A palladium-catalyzed reaction of aryl halides, potassium metabisulfite, and hydrazines

Article abstract of DOI:10.1039/c2cc34957d

Aryl N-aminosulfonamides could be easily produced via a palladium-catalyzed coupling of aryl halides, potassium metabisulfite, and hydrazines. Potassium metabisulfite is an excellent equivalent of sulfur dioxide in the reaction of palladium-catalyzed aminosulfonylation. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc34957d

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COMMUNICATION
A palladium-catalyzed reaction of aryl halides, potassium metabisulfite,
and hydrazinesw
Shengqing Yea and Jie Wu*ab
Received 11th July 2012, Accepted 23rd August 2012
DOI: 10.1039/c2cc34957d
Aryl N-aminosulfonamides could be easily produced via a palladium-
catalyzed coupling of aryl halides, potassium metabisulfite,
and hydrazines. Potassium metabisulfite is an excellent equiva-
lent of sulfur dioxide in the reaction of palladium-catalyzed
Scheme 1 Proposed synthetic route to sulfonyl derivatives via a
aminosulfonylation.
palladium-catalyzed reaction of aryl halides, sulfite, with nucleophiles.
Significant efforts continue to be underway for the applications of
sulfur dioxide in organic synthesis, due to the enormous scale of
annual production.1 Although using sulfur dioxide as a reagent or
a coordination partner has been demonstrated in several organic
transformations,2–4 applications of sulfur dioxide in organic syn-
thesis are restricted, presumably due to the handling problem
associated with this toxic gaseous reagent.5 Recently, there has
been a breakthrough by using DABCO–bis(sulfur dioxide) as
the source of sulfur dioxide in several organic reactions, as
reported by Willis and co-workers.6 This bench-stable solid
overcomes the defects of gaseous sulfur dioxide as mentioned
above.6,7 However, the scope of the reported process is limited.
For example, only aryl/vinyl iodide could be utilized in the
palladium-catalyzed coupling reactions. Additionally, the pre-
paration of DABCO–bis(sulfur dioxide) is difficult, which is an
energy consuming process.6 Moreover, an excess amount of
DABCO has to be which is wasteful.
Our initial studies were performed for a model reaction of
1-iodo-4-methylbenzene 1a, sodium hydrogensulfite, with
morpholin-4-amine 2a (Table 1). The reaction was catalyzed
by palladium acetate (5 mol%) with PtBu3ÁHBF4 (10 mol%) in
the presence of TBAB (tetrabutylammonium bromide) in
DMF at 80 1C (Table 1, entry 1). We envisioned that the
presence of TBAB would act as a base as well as a phase
transfer reagent in the reaction.7 However, only a trace
amount of product was detected. The result was not improved
when the solvent was changed to MeCN (Table 1, entry 2).
Gratifyingly, the desired 4-methyl-N-morpholinobenzene-
sulfonamide 3a was isolated in 11% yield when the reaction
occurred in toluene (Table 1, entry 3). Further screening of solvents
revealed that the reaction worked efficiently in 1,4-dioxane, which
afforded the product in 21% yield (Table 1, entries 4–6). Other
inorganic sulfites were examined subsequently. The reactions
failed when sodium sulfite, potassium sulfite, or sodium
metabisulfite was employed in the reaction as the source of
sulfur dioxide (Table 1, entries 7–9). Compound 3a could be
generated in 15% yield when zinc sulfite was used as a
replacement (Table 1, entry 10). To our delight, the outcome
could be improved when potassium metabisulfite was utilized
as a sulfur dioxide equivalent, which furnished the expected
product 3a in 67% yield (Table 1, entry 11). The presence of
TBAB is essential, and the yield was decreased to 26% in the
absence of TBAB (Table 1, entry 12). Further exploration of
the ligand effects led to poor results. No better yields were
obtained when various phosphine ligands or N-heterocyclic
carbene were employed in the reaction (Table 1, entries 13–24).
We envisioned that the electron enriched PtBu3 would
promote the oxidative addition of Pd(0) to aryl halide, and
the bulkiness of PtBu3 would promote the reductive elimina-
tion during the reaction process. The yield was dramatically
increased to 98% when 20 mol% of PtBu3ÁHBF4 was used in
the reaction (Table 1, entry 25). However, the reaction was
retarded under lower temperature (Table 1, entries 26 and 27).
A comparable yield (97%) was obtained when the reaction
It is well known that there are many sulfites in Nature, which
are formed directly by absorption of the gaseous sulfur dioxide
from air. It would be highly desirable and attractive for incorpora-
tion of sulfonyl groups into organic molecules if the inorganic
sulfites could serve as the source of sulfur dioxide in organic
transformations, especially in transition metal catalyzed reactions
(Scheme 1). This environmentally benign process would open a
new avenue for the synthesis of sulfonyl derivatives. Herein, we
report the first example of using potassium metabisulfite as a
sulfur dioxide equivalent in the reaction of palladium-catalyzed
aminosulfonylation under mild conditions. Not only aryl iodides
but also aryl bromides are workable during the reaction process.
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
w Electronic supplementary information (ESI) available: Experimental
procedure, characterization data, 1H and 13C NMR spectra of com-
pound 3. See DOI: 10.1039/c2cc34957d
c
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Chem. Commun., 2012, 48, 10037–10039 10037

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Table 1 Initial studies for the palladium-catalyzed reaction of 1-iodo-
4-methylbenzene 1a, inorganic sulfite, with morpholin-4-amine 2aa
Table 2 Palladium-catalyzed three-component reaction of aryl iodide 1,
potassium metabisulfite, with hydrazines 2a
Entry MSO3
Ligand
Additive
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
NaHSO3 PtBu3ÁHBF4 TBAB
NaHSO3 PtBu3ÁHBF4 TBAB
NaHSO3 PtBu3ÁHBF4 TBAB
NaHSO3 PtBu3ÁHBF4 TBAB
NaHSO3 PtBu3ÁHBF4 TBAB
NaHSO3 PtBu3ÁHBF4 TBAB
Na2SO3 PtBu3ÁHBF4 TBAB
K2SO3 PtBu3ÁHBF4 TBAB
Na2S2O5 PtBu3ÁHBF4 TBAB
ZnSO3 PtBu3ÁHBF4 TBAB
K2S2O5 PtBu3ÁHBF4 TBAB
DMF
MeCN
Toluene
Trace
Trace
11
1,4-Dioxane 21
DCE
10
Trace
tBuOH
1,4-Dioxane Trace
1,4-Dioxane Trace
1,4-Dioxane Trace
1,4-Dioxane 15
1,4-Dioxane 67
1,4-Dioxane 26
1,4-Dioxane nr
1,4-Dioxane 18
1,4-Dioxane Trace
1,4-Dioxane 16
1,4-Dioxane Trace
1,4-Dioxane Trace
1,4-Dioxane Trace
1,4-Dioxane Trace
1,4-Dioxane Trace
1,4-Dioxane Trace
1,4-Dioxane 28
1,4-Dioxane Trace
1,4-Dioxane 98
1,4-Dioxane 21
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25c
K2S2O5 PtBu3ÁHBF4
K2S2O5 PCy3
K2S2O5 PPh3
—
TBAB
TBAB
TBAB
TBAB
K2S2O5 BINAP
K2S2O5 S-Phos
K2S2O5 Xant-Phos TBAB
K2S2O5 DPPF TBAB
K2S2O5 John-Phos TBAB
K2S2O5 X-Phos
K2S2O5 DPPP
K2S2O5 Ru-Phos
TBAB
TBAB
TBAB
K2S2O5 DPE-Phos TBAB
TBAB
a
b
Isolated yield based on aryl iodide 1. 10 mol% of Pd(OAc)2, 30 mol%
K2S2O5 IPrÁHCl
K2S2O5 PtBu3ÁHBF4 TBAB
of PtBu3ÁHBF4. 5 mol% of Pd(OAc)2, 20 mol% of PtBu3ÁHBF4.
c
26c,d K2S2O5 PtBu3ÁHBF4 TBAB
27c,e K2S2O5 PtBu3ÁHBF4 TBAB
1,4-Dioxane Trace
K2S2O5 PtBu3ÁHBF4 TBAB/HBF4 1,4-Dioxane 84
28f
29g
Furthermore, the substituents of chloro and bromo on the
aromatic ring were retained under the standard conditions.
Additionally, other hydrazines 2 such as piperidin-1-amine
and 1-methyl-1-phenylhydrazine were examined in the reac-
tions, which provided the expected products in good yields.
K2S2O5 PtBu3ÁHBF4 TBAB/HBF4 1,4-Dioxane 97
a
Reaction conditions: 4-methylbenzene 1a (0.5 mmol), sulfate (0.5 mmol),
morpholin-4-amine 2a (0.6 mmol), Pd(OAc)2 (5 mol%), ligand (10 mol%),
additive (1.5 equiv.), solvent (2.0 mL). b Isolated yield based on 4-methyl-
benzene 1a. c In the presence of PtBu3ÁHBF4 (20 mol%). d The reaction
e
f
occurred at 60 1C. The reaction was performed at 50 1C. In the
Table 3 Palladium-catalyzed three-component reaction of aryl bromide 4,
potassium metabisulfite, with hydrazines 2a
g
presence of HBF4 (10 mol%). In the presence of HBF4 (20 mol%).
occurred in the presence of PtBu3ÁHBF4 (10 mol%) and HBF4
(20 mol%) (Table 1, entry 29). A lower reactivity was observed
when the catalytic amount of palladium catalyst and phosphine
ligand was reduced to 2 mol% (data not shown in Table 1).
The generality of this palladium-catalyzed three-component
reaction of aryl iodides, potassium metabisulfite, with hydra-
zines was then explored under the optimized conditions
(5 mol% of Pd(OAc)2, 10 mol% of PtBu3ÁHBF4, 20 mol%
of HBF4, 1.5 equiv. of TBAB, 1,4-dioxane, 80 1C). The results
are summarized in Table 2. This palladium-catalyzed amino-
sulfonylation was found to be workable with aryl iodides 1
bearing electron-withdrawing and -donating substituents
on the aromatic backbone. Notably, amino and hydroxyl
functionalities were all tolerated, and the corresponding aryl
N-aminosulfonamides 3 were obtained in good yields. For instance,
4-hydroxyphenyl iodide reacted with morpholin-4-amine 2a leading
to the product 3h in 71% yield. The reaction of 4-aminophenyl
iodide with morpholin-4-amine 2a gave rise to the corresponding
product 3i in 83% yield. Moreover, the ester incorporated
phenyl iodide was compatible as well in this reaction, although
the final outcome is not as good as expected (3p, 55% yield).
a
Isolated yield based on aryl bromide 4.
c
10038 Chem. Commun., 2012, 48, 10037–10039
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However, anilines and aliphatic amines are not workable
under the optimal conditions, and the results are similar to
the previous reports.6,7
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In a second set of experiments, the scope of the process with
respect to aryl bromides was explored. The results are pre-
sented in Table 3. Interestingly, we found that the reactions
proceeded smoothly in the presence of 30 mol% of PtBu3Á
HBF4 at 100 1C. Again, amino, hydroxyl and ester groups
were all compatible during the reaction process. Cyano and
chloro groups survived during the transformation. From the
results, potassium metabisulfite as the source of sulfur dioxide
worked well under the palladium-catalyzed aminosulfonyla-
tion of aryl halides.
In summary, we have demonstrated that potassium meta-
bisulfite is an excellent equivalent of sulfur dioxide in the
reaction of palladium-catalyzed aminosulfonylation. Aryl
N-aminosulfonamides could be easily produced via a palladium-
catalyzed three-component reaction of aryl halides, potassium
metabisulfite, with hydrazines. Not only aryl iodides but also aryl
bromides are workable during the reaction process. Employing
inorganic sulfites as the source of sulfur dioxide in other transition
metal-catalyzed reactions is under investigation currently, and the
results will be reported in due course.
Financial support from the National Natural Science Founda-
tion of China (No. 21032007, 21172038) is gratefully acknowledged.
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 10037–10039 10039