Electrochemical Imination of Sulfoxides Using N-Aminophthalimide

Article abstract of DOI:10.1021/ol0257530

(Equation Presented) A novel electrochemical sulfoxide imination process is described. Our approach starts with a highly selective nitrene transfer from N-aminophthalimide to a variety of sulfoxides. This oxidative treatment is followed by reductive N-N bond cleavage under the controlled current conditions, which leads to a range of parent NH sulfoximines. In addition to solving the challenging problem of removing the N-phthalimido group, the overall process avoids the use of toxic oxidants and metal additives.

Full text of DOI:10.1021/ol0257530

ORGANIC
LETTERS
2002
Vol. 4, No. 11
1839-1842
Electrochemical Imination of Sulfoxides
Using N-Aminophthalimide
Tung Siu and Andrei K. Yudin*
Department of Chemistry, UniVersity of Toronto, 80 St. George Street,
Toronto, Ontario M5S 3H6, Canada
ayudin@chem.utoronto.ca
Received February 20, 2002 (Revised Manuscript Received April 22, 2002)
ABSTRACT
A novel electrochemical sulfoxide imination process is described. Our approach starts with a highly selective nitrene transfer from
N-aminophthalimide to a variety of sulfoxides. This oxidative treatment is followed by reductive N−N bond cleavage under the controlled
current conditions, which leads to a range of parent NH sulfoximines. In addition to solving the challenging problem of removing the N-phthalimido
group, the overall process avoids the use of toxic oxidants and metal additives.
The general interest in the chemistry of sulfoximines dates
back to the work of Whitehead and Bentley1 in the 1950s,
when they found that the sulfoximine of methionine is the
compound produced when wheat flour is treated with
nitrogen trichloride. Methionine sulfoximine is still the most
studied biologically active sulfoximine and has been identi-
fied as a selective inhibitor of γ-glutamylcysteine synthase
which catalyses the rate-limiting step in glutathione biosyn-
thesis.2 Buthionine sulfoximine was shown to restore the
sensitivity of cancer tumors resistant to melphalan.3 Other
sulfoximines have been studied as antibiotics, antithrombot-
ics, and tumor metastasis inhibitors.4
The versatile chemistry of sulfoximines is made possible by
the presence of amphoteric nitrogen, acidic R-protons, and
a stereogenic sulfur atom (Figure 1). The ability of sulfox-
Figure 1. The sulfoximine functional group.
Sulfoximines have also attracted the attention of synthetic
chemists, largely due to the pioneering work by Johnson.5,6
imines to stabilize adjacent carbanions (thus allowing C-C
bond formation with carbon electrophiles) as well as to serve
as leaving groups in reactions with nucleophiles led Trost
to refer to them as “chemical chameleons” for asymmetric
synthesis.7
A number of routes to sulfoximines have been de-
veloped.5,6d,e A variety of oxidants can be used for the
oxidative imination of sulfoxides, e.g., hydrazoic acid (HN3,
generated in situ by reaction of NaN3 with concentrated H2-
(1) (a) Bentley, H. R.; McDermott, E. E.; Pace, J.; Whitehead, J. K.;
Moran, T. Nature 1950, 165. (b) Whitehead, J. R.; Bentley, H. R. J. Chem.
Soc. 1952, 1572.
(2) (a) Griffith, O. W.; Meister, A. J. Biol. Chem. 1979, 254, 7558. (b)
Bailey, H. H. Chem.-Biol. Interact. 1998, 8, 23.
(3) O’Dwyer, P. J.; Hamilton, T. C.; LaCreta, F. P.; Gallo, J. M.;
Kilpatrick, D.; Halbherr, T.; Brennan, J.; Bookman, M. A.; Hoffman, J.;
Young, R. C.; Comis, R. L.; Ozols, R. F. J. Clin. Oncol. 1996, 14, 249.
(4) Mueller, E. Sulfoximines; German Patent 3,129,444, 1984.
(5) Johnson, C. R. Acc. Chem. Res. 1973, 6, 341.
(6) For reviews on sulfoximine chemistry, see: (a) Kennewell, P. D.;
Taylor, J. B. Chem. Soc. ReV. 1975, 4, 189. (b) Kennewell, P. D.; Taylor,
J. B. Chem. Soc. ReV. 1980, 9, 477. (c) Johnson, C. R. Aldrichimica Acta
1985, 18, 3. (d) Pyne, S. G. Sulfur Rep. 1992, 12, 57. (e) Reggelin, M.;
Zur, C. Synthesis 2000, 1.
(7) Trost, B. M.; Matsuoka, R. T. Synlett 1992, 27.
10.1021/ol0257530 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/07/2002

SO4),8 N-amino-substituted compounds with Pb(OAc)4,9
TsN3,10 N-tosylimino phenyl iodinane and catalytic CuOTf 11a
or Cu(OTf)2,11b BocN3 with FeCl2,12 o-mesitylene sulfonyl
hydroxylamine (MSH),13 and tert-butyl hypochlorite with
aromatic amines.14 All of these processes involve toxic
oxidants and/or metal additives. Here we demonstrate an
alternative method for making sulfoximines using electro-
chemistry that avoids metal-based reagents, catalysts, and
stoichiometric oxidants.
underscores the facility with which the N-N bond can be
cleaved using electrochemistry.
In our previous study18 we found that oxidation of olefins
on platinum anode is kinetically disfavored over the oxidation
of N-aminophthalimide. This phenomenon of overpotential
appears to be the key factor for the successful nitrene transfer
to olefins. At the outset of the present study, we compared
the redox behavior of N-aminophthalimide and sulfoxides
using cyclic voltammetry (CV). The CV of N-aminophthal-
imide (0.01 M in acetonitrile) on a platinum electrode shows
two irreversible one-electron oxidation processes with anodic
peak potentials at +1.35 V and +1.68 V (vs Ag/AgCl).18
At the second peak potential of +1.68 V, tetramethylene
sulfoxide (0.01 M in acetonitrile) produces an anodic current
of -7.52 µA, which is considerably smaller than the current
recorded for N-aminophthalimide (-152 µA). This indicates
that the background oxidation of sulfoxides on a platinum
electrode is kinetically sluggish, paving the way to direct
electrochemical nitrogen transfer to sulfoxides. It should be
emphasized that the nature of the electrode material is crucial
to the success of the reaction. The CV of tetramethylene
sulfoxide (0.01 M in acetonitrile) on a glassy carbon electrode
shows two irreversible oxidation processes with peak po-
tentials at +1.64 V and +1.82 V and a much higher anodic
current (-272 µA) than that of N-aminophthalimide at +1.68
V. Thus, bulk electrolysis of tetramethylene sulfoxide in the
presence of N-aminophthalimide on a graphite anode gave
tetramethylene sulfone as the major product with no evidence
of sulfoximine formation.
Electrochemical reactions involve electron transfer in the
Helmholtz layer at the electrode-solution interface.15 Highly
reactive intermediates can be generated under very mild
conditions, such as ambient temperatures, normal pressure,
and often in non-halogenated solvents.16 As opposed to
conventional chemical reactions, in which stoichiometric
amounts of reductants or oxidants are used, direct electro-
chemical reductions/oxidations of substrates utilize practically
mass-free electrons as the only reagents. In this sense,
electrochemistry is frequently referred to as one of the
prototypical green technologies of the future.17
In our effort to develop general electrochemical solutions
to the selective functionalization of organic molecules, we
recently found a practical process for olefin aziridination with
N-aminophthalimide.18 The development of this reaction was
based on a logical emulation of metal-based selectivity and
accomplished the replacement of the conventional method
that calls for excess Pb(OAc)4. We suggested that there must
be a possibility to develop a set of guidelines for emulating
a variety of metal-based redox processes via optimization
of reaction conditions with the goal of maximizing the
difference in overpotentials between the reacting molecules.
This Letter extends electrochemical oxidative methodology
to sulfoximine synthesis. Furthermore, this contribution
On the platinum anode, the electrolysis conditions were
similar to those of aziridination.18 A small excess of
N-aminophthalimide relative to the sulfoxide was used. The
electrolysis was performed in a divided cell using a silver
wire as a pseudo-reference electrode, which was calibrated
against the ferrocene/ferricinium couple in the electrolysis
medium (Epa ) 0.47 V, Epc ) 0.30 V). No special precautions
to exclude moisture or air were taken. The reaction was
stopped when the cell current dropped to less than 5% of its
original value. Table 1 illustrates the substrate scope of this
process. For sulfoxide 2d (entry 4), no aziridination product
was observed, indicating the possibility of achieving chemo-
selective nitrene transfer to the sulfoxide moiety.19 There was
no evidence for the background formation of sulfone
byproduct. Furthermore, the electrochemical nitrene transfer
is stereospecific. An enantiomerically enriched (93% ee of
the R-enantiomer) sample20 of 1b was electrolyzed under
the same conditions as above. The ee value measured by
HPLC for the product sulfoximine 2b was the same (97%)
within experimental error, and the X-ray crystallographic
analysis (anomalous dispersion) showed retention of con-
figuration,21 indicating that no racemization occurred during
the nitrene transfer process.
(8) (a) Johnson, C. R.; Haake, M.; Schroeck, C. W. J. Am. Chem. Soc.
1970, 92, 6594. (b) Stoss, P.; Satzinger, G. Angew. Chem., Int. Ed. Engl.
1971, 10, 76. (c) Rynbrandt, R. H.; Balgoyen, D. P. J. Org. Chem. 1978,
43, 1824.
(9) (a) Ohashi, T.; Masunaga, K.; Okahara, M.; Komori, S. Synthesis
1971, 96. (b) Colonna, S.; Stirling, C. J. M. J. Chem. Soc., Perkin Trans.
1 1974, 2120. (c) Kim, M.; White, J. D. J. Am. Chem. Soc. 1977, 99, 1172.
(d) Kemp, J. E. G.; Closier, M. D.; Stefanich, M. H. Tetrahedron Lett.
1979, 3785.
(10) (a) Kwart, H.; Kahn, A. A. J. Am. Chem. Soc. 1967, 89, 1950. (b)
Tanaka, R.; Yamabe, K. J. Chem. Soc., Chem. Commun. 1983, 329.
(11) (a) Muller, J. F. K.; Vogt, P. Tetrahedron Lett. 1998, 39, 4805. (b)
Lacoˆte, E.; Amatore, M.; Fensterbank, L.; Malacria, M. Synlett 2002, 116.
(12) (a) Bach, T.; Ko¨rber, C. Tetrahedron Lett. 1998, 39, 5015. (b) Bach,
T.; Ko¨rber, C. Eur. J. Org. Chem. 1999, 1033.
(13) (a) Tamura, Y.; Sumoto, K.; Minamikawa, J.; Ikeda, M. Tetrahedron
Lett. 1972, 4137. (b) Johnson, C. R.; Kirchhoff, R. A.; Corkins, H. G. J.
Org. Chem. 1974, 39, 2458. (c) Tamura, Y.; Minamikawa, J.; Ikeda, M.
Synthesis 1977, 1.
(14) (a) Claus, P. K.; Rieder, W.; Hofbauer, P.; Vilsmaier, E. Tetrahedron
1975, 31, 505. (b) Heintzelman, R. W.; Bailey, R. B.; Swern, D. J. Org.
Chem. 1976, 41, 2207.
(15) Bard, A. J.; Faulkner, L. K. Electrochemical Methods: Fundamen-
tals and Applications, Ed. 2; John Wiley & Sons: New York, 2001; Chapter
1.
(16) (a) Lund, H.; Baizer, M. M. Organic Electrochemistry: An
Introduction and a Guide, Ed. 3; M. Dekker: New York, 1991. (b) Shono,
T. Electroorganic Chemistry as a New Tool in Organic Synthesis; Springer-
Verlag: New York, 1984. (c) Torii, S., Ed. NoVel Trends in Electroorganic
Synthesis; Springer-Verlag: New York, 1998. (d) Little, R. D.; Norman,
L. Electroorganic Synthesis; M. Dekker: New York, 1991.
(17) Steckhan, E.; Arns, T.; Heineman, W. R.; Hilt, G.; Hoormann, D.;
Jorissen, J.; Kroner, L.; Lewall, B.; Putter, H. Chemosphere 2001, 43, 63.
(18) Siu, T.; Yudin, A. K. J. Am. Chem. Soc. 2002, 124, 530.
(19) Attempted oxidative imination of sulfides (resulting in sulfimines)
using the same methodology was not successful. Due to the less positive
oxidation potential of sulfides compared to N-aminophthalimide, a mixture
of products consisting mainly of sulfoxide and sulfoximine was obtained.
(20) For preparation of enantiomerically enriched sulfoxide, see: Ko-
matsu, N.; Hashizume, M.; Sugita, T.; Uemura, S. J. Org. Chem. 1993, 58,
4529.
1840
Org. Lett., Vol. 4, No. 11, 2002

conditions. Recently Bolm et al. developed procedures for
the TiCl4- or AlCl3-catalyzed deprotection of N-Boc group
in the synthesis of chiral benchrotrenes.24 However, no
deprotection liberating the “free” sulfoximines 3 from the
N-phthalimido derivatives 2 is described in the literature. We
have found that electrolysis of 2 in methanol with water as
a proton source under galvanostatic conditions (Scheme 1)
Table 1. Electrochemical Synthesis of Sulfoximines and N-N
Bond Cleavage
Scheme 1. Electrosynthesis of Sulfoximines and N-N Bond
Cleavagea
a (i) +1.80 V (vs Ag wire), platinum anode, 1.3 equiv of
N-aminophthalimide, 1.0 equiv of NEt3H+OAc-, rt, 3.5-4.0 h. (ii)
10 mA/cm2, platinum cathode, MeOH, 0.05 M Bu4N+BF4-, rt, 2.0
h.
gave the desired products in good yields for the dialkyl- and
diaryl-substituted sulfoximines. A small excess of electricity
(2.4 F, theoretical charge 2.0 F) was passed in order to ensure
complete conversion of the starting material. For some
alkyl-aryl-substituted sulfoximines (i.e., 2d, 2e, and 2f),
decomposition of the starting material was observed, resulting
in complicated product mixtures. Isolation by flash chroma-
tography (silica gel, hexane/EtOAc eluent) was sufficient to
afford pure product except in the case of 2a where separation
of 3a from supporting electrolyte (Bu4NBF4) was problem-
atic. In this instance, we utilized a benzoylation procedure
(Scheme 2) by treating the crude product 3a with benzoyl
Scheme 2. Benzoylation of Sulfoximines 3
a Starting material decomposed.
Various methods for removal of the N-bound substituent
to generate “free” sulfoximine 3 have been reported in the
literature. The detosylation with concentrated sulfuric acid
is often used but is complicated by a considerable loss of
material.22 An alternative way of detosylation is the sodium
anthracenide method introduced by Johnson but it only works
for the dialkyl-substituted sulfoximines.23 In comparison, the
removal of the N-Boc group is performed under mild
chloride and triethylamine to afford isolable sulfoximine 4a
in 92% overall yield. The same strategy was used to
transform the unstable compound 3g to 4g in 77% overall
yield.
In summary, we have extended our electrochemical
nitrogen transfer methodology18 to the synthesis of sulfox-
imines. This finding underscores the rational approach that
bypasses the requirement for stoichiometric amounts of toxic
oxidants and metal additives in organic redox reactions. We
have also demonstrated that the chemically “impossible” 6e
removal of the N-phthalimido group in sulfoximines can be
(21) X-ray data for R-2b (recrystallized from toluene): C16H14N2O3S,
MW ) 314.35, colorless prismatic crystal, crystal size 0.30 × 0.12 × 0.10
mm3, orthorhombic, space group P21/21/21, a ) 7.9615(2) Å, b ) 9.9599-
(2) Å, c ) 38.3334(10) Å, V ) 3039.68(13) Å3, Z ) 8, dcalc ) 1.374 g/cm3,
F(000) ) 1312, µ ) 0.227 mm-1, T ) 150(1) K, 12041 reflections collected,
6335 independent reflections, R ) 0.0614, Rw ) 0.0936, GOF on F2
)
1.022.
(22) (a) Whitehead, J. K.; Bentley, H. R. J. Chem. Soc. 1950, 2081. (b)
Johnson, C. R.; Schroeck, C. W. J. Am. Chem. Soc. 1973, 95, 7418. (c)
Hambley, T. W.; Raguse, B.; Ridley, D. D. Aust. J. Chem. 1986, 39, 1833.
(d) Kawanishi, H.; Morimoto, H.; Nakano, T.; Miyajima, T.; Oda, K.;
Takeda, K.; Yano, S.; Hirano, N.; Tsujihara, K. Heterocycles 1998, 49,
169.
(23) Johnson, C. R.; Lavergne, O. J. Org. Chem. 1989, 54, 986.
(24) Bolm, C.; Muniz, K.; Aguilar, N.; Kesselgruber, M.; Raabe, G.
Synthesis 1999, 1251.
Org. Lett., Vol. 4, No. 11, 2002
1841

readily achieved by electrochemistry. This methodology may
also be used for the deprotection of the N-phthalimido
aziridines18 and is within the scope of our future studies.
We are also aiming at the adaptation of these methodologies
into our recently developed parallel electrosynthesis plat-
form.25
for Innovation, ORDCF, and the University of Toronto for
financial support. Andrei Yudin is a Cottrell Scholar of
Research Corporation. We also thank Ms. Leslie Fradkin and
Dr. Alan Lough for their help in the X-ray crystal structure
determination.
Acknowledgment. We thank the National Science and
Engineering Research Concil (NSERC), Canada Foundation
Supporting Information Available: Experimental pro-
cedures and characterization data for the sulfoximines; X-ray
data of compound R-2b in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
(25) (a) Siu, T.; Li, W.; Yudin, A. K. J. Comb. Chem. 2000, 2, 545. (b)
Siu, T.; Yekta, S.; Yudin, A. K. J. Am. Chem. Soc. 2000, 122, 11787. (c)
Yudin, A. K.; Siu, T. Curr. Opin. Chem. Biol. 2001, 5, 269. (d) Siu, T.; Li,
W.; Yudin, A. K. J. Comb. Chem. 2001, 3, 554.
OL0257530
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