Ortho-Lithiation of S-tert-butyl-S-phenylsulfoximines. New route to enantiopure sulfinamides via a de-tert-butylation reaction

Article abstract of DOI:10.1016/j.tet.2005.06.047

The sulfoximine group proved to be an excellent ortho-directing group in lithiation reactions. Several electrophiles were used to afford the corresponding ortho-functionalized aryl sulfoximines in good yields. The use of prochiral electrophiles lead to mo

Full text of DOI:10.1016/j.tet.2005.06.047

Tetrahedron 61 (2005) 8138–8147
ortho-Lithiation of S-tert-butyl-S-phenylsulfoximines. New route
to enantiopure sulfinamides via a de-tert-butylation reaction
* *
´
Stephane Gaillard, Cyril Papamicael, Georges Dupas, Francis Marsais and Vincent Levacher
¨
´ ´ ´
Laboratoire de Chimie Organique Fine et Heterocyclique UMR 6014 IRCOF, CNRS, Universite et INSA de Rouen, BP 08, 76131
´
Mont-Saint-Aignan Cedex, France
Received 29 March 2005; revised 15 June 2005; accepted 16 June 2005
Available online 5 July 2005
Abstract—The sulfoximine group proved to be an excellent ortho-directing group in lithiation reactions. Several electrophiles were used to
afford the corresponding ortho-functionalized aryl sulfoximines in good yields. The use of prochiral electrophiles lead to modest to good
diastereoselectivities up to 95%. During this study, we observed a side reaction due to a S-de-tert-butylation. After optimization of this S-de-
tert-butylation reaction, the corresponding enantiopure sulfinamides could be obtained in good yields.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
our previous paper.2 The starting material for the synthesis
was rac-1a, which was converted quantitatively into 1b
(Scheme 1). Repeated lateral lithiation of 1b followed by
quenching with CH3I afforded 1c in 86% yield. We also
turned our interest in the stereoselective preparation of
sulfoximine (S)-1c by using the same procedure. For that
purpose, (S)-S-phenyl-S-methylsulfoximine ((S)-1a) was
prepared in 80% optical purity by resolution of the racemic
(G)-1a according to a published procedure.4 In order to
study the influence of the N-substituent sulfoximine on the
ortho-lithiation properties, we first prepared a series of
N-functionalized sulfoximines 1d–i (Table 1). N-silylation
could be achieved by reacting 1c2 with HMDS leading to
compound 1d in a quantitative yield (Table 1, entry 1). First
attempts to alkylate sulfoximine 1c in the presence of
The directed ortho-lithiation reaction is a very powerful
method for the functionalization of aromatic compounds
and synthesis of polysubstituted homoaromatic and hetero-
aromatic compounds.1 In a previous paper,2 we reported our
first results concerning the sulfoximine3a group as an ortho-
directing group3b for the lithiation reaction of homoaro-
matic systems. The reaction with n-butyllithium in THF at
K78 8C afforded the corresponding ortho-lithiated species,
which could be trapped with different electrophiles in good
yields. Addition of benzaldehyde proceeded with modest
diastereoselectivity (deZ52%). The aim of this paper is to
provide full details concerning the scope and limitations of
this new ortho-directing group and to improve the
stereoselectivity in the case of prochiral electrophiles.
During the course of this study, we observed a troubleshoot-
ing de-tert-butylation side-reaction leading to sulfinamides
or in some cases to cyclic sulfinic esters. We found it
interesting to define optimal conditions leading to enantio-
pure ortho-substituted sulfinamides.
2. Results and discussion
2.1. Synthesis of N-substituted sulfoximines 1a–i
Racemic sulfoximine 1c has been prepared as described in
Keywords: Sulfoximine; Lithiation; Sulfinamide; Asymmetric synthesis.
*
Corresponding authors. Tel.: C33 235 522 484; fax: C33 235 522 962;
e-mail addresses: cyril.papamicael@insa-rouen.fr;
georges.dupas@insa-rouen.fr
Scheme 1. (a) HMDS (5 equiv), 85 8C, 40 min (100%); (b) n-BuLi, THF,
0 8C then CH3I, 30 min, 20 8C repeated twice (86%); (c) (1S)-(C)-
camphorsulfonic acid, acetone.4
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.047

S. Gaillard et al. / Tetrahedron 61 (2005) 8138–8147
Table 1. N-functionalization of sulfoximine 1c and (S)-1c
8139
Entry
Conditions
Product
R1
Yield%
1
2
3
4
HMDS (5 equiv), 85 8C, 40 min (100%)
1d
1e
(S)-1e
1f
Si(CH3)3
CH3
CH3
100
86
86
92
KH (1 equiv), DME, 20 8C, 1 h then CH3I, PTC, 20 8C, 12 h
KH (1 equiv), DME, 20 8C, 1 h then CH3I, PTC, 20 8C, 12 h
KH (1 equiv), DME, 20 8C, 1 h then Br-(CH2)2OCH3, PTC,
20 8C, 12 h
(CH2)2OCH3
5
KH (1 equiv), DME, 20 8C, 1 h then Br–CH2–CH]CH2, PTC,
20 8C, 12 h
KH (1 equiv), DME, 20 8C, 1 h then Boc2O, PTC, 20 8C, 12 h
(CH3)3COCl, Na2CO3, CH2Cl2, 20 8C, 2 h
1g
CH2–CH]CH2
95
6
7
1h
1i
COOtBu
COtBu
63
44
sodium hydride afforded low yields, most likely due to steric
hindrance of the tert-butyl group and the poor nucleophi-
licity of the sulfoximine nitrogen. Finally, sulfoximine 1c
could be alkylated with success according to a literature
procedure by deprotonation with potassium hydride in
DME5 in the presence of tetrabutylammonium bromide
and quenching with various electrophiles to afford the
N-substituted sulfoximines 1e–h in good yields (Table 1,
entries 2, 4–6). tert-Butylsulfoximine2 (S)-1e (Table 1, entry
3) was obtained without erosion of the optical purity (eeZ
80%) by using this procedure. Treatment of sulfoximine 1c
with pivaloyl chloride and sodium carbonate in a biphasic
mixture of water and dichloromethane afforded, in a
moderate yield, the instable6 crude N-pivaloyl sulfoximine
1i (Table 1, entry 7).
2.2. Metalation reaction of sulfoximines 1c–g
Preliminary experiments using various conditions have been
described before by us.2 We summarize here the main
results. With the N-unprotected sulfoximine 1c, 2 equiv of
n-BuLi followed by quenching with methyl iodide or
methanol-d afforded, respectively, products 2a and 2b in
low yields (Table 2, entries 1 and 2). To examine the scope
of this reaction with several other electrophiles, we then
studied the ortho-functionalization of the N-protected
sulfoximines 1d–g (Table 2, entries 3–18). ortho-Lithiation
of the N-trimethylsilyl sulfoximine 1d with n-BuLi at
K78 8C is very fast and, the intermediate lithio species was
quenched after 10 min with methanol-d to afford compound
2f in 95% yield (Table 2, entry 7). However, a small amount
Table 2. Metalation reaction of sulfoximines 1c–g and quenching with electrophiles
Entry
Sulfoximine
R1
Electrophile
E
R2
Product
Yield%
1
2
3
4
5
6
7
8
1c
1c
1d
1d
1d
1d
1d
1d
1e
1e
1e
1e
1e
1f
H
H
CH3I
CH3OD
CH3I
(CH3)2S2
I2
C2Cl6
CH3OD
—
CH3I
(CH3)2S2
I2
C2Cl6
CH3OD
CH3I
(CH3)2S2
CH3I
CH3
D
CH3
SCH3
I
Cl
D
Si(CH3)3
CH3
SCH3
I
H
H
H
H
H
H
2a
2b
2a
2c
2d
2e
2f
2g
50
60
90
95
75
76
95a
95
95
78
—
—
92a
55
65
96
90
95a
Si(CH3)3
Si(CH3)3
Si(CH3)3
Si(CH3)3
Si(CH3)3
Si(CH3)3
CH3
CH3
CH3
CH3
CH3
(CH2)OCH3
(CH2)OCH3
CH2CH]CH2
CH2CH]CH2
CH2CH]CH2
Si(CH3)3
H
CH3
CH3
CH3
9
2h
2i
10
11
12
13
14
15
16
17
18
2jC3ab
2kC3bb
2l
Cl
D
CH3
CH3
CH3
SCH3
CH3
SCH3
D
(CH2)OCH3
(CH2)OCH3
CH2CH]CH2
CH2CH]CH2
CH2CH]CH2
2m
2n
2o
2p
1f
1g
1g
1g
(CH3)2S2
CH3OD
2q
(a) Reaction performed with n-BuLi (1.2 equiv), THF, K78 8C (2 equiv of n-BuLi with 1c to obtain 2a, 2b; 0 8C with 1d to obtain 2g), 10 min then
electrophile, 2 h (1 h for 1d), K78 8C.
a Conversion determined by 1H NMR.
b Conversion into the sulfinamide occured during the purification.

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S. Gaillard et al. / Tetrahedron 61 (2005) 8138–8147
of compound 2g corresponding to the migration of the
trimethylsilyl group could be isolated. When the ortho-
lithiated species was allowed to reach 0 8C, compound 2g
was obtained in 95% yield (Table 2, entry 8).
ortho-directing group as a new synthetic tool for asym-
metric induction, we decided to test various prochiral
electrophiles. The first experiments were carried out with
sulfoximine 1d in THF and various aldehydes (Table 3).
Acetaldehyde and pivaldehyde (Table 3, entries 1 and 7)
gave satisfactory yields and medium stereocontrol, while no
stereocontrol was obtained with benzaldehyde (Table 3,
entry 2). Decreasing the solvent polarity by means of
toluene in the presence of sec-BuLi/TMEDA allowed us to
improve somewhat the level of stereocontrol (deZ50%)
with benzaldehyde (Table 3, entry 6). Under the same
conditions, N-methylsulfoximine 1e afforded along with the
desired ortho-functionalized sulfoximines 2u,v, sulfinic
esters 4a–c (Table 4). These by-products result from a
de-tert-butylation reaction followed by an intramolecular
cyclisation of the resultant sulfinamide with the hydroxy
group. With acetaldehyde, the sulfinic ester 4a is the sole
product observed with modest diastereoselectivity (Table 4,
entry 1). In the case of benzaldehyde, alcohol 2u was
recovered quantitatively in the crude reaction mixture, but
flash chromatography led to the sulfinic ester 4b in a
quantitative yield and once again with a modest diastereoiso-
meric excess (Table 4, entry 2). Pivaldehyde gave a 1/1
mixture of ortho-substituted sulfoximine 2v and sulfinic ester
4c in moderate yields and excellent stereocontrol in both cases
(Table 4, entry 3). It is interesting to point out that this de-tert-
butylation reaction seems to be easier with ortho-substituted
sulfoximines. Indeed, no de-tert-butylation reaction is
detected during flash chromatography of the starting material
1e. Inspiteoftheseinterestingresultsintermsofstereocontrol,
the de-tert-butylation reaction limits the yields and the
reproducibility of this ortho-functionalization of aryl-sulfox-
imines. Since we could not get away from this side reaction,
we optimized the conditions to obtain a clean stereoselective
de-tert-butylation reaction to improve the overall yield of
this process. Given the impressive applications of chiral
sulfinamides reported these last years in literature,7 efficient
stereoselective routes to new ortho-substituted sulfinamides
may be highly desirable.
It is interesting to note that this migration also occurred
when LDA is used as lithiating agent. When a lithium amide
is employed, the formation of 2g probably proceeded via
an equilibrium between the starting sulfoximine 1d and
the ortho-lithiated sulfoximine, which is trapped by the
trimethylsilyl group shifting the equilibrium to the
formation of 2g (Scheme 2).
Scheme 2. Lithiation of N-trimethylsilysulfoximine 1d: Path A: Non-
reversible conditions (n-BuLi). Path B: Reversible conditions (LDA).
Trapping of the intermediate lithio species obtained from
1d–g with methyl iodide and dimethyl disulfide, afforded
the corresponding ortho-substituted sulfoximines in good
yields (Table 2, respectively, entries 3, 9, 14, and 16
and entries 4, 10, 15, and 17). These last results clearly
show that N-protected sulfoximines 1d–g are superior to
the N-unprotected sulfoximine 1c to provide satisfactory
yields. Use of iodine or hexachloroethane as
electrophiles proceeded smoothly with the N-silylated
sulfoximine 1d (Table 2, entries 5 and 6). With
sulfoximine 1e, an unseparable mixture of ortho-
substituted sulfoximines 2j,k and their corresponding
sulfinamides 3a,b was observed (Table 2, entries 11 and
12). Optimization of this reaction giving rise to the
exclusive formation of sulfinamides will be further
described in this paper.
2.4. Optimization of the de-tert-butylation reaction
Many papers8–11 report the conversion of sulfoximines into
sulfinamides. These include the preparation of epoxides
and cyclopropanes from b-hydrosulfoximines10 and
g-ketosulfoximines,8b respectively, which is accompanied
in both cases by the formation of sulfinamides (Scheme 3a
2.3. Quenching with prochiral electrophiles
In order to investigate the potential of the chiral sulfoximine
Table 3. Metalation reaction of sulfoximine 1d followed by trapping with prochiral electrophiles
Entry
Conditions
Product
Yield%
de%
1
2
3
4
5
6
7
n-BuLi (1.2 equiv), THF, K78 8C, 10 min then CH3CHO, K78 8C, 1 h
n-BuLi (1.2 equiv), THF, K78 8C, 10 min then PhCHO, K78 8C, 1 h
n-BuLi (1.2 equiv), TMEDA, THF, K78 8C, 10 min then PhCHO, K78 8C, 1 h
n-BuLi (1.2 equiv), TMEDA, ether, K78 8C, 10 min then PhCHO, K78 8C, 1 h
n-BuLi (1.2 equiv), TMEDA, toluene, K78 8C, 10 min then PhCHO, K78 8C, 1 h
2r
2s
2s
2s
2s
76
60
60
60
60
60
71
50
0
25
40
40
50
67
sec-BuLi (1.2 equiv), TMEDA, toluene, K78 8C, 10 min then PhCHO, K78 8C, 1 h 2s
2t
n-BuLi (1.2 equiv), THF, K78 8C, 10 min then tBuCHO, K78 8C, 1 h

S. Gaillard et al. / Tetrahedron 61 (2005) 8138–8147
8141
Table 4. Quenching of the ortho-lithiated N-methylsulfoximine 1e with prochiral electrophiles
Entry
Electrophile
Product
Yield%
de%a
Product
Yield%
de%b
1
2
3
CH3CHO
PhCHO
—
2u
2v
—
—
10
95
4a
4b
4c
100
100c
25
13
10
95
100c
25
tBuCHO
(a) Reaction performed with n-BuLi (1.2 equiv), THF, K78 8C, 10 min, then electrophile, K78 8C, 2 h.
1
a Determined by H NMR from the crude product.
b After purification on silica gel.
c Before purification.
and b). More closely related to our case, is the b-elimination
of benzothiazines reported by Harmata11 in the presence of
KDMSO (Scheme 3c). The driving force of this rearrange-
ment seems to be the apparition of an anion at the b- or
g-position related to the sulphur atom generated by the use
of a base. A second driving force might also appear after
complexation of the lone pair of the nitrogen atom by an
electron poor species (proton or Lewis acid).12 This fact
would explain the observed instability of 1i bearing an
electron withdrawing group on the nitrogen atom.6
Sulfoximine 1e was first subjected to Harmata conditions10
using KDMSO at 50 8C. The racemic sulfinamide 3c was
obtained in 70% yield (Table 5, entry 1). A weaker base
such as potassium tert-butoxide yielded the starting
sulfoximine 1e besides traces of the desired sulfinamide
3c. During the course of our study, Bolm et al.13 described
the conversion of C2 symmetric bis(sulfoximines) into
bis(sulfinamides) by using diborane. These results prompted
us to test these new conditions with the sulfoximine 1e
(Table 5, entry 2). A clean de-tert-butylation reaction was
achieved with 2 equiv of BH3 affording sulfinamide 3c in
76% yield. The formation of sulfinamide 3c could be
explained by both the Lewis acid property and the hydride
donor ability of diborane.
We also tried other hydride donors such as lithium
tetrahydruroaluminate or sodium cyanoborohydride
(Table 5, entries 3–7). The best result was obtained with 3
equiv of lithium tetrahydruroaluminate in THF affording 3c
in 60% yield (Table 5, entry 7) whereas other reducing
agents gave only poor yields. Finally, the de-tert-butylation
¨
reaction was studied in the presence of Bronsted or Lewis
¨
acids. Strong Bronsted acids (2 M hydrochloric acid or
Amberlystw 15) gave rise to degradation products.
Similarly, zinc or magnesium bromides and copper(II)
chloride (Table 5, entries 8–10) afforded sulfinamide 3c in a
poor yield together with degradation products while
magnesium perchlorate in THF gave sulfinamide 3c in
76% yield (Table 5, entry 12).
Having at hand good conditions (BH3 or Mg(ClO4)2) to
convert tert-butyl-arylsulfoximines to racemic arylsulfina-
mides, we focused then our attention on the stereoselectivity
of this de-tert-butylation reaction. The sulfinamide (S)-3c
was obtained using diborane or magnesium perchlorate in
76% yield, and this, without detectable loss in optical purity
(eeZ80%). Comparison of the optical rotation with
literature data14 allowed us to assign the S-absolute
configuration showing that the de-tert-butylation reaction
proceeded with complete retention of configuration.
Scheme 3. Conversion of sulfoximines into sulfinamides. (a) Epoxide and
sulfinamide preparation from sulfoximine;10 (b) Cyclopropane and
sulfinamide prepared from a sulfoximine;8b (c) b-elimination of a
benzothiazine.11

8142
S. Gaillard et al. / Tetrahedron 61 (2005) 8138–8147
Table 5. Study of the de-tert-butylation reaction of 1e to obtain sulfinamide 3c
Entry
Conditions
Solvent
Yield%
1
2
3
4
5
6
7
8
KDMSO (2 equiv), 30 min, 50 8C
BH3 (2 equiv), 12 h, 20 8C
DMSO
THF
CDCl3
CDCl3
CDCl3
THF
70a
76a
5b
NaBH4 (1 equiv), 5 days, 20 8C
NaBH3CN (1 equiv), 5 days, 20 8C
LiAlH4 (1 equiv), 5 days, 20 8C
LiAlH4 (1 equiv), 24 h, 20 8C
LiAlH4 (3 equiv), 24 h, 20 8C
ZnBr2 (1 equiv), 5 days, 20 8C
MgBr2 (1 equiv), 5 days, 20 8C
CuCl2 (1 equiv), 5 days, 20 8C
Mg(ClO4)2 (1 equiv), 24 h, 20 8C
Mg(ClO4)2 (1 equiv), 24 h, 20 8C
5b
10b
20b
60b
35b,c
43b,c
THF
CDCl3
CDCl3
CDCl3
CDCl3
THF
9
c
10
11
12
—
—
c
84b (76a)
a Isolated yield.
b Determined by 1H NMR.
c Degradation.
2.5. Optimization of the ortho-functionalization/de-tert-
butylation sequence
3. Conclusion
The sulfoximine group has shown to be an excellent ortho-
directing group in lithiation reactions. Several electrophiles
were used to afford the corresponding ortho-functionalized
arylsulfoximines in good yields. We had better to use
N-substituted sulfoximines. The use of prochiral electro-
philes afford modest to good diastereoselectivities up to
95%. During this study, we observed a side reaction due to a
S-de-tert-butylation. This side S-de-tert-butylation reaction
has been optimized and allowed us to open a new route to
ortho-substituted enantiopure sulfinamides and sulfinic
esters.
We next examined various conditions in order to develop a
procedure affording the ortho-substituted sulfinamides from
sulfoximines 1d,e. The best results were obtained by
treating the residue of the ortho-lithiation step in THF
with magnesium perchlorate (Scheme 4). According to this
procedure, the sulfinamides 3a,b,d–f were obtained in fair to
good yields (Table 6). In the case of prochiral electrophiles,
the sulfinic esters 4a and 4c,d were obtained in moderate
yields and 28–95% diastereoisomeric excess (Scheme 4,
Table 7). At this stage of the study, it seems difficult to
provide additional information on the origin of the
stereoselectivity. Curiously, no stereocontrol was observed
with benzaldehyde (Table 7, entry 2).
Table 6. ortho-Functionalization/de-tert-butylation sequence
Entry
Sulfoximine Electrophile Product
Yield%
a
1
2
3
4
5
1d
1e
1e
1e
1e
—
I2
3d
3a
3b
3e
3f
71
80
82
95b
66
C2Cl6
CH3OD
(CH3)2S2
a The electrophile is sulfoximine 1d itself.
1
b Conversion determined by H NMR
Table 7. Synthesis of sulfinic esters 4a–d
Entry
Electrophile
Product
Yield%
de%
1
2
3
4
CH3CHO
PhCHO
4a
4b
4c
4d
58
45
40
35
28
0
O95
48
tBuCHO
i-PrCH2CHO
4. Experimental
Scheme 4. (a) n-BuLi (1.5 equiv), THF, K78 8C, 10 min then electrophile
(Table 6), 2 h, 0 8C and quenching with NH4Cl, extraction, evaporation
then Mg(ClO4)2 (1 equiv), THF, 24 h (66 to 95%); (b) n-BuLi (1.5 equiv),
THF, K78 8C, 10 min then aldehyde (Table 7), 2 h, K78 8C and quenching
with NH4Cl, extraction, evaporation then Mg(ClO4)2 (1 equiv), THF
followed for 4b–d by MgBr2 (1 equiv) in CHCl3 (35 to 58%).
4.1. General details
Infrared spectra were recorded on a Beckmann IR 4250
spectrometer. 1H and 13C NMR spectra were recorded on a

S. Gaillard et al. / Tetrahedron 61 (2005) 8138–8147
8143
200 or 300 MHz Bruker apparatus and calibrated with the
residual undeuterated solvent. Spectra were recorded in
deuteriochloroform. Chemicals were purchased from
Aldrich Co. and Janssen Co. and, unless otherwise stated,
were used without further purification. Tetrahydrofuran was
distilled from sodium–benzophenone ketyl. Flash chroma-
tography was performed with silica gel 60 (70–230 mesh
from Merck) and monitored by thin layer chromatography
(TLC) with silica plates (Merck, Kieselgel 60 F254).
The sulfoximine 1c was obtained as a yellow oil (3.72 g,
86%). 1H NMR (200 MHz, CDCl3) d 1.34 (s, 9H), 2.50 (br s,
1H), 7.54 (m, 3H), 7.94 (d, JZ8 Hz, 2H). 13C NMR
(75 MHz, CDCl3) d 24.4, 60.7, 128.9, 131.1, 133.3, 138.2.
IR (cmK1, KBr): nZ3256, 2975, 1476, 1448, 1366, 1210,
1107, 1075. MS (ICC, isobutane, m/z): MCHCZ198.
Conditions for the separation of the two enantiomers:
CHIRALCEL OJ. Eluent: heptane/isopropanol 90:10.
Temperature: 19 8C. lZ220 nm, flow rate: 1 mL minK1
.
Retention times: 13 and 16 min.
4.1.1. S-Methyl-S-phenylsulfoximine (1a). In a 500 mL
round-bottomed flask were introduced NaN3 (4.8 g, 73.7 mmol),
CHCl3 (20 mL) and methyl-phenylsulfoxide15 (9.4 g, 67 mmol)
previously dissolved in CHCl3 (60 mL). The mixture was
cooled at 0 8C and concentrated H2SO4 (17.5 mL) was
added dropwise. The solution was stirred and heated at
45 8C for 5 h. After cooling at 0 8C, 150 mL of water were
added and stirring was continued until dissolution is
complete. The aqueous layer was extracted three times
with CH2Cl2 (100 mL). The combined organic layers were
dried on MgSO4 and the solvent was removed under
reduced pressure. The residue was purified by flash
chromatography on silica gel (AcOEt) to yield 8.1 g
4.1.4. S-tert-Butyl-N-trimethylsilyl-S-phenylsulfoximine
(1d). As described for 1b starting from sulfoximine 1c
(2.0 g, 10.1 mmol) and HMDS (10.7 mL, 50.5 mmol). The
compound 1d was obtained as a yellow oil in a quantitative
1
yield. H NMR (200 MHz, CDCl3) d 0.08 (s, 9H), 1.25 (s,
9H), 7.51 (m, 3H), 7.85 (d, JZ6 Hz, 2H). 13C NMR
(75 MHz, CDCl3): d 2.6, 23.8, 60.9, 128.2, 130.4, 132.1,
140.1. IR (cmK1, KBr): nZ3066, 2955, 2897, 1445, 1286,
1137, 1083, 837, 756, 694, 633. Anal. Calcd for C13H23-
NOSSi: C, 57.94; H, 8.60; N, 5.20; S, 11.90. Found: C,
58.19; H, 8.31; N, 5.07; S, 12.27.
1
(78%) of 1a as a yellow oil. H NMR (200 MHz, CDCl3)
4.1.5. S-tert-Butyl-N-methyl-S-phenylsulfoximine (1e). In
a 250 mL round-bottomed flask were introduced DME
(40 mL) and sodium hydride (30% dispersion in mineral oil,
2.04 g, 15.2 mmol). A solution of S-phenyl-S-tert-butylsul-
foximine (1c) (3.0 g, 15.2 mmol) in DME (20 mL) was then
added dropwise in the sodium hydride solution. The mixture
was stirred for 1 h at 20 8C. Methyl iodide (4.7 mL,
76 mmol) was added and the solution stirred for 12 h at
20 8C. The mixture was quenched with a saturated aqueous
solution of NH4Cl (100 mL), and extracted with CH2Cl2
(3!100 mL). The collected organic layers were dried
(MgSO4), filtered and concentrated under reduced pressure.
The product was purified by flash chromatography on silica
gel (AcOEt/cyclohexane 1:1). The sulfoximine 1e was
obtained as a white solid (2.76 g, 86%). 1H NMR
(300 MHz, CDCl3) d 1.31 (s, 9H), 2.64 (s, 3H), 7.55 (m,
3H), 7.75 (d, JZ8 Hz, 2H). 13C NMR (75 MHz, CDCl3) d
d 2.70 (br s, 1H), 3.10 (s, 3H), 7.60 (m, 3H), 8.06 (d, JZ
8 Hz, 2H). 13C NMR (75 MHz, CDCl3) d 46.5, 128.0, 129.7,
133.5, 143.7. IR (cmK1, KBr): nZ3269, 1645, 1445, 1221,
1099. Anal. Calcd for C7H9NOS: C, 54.17; H, 5.84; N, 9.02;
S, 20.66. Found: C, 54.40; H, 5.72; N, 9.02; S, 20.31.
Conditions for the separation of the two enantiomers:
CHIRALCEL OJ. Eluent: heptane/isopropanol 90:10.
Temperature: 18 8C. lZ230 nm, flow rate: 1 mL minK1
Retention times: 24 min (R) and 30 min (S).
.
4.1.2. N-Trimethylsilyl-S-methyl-S-phenylsulfoximine
(1b). In a 250 mL round-bottomed flask were introduced
the sulfoximine 1a (3.4 g, 22.0 mmol) and HMDS
(23.3 mL, 110 mmol). The mixture was heated at 85 8C
for 40 min under a vigorous stirring. The solvent was
removed under reduced pressure. The compound 1b was
1
obtained as a yellow oil in a quantitative yield. H NMR
24.4, 30.2, 60.3, 129.2, 132.1, 133.0, 134.3. IR (cmK1
,
(200 MHz, CDCl3) d 0.10 (s, 9H), 3.00 (s, 3H), 7.50 (m,
3H), 8.00 (d, JZ8 Hz, 2H). 13C NMR (75 MHz, CDCl3) d
2.7, 49.7, 127.4, 129.3, 132.7, 145.2. IR (cmK1, KBr): nZ
3270, 2955, 1446, 1320, 1285, 1247, 1228, 1151, 1089.
Anal. Calcd for C10H17NOSSi: C, 52.82; H, 7.54; N, 6.16; S,
14.10. Found: C, 52.83; H, 7.26; N, 5.98; S, 14.16.
KBr): nZ1446, 1232, 1130, 1101, 1068. Anal. Calcd for
C11H17NOS: C, 62.52; H, 8.05; N, 6.63; S, 15.17. Found: C,
62.46; H, 7.98; N, 6.72; S, 15.10. Conditions for the
separation of the two enantiomers: CHIRALCEL OJ.
Eluent: heptane/isopropanol 95:5. Temperature: 19 8C.
lZ220 nm, flow rate: 1 mL minK1. Retention times: 6
and 9 min.
4.1.3. S-tert-Butyl-S-phenylsulfoximine (1c). To a solution
of sulfoximine 1b (4.98 g, 21.9 mmol) in anhydrous THF
(50 mL) under a nitrogen atmosphere at K0 8C, a 2.5 M
solution of n-BuLi in hexanes (8.76 mL, 21.9 mmol) was
slowly added. Then, methyl iodide (1.36 mL, 21.9 mmol)
was added and the mixture was stirred for 30 min at 20 8C.
The solution was cooled at 0 8C and the same procedure was
repeated two more times. Hydrolysis was carried out with
MeOH (20 mL) and stirred for an additional 30 min. So, a
saturated aqueous solution of NH4Cl (20 mL) and water
(20 mL) were added. The mixture was extracted with
CH2Cl2 (3!100 mL). The collected organic layers were
dried (MgSO4) and concentrated under reduced pressure to
give a yellow oil. The residue was purified by flash
chromatography on silica gel (AcOEt/cyclohexane 1:1).
4.1.6. S-tert-Butyl-N-2-methoxyethyl-S-phenylsulfoxi-
mine (1f). In a 250 mL round-bottomed flask were
introduced DME (30 mL) and potassium hydride (30%
dispersion in mineral oil, 1.35 g, 10.1 mmol). A solution of
S-phenyl-S-tert-butylsulfoximine (1c) (2.0 g, 10.1 mmol) in
DME (15 mL) was then added dropwise in the potassium
hydride solution. The mixture was stirred for 1 h at 20 8C.
Tetrabutylammonium bromide (150 mg, 0.5 mmol) and
2-bromoethylmethylether (1.9 mL, 20.2 mmol) were then
added and the resulting mixture was stirred for 12 h. The
mixture was hydrolyzed with a saturated aqueous solution of
NH4Cl (100 mL) and extracted with CH2Cl2 (3!100 mL).
The work-up was the same as above. The product was
purified by flash chromatography on silica gel (AcOEt/

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S. Gaillard et al. / Tetrahedron 61 (2005) 8138–8147
cyclohexane 1:2). Product 1f was obtained as a colorless oil
(2.37 g, 92%). 1H NMR (300 MHz, CDCl3) d 1.31 (s, 9H),
3.12 (m, 2H), 3.31 (s, 3H), 3.49 (m, 2H), 7.50 (m, 3H), 7.80
(d, JZ8.0 Hz, 2H). 13C NMR (75 MHz, CDCl3) d 24.4,
4.2.1. S-tert-Butyl-S-(2-tolyl)sulfoximine (2a). According
to the general procedure A from 1d, the electrophile was
MeI (0.22 mL, 3.55 mmol). The yield was 0.135 g (90%) of
an oil. 1H NMR (200 MHz, CDCl3) d 1.33 (s, 9H), 2.74 (s,
3H), 7.30–7.48 (m, 3H), 8.00 (d, JZ11 Hz, 1H). 13C NMR
(75 MHz, CDCl3) d 22.3, 24.4, 62.1, 126.4, 133.3, 133.6,
134.0, 136.8, 141.0. IR (cmK1, KBr): nZ3200, 2974, 2931,
1478, 1459, 1221, 1189, 1065, 976, 775. Anal. Calcd for
C11H17NOS: C, 62.52; H, 8.11; N, 6.63; S, 13.51. Found: C,
62.15; H, 8.10; N, 6.67; S, 13.37.
43.8, 59.2, 60.4, 75.0, 129.1, 132.1, 133.0, 135.1. IR (cmK1
,
KBr): 3220, 2927, 1444, 1123, 1087, 1055. Anal. Calcd for
C13H21NO2S: C, 61.14; H, 8.29; N, 5.48; S, 12.56. Found:
C, 60.86; H, 8.34; N, 5.68; S, 12.46.
4.1.7. N-Allyl-S-tert-butyl-S-phenylsulfoximine (1g). As
above reaction of S-phenyl-S-tert-butylsulfoximine (1c)
(2 g, 10.1 mmol) in DME (20 mL), potassium hydride
(30% dispersion in mineral oil, 1.35 g, 10.1 mmol) in DME
(30 mL), tetrabutylammonium bromide (150 mg, 0.5 mmol)
and allyl bromide (1.7 mL, 20.2 mmol) afforded after flash
chromatography on silica gel (AcOEt/cyclohexane 1:2)
product 1g as a colorless oil (2.27 g, 95%). 1H NMR
(300 MHz, CDCl3) d 1.34 (s, 9H), 3.45 (ddt, JZ16, 5, 2 Hz,
1H), 3.64 (ddt, JZ16, 5, 2 Hz, 1H), 5.05 (dq, JZ10, 2 Hz,
1H), 5.25 (dq, JZ17, 2 Hz, 1H), 5.96 (dq, JZ17, 5 Hz, 1H),
7.55 (m, 3H), 7.76 (d, JZ8 Hz, 2H). 13C NMR (75 MHz,
CDCl3) d 24.4, 46.3, 60.6, 114.0, 129.1, 132.0, 133.0, 135.0,
138.9. IR (cmK1, KBr): 2976, 1444, 1266, 1214, 1133,
1083. Anal. Calcd for C13H19NOS: C, 65.78; H, 8.01; N,
5.90; S, 13.51. Found: C, 65.93; H, 8.40; N, 6.07; S, 13.57.
4.2.2. S-tert-Butyl-S-(2-methylthiophenyl)sulfoximine
(2c). According to the general procedure A from 1d, the
electrophile was Me2S2 (0.32 mL, 3.55 mmol). The yield
was 0.164 g (95%) of an oil. 1H NMR (200 MHz, CDCl3) d
1.42 (s, 9H), 2.43 (s, 3H), 7.25 (m, 2H), 7.50 (t, JZ11 Hz,
1H), 8.00 (d, JZ11 Hz, 1H). 13C NMR (75 MHz, CDCl3) d
15.9, 24.2, 62.8, 123.6, 125.1, 133.0, 134.4, 134.5, 143.2. IR
(cmK1, KBr): nZ3273, 2968, 2919, 1447, 1432, 1217,
1072, 971, 774. HRMS (IE, m/z): calcd for C11H17NOS2:
243.0752. Found: 243.0748.
4.2.3. S-tert-Butyl-S-(2-iodophenyl)sulfoximine (2d).
According to the general procedure A from 1d, the
electrophile was I2 (0.432 g, 1.7 mmol). The yield was
0.172 g (75%) of a white solid. 1H NMR (200 MHz, CDCl3)
d 1.44 (s, 9H), 7.16 (t, JZ11 Hz, 1H), 7.51 (t, JZ11 Hz,
1H), 8.17 (d, JZ11 Hz, 1H), 8.25 (d, JZ11 Hz, 1H). 13C
NMR (75 MHz, CDCl3) d 27.0, 54.9, 93.9, 125.7, 129.0,
132.5, 140.1, 147.1. HRMS (IE, m/z): calcd for
C10H14INOS: 322.9841. Found: 322.9842.
4.1.8. S-tert-Butyl-N-tert-butyloxycarbonyl-S-phenylsul-
foximine (1h). As above, reaction of S-phenyl-S-tert-
butylsulfoximine (1c) (1.0 g, 5 mmol) in DME (10 mL),
potassium hydride (30% dispersion in mineral oil, 0.70 g,
5.2 mmol) in DME (20 mL), tetrabutylammonium bromide
(75 mg, 0.25 mmol) and di-tert-butyl dicarbonate (2.18 g,
10 mmol) afforded, after purification by chromatography on
silica gel (AcOEt/petroleum ether 1:2), the product 1h as a
sticky colorless oil (0.95 g, 63%). 1H NMR (300 MHz,
CDCl3) d 1.23 (s, 9H), 1.37 (s, 9H), 7.56 (m, 3H), 7.83 (d,
JZ8 Hz, 2H). 13C NMR (75 MHz, CDCl3) d 23.7, 28.3,
4.2.4. S-tert-Butyl-S-(2-chlorophenyl)sulfoximine (2e).
According to the general procedure A from 1d, the
electrophile was C2Cl6 (0.113 mL, 0.99 mmol). Yield
0.125 g (76%) of a white solid. 1H NMR (200 MHz,
CDCl3) d 1.39 (s, 9H), 7.40 (m, 3H), 8.13 (d, JZ11 Hz, 1H).
13C NMR (50 MHz, CDCl3): d 24.1, 62.5, 126.7, 132.7,
133.9, 134.7, 135.2, 136.0. HRMS (IE, m/z): calcd for
C10H14ClNOS: 231.0485. Found: 231.0480.
61.6, 80.4, 129.3, 130.6, 133.7, 134.7, 158.4. IR (cmK1
,
KBr): 2977, 1693, 1668, 1274, 1154. Anal. Calcd for
C15H23NO3S: C, 60.58; H, 7.74; N, 4.71; S, 10.78. Found:
C, 60.56; H, 7.34; N, 4.68; S, 10.46.
4.2.5. S-tert-Butyl-N-trimethylsilyl-S-(2-2H-phenyl)sul-
foximine (2f) According to the general procedure A from
1d, the electrophile was MeOD (0.144 mL, 3.55 mmol). No
methanolysis at the end of the reaction. The yield was 95%
determined by 1H NMR. 1H NMR (200 MHz, CDCl3) d 0.11
(s, 9H), 1.28 (s, 9H), 7.52 (m, 3H), 7.90 (d, JZ8 Hz, 1H).
4.2. General procedure A for the metalation reaction of
compounds 1d–g
To a cooled (K78 8C) solution of the corresponding N-
protected-S-phenyl-S-tert-butylsulfoximine 1d–g (0.71 mmol)
in anhydrous THF (10 mL) under a nitrogen atmosphere
was added a 2.5 M solution in hexanes of n-BuLi (0.34 mL,
0.85 mmol) while maintaining the temperature at K78 8C.
The mixture was stirred for 10 min at this temperature
before addition of the appropriate electrophile. The
resulting solution was then stirred for 1 h at K78 8C with
1d and 2 h with 1e–g. The reaction was quenched with a
saturated aqueous solution of NH4Cl (10 mL) and extracted
with dichloromethane (3!10 mL). The organic layers were
dried on MgSO4 and the solvent was removed under
reduced pressure. The residues obtained from 1e–g were
purified by flash chromatography on silica gel (AcOEt/
cyclohexane) whereas the oil obtained from 1d was
dissolved in methanol and stirred for 1 h at 20 8C. Methanol
was removed under reduced pressure and the product was
purified by flash chromatography on silica gel (AcOEt).
4.2.6. S-tert-Butyl-S-(2-trimethylsilylphenyl)-sulfoxi-
mine (2g). In a round-bottomed flask flushed with nitrogen,
a solution of N-trimethylsilyl-S-phenyl-S-tert-butylsulfox-
imine (1d) (0.2 g, 0.74 mmol) in THF (5 mL) was cooled at
K78 8C. A 2.5 M solution in hexanes of n-BuLi (0.35 mL,
0.87 mmol) was then added. The mixture was allowed to
warm to 0 8C and stirred for 1 h. Hydrolysis was carried out
with a saturated aqueous solution of NH4Cl (5 mL) and the
aqueous layer was extracted with dichloromethane (3!
5 mL). The yield was 0.19 g (95%) of 2g as a yellow oil. 1H
NMR (200 MHz, CDCl3) d 0.41 (s, 9H), 1.35 (s, 9H), 7.54
(m, 2H), 7.85 (d, JZ9 Hz, 1H), 8.01 (d, JZ9 Hz, 1H). 13C
NMR (75 MHz, CDCl3) d 2.5, 24.7, 61.5, 129.0, 131.8,
131.9, 136.9, 143.0, 143.7. IR (cmK1, KBr): nZ3333, 3256,
2955, 1245, 1214, 1109, 966, 846, 760. Anal. Calcd for

S. Gaillard et al. / Tetrahedron 61 (2005) 8138–8147
8145
C13H23NOSSi: C, 57.94; H, 8.60; N, 5.20; S, 11.90. Found:
C, 58.03; H, 8.40; N, 5.07; S, 12.37.
4.2.12. N-Allyl-S-tert-butyl-S-(2-methylthiophenyl)sul-
foximine (2p). According to the general procedure A
from 1g, the electrophile was Me2S2 (0.32 mL, 3.55 mmol).
1
The yield was 0.151 g (90%) of a white solid. H NMR
4.2.7. S-tert-Butyl-N-methyl-S-(2-tolyl)sulfoximine (2h).
According to the general procedure A from 1e, the
electrophile was MeI (88 mL, 1.42 mmol). The yield was
0.152 g (95%) of a yellow solid. 1H NMR (300 MHz,
CDCl3) d 1.32 (s, 9H), 2.65 (s, 3H), 2.69 (s, 3H) 7.29 (m,
2H), 7.42 (t, JZ8 Hz, 1H), 7.76 (d, JZ8 Hz, 1H). 13C NMR
(75 MHz, CDCl3) d 24.3, 30.0, 60.3, 61.7, 126.3, 128.7,
132.6, 134.0, 134.6, 142.0. Anal. Calcd for C12H19NOS: C,
63.96; H, 8.50; N, 6.22; S, 14.23. Found: C, 63.93; H, 8.39;
N, 6.07; S, 14.57.
(300 MHz, CDCl3) d 1.39 (s, 9H), 2.39 (s, 3H), 3.46 (m,
1H), 3.67 (m, 1H), 5.02 (d, JZ11 Hz, 1H), 5.33 (d, JZ
17 Hz, 1H), 5.95 (m, 1H), 7.14 (t, JZ7.9 Hz, 1H), 7.26 (d,
JZ7.9 Hz, 1H), 7.44 (t, JZ7.8 Hz, 1H), 7.74 (d, JZ7.8 Hz,
1H). 13C NMR (75 MHz, CDCl3) d 16.1, 24.6, 46.3, 63.3,
114.1, 123.7, 125.6, 129.1, 131.8, 133.1, 135.1, 144.9. Anal.
Calcd for C14H21NOS2: C, 59.32; H, 7.47; N, 4.94; S, 22.62.
Found: C, 59.52; H, 7.63; N, 5.07; S, 22.97.
4.2.13. S-tert-Butyl-S-[2-(1-hydroxyethyl)phenyl]-sulfox-
imine (2r). According to the general procedure A from 1d,
the electrophile was CH3CHO (large excess). The yield was
0.13 g (76%) of an oil consisting in an unseparable mixture
of two diastereoisomers, deZ50%. Minor diastereoisomer:
1H NMR (200 MHz, CDCl3): 1.35 (s, 9H), 1.52 (d, JZ7 Hz,
3H), 5.80 (q, JZ7 Hz, 1H), 7.35 (t, JZ8 Hz, 1H), 7.56 (t,
JZ8 Hz, 1H), 7.69 (d, JZ8 Hz, 1H), 7.97 (d, JZ7.7 Hz,
1H). Major diastereoisomer: 1H NMR (200 MHz, CDCl3) d
1.31 (s, 9H), 1.52 (d, JZ7 Hz, 3H), 5.69 (q, JZ7 Hz, 1H),
7.38 (t, JZ8 Hz, 1H), 7.57 (t, JZ8 Hz, 1H), 7.72 (d, JZ
8 Hz, 1H), 7.98 (d, JZ7.7 Hz, 1H). 13C NMR (75 MHz,
CDCl3) d 147.4, 136.0, 133.8 (3), 133.7, 133.3, 127.8,
127.6, 127.5, 127.4, 65.3, 65.1, 62.9, 61.7, 24.2, 22.8. IR
(cmK1, KBr): nZ3459, 3310, 2974, 2931, 1466, 1206,
1184, 979, 782, 770. HRMS (IE, m/z): calcd for
C12H19NO2S: 241.1136. Found: 241.1134.
4.2.8. S-tert-Butyl-N-methyl-S-(2-methylthiophenyl)sul-
foximine (2i). According to the general procedure A from
1e, the electrophile was Me2S2 (0.32 mL, 3.55 mmol). The
yield was 0.142 g (78%) of a yellow solid. 1H NMR
(300 MHz, CDCl3) d 1.36 (s, 9H), 2.40 (s,3H), 2.68 (s, 3H),
7.18 (t, JZ7 Hz, 1H), 7.26 (d, JZ8 Hz, 1H), 7.47 (t, JZ
7 Hz, 1H), 7.75 (d, JZ8 Hz, 1H). 13C NMR (75 MHz,
CDCl3) d 15.8, 24.3, 29.9, 62.7, 123.5, 125.3, 130.9, 132.8,
135.2, 144.4. HRMS (IE, m/z): calcd for C12H19NOS2:
257.0908. Found: 257.0904.
4.2.9. S-tert-Butyl-N-(2-methoxyethyl)-S-(2-tolyl)sulfoxi-
mine (2m). According to the general procedure A from 1f,
the electrophile was MeI (88 mL, 1.42 mmol). The yield was
0.105 g (55%) of an oil. 1H NMR (300 MHz, CDCl3) d 1.32
(s, 9H), 2.69 (s, 3H), 3.00–3.20 (m, 2H), 3.32 (s, 3H), 3.49
(m, 2H), 7.28 (m, 1H), 7.41 (t, JZ7 Hz, 1H), 7.54 (m, 1H),
7.78 (d, JZ7 Hz, 1H). IR (cmK1, KBr): nZ2974, 2928,
1455, 1245, 1191, 1124, 763. 13C NMR (75 MHz, CDCl3): d
21.5, 24.0, 43.4, 58.8, 61.5, 74.6, 125.9, 132.6, 133.2, 133.5,
134.2, 141.7. Anal. Calcd for C14H23NO2S: C, 62.42; H,
8.61; N, 5.20; S, 11.90. Found: C, 62.59; H, 8.41; N, 5.07; S,
12.27.
4.2.14. S-tert-Butyl-S-[2-(1-hydroxybenzyl)phenyl]-sul-
foximine (2s). According to the general procedure A from
1d, the solvent was toluene and TMEDA (129 mL,
0.85 mmol) was added. sec-BuLi was used instead of
n-BuLi. The electrophile was benzaldehyde (0.172 mL,
1.7 mmol). The yield was 0.13 g (60%) of an oil consisting
1
in a mixture of two diastereoisomers (deZ50%). H NMR
(200 MHz, CDCl3) d 1.49 (s, 9H), 6.75 (s, 1H), 7.12 (d, JZ
13 Hz, 1H), 7.43 (m, 7H), 8.10 (d, JZ13 Hz, 1H). 13C NMR
(75 MHz, CDCl3) d 146.7, 141.8, 133.9, 133.8, 133.3, 130.8,
4.2.10. S-tert-Butyl-N-(2-methoxyethyl)-S-(2-methylthio-
phenyl)sulfoximine (2n). According to the general pro-
cedure A from 1f, the electrophile was Me2S2 (0.32 mL,
3.55 mmol). The yield was 0.14 g (65%) of an oil. 1H NMR
(300 MHz, CDCl3) d 1.36 (s, 9H), 2.39 (s, 3H), 3.04–3.16
(m, 2H), 3.32 (s, 3H), 3.50 (m, 2H), 7.22 (m, 1H), 7.41 (m,
2H), 7.81 (d, JZ7 Hz, 1H). 13C NMR (75 MHz, CDCl3): d
15.7, 24.1, 43.4, 58.8, 62.7, 74.4, 123.4, 125.2, 131.4, 132.7,
134.9, 144.3. IR (cmK1, KBr): nZ2923, 2872, 1436, 1246,
1120, 768. HRMS (IE, m/z): calcd for C14H23NO2S2:
301.1170. Found: 301.1166.
128.3, 127.7, 127.3, 126.8, 71.2, 63.9, 24.4. IR (cmK1
,
KBr): nZ3273, 2972, 1451, 1205, 1176, 986, 755, 707.
HRMS (IE, m/z): calcd for C17H21NO2S: 303.1293. Found:
303.1298 and H NMR (200 MHz, CDCl3) d 1.52 (s, 9H),
1
4.03 (m, 1H), 6.84 (s, 1H), 7.17 (d, JZ13 Hz, 1H), 7.36 (m,
7H), 8.07 (d, JZ13 Hz, 1H). 13C NMR (75 MHz, CDCl3) d
146.7, 141.9, 134.0, 133.7, 133.1, 130.9, 128.4, 128.0,
127.5, 126.9, 71.3, 61.9, 24.3. IR (cmK1, KBr): nZ3271,
2972, 1447, 1206, 980, 759, 707. HRMS (IE, m/z): calcd for
C17H21NO2S: 303.1293. Found: 303.1289.
4.2.11. N-Allyl-S-(2-tolyl)-S-tert-butylsulfoximine (2o).
According to the general procedure A from 1g, the
electrophile was MeI (88 mL, 1.42 mmol). The yield was
0.171 g (96%) of a white solid. 1H NMR (300 MHz, CDCl3)
d 1.36 (s, 9H), 2.69 (s, 3H), 3.45 (m, 1H), 3.65 (m, 1H), 5.04
(d, JZ10 Hz, 1H), 5.34 (d, JZ17 Hz, 1H), 5.97 (m, 1H),
7.29 (m, 2H), 7.42 (t, JZ7 Hz, 1H), 7.78 (d, JZ7 Hz, 1H).
13C NMR (75 MHz, CDCl3): d 21.6, 24.1, 46.0, 61.8, 113.7,
4.2.15. S-tert-Butyl-S-[2-(1-hydroxy-2,2-dimethyl-pro-
pyl)phenyl]sulfoximine (2t). According to the general
procedure A from 1d, the electrophile was pivaldehyde
(0.19 mL, 1.7 mmol). The yield was 0.143 g (71%) of an oil
consisting in a mixture of two diastereoisomers (deZ67%).
1H NMR (200 MHz, CDCl3) d 0.99 (s, 9H), 1.32 (s, 9H),
6.02 (s, 1H), 7.42 (t, JZ11 Hz, 1H), 7.53 (t, JZ11 Hz, 1H),
7.78 (d, JZ11 Hz, 1H), 8.10 (d, JZ11 Hz, 1H). 13C NMR
(75 MHz, CDCl3): d 24.1, 26.4, 27.0, 36.7, 62.1, 127.1, 129.9,
132.5, 133.5, 135.7, 144.7. IR (cmK1, KBr): nZ3413, 3140,
2955, 1480, 1202, 1180, 1100, 976, 736. HRMS (IE, m/z):
126.0, 132.7, 133.1, 133.6, 134.1, 138.7, 141.9. IR (cmK1
,
KBr): nZ3057, 2976, 2930, 1455, 1270, 1216, 1118, 762.
Anal. Calcd for C14H21NOS: C, 66.89; H, 8.42; N, 5.57; S,
12.76. Found: C, 66.59; H, 8.53; N, 5.57; S, 13.17.

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S. Gaillard et al. / Tetrahedron 61 (2005) 8138–8147
calcd for C15H25NO2S: 283.1606. Found: 283.1606. 1H NMR
(200 MHz, CDCl3) d 0.97 (s, 9H), 1.33 (s, 9H), 5.86 (s, 1H),
7.43 (t, JZ11 Hz, 1H), 7.61 (t, JZ11 Hz, 1H), 7.79 (d, JZ
11 Hz, 1H), 8.11 (d, JZ11 Hz, 1H). 13C NMR (75 MHz,
CDCl3): d 24.1, 26.5, 27.0, 36.6, 61.6, 127.0, 129.6, 132.5,
133.3, 135.9, 145.3. IR (cmK1, KBr): nZ3333, 2955, 2871,
1480, 1364, 1211, 1183, 1097, 978, 760. HRMS (IE, m/z):
calcd for C15H25NO2S: 283.1606. Found: 283.1605.
saturated aqueous solution of NH4Cl (10 mL) and the
mixture was extracted with CH2Cl2 (3!10 mL). The
collected organic layers were dried (MgSO4) and concen-
trated under reduced pressure. The residue was dissolved in
anhydrous THF (10 mL) under a nitrogen atmosphere.
Magnesium perchlorate (0.212 g, 0.95 mmol) was then
added and the solution was stirred for 24 h. Hydrolysis
was again achieved with a saturated aqueous solution of
NH4Cl (10 mL) and the mixture was extracted with CH2Cl2
(3!10 mL). The organic layers were dried (MgSO4),
concentrated and the residue was purified by flash
chromatography on silica gel.
4.3. De-tert-butylation reaction
4.3.1. N-Methylbenzenesulfinamide ((S)-3c). To a sol-
ution of sodium borohydride (0.225 g, 5.94 mmol) in
anhydrous THF (5 mL) was added at 0 8C a solution of
iodine16 (0.603 g, 2.36 mmol) in anhydrous THF (10 mL).
The sulfoximine (S)-1e (0.25 g, 1.18 mmol) was dissolved
in anhydrous THF (5 mL) and the previously prepared BH3
solution was added. The mixture was stirred for 1 h at 0 and
20 8C overnight. The excess of BH3 was cautiously
destroyed with MeOH (10 mL). After 30 min, a 20%
aqueous solution of potassium hydroxide (10 mL) was
added and the mixture was stirred for 4 h. The product was
extracted with CH2Cl2 (3!10 mL) and the organic layers
were dried on MgSO4. After removing of the solvents under
reduced pressure, the residue was purified on silica gel
(AcOEt/cyclohexane 1:1). The yield was 0.14 g (76%).
RMN 1H NMR (300 MHz, CDCl3) d 2.53 (d, JZ6 Hz, 3H),
4.07 (q, JZ6 Hz, 1H), 7.47 (m, 3H), 7.67 (d, JZ9 Hz, 2H).
IR (cmK1, KBr): 3224, 1444, 1086, 1051. MS (ICC,
isobutane, m/z): MCHCZ156. HRMS (IE, m/z): calcd for
C7H9NOS: 155.0405. Found: 155.0405. Separation of the
enantiomers was achieved on a CHIRALPAK AD. Eluent:
heptane/isopropanol: 95:5. Temperature: 18 8C. lZ230 nm,
flow rate: 1 mL minK1. Retention times: 10.6 and 12 min.
Enantiomeric excessZ80%.
4.4.1. S-(2-Iodophenyl)-N-methylbenzenesulfinamide
(3a). The starting sulfoximine was 1e. According to the
general procedure B, the electrophile was I2 (0.96 g,
3.78 mmol). Hydrolysis was carried out with an aqueous
saturated solution of Na2S2O3. The eluent for purification
was AcOEt/cyclohexane 1:1. The yield was 0.213 g (80%)
of an oil. 1H NMR (300 MHz, CDCl3) d 2.50 (d, JZ5.3 Hz,
3H), 4.14 (br s, 1H), 7.14 (m, 1H), 7.84 (m, 2H). 13C NMR
(75 MHz, CDCl3) d 26.5, 94.4, 127.6, 128.7, 132.7, 140.5,
145.0. IR (cmK1, KBr): 3228, 1443, 1088, 1059. HRMS (IE,
m/z): calcd for C7H8INOS: 281.9450. Found: 281.9453.
4.4.2. S-(2-Chlorophenyl)-N-methylbenzenesulfinamide
(3b). The starting sulfoximine was 1e. According to the
general procedure B, the electrophile was C2Cl6 (0.43 mL,
3.8 mmol). Eluent: AcOEt/cyclohexane 1:1. The yield was
0.147 g (82%) of an oil. 1H NMR (300 MHz, CDCl3) d 2.50
(d, JZ5.6 Hz, 3H), 4.17 (br s, 1H), 7.38 (m, 3H), 7.92 (d,
JZ6.0 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 26.3, 127.4,
127.5, 130.7, 132.3, 132.7, 140.9. IR (cmK1, KBr): 3229,
2925, 1450, 1066, 1029. HRMS (IE, m/z): calcd for
C7H8ClNOS: 189.0015. Found: 189.0020.
4.4.3. S-(2-Trimethylsilylphenyl)benzenesulfinamide
(3d). According to the general procedure B, the starting
sulfoximine was 1d. Migration of the trimethylsilyl group
occurred while stirring the solution at 0 8C. Eluent for
purification: AcOEt. The yield was 0.143 g (71%) of a white
solid. 1H NMR (300 MHz, CDCl3) d 0.36 (s, 9H), 4.16 (br s,
2H), 7.50 (m, 3H), 8.11 (d, JZ7.5 Hz, 1H). 13C NMR
(75 MHz, CDCl3) d 0.0, 121.0, 128.9, 129.2, 134.1, 137.3,
152.4. IR (cmK1, KBr): 2954, 1474, 1250, 1108, 1051.
4.3.2. N-tert-Butylcarbonylbenzenesulfinamide (3g). To a
solution of S-phenyl-S-tert-butylsulfoximine (1c) (2.0 g,
10.1 mmol) in CH2Cl2 (20 mL) was added a solution of
Na2CO3 (0.53 g, 5.0 mmol) in water (15 mL). The mixture
was cooled at 10 8C and pivaloyl chloride (1.25 mL,
10.1 mmol) was added. The mixture was stirred for 2 h at
20 8C. The organic layer was dried on MgSO4, filtered and
the solvent was removed under reduced pressure. Flash
chromatography on silica gel (AcOEt/ cyclohexane 1:2)
afforded 3g as a white solid (1.0 g, 45%). 1H NMR
(300 MHz, CDCl3) d 1.19 (s, 9H), 7.52 (m, 3H), 7.65 (m,
2H), 7.90 (br s, 1H). 13C NMR (75 MHz, CDCl3) d 27.4,
40.1, 125.1, 129.8, 132.2, 144.4, 179.2. IR (cmK1, KBr):
3205, 1686. MS (ICC, isobutane, m/z): MCHCZ226.
Anal. Calcd for C11H15NO2S: C, 58.64; H, 6.71; N, 6.22; S,
14.23. Found: C, 58.59; H, 6.51; N, 6.15; S, 14.28.
4.4.4. N-Methyl-S-(2-methylthiophenyl)benzenesulfina-
mide (3f). The starting sulfoximine was 1e. According to
the general procedure B, the electrophile was Me2S2
(0.34 mL, 3.78 mmol). Eluent for purification: AcOEt/
cyclohexane 1:1. The yield was 0.125 g (66%) of an oil.
1H NMR (300 MHz, CDCl3) d 2.42 (s, 3H), 2.48 (d, JZ
5.3 Hz, 3H), 4.15 (d, JZ4.9 Hz, 1H), 7.25 (m, 3H), 7.83 (d,
JZ7.9 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 16.9, 26.4,
125.5, 127.3, 129.2, 131.7, 137.8, 141.3. IR (cmK1, KBr):
3226, 1434, 1097, 1066, 1032. HRMS (IE, m/z): calcd for
C8H11NOS2: 201.0282. Found: 201.0280.
4.4. General procedure B for the sequence metalation/
de-tert-butylation of sulfoximines 1d,e
To a solution of the corresponding sulfoximine 1d,e
(0.95 mmol) in anhydrous THF (10 mL) under a nitrogen
atmosphere at K78 8C, a 2.5 M solution of n-BuLi in
hexanes (0.57 mL, 1.42 mmol) was slowly added. The
mixture was stirred for 10 min and the electrophile was
added. The solution was stirred for a further 2 h at 0 8C or at
K78 8C for aldehydes. Hydrolysis was carried out with a
4.4.5. 3-Methyl-3H-2,1-benzoxathiol-1-oxide (4a). The
starting sulfoximine was 1e. According to the general
procedure B, the electrophile was acetaldehyde (0.265 mL,
4.74 mmol). Eluent for purification: AcOEt/CH2Cl2 1:1.
The yield was 0.092 g (58%) of an oil consisting in a

S. Gaillard et al. / Tetrahedron 61 (2005) 8138–8147
8147
mixture of two diastereoisomers (deZ13%). 1H NMR
(300 MHz, CDCl3) d 1.65 (d, JZ6.4 Hz, 1.8H), 1.81 (d, JZ
6.4 Hz, 1.2H), 5.80 (q, JZ6.6 Hz, 0.4H), 6.23 (q, JZ
6.6 Hz, 0.6H), 7.36 (t, JZ7.5 Hz, 1H), 7.55 (m, 2H), 7.72
(d, JZ7.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) d 20.7,
24.0, 87.1, 90.1, 122.5, 122.6, 123.7, 124.0, 129.7, 129.8,
132.6, 132.7, 142.6, 143.0, 146.6, 147.4. IR (cmK1, KBr):
2972, 2926, 1734, 1083, 1044. HRMS (IE, m/z): calcd for
C8H8O2S: 168.0245. Found: 168.0241.
146.9, 147.4. IR (cmK1, KBr): 2958, 1467, 1126. HRMS
(IE, m/z): calcd for C11H14O2S: 210.0715. Found: 210.0721.
References and notes
1. For comprehensive reviews see: (a) Snieckus, V. Chem. Rev.
´
1990, 879, 933. (b) Queguiner, G.; Marsais, F.; Snieckus, V.;
4.4.6. 3-Phenyl-3H-2,1-benzoxathiol-1-oxide (4b). The
starting sulfoximine was 1e. According to the general
procedure B, the electrophile was benzaldehyde (0.192 mL,
1.89 mmol). The Lewis acid was Mg(ClO4)2 followed by
MgBr2 (0.175 g, 0.95 mmol) in CHCl3. Eluent for purifi-
cation: cyclohexane/CH2Cl2 1:1. The yield was 0.098 g
(45%) of an oil containing a mixture of two diastereoi-
somers. 1st diastereoisomer: 1H NMR (300 MHz, CDCl3) d
7.01 (s, 1H), 7.09 (m, 1H), 7.21 (m, 2H), 7.32 (m, 3H), 7.46
(m, 2H), 7.73 (m, 1H). 13C NMR (75 MHz, CDCl3) d 95.7,
123.9, 124.0, 128.4, 129.3, 129.5, 130.0, 133.0, 138.4,
141.6, 146.6. 2nd diastereoisomer: 1H NMR (300 MHz,
CDCl3) d 6.54 (s, 1H), 7.24 (m, 1H), 7.26 (m, 2H), 7.30 (m,
3H), 7.45 (m, 2H), 7.71 (m, 1H). 13C NMR (75 MHz,
CDCl3) d 92.7, 95.8, 123.7, 123.9, 128.5, 129.4, 132.9,
136.9, 141.6, 147.9. IR (cmK1, KBr): 1456, 1116. HRMS
(IE, m/z): calcd for C13H10O2S: 230.0402. Found: 230.0400.
Epsztajn, J. Adv. Heterocycl. Chem. 1991, 52, 187–304.
2. Levacher, V.; Langer Eriksen, B.; Begtrup, M.; Dupas, G.;
´
Queguiner, G.; Duflos, J.; Bourguignon, J. Tetrahedron Lett.
1999, 40, 1665–1668.
3. (a) Reggelin, M.; Zur, C. Synthesis 2000, 1–64. (b) The
sufoximine group proved to be an ortho-directing group in an
anecdotic way: Jackson, R. F. W.; Briggs, A. D.; Brown, P. A.;
Clegg, W.; Elsegood, M. R. J.; Frampton, C. J. Chem. Soc.,
Perkin Trans. 1 1996, 1673–1682.
4. Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 8,
909–912.
5. Johnson, C. R.; Lavergne, O. M. J. Org. Chem. 1993, 58,
1922–1923.
6. During purification on silica gel, sulfinamide 3g was obtained
in 45% yield resulting from a de-tert-butylation reaction of 1i.
4.4.7. 3-tert-Butyl-3H-2,1-benzoxathiol-1-oxide (4c). The
starting sulfoximine was 1e. According to the general
procedure B, the electrophile was pivaldehyde (0.233 mL,
1.89 mmol). The Lewis acid was Mg(ClO4)2 followed by
MgBr2 (0.175 g, 0.95 mmol) in CHCl3. The eluent for
purification on silica gel was cyclohexane/CH2Cl2 1:1. An
other flash chromatography was performed on basic alumina
with cyclohexane/CH2Cl2 gradient from 3:1 to 1:3. The
7. Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984–995.
8. (a) Pyne, S. G.; Dong, Z.; Skelton, B. W.; White, A. H. J.
Chem. Soc., Chem. Commun. 1994, 751–752. (b) Pyne, S. G.;
Dong, Z.; Skelton, B. W.; White, A. H. J. Org. Chem. 1997,
62, 2337–2343. (c) Gais, H.-J.; Scommoda, M.; Lenz, D.
Tetrahedron Lett. 1994, 35, 7361–7364. (d) Pyne, S. G.; Dong,
Z. J. Org. Chem. 1996, 61, 5517–5522.
1
yield was 0.079 g (40%, deO95%) of a yellow solid. H
NMR (300 MHz, CDCl3) d 1.08 (s, 9H), 5.41 (s, 1H), 7.51
(d, JZ7.5 Hz, 3H), 7.72 (d, JZ6.4 Hz, 1H). 13C NMR
(75 MHz, CDCl3) d 26.6, 36.1, 102.2, 124.4, 129.7, 132.0,
139.8, 146.9. IR (cmK1, KBr): 2958, 1468, 1109. HRMS
(ICC, isobutane, m/z): calcd for C11H14O2S: 211.0793.
Found: 211.0789.
9. (a) Gais, H.-J.; Mueller, H.; Bund, J.; Scommoda, M.; Brandt,
J.; Raabe, G. J. Am. Chem. Soc. 1995, 117, 2453–2466. (b)
Scommoda, M.; Gais, H.-J.; Bosshammer, S. J. Org. Chem.
1996, 61, 4379–4390.
4.4.8. 3-Isobutyl-3H-2,1-benzoxathiol-1-oxide (4d). The
starting sulfoximine was 1e. According to the general
procedure B, the electrophile was 3-methylbutyraldehyde
(0.204 mL, 1.89 mmol). The Lewis acid was Mg(ClO4)2
followed by MgBr2 (0.175 g, 0.95 mmol) in CHCl3. The
eluent for purification was cyclohexane/CH2Cl2 1:1. The
yield was 0.069 g (35%) of an oil consisting in a mixture of
two diastereoisomers (deZ48%). 1H NMR (300 MHz,
CDCl3) d 0.89 (m, 6H), 1.50–2.10 (m, 3H), 5.66 (d, JZ
10.2 Hz, 0.4H), 6.12 (d, JZ9.8 Hz, 0.6H), 7.29 (m, 1H),
7.40 (m, 2H), 7.64 (m, 1H). 13C NMR (75 MHz, CDCl3) d
22.1, 22.2, 23.9, 24.1, 25.7, 25.8, 38.3, 49.1, 89.4, 92.4,
122.6, 122.8, 124.0, 123.8, 130.5, 132.5, 142.1, 142.6,
10. Taj, S. S.; Shah, A. C.; Lee, D.; Newton, G.; Soman, R.
Tetrahedron: Asymmetry 1995, 6, 1731–1740.
11. (a) Harmata, M.; Herron, B. F. Tetrahedron 1991, 47,
8855–8862. (b) Harmata, M.; Jones, D. E. Tetrahedron Lett.
1995, 36, 4769–4772.
12. Trost, B. M.; Matsuoka, R. T. Synlett 1992, 27–30.
13. Bolm, C.; Simic, O.; Martin, M. Synlett 2001, 1878–1880.
14. Schroeck, C. W.; Johnson, C. R. J. Am. Chem. Soc. 1971, 93,
5303–5305.
15. Johnson, C. R. Aldrichim. Acta 1985, 18, 3–10.
16. McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M. J.
Org. Chem. 1993, 58, 3568–3571.