Synthesis of bis(4-methylphenylsulfonimidoyl)methane - The first free' geminal bis(sulfoximine)

Article abstract of DOI:10.1055/s-0031-1290759

The synthesis of the first free' geminal bis(sulfoximine) bis(4-methylphenylsulfonimidoyl)methane is described. Herein we present two different synthetic routes leading either to the racemate or the enantiomerically pure compound. This representative of a new substance class can be regarded as a chiral analogue of the bis(iminophosphorane)s which are used as ligands in rare-earth-metal-catalyzed hydroamination reactions. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290759

LETTER
▌1095
LSeyttenr thesis of Bis(4-methylphenylsulfonimidoyl)methane – The First ‘Free’
Geminal Bis(sulfoximine)
Bis(4-methylphenylsulfonimidoyl)methane
Michael Reggelin,* Christian Mehler, Jan Philipp Kaiser
Technical University Darmstadt, Institute of Organic Chemistry and Biochemistry, Petersenstraße 22, 64287 Darmstadt, Germany
Fax +49(6151)165531; E-mail: re@punk.oc.chemie.tu-darmstadt.de
Received: 02.02.2012; Accepted after revision: 15.02.2012
bridge and heteroatom-bound imino functions as possible
coordination sites.
Abstract: The synthesis of the first ‘free’ geminal bis(sulfoximine)
bis(4-methylphenylsulfonimidoyl)methane is described. Herein we
present two different synthetic routes leading either to the racemate
or the enantiomerically pure compound. This representative of a
new substance class can be regarded as a chiral analogue of the
bis(iminophosphorane)s which are used as ligands in rare-earth-
metal-catalyzed hydroamination reactions.
For the sake of maximum structural flexibility we envi-
sioned the synthesis of the double N-unsubstituted (‘free’)
parent compound 2 which has proven to be highly reluc-
tant to its synthesis.17 Herein we describe two different
routes for its preparation starting from bis(sulfoximine)s
rac-3 (PMP = 4-methoxyphenyl) and 4, respectively
(Scheme 1).
Key words: sulfoximine, asymmetric catalysis, ligands, elimina-
tion, oxidative cleavage, sulfur, zinc, chirality
O
O
Bis(iminophosphorane)s are used as ligands in various
metal-catalyzed reactions, for example, the polymeriza-
tion of ethane1–3 or the ring-opening polymerization of
lactides4,5 and ε-caprolactam.6–9 Furthermore, the rare-
earth-metal complexes of iminophosphoranes serve as
catalysts in hydroamination reactions.10–13 Since 2001 a
number of bis(iminophosphorane) rare-earth-metal com-
plexes have been prepared by Roesky et al. starting from
precursor 1 (Figure 1).14
p-Tol
p-Tol
S
S
N
N
H
H
2
oxidative
cleavage
β-elimination
O
O
O
O
p-Tol
PMP
p-Tol
p-Tol
p-Tol
S
S
S
S
Ph
Ph
O
O
N
N
PMP
OH
N
N
Ph
p-Tol
Ph
p-Tol
P
P
S
S
N
N
N
N
HO
Br
Br
TMS
TMS
H
H
rac-3
4
1
2
Scheme 1 Retrosynthetic analysis bis(sulfoximine) 2
Figure 1 Comparison of bis(iminophosphorane) 1 and the ‘free’
geminal bis(sulfoximine) 2
The first route relies on an oxidative cleavage of the new
bis(sulfoximine) rac-3 derived from the non-natural ami-
no acid rac-5 (Scheme 2). Its reduction and O-protection
delivered the TMS-protected amino alcohol rac-6 in good
yields.
The application in intramolecular hydroamination–cycli-
zation reactions of terminal aminoalkenes delivered the
corresponding azacycles in almost quantitative yields.15
Naturally, due to the achirality of the ligand, all products
were formed as racemic mixtures.
Following the established synthetic procedure developed
in our group,23,24 the cyclic sulfonimidate rac-8 was ob-
tained by sulfinylation and diastereoselective cyclization
via the epimers rac-7 in good yield and diastereomeric ra-
tio.
To render the process enantioselective we were interested
in chiral analogues of the bis(iminophosphorane)s. Some
years ago we16,17 and others18–22 demonstrated the applica-
bility of sulfoximines in general and bis(sulfoximine)s17
in particular as chiral ligands in metal-catalyzed reactions.
Based on our work with the latter compounds we antici-
pated that bis(sulfoximine)-based ligands such as 2 may
act as a chiral equivalent of the bis(iminophosphorane) 1.
Both structures are characterized by an acidic methylene
After removal of the minor diastereomer by crystalliza-
tion, the sulfonimidate was opened by methyllithium, the
product deprotonated with LiHMDS and treated with an-
other equivalent of rac-8. The resulting bis(sulfoximine)
rac-3 was obtained in a very good yield with a diastereo-
meric ratio of 11:1 favoring the C2-symmetric isomer
which was isolated in diastereomerically pure form by
flash chromatography (Scheme 3).
SYNLETT 204012, 237, 1095–1098
Advanced online publication: 05.04.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290759; Art ID: ST-2012-B0101-L
© Georg Thieme Verlag Stuttgart · New York

1096
M. Reggelin et al.
LETTER
diately remove the basic product from the reacting system
(Table 1, entry 5). We were pleased to find no evidence
for partial epimerization under the given reaction condi-
tions.
1. LiAlH4
2. TMSCl, EtNMe2
PMP
PMP
OTMS
83%
H2N
CO2H
rac-5
H2N
rac-6
O
S
1.
Table 1 Optimization of the Oxidative Cleavage Reaction
p-Tol
Cl
O
O
oxidant (2.2 equiv)
solvent
temperature
O
O
p-Tol
PMP
p-Tol
PMP
2. K2CO3, MeOH
S
S
p-Tol
p-Tol
S
S
O
N
N
PMP
OH
N
N
S
H
H
p-Tol
N
TBSO
OTBS
H
rac-9
rac-2
O
S
rac-7
49%
1. KBr, 18-C-6, t-BuOCl
2. EtNMe2
p-Tol
O
Entry Solvent
Ratio Oxidant tinitiation Temp
Yield
(%)
N
(°C)a
63%, dr>14:1
O
PMP
OH
PMP
rac-8
1b
2
CH2Cl2–H2O
p-xylene
20:1
–
DDQ
–
20
138
20
0
8
S
p-Tol
N
H
C6O2Cl4
DDQ
–
–
49%
rac-epi-7
3
THF–H2O
10:1
20:1
1:2
–
<5
27
54
Scheme 2 Synthesis of the cyclic sulfonimidate rac-8
4
CH2Cl2–H2O
CH2Cl2–HClc
DDQ
–
O
O
5
DDQ
d 20
20 min
O
S
1. MeLi
2. LiHMDS
3. rac-8
p-Tol
PMP
p-Tol
PMP
S
N
S
p-Tol
O
a Reaction temperature after initiation, 16 h.
b 2.1 equiv DDQ were used.
N
N
one-pot
c Degassed solvents under argon
PMP
rac-8
d –20 °C in pure CH2Cl2, then addition of HCl.
RO
rac-3 99%, 83% de
OR
R = H
R = TBS
TBSCl
DMAP
99%
rac-9
Scheme 3 Synthesis of the bis(sulfoximine) rac-3 and its OTBS-pro-
tected derivative rac-9
After protection as TBS-ether yielding rac-9, the key step
involving the oxidative cleavage with 2,3-dichloro-5,6-di-
cyanobenzoquinone (DDQ) was studied (Table 1). Treat-
ing the substrate rac-9 with 1.05 equivalents DDQ per
PMP
group
under
standard
conditions25,26
(CH2Cl2/H2O = 20:1, r.t.) instantaneously gave a dark col-
ored solution indicating the formation of a charge-transfer
complex. After 20 minutes the starting material was com-
pletely consumed accompanied by precipitation of
DDQH. NaHCO3 workup turned out to be rather sluggish,
for which reason we took advantage of the basicity of the
sulfoximine moiety and extracted the reaction product
with 5 M HCl into the aqueous phase. Re-extraction after
pH adjustment gave the desired highly crystalline
bis(sulfoximine) rac-2 albeit in poor 8% yield (Table 1,
entry 1).
Figure 2 Solid-state structure of rac-2 (left: 50% probability aniso-
tropic thermal ellipsoids; right: plot of 1 × 2 × 1 unit cells)
We succeeded in growing single crystals of rac-2 that
were suited for a crystal structural analysis (Figure 2). It
crystallizes in the centrosymmetric space group P1 with
two symmetry-related molecules (2/ent-2) present in the
unit cell.
In contrast to the crystal structure of OTBS-protected 11
(Scheme 4),17 which displays an almost C2-symmetric
conformation, the solid-state conformation of rac-2 fea-
tures an asymmetric, almost coplanar arrangement of both
aromatic rings. These tolyl substituents form columnar
stacks with adjacent molecules, which are additionally
No other sulfoximine-containing components could be
isolated from the aqueous acidic phase. TLC analysis of
the organic phase indicated considerable decomposition.
The application of chloranil (C6O2Cl4, Table 1, entry 2) as
a less powerful oxidation agent was equally unsuccessful
as was a solvent change to THF (Table 1, entry 3). A sub-
stantial improvement was achieved at lower temperatures
(Table 1, entry 4) but most successful was the application
of a biphasic reaction system (CH2Cl2/5 M HCl) to imme-
held together via S=O···HN=S hydrogen bonds (dH···O
=
2.159 Å).
Simultaneously, we developed another route to the title
compound in enantiomerically pure form including a met-
al-induced β-elimination. Towards this end L-valine (10)
Synlett 2012, 23, 1095–1098
© Georg Thieme Verlag Stuttgart · New York

LETTER
Bis(4-methylphenylsulfonimidoyl)methane
1097
in moderate yield after a prolonged reaction time (Scheme
6).
O
O
p-Tol
p-Tol
S
S
N
N
O
O
HO2C
NH2
O
O
p-Tol
p-Tol
Zn, I2
S
S
HO
OH
p-Tol
DMF, 45 °C, 12 h p-Tol
S
S
10
79% over 5 steps
11
N
N
25%
N
N
MsCl, Et3N
H
H
Br
Br
(R,R)-2
99%
O
15
O
O
O
p-Tol
p-Tol
Scheme 6 Zinc-induced β-elimination of the rearranged halogenated
bis(sulfoximine) 15
S
S
p-Tol
p-Tol
S
S
N
NH4Br
N
N
N
In conclusion we have developed two different synthetic
routes for the first geminal ‘free’ bis(sulfoximine) 2 in-
cluding its preparation in enantiomerically pure state
(R,R)-2. This new kind of ligand represents a chiral ana-
logue of bis(iminophosphorane)s and may therefore be
suited as a ligand for asymmetric hydroamination reac-
tions employing rare-earth metals as central atoms. More-
over, compound 2 offers the opportunity to modify both
the acidic methylene bridge and the ‘free’ NH’s to obtain
a whole family of new sulfoximine-based ligand systems.
Work along these lines is in progress.
R
a)
b)
MsO
OMs
Br
12
R = OMs
Br
13
14
path a
path b
O
O
O
O
p-Tol
p-Tol
p-Tol
p-Tol
S
N
S
S
N
S
N
N
Br
Br
Br
Br
Acknowledgment
15 27%
4
70%
Thanks are due to Mrs. Foro (Institut für Organische Chemie und
Biochemie, TU-Darmstadt, Germany) for her careful work on the
X-ray of compound 2. We gratefully acknowledge Merck KGaA
(Darmstadt, Germany) for their generous support of this work and
Dr. Stefan Immel for his careful work on Figure 1.
Scheme 4 Synthesis of the brominated bis(sulfoximine)s 4 and 15
starting from enantiomerically pure L-valine (10)
was converted in five steps into the known bis(sulfox-
imine) 11 in 79% yield (Scheme 4).17
Mesylation followed by halogenation with NH4Br deliv- Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.onmornifIatngonimSorfniturItagponiSutpor
ered the dibrominated compound 4 in 70% yield, albeit
accompanied by 27% of the isomeric compound 15. This
observation is in accordance with the initial formation of
aziridinium ions 13 or 14 which can be attacked either via
path a) or path b). Furthermore, the formation of the rear-
ranged product 15 can be observed in solutions of 4 after
References
(1) Cavell, R. G.; Aparna, K.; Babu, R. P. K.; Wang, Q. Y.
J. Mol. Catal. A: Chem. 2002, 189, 137.
(2) Klemps, C.; Buchard, A.; Houdard, R.; Auffrant, A.;
a few days most probably via the intermediate 14.
Mezailles, N.; Le Goff, X. F.; Ricard, L.; Saussine, L.;
Magna, L.; Le Floch, P. New J. Chem. 2009, 33, 1748.
(3) Wei, P. R.; Stephan, D. W. Organometallics 2002, 21, 1308.
(4) Hill, M. S.; Hitchcock, P. B. J. Chem. Soc., Dalton Trans.
2002, 4694.
(5) Buchard, A.; Platel, R. H.; Auffrant, A.; Le Goff, X. F.; Le
Floch, P.; Williams, C. K. Organometallics 2010, 29, 2892.
(6) Gamer, M. T.; Rastatter, M.; Roesky, P. W.; Steffens, A.;
Glanz, M. Chem.–Eur. J. 2005, 11, 3165.
(7) Gamer, M. T.; Roesky, P. W.; Palard, I.; Le Hellaye, M.;
Guillaume, S. M. Organometallics 2007, 26, 651.
(8) Jenter, J.; Roesky, P. W.; Ajellal, N.; Guillaume, S. M.;
Susperregui, N.; Maron, L. Chem.–Eur. J. 2010, 16, 4629.
(9) Wiecko, M.; Roesky, P. W.; Burlakov, V. V.; Spannenberg,
A. Eur. J. Inorg. Chem. 2007, 876.
With this halogenated compound 4 in hand we tried the
zinc-induced β-elimination using Huo’s method.27 After
optimization of the reaction conditions the ‘free’ geminal
bis(sulfoximine) (R,R)-2 was obtained in good yields and
in enantiomerically pure form (Scheme 5).28
O
O
O
O
p-Tol
p-Tol
Zn, I2
DMF, 45 °C, 3 h
S
S
p-Tol
p-Tol
S
S
N
N
63%
N
N
H
H
Br
Br
4
(R,R)-2
(10) Panda, T. K.; Zulys, A.; Gainer, M. T.; Roesky, P. W.
Organometallics 2005, 24, 2197.
(11) Panda, T. K.; Zulys, A.; Gamer, M. T.; Roesky, P. W.
J. Organomet. Chem. 2005, 690, 5078.
Scheme 5 Zinc-induced β-elimination of the brominated bis(sulfox-
imine) 4 to the title compound (R,R)-2
(12) Zulys, A.; Panda, T. K.; Gamer, M. T.; Roesky, P. W. Chem.
Commun. 2004, 2584.
We also used the rearranged compound 15 for the elimi-
nation reaction and obtained the desired bis(sulfoximine)
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1095–1098

1098
M. Reggelin et al.
LETTER
(13) Rastaetter, M.; Zulys, A.; Roesky, P. W. Chem. Eur. J. 2007,
13, 3606.
(14) Gamer, M. T.; Dehnen, S.; Roesky, P. W. Organometallics
2001, 20, 4230.
(15) Rastatter, M.; Zulys, A.; Roesky, P. W. Chem. Commun.
2006, 874.
(28) Reaction Procedure for the Zinc-Induced β-Elimination:
In a Schlenk flask, zinc dust (10.1 g, 155 mmol, 12 equiv)
was suspended in dry DMF (12.9 mL) and elemental iodine
(6.88 g, 27.1 mmol, 2.1 equiv) was added at 0 °C. After
disappearance of the brown color the brominated
bis(sulfoxmine) 4 (8.00 g, 12.9 mmol), dissolved in dry
DMF (32 mL), was added dropwise to the grey suspension
via cannula, and the reaction mixture was stirred at 45 °C for
3 h. After complete conversion (controlled by TLC) the
excess zinc was removed by filtration over a pad of Celite.
The solvent was removed by vacuum distillation and freeze-
drying with toluene (3 × 250 mL). The residue was taken up
in CH2Cl2 (130 mL), the organic phase was washed with a
sat. NH4Cl solution (130 mL) and 0.1 M EDTA solution
(130 mL). Drying over Na2SO4 and removal of the solvent
delivered the crude product as a pale yellow oil. The pure
bis(sulfoximine) was obtained by recrystallization from
toluene (2.45g, 63%). [α]D25 –59.1 (c 1.05, CH2Cl2); mp
132–133 °C (from toluene); EA calcd for C13H18N2O2S2: C,
55.87; H, 5.63; N, 8.69; found: C, 55.79; H, 5.57; N, 8.53. 1H
NMR (500 MHz, CDCl3): δ = 7.90 (4 H, d, J = 8.4 Hz, 4-H),
7.32 (4 H, d, J = 8.4 Hz, 3-H), 4.53 (2 H, s, 6-H), 4.12 (2 H,
br s, NH), 2.43 (6 H, s, 1-H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 145.04 (C-2), 137.18 (C-5), 129.86 (C-3),
128.89 (C-4), 77.00 (C-6), 21.59 (C-1) ppm.
(16) Spohr, V.; Kaiser, J. P.; Reggelin, M. Tetrahedron:
Asymmetry 2006, 17, 500.
(17) Reggelin, M.; Weinberger, H.; Spohr, V. Adv. Synth. Catal.
2004, 346, 1295.
(18) Bolm, C.; Martin, M.; Simic, O.; Verrucci, M. Org. Lett.
2003, 5, 427.
(19) Harmata, M.; Ghosh, S. K. Org. Lett. 2001, 3, 3321.
(20) Bolm, C.; Simic, O.; Martin, M. Synlett 2001, 1878.
(21) Bolm, C.; Simic, O. J. Am. Chem. Soc. 2001, 123, 3830.
(22) Bolm, C.; Kaufmann, D.; Zehnder, M.; Neuburger, M.
Tetrahedron Lett. 1996, 37, 3985.
(23) Reggelin, M.; Welcker, R. Tetrahedron Lett. 1995, 36, 5885.
(24) Reggelin, M.; Junker, B. Chem.–Eur. J. 2001, 7, 1232.
(25) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.;
Yonemitsu, O. Tetrahedron 1986, 42, 3021.
(26) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett.
1982, 23, 885.
(27) Huo, S. Q. Org. Lett. 2003, 5, 423.
Synlett 2012, 23, 1095–1098
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.