Angewandte
Chemie
Rather than focus on the synthesis of a single class of
sulfonyl derivative, a catalytic synthesis of sulfinates would
potentially allow access to a host of sulfonyl-derived func-
tional groups through established reactions.[16] Although we
have recently shown that aminosulfonamides, prepared from
the palladium-catalyzed combination of aryl halides, DABSO,
and hydrazines, can be converted into the corresponding
sulfinates by way of a base-promoted degradation, the process
is cumbersome in that it requires the initial introduction and
then expulsion of an expensive hydrazine derivative
[Eq. (2)].[17] Shavnya and Miscitti have also shown that
sulfinates can be prepared using palladium catalysis, in this
case, from the combination of aryl halides and K2S2O5.
However, the process requires high ligand loadings
(30 mol%), the use of an excess of inorganic reductant, as
well as a stoichiometric additive (TBAB).[18] Herein we
describe an operationally simple protocol which employs
only DABSO, triethylamine, and isopropyl alcohol, in combi-
nation with a low palladium and ligand loading to convert aryl
halides into the corresponding ammonium sulfinates
[Eq. (3)]. No inorganic reducing agent is needed, with
isopropyl alcohol serving as both the reaction solvent and
the formal reductant. The process is high yielding across
a broad range of aryl and heteroaryl halides, and the
ammonium sulfinate products display good reactivity in
their conversion into a number of sulfonyl derivatives.
alcohol was employed (entry 1).[19] The use of calcium
formate provided a small improvement in efficiency (entries 2
and 3), and these conditions were then used to evaluate
a number of alternative phosphine ligands (entries 4–9).
Significant improvements in yields were obtained with both
PCy3 and PtBu2Me (used as their HBF4 salts), and the optimal
ligand proved to be PdAd2Bu[20] (entry 9), which in addition
to providing a small improvement in yield also delivered
a practical advantage because of its improved stability.[20] We
were aware that the iPrOH, used as solvent, could also
function as a reductant in palladium catalysis,[21] and accord-
ingly we then performed a duplicate experiment but without
the addition of any external inorganic reducing agent.
Pleasingly, an identical yield was obtained for the reductant-
free transformation (entry 10). As far as we are aware, these
experiments represent the first example of an alcohol being
employed as a reductant in combination with a sulfinyl
derivative. Finally, decreasing the palladium loading to
5 mol%, the ligand loading to 7.5 mol%, and the number of
DABSO equivalents to 0.6 (1.2 equivalents of SO2) delivered
the optimized reaction conditions (entry 11). The catalyst
loading could be reduced further, for example, using only
0.5 mol% palladium and 0.75% ligand led to a 91% con-
version into the sulfinate (entry 12).
Sulfinates are versatile intermediates, but they are rarely
the desired final product of a transformation. To evaluate the
scope of the developed reaction we elected to derivatize the
newly formed sulfinates in situ. Using a-bromo tert-butyl
acetate as the electrophile allowed the corresponding sulfones
to be readily prepared, and was preferable to attempting to
isolate and purify individual ammonium sulfinate salts
(Table 2). In general, a broad range of functionalized aryl
iodides could be converted smoothly into the corresponding
sulfinates, and then into the isolable sulfone products.
Electron-rich substrates performed well, with a variety of
electron-donating substituents being tolerated in all positions
of the aromatic ring (3a–f). Notable examples include the
mixed sulfide-sulfone 3d, a product difficult to prepare using
traditional sulfone methodology, and sulfones 3e and 3 f,
featuring unprotected OH and NH2 substituents, respectively.
A selection of electron-neutral substrates were employed
without incident (3g–j). Electron-withdrawing functional
groups were likewise compatible with the reaction conditions,
with ester, ketone, amide, nitrile, and trifluoromethyl-sub-
stituted products being isolated in good yields (3k–o). The
greater reactivity of aryl iodide substrates allowed sulfones
featuring bromo, chloro, and fluoro substituents to be
prepared (3p–r). Finally, although aryl iodide substrates
proved to be most efficient, it was possible to employ aryl
bromide starting materials, with the sulfones 3k and 3o being
prepared from both aryl halide substrates.
We selected the conversion of 4-iodotoluene (1a) into the
corresponding sulfinate (2a) as a model transformation
(Table 1). Our initial reagent and catalyst selections were
based on our earlier developed aminosulfonylation chemistry,
with the exchange of the hydrazine nucleophile for a range of
reductants. The desired sulfinate was only observed in
significant quantities when sodium formate in isopropyl
Table 1: Optimization of reaction conditions for the formation of the
sulfinate 2a from 4-iodotoluene.[a]
Entry
Ligand
Reductant
Yield [%][b]
1
2
3
4
5
6
7
8
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
binap
HCO2Na
HCO2K
68
38
71
23
84
25
88
95
96
96
99
91
(HCO2)2Ca
(HCO2)2Ca
(HCO2)2Ca
(HCO2)2Ca
(HCO2)2Ca
(HCO2)2Ca
(HCO2)2Ca
none
dppf
dccp·(HBF4)2
PCy3·HBF4
PtBu2Me·HBF4
PAd2Bu
PAd2Bu
PAd2Bu
9
10
11[c]
12[d]
none
none
We next explored the use of the heteroaryl halides as
substrates (Table 3). Examples of indole, benzofuran, benzo-
thiophene, thiophene, pyridine, and quinolone ring systems
were all converted into the expected sulfone products,
although in general the yields were reduced relative to the
benzene-derived examples (3s–x). Several alkenyl iodides
were also investigated, and proved to be compatible with the
reaction (3y,z).
PAd2Bu
[a] Reaction conditions: Pd(OAc)2 (10 mol%), ligand (20 mol%),
DABSO (1.1 equiv), Et3N (3.0 equiv), iPrOH [0.2m], 758C, 16 h. [b] HPLC
yield relative to an internal standard. [c] Pd(OAc)2 (5 mol%), PAd2Bu
(7.5 mol%), DABSO (0.6 equiv). [d] Pd(OAc)2 (0.5 mol%), PAd2Bu
(0.75 mol%). binap=2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl,
dccp=1,3-bis(dicyclohexylphosphino)propane, dppf=1,1’-bis(diphe-
nylphosphino)ferrocene.
Angew. Chem. Int. Ed. 2014, 53, 10204 –10208
ꢀ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim