Copper-catalysed direct C-H bond oxidative acetoxylation and iodination of indoles

Article abstract of DOI:10.3184/174751912X13360637793465

A novel Cu(OAc)₂-catalysed direct C-H bond oxidative acetoxylation and iodination of indoles using PhI(OAc)₂ as a terminal oxidant is reported. Adopting this method, a series of 3-iodoindoles and indol-3-yl acetates were obtained in nearly 1:1 ratio yield.

Full text of DOI:10.3184/174751912X13360637793465

356 RESEARCH PAPER
JUNE, 356–359
JOURNAL OF CHEMICAL RESEARCH 2012
Copper-catalysed direct C–H bond oxidative acetoxylation and iodination
of indoles
Shao-peng Gea, Xiao-hong Zhanga*, Jiang-sheng Hana and Ping Zhonga,b
aCollege of Chemistry and Materials Science, Wenzhou University, Wenzhou 325035, P. R. China
bOujiang College, Wenzhou University, Wenzhou 325035, P. R. China
A novel Cu(OAc)2-catalysed direct C–H bond oxidative acetoxylation and iodination of indoles using PhI(OAc)2 as a
terminal oxidant is reported. Adopting this method, a series of 3-iodoindoles and indol-3-yl acetates were obtained
in nearly 1:1 ratio yield.
Keywords: Cu-catalysed, acetoxylation, iodination, indoles
Indole derivatives are an important class of compounds in
the pharmaceutical chemistry owing to their biological activi-
ties.1–4 In particular, 3-acetoxyindole is commonly used for the
detection of acetylcholinesterase in tissue slices and for the
identification of this enzyme in serum.5 Consequently there is
growing interest in efficiently synthesising 3-acetoxyindol.6
The most straightforward C–O bond forming reaction is the
metal-catalysed direct C–H bond oxidation.7,8 For example,
Sanford,9 Chen10 and Wu11 used the Pd-catalysed acetoxylation
of Sp2 C–H bond based on different aromatic substances using
PhI(OAc)2 and K2S2O8 as terminal oxidants respectively.
However, there are few reports on the C-3 acetoxylation of the
indole moiety12–14 and the limited reports were restricted to the
use of the expensive Pd catalyst. In order to expand the diver-
sity of the catalyst, copper was examined as a catalyst for the
acetoxylation of the 1H-indole or N-substituted indole nucleus.
It was interesting to find that the 3-iodination of indole occurred
along with acetoxylation when using PhI(OAc)2 as terminal
oxidants and gave the corresponding products in nearly 1:1
ratio yield. In general, iodination is a relatively difficult
process compared to bromination and several additives, such
as NIS,15 I2,16 H5IO6,17 ICl18 or HIO3,19 have been used for the
iodination reaction. PhI(OAc)2 has seldom been tested for the
synthesis of the iodo compounds. Here, we wish to describte a
new process for the Cu-catalysed direct C–H bond oxidative
3-acetoxylation and 3-iodination of indoles. Furthermore, the
products of 3-iodoindoles can be used as starting materials to
synthesise a series of complicated indole derivatives.
are summarised in Table 2. It can be seen that the N-substituted
groups had little effect on the reactions and about 50% acetox-
ylation products and 40% iodination products were obtained
respectively. N-substituted indoles with a wide range of substi-
tuted groups, such as methyl, chloro and fluoro, underwent the
acetoxylation and iodination reaction smoothly and gave the
corresponding products in nearly 1:1 ratio yield. Moreover, all
the acetoxylation and iodination products were identified by
the 1H NMR and 13C NMR spectrum. The 1H NMR spectrum
of 6a for example, displayed singlets at δ 2.27 and 3.66 due to
CH3 groups (six protons) connected with N atom and C=O
respectively, four multiplet-signals at δ 7.01–7.47 due to the
benzene ring (four protons) and a singlet signal at δ 7.15 due
1
to the 2-position-H of indole (one proton). The H NMR
spectrum of 6b for example, displayed a singlet at δ 3.70 due
to CH3 groups (three protons) connected with N atom, four
multiplet-signals at δ 7.09–7.37 due to the benzene ring (four
protons) and a singlet signal at δ 7.03 due to the H–C atom
adjacent to N atom (one proton). The detailed 1H NMR and 13C
NMR data for the acetoxylation and iodination products can be
seen in the experimental part.
Experimental
Chemicals were either purchased or purified by standard techniques.
NMR spectroscopy was performed on a Bruker Avance-500 spectro-
meter operating at 500 MHz (1H NMR) and 125 MHz (13C NMR),
using CDCl3 as the solvent with tetramethylsilane (TMS) as an
internal standard at room temperature. The high resolution mass
Results and discussion
Table 1 Evaluation of the acetoxylation and iodination
The reaction of 1-benzyl-1H-indole (1) with PhI(OAc)2 was
chosen to identify the optimal conditions (Table 1). After many
attempts, we obtained the best conditions for the formation of
1a in 56% yield associated with the formation of 1b in 40%
yield, involving Cu(OAc)2 as the catalyst precursor, KOAc
as the base and MeCN as the solvent at 100 °C (entry 3). Cu
precursors were critical for the reaction. When CuBr2 and
CuCl2 were employed as catalyst precursors, the reactions gave
poor yields of 1a and 1b (entries 1 and 2). When Cu (I) or Fe
catalyst replaced the Cu (II) or the Cu catalyst was absent, only
a trace of product was detected (entries 4, 5 and 6). Among the
bases screened, KOAc gave better result than KOH and K2CO3
(entries 8 and 9). No acetoxylation or iodination occurred
without the base (entry 7). Examination of the solvent effects
showed that the reaction proceeded best in CH3CN compared
to DMF or DMSO (entries 10 and 11).
conditionsa
Entry
Catalyst
Base
Solvent 1a Yield/%b 1b Yield/%b
1
2
CuBr2
CuCl2
Cu(OAc)2
CuBr
FeCl3
-
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2 K2CO3
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
-
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
20
10
21
12
3
56
40
4
Trace
Trace
Trace
Trace
24
trace
trace
trace
trace
22
5
6
7
8
KOH
With the optimal reaction conditions to hand, the substrate
scope of the indole substrate was extended to N-benzylindole
(entries 1–5), N-methylindole (entry 6), N-isobutenylindole
(entries 7–12), N-n-butylindole (entries 13–18), and the results
9
10
11
10
11
Cu(OAc)2
Cu(OAc)2
KOAc
KOAc
36
35
DMSO
20
21
a Reaction conditions: 1 (0.5 mmol), PhI(OAc)2 (1.0 mmol), base
(0.5 mmol), [Cu/Fe] (10 mol%) and CH3CN (2 ml) at 100 °C for
3h.
* Correspondent. E-mail: kamenzxh@163.com
b Isolated yield.

JOURNAL OF CHEMICAL RESEARCH 2012 357
Table 2 Scope of the direct 3-acetoxylation and iodination of
spectrometer was Bruker (ESI-Q-Tof). Column chromatography was
performed using EM Silica gel 60 (300–400 mesh).
indolesa
N-alkyl (aryl) protected indoles; general procedure
A mixture of 1H-indole (0.10 mol) and KOH (0.11 mol) was stirred in
DMF (20 ml) under N2 at room temperature for 30 min. When the
solid had dissolved, the halohydrocarbon (0.11 mol) was added and
the mixture was stirred overnight. After the reaction was completed,
H2O (20 ml) was added and stirred for 30 min, then extracted with
EtOAc (3×10 ml). The organic layer was dried (MgSO4), filtered and
concentrated. The residue was purified by chromatography on a silica
gel column to obtain N-alkyl (aryl) protected indoles.
Entry
1
indole
Product a (yield/%)b Product b (yield/%)b
1a (56)
2a (54)
3a (53)
4a (52)
5a (53)
6a (54)
7a (54)
1b (40)
2b (42)
3b (44)
4b (46)
5b (40)
6b (43)
7b (41)
Direct 3-acetoxylation and iodination of indoles; typical procedure
A mixture of N-alkyl(aryl) indole (0.5 mmol), PhI(OAc)2 (1.0 mmol),
KOAc (0.5 mmol) and Cu(OAc)2 (10 mmol%) was stirred in CH3CN
(2 ml) under N2 at room temperature for 10 min and then refluxed for
3h at 100 °C until the complete consumption of starting material
occurred as monitored by TLC or GC-MS analysis. After the reaction
had finished, the mixture was poured into saturated NaHSO3 and
extracted with EtOAc (3×10 ml). The organic layers were dried over
anhydrous MgSO4 and evaporated under vacuum. The residue was
purified by flash column chromatography (PE/EA = 40:1) to afford
the pure iodination and 3-acetoxylation products of the indoles in this
order.
2
3
4
5
6
7
1-Benzyl-1H-indol-3-yl acetate (1a):20 Yellow liquid; 1H NMR
(500 MHz, CDCl3) δ ppm 2.26 (s, 3H), 5.17 (s, 2H),7.02–7.06 (m,3H),
7.09–7.13 (m, 1H), 7.15–7.22 (m, 4H), 7.25 (s, 1H), 7.47–7.51 (m,
1H); 13C NMR (125 MHz, CDCl3): 19.9, 49.0, 108.6, 116.2, 116.6,
118.5, 119.3, 121.5, 125.7, 126.6, 127.7, 128.7, 132.3, 136.1, 167.4;
LRMS (EI): (%) 265 (M+, 20), 223 (89), 91 (100); HRMS Calcd for
C17H15NO2 (M+1): 266.1176; Found: 266.1193.
8
9
8a (51)
9a (52)
8b (42)
9b (38)
1-Benzyl-1H-3-iodoindole (1b):Yellow liquid; 1H NMR (500 MHz,
CDCl3) δ: 5.2 (s, 2H), 7.02–7.07 (m, 2H), 7.10–7.25 (m, 7H), 7.35–
7.40 (m, 1H). 13C NMR(125 MHz, CDCl3) δ: 49.4, 54.9, 108.6, 119.5,
120.2, 120.5, 121.8, 126.0, 127.0, 127.9, 131.0, 135.4, 135.7; HRMS
Calcd for C15H12IN (M+1): 334.0087; Found: 334.0089.
1-Benzyl-5-methyl-1H-indol-3-yl acetate (2a):20 Yellow liquid;
1H NMR (500 MHz, CDCl3) δ ppm 2.23 (s, 3H), 2.34(s, 3H), 5.10 (s,
2H), 6.90–6.92 (m, 1H), 6.99–7.04(m, 3H), 7.1–7.2 (m, 4H), 7.25 (s,
1H); 13C NMR (125 MHz, CDCl3): 19.9, 20.3, 49.1 108.4, 116.1,
116.3, 119.5, 123.2, 125.7, 126.5, 127.6, 127.8, 128.3, 130.8, 136.4,
167.5; LRMS (EI): (%) 279 (M+, 21), 257 (100), 146 (31), 91 (94);
HRMS Calcd for C18H17NO2 (M+1): 280.1332; Found: 280.1348.
10
11
10a (53)
11a (53)
10b (41)
11b (43)
1
1-Benzyl-5-methyl-1H-3-iodoindole (2b): Yellow liquid; H NMR
(500 MHz, CDCl3) δ ppm 2.35 (s, 3H), 5.10 (s, 2H), 6.91–7.02 (m,
5H), 7.14–7.17 (m, 4H). 13C NMR(125 MHz, CDCl3): 20.0, 49.1,
54.2, 108.5, 119.7, 120.5, 123.4, 125.8, 126.7, 127.7, 128.4, 128.9,
131.0, 135.8; HRMS Calcd for C16H14IN (M+1): 348.0244; Found:
348.0248.
12
13
12a (54)
13a (50)
12b (42)
13b (42)
1-Benzyl-7-methyl-1H-indol-3-yl acetate (3a):20 Purple solid; m.p.
1
105–106 °C. H NMR (500 MHz, CDCl3) δ ppm 2.28 (s, 3H), 2.44
(s, 3H), 5.45 (s, 2H), 6.81–6.87 (m, 3H), 6.93–6.96 (m, 1H),7.14–7.22
(m, 4H), 7.34–7.37 (m,1H); 13C NMR (125 MHz, CDCl3): 18.5, 19.8,
51.3, 114.6, 117.7, 118.9, 120.2, 120.5, 124.3, 124.4, 126.3, 127.8,
128.7, 131.2, 131.5, 167.3; LRMS (EI): (%) 279 (M+, 25), 237 (83),
146 (41), 91 (100); HRMS Calcd for C18H17NO2 (M+1): 280.1332;
Found: 280.1348.
1-Benzyl-7-methyl-1H-3-iodoindole (3b): Yellow solid; m.p. 87–88
°C. 1H NMR (500 MHz, CDCl3) δ ppm 2.5 (s, 3H), 5.5 (s, 2H), 6.88–
6.94 (m, 3H), 7.06–7.12 (m, 2H), 7.20–7.29 (m, 3H), 7.31–7.34 (m,
1H). 13C NMR(125 MHz, CDCl3): 19.1, 52.5, 56.8, 116.6, 119.6,
120.9, 121.4, 125.8, 127.6, 129.0, 131.6, 134.0, 135.2, 138.9; HRMS
Calcd for C16H14IN (M+1): 348.0244; Found: 348.0191.
14
15
14a (59)
15a (51)
14b (36)
15b (44)
16
16a (52)
16b (38)
1-Benzyl-5-chloro-1H-indol-3-yl acetate (4a):21 Yellow solid; m.p.
82–83 °C (lit.21 83–84 °C). 1H NMR (500 MHz, CDCl3) δ ppm 2.25 (s,
3H), 5.17(s, 2H), 7.01–7.08 (m, 4H), 7.17–7.23 (m, 3H), 7.27 (s, 1H),
7.46–7.47 (m, 1H) ; 13C NMR (125 MHz, CDCl3): 28.6, 49.3, 109.8,
116.5, 117.6, 120.4, 121.9, 124.5, 125.7, 126.7, 127.8, 128.1, 130.6,
135.7, 167.3; LRMS (EI): (%) 299 (M+, 9), 257 (40), 91 (100).
17
18
17a (53)
18a (54)
17b (40)
18b (41)
1
1-Benzyl-5-chloro-1H-3-iodoindole (4b): Yellow liquid; H NMR
(500 MHz, CDCl3) δ ppm 5.18 (s, 2H), 6.98–7.03 (m, 2H), 7.04–7.08
(m, 2H), 7.11 (s, 1H), 7.19–7.25 (m, 3H), 7.34–7.37 (m, 1H). 13C
NMR(125 MHz, CDCl3) δ: 49.6, 54.0, 110.0, 119.8, 120.5, 122.2,
125.9, 127.1, 127.9, 128.4, 130.8, 132.4, 135.3; HRMS Calcd for
C15H11ClIN (M+1): 367.9698; Found: 367.9673.
a Reaction conditions: Indole (0.5 mmol), PhI(OAc)2 (1.0 mmol),
KOAc (0.5 mmol), Cu(OAc)2 (10 mol%) and CH3CN (2 ml) at
100 °C for 3h.
b Isolated yield.

358 JOURNAL OF CHEMICAL RESEARCH 2012
1-Benzyl-6-fluoro-1H-indol-3-yl acetate (5a):22 Red solid; m.p.
66–67 °C. H NMR (500 MHz, CDCl3) δ ppm 2.25 (s, 3H), 5.12
125.4, 128.9, 131.8, 140.6, 168.4. LRMS (EI): (%) 263 (M+, 33), 55
(39), 166 (60), 221 (100); HRMS Calcd for C14H14ClNO2 (M+1):
264.0713; Found: 264.0785.
1
(s, 2H), 6.77–6.86 (m, 2H), 7.02–7.07 (m, 2H), 7.17–7.25 (m, 4H),
7.37–7.42 (m, 1H); 13C NMR (125 MHz, CDCl3): 19.9, 49.4, 95.1
(J = 27.5 Hz), 107.6 (J = 12.5 Hz), 116.2, 116.5 (J = 3.75 Hz), 117.7
(J = 10 Hz), 125.8, 126.8, 127.8, 128.8, 132.4 (J = 11.25 Hz), 135.7,
159.3 (J = 237.5 Hz), 167.3; LRMS (EI): (%) 283 (M+, 13), 241 (53),
91 (100).
1-Benzyl-6-fluoro-1H-3-iodoindole (5b): Yellow solid; m.p. 66–
67 °C. 1H NMR (500 MHz, CDCl3) δ ppm 5.14 (s, 2H), 6.84–6.88 (m,
2H), 7.02–7.04 (m, 2H), 7.08 (s, 1H), 7.16–7.25 (m, 3H), 7.27–7.30
(m, 1H). 13C NMR (125 MHz, CDCl3): 50.6, 96.3 (J = 27.5 Hz), 109.4
(J = 25 Hz), 122.4 (J = 10 Hz), 126.9, 127.2, 128.1, 128.9, 132.6
(J = 3.75 Hz), 136.1, 136.2, 136.3, 160.5 (J = 237.5 Hz); HRMS
Calcd for C15H11FIN (M+1): 351.9993; Found: 351.9974.
1-Isobutenyl-5-chloro-1H-3-iodoindole (10b): Yellow liquid. 1H
NMR (500 MHz, CDCl3) δ ppm 1.64 (s, 3H), 4.58 (s, 2H), 4.72
(s, 1H), 4.92 (m, 1H), 7.14–7.20 (m, 3H), 7.40–7.43 (m, 1H). 13C
NMR(125 MHz, CDCl3) δ ppm 19.8, 52.6, 55.5, 111.1, 113.5, 120.8,
123.1, 126.4, 131.7, 133.5, 134.9, 140.3; HRMS Calcd for C12H11ClIN
(M+1): 331.9698; Found: 331.9701.
1-Isobutenyl-4-chloro-1H-indol-3-yl acetate (11a): Yellow solid;
m.p. 68–69 °C. 1H NMR (500 MHz, CDCl3) δ ppm 1.66 (s, 3H), 2.35
(s, 3H), 4.57 (s, 2H), 4.72–4.75 (m, 1H), 4.91–4.94 (m, 1H), 7.04–
7.10 (m, 2H), 7.12 (s, 1H), 7.16–7.18 (m, 1H). 13C NMR (125 MHz,
CDCl3) δ ppm 19.8, 20.4, 52.7, 108.6, 113.3, 118.1, 119.1, 120.5,
122.9, 124.5, 128.5, 135.2, 140.4, 169.9. LRMS (EI): (%) 263 (M+,
25), 55 (27), 223 (32), 166 (64), 221 (100); HRMS Calcd for
C14H14ClNO2 (M+1): 264.0713; Found: 264.0780.
1-Methyl-1H-indol-3-yl acetate (6a):20,23 Yellow solid; m.p. 52–
54 °C (lit.23 56.5 °C); 1H NMR (500 MHz, CDCl3) δ ppm 2.39 (s, 3H),
3.78 (s, 3H), 7.14–17 (m, 1H), 7.27–7.29 (m, 1H), 7.32–7.33 (m, 1H),
7.57–7.59 (m, 1H); 13C NMR (125 MHz, CDCl3): 19.9, 31.7, 108.2,
116.4, 116.8, 118.2, 119.1, 121.2, 128.1, 132.7, 167.7; LRMS (EI,
70eV): (%) 189 (M+, 21), 147 (100), 132 (11), 77 (13).
1-Isobutenyl-4-chloro-1H-3-iodoindole (11b): Yellow liquid. 1H
NMR (500 MHz, CDCl3) δ ppm 1.65 (s, 3H), 4.60 (s, 2H), 4.72 (s,
1H), 4.90–4.95 (m, 1H), 7.06–7.11 (m, 2H), 7.20 (s, 1H), 7.21–7.25
(m, 1H). 13C NMR (125 MHz, CDCl3) δ ppm 19.6, 50.5, 53.0, 109.0,
113.5, 121.5, 122.7, 124.4, 126.7, 135.0, 137.5, 140.0; HRMS Calcd
for C12H11ClIN (M+1): 331.9698; Found: 331.9690.
1-Isobutenyl-6-fluoro-1H-indol-3-yl acetate (12a): Orange liquid.
1H NMR (500 MHz, CDCl3) δ ppm 1.66 (s, 3H), 2.34 (s, 3H), 4.52 (s,
2H), 4.75 (s, 1H), 4.92–4.93 (m, 1H), 6.85–6.90 (m, 1H), 6.94–6.96
(m, 1H), 7.26 (s, 1H), 7.44–7.48 (m, 1H). 13C NMR (125 MHz, CDCl3)
δ ppm 19.7, 20.9, 52.8, 96.1 (J = 27.5 Hz), 108.5 (J = 23.8 Hz),
113.2, 117.0, 117.5 (J = 3.75 Hz), 118.6 (J = 10 Hz), 129.6, 133.4
(J = 11.25 Hz), 140.5, 160.3 (J = 237.5 Hz), 168.4. LRMS (EI): (%)
247 (M+, 37), 205 (87), 150 (100); HRMS Calcd for C14H14FNO2
(M+1): 248.1009; Found: 248.1089.
1-Methyl-1H-3-iodoindole (6b): Yellow solid; m.p. 58–59 °C(lit.24
58–59 °C). 1H NMR (500 MHz, CDCl3) δ: 3.70 (s, 3H), 7.03 (s, 1H),
7.09–7.14 (m, 1H), 7.15–7.22 (m, 2H), 7.34–7.37 (m, 1H). 13C NMR
(125 MHz, CDCl3) δ: 32.0, 53.7, 108.2, 119.1, 120.1, 121.5, 129.5,
131.6, 135.7; HRMS Calcd for C9H8IN (M+1): 257.9774; Found:
258.0672.
1
1-Isobutenyl-1H-indol-3-yl acetate (7a): Brown liquid; H NMR
(500 MHz, CDCl3) δ ppm 1.67(s, 3H), 2.35(s, 3H), 4.58 (s, 2H), 4.75
(s, 1H), 4.91 (s, 1H), 7.08–7.13 (m, 1H), 7.18–7.23 (m, 1H), 7.25–
7.28 (m, 1H), 7.29 (s, 1H), 7.53–7.56 (m, 1H); 13C NMR (125 MHz,
CDCl3): δ ppm 19.7, 21.0, 52.5, 109.6, 112.9, 117.3, 117.6, 119.4,
120.3, 122.4, 129.6, 133.4, 140.9, 168.5. LRMS (EI): (%) 229 (M+,
38), 55 (31), 187 (90), 132 (100); HRMS Calcd for C14H15NO2 (M+1):
230.1103; Found: 230.1178.
1-Isobutenyl-6-fluoro-1H-3-iodoindole (12b): Yellow liquid; 1H
NMR (500 MHz, CDCl3) δ ppm 1.66 (s, 3H), 4.55 (s, 2H), 4.75 (s,
1H), 4.94 (s, 1H), 6.92–6.98 (m, 2H), 7.12 (s, 1H), 7.32–7.36 (m, 1H).
13C NMR (125 MHz, CDCl3) δ ppm 19.8, 53.0, 55.5, 96.3 (J =
26.3 Hz), 109.2 (J = 25 Hz), 113.6, 122.3 (J = 10 Hz), 127.1, 132.7
(J = 3.75 Hz), 136.3 (J = 11.25 Hz), 140.2, 160.5 (J = 238.75 Hz);
HRMS Calcd for C12H11FIN (M+1): 315.9993; Found: 315.9991.
1-n-Butyl-1H-indol-3-yl acetate (13a): Brown liquid. 1H NMR
(500 MHz, CDCl3) δ ppm 0.91–0.95 (t, J = 7.5 Hz, 3H), 1.30–1.38
(m, 2H), 1.76–7.84 (m, 2H), 2.35 (s, 3H), 4.04–4.09 (t, J = 7.5 Hz,
2H), 7.08–7.12 (m, 1H), 7.19–7.25 (m, 1H), 7.28–7.32 (m, 2H),
7.52–7.56 (m, 1H). 13C NMR (125 MHz, CDCl3) δ ppm 13.6, 20.1,
21.0, 32.3, 46.1, 109.4, 116.7, 117.6, 119.2, 120.2, 122.2, 129.3,
133.0, 168.6. LRMS (EI): (%) 231 (M+, 28), 189 (71), 146 (100);
HRMS Calcd for C14H17NO2 (M+1): 232.1259; Found: 232.1335.
1-n-Butyl-1H-3-iodoindole (13b): Yellow liquid. 1H NMR
(500 MHz, CDCl3) δ ppm 0.91–0.94 (t, J = 7.5, 3H), 1.31–1.35 (m,
2H), 1.78–1.81 (m, 2H), 4.08–4.11 (t, J = 7.5, 2H), 7.16–7.18 (m,
2H), 7.23–7.26 (m, 1H), 7.29–7.31 (m, 1H), 7.42–7.44 (m, 1H). 13C
NMR (125 MHz, CDCl3) δ ppm 13.7, 20.1, 32.4, 46.5, 109.6, 118.4,
120.2, 122.5, 129.8, 130.5, 131.8, 136.2; HRMS Calcd for C12H14IN
(M+1): 300.0244; Found:300.0232.
1-Isobutenyl-1H-3-iodoindole (7b): Brown liquid; 1H NMR
(500 MHz, CDCl3) δ ppm 1.66 (s, 3H), 4.62 (s, 2H), 4.75 (s, 1H), 4.92
(s, 1H), 7.14–7.21 (m, 2H), 7.21–7.26 (m, 1H), 7.26–7.30 (m, 1H),
7.42–7.45 (m, 1H). 13C NMR (125 MHz, CDCl3) δ ppm 20.0, 53.0,
55.6,109.8, 113.3, 120.4, 121.2, 122.7, 130.5, 132.2, 136.5, 140.7;
HRMS Calcd for C12H12IN (M+1): 298.0087; Found: 298.0081.
1-Isobutenyl-5-methyl-1H-indol-3-yl acetate (8a): Brown liquid;
1H NMR (500 MHz, CDCl3) δ ppm 1.58 (s, 3H), 2.26 (s, 3H), 2.36 (s,
3H), 4.48 (s, 2H), 4.66 (s, 1H), 4.82 (s, 1H), 6.95–6.96 (m, 1H), 7.08–
7.11 (m, 1H), 7.15 (s, 1H), 7.24 (s, 1H). 13C NMR (125 MHz, CDCl3)
δ ppm 18.8, 19.9, 20.6, 51.6, 108.4, 111.8, 115.9, 116.2, 119.5, 123.1,
127.8, 128.2, 130.9, 140.1, 167.6. LRMS (EI): (%) 243 (M+, 46), 146
(89), 201 (100); HRMS Calcd for C15H17NO2 (M+1): 244.1259;
Found: 244.1332.
1-Isobutenyl-5-Methyl-1H-3-iodoindole (8b): Yellow liquid; 1H
NMR (500 MHz, CDCl3) δ: 2.31 (s, 3H), 2.42 (s, 3H), 4.50 (s, 2H),
4.71 (s, 1H), 4.81 (s, 1H), 6.94–6.98 (m, 1H), 7.08–7.11 (m, 1H), 7.15
(s, 1H), 7.25 (s, 1H). 13C NMR(125 MHz, CDCl3) δ: 18.7, 20.0, 20.2,
51.6, 108.2, 111.8, 116.0, 116.3, 123.0, 127.8, 131.0, 140.0, 167.5;
HRMS Calcd for C13H14IN (M+1): 312.0244; Found: 312.0228.
1-Isobutenyl-7-methyl-1H-indol-3-yl acetate (9a): Brown solid;
m.p. 64–65 °C. 1H NMR (500 MHz, CDCl3) δ ppm 1.75 (s, 3H), 2.34
(s, 3H), 2.61 (s, 3H), 4.30 (s, 1H), 4.75 (s, 2H), 4.84 (s, 1H), 6.91–6.92
(m, 1H), 6.97–7.01 (m, 1H), 7.21–7.25(m, 1H), 7.37–7.40 (m, 1H).
13C NMR (125 MHz, CDCl3) δ ppm 19.3, 19.9, 21.0, 54.3, 111.2,
121.3, 115.5, 118.9, 119.6, 121.2, 125.3, 129.5, 132.2, 142.9, 168.5.
LRMS (EI): (%) 243 (M+, 33), 201 (58), 146 (100); HRMS Calcd for
C15H17NO2 (M+1): 244.1259; Found: 244.1319.
1
1-n-Butyl-5-methyl-1H-indol-3-yl acetate (14a): Brown liquid. H
NMR (500 MHz, CDCl3) δ ppm 0.87–0.92 (t, J = 7.5 Hz, 3H), 1.26–
1.35 (m, 2H), 1.72–1.80 (m, 2H), 2.32 (s, 3H), 2.44 (s, 3H), 4.00–4.03
(t, J = 7.5 Hz, 2H), 7.01–7.03 (m, 1H), 7.17–7.19 (m, 1H), 7.22
(s, 1H), 7.31 (s, 1H). 13C NMR (125 MHz, CDCl3) δ ppm 13.71, 20.16,
20.98, 21.40, 32.35, 46.15, 109.2, 116.9, 117.1, 123.9, 128.5, 128.9,
129.4, 131.6, 168.7. LRMS (EI): (%) 245 (M+, 36), 203 (89), 160
(100); HRMS Calcd for C15H19NO2 (M+1): 246.1416; Found:
246.1493.
1-Isobutenyl-7-methyl-1H-3-iodoindole (9b): Brown liquid. 1H
NMR (500 MHz, CDCl3) δ ppm 1.75 (s, 3H), 2.62 (s, 3H), 4.29
(s, 1H), 4.77 (s, 2H), 4.85 (s, 1H), 6.95–6.96 (m, 1H), 7.05–7.08
(m, 2H), 7.25–7.30 (m, 1H). 13C NMR (125 MHz, CDCl3) δ ppm 19.0,
19.8, 54.5, 56.2, 111.5, 119.5, 120.6, 121.3, 125.6, 131.3, 133.9,
135.1, 142.6; HRMS Calcd for C13H14IN (M+1): 312.0243; Found:
312.0219.
1-Isobutenyl-5-chloro-1H-indol-3-yl acetate (10a): Brown liquid.
1H NMR (500 MHz, CDCl3) δ ppm 1.65 (s, 3H), 2.34 (s, 3H), 4.56 (s,
2H), 4.73 (s, 1H), 4.91–4.92 (m, 1H), 7.13–7.16 (m, 1H), 7.18–7.20
(m, 1H), 7.31 (s, 1H), 7.53–7.54 (m, 1H). 13C NMR (125 MHz, CDCl3)
δ ppm 19.8, 21.9, 52.8, 111.9, 113.2, 117.2, 118.7, 121.2, 122.8,
1
1-n-Butyl-5-methyl-1H-3-iodoindole (14b): Pink liquid. H NMR
(500 MHz, CDCl3) δ ppm 0.90–0.94 (t, J = 7.5 Hz, 3H), 1.26–1.35
(m, 2H), 1.73–1.80 (m, 2H), 2.48 (s, 3H), 4.0–4.1 (t, J = 7.5, 2H),
7.04–7.08 (m, 1H), 7.11 (s, 1H), 7.16–7.23 (m, 2H). 13C NMR
(125 MHz, CDCl3) δ ppm 13.9, 20.0, 21.2, 32.2, 46.5, 54.0, 109.4,
120.8, 124.0, 129.6, 130.6, 131.7, 134.5; HRMS Calcd for C13H16IN
(M+1): 314.0400; Found: 314.0369.
1
1-n-Butyl-7-methyl-1H-indol-3-yl acetate (15a): Brown liquid. H
NMR (500 MHz, CDCl3) δ ppm 0.90–0.95 (t, J = 7.5 Hz, 3H), 1.33–
1.40 (m, 2H), 1.72–1.79 (m, 2H), 2.33 (s, 3H), 2.69 (s, 3H), 4.22–4.27
(t, J = 7.5 Hz, 2H), 6.91–6.94 (m, 1H), 6.96–7.00 (m, 1H), 7.22
(s, 1H), 7.34–7.39 (m, 1H). 13C NMR (125 MHz, CDCl3) δ ppm 13.7,

JOURNAL OF CHEMICAL RESEARCH 2012 359
19.9, 20.1, 21.0, 34.5, 48.7, 115.5, 118.2, 119.4, 120.9, 121.4, 125.2,
129.3, 131.7, 168.5. LRMS (EI): (%) 245 (M+, 32), 203 (83), 160
(100); HRMS Calcd for C15H19NO2 (M+1): 246.1416; Found:
246.1491.
1-n-Butyl-6-fluoro-1H-3-iodoindole (18b): Yellow liquid. 1H NMR
(500 MHz, CDCl3) δ ppm 0.90–0.96 (t, J = 7.5, 3H), 1.28–1.37 (m,
2H), 1.73–1.80 (m, 2H), 4.0–4.05 (t, J = 7.5, 2H), 6.9–6.96 (m, 1H),
6.97–7.01 (m, 1H), 7.13 (s, 1H), 7.31–7.36 (m, 1H). 13C NMR
(125 MHz, CDCl3) δ ppm 13.6, 20.0, 32.2, 46.7, 55.0, 95.9
(J = 25 Hz), 109.1 (J = 23.75 Hz), 122.2 (J = 11.25 Hz), 127.0, 132.3
(J = 3.75 Hz), 135.9 (J = 11.25 Hz), 160.4 (J = 237.5 Hz). HRMS
Calcd for C12H13FIN (M+1): 318.0150; Found: 318.0129.
1-n-Butyl-7-methyl-1H-3-iodoindole (15b): Brown liquid. 1H NMR
(500 MHz, CDCl3) δ ppm 0.91–0.96 (t, J = 7.5 Hz, 3H), 1.30–1.40
(m, 2H), 1.70–1.80 (m, 2H), 2.70 (s, 3H), 4.24–4.31 (t, J = 7.5 Hz,
2H), 6.94–6.98 (m, 1H), 7.02–7.08 (m, 1H), 7.09 (s, 1H), 7.26–7.30
(m, 1H). 13C NMR (125 MHz, CDCl3) δ ppm 13.8, 19.7, 20.0, 35.0,
49.0, 55.8, 119.5, 120.4, 121.0, 125.6, 131.5, 133.4, 134.7; HRMS
Calcd for C13H16IN (M+1): 314.0400; Found: 314.0473.
The authors thank the National Natural Science Foundation of
China (No. 20972114) and the Zhejiang Provincial Natural
Science Foundation of China (No. Y4100578) and the Open-
ing Foundation of Zhejiang Provincial Top Key Discipline
(100061200140).
1-n-Butyl-5-chloro-1H-indol-3-yl acetate (16a): Brown liquid.
1H NMR (500 MHz, CDCl3) δ ppm 0.90–0.94 (t, J = 7.5 Hz, 3H),
1.27–1.36 (m, 2H), 1.74–1.81 (m, 2H), 2.33 (s, 3H), 4.01–4.05 (t,
J = 7.5 Hz, 2H), 7.13–7.16 (m, 1H), 7.19–7.22 (m, 1H), 7.30 (s, 1H),
7.50–7.51 (m, 1H). 13C NMR (125 MHz, CDCl3) δ ppm 13.8, 20.0,
21.9, 32.1, 46.3, 110.5, 117.1, 118.2, 121.0, 122.5, 125.2, 128.4,
131.4, 168.5. LRMS (EI): (%) 265 (M+, 32), 225 (33), 180 (85), 223
(100); HRMS Calcd for C14H16ClNO2 (M+1): 266.0870; Found:
266.0951.
Received 12 February 2012; accepted 31 March 2012
Paper 1201161 doi: 10.3184/174751912X13360637793465
Published online: 4 June 2012
1-n-Butyl-5-chloro-1H-3-iodoindole (16b): Brown liquid. 1H NMR
(500 MHz, CDCl3) δ ppm 0.90–0.96 (t, J = 7.5 Hz, 3H), 1.27–1.36
(m, 2H), 1.74–1.81 (m, 2H), 4.04–4.09 (t, J = 7.5 Hz, 2H), 7.07–7.12
(m, 2H), 7.21 (s, 1H), 7.24–7.26 (m, 1H). 13C NMR (125 MHz, CDCl3)
δ ppm 13.5, 20.0, 32.0, 46.8, 108.6, 121.4, 122.5, 124.4, 126.8, 134.4,
134.5, 137.2; HRMS Calcd for C12H13ClIN (M+1):333.9854; Found:
333.9861.
1-n-Butyl-4-chloro-1H-indol-3-yl acetate (17a): Yellow solid; m.p.
47–48 °C.1H NMR (500 MHz, CDCl3) δ ppm 0.82–0.87 (t, J = 7.5 Hz,
3H), 1.20–1.29 (m, 2H), 1.66–1.74 (m, 2H), 2.25 (s, 3H), 3.93–3.99
(t, J = 7.5 Hz, 2H), 6.95–7.03 (m, 2H), 7.05 (s, 1H), 7.09–7.13 (m,
1H). 13C NMR (125 MHz, CDCl3) δ ppm 13.5, 20.0, 21.9, 32.0, 46.3,
108.2, 117.7, 118.6, 120.2, 122.5, 124.4, 128.1, 134.8, 169.9. LRMS
(EI): (%) 265 (M+, 35), 225 (31), 180 (85), 223 (100); HRMS Calcd
for C14H16ClNO2 (M+1): 266.0870; Found: 266.0940.
References
1
2
3
S. Cacchi and G. Fabrisi, Chem. Rev., 2005, 105, 2873.
D. Crich and A. Banerjee, Acc. Chem. Res., 2007, 40, 151.
Z. Shi, C. Zhang, S. Li, D. Pan, S. Ding, Y. Cui and N. Jiao, Angew. Chem.,
2009, 121, 4642.
4
5
6
7
8
Z. Liang, J. Zhao and Y. Zhang, J. Org. Chem., 2010, 75, 170.
R.D. Arnold, W.M. Nutter and W.L. Stepp, J. Org. Chem., 1959, 24, 117.
K.X. Liu, P. Wen, J.Liu and G.S. Huang, Synthesis., 2010, 21, 3623.
D. Lubriks, I. Sokolovs and E. Suna, Org. Lett., 2011, 13, 4324.
D. Qiu, Z.T. Zheng, F.Y. Mo, Q. Xiao, Y. Tian, Y. Zhang and J.B. Wang,
Org. Lett., 2011, 13, 4988.
9
K.J. Stowers and M.S. Sanford, Org. Lett., 2009, 11, 4584.
10 S.J. Gu, C. Chen and W.Z. Chen, J. Org. Chem., 2009, 74, 7203.
11 G.W. Wang, T.T. Yuan and X.L. Wu, J. Org. Chem., 2008, 73, 4717.
12 Q. Liu, G. Li, H. Yi, P. Wu, J. Liu and A.W. Lei, Chem. Eur. J., 2011, 17,
2353.
1-n-Butyl-4-chloro-1H-3-iodoindole (17b): Yellow liquid. 1H NMR
(500 MHz, CDCl3) δ ppm 0.90–0.96 (t, J = 7.5, 3H), 1.27–1.36 (m,
2H), 1.74–1.81 (m, 2H), 4.04–4.09 (t, J = 7.5, 2H), 7.07–7.12 (m,
2H), 7.21 (s, 1H), 7.24–7.26 (m, 1H). 13C NMR (125 MHz, CDCl3)
δ ppm 13.5, 20.0, 32.0, 46.8, 50.0, 108.6, 121.4, 122.5, 124.4, 126.8,
134.5, 137.2; HRMS Calcd for C12H13ClIN (M+1): 333.9854; Found:
333.9830.
13 I. Mutule, E. Suna, K. Olofsson and B. Pelcman, J. Org. Chem., 2009, 74,
7195.
14 P.Y. Choy, C.P. Lau and F.Y. Kwong, J. Org. Chem., 2011, 76, 80.
15 G.A. Olah, Q. Wang, G. Sandford and G.K.S. Prakash, J. Org. Chem.,
1993, 58, 3194.
16 G.J. Bodwell and J. Li, Org. Lett., 2002, 4, 127.
17 M.A. Zolfigol, A. Khazaei, E. Kolvari, N. Koubaki, H. Soltani and
M. Behjunia, HeIv. Chim. Acta, 2010, 93, 587.
18 A.K. Mohanakrishnan, C. Prakash and N. Ramesh, Tetrahedron, 2006, 62,
3242.
19 M.A. Zolfigol,A. Khazaei, E. Kolvari, N. Koukabi, H. Soltani, M. Behjunia,
V. Khakyzadeh. Arkivoc., 2009, xiii, 200.
20 P.Y. Choy, C.P. Lau, and F.Y. Kwong, J. Org. Chem., 2011, 76, 80.
21 D. Lubriks, I. Sokolovs, and E. Suna. Org. Lett., 2011, 13, 4324.
22 Q. Liu, G. Li, H. Yi, P. Wu, J. Liu and A.W. Lei, Chem. Eur. J., 2011, 17,
2353.
23 E. Zaha A, Alex. J. Pharm. Sci., 2005, 19, 129.
24 M.S. Shvartsberg, S.F. Vaslievski, T.A. Prikhod’ko, Izv. Akad. Nauk SSSR,
Ser. Khim., 1982, 11, 2524.
1
1-n-Butyl-6-fluoro-1H-indol-3-yl acetate (18a): Brown liquid. H
NMR (500 MHz, CDCl3) δ ppm 0.91–0.95 (t, J = 7.5 Hz, 3H),
1.29–1.38 (m, 2H), 1.74–1.82 (m, 2H), 2.33 (s, 3H), 3.97–4.01 (t,
J = 7.5 Hz, 2H), 6.84–6.89 (m, 1H), 6.94–6.98 (m, 1H), 7.26 (s, 1H),
7.42–7.47 (m, 1H). 13C NMR (125 MHz, CDCl3) δ ppm 13.7, 20.1,
21.0, 32.1, 46.3, 95.7 (J = 26.25 Hz), 108.2 (J = 25 Hz), 116.8, 117.0
(J = 3.75 Hz), 118.6 (J = 10 Hz), 129.4, 133.0 (J = 11.25 Hz), 160.2
(J = 237.5 Hz), 168.5. LRMS (EI): (%) 249 (M+, 36), 165 (34), 164
(99), 207 (100); HRMS Calcd for C14H16FNO2 (M+1): 250.1165;
Found: 250.1243.

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.