Copper(I)-catalyzed, one-pot synthesis of multisubstituted indoles from 2-iodoanilines and ethyl buta-2,3-dienoate

Article abstract of DOI:10.1055/s-0031-1289743

Reactions of 2-iodoanilines with ethyl buta-2,3-dienoate catalyzed by potassium carbonate and CuI in one pot generate the corresponding ethyl 2-methyl-1H-indole-3-carboxylate products in moderate yields under mild conditions. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289743

PAPER
1037
Copper(I)-Catalyzed, One-Pot Synthesis of Multisubstituted Indoles from
2-Iodoanilines and Ethyl Buta-2,3-dienoate
M
ultisubstituted In
i
doles
f
a
r
om 2-Iodo
n
a
nilines and
x
Allene
s
ue Wang, Jin Liu, Han Guo, Chao Ma, Xiai Gao, Kang Zhou, Guosheng Huang*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8912582; E-mail: hgs@lzu.edu.cn
Received 30 December 2011; revised 24 January 2012
When a mixture of 1a and 2a in dioxane was heated
(100 °C, 8 h; t1) and cooled to room temperature, then a
catalytic amount of CuI was added and the mixture again
heated (120 °C, 7 h; t2), to our delight, 3aa was obtained
Abstract: Reactions of 2-iodoanilines with ethyl buta-2,3-dienoate
catalyzed by potassium carbonate and CuI in one pot generate the
corresponding ethyl 2-methyl-1H-indole-3-carboxylate products in
moderate yields under mild conditions.
Key words: indoles, aniline, allenes, copper, catalysis
Table 1 Survey of Catalysts, Bases, and Solvent Effects in the Re-
action of 1a with 2aa
COOEt
1. base, solvent, 100 °C, t1
2. catalyst, 120 °C, t2
I
The indole moiety exists in a wide range of natural prod-
ucts and pharmaceuticals.1 Their importance in medicinal
chemistry has stimulated considerable interest from or-
ganic chemists, and has encouraged the development of
new synthetic methods to prepare these compounds.2
Many strategies for the synthesis of the indole moiety,3 in
addition to the classical Fisher indole synthesis,4 have al-
ready been reported. Recent progress in metal-catalyzed
construction of the indole skeleton5 has achieved remark-
able improvements regarding efficiency and functional
group compatibility. In particular, the palladium-cata-
lyzed ring-closing reaction of aniline derivatives with
alkynes was been widely investigated and can efficiently
produce multisubstituted indoles.6 In addition, transition-
metal-catalyzed intermolecular cyclization of N-(2-halo-
aryl)enamine or N-aryl enamine, derived from alkynes or
acyclic b-diketones, has been used in the synthesis of mul-
tisubstituted indoles.7 Direct construction of multi-substi-
tuted indoles from allenes has received less attention.
Only Mukai and Takahashi synthesized 2,3-disubstituted
indoles with N-acyl-2-iodoanilines and the 1-(tributyl-
stannyl)-1-substituted allenes.8 In this reaction, a tin re-
agent was used as substrate that is not readily accessible
and is harmful to environment. Therefore, methods of
•
+
N
NH2
H
COOEt
2a
1a
3aa
Entry Base
t1
(h)
Catalyst
t2
(h)
Solvent
Conv. Yield
(%)b (%)c
1
K2CO3
K2CO3
0
8
4
8
8
8
8
8
8
8
8
8
8
8
8
8
8
CuI
12 1,4-dioxane 32 28
2
CuI
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
1,4-dioxane 100 70
1,4-dioxane 51 45
1,4-dioxane 100 72
1,4-dioxane 100 70
3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
KOH
CuI
4d
5e
6
CuI
CuI
–
1,4-dioxane 100
0
7
Cu2O
CuBr
Cu(OAc)2
[Cu]f
CuI
1,4-dioxane 100 44
1,4-dioxane 100 40
1,4-dioxane 100 50
1,4-dioxane 100 53
8
9
10
11
THF
80 30
synthesis of multisubstituted indoles with allenes need 12
CuI
DMSO
DMF
NMP
0
0
improvement. As a part of our continuing study on the use
13
CuI
70 36
of copper catalysis in the synthesis of heterocycles,9 here-
in, we report a straightforward, one-pot synthesis of mul-
tisubstituted indoles from 2-iodoanilines and ethyl buta-
2,3-dienoate.
14
15
16
17
CuI
0
0
CuI
1,4-dioxane 63 34
1,4-dioxane 26 20
CuI
Our initial study began with the reaction of 2-iodoaniline
(1a) and ethyl buta-2,3-dienoate (2a) in the presence of
1.5 equivalents of K2CO3 in 1,4-dioxane at 120 °C. The
desired ethyl 2-methyl-1H-indole-3-carboxylate (3aa)
was obtained in 32% conversion and 28% yield in the re-
action catalyzed by CuI after 12 hours (Table 1, entry 1).
CuI
1,4-dioxane 40
0
a Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol) and base
(0.3 mmol) in solvent (0.9 mL), 100 °C for t1, then cooled to r.t. and
catalyst (0.02 mmol) was added and the mixture was heated at 120 °C
for t2.
b Conversions are given for 1a.
c Isolated yield.
SYNTHESIS 2012, 44, 1037–1042
x
x.
x
x.
2
0
1
2
d Reaction was carried out with 2 equiv base.
e Reaction was carried out with 1.5 equiv base under nitrogen.
f [Cu] = CuI-phenanthroline.
Advanced online publication: 14.03.2012
DOI: 10.1055/s-0031-1289743; Art ID: F120011SS
© Georg Thieme Verlag Stuttgart · New York

1038
X. Wang et al.
PAPER
in 100% conversion and 70% yield (Table 1, entry 2). uated (Table 1, entries 15–17), and K2CO3 was found to
When t1 was reduced, a lower conversion of 3aa was ob- provide the product in good yield. It is worth mentioning
tained (Table 1, entry 3). By increasing the base loading that when the reaction was carried out under nitrogen,
to two equivalents, the conversion of 3aa changed only product 3aa was also obtained in 70% yield (Table 1, en-
slightly (Table 1, entry 4).
try 5). Thus, the most suitable reaction conditions for the
formation of 3aa was found to be 1.5 equivalent of
K2CO3, 1,4-dioxane, and 10 mol% CuI (Table 1, entry 2),
which provided product 3aa in good yield.
A range of copper salts such as Cu2O, CuBr, Cu(OAc)2
and CuI-phenanthroline were then examined (Table 1, en-
tries 7–10), but no better results were obtained. In addi-
tion, in the absence of metal salts, no desired product was Under the optimized reaction conditions, we then attempt-
found, but ethyl 3-(2-iodophenylamino)but-2-enoate was ed to extend the scope of this reaction to test the generality
detected (Table 1, entry 6). Among the solvent systems of this method; the results are illustrated in Table 2. Gen-
examined, changing the solvent to THF, DMSO, DMF, or erally, reaction of 2-iodoanilines with ethyl buta-2,3-di-
NMP did not improve the conversions or yields (Table 1, enoate proceeded smoothly and led to the desired
entries 11–14). The results indicated that the choice of multisubstituted indoles in moderate yields. Thankfully,
1,4-dioxane as solvent was crucial for the reaction. Other the reaction was found to tolerate a range of functional-
bases such as Na2CO3, Cs2CO3, and KOH were also eval- ities, including alkyl-substituted, cyano-substituted, keto-
Table 2 Synthesis of Ethyl 2-Methyl-1H-indole-3-carboxylate
1. K2CO3, 1,4-dioxane,
100 °C, t1
2. CuI, 120 °C, t2
R1
R1
COOEt
R5
R2
R3
R2
R3
I
+
•
R5
N
NH2
H
COOEt
R4
R4
Entry
1
1
R1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
R2
R3
R4
H
2
R5
H
t1 (h)
8
t2 (h)
7
Product
3aa
3ab
3ac
3ad
3ae
3ba
3ca
3da
3ea
3fa
Conv. (%)a Yield (%)b
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
H
H
2a
2b
2c
2d
2e
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
100
84
70
51
50
46
56
72
76
81
71
43
47
44
37
31
82
74
45
43
40
52
2
H
H
H
Me
Ec
Fc
Gc
H
8
7
3
H
H
H
8
7
83
4
H
H
H
8
7
80
5
H
H
H
6
4
100
100
100
100
100
60
6
Me
H
H
8
7
7
Et
H
H
H
7
7
8
Me2CH
H
H
H
7
7
9
H
Cl
Br
I
Me
H
H
H
8
7
10
11
12
13
14
15
16
17
18
19
20
H
H
8
7
1g
1h
1i
H
H
H
8
7
3ga
3ha
3ia
65
H
H
H
8
7
61
Ac
CN
Me
I
H
H
H
8
7
51
1j
H
H
H
16
5.5
7
7
3ja
62
1k
1l
Me
Me
H
H
H
7
3ka
3la
100
100
60
Me
Me
Me
Et
H
H
7
1m
1n
1o
I
H
8
7
3ma
3na
3oa
3pa
I
H
H
8
7
54
I
H
H
8
7
62
1p
–(CH=CH)2–
H
H
8
7
80
a Conversions are given for 1.
b Isolated yield.
c E = n-Bu; F = i-Pr; G = COOEt.
Synthesis 2012, 44, 1037–1042
© Thieme Stuttgart · New York

PAPER
Multisubstituted Indoles from 2-Iodoanilines and Allenes
1039
R
substituted, and halogenated 2-iodoanilines. Good con-
versions and yields of indole products 3 were usually ob-
tained with 2-iodoanilines containing electron-donating
substituents (Table 2, entries 6–9 and 15). In addition, the
conversions and yields of para- and meta-substituted 2-
iodoanilines changed only slightly (Table 2, entries 6 and
9).
R
I
I
COOEt
K2CO3
•
+
NH2
N
H
COOEt
2
1
A
COOEt
R
B
Cu(I)I
+BHI–
N
H
3
Under the same experimental conditions, 2-iodoanilines
with electron-withdrawing substituents gave lower con-
versions and yields (Table 2, entries 10–14). Spatial ef-
fects had little impact on the conversions or yield of the
reaction (Table 2, entries 12 and 16–19). 2-Iodoanilines
bearing benzo rings, such as 1-iodonaphthalen-2-amine
could also react to give 3pa in 52% yield (Table 2, entry
20). Further investigations demonstrated that allenes with
electron-withdrawing substituents gave higher yields than
those with electron-donating groups (Table 2, entries 2–
5). To our delight, 3af was also obtained in 65% yield
(Equation 1).
I
R
Cu(III)COOEt
O
Cu(I)
COOEt
OEt
R
R
I
I
N
H
Cu(I)
C
N
H
N
B
Scheme 2 Possible reaction pathway
In summary, we have developed a novel methodology for
the synthesis of 2-methyl-1H-indole-3-carboxylates,
based on the addition of 2-iodoaniline and ethyl buta-2,3-
dienoate followed by intramolecular cyclization, in the
presence of a common and inexpensive catalyst. In addi-
tion, several multisubstituted indoles were synthesized in
a one-pot process that consist of a Michael addition reac-
tion and a Heck coupling reaction of 2-iodoanilines with
ethyl buta-2,3-dienoate. Further application of this meth-
od to the synthesis of bioactive compounds and natural
products with the indole skeleton as a core framework will
be reported in due course.
1. K2CO3, 1,4-dioxane,
100 °C, 8 h
2. CuI, 120 °C, 5 h
I
Ph
+
•
NH2
N
H
Ph
Equation 1 Reactions of 1a and 2f to give 3af
The reaction of 1a and 2a in the presence of K2CO3 af-
forded ethyl 3-(2-iodophenyl-amino)but-2-enoate (3aa¢;
Scheme 1),10 which was detected by NMR analysis. On
the basis of the results obtained above, a plausible path-
way for this reaction is illustrated in Scheme 2. The reac-
NMR spectra were recorded at 400 (1H) and 100 MHz (13C) with a
Bruker ARX 400 spectrometer, using CDCl3 as solvent and TMS as
tion consists of a Michael addition reaction and an internal standard. IR spectra were recorded with an FT-IR spec-
trometer and only major peaks are reported. Melting points were de-
termined with a microscopic apparatus and are uncorrected. All new
products were further characterized by HRMS analysis. For product
purification by flash column chromatography, silica gel (200–300
intramolecular Heck coupling reaction of 2-iodoanilines
and ethyl buta-2,3-dienoate. The reaction of 1 and 2 in the
presence of K2CO3 leads to the formation of intermediate
A. The next step involves initial coordination of carbon
mesh) was used. Petroleum ether (PE), where used, had a boiling
range 30–60 °C. Allenes were prepared according to the literature.11
Multisubstituted 2-iodoanilines were prepared according to the
literature.12
with copper (Scheme 2). The resulting complex B under-
goes an oxidative addition of the C–X bond7e to copper to
obtain the Cu(III) intermediate C. Reductive elimination
of C then releases the desired product with concomitant
regeneration of the Cu(I) species. Another possible mech-
anism involves the formation of C through oxidative ad-
dition of the C–I bond to CuI to produce a Cu(II)
intermediate, which is followed by nucleophilic displace-
ment of iodide by the anionic fragment. However, neither
2 nor the byproducts of 2 were found at the end of the re-
action; this may be because unreacted 2 decomposes.
Ethyl 2-Methyl-1H-indole-3-carboxylate (3aa); Typical Proce-
dure
A mixture of 1a (43.8 mg, 0.2 mmol) and 2a (26.9 mg, 0.24 mmol)
in 1,4-dioxane (0.9 mL) was heated at 100 °C for 8 h in a sealed re-
action tube. After cooling to r.t., CuI (3.8 mg, 0.02 mmol) was add-
ed and the mixture was heated at 120 °C for 7 h. After removal of
the solvent under reduced pressure, the crude product was purified
by column chromatography on silica gel (EtOAc–PE, 1:6) to give
3aa.
Yield: 28.5 mg (70%); white solid; mp 135–136 °C.
IR (KBr): 3301, 2291, 1660, 1456, 732 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.45 (br, 1 H), 8.11 (d, J = 7.2 Hz,
1 H), 7.28 (d, J = 6.8 Hz, 1 H), 7.21 (m, 2 H), 4.40 (q, J = 7.2 Hz,
2 H), 2.73 (s, 3 H), 1.44 (t, J = 7.2 Hz, 3 H).
I
I
COOEt
K2CO3, 100 °C
•
+
NH2
N
H
3aa'
COOEt
2a
1a
Scheme 1 Reactions of 1a and 2a in the presence of K2CO3 at
100 °C
13C NMR (100 MHz, CDCl3): d = 166.1, 143.9, 134.5, 127.2, 122.3,
121.7, 121.3, 110.5, 104.7, 59.5, 14.6, 14.2.
HRMS: m/z [M + H]+ calcd for C12H13NO2: 204.1025; found:
204.1019.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 1037–1042

1040
X. Wang et al.
PAPER
Ethyl 2-Ethyl-1H-indole-3-carboxylate (3ab)
IR (KBr): 3292, 2977, 2922, 1656, 1457, 779 cm–1.
Yield: 22.0 mg (51%); colorless solid; mp 104–106 °C.
IR (KBr): 3303, 2978, 1665, 1456, 746 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.55 (br, 1 H), 8.15 (d, J = 7.2 Hz,
1 H), 7.34 (d, J = 4.8 Hz, 1 H), 7.20 (m, 2 H), 4.42 (q, J = 7.2 Hz,
2 H), 3.21 (q, J = 7.6 Hz, 2 H), 1.46 (t, J = 7.2 Hz, 3 H), 1.36 (t,
J = 7.6 Hz, 3 H).
1H NMR (400 MHz, CDCl3): d = 8.34 (br, 1 H), 7.92 (s, 1 H), 7.19
(d, J = 8.0 Hz, 1 H), 7.02 (d, J = 8.0 Hz, 1 H), 4.41 (q, J = 7.2 Hz,
2 H), 2.73 (s, 3 H), 2.48 (s, 3 H), 1.46 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 166.2, 143.8, 132.7, 131.1, 127.5,
123.7, 121.08, 110.1, 104.2, 59.4, 21.7, 14.6, 14.3.
HRMS: m/z [M + H]+ calcd for C13H15NO2: 218.1181; found:
218.1176.
13C NMR (100 MHz, CDCl3): d = 165.9, 149.5, 134.5, 127.3, 122.3,
121.7, 121.5, 110.6, 103.7, 59.4, 21.3, 14.6, 13.2.
Ethyl 5-Ethyl-2-methyl-1H-indole-3-carboxylate (3ca)
Yield: 35.1 mg (76%); white solid; mp 131–132 °C.
IR (KBr): 3299, 2966, 2926, 1658, 1433, 783 cm–1.
HRMS: m/z [M + H]+ calcd for C13H15NO2: 218.1181; found:
218.1179.
Ethyl 2-Pentyl-1H-indole-3-carboxylate (3ac)
Yield: 26.0 mg (50%); white solid; mp 49–51 °C.
IR (KBr): 3298, 2957, 2930, 1664, 1458, 742 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.43 (br, 1 H), 8.13 (d, J = 7.2 Hz,
1 H), 7.29 (m, 1 H), 7.21 (m, 2 H), 4.40 (q, J = 6.8 Hz, 2 H), 3.16 (t,
J = 7.6 Hz, 2 H), 1.74 (m, 2 H), 1.45 (t, J = 6.8 Hz, 3 H), 1.36 (m,
4 H), 0.89 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 166.1, 148.6, 134.5, 127.2, 122.2,
121.6, 121.4, 110.6, 103.8, 59.5, 31.6, 29.0, 28.0, 22.4, 14.5, 13.9.
1H NMR (400 MHz, CDCl3): d = 8.57 (br, 1 H), 7.97 (s, 1 H), 7.22
(d, J = 8.4 Hz, 1 H), 7.07 (d, J = 8.4 Hz, 1 H), 4.44 (q, J = 7.2 Hz,
2 H), 2.79 (q, J = 7.6 Hz, 2 H), 2.71 (s, 3 H), 1.49 (t, J = 7.2 Hz,
3 H), 1.33 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 166.3, 144.0, 137.8, 131.0, 127.5,
122.7, 119.8, 110.3, 104.2, 59.4, 29.2, 16.4, 14.6, 14.2.
HRMS: m/z [M + H]+ calcd for C14H17NO2: 232.1338; found:
232.1333.
Ethyl 5-Isopropyl-2-methyl-1H-indole-3-carboxylate (3da)
Yield: 39.7 mg (81%); white solid; mp 154–155 °C.
IR (KBr): 3287, 2958, 1652, 1455, 812 cm–1.
HRMS: m/z [M + Na]+ calcd for C16H21NO2: 282.1465; found:
282.1461.
Ethyl 2-Isobutyl-1H-indole-3-carboxylate (3ad)
Yield: 22.5 mg (46%); yellow solid; mp 74–75 °C.
IR (KBr): 3326, 2956, 1676, 1660, 1441, 1190, 748 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.41 (br, 1 H), 8.14 (m, 1 H), 7.32
(m, 1 H), 7.22 (m, 2 H), 4.39 (q, J = 6.8 Hz, 2 H), 3.03 (d,
J = 7.2 Hz, 2 H), 2.12 (m, 1 H), 1.45 (t, J = 7.2 Hz, 3 H), 0.97 (d,
J = 7.2 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 166.0, 147.6, 134.5, 127.3, 122.3,
121.6, 121.5, 110.6, 104.5, 59.5, 37.0, 29.2, 22.5, 14.5.
1H NMR (400 MHz, CDCl3): d = 8.64 (br, 1 H), 8.01 (s, 1 H), 7.23
(d, J = 8.4 Hz, 1 H), 7.11 (d, J = 8.4 Hz, 1 H), 4.44 (q, J = 7.2 Hz,
2 H), 3.10 (m, 1 H), 2.71 (s, 3 H), 1.48 (t, J = 7.2 Hz, 3 H), 1.34 (s,
3 H), 1.32 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 166.4, 144.0, 142.5, 133.1, 127.4,
121.3, 118.3, 110.3, 104.2, 59.4, 34.3, 24.5, 14.5, 14.2.
HRMS: m/z [M + H]+ calcd for C15H19NO2: 246.1494; found:
246.1490.
Ethyl 2,6-Dimethyl-1H-indole-3-carboxylate (3ea)
Yield: 30.8 mg (71%); white solid; mp 191–192 °C.
IR (KBr): 3371, 2976, 2918, 1656, 1408, 801 cm–1.
HRMS: m/z [M + Na]+ calcd for C15H19NO2: 268.1308; found:
268.1306.
Ethyl 2-(2-Ethoxy-2-oxoethyl)-1H-indole-3-carboxylate (3ae)
Yield: 30.8 mg (56%); yellow oil.
IR (KBr): 3321, 3061, 2982, 1691, 1457, 748 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.39 (br, 1 H), 7.99 (d, J = 8.0 Hz,
1 H), 7.07 (d, J = 8.8 Hz, 2 H), 4.41 (q, J = 7.2 Hz, 2 H), 2.71 (s,
3 H), 2.45 (s, 3 H), 1.46 (t, J = 7.2 Hz, 3 H).
1H NMR (400 MHz, CDCl3): d = 9.83 (br, 1 H), 8.14 (t, J = 4.0 Hz,
1 H), 7.38 (m, 1 H), 7.25 (m, 2 H), 4.44 (q, J = 7.2 Hz, 2 H), 4.37
(s, 2 H), 4.29 (q, J = 7.2 Hz, 2 H), 1.48 (t, J = 7.2 Hz, 3 H), 1.34 (t,
J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 171.0, 165.7, 138.7, 134.8, 126.4,
122.8, 121.8, 121.5, 111.1, 105.2, 61.5, 59.7, 32.3, 14.5, 14.1.
13C NMR (100 MHz, CDCl3): d = 166.2, 143.4, 134.9, 132.1, 124.9,
123.3, 120.9, 110.5, 104.4, 59.4, 21.5, 14.6, 14.1.
HRMS: m/z [M + H]+ calcd for C13H15NO2: 218.1181; found:
218.1177.
Ethyl 5-Chloro-2-methyl-1H-indole-3-carboxylate (3fa)
Yield: 20.4 mg (43%); white solid; mp 181–182 °C.
IR (KBr): 3286, 2978, 2921, 1663, 1453, 776 cm–1.
HRMS: m/z [M + H]+ calcd for C15H17NO4: 276.1236; found:
276.1240.
1H NMR (400 MHz, CDCl3): d = 8.41 (br, 1 H), 8.08 (s, 1 H), 7.21
(d, J = 8.8 Hz, 1 H), 7.15 (d, J = 8.8 Hz, 1 H), 4.40 (q, J = 7.2 Hz,
2 H), 2.75 (s, 3 H), 1.46 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 165.6, 145.0, 132.8, 128.3, 127.6,
122.7, 121.0, 111.4, 104.7, 59.7, 14.6, 14.3.
HRMS: m/z [M + H]+ calcd for C12H12ClNO2: 238.0635; found:
238.0633.
2-Methyl-3-phenyl-1H-indole (3af)
Yield: 26.9 mg (65%); colorless oil.
IR (KBr): 3401, 1603, 1496, 1459, 1258, 908, 748, 702 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.96 (br, 1 H), 7.67 (d, J = 7.8 Hz,
1 H), 7.54 (m, 4 H), 7.35 (m, 2 H), 7.19 (m, 2 H), 2.52 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 135.4, 135.1, 131.4, 129.4, 128.5,
127.7, 125.7, 121.4, 119.9, 118.7, 114.3, 110.3, 12.4.
Ethyl 5-Bromo-2-methyl-1H-indole-3-carboxylate (3ga)
Yield: 26.4 mg (47%); gray-green solid; mp 163–165 °C.
IR (KBr): 3282, 2975, 2921, 1665, 1455, 779 cm–1.
HRMS: m/z [M + H]+ calcd for C15H13N: 208.1126; found:
208.1124.
Ethyl 2,5-Dimethyl-1H-indole-3-carboxylate (3ba)
Yield: 31.2 mg (72%); white solid; mp 177–178 °C.
Synthesis 2012, 44, 1037–1042
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Multisubstituted Indoles from 2-Iodoanilines and Allenes
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1H NMR (400 MHz, CDCl3): d = 8.37 (br, 1 H), 8.24 (s, 1 H), 7.29
(d, J = 8.8 Hz, 1 H), 7.17 (d, J = 8.8 Hz, 1 H), 4.40 (q, J = 7.2 Hz,
2 H), 2.75 (s, 3 H), 1.46 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 165.5, 144.8, 133.1, 128.9, 125.3,
124.0, 115.2, 111.8, 104.6, 59.7, 14.6, 14.2.
13C NMR (100 MHz, CDCl3): d = 165.7, 143.7, 134.5, 131.5, 129.3,
126.8, 118.2, 104.3, 95.1, 59.6, 24.8, 15.0, 14.6, 14.2.
HRMS: m/z [M + H]+ calcd for C14H16INO2: 358.0304; found:
358.0301.
Ethyl 5-Iodo-2,7-dimethyl-1H-indole-3-carboxylate (3ma)
Yield: 30.9 mg (45%); colorless solid; mp 226–227 °C.
IR (KBr): 3299, 2976, 2923, 1665, 1444, 867 cm–1.
HRMS: m/z [M + H]+ calcd for C12H12BrNO2: 282.0130; found:
282.0127.
Ethyl 5-Iodo-2-methyl-1H-indole-3-carboxylate (3ha)
Yield: 29.0 mg (44%); white solid; mp 185–186 °C.
IR (KBr): 3384, 3268, 2922, 1652, 1429, 776 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.30 (s, 1 H), 8.27 (br, 1 H), 7.31
(s, 1 H), 4.40 (q, J = 7.2 Hz, 2 H), 2.76 (s, 3 H), 2.43 (s, 3 H), 1.45
(t, J = 7.2 Hz, 3 H).
1H NMR (400 MHz, CDCl3): d = 8.46 (s, 1 H), 8.40 (br, 1 H), 7.46
(d, J = 8.4 Hz, 1 H), 7.09 (d, J = 8.4 Hz, 1 H), 4.40 (q, J = 7.2 Hz,
2 H), 2.74 (s, 3 H), 1.45 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 165.5, 144.4, 133.6, 130.8, 130.2,
129.5, 112.3, 104.2, 85.8, 59.7, 14.6, 14.2.
13C NMR (100 MHz, CDCl3): d = 165.6, 143.9, 133.2, 131.3, 128.9,
127.9, 121.7, 104.5, 85.9, 59.7, 16.1, 14.6, 14.2.
HRMS: m/z [M + H]+ calcd for C13H14INO2: 344.0147; found:
344.0145.
Ethyl 5-Iodo-2,4,7-trimethyl-1H-indole-3-carboxylate (3na)
Yield: 30.7 mg (43%); brown-black solid; mp 55–56 °C.
IR (KBr): 3313, 2976, 2923, 1672, 1439, 1088, 739 cm–1.
HRMS: m/z [M + H]+ calcd for C12H12INO2: 329.9991; found:
329.9987.
Ethyl 5-Acetyl-2-methyl-1H-indole-3-carboxylate (3ia)
Yield: 18.1 mg (37%); white solid; mp 180–181 °C.
1H NMR (400 MHz, CDCl3): d = 8.19 (br, 1 H), 7.48 (s, 1 H), 4.39
(q, J = 7.2 Hz, 2 H), 2.73 (s, 3 H), 2.63 (s, 3 H), 2.38 (s, 3 H), 1.41
(t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 166.2, 141.0, 134.2, 133.4, 131.2,
125.5, 119.0, 107.5, 94.9, 60.2, 26.8, 15.6, 14.4, 14.2.
HRMS: m/z [M + H]+ calcd for C14H16INO2: 358.0304; found:
358.0300.
IR (KBr): 3219, 3187, 3044, 2976, 2924, 1685, 1650, 1473,
729 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.89 (br, 1 H), 8.78 (s, 1 H), 7.91
(q, J = 8.4 Hz, 1 H), 7.36 (d, J = 8.4 Hz, 1 H), 4.47 (q, J = 7.2 Hz,
2 H), 2.78 (s, 3 H), 2.70 (s, 3 H), 1.50 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 198.7, 165.6, 145.3, 137.3, 131.5,
126.9, 123.6, 122.5, 110.6, 105.9, 59.8, 26.6, 14.5, 14.3.
Ethyl 7-Ethyl-5-iodo-2-methyl-1H-indole-3-carboxylate (3oa)
Yield: 28.6 mg (40%); colorless solid; mp 179–180 °C.
IR (KBr): 3298, 2970, 2929, 1666, 1446, 860 cm–1.
HRMS: m/z [M + H]+ calcd for C14H15NO3: 246.1130; found:
246.1136.
1H NMR (400 MHz, CDCl3): d = 8.31 (s, 2 H), 7.32 (s, 1 H), 4.40
(q, J = 7.2 Hz, 2 H), 2.80 (q, J = 7.6 Hz, 2 H), 2.76 (s, 3 H), 1.45 (t,
J = 7.2 Hz, 3 H), 1.34 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 165.6, 143.8, 132.5, 129.5, 129.1,
127.9, 104.6, 86.3, 59.7, 23.50, 14.6, 14.2, 13.8.
HRMS: m/z [M + H]+ calcd for C14H16INO2: 358.0304; found:
358.0302.
Ethyl 5-Cyano-2-methyl-1H-indole-3-carboxylate (3ja)
Yield: 14.1 mg (31%); white solid; mp 245–246 °C.
IR (KBr): 3276, 2984, 2922, 2853, 2217, 1665, 1467 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.62 (br, 1 H), 8.46 (s, 1 H), 7.47
(d, J = 8.4 Hz, 1 H), 7.39 (d, J = 8.4 Hz, 1 H), 8.46 (q, J = 7.2 Hz,
2 H), 2.80 (s, 3 H), 1.49 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 165, 145.9, 136.2, 127.0, 126.8,
125.6, 120.5, 105.6, 105.0, 60.0, 14.6, 14.2.
Ethyl 2-Methyl-3H-benzo[e]indole-1-carboxylate (3pa)
Yield: 26.3 mg (52%); white solid; mp 174–175 °C.
IR (KBr): 3327, 2984, 2905, 1669, 1439, 804 cm–1.
HRMS: m/z [M + H]+ calcd for C13H12N2O2: 229.0977; found:
229.0980.
1H NMR (400 MHz, CDCl3): d = 9.33 (d, J = 8.8 Hz, 1 H), 8.56 (br,
1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.63 (d, J = 4.4 Hz, 1 H), 7.58 (m,
1 H), 7.46 (m, 2 H), 4.50 (q, J = 7.2 Hz, 2 H), 2.72 (s, 3 H), 1.49 (t,
J = 7.2 Hz, 3 H).
Ethyl 2,5,6-Trimethyl-1H-indole-3-carboxylate (3ka)
Yield: 37.9 mg (82%); colorless solid; mp 196–197 °C.
IR (KBr): 3275, 2922, 1653, 1416, 778 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.40 (br, 1 H), 7.89 (s, 1 H), 7.04
(s, 1 H), 4.42 (q, J = 7.2 Hz, 2 H), 2.69 (s, 3 H), 2.38 (s, 3 H), 2.35
(s, 3 H), 1.46 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 166.4, 143.1, 133.4, 131.1, 130.3,
125.5, 121.3, 111.0, 103.9, 59.4, 20.3, 20.2, 14.6, 14.2.
13C NMR (100 MHz, CDCl3): d = 166.6, 140.2, 131.6, 130.6, 128.6,
128.1, 126.1, 125.6, 124.5, 123.8, 111.7, 108.3, 60.1, 15.3, 14.5.
HRMS: m/z [M + H]+ calcd for C16H15NO2: 254.1181; found:
254.1175.
Ethyl 3-[(2-Iodophenyl)amino]but-2-enoate (3aa¢)
HRMS: m/z [M + H]+ calcd for C14H17NO2: 232.1338; found:
232.1332.
Yellow oil.
IR (KBr): 3458, 3363, 3061, 2979, 1613, 1478, 748 cm–1.
Ethyl 5-Iodo-2,6,7-trimethyl-1H-indole-3-carboxylate (3la)
Yield: 52.8 mg (74%); white solid; mp 230–232 °C.
IR (KBr): 3339, 2985, 2925, 1696, 1659, 1441, 799 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.47 (s, 1 H), 8.15 (br, 1 H), 4.41
(q, J = 7.2 Hz, 2 H), 2.75 (s, 3 H), 2.53 (s, 3 H), 2.45 (s, 3 H), 1.45
(t, J = 7.2 Hz, 3 H).
1H NMR (400 MHz, CDCl3): d = 10.18 (br, 1 H), 7.89 (d,
J = 8.0 Hz, 1 H), 7.32 (t, J = 7.6 Hz, 1 H), 7.17 (d, J = 7.6 Hz, 1 H),
6.94 (t, J = 8.0 Hz, 1 H), 4.78 (s, 1 H), 4.21 (q, J = 7.2 Hz, 2 H),
1.87 (s, 3 H), 1.32 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.2, 158.1, 141.3, 139.4, 128.7,
127.2, 126.8, 97.7, 86.9, 58.86, 20.1, 14.5.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 1037–1042

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X. Wang et al.
PAPER
(3) (a) Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic
HRMS: m/z [M + H]+ calcd for C12H14INO2: 332.0147; found:
332.0144.
Chemistry; Stanley Thornes Ltd.: Cheltenham, 1995.
(b) Gilchrist, T. L. Heterocyclic Chemistry; Addison-
Wesley Longman Limited: Singapore, 1997. (c) Gilchrist,
T. L. J. Chem. Soc., Perkin Trans. 1 2001, 2491. (d) He, Z.;
Li, H.; Li, Z. J. Org. Chem. 2010, 75, 4636. (e) He, Z.; Liu,
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Acknowledgment
The authors thank the State Key Laboratory of Applied Organic
Chemistry for financial support.
(4) Robinson, B. The Fischer Indole Synthesis; John Wiley and
Sons: New York, 1982.
(5) For recent reviews, see: (a) Cacchi, S.; Fabrizi, G. Chem.
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Synthesis 2012, 44, 1037–1042
© Thieme Stuttgart · New York