Copper-Catalyzed Domino Synthesis of Benzo[4,5]imidazo[1,2-a]pyrimidin-4(10H)-ones using Cyanamide as a Building Block

Article abstract of DOI:10.1002/adsc.201500577

An efficient and practical copper-catalyzed domino synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-4(10H)-ones has been developed. The protocol uses N-(2-halophenyl)-3-alkylpropiolamides and cyanamide as the starting materials, inexpensive copper(I) iodide and pipecolinic acid as the catalyst and ligand, and the corresponding products were obtained in moderate to good yields.

Full text of DOI:10.1002/adsc.201500577

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DOI: 10.1002/adsc.201500577
Copper-Catalyzed Domino Synthesis of Benzo[4,5]imidazo[1,2-
a]pyrimidin-4(10H)-ones using Cyanamide as a Building Block
Zhenbang Lou,a,b Xudong Wu,b Haijun Yang,b Changjin Zhu,a and Hua Fua,b,*
a
Department of Applied Chemistry, Beijing Institute of Technology, Beijing 100081, Peopleꢀs Republic of China
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of
b
Chemistry, Tsinghua University, Beijing 100084, Peopleꢀs Republic of China
Fax: (+86)-10-6278-1695; e-mail: fuhua@mail.tsinghua.edu.cn
Received: June 15, 2015; Revised: August 27, 2015; Published online: November 26, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500577.
Abstract: An efficient and practical copper-catalyzed ligand, and the corresponding products were ob-
domino synthesis of benzo[4,5]imidazo[1,2-a]pyrimi- tained in moderate to good yields.
din-4(10H)-ones has been developed. The protocol
uses N-(2-halophenyl)-3-alkylpropiolamides and cy- Keywords:
benzo[4,5]imidazo[1,2-a]pyrimidin-
anamide as the starting materials, inexpensive cop- 4(10H)-ones; copper; cyanamide; domino reaction;
per(I) iodide and pipecolinic acid as the catalyst and synthetic methods
Introduction
for the synthesis of benzo[4,5]imidazo[1,2-a]pyrimi-
din-4(10H)-ones (Scheme 1b).
Nitrogen-containing heterocycles widely occur in nat-
ural products as well as biologically and pharmaceuti-
cally active molecules[1] and they have been assigned Results and Discussion
as privileged structures in drug development.[2] Benz-
imidazoles are often found in enzyme inhibitors,[3] The reaction of N-(2-bromophenyl)-3-phenylpropiol-
drugs,[4] dyes,[5] and polymers.[6] The pyrimidinone unit amide (1a) with cyanamide leading to 2-phenylben-
is a key motif in various fields.[7] For example, they zo[4,5]imidazo[1,2-a]pyrimidin-4(10H)-one (2a) was
are used as the potent inhibitors of HIV integrase[8] applied as the model to optimize conditions including
and poly(ADP-ribose) polymerase-1 (PARP-1),[9] and catalysts, ligands, bases, solvents and temperature
they also exhibit anticancer and antimicrobial activi-
ties, inhibition of thymidylate synthase and dihydrofo-
late reductase.[10] Nitrogen-used molecules with both
benzimidazole and pyrimidinone motifs, namely ben-
zo[4,5]imidazo[1,2-a]pyrimidin-4(10H)-ones
(Scheme 1), are valuable molecules, and they show
antimicrobial, antitumor and anticancer activities.[11]
However, the methods for their preparation are very
limited, and the common route is through the reaction
of substituted 5-aminobenzimidazoles with b-keto
esters (Scheme 1a).[11,12] Unfortunately, many draw-
backs are found such as long reaction times, drastic
conditions, tedious experimental procedure and low
yields. Therefore, it is necessary to develop an effi-
cient approach to this kind of compounds. Recently,
many useful reactions have been developed using
copper catalyst systems with low cost and low toxici-
ty,[13] and nitrogen heterocycles were prepared by us
Scheme 1. Synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-
4(10H)-ones. (a) The previous common method. (b) Our
and other groups.[14,15] Herein, we report a novel, effi-
cient and practical copper-catalyzed domino method strategy under copper-catalyzed conditions.
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Table 1. Optimization of the conditions for copper-catalyzed synthesis of 2-phenylbenzo[4,5]imidazo[1,2-a]pyrimidin-4(10H)-
one (2a) via reaction of N-(2-bromophenyl)-3-phenylpropiolamide (1a) with cyanamide.[a]
Entry
Catalyst
Ligand
Base
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
CuCl
CuBr
CuI
Cu2O
CuBr2
Cu(OAc)2
Cu(OTf)2
–
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-1
L-2
L-3
L-4
L-5
L-6
L-7
L-2
L-2
L-2
L-2
L-2
L-2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
DMSO
MeCN
DMF
71
75
77
57
72
68
76
0
84
72
54
53
50
52
54
46
80
82
76
67c
9
10
11
12
13
14
15
16
17
18
19
20
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
[a]
Reaction conditions: under nitrogen atmosphere, N-(2-bromophenyl)-3-phenylpropiolamide (1a) (0.2 mmol), cyanamide
(0.4 mmol), catalyst (0.02 mmol), ligand (0.02 mmol), base (0.4 mmol), solvent (3.0 mL), reaction temperature: 1208C, re-
action time: 12 h, in a sealed Schlenk tube.
Isolated yield.
Reaction temperature: 808C.
[b]
[c]
under a nitrogen atmosphere. As shown in Table 1, creased when the reaction temperature was lowered
seven copper catalysts were screened using l-proline to 808C (entry 20).
as the ligand, Cs2CO3 as the base, DMF as the solvent
After defining the optimized conditions, the scope
at 1208C for 12 h (entries 1–7), and they provided 57– of this copper-catalyzed synthesis of benzo[4,5]imid-
76% yields, whereby CuI was the most efficient cata- azo[1,2-a]pyrimidin-4(10H)-ones (2) was investigated.
lyst (entry 3). No target product was found in the ab- As shown in Table 2, the examined substrates provid-
sence of a copper catalyst (entry 8). Other ligands ed moderate to good yields. For the substituent R1,
were investigated (entries 9–14), and pipecolinic acid the substrates (1) with neutral and electron-donating
(PA, L-2) was found to be a suitable ligand (entry 9). groups provided higher yields than those with elec-
K2CO3 and K3PO4 were attempted as the bases (en- tron-withdrawing groups (see entries 1, 3 and 6). For
tries 15 and 16), and they were inferior to Cs2CO3. the substituent R2, the substrates (1) with aryl groups
Effect of solvents was explored (compare entries 9, gave the better results than those with alkyl groups
17–19), and DMF was a suitable solvent. Yields de- (see entries 18–20). For halogen X, aryl bromides
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Copper-Catalyzed Domino Synthesis of Benzo[4,5]imidazo[1,2-a]pyrimidin-4(10H)-ones
Table 2. Copper-catalyzed synthesis of benzo[4,5]imidazo[1,2-a]pyrimidin-4(10H)-ones (2).[a]
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Table 2. (Continued)
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Copper-Catalyzed Domino Synthesis of Benzo[4,5]imidazo[1,2-a]pyrimidin-4(10H)-ones
Table 2. (Continued)
[a]
Reaction conditions: under nitrogen atmosphere, substituted N-(2-halophenyl)-3-alkylpropiolamide (1) (0.2 mmol), cyan-
amide (0.4 mmol), CuI (0.02 mmol), pipecolinic acid (PA) (0.02 mmol), Cs2CO3 (0.4 mmol), DMF (3.0 mL), reaction tem-
perature: 120 or 1508C, reaction time: 12 or 20 h, in a sealed Schlenk tube.
[b]
Isolated yield.
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Scheme 2. (a) Reaction of N-(2-bromophenyl)acetamide (3)
with cyanamide under the standard conditions. (b) Reaction
of 3-phenyl-N-p-tolylpropiolamide (4) with cyanamide in
the presence of base.
Scheme 3. Possible mechanism for the copper-catalyzed syn-
thesis of benzo[4,5]imidazo[1,2-a]pyrimidin-4(10H)-one de-
rivatives.
showed higher reactivity than aryl chlorides, but aryl
chlorides also afforded the reasonable yields when nism is suggested in Scheme 3 according to the results
the reaction temperature was raised and time was ex- above. First, Michael addition of cyanamide to 1 in
tended (see entries 21 and 22). The copper-catalyzed the presence of base (Cs2CO3) gives I, then nucleo-
synthesis
of
benzo[4,5]imidazo[1,2-a]pyrimidin- philic attack of NH to the cyano group in I produces
4(10H)-ones (2) could tolerate some functional II, and isomerization of II leads to III. Finally,
À
À
groups including C Cl bond (entries 4, 15–17), C Br a copper-catalyzed intramolecular Ullmann-type cou-
bond (entry 5), CF3 (entry 6), and ether (entries 12– pling furnishes the target product (2) in the presence
14).
In order to explore the reaction mechanism, two
of pipecolinic acid (L-2) as the ligand.[16]
We have extended the applications of the present
control experiments were performed (Scheme 2). As method. As shown in Scheme 4, a three-component
shown in Scheme 2a, reaction of N-(2-bromophenyl)- reaction of N-(2-bromophenyl)-3-phenylpropiolamide
acetamide (3) with cyanamide did not work under the (1a), cyanamide and bromobenzene (6) was carried
standard conditions. Treatment of 3-phenyl-N-p-tolyl- out under the standard conditions. Interestingly, prod-
propiolamide (4) with cyanamide in the presence of uct 7 was obtained in 52% yield, and the reaction un-
base (Cs2CO3) provided 2-amino-6-phenyl-3-p-tolyl- derwent sequential base-mediated and copper-cata-
pyrimidin-4(3H)-one (5) in 80% yield (Scheme 2b), lyzed formation of 2a from treatment of 1a with cyan-
and the result showed that the copper-catalyzed syn- amide, and copper-catalyzed Ullmann-typed coupling
thesis of benzo[4,5]imidazo[1,2-a]pyrimidin-4(10H)- of 2a with 6. Therefore, the three-component method
ones (2) initiated from Michael addition of cyanamide can provide diverse dihydrobenzo[4,5]imidazo[1,2-
to propiolamide in 1. Therefore, a possible mecha- a]pyrimidin-4(10H)-ones.
Scheme 4. Three-component reaction of N-(2-bromophenyl)-3-phenylpropiolamide (1a), cyanamide and bromobenzene (6).
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Copper-Catalyzed Domino Synthesis of Benzo[4,5]imidazo[1,2-a]pyrimidin-4(10H)-ones
2-(4-Chlorophenyl)-8-methylbenzo[4,5]imidazo[1,2-a]pyr-
Conclusions
imidin-4(10H)-one (2q): Eluent: DCM/PE/MeOH (5:5:1);
isolated yield: 67% (41.5 mg); yellow solid; mp 170–1728C;
1H NMR (400 MHz, DMSO-d6): d=8.31 (d, J=8.2 Hz, 1H),
8.00 (d, J=8.1 Hz, 2H), 7.32–7.27 (m, 3H), 7.14 (d, J=
8.2 Hz, 1H), 6.56 (s, 1H), 2.46 (s, 3H); 13C NMR (76 MHz,
DMSO-d6): d=161.1, 160.2, 150.0, 146.7, 136.5, 135.1, 131.3,
128.6 (2”CH), 127.5 (2”CH), 124.3, 123.3, 115.8, 111.5,
97.1, 21.9. ESI-MS: m/z=310.1, C17H13ClN3O [M+H]+.
We have developed a simple, efficient and practical
copper-catalyzed domino synthesis of benzo[4,5]im-
idazo[1,2-a]pyrimidin-4-ones, and the corresponding
target products were prepared in moderate to good
yields. The protocol uses N-(2-halophenyl)-3-alkylpro-
piolamides and cyanamide as the starting materials,
inexpensive CuI and pipecolinic acid as the catalyst
system, and the domino reactions underwent the se-
quential base-mediated Michael addition, nucleophilic
attack of NH to cyano and copper-catalyzed Ull-
mann-type coupling. The method exhibited some tol-
erance of functional groups, and the three-component
reaction extended the diversity of benzo[4,5]imid-
azo[1,2-a]pyrimidin-4(10H)-ones. Therefore, the pres-
ent method provides a novel strategy for synthesis of
nitrogen heterocycles.
Acknowledgements
The authors wish to thank the National Natural Science
Foundation of China (Grant Nos. 21172128, 21372139 and
21221062), and the Ministry of Science and Technology of
China (Grant No. 2012CB722605) for financial support.
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(0.4 mmol, 16.8 mg). The tube was evacuated and recharged
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8-Methyl-2-phenylbenzo[4,5]imidazo[1,2-a]pyrimidin-
4(10H)-one (2b): Eluent: DCM/PE/MeOH (5:5:1); isolated
yield: 87% (47.8 mg) for X=Br in substrate 1; 60% (33 mg)
for X=Cl in substrate 1; yellow solid; mp 297–2998C;
1H NMR (400 MHz, DMSO-d6): d=8.32 (d, J=8.2 Hz, 1H),
8.10 (dd, J=6.6, 3.1 Hz, 2H), 7.53–7.47 (m, 3H), 7.31 (s,
1H), 7.14 (d, J=8.1 Hz, 1H), 6.60 (s, 1H), 2.46 (s, 3H);
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137.5, 136.4, 130.9, 130.6, 129.1 (2”CH), 127.4 (2”CH),
124.1, 123.2, 115.7, 111.5, 97.3, 21.7; ESI-MS: m/z=276.1,
C17H14N3O [M+H]+.
2-(p-Tolyl)benzo[4,5]imidazo[1,2-a]pyrimidin-4(10H)-one
(2g): Eluent: DCM/PE/MeOH (5:5:1); isolated yield: 88%
1
(48.4 mg); yellow solid; mp 292–2938C; H NMR (400 MHz,
DMSO-d6): d=8.42 (d, J=8.0 Hz, 1H), 7.96 (d, J=7.9 Hz,
2H), 7.44 (s, 2H), 7.27 (dd, J=12.4, 5.5 Hz, 3H), 6.53 (s,
1H), 2.31 (s, 3H); 13C NMR (101 MHz, DMSO-d6): d=
160.6, 159.8, 149.5, 140.1, 134.2, 130.7, 129.3 (2”CH), 127.0
(2”CH), 126.1, 125.8, 121.8, 115.7, 111.1, 96.5, 20.9; ESI-
MS:m/z=276.1, C17H14N3O [M+H]+ .
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