Synthesis of Sulfonated Benzo[d][1,3]oxazines by Merging Photoredox Catalysis and Insertion of Sulfur Dioxide

Article abstract of DOI:10.1002/adsc.201701187

A photocatalytic reaction of N-(2-vinylphenyl)amides, DABCO?(SO₂)₂ and arenediazonium tetrafluoroborates for the synthesis of 4-((arylsulfonyl)methyl)-4H-benzo[d][1,3]oxazines under mild conditions is reported. This synthetic approac

Full text of DOI:10.1002/adsc.201701187

Title: Synthesis of Sulfonated Benzo[d][1,3]oxazines by Merging
Photoredox Catalysis and Insertion of Sulfur Dioxide
Authors: Tong Liu, Danqing Zheng, Zhenhua Li, and Jie Wu
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Advanced Synthesis & Catalysis
10.1002/adsc.201701187
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of Sulfonated Benzo[d][1,3]oxazines by Merging
Photoredox Catalysis and Insertion of Sulfur Dioxide
a
a
a,
a,b,
Tong Liu, Danqing Zheng, Zhenhua Li, * and Jie Wu *
a
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China. E-mail:
lizhenhua@fudan.edu.cn; jie_wu@fudan.edu.cn
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
b
Sciences, 345 Lingling Road, Shanghai 200032, China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract.
vinylphenyl)amides, DABCO•(SO
tetrafluoroborates for the
(arylsulfonyl)methyl)-4H-benzo[d][1,3]oxazines
mild conditions is reported. This synthetic approach is
enabled by merging photoredox catalysis and insertion of
sulfur dioxide via a radical process. The specific role of
photoredox catalysis in this transformation is supported by
mechanistic investigations and theoretical calculations.
A
photocatalytic reaction of N-(2-
(
a) previous work: sulfonylation under catalyst-free conditions
2 2
)
and arenediazonium
R2
R2
synthesis
of
4-
under
O
O
R1
S
DABCO (SO2)2
Ar N2BF4
DCE, 60 o
(
C
Ar
R1
O
O
O
O
(b) previous work: sulfonylation under copper catalysis
X
DABCO (SO2)2
Ar N2BF4
O
O
CuCl (10 mol %)
R
KX
S
CH3CN, 80 oC or rt.
Ar
R
X = I or Br
Keywords: arenediazonium tetrafluoroborate, N-(2-
vinylphenyl)amide, benzo[d][1,3]oxazine, sulfur dioxide,
photoredox catalysis
(c) this work: oxysulfonylation of alkenes via photoredox catalysis
R2
O
R2
O
S
catalyst-free conditions: X
DABCO (SO2)2
Ar
+
O
copper catalysis:
X
NH
Ar N2BF4
R1
photoredox catalysis:
N
1
R1
2
3
O
Since the importance of sulfones in agrochemicals,
Scheme 1. Design and synthesis of sulfonated
benzo[d][1,3]oxazines by using sulfur dioxide as the
sulfonyl source
pharmaceuticals,
and
organic
synthesis
is
established,[ the methods for the generation of
1]
sulfones are continuously appeared. Typically, the
routes to sulfones include oxidation of sulfides and
Encouraged by the advances of sulfur dioxide
[2]
[4-8]
alkylation of sulfinate salts. However, substrates
with sensitive functional groups are usually not
insertion chemistry,
we envisioned that sulfur
dioxide could be involved in the generation of
tolerated under the oxidative conditions. Additionally, sulfonated benzo[d][1,3]oxazines. Therefore, we
only a few sulfinate salts are commercial available,
and they are usually prepared starting from the
initiated a program for the design and synthesis of
sulfonated benzo[d][1,3]oxazines by using sulfur
[3]
corresponding sulfonyl chlorides. In the past decade, dioxide as the sulfonyl source.
using sulfur dioxide as the sulfonyl source has
become an efficient and attractive strategy for the
synthesis of sulfones.[ It provides a facile route for
In 2016, our group reported an efficient route for
the generation of sulfonyl radicals from
arenediazonium tetrafluoroborates and
DABCO•(SO under mild conditions (Scheme 1, eq
a). It was found that the sulfonyl radicals and
tertiary amine (DABCO) radical cation could be
produced directly through a single electron transfer
(SET) without the addition of any catalysts or
additives. The in-situ generated arylsulfonyl radicals
could be trapped by several partners to provide
diverse sulfonyl compounds. Further investigation
revealed that the catalyst-free process could not work
efficiently for other applications. For example, a four-
4-8]
the introduction of sulfonyl (-SO
2
-) moiety from
)
2 2
[11]
simple materials. Recently, we are interested in the
synthesis of sulfonyl-containing natural product-like
compounds starting from sulfur dioxide for further
biological evaluations.[
8]
Benzo[d][1,3]oxazine is a privileged scaffold,
which can be found in many natural products and
biologically active molecules.[9] Due to the
importance
of
sulfonyl
compounds
in
pharmaceuticals,[
1d,e]
we conceived that the sulfonated
benzo[d][1,3]oxazines would be beneficial for our
component
reaction
of
arenediazonium
specific biological assays.[
10]
tetrafluoroborates, DABCO•(SO
2
)
2
, terminal alkynes
and potassium halides required the addition of 10
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201701187
mol % copper(I) chloride as the catalyst (Scheme 1,
eq b).[12] The copper catalyst was supposed to assist
Table 1. Initial studies for the reaction of N-(2-(prop-
1
-en-2-yl)phenyl)benzamide 1a, DABCO•(SO
2
)
2
and
the oxidation of the alkenyl radical intermediate to
alkenyl cation. Apparently, the introduction of metal
catalysis enables broader applications of the
developed strategy, combined with the generation of
arylsulfonyl radicals. Thus, more valuable
functionalized sulfonyl compounds would be
obtained through the insertion of sulfur dioxide.
Prompted by the above achievements, we
postulated that the oxysulfonylation of alkenes with
the in-situ generation of arylsulfonyl radicals starting
from sulfur dioxide would provide a feasible route to
sulfonated benzo[d][1,3]oxazines (Scheme 1, eq c).
Initially, a model reaction of N-(2-(prop-1-en-2-
benzenediazonium tetrafluoroborate 2a[
a]
O
O
DABCO (SO2)2
catalyst
S
Ph
+
O
NH
Ph
Ph N BF
solvent
hn
2
4
N
Ph
2a
1a
O
3a
Entry Photocatalyst
Solvent
DCE
DCE
Yield (%)b
0
1
2
3
4
5
6
7
8
9
1
1
1
-
fac-Ir(ppy)3
18
13
55
31
53
20
51
fac-Ir(ppy)
fac-Ir(ppy)
fac-Ir(ppy)
Ru(bpy)
Eosin Y
Ru(bpy)
3
3
3
DMF
MeCN
1,4-dioxane
MeCN
MeCN
MeCN
1,4-dioxane/MeCN 64
1,4-dioxane/MeCN 83
1,4-dioxane/MeCN 63
1,4-dioxane/MeCN nr
yl)phenyl)benzamide
1a,
benzenediazonium
was carried
3
(PF
6 2
)
tetrafluoroborate 2a, and DABCO•(SO
2 2
)
out in 1,2-dichloroethane (DCE) under catalyst-free
conditions (Table 1, entry 1). However, this attempt
was unsuccessful. The addition of various copper
catalysts under different conditions in this
transformation also failed to provide the positive
outcome. We suspected that the oxidative ability of
the tertiary amine (DABCO) radical cation might be
the key issue in the process. Recently, visible-light-
induced reactions under photoredox catalysis have
3
Cl
2
c
fac-Ir(ppy)3
c,d
c,e
c,f
0
1
2
fac-Ir(ppy)
fac-Ir(ppy)
fac-Ir(ppy)
3
3
3
a
Reaction
conditions:
N-(2-(prop-1-en-2-
(0.2
2 2
yl)phenyl)benzamide 1a (0.2 mmol), DABCO•(SO )
[13]
shown power in organic synthesis. To our surprise,
the application of photoredox catalysis with the
insertion of sulfur dioxide is still rare.[ We noticed
that the oxidized forms of the photocatalysts are
mmol), benzenediazonium tetrafluoroborate 2a (0.3
mmol), photocatalyst (2 mol %), solvent (2.0 mL), under
14]
2
N atmosphere, room temperature, irradiation with a 35 W
b
compact fluorescent lamp (CFL), 12 h. Isolated yield
3
+
III/II
usually strong oxidants (e.g., Ru(bpy)
3
, E1/2
=
c
based on N-(2-(prop-1-en-2-yl)phenyl)benzamide 1a. 1,4-
IV/III
+
1.29 V vs SCE, fac-Ir(ppy)
3
, E1/2
= +0.77 V vs
d
dioxane/MeCN (v/v
3
:
1).
Benzenediazonium
[13f]
SCE),
which are stronger than the radical cation
e
tetrafluoroborate 2a (0.4 mmol). DABCO•(SO
mmol). The reaction was carried out in dark.
2
)
2
(0.16
red
[15]
DABCO (DABCO, E1/2
= +0.69 V vs SCE).
f
Therefore, we conceived that the merger of
photoredox catalysis with the insertion of sulfur
dioxide might give a solution for the transformation
8). In the meantime, we found that benzenediazonium
tetrafluoroborate 2a could react with acetonitrile and
water, leading to a byproduct of N-phenylacetamide
when MeCN was used as the solvent. Thus, we
considered to add another solvent into the reaction
system, with a hope to hamper the side reaction. To
our delight, the yield was enhanced to 83% when 1,4-
dioxane and MeCN (v/v = 3:1) were used as the co-
solvent in the presence of benzenediazonium
tetrafluoroborate 2a (2.0 equivalents) (Table 1,
entries 9-11). No desired product was observed when
the reaction was carried out in dark (Table 1, entry
12).
(
(
Scheme 1, eq c). To our delight, the reaction of N-(2-
prop-1-en-2-yl)phenyl)benzamide
and
1a,
DABCO•(SO
2
)
2
benzenediazonium
tetrafluoroborate 2a in the presence of fac-Ir(ppy) (2
3
mol %) in DCE under the irradiation of visible light
provided the desired sulfonated benzo[d][1,3]oxazine
3
a in 18% yield (Table 1, entry 2). This promising
result encouraged us for further explorations. After
screening other solvents and photocatalysts, it was
found that the yield was improved to 55% in the
presence of fac-Ir(ppy) in MeCN (Table 1, entries 3-
3
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201701187
yl)benzamide
toluenediazonium tetrafluoroborate 2b was carried
out under the conditions as shown in Table 2
4,
DABCO•(SO
2
)
2
,
and
p-
Table 2. Scope investigation for the reaction of N-(2-
vinylphenyl)amides
arenediazonium tetrafluoroborates 2
1,
DABCO•(SO
2
)
2
,
and
a,b
(
Scheme 2). As expected, the corresponding N-(3-
R2
O
R2
O
methyl-3-(tosylmethyl)isobenzofuran-1(3H)-
ylidene)aniline 5 was produced in 56% yield.
Moreover, the (E)-configuration of the product was
confirmed by COSY experiment.
S
DABCO (SO2)2
fac-Ir(ppy)3 (2 mol %)
+
Ar
O
NH
R1
Ar N2BF4
1,4-dioxane/MeCN, rt
hn, 35 W CFL
N
R1
2
1
O
3
3
a: Ar = Ph, 83% yield
O
O
O
O
3b: Ar = C6H4p-Me, 72% yield
S
O
t
DABCO (SO2)2
S
O 3c: Ar = C H p- Bu, 80% yield
fac-Ir(ppy)3 (2 mol %)
6
4
O
Ph
S
+
p-Tol
3
d: Ar = C6H4p-OMe, 80% yield
e: Ar = C6H4p-F, 73% yield
O
O
Ar
p-Tol N2BF4 1,4-dioxane/MeCN, rt
O
3
N
hn, 35 W CFL
2b
4
NHPh
N
Ph
N
Ph 3f: Ar = C6H4p-Cl, 77% yield
3g: Ar = C6H4p-Br, 78% yield
3h: Ar = C6H4p-CO2Et, 80% yield
3i: Ar = C6H4p-NO2, 86% yield
3j: Ar = C6H4m-CO2Me, 90% yield
3k: Ar = C6H4o-Cl, 65% yield
3
q, 76% yield
5, 56% yield
Scheme
2.
Synthesis
of
N-(3-methyl-3-
(tosylmethyl)isobenzo-furan-1(3H)-ylidene)aniline 5
O
O
S
Ph
O
O
N
To obtain more insights of this transformation,
the model reaction in Table 1 was performed in
O
O
l: R1 = C6H4p-Me, 81% yield
3
S
m: R1 = C6H4p-OMe, 86% yield
3r, 70% yield
3
Ph
O
the
presence
of
2,2,6,6-tetramethyl-1-
3
n: R1 = C6H4p-NO2, 66% yield
O
S
3o: R1 = C6H4o-Me, 77% yield
O
piperidinyloxy (TEMPO) under the optimized
conditions (Scheme 3, eq a). The standard reaction
was hampered, and no desired product of 3a was
detected with the recovery of the starting material
R1
N
N
3
p: R1 = Me, 50% yield
Ph
O
O
O
O
S
N
O
H
S
Ph
S
Ph
Ph
O
O
3
s, 68% yield
1a. In order to trap the in-situ generated aryl radical
Ph
N
Ph
and arylsulfonyl radical, 1,1-diphenylethylene was
added to the above reaction (Scheme 3, eq b). As
3
t, 58% yield
3u, 52% yield
a
Reaction conditions: N-(2-vinylphenyl)amide 1 (0.2
mmol), DABCO•(SO (0.2 mmol), arenediazonium
tetrafluoroborate 2 (0.4 mmol), fac-Ir(ppy) (2 mol %) in
,4-dioxane/MeCN (v/v 3 : 1) (2.0 mL), N , rt, irradiation
with a 35 W compact fluorescent lamp (CFL), 12 h.
Isolated yield based on N-(2-vinylphenyl)amide 1.
a result, ethene-1,1,2-triyltribenzene
6 and (2-
2 2
)
(phenylsulfonyl)ethene-1,1-diyl)dibenzene
7
3
were isolated in 10% and 31% yields,
respectively, accompanied with the formation of
product 3a (33%). These results suggested that
the reaction experienced a radical process, and
both aryl radical and arylsulfonyl radical were
existed in the transformation (Scheme 3).
1
2
b
After establishing the optimized reaction
conditions, we subsequently explored the reaction
scope of this three-component reaction of N-(2-
Based on the above result, a plausible synthetic
pathway is proposed in Scheme 4. Arenediazonium
vinylphenyl)amides
1,
DABCO•(SO
2
)
2
,
and
arenediazonium tetrafluoroborates 2 (Table 2). All
reactions took place smoothly to afford the sulfonated
benzo[d][1,3]oxazines in moderate to good yields.
Electronic effects showed minimal influence on the
outcome of the transformation. Various functional
groups including tert-butyl, methoxy, fluoro, bromo,
chloro, ester, and even the nitro group[ were all
compatible under the standard conditions.
Furthermore, substrates bearing a hydrogen or phenyl
group at the α-position of the styrene reacted with
tetrafluoroborate would react with DABCO•(SO
)
2 2
leading to arylsulfonyl radical A and tertiary amine
[11,12]
(DABCO) radical cation intermediate B.
Then
arylsulfonyl radical A would undergo an addition to
the double bond of N-(2-vinylphenyl)amide 1 to
afford a radical intermediate C. We reasoned that
radical intermediate C would be oxidized by the
photocatalyst, producing cation intermediate D.
16]
(a)
DABCO•(SO
2
)
2
and
benzenediazonium
O
tetrafluoroborate 2a smoothly, providing the desired
products 3t and 3u in 58% and 52% yields,
respectively. We further examined the reactions of
O
DABCO (SO2)2
S
fac-Ir(ppy)3 (2 mol %)
Ph
+
O
NH
Ph
N2BF4 1,4-dioxane/MeCN, rt
hn, 35 W CFL
N
Ph
DABCO•(SO
tetrafluoroborate
styrylphenyl)benzamide and N-(2-(3-methylbut-2-en-
-yl)phenyl)benzamide as the substrates under the
conditions. However, no desired products were
obtained and the starting materials were recovered.
To further expand the synthetic potential of this
methodology, a reaction of N-phenyl-2-(prop-1-en-2-
2
)
2
and
benzenediazonium
O
1a
2a
TEMPO (2.0 equiv.)
3
a, n.d.
2a
by
using N-(2-
(b)
DABCO (SO2)2
3a, 33% yield
2
Ph
Ph PhO2S
+
Ph
Ph N2BF4 2a
fac-Ir(ppy)3 (2 mol %)
+
Ph
NH
1,4-dioxane/MeCN, rt
Ph
Ph
hn, 35 W CFL
6
, 10% yield
7, 31% yield
O
a
Ph
Ph
1
Scheme 3. Mechanistic investigation
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201701187
Further deprotonation assisted by the released
DABCO would promote the intramolecular
nucleophilic attack of amide to cation, giving rise to
the desired sulfonated benzo[d][1,3]oxazine 3.
affording sulfonated benzo[d][1,3]oxazines in good
yields. This radical process is efficient, enabled by
merging photoredox catalysis and insertion of sulfur
dioxide. The photoredox catalysis is found to assist
the oxidation of the key radical intermediate, which is
supported by density functional theory calculations.
N
N
ArSO2
A
Ar
O
(DABCO)
O
O
S
N
O
N
R
S
R
R
Experimental Section
R
R
N
R
N
Ar N2
2
R
R
B
R
R
R
R
N2
DABCO (SO2)2
General experimental procedure for the reaction of N-
(
2-vinylphenyl)amides 1, DABCO•(SO
2
)
2
,
and
N-(2-
vinylphenyl)amide 1 (0.2 mmol) and arenediazonium
tetrafluoroborate 2 (0.4 mmol) were combined with
DABCO•(SO (0.2 mmol) and fac-Ir(ppy) (2
mol %) in a tube. The tube was evacuated and
backfilled with N three times before co-solvent of
O
arenediazonium
tetrafluoroborates
2:
R2
O
IrIV
S
O
O
IrIII*
Ar
S
O
A
Ar
2
)
2
3
hn
N
R1
R2
IrIII
H
C
2
1
,4-dioxane/MeCN (v/v 3 : 1, 2.0 mL) was added.
O
R2
O
O
1
The mixture was then placed around a visible light
bulb (CLF, 25 W) with a distance of 10 centimeters,
and was stirred under visible light irradiation for 12
hours at room temperature. After completion of
reaction as indicated by TLC, the mixture was
purified directly by flash column chromatography
S
O
R2
NH
S
Ar
O
Ar
O
R1
O
N
R1
R1
N
DABCO
H
D
3
(
EtOAc/n-hexane, 1:4) to provide the desired product
Scheme 4. A plausible mechanism for the synthesis of
sulfonated benzo[d][1,3]oxazines
3.
Acknowledgements
To further illustrate the reaction process, the
free-energy changes for the oxidation of radical
Financial support from National Natural Science Foundation of
China (Nos. 21672037, 21532001) is gratefully acknowledged.
We thank Prof. Tianning Diao (Department of Chemistry, The
New York University) for English review.
intermediate
C to cation intermediate D by
IV
DABCO (path I) or Ir (path II) at 298.15 K
were calculated through DFT theoretical
calculations. From the computational results for
the two redox reactions in Table 3, we could
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the redox potential of
approximately computed to be 0.75 V, which was
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C + IrIV  D + IrIII
0.14
-0.11
In summary, we herein report a visible-light-
promoted photoredox approach for the synthesis of
sulfonated benzo[d][1,3]oxazines through a three-
component reaction of N-(2-vinylphenyl)amides,
arenediazonium
DABCO•(SO
tetrafluoroborates
and
2 2
)
under mild conditions. This
2
017, 15, 1947.
transformation takes place smoothly at room
temperature under the irradiation of visible light,
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201701187
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5
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.201701187
FULL PAPER
R2
Synthesis of Sulfonated Benzo[d][1,3]oxazines by
Merging Photoredox Catalysis and Insertion of
Sulfur Dioxide
O
R2
O
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DABCO (SO2)2 fac-Ir(ppy)3 (2 mol %)
+
Ar
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NH
Ar N2BF4
1,4-dioxane/MeCN, rt
R1
hn, 35 W CFL
N
O
R1
insertion of sulfur dioxide
under photoredox catalysis
Adv. Synth. Catal. 2017, Volume, Page – Page
O
O
O
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O
R2
R2
S
S
a
a
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SO2
R1
Ar
Tong Liu , Danqing Zheng, Zhenhua Li, * and Jie
O
Ar
Ar
O
O
a,b,
Wu *
N
R1
R1
N
N
H
H
H
6
This article is protected by copyright. All rights reserved.