Regioselective synthesis of fused imidazo[1,2- a ]pyrimidines via intramolecular C-N bond formation/6- endo-dig cycloisomerization

Article abstract of DOI:10.1021/jo5007762

An efficient regioselective cascade synthesis of N-fused imidazo heterocycles has been developed. This cascade transformation proceeds via a transition-metal (copper/silver) catalyzed coupling reaction between 2-aminobenzimidazole, aldehydes, and alkynes leading to the formation of propargylamine intermediate, which regioselectively undergoes 6-endo-dig cyclization through intramolecular N-H bond activation interceded C-N bond formation leading to highly functionalized imidazo[1,2-a]pyrimidines in good to excellent yields.

Full text of DOI:10.1021/jo5007762

Article
pubs.acs.org/joc
Regioselective Synthesis of Fused Imidazo[1,2‑a]pyrimidines via
Intramolecular C−N Bond Formation/6-Endo-Dig Cycloisomerization
,†
†
†
‡
Atul Kumar,* Mukesh Kumar, Shivam Maurya, and Ranjana S. Khanna
†Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow
2
26031 India
‡
Department of Chemistry, Faculty of Science, BHU, Varanasi 221005, India
S Supporting Information
*
ABSTRACT: An efficient regioselective cascade synthesis of
N-fused imidazo heterocycles has been developed. This
cascade transformation proceeds via a transition-metal
(copper/silver) catalyzed coupling reaction between 2-amino-
benzimidazole, aldehydes, and alkynes leading to the formation
of propargylamine intermediate, which regioselectively under-
goes 6-endo-dig cyclization through intramolecular N−H bond
activation interceded C−N bond formation leading to highly functionalized imidazo[1,2-a]pyrimidines in good to excellent
yields.
INTRODUCTION
involving 2-aminopyridines, alkynes, and aldehydes using
12
■
copper sulfate/glucose via exo-dig cyclization. All these
methods lead to the formation of five-membered ring systems.
However, an efficient synthesis of multisubstituted imidazo-
pyrimidines with high regioselectivity still remains a challenge.
To the best of our knowledge, synthesis of fused imidazopyr-
imidines via intramolecular N−H bond activation mediated C−
N bond formation through regioselective 6-endo-dig cyclo-
isomerization in the presence of Cu/Ag bimetallic catalyst
system has not yet been explored. Functionalized imidazopyr-
imidine is an important pharmacophore and is extensively
found in many biologically active molecules. In particular, aryl-
and heteroarylimidazo[1,2-a]pyrimidines have significant im-
portance in the pharmaceutical industry owing to their broad
Nitrogen-containing fused heterocyclic molecules can be
extremely valuable for obtaining biological leads and exploring
drug discovery programs. Imidazo-fused heterocyclic frag-
ments are important in pharmaceutical and biomedical research
since these scaffolds occur in several natural and biologically
active molecules and exhibit promising biological profiles such
as anticancer, antimicrobial, and antitubercular agents,
benzodiazepine receptor agonists, and calcium channel block-
ers. Imidazo-fused fragments also constitute the core structure
of several currently marketed drugs,
pyrimidines also have immense importance in the pharmaceut-
ical industry owing to their broad range of interesting
pharmacological activity. Several anxiolytic drugs such as
fasiplon, taniplon, and divaplon holding imidazopyrimidine
1
2
3
−6
and imidazo-fused
13
range of interesting pharmacological activity.
As part of our ongoing efforts in the synthesis of N-
7
fragments are currently used in clinics. Therefore, the
14
containing heterocycles, for the first time herein we describe a
availability of efficient and practical synthetic routes to generate
heterocyclic units for the synthesis of natural and biomimetic
compounds is of great demand. One of the ways to achieve this
goal is the development of cascade reactions that allow the
sequential transformations of two or more reactions in the same
reaction vessel, thereby minimizing the number of laboratory
operations, the generation of waste chemicals, time, and cost.
Several synthetic type of methods have been described for the
synthesis of these heterocycles. In 2007, Yan and Liu reported
a Au(III)-catalyzed multicomponent coupling/cycloisomeriza-
tion reaction of heteroaryl aldehydes, amines, and alkynes for
the synthesis of aminoindolizines. In 2010, Gevorgyan et al.
highly efficient, regioselective approach for the synthesis of
functionalized imidazo[1,2-a]pyrimidine derivatives from 2-
aminobenzimidazole, benzaldehydes, and alkynes using a Cu/
Ag coinage bimetallic catalyst system through a multi-
component cascade coupling (MCC) reaction involving 6-
endo-dig intramolecular N−H bond activation interceded C−N
bond formation and cycloisomerization (Scheme 1).
8
RESULTS AND DISCUSSION
■
We commenced this project by investigating the reaction of 2-
aminobenzimidazole (1a), 4-chlorobenzaldehyde (2a), and
phenylacetylene (3a) in the absence of catalyst in MeCN at
9
reported the Cu-promoted synthesis of imidazopyridine via exo-
dig cycloisomerization using aldehydes, 2-aminopyridines, and
8
1−83 °C, but no desired compound was identified (Table 1,
1
0
entry 1). When the same reaction was carried out in toluene at
alkynes. Ji et al. described an approach toward the synthesis of
complex butenolides from alkynes, amines, and glyoxylic acids
1
1
in the presence of gold catalysts. More recently, Guchhait et
Received: May 6, 2014
al. reported the synthesis of imidazo-fused heterocycles
©
XXXX American Chemical Society
A
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Scheme 1. Comparison between Previous Approach and Our Approach
8
1−83 °C in the presence of CuI (15 mol %) and Cu(OTf) /
reaction conditions [Cu (15 mol %)/Ag (15 mol %) in
2
CuSO (15 mol %) following previously reported proto-
cols,
coupling product and instead gave previously reported
exocyclic analogues 5 (Table 1, entry 2).
the reaction produced the desired coupling product 4a in 72%
CH CN] at which coupling product 4a was obtained in 72%
4
3
1
0a,12
unfortunately the reaction failed to provide desired
yield. It is worth mentioning that the reaction was successful
only when the bimetallic Cu/Ag catalyst system was used. The
obtained poly-heterocyclic product of the reaction was fully
10a,12
Fortunately,
1
13
characterized by H and C NMR methods and mass
spectrometric data. The disappearance of the two characteristic
peaks of propargylamine (C) in the 13C NMR spectrum
confirmed the formation of either compound 4a or 5a, but
initially it was difficult to confirm the structure of the
regioisomer as either 4a or 5a (Scheme 1). X-ray crystallo-
graphic analysis of the product confirmed the formation of 4a
(see the Supporting Information). To demonstrate the
generality of this method, the substrate scope of the reaction
was investigated under optimized conditions, and results are
illustrated in Figure 1. First, a wide range of aromatic aldehydes
2a bearing electron-neutral, electron-withdrawing, and electron-
donating groups could be employed as coupling partners with
2-aminobenzimidazole 1a, which were smoothly transformed to
the corresponding benzoimidazo[1,2-a]pyrimidines 4a with
alkyne 3a in good to moderate yields (Figure 1, entries 4a−k).
All para-, meta-, and ortho-substituted aldehydes were easily
converted into the desired products, which indicated that steric
bulk did not significantly affect the reactivity. Aldehydes bearing
dioxo groups furnished the corresponding products in
moderate yield (Figure 1, entries 4l−m). Moreover, aliphatic
aldehydes also reacted smoothly to give the desired coupling
products in good yields (Figure 1, entries 4n−p). Unfortu-
nately, aromatic nitrogen-containing aldehydes such as
pyridine-4-carboxyaldehyde and N,N-dimethylbenzaldehyde
failed to provide the desired coupling products. Substituted
2-aminobenzimidazoles smoothly coupled with aldehydes and
yield in MeCN when we used the combination of CuI (15 mol
%
) and Ag CO (15 mol %) at refluxing temperature (81−83
2
3
°
C) for 8 h in place of Cu(I) and Cu(II) salt combination
Table 1, entry 3). The above result prompted us to examine
(
other silver salts. In light of these results, a series of other silver
salts were evaluated in combination with CuI (15 mol %), and
only Ag CO displayed the best results (Table 1, entries 8−11).
2
3
We have also used some other copper salts in combination with
silver carbonate, and we found copper iodide to be the best
(Table 1 entries 12−16). Several solvents were also screened
for this reaction, and MeCN was seen to be the best (Table 1,
compare entries 3 and 4−7). Catalyst loadings have also been
studied for developing an efficient combination for a bimetallic
catalyst catalyst system. We first modulated loading of Cu,
keeping the Ag loading constant and decreasing the amount of
CuI loading, resulting in a decreased yield of desired product
(Table 1, compare entries 3, 18, and 19), whereas reducing the
amount of silver salt with a constant loading of CuI also
furnished a lower yield of the product 4a (Table 1, compare
entries 3, 20, and 21). Control experiments showed that both
CuI and Ag CO catalysts are necessary for this reaction (see
2
3
the Supporting Information, Table 1, entries 22 and 23). In
control experiments, we found a lower yield of coupling
product when we decreased the amount of both catalysts
(Table 1, entry 17). After the various combinations of copper
and silver catalysts were screened, we finally found the optimal
B
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Article
a
Table 1. Optimization of Reaction Conditions
deficient center of triple bond via 6-endo-dig cyclization leading
to C−N bond formation and gave vinyl silver species (E).
Complex E then subsequently undergoes demetalation as well
as auto-oxidation leading to the formation of 4a.
On the basis of the above results illustrated in Figures 1 and
, the reactions displayed very high regioselectivity. Only the
2
six-membered ring imidazopyrimidine formed via 6-endo-dig
cyclization. Most likely, the reaction via 6-endo-dig cyclization
can produce a stable product and undergo a similar mechanism,
c
15
entry
Cu (mol %)
Ag (mol %)
solvent time (h) yield (%)
which has been supported in the literature.
1
2
3
4
5
6
7
8
9
MeCN
toluene
MeCN
THF
8
8
On the basis of the crystallographic results (see the
Supporting Information), the formation of product 5 was
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuCl (15)
CuBr (15)
b
Ag CO (15)
8
72
45
15
10
15
25
40
20
20
40
38
nd
nd
nd
65
50
48
52
45
ruled out by path C ′, clearly suggesting that product 4a must
1
2
3
Ag CO (15)
8
be formed by intramolecular attack of the nitrogen onto the
2
3
Ag CO (15)
DMF
8
carbon−carbon triple bond (Scheme 3, path C ′).
2
2
3
Ag CO (15)
DMSO
DMA
10
10
8
On the application of this protocol we have synthesized 2-(4-
chlorophenyl)-4-phenyl-2H-benzo[4,5]thiazolo[3,2-a]-
pyrimidine (Scheme 2). To further demonstrate the advantage
of this method, we attempted scale-up synthesis of imidazo[1,2-
a]pyrimidine 4a using of 2-aminobenzimidazole (1a) with p-
chlorobenzaldehyde (2a) and phenylacetylene (3a), and 65%
yield was afforded (Scheme 4).
2
3
Ag CO (15)
2
3
AgOAc (15)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
AgNO (15)
8
3
10
11
12
13
14
15
16
17
18
19
20
21
Ag O (15)
8
2
AgI (15)
8
Ag CO (15)
8
2
3
Ag CO (15)
12
12
12
8
2
3
CuCl (15)
Ag CO (15)
CONCLUSION
2
2
3
■
Cu O (15)
2
Ag CO (15)
2 3
In conclusion, we have developed a Cu/Ag-catalyzed three-
component cascade coupling cyclization reaction, which can be
tuned to proceed via tandem C−H bond functionalization of
alkynes followed by intramolecular N−H activation mediated
C−N bond formation through regioselective 6-endo-dig cyclo-
isomerization sequence to afford substituted imidazopyrimi-
dines. This methodology is amenable to one-pot efficient
synthesis of thiazolopyrimidine framework. The products
generated herein tolerate functional groups viable for further
derivatization. From a synthetic point of view, and taking into
deliberation the easily availability of the starting materials, the
experimental simplicity of the reactions, and the importance of
pyrimidines, especially in medicinal chemistry and material
science, this methodology may become a very helpful device for
synthetic as well as medicinal chemists.
Cu(OTf) (15)
Ag CO (15)
2 3
2
CuI (10)
CuI (10)
CuI (5)
Ag CO (10)
10
10
10
10
10
2
3
Ag CO (15)
2
3
Ag CO (15)
2
3
CuI (15)
CuI (15)
Ag CO (10)
2 3
Ag CO (5)
2
3
a
Reaction conditions: All reactions were performed with 2-amino-
benzimidazole 1a (1.0 mmol), 4-chlorobenzaldehyde 2a (1.0 mmol),
and phenylacetylene 3a (2.0 mmol) in 5 mL of solvent under refluxing
conditions. Copper triflate/copper sulfate. Isolated yield. nd = not
b
c
detected.
alkynes to afford the desired coupling products 4r−v in good
yields (Figure 1, entries 4r−v). Next we evaluated the scope of
several alkynes, which were reacted under optimized reaction
conditions, and results are shown in Figure 2. Aromatic alkynes
bearing methyl groups at the para- and meta-position afforded
the corresponding products in good yields (Figure 2, entries 4z
and 4aa). Methyl propiolate, pent-1-yne, and ethynyltrime-
thylsilane furnished the corresponding products in better yield
EXPERIMENTAL SECTION
■
Typical Procedure for the Synthesis of Benzoimidazo[1,2-
a]pyrimidines (4a). 2-Aminobenzimidazole (1a) (133.1 mg, 1.0
mmol), p-chloro-benzaldehyde (2a) (140 mg, 1.0 mmol), and
phenylacetylene (3a) (0.220 mL, 2.0 mmol) was dissolved in 5 mL
of acetonitrile in a round-bottom flask, Cul (38 mg, 20 mol %) was
added, the mixture was stirred at room temperature for 10 min under
nitrogen, silver carbonate (54 mg, 20 mol %) was added, and the
reaction mixture was refluxed (81−83 °C) until full consumption of 2-
aminobenzimidazole as monitored through TLC. Upon completion
(
Figure 2, entries 4w, 4x, and 4y). Furthermore, we have used
benzyl-protected hydroxyl benzaldehyde for the synthesis of
imidazo[1,2-a]pyrimidine and found that it is well tolerated and
afforded good yield (Figure 1, entry 4q). The tolerance of
functional groups such as chloro, fluoro, bromo, nitro, methoxy,
and cyano in this method provides an opportunity for further
chemical transformations. Several pharmaceutically relevant
scaffolds could be easily generated with the help of this
protocol into N-fused imidazopyrimidines. The proposed
mechanism for the formation of imidazopyrimidine 4a is
illustrated in Scheme 3. First, the Cu(I) salt reacts with the
terminal alkyne to form copper acetylide. The imine (A)
formed in situ is attacked by the copper acetylide, resulting in
the Cu complex intermediate (B) followed by elimination of
copper via reductive elimination, producing alkynyl moiety (C).
The formed alkynyl moiety (C) is coordinated to the silver salt
to generate complex (D), which underwent intramolecular N−
H bond activation and regioselectively attacked at the electron-
(
6−8 h) of the reaction, the mixture was filtered on Celite. The filtrate
was concentrated under reduced pressure to give the crude material,
which was purified by column chromatography on silica gel (eluent:
EtOAc/hexane) and afforded benzoimidazopyrimidine 4a in 72−60%
yield.
Typical Procedure for the Synthesis of 2-(4-Chlorophenyl)-
-phenyl-2H-benzo[4,5]thiazolo[3,2-a]pyrimidine (7). 2-Amino-
benzothiazole (6) (150.1 mg, 1.0 mmol), p-chlorobenzaldehyde (2a)
140 mg, 1.0 mmol), and phenylacetylene (3a) (0.220 mL, 2.0 mmol)
was dissolved in 5 mL of acetonitrile in a round-bottom flask, Cul (38
mg, 20 mol %) was added, the mixture was stirred at room
temperature for 10 min under nitrogen, silver carbonate (54 mg, 20
mol %) was added, and the reaction mixture (81−83 °C) was refluxed
until full consumption of 2-aminobenzothiazole as monitored through
TLC. Upon completion (6−8 h) of the reaction, the mixture was
4
(
C
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The Journal of Organic Chemistry
Article
Figure 1. Synthesis of imidazopyrimidine derivatives using different aldehydes.
filtered on Celite. The filtrate was concentrated under reduced
pressure to give the crude material, which was purified by column
chromatography on silica gel (eluent: EtOAc/hexane), and afforded 2-
NMR (75 MHz, CDCl ) δ 104.8, 114.5, 120.2, 121.3, 126.0, 127.4,
3
128.3, 129.0, 129.2, 129.4, 131.1, 132.4, 135.1, 137.6, 145.5, 149.5,
−1
159.7; IR (KBr) 3429, 2921, 2854, 1013, 827, 768 cm ; ESI MS (m/
+
(
4-chlorophenyl)-4-phenyl-2H-benzo[4,5]thiazolo[3,2-a]pyrimidine
z) = 356 (M + H) . Anal. Calcd for C H ClN : C, 74.26; H, 3.97; N,
22
14
3
(7) in 70% yield.
11.81. Found: C, 74.28; H, 3.98; N, 11.80.
2
-(4-Chlorophenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]-
2-(3,4-Dichlorophenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]-
pyrimidine (4a): yield 256.1 mg (72%); physical state: solid; mp =
97−199 °C; H NMR (300 MHz, CDCl ) δ 6.65 (d, J = 8.3 Hz, 1H),
.01 (t, J = 7.8 Hz, 1H), 7.16 (s, 1H), 7.46 (t, J = 8.5 Hz, 3H), 7.66 (t,
pyrimidine (4b): yield 273.1 mg (70%); physical state: solid; mp =
1
1
1
7
206−208 °C; H NMR (300 MHz, CDCl ) δ 6.39 (s, 1H), 7.00−6.98
3
3
(m, 2H), 7.20 (s, 1H), 7.32−7.30 (m, 2H), 7.72−7.43 (m, 6H), 7.97
(d, J = 7.8 Hz, 1H); C NMR (75 MHz, CDCl ) δ 110.4, 112.0,
13
13
J = 7.7 Hz, 5H), 7.93 (d, J = 8.0 Hz, 1H), 8.22 (d, J = 8.4 Hz, 2H);
C
3
D
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The Journal of Organic Chemistry
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Figure 2. Synthesis of imidazopyrimidine analogues using different alkynes.
Scheme 2. Synthesis of Thiazolopyrimidine
+
1
1
2
15.3, 119.8, 122.4, 126.6, 127.8, 128.5, 129.8, 129.9, 130.9, 131.8,
32.5, 133.9, 134.4, 137.4, 139.1, 144.4, 151.6, 162.1; IR (KBr) 3428,
920, 2853, 1010, 824, 765 cm ; ESI MS (m/z) = 390 (M + H) .
H) . Anal. Calcd for C H N : C, 79.75; H, 4.07; N, 16.17. Found: C,
23 14 4
79.77; H, 4.05; N, 16.18.
2-(4-Fluorophenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]-
pyrimidine (4f): yield 227.3 mg (67%); physical state: solid; mp =
−1
+
Anal. Calcd for C H Cl N : C, 67.71; H, 3.36; N, 10.77. Found: C,
22
13
2
3
1
1
93−195 °C; H NMR (300 MHz, CDCl ) δ 6.68 (d, J = 8.1 Hz, 1H),
6
7.72; H, 3.35; N, 10.78.
-(4-Nitrophenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]-
pyrimidine (4c): yield 260.1 mg (71%); physical state: solid; mp
3
7
.05 (t, J = 7.9 Hz, 1H), 7.25−7.17 (m, 3H), 7.47 (t, J = 7.4 Hz, 1H),
2
7.69 (t, J = 7.8 Hz, 5H), 7.97 (d, J = 8.2 Hz, 1H), 8.33 (q, J = 5.5 Hz,
1
2
1
1
H); 13C NMR (75 MHz, CDCl + DMSO-d ) δ 110.2, 119.5, 120.7,
=
199−201 °C; H NMR (300 MHz, CDCl ) δ 6.75 (d, J = 8.2 Hz,
3 6
3
20.9, 124.4, 125.9, 130.6, 133.4, 134.2, 135.1, 135.2, 136.0, 137.3,
37.8, 154.6, 164.6; IR (KBr) 3428, 2922, 2851, 1218, 1015, 828, 766
1
H), 7.12 (t, J = 7.6 Hz, 2H), 7.31 (s, 1H), 7.53 (t, J = 7.5 Hz, 2H),
.70 (br, 3H), 8.01 (d, J = 7.5 Hz, 1H), 8.47 (dd, J = 8.1, 7.9 Hz, 4H);
7
−
1
+
1
3
cm ; ESI MS (m/z) = 340 (M + H) . Anal. Calcd for C H FN : C,
C NMR (75 MHz, CDCl ) δ 102.3, 114.6, 116.3, 122.5, 124.8, 125.4,
22 14 3
3
7
7.86; H, 4.16; N, 12.38. Found: C, 77.88; H, 4.13; N, 12.39.
2-(4-Bromophenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]-
pyrimidine (4g): yield 288.1 mg (72%); physical state: solid; mp =
1
3
29.6, 130.2, 133.4, 135.5, 138.8, 143.7, 152.5, 153.4, 160.2; IR (KBr)
375, 2922, 2854, 1377, 1217, 767 cm ; ESI MS (m/z) = 367 (M +
−1
+
H) . Anal. Calcd for C H N O : C, 72.12; H, 3.85; N, 15.29. Found:
1
22
14
4
2
2
6
7
07−209 °C; H NMR (300 MHz, CDCl ) δ 6.62 (d, J = 8.3 Hz, 1H),
3
C, 72.11; H, 3.84; N, 15.31.
-(3-Nitrophenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]-
pyrimidine (4d): yield 263.7 mg (72%); Physical state: solid; mp
.98 (t, J = 7.5 Hz, 1H), 7.14 (s, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.65−
2
13
.57 (m, 7H), 7.90 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.5 Hz, 2H);
C
1
NMR (75 MHz, CDCl
28.1, 129.6, 132.2, 133.4, 135.5, 136.2, 138.4, 152.5, 153.4, 160.0; IR
KBr) 3431, 2920, 2855, 1217, 1012, 827, 768 cm ; ESI MS (m/z) =
00 (M + H) . Anal. Calcd for C H BrN : C, 66.01; H, 3.53; N,
3
) δ 102.6, 114.6, 116.4, 122.4, 125.4, 127.9,
=
200−202 °C; H NMR (300 MHz, CDCl ) δ 6.76 (d, J = 8.3 Hz,
3
1
(
4
1
1
7
8
9
1
2
H), 7.12 (t, J = 7.9 Hz, 1H), 7.33 (s, 1H), 7.53 (t, J = 7.6 Hz, 1H),
−1
.78−7.71 (m, 6H), 8.02 (d, J = 6.9 Hz, 1H), 8.40 (d, J = 8.2 Hz, 1H),
+
.78 (d, J = 7.2 Hz, 1H), 9.07 (br, 1H); 13C NMR (75 MHz, CDCl ) δ
22 14 3
3
0.50. Found: C, 65.99; H, 3.54; N, 10.51.
-(2,6-Dichlorophenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]-
pyrimidine (4h): yield 277.1 mg (71%); physical state: solid; mp =
0.4, 100.4, 106.1, 107.4, 108.1, 111.2, 112.1, 114.0, 115.2, 115.7,
17.1, 117.8, 119.2, 123.9, 131.3, 134.4, 136.0,143.8; IR (KBr) 3415,
2
−1
+
924, 2852, 1371, 835, 770 cm ; ESI MS (m/z) = 367 (M + H) .
1
2
06−208 °C; H NMR (300 MHz, CDCl ) δ 6.81 (d, J = 6.9 Hz, 2H),
3
Anal. Calcd for C H N O : C, 72.12; H, 3.85; N, 15.29. Found: C,
22
14
4
2
7.10 (t, J = 7.4 Hz, 1H), 7.36 (s, 1H), 7.67−7.45 (m, 8H), 8.04 (d, J =
7
2.11; H, 3.85; N, 15.30.
-(4-Phenylbenzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-
benzonitrile (4e): yield 242.4 mg (70%); Physical state: solid; mp =
8
1
1
.2 Hz, 1H); 13C NMR (300 MHz, CDCl ) δ 104.6, 109.5, 114.8,
3
4
19.2, 120.6, 121.5, 126.2, 127.4, 128.3, 128.4, 128.9, 129.4, 129.6,
30.6, 131.2, 132.1, 134.1, 135.7, 136.7, 145.3, 149.4, 160.3; IR (KBr)
3424, 2919, 2854, 1217, 1011, 829, 771 cm ; ESI MS (m/z) = 390
M + H) . Anal. Calcd for C H Cl N : C, 67.71; H, 3.36; N, 10.77.
Found: C, 67.72; H, 3.34; N, 10.79.
2,4-Diphenylbenzo[4,5]imidazo[1,2-a]pyrimidine (4i): yield
224.8 mg (70%); physical state: solid; mp = 194−196 °C; H NMR
(300 MHz, CDCl ) δ 6.64 (br, 1H), 6.99 (d, J = 6.9 Hz, 1H), 7.20 (s,
1
1
7
5
95−197 °C; H NMR (300 MHz, CDCl ) δ 6.75 (d, J = 8.1 Hz, 1H),
−1
3
+
.11 (t, J = 7.6 Hz, 1H), 7.42 (s, 1H), 7.51 (br, 1H), 7.74−7.56 (m,
(
22 13 2 3
H), 7.84 (d, J = 7.2 Hz, 2H), 8.01 (br, 1H), 8.42 (d, J = 7.3 Hz, 2H);
1
3
C NMR (75 MHz, CDCl ) δ 105.1, 113.5, 114.7, 118.3, 121.8, 126.4,
3
1
1
2
28.3, 129.5, 131.4, 132.6, 142.8, 148.2, 151.7, 160.6; IR (KBr) 3436,
921, 2853, 2245, 1218, 822, 769 cm ; ESI MS (m/z) = 347 (M +
−1
3
E
dx.doi.org/10.1021/jo5007762 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 3. Proposed Mechanism
Scheme 4. Scale-up Synthesis of Imidazopyrimidine (4a) from 2-Aminobenzimidazole (1a), p-Chlorobenzaldehyde (2a), and
Phenylacetylene (3a)
1
H), 7.61−7.39 (m, 9H), 7.93 (br, 1H), 8.25 (br, 2H); 13C NMR (75
MHz, CDCl ) δ 102.4, 114.9, 116.2, 122.5, 125.4, 128.2, 129.0, 132.6,
MHz, CDCl ) δ 56.8, 102.1, 113.6, 114.2, 166.2, 122.5, 123.1, 125.4,
3
128.3, 129.6, 130.6, 133.3, 135.5, 138.8, 150.1, 151.9, 154.8, 161.0; IR
3
−1
1
33.3, 135.5, 138.4, 152.1, 153.4, 160.3; ESI MS (m/z) = 322 (M +
(KBr) 3436, 2951, 2922, 2855, 1113, 849, 762 cm ; ESI MS (m/z) =
+
+
H) . Anal. Calcd for C H N : C, 82.22; H, 4.70; N, 13.08. Found: C,
382 (M + H) . Anal. Calcd for C H N O : C, 75.57; H, 5.02; N,
22
15
3
24 19
3
2
8
2.19; H, 4.72; N, 13.06.
-(2,4-Dichlorophenyl)-4-phenylbenzo[4,5]imidazo[1,2-a]-
pyrimidine (4j): yield 280.9 mg (72%); physical state: solid; mp =
11.02. Found: C, 75.58; H, 5.01; N, 11.04.
2
2-(Benzo[d][1,3]dioxol-5-yl)-4-phenylbenzo[4,5]imidazo[1,2-
a]pyrimidine (4l): yield 263.1 mg (72%); physical state: solid; mp =
1
1
2
7
4
1
1
1
06−208 °C; H NMR (300 MHz, CDCl ) δ 6.79 (d, J = 8.4 Hz, 1H),
198−200 °C; H NMR (300 MHz, CDCl ) δ 5.98 (s, 2H), 6.58 (d, J =
3
3
.11 (t, J = 7.6 Hz, 1H), 7.25 (s, 1H), 7.54−7.43 (m, 4H), 7.68 (br,
7.6 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 7.07 (s,
H), 8.02 (dd, J = 7.9, 8.0 Hz, 2H); 13C NMR (50 MHz, CDCl ) δ
1H), 7.35 (br, 1H), 7.70−7.56 (m, 6H), 7.82 (br, 2H); C NMR (75
13
3
09.4, 114.7, 120.4, 121.5, 126.2, 127.8, 128.3, 129.4, 130.2, 131.2,
32.2, 133.0, 136.6, 145.7, 151.5, 160.4; IR (KBr) 3427, 2924, 2850,
MHz, CDCl ) δ 101.7, 104.9, 107.8, 108.4, 114.4, 119.9, 120.9, 122.7,
3
125.7, 128.4, 129.3, 131.0, 132.5, 148.5, 149.0, 150.5, 160.3; IR (KBr)
−1
+
−1
009, 828, 767 cm ; ESI MS (m/z) = 390 (M + H) . Anal. Calcd for
3430, 2928, 2910, 2854, 1106, 834, 771 cm ; ESI MS (m/z) = 366
+
C H Cl N : C, 67.71; H, 3.36; N, 10.77. Found: C, 67.72; H, 3.35;
(M + H) . Anal. Calcd for C H N O : C, 75.60; H, 4.14; N, 11.50.
2
2
13
2
3
23 15
3
2
N, 10.78.
-(3,4-Dimethoxyphenyl)-4-phenylbenzo[4,5]imidazo[1,2-
a]pyrimidine (4k): yield 228.8 mg (60%); physical state: solid; mp =
Found: C, 75.59; H, 4.12; N, 11.52.
2
2-(6-Nitrobenzo[d][1,3]dioxol-5-yl)-4-phenylbenzo[4,5]-
imidazo[1,2-a]pyrimidine (4m): yield 279.1 mg (68%); physical
1
1
2
3
7
05−207 °C; H NMR (300 MHz, CDCl ) δ 3.99 (s, 3H), 4.05 (s,
state: solid; mp = 205−207 °C; H NMR (300 MHz, CDCl ) δ 6.22
3
3
H), 6.68 (d, J = 7.4 Hz, 1H), 7.25−6.96 (m, 4H), 7.46 (s, 1H), 7.73−
(s, 2H), 6.72 (s, 1H), 6.77 (s, 1H), 7.11 (t, J = 7.7 Hz, 1H), 7.28 (s,
1H), 7.52 (t, J = 7.4 Hz, 1H), 7.567 (s, 1H), 7.72−7.64 (m, 5H), 8.03
.68 (m, 5H), 7.97 (d, J = 7.8 Hz, 1H), 8.14 (br, 1H); 13C NMR (75
F
dx.doi.org/10.1021/jo5007762 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
d, J = 8.2 Hz, 1H); 13C NMR (75 MHz, CDCl ) δ 103.5, 105.6,
Calcd for C H Cl N : C, 68.33; H, 3.74; N, 10.39. Found: C, 68.35;
3
23 15
2
3
1
1
1
01.1, 110.5, 114.7, 120.4, 121.6, 126.1, 128.3, 129.4, 130.5, 131.3,
31.9, 142.8, 148.9, 151.7, 160.7; IR (KBr) 3429, 2930, 2915, 2855,
109, 821, 769 cm ; ESI MS (m/z) = 411 (M + H) . Anal. Calcd for
H, 3.71; N, 10.40.
4-(4-Chlorophenyl)-2-(3-methoxyphenyl)-8-methylbenzo-
[4,5]imidazo[1,2-a]pyrimidine (4t). The general procedure was
followed using 5-methyl-1H-benzo[d]imidazol-2-amine (147.1 mg, 1.0
−1
+
C H N O : C, 67.31; H, 3.44; N, 13.65. Found: C, 67.33; H, 3.42;
2
3
14
4
4
N, 13.66.
-Isopropyl-4-phenylbenzo[4,5]imidazo[1,2-a]pyrimidine
4n): yield 195.4 mg (68%); physical state: solid; mp = 192−194 °C;
mmol): yield 287.9 mg (72%); physical state: solid; mp = 205−207
1
2
°C; H NMR (400 MHz, CDCl
3
) δ 2.35 (s, 3 H), 3.95 (s, 3 H), 6.66
(
(d, J = 8.5 Hz, 1 H), 6.90−6.95 (m, 1 H), 7.10 (ddd, J = 8.2, 2.6, 0.7
1
H NMR (300 MHz, CDCl ) δ 1.45 (d, J = 6.2 Hz, 6H), 3.21 (br,
Hz, 1 H), 7.19−7.23 (m, 1 H), 7.43 (t, J = 8.0 Hz, 1 H), 7.61−7.66
3
1
(
H), 6.68 (s, 2H), 7.04 (t, J = 7.6 Hz, 1H), 7.44 (br, 1H), 7.68−7.62
(m, 2 H), 7.66−7.70 (m, 2 H), 7.74−7.77 (m, 2 H), 7.98−8.02 (m, 1
m, 5H), 7.96 (br, 1H); 13C NMR (75 MHz, CDCl ) δ 21.5, 37.1,
13
H); C NMR (100 MHz, CDCl ) δ 21.85, 55.58, 105.30, 112.02,
3
3
1
1
06.9, 114.4, 120.1, 120.7, 125.5, 127.8, 128.3, 128.8, 129.3, 130.9,
32.7, 148.9, 173.5; IR (KBr) 3427, 2954, 2921, 2851, 1101, 846, 766
113.83, 118.17, 119.89, 120.04, 123.13, 125.30, 127.82, 129.64, 129.75,
129.87, 130.98, 136.31, 137.34, 137.98, 145.87, 147.70, 152.06, 160.25,
−1
+
−1
cm ; ESI MS (m/z) = 288 (M + H) . Anal. Calcd for C H N : C,
160.29; IR (KBr) 3429, 2923, 2854, 1384, 1217, 1067, 770 cm ; ESI
19
17
3
+
7
9.41; H, 5.96; N, 14.62. Found: C, 79.42; H, 5.97; N, 14.61.
-Isobutyl-4-phenylbenzo[4,5]imidazo[1,2-a]pyrimidine
4o): yield 198.9 mg (66%); physical state: solid; mp = 140−142 °C;
MS (m/z) = 400 (M + H) . Anal. Calcd for C H ClN O: C, 72.09;
24
18
3
2
H, 4.54; N, 10.51. Found: C, 72.07; H, 4.55; N, 10.52.
(
8-Chloro-4-(4-chlorophenyl)-2-phenylbenzo[4,5]imidazo-
[1,2-a]pyrimidine (4u). The general procedure was followed using 5-
chloro-1H-benzo[d]imidazol-2-amine (167.5 mg, 1.0 mmol): yield
1
H NMR (300 MHz, CDCl ) δ 1.07 (d, J = 6.4 Hz, 6H), 2.39−2.34
3
(
m, 1H), 2.84 (d, J = 7.0 Hz, 2H), 6.69−6.63 (m, 2H), 7.04 (t, J = 7.7
1
Hz, 1H), 7.46 (t, J = 7.1 Hz, 1H), 7.68−7.61 (m, 5H), 7.98 (d, J = 7.5
264.5 mg (68%); physical state: solid; mp = 202−204 °C; H NMR
Hz, 1H); 13C NMR (75 MHz, CDCl ) δ 22.6, 28.4, 47.9, 108.9, 114.5,
(400 MHz, CDCl ) δ 7.14 (dd, J = 8.9, 2.0 Hz, 1 H), 7.45−7.53 (m, 1
3
3
1
1
20.2, 120.8, 125.6, 127.8, 128.3, 129.3, 130.9, 132.3, 144.9, 148.5,
H), 7.61−7.65 (m, 3 H), 7.68 (d, J = 1.0 Hz, 1 H), 7.81−7.88 (m, 3
−1
13
68.4; IR (KBr) 3427, 2954, 2920, 2854, 1100, 848, 765 cm ; ESI MS
H), 7.92−7.98 (m, 2 H), 8.43−8.46 (m, 2 H); C NMR (100 MHz,
+
(m/z) = 302 (M + H) . Anal. Calcd for C H N : C, 79.70; H, 6.35;
CDCl ) δ 105.07, 114.29, 115.99, 116.20, 120.42, 121.48, 126.14,
20
19
3
3
N, 13.94. Found: C, 79.71; H, 6.34; N, 13.92.
127.24, 129.83, 129.91, 130.00, 130.83, 132.68, 137.51, 145.51, 148.23,
151.88, 159.84, 163.72; IR (KBr) 3423, 2955, 2915, 1215, 1103, 929,
758, 669 cm ; ESI MS (m/z) = 391 (M + H) . Anal. Calcd for
4
-Phenyl-2-propylbenzo[4,5]imidazo[1,2-a]pyrimidine (4p):
1
−1
+
yield 201.1 mg (70%); physical state: solid; mp = 148−150 °C; H
NMR (300 MHz, CDCl ) δ 1.08 (t, J = 6.9 Hz, 3H), 1.96 (q, J = 7.3
C H Cl N : C, 67.71; H, 3.36; N, 10.77. Found: C, 67.72; H, 3.35;
3
22 13
2
3
Hz, 2H), 2.94 (t, J = 6.9 Hz, 2H), 6.63 (s, 1H), 6.66 (s, 1H), 7.02 (t, J
N, 10.78.
=
=
7.2 Hz, 1H), 7.44 (t, J = 7.1 Hz, 1H), 7.66−7.59 (m, 5H), 7.95 (d, J
8-Chloro-2,4-bis(4-chlorophenyl)benzo[4,5]imidazo[1,2-a]-
pyrimidine (4v). The general procedure was followed using 5-chloro-
1H-benzo[d]imidazol-2-amine (167.5 mg, 1.0 mmol): yield 297.2 mg
8.2 Hz, 1H); 13C NMR (75 MHz, CDCl ) δ13.9, 21.6, 40.8, 108.5,
3
1
1
14.4, 120.2, 120.8, 125.6, 127.4, 128.3, 129.3, 130.9, 132.4, 144.9,
48.6, 152.1, 168.9; IR (KBr) 3427, 2954, 2920, 2854, 1100, 848, 765
1
(70%); physical state: solid; mp = 203−205 °C; H NMR (400 MHz,
−1
+
cm ; ESI MS (m/z) = 288 (M + H) . Anal. Calcd for C H N : C,
CDCl ) δ 7.04 (dd, J = 8.9, 2.0 Hz, 1 H), 7.17−7.24 (m, 4 H), 7.62−
3
19
17
3
7
9.41; H, 5.96; N, 14.62. Found: C, 79.42; H, 5.96; N, 14.61.
7.66 (m, 2 H), 7.68−7.74 (m, 2 H), 7.81−7.88 (m, 1 H), 8.24−8.29
(m, 2 H); 13C NMR (100 MHz, CDCl
) δ 105.54, 116.05, 116.27,
2
-(4-(Benzyloxy)phenyl)-4-(4-chlorophenyl)benzo[4,5]-
3
imidazo[1,2-a]pyrimidine (4q): yield 332.5 mg (72%); physical
119.66, 121.05, 122.01, 126.91, 129.72, 129.77, 129.99, 130.17, 130.35,
131.94, 132.30, 137.80, 137.92, 143.68, 146.00, 148.18, 152.49, 160.39;
1
state: solid; mp = 207−209 °C; H NMR (400 MHz, CDCl ) δ 5.20
3
−1
(
s, 2 H), 7.06 (s, 2 H), 7.14−7.27 (m, 3 H), 7.50−7.64 (m, 7 H),
IR (KBr) 3429, 2956, 2919, 1158, 1064, 757, 669 cm ; ESI MS (m/z)
+
7
.64−7.77 (m, 4 H), 7.77−7.90 (m, 1 H), 8.20 (d, J = 8.6 Hz, 1 H);
= 425 (M + H) . Anal. Calcd for C H Cl N : C, 62.22; H, 2.85; N,
22
12
3
3
1
3
C NMR (100 MHz, CDCl ) δ 70.11, 109.72, 115.48, 116.18, 119.02,
9.89. Found: C, 62.21; H, 2.84; N, 9.91.
3
1
1
1
2
20.07, 121.89, 122.74, 123.86, 126.76, 127.39, 127.49, 127.58, 127.95,
28.04, 128.57, 128.61, 128.80, 129.08, 129.44, 132.25, 134.02, 134.90,
36.51, 138.52, 141.41, 148.52, 158.87; IR (KBr) 3425, 2931, 2916,
Methyl 2-(4-chlorophenyl)benzo[4,5]imidazo[1,2-a]-
pyrimidine-4-carboxylate (4w): yield 246.5 mg (73%); physical
1
state: solid; mp = 192−195 °C; H NMR (300 MHz, CDCl
) δ 3.87
3
−1
+
856, 1250, 1108, 833, 749 cm . ESI MS (m/z) = 462 (M + H) .
(s, 3H), 7.39 (br, 2H), 7.52 (d, J = 7.1 Hz, 2H), 7.75 (dd, J = 5.2, 5.4,
Hz, 2H), 8.02 (d, J = 8.2 Hz, 2H), 9.44 (s, 1H); 13C NMR (75 MHz,
Anal. Calcd for C H ClN O: C, 75.40; H, 4.36; N, 9.10. Found: C,
29
20
3
7
5.42; H, 4.37; N, 9.09.
-(4-Chlorophenyl)-8-methyl-2-phenylbenzo[4,5]imidazo-
1,2-a]pyrimidine (4r). The general procedure was followed using 5-
methyl-1H-benzo[d]imidazol-2-amine (147.1 mg, 1.0 mmol): yield
CDCl
) δ 51.8, 105.6, 112.2, 120.3, 124.4, 124.7, 129.4, 131.4, 132.8,
3
4
133.4, 136.2, 139.8, 142.4, 154.7, 165.6, 167.4; IR (KBr) 3436, 2923,
−
1
+
[
2856, 1730, 1310, 821, 770 cm ; ESI MS (m/z) = 338 (M + H) .
Anal. Calcd for C H ClN O : C, 64.01; H, 3.58; N, 12.44. Found: C,
18
12
3
2
1
2
62.5 mg (71%); physical state: solid; mp = 204−206 °C; H NMR
64.04; H, 3.56; N, 12.45.
(
6
400 MHz, CDCl ) δ 2.27 (s, 3 H), 6.58 (s, 1 H), 6.69−6.75 (m, 1 H),
2-(4-Chlorophenyl)-4-propylbenzo[4,5]imidazo[1,2-a]-
3
.81 (dd, J = 8.3, 1.2 Hz, 2 H), 7.11−7.17 (m, 2 H), 7.25−7.33 (m, 3
pyrimidine (4x): yield 164.1 mg (51%); physical state: solid; mp =
1
H), 7.42−7.49 (m, 1 H), 7.57−7.71 (m, 1 H), 7.94−8.03 (m, 2 H);
154−156 °C; H NMR (400 MHz, CDCl ) δ 0.89 (t, J = 7.3 Hz, 3 H),
3
1
3
C NMR (100 MHz, CDCl ) δ 21.84, 105.56, 112.08, 114.32, 118.25,
1.52−1.62 (m, 2H), 2.82 (t, J = 7.6, Hz, 2H), 7.04−7.20 (m, 2 H)
7.20−7.30 (m, 1 H) 7.30−7.47 (m, 3 H) 7.96 (d, J = 7.7 Hz, 2 H) 8.16
3
1
1
2
20.09, 120.34, 121.40, 126.06, 127.25, 129.78, 129.89, 130.88, 137.41,
37.85, 145.46, 147.98, 151.93, 160.24, 160.72; IR (KBr) 3428, 2921,
(dd, J = 7.8, 1.2 Hz, 1 H); 13C NMR (100 MHz, CDCl
) δ 14.02,
3
−1
+
850, 1079, 760, 669 cm ; ESI MS (m/z) = 370 (M + H) . Anal.
24.84, 36.47, 109.82, 112.65, 123.89, 128.39, 128.81, 128.92, 129.59,
130.37, 131.56, 133.27, 135.39, 136.31, 142.41, 149.72, 157.98; IR
Calcd for C H ClN : C, 74.69; H, 4.36; N, 11.36. Found: C, 74.71;
23
16
3
−1
H, 4.34; N, 11.37.
,4-Bis(4-chlorophenyl)-8-methylbenzo[4,5]imidazo[1,2-a]-
pyrimidine (4s). The general procedure was followed using 5-methyl-
H-benzo[d]imidazol-2-amine (147.1 mg, 1.0 mmol): yield 278.9 mg
(KBr) 3428, 2953, 2921, 2853, 1100, 849, 764 cm ; ESI MS (m/z) =
+
2
322 (M + H) . Anal. Calcd for C19
H16ClN : C, 70.91; H, 5.01; N,
3
13.06. Found: C, 70.92; H, 4.99; N, 13.08.
1
2-(4-Chlorophenyl)-4-(trimethylsilyl)benzo[4,5]imidazo[1,2-
1
(
69%); physical state: solid; mp = 203−205 °C; H NMR (400 MHz,
a]pyrimidine (4y): yield 242.8 mg (69%); physical state: solid; mp =
1
CDCl ) δ 2.28 (s, 3 H), 6.50−6.67 (m, 1 H), 6.69−6.83 (m, 2 H),
196−198 °C; H NMR (300 MHz, CDCl
3
+ DMSO-d
6
) δ 1.23 (s,
3
6
8
1
1
2
.93−7.19 (m, 4 H), 7.27−7.37 (m, 3 H), 7.61−7.71 (m, 1 H), 7.94−
9H), 7.18−7.16 (m, 2H), 7.51 (d, J = 8.2 Hz, 3H), 7.79 (s, 1H), 7.97
(d, J = 8.3 Hz, 2H), 9.41 (s, 1H); C NMR (75 MHz, DMSO-d ) δ
.04 (m, 1 H); 13C NMR (100 MHz, CDCl ) δ 21.88, 105.66, 114.37,
13
3
6
20.22, 121.52, 126.20, 127.21, 127.81, 129.05, 129.84, 130.80, 131.50,
36.42, 137.51, 145.25, 148.21, 151.94, 161.28; IR (KBr) 3430, 2923,
854, 1091, 844, 758 cm ; ESI MS (m/z) = 405 (M + H) . Anal.
116.7, 124.3, 127.3, 134.5, 134.6, 136.2, 136.3, 139.2, 140.1, 142.6,
143.7, 144.6, 160.6, 169.3, 197.3; IR (KBr) 3422, 2910, 2849, 1006,
−1
+
−1
+
826, 759 cm ; ESI MS (m/z) = 352 (M + H) . Anal. Calcd for
G
dx.doi.org/10.1021/jo5007762 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
C H ClN Si: C, 64.85; H, 5.16; N, 11.94. Found: C, 64.86; H, 5.14;
for the X-ray data. We acknowledge CSIR Network Project
BSC0108 for financial support. CDRI communication no. 8737.
1
9
18
3
N, 11.96.
-(4-Chlorophenyl)-4-p-tolylbenzo[4,5]imidazo[1,2-a]-
pyrimidine (4z): yield 262.5 mg (71%); physical state: solid; mp =
2
REFERENCES
1
■
2
8
7
02−204 °C; H NMR (300 MHz, CDCl ) δ 2.57 (s, 3H), 6.80 (d, J =
3
(
1) (a) Leeson, P. D.; Springthorpe, B. Nat. Rev. Drug Discovery 2007,
6, 881. (b) DeSimone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow, J.
.1 Hz, 1H), 7.08 (t, J = 7.9 Hz, 1H), 7.19 (s, 1H), 7.55−7.47 (m,
H), 7.98 (d, J = 7.2 Hz, 1H), 8.26 (d, J = 8.1 Hz, 2H); 13C NMR (75
W.; Pippin, D. A. Comb. Chem. High Throughput Screening 2004, 7,
MHz, CDCl ) δ 21.2, 104.8, 114.5, 119.2, 120.8, 125.5, 127.8, 128.6,
3
4
73.
1
1
28.8, 129.6, 141.0, 148.9, 151.7, 160.7; IR (KBr) 3437, 2920, 2853,
012, 820, 761 cm ; ESI MS (m/z) = 370 (M + H) . Anal. Calcd for
−1
+
(2) (a) Kaminski, J. J.; Wallmark, B.; Briving, C.; Andersson, B. M. J.
Med. Chem. 1991, 34, 533. (b) Rival, Y.; Grassy, G.; Michel, G. Chem.
Pharm. Bull. 1992, 40, 1170. (c) Margiotta, N.; Ostuni, R.; Ranaldo,
R.; Denora, N.; Laquintana, V.; Trapani, G.; Liso, G.; Natile, G. J. Med.
Chem. 2007, 50, 1019. (d) Veron, J. B.; Allouchi, H.; Enguehard
Gueiffier, C.; Snoeck, R.; De Clercq, G. A. E.; Gueiffier, A. Bioorg. Med.
Chem. 2008, 16, 9536.
(3) (a) George, P. G.; Rossey, G.; Sevrin, M.; Arbilla, S.; Depoortere,
H.; Wick, A. E. L. E. R. S. Monogr. Ser. 1993, 8, 49. (b) Berson, A.;
Descatoire, V.; Sutton, A.; Fau, D.; Maulny, B.; Vadrot, N.; Feldmann,
G.; Berthon, B.; Tordjmann, T.; Pessayre, D. J. Pharmacol. Exp. Ther.
2001, 299, 793. (c) Saletu, J.; Grunberger, B.; Linzmayer, L. Int. Clin.
Psychopharmacol. 1986, 1, 145.
(4) (a) Harrison, T. S.; Keating, G. M. CNS Drugs 2005, 19, 65.
(b) Hanson, S. M.; Morlock, E. V.; Satyshur, K. A.; Czajkowski, C. J.
Med. Chem. 2008, 51, 7243. (c) Monti, J. M.; Warren, S. D.; Pandi-
Perumal, S. R.; Langer, S. Z.; Hardeland, R. Clin. Med. Ther. 2009, 1,
123.
C H ClN : C, 74.69; H, 4.36; N, 11.36. Found: C, 74.71; H, 4.33; N,
2
3
16
3
1
1.37.
-(4-Chlorophenyl)-4-m-tolylbenzo[4,5]imidazo[1,2-a]-
pyrimidine (4aa): yield 258.8 mg (70%); physical state: solid; mp =
2
1
2
1
8
1
1
01−203 °C; H NMR (300 MHz, CDCl ) δ 2.49 (s, 3H), 6.75 (br,
3
H), 7.03 (s, 1H), 7.24 (br, 2H), 7.50−7.43 (m, 6H), 7.99 (br, 1H),
.24 (br, 2H); 13C NMR (50 MHz, CDCl +DMSO-d ) δ 26.2, 109.9,
19.6, 124.4, 126.1, 130.2, 130.7, 133.6, 133.9, 134.1, 136.9, 140.1,
41.9, 144.1, 154.9, 164.4; IR (KBr) 3440, 2919, 2855, 1009, 821, 765
3
6
−1
+
cm ; ESI MS (m/z) = 370 (M + H) . Anal. Calcd for C H ClN : C,
23
16
3
7
4.69; H, 4.36; N, 11.36. Found: C, 74.70; H, 4.35; N, 11.34.
-(4-Chlorophenyl)-4-phenyl-2H-benzo[4,5]thiazolo[3,2-a]-
pyrimidine (7): yield 262.4 mg (70%); physical state: solid; mp =
2
1
2
6
2
03−205 °C; H NMR (300 MHz, CDCl ) δ 5.48 (d, J = 4.1 Hz, 1H),
3
.03 (d, J = 4.1 Hz, 1H), 6.62 (d, J = 7.4 Hz, 1H), 7.01 (q, J = 7.2 Hz,
H) 7.22−7.17 (m, 8H), 7.61 (d, J = 8.4 Hz, 2H); C NMR (75
MHz, CDCl +DMSO-d ) δ 59.6, 104.4, 111.8, 121.7, 123.0, 123.2,
13
3
6
1
1
26.1, 127.0, 128.2, 128.3, 129.3, 133.7, 136.4, 138.6, 139.5, 141.7,
(5) (a) Boerner, R. J.; M?ller, H. J. Psychopharmakother. 1997, 4, 145.
(b) Sanger, D. J. Behav. Pharmacol. 1995, 6, 116.
(6) (a) Enguehard-Gueiffier, C.; Gueiffier, A. Mini-Rev. Med. Chem.
−1
61.1; IR (KBr) 3439, 2928, 2855, 1112, 845, 773 cm ; ESI MS (m/
+
z) = 375 (M + H) . Anal. Calcd for C H ClN S: C, 70.48; H, 4.03
22
15
2
N, 7.47. Found: C, 70.50; H, 4.01 N, 7.46.
2007, 7, 888.
N-(1-(4-Chlorophenyl)-3-phenylprop-2-yn-1-yl)-1H-benzo-
d]imidazol-2-amine (C). The reaction using 2-aminobenzimidazole
(7) (a) Tully, W. R.; Gardner, C. R.; Gillespie, R. J.; Westwood, R. J.
[
Med. Chem. 1991, 34, 2060. (b) Clements-Jewery, S.; Danswan, G.;
Gardner, C. R.; Matharu, S. S.; Murdoch, R.; Tully, W. R.; Westwood,
W. J. Med. Chem. 1988, 31, 1220.
(1a) (133.1 mg, 1.0 mmol), 4-chlorobenzaldehyde (2a) (140 mg, 1.0
mmol), and phenylacetylene (3a) (0.220 mL, 2.0 mmol) in the
presence of only CuI (15 mol %) in acetonitrile was subjected to
(8) (a) Gudmundsson, K. S.; Johns, B. A. Org. Lett. 2003, 5, 1369.
refluxing temperature (81−83 °C) afforded intermediate C: yield
(b) Denora, N.; Laquintana, V.; Pisu, M. G.; Dore, R.; Murru, L.;
1
7
5.14 mg (21%); physical state: gummy liquid; H NMR (400 MHz,
Latrofa, A.; Trapani, G.; Sanna, E. J. Med. Chem. 2008, 51, 6876.
(c) Trapani, G.; Laquintana, V.; Denora, N.; Trapani, A.; Lopedota, A.;
Latrofa, A.; Franco, M.; Serra, M.; Pisu, M. G.; Floris, I.; Sanna, E.;
Biggio, G.; Liso, G. J. Med. Chem. 2005, 48, 292. (d) Jensen, M. S.;
Hoerrner, R. S.; Li, W.; Nelson, D. P.; Javadi, G. J.; Dormer, P. G.; Cai,
D.; Larsen, R. D. J. Org. Chem. 2005, 70, 6034. (e) Al-Tel, T. H.; Al-
Qawasmeh, R. A.; Voelter, W. Eur. J. Org. Chem. 2010, 5586.
CDCl ) δ 4.35 (br, 1H), 5.49 (s, 1 H), 6.98−7.03 (m, 2 H), 7.04−7.08
3
(
m, 3 H), 7.45 (d, J = 7.7 Hz, 1 H), 7.62−7.65 (m, 2 H), 7.84 (s, 1 H),
13
7
.82 (s, 1 H), 8.17−8.20 (m, 2 H), 8.44 (d, J = 8.5 Hz, 1 H);
C
NMR (100 MHz, CDCl ) δ 55.64, 84.54, 88.92, 112.12, 120.64,
3
1
21.57, 123.61, 128.04, 129.23, 129.34, 129.85, 129.93, 130.60, 132.02,
1
33.34, 136.11, 136.86, 137.40, 139.53, 139.56, 140.24, 148.12; IR
−1
(
KBr) 3479, 3403, 3050, 2941, 1615, 784, 692 cm ; ESI MS (m/z) =
(9) Yan, B.; Liu, Y. Org. Lett. 2007, 9, 4323.
+
3
58 (M + H) . Anal. Calcd for C H ClN : C, 73.84; H, 4.51; N,
22 16 3
(10) (a) Chernyak, N.; Gevorgyan, V. Angew. Chem. 2010, 122, 2803.
1
1.74. Found: C, 73.82; H, 4.52; N, 11.75.
(
b) Chernyak, N.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49,
743. (c) Chernyak, D.; Chernyak, N.; Gevorgyana, V. Adv. Synth.
Catal. 2010, 352, 961.
11) Zhang, Q.; Cheng, M.; Hu, X.; Li, B.-G.; Ji, J.-X. J. Am. Chem.
Soc. 2010, 132, 7256.
12) Guchhait, S. K.; Chandgude, A. L.; Priyadarshani, G. J. Org.
2
ASSOCIATED CONTENT
■
(
* Supporting Information
S
Optimization of reaction conditions, copies of H and 13C
NMR spectra for all compounds, and X-ray crystallographic
data for compound 4a (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
1
(
Chem. 2012, 77, 4438.
(13) (a) Moraski, G. C.; Markley, L. D.; Hipskind, P. A.; Boshoff, H.;
Cho, S.; Franzblau, S. G.; Miller, M. J. ACS Med. Chem. Lett. 2011, 2,
4
66. (b) Blackaby, W. P.; Atack, J. R.; Bromidge, F.; Castro, J. L.;
Goodacre, S. C.; Hallett, D. J.; Lewis, R. T.; Marshall, G. R.; Pike, A.;
Smith, A. J.; Street, L. J.; Tattersall, D. F. D.; Wafford, K. A. Bioorg.
Med. Chem. Lett. 2006, 16, 1175. (c) Almansa, C.; De Arriba, A. F.;
AUTHOR INFORMATION
■
*
9
Corresponding Author
E-mail: dratulsax@gmail.com.Fax: (+) 91-5222623405. Tel:
1-522-2612411.
Cavalcanti, F. L.; Gom
Rafanell, J.; Forn, J. J. Med. Chem. 2001, 44, 350.
14) (a) Kumar, A.; Gupta, G.; Srivastava, S. Org. Lett. 2011, 13,
366. (b) Kumar, A.; Gupta, M. K.; Kumar, M. Green Chem. 2012, 14,
290. (c) Kumar, A.; Gupta, L. P.; Kumar, M. RSC Adv. 2013, 3, 18771.
d) Kumar, A.; Kumar, M.; Gupta, L. P.; Gupta, M. K. RSC Adv. 2014,
, 9412.
15) (a) Gilmore, K., IV. Chem. Rev. 2011, 111, 6513. (b) Baldwin, J.
́
́
ez, L. A.; Miralles, A.; Merlos, M.; Garcya-
(
6
Notes
The authors declare no competing financial interest.
(
4
(
ACKNOWLEDGMENTS
■
M.K. and S.M. are thankful to CSIR-UGC for financial support.
We thank the SAIF division, CDRI, for providing the
spectroscopic and analytical data and Dr. Ranjana S. Khanna
E. J. Chem. Soc., Chem. Commun. 1976, 734. (c) Peng, A.-Y.; Ding, Y.-
X. Org. Lett. 2005, 7, 3299.
H
dx.doi.org/10.1021/jo5007762 | J. Org. Chem. XXXX, XXX, XXX−XXX