Venting-while-heating microwave-assisted synthesis of 3-arylthioindoles

Article abstract of DOI:10.1021/co200165j

We report the first example of venting-while-heating microwave-assisted synthesis of a small library of 3-arylthioindoles. Compounds were prepared in excellent isolated yields (90-98%) within 4 min in a closed vessel by treating indoles with disulfides in the presence of sodium hydride in anhydrous N,N-dimethylformamide. The method was not affected by electron-donating and -withdrawing substituents both on 3-arylthio moiety and at 2- and 5-positions of the indole nucleus.

Full text of DOI:10.1021/co200165j

Letter
pubs.acs.org/acscombsci
Venting-while-Heating Microwave-Assisted Synthesis
of 3-Arylthioindoles
Giuseppe La Regina,* Valerio Gatti, Valeria Famiglini, Francesco Piscitelli, and Romano Silvestri
Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Universita
Piazzale Aldo Moro 5, I-00185, Rome, Italy
̀
di Roma,
S
* Supporting Information
ABSTRACT: We report the first example of venting-while-
heating microwave-assisted synthesis of a small library of 3-
arylthioindoles. Compounds were prepared in excellent isolated
yields (90−98%) within 4 min in a closed vessel by treating
indoles with disulfides in the presence of sodium hydride in
anhydrous N,N-dimethylformamide. The method was not
affected by electron-donating and -withdrawing substituents
both on 3-arylthio moiety and at 2- and 5-positions of the indole
nucleus.
KEYWORDS: microwave-assisted organic synthesis, dielectric heating, venting while heating, sulfenylation, 3-arylthioindoles, indole
3-Arylthioindoles are endowed with a large spectrum of
biological activities, being potentially useful for the treatment
of some diseases, such as affective (e.g., 1),1 vascular (e.g., 2),2
and respiratory disorders (e.g., 3)3 (Chart 1). Among these,
we reported the strong antitumor activity of 3-((3,4,5-
trimethoxyphenyl)thio)-1H-indoles (e.g., 4) and some related
bioisosteres at the sulfur bridge as potent inhibitors of both
tubulin polymerization and of cancer cell, by binding the
colchicine site of tubulin.4
Chart 1. 3-Arylthioindoles Exhibiting Biological Activities
The synthesis of 3-arylthioindoles included the direct
sulfenylation of the indole ring by disulfides,5−7 quinone
mono-O,S-acetals,8,9 sulfenyl halides,10,11 N-(arylthio)-
succinimides,12 N-(arylthio)phthalimides,13 and activated
thiols.14−20 3-Sulfenylindoles were also prepared by palladium-
catalyzed annulation of 2-(1-alkynyl)benzenamines with
disulfides21 and by tetrabutylammonium iodide-induced
electrophilic cyclization of the same starting materials with
arylsulfenyl chlorides.22,23
Our interest in new anticancer agents required a general,
simple, high-yielding and very fast method to synthesize
3-arylthioindoles. First, our attention was focused on 3-((3,4,5-
trimethoxyphenyl)thio)-1H-indoles, being the 3,4,5-trimethox-
yphenyl portion crucial for small molecules that bind the
colchicine site of tubulin.24 Our experiments showed that
2-carboxylate derivatives can be synthesized in very low yields
by reacting the appropriate indole with 3,4,5-trimethoxythio-
phenol in the presence of N-chlorosuccinimide.4a,b Further-
more, treatment of 2H- or 2-methylindole with 3,4,5-tri-
methoxythiophenol in the presence of iodine/potassium iodide
gave the corresponding 3-arylthioindoles in moderate yields.4c
Our experience suggested that these results could be explained
mainly by taking into account the high instability of the 3,4,5-
trimethoxybenzenethiol, even at very low temperatures, leading
us to explore the use of the more stable and easy to handle
corresponding disulfide.
Pursuing our recent interest in microwave-assisted organic
synthesis of heterocyclic compounds of biological interest,25
we wish to report the preparation of a small library of
3-arylthioindoles under venting-while-heating. Compounds
5−58 were quickly prepared in high yields by reacting indoles
59−69 with disulfide 70−79 in a closed vessel (Scheme 1).
To the best of our knowledge, methods involving the use of
microwave heating for the synthesis of 3-arylthioindoles have
not been reported. Furthermore, potential advantages of the
Received: October 9, 2011
Revised: February 23, 2012
Published: March 20, 2012
© 2012 American Chemical Society
258
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ACS Combinatorial Science
Letter
Scheme 1. Venting-while-Heating Microwave-Assisted
Synthesis of 3-Arylthioindoles 5-58
Table 2. Venting-while-Heating Microwave-Assisted
Synthesis of 3-((3,4,5-trimethoxyphenyl)thio)-1H-indoles
5−13
technology of venting-while-heating (ActiVent)26 in microwave-
assisted organic synthesis have never been explored.
As a model study, we investigated the reaction of 1H-indole
(59) with 1,2-bis(3,4,5-trimethoxyphenyl)disulfide4a (79) in
the presence of sodium hydride (NaH) in anhydrous N,N-di-
methylformamide (DMF) to furnish 3-((3,4,5-trimethoxy-
phenyl)thio)-1H-indole (5) (Table 1). The best molar ratio
lit. yield/
a
b
yield
time
entry indole product
R1
R2
(%)
(%/min)
method
c
1
2
3
4
5
6
7
8
9
59
60
63
64
65
66
67
68
69
5
H
H
97
96
88
98
94
96
93
92
90
47/604d
53/604d
1/754c
A
6
Me
COOEt
H
H
A
d
7
H
B
8
Cl
59/604d
30/604d
54/604d
29/604d
6/754c
A
A
A
A
B
B
9
H
OMe
Cl
10
11
12
13
Me
Me
Table 1. Optimization of Reaction Conditions for
Compound 5
OMe
COOEt Cl
COOEt OMe
4/754c
a
b
c
Isolated yield. Yield and time from indicated reference. Indole
(1 equiv), disulfide (1.1 equiv), NaH (2.2 equiv), closed vessel,
d
130 °C, 120 W, 2 min, ActiVent. Indole (1 equiv), disulfide (1.1
equiv), NaH (2.2 equiv), closed vessel, 130 °C, 120 W, 4 min,
ActiVent.
to 4 and 8 min caused a decrease of the yield as a probable
consequence of the dielectric overheating (entries 6 and 7,
Table 1). On the contrary, compound 5 was isolated in 65%
yield when the reaction mixture was vented while heating at
100 °C for 2 min with a power of 90 W (entry 8, Table 1).
Thus, the optimal yield (98%) was reached when the reaction
mixture was irradiated with a power of 120 W at 130 °C for
2 min in the same conditions (entry 9, Table 1). At the same
temperature and in a comparable short time period, derivative 5
was obtained in very low yield when we heated the reaction
mixture in an oil bath (entry 2, Table 1).
The result could be explained by taking into account that the
venting of the reaction mixture allows the release of the internal
pressure of the vial during the experiment and maintain a high
power of microwave irradiation for all reaction time. In fact,
when we performed the sulfenylation without venting the
mixture (Figure 1A), the hydrogen pressure (resulted from the
reaction of NaH with indole) limited the microwave irradiation
because the instrument automatically reduces the irradiation
power to a lower level to not exceed the operational limits of the
system. On the contrary, venting of the hydrogen gas during the
microwave heating allowed a higher level of microwave power
to be directly transferred to the reaction mixture, driving the
reaction to proceed to completion (Figure 1B).
a
b
entry heating temp (°C) time power (W) ActiVent
yield (%)
1
2
3
4
5
6
7
8
9
oil bath
oil bath
60
12 h
90
2
130
100
130
160
130
130
100
130
10 min
2 min
2 min
2 min
4 min
8 min
2 min
2 min
c
MW
70
off
off
off
off
off
on
on
35
45
40
25
15
65
98
MW
MW
MW
MW
MW
MW
100
130
100
100
90
120
a
b
c
Venting-while-heating. Isolated yield. Microwave.
indole/disulfide/NaH was found to be 1/1.1/2.2 (data not
shown). Despite a non optimal loss tangent value (tan δ =
0.161),27 DMF was chosen as solvent mainly because of the
very low solubility of the starting disulfide. By comparison, the
same reaction needed an oil bath heating time of 12 h to
furnish compound 5 in high yield (entry 1, Table 1). Alter-
natively, derivative 5 was prepared in fair yield (47%) by
reacting 1H-indole with 3,4,5-trimethoxybenzenethiol in the
presence of iodine/potassium iodide for 1 h at 25 °C.4d
When we heated the reaction mixture at 100 °C for 2 min by
applying a microwave irradiation of 70 W, derivative 5 was
isolated in low yield (entry 3, Table 1). The latter did not
significantly improve when the temperature was raised to 130
and 160 °C, using a power of 100 and 130 W, respectively
(entries 4 and 5, Table 1). Furthermore, extending the time up
Optimized reaction conditions were further validated by
reacting 1,2-bis(3,4,5-trimethoxyphenyl)disulfide (79) with
2- (60 and 63), 5- (64 and 65), and 2,5-(di)substituted
indoles (66−69) to furnish the corresponding 3-arylthioindoles
6 and 7 (entries 2 and 3, Table 2), 8 and 9 (entries 4 and 5,
Table 2), and 10−13 (entries 6−9, Table 2), respectively.
By comparing with our previously reported results, it should be
noted that the new method not only considerably reduced the
259
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ACS Combinatorial Science
Letter
Figure 1. Reaction pressure, power, and temperature profiles using standard (A) and venting-while-heating (B) microwave-assisted synthesis.
time, but above all significantly increases the yield of the
reactions. In particular, 2-carboxylate derivatives (63, 68, and
69) benefited from the new method, jumping yields from 1−
6% to 85−88%. Furthermore, the same compounds required
a longer microwave irradiation time, because of the strong
electron-withdrawing effect of the ester group (method B).
Nevertheless, in contrast to that observed by Atkinson and co-
workers,5 prolonged microwave irradiation did not lead to
competing ester cleavage with formation of thioanisole. Likely,
the venting of the mixture removed at the same time hydrogen
and thiol, allowing the reaction to proceed.
These encouraging results prompted us to investigate the
reaction of indoles 59−63 with disulfides 70−78 (Table 3). The
latter were quickly prepared by oxidation of the appropriate
thiol with 1,3-dibromo-5,5-dimethylhydatoin according to Alam
and co-workers.28
Thus, 3-arylthioindoles 14−40 (entries 1−27, Table 3) were
prepared in only 2 min by treating 2-H (59), 2-Me (60), and
2-Ph (61) indoles with diphenyl- (70), bis(2-chlorophenyl)-
260
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ACS Combinatorial Science
Letter
bis(4-methoxyphenyl) (76), bis(2,4-dichlorophenyl) (77), and
bis(2,5-dimethoxyphenyl) (78) disulfides in the presence of
NaH (2.2 equiv) (method A). Reaction products were isolated in
excellent yields ranging from 90% to 98%. The method was not
affected both by electron-donating and -withdrawing substituents
on 3-arylthio moiety and by methyl and phenyl groups at
2-position of the indole nucleus.
Table 3. Venting-while-Heating Microwave-Assisted
Synthesis of 3-Arylthioindoles 14−58
However, the presence of a withdrawing group at 2-position
of the indole ring, such as carboxylic acid or ethyl carboxylate
functions, did not allow to have in high yields 3-arylthioindoles
41−49 (entries 28−36, Table 3) and 50−58 (entries 37−45,
Table 3), respectively. On the contrary, they were successfully
prepared by treating 1H-indole-2-carboxylic acid (62) or ethyl
1H-indole-2-carboxylate (63) with disulfides 70−78 in the
presence of 3.3 equiv (method C) or 2.2 equiv (method B) of
NaH at 130 °C for 4 min with a power of 120 W.
In conclusion, we report the first example of venting-while-
heating microwave-assisted synthesis of 3-arylthioindoles. Com-
pounds were prepared in excellent isolated yields (90−98%)
within 4 min, by treating indoles with disulfides in the presence of
NaH in a closed vessel. Electron-donating and -withdrawing
substituents on 3-arylthio moiety as well as at 2- and 5-positions of
the indole nucleus were well tolerated. The time of the reaction
was significantly shortened by microwave heating. At the same
time, the venting of the reaction mixture permitted the use of a
higher level of microwave irradiation, allowing the reaction to
proceed. Finally, the method could provide a rapid, simple, and
efficient access to a wide range of 3-sulfenylindoles of biological
interest by a combinatorial approach.
a
entry indole disulfide product
R1
R3
yield (%) method
b
1
2
3
4
59
59
59
59
59
59
59
59
59
60
60
60
60
60
60
60
60
60
61
61
61
61
61
61
61
61
61
62
62
62
62
62
62
62
62
62
63
63
63
63
63
63
63
63
63
70
71
72
73
74
75
76
77
78
70
71
72
73
74
75
76
77
78
70
71
72
73
74
75
76
77
78
70
71
72
73
74
75
76
77
78
70
71
72
73
74
75
76
77
78
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
H
H
H
H
H
H
H
H
H
H
98
95
96
98
95
96
95
98
95
94
96
98
96
94
93
95
98
92
96
97
95
96
94
92
90
96
93
92
93
94
96
91
89
90
95
90
93
89
94
95
91
90
91
93
89
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
C
C
C
C
C
C
C
C
C
2-Cl
3-Cl
4-Cl
2-OMe
3-OMe
4-OMe
2,4-Cl2
2,5-OMe2
H
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
2-Cl
3-Cl
4-Cl
2-OMe
3-OMe
4-OMe
2,4-Cl2
2,5-OMe2
H
ASSOCIATED CONTENT
* Supporting Information
Ph
Ph
Ph
Ph
2-Cl
3-Cl
4-Cl
2-OMe
3-OMe
4-OMe
2,4-Cl2
2,5-OMe2
H
■
S
Experimental procedures, characterization data of all synthe-
sized compounds, example of microwave output graphics, and
1
Ph
copies of H NMR spectra of compounds 15, 16, 18, 21, 22,
Ph
Ph
Ph
24, 25, 27, 28, 30, 31, 33, 34, 36, 37, 39, 40, 42−49, 51−53,
57, 58, 72, 77, and 78. This material is available free of charge
via the Internet at http://pubs.acs.org.
c
COOH
COOH 2-Cl
AUTHOR INFORMATION
Corresponding Author
*E-mail: giuseppe.laregina@uniroma1.it. Phone: +39
0649913404. Fax: +39 0649913133.
■
COOH 3-Cl
COOH 4-Cl
COOH 2-OMe
COOH 3-OMe
COOH 4-OMe
COOH 2,4-Cl2
COOH 2,5-OMe2
COOEt
COOEt 2-Cl
COOEt 3-Cl
Funding
The authors wish to thank Ministero dell'Istruzione, dell’Universita
e della Ricerca (Bando PRIN 2008, Protocollo 200879X9N9;
Bando Futuro in Ricerca 2010, Protocollo RBFR10ZJQT),
̀
d
H
B
B
B
B
B
B
B
B
B
̀
Universita La Sapienza (Finanziamento Progetti di Ricerca,
Grant 2011), and FILAS (Finanziaria Laziale di Sviluppo, Grant
2010) for financial support. This research was also supported by
international FIRB grant n. RBIN06E9Z8
COOEt 4-Cl
COOEt 2-OMe
COOEt 3-OMe
COOEt 4-OMe
COOEt 2,4-Cl2
COOEt 2,5-OMe2
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors wish to thank Andrea Rota (CEM srl, Italy) for
skilful technical assistance.
■
a
b
Isolated yield. Indole (1 equiv), disulfide (1.1 equiv), NaH (2.2
equiv), closed vessel, 130 °C, 120 W, 2 min, ActiVent. Indole (1
equiv), disulfide (1.1 equiv), NaH (3.3 equiv), closed vessel, 130 °C,
120 W, 4 min, ActiVent. Indole (1 equiv), disulfide (1.1 equiv), NaH
c
d
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■
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ACS Combinatorial Science
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