Synthesis of 3-substituted indole by AlCl3-promoted reaction of β,γ-unsaturated ketone with indole

Article abstract of DOI:10.1007/s11164-014-1605-x

A one-pot Lewis acid-promoted reaction condition of β,γ- unsaturated ketone with indole was developed for the synthesis of 3-substituted indoles with moderate to good yields. A Lewis acid such as AlCl₃ was shown to be a promising promoter for in situ isomerization of β,γ-unsaturated ketone to its corresponding α,β- unsaturated ketone, then undergoing Friedel-Crafts Michael addition reaction with indole to afford 3-substituted indole.

Full text of DOI:10.1007/s11164-014-1605-x

Res Chem Intermed (2014) 40:2277–2285
DOI 10.1007/s11164-014-1605-x
Synthesis of 3-substituted indole by AlCl3-promoted
reaction of b,c-unsaturated ketone with indole
•
Adam Shih-Yuan Lee Yu-Chi Wu
•
•
Yu-Ting Chang Bo-Cheng Wang
Received: 20 January 2014 / Accepted: 15 February 2014 / Published online: 27 March 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract A one-pot Lewis acid-promoted reaction condition of b,c-unsaturated
ketone with indole was developed for the synthesis of 3-substituted indoles with
moderate to good yields. A Lewis acid such as AlCl3 was shown to be a promising
promoter for in situ isomerization of b,c-unsaturated ketone to its corresponding
a,b-unsaturated ketone, then undergoing Friedel–Crafts Michael addition reaction
with indole to afford 3-substituted indole.
Keywords Friedel–Crafts reaction Michael reaction Á 3-Substituted
indole Á b,c-Unsaturated ketone Á a,b-Unsaturated ketone
Introduction
Indoles are widely distributed in biological systems and well known as biologically
active substances [1–3]. The indole nucleus is a privileged structural moiety with a
broad spectrum of pharmaceutical and biological activities across the entire chemical
industry [4–8]. Synthetic multistep procedures for the synthesis of two carbon–carbon
bonds catalyzed by single multiacting Lewis acids are poorly documented [9–14], and
several manipulations of functional groups such as protection or activation are
required. In the last few years, several Lewis acid-mediated Friedel–Crafts-type
additions of electron-rich aromatic compounds such as indoles to enones, in the
presence of a catalytic or stoichiometric amount of Lewis acids, have been published
[15–17]. 3-Alkylation of indole can be accomplished even with mild electrophiles
such as alkenes with electron-withdrawing groups under acidic catalysis. However,
since the indole ring is quite reactive against protic and Lewis acids, only procedures
which generate electrophilic species under relatively mild conditions are likely to
A. S.-Y. Lee (&) Á Y.-C. Wu Á Y.-T. Chang Á B.-C. Wang
Department of Chemistry, Tamkang University, New Taipei 251, Taiwan
e-mail: adamlee@mail.tku.edu.tw
123

2278
A. S.-Y Lee et al.
produce good yields [18–20]. Friedel–Crafts alkylation of indoles with a,b-
unsaturated carbonyl compounds can give rise to the specific formation of a new b-
position bond of carbonyl compounds [21–27]. Combination of Friedel–Crafts
alkylation of indole with a,b-unsaturated carbonyl compound presents a molecularly
economic reaction and is among the most practical and widely used methods for the
synthesis of 3-substituted indoles [28, 29]. Our group reported that a Barbier-type
reaction of allylic bromide with nitrile could generate b,c-unsaturated ketone at room
temperature [30, 31], and this b,c-unsaturated ketone was isomerized to a,b-
unsaturated ketone under DABCO (1,4-Diazabicyclo-[2.2.2]octane)/iPrOH reaction
condition [32]. Thus, we expected that the preparation of 3-substituted indole might be
achieved by the one-pot isomerization of b,c-unsaturated ketone to a,b-unsaturated
ketone followed by Friedel–Crafts Michael addition reaction with indole (Scheme 1).
Experimental
General
All reagents (Table 1) were purchased from Aldrich, Merck, and Riedel–deHaen,
and all were used directly without further purification. b,c-Unsaturated ketones
(which are shown in Table 1, below) were prepared by the reported method [30].
Methylene chloride was distilled from calcium hydride and recirculated prior to use.
Hexane and ethyl acetate were distilled from calcium hydride. The 1H-NMR (proton
nuclear magnetic resonance) spectra were recorded at 300 MHz (Bruker-AC300P)
with deuteriochloroform (CDCl3, Aldrich, 99.8 atom % D) as the solvent and the
internal standard. The 13C-NMR (carbon nuclear magnetic resonance) spectra were
recorded at 75.5 MHz (Bruker-AC300P) with CDCl3 as the solvent and the internal
standard. MS spectra (MS) were recorded on a Finnigan MAT 95S spectropho-
tometer. Column chromatography was performed using silica gel (Merck 230–400
mesh) and ethyl acetate/hexane mixture as the eluent.
A representative procedure for synthesis of 3-substituted indoles
AlCl3 (0.5 mmol) was added to a reaction mixture of b,c-unsaturated ketone
(1.0 mmol) and indole (1.5 mmol) in CH2Cl2 (5 mL) at room temperature and the
reaction mixture was refluxed for 4 h. After the reaction was completed (monitored
by TLC), the reaction mixture was extracted with ethyl acetate (20 mL 9 3). The
N
H
O
CH3
O
O
R
R
R
N
H
Scheme 1 Synthetic scheme of 3-substituted indoles
123

Synthesis of 3-substituted indole by AlCl3
2279
Table 1 Syntheis of 3-substituted indoles
O
CH3
O
1.5
, 0.5 AlCl3
N
H
R
R
N
H
CH2Cl2, Reflux, 4h
Entry
1
Substrate
Product
Yield (%)
87
O
O
CH3
Ph
Ph
N
H
2
3
4
5
45
57
63
72
O
O
CH3
Ph
Ph
N
H
O
O
CH3
N
H
O
O
CH3
Br
Br
N
H
S
S
O
O
O
CH3
N
H
6
68
O
CH3
N
H
123

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A. S.-Y Lee et al.
Table 1 continued
Entry
7
Substrate
Product
Yield (%)
73
O
O
CH3
N
H
8
78
O
O
CH3
N
H
MeO
MeO
combined organic layer was washed with brine (20 mL), dried with MgSO4, and the
organic solvent was removed under reduced pressure. Further purification was
achieved on a flash chromatograph with ethyl acetate/hexane as eluent.
4-(1H-indol-3-yl)-1-phenylpentan-2-one (Table 1, Entry 1)
1H-NMR: d 1.33 (3H, H5, d, J = 6.0 Hz), 2.67 (1H, H3, dd, J = 16.5, 7.5 Hz), 2.93
(1H, H3, dd, J = 15.0, 6.0 Hz), 3.59 (2H, H1, s), 3.65 (1H, H4, m), 6.89 (1H, d,
J = 2.3 Hz), 7.08–7.36 (8H, m), 7.57 (1H, d, J = 6.0 Hz), 7.94 (1H, br). 13C-NMR:
d 21.3, 27.3, 49.9, 50.9, 111.5, 119.4, 119.5, 120.4, 121.2, 122.3, 126.5, 127.1,
128.9, 129.7, 134.3, 136.7, 208.1. HRMS: m/z 277.1477 (calcd. for C19H19NO,
277.1467).
3-(1H-indol-3-yl)-1-phenylbutan-1-one (Table 1, Entry 2)
1H-NMR: d 1.45 (3H, H4, d, J = 6.8 Hz), 3.20 (1H, H2, dd, J = 16.3 Hz, 8.8), 3.45
(1H, H2, dd, J = 16.3, 4.8 Hz), 3.84 (1H, H3, m), 7.02 (1H, d, J = 2.2 Hz),
7.12–7.22 (2H, m), 7.34 (1H, d, J = 7.8 Hz), 7.41 (2H, t, J = 5.7 Hz), 7.52 (1H, t,
J = 5.9 Hz), 7.67 (1H, d, J = 7.7 Hz), 7.94 (2H, d, J = 7.4 Hz), 7.97 (1H, br). 13C-
NMR: d 21.2, 27.4, 46.7, 111.5, 119.5, 120.4, 121.8, 122.3, 126.6, 128.3, 128.8,
133.1, 136.8, 137.6, 200.0.
1-(cyclopent-1-en-1-yl)-4-(1H-indol-3-yl)pentan-2-one (Table 1, Entry 3)
1H-NMR: d 1.37 (3H, H5, d, J = 6.9 Hz), 1.77-1.87 (2H, m), 2.15-2.31 (4H, m),
2.66 (1H, H3, dd, J = 16.2, 8.2 Hz), 2.93 (1H, H3, dd, J = 16.2, 5.7 Hz), 3.11 (2H,
H1, s), 3.64 (1H, H4, m), 5.44 (1H, t, J = 1.9 Hz), 6.96 (1H, d, J = 2.2 Hz),
7.08–7.21 (2H, m), 7.34 (1H, d, J = 8.1 Hz), 7.62 (1H, d, J = 7.8 Hz), 7.93 (1H,
br). 13C-NMR: d 21.3, 23.7, 27.2, 32.8, 35.4, 46.4, 49.9, 111.4, 119.4, 120.4, 121.4,
123

Synthesis of 3-substituted indole by AlCl3
2281
122.2, 126.5, 128.9, 136.8, 137.3, 208.6. HRMS: m/z 267.1633 (calcd. for
C18H21NO, 267.1623).
1-bromo-6-(1H-indol-3-yl)heptan-4-one (Table 1, Entry 4)
1H-NMR: d 1.38 (3H, H7, d, J = 6.9 Hz), 2.00-2.09 (2H, H2, m), 2.49 (2H, H3, t,
J = 7.2 Hz), 2.66 (1H, H5, dd, J = 15.7, 7.9 Hz), 2.89 (1H, H5, dd, J = 15.7,
6.2 Hz), 3.31–3.37 (2H, H1, m), 3.65 (1H, H6, m), 6.98 (1H, d, J = 2.1 Hz),
7.09–7.21 (2H, m), 7.34 (1H, d, J = 8.2), 7.62 (1H, d, J = 8.0 Hz), 7.94 (1H, br).
13C-NMR: d 21.5, 26.5, 27.4, 30.6, 33.5, 41.4, 51.0, 111.5, 119.4, 120.4, 121.2,
122.3, 127.4, 136.8, 209.4.
4-(1H-indol-3-yl)-1-(thiophen-3-yl)pentan-2-one (Table 1, Entry 5)
1H-NMR: d 1.35 (3H, H5, d, J = 6.9 Hz), 2.68 (1H, H3, dd, J = 15.9, 8.1 Hz), 2.93
(1H, H3, dd, J = 16.0, 6.0 Hz), 3.62 (2H, H1, s), 3.58 (1H, H4, m), 6.85 (1H, t,
J = 4.1 Hz), 6.91 (1H, J = 2.3 Hz), 6.97 (1H, d, J = 0.8 Hz), 7.08–7.26 (3H, m),
7.33 (1H, d, J = 7.8 Hz), 7.58 (1H, d, J = 7.8 Hz), 7.94 (1H, br). 13C-NMR: d
21.3, 27.3, 45.1, 49.8, 111.5, 119.4, 119.5, 120.4, 121.2, 122.3, 123.1, 126.0, 126.4,
128.8, 134.0, 136.7, 207.6. HRMS: m/z 283.1044 (calcd. for C17H17NOS,
283.1031).
2-(1H-indol-3-yl)octan-4-one (Table 1, Entry 6)
1H-NMR: d 0.82 (3H, H1, t, J = 7.2 Hz), 1.20-1.28 (2H, H2, m), 1.36 (3H, H8, d,
J = 6.9 Hz), 1.45 (2H, H3, m), 2.31 (2H, H4, t, J = 7.4 Hz), 2.63 (1H, H6, dd,
J = 15.9, 8.4 Hz), 2.87 (1H, H6, dd, J = 15.9, 5.7 Hz), 3.62 (1H, H7, m), 6.97 (1H,
d, J = 2.3 Hz), 6.97 (1H, d, J = 2.3 Hz), 7.11–7.21 (2H, m), 7.34 (1H, d, J = 7.8
HZ), 7.63 (1H, d, J = 7.5 Hz), 7.94 (1H, br). 13C-NMR: d 14.0, 21.4, 22.5, 26.0,
27.2, 43.3, 50.8, 111.4, 119.4, 119.5, 120.3, 121.5, 122.3, 126.5, 136.8, 211.1.
4-(1H-indol-3-yl)-1-(naphthalen-1-yl)pentan-2-one (Table 1, Entry 7)
1H-NMR: d 1.30 (3H, H5, d, J = 6.8 Hz), 2.65 (1H, H3, dd, J = 16.0, 7.9 Hz), 2.93
(1H, H3, dd, J = 16.0, 6.4 Hz), 4.02 (2H, H1, s), 6.84 (1H, d, J = 2.2 Hz),
7.07–7.25 (4H, m), 7.32–7.52 (6H, m), 7.68–7.84 (3H, m), 7.85 (1H, br). 13C-NMR:
d 21.4, 27.4, 49.2, 49.4, 111.4, 119.4, 119.5, 120.5, 121.1, 122.3, 124.1, 125.7,
126.0, 126.4, 126.6, 128.2, 128.5, 128.9, 131.1, 132.5, 134.1, 136.7, 208.5. HRMS:
m/z 327.1638 (calcd. for C23H21NO, 327.1623).
3-(1H-indol-3-yl)-1-(4-methoxyphenyl)butan-1-one (Table 1, Entry 8)
1H-NMR: d 1.43 (3H, H4, d, J = 6.7 Hz), 3.14 (1H, H2, dd, J = 16.1, 8.9 Hz), 3.38
(1H, H2, dd, J = 15.9, 4.8 Hz), 3.80 (1H, H3, m), 3.83 (3H, s), 6.89 (2H, d,
J = 6.8 Hz), 7.02 (1H, d, J = 2.3 Hz), 7.09-7.21 (2H, m), 7.35 (1H, J = 7.1 Hz),
7.67 (1H, d, J = 8.0 Hz), 7.92 (2H, d, J = 6.8 Hz), 7.95 (1H, br). 13C-NMR: d 21.2,
123

2282
A. S.-Y Lee et al.
27.6, 46.3, 55.7, 111.4, 113.9, 119.5, 120.3, 122.0, 122.2, 126.6, 130.6, 130.7,
136.8, 163.6, 198.5.
Results and discussion
The first feasibility of our approach was to investigate the isomerization of
1-phenyl-pent-3-en-one by the reported reaction condition (DABCO/iPrOH) [21–
27] followed by treatment of Lewis acids and indole at room temperature to
generate Friedel–Crafts Michael reaction product 3-substituted indole (Scheme 2).
A reaction mixture of of 1-phenyl-pent-3-en-one (1.0 eq.) and DABCO (2.0 eq.)
in iPrOH was stirred at room temperature for 2 h and then AlCl3 (1.5 eq.) and
indole (1.0 eq.) were added to the reaction mixture. The reaction mixture was stirred
at room temperature for 7 h and the expected 3-substituted indole was produced
with 79 % yield. Lewis acids such as TiCl4 can also behave as the promoters for this
one-pot reaction to generate 3-substituted indole. Other Lewis acids such as SnCl4,
BBr3, FeCl3, ZnCl2, BF.3OEt2 and Me3SiOTf were investigated and isomerized
compound A was obtained as the major product with minor product 3-substituted
indole. The experimental results showed that AlCl3 is the best choice of promoter
for the one-pot isomerization and Friedel–Crafts Michael reaction for synthesis of
3-substituted indoles. The introduction of AlCl3 may promote the isomerization
reaction and Friedel–Crafts Michael reaction in one-pot reaction condition. Thus,
we investigated the existence of AlCl3 as isomerizing and Friedel–Crafts alkylating
agent without using DABCO/iPrOH for the isomerization step and the results
showed that 3-substituted indole could also be produced under the reaction
condition. The introduced amount of AlCl3 was investigated and the results are
shown in Scheme 3.
O
CH3
O
A
O
1. 1.0 DABCO, iPrOH, 2h
Ph
+
Ph
Ph
2. 1.5 L.A., 1.0 Indole, rt
N
H
AlCl3, 7h
TiCl4, 7h
79%
76%
SnCl4, 69h
BBr3, 71h
26% + A (37%)
20% + A (52%)
7%
InCl3, 72h
FeCl3, 18h
ZnCl2, 73h
15% + A (36%)
1% + A (67%)
BF3 . OEt2, 71h
Me3SiOTf, 71h
7% + A (55%)
9% + A (44%)
Scheme 2 Optimization of introducing Lewis acid
123

Synthesis of 3-substituted indole by AlCl3
2283
O
CH3
O
1.5 N
H
AlCl
,
Ph
3
Ph
N
H
CH2Cl2, rt, 6h
0.3 AlCl3
34% + S.M. (37%)
0.5 AlCl3
1.0 AlCl3
48%
37%
Scheme 3 Optimization of introducing amount of AlCl3
O
CH3
0.5 AlCl
,
1.5
O
N
H
3
Ph
Ph
µ
CH2Cl2,
w
N
H
50 W, 50 oC, 40 min
62%
72%
100 W, 100 oC, 10 min
150 W, 110 oC, 10 min
Reflux, 4h
60%
87%
Scheme 4 Optimization of energy source
Introducing 0.5 equivalent of AlCl3 to 1-phenyl-pent-3-en-one in CH2Cl2
afforded 48 % yield of 3-substituted indole. Introducing 0.3 or 1.0 equivalent of
AlCl3 to the substrate did not increase the formation yield of 3-substituted indole.
Therefore, the amount of 0.5 equivalent AlCl3 was determined and tested by
different energy sources for this reaction condition. The reaction mixture of AlCl3,
1-phenyl-pent-3-en-one, and indole in CH2Cl2 was irradiated by microwave at
50–110 °C and improved the formation yield to 72 % (Scheme 4). It is worth noting
that a traditional energy source (refluxing CH2Cl2, b.p. = 39 °C) dramatically
improved the yield from 48 % (room temperature) to 87 %.
Other solvents of higher refluxing temperature were investigated for this reaction
condition (Scheme 5). It is interesting to note that the investigated higher refluxing
temperature solvents such as CHCl3 (b.p. = 61 °C), CH3CN (b.p. = 81 °C), and
iPrOH (b.p. = 82 °C) afforded lower formation yields of 3-substituted indoles.
Different Lewis acids were investigated for the optimization of this b-substitution
of b,c-unsaturated ketone with indole reaction (Scheme 6). The experimental results
showed that AlCl3 is the best choice of promoter for the production of 3-substituted
indole by the reaction of b,c-unsaturated ketone with indole.
To understand the scope of this one-pot AlCl3 promoted isomerization of b,c-
unsaturated ketone and then the Michael addition reaction of indole, a series of b,c-
unsaturated ketones were investigated under the reaction condition and the results
are shown in Table 1. As shown, all b,c-unsaturated ketones were transformed to
their corresponding 3-substituted indoles with moderate to high yields. Both alkyl-
123

2284
A. S.-Y Lee et al.
O
CH3
0.5 AlCl
,
1.5
N
H
O
3
Ph
Ph
Solvent, reflux 4h
N
H
CH2Cl2
CHCl3
CH3CN
iPrOH
87%
63%
83%
49%
Scheme 5 Optimization of solvent
H
C
O
3
0.5 L.A.
,
1.5
O
N
H
Ph
Ph
CH2Cl2, reflux, 4h
N
H
AlCl3
87%
InCl3
23% + S.M. (52%)
17% + S.M. (24%)
FeCl3
FeBr3
16%
.
FeF3 3H2O, 1 day
0% + S.M. (86%)
Yb(OTf)3
TiCl4
11% + S.M. (81%)
45% + S.M. (32%)
ZrCl4
47%
SnCl4
12% + S.M. (87%)
Scheme 6 Optimization of Lewis acid promoters
and aryl-b,c-unsaturated ketones can undergo this Friedel–Crafts Michael reaction
and give the desired products.
In conclusion, this one-pot Lewis acid promoted in situ isomerization of b,c-
unsaturated ketone to their corresponding a,b-unsaturated ketone, then undergoing
Michael addition reaction with indole to afford 3-substituted indole which provides
a selective C–C bond formation at b-position of ketone and 3-position of indole.
Acknowledgments We thank the National Science Council in Taiwan (NSC 101-2113-M-032-003) and
Tamkang University for financial support.
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Synthesis of 3-substituted indole by AlCl3
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