Cupric halide-mediated intramolecular halocyclization of N-electron-withdrawing group-substituted 2-alkynylanilines for the synthesis of 3-haloindoles

Article abstract of DOI:10.1002/adsc.200900609

A convenient and efficient method for the synthesis of 3-haloindoles has been developed. Both 3-chloro-and 3-bromoindole derivatives can be obtained in high yields by the reaction of N-electron-withdrawing group-substituted 2-alkynylanilines with cupric h

Full text of DOI:10.1002/adsc.200900609

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DOI: 10.1002/adsc.200900609
Cupric Halide-Mediated Intramolecular Halocyclization of N-
Electron-Withdrawing Group-Substituted 2-Alkynylanilines for
the Synthesis of 3-Haloindoles
Zengming Shena and Xiyan Lua,*
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-64166128; e-mail: xylu@mail.sioc.ac.cn
Received: September 3, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900609.
Abstract: A convenient and efficient method for
the synthesis of 3-haloindoles has been developed.
Both 3-chloro- and 3-bromoindole derivatives can
be obtained in high yields by the reaction of N-elec-
tron-withdrawing group-substituted 2-alkynylani-
lines with cupric halide in dimethyl sulfoxide
(DMSO) within a short period of time. Investiga-
tion of the reaction mechanism reveals that two
equivalents of cupric halide are necessary.
action of 2-alkynylanilines in the presence of CuX2
(3 equiv., X=Cl, Br) to form 3-bromo- and 3-chloro-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
dium and moderate yields in most cases prevent its in-
dustrial applications. Thus, the development of a prac-
tical and efficient approach to synthesize 3-halo-
AHCTUNGTREGiNNUN ndoles is still a challenge. Herein, we wish to report
our recent results that 3-chloro- and 3-bromoindoles
can be prepared conveniently and efficiently by CuX2
(X=Cl, Br) mediated intramolecular halocyclization
of N-electron-withdrawing group-substituted 2-alk-
Keywords: alkynes; copper; cyclization; halogena-
tion; nitrogen heterocycles
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Indoles are important compounds which exhibit a va- lents of CuCl2 and 3 equivalents of LiCl (Table 1,
riety of biological activities.[1] It is well known that entry 1). Subsequently, we found that the Pd catalyst
many naturally occurring compounds contain the was not necessary for the halocyclization (Table 1,
indole skeleton as a backbone of their structural entry 2). In the absence of LiCl, however, 3-chloro-
frameworks. Because of their applications in pharma-
ACHTUNGTRENiNGNU ndole 2a was also synthesized in 90% yield within 5 h
ceutical fields, investigations on indole derivatives (Table 1, entry 3). Furthermore, it was found that the
from aspects of both their reactivity and the develop- solvent was important for the reaction. The use of
ment of efficient preparative methods have continu- polar solvents, such as DMSO, DMF and HMPA, af-
ously attracted the attention of chemists. Especially, forded 3-chloroindole 2a exclusively in 77–90% yields
3-haloindoles appear as a class of important building (Table 1, entries 3–5), and the rate of reaction in
blocks for the connection of different types of R DMSO was faster than that in DMF and HMPA. Sur-
groups with indoles at the 3-position. Traditional prisingly, reactions in CH3CN, acetone, or toluene all
methods for making 3-haloindoles involve direct halo- provided the protonolysis product 3a in good yields
genation of indoles with halogenating reagents, such (Table 1, entries 6–8). Strangely, neither 3-chloro-
as halogen,[2] N-halosuccinimides,[3] POX3/imidazole[4]
ACHTUNGTRENiNGNU ndole 2a nor the protonolysis product 3a was formed
and others.[5] Recently, Barluenga,[6] Knight[7] and in THF (Table 1, entry 9). Accordingly, the best con-
Larock,[8] reported the electrophilic cyclizations of 2- ditions for the preparation of 3-chloroindoles were
alkynylanilines to synthesize 3-iodoindoles using 2.5 equivalents of CuCl2 and 1 equivalent of K2CO3 in
IPy2BF4/HBF4, I2/K2CO3 and I2, respectively. How- DMSO at 508C. When CuBr2 was used to generate 3-
ACHTUNGTRENNUNGever, the synthesis of 3-chloro- and 3-bromoindoles bromoindole, it was found that the base played an im-
starting from 2-alkynylanilines was rarely reported.[9] portant role in promoting the formation of 3-bromo-
More recently, the PdX2-catalyzed halocyclization re-
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Table 1. CuX2-mediated halocyclization of 1a.[a]
Entry CuX2
Additive
Solvent Time [h] Yield [%] (2a or 4a)[b] Yield [%] (3a)[b]
1
2
3
4
5
6
7
8
9
CuCl2 PdCl
G
3
1
5
36
28
19
21
3
36
4
32
72
73 (2a)
92 (2a)
90 (2a)
77 (2a)
90 (2a)
– (2a)
–
–
–
–
–
91
86
94
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuBr2
CuBr2
trace (2a)
– (2a)
N.R.
10
54 (4a)
83 (4a)
96 (4a)
10
trace
–
11[c]
12[d] CuBr2
[a]
Reaction conditions: substrate (0.2 mmol, 0.1M), CuX2 (X=Cl, Br) (0.5 mmol, 2.5 equiv.), K2CO3 (0.2 mmol, 1 equiv.),
DMSO (2 mL), 508C.
Isolated yield.
Cs2CO3 (0.1 mmol, 0.5 equiv.), room temperature.
Et3N (0.2 mmol, 1.0 equiv), room temperature.
[b]
[c]
[d]
ACHTUNGTRENNUNG
With the optimized reaction conditions in hand, we with no substitutent on the nitrogen. In addition,
attempted to extend the scope of this halocyclization owing to the autoxidation-reduction of CuBr2
reaction by varying the substituents on the nitrogen
atom and alkyne component (Table 2). When the sub-
stituent on the nitrogen atom was a tosyl or a mesyl
group, a variety of alkynylanilines bearing an R1
group, including Ph, n-Bu, CH2OCH3, and CH2OH
could afford 3-haloindoles 2 or 4 exclusively in 79–
100% yields (Table 2, entries 1–6 and 9–16). However,
the terminal acetylene 1j gave 3-chloroindole 2j and
3-bromoindole 4j only in 22% and 23% yields, respec-
tively (Table 2, entries 17 and 18). Compound 1k with
the sterically bulky TMS group on the alkyne could
not form the desired 3-haloindoles (Table 2, entries 19
and 20). It is worth noting that when the substitutent
on the nitrogen atom was an acetyl group (1e) or a
hydrogen (1l), the reactions did not occur, which may
be due to the lower acidity of the N H group as com- nitrogen.
pared to those of N-trifluoroacetyl or N-sulfonyl ana-
Scheme 1. Synthesis of 3-haloindoles with no substitutent on
ꢀ
logues (Table 2, entries 7, 8, 21 and 22).
Importantly, when substrate 1m with a trifluoroace- (2CuBr2!2CuBr+Br2),[10] 1 equivalent of Br2 instead
tyl group on nitrogen was treated with 2.5 equivalents of CuBr2 was used to test the reaction under the typi-
of CuX2 (X=Cl, Br), K2CO3 (2.0 equiv.) and H2O cal bromocyclization conditions [Eq. (1)]. The reac-
(7.0 equiv.) in DMSO at room temperature or 508C, tion did not occur and most of the substrate 1d was
3-haloindoles 2m and 4m with cleavage of the recovered, indicating that the bromocyclization reac-
trifluoroACHTUNGTRENNUNGacetyl group were obtained in moderate to tion of 2-hexynylanilines is promoted by CuBr2 but
good yields through the in situ hydrolysis of the not Br2.
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Cupric Halide-Mediated Intramolecular Halocyclization
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Table 2. Intramolecular halocyclization of 1 mediated by
CuX2.
Entry R1
R2 Time Condi-
X
Yield
[%][b]
[h]
tions[a]
1
2
3
4
5
6
7
8
Ph (1b)
Ph (1b)
Ts
Ts 48
Ts
Ts
Ms
Ms
Ac 72
Ac 72
4
A
B
A
C
A
C
A
C
A
C
A
C
A
C
A
C
A
C
A
C
A
B
Cl 85 (2b)
Br 87 (4b)
Cl 96 (2c)
Br 94 (4c)
Cl 95 (2d)
Br 89 (4d)
Cl N.R.
product 3d in 47% yield [Eq. (2)], indicating that 2
equivalents of CuCl2 are necessary in this reaction.
Secondly, we found that the CuX2-mediated reaction
could not proceed in the absence of a base. Thirdly,
the direct chlorination of 2-methyl-1H-indole mediat-
ed by CuCl2 has been reported by Speier.[12] We won-
dered if the product 2 was derived from the inter-
mediate 3d bearing the electron-withdrawing meth-
n-Bu (1c)
n-Bu (1c)
n-Bu (1d)
n-Bu (1d)
n-Bu (1e)
n-Bu (1e)
CH2OCH3 (1f) Ms
CH2OCH3 (1f) Ms 1.5
CH2OCH3 (1g) Ts
CH2OCH3 (1g) Ts
1
3
1
5
Br N.R.
9
1
Cl 88 (2f)
Br 95 (4f)
Cl 93 (2g)
Br 100 (4g)
Cl 91 (2h)
Br 93 (4h)
Cl 79 (2i)
Br 95 (4i)
Cl 22 (2j)
Br 23 (4j)
Cl N.R.
10
11
12
13
14
15
16
17
18
19
20
21
22
1
2
1
5
1
AHCTUNGTREGaNNUN nesulfonyl group on nitrogen (Scheme 2). A control
experiment showed that indole 3d did not afford the
desired 3-chloroindole 2d under our standard chlori-
nation conditions (Scheme 2, a) or under the condi-
tions reported in the literature[12] (Scheme 2, b).
These experiments indicated that the formation of 3-
haloindoles mediated by CuX2 did not proceed via
the protonolysis product 3d.
CH
3A
CH
CHTUNGTRENNUNG
CH2OH (1i)
CH2OH (1i)
H (1j)
Ms
Ms 1.5
Ms
Ms
Ms 48
Ms 48
3
3
H (1j)
TMS (1k)
TMS (1k)
Ph (1l)
Br N.R.
Cl N.R.
Br N.R.
To further investigate the role of the two equiva-
lents of CuX2 in the reaction, electron paramagnetic
resonance (EPR) experiments[13] were carried out.
The EPR spectra of the CuCl2 solution in DMSO
H
H
168
168
Ph (1l)
[a]
Conditions A: substrates (0.22 mmol), CuCl2 (0.55 mmol,
2.5 equiv.), K2CO3 (0.22 mmol, 1.0 equiv.), DMSO have a strong absorption at 3200 gauss. The reaction
(1.1 mL), 508C; B: substrates (0.22 mmol), CuBr2
(0.44 mmol, 2.0 equiv.), Et3N (0.22 mmol, 1.0 equiv.),
DMSO, room temperature; C: substrates (0.22 mmol),
CuBr2 (0.55 mmol, 2.5 equiv.), K2CO3 (0.22 mmol,
1.0 equiv.), DMSO, room temperature.
of compound 1d and CuCl2 (2 equiv.) in DMSO was
monitored by EPR. After 5 min, it was observed that
the intensity of EPR signal was slowly decreasing and
completely disappeared after 1 hour, implying that
CuCl2 might turn into CuCl at the end of the reaction.
Similar EPR phenomena were observed in the bro-
mocyclization reaction (see Supporting Information).
In order to confirm whether CuCl was formed in
the reaction, two control experiments were carried
out. It was found that the residual solid of the chloro-
cyclization reaction (containing CuCl) and the com-
mercially available CuCl could both efficiently pro-
mote the cyclization of the 2-hexynylaniline derivative
1d to afford the protonolysis product 3d in 80% and
85% yields, respectively (Scheme 3).[14] These control
experiments indicated that CuX was formed indeed
during the halocyclization reaction.
[b]
Isolated yield.
To gain an insight into the mechanism of the CuX2-
On the basis of the studies described above, the
mediated halocyclization reactions,[11] detailed studies proposed reaction mechanism is shown in Scheme 4.
toward our reaction were carried out. Firstly, the reac- The interaction of 2-alkynylaniline 1 and the solvated
tion of compound 1d with less CuCl2 (1 equiv.) under CuX2 gives the coordination complex 5. Under the as-
the chlorocyclization conditions provided 3-chloroin- sistance of a base, the nitrogen atom acts as a nucleo-
doles 2d in 38% yield and the competing protonolysis phile and attacks the copper-coordinated alkyne
Adv. Synth. Catal. 2009, 351, 3107 – 3112
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Zengming Shen and Xiyan Lu
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Scheme 2. Control experiments for the reaction of indoles in the presence of CuCl2.
Both 3-chloro- and 3-bromoindole derivatives can be
obtained in high yields by the reaction of N-electron-
withdrawing group-substituted 2-alkynylanilines with
two equivalents of CuX2 (X=Cl, Br) in DMSO in the
presence of a base within a short period of time. De-
tailed investigation of the reaction suggests that two
equivalents of CuX2 are required and completely
turned into Cu(I) halide at the end of the reaction.
Experimental Section
General
Scheme 3. Reactions of CuCl with 1d.
All reactions were carried out under nitrogen atmosphere
unless otherwise indicated. Reactions were monitored using
thin-layer chromatography (TLC). All of copper reagents
were purified according to the standard methods.
moiety to give the indole-containing copper inter-
mediate 6. Reductive elimination of 6 can provide the
3-haloindole derivative 2 (or 4) and Cu(0). The
formed Cu(0) can be oxidized by CuX2 to produce
CuX.[15] Thus, two equivalents of CuX2 are necessary
in this reaction.
General Procedure for the Synthesis of 3-Chloro-
indoles Mediated by CuCl2 (Conditions A)
Under nitrogen,
a
solution of 2-ethynylaniline
1
(0.22 mmol), CuCl2 (74 mg, 0.55 mmol) and K2CO3 (30.5 mg,
0.22 mmol) in DMSO (1.1 mL) was stirred at 508C for 1–
4 h. The mixture was then diluted with saturated NaCl solu-
In conclusion, we have developed a convenient and
efficient method for the synthesis of 3-haloindoles.
Scheme 4. Proposed mechanism of CuX2-mediated halocyclization reaction.
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Cupric Halide-Mediated Intramolecular Halocyclization
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tion and extracted four times with diethyl ether. The organic
layers were combined and dried over Na2SO4. After evapo-
ration, the residue was purified by flash chromatography on
silica gel with petroleum ether/ethyl acetate [20/1 (v/v)] as
the eluent to afford 3-chloroindoles (2).
(6.31), 405 [M+ (79Br)] (6.86), 406 [(Mꢀ1)+ (81Br)] (31.46),
404 [(Mꢀ1)+ (79Br)] (27.59), 284, 210, 208, 171, 91, 65; HR-
MS: m/z=428.0292, calcd for (C19H20BrNO2S+Na+):
428.0290.
3-Chloro-N-methanesulfonyl-2-phenylindole (2a): white
solid; yield: 90%; m.p 105–1068C (recrystallization from pe-
troleum ether-dichloromethane). 1H NMR (300 MHz,
CDCl3): d=2.79 (s, 3H) 7.43–7.57 (m, 7H), 7.66–7.69 (m,
1H), 8.13–8.16 (m, 1H); 13C NMR (75 MHz, CDCl3): d=
39.9, 115.3, 115.6, 119.0, 125.0, 126.4, 127.8, 128.2, 128.9,
129.4, 131.0, 135.6, 135.9; IR (KBr): n=3011, 2929, 1448,
1365, 1176 cmꢀ1; MS (EI): m/z=307 [M+ (37Cl)] (25.88), 305
Acknowledgements
The National Basic Research Program of China
(2006CB806105) is acknowledged. We also thank the Nation-
al Natural Sciences Foundation of China (20472099) and
Chinese Academy of Sciences for financial support. We also
thank Professor Zhaoguo Zhang of Shanghai Jiao Tong Uni-
versity for his help.
[M CHTUNGTRENNUNG
+A(35Cl)] (71.06), 228, 226, 201, 199, 190; anal. calcd. for
C15H12ClNO2S: C 58.92, H 3.96, N 4.58, Cl 11.59; found: C
58.93, H 4.22, N 4.43, Cl 11.31.
Typical Procedure for the Preparation of 3-Bromo-
indoles Mediated by CuBr2 (Conditions B). Synthesis
of 3-Bromo-N-methanesulfonyl-2-phenylindole (4a)
as an Example
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Under nitrogen, a solution of 1a (60 mg, 0.22 mmol), CuBr2
(98 mg, 0.44 mmol) and Et3N (31 mL, 0.22 mmol) in DMSO
(1.1 mL) was stirred at room temperature for 3 days. The
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indoles Mediated by CuBr2 (Conditions C). Synthesis
of 3-Bromo-2-n-butyl-N-(p-toluenesulfonyl)indole
(4c) as an Example
Under nitrogen, a solution of 1c (80 mg, 0.24 mmol), CuBr2
(136 mg, 0.61 mmol) and K2CO3 (33.7 mg, 0.24 mmol) in
DMSO (1.2 mL) was stirred at room temperature for 3 h.
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3H), 1.38–1.50 (m, 2H), 1.65–1.73 (m, 2H), 2.32 (s, 3H),
3.08 (t, J=7.2 Hz, 2H), 7.16 (d, J=7.8 Hz, 2H), 7.25–7.34
(m, 2H), 7.40–7.43 (m, 1H), 7.59 (d, J=7.8 Hz, 2H), 8.16–
8.19 (m, 1H); 13C NMR (75 MHz, CDCl3): d=13.8, 21.5,
22.5, 27.3, 31.9, 101.8, 115.0, 119.2, 124.1, 125.1, 126.3, 129.2,
129.8, 135.5, 135.9, 138.9, 144.9; IR (KBr): n=3069, 2959,
1598, 1450, 1374, 1176 cmꢀ1; MS (EI): m/z=407 [M+ (81Br)]
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3112
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