Synthesis and alkylation of cyclic α-sulfonimidoyl carbanions: Non- transferable chiral carbanionic ligands in copper-mediated enantioselective conjugate addition

Article abstract of DOI:10.1055/s-1998-2071

The cyclic sulfoximines 4a and 4b have been prepared from (+)-(S)-S- methyl-S-phenylsulfoximine (1). Deprotonation of 4a and 4b and alkylation of lithiosulfoximines Li-4a and Li-4b gave α-alkyl substituted sulfoximines 5a (89% de), 5b (90% de), 6a (≤98% de), 6b (≤98% de), 7b (≤98% de) and 8b (≤98% de). The configuration of 6b was determined by X-ray structure analysis. Consecutive treatment of 5b, 6b and 8b with BuLi and CF₃CO₂H gave epimers epi-5b (64% de), epi-6b (89% de) and epi-8b (81% de). α,α -Dialkyl substituted sulfoximines 9 (≤98% de) and epi-9 (≤98% de) were obtained by alkylation of Li-5b and Li-6b. Conjugate addition of cuprates 11-14, containing the acyclic sulfonimidoyl carbanions Ia-c, to cyclohex-2-en-1-one gave ketones 15 and 16 in good yields but with low asymmetric induction (8- 49% ee). However, conjugate addition of cuprates 19b, 20b, 21b and 22b, derived from the cyclic lithiosulfoximines Li-7b and Li-8b, to cyclopent-2- en-1-one, cyclohex-2-en-1-one and cyclohept-2-en-1-one gave ketones 15a-c, 23b and 24b with good to high asymmetric inductions (77-99% ee) in good yields. The bicyclic ketone 27 (79% ee) was prepared from cyclohex-2-en-1- one via 24b in three steps.

Full text of DOI:10.1055/s-1998-2071

FEATURE ARTICLE
919
a
Synthesis and Alkylation of Cyclic -Sulfonimidoyl Carbanions: Non-transferable
Chiral Carbanionic Ligands in Copper-Mediated Enantioselective Conjugate Addition
Stephan Boßhammer, Hans-Joachim Gais*
Institut für Organische Chemie der Rheinisch-Westfälischen Technischen Hochschule Aachen, Professor-Pirlet-Straße 1, D-52056 Aachen, Germany
Fax +49(241)8888127; E-mail: Gais@RWTH-Aachen.de
Received 31 January 1998
Abstract: The cyclic sulfoximines 4a and 4b have been prepared synthesis and alkylation of carbanions II as well as their
from (+)-(S)-S-methyl-S-phenylsulfoximine (1). Deprotonation
of 4a and 4b and alkylation of lithiosulfoximines Li-4a and Li-4b
gave a-alkyl substituted sulfoximines 5a (89% de), 5b (90% de),
6a (≥98% de), 6b (≥98% de), 7b (≥98% de) and 8b (≥98% de).
The configuration of 6b was determined by X-ray structure analy-
conversion to III and the use of the latter in enantioselec-
tive conjugate addition.
Results and Discussion
sis. Consecutive treatment of 5b, 6b and 8b with BuLi and
CF3CO2H gave epimers epi-5b (64% de), epi-6b (89% de) and
epi-8b (81% de). a,a-Dialkyl substituted sulfoximines 9 (≥98%
de) and epi-9 (≥98% de) were obtained by alkylation of Li-5b and
Li-6b. Conjugate addition of cuprates 11–14, containing the acy-
clic sulfonimidoyl carbanions Ia–c, to cyclohex-2-en-1-one gave
ketones 15 and 16 in good yields but with low asymmetric induc-
tion (8–49% ee). However, conjugate addition of cuprates 19b,
20b, 21b and 22b, derived from the cyclic lithiosulfoximines Li-
7b and Li-8b, to cyclopent-2-en-1-one, cyclohex-2-en-1-one and
cyclohept-2-en-1-one gave ketones 15a–c, 23b and 24b with good
to high asymmetric inductions (77–99% ee) in good yields. The
bicyclic ketone 27 (79% ee) was prepared from cyclohex-2-en-1-
one via 24b in three steps.
Synthesis and Alkylation of Cyclic Sulfonimidoyl
Carbanions
The unsubstituted 5- and 6-membered sulfoximines 4a
and 4b were prepared in three steps from (+)-(S)-S-meth-
yl-S-phenylsulfoximine (1), which is readily available by
an efficient racemate separation6 (Scheme 1). Alkylation
of 1 at the N-atom7 with THP-protected bromoethanol and
chloropropanol8 and cleavage of the acetals formed gave
the N-hydroxyalkyl sulfoximines 2a and 2b in 77 and
72% yield. Tosylation of 2a and 2b afforded tosylates 3a
and 3b, each in 92% yield. Treatment of 3a and 3b with t-
BuOK/BuLi in THF led to their cyclization and afforded
the cyclic sulfoximines 4a9 and 4b in 66 and 57% yield.
Key words: cyclic lithiosulfoximines, diastereoselective alkyla-
tion, Cu(I)-mediated enantioselective conjugate addition, chiral
non-transferable C-ligands, acyclic lithiosulfoximines
Introduction
The chemistry of acyclic sulfonimidoyl carbanions, I,
which have found many applications in asymmetric syn-
thesis,1 is well established.2 Cyclic sulfonimidoyl carban-
ions, II, however, have escaped attention so far almost
completely.3 Because of the incorporation of the anionic
C-atom and the S-atom in a ring, reactions with electro-
philes should be highly stereoselective, and, thus, interest-
ing applications of II in asymmetric synthesis can be
envisioned. We were especially interested in the synthesis
of chiral cuprates of type III from II and in the use of the
former in enantioselective conjugate addition. The cu-
prates studied so far in enantioselective conjugate addi-
tion contained as chiral non-transferable ligands either
alkoxides, amides, thiolates or phosphanes but not carban-
ions.4 We have observed some time ago that Ia (R1 = Ph,
R2 = Me, R3 = R4 = H) serves as a non-transferable ligand
in conjugate addition of cuprates.5 However, the asym-
metric induction in conjugate addition of cuprates derived
from Ia was only very low. In this paper we describe the
Scheme 1
Metallation and deuteration experiments showed that sulf-
oximines 4a and 4b are readily deprotonated by BuLi in
THF in the a-position (Scheme 2, Table 1, Entries 1 and
4). Deuteration of Li-4a and Li-4b occurred stereoselec-
tively and gave D-4a and D-4b. The configurations of D-
4a and D-4b were determined by NOE experiments on the
1
basis of a complete assignment of the signals in the H
NMR spectra of 4a, 4b, D-4a and D-4b. Consecutive
treatment of 4a and 4b with BuLi and an alkylating re-
agent readily furnished the corresponding a-alkyl substi-
tuted sulfoximines with high diastereoselectivity (Table

920
Feature Article
SYNTHESIS
1). With methyl iodide as the alkylating reagent the dia- The similar stereochemical course of the deuteration and
stereomerically enriched sulfoximines 5a and 5b were ob- the alkylation of lithiosulfoximines Li-4a and Li-4b sug-
tained in high yields (Table 1, Entries 2 and 5). The use of gested, however, a facile synthesis of the epimeric alkyl
the sterically more demanding benzyl bromide, isopropyl sulfoximines as well. Thus, treatment of 5b, 6b and 8b
iodide and 2,4,6-trimethylbenzyl chloride as the alkylat- with BuLi and protonation of Li-5b, Li-6b and Li-8b with
ing reagents afforded the diastereomerically pure sulfox- CF3CO2H gave the diastereomerically enriched epimeric
imines 6a, 6b, 7b and 8b in good to high yields (Table 1, sulfoximines epi-5b, epi-6b and epi-8b in high yields
Entries 3, 6, 7 and 8). In these cases formation of the (Scheme 3). Sulfoximines epi-6b and epi-8b could be ob-
epimeric sulfoximines could not be detected by NMR tained diastereomerically pure by chromatography.
spectroscopy.
Scheme 2
Scheme 3
Table 1. Deuteration and Alkylation of Cyclic Lithiosulfoximines
The configurations of 5a, 6a, 6b, 7b and 8b as well as of
Entry
Sub-
strate
Product
Yielda
(%)
de
(%)
epimers epi-5b, epi-6b and epi-8b were determined by
NOE experiments on the basis of a complete assignment
of the signals in their 1H NMR spectra. The NMR spectro-
scopic assignment of configuration was substantiated in
the case of 6b by an X-ray structure analysis (Figure)10
which showed 6b to have the S,S-configuration. In the
crystal and in solution 6b adopts a conformation in which
the phenyl and the benzyl group occupy the pseudo-equa-
torial position.
1
2
3
4
5
6
7
8
4a
4a
4a
4b
4b
4b
4b
4b
D-4a: R = D (> 95% D) 95
5a: R = Me
6a: R = CH2Ph
D-4b: R = D (≥ 95% D) 95
74
89
≥98
81
94
85
5b: R = Me
88
71
57
69b
90
6b: R = CH2Ph
7b: R = CHMe2
8b: R = CH2C6H2Me3
≥98
≥98
≥98
a Reaction time: 3 h.
b Reaction time: 15 h.
Not only the protonation but also the alkylation of Li-5b
and Li-6b occurred with high diastereoselectivity. Thus,
Biographical Sketches
Hans-Joachim Gais was born in 1942 in Darmstadt, Germany. He studied chemistry at
the TH Darmstadt where he received a diploma in chemistry and a Dr. Ing. in 1973, work-
ing under the supervision of Professor Hafner. After postdoctoral studies with Professor
Woodward at Harvard University in 1974–1975, he returned to the TH Darmstadt. There
he began his independent research and was appointed Privatdozent in 1981. In 1986 he
joined the faculty at the University of Freiburg as Professor of Organic Chemistry. Since
1991 he has been a Professor of Organic Chemistry at the RWTH Aachen. He is a recip-
ient of the Carl Duisberg Award of the Gesellschaft Deutscher Chemiker. His research
interests comprise the synthesis of cyclopentanoid natural and non-natural compounds,
the application of enzymes in asymmetric synthesis, the structure and reactivity of chiral
sulfur-stabilized carbanions and the use of sulfoximines in asymmetric synthesis.
Stephan Boßhammer was born in 1968 in Würselen, Germany. He studied chemistry at
the RWTH Aachen and received his diploma degree in 1995. He joined the research
group of Professor Gais and received his Ph. D. degree in 1998. In his thesis he concen-
trated on new applications of sulfoximines in asymmetric synthesis.

June 1998
SYNTHESIS
921
midalized. In diastereomer B the lone-pair orbital is
periplanar to the S-O bond, the Ca-atom is pyramidalized
and the substituents at the S-atom and the Ca-atom occupy
the pseudo-equatorial position. Whereas the (THF)nLi
group and the phenyl ring are trans in A they are cis in B.
The attainment of an equilibrium between A and B is ex-
pected to be fast even at low temperatures because of the
low barriers towards Ca-S rotation and Ca-inversion. At-
tack of the electrophile at the Ca-atom in A syn to the O-
atom is preferred because of the direction of the Ca-pyra-
midalization and a lack of a steric hindrance. Diastere-
omer B should be less reactive than A. Attack of E+ at the
Ca-atom syn as well as anti to the O-atom in B is disfa-
vored because of the opposite direction of Ca-pyramidal-
ization and the shielding by the phenyl group. A similar
rationalization can be applied to the reactions of the five-
membered lithiosulfoximines Li-4a and Li-6a which are
expected to adopt similar structures.
Figure. X-ray Crystal Structure of Sulfoximine 6b. Selected bond
lengths (Å): S-O 1.450(2), S-N 1.528(3), S-Ca 1.794(3).
consecutive treatment of 5b with BuLi and benzyl bro-
mide gave the a,a-dialkyl substituted sulfoximine 9 of
≥98% de in acceptable yield (Scheme 4). By the same se-
quence, but starting with sulfoximine 6b and using methyl
iodide as the alkylating reagent, sulfoximine epi-9 of
≥98% de was obtained in high yield.
Scheme 5
Conjugate Addition of Cuprates Containing
Sulfonimidoyl Carbanions
Scheme 4
The asymmetric induction in the reaction of cuprate 11,
containing the acyclic carbanion Ia (R1 = Ph, R2 = Me, R3
= R4 = H),12a with cyclohex-2-en-1-one (10b), was very
low (Scheme 6). Ketone 15b was isolated, however, in
good yield. This showed that Ia can function like
methylsulfinyl methanide and methylsulfonyl metha-
nide13 as a non-transferable ligand in conjugate addition
of cuprates. Reaction of cuprates 12 and 13, derived from
the acylic carbanions Ib (R1 = Ph, R2 = CPh3, R3 = R4 =
H) (the precursor of Ib is designated as H-Ib, see experi-
mental) and Ic (R1 = Ph, R2 = SiPh2-t-Bu, R3 = R4 = H)12b
The above results show that attack of an electrophile at the
anionic C-atom of lithiosulfoximines Li-4a, Li-6a, Li-4b,
Li-5b, Li-6b, Li-7b and Li-8b occurs preferentially from
the side of the sulfoximine O-atom, irrespective of the
substituent at the Ca-atom. Similar observations were
made in reactions of a racemic bicyclic lithiosulfoximine
with electrophiles.3 We propose structures A and B for the
six-membered lithiosulfoximines Li-4b, Li-5b, Li-6b, Li-
7b and Li-8b, on the basis of the structure of Li-I11
(Scheme 5). The cyclic lithiosulfoximines are in THF so-
lution most likely to be monomeric and/or dimeric contact
ion pairs in which the Li-atom is coordinated to the N-
atom in the monomer and to the N- and O-atoms in the
dimer. The anion in A has a Ca-S-conformation in which
the lone-pair orbital at the Ca-atom is periplanar to the
S–Ph bond, because of a stabilizing nC-s*-interaction.11c
As a result the phenyl group occupies the pseudo-axial
and the substituent R the pseudo-equatorial position, Be-
cause of a minimization of torsional interaction between
the S–O bond and the substituent R, the Ca-atom is pyra-
Scheme 6

922
Feature Article
SYNTHESIS
which carry bulky groups at the N-atom, with cyclohex-2- Entries 4 and 5). Treatment of 10b with the functional-
en-1-one gave ketone 15b, having a higher ee-value. The ized cuprate 22b resulted in a transfer of the
highest enantioselectivity was observed in the case of re- (CH2)3OCH(Me)OEt group and gave ketone 24b of 79%
action of cuprate 14 with 10b which gave ketone 16b of ee in 70% yield. In the above described conjugate addi-
49% ee in 78% yield.
tions sulfoximines 4b, 6a, 6b, 7b and 8b were recovered
almost quantitatively upon aqueous workup. Surprisingly,
sulfoximines 6b, 7b and 8b were mixed with epi-6b, epi-
7b and epi-8b, respectively, in ratios of approximately
1:1. Because of the complete lack of information about the
structures of cuprates 17b, 18a, 18b, 19b, 20b, 21b and
22b as well as of cuprates 11–14, rationalization of this
observation is difficult at present.
Because of the low asymmetric induction recorded in con-
jugate addition with cuprates derived from flexible acy-
clic sulfonimidoyl carbanions I, we speculated that
cuprates containing the more rigid cyclic sulfonimidoyl
carbanions II would give perhaps better results. Thus, cu-
prates 17b, 18a, 18b, 19b, 20b, 21b and 22b (Table 2)
were prepared by the consecutive treatment of lithio-
sulfoximines Li-4b, Li-6a, Li-6b, Li-7b and Li-8b in Determination of the absolute configurations of 15a,15a
THF with CuI (1 equiv) and BuLi, MeLi and 15b,15b 15c,15c 16b15b and 23b15d was accomplished by
Li(CH2)3OCH(Me)OEt14 (0.9 equiv) (Scheme 7). Disap- comparison of their chiroptical data with those reported in
pointingly, conjugate addition of unsubstituted and benzyl the literature. The absolute configuration of 24b was as-
substituted cuprates 17b, 18a and 18b to 10b in THF pro- signed by chemical correlation. Thus, acetal 24b was con-
ceeded with only very low asymmetric induction (Table 2, verted via alcohol 25 to tosylate 26 in 42% overall yield
Entries 1–3). However, addition of the isopropyl and tri- from 10b (Scheme 8). Treatment of tosylate 26 with
methylbenzyl substituted cuprates 19b, 20b and 21b to LiCuMe2 gave not 15b, as expected, but led to cyclization
cyclopent-2-en-1-one (10a), cyclohex-2-en-1-one (10b) of 26 and afforded ketone 27 in 90% yield. Comparison of
and cyclohept-2-en-1-one (10c) afforded ketones 15a–c the chiroptical data of 27 with those of its 7-methyl
and 23b, having ee-values of 77–99%, in good yields (Ta- derivatives16 led to assignment of the R-configuration to
ble 2, Entries 4–9). Interestingly, conjugate addition of the 24b.
isopropyl substituted cuprate 19b and of the trimethylben-
zyl substituted cuprate 20b to cyclohex-2-en-1-one (10b)
proceeded with opposite asymmetric induction (Table 2,
Reagents and conditions: a) HCl/HK2O; ab) TsCl/NEt3/CH2Cl2, 0°C;
c) LiCuMe2/THF, –78°C
Scheme 8
Conclusion
We have shown that enantiomerically pure cyclic a-sul-
fonimidoyl carbanions are easily accessible from the cor-
responding sulfoximines upon deprotonation with BuLi.
Scheme 7
Reaction of these carbanions with alkylating reagents pro-
ceeded highly stereoselective syn to the sulfoximine O-
Table 2. Conjugate Addition of Cuprates Containing Cyclic Sulfoni-
atom, giving the corresponding mono- and disubstituted
cyclic sulfoximines. We have observed that acyclic and
cyclic a-sulfonimidoyl carbanions are capable to act as
non-transferable carbanionic ligands in conjugate addi-
tion of cuprates. High asymmetric induction was observed
with cuprates derived from a six-membered cyclic a-sul-
fonimidoyl carbanion, bearing a trimethylbenzyl group at
the anionic carbon atom.
midoyl Carbanions
Entry
Cuprate Sub-
Prod-
uct
Yield
(%)
ee
(%)
Abs.
Conf.
strate
1
2
3
4
5
6
7
8
9
17b
18a
18b
19b
20b
20b
20b
21b
22b
10b
10b
10b
10b
10b
10a
10c
10b
10b
15b
15b
15b
15b
15b
15a
15c
23b
24b
45
61
95
82
90
80
90
50
70
12
10
20
81
99
93
77
86
79a
S
R
R
R
S
S
S
S
R
All manipulations except workup and chromatography were per-
formed in an atmosphere of dry argon, with Schlenk and syringe tech-
niques in oven-dried glassware. Et2O was distilled from sodium
benzophenone ketyl, and THF was distilled from potassium ben-
zophenone ketyl. Dimethoxyethane (DME) and NEt3 were distilled
a For alcohol 25.

June 1998
SYNTHESIS
923
from CaH2. MeOH was distilled from magnesium turnings. CuI was
purified by the method described by Kauffman and Teter.17 TLC was
performed on E. Merck precoated plates (silica gel 60 F254, 0.2 mm).
Column chromatography was performed with E. Merck silica gel 60
(230–400 mesh). Melting points are uncorrected. 1H NMR (300 MHz,
CDCl3) chemical shifts are reported in ppm relative to TMS as internal
standard. Splitting patterns are designated as s, singlet; d, doublet; dd
double doublet; t, triplet; m, multiplet; br, broad. 13C NMR (75 MHz,
CDCl3) chemical shifts are reported in ppm relative to TMS as internal
standard. Peaks in 13C NMR spectra are denoted as “u” for carbons with
zero or two attached protons or with “d” for carbons with one or three
attached protons, as determined from theAPT puls sequence. Determi-
nation of ee-values was performed by capillary GC analysis on an
octakis-(2,3-di-O-pentyl-6-O-methyl)-g-cyclodextrin column, a per-
methyl-b-cyclodextrin column and an octakis-(2,6-di-O-pentyl-3-O-
butyryl)-g-cyclodextrin column. Optical rotations were measured at
room temperature. Elemental analyses were performed by the Institut
für Organische Chemie Microanalytical Laboratory, Aachen.
was added and the mixture was extracted with EtOAc (3 ´ 50 mL).
The combined organic phases were dried (MgSO4) and concentrated
in vacuum. Purification of the residue by chromatography (10%
MeOH/EtOAc) gave 3a (21.6 g, 92%) as a colorless oil; [a]D +87.6
(c = 1.77, CHCl3).
1H NMR: d = 2.43 (s, 3 H, ArCH3), 3.01–3.21 (m, 2 H, NCH2), 3.07
(s, 3 H, SCH3), 4.04–4.15 (m, 2 H, OCH2), 7.30–7.34 (m, 2 H, m-
SO2ArH), 7.53–7.67 (m, 3 H, m/p-PhH), 7.75–7.79 (m, 2 H, o-
SO2ArH), 7.86–7.90 (m, 2 H, o-PhH).
13C NMR: d = 21.60 (d, ArCH3), 42.49 (u, NCH2), 44.82 (d, SCH3),
71.00 (u, OCH2), 127.91 (d), 128.64 (d), 129.54 (d), 129.76 (d) (o/m-
PhC), 133.02 (u, p-PhC), 133.24 (d, p-TolC), 138.54 (u), 144.66 (u)
(ipso-PhC).
MS (EI, 70 eV): m/z (%) = 182 (M+ – TsO, 3), 181 (19), 168 (100),
141 (22), 125 (12), 91 (18).
Anal. C16H19NO4S2 (353.4): calcd C, 54.37; H, 5.42; N, 3.96; found
C, 54.21; H, 5.43 ; N, 3.98.
(+)-(S)-S-Methyl-S-phenyl-N-(3-p-tosyloxypropyl)sulfoximine (3b):
Following the above procedure, 3b (18.9 g, 92%) was obtained from
2b (13.0 g, 61.1 mmol) as a colorless oil; [a]D +91.3 (c = 1.50,
CHCl3).
(+)-(S)-N-(2-Hydroxyethyl)-S-methyl-S-phenylsulfoximine (2a);
Typical Procedure:
A solution of 1 (15.0 g, 96.6 mmol) in DME (80 mL) was added to a
suspension of KH (106 mmol, 14.2 g, 35% in mineral oil) in DME
(80 mL). After stirring the suspension for 3 h at r.t., Bu4NBr (1.56 g,
4.83 mmol) and 2-(2-bromoethoxy)tetrahydropyrane (30.3 g,
145 mmol) were added at 0 °C. The mixture was stirred for 20 h at r.t.
and was subsequently poured into 2 M HCl (200 mL). The mixture
was extracted with Et2O (150 mL) and the aqueous phase was neutral-
ized by the careful addition of solid Na2CO3. The aqueous phase was
extracted with EtOAc (4 ´ 200 mL) and the combined organic phases
were dried (MgSO4) and concentrated in vacuum. Purification of the
residue by chromatography (10% MeOH/EtOAc) gave 2a (14.8 g,
77%) as a colorless oil; [a]D +141.3 (c = 1.52, THF).
1H NMR: d = 1.82–1.92 (m, 2 H, CH2CH2CH2), 2.44 (s, 3 H, ArCH3),
2.85 (m, 1 H, NCH2), 2.99 (m, 1 H, NCH2), 3.04 (s, 3 H, SCH3), 4.13
(m, 1 H, OCH2), 4.27 (m, 1 H, OCH2), 7.30–7.35 (m, 2 H, SO2-m-
ArH), 7.54–7.66 (m, 3 H, m/p-PhH), 7.75–7.80 (m, 2 H, SO2-o-ArH),
7.85–7.89 (m, 2 H, o-PhH).
13C NMR: d = 21.63 (d, ArCH3), 31.61 (u, CH2CH2CH2), 39.45 (u,
NCH2), 44.98 (d, S CH3), 68.68 (u, OCH2), 127.92 (d), 128.60 (d),
129.53 (d), 129.77 (d) (o/m-PhC), 133.00 (d, p-PhC), 133.21 (u, p-
TolC), 139.14 (u), 144.56 (u) (ipso-PhC).
MS (EI, 70 eV): m/z (%) = 368 (M+ + 1, 0.1), 212 (15), 168 (88), 142
(10), 141 (100), 140 (34), 125 (34), 124 (26), 94 (11), 91 (43), 78 (20),
77 (19), 65 (19), 56 (30), 51 (14).
1H NMR: d = 2.98–3.14 (m, 2 H, NCH2), 3.17 (s, 3 H, CH3), 3.50 (br
s, 1 H, OH), 3.65–3.70 (m, 2 H, OCH2), 7.55–7.68 (m, 3 H, m/p-PhH),
7.91–7.96 (m, 2 H, o-PhH).
Anal. C17H21NO4S2 (367.4): calcd C, 55.56; H, 5.76; N, 3.81; found
C, 55.30; H, 5.78; N, 3.89.
13C NMR: d = 44.97 (d, CH3), 46.63 (u, NCH2), 63.41 (u, OCH2),
128.70 (d), 129.55 (d) (o/m-PhC), 133.12 (d, p-PhC), 138.78 (u, ipso-
PhC).
(+)-(S)-1-Phenyl-4,5-dihydro-3H-isothiazol-1-oxide (4a); Typical
Procedure:
MS (EI, 70 eV): m/z (%) = 199 (M+, 1), 170 (12), 169 (22), 168 (100),
142 (13), 141 (97), 140 (11), 126 (31), 125 (64), 124 (37), 97 (27), 91
(10), 78 (29), 77 (43), 65 (12), 63 (14), 51 (34).
To a solution of t-BuOK (7.20 g, 64.2 mmol) in THF (160 mL) at
–78 °C was added BuLi (64.2 mmol, 41.1 mL of 1.6 M in hexane). Af-
ter stirring the mixture for 30 min at –78 °C, a cold solution of sulfox-
imine 3a (21.6 g, 61.1 mmol) in THF (160 mL) was added.
Subsequently the mixture was warmed slowly to r.t. After stirring the
mixture for 20 h, satd aq NH4Cl solution (200 mL) was added and the
mixture was extracted with EtOAc (4 ´ 150 mL). The combined or-
ganic phases were dried (MgSO4) and concentrated in vacuum. Puri-
fication of the residue by chromatography (10% MeOH/EtOAc) gave
4a (7.3 g, 66%) as a colorless solid; mp 108–109°C; [a]D +25.1 (c =
0.90, EtOAc).
Anal. C9H13NO2S (199.2): calcd C, 54.25; H, 6.58; N 7.03; found C,
54.20; H, 6.64; N, 7.04.
(+)-(S)-N-(3-Hydroxypropyl)-S-methyl-S-phenylsulfoximine (2b):
Following the above procedure, 2b (14.8 g, 72%) was obtained from
1 (15.0 g, 96.6 mmol) and 2-(3-chloropropoxy)tetrahydropyrane
(25.9 g, 145 mmol) as a colorless oil; [a]D +147.7 (c = 1.36, THF).
1H NMR: d = 1.74–1.83 (m, 2 H, CH2CH2CH2), 2.95 (ddd, J = 12.0,
6.4, 5.8 Hz, 1 H, NCH2), 3.10 (s, 3 H, CH3), 3.15 (ddd, J = 12.1, 6.7,
5.7 Hz, 1 H, NCH2), 3.79–3.84 (m, 2 H, OCH2), 7.55–7.67 (m, 3 H,
m/p-PhH), 7.90–7.94 (m, 2 H, o-PhH).
1H NMR: d = 2.19–2.35 (m, 1 H, NCH2CH2), 2.39–2.49 (m, 1 H,
NCH2CH2), 3.17–3.29 (ddd, J = 12.9, 9.1, 8.2 Hz, 1 H, SCH2),
3.35–3.46 (ddd, J = 12.9, 7.7, 5.8 Hz, 1 H, SCH2), 3.82–3.92 (m, 1 H,
NCH2), 4.04–4.14 (m, 1 H, NCH2), 7.51–7.58 (m, 2 H, m-PhH),
7.60–7.67 (m, 1 H, p-PhH), 7.93–7.99 (m, 2 H, o-PhH).
13C NMR: d = 26.11 (u, NCH2CH2), 56.15 (u, NCH2), 56.70 (u,
SCH2), 129.27 (d), 129.41 (d) (o/m-PhC), 133.48 (d, p-PhC), 139.78
(u, ipso-PhC).
13C NMR: d = 33.70 (u, CH2CH2CH2), 42.02 (u, NCH2), 45.07 (d,
CH3), 62.34 (u, O CH2), 128.66 (d), 129.56 (d) (o/m-PhC), 133.09 (d,
p-PhC), 138.99 (u, ipso-PhC).
MS (EI, 70 eV): m/z (%) = 213 (M+, 0.4), 180 (19), 168 (100), 141
(55), 140 (29), 126 (12), 125 (39), 124 (13), 117 (27), 92 (21), 91 (10),
78 (14), 77 (30), 51 (20).
MS (EI, 70 eV): m/z (%) = 181 (M+, 12), 180 (4), 153 (31), 125 (100),
97 (11), 77 (18), 51 (13).
Anal. C9H11NOS (181.2): calcd C, 59.63; H, 6.12; N, 7.73; found C,
59.41; H, 6.14; N, 7.66.
Anal. C10H15NO2S (213.3): calcd C, 56.31; H, 7.09; N, 6.57; found C,
55.86; H, 7.18; N, 6.34.
(+)-(S)-S-Methyl-S-phenyl-N-(2-p-tosyloxyethyl)sulfoximine
(3a); Typical Procedure:
To a solution of 2a (13.3 g, 66.7 mmol) and p-TsCl (14.4 g,
75.3 mmol) in CH2Cl2 (55 mL) was added NEt3 (15 mL) at 0°C. After
stirring the mixture for 20 h at r.t., satd aq NH4Cl solution (100 mL)
(+)-(S)-1-Phenyl-3,4,5,6-tetrahydro[1,2]thiazin-1-oxide (4b):
Following the above procedure, 4b (3.6 g, 57%) was obtained from
3b (12.0 g, 32.6 mmol) as a colorless solid; mp 64 °C; [a]D +69.4 (c
= 1.11, CHCl3).

924
Feature Article
SYNTHESIS
1H NMR: d = 1.74–1.87 (m, 2 H, NCH2CH2), 2.18–2.26 (m, 1 H,
SCH2CH2), 2.50–2.60 (m, 1 H, SCH2CH2), 2.90–2.97 (ddd, J = 13.5,
11.8, 4.9 Hz, 1 H, SCH2), 3.15–3.20 (ddd, J = 11.8, 3.8, 3.8 Hz, 1 H,
SCH2), 3.50–3.56 (m, 1 H, NCH2), 3.68–3.74 (m, 1 H, NCH2),
7.53–7.58 (m, 2 H, m-PhH), 7.60–7.65 (m, 1 H, p-PhH), 8.05–8.09
(m, 2 H, o-PhH).
1H NMR: d = 1.11 (d, J = 6.6 Hz, 3 H, CH3), 1.77–1.83 (m, 1 H,
NCH2CH2), 1.89–1.99 (m, 1 H, NCH2CH2), 2.04–2.10 (m, 1 H,
SCHCH2), 2.14–2.24 (m, 1 H, SCHCH2), 2.94 (dqd, J = 12.7, 6.6, 4.3
Hz, 1 H, SCH), 3.44–3.49 (m, 1 H, NCH2), 3.57–3.64 (m, 1 H,
NCH2), 7.51–7.56 (m, 2 H, m-PhH), 7.60–7.64 (m, 1 H, p-PhH),
8.0l–8.05 (m, 2 H, o-PhH).
13C NMR: d = 21.61 (u, SCH2CH2), 23.52 (u, NCH2CH2), 43.46 (u,
NCH2), 51.75 (u, SCH2), 128.37 (d), 129.13 (d) (o/m-PhC), 133.28 (d,
p-PhC), 139.64 (u, ipso-PhC).
13C NMR: d = 16.51 (d, CH3), 26.10 (u), 29.97 (u) (NCH2CH2,
SCHCH2), 43.46 (u, NCH2), 56.61 (d, SCH), 128.96 (d), 129.13 (d)
(o/m-PhC), 133.22 (d, p-PhC), 137.16 (u, ipso-PhC).
MS (EI, 70 eV): m/z (%) = 209 (M+, 26), 126 (15), 125 (100), 105
(12), 97 (11), 91 (10), 84 (72), 78 (16), 77 (16), 69 (16), 56 (11), 55
(14), 51 (12).
MS (EI, 70 eV): m/z (%) = 195 (M+, 31), 126 (19), 125 (100), 118
(11), 117 (13), 110 (13), 105 (11), 97 (19), 91 (40), 78 (19), 77 (29),
70 (30), 69 (53), 68 (13), 55 (10), 51 (25).
Anal. C10H11NOS (195.2): calcd C, 61.50; H, 6.71; N, 7.17; found C,
61.28; H, 6.97; N, 7.18.
Anal. C11H15NOS (209.3): calcd C, 63.12; H, 7.22; N 6.69; found C,
63.09; H, 7.39; N 6.41.
(+)-(1S,6S)-6-Benzyl-1-phenyl-3,4, 5,6-tetrahydro[1,2]thiazin-1-ox-
ide (6b):
a-Alkyl Sulfoximines 5–9; General Procedure:
To a solution of the sulfoximine 4 in THF (10 mL/mmol) was added
BuLi (1.6 M in hexane, 1.1 equiv) at –50°C. The resulting orange so-
lution was warmed to r.t. for 10 min and cooled to –78°C. Then the
alkylating reagent (1.1 to 1.5 equiv) was added and the mixture was
stirred for the appropriate time. Satd aq NH4Cl solution was added
and the mixture was extracted with EtOAc. The combined organic
phases were dried (MgSO4) and concentrated in vacuum. Purification
of the residue by chromatography on silica gel gave the pure product.
From4b(409mg,2.09mmol)andbenzylbromide;yield:441mg(7l%);
colorless solid; mp 110°C; [a]D +60.7 (c = 1.11, CHCl3); de ≥98%.
1H NMR: d = 1.73–1.88 (m, 2 H, NCH2CH2), 2.00–2.07 (m, 1 H,
SCHCH2), 2.10–2.20 (m, 1 H, SCHCH2), 2.69 (dd, J = 14.1, 10.1 Hz,
1 H, PhCH2), 2.91 (dd, J = 14.1, 4.4 Hz, 1 H, PhCH2), 3.09 (dddd, J
= 12.6, 10.1, 4.4, 4.4 Hz, 1 H, SCH), 3.42–3.47 (m, 1 H, NCH2),
3.59–3.66 (m, 1 H, NCH2), 6.89–6.92 (m, 2 H, C-o-PhH), 7.12–7.19
(m, 3 H, C-m/p-PhH), 7.50–7.54 (m, 2 H, S-m-PhH), 7.59–7.63 (m, l
H, S-p-PhH), 8.00–8.03 (m, 2 H, S-o-PhH).
(+)-(1S,5R)-5-Methyl-1-phenyl-4,5-dihydro-3H-isothiazol-1-oxide
(5a):
13C NMR: d = 25.81 (u), 27.09 (u) (NCH2CH2, SCHCH2), 37.08 (u,
PhCH2), 43.52 (u, NCH2), 61.73 (d, SCH), 126.67 (d, C-p-PhC),
128.48 (d), 128.97 (d), 129.09 (d), 129.10 (d, o/m-PhC), 133.21 (d, S-
p-PhC), 136.39 (u), 137.17 (u) (ipso-PhC).
From 4a (501 mg, 2.76 mmol) and MeI; yield: 508 mg (94 %); color-
less solid; mp 85-86°C; [a]D +68.8 (c = 0.99, CHCl3); de = 89%.
1H NMR: d = 1.44 (d, J = 6.7 Hz, 3 H, CH3), 2.00–2.15 (m, 1 H,
NCH2CH2), 2.39–2.49 (m, 1 H, NCH2CH2), 3.19 (dq, J = 19.8,
6.7 Hz, 1 H, SCH), 3.63–3.72 (m, 1 H, NCH2), 3.99–4.06 (m, 1 H,
NCH2), 7.51–7.58 (m, 2 H, m-PhH), 7.60–7.66 (m, 1 H, p-PhH),
7.92–7.99 (m, 2 H, o-PhH).
MS (EI, 70 eV): m/z (%) = 285 (M+, 15), 194 (17), 160 (20), 131 (14),
125 (100), 91 (60), 77 (11), 70 (15), 65 (10).
Anal. C17H19NOS (285.4): calcd C, 71.54; H, 6.71 ; N, 4.91; found C,
71.38; H, 6.50; N, 4.88.
13C NMR: d = 12.96 (d, CH3), 32.67 (u, NCH2 CH2), 53.41 (u, NCH2),
62.16 (d, SCH), 129.30 (d), 129.60 (d) (o/m-PhC), 133.39 (d, p-PhC),
139.02 (u, ipso-PhC).
(+)-(1S,6S)-6-Isopropyl-1-phenyl-3,4,5,6-tetrahydro[1,2]thiazin-1-
oxide (7b):
From 4b (353 mg, 1.81 mmol) and isopropyl iodide; yield: 243 mg
(57%); colorless solid; mp 70°C; [a]D +54.8 (c =0.98, CHCl3); de
≥98%.
MS (EI, 70 eV): m/z (%) = 195 (M+, 9), 153 (29), 126 (11), 125 (100),
97 (13), 77 (14), 51 (12).
1H NMR: d = 0.70 (d, J = 6.7 Hz, 3 H, CH3), 1.00 (d, J = 6.7 Hz, 3 H,
CH3), 1.86–2.00 (m, 3 H, NCH2CH2, CHMe2), 2.14–2.29 (m, 2 H,
SCHCH2), 2.86 (ddd, J = 11.8, 4.7, 4.0 Hz, 1 H, SCH), 3.41–3.46 (m,
1 H, NCH2), 3.58–3.64 (m, 1 H, NCH2), 7.52–7.56 (m, 2 H, m-PhH),
7.59–7.63 (m, 1 H, p-PhH), 8.01–8.04 (m, 2 H, o-PhH).
13C NMR: d = 17.32 (d), 21.48 (d, CH3), 23.40 (u), 26.59 (u,
NCH2CH2, SCHCH2), 28.37 (d, CHMe2), 43.66 (u, NCH2), 66.52 (d,
S CH), 128.93 (d), 128.99 (d, o/m-PhC), 133.07 (d, p-PhC), 138.50 (u,
ipso-PhC).
Anal. C10H13NOS (195.2): calcd C, 61.50; H, 6.71; N, 7.17; found C,
61.11; H, 6.39; N 7.02.
(+)-(1S,5R)-5-Benzyl-1-phenyl-4,5-dihydro-3H-isothiazol-1-oxide
(6a):
From 4a (480 mg, 2.65 mmol) and benzyl bromide; yield: 611 mg
(85%); colorless solid; mp 108 °C; [a]D +91.3 (c = 0.75, CHCl3); de
≥98%.
1H NMR: d = 2.10–2.25 (m, 1 H, NCH2CH2), 2.32–2.34 (m, 1 H,
NCH2CH2), 3.07 (dd, J = 14.4, J = 8.4 Hz, 1 H, PhCH2), 3.21 (dd, J
= 14.1, 6.7 Hz, 1 H, PhCH2), 3.34–3.46 (m, 1 H, SCH), 3.61–3.70 (m,
1 H, NCH2), 4.0l–4.08 (m, 1 H, NCH2), 7.09–7.13 (m, 2 H, C-o-
PhH), 7.15–7.21 (m, 3 H, C-m/p-PhH), 7.39–7.45 (m, 2 H, S-m-PhH),
7.52–7.57 (m, 1 H, S-p-PhH), 7.72–7.75 (m, 2 H, S-o-PhH).
13C NMR: d = 30.95 (u), 34.69 (u) (NCH2CH2, PhCH2), 53.22 (u,
NCH2), 68.29 (d, SCH), 126.78 (d, C-p-PhC), 128.57 (d), 128.95 (d),
128.98 (d), 129.55 (d) (o/m-PhC), 133.11 (d, S-p-PhC), 137.43 (u),
138.81 (u) (ipso-PhC).
MS (EI, 70 eV): m/z (%) = 237 (M+, 5), 194 (7), 125 (100), 112 (11),
70 (20), 55 (14).
Anal. C13H19NOS (237.3): calcd C, 65.78; H, 8.07; N, 5.90; found C,
65.42, H, 8.10; N, 5.81.
(+)-(1S,6S)-1-Phenyl-6-(2,4,6-trimethylbenzyl)-3,4,5,6-tetrahydro-
[1,2]thiazin-1-oxide (8b):
From 4b (864 mg, 4.42 mmol) and 2,4,6-trimethylbenzyl chloride;
yield: 1.00 g (69%); colorless solid; mp 172–173°C; [a]D +106.5 (c
= 1.17, CHCl3); de ≥98%.
MS (EI, 70 eV): m/z (%) = 271 (M+, 4), 154 (18), 126 (11), 125 (100),
118 (20), 117 (38), 97 (10), 91 (21), 77 (14), 44 (40).
Anal. C16H17NOS (271.3): calcd C, 70.81; H, 6.31; N, 5.16; found C,
70.60; H, 6.51; N, 4.85.
1H NMR: d = 1.70–1.83 (m, 2 H, NCH2CH2), 1.91 [br s, 6 H, o-
C6H2(CH3)3CH2], 1.90–2.00 (m, 1 H, SCHCH2), 2.19 [s, 3 H, p-
C6H2(CH3)3CH2], 2.20–2.35 (m, 1 H, SCHCH2), 2.70 (dd, J = 13.4,
2.7 Hz, 1 H, C6H2Me3CH2), 2.89 (dd, J = 13.4, 11.1 Hz, 1 H,
C6H2Me3CH2), 2.99 (dddd, J = 12.4, 11.1, 3.7, 2.7 Hz, 1 H, SCH),
3.40–3.49 (m, 1 H, NCH2), 3.57–3.72 (m, 1 H, NCH2), 6.73 (s, 2 H,
C6H2Me3CH2), 7.53–7.60 (m, 2 H, m-PhH), 7.62–7.68 (m, 1 H, p-
PhH), 8.09–8.13 (m, 2 H, o-PhH).
(+)-(1S,6R)-6-Methyl-1-phenyl-3,4,5,6-tetrahydro[1,2]thiazin-1-ox-
ide (5b):
From 4b (394 mg, 2.02 mmol) and MeI; yield: 372 mg (88%); color-
less oil; [a]D +102.1 (c = 0.82, CHCl3); de = 90%.

June 1998
SYNTHESIS
925
13C NMR:
d = 19.78 [d, o-C6H2(CH3)3CH2], 20.72 [d, p-
C6H2Me3CH2), 133.53 (d, S-p-PhC), 136.21 (u, o-C6H2Me3CH2),
136.66 (u, S-ipso-PhC).
C6H2(CH3)3CH2], 26.21 (u), 26.68 (u) (NCH2CH2, SCHCH2), 29.64
(u, C6H2Me3CH2), 43.55 (u, NCH2), 60.61 (d, SCH), 129.01 (d),
129.25 (d), 129.37 (d) (S-o/m-PhC, m-C6H2Me3CH2), 130.07 (u, p-
C6H2Me3CH2), 133.37 (d, S-p-PhC), 135.99 (u, ipso-C6H2Me3CH2),
136.86 (u, o-C6H2Me3CH2), 138.71 (u, S-ipso-PhC).
MS (EI, 70 eV): m/z (%) = 327 (M+, 2), 202 (21), 194 (14), 159 (10),
134 (11), 133 (100), 131 (12), 129 (10), 125 (90), 118 (15), 117 (18),
105 (14), 97 (10), 91 (14), 77 (23), 70 (47).
Anal. C20H25NOS (327.4): calcd C, 73.35; H, 7.69; N, 4.28; found C,
72.97; H, 7.84; N, 3.96.
MS (EI, 70 eV): m/z (%) = 327 (M+, 7), 202 (22), 194 (21), 159 (12),
134 (11), 133 (98), 131 (12), 129 (11), 125 (100), 119 (11), 118 (16),
117 (20), 115 (10), 105 (13), 91 (14), 77 (19), 70 (48).
(+)-(1S,6S)-6-Benzyl-6-methyl-1-phenyl-3,4,5,6-tetrahydro[1,2]thi-
azin-1-oxide (9):
Anal. C20H25NOS (327.4): calcd C, 73.35; H, 7.69; N, 4.28; found C,
73.12; H, 7.83; N, 4.25.
From 5b (198 mg, 0.95 mmol) and benzyl bromide; yield: 119 mg
(42%); colorless oil; [a]D +45.05 (c = 1.90, CHCl3); de ≥98%.
1H NMR: d = 1.14 (s, 3 H, CH3), 1.50–1.56 (m, 1 H, NCH2CH2),
1.70–l.80 (m, 1 H, NCH2CH2), 1.81–1.99 (m, 1 H, SCCH2),
2.44–2.56 (m, 1 H, SCCH2), 2.72 (d, J = 13.1 Hz, 1 H, PhCH2), 3.38
(d, J = 13.1 Hz, 1 H, PhCH2), 3.40–3.48 (m, 1 H, NCH2), 3.62–3.74
(m, 1 H, NCH2), 7.01–7.04 (m, 2 H, C-o-PhH), 7.21–7.24 (m, 3 H, C-
m/p-PhH), 7.52–7.59 (m, 2 H, S-m-PhH), 7.62–7.69 (m, 1 H, S-p-
PhH), 8.05–8.08 (m, 2 H, S-o-PhH).
(+)-(1S,6S)-6-Methyl-1-phenyl-3,4,5,6-tetrahydro[1,2]thiazin-1-ox-
ide (epi-5b):
From 5b (30 mg, 0.14 mmol) and CF3CO2H (82 mg, 0.72 mmol), a
mixture of epi-5b and 5b in a ratio of 82:18 (27 mg, 90%) was ob-
tained as a colorless oil; [a]D +30.8 (c = 1.30, CHCl3).
1H NMR: d = 1.07 (d, J = 7.1 Hz, 3 H, CH3), 1.43–1.54 (m, 1 H,
NCH2CH2), 1.73–2.03 (m, 2 H, NCH2CH2, SCHCH2), 2.72–2.85 (m,
1 H, SCHCH2), 3.21 (qdd, J = 7.1, 3.7, 3.5 Hz, 1 H, SCH), 3.47–3.53
(m, 1 H, NCH2), 3.65–3.76 (m, 1 H, NCH2), 7.50–7.57 (m, 2 H, m-
PhH), 7.58–7.65 (m, 1 H, p-PhH), 8.00–8.05 (m, 2 H, o-PhH).
13C NMR: d = 16.28 (d, CH3), 17.41 (u, NCH2CH2), 27.86 (u,
SCHCH2), 43.28 (u, NCH2), 52.88 (d, SCH), 128.80 (d), 129.25 (d, o/
m-PhC), 133.12 (d, p-hC), 136.63 (u, ipso-PhC).
13C NMR: d = 20.62 (d, CH3), 20.34 (u), 32.37 (u) (NCH2CH2,
SCCH2), 43.11 (u), 43.53 (u) (NCH2, PhCH2), 58.96 (u, SC), 126.76
(d, C-p-PhC), 128.05 (d), 128.61 (d), 130.53 (d), 130.80 (d) (o/m-
PhC), 133.22 (d, S-p-PhC), 134.30 (u), 134.91 (u) (ipso-PhC).
MS (EI, 70 eV): m/z (%) = 299 (M+, 2), 208 (60), 174 (10), 126 (10),
125 (100), 91 (36), 77 (12).
HRMS (C18H21NOS): m/z calcd 299.134387; found 299.134580.
(–)-(1S,6R)-6-Benzyl-1-phenyl-3,4,5,6-tetrahydro(1,2)thiazin-1-ox-
ide (epi-6b):
From 6b (225 mg, 0.79 mmol) and CF3CO2H (0.45 g, 3.94 mmol),
epi-6b (205 mg, 91%) was obtained with de = 89%. Chromatography
(EtOAc) gave pure epi-6b (180 mg, 80%) as a colorless solid; mp
63–64 °C; [a]D –35.4 (c = 1.18, CHCl3).
(+)-(1S,6R)-6-Benzyl-6-methyl-1-phenyl-3,4,5,6-tetrahydro[1,2]thi-
azin-1-oxide (epi-9):
From 6b (216 mg, 0.76 mmol) and MeI; yield: 218 mg (96%); color-
less oil; [a]D +31.98 (c = 1.06, CHCl3); de ≥98%.
1H NMR: d = 1.24 (s, 3 H, CH3), 1.54–1.63 (m, 1 H, NCH2CH2),
1.72–l.81 (m, 1 H, NCH2CH2), 1.98 (d, J = 13.1 Hz, 1 H, PhCH2),
2.16–2.41 (m, 2 H, SCCH2), 3.50–3.58 (m, 1 H, NCH2), 3.58 (d, J =
13.1 Hz, 1 H, PhCH2), 3.65–3.77 (m, 1 H, NCH2), 7.00–7.05 (m, 2 H,
C-o-PhH), 7.19–7.28 (m, 3 H, C-m/p-PhH), 7.53–7.60 (m, 2 H, S-m-
PhH), 7.61–7.68 (m, 1 H, S-p-PhH), 8.06–8.09 (m, 2 H, S-o-PhH).
13C NMR: d = 22.70 (d, CH3), 21.11 (u), 30.82 (u) (NCH2CH2,
SCCH2), 39.38 (u), 43.29 (u) (NCH2, PhCH2), 59.87 (u, SC), 127.00
(d, C-p-PhC), 128.33 (d), 128.82 (d), 130.43 (d), 130.47 (d) (o/m-
PhC), 133.36 (d, S-p-PhC), 134.37 (u), 135.57 (u) (ipso-PhC).
MS (EI, 70 eV): m/z (%) = 299 (M+, 3), 208 (49), 174 (13), 126 (11),
125 (100), 91 (28), 57 (14), 55 (11).
1H NMR: d = 1.44–1.48 (m, 1 H, NCH2CH2), 1.86–2.03 (m, 2 H,
NCH2CH2, SCHCH2), 2.50 (dd, J = 13.7, 4.3 Hz, 1 H, PhCH2),
2.53–2.61 (m, 1 H, SCHCH2), 2.83 (dd, J = 13.7, 11.3 Hz, 1 H,
PhCH2), 3.32 (dddd, J = 11.3, 4.3, 4.3, 4.0 Hz, 1 H, SCH), 3.54–3.58
(m, 1 H, NCH2), 3.71–3.77 (m, 1 H, NCH2), 6.94–6.96 (m, 2 H, C-o-
PhH), 7.15–7.24 (m, 3 H, C-m/p-PhH), 7.54–7.57 (m, 2 H, S-m-PhH),
7.61–7.64 (m, 1 H, S-p-PhH), 8.07–8.10 (m, 2 H, S-o-PhH).
13C NMR: d = 17.59 (u, NCH2CH2), 23.61 (u, SCH CH2), 34.99 (u,
PhCH2), 43.31 (u, NCH2), 58.41 (d, SCH), 126.73 (d, C-p-PhC),
128.68 (d), 128.97 (d), 129.39 (d) (o/m-PhC), 133.30 (d, S-p-PhC),
136.49 (u), 136.77 (u) (ipso-PhC).
MS (EI, 70 eV): m/z (%) = 285 (M+, 10), 194 (15), 160 (57), 131 (16),
126 (10), 125 (100), 117 (11), 104 (10), 97 (13), 91 (57), 78 (10), 77
(17), 65 (10), 51 (10).
HRMS (C18H21NOS): m/z calcd 299.134387; found 299.134292.
Anal. C17H19NOS (285.4): calcd C, 71.54; H, 6.71; N, 4.91; found C,
71.21; H, 6.78; N, 4.87.
(+)-(S)-S-Methyl-S-phenyl-N-triphenylmethylsulfoximine (H-Ib):
To a solution of 1 (0.50 g, 3.22 mmol) in pyridine (15 mL) was added
slowly chlorotriphenylmethane (1.80 g, 6.44 mmol). After stirring the
mixture for 7 h at r.t., brine (30 mL) was added and the mixture was
extracted with EtOAc (3 ´ 50 mL). After washing the combined or-
ganic phases with 0.1 M HCl (3 ´ 50 mL), satd aq NaHCO3 solution
(2 ´ 50 mL) and water, they were dried (MgSO4) and concentrated in
vacuum. Purification of the residue by chromatography (50% hexane/
EtOAc) gave H-Ib (0.85 g, 66%) as a colorless solid; mp 212–213°C,
[a]D +110.0 (c = 1.01, THF).
(–)-(1S, 6R)- 1-Phenyl-6-(2,4,6-trimethylbenzyl)-3,4,5,6-tetrahydro-
[1,2]thiazin-1-oxide (epi-8b):
From 8b (642 mg, 1.96 mmol) and CF3CO2H (671 mg, 5.88 mmol),
epi-8b (578 mg, 90%) was obtained with de = 81%. Chromatography
(EtOAc) gave pure epi-8b (480 mg, 75%) as a colorless solid; mp
125–126°C; [a]D –64.0 (c = 1.09, CHCl3).
1H NMR: d = 1.54–1.63 (m, 1 H, NCH2CH2), 1.79–l.90 (m, 1 H,
NCH2CH2), 2.10 [br s, 6 H, o-C6H2(CH3)3CH2], 2.06–2.17 (m, 1 H,
SCHCH2), 2.22 [s, 3 H, p-C6H2(CH3)3CH2], 2.40 (dd, J = 14.4,
2.4 Hz, 1 H, C6H2Me3CH2), 2.42–2.53 (m, 1 H, SCHCH2), 2.85 (dd,
J = 13.8, 12.1 Hz, 1 H, C6H2Me3CH2), 3.19 (dddd, J = 12.1, 4.7, 4.4,
2.4 Hz, 1 H, SCH), 3.55–3.64 (m, 1 H, NCH2), 3.72–3.83 (m, 1 H,
NCH2), 6.79 (s, 2 H, C6H2Me3CH2), 7.57–7.72 (m, 3 H, m/p-PhH),
8.16–8.20 (m, 2 H, o-PhH).
1H NMR: d = 2.75 (s, 3 H, CH3), 7.06–7.20 (m, 9 H, PhH), 7.24–7.41
(m, 3 H, m/p-PhH), 7.50–7.55 (m, 6 H, C-o-PhH), 7.64–7.68 (m, 2 H,
S-o-PhH).
13C NMR: d = 42.88 (u, CPh3), 47.81 (d, CH3), 126.26 (d, C-p-PhC),
127.31 (d), 128.53 (d) (S-o/m-PhC), 127.35 (d), 129.16 (d) (C-o/m-
PhC), 131.39 (d, S-p-PhC), 143.33 (u, S-ipso-PhC), 147.48 (u, C-
ipso-PhC).
MS (El, 70 eV): m/z (%) = 320 (M+ - Ph, 35), 258 (21), 257 (100),
256 (12), 243 (15), 180 (52), 165 (20), 77 (33).
13C NMR: d = 19.08 (u), 23.64 (u), 28.43 (u) (NCH2CH2, SCHCH2,
C6H2Me3CH2), 20.38 [d, o-C6H2(CH3)3CH2], 20.81 [d, p-
C6H2( CH3)3CH2], 43.43 (u, NCH2), 57.78 (d, SCH), 128.96 (d),
129.51 (d), 129.84 (d) (S-o/m-PhC, m-C6H2Me3CH2), 130.93 (u. p-
Anal. C26H23NOS (397.5): calcd C, 78.55 ; H, 5.83; N, 3.52; found C,
78.20; H, 6.05; N, 3.72.

926
Feature Article
SYNTHESIS
1H NMR: d = 1.28–2.10 (m, 11 H), 2.20–2.49 (m, 3 H), 3.65 (t, J =
6.4 Hz, 2 H, OCH2).
Conjugate Addition with Cuprates Containing Sulfonimidoyl
Carbanions (Scheme 6); General Procedure:
13C NMR: d = 25.23 (u), 29.85 (u), 31.29 (u), 32.71 (u) (COCH2CH2,
COCH2CH2CH2, OCH2CH2, OCH2CH2CH2), 38.94 (d, CHCH2),
41.48 (u), 48.14 (u) (COCH2, COCH2), 62.88 (u, OCH2).
MS (EI, 70 eV): m/z (%) = 157 (M+ + 1, 9), 156 (M+, 6), 112 (12), 98
(10), 97 (100), 96 (10), 69 (19), 68 (14), 67 (41), 57 (13), 56 (13), 55
(55), 53 (10).
To a solution of the sulfoximine (1.0 mmol) in THF (5 mL) at –50°C
was added BuLi (1.0 mmol, 0.62 mL of 1.6 M in hexane). The result-
ing mixture was warmed to r.t. and stirred for 10 min. Subsequently
CuI (190 mg, 1.0 mmol) was added at 0 °C and the mixture was stirred
for 10 min at this temperature. After cooling the mixture to –78°C, the
lithiumorganyl (1.0 mmol) was added and the mixture was stirred for
l0 min at 0°C. The resulting mixture was cooled to –78°C and the
enone (1.0 mmol) was added dropwise. After stirring the mixture for
1.5 to 2 h at this temperature, a 10:1 mixture of satd aq NH4Cl and
concd aq NH3 was added. The resulting mixture was extracted with
Et2O (3 ´ 20 mL). The combined organic phases were dried (MgSO4)
and concentrated in vacuum. Purification of the residue by chroma-
tography (50% hexane/EtOAc) afforded the addition product. In ad-
dition, the sulfoximine was recovered quantitatively by chroma-
tography. a-Alkylated sulfoximines were isolated as a mixture of
epimers.
HRMS (C9H16O2): m/z calcd 156.11503 ; found 156.11573.
(–)-(R)-Toluene-4-sulfonic Acid 3-(3-Oxocyclohexyl)propyl Ester
(26):
To a solution of 25 (90 mg, 0.58 mmol) and p-TsCl (121 mg,
0.63 mmol) in CH2Cl2 (3 mL) at 0°C was added NEt3 (0.2 mL). After
stirring the mixture 20 h at this temperature, satd aq NH4Cl solution
was added. The resulting mixture was extracted with CH2Cl2 (3 ´ 20
mL). The combined organic phases were dried (MgSO4) and concen-
trated in vacuum. Purification of the residue by chromatography
(50% hexane/EtOAc) afforded 26 (107 mg, 60%) as a colorless oil;
[a]D –4.35 (c = 2.0, CH2Cl2).
(+)-(R)-3-Phenylcyclohexanone (16b):
1H NMR: d = 1.22–1.46 (m, 3 H), 1.51–1.75 (m, 4 H), 1.77–2.08 (m,
3 H), 2.17–2.38 (m, 3 H), 2.46 (s, 3 H, CH3), 4.01 (t, J = 6.2 Hz, 2 H,
OCH2), 7.36 (m, 2 H, SO2-m-PhH), 7.78 (m, 2 H, SO2-o-PhH).
13C NMR: d = 21.69 (d, CH3), 25.12 (u), 26.15 (u), 31.06 (u), 32.23
(u) (COCH2CH2, COCH2CH2CH2, OCH2CH2, OCH2CH2CH2),
38.44 (d, CHCH2), 41.40 (u), 47.87 (u, COCH2, COCH2), 70.48 (u,
OCH2), 127.92 (d), 129.96 (d) (o/m-PhC), 133.08 (u, p-PhC), 144.94
(u, ipso-PhC), 211.31 (u, CO).
From 10b (101 mg, 1.05 mmol), H-Ib (413 mg, 1.05 mmol), BuLi
(1.05 mmol, 0.66 mL of 1.6 M in hexane) and PhLi (1.05 mmol,
0.58 mL of 1.8 M in cyclohexane/ether, 7:3), 16b (143 mg, 78%) was
obtained as a colorless oil; [a]D +9.0 (c = 0.90, CHCl3); ee = 49%
[GC, octakis-(2,3-O-dipentyl-6-O-methyl)-g-cyclodextrin column:
Rf (16b) = 24.6 min, Rf (ent-16b) = 24.8 min].
(–)-(S)-3-Butylcyclopentanone (15a):
MS (EI, 70 eV): m/z (%) = 311 (M+ + 1, 9), 310 (M+, 29), 155 (44),
139 (16), 138 (11), 137 (11), 110 (84), 97 (100), 96 (23), 95 (24), 91
(45), 82 (21), 81 (11), 69 (13), 68 (10), 67 (35), 65 (15), 55 (39).
Anal. C16H22O4S (310.4): calcd C, 61.91; H, 7.14; found C, 61.68; H,
7.36.
From 10a (35 mg, 0.43 mmol), 8b (156 mg, 0.48 mmol), BuLi
(0.48 mmol, 0.30 mL of 1.6 M in hexane) and BuLi (0.43 mmol, 0.27
mL of 1.6 M in hexane), 15a (48 mg, 80%) was obtained as a color-
less oil; ee = 93% [GC, octakis-(2,3-di-O-pentyl-6-O-methyl)-g-cy-
clodextrin column: Rf (15a) = 20.2 min, Rf (ent-15a) = 21.0 min].
ent-15a: [a]D +66.5 (c = 1.65, toluene); ee = 49%.
(+)-(1S,6S)-Bicyclo[4.3.0]nonan-2-one (27):
To a solution of CuI (74 mg, 0.39 mmol) in THF (3 mL) at –40°C was
added MeLi (0.39 mmol, 0.24 mL of 1.6 M in Et2O) and the mixture
was stirred for 45 min at this temperature. After cooling the mixture
to –78°C, it was treated with a solution of 26 (0.13 mmol, 40 mg) in
THF (3 mL). The mixture was stirred for 15 h and warmed slowly to
r.t. Subsequently a mixture of satd aq NH4Cl and concd aq NH3 (10:1)
was added and the solution was extracted with Et2O (3 ´ 30 mL). The
combined organic phases were dried (MgSO4) and concentrated in
vacuum. Purification of the residue by chromatography (50% hexane/
EtOAc) afforded 27 (16 mg, 90%) as a colorless oil; [a]D +16.9 (c =
0.80, THF); ee = 78% [GC, octakis-(2,3-di-O-pentyl-6-O-methyl)-g-
cyclodextrin column: Rf (27) = 31.4 min, Rf (ent-27) = 30.3 min].
1H NMR: d = 1.25–2.11 (m, 10 H), 2.24–2.51 (m, 3 H), 2.56–2.66 (m,
1 H).
(–)-(S)-3-Butylcyclohexanone (15b):
From 10b (40 mg, 0.41 mmol), 8b (151 mg, 0.46 mmol), BuLi
(0.46 mmol, 0.29 mL of 1.6 M in hexane) and BuLi (0.41 mmol, 0.26
mL of 1.6 M in hexane), 15b (58 mg, 90%) was obtained as a color-
less oil; [a]D –7.84 (c = 1.70, toluene); ee = 99% [GC, octakis-(2,3-di-
O-pentyl-6-O-methyl)-g-cyclodextrin column: Rf (15b) = 44.7 min,
Rf (ent-15b) = 44.0 min].
(–)-(S)-3-Butylcycloheptanone (15c):
From 10c (51 mg, 0.47 mmol), 8b (173 mg, 0.53 mmol), BuLi
(0.52 mmol, 0.32 mL of 1.6 M in hexane) and BuLi (0.47 mmol, 0.29
mL of 1.6 M in hexane), 15c (70 mg, 90%) was obtained as a colorless
oil; ee = 77% [GC, octakis-(2,3-di-O-pentyl-6-O-methyl)-g-cyclo-
dextrin column: Rf (15c) = 23.0 min, Rf (ent-15c) = 23.6 min].
ent-15c: [a]D = +14.7 (c = 1.11, CHCl3); ee = 43%.
13C NMR: d = 23.14 (u), 23.88 (u), 26.77 (u), 27.31 (u), 31.09 (u),
39.69 (u, CH2), 43.01 (d), 53.21 (d, CH), 216.52 (u, CO).
GC/MS: m/z (%) = 138 (M+, 26), 110 (25), 97 (100), 95 (36), 94 (32),
82 (12), 81 (13), 79 (35), 68 (11), 67 (73), 55 (12), 54 (12), 53 (11).
Anal. C9H14O (138.2): calcd C, 78.21; H, 10.21; found C, 77.93; H,
10.31.
(–)-(S)-3-Methylcyclohexanone (23b):
From 10b (46 mg, 0.48 mmol), 8b (174 mg, 0.53 mmol), BuLi
(0.53 mmol, 0.33 mL of 1.6 M in hexane) and MeLi (0.48 mmol,
0.30 mL of 1.6 M in Et2O was evaporated and the residue dissolved
in 3 mL THF), 23b (27 mg, 50%) was obtained as a colorless oil; [a]D
–14.3 (c = 0.48, MeOH), ee = 86% [GC, permethyl-b-cyclodextrin
column: Rf (18) = 19.0 min, Rf (ent-18) = 18.9 min].
Financial support of this work by the Deutsche Forschungsgemein-
schaft (SFB 380) and the Fonds der Chemischen Industrie is grate-
fully acknowledged. We thank Dr. G. Raabe for the X-ray structure
analysis and Dr. J. Runsink for NOE experiments.
(+)-(R)-3-(3-Hydroxypropyl)cyclohexanone (25):
From 10b (81 mg, 0.85 mmol) and 3-(1-ethoxyethoxy)-
propyllithium14 (0.85 mmol, 1.30 mL of 0.65 M in THF), 25 (92 mg,
70%) was obtained after treatment of 24b with 2 M HCl and neutral-
ization with satd aq Na2CO3 solution as a colorless oil; [a]D +1.26 (c
= 1.03, MeOH); ee = 79% [GC, octakis-(2,6-di-O-pentyl-3-O-butyr-
yl)-g-cyclodextrin column: Rf (25) = 30.6 min, Rf (ent-25) =
30.7 min].
(1) For recent examples, see: (a) Hainz, R.; Gais, H.-J.; Raabe, G.
Tetrahedron: Asymmetry 1996, 7, 2505.
(b) Pyne, S. G.; Dong, Z. J. Org. Chem. 1996, 61, 5517.
(c) Reggelin, M.; Weinberger, H.; Gerlach, M.; Welcker, R.
J. Am. Chem. Soc. 1996, 118, 4765.

June 1998
(d) Pyne, S. G.; Dong, Z.; Skelton, B. W.; White, A. H. J. Org.
SYNTHESIS
927
treated as observed. The structure was solved by means of direct
methods as implemented in the XTAL3.2 package of crystallo-
graphic routines, employing GENSIN to generate structure in-
variant relationships and GENTAN for the general tangent
phasing procedure. The final full-matrix least-squares refine-
Chem. 1997, 62, 2337.
(2) (a) Johnson, C. R. In Comprehensive Organic Chemistry; Bar-
ton, D.; Ollis, W. D., Eds.; Pergamon Press: Oxford, 1979; Vol.
1, p 223.
(b) Barbachyn, M. R.; Johnson, C. R. In Asymmetric Synthesis;
Morrison, J. D.; Scott, J. W., Eds.; Academic Press: New York,
1984; Vol. 4, 227.
(c) Johnson, C. R. Aldrichimica Acta 1985, 18, 3.
(d) Pyne, S. G. Sulfur Reports 1992, 12, 57.
ment (on F) of 180 parameters terminated at R = 0.044 (Rw =
0.047) and an error of fit of 2.174. The chirality of 6b as shown
in the Figure was determined by calculation of Flack’s absolute
structure parameter [Xabs = 0.003(33)]. Crystallographic data
(excluding structure factors) for the structure have been deposi-
ted with the Cambridge Crystallographic Data Centre as supple-
mentary publication. Copies of the data can be obtained free of
charge from The Director, CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [fax:(internat.) +44 (0)1223 336033, e-mail: de-
posit@chemcrys.cam.ac.uk].
(3) (a) Harmata, M.; Jones, D. E. Tetrahedron Lett. 1995, 36, 4769.
(b) Harmata, M.; Herron, B. F. Tetrahedron 1991, 47, 8855.
(4) (a) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92, 771.
(b) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135.
(c) Lipshutz, B. H. In Organometallics in Synthesis; Schlosser,
M., Ed.; Wiley: New York, 1994; p 283.
(11) (a) Gais, H.-J.; Erdelmeier, I.; Lindner, H. J.; Vollhardt, J. An-
gew. Chem. 1986, 98, 914; Angew. Chem., Int. Ed. Engl. 1986,
25, 938.
(d) Alexakis, A. In Organocopper Reagents; Taylor, R. J. K.,
Ed.; Oxford University Press: Oxford; 1994, pp 159.
(e) Yamamoto, Y. In Stereoselective Synthesis (Houben-Weyl);
Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.,
Eds.; Thieme: Stuttgart, 1996; E21 Vol. 4, p 2041.
(f) Krause, N.; Gerold, A. Angew. Chem, 1997, 109, 194; An-
gew. Chem., lnt. Ed. Engl. 1997, 36, 186.
(b) Gais, H.-J.; Dingerdissen, U.; Krüger, C.; Angermund, K.
J. Am. Chem. Soc. 1987, 109, 3775.
(c) Gais, H.-J.; Lenz, D.; Raabe, G. Tetrahedron Lett. 1995, 36,
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(d) Müller, J. F. K.; Batra, R.; Spingler, B.; Zehnder, M. Helv.
Chim. Acta 1996, 79, 820.
(e) Müller, J. F. K.; Neuburger, M.; Zehnder, M. Helv. Chim.
Acta 1997, 80, 2182.
(5) Bund, J. Ph. D. Thesis, Universität Freiburg, 1991.
(6) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 8, 909.
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(8) 2-(2-Bromoethoxy)tetrahydropyrane
and
2-(3-chloropro- (12) (a) Johnson, C. R.; Zeller, J. R. Tetrahedron 1984, 40, 1225.
(b) S. G. Pyne, B. Dikic, Tetrahedron Lett. 1990, 36, 5231.
poxy)tetrahydropyrane were prepared from 2-bromoethanol
and 3-chloropropan-1-ol, respectively, according to Genardy, (13) Johnson, C. R.; Dhanoa, D. S. J. Org. Chem. 1987, 52, 1885.
K. F.; Floyd, M. B.; Poletto, J. F.; Weiss, M. J. J. Org. Chem. (14) Eaton, P. E.; Cooper, G. F.; Johnson, R. C.; Mueller, H. J. Org.
1979, 44, 1438.
Chem. 1972, 37, 1947.
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R.; Katekar, G. F.; Huxol, R. F.; Janiga, E. R. J. Am. Chem. Soc.
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(10) X-ray crystallographic analysis of 6b:
108, 7114.
(b) Posner, G. H.; Frye, L. L. Isr. J. Chem. 1984, 24, 88.
(c) Rossiter, B. E.; Eguchi, M.; Miao, G.; Swingle, N. M.; Her-
nandez, A. E.; Vickers, D.; Fluckiger, E.; Patterson, R. G.; Red-
dy, K. V. Tetrahedron 1993, 49, 965.
C17H19NOS (Mr = 267.27), monoclinic, space group P 21 (No.
4), a = 5.8377(5) Å, b = 9.173(2) Å, c = 14.6265(5) Å, a = 90.0°,
b = 97.665(5)°, g = 90.0°, V = 776.22 Å3, Z = 2, Dcalc = 1.221
(d) Langer, W.; Seebach, D. Helv. Chim. Acta 1979, 62, 1710.
g·cm–3, CuKa radiation, crystal dimensions = 0.3 ´ 0.3 ´ (16) (a) Cicero, B. L.; Weisbuch, F.; Dana, G. J. Org. Chem. 1981,
0.3 mm, 3641 reflections were measured up to qmax = 75.2° at
298 K on an CAD4 Enraf-Nonius diffractometer with graphite
employing monochromated CuKa radiation (l = 1.54179 Å).
46, 914.
(b) Dana, G.; Weisbuch, F.; Drancourt, J.-M. Tetrahedron 1985,
41, 1233.
3122 symmetry independent reflections, m(CuKa) = 17.5 cm–1, (17) Kauffman, G. B.; Teter, L. A. Inorg. Synth. 1963, 7, 10.
no absorption correction, 2842 reflections with I > 2s (I) were