Metal-free aminosulfonylation of aryldiazonium tetrafluoroborates with DABCO×(SO2)2 and hydrazines

Article abstract of DOI:10.1002/anie.201309851

The coupling of aryldiazonium tetrafluoroborates, DABCO×(SO ₂)₂, and hydrazines under metal-free conditions leads to the formation of aryl N-aminosulfonamides. The reaction proceeds smoothly at room temperature and shows broad functional-group tolerance. A radical process is proposed for this transformation. The coupling of aryldiazonium tetrafluoroborates, DABCO×(SO₂)₂, and hydrazines under metal-free conditions leads to the formation of aryl N-aminosulfonamides. The reaction proceeds under mild reaction conditions, is fast, has a broad substrate scope, and gives the products in high yiels (21 examples). A plausible mechanism that involves a radical process is also proposed. Copyright

Full text of DOI:10.1002/anie.201309851

Angewandte
Chemie
DOI: 10.1002/anie.201309851
Aminosulfonylation
Metal-Free Aminosulfonylation of Aryldiazonium Tetrafluoroborates
with DABCO·(SO2)2 and Hydrazines**
Danqing Zheng, Yuanyuan An, Zhenhua Li,* and Jie Wu*
Abstract: The coupling of aryldiazonium tetrafluoroborates,
DABCO·(SO2)2, and hydrazines under metal-free conditions
leads to the formation of aryl N-aminosulfonamides. The
reaction proceeds smoothly at room temperature and shows
broad functional-group tolerance. A radical process is pro-
posed for this transformation.
It is well known that aryldiazonium salts are commonly
used chemicals and important intermediates in organic
chemistry because of their relatively high reactivity and
several possible functional-group transformation.[11,12] Addi-
tionally, aryldiazonium salts can be easily prepared by
diazotization of aromatic amines, which are available in
great structural diversity. Recently, aryldiazonium salts were
used as starting materials or key intermediates in trifluoro-
methylations under mild conditions through a new type of
Sandmeyer reaction.[13] Inspired by this result, we envisioned
that aryldiazonium salts might be employed in the amino-
sulfonylation as well. Herein, we report the simple prepara-
tion of N-aminosulfonamides under metal-free conditions
through the coupling of aryldiazonium tetrafluoroborates,
DABCO·(SO2)2, and hydrazines at room temperature.
We began our investigation with the addition of morpho-
lin-4-amine (2a) to a solution of Pd(OAc)2 (10 mol%),
phenyldiazonium tetrafluoroborate (1a), and DABCO·(SO2)2
in 1,4-dioxane at 258C. Pleasingly, the desired product 3a was
obtained in 35% yield. To our surprise, the reaction also
proceeded smoothly in a control experiment without the
addition of the Pd catalyst. A similar yield of 37% was
obtained under the conditions (Table 1, entry 1). This unex-
pected result showed that the Pd catalyst was not involved in
T
he sulfonamide group is widely present in top-selling
pharmaceuticals.[1] Celecoxib,[2] Tipranavir,[3] and Zonis-
amide[4] are some examples of marketed drugs that feature
this functional group. Sulfonamides can be generally prepared
by direct amination of sulfonyl chlorides with the correspond-
ing amines.[1a] However, traditional methods to access sulfo-
nyl chloride, including electrophilic aromatic substitution
with chlorosulfonic acid and oxidative chlorination of organo-
sulfurs, usually suffer from significant limitations.[5–7] Harsh
conditions are often required and the substrate scope is
limited. Therefore, the development of efficient methods for
the formation of sulfonamides is of great importance.
To obviate these problems, recent efforts were directed to
the transition-metal-catalyzed aminosulfonylation.[1a,8,9] An
interesting result was reported by Willis and co-workers, who
described a Pd-catalyzed coupling reaction of aryl iodides,
DABCO·(SO2)2, and hydrazines to generate N-aminosulfon-
amides.[8a] The application of the bench-stable solid DABCO·-
(SO2)2 as the source of sulfur dioxide was a breakthrough, as
other reagents for sulfonylation were usually harmful. Addi-
tionally, this method opens a pathway to introduce sulfur
dioxide into small organic molecules. We also conducted
studies in this field to expand the scope of the reported
process.[9] Recently, an alternative route to aryl sulfonamides
through Pd-catalyzed chlorosulfonylation of arylboronic acids
was achieved by Buchwald and co-workers.[10] As these
approaches required expensive metal catalysts, ligands,
bases, and relatively high temperatures, it is still highly
desirable to explore new methods for this transformation.
Table 1: Optimizing conditions for the reaction of phenyldiazonium
tetrafluoroborate (1a), DABCO·(SO2)2, and morpholin-4-amine (2a).[a]
Entry
Solvent
T [8C]
DABCO·(SO2)2
Yield [%][b]
1
2
3
4
5
6
7
1,4-dioxane
toluene
CH3OH
MeCN
DCE
25
25
25
25
25
25
25
25
25
25
25
0
1.2 equiv
1.2 equiv
1.2 equiv
1.2 equiv
1.2 equiv
1.2 equiv
1.2 equiv
1.2 equiv
1.2 equiv
0.8 equiv
0.6 equiv
0.6 equiv
0.6 equiv
37
trace
trace
54
34
36
28
39
94
94
DMF
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
8[c]
9[d]
10[d]
11[d]
12[d]
13[d]
[*] D. Zheng, Y. An, Dr. Z. Li, Prof. Dr. J. Wu
Department of Chemistry, Fudan University
220 Handan Road, Shanghai 200433 (China)
E-mail: jie_wu@fudan.edu.cn
93
81
85
Prof. Dr. J. Wu
40
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (China)
[a] Reaction conditions: DABCO·(SO2)2 (0.36 mmol) and 1a
(0.30 mmol) in solvent (4.0 mL), followed by the dropwise addition of 2a
(0.36 mmol) under N2 in 10 min. [b] Yield of isolated product based on
1a. [c] Under air atmosphere. [d] Reaction conditions: DABCO·(SO2)2
and 2a (0.36 mmol) in CH3CN (3.0 mL), followed by dropwise addition
of 1a (0.30 mmol) in CH3CN (1.0 mL) under N2 in 10 min.
[**] Financial support from National Natural Science Foundation of
China (Nos. 21032007, 21372046) is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309851.
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.
Angewandte
Communications
this transformation, thus suggesting that this transformation is
different from the one previously reported by Willis.[8]
Considering that this process involved a totally different
reaction route, and the advantage of non-metal catalysis, we
continued to further optimize this reaction. The reaction
failed when toluene and methanol were used as the solvent
(Table 1, entries 2 and 3). Further screening of solvents
showed that the reaction proceeded efficiently in acetonitrile,
furnishing the expected product 3a in 54% yield (Table 1,
entry 4). No improvement was observed when the reaction
was performed under air atmosphere (Table 1, entry 8).
Considering the relatively high reactivity of aryldiazonium
tetrafluoroborates, we suspected that the experimental pro-
cedure had a significant influence on the outcome of the
reaction. When 1a in 1.0 mL of CH3CN was added in
a dropwise manner to a solution of DABCO·(SO2)2 and 2a
in 3.0 mL of CH3CN, the yield was significantly increased to
94% (Table 1, entry 9). Similar results were obtained when
the amount of DABCO·(SO2)2 was decreased to 0.8 or 0.6
equivalents (Table 1, entries 10 and 11). The reaction pro-
ceeded smoothly at 08C as well, while the yield decreased to
81% (Table 1, entry 12). No better result was obtained at
a higher temperature (Table 1, entry 13).
donating groups on the aromatic ring of aryldiazonium
tetrafluoroborates were compatible under the standard con-
ditions, leading to the products in similarly high yields.
Moreover, substrates that feature common functional groups,
including ethers, esters, halogen atoms, and even a nitro
group, were smoothly coupled. Aryldiazonium tetrafluoro-
borates that bear ortho substitutents, including methyl and
chloro groups, also reacted well to give the desired products
3j and 3k in good yields. Polysubstituted aryldiazonium
tetrafluoroborates could be utilized in this transformation
too. Other hydrazines 2 were subsequently explored, and the
reactions proceeded efficiently to produce the corresponding
products 3p–3u in good yields. However, no reaction took
place when anilines and aliphatic amines were employed in
the transformation under the optimal conditions, which was
similar to the previous reports.[8,9]
To understand the mechanism of this metal-free coupling
reaction, preliminary mechanistic investigation was carried
out. When we used 2-(allyloxy)phenyldiazonium tetrafluoro-
borate (4) in this aminosulfonylation, only the cyclized
product 5 was obtained in 90% yield, whereas the normal
product 6 was not detected [Scheme 1, Eq. (a)]. This result
With the optimized reaction conditions in hand, we next
investigated the scope of the aminosulfonylation reaction of
aryldiazonium tetrafluoroborates 1 with DABCO·(SO2)2 and
hydrazines 2 (Table 2). A range of aryldiazonium tetrafluoro-
borates were examined first. Interestingly, all reactions were
complete within 10 minutes. Various aryldiazonium tetra-
fluoroborates 1 reacted with DABCO·(SO2)2 and 2a, giving
rise to the aminosulfonylation products 3a–3o in good to
excellent yields. Both electron-withdrawing and electron-
Table 2: Scope of the aminosulfonylation reaction of aryldiazonium
tetrafluoroborates 1 with DABCO·(SO2)2 and hydrazines 2.[a,b]
Scheme 1. Investigation of the mechanism. n.d.=not determined,
n.o.=not observed.
suggested that an aryl radical is involved as the intermediate,
which was presumably produced from the aryldiazonium salt.
In the Sandmeyer-type reaction, it is plausible that copper-
mediated single-electron transfer (SET) generates the aryl
radical.[14] Therefore, we were curious about the pathway
through which the aryl radical was formed without a metal
catalyst. Thus, we tested the reaction with 2,2,6,6-tetramethyl-
1-piperidinyloxy (TEMPO) as the additive under the stan-
dard reaction conditions [Scheme 1, Eq. (b)]. After subject-
ing TEMPO to the standard aminosulfonylation procedure,
TEMPO-Ph 7 was isolated in 40% yield, further proving that
a phenyl radical was produced under the reaction conditions.
Only a trace amount of TEMPO-Ph 7 was observed when
DABCO·(SO2)2 or 2a were absent [Scheme 1, Eq. (c) and
(d)], thus demonstrating that both DABCO·(SO2)2 and 2a
[a] Reaction conditions: DABCO·(SO2)2 (0.18 mmol) and 2 (0.36 mmol)
in CH3CN (3.0 mL), followed by dropwise addition of 1 (0.30 mmol) in
CH3CN (1.0 mL) under N2 atmosphere in 10 min. [b] Yields of isolated
products based on 1.
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were indispensable in the introduction of the phenyl radical.
Additionally, it was known that 2a could be employed as an
SO2 carrier with the formation of an N-aminomorpholine/SO2
complex.
On the basis of the above-mentioned experimental
observations and according to our own theoretical calcula-
tions, we suggest that the metal-free aminosulfonylation
reaction proceeds through the route shown in Scheme 2.
First, barrierless exchange of sulfur dioxide occurs between
In conclusion, we have described an efficient route to aryl
N-aminosulfonamides by coupling aryldiazonium tetrafluoro-
borates, DABCO·(SO2)2, and hydrazines under metal-free
conditions. The reaction proceeds smoothly at room temper-
ature and shows broad functional-group tolerance. A plau-
sible mechanism is proposed as well, which involves a radical
process. We believe that the efficiency of the transformation,
the extremely mild conditions, and the broad reaction scope
will make the method attractive for further applications.
Experimental Section
General experimental procedure for the aminosulfonylation reaction
of aryldiazonium tetrafluoroborates 1 with DABCO·(SO2)2 and
hydrazines 2: Aryldiazonium tetrafluoroborate 1 (0.30 mmol) in
CH3CN (1.0 mL) was added in a dropwise manner to a solution of
DABCO·(SO2)2 (0.18 mmol) and hydrazine 2 (0.36 mmol) in CH3CN
(3.0 mL) under N2 atmosphere in 10 min. The mixture was stirred at
room temperature for another 10 min. The solvent was evaporated
and the residue was purified directly by flash column chromatography
(eluent: EtOAc/n-hexane = 1:2) to give the desired product 3.
Received: November 13, 2013
Revised: December 12, 2013
Published online: January 29, 2014
Keywords: aminosulfonylation · aryldiazonium salt · hydrazine ·
metal-free conditions · sulfur dioxide
Scheme 2. Proposed mechanism for the aminosulfonylation reaction of
aryldiazonium tetrafluoroborates 1 with DABCO·(SO2)2 and hydrazines
2. The numbers in brackets are the changes in Gibbs free energy
relative to those of the initial reactants at 298 K. TS=transition state.
.
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DABCO·(SO2)2 and hydrazine to generate the hydrazine-SO2
complex 8. Then complex 9 is formed through electrostatic
interaction between the hydrazine–SO2 complex 8 and the
À
arydiazonium cation 1. Homolytic cleavage of the N S
bond[15] and a single-electron transfer produces the arydiazo-
nium radical 10, SO2 (11) and radical cation intermediate 12.
Then, the arydiazonium radical 10 releases one equivalent of
nitrogen, leading to the aryl radical 13. The aryl radical
attacks sulfur dioxide to give the radical intermediate 15 (also
a barrierless process), which reacts with the hydrazinium
radical 14 (generated from deprotonation of the radical cation
intermediate 12) to afford the desired product 3. Orbital
analysis suggests that the electrostatic interaction in complex
À
9 makes the homolytic cleavage of the N S bond more
favorable (the structure and Cartesian coordinates of com-
plex 9 are shown in Supporting Information). According to
our theoretical calculations, the overall Gibbs free energy
barrier of this route is 19.4 kcalmolÀ1 (at 298 K), which is
reasonable from the perspective of thermodynamics. When
hydrazine was replaced by morpholine as a representative of
simple amines, the theoretical calculations showed that the
overall Gibbs free energy barrier of this route is 37.7 kcal
molÀ1 (at 298 K), which indicates that this process is infeasible
(the Gibbs free energy of each step is provided in Supporting
Information). This theoretical result might explain why only
hydrazines were efficient and amines were unsuccessful in this
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