A mild synthetic procedure for the preparation of N-alkylated sulfoximines

Article abstract of DOI:10.1055/s-2002-28514

N-Alkylated sulfoximines have been synthesized in good yields by acylation of NH-sulfoximines followed by carbonyl reduction with complexed boranes. Enantiopure substrates react without racemization, and stereogenic centers originating from the acylating component are retained. If the acylation is performed by DCC coupling, this two-step procedure represents a rare example of a formal N-alkylation of sulfoximines under base-free conditions.

Full text of DOI:10.1055/s-2002-28514

PAPER
879
A Mild Synthetic Procedure for the Preparation of N-Alkylated Sulfoximines
P
rocedure for the
a
Preparatio
r
nof
N
-A
s
lkylated
S
t
ulfoxim
e
ine
s
n Bolm,* Christian P. R. Hackenberger, Oliver Simi , Marinella Verrucci, Dirk Müller, Frank Bienewald
Institut für Organische Chemie der RWTH Aachen, Professor-Pirlet-Strasse 1, 52056 Aachen, Germany
Fax +49(241)8092391; E-mail: Carsten.Bolm@oc.rwth-aachen.de
Received 14 February 2002; revised 27 March 2002
Dedicated to Professor Dr. H.-J. Gais with best wishes on the occasion of his 60th birthday
a straightforward alternative for the preparation of N-
Abstract: N-Alkylated sulfoximines have been synthesized in good
yields by acylation of NH-sulfoximines followed by carbonyl re-
duction with complexed boranes. Enantiopure substrates react with-
out racemization, and stereogenic centers originating from the
alkylated sulfoximines 6 and found that through acylation
of 1 to give 5 and subsequent borane reduction, a wide va-
riety of 6 can be obtained in good yield.14 Furthermore, we
acylating component are retained. If the acylation is performed by ensured that the mild reaction conditions of this two-step
DCC coupling, this two-step procedure represents a rare example of
protocol allow a racemization-free preparation of chiral
a formal N-alkylation of sulfoximines under base-free conditions.
sulfoximines with stereogenic centers in the alkyl substi-
Keywords: acylation, borane, chirality, reduction, sulfoximine
tuent of the imine nitrogen.
O
Me
( )2
Eschweiler-Clark
S
N
N
N
Sulfoximines, the monoaza analogues of sulfones, gained
much attention in synthetic organic chemistry1 due to their
high stability towards racemization. Chiral sulfoximines
have been attractive auxiliaries in asymmetric synthesis,2
ligands in enantioselective catalysis,3 and building-blocks
of pseudopeptides.4 Such extensive use demands an easy
access to a variety of enantiopure compounds in high
quantities and in both enantiomeric forms. Common syn-
thetic protocols of NH-sulfoximines 1 rely on the resolu-
tion of diastereomeric sulfoximine salts5 or the
stereospecific imination of the corresponding enantiomer-
ically pure sulfoxides.6 The latter are readily available by
asymmetric oxidation of sulfides7 or stereospecific substi-
tution of chiral sulfinyl derivatives with organometallic
reagents.8
R2
R1
2
Michael-type
additions
CO2R3
O
S
R2
R1
3
R4
Pd-catalyzed
arylation
O
O
H
S
S
N
R2
R2
R1
R1
4
1
O
N
O
R5
acylation
S
R2
R1
5
reduction
R5
nucleophilc
substitution
N-Substituted sulfoximines are also of substantial interest,
and several methods for their synthesis starting from NH-
sulfoximines 1 have been developed (Scheme).1 For ex-
ample, Eschweiler–Clark conditions allow the introduc-
tion of a methyl group to give 2,9,10 base-catalyzed
Michael-type additions to , -unsaturated esters afford
sulfoximines 3,10a and palladium catalyzed N-arylations
yield 4.11 Nucleophilic substitutions have also been used
for N-alkylations of sulfoximines.12 They involve a strong
base such as butyl lithium or metal hydrides, which depro-
tonate the rather acidic imine hydrogen13 giving a weakly
nucleophilic anion, which is then expected to react with an
appropriate electrophile. Unfortunately, by this route cer-
tain compounds remain inaccessible because either the
anion or the electrophile is not reactive enough due to
their steric or electronic properties. In addition, if optical-
ly active products are to be synthesized the requirement of
a base limits the substrate range, to those compounds that
are not prone to racemization. We therefore searched for
O
S
N
R2
R1
6
Scheme
We began our studies by investigating the reduction of
simple N-acylated sulfoximines, which are accessible in
very high yields by treatment of NH-sulfoximines with al-
iphatic or aromatic acyl chlorides in the presence of weak
bases such as pyridine or triethylamine (Table 1). Based
on the work by Brown and coworkers, who have demon-
strated the use of boron reagents in the reduction of
amides to amines,15 we expected complexed boranes to be
applicable to the reduction of acylated sulfoximines. To
our delight we found that 5a, derived from (S)-S-phenyl-
S-methyl-sulfoximine (1a)16 and acetyl chloride, reacted
smoothly with borane–dimethylsulfide complex affording
6a in 70% yield (Table 1, entry 1). Other acylated sulfox-
imines prepared from 1a and aliphatic acyl chlorides
could be reduced equally well furnishing the desired prod-
ucts in good yields (Table 1). Particularly noteworthy is
the synthesis of 6b, which contains a neo-pentyl group,
Synthesis 2002, No. 7, 21 05 2002. Article Identifier:
1437-210X,E;2002,0,07,0879,0887,ftx,en;T02002SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

880
C. Bolm et al.
PAPER
since this compound cannot be obtained by standard SN2 Recently, we described novel pseudopeptides with sulfox-
type substitution reactions. In the reduction of 5c the ap- imines in the peptide chain.4 Their synthesis involved
plicability of catecholborane and borane–THF adduct as DCC/HOBt couplings between appropriately substituted
reducing agent was tested. Both proved to be excellent al- sulfoximines and N-protected -amino acids, affording N-
ternatives to BH3 SMe2, giving 6c in 87% and 70% yield, acylated sulfoximines 9 in excellent yields. We now won-
respectively. To our surprise, benzoyl-containing sub- dered if such amino acid-derived compounds could also
strates did not react at all or afforded the corresponding re- be reduced with complexed boranes to give -aminoalkyl-
duction products in low yield (Table 1, entries 5–9). In substituted sulfoximines 10.22 Formally, this reaction se-
this case, changing the borane source and extending the quence with the initial DCC/HOBt mediated acylation,
reaction time resulted only in a marginal improvement of would then represent an example of an N-alkylation of
the chemical yield.17 Furthermore, with BH3 THF as the sulfoximines under base-free conditions. Furthermore,
reductant, significant amounts of acyl cleavage products such transformations were expected to be mild enough to
were observed. Thus, for these substrates the standard SN2 fully retain the stereochemistry at the stereogenic carbon
type substitution reaction with benzyl halides12 is still ad- atom in the alkyl substituent.
vantageous over the two-step acylation/reduction se-
quence described here.
The reaction protocol was first optimised, by studying the
reduction of 9a with different reagents (Table 3, Entries
Next, we focused our attention on the synthesis of ethyl- 1–3). Clearly, BH3 THF was the best reductant giving 10a
ene-bridged C2-symmetric bissulfoximines 8.18 These in 68% yield. With BH3 SMe2 the yield of 10a was lower,
compounds appeared attractive due to their potential ap- and with catecholborane no conversion of 9a was ob-
plication as ligands in metal catalysis and their structural served. In light of the smooth reduction of 5d with cate-
analogy to salens.19,20 Again, the first studies were per- cholborane (Table 1, entry 4), the latter result was
formed with (S)-S-methyl-S-phenylsulfoximine (1a). surprising. It was analogous to the attempts to reduce ben-
Treatment of 1a with oxalyl chloride afforded 7a in 90% zoylated compounds 5e and 5f, which also did not react
yield. Subsequent reduction with BH3 THF gave the de- when treated with catecholborane. Leucine and phenyla-
sired product 8a in 68% yield. This reaction sequence was lanine derived compounds 9b and 9c reacted with
then applied to a variety of sulfoximines containing differ- BH3 THF in a similar manner to 9a, giving the corre-
ent alkyl and aryl groups.21 Generally, very good yields sponding products in good yields (Table 3, Entries 4 and
were achieved in the acylation step (up to 97%). The 5).
yields of the reduction varied between 50% and 71%
(Table 2).
Table 1 Reaction Sequence for the Synthesis of N-Alkylated Sulfoximinesa
O
RCOCl,
DMAP (cat.)
O
H
O
R
HBX2
O
R
S
N
S
N
S
N
pyridine or
NEt3 in CH2Cl2
Ph
Me
CH2Cl2
Ph
Me
Ph
Me
1a
5
6
Entry
5, 6
R
Yield (%) 1
5
Reducing Agent
BH3 SMe2
Yield (%) 5 6
1
2
3
4
5
6
7
8
9
(S)-a
(S)-b
(S)-c
(S)-c
(S)-d
(S)-d
(S)-e
(S)-e
(S)-e
Me
t-Bu
99
98
87
70
62
87
70
0b
BH3 SMe2
n-Heptyl
n-Heptyl
2-BrPh
2-BrPh
4-ClPh
4-ClPh
4-ClPh
Catecholborane
BH3 THF
97
97
Catecholborane
BH3 THF
0c
Catecholborane
BH3 SMe2
0b
12
37
BH3 THF
a For conditions see experimental part.
b No conversion.
c No starting material recovered; mainly acyl cleavage product.
Synthesis 2002, No. 7, 879–887 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Procedure for the Preparation of N-Alkylated Sulfoximines
881
Table 2 Synthesis of C2-Symmetric Ethylene-bridged Bissulfoximinesa
O
N
O
N
(COCl)2,
DMAP (cat.)
H
O
O
O
O
O
HBX2
S
N
R2
R1
S
N
N S
S
S
R1
R2
R1
R2
CH2Cl2, 0 °C
R2
R1
CH2Cl2, 0 °C
R2
R1
1
7
8
Entry
1b
7 or 8
R1 for 1, 7 or 8
Me
R2 for 1, 7 or 8
Yield (%) 1
8
Yield (%) 7 8
(S,S)-a
(S,S)-b
(S,S)-c
(R,R)-d
(R,R)-e
(R,R)-f
(R,R)-g
(S,S)-h
Ph
80
88
85
68
72
93
85
97
68
66
65
50
66
69
54
71
2b
i-Pr
Ph
3b
c-Pentyl
Biphen
Ph
4c
Me
5c
3,5-(t-Bu)2-Ph
2-MeOPh
2-MeONaphth
Tol
Me
6b
Me
7c
Me
8c
2-MeOPh
a For conditions see experimental part.
b Entries taken from ref.19
c With catecholborane as the reducing agent.
Table 3 Synthesis of Amino Acid-derived Alkylated Sulfoximinesa
O
N
R
R
H
O
N-Boc-amino acid,
O
O
BH3•THF
S
N
DCC, HOBt
S
NHBoc
S
N
NHBoc
Ph
Me
CH2Cl2, 0 °C
CH2Cl2, 0 °C
Ph
Me
Ph
Me
1a
9
10
Entry
9 or 10
(S,S)-a
(S,S)-a
(S,S)-a
(S,S)-b
(S,S)-c
(S,S)-d
(S,R)-d
(S,S/R)-d
Amino acid
(S)-Ala
(S)-Ala
(S)-Ala
(S)-Leu
(S)-Phe
(S)-Val
(S)-Val
rac-Val
R
Yield (%)b 1
7
Time (h) 9 10
Yield (%)c 9 10
1
Me
Me
Me
i-Bu
Bn
92
14
6
68
50
0d
2c
3c
4
48
12
16
14
14
14
97
91
96
97
97
71
63
66
62
67
5
6
i-Pr
i-Pr
i-Pr
7
8
a For conditions see experimental part.
b Entries taken from ref.4b
c Use of BH3 THF as the reductant except in entry 2 (BH3 SMe2) and entry 3 (catecholborane).
d No conversion.
In order to ensure that the reduction process proceeded diastereomers and confirmed that no racemization had oc-
without racemization of the stereogenic center at the - curred during the carbonyl reduction.
carbonyl carbon, both diastereoisomers of 9d steming
In summary, we have described a straightforward synthet-
from (S)-1a and (S)-valine as well as (S)-1a and (R)-valine
ic route to N-alkylated sulfoximines including derivatives,
were synthesized and reduced (both separately and as a di-
which have previously been inaccessible. If a DCC/HOBt
astereomeric mixture; Table 3, Entries 6–8). Analysis by
mediated acylation is applied, the N-alkylation can be per-
1H NMR spectroscopy revealed the absence of undesired
formed under base-free conditions. As a consequence, this
Synthesis 2002, No. 7, 879–887 ISSN 0039-7881 © Thieme Stuttgart · New York

882
C. Bolm et al.
PAPER
tained by flash chromatography of the residue using silica gel and
EtOAc–hexanes, 1:1.
two-step process allows the preparation of chiral com-
pounds having stereogenic centers in N-alkyl substituents
without racemization. Further investigations are directed
towards the application of this methodology in the synthe-
sis of more complex molecules and pharmaceutical exper-
iments using the synthesized products are currently being
carried out.
(S)-N-Acetyl-S-methyl-S-phenyl-sulfoximine [(S)-5a]
[ ]D +11.1 (c 1.0, CHCl3).
IR (KBr): 3015, 2926, 1639, 1263, 1216, 1099, 1035, 977, 824, 747,
687 cm–1.
1H NMR (300 MHz, CDCl3): = 2.16 (s, 3 H), 3.34 (s, 3 H), 7.47–
7.61 (m, 3 H), 7.85–7.91 (m, 2 H).
All reactions employing anhydrous conditions were performed un-
der argon using standard Schlenk techniques. Solvents were dried
and distilled prior to use under an inert atmosphere (CH2Cl2 from
lithium aluminum hydride). Unless otherwise specified all starting
materials were purchased from commercial suppliers and were used
without further purification. (S)-S-Methyl S-phenyl sulfoximine
(1a) was prepared according to literature procedures.5e All other
sulfoximines were synthesized according to standard literature pro-
cedures.21 1H NMR and 13C NMR spectra were recorded using tet-
ramethyl silane (TMS) as internal standard. The abbreviation for
pseudo. Mass spectra were obtained with a Finnigan SSQ 7000 and
with a Varian MAT 212 S spectrometer. FT-IR spectra were record-
ed on a Perkin-Elmer PE-1760 FT. Elemental analyses were carried
out on a HERAEUS CHNO-Rapid instrument. Melting points were
measured with a Büchi B-540 and are uncorrected. Optical rotations
were obtained with a Perkin-Elmer PE-241 and were measured at
23 °C. Flash chromatography was performed using Merck silica gel
60, mesh 37–70 m or 230–400 m.
13C NMR (75 MHz, CDCl3): = 26.6, 43.9, 126.9, 129.5, 133.6,
138.6, 179.9.
+
MS (EI, 70 eV): m/z (%) = 182 [M – CH3 , 100], 156 (34), 94 (64),
77 (68), 65 (35), 51 (31).
Anal. Calcd for C9H11NO2S: C, 54.80; H, 5.62; N, 7.10. Found C,
54.62; H, 5.78; N, 7.33.
(S)-Pivaloyl-S-methyl-S-phenyl-sulfoximine [(S)-5b]
[ ]D +14.6 (c 1.0, CHCl3).
IR (KBr): 3054, 3021, 2982, 2957, 1636, 1288, 1213, 1184, 985,
847, 750, 531 cm–1.
1H NMR (300 MHz, CDCl3): = 1.15 (s, 9 H), 3.24 (s, 3 H), 7.48–
7.63 (m, 3 H), 7.86–7.91 (m, 2 H).
13C NMR (CDCl3) = 27.6, 41.3, 44.1, 127.0, 129.5, 133.5, 139.4,
188.3.
MS (EI, 70 eV): m/z (%) = 196 (2), 184 (5), 183 (10), 182 (M+–
Compounds 5 and 7 were prepared according to general procedure
A and compounds 9 according to general procedure C.4b The reduc-
tion of the acylated sulfoximines to compounds 6, 8, and 10 was
performed according to general procedure B.
C(CH3)3, 100), 125 (5), 93 (2).
Anal. Calcd for C12H17NO2S: C, 60.22; H, 7.16; N, 5.85. Found C,
60.15; H, 7.25; N, 5.80.
(S)-N-Octanoyl-S-methyl-S-phenyl-sulfoximine [(S)-5c]
[ ]D +9.8 (c 1.1, CHCl3); mp 142–145 °C.
Acylation of Sulfoximines; General Procedure A
To a solution of the sulfoximine (1 equiv) in CH2Cl2 (8 mL/mmol
reagent), was added base (pyridine or triethylamine, 1.3 equiv) at
0 °C followed by dropwise addition of the acyl chloride or acyl bro-
mide (1 equiv; with oxalyl chloride only 0.5 equiv). After stirring
for about 1 h the mixture was warmed to r.t. and stirred overnight.
Then, the solution was poured into ice water, and the resulting mix-
ture was extracted with CH2Cl2 (for a 1 mmol scale: 3 ca. 10 mL).
The combined organic extracts were dried (MgSO4), and the solvent
was evaporated under reduced pressure. Subsequent silica gel chro-
matography of the residue yielded the pure products.
IR (KBr): 3064, 3016, 2955, 2967, 2855, 1641, 1448, 1412, 1360,
1311, 1266, 1220, 1103, 1037, 1014, 996, 979, 848, 747, 687, 514
cm–1.
1H NMR (400 MHz, CDCl3): = 0.87 (t, J = 6.6 Hz, 3 H), 1.24–
1.36 (m, 8 H), 1.60–1.68 (m, 2 H), 2.40 (t, J = 7.6 Hz, 2 H), 3.34 (s,
3 H), 7.58–7.69 (m, 3 H), 7.95–7.99 (m, 2 H).
13C NMR (100 MHz, CDCl3): = 14.2, 22.3, 25.7, 29.1, 29.3, 31.8,
39.8, 44.2, 127.1, 129.7, 133.8, 139.1, 183.2.
MS (EI, DIP): m/z (%) = 281 (M+ + 1, 1), 210 (4), 197 (15), 182
(100), 156 (18), 92 (8).
Reduction of Acylated Sulfoximines; General Procedure B
At 0 °C in a vacuum dried Schlenck-flask a solution of the acylated
sulfoximine in freshly distilled CH2Cl2 (10 mL/mmol reagents) was
treated dropwise with the borane complex (3 equiv). After stirring
for 3 h at this temperature, the mixture was warmed to r.t., and stir-
ring was continued overnight. The mixture was carefully quenched
with MeOH and H2O (for a 1 mmol scale: 5 mL), and the resulting
mixture was extracted with CH2Cl2 (for a 1 mmol scale: 3 ca. 10
mL). The combined organic extracts were dried (MgSO4), and the
solvent was evaporated under reduced pressure. Subsequent silica
gel chromatography of the residue yielded the pure products.
Anal. Calcd for C15H23NO2S: C, 64.02; H, 8.24; N, 4.98. Found: C,
63.77; H, 8.29; N, 5.23.
(S)-N-2-Brombenzoyl-S-methyl-S-phenyl-sulfoximine [(S)-5d]
[ ]D +13.2 (c 0.5, CHCl3).
IR (KBr): 3064, 3018, 2927, 1733, 1634, 1587, 1476, 1467, 1448,
1430, 1299, 1257, 1222, 1148, 1117, 1095, 1046, 1028, 980, 837,
747, 686, 502 cm–1.
1H NMR (400 MHz, CDCl3): = 3.48 (s, 3 H), 7.22–7.35 (m, 2 H),
7.58–7.73 (m, 4 H), 7.79–7.82 (m, 1 H), 8.09–8.12 (m, 2 H).
13C NMR (100 MHz, CDCl3): = 44.3, 120.4, 127.2, 127.4, 129.8,
130.7, 131.3, 133.8, 134.1, 138.3, 138.4, 175.1.
MS (EI, DIP): m/z (%) = 340 (100), 339 (16), 338 (M+, 80), 260
(14), 246 (4), 244 (8), 236 (4), 202 (9), 200 (10), 198 (43), 180 (5),
156 (10), 141 (15), 122 (16).
DCC/HOBt Couplings of Sulfoximines with Amino Acids; Gen-
eral Procedure C
A solution of the N-Boc-protected amino acid (1 equiv), (S)-S-me-
thyl-S-phenyl sulfoximine (1a) (1 equiv), and HOBt (1 equiv) in
CH2Cl2 (8 mL/mmol reagents) was cooled to 0 °C and treated with
a solution of DCC (1 equiv) in CH2Cl2 (1 mL/mmol reagents). The
resulting mixture was stirred for 1 h at 0 °C and for 12 h at r.t. The
precipitate was filtered off, and the solvent was evaporated under
reduced pressure. If not otherwise stated, the pure product was ob-
Anal. Calcd for C14H12NO2SBr: C, 49.72; H, 3.58; N, 4.14. Found:
C, 49.71; H, 3.83; N, 4.23.
Synthesis 2002, No. 7, 879–887 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Procedure for the Preparation of N-Alkylated Sulfoximines
883
(S)-N-4-Chlorbenzoyl-S-methyl-S-phenyl-sulfoximine [(S)-5e]
[ ]D +10.4 (c 0.34, CHCl3).
(S)-N-(4-Chlorbenzyl)-S-methyl-S-phenyl-sulfoximine [(S)-6e]
[ ]D +10.1 (c 0.34, CHCl3).
IR (KBr): 3030, 2930, 1634, 1590, 1571, 1484, 1445, 1399, 1328,
1300, 1287, 1218, 1167, 1137, 1090, 1015, 979, 963, 930, 833, 763,
746, 687, 530 cm–1.
1H NMR (400 MHz, CDCl3): = 3.46 (s, 3 H), 7.35–7.40 (m, 2 H),
7.58–7.73 (m, 3 H), 8.01–8.12 (m, 4 H).
IR (KBr): 3062, 2926, 2853, 1466, 1445, 1408, 1310, 1241, 1174,
1141, 1086, 1068, 978, 956, 851, 784, 744, 690, 525 cm-1.
1H NMR (400 MHz, CDCl3): = 3.13 (s, 3 H), 3.95 [d (AB),
J = 14.6 Hz, 1 H], 4.14 [d (AB), J = 14.6 Hz, 1 H], 7.21–7.31 (m, 4
H), 7.51–7.65 (m, 3 H), 7.88–7.95 (m, 2 H).
13C NMR (100 MHz, CDCl3): = 44.4, 127.1, 128.2, 129.7, 130.8,
133.9, 134.1, 138.4, 138.8, 173.2.
13C NMR (100 MHz, CDCl3): = 45.1, 46.6, 128.1, 128.4, 128.8,
129.3, 131.9, 132.8, 139.3, 139.7.
MS (EI, DIP): m/z (%) = 293 (M+, 1), 279 (4), 278 (7), 200 (5), 182
(50), 156 (100), 141 (14), 140 (17), 139 (32), 138 (40), 125 (14),
111 (20), 97 (5), 94 (52), 93 (12), 91 (4), 77 (20), 65 (9), 63 (8), 51
(15).
MS (EI, DIP): m/z (%) = 281 (M+, 5), 280 (7), 278 (17), 244 (39),
140 (49), 125 (100).
HRMS: m/z calcd for C14H14NOSCl: 278.04064; found: 278.03882.
Anal Calcd for C14H12NO2SCl: C, 57.24; H, 4.12; N, 4.77. Found:
C, 57.23; H, 4.12; N, 4.73.
(S,S)-N,N -Oxalyl-bis(S-methyl-S-phenyl-sulfoximine) [(S,S)-
7a]
Mp 172–174 °C.
(S)-N-Ethyl-S-methyl-S-phenyl-sulfoximine [(S)-6a]
[ ]D +18.0 (c 1.15, CHCl3).
IR (KBr): 3448, 3016, 2927, 1644, 1621, 1363, 1234, 1205, 1098,
878, 820, 747, 497 cm–1.
IR (KBr): 2963, 2929, 1445, 1236, 1143, 1090, 995, 746, 692, 537,
522 cm–1.
1H NMR (300 MHz, CDCl3): = 1.06 (t, J = 7.2 Hz, 3 H), 2.66–
2.95 (m, 2 H), 2.96 (s, 3 H), 7.41–7.53 (m, 3 H), 7.77–7.82 (m, 2 H).
13C NMR (75 MHz, CDCl3) = 19.1, 38.3, 45.1, 128.5, 129.2,
132.6, 140.0.
1H NMR (300 MHz, CDCl3): = 3.34 (s, 6 H), 7.56–7.70 (m, 6 H),
8.01–8.05 (m, 4 H).
13C NMR (75 MHz, CDCl3): = 44.2, 127.1, 129.5, 133.9, 137.8,
169.3.
MS (EI, DIP): m/z (%) = 365 ([M + 1]+, 0.2) 182 (100), 140 (14), 92
(18), 77 (13), 109 (43), 65 (16), 51 (14).
MS (EI, 70 eV): m/z (%) = 183 (M+, 9), 168 (100), 141 (55), 125
(29), 77 (35).
Anal. Calcd for C16H16N2O4S2: C, 52.73; H, 4.43; N, 7.69. Found:
C, 52.67; H, 4.41; N, 7.70.
HRMS: m/z calcd for C9H13NOS: 183.07178; found: 183.07182.
(S,S)-N,N -Oxalyl-bis(S-isopropyl-S-phenyl-sulfoximine)
(S)-N-(2,2-Dimethylpropyl)-S-methyl-S-phenyl-sulfoximine
[(S,S)-7b]
[(S)-6b]
Mp 154–155 °C.
[ ]D +10.1 (c 1.15, CHCl3).
IR (KBr): 2985, 2945, 1647, 1618, 1446, 1345, 1219, 1187, 1171,
1103, 1090, 1052, 886, 750, 558, 515 cm–1.
1H NMR (400 MHz, CDCl3): = 1.25 (d, J = 6.9 Hz, 6 H), 1.43 (d,
J = 6.9 Hz, 6 H), 3.75 (heptet, J = 6.9 Hz, 2 H), 7.53–7.68 (m, 6 H),
7.92–7.95 (m, 4 H).
13C NMR (100 MHz, CDCl3): = 15.4, 16.1, 56.7, 129.1, 129.6,
134.0, 170.6.
MS (EI, DIP): m/z (%) = 210 (1/2 M+, 100), 168 (47), 125 (19), 78
IR (KBr): 2951, 2903, 1477, 1445, 1261, 1242, 1138, 1085, 980,
742, 690, 537 cm–1.
1H NMR (300 MHz, CDCl3): = 0.84 (s, 9 H), 2.42 [d (AB),
J = 11.7 Hz, 1 H], 2.60 [d (AB), J = 11.7 Hz, 1 H], 3.00 (s, 3 H),
7.43–7.55 (m, 3 H); 7.80–7.85 (m, 2 H).
13C NMR (75 MHz, CDCl3): = 27.4, 32.2, 44.9, 55.5, 128.5,
129.1, 132.4, 140.2.
MS (EI, 70 eV): m/z (%) = 225 (M+, 1), 210 (4), 168 (100), 141 (53),
(7).
125 (21).
Anal. Calcd for C20H24N2O4S2: C, 57.12; H, 5.75; N, 6.66. Found:
C, 57.12; H, 5.61; N, 6.52.
Anal. Calcd for C12H19NOS: C, 63.92; H, 8.50; N, 6.22. Found: C,
63.51; H, 8.76; N, 6.62.
(S,S)-N,N -Oxalyl-bis(S-cyclopentyl-S-phenyl-sulfoximine)
(S)-N-Octyl-S-methyl-S-phenyl-sulfoximine [(S)-6c]
[ ]D +8.1 (c 1.0, CHCl3).
[(S,S)-7c]
Mp >200 °C (dec.).
IR (KBr): 2926, 2853, 1445, 1408, 1375, 1238, 1141, 1086, 978,
852, 744, 690, 524 cm-1.
1H NMR (400 MHz, CDCl3): = 0.80 (t, J = 6.9 Hz, 3 H), 1.16–
1.27 (m, 10 H), 1.45–1.53 (m, 2 H), 2.70 (dt, J = 7.0, 14.0 Hz, 1 H),
2.88 (dt, J = 7.0, 14.0 Hz, 1 H), 3.02 (s, 3 H), 7.48–7.57 (m, 3 H),
7.83–7.86 (m, 2 H).
IR (KBr): 2990, 2942, 2720, 2679, 2603, 2498, 1650, 1478, 1445,
1399, 1218, 1175, 1039, 904, 872, 851, 810, 750, 685, 581, 556
cm–1.
1H NMR (400 MHz, CDCl3): = 1.50–1.80 (m, 10 H), 1.85–1.99
(m, 2 H), 2.07–2.18 (m, 2 H), 2.25–2.36 (m, 2 H), 3.94 (quintet,
J = 7.7 Hz, 2 H), 7.50–7.65 (m, 6 H), 7.92–7.95 (m, 4 H).
13C NMR (100 MHz, CDCl3): = 14.5, 23.1, 27.6, 29.6, 29.7, 32.2,
33.2, 44.3, 45.5, 128.9, 129.6, 133.0, 139.9.
13C NMR (100 MHz, CDCl3): = 25.7, 25.8, 26.9, 27.0, 64.6,
128.1, 129.4, 133.5, 136.1, 170.0.
MS (EI, DIP): m/z (%) = 267 (M+, 2), 252 (2), 224 (6), 170 (5), 169
MS (EI, DIP): m/z (%) = 236 (1/2 M+, 5), 210 (14), 168 (24), 145
(10), 168 (100), 141 (45), 140 (20), 125 (4), 92 (6), 77 (6), 51 (4).
(12), 125 (34), 93 (13), 78 (16), 67 (100), 57 (15), 53 (14).
Anal. Calcd for C15H25NOS: C, 67.41; H, 9.36; N, 5.24. Found: C,
67.33; H, 9.10; N, 5.47.
Anal. Calcd for C24H28N2O4S2: C, 60.99; H, 5.97; N, 5.93. Found:
C, 60.72; H, 5.78; N, 5.88.
Synthesis 2002, No. 7, 879–887 ISSN 0039-7881 © Thieme Stuttgart · New York

884
C. Bolm et al.
PAPER
(S,S)-N,N -Oxalyl-bis[S-(2-methoxyphenyl)-S-(4-methylphe-
(R,R)-N,N -Oxalyl-bis(S-biphenyl-S-methyl-sulfoximine)
[(R,R)-7d]
nyl)-sulfoximine] [(S,S)-7h]
Mp 221–222 °C.
IR (KBr): 3068, 3018, 2982, 2942, 1656, 1634, 1479, 1281, 1196,
1180, 1096, 900, 550 cm–1.
IR (KBr): 3448, 3020, 2925, 1637, 1620, 1341, 1217, 1200, 1093,
978, 961, 897, 845, 816, 770, 747, 698, 501 cm–1.
1H NMR (400 MHz, DMSO-d6): = 3.64 (s, 6 H), 7.46–7.57 (m, 6
H), 7.78 (d, J = 7.1 Hz, 4 H), 8.00 [d (AA XX ), J = 8.5 Hz, 4 H],
8.06 [d (AA XX ), J = 8.5 Hz, 4 H].
13C NMR (100 MHz, DMSO-d6): = 43.0, 126.9, 127.4, 127.5,
128.5, 128.9, 136.2, 137.9, 145.2, 169.7.
1H NMR (300 MHz, CDCl3): = 2.38 (s, 3 H), 3.68 (s, 3 H), 6.85
(d, J = 8.3 Hz, 2 H), 7.10 ( td, J = 7.7, 1.1 Hz, 2 H), 7.25 (d, J = 8.2
Hz, 4 H), 7.50 ( td, J = 7.9, 1.6 Hz, 2 H), 7.96 (d, J = 8.4 Hz, 4 H),
8.37 (dd, J = 8.0, 1.6 Hz, 2 H).
13C NMR (75 MHz, CDCl3): = 21.5, 56.0, 112.8, 120.8, 126.5,
128.5, 129.2, 130.9, 135.5, 136.0, 144.0, 156.8, 169.1.
MS (EI, 70 eV): m/z (%) = 288 (1/2 M+, 100).
MS (EI, DIP): m/z (%) = 258 (1/2 M+, 100), 216 (8), 201 (33), 168
(43), 152 (30), 141 (12), 115 (4), 76 (2).
HRMS: m/z calcd for (C30H28N2O6S2)/2: 288.06944; found:
288.06799.
Anal. Calcd for C28H24N2O4S2: C, 65.09; H, 4.68; N, 5.42. Found:
C, 64.76; H, 4.76; N, 5.31.
(S,S)-N,N -1,2-Bis(S-methyl-S-phenyl-sulfonimidoyl)-ethane
[(S,S)-8a]
[ ]D +225.1 (c 1.0, CHCl3); mp 167–168 °C.
(R,R)-N,N -Oxalyl-bis[S-(3,5-di-tert-butyl-phenyl)-S-methyl-
sulfoximine] [(R,R)-7e]
Mp >250 °C (dec.).
IR (KBr): 3052, 3020, 3006, 2925, 2896, 2842, 1582, 1475, 1446,
1408, 1297, 1271, 1234, 1137, 1084, 983, 796, 762, 739, 690, 551,
523 cm–1.
1H NMR (400 MHz, CDCl3): = 2.94–3.04 (m, 2 H), 3.08 (s, 6 H),
3.10–3.18 (m, 2 H), 7.49–7.60 (m, 6 H), 7.88–7.93 (m, 4 H).
13C NMR (100 MHz, CDCl3): = 45.0, 46.6, 128.7, 129.3, 132.8,
139.5.
MS (EI, DIP): m/z (%) = 337 ([M + 1]+, 1), 196 (11), 181 (11), 168
IR (KBr): 3449, 2870, 1655, 1633, 1337, 1219, 1200, 977, 884, 810,
701, 490 cm–1.
1H NMR (400 MHz, CDCl3): = 1.33 (s, 36 H), 3.44 (s, 6 H), 7.69
(t, J = 1.7 Hz, 2 H), 7.82 (d, J = 1.7 Hz, 4 H).
13C NMR (100 MHz, CDCl3): = 31.2, 35.3, 44.4, 120.9, 128.3,
137.2, 152.7, 169.5.
MS (EI, DIP): m/z (%) = 294 (1/2 M+, 100), 267 (40), 252 (67), 237
(26), 204 (97), 189 (24), 148 (17), 133 (22), 91 (13), 57 (51).
(100), 141 (66), 125 (24), 97 (14), 77 (14), 65 (5), 51 (8).
Anal. Calcd for C16H20N2O2S2: C, 57.11; H, 5.99; N, 8.33. Found:
C, 57.06; H, 6.07; N, 8.27.
Anal Calcd for C32H48N2O4S2: C,65.27; H, 8.22; N, 4.76. Found: C,
65.01; H, 8.06; N, 4.67.
(S,S)-N,N -1,2-Bis(S-isopropyl-S-phenyl-sulfonimidoyl)-ethane
[(S,S)-8b]
[ ]D –168.4 (c 0.5, CHCl3); mp 124–126 °C.
(R,R)-N,N´-Oxalyl-bis[S-(2-methoxyphenyl)-S-methyl-sulfox-
imine] [(R,R)-7f]
Mp: 211–213 °C.
IR (KBr): 3840, 2908, 2853, 1470, 1449, 1237, 1138, 869, 765, 720,
693, 669, 563 cm–1.
1H NMR (400 MHz, CDCl3): = 1.17 (d, J = 6.9 Hz, 6 H), 1.33 (d,
J = 6.9 Hz, 6 H), 3.01–3.11 (m, 2 H), 3.12–3.21 (m, 2 H), 3.27 (hep-
tet, J = 6.9 Hz, 2 H) 7.48–7.61 (m, 6 H), 7.82–7.86 (m, 4 H).
13C NMR (100 MHz, CDCl3): = 16.0, 16.9, 46.8, 55.9, 129.2,
130.7, 132.8, 136.3.
MS (EI, DIP): m/z (%) = 224 (16), 196 (1/2 M+, 100), 154 (33), 125
IR (KBr): 3100, 3040, 3020, 2940, 1625, 1590, 1480, 1281, 1252,
1190, 1010, 970, 950, 870, 800, 765 cm–1.
1H NMR (400 MHz, DMSO-d6): = 3.52 (s, 6 H), 3.91 (s, 6 H),
7.22 (dt, J = 8.5, 0.8 Hz, 2 H), 7.32 (dd, J = 8.5, 0.8 Hz, 2 H), 7.73
(ddd, J = 8.5, 7.4, 1.7 Hz, 2 H), 7.87 (dd, J = 8.0, 1.7 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): = 42.0, 56.6, 113.4, 120.5,
124.4, 129.5, 135.8, 156.0, 169.2.
MS (EI, DIP): m/z (%) = 212 (1/2 M+, 100), 153 (15), 124 (6), 92
(8), 77 (14).
(60), 109 (3), 78 (8).
Anal. Calcd for C20H28N2O2S2: C, 61.19; H, 7.19; N, 7.14. Found:
C, 60.95; H, 7.41; N, 7.02.
Anal. Calcd for C18H20N2O4S2: C, 50.93; H, 4.75; N, 6.60. Found:
C, 50.69; H, 4.81; N, 6.49.
(S,S)-N,N -1,2-Bis(S-cyclopentyl-S-phenyl-sulfonimidoyl)-
ethane [(S,S)-8c]
[ ]D –159.6 (c 0.5, CHCl3); mp 130–133 °C.
(R,R)-N,N -Oxalyl-bis[S-(2-methoxynaphthyl)-S-methyl-sulf-
oximine] [(R,R)-7g]
Mp 230–235 °C.
IR (KBr): 3079, 2980, 2841, 1442, 1500, 1227, 1125, 1083, 1070,
932, 905, 721, 692, 613, 559 cm–1.
1H NMR (400 MHz, CDCl3): = 1.45–1.72 (m, 10 H), 1.77–1.86
(m, 2 H), 1.93–2.07 (m, 2 H), 2.18–2.28 (m, 2 H), 2.95–3.05 (m, 2
H), 3.08–3.19 (m, 2 H), 3.53–3.63 (m, 2 H), 7.46–7.58 (m, 6 H),
7.83–7.86 (m, 4 H).
13C NMR (100 MHz, CDCl3): = 25.5, 25.7, 26.9, 27.7, 46.4, 64.2,
128.9, 129.6, 132.3, 138.0.
MS (EI, DIP): m/z (%) = 250 (19), 222 (1/2 M+, 100), 154 (52), 125
IR (KBr): 3060, 3015, 2940, 1640, 1620, 1510, 1351, 1280, 1255,
1195, 987, 815, 771, 591 cm–1.
1H NMR (400 MHz, DMSO-d6): = 3.67 (s, 6 H), 3.99 (s, 6 H),
7.48–7.50 ( dt, J = 6.7, 1.1 Hz, 2 H), 7.58–7.64 (m, 4 H), 7.98 (dd,
J = 8.5, 0.8 Hz, 2 H), 8.27 (d, J = 9.1 Hz, 2 H), 9.07–9.10 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): = 45.1, 57.5, 114.2, 117.1,
122.9, 124.2, 128.1, 128.6, 128.7, 131.1, 136.7, 156.4, 169.2.
MS (EI, DIP): m/z (%) = 284 (19), 262 (1/2 M+, 100), 235 (54), 205
(80), 185 (39), 158 (54), 127 (80), 115 (88), 85 (31), 73 (49), 57
(64).
(70), 78 (7), 69 (5).
Anal. Calcd for C24H32N2O2S2: C, 64.83; H, 7.25; N, 6.30. Found:
C, 64.45; H, 7.00; N, 6.24.
Anal. Calcd for C26H24N2O6S2: C, 59.53; H, 4.61; N, 5.34. Found:
C, 59.22; H, 4.84; N, 5.07.
Synthesis 2002, No. 7, 879–887 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Procedure for the Preparation of N-Alkylated Sulfoximines
885
(R,R)-N,N -1,2-Bis(S-biphenyl-S-methyl-sulfonimidoyl)-ethane
[(R,R)-8d]
13C NMR (100 MHz, CDCl3): = 46.6, 47.3, 57.1, 113.4, 119.8,
124.6, 124.7, 128.6, 128.7, 129.5, 133.2, 135.8, 156.7.
[ ]D +195.3 (c 1, CHCl3); mp 177–179 °C.
MS (EI, DIP): m/z (%) = 248 (1/2 M+, 95), 210 (100), 205 (67), 188
(13), 175 (14), 158 (39), 147 (28), 143 (12), 131 (29), 127 (24), 115
(42).
IR (KBr): 3060, 3020, 2922, 2850, 1591, 1562, 1479, 1395, 1300,
1250, 1200, 1140, 1091, 985, 965, 863, 839, 760, 748, 721, 699,
651, 560, 527, 515 cm–1.
1H NMR (400 MHz, CDCl3): = 3.02–3.11 (m, 2 H), 3.13 (s, 6 H),
3.15–3.24 (m, 2 H), 7.39–7.50 (m, 6 H), 7.56–7.61 (m, 4 H), 7.71 (d
(AA XX ), J = 8.3 Hz, 4 H), 7.97 [(d (AA XX ), J = 8.3 Hz, 4 H].
Anal. Calcd for C26H28N2O4S2: C, 62.87; H, 5.69; N, 5.64. Found:
C, 61.80; H, 5.64; N, 5.40.
(S,S)-N,N -1,2-Bis[S-(2-methoxyphenyl)-S-(4-methylphenyl-
sulfonimidoyl]-ethane [(S,S)-8h]
[ ]D +76.0 (c 0.81, CHCl3).
13C NMR (100 MHz, CDCl3): = 45.4, 46.8, 127.6, 128.2, 128.7,
129.3, 129.5, 138.0, 139.6, 146.1.
IR (KBr): 2914, 2851, 1529, 1477, 1468, 1278, 1252, 1142, 1092,
1057, 768, 688, 570, 557 cm–1.
1H NMR (300 MHz, CDCl3): = 2.24 (s, 6 H), 3.04–3.25 (m, 4 H),
3.52 (s, 6 H), 6.67 (d, J = 8.3 Hz, 2 H), 6.90 ( t, J = 7.6 Hz, 2 H),
7.07 (d, J = 8.3 Hz, 4 H), 7.31 ( td, J = 7.8 Hz, 2 H), 7.77 (d,
J = 8.3 Hz, 4 H), 8.05 (dd, J = 7.9 Hz, 2 H).
MS (EI, DIP): m/z (%) = 272 (12), 244 (1/2 M+, 100), 217 (28), 201
(22), 152 (7).
Anal Calcd for C28H28N2O2S2: C, 68.82; H, 5.78; N, 5.73. Found: C,
68.49; H, 5.96; N, 5.42.
(R,R)-N,N -1,2-Bis[S-(3,5-di-tert-butyl-phenyl)-S-methyl-sul-
fonimidoyl]-ethane [(R,R)-8e]
[ ]D +148.2 (c 1.0, CHCl3); mp 216–218 °C.
13C NMR (75 MHz, CDCl3): = 21.3, 47.0, 55.4, 112.2, 120.4,
127.9, 128.8, 129.4, 131.8, 134.2, 137.7, 142.5, 156.9.
IR (KBr): 2955, 2868, 1598, 1476, 1365, 1233, 1135, 985, 890, 792,
704, 538 cm–1.
1H NMR (400 MHz, CDCl3): = 1.34 (s, 36 H), 2.97–3.06 (m, 2 H),
3.09 (s, 6 H), 3.11–3.18 (m, 2 H), 7.63 (t, J = 1.7 Hz, 2 H), 7.72 (d,
J = 1.7 Hz, 4 H).
MS (EI, 70 eV): m/z (%) = 302 (8), 274 (M/2+, 100), 247 (39).
MS (FD): 549 (M+), 274 (1/2 M+).
Anal. Calcd for C30H32N2O4S2: C, 65.67; H, 5.88; N, 5.11. Found C,
65.45; H, 5.70; N, 4.90.
13C NMR (100 MHz, CDCl3): = 31.3, 35.1, 45.2, 46.6, 122.5,
126.9, 138.4, 152.3.
(S,S)-N-[(2-N-tert-Butyloxycarbonylaminyl)propyl]-S-methyl-
S-phenyl-sulfoximine [(S,S)-10a]
[ ]D +15.6 (c 0.67, CHCl3).
MS (EI, DIP): m/z (%) = 308 (18), 280 (1/2 M+, 100), 253 (16), 237
(9), 203 (4), 175 (2), 148, 57 (3).
IR (KBr): 3025, 2974, 2930, 1693, 1511, 1446, 1365, 1315, 1274,
1243, 1171, 1144, 1113, 1059, 981, 788, 742, 505 cm–1.
1H NMR (400 MHz, CDCl3): = 1.15 (d, J = 6.6 Hz, 3 H), 1.36 (s,
9 H), 2.76 [d (AB), J = 13.0 Hz, 1 H], 2.96 [d (AB), J = 13.0 Hz, 1
H], 3.04 (s, 3 H), 3.63–3.67 (m, 1 H), 5.01 (br s, 1 H) 7.46–7.57 (m,
3 H), 7.79–7.85 (m, 2 H).
Anal. Calcd for C32H52N2O2S2: C, 68.52; H, 9.34; N, 4.99. Found:
C, 68.42; H, 9.13; N, 4.87.
(R,R)-N,N´-1,2-Bis[S-(2-methoxyphenyl)-S-methyl-sulfonimi-
doyl]-ethane [(R,R)-8f]
[ ]D –291.0 (c 1, CHCl3); mp 180–182 °C.
13C NMR (100 MHz, CDCl3): = 19.0, 28.8, 45.6, 47.3, 49.3, 78.9,
128.8, 129.6, 133.2, 139.3, 155.6.
IR (KBr): 3006, 2840, 1588, 1475, 1437, 1254, 1140, 1061, 1015,
981, 858, 800, 770, 558, 533 cm–1.
1H NMR (400 MHz, CDCl3): = 2.80–2.84 (m, 2 H), 2.96–3.05 (m,
2 H), 3.19 (s, 6 H), 3.85 (s, 6 H), 6.96 (dd, J = 8.2, 0.8 Hz, 2 H), 7.07
(dt, J = 7.4, 1.1 Hz, 2 H), 7.53 (dd, J = 7.4 Hz, 1.9 Hz, 1 H), 7.55
(dd, J = 7.4, 1.9 Hz, 1 H), 7.90 (dd, J = 7.9, 1.7 Hz, 2 H).
13C NMR (100 MHz, CDCl3): = 43.0, 46.7, 55.8, 111.9, 120.5,
125.9, 132.0, 134.4, 156.6.
MS (EI, DIP): m/z (%) = 226 (16), 198 (1/2 M+, 100), 171 (45), 153
+
MS (EI, DIP): m/z (%) = 285 (2), 239 [M – OC(CH)3 , 10], 170 (5),
169 (10), 168 (100), 142 (7), 141 (76), 140 (25), 125 (14), 124 (6),
117 (5), 77 (4), 57 (24).
Anal. Calcd for C15H24N2O3S: C, 57.70; H, 7.70; N, 8.97. Found: C,
57.58; H, 7.74; N, 8.67.
(S,S)-N-[(2-N-tert-Butyloxycarbonylaminyl)(4-methyl)pentyl]-
S-methyl-S-phenyl-sulfoximine [(S,S)-10b]
[ ]D +5.1 (c 0.5, CHCl3).
(9), 125 (5), 97 (3), 77 (2).
IR (KBr): 3045, 2969, 2934, 1696, 1504, 1446, 1250, 1230, 1170,
1131, 741, 687, 514 cm–1.
1H NMR (400 MHz, CDCl3): = 0.81 (t, J = 6.6 Hz, 6 H), 0.97–
1.03 (m, 1 H), 1.39 (s, 9 H), 1.83–1.89 (m, 2 H), 2.79–2.83 (m, 2 H),
3.01 (s, 3 H), 3.37–3.41 (m, 1 H), 4.85 (d, J = 10 Hz, 1 H), 7.48–
7.56 (m, 3 H), 7.80–7.86 (m, 2 H).
Anal. Calcd for C18H24N2O4S2: C, 54.52; H, 6.10; N, 7.06. Found:
C, 54.30; H, 6.10; N, 7.00.
(R,R)-N,N -1,2-Bis[S-(2-methoxynaphthyl)-S-methyl-sulfonim-
idoyl]-ethane [(R,R)-8g]
[ ]D –90.4 (c 1.1, CHCl3); mp: 142–145 °C.
IR (KBr): 3009, 2927, 2837, 1617, 1596, 1555, 1507, 1459, 1428,
1355, 1323, 1257, 1190, 1154, 1136, 1063, 1028, 989, 971, 941,
863, 808, 750, 519, 504, 492 cm–1.
1H NMR (400 MHz, CDCl3): = 2.77–2.87 (m, 2 H), 3.18–3.28 (m,
2 H), 3.34 (s, 6 H), 3.76 (s, 6 H), 7.03 (d, J = Hz, 2 H), 7.38–7.43
(m, 2 H), 7.51 ( dt, J = 6.9, 1.4 Hz, 2 H), 7.78 (dd, J = 8.0, 0.8 Hz,
2 H), 7.89 (d, J = 9.1 Hz, 2 H), 9.27 (d, J = 9.1 Hz, 2 H).
13C NMR (100 MHz, CDCl3): = 12.0, 15.7, 25.7, 28.9, 36.6, 44.7,
45.3, 56.0, 78.9, 128.8, 129.6, 133.1, 156.2.
+
MS (EI, DIP): m/z (%) = 355 (1), 327 (3), 281 [M – OC(CH)3 , 8],
226 (4), 224 (2), 170 (6), 169 (10), 168 (100), 159 (5), 143 (5), 142
(9), 141 (93), 140 (22), 130 (10), 125 (12), 124 (8), 86 (21), 57 (24).
HRMS: m/z: calcd for C18H30N2O3S – C4H9O: 281.132376; found:
281.132370.
Synthesis 2002, No. 7, 879–887 ISSN 0039-7881 © Thieme Stuttgart · New York

886
C. Bolm et al.
PAPER
(S,S)-N-[(2-N-tert-Butyloxycarbonylaminyl)(3-phenyl)propyl]-
S-methyl-S-phenyl-sulfoximine [(S,S)-10c]
[ ]D +4.6 (c 0.4, CHCl3).
13C NMR (100 MHz, CDCl3): = 18.7, 19.4, 28.4, 29.4, 44.7, 45.2,
56.5, 78.8, 128.4, 129.3, 132.6, 132.7, 156.3.
+
MS (EI, DIP): m/z (%) = 313 (1), 267 [M – OC(CH)3 , 10], 169 (9),
IR (KBr): 3010, 2974, 2929, 1699, 1496, 1336, 1391, 1366, 1233,
1168, 1144, 1087, 1068, 754, 701, 690, 510 cm–1.
168 (100), 145 (5), 143 (4), 142 (5), 141 (82), 140 (22), 126 (5), 125
(12), 124 (8), 116 (5), 78 (4), 72 (5).
1H NMR (400 MHz, CDCl3): = 1.34 (s, 9 H), 2.74–3.02 (m, 4 H),
3.07 (s, 3 H), 3.78–3.82 (m, 1 H), 5.15 (d, J = 10.0 Hz, 1 H), 7.08–
7.21 (m, 5 H), 7.45–7.55 (m, 3 H), 7.76–7.82 (m, 2 H).
HRMS: m/z calcd for C17H28N2O3S – C4H9O: 267.116725; found:
267.116775.
13C NMR (100 MHz, CDCl3): = 28.8, 38.6, 45.6, 46.0, 52.7,
126.3, 128.4, 128.8, 129.7, 129.8, 133.2, 139.1, 155.5.
Acknowledgement
We thank the Deutsche Forschungsgemeinschaft (DFG) within the
Collaborative Research Centre (SFB 380) ‘Asymmetrische Synthe-
se mit chemischen und biologischen Methoden’and the Fonds der
Chemischen Industrie for financial support of this work. C.P.R.H.
acknowledges scholarships from the FCI and the BMBF. We also
thank Nicole Brendgen, Susanne Grünebaum and Guido Moll for
experimental contributions as well as Sandra Saladin and David F.
Hook for helpful discussions.
+
MS (EI, DIP): m/z (%) = 361 (3), 315 [M – OC(CH)3 , 11], 297 (7),
260 (4), 248 (2), 241 (10), 197 (5), 193 (6), 192 (5), 170 (5), 169 (9),
168 (98), 163 (5), 142 (8), 141 (100), 140 (12), 126 (5), 125 (11),
120 (26), 91 (11), 78 (5), 77 (5), 57 (37).
HRMS: m/z calcd for C21H28N2O3S – C4H9O: 315.116725; found:
315.116560.
(S,S)-N-[(2-N-tert-Butyloxycarbonylaminyl)(3-methyl)butyl]-S-
methyl-S-phenyl-sulfoximine [(S,S)-10d]
[ ]D +6.1 (c 0.6, CHCl3).
References and Notes
IR (KBr): 3006, 2975, 2922, 1708, 1500, 1451, 1447, 1356, 1313,
1261, 1248, 1226, 1151, 1143, 1085, 741, 688, 630, 512 cm–1.
(1) (a) Johnson, C. R. Aldrichimica Acta 1985, 18, 3.
(b) Johnson, C. R. Acc. Chem. Res. 1973, 6, 341.
1H NMR (400 MHz, CDCl3): = 0.86–0.90 (m, 6 H), 1.42 (s, 9 H),
1.94–2.02 (m, 1 H), 2.96 [d (AB), J = 13.0 Hz, 1 H], 3.06 [d (AB),
J = 13.0 Hz, 1 H], 3.14 (s, 3 H), 3.32–3.36 (m, 1 H), 5.06 (d, J = 10
Hz, 1 H) 7.56–7.66 (m, 3 H), 7.91–7.95 (m, 2 H).
(c) Johnson, C. R. In Comprehensive Organic Chemistry,
Vol. 3; Barton, D.; Ollis, W. D., Eds.; Pergamon Press:
Oxford, 1979, 223. (d) Pyne, S. G. Sulfur Rep. 1992, 12, 57.
(e) Reggelin, M.; Zur, C. Synthesis 2000, 1.
(2) For representative examples see: (a) Pyne, S. G.; Dong, Z.;
Skelton, B. W.; White, A. H. J. Org. Chem. 1997, 62, 2337.
(b) Reggelin, M.; Heinrich, T. Angew. Chem. Int. Ed. 1998,
37, 2883; Angew. Chem. 1998, 110, 3005. (c) Bosshammer,
S.; Gais, H.-J. Synthesis 1998, 919. (d) Hachtel, J.; Gais, H.-
J. Eur. J. Org. Chem. 2000, 1457. (e) Gais, H.-J.; Loo, R.;
Das, P.; Raabe, G. Tetrahedron Lett. 2000, 41, 2851.
(f) Paquette, L. A.; Gao, Z.; Ni, Z.; Smith, G. F. J. Am. Chem.
Soc. 1998, 120, 2543. (g) Harmata, M.; Kahraman, M.;
Jones, D. E.; Pavri, N.; Weatherwax, S. E. Tetrahedron
1998, 54, 9995. (h) Harmata, M.; Pavri, N. Angew. Chem.
Int. Ed. 1999, 38, 2419; Angew. Chem. 1999, 111, 2577.
(i) Bolm, C.; Muñiz, K.; Aguilar, N.; Kesselgruber, M.;
Raabe, G. Synthesis 1999, 1251. (j) Bolm, C.;Kesselgruber,
M.; Muñiz, K.; Raabe, G. Organometallics 2000, 19, 1648.
(3) (a) Bolm, C.; Felder, M.; Müller, J. Synlett 1992, 439.
(b) Bolm, C.; Felder, M. Tetrahedron Lett. 1993, 34, 6041.
(c) Bolm, C.; Müller, J.; Schlingloff, G.; Zehnder, M.;
Neuburger, M. J. Chem. Soc., Chem. Commun. 1993, 182.
(d) Bolm, C.; Seeger, A.; Felder, M. Tetrahedron Lett. 1993,
34, 8079. (e) Bolm, C.; Felder, M. Synlett 1994, 655.
(f) Bolm, C.; Müller, P. Tetrahedron Lett. 1995, 36, 1625.
(g) Bolm, C.; Müller, P. Acta Chem. Scand. 1996, 50, 305.
(h) Bolm, C.; Kaufmann, D.; Zehnder, M.; Neuburger, M.
Tetrahedron Lett. 1996, 37, 3985. (i) Bolm, C.; Simi , O. J.
Am. Chem. Soc. 2001, 123, 3830. (j) Harmata, M.; Ghosh,
S. K. Org. Lett. 2001, 3, 3321.
13C NMR (100 MHz, CDCl3): = 19.0, 20.1, 28.8, 29.8, 45.5, 46.1,
57.0, 78.8, 128.8, 129.6, 131.0, 133.1, 155.3.
+
MS (EI, DIP): m/z (%) = 313 (4), 267 [M – OC(CH)3 , 7], 212 (5),
169 (9), 168 (100), 145 (6), 143 (4), 142 (7), 141 (78), 140 (22), 125
(10), 124 (7), 116 (6), 72 (18), 57 (20).
HRMS: m/z calcd for C17H28N2O3S – C4H9O: 267.116725; found:
267.116869.
(S,R)-N-[(2-N-tert-Butyloxycarbonylaminyl)(3-methyl)butyl]-
S-methyl-S-phenyl-sulfoximine [(S,R)-10d]
[ ]D +21.6 (c 0.5, CHCl3).
IR (KBr): 3007, 2977, 2926, 1705, 1506, 1474, 1447, 1366, 1326,
1313, 1262, 1226, 1160, 1131, 1085, 1050, 1020, 743, 688, 618,
529 cm–1.
1H NMR (400 MHz, CDCl3): = 0.88–0.92 (m, 6 H), 1.46 (s, 9 H),
1.90–1.98 (m, 1 H), 2.84 [d (AB), J = 13.0 Hz, 1 H], 2.90 [d (AB),
J = 13.0 Hz, 1 H], 3.07 (s, 3 H), 3.38–3.42 (m, 1 H), 4.93 (d, J = 10
Hz, 1 H) 7.54–7.63 (m, 3 H), 7.89–7.93 (m, 2H).
13C NMR (100 MHz, CDCl3): = 18.9, 19.8, 28.8, 29.9, 45.0, 45.1,
57.1, 78.8, 128.7, 129.6, 131.0, 133.1, 156.3.
+
MS (EI, DIP): m/z (%) = 313 (4), 267 [M – OC(CH)3 , 10], 241 (3),
212 (5), 169 (10), 168 (100), 145 (4), 142 (6), 141 (78), 140 (20),
125 (9), 124 (5), 116 (4), 72 (21), 57 (11).
HRMS: m/z calcd for C17H28N2O3S – C4H9O: 267.116725; found:
(4) (a) Bolm, C.; Kahmann, J. D.; Moll, G. Tetrahedron Lett.
1997, 38, 1169. (b) Bolm, C.; Moll, G.; Kahmann, J. D.
Chem.–Eur. J. 2001, 7, 1118. (c) Bolm, C.; Müller, D.;
Hackenberger, C. P. R. Org. Lett. 2002, 4, 893.
(5) (a) Fusco, R.; Tericoni, F. Chim. Ind. 1965, 47, 61.
(b) Johnson, C. R.; Schroeck, C. W. J. Am. Chem. Soc. 1973,
95, 7418. (c) Shiner, C. S.; Berks, A. H. J. Org. Chem. 1988,
53, 5542. (d) Mori, K.; Toda, F. Chem. Lett. 1988, 1997.
(e) Brandt, J.; Gais, H.-J. Tetrahedron: Asymmetry 1997, 6,
909.
267.116745.
(S,S/R)-N-[(2-N-tert-Butyloxycarbonylaminyl)(3-methyl)bu-
tyl]-S-methyl-S-phenyl-sulfoximine [(S,S/R)-10d]
[ ]D +15.6 (c 0.5, CHCl3).
IR (KBr): 3006, 2976, 2926, 1708, 1505, 1447, 1387, 1366, 1313,
1270, 1226, 1161, 1134 1086, 1050, 743, 688, 531, 514 cm–1.
1H NMR (400 MHz, CDCl3): = 0.87–0.93 (m, 12 H), 1.44 (s, 18
H), 1.88–2.02 (m, 2 H), 2.86–3.08 (m, 4 H), 3.10 (s, 6 H), 3.25–3.40
(m, 2 H), 4.91 (d, J = 10.0 Hz, 1 H), 5.06 (d, J = 10.0 Hz, 1 H),
7.52–7.64 (m, 6 H), 7.83–7.91 (m, 4 H).
Synthesis 2002, No. 7, 879–887 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
(6) (a) Tamura, Y.; Sumoto, K.; Minamikawa, J.; Ikeda, M.
Procedure for the Preparation of N-Alkylated Sulfoximines
887
(11) (a) Bolm, C.; Hildebrand, J. P. Tetrahedron Lett. 1998, 39,
5731. (b) Bolm, C.; Hildebrand, J. P. J. Org. Chem. 2000,
65, 169. (c) Bolm, C.; Hildebrand, J. P.; Rudolph, J.
Synthesis 2000, 911.
Tetrahedron Lett. 1972, 37, 4137. (b) Johnson, C. R.;
Kirchhoff, R. A.; Corkins, H. G. J. Org. Chem. 1974, 39,
2458. (c) Müller, J. F. K.; Vogt, P. Tetrahedron Lett. 1998,
39, 4805. (d) Bach, T.; Körber, C. Eur. J. Org. Chem. 1999,
1033. (e) Lacote, E.; Amatore, M.; Fensterbank, L.;
Malacria, M. Synlett 2002, 116.
(12) Johnson, C. R.; Lavergne, O. M. J. Org. Chem. 1993, 58,
1922.
(13) The NH proton has a pKa value of 243 (compare ref.1a). For
a list of related values see: Bordwell, F. G.; Brance, J. C.;
Johnson, C. R.; Vanier, N. R. J. Org. Chem. 1980, 45, 3884.
(14) For N-trifluoromethanesulfonations of sulfoximines see:
Craig, D.; Geach, N. J. Synlett 1993, 481.
(7) (a) Kagan, H. B.; Diter, P. In Organosulfur Chemistry, Vol.
2; Page, P. C. B., Ed.; Academic Press: New York, 1998, 1.
(b) Kagan, H. B.; Luukas, T. In Transition Metals for
Organic Synthesis, Vol. 2; Beller, M.; Bolm, C., Eds.;
Wiley-VCH: Weinheim, 1998, 361. (c) Kagan, H. B. In
Catalytic Asymmetric Synthesis, 2nd Ed.; Ojima, I., Ed.;
VCH Publisher: New York, 2000, 327. (d) Bolm, C.;
Muñiz, K. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer
Verlag: Berlin, 1999, 697.
(8) (a) Andersen, K. K. Tetrahedron Lett. 1962, 3, 93.
(b) Andersen, K. K. J. Org. Chem. 1964, 29, 1952.
(c) Solladié, G.; Hutt, J.; Girardin, A. Synthesis 1987, 173.
(d) Fernandez, I.; Khiar, N.; Llera, J. M.; Alcudia, F. J. Org.
Chem. 1992, 57, 6789. (e) Fernandez, I.; Llera, J. M.;
Alcudia, F. Tetrahedron Lett. 1991, 32, 7299. (f) Guerrero-
de la Rosa, V.; Ordonez, M.; Llera, J. M.; Alcudia, F.
Synthesis 1995, 761. (g) Capozzi, M. A. M.; Cardellicchio,
C.; Naso, F.; Tortorella, P. J. Org. Chem. 2001, 66, 5933.
(9) (a) Williams, T. R.; Booms, R. E.; Cram, D. J. J. Am. Chem.
Soc. 1971, 93, 7338. (b) Schmidbaur, H.; Kammer, G.
Chem. Ber. 1971, 104, 3234. (c) Johnson, C. R.; Schroeck,
C. W.; Shanklin, J. R. J. Am. Chem. Soc. 1973, 95, 7424.
(10) N-Methyl and N-ethyl sulfoximines can also be obtained by
alkylations with trialkyloxonium salts: (a) Johnson, C. R.;
Rigan, J. J.; Haake, M.; McCants, D. Jr.; Keiser, J. E.;
Gertsema, A. Tetrahedron Lett. 1968, 3719. (b) Johnson, C.
R.; Haake, M.; Schroeck, C. W. J. Am. Chem. Soc. 1970, 92,
6594.
(15) Brown, H. C.; Heim, P. J. Org. Chem. 1973, 38, 912.
(16) Both enantiomers of S-methyl-S-phenyl-sulfoximine (1a)
are commercially available (Lancaster). To prepare 1a on a
large scale we recommend the improved protocol described
in ref.5e
(17) The reaction was monitored by TLC after 4, 8, 16 and 36
hours and quenched when the product formation was
complete.
(18) Bolm, C.; Bienewald, F.; Harms, H. Synlett 1996, 775.
(19) Bolm, C.; Simi , O.; Martin, M. Synlett 2001, 1878.
(20) For a discussion on this analogy see ref.18
(21) The sulfoximines mentioned in entries 2 and 3 of Table 2
were prepared from TMS-protected (S)-S-methyl-S-phenyl-
sulfoximine by metalation/alkylation sequence. Those
shown in entries 4–8 (Table 2) were obtained by the
procedure described in ref.6 (MSH imination of the
corresponding enantiopure sulfoxide).
(22) N- -Aminoalkylated diarylsulfoximines have been shown
for example to be spasmolytically highly active compounds.
Satzinger, G.; Stoss, P. Arzneim.-Forsch. 1970, 20, 1214.
Synthesis 2002, No. 7, 879–887 ISSN 0039-7881 © Thieme Stuttgart · New York