The synthesis of 2-substituted azoles through a one-pot three-component reaction

Article abstract of DOI:10.1016/S0040-4039(01)02110-4

We have discovered a new reaction whereby 2-substituted azoles are formed in the reaction of an azolium ylide with reactive carbonyl compounds. These products contain a leaving group in the α-position, which on solvolysis in the presence of nucleophiles yield azoles with a variety of α-substituents. We have developed new aspects of this chemistry and expanded the scope to include imidazoles, thiazoles, benzimidazoles and triazoles, such that in two reaction steps a wide diversity of substitution patterns are obtained.

Full text of DOI:10.1016/S0040-4039(01)02110-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 189–192
The synthesis of 2-substituted azoles through a one-pot
three-component reaction
Yijun Deng and Dennis J. Hlasta*
Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Welsh and McKean Roads, Spring House,
PA 19477-0776, USA
Received 15 August 2001; accepted 2 November 2001
Abstract—We have discovered a new reaction whereby 2-substituted azoles are formed in the reaction of an azolium ylide with
reactive carbonyl compounds. These products contain a leaving group in the a-position, which on solvolysis in the presence of
nucleophiles yield azoles with a variety of a-substituents. We have developed new aspects of this chemistry and expanded the
scope to include imidazoles, thiazoles, benzimidazoles and triazoles, such that in two reaction steps a wide diversity of substitution
patterns are obtained. © 2002 Elsevier Science Ltd. All rights reserved.
A number of biologically active molecules contain func-
tionalized azole heterocycles.1 Structurally diverse
libraries of substituted azoles are therefore likely to give
lead compounds after high-throughput screening
against biological drug targets.2 As part of our research
effort, we seek to discover new synthetic methods that
generate structurally diverse drug-like compounds.
Recently, we reported our discovery where an imida-
zolium ylide was used in a novel way to synthesize
2-substituted imidazoles under mild conditions.3 The
reaction of 1-benzylimidazole was quite general with a
variety of reactive carbonyl compounds, such as alde-
hydes, trifluoromethylketones, a-keto esters, and iso-
cyanates. We subsequently found that when our
previously described reaction conditions were applied
to less reactive azoles, like thiazole, that poor yields of
the desired product were obtained (10–30%). Herein,
we report our recent results in developing new aspects
of this reaction. We have improved the reaction condi-
tions to obtain good yields with less reactive and previ-
ously problematic azoles. We also wish to report our
findings on using a variety of nucleophiles to expand
the scope of the solvolysis chemistry to 2-substituted
imidazoles and 2-substituted thiazoles.
to II required about 48 h in the reaction of 1-methylim-
idazole with diisopropylcarbamyl chloride in CD3CN;
(2) complete H/D exchange (>95%) of the C-2 proton
of 1-methylimidazolium II occurred in <10 min in
presence of Et3N; however, in the absence of base the
exchange required about 24 h, and (3) no H/D
exchange of the C-2 proton of 1-methylimidazole was
observed after 72 h, even in presence of Et3N.6 These
results support our contention that an azolium ylide III
is an important intermediate in this reaction (Scheme
1). In the presence of a reactive electrophile, the
azolium ylide can be trapped to form a 2-substituted
azole derivative.
CON(i-Pr)2
N
N
ClCON(i-Pr)2
CD3CN
N
Et3N
H
N
CH3
CH3
II
I
CON(i-Pr)2
CON(i-Pr)2
CON(i-Pr)2
N
N
N
D2O
D
The rate of C-2 proton exchange in imidazole and
N
N
N
thiazole is known to be enhanced by N-protonation or
CH3
CH3
IV
CH3
1
N-alkylation.4 Our H NMR spectroscopy study on the
isotopic H/D exchange at C-2 of imidazolium species5
(II) showed that (1) conversion (>95%) of imidazole I
III
Scheme 1.
The reactive intermediate III can also be described by a
carbene resonance structure IV, where the singlet state
* Corresponding author. Tel.: 215-628-5489; fax: 215-628-3297;
e-mail: dhlasta@prius.jnj.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02110-4

190
Y. Deng, D. J. Hlasta / Tetrahedron Letters 43 (2002) 189–192
1
carbene at C-2 is stabilized by push–pull stabilization.
Stabilization of the singlet carbene has been proposed
based on the p-electron donation of the two adjacent
nitrogen lone pairs to the vacant p orbital at C-2 of the
carbene, and on the s-electron withdrawal by the elec-
tronegative nitrogen from the carbene pair of electrons
in the s orbital at C-2. Diaminocarbenes have been
previously described, and their reactivity is best
described by the ylide resonance structure III. Indeed,
the reactivity described in this paper mimics the reactiv-
ity of anion chemistry and not the typical reactivity of
carbenes.7
tionship was also found in our studies. Our H NMR
experiments showed that the rate of formation of the
azolium intermediate II depends on both the reactivity
of the acylation species and the nucleophilicity of the
azoles. For example, after 48 h, only 5% of thiazolium
chloride but 95% of imidazolium chloride was detected
by NMR in the reaction of diisopropylcarbamyl chlo-
ride with thiazole and 1-methylimidazole, respectively.
Also, in the series of 1-methylimidazole (pKa 7), thia-
zole (pKa 2.5), and oxazole (pKa 0.8),9 the best product
yields were found with 1-methylimidazole, and thiazole
only gave good yields with more reactive acylation
species. In reactions with oxazole, 2-substituted oxazole
products were not detected, probably since N-acylation
is very slow due to the low nucleophilicity of oxazole.
Both steric hindrance and the reactivity of the acylation
species effect the outcome of this reaction. We initially
expected that steric hindrance was the key factor to
obtain a good yield in this reaction. Therefore, our first
experiments focused on the use of diisopropylcarbamyl
chloride and we obtained 2-substituted imidazoles in
good yields (e.g. Table 1, entry 1). In exploring the
effect of steric hindrance and reactivity, we found that
less sterically hindered carbamyl chlorides gave even
Furthermore, the use of an appropriate acylation spe-
cies can be critical in affording good yields in these
reactions. Earlier we discussed the improved yields that
were obtained with imidazoles when the less sterically
hindered and more reactive dimethylcarbamyl chloride
were used in comparison to diisopropylcarbamyl chlo-
ride (Table 1, entries 1–3). This difference in reactivity
was even more pronounced in the reaction of less
reactive azoles. In reactions where we used our previ-
ously described conditions with diisopropylcarbamyl
chloride and benzaldehyde on less reactive azoles, we
consistently obtained poor to moderate yields (Table 2,
entries 4, 7, and 9). When more reactive acyl chlorides
were used, the yields were improved (Table 2, entries 5,
8 and 10).
1
better yields (entries 2 and 3). In a H NMR experi-
ment, dimethylcarbamyl chloride was shown to com-
pletely form an imidazolium chloride in 6 h, much
faster than diisopropylcarbamyl chloride (48 h). Since
an improved yield of the 2-substituted imidazole in
entry 3 was found, we suggest that the rate-limiting step
in entry 1 is the formation of the imidazolium chloride.
The reaction di-t-butyl dicarbonate (entry 4) did not
required base. We presume that in the formation of the
imidazolium salt, carbon dioxide and the base t-butox-
ide are liberated. Thus, the t-butoxide then deproto-
nates the C-2 position of the imidazolium to form the
ylide/carbene leading to the formation of the 2-substi-
tuted imidazole in 77% yield. The less sterically encum-
bered diethyl dicarbonate gave very poor results (entry
5), as did isopropyl chloroformate (entry 6).
CONR'2
CONR'2
CONR'2
CONR'2
+
+
+
N
N
N
N
-
:
-
:
N
N
N
N
N
N
N
N
-
Bn
Bn
Bn
VII
Bn
V
VI
VIII
Interestingly, the reaction of 1,2-dimethylimidazole
gave an a-C extended product in very good yield (entry
12). The reactive intermediate presumably is a 1,3
dipole like ylide (isoelectronic with an exocyclic bisen-
amine), which is sufficiently reactive to form the iso-
lated product. Unexpectedly, only the 5-substituted
isomer was isolated in the reaction of the unsymmetri-
cal 1,2,4-triazole (Table 2, entry 14). The regioselectiv-
ity for exclusive reaction at the 5-position can be
explained by the ylide/carbene resonance structures.
Formation of an ylide/carbene V/VI at the 5-position is
favored by the same electron effects described earlier
for resonance structures III and IV. While formation of
an ylide/carbene VII/VIII at the 3-position is not
favored, even though the C-3 carbon is adjacent to two
nitrogen atoms. An empty p orbital at C-3 can not be
stabilized by p-electron donation, since the lone pairs
on the adjacent nitrogens are not available for donation
through the p-system. In order to assess the relative
stabilities of the two possible ylidenes V/VI and VII/
VIII, ab initio calculations11 were carried out using
density functional theory (DFT) at the B3-LYP/6-31G*
level of theory.12 These calculations showed a strong
preference for V/VI, with V/VI being calculated to be
16.9 kcal/mol more stable than VII/VIII.
Table 1. Acylator modifications
OCOR
Ph
N
N
N
XCOR
PhCHO
DIEA
N
CH3
CH3
Entry XCOR
Conditions
Product
(R)
Yield
(%)
(°C/h)
1
2
3
4
5
6
ClCON(i-Pr)2
ClCONEt2
ClCONMe2
O(COO-t-Bu)2
O(COOEt)2
60/24
60/20
60/20
25/3
N(i-Pr)2
NEt2
NMe2
O-t-Bu
OEt
85
92
93
77a
4
25/20
ClCOOCH(CH3)2 25/20
OCH(CH3)2 20
a No base was used in the reaction of entry 4.
Nucleophilicity and basicity (pKa) are known to corre-
late when the structure of the nucleophiles are very
similar, and linear relationships have been reported
between nucleophilic rates and pKa values.8 This rela-

Y. Deng, D. J. Hlasta / Tetrahedron Letters 43 (2002) 189–192
191
Table 2. Reaction of azoles with benzaldehyde and carbamyl chlorides ClCONR%210
Table 3. Solvolysis reactions of carbamates13
Nu
Ph
OCON(i-Pr)2
Ph
N
X
N
X
Nu-H
TFA / THF
Entry
Heterocycle (X)
Nucleophile (Nu–H)
Product (Nu)
Yield (%)
1
2
3
4
5
6
7
8
9
NMe
NMe
NMe
NMe
NMe
NMe
NMe
S
H2O
OH
OCH3
NHCOCH3
OPh
NHPh
Morpholin-1-yl
N3
OH
NHSO2CH3
Morpholin-1-yl
100
85
63
85
80
82
80a
80
65
68
CH3OH
CH3CONH2
PhOH
PhNH2
Morpholine
NaN3
H2O
CH3SO2NH2
Morpholine
S
S
10
a The reaction was run with BF3·Et2O in DMF at 70°C overnight.

192
Y. Deng, D. J. Hlasta / Tetrahedron Letters 43 (2002) 189–192
The diversity of the azoles in Table 2 that afford
2-substituted azole products in good yield is notewor-
thy, and highlights the broad scope of this chemistry.
The products in Table 2 can be readily transformed by
direct solvolysis chemistry into a range of functional-
ized azole derivatives, since the a-carbamyl group is a
good leaving group. We previously described a limited
number of nucleophile examples in the solvolysis reac-
tions of 2-(a-diisopropylcarbamoylbenzyl)-1-benzylimi-
dazole. In Table 3 are shown additional examples of
this chemistry. Solvolysis reactions of both the 2-substi-
tuted-1-methylimidazole and the 2-substituted-thiazole
gave good yields of the desired products.
1–38 and references cited therein; (f) Itoh, T.; Miyazaki,
M.; Nagata, K.; Ohsawa, A. Tetrahedron 2000, 56, 4383–
4395.
3. Hlasta, D. J. Org. Lett. 2001, 3, 157–159.
4. Clement, O.; Roszak, A. W.; Buncel, E. J. Am. Chem.
Soc. 1996, 118, 612–620.
5. The formation of N-acylimidazolium salts by the reaction
of N-methyl imidazole with a carbamoyl chloride was
reported previously: Dadali, V. A.; Lapshin, L. M.;
Litvinenko, L. M.; Simanenko, Yu. S.; Tishchenko, N. A.
J. Org. Chem. USSR (Engl. Transl.) 1978, 14, 2076–2082.
6. Similar observations were made on carbamoyl imida-
zolium salts in CD3OD (personal communication from
Robert A. Batey). For synthetic examples on the use of
carbamoyl imidazolium salts as carbamoylating reagents,
see: Batey, R. A.; Yoshina-Ishii, C.; Taylor, S. D.; San-
thakumar, V. Tetrahedron Lett. 1999, 40, 2699–2672;
Batey, R. A.; Santhakumar, V.; Yoshina-Ishii, C.; Tay-
lor, S. D. Tetrahedron Lett. 1998, 39, 6267–6270.
7. Bourissou, D.; Guerret, O.; Gabbai, F. P.; Bertrand, G.
Chem. Rev. 2000, 100, 39–91.
The breadth and scope of the chemistry described
herein demonstrates the broad application of this chem-
istry in the synthesis of azoles, including imidazoles,
thiazoles, benzimidazoles, and triazoles, with a wide
diversity of substitution patterns. The simplicity and
efficiency of these reactions make this method particu-
larly appealing for application to the solid-phase syn-
thesis of compound libraries for high-throughput
screening against therapeutic targets. In due course, the
extension of this reaction to solid-phase synthesis will
be reported.
8. (a) Bordwell, F. G.; Hughes, D. L. J. Am. Chem. Soc.
1984, 106, 3234–3240; (b) Bordwell, F. G.; Hughes, D. L.
J. Org. Chem. 1984, 48, 2206–2215; (c) Bunting, J. W.;
Mason, J. M.; Heo, C. K. M. J. Chem. Soc., Perkin
Trans. 1 1994, 2291–2300.
9. Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.;
Blackwell Science, 2000; pp. 402–430.
Acknowledgements
10. Typical procedure: To a solution of 1-methyl imidazole
(164 mg, 2.0 mmol) in acetonitrile (5 mL) under nitrogen,
was added subsequently diisopropylcarbamyl chloride
(360 mg, 2.2 mmol), benzaldehyde (0.31 mL, 3.0 mmol)
and diisopropylethylamine (1.0 mL, 6 mmol) at room
temperature. The resulting mixture was stirred at reflux
for about 24 h. The solvent was then removed. The
residue was purified by flash chromatography on a silica
gel with 50% ethyl acetate in hexanes to give entry 1
product in 85% yield.
We thank the Johnson & Johnson Corporate Office of
Science and Technology for postdoctoral fellowship
funding for Y.D. through the Excellence in Science
Award Program. We also thank Diane Gauthier for
assistance in the 2D NMR structure assignments of
these compounds, and Dr. Charles Reynolds for the ab
initio calculations.
11. Jaguar 4.1, Schrodinger, Inc., Portland, OR, 1991–2000.
12. (a) Becke, A. D. Phys. Rev. A 1988, 38, 3098–3100; (b)
Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37,
785–789.
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13. Typical procedure for solvolysis: To a solution of imida-
zole carbamate (315 mg, 1.0 mmol, Table 3, entry 1) in
THF (5 mL), was added morpholine (0.9 mL, 10 mmol)
and TFA (0.44 mL, 6 mmol) under nitrogen at room
temperature. The resulting mixture was refluxed
overnight. After cooling to room temperature, saturated
NaHCO3 aqueous solution (10 mL) was added into the
reaction mixture, followed by extraction with CH2Cl2.
The organic phases were combined, dried and concen-
trated in vacuo. The residue was purified by flash chro-
matography on a silica gel column with 2% MeOH in
ethyl acetate to yield the desired product in 82% yield.