Synthesis of enantiopure sulfonimidamides and elucidation of their absolute configuration by comparison of measured and calculated CD spectra and X-ray crystal structure determination

Article abstract of DOI:10.1002/chem.200901715

Straightforward syntheses of enantiopure N-benzoyl- and N-tert-butyloxycarbonyl-protected sulfonimidamides, which can be used as building blocks in newly designed catalysts, are presented. Key synthetic step is a dynamic resolution of a racemic sulfinic acid sodium salt. All subsequent transformations proceed stereospecifically. The absolute configurations at the sulfur atoms of both sulfonimidamides were determined by comparison of measured and calculated CD spectra. An X-ray crystal structure determination of a sulfonimidoylguanidine derivative confirmed this result.

Full text of DOI:10.1002/chem.200901715

FULL PAPER
DOI: 10.1002/chem.200901715
Synthesis of Enantiopure Sulfonimidamides and Elucidation of Their
Absolute Configuration by Comparison of Measured and Calculated CD
Spectra and X-Ray Crystal Structure Determination
Christin Worch, Iuliana Atodiresei, Gerhard Raabe, and Carsten Bolm*[a]
Abstract: Straightforward syntheses of
enantiopure N-benzoyl- and N-tert-bu-
tyloxycarbonyl-protected sulfonimid-
amides, which can be used as building
blocks in newly designed catalysts, are
presented. Key synthetic step is a dy-
namic resolution of a racemic sulfinic
acid sodium salt. All subsequent trans-
formations proceed stereospecifically.
The absolute configurations at the
sulfur atoms of both sulfonimidamides
were determined by comparison of
measured and calculated CD spectra.
An X-ray crystal structure determina-
tion of a sulfonimidoylguanidine deriv-
ative confirmed this result.
Keywords: absolute configuration ·
circular dichroism
sulfonimidamide
· resolution ·
Introduction
nesulfinic acid sodium salt (1) was converted into menthyl
ester 2 via the corresponding sulfinic acid chloride.[9] An epi-
merization shifted the equilibrium of the diastereomers and
allowed sulfinate ester 2 to be obtained with >99% de in
up to 70% yield after recrystallization. Next, ester 2 was re-
acted with lithium hexamethyldisilazide (LiHMDS) forming
a bis(trimethylsilylamide) which upon hydrolysis gave (S)-
sulfinamide 3 with >99% ee in 87% yield after recrystalli-
zation.[10] For the preparation of N-acylsulfinamides 4 or 5,
sulfinamide 3 was treated with 2.5 equiv of n-butyl lithium
followed by the addition of di-tert-butyl dicarbonate or ben-
zoic acid anhydride, respectively.[11] The N-substituted sulfi-
namides 4 and 5 were obtained in good yields with complete
retention of configuration. Subsequent oxidative chlorina-
tion using tert-butyl hypochlorite[12–14] and treatment of the
resulting (R)-sulfonimidoyl chlorides 6 and 7 with an aque-
ous solution of ammonia afforded N-substituted sulfonimi-
damides 8 and 9 with >99% ee in 78 and 97% yield, respec-
tively.
Sulfonimidamides have recently been applied as nitrene
[1]
ꢀ
sources in rhodium-catalyzed C H aminations, metal-cata-
lyzed olefin aziridinations[2] and preparation of sulfimides
and sulfoximines.[2a,3] Coupling reactions of sulfonimida-
mides with uronium reagents yielded sulfonimidoylguani-
dines,[4] and N-arylated derivatives were obtained by copper-
[5]
ꢀ
mediated C N bond formation. Mitsunobu reactions in-
volving the free amino group afforded N-heterocycles.[6–8]
In most of the reactions described the sulfonimidamides
were used as racemates. Only a few enantiopure sulfonimi-
damides are known and most of them have N-methyl, N-
tosyl or N-nosyl groups.[1,2c,3,7] Herein we report the synthe-
sis of N-benzoyl- (N-Bz) and N-tert-butyloxycarbonyl- (N-
Boc) protected sulfonimidamides and the determination of
their absolute configuration by comparison of calculated
and measured CD spectra.
The findings of Johnson[7d] and Reggelin[13] on related sys-
tems suggested that the nucleophilic chloride displacement
of sulfonimidoyl chlorides 6 and 7 with ammonia occurred
with inversion of configuration. In order to confirm this hy-
pothesis and to ensure the stereochemistry of the products it
was decided to determine their absolute configuration by ex-
perimental and theoretical CD spectroscopy, which allowed
establishing the spatial arrangement of the substituents at
the chiral sulfur atom with a high degree of probability.
Results and Discussion
As outlined in Scheme 1, the N-protected enantiopure sulfo-
nimidamides could readily be prepared by a four-step reac-
tion sequence: First, commercially available racemic 4-tolue-
[a] C. Worch, Dr. I. Atodiresei, Prof. Dr. G. Raabe, Prof. Dr. C. Bolm
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52056 Aachen (Germany)
Fax : (+49)241-8092391
E-mail: carsten.bolm@oc.rwth-aachen.de
Chem. Eur. J. 2010, 16, 677 – 683
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
677

Table 1. Structures of the six most stable conformers of (R)-8 (8a–f) op-
timized at the MP2/6-31+G* level and their total (in Hartrees) and rela-
tive energies (in kcalmolꢀ1) including the ZPE correction.
ZPE+MP2/6-311++G**//MP2/6-31+G*[a]
Scheme 1. Synthesis of the sulfonimidamides
8
and 9: a) SOCl2
(1.2 equiv), Et2O (0.6 mmolmLꢀ1), 08C
!
RT, 2 h; then l-menthol
Entry
Conformer
Etot
Erel
W[b]
(1.1 equiv), pyridine (1.5 equiv), Et2O (1.0 mmolmLꢀ1), RT, overnight;
recrystallization from acetone, 70%; b) LiHMDS (1.06m in THF,
1.5 equiv), THF (0.2 mmolmLꢀ1), ꢀ788C ! RT, 2 h; then sat. aq. NH4Cl
(2.5 mL pro mmol of 2), RT, 1.5 h, 87%; c) n-butyl lithium (1.6m in
1
2
3
4
5
6
8a
8b
8c
8d
8e
8 f
ꢀ1198.576958
ꢀ1198.575065
ꢀ1198.574368
ꢀ1198.574347
ꢀ1198.574169
ꢀ1198.572997
0.000
1.188
1.625
1.638
1.750
2.486
0.7526
0.1012
0.0484
0.0473
0.0392
0.0113
hexane, 2.5 equiv), Boc2O (1.2 equiv), THF (0.8 mmolmLꢀ1), ꢀ78
!
08C, 3 h, 63% d) n-butyl lithium (1.6m in hexane, 2.5 equiv), Bz2O
(1.2 equiv), THF (0.2 mmolmLꢀ1), ꢀ78 ! 08C, 3 h, 61%; e) tert-butyl
hypochlorite (1.3 equiv), THF (0.06-0.13 mmolmLꢀ1), 08C, 2 h; then NH3
(25% in H2O, 4 mL pro mmol of 4 or 5), RT, overnight, 78% for 8 and
97% for 9.
[a] Zero-point energy calculated at the MP2/6-31G* level of theory. [b] w
is the Boltzmann factor calculated at 298 K.
Table 2. Structures of the five stable conformers found for (R)-9 (9a–f)
optimized at the MP2/6-31+G* level and their total (in Hartrees) and
relative energies (in kcalmolꢀ1) including the ZPE correction.
Computational Details
A Monte-Carlo conformational search[15] using the program
Spartan ꢁ02[16] with default parameters and convergence cri-
teria and the MMFF[17] provided initial sets of geometries
for sulfonimidamides 8 and 9. The subsequent ab initio ge-
ometry optimizations were performed for isolated molecules
in the gas phase using a medium size basis set (6-31+G*)
and including correlation energy by means of second-order
Møller-Plesset perturbation theory as implemented in the
program Gaussian 03.[18] Starting with the arbitrarily chosen
R enantiomer, 11 and 5 stationary points were located at the
MP2/6-31+G* level for 8 and 9, respectively. Additional
single point energy calculations were then performed at the
MP2/6-311++G**//MP2/6-31+G* level, and the final ener-
gies were corrected with the unscaled zero-point energy
(ZPE) calculated at the MP2/6-31G* level. The relative en-
ergies as well as the geometries of the six most stable con-
formers of 8 (Erel <2.5 kcalmolꢀ1) and all conformers of 9
are presented in Tables 1 and 2, respectively.[19]
ZPE+MP2/6-311++G**//MP2/6-31+G*[a]
Entry
Conformer
Etot
Erel
W[b]
1
2
3
4
5
9a
9b
9c
9d
9e
ꢀ1197.152699
ꢀ1197.151517
ꢀ1197.150607
ꢀ1197.150605
ꢀ1197.149935
0.000
0.742
1.313
1.314
1.734
0.6423
0.1836
0.0700
0.0698
0.0343
[a] Zero point energy calculated at the MP2/6-31G* level of theory. [b] w
is the Boltzmann factor calculated at 298 K.
Theoretical CD spectra were obtained using the time-de-
pendent density functional theory (TDDFT)[20] employing
the B3LYP functional[21] and a valence triple zeta basis set,
including polarization and diffuse functions (6-311++G**).
The rotational strengths have been calculated using the
origin-independent dipole-velocity formalism.[22] The CD
curve (Dei) of each conformer i was represented as a sum of
Gaussian curves. Each of the Gaussians is centered at the
calculated wavelength of the corresponding transition and
multiplied with its rotational strength.[23] The half bandwidth
G at Demax/e was obtained using the empirical formula G=
k·l1.5 where l is the transition wavelength and k an empirical
parameter.[24] In our study we used a value of k=0.00375[25]
yielding half bandwidths covering the range from 6.9 to 30.0
between 150 and 400 nm. The final CD curve (De) was gen-
erated by Boltzmann-weighted superposition of the N CD
spectra of the single conformers. The Boltzmann factors
(298 K) were calculated by using the ZPE+MP2/6-311++
G**//MP2/6-31+G* relative energies.
678
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 677 – 683

Enantiopure Sulfonimidamides
FULL PAPER
N
X
De ¼
wi ꢁ Dei
i¼1
with
N
X
wi ¼ ½expðꢀEi=RTÞꢂ=½ expðꢀEj=RTÞꢂ
j¼1
where wi and Ei are the Boltzmann factor and the energy of
the ith local minimum, respectively.
The six most stable conformers (8a–f) were included in
the calculation of the CD curve of 8. The leading electronic
configurations and calculated rotational strengths for the
lowest excited states of the most stable conformer 8a
(Boltzmann factor w=0.75) which dominates the shape of
the averaged CD spectrum (Figure 2a) are listed in Table 3.
The highest occupied and lowest unoccupied Kohn–Sham
orbitals of 8a are shown in Figure 1.
According to the TDDFT calculations the first calculated
Cotton effect in the averaged CD spectrum is positive and
has a maximum around 246 nm. We assign this Cotton effect
Figure 2. a) Averaged calculated CD spectrum of (R)-8. b) Experimental
CD spectrum of 8.
to the negative experimental
one with a minimum at 231 nm
(see Figure 3b). It is mainly
due to p+n ! p* and p+n+s
!
p* transitions from the
HOMO (Y72) and HOMOꢀ1
(Y71) to the LUMO (Y73)
which occur between 249 and
237 nm for the most stable con-
former. The next calculated
Cotton effect is more intense
and has a maximum around
193 nm and
a
shoulder at
210 nm. The main contributions
to this band come from n+s !
p* transitions from HOMOꢀ5
(Y67) to LUMO+1 (Y74), p+
Figure 1. Kohn–Sham orbitals of the most stable conformer 8a, Y72: HOMO, Y73: LUMO.
Table 3. Electronic configurations and calculated rotational strengths for the lowest excited states of the most
n
!
p* transitions from
stable conformer 8a (Boltzmann factor w=0.75).
Entry
l [nm]
Transition
Type
Angle[a]
V [8]
Rotational
strength[b]
HOMOꢀ3 (Y69) to LUMO+1
(Y74), and p+n ! Ry* transi-
tions from HOMOꢀ3 (Y69)
and HOMOꢀ2 (Y70) to
LUMO+2 (Y75). This band is
positive and we correlate it
with the negative one observed
at 197 nm. The two calculated
Cotton effects are separated by
1
2
3
249.3
237.0
224.1
HOMO ! LUMO
p+n ! p*
68.2
71.4
80.1
20.7
7.4
3.4
HOMOꢀ1 ! LUMO
p+n+s ! p*
p+n ! p*
HOMO ! LUMO+1
HOMOꢀ1 ! LUMO+1
HOMOꢀ1 ! LUMO+1
HOMOꢀ2 ! LUMO+1
HOMOꢀ1 ! LUMO+6
HOMO ! LUMO+6
HOMOꢀ5 ! LUMO+1
HOMOꢀ3 ! LUMO+2
HOMOꢀ2 ! LUMO+2
HOMOꢀ3 ! LUMO+1
HOMOꢀ2 ! LUMO+2
p+n+s ! p*
p+n+s ! p*
p+n ! p*
4
5
216.8
206.5
60.7
34.4
4.4
p+n+s ! p*+ s*
p+n ! p*+ s*
n+s ! p*
17.1
6
7
8
193.0
191.9
190.1
65.6
25.1
86.2
55.7
34.2
25.1
a
minimum around 225 nm
p+n ! Ry*
p+n ! Ry*
p+n ! p*
which has its experimental
counterpart in the maximum at
216 nm in the recorded spec-
trum. As can be seen from Fig-
ures 2a and b the shape of the
9
189.3
p+n ! Ry*
85.5
25.9
[a] V is the angle between the electric and the magnetic transition moments. [b] Rotational strength is given in
10ꢀ40 ergesucmGaussꢀ1
.
Chem. Eur. J. 2010, 16, 677 – 683
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
679

C. Bolm et al.
highest occupied and lowest un-
occupied Kohn–Sham orbitals
of 9a are shown in Figure 3.
According to the TDDFT
calculations the first calculated
Cotton effect in the averaged
CD spectrum is positive and
has a maximum around 251 nm
and a tail in the long wave-
length region. We assign this
Cotton effect to the negative
experimental one at around
247 nm (see Figure 4b). It is
mainly due to p+n ! p* tran-
sitions from the HOMO (Y72)
to the LUMO (Y73) which
occur in a region between 262
and 249 nm for the most stable
conformer. The next calculated
Cotton effect occurs at about
226 nm and it is due to several
p+n
!
p*
transitions
(HOMOꢀ5 (Y67) to LUMO
(Y73), HOMOꢀ4 (Y68) to
LUMO (Y73) and HOMOꢀ3
(Y69) to LUMO+1 (Y74)). It
is negative and we correlate it
Figure 3. Kohn–Sham orbitals of the most stable conformer 9a, Y72: HOMO, Y73: LUMO.
calculated CD spectrum closely resembles the mirror image
of the measured spectrum. Since the CD spectrum was cal-
culated for the R enantiomer, we conclude that the absolute
configuration of sulfonimidamide 8 is most likely S.
The calculated and recorded CD spectra of 9 are present-
ed in Figure 4a and b, respectively. All five stable conform-
ers found for 9 (9a–e) were included in the calculation of
the CD curve of 9. The leading electronic configurations
and calculated rotational strengths for the lowest excited
states of the most stable conformer 9a (Boltzmann factor
w=0.64) which determine the shape of the averaged theo-
retical CD spectrum (Figure 4a) are listed in Table 4. The
with the positive one observed at 228 nm. The third calculat-
ed Cotton effect with a maximum at 202 nm is also negative
and corresponds most likely to the positive band at 205 nm
in the recorded spectrum. The main contribution to this
band is given by a p+n ! p* transition from HOMO
(Y72) to LUMO+3 (Y76). As it can be seen from Fig-
ure 4a and b the shape of the calculated CD spectrum close-
ly reflects the mirror image of the measured spectrum.
Since the CD spectrum was calculated for the R enantio-
mer, we conclude that the absolute configuration of sulfoni-
midamide 9 is most likely S.
The assignment of the abso-
lute configuration of 9 was sup-
ported by single crystal X-ray
analysis[26] (Figure 5) of sulfoni-
Table 4. Electronic configurations and calculated rotational strengths for the lowest excited states of the most
stable conformer 9a (Boltzmann factor w=0.64).
midoylguanidine
derivative
10.[4] Since the synthesis of 10
starting from 9 does not affect
the absolute configuration at
sulfur this result confirms that
the final step in the synthesis of
the sulfonimidamides, that is,
the displacement of chloride
atom with ammonia, takes
place with inversion of configu-
ration at the sulfur atom.
Entry
1
l [nm]
Transition
Type
Angle[a]
V [8]
Rotational
strength[b]
262.2
HOMOꢀ1 ! LUMO
HOMO ! LUMO
p+n ! p*
p+n ! p*
s+n ! p*
p+n ! p*
p+n ! p*
p+n ! p*
p+n ! p*
p+n ! p*
p+n ! p*
s+n ! p*
s+n ! p*
p+n ! p*
77.9
13.8
2
3
4
5
253.0
248.5
239.7
227.9
HOMOꢀ2 ! LUMO+1
HOMO ! LUMO
62.5
83.7
74.6
121.8
7.0
44.6
6.8
HOMOꢀ3 ! LUMO
HOMOꢀ4 ! LUMO
HOMOꢀ5 ! LUMO
HOMOꢀ3 ! LUMO+1
HOMOꢀ5 ! LUMO
HOMOꢀ6 ! LUMO
HOMOꢀ6 ! LUMO+1
HOMO ! LUMO+3
-56.1
6
7
8
9
224.4
217.3
212.0
202.5
84.3
176.2
67.5
5.4
ꢀ10.6
6.9
107.9
ꢀ81.1
[a] V is the angle between the electric and the magnetic transition moments. [b] Rotational strength is given in
10ꢀ40 ergesucmGaussꢀ1
.
680
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 677 – 683

Enantiopure Sulfonimidamides
FULL PAPER
Experimental Section
General methods: All experiments were carried out under an argon at-
mosphere using standard Schlenk techniques. If necessary, solvents were
dried and deoxygenated by standard procedures. NMR spectra were re-
corded in CDCl3 or [D6]acetone containing TMS as an internal standard
on a Varian Mercury 300 spectrometer (300 and 75 MHz for 1H and
13C NMR spectra, respectively) or a Varian Inova 400 spectrometer (400
and 100 MHz for 1H and 13C NMR spectra, respectively). IR spectra
were measured on a Perkin–Elmer Spectrum 100 FT-IR spectrometer
with an attached UATR device Diamond/KRS-5 as KBr pellets. MS spec-
tra were recorded on a Finnigan SSQ 7000 using EI as an ionization tech-
nique. TLC was carried out on silica gel 60 F254 aluminium sheets
(Merck) with spot detection under UV light. Optical rotation measure-
ments were conducted at room temperature with a Perkin–Elmer PE 241
polarimeter at a wavelength of 589 nm. Elemental analyses were mea-
sured with an Elementar Vario EL. The HPLC measurements were per-
formed on an Agilent system (1100 series) consisting of a degasser
G1379 A, a quaternary pump G1311 A, an autosampler G1313A, an
oven G1316A and an UV detector G1315B. The CD spectra were mea-
sured on a circular dichroism spectrometer (AVIV Model 62DS) at room
temperature in acetonitrile.
All starting materials were obtained from commercial suppliers and used
without further purification. Menthyl ester 2 was prepared according to
the literature procedure.[9]
Figure 4. a) Averaged calculated CD spectrum of (R)-9. b) Experimental
CD spectrum of 9.
(S)-4-Toluenesulfinamide (3):[9] To a solution of (S)-4-toluenesulfinic acid
(1R,2S,4R)-menthyl ester (2) (6.00 g, 20.4 mmol) in anhydrous THF
(100 mL) lithium hexamethyldisilazide (1.06m in THF, 30.6 mmol,
28.8 mL) was added dropwise over 10 min at ꢀ788C. The mixture was
stirred for 10 min at ꢀ788C and 1.5 h at room temperature. Then a satu-
rated NH4Cl solution (in H2O, 50 mL) was added and stirred for 1 h at
room temperature. The reaction mixture was diluted by addition of ethyl
acetate (100 mL), the organic layer was separated and the aqueous phase
was extracted with ethyl acetate (3ꢂ35 mL). The combined organic
layers were washed with brine (70 mL), dried (MgSO4), filtered and con-
centrated under reduced pressure. The product was recrystallized from
hexane/ethyl acetate 2:1 (100 mL). (S)-4-Toluenesulfinamide (3) was iso-
lated as colorless needles (2.75 g, 17.7 mmol, 87%, >99% ee). M.p. 115–
1168C [lit.:[10] m.p. 1138C]; [a]2D0
=
+84.5 (c=1.0 in CHCl3) [lit.:[10]
[a]2D0 =+80.2 (c=1.2 CHCl3)]; 1H NMR (400 MHz, CDCl3): d=2.41 (s,
3H, CH3), 4.35 (s, 2H, NH2), 7.26–7.32 (m, 2H, Ar-H), 7.59–7.63 ppm
(m, 2H, Ar-H); 13C NMR (100 MHz, CDCl3): d=21.4 (CH3), 125.2
(2CH), 129.5 (2CH), 141.3 (C), 143.3 ppm (C); HPLC: tr(S)=20.2 min,
tr(R)=26.2 min (Chiralpak AD, flow rate 0.7 mLminꢀ1, heptane/iPrOH
93:7, l=210 nm, 208C).
(S)-tert-Butyl-(4-tolylsulfinyl)-carbamate (4): To a round bottom Schlenk
flask was added (S)-4-toluenesulfinamide (3) (800 mg, 5.15 mmol) and
anhydrous THF (23 mL). After cooling to ꢀ788C n-butyl lithium (1.6m
in hexane, 12.9 mmol, 8.05 mL) was added dropwise over 10 min. The
mixture was stirred for 10 min at ꢀ788C, followed by rapid addition of
di-tert-butyl dicarbonate (6.18 mmol, 1.35 g). Stirring was continued for
10 min at ꢀ788C and 3.0 h at room temperature. Then saturated
NaHCO3 solution (in H2O, 23 mL) was added and the reaction mixture
was diluted with dichloromethane (45 mL). The organic layer was sepa-
rated and the aqueous phase was extracted with dichloromethane (5ꢂ
15 mL). The combined organic layers were dried (MgSO4), filtered and
concentrated under reduced pressure. The product was recrystallized
from hexane/ethyl acetate 3:1 (23 mL). (S)-tert-Butyl-(4-tolylsulfinyl)-car-
bamate (4) was isolated in colorless crystals (828 mg, 3.24 mmol, 63%,
>99% ee). M.p. 115–1168C; [a]2D0 =+121 (c=1.0 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=1.51 (s, 9H, CH3), 2.42 (s, 3H, CH3), 6.66 (s, 1H,
NH), 7.31–7.35 (m, 2H, Ar-H), 7.60–7.64 ppm (m, 2H, Ar-H); 13C NMR
(100 MHz, CDCl3): d=21.5 (CH3), 28.1 (3CH3), 83.5 (C), 124.6 (2CH),
129.9 (2CH), 140.5 (C), 142.3 (C), 152.3 ppm (CO); IR (KBr): n˜ = 709,
812, 1063, 1093, 1152, 1238, 1413, 1712, 3116 cmꢀ1; MS (EI, 70 eV): m/z
(%): 256 (1) [M+H]+, 199 (60), 139 (58), 108 (21), 91 (17), 77 (7), 65
(14), 57 (100); elemental analysis calcd (%) for C12H17NO3S: C 56.45, H
6.71, N 5.49; found: C 56.50, H 6.90, N 5.44; HPLC: tr(S)=12.2 min,
Figure 5. X-ray crystal structure of sulfonimidoylguanidine derivative 10
[Flack parameter Xabs =ꢀ0.01(5)].
Conclusions
We presented four-step syntheses of enantiopure N-Bz and
N-Boc sulfonimidamides with 37 and 29% overall yields, re-
spectively. The approach involves a dynamic resolution of a
racemic sulfinic acid sodium salt, and all subsequent steps
proceed stereospecifically. The absolute configurations of
both products were determined by comparison of measured
and calculated CD spectra. The result was confirmed by an
X-ray crystal structure determination of a sulfonimidoylgua-
nidine derivative. The enantiopure sulfonimidamides shall
now be used as building blocks in newly designed cata-
lysts.[28]
Chem. Eur. J. 2010, 16, 677 – 683
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
681

C. Bolm et al.
tr(R)=17.7 min (Chiralcel OG, flow rate 1.0 mLminꢀ1, heptane/iPrOH
95:5, l=230 nm, 208C).
[1] a) C. Liang, F. R. Peillard, C. Fruit, P. Mꢃller, R. H. Dodd, P.
Dauban, Angew. Chem. 2006, 118, 4757–4760; Angew. Chem. Int.
Ed. 2006, 45, 4641–4644; b) C. Liang, F. Collet, F. R. Peillard, P.
Mꢃller, R. H. Dodd, P. Dauban, J. Am. Chem. Soc. 2008, 130, 343–
350.
[2] a) D. Leca, A. Toussaint, C. Mareau, L. Fensterbank, E. Lacꢄte, M.
Malacria, Org. Lett. 2004, 6, 3573–3575; b) P. H. Di Chenna, F.
Robert-Peillard, P. Dauban, R. H. Dodd, Org. Lett. 2004, 6, 4503–
4505; c) C. Fruit, F. Robert-Peillard, G. Bernardinelli, P. Mꢃller,
R. H. Dodd, P. Dauban, Tetrahedron: Asymmetry 2005, 16, 3484–
3487.
[3] F. Collet, R. H. Dodd, P. Dauban, Org. Lett. 2008, 10, 5473–5476.
[4] C. Worch, C. Bolm, Synthesis 2007, 1355–1358.
[5] C. Worch, C. Bolm, Synthesis 2008, 739–742.
[6] S. Azzaro, L. Fensterbank, E. Lacꢄte, M. Malacria, Synlett 2008,
2253–2256.
[7] For early studies of sulfonimidamides, see: a) E. S. Levchenko, N. Y.
Derkach, A. V. Kirsanov, Zh. Obshch. Khim. 1962, 32, 1208–1212;
b) C. R. Johnson, E. U. Jonsson, C. C. Bacon, J. Org. Chem. 1979,
44, 2055–2061; c) E. U. Jonsson, C. C. Bacon, C. R. Johnson, J. Am.
Chem. Soc. 1971, 93, 5306–5308; d) E. U. Jonsson, C. R. Johnson, J.
Am. Chem. Soc. 1971, 93, 5308–5309; e) J. E. Toth, J. Ray, J. Deeter,
J. Org. Chem. 1993, 58, 3469–3472.
[8] For interesting bioactive sulfonimidamide derivatives, see: a) C. L.
Hillemann (Du Pont), US Patent 4666506, 1987; b) J. E. Toth, G. B.
Grindey, W. J. Ehlhardt, J. E. Ray, G. B. Boder, J. R. Bewley, K. K.
Klingerman, S. B. Gates, S. M. Rinzel, R. M. Schultz, L. C. Weir, J. F.
Worzalla, J. Med. Chem. 1997, 40, 1018–1025; c) B. E. Cathers, J. V.
Schloss, Bioorg. Med. Chem. Lett. 1999, 9, 1527–1532.
(S)-N-(4-Tolylsulfinyl)-benzamide (5): Same procedure as described for
4, but use of benzoic anhydride (6.18 mmol, 1.40 g) instead of di-tert-
butyl dicarbonate. The product was recrystallized from hexane/ethyl ace-
tate (2/1, 30 mL) and (S)-N-(4-tolylsulfinyl)-benzamide (5) was isolated
in colorless crystals (814 mg, 3.14 mmol, 61%, >99% ee). M.p. 121–
1228C; [a]2D0 =+118 (c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=
2.43 (s, 3H, CH3), 7.31–7.36 (m, 2H, Ar-H), 7.40–7.47 (m, 2H, Ar-H),
7.52–7.59 (m, 1H, Ar-H), 7.61–7.66 (m, 2H, Ar-H), 7.79–7.84 (m, 2H,
Ar-H), 8.56 ppm (s, 1H, NH); 13C NMR (75 MHz, CDCl3): d=21.5
(CH3), 124.8 (2CH), 127.9 (2CH), 128.8 (2CH), 130.1 (2CH), 131.6 (C),
133.1 (CH), 140.7 (C), 142.6 (C), 167.3 ppm (CO); IR (KBr): n˜ = 720,
756, 807, 883, 1069, 1095, 1244, 1387, 1648, 3225 cmꢀ1; MS (EI, 70 eV):
m/z (%): 259 (19) [M+], 151 (2), 139 (33), 108 (50), 105 (100), 91 (22); el-
emental analysis calcd (%) for C14H13NO2S: C 64.84, H 5.05, N 5.40;
found: C 65.10, H 5.31, N 5.45; HPLC: tr(R)=24.9 min, tr(S)=33.0 min
(Chiralcel OD-H, flow rate 1.0 mLminꢀ1
, heptane/iPrOH 95:5, l=
230 nm, 208C).
(S)-N-tert-Butyloxycarbonyl-4-toluenesulfonimidamide (8): A solution of
(S)-tert-Butyl-(4-tolylsulfinyl)-carbamate (4) (850 mg, 3.33 mmol) in THF
(25 mL) was cooled to 08C, and tert-butyl hypochlorite (4.33 mmol,
470 mg, 0.489 mL) was then slowly added. The reaction was stirred at
08C for 1 h. At 08C an aqueous ammonia solution (25%, 13.3 mL) was
added and the reaction mixture was stirred a room temperature over-
night. After neutralization of the reaction mixture by addition of a 6m
HCl solution, the organic layer was separated and the aqueous phase was
extracted with dichloromethane (4ꢂ20 mL). The combined organic
layers were dried (MgSO4), filtered and the solvent was removed under
reduced pressure. (S)-N-tert-Butyloxycarbonyl-4-toluenesulfonimidamide
(8) was isolated as a white powder (703 mg, 2.60 mmol, 78%, >99% ee).
M.p. 123–1248C; [a]2D0 =+14.5 (c=1.0 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=1.37 (s, 9H, CH3), 2.43 (s, 9H, CH3), 5.85 (brs, 2H, NH2),
7.29–7.33 (m, 2H, Ar-H), 7.85–7.89 ppm (m, 2H, Ar-H); 13C NMR
(100 MHz, CDCl3): d=21.6 (CH3), 28.1 (3CH3), 80.6 (C), 127.1 (2CH),
129.6 (2CH), 137.8 (C), 144.0 (C), 157.1 ppm (CO); IR (KBr): n˜ = 697,
739, 799, 849, 952, 1120, 1154, 1238, 1311, 1623, 3280 cmꢀ1; MS (EI,
70 eV): m/z (%): 271 (1) [M+H]+, 215 (7), 197 (35), 171 (7), 154 (24),
139 (6), 108 (100), 91 (27); elemental analysis calcd (%) for
C12H18N2O3S: C 53.31, H 6.71, N 10.36; found: C 53.32, H 6.66, N 10.40;
HPLC: tr(R)=17.3 min, tr(S)=22.4 min (Chiralcel OD, flow rate
1.0 mLminꢀ1, heptane/iPrOH 90:10, l=254 nm, 208C).
[9] a) L. B. Krasnova, A. K. Yudin, J. Org. Chem. 2004, 69, 2584–2587;
b) G. Solladiꢅ, Synthesis 1981, 185–196; c) C. Mioskowski, G. Solla-
diꢅ, Tetrahedron 1980, 36, 227–236.
[10] F. A. Davis, Y. Zhang, Y. Andemichael, T. Fang, D. L. Fanelli, H.
Zhang, J. Org. Chem. 1999, 64, 1403–1406.
[11] B. J. Backes, D. R. Dragoli, J. A. Ellman, J. Org. Chem. 1999, 64,
5471–5478.
[12] M. J. Mintz, C. Walling, Org. Synth. 1973, 5, 184–187.
[13] For related sulfinamides it was shown that the oxidative chlorination
using tert-butyl hypochlorite proceeds with retention of configura-
tion. M. Reggelin, B. Junker, Chem. Eur. J. 2001, 7, 1232–1239.
[14] For oxidative chlorinations of sulfinamides with N-chlorosuccin-
imide, where the stereochemical path remained undetermined, see:
O. Garcia Mancheno, C. Bolm, Beilstein J. Org. Chem. 2007, 3, 25.
[15] The Monte–Carlo method used in our calculations is based on a
standard simulated annealing algorithm with a temperature ramp of
(S)-N-Benzoyl-4-toluenesulfonimidamide (9): Same procedure as for the
synthesis of 8, but use of (S)-N-(4-tolylsulfinyl)-benzamide (5) (800 mg,
3.08 mmol) in THF (50 mL), tert-butyl hypochlorite (4.01 mmol, 435 mg,
0.454 mL) and an aqueous ammonia solution (25%, 12.4 mL). (S)-N-
Benzoyl-4-toluenesulfonimidamide (9) was isolated as a white powder
(822 mg, 3.00 mmol, 97%, >99% ee). M.p. 137–1398C; [a]2D0 =+64.2 (c=
0.9 in CHCl3); 1H NMR (400 MHz, [D6]acetone): d=2.41 (s, 3H, CH3),
7.23 (brs, 2H, NH2), 7.38–7.43 (m, 4H, Ar-H), 7.48–7.53 (m, 1H, Ar-H),
7.91–7.95 (m, 2H, Ar-H), 8.05–8.09 ppm (m, 2H, Ar-H); 13C NMR
(100 MHz, [D6]acetone): d=22.4 (CH3), 128.5 (2CH), 129.6 (2CH), 130.7
(2CH), 131.1 (2CH), 133.4 (CH), 138.2 (C), 141.6 (C), 145.2 (C),
173.4 ppm (CO); IR (KBr): n˜ = 716, 806, 838, 980, 1152, 1217, 1298,
1324, 1449, 1573, 1600, 3288 cmꢀ1; MS (EI, 70 eV): m/z (%): 275 (1) [M+
H]+, 197 (4), 154 (1), 139 (4), 108 (100), 91 (17); elemental analysis calcd
(%) for C14H14N2O2S: C 61.29, H 5.14, N 10.21; found: C 61.31, H 5.22, N
9.89; HPLC: tr(R)=37.1 min, tr(S)=55.8 min (Chiralcel OJ, flow rate
0.7 mLminꢀ1, heptane/iPrOH 85:15, l=230 nm, 208C).
T=TfꢀDT
ACHTUNGTRENNUNG
and T are the initial, final and the current temperature. I and Imax
represent the current step number and the maximal number of
steps. Imax depends on the number of flexible centres of the studied
molecule as well as the number of increments in the rotation. Final-
ly, the new conformation is weighted via the Boltzmann criteria.
[16] Spartan, Version 02, Wavefunction, Inc. 18401 Von Karman Ave.,
Suite 370, Irvine, CA 92612.
[17] T. A. Halgren, J. Comput. Chem. 1996, 17, 490–519.
[18] Gaussian 03, Revision D.02, M. J. Frisch, G. W. Trucks, H. B. Schle-
gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgom-
ery, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S.
Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani,
N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W.
Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J.
Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C.
Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari,
J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cio-
slowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaro-
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG, SPP 1179) and the Fonds der Chemischen Industrie.
682
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 677 – 683

Enantiopure Sulfonimidamides
FULL PAPER
mi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng,
A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian, Inc., Wall-
ingford CT, 2004.
ꢀ23ꢃlꢃ23 (qmax =67.98), merged to give 3959 independent reflec-
tions (Rint =0.02(4)). The structure was solved by direct methods as
implemented in the XTAL3.7 package of crystallographic routines[27]
employing GENSIN[27] to generate structure-invariant relationships
and GENTAN[27] for the general tangent phasing procedure. 3783
observed reflections (I>2s(I)) were included in a full-matrix least
squares refinement of 271 parameters converging at R(Rw)=
0.07(0.09; w=1/s2(F)), and a residual electron density of ꢀ0.90/+
0.53 eꢆꢀ3. Most of the hydrogen atoms were located and the rest
were calculated in idealized positions. No refinement of hydrogen
parameters. Flack parameter Xabs =ꢀ0.01(5) for the structure shown
in Figure 5. CCDC 734215 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[19] Graphics obtained by MOLEKEL 4.3, P. Flꢃkiger, H. P. Lꢃthi, S.
Portmann, J. Weber, Swiss Center for Scientific Computing, Manno,
2000–2002.
[20] R. Bauernschmitt, R. Ahlrichs, Chem. Phys. Lett. 1996, 256, 454–
464.
[21] a) C. Lee, W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–789;
b) B. Miehlich, A. Savin, H. Stoll, H. Preuss, Chem. Phys. Lett. 1989,
157, 200–206; c) A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652.
[22] A. Moscowitz in Modern Quantum Chemistry, Vol. 3 (Ed.: O. Sina-
noglu), Academic Press, New York, 1965, pp. 31–44.
[23] J. A. Schellman, Chem. Rev. 1975, 75, 323–331.
[24] A. Brown, C. M. Kemp, S. F. Mason, J. Chem. Soc. A 1971, 751–
755.
[27] a) XTAL3.7 System, S. R. Hall, D. J. du Boulay, R. Olthof-Haze-
kamp, University of Western Australia, Perth, 2000; b) GENSIN,
XTAL3.7 System, V. Subramanian, S. R. Hall, University of Western
Australia, Perth, 2000; c) GENTAN, XTAL3.7 System, S. R. Hall,
S. R. Hall, D. J. du Boulay, R. Olthof-Hazekamp, University of
Western Australia, Perth, 2000.
[25] R. W. Woody, private communication.
[26] Suitable crystals were obtained from ethyl acetate. The compound
(C23H28N4O2S) crystallizes in orthorhombic space group P212121 (19)
with cell constants a=8.643(2), b=13.364(15), and c=19.173(4) ꢆ.
At
a
molecular weight of 424.57, Z=4 and
a
cell volume of
[28] For initial investigations along these lines, see: C. Worch, C. Bolm,
Synlett 2009, 2425–2428.
2215(3) ꢆ3 the density and the linear absorption coefficients are
1.273 gcmꢀ3 and 1.509 mmꢀ1, respectively. No absorption correction.
Diffraction data were collected at 298 K on an Enraf Nonius CAD4
diffractometer employing CuKa radiation (l=1.54179 ꢆ). 4565 re-
flections were collected in the range ꢀ10ꢃhꢃ10, ꢀ16ꢃkꢃ14, and
Received: June 22, 2009
Revised: September 10, 2009
Published online: November 24, 2009
Chem. Eur. J. 2010, 16, 677 – 683
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
683