Cu(I)/chiral bisoxazoline-catalyzed enantioselective sommelet-hauser rearrangement of sulfonium ylides

Article abstract of DOI:10.1021/acs.joc.0c01590

Catalytic asymmetric thia-Sommelet-Hauser rearrangement of sulfonium ylides remains a great challenge due to its multistep reaction mechanism involving metal carbene formation, proton transfer, and [2,3]-sigmatropic rearrangement. In particular, the key problem of such reactions is the differentiation of the enantiotopic lone pair electrons of sulfur, which generates the sulfonium ylide intermediate bearing chirality on the sulfur atom. With a modified chiral bisoxazoline ligand, we developed a Cu(I)- catalyzed asymmetric thia-Sommelet-Hauser rearrangement with good to excellent enantioselectivities. Mechanistic studies provide insights into the details of the reaction mechanism.

Full text of DOI:10.1021/acs.joc.0c01590

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Article
Cu(I)/Chiral Bisoxazoline-Catalyzed Enantioselective
Sommelet-Hauser Rearrangement of Sulfonium Ylides
Shu-Sen Li, and Jianbo Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01590 • Publication Date (Web): 03 Sep 2020
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Cu(I)/Chiral Bisoxazoline-Catalyzed Enantioselective
Sommelet-Hauser Rearrangement of Sulfonium Ylides
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†
,†,‡
Shu-Sen Li, Jianbo Wang*
†
Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic
Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking
University, Beijing 100871, China
‡
The State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
ABSTRACT：Catalytic asymmetric thia-Sommelet-Hauser rearrangement of sulfonium ylides
remains a great challenge due to its multi-step reaction mechanism involving metal carbene
formation, proton transfer and [2,3]-sigmatropic rearrangement. In particular, the key problem of
such reactions is the differentiation of the enantiotopic lone pair electrons of sulfur, which
generates the sulfonium ylide intermediate bearing chirality on the sulfur atom. With a modified
chiral bisoxazoline ligand, we have developed a Cu(I)-catalyzed asymmetric thia-Sommelet–
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Hauser rearrangement with good to excellent enantioselectivities. Mechanistic studies provide
insights into the details of the reaction mechanism.
INTRODUCTION
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[
2,3]-Sigmatropic rearrangement reaction represents one of the important types of bond
1
reorganization in organic chemistry. These reactions have found wide applications in organic
synthesis, among which the [2,3]-sigmatropic rearrangement with sulfonium ylides is a powerful
method to convert a C-S bond into C-C bond. The generation of sulfonium ylides with catalytic
carbene transfer process for this rearrangement, which is called Doyle-Kirmse reaction, further
enhance the practicability of this transformation.2,3 In a typical Doyle-Kirmse reaction, the α-
diazocarbonyl compound is catalyzed by Rh(II) or Cu(I) complex to generate a metal carbene
species, which reacts with allyl or propargyl sulfide to form ylide intermediate for the subsequent
[
2,3]-sigmatropic rearrangement. Since a chiral center containing C-S bond is generated in such
process, the corresponding asymmetric catalysis has been explored and significant progresses have
been made recently.4-6 For example, we have reported a highly enantioselective Doyle-Kirmse
5
a
reaction by employing allyl or propargyl trifluoromethyl sulfides. The reaction is served as an
3
efficient method for the construction of C(sp )-SCF
3
bonds bearing chiral centers.
On the other hand, thia-Sommelet-Hauser reaction is a unique type of [2,3]-sigmatropic
rearrangement of sulfonium ylides, in which an unsaturated aromatic ring is involved.7-11 While
the classic thia-Sommelet-Hauser reaction is performed under stoichiometric conditions, we have
previously developed a catalytic version of thia-Sommelet-Hauser reaction through Rh(II)-
1
0
catalyzed carbene transfer (Scheme 1a). We also attempted asymmetric variant of this reaction,
however, when Rh (S-DOSP) was used as the chiral Rh(II) catalyst, the reaction showed no
2
4
enantioselectivity.10a In connection to our continued interest in the asymmetric catalytic Doyle-
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Scheme 1. Transition-metal-catalyzed thia-Sommelet-Hauser rearrangement
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Kirmse reaction,4,5 we conceived to further explore the asymmetric catalytic thia-Sommelet-
Hauser reaction. The challenge to achieve high enantioselectivity in this type of reactions lies in
5
a
the fact the chiral metal catalyst is likely to dissociate from the ylide (Scheme 1b). Thus, the
enantiocontrol must be in the step of ylide generation from chiral metal carbene intermediate A,
in which the chiral metal carbene complex should differentiate the enantiotopic lone pair electrons
of the sulfur to generate metal-complexed sulfonium ylide intermediate B (Scheme 1b, the chiral
induction process). Dissociation of the chiral catalyst generates free sulfonium ylide C, which
bears chiral center on the sulfur. Subsequently, proton transfer occurs to form chiral ylide D, which
undergoes [2,3]-sigmatropic rearrangement via a five-membered envelope transition state to afford
3
the intermediate E, in which the chiral center is transferred from sulfur to the C(sp ) carbon of the
2
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newly formed C(sp )-C(sp ) bond. It is anticipated that catalytic asymmetric Sommelet-Hauser
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rearrangement is more arduous than the Doyle-Kirmse reaction, because a 1,3-proton transfer
process and a dearomatization rearrangement step are involved, which increases the possibility of
racemization of the active ylide intermediates and thus decrease the efficiency of chirality transfer.
While our research was ongoing, Feng and coworkers reported an asymmetric catalytic thia-
Sommelet-Hauser reaction with modest enantioselectivity. It is noteworthy that in their reaction a
pyrazole moiety in the diazo substrate is necessary for achieving both reactivity and stereocontrol
of the reaction. The chiral catalyst is proposed to be bonded to pyrazole group in the substrate to
form a “temporary chiral auxiliary”, which governs the stereoselectivity of the rearrangement
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process. We have conceived that a purely ligand-controlled approaches is desirable in order to
significantly expand the scope of the substrates. Herein, we demonstrate a chiral bisoxazoline/Cu(I)
complex-catalyzed asymmetric thia-Sommelet-Hauser rearrangement. This catalytic system can
be applied to a wide range of diazoester substrates, providing an efficient method to access chiral
sulfur-containing compounds bearing benzylic stereocenters.
RESULTS AND DISCUSSION
Inspired by our previous work on asymmetric catalytic Doyle-Kirmse reaction,5a chiral
bisoxazoline-Cu(I) complexes were chosen as the catalytic system for the study. With the diazo
compound 1a and sulfide 2a as the model substrates, we began to optimize the reaction conditions
(Table 1). Gratifyingly, almost no reaction occurred in the absence of a ligand (Table 1, entry 1),
which is consistent with our previous work10a and would be beneficial for asymmetric catalysis
controlled by chiral ligands. We reasoned that this might be attributed to the fact that sulfide could
poison the Cu(I) catalyst through complexation as a bidentate ligand and the resulted Cu(I)-sulfide
complex is inactive to catalyze the dinitrogen extrusion of the diazo substrate. Subsequently,
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several commercially available chiral oxazoline ligands L1 to L7 were evaluated. No reaction
occurred with ligand L1 and L2, while with ligand L3 the reaction afforded the desired product in
very low yield and with essentially no enantioselectivity.
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Subsequently, we observed that modest enantioselectivities could be achieved by employing
chiral ligand L4 to L7 (Table 1, entries 2-5). While the sterically encumbered L4 manifested better
stereochemical control, the catalytic activity of this ligand was unsatisfactory (Table 1, entry 2).
Replacing the tert-butyl group with phenyl group in the ligand improved the reactivity, with slight
erosion of the enantioselectivities (Table 1, entries 3-5). These results suggest that less bulky aryl
substituent may be favorable for achieving sufficient catalytic activity at 0 ℃. We thus envisaged
that ligands with spatially extended substituents on oxazoline rings may promote both the catalytic
activity and stereochemical induction. Bearing this in mind, we synthesized chiral ligand L8 and
L9 and investigated their performance in the model reaction. Although using L8 afforded the
similar enantioselectivity as L7, an improved yield was acquired (Table 1, entry 6). Gratifyingly,
high enantioselectivity and increased catalytic activity were observed with ligand L9 (Table 1,
entry 7). With this promising result, we next screened the molar ratio of the ligand and
Cu(MeCN)
4
PF
6
. To our surprise, we found that excess Cu(MeCN)
4
PF compared to ligand could
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increase the catalytic activity without compromising the enantioselectivity (Table 1, entries 7-10).
The reactivity enhancement effect was especially pronounced for the less reactive diazo substrate
1
g (Table 1, entries 11-12).
We also screened the sources of copper salts and observed that the reaction with neutral Cu(I)
showed poor catalytic activity and unfavorable enantioselectivity (for more details, see Supporting
Information). Cu(II) salts showed almost no catalytic activity, presumably due to the inefficacy of
reducing Cu(II) to the active Cu(I) by diazo substrate at 0 ℃. The cationic Cu(I) sources, especially
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Cu(MeCN)
4
PF
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, exhibited high enantioselectivity and reactivity. Further investigation of the effect
of solvent indicated that toluene afforded better results than other solvents, such as CH
2
Cl , THF
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and MeCN. The reactivity in n-hexane was poor due to the low solubility of the chiral
bisoxazoline-Cu complex.
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Table 1. Optimization of the reaction conditions
a
PF
(mol%) time (h) yield (%)b erc
entry ligand (mol%) Cu(MeCN)
4
6
1
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none
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traced
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--
L4 (2)
L5 (2)
L6 (2)
L7 (2)
L8 (2)
L9 (2)
L9 (2)
L9 (2.4)
L9 (3)
90:10
12:88
15:85
14:86
87:13
95:5
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70
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66
95:5
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66
95:5
10
65
95:5
1
1
1e L9 (2)
2e L9 (2)
72
87:13
83:17
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aUnless otherwise noted, the reactions were carried out with 1a (0.1 mmol) and 2a (1.0 equiv) in
b
c
PhMe (1 mL) under N
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at 0 ℃. Isolated yields. Determined by HPLC on a chiral stationary phase.
d
e
Both 1a and 2a remained. Reactions were carried out with 1g (0.1 mmol) and 2a (1.0 equiv).
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With the optimized reaction conditions in hand, we firstly explored the scope of diazo substrates
Scheme 2). The reaction with diazo arylacetates bearing various substituents on the aromatic rings
(
occurred smoothly with modest to high enantioselectivities. As expected, performing the reaction
with ent-L9 afforded the opposite enantiomer with same efficiency and opposite stereochemical
outcome (3a). Compared with diazo arylacetates 1a, substituents at ortho- or para-position of the
benzene rings had an obviously negative effect on the enantioselectivity (3b-g), but halogens and
electron-rich substituents at meta-position only showed a slight erosion of the enantioselectivities
in most cases (3h-m). We also noticed that replacing tert-butyl ester with methyl (3r) or ethyl (3s)
ester showed a slight decrease in enantioselectivities, whereas trifluoroethyl ester (3t) gave a
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noticeably diminished enantioselectivity, indicating that both the steric and electronic property of
ester group have impact on stereochemical control. On the other hand, electron-rich diazo
arylacetates showed high reactivities, and the reactions with these substrates were carried out at
lower temperature (3b, 3d and 3l). To our delight, functional groups such as halogens (3c, 3e-f,
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h-k and 3q), cyano (3o) and nitro (3p) group were all compatible, providing the possibilities for
further modification. For the meta-substituted substrates, all the rearrangements occurred at the
less sterically hindered ortho-position on the benzene rings.
Scheme 2. Substrate scope of the diazo acetatesa
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aThe reaction temperatures were justified to acquire appropriate reactivity. Reactions were
terminated when the color of the diazo compounds completely disappeared or the reaction time
reached 24 h.
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When the diazo arylacetate bearing two ortho substituents on the aromatic ring, the
corresponding reaction is expected to provide dearomatized product. Thus, tert-butyl 2-diazo-2-
(2,6-difluorophenyl)acetate was used as the substrate in the reaction. However, no reaction
o
occurred under the standard condition after 24 h. When the temperature was raised to 50 C, the
reaction resulted in a complex mixture. Besides, we also examined the reaction with diaryl
diazoalkanes. However, the diaryl diazoalkanes decomposed fast and only dimers of the diazo
compounds
were
obtained
under
the
standard
conditions
when
4,4'-
(diazomethylene)bis(chlorobenzene) were employed as the substrate. This result might be
attributed to the high reactivity of diaryl diazoalkanes toward copper complex under the standard
conditions.
Next, we examined the scope of sulfides. As summarized in Scheme 3, for most sulfides, modest
to high yields and high to excellent enantioselectivities were achieved. Notably, sulfides bearing
methyl or dimethyl groups at various position on the aromatic moiety afforded the corresponding
products with high yields and excellent enantioselectivities (4a, 4d, 4j and 4l-m). Additionally,
ethyl or bulky tert-butyl at the para-position to the C-S bond had a slightly unfavorable effect on
the enantioselectivity (4e-f). 2-Naphthyl or 1-naphthylsulfide also showed high
enantioselectivities (4n-o). These results implied that the reactions are insensitive to steric
hindrance of sulfides. However, the substituents bearing electronegative substituents such as
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halogens (4c, 4h, and 4k) and trifluoromethyl (4i) on the aromatic rings gave decreased
enantioselectivities, presumably attributed to the electronic repulsion in the corresponding
transition states. Moreover, sulfide with a thiophene ring provided a modest yield and
enantioselectivity (4p), which might be due to the coordination of the sulfur in thiophene to catalyst
and unfavorable stereoelectronic effect respectively. Finally, replacing ethyl ester with benzyl ester
afforded a similar enantioselectivity and yield (4q), while replacing ethyl ester with an amide
moiety reduced the reactivity and the reaction had to be performed at a higher temperature, albeit
with high yield and enantioselectivity (4r).
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Scheme 3. Substrate scope of the sulfidesa
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a
b
The reaction temperatures were justified to acquire appropriate reactivity. Reactions were
terminated when the color of the diazo compounds completely disappeared or the reaction time
reached 24 h.
To demonstrate the reaction efficiency and synthetic potential of this asymmetric rearrangement
process, a grame-scale experiment was conducted (Scheme 4). With reduced loading of
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Cu(MeCN)
4
PF
6
and chiral ligand ent-L9, 1a and 2a reacted smoothly to give 1.21 g of 5, with
comparably high yield and enantioselectivity. Furthermore, the product 5 was converted to diol 6
by reduction, and the absolute configuration of the carbon stereocenter of ent-3a was
unambiguously assigned as S according to the X-ray crystallographic analysis of 6 (for more
details, see Supporting Information).
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Scheme 4. Gram-scale experiment and absolute configuration determination
To gain insight into the mechanistic details of this asymmetric Sommelet-Hauser rearrangement,
several control experiments were carried out (Scheme 5). In order to determine whether the
rearrangement occurred via a free ylide process, we firstly tested the reaction of diazo arylacetates
1r and symmetric sulfide 7 under standard conditions (Scheme 5a). With several different chiral
bisoxazoline ligands, the corresponding product 8 was obtained with modest yields and uniformly
low enantioselectivities. The poor enantioselectivities are indicative of a free ylide process, which
is in line with our previous studies.4e,5a In such case, the free ylide is achiral because of the lack of
chirality on sulfur. This will inevitably lead to racemic final product according to the mechanism
shown in Scheme 1b. The low but not zero enantioselectivity of 8 in the presence of L9 might be
attributed to a weak coordination effect of the ylide intermediate to chiral copper catalyst (for more
details, see Supporting Information).
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Scheme 5. Control experiments for mechanistic study
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0
In addition, it is also interesting to compare the reactivity and enantioselectivity between the
Doyle-Kirmse reaction and the thia-Sommelet-Hauser rearrangement. Hence, the reaction of
sulfide 9 bearing an allyl group and diazoester 1a was tested and the product 10 was obtained in
high yield but with low enantioselectivity, where the rearrangement of the sulfonium ylide
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6
occurred at the allyl moiety (Scheme 5b). The product of thia-Sommelet-Hauser rearrangement,
in which additional 1,3-proton transfer process and an energy-demanding dearomatization step are
involved, was not observed. The results indicate that the Doyle-Kirmse reaction, in which direct
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[
2,3]-sigmatropic rearrangement is involved, is a more facile process as compared with the
corresponding thia-Sommelet-Hauser rearrangement. To further inspect the difference of chirality
transfer between these two rearrangements, we performed a control reaction of sulfide 11 and
diazoester 1a, where the Doyle-Kirmse reaction could not occur because of the lack of the allyl
group in the substrate (Scheme 5c). In this case, the thia-Sommelet-Hauser rearrangement occurred
with high yield. In accordance with our speculation, the enantioselectivity was essentially same as
the reaction of Scheme 5b. These results again support a free ylide mechanism shown in Scheme
1
b. Moreover, the poor enantioselectivities obtained in Scheme 5b and Scheme 5c reveal that the
aromatic ring in the sulfide is crucial for differentiating the enantiotopic lone pair electrons of
sulfur in the generation of chiral sulfonium ylide.
Furthermore, deuterium-labelling experiments were conducted to gain insights on the details of
proton transfer process. With deuterated sulfide D-2a (94% D) as the substrate, D-3a was obtained
with a decrease of deuterated contents (76% D, Scheme 5d), which is rationally attributed to the
deuteration of the trace water in the reaction system. Moreover, performing the reaction of 1a and
2
a in the presence of D
2
O (1.0 equiv) provided the product D-3a’ with a 36% deuterated ratio
(Scheme 5e). These results suggest that water is involved in the reaction and proton transfer is
possibly assisted by water through a six-membered cyclic transition state (vide infra). It is reasoned
that, under standard conditions, the proton transfer is facilitated by trace water from the reactant
and catalyst.11a We also noticed that, in the first deuterium-labelling experiment, the deuterated
1
content of H in the product D-3a decreased (D-2a: 94% vs D-3a: 86%, Scheme 5d), while in the
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second deuterium-labelling experiment the corresponding position in D-3a’ was 12% deuterated
(Scheme 5e). We attribute these results to the reversibility of the proton transfer process, otherwise
1
the deuterated content of H would be equal to the deuterated content of SCH
2
in sulfide. These
1
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observations are consistent with those reported by Feng and co-workers.11a
Next, we performed kinetic experiments with 1a and 2r through the ReactIR instrument (Figure
). While the infrared absorption of carbonyl of amide group in 4r is covered by the absorption of
1
same functional group in 2r (for more details, see Supporting Information, Figure S2), the infrared
absorption of carbonyl of ester group in 4r has no overlap with others and was selected to acquire
kinetic data. According to the initial rates based on several concentrations of 1a, 2r and catalyst,
we found that the reaction rate showed a first-order dependence on the concentration of diazo
substrate 1a and the chiral catalyst. This feature of kinetics indicates that the reaction of the diazo
substrate and the Cu(I) catalyst to form Cu(I) carbene is likely the rate-limiting step. On the
contrary, the reaction rate approximately showed a negative first-order dependence on the
concentration of sulfide 2r, implying that a pre-equilibrium between CuL* and sulfide 2r occurs
1
2
to generate an inactive complex CuL*∙2r. As a result, the sulfide 2r decreased the concentration
of the active catalyst CuL* and suppressed the decomposition of diazo substrate 1a, namely the
poisoning of the catalyst by substrate.
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0
.0007
.0006
.0005
.0004
0
.00050
.00045
0
y = 0.1792x + 0.000023
y = 0.00202x + 0.000027
2
R
= 0.9940
2
R
= 0.9956
0.00040
0.00035
0.00030
0.00025
0.00020
0.00015
0.00010
0.0003
0.00005
0.0002
0.0005
0.0010
0.0015
0.0020
0.0025
0.10
0.15
0.20
0.25
0.30
[
Cat] (mol/L)
[1a] (mol/L)
0.00040
0.00035
-1.17
y = 2.62E-5 x
0.00030
2
R
= 0.9730
0.00025
0.00020
0.00015
0.00010
0
.08 0.10 0.12 0.14 0.16 0.18 0.20 0.22 0.24 0.26
[2r] (mol/L)
-1
Figure 1. Kinetic experiments. ConcIRT Spectrum of the 4r with peak at 1730 cm was
selected to acquire kinetic data
Applying steady state approximation to the proposed reaction process (Scheme 6a) and
*
considering the function relationship between the concentration of active complex CuL and the
added catalyst (Scheme 6e), we have derived a theoretical kinetic equation of this reaction (Scheme
6
f, for more details, see Supporting Information), which is in line with the kinetic characteristics
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obtained from the experimental results shown in Figure 1. Among the various coordination
equilibria of the reaction components (Scheme 6b, 6c), we speculate that the coordinatively
*
unsaturated copper species Cu or Cu∙S accelerate the dissociation of the sulfide 2r from CuL ∙S
1
1
1
1
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to regenerate the active catalyst CuL* (Scheme 6d), which may explain why excess copper salt
could increase the reaction rate (Table 1, entries 7-12).
Scheme 6. The kinetic equations and the coordination equilibria among copper salt, ligand
and sulfide
Based on the above experiments and our previous study on catalytic asymmetric Doyle-Kirmse
5
a
reaction, a stereochemical model for this catalytic asymmetric Sommelet-Hauser rearrangement
is proposed (Scheme 7). It is noteworthy that both ester group and substituent on aromatic rings of
the diazo substrate have effects on the enantioselectivities. We thus propose that the sulfide may
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attack the carbenic carbon from top right or bottom left in consideration of the steric hindrance of
the C -symmetric (S,S)-bisoxazoline ligand. The pathways in which sulfide attack the carbenic
2
carbon with its pro-S lone pair electrons may be disfavored because of the electronic repulsion
interactions between the ester moiety in sulfide and the oxazoline rings in ligand (Model A). On
the contrary, when sulfide attacks the carbenic carbon with its pro-R lone pair electrons (Model
B), the disfavored electronic repulsion interactions are avoided. Moreover, attractive π-π
interactions between the aromatic moiety in the sulfide and the triphenyl scaffold in the ligand may
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13
exist, which could possibly provide stabilization for the corresponding transition state. As a result,
free sulfonium ylide C with S configuration at sulfur center is generated, followed by the
diastereoselective proton transfer through a water-involved six-membered chair-like transition
14
state TS1. The resulted free ylide D further undergoes thia-Sommelet-Hauser rearrangement via
15
transition state TS2, where the carbanion attacks the aromatic ring with its si-face, affording the
major enantiomer with R configuration at the newly formed carbon stereocenter.
Scheme 7. Stereochemical model for the asymmetric induction
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CONCLUSION
In summary, we have developed a Cu(I)/chiral bisoxazoline-catalyzed asymmetric thia-
Sommelet-Hauser rearrangement in which reactions occur under mild conditions with modest to
high yield and with good to excellent enantioselectivities. The reaction provides a unique way to
construct chiral sulfur-containing compounds. Contrasting the previous studies on the related
asymmetric [2,3]-sigmatropic rearrangement of sulfonium ylides in which a pyrazole auxiliary is
required in the substrates, this reaction represents a different strategy for achieving asymmetric
catalysis in this type of sulfonium ylide rearrangement, in which the enantiotopic lone pair
electrons of sulfur are successfully discriminated by the chiral Cu(I) catalyst bearing a newly
designed chiral bisoxazoline ligand.
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EXPERIMENTAL SECTION
General methods. All the reactions were performed with a dried reaction tube. All solvents
were distilled under nitrogen atmosphere prior to use. Toluene was distilled over Na. For
chromatography, 200-300 mesh silica gel was employed. Cu(CH
3
CN)
4
PF
6
was purchased from
1
13
Energy Chemical and some chiral ligands were purchased from Daicel. H and C NMR spectra
1
9
were recorded at 400 MHz and 101 MHz with Brucker ARX 400 spectrometer. F NMR was
recorded at 471 MHz with Brucker ARX 500. Chemical shifts are reported in ppm using
1
tetramethylsilane (0) as internal standard when using CDCl
3
or CD
3
OD as solvent for H NMR
1
3
spectra. For C NMR spectra, CDCl
3
(or CD
3
OD) was used as the internal standard with chemical
was used as the reference with
19
shift at 77.16 ppm (or 49.00 ppm). For F NMR spectra, CFCl
3
chemical shift at 0 ppm. The data for NMR spectra were reported as following: chemical shifts (δ)
were reported in ppm, and coupling constants (J) were reported in Hertz (Hz). The following
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6
abbreviations were used to symbolize the multiplicities: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet. HRMS was detected through Bruker Solarix XR FTMS by ESI. Optical
rotations were measured with JH-P300 Polarimeter (Shanghai Precious Instrument).
Enantioselectivities were measured with HPLC (Agilent Technologies 1200 series) with Daicel
chiral column, eluted with n-hexane and isopropanol. The low temperature was controlled by
model DHJF-8002 cryostat, whose error range is -4 ℃ to +2 ℃.
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6
All the diazo compounds were prepared according to the reported literature. All the sulfides
17
were prepared according to the reported literature. The new ligands L8 and L9 were synthesized
following literature procedure.18
Preparation of 3,5-diphenylphenylmagnesium bromide
A 100 mL Schlenk tube equipped with a stirring bar was charged with Mg (291.7 mg, 12.00
mmol, 2.0 equiv). The sealed tube was evacuated and refilled with nitrogen three times, then a
solution of 3,5-diphenylbromobenzene (100 mg), small portion of I and 1,2-dibromoethane (50
2
μL) in anhydrous THF (0.5 mL) was added. The resulted mixture was heated until the dark yellow
was faded. Then the solution of 3, 5-diphenylbromobenzene (2782.8 mg, 9.00 mmol, 1.5 equiv) in
3
0 mL anhydrous mixed solvent (THF: ether = 1:5) was added, and the reaction system was
allowed to stirred at 45 ℃ for 3 h. When the reaction was completed, the red system was allowed
to cool to room temperature (the mixture separated into two layers after standing, both the layers
were added into the solution of imine 13, vide infra).
Preparation of 3,5-di-tert-butylphenylmagnesium bromide
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A 100 mL Schlenk tube equipped with a stirring bar was charged with Mg (291.7 mg, 12.00
mmol, 3.0 equiv). The sealed tube was evacuated and refilled with nitrogen three times, then a
1
1
1
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1
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1
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solution of 3,5-tert-butylbromobenzene (100 mg), small portion of I and 1,2-dibromoethane (50
2
μL) in anhydrous THF (0.5 mL) was added. The resulted mixture was heated until the dark yellow
was faded. Then the solution of 3,5-tert-butylbromobenzene (2153.8 mg, 8.00 mmol, 2.0 equiv)
in 20 mL anhydrous ether was added, and the reaction system was allowed to stirred at 45 ℃ for
3
h. When the reaction was completed, the yellow system was allowed to cool to room temperature
Preparation
of
(S)-N-((S)-1-([1,1':3',1''-terphenyl]-5'-yl)-2-((4-
methoxybenzyl)oxy)ethyl)-2-methylpropane-2-sulfinamide (14)
The prepared solution of 3, 5-diphenylphenylmagnesium bromide was added to a solution of
imine 13 (1700.3 mg, 6.00 mmol, 1.0 equiv) in toluene (30 mL, 0.2 M) at -78 ℃ under nitrogen
atmosphere. The mixture was stirred at -78 ℃ for 2 h, then the reaction system was allowed to
warm to 0 ℃ and quenched with saturated ammonium chloride solution. The mixture was
extracted with ether three times, then the combined organic layers were dried over anhydrous
Na
2
SO . The solvent was removed under reduced pressure and the residue was purified via column
4
chromatography on silica gel (eluents: petroleum ether/ethyl acetate = 5:1−2:1) to afford the
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desired product 14 as white solid (the diastereoisomers can be distinguished by silica gel). Note:
although part of product was mixed with small amount of its diastereoisomer, high diastereomeric
ratio (>20:1) can be obtained after the recrystallization in petroleum ether/ethyl acetate. Product
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1
2
3
4
5
6
7
8
9
0
1
1
7
6
4: White solid, mp = 110-112 ℃. H NMR (400 MHz, CDCl
3
) δ: 7.73 (t, J = 1.8 Hz, 1H), 7.62–
.58 (m, 4H), 7.53 (d, J = 1.8 Hz, 2H), 7.48–7.43 (m, 4H), 7.40–7.34 (m, 2H), 7.29–7.23 (m, 2H),
.89–6.84 (m, 2H), 4.83 (ddd, J = 9.2, 4.0, 1.9 Hz, 1H), 4.58 (d, J = 11.6 Hz, 1H), 4.47 (d, J = 11.6
Hz, 1H), 4.27 (d, J = 1.9 Hz, 1H), 3.79 (s, 3H), 3.71 (dd, J = 10.0, 4.0 Hz, 1H), 3.63 (t, J = 9.5 Hz,
13
1
1
H), 1.27 (s, 9H). C{1H} NMR (101 MHz, CDCl
3
) δ: 159.5, 142.2, 141.0, 140.0, 129.8, 129.7,
29.0, 127.7, 127.3, 126.0, 125.9, 114.0, 73.9, 72.5, 57.5, 55.7, 55.4, 22.8. HRMS (ESI, m/z): calcd
+
for C32
H36NO
3
S [M+H] : 514.2410, found: 514.2415.
Preparation of (S)-N-((S)-1-(3,5-di-tert-butylphenyl)-2-((4-methoxybenzyl)oxy)ethyl)-2-
methylpropane-2-sulfinamide (15)
The prepared solution of 3, 5-di-tert-butylphenylmagnesium bromide was added to a solution
of imine 13 (1133.6 mg, 4.00 mmol, 1.0 equiv) in toluene (20 mL, 0.2 M) at -78 ℃ under nitrogen
atmosphere. The mixture was stirred at -78 ℃ for 2 h, then the reaction system was allowed to
warm to 0 ℃ and quenched with saturated ammonium chloride solution. The mixture was
extracted with ether three times, then the combined organic layers were dried over anhydrous
Na
2
SO . The solvent was removed under reduced pressure and the residue was purified via column
4
chromatography on silica gel (eluents: petroleum ether/ethyl acetate = 4:1−2:1) to afford the
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desired product 15 as pale-yellow oil (almost a single diastereoisomer, dr>20:1). H NMR (400
MHz, CDCl ) δ: 7.33 (t, J = 1.8 Hz, 1H), 7.29–7.27 (m, 1H), 7.27–7.24 (m, 1H), 7.15 (d, J = 1.8
Hz, 2H), 6.91–6.85 (m, 2H), 4.70 (ddd, J = 9.8, 4.0, 1.5 Hz, 1H), 4.57 (d, J = 11.5 Hz, 1H), 4.46
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
d, J = 11.5 Hz, 1H), 4.18 (d, J = 1.5 Hz, 1H), 3.81 (s, 3H), 3.62 (dd, J = 10.0, 4.0 Hz, 1H), 3.52
1
3
(
t, J = 9.9 Hz, 1H), 1.30 (s, 18H), 1.23 (s, 9H). C{1H} NMR (101 MHz, CDCl
3
) δ: 159.4, 150.8,
1
37.8, 129.9, 129.6, 122.2, 122.1, 113.9, 74.3, 72.4, 57.6, 55.5, 55.4, 35.0, 31.6, 22.7. HRMS (ESI,
+
m/z): calcd for C28
H
44NO S [M+H] : 474.3036, found: 474.3035.
3
Preparation of amino alcohol 16 and 17
To the solution of 14 (or 15) (2.50 mmol) in methanol (5mL, 0.5 M) was added the 4 N HCl
(
25 mL), then the mixture was allowed to stir at room temperature for 16 h. After the reaction was
completed, the mixture was cooled to 0 ℃ and neutralized by a solution of NaOH in water until
the mixture was weak basic. Ether was added, and the organic layer was separated from the mixture
via separating funnel. The water layer was extracted with ether three times and the combined
organic layers were dried over anhydrous Na
2
SO . The solvent was removed under reduced
4
pressure and the residue was purified via column chromatography on silica gel (eluents:
dichloromethane /methanol = 50:1−10:1) to afford the desired product 16 (or 17) as white solid.
(S)-2-([1,1':3',1''-Terphenyl]-5'-yl)-2-aminoethan-1-ol (16). White solid, mp = 141-143 ℃.
1H NMR (400 MHz, CD
OD) δ: 7.72 (t, J = 1.7 Hz, 1H), 7.72–7.64 (m, 4H), 7.61 (d, J = 1.7 Hz,
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
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5
6
2
H), 7.48–7.41 (m, 4H), 7.37–7.32 (m, 2H), 4.87 (s, 3H), 4.09 (dd, J = 7.6, 4.9 Hz, 1H), 3.79 (dd,
1
3
J = 10.9, 4.9 Hz, 1H), 3.66 (dd, J = 10.9, 7.6 Hz, 1H). C{1H} (101 MHz, CD OD) δ: 144.8,
3
143.3, 142.4, 129.9, 128.5, 128.2, 125.8, 68.9, 58.9. HRMS (ESI, m/z): calcd for C20
H20NO
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
[
M+H] : 290.1539, found: 290.1537.
1
(
S)-2-Amino-2-(3,5-di-tert-butylphenyl)ethan-1-ol (17). White solid, mp = 98-100 ℃. H
NMR (400 MHz, CDCl
3
) δ: 7.36 (t, J = 1.8 Hz, 1H), 7.17 (d, J = 1.8 Hz, 2H), 4.06 (dd, J = 8.5,
4
1
.4 Hz, 1H), 3.76 (dd, J = 10.7, 4.4 Hz, 1H), 3.58 (dd, J = 10.7, 8.5 Hz, 1H), 1.93 (s, 3H), 1.33 (s,
13
8H). C{1H} (101 MHz, CD
3
OD) δ: 151.2, 141.7, 121.8, 120.7, 68.2, 58.1, 35.0, 31.6. HRMS
+
(ESI, m/z): calcd for C16
H
27NO [M+H] : 250.2165, found: 250.2165.
Preparation of L8 and L9
To a solution of 1,3-dihydro-2H-indene-2,2-dicarboxylic acid (206.2 mg, 1.0 mmol) in DCM
5 mL,0.2 M) was added oxalyl chloride (186 μL 2.2 equiv) at 0 ℃, then DMF (cat., 1 drop) was
(
added. The mixture was allowed to stirred at 0 ℃ for 10 min, then the reaction system was stirred
at 45 ℃ for 2 h. solvent and excess oxalyl chloride were removed under reduced pressure. The
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dicarbonyl dichloride was re-dissolved in DCM (5 mL, 0.2 M) and added dropwise to a suspension
of amino alcohol (2.0 equiv) and triethylamine (695 μL 5.0 equiv) in DCM (15 mL, 0.13 M) at 0 ℃
for 30 min, then the reaction was stirred at room temperature for 12 h. Water was added, and the
organic layer was separated from the mixture via separating funnel. The water layer was extracted
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
with DCM two times and the combined organic layers were dried over anhydrous Na
2
SO . The
4
solvent was removed under reduced pressure to afford the crude amide. To the suspension (or
solution) of the crude amide, DMAP (12.2 mg, 10 mol%) and triethylamine (611 μL 4.4 equiv) in
DCM (10 mL, 0.1 M) was added dropwise a solution of TsCl (419.4mg, 2.2 equiv) in DCM (11
mL, 0.2 M) at room temperature for 30 min. The reaction was stirred at room temperature for more
12 h. The solvent was removed under reduced pressure and the residue was purified via column
chromatography on silica gel (eluents: petroleum ether/ethyl acetate = 20:1−10:1 for L8;
petroleum ether/ethyl acetate = 5:1−3:1 for L9) to afford the desired chiral ligand as white solid.
(4S,4'S)-2,2'-(2,3-Dihydro-1H-indene-2,2-diyl)bis(4-(3,5-di-tert-butylphenyl)-4,5-
21
dihydrooxazole) (L8). White solid. Mp: 79-81 ℃. Yield: 480.6mg, 76%. []
D
= -92.9 (c = 1.0
1
in HCCl
3
). H NMR (400 MHz, CDCl
3
) δ: 7.30 (t, J = 1.8 Hz, 2H), 7.25–7.21 (m, 2H), 7.19–7.13
(m, 2H), 7.02 (d, J = 1.8 Hz, 4H), 5.18 (dd, J = 10.1, 7.1 Hz, 2H), 4.68 (dd, J = 10.1, 8.3 Hz, 2H),
.25 (dd, J = 8.3, 7.1 Hz, 2H), 3.89 (d, J = 16.2 Hz, 2H), 3.77 (d, J = 16.2 Hz, 2H), 1.25 (s, 36H).
4
13C{1H} NMR (101 MHz, CDCl
) δ: 168.7, 151.1, 141.7, 140.6, 127.0, 124.5, 121.8, 121.1, 76.4,
3
+
70.3, 49.3, 42.0, 35.0, 31.6. HRMS (ESI, m/z): calcd for C43
33.4413.
-)-(4S,4'S)-2,2'-(2,3-Dihydro-1H-indene-2,2-diyl)bis(4-([1,1':3',1''-terphenyl]-5'-yl)-4,5-
H
57
N
2
O
2
[M+H] : 633.4415, found:
6
(
2
1
dihydrooxazole) (L9). White solid. Mp: 98-101 ℃. Yield: 634.5 mg, 89%. []
D
= -82.0 (c = 1.0
1
in HCCl
3
). H NMR (400 MHz, CDCl
3
) δ: 7.67 (t, J = 1.7 Hz, 2H), 7.57–7.51 (m, 8H), 7.42–7.36
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1
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2
2
2
2
2
2
2
2
2
2
3
3
3
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3
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(
m, 12H), 7.36–7.30 (m, 4H), 7.28–7.23 (m, 2H), 7.20–7.15 (m, 2H), 5.34 (dd, J = 10.0, 6.9 Hz,
2
H), 4.71 (t, J = 10.0, 8.4 Hz, 2H), 4.23 (dd, J = 8.4, 6.9 Hz, 2H), 3.92 (d, J = 16.2 Hz, 2H), 3.81
1
3
(d, J = 16.2 Hz, 2H). C{1H} NMR (101 MHz, CDCl
3
) δ: 169.2, 143.6, 142.4, 141.1, 140.5, 128.9,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
27.6, 127.4, 127.4, 127.0, 125.6, 124.5, 76.1, 69.8, 49.7, 41.9. HRMS (ESI, m/z): calcd for
+
C
51
H
41
N
2
O
2
[M+H] : 713.3163, found: 713.3164.
General Procedures for the thia-Sommelet-Hauser rearrangement. A 10 mL Schlenk
tube equipped with a stirring bar was charged with Cu(MeCN) PF (2.2 mg, 3 mol%) and the
4
6
Ligand L9 (2 mol%). The sealed tube was evacuated and refilled with nitrogen for five times. Then
toluene (2 mL, 0.1 M) was added and the mixture was stirred at room temperature for 1 h. Sulfide
(0.2 mmol, 1.0 equiv) was added and the mixture was stirred at room temperature for another10
min. Then the reaction tube was put into cryostat with the preset temperature. After 10 min, the
diazo compound (0.2 mmol, 1.0 equiv) was added to the reaction tube and the color of reaction
system turned to yellow. The reaction was terminated when the yellow color completely
disappeared or the reaction time reached 24 h. The reaction mixture was filtered through a short
path of silica gel and eluted with ethyl acetate, then the filtrate was evaporated in vacuo to remove
the solvent. The residue was purified by preparative thin layer chromatography on silica gel
(300−400 mesh) using petroleum ether/ethyl acetate (20:1) as eluting solvent to afford the desired
product. The corresponding racemic products were prepared with Rh (OOCF -catalyzed reaction
2
)
3 4
in toluene at room temperature. The er values were determined by HPLC on a chiral stationary
phase.
Procedures for Gram-scale experiment. Procedure: A 100 mL Schlenk tube equipped with a
stirring bar was charged with Cu(MeCN)
4
PF (22.4 mg, 1.5 mol%) and ent-L9 (28.5mg, 1.0 mol%).
6
The sealed tube was evacuated and refilled with nitrogen five times. Then toluene (40 mL, 0.1 M)
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was added and the mixture was stirred at room temperature for 1 h. Sulfide 2a (780.5 mg, 4.0
mmol, 1.0 equiv) was added and the mixture was stirred at room temperature for more 10 min.
Then the reaction tube was put into cryostat (0 ℃). After 10 min, the diazo compound 1a (873.0
mg, 4.0 mmol, 1.0 equiv) was added to the reaction tube and the mixture was allowed to stirred at
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
℃ for 30 h. The reaction mixture was filtered through a short path of silica gel and eluted with
ethyl acetate, then the filtrate was evaporated in vacuo to remove the solvent. The residue was
purified by column chromatography on silica gel (200-300 mesh) using petroleum ether/ethyl
acetate (20:1) as eluting solvent to afford the desired product 5 (1207.1mg, 81%) as a colorless oil.
(-)-Ethyl 2-(2-(2-(tert-butoxy)-2-oxoethyl)phenyl)-2-(phenylthio)acetate (3a). Reaction time: 16
h. Reaction temperature: 0 ℃. Yield: 58.0 mg, 75%, colorless oil. 95:5 er, HPLC conditions:
27
Daicel chiral column AD-H, isopropanol/hexane = 1:50, flow: 1.0 mL/min, λ = 210 nm. []
D
=
1
-
30.1 (c = 1.0 in HCCl
3
). H NMR (400 MHz, CDCl
3
) δ: 7.62–7.56 (m, 1H), 7.47–7.40 (m, 2H),
7.31–7.21 (m, 6H), 5.26 (s, 1H), 4.22–3.96 (m, 2H), 3.70 (d, J = 15.3 Hz, 1H), 3.61 (d, J = 15.3
13
Hz, 1H), 1.41 (s, 9H), 1.12 (t, J = 7.2 Hz, 3H). C{1H} NMR (101 MHz, CDCl
3
) δ: 170.7, 170.4,
1
34.1, 133.9, 133.5, 132.7, 131.3, 129.1, 128.9, 128.5, 128.1, 127.8, 81.4, 61.8, 52.5, 40.4, 28.1,
+
14.1. HRMS (ESI, m/z): calcd for C22
H
27
O S [M+H] : 387.1625, found: 387.1622.
4
(-)-Ethyl
2-(2-(2-(tert-butoxy)-2-oxoethyl)-3-methylphenyl)-2-(phenylthio)acetate
(3b).
Reaction time: 24 h. Reaction temperature: -10 ℃. Yield: 68.1 mg, 85%, colorless oil. 90:10 er,
HPLC conditions: Daicel chiral column AD-H, isopropanol/hexane = 1:100, flow: 0.5 mL/min, λ
28
1
=
210 nm. []
D
= -35.3 (c = 1.0 in HCCl
3
). H NMR (400 MHz, CDCl ) δ: 7.47–7.43 (m, 2H),
3
7
.41 (t, J = 4.6 Hz, 1H), 7.31–7.22 (m, 3H), 7.18–7.11 (m, 2H), 5.32 (s, 1H), 4.19–3.99 (m, 2H),
1
3
3.75 (s, 2H), 2.38 (s, 3H), 1.41 (s, 9H), 1.12 (t, J = 7.1 Hz, 3H). C{1H} NMR (101 MHz, CDCl )
3
δ: 170.9, 170.2, 138.3, 134.5, 134.2, 132.3, 132.3, 130.6, 129.1, 127.9, 127.4, 126.5, 81.3, 61.8,
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
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4
4
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4
5
5
5
5
5
5
5
5
5
5
6
+
5
3.0, 36.4, 28.1, 20.8, 14.1. HRMS (ESI, m/z): calcd for C23
H
29
O S [M+H] : 401.1781, found:
4
4
01.1775.
(-)-Ethyl
2-(2-(2-(tert-butoxy)-2-oxoethyl)-3-fluorophenyl)-2-(phenylthio)acetate
(3c).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Reaction time: 24 h. Reaction temperature: 0 ℃. Yield: 61.5 mg, 76%, colorless oil. 85:15 er,
HPLC conditions: Daicel chiral column AD-H, isopropanol/hexane = 1:50, flow: 1.0 mL/min, λ =
2
6
1
210 nm. []
d, J = 7.8 Hz, 1H), 7.30–7.25 (m, 3H), 7.22 (td, J = 8.0, 5.8 Hz, 1H), 7.07–6.99 (m, 1H), 5.11 (s,
H), 4.20–4.03 (m, 2H), 3.78 (dd, J = 16.4, 1.7 Hz, 1H), 3.69 (dd, J = 16.4, 2.0 Hz, 1H), 1.42 (s,
D
= -26.6 (c = 1.0 in HCCl
3
). H NMR (400 MHz, CDCl
3
) δ: 7.47–7.38 (m, 2H), 7.36
(
1
1
3
9H), 1.14 (t, J = 7.1 Hz, 3H). C{1H} NMR (101 MHz, CDCl
3
) δ: 170.2, 169.4, 161.4 (d, J =
2
3
=
46.5 Hz), 136.4 (d, J = 3.5 Hz), 133.5, 133.1, 129.1, 128.7 (d, J = 9.1 Hz), 128.4, 124.6 (d, J =
.3 Hz), 121.5 (d, J = 16.2 Hz), 115.3 (d, J = 22.9 Hz), 81.5, 62.0, 52.8 (d, J = 2.7 Hz), 32.4 (d, J
19
4.6 Hz), 28.1, 14.1. F NMR (471 MHz, CDCl ) δ: -114.6 (t, J = 7.8 Hz). HRMS (ESI, m/z):
3
+
calcd for C22
-)-Ethyl
H26FO
4
S [M+H] : 405.1530, found: 405.1524.
(
2-(2-(2-(tert-butoxy)-2-oxoethyl)-5-methylphenyl)-2-(phenylthio)acetate
(3d).
Reaction time: 24 h. Reaction temperature: -20 ℃. Yield: 50.1 mg, 63%, colorless oil. 93:7 er,
HPLC conditions: Daicel chiral column AD-H, isopropanol/hexane = 1:50, flow: 1.0 mL/min, λ =
28
1
2
10 nm. []
D
= -38.9 (c = 1.0 in HCCl
3
). H NMR (400 MHz, CDCl
3
) δ: 7.49–7.41 (m, 2H), 7.39
(
s, 1H), 7.33–7.21 (m, 3H), 7.13 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 5.23 (s, 1H), 4.20–
4.01 (m, 2H), 3.66 (d, J = 15.3 Hz, 1H), 3.58 (d, J = 15.3 Hz, 1H), 2.30 (s, 3H), 1.41 (s, 9H), 1.12
13
(t, J = 7.1 Hz, 3H). C{1H} NMR (101 MHz, CDCl
3
) δ: 170.8, 170.6, 137.6, 134.3, 133.5, 132.5,
1
31.2, 130.4, 129.4, 129.0, 128.0, 81.2, 61.8, 52.4, 40.0, 28.1, 21.2, 14.1. HRMS (ESI, m/z): calcd
+
for C23
H
29
O S [M+H] : 401.1781, found: 401.1780.
4
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Page 29 of 50
The Journal of Organic Chemistry
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(
-)-Ethyl
2-(2-(2-(tert-butoxy)-2-oxoethyl)-5-chlorophenyl)-2-(phenylthio)acetate
(3e).
Reaction time: 20 h. Reaction temperature: 0 ℃. Yield: 57.4 mg, 68%, colorless oil. 91:9 er, HPLC
conditions: Daicel chiral column AD-H, isopropanol/hexane = 1:100, flow: 1.0 mL/min, λ = 210
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nm. []
D
= -33.1 (c = 1.0 in HCCl
3
). H NMR (400 MHz, CDCl
3
) δ: 7.61 (d, J = 2.2 Hz, 1H),
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.46–7.39 (m, 2H), 7.33–7.26 (m, 3H), 7.23 (dd, J = 8.2, 2.2 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H),
5.16 (s, 1H), 4.21–4.03 (m, 2H), 3.63 (d, J = 15.5 Hz, 1H), 3.55 (d, J = 15.5 Hz, 1H), 1.41 (s, 9H),
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.14 (t, J = 7.1 Hz, 3H). C{1H} NMR (101 MHz, CDCl
3
) δ: 170.1, 169.9, 135.9, 133.6, 133.3,
33.2, 132.5, 132.0, 129.1, 128.6, 128.5, 81.6, 62.0, 52.1, 39.8, 28.1, 14.1. HRMS (ESI, m/z): calcd.
+
for C22
H26ClO
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S [M+H] : 421.1235, found: 421.1235.
(-)-Ethyl 2-(2-(2-(tert-butoxy)-2-oxoethyl)-5-fluorophenyl)-2-(phenylthio)acetate (3f). Reaction
time: 12 h. Reaction temperature: 0 ℃. Yield: 53.1 mg, 66%, colorless oil. 89:11 er, HPLC
conditions: Daicel chiral column AD-H, isopropanol/hexane = 1:50, flow: 1.0 mL/min, λ = 210
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nm. []
dd, J = 10.1, 2.8 Hz, 1H), 7.32–7.26 (m, 3H), 7.20 (dd, J = 8.5, 5.8 Hz, 1H), 6.96 (td, J = 8.2, 2.8
Hz, 1H), 5.17 (d, J = 1.0 Hz, 1H), 4.20–4.04 (m, 2H), 3.63 (d, J = 15.6 Hz, 1H), 3.56 (d, J = 15.6
D
= -11.8 (c = 1.0 in HCCl
3
). H NMR (400 MHz, CDCl
3
) δ: 7.46–7.40 (m, 2H), 7.37
(
1
3
Hz, 1H), 1.41 (s, 9H), 1.14 (t, J = 7.1 Hz, 3H). C{1H} NMR (101 MHz, CDCl
3
) δ: 170.2 (d, J =
.4 Hz), 170.2, 162.0 (d, J = 246.2 Hz), 136.1 (d, J = 7.7 Hz), 133.4, 133.1, 132.7 (d, J = 8.2 Hz),
29.3 (d, J = 3.4 Hz), 129.1, 128.4, 116.1 (d, J = 23.6 Hz), 115.4 (d, J = 21.3 Hz), 81.5, 62.0, 52.2
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(d, J = 1.5 Hz), 39.6, 28.1, 14.1. F NMR (471 MHz, CDCl ) δ: -104.20 – -123.09 (m). HRMS
3
+
(
ESI, m/z): calcd for C22
H
26FO
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S [M+H] : 405.1530, found: 405.1532.
(-)-Ethyl
2-(2-(2-(tert-butoxy)-2-oxoethyl)-5-(trifluoromethyl)phenyl)-2-(phenylthio)acetate
(3g). Reaction time: 24 h. Reaction temperature: 0 ℃. Yield: 67.5 mg, 74%, colorless oil. 87:13
er, HPLC conditions: Daicel chiral column AD-H, isopropanol/hexane = 5:95, flow: 0.3 mL/min,
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