An unexpected reaction of 2-alkynylaryldiazonium tetrafluoroborate with sulfur dioxide

Article abstract of DOI:10.1039/c4cc07938h

An unexpected result from the reaction of 2-alkynylaryldiazonium tetrafluoroborate with sulfur dioxide is described. In the presence of morpholin-4-amine, this transformation catalyzed by copper(i) bromide proceeds through insertion of sulfur dioxide and

Full text of DOI:10.1039/c4cc07938h

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An unexpected reaction of 2-alkynylaryldiazonium
tetrafluoroborate with sulfur dioxide†
Cite this:DOI: 10.1039/c4cc07938h
Yong Luo,‡a Xiaolin Pan,‡a Chen Chen,b Liangqing Yao*b and Jie Wu*ac
Received 8th October 2014,
Accepted 30th October 2014
DOI: 10.1039/c4cc07938h
www.rsc.org/chemcomm
An unexpected result from the reaction of 2-alkynylaryldiazonium
tetrafluoroborate with sulfur dioxide is described. In the presence
of morpholin-4-amine, this transformation catalyzed by copper(I)
bromide proceeds through insertion of sulfur dioxide and intra-
molecular 5-endo cyclization, leading to benzo[b]thiophene
1,1-dioxides in moderate to good yields.
Currently, fixation of sulfur dioxide into small organic mole-
cules has attracted much attention. It will be highly desirable
to find its application in organic synthesis, considering the
enormous production of sulfur dioxide. Since Willis reported
the first example through palladium-catalyzed aminosulfonyla-
tion by using DABCO-bis(sulfur dioxide) as the source of sulfur
dioxide,1a continuous efforts have been underway.1–3 For instance,
Wang and co-workers reported a copper(II)-catalyzed, three-
component reaction of triethoxysilanes, sulfur dioxide, and
hydrazines, leading to N-aminosulfonamides in good yields.2i
Recently, we described an efficient route to N-aminosulfon-
amides via a three-component reaction of sulfur dioxide, aryldiazo-
Scheme 1 Proposed three-component reaction of 2-alkynylaryldiazonium
tetrafluoroborate, sulfur dioxide, with hydrazine.
nium salt, and hydrazines.3 The transformation proceeded through reaction system (Scheme 1, eqn (1)). This tandem approach seemed
a radical process under extremely mild conditions. Prompted by feasible, which combined the insertion of sulfur dioxide and metal-
this result, we hypothesized that 2-alkynylaryldiazonium tetra- catalyzed 6-endo cyclization in a one-pot procedure.
fluoroborate 1 could be utilized in the reaction of sulfur dioxide
Due to the importance of benzo[e][1,2]thiazine 1,1-dioxide
with hydrazine as well. We envisioned that an intramolecular (compound A, Scheme 1) in many natural products and pharmaceu-
6-endo cyclization would happen to afford 2H-benzo[e][1,2]thiazine ticals (e.g., ampiroxicam, an anti-inflammatory and analgesic drug A),5
1,1-dioxide A4 if a suitable metal catalyst was presented in the we started to explore the possibility of this three-component reaction
of 2-alkynylaryldiazonium tetrafluoroborate 1, sulfur dioxide and
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
China. E-mail: jie_wu@fudan.edu.cn; Fax: +86 21 6564 1740;
Tel: +86 21 6510 2412
b Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road,
Shanghai 200011, China. E-mail: yaoliangqingcn@126.com
c State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032,
China
hydrazine. Initial studies were performed by using 2-alkynylphenyl-
diazonium tetrafluoroborate 1a, DABCO-bis(sulfur dioxide) 2, and
morpholin-4-amine as the starting materials (Scheme 1, eqn (2)).
Only N-morpholino-2-(phenylethynyl)benzenesulfonamide B1 was
generated in the absence of a metal catalyst. To our surprise, we
did not observe the formation of the desired benzo[e][1,2]thiazine
1,1-dioxide A1 under palladium catalysis. Instead, a small amount
of benzo[b]thiophene 1,1-dioxide 3a was obtained. This result was
interesting, since morpholin-4-amine was not incorporated
in the final product and two new C–S bonds were formed. It
is well known that benzo[b]thiophene 1,1-dioxide derivatives
† Electronic supplementary information (ESI) available: Experimental procedure,
characterization data, CIF file of compound 3i, 1H and 13C NMR spectra of
compounds 3. CCDC 1011150. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c4cc07938h
‡ Y. Luo and X. Pan contributed equally.
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can behave as an absorbance and fluorescence switch, leading to a yield when the base was changed to potassium carbonate (Table 1,
multi-addressable system when triggered by ions, protons and light.6 entry 3). Further screening of bases revealed that the reaction worked
Additionally, they have been found as inhibitors of hepatitis C virus efficiently in the presence of sodium acetate, giving rise to the
NS5B polymerase as well as carbonic anhydrase inhibitors of expected product 3a in 60% yield (Table 1, entries 4–10). We sub-
cytosolic/tumor-associated carbonic anhydrase isozymes.7 Moreover, sequently examined the reaction in different solvents (Table 1,
complex molecules could be obtained using benzo[b]thiophene entries 11–15). Unfortunately, no better results were obtained. There-
1,1-dioxides as the starting materials.8 Thus, considering the impor- fore, we shifted our focus to other metal catalysts, such as rhodium
tance of the benzo[b]thiophene 1,1-dioxide scaffold in material and copper salts. The yield was improved when copper(I) bromide was
science, medicinal chemistry and organic synthesis, this novel used as the catalyst, providing the desired product 3a in 70% yield
observation encouraged us for its further exploration.
(Table 1, entry 25). A similar result was obtained when the reaction
Since N-morpholino-2-(phenylethynyl)benzenesulfonamide B1 was was performed at a higher temperature (Table 1, entry 26). However,
obtained in the absence of a metal catalyst, we wondered whether at 50 1C, no reaction occurred (Table 1, entry 27). The yield could
benzo[b]thiophene 1,1-dioxide 3a was produced from the reaction of increase to 80% when 3.0 equiv. of base was added to the reaction
N-morpholino-2-(phenylethynyl)benzene-sulfonamide B1. Therefore, (Table 1, entry 28). An inferior result was obtained when the amount
the reactions of N-morpholino-2-(phenylethynyl)benzenesulfonamide of copper(I) bromide decreased (data not shown in Table 1).
B1 catalyzed by palladium acetate in acetonitrile at 80 1C were
With the above results in hand, we re-investigated the reaction of
examined. The results are presented in Table 1. It was found that 2-alkynylphenyldiazonium tetrafluoroborate 1a with DABCO-bis(sulfur
the presence of base affected the final outcome. No reaction occurred dioxide) 2 in the presence of copper(I) bromide (10 mol%), morpholin-
when t-BuOK acted as the base in the reaction system (Table 1, 4-amine (1.0 equiv.) and NaOAc (3.0 equiv.) in MeCN. As expected, the
entry 1). A trace amount of product 3a was detected when cesium corresponding product 3a was generated in 65% yield. A control
carbonate was used as a replacement (Table 1, entry 2). Gratifyingly, experiment revealed that no reaction occurred in the absence of
benzo[b]thiophene 1,1-dioxide 3a was isolated and obtained in 37% morpholin-4-amine, which demonstrated that the reaction proceeded
through the intermediate of N-morpholino-2-(phenylethynyl)benzene-
sulfonamide B1. Moreover, other hydrazines were examined in the
Table 1 Metal-catalyzed reaction of N-morpholino-2-(phenylethynyl)-
reaction, such as 1-methyl-1-phenylhydrazine, 1-ethyl-1-phenylhydr-
benzenesulfonamide B1
azine, 1,1-diphenylhydrazine. However, the yields were lower (37–
40%). Therefore, the scope generality of this insertion of sulfur dioxide
was then explored. The results are shown in Table 2. We found that all
reactions took place smoothly under the optimized conditions to afford
the desired benzo[b]thiophene 1,1-dioxides 3 in moderate to good
yields. Various functional groups (such as fluoro, chloro, methyl, and
ester) were compatible. The thiophenyl-substituted product 3n could be
produced in 54% yield as well under standard conditions. In the
meantime, the structure of compound 3i was unambiguously identified
via X-ray crystallography analysis (Fig. 1).
It was reported that metal sulfinates could be easily generated
from N-aminosulfonamide derivatives in the presence of a suitable
base.9 Thus, the formation of benzo[b]thiophene 1,1-dioxide was
reasonable, although the result was not expected initially, since the
N-aminosulfonamide would serve as a masked sulfinate. The
presence of a metal catalyst would activate the triple bond in the
substrate, which in turn would facilitate the intramolecular cycliza-
tion of sulfinate (generated in situ) to alkyne. Cleavage of the S–N
bond in N-aminosulfonamide in the presence of a base at high
temperature was also observed by Willis and Toste.1c,2c Based on
the experimental results and previous reports as mentioned above,
a possible mechanism was proposed (Scheme 2). We reasoned
that 2-alkynylphenyldiazonium tetrafluoroborate 1 would react with
DABCO-bis(sulfur dioxide) 2 and morpholin-4-amine, leading to
N-morpholino-2-(phenylethynyl)benzenesulfonamide B. Sodium
sulfinate C would be formed in the presence of base, with the
cleavage of the S–N bond of N-aminosulfonamide. Subsequently,
a metal-catalyzed intramolecular 5-endo cyclization followed by
protonation would produce the corresponding product 3.
Entry
[M]
Base
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(TFA)2
[Rh(COD)Cl]2
Cu(OAc)2
Cu(OTf)2
CuI
CuCl2
CuBr2
t-BuOK
Cs2CO3
K2CO3
Na2CO3
K3PO4
KHCO3
NaHCO3
DABCO
KOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Toluene
1,4-Dioxane
AmylOH
DMSO
DMF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
nr
Trace
37
41
17
33
36
29
43
60
12
15
41
40
56
28
17
25
54
43
39
62
58
64
70
68
nr
80
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26b
27c
28d
CuCl
CuBr
CuBr
CuBr
CuBr
a
Isolated yield based on N-morpholino-2-(phenylethynyl)benzene-
b
c
In conclusion, we developed a copper(I)-catalyzed reaction
of 2-alkynylaryldiazonium tetrafluoroborate with sulfur dioxide.
sulfonamide B1. The reaction was performed at 90 1C. The reaction
occurred at 50 1C. In the presence of 3.0 equiv. of base.
d
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Table 2 Copper(I)-catalyzed reaction of aryldiazonium tetrafluoroborate
1 with sulfur dioxidea
generate benzo[b]thiophene 1,1-dioxides in moderate to good
yields. During the process, two new C–S bonds were formed.
Exploration of the insertion of sulfur dioxide for the synthesis
of other heterocycles is ongoing in our laboratory.
Financial support from the National Natural Science Founda-
tion of China (21172038, 21372046) is gratefully acknowledged.
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Scheme 2 Possible mechanism for reaction of 2-alkynylaryldiazonium
tetrafluoroborate with sulfur dioxide.
The transformation involving the insertion of sulfur dioxide
and intramolecular 5-endo cyclization proceeds efficiently to
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