The triple role of rongalite in aminosulfonylation of aryldiazonium tetrafluoroborates: synthesis of N-aminosulfonamides via a radical coupling reaction

Article abstract of DOI:10.1039/c8cc03778g

A simple and convenient method for N-aminosulfonamide synthesis from the cross-coupling of aryldiazonium tetrafluoroborates and rongalite under metal-free, oxidant-free, and room-temperature conditions is reported. This method does not require an external amine source, with the aryldiazonium tetrafluoroborates participating as both an aryl radical and a potential amine source in the transformation. Mechanistic studies revealed that rongalite could act as a radical initiator, a sulfur dioxide surrogate and a reducing reagent simultaneously in this reaction.

Full text of DOI:10.1039/c8cc03778g

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The Triple Role of Rongalite in Aminosulfonylation of Aryldiazon-
ium Tetrafluoroborates: Synthesis of N-aminosulfonamides via a
Radical Coupling Reaction
Received 00th January 20xx,
Accepted 00th January 20xx
Miao Wang,a Bo-Cheng Tang,a Jun-Gang Wang,b Jia-Chen Xiang,a Ao-Yu Guan,a Ping-Ping Huang,a
DOI: 10.1039/x0xx00000x
Wu-Yinzheng Guo,a Yan-Dong Wu,a and An-Xin Wu*,a
www.rsc.org/
A
simple and convenient method for N-aminosulfonamide sulfonamides. Despite this progress, simpler and more convenient
synthesis from the cross-coupling of aryldiazonium methods for sulfonamide synthesis, especially those incorporating
tetrafluoroborates and rongalite under metal-free, oxidant-free, new and cheap SO2 sources into molecules and avoiding the
and room-temperature conditions is reported. This method does addition of an external amine source, are highly desirable.
−
Rongalite (Na+HOCH2SO2 ·2H2O) is a useful and cheap industrial
not require an external amine source, with the aryldiazonium
tetrafluoroborates participating as both an aryl radical and
product that has been widely used in the dye, rubber, and
veterinary industries.8 Rongalite is also used as a versatile reagent
potential amine source in the transformation. Mechanistic studies
in synthetic chemistry.9 However, examples where rongalite is
revealed that rongalite could act as radical initiator, sulfur dioxide
surrogate and reduction reagent simultaneously in this reaction.
used as a source of SO2 for incorporation into molecules are rare.
In 2016 Shavnya and coworkers reported a three-step method for
Due to their distinctive structural and electronic features,
the preparation of aliphatic sulfonamides using alkyl halides and
sulfones have been widely applied in pharmaceuticals,
rongalite.10a Furthermore, Luo reported a Fe-catalyzed radical
agrochemicals, materials, and important synthetic intermediates.1
coupling reaction of diaryliodonium salts, rongalite, and amines in
Among sulfonyl-containing molecules, sulfonamides are the most
a two-step synthesis of sulfonamides (Scheme 1c).10b However, the
important owing to their medical significance.2 Many
direct using rongalite as SO2 source incorporate into molecules for
anticonvulsants, HIV protease inhibitors, and anticancer,
sulfonamides under metal-free conditions in one step has not
antibacterial, anti-inflammatory, and antiviral agents contain
been reported. In conjunction with our ongoing research into
sulfonamide skeletons.3 Accordingly, many methods for the
construction of sulfonamides have been developed. Traditionally,
(a) Traditional method for the synthesis of sulfonamides
O
H
Cl
base
the direct route to sulfonamide construction is the nucleophilic
reaction of sulfonyl chlorides and amines (Scheme 1a).4 However,
this method suffers from significant limitations, including a limited
substrate scope and the cumbersome procedures necessary to
obtain some sulfonyl chlorides. To prevent these problems, recent
efforts have been directed toward incorporating sulfur dioxide into
molecules for the synthesis of sulfonamides.5-7 Breakthrough work
was reported by Willis and coworkers, who described a Pd-
catalyzed coupling reaction of aryl iodides, DABCO·(SO2)2, and
hydrazines to generate N-aminosulfonamides (Scheme 1b).6a
Recently, several groups have reported reacting aryl
R1
N
O
S
R2
R3
+
S
O
R2
O
R1
N
R3
(b) Recent advances of incorporation of SO2 into molecules for sulfonamides
X
R2
R3
R2
N
Pd,Au,Cu cat R1
O
H2N
+
N
"SO2 source"
+
R1
S
N
R3
O
H
X=Cl;Br;I;B(OH)2,Si(OEt)3
"SO2 source"=DABSO,K2S2O5
(c) Limited examples of using rongalite as SO2 source for sulfonamides
O
O
S
(1)rt 18h
R1
Br/I
HO
S
Alkyl
Alkyl
+
ONa 2H2
O
N
(2)H3PO4
O
R2
(3)DIPEA,DCDMH,amine
BF4
O
S
I
(1)FeCl3,air
HO
+
R
R
R
O
ONa 2H2O
(2)NCS,piperidine
S
N
O
chlorides/bromides,7a arylboronic acids,7b and triethoxysilanes7c
(d) This work
7d
N2BF4
H
O
O
Metal
cat.
External
amine
with DABCO·(SO2)2 or K2S2O5
and hydrazines to prepare
N
S
O
R
N
H
R
R
+
HO
S
rt,10min
ONa 2H2O
N2BF4
Rongalite (~0.03$/g)
industrial product
R
Without external amine source
Rongalite act as SO2 source,radical initiator, reduction reagent
Metal-free,Oxidant-free, at room temperature in one step
Scheme 1. Tradition Synthesis and Recent Advances for the Preparation of
Sulfonamides
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J. Name., 2013, 00, 1-3 | 1
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developing methodologies for rongalite-based cleavage and
The substrate scope of this transformation was then evaluated,
incorporation into molecules to obtain valuable skeletons,11 with the optimized reaction conditions found to be applicable to a
we now present a simple preparation of N-aminosulfonamides broad range of substrates. As shown in Scheme 2, aryldiazonium
under metal-free and oxidant-free conditions through coupling tetrafluoroborates bearing electronically neutral (4-H), electron-
tetrafluoroborates and rongalite at room temperature donating (4-Me, 4-OMe, 3-Me), and electron-withdrawing (4-CN, 4-
(Scheme 1d). Notably, this method did not require an external COMe, 3-COMe, 2-NO2, 3-NO2, 4-NO2, 4-CO2Me, 4-CO2Et)
amine source, with the aryldiazonium tetrafluoroborates substituents all reacted smoothly, affording the corresponding N-
participating as both aryl radicals and the potential amine aminosulfonamides in moderate to excellent yields (45–81%, 3a–3l).
source in the transformation. To our knowledge, this Pleasingly, the conditions were mild enough to be compatible with
represents the first reported example of rongalite being used halogenated (4-F, 4-Cl, 4-Br, 4-I) and alkynyl (3-ethynyl) substrates
as a source of SO2 for incorporation into two molecules of (43–78%, 3m–3q), which provided the potential for further
aryldiazonium
tetrafluoroborates
to
obtain
N- functionalization. Meanwhile, sterically hindered 2-naphthyl
aminosulfonamides under metal-free, oxidant-free, and room- diazonium tetrafluoroborates and 1-naphthyl diazonium
temperature conditions.
tetrafluoroborates furnished desired products 3r and 3s in 61% and
58% yields, respectively. Furthermore, the optimal conditions were
successfully applied to diazonium tetrafluoroborates bearing fused
rings, such as fluorenyl groups, affording the corresponding
products in good yields (63%, 3t). The structure of 3b was
confirmed by single-crystal X-ray diffraction (see Supporting
Information (SI)).
Initial investigations focused on the model reaction of rongalite
(1) with 4-(ethoxycarbonyl)benzenediazonium tetrafluoroborate
(2l) in MeCN at 60 °C. To our delight, the desired compound, ethyl-
4-((2-(4-(ethoxycarbonyl)phenyl) hydrazinyl)sulfonyl)benzoate (3l),
was obtained in 41% yield (entry 1). Solvent screening suggested
that DMSO was the best solvent for this reaction, increasing the
yield of 3l to 72% (entries 2–9). Next, we investigated the ratios of
the two reactants, with the optimum ratio of 1/2l found to be
2.0:1.0 (entries 10–13). Finally, a range of different temperatures
were screened, which showed that the reaction proceeded well at
room temperature (entries 14–17).
Scheme 2. Scope of aryldiazonium tetrafluoroboratesa,b
Table 1. Optimization of the Reaction Conditionsa
temp
(°C)
yieldb
(%)
entry
1a:2l
solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
MeCN
DCE
PhMe
CHCl3
EtOH
2.0:1.0
2.0:1.0
2.0:1.0
2.0:1.0
2.0:1.0
2.0:1.0
2.0:1.0
2.0:1.0
2.0:1.0
0.5:1.0
1.0:1.0
1.5:1.0
2.5:1.0
2.0:1.0
2.0:1.0
2.0:1.0
2.0:1.0
60
60
60
60
60
60
60
60
60
60
60
60
60
rt
41
trace
trace
0
58
72
37
trace
0
trace
52
69
DMSO
acetone
1,4-dioxane
THF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
71
74
72
71
68
aReaction conditions: 1 (1.2 mmol), 2 (0.6 mmol) in solvent (3.0 mL) at room
temperatures. The reaction was performed for 10miuntes. bisolated yields based
on 2.
40
50
70
aReaction conditions: 1 (1.2 mmol), 2l in solvent (3.0 mL) at different
temperatures. The reaction was performed for 10miuntes. bisolated yields based
on 2l.
To gain insight into the reaction mechanism, a series of control
experiments were performed (Scheme 3). When rongalite (1) was
treated
with
4-(ethoxycarbonyl)benzenediazonium
2 | J. Name., 2012, 00, 1-3
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tetrafluoroborate (2l) in the presence of 2,2,6,6-tetramethyl-1- molecule of formaldehyde. Subsequently, arydiazonium cation 2a
piperidinyloxy (TEMPO), butylhydroxytoluene (BHT),
or would combine with an HSO2– anion to generate complex A through
hydroquinone (Scheme 3a), no desired product (3l) was observed. electrostatic interaction. Next, aryl radical B and sulfoxylate anion
–
•
In the reaction containing TEMPO, a TEMPO-PhCO2Et product 4 was radical SO2 could be produced by single-electron transfer. The
–
•
detected by GC−MS, which suggested that the reacꢀon might radical coupling of sulfoxylate anion radical SO2 and aryl radical B
involve a radical process. A further radical trapping experiment would provide the desired arylsulfinate C, which would then attack
using rongalite (1), 2l, and 1,1-diphenylethylene (5) under the another molecule of 2a to afford intermediate sulfonyl diazo
optimized conditions was performed, with ethane-1,1,2- intermediate D. Finally, D would be reduced by rongalite to give the
triyltribenzene (6) obtained as a product in 38% yield (Scheme 3b). corresponding sulfonyl hydrazide 3a.
This result was different to that previously reported for a similar
trapping experiment, where the product was triphenylethylene,10b,
12 which indicated that the reaction system in this reaction might be
reducing. Furthermore, when the reaction of rongalite (1) and 2l
under the standard conditions was stopped at
2 min, the
corresponding sulfonyl diazo (7) was obtained in 31% yield (Scheme
3c), which was then reduced to corresponding sulfonyl hydrazide (3l)
in 88% yield by rongalite (1) (Scheme 3d). The reaction of sodium
benzenesulfinate and 2l gave corresponding sulfonyl diazo (8) in 95%
yield, which can also be reduced to corresponding sulfonyl
hydrazide (9) in 91% yield by rongalite (1) (see Supporting
Information (SI)). These results indicated that the benzene
sulfonate anion and sulfonyl diazo species might be the key
intermediates, and that rongalite could reduce the sulfonyl diazo
intermediate to the final sulfonyl hydrazide product. Finally,
deuterated rongalite (1-D) and 2l was also reacted in DMSO-d6 and
the deuterated product 3l-D generated in 72% yield with 85% and
91% deuteration of the two N–H groups, respectively (Scheme 3e).
This clearly confirmed that hydrogen atom in the N–H groups of
sulfonyl hydrazide (3l) was mainly from water.
Scheme 4. Possible mechanism
We further explored the applications of this radical coupling
reaction and sulfonyl hydrazide product 3 in organic synthesis, as
shown in Scheme 5. This method is attractive for the incorporation
of sulfonyl hydrazide groups into natural products and drug
candidates containing an aniline backbone. Late-stage modification
was conducted using naturally occurring coumarin 120, with
corresponding product 3u obtained in 53% yield. Derivatives of
chiral lactone (1S)-(–)-camphanic acid chloride also participated in
this reaction to generate desired sulfonyl hydrazide 3v in 58% yield.
Next, transformation of sulfonyl hydrazide product 3 was studied,
using 3b as an example. Compound 3b was converted into the
corresponding sulfonyl diazo compound 10a in 89% yield in the
presence of CuSO4•5H2O and K2CO3. Pleasingly, sulfonyl hydrazide
3b was successfully used as a coupling partner in classic coupling
reactions with an arylboronic acid and aryl olefin, yielding
corresponding coupling products 10b and 10c in 74% and 85%
yields, respectively. Finally, 3b was also transformed into 4,4'-
dimethylbiphenyl (10d) in 90% yield accompanied by the release of
N2 and SO2.
Scheme 3. Control experiments
aEthyl 4-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)benzoate (4) was in situ deteced
by GC-MS analysis
Based on the results in the current study and previous reports,9,13
a possible mechanism has been proposed using 1 and 2a as
examples (Scheme 4). Initially, the decomposition of rongalite
–
generated an HSO2 anion, accompanied by the release of a
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5
6
For reviews: (a) P. Bisseret and N. Blanchard, Org. Biomol.
Chem., 2013, 11, 5393; (a) G. Liu, C. Fan and J. Wu, Org. Biomol.
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Org. Chem., 2015, 4, 602; (d) D. Zheng and J. Wu, Sulfur Dioxide
Insertion Reactions for Organic Synthesis; Nature Springer:
Berlin, 2017; (e) G. Qiu, K. Zhou, L. Gao and J. Wu, Org. Chem.
Front., 2018, 5, 691.
For selected examples, see: (a) B. Nguyen, E. J. Emmett and M.
C. Willis, J. Am. Chem. Soc., 2010, 132, 16372; (b) D. Zheng, Y.
An, Z. Li and J. Wu, Angew. Chem., Int. Ed., 2014, 53, 2451; (c) K.
Zhou, H. Xia and J. Wu, Org. Chem. Front., 2017, 4, 1121; (d) F.
Zhang, D. Q. Zheng, L. F. Lai, J. Cheng, J. T. Sun and J. Wu, Org.
Scheme 5. Synthetic applications of the methodology
In summary, we have developed a novel method for the
synthesis
of
N-aminosulfonamides
from
aryldiazonium
tetrafluoroborates and rongalite under metal-free, oxidant-free,
and room-temperature conditions. Notably, aryldiazonium
tetrafluoroborates participated as both an aryl radical and potential
amine source in the subsequent transformation. This method is
facile and highly efficient, with
a broad substance scope.
Mechanistic studies revealed that rongalite could act as radical
initiator, sulfur dioxide surrogate and reduction reagent
simultaneously in this reaction. Further applications of rongalite as
a source of SO2 for the synthesis of other interesting sulfones are
currently underway in our laboratory.
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Acknowledgements
We are grateful to the National Natural Science Foundation of
China (Grant Nos. 21472056 and 21602070) and the Fundamental
Research Funds for the Central Universities (CCNU15ZX002 and
CCNU16A05002) for financial support. This work was also
supported by the 111 Project B17019 and Hubei Provincial Natural
Science Foundation of China (2017CFB355).
Zheng, Y. Li, Y. An and J. Wu, Chem. Commun., 2014, 50
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4 | J. Name., 2012, 00, 1-3
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