Palladium-catalyzed aminosulfonylation of aryl halides

Article abstract of DOI:10.1021/ja1081124

The palladium-catalyzed three-component coupling of aryl iodides, sulfur dioxide, and hydrazines to deliver aryl N-aminosulfonamides is described. The colorless crystalline solid DABCO· (SO₂)₂ was used as a convenient source of sulfur dioxide. The reaction tolerates significant variation of both the aryl iodide and hydrazine coupling partners.

Full text of DOI:10.1021/ja1081124

Published on Web 10/28/2010
Palladium-Catalyzed Aminosulfonylation of Aryl Halides
Bao Nguyen, Edward J. Emmett, and Michael C. Willis*
Department of Chemistry, UniVersity of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, U.K.
Received September 8, 2010; E-mail: michael.willis@chem.ox.ac.uk
ing as dehydrating agents,8 but as far as we are aware, they have
not been exploited as a source of SO2 for catalysis. We chose to
Abstract: The palladium-catalyzed three-component coupling of
aryl iodides, sulfur dioxide, and hydrazines to deliver aryl N-
aminosulfonamides is described. The colorless crystalline solid
DABCO·(SO2)2 was used as a convenient source of sulfur
dioxide. The reaction tolerates significant variation of both the
aryl iodide and hydrazine coupling partners.
explore the use of the known complex DABCO·(SO2)2 (1; DABCO
) 1,4-diazabicyclo[2.2.2]octane),9 which is an air-stable, colorless
solid, in the proposed coupling chemistry. Given the importance
of sulfonamides in medicinal chemistry, we decided to focus our
initial investigation on the formation of C-SO2-N linkages.
Using reaction conditions we had previously employed in related
palladium-catalyzed aminocarbonylation chemistry,10 we were able
There is an extensive body of literature documenting the varied
coordination modes between sulfur dioxide and metal centers.1
Despite these numerous reports, applications of sulfur dioxide in
transition-metal-catalyzed processes remain scarce.2,3 A comparison
with the transition-metal chemistry of carbon monoxide is striking:
catalytic carbonylation processes, such as the palladium-catalyzed
conversion of aryl halides into aryl aldehydes, esters, and amides,
are established transformations routinely employed in synthetic
sequences (eq 1 in Scheme 1).4 In view of the wide occurrence of
sulfonyl motifs (-SO2-) in useful organic functional groups (e.g.,
sulfones, sulfonates, and sulfonamides) together with the enormous
scale of annual sulfur dioxide production,5 a catalytic method to
introduce SO2 into simple organic molecules would represent an
attractive technology. By analogy to established carbonylation
chemistry, we were interested in developing palladium-catalyzed
reactions to combine aryl halides, sulfur dioxide, and C, O, or N
nucleophiles (eq 2 in Scheme 1). The documented examples in
which SO2 undergoes the required insertions into metal-carbon
bonds suggested that such reactions are viable.1-3 In this com-
munication, we report the first examples of the proposed sulfony-
lation chemistry and in doing so describe a palladium-catalyzed
route to N-aminosulfonamides.
to establish the formation of the key of C-SO2-N bonds using a
hydrazine nucleophile: the coupling of iodotoluene, DABCO ·(SO2)2,
and N-aminomorpholine was achieved using a Pd(OAc)2/PtBu3 catalyst
in combination with Cs2CO3 in toluene at 70 °C, delivering N-
aminosulfonamide 2a in 77% yield (Table 1, entry 1). Although the
original conditions featured the use of Cs2CO3, we found that the
addition of the external base was not required when the solvent was
changed from toluene to dioxane (entries 3 and 4). We next explored
the loading of DABCO·(SO2)2 needed to maintain an efficient reaction;
reducing the amount to 1.1 equiv resulted in an increased yield of
89% (entry 5). However, employing 0.6 equiv of complex 1 (1.2 equiv
of SO2) reduced this to 64% (entry 6). Reasoning that the process no
longer had sufficient base, we performed an identical reaction including
0.5 equiv of DABCO, which pleasingly resulted in 99% conversion
to sulfonamide 2a (entry 7).
Table 1. Effect of the Amount of DABCO ·(SO2)2 and Base on the
Preparation of Aminosulfonamide 2aa
entry
base (equiv)
equiv of DABCO·(SO2)2
solvent
yield (%)b
Scheme 1. Palladium-Catalyzed Carbonylation and Sulfonylation
Reactions
1
2
3
4
5
6
7
Cs2CO3 (2.2)
2.2
2.2
2.2
2.2
1.1
0.6
0.6
toluene
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
77
12
17
83
89
64
99c
-
Cs2CO3 (2.2)
-
-
-
DABCO (0.5)
a Conditions: iodotoluene (1.0 equiv), hydrazine (1.5 equiv),
DABCO·(SO2)2 (as indicated), Pd(OAc)2 (10 mol %), PtBu3 ·HBF4 (20
mol %), solvent, 70 °C, 16 h. b Determined by 1H NMR spectroscopy.
c Corresponding to a 93% isolated yield.
Exploratory reactions employing a variety of nucleophiles and
catalysts in combination with gaseous sulfur dioxide were uniformly
unsuccessful. Reasoning that the multiple binding modes and
amphoteric nature of sulfur dioxide may be the cause of these
difficulties, we explored the possibility of employing an SO2
equivalent and were attracted to the use of amine-SO2 charge-
transfer complexes. Amine-SO2 adducts have been known since
at least 1900 and have been primarily studied to explore the nature
of their structure and bonding.6 Tertiary amine-SO2 complexes
have received some attention as organic reagents,7 mainly function-
Table 2 documents the scope of the developed aminosulfony-
lation chemistry. We first evaluated a range of aryl iodide coupling
partners and were able to introduce a variety of electron-donating
substituents using the optimized conditions (products 2b-d).
However, although both p- and m-iodoanisole were effective
substrates, the use of the ortho isomer resulted in only moderate
yields. For slow-reacting substrates, we found that the use of 1.1
equiv of DABCO ·(SO2)2 without the addition of extra DABCO
was more efficient; under these conditions o-iodoanisole was
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16372 J. AM. CHEM. SOC. 2010, 132, 16372–16373
10.1021/ja1081124  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of Pd-Catalyzed Coupling of Aryl Iodides,
corresponding aryl bromides could be employed, albeit to deliver
products in reduced yields. For example, sulfonamide 2a was
isolated in 93% yield when iodotoluene was used but only 56%
yield when bromotoluene was employed and the reaction was
performed at the increased temperature of 90 °C. Several alternative
hydrazine coupling partners were also utilized successfully
(2n-q).11 Finally, a preparative-scale reaction employing 500 mg
of iodotoluene (2.29 mmol) using the standard reaction conditions
delivered aminosulfonamide 2a in 92% isolated yield.
DABCO·(SO2)2, and Hydrazinesa b
,
In conclusion, we have shown for the first time that it is possible
to prepare C-SO2-N linkages using a palladium-catalyzed ami-
nosulfonylation process. Key to the success of the chemistry was
the use of solid DABCO ·(SO2)2 as an easy to handle equivalent of
sulfur dioxide. With this reagent, it was possible to achieve efficient
aminosulfonylation reactions between a range of aryl iodides and
N,N-dialkylhydrazines, providing aryl N-aminosulfonamides in good
to excellent yields. The reactions are operationally simple and
employ only a slight excess (1.2 equiv) of sulfur dioxide. Studies
aimed at elucidating the mechanism of the process and developing
related transformations are underway.
Acknowledgment. We thank the EPSRC for the award of an
Advanced Research Fellowship (to M.C.W.).
Supporting Information Available: Experimental procedures and
full characterization for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
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a Conditions: aryl halide (1.0 equiv), hydrazine (1.5 equiv),
DABCO·(SO2)2 (0.6 equiv), DABCO (0.5 equiv), Pd(OAc)2 (10 mol
%), PtBu3 ·HBF4 (20 mol %), 1,4-dioxane, 70 °C, 16 h. b Isolated yields.
c DABCO·(SO2)2 (1.1 equiv.) was used, and no DABCO was added.
d With 95% conversion.
coupled in 76% yield (2e). With the use of either set of conditions
as appropriate, substrates featuring a variety of functional groups,
including free hydroxyl (2i), electron-withdrawing trifluoromethyl
(2j) and methyl ester (2k), and 3-thienyl (2l), were smoothly
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Although aryl iodides were the most efficient substrates, the
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