Enantioselective synthesis of diverse sulfinamides and sulfinylferrocenes from phenylglycine-derived chiral sulfinyl transfer agent

Article abstract of DOI:10.1021/jo200715c

A new chiral sulfinyl transfer auxiliary derived from readily available phenylglycine was developed. This auxiliary is utilized to synthesize a diverse array of alkyl- and arylsulfinamides and sulfinylferrocenes in high yields and excellent ee's. The desired products are produced in a one-pot sequence from the oxathiazolidine 2-oxide by two sequential nucleophilic additions that proceed in a stereospecific manner.

Full text of DOI:10.1021/jo200715c

NOTE
pubs.acs.org/joc
Enantioselective Synthesis of Diverse Sulfinamides and
Sulfinylferrocenes from Phenylglycine-Derived Chiral
Sulfinyl Transfer Agent
Zhengxu S. Han,* Angelica M. Meyer, Yibo Xu, Yongda Zhang, Robert Busch, Sherry Shen, Nelu Grinberg,
Bruce Z. Lu, Dhileep Krishnamurthy, and Chris H. Senanayake
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., 900 Old Ridgebury Road, P.O. Box 368, Ridgefield,
Connecticut 06877, United States
S Supporting Information
b
ABSTRACT: A new chiral sulfinyl transfer auxiliary derived
from readily available phenylglycine was developed. This aux-
iliary is utilized to synthesize a diverse array of alkyl- and
arylsulfinamides and sulfinylferrocenes in high yields and ex-
cellent ee’s. The desired products are produced in a one-pot
sequence from the oxathiazolidine 2-oxide by two sequential
nucleophilic additions that proceed in a stereospecific manner.
Scheme 1. Synthesis of Sulfinamide via Amino Alcohol or
Norephedrine
hiral sulfinyl-containing reagents, such as sulfoxides and
sulfinamides, have been recognized as useful tools in the
C
asymmetric synthesis of complex organic molecules.1 Although
the power of chiral sulfinyl reagents in synthetic chemistry has
long been recognized, methods for their synthesis have emerged
slowly.1c A few methods have been developed in the past few
decades, but a more general and economic method for their
synthesis is necessary in order to meet today’s need.2
Primarily, chiral sulfinyl transfer agents only have been used in
the synthesis of chiral sulfoxides. Because of their limitation, few
methods have been used in the synthesis of chiral sulfinamides.2aꢀf
With the pioneering work by Davis et al.3 for the synthesis of
chiral p-toluenesulfinamide (p-TSA) from Anderson’s reagent,4
followed by Ellman et al.5 for the synthesis of tert-butanesulfina-
mide (t-BSA), the power of their applications to the asymmetric
synthesis of chiral amines was quickly realized. A wide range of
natural products as well as many important pharmaceutical
agents with chiral amine functionalities have been synthesized
using this technology.5
Because of the limited availability of other sulfinamides, t-BSA
and p-TSA have been commonly used in the asymmetric
synthesis.6,7 Many times, sulfinamides with diverse functional-
ities are needed in order to fine-tune for high stereoselectivity. To
meet this need, we developed a unique double displacement
method to prepare a variety of both alkane- and arenesulfina-
mides (Scheme 1).8 This method is based on the use of a chiral
and functionality differentiated oxathiazolidine S-oxide 7a or 7b
derived from cis-(R,S)- or (S,R)-amino alcohols, such as
N-tosylaminoindanol (6a) or N-tosylnorephedrine (6b). This
technology was also employed successfully in the synthesis of a
variety of important sulfoxides. However, the relatively expensive
aminoindanol and regulated substance norephedrine hindered
production of sufinamides on a large scale and in a more
economic manner.
Recently, we have used 1 as a recyclable auxiliary in the
asymmetric synthesis of sibutramine.9 Reaction of an imine
intermediate with 1 derived oxathiazolidine S-oxide (2) gener-
ates a chiral sulfinate imine that was reduced to provide the
desired amine in high stereoselectivity. However, the application
of 1 in the synthesis of chiral sulfinyl-containing compounds,
Received: April 5, 2011
Published: May 20, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo200715c J. Org. Chem. 2011, 76, 5480–5484
|

The Journal of Organic Chemistry
NOTE
Scheme 2. Preparation of Auxiliary 1 from Phenylglycine
Table 1. Synthesis of Sulfinamides with Different
Functionalities
Scheme 3. Synthesis of 2 from 1
such as sulfinamides and sulfoxides, was never reported. Herein,
we report the application of 1, which contains one stereocenter,
as a useful and inexpensive chiral sulfinyl transfer agent in the
synthesis of sulfinamides and sulfoxides in high yields and
excellent enantiopurity.
Both (R) - and (S)-phenylglycines are readily available and
abundant. Its methyl ester (8) was easily converted to 9 via
tosylation under SchottenꢀBaumann reaction conditions in
excellent yield.9 Reaction of 9 with 3 equiv of methylmagnesium
bromide in THF yielded the desired amino alcohol 1 in 95% yield
(Scheme 2). In contrary, reaction of methylmagnesium bromide
with 8 resulted in very poor yield in the synthesis of the
corresponding amino alcohol.
With 1 in hand, the synthesis of 2 in diastereomerically pure
form on a large scale was investigated. Previously, we have
demonstrated a methodology for the preparation of N-tosyl-
1,2,3-oxathiazolidine 2-oxide 7a or 7b in high diastereoselec-
tivity. The synthesis was achieved by a slow addition of an
appropriate base to a mixture of either 6a or 6b and thionyl
chloride in THF solution.8b Following a similar protocol, by
slow addition of pyridine to a mixture of 1 with thionyl chloride
in THF at ꢀ40 °C, (2S,4R)-5,5-dimethyl-4-phenyl-N-tosyl-
1,2,3-oxathiazolidine 2-oxide (2)10 was prepared in 96% yield
and >90% de on 200 g scale. Compound 2 is crystalline, and its
diastereomeric purity was enriched to 99% de by recrystallization
from ethyl acetate/hexane in 90% yield (Scheme 3).
The synthesis of sulfinamides by using 2 was next investigated.
Using different Grignard reagents and lithium bis(trimethylsilyl)-
amide (LHMDS), as shown in Table 1, a series of enantiopure
sulfinamides 4aꢀg were synthesized in a one-pot fashion. Slow
addition of a Grignard reagent to a solution of 2 in THF
at ꢀ78 °C generated the sulfinate intermediate 3 in high yield by
selectively opening the SꢀN bond.8 After completion of the
reaction, LHMDS was added directly to the reaction mixture, and
the reaction mixture was warmed to ambient temperature to
yield the desired sulfinamides in good yield and optical purity
with recovery of auxiliary 1. Sulfinamides with different func-
tional groups, for example, of alkyl (4a,b), electron-withdrawing
(4c), electron-donating (4d), phenyl (3e), and thiophene (4g),
were prepared successfully.
a Isolated yield. b ee monitored by chiral HPLC. c One-pot protocol by
using LHMDS as nucleophile. d Two-step protocol by using LiNH2/
NH3 as nucleophile
and use of 4f gave a better selectivity than both pTSA and tBSA
in the synthesis of the key chiral amine intermediate.
For comparison purposes, the above method was applied to
synthesize the more sterically hindered tert-butanesulfinamide
(t-BSA) as well as triisopropylbenzenesulfinamide (TIPPSA) in
excellent ee and in high yield. However, because of the increased
steric bulk of both the tert-butyl and triisopropylphenyl groups,
the above-discussed one-pot procedure cannot be used because
there was no reaction was observed when LHMDS was used as
nucleophile. Instead, LiNH2 in ammonia was needed to make
these sulfinamides.5a,8a
Synthesis of chiral 4c via subtilisin-catalyzed resolution of
N-acylarylsulfinamide was reported but in very low yield.11a No
synthesis of 4d or 4e in optically pure form has been
reported.11b The application of 4f in the synthesis of
(S)-(ꢀ)-xylopinine was reported by Davis and co-workers,11c
The scope of 2 in the synthesis of chiral sulfinyl compounds
was extended to the synthesis of chiral sulfoxides and ferroce-
neꢀsulfinyl derivatives in particular. The ferrocene-bearing
stereogenic sulfinyl group has recently emerged as highly service-
able agent in many asymmetric processes because it can act as an
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NOTE
Scheme 4. Synthesis of Ferrocene Derivatives from Ferro-
ceneꢀSulfinyl Compound
ortho-directing group to afford ferrocene derivatives with planar
and central chirality (scheme 4). On the other hand, they can be
easily removed or substituted, providing a key method in the
synthesis of enantiopure 1,2-disubstituted ferrocenyl ligands.12
Few methods have addressed this issue except in the synthesis of
p-tolylsulfinyl- and tert-butylsulfinylferrocenes in a tedious man-
ner. In this case, the chiral sulfinyl transfer reagents have to be
prepared individually, and therefore, it lacks generality and
efficiency.12a,i
Figure 1. Synthesis of ferrocenyl sulfoxides.
Use of 2 provides a general method for the synthesis of a
variety of alkyl- or arylsulfinylferrocenes. The preparations of
these ferrocenyl derivatives were accomplished in a one-pot
process by double displacement. Addition of Grignard reagent
afforded the sulfinate intermediate 3 and subsequent addition of
ferrocenyllithium that was generated in THF by treatment of
ferrocene with t-BuLi in the presence of t-BuOK as catalyst12b
afforded the desired 5 in good yield and high enantiopurity. As
shown in Figure 1, a few examples of structural diverse sulfoxides
were prepared, which include alkyl and aryl groups. Attempts to
prepare the ferrocenyl sulfinate intermediate by addition of
ferrocenyllithium to 2 resulted in low yield. The major product
is diferrocenyl sulfoxide, which is from the double addition due to
the high reactivity of ferrocenyllithium as a nucleophile.
With sulfoxide 5 in hand, reactions with aldehydes in the
synthesis of chiral alcohol 10 were investigated. Ferrocenyl chiral
alcohols are also important intermediates used as transit in the
synthesis of P- or N-containing ligands, and their synthesis in
optically pure form was a tedious process.12,13 On the other hand,
the chiral alcohol generated from ferrocenyl sulfoxide would
potentially provide a quick way in accessing S,O-ferrocenyl
ligands. However, to the best of our knowledge, only the addition
of lithiated tert-butylsulfinylferrocene to benzaldehyde was re-
ported but the reaction yielded racemic alcohol.12g
The reactions of benzaldehyde with sulfoxides 5a (t-Bu-
FcSO), 5b (Mes-FcSO), and 5c (TIPP-FcSO) were primarily
investigated in the synthesis of chiral alcohols (Figure 2). Sulf-
oxide was first lithiated with t-BuLi in THF at ꢀ78 °C, and then a
THF solution of benzaldehyde was added dropwise. Upon
completion, the reaction was quenched by addition of water.
The conversion and dr were easily determined on the basis of the
LC analysis. Reaction of 5a with benzaldehyde resulted in the
desired product 10a in a high isolated yield of 92% but in poor
stereoselectivity of 57:43 dr. When 2-mesitylsulfinylferrocene 5b
was used, the reaction was sluggish and the isolation of the
desired product was not successful, which might be caused by the
decomposition of the lithated product or other side reactions as
observed in the case of p-tolylsulfinylferrocene.12a Use of nBuLi
or LDA as lithiation reagent was found also not productive.
However, when hindered 5c was used, the reaction afforded the
product 10c in high yield of 94% with good dr of 82:18. Attempts
to improve the selectivity by adding Lewis acids or Lewis bases,
Figure 2. Synthesis of alcohol from ferrocenyl sulfoxides.
were separated by chromatography on silica gel to provide
optically pure products.
In summary, a new and easily accessible chiral sulfinyl transfer
agent 2 was developed. Its utilities have been extended to the
synthesis of structurally diverse sulfinamides and ferrocenyl
sulfoxides in excellent yields and enantiomeric purities. Ferroce-
nyl sulfixide 5c that contains a triisopropylphenyl functionality
shows superior stereoselectivity as compared to tert-butyl con-
taining sulfoxide 5a in the synthesis of chiral benzyl alcohol. The
applications of 5c in the synthesis of other ferrocenyl alcohols as
well as the application of alcohols as ligands in asymmetric
synthesis are under further investigation.
’ EXPERIMENTAL SECTION
Large-Scale Synthesis of (2S,4R)-5,5-Dimethyl-4-phenyl-
N-tosyl-1,2,3-oxathiazolidine 2-Oxide (2). To a stirred solution
of 1 (200 g, 629 mmol) in THF (1 L) at ꢀ45 °C was slowly added
thionyl chloride (69 mL, 944 mmol). Subsequently, pyridine (127 mL,
1.57 mol) diluted in THF (100 mL) was added slowly via an addition
funnel. After addition, TLC analysis indicated no remaining starting
material, and the reaction was quenched with aqueous NaHCO3
(500 mL) and diluted with EtOAc (1 L). The reaction mixture was
allowed to warm to ambient temperature, and the phases were separated.
The organic layer was washed with brine, dried with Na2SO4, filtered,
and concentrated under rotary evaporation to afford 2 (221 g, 96%) as a
white solid with a dr = 95:5. Recrystallization of 2 from EtOAc and
such as LiCl, MgBr2, AlMe3, BF3 OEt2, ZnCl2, and TMEDA, to
3
the reaction mixture were not successful. Those two diastereomers
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NOTE
hexanes gave the desired product in >99:1 dr in 90% overall yield.
Characterization data matches previously reported data.9
Typical Procedure for the Synthesis of (R)-2,4,6-Triisopro-
pylphenylsulfinylferrocene (5c). In a separate flask, triisopropyl-
phenylmagnesium bromide (2.48 mL, 0.65 M in THF) was added to a
solution of 2 (0.59 g, 1.6 mmol) in THF (5 mL) at ꢀ78 °C. The mixture
was stirred for 1 h, warmed to rt, and stirred for 1 h to form sulfinate
intermediate 3i.
To a mixture of ferrocene (0.45 g, 2. 42 mmol) and t-BuOK (0.3 mL,
1 M in THF) in THF (7 mL) at ꢀ78 °C was added t-BuLi (3 mL, 1.6 M)
dropwise under an inert atmosphere. The mixture was stirred for 15 min,
warmed to rt, and stirred for 1 h.
General Procedure for Grignard Addition to 2 in the
Synthesis of 3i. To a stirred solution of 2 (1 g, 2.7 mmol) in THF
(10 mL) at ꢀ78 °C was added freshly prepared triisopropyphenylmag-
nesium bromide solution (5.5 mL, 0.5 M in THF) dropwise. Upon
completion of addition, TLC analysis showed no remaining starting
material, and the reaction was quenched with aqueous NaHCO3 (5 mL)
and diluted with EtOAc (20 mL). The reaction mixture was allowed to
warm to ambient temperature, and the phases were separated. The
organic layer was washed with brine, dried with Na2SO4, filtered, and
concentrated under rotary evaporation. The solid residue was purified
with flash chromatography (0% f 50% EtOAc/hexanes) to afford 3i in
91% yield (1.42 g): 1H NMR (400 MHz, CDCl3) δ 1.17ꢀ1.27
(m, 21H), 1.18 (s, 3H), 2.26 (s, 3H), 2.89 (sep, J = 6.8 Hz, 1H), 3.98
(sep, J = 6.8 Hz, 2H), 4.24 (d, J = 9.6 Hz, 1H), 6.15 (d, J = 9.6 Hz, 1H),
6.94 (d, J = 8.2 Hz, 2H), 6.98ꢀ7.03 (m, 4H), 7.07ꢀ7.09 (m, 3H), 7.37
(d, J = 8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.3, 23.6, 23.7,
24.2, 24.5, 24.5, 26.5, 26.7, 28.1, 34.4, 65.7, 86.3, 122.8, 126.8, 127.3,
127.6, 128.7, 128.9, 136.5, 137.6, 137.7, 142.5, 148.6; 152.9; HRMS
calcd for C32H44NO4S2 (M þ 1) 570.2718, found 570.2709.
Both flasks were cooled to ꢀ78 °C, and the lithiated ferrocene
solution was transferred to the 3i solution. The mixture was stirred
at ꢀ78 °C for 15 min, warmed to rt, and stirred for 1 h to furnish the
reaction. The reaction was quenched by addition of water and diluted
with EtOAc and brine. The aqueous phase was removed and extracted
once with EtOAc. The combined organic phases were dried over
Na2SO4 and concentrated. The residue was purified on column to give
0.66 g of 5c in 94% yield and 98% ee: 1H NMR (400 MHz, CDCl3) δ
1.09 (bs, 6H), 1.22 (d, J = 6.9 Hz, 6H), 1.28 (d, J = 6.7 Hz, 6H), 2.85
(sep, J = 6.9 Hz, 1H), 3.89ꢀ3.96 (m, 3H), 4.21 (s, 1H), 4.33 (s, 5H),
4.35 (s, 1H), 4.99 (s, 1H), 7.02 (s, 2H); 13C NMR (100 MHz, CDCl3) δ
23.8, 24.0, 24.9, 28.5, 34.3, 66.4, 67.3, 68.8, 69.3, 69.9, 93.6, 122.9, 137.2,
152.5; HRMS calcd for C25H33FeOS (M þ 1) 437.1602, found
437.1596 (0.031 ppm). Chiral HPLC conditions: Chiralcel OD, 4.6 ꢁ
250 mm, 5 μm; 98:2, hexanes/IPA, 0.7 mL/min; 254 nm; (R)-5c,
tR = 9.0 min; (S)-5c, tR = 6.8 min.
(1R,RS)-3h was obtained in 95% yield: 1H NMR (400 MHz, CDCl3)
δ 1.09 (s, 3H), 1.14 (s, 9H), 1.75 (s, 3H), 2.25 (s, 3H), 4.25 (d, J = 10.0
Hz, 1H), 6.52 (d, J = 10.0 Hz, 1H), 6.92 (d, J = 8.1 Hz, 2H), 7.04 (d,
J = 4.2 Hz, 4H), 7.08 (m, 1H), 7.36 (d, J = 8.2 Hz, 2H); 13C NMR (100
MHz, CDC13) δ 21.3, 21.8, 25.4, 27.2, 57.3, 64.9, 85.5, 126. 7, 127.2,
127.5, 128.9, 129.1, 136.5, 138.0, 142.3; HRMS calcd for C21H30NO4S2
(M þ 1) 424.1616, found 424.1611.
1
(R)-tert-Butylsulfinylferrocene (5a). The H- and 13C NMR
and the chiral HPLC data match that reported.15
(R)-2,4,6-Trimethylphenysulfinylferrocene (5b): 1H NMR
(400 MHz, CDCl3) δ 2.24 (s, 3H), 2.52 (s, 6H), 4.02 (s, 1H), 4.22
(s, 1H), 4.43 (s, 5H), 4.35 (s, 1H), 4.94 (s, 1H), 6.81 (s, 2H); 13C
NMR δ 19.4, 21.1, 66.1, 67.6, 69.0, 69.6, 69.9, 130.6, 138.4, 141.2;
HRMS calcd for C19H21FeOS (M þ 1) 353.0662, found 353.0659
(0.52 ppm). Chiral HPLC conditions: Chiralcel OD, 4.6 ꢁ 250 mm,
5 μm; 98:2, hexanes/IPA, 0.7 mL/min; 220 nm; (R)-5b, tR = 24.6 min;
(S)-5b, tR = 26.9 min.
Typical Procedure for One-Pot Synthesis of (R)-2-Pheny-
benzenesulfinamide (4e). To a stirred solution of 2 (1 g, 2.7 mmol)
ο
in THF (10 mL) at ꢀ78 C was added 0.5 M biphenyl-2-magnesium
bromide (5.5 mL) in diethyl ether dropwise. Upon completion of
addition, TLC analysis showed no remaining starting material, 1.0 M
lithium bis(trimehtylsilyl)amide (4.1 mL) in THF was added, and the
reaction mixture was allowed to slowly warm to ambient temperature.
After completion of the reaction, water (5 mL) was added and the
mixture diluted with EtOAc (20 mL). The phases were separated, and
the organic phase was washed with brine (5 mL), dried with Na2SO4,
filtered, and concentrated under rotary evaporation. The crude mixture
was purified with flash chromatography (20% f100% EtOAc/hexanes)
to afford 4e (547 mg) in 92% yield and 99% ee and 1 (777 mg) in 89%
Typical Procedure for the Synthesis of 10c. To a stirred
solution of sulfinylferrocene 5c (0.16 mmol) in dry THF (1 mL) at ꢀ78 °C
under argon was added tert-butyllithium (1.3 equiv). After 30 min, the
aldehyde (2 equiv) in 1 mL of THF was slowly added. The reaction mixture
was stirred for an additional 30 min at ꢀ78 °C before it was quenched with
H2O, extracted with EtOAc, dried (Na2SO4), and concentrated. The
reaction products were then analyzed by LC/MS and NMR and purified
by chromatography to separate the diastereomers. 10c major diasteromer:
1H NMR (400 MHz, CDCl3) δ1.06 (d, J= 6.9 Hz, 6H), 1.24 (d, J=6.9Hz,
6H), 1.30 (d, J = 6.8 Hz, 6H), 2.88 (sep, J = 6.9 Hz, 1H), 3.67ꢀ3.71 (m,
2H), 3.87 (sep, J = 6.6 Hz, 2H), 3.99 (t, J = 2.5 Hz, 1H), 4.39 (s, 5H), 5.24
(d, J = 3.2 Hz, 1H), 5.89 (d, J = 3.1, 1H), 7.06 (s, 2H), 7.30ꢀ7.35 (m, 1H),
7.40 (t, J = 7.4 Hz, 2H), 7.60 (d, J = 7.3 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 23.8, 24.8, 29.5, 34.4, 66.8, 67.4, 70.6, 71.6, 90.7, 95.1, 123.2,
127.2, 127.4, 128.0, 130.2, 133.5, 135.4, 142.0, 150.7, 153.5; HRMS calcd for
C32H37FeOS (M ꢀ OH) (major) 525.1915, found 525.1908 (0.293 ppm);
calculated for C32H38FeO2S(Mþ) 542.1942, found 524.1938 (0.381 ppm).
LCꢀMS for the separation of diastereomers, major, tR = 8.04 min, minor,
tR = 8.26 min.
1
yield: H NMR (400 MHz, CDCl3) δ 3.95 (s, 2H), 7.34 (m, 1H),
7.39ꢀ7.44 (m, 5H), 7.54ꢀ7.60 (m, 2H), 8.19 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 122.63, 127.81, 128.15, 128.24, 126.49, 130.69,
131.09, 138.34, 140.34, 145.24; HRMS calcd for C12H12NOS (M þ 1)
218.0640, found 218.0634. Chiral HPLC conditions: Chiralpak AS-H
Column, 4.6 ꢁ 250 mm, 5 μm; 90:10 hexanes/ethanol, 1.0 mL/min;
254 nm; (R)-4e, tR = 5.7 min; (S)-4e tR = 29.0 min.
The following known compounds were isolated as pure samples and
showed NMR spectra and the enantiomerically purity matching those of
the reported compounds: p-TSA (4a),2a TMBSA (4b),2a p-ClBSA
(4c),11a o-MNSA (4f),14 t-BSA (4h),2a and TIPPSA (4i).5b
(R)-2-Methoxyphenylsulfinamide (4d). The 1H NMR and 13
C
NMR data match that reported.11b
Chiral HPLC conditions: Chiralcel OD Column, 4.6 ꢁ 250 mm,
10c minor diastereomer: 1H NMR δ 1.12 (bs, 5H), 1.26 (d, J = 7.0
Hz, 13H), 2.90 (sep, J = 7.0 Hz, 1H), 3.61ꢀ3.62 (m, 1H), 3.76 (sep, 6.7
Hz, 2H), 3.97ꢀ3.98 (m, 1H), 4.05 (t, J = 2.6 Hz, 1H), 4.24 (s, 5H), 5.55
(d, J = 5.3 Hz, 1H), 6.05 (d, J = 5.2 Hz, 1H), 7.09 (s, 2H), 7.30ꢀ7.34 (m,
1H), 7.37ꢀ7.43 (m, 2H), 7.62 (d, J = 7.2 Hz, 2H); 13C NMR δ 23.8,
24.8, 29.5, 34.4, 66.8, 67.4, 70.6, 71.6, 90.7, 95.1, 123.2, 127.2, 127.4,
128.0, 130.2, 133.5, 135.4, 142.0, 150.7, 153.5.
5 μm; 90:10 hexanes/ethanol, 1.0 mL/min; 254 nm; (S)-4d, tR
=
12.1 min; (R)-4d, tR = 25.9 min.
1
(R)-3-Methylthiophene-2-sulfinamide (4g): H NMR (400
MHz, CDCl3) δ 2.31 (s, 3H), 4.90 (br s, 2H), 6.85 (d, J = 5 Hz, 1H),
7.35 (d, J = 5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.19, 128.13,
131.44, 139.02, 142.65; HRMS calcd for C5H8NOS2 (M þ 1) 162.0047,
found 162.0041. Chiral HPLC conditions: Chiralpak AS-H Column,
4.6 ꢁ 250 mm, 5 μm; 90:10 hexanes/ethanol, 1.0 mL/min; 254 nm;
(R)-4g, tR = 5.7 min; (S)-4g, tR = 29.0 min.
10a. The 1H and 13C NMR data match those reported.12a Retention
time for the diastereomers: major tR = 5.83 min, minor tR = 6.09 min.
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NOTE
’ ASSOCIATED CONTENT
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S
Supporting Information. Additional procedures, spec-
b
tral data and characterizations (1H and 13C NMR), and HRMS of
all new products. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: shan@rdg.boehringer-ingelheim.com.
(14) Davis, F. A.; Mohanty, P. K. J. Org. Chem. 2002, 67, 1290.
(15) Priego, J.; Mancheno, G. M.; Cabrera, S.; Carretero, J. C. J. Org.
Chem. 2002, 67, 1346.
’ ACKNOWLEDGMENT
We thank Dr. Fenghe Qiu and Scott Pennino for HRMS
analysis.
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