PdX2/CuX2-catalyzed annulation of 2-ethynylbenzeneamines: Selective synthesis of 2-substituted 3-halo-1H-indoles

Article abstract of DOI:10.1055/s-2007-983717

A novel and effective protocol for the synthesis of 2-substituted 3-halo-1H-indoles by PdX₂/CuX₂-catalyzed annulations of 2-ethynylbenzeneamines has been developed. In the presence of PdX₂ and CuX₂, the annulati

Full text of DOI:10.1055/s-2007-983717

PAPER
1841
PdX /CuX -Catalyzed Annulation of 2-Ethynylbenzeneamines:
2
2
Selective Synthesis of 2-Substituted 3-Halo-1H-indoles
a
a
b
Synthesis of
2h
i
H
-
in
T
a
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education), College of Chemistry and
Chemical Engineering, Hunan Normal University, Changsha 410081, P. R. of China
Fax +86(731)8872531; E-mail: jhli@hunnu.edu.cn
b
Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100101, P. R. of China
Received 6 March 2007; revised 10 April 2007
X
Abstract: A novel and effective protocol for the synthesis of 2-sub-
stituted 3-halo-1H-indoles by PdX /CuX -catalyzed annulations of
R'
PdX /CuX2
2
R'
2
2
2
-ethynylbenzeneamines has been developed. In the presence of
N
NHAc
DCE
R
PdX and CuX , the annulation reactions of a variety of 2-ethynyl-
R
Ac
2
2
benzeneamines were conducted in moderate to good yields. It is
noteworthy that only N-acetyl-protected 2-ethynylbenzeneamines
can undergo the reaction successfully.
X = Cl, Br
R = C8H17, Ph, Bu, CH2CH2OAc
R = H, F, Cl, NO2
'
n
t
Key words: palladium(II) halide, copper(II) halide, annulation,
Scheme 1
2
-ethynylbenzeneamine, 2-substituted 3-halo-1H-indoles
8
In an earlier report, we demonstrated that with the aid of
HEt NX, 2-substituted 3-halobenzo[b]furans were pre-
3
Indoles, in particular 3-halo-substituted ones, have at-
tracted considerable interest on their synthesis because
this structural motif is common to a variety of biologically
active alkaloids and important pharmaceuticals and valu-
pared selectively from the annulation of 2-alkynylphenols
using PdX and CuX as the catalytic system. We have
2
2
since extended the application of the PdX /CuX /HEt NX
2
2
3
system to the annulation of 2-ethynylbenzeneamines
Table 1). As expected, the PdX /CuX /HEt NX system
1
–7
able intermediates for organic synthesis.
The most
(
2
2
3
common synthetic approach to 3-haloindoles is direct ha-
was effective for the annulation of N-[2-(dec-1-ynyl)phe-
nyl]acetamide (1a) using DCE (1,2-dichloroethane) as the
solvent. In the presence of PdBr (5 mol%), CuBr (3
3
4
logenation of indoles with N-halosuccinimides, halogen,
5
6
POX /imidazole, and others. However, the reaction con-
3
2
2
ditions of these methods generally involve highly acidic
or basic media. Other drawbacks of these methods include
poor selectivity, overhalogenation, sensitivity to air/wa-
ter, and limited functional group tolerance. Recently, the
electrophilic cyclizations of 2-ethynylbenzeneamines
proved especially efficient for the synthesis of 3-haloin-
equiv) and HEt NI (0.2 equiv), 91% GC yield of 1-(3-bro-
3
mo-2-octyl-1H-indol-1-yl)ethanone (3a) was obtained
along with 8% GC yield of a by-product, 1-(2-octyl-1H-
indol-1-yl)ethanone (2a), from the reaction of substrate 1a
(
entry 1). The yield of the target product 3a was decreased
to some extent when HEt NBr, NaOH, or AcOH was used
3
7
doles. However, only 3-iodoindoles were prepared from
the reaction of the corresponding 2-ethynylbenzeneam-
to instead HEt NI (entries 2–4). N-[2-(Dec-1-ynyl)phe-
3
nyl]acetamide (1a) could undergo the annulation reaction
ines with I or IPy BF . Therefore, the development of a
2
2
4
smoothly without HEt NI (entry 5). Subsequently, other
3
new and general approach for forming 3-haloindoles is
still significant. Very recently, we have reported a novel
and selective palladium-catalyzed annulation of 2-alky-
solvents including MeCN, CH Cl and THF were exam-
2
2
ined, and they were less effective for the annulation reac-
tion than DCE (entries 5–8). Screening results showed
nylphenols for the synthesis of 2-substituted 3-haloben-
that three equivalents of CuBr provided the best results
2
8
zo[b]furans. In the presence of PdX and CuX (X = Br,
2
2
(entries 5 and 9–11). Without CuBr , 1-(2-octyl-1H-indol-
2
Cl), 2-substituted 3-halobenzo[b]furans were selectively
1
-yl)ethanone (2a) was isolated as the major product to-
obtained as the major products using HEt NX as the pro-
3
gether with 5% GC yield of the target product 3a (entry 9),
whereas the yield of the target product 3a was enhanced
moter. Herein, we wish to report that the PdX /CuX sys-
2
2
tem was extended to the annulation of 2-
ethynylbenzeneamines successfully to synthesize 2-sub-
stituted 3-haloindoles in moderate to good yields. This
process represents a novel approach for the synthesis of 2-
substituted 3-haloindoles (Scheme 1).
sharply when CuBr was added (32% yield/2 equiv of
2
CuBr , 96% yield/3 equiv of CuBr and 90% yield/5 equiv
2
2
9
of CuBr ; entries 5, 10 and 11). The other blank experi-
2
ments indicated that both PdBr and CuBr played a curial
2
2
role in the reactions. Without a Pd source, a messy result
was observed in the presence of CuBr alone (entry 12),
2
but in the absence of CuBr 1-(2-octyl-1H-indol-1-yl)eth-
2
anone (2a) was obtained as the major product using 5
SYNTHESIS 2007, No. 12, pp 1841–1847
x
x.
x
x
.
2
0
0
7
mol% of PdBr (entry 9). Note that good isolated yield of
Advanced online publication: 08.06.2007
DOI: 10.1055/s-2007-983717; Art ID: F04907SS
Georg Thieme Verlag Stuttgart · New York
2
3a is still achieved at room temperature after prolonging
©

1
842
S. Tang et al.
PAPER
Table 1 Palladium-Catalyzed Annulation Reactions of 2-(Dec-1-ynyl)benzeneaminesa
H
Br
nC8H17
PdBr2/CuBr2
solvent
nC8H17
nC8H17
+
NHR
N
N
R
R
1
2
3
Entry
R
Additive (equiv)
Time (h)
GC yield (%)b
2
a
3a
1
Ac (1a)
Ac (1a)
Ac (1a)
Ac (1a)
Ac (1a)
Ac (1a)
Ac (1a)
Ac (1a)
Ac (1a)
Ac (1a)
Ac (1a)
Ac (1a)
Ac (1a)
H (1b)
Et NHI (0.2)
DCE
DCE
DCE
DCE
DCE
MeCN
CH Cl
8 (6)
91 (88)
17
3
2
Et NHBr (0.2)
35
3
3
NaOH (2.0)
64
21
4
AcOH (2.0)
21
64
5
–
–
–
–
–
–
–
–
–
–
–
–
0
96(92)
12
6
21
7
34
23
2
2
8c
9d
0e
1f
2c,g
3h
4c
5c
6c
THF
nd
nd
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
95 (94)
30
5 (3)
32
1
1
1
1
1
1
10 (8)
nd
90 (88)
nd
(7)
nd
(89)
nd
PhCO (1c)
Bn (1d)
nd
nd
1
nd
nd
a
Unless otherwise indicated, the reaction conditions were as follows: 1 (0.3 mmol), PdBr (5 mol%) and CuBr (3 equiv) in DCE (5 mL) under
2
2
argon at 40 °C for 5 h.
b
Yield was determined by GC-MS analysis. Isolated yield is given in the parenthesis.
No determined.
Without CuBr2.
c
d
e
CuBr (2 equiv).
2
f
CuBr (5 equiv).
2
g
Without PdBr2.
For 24 h at r.t.
h
the reaction time in the presence of PdBr (5 mol%) and also react with PdCl and CuCl smoothly to afford the
2
2
2
CuBr (3 equiv) (entry 13). Finally, N-protected groups corresponding 1-(3-chloro-2-octyl-1H-indol-1-yl)etha-
2
were also tested under the PdBr /CuBr catalytic system. none (4a) in a 56% yield (entry 1). Unfortunately, the
2
2
Unfortunately, 2-(dec-1-ynyl)benzeneamine (1b), N-[2- reaction of N-[2-(3,3-dimethylbut-1-ynyl)phenyl]acet-
dec-1-ynyl)phenyl]benzamide (1c) and N-benzyl-2-(dec- amide (1e), a substrate bearing a bulky group at the termi-
(
1
-ynyl)benzeneamine (1d) were not suitable substrates nal of alkyne, with PdBr and CuBr was unsuccessful
2 2
for the annulation reaction (entries 14–16).
providing a low yield of the target product 3e even at
0 °C (entry 2). However, treatment of substrate 1e with
PdCl and CuCl were conducted smoothly to afford 2-
7
We then investigated the reaction scope of this PdX2/
2
2
CuX catalytic system and its tolerance of functional
2
tert-butyl-3-chloro-1H-indole (4e¢), an N-deprotected
product, in an 88% yield (entry 3). To our delight, the oth-
er substrates 1f and 1g bearing a phenyl and an ester
groups at the terminal of alkyne also worked well with
PdX and CuX to give the corresponding products 3f, 4f
groups both at the terminal of alkynes and on the aromatic
rings (Table 2). We rapidly noticed the broad field of ap-
plication of the process and its remarkable functional
group compatibility on both parts. We were pleased to ob-
serve that N-[2-(dec-1-ynyl)phenyl]acetamide (1a) could
2
2
Synthesis 2007, No. 12, 1841–1847 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Substituted 3-Halo-1H-indoles
1843
and 3g in 64%, 59% and 57% yields, respectively (entries prove the annulation reactions of substrates 1h and 1i
–6). The results also indicated that substituents, such as (entries 7–10). Substrate 1h bearing two fluoro groups, for
4
fluoride, chloride and nitro, on the aromatic rings were example, was annulated to produce the corresponding
tolerated well under the standard reaction conditions (en- products 3h and 4h in moderate yields using a mixture of
tries 7–12). Noteworthy is that MeCN is required to im- DCE and MeCN as the solvent (entries 7 and 8).
a
Table 2 Annulation Reactions of 2-Ethynylbenzeneamines 1 in the Presence of PdX and CuX
2
2
X
R
PdX2/CuX2
DCE
R
N
NHAc
R'
R'
Ac
1
3: X = Br
4: X = Cl
Entry
1
Substrate
X
Time (h)
Yield (%)b
2
3 or 4
Cl
5
25 (2a)
56 (4a)
nC8H17
NHAc
(
(
1a)
1e)
2c
Br
15
<5 (2e)
<5 (3e)
tBu
NHAc
3c
4
(1e)
Cl
Br
15
12
<5 (2e)
18 (2f)
88 (4e¢)
64 (3f)
Ph
NHAc
NHAc
(
1f)
5
6
(1f)
Cl
Br
12
5
20 (2f)
<5 (2g)
59 (4f)
57 (3g)
OAc
(
F
1g)
7d
8d
9d
Br
Cl
Br
11
11
5
30 (2h)
40 (2h)
50 (2i)
62 (3h)
45 (4h)
41 (3i)
nC8H17
nC8H17
nC8H17
F
NHAc
(
F
1h)
F
NHAc
(
Cl
1h)
NHAc
Cl
(
1i)
1
0d
1
(1i)
Cl
Br
5
5
41 (2i)
18 (2j)
54 (4i)
58 (3j)
1
O N
2
nC8H17
NHAc
(
1j)
12
(1j)
Cl
5
13 (2j)
65 (4j)
a
b
c
d
Reaction conditions: 1 (0.3 mmol), PdX (5 mol%) and CuX (3 equiv) in DCE (5 mL) under argon at 40 °C.
Isolated yield.
At 70 °C.
2
2
1
mL of MeCN was added and 20–30% of substrate 1i was recovered.
Synthesis 2007, No. 12, 1841–1847 © Thieme Stuttgart · New York

1
844
S. Tang et al.
PAPER
CuX
PdX2
R
H
CuX2
NHAc
PdX2
R
R
1
N
2
Ac
Pd(0)
NHAc
HX
5
CuX2
X
X
PdX
Path I
HX
Path II
R
R
R
N
N
N
Ac
Ac
Ac
6
3
4
: X = Br
: X = Cl
3: X = Br
4: X = Cl
Scheme 2
A working mechanism for the present annulation reaction cyclization of 2-ethynylbenzeneamine. Indeed, we found
1
,7–12
is proposed as shown in Scheme 2.
Firstly, attack of that in the presence of three equivalents of CuBr the cy-
2
the active palladium species with ethynylbenzeneamine 1 clization of 2-ethynylbenzeneamine provided messy re-
provides intermediate 5, followed by the addition of the sults (entry 12 in Table 1). It is worth noting that 3% yield
nitrogen nucleophile to the PdX -activated intermediate 5 of 3a is observed form the cyclization of 2-ethynylben-
2
9
affording intermediate 6 and HX. With the aid of CuX , zeneamine only in the presence of 5 mol% of PdBr (entry
2
2
the cleavage of the C–Pd s-bond of intermediate 6 occurs 9 in Table 1). Furthermore, the results of entry 11 in
readily to form 2-substituted 3-haloindole 3/4 and the Table 1 demonstrated that the unhalogenated product 2a
1
0
Pd(0) species. The active Pd(II) species is regenerated was still isolated in an 8% yield even in the presence of
by the oxidation reaction of Pd(0) with CuX to start a new five equivalents of CuBr . The above results suggested
2
2
catalytic cycle. During the process, protonolysis of inter- that the products 3 or 4 were generated mainly via path-
mediate 6 also takes place to form 2-substituted indole 2 way 1 in Scheme 2. Further studies are in progress to elu-
1
1
and regenerates the active Pd(II) species. 2-Substituted cidate the exact mechanism.
indole 2 can also undergo the halogenation reaction to af-
In summary, we have developed a novel and selective
method for the synthesis of 2-substituted 3-halo-1H-in-
Two control reactions were carried out to further elucidate doles by PdX /CuX -catalyzed annulation of 2-ethynyl-
ford the product 3/4 in the presence of CuX2.
2
2
the mechanism of the annulation reaction (Scheme 3). benzeneamines. In the presence of PdX and CuX , the
2
2
The results showed that both PdBr and CuBr have a fun- annulation reactions of a variety of 2-ethynylbenzeneam-
2
2
damental influence on the reaction. It was found that treat- ines were conducted in moderate to good yields.
ment of N-[2-(dec-1-ynyl)phenyl]acetamide (1a) with one Noteworthy is that only N-acetyl protected 2-ethynyl-
equivalent of PdBr for 24 hours afforded two products, benzeneamines can undergo the reaction successfully.
2
2
a and 3a, in 21% and 75% yields, respectively Further efforts to extend the application of the catalytic
(
Scheme 3, eq 1). On the other hand, the reaction of 1-(2- system and the products in organic synthesis are under-
octyl-1H-indol-1-yl)ethanone (2a) with three equivalents way in our laboratory.
of CuBr directly at 40 °C was also tested, and only 58%
2
yield of 3a was observed by GC-MS analysis after 24
NMR spectroscopy was performed on an Inova-400 (Varian) spec-
trometer operating at 400 MHz ( H NMR) and 100 MHz ( C
hours (Scheme 3 eq 2).6e,f Hiroya and co-workers have
12
1
13
reported that a catalytic amount of CuBr was inert for the NMR). TMS was used an internal standard and CDCl was used as
2
3
H
Br
nC8H17
PdBr2 (1 equiv)
nC8H17
nC8H17
(1)
+
NHAc
H
DCE, 40 °C, 24 h
N
N
Ac
Ac
1a
2
a (21%)
3a (75%)
H
Br
CuBr2 (3 equiv)
nC8H17
nC8H17
nC8H17
+
(2)
DCE, 40 °C, 24 h
N
N
N
Ac
Ac
Ac
2
a (41%)
3a (58%)
Scheme 3
Synthesis 2007, No. 12, 1841–1847 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Substituted 3-Halo-1H-indoles
1845
7
9
+
the solvent. Mass spectrometric analyses were performed on GC-
MS analysis (Shimadzu GCMS-QP2010). All melting points are
uncorrected.
HRMS (EI): m/z calcd for C H BrNO (M ): 349.1041;, found:
1
8
24
349.1040.
-(3-Bromo-2-phenyl-1H-indol-1-yl)ethanone (3f)
1
2
-Substituted Indoles 2a, 2h and 2i, and 2-Substituted 3-Haloin-
Pale yellow solid; mp 101.8–102.0 °C.
doles 3 and 4; General Procedure
A mixture of ethynylbenzeneamine 1 (0.3 mmol), PdX (5 mol%),
CuX (3 equiv) and DCE (5 mL) was stirred at 40 or 70 °C (see
Tables 1 and 2 for the reaction temperature) for 5–15 h until com-
plete consumption of starting material as monitored by TLC and
GC-MS analysis. Then the mixture was filtered and evaporated, and
the residue was purified by flash column chromatography to afford
1
H NMR (400 MHz, CDCl ): d = 8.40 (d, J = 8.0 Hz, 1 H), 7.60–
3
2
7
.31 (m, 8 H), 1.99 (s, 3 H).
2
1
3
C NMR (100 MHz, CDCl ): d = 170.7, 136.2, 136.0, 132.2, 130.4,
3
1
29.4, 128.9, 128.5, 126.5, 124.3, 119.5, 116.3, 102.6, 27.6.
+
+
LRMS (EI, 70 eV): m/z (%) = 315 (M + 2, 20), 313 (M , 20), 273
96), 271 (100), 190 (26), 189 (27), 165 (41).
(
2, 3, or 4 (hexane–EtOAc).
7
9
+
HRMS (EI): m/z calcd for C H BrNO (M ): 313.0102; found:
1
6
12
3
13.0102.
1
-(2-Octyl-1H-indol-1-yl)ethanone (2a)
Pale yellow oil.
2
-(1-Acetyl-3-bromo-1H-indol-2-yl)ethyl Acetate (3g)
1
H NMR (400 MHz, CDCl ): d = 7.84 (d, J = 8.8 Hz, 1 H), 7.48 (d,
3
Pale yellow oil.
J = 8.8 Hz, 1 H), 7.26–7.21 (m, 2 H), 6.41 (s, 1 H), 2.99 (t, J = 7.2
1
H NMR (400 MHz, CDCl ): d = 7.68 (d, J = 8.4 Hz, 1 H), 7.56 (d,
3
Hz, 2 H), 2.76 (s, 3 H), 1.72–1.68 (m, 2 H), 1.43–1.25 (m, 10 H),
J = 8.8 Hz, 1 H), 7.38–7.32 (m, 2 H), 4.40 (t, J = 6.4 Hz, 2 H), 3.51
0
.89 (t, J = 6.8 Hz, 3 H).
(
t, J = 6.4 Hz, 2 H), 2.83 (s, 3 H), 2.01 (s, 3 H).
1
3
C NMR (100 MHz, CDCl ): d = 170.4, 143.0, 136.3, 129.9, 123.4,
3
13
C NMR (100 MHz, CDCl ): d = 170.9, 169.7, 135.4, 134.8, 129.1,
3
1
2
22.9, 120.1, 114.8, 108.1, 31.9, 30.5, 29.5 (2 C), 29.3, 28.9, 27.7,
2.7, 14.1.
1
25.2, 123.7, 120.0, 114.3, 103.8, 62.7, 29.7, 28.2, 27.7, 21.0.
+
+
+
LRMS (EI, 70 eV): m/z (%) = 325 (M + 2, 0.1), 323 (M , 0.1), 283
LRMS (EI, 70 eV): m/z (%) = 271 (M , 11), 229 (5), 173 (12), 144
(
1), 281 (1), 265 (2), 263 (2), 223 (13), 221 (13), 115 (11), 43 (100).
(
23), 130, (92), 103 (32), 77 (28), 43 (100).
1479BrNO
(M ): 323.0157; found:
+
+
HRMS (EI): m/z calcd for C14
3
H
3
HRMS (EI): m/z calcd for C H NO (M ): 271.1936; found:
1
8
25
23.0155.
2
71.1936.
1
-(3-Bromo-5,6-difluoro-2-octyl-1H-indol-1-yl)ethanone (3h)
1
-(5,6-Difluoro-2-octyl-1H-indol-1-yl)ethanone (2h)
White solid; mp 91.2 °C.
1H NMR (400 MHz, CDCl
): d = 7.01 (d, J = 8.0 Hz, 1H), 6.82 (t,
3
Pale yellow oil.
1
H NMR (400 MHz, CDCl ): d = 6.97 (d, J = 8.0 Hz, 1 H), 6.75 (t,
3
J = 8.8 Hz, 1 H), 2.96 (t, J = 7.8 Hz, 2 H), 2.62 (d, J = 6.4 Hz, 3 H),
.63–1.59 (m, 2 H), 1.38–1.27 (m, 10 H), 0.88 (t, J = 6.4 Hz, 3 H).
J = 8.8 Hz, 1 H), 6.33 (s, 1 H), 2.86 (t, J = 8.0 Hz, 2 H), 2.61 (s, 3
1
H), 1.72–1.64 (m, 2 H), 1.40–1.28 (m, 10 H), 0.88 (t, J = 6.8 Hz, 3
H).
13C NMR (100 MHz, CDCl
): d = 170.6, 160.1 (d, J = 10.7 Hz, 1
C), 157.7 (d, J = 10.7 Hz, 1 C), 149.9 (d, J = 13.8 Hz, 1 C), 147.4
d, J = 13.0 Hz, 1 C), 142.8, 132.6, 118.7, 101.2 (dd, J = 3.8 Hz, 3.9
3
+
LRMS (EI, 70 eV): m/z (%) = 307 (M , 1), 264 (26), 180 (3), 166
(
(
64), 43 (100).
Hz, 1 C), 100.2 (dd, J = 24.4 Hz, 24.5 Hz, 1 C), 98.1, 31.8, 29.4,
29.3, 29.2, 27.2, 26.7, 26.5, 22.6, 14.1.
+
HRMS (EI): m/z calcd for C H F NO (M ): 307.1748; found:
3
1
8
23
2
07.1747.
+
+
LRMS (EI, 70 eV): m/z (%) = 387 (M + 2, 7), 385 (M , 6), 345 (13),
43 (14), 264 (20), 166 (46), 43 (100).
3
1
-(5,7-Dichloro-2-octyl-1H-indol-1-yl)ethanone (2i)
2279BrF
+
Pale yellow oil.
HRMS (EI): m/z for C18H NO (M ): 385.0853; found:
2
1
385.0852.
H NMR (400 MHz, CDCl ): d = 7.39 (s, 1 H), 7.20 (s, 1 H), 6.28
3
(
1
s, 1 H), 2.74 (t, J = 8.0 Hz, 2 H), 2.58 (s, 3 H), 1.71–1.65 (m, 2 H),
1
-(3-Bromo-5,7-dichloro-2-octyl-1H-indol-1-yl)ethanone (3i)
.39–1.28 (m, 10 H), 0.88 (t, J = 6.8 Hz, 3 H).
Pale yellow oil.
+
LRMS (EI, 70 eV): m/z (%) = 341 (M , 5), 339 (7), 299 (6), 297 (9),
2
(
1
H NMR (400 MHz, CDCl ): d = 7.41 (s, 1 H), 7.27 (s, 1 H), 2.83
3
14 (4), 212 (7), 201 (15), 200 (13), 199 (24), 198 (19), 179 (1), 177
+
+
(t, J = 8.0 Hz, 2 H), 2.58 (s, 3 H), 1.64–1.59 (m, 2 H), 1.37–1.27 (m,
M – Cl, 3), 142 (M – 2 Cl, 1), 56 (16), 43 (100).
1
0 H), 0.88 (t, J = 6.8 Hz, 3 H).
+
HRMS (EI): m/z calcd for C H Cl NO (M ): 339.1157; found:
3
1
8
23
2
13
C NMR (100 MHz, CDCl ): d = 172.4, 141.4, 132.0, 130.3, 128.9,
3
39.1156.
1
24.7, 118.8, 117.7, 95.2, 31.8, 29.4, 29.3, 29.2 (2 C), 26.4, 22.6,
14.1.
1
-(3-Bromo-2-octyl-1H-indol-1-yl)ethanone (3a)6f
+
Pale yellow oil.
LRMS (EI, 70 eV): m/z (%) = 417 (M , 0.5), 379 (5), 377 (11), 375
1
(3), 298 (7), 296 (11), 280 (11), 278 (18), 200 (31), 198 (41), 69
H NMR (400 MHz, CDCl ): d = 7.77 (d, J = 8.8 Hz, 1 H), 7.50 (d,
3
(
26), 55 (41), 41 (100).
J = 8.8 Hz, 1 H), 7.33–7.21 (m, 2 H), 3.11 (t, J = 7.6 Hz, 2 H), 2.76
(
7
9
35
+
s, 3 H), 1.69–1.58 (m, 2 H), 1.40–1.27 (m, 10 H), 0.87 (t, J = 6.4
HRMS (EI): m/z calcd for C18H22 Br Cl NO (M ): 417.0262;
2
Hz, 3 H).
found: 417.0261.
1
3
C NMR (100 MHz, CDCl ): d = 169.5, 139.7, 135.0, 129.1, 124.8,
3
1
-(3-Bromo-6-nitro-2-octyl-1H-indol-1-yl)ethanone (3j)
1
2
23.6, 119.5, 114.6, 101.7, 31.9, 29.5, 29.4, 29.3, 29.2, 28.2, 27.5,
2.7, 14.2.
Yellow solid; mp 75.9–76.6 °C.
1H NMR (400 MHz, CDCl
): d = 8.38 (s, 1 H), 8.19 (d, J = 9.6 Hz,
H), 7.99 (d, J = 9.2 Hz, 1 H), 3.12 (t, J = 7.6 Hz, 2 H), 2.83 (s, 3
H), 1.66–1.62 (m, 2 H), 1.32–1.25 (m, 10 H), 0.89 (t, J = 6.8 Hz, 3
+
+
3
LRMS (EI, 70 eV): m/z (%) = 351 (M + 2, 18), 349 (M , 18), 309
24), 307 (26), 228 (82), 130 (100).
1
(
H).
Synthesis 2007, No. 12, 1841–1847 © Thieme Stuttgart · New York

1
846
S. Tang et al.
PAPER
1
3
C NMR (100 MHz, CDCl ): d = 169.2, 144.0, 142.3, 138.0, 129.1,
1-(3,5,7-Trichloro-2-octyl-1H-indol-1-yl)ethanone (4i)
Pale yellow oil.
3
1
2
19.8, 115.4, 115.1, 101.2, 31.8, 29.3, 29.2, 29.1 (2 C), 28.1, 27.2,
2.6, 14.1.
1
H NMR (400 MHz, CDCl ): d = 7.45 (s, 1 H), 7.27 (s, 1 H), 2.83
3
+
+
LRMS (EI, 70 eV): m/z (%) = 396 (M + 2, 14), 394 (M , 14), 366
(t, J = 7.6 Hz, 2 H), 2.58 (s, 3 H), 1.64–1.60 (m, 2 H), 1.38–1.29 (m,
(
(
10), 364 (11), 354 (33), 352 (35), 324 (11), 322 (11), 273 (63), 175
98), 43 (100).
10 H), 0.88 (t, J = 6.4 Hz, 3 H).
13
C NMR (100 MHz, CDCl ): d = 172.3, 139.8, 130.6, 129.7, 128.9,
3
7
9
+
HRMS (EI): m/z calcd for C H BrN O (M ): 394.0892; found:
3
124.7, 119.0, 116.7, 108.0, 31.8, 29.4, 29.3, 29.2 (2C), 29.1, 25.3,
22.6, 14.1.
1
8
23
2
3
94.0892.
+
+
LRMS (EI, 70 eV): m/z (%) = 375 (M + 2, 12), 373 (M , 12), 332
9), 330 (9), 276 (14), 274 (13), 242 (6), 240 (8), 216 (6), 214 (9),
11 (4), 109 (12), 74 (8), 55 (29), 43 (100).
1
-(3-Chloro-2-octyl-1H-indol-1-yl)ethanone (4a)
(
1
Pale yellow oil.
1
H NMR (400 MHz, CDCl ): d = 7.81 (d, J = 8.0 Hz, 1 H), 7.56 (d,
79
35
+
3
HRMS (EI): m/z calcd for C H Br Cl NO (M ): 373.0767;
1
8
22
2
J = 8.8 Hz, 1 H), 7.32 (t, J = 3.6 Hz, 2 H), 3.10 (t, J = 7.2 Hz, 2 H),
found: 373.0766.
2
.78 (s, 3 H), 1.64–1.59 (m, 2 H), 1.39–1.26 (m, 10 H), 0.87 (t,
J = 6.8 Hz, 3 H).
1
-(3-Chloro-6-nitro-2-octyl-1H-indol-1-yl)ethanone (4j)
1
3
C NMR (100 MHz, CDCl ): d = 169.5, 137.8, 134.5, 127.8, 123.5,
Yellow solid; mp 62.8 °C.
3
1
18.3, 114.7, 113.1, 31.9, 29.4, 29.3 (2C), 29.2, 27.5, 22.7, 14.1.
1
H NMR (400 MHz, CDCl ): d = 8.46 (s, 1 H), 8.22 (d, J = 9.6 Hz,
3
+
+
LRMS (EI, 70 eV): m/z (%) = 307 (M + 2, 2.4), 305 (M , 7.1), 265
5), 263 (13), 228 (8), 166 (11), 164 (31), 130 (26), 43 (100).
1 H), 8.04 (d, J = 9.2 Hz, 1 H), 3.11 (t, J = 7.6 Hz, 2 H), 2.82 (s, 3
(
H), 1.66–1.61 (m, 2 H), 1.32–1.25 (m, 10 H), 0.88 (t, J = 6.8 Hz, 3
3
5
+
H).
HRMS (EI): m/z calcd for C H ClNO (M ): 305.1546; found:
1
8
24
1
3
3
05.1546.
C NMR (100 MHz, CDCl ): d = 169.3, 144.0, 140.5, 137.4, 127.7,
3
1
20.0, 115.2, 114.4, 104.3, 31.8, 29.4, 29.2 (2C), 29.1, 27.3, 26.8,
2
-tert-Butyl-3-chloro-1H-indole (4e¢)
22.6, 14.1.
Pale yellow oil.
+
+
LRMS (EI, 70 eV): m/z (%) = 352 (M + 2, 7), 350 (M , 21), 310
(30), 308 (92), 280 (7), 278 (17), 273 (33), 209 (41), 163 (26), 43
(100).
1
H NMR (400 MHz, CDCl ): d = 7.89 (br s, 1 H), 7.56 (d, J = 8.8
3
Hz, 1 H), 7.31–7.24 (m, 1 H), 7.19–7.13 (m, 2 H), 1.51 (s, 9 H).
1
3
35
+
C NMR (100 MHz, CDCl ): d = 140.6, 132.5, 127.3, 122.1, 120.2,
HRMS (EI): m/z calcd for C H ClN O (M ): 350.1397; found:
18 23 2 3
350.1397.
3
1
17.4, 110.7, 101.5, 32.5, 28.8.
+
+
LRMS (EI, 70 eV): m/z (%) = 209 (M + 2, 15), 207 (M , 45), 194
33), 192 (100), 157 (34).
(
Acknowledgment
3
5
+
HRMS (EI): m/z for C H ClN (M ): 207.0815; found: 207.0814.
1
2
14
The authors thank Specialized Research Fund for the Doctoral Pro-
gram of Higher Education (No. 20060542007), the National Natural
Science Foundation of China (No 20572020 and 20472090), Fok
Ying Tung Education Foundation (No. 101012), the Key Project of
Chinese Ministry of Education (No. 206102), and Hunan Provincial
Natural Science Foundation of China (No. 05JJ1002) for financial
support.
1
-(3-Chloro-2-phenyl-1H-indol-1-yl)ethanone (4f)
Pale yellow solid; mp 83.1 °C.
1
H NMR (400 MHz, CDCl ): d = 8.41 (d, J = 8.0 Hz, 1 H), 7.62 (d,
3
J = 8.0 Hz, 1 H), 7.55–7.36 (m, 7 H), 2.00 (s, 3 H).
1
3
C NMR (100 MHz, CDCl ): d = 170.8, 136.8, 134.0, 131.3, 130.2,
3
1
29.3, 128.9, 127.1, 126.5, 124.2, 118.4, 116.3, 114.3, 27.6.
+
+
LRMS (EI, 70 eV): m/z (%) = 271 (M + 2, 3), 269 (M , 10), 229
13), 227 (46), 201 (2), 199 (6), 165 (11), 89 (70), 43 (100).
References
(
(1) For recent reviews, see: (a) Crisp, G. T. Chem. Soc. Rev.
3
5
+
HRMS (EI): m/z calcd for C H ClNO (M ): 269.0607; found:
1
6
12
1
998, 27, 427. (b) Gribble, G. W. Chem. Soc. Rev. 1999, 28,
2
69.0607.
335. (c) Li, J. J.; Gribble, G. W. In Palladium in
Heterocyclic Chemistry; Pergamon: Amsterdam, 2000.
1
-(3-Chloro-5,6-difluoro-2-octyl-1H-indol-1-yl)ethanone (4h)
(
(
d) Gribble, G. W. Environ. Sci. Pollut. Res. 2000, 7, 37.
e) Lu, X. In Handbook of Organopalladium Chemistry for
Pale yellow oil.
1
H NMR (400 MHz, CDCl ): d = 6.96 (d, J = 8.8 Hz, 1 H), 6.77–
3
Organic Synthesis, Vol. 2; Negishi, E., Ed.; Wiley-
Interscience: New York, 2002, 2267–2288. (f) Knölker, H.
J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303.
(g) Chinchilla, R.; Nájera, C.; Yus, M. Chem. Rev. 2004,
104, 2667. (h) Lloyd-Williams, P.; Giralt, E. Chem. Soc.
Rev. 2001, 30, 145. (i) Cacchi, S.; Fabrizi, G. Chem. Rev.
6
.71 (m, 1 H), 6.33 (s, 1 H), 2.86 (t, J = 7.8 Hz, 2 H), 2.62 (d,
J = 6.0 Hz, 3 H), 1.70–1.64 (m, 2 H), 1.40–1.28 (m, 10 H), 0.88 (t,
J = 6.8 Hz, 3 H).
1
3
C NMR (100 MHz, CDCl ): d = 171.5, 160.0 (d, J = 11.3 Hz, 1
3
C), 157.6 (d, J = 11.3 Hz, 1 C), 149.9 (d, J = 14.2 Hz, 1 C), 147.6
d, J = 14.2 Hz, 1 C), 146.2, 133.7, 119.9, 105.9, 101.6 (dd, J = 3.6
Hz, 2.8 Hz, 1 C), 98.9 (dd, J = 25.1 Hz, 25.1 Hz, 1 C), 31.9, 29.4,
9.3, 29.1, 28.7, 26.9, 26.8, 22.7, 14.1.
2005, 105, 2873. (j) Humphrey, G. R.; Kuethe, J. T. Chem.
(
Rev. 2006, 106, 2875.
(
2) For selected papers, see: (a) Carter, G. T.; Rinehart, K. L.
Jr.; Li, H. L.; Connor, S. L. K. L. Tetrahedron Lett. 1978, 19,
2
+
+
LRMS (EI, 70 eV): m/z (%) = 343 (M + 2, 5), 341 (M , 15), 301
9), 299 (28), 264 (18), 165 (15), 43 (100).
4479. (b) Tarzia, G.; Diamantini, G.; Giacomo, B. D.;
(
Spadoni, G. J. Med. Chem. 1997, 40, 2003. (c) He, F.;
Foxman, B. M.; Snider, B. B. J. Am. Chem. Soc. 1998, 120,
6417. (d) Kanekiyo, N.; Kuwada, T.; Choshi, T.; Nobuhiro,
J.; Hibino, S. J. Org. Chem. 2001, 66, 8793. (e) Zhang, H.;
Larock, R. C. Org. Lett. 2001, 3, 3083. (f) Zhang, H.;
3
5
+
HRMS (EI): m/z calcd for C H ClF NO (M ): 341.1358; found:
3
1
8
22
2
41.1357.
Synthesis 2007, No. 12, 1841–1847 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Substituted 3-Halo-1H-indoles
1847
Larock, R. C. J. Org. Chem. 2002, 67, 9318. (g) Hooper,
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4
9, 2611.
concentration of the halide ions can stabilize intermediate 6
in Scheme 2. However, more halide ions result in some side-
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(
3) For representative papers on the synthesis 3-haloindole
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(
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1
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(
4) (a) Bocchi, V.; Palla, G. Synthesis 1982, 1096. (b) Martin,
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(
6
e) Billimoria, A. D.; Cava, M. P. J. Org. Chem. 1994, 59,
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(
(
(
b) Tarzia, G.; Diamantini, G.; Giacomo, B. Di.; Spadoni, G.
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(
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Synthesis 2007, No. 12, 1841–1847 © Thieme Stuttgart · New York