Palladium-catalyzed annulation of 2-(1-Alkynyl)benzenamines with disulfides: Synthesis of 3-sulfenylindoles

Article abstract of DOI:10.1002/adsc.200900055

3-Sulfenylindoles can be efficiently prepared in moderate to good yields from 2-(1-alkynyl)benzenamines and disulfides using the palladium/air catalytic systems. The study also provides a useful route to the synthesis of fipronil analogues.

Full text of DOI:10.1002/adsc.200900055

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DOI: 10.1002/adsc.200900055
Palladium-Catalyzed Annulation of 2-(1-Alkynyl)benzenamines
with Disulfides: Synthesis of 3-Sulfenylindoles
Yan-Jin Guo,a Ri-Yuan Tang,a Jin-Heng Li,a,b,* Ping Zhong,a
and Xing-Guo Zhanga,*
a
College of Chemistry and Materials Science, Wenzhou University, Wenzhou 325035, Peopleꢀs Republic of China
Fax : (+86)-577-8836-8607; phone: (+86)-577-8836-8607; e-mail: jhli@hunnu.edu.cn or xgzhang99@yahoo.com.cn
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education), Hunan Normal
b
University, Changsha 410081, Peopleꢀs Republic of China
Received: January 25, 2009; Revised: May 17, 2009; Published online: October 21, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900055.
Abstract: 3-Sulfenylindoles can be efficiently pre-
pared in moderate to good yields from 2-(1-alkyn-
ACHTUNGTRENNUNGyl)benzenamines and disulfides using the palladium/
air catalytic systems. The study also provides a
useful route to the synthesis of fipronil analogues.
conditions. Our investigation began with an attempted
annulation of substrate 1a with disulfide 2a in the ab-
sence of Pd catalysts, but no reaction was observed
(entry 1). After a series of trials, we found that the re-
action could be conducted successfully to afford an
88% yield of the target product 3 in the presence of
10 mol% of PdCl2 (entry 2), and a satisfactory yield
was still achieved at 5 mol% of PdCl2 (entry 3). Other
Keywords: 2-(1-alkynyl)benzenamines; annulation;
disulfides; palladium; 3-sulfenylindoles
Pd catalysts, PdCl2/PPh3, PdACHTUNTRGENNUG(OAc)2 and PdACHTUNGTERN(NUNG PPh3)4,
were also tested, and they were less effective than
PdCl2 (entries 4–6). The results indicated that the in-
creased amount of 1,2-diphenyl disulfide (2a) has no
The indole moiety is a basic component of many effect on the reaction (entry 7). Among the solvents
pharmacophores, natural products, and synthetic and reaction temperatures examined, DMSO com-
building blocks.[1] 3-Sulfenylindoles, important topical bined with 808C gave the best results (entries 3 and
indoles, were identified for their potential in many 8–12). Finally, the role of oxidation reagents was eval-
major therapeutic areas, such as oncology, HIV, and uated. The results revealed that the addition of CuCl2
heart disease.[2] Therefore, many efficient methods affected the reaction slightly (entry 13). One equiva-
have been developed for their preparation.[3–9] The lent of CuCl2 instead of air provided the same results
vast majority of these transformations are the direct under air or argon atmosphere (entries 14 and 16).
sulfenylation of indoles with thiols,[2a,3] disulfides,[4] However, without CuCl2 the reaction under argon at-
quinone
ACHTUNGTRENNUNG
mono-O,S-acetals,[5]
N-thioalkylACTHNGUTRENNU(G aryl)- mosphere gave the target product 3 in a low yield to-
phthalimides,[6] and ammonium thiocyanates.[7] Thus, gether with another product 4, 2-phenyl-1H-indole, in
the development of some novel alternative strategies 50% yield (entry 15). These results suggested that air
for synthesizing 3-sulfenylindoles remains a challeng- played a crucial role in the reaction.
ing area. During our preparation of this paper,
With the optimal reaction in hand, we decided to
Larock and co-workers described a novel synthetic explore the scope of 2-(1-alkynyl)benzenamines first.
route to 3-sulfenylindoles by (n-Bu)4NI-induced elec- As listed in Table 2, a variety of 2-(1-alkynyl)benzen-
trophilic cyclization of N,N-dialkyl 2-(1-alkynyl)ben-
zenamines with arylsulfenyl chlorides.[8] Here, we
report another new route to the synthesis of 3-sulfe-
nylindoles by palladium-catalyzed annulation of 2-(1-
alkynyl)benzenamines with disulfides in the presence
of air (Scheme 1).[10]
As shown in Table 1, the reaction between 2-(2-
phenylethynyl)benzenamine (1a) and 1,2-diphenyl di-
Scheme 1. Palladium-catalyzed annulation of 2-(1-alkynyl)-
sulfide (2a) was screened to optimize the reaction benzenamines with disulfides.
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Table 1. Screening conditions for the synthesis of 3-sulfen-
A
Table 2. PdCl2-catalyzed annulation of 2-(2-ethynyl)benzen-
ylindoles.[a]
amines (1) with 1,2-diphenyldisulfane (2a).[a]
ACHTUNGTRENNUNG
Entry
Substrate 1
Time Isolated yield
[h]
[%] (Product)
Entry [Pd]
(mol%)
Solvent Temp. Isolated Yield
G
[oC]
[%] (Product)
1
1b
1c
24
65 (5)
1
2
–
DMSO 80
0 (3)
PdCl2 (10)
PdCl2 (5)
PdCl2 (10)
Pd
Pd
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
DMSO 80
DMSO 80
DMSO 80
88 (3)
76 (3)
65 (3)
18 (3)
trace (3)
89 (3)
25 (3)
72 (3)
29 (3)
trace (3)
52 (3)
92 (3)
86 (3)
25 (3)
85 (3)
3
4[b]
5
2[b]
24
24
trace (6)
35 (7)
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
6[c]
7[d]
8
DMSO 80
DMF
MeCN
NMP
80
80
80
3
4
1d
1e
9
10
11[c]
12
13[e]
14[f]
15[g]
16[f,g]
DMSO 25
DMSO 100
DMSO 80
DMSO 80
DMSO 80
DMSO 80
30
59 (8)
5
1f
1g
1h
24
96
24
19 (9)
[a]
Reaction conditions: 1 (0.2 mmol), 2a (0.1 mmol), [Pd]
and solvent (2 mL) for 24 h under air atmosphere.
PPh3 (20 mol%) was added.
>95% of 1a was recovered.
2a (0.2 mmol) was added.
[b]
[c]
[d]
[e]
[f]
6[c]
trace (10)
82 (11)
CuCl2 (20 mol%) was added.
CuCl2 (100 mol%) was added under argon atmosphere.
Under an argon atmosphere. 2-phenyl-1H-indole (4) was
obtained in 50% yield.
7
[g]
8
9
1i
1j
24
24
56 (12)
83 (13)
ACHTUNGTRENNUNGamines 1b–1l were tested by treating with 1,2-diphen-
yl disulfide (2a), PdCl2 and air. We were pleased to
disclose that satisfactory results were still obtained
from the analogous amine with the hydrogen group
replaced by a methyl group in the presence PdCl2 and
air (entry 1), but replacement by an acetyl group gave
only a trace amount of the target product 6 (entry 2).
Subsequently, substituents at the terminal alkyne
moiety of 2-(1-alkynyl)benzenamine were evaluated,
and the results demonstrated that both electronic and
steric effects of substituents affected the reaction to
some extent (entries 3–9). We found that 2-bromo-
phenyl, thiophen-2-yl and alkyl groups favored the re-
actions providing moderate to good yields (entries 4
and 7–9), but 2-methoxyphenyl, pyridin-4-yl and 4-
acetylphenyl groups gave low yields (entries 3, 5 and
6). To our delight, substrates 1k and 1l, having a
chloro or a methyl group on the corresponding aro-
10
1k
1l
24
24
95 (14)
61 (15)
11
[a]
Reaction conditions: 1a (0.2 mmol), 2 (0.1 mmol), PdCl2
(10 mol%) and DMSO (2 mL) at 808C under air atmos-
phere.
Some unidentified products were observed by GC-MS
analysis.
[b]
[c]
>95% of 1g was recovered.
matic ring of benzenamine, also underwent the annu- smoothly in 95% and 61% yields, respectively (en-
lation reaction with disulfide 2a, PdCl2, and air tries 10 and 11).
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Palladium-Catalyzed Annulation of 2-(1-Alkynyl)benzenamines with Disulfides
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Table 3. PdCl2-catalyzed annulation of 2-(2-phenylethynyl)-
benzenamine (1a) with disulfides (2).[a]
and air smoothly in moderate to excellent yields (en-
tries 1–9), but 1,2-dibenzyl disulfide (2k) was found to
be an unsuitable substrate under the same conditions
(entry 10). We were pleased to observe that several
functional groups, such as methyl, methoxy, amino,
cyano, trifluoromethyl, fluoro, chloro, and nitro
groups, on the aromatic moiety of disulfides were per-
fectly tolerated, and disulfides having electron-defi-
cient aryl groups gave the better results (entries 1–8).
Substrate 2b bearing a para-methyl group, for exam-
ple, was treated with 1a, PdCl2 and air to afford the
corresponding desired product 16 in 58% yield
(entry 1). Gratifyingly, disulfide 2h with an electron-
withdrawing nitro group offered the product 22 in
96% yield (entry 7). Noteworthy is that a new fipronil
analogue 19 is readily synthesized in high yield under
the standard conditions (entry 4).[11] We were pleased
to discover that the standard conditions were also
compatible with 2-[2-(pyridin-2-yl)disulfanyl]pyridine
(2i). In the presence of PdCl2 and air, treatment of
substrate 2i with disulfide 1a gave the desired product
23 in 74% yield (entry 8).
In summary, we have described the first example of
synthesizing 3-sulfenylindoles by palladium-catalyzed
annulation of 2-(1-alkynyl)benzenamines with disul-
fides under an air atmosphere. In the presence of
PdCl2 and air, a variety of 2-(1-alkynyl)benzenamines
underwent the annulation reaction with disulfides
smoothly to afford the corresponding 3-sulfenylin-
doles in moderate to good yields. It is worth noting
that a new fipronil analogue is prepared in a good
yield via the present protocol.[12] Efforts to explore
the detailed mechanism and extend the applications
of the transformation in organic synthesis are under-
way in our laboratory.
Entry
Disulfide 2
Time Isolated yield
[h]
[%] (Product)
1
2
2b
2c
25
58 (16)
24
48
70 (17)
27 (18)
3
4
2d
2e
24
95 (19)
5
6
7
2f
2g
2h
24
24
24
89 (20)
92 (21)
96 (22)
Experimental Section
8
2i
24
24
24
74 (23)
Typical Experimental Procedure for Palladium-
Catalyzed Annulation of 2-(1-Alkynyl)benzenamines
(1) with Disulfides (2)
9
2j
2k
78 (24)
A mixture of 2-(1-alkynyl)benzenamine 1 (0.2 mmol), disul-
fide 2 (0. 1 mmol) and PdCl2 (10 mol%) in DMSO (2 mL)
was stirred at 808C under an air atmosphere for the indicat-
ed time until complete consumption of starting material as
monitored by TLC and GC-MS analysis. After the reaction
was finished, the mixture was poured into ethyl acetate,
which was washed with saturated NaCl (5ꢂ3 mL). After the
aqueous layer was extracted with ethyl acetate, the com-
bined organic layers were dried over anhydrous Na2SO4 and
evaporated under vacuum. The residue was purified by flash
column chromatography (hexane/ethyl acetate) to afford the
desired product.
10[b]
trace (25)
[a]
Reaction conditions: 1a (0.2 mmol), 2 (0.1 mmol), PdCl2
(10 mol%) and DMSO (2 mL) at 808C under air atmos-
phere.
[b]
>95% of 1a was recovered.
Next, a set of disulfides 2b–2k were examined
under the standard conditions, and the results are
summarized in Table 3. The results indicated that
diaryl disulfides 2b–2i or dimethyl disulfide 2j, react-
2-Phenyl-3-(phenylthio)-1H-indole (3): Pale yellow oil;
1H NMR (300 MHz, CDCl3): d=8.57 (brs, 1H), 7.78 (d, J=
ed with 2-(2-phenylethynyl)benzenamine (1a), PdCl2 8.2 Hz, 2H), 7.67 (d, J=7.8 Hz, 1H), 7.49–7.42 (m, 4H),
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Yan-Jin Guo et al.
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7.30–7.27 (m, 1H), 7.22–7.12 (m, 6H); 13C NMR (75 MHz,
CDCl3): d=142.1, 139.3, 135.9, 131.4, 131.2, 128.9, 128.8,
128.7, 128.1, 125.6, 124.6, 123.4, 121.2, 120.0, 111.2, 99.4;
LR-MS (EI, 70 eV): m/z (%)=301 (M+, 100), 268 (13), 223
(31); HR-MS (EI): m/z=301.0925, calcd. for C20H15NS
(M+): 301.0925.
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We thank the National Natural Science Foundation of China
(No. 20872112), Zhejiang Provincial Natural Science Foun-
dation of China (Nos. Y407116, Y407079 and Y4080027),
and Program for New Century Excellent Talents in Universi-
ty (No. NCET-06-0711) for financial support.
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