Iron-catalyzed imination of sulfoxides and sulfides

Article abstract of DOI:10.1021/ol060640s

The Fe(III)-catalyzed imination of sulfoxides and sulfides with sulfonylamides in the presence of iodinanes has been investigated. The best results were obtained when Fe(acac)₃ was used as a catalyst in combination with iodosylbenzene, providin

Full text of DOI:10.1021/ol060640s

ORGANIC
LETTERS
2006
Vol. 8, No. 11
2349-2352
Iron-Catalyzed Imination of Sulfoxides
and Sulfides
Olga Garc´ıa Manchen˜o and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen UniVersity, Landoltweg 1,
D-52056 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received March 15, 2006
ABSTRACT
The Fe(III)-catalyzed imination of sulfoxides and sulfides with sulfonylamides in the presence of iodinanes has been investigated. The best
results were obtained when Fe(acac)3 was used as a catalyst in combination with iodosylbenzene, providing an effective alternative (stereospecific)
access to sulfoximines and sulfilimines.
Since the discovery of sulfoximines in the early 1950s by
Whitehead and Bentley,1 sulfoximines and sulfilimines have
attracted great attention among organic chemists. Due to the
presence of an amphoteric nitrogen and a stereogenic sulfur
atom, they have been widely used as building blocks for
chiral ligands2 and as structural units in pseudopeptides.3
Several strategies for their preparation have been developed.4
However most of them require the use of toxic and
potentially explosive reagents such as hydrazoic acid (NaN3/
H2SO4)5 or O-mesitylenesulfonylhydroxylamine (MSH).6
Recently, to avoid such reagents, interest has grown in metal-
catalyzed nitrene transfer reactions to sulfur compounds. In
this context, copper salts7 and manganese or ruthenium
complexes8 have been described as catalysts for this trans-
formation. However, those methods generally lead to N-
substituted products with protecting groups such as tosyl,
(1) Bentley, H. R.; McDermott, E. E.; Pace, J.; Whitehead, J. K.; Moran,
T. Nature 1950, 165, 150. (b) Whitehead, J. R.; Bentley, H. R. J. Chem.
Soc. 1952, 1572.
(4) Reviews concerning 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. (e) Bentley R. Chem. Soc. ReV. 2005, 34, 609.
(5) NaN3/H2SO4: (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. Tetrahe-
dron: Asymmetry 1997, 6, 909. For the toxicity of NaN3, see: (d) Merck
Index, 12th ed.; Budavari, S., Ed.; Merck & Co., Inc.: Rahway, NJ, 1996;
p 451.
(6) 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. See also: (e) Allenmark, S.; Claeson,
S.; Lowendahl, C. Tetrahedron: Asymmetry 1996, 7, 361.
(2) For 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. (g) Langner,
M.; Bolm, C. Angew. Chem., Int. Ed. 2004, 43, 5984. (h) Mo¨ssner, C.;
Bolm C. Angew. Chem., Int. Ed. 2005, 44, 7564. (i) Langner, M.; Re´my,
P.; Bolm, C. Synlett 2005, 781. (j) Langner, M.; Re´my, P.; Bolm, C. Chem.
Eur. J. 2005, 11, 6254. (k) Reetz, M. T.; Bondarev, O. G.; Gais, H.-J.;
Bolm, C. Tetrahedron Lett. 2005, 46, 5643. Reviews: (l) Harmata, M.
Chemtracts 2003, 16, 660. (m) Okamura, H.; Bolm, C. Chem. Lett. 2004,
33, 482.
(3) (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) (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.
10.1021/ol060640s CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/04/2006

which are difficult to cleave to give the synthetically more
valuable NH-sulfoximines.9 Iron-catalyzed iminations of
sulfides and sulfoxides affording products with more easily
removable Boc and SES protecting groups appear attrac-
tive,10,11 but since they involve the use of potentially
explosive azides as nitrogen sources, their applicability in
large-scale synthesis is rather limited.
Table 1. Optimization of the Iron-Catalyzed Imination with
Ns-NH2
a
In 2004, we described that Rh2(OAc)4 is an effective
catalyst for the imination of sulfur compounds at room
temperature with readily available trifluoroacetamide or
p-nosylamide as safe nitrene precursors.12 The synthetically
interesting NH-products can then be obtained by subsequent
easy-to-perform cleavage reactions. A limiting feature of this
protocol is the high cost of the rhodium catalyst. Further
investigations have led to the discovery that less costly silver
nitrate (in combination with a terpyridine ligand) is also an
efficient catalyst for sulfur imination reactions.13,14 Extending
our interest in improving and simplifying such transforma-
tions, and in connection with our ongoing program showing
the wide potential of sulfoximines as ligands and building
blocks in organic synthesis, we herein describe the applica-
tion of simple iron catalysts for the imination of sulfoxides
and sulfides with sulfonylamides under mild conditions.
As a model reaction the imination of methyl phenyl
sulfoxide (1a) with a combination of N-nosylamide (NsNH2)
and iodobenzene diacetate [PhI(OAc)2] in the presence of
an iron salt was investigated. In the first attempt, 10 mol %
of FeCl2 in acetonitrile was applied. In contrast to the system
studied by Bach, which involved BocN3 as nitrogen
source,10a-c a low reactivity was observed here both at room
temperature and at reflux (Table 1, entry 1).
a Reaction conditions: sulfoxide 1a (1 equiv), Fe catalyst (10 mol %),
NsNH2 (1.5 equiv), and ArI(X)2 (1.6 equiv) in CH3CN (0.1 M) at room
temperature. b Yield after columm chromatography. c Reaction time and
yield in refluxing CH3CN specified in parentheses. d See comment in ref
16. e Use of 1.6 equiv of PhIdNNs.
doiodinane (PhIdNNs) as the nitrene source proceeded
faster. Thus, sulfoximine 2 was obtained in 88% yield after
only 1 h (entry 5). Acetonitrile proved to be superior to other
solvents such as THF or dichloromethane, which did not give
2 at all or only in low yield (20%), respectively.
At this stage, other iodinanes were evaluated as oxidants
for this process (entries 6-8). As shown in Table 1, both
the aromatic and hetereoatomic substituents at iodine had a
strong effect on the reactivity. The best results were obtained
with iodosylbenzene (PhIdO), which provided 2 in 97%
yield after 30 min (entry 8).17
Other iron salts proved more reactive (Table 1, entries
2-4), and to our delight, iron(II) or iron(III) acetylacetonate
exhibited excellent reactivity, giving sulfoximine 2 in 83 or
90% yield after only 7 or 3 h, respectively (entries 3 and
4).15,16 As expected, reaction with preformed N-nosylimi-
The reduction of the catalyst loading from 10 to 5 mol %
had no significant effect on the catalyst efficiency, and
sulfoximine 2 was formed in similar yield (Table 2, entries
1 and 2). With 5 mol % of the catalyst a 3.5-fold increase
of the reaction scale was well tolerated and the catalyst
activity remained high (entry 3). Further reduction of the
catalyst loading to 1 mol % led to an incomplete conversion
of 1a even after an extended reaction time and consequently,
only a modest yield of 2 was obtained (54%, entry 4).
Under the optimized conditions, which involved the use
of 5 mol % of Fe(acac)3 and PhIdO in acetonitrile at room
temperature, a variety of sulfonylamides were tested as
iminating agents for sulfoxide 1a (Table 3, entries 2-6).
Gratifyingly, albeit over longer reaction times compared
to the parent p-nosylamide (NsNH2), the iron-catalyzed
iminations of 1a with p-tosylamide (TsNH2), 2-trimethylsi-
lylethylsulfonylamide (SESNH2), p-methyl-2-pyridinylsul-
fonylamide, and 2-benzothiazolesulfonylamide proceeded
well at room temperature, affording the corresponding
sulfoximines 3-6 in moderate to good yields (66-88%).
(8) 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.
See also in: (g) Katsuki, T. Chem. Lett. 2005, 34, 1304..
(9) For alternatve metal-free sulfoxide iminations, see: (a) Siu, T.; Picard,
C. J.; Yudin, A. K. J. Org. Chem. 2005, 70, 932. (b) Krasnova, L. B.; Hili,
R. M.; Chernoloz, O. V.; Yudin, A. K. ArkiVoc 2005, iV, 26. (c) Karabuga,
S.; Kazaz, C.; Kilic, H.; Ulukanli, S.; Celik, A. Tetrahedron Lett. 2005,
46, 5225.
(10) BocN3: (a) Bach, T.; Ko¨rber, C. Tetrahedron Lett. 1998, 39, 5015.
(b) Bach, T.; Ko¨rber, C. Eur. J. Org. Chem. 1999, 64, 1033. (c) Bolm, C.;
Mun˜iz, K.; Aguilar, N.; Kesselgruber, M.; Raabe, R. Synthesis 1999, 1251.
SESN3: (d) Reggelin, M.; Weinberger, H.; Spohr, V. AdV. Synth. Catal.
2004, 346, 1295.
(11) For a general review on iron-catalyzed reactions, see: Bolm, C.;
Legros, J.; Le Paih, J.; Zani, L. Chem. ReV. 2004, 104, 6217.
(12) Okamura, H.; Bolm, C. Org. Lett. 2004, 6, 1305.
(13) Cho, G. Y.; Bolm, C. Org. Lett. 2005, 7, 4983.
(14) For a recent contribution on metal-free iminations allowing access
to NH derivatives, see: Cho, G. Y.; Bolm, C. Tetrahedron Lett. 2005, 46,
8007.
(15) The use of 1.1 equiv instead of 1.5 equiv of NsNH2 hampered the
conversion, providing sulfoximine 2 in a moderate yield (57%).
(16) Contaminating traces of Fe(III) salts could not be excluded from
the Fe(acac)2 here used. Attempts to determine the precise nature of the Fe
species remained inconclusive.
(17) Iron(III) benzoylacetonate, [Fe(bzac)3], is also a good catalyst under
these reaction conditions, furnishing 2 in 97% yield after 45 min.
2350
Org. Lett., Vol. 8, No. 11, 2006

reaction times. Even sulfoxides with a bulky tert-butyl group
or a vinyl substituent (entries 8 and 10) reacted well affording
sulfoximines in good yields. Only the imination of a substrate
with a sterically demanding (2,4,6-trisubstituted) aromatic
group remained unsuccessful (entry 7).
Table 2. Optimization of the Catalyst Loadinga
Next, the stereospecificity of both the iron-catalyzed
imination process (with a combination of PhIdO and NsNH2
as NNs source) and the subsequent conversion of the
resulting product into the corresponding NH-sulfoximine
were studied.19 For this purpose, sulfoxide (S)-1a with 83%
ee20 was reacted under standard imination conditions to give
N-nosylsulfoximine 2, which was deprotected at room
temperature by nucleophilic aromatic substitution with
thiophenolate, generated in situ from Cs2CO3 and thiophenol
(Scheme 1).18,19 “Free” NH-sulfoximine (S)-11 was thus
entry
Fe(acac)3 (mol %)
t (h)
yieldb (%)
1
2
3
4
10
5
5
0.5
1
1.5c
20
97
96
95
54
1
a Reaction conditions: sulfoxide 1a (0.285 mmol, 1 equiv), NsNH2 (1.5
equiv), and PhIdO (1.6 equiv) in CH3CN (0.1 M) at room temperature.
b Yield after columm chromatography. c Reaction scaled up to 1 mmol of
1a.
Scheme 1
Table 3. Iron-Catalyzed Imination of Sulfoxidesa
obtained in good yield (79% over two steps), and the ee
analysis of 1121 revealed that the reaction sequence had
proceeded without epimerization and with retention of
configuration at the stereogenic sulfur.
With the goal to determine the generality of the iron-
catalyzed sulfur imination, the reactions of several sulfides
with combinations of PhIdO and NsNH2 were examined
next. Under the same reaction conditions as those employed
for the sulfoxide imination, the more nucleophilic sulfides
showed high reactivities providing the corresponding sulfil-
imines 12-16 in excellent yields after reaction times of 40
min to 8 h (Figure 1).
Additionally, a competition experiment using a 1:1 mixture
of methyl phenyl sulfoxide (1a) and methyl phenyl sulfide
was carried out. After 50 min, a quantitative conversion of
the sulfide into sulfilimine 12 was observed, and only 15%
of nitrene transfer to sulfoxide 1a had occurred.22 The greater
reactivity of the sulfides also allowed the imination to
proceed with substrates bearing bulky aromatic substituents
(such as a 2,4,6-trimethylphenyl group) at sulfur, whereas
the corresponding sulfoxides had failed to react in the same
a Reaction conditions: sulfoxide 1 (1 equiv), Fe(acac)3 (5 mol %), NsNH2
(1.5 equiv), and PhIdO (1.6 equiv) in CH3CN (0.1 M) at room temperature.
b Yield after column chromatography.
Only the very bulky tert-butylsulfonyl amide (BusNH2) could
not iminate sulfoxide 1a (Table 3, entry 6). These results
are of particular significance, since they offer various
possibilities for the deprotection of the sulfoximine nitro-
gen.18
To evaluate the scope of the imination reaction various
sulfoxides were applied as substrates (Table 3, entries 7-11).
In general, their conversion was smooth and the correspond-
ing sulfoximines were formed (with g72% yield) after short
(19) For the pioneering work on the use of the nosyl group, see:
Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373.
(20) Sulfoxide (S)-1a was prepared by iron-catalyzed asymmetric oxida-
tion of the corresponding sulfide with H2O2 as oxidant as previously
described by our group. (a) Legros, J.; Bolm, C. Angew. Chem., Int. Ed.
2003, 42, 5487. (b) Legros, J.; Bolm, C. Angew. Chem., Int. Ed. 2004, 43,
4225. (c) Legros, J.; Bolm, C. Chem. Eur. J. 2005, 11, 1086. The ee of 1a
was determined by HPLC using a chiral column: Chiralcel OD; heptane/
i-PrOH ) 90:10; 0.5 mL/min; 254 nm; tR(R): 23.4 min, tR(S): 29.7 min.
(21) The enantiomeric excess of 11 was determined by HPLC using a
chiral column: Chiralcel OJ; heptane/i-PrOH ) 85:15; 0.5 mL/min; 254
nm; tR(R): 36.9 min, tR(S): 48.9 min.
(18) For example, nosyl- and benzothiazolesulfonylamides can be easily
cleaved using thiolates, SES-amide react upon treatment with fluorides to
give amines, and deprotection of the pyridinyl derivative could be achieved
by reaction with Mg. For general methods for the deprotection of
sulfonylamides, see: Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in
Organic Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999; p 603.
(22) Conversion ratios were determined by 1H NMR on the crude
mixture.
Org. Lett., Vol. 8, No. 11, 2006
2351

attacked by the sulfur nucleophile to yield the corresponding
sulfoximine (or sulfilimine) and to regenerate the original
iron catalyst.
Noteworthy is the fact that even in the absence of sulfonyl
amides neither sulfones nor sulfoxides (obtained from
sulfoxides and sulfides, respectively) have been observed.
This indicates that if (oxo)Fe complexes are formed by direct
oxidation of the catalytically active iron salt with PhIdO,
those species are less reactive oxidants than the iron-nitrene
intermediates. Nevertheless, their presence might reduce the
efficiency of the catalyst system as observed in an imination
of 1a performed under aerobic conditions, which led to a
low conversion of the sulfoxide and the formation of 2 in
only 43% yield.
Figure 1. Protected sulfilimines obtained by Fe-catalyzed imina-
tion.
In summary, the imination of a variety of sulfoxides and
sulfides has been achieved under mild reaction conditions
at room temperature using inexpensive Fe(acac)3 as a
catalyst26 and sulfonylamides in combination with iodosyl-
benzene as nonhazardous nitrogen sources. The reaction
proceeds in a stereospecific manner with retention of
configuration at sulfur, constituting an alternative access to
enantiopure sulfoximines from the corresponding sulfoxides.
The deprotection of the N-nosyl products under standard
reaction conditions gives, without epimerization, synthetically
valuable (“free”) NH-sulfoximines. Finally, an iron-nitrene
complex is proposed as a reactive intermediate in this
process, more readily iminating sulfides than sulfoxides.
process. Likewise, methyl phenyl sulfide could be iminated
with the sterically demanding BusNH2 to give sulfilimine
17, whereas the use of this sulfonamide was unsuccessful in
the imination of sulfoxide 1a.23
Although iron imido complexes are rare,24 we assume that
the iron-catalyzed imination of the sulfur compounds in-
volves iron-nitrene species as intermediates. As shown in
Scheme 2, the reaction of the iron catalyst with PhIdNNs,
Scheme 2
Acknowledgment. The Deutsche Forschungsgemein-
schaft within the SFB 380 and the Fonds der Chemischen
Industrie are gratefully acknowledged for financial support.
O.G.M. thanks the Spanish Ministerio de Educacio´n y
Ciencia (M.E.C.) for a postdoctoral fellowship. We also
appreciate the donation and preparation of various reagents
by Prof. Dr. Sedelmeier (Novartis), Dr. Harfoot, and Dr. Cho
(both RWTH Aachen University). Furthermore, we thank
Prof. Dr. Ko¨lle (RWTH Aachen University) for helpful
discussions and collaborative studies toward the determina-
tion of the precise nature of iron species.
generated in situ from PhIdO and NsNH2, leads to an iron
nitrene complex with the concomitant formation of iodo-
benzene.25 The newly generated iron intermediate is then
Supporting Information Available: Experimental pro-
cedures, full characterization of new compounds, and 1H and
13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(23) Attempts to prepare NH-sulfilimines from the corresponding N-nosyl
derivatives remained unsuccessful. For example, at room temperature 14
did not react with thiophenolate, generated in situ from Cs2CO3 and
thiophenol, and at elevated temperature decomposition occurred.
(24) (a) Verma, A. K.; Nazif, T. N.; Achim, C.; Lee, S. C. J. Am. Chem.
Soc. 2000, 122, 11013. (b) Brown, S. D.; Betley, T. A.; Peters, J. C. J. Am.
Chem. Soc. 2003, 125, 323. (c) Jensen, M. P.; Mehn, M. P.; Que, L., Jr.
Angew. Chem., Int. Ed. 2003, 42, 4357. (d) Vyas, R.; Gao, G.-Y.; Harden,
J. D.; Zhang, X. P. Org. Lett. 2004, 6, 1907 and references therein.
OL060640S
(25) In Scheme 2, we suggest the involvement of Fe(III) and Fe(V)
species. However, it is possible that the iron intermediates have other
oxidation states.
(26) It is noteworthy that Rh2(OAc)4 is about 100 times more expensive
than AgNO3 and that Fe(acac)3 costs ca. 600 times less than Rh2(OAc)4
(Aldrich prices per gram in 2005/2006).
2352
Org. Lett., Vol. 8, No. 11, 2006