Highly modular synthesis of C1-symmetric aminosulfoximines and their use as ligands in copper-catalyzed asymmetric Mukaiyama-Aldol reactions

Article abstract of DOI:10.1002/chem.200500497

The development of C₁-symmetric aminosulfoximines, their highly modular synthesis, and their application in enantioselective copper-catalyzed Mukaiyama-type aldol reactions between pyruvates and enolsilanes is described. In this context, the in

Full text of DOI:10.1002/chem.200500497

DOI: 10.1002/chem.200500497
Highly Modular Synthesis of C1-Symmetric Aminosulfoximines and Their
Use as Ligands in Copper-Catalyzed Asymmetric Mukaiyama-Aldol
Reactions
Martin Langner, Pauline RØmy, and Carsten Bolm*[a]
Abstract: The development of C1-sym-
metric aminosulfoximines, their highly
modular synthesis, and their applica-
tion in enantioselective copper-cata-
lyzed Mukaiyama-type aldol reactions
between pyruvates and enolsilanes is
described. In this context, the influence
of the ligand architecture as well as the
optimization of the reaction conditions
are discussed. In detail, the depend-
ence of the catalyst efficiency on the
solvent, the metal source and the tem-
perature are reported, and an interest-
ing additive effect is highlighted. Fur-
thermore, the substrate scope will be
presented. With the optimized catalyst
system, a number of aldol products
with quaternary stereogenic centers
have been obtained in high yields and
with enantiomeric excesses up to 99%.
Keywords: aldol reaction · asym-
metric catalysis · copper · sulfoxi-
mines
Introduction
commonly restricted.[13] Parallel to the versatile utilizations
of sulfoximines[14] as chiral auxiliaries[15] and precursors for
biologically active molecules[16] such as pseudopeptides,[17]
several powerful sulfoximine-based ligands have been devel-
oped for enantioselective metal catalysis.[18,19] Motivated by
their effective applications in for example, asymmetric palla-
dium and copper catalyses[20,21] by us and others, we recently
focused our attention on studying the efficiency of these li-
gands in CuII-promoted Mukaiyama-type aldol reactions. In
this context, we also prepared novel C1-symmetric aminosul-
foximines 4, which represent a new class of electron-rich
aryl-bridged sulfoximine ligands (Scheme 1).
Throughout the last two decades, the enantioselective
metal-catalyzed Mukaiyama-type aldol reaction has become
a useful tool in organic synthesis.[1] This elegant approach
allows the convenient preparation of valuable enantiomeri-
cally enriched alcohols by using chiral Lewis acids in catalyt-
ic amounts. Consequently, a multitude of catalysts derived
from metals such as tin,[2] boron,[3] titanium,[4] zirconium,[5]
copper,[6] silver,[7] and scandium[8] have been reported. Most
of them have been applied in additions of enolsilanes 1 to
aldehydes and high enantioselectivities have been achieved.
In contrast, for reactions involving activated ketones such as
pyruvates 2, the number of such powerful systems has re-
mained rather limited.[2d,9] Thus, for the latter process, the
development of new chiral Lewis acids still represents a
major challenge because the resulting tertiary a-hydroxy
ester derivatives 3 (Scheme 1) are desirable building blocks
for biologically active molecules[10] such as pharmaceuti-
cals.[11] Furthermore, several natural products contain terti-
ary alcohol groups with stereogenic centers,[12] but the access
to enantiopure products of this type by aldol reactions is
Scheme 1. Mukaiyama-type aldol reaction catalyzed by aminosulfoximine
copper complexes.
[a] Dr. M. Langner, Dipl.-Chem. P. RØmy, Prof. Dr. C. Bolm
Institut für Organische Chemie
der Rheinisch-Westfälischen Technischen Hochschule Aachen
Landoltweg 1, 52056 Aachen (Germany)
Fax : (+49)241-809-2391
In a previous communication, we disclosed the successful
employment of aminosulfoximines (4 with R1 = R2 = R3 =
H) in the CuII-catalyzed Mukaiyama-aldol reaction between
E-mail: carsten.bolm@oc.rwth-aachen.de
6254
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Chem. Eur. J. 2005, 11, 6254 – 6265

FULL PAPER
pyruvates and enolsilanes.[22,23]
Several aldol products were
provided in good yields and
with excellent enantiomeric ex-
cesses. Here, we present a full
account on the synthesis of ami-
nosulfoximines, the optimiza-
tion process and the scope of
the reaction.
Table 1. Structural identification code of aminosulfoximines 4.
Entry
Product
R1
R2
R3
R4
R5
Ar
Method[a]
Yield [%][a]
1
2
3
4
5
6
7
8
(S)-4aAa
(S)-4aAb
(S)-4aAg
(S)-4aAd
(S)-4aAe
(S)-4aAf
(R)-4aBd
(R)-4aBe
(S)-4bAd
(S)-4cAd
(S)-4dAd
(S)-4eAd
(S)-4 fAd
(S)-4gAd
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
2-MeO-Ph
2-MeO-Ph
Me
Me
Me
Me
Me
Ph
d
d
d
e
d
d
e
d
e
e
e
e
e
e
81
85
81
85
82
85
72
64
59
86
78
30[b]
83
58
1-Naph
2-MeO-Ph
Mes
2,4,6-(iPr)3-Ph
2,4,6-(MeO)3-Ph
Mes
2,4,6-(iPr)3-Ph
Mes
Mes
Mes
Mes
Mes
Mes
9
H
10
11
12
13
14
Me
Me
OMe
F
Results and Discussion
CF3
Me
As outlined in Scheme 2, the
novel aminosulfoximines can be
readily prepared by a short and
[a] Referring to the reductive amination to give 4; for details see Scheme 2 and Experimental Section.
[b] Over two steps: nitro group reduction and reductive amination.
high-yielding
reaction
se-
quence: First, enantiopure sul-
foximines (here 6A or 6B) are coupled with o-halonitroben-
zenes 5a–g in palladium-catalyzed Buchwald–Hartwig-type
reactions or copper-mediated cross-couplings,[24] and then,
the nitro groups of the resulting compounds 7 are reduced
to give anilines 8. Subsequent reductive aminations of 8
with a number of aldehydes in the presence of NaBH4 or
NaBH3CN afford the desired target compounds 4 in good
yields ranging from 58 to 85% with respect to anilines 8.
This procedure allows the combination of diverse sulfoxi-
mine precursors, different aromatic bridging units and nu-
merous carbonyl compounds and thereby, a library of modu-
lar ligands can be easily generated. Synthetic details of the
reductive amination step and the structural identification
code for the aminosulfoximines 4 are depicted in Table 1.
In order to find the best ligand structure for the Mukaiya-
ma-type aldol reaction (Scheme 1) and to establish a struc-
ture/activity/selectivity profile (SASP), the newly prepared
aminosulfoximines were employed as ligands in a copper(ii)
catalysis by using 1-phenyl-1-(trimethylsilyloxy) ethene (1a)
and methyl pyruvate (2a) as substrates. This model reaction
was performed at ambient temperature in THF, and with
copper(ii) triflate as metal source. The results are summar-
ized in Table 2.
Table 2. Influence of the ligand structure on the test reaction to give
3a.[a]
Entry
Sulfoximine
Yield 3a [%][b]
ee 3a [%][c,d]
1
2
3
4
5
6
7
8
(S)-4aAa
(S)-4aAb
(S)-4aAg
(S)-4aAd
(S)-4aAe
(S)-4aAf
(R)-4aBd
(S)-4bAd
(S)-4cAd
(S)-4dAd
(S)-4eAd
(S)-4 fAd
(S)-4gAd
64
77
72
88
>99
17
87
50
75
84
77
84
60
70 (R)
83 (R)
86 (R)
93 (R)
93 (R)
72 (R)
86 (S)
91 (R)
90 (R)
91 (R)
90 (R)
93 (R)
82 (R)
9
10
11
12
13
Scheme 2. Synthesis of the aminosulfoximines 4. a) Ar-Br 5 (1.0 equiv),
sulfoximine
(7.5mol%), Cs2CO3 (1.4 equiv), toluene (0.05–0.20 mmolmLꢀ1), 1108C,
24 h, 73–95%; b) Ar-X (2.0 equiv), sulfoximine (1.0 equiv), CuI
6
(1.0–1.3 equiv), Pd(OAc)2 (5mol%), rac-BINAP
5
6
(1.0 equiv), CsOAc (2.5 equiv), DMSO (1 mmolmLꢀ1), 908C, 12 h, 80–
94%; c) Fe (3.0–4.5 equiv), AcOH (1.8 equiv), EtOH/H2O, D, 3–5 h, 25–
91%; d) ArCHO (1.1–1.2 equiv), AcOH (1.0–1.1 equiv), NaBH4
(2.5 equiv), MeOH, 08C ! RT, overnight, 81–85%; e) ArCHO (1.2–
2.5 equiv), NaBH3CN (0.9–1.0 equiv), AcOH (pH 6), MeOH, 08C ! RT,
overnight, 58–86%.
[a] Reaction conditions: 1a (0.6 mmol), 2a (0.5 mmol), Cu(OTf)2
(0.05 mmol), aminosulfoximine (0.05 mmol), THF, RT, 19–24 h.
[b] After column chromatography. [c] Determined by HPLC, using a
column with a chiral stationary phase (Chiralcel OD). [d] The absolute
configuration of 3a was determined by measuring the optical rotation
and compared to the literature value[9] of the corresponding enantiomer.
4
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6255

C. Bolm et al.
The application of the aminosulfoximine 4aAa was found
to afford the aldol product 3a in moderate 64% yield with a
promising enantiomeric excess (ee) of 70% (Table 2,
entry 1). Assuming that electron-donating ortho-substituents
on the benzylamino moiety could have a positive effect on
both yield and enantioselectivity due to a higher steric com-
pression on the metal center combined with an increased
metal–ligand interaction, sulfoximines with substituted
benzyl groups were next applied. Indeed, by using the analo-
gous 1-naphthyl and o-methoxy derivative 4aAb and 4aAg,
respectively (Table 2, entries 2 and 3), higher yields and in-
creased enantioselectivities were achieved. The introduction
of a second ortho-substituent resulted in a further improve-
ment of both the yield and the selectivity. Thus, mesitylene
derivative 4aAd as well as the triisopropyl analogue 4aAe
furnished 3a with 93% ee (entries 4 and 5). With the latter
sulfoximine, also the best yield (>99%) was obtained. Ap-
parently, the results of this first ligand screening confirmed
our initial hypothesis. The aminosulfoximines with electron-
rich ortho-dialkylated benzyl groups led to the highest cata-
lytic activities and enantioselectivities. In an attempt to fur-
ther utilize this effect, sulfoximine 4aAf with a 2,4,6-trime-
thoxybenzyl group was applied. However, in this case a sig-
nificant decrease of the product yield (17%) and the ee
(72%) was observed (entry 6). Probably, this reduced cata-
lytic efficiency was caused by the ortho-methoxy groups,
which interacted with the copper(ii) center (intra- or inter-
molecularly) and thereby interfered with the course of the
reaction. An analogous observation was made in a catalysis
with a ligand bearing a modified sulfoximine unit. Thus,
4aBd having a 2-methoxy group at the sulfoximine part
gave 3a with only 86% ee (Table 2, entry 7).[25]
such as the dependence of the reaction course on the tem-
perature and the catalyst loading were also taken into con-
sideration.
First, the variation of the solvent was investigated with a
catalyst bearing 4aAd as ligand. Expectedly, the change
from THF to the related solvent diethyl ether had only a
minor effect on the enantioselectivity (Table 3, entries 1 and
Table 3. Influence of the solvent and the counterion on the test reaction
to give 3a.[a]
Entry
CuX2
Solvent
Yield 3a [%][b]
ee 3a [%][c,d]
1
2
3
4
5
6
7
8
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
THF
Et2O
88
61
41
79
90
57
–
19
48
67
>99
93
92
91
86
82
87
–
toluene
dioxane
CH2Cl2
CHCl3
EtCN
THF
THF
THF
THF
[e]
Cu(PF6)2
Cu(BF4)2
0
[e]
9
10
11
69
62
81
[e]
Cu(SbF6)2
Cu(ClO4)2
[e]
[a] Reaction conditions: 1a (0.6 mmol), 2a (0.5 mmol), CuX2
(0.05 mmol), aminosulfoximine 4aAd (0.05 mmol), solvent, RT, 19–24 h.
[b] After column chromatography. [c] Determined by HPLC, using a
column with a chiral stationary phase (Chiralcel OD). [d] The absolute
configuration of 3a was determined by measuring the optical rotation
and compared to the literature value[9] of the corresponding enantiomer.
[e] Prepared in situ from CuCl2 (0.05 mmol) and AgX (0.1 mmol).
2). Thus, in the latter solvent aldol product 3a was isolated
with comparably high 92% ee, albeit the yield was signifi-
cantly lower (61%). A similar trend was observed when tol-
uene was applied as solvent (entry 3). In this case, the prod-
uct was obtained with high 91% ee, but the yield further de-
creased to 41%. Use of dioxane slightly reduced the ee
value to 86% (entry 4). The change to the chlorinated sol-
vents dichloromethane and chloroform led to 82 and 87%
ee, respectively (entries 5 and 6), and the catalysis in CH2Cl2
gave the best yield (90%). Propionitrile, however, proved to
be an unsuitable solvent, which completely inhibited the
conversion (entry 7). From these experiments we deduced
that weakly coordinating or aromatic solvents such as THF,
diethyl ether or toluene were important for high enantiose-
lectivities. With regard to the catalytic activity, THF proved
to be the most suitable solvent.
Inspired by previous findings that counterions participate
in the formation of CuII–sulfoximine complexes,[26] we subse-
quently studied the effect of the kind of copper salt on the
enantioselectivity. In general, the application of counterions
different from triflate (Table 3, entry 1) resulted in a signifi-
cant reduction of the product ee. Cu(PF6)2 showed to be an
inappropriate copper(ii) salt, since 3a was obtained as a
racemate in low yield (entry 8). In contrast, Cu(BF4)2 and
Cu(SbF6)2 gave moderate results in terms of yield and ee (69
and 62% ee, respectively, entries 9 and 10). With respect to
the yield, the copper(ii) perchlorate derived catalyst
(entry 11) proved superior over all other ones (>99%), but
the ee was only 81%.
With respect to the absolute configuration of the product
it was found that (R)-configured sulfoximine 4aBd favored
the formation of the (S)-enantiomer of 3a, whereas all other
(S)-configured aminosulfoximines (with S-phenyl and S-
methyl substituents) preferentially provided the (R)-enan-
tiomer of 3a. Thus using this approach, both enantiomers of
the products are available.
In copper-catalyzed Diels–Alder[21b] and carbonyl–ene re-
actions[23] we had previously observed an effect of the substi-
tution pattern of the bridging arene on the catalyst perfor-
mance. Therefore, we included aminosulfoximines 4bAd–
4gAd in the study reported here. As revealed by the data
presented in Table 2 (entries 8–13), a modification of the
bridging arene with electron-donating and -withdrawing sub-
stituents had only a minor impact on yield and ee in this
case. With the exception of CF3-substituted sulfoximine
4gAd which furnished 3a with only 82% ee, all other li-
gands performed very well affording the aldol product with
>90% ee. From this set of sulfoximines fluoro-substituted
4 fAd proved to be the best giving 3a with 93% ee in 84%
yield.
For a further optimization we focused our attention on
the reaction conditions and investigated the effect of the sol-
vent and the copper(ii) salt on the catalyzed reaction be-
tween 1a and 2a to give 3a. Other important parameters
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Chem. Eur. J. 2005, 11, 6254 – 6265

Aminosulfoximines
FULL PAPER
Next, we concentrated on the reduction of the catalyst
loading. The reaction was found to proceed smoothly when
the amount of the catalyst precursors [Cu(OTf)2 and sulfoxi-
mine 4aAe] was decreased from 10 mol% (Table 4, entry 1)
to 5 mol% and to 1 mol% (entries 2 and 3, respectively). In
both cases, the product was obtained in good yield and with
unchanged ee (93%). However, a further lowering of the
catalyst loading to 0.5 mol% resulted in a drastic decrease
of the yield and for the first time, in a diminution of the
enantioselectivity (to 89% ee, entry 4). Apparently, a mini-
mal catalyst amount of 1 mol% is essential in order to ach-
ieve high yields without affecting the ee.
Having optimized the system consisting of sulfoximine
4aAe as the ligand, THF as the solvent, copper(ii) triflate as
the copper(ii) source and 2,2,2-trifluoroethanol as additive
at low temperatures, we subsequently studied the substrate
scope of the process and assessed various enolsilanes as well
as a-keto esters. First, the ester substituent was varied and
the reaction of benzyl pyruvate (2b) with enolsilane 1a at
ꢀ508C was studied. The corresponding aldol product 3b
was isolated in high yield with excellent 98% ee (Table 5,
entry 2). Use of isopropyl pyruvate (2c) furnished 3c with
99% ee (entry 3). Hence, the catalytic system featured a
Finally, the temperature de-
Table 4. Effect of the catalyst loading and the temperature on the test reaction to give 3a.[a]
pendence of the reaction course
was evaluated. As shown in
Table 4 (entries 1 and 5), the ee
increased by lowering the reac-
tion temperature from room
temperature to ꢀ108C yielding
aldol product 3a with 96% ee.
Performing the catalysis at
ꢀ408C led to a further increase
of the ee (97%; entry 6), and by
lowering the temperature to
ꢀ558C, the enantioselectivity
was even improved to give 3a
with 98% ee (entry 7). Howev-
er, under these conditions the
reaction time had to be extend-
ed up to 10 days (entries 6 and
7) in order to isolate the prod-
uct in respectable yield. At
ꢀ788C a complete inhibition of
the catalysis was observed.
Entry
Cat. [mol%]
T [8C]
t [h]
Yield 3a [%][b]
ee 3a [%][c,d]
1
2
3
4
5
6
10
5
1
0.5
10
10
10
10
RT
RT
RT
19
24
24
24
5
122
235
15
>99
87
86
16
43
78
83
89
93 (R)
93 (R)
93 (R)
89 (R)
96 (R)
97 (R)
98 (R)
98 (R)
RT
ꢀ10
ꢀ40
ꢀ55
ꢀ30
7
8[e]
[a] Reaction conditions: 1a (0.6 mmol), 2a (0.5 mmol), Cu(OTf)2, aminosulfoximine 4aAe, THF. [b] After
column chromatography. [c] Determined by HPLC, using a column with a chiral stationary phase (Chiralcel
OD). [d] The absolute configuration of 3a was found to be R in all cases as determined by measuring the opti-
cal rotation and comparing it to the literature value[9] of the corresponding enantiomer. [e] Performed in the
presence of CF3CH2OH (0.6 mmol).
Table 5. Substrate scope under optimized conditions.[a]
Based on earlier reports de-
scribing an accelerating effect
of 2,2,2-trifluoroethanol on the
catalytic turnover in Mukaiya-
ma-type Michael reactions,[27]
we decided to test this additive
in the aldol reaction described
here. Gratifyingly, the same
positive effect was observed.
After a significantly reduced re-
action period of 15 h at ꢀ308C,
aldol product 3a could be ob-
tained in high yield (89%) with
excellent ee (98%) (entry 8).
Hence, also in this system a
strong acceleration effect (with-
out affecting the enantioselec-
tivity) became evident. Un-
fortunately, the additive had no
effect on the catalysis per-
formed at ꢀ788C, and still no
product formation was ob-
served.
Entry
Sulfoximine
Enol ether
Keto ester
Product
T [8C]
t [h]
Yield [%][b]
ee [%][c,d]
1
2
3
4
5
6
7
8
(S)-4aAe
(S)-4aAe
(S)-4aAe
(S)-4aAe
(S)-4aAe
(S)-4aAe
(S)-4aAe
(R)-4aBd
(R)-4aBe
(R)-4aBd
(R)-4aBd
(R)-4aBd
(R)-4aBd
(R)-4aBd
1a
1a
1a
1a
1a
1b
1c
1c
1c
1c
1c
1d
1d
1d
2a
2b
2c
2d
2e
2b
2a
2a
2a
2b
2c
2a
2b
2c
3a
3b
3c
3d
3e
3 f
3g
3g
3g
3h
3i
ꢀ30
ꢀ50
ꢀ40
ꢀ20
RT
15
47
28
40
20
46
109
51
48
49
72
6
89
86
90
86
78
71
66
86
44
79
82
76
58
76
98 (R)
98 (R)
99 (R)
96 (R)
89 (R)
91 (R)
77 (R)
91 (S)
67 (S)
93 (S)
98 (S)
91 (S)
91 (S)
93 (S)
ꢀ40
ꢀ45
ꢀ40
ꢀ55
ꢀ50
ꢀ50
ꢀ5
9
10
11
12
13
14
3g
3h
3i
ꢀ5
6
6
ꢀ5
[a] Reaction conditions: 1a–d (0.6–0.75 mmol), 2a–e (0.5 mmol), CF3CH2OH (0.6 mmol), Cu(OTf)2
(0.05 mmol), aminosulfoximine 4 (0.05 mmol). [b] After column chromatography. [c] Determined by HPLC
using chiral columns (Chiralcel AS, OD, OD-H or OJ). [d] The absolute configurations of 3a, 3g and 3h were
determined by measuring the optical rotations and compared to the literature values[9] of the corresponding
enantiomers. For the other products it was assigned in analogy.
Chem. Eur. J. 2005, 11, 6254 – 6265
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6257

C. Bolm et al.
pronounced flexibility with respect to the nature of the ester
moiety.
Conclusion
Next, the acyl part of 2 was modified, and ethyl 2-oxo-4-
phenyl butyrate (2d) having an extended substituent on the
ketone carbonyl of 2, was treated with nucleophile 1a at
ꢀ208C. Also in this case, the corresponding a-hydroxy ester
3d was obtained with a very good enantioselectivity of 96%
ee (Table 5, entry 4). Treatment of methyl a-keto butyrate
(2e) with 1a yielded product 3e with a slightly lower ee
(89%) at room temperature (entry 5), and surprisingly, no
conversion was observed at lower temperatures. These re-
sults reveal that the nature of the acyl substituent influences
the efficiency of the catalyst, which contrasts the observa-
tions made with substrates having a structural modification
in the ester moiety of 2 (see above).
We have described the development of a new ligand class
consisting of C1-symmetric aryl-bridged aminosulfoximines
which proved to be powerful ligands in copper(ii)-catalyzed
enantioselective Mukaiyama-type aldol reactions. Their ap-
plication allows the preparation of a variety of synthetically
interesting a-hydroxy esters with quaternary stereogenic
centers. The high yields (up to 90%) and the outstanding
enantioselectivities (up to 99% ee) compare well with the
results obtained with Evansꢁ well-established [CuII-
tBubox]2+ and [SnII-pybox]2+ complexes.[2d,9] Currently, in-
vestigations to identify relevant intermediates by spectro-
scopic means and computational studies are in progress.
Here, it appears reasonable to find copper-ligand-substrate
complexes, which are similar to the one, which has recently
been identified in mixtures of bissulfoximines, copper(ii) tri-
flate and chelating substrates related to pyruvates.[26]
Through those explorations, we hope to be able to establish
a mechanistic model and to explain the origin of the high
enantioselectivities.
Finally, the effect of the nucleophile was examined and
the reaction between the acetone-derived enolsilane 1b and
benzyl pyruvate (2b) was studied (Table 5, entry 6). Al-
though the steric hindrance of enolsilane 1b is very different
to that of 1a, product 3 f was also obtained with a remarka-
ble enantioselectivity (91% ee at ꢀ408C). Disappointingly,
treatment of thioketene acetal 1c with methyl pyruvate (2a)
gave succinate derivate 3g with only a moderate ee (77%,
entry 7). A modification of the ligand architecture, however,
and use of aminosulfoximine 4aBd having a 2-methoxy-
phenyl moiety on the sulfoximine part[25] caused a significant
increase of the asymmetric induction and the corresponding
product 3g was obtained with an ee of 91% (entry 8). On
the other hand, a negative impact on the course of the reac-
tion was observed, when the more bulky triisopropyl ana-
logue 4aBe was applied. In this case both the activity and
the selectivity (67% ee) of the catalytic species were affect-
ed (entry 9). Guided by this discovery, aminosulfoximine
4aBd was also selected as ligand in other reactions involving
thioketene acetals. To our delight this approach proved suc-
cessful and catalyses with 1c in combination with a-keto
esters 2b and 2c having sterically more demanding ester
substituents (entries 10 and 11) afforded the corresponding
succinate derivatives (3h and 3i, respectively) with even
higher ee values (than the 91% ee for the conversion of 2a).
Thus, by reacting 1c with benzyl pyruvate (2b) product 3h
with 93% ee was obtained, and the catalysis between isopro-
pyl pyruvate (2c) and 1c provided 3i with 98% ee.
TBDMS-analogue 1d proved to be a suitable enolsilane for
the synthesis of 3g, 3h and 3i as well and similarly good re-
sults as with 1c were obtained (entries 12–14). Unfortunate-
ly, the increased steric bulk of 1d showed no further positive
effect on the enantioselectivities.
Experimental Section
General methods: All experiments were carried out under Ar using stan-
dard Schlenk techniques. If necessary, solvents were dried and deoxygen-
ated by standard procedures. Flash chromatography was carried out with
Merck silica gel 60 (63–100 mesh). Analytical TLC was performed with
Merck silica gel 60 F254 plates, and the products were visualized by UV
detection or by utilization of phosphomolybdic acid. The optical rotations
were measured at room temperature, l=589 nm using a Perkin–Elmer
Model 241. Melting points are uncorrected and were obtained on a Büchi
B-450 apparatus in open capillaries. The NMR spectra were recorded on
a Varian Inova 400 (1H NMR: 400 MHz, 13C NMR: 100 MHz) or a
Varian Gemini (1H NMR: 300 MHz, 13C NMR: 75 MHz) instrument, the
spectra were recorded in CDCl3 by using TMS as internal standard, and
the positions of the signals are reported in ppm. 1H NMR data are re-
ported as: (br=broad, s=singlet, d=doublet, t=triplet, q=quartet, m=
multiplet; coupling constant(s) in Hz; integration, proton assignment).
The IR spectra were measured on a Perkin–Elmer FT/IR 1760 instru-
ment, the samples were prepared as KBr pellets or as films. The MS
spectra were recorded on a Varian MAT 212 system. Elemental analyses
were measured with a Heraeus Model CHN Rapid. Analytical HPLC
measurements were carried out on a Gynkotek (Dionex) machine (auto-
sampler GINA 50, UV/VIS detector UVD 170S, gradient pump M480G,
degasser DG 503) using a Chiralcel AS, OD, OD-H or OJ column
(0.46 cm”25 cm) from Daicel. Alternatively, an Agilent system (1100
series) was employed consisting of a degasser G1379A, a quaternary
pump G1311A, an autosampler G1313A, an oven G1316A, and an UV-
detector G1315B.
o-Bromonitrobenzene (5a), methyl pyruvate (2a), o-anisaldehyde and
2,4,6-trimethylbenzaldehde were purchased from Aldrich. 1-Bromo-3-
methyl-2-nitrobenzene (5b), 1-bromo-4-methyl-2-nitrobenzene (5c) and
CsOAc were obtained from Acrôs. 4,5-Dimethyl-2-nitroaniline, 1-iodo-4-
methoxy-2-nitrobenzene (5e), 4-fluoro-1-iodo-2-nitrobenzene (5 f), 1-
bromo-2-nitro-4-trifluoromethylbenzene (5g) were purchased from Lan-
caster. The silyl enol ethers 1a and 1b, benzaldehyde and 1-naphthalde-
hyde were purchased from Fluka. Silyl enol ethers 1c and 1d,[28] a-keto
esters 2b, 2c and 2e,[29] sulfoximines 6A[30] and 6B[19g] and triisopropyl-
benzaldehyde[31] were prepared according to literature procedures.
In the light of the results presented in this part it can be
stated, that the catalytic system is sensitive to the nature of
the enolsilane, and that the high modularity of the aminosul-
foximines has so far allowed to rapidly find an effective
ligand for every substrate pair.
1-Bromo-4,5-dimethyl-2-nitrobenzene (5d): A solution of 4,5-dimethyl-2-
nitroaniline (3.0 g, 18.0 mmol) in a mixture of distilled water (114 mL)
6258
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 6254 – 6265

Aminosulfoximines
FULL PAPER
and an aqueous solution of HBr (48%, 32 mL) was stirred for 30 min to
708C. After cooling to ꢀ58C a solution of NaNO2 (7.8 g, 113.0 mmol) in
distilled water (38 mL) was added. The temperature was maintained at
ꢀ58C for 15 min and then a freshly prepared and cooled solution of
CuBr (32.7 g, 243.0 mmol) in an aqueous solution of HBr (48%, 62 mL)
was added to the resulting mixture. After heating for 15 min to 708C, the
mixture was extracted three times with chloroform (200 mL). The com-
bined organic extracts were washed with an aqueous solution of NaOH
(10%, 200 mL), dried over MgSO4 and the solvent was removed under
reduced pressure. The product was purified by flash chromatography
(silica gel, pentane/EtOAc 9:1) to afford (5d) as a yellow solid (3.6 g,
15.7 mmol, 87%). M.p. 608C; 1H NMR (400 MHz, CDCl3): d=2.28 (s,
3H, CH3), 2.30 (m, 3H, CH3), 7.45 (s, 1H, Ar-H), 7.64 ppm (s, 1H, Ar-
H); 13C NMR (100 MHz, CDCl3): d=19.4, 19.7, 111.2, 126.5, 135.5, 137.6,
EI): m/z (%): 306 (100) [M]+, 171 (23), 156 (34), 141 (21), 125 (23), 97
(15), 77 (23); elemental analysis calcd (%) for C14H14N2O4S (306.34): C
54.89, H 4.61, N 9.14; found: C 54.77, H 4.21, N 9.03.
(S)-N-[3-Methyl-2-nitrophenyl]-S-methyl-S-phenylsulfoximine [(S)-7bA]:
The product was prepared according to the general procedure 1 by using
1-bromo-3-methyl-2-nitrobenzene (5b, 1.00 g, 4.6 mmol), (S)-S-methyl-S-
phenylsulfoximine [(S)-6A, 0.90 g, 5.8 mmol], Pd(OAc)2 (52 mg,
0.23 mmol), rac-BINAP (215 mg, 0.35 mmol), Cs2CO3 (2.10 g, 6.4 mmol)
and toluene (80 mL). The target compound was afforded as a yellow
solid (1.28 g, 4.4 mmol, 95%) after flash chromatography (silica gel, pen-
tane/EtOAc 4:1). [a]2D0 =ꢀ51.7 (c=1.15 in CHCl3); m.p. 75–818C;
1H NMR (400 MHz, CDCl3): d=2.23 (s, 3H, CH3), 3.23 (s, 3H, CH3),
6.71–6.75 (m, 1H, Ar-H), 6.97–7.05 (m, 2H, Ar-H), 7.51–7.64 (m, 3H,
Ar-H), 7.96–7.99 ppm (m, 2H, Ar-H); 13C NMR (100 MHz, CDCl3): d=
16.9, 45.7, 120.3, 123.1, 128.3, 129.5, 129.6, 133.5, 137.0, 138.2, 147.2 ppm;
IR (KBr): n˜ =3022, 1527, 1306, 1109, 750 cmꢀ1; MS (70 eV, EI): m/z (%):
290.1 (100) [M]+, 181.1 (13), 141 (42), 125 (22), 77.1 (60); elemental anal-
ysis calcd (%) for C14H14N2O3S (290.34): C 57.92, H 4.86, N 9.65; found:
C 57.99, H 4.67, N 10.01.
143.8, 147 ppm; IR (KBr): n˜ = 2926, 2863, 1521, 1347, 1021, 889 cmꢀ1
;
MS (70 eV, EI): m/z (%): 229.0 (99) [M]+; elemental analysis calcd (%)
for C8H8BrNO2 (230.06): C 41.77, H 3.50, N 6.09; found: C 41.64, H 3.75,
N 5.87.
General procedure 1 (Pd-catalyzed Buchwald–Hartwig-type reaction): A
flame-dried Schlenk-flask was charged with the bromonitrobenzene (5a–
c, 1.0 equiv), (S)-S-methyl-S-phenylsulfoximine [(S)-6A] or (R)-S-(me-
thoxyphenyl)-S-methylsulfoximine [(R)-6B, 1.00–1.25 equiv], Pd(OAc)2
(5 mol-%), rac-BINAP (7.5 mol-%) and Cs2CO3 (1.4 equiv). Subsequent-
ly, dry toluene (c=0.05–0.20 mmolmLꢀ1) was added, and the mixture
was heated to 1108C for 24 h. The suspension was then filtered over
Celite with ethyl acetate as eluent. Subsequently, the solvent was evapo-
rated and the product was purified by flash chromatography (silica gel).
(S)-N-[4-Methyl-2-nitrophenyl]-S-methyl-S-phenylsulfoximine [(S)-7cA]:
The product was prepared according to the general procedure 1 by using
1-bromo-4-methyl-2-nitrobenzene (5c, 500 mg, 2.31 mmol) and (S)-S-
methyl-S-phenylsulfoximine [(S)-6A, 450 mg, 2.89 mmol], Pd(OAc)2
(26 mg, 0.12 mmol), rac-BINAP (108 mg, 0.17 mmol), Cs2CO3 (1.05 g,
3.2 mmol) and toluene (40 mL). The target compound was afforded as a
yellow oil (630 mg, 2.2 mmol, 95%) after flash chromatography (silica
gel, pentane/EtOAc 4:1). [a]2D0 =ꢀ85.1 (c=1.02 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=2.19 (s, 3H, CH3), 3.18 (s, 3H, CH3), 7.11 (d, J=
8.2 Hz, 1H, Ar-H), 7.38 (d, J=1.9 Hz, 1H, Ar-H), 7.98–8.00 (m, 2H, Ar-
H), 7.45–7.58 (m, 3H, Ar-H), 7.98 ppm (dd, J=8.2, 1.9 Hz, 1H, Ar-H);
13C NMR (100 MHz, CDCl3): d=20.5, 45.7, 124.5, 124.7, 128.6, 129.6,
131.5, 133.40, 133.7, 136.3, 138.7, 144.8 ppm; IR (KBr): n˜ =3064, 1496,
1278, 1213, 756 cmꢀ1; MS (70 eV, EI): m/z (%): 290.1 (100) [M]+; elemen-
tal analysis calcd (%) for C14H14N2O3S (290.34): C 57.92, H 4.86, N 9.65;
found: C 57.61, H 4.90, N 9.69.
General procedure 2 (Cu-mediated cross-coupling reaction): Under an
argon atmosphere a dry Schlenk tube was charged with (S)-S-methyl-S-
phenylsulfoximine [(S)-6A, 1.0 equiv], the aryl halide (2.0 equiv), CuI
(1 equiv) and CsOAc (2.5 equiv). The mixture was dissolved in degassed
DMSO (1.0 mmolmLꢀ1). After heating to 908C for 12 h, the mixture was
cooled to room temperature and neutralized with aqueous HCl (20 mL).
The aqueous layer was extracted with dichloromethane three times (3”
20 mL). The combined organic extracts were dried (MgSO4), filtered and
concentrated under reduced pressure. Purification by flash chromatogra-
phy (silica gel) afforded the N-arylated sulfoximines.
(S)-N-[4,5-Dimethyl-2-nitrophenyl]-S-methyl-S-phenylsulfoximine [(S)-
7dA]: The product was prepared according to the general procedure 2
by using 1-bromo-4,5-dimethyl-2-nitrobenzene (5d, 1.0 g, 4.35 mmol),
(S)-S-methyl-S-phenylsulfoximine [(S)-6A, 337 mg, 2.18 mmol]. The
target compound was afforded as a yellow solid (527 mg, 1.73 mmol,
(S)-N-(2-Nitrophenyl)-S-methyl-S-phenylsulfoximine [(S)-7aA]: The
product was prepared according to the general procedure 1 by using o-
bromonitrobenzene (5a, 2.42 g, 12.0 mmol), (S)-S-methyl-S-phenylsulfox-
imine [(S)-6A, 1.86 g, 12.0 mmol], Pd(OAc)2 (135 mg, 0.60 mmol), rac-
BINAP (561 mg, 0.90 mmol), Cs2CO3 (5.47 g, 16.8 mmol) and toluene
(60 mL). The product was purified by flash chromatography (silica gel,
pentane/EtOAc 4:1) to yield (S)-7aA as a yellow oil (2.96 g, 10.7 mmol,
89%). [a]2D0 =ꢀ33.5 (c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=
3.27 (s, 3H, CH3), 6.91–6.96 (m, 1H, Ar-H), 7.21–7.30 (m, 2H, Ar-H),
7.54–7.67 (m, 4H, Ar-H), 8.05–8.09 ppm (m, 2H, Ar-H); 13C NMR
(75 MHz, CDCl3): d=45.8, 121.3, 124.4, 124.5, 128.6, 129.7, 132.5, 133.8,
138.6, 139.1 ppm; IR (film): n˜ =3066, 3025, 2930, 1601, 1522, 1479, 1359,
1289, 1209, 1099, 1021, 774, 747, 689, 508 cmꢀ1; MS (70 eV, EI): m/z (%):
276 (100) [M]+, 167 (26), 141 (40), 125 (31), 77 (56), 51 (13); elemental
analysis calcd (%) for C13H12N2O3S (276.31): C 56.51, H 4.38, N 10.14;
found: C 56.50, H 4.65, N 10.12.
80%) after flash chromatography (silica gel, pentane/EtOAc 4:1). [a]D20
=
ꢀ62.0 (c=1.2 in CHCl3); m.p. 1048C; 1H NMR (300 MHz, CDCl3): d=
2.16 (s, 3H, CH3), 2.17 (s, 3H, CH3), 3.25 (s, 3H, CH3), 7.11 (s, 1H, Ar-
H), 7.51 (s, 1H, Ar-H), 7.53–7.66 (m, 3H, Ar-H), 8.08–8.10 ppm (m, 2H,
Ar-H); 13C NMR (75 MHz, CDCl3): d=18.8, 19.9, 45.4, 125.3, 125.6,
128.4, 129.4, 130.3, 133.4, 136.7, 138.7, 142.4, 142.5 ppm; IR (KBr): n˜ =
3031, 2936, 1521, 1300, 1221, 1105, 989, 726 cmꢀ1; MS (70 eV, EI): m/z
(%): 304.2 (100) [M]+; elemental analysis calcd (%) for C15H16N2O3S
(304.36): C 59.19, H 5.30, N 9.20; found: C 59.14, H 5.32, N 9.25.
(S)-N-[4-Methoxy-2-nitrophenyl]-S-methyl-S-phenylsulfoximine
[(S)-
7eA]: The product was prepared according to the general procedure 2 by
using 1-iodo-4-methoxy-2-nitrobenzene (5e, 502 mg, 1.80 mmol), (S)-S-
methyl-S-phenylsulfoximine [(S)-6A, 140 mg, 0.90 mmol]. The target
compound was afforded as an orange oil (220 mg, 0.72 mmol, 80%) after
flash chromatography (silica gel, pentane/EtOAc 7:3). [a]2D0 =ꢀ124.5 (c=
0.59 in CHCl3); 1H NMR (300 MHz, CDCl3): d=3.19 (s, 3H, CH3), 3.69
(s, 3H, OCH3), 6.79 (dd, J=9.1, 3.1 Hz, 1H, Ar-H), 7.13 (d, J=3.1 Hz,
1H, Ar-H), 7.17 (d, J=9.1 Hz, 1H, Ar-H), 7.46–7.59 (m, 3H, Ar-H),
7.97–8.00 ppm (m, 2H, Ar-H); 13C NMR (75 MHz, CDCl3): d=45.4, 55.9,
109.0, 119.8, 126.1, 128.7, 129.7, 132.0, 133.8, 138.7, 145.2, 154.2 ppm; IR
(KBr): n˜ =2928, 1524, 1494, 1278, 1225, 1098 cmꢀ1; MS (70 eV, EI): m/z
(%): 306.0 (100) [M]+; elemental analysis calcd (%) for C14H14N2O4S
(306.34): C 54.89, H 4.61, N 9.14; found: C 54.87, H 4.24, N 9.28.
(R)-N-(2-Nitrophenyl)-S-2-(methoxyphenyl)-S-methylsulfoximine [(R)-
7aB]: The product was prepared according to the general procedure 1 by
using o-bromonitrobenzene (5a, 808 mg, 4.00 mmol), (R)-S-(methoxy-
phenyl)-S-methylsulfoximine [(R)-6B, 741 mg, 4.00 mmol], Pd(OAc)2
(45 mg, 0.20 mmol), rac-BINAP (187 mg, 0.30 mmol), Cs2CO3 (1.83 g,
5.62 mmol) and toluene (40 mL). The product was purified by flash chro-
matography (silica gel, pentane/EtOAc 4:1 ! 2:1) to yield (R)-7aB as a
yellow solid (893 mg, 2.92 mmol, 73%). [a]2D0 =+133.9 (c=0.99 in
CHCl3); m.p. 958C; 1H NMR (400 MHz, CDCl3): d=3.42 (s, 3H, CH3),
3.89 (s, 3H, OCH3), 6.84–6.89 (m, 1H, Ar-H), 6.94–6.98 (d, J=8.5 Hz,
1H, Ar-H), 7.04–7.09 (m, 1H, Ar-H), 7.14–7.23 (m, 2H, Ar-H), 7.50–7.57
(m, 2H, Ar-H), 8.02–8.06 ppm (m, 1H, Ar-H); 13C NMR (100 MHz,
CDCl3): d=44.1, 55.8, 112.1, 120.3, 120.8, 123.9, 124.1, 125.0, 131.6, 131.7,
135.4, 138.9, 156.7 ppm; IR (KBr): n˜ =3043, 3018, 1596, 1517, 1477, 1440,
1359, 1319, 1288, 1249, 1197, 1165, 1013, 766, 747, 659 cmꢀ1; MS (70 eV,
(S)-N-[4-Fluoro-2-nitrophenyl]-S-methyl-S-phenylsulfoximine [(S)-7 fA]:
The product was prepared according to the general procedure 2 by using
4-fluoro-1-iodo-2-nitrobenzene (5 f, 51 mg, 0.19 mmol), (S)-S-methyl-S-
phenylsulfoximine [(S)-6A, 15 mg, 0.10 mmol]. The target compound was
afforded as a yellow solid (27 mg, 0.09 mmol, 94%) after flash chroma-
Chem. Eur. J. 2005, 11, 6254 – 6265
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6259

C. Bolm et al.
tography (silica gel, dichloromethane/methanol 99:1). [a]2D0 =ꢀ98.5 (c=
0.99 in CHCl3); m.p. 818C; 1H NMR (300 MHz, CDCl3): d=3.19 (s, 3H,
CH3), 6.95–6.98 (m, 1H, Ar-H), 7.18–7.22 (m, 1H, Ar-H), 7.30–7.33 (m,
1H, Ar-H), 7.47–7.61 (m, 3H, Ar-H), 7.85–7.98 ppm (m, 2H, Ar-H);
13C NMR (75 MHz, CDCl3): d=45.8, 111.8 (d, JCF =24 Hz, CH), 119.9 (d,
C14H16N2O2S (276.35): C 60.85, H 5.84, N 10.14; found: C 60.90, H 6.05,
N 9.88.
(S)-N-[2-Amino-3-methylphenyl]-S-methyl-S-phenylsulfoximine
[(S)-
8bA]: Compound (S)-7bA (700 mg, 2.41 mmol) was dissolved in a mix-
ture of EtOH (20 mL) and H2O (30 mL) and then treated with glacial
acetic acid (2.40 mL, 4.19 mmol) and Fe (403 mg, 7.23 mmol). After re-
fluxing for 5 h and cooling to room temperature, the mixture was parti-
tioned between H2O (20 mL) and CH2Cl2 (50 mL). The aqueous layer
was extracted three times with CH2Cl2 (50 mL), and the combined organ-
ic layers were dried over MgSO4. The solvent was removed, and the
product was purified by flash chromatography (silica gel, dichlorome-
thane/methanol 99:1 with 1% of Et3N) to afford (S)-8bA as a beige solid
(157 mg, 0.60 mmol, 25%). [a]2D0 =ꢀ40.2 (c=0.522 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=2.20 (s, 3H, CH3), 3.28 (s, 3H, CH3), 4.19 (brs,
NH2), 6.46 (t, J=7.7 Hz, 1H, Ar-H), 6.65 (d, J=7.7 Hz, 1H, Ar-H), 6.79
(d, J=7.7 Hz, 1H, Ar-H), 7.47–7.62 (m, 3H, Ar-H), 7.96–8.00 ppm (m,
2H, Ar-H); 13C NMR (75 MHz, CDCl3): d=17.8, 45.9, 118.6, 119.4,
123.2, 124.0, 128.5, 129.6, 131.9, 133.2, 137.6, 139.3 ppm; IR (KBr): n˜ =
3456, 3364, 3060, 1444, 1174, 667 cmꢀ1; MS (70 eV, EI): m/z (%): 260.1
(100) [M]+; elemental analysis calcd (%) for C14H16N2OS (260.35): C
64.58, H 6.19, N 10.76; found: C 64.67, H 6.10, N 10.59.
J
CF =24 Hz, CH), 125.7 (d, JCF =8 Hz, CH), 128.6, 129.8, 133.9, 135.5,
138.4, 142.0, 156.4 ppm (d, JCF =241 Hz, CF); IR (KBr): n˜ =1532, 1485,
1214 cmꢀ1; MS (70 eV, EI): m/z (%): 294.0 (100) [M]+; elemental analysis
calcd (%) for C13H11FN2O3S (294.30): C 53.05, H 3.77, N 9.52; found: C
52.67, H 4.13, N 9.20.
(S)-N-[2-Nitro-4-trifluoromethylphenyl]-S-methyl-S-phenylsulfoximine
[(S)-7gA]: The product was prepared according to the general procedure
2
by using 1-bromo-2-nitro-4-trifluoromethylbenzene (5g, 1.0 g,
3.70 mmol), (S)-S-methyl-S-phenylsulfoximine [(S)-6A, 286 mg,
1.85 mmol]. The target compound was afforded as a yellow oil (540 mg,
1.57 mmol, 85%) after flash chromatography (silica gel, pentane/EtOAc
4:1). [a]2D0 =ꢀ14.1 (c=1.03 in CHCl3); 1H NMR (300 MHz, CDCl3): d=
3.24 (s, 3H, CH3), 7.26 (d, J=8.7 Hz, 1H, Ar-H), 7.36 (dd, J=8.7, 2.2 Hz,
1H, Ar-H), 7.49–7.63 (m, 3H, Ar-H), 7.81 (d, J=2.2 Hz, 1H, Ar-H),
7.96–8.01 ppm (m, 2H, Ar-H); 13C NMR (75 MHz, CDCl3): d=46.5,
121.5, 123 (q, JCF =35 Hz, C), 123.4 (q, JCF =272 Hz, CF3), 124.1, 128.5,
129.1, 130.0, 134.3, 138.0, 142.7, 144.5 ppm; IR (KBr): n˜ =1623, 1534,
1324, 1215, 1125 cmꢀ1; MS (70 eV, EI): m/z (%): 344.0 (100) [M]+; ele-
mental analysis calcd (%) for C14H11F3N2O3S (344.31): C 48.84, H 3.22, N
8.14; found: C 48.91, H 3.29, N 8.12.
(S)-N-[2-Amino-4-methylphenyl]-S-methyl-S-phenylsulfoximine
[(S)-
8cA]: Compound (S)-7cA (5OO mg, 1.72 mmol) was dissolved in a mix-
ture of EtOH (14 mL) and H2O (21 mL) and then treated with glacial
acetic acid (1.70 mL, 2.97 mmol) and Fe (288 mg, 5.16 mmol). After re-
fluxing for 5 h and cooling to room temperature, the mixture was parti-
tioned between H2O (20 mL) and CH2Cl2 (50 mL). The aqueous layer
was extracted three times with CH2Cl2 (50 mL), and the combined organ-
ic layers were dried over MgSO4. The solvent was removed, and the
product was purified by flash chromatography (silica gel, EtOAc/petro-
lum ether 3:7 with 1% of Et3N) to afford (S)-8cA as a brown oil
(144 mg, 0.55 mmol, 25%). [a]2D0 =+6.33 (c=0.50 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=2.12 (s, 3H, CH3), 3.20 (s, 3H, CH3), 4.10 (brs,
NH2), 6.29 (d, J=8.0 Hz, 1H, Ar-H), 6.50 (s, 1H, Ar-H), 6.77 (d, J=
8.0 Hz, 1H, Ar-H), 7.54–7.56 (m, 3H, Ar-H), 7.93–7.97 ppm (m, 2H, Ar-
H); 13C NMR (100 MHz, CDCl3): d=20.8, 45.5, 115.7, 118.9, 121.7, 128.2,
128.9, 129.3, 131.9, 132.9, 139.1, 140.1 ppm; IR (KBr): n˜ =3564, 3229,
3013, 1612, 1507, 748 cmꢀ1; MS (70 eV, EI): m/z (%): 260.1 (88%) [M]+;
elemental analysis calcd (%) for C14H16N2OS (260.35): C 64.58, H 6.19, N
10.76; found: C 64.46, H 5.91, N 11.04.
(S)-N-(2-Aminophenyl)-S-methyl-S-phenylsulfoximine [(S)-8aA]: Com-
pound (S)-7aA (2.96 g, 10.7 mmol) was dissolved in a mixture of EtOH
(70 mL) and H2O (35 mL) and then treated with glacial acetic acid
(11.0 mL, 19.2 mmol) and Fe (2.68 g, 48.2 mmol). After refluxing for 3 h,
the mixture was cooled to room temperature and then partitioned be-
tween H2O (20 mL) and CH2Cl2 (50 mL). The aqueous layer was extract-
ed with CH2Cl2 (3”50 mL), and the combined organic layers were
washed with sat. aqueous Na2CO3 (50 mL) and dried over MgSO4. The
solvent was removed, and the product was purified by flash chromatogra-
phy on silica gel (EtOAc/pentane 4:1 with 1% of Et3N) to afford (S)-
8aA as a beige solid (2.2 g, 8.83 mmol, 83%). [a]2D0 =ꢀ6.8 (c=1.0 in
CHCl3); m.p. 116–1188C; 1H NMR (300 MHz, CDCl3): d=3.25 (s, 3H,
CH3), 3.74 (brs, 2H, NH2), 6.45–6.51 (m, 1H, Ar-H), 6.68–6.77 (m, 2H,
Ar-H), 6.88–6.91 (m, 1H, Ar-H), 7.49–7.61 (m, 3H, Ar-H), 7.96–8.00 ppm
(m, 2H, Ar-H); 13C NMR (75 MHz, CDCl3): d=45.9, 114.9, 118.5, 122.0,
122.7, 128.5, 129.5, 131.6, 133.3, 139.3, 140.7 ppm; IR (KBr): n˜ =3418,
3335, 3020, 1610, 1585, 1499, 1446, 1291, 1251, 1190, 1146, 1096, 1018,
966, 751, 688, 538 cmꢀ1; MS (70 eV, EI): m/z (%): 246 (100) [M]+, 141
(48), 125 (20), 106 (37), 79 (12); elemental analysis calcd (%) for
C13H14N2OS (246.33): C 63.39, H 5.73, N 11.37; found: C 63.41, H 5.73, N
11.49.
(S)-N-[2-Amino-4,5-dimethylphenyl]-S-methyl-S-phenylsulfoximine [(S)-
8dA]: Compound (S)-7dA (721 mg, 2.37 mmol) was dissolved in a mix-
ture of EtOH (20 mL) and H2O (30 mL) and then treated with glacial
acetic acid (2.4 mL, 4.19 mmol) and Fe (396 mg, 7.10 mmol). After re-
fluxing for 5 h and cooling to room temperature, the mixture was parti-
tioned between H2O (20 mL) and CH2Cl2 (50 mL). The aqueous layer
was extracted three times with CH2Cl2 (50 mL), and the combined organ-
ic layers were dried over MgSO4. The solvent was removed, and the
product was purified by flash chromatography (silica gel, dichlorome-
thane/methanol 99:1 with 1% of Et3N) to afford (S)-8dA as a brown oil
(459 mg, 1.68 mmol, 71%). [a]2D0 =+35.0 (c=1.10 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=1.98 (s, 3H, CH3), 2.06 (s, 3H, CH3), 3.21 (s, 3H,
CH3), 3.87 (brs, NH2), 6.50 (s, 1H, Ar-H), 6.72 (s, 1H, Ar-H), 7.49–7.61
(m, 3H, Ar-H), 7.98–8.01 ppm (m, 2H, Ar-H); 13C NMR (75 MHz,
CDCl3): d=18.8, 19.2, 45.5, 116.6, 123.4, 126.0, 128.3, 128.9, 129.3, 130.4,
132.9, 138.2, 139.4 ppm; IR (KBr): n˜ =3073, 3000, 2963, 2863, 1621, 1515,
1452, 1226, 757 cmꢀ1; MS (70 eV, EI): m/z (%): 274.1 (100) [M]+; HRMS
(EI): m/z: calcd for C15H18N2OS: 274.1140; found 274.1140 [M]+.
(R)-N-(2-Aminophenyl)-S-2-(methoxyphenyl)-S-methylsulfoximine [(R)-
8aB]: Compound (R)-7aB (893 mg, 2.9 mmol) was dissolved in a mixture
of EtOH (50 mL) and H2O (25 mL) and then treated with glacial acetic
acid (3.0 mL, 5.2 mmol) and Fe (734 mg, 13.1 mmol). After refluxing for
3 h and cooling to room temperature, the pH was adjusted to 14 by care-
ful addition of solid NaOH. Subsequently, the resulting suspension was
refluxed for 5 min, then filtered immediately, and the remaining residue
was washed with EtOH (40 mL) and CH2Cl2 (60 mL). The aqueous layer
was extracted with CH2Cl2 (3”20 mL), and the combined organic layers
were dried over MgSO4. The solvent was removed, and the product was
purified by flash chromatography (silica gel, EtOAc/pentane 4:1 with 1%
of Et3N) to afford (R)-8aB as a brownish solid (700 mg, 2.53 mmol,
87%). [a]2D0 =ꢀ149.5 (c=1.0 in CHCl3); m.p. 72–758C; 1H NMR
(300 MHz, CDCl3): d=3.38 (s, 3H, CH3), 3.70 (brs, 2H, NH2), 3.95 (s,
3H, OCH3), 6.46–6.53 (m, 1H, Ar-H), 6.62–6.66 (m, 1H, Ar-H), 6.70–
6.77 (m, 1H, Ar-H), 6.92–7.10 (m, 3H, Ar-H), 7.49–7.56 (m, 1H, Ar-H),
8.01–8.05 ppm (m, 1H, Ar-H); 13C NMR (75 MHz, CDCl3): d=43.1, 56.0,
112.3, 114.8, 118.3, 120.8, 122.9, 123.1, 126.8, 131.5, 131.7, 135.1, 141.3,
156.7 ppm; IR (KBr): n˜ =3435, 3347, 1593, 1491, 1282, 1249, 1187, 1014,
749 cmꢀ1; MS (70 eV, EI): m/z (%): 276 (100) [M]+, 171 (69), 153 (66),
125 (17), 106 (16), 97 (8), 79 (9); elemental analysis calcd (%) for
(S)-N-[2-Amino-4-methoxyphenyl]-S-methyl-S-phenylsulfoximine [(S)-
8eA]: Compound (S)-7eA (438 mg, 1.43 mmol) was dissolved in a mix-
ture of EtOH (12 mL) and H2O (18 mL) and then treated with glacial
acetic acid (1.4 mL, 2.44 mmol) and Fe (239 mg, 4.29 mmol). After re-
fluxing for 5 h and cooling to room temperature, the mixture was parti-
tioned between H2O (20 mL) and CH2Cl2 (50 mL). The aqueous layer
was extracted three times with CH2Cl2 (50 mL), and the combined organ-
ic layers were dried over MgSO4. The solvent was removed, and the
product was purified by flash chromatography (silica gel, dichlorome-
thane/methanol 99:1 with 1% of Et3N) to afford (S)-8eA. Without fur-
6260
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 6254 – 6265

Aminosulfoximines
FULL PAPER
ther characterization this product was directly used in the reductive ami-
nation. (The yield is then given for the two-step sequence.)
(271 mg, 0.81 mmol, 81%) after flash chromatography (silica gel, pen-
tane/EtOAc 3:1 ! 2:1 with 1% Et3N). [a]2D0 =ꢀ82.6 (c=1.0 in CHCl3);
1
m.p. 129–1318C; H NMR (300 MHz, CDCl3): d=3.23 (s, 3H, CH3), 4.43
(S)-N-[2-Amino-4-fluorophenyl]-S-methyl-S-phenylsulfoximine
[(S)-
(s, 2H, CH2), 5.20 (brs, 1H, NH), 6.40–6.45 (m, 1H, Ar-H), 6.54 (dd, J=
8.0, 1.4 Hz, 1H, Ar-H), 6.75–6.79 (m, 1H, Ar-H), 6.90 (dd, J=8.0, 1.4 Hz,
1H, Ar-H), 7.26–7.29 (m, 1H, Ar-H), 7.33–7.37 (m, 2H, Ar-H), 7.40–7.42
(m, 2H, Ar-H), 7.49–7.53 (m, 2H, Ar-H), 7.56–7.61 (m, 1H, Ar-H), 7.93–
7.96 ppm (m, 2H, Ar-H); 13C NMR (75 MHz, CDCl3): d=45.9, 48.1,
110.0, 116.6, 121.0, 122.6, 126.8, 127.1, 128.2, 128.3, 129.3, 130.9, 133.1,
139.1, 140.0, 142.1 ppm; IR (KBr): n˜ =3416, 3015, 1582, 1512, 1443, 1253,
1206, 1128, 1096, 1021, 742, 686 cmꢀ1; MS (70 eV, EI): m/z (%): 336 (39)
[M]+, 195 (64), 119 (100), 105 (16), 91 (26), 78 (8); elemental analysis
calcd (%) for C20H20ON2S (336.45): C 71.40, H 5.99, N 8.33; found: C
71.30, H 5.74, N 8.30.
8 fA]: Compound (S)-7 fA (100 mg, 0.34 mmol) was dissolved in EtOH
(0.93 mL) and H2O (1.40 mL) and then treated with glacial acetic acid
(0.34 mL, 0.59 mmol) and Fe (57 mg, 1.02 mmol). After refluxing for 5 h
and cooling to room temperature, the mixture was partitioned between
H2O (20 mL) and CH2Cl2 (50 mL). The aqueous layer was extracted
three times with CH2Cl2 (50 mL), and the combined organic layers were
dried over MgSO4. The solvent was removed, and the product was puri-
fied by flash chromatography (silica gel, dichloromethane with 1% of
Et3N) to afford (S)-8 fA as a brown oil (48 mg, 0.18 mmol, 53%). [a]D20
=
ꢀ3.4 (c=0.80 in CHCl3); 1H NMR (300 MHz, CDCl3): d=3.22 (s, 3H,
CH3), 4.33 (brs, NH2), 6.10–6.19 (m, 1H, Ar-H), 6.36–6.43 (m, 1H, Ar-
H), 7.75–7.84 (m, 1H, Ar-H), 7.46–7.60 (m, 3H, Ar-H), 7.90–7.95 ppm
(S)-N-{2-[(Naphthalene-1-ylmethyl)-amino]-phenyl}-S-methyl-S-phenyl-
sulfoximine [(S)-4aAb]: The product was prepared according to the gen-
eral procedure 3 by using 1-naphthaldehyde (82 mL, 0.60 mmol), amino-
sulfoximine (S)-8aA (123 mg, 0.50 mmol), glacial acetic acid (31 mL,
0.54 mmol) and NaBH4 (47.3 mg, 1.25 mmol). The target compound was
afforded as a yellow solid (164 mg, 0.42 mmol, 85%) after flash chroma-
tography (silica gel, pentane/EtOAc 4:1 with 1% Et3N). [a]2D0 =ꢀ140.5
(m, 2H, Ar-H); 13C NMR (75 MHz, CDCl3): d=45.6, 101.8 (d, JCF
=
26 Hz, CH), 104.2 (d, JCF =22 Hz, CH), 122.4 (d, JCF =10 Hz, CH), 127.5,
128.4, 129.6, 134.4, 138.8, 141.8 (d, JCF =11 Hz, C), 159.0 ppm (d, JCF
=
238 Hz, CF); IR (KBr): n˜ =3364, 3063, 3014, 1503, 1247, 753 cmꢀ1; MS
(70 eV, EI): m/z (%): 264.1 (100) [M]+; elemental analysis calcd (%) for
C13H13FN2OS (264.32): C 59.07, H 4.96, N 10.60; found: C 59.16, H 5.04,
N 10.76.
1
(c=1.0 in CHCl3); m.p. 170–1718C; H NMR (300 MHz, CDCl3): d=3.13
(s, 3H, CH3), 4.80/4.86 (AB system, J=14.1 Hz, 2H, CH2), 6.43–6.49 (m,
1H, Ar-H), 6.65–6.68 (dd, J=7.9, 1.5 Hz, 1H, Ar-H), 6.80–6.85 (m, 1H,
Ar-H), 6.93–6.96 (dd, J=7.9, 1.4 Hz, 1H, Ar-H), 7.40–7.58 (m, 7H, Ar-
H), 7.80–7.85 (m, 3H, Ar-H), 7.90–7.93 (m, 1H, Ar-H), 8.14–8.18 ppm
(m, 1H, Ar-H); 13C NMR (75 MHz, CDCl3): d=45.8, 46.4, 110.1, 116.9,
121.2, 122.9, 123.6, 125.6, 125.7, 125.8, 126.1, 127.8, 128.4, 128.8, 129.5,
131.2, 131.6, 133.2, 133.9, 135.0, 139.2, 142.7 ppm; IR (KBr): n˜ =3411,
(S)-N-[2-Amino-4-trifluoromethylphenyl]-S-methyl-S-phenylsulfoximine
[(S)-8gA]: Compound (S)-7gA (540 mg, 1.57 mmol) was dissolved in
EtOH (13 mL) and H2O (19.5 mL) and then treated with glacial acetic
acid (1.6 mL, 2.79 mmol) and Fe (262 mg, 4.70 mmol). After refluxing for
5 h and cooling to room temperature, the mixture was partitioned be-
tween H2O (20 mL) and CH2Cl2 (50 mL). The aqueous layer was extract-
ed three times with CH2Cl2 (50 mL), and the combined organic layers
were dried over MgSO4. The solvent was removed, and the product was
purified by flash chromatography (silica gel, dichloromethane/methanol
99:1 with 1% of Et3N) to afford (S)-8gA as a brown solid (449 mg,
1.43 mmol, 91%). [a]2D0 =ꢀ20.0 (c=1.20 in CHCl3); m.p. 90–928C;
1H NMR (300 MHz, CDCl3): d=3.29 (s, 3H, CH3), 4.21 (brs, NH2), 6.70
(d, J=8.4 Hz, 1H), 6.89 (s, 1H, Ar-H), 6.90 (d, J=8.4 Hz, 1H, Ar-H),
7.51–7.66 (m, 3H, Ar-H), 7.93–7.96 ppm (m, 2H, Ar-H); 13C NMR
(100 MHz, CDCl3): d=46.3, 110.9, 115.2, 120.8, 124.2 (q, JCF =30 Hz, C),
124.6 (q, JCF =272 Hz, CF3), 128.4, 129.8, 133.6, 134.8, 138.6, 140.8 ppm;
IR (KBr): n˜ =3463, 3357, 3105, 3000, 2926, 1621, 1515, 1442, 1336, 1242,
1105, 747 cmꢀ1; MS (70 eV, EI): m/z (%): 314.1 (100) [M]+; elemental
analysis calcd (%) for C14H13F3N2OS (314.33): C 53.50, H 4.17, N 8.91;
found: C 53.32, H 4.18, N 8.66.
3056, 2918, 1586, 1513, 1438, 1253, 1207, 1132, 1094, 1020, 789, 739, cmꢀ1
;
MS (70 eV, EI): m/z (%): 386 (21) [M]+, 245 (40), 141 (34), 128 (6), 119
(100), 105 (5), 78 (3); elemental analysis calcd (%) for C24H22ON2S
(386.51): C 74.58, H 5.74, N 7.25; found: C 74.48, H 5.99, N 7.56.
(S)-N-[2-(2-Methoxybenzylamino)phenyl]-S-methyl-S-phenyl-sulfoximine
[(S)-4aAg]: The product was prepared according to the general proce-
dure 3 by using o-anisaldehyde (99.0 mg, 0.73 mmol), aminosulfoximine
(S)-8aA (150 mg, 0.61 mmol), glacial acetic acid (37.0 mL, 0.65 mmol)
and NaBH4 (57.5 mg, 1.52 mmol). The target compound was afforded as
a colorless solid (181 mg, 0.49 mmol, 81%) after flash chromatography
(silica gel, pentane/EtOAc 2:1 with 1% Et3N). [a]2D0 =ꢀ95.5 (c=1.0 in
CHCl3); m.p. 144–1458C; 1H NMR (300 MHz, CDCl3): d=3.24 (s, 3H,
CH3), 3.89 (s, 3H, OCH3), 4.45 (s, 2H, CH2), 5.30 (brs, 1H, NH), 6.39–
6.44 (m, 1H, Ar-H), 6.57 (dd, J=8.1, 1.4 Hz, 1H, Ar-H), 6.75–6.81 (m,
1H, Ar-H), 6.90–6.95 (m, 3H, Ar-H), 7.22–7.28 (m, 1H, Ar-H), 7.33–7.35
(m, 1H, Ar-H), 7.47–7.62 (m, 3H, Ar-H), 7.94–7.98 ppm (m, 2H, Ar-H);
13C NMR (75 MHz, CDCl3): d=43.0, 45.9, 55.3, 110.1, 110.3, 116.5, 120.5,
121.2, 122.9, 127.9, 128.1, 128.4, 128.5, 129.5, 131.2, 133.2, 139.4, 142.5,
157.3 ppm; IR (KBr): n˜ =3428, 2919, 1585, 1513, 1490, 1437, 1271, 1245,
1204, 1132, 1110, 1020, 740 cmꢀ1; MS (70 eV, EI): m/z (%): 366 (26) [M]+
, 225 (75), 122 (24), 119 (100), 105 (6), 91 (26), 77 (6); elemental analysis
calcd (%) for C21H22O2N2S (366.48): C 68.82, H 6.05, N 7.64; found: C
68.53, H 5.82, N 7.42.
General procedure 3 (reductive amination with NaBH4): A solution of
aminosulfoximines 8aA or 8aB in MeOH (c=0.1 mmolmLꢀ1) was treat-
ed with the corresponding aldehyde (1.1–1.2 equiv) and glacial acetic
acid (1.0–1.1 equiv) After stirring at room temperature for 3 h, the mix-
ture was cooled to 08C and NaBH4 (2.5 equiv) was added in small por-
tions over a period of 10–20 min. The resulting mixture was stirred over
night at room temperature and then partitioned between 10% aqueous
K2CO3 (10–20 mL) and CH2Cl2 (20 mL). The aqueous layer was extract-
ed with CH2Cl2 (3”10–20 mL), the combined organic layers were dried
over MgSO4 and the solvent was evaporated. The product was then puri-
fied by flash chromatography (silica gel).
(S)-N-[2-(2,4,6-Trimethylbenzylamino)phenyl]-S-methyl-S-phenylsulfoxi-
mine [(S)-4aAd]: The product was prepared according to the general
procedure 4 by using 2,4,6-trimethylbenzaldehyde (369 mL, 2.50 mmol),
aminosulfoximine (S)-8aA (246 mg, 1.00 mmol) and NaBH3CN (62.9 mg,
General procedure 4 (reductive amination with NaBH3CN): A solution
of aminosulfoximines 8aA–gA or 8aB in MeOH (c=0.5 mmolmLꢀ1) and
the corresponding aldehyde (1.2–2.5 equiv) was treated with NaBH3CN
(0.9–1.0 equiv) at 08C. Then the pH was adjusted to 6 by dropwise addi-
tion of glacial acetic acid. After stirring at room temperature over night,
the mixture was diluted with CH2Cl2 (20 mL) and hydrolyzed with 10%
aqueous K2CO3 (10 mL). The aqueous layer was extracted with CH2Cl2
(3”10 mL), the combined organic layers were dried over MgSO4 and the
solvent was evaporated. Then the product was purified by flash chroma-
tography (silica gel).
1.00 mmol). The target compound was afforded as
a yellow solid
(320 mg, 0.85 mmol, 85%) after flash chromatography (silica gel, pen-
tane/EtOAc 6:1 ! 4:1 ! 2:1 with 1% Et3N). [a]2D0 =ꢀ177.3 (c=0.4 in
CHCl3); m.p. 178–1808C; 1H NMR (300 MHz, CDCl3): d=2.31 (s, 3H,
CH3), 2.41 (s, 6H, CH3), 3.14 (s, 3H, CH3), 4.19/4.27 (AB system, J=
11.4 Hz, 2H, CH2), 6.42–6.47 (m, 1H, Ar-H), 6.73 (dd, J=8.0, 1.5 Hz,
1H, Ar-H), 6.86–6.93 (m, 4H, Ar-H), 7.42–7.48 (m, 2H, Ar-H), 7.52–7.57
(m, 1H, Ar-H), 7.83–7.87 (m, 2H, Ar-H) ppm; 13C NMR (75 MHz,
CDCl3): d=19.5, 21.0, 42.7, 46.1, 109.9, 116.6, 121.2, 122.9, 128.5, 129.0,
129.5, 131.3, 132.8, 133.1, 137.0, 137.7, 139.4, 142.9 ppm; IR (KBr): n˜ =
3398, 2920, 1587, 1509, 1428, 1256, 1190, 1124, 1022, 734, 688, cmꢀ1; MS
(70 eV, EI): m/z (%): 378 (74) [M]+, 246 (14), 237 (44), 221 (20), 181 (9),
(S)-N-(2-Benzylaminophenyl)-S-methyl-S-phenylsulfoximine [(S)-4aAa]:
The product was prepared according to the general procedure 3 by using
benzaldehyde (122 mL, 1.20 mmol), aminosulfoximine (S)-8aA (246 mg,
1.00 mmol), glacial acetic acid (570 mL, 1.0 mmol) and NaBH4 (94.6 mg,
2.50 mmol). The target compound was afforded as a colorless solid
Chem. Eur. J. 2005, 11, 6254 – 6265
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6261

C. Bolm et al.
133 (58), 119 (100), 105 (10), 91 (6), 77 (5); elemental analysis calcd (%)
for C23H26N2OS (378.53): C 72.98, H 6.92, N 7.40; found: C 73.15, H 6.86,
N 7.53.
1% Et3N), which slowly crystallized under reduced pressure. [a]D20
=
ꢀ45.4 (c=2.85 in CHCl3); m.p. 568C; 1H NMR (400 MHz, CDCl3): d=
1.22 (d, J=6.9 Hz, 6H, CH3), 1.27 (d, J=6.9 Hz, 12H, CH3), 2.92 (sep.,
J=6.9 Hz, 1H, CH), 3.13 (s, 3H, CH3), 3.18 (s, 3H, OCH3), 3.28 (sep.,
J=6.8 Hz, 2H, CH), 4.23 (s, 2H, CH2), 4.7 (brs, 1H, NH), 6.53–6.59 (m,
1H, Ar-H), 6.74 (dd, J=8.0 Hz, 1.1 Hz, 1H, Ar-H), 6.83 (d, J=8.2 Hz,
1H, Ar-H), 6.94–6.99 (m, 1H, Ar-H), 7.00–7.05 (m, 1H, Ar-H), 7.07 (s,
2H, Ar-H), 7.11 (dd, J=7.6, 1.3 Hz, 1H, Ar-H), 7.45–7.50 (m, 1H, Ar-
H), 7.99 ppm (dd, J=7.7 Hz, 1.6 Hz, 1H, Ar-H); 13C NMR (100 MHz,
CDCl3): d=24.1, 24.5, 24.7, 29.2, 34.3, 40.5, 42.1, 54.8, 109.3, 111.9, 116.2,
120.4, 121.0, 123.1, 123.2, 127.1, 130.1, 130.6, 130.8, 134.7, 143.4, 148.1,
148.2, 156.4 ppm; IR (KBr): n˜ =3383, 2961, 2868, 1590, 1501, 1431, 1265,
1191, 1070, 1047, 1021, 801, 742 cmꢀ1; MS (70 eV, EI): m/z (%): 492 (58)
[M]+, 307 (72), 276 (100), 217 (10), 171 (9), 153 (8); elemental analysis
calcd (%) for C30H40N2O2S (492.72): C 73.13, H 8.18, N 5.69; found: C
73.32, H 8.25, N 5.37.
(S)-N-[2-(2,4,6-Triisopropylbenzylamino)phenyl]-S-methyl-S-phenylsul-
foximine [(S)-4aAe]: The product was prepared according to the general
procedure
3
by using 2,4,6-triisopropylbenzaldehyde (837 mg,
3.60 mmol), aminosulfoximine (S)-8aA (739 mg, 3.00 mmol), glacial
acetic acid (172 mL, 3.00 mmol) and NaBH4 (284 mg, 7.50 mmol). The
target compound was afforded as a colorless solid (1.14 g, 2.46 mmol,
82%) after flash chromatography (silica gel, pentane/EtOAc 10:1).
[a]2D0 =ꢀ164.2 (c=0.5 in CHCl3); m.p. 129–1308C; 1H NMR (300 MHz,
CDCl3): d=1.30 (d, J=6.9 Hz, 18H, CH3), 2.89–2.98 (m, 1H, CH), 3.12
(s, 3H, CH3), 3.28–3.38 (m, 2H, CH), 4.22/4.31 (AB system, J=11.5 Hz,
2H, CH2), 4.58 (brs, 1H, NH), 6.44 (t, J=7.7 Hz, 1H, Ar-H), 6.74 (d, J=
7.6 Hz, 1H, Ar-H), 6.87–6.90 (m, 2H, Ar-H), 7.10 (s, 2H, Ar-H), 7.42–
7.47 (m, 2H, Ar-H), 7.52–7.57 (m, 1H, Ar-H), 7.84 ppm (d, J=7.4 Hz,
2H, Ar-H); 13C NMR (75 MHz, CDCl3): d=24.0, 24.7, 24.8, 29.4, 34.3,
40.8, 46.3, 109.6, 116.5, 120.8, 121.2, 122.6, 128.5, 129.5, 130.3, 131.3,
133.1, 139.3, 142.5, 148.2 ppm; IR (KBr): n˜ =3408, 2960, 2867, 1590, 1502,
1426, 1261, 1241, 1195, 1125, 1094, 1024, 740, 688 cmꢀ1; MS (70 eV, EI):
m/z (%): 462 (39) [M]+, 307 (34), 246 (100), 216 (27), 201 (21), 173 (6),
119 (8), 105 (7); elemental analysis calcd (%) for C29H38N2OS (462.69): C
75.28, H 8.28, N 6.05; found: C 75.43, H 8.19, N 5.86.
(S)-N-[3-Methyl-2-(2,4,6-trimethylbenzylamino)phenyl]-S-methyl-S-phe-
nylsulfoximine [(S)-4bAd]: The product was prepared according to the
general procedure
4 by using 2,4,6-trimethylbenzaldehyde (90 mg,
0.61 mmol), aminosulfoximine (S)-8bA (132 mg, 0.51 mmol), NaBH3CN
(32 mg, 0.51 mmol) and methanol (7 mL). The target compound was af-
forded as a yellow oil (117 mg, 0.30 mmol, 59%) after flash chromatogra-
phy (silica gel, dichloromethane/methanol 99:1). [a]2D0 =ꢀ56.5 (c=1.32 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=2.28 (s, 3H, CH3), 2.44 (s, 3H,
CH3), 2.46 (s, 6H, CH3), 3.08 (s, 3H, CH3), 4.12/4.22 (AB system, J=
11.5 Hz, 2H, CH2), 6.26 (d, J=8.0 Hz, 1H, Ar-H), 6.53–6.58 (m, 1H, Ar-
H), 6.67–6.75 (m, 1H, Ar-H), 6.89 (s, 2H, Ar-H), 7.38–7.56 (m, 3H, Ar-
H), 7.65–7.69 ppm (m, 2H, Ar-H); 13C NMR (100 MHz, CDCl3): d=19.6,
20.0, 21.2, 45.7, 46.7, 118.4, 121.1, 124.8, 128.4, 129.0, 129.4, 129.5, 133.1,
134.5, 136.3, 136.6, 137.4, 139.2, 142.2 ppm; IR (KBr): n˜ =3326, 3011,
1445, 1264, 746 cmꢀ1; MS (70 eV, EI): m/z (%): 392.2 (22) [M]+; elemen-
tal analysis calcd (%) for C24H28N2OS (392.56): C 73.43, H 7.19, N 7.14;
found C 73.54, H 7.30, N 7.03.
(S)-N-[2-(2,4,6-Trimethoxybenzylamino)phenyl]-S-methyl-S-phenylsul-
foximine [(S)-4aAf]: The product was prepared according to the general
procedure 1 by using 2,4,6-trimethoxybenzaldehyde (108 mg, 0.55 mmol),
aminosulfoximine (S)-8aA (123 mg, 0.50 mmol), glacial acetic acid
(31 mL, 0.54 mmol) and NaBH4 (47.3 mg, 1.25 mmol). The target com-
pound was afforded as a colorless solid (182 mg, 0.42 mmol, 85%) after
flash chromatography (silica gel, pentane/EtOAc 3:2 ! 1:1 with 1%
Et3N). [a]2D0 =ꢀ40.0 (c=0.38, CHCl3); m.p. 1998C; 1H NMR (400 MHz,
CD2Cl2): d=3.09 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 3.77 (s, 6H, OCH3),
4.21/4.27 (AB system, 2H, CH2), 5.10 (brs, 1H, NH), 6.09 (s, 2H, Ar-H),
6.19–6.25 (m, 1H, Ar-H), 6.65–6.74 (m, 3H, Ar-H), 7.37–7.43 (m, 2H,
Ar-H), 7.47–7.52 (m, 1H, Ar-H), 7.74–7.78 ppm (m, 2H, Ar-H);
13C NMR (100 MHz, CD2Cl2): d=36.1, 45.9, 55.4, 55.8, 90.7, 108.7, 110.5,
115.8, 120.7, 122.6, 128.4, 129.4, 131.6, 133.1, 139.5, 142.9, 159.3,
160.5 ppm; IR (KBr): n˜ =3406, 2932, 1591, 1507, 1464, 1417, 1255, 1224,
1194, 1134, 812, 742 cmꢀ1; MS (70 eV, EI): m/z (%): 426 (26) [M]+, 285
(93), 181 (100), 168 (8), 136 (10), 121 (13); elemental analysis calcd (%)
for C23H26N2O4S (426.53): C 64.77, H 6.14, N 6.57; found: C 64.44, H
5.78, N 6.32.
(S)-N-[4-Methyl-2-(2,4,6-trimethylbenzylamino)phenyl]-S-methyl-S-phe-
nylsulfoximine [(S)-4cAd]: The product was prepared according to the
general procedure
4 by using 2,4,6-trimethylbenzaldehyde (66 mg,
0.45 mmol), aminosulfoximine (S)-8cA (97 mg, 0.37 mmol), NaBH3CN
(23 mg, 0.37 mmol) and methanol (5 mL). The target compound was af-
forded as a brown solid (125 mg, 0.32 mmol, 86%) after flash chromatog-
raphy (silica gel, dichloromethane/methanol 99:1). [a]2D0 =ꢀ128.8 (c=1.09
in CHCl3); m.p. 1408C; 1H NMR (400 MHz, CDCl3): d=2.24 (s, 3H,
CH3), 2.31 (s, 3H, CH3), 2.40 (s, 6H, CH3), 3.11 (s, 3H, CH3), 4.17/4.26
(AB system, J=11.3 Hz, 2H, CH2), 4.40 (brs, NH), 6.26 (d, J=8.0 Hz,
1H, Ar-H), 6.54 (s, 1H, Ar-H), 6.82 (d, J=8.0 Hz, 1H, Ar-H), 6.93 (s,
2H, Ar-H), 7.40–7.55 (m, 3H, Ar-H), 7.83–7.85 ppm (m, 2H, Ar-H);
13C NMR (100 MHz, CDCl3): d=19.5, 20.9, 21.4, 42.6, 45.9, 100.7, 116.8,
120.9, 128.2, 128.4, 128.8, 129.2, 132.1, 132.6, 132.8, 136.7, 137.4, 139.2,
142.4 ppm; IR (KBr): n˜ =3393, 2915, 1578, 1244, 1090 cmꢀ1; MS (70 eV,
EI): m/z (%): 392.2 (39) [M]+; elemental analysis calcd (%) for
C24H28N2OS (392.56): C 73.43, H 7.19, N 7.14; found C 73.20, H 7.46, N
6.92.
(R)-N-[2-(2,4,6-Trimethylbenzylamino)phenyl]-S-(2-methoxy-phenyl)-S-
methylsulfoximine [(R)-4aBd]: The product was prepared according to
the general procedure 4 by using 2,4,6-trimethylbenzaldehyde (184 mL,
1.25 mmol), aminosulfoximine (R)-8aB (138 mg, 0.5 mmol) and
NaBH3CN (31.4 mg, 0.50 mmol). The target compound was afforded as a
colorless solid (148 mg, 0.36 mmol, 72%) after flash chromatography
(silica gel, pentane/EtOAc 3:1 with 1% Et3N). [a]2D0 =ꢀ64.7 (c=1.0 in
CHCl3); m.p. 121–1238C; 1H NMR (400 MHz, CDCl3): d=2.30 (s, 3H,
CH3), 2.33 (s, 6H, CH3), 3.24 (s, 3H, CH3), 3.38 (s, 3H, OCH3), 4.16 (s,
2H, CH2), 4.54 (brs, 1H, NH), 6.49–6.54 (m, 1H, Ar-H), 6.67–6.70 (m,
1H, Ar-H), 6.83–6.87 (m, 1H, Ar-H), 6.89–6.95 (m, 3H, Ar-H), 7.00–7.07
(m, 2H, Ar-H), 7.46–7.51 (m, 1H, Ar-H), 7.95–7.99 ppm (m, 1H, Ar-H);
13C NMR (100 MHz, CDCl3): d=19.5, 20.9, 42.5, 42.8, 55.1, 109.4, 112.0,
116.1, 120.4, 122.9, 123.1, 128.7, 130.2, 131.0, 132.8, 134.6, 136.6, 137.6,
143.5, 156.4 ppm; IR (KBr): n˜ =3386, 2933, 1587, 1508, 1478, 1432, 1259,
1190, 1018, 765, 737 cmꢀ1; MS (70 eV, EI,): m/z (%): 408 (42) [M]+, 237
(32), 221 (14), 171 (6), 133 (49), 119 (100), 105 (5); elemental analysis
calcd (%) for C24H28N2O2S (408.56): C 70.55, H 6.91, N 6.86; found: C
70.87, H 6.60, N 6.74.
(S)-N-[4,5-Dimethyl-2-(2,4,6-trimethylbenzylamino)phenyl]-S-methyl-S-
phenylsulfoximine [(S)-4dAd]: The product was prepared according to
the general procedure 4 by using 2,4,6-trimethylbenzaldehyde (110 mg,
0.74 mmol), aminosulfoximine (S)-8dA (204 mg, 0.74 mmol), NaBH3CN
(42 mg, 0.67 mmol) and methanol (11.9 mL). The target compound was
afforded as an orange solid (236 mg, 0.58 mmol, 78%) after flash chro-
matography (silica gel, pentane/EtOAc 8.5:1.5). [a]2D0 =ꢀ78 (c=1.14 in
CHCl3); m.p. 1578C; 1H NMR (300 MHz, CDCl3): d=2.01 (s, 3H, CH3),
2.17 (s, 3H, CH3), 2.31 (s, 3H, CH3), 2.41 (s, 6H, CH3), 3.11 (s, 3H, CH3),
4.16/4.25 (AB system, J=11.1 Hz, 2H, CH2), 6.54 (s, 1H, Ar-H), 6.75 (s,
1H, Ar-H), 6.92 (s, 2H, Ar-H), 7.40–7.57 (m, 3H, Ar-H), 7.84–7.88 (m,
2H, Ar-H) ppm; 13C NMR (75 MHz, CDCl3): d=19.5, 19.6, 21.0, 43.1,
45.9, 112.0, 123.1, 124.1, 128.5, 128.8, 129.0, 129.4, 130.4, 133.0, 133.1,
136.8, 137.6, 139.7, 140.9 ppm; IR (KBr): n˜ =3421, 3000, 2915, 2852, 1610,
1515, 1442, 1242, 1126, 1015, 852 cmꢀ1; MS (70 eV, EI): m/z (%): 406.2
(76) [M]+; elemental analysis calcd (%) for C25H30N2OS (406.58): C
73.85, H 7.44, N 6.89; found C 73.63, H 7.17, N 6.65.
(R)-N-[2-(2,4,6-Triisopropylbenzylamino)phenyl]-S-(2-methoxyphenyl)-
S-methylsulfoximine [(R)-4aBe]: The product was prepared according to
the general procedure 3 by using 2,4,6-triisopropylbenzaldehyde (139 mg,
0.60 mmol), aminosulfoximine (R)-8aB (138 mg, 0.50 mmol), glacial
acetic acid (30 mL, 0.54 mmol), and NaBH4 (47.3 mg, 1.25 mmol). The
target compound was afforded as a colorless oil (157 mg, 0.32 mmol,
64%) after flash chromatography (silica gel, pentane/EtOAc 10:1 with
6262
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 6254 – 6265

Aminosulfoximines
FULL PAPER
(S)-N-[4-Methoxy-2-(2,4,6-trimethylbenzylamino)phenyl]-S-methyl-S-
phenylsulfoximine [(S)-4eAd]: The product was prepared according to
the general procedure 4 by using 2,4,6-trimethylbenzaldehyde (114 mg,
0.77 mmol), aminosulfoximine (S)-8eA (214 mg, 0.77 mmol), NaBH3CN
(44 mg, 0.70 mmol) and methanol (12.4 mL). The target compound was
afforded as a yellow oil [172 mg, 0.42 mmol, 30% yield over two steps
(nitro group reduction and reductive amination)] after flash chromatog-
raphy (silica gel, pentane/EtOAc 8.5:1.5). [a]2D0 =ꢀ101 (c=1.00 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=2.31 (s, 3H, CH3), 2.40 (s, 6H,
CH3), 3.11 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 4.16/4.23 (AB system, J=
11.5 Hz, 2H, CH2), 4.47 (brs, NH), 5.98 (dd, J=8.5, 2.8 Hz, 1H, Ar-H),
6.30 (d, J=2.8 Hz, 1H, Ar-H), 6.84 (d, J=8.5 Hz, 1H, Ar-H), 6.92 (s,
2H, Ar-H), 7.41–7.56, (m, 3H, Ar-H), 7.81–7.85 ppm (m, 2H, Ar-H);
13C NMR (100 MHz, CDCl3): d=19.5, 20.9, 42.4, 45.7, 55.1, 97.3, 99.2,
121.5, 124.5, 128.3, 128.8, 129.2, 132.3, 132.9, 136.8, 137.4, 139.2, 143.7,
155.9 ppm; IR (KBr): n˜ =3410, 3063, 3010, 2926, 2873, 1621, 1584, 1510,
1447, 1421, 1258, 1211, 1052, 752 cmꢀ1; MS (70 eV, EI): m/z (%): 408.2
(100) [M]+; elemental analysis calcd (%) for C24H28N2O2S (408.56): C
70.55, H 6.91, N 6.86; found C 70.31, H 6.61, N 6.70.
(ꢀ)-(R)-Methyl 2-hydroxy-2-methyl-4-oxo-4-phenyl butanoate [(R)-3a]:
The product was prepared according to the general procedure 5 by using
methyl pyruvate (2a, 46 mL, 0.50 mmol), enolsilane 1a (123 mL,
0.60 mmol) and aminosulfoximine (S)-4aAe (23.1 mg, 0.05 mmol). After
stirring for 15 h at ꢀ308C, the product was obtained as a colorless oil
(99 mg, 0.45 mmol, 89%, 98% ee) after flash chromatography (silica gel,
pentane/EtOAc 10:1 ! 4:1). [a]2D0 =ꢀ86.7 (c=1.0 in CHCl3); lit: [a]2D0
=
+84.4 (c=3.5 in CHCl3) for (S), 99% ee;[9] 1H NMR (400 MHz, CDCl3):
d=1.52 (s, 3H, CH3), 3.36 (d, J=17.6 Hz, 1H, CH2), 3.67 (d, J=17.9 Hz,
1H, CH2), 3.78 (s, 3H, CH3), 3.99 (brs, 1H, OH), 7.45–7.49 (m, 2H, Ar-
H), 7.57–7.61 (m, 1H, Ar-H), 7.93–7.96 ppm (m, 2H, Ar-H); 13C NMR
(100 MHz, CDCl3): d=26.4, 47.9, 52.7, 72.6, 128.0, 128.5, 133.5, 136.1,
176.2, 198.6 ppm; IR (film): n˜ =3512, 2985, 2953, 1742, 1683, 1597, 1450,
1365, 1218, 1115, 1008, 986, 759, 692 cmꢀ1; MS (70 eV, CI, CH4): m/z (%):
223 (49) [M+H]+, 163 (100), 105 (22); elemental analysis calcd (%) for
C12H14O4 (222.24): C 64.85, H 6.35; found: C 65.20, H 6.62; HPLC: tr(R)
= 25.3 min, tr(S) = 31.5 min (Chiralcel OD, flow rate 0.5 mLminꢀ1, hep-
tane/iPrOH 95:5, l=254 nm, 258C).
(ꢀ)-(R)-Benzyl 2-hydroxy-2-methyl-4-oxo-4-phenyl butanoate [(R)-3b]:
The product was prepared according to the general procedure 5 by using
benzyl pyruvate (2b, 123 mg, 0.69 mmol), silyl enol ether 1a (170 mL,
0.83 mmol), aminosulfoximine (S)-4aAe (32 mg, 0.07 mmol) and 2,2,2-tri-
fluoroethanol (61 mL, 0.83 mmol). After stirring for 47 h at ꢀ508C, the
product was obtained as a colorless oil (176 mg, 0.59 mmol, 86%, 98%
ee) after flash chromatography (silica gel, pentane/EtOAc 10:1 ! 4:1).
[a]2D0 =ꢀ41.8 (c=1.1 in CHCl3); 1H NMR (400 MHz, CDCl3): d=1.52 (s,
3H, CH3), 3.35 (d, J=17.6 Hz, 1H, CH2), 3.67 (d, J=17.5 Hz, 1H, CH2),
4.03 (brs, 1H, OH), 5.18/5.22 (AB system, J=12.3 Hz, 2H, CH2), 7.28–
7.30 (m, 5H, Ar-H), 7.44–7.48 (m, 2H, Ar-H), 7.56–7.60 (m, 1H, Ar-H),
7.90–7.93 ppm (m, 2H, Ar-H); 13C NMR (100 MHz, CDCl3): d=26.4,
47.8, 67.3, 72.7, 127.9, 128.0, 128.1, 128.3, 128.5, 133.5, 135.3, 136.1, 175.5,
198.5 ppm; IR (film): n˜ =3533, 2981, 1740, 1682, 1597, 1452, 1365, 1217,
1111, 754, 693, cmꢀ1; MS (70 eV, CI, CH4): m/z (%): 299 (25) [M+H]+,
163 (20), 121 (41), 91 (100); elemental analysis calcd (%) for C18H18O4
(S)-N-[4-Fluoro-2-(2,4,6-trimethylbenzylamino)phenyl]-S-methyl-S-phe-
nylsulfoximine [(S)-4 fAd]: The product was prepared according to the
general procedure
4 by using 2,4,6-trimethylbenzaldehyde (22 mg,
0.15 mmol), aminosulfoximine (S)-8 fA (33 mg, 0.12 mmol), NaBH3CN
(7.5 mg, 0.12 mmol) and methanol (2 mL). The target compound was af-
forded as a yellow solid (40 mg, 0.10 mmol, 83%) after flash chromatog-
raphy (silica gel, dichloromethane/methanol 99:1). [a]2D0 =ꢀ174.4 (c=1.01
in CHCl3); m.p. 1658C; 1H NMR (400 MHz, CDCl3): d=2.31 (s, 3H,
CH3), 2.40 (s, 6H, CH3), 3.13 (s, 3H, CH3), 4.14/4.21 (AB system, J=
11.4 Hz, 2H, CH2), 4.56 (brs, NH), 6.08–6.13 (m, 1H, Ar-H), 6.39–6.44
(m, 1H, Ar-H), 6.79–6.83 (m, 1H, Ar-H), 6.93 (s, 2H, Ar-H), 7.44–7.58
(m, 3H, Ar-H), 7.80–7.83 ppm (m, 2H, Ar-H); 13C NMR (100 MHz,
CDCl3): d=19.5, 20.9, 42.3, 45.9, 97.0 (d, JCF =27 Hz, CH), 101.4 (d, JCF
=
22 Hz, CH), 121.1 (d, JCF =10 Hz, CH), 126.6, 128.2, 128.7, 129.3, 131.9,
133.0, 136.9, 137.4, 138.9, 143.8 (d, JCF =11 Hz, C), 159.5 ppm (d, JCF
=
237 Hz, CF); IR (KBr): n˜ =3019, 2926, 1257, 759 cmꢀ1; MS (70 eV, EI):
m/z (%): 396.2 (54) [M]+; elemental analysis calcd (%) for C23H25FN2OS
(396.52): C 69.67, H 6.35, N 7.06; found C 69.91, H 6.61, N 6.73.
(298.34): C 72.47, H 6.08; found: C 72.27, H 5.98; HPLC: tr(R) =
29.7 min, tr(S) = 34.4 min (Chiralcel OD, flow rate 0.5 mLminꢀ1, hep-
tane/iPrOH 95:5, l=254 nm, 258C). The absolute configuration was as-
signed in analogy to 3a.
(S)-N-[4-Trifluoromethyl-2-(2,4,6-trimethylbenzylamino)phenyl]-S-
methyl-S-phenylsulfoximine [(S)-4gAd]: The product was prepared ac-
cording to the general procedure 4 by using 2,4,6-trimethylbenzaldehyde
(73 mg, 0.49 mmol), aminosulfoximine (S)-8gA (154 mg, 0.49 mmol),
NaBH3CN (28 mg, 0.44 mmol) and methanol (7.9 mL). The target com-
pound was afforded as a yellow solid (127 mg, 0.29 mmol, 58%) after
flash chromatography (silica gel, pentane/EtOAc 8.5:1.5). [a]2D0 =ꢀ170
(c=1.05 in CHCl3); m.p. 45–508C; 1H NMR (400 MHz, CDCl3): d=2.31
(s, 3H, CH3), 2.41 (s, 6H, CH3), 3.16 (s, 3H, CH3), 4.19/4.27 (AB system,
J=11.5 Hz, 2H, CH2), 4.63 (brs, NH), 6.66 (d, J=8.0 Hz, 1H, Ar-H),
6.85 (s, 1H, Ar-H), 6.89 (d, J=8.0 Hz, 2H, Ar-H), 6.94 (s, 1H, Ar-H),
7.44–7.59 (m, 3H, Ar-H), 7.79–7.83 ppm (m, 2H, Ar-H); 13C NMR
(100 MHz, CDCl3): d=19.7, 21.1, 42.6, 46.6, 105.6, 113.4, 119.8, 124.3 (q,
(ꢀ)-(R)-Isopropyl 2-hydroxy-2-methyl-4-oxo-4-phenyl butanoate [(R)-
3c]: The product was prepared according to the general procedure 5 by
using isopropyl pyruvate (2c, 65 mg, 0.50 mmol), enolsilane 1a (123 mL,
0.60 mmol) and aminosulfoximine (S)-4aAe (23.1 mg, 0.05 mmol). After
stirring for 28 h at ꢀ408C, the product was obtained as a colorless oil
(112 mg, 0.45 mmol, 90%, 99% ee) after flash chromatography (silica
gel, pentane/EtOAc 12:1
!
10:1). [a]2D0 =ꢀ58.6 (c=2.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=1.20 (d, J=6.3 Hz, 3H, CH3), 1.27 (d,
J=6.3 Hz, 3H, CH3), 1.50 (s, 3H, CH3), 3.34 (d, J=17.6 Hz, 1H, CH2),
3.64 (d, J=17.6 Hz, 1H, CH2), 3.96 (brs, 1H, OH), 5.07–5.12 (m, J=
6.3 Hz, 1H, CH), 7.45–7.49 (m, 2H, Ar-H), 7.57–7.61 (m, 1H, Ar-H),
7.93–7.95 ppm (m, 2H, Ar-H); 13C NMR (100 MHz, CDCl3): d=21.5,
21.6, 26.4, 47.8, 69.2, 72.5, 127.9, 128.5, 133.4, 136.3, 175.2, 198.4 ppm; IR
(film): n˜ =3533, 3019, 2983, 1732, 1684, 1598, 1451, 1375, 1217, 1104, 757,
690 cmꢀ1; MS (70 eV, CI, CH4): m/z (%): 251 (48) [M+H]+, 209 (100),
191 (22), 163 (74); elemental analysis calcd (%) for C14H18O4 (250.29): C
67.18, H 7.25; found C 67.47, H 7.05; HPLC: tr(S) = 18.7 min, tr(R) =
22.2 min (Chiralcel OJ, flow rate 0.5 mLminꢀ1, heptane/iPrOH 90:10, l=
254 nm, 258C). The absolute configuration was assigned in analogy to 3a.
J
CF =32 Hz, C), 125.0 (q, JCF =271 Hz, CF3), 128.3, 129.1, 129.7, 132.1,
133.5, 134.5, 137.2, 137.6, 138.6, 142.6 ppm; IR (KBr): n˜ =3389, 3105,
3031, 2926, 2873, 1605, 1521, 1442, 1263, 1105, 1015, 742 cmꢀ1; MS (70 eV,
EI): m/z (%): 446.2 (60) [M]+; elemental analysis calcd (%) for
C24H25F3N2OS (446.53): C 64.55, H 5.64, N 6.27; found C 64.38, H 5.64, N
6.23.
General procedure
Schlenk-flask under argon atmosphere was charged with Cu(OTf)2
(18 mg, 0.05 mmol) and the corresponding aminosulfoximine
5 (Mukaiyama-aldol reaction): A flame-dried
(ꢀ)-(R)-Ethyl 2-hydroxy-4-oxo-4-phenyl-[2-phenylethyl] butanoate [(R)-
3d]: The product was prepared according to the general procedure 5 by
using ethyl 2-oxo-4-phenyl butyrate (2d, 95 mL, 0.50 mmol), enolsilane 1a
(123 mL, 0.60 mmol) and aminosulfoximine (S)-4aAe (23.1 mg,
0.05 mmol). After stirring for 40 h at ꢀ208C, the product was obtained as
a colorless oil (140 mg, 0.43 mmol, 86%, 96% ee) after flash chromatog-
raphy (silica gel, pentane/EtOAc 10:1). [a]2D0 =ꢀ28.5 (c=0.8 in CHCl3);
1H NMR (400 MHz, CDCl3): d=1.28 (t, J=7.1 Hz, 3H, CH3), 2.07–2.11
(m, 2H, CH2), 2.53–2.61 (m, 1H, CH2), 2.86–2.93 (m, 1H, CH2), 3.44 (d,
J=17.3 Hz, 1H, CH2), 3.58 (d, J=17.3 Hz, 1H, CH2), 3.98 (brs, 1H,
OH), 4.24 (q, J=7.1 Hz, 2H, CH2), 7.18–7.21 (m, 3H, Ar-H), 7.27–7.31
4
(0.05 mmol). Then, dry THF (2 mL) was added and the resulting deep
green solution was stirred for 30 min at room temperature. Subsequently,
the selected temperature was adjusted and the corresponding a-keto
ester 2a–e (0.50 mmol), the corresponding enolsilane 1a–d (0.60–
0.75 mmol) and 2,2,2-trifluoroethanol (0.60 mmol, 44 mL) were added.
After stirring for the indicated period of time, the mixture was warmed
to room temperature and filtered through a plug of silica gel with Et2O
(50 mL). The solvent was evaporated and the product was purified by
flash chromatography (silica gel).
Chem. Eur. J. 2005, 11, 6254 – 6265
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6263

C. Bolm et al.
(m, 2H, Ar-H), 7.45–7.49 (m, 2H, Ar-H), 7.57–7.61 (m, 1H, Ar-H), 7.91–
7.94 ppm (m, 2H, Ar-H); 13C NMR (100 MHz, CDCl3) d=14.2, 29.5,
41.3, 47.2, 61.8, 74.9, 125.8, 128.0, 128.2, 128.3, 128.5, 133.4, 136.3, 141.2,
175.0, 198.1 ppm; IR (film): n˜ =3516, 2980, 2929, 1735, 1684, 1598, 1451,
1363, 1215, 1090, 1019, 755, 695 cmꢀ1; MS (70 eV, CI, CH4): m/z (%): 327
(74) [M+H]+, 309 (20), 253 (100), 189 (41), 121 (54); elemental analysis
calcd (%) for C20H22O4 (326.39): C 73.60, H 6.79; found: C 73.92, H 7.08;
HPLC: tr(R) = 33.1 min, tr(S) = 43.8 min (Chiralcel OD column, flow
rate 0.5 mLminꢀ1, heptane/iPrOH 95:5, l=254 nm, 258C). The absolute
configuration was assigned in analogy to 3a.
0.60 mmol) and aminosulfoximine (R)-4aBd (20 mg, 0.05 mmol). After
stirring for 49 h at ꢀ508C, the product was obtained as a colorless oil
(123 mg, 0.39 mmol, 79%, 93% ee) after flash chromatography (silica
gel, pentane/EtOAc 15:1). [a]2D0 =ꢀ19.3 (c=0.93 in CHCl3); lit: [a]2D0
=
ꢀ18.1 (c=6.3 in CHCl3) for (S), 99% ee;[9] 1H NMR (300 MHz, CDCl3):
d=1.41 (s, 3H, CH3), 1.43 (s, 9H, CH3), 2.85 (d, J=16.2 Hz, 1H, CH2),
3.10 (d, J=15.9 Hz, 1H, CH2), 3.74 (brs, 1H, OH), 5.19/5.23 (AB system,
J=12.1 Hz, 2H, CH2), 7.32–7.37 ppm (m, 5H, Ar-H); 13C NMR
(75 MHz, CDCl3): d=26.1, 29.7, 48.6, 52.9, 67.5, 72.8, 128.1, 128.2, 128.4,
135.2, 175.1, 197.9 ppm; IR (film): n˜ =3523, 3034, 2963, 1740, 1681, 1456,
1394, 1366, 1272, 1202, 1113, 1006, 965, 783, 747, 699 cmꢀ1; MS (70 eV,
CI, CH4): m/z (%): 311 (42) [M+H]+, 193 (22), 181 (30), 119 (11), 91
(100); elemental analysis calcd (%) for C16H22O4S (310.41): C 61.91, H
7.14; found: C 61.58, H 7.25; HPLC: tr(R) = 9.7 min, tr(S) = 10.8 min
(ꢀ)-(R)-Methyl 2-ethyl-2-hydroxy-4-oxo-4-phenyl butanoate [(R)-3e]:
The product was prepared according to the general procedure 5 by using
methyl 2-oxobutyrate (2e, 58 mg, 0.50 mmol), enolsilane 1a (123 mL,
0.60 mmol) and aminosulfoximine (S)-4aAe (23 mg, 0.05 mmol). After
stirring for 20 h at room temperature, the product was obtained as a
yellow oil (92 mg, 0.39 mmol, 78%, 89% ee) after flash chromatography
(silica gel, pentane/EtOAc 10:1 ! 5:1). [a]2D0 =ꢀ46.0 (c=1.8 in CHCl3);
1H NMR (400 MHz, CDCl3): d=0.96 (t, J=7.5 Hz, 3H, CH3), 1.82 (q,
J=7.4 Hz, 2H, CH2), 3.41 (d, J=17.6 Hz, 1H, CH2), 3.57 (d, J=17.6 Hz,
1H, CH2), 3.72 (brs, 1H, OH), 3.78 (s, 3H, OCH3), 7.45–7.49 (m, 2H,
Ar-H), 7.57–7.61 (m, 1H, Ar-H), 7.93–7.96 ppm (m, 2H, Ar-H);
13C NMR (100 MHz, CDCl3): d=7.6, 32.5, 46.9, 52.6, 75.5, 128.0, 128.5,
133.4, 136.3, 175.7, 198.4 ppm; IR (film): n˜ =3522, 2971, 1740, 1684, 1597,
1449, 1360, 1248, 1218, 1020, 757, 692 cmꢀ1; MS (70 eV, CI, CH4): m/z
(%): 237 (61) [M+H]+, 219 (18), 177 (100), 121 (20); elemental analysis
calcd (%) for C13H16O4 (236.27): C 66.09, H 6.83; found: C 65.84, H 6.76;
HPLC: tr(R) = 19.8 min, tr(S) = 27.0 min (Chiralcel OD column, flow
rate 0.5 mLminꢀ1, heptane/iPrOH 95:5, l=254 nm, 258C). The absolute
configuration was assigned in analogy to 3a.
(Chiralcel OD-H, flow rate 1.0 mLminꢀ1
, heptane/iPrOH 99:1, l=
230 nm, 258C).
(+)-(S)-tert-Butyl 3-hydroxy-3-isopropoxycarbonyl butanthioate [(S)-3i]:
The product was prepared according to the general procedure 5 by using
isopropyl pyruvate (2c, 65 mg, 0.50 mmol), enolsilane 1c (153 mL,
0.60 mmol) and aminosulfoximine (R)-4aBd (20 mg, 0.05 mmol). After
stirring for 72 h at ꢀ508C, the product was obtained as a colorless oil
(107 mg, 0.41 mmol, 82%, 98% ee) after flash chromatography (silica
gel, pentane/EtOAc 20:1). [a]2D0 =+0.5 (c=0.53 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=1.27 (d, J=6.2 Hz, 6H, CH3), 1.38 (s, 3H, CH3),
1.45 (s, 9H, CH3), 2.83 (d, J=16.1 Hz, 1H, CH2), 3.08 (d, J=16.3 Hz,
1H, CH2), 3.73 (brs, 1H, OH), 5.10 ppm (sep. J=6.3 Hz, 1H, CH);
13C NMR (100 MHz, CDCl3): d=21.6, 21.7, 26.2, 29.7, 48.6, 52.9, 69.6,
72.7, 174.9, 198.0 ppm; IR (film): n˜ =3515, 2977, 2929, 1735, 1684, 1457,
1370, 1274, 1214, 1166, 1106, 1005, 945, 918, 790, 634 cmꢀ1; MS (70 eV,
CI, CH4): m/z (%): 263 (100) [M+H]+, 173 (67), 145 (23), 131 (34), 119
(10), 103 (30); elemental analysis calcd (%) for C12H22O4S (262.37): C
54.93, H 8.45; found: C 55.08, H 8.26; HPLC: tr(R) = 11.1 min, tr(S) =
11.9 min (Chiralcel OD-H, flow rate 0.5 mLminꢀ1, heptane/iPrOH 99:1,
l=230 nm, 258C). The absolute configuration was assigned in analogy to
3g and 3h.
(ꢀ)-(R)-Benzyl-(2-hydroxy-2-methyl-4-methyl-4-oxo)-butanoate
[(R)-
3 f]: The product was prepared according to the general procedure 5 by
using benzyl pyruvate (2b, 89 mg, 0.50 mmol), enolsilane 1b (147 mL,
0.75 mmol) and aminosulfoximine (S)-4aAe (23.1 mg, 0.05 mmol). After
stirring for 46 h at ꢀ408C, the product was obtained as a colorless oil
(84 mg, 0.35 mmol, 71%, 91% ee) after flash chromatography (silica gel,
pentane/EtOAc 10:1 ! 3:1). [a]2D0 =ꢀ29.6 (c=0.5 in CHCl3); lit: [a]2D0
=
+42.9 (c=3.7 in CHCl3) for (S), 93% ee;[9] 1H NMR (400 MHz, CDCl3):
d=1.40 (s, 3H, CH3), 2.12 (s, 3H, CH3), 2.80 (d, J=17.5 Hz, 1H, CH2),
3.12 (d, J=17.5 Hz, 1H, CH2), 3.87 (brs, 1H, OH), 5.18 (s, 2H, CH2),
7.30–7.39 ppm (m, 5H, Ar-H); 13C NMR (100 MHz, CDCl3): d=26.1,
30.5, 52.2, 67.3, 72.5, 128.0, 128.2, 128.4, 135.2, 175.3, 207.4 ppm; IR
(film): n˜ =3510, 2982, 1739, 1498, 1456, 1367, 1282, 1179, 1121, 968, 752,
700 cmꢀ1; MS (70 eV, CI, CH4): m/z (%): 237 (4) [M+H]+, 181 (5), 119
(5), 101 (23), 91 (100); elemental analysis calcd (%) for C13H16O4
Acknowledgements
We are grateful to the Fonds der Chemischen Industrie and to the Deut-
sche Forschungsgemeinschaft (DFG) within the SFB 380 and the GRK
440 for financial support.
(236.26): C 66.09, H 6.83; found: C 65.97, H 6.58; HPLC: tr(R)
=
[1] For reviews on enantioselective Mukaiyama-type aldol reactions,
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W. J. Lee, J. Am. Chem. Soc. 1995, 117, 3649–3650.
26.6 min, tr(S)=34.3 min (Chiralcel AS, flow rate 0.5 mLminꢀ1, heptane/
iPrOH 90:10, l=210 nm, 258C).
(+)-(S)-tert-Butyl 3-hydroxy-3-methoxycarbonyl butanthioate [(S)-3g]:
The product was prepared according to the general procedure 5 by using
methyl pyruvate (2a, 46 mL, 0.50 mmol), enolsilane 1c (153 mL,
0.60 mmol) and aminosulfoximine (R)-4aBd (20.4 mg, 0.05 mmol). After
stirring for 51 h at ꢀ408C, the product was obtained as a colorless oil
(101 mg, 0.43 mmol, 86%, 91% ee) after flash chromatography (silica
gel, pentane/EtOAc 10:1). [a]2D0 =+24.3 (c=0.54 in CHCl3); lit: [a]2D0
=
+25.1 (c=5.2 in CHCl3) for (S), 99% ee;[9] 1H NMR (400 MHz, CDCl3):
d=1.41 (s, 3H, CH3), 1.45 (s, 9H, CH3), 2.84 (d, J=15.9 Hz, 1H, CH2),
3.07 (d, J=16.0 Hz, 1H, CH2), 3.73 (brs, 1H, OH), 3.80 ppm (s, 3H,
CH3); 13C NMR (100 MHz, CDCl3): d=26.1, 29.7, 48.6, 52.8, 52.9, 72.9,
175.6, 198.0 ppm; IR (film): n˜ =3514, 2961, 2926, 1743, 1682, 1456, 1395,
1367, 1271, 1216, 1163, 1117, 1008, 958, 932, 787 cmꢀ1; MS (70 eV, CI,
CH4): m/z (%): 235 (5) [M+H]+, 179 (8), 175 (8), 145 (82), 117 (100), 85
(6); elemental analysis calcd (%) for C10H18O4S (234.31): C 51.26, H
7.74; found: C 51.23, H 7.68; HPLC: tr(R) = 17.7 min, tr(S) = 19.3 min
(Chiralcel OD-H, flow rate 1.0 mLminꢀ1
, heptane/iPrOH 99:1, l=
230 nm, 258C).
(+)-(S)-tert-Butyl 3-benzoylcarboxy-3-hydroxy butanthioate [(S)-3h]:
The product was prepared according to the general procedure by using
benzyl pyruvate (2b, 89 mg, 0.50 mmol), enolsilane 1c (153 mL,
6264
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2005, 11, 6254 – 6265

Aminosulfoximines
FULL PAPER
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Received: May 3, 2005
Published online: August 1, 2005
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ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6265