A palladium-catalyzed three-component coupling of arylboronic acids, sulfur dioxide and hydrazines

Article abstract of DOI:10.1039/c2cc33725h

A novel and efficient route to aryl N-aminosulfonamides via a palladium-catalyzed three-component coupling of arylboronic acids, sulfur dioxide and hydrazines in the presence of a balloon of dioxygen is reported. The reaction proceeded smoothly under mild conditions and DABCO·(SO ₂)₂ was used as the source of sulfur dioxide.

Full text of DOI:10.1039/c2cc33725h

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COMMUNICATION
A palladium-catalyzed three-component coupling of arylboronic acids,
sulfur dioxide and hydrazinesw
Shengqing Yea and Jie Wu*ab
Received 24th May 2012, Accepted 11th June 2012
DOI: 10.1039/c2cc33725h
A novel and efficient route to aryl N-aminosulfonamides via a
palladium-catalyzed three-component coupling of arylboronic
acids, sulfur dioxide and hydrazines in the presence of a balloon
of dioxygen is reported. The reaction proceeded smoothly under
mild conditions and DABCOÁ(SO2)2 was used as the source of
sulfur dioxide.
Due to the importance of sulfonamides in medicinal chemistry
and pharmaceuticals, the initial studies were performed for the
reaction of p-methylphenylboronic acid 1a, DABCO-bis(sulfur
dioxide) and morpholin-4-amine 2a (Table 1). At the outset, the
reaction was catalyzed by palladium acetate (5 mol%) with PtBu3
(10 mol%) in the presence of DABCO and O2 (balloon) in
1,4-dioxane at 90 1C (Table 1, entry 1). However, the result
was poor with a trace amount of the desired product 3a
detected. A similar outcome was achieved when the base was
changed to cesium carbonate (Table 1, entry 2). To our delight,
the expected 4-methyl-N-morpholinobenzenesulfonamide 3a was
generated in 33% yield when the base was replaced by potassium
carbonate (Table 1, entry 3). The reactions all failed when other
bases were employed (Table 1, entries 4–9: K3PO4, Na2CO3,
NaHCO3, CsF, KF, KOAc). Further exploration found that the
yield was increased to 40% when TBAB (tetrabutylammonium
bromide) was utilized as the base (Table 1, entry 10). Screening of
reaction temperature revealed that the transformation worked
efficiently at 80 1C, affording the desired product, 3a, in 56%
yield (Table 1, entries 11–15). The yield was lower when the
reaction occurred in air (Table 1, entry 16). A control experiment
indicated that the palladium catalyst was essential for the
successful conversion (Table 1, entry 17). Gratifyingly, the yield
was increased to 90% in the absence of the phosphine ligand
(Table 1, entry 18). A similar result was furnished when the
amount of palladium catalyst was increased to 10 mol%
(Table 1, entry 19). However, a lower reactivity was observed
when 2 mol% of Pd(OAc)2 was utilized (Table 1, entry 20). Other
palladium sources were then screened and no better results
were obtained (Table 1, entries 21–24). Further examination
of solvents demonstrated that 1,4-dioxane was the best choice
(Table 1, entries 25–29).
Due to the enormous scale of annual sulfur dioxide production,
applications of sulfur dioxide in organic synthesis are of high
interest.1 So far, various transformations, including cycloaddition
reactions, nucleophilic additions and ene reactions, using
sulfur dioxide as a reagent have been reported.2,3 Additionally,
the coordination of sulfur dioxide with metal centers is
common.4 Transition metal-catalyzed insertion reactions of
sulfur dioxide are rare,5 although organic sulfonic acids could
be prepared through a reaction of sulfur trioxide with different
nucleophilic organometallic reagents.6 Recently, Willis and
co-workers described an interesting result using DABCO-
bis(sulfur dioxide) as a sulfur dioxide equivalent in several
organic transformations.7 Since the limitation of sulfur dioxide
application in organic synthesis is mainly due to the difficulties
associated with the handling and use of a toxic gaseous
reagent,8 this bench-stable solid as a replacement for gaseous
sulfur dioxide would open a new window to introduce sulfur
dioxide into simple organic molecules.
Due to their easy handling and long shelf life, arylboronic
acids have been widely used in organic synthesis.9 Encouraged
by the advantages of DABCO-bis(sulfur dioxide) and the
chemistry of arylboronic acids, we conceived that the sulfonyl
group could be incorporated via a palladium-catalyzed three-
component reaction of arylboronic acids and DABCO-
bis(sulfur dioxide) with nucleophiles (Scheme 1). We anticipated
that the sulfonyl derivatives would be generated through an
efficient and environmentally benign process.
With the optimized reaction condition in hand, we set out to
explore the scope of this palladium-catalyzed three-component
reaction of arylboronic acids 1 and DABCO-bis(sulfur dioxide)
with hydrazines 2. The results are presented in Table 2. The
conditions are mild, and the reaction proceeds smoothly in the
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 State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
Scheme 1 A proposed synthetic route for the generation of sulfonyl
derivatives via a palladium-catalyzed reaction of arylboronic acids and
DABCO-bis(sulfur dioxide) with nucleophiles.
w Electronic supplementary information (ESI) available: Experimental
procedure, characterization data, 1H and 13C NMR spectra of compound
3. See DOI: 10.1039/c2cc33725h
c
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Chem. Commun., 2012, 48, 7753–7755 7753

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Table
1
Initial studies for the palladium-catalyzed reaction of
Table 2 Palladium-catalyzed three-component reaction of arylboronic
acids 1 and DABCO-bis(sulfur dioxide) with amines 2a
p-methylphenylboronic acid 1a, DABCO-bis(sulfur dioxide) and
morpholin-4-amine 2aa
Base/
Ligand additive Solvent Temp (%)
Yieldb
Entry [Pd]
1
2
3
4
5
6
7
8
Pd(OAc)2
PtBu3 DABCO Dioxane 90
Trace
Trace
33
Trace
Trace
Trace
Trace
Trace
Trace
40
39
56
43
Trace
Trace
45
nr
90
89
58
75
66
59
64
67
64
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
—
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd2(dba)3
Pd(PPh3)2Cl2
Pd(PhCN)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PtBu3 Cs2CO3
PtBu3 K2CO3
PtBu3 K3PO4
Dioxane 90
Dioxane 90
Dioxane 90
PtBu3 Na2CO3 Dioxane 90
PtBu3 NaHCO3 Dioxane 90
PtBu3 CsF
Dioxane 90
Dioxane 90
Dioxane 90
Dioxane 90
Dioxane 100
Dioxane 80
Dioxane 70
Dioxane 50
Dioxane 30
Dioxane 80
Dioxane 80
Dioxane 80
Dioxane 80
Dioxane 80
Dioxane 80
Dioxane 80
Dioxane 80
Dioxane 80
toluene 80
PtBu3 KF
9
PtBu3 KOAc
PtBu3 TBAB
PtBu3 TBAB
PtBu3 TBAB
PtBu3 TBAB
PtBu3 TBAB
PtBu3 TBAB
PtBu3 TBAB
PtBu3 TBAB
10
11
12
13
14
15
16c
17
18
19d
20e
21
22
23
24
25
26
27
28
29
—
—
—
—
—
—
—
—
—
—
—
—
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
DMF
MeCN
DCE
80
80
80
63
62
81
tBuOH 80
a
Reaction conditions: p-methylphenylboronic acid 1a (1.0 mmol),
morpholin-4-amine 2a (0.5 mmol), DABCOÁ(SO2)2 (1.0 mmol), palladium
catalyst (5 mol%), ligand (10 mol%), base (1.5 equiv.), solvent (2.0 mL),
a
Isolated yield based on hydrazine 2.
b
c
O2 (balloon). Isolated yield based on morpholin-4-amine 2a. The
d
reaction was performed in air. In the presence of Pd(OAc)2 (10 mol%).
DABCO-bis(sulfur dioxide) with morpholin-4-amine 2a was
examined in the meantime, which gave rise to the desired
product 3m in 50% yield. Palladium-catalyzed reactions of
piperidin-1-amine or 1-methyl-1-phenylhydrazine were explored,
and all reactions worked well to produce the corresponding aryl
N-aminosulfonamides in good yields. However, no reaction took
place when piperidine or p-toluidine were employed in the trans-
formation under the optimal conditions, which was similar to the
results reported by Willis.7 This might be due to the difference of
nucleophilicity and basicity between amines and hydrazines.
A possible catalytic cycle is presented in Scheme 2. We
hypothesized that a transmetallation of Pd(II) with arylboronic
acid 1 would occur first to generate a Pd(II) species A. The
subsequent coordination and insertion of sulfur dioxide4
would result in the formation of intermediate B. Then a
nucleophilic attack of hydrazine would take place to produce
the coupling product 3 and Pd(0). The latter would be oxidized in
the presence of dioxygen to afford Pd(II), which would re-enter
the catalytic cycle.
e
In the presence of Pd(OAc)2 (2 mol%). TBAB: tetrabutylammonium
bromide.
presence of dioxygen (balloon) at 80 1C. A range of arylboronic
acids and amines were examined under the standard conditions.
For most cases, the expected products 3 were formed in good to
excellent yields. For instance, 2-methylphenylboronic acid or
4-methoxyphenylboronic acid reacted with DABCO-bis(sulfur
dioxide) and morpholin-4-amine 2a leading to the corresponding
aryl N-aminosulfonamide 3b or 3c in almost quantitative yields.
4-tert-Butylphenylboronic acid or naphthalenylboronic acid were
good reactants as well in the reaction of DABCO-bis(sulfur
dioxide) and morpholin-4-amine 2a. However, the results were
inferior when arylboronic acids 1 with electron-withdrawing
groups attached on the aromatic ring were examined. For
example, a moderate yield was afforded when 4-halophenyl-
boronic acid was employed in the palladium-catalyzed, three-
component reaction. Interestingly, the free hydroxyl and amino
groups could be tolerated under the conditions, and the expected
products 3k or 3l were generated in 75% and 50% yields,
respectively. However, 3-pyridinylboronic acid was not a good
partner in the reaction. Reaction of (E)-styrylboronic acid and
In summary, we have developed a novel and efficient route to
aryl N-aminosulfonamides via a palladium-catalyzed three-
component coupling of arylboronic acids, sulfur dioxide
and hydrazines in the presence of a balloon of dioxygen.
c
7754 Chem. Commun., 2012, 48, 7753–7755
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Scheme 2 A possible mechanism for the palladium-catalyzed reaction
of arylboronic acids, DABCO-bis(sulfur dioxide), with hydrazines.
The reaction proceeded smoothly under mild conditions and
DABCOÁ(SO2)2 was used as the source of sulfur dioxide.
Employing DABCO-bis(sulfur dioxide) in other coupling
reactions is under investigation currently, and the results will
be reported in due course.
Financial support from the National Natural Science
Foundation of China (Nos. 21032007, 21172038) is gratefully
acknowledged.
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 7753–7755 7755