A simple and convenient one-pot method for the preparation of heteroaryl-2-imidazoles from nitriles

Article abstract of DOI:10.1016/j.tet.2007.11.009

A simple, convenient and high-yielding one-pot method for the synthesis of 2-heterocycle-substituted imidazoles from the corresponding nitriles has been developed. The procedure is easily scaleable and the workup does not involve chromatography. This synthesis is also applicable to the preparation of imidazoles with electron-poor aryl substituents.

Full text of DOI:10.1016/j.tet.2007.11.009

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 645e651
www.elsevier.com/locate/tet
A simple and convenient one-pot method for the preparation of
heteroaryl-2-imidazoles from nitriles
Matthew E. Voss a, Catherine M. Beer a, Scott A. Mitchell b,
Peter A. Blomgren b, Paul E. Zhichkin a,
*
a AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212, USA
b CGI Pharmaceuticals, Inc., 36 East Industrial Road, Branford, CT 06405, USA
Received 12 September 2007; received in revised form 30 October 2007; accepted 1 November 2007
Available online 6 November 2007
Abstract
A simple, convenient and high-yielding one-pot method for the synthesis of 2-heterocycle-substituted imidazoles from the corresponding
nitriles has been developed. The procedure is easily scaleable and the workup does not involve chromatography. This synthesis is also applicable
to the preparation of imidazoles with electron-poor aryl substituents.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Heterocycles; Imidazoles; Nitriles; Cyclization
1. Introduction
corresponding aldehydes, via imidazole-4,5-dicarboxylic acids
resulted in 26% yield of 4-pyridinyl-2-imidazole (11a) and
31% yield of 3-pyridinyl-2-imidazole (11b).5a The classical
Many imidazoles with a single heterocyclic substituent in
the 2-position serve as key intermediates in the synthesis of
pharmacologically active compounds (Scheme 1). These tar-
gets include agonists of serotonin 1A receptors (1),1a antimi-
crobials (2),1b as well as 5-lipoxygenase (3),1c kinase domain
insert receptors (KDR, 4),1d and glycogen synthase kinase 3
(5)1e inhibitors, as well as selective g-aminobutyric acid A re-
ceptors ligands (6).1f,g Additionally, pyridinyl-2-imidazoles
have been shown to have dramatically decreased Cytochrome
P450 binding as compared to imidazoles with other substitu-
tion patterns.2 Due to its ability to complex metals, 2-pyri-
dinyl-2-imidazole has also found the application as a ligand
in palladium-catalyzed coupling reactions.3
NH2
S
N
O
Cl
Cl
N
C
H
N
N
OCH3
O
N
NH
S
N
H
1
2
N
N+
N
H
N
O
-
CO2
N
N
OCH3
H
N
O
H3C
N
N
O
N
N
N
CH3
4
As a part of recent research on KDR inhibitors, we required
a short and potentially scaleable route to 2-heterocycle-
substituted imidazoles, particularly pyridinyl-2-imidazoles.
To our surprise, we were not able to find a satisfactory general
procedure.4 For instance, a two-step route, beginning with the
N
N
3
N
NH2
N
Cl
Cl
NO2
N
N
N
N
H
N
N
N
N
H
N
S
N
N
Chir 98014
(5)
CP-885,316
6
H3C
NH
* Corresponding author. Tel.: þ1 518 512 2364; fax: þ1 518 512 2079.
E-mail address: paul.zhichkin@amriglobal.com (P.E. Zhichkin).
Scheme 1. Pharmacologically active 2-heterocycle-substituted imidazoles.
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.009

646
M.E. Voss et al. / Tetrahedron 64 (2008) 645e651
imidazole preparation (Scheme 2, Eq. 1) from the correspond-
ing aldehydes, glyoxal, and ammonia afforded only 55% of
2-pyridinyl-2-imidazole (11c)5b and 20% of 11a.5c Due to the
lack of imidazoles with 2-heterocyclic substituent in the liter-
ature we turned to the methods of the synthesis of aryl-2-imid-
azoles. These compounds are generally prepared through
the conversion of the corresponding nitrile into the imidazo-
line followed by oxidation to the desired imidazole (Scheme
2, Eq. 2).1aec,h,6e8 The first step requires either heating to
high temperature, usually over 200 ꢀC,6a,b or the use of equi-
molar amount of transition metal salts.6c Metal salts serving
as oxidants are also often employed in the second step.1a,b,7,8
High temperatures, the need for the subsequent separation of
inorganic byproducts, and low to moderate overall yield
have made this approach unattractive to us.
prepare heterocyclic imidazoles 11, following this route, in-
cluded tedious isolation of intermediates 8 or 10 and afforded
low to moderate overall yield of 11,12,13,19 discouraging fur-
ther research in this direction. However, it occurred to us
that, if imidate 8 could be formed cleanly from the corre-
sponding nitrile (for example, under alkaline catalysis), reac-
tion of 8 in situ with aminoacetaldehyde derivative 9 would
bring about a one-pot preparation of 2-substituted imidazoles
11 from nitriles (Scheme 3).
2. Results and discussion
To our delight, the very first application of the above ap-
proach to the preparation of 4-pyridinyl-2-imidazole (11a)
was successful. Treatment of a methanolic solution of 4-cya-
nopyridine (7a) with sodium methoxide (0.1 equiv) at rt for
1 h resulted in complete conversion to imidate 8a. The reac-
tion mixture was acidified with acetic acid, and the subsequent
addition of aminoacetal 9a produced 10a. Deprotection and
concomitant cyclization to 11a were achieved by treating
10a with hydrochloric acid and then bringing the reaction to
reflux. The entire sequence was run in the same pot, and the
intermediates were not isolated. Over three steps, a remarkable
82% yield of pure imidazole 11a was obtained (Table 1, entry
1). Alternatively, it was found that catalytic cesium carbonate
(10 mol %) could be used as a base in place of sodium meth-
oxide affording 72% yield of 11a.
N
glyoxal
(1)
ArCHO
N
H
NH3
Ar
H2N
NH2
Ar
N
N
[O]
(2)
(3)
ArCN
N
N
H
Ar
200 °C
H
or
Cu(I), Δ
N
N
ArBr
"Pd"
N
N
n-BuLi
ZnCl2 ClZn
N
Ar
N
PG
PG
PG
Scheme 2. Literature syntheses of aryl-2-imidazoles.
The above procedure was then successfully applied to other
heterocyclic nitriles (Table 1, entries 2e13). Pyridinyl-2-imid-
azoles 11bef (Table 1, entries 2e6), including functionalized
compounds 11e,f, were prepared in good to excellent yield.
The method is applicable to other six-membered cyano-het-
erocycles, affording moderate to good yield of pyrazinyl and
pyrimidinyl-substituted imidazoles 11gei (Table 1, entries
7e9). Novel imidazolyl quinoline 11j and isoquinoline 11k
as well as imidazoles substituted with five-membered hetero-
cycles thiophene (11l) and thiazole (11m) were easily
obtained in moderate to good yield (Table 1, entries 10e13).
The procedure is robust and easily scaleable: for example,
the preparation of 11a was performed several times on
20e150-g scale, without any significant changes, affording
74e82% yield of 11a. Similarly, 11b was synthesized on a
100-g scale in 56% yield.
Notably, the yield of heterocyclic imidazoles obtained by
our one-pot method was almost uniformly higher than the
overall yield achieved via various two and three-step proce-
dures in the literature (see Table 1, entries 1e4, 7, 12 and
13). One exception is the synthesis of 11c via Negishi reaction
in 87% overall yield; however, it involved three steps, includ-
ing n-butyllithium metalation at ꢁ70 ꢀC, and required strict
air-free and water-free conditions.9a Interestingly, 2-cyanothi-
azole (7m) was converted into a key intermediate in the syn-
thesis of CP-885,316 imidazole 11m in 93% yield, while in
the literature 11m was obtained via a lithiation procedure in
60% yield.1g
Recently, several examples of the transition metal catalyzed
2-arylation of imidazoles under Negishi or Stille conditions
have appeared in the literature (Scheme 2, Eq. 3).1f,9 The
downside of this approach is the necessity of protecting and
then deprotecting the NH-group of imidazole, as well as the
use of n-butyllithium and of strict water- and air-free condi-
tions. Direct arylation of imidazole in the presence of copper(I)
and palladium salts has been advanced by Bellina and Rossi,10
and appears to be a promising method for the synthesis of aryl-
2-imidazoles. However, this method requires high temperature
(140 ꢀC) and 2 equiv of both copper(I) iodide and aryl iodide.
In addition, this reaction has no precedent with heterocycles.
At the same time, a rarely used method, which consists of
the nucleophilic substitution of an imidate with the acetal-pro-
tected aminoacetaldehyde followed by deprotection-cycliza-
tion, attracted our attention (Scheme 3).11 Earlier attempts to
OR1
H2N
NH
OCH3
8
9
OR1
RCN
R
CH3CO2H, 50 °C
7
9a R1 = CH3
9b R2 = CH2CH3
NH
N
6N HCl
reflux
OR1
OR1
N
H
R
N
R
H
10
11
Encouraged by these results, we applied the one-pot proce-
dure to the synthesis of aryl-2-imidazoles from the
Scheme 3. Synthesis of aryl and heteroaryl-2-imidazoles from nitriles.

M.E. Voss et al. / Tetrahedron 64 (2008) 645e651
647
corresponding nitriles (Table 1, entries 14e17). Somewhat
lower yields than for the heterocyclic derivatives were ob-
tained. Nevertheless, in some cases, for example, for imid-
azoles 11n (Table 1, entry 14) and 11p (Table 1, entry 16) our
procedure is preferable to the earlier reported methods.
It should be noted that, when necessary, imidazoles 11
could be easily separated from the side products and unreacted
nitriles 7 by a simple acidebase workup. This allowed us to
isolate analytically pure imidazoles 11 without resorting to
chromatography in all examples with the exception of 11j
(Table 1, entry 10). When conversion of 7 to 8 was incomplete,
the potentially re-usable nitrile 7 could be recovered cleanly
from the organic extract. This also increased the effective
yield, which is calculated in the parentheses in Table 1 (entries
10, 11, 14e16).
spectrometer at 500 MHz for proton and 125 MHz for carbon.
NMR chemical shifts (d) are reported in parts per million and
coupling constants (J ) are reported in hertz. Tetramethylsilane
was used as an internal standard for proton and carbon NMR
spectra. Mass spectra were obtained on a Finnigan LCQ Duo
LCMS ion trap electrospray ionization (ESI) mass spectrome-
ter or a PESCiex API 150EX mass spectrometer using atmo-
spheric chemical ionization (APCI). High resolution mass
spectra were obtained on a TOF mass spectrometer using elec-
trospray ionization at the Center for Functional Genomics,
University at Albany (Albany, NY). Melting points were deter-
mined on an Electrothermal Mel-Temp apparatus and are
uncorrected. Ethyl 4-cyanopicolinate (7f) and thiazole-2-car-
bonitrile (7m) were prepared according to the literature.20
All isolated compounds had purity greater than 95% (area per-
cent) as judged by HPLC analysis.
During our efforts to expand the scope of the synthesis, we
found that the overall yield in the reaction sequence depends
mostly on the degree of conversion of nitrile 7 to imidate ester
8. It has long been known that this transformation under basic
conditions is reversible,14 reaching equilibrium within several
hours at rt. The behavior of the equilibrium constant can be
described by the Hammett equation and shows good correla-
tion with the s-constant.15a The equilibrium is shifted in favor
of the imidate 8 in the case of nitriles 7 substituted with elec-
tron-withdrawing groups. It should be noted that for more
electron-rich or ortho-substituted nitriles the equilibrium is
shifted in favor of the nitrile 7.14,15 Our results are consistent
with this observation. For example, thiophene (11l) and benzo-
ate (11p) substituted imidazoles were obtained in a lower yield
than pyridine (11aef) or nitrobenzene (11n,o) substituted im-
idazoles. At the same time, ortho-substituted nitriles, such as
o-nitrobenzonitrile (7r), 1-cyanoisoquinoline, and o-chloro-
benzonitrile as well as more electron-rich unsubstituted benzo-
nitrile (7s) and 5- and 7-cyanoindoles gave little or no desired
imidazole (not shown in Table 1; 7% of 11r and 6% of 11s; no
reaction in other cases).
4.2. General procedure used for the water-soluble
imidazoles (Method A, Table 1, entries 1e3, 5e6, 8, 9,
and 12)
To 250-mL flask containing 7 (50 mmol) and MeOH
(20 mL) a 30% solution of NaOMe in MeOH (0.94 mL,
5 mmol) was added. The reaction mixture was stirred for the
time period needed for equilibrium to be reached between 7
and 8 (see Table 1). Compound 9a (0.6e1.0 equiv; see Table
1) followed by AcOH (5.5 mL, 96 mmol) was added dropwise.
The reaction mixture was then heated to reflux for 30 min. Af-
ter cooling to rt, MeOH (30 mL) and 6 N HCl in H2O (25 ml)
were added, and the mixture was heated to reflux for 3e12 h
(see Table 1). Once the cyclization was complete, the solution
was evaporated to dryness on a rotary evaporator (15 mmHg,
50 ꢀC). A freshly prepared warm solution of K2CO3 (27.5 g)
in H2O (27.5 g) was added carefully, bringing pH to 10. The
resulting suspension was allowed to cool to rt and filtered or
extracted affording 11, which was purified by recrystallization.
3. Conclusion
4.3. General procedure used for other imidazoles
(Method B, Table 1, entries 4, 7, 10e12, 14e17)
An efficient one-pot synthesis of imidazoles with a single
heterocyclic substituent in 2-position from the corresponding
nitriles is described. The synthesis affords high yields of imid-
azoles substituted by electron-poor heterocycle. This method
also works well if applied to benzonitriles with strong elec-
tron-withdrawing groups. The yield decreases with either
ortho-substitution or increase electron density in the aromatic
or heteroaromatic ring.
A 100-mL flask was charged with 7 (10 mmol), MeOH
(10 mL), and a 30% solution of NaOMe in MeOH (0.38 mL,
1 mmol). The reaction mixture was stirred for the time period
needed for equilibrium to be reached between 7 and 8 (see
Table 1). Compound 9a or 9b (0.78e2 equiv; see Table 1)
was added to the reaction mixture followed by AcOH (1.2 mL,
20 mmol). The reaction mixture was heated to 50 ꢀC for 1 h
and then cooled to rt. MeOH (20 mL) and 6 N HCl in H2O
(5 mL) were added, and the reaction mixture was heated to re-
flux for 5 h. Once the cyclization was complete, the solution
was removed on a rotary evaporator, and the residue was taken
up in a 1:1 mixture of H2O and Et2O (30 mL). The layers were
separated. (Note: To recover starting material 7, the aqueous
phase was further extracted with Et2O (2ꢂ10 mL) and the
combined ethereal extracts were washed with brine (10 mL),
dried over MgSO4, and evaporated to dryness under reduced
pressure.) The pH of the aqueous layer was adjusted to pH
4. Experimental
4.1. General
Unless otherwise noted, reagents and solvents were used as
received from commercial suppliers. Proton and carbon nu-
clear magnetic resonance spectra were obtained on a Bruker
AVANCE 300 spectrometer at 300 MHz for proton and
75 MHz for carbon, or on
a Bruker AVANCE 500

648
M.E. Voss et al. / Tetrahedron 64 (2008) 645e651
Table 1
Preparation of 2-substituted imidazoles 11 from nitriles 7
Entry
Nitrile
7/8 Time (h),
temperature
9 (equiv)
10/11
Time (h)
Imidazole
Yielda (%)
Lit. yield (%) (method:
Scheme 2, Eq. #)Ref.
N
20 (1);5c 26 (NA);5a
25 (NA)12a
N
N
CN
7a
1
2
3
1, rt
9a (1.0)
9a (1.0)
9a (1.0)
3
82
99
75
N
H
11a
11b
11c
N
1, 35 ꢀC
1, 40 ꢀC
8
31 (NA)5a
CN
CN
N
H
N
N
7b
N
55 (1);5b 42 (1);3b
62 (Scheme 3,b);12b 87 (3)9a
4.5
N
H
N
N
7c
N
N
4
2, rt
9b (2.0)
9a (1.0)
9a (1.0)
9b (1.0)
9a (0.6)
9a (1.0)
9b (1.0)
9b (1.0)
9a (0.8)
9a (1.0)
5
8
85
50 (3)9b
N
NC
Cl
N
CN
7d
NH
N
HN
11d
N
CN
Cl
5
1, 40 ꢀC
0.5, rt
0.33, rt
1.5, rt
1, rt
74
N
H
N
7e
11e
N
EtO2C
CN
MeO2C
6
6
N
82
N
N
H
7f
N
11f
N
N
45 (Scheme 3,b)12b
No yield (Scheme 3,b)19
No yield (1)17
CN
7
5
69
N
H
N
N
7g
11g
11h
11i
N
N
N
N
8
CN
5
40
N
H
N
7h
N
N
N
N
N
9
CN
5
62
N
H
7i
N
CN
10
11
12
13
4, rt
5
77 (85)
51 (67)
49
N
N
H
7j
N
11j
N
CN
N
H
15, rt
16, rt
1, rt
5
N
11k
7k
N
N
5
31 (2)16
CN
CN
S
N
H
S
7l
11l
N
N
N
12
93
60 (NA);1g 26 (3)19
S
N
H
S
7m
11m
N
14
16, rt
9b (1.0)
5
68 (79)
40 (NA)18
O2N
CN
7n
O2N
HN
11n

M.E. Voss et al. / Tetrahedron 64 (2008) 645e651
649
Table 1 (continued)
Entry
Nitrile
7/8 Time (h),
temperature
9 (equiv)
9b (1.0)
10/11
Time (h)
Imidazole
Yielda (%)
64 (83)
Lit. yield (%) (method:
Scheme 2, Eq. #)Ref.
N
72 (2)8
O2N
O2N
CN
7o
15
4, rt
5
N
H
11o
N
For the corresponding
ethyl ester: 28 (2)1c,h
H3CO2C
F3C
H3CO2C
F3C
CN
7p
16
6, rt
2, rt
9b (1.0)
9b (1.0)
5
5
31 (57)
58
N
H
11p
N
CN
17
44 (Scheme 3,b);11b 84(NA)10
N
H
7q
11q
a
Isolated yield, based on the total amount of 7 used in the reaction. Yield corrected for the recovered starting material 7 is in parenthesis.
Prepared in the literature by a version of the procedure depicted in Scheme 3.
b
1
8e9 with 2 N aqueous NaOH, and aqueous mixture was
118.6 (br s, C4-imid); MS (ESI) m/z 146 (MþH). The H and
stirred for 30 min to allow complete precipitation of the prod-
uct. The solid was collected by filtration and dried under vac-
uum to provide pure 11.
13C NMR spectra of this product were consistent with the liter-
ature data.3b,12b
4.4.4. 2,6-Di(imidazol-2-yl)pyridine (11d)
Compound 11d (1.79 g, 85%) was obtained as a white solid
4.4. Examples
1
following Method B: mp 272e276 ꢀC; H NMR (300 MHz,
CDCl3) d 8.10 (d, 2H, J¼7.9 Hz), 7.84 (dd, 1H, J¼8.0,
7.8 Hz), 7.22 (s, 4H); 13C NMR (75 MHz, DMSO-d6) d 145.4,
144.0, 136.2, 122.9, 119.5; MS (ESI) m/z 212 (MþH). The 1H
NMR spectrum of this product was consistent with the litera-
ture data.9b
4.4.1. 4-(Imidazol-2-yl)pyridine (11a)
The crude reaction product obtained as a filter cake accord-
ing to Method A was recrystallized from boiling water
(40 mL) to give 11a as an off-white solid (5.95 g, 82%): mp
210e211 ꢀC (lit.5a 206e208 ꢀC); 1H NMR (300 MHz,
DMSO-d6) d 12.90 (br s, 1H), 8.64 (dd, 2H, J¼4.5, 1.5 Hz),
7.88 (dd, 2H, J¼4.5, 1.5 Hz), 7.28 (br s, 2H); 13C NMR
(75 MHz, DMSO-d6) d 150.1, 143.1, 137.3, 130e120 (br s),
4.4.5. 2-Chloro-4-(imidazol-2-yl)pyridine (11e)
The crude reaction product obtained as a filter cake accord-
ing to Method A was heated to reflux with water (65 mL) to
give, after cooling to rt and filtration, 11e as a light brown
1
118.7; (ESI) m/z 146 (MþH). The H NMR spectrum of this
product was consistent with the literature data.5a
1
solid (6.62 g, 74%): mp 186e188 ꢀC; H NMR (300 MHz,
DMSO-d6) d 13.04 (br s, 1H), 8.46 (d, 1H, J¼5.2 Hz), 7.96
(d, 1H, J¼0.6 Hz), 7.89 (dd, 1H, J¼5.2, 1.2 Hz), 7.25 (br s,
2H); 13C NMR (75 MHz, DMSO-d6) d 150.0, 149.5, 140.9,
139.7, 130e118 (br s), 117.6, 117.1; HRMS Calcd for
(C8H6ClN3þHþ): 180.0328. Found: 180.0329.
4.4.2. 3-(Imidazol-2-yl)pyridine (11b)
The crude reaction product obtained as a filter cake accord-
ing to Method A was recrystallized from boiling water
(40 mL) to give 11b as an off-white solid (7.17 g, 99%): mp
208e209 ꢀC (lit.5a 206e207 ꢀC); 1H NMR (300 MHz,
DMSO-d6) d 12.87 (br s, 1H), 9.17 (d, 1H, J¼1.5 Hz), 8.53 (dd,
1H, J¼4.8, 1.5 Hz), 8.30 (dt, 1H, J¼8.0, 1.8 Hz), 7.47 (dd, 1H,
J¼8.0, 4.8 Hz), 7.21 (br s, 2H); 13C NMR (75 MHz, DMSO-d6)
d 148.6, 146.0, 142.9, 131.8, 131e127 (br s), 126.6, 123.7,
120e117 (br s); MS (ESI) m/z 146 (MþH). The 1H NMR spec-
trum of this product was consistent with the literature data.5a
4.4.6. Methyl 4-(imidazol-2-yl)pyridine-2-carboxylate (11f)
Pure 11f (8.32 g, 82%) was obtained as a white solid after
extracting the basic reaction mixture with EtOAc (5ꢂ65 mL)
followed by drying and evaporating the extract: mp 92e
1
95 ꢀC; H NMR (300 MHz, CDCl3) d 8.68 (dd, 1H, J¼5.2,
0.6 Hz), 8.63 (m, 1H), 8.04 (dd, 1H, J¼5.1, 1.8 Hz), 7.31 (s,
2H), 3.93 (s, 3H); 13C NMR (75 MHz, CDCl3) d 165.9, 150.7,
148.7, 143.7, 139.5, 122.9, 121.26, 53.3; HRMS Calcd for
(C10H9N3O2þHþ): 204.0773. Found: 204.0774.
4.4.3. 2-(Imidazol-2-yl)pyridine (11c)
The product was extracted with CH2Cl2 (50 mL) from the
crude filter cake obtained according to Method A and, after
evaporating the extract, recrystallized from boiling EtOAc
(25 mL) to afford 11c (5.43 g, 75%) as an off-white solid: mp
137e138 ꢀC (lit.12b 134e135 ꢀC); 1H NMR (300 MHz,
DMSO-d6) d 12.79 (br s, 1H), 8.59 (d, 1H, J¼4.4 Hz), 8.05 (d,
1H, J¼7.9 Hz), 7.88 (td, 1H, J¼7.9, 1.5 Hz), 7.35 (m, 1H),
7.23 (br s, 1H), 7.08 (br s, 1H); 13C NMR (75 MHz, DMSO-d6)
d 148.9 (C2-Py), 148.8 (C6-Py), 145.5 (C2-imid), 137.1 (C4-
Py), 129.4 (br s, C5-imid), 122.8 (C3-Py), 119.3 (C5-Py),
4.4.7. 2-(Imidazol-2-yl)pyrazine (11g)
Compound 11g (1.01 g, 69%) was obtained as a white solid
following Method B: mp 199e201 ꢀC (lit.12b 202e203 ꢀC);
1H NMR (300 MHz, CDCl3) d 13.10 (br s, 1H), 9.29 (d, 1H,
J¼1.5 Hz), 8.67 (m, 1H), 8.62 (d, 1H, J¼2.6 Hz), 7.37 (br s,
1H), 7.22 (br s, 1H); 13C NMR (75 MHz, DMSO-d6) d 144.8,
144.1, 143.8, 143.6, 141.7, 130.5, 120.1; HRMS Calcd for

650
M.E. Voss et al. / Tetrahedron 64 (2008) 645e651
1
(C7H6N4þHþ): 147.0670. Found: 147.0669. The 1H NMR and
13C spectra of this product were consistent with the literature
data.12b
MS (ESI) m/z 151 (MþH). The H and 13C NMR spectra of
this product were consistent with the literature data.22
4.4.13. 2-(Imidazol-2-yl)thiazole (11m)
Compound 11m (7.02 g, 93%) was obtained as a light
yellow solid following Method A and the workup procedure
described for 11i: mp 174e175 ꢀC; 1H NMR (300 MHz,
DMSO-d6) d 13.09 (br s, 1H), 7.90 (d, 1H, J¼3.1 Hz), 7.73
(d, 1H, J¼3.1 Hz), 7.28 (br s, 1H), 7.07 (br s, 1H); 13C
NMR (75 MHz, DMSO-d6) d 158.9, 143.1, 140.9, 129.5,
4.4.8. 2-(Imidazol-2-yl)pyrimidine (11h)
The crude reaction product obtained as a filter cake accord-
ing to Method A was washed with ice-cold water (2ꢂ5 mL)
(40 mL) to give pure 11h as a white solid (2.91 g, 40%): mp
1
196e197 ꢀC; H NMR (300 MHz, DMSO-d6) d 12.98 (br s,
1H), 8.87 (d, 2H, J¼4.8 Hz), 7.44 (t, 1H, J¼4.8 Hz), 7.24 (s,
2H); 13C NMR (75 MHz, DMSO-d6) d 157.5, 156.8, 144.3,
124.9 (br s), 119.8; MS (ESI) m/z 147 (MþH). The 1H
NMR spectrum of this product was consistent with the litera-
ture data.19
1
120.1, 118.9; MS (ESI) m/z 152 (MþH). The H and 13C
NMR spectra of this product were consistent with the litera-
ture data.1g
4.4.14. 2-(3-Nitrophenyl)imidazole (11n)
Compound 11n (1.29 g, 68%) was obtained as a light yel-
low solid following Method B: mp 190e191 ꢀC (lit.18 193e
4.4.9. 5-(Imidazol-2-yl)pyrimidine (11i)
The product was extracted with EtOAc (5ꢂ500 mL) from
the basic solution obtained according to Method A. After
evaporating the extract, 11i (4.54 g, 62%) was obtained as
a brown solid: mp 188e189 ꢀC; 1H NMR (300 MHz,
DMSO-d6) d 12.88 (br s, 1H), 9.27 (s, 2H), 9.15 (s, 1H),
7.29 (br s, 2H); 13C NMR (75 MHz, DMSO-d6) d 157.2,
152.8, 140.1, 124.8; MS (ESI) m/z 147 (MþH). The 1H
NMR spectrum of this product was consistent with the litera-
ture data.17
1
194 ꢀC); H NMR (300 MHz, DMSO-d6) d 12.92 (br s, 1H),
8.80 (s, 1H), 8.39 (d, 1H, J¼7.8 Hz), 8.18 (dd, 1H, J¼8.2,
1.5 Hz), 7.75 (t, 1H, J¼8.0 Hz), 7.37 (br s, 1H), 7.13 (br s,
1H); 13C NMR (75 MHz, DMSO-d6) d 148.7, 143.9, 132.7,
131.1, 130.7, 130.0, 122.6, 119.4, 119.1; HRMS Calcd for
1
(C9H7N3O2þHþ): 190.0616. Found: 190.0614. The H NMR
spectrum of this product was consistent with the literature
data.21
4.4.15. 2-(4-Nitrophenyl)imidazole (11o)
4.4.10. 3-(Imidazol-2-yl)isoquinoline (11j)
Compound 11o (0.62 g, 64%) was obtained as a yellow
solid following Method B: mp 304 ꢀC (dec) (lit.22 309e
The solid obtained according to Method B was purified by
flash chromatography on silica gel (60e200 mm) eluting with
2% methanol in chloroform (0.2% concentrated ammonium
hydroxide) to afford 11j (1.50 g, 77%) as a white solid: mp
141e143 ꢀC; 1H NMR (300 MHz, CDCl3) d 11.13 (br s,
1H), 9.17 (s, 1H), 8.57 (s, 1H), 7.95 (d, 1H, J¼8.3 Hz), 7.89
(d, 1H, J¼8.2 Hz), 7.69 (dt, 1H, J¼7.0, 1.2 Hz), 7.58 (dt,
1H, J¼7.0, 1.1 Hz), 7.28 (br s, 1H), 7.17 (br s, 1H); 13C
NMR (75 MHz, DMSO-d6) d 152.2, 147.2, 142.8, 137.0,
131.5, 130.9, 128.7, 128.1, 127.9, 127.6, 117.2, 116.7.
HRMS Calcd for (C12H9N3þHþ): 196.0874. Found:
196.0870.
1
311 ꢀC); H NMR (300 MHz, DMSO-d6) d 12.99 (br s, 1H),
8.33 (d, 1H, J¼9.0 Hz), 8.18 (d, 1H, J¼9.0 Hz), 7.30 (br s,
2H); 13C NMR (75 MHz, DMSO-d6) d 146.8, 144.0, 137.0,
125.7, 124.6; HRMS Calcd for (C9H7N3O2þHþ): 190.0616.
Found: 190.0619. The 1H NMR spectrum of this product
was consistent with the literature data.22
4.4.16. Methyl 4-(imidazol-2-yl)benzoate (11p)
Compound 11p (1.20 g, 31%) was obtained as a white solid
following Method B: mp 227e230 ꢀC; H NMR (300 MHz,
1
DMSO-d6) d 12.80 (br s, 1H), 8.09 (d, 1H, J¼8.6 Hz), 8.03
(d, 1H, J¼8.6 Hz), 7.24 (s, 2H); 13C NMR (75 MHz,
DMSO-d6) d 166.3, 144.8, 135.3, 130.0, 128.9, 125.1, 52.5;
HRMS Calcd for (C11H10N2O2þHþ): 203.0820. Found:
4.4.11. 3-(Imidazol-2-yl)quinoline (11k)
Compound 11k (0.99 g, 51%) was obtained as a white solid
1
following Method B: mp 257e260 ꢀC; H NMR (300 MHz,
1
203.0817. The H NMR spectrum of this product was consis-
tent with the literature data.23
DMSO-d6) d 12.91 (s, 1H), 9.50 (d, 1H, J¼2.2 Hz), 8.78 (d,
1H, J¼2.1 Hz), 8.03 (t, 2H, J¼8.0 Hz), 7.77 (dt, 1H, J¼6.9,
1.5 Hz), 7.67 (dt, 1H, J¼7.0, 1.2 Hz), 7.27 (br s, 2H); 13C
NMR (75 MHz, DMSO-d6) d 148.4, 147.3, 143.6, 130.8,
129.9, 129.2, 128.7, 127.7, 127.6, 124.3, 124.2. HRMS Calcd
for (C12H9N3þHþ): 196.0874. Found: 196.0871.
4.4.17. 2-(4-(Trifluoromethyl)phenyl)imidazole (11q)
Compound 11q (1.23 g, 58%) was obtained as a white solid
following Method B: mp 233e235 ꢀC (lit.10b 219e221 ꢀC);
1H NMR (300 MHz, DMSO-d6) d 12.82 (br s, 1H), 8.16 (d,
2H, J¼8.2 Hz), 7.82 (d, 2H, J¼8.2 Hz), 7.12 (br s, 1H), 7.09
(br s, 1H); 13C NMR (75 MHz, DMSO-d6) d 144.1, 134.4,
129.7, 127.8 (q, JCeF¼31.9 Hz), 125.7 (q, JCeF¼3.8 Hz),
125.1, 124.3 (q, JCeF¼247.1 Hz), 118.7; HRMS Calcd for
4.4.12. 2-(Thiophen-2-yl)imidazole (11l)
Compound 11l (0.73 g, 49%) was obtained as a white solid
following Method B: mp 194e195 ꢀC (lit.16 197e198 ꢀC); 1H
NMR (300 MHz, DMSO-d6) d 12.53 (br s, 1H), 7.49 (m, 2H),
7.10 (dd, 1H, J¼5.1, 3.6 Hz), 7.07 (br s, 2H); 13C NMR
(75 MHz, DMSO-d6) d 141.4, 134.5, 127.6, 125.5, 123.2;
(C9H7N3O2þHþ): 213.0639. Found: 213.0646. The H and
1
13C NMR spectra of this product were consistent with the
literature data.10b

M.E. Voss et al. / Tetrahedron 64 (2008) 645e651
651
9. (a) Bell, A. S.; Roberts, D. A.; Ruddock, K. S. Tetrahedron Lett. 1988, 29,
5013; (b) Stupka, G.; Gremaud, L.; Bernardinelli, G.; Williams, A. F.
J. Chem. Soc., Dalton Trans. 2004, 407.
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