Asymmetric synthesis of sulfinamides using (-)-quinine as chiral auxiliary

Article abstract of DOI:10.1021/jo201825b

A process has been designed and demonstrated for the asymmetric synthesis of sulfinamides using quinine as auxiliary. A variety of chiral sulfinamides including N-alkyl sulfinamides with diverse structure were prepared in good yields and excellent enantioselectivity starting from easily available and inexpensive reagents. The auxiliary quinine could be recovered and recycled.

Full text of DOI:10.1021/jo201825b

Note
pubs.acs.org/joc
Asymmetric Synthesis of Sulfinamides Using (−)-Quinine as Chiral
Auxiliary
Yongda Zhang,* Sampada Chitale, Navneet Goyal, Guisheng Li, Zhengxu S. Han, Sherry Shen,
Shengli Ma, Nelu Grinberg, Heewon Lee, Bruce Z. Lu, and Chris H. Senanayake
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield,
Connecticut 06877, United States
S
* Supporting Information
ABSTRACT: A process has been designed and demonstrated for the
asymmetric synthesis of sulfinamides using quinine as auxiliary. A
variety of chiral sulfinamides including N-alkyl sulfinamides with
diverse structure were prepared in good yields and excellent enan-
tioselectivity starting from easily available and inexpensive reagents.
The auxiliary quinine could be recovered and recycled.
is highly desirable to further investigate and develop efficient
and economic methods for convenient synthesis of chiral sul-
finamides with different steric and stereoelectronic character-
istics. We envision that will help further realize and expand the
potential of chiral sulfinamides in the area of asymmetric
organic synthesis.
Previously, we reported that chiral sulfoxides could be pre-
pared in excellent enantiopurity and high yields via a pseudo-
five-membered ring oxathiazolidine 1 using the inexpensive
natural product cinchona alkaloid (−)-quinine as chiral auxiliary
(Scheme 1).8
We speculated that application of the novel sulfinyl transfer
reagent could lead to formation of important chiral sulfina-
mides by treatment of the resulting chiral sulfinates with suitable
amide anions (Scheme 2). Herein, we report our efforts regarding
efficient asymmetric synthesis of chiral sulfinamides using inex-
pensive (−)-quinine as chiral auxiliary.
Our work commenced with the synthesis of chiral quinine
sulfinates, and the results are summarized in the Table 1. All the
quinine sulfinates were easily prepared in high yields with
excellent diastereoselectivity. In the case of alkyl sulfinate, bulky
alkyl Grignard such as t-butyl magnesium chloride could be
used directly. Typically, the reaction went to completion in less
than 0.5 h and gave the desired product 2a and 2b in high yield.
Formation of symmetric sulfoxides such as di-tert-butyl sulfoxide
ver the past three decades, chiral sulfinamides such
as p-toluenesulfinamide and tert-butanesulfinamide have
O
been widely exploited and exercised by academia and industry
because of their unique roles and importance in the asymmetric
synthesis of chiral nitrogen-contained functionalities.1 The cor-
responding sulfinylimines, derived from the condensation of
sulfinamides with aldehydes and ketones, have been extensively
utilized as versatile chiral nitrogen vehicles for synthesis of a
variety of chiral amines, including α-branched amines, α- and
β- amino acids, 1,2-amino alcohols, 1,3-amino alcohols, aziridines,
aminooxetanes, and amino phosphoric acids.2 Particularly, addition
to chiral sulfinketimines has provided an indispensable and reliable
tool in modern organic synthesis for preparation of chiral tertiary
carbinamines, which are prevalent in natural products, synthetic
pharmaceuticals, and catalysts but not accessible from well-
developed transition-metal catalyzed asymmetric hydrogenation
of imines.3 Moreover, chiral sulfinamides have been inves-
tigated as novel chiral ligands or essential chiral motif in catalyst
design to achieve high-level asymmetric induction.4 Typically,
chiral tert-butanesulfinamides could be practically prepared via
two-step process of an asymmetric catalytic oxidation of tert-
butyl disulfide and subsequent reaction with an amide anion.5
In 2002, Senanayake and co-workers reported a modular synthesis
of a variety of structurally diverse enantiopure sulfinamides
from N-sulfonyl-1,2,3-oxathiazolidine-2-oxide agents.6 Recently,
we also developed a new process for the synthesis of chiral sul-
finamides using a chiral sulfinyl transfer auxiliary derived from
readily available phenylglycine.7 Considering the vast potential
of these chiral sulfinamides as chiral N-auxiliaries and ligands, it
Received: September 8, 2011
Published: November 29, 2011
© 2011 American Chemical Society
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Scheme 1. Asymmetric Synthesis of Chiral Sulfoxides via a
Pseudo-Five-Membered Ring Oxathiazolidine
Table 1. Synthesis of Chiral Sulfinates Using (−)-Quinine as
Chiral Auxiliaries
was not observed even in the presence of excessive t-butyl
magnesium chloride.10 However, exclusive formation of racemic
di(p-tolyl)sulfoxide was observed even with 1 equiv of p-tolyl
magnesium chloride as reported before.6 The issue was over-
come with the use of arylzinc halides, which were easily pre-
pared in situ from aryl Grignard reagents and equal amount of
zinc chloride. The resulting quinine sulfinates 2c, 2d, and 2e
were prepared in good to high yield with 96:4 diastereose-
lectivity. To avoid the formation of sulfoxides, in situ generated
n-BuZnCl was applied also for the synthesis of 2f. The stereo-
chemistry of the quinine sulfinates 2a−f at sulfur center was
assigned according to the X-ray structure of 2d (Figure 1). All
the products were easily isolated and purified by column chro-
matography on silica gel.
With chiral quinine sulfinates at hand, we started to
investigate the synthesis of chiral sulfinamides. When 2a was
heated with BnNH2 in THF at 70 °C even for 12 h, no sulfina-
mide 3a was detected, and 2a was recovered.11 No reaction
was observed either when the sulfinate 2a was treated with
commercially available metal amides (LiNH2 and NaNH2) at
−78 °C in THF. When the reaction mixture was warmed to
room temperature overnight, only a small amount of nearly racemic
sulfinamide was obtained. Further studies indicated that treat-
ment with bulky LHMDS at −78 °C or aqueous ammonium
hydroxide at 23 °C gave no reaction. At this stage, we per-
formed the reaction with Li/NH3 with THF as cosolvent, which
has been extensively utilized for synthesis of sulfinamides. The
reaction proceeded immediately and went to completion in
15 min. As shown in Table 2, the tert-butanesulfinamide 3a was
prepared in 79% yield and 99% e.e. with stereospecific inversion
at sulfur center. In the case of alkyl sulfinate 2b, the resulting
sulfinamide 3b was obtained with 99% e.e. However, only
moderate selectivity was observed when p-tolylsulfinate 2c was
treated with Li/NH3 in THF. Considering the low solubility
and slow dissolution of p-tolylsulfinate 2c in THF, we speculated
a
Absolute configurations of 2a−f were assigned according to X-ray
b
structure of 2e. Isolated yield after purification by column chro-
c
matography. Diastereomeric ratio was determined by HPLC analysis
of the crude product.9
Scheme 2. Asymmetric Synthesis of Chiral Sulfinamides via a Pseudo-Five-Membered Ring Oxathiazolidine
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78:22 enantiomeric ratio. The enantioselectivity was improved
to 96% e.e. when the reaction was performed at −78 °C.
Chiral N-alkyl sulfinamide derivatives have been used as ligands
and catalysts and exhibit unique properties in organic tran-
sformation13 but are still not widely explored. We envisioned
that chiral N-alkyl sulfinamides could be also prepared when
our chiral quinine sulfinates were treated with easily prepared
lithium alkylamides such as lithium benzylamide. N-Alkyl sulfi-
namides were isolated with excellent enantiopurity and high
yield (Table 3). Because of the acidity of NH in the product, at
Figure 1. X-ray structure of 2d. Hydrogen atoms have been omitted
for clarity.
Table 3. Synthesis of N-alkyl Chiral Sulfinamides Starting
from Quinine Sulfinate
Table 2. Synthesis of Chiral Sulfinamides Starting from
Quinine Sulfinates
a
Absolute configurations of 4a−f were deduced from the correspond-
ing sulfinates assuming each nucleophilic substitution inverts the con-
formation of the sulfinyl center. Isolated yield after purification by
column chromatography. Enantiomeric excess was determined by chiral
b
c
a
Absolute configurations of 3a−f were deduced from the correspond-
HPLC analysis.
ing sulfinates assuming each nucleophilic substitution inverts the
conformation of the sulfinyl center. Isolated yield after purified by
column chromatography. Enantiomeric excess was determined by
chiral HPLC analysis. DMF was used as solvent.
b
least 2 equiv of lithium amide were used. When t-butyl sulfinate
2a was treated with in situ generated LiNHBn, the reaction
proceeded instantaneously even at −78 °C and gave the pro-
duct 4a with 88% yield and 99% e.e. The use of LiNHallyl gave
N-allyl t-butylsulfinamide 4b with 85% yield and 98% e.e. In the
case of p-tolyl sulfinate 2c, the product N-benzyl p-tolylsul-
finamide 4c was obtained in 82% yield and 99% e.e. The treat-
ment of p-tolyl sulfinate 2c with N-allyl lithium amide gave
the product N-allyl p-tolylsulfinamide 4d with 68% yield and
99% e.e. With more sterically hindered mesityl sulfinate 2d, the
reaction with N-benzyl lithium amide still proceeded at −78 °C
immediately and generated the product N-benzyl mesity sulfi-
namide 4e with 80% yield and over 99% e.e. In the case of N-allyl
lithium amide, the product N-allyl mesityl sulfinamide 4f was
isolated with 76% yield and 99% e.e.
c
d
that byproduct lithium quinine alkoxide could competitively
racemize quinine sulfinate. To solve the problem and improve
the enantiopurity of the product, more polar DMF was chosen
as the solvent for the reaction. The reaction of p-tolylsulfinate
2c with LHMDS in DMF proceeded smoothly and gave the
p-tolylsulfinamide 3c with 99% e.e.12 Excellent enantioselectiv-
ity was also obtained when mesityl sulfinate 2d was treated with
LHMDS in THF. The use of Li/NH3 just gave the product 3d
with moderate enantiopurity. In the case of more bulky 2,4,6-
triisopropylphenyl sulfinate 2e, no reaction was observed when
LHMDS was used. However, treatment with Li/NH3 in THF
led to the formation of 2,4,6-triisopropylphenyl sulfinamide 3e
with 99% e.e. and 84% yield. When n-butyl sulfinate 2f was
treated with LHMDS at 23 °C, the product 3f was isolated with
In summary, we have developed and demonstrated a method
for the asymmetric synthesis of sulfinamides in high yields and
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The known compounds sulfinamide 2c was isolated as pure sample
and the NMR spectra matched the reported compound.8
excellent enantioselectivity from chiral quinine sulfinates, which
could be easily prepared from cheap and easily available starting
material.14 Moreover, the quinine after the reactions could be
recovered and recycled. We believe the expedient route could
find wide application in the synthesis of chiral sulfinamides.
Further application of these chiral sulfinamides in asymmetric
organic synthesis is ongoing and will be reported in near future.
Quinine (Rs)-2,4,6-Trimethylbenzenesulfinate 2d. To a sol-
ution of 2,4,6-trimethylbenzenemagnesium bromide (77 mL, 77 mmol,
1 M in THF) was added a solution of 0.5 M ZnCl2 (145 mL, 145 mmol)
in THF at 0 °C. After 0.5 h, the resulting solution was ready for
synthesis of sulfinate 2d.
The general procedure above was followed, using quinine (10.0 g,
30.8 mmol), SOCl2 (2.47 mL, 33.9 mmol, 1.1 equiv), Et3N (6.44 mL,
46.2 mmol, 1.5 equiv), and THF (100 mL). After the reaction mixture
was stirred for 15 min below −70 °C, the mixture was further treated
with mesityl ZnCl prepared above. Column chromatography on silica
gel (eluting with 0−5% MeOH in EtOAc) afforded the product 2d as
a pale yellow oil (14.2 g, 94%, 96:4 d.r.): 1H NMR (400 MHz, CDCl3)
δ 8.72 (bs, 1H), 7.99 (dd, 1H, J = 3.6 Hz, 9.2 Hz), 7.46 (bs, 1H), 7.34
(m, 1H), 7.24 (m, 1H), 6.72−6.70 (m, 2H), 5.79−5.73 (m, 2H),
4.96−4.90 (m, 2H), 3.86 (s, 3H), 3.33 (bs, 1H), 3.00−2.95 (m, 2H),
2.58−2.52 (m, 2H), 2.48 (s, 6H), 2.20−2.18 (m, 4H), 1.79 (bs, 2H),
1.65 (bs, 1H), 1.49−1.41 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
157.7, 147.4, 144.6, 143.5, 142.2, 141.7, 138.3, 137.4, 131.9, 130.7,
126.5, 121.6, 119.9, 114.5, 101.5, 80.6, 60.1, 56.8, 55.6, 42.4, 39.8, 27.7,
27.6, 24.1, 21.1, 19.2; HRMS (ES pos.) m/z calcd for C29H35N2O3S+
(M + H+) 491.2362, found 491.2368.
EXPERIMENTAL SECTION
■
General Methods. All reactions were run in an oven-dried flask
under nitrogen. Unless otherwise noted, reagents were commercially
available and used without purification. The racemic sulfinamides were
prepared following the literature procedure.15 Chemical shifts are
reported in δ (ppm) relative to TMS in CDCl3 as internal standard
(1H NMR) or the residual CHCl3 signal (13C NMR).
General Experimental Procedure for Synthesis of Quinine
Sulfinates. A dry flask fitted with a stir bar was charged with THF
(20 mL) under nitrogen. After the solution was cooled to −78 °C,
SOCl2 (2.47 mL, 33.9 mmol, 1.1 equiv) was added. Then, a solution of
quinine (10 g, 30.8 mmol) and Et3N (6.44 mL, 46.2 mmol, 1.5 equiv)
in THF (80 mL) was added dropwise while the internal temperature
was maintained below −70 °C. After 15 min at below −70 °C, orga-
nometallic reagent (2.5 equiv) was added while the internal tem-
perature was maintained below −70 °C. After 30 min at below −70 °C,
the reaction was then quenched with saturated aqueous NH4Cl (50 mL).
After the mixture was warmed to room temperature, the aqueous layer
was extracted with EtOAc (3 × 150 mL). The combined organic layers
were washed with brine (100 mL), dried over anhydrous Na2SO4, and
concentrated. Purification of the crude product by column
chromatography on silica gel gave analytically pure product.
Quinine (Rs)-2,4,6-Triisopropylbenzenesulfinate 2e. To a
solution of 2,4,6-triisopropylbenzenemagnesiumbromide (77 mmol)
was added a solution of 0.5 M ZnCl2 (145 mL, 145 mmol) in THF
at 0 °C. After 0.5 h, the resulting solution was ready for synthesis of
sulfinate 2e.
The general procedure above was followed, using quinine (10.0 g,
30.8 mmol), SOCl2 (2.47 mL, 33.9 mmol, 1.1 equiv), Et3N (6.44 mL,
46.2 mmol, 1.5 equiv), and THF (100 mL). After the reaction mixture
was stirred for 15 min below −70 °C, the mixture was further treated
with 2,4,6-triisopropylbenzeneZnCl (2.5 equiv) prepared above.
Column chromatography on silica gel (eluting with 0−5% MeOH in
EtOAc) afforded the product 2e as a pale yellow oil (14.2 g, 80%, 96:4
Quinine (Rs)-tert-Butylsulfinate 2a.8 The general procedure
above was followed, using quinine (10.0 g, 30.8 mmol), SOCl2
(2.47 mL, 33.9 mmol, 1.1 equiv), Et3N (6.44 mL, 46.2 mmol, 1.5 equiv),
and THF (100 mL). After the reaction mixture was stirred for 15 min
below −70 °C, the mixture was further treated with t-BuMgCl (77 mL,
77 mmol, 1 M in THF, 2.5 equiv). Column chromatography on silica
gel (eluting with 0−5% MeOH in EtOAc) afforded the product 2a as a
pale yellow oil (12.0 g, 91%, >99:1 d.r.).
1
d.r.): H NMR (400 MHz, CDCl3) δ 8.79 (d, 1H, J = 4.4 Hz), 8.04
(d, 1H, J = 9.2 Hz), 7.54 (bs, 1H), 7.39−7.33 (m, 2H), 7.06 (s, 2H), 5.90
(bs, 1H), 5.80−5.75 (m, 1H), 4.90−4.93 (m, 2H), 3.91 (s, 3H), 3.40
(bs, 1H), 3.02−2.85 (m, 3H), 2.65−2.54 (m, 2H), 2.23 (bs, 1H),
1.81−1.45 (m, 5H), 1.23−1.17 (m, 18H); 13C NMR (100 MHz,
CDCl3) δ 157.9, 153.3, 148.8, 147.5, 144.8, 143.3, 141.7, 138.1, 131.9,
126.7, 122.7, 121.6, 120.0, 114.5, 101.4, 81.3, 59.7, 56.7, 55.7, 42.4,
39.9, 34.4, 28.2, 27.6, 24.8, 24.1, 23.7; HRMS (ES pos.) m/z calcd for
C35H47N2O3S+ (M + H+) 575.3301, found 575.3305.
Quinine (Rs)-n-Butylsulfinate 2f. To a solution of 0.5 M ZnCl2
(77 mL, 38.5 mmol) in THF was added a solution of n-BuLi (15.4 mL,
38.5 mmol, 2.5 M in hexane) at 0 °C. After 0.5 h, the resulting solution
was ready for synthesis of sulfinate 2f.
The general procedure above was followed, using quinine (5.0 g,
15.4 mmol), SOCl2 (2.02 g, 16.95 mmol, 1.1 equiv), Et3N (3.22 mL,
23.1 mmol, 1.5 equiv), and THF (50 mL). After the reaction mixture
was stirred for 15 min below −70 °C, the mixture was further treated
with n-BuZnCl (2.5 equiv) prepared above. Column chromatography
on silica gel (eluting with 0−5% MeOH in EtOAc) afforded the
product 2f as a pale yellow oil (5.68 g, 86%, 99:1 d.r.): 1H NMR (400 MHz,
CDCl3) δ 8.76 (d, 1H, J = 4.5 Hz), 8.04 (d, 1H, J = 9.1 Hz), 7.50
(d, 1H, J = 4.5), 7.39−7.34 (m, 2H), 5.95 (d, 1H, J = 5.5 Hz), 5.78
(m, 1H), 5.0−4.96 (m, 2H), 3.96 (s, 3H), 3.34 (m, 1H), 3.15 (bs, 1H),
3.05 (m, 1H), 2.73−2.61 (m, 4H), 2.29 (bs, 1H), 1.88−1.54 (m, 7H),
1.36−1.30 (m, 2H), 0.85 (t, 3H, J = 7.32 Hz); 13C NMR (100 MHz,
CDCl3) δ 158.0, 147.4, 144.7, 143.5, 141.4, 132.0, 126.4, 121.8, 120.0,
114.7, 101.3, 78.4, 60.1, 57.3, 56.7, 55.8, 42.6, 39.6, 27.6, 27.5, 23.8,
23.2, 21.9, 13.6; HRMS (ES pos.) m/z calcd for C24H33N2O3S+
(M + H+) 429.2206, found 429.2221.
The known compounds sulfinamide 2a was isolated as pure sample
and the NMR spectra matched the reported compound.8
Quinine (Rs)-1,1-Dimethylpropylsulfinate 2b. The general
procedure above was followed, using quinine (10.0 g, 30.8 mmol),
SOCl2 (2.47 mL, 33.9 mmol, 1.1 equiv), Et3N (6.44 mL, 46.2 mmol,
1.5 equiv), and THF (100 mL). After the reaction mixture was stirred
for 15 min below −70 °C, the mixture was further treated with
2-methyl-2-butylMgCl (77 mL, 77 mmol, 1 M in ether, 2.5 equiv).
Column chromatography on silica gel (eluting with 0−5% MeOH in
EtOAc) afforded the product 2b as a pale yellow oil (12.6 g, 92%,
1
>99:1 d.r.): H NMR (400 MHz, CDCl3) δ 8.71(d, 1H, J = 1.6 Hz),
7.98 (dd, 1H, J = 3.6 Hz, 9.2 Hz), 7.40−7.30 (m, 3H), 5.79−5.77(m,
1H), 5.65 (bs, 1H), 4.98−4.94 (m, 2H), 3.89 (s, 3H), 3.45 (bs, 1H),
2.97−2.94 (m, 2H), 2.58−2.56 (m, 2H), 2.21 (bs, 1H), 1.99−1.83 (m,
2H), 1.64−1.50 (m, 5H), 1.14 (s, 3H), 1.11 (s, 3H), 0.90 (t, 3H, J =
2.4 HZ); 13C NMR (100 MHz, CDCl3) δ 157.6, 147.2, 144.8, 143.7,
141.7, 131.7, 126.8, 121.4, 120.2, 114.4, 101.8, 61.6, 60.6, 56.3, 55.4,
42.1, 39.7, 27.8, 27.7, 27.5, 18.6, 18.4, 7.7; HRMS (ES pos.) m/z calcd
for C25H35N2O3S+ (M + H+) 443.2362, found 443.2372.
Quinine (Rs)-p-Tolylsulfinate 2c.8 To a solution of 4-methyl-
benzenemagnesium bromide (77 mL, 1 M in THF) was added a solu-
tion of ZnCl2 (145 mL, 0.5 M) in THF at 0 °C. After 0.5 h, the result-
ing solution was ready for synthesis of sulfinate 2c.
The general procedure above was followed, using quinine (10.0 g,
30.8 mmol), SOCl2 (2.47 mL, 33.9 mmol, 1.1 equiv), Et3N (6.44 mL,
46.2 mmol, 1.5 equiv), and THF (100 mL). After the reaction mixture
was stirred for 15 min below −70 °C, the mixture was further treated
with p-MePhZnCl prepared above. Column chromatography on silica
gel (eluting with 0−5% MeOH in EtOAc) afforded the product 2c as a
pale yellow oil (10.8 g, 76%, 96:4 d.r.).
General Experimental Procedure for Synthesis of Chiral
Sulfinamides 3a, 3b, and 3e. A 250 mL three-neck flask fitted with
a stir bar and temperature probe was charged with anhydrous liquid
ammonia (50 mL) at −78 °C. After a few crystals of Fe(NO3)3 (50 mg)
were added to the flask, Li wire was added in portions (0.22 g, 31.0 mmol)
while the temperature was maintained at −45 °C. The reaction mixture
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was stirred at −45 °C for 2 h and then cooled to −78 °C (dark
brown-gray suspension formed). A solution of quinine sulfinate
(3.1 mmol) in THF (6 mL) was then added to the reaction mixture
dropwise over a period of 45 min. After 15 min, solid NH4Cl (1.1 g) was
added to the reaction mixture in portions to quench the reaction. The
reaction mixture was then warmed slowly to room temperature. After
water (10 mL) was added slowly into the flask, EtOAc (15 mL) was added
to extract the product. The organic layer was washed with brine (10 mL),
dried over anhydrous Na2SO4, and concentrated. Purification of the crude
product by column chromatography on silica gel gave analytically pure
product.
chromatography on silica gel (20−30% EtOAc in hexane) gave analy-
tically pure product.
(Rs)-N-Benzyl-2-methylpropane-2-sulfinamide 4a.16 88%
1
yield: [α]22 −29.3 [c 1.27, CHCl3]; H NMR (400 MHz, CDCl3)
D
δ 7.36−7.28 (m, 5H), 4.30 (dd, 2H, J = 4.8, 13.8 Hz), 3.52 (s, 1H),
1.24 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 138.4, 128.5, 128.0,
127.6, 55.9, 49.4, 22.6. Chiral HPLC conditions: Chiralpak AD-H, 4.6
× 250 mm, 5 μm; 94:6 heptane/ethanol, 1.5 mL/min; 220 nm; (S)-4a,
tR = 16.74 min; (R)-4a, tR = 23.31 min.
(Rs)-N-Allyl-2-methylpropane-2-sulfinamide 4b.12 85% yield:
[α]22 −66.0 [c 4.77, CHCl3]; 1H NMR (400 MHz, CDCl3) δ 5.96−
D
The known compounds sulfinamides 3a, 3b, 3e were isolated as
pure samples, which showed NMR spectra matching the reported
compounds.6,7
5.86 (m, 1H), 5.29−5.14 (m, 2H), 3.84−3.67 (m, 2H), 3.21 (s, 1H),
1.23 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 135.3, 117.2, 128.0,
55.8, 48.2, 22.6; HRMS (ES pos.) m/z calcd for C7H16NOS+
(M + H+) 162.0947, found 162.0950. Chiral HPLC conditions:
Chiralpak AD-H, 4.6 × 250 mm, 5 μm; 97:3 heptane/ethanol, 1.5 mL/min;
220 nm; (R)-4a, tR = 6.49 min; (S)-4a, tR = 7.74 min.
(Rs)-4-Methylbenzenesulfinamide 3c.6,7 A 50 mL three-neck
flask fitted with a stir bar and temperature probe was charged with
quinine (Rs)-p-tolylsulfinate 2c (0.5 g, 1.08 mmol) in DMF (7 mL).
LiHMDS (1.1 mL, 1.08 mmol, 1.0 equiv, 1 M in THF) was then
added to the reaction mixture at room temperature dropwise. After
30 min, the reaction was then quenched with water (5 mL). The
aqueous layer was extracted with EtOAc (3 × 10 mL). The combined
organic layers were extracted with water (3 × 15 mL) and brine (1 ×
15 mL), dried over Na2SO4, and concentrated. Purification of the
crude product by column chromatography (0.5% Et3N in EtOAc) on
silica gel gave (R)-p-tolylsulfinamide 3c as a white solid (105 mg,
84%).
(Rs)-N-Benzyl-4-methylbenzenesulfinamide 4c.17 82% yield:
[α]22D −15.4 [c 1.59, CHCl3]; 1H NMR (400 MHz, CDCl3) δ 7.65 (d,
2H, J = 8.5 Hz), 7.34−7.24 (m, 7H), 4.30 (t, 1H, J = 5.5 Hz), 4.24 (dd,
1H, J = 4.9, 13.1 Hz), 3.90 (q, 1H, J = 7.1 Hz), 2.41 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 141.4, 140.8, 137.8, 129.6, 128.7, 128.3, 127.7,
126.0, 44.6, 21.3; HRMS (ES pos.) m/z calcd for C14H16NOS+
(M + H+) 246.0947, found 246.0957. Chiral HPLC conditions:
Chiralpak AD-H, 4.6 × 250 mm, 5 μm; 94:6 heptane/ethanol, 1.5 mL/min;
220 nm; (R)-4c, tR = 5.75 min; (S)-4c, tR = 7.94 min.
The known compound sulfinamide 3c was isolated as pure sample,
which showed NMR spectra and enantiomeric purity matching the
reported compound.6,7
(Rs)-N-Allyl-4-methylbenzenesulfinamide 4d.18 68% yield:
[α]22 −122.8 [c 1.79, CHCl3]; 1H NMR (400 MHz, CDCl3) δ
D
(Rs)-2,4,6-Trimethylbenzenesulfinamide 3d.7 A 50 mL three-
neck flask fitted with a stir bar and temperature probe was charged
with quinine (Rs)-mesitylsulfinate 2d (0.35 g, 0.71 mmol) in THF
(4.5 mL). LiHMDS (0.71 mL, 1.0 equiv, 1 M in THF) was then added
to the reaction mixture at room temperature dropwise. After 30 min,
the reaction was then quenched with water (5 mL). The aqueous layer
was extracted with EtOAc (3 × 10 mL). The combined organic layers
were washed with brine (10 mL), dried over anhydrous Na2SO4, and
concentrated. Purification of the crude product by column chro-
matography (0.5% Et3N in EtOAc) gave (Rs)-2,4,6-trimethylbenze-
nesulfinamide 3d as a white crystal (107 mg; 82%).
7.56 (d, 1H, J = 8.4 Hz), 7.27 (d, 1H, J = 8.4 Hz), 5.83 (m, 1H), 5.18
(dd, 1H, J = 1.6, 17.2 Hz), 5.09 (d, 1H, J = 10.4 Hz), 4.14 (1H, bs),
3.68 (m, 1H), 3.40 (m, 1H), 2.38 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 141.5, 1412, 134.9, 129.8, 126.1, 117.5, 42.9, 21.5; HRMS
(ES pos.) m/z calcd for C10H14NOS+ (M + H+) 196.0791, found
196.0797. Chiral HPLC conditions: Chiralpak AD-H, 4.6 × 250 mm,
5 μm; 94:6 heptane/ethanol, 1.5 mL/min; 220 nm; (S)-4d, tR
5.58 min; (R)-4d, tR = 10.02 min.
=
(Rs)-N-Benzyl-2,4,6-trimethylbenzenesulfinamide 4e.19 80%
1
yield: [α]22 −141 [c 0.62, CHCl3]; H NMR (400 MHz, CDCl3) δ
D
7.33−7.24 (m, 5H), 6.84 (s, 2H), 4.39−4.27 (m, 3H), 2.56 (s, 6H),
2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 139.7, 137.1, 136.3,
135.9, 129.8, 127.6, 127.2, 126.7, 47.4, 19.9, 18.5; HRMS (ES pos.)
m/z calcd for C16H20NOS+ (M + H+) 274.1260, found 274.1272;
HRMS (ES pos.) m/z calcd for C16H20NOS+ (M + H+) 274.1260,
found 274.1272. Chiral HPLC conditions: Chiralpak AS-H, 4.6 ×
250 mm, 5 μm; 97:3 heptane/ethanol, 1.0 mL/min; 220 nm; (S)-4e,
tR = 16.74 min; (R)-4e, tR = 18.30 min.
The known compound sulfinamide 3d was isolated as pure sample,
and the NMR spectra matched the reported compound.7
(Rs)-n-Butylsulfinamide 3f. A 50 mL three-neck flask fitted with
a stir bar and temperature probe was charged with a solution of
quinine (Rs)-n-butylsulfinate 2f (5 g, 11.7 mmol) in THF (10 mL).
LiHMDS (11.7 mL, 1.0 equiv, 1 M in THF) was then added to the
solution at −78 °C dropwise. After 10 min, the reaction was quenched
with water (10 mL). The aqueous layer was extracted with EtOAc
(3 × 10 mL). The combined organic layers were washed with brine
(10 mL), dried over anhydrous Na2SO4, and concentrated. Purification
of the crude product by column chromatography (0.5% MeOH in
EtOAc) gave (Rs)-n-butylsulfinamide 3f as a solid (1.23 g; 87%, 98:2
(Rs)-N-Allyl-2,4,6-trimethylbenzenesulfinamide 4f. 76%
1
yield: [α]22 −191 [c 1.75, CHCl3]; H NMR (400 MHz, CDCl3) δ
D
6.85 (s, 2H), 5.98−5.87 (m, 1H), 5.29−5.12 (m, 2H), 4.16 (t, 1H, J =
6.3 Hz), 3.86−3.73 (m, 2H), 2.56 (s, 6H), 2.27 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 140.6, 137.5, 136.7, 134.9, 130.8, 117.4, 47.4,
20.9, 19.4; HRMS (ES pos.) m/z calcd for C12H18NOS+ (M + H+)
224.1103, found 224.1118. Chiral HPLC conditions: Chiralpak AS-H,
4.6 × 250 mm, 5 μm; 94:6 heptane/ethanol, 1.0 mL/min; 220 nm;
(R)-4f, tR = 10.78 min; (S)-4f, tR = 13.0 min.
1
e.r.): H NMR (400 MHz, CDCl3) δ 4.37 (bs, 2H), 2.83−2.71 (m,
2H), 1.75−1.64 (m, 2H), 1.54−1.40 (m, 2H), 0.96 (t, 3H, J = 7.3 Hz);
13C NMR (100 MHz, CDCl3) δ 57.2, 24.9, 21.8, 13.7; HRMS (ES
pos.) m/z calcd for C4H12NOS+ (M + H+) 122.0634, found 122.0639.
Chiral HPLC conditions: Chiralpak AD-H, 4.6 × 250 mm, 5 μm; 97:3
heptane/ethanol, 1.0 mL/min; 220 nm; (R)-3f, tR = 29.13 min; (S)-3f,
tR = 32.55 min.
ASSOCIATED CONTENT
■
General Experimental Procedure for Synthesis of N-Alkyl
Chiral Sulfinamides. A solution of the corresponding amine (5.09
mmol, 5 equiv) in anhydrous THF (5 mL) was cooled to −78 °C.
Then, n-BuLi (4.5 equiv) was added slowly at the same temperature.
After 45 min, a solution of quinine sulfinate (1.02 mmol) in THF
(5 mL) was added to the reaction mixture at −78 °C. After 10 min,
the reaction mixture was quenched with aqueous ammonium chloride
(10 mL). The product was extracted with ethyl acetate (20 mL). The
aqueous layer was extracted using ethyl acetate (3 × 10 mL). The
combined organic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated. Purification of the crude product by column
S
* Supporting Information
1
Copies of H and 13C NMR of all new compounds and crystal
data for 2d. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yongda.zhang@boehringer-ingelheim.com.
694
dx.doi.org/10.1021/jo201825b | J. Org. Chem. 2012, 77, 690−695

The Journal of Organic Chemistry
Note
Rev. 2007, 107, 5133. (d) Beck, E. M.; Hyde, A. M.; Jacobsen, E, N.
Org. Lett. 2011, 13, 4263.
(14) The other enantioisomers Ss-sulfinamides could be synthesized
in the same way using quinidine as auxiliary.
(15) Brak, K.; Barrett, K. T.; Ellman, J. A. J. Org. Chem. 2009, 74,
3606.
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