Iron(ii) triflate as an efficient catalyst for the imination of sulfoxides

Article abstract of DOI:10.1021/ol900660x

The challenging imination of benzyl-, sterically demanding alkyl-, and heteroaryl-substituted sulfoxides has been studied. Iron(II) triflate was identified as a highly efficient and robust catalyst for sulfur imination reactions. A variety of sulfoxides a

Full text of DOI:10.1021/ol900660x

ORGANIC
LETTERS
2009
Vol. 11, No. 11
2429-2432
Iron(II) Triflate as an Efficient Catalyst
for the Imination of Sulfoxides
Olga Garc´ıa Manchen˜o,† Jonathan Dallimore,‡ Andrew Plant,‡ and
Carsten Bolm*,†
Institute of Organic Chemistry, RWTH Aachen UniVersity, Landoltweg 1,
D-52056 Aachen, Germany and Syngenta, Jealott’s Hill International Research Centre,
Bracknell, Berkshire RG42 6EY, United Kingdom
carsten.bolm@oc.rwth-aachen.de
Received March 31, 2009
ABSTRACT
The challenging imination of benzyl-, sterically demanding alkyl-, and heteroaryl-substituted sulfoxides has been studied. Iron(II) triflate was
identified as a highly efficient and robust catalyst for sulfur imination reactions. A variety of sulfoxides and sulfides were efficiently iminated
with sulfonyliminoiodinanes (PhIdNSO2R) at room temperature to give the corresponding sulfoximines and sulfilimines in good yields and
with short reaction times.
Sulfoximines can be bioactive,1 and they have been used as
building blocks for the preparation of chiral ligands2 and
pseudopeptides.3 A number of approaches for their synthesis
have been developed, the most straightforward being direct
nitrogen transfer onto the corresponding sulfoxide.4-6 Vari-
ous metal-based catalysts including copper,7 rhodium,8 and
silver9 complexes have been described for this reaction.10
The use of cheap and environmentally friendly iron salts
presents an attractive alternative.11 Bach and Ko¨rber reported
the first iron-catalyzed sulfur imination, which employed
(3) (a) Bolm, C.; Kahmann, J. D.; Moll, G. Tetrahedron Lett. 1997, 38,
1169. (b) Bolm, C.; Moll, G.; Kahmann, J. D. Chem.sEur. 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.
† RWTH Aachen University.
‡ Syngenta, Jealott’s Hill International Research Centre.
(1) For recent examples of the patent literature related to agrochemicals,
see: (a) Jeanguenat, A.; O’Sullivan, A. C. WO 032462 A1, 2006 (Syngenta).
(b) Jeanguenat, A.; O’Sullivan, A. C. WO 061200 A1, 2006 (Synge-
nta). (c) Plant, A.; Boehmer, J. E.; Peace, A. L. WO 037945 A1, 2006
(Syngenta). (d) Huang, J. X.; Rogers, R. B.; Orr, N.; Sparks, T. C.; Gifford,
J. M.; Loso, M. R.; Zhu, Y.; Meade, T. WO 2007149134 A1, 2007 (Dow
Agrosciences). (e) Loso, M. R.; Nugent, B. M.; Huang, J. X. WO
2008027073 A1, 2008 (Dow Agrosciences). (f) Loso, M. R.; Nugent, B. M.;
Zhu, Y.; Siddall, T. L.; Tisdell, F. E.; Huang, J. X.; Benko, Z. L. WO
2008027539 A1 (Dow Agrosciences). (g) Zhu, Y.; Loso, M. R.; Nugent,
B. M.; Huang, J. X.; Rogers, R. B. WO 2008057129 A1 (Dow Agro-
sciences).
(4) For classical methods, see the following. NaN3/H2SO4: (a) Fusco,
R.; Tenconi, F. Chim. Ind. (Milan) 1965, 47, 61. (b) Johnson, C. R.;
Schroeck, C. W. J. Am. Chem. Soc. 1973, 95, 7418. (c) Brandt, J.; Gais,
H.-J. Tetrahedron: Asymmetry 1997, 6, 909. O-Mesitylenesulfonyl hy-
droxylamine (MSH): (d) Tamura, Y.; Minamikawa, J.; Sumoto, K.; Fujii,
S.; Ikeda, M. J. Org. Chem. 1973, 38, 1239. (e) Johnson, C. R.; Kirchhoff,
R. A.; Corkins, H. G. J. Org. Chem. 1974, 39, 2458. (f) Tamura, Y.;
Matushima, H.; Minamikawa, J.; Ikeda, M.; Sumoto, K. Tetrahedron 1975,
31, 3035. (g) Fieser, M.; Fieser, L. F. Reagents for Organic Synthesis; John
Wiley & Sons: New York, 1975; Vol. 5, p 430. See also: (h) Allenmark,
S.; Claeson, S.; Lowendahl, C. Tetrahedron: Asymmetry 1996, 7, 361.
(5) For reviews on synthetic approaches to sulfoximines, see: (a)
Johnson, C. R. Acc. Chem. Res. 1973, 6, 341. (b) Methoden Org. Chem.
(Houben-Weyl); Klamann, D., Ed.; VCH Thieme: Stuttgart, 1985; Vol.
E11, Parts 1 and 2. (c) Pyne, S. Sulfur Rep. 1992, 12, 57. (d) Mikolajczk,
M.; Drabowicz, J.; Kielbasinski, P. In Chiral Sulfur Reagents; CRC Press:
Boca Raton, 1997. (e) Taylor, P. C. Sulfur Rep. 1999, 21, 241. (f) Reggelin,
M.; Zur, C. Synthesis 2000, 1. (g) Bentley, R. Chem. Soc. ReV. 2005, 34,
609.
(2) Reviews: (a) Harmata, M. Chemtracts 2003, 16, 660. (b) Okamura,
H.; Bolm, C. Chem. Lett. 2004, 33, 482. (c) Bolm, C. In Asymmetric
Synthesis with Chemical and Biological Methods; Enders, D., Jaeger, K.-
E., Eds.; Wiley-VCH: Weinheim, 2007; p 149. (d) Worch, C.; Mayer, A. C.;
Bolm, C. In Organosulfur Chemistry in Asymmetric Synthesis; Toru, T.,
Bolm, C., Eds.; Wiley-VCH: Weinheim, 2008; p 209. For recent examples,
see: (e) Lu, S.-M.; Bolm, C. AdV. Synth. Catal. 2008, 350, 1101. (f) Lu,
S.-M.; Bolm, C. Chem.sEur. J. 2008, 14, 7513. (g) Lu, S.-M.; Bolm, C.
Angew. Chem., Int. Ed. 2008, 47, 8920. (h) Frings, M.; Atodiresei, I.;
Runsink, J.; Raabe, G.; Bolm, C. Chem.sEur. J. 2009, 15, 1566.
(6) For an excellent review on metal-catalyzed nitrogen transfer reactions,
see: Mu¨ller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905.
10.1021/ol900660x CCC: $40.75
Published on Web 05/08/2009
 2009 American Chemical Society

FeCl2 as the catalyst.12 However, high catalyst loadings, the
need for large excesses of the sulfoxide, and the use of
potentially explosive BocN3 as a nitrogen source have limited
the applicability of this method.
acetonitrile was chosen as a model reaction (Table 1). A short
optimization study of the reaction conditions showed that
Subsequently, we discovered that Fe(acac)3 conveniently
catalyzes the imination of various sulfides and sulfoxides
using sulfonyl amides in combination with iodosylbenzene
(PhIdO).13 However, iminations of heteroaromatic substrates
or sulfoxides bearing bulky substituents remained unsatisfac-
tory.14 To overcome this limitation, the development of more
efficient iron catalysts was envisaged. In the course of this
search,15 we found that iron(II) triflate, which is easily
prepared from iron powder or iron(II) chloride and trifluo-
romethanesulfonic acid,16 catalyzed the imination of thio-
anisole and methyl phenyl sulfoxide (1a). Using only 2.5
mol % of Fe(OTf)2, both substrates (used in 2-fold excess)
reacted well with iminoiodinane (PhIdNNs) affording the
corresponding sulfilimine and sulfoximine in 91% and 98%
yield, respectively.17 Compared to the previously reported
Fe(acac)3-based system, which required 5-10 mol % of the
iron salt, this new catalyst appeared favorable.18 In order to
assess the real value of these findings, an in depth investiga-
tion into the Fe(OTf)2-catalyzed sulfur imination was initi-
ated, and the current status of this research is described here.
The imination of methyl phenyl sulfoxide (1a) with
PhIdNNs in the presence of 2.5 mol % of Fe(OTf)2 in
Table 1. Optimization of the Fe(OTf)2-Catalyzed Imination of
Methyl Phenyl Sulfoxide (1a)a
sulfoxide
(equiv)
time
(min)
yieldb
(%)
entry
PhIdX (equiv)
PhIdNNs (1.0)
PhIdNNs (1.1)
PhIdNNs (1.1)
PhIdNNs (1.3)
NsNH2 (1.2), PhIdO (1.3)
1
2
1
1
1
1
60
30
30
30
20
98
51
66
92
85
2c
3
4
5
a Reaction conditions: Sulfoxide 1a, 2.5 mol % of Fe(OTf)2, PhIdX,
and MS 4 Å in acetonitrile (0.1 M) at rt. b After column chromatography.
c Performed without MS 4 Å.
the sulfoxide-to-iminoiodinane ratio could be reduced (entries
2-4). However, the use of a slight excess of iminoiodinane
(1.3 equiv) was required to achieve complete conversion of
the sulfoxide 1a and high yields of sulfoximine 2a (entry
4). The use of molecular sieves (4 Å) also proved to be
beneficial to the reaction yields (entries 2 and 3). The
reactions were efficient, allowing for short reaction times
(30 min). Moreover, the combination of p-nosylamide
(NsNH2) and iodosylbenzene (PhIdO) to generate the
corresponding iminoiodinane in situ was also effective,
providing sulfoximine 2a in 85% yield after 20 min (entry
5).
(7) (a) Kwart, H.; Kahn, A. A. J. Am. Chem. Soc. 1967, 89, 1950. (b)
Mu¨ller, J. F. K.; Vogt, P. Tetrahedron Lett. 1998, 39, 4805. (c) Bolm, C.;
Mun˜iz, K.; Aguilar, N.; Kesselgruber, M.; Raabe, R. Synthesis 1999, 1251.
(d) Takada, H.; Ohe, K.; Uemura, S. Angew. Chem., Int. Ed. 1999, 38,
1288. (e) Nakayama, J.; Otani, T.; Sugihara, Y.; Sano, Y.; Ishii, A.;
Sakamoto, A. Heteroatom Chem. 2001, 12, 333. (f) Cren, S.; Kinahan, T. C.;
Skinner, C. L.; Tye, H. Tetrahedron Lett. 2002, 43, 2749. (g) Lacoˆte, E.;
Amatore, M.; Fensterbank, L.; Malacria, M. Synlett 2002, 116.
(8) Okamura, H.; Bolm, C. Org. Lett. 2004, 6, 1305.
The use of alternative nitrogen sources to PhIdNNs was
explored under the optimized conditions (Table 1, entries 4
and 5). Whereas simple amides such as BnCONH2 or
CF3CONH2 with PhIdO were unreactive, a variety of
iminoiodinanes (PhIdNPy and PhIdNTs) or sulfonamides
(ThiophSO2NH2, BusNH2, and SESNH2) in combination with
PhIdO could be efficiently employed. Thus, the correspond-
ing N-substituted 5-methyl-2-pyridinyl- (Py), p-tolyl- (Ts),
tert-butyl- (Bus), 2-thiophenyl- (Thioph), and 2-trimethyl-
silylethylsulfonyl (SES) sulfoximines 2b-f (Figure 1) were
obtained in moderate to good yields (65-95%), offering a
(9) Cho, G. Y.; Bolm, C. Org. Lett. 2005, 7, 4983.
(10) For alternative metal-free sulfur iminations, see: (a) Cho, G. Y.;
Bolm, C. Tetrahedron Lett. 2005, 46, 8007. (b) Siu, T.; Picard, C. J.; Yudin,
A. K. J. Org. Chem. 2005, 70, 932. (c) Karabuga, S.; Kazaz, C.; Kilic, H.;
Ulukanli, S.; Celik, A. Tetrahedron Lett. 2005, 46, 5225. (d) Krasnova,
L. B.; Hili, R. M.; Chernoloz, O. V.; Yudin, A. K. ArkiVoc 2005, iV, 268.
(e) Garc´ıa Manchen˜o, O.; Bistri, O.; Bolm, C. Org. Lett. 2007, 9, 3809.
(11) For reviews on iron catalysis, see: (a) Bolm, C.; Legros, J.; Le
Paih, J.; Zani, L. Chem. ReV. 2004, 104, 6217. (b) Fu¨rstner, A.; Martin, R.
Chem. Lett. 2005, 624. (c) Diaz, D. D.; Miranda, P. O.; Padro´n, J. I.; Martin,
V. S. Curr. Org. Chem. 2006, 10, 457. (d) Enthaler, S.; Junge, K.; Beller,
M. Angew. Chem., Int. Ed. 2008, 47, 3317. (e) Sherry, B. D.; Fu¨rstner, A.
Acc. Chem. Res. 2008, 41, 1500. (f) Enthaler, S.; Junge, K.; Beller, M.
Angew. Chem., Int. Ed. 2008, 47, 3317. (g) Bauer, E. B. Curr. Org. Chem.
2008, 12, 1341. (h) Gaillard, S.; Renaud, J.-L. ChemSusChem 2008, 1, 505.
(i) Correa, A.; Garc´ıa Manchen˜o, O.; Bolm, C. Chem. Soc. ReV. 2008, 37,
1108. (j) Fu¨rstner, A. Angew. Chem., Int. Ed. 2009, 48, 1364.
(12) (a) Bach, T.; Ko¨rber, C. Tetrahedron Lett. 1998, 39, 5015. (b) Bach,
T.; Ko¨rber, C. Eur. J. Org. Chem. 1999, 64, 1033.
(13) Garc´ıa Manchen˜o, O.; Bolm, C. Org. Lett. 2006, 8, 2349.
(14) Garc´ıa Manchen˜o, O.; Bolm, C. Chem.sEur. J. 2007, 13, 6674.
(15) Iron(II)/(III) perchlorates and iron(III) diketonates such as 1-acetyl-
2-oxo-1-cyclopentanide and 2-methyl acetylacetonate catalyzed sulfoxide
iminations, but they were less efficient than Fe(acac)3.
(16) (a) Haynes, J. S.; Sams, J. R.; Thomson, R. C. Can. J. Chem. 1981,
59, 669. (b) Hagen, K. S. Inorg. Chem. 2000, 39, 5867.
(17) For preliminary results, see: Nakanishi, M., Dissertation, RWTH
Aachen University, 2007.
(18) For the application of Fe(OTf)2-based catalytic systems in nitrene
transfer reactions onto enol silyl ethers and olefins, see: (a) Nakanishi, M.;
Salit, A.-F.; Bolm, C. AdV. Synth. Catal. 2008, 350, 1835. (b) Mayer, A.;
Salit, A.-F.; Bolm, C. Chem. Commun. 2008, 5975. For the use of related
iron triflate catalysts, see: (c) Klotz, K. L.; Slominski, L. M.; Hull, A. V.;
Gottsacker, V. M.; Mas-Balleste´, R.; Que, L; Halfen, J. A. Chem. Commun.
2007, 2063.
Figure 1. Various products obtained in iminations of 1a.
2430
Org. Lett., Vol. 11, No. 11, 2009

Table 2. Fe(OTf)2-Catalyzed Sulfoxide Imination Scopea
a Reaction conditions: sulfoxide (1 equiv), Fe(OTf)2, PhIdNNs (1.3 equiv), and MS 4 Å in acetonitrile (0.1 M) at rt. b After column chromatography.
c Yield obtained by using 10 mol % of Fe(acac)3 as catalyst. d See ref 13. e See ref 14.
variety of possibilities for the deprotection of the sulfoximine
nitrogen.19 The enhanced reactivity of this catalyst compared
to previously reported iron systems12-14 was demonstrated
by the sulfoxide imination of 1a with the bulky BusNH2,
which could be performed with only 5 mol % of Fe(OTf)2
to afford the sulfoximine in 65% yield. Additionally, the use
of perfluorinated alkylic sulfonamide CF3(CF2)3SO2NH2 as
a nitrogen source was also possible, albeit in poor yield (20%
for 2g).
The unexpectedly high catalytic activity of the Fe(OTf)2-
based system prompted further investigation into its ap-
plicability to the imination of more challenging substrates
(19) For example, nosylamides can be easily cleaved using thiolates,
SES-amides react upon treatment with fluorides to give amines, tert-butyl
sulfonylamides are deprotected under acidic conditions, and deprotection
of the pyridinyl and thiophenyl derivatives could be achieved by reaction
with Mg. For general methods for the deprotection of sulfonylamides, see:
(a) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthesis,
3rd ed.; John Wiley & Sons: New York, 1999; p 603.
Org. Lett., Vol. 11, No. 11, 2009
2431

such as sulfoxides bearing benzylic, bulky alkyl or heteroaryl
substituents (Table 2). Initially, the imination of benzyl
sulfoxides 1h and 1i with PhIdNNs was explored (entries 1
and 2). Whereas the use of 10 mol % of Fe(acac)3 had led
to only moderate yields (46 and 44%, respectively), 5 mol
% of Fe(OTf)2 was sufficiently active to drive both reactions
to completion. Interestingly, and in contrast to the previously
observed limitations of iron-catalyzed sulfur iminations, the
presence of a coordinating substituent such as an alkoxy
group (as present in 1i) did not inhibit the reaction, and both
sulfoximines 2h and 2i were obtained in excellent yield
(96%). The use of 5 mol % of Fe(OTf)2 was also effective
in the imination of dialkyl sulfoxides with bulky isopropyl,
tert-butyl, or sec-butyl substituents leading to good yields
of the corresponding sulfoximines 2j-l (55-86%, entries
3-5).
Figure 2. Heteroaryl-substituted sulfilimines 3a and 3b prepared
under iron catalysis and optically active sulfoximine (R)-4 obtained
from sulfoxide (R)-1r.
provided the corresponding sulfilimines 3a and 3b in good
yields (63 and 66%, respectively).
Iminations of sulfoxides with heteroaryl substituents were
subsequently studied (entries 6-11). Benzothiazolyl- and
pyridinyl-substituted sulfoxides (1m and 1n) were success-
fully iminated with only 5 mol % of Fe(OTf)2, while the
Lastly, the stereospecificity of the imination reaction was
investigated by using optically pure (R)-methyl p-tolylsul-
foxide (1r). Iron-catalyzed imination and subsequent standard
nitrogen deprotection of the resulting N-nosylsulfoximine
afforded enantiopure NH-sulfoximine (R)-4 in good yield
(77% over two steps).20 Both the ee analysis of 4 by chiral
HPLC (>99% ee) and the optical rotation revealed that the
imination reaction had occurred without epimerization and
retention of configuration at the stereogenic sulfur.
14
equivalent reactions with Fe(acac)3 required 10 mol % to
achieve comparable yields (83 and 80% vs 86 and 92%,
respectively; entries 6 and 7).
Pleasingly, the more challenging imination of oxadiazolyl
sulfoxide 1o was clearly improved by use of Fe(OTf)2. When
5 mol % of this iron salt was employed, a 45% yield of
sulfoximine 2o was obtained (entry 8), signifying a 2-fold
improvement in yield compared to Fe(acac)3 (10 mol %).14
Increasing the catalytic loading to 15 mol % to circumvent
potential deactivation of the iron catalyst by coordination to
the heteroatom-containing substrate or product, afforded a
62% yield of 2o (entry 9).
In summary, we have demonstrated the use of Fe(OTf)2
in the preparation of challenging sulfoximines and sulfil-
imines with benzylic, bulky alkyl, or heteroaryl substituents.
Acknowledgment. We thank the Fonds der Chemischen
Industrie for financial support and Syngenta for a postdoctoral
fellowship for O.G.M. Dr. Nakanishi (RWTH Aachen
University) is acknowledged for the preparation of various
reagents.
Even in iminations of challenging substrates bearing
imidazolyl and tetrazolyl substituents (entries 10-11) re-
markable yields of the corresponding heteroaromatic sul-
foximines were achieved (up to 57%).
Supporting Information Available: Experimental pro-
cedures, full characterization of new products, and copies
of NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
Finally, the reactions of a representative array of hetero-
cyclic sulfides, such as imidazolyl and tetrazolyl substituted
substrates, were examined (Figure 2). Under the same
reaction conditions as described for the iminations of
heteroaromatic sulfoxides (15 mol % of Fe(OTf)2 and
PhIdNNs as nitrene source), the more nucleophilic sulfides
OL900660X
(20) For experimental details, see the Supporting Information.
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Org. Lett., Vol. 11, No. 11, 2009