Base-catalyzed conjugate addition of thiols to indolyl acrylic acids and in situ decarboxylation: An expedient synthesis of functionalized 3-(1-thio)ethyl-1H-indoles

Article abstract of DOI:10.1055/s-0029-1218294

A one-pot, two-step method for the synthesis of 3-(1-thio)ethyl- 1H-indoles is described herein. This simple procedure in-volves the Michael addition of thiols to 3-indoleacrylic acids fol-lowed by in situ decarboxylation of the Michael adduct in the pres

Full text of DOI:10.1055/s-0029-1218294

LETTER
3201
Base-Catalyzed Conjugate Addition of Thiols to Indolyl Acrylic Acids and
in situ Decarboxylation: An Expedient Synthesis of Functionalized
3-(1-Thio)ethyl-1H-indoles
Synthesis of
F
h
unctionalized
i
3-(1-T
j
hio)eth
a
yl-1
H
-indo
y
les Gao, Chi Tseng, B. Rama Raju, Chen Hsuan Tsai, Ching-Fa Yao*
Department of Chemistry, National Taiwan Normal University, 88 Tingchow Road, Section 4, Taipei 11677, Taiwan
Fax +886(2)29324249; E-mail: cheyaocf@ntnu.edu.tw
Received 2 July 2009
fused heterocyclic system containing both thiol and indole
moieties are found to exhibit biological activity.10 More-
over, indolyl aryl sulfones act as resistant against HIV-1
carrying NNRTI resistance mutations.11
Abstract: A one-pot, two-step method for the synthesis of 3-(1-
thio)ethyl-1H-indoles is described herein. This simple procedure in-
volves the Michael addition of thiols to 3-indoleacrylic acids fol-
lowed by in situ decarboxylation of the Michael adduct in the
presence of a catalytic amount of K2CO3 in DMF at 100 °C. The
method was found to be fairly general with various thiols and dif-
ferent 3-indoleacrylic acids.
In general, the elimination of CO2 (decarboxylation) from
the carboxylic acids is difficult and often requires harsh
and forcing conditions, such as high pressures or temper-
atures,12 except for some activated acids such as b-carbo-
nyl acetic acids. However, the decarboxylation of a-
amino acids is a well-known reaction, and this strategy is
employed for the decarboxylation of tryptophan towards
the synthesis of tryptamine which is the potential com-
pound for the synthesis of indole alkaloids.13 In continua-
tion of our research work on indoles14 and thiols15 we were
interested to study the Michael addition of thiols to 3-in-
doleacrylic acids and interestingly found that Michael ad-
dition was followed by in situ decarboxylation. Hence, we
have developed a one-pot, two-step reaction for the syn-
thesis of 3-[1-(thio)ethyl]-1H-indoles from thiols and 3-
indoleacrylic acids catalyzed by base in good to excellent
yields (Scheme 1).
Key words: indole, thiol, conjugate addition, decarboxylation, 3-
[1-(thio)ethyl]-1H-indole
Indole and many of its derivatives are most important
structural units in many naturally occurring compounds as
they possess a variety of pharmacological and biological
properties.1 The importance of indole is due to their use as
key intermediates in the synthesis of numerous natural
compounds, including uleine,2 aspidospermidine,3 ibo-
phyllidine alkaloids,4 and hapalindole alkaloids,5 which
exhibit significant antibacterial and antimycotic activity.
In particular, 3-substituted indoles are versatile intermedi-
ates for the synthesis of a wide variety of indole scaf-
folds.6 Owing to the synthetic importance, various
methods were developed to introduce functionalized
groups at the 3-position of indole. The most frequently
employed procedure for the synthesis of 3-substituted in-
dole derivatives include the Friedel–Crafts/Michael-type
reaction of indoles with a,b-unsaturated systems employ-
ing an array of catalysts or reagents.7
Preliminary investigation was mainly focused on the eval-
uation of various inorganic bases including NaOH, KOH,
Na2CO3, and K2CO3. All of these bases were found to be
effective for alkylation of thiols (entries 2–5, Table 1).
Among them, K2CO3 was found to be the best choice of
base for the alkylation of thiol with 3-indoleacrylic acid
(entry 5, Table 1). Similarly, the effect of various solvents
was examined in conjunction with K2CO3. Trace amount
of the desired product was obtained in toluene (entry 6),
and no detectable product was observed with EtOH,
CH2Cl2, THF, and Et2O (entries 7–10, Table 1). With
DMF as the solvent, product yields were high which may
be due to the high solvating property of DMF. According
Organosulfur compounds play an important role in organ-
ic synthesis due to the ease of incorporation of the element
into complex structures and the ability to modify the oxi-
dation state of the atom.8 Therefore, the interconversion of
one oxidation state to another is the crucial aspect of the
successful use of sulfur in synthetic applications.9 The
COOH
R2S
R2S
R1
R1
COOH
R1
base
– CO2
R2SH
+
N
H
N
H
N
H
1a
2a
3a
Scheme 1 Synthesis of 3-[1-(thio)ethyl]-1H-indoles via conjugate addition and in situ decarboxylation; for R1 and R2, see Tables 2 and 3
SYNLETT 2009, No. 19, pp 3201–3205
x
x
.x
x
.2
0
0
9
Advanced online publication: 13.10.2009
DOI: 10.1055/s-0029-1218294; Art ID: W10409ST
© Georg Thieme Verlag Stuttgart · New York

3202
S. Gao et al.
LETTER
to Table 1, the best yield of the 3-[1-(thio)ethyl]-1H- rically hindered reactants such as naphthalene thiols (en-
indole was obtained with K2CO3 (20 mol%) in DMF at tries 6 and 7) also reacted well under these reaction
100 °C (entry 5, Table 1).
conditions. In general, aromatic thiols are less reactive
than aliphatic thiols, because the aromatic thiolate ion is
more resonance-stabilized than the aliphatic thiolate ion.
In contrast, we observed that aliphatic thiols undergo
Michael addition in longer reaction times (entries 13 and
14, Table 2).
To further explore the scope and limitations of this meth-
odology, we tested the alkylation reaction of various thi-
ols with 3-indoleacrylic acid (Table 2). As can be seen
from Table 2, alkylation of various aryl and alkyl thiols
proceeded well with 3-indoleacrylic acid to afford the cor-
responding 3-[1-(thio)ethyl]-1H-indoles in moderate to
excellent yields. Excellent yield was obtained with
thiophenol (entry 1, Table 2). Other than thiophenol, var-
ious substituted aromatic thiols containing electron-
donating or -withdrawing groups proceeded well to give
the corresponding alkylated products in good yields.
Moreover, the Michael addition of 3-indoleacrylic acid
with thiols containing electron-withdrawing groups re-
quired shorter reaction times compared to the reaction of
thiols with electron-donating groups.
Table 2 Michael Addition of 3-Indoleacrylic Acid with Various
a
Thiols Catalyzed by K2CO3
CO2H
S
R2
K2CO3 (20 mol%)
R2SH
+
100 °C, DMF
N
N
H
H
2a–n
1a
3a–n
Entry
1
Product 316
Time (h) Yield (%)b
Table 1 Reaction of 3-Indoleacrylic Acid with Thiolphenol under
Different Reaction Conditionsa
S
S
S
COOH
1
93
91
88
90
86
91
S
N
H
SH
additive
3a
+
solvent, 1 h
N
N
H
H
1a
2a
3a
2
3
4
5
6
7
1.5
Entry
Additive
Solvent
DMF
DMF
DMF
DMF
DMF
toluene
EtOH
CH2Cl2
THF
Temp (°C) Yield of 3a (%)b
N
H
OMe
OMe
1
2
none
100
4
77
79
83
93
trace
0c
3b
NaOH
KOH
100
3
3
100
N
H
4
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
100
3c
5
100
S
S
S
6
100
1
7
reflux
reflux
reflux
reflux
N
H
8
0c
3d
9
0c
10
Et2O
0c
3
a Conditions: 1a (1 mmol), 2a (1.5 mmol), additive (20 mol%), sol-
vent (1 mL).
b NMR yield.
c No reaction.
N
H
3e
1.5
This can be attributed to differences in acidity between the
various thiols (entries 2 and 9, 13 and 14, Table 2). Micha-
el addition of 3-indoleacrylic acid with thiols was con-
trolled by the steric factors of the reactant thiol partner.
For example, addition of 3-indoleacrylic acid with para-
substituted thiophenols occurred with high efficiency in
short reaction times (entries 2, 8, 9, and 11), whereas
ortho-substituted thiophenols required longer reaction
times for the respective alkylation (entries 3 and 5). Ste-
N
H
3f
S
3.5
94
N
H
3g
Synlett 2009, No. 19, 3201–3205 © Thieme Stuttgart · New York

LETTER
Synthesis of Functionalized 3-(1-Thio)ethyl-1H-indoles
3203
Table 2 Michael Addition of 3-Indoleacrylic Acid with Various
Thiols Catalyzed by K2CO3 (continued)
reacted faster with higher yields, whereas alkylation of 3-
indoleacrylic acid containing electron-donating groups
was sluggish and showed a marginal decline in the yield
(entry 10, Table 3).
a
CO2H
S
R2
K2CO3 (20 mol%)
100 °C, DMF
R2SH
Table 3 Reaction of Different 3-Indoleacrylic Acids with Various
+
a
Thiols Catalyzed by K2CO3
N
N
H
H
CO2H
2a–n
1a
3a–n
S
R2
R1
R1
Entry
8
Product 316
Time (h) Yield (%)b
K2CO3 (20 mol%)
100 °C, DMF
R2SH
+
N
H
N
S
S
S
S
H
2a,b,f,j–l
1b R1 = Br
1c R1 = Cl
1d R1 = Me
4a–j
1.5
90
92
90
91
63
54
71
N
H
Me
Entry Product 416
Time (h) Yield (%)b
3h
S
S
S
S
9
10
11
12
13
14
1
Cl
1
1.5
94
87
95
90
34
82
91
N
H
F
N
H
3i
4a
0.6
0.6
2
Cl
2
1
N
H
Cl
Br
N
H
OMe
3j
4b
Cl
3
1
N
H
N
H
Br
3k
4c
S
S
S
Cl
4
0.3
0.5
2.5
N
H
N
H
3l
4d
S
S
S
10
Cl
5
N
H
N
H
3m
O
4e
OMe
8
Br
6
N
H
N
H
3n
4f
a Conditions: 1 (1 mmol), 2 (1.5 mmol), K2CO3 (20 mol%), DMF (1
mL), 100 °C.
b Isolated yield.
Br
7
13
N
H
OMe
Similarly, the alkylation of various thiols was examined
with structurally divergent 3-indoleacrylic acid deriva-
tives, and the results are shown in Table 3. The results
demonstrated that 3-indoleacrylic acid containing elec-
tron-withdrawing groups (Cl and Br, entries 1–9, Table 3)
4g
Synlett 2009, No. 19, 3201–3205 © Thieme Stuttgart · New York

3204
S. Gao et al.
LETTER
Table 3 Reaction of Different 3-Indoleacrylic Acids with Various
Thiols Catalyzed by K2CO3 (continued)
have demonstrated that the present protocol is equally fac-
ile with various substituted thiols and structurally diver-
gent 3-indoleacrylic acids. The cheap and commercially
available catalyst, the simple procedure, and the mild con-
ditions make this method potentially useful in organic
synthesis.
a
CO2H
S
R2
R1
R1
K2CO3 (20 mol%)
100 °C, DMF
R2SH
+
N
H
N
H
2a,b,f,j–l
1b R1 = Br
1c R1 = Cl
1d R1 = Me
4a–j
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Entry Product 416
Time (h) Yield (%)b
Acknowledgment
S
S
Financial support of this work by the National Science Council of
the Republic of China and Nation Taiwan Normal University (TOP
001) is gratefully acknowledged.
Br
8
3.5
0.5
0.6
94
89
71
N
H
Cl
References and Notes
4h
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9
N
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S
Me
10
N
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4j
a Conditions: 1 (1 mmol), 2 (1.5 mmol), K2CO3 (20 mol%), DMF (1
mL), 100 °C.
b Isolated yield.
The study was also extended to probe the alkylation of
thiophenol
with
3-indole-2-phenylacrylic
acids
(Scheme 2). Michael addition of 3-indolylacrylic acid
containing a-substituted anisole (5a) with thiophenol re-
quired longer reaction times to afford the Michael adduct
in moderate yields. On the other hand, 4-chlorophenyl-3-
(1H-indol-3-yl)acrylic acid (5b) proceeded relatively in
shorter reaction time with high yields of Michael addition
product (6b). This may be due to the presence of electron-
withdrawing 4-ClC6H4 in the a-position of 3-indolylacryl-
ic acid that makes it more electrophilic (5b), which favors
the nucleophilic attack of the incoming thiolate ion.
In summary, we have developed a tandem Michael addi-
tion–decarboxylation reaction for the synthesis of 3-[1-
(thio)ethyl]-1H-indoles catalyzed by K2CO3. Notably, we
COOH
SH
S
X
K2CO3 (20 mol%)
+
X
100 °C, DMF
N
H
N
H
48 h (for 6a)
6 h (for 6b)
2a
5a X = OMe
5b X = Cl
6a X = OMe 59%
6b X = Cl 81%
Scheme 2 The reaction of a-substituted 3-(1H-indol-3-yl)-2-phenylacrylic acids with thiophenols
Synlett 2009, No. 19, 3201–3205 © Thieme Stuttgart · New York

LETTER
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Synthesis of Functionalized 3-(1-Thio)ethyl-1H-indoles
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(16) Typical Procedure for the Synthesis of 3-[1-(Phenyl-
thio)ethyl]-1H-indole (3a)
A mixture containing 3-indoleacrylic acid (187 mg, 1
mmol), thiophenol (165 mg, 1.5 mmol), and K2CO3 (27 mg,
0.2 mmol) in DMF (1 mL) was stirred at 100 °C for 1 h
(monitored by TLC). After completion of the reaction, the
mixture was poured into an ice-cold dilute HCl (aq) solution
and the solution then extracted with CH2Cl2 (3 × 25 mL).
The CH2Cl2 layers were washed with brine and dried over
anhyd MgSO4. After evaporation of the organic solvent, the
crude product was purified by flash column chromatog-
raphy, to afford 3-[1-(phenylthio)ethyl]-1H-indole (3a, 258
mg, 98% isolated yield). Colorless solid; mp 86–88 °C. 1H
NMR (400 MHz, CDCl3): d = 7.96 (s, 1 H), 7.82 (d, J = 7.8
Hz, 1 H), 7.36–7.33 (m, 3 H), 7.25–7.14 (m, 5 H), 7.03 (d,
J = 2.4 Hz, 1 H), 4.71 (q, J = 7.0 Hz, 1 H), 1.75 (d, J = 7 Hz,
3 H). 13C NMR (100 MHz, CDCl3): d = 136.7, 135.9, 132.6,
128.8, 127.0, 126.3, 122.5, 122.0, 119.9, 119.7, 118.2,
111.4, 40.3, 22.1. HRMS: m/z calcd for C16H15NS [M+]:
253.0925; found: 253.0919.
(11) Silvestri, R.; De Martino, G.; La Regina, G.; Artico, M.;
Massa, S.; Vargiu, L.; Mura, M.; Loi, A. G.; Marceddu, T.;
Colla, P. L. J. Med. Chem. 2003, 46, 2482.
3-[1-(4-Methoxyphenylthio)ethyl]-1H-indole (3b)
Colorless oil. 1H NMR (400 MHz, CDCl3): d = 7.92 (s, 1 H),
7.83 (d, J = 7.8 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.25 (d,
J = 8.3 Hz, 2 H), 7.21 (t, J = 7.5 Hz, 1 H), 7.15 (t, J = 7.4 Hz,
1 H), 6.91 (d, J = 2.1 Hz, 1 H), 6.76 (d, J = 8.6 Hz, 2 H), 4.53
(q, J = 7.0 Hz, 1 H), 3.77 (s, 3 H) 1.69 (d, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 159.7, 136.7, 136.3, 126.3,
125.8, 122.4, 121.9, 120.1, 119.7, 118.3, 114.3, 111.4, 55.5,
41.4, 21.8. HRMS: m/z calcd for C17H17NOS [M+]:
283.1031; found: 283.1035.
5-Chloro-3-[1-(phenylthio)ethyl]-1H-indole (4a)
Colorless oil. 1H NMR (400 MHz, CDCl3): d = 7.99 (s, 1 H),
7.76 (d, J = 1.8 Hz, 1 H), 7.34–7.31 (m, 2 H), 7.28–7.21 (m,
4 H), 7.16 (dd, J = 8.6, 1.9 Hz, 1 H), 7.04 (d, J = 2.4 Hz, 1
H), 4.63 (q, J = 7.0 Hz, 1 H), 1.73 (d, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 135.5, 135.0, 132.9, 128.9,
127.4, 127.3, 125.6, 123.3, 122.9, 119.5, 118.2, 112.4, 40.1,
21.9. HRMS: m/z calcd for C16H14ClNS [M+]: 287.0535;
found: 287.0533.
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