Asymmetric syntheses of S, S-dialkyl-substituted sulfoximines and related heterocycles

Article abstract of DOI:10.1055/s-0030-1260260

Enantiomerically enriched forms of a sulfoximine-based myristic acid analogue are prepared using either an asymmetric desymmetrization with a chiral base, or an enantioselective oxidation procedure as key steps. Additionally, a variety of 2-oxa-2-alkyl 3,

Full text of DOI:10.1055/s-0030-1260260

PAPER
3827
Asymmetric Syntheses of S,S-Dialkyl-Substituted Sulfoximines and Related
Heterocycles
S
,
S
-Dialkyl-Substi
n
tuted Sulfoxi
k
mines and
R
u
elated Heter
o
r
cycles G. Pandey, Matthew J. McGrath, Olga García Mancheño, Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52056 Aachen, Germany
Fax +49(241)8092391; E-mail: Carsten.Bolm@oc.rwth-aachen.de
Received 30 August 2011
HN
Me
O
S
COOH
NH2
Abstract: Enantiomerically enriched forms of a sulfoximine-based
myristic acid analogue are prepared using either an asymmetric de-
symmetrization with a chiral base, or an enantioselective oxidation
procedure as key steps. Additionally, a variety of 2-oxa-2-alkyl 3,4-
dihydro 2,1-benzothiazines are synthesized via intramolecular
metal-catalyzed N-arylation of appropriately functionalized sulfox-
imines with tethered 2-bromoaryl substituents. In turn, the sulfox-
imines are prepared by lithiation–alkylation sequences including
enantioselective deprotonation steps or the use of an optically active
sulfoxide. Using this methodology, the range of accessible 3,4-di-
hydro 2,1-benzothiazine derivatives is expanded.
(S,S)-1
N
HN
Me
O
O
S
S
Me
Me
CF3
rac-3
rac-2
Figure 1 Bioactive S,S-dialkyl sulfoximines and a related hetero-
cycle
tiomerically enriched forms of such compounds. Thus,
asymmetric syntheses of S,S-dialkyl-substituted sulfox-
imines and related heterocycles with potential biological
relevance became prime targets of choice.
Key words: alkyl sulfoximines, dihydro benzothiazines, desymme-
trization, cyclizations, copper
In the study reported here, two main synthetic strategies
were followed: the first utilized a desymmetrization of N-
protected dimethyl sulfoximine 4 with a chiral base,9
opening direct access to enantioenriched methyl alkyl sul-
foximines [such as (S)-2] by formal alkylation of chiral
carbanion 5 (Scheme 1).
In recent years, the potential of sulfoximines as versatile
compounds in asymmetric synthesis has been recog-
nized,1 and several derivatives have found interest in me-
dicinal and crop protection chemistry.2 Since the first
report on methionine sulfoximine [(S,S)-1, Figure 1] in
1950,3 various strategies for the preparation of enantio-
merically enriched sulfoximines with a stereogenic center
at the sulfur atom have been developed. These synthetic
activities, however, have largely been focused on the
preparation of S-alkyl-S-aryl sulfoximines.1,4 In contrast,
approaches toward stereochemically homogeneous S,S-
dialkyl-substituted derivatives, which would also be of in-
terest for methionine sulfoximine, have seldom been con-
sidered despite the fact that several sulfoximines with two
alkyl substituents on sulfur have shown pronounced bio-
activities.5 Mostly, these have been applied as racemates,6
presumably due to preparative difficulties, which ham-
pered their accessibility in enantiopure form. Consequent-
ly, the effect of the absolute configuration at sulfur on the
potency of such compounds is often unknown. Two ex-
amples are depicted in Figure 1. In replication studies of
the Moloney leukemia virus (MoLV), myristic acid ana-
logue 2 was found to be a functional myrsitoylation antag-
onist,7 and 2-oxa-2-methyl 1,2-benzoisothiazole 3 proved
to be a central nervous system (CNS) depressant agent.8 In
the respective studies, both sulfoximines were applied as
racemates.
deprotonation
PG-N
Me
O
PG-N
Me
O
with a chiral base
S
S
CH2
Me
(desymmetrization)
4
5
HN
O
1. alkylation
2. N-deprotection
S
5
Me
(S)-2
C13H27
Scheme 1 Desymmetrization strategy for the synthesis of S,S-dial-
kyl sulfoximine (S)-2
The second approach made use of readily available enan-
tiopure sulfoxide 6,10 which was converted into the de-
sired S,S-dialkyl sulfoximines
7
by sequential
stereospecific substitution and imination. Both strategies
allowed the preparation of functionalized sulfoximines 8,
which proved useful for syntheses of 3,4-dihydro 2,1-ben-
zothiazines 9 via metal-catalyzed intramolecular N-aryla-
tions (Scheme 2).11,12
Our initial studies focused on the preparation of enantio-
merically enriched myristic acid analogue 2. Following
our previously reported desymmetrization methodology,9
treatment of N-silylated dimethyl sulfoximine 4a with
lithium (S,S)-bis(a-methylbenzyl)amide [(S,S-10)] in the
presence of lithium chloride at –105 °C, followed by trap-
ping of the resulting anion with dodecyl iodide, gave N-
protected sulfoximine 7a (Scheme 3). To our disappoint-
ment, however, the product was racemic.
Our general interest in sulfoximine chemistry1d motivated
us to focus our attention on the preparative access of enan-
SYNTHESIS 2011, No. 23, pp 3827–3838
x
x.
x
x
.
2
0
1
1
Advanced online publication: 17.10.2011
DOI: 10.1055/s-0030-1260260; Art ID: Z84711SS
© Georg Thieme Verlag Stuttgart · New York

3828
A. G. Pandey et al.
PAPER
O
(er >99.7:0.3) could be detected by HPLC analysis using
a chiral column.10b Iron-catalyzed nitrogen transfer14 with
hypervalent iodine reagent 1315 provided N-nosyl sulfox-
imine (R)-7c in 65% yield (er >99.5:0.5). Cleavage of the
nosyl group with thiophenol and cesium carbonate16 af-
forded the desired myristic acid analogue (–)-(R)-2 in
96% yield. As no adequate HLPC conditions for the deter-
mination of the enantiomeric ratio of S,S-dialkyl-substi-
tuted sulfoximine 2 were found, the final product was re-
nosylated by treatment with nosyl chloride in pyridine
(54% yield). The enantiomeric ratio of (R)-7c (er
>99.5:0.5) revealed that no racemization had occurred in
this reaction sequence, and we conclude that we have
achieved the synthesis of essentially enantiopure13 myris-
tic acid analogue (–)-(R)-2.
1. substitution
2. imination
S
O
N-PG
Me
Me
S
Alk
Br
6
7
O
O
NH
metal-catalyzed
cyclization
Br
Ar
N
S
S
Alk
Ar
Alk
8
9
Scheme 2 General strategies for the syntheses of S,S-dialkyl sulf-
oximines and 3,4-dihydro 2,1-benzothiazines
Taking earlier observations9 into account the desymmetri-
zation strategy was modified. The intermediate anion,
which was prepared as described above, was first trapped
with trimethylsilyl chloride to give a-silylated sulfox-
imine 7b in 81% yield. Pleasingly, an enantiomeric ratio
(er) of 79:21 was found. Based on the previous assign-
ment,9 the S-enantiomer was formed in excess. Treatment
of this product with n-butyllithium followed by dodecanal
led to an olefin with mixed double bond geometry via a
Peterson-type reaction. Subsequent palladium-catalyzed
hydrogenation afforded saturated sulfoximine (S)-7a in
37% yield over two steps. This product had an enantio-
meric ratio of 79:21. Desilylation with tetrabutylammoni-
um fluoride in tetrahydrofuran then completed the
reaction sequence providing myristic acid analogue (+)-
(S)-2 in 53% yield (Scheme 3).
S
Me
Ti(Oi-Pr)4, (–)-(S,S)-DET
CHP, CH2Cl2
(–)-(S)-6
Br
11
PhI=NNs (13)
Fe(OTf)2 (5 mol%)
O
O N Ns
H27C13MgBr
THF
S
S
Me
C13H27
MeCN
Me
C13H27
(–)-(R)-12
(–)-(R)-7c
NsCl, pyridine
O
NH
PhSH, Cs2CO3
S
for determination of er
by HPLC (chiral column)
Me
C13H27
(–)-(R)-2
Scheme 4 Asymmetric synthesis of myristic acid analogue (–)-(R)-2
1.
Using these two synthetic strategies, it was envisaged that
aryl alkyl-substituted sulfoximines could be prepared,
which would allow access to enantiomerically enriched 2-
oxa-2-alkyl 3,4-dihydro 2,1-benzothiazines by metal-
catalyzed cyclization. Initial optimization studies were
performed with racemic N-silyl-protected dimethyl
sulfoximine 4a as starting material. Addition of n-butyl-
lithium to 4a at –78 °C and subsequent treatment of the
resulting anion with benzyl bromides 14 afforded sulfox-
imines 15 in yields ranging from 39–70% (Table 1). De-
silylations of these products with tetrabutylammonium
fluoride gave NH-sulfoximines 8 in yields of up to 87%.
Ph
N
Ph
Li 10
O
N-TBDPS
C13H27
O
N-TBDPS
Me
LiCl, –105 °C
S
S
Me
rac-7a
Me
2. dodecyl iodide
4a
anion formation as above,
then TMSCl
1. n-BuLi, –78 °C
then dodecanal
O
NR
O
N-TBDPS
SiMe3
S
S
Me
C13H27
2. H2, Pd/C EtOAc
Me
(S)-7b
(S)-7a: R = TBDPS
(+)-(S)-2: R = H
TBAF, THF
Scheme 3 Asymmetric synthesis of myristic acid analogue (+)-(S)-2
Although the desymmetrization protocol led to the desired
S,S-dialkyl sulfoximine (S)-2 in enantiomerically en-
riched form, the enantiomeric ratio remained unsatisfy-
ing. Consequently, an alternative approach had to be
developed. A reaction sequence involving a metal-cata-
lyzed asymmetric sulfide oxidation to provide enan-
tiopure sulfoxide (S)-6 as the key step (Scheme 4)
appeared most attractive.10 Thus, starting from the corre-
sponding aryl methyl sulfide 11, asymmetric oxidation
with titanium tetraisopropoxide and cumyl hydroperoxide
(CHP) in the presence of (–)-(S,S)-diethyl tartrate [(–)-
(S,S)-DET] gave (–)-(S)-6 in 77% yield. After recrystalli-
zation from hexane, the enantiomeric ratio of the product
was 99.7:0.3 (chiral HPLC analysis).10,13 Nucleophilic
displacement of the 4-bromophenyl group with tridecyl-
magnesium bromide gave S,S-dialkyl sulfoxide (R)-12 in
92% yield. After recrystallization, only one enantiomer
To enlarge the substrate range in the subsequent metal-
catalyzed cyclization study, two further 2-bromophenyl-
ethyl substituted sulfoximines, 17 and 8e, having a phenyl
and a tert-butyl group at the sulfur atom, respectively,
were synthesized (Scheme 5). Both compounds made use
of known starting materials, and they were prepared in ra-
cemic form. Accordingly, N-silyl S-phenyl sulfoximine
1617 was lithiated with n-butyllithium, and trapping of the
resulting anion with 1-bromo-2-(bromomethyl)benzene
(14a), followed by reaction with tetrabutylammonium
fluoride gave NH-sulfoximine 17 in 62% overall yield.
An analogous approach was used for the conversion of N-
cyano S-tert-butyl derivative 7d.18 Here, the alkylated N-
cyano sulfoximine intermediate 18 was treated with tri-
fluoroacetic anhydride followed by potassium carbonate
in methanol to give tert-butyl-substituted NH-sulfoximine
8e in 74% overall yield (Scheme 5).
Synthesis 2011, No. 23, 3827–3838 © Thieme Stuttgart · New York

PAPER
S,S-Dialkyl-Substituted Sulfoximines and Related Heterocycles
3829
give products 9b and 9b¢, respectively (Table 2, entry 5).21
In contrast, sulfoximines 8c and 8d with a p-methoxy-
substituted bromoarene and a 3-pyridinyl group gave 9c
and 9d in only moderate to good yields (66% and 81%, re-
spectively, Table 2, entries 6 and 7). Finally, S-tert-butyl
sulfoximine 8e afforded the cyclization product 9e in 63%
yield (Table 2, entry 8), which compares well to the other
cyclization results considering the increased buttressing
effect of the tert-butyl group at the sulfur atom.
Table 1 Syntheses of S-Arylethyl-S-methyl Sulfoximines 8a–d
NR1
R2
O
O
N-TBDPS
Br
n-BuLi, –78 °C, then
S
S
ArCH(R2)Br (14a–d)
Me
Me
Me
Ar
4a
15a–d (R1 = TBDPS)
8a–d (R1 = H)
TBAF, THF
Br
Br
N
Br
MeO
Br
Br
Br
Br
Br
Me
14a
14b
14d
14c
Table 2 Syntheses of 3,4-Dihydro 2,1-Benzothiazines 9a
Entry 14
R2
15
a
Yield (%)a
70
8
Yield (%)a
O
R2
NH
Br
N
O
1
2
3
4
a
b
c
H
a
79
S
R1
conditions A or B
S
Ar
R1
Me
H
b + b¢b 39 (17)c
b + b¢
86 (91)c
87
Ar
R2
9a–f
8a–e, 17
c
72
c
Entry R1
Substrate R2
Conditions Product Yield (%)b
d
H
d
61d
d
79
1
2
3
4
5d
6
7
8
Ph
17
17
H
H
H
H
A
B
A
B
B
B
B
B
9f
9f
9a
9a
98
97
a Yield after column chromatography.
b A 2:1 mixture of diastereoisomers (b and b¢) was obtained.
c Yield of the minor isomer in brackets.
Ph
c
d Instead of n-BuLi, lithium (S,S)-bis(a-methylbenzyl)amide was
used as the base.
Me
Me
Me
Me
Me
t-Bu
8a
8a
–
89
n-BuLi, –78 °C; then
O
NH
1.
Br
Br
O
NTBDPS
Me
8b/8b¢ Me
9b/9b¢ 92 (92)
14a
S
S
S
Ph
Ph
2. TBAF, THF, r.t.
8c
8d
8e
H
H
H
9c
9d
9e
66
81
63
17
16
n-BuLi, –78 °C; then
14a
O
NCN
O
NR
S
t-Bu
Me
t-Bu
7d
a Conditions A: Pd(OAc)2, BINAP; conditions B: CuI, DMEDA. For
details see the experimental section.
18 (R = CN)
8e (R = H)
1. TFAA, CH2Cl2, r.t.
2. K2CO3, MeOH, r.t.
b Yield after column chromatography.
Scheme 5 Syntheses of NH-sulfoximines 17 and 8e
c A complex reaction mixture was obtained.
d Cyclization yield of the minor diastereoisomer in brackets.
Next, the conditions for the metal-catalyzed cyclizations
of 8a–e and 17 to give compounds 9a–f were studied
(Table 2). Following our previously published protocol
for N-arylations of sulfoximines by palladium catalysis
using palladium(II) acetate [Pd(OAc)2] (10 mol%),
BINAP (15 mol%) and potassium carbonate in toluene,19
S-phenyl sulfoximine 17 reacted well affording heterocyclic
sulfoximine 9f in 98% yield (Table 2, entry 1). However,
when these conditions were applied to the corresponding
S-methyl sulfoximine 8a no clean product was obtained
(Table 2, entry 3). Consequently, the approach was modi-
fied and a copper-catalyzed cyclization was attempted. As
in the intermolecular N-arylation,20 copper(I) iodide (10
mol%) in combination with N,N¢-dimethylethylenedi-
amine (DMEDA) (20 mol%) and potassium carbonate in
toluene were applied. Both S-phenyl and S-methyl sulfox-
imines 17 and 8a reacted well providing the correspond-
ing 3,4-dihydro 2,1-benzothiazines 9f and 9a in yields of
97% and 89%, respectively (Table 2, entries 2 and 4). En-
couraged by these results, the behavior of the other sub-
strates was studied and the results are shown in Table 2.
High yields (92%) were observed in cyclizations of dia-
stereomeric S-methyl sulfoximines 8b and 8b¢, which
both have a methyl substituent at the benzylic position to
To demonstrate the applicability of the devised protocols
for the preparation of enantiomerically enriched 2-oxa-2-
alkyl 3,4-dihydro 2,1-benzothiazines, two approaches
were followed (Scheme 6). The first made use of optically
active S-arylethyl S-methyl sulfoximine 15a. This inter-
mediate was obtained by asymmetric deprotonation of
N-silylated dimethyl sulfoximine 4a with lithium (S,S)-
bis(a-methylbenzyl)amide (10) in the presence of lithium
chloride at –105 °C9 and trapping of the resulting anion
with 1-bromo-2-(bromomethyl)benzene (14a). After
aqueous work-up, N-protected sulfoximine (S)-15a was
obtained with an enantiomeric ratio of 77:23 in 70% yield.
Subsequent cleavage of the silyl group with tetrabutylam-
monium fluoride to give (S)-8a followed by copper-cata-
lyzed cyclization under standard conditions afforded 2-
oxa-2-methyl 3,4-dihydro 2,1-benzothiazine [(S)-9a] in
70% yield over two steps. Analysis of the enantiomeric ra-
tio by HPLC using a chiral stationary phase revealed the
stereospecificity of the reaction sequence (er = 77:23).
The potential of this cyclization strategy for the synthesis
of an enantiomerically enriched 2-oxa-2-alkyl 3,4-dihy-
dro 2,1-benzothiazine was further illustrated for S-tert-bu-
tyl-substituted 9e, an example of a substrate with a
Synthesis 2011, No. 23, 3827–3838 © Thieme Stuttgart · New York

3830
A. G. Pandey et al.
PAPER
Ph
N
Ph
Li
10
LiCl, –105 °C
then
O
Br
O
NTBDPS
N
O
NTBDPS
Me
1. TBAF
S
S
Me
S
Me
2. CuI (10 mol%)
DMEDA (20 mol%)
Me
Br
14a
Br
4a
er = 77:23
(S)-9a
er = 77:23
(S)-15a
1. PhSH, Cs2CO3, 50 ºC
2. TBDMSOTf, 2,6-lutidine
Br
O
O
NH
N
O
O
NNs
1. MeMgBr
CuI
DMEDA
S
S
S
S
t-Bu
t-Bu
t-Bu
3. n-BuLi, then 14a
4. TBAF, THF
t-Bu
2. Fe(acac)3
PhI=NNs
Me
t-Bu
S
(S)-7e
(R)-19 (er = 91:9)
(S)-8e
(S)-9e (er = 91:9)
Scheme 6 Syntheses of enantiomerically enriched 2-oxa-2-alkyl 3,4-dihydro 2,1-benzothiazines 9a and 9e
on a Buchi B-540 melting point apparatus and are uncorrected. Op-
tical rotations were measured with a Perkin-Elmer PE-241 instru-
ment. IR spectra were obtained using a Perkin-Elmer FT/IR 1760
and were recorded as KBr pellets, as neat liquids or in CHCl3 soln.
1H and 13C NMR spectra were recorded on Varian Innova 400 (400
and 100 MHz) or Mercury 300 (300 and 75 MHz) instruments.
Chemical shifts are given in ppm and spin-spin coupling constants,
J, are given in Hz. Mass spectra were acquired on a Varian MAT
212 spectrometer (CI, 100 eV and EI, 70 eV) and HRMS were re-
corded on a Finnegan MAT 95 spectrometer. Microanalyses were
obtained with a Vario EL element analyzer. HPLC was performed
on a Gynkotek M480 instrument or on a Merck Hitachi instrument
with a D7000 interface, L7100 pump and L7400 UV detector with
Daicel Chiralcel AD-H, OB-H, OD-H, OJ and Daicel Chiralpack
AS columns.
sterically hindered S-alkyl group. Here, (R)-tert-butyl-
thiosulfinate [(R)-19]22 served as an intermediate. Treat-
ment of (R)-19 (having an enantiomeric ratio of 91:9)23
with methylmagnesium bromide22c followed by imination
of the resulting sulfoxide under iron-catalysis (10 mol%
of iron(III) acetylacetonate [Fe(acac)3] as catalyst and a
mixture of iodosobenzene and p-nitrobenzenesulfon-
amide (PhI=O/NsNH2) or [N-(p-nosylsulfonyl)imi-
no]phenyliodinane (PhI=NNs) as nitrene sources in
acetonitrile at room temperature)24 gave N-nosyl protect-
ed sulfoximine (S)-7e in 80% yield (over two steps).25 In
order to introduce the 2-bromoaryl group required for the
copper-catalyzed cyclization, the N-substituent had to be
changed from nosyl to tert-butyldimethylsilyl. This was
achieved in 75% yield (over two steps) by treatment of
(S)-7e with thiophenol in the presence of cesium
carbonate16 and subsequent silylation of the intermediate
NH-sulfoximine with tert-butyldimethylsilyl triflate to
give (S)-7f. Alkylation under standard conditions [n-bu-
tyllithium, 1-bromo-2-(bromomethyl)benzene (14a);
88% yield] followed by desilylation with tetrabutylam-
monium fluoride afforded sulfoximine (S)-8e (67%
yield). Finally, applying the aforementioned copper catal-
ysis to this optically active substrate gave (S)-2-oxa-2-
tert-butyl 3,4-dihydro 2,1-benzothiazine [(S)-9e] in 72%
yield. HPLC analysis of (S)-9e using a chiral stationary
phase revealed an enantiomeric ratio of 91:9 confirming
the expected stereospecificity of the overall reaction se-
quence.
Chiral Base-Promoted Reactions; General Procedure A
To a suspension of (S,S)-bis(a-methylbenzyl)amine hydrochloride
(1.5 equiv) in THF (0.3 M) was added n-BuLi (2.7 equiv, 1.4–1.6
M in hexanes) at –105 °C and the resulting soln was allowed to
warm to r.t. over 30 min before being re-cooled to –105 °C. A soln
of sulfoximine (1.0 equiv) in THF (0.2 M) was added and the mix-
ture was stirred for a further 1 h at –105 °C. A soln/suspension of
the electrophile in THF (0.2 M) was added and the mixture was
stirred at –105 °C and then at r.t. for the indicated period of time.
The reaction was quenched by addition of 5% H3PO4 (aq) and the
mixture extracted with Et2O. The combined aq layers were washed
with 5% H3PO4 (aq) and NaHCO3 (aq) and dried over MgSO4. Con-
centration under reduced pressure afforded the product, which was
purified by flash chromatography.
Lithiation–Electrophilic Trapping; General Procedure B
To a soln of sulfoximine (1 equiv) in THF (0.1 M) at –78 °C was
added n-BuLi (1.1 equiv, 1.4–1.6 M in hexanes) and the soln was
stirred at this temperature for 20 min. A soln of the electrophile (2
equiv) in THF (0.5 M) was added and the resulting soln was allowed
to warm to r.t. The mixture was quenched with H2O or H3PO4 and
the aq layer was extracted with Et2O or CH2Cl2. The combined or-
ganic layers were dried over MgSO4, concentrated and the residue
purified by flash chromatography.
In conclusion, we have demonstrated the synthesis of a
sulfoximine-based myristic acid analogue in enantiomeri-
cally enriched form through a desymmetrization strategy
using lithium (S,S)-bis(a-methylbenzyl)amide as the
chiral base. Moreover, a range of 2-oxa-2-alkyl 3,4-dihy-
dro 2,1-benzothiazines has been prepared by copper-cata-
lyzed intramolecular N-arylation. Finally, the possibility
of synthesizing optically active dialkyl sulfoximines from
sulfoxides was also investigated.
tert-Butyldiphenylsilyl Deprotection; General Procedure C
Silyl protected sulfoximine (1 equiv) was dissolved in THF (0.04–
0.06 M) and a 1 M soln of TBAF in THF (3 equiv) was added. The
resulting soln was stirred at r.t. until TLC indicated complete con-
sumption of the starting material. The soln was concentrated and the
residue was subjected to flash chromatography to afford the desired
product.
All reactions were carried out under an atmosphere of N2 or Ar us-
ing oven-dried glassware. Et2O and THF were freshly distilled from
benzophenone ketyl. All other reagents were purchased from com-
mercial suppliers and used without further purification. Flash col-
umn chromatography was carried out using Silica gel 60 (Merck).
TLC was carried out using Merck F254 alumina-backed silica
plates. Melting points were determined in open-end capillary tubes
Copper-Catalyzed Cyclization; General Procedure D
Under Ar, DMEDA (20 mol%) was added to a suspension of K2CO3
(4 equiv), sulfoximine (1 equiv) and CuI (10 mol%) in toluene
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S,S-Dialkyl-Substituted Sulfoximines and Related Heterocycles
3831
(0.07–0.25 M) and the resulting soln heated in a sealed tube at 140
°C for 8–20 h. The reaction mixture was cooled to r.t. and then sub-
jected to purification by flash chromatography to afford the cyclized
product.
the title compound as a white solid (10.2 mg, 53%). For analytical
data, see the description of (R)-2.
[a]D +1.7 (c 0.20, CHCl3).
(S)-4-Bromophenyl Methyl Sulfoxide [(S)-6]10
Palladium-Catalyzed Cyclization; General Procedure E
Under Ar, a mixture of sulfoximine (1 equiv), BINAP (20 mol%),
K2CO3 (5 equiv) and Pd(OAc)2 (10 mol%) in toluene (0.1 M) was
heated in a sealed tube at 140–160 °C for 1 h. The mixture was
cooled to r.t. and then subjected to purification by flash chromatog-
raphy to afford the cyclized product.
In a flask containing (–)-(S,S)-DET (1.22 g, 5.91 mmol) dissolved
in anhyd CH2Cl2 (10 mL) a soln of Ti(Oi-Pr)4 (840 mg, 2.95 mmol)
dissolved in anhyd CH2Cl2 (6 mL) was added and the mixture
stirred vigorously for 2 min, after which distilled H2O (16 mL) was
added. This mixture was stirred for 20 min at r.t. and then cooled to
–20 °C. p-Bromophenyl methyl sulfide (11) (600 mg, 2.95 mmol)
in anhyd CH2Cl2 (6 mL) and cumene hydroperoxide (3.25 mmol)
were then added to the cooled mixture. The mixture was stirred at
–20 °C for 3 h after which the reaction was allowed to warm to r.t.
The reaction was quenched by addition of a sat. soln of NH4Cl (25
mL). The reaction mixture was filtered over Celite and the aqueous
layer was extracted with CH2Cl2 (3 × 20 mL). The organic layers
were collected, washed with H2O (2 × 50 mL) and then dried over
anhyd MgSO4. The solvent was evaporated in vacuo and the residue
purified by column chromatography (pentane–EtOAc, 3:7) to give
(S)-6 as a white solid [501.0 mg, 77%, er = 99.7:0.3 (after recrystal-
lization from hexane)].
(S)-N-tert-Butyldiphenylsilyl Methyl Trimethylsilylmethyl
Sulfoximine [(S)-7b]
Using general procedure A, reaction of 4a (668 mg, 2.02 mmol),
(S,S)-bis(a-methylbenzyl)amine hydrochloride (792 mg, 3.03
mmol), n-BuLi (3.6 mL, 1.5 M, 5.45 mmol) and TMSCl (0.76 mL,
3.03 mmol) in THF (22 mL) gave the crude product. Purification by
flash chromatography (pentane–EtOAc, 11:1) gave the title com-
pound as a white solid (659 mg, 81%, er = 79:21). Spectroscopic
data were consistent with the literature.9
HPLC: Chiralcel OD-H, heptane–i-PrOH, 99:1, 0.5 mL·min–1; 210
nm; tR1 = 18 min, tR2 = 29 min.
[a]D –106.2 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.66–7.63 (m, 2 H), 7.51–7.48 (m,
(S)-N-tert-Butyldiphenylsilyl Methyl n-Tridecyl Sulfoximine
[(S)-7a]
2 H), 2.69 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 145.0 (C), 132.7 (CH), 125.6 (C),
125.3(CH), 44.3 (CH3).
To a soln of sulfoximine (S)-7b (179.0 mg, 0.444 mmol) in THF (4
mL) at –78 °C was added n-BuLi (0.33 mL, 1.5 M in hexanes, 0.489
mmol) and the mixture was stirred at –78 °C for 20 min. A soln of
dodecanal (185.0 mg, 1 mmol) in THF (2 mL) was added and the
resulting soln allowed to warm to r.t. overnight. 5% H3PO4 (aq) (10
mL) was added and the aq layer was extracted with CH2Cl2 (3 × 20
mL).The combined organic layers were dried over MgSO4 and con-
centrated and the residue filtered through a plug of silica. The result-
ing oil was dissolved in EtOAc (20 mL), 10% Pd/C (69.0 mg) was
added and the suspension was stirred under an atm of H2 for 12 h.
The suspension was filtered through Celite, the filter cake washed
with EtOAc (30 mL) and the filtrate concentrated. Flash chromatog-
raphy (5% EtOAc–pentane) afforded the title compound as an oil
(81.0 mg, 37%, er = 79:21).
HPLC: Daicel Chiralcel OB-H column, n-heptane–i-PrOH, 70:30,
0.7 mL·min–1; 254 nm; tR1 = 10.3 min (major), tR2 = 13.4 min (mi-
nor).
(R)-Methyl n-Tridecyl Sulfoxide [(R)-12]10b
A soln of (S)-6 (150 mg, 0.68 mmol) in THF (5 mL) was cooled to
0 °C under an Ar atm. A 0.1 M soln of n-tridecylmagnesium bro-
mide (295.4 mg, 1.03 mmol) in THF was added dropwise to the
above cooled soln over a period of 30 min. After addition, the mix-
ture was stirred at 0 °C for 1.5 h, after which it was allowed to warm
to r.t. and then quenched with a sat. soln of NH4Cl (10 mL). The
aqueous layer was extracted with CH2Cl2 (3 × 12 mL), washed with
H2O (1 × 25 mL), dried over MgSO4 and the solvent removed in
vacuo. Purification by column chromatography (EtOAc) gave (R)-
12 as a white solid [155.0 mg, 92%, er >99.7:0.3 (after recrystalli-
zation from a minimum amount of hexane)].
[a]D –7.9 (c 0.7, CHCl3).
IR (capillary): 2926, 2855, 1464, 1327, 1299, 1154, 1108, 704 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.69–7.62 (m, 4 H), 7.34–7.24 (m,
6 H), 2.82–2.72 (m, 2 H), 2.58 (s, 3 H, CH3S), 1.73–1.63 (m, 2 H,
CH2), 1.25–1.12 (m, 20 H, CH2), 0.99 (s, 9 H, t-Bu), 0.81 (t, J = 6.5
Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): d = 136.6 (C), 136.5 (C), 135.6 (CH),
135.5 (CH), 129.0 (CH), 127.4 (CH), 59.0 (CH2), 44.4 (CH3), 32.1
(CH2), 29.8 (CH2), 29.7 (CH2), 29.6 (CH2), 29.5 (CH2), 29.4 (CH2),
29.2 (CH2), 28.5 (CH2), 27.3 (CH3), 23.5 (CH2), 22.8 (CH2), 19.4
(CH2), 14.3 (CH3).
[a]D –15.2 (c 0.7, CHCl3).
1H NMR (400 MHz, CDCl3): d = 2.74–2.58 (m, 2 H), 2.53 (s, 3 H),
1.76–1.68 (m, 2 H), 1.48–1.37 (m, 2 H), 1.35–1.22 (m, 18 H), 0.85
(t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 55.1 (CH2), 38.9 (CH3), 32.2
(CH2), 29.9 (CH2), 29.83 (CH2), 29.81 (CH2), 29.6 (CH2), 29.5
(CH2), 29.3 (CH2), 29.1 (CH2), 28.7 (CH2), 23.0 (CH2), 22.9 (CH2),
14.4 (CH3).
MS (EI): m/z (%) = 470 (1) [M – Et]+, 444 (21), 443 (65), 442 (100)
[M – t-Bu]+, 260 (1), 244 (10), 212 (22), 199 (4), 197 (6), 183 (4),
57 (12).
HPLC: Daicel Chiralcel OB-H column, n-heptane–i-PrOH, 99:1,
0.5 mL·min–1; 230 nm; tR1 = 22.9 min (minor), tR2 = 25.5 min (ma-
jor).
HRMS: m/z [M – C4H9]+ calcd for C26H40NOSSi: 442.2600; found:
442.2615.
(R)-N-(4-Nitrobenzenesulfonyl Methyl n-Tridecyl) Sulfoximine
[(R)-7c]
HPLC: Daicel Chiralcel OD-H, heptane–i-PrOH, 99:1, 0.5 mL·min–1;
210 nm; tR1 = 19.0 min, tR2 = 22.0 min.
A mixture of sulfoxide (R)-12 (70 mg, 0.28 mmol), Fe(OTf)2 (5
mol%), powdered 4 Å MS (0.5 g/mmol), and PhI=NNs15 (125.8 mg,
0.37 mmol) in MeCN (3 mL) was stirred at r.t. for 1.5 h. The solvent
was evaporated in vacuo and the residue purified by column chro-
matography (EtOAc–pentane, 1:1) to afford (R)-7c as a white solid
(82.0 mg, 65%, er >99.5:0.5).
(S)-NH-Methyl n-Tridecyl Sulfoximine [(S)-2]7
According to general procedure C, sulfoximine (S)-7a (60.0 mg,
0.12 mmol) and TBAF (0.48 mL, 1 M in THF, 0.48 mmol) were re-
acted together in THF (3 mL) to give a crude product. Flash chro-
matography (50% EtOAc–pentane then 10% EtOH–EtOAc) gave
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3832
A. G. Pandey et al.
PAPER
Mp 100–101 °C; [a]D –4.4 (c 1.0, CHCl3).
HRMS: m/z [M – t-Bu]+ calcd for C21H21NO79BrSSi: 442.0297;
found: 442.0297.
HPLC: Daicel Chiralcel OD-H, heptane–i-PrOH, 99:1, 0.5 mL·min–1;
230 nm; tR1 = 51 min, tR2 = 92 min.
IR (KBr): 3117, 3026, 2916, 2849, 1606, 1526, 1466, 1417, 1399,
1351, 1298, 1223, 1164, 1073, 967, 854, 733, 681 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.32–8.29 (m, 2 H), 8.15–8.11 (m,
2 H), 3.43–3.35 (m, 2 H), 3.34 (s, 3 H), 1.94–1.77 (m, 2 H), 1.47–
1.39 (m, 2 H), 1.31–1.23 (m, 18 H), 0.86 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 149.2 (C), 141.1 (C), 128.2 (CH),
124.2 (CH), 56.7 (CH2), 41.9 (CH3), 32.2 (CH2), 29.8 (CH2), 29.7
(CH2), 29.7 (CH2), 29.6 (CH2), 29.5 (CH2), 29.4 (CH2), 29.1 (CH2),
28.2 (CH2), 22.9 (CH2), 22.7 (CH2), 14.3 (CH3).
MS (CI): m/z (%) = 447 (100) [M]+, 262 (25), 247 (24), 215 (8), 173
(28), 156 (17), 107 (15), 97 (73).
HRMS: m/z [M + H]+ calcd for C20H35N2O5S2: 447.1982; found:
447.1982.
(S)-(2-Bromophenyl)ethyl Methyl Sulfoximine [(S)-8a]
According to general procedure C, sulfoximine (S)-15a (173.0 mg,
0.35 mmol) and TBAF (0.69 mL, 1 M in THF, 0.69 mmol) were re-
acted together to give the crude product. Purification by flash chro-
matography (50% EtOAc–PE then 10% MeOH–EtOAc) gave the
title compound as an oil (72.0 mg, 79%).
[a]D +6.8 (c 0.25, CHCl3).
IR (CHCl3): 3335, 2969, 1465, 1217, 1025, 949, 758 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.55 (dd, J = 8.0, 0.8 Hz, 1 H,
CH), 7.32–7.25 (m, 2 H, ArH), 7.13 (td, J = 8.0, 2.0 Hz, 1 H, CH),
3.39–3.35 (m, 2 H, CH2), 3.28–3.24 (m, 2 H, CH2), 2.98 (s, 3 H,
CH3), 2.43 (br s, 1 H, NH).
HPLC: Daicel Chiralcel AD-H column, n-heptane–i-PrOH, 9:1, 0.6
mL·min–1; 210 nm; tR1 = 45.6 min (minor), tR2 = 49.5 min (major).
13C NMR (100 MHz, CDCl3): d = 136.9 (C), 133.2 (CH), 130.9
(CH), 128.6 (CH), 128.0 (CH), 124.2 (C), 56.6 (CH2), 43.0 (CH3),
30.7 (CH2).
MS (EI): m/z (%) = 263 (1) [M (81Br)]+, 261 (1) [M (79Br)]+, 184
(26), 183 (23), 181 (100).
HRMS: m/z [M – Br]+ calcd for C9H12NOS: 182.0640; found:
182.0636.
(R)-NH-Methyl n-Tridecyl Sulfoximine [(R)-2]7
A mixture of sulfoximine (R)-7c (90 mg, 0.20 mmol), PhSH (32.9
mL, 0.32 mmol) and Cs2CO3 (118.2 mg, 0.36 mmol) in MeCN (3
mL) was stirred at 30 °C for 9 h. H2O (10 mL) was then added and
the mixture was extracted with CH2Cl2 (3 × 7 mL), dried over
MgSO4 and the solvent removed in vacuo. The residue was purified
by column chromatography (EtOAc–acetone, 1:0.2) to give (R)-2 as
a white solid (51.0 mg, 97%).
Mp 62.5–64.8 °C; [a]D –2.2 (c 1.05, CHCl3).
2l4-2,1-Benzothiazine-3,4-dihydro-2-methyl-2-oxide [(S)-9a]
Following general procedure D, sulfoximine (S)-8a (105.0 mg, 0.40
mmol), CuI (7.6 mg, 0.04 mmol), DMEDA (7.0 mg, 0.08 mmol)
and K2CO3 (225.0 mg, 1.6 mmol) were reacted together in toluene
(2 mL). The residue was subjected to flash chromatography (EtOAc
then 10% MeOH–EtOAc) to give the title compound as a white sol-
id (65.0 mg, 89%, er = 77:23).
IR (KBr): 3289, 3008, 2914, 2848, 1650, 1548, 1466, 1375, 1313,
1188, 1100, 1011, 982, 936, 764, 722, 663 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.70 (br s, 1 H), 3.07–3.03 (m, 2
H), 2.95 (s, 3 H), 1.86–1.77 (m, 2 H), 1.45–1.38 (m, 2 H), 1.35–1.23
(m, 18 H), 0.85 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 57.4 (CH2), 43.1 (CH3), 32.1
(CH2), 29.81 (CH2), 29.79 (CH2), 29.76 (CH2), 29.7 (CH2), 29.51
(CH2), 29.46 (CH2), 29.3 (CH2), 28.6 (CH2), 23.3 (CH2), 22.9
(CH2), 14.3 (CH3).
MS (CI): m/z (%) = 262 (100) [M]+, 247 (8), 83 (7).
HRMS: m/z [M + H]+ calcd for C14H32NOS: 262.2199; found:
Mp 153–154 °C; [a]D +46.0 (c 0.4, CHCl3).
IR (KBr): 2971, 1596, 1567, 1480, 1452, 1265, 1189, 1048, 1018,
753 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.16 (td, J = 8.0, 1.0 Hz, 1 H),
7.02 (br d, J = 6.5 Hz, 1 H), 6.89 (dd, J = 8.0, 1.0 Hz, 1 H), 6.84 (td,
J = 6.5, 1.0 Hz, 1 H), 3.42–3.06 (m, 4 H), 3.21 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 144.2 (C), 128.7 (CH), 128.4
(CH), 122.9 (CH), 120.4 (CH), 44.5 (CH2), 42.5 (CH3), 24.0 (CH2).
262.2197.
(S)-N-(tert-Butyldiphenylsilyl) (2-Bromophenyl)ethyl Methyl
Sulfoximine [(S)-15a]
MS (EI): m/z (%) = 182 (11) [M + H]+, 181 (100) [M]+, 138 (24),
Using general procedure A, reaction of n-BuLi (1.2 mL, 1.43 M in
hexanes, 1.74 mmol), (S,S)-(1-phenylethyl)amine hydrochloride
(253 mg, 0.97 mmol), sulfoximine 4a (213.0 mg, 0.645 mmol), and
1-bromo-2-(bromomethyl)benzene (14a) (400.0 mg, 1.84 mmol)
gave the crude product. Purification by flash chromatography (10%
then 20% EtOAc–pentane) gave the title compound as a colorless
oil (223.0 mg, 70%, er = 77:23).
118 (35), 117 (40), 91 (25).
Anal. Calcd for C9H11NOS: C, 59.64; H, 6.12; N, 7.73. Found: C,
59.24; H, 6.30; N, 7.86.
HPLC: Daicel Chiralcel OD-H, heptane–i-PrOH, 75:25, 0.6
mL·min–1, 230 nm; tR1 = 23.4 min, tR2 = 37.7 min.
N-(tert-Butyldiphenylsilyl) 2-(2-Bromophenyl)propyl Methyl
Sulfoximines [(R*,R*)-15b] and [(R*,S*)-15b¢]21
[a]D –7.7 (c 1.7, CHCl3).
IR (CHCl3): 3067, 3014, 2931, 2890, 2855, 1472, 1427, 1299, 1158,
1107, 1025, 941, 822, 753, 704, 640, 600, 503 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.80–7.76 (m, 4 H), 7.53 (dd,
J = 8.0, 1.0 Hz, 1 H), 7.40–7.37 (m, 7 H), 7.25–7.21 (m, 1 H), 7.11
(t, J = 7.0 Hz, 1 H), 3.22–3.14 (m, 4 H), 2.73 (s, 3 H), 1.11 (s, 9 H,
t-Bu).
13C NMR (100 MHz, CDCl3): d = 137.4 (C), 136.4 (C), 136.2 (C),
135.5 (CH), 135.4 (CH), 132.9 (CH), 130.6 (CH), 129.0 (CH),
128.5 (CH), 127.8 (CH), 127.4 (CH), 124.2 (C), 58.1 (CH2), 44.6
(CH3), 30.7 (CH2), 27.2 (CH3), 19.3 (C).
Following general procedure B, sulfoximine 4a (86.1 mg, 0.26
mmol), n-BuLi (200 mL, 1.6 M in hexanes, 0.32 mmol) and 1-bro-
mo-2-(1-bromoethyl)benzene (14b) (84.0 mg, 0.32 mmol) were re-
acted together in THF. Purification by flash chromatography (10%
then 20% EtOAc–pentane) gave a 2:1 mixture of diastereoisomers
15b/15b¢ as colorless oils (52.0 mg, 39% major isomer 15b; 22.5
mg, 17% minor isomer 15b¢).
Major Isomer (R*,R*)-15b
IR (capillary): 3067, 2932, 2856, 1471, 1429, 1297, 1151, 1107,
704 cm–1.
MS (EI): m/z (%) = 444 (100) [M – t-Bu (81Br)]+, 442 (96) [M –
1H NMR (300 MHz, CDCl3): d = 7.69–7.61 (m, 4 H), 7.60 (dd,
J = 7.9, 1.5 Hz, 1 H), 7.31–7.25 (m, 6 H), 7.18 (td, J = 7.7, 1.5 Hz,
t-Bu (79Br)]+, 366 (18), 364 (15), 212 (8), 199 (23), 104 (9).
Synthesis 2011, No. 23, 3827–3838 © Thieme Stuttgart · New York

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S,S-Dialkyl-Substituted Sulfoximines and Related Heterocycles
3833
1 H), 7.10 (td, J = 7.9, 1.7 Hz, 1 H), 6.85 (ddd, J = 7.9, 7.2, 1.7 Hz,
1 H), 3.89–3.75 (m, 1 H), 3.25 (dd, J = 14.6, 5.2 Hz, 1 H), 2.92 (ddd,
J = 14.6, 7.9, 0.7 Hz, 1 H), 2.47 (s, 3 H), 1.32 (d, J = 6.9 Hz, 3 H),
0.98 (s, 9 H, t-Bu).
13C NMR (100 MHz, CDCl3): d = 143.4 (C), 136.5 (C), 136.4 (C),
135.7 (CH), 135.6 (CH), 133.4 (CH), 129.1 (CH), 128.4 (CH),
128.1 (CH), 127.9 (CH), 127.5 (CH), 123.8 (C), 65.3 (CH2), 45.2
(CH3), 35.1 (CH), 27.2 (CH3), 21.1 (CH3), 19.2 (C).
IR (KBr): 3323, 2987, 2916, 1472, 1422, 1202, 1159, 1034, 759
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.51 (d, J = 8.0 Hz, 1 H), 7.29–
7.19 (m, 2 H), 7.08–7.02 (m, 1 H), 3.92 (sext, J = 6.9 Hz, 1 H), 3.46
(dd, J = 13.7, 6.0 Hz, 1 H), 3.21 (dd, J = 13.7, 7.4 Hz, 1 H), 2.78 (s,
3 H), 2.40 (br s, 1 H), 1.43 (d, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 142.6 (C), 133.5 (CH), 128.6
(CH), 128.1 (CH), 127.9 (CH), 123.8 (C), 63.1 (CH2), 44.0 (CH3),
34.7 (CH), 21.2 (CH3).
MS (EI): m/z (%) = 458 (100) [M – t-Bu (81Br)]+, 456 (95) [M – t-
Bu (79Br)]+, 199 (26).
MS (EI): m/z (%) = 196 (100) [M – Br]+, 171 (44), 169 (45), 133
(26), 117 (45), 115 (37).
HRMS: m/z [M – t-Bu]+ calcd for C22H23NOSiSBr: 457.0531;
found: 457.0531.
HRMS: m/z [M – Br]+ calcd for C10H14NOS: 196.0796; found:
196.0797.
Minor Isomer (R*,S*)-15b¢
IR (CHCl3): 3064, 2932, 2856, 1471, 1297, 1149, 1107, 757, 703
(R*,R*)-(RS,R)-2l4–2,1-Benzothiazine-3,4-dihydro-2,4-dimeth-
yl-2-oxide [(R*,R*)-9b]21
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.74–7.62 (m, 4 H), 7.47 (dd,
J = 7.9, 1.2 Hz, 1 H), 7.32–7.21 (m, 6 H), 7.18 (dd, J = 7.4, 1.2 Hz,
1 H), 7.11 (dd, J = 7.7, 1.7 Hz, 1 H), 7.00 (ddd, J = 7.9, 7.2, 1.7 Hz,
1 H), 4.03–3.90 (m, 1 H), 3.31 (dd, J = 13.6, 5.2 Hz, 1 H), 2.99 (dd,
J = 13.6, 7.9 Hz, 1 H), 2.40 (s, 3 H), 1.33 (d, J = 6.9 Hz, 3 H), 1.02
(s, 9 H, t-Bu).
Following general procedure D, (R*,R*)-8b (65.0 mg, 0.236
mmol), CuI (4.5 mg, 0.024 mmol), DMEDA (4.2 mg, 0.048 mmol)
and K2CO3 (130.3 mg, 0.944 mmol) were reacted together in tolu-
ene (1 mL). The residue was subjected to flash chromatography
(50% EtOAc–pentane then EtOAc) to give the title compound as a
colorless oil (42.5 mg, 92%).
13C NMR (100 MHz, CDCl3): d = 143.5 (C), 136.5 (C), 136.3 (C),
135.8 (CH), 135.7 (CH), 133.4 (CH), 129.1 (CH), 129.0 (CH),
128.3 (CH), 128.0 (CH), 127.5 (CH), 123.8 (C), 64.2 (CH2), 45.9
(CH3), 34.5 (CH), 27.2 (CH3), 21.1 (CH3), 19.3 (C).
IR (CHCl3): 2971, 2926, 1598, 1476, 1447, 1268, 1208, 1038, 757
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.10 (ddd, J = 8.4, 7.7, 1.5 Hz, 1
H), 7.03 (d, J = 7.4 Hz, 1 H), 6.90–6.79 (m, 2 H), 3.38 (dd, J = 13.0,
4.9 Hz, 1 H), 3.33–3.19 (m, 1 H), 3.12 (s, 3 H), 3.07 (dd, J = 13.1,
8.2 Hz, 1 H), 1.44 (d, J = 7.2 Hz, 3 H).
MS (EI): m/z (%) = 458 (100) [M – t-Bu (81Br)]+, 456 (91) [M – t-Bu
(79Br)]+, 199 (29).
HRMS: m/z [M – t-Bu]+ calcd for C22H23NOSiSBr: 456.0453;
found: 456.0454.
13C NMR (75 MHz, CDCl3): d = 143.9 (C), 128.4 (CH), 126.9 (C),
126.4 (CH), 123.3 (CH), 121.0 (CH), 52.1 (CH2), 43.6 (CH2), 31.3
(CH), 19.5 (CH3).
(R*,R*)-2-(2-Bromophenyl)propyl Methyl Sulfoximine
[(R*,R*)-8b]
According to general procedure C, (R*,R*)-15b (155.0 mg, 0.30
mmol) and TBAF (0.9 mL, 1 M in THF, 0.90 mmol) were reacted
together to give the crude product. Purification by flash chromatog-
raphy (50% EtOAc–pentane to EtOAc, then acetone) gave the title
compound as a white solid (71.3 mg, 86%).
MS (EI): m/z (%) = 195 (100) [M]+, 180 (9), 132 (36), 130 (52), 117
(63).
HRMS: m/z [M]+ calcd for C10H13NOS: 195.0718; found: 195.0719.
(R*,S*)-2l4–2,1-Benzothiazine-3,4-dihydro-2,4-dimethyl-2-ox-
ide [(R*,S*)-9b¢]21
Following general procedure D, (R*,S*)-8b¢ (34.0 mg, 0.123
mmol), CuI (2.3 mg, 0.012 mmol), DMEDA (2.2 mg, 0.024 mmol)
and K2CO3 (68.0 mg, 0.493 mmol) were reacted together in toluene
(1 mL). The residue was subjected to flash chromatography (50%
EtOAc–pentane then EtOAc) to give the title compound as a white
solid (42.5 mg, 92%).
Mp 90–91 °C.
IR (KBr): 3282, 2984, 1474, 1415, 1208, 1030, 757 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.57 (dd, J = 7.9, 1.2 Hz, 1 H),
7.36–7.25 (m, 2 H), 7.11 (ddd, J = 8.9, 7.9, 2.2 Hz, 1 H), 3.95 (sext,
J = 6.9 Hz, 1 H), 3.55 (dd, J = 14.3, 6.4 Hz, 1 H), 3.25 (ddd,
J = 14.3, 7.2, 0.7 Hz, 1 H), 2.84 (s, 3 H), 2.65 (br s, 1 H), 1.47 (d,
J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 142.7 (C), 133.5 (CH), 128.6
(CH), 128.2 (CH), 127.9 (CH), 123.9 (C), 63.5 (CH2), 43.7 (CH3),
34.9 (CH), 21.2 (CH3).
Mp 123–125 °C.
IR (KBr): 2979, 2923, 1597, 1474, 1441, 1295, 1261, 1200, 1025,
753 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.14 (d, J = 7.9 Hz, 1 H), 7.08 (d,
J = 7.7 Hz, 1 H), 6.84 (d, J = 7.7 Hz, 2 H), 3.48–3.33 (m, 1 H), 3.30
(dd, J = 12.4, 4.2 Hz, 1 H), 3.11 (s, 3 H), 2.81 (t, J = 12.4 Hz, 1 H),
1.50 (d, J = 6.9 Hz, 3 H).
MS (EI): m/z (%) = 196 (100) [M – Br]+, 171 (52), 169 (51), 117
(45), 115 (38).
HRMS: m/z [M – Br]+ calcd for C10H14NOS: 196.0796; found:
196.0797.
13C NMR (75 MHz, CDCl3): d = 144.1 (C), 128.3 (CH), 126.3 (C),
125.3 (CH), 122.6 (CH), 120.6 (CH), 51.4 (CH2), 43.2 (CH2), 27.6
(CH), 18.4 (CH3).
(R*,S*)-2-(2-Bromophenyl)propyl Methyl Sulfoximine
[(R*,S*)-8b¢]
According to general procedure C, (R*,S*)-15b¢ (75.5 mg, 0.15
mmol) and TBAF (428 mL, 1 M in THF, 0.43 mmol) were reacted
together to give the crude product. Purification by flash chromatog-
raphy (gradient 50% EtOAc–pentane to EtOAc, then acetone) gave
the title compound as a white solid (37.0 mg, 91%).
MS (EI): m/z (%) = 195 (100) [M]+, 180 (6), 132 (28), 130 (71), 117
(55).
HRMS: m/z [M]+ calcd for C10H13NOS: 195.0718; found: 195.0721.
N-(tert-Butyldiphenylsilyl) 2-Bromo-5-methoxyphenyl)ethyl
Methyl Sulfoximine (15c)
Following general procedure B, sulfoximine 4a (324.4 mg, 0.98
mmol), n-BuLi (730 mL, 1.6 M in hexanes, 1.17 mmol) and 2-bro-
mo-1-(bromomethyl)-4-methoxybenzene (302.4 mg, 1.08 mmol)
Mp 75–76 °C.
Synthesis 2011, No. 23, 3827–3838 © Thieme Stuttgart · New York

3834
A. G. Pandey et al.
PAPER
N-(tert-Butyldiphenylsilyl) (2-Bromo-3-pyridyl)ethyl Methyl
were reacted together in THF. Purification by flash chromatography
(10% then 20% EtOAc–pentane) gave 15c as an oil (374.6 mg,
72%).
Sulfoximine (15d)
Following general procedure A, reaction of sulfoximine 4a (292.0
mg, 0.88 mmol), n-BuLi (1.6 mL, 1.5 M in hexanes, 2.40 mmol),
(S,S)-bis(a-methylbenzyl)amine hydrochloride (346.0 mg, 1.32
mmol) and 2-bromo(3-bromomethyl)pyridine (14d) (442.0 mg,
1.76 mmol) in THF (22 mL) gave the crude product. Purification by
flash chromatography (20% then 40% EtOAc–pentane) gave the ti-
tle compound as a colorless oil (272.0 mg, 61%).
IR (CHCl3): 3068, 2933, 2855, 1473, 1330, 1154, 1108, 1018, 703
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.86–7.78 (m, 4 H), 7.45–7.37 (m,
7 H), 6.71–6.65 (m, 2 H), 3.77 (s, 3 H, CH3), 3.32–3.10 (m, 4 H),
1.68 (s, 3 H, CH3), 1.14 (s, 9 H, t-Bu).
13C NMR (100 MHz, CDCl3): d = 159.3 (C), 138.5 (C), 136.5 (C),
136.3 (C), 135.7 (CH), 135.6 (CH), 133.6 (CH), 129.2 (CH), 127.6
(CH), 114.6 (C), 114.5 (CH), 58.1 (CH2), 55.5 (CH3), 44.6 (CH3),
30.9 (CH2), 27.2 (CH3), 19.3 (C).
IR (CHCl3): 3051, 3013, 2930, 2891, 2855, 1560, 1405, 1303, 1158,
1108, 1053, 745, 703 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.14 (dd, J = 4.0, 2.0 Hz, 1 H),
7.72–7.64 (m, 4 H), 7.35–7.22 (m, 7 H), 7.07 (dd, J = 6.0, 4.0 Hz, 1
H), 3.16–3.04 (m, 4 H), 2.67 (s, 3 H, CH3), 1.01 (s, 9 H, t-Bu).
13C NMR (100 MHz, CDCl3): d = 148.6 (CH), 144.0 (C), 138.9
(CH), 136.3 (C), 136.1 (C), 135.6 (CH), 135.5 (CH), 135.1 (C),
129.2 (CH), 127.6 (CH), 123.1 (CH), 57.4 (CH3), 44.9 (CH2), 29.7
(CH2), 27.2 (CH3), 19.4 (C).
MS (EI): m/z (%) = 474 (100) [M – t-Bu (81Br)]+, 472 (100) [M – t-Bu
(79Br)]+, 396 (12), 394 (11), 199 (36).
HRMS: m/z [M – t-Bu]+ calcd for C22H23BrNO2SSi: 474.0384;
found: 474.0374.
(2-Bromo-5-methoxyphenyl)ethyl Methyl Sulfoximine (8c)
According to general procedure C, sulfoximine 15c (175.0 mg, 0.33
mmol) and TBAF (1.0 mL, 1 M in THF, 1.00 mmol) were reacted
together to give the crude product. Purification by flash chromatog-
raphy (50% EtOAc–pentane to EtOAc, then acetone) gave the title
compound as a white solid (84.0 mg, 87%).
MS (EI): m/z (%) = 445 (100) [M – t-Bu (81Br)]+, 443 (95) [M – t-
Bu (79Br)]+, 263 (15), 261 (15), 199 (9), 197 (7), 128 (10), 104 (9).
HRMS: m/z [M – t-Bu]+ calcd for C20H20BrN2OSSi: 445.0230;
found: 445.0244.
(2-Bromo-3-pyridyl)ethyl Methyl Sulfoximine (8d)
Following general procedure C, reaction of sulfoximine 15d (270.0
mg, 0.54 mmol) and TBAF (1.6 mL, 1 M in THF, 1.60 mmol) gave
the crude product. Purification by flash chromatography (50%
EtOAc–pentane to EtOAc, then acetone) gave the title compound as
a colorless oil (111.0 mg, 79%).
IR (CHCl3): 3276, 2933, 1593, 1576, 1475, 1414, 1243, 1211, 1018,
755 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.38 (d, J = 8.8 Hz, 1 H), 6.82 (d,
J = 3.0 Hz, 1 H), 6.66 (dd, J = 8.8, 3.0 Hz, 1 H), 3.74 (s, 3 H), 3.36–
3.28 (m, 2 H), 3.21–3.12 (m, 2 H), 2.96 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 159.2 (C), 137.8 (C), 133.7 (CH),
116.4 (CH), 114.6 (CH), 114.4 (C), 56.5 (CH2), 55.6 (CH3), 43.0
(CH3), 30.9 (CH2).
MS (EI): m/z (%) = 214 (25), 212 (56) [M – Br]+, 149 (100), 134
(29), 132 (27).
HRMS: m/z [M – Br]+ calcd for C10H14NO2S: 212.0745; found:
212.0736.
IR (CHCl3): 3245, 3007, 2925, 1561, 1407, 1210, 1114, 1048, 804,
751, 664 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.25 (dd, J = 4.5, 2.0 Hz, 1 H),
7.60 (ddd, J = 7.5, 5.0, 2.0 Hz, 1 H), 7.17 (dd, J = 7.5, 5.0 Hz, 1 H),
4.1 (br s, 1 H), 3.40–3.25 (m, 2 H), 3.25–3.15 (m, 2 H), 2.92 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 148.9 (CH), 144.0 (C), 139.2
(CH), 134.6 (C), 123.3 (CH), 55.8 (CH2), 43.3 (CH3), 29.7 (CH2).
MS (EI): m/z (%) = 183 (100) [M – Br]+, 119 (20), 104 (82), 78 (20),
77 (36), 51 (25).
HRMS: m/z [M – Br]+ calcd for C8H11BrN2OS: 183.0598; found:
183.0595.
2l4-2,1-Benzothiazine-3,4-dihydro-2-methyl-6-methoxy-2-ox-
ide (9c)
Following general procedure D, 8c (72.0 mg, 0.246 mmol), CuI (4.7
mg, 0.025 mmol), DMEDA (4.3 mg, 0.049 mmol) and K2CO3
(135.8 mg, 0.984 mmol) were reacted together in toluene (1 mL).
The residue was subjected to flash chromatography (50% EtOAc–
pentane then EtOAc) to give the title compound as a white solid
(34.0 mg, 66%).
2l4-Pyrido[2,3-c][1,2]thiazine-3,4-dihydro-2-methyl-2-oxide
(9d)
Following general procedure D, sulfoximine 8d (72.5 mg, 0.276
mmol), CuI (5.2 mg, 0.027 mmol), DMEDA (4.8 mg, 0.054 mmol)
and K2CO3 (152.0 mg, 1.10 mmol) were reacted together in THF–
toluene (1:1, 4 mL) to give the crude product. Purification by flash
chromatography (50% EtOAc–pentane then EtOAc) gave the title
compound as a white solid (40.5 mg, 81%).
Mp 169–170 °C.
IR (KBr): 2923, 1609, 1489, 1422, 1266, 1232, 1187, 1020, 819
cm–1.
1H NMR (300 MHz, CDCl3): d = 6.84 (d, J = 8.7 Hz, 1 H), 6.75 (dd,
J = 8.7, 3.0 Hz, 1 H), 6.61 (d, J = 3.0 Hz, 1 H), 3.76 (s, 3 H), 3.44–
3.29 (m, 2 H), 3.23–3.08 (m, 2 H), 3.20 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 153.7 (C), 137.5 (C), 123.5 (CH),
121.4 (C), 114.2 (CH), 113.8 (CH), 55.6 (CH3), 44.6 (CH2), 42.4
(CH3), 24.3 (CH2).
Mp 174–175 °C.
IR (KBr): 2986, 2909, 1586, 1561, 1434, 1291, 1200, 1028, 788
cm–1.
1H NMR (400 MHz, CDCl3): d = 8.20 (d, J = 4.0 Hz, 1 H), 7.31 (d,
J = 7.0 Hz, 1 H), 6.77 (dd, J = 7.0, 4.0 Hz, 1 H), 3.45–3.00 (m, 4 H),
3.27 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): d = 155.5 (C), 148.2 (CH), 136.8
(CH), 116.2 (CH), 115.3 (C), 43.7 (CH2), 42.7 (CH3), 23.1 (CH2).
MS (EI): m/z (%) = 211 (100) [M]+, 196 (37), 168 (29), 132 (26).
HRMS: m/z [M]+ calcd for C10H13NO2S: 211.0667; found:
211.0670.
MS (EI): m/z (%) = 182 (100) [M]+, 167 (9), 120 (9), 119 (65), 92
(21).
Anal. Calcd for C10H13NO2S·1/5H2O: C, 55.89; H, 6.29; N, 6.52.
Found: C, 55.95; H, 6.21; N, 6.54.
HRMS: m/z [M]+ calcd for C8H10N2OS: 182.0514; found: 182.0512.
Synthesis 2011, No. 23, 3827–3838 © Thieme Stuttgart · New York

PAPER
S,S-Dialkyl-Substituted Sulfoximines and Related Heterocycles
3835
N-(tert-Butyldiphenylsilyl) Methyl Phenyl Sulfoximine (16)17
TBDPSCl (425 mL, 2.43 mmol) was added dropwise to a soln of
methyl phenyl sulfoximine (300.0 mg, 1.94 mmol) and imidazole
(263.8 mg, 3.88 mmol) in DMF (4 mL) at 0 °C under Ar. The result-
ing soln was heated at 60 °C for 48 h, poured into H2O (6 mL) and
extracted with CH2Cl2 (3 × 10 mL). The combined CH2Cl2 layers
were dried over MgSO4 and concentrated to afford the crude prod-
uct. Purification by flash chromatography (4% then 10% EtOAc–
pentane) gave 16 as an oil (700.0 mg, 92%).
HRMS: m/z [M]+ calcd for C14H15NO79BrS: 324.0058; found:
324.0052.
2l4-2,1-Benzothiazine-3,4-dihydro-2-phenyl-2-oxide (9f)
Following general procedure D, sulfoximine 17 (46.9 mg, 0.145
mmol), CuI (2.8 mg, 0.015), DMEDA (2.6 mg, 0.029 mmol) and
K2CO3 (60.0 mg, 0.43 mmol) were reacted together in toluene (1
mL) to afford the crude product. Purification by flash chromatogra-
phy (30% EtOAc–pentane then EtOAc) gave the title compound as
a pale-yellow solid (34.0 mg, 97%).
IR (capillary): 3062, 2936, 2858, 1428, 1331, 1164, 1105, 703 cm–1.
Following general procedure E, sulfoximine 17 (64.0 mg, 0.198
mmol), Pd(OAc)2 (4.4 mg, 0.0198 mmol), BINAP (18.4 mg, 0.0295
mmol) and K2CO3 (137.0 mg, 0.99 mmol) were dissolved in toluene
(2 mL) and the resulting soln was degassed. The reaction mixture
was heated in a sealed tube at 160 °C for 1 h and then cooled to r.t.
Purification by flash chromatography (30% EtOAc–pentane) gave
the title compound as a pale-yellow solid (48.0 mg, 98%).
1H NMR (300 MHz, CDCl3): d = 7.96 (d, J = 8.2 Hz, 2 H), 7.57 (d,
J = 8.2 Hz, 2 H), 7.47 (d, J = 8.2 Hz, 2 H), 7.58–7.28 (m, 9 H), 2.88
(s, 3 H), 1.12 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 144.5 (C), 136.6 (C), 136.4 (C),
135.7 (CH), 135.6 (CH), 132.2 (CH), 129.1 (CH), 129.0 (CH),
128.9 (CH), 127.4 (CH), 127.3 (CH), 127.0 (CH), 49.0 (CH2), 27.2
(CH3), 19.4 (C).
Mp >100 °C (dec.).
MS (EI): m/z (%) = 336 (100) [M – t-Bu]+.
IR (KBr): 1594, 1565, 1475, 1447, 1263, 1195, 1110, 1002, 750
cm–1.
1H NMR (400 MHz, CDCl3): d = 8.06 (dt, J = 5.0, 1.5 Hz, 2 H),
7.69 (tt, J = 8.0, 2.0 Hz, 1 H), 7.64–7.56 (m, 2 H), 7.21 (td, J = 7.5,
1.5 Hz, 1 H), 7.15–7.08 (m, 2 H), 6.89 (td, J = 7.0, 1.0 Hz, 1 H),
3.48–3.03 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 144.9 (C), 138.4 (C), 133.9 (CH),
129.4 (CH), 129.0 (CH), 128.6 (CH), 128.4 (CH), 123.5 (CH),
120.9 (C), 120.5 (CH), 47.3 (CH2), 24.8 (CH2).
(2-Bromophenyl)ethyl Phenyl Sulfoximine (17)
Step 1: N-(tert-Butyldiphenylsilyl) (2-Bromophenyl)ethyl Phe-
nyl Sulfoximine
According to general procedure B, sulfoximine 16 (400.0 mg, 1.02
mmol), n-BuLi, (762 mL, 1.6 M in hexanes, 1.22 mmol) and 1-bro-
mo-2-(bromomethyl)benzene (14a) (305.0 mg, 1.22 mmol) were
reacted together. Purification by flash chromatography (10% then
20% EtOAc–pentane) gave the corresponding N-TBDPS protected
sulfoximine as a colorless oil (400.0 mg, 70%).
MS (EI): m/z (%) = 244 (36) [M + H]+, 243 (100) [M]+.
HRMS: m/z [M]+ calcd for C14H13NOS: 243.0718; found: 243.0721.
IR (capillary): 3062, 2934, 1440, 1382, 1155, 1104, 703 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.83 (d, J = 7.4 Hz, 2 H), 7.71 (dd,
J = 7.2, 1.7 Hz, 2 H), 7.66 (dd, J = 7.7, 1.7 Hz, 2 H), 7.46–7.18 (m,
10 H), 7.04 (td, J = 7.4, 1.4 Hz, 1 H), 6.92 (td, J = 7.7, 1.7 Hz, 1 H),
6.81 (dd, J = 7.7, 1.7 Hz, 1 H), 3.20 (ddd, J = 13.5, 9.9, 7.2 Hz, 1
H), 3.08 (ddd, J = 13.5, 10.4, 6.4 Hz, 1 H), 2.95–2.79 (m, 2 H), 1.04
(s, 9 H).
N-Cyano tert-Butyl Methyl Sulfoximine (7d)
The title product was prepared according to literature procedures.14
Mp 56–58 °C.
IR (KBr): 2996, 2924, 2192, 1471, 1236, 1162, 969, 836 cm–1.
13C NMR (75 MHz, CDCl3): d = 142.3 (C), 137.6 (C), 136.4 (C),
136.3 (C), 135.7 (CH), 135.6 (CH), 132.9 (CH), 132.3 (CH), 130.5
(CH), 129.0 (CH), 128.9 (CH), 128.8 (CH), 128.4 (CH), 127.9
(CH), 127.7 (CH), 127.4 (CH), 127.3 (CH), 124.2 (C), 59.4 (CH2),
30.6 (CH2), 27.2 (CH3), 19.5 (C).
1H NMR (400 MHz, CDCl3): d = 3.15 (s, 3 H), 1.56 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 111.6 (CN), 63.3 (C), 34.4 (CH3),
23.4 (CH3).
MS (EI): m/z (%) = 161 (25) [M + H]+, 145 (11) [M – Me]+, 105
(34), 57 (100).
MS (EI): m/z (%) = 506 (93) [M – t-Bu (81Br)]+, 504 (100) [M – t-Bu
(79Br)]+, 426 (15), 199 (29).
Anal. Calcd for C6H12N2OS: C, 44.97; H, 7.55; N, 17.48. Found: C,
45.03; H, 7.48; N, 17.47.
HRMS: m/z [M – t-Bu (81Br)]+ calcd for C26H23NO79BrSSi:
504.0453; found: 504.0453.
tert-Butyl (2-Bromophenyl)ethyl Sulfoximine (8e)
Step 1: N-Cyano tert-Butyl (2-Bromophenyl)ethyl Sulfoximine
(18)
Following general procedure B, sulfoximine 7d (248.0 mg, 1.55
mmol), n-BuLi (1.1 mL, 1.6 M in hexanes, 1.70 mmol) and 1-bro-
mo-2-(bromomethyl)benzene (14a) (775.0 mg, 3.10 mmol) were
reacted together in THF. Purification by flash chromatography
(20% EtOAc–pentane) gave the desired N-cyano sulfoximine as an
oil (383.0 mg, 75%).
Step 2: Desilylation
Following general procedure C, reaction of the N-TBDPS protected
sulfoximine (175.0 mg, 0.31 mmol), prepared via step 1, and TBAF
(930 mL, 1 M in THF, 0.93 mmol) gave the crude product. Purifica-
tion by flash chromatography (50% EtOAc–pentane to EtOAc, then
acetone) gave compound 17 as a colorless oil (88.7 mg, 88%).
IR (capillary): 3269, 3062, 1444, 1221, 1112, 988, 755 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.96 (dd, J = 8.0, 1.5 Hz, 2 H),
7.59–7.53 (m, 1 H), 7.49 (t, J = 8.0 Hz, 2 H), 7.39 (d, J = 7.5 Hz, 1
H), 7.17–7.10 (m, 2 H), 7.00 (ddd, J = 7.0, 6.5, 3.0 Hz, 1 H), 3.34
(dd, J = 9.1, 7.7 Hz, 2 H), 3.12–2.97 (m, 2 H), 2.71 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 141.5 (C), 137.0 (C), 133.1 (CH),
133.0 (CH), 130.7 (CH), 129.2 (CH), 128.7 (CH), 128.5 (CH),
127.8 (CH), 124.2 (CH), 56.7 (CH2), 30.4 (CH2).
IR (CHCl3): 2990, 2196, 1465, 1370, 1263, 1204, 1156, 1023, 845,
811, 767, 659 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.56 (dd, J = 7.5, 1.5 Hz, 1 H),
7.37 (dd, J = 7.5, 2.0 Hz, 1 H), 7.31 (td, J = 7.5, 1.5 Hz, 1 H), 7.17
(td, J = 7.5, 2.0 Hz, 1 H), 3.52–3.37 (m, 4 H), 1.58 (s, 9 H, t-Bu).
13C NMR (100 MHz, CDCl3): d = 135.9 (C), 133.1 (CH), 131.1
(CH), 129.3 (CH), 128.1 (CH), 124.0 (C), 113.0 (CN), 65.3 (C),
46.8 (CH2), 28.3 (CH2), 23.5 (CH3).
MS (EI): m/z (%) = 326 [17, M (81Br)]+, 324 [15, M (79Br)]+, 244
[100, M – Br]+.
MS (EI): m/z (%) = 331 (1) [M + H (81Br)]+, 329 (1) [M + H (79Br)]+,
193 (23), 185 (43), 183 (43), 104 (28), 103 (15), 77 (17), 57 (100).
Synthesis 2011, No. 23, 3827–3838 © Thieme Stuttgart · New York

3836
A. G. Pandey et al.
PAPER
Anal. Calcd for C13H17N2OSBr: C, 47.42; H, 5.20; N, 8.51. Found:
C, 47.24; H, 5.40; N, 8.37.
Step 2: (S)-N-(tert-butyldimethylsilyl) tert-Butyl Methyl Sulfox-
imine (7f)
To a soln of the NH-sulfoximine (150.0 mg, 1.10 mmol), prepared
via step 1, and 2,6-lutidine (140.0 mL, 1.20 mmol) in CH2Cl2 (10
mL) at 0 °C was added dropwise TBDMSOTf (380 mL, 1.65 mmol).
The resulting soln was stirred at 0 °C for 1 h and then concentrated
under vacuum to afford the crude product. Purification by flash
chromatography (4% then 10% EtOAc–pentane) gave the N-
TBDMS protected sulfoximine as a colorless oil (206.0 mg, 75%).
Step 2: Cyano Group Cleavage
TFAA (376 mL, 2.66 mmol) was added to a soln of N-cyano sulfox-
imine 18 (309.0 mg, 0.94 mmol), prepared via step 1, at 0 °C and
the resulting soln was stirred until TLC indicated complete con-
sumption of the starting material. The soln was concentrated and
then K2CO3 (684.0 mg, 4.96 mmol) and MeOH (10 mL) were added
and the soln stirred overnight at r.t. Purification by flash chromatog-
raphy gave 8e as a colorless oil (286.0 mg, 99%).
[a]D –10.0 (c 1.0, CHCl3).
IR (capillary): 2950, 1296, 1136, 831 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.66 (s, 3 H), 1.28 (s, 9 H), 0.81
(S)-N-(p-Nitrobenzenesulfonyl) tert-Butyl Methyl Sulfoximine
[(S)-7e]; Asymmetric Synthesis
(s, 9 H), 0.00 (s, 6 H).
Step 1: (S)-tert-Butyl Methyl Sulfoxide22c
13C NMR (75 MHz, CDCl3): d = 59.9 (C), 38.7 (CH3), 26.0 (CH3),
23.7 (CH3), 18.0 (C), –2.3 (CH3), –2.4 (CH3).
MS (EI): m/z (%) = 192 (34) [M – t-Bu]+, 136 (100), 85 (31), 83
(41), 57 (46).
HRMS: m/z [M – t-Bu]+ calcd for C7H18NOSSi: 192.0878; found:
192.0871.
To a soln of (R)-tert-butyl tert-butanethiosulfinate [(R)-19] (1.5 g,
7.73 mmol, er = 91:9), obtained at r.t. by the asymmetric vanadium
oxidation procedure reported by Ellman,22 in THF at –78 °C was
added slowly a 1 M soln of MeMgBr in Et2O (23.2 mL, 23.2 mmol).
The temperature was allowed to reach –20 °C, and the mixture was
stirred at this temperature until the starting material was consumed.
The reaction was quenched with an aq sat. soln of NH4Cl (20 mL)
and the mixture extracted with EtOAc (3 × 15 mL). The combined
organic layers were dried over MgSO4 and concentrated under vac-
uum. The product was purified by flash chromatography (50%
EtOAc–pentane then EtOAc) to afford (S)-(+)-tert-butyl methyl
sulfoxide (649.3 mg, 70%).
Step 3: (S)-N-(tert-butyldimethylsilyl) tert-Butyl (2-Bromophe-
nyl)ethyl Sulfoximine
According to general procedure B, to the N-TBDMS protected sul-
foximine (176.0 mg, 0.71 mmol), prepared via step 2, n-BuLi, (530
mL, 1.6 M in hexanes, 0.85 mmol) and 1-bromo-2-(bromometh-
yl)benzene (14a) (212.0 mg, 0.85 mmol) were reacted together at
–78 °C. Purification by flash chromatography (4% then 20%
EtOAc–pentane) gave the corresponding N-TBDMS protected sulf-
oximine as a colorless oil (259.3 mg, 88%).
[a]D +6.4 (c 0.88, CHCl3).
1H NMR (400 MHz, CDCl3): d = 2.21 (s, 3 H), 1.87 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 52.3 (C), 31.4 (CH3), 22.2 (CH3).
[a]D –33.4 (c 0.32, CHCl3).
IR (capillary): 2953, 2854, 1470, 1295, 1129, 832, 770 cm–1.
Step 2: Imination14
(S)-tert-Butyl methyl sulfoxide (600.0 mg, 5.0 mmol), prepared via
step 1, was reacted with PhI=NNs15 (2.6 g, 6.4 mmol) in the pres-
ence of Fe(acac)3 (176.5 mg, 0.5 mmol) in MeCN (45 mL) at r.t.
The reaction mixture was concentrated and subjected to column
chromatography (CH2Cl2) to give sulfoximine (S)-7e as a white sol-
id (1.28 g, 80%).
1H NMR (300 MHz, CDCl3): d = 7.42 (d, J = 7.9 Hz, 1 H), 7.17–
7.12 (m, 2 H), 6.98 (ddd, J = 7.9, 5.7, 3.2 Hz, 1 H), 3.20–2.90 (m, 4
H), 1.25 (s, 9 H), 0.81 (s, 9 H), 0.04 (s, 3 H), 0.00 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 138.9 (C), 133.1 (CH), 130.7
(CH), 128.4 (CH), 127.9 (CH), 124.5 (C), 61.0 (C), 49.2 (CH2), 28.7
(CH2), 26.2 (CH3), 24.0 (CH3), 18.3 (C), –1.7 (CH3), –1.9 (CH3).
MS (EI): m/z (%) = 362 (44) [M + H – t-Bu (81Br)]+, 360 (41) [M +
H – t-Bu (79Br)]+, 306 (100) [M + H – 2t-Bu (81Br)]+, 304 (93) [M +
H – 2t-Bu (79Br)]+, 225 (17).
Mp 155–156 °C (dec.); [a]D –103.0 (c 0.66, acetone).
1H NMR (400 MHz, CDCl3): d = 8.25 (d, J = 9.1 Hz, 2 H), 8.08 (d,
J = 9.1 Hz, 2 H), 3.33 (s, 3 H), 1.40 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 149.6 (C), 149.4 (C), 127.8 (CH),
123.9 (CH), 62.5 (C), 35.5 (CH3), 22.8 (CH3).
HRMS: m/z [M – t-Bu]+ calcd for C14H24BrNOSSi: 360.0453;
found: 360.0457.
(S)-tert-Butyl (2-Bromophenyl)ethyl Sulfoximine [(S)-8e]
Step 1: (S)-tert-Butyl Methyl Sulfoximine14
Step 4: Desilylation
A mixture of (S)-7e (640.0 mg, 2.0 mmol), Cs2CO3 (1.17 g, 3.6
mmol) and PhSH (328 mL, 3.2 mmol) in MeCN (20 mL) was stirred
at 50 °C overnight. H2O (15 mL) was added to the reaction mixture
and the product was extracted with CH2Cl2 (3 × 15 mL). The com-
bined organic layers were dried over MgSO4 and concentrated. Pu-
rification by flash column chromatography (EtOAc then acetone)
gave the corresponding NH-sulfoximine as a white solid (270.0 mg,
>99%).
Following general procedure C, reaction of the sulfoximine (205.0
mg, 0.49 mmol), prepared via step 3, and TBAF (1.5 mL, 1 M in
THF, 1.50 mmol) gave the crude product. Purification by flash
chromatography (50% EtOAc–pentane to EtOAc, then acetone)
gave compound (S)-8e as a colorless oil (100.0 mg, 67%).
[a]D –12.0 (c 0.25, CHCl3).
IR (CHCl3): 3332, 3279, 2971, 2874, 1683, 1366, 1203, 1092, 1023,
989, 957, 756, 662, 637 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.54 (dd, J = 8.0, 1.0 Hz, 1 H),
7.34 (dd, J = 7.5, 2.0 Hz, 1 H), 7.27 (td, J = 7.5, 1.5 Hz, 1 H), 7.13
(td, J = 8.0, 2.0 Hz, 1 H), 3.37–3.21 (m, 4 H), 2.27 (br s, 1 H, NH),
1.46 (s, 9 H, t-Bu).
13C NMR (100 MHz, CDCl3): d = 137.9 (C), 133.0 (CH), 130.9
(CH), 128.6 (CH), 127.9 (CH), 124.3 (C), 60.8 (C), 46.8 (CH2), 28.5
(CH2), 23.9 (CH3).
Mp 100–103 °C; [a]D +6.0 (c 0.5, acetone).
IR (KBr): 3446, 3298, 2984, 1467, 1197, 1086, 1002, 935, 748
cm–1.
1H NMR (400 MHz, acetone-d6): d = 2.78 (s, 3 H), 1.36 (s, 9 H).
13C NMR (100 MHz, acetone-d6): d = 58.9 (C), 36.0 (CH3), 23.2
(CH3).
MS (EI): m/z (%) = 120 (13) [M – 15]+, 85 (55), 83 (85), 57 (100).
Synthesis 2011, No. 23, 3827–3838 © Thieme Stuttgart · New York

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S,S-Dialkyl-Substituted Sulfoximines and Related Heterocycles
3837
MS (EI): m/z (%) = 249 (1) [M – t-Bu + H (81Br)]+, 247 (1) [M – t-Bu
+ H (79Br)]+, 185 (17), 182 (23), 168 (44), 104 (25), 77 (20), 57
(100).
HRMS: m/z [M – Br]+ calcd for C12H18NOS: 224.1109; found:
224.1110.
1952, 169, 415. (b) Meister, A. Science 1983, 220, 472.
From these and subsequent studies it is known that for this
particular dialkyl sulfoximine the (S,S)-diastereoisomer is
the most active.
(6) For a recent example, where a mixture of stereoisomers of
buthionine sulfoximine (BSO) was used to study induced
apoptotic cell death, see: Takahashi, K.; Tatsunami, R.; Oba,
T.; Tampo, Y. Biol. Pharm. Bull. 2010, 33, 556.
(7) McDonald, I. A.; Nyce, P. L.; Ku, G. S.; Bowlin, T. L.
Bioorg. Med. Chem. Lett. 1993, 3, 1717.
(8) Jackson, T. E. (Sandoz-Wander, Inc., USA) US Patent
4031227, 1977; Chem. Abstr. 1977, 87, 102318.
(9) McGrath, M. J.; Bolm, C. Beilstein J. Org. Chem. 2007, 3,
33.
(10) (a) Kagan, H. B.; Dunach, E.; Nemecek, C.; Pitchen, P.;
Samuel, O.; Zhao, S.-H. Pure Appl. Chem. 1985, 1911.
(b) Capozzi, M. A. M.; Cardellicchio, C.; Naso, F.;
Tortorella, P. J. Org. Chem. 2000, 65, 2843. (c) For a
review, see: Capozzi, M. A. M.; Cardellicchio, C.; Naso, F.
Eur. J. Org. Chem. 2004, 1855.
(11) For syntheses of structurally related 2,1-benzothiazine and
1,2-benzoisothiazole derivatives by alternative pathways,
see: (a) Harmata, M.; Kahraman, M. J. Org. Chem. 1998, 63,
6845. (b) Harmata, M.; Pavri, N. Angew. Chem. Int. Ed.
1999, 38, 2419. (c) Hong, X.; Harmata, M. J. Am. Chem.
Soc. 2003, 125, 5754. (d) Harmata, M.; Rayanil, K.-o.;
Gomes, M. G.; Zheng, P.; Calkins, N. L.; Kim, S.-Y.; Fan,
Y.; Bumbu, V.; Lee, D. R.; Wacharasindhu, S.; Hong, X.
Org. Lett. 2005, 7, 143. (e) Harmata, M.; Calkins, N. L.;
Baughman, R. G.; Barnes, C. L. J. Org. Chem. 2006, 71,
3650. (f) Harmata, M.; Chen, Y.; Barnes, C. L. Org. Lett.
2007, 9, 4701. (g) Harmata, M.; Ying, W.; Hong, X.;
Barnes, C. L. Synthesis 2008, 594. (h) Harmata, M.;
Rayanil, K.-o.; Espejo, V. R.; Barnes, C. L. J. Org. Chem.
2009, 74, 3214. (i) Harmata, M.; Cai, Z.; Chen, Y. J. Org.
Chem. 2009, 74, 5559. (j) For a review, see: Harmata, M.;
Hong, X. Prog. Heterocycl. Chem. 2008, 19, 1.
(S)-2l4-2,1-Benzothiazine-3,4-dihydro-2-tert-butyl-2-oxide
[(S)-9e]
Following general procedure D, sulfoximine (S)-8e (50.0 mg, 0.16
mmol), CuI (3.1 mg, 0.016 mmol), DMEDA (2.9 mg, 0.032 mmol),
K2CO3 (68 mg, 0.49 mmol) and toluene (1.0 mL) were reacted to-
gether at 140 °C for 20 h to afford the crude product. Purification by
flash chromatography (50% EtOAc–pentane) afforded the title
compound as a colorless oil (25.7 mg, 72%).
[a]D +94.5 (c 0.33, CHCl3).
IR (CHCl3): 2984, 2936, 1599, 1568, 1479, 1454, 1270, 1207, 1161,
1105, 1044, 1013, 816, 755, 490, 459 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.13 (t, J = 7.6 Hz, 1 H), 7.00 (d,
J = 7.5 Hz, 1 H), 6.93 (dd, J = 8.0, 1.0 Hz, 1 H), 6.79 (td, J = 7.5,
1.5 Hz, 1 H), 3.45–3.33 (m, 1 H), 3.19–3.12 (m, 2 H), 3.01–2.91 (m,
1 H), 1.51 (s, 9 H, t-Bu).
13C NMR (100 MHz, CDCl3): d = 145.4 (C), 128.3 (CH), 128.1
(CH), 122.8 (CH), 121.1 (C), 119.5 (CH), 59.8 (C), 37.0 (CH2), 23.5
(CH2), 23.5 (CH3).
MS (EI): m/z (%) = 224 (11) [M + H]+, 223 (63) [M]+, 168 (12), 167
(63), 150 (39), 119 (100), 118 (67), 117 (29), 91 (29), 57 (49).
HRMS: m/z [M]+ calcd for C12H17NOS: 223.1031; found: 223.1036.
HPLC: Chiralcel OJ, heptane–i-PrOH, 75:25, 0.6 mL·min–1, 230
nm, tR1 = 14.4 min, tR2 = 19.2 min.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
(12) For the synthesis of isomeric dihydro benzothiazines by
intramolecular a-arylation of sulfoximines, see: Bolm, C.;
Okamura, H.; Verrucci, M. J. Organomet. Chem. 2003, 687,
444.
(13) For the possible precision of such data, see: Wernerova, M.;
Hudlicky, T. Synlett 2010, 2701.
(14) (a) García Mancheño, O.; Dallimore, J.; Plant, A.; Bolm, C.
Org. Lett. 2009, 11, 2429. (b) See also reference 2.
(15) Taylor, S.; Gullick, J.; McMorn, P.; Bethell, D.; Page, P. C.
B.; Hancock, E. F.; King, F.; Hutchings, G. J. Top. Catal.
2003, 24, 43.
(16) (a) For pioneering work on the use of the nosyl group, see:
Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
1995, 36, 6373. (b) Here the N-nosyl deprotection was
performed following procedures reported in: Greene, T. W.;
Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd
ed.; John Wiley & Sons: New York, 1999, 603.
(17) Johnson, C. R.; Kirchoff, R. A.; Reischer, R. J.; Katekar, G.
F. J. Am. Chem. Soc. 1973, 95, 4287.
(18) (a) N-Cyano sulfoximine 7d was prepared following
reported procedures, see: García Mancheño, O.; Bistri, O.;
Bolm, C. Org. Lett. 2007, 9, 3809. (b) See also in: Pandey,
A.; Bolm, C. Synthesis 2010, 2922.
(19) (a) Bolm, C.; Hildebrand, J. P. Tetrahedron Lett. 1998, 39,
5731. (b) Bolm, C.; Hildebrand, J. P. J. Org. Chem. 2000,
65, 169. (c) Bolm, C.; Hildebrand, J. P.; Rudolph, J.
Synthesis 2000, 911. (d) Bolm, C.; Martin, M.; Gibson, L.
Synlett 2002, 832. See also: (e) Harmata, M.; Hong, X.;
Ghosh, S. K. Tetrahedron Lett. 2004, 45, 5233.
Acknowledgment
M.J.M. is grateful to the Alexander von Humboldt foundation for a
fellowship. O.G.M. thanks Syngenta for Postdoctoral funding. The
authors also acknowledge the Fonds der Chemischen Industrie for
financial support.
References
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Synthesis 2011, No. 23, 3827–3838 © Thieme Stuttgart · New York

3838
A. G. Pandey et al.
PAPER
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(23) The enantiomeric ratio of 19 was determined by HPLC:
Daicel Chiralpack AS, heptane–i-PrOH, 97:3, 0.9 mL·min–1,
254 nm, tR1 = 6.3 min, tR2 = 7.7 min.
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proceeded with inversion of configuration and that the
imination occurred under retention. For respective details,
see references 22 and 24.
Synthesis 2011, No. 23, 3827–3838 © Thieme Stuttgart · New York