.
Angewandte
Communications
[
a]
In such a system, an acid–base bifunctional organic catalyst
may achieve good chiral induction in the asymmetric reaction
of the o-QMs through the simultaneous electrophilic activa-
tion of o-QMs by hydrogen-bonding interactions and activa-
tion of the nucleophile by deprotonation by the base
Table 1: Optimization of reaction conditions.
[
11]
(
Scheme 1).
With this concept in mind, we envisaged that an asym-
[b]
[c]
Entry
Cat.
No
Base
t [h]
Conv. [%]
e.r.
1
2
3
4
5
6
7
8
9
Na CO
48
12
12
12
12
12
12
12
12
12
12
12
4
65
–
–
2
3
3
3
3
3
3
3
3
3
3
metric catalytic reaction of o-QMs with sulfur nucleophiles
would provide access to chiral a-aryl- or a-alkyl-substituted
benzyl mercaptans (Scheme 1). These sulfur-containing struc-
tural units are widely found in biologically interesting
Et N
Na CO
>95
>95
>95
>95
>95
60
>95
>95
>95
75
3
2
1a
1b
1c
1d
1e
1 f
1g
1h
1h
1h
1h
1h
1h
Na CO
65:35
91:9
79:21
93:7
77:25
93.5:6.5
84:16
2
Na CO
2
Na CO
2
[12]
compounds and in protected reagents for the synthesis of
Na
CO
2
[
13]
Na CO
chiral metal clusters. Currently, such thiol compounds are
mainly accessible through O–S exchange using chiral benzyl
2
Na CO
2
[
14]
Na
CO
2
alcohols as the starting materials. This reaction will supply
a unique catalytic method for the enantioselective synthesis of
both a-aryl- and a-alkyl-substituted benzyl mercaptans, as
1
1
1
0
1
2
Na CO
96:4
2
NaHCO3
NaOAc
NaOH
93.5:6.5
91.5:8.5
81:19
95.5:4.5
92.5:7.5
45
[
15]
[16]
sulfa-Michael additions, sulfa-1,2 additions, sulfa-allyla-
13
14
>95
>95
>95(93)
[
17]
[18]
tions, and the kinetic resolution of thiols generally do not
afford a-aryl-substituted benzyl mercaptans. We report
herein the first conjugate addition of tritylthiol to in situ
generated o-QMs catalyzed by a chiral organic base with good
to excellent enantioselectivities (91:9–97:3 e.r.) using water as
the solvent. Moreover, this catalytic system tolerates various
substrate precursors in the in situ generation of both aryl- and
alkyl-substituted o-QMs. The spatial separation between the
compounds in the inorganic and organic phase was crucial for
achieving the high reactivity and stereoselectivity.
Cs
2
CO
3
4
36
[
d]
15
Na CO
2
3
[a] Unless otherwise specified, all reactions were conducted with 2a
(0.1 mmol), tritylthiol (3a, 1.2 equiv, 0.12 mmol), and catalyst
0.01 mmol, 10 mol%) in water (1 mL, 50 mL CH Cl added to dissolve
the substrates) at room temperature. [b] Determined by H NMR
spectroscopy of the crude mixture; the data in parentheses are the yields
of isolated products after column chromatography. [c] Determined by
HPLC analysis using a chiral stationary phase (Daicel Chiralpak AD-H
column). [d] Catalyst loading: 2 mol%, 2a: 0.4 mmol.
(
2 2
1
2
-(Tosylmethyl)phenols 2 were chosen as the substrates,
as they had been employed previously as the precursors for
[19]
the in situ formation of o-QMs under basic conditions.
Tritylthiol (3a) was chosen as the sulfur nucleophile, because
the trityl group in products 4 could be readily cleaved under
mild conditions to unmask the thiol functionality. In our
initial test, we examined the reaction between 2-(phenyl-
(
tosyl)methyl)phenol (2a) and 3a, using Na CO (1.2 equiv)
2 3
as the inorganic base and water as the solvent. A trace amount
of methylene chloride was added to fully dissolve the
substrates. In the absence of an organic base, the reaction
proceeded slowly at room temperature to 65% conversion in
4
8 h (Table 1, entry 1). When a catalytic amount of Et N
3
(
10 mol%) was added to the reaction system as the organic
base, the reaction proceeded to the corresponding racemic
product with almost full conversion after 12 h (Table 1,
entry 2).
Figure 1. Chiral bifunctional organocatalysts employed in this study.
Encouraged by this result, we continued to examine the
catalytic potential of some well-established bifunctional
organocatalysts (Figure 1), including Cinchona alkaloid-
derived thiourea (1a) and squaramide catalysts (1b–1d).
Quinidine-derived thiourea 1a exhibited high catalytic activ-
ity, completing the reaction in 12 h, but the desired product 4a
was obtained with only a moderate e.r. of 65:35 (Table 1,
entry 3). To our delight, quinidine-derived squaramides 1b–d
significantly improved the enantioselectivities without loss of
activities (Table 1, entries 4–6). Catalyst 1d with a 3,5-bis(tri-
fluoromethyl)benzene substituent led to an e.r. of 93:7. To
further improve the enantioselectivity, chiral (R,R)-cyclohex-
ane-1,2-diamine-derived thiourea or squaramide catalysts 1e
access to 4a in 96:4 e.r. (Table 1, entry 10). Several other
inorganic bases were then investigated, which displayed
a significant effect on the reactivity and enantioselectivity.
For example, the reactions using weaker bases, such as
NaHCO or NaOAc, furnished products with lower reactiv-
3
ities and enantioselectivities (Table 1, entries 11 and 12 versus
10), whereas stronger inorganic bases, such as NaOH and
Cs CO , led to much higher reactivities (full conversion in
2
3
4 h), albeit with lower enantioselectivities (Table 1, entries 13
and 14 vs. 10). To further explore the efficiency of this
catalytic system, the model reaction was carried out with
a reduced catalyst loading (2 mol%), thereby affording 4a in
[
20]
and 1h were also evaluated, the latter of which provided
2
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
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