Rhodium-catalyzed imination of sulfoxides and sulfides: Efficient preparation of N-unsubstituted sulfoximines and sulfilimines

Article abstract of DOI:10.1021/ol049715n

The Rh(II)-catalyzed imination of sulfoxides and sulfides using [Rh ₂(OAc)₄] as a catalyst and trifluoroacetamide or sulfonylamides in combination with iodobenzene diacetate and magnesium oxide affords sulfoximines and sulfilimines, respectively, in a stereospecific manner.

Full text of DOI:10.1021/ol049715n

ORGANIC
LETTERS
2004
Vol. 6, No. 8
1305-1307
Rhodium-Catalyzed Imination of
Sulfoxides and Sulfides: Efficient
Preparation of N-Unsubstituted
Sulfoximines and Sulfilimines
Hiroaki Okamura and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen, Professor-Pirlet-Str. 1,
D-52056 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received February 17, 2004
ABSTRACT
The Rh(II)-catalyzed imination of sulfoxides and sulfides using [Rh2(OAc)4] as a catalyst and trifluoroacetamide or sulfonylamides in combination
with iodobenzene diacetate and magnesium oxide affords sulfoximines and sulfilimines, respectively, in a stereospecific manner.
Recently, sulfoximines and sulfilimines have attracted sig-
nificant attention due to their use as building blocks for chiral
ligands1 and pseudopeptides.2 A number of synthetic ap-
proaches have been developed that allow the preparation of
various derivatives in a relatively straightforward manner.3
Most of them, however, rely on the use of toxic and
potentially explosive reagents such as combinations of NaN3
and H2SO4 or O-mesitylenesulfonylhydroxylamine (MSH).4,5
More recently, metal-catalyzed iminations of sulfoxides and
sulfides giving sulfoximines and sulfilimines, respectively,
have been described, which utilize copper or iron salts6 and
manganese or ruthenium complexes as catalysts.7 Further-
more, an electrochemical iminaton of sulfoxides has been
reported.8 The limitations of most of those methods stem
from the fact that often N-substituted products such as
tosylated imine derivatives are obtained, which are difficult
(4) NaN3/H+: (a) Fusco, R.; Tericoni, F. Chim. Ind. (Milan) 1965, 47,
61. (b) Johnson, C. R.; Schroeck, C. W. J. Am. Chem. Soc. 1973, 95, 7418.
(c) For an improved protocol, see: Brandt, J.; Gais, H.-J. Tetrahedron:
Asymmetry 1997, 6, 909. (d) For the toxicity of NaN3: Merck Index, 12th
ed.; Budavari, S., Ed.; Merck & Co., Inc.: Rahway, NJ, 1996; p 451.
(5) MSH: (a) Tamura, Y.; Minamikawa, J.; Sumoto, K.; Fujii, S.; Ikeda,
M. J. Org. Chem. 1973, 38, 1239. (b) Johnson, C. R.; Kirchhoff, R. A.;
Corkins, H. G. J. Org. Chem. 1974, 39, 2458. (c) Tamura, Y.; Matushima,
H.; Minamikawa, J.; Ikeda, M.; Sumoto, K. Tetrahedron 1975, 31, 3035.
(d) Fieser, M.; Fieser, L. F. Reagents for Organic Synthesis; John Wiley &
Sons: New York, 1975; Vol. 5, p 430.
(6) Cu salts: (a) Mu¨ller, J. F. K.; Vogt, P. Tetrahedron Lett. 1998, 39,
4805. (b) Lacoˆte, E.; Amatore, M.; Fensterbank, L.; Malacria, M. Synlett
2002, 116. (c) Cren, S.; Kinahan, T. C.; Skinner, C. L.; Tye, H. Tetrahedron
Lett. 2002, 43, 2749. (d) Tomooka, C. S.; Carreira, E. M. HelV. Chim.
Acta 2003, 85, 3773. (e) Takada, H.; Ohe, K.; Uemura, S. Angew. Chem.,
Int. Ed. 1999, 38, 1288. Fe salts: (f) Bach, T.; Ko¨rber, C. Tetrahedron
Lett. 1998, 39, 5015. (g) Bach, T.; Ko¨rber, C. Eur. J. Org. Chem. 1999,
1033.
(1) For recent examples, see: (a) Bolm, C.; Simic, O. J. Am. Chem.
Soc. 2001, 123, 3830. (b) Harmata, M.; Ghosh, S. K. Org. Lett. 2001, 3,
3321. (c) Bolm, C.; Martin, M.; Simic, O.; Verrucci, M. Org. Lett. 2003,
5, 427. (d) Bolm, C.; Verrucci, M.; Simic, O.; Cozzi, P. G.; Raabe, G.;
Okamura, H. Chem. Commun. 2003, 2816. (e) Bolm, C.; Martin, M.;
Gescheidt, G.; Palivan, C.; Neshchadin, D.; Bertagnolli, H.; Feth, M. P.;
Schweiger, A.; Mitrikas, G.; Harmer, J. J. Am. Chem. Soc. 2003, 125, 6222.
(f) Review: Harmata, M. Chemtracts 2003, 16, 660 and references therein.
(2) (a) Bolm, C.; Kahmann, J. D.; Moll, G. Tetrahedron Lett. 1997, 38,
1169. (b) Bolm, C.; Moll, G.; Kahmann, J. D. Chem. Eur. J. 2001, 7, 1118.
(c) Tye, H.; Skinner, C. L. HelV. Chim. Acta 2002, 85, 3272. (d) Bolm, C.;
Mu¨ller, D.; Hackenberger, C. P. R. Org. Lett. 2002, 4, 893. (e) Bolm, C.;
Mu¨ller, D.; Dalhoff, C.; Hackenberger, C. P. R.; Weinhold, E. Bioorg. Med.
Chem. Lett. 2003, 13, 3207.
(7) Mn complexes: (a) Nishikori, H.; Ohta, C.; Oberlin, E.; Irie, R.;
Katsuki, T. Tetrahedron 1999, 55, 13937. (b) Ohta, C.; Katsuki, T.
Tetrahedron Lett. 2001, 42, 3885. Ru complexes: (c) Murakami, M.;
Uchida, T.; Katsuki, T. Tetrahedron, Lett. 2001, 42, 7071. (d) Tamura, Y.;
Uchida, T.; Katsuki, T. Tetrahedron Lett. 2003, 44, 3301. (e) Murakami,
M.; Uchida, T.; Saito, B.; Katsuki, T. Chirality 2003, 15, 116. (f) Uchida,
T.; Tamura, Y.; Ohba, M.; Katsuki, T. Tetrahedron Lett. 2003, 44, 7965.
(3) Reviews on sulfoximines and sulfilimines: (a) Johnson, C. R. Acc.
Chem. Res. 1973, 6, 341. (b) Pyne, S. G. Sulfur Rep. 1999, 21, 281. (c)
Reggelin, M.; Zur, C. Synthesis 2000, 1. (d) Taylor, P. C. Sulfur Rep. 1999,
21, 241.
10.1021/ol049715n CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/16/2004

Scheme 1
Table 2. Rhodium-Catalyzed Iminations of Sulfoxides to Give
NH-sulfoximinesa
entry substrate
R
R′
product
yield (%)
1
2
3
4
1
3
Ph
Ph
Me
Ph
9
10
12
(R)-14
71
66
88
76
11
(R)-13
-[CH2CH2]2-
p-Tol
Me
a Reaction conditions: Sulfoximine (1.0 mmol), CF3CONH2 (2.0 mmol),
PhI(OAc)2 (1.5 mmol), MgO (4.0 mmol), and [Rh2(OAc)4] (2.5 mol %) in
CH2Cl2 (10 mL) at room temperature; then K2CO3 (5 equiv) in MeOH (10
mL).
to convert into the synthetically more valuable (“free”) NH
compounds. Accordingly, it appeared attractive to search for
a novel alternative protocol, which allowed the reaction to
be performed with readily available and safe iminating agents
and which finally would lead to products with “free” NH-
imino groups.
Focusing the attention on catalytic transformations we
found that [Rh2(OAc)4], which is known to be a catalyst for
nitrene insertion reactions into C-H bond and nitrene
additions to C-C double bonds,9 is an efficient catalyst for
the imination of sulfoxides and sulfides (Scheme 1).
The results of imination reactions of sulfoxides are listed
in Table 1. Accordingly, the conversion of methylphenyl-
preformed iminating agent, mixtures of NsNH2, MgO, and
PhI(OAc)2 instead of NsNdIPh were applied next.11 Again,
2a was obtained from 1 in good yield (entry 2), albeit under
those conditions the reaction time was longer. Iminations of
1 with MsNH2 (entry 3) and CF3CONH2 (entry 4) also
proceeded well, affording sulfoximines 2b and 2c bearing
N-mesyl and N-trifluoroacetyl groups, respectively. With
regard to the synthesis of NH-sulfoximines, the latter result
was particularly important (vide infra).
Cu(OTf)2, which is a known catalyst for the imination of
sulfoxides,6b showed a much lower catalytic activity than
[Rh2(OAc)4] under these conditions (entry 5). Attempts to
use acetamide or benzamide as nitrogen sources in the Rh-
catalyzed conversions of 1 failed (entries 6 and 7), indicating
that the intermediate iminoiodanes should be stabilized by
strong electron-withdrawing substituents.
To investigate the scope of the reaction, several sulfoxides
were used as substrates. All of them were readily converted
into sulfoximines, albeit in the reactions with sulfoxides 5
and 7 (entries 9 and 10) the yields of the corresponding
sulfoximines 6a and 8a were only moderate (50 and 49%,
respectively). Presumably, the steric hindrance of the bulky
tert-butyl group of 7 hampered its smooth conversion.
The novel rhodium-catalyzed protocol for the imination
of sulfoxides to give sulfoximines described here has several
advantages over the existing methodology. Since the reagents
and the catalyst are stable toward atmospheric moisture and
oxygen, the imination requires neither dried solvents nor an
inert atmosphere. Furthermore, iodobenzene diacetate is
known as a mild and nonexplosive compound, which renders
this process safer than the known ones, which rely on the
use of potentially dangerous iminating agents such as azido
derivatives or MSH.4, 5
For synthetic purposes, the resulting N-trifluoroacetyl
sulfoximines are highly valuable since they can easily be
hydrolyzed to give synthetically useful NH-sulfoximines.
Consequently, a simple two-step process, which does not
even require the isolation of intermediates, allows the
preparation of those N-unprotected products in high yields
(Table 2). Their subsequent conversions have been described
and lead to ligands for asymmetric catalysis and building
blocks of pseudopeptides.1,2
Table 1. Metal-Catalyzed Iminations of Sulfoxidesa
time
yield
entry substrate
(h) product (%)
1
2
3
4
5b
6
7
8
9
1
1
1
1
1
1
1
3
5
7
PhIdNNs
NsNH2, PhI(OAc)2, MgO
MsNH2, PhI(OAc)2, MgO
CF3CONH2, PhI(OAc)2, MgO 12
CF3CONH2, PhI(OAc)2, MgO 24
AcNH2, PhI(OAc)2, MgO
BzNH2, PhI(OAc)2, MgO
NsNH2, PhI(OAc)2, MgO
NsNH2, PhI(OAc)2, MgO
NsNH2, PhI(OAc)2, MgO
1
6
6
2a
2a
2b
2c
93
86
79
84
0c
24
24
6
6
6
0d
0c
68
50
49
4a
6a
8a
10
a Reaction conditions: sulfoximine (1.0 mmol), PhIdNNs (1.5 mmol)
and [Rh2(OAc)4] (2.5 mol %) in CH2Cl2 (10 mL) at room temperature (for
entry 1) or sulfoximine (1.0 mmol), X-NH2 (2.0 mmol), PhI(OAc)2 (1.5
mmol), MgO (4.0 mmol), and [Rh2(OAc)4] (2.5 mol %) in CH2Cl2 (10
mL) at room temperature (for entries 2-10). b Cu(OTf)2 (2.5 mol %) was
used as a catalyst. c Sulfoximine was almost quantitatively recovered.
d Complex mixture was formed, and small amounts of the sulfoximine were
recovered.
sulfoxide (1) with NsNdIPh10 as an iminating agent and
[Rh2(OAc)4] as a catalyst proceeded very rapidly, and after
1 h, N-nosyl sulfoximine 2a was obtained in high yield (entry
1). To simplify the process and to avoid the use of a
(8) Siu, T.; Yudin, A. K. Org. Lett. 2002, 4, 1839. The authors also
report the preparation of “free” sulfoximines by electrolysis of the
corresponding N-phthalimido derivatives.
(9) For recent reviews including Rh-catalyzed nitrene transfer reactions,
see: (a) Dauban, P.; Dodd, R. H. Synlett 2003, 1571. (b) Mu¨ller, P.; Fruit,
C. Chem. ReV. 2003, 103, 2905.
(10) For the use of NsNdIPh in copper-catalyzed sulfoxide iminations,
see: (a) Bolm, C.; Mun˜iz, K.; Aguilar, N.; Kesselgruber, M.; Raabe, G.
Synthesis 1999, 1251. (b) ref 6c.
1306
Org. Lett., Vol. 6, No. 8, 2004

Table 3. [Rh2(OAc)4]-Catalyzed Imination of Sulfidesa
Scheme 2
entry substrate X-NH2 reagents product time (h) yield (%)
1
2
3
4
5
15
15
17
17
19
NsNH2
CF3CONH2
NsNH2
CF3CONH2
NsNH2
16a
16b
18a
18b
20a
6
6
6
6
6
90
87
98
98
61
a Reaction conditions: sulfide (1.0 mmol), X-NH2 (2.0 mmol), PhI(OAc)2
(1.5 mmol), MgO (4.0 mmol), and [Rh2(OAc)4] (2.5 mol %) in CH2Cl2
(10 mL) at room temperature.
The stereospecificity of this reaction was examined by
using optically pure sulfoxide (R)-13 (Scheme 2). Rhodium-
catalyzed imination and subsequent methanolysis afforded
enantiopure sulfoximine (R)-14 in good yield (76%). The
sign of the optical rotation of the product5b revealed that the
reaction had occurred with retention of configuration.
Next, the rhodium-catalyzed imination of sulfides leading
to sulfilimines was examined (Scheme 3). Under the same
(OAc)2 in the presence of 2.5 mol % of [Rh2(OAc)4] only
afforded sulfilimine 16a (90% yield). This result suggested
that the second imination reaction was hampered by the
strongly electron-withdrawing N-nosyl group of 16a. Con-
sequently, the electron density at the sulfur atom was too
low to allow a second nitrene transfer.
In summary, various sulfoxides and sulfides have been
converted into their corresponding sulfoximines and sulfil-
imines, respectively, using [Rh2(OAc)4] as a catalyst and
trifluoroacetamide or sulfonylamides in combination with
iodobenzene diacetate and magnesium oxide. Synthetically
valuable NH-sulfoximines and sulfilimines can easily be
obtained by cleavage of the N-acyl bond of the resulting
N-trifluoroacetyl-protected derivatives. The imination reac-
tion is stereospecific and proceeds with retention of config-
uration at the stereogenic center. Consequently, enantiomer-
ically pure sulfoximines are accessible by starting from
enantiopure sulfoxides. Asymmetric iminations using chiral
rhodium catalysts are currently under investigation.
Scheme 3
reaction conditions, sulfides were more reactive than sul-
foxides, and all the reactions listed in Table 3 were finished
within 6 h giving sulfilimines in high yields.
To demonstrate the applicability of the process in the
preparation of NH derivatives, N-trifluoroacetyl-protected
sulfilimine 18b was subjected to methanolysis using MeOH-
KOH, which led to the corresponding “free” sulfilimine 18c
in 88% yield.12
Acknowledgment. The Deutsche Forschungsgemein-
schaft within the SFB 380 and the Fonds der Chemischen
Industrie are gratefully acknowledged for financial support.
H.O. thanks the Alexander von Humboldt-Stiftung for a
postdoctoral fellowship.
Supporting Information Available: Experimental pro-
cedures and full characterization (1H and 13C NMR data and
spectra, MS, IR, and CHN analyses) for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The attempted synthesis of sulfodiimine 21 by double
imination of sulfide 15 remained unsuccessful.13 Thus,
treatment of 15 with 3 equiv of NsNH2 and 2 equiv of PhI-
OL049715N
(11) Recently, several nitrogen transfer reactions using in-situ-formed
iminoiodanes have been reported. For examples, see ref 9.
(12) Acid hydrolysis of N-sulfonylated sulfilimines is known. (a)
Furukawa, N.; Omata, T.; Yoshimura, T.; Aida, T.; Oae, S. Tetrahedron
Lett. 1972, 1619. (b) Yoshimura, T.; Omata, T.; Furukawa, N.; Oae, S. J.
Org. Chem. 1976, 41, 1728.
(13) For a review on sulfodiimines, see: (a) Haake, M. In Topics in
Sulfur Chemistry; Senning, A., Ed; Thieme: Stuttgart, 1976; Vol. 1, p 185.
For recent reports on the use of sulfodiimines, see: (b) Diederich, W. E.;
Haake, M. J. Org. Chem. 2003, 68, 3817. (c) Stoller, A.; Kreuz, K.; Haake,
M.; Wenger, J. Chimia 2003, 57, 725.
Org. Lett., Vol. 6, No. 8, 2004
1307