A practical approach to N-(trifluoroacetyl)sulfilimines

Article abstract of DOI:10.1055/s-0034-1378328

A new, simple method for the synthesis of N-(trifluoroacetyl)-protected sulfilimines from sulfides by a transition-metal-free, one-pot protocol is presented. The salient features of this process include the use of low-cost 1,3-dibromo-5,5-dimethylhydantoin, mild reaction conditions, and a broad substrate scope. The safety and robustness of the method has also been demonstrated by operations on a kilogram scale. In addition, a chiral resolution of a corresponding sulfoximine was achieved on a large scale. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0034-1378328

LETTER
▌1831
lAettePr ractical Approach to N-(Trifluoroacetyl)sulfilimines
A Practical Approach to N-(Trifluoroacetyl)sulfilimines
Jörg Gries, Jochen Krüger*
Bayer Pharma AG, Global Drug Discovery – Chemical Development, Friedrich-Ebert-Str. 217–333, 42117 Wuppertal, Germany
Fax +49(202)362566; E-mail: joachim.krueger1@bayer.com
Received: 17.04.2014; Accepted after revision: 20.05.2014
O
Abstract: A new, simple method for the synthesis of N-(trifluoro-
imination
oxidation
S
acetyl)-protected sulfilimines from sulfides by a transition-metal-
free, one-pot protocol is presented. The salient features of this pro-
cess include the use of low-cost 1,3-dibromo-5,5-dimethylhydanto-
in, mild reaction conditions, and a broad substrate scope. The safety
and robustness of the method has also been demonstrated by opera-
tions on a kilogram scale. In addition, a chiral resolution of a corre-
sponding sulfoximine was achieved on a large scale.
R2
R1
sulfoxide
O
NPG
R2
S
R2
S
R1
sulfide
R1
sulfoximine
Key words: N-(trifluoroacetyl)sulfilimines, sulfilimines, sulfox-
imines, chiral resolution
NPG
S
R1
R2
imination
oxidation
sulfilimine
Methods for the preparation of sulfilimines have recently
received an increasing level of attention, not least due to
the role of sulfilimines as intermediates in the preparation
of sulfoximines. The applications of sulfoximines range
from chiral ligands1 in asymmetric catalysis to the design
of active ingredients in the life science arena.2
Scheme 1 Synthetic approaches to sulfoximines (PG: protecting
group)
When we embarked on this chemistry, we were seeking a
transition-metal-free process which makes use of safe, in-
expensive reagents and proceeds under mild conditions in
one pot, to transfer sulfides into sulfilimines. In particular,
we were interested in N-(trifluoroacetyl)-protected sul-
filimines as the N-protecting group can be easily removed
under mild conditions.12a
The most commonly used synthetic approach to sulfox-
imines is based on an oxidation–imination protocol com-
mencing from readily available sulfides (Scheme 1).
Imination of a sulfoxide is typically accomplished by the
use of, for example, sodium azide with sulfuric acid3 or
O-mesitylsulfonylhydroxylamine (MSH);4 however,
these reagents are thermally labile and their use for batch
operations beyond the laboratory scale is demanding.5 Ac-
cordingly, new imination protocols utilizing (diacetoxyio-
do)benzene6 or electrochemical oxidation7 have been
developed. More recently, catalytic iminations8 using for
example, iron,9 silver,10 copper,11 rhodium,12 or
ruthenium13 catalysis have been introduced.
The starting point for our investigations was Bolm’s re-
port on the conversion of sulfides into N-cyanosulfilim-
ines, which can serve as precursors for sulfoximines,
employing cyanogen amine and N-bromosuccinimide
(NBS) or iodine in the presence of potassium tert-butox-
ide.16
Under this protocol, our reference sulfide 1, which is a key
structural element of a drug candidate,17 was converted
smoothly into the N-cyanosulfilimine 2 (Scheme 2); how-
ever, concomitant formation of the corresponding sulfox-
ide 4 was observed at a considerable level, which reduced
the yield of 2 to 62% on a 0.5 mol scale.
Alternatively, the oxidative imination of sulfides to sul-
filimines, followed by an oxidation step, can also furnish
sulfoximines (Scheme 1). For the sulfilimine synthesis,
Bolm’s rhodium protocol [Rh2(OAc)4, MgO, PhI(OAc)2,
F3CCONH2]12a and Carreira’s method using copper catal-
ysis and lithiated N,O-bis(trifluoroacetyl)hydroxyl-
amine14 are noteworthy. Both procedures deliver a broad
range of synthetically useful N-(trifluoroacetyl)-protected
sulfilimines. More recently, a metal-free process was re-
ported by Ochiai, Nakanishi, and coworkers who intro-
duced a sulfonylimino-λ3-bromane reagent.15
CN
N
NBS, H2NCN
S
S
t-BuOK, MeOH, r.t.
62%
O2N
O2N
2
1
Scheme 2 Initial oxidative imination of sulfide 1
Subsequently, we replaced cyanogen amine by trifluoro-
acetamide as the nitrene source under otherwise similar
conditions. To our dismay, we obtained sulfoxide 4 as the
major product (Table 1, entry 1). We further investigated
SYNLETT 2014, 25, 1831–1834
Advanced online publication: 25.06.2014
DOI: 10.1055/s-0034-1378328; Art ID: st-2014-b0329-l
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1832
J. Gries, J. Krüger
LETTER
the influence of the reaction components (oxidation agent, filimine 3 (Table 2, entry 1) on a 7.4 mol scale to give 1.84
base, solvent) on the transformation. To this end, we kg of sulfilimine per batch, with an average yield of 81%.
found that replacement of NBS by the low-cost bromina-
Table 2 Scope of the Sulfide Iminationa,18
tion agent 1,3-dibromo-5,5-dimethylhydantoin (DBDMH)
significantly improved the ratio of sulfilimine 3 to sulfox-
O
ide 4 (Table 1, entries 3–9). Additionally, the choice of
Br
Br
N
N
solvent had a dramatic impact on the 3/4 ratio. When the
DBDMH-promoted conversion was conducted in metha-
nol (Table 1, entry 3), desired 3 and undesired 4 were
formed to similar extent, while the use of dichlorometh-
ane (Table 1, entry 4) suppressed formation of the sulfox-
ide 4 almost completely. Furthermore, a variety of bases,
such as sodium hydride, cesium carbonate, and potassium
tert-butoxide are tolerated with DBDMH as oxidation
agent to yield a high preference for sulfilimine formation.
O
Me
O
Me
S
N
S
CF3
R1
R2
NaH, CF3CONH2
THF, r.t.
R1
R2
Entry
1
Sulfilimine product
Yield (%)
O
N
S
CF3
Table 1 Imination of Sulfide 1a
81
O
O2N
base, oxidant
trifluoroacetamide
solvent, r.t.
N
S
CF3
O
S
O
1
+
N
CF3
2
3
88
81
O2N
S
O2N
Me
3
4
Me
Solvent
MeOH
MeOH
MeOH
CH2Cl2
THF
Oxidant
NBS
Base
Ratio 3/4b
Entry
O
1
2
3
4
5
6
7
8
9
t-BuOK
NaOMe
t-BuOK
t-BuOK
NaH
39:61
45:55
58:42
98:2
N
S
CF3
NBS
Me
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
DBDMH
MeO
O
97:3
N
S
CF3
4
5
74
77
MeCN
MeCN
MTBE
1,4-dioxane
Cs2CO3
NaH
87:13
98:2
Me
Cl
O
NaH
97:3
N
S
CF3
t-BuOK
83:17
a Reaction conditions: sulfide 1 (1 equiv), trifluoroacetamide (1.5
Me
equiv), base (1.5 equiv), oxidant (1.5 equiv), solvent (c 0.3 M sulfide),
20 °C.
b Ratio derived from the HPLC trace (area%) of the reaction mixture
after 3 h.
O
N
S
CF3
6
Me
71
In order to evaluate the scope of this transformation, we
selected the conditions listed in Table 1, entry 5 (NaH,
THF) for additional studies, due to the good solubility of
DBDMH in tetrahydrofuran.18
As illustrated in Table 2,19 a variety of sulfides can be con-
verted into the corresponding N-(trifluoroacetyl)-protect-
ed sulfilimines. The substrates included aromatic sulfides
with a range of electronic properties (Table 2, entries 1–4)
and aliphatic sulfides (Table 2, entries 5 and 6), demon-
strating the scope of this reaction.
a Reaction conditions: sulfide (1 equiv), trifluoroacetamide (1.5
equiv), NaH (1.5 equiv), DBDMH (1.5 equiv), THF, 20 °C; see the
Supporting Information for product analytical data.
Because unsymmetrically substituted sulfilimines and
sulfoximines bear a stereogenic sulfur atom, a stereoselec-
tive imination process is highly desirable. To date, the di-
rect asymmetric imination of sulfides remains a
challenge,12b,20 and oxidative imination of optically active
Additionally, we were interested in the robustness of this
method. Therefore, we produced several batches of sul-
Synlett 2014, 25, 1831–1834
© Georg Thieme Verlag Stuttgart · New York

LETTER
A Practical Approach to N-(Trifluoroacetyl)sulfilimines
1833
Oxone, MeOH
sulfolane, H2O
K2CO3, r.t.
NH⋅tartrate
O
NH
O
(+)-di-p-tolyl-D-tartrate
S
S
MeCN, r.t.
3
86%
41%, 99.5% de
O2N
O2N
5
6
Scheme 3 Synthesis of optically pure sulfoximine 6 (see Supporting Information for experimental details)
sulfoxides under retention of the sulfoxide configuration
has been more widely employed.12a,21
References and Notes
(1) See, for instance: (a) Okamura, H.; Bolm, C. Chem. Lett.
2004, 33, 482. (b) Reggelin, M.; Zur, C. Synthesis 2000, 1.
(c) Gais, H.-J. Heteroat. Chem. 2007, 18, 472. (d) Frings,
M.; Atodiresei, I.; Wang, Y.; Runsink, J.; Raabe, G.; Bolm,
C. Chem. Eur. J. 2010, 16, 4577; and references cited
therein.
Especially for larger scale operations, resolution of the
sulfoximine racemate via diastereoselective salt forma-
tion is a powerful method. For instance, (+)-S-methyl-S-
phenylsulfoximine has been prepared in enantiopure form
by resolution with (+)-10-camphorsulfonic acid.22
(2) (a) Kahraman, M.; Sinishtaj, S.; Dolan, P. M.; Kensler, T.
W.; Peleg, S.; Saha, U.; Chuang, S. S.; Berstein, G.;
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(b) Raza, A.; Sham, Y. Y.; Vince, R. Bioorg. Med. Chem.
Lett. 2008, 18, 5406. (c) Walker, D. P.; Zawistoski, M. P.;
McGlynn, M. A.; Li, J.-C.; Kung, D. W.; Bonnette, P. C.;
Baumann, A.; Buckbinder, L.; Houser, J. A.; Boer, J.;
Mistry, A.; Han, S.; Xing, L.; Guzman-Perez, A. Bioorg.
Med. Chem. Lett. 2009, 19, 3253. (d) Luecking, U.;
Siemeister, G.; Lienau, P.; Jautelat, R.; Schulze, J. EP
2179991, 2010. (e) Lücking, U.; Jautelat, R.; Krüger, M.;
Brumby, T.; Lienau, P.; Schäfer, M.; Briem, H.; Schulze, J.;
Hillisch, A.; Reichel, A.; Wengner, A. M.; Siemeister, G.
ChemMedChem 2013, 8, 1067. (f) Lücking, U. Angew.
Chem. Int. Ed. 2013, 52, 9399.
Along these lines, we explored a method to resolve the
sulfoximine derived from our lead sulfilimine 3. Accord-
ingly, 3 was converted into the sulfoximine using potassi-
um peroxymonosulfate (Oxone®)23 as oxidant, which is
available in bulk quantities (Scheme 3). The ternary sol-
vent mixture sulfolane–water–methanol proved beneficial
for this protocol, since good solubility of all reaction com-
ponents was achieved. When the pH was adjusted to pH
10 during the reaction, the oxidation rate was accelerated
and the N-(trifluoroacetyl)-protecting group was cleaved
in one pot to give sulfoximine 5 in 86% yield.
Finally, we found that rac-5 can be resolved by a single
crystallization with (+)-di-p-tolyl-D-tartrate in acetonitrile
to give the corresponding tartrate salt with high optical
(99.5% de) and chemical purity in 41% yield. This proto-
col was performed on an 8.5 mol scale to give 2.1 kg of
the tartrate salt per batch.
(3) Bentley, H. R.; Whitehead, J. K. J. Chem. Soc. 1952, 1572.
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In conclusion, we have presented a new method for the
synthesis of N-(trifluoroacetyl)-protected sulfilimines
from sulfides by a simple, one-pot transition-metal-free
protocol that is also applicable for large-scale operations.
The salient features of this process include the use of safe,
low-cost, commercially available reagents, mild reaction
conditions, and a broad substrate scope. We have also
demonstrated that downstream chemistry can lead to opti-
cally active sulfoximines by employing a new resolution
process with (+)-di-p-tolyl-D-tartrate. The scope of this
crystallization process will be the subject of further inves-
tigations.
Acknowledgment
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(b) Collet, F.; Dodd, R. H.; Dauban, P. Org. Lett. 2008, 10,
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2014, 53, 5639.
We thank Dr. D. Heitkamp for conducting DSC measurements and
G. Quabeck, M. Reinke and J. Schilling for their skillful laboratory
work. We are grateful to H. Lorenz and T. Friede and their teams for
supporting scaleup activities.
(14) Tomooka, C. S.; LeCloux, D. D.; Sasaki, H.; Carreira, E. M.
Org. Lett. 1999, 1, 149.
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3809. (b) Pandey, A.; Bolm, C. Synthesis 2010, 2922.
(17) Luecking, U.; Krueger, M.; Jautelat, R.; Siemeister, G.
WO 2005037800, 2005.
Supporting Information for this article, including analytical
data for the sulfilimine products in Table 2 and for products 5 and
6, as well as details for the large-scale procedures, is available
online at http://www.thieme-connect.com/products/ejournals/
journal/10.1055/s-00000083.SunpfgIopi
o
nr
itartSunpIfoirgpmnrti
oat
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1831–1834

1834
J. Gries, J. Krüger
LETTER
removed by distillation, and the residue was purified by
silica gel chromatography (EtOAc–n-heptane = 1:1).
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(18) Calorimetric measurements revealed that THF solutions of
DBDMH have a limited stability at 20 °C and should
therefore be handled at 2–8 °C. Solutions of DBDMH in, for
example, 1,4-dioxane are more robust and can be used as an
alternative without a detrimental effect on quality or yield.
(19) General Experimental Procedure for the Formation of
N-(Trifluoroacetyl)-Protected Sulfilimines on a
Laboratory Scale
In an inert gas atmosphere, a mixture of the sulfide (34.7
mmol) and trifluoroacetamide (5.89 g, 52.1 mmol) in THF
(20 mL) was added under ice cooling within 45 min to a
suspension of NaH (60% in mineral oil; 1.25 g, 31.3 mmol)
in THF (25 mL). Then, a freshly prepared solution of 1,3-
dibromo-5,5-dimethylhydantoin (14.9 g, 52.1 mmol) in THF
(37 mL) was added within 60 min at 20 °C. The mixture was
stirred for 3 h; the reaction was quenched with 10% aq citric
acid solution (35 mL), and toluene (70 mL) was added. The
organic layer was washed with 25% aq sodium sulfite
solution (35 mL) and water (3 × 40 mL). The solvent was
(23) S-Oxidations with Oxone® leading to sulfones and
sulfoxides are well documented; see, for instance:Trost,
B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22, 1287.
Synlett 2014, 25, 1831–1834
© Georg Thieme Verlag Stuttgart · New York