Metal-free imination of sulfoxides and sulfides

Article abstract of DOI:10.1016/j.tetlet.2005.09.070

Using a nitrogen transfer agent obtained in situ by mixing of NsNH ₂ and PhI(OAc)₂, various N-nosyl sulfoximines and N-nosyl sulfilimines have been prepared under metal-free conditions starting from the corresponding sulfoxides and s

Full text of DOI:10.1016/j.tetlet.2005.09.070

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8007–8008
Metal-free imination of sulfoxides and sulfides
Gae Young Cho and Carsten Bolm*
Institut fu¨r Organische Chemie der RWTH Aachen, RWTH Aachen University, Landoltweg 1, 52056 Aachen, Germany
Received 14 August 2005; revised 9 September 2005; accepted 12 September 2005
Available online 29 September 2005
Abstract—Using a nitrogen transfer agent obtained in situ by mixing of NsNH2 and PhI(OAc)2, various N-nosyl sulfoximines and
N-nosyl sulfilimines have been prepared under metal-free conditions starting from the corresponding sulfoxides and sulfides,
respectively.
Ó 2005 Elsevier Ltd. All rights reserved.
In recent years, various procedures for the imination of
sulfoxides and sulfides giving synthetically valuable sulf-
oximines and sulfilimines,1,2 respectively, have been
developed (Scheme 1). In general, two approaches—
metal-catalyzed and metal-free ones—can be distinguished.
For the former, a variety of metal complexes proved
applicable, and for conversions of (pro)chiral substrates
a number of asymmetric and stereospecific versions have
been introduced.3 Metal-free imination reactions mostly
involve the use of a mixture of sodium azide and sulfuric
acid4 or MSH (O-mesitylenesulfonylhydroxylamine).5,6
Those methods are particularly useful for the prepara-
tion of ÔfreeÕ NH-derivatives (X = H), which are key
building blocks for more complex sulfur-based mole-
cular arrays.2
particular, for large-scale syntheses, finding and develop-
ment of more practical iminations based on the use
of stable, non-toxic reagents are desirable. In this context,
a recent report by Yudin and co-workers caught our
attention, who described the imination of sulfoxides with
N-amino- phthalimide and iodobenzene diacetate as
mild oxidant.7 Most interestingly and in contrast to pre-
vious studies,8 no metal was required for this apparently
rather facile (formal) nitrene-transfer reaction. This
observation was in line with results from our own inves-
tigations. During the development of silver-catalyzed
sulfoxide imination reactions with mixtures of p-nitro-
benzenesulfonylamide (Ns–NH2) and PhI(OAc)2,3g we
had observed the formation of nosyl-protected sulfox-
imine 2, which under reflux even occurred in the absence
of metal catalyst. Since compound 2 had an easy-to-
cleave protecting group on the sulfoximine nitrogen
(allowing access to the corresponding NH-derivative),
we wondered about the generality of this metal-free
imination process. After optimization of the reaction
conditions with methyl phenyl sulfoxide (1) as substrate,
a high yield (75%) of N-nosyl sulfoximine 2 was
achieved (Scheme 2).
Despite the wide applications of the aforementioned
metal-free methods, a major drawback of them is
the use of toxic and potentially explosive reagents. In
O
S
O
N X
S
R1
R1
R2
R2
R1 R2
metal-catalyzed
or
or
S
or
The best conditions involved the use of an acetonitrile
solution of all reaction components, which was kept
under reflux for 16 h.9 Acetonitrile proved superior to
metal-free
X
N
imination reactions
S
R1
R2
Scheme 1.
NsNH2 (1.2 equiv),
O
S
O
N Ns
PhI(OAc)2 (1.5 equiv)
S
Keywords: Asymmetric synthesis; Iminations; Metal-free; Sulfoxides;
Ph Me
Ph
Me
CH3CN, reflux, 16 h
(75% yield)
Sulfoximines.
1
2
*
Corresponding author. Tel.: +49 241 8094675; fax: +49 241
8092391; e-mail: Carsten.Bolm@oc.rwth-aachen.de
Scheme 2.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.070

8008
G. Y. Cho, C. Bolm / Tetrahedron Letters 46 (2005) 8007–8008
the other solvents, such as dichloroethane and THF,
which afforded 2 in only 60% and 33% yield, respec-
tively. At room temperature, no reaction occurred.
Addition of a base such as MgO did not affect the reac-
tion yield. Unfortunately, no conversions or very low
yields were observed with other nitrogen sources such
as p-toluenesulfonylamide (TsNH2), p-methyl-2-pyri-
dinesulfonylamide, trimethylsilylethyl sulfonyl amide
(SesNH2) and trifluoroacetamide.
Acknowledgements
Support from the Fonds der Chemischen Industrie and
the Deutsche Forschungsgemeinschaft (SFB 380) is
gratefully acknowledged.
References and notes
1. 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) Taylor, P. C. Sulfur Rep. 1999, 21, 241; (d)
Reggelin, M.; Zur, C. Synthesis 2000, 1.
2. For selected applications of sulfoximines, see: (a) asym-
metric catalysis: Okamura, H.; Bolm, C. Chem. Lett. 2004,
In order to investigate the scope of the substrate, the
imination of several other sulfoxides with Ns–NH2
was examined. Gratifyingly, most substrates were con-
verted equally well under the condition described
above affording the corresponding N-nosyl protected
sulfoximines (compounds 3–5) in good yields (up to
74%). Attempted iminations of benzyl phenyl sulfoxide
and phenyl vinyl sulfoxide proceeded inefficiently.
Furthermore, the nitrogen transfer onto sulfides was
tested and without further optimizing the reaction
conditions sulfilimines 6 and 7 were obtained from
the corresponding sulfides in 79% and 82% yield,
respectively.
33, 482; pseudopeptides: (b) Bolm, C.; Muller, D.; Dalhoff,
C.; Hackenberger, C. P. R.; Weinhold, E. Bioorg. Med.
Chem. Lett. 2003, 13, 3207; material sciences: (c) Kirsch, P.;
¨
Lenges, M.; Kuhne, D.; Wancek, K.-P. Eur. J. Org. Chem.
¨
2005, 797.
3. Selected examples: Cu salts: (a) Muller, J. F. K.; Vogt, P.
¨
Tetrahedron Lett. 1998, 39, 4805; (b) Lacoˆte, E.; Amatore,
M.; Fensterbank, L.; Malacria, M. Synlett 2002, 116; Fe
salts: (c) Bach, T.; Ko¨rber, C. Eur. J. Org. Chem. 1999, 64,
1033; Mn and Ru complexes: (d) Ohta, C.; Katsuki, T.
Tetrahedron Lett. 2001, 42, 3885; (e) Uchida, T.; Tamura,
Y.; Ohba, M.; Katsuki, T. Tetrahedron Lett. 2003, 44, 7965;
Rh complex: (f) Okamura, H.; Bolm, C. Org. Lett. 2004, 6,
1305; (g) Ag complex: Cho, G. Y.; Bolm, C., submitted for
publication.
O
N
Ns
O
N Ns
O
N Ns
S
S
S
CH3
Ph Ph
4. (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; For an improved protocol, see: (c) 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.: Whitehouse Station, NJ, 1996; p 451.
5. (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)
Reagents for Organic Synthesis; Fieser, M., Fieser, L. F.,
Eds.; John-Wiley & Sons: New York, 1975; Vol. 5, p 430.
6. For a recent report on a metal-free imination utilizing
QNHOAc (a 3-acetoxyaminoquinazolinone, which requires
the use of toxic Pb(OAc)4 for its preparation), see:
Karabuga, S.; Kazaz, C.; Kilic, H.; Ulukanli, S.; Celik, A.
Tetrahedron Lett. 2005, 46, 5225.
7. (a) Krasnova, L. B.; Hili, R. M.; Chernoloz, O. V.; Yudin,
A. K. Arkivoc 2005, iv, 26; For a related electrochemical
approach, see: (b) Siu, T.; Picard, C. J.; Yudin, A. K. J.
Org. Chem. 2005, 70, 932; (c) Siu, T.; Yudin, A. K. Org.
Lett. 2002, 4, 1839.
8. (a) Anderson, D. J.; Horwell, D. C.; Stanton, E.; Gilchrist,
T. L.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1972,
1317; (b) Colonna, S.; Stirling, C. J. M. J. Chem. Soc.,
Perkin Trans. 1 1974, 18, 2120.
Br
Br
3 (74%)
4 (71%)
5 (72%)
Ns
N
S
Ns
N
O
N H
CH3
S
S
Ph
CH3
Ph Me
6 (79%)
7 (82%)
8
As demonstrated previously,3g the deprotection of 2 by
treatment with Cs2CO3 and thiophenol in acetonitrile
at ambient temperature for 16 h proceeded smoothly
affording NH-free methyl phenyl sulfoximine (8) in
76% yield. Unfortunately, when enantiomerically
enriched (S)-methyl phenyl sulfoxide (1) with 83% ee
was applied in this two-step reaction sequence, NH-sulf-
oximine 8 with 43% ee was obtained. Since the nosyl
deprotection was shown to proceed without epimeriza-
tion, we attribute this partial racemization to the high
reaction temperature (over a period of 16 h), which
was required for the metal-free imination.
In conclusion, a metal-free imination of sulfoxides and
sulfides with mixtures of NsNH2 and PhI(OAc)2 was
developed. The discovery of this safe, non-toxic
method advances the chemistry of sulfoximines since
the resulting N-nosyl products can readily be depro-
tected under standard reaction conditions giving
synthetically most valuable NH-sulfoximines. Further
studies are directed towards the search for new imina-
ting agents avoiding the use of high-molecular weight
oxidants.
9. Representative procedure for the imination of sulfoxides:
To the solution of sulfoxide 1 (70 mg, 0.5 mmol) in
anhydrous acetonitrile (4 mL) was added NsNH2 (121 mg,
0.6 mmol) and PhI(OAc)2 (242 mg, 0.8 mmol) at rt under
argon, and the reaction mixture was then heated to reflux
for 16 h. Subsequently, the mixture was cooled to ambient
temperature and concentrated under reduced pressure.
Purification of the remaining product by column chroma-
tography gave N-nosyl sulfoximine 2 in 75% yield (128 mg).