construction in modern
organic chemistry and drug design cannot be overempha-
sized. In particular, 2-aryimidazoles represent an important
class of structures as a result of their reported antifungal,1
NPY5 receptor antagonism,2 and macromolecular ligand3
properties. 2-Substituted imidazoles have been prepared
by palladium-catalyzed couplings4 or cyclocondensation
chemistry.5a-c
Recently, we became interested in the preparation of
2-arylimidazoles having a carboxylic acid functional group
in the 4-position. Since arylamidines are known to undergo
cyclocondensations with R-halo ketones,6 the use of aryl-
amidines and halogenated acetoacetates seemed like a
reasonable place to begin. Moreover, the proposed transfor-
mation would install the requisite carboxylic acid directly.
Halogenated acetoacetates have been shown to undergo five-
membered ring forming reactions with a variety of similar
bidentate nucleophiles such as aminopyridines,7 aminopy-
razines,8 aminopyridazines,9 aromatic thiols,10 arylcarboxa-
mides,11 and arylthiocarboxamides.12
Surprisingly, there are relatively few reports related to the
preparation of 2-arylimidazoles from acetoacetates and
arylamidines (Scheme 1). For example, Campbell and co-
workers prepared a pyrrolopyrimidine from a substituted
2-chloroacetoacetate that could not cyclize to the imida-
zole.13 DeAncos reported that the reaction between benza-
(6) Shankaran, K.; Donnelly, K. L.; Shah, S. K.; Guthikonda, R. N.;
MacCoss, M.; Mills, S. G.; Gould, S. L.; Malkowitz, L.; Siciliano, S. J.;
Springer, M. S.; Carella, A.; Carver, G.; Hazuka, D.; Holmes, K.; Kessler,
J.; Lineberger, J.; Miller, M. D.; Emini, E. A.; Schleif, W. A. Bioorg. Med.
Chem. Lett. 2004, 14, 3419.
(1) Bartroli, J.; Turmo, E.; Alguero, M.; Boncompte, E.; Vericat, M. L.;
Conte, L.; Ramis, J.; Merlos, M.; Garcia-Rafanell, J.; Forn, J. J. Med. Chem.
1998, 41, 1855.
(2) Elliott, R. L.; Oliver, R. M.; LaFlamme, J. A.; Gillaspy, M. L.;
Hammond, M.; Hank, R. F.; Maurer, T. S.; Baker, D. L.; DaSilva-Jardine,
P. A.; Stevenson, R. W.; Mack, C. M.; Cassella, J. V. Bioorg. Med. Chem.
Lett. 2003, 13, 3593.
(7) Starrett, J. E.; Montzka, T. A.; Crosswell, A. R.; Cavanagh, R. L. J.
Med. Chem. 1989, 32, 2204.
(8) Abignente, E.; Decaprariis, P.; Rimoli, M. G.; Capasso, F.; Autore,
G. Farmaco 1992, 47, 919.
(9) Abignente, E.; Arena, F.; Luraschi, E.; Saturnino, C.; Rossi, R.;
Berrino, L.; Cenicola, M. L. Farmaco 1992, 47, 931.
(10) Pignatello, R.; Mazzone, S.; Panico, A. M.; Mazzone, G.; Pennisi,
G.; Castana, R.; Matera, M.; Blandino, G. J. Med. Chem. 1991, 26, 929.
(11) Sznaidman, M. L.; Haffner, C. D.; Maloney, P. R.; Fivush, A.; Chao,
E.; Goreham, D.; Sierra, M. L.; LeGrumelec, C.; Xu, H. E.; Montana, V.
G.; Lambert, M. H.; Willson, T. M.; Oliver, W. R.; Sternbach, D. D. Bioorg.
Med. Chem. Lett. 2003, 13, 1517.
(3) Street, J. P. Tetrahedron Lett. 1991, 32, 3333.
(4) Wang, D. M.; Haseltine, J. A. J. Heterocycl. Chem. 1994, 31, 1637.
(5) (a) From 2-bromoacetoacetaldehyde: Lipinski, C. A.; Blizniak, T.
E.; Craig, R. H. J. Org. Chem. 1984, 49, 566. (b) From hydroximines:
Gopalsamy, A.; Shi, M. X. Org. Lett. 2003, 5, 3907. (c) From vicinal
tricarbonyls: Brackeen, M. F.; Stafford, J. A.; Feldman, P. L.; Karanewsky,
D. S. Tetrahedron Lett. 1994, 35, 1635.
(12) Chauhan, P. M. S.; Crew, A. P. A.; Jenkins, G.; Storr, R. C.; Walker,
S. M.; Yelland, M. Tetrahedron Lett. 1990, 31, 1487.
10.1021/ol0514855 CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/23/2005

Table 1. Optimization of Reaction Conditionsa
Scheme 1. Related Arylamidine Cylizations
no.
base (mol %)
solvent
MeCN
ratio 3:4
1
none
nr
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18b
19b
20c
21c
NaOH (120)
NaOH (120)
NaOH (120)
NaOH (120)
NaOH (120)
Na2CO3 (120)
K2HPO4 (120)
KOH (120)
KOH (500)
Et3N (120)
Et3N (120)
Et3N (120)
Et3N (120)
Et3N (120)
Et3N (500)
DBU (120)
NaOH (120)
Et3N (120)
NaOH (120)
Et3N (120)
MeCN
DMA
MeOH
EtOH/H2O (2:1 v/v)
H2O
H2O
H2O
H2O
H2O
1:1
trace
1:2
1:1
1:3
1:1
1:1
1:4
trace
1:1
5:1
trace
3:1
5:1
5:1
trace
1:2
4:1
1:1
4:1
H2O
acetone
DMA
midine and a 2-bromoacetoacetate in chloroform led to
pyrimidine formation in 82% yield.14 Alternatively, a 2-arylim-
idazole was prepared in 57% yield from benzamidine and a
diketone but hydroxy(tosyloxy)iodobenzene, a hypervalent
iodine sourse, was required.15 Finally, Jezewski reacted a
2-methoxyacetoacetate and reported the formation of a
2-arylimidazole as a decomposition product isolated in 5%
yield under nonideal reaction conditions (10.0 kbar, 65 h).16
Intrigued by the untapped potential of this reaction, we
set out to establish reaction conditions that would provide
the desired 2-arylimidazole-4-carboxylic acids more ef-
ficiently. Herein, we report that arylimidazole analogues can
be selectively formed under aqueous basic conditions.
Optimized reaction conditions are depicted in Table 1.
In general, reactivity was observed under most conditions
with the exception of no base (entry 1), large excess of base
(entry 10), or some solvents such as DMA (entry 3).
Optimization of arylimidazole formation began with the
screening of numerous bases in water (partial data shown).
The best chemoselectivity was observed in the presence
of hydroxide bases (entries 6-9). Tertiary amine bases in
water provided weaker selectivity (entry 11) as did elevated
temperatures (entry 18) or excess acetoacetate (entry 20).
Selectivity for arylpyrimidine formation was observed under
most nonaqueous conditions with the exception of DBU in
acetonitrile (entry 17). Triethylamine in acetone (entry 12),
THF (entry 14), or acetonitrile (entry 15) provided the best
selectivity, with acetonitrile having a slightly cleaner reaction
profile. Excess base in this solvent system provided little
advantage (entry 16).
THF
MeCN
MeCN
MeCN
H2O
MeCN
H2O
MeCN
a All reactions were run under nitrogen and at 600 mM, 1 (100 mol %),
and 2 (100 mol %) unless noted otherwise. Ratios were measured by HPLC
with UV detection at 220 nm and indicate apparent crude reaction profiles.
b 80 °C. c 1 (200 mol %).
amidine (k3). Therefore, displacement of the chloride (rate
) k2) becomes preferred. This route results in imidazole
formation. Alternatively, in the absence of ester hydrolysis,
amidine condensation with the methyl ester (rate ) k3) is
preferred to chloride displacement (rate ) k2) and this path
proceeds towards the formation of the pyrimidine.
Scheme 2. Rationale for Selectivity
Mechanistically, it is presumed that the amidine has three
paths of reactivity (Scheme 2). Condensation with the ketone
(rate ) k1) must occur regardless of which biaryl system is
ultimately formed. Under aqueous basic conditions, formation
of the carboxylate slows the rate of condensation with the
(13) Campbell, J. B.; Firor, J. W. J. Org. Chem. 1995, 60, 7687.
(14) DeAncos, B.; Delgado, F.; Martin, M. R. An. Quim. 1995, 91, 413.
(15) Zhang, P. F.; Chen, Z. C. Synthesis-Stuttgart 2001, 14, 2075.
(16) Jezewski, A.; Jurczak, J.; Lidert, Z.; Tice, C. M. J. Heterocycl. Chem.
2001, 38, 645.
3802
Org. Lett., Vol. 7, No. 17, 2005

as hypervalent iodine, high temperature, or high pressure.
Second, the resulting 2-arylimidazoles contain a useful
carboxylic acid functional group in the 4-position that is
easily derivatizable. Finally, the biaryl product profile of the
reaction can be tuned by a simple adjustment in reaction
conditions. This unique attribute can be fully exploited in
biaryl library format where clever access to diversity and
ease of reagent selection are critical.
Table 2. Representative Amidine Substratesa
Application of these two sets of optimal conditions (Table
1, entries 9 and 15) to the synthesis of a small series of simple
heterocyclic biaryls is depicted in Table 2. All reactions
led cleanly to the formation of arylimidazoles and aryl-
pyrimidines with the predicted biaryl product preferred. The
same reactions performed under microwave irradiation (see
General Procedure, Condition C) resulted in similar chemo-
selectivity and mass balance but reduced reaction times (data
not shown).
These simple protocols for selectivity provide rapid access
to a wide variety of novel biaryls starting from inexpensive
and readily available starting materials reacting under simple
chemical conditions.
a Percentages indicate isolated yields. Ratios were measured by HPLC
with UV detection at 220 nm and indicate apparent crude reaction profiles.
Conditions A and B are described in the general procedure section of
Supporting Information.
Supporting Information Available: Spectroscopic and
analytical data are available for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
The current route offers a number of advantages over
previous strategies. First, the reaction conditions are one-
pot, fast, and mild; there is no need for harsh oxidants such
OL0514855
Org. Lett., Vol. 7, No. 17, 2005
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