Copper-catalyzed domino synthesis of 4-oxopyrimido[1,2-a] indole derivatives

Article abstract of DOI:10.1002/adsc.201300475

A novel, convenient and efficient copper-catalyzed domino method for the synthesis of 4-oxopyrimido[1,2-a]indole derivatives has been devel-oped, and the corresponding target products were obtained in moderate to good yields. The domino re-actions involved sequential copper-catalyzed inter-molecular C-arylation, intramolecular addition of NH to nitrile and nucleophilic attack of amino to carbonyl, and the obtained N-(2-halophenyl)-3-oxo-alkanamides carry various functional groups.

Full text of DOI:10.1002/adsc.201300475

FULL PAPERS
DOI: 10.1002/adsc.201300475
Copper-Catalyzed Domino Synthesis of 4-Oxopyrimido[1,2-
N
a]indole Derivatives
Yuyuan Wang,a Ruji Wang,b Yuyang Jiang,a Chunyan Tan,a,* and Hua Fua,b,*
a
Key Laboratory of Chemical Biology (Guangdong Province), Graduate School of Shenzhen, Tsinghua University,
Shenzhen 518057, Peopleꢀs Republic of China
Fax : (+86)-10-6278-1695; e-mail: tancy@sz.tsinghua.edu.cn or fuhua@mail.tsinghua.edu.cn
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of
b
Chemistry, Tsinghua University, Beijing 100084, Peopleꢀs Republic of China
Received: May 31, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300475.
Abstract: A novel, convenient and efficient copper- NH to nitrile and nucleophilic attack of amino to
catalyzed domino method for the synthesis of 4- carbonyl, and the obtained N-(2-halophenyl)-3-oxo-
oxopyrimido
oped, and the corresponding target products were
obtained in moderate to good yields. The domino re- Keywords: C-arylation; copper-catalyzed reaction;
A
ACHTUNGTRENaNUNG lkanamides carry various functional groups.
actions involved sequential copper-catalyzed inter- domino reaction; N-heterocycles; 4-oxopyrimidoACHTUNGTRENNUNG[1,2-
molecular C-arylation, intramolecular addition of a]indoles
Introduction
treatment of cluster headache.[9] To the best of our
knowledge, N-fused compounds of pyrimidinone and
Nitrogen heterocycles are widely found in natural indole motifs, 4-oxopyrimido[1,2-a]indoles (Figure 1),
AHCTUNGTRENNUNG
products including biologically and pharmaceutically have not been developed with regard to their synthe-
active molecules.[1] The pyrimidinone derivatives are sis and biological activity thus far. Therefore, it is nec-
ubiquitous in various fields.[2] For example, they have essary to search for an efficient approach to this kind
been used as potent inhibitors of HIV integrase[3] and of compound. Recently, some important reactions
poly(ADP-ribose) polymerase-1 (PARP-1),[4] and have been developed by using copper catalyst systems
they have shown anticancer activity, antimicrobial ac- with low cost and low toxicity.[10] For example,
tivity against Streptococcus faecium, inhibition of thy- copper-catalyzed a-C-arylations have achieved signifi-
midylate synthase and dihydrofolate reductase.[5] The cant progress,[11] and some heterocycles were con-
indole core is a privileged structural motif found in structed via a-C-arylations by us[12] and other
both designed medicinal agents and natural products. groups.[13] Herein, we report a novel and efficient
The indole derivatives are antihypertensive[6] and an- copper-catalyzed approach to 4-oxopyrimido
tibiotic agents,[7] an 5-HT3 receptor antagonist used in a]indole derivatives.
the treatment of chemotherapy-induced nausea and
ACHTUNGTRENNUNG[1,2-
vomiting,[8] and an 5HT1 receptor agonist used in the
Results and Discussion
First, the reaction of N-(2-bromophenyl)-3-oxobutan-
AHCTUNGTREGaNNUN mide (1a) with ethyl 2-cyanoacetate (2b) was used as
the model to screen for experimental conditions in-
cluding catalysts, ligands, bases, solvents, temperature
and time under a nitrogen atmosphere. As shown in
Table 1, four ligands were tested for the copper cata-
lysts (20 mol%) using 10 mol% CuI as the catalyst,
three equivalents of K2CO3 as the base (relative to
the amount of 1a) in DMSO, and the reaction was
performed at 908C for 16 h (entries 1–5), thereby pi-
Figure 1. Structure of 4-oxopyrimidoACHTUNTRGNEUNG[1,2-a]indole containing
pyrimidinone and indole frameworks.
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Table 1. Copper-catalyzed reaction of N-(2-bromophenyl)-3-oxobutanamide (1a) with ethyl 2-cyanoacetate (2b) leading to
ethyl 1,4-dihydro-2-methyl-4-oxopyrimido
[1,2-a]indole-10-carboxylate (3b): optimization of the reaction conditions.[a]
AHCTUNGTRENNUNG
Entry
Catalyst
Ligand
Base
Solvent
Temperature [oC]
Yield [%][b]
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
Cu2O
CuO
L-1
L-2
L-3
L-4
L-5
–
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
K3PO4
t-BuOK
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
70
110
90
16
21
67
40
37
36
37
45
19
38
0
60
26
51
20
55
24
trace
43
63
77
L-3
L-3
L-3
L-3
L-3
L-3
L-3
L-3
L-3
L-3
L-3
L-3
L-3
L-3
L-3
9
10
11
12
13
14
15
16
17
18
19
20
21
CuACHTUNGTRENNUNG(OAc)2
–
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
1,4-dioxane
toluene
DMSO
DMSO
DMSO
[a]
Reaction conditions: N-(2-bromophenyl)-3-oxobutanamide (1a) (0.25 mmol), ethyl 2-cyanoacetate (2b) (0.375 mmol), cat-
alyst (0.025 mmol), ligand (0.05 mmol), base (0.75 mmol), solvent (2.0 mL), reaction time (16 h for entries 1–20; 24 h for
entry 21) under nitrogen atmosphere.
Isolated yield.
[b]
pecolinic acid provided the highest efficiency
(entry 3) with a small amount of the benzoxazole ap- copper-catalyzed synthesis of 4-oxopyrimido
pearing from the intramolecular coupling of N-(2-bro- a]indole derivatives (3) was investigated under our
mophenyl)-3-oxobutanamide (1a). lower yield optimized conditions (using 10 mol% CuI as the cata-
As shown in Table 2, the substrate scope for the
ACHTUNGTRENNUNG
A
(37%) was obtained in the absence of ligand lyst, 20 mol% pipecolinic acid as the ligand, three
(entry 6). Another four copper catalysts were tested equivalents of K2CO3 or two equivalents of Cs2CO3 as
(entries 7–10), and CuI gave the highest yield (com- the base, DMSO as the solvent under nitrogen atmos-
pare entries 3, 7–10). No target product was observed phere), the tested substrates afforded moderate to
in the absence of copper catalyst (entry 11). The good yields. For N-(2-halophenyl)-3-oxoalkanamides
effect of bases was investigated (compare entries 3, (1), the electronic effect of substituents on the aro-
12–15), and K2CO3 afforded the best result (entry 3). matic ring including neutral, electron-donating and
DMF, 1,4-dioxane and toluene were also used as the electron-withdrawing groups did not show the evident
solvents (entries 16–18), and they were inferior to difference in reactivity. Interestingly, N-(2-chloro-
DMSO (compare entries 3, 16–18). When reaction phenyl)-3-oxobutanamide (1i) also gave higher yields
temperature was changed into 70 or 1108C (entries 19 when the temperature was raised to 1108C using
and 20), the corresponding yields decreased. A higher Cs2CO3 as the base instead of K2CO3 (entries 23 and
yield was provided when reaction time was elongated 24). Actually, aryl chlorides were weak substrates in
to 24 h from 16 h (entry 21).
the previous Ullmann-type couplings,[10] so the results
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Copper-Catalyzed Domino Synthesis of 4-OxopyrimidoACHTUNGTRENNUNG
Table 2. Copper-catalyzed domino synthesis of 4-oxopyrimidoACHTUGNTRENNNUG
Entry
1
1
Temperature [oC]
Product 3 (Yield[b])
90
2
3
1a
1a
90
90
4
5
1a
1a
90
90
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Table 2. (Continued)
Entry
1
Temperature [oC]
Product 3 (Yield[b])
6
90
7
8
9
1b
1b
110
90
90
10
11
12
1c
1c
110
90
90
13
14
1d
90
90
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Copper-Catalyzed Domino Synthesis of 4-OxopyrimidoACTHNUGRTNEUNG[1,2-a]indole Derivatives
Table 2. (Continued)
Entry
15
1
Temperature [oC]
Product 3 (Yield[b])
1f
90
16
17
18
1f
1f
110
90
90
19
1g
1g
110
90
20
21[c]
110
110
22[c]
1h
1i
23[c]
110
110
3b (70%)
3e (67%)
24[c]
[a]
Reaction conditions: N-(2-halophenyl)-3-oxoalkanamide (1) (0.25 mmol), substituted nitrile (2) (0.375 mmol), CuI
(0.025 mmol), pipecolinic acid (0.05 mmol), K2CO3 (0.75 mmol), DMSO (2.0 mL), reaction time (24 h) under a nitrogen
atmosphere.
[b]
[c]
Isolated yield.
N-(2-Halophenyl)-3-oxoalkanamide (1) (0.5 mmol), substituted nitrile (2) (0.75 mmol), CuI (0.05 mmol), pipecolinic acid
(0.1 mmol), Cs2CO3 (1 mmol), DMSO (2.0 mL), reaction time (24 h) under a nitrogen atmosphere.

Yuyuan Wang et al.
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The target products carry ester or cyano groups,
which is favourable for their further modification.
Compound 3v as a white powder was dissolved in
DMSO at 708C, and the resulting solution was cooled
to room temperature. After static standing for 24 h,
a single crystal of 3v appeared, and its structure was
determined by X-ray diffraction analysis at room tem-
perature (Figure 2).[14] We found 3v complexing one
DMSO, and the trifluoromethyl group was diorienta-
À
tionally disordered because of the rotation of C C
single bond at room temperature, which was repre-
sented by F(1), F(2), F(3) and F(1’), F(2’), F(3’), re-
spectively. Therefore, the structure of 3v was unam-
biguously confirmed (see the Supporting Information
for details).
A possible mechanism for the copper-catalyzed syn-
thesis of 4-oxopyrimidoACTHNUTRGNE[NUG 1,2-a]indole derivatives is
proposed in Scheme 1. First, copper-catalyzed C-ary-
lation of substituted nitrile (2) with 1 afforded I, and
intramolecular addition of NH to CN in I leads to II
in the presence of base (K2CO3). Isomerization of II
affords III, nucleophilic attack of amino to carbonyl
in III gives imine (IV), and transfer of the double
bond in IV provides the target product (3).
Conclusions
We have developed a novel, convenient and efficient
copper-catalyzed method for the synthesis of 4-
oxopyrimidoACTHUNTGRNEUNG[1,2-a]indole derivatives. The protocol
uses inexpensive CuI as the catalyst, pipecolinic acid
as the ligand, readily available substituted N-(2-halo-
phenyl)-3-oxoalkanamides, alkyl 2-cyanoacetates and
malononitrile as the starting materials, and the corre-
Figure 2. Crystal structure of compound 3v.[14]
exhibited ortho-substituent effect of 3-oxoalkana- sponding 4-oxopyrimidoACTHNUTRGNE[NUG 1,2-a]indole derivatives were
mides in 1i. For nitriles (2), malononitrile (2e) (en- obtained in moderate to good yields. The domino re-
tries 5, 8, 11, 17, 20, 22 and 24) afforded higher yields actions comprised sequential copper-catalyzed inter-
than alkyl 2-cyanoacetates (2a–d). The reactions molecular C-arylation, intramolecular addition of NH
showed good tolerance of functional groups including to nitrile and nucleophilic attack of amino to carbon-
À
ester groups, amides, C Br bond (entries 18–20), and yl, and the synthesized N-(2-halophenyl)-3-oxoalkan-
trifluoromethyl (entries 21 and 22) in the substrates.
ACHTUNGTRENNaUNG mides carry various functional groups.
Scheme 1. Possible mechanism for copper-catalyzed synthesis of 4-oxopyrimidoACTHNUGTRNEUNG[1,2-a]indoles.
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Copper-Catalyzed Domino Synthesis of 4-OxopyrimidoACTHNUGRTNEUNG[1,2-a]indole Derivatives
solid; mp >2508C; 1H NMR (DMSO-d6, 300 MHz): d=
13.13 (s, 1H), 8.77 (s, 1H), 7.69–7.65 (m, 2H), 5.77 (s, 1H),
2.34 (s, 3H); 13C NMR (DMSO-d6, 75 MHz): d=158.9,
152.8, 145.6, 130.9, 127.9, 125.3 (q, J=271.7 Hz) 122.5 (q, J=
31.8 Hz), 122.1, 118.0, 114.6, 113.3, 98.6, 66.7, 19.2; ESI-MS:
m/z=291.3 [M+H]+.
Experimental Section
General Procedure for the Synthesis of Compounds
3a–t using 1a–g as the Substrates
A 25-mL Schlenk tube was charged with a magnetic stirrer
and DMSO (2.0 mL). CuI (0.025 mmol, 4.8 mg), pipecolic
acid (0.05 mmol, 6.4 mg), K2CO3 (0.75 mmol, 104 mg), N-(2-
halophenyl)-3-oxoalkanamide (1) (0.25 mmol), and substi-
tuted nitrile (2) (0.375 mmol) were added to the tube. The
reaction was performed at 90 or 1108C for 24 h under a ni-
trogen atmosphere in the sealed tube (see Table 2 for de-
tails). After being cooled to room temperature, the mixture
was poured into 10 mL of water, and the resulting solution
was extracted with ethyl acetate (3ꢂ10 mL). The combined
organic layer was concentrated, and the residue was purified
by flash chromatography on silica gel (eluent: petroleum
ether/ethyl acetate=5:1 to 1:1) to afford the target products
3a–t.
Acknowledgements
The authors wish to thank the National Natural Science
Foundation of China (Grant Nos. 21172128 and 21221062),
and the Ministry of Science and Technology of China (Grant
No. 2012CB722605) for financial support.
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General Procedure for the Synthesis of Compounds
3b, 3e, 3u and 3v using 1h and 1i as the Substrates
A 25-mL Schlenk tube was charged with a magnetic stirrer
and DMSO (2.0 mL). CuI (0.05 mmol, 9.6 mg), pipecolic
acid (0.10 mmol, 12.8 mg), Cs2CO3 (1 mmol, 326 mg), N-(2-
halophenyl)-3-oxoalkanamide (1) (0.5 mmol), and substitut-
ed nitrile (2) (0. 75 mmol) were added to the tube. The reac-
tion was performed at 1108C for 24 h under a nitrogen at-
mosphere in the sealed tube (see Table 2 for details). After
being cooled to room temperature, the mixture was poured
into 10 mL of water, and the resulting solution was extracted
with ethyl acetate (3ꢂ10 mL). The combined organic layer
was concentrated, and the residue was purified by flash
chromatography on silica gel (eluent: petroleum ether/ethyl
acetate=5:1 to 1:1) to afford the target products 3b, 3e, 3u
and 3v). Three representative examples are presented
below.
Butyl 2-methyl-4-oxo-1,4-dihydropyrimidoACTHUNRTGNEUNG[1,2-a]indole-
10-carboxylate (3c): Eluent: petroleum ether/ethyl acetate
1
(3:1); yield: 54 mg (73%); colorless oil; H NMR (CDCl3,
300 MHz): d=10.01 (s, 1H), 8.64 (d, 1H, J=8.3 Hz), 7.92
(d, 1H, J=7.9 Hz), 7.41 (t, 1H, J=7.2 Hz), 7.29 (t, 1H, J=
7.2 Hz), 5.66 (s, 1H), 4.38 (t, 2H, J=6.5 Hz), 2.34 (s, 3H),
1.88–1.78 (m, 2H), 1.61–1.49 (m, 2H), 1.02 (t, 3H, J=
7.4 Hz); 13C NMR (CDCl3, 75 MHz): d=166.9, 159.4, 148.3,
143.5, 129.9, 125.7, 125.4, 122.3, 119.5, 116.3, 99.2, 87.8, 64.2,
31.1, 19.7, 19.5, 13.9; ESI-MS: m/z=299.6 [M+H]+.
Butyl 8-bromo-2-methyl-4-oxo-1,4-dihydropyrimidoACHTUNTRGNEUNG[1,2-
a]indole-10-carboxylate (3s): Eluent: petroleum ether/ethyl
acetate (5:1 to 3:1); yield: 58 mg (62%); white solid; mp
187–1898C; 1H NMR (CDCl3, 300 MHz): d=9.99 (s, 1H),
8.49 (d, 1H, J=8.6 Hz), 8.01 (d, 1H, J=1.4 Hz), 7.37 (dt,
1H, J=8.8 Hz, J=1.9 Hz), 5.70 (s, 1H), 4.39 (t, 2H, J=
6.71 Hz), 2.39 (s, 3H), 1.89–1.79 (m, 2H), 1.61–1.48 (m, 2H),
1.04 (t, 3H, J=7.4 Hz); 13C NMR (CDCl3, 75 MHz): d=
166.4, 158.9, 148.6, 143.9, 128.5, 127.4, 125.2, 122.3, 119.2,
117.6, 99.5, 87.4, 64.4, 31.1, 19.9, 19.5, 13.9; ESI-MS: m/z=
379.0 [M+H]+.
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Copper-Catalyzed Domino Synthesis of 4-Oxopyrimido
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Adv. Synth. Catal. 2013, 355, 1 – 9
Yuyuan Wang, Ruji Wang, Yuyang Jiang, Chunyan Tan,*
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