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molecules. In the past several years, our research group and
those of others have developed many nucleophilic fluoroal-
kylation reactions using a-fluoro carbanions generated from
a-fluorinated sulfones.[9] The phenylsulfonyl functionality was
found to be a highly useful modulating group to tackle the
“negative fluorine effect” (NFE) of a-fluoro carbanions.[9,10]
However, an additional step was needed to remove the
phenylsulfonyl group after the desired fluoroalkylation step.[9]
Therefore, we have been interested in seeking new removable
modulating groups for designing efficient nucleophilic fluo-
roalkylation reactions in one pot, that is, the modulating
group can be removed spontaneously during the one-pot
reaction process.
Owing to their physiological and diverse chemical proper-
ties, sulfoximines, which contain a stereogenic sulfur center,
have been widely used in organic synthesis.[11] Recently, the
use of fluorinated sulfoximines as fluoroalkylation reagents
has also attracted much attention.[12,13] However, there have
been no reports on stereoselective fluoroalkylations using
enantiopure fluorinated sulfoximines as the reagents. We
envisioned that, because of the good leaving-group ability of
the sulfoximine functionality, a Michael-type addition–elim-
ination reaction could be achieved between the chiral anion
of (R)-N-tosyl-S-fluoromethyl-S-phenylsulfoximine (2) and
a,b-unsaturated carbonyl compounds (see Scheme 1d).
Importantly, the sulfoximine group could be removed
during the subsequent one-pot cyclopropanation process.
Therefore, the unique properties of the sulfoximine group
offer excellent opportunities to design new fluoroalkylation
reactions.
Scheme 3. Reaction of (R)-N-tosyl-S-fluoromethyl-S-phenylsulfoximine
(2) with D2O.
were chosen as the Michael acceptor, because of their wide
synthetic applications.[15] N-Methoxy-N-methylcinnamamide
3a was used as a model compound to study the addition–
elimination reaction under the carefully optimized reaction
conditions, which are listed in Table 1. When we used
LiHMDS as the base, the reaction took place smoothly in
Table 1: Survey of reaction conditions.[a]
Entry 3a/2/Base Solvent
T [oC] Yield d.r.[c] ee[d]
[%][b]
[%]
1
2
3
4
1:1.2:1.5
1:1.5:1.5
1:1.5:1.3
1:1.5:1.3
1:1.5:1.3
1:1.5:1.3
1:1.5:1.3
1:1.5:1.3
THF
THF
THF
THF
PhCH3
PhCH3
RT
RT
RT
80
96
90
91:9 92
99:1 93
99:1 94
99:1 94
95:5 97
95:5 97
98:2 94
96:4 96
À30 92
5
RT 94
6[e]
7[f]
8[f]
À15 90
THF/PhCH3 (v/v=3:1) RT
THF/PhCH3 (v/v=1:3) RT
70
75
[a] Typical procedure: LiHMDS (1m in THF or PhCH3) was added to
a mixture of 3a and 2 (0.2 mmol) in solvent at À788C. After 20 min, the
dry-ice bath was removed and the reaction mixture was stirred at the
corresponding temperature (T) for 3 h. [b] Yield of isolated product.
[c] Determined by 19F NMR spectroscopy. [d] Determined by HPLC on
chiral stationary phase column. [e] Stirred at À158C for 4 h. [f] Yield was
determined by 19F NMR spectroscopy with PhCF3 as internal standard.
(S)-N-Tosyl-S-methyl-S-phenylsulfoximine (1) was read-
ily prepared according to the literature procedures.[14] The
fluorination of 1 by using N-fluorodibenzenesulfonamide
(NFSI) as the fluorinating reagent gave (R)-N-tosyl-S-fluoro-
methyl-S-phenylsulfoximine (2) in 72% yield (Scheme 2).
THF or PhCH3. More importantly, we found that the relative
amounts of 3a, 2, and base was crucial to the diastereoselec-
tivity and enantioselectivity of the reaction (Table 1,
entries 1–3). When the ratio of 3a/2/base was 1:1.2:1.5, the
product was obtained with a d.r. of 91:9 and an ee value of
92% (Table 1, entry 1). When the ratio was changed to
1:1.5:1.5, the d.r. increased to 99:1 and the ee value was
slightly increased (Table 1, entry 2). However, when the
amount of LiHMDS was decreased to 1.3 equivalents, the
ee value increased to 94% (Table 1, entry 3). When toluene
was used as a solvent, the ee value was increased to 97%,
albeit the d.r. was decreased to 95:5 (Table 1, entry 5).
Lowering the reaction temperature did not improve the
diastereoselectivity or the enantioselectivity (Table 1,
entries 4 and 6) and the use of a mixed solvent system did
not result in any improvement either (Table 1, entries 7 and
8). It is noteworthy that only one pair of diastereoisomers was
detected amongst the products of the reaction, as determined
by 19F NMR spectroscopy.
Scheme 2. Preparation of (R)-N-tosyl-S-fluoromethyl-S-phenylsulfoxi-
mine (2).
With compound 2 in hand, we first tested the reaction
between the anion, which was formed in situ from the
reaction of 2 and lithium hexamethyldisilazide (LiHMDS),
and D2O. Thus, under N2 atmosphere, LiHMDS (1m in THF,
0.375 mL, 0.375 mmol) was added to a solution of 2 (98 mg,
0.3 mmol) in THF (3 mL), at À788C. After stirring the
reaction mixture for 20 minutes at À788C, the reaction was
quenched by adding D2O (0.5 mL); the resulting mixture was
then acidified by adding CF3COOH (0.3 mL). High diaste-
reoselectivity (> 99:1) was observed for monodeuterated
product 2’ (Scheme 3).
Encouraged by this result, we started to investigate the
chiral fluorocarbanion strategy for the stereoselective syn-
thesis of cyclopropanes that bear a fluorinated tertiary
stereogenic carbon center. a,b-Unsaturated Weinreb amides
Eventually, we chose entry 3 (conditions A) and entry 5
(conditions B) shown in Table 1 as the standard conditions to
study the scope of the reaction between a,b-unsaturated
2
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
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