Catalytic asymmetric 1,6-michael addition of arylthiols to 3-methyl-4-nitro-5-alkenyl-isoxazoles with bifunctional catalysts

Article abstract of DOI:10.1021/jo2012779

(Figure presented) An enantioselective 1,6-Michael addition reaction of arylthiols to a wide range of 3-methyl-4-nitro-5-alkenyl-isoxazoles catalyzed by readily available Takemoto's thiourea catalyst has been developed. This reaction provides a useful cat

Full text of DOI:10.1021/jo2012779

ARTICLE
pubs.acs.org/joc
Catalytic Asymmetric 1,6-Michael Addition of Arylthiols to
3-Methyl-4-nitro-5-alkenyl-isoxazoles with Bifunctional Catalysts
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||
Qing-Lan Pei,†, Hong-Wei Sun,†, Zhi-Jun Wu,‡ Xi-Lin Du,§ Xiao-Mei Zhang,† and Wei-Cheng Yuan*,†
†National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences,
Chengdu 610041, China
‡Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
§Department of General Surgery, TangDu Hospital, The Fourth Military Medical University, Xi’an 710038, China
Graduate School of Chinese Academy of Sciences, Beijing, 100049, China
S Supporting Information
b
ABSTRACT:
An enantioselective 1,6-Michael addition reaction of arylthiols to a wide range of 3-methyl-4-nitro-5-alkenyl-isoxazoles catalyzed by
readily available Takemoto’s thiourea catalyst has been developed. This reaction provides a useful catalytic method for the synthesis
of optically active chiral sulfur compounds bearing a 4-nitroisoxazol-5-yl moiety in high to excellent yields (up to 97%) and high
enantioselectivities (up to 91% ee). Significantly, the potential utilities of the protocol had been further demonstrated by gram-scale
reaction and the versatile conversions of some resulting products into other functionalized and useful compounds.
’ INTRODUCTION
contrast, we are not aware of any method for catalytic enantio-
selective δ addition (1,6-Michael addition) of sulfur nucleophiles
to electro-deficient olefins.8 Accordingly, the development of
efficient synthetic protocols for the 1,6-Michael addition of thiols
to new electro-deficient Michael acceptors is highly desirable and
particularly attractive.
As part of our research program relevant to the develop-
ment of synthetic methods with asymmetric organocatalysis,9
we recently developed a simple and efficient method for the
enantioselective 1,6-Michael addition reaction of anthrone to
a series of 3-methyl-4-nitro-5-alkenyl-isoxazoles with a bi-
functional thiourea-tertiary amine as catalyst.9i 3-Methyl-4-
nitro-5-alkenyl-isoxazoles, developed by Adamo and co-
workers,10 are able to be regarded as cinnamate equivalents
that show high reactivity toward stabilized nucleophiles.8,9i,11
Therefore, we take two facts into consideration: one is that
3-methyl-4-nitro-5-alkenyl-isoxazole compounds are very
The optically active chiral thiols and sulfides are a key
structural feature of several classes of pharmaceuticals and natural
products and are extremely versatile building blocks that can
undergo synthetically useful transformations,1 as well as have
very important applications in asymmetric synthesis serving as
ligands for metal-based catalysts,2 as catalysts themselves,3 and as
chiral auxiliaries.3a,4 The catalytic asymmetric sulfa-Michael
addition of thiols to electro-deficient olefins represents a straight-
forward and versatile approach toward such valuable optically
active sulfur-containing compounds.5 As a consequence of this,
many different catalytic enantioselective versions of this funda-
mental transformation have been reported, which use metal-
based chiral complex catalysts or organocatalysts.6,7 However, to
the best of our knowledge, the Michael acceptors have generally
been limited to nitroolefins, enones, α,β-unsaturated aldehydes,
α,β-unsaturated ketones, and carboxylic acid derivatives among
all the reported methods. Moreover, the reported methods have
also mainly focused on the conjugate addition of thiols to the β
position (1,4-Michael addition) of electro-deficient olefins. In
Received: June 16, 2011
Published: August 30, 2011
r
2011 American Chemical Society
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Scheme 1. Strategy of Bifunctional Thiourea-tertiary Amine
Catalyzed 1,6-Michael Additions of Sulfur Nucleophiles to
3-Methyl-4-nitro-5-alkenyl-isoxazoles
bifunctional thiourea-tertiary amine catalysts 1bÀk with di-
versely structured scaffold were further investigated under the
same reaction conditions (Table 1, entries 4À13).16 It was
found that the thiourea catalysts 1aÀc and 1g derived from
cyclohexane-diamine showed high catalytic activity but poor
stereochemical induction with 1bÀc and 1g (Table 1, entries
4, 5, and 9) and good enantioselectivity with 1a (Table 1, entry 3).
Meanwhile, catalysts 1dÀf possessing a chiral 1,2-dipheny-
lethylene-diamine (DPEN) skeleton showed lower catalytic
activity than catalysts bearing a cyclohexane-diamine skeleton
and induced particularly low enantioselectivities (Table 1,
entries 6À8). In particular, catalysts 1e and 1f including a
pyrrolidine ring gave the Michael adduct as a nearly racemic
mixture (Table 1, entries 7À8). Additionally, thiourea cinch-
ona alkaloid catalysts 1hÀk were also demonstrated to be
inferior to 1a in regard to enantioselectivity (Table 1, entries
10À13 vs entry 3); among them, reaction with 1h as catalyst
generated the product also as a nearly racemic mixture, and the
exact reason for this was unclear (Table 1, entry 10). Conse-
quently, via the various thiourea catalysts probed, catalyst 1a
was demonstrated to be the superior one in regard to the
enantioselectivity (Table 1, entry 3).
Having identified the readily available Takemoto’s thiourea
catalyst 1a as the best one among the catalysts probed, optimiza-
tion of other reaction conditions for the process was carried out
next. First, the effect of solvent on the 1,6-Michael addition
reactions was examined (Table 1, entries 14À18), and it was
found that the use of chlorobenzene as a reaction medium was
superior to others.15 In this solvent, the highest enantioselectivity
(81% ee) was obtained (Table 1, entry 18). Afterward, the effects
of catalyst loading (Table 1, entries 19À20) and substrate
concentration (Table 1, entries 21À22) on the process were
determined. Evidently, the optimal results could be obtained
with 10 mol % of catalyst 1a for 0.1 mmol of 3a in 3.0 mL of
solvent. Finally, we found that the amount of 4 Å molecular sieves
had significant influence on the yield and enantioselectivity
(Table 1, entries 23À24). Notably, when the reaction was
performed with 200 mg of freshly activated 4 Å molecular sieves
under the conditions as illustrated in entry 18 of Table 1, hardly
any improvement in the enantioselectivity was observed. As a
result, these studies provided a standard reaction protocol:
addition of benzenethiol (2a) to a solution of 3-methyl-4-
nitro-5-alkenyl-isoxazoles in chlorobenzene in the presence of
10 mol % 1a at À40 °C with 200 mg of activated 4 Å molecular
sieves (Table 1, entry 24).
attractive 1,6-Michael acceptors,8,9i,11 and the other is that the
nitro moiety of these compounds is a strong electro-with-
drawing group that can be readily transformed into an amino
group,11d,12 and the 4-nitroisoxazol-5-yl core is able to be
readily converted to a carboxylic acid group.11a,13,14 Espe-
cially, based on the research that 3-methyl-4-nitro-5-alkenyl-
isoxazoles have been successfully applied to the 1,6-Michael
addition of various nucleophiles by us and Adamo,8,9i,11 we
envisaged that the corresponding 1,6-Michael addition of
sulfur nucleophiles might be readily accessed by the bifunc-
tional thiourea-tertiary amine catalysts with the synergistic
cooperative activation of the nucleophilic thiols and electro-
philic 3-methyl-4-nitro-5-alkenyl-isoxazoles (Scheme 1). Herein,
we present our results on the organocatalytic asymmetric 1,
6-Michael addition reaction of arylthiols to 3-methyl-4-nitro-5-
alkenyl-isoxazoles, leading to a new array of enantioenriched
sulfur-containing compounds in high to excellent yields (up to
97%) and high enantioselectivities (up to 91% ee), and further on
the versatile conversions of the resulting adducts into other
functionalized compounds.
’ RESULTS AND DISCUSSION
Initially, the DABCO-catalyzed test reaction between
benzenethiol (2a) and (E)-3-methyl-4-nitro-5-styrylisoxazole
(3a) was conducted in CH2Cl2 at room temperature. It is
pertinent to note that the reaction proceeded smoothly to
completion even in 5 min for delivering the desired product 4a
in quantitative yield. Encouraged by this preliminary reaction,
the corresponding asymmetric version of the same reaction
was promptly investigated at room temperature with readily
available Takemoto’s thiourea catalyst 1a. Gratifyingly, com-
pound 4a could also be produced in quantitative yield within
5 min but with only 4% ee (Table 1, entry 1). After detailed
analysis, we thought that the unduly high reaction activity was
unfavorable to the asymmetric induction of catalyst 1a. There-
fore, the reaction was carried out at À30 °C and still gave 4a in
92% yield with 50% ee after 8 h (Table 1, entry 2). To our
delight, the enantioselectivity could be further improved to
72% by adding 100 mg of activated 4 Å molecular sieves (MS)
as additive (Table 1, entry 3).15 The most likely reason for this
was that the 4 Å molecular sieves were able to remove the trace
amount of residual water in the reaction system because
we found that the dried solvent was of paramount importance
for the enantioselectivity. Subsequently, some other chiral
With optimized reaction conditions in hand, we next
explored the scope of the process with respect to the 3-methyl-
4-nitro-5-alkenyl-isoxazoles component. As shown in Table 2,
the reaction scope generally proved to be broad to the Michael
acceptor 3-methyl-4-nitro-5-styrylisoxazoles. We found that
various electron-rich and -poor reagents 3 with different
substitution patterns on the phenyl ring were equally good
substrates (Table 2, entries 1À10). In the cases of 3j and 3k
with the methoxyl group substituent on the phenyl ring as
substrate, the corresponding products were obtained in good
yields with good enantioselectivities (Table 2, entries 9À10).
In addition, more sterically demanding substrates 3l and 3m
also smoothly gave rise to the formation of products 4l and 4m
in good yields and ee’s (Table 2, entries 11À12). At the same
time, heteroaromatic 3-methyl-4-nitro-5-styrylisoxazole 3n
was readily accommodated to the standard reaction condi-
tions (Table 2, entry 13). More importantly, we also verified
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Table 1. Effect of Reaction Parameters on the Catalytic Asymmetric 1,6-Michael Addition of Benzenethiol (2a) to
3-Methyl-4-nitro-5-styrylisoxazole (3a)a
entry
1
solvent
T (°C)
time (h)
yield (%)b
ee (%)c
1
2
1a
1a
1a
1b
1c
1d
1e
1f
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
DCE
rt
5 min
8
quant.
92
93
95
91
83
71
50
94
98
71
68
94
81
93
52
85
91
76
93
82
90
76
93
4d
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
À40
50d
72
35
20
37
2e
8e
27e
2e
3
8
4
8
5
8
6
8
7
8
8
8
9
1g
1h
1i
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
8
8
49
56e
54e
44
68
44
13
81
81f
76g
79h
81i
75j
84k
1j
8
1k
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
8
8
8
toluene
THF
8
8
PhCl
8
PhCl
8
PhCl
8
PhCl
8
PhCl
8
PhCl
8
PhCl
30
a Unless noted, reactions were carried out with 2a (0.2 mmol), 3a (0.1 mmol), 1 (10 mol %), and freshly activated 4 Å MS (100 mg) in solvent (3.0 mL).
b Isolated yield. c Determined by chiral HPLC analysis. d No additive 4 Å MS. e Opposite enantiomer was obtained as the major product. f 5 mol % of 1a
was used. g 20 mol % of 1a was used. h Run in 1.0 mL of chlorobenzene. i Run in 6.0 mL of chlorobenzene. j Freshly activated 4 Å MS (50 mg) were used.
k Freshly activated 4 Å MS (200 mg) were used. DCM = Dichloromethane, DCE = 1,2-Dichloroethane.
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Table 2. Scope of 1a-Catalyzed 1,6-Michael Addition of Benzenethiol (2a) to Various 3-Methyl-4-nitro-5-alkenyl-isoxazolesa
a Unless noted, reactions were carried out with 2a (0.2 mmol), 3 (0.1 mmol), 1a (10 mol %), and freshly activated 4 Å MS (200 mg) in PhCl (3.0 mL) at
À40 °C for 30 h. b Isolated yield. c Determined by chiral HPLC analysis. d Run for 45 h with 5 mol % of 1a.
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Table 3. Scope of 1a-Catalyzed 1,6-Michael Additions of Various Thiols to 3ea
a Unless noted, reactions were carried out with 2 (0.2 mmol), 3e (0.1 mmol), 1a (5 mol %), and freshly activated 4 Å MS (200 mg) in PhCl (3.0 mL) at
À40 °C for 45 h. b Isolated yield. c Determined by chiral HPLC analysis. d The data in parentheses mean the ee value of product after a single
recrystallization from anhydrous ethanol. e Run at room temperature without 4 Å MS. f Run at room temperature with freshly activated 4 Å MS (200 mg).
that isoxazole derivative 3o, in which the R group was
represented by a cyclopropyl group, was a viable substrate
for this asymmetric transformation, affording the correspond-
ing product 4o in 95% yield with 80% ee (Table 2, entry 14).
In light of the previous investigation (Table 2, entry 4) in
which substrate 3e reacted with benzenethiol (2a) in the
presence of 5 mol % of catalyst 1a furnishing the correspond-
ing product 4e in 96% yield and up to 91% ee just with an
extended reaction time of 45 h, we attempted to probe the
effect of altering the structure of the thiol on the reactivity and
enantioselectivity of the reaction. As shown in Table 3, some
arenethiols, regardless of their electronic and steric properties,
underwent efficient reactions affording corresponding adducts
in excellent yields (83À97%) with high enantioselectivities
(81À91% ee). As revealed from entries 1À3, electron-rich
thiols reacted efficiently with over 90% enantioselectivity. In
contrast, electro-deficient thiol reacted also efficiently but
with a little poor enantioselectivity (Table 3, entry 4). Mean-
while, naphthalene-2-thiol smoothly gave rise to the desired
product in 97% yield with 88% ee, and the ee value of product
4t could be readily improved to 99% after a single recrystalli-
zation from anhydrous ethanol (Table 3, entry 5). However,
we found that the reactivity of less active alkanethiols 2g was
poor, and the desired adduct could not be observed under the
standard reaction conditions. Even though the reaction was
carried out at room temperature, the product could be
obtained only in 47% yield with very poor enantioselectivity
(Table 3, entry 6) and in 43% yield with 45% ee value by
adding 200 mg 4 Å molecular sieves (Table 3, entry 7).
Notably, it can be deduced that the molecular sieves plays
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an important role in improving the enantioselectivity for the
reaction.
eq 1, right).17 However, treatment of Michael adduct 4a with
1.0 M aqueous NaOH in THF according to the procedure,13a
described by Sarti-Fantoni and co-workers, could not deliver
the desired product β-thio-carboxylic acid 7 (Scheme 3, eq 2,
up) but furnishes the corresponding starting material, Michael
acceptor 3a (Scheme 3, eq 2, down). We assumed that a retro-
Michael reaction probably took place during the course of the
reaction process. In addition, the potential synthetic useful-
ness of our methodology was also demonstrated by the
transformation of Michael adduct 4b into sulfone 8 with the
oxidation of 3-chlorobenzoperoxoic acid in dichloromethane
(Scheme 3, eq 3).17
The significance of the current protocol and the high
catalytic efficiency of 1a were further demonstrated by a
gram-scale experiment under the standard reaction condi-
tions. As highlighted in Scheme 2, 10 mol % of 1a was
sufficient for the completion of the reaction of 2a addition
to 3d within 30 h, and the corresponding adduct 4d was
obtained smoothly in 91% yield with 86% ee value. It is
worthwhile to note that these results obtained in gram-scale
reaction are very similar to those observed in a previous
investigation (entry 3 of Table 2).
After completing the research of methodology for the
catalytic asymmetric 1,6-Michael additions of various thiols
to a wide range of 3-methyl-4-nitro-5-alkenyl-isoxazoles and
the investigation into the gram-scale reaction, we attempted to
demonstrate the significance of the current protocol by the
versatile transformation of some Michael adducts into other
functionalized and useful compounds (Scheme 3). For exam-
ple, the nitro group of compound 4e could be readily reduced
to an amino group in 5 with tin dichloride at room tempera-
ture (Scheme 3, eq 1, left).17 Interestingly, the 4-nitroisoxazol-
5-yl core of 4e could be converted into a carboxylic acid group
in compound 6 with the promotion of tin dichloride in a
mixture solvent of THF/H2O after refluxing 16 h (Scheme 3,
Similarly, as shown in Scheme 4, for adduct 4a, which had
been obtained with 84% ee, we were also able to transform it
into the corresponding acidic derivative 7 with retention of
stereochemistry.17 This allowed us to establish the absolute
configuration of the stereocenter that had been generated in
the 1,6-Michael addition reaction as S configuration in 4a by
comparison of the optical rotation of 7 with the reported value
of the same compound.18 On the basis of this absolute
configuration result, we tentatively propose a transition state
for the reaction. As shown in Scheme 4, a double hydrogen
bonding interaction might be formed between two NÀH of
thiourea and the nitro group of the Michael acceptor. Syn-
chronously, another single hydrogen-bonding interaction
would be generated between the protonated tertiary amine
group and nucleophilic thiol. Subsequently, the Michael
donor thiol approaches the Michael acceptor from its si face
to afford the desired adduct 4a with S configuration. Accord-
ing to the stereostructure obtained for compound 4a, addi-
tionally, all the products in this work were delivered with the
same thiourea catalyst 1a and via the same reaction mechan-
ism, and the configuration of all other products in this work
was tentatively established by analogy. Notably, in view of the
reported procedure,18,19 we know that compound 7 could be
Scheme 2. Asymmetric 1,6-Michael Addition Reaction of 2a
to 3d in Gram Scale
Scheme 3. Transformation of Some Adducts into Other Functionalized Compounds
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Scheme 4. Confirmation of the Absolute Configuration of 4a and Proposed Transition State for the Reaction and the Potential
Application in the Synthesis of S-(+)-Thiazesim
easily transformed into S-(+)-thiazesim,20 the simplest mem-
ber of the benzothiazepin family, via four steps of normal
reactions.
ESI ionization. High-performance liquid chromatography (HPLC)
analysis was performed on chiral columns. Optical rotations were
measured in the solvent indicated. The solvents used in this work must
be thoroughly dried solvents.
General Experimental Procedure for the 1,6-Michael Ad-
dition of Benzenethiol to Various 3-Methyl-4-nitro-5-alke-
nyl-isoxazoles Catalyzed by 1a (Table 2). In an ordinary tube
equipped with a magnetic stirring bar, the solution of 3-methyl-4-nitro-
5-alkenyl-isoxazoles 3 (0.1 mmol), catalyst 1a (0.01 mmol), and freshly
activated 4 Å MS (200 mg) in PhCl (2.0 mL) was stirred at À40 °C for
30 min, and then benzenethiol 2a (0.2 mmol, 1.0 mL of cold benze-
nethiol solution in PhCl (À40 °C, c = 0.2 M)) was added. After the
reaction mixture was stirred for 30 h at À40 °C, the reaction mixture was
directly loaded onto a silica gel and purified by flash chromatography
(eluent: petroleum ether/ethyl acetate = 25:1) to give products 4.
General Experimental Procedure for the 1,6-Michael Ad-
dition of Various Thiols to 3e Catalyzed by 1a (Table 3). In an
ordinary tube equipped with a magnetic stirring bar, the solution of (E)-
5-(2-bromostyryl)-3-methyl-4-nitro-isoxazole 3e (0.1 mmol), catalyst
1a (0.005 mmol), and freshly activated 4 Å MS (200 mg) in PhCl
(2.0 mL) was stirred at À40 °C for 30 min, and then thiol 2 (0.2 mmol,
1.0 mL of cold benzenethiol solution in PhCl (À40 °C, c = 0.2 M)) was
added. After the reaction mixture was stirred for 45 h at À40 °C, the
reaction mixture was directly loaded onto a silica gel and purified by flash
chromatography (eluent: petroleum ether/ethyl acetate = 25:1) to give
products 4.
’ CONCLUSION
In conclusion, we have developed the first procedure for
carrying out enantioselective organocatalytic 1,6-Michael addi-
tion of arylthiols to various 3-methyl-4-nitro-5-alkenyl-isoxazole
compounds in the presence of a catalytic amount of chiral
bifunctional thiourea-tertiary amine (10 or 5 mol %) in chlor-
obenzene at À40 °C. A wide range of chiral sulfur-containing
compounds were obtained smoothly in high to excellent yields
(up to 97%) and high enantioselectivities (up to 91% ee). These
studies carried out in this report further demonstrate that
3-methyl-4-nitro-5-alkenyl-isoxazole belongs to a kind of pro-
mising Michael acceptor in organic synthesis.8,9i,11 Significantly,
the potential utilities of the protocol also had been demonstrated
by gram-scale reaction and the versatile conversions of some
resulting products into other functionalized and useful com-
pounds with retention of stereochemistry. Further studies in our
laboratories will focus on applying the 3-methyl-4-nitro-5-alkenyl-
isoxazole compounds into asymmetric synthesis and expanding the
synthetic utility of the related reactions.
’ EXPERIMENTAL SECTION
(S)-3-Methyl-4-nitro-5-(2-phenyl-2-(phenylthio)ethyl)iso-
xazole (4a). White solid; 31.5 mg, 93% yield; 84% ee; [α]D25 = À67.5
General Information. Various 3-methyl-4-nitro-5-alkenyl-isoxa-
zoles substrates 3aÀo were synthesized according to the previously
reported methods,10 and the purity of these compounds was determined
1
(c 0.83, CHCl3); mp 61.8À62.4 °C; H NMR (300 MHz, CDCl3)
δ 7.34À7.23 (m, 10H), 4.84 (t, J = 7.8 Hz, 1H), 3.81 (d, J = 7.8 Hz, 2H),
2.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 11.4, 34.4, 50.0, 127.3,
127.9, 128.1, 128.6, 128.8, 130.3, 132.7, 133.1, 138.9, 155.2, 171.4;
IR (KBr) v 3076, 2921, 1597, 1513, 1410, 1371, 1148, 829, 696.
HRMS (ESI) calcd for C18H16N2NaO3S [M+Na]+: 363.0774. Found:
363.0765. HPLC analysis: Chiralpak AD-H, ethanol/hexane = 30:70,
flow rate 1.0 mL/min, λ = 254 nm, tminor = 6.9 min, tmajor = 9.0 min.
(S)-5-(2-(2-Chlorophenyl)-2-(phenylthio)ethyl)-3-methyl-
4-nitroisoxazole (4b). Yellow solid; 35.8 mg, 96% yield; 89% ee;
1
with H NMR. NMR spectra were recorded on a 300 MHz spectro-
meter. 1H NMR chemical shifts were reported in parts per million with
tetramethylsilane (TMS) as the internal standard. Data for 1H NMR are
reported as follows: chemical shift (in ppm) and multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet, br = broad). Splitting
patterns that could not be clearly distinguished are designated as
multiplets (m). Data for 13C NMR are reported in parts per million.
High-resolution mass spectral analyses (HRMS) were measured using
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25
1
[α]D = À33.8 (c 0.97, CHCl3); mp 73.4À74.5 °C; H NMR (300
MHz, CDCl3) δ 7.50À7.47 (m, 1H), 7.38À7.20 (m, 8H), 5.41 (t, J = 7.8
Hz, 1H), 3.86 (dd, J = 14.7, 7.8 Hz, 1H), 3.75 (dd, J = 14.7, 7.8 Hz, 1H),
2.44 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 11.5, 33.9, 46.0, 127.3,
128.0, 128.4, 128.7, 129.0, 129.2, 129.8, 130.6, 132.8, 133.3, 136.5, 155.4,
171.1; IR (KBr) v 2926, 1606, 1521, 1477, 1419, 1381, 1364, 831,
756 cmÀ1. HRMS (ESI) calcd for C18H15ClN2NaO3S [M+Na]+:
397.0384. Found: 397.0383. HPLC analysis: Chiralpak AD-H, i-propa-
nol/hexane = 20:80, flow rate 1.0 mL/min, λ = 254 nm, tmajor = 6.0 min,
tminor = 6.5 min.
analysis: Chiralpak AD-H, ethanol/hexane = 30:70, flow rate 1.0 mL/min,
λ = 254 nm, tminor = 9.8 min, tmajor = 14.7 min.
(S)-3-Methyl-4-nitro-5-(2-(phenylthio)-2-m-tolylethyl)iso-
xazole (4h). Colorless oil; 32.4 mg, 91% yield; 82% ee; [α]D25 = À61.2
(c 0.53, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.36À7.33 (m, 2H),
7.29À7.05 (m, 7H), 4.78 (t, J = 7.8 Hz, 1H), 3.79 (d, J = 7.8, 2H), 2.43 (s,
3H), 2.32 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 11.5, 21.3, 34.6, 50.1,
124.3, 127.8, 128.0, 128.6, 128.8, 128.9, 132.8, 133.3, 138.4, 138.8, 155.3,
171.7; IR (KBr) v 3014, 2924, 1604, 1521, 1377, 1133, 831, 755,
699 cmÀ1. HRMS (ESI) calcd for C19H18N2NaO3S [M+Na]+:
377.0930. Found: 377.0934. HPLC analysis: Chiralpak AD-H, etha-
nol/hexane = 30:70, flow rate 1.0 mL/min, λ = 254 nm, tminor = 5.3 min,
tmajor = 6.9 min.
(S)-3-Methyl-4-nitro-5-(2-(phenylthio)-2-p-tolylethyl)iso-
xazole (4i). White solid; 32.7 mg, 92% yield; 84% ee; [α]D25 = À62.7
(c 0.77, CHCl3); mp 103.0À103.8 °C; 1H NMR (300 MHz, CDCl3) δ
7.37À7.35 (m, 2H), 7.26À7.09 (m, 7H), 4.81 (t, J = 7.8 Hz, 1H), 3.79
(d, J = 7.8 Hz, 2H), 2.44 (s, 3H), 2.32 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 11.5, 21.1, 34.6, 49.8, 126.9, 127.2, 127.7, 128.9, 129.4, 130.3,
132.7, 133.4, 135.9, 137.8, 155.3, 171.7; IR (KBr) v 3021, 2969, 1601,
1529, 1414, 1383, 1127, 826, 743 cmÀ1; HRMS (ESI) calcd for
C19H18N2NaO3S [M+Na]+: 377.0930. Found: 377.0927. HPLC analy-
sis: Chiralpak AD-H, ethanol/hexane = 30:70, flow rate 1.0 mL/min,
λ = 254 nm, tminor = 6.9 min, tmajor = 7.6 min.
(S)-5-(2-(3-Chlorophenyl)-2-(phenylthio)ethyl)-3-methyl-
4-nitroisoxazole (4c). Yellow solid; 32.2 mg, 86% yield; 85% ee;
25
1
[α]D = À66.5 (c 0.97, CHCl3); mp 66.4À67.0 °C; H NMR (300
MHz, CDCl3) δ 7.32À7.17 (m, 9H), 4.75 (t, J = 7.8 Hz, 1H), 3.77 (d, J =
7.8 Hz, 2H), 2.45 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 11.5, 34.3,
49.7, 125.5, 127.6, 128.2, 129.0, 129.9, 130.5, 132.5, 133.2, 134.5, 141.2,
155.4, 171.1; IR (KBr) v 2903, 1612, 1520, 1418, 1381, 1140, 830, 755,
693 cmÀ1. HRMS (ESI) calcd for C18H15ClN2NaO3S [M+Na]+:
397.0384. Found: 397.0378. HPLC analysis: Chiralpak AD-H, etha-
nol/hexane = 30:70, flow rate 1.0 mL/min, λ = 254 nm, tminor = 6.4 min,
tmajor = 8.9 min.
(S)-5-(2-(4-Chlorophenyl)-2-(phenylthio)ethyl)-3-methyl-
4-nitroisoxazole (4d). White solid; 34.9 mg, 93% yield; 84% ee;
25
1
[α]D = À74.3 (c 0.83, CHCl3); mp 67.3À68.6 °C; H NMR (300
MHz, CDCl3) δ 7.33À7.21 (m, 9H), 4.77 (t, J = 7.8 Hz, 1H), 3.77 (d, J =
7.8 Hz, 2H), 2.45(s, 3H); 13C NMR (75 MHz, CDCl3) δ 11.5, 34.2,
49.5, 128.2, 128.7, 128.8, 129.0, 130.4, 132.6, 133.2, 133.7, 137.6, 155.4,
171.2; IR (KBr) v 3033, 1603, 1514, 1414, 1381, 1362, 1094, 831,
748 cmÀ1. HRMS (ESI) Calcd for C18H15ClN2NaO3S [M+Na]+:
397.0384. Found: 397.0387. HPLC analysis: Chiralpak AD-H, etha-
nol/hexane = 30:70, flow rate 1.0 mL/min, λ = 254 nm, tminor = 9.1 min,
tmajor = 13.7 min.
(S)-5-(2-(2-Methoxyphenyl)-2-(phenylthio)ethyl)-3-meth-
yl-4-nitroisoxazole (4j). Yellow solid; 27.6 mg, 75% yield; 78% ee;
25
1
[α]D = À33.3 (c 0.75, CHCl3); mp 71.0À72.6 °C; H NMR (300
MHz, CDCl3) δ 7.39À7.22 (m, 7H), 6.92À6.83 (m, 2H), 5.32 (t, J = 7.8
Hz, 1H), 3.87 (dd, J = 14.7, 7.8 Hz, 1H), 3.82 (s, 2H), 3.76 (dd, J = 14.7,
7.8 Hz, 1H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 11.4, 33.8,
43.6, 55.5, 110.7, 120.7, 127.2, 127.4, 128.8, 129.1, 132.2, 134.1, 155.2,
156.3, 171.9; IR (KBr) v 3018, 2935, 1601, 1513, 1385, 1253, 1110, 831,
760 cmÀ1. HRMS (ESI) calcd for C19H18N2NaO4S [M+Na]+:
393.0879. Found: 393.0886. HPLC analysis: Chiralpak AD-H, etha-
nol/hexane = 30:70, flow rate 1.0 mL/min, λ = 254 nm, tminor = 5.6 min,
tmajor = 6.2 min.
(S)-5-(2-(2-Bromophenyl)-2-(phenylthio)ethyl)-3-methyl-
4-nitroisoxazole (4e). Yellow solid; 40.3 mg, 96% yield; 91% ee;
[α]D25 = À29.6 (c 1.0, CHCl3); mp 67.6À69.3 °C; 1H NMR (300 MHz,
CDCl3) δ 7.53À7.49 (m, 2H), 7.39À7.12 (m, 7H), 5.41 (t, J = 7.8 Hz,
1H), 3.84 (dd, J = 14.7, 7.8 Hz, 1H), 3.74 (dd, J = 14.7, 7.8 Hz, 1H), 2.44
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 11.5, 34.0, 48.7, 124.1, 127.9,
128.0, 128.6, 128.8, 129.0, 129.5, 132.8, 133.1, 138.1, 155.4, 171.0; IR
(S)-5-(2-(4-Methoxyphenyl)-2-(phenylthio)ethyl)-3-meth-
yl-4-nitroisoxazole (4k). Yellow solid; 26.2 mg, 71% yield; 74% ee;
[α]D25 = À17 (c 0.23, CHCl3); mp 95.3À96.1 °C; 1H NMR (300 MHz,
CDCl3) δ 7.37À7.22 (m, 7H), 6.82À6.79 (m, 2H), 4.80 (t, J = 7.8 Hz,
1H), 3.77 (d, J = 7.8 Hz, 2H), 3.76 (s, 3H), 2.43 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 11.5, 34.6, 49.5, 55.1, 114.0, 127.8, 128.5, 128.9,
130.8, 132.8, 133.3, 155.3, 159.1, 171.7; IR (KBr) v 3004, 2969, 2836,
1608, 1513, 1364, 1255, 828, 748 cmÀ1. HRMS (ESI) calcd for
C19H18N2NaO4S [M+Na]+: 393.0879. Found: 393.0891. HPLC anal-
ysis: Chiralpak AD-H, ethanol/hexane = 30:70, flow rate 1.0 mL/min,
λ = 254 nm, tminor = 9.7 min, tmajor = 10.8 min.
(S)-3-Methyl-5-(2-(naphthalen-1-yl)-2-(phenylthio)ethyl)-
4-nitroisoxazole (4l). Yellow solid; 32.2 mg, 82% yield; 86% ee;
[α]D25 = À67.5 (c 1.15, CHCl3); mp 108.7À110.2 °C; 1H NMR (300
MHz, CDCl3) δ 8.27 (m, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 8.1
Hz, 1H), 7.62À7.23 (m, 9H), 5.74 (s, 1H), 3.94 (m, 2H), 2.40 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 11.4, 34.5, 45.0, 122.5, 124.9, 125.2,
125.9, 126.7, 127.9, 128.8, 129.0, 129.1, 130.5, 132.9, 133.3, 133.9, 134.6,
155.3, 171.6; IR (KBr) v 3066, 2935, 1601, 1511, 1377, 1363, 1127, 831,
736 cmÀ1. HRMS (ESI) calcd for C22H18N2NaO3S [M+Na]+:
413.0930. Found: 413.0944. HPLC analysis: Chiralpak AD-H, etha-
nol/hexane = 30:70, flow rate 1.0 mL/min, λ = 254 nm, tminor = 6.5 min,
tmajor = 7.2 min.
(KBr) v 3052, 2926, 1606, 1519, 1416, 1379, 1362, 831, 753 cmÀ1
.
HRMS (ESI) calcd for C18H15BrN2NaO3S [M+Na]+: 440.9879.
Found: 440.9881. HPLC analysis: Chiralpak AD-H, i-propanol/
hexane = 20:80, flow rate 1.0 mL/min, λ = 254 nm, tmajor = 6.2 min,
tminor = 6.9 min.
(S)-5-(2-(3-Bromophenyl)-2-(phenylthio)ethyl)-3-methyl-
4-nitroisoxazole (4f). Yellow solid; 37.2 mg, 89% yield; 81% ee;
25
1
[α]D = À56.9 (c 0.80, CHCl3); mp 79.6À81.1 °C; H NMR (300
MHz, CDCl3) δ 7.44 (s, 1H), 7.39À7.13 (m, 8H), 4.73 (t, J = 7.8 Hz,
1H), 3.77 (d, J = 7.8 Hz, 2H), 2.46 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 11.5, 34.3, 49.7, 122.6, 126.0, 128.3, 129.0, 130.2, 130.5, 131.2, 132.4,
133.2, 141.4, 155.4, 171.1; IR (KBr) v 3054, 2905, 1605, 1517, 1375,
1136, 830, 753, 693 cmÀ1. HRMS (ESI) calcd for C18H15BrN2NaO3S
[M+Na]+: 440.9879. Found: 440.9862. HPLC analysis: Chiralpak AD-
H, ethanol/hexane = 30:70, flow rate 1.0 mL/min, λ = 254 nm, tminor
6.6 min, tmajor = 8.9 min.
=
(S)-5-(2-(4-Bromophenyl)-2-(phenylthio)ethyl)-3-methyl-
4-nitroisoxazole (4g). Yellow solid; 37.8 mg, 90% yield; 81% ee;
[α]D25 = À62.5 (c 0.65, CHCl3); mp 103.5À104.2 °C; 1H NMR (300
MHz, CDCl3) δ 7.40 (d, J = 8.4 Hz, 2H), 7.32À7.26 (m, 5H), 7.17 (d,
J = 8.4 Hz, 2H), 4.75 (t, J = 7.8 Hz, 1H), 3.77 (d, J = 7.8 Hz, 2H), 2.45 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 11.5, 34.2, 49.6, 121.9, 128.2, 129.0,
129.1, 130.4, 131.8, 132.5, 133.1, 138.1, 155.4, 171.1; IR (KBr) v 3047,
2938, 1607, 1524, 1491, 1413, 1385, 822, 752 cmÀ1. HRMS (ESI) calcd
for C18H15BrN2NaO3S [M+Na]+: 440.9879. Found: 440.9870. HPLC
(S)-5-(2-(Anthracen-9-yl)-2-(phenylthio)ethyl)-3-methyl-
4-nitroisoxazole (4m). Yellow solid; 32.5 mg, 74% yield; 71% ee;
[α]D25 = À103.4 (c 0.55, CHCl3); mp 153.5À154.7 °C; 1H NMR (300
MHz, CDCl3) δ 8.81À8.78 (m, 1H), 8.41À8.33 (m, 2H), 8.04À7.98
(m, 2H), 7.68À7.40 (m, 6H), 7.26À7.24 (m, 3H), 6.44À6.39 (m, 1H),
7856
dx.doi.org/10.1021/jo2012779 |J. Org. Chem. 2011, 76, 7849–7859

The Journal of Organic Chemistry
ARTICLE
4.40 (dd, J = 14.4, 10.2 Hz, 1H), 3.91 (dd, J = 14.4, 6.0 Hz, 1H), 2.33 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 11.3, 34.7, 46.9, 122.3, 124.9, 125.0,
125.4, 125.9, 127.1, 127.8, 128.7, 128.8, 129.1, 129.4, 129.5, 129.8, 131.1,
131.3, 131.8, 132.3, 135.7, 155.1, 171.5; IR (KBr) v 3066, 2935, 1601,
1511, 1377, 1363, 1127, 831, 736 cmÀ1. HRMS (ESI) calcd for
C26H20N2NaO3S [M+Na]+: 463.1087. Found: 463.1090. HPLC anal-
ysis: Chiralpak OD-H, i-propanol/hexane = 30:70, flow rate 1.0 mL/
min, λ = 254 nm, tmajor = 6.2 min, tminor = 6.7 min.
1377, 1248, 831, 748 cmÀ1. HRMS (ESI) calcd for C19H17BrN2NaO4S
[M+Na]+: 470.9985. Found: 470.9982. HPLC analysis: Chiralpak AD-H,
i-propanol/hexane = 20:80, flow rate 1.0 mL/min, λ = 254 nm, tmajor
8.0 min, tminor = 9.4 min.
=
(S)-5-(2-(2-Bromophenyl)-2-(4-chlorophenylthio)ethyl)-3-
methyl-4-nitroisoxazole (4s). Yellow solid; 43.0 mg, 95% yield;
81% ee; [α]D25 = À29.5 (c 1.13, CHCl3); mp 108.4À109.3 °C; 1H NMR
(300 MHz, CDCl3) δ 7.53À7.46 (m, 2H), 7.31À7.12 (m, 6H), 5.37 (t,
J = 7.8 Hz, 1H), 3.84 (dd, J = 14.7, 7.8 Hz, 1H), 3.71 (dd, J = 14.7, 7.8 Hz,
1H), 2.46 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 11.4, 33.8, 48.8, 124.0,
128.0, 128.5, 129.1, 129.6, 131.1, 133.1, 134.1, 134.3, 137.7, 155.4, 170.7;
IR (KBr) v 3063, 2900, 1601, 1518, 1475, 1416, 1381, 1094, 831,
772 cmÀ1. HRMS (ESI) calcd for C18H14BrClN2NaO3S [M+Na]+:
474.9489. Found: 474.9493. HPLC analysis: Chiralpak AD-H, i-propa-
nol/hexane = 20:80, flow rate 1.0 mL/min, λ = 254 nm, tmajor = 6.5 min,
tminor = 7.1 min.
(S)-3-Methyl-4-nitro-5-(2-(phenylthio)-2-(thiophen-2-yl)-
ethyl)isoxazole (4n). Yellow solid; 24.3 mg, 70% yield; 72% ee;
25
1
[α]D = À60.7 (c 0.47, CHCl3); mp 72.9À74.5 °C; H NMR (300
MHz, CDCl3) δ 7.37À7.20 (m, 6H), 6.87 (d, J = 3.3 Hz, 2H), 5.10 (t, J =
7.8 Hz, 1H), 3.83 (d, J = 7.8 Hz, 2H), 2.47 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 11.4, 35.5, 45.4, 125.3, 125.7, 126.7, 128.2, 132.7, 133.2, 142.7,
155.4, 171.1; IR (KBr) v 3115, 2931, 1611, 1521, 1413, 1377, 831, 748,
724 cmÀ1. HRMS (ESI) calcd for C16H14N2NaO3S2 [M+Na]+:
369.0338. Found: 369.0342. HPLC analysis: Chiralpak AD-H, etha-
nol/hexane = 30:70, flow rate 1.0 mL/min, λ = 254 nm, tminor = 8.0 min,
tmajor = 10.5 min.
(S)-5-(2-(2-Bromophenyl)-2-(naphthalen-2-ylthio)ethyl)-
3-methyl-4-nitroisoxazole (4t). Yellow solid; 45.5 mg, 97% yield;
25
88% ee; [α]D = À67.5 (c 1.15, CHCl3); mp 108.9À110.1 °C; 1H
(S)-5-(2-Cyclopropyl-2-(phenylthio)ethyl)-3-methyl-4-ni-
NMR (300 MHz, CDCl3) δ 7.84 (s, 1H), 7.80À7.72 (m, 3H),
7.56À7.47 (m, 5H), 7.34À7.29 (m, 1H), 7.15À7.13 (m, 1H), 5.57 (t,
J = 7.8 Hz, 1H), 3.89 (dd, J = 14.7, 7.8 Hz, 1H), 3.75 (dd, J = 14.7, 7.8
Hz, 1H), 2.23 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 11.2, 34.2,
48.4, 124.0, 126.5, 126.6, 127.5, 128.0, 128.5, 128.7, 129.3, 129.5,
130.1, 131.5, 132.4, 133.1, 133.3, 138.1, 155.3, 170.9; IR (KBr) v
25
troisoxazole (4o). Yellow solid; 29.0 mg, 95% yield; 80% ee; [α]D
=
À27.8 (c 0.73, CHCl3); mp 53.2À54.7 °C; 1H NMR (300 MHz,
CDCl3) δ 7.44À7.41 (m, 2H), 7.30À7.25 (m, 3H), 3.52 (d, J = 7.5
Hz, 2H), 2.89 (m, 1H), 2.47 (s, 3H), 1.01À0.66 (m, 1H), 0.65À0.50 (m,
2H), 0.39À0.0.34 (m, 1H), 0.18À0.15 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 5.4, 6.2, 11.5, 16.1, 34.6, 52.0, 127.8, 128.9, 132.7, 133.5,
155.3, 172.5; IR (KBr) v 3082, 3003, 1602, 1516, 1377, 1362, 1128, 831,
751 cmÀ1. HRMS (ESI) calcd for C15H16N2NaO3S [M+Na]+:
327.0774. Found: 327.0775. HPLC analysis: Chiralpak AD-H, etha-
nol/hexane = 30:70, flow rate 1.0 mL/min, λ = 254 nm, tminor = 7.0 min,
tmajor = 8.8 min.
3047, 2928, 1604, 1511, 1379, 1361, 1133, 831, 804, 780, 760 cmÀ1
.
HRMS (ESI) calcd for C22H17BrN2NaO3S [M+Na]+: 491.0035.
Found: 491.0040. HPLC analysis: Chiralpak AD-H, i-propanol/
hexane = 20:80, flow rate 1.0 mL/min, λ = 254 nm, tmajor
9.2 min, tminor = 10.0 min.
=
(S)-5-(2-(Benzylthio)-2-(2-bromophenyl)ethyl)-3-methyl-
4-nitroisoxazole (4u). Yellow solid; 18.6 mg, 43% yield; 45% ee; mp
61.2À61.9 °C; [α]D25 = À30.4 (c 0.75, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.65À7.60 (m, 1H), 7.51À7.48 (m, 1H), 7.36À7.28 (m, 1H),
7.27À7.18 (m, 5H), 7.16À7.13 (m, 1H), 4.87 (t, J = 7.8 Hz, 1H), 3.73
(dd, J = 14.7, 7.8 Hz, 1H), 3.61 (dd, J = 14.7, 8.4 Hz, 1H), 3.65 (s, 2H),
2.51 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 11.6, 33.8, 36.2, 45.3, 123.9,
127.1, 128.1, 128.5, 128.8, 129.1, 129.3, 132.9, 136.9, 139.0, 155.3, 170.9;
IR (KBr) v 3052, 2938, 1607, 1517, 1416, 1380, 1024, 826, 752,
723 cmÀ1. HRMS (ESI) calcd for C19H17BrN2NaO3S [M+Na]+:
455.0035. Found: 455.0044. HPLC analysis: Chiralpak AD-H, i-propa-
nol/hexane = 20:80, flow rate 1.0 mL/min, λ = 254 nm, tmajor = 6.3 min,
tminor = 7.1 min.
(S)-5-(2-(2-Bromophenyl)-2-(p-tolylthio)ethyl)-3-methyl-
4-nitroisoxazole (4p). Yellow solid; 41.6 mg, 96% yield; 90% ee;
25
1
[α]D = À28.7 (c 1.13, CHCl3); mp 93.8À95.0 °C; H NMR (300
MHz, CDCl3) δ 7.53À7.45 (m, 2H), 7.32À7.05 (m, 6H), 5.35 (t, J = 7.8
Hz, 1H), 3.82 (dd, J = 14.7, 7.8 Hz, 1H), 3.72 (dd, J = 14.7, 7.8 Hz, 1H),
2.44 (s, 3H), 2.31 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 11.5, 21.1,
33.9, 48.9, 124.0, 127.8, 128.5, 128.9, 129.3, 129.7, 133.0, 133.3, 138.1,
138.3, 155.3, 171.1; IR (KBr) v 3063, 2924, 1601, 1511, 1381, 1129,
1025, 831, 774 cmÀ1. HRMS (ESI) calcd for C19H17BrN2NaO3S [M
+Na]+: 455.0035. Found: 455.0035. HPLC analysis: Chiralpak AD-H, i-
propanol/hexane = 20:80, flow rate 1.0 mL/min, λ = 254 nm, tmajor
5.9 min, tminor = 6.6 min.
=
(S)-5-(2-(2-Bromophenyl)-2-(o-tolylthio)ethyl)-3-methyl-
4-nitroisoxazole (4q). Yellow solid; 35.9 mg, 83% yield; 91% ee;
(À)-5-(2-(2-Bromophenyl)-2-(4-methoxyphenylthio)ethyl)-
3-methylisoxazol-4-amine (5). To a solution of 4e (0.419 g,
25
1
[α]D = À24.4 (c 0.95, CHCl3); mp 72.0À72.8 °C; H NMR (300
MHz, CDCl3) δ 7.60À7.32 (m, 4H), 7.18À7.09 (m, 4H), 5.39 (t, J = 7.8
Hz, 1H), 3.84 (dd, J = 14.7, 7.8 Hz, 1H), 3.73 (dd, J = 14.7, 7.8 Hz, 1H),
2.44 (s, 3H), 2.40 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 11.5, 20.6,
34.2, 47.8, 124.0, 126.5, 128.0, 128.2, 128.7, 129.4, 130.5, 131.9, 133.0,
133.5, 138.2, 140.7, 155.3, 171.0; IR (KBr) v 3056, 2903, 1599,
1513, 1470, 1418, 1384, 831, 753 cmÀ1. HRMS (ESI) calcd for
C19H17BrN2NaO3S [M+Na]+: 455.0035. Found: 455.0021. HPLC
analysis: Chiralpak AD-H, i-propanol/hexane = 20:80, flow rate
1.0 mL/min, λ = 254 nm, tmajor = 5.2 min, tminor = 5.6 min.
(S)-5-(2-(2-Bromophenyl)-2-(4-methoxyphenylthio)ethyl)-
3-methyl-4-nitroisoxazole (4r). Yellow solid; 41.6 mg, 93% yield;
91% ee; [α]D25 = À19.6 (c 1.33, CHCl3); mp 101.8À102.6 °C; 1H NMR
(300 MHz, CDCl3) δ 7.52À7.50 (m, 1H), 7.40À7.37 (m, 1H)
7.31À7.26 (m, 3H) 7.12À7.10 (m, 1H), 6.78 (d, J = 8.7 Hz, 2H), 5.25
(t, J = 7.8 Hz, 1H), 3.82 (dd, J = 15.0, 7.8 Hz, 1H), 3.78 (s, 3H), 3.71 (dd,
J = 15.0, 7.8 Hz, 1H), 2.45 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 11.5,
33.7, 49.3, 55.2, 114.5, 122.7, 124.2, 127.8, 128.5, 129.3, 133.1, 136.0,
138.2, 155.4, 160.1, 171.3; IR (KBr) v 3010, 2838, 1606, 1521, 1494,
1.0 mmol) in 20 mL of THF was added SnCl2 2H2O (0.677 g, 3.0 mmol)
3
and dropwised conc. HCl (1.0 mL). The reaction mixture was stirred at
room temperature for 2 h, poured into a cold solution of 10% NaOH
(20 mL), and extracted with ethyl acetate (3 Â 20 mL). The combined
organic layer was washed with water and then dried over Na2SO4 and
finally concentrated. The residue mixture was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate = 3:1) to give
25
compound 5 as a colorless oil in 335.5 mg. 80% yield; 91% ee; [α]D
=
À19.6 (c 1.33, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.49À7.47 (m,
1H), 7.42À7.40 (m, 1H), 7.28À7.23 (m, 3H), 7.09À7.04 (m, 1H),
6.77À6.74 (m, 2H), 4.50 (t, J = 7.5 Hz, 1H), 3.76 (s, 3H), 3.30À3.16 (m,
2H), 2.39 (br, 2H), 2.17 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 9.2, 31.5,
50.8, 55.2, 114.4, 122.1, 123.5, 124.5, 127.5, 128.7, 128.8, 132.9, 135.6,
139.8, 153.7, 154.9, 159.8; IR (KBr) v 2926, 2852, 1646, 1494, 1468,
1401, 1387, 1250, 1028, 831, 750 cmÀ1. HRMS (ESI) calcd for
C19H19BrN2NaO2S [M+Na]+: 441.0243. Found: 441.0264. HPLC anal-
ysis: Chiralpak AD-H, ethanol/hexane = 30:70, flow rate 1.0 mL/min, λ =
254 nm, tmajor = 7.8 min, tminor = 15.2 min.
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The Journal of Organic Chemistry
ARTICLE
(+)-3-(2-Bromophenyl)-3-(4-methoxyphenylthio)propa-
noic acid (6). The mixture of compound 4e (1.0 mmol), SnCl2 2H2O
’ ACKNOWLEDGMENT
3
We are grateful for financial support from the National Natural
Science Foundation of China (No. 20802074) and the National
Basic Research Program of China (973 Program) (2010CB833300).
(0.677 g, 3.0 mmol), THF (20.0 mL), water (20.0 mL), and 36% HCl
(1.0 mL) was heated at reflux for 16 h and then cooled to room
temperature. THF was evaporated in vacuo, and the water layer was
extracted with ethyl acetate (3 Â 20 mL). The organic layer was dried
over MgSO4. After evaporation of solvent, the residue mixture was
purified by silica gel column chromatography (petroleum ether/ethyl
acetate 3:1) to afford product 6 as a white solid in 312.2 mg. 85% yield;
90% ee; [α]D25 = +24.5 (c 0.97, CHCl3); mp 144.9À147.3 °C; 1H NMR
(300 MHz, DMSO) δ 12.2 (br, 1H), 7.60À7.58 (m, 1H), 7.29À7.20
(m, 5H), 6.88 (d, J = 7.5 Hz, 2H), 4.84 (t, J = 7.2 Hz, 1H), 3.73 (s, 3H),
2.97À2.77 (m, 2H); 13C NMR (75 MHz, DMSO) δ 39.3, 48.2, 55.3,
114.7, 122.3, 124.1, 127.8, 128.5, 129.1, 132.8, 136.4, 139.4, 159.9, 171.6;
IR (KBr) v 2926, 2852, 1646, 1494, 1468, 1401, 1387, 1250, 1028, 831,
750 cmÀ1. HRMS (ESI) calcd for C16H15BrNaO3S [M+Na]+:
388.9817. Found: 388.9822. HPLC analysis: Chiralpak OD-H, i-propa-
nol/hexane/TFA = 30:70:0.1, flow rate 1.0 mL/min, λ = 254 nm,
tminor = 4.3 min, tmajor = 5.0 min.
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(À)-3-Phenyl-3-(phenylthio)propanoic Acid (7). The mix-
ture of compound 4a (1.0 mmol), SnCl2 2H2O (0.677 g, 3.0 mmol),
3
THF (20.0 mL), water (20.0 mL), and 36% HCl (1.0 mL) was heated at
reflux for 16 h and then cooled to room temperature. THF was
evaporated in vacuo, and the water layer was extracted with ethyl acetate
(3 Â 20 mL). The organic layer was dried over MgSO4. After
evaporation of solvent, the residue was purified by silica gel column
chromatography (petroleum ether/ethyl acetate 3:1) to afford product 7
as a colorless oil in 212.0 mg, 82% yield; 84% ee; [α]D25 = À121.9 (c
0.80, CHCl3); 1H NMR (300 MHz, CDCl3) δ 10.4 (br, 1H), 7.32À7.27
(m, 10H), 4.64 (t, J = 7.5 Hz, 1H), 3.50 (d, J = 7.5 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ 40.5, 48.6, 127.5, 127.6, 127.9, 128.5, 128.8 133.3,
133.5, 140.1, 177.0; IR (KBr) v 3042, 2908, 1703, 1404, 1243, 1172, 755,
692 cmÀ1. HRMS (ESI) calcd for C15H14NaO2S [M+Na]+: 281.0607.
Found: 281.0610. HPLC analysis: Chiralpak AD-H, i-propanol/hexane/
TFA = 9:91:0.03, flow rate 1.0 mL/min, λ = 220 nm, tmajor = 7.8 min,
tminor = 8.5 min.
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(8) As we were preparing to submit this manuscript, a nonenantio-
selective Michael addition of reaction of phenylmethanethiol to 3-meth-
yl-4-nitro-5-styryl-isoxazoles with 0.1 equiv of piperidine was reported
(+)-5-(2-(2-Chlorophenyl)-2-(phenylsulfonyl)ethyl)-3-methyl-
4-nitroisoxazole (8). To a solution of 4b (375 mg, 1.0 mmol) in CH2Cl2
(20.0 mL) was added 701 mg of m-CPBA (70%, 3.0 mmol), and the reaction
was stirred at room temperature for 30 min. The solvent was evaporated, and
the crude residue was treated with sat. NaHCO3 solution (30 mL). The
product 8 was obtained after purification by flash column chromatography on
silica gel (petroleum ether/ethyl acetate 1:2) as a white solid in 390.1 mg. 96%
yield; 89% ee; [α]D25 =+3.8(c0.85, CHCl3); mp 114.8À116.6 °C; 1HNMR
(300 MHz, CDCl3) δ7.78À7.58 (m, 4H), 7.44À7.12 (m, 5H), 5.57 (dd, J=
10.2, 5.4 Hz, 1H), 4.23 (dd, J = 15.3, 5.4 Hz, 1H), 4.10 (dd, J = 15.3, 10.5 Hz,
1H), 2.44 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 11.4, 27.1, 61.5, 127.4,
128.4, 128.9, 129.0, 129.6, 129.7, 130.7, 134.3, 135.7, 136.5, 155.6, 169.6; IR
(KBr) v3094, 2928, 1610, 1523, 1385, 1151, 831, 767, 738, 608 cmÀ1.HRMS
(ESI): calcd for C18H15ClN2NaO5S [M+Na]+: 429.0282. Found: 429.0283.
HPLC analysis: Chiralpak AD-H, i-propanol/hexane = 20:80, flow rate
1.0 mL/min, λ = 254 nm, tmajor = 17.4 min, tminor = 22.5 min.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed spectral data for pro-
b
ducts. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: yuanwc@cioc.ac.cn
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The Journal of Organic Chemistry
ARTICLE
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