A simple copper-catalyzed cascade synthesis of 2-amino-1H-indole-3- carboxylate derivatives

Article abstract of DOI:10.1002/adsc.200900887

We have developed a simple and efficient copper-catalyzed method for the synthesis of 2-amino-1H-indole-3-carboxylate derivatives via cas-cade reactions of substituted N-(2-halophenyl)-2, 2, 2-trifluoroacetamide with alkyl 2-cyanoacetate or malononitrile under mild conditions, and the method is of wide practical application.

Full text of DOI:10.1002/adsc.200900887

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DOI: 10.1002/adsc.200900887
A Simple Copper-Catalyzed Cascade Synthesis of 2-Amino-1H-
indole-3-carboxylate Derivatives
Xiaobo Yang,a,b Hua Fu,a,* Renzhong Qiao,b,* Yuyang Jiang,a,c and Yufen Zhaoa
a
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of
Chemistry, Tsinghua University, Beijing 100084, Peopleꢀs Republic of China
Fax : (+ 86)-10-6278-1695; e-mail: fuhua@mail.tsinghua.edu.cn
State Key Laboratory of Chemical Resource Engineering, Department of Pharmaceutical Engineering, College of Life
b
Science and Technology, Beijing University of Chemical Technology, Beijing 100029, Peopleꢀs Republic of China
E-mail: qiaorz@mail.buct.edu.cn
Key Laboratory of Chemical Biology (Guangdong Province), Graduate School of Shenzhen, Tsinghua University,
c
Shenzhen 518057, Peopleꢀs Republic of China
Received: December 21, 2009; Revised: March 19, 2010; Published online: April 7, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900887.
Abstract: We have developed a simple and efficient lononitrile under mild conditions, and the method is
copper-catalyzed method for the synthesis of 2- of wide practical application.
amino-1H-indole-3-carboxylate derivatives via cas-
cade reactions of substituted N-(2-halophenyl)-2,2,2- Keywords: 2-amino-1H-indole-3-carboxylates; cas-
trifluoroacetamide with alkyl 2-cyanoacetate or ma- cade reactions; copper; nitrogen heterocycles; syn-
thetic methods
Introduction
Some approved drugs have this core in their struc-
tures, for example, the 5-HT3 receptor antagonist on-
Nitrogen-containing heterocyclic compounds in the dansetron (4) used for the treatment of chemothera-
form of biologically active drugs or agents play an im- py-induced nausea and vomiting,[4] the 5HT1 receptor
portant role in the pharmaceutical and agrochemical agonist sumatriptan (5) used for the treatment of clus-
industries.[1] The indole core is a privileged structural ter headache.[5] The diversity of indole-based mole-
motif found in both designed medicinal agents and in cules found in naturally occurring alkaloids as well as
natural products. As shown in Figure 1, the neuro- their biological and pharmaceutical relevance have
transmitter serotonin [1, 5-hydroxytryptamine, (5- stimulated research into the development of new
HT)], the antihypertensive reserpine (2),[2] and the strategies for the synthesis of readily functionalized
antibiotic indolmycin (3)[3] are indole derivatives. indole ring systems.[6] In comparison to classical
Figure 1. Relevant biologically active molecules with an indole moiety.
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Xiaobo Yang et al.
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indole synthetic methods,[7] the transition metal-cata- structed via the Ullmann-type couplings by us[16] and
lyzed strategy has the advantages of increased func- other research groups.[17] Herein, we report a simple,
tional group tolerance, as well as providing indoles convenient one-pot copper-catalyzed cascade method
with greater structural diversity and often higher for the synthesis of 2-amino-1H-indole-3-carboxylate
overall yields.[8,9] The 2-amino-1H-indole-3-carboxyl- derivatives under mild conditions.
ate derivatives are found to be biologically active
molecules and important intermediates for construc-
tion of medicinal molecules.[10,11] Unfortunately, only a Results and Discussion
few of examples were reported for their synthe-
ACHTUNGTRENNUNG
sis,[11a,12] and the starting materials often are not readily Initially, N-(2-bromophenyl)-2,2,2-trifluoroacetamide
available and difficult to prepare. Volovenko et al. at- and ethyl 2-cyanoacetate were chosen as the model
tempted a synthesis of 2-amino-6-nitroindoles via the substrates to optimize reaction conditions including
reaction of 2-halo-5-nitroanilines and substituted ace- the catalysts, bases and solvents under nitrogen at-
tonitriles,[13] the result showed that only 2-fluoro-5-ni- mosphere. As shown in Table 1, four copper catalysts
troaniline containing a strong electron-withdrawing (10 mol% amount) were tested at 608C using
group (nitro) was effective, however, other 2-haloani- 20 mol% l-proline as the ligand, 2 equiv. of K2CO3 as
lines did not work, so the method could not construct the base [relative to the amount of N-(2-bromophen-
diverse 2-amino-1H-indole derivatives. Recently, yl)-2,2,2-trifluoroacetamide] in the mixed solvent of
great progress for copper-catalyzed Ullmann-type DMSO and water (volume ratio 1:1) (entries 1–4),
couplings has been made,[14] and we have also devel- and CuI showed the highest activity (entry 1). We at-
oped some copper catalyst systems that were used in tempted other ligands (entries 5–7), and l-proline was
N-arlyations.[15] Some N-heterocycles have been con- proved to be the most effective. A 61% yield of the
Table 1. Copper-catalyzed cascade coupling of N-(2-bromophenyl)-2,2,2-trifluoroacetamide with ethyl 2-cyanoacetate to
ethyl 2-amino-1H-indole-3-carboxylate: optimization of the reaction conditions.[a]
Entry
Cu catalyst
Ligand
Base
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
CuI
CuBr
L1
L1
L1
L1
L2
L3
L4
–
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMF/H2O
84
67
45
39
69
26
16
61
0
0
82
43
29
27
Cu
N
Cu
CuI
CuI
CuI
CuI
–
9
L1
–
10
11
12
13
14
15
16
–
CuI
CuI
CuI
CuI
CuI
CuI
L1
L1
L1
L1
L1
L1
CH3CN/H2O
dioxane/H2O
toluene/H2O
DMSO/H2O
trace
trace[c]
[a]
Reaction conditions: N-(2-bromophenyl)-2,2,2-trifluoroacetamide (0.5 mmol), ethyl 2-cyanoacetate (0.6 mmol), catalyst
(0.05 mmol), ligand (0.1 mmol), base (1 mmol), water (0.5 mL), the other solvent (0.5 mL), reaction temperature (608C)
under nitrogen atmosphere, reaction time (12 h).
Isolated yield.
Using N-(2-bromophenyl)acetamide as the substrate.
[b]
[c]
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A Simple Copper-Catalyzed Cascade Synthesis of 2-Amino-1H-indole-3-carboxylate Derivatives
Scheme 1. Possible mechanism of formation of 2-amino-1H-indole-3-carboxylate derivatives.
target product was obtained in the absence of ligand
ACHTUNGTRENaNGNU mide provided higher yields than N-(2-bromophen-
(entry 8), which implies an ortho-substituent effect of yl)-2,2,2-trifluoroacetamide (compare entries 1–4 and
À
the NHCOCF3 group (see reaction mechanism in 17–20). Interestingly, reactions of N-(2,4-dibromo-
Scheme 1). However, no target product was observed phenyl)-2,2,2-trifluoroacetamide with alkyl 2-cyano-
in the absence of copper catalyst (entry 9) or copper
ACHTUNGTRENaNGNU cetates or malononitrile only occurred at the ortho-
À
À
catalyst/ligand (entry 10). The reactivity slightly de- sited C Br bond of the NHCOCF3 group which in-
creased when K2CO3 was replaced with Cs2CO3 as the dicated a copper-catalyzed ortho-substituent effect
base (compare entries 1 and 11). Several mixed sol- (see reaction mechanism in Scheme 1). For alkyl 2-cy-
vents, DMF/H2O, CH3CN/H2O, dioxane/H2O and tol- anoacetates and malononitrile, malononitrile showed
uene/H2O, were screened, and DMSO/H2O was found higher reactive activity than alkyl 2-cyanoacetates. It
to be the most effective (compare entries 1, 12–15). is worthwhile to note that water was not added until
The reaction temperature was also changed, and 608C the Ullmann-type coupling was completed (TLC de-
À
was the best choice. When the group NHCOCF3 in termination) when methyl 2-cyanoacetate was used as
the N-(2-halophenyl)-2,2,2-trifluoroacetamide was re- the substrate because a small amount of the methyl
À
placed with NHCOMe (entry 16), only a trace ester could be hydrolyzed under a long-term incuba-
amount of the target product was observed. A possi- tion of an aqueous base system.
À
ble reason is that group COCF3 is of stronger elec-
tron-withdrawing power compared with COCH3, with ethyl 2-cyanoacetate (2b) under our standard
which is helpful for C-arylation (see intermediate IV conditions, but it did not work even when the reaction
We attempted the reaction of 2-bromoaniline (4)
À
À
in Scheme 1), and deprotection of the group COCF3 temperature was raised to 1008C (Figure 2). There-
is easier than for COCH3 in aqueous base medium fore, a possible formation mechanism of 2-amino-1H-
after intermediate VI in Scheme 1 is formed.
À
indole-3-carboxylate derivatives was proposed in
The scope of the copper-catalyzed cascade reactions Scheme 1 according to the results mentioned above
of substituted N-(2-halophenyl)-2,2,2-trifluoroacet- and the ortho-substituent effect.[18] Complexation of
ACHTUNGTRENNUNGamides with alkyl 2-cyanoacetates or malononitrile l-proline with CuI in the presence of base (K2CO3)
was investigated under optimized condition (10 mol% forms the coordinated CuL, and treatment of CuL
CuI as the catalyst, 20 mol% l-proline as the ligand, with substituted N-(2-halophenyl)-2,2,2-trifluoroaceta-
2 equiv. of K2CO3 as the base). As shown in Table 2, mide forms complex I. The oxidative adduct of I gives
most of the substrates examined provided good yields II releasing the ligand. Conjugation of II with depro-
at 608C. For the substituted N-(2-halophenyl)-2,2,2- tonated alkyl 2-cyanoacetate or malononitrile in the
trifluoroacetamides, the electronic effect of the sub- presence of base provides III, and reductive elimina-
stituent groups could affect the reactivity of the sub- tion of III gives the coupling product IV. Addition of
À
strates. For example, N-[2-bromo-5-(trifluoromethyl)- N H of NHCOCF3 to CN in IV produces intermedi-
phenyl]-2,2,2-trifluoroacetamide containing an elec- ate V, isomerization of V leads to VI, and hydrolysis
tron-withdrawing group (CF3) showed higher reaction of VI in the presence of base affords the desired
rates than the substrates containing electron-rich, target product (3).
neutral groups. N-(2-Iodophenyl)-2,2,2-trifluoroacet-
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Xiaobo Yang et al.
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Table 2. Copper-catalyzed synthesis of 2-amino-1H-indole-3-carboxylate derivatives.[a]
Entry
1
1
2
Product (3)
Yield [%][b]
71
2
3
4
5
1a
1a
1a
84
81
85
75
2a
6
1b
1b
1b
2b
2c
2d
2a
2b
2c
2d
87
74
92
65
73
73
72
7
8
9
10
11
12
1c
1c
1c
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A Simple Copper-Catalyzed Cascade Synthesis of 2-Amino-1H-indole-3-carboxylate Derivatives
Table 2. (Continued)
Entry
1
2
Product (3)
Yield [%][b]
72
13
2a
14
15
16
1d
1d
1d
2b
2c
2d
85
79
93
17
2a
3a
73
18
19
20
1e
1e
1e
2b
2c
2d
3b
3c
3d
87
83
97
[a]
Reaction conditions: substituted N-(2-bromophenyl)-2,2,2-trifluoroacetamide (0.5 mmol), alkyl 2-cyanoacetate
(0.6 mmol), malononitrile (0.6 mmol), CuI (0.05 mmol), l-proline (0.1 mmol), K2CO3 (1 mmol), DMSO (0.5 mL), H2O
(0.5 mL), reaction temperature (608C), reaction time (12 h for entries 1–12 and 17–20; 9 h for entries 13–16).
Isolated yield.
[b]
Experimental Section
General Procedure for Synthesis of Compounds 3a–p
A 10-mL round-bottom flask was charged with a magnetic
stirrer and DMSO (0.5 mL) and water (0.5 mL) [water was
not added until the Ullmann-type coupling was completed
(TLC determination) when methyl 2-cyanoacetate was used
as the substrate], substituted N-(2-halophenyl)-2,2,2-tri-
Figure 2. Reaction of 2-bromoaniline (4) with ethyl 2-cya-
noacetate (2b) under our standard conditions.
AHCTUNGTREGfNNNU luoroacetamide (1) (0.5 mmol), alkyl 2-cyanoacetates or
malononitrile (2) (0.6 mmol), l-proline (0.1 mmol, 12 mg)
and K2CO3 (1 mmol, 138 mg), after stirring of the mixture
for 15 min under nitrogen atmosphere, and CuI (0.05 mmol,
10 mg) was added to the flask. The mixture was stirred at
608C for 9 h or 12 h under a nitrogen atmosphere. The re-
sulting mixture was cooled to room temperature and fil-
tered. The solid was washed with methanol two times (2ꢂ
3 mL), and the combined filtrate was concentrated on the
rotary evaporator, and the residue was purified by column
chromatography on silica gel using petroleum ether/ethyl
acetate (1:1 to 1:2) as eluent to give the desired product.
Conclusions
We have developed a simple and efficient method for
the synthesis of 2-amino-1H-indole-3-carboxylate de-
rivatives. The cascade reactions of substituted N-(2-
halophenyl)-2,2,2-trifluoroacetamide with alkyl 2-cya-
noacetate or malononitrile were performed well
under mild conditions, the corresponding indole de-
rivatives containing amino and carboxylate groups
were obtained in good yields, and they are biological-
ly active molecules and important intermediates for
the construction of medicinal molecules. The present
method shows practical advantages over the previous
methods and its starting materials are readily avail-
able, so it will provide an opportunity for the con-
struction of diverse and useful molecules in organic
chemistry and medicinal chemistry.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Grant Nos. 20672065, 20732004,
20872010, 20972083), Chinese 863 Project (Grant Nos.
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Xiaobo Yang et al.
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