Diastereoselective α-Sulfenylation of N- tert-Butanesulfinyl Imidates

Article abstract of DOI:10.1021/acs.joc.8b01403

A diastereoselective α-sulfenylation of chiral α-aryl/alkyl N-tert-butanesulfinyl imidates has been developed. Suitable sulfur electrophiles can be used as sulfenylating reagents to intercept aza-enolates generated from imidate deprotonation, giving α-thiofunctionalized imidates in good yields with high diastereocontrol. This protocol for C-S bond formation can efficiently synthesize enantioenriched 1,2-sulfanyl amine derivatives such as sulconazole.

Full text of DOI:10.1021/acs.joc.8b01403

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pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Diastereoselective α‑Sulfenylation of N-tert-Butanesulfinyl Imidates
Sheng-Tong Niu,†,‡ Hui Liu,† Yan-Jun Xu,† and Chong-Dao Lu*,†
†Key Laboratory of Plant Resources and Chemistry of Arid Zones, Xinjiang Technical Institute of Physics & Chemistry, Chinese
Academy of Sciences, Urumqi 830011, China
‡University of the Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: A diastereoselective α-sulfenylation of chiral α-aryl/alkyl
N-tert-butanesulfinyl imidates has been developed. Suitable sulfur
electrophiles can be used as sulfenylating reagents to intercept aza-
enolates generated from imidate deprotonation, giving α-thiofunctional-
ized imidates in good yields with high diastereocontrol. This protocol for
C−S bond formation can efficiently synthesize enantioenriched 1,2-
sulfanyl amine derivatives such as sulconazole.
hiral sulfides are important structural motifs in some
bioactive agents and are useful precursors for synthetic
pathway to access functionalized chiral α-aryl β-amino sulfides
is nucleophilic addition of chiral α-sulfenylated benzyl
carbanions and their equivalents to imines.13 In addition,
chiral β-amino sulfides can be flexibly synthesized via
diastereoselective α-alkylation of α-sulfanylated acetaldehyde-
SAMP hydrazones, followed by nucleophilic addition to the
hydrazone CN double bond. However, this reaction is
limited to α-alkyl products, and in some cases, it gives
moderate yields in the late-stage cleavage of N−N bonds.14
In order to improve on the available routes for α-
sulfenylation of α-aryl-substituted substrates, we describe
here diastereoselective α-sulfenylation of N-tert-butanesulfinyl
imidates. This reaction is suitable for α-aryl and alkyl-
substituted substrates and allows quick access to chiral
precursors for α-sulfenylated acid derivatives and β-amino
sulfides.
C
transformations.1 Enantioselective C−S bond formation via
nucleophilic addition of an enolate or its equivalents to sulfur-
based electrophiles can generate α-thio-functionalized acid
derivatives in a straightforward manner.2 Asymmetric catalytic
methods have recently been described for α-sulfenylation of
suitable functionalized acid derivatives with activated α-C−H
bonds,3 such as β-ketoesters and related compounds,4
functionalized oxindoles, azalactones, and isoxazolidin-5-
ones.5 In the case of common acid derivatives without a
highly acidic α-CH, using chiral auxiliaries such as chiral
imidazolidinones,6 oxazolidinones,7 and pyrazoles8,9 can
induce facial selectivity of α-thio-functionalization. However,
these chiral auxiliaries have rarely been used with α-aryl-
substituted substrates for α-sulfenylation. A notable exception
is α-CF3S functionalization using Evans oxazolidinones,
resulting in diastereoselectivities ranging from 97:3 to 70:30.7b
It is important to develop α-sulfenylation reactions using α-
aryl-substituted substrates because such substitutions are found
in many bioactive nontrifluoromethylthiolated sulfides. Efluci-
mibe, for example, is a chiral α-aryl α-n-dodecylthiolated amide
used in the treatment of atherosclerosis and lipoprotein
disorders (Scheme 1).10 Sulconazole11 (Scheme 1) is an
antifungal medicine with an α-aryl β-amino sulfide (1,2-
sulfanyl amine) substructure.12 This substructure can be
accessed via enantioselective 1,4-addition of thioacetic acid
to aromatic nitroalkenes, followed by reduction.11b Another
N-tert-Butanesulfinyl (N-tBS) imidates are Ellman auxil-
iary15-based chiral ester equivalents and have been successfully
applied to diastereoselective formation of C−C,16−19 C−N,20
and C−O bonds21 at the α-position (Scheme 2a). To date, no
Scheme 2. Transformations Involving the α-Position of N-
tert-Butanesulfinyl Imidates
Scheme 1. Representative Bioactive Compounds Containing
an Aryl Group on the Chiral α-Carbon of Sulfides
Received: June 4, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b01403
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
C−S bond formation involving N-tBS imidate has been
reported (Scheme 2b). We reasoned that diastereoselective
α-sulfenylation of N-tBS imidates would provide efficient paths
to functionalized chiral sulfides with (S)- or (R)-configurations
as both enantiomers of tert-butanesulfinamide (tBSNH2), the
chiral starting materials for N-tBS imidates, are easily available
and inexpensive, and the N-tBS imidate group can easily be
converted to a range of functionalities such as amides, esters,
N-tBS imines, and amines.20,21
We began our studies by lithiating α-phenyl N-(RS)-tert-
butanesulfinyl imidate 1a in THF using lithium bis(trimethyl-
silyl)amide and then treating it with the common sulfenylating
agent N-phenylthiophthalimide (2) (Table 1, entry 1). The α-
improved diastereoselectivity (1:10 dr) were achieved by using
phenyl disulfide as a sulfenylating reagent and 2.0 equiv of base
in dichloromethane (entry 10). Under these conditions,
introduction of HMPA did not affect dr (entry 11). In this
way, we defined the optimal conditions for reaction of α-aryl
and α-alkyl N-tBS imidates with suitable sulfenylating agents
(entries 3 and 10).
With the optimized reaction conditions in hand, we
evaluated the range of N-R′S-phthalimides and α-aryl N-tBS
imidates compatible with α-sulfenylation. The reaction of α-
PMP N-tBS imidate 1c with N-phenylthiophthalimide (2) gave
α-phenylthiolated product 4c with high diastereoselectivity
(Table 2, entry 2:30:1 dr), and its absolute configuration was
determined as (RS, 2S) by X-ray crystallography. Phthalimide-
based alkylthio-functionalization reagents 6−9 (R′ = Et, Bn, 4-
Table 1. Optimization of α-Sulfenylation of N-tert-
a
Butanesulfinyl Imidates
Table 2. Substrate Scope of the α-Sulfenylation of N-tert-
a
Butanesulfinyl Imidates
b
entry
imidate
PhS+
solvent
conv (%)
dr (4:5)
yield
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
2
2
2
3
3
2
2
3
3
3
3
THF
100
77
100 (99)
50
∼1:1
9:1
9:1
1:4
1:4
3:1
−
1:7
1:10
1:10
1:10
b
c
entry
imidate (R)
1a (Ph)
1c
sulfur reagent (R′) product (%)
dr
CH2Cl2
CH2Cl2
THF
CH2Cl2
THF
CH2Cl2
THF
CH2Cl2
CH2Cl2
CH2Cl2
d
c
d
1
2
2 (Ph)
2 (Ph)
4a
4c
99
91
9:1
d
30:1
(4-MeOC6H4)
83
3
4
5
1a (Ph)
1a (Ph)
1a (Ph)
1a (Ph)
6 (Et)
7 (Bn)
8 (4-ClC6H4CH2)
9 (n-C12H25)
6 (Et)
4d
4e
4f
4g
4h
93
86
98
97
92
>30:1
25:1
20:1
>30:1
30:1
50%
<10%
100
65
100 (97)
33
d
d
e
6
7
1c
c
d
10
11
(4-MeOC6H4)
ce
,
8
9
1d (4-FC6H4)
1e (4-ClC6H4)
1f (4-CF3C6H4)
1g (4-MeC6H4)
1h (3-MeC6H4)
1i (2-MeC6H4)
6 (Et)
6 (Et)
6 (Et)
6 (Et)
6 (Et)
6 (Et)
6 (Et)
4i
4j
92
86
83
96
99
99
90
30:1
25:1
17:1
28:1
>30:1
>30:1
25:1
a
f
Reaction conditions: 1a or 1b (0.20 mmol), base (1.2 equiv), and
sulfenylating reagent (1.3 equiv) in anhydrous solvent (2.0 mL) at
−78 °C. Reactions were stirred at −78 °C for 1 h after addition of
sulfenylating reagent unless otherwise noted. Conversion and
diastereoselective ratios were determined by H NMR spectroscopy
of the crude reaction mixture. 2.0 equiv of base were used. Isolated
yield of inseparable diastereomers after silica gel chromatography. 3.0
equiv of HMPA were used.
f
10
4k
4l
4m
4n
4o
11
12
13
b
1
c
d
f
14
1j
e
(2,4-diClC6H3)
f
d
d
d
15
1j
8 (4-ClC6H4CH2)
8 (4-ClC6H4CH2)
4p
94
93
25:1
25:1
(2,4-diClC6H3)
f
16
ent-1j
(2,4-diClC6H3)
1b (Me)
ent-4p
sulfenylation reaction proceeded smoothly but with poor facial
selectivity (∼1:1 dr). A limited screen of bases including
LiHMDS, NaHMDS, and KHMDS as well as solvents such as
toluene, ether, and dichloromethane showed that the best
diastereoselectivity (9:1 dr) was achieved by using LiHMDS as
a base and dichloromethane as solvent, albeit with only 77%
conversion (entry 2). This incomplete conversion was
overcome by using 2.0 equiv of base, without loss of
diastereoselectivity (entry 3). Phenyl disulfide (3), another
typical sulfur electrophile, led to sulfenylation of 1a in THF or
dichloromethane, giving the desired products with moderate
diastereocontrol that was inverted relative to that obtained
with 2 (1:4 dr in entries 4 and 5 vs 9:1 dr in entries 2 and 3).
The α-methyl N-tBS imidate 1b resulted in a similar inversion
of diastereoselectivity (3:1 dr using 2 in entry 6 vs 1:7 dr using
3 in entry 8). Complete α-thiofunctionalization of 1b and
17
18
3 (Ph)
3 (Ph)
5b
5c
97
80
10:1
30:1
1k
(PhCCCH2)
d
d
19
20
21
1l (Pr)
3 (Ph)
3 (Ph)
3 (Ph)
5d
5e
5f
88
99
91
9:1
1m (allyl)
1n (Bn)
15:1
9:1
a
Reaction conditions: 1 (0.20 mmol), LiHMDS (0.40 mmol), and
sulfenylating reagent (0.26 mmol) in anhydrous CH2Cl2 (2.0 mL) at
−78 °C. Reactions were complete within 1 h unless otherwise noted.
b
c
Isolated yield after silica gel chromatography. Diastereoselective
ratios were determined by 1H NMR spectroscopy of the crude
d
reaction mixture. Yield of a mixture of inseparable diastereomers.
1.3 equiv of imidate 1a was used to facilitate the isolation of product
due to similar Rf values of 9 and 4g on TLC; 1-g scale reaction. 1.1
equiv of LiHMDS was used to avoid the erosion of dr.
e
f
B
DOI: 10.1021/acs.joc.8b01403
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
ClC6H4CH2, and C12H25) were also good reaction partners,
furnishing the corresponding α-thio-functionalized imidates
4d−g in good yields with high diastereoselectivities (entries
3−6). The sulfenylated product α-n-dodecylthiolated imidate
4g, a synthetic precursor for eflucimibe, was easily prepared on
the 1-g scale in 97% yield with excellent dr. In the presence of
N-EtS-phthalimide as a sulfenylation reagent, α-aryl N-tBS
imidates containing electron-donating (entry 7) or electron-
withdrawing (entries 8−11 and 14) groups on the aromatic
ring were suitable substrates, generally affording high yields
and diastereoselectivities. Yield and diastereoselectivity varied
only slightly when a methyl substitution was shifted among the
ortho, meta, and para positions on the phenyl ring (entries 11−
13). In the case of several electron-deficient α-aryl N-tBS
imidates such as 1e, 1f, and 1j, reducing the amount of base
from 2.0 to 1.1 equiv was necessary to avoid loss of
diastereoselectivity because of the relatively high acidity of
the α-proton (entries 9, 10, and 14). Under these modified
reaction conditions, 4-chlorobenzylthiolation of both enan-
tiomers of α-2,4-dichlorophenyl imidate proceeded well and
produced 4p and ent-4p in excellent yields with excellent
diastereocontrol (entries 15 and 16).
Next, several α-alkyl N-tBS imidates 1k−n were examined
using phenyl disulfide (3) as the α-sulfenylation reagent,
providing α-phenylthiolated products 5c−f as inseparable
mixtures of diastereomers in high yields with high diaster-
eoselectivities (entries 18−21). We assigned the absolute
configuration of the major isomer of 5c as (RS, 2R) using X-ray
crystallography. Other disulfides, such as ethyl, benzyl, and tert-
butyl disulfides, did not react, with the substrate imidate 1b
remaining intact.
We rationalized the diastereoselectivity of α-sulfenylation
with N-SR′-phthalimide based on the chelated chair−chair-like
8/4 bicyclic transition state TS-1 (Scheme 4).24 In this
Scheme 4. Rationalization of Stereochemistry
scheme, the reaction occurs preferentially on the Si-face of the
trans-(RS)-aza-enolate in order to minimize nonbonding
interactions between the phthalimide group and the tBu
group in the imidate. In contrast, the nucleophilic attack of
imidates on disulfide may involve C−S bond formation via a
nonchelated open transition state (TS-2), which would explain
the observed inversion of facial selectivity.25
In summary, we have described a highly diastereoselective α-
sulfenylation of N-tert-butanesulfinyl imidates, allowing
efficient construction of chiral α-thiofunctionalized imidates.
Enantioenriched sulconazoles in (S)- or (R)-configurations
were rapidly synthesized, proving the effectiveness of the
protocol for synthesizing chiral β-sulfanyl amines.
Sulconazole was used as a racemate, and antifungal
inhibitory activity data for its enantiomers are not available.
The reported in vitro studies of some other azole antifungals
showed that one enantiomer can be significantly more active
than another enantiomer.22 We synthesized both enantioen-
riched isomers of sulconazole to demonstrate the synthetic
utility of this method. The enantioenriched (S)-sulconazole
was prepared by using α-sulfenylated N-tBS imidate 4p via
DIBAL-H reduction, iodine-mediated desulfinylation,23 and
condensation (Scheme 3). Similarly, the (R)-sulconazole10b
was easily synthesized in 97.5:2.5 er and good yield (57% over
three steps) using ent-4p as the starting material.
EXPERIMENTAL SECTION
■
General Experimental Details. All reactions were performed
under an argon atmosphere in flame-dried glassware with magnetic
stirring. All solvents were purified according to the standard
procedures. HMPA was freshly distilled before use. Purification of
the reaction products was carried out by flash column chromatog-
raphy using 200−300 mesh silica gel. Visualization on TLC (analytical
thin layer chromatography) was achieved by the use of UV light (254
nm) and treatment with aqueous ceric ammonium molybdate staining
followed by heating. High-resolution mass spectra (HRMS) were
recorded using electron spray ionization with a time-of-flight mass
analyzer (ESI-TOF). Proton and carbon magnetic resonance spectra
(1H NMR and 13C NMR) were recorded on a 400 MHz (1H NMR at
400 MHz and 13C NMR at 100 MHz) spectrometer with solvent
resonance as the internal standard (1H NMR: CDCl3 at 7.26 ppm;
Scheme 3. Synthesis of Enantioenriched (S)- and (R)-
Sulconazole
1
13C NMR: CDCl3 at 77.16 ppm). H NMR data are reported as
follows: chemical shifts, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet), coupling constant(s) in Hz, and
integration.
Materials. Dichloromethane was distilled from CaH2. THF was
distilled from sodium/benzophenone. (RS)-tert-Butanesulfinamide
with ee > 99.0% was purchased from a commercial source and used
as received. N-tert-Butanesulfinyl imidates 1a−e, 1g−i, and 1k−n are
known compounds and were prepared according to the reported
procedure.16a,20,21 Imidates 1f, 1j, and ent-1j are new compounds and
were prepared with the following procedure. Sulfenylation reagents 2
and 3 were purchased from a commercial source. Sulfenylation
reagents 6 and 7 are known compounds and were prepared according
to the reported procedure.26 Sulfenylation reagents 8 and 9 are new
compounds and were prepared according to refs 27 and 26,
respectively.26,27
C
DOI: 10.1021/acs.joc.8b01403
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
General Procedure for the Preparation of Imidates 1f, 1i,
and ent-1j. The mixture of N-tert-butanesulfinamide (1.0 equiv),
orthoester (1.1 equiv), and p-toluenesulfonic acid (0.01 equiv) was
stirred at 100 °C for 10 h. After cooling to room temperature, the
reaction mixture was purified by silica gel chromatography.
Hz, 2H), 1.61−1.54 (m, 2 H), 1.44−1.23 (m, 18 H), 0.87 (t, J = 6.8
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.5, 134.5, 132.1, 123.8,
38.6, 31.9, 29.6, 29.5, 29.4, 29.3, 29.2, 28.4, 28.1, 22.7, 14.1; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C20H30NO2S 348.1992; found
348.1991.
(RS)-Methyl N-tert-Butylsulfinyl-2-(4-(trifluoromethyl)phenyl)-
acetimidate (1f). The general procedure was followed with (RS)-
tert-butanesulfinamide (1.21 g, 10 mmol), trimethyl 4-trifluoromethyl
orthophenylacetate (2.90 g, 11.0 mmol), and p-toluenesulfonic acid
(17.2 mg, 0.10 mmol), and column chromatography afforded 1f
(yellow solid, 1.53 g, 48% yield). Analytical data for 1f: Rf = 0.30
(petroleum ether/ethyl acetate = 8/1), mp 52−53 °C; [α]D25 = −68.0
(c 0.10, MeOH); 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz,
2H), 7.45 (d, J = 4.0 Hz, 2H), 4.11 (d, J = 14.0 Hz, 1H), 4.05 (d, J =
14.0 Hz, 1Hc), 3.75 (s, 3H), 1.22 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 172.3, 138.6, 129.9, 129.5 (d, JC−F = 32.1 Hz), 125.6 (q,
JC−F = 3.8 Hz), 124.3 (d, JC−F = 279.7 Hz), 56.6, 54.7, 38.5, 22.1;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H19F3NO2S
322.1083; found 322.1085.
General Procedure A for the Preparation of Products 4a−
4f, 4h, 4i, 4l−4n, 5b−5e. To a cooled solution of N-tert-
butanesulfinyl imidate (1.0 equiv) in dichloromethane was added
LiHMDS (1.0 M in THF, 2.0 equiv) at −78 °C. After the reaction
mixture was stirred for 30 min at −78 °C, a solution of sulfenylation
reagent (1.3 equiv) in dichloromethane was added. Afterward, the
reaction mixture was stirred for 1 h at −78 °C. The reaction was
quenched with saturated aqueous ammonium chloride and extracted
with ethyl acetate (3 times). The combined organic layers were
washed with brine, dried over Na2SO4, filtered, and concentrated
under vacuum. The residue was purified by flash column
chromatography on silica gel.
General Procedure B for the Preparation of Products 4j, 4k,
4o, 4p, ent-4p. Procedure A was followed except the use of a
decreased amount of LiHMDS (1.0 M in THF, 1.1 equiv).
(S)-Methyl N-((RS)-tert-Butylsulfinyl)-2-phenyl-2-(phenylthio)-
acetimidate (4a). According to procedure A, the reaction of imidate
1a (75.9 mg, 0.30 mmol), LiHMDS (1.0 M in THF, 600 μL, 0.60
mmol), and sulfenylating reagents 2 (99.0 mg, 0.26 mmol) generated
product 4a with a diastereomeric ratio of 9:1. Column chromatog-
raphy (petroleum ether/ethyl acetate = 7/1) afforded 4a (colorless
oil, 108.1 mg, 99% yield). Analytical data for 4a: Rf = 0.30 (petroleum
ether/ethyl acetate = 6/1); 1H NMR (400 MHz, CDCl3) δ 7.50−7.47
(m, 2H), 7.41−7.38 (m, 2H), 7.31−7.21 (m, 6H), 6.16 (s, 1H), 3.79
(s, 3H), 1.13 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 169.4, 136.3,
133.9, 132.4, 129.1, 128.9, 128.8, 128.4, 127.8, 57.1, 55.0, 52.5, 22.1;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H24NO2S2 362.1243;
found 362.1241.
(RS)-Methyl N-tert-Butylsulfinyl-2-(2,4-dichlorophenyl)-
acetimidate (1j). The general procedure was followed with (RS)-
tert-butanesulfinamide (1.21 g, 10 mmol), trimethyl 2,4-dichloro
orthophenylacetate (2.65 g, 11.0 mmol), and p-toluenesulfonic acid
(17.2 mg, 0.10 mmol), and column chromatography afforded 1j
(yellow oil, 1.1 g, 34% yield). Analytical data for 1j: Rf = 0.30
25
(petroleum ether/ethyl acetate = 8/1), [α]D = −88.0 (c 0.10,
1
MeOH); H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 1.6 Hz, 1H),
7.24−7.18 (m, 2H), 4.22 (d, J = 16.0 Hz, 1H), 4.05 (d, J = 16.0 Hz,
1H), 3.73 (s, 3H), 1.24 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
172.7, 135.1, 133.8, 132.2, 131.5, 129.4, 127.3, 56.4, 54.7, 36.4, 22.1;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H18Cl2NO2S
322.0430; found 322.0437.
(SS)-Methyl N-tert-Butylsulfinyl-2-(2,4-dichlorophenyl)-
acetimidate (ent-1j). The general procedure was followed with
(SS)-tert-butanesulfinamide (1.82 g, 15 mmol), corresponding
orthoester (3.98 g, 16.5 mmol), and p-toluenesulfonic acid (26.2
mg, 0.15 mmol), and column chromatography afforded ent-1j (yellow
oil, 1.8 g, 38% yield). Analytical data for ent-1j: Rf = 0.30 (petroleum
ether/ethyl acetate = 8/1); [α]D25 = 84.0 (c 0.10, MeOH); 1H NMR
(400 MHz, CDCl3) δ 7.38 (d, J = 1.6 Hz, 1H), 7.24−7.18 (m, 2H),
4.22 (d, J = 16.0 Hz, 1H), 4.05 (d, J = 16.0 Hz, 1H), 3.73 (s, 3H),
1.24 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.7, 135.1, 133.8,
132.2, 131.5, 129.4, 127.3, 56.4, 54.7, 36.4, 22.1; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C13H18Cl2NO2S 322.0430; found 322.0434.
2-((4-Chlorobenzyl)thio)isoindoline-1,3-dione (8). The mixture of
N-bromophthalimide (6.8 g, 30.0 mmol) and 4-chlorophenyldisulfide
(12.3 g, 50.0 mmol) in 20 mL of dry benzene was refluxed for 40 min.
The red reaction mixture was allowed to cool to room temperature
before addition of 30 mL of n-hexane. The crystals formed were
filtered off, and further recrystallization using hot EtOH afforded 8
(white solid, 4.5 g, 49% yield). Analytical data for 8: mp 175−176 °C;
1H NMR (400 MHz, CDCl3) δ 7.88−7.84 (m, 2H), 7.77−7.73 (m,
(S)-Methyl N-((RS)-tert-Butylsulfinyl)-2-(4-methoxyphenyl)-2-
(phenylthio)acetimidate (4c). According to procedure A, the
reaction of imidate 1c (84.9 mg, 0.30 mmol), LiHMDS (1.0 M in
THF, 600 μL, 0.6 mmol), and sulfenylating reagents 2 (99.0 mg, 0.26
mmol) generated product 4c with a diastereomeric ratio of 30:1.
Column chromatography (petroleum ether/ethyl acetate = 8/1)
afforded 4c (white solid, 106.1 mg, 91% yield). Analytical data for 4c:
Rf = 0.30 (petroleum ether/ethyl acetate = 7/1); 1H NMR (400
MHz, CDCl3) δ 7.41−7.38 (m, 4H), 7.26−7.18(m, 3H), 6.85−6.81
(m, 2H), 6.11 (s, 1H), 3.79 (s, 3H), 3.78 (s, 3H) 1.11 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 169.6, 159.6, 134.1, 132.3, 130.1, 129.1,
128.2, 127.7, 114.2, 57.0, 55.4, 55.0, 55.8, 22.1; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C20H26NO3S2 392.1349; found 392.1346.
(S)-Methyl N-((RS)-tert-Butylsulfinyl)-2-(ethylthio)-2-phenyl-
acetimidate (4d). According to procedure A, the reaction of imidate
1a (50.6 mg, 0.20 mmol), LiHMDS (1.0 M in THF, 400 μL, 0.4
mmol), and sulfenylating reagents 6 (53.8 mg, 0.26 mmol) generated
product 4d with a diastereomeric ratio of >30:1. Column
chromatography (petroleum ether/ethyl acetate = 8/1) afforded 4d
(colorless oil, 58.3 mg, 93% yield). Analytical data for 4d: Rf = 0.38
2H), 7.23−7.18 (m, 4 H) 4.08 (s, 2H); 13C NMR (100 MHz, CDCl3)
δ 167.9, 134.7, 133.9, 133.0, 131.9, 130.9, 128.9, 124.0, 41.9; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C15H11ClNO2S 304.0194; found
304.0195.
25
(petroleum ether/ethyl acetate = 7/1); [α]D = −140.0 (c 0.10,
1
MeOH); H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.2 Hz, 2H),
7.35−7.27 (m, 3H), 5.74 (s, 1H), 3.81 (s, 3H), 2.63−2.50 (m, 2H),
1.24 (t, J = 7.2 Hz, 3H), 1.19 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 171.2, 136.9, 128.84, 128.81, 128.2, 55.9, 55.0, 48.8, 26.6, 22.2, 14.5;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H24NO2S2 314.1243;
found 314.1242.
(S)-Methyl N-((RS)-tert-Butylsulfinyl)-2-(benzylthio)-2-phenyl-
acetimidate (4e). According to procedure A, the reaction of imidate
1a (50.6 mg, 0.20 mmol), LiHMDS (1.0 M in THF, 400 μL, 0.4
mmol), and sulfenylating reagents 7 (70.1 mg, 0.26 mmol) generated
product 4e with a diastereomeric ratio of 25:1. Column chromatog-
raphy (petroleum ether/ethyl acetate = 10/1) afforded 4e (colorless
oil, 64.6 mg, 86% yield). Analytical data for 4e: Rf = 0.30 (petroleum
ether/ethyl acetate = 8/1); 1H NMR (400 MHz, CDCl3) δ 7.46−7.43
(m, 2H), 7.33−7.27 (m, 7H), 7.23−7.20 (m, 1H), 5.66 (s, 1H),
3.80−3.69 (m, 5H), 1.14 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
2-(Dodecylthio)isoindoline-1,3-dione (9). SO2Cl2 (2.68 g, 20
mmol) was added dropwise to a solution of 1-dodecanethiol (4.04 g,
20 mmol) and Et3N (202 mg, 2.0 mmol) in 20 mL of
dichloromethane at 0 °C. After stirring for 15 min, the mixture was
warmed to room temperature, stirred for 30 min, and then cooled to 0
°C. The resulting solution was transferred dropwise via cannula to a
solution of phthalimide (2.94 g, 20 mmol) in dichloromethane and
Et3N (2.63 g, 26 mmol) at 0 °C, and the mixture was then warmed to
room temperature over 1 h. The solution was diluted with water,
extracted with CH2Cl2, dried over Na2SO4, filtered, and concentrated
under vacuum to give a crude product that was subjected to
recrystallization using hot EtOH affording 9 (white solid, 3.7 g, 53%
1
yield). Analytical data for 9: mp 70−71 °C; H NMR (400 MHz,
CDCl3) δ 7.94−7.90 (m, 2H), 7.79−7.75 (m, 2 H), 2.87 (t, J = 7.6
D
DOI: 10.1021/acs.joc.8b01403
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
170.9, 137.2, 136.5, 129.2, 128.9, 128.8, 128.6, 128.2, 127.2, 56.8,
55.0, 49.4, 37.1, 22.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C20H26NO2S2 376.1399; found 376.1396.
2H), 1.24 (t, J = 7.2 Hz, 3H), 1.20 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 170.2, 135.6, 134.2, 130.2, 129.0, 57.1, 55.0, 48.0, 26.6,
22.2, 14.4; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C15H23ClNO2S2 348.0853; found 348.0856.
(S)-Methyl N-((RS)-tert-Butylsulfinyl)-2-((4-chlorobenzyl)thio)-2-
phenylacetimidate (4f). According to procedure A, the reaction of
imidate 1a (50.6 mg, 0.20 mmol), LiHMDS (1.0 M in THF, 400 μL,
0.4 mmol), and sulfenylating reagents 8 (78.9 mg, 0.26 mmol)
generated product 4f with a diastereomeric ratio of 20:1. Column
chromatography (petroleum ether/ethyl acetate = 8/1) afforded 4f
(colorless oil, 80.6 mg, 98% yield). Analytical data for 4f: Rf = 0.30
(petroleum ether/ethyl acetate = 8/1); 1H NMR (400 MHz, CDCl3)
δ 7.44−7.41 (m, 2H), 7.33−7.23 (m, 7H), 5.67 (s, 1H), 3.76−3.67
(m, 5H), 1.15 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.1, 136.6,
136.2, 133.3, 130.9, 129.1, 129.0, 128.6, 57.1, 55.3, 49.6, 36.7, 22.4;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H25ClNO2S2
410.1010; found 410.1006.
(S)-Methyl N-((RS)-tert-Butylsulfinyl)-2-(ethylthio)-2-(4-(trifluoro-
methyl)phenyl)acetimidate (4k). According to procedure B, the
reaction of imidate 1f (64.2 mg, 0.20 mmol), LiHMDS (1.0 M in
THF, 220 μL, 0.22 mmol), and sulfenylating reagents 6 (53.8 mg,
0.26 mmol) generated product 4k with a diastereomeric ratio of 17:1.
Column chromatography (petroleum ther/ethyl acetate = 8/1)
afforded 4k (colorless oil, 76.4 mg, 83% yield). Analytical data for
4k: Rf = 0.30 (petroleum ether/ethyl acetate = 7/1); [α]D25 = −128.0
(c 0.10, MeOH); 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.4 Hz,
2H), 7.59 (d, J = 8.4 Hz, 2H), 5.86 (s, 1H), 3.79 (s, 3H), 2.63−2.50
(m, 2H), 1.24 (t, J = 7.2 Hz, 3H), 1.22 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 168.9, 141.5, 130.7 (q, JC−F = 32.3 Hz), 129.6, 126.1 (q,
(S)-Methyl N-((RS)-tert-Butylsulfinyl)-2-(dodecylthio)-2-phenyl-
acetimidate (4g). According to procedure A, the reaction of imidate
1a (1.05 g, 4.16 mmol), LiHMDS (1.0 M in THF, 4.6 mL, 4.6 mmol),
and sulfenylating reagents 8 (1.1 g, 3.2 mmol) generated product 4g
with a diastereomeric ratio of 20:1. Column chromatography
(petroleum ether/ethyl acetate = 20/1) afforded 4g (colorless oil,
1.34 g, 97% yield). Analytical data for 4g: Rf = 0.20 (petroleum ether/
ethyl acetate = 20/1); [α]D = −120.0 (c 0.10, MeOH); H NMR
(400 MHz, CDCl3) δ 7.51−7.49 (m, 2H), 7.35−7.28 (m, 3H), 5.70
(s, 1H), 3.82 (s, 3H), 2.56−2.52 (m, 2H), 1.59−1.51 (m, 2H), 1.33−
1.22 (m, 18H), 1.17 (s, 9H), 0.88 (t, J = 6.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 171.9, 137.0, 128.8, 128.2, 128.2, 56.8, 55.0, 49.2,
32.6, 32.1, 29.8, 29.7, 29.7, 29.6, 29.5, 29.3, 29.2, 28.9, 22.8, 22.2,
14.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H44NO2S2
454.2808; found 454.2807.
JC−F = 3.6 Hz), 124.4 (q, JC−F = 270 Hz), 57.5, 55.4, 48.4, 27.0, 22.5,
14.7; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H23NO2S2F3
382.1117; found 382.1118.
(S)-Methyl N-((RS)-tert-Butylsulfinyl)-2-(ethylthio)-2-(p-tolyl)-
acetimidate (4l). According to procedure A, the reaction of imidate
1g (53.4 mg, 0.20 mmol), LiHMDS (1.0 M in THF, 400 μL, 0.4
mmol), and sulfenylating reagents 6 (53.8 mg, 0.26 mmol) generated
product 4l with a diastereomeric ratio of 28:1. Column chromatog-
raphy (petroleum ether/ethyl acetate = 10/1) afforded 4l (colorless
oil, 63.3 mg, 96% yield). Analytical data for 4l: Rf = 0.30 (petroleum
25
1
25
1
ether/ethyl acetate = 7/1); [α]D = −132.0 (c 0.10, MeOH); H
NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0
Hz, 2H), 5.70 (s, 1H), 3.81 (s, 3H), 2.62−2.51 (m, 2H), 2.33 (s, 3H),
1.24 (t, J = 7.2 Hz, 3H), 1.18 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 171.5, 138.1, 133.9, 129.6, 128.7, 56.8, 55.0, 48.5, 26.6, 22.2, 21.3,
14.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H26NO2S2
328.1399; found 328.1395.
(S)-Methyl N-((RS)-tert-Butylsulfinyl)-2-(ethylthio)-2-(4-methoxy-
phenyl)acetimidate (4h). According to procedure A, the reaction of
imidate 1c (56.6 mg, 0.20 mmol), LiHMDS (1.0 M in THF, 400 μL,
0.4 mmol), and sulfenylating reagents 6 (53.8 mg, 0.26 mmol)
generated product 4h with a diastereomeric ratio of 30:1. Column
chromatography (petroleum ether/ethyl acetate = 8/1) afforded 4h
(colorless oil, 63.4 mg, 92% yield). Analytical data for 4h: Rf = 0.30
(S)-Methyl N-((RS)-tert-Butylsulfinyl)-2-(ethylthio)-2-(m-tolyl)-
acetimidate (4m). According to procedure A, the reaction of imidate
1h (53.4 mg, 0.20 mmol), LiHMDS (1.0 M in THF, 400 μL, 0.4
mmol), and sulfenylating reagents 6 (53.8 mg, 0.26 mmol) generated
product 4m with a diastereomeric ratio of >30:1. Column
chromatography (petroleum ether/ethyl acetate = 10/1) afforded
4m (colorless oil, 64.8 mg, 99% yield). Analytical data for 4m: Rf =
0.30 (petroleum ether/ethyl acetate = 7/1); [α]D25 = −122.0 (c 0.10,
25
(petroleum ether/ethyl acetate = 7/1); [α]D = −123.0 (c 0.10,
1
MeOH); H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.8 Hz, 2H),
6.85 (d, J = 8.8 Hz, 2H), 5.69 (s, 1H), 3.81 (s, 3H), 3.79 (s, 3H),
2.61−2.48 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H), 1.18 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 171.3, 159.4, 129.8, 128.6, 114.1, 56.6, 55.3,
54.8, 48.0, 26.4, 22.0, 14.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C16H26NO3S2 344.1349; found 344.1345.
1
MeOH); H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.0 Hz, 2H),
7.21 (t, J = 7.2 Hz, 2H), 7.09 (d, J = 8.0 Hz, 1H), 5.71 (s, 1H), 3.82
(s, 3H), 2.64−2.50 (m, 2H), 2.34 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H),
1.18 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 171.3, 138.5, 136.7,
129.3, 129.0, 128.6, 125.8, 56.8, 55.0, 48.7, 26.6, 22.1, 21.5, 14.4;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H26NO2S2 328.1399;
found 328.1394.
(S)-Methyl N-((RS)-tert-Butylsulfinyl)-2-(ethylthio)-2-(4-fluoro-
phenyl)acetimidate (4i). According to procedure A, the reaction of
imidate 1d (54.2 mg, 0.20 mmol), LiHMDS (1.0 M in THF, 400 μL,
0.4 mmol), and sulfenylating reagents 6 (53.8 mg, 0.26 mmol)
generated product 4i with a diastereomeric ratio of 30:1. Column
chromatography (petroleum ether/ethyl acetate = 8/1) afforded 4i
(colorless oil, 66.2 mg, 92% yield). Analytical data for 4i: Rf = 0.30
(S)-Methyl N-((RS)-tert-Butylsulfinyl)-2-(ethylthio)-2-(o-tolyl)-
acetimidate (4n). According to the general procedure A, the reaction
of imidate 1i (53.4 mg, 0.20 mmol), LiHMDS (1.0 M in THF, 400
μL, 0.4 mmol), and sulfenylating reagents 6 (53.8 mg, 0.26 mmol)
generated product 4n with a diastereomeric ratio of >30:1. Column
chromatography (petroleum ether/ethyl acetate = 10/1) afforded 4n
(colorless oil, 64.7 mg, 99% yield). Analytical data for 4n: Rf = 0.30
25
(petroleum ether/ethyl acetate = 7/1); [α]D = −44.0 (c 0.10,
1
MeOH); H NMR (400 MHz, CDCl3) δ 7.52−7.47 (m, 2H), 7.05−
6.99 (m, 2H), 5.76 (s, 1H), 3.80 (s, 3H), 2.62−2.48 (m, 2H), 1.24 (t,
J = 7.2 Hz, 3H), 1.19 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.1,
162.6 (d, J = 245.9 Hz), 132.7 (d, J = 3.2 Hz), 130.5 (d, J = 8.4 Hz),
115.7 (d, J = 21.4 Hz), 57.0, 55.0, 47.9, 26.6, 22.2, 14.4; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C15H23NO2S2F 332.1149; found
332.1151.
25
(petroleum ether/ethyl acetate = 7/1); [α]D = −126.0 (c 0.10,
1
MeOH); H NMR (400 MHz, CDCl3) δ 7.51−7.48 (m, 1H), 7.14−
7.20 (m, 3H), 5.84 (s, 1H), 3.88 (s, 3H), 2.72−2.54 (m, 2H), 2.50 (s,
3H), 1.26 (t, J = 7.2 Hz, 3H), 1.13 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 171.9, 136.5, 134.9, 130.8, 128.7, 128.1, 126.5, 56.8, 55.2,
45.7, 26.9, 22.1, 19.9, 14.6; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C16H26NO2S2 328.1399; found 328.1396.
(S)-Methyl N-((RS)-tert-Butylsulfinyl)-2-(ethylthio)-2-(4-chloro-
phenyl)acetimidate (4j). According to procedure B, The title
compound was prepared using imidate 1e (57.4 mg, 0.20 mmol, 1.0
equiv), LiHMDS (1.0 M in THF, 220 μL, 0.22 mmol, 1.1 equiv), and
sulfenylating reagents 6 (53.8 mg, 0.26 mmol, 1.3 equiv). Column
chromatography (petroleum ether/ethyl acetate = 8/1) afforded 4j
(colorless oil, 66.2 mg, 86% yield). Analytical data for 4j: Rf = 0.38
(S)-Methyl N-((RS)-tert-Butylsulfinyl)-2-(2,4-dichlorophenyl)-2-
(ethylthio)acetimidate (4o). According to procedure B, the reaction
of imidate 1j (64.2 mg, 0.20 mmol), LiHMDS (1.0 M in THF, 220
μL, 0.22 mmol), and sulfenylating reagents 6 (53.8 mg, 0.26 mmol)
generated product 4o with a diastereomeric ratio of >30:1. Column
chromatography (petroleum ether/ethyl acetate = 10/1) afforded 4o
(colorless oil, 76.4 mg, 90% yield). Analytical data for 4o: Rf = 0.30
25
(petroleum ether/ethyl acetate = 7/1); [α]D = −115.0 (c 0.10,
1
MeOH); H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 4.4 Hz, 2H),
25
7.30 (d, J = 8.8 Hz, 2H), 5.76 (s, 1H), 3.79 (s, 3H), 2.62−2.48 (m,
(petroleum ether/ethyl acetate = 7/1); [α]D = −134.0 (c 0.10,
E
DOI: 10.1021/acs.joc.8b01403
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
MeOH); H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.4 Hz, 1H),
(petroleum ether/ethyl acetate = 6/1); 1H NMR (400 MHz, CDCl3)
δ 7.48−7.46 (m, 2H), 7.29−7.23 (m, 3H), 4.76−4.73 (m, 1H), 3.70
(s, 3H), 1.93−1.71 (m, 2H), 1.52−1.30 (m, 2H), 1.09 (s, 9H), 0.92
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.3, 134.1,
132.9, 129.0, 128.4, 56.1, 54.3, 48.3, 34.5, 22.0, 20.7, 13.8; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C16H26NO2S2 328.1399; found
328.1398.
7.37 (d, J = 2.0 Hz, 1H), 7.28−7.25 (m, 1H), 5.99 (s, 1H), 3.77 (s,
3H), 2.78−2.61 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H), 1.22 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 169.7, 134.5, 134.2, 133.9, 132.3, 129.2,
127.6, 57.0, 55.2, 45.2, 27.2, 22.2, 14.6; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C15H22Cl2NO2S2 382.0464; found 382.0466.
(S)-Methyl N-((RS)-tert-Butylsulfinyl)-2-((4-chlorobenzyl)thio)-2-
(2,4-dichlorophenyl)acetimidate (4p). According to general proce-
dure B, the reaction of imidate 1j (64.2 mg, 0.20 mmol), LiHMDS
(1.0 M in THF, 220 μL, 0.22 mmol), and sulfenylating reagents 8
(78.9 mg, 0.26 mmol) generated product 4p with a diastereomeric
ratio of 25:1. Column chromatography (petroleum ether/ethyl acetate
= 10/1) afforded 4p (colorless oil, 89.5 mg, 93% yield). Analytical
(R)-Methyl N-((RS)-tert-Butylsulfinyl)-2-(phenylthio)pent-4-enimi-
date (5e). According to general procedure A, the reaction of imidate
1m (65.1 mg, 0.30 mmol), LiHMDS (1.0 M in THF, 600 μL, 0.6
mmol), and sulfenylating reagents 3 (85.0 mg, 0.39 mmol) generated
product 5e with a diastereomeric ratio of 15:1. Column chromatog-
raphy (petroleum ether/ethyl acetate = 7/1) afforded 5e (colorless
oil, 97.0 mg, 99% yield). Analytical data for 5e: Rf = 0.20 (petroleum
ether/ethyl acetate = 6/1); 1H NMR (400 MHz, CDCl3) δ 7.50−7.47
(m, 2H), 7.31−7.29 (m, 3H), 5.84−5.75 (m, 1H), 5.15−5.07 (m,
2H), 4.88−4.85 (m, 1H), 3.69 (s, 1H), 2.66−2.51 (m, 2H), 1.21 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 171.9, 134.2, 134.0, 132.5,
129.1, 128.5, 118.2, 56.3, 54.3, 47.6, 36.6, 22.1; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C16H24NO2S2 326.1243; found 326.1244.
(R)-Methyl N-((RS)-tert-Butylsulfinyl)-3-phenyl-2-(phenylthio)-
propanimidate (5f). According to general procedure A, the reaction
of imidate 1n (80.2 mg, 0.30 mmol), LiHMDS (1.0 M in THF, 600
μL, 0.6 mmol), and sulfenylating reagents 3 (85.0 mg, 0.39 mmol)
generated product 5f with a diastereomeric ratio of 9:1. Column
chromatography (petroleum ether/ethyl acetate = 7/1) afforded 5f
(colorless oil, 97.0 mg, 91% yield). Analytical data for 5f: Rf = 0.20
1
data for 4p: Rf = 0.30 (petroleum ether/ethyl acetate = 7/1); H
NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 2.0
Hz, 1H), 7.24−7.18 (m, 5H) 5.91 (s, 1H), 3.94 (d, J = 13.6 Hz, 1H),
3.81 (d, J = 13.2 Hz, 1H), 3.71 (s, 3H), 1.20 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 169.2, 135.5, 134.5, 134.2, 133.3, 133.1, 132.2, 130.7,
129.2, 128.7, 127.5, 57.0, 55.2, 45.8, 37.0, 22.1; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C20H23Cl3NO2S2 478.0230; found 478.0226.
(R)-Methyl N-((SS)-tert-Butylsulfinyl)-2-((4-chlorobenzyl)thio)-2-
(2,4-dichlorophenyl)acetimidate (ent-4p). According to general
procedure B, the reaction of imidate ent-1j (64.2 mg, 0.20 mmol),
LiHMDS (1.0 M in THF, 220 μL, 0.22 mmol), and sulfenylating
reagents 8 (78.9 mg, 0.26 mmol) generated product ent-4p with a
diastereomeric ratio of 25:1. Column chromatography (petroleum
ether/ethyl acetate = 10/1) afforded ent-4p (colorless oil, 90.2 mg,
94% yield). Analytical data for ent-4p: Rf = 0.30 (petroleum ether/
ethyl acetate = 7/1); 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.4
Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.24−7.18 (m, 5H) 5.91 (s, 1H),
3.94 (d, J = 13.6 Hz, 1H), 3.81 (d, J = 13.2 Hz, 1H), 3.71 (s, 3H),
1.20 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 169.2, 135.5, 134.5,
134.2, 133.3, 132.2, 133.1, 130.7, 129.2, 128.7, 127.5, 57.0, 55.2, 45.8,
37.0, 22.1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C20H23Cl3NO2S2 478.0230; found 478.0227.
(R)-Methyl N-((RS)-tert-Butylsulfinyl)-2-(phenylthio)-
propanimidate (5b). According to general procedure A, the reaction
of imidate 1b (96.0 mg, 0.50 mmol), LiHMDS (1.0 M in THF, 1 mL,
1.0 mmol), and sulfenylating reagents 3 (192.5 mg, 0.65 mmol)
generated product 5b with a diastereomeric ratio of 10:1. Column
chromatography (petroleum ether/ethyl acetate = 7/1) afforded 5b
(colorless oil, 108.1 mg, 97% yield). Analytical data for 5b: Rf = 0.20
(petroleum ether/ethyl acetate = 6/1); 1H NMR (400 MHz, CDCl3)
δ 7.48−7.46 (m, 2H), 7.30−7.28 (m, 3H), 4.84 (q, J = 7.2 Hz, 1H),
3.70 (s, 1H), 1.51 (d, J = 6.8 Hz, 3H), 1.13 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 173.8, 134.1, 132.7, 129.0, 128.5, 56.2, 54.5, 43.4,
22.0, 18.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H22NO2S2
300.1086; found 300.1088.
(R)-Methyl N-((RS)-tert-Butylsulfinyl)-5-phenyl-2-(phenylthio)-
pent-4-ynimidate (5c). According to general procedure A, the
reaction of imidate 1l (58.4 mg, 0.20 mmol), LiHMDS (1.0 M in
THF, 400 μL, 1.0 mmol), and sulfenylating reagents 3 (77.0 mg, 0.26
mmol) generated product 5c with a diastereomeric ratio of 30:1.
Column chromatography (petroleum ether/ethyl acetate = 7/1)
afforded 5c (white solid, 64.0 mg, 80% yield). Analytical data for 5c:
Rf = 0.20 (petroleum ether/ethyl acetate = 6/1), mp 107−108 °C;
[α]D = −179.0 (c 0.10, MeOH); H NMR (400 MHz, CDCl3) δ
7.57−7.55 (m, 2H), 7.38−7.36 (m, 2H), 7.33−7.32 (m, 3H), 7.26−
7.15 (m, 3H), 5.10−5.07 (m, 1H), 3.71 (s, 3H), 3.04−2.83 (m, 2H),
1.12 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 169.9, 134.5, 131.9,
131.8, 129.2, 128.8, 128.2, 127.9, 123.4, 85.8, 83.0, 56.7, 54.5, 46,2,
23.5, 22.3; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H26NO2S2
400.1399; found 400.1398.
25
(petroleum ether/ethyl acetate = 6:1); [α]D = −262.0 (c 0.10,
1
MeOH); H NMR (400 MHz, CDCl3) δ 7.45−7.42 (m, 2H), 7.28−
7.24 (m, 7H), 7.21−7.17 (m, 1H), 5.19 (t, J = 7.6 Hz, 1H), 3.67 (s,
3H), 3.25−3.20 (m, 1H), 3.07−3.02 (m, 1H), 1.00 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 170.6, 137.6, 134.0, 132.8, 129.4, 129.0,
128.5, 128.4, 126.9, 56.6, 54.3, 49.3, 38.5, 22.0; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C20H26NO2S2 376.1399; found 376.1400.
(RS)-N-((S)-2-((4-Chlorobenzyl)thio)-2-(2,4-dichlorophenyl)ethyl)-
2-methylpropane-2-sulfinamide (10). To a stirred solution of 4p
(410 mg, 0.86 mmol) in 20 mL of THF was added DIBAL-H (1.0 M
in hexane, 2.15 mL, 2.15 mmol) at −78 °C. The resultant solution
was stirred for 1 h at −78 °C before being quenched with saturated
aqueous ammonium chloride. The organic layer was separated, and
the aqueous layer was extracted with ethyl acetate. The combined
organic extracts were washed with brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The residue was
purified by flash column chromatography (petroleum ether/ethyl
acetate = 2/1), achieving 354 mg (92% yield) of 10 as a white solid.
Analytical data for 10: Rf = 0.30 (petroleum ether/ethyl acetate =
1
1:1); H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.4 Hz, 1H), 7.34
(d, J = 2.0 Hz, 1H), 7.24−7.21 (m, 3H), 7.14 (d, J = 8.4 Hz, 2H),
4.44 (t, J = 7.2 Hz, 1H), 3.65 (q, J = 13.2 Hz, 2H), 3.59−3.46 (m,
2H), 3.37−3.30 (m, 1H), 1.16 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 136.1, 135.9, 134.5, 133.9, 133.1, 130.3, 129.5, 128.7, 127.7, 56.3,
49.8, 46.8, 35.6, 22.6; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C19H23Cl3NOS2 450.0281; found 450.0280.
(S)-2-((4-Chlorobenzyl)thio)-2-(2,4-dichlorophenyl)ethanamine
(11). To a stirred solution of 10 (134.8 mg, 0.3 mmol) in THF/H2O
(v/v = 5/1) was added iodine (15.2 mg, 0.06 mmol). The reaction
mixture was then stirred at 50 °C for 8 h. The reaction mixture was
cooled to room temperature and diluted with water. After removal of
THF under reduced pressure, an aqueous solution of sodium
thiosulfate (0.2 N, 0.2 mL) was added. The resulting mixture was
then washed with Et2O, and the aqueous phase was treated with a
saturated aqueous solution of NaHCO3. The resulting aqueous
mixture was then extracted with CH2Cl2, and the combined organic
phases were washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography (CH2Cl2/MeOH = 25:1), achieving 94.2 mg (91%
yield) of 11 as a colorless oil. Analytical data for 10: Rf = 0.30
(CH2Cl2/MeOH = 25:1); [α]D25 = −179 (c 0.10, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.53 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 2.0 Hz,
1H), 7.27 (d, J = 2.0 Hz, 1H), 7.24−7.22 (m, 2H), 7.12−7.10 (m,
25
1
(R)-Methyl N-((RS)-tert-Butylsulfinyl)-2-(phenylthio)-
pentanimidate (5d). According to general procedure A, the reaction
of imidate 1l (66.0 mg, 0.30 mmol), LiHMDS (1.0 M in THF, 600
μL, 0.6 mmol), and sulfenylating reagents 3 (85.0 mg, 0.39 mmol)
generated product 5d with a diastereomeric ratio of 9:1. Column
chromatography (petroleum ether/ethyl acetate = 7/1) afforded 5d
(colorless oil, 87.0 mg, 88% yield). Analytical data for 5d: Rf = 0.20
F
DOI: 10.1021/acs.joc.8b01403
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
2H), 4.24 (t, J = 6.4 Hz, 1H), 3.59 (d, J = 13.6 Hz, 1H), 3.50 (d, J =
13.6 Hz, 1H), 2.95 (d, J = 6.4 Hz, 2H), 1.25 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 136.8, 136.3, 134.8, 133.6, 133.0, 130.4, 130.3, 129.4,
128.7, 127.8, 49.0, 47.0, 35.2; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C15H15Cl3NS 345.9985; found 345.9983.
acetate (31.7 mg, 0.4 mmol) were added to the reaction mixture. The
reaction flask was fitted with a reflux condenser and heated to 95 °C.
The reaction mixture was stirred at reflux for 16 h. After cooling to
room temperature, the crude mixture was concentrated and made
basic by addition of aqueous potassium hydroxide (2 M) and
extracted with dichloromethane (3 × 5 mL). The combined organic
phases were dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash column chromatography
CH2Cl2/MeOH = 60:1), achieving 56.0 mg (71% yield) of (R)-
sulconazole as a yellow oil. Analytical data for (R)-sulconazole: Rf =
0.30 (CH2Cl2/MeOH = 60:1); [α]D = 145 (c 0.10, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.37−7.35 (m, 2H), 7.27−7.22 (m, 4H),
7.05 (d, J = 8.4 Hz, 2H), 6.99 (s, 1H), 6.72 (s, 1H), 4.31 (t, J = 6.4
Hz, 1H), 4.23−4.11 (m, 2H), 3.50 (d, J = 13.2 Hz, 1H), 3.41 (d, J =
13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 137.6, 135.4, 134.7,
134.6, 134.4, 133.4, 130.3, 129.7, 128.9, 128.0, 119.4, 51.3, 46.1, 35.7;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H16Cl3N2S 397.0094;
found 397.0093.
(S)-Sulconazole. Thioether amine 11 (70 mg, 0.2 mmol) was
dissolved in 1.2 mL of methanol. Glyoxal (58 μL, 40 wt %, 0.40
mmol), formaldehyde (34 μL, 36 wt %, 0.40 mmol), and ammonium
acetate (31.7 mg, 0.4 mmol) were added to the reaction mixture. The
reaction flask was fitted with a reflux condenser and heated to 95 °C.
The reaction mixture was stirred at reflux for 16 h. After cooling to
room temperature, the crude mixture was concentrated and made
basic by addition of aqueous potassium hydroxide (2 M) and
extracted with dichloromethane (3 × 5 mL). The combined organic
phases were dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash column chromatography
CH2Cl2/MeOH = 60:1), achieving 56.8 mg (72% yield) of (S)-
sulconazole as a yellow oil. Analytical data for (S)-sulconazole: Rf =
25
1
25
0.30 (CH2Cl2/MeOH = 60:1); [α]D = −144 (c 0.10, CHCl3) (lit
11b
23
[α]D = −163 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.37−7.35 (m, 2H), 7.27−7.22 (m, 4H), 7.05 (d, J = 8.4 Hz, 2H),
6.99 (s, 1H), 6.72 (s, 1H), 4.31 (t, J = 6.4 Hz, 1H), 4.23−4.11 (m,
2H), 3.50 (d, J = 13.2 Hz, 1H), 3.41 (d, J = 13.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 137.6, 135.4, 134.7, 134.6, 134.4, 133.4, 130.3,
129.7, 128.9, 128.0, 119.4, 51.3, 46.1, 35.7; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C18H16Cl3N2S 397.0094; found 397.0093.
(SS)-N-((R)-2-((4-Chlorobenzyl)thio)-2-(2,4-dichlorophenyl)ethyl)-
2-methylpropane-2-sulfinamide (ent-10). To a stirred solution of
ent-4p (300 mg, 0.63 mmol) in THF at −78 °C was added DIBAL-H
(1.0 M in hexane, 1.57 mL, 1.57 mmol). The resultant solution was
stirred for 1 h at −78 °C before being quenched with saturated
aqueous ammonium chloride. The organic layer was separated, and
the aqueous layer was extracted with ethyl acetate. The combined
organic extracts were washed with brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The residue was
purified by flash column chromatography (petroleum ether/ethyl
acetate = 2/1), achieving 248 mg (88% yield) of ent-10 as a white
solid. Analytical data for ent-10: Rf = 0.30 (petroleum ether/ethyl
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b01403.
■
S
1H and 13C NMR spectra of all new compounds, chiral
HPLC analysis of compounds 11 and sulconazole, and
X-ray crystal structures of compounds 4c (CCDC
1839974) and 5c (CCDC 1839975) (PDF)
Crystallographic data for 4c (CIF)
Crystallographic data for 5c (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: clu@ms.xjb.ac.cn.
■
ORCID
Chong-Dao Lu: 0000-0001-8968-0134
Notes
The authors declare no competing financial interest.
1
acetate = 1:1); H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.4 Hz,
1H), 7.34 (d, J = 2.0 Hz, 1H), 7.24−7.21 (m, 3H), 7.14 (d, J = 8.4
Hz, 2H), 4.44 (t, J = 7.2 Hz, 1H), 3.65 (q, J = 13.2 Hz, 2H), 3.59−
3.46 (m, 2H), 3.37−3.30 (m, 1H), 1.16 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 136.1, 135.9, 134.5, 133.9, 133.1, 130.3, 129.5, 128.7,
127.7, 56.3, 49.8, 46.8, 35.6, 22.6; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C19H23Cl3NOS2 450.0281; found 450.0280.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (U1403301 and 21572262), the
Recruitment Program of Global Experts (Xinjiang Program),
and the Director Foundation of XTIPC (2015RC014).
(R)-2-((4-Chlorobenzyl)thio)-2-(2,4-dichlorophenyl)ethanamine
(ent-11). To a stirred solution of ent-10 (200.0 mg, 0.45 mmol) in
THF/H2O (v/v = 5/1) was added iodine (22.7 mg, 0.09 mmol). The
reaction mixture was then stirred at 50 °C for 8 h. The reaction
mixture was cooled to room temperature and diluted with water. After
removal of THF under reduced pressure, an aqueous solution of
sodium thiosulfate (0.2 N, 0.2 mL) was added. The resulting mixture
was then washed with Et2O, and the aqueous phase was treated with
saturated aqueous solution of NaHCO3. The resulting aqueous
mixture was then extracted with CH2Cl2, and the combined organic
phases were washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography CH2Cl2/MeOH = 25:1), achieving 138 mg (90%
yield) of ent-11 as a colorless oil. Analytical data for ent-11: Rf = 0.30
(CH2Cl2/MeOH = 25:1); [α]D25 = −179 (c 0.10, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.53 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 2.0 Hz,
1H), 7.27 (d, J = 2.0 Hz, 1H), 7.24−7.22 (m, 2H), 7.12−7.10 (m,
2H), 4.24 (t, J = 6.4 Hz, 1H), 3.59 (d, J = 13.6 Hz, 1H), 3.50 (d, J =
13.6 Hz, 1H), 2.95 (d, J = 6.4 Hz, 2H), 1.25 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 136.8, 136.3, 134.8, 133.6, 133.0, 130.4, 130.3, 129.4,
128.7, 127.8, 49.0, 47.0, 35.2; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C15H15Cl3NS 345.9985; found 345.9983.
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