Angewandte
Chemie
ATRA.[6b,16] Preventing autoxidation of a sulfinic acid to
a sulfonic acid by introducing 2,6-lutidine into the reaction
medium greatly improved formation of the desired prod-
uct.[17] After stirring at room temperature for 8 h, b-ketosul-
fone 3a was isolated in 70% yield, to the complete exclusion
of the corresponding vinylsulfone.
Optimization of this conversion documented its depend-
ence on several reaction variables, including 1) the choice of
surfactant; 2) source of oxygen; 3) temperature; 4) base; 5)
conditions for neutralization of the sodium arylsulfinate with
HCl; 6) ratio of arylsulfinic acid to base; 7) equivalents of
sulfinic acid needed to drive the reaction to completion; 8)
surfactant concentration in water; 9) arylacetylene concen-
tration in the surfactant; and 10) portion-wise addition of
reagents. After extensive screening (see Supporting Informa-
tion), the optimum conditions were determined to be: TPGS-
750-M (2% weight percent) as surfactant in water, 2,6-
lutidine as base, 4.0 equivalents of arylsulfinic acid, 0.3m
arylacetylene in the aqueous medium, along with ambient
temperature and light.
and amide (25 and 26; Scheme 4) residues, Similarly, a repre-
sentative alkylsulfinic acid also led to the desired sulfone 17.
Electronic rather than steric effects were found to be of
greater consequence, as no reaction was observed with
a substrate containing CF3 groups in the 3- and 5-positions
of the aromatic ring of an arylacetylene. It is noteworthy that
only one ethynyl group showed reactivity in 3-ethynyl
phenylacetylene to afford product 12. A cycloalkenyl group
was also well tolerated (14).[18]
Sequential reactions involving initial b-ketosulfone for-
mation are also possible. For example, after an initial reaction
giving b-ketosulfone 10, Suzuki–Miyaura couplings with
either an arylboronic acid or MIDA boronate[19] within the
same pot led to final products 15 and 20 in 62% and 55%
overall yields, respectively (Scheme 3).
Substrate scope was next explored (Table 1). Good-to-
excellent yields were obtained with electron-donating sub-
stituents on the aryl ring of the alkynes, leading to products 4,
5 and 18. Heteroaromatic and sensitive nitrile functional
groups were all well tolerated, and 69–78% yields were
obtained for aducts 6–8. Challenging electron-withdrawing
groups in the educts, nonetheless, afforded products bearing
bromo (9 and 10), acetyl (11), ethynyl (12), cyano (7 and 8),
Table 1: Substrate scope of micellar aerobic difunctionalization of aryl
acetylenes.
Scheme 3. Sequential 1-pot aerobic oxidation/Suzuki–Miyaura cou-
pling.
To gain insight regarding the location of the reaction
under micellar conditions, an arylalkyne 21 bearing a p-
dimethylamino group on the aryl ring of the alkyne was
subjected to protonation (aq. HCl) under aerobic oxidation
conditions (Scheme 4A). Rather than the expected b-keto-
sulfone, only arylvinylsulfone 22 was obtained (89%). The
water-soluble ammonium salt is unlikely to enter the oxygen-
rich nonpolar lipophilic core of the micelle and hence,
dioxygen trapping is precluded. Instead, the vinyl radical is
converted to the corresponding olefin 22 by an ATRA
process. In the presence of twice the typical amount of sulfinic
acid, a second addition of arylsulfonyl to 22 ensues forming 23
in 81% yield. Similar results were obtained when 22 was
isolated and re-subjected to the optimized reaction condi-
tions, leading to 23 in 84% isolated yield. Protection of the
amine functionality in 21 (X = NH) as the derived acetamide
24 (X = NHCO) negated salt formation and led, exclusively,
to b-ketosulfone 25 in 69% yield. Inverting the location of the
acetamide group from arylacetylene 24 to the arylsulfinic acid
coupling partner gave similar results (Scheme 4B): b-keto-
sulfone product 26 was isolated in 72% yield. Replacing
nitrogen in the arylalkyne with oxygen (i.e., 27, X = O)
afforded results similar to those from 24, again suggesting that
the reaction is taking place within the micellar core. In this
case, b-ketosulfone 28 was obtained in 70% isolated yield
(91% yield based on recovered starting material).
Conditions: 1 mmol, 0.3m phenylacetylene in 2 wt.% TPGS-750-M in
water, 4.0 mmol sodium p-toluenesulfinate, 4.0 mmol aq. HCl*,
3.5 mmol 2,6-lutidine (all these reagents were added in two portions in
80 min intervals), RT, air balloon. *After HCl addition to the solution of
sodium p-toluenesulfinate in TPGS-750-M, the mixture was stirred for
2–3 min before addition of 2,6-lutidine (for details, see the Supporting
Information).
Angew. Chem. Int. Ed. 2014, 53, 3432 –3435
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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