Chemoselective electrophilic oxidation of heteroatoms by hydroperoxy sultamst

Article abstract of DOI:10.1021/jo0202841

The synthesis of novel hydroperoxy sultams 1b-d and their potential as renewable chemoselective electrophilic oxidants for a wide range of nitrogen, sulfur, and phosphorus heteroatoms in nonaqueous media is described. Reactions of 1b,c with secondary amines 10f,g yielded the hydroxysultams 2b,c and nitrone 11f or radical 11g depending on the substrate and stoichiometry, while tertiary amines 10a-d gave amine oxides 11a-d. Compounds 1c,d oxidized various thioethers 12a-g to sulfoxides 13a-g smoothly that were isolated by chromatography in nearly quantitative yields. 1c was regenerated from 2c by treatment of the latter with acidified H₂O₂. Kinetic studies of the reaction of 1c with 1,4-thioxane 12f suggest that the reaction follows the second-order kinetics, first order in substrate and first order in oxidant with the second-order rate constant several orders of magnitude larger than that of the corresponding reaction with hydrogen peroxide and tert-butyl hydroperoxide without the need for any acid or heavy metal catalysts. The phosphines 14a,b were also oxidized by 1c to the respective phosphine oxides 15a,b readily in quantitative yields. The reactions may be conducted at ambient temperature or lower and appear to proceed via a nonradical mechanism. Reactions are sensitive to steric as well as electronic factors.

Full text of DOI:10.1021/jo0202841

Ch em oselective Electr op h ilic Oxid a tion of Heter oa tom s by
Hyd r op er oxy Su lta m s†
Feyissa Gadissa Gelalcha* and Ba¨rbel Schulze*
Universita¨t Leipzig, Institut fu¨r Organische Chemie, J ohannisallee 29, D-04103 Leipzig, Germany
bschulze@organik.chemie.uni-leipzig.de; gadissa@rz.uni-leipzig.de
Received April 22, 2002
The synthesis of novel hydroperoxy sultams 1b-d and their potential as renewable chemoselective
electrophilic oxidants for a wide range of nitrogen, sulfur, and phosphorus heteroatoms in
nonaqueous media is described. Reactions of 1b,c with secondary amines 10f,g yielded the
hydroxysultams 2b,c and nitrone 11f or radical 11g depending on the substrate and stoichiometry,
while tertiary amines 10a -d gave amine oxides 11a -d . Compounds 1c,d oxidized various thioethers
12a -g to sulfoxides 13a -g smoothly that were isolated by chromatography in nearly quantitative
yields. 1c was regenerated from 2c by treatment of the latter with acidified H2O2. Kinetic studies
of the reaction of 1c with 1,4-thioxane 12f suggest that the reaction follows the second-order kinetics,
first order in substrate and first order in oxidant with the second-order rate constant several orders
of magnitude larger than that of the corresponding reaction with hydrogen peroxide and tert-butyl
hydroperoxide without the need for any acid or heavy metal catalysts. The phosphines 14a ,b were
also oxidized by 1c to the respective phosphine oxides 15a ,b readily in quantitative yields. The
reactions may be conducted at ambient temperature or lower and appear to proceed via a nonradical
mechanism. Reactions are sensitive to steric as well as electronic factors.
In tr od u ction
tal constraints, etc.sthe use of many reagents is re-
stricted to specially favorable cases. Thus, the demand
for suitable, cost-effective, and environmentally friendly
selective oxidants with a wide range of application
continues to increase to cope with the ever-growing
complexity of chemical oxidations.5
Sultams such as Oppolzer’s camphorsultam and toluene-
2,R-sultam6 are among the most reliable and widespread
chiral auxiliaries for π-facial discrimination of various
reactions, whereas the chiral N-sulfonyloxaziridines that
are accessible by oxidation of respective N-sulfonylimines
enjoy an important place in the stereoselective O-transfer
reactions.7 On the other hand, many cyclic and acyclic
R-heterosubstituted hydroperoxides are also known to
effect the selective electrophilic oxidation of various
nucleophilic substrates. Prominent examples are the
R-azohydroperoxides,3d,e perhydrates,1b 3-hydroperoxy-
1,2-dioxolanes,3e 4a-hydroperoxyflavins,4d peroxyisoureas,8
The chemo-, regio-, and stereoselective oxyfunctional-
ization of heteroatoms is an important area of oxidation
chemistry.1 Thus, to date, a number of oxidants have
been developed to effect the selective oxidative transfor-
mation of N,1f,2,3 S,4 and P1a heteroatoms. However, for
various reasonssselectivity, cost, efficiency, environmen-
* To whom correspondence should be addressed. Phone: +49-341-
9736540.
† Dedicated to Professor Dr. Peter Welzel on the occasion of his 65th
birthday.
(1) (a) Hudlicky, M. Oxidations in Organic Chemistry; ACS Mono-
graph 186; American Chemical Society: Washington, DC, 1990. (b)
Adam, W.; Saha-Mo¨ller, C. R.; Ganeshpure, P. A. Chem. Rev. 2001,
101, 3498-3548. (c) Gilchrist, T. L. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: New York, 1991;
Vol. 7, Chapter 6.1, pp 735-756. (d) Uemura, S. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: New
York, 1991; Vol. 7, Chapter 6.2, pp 757-787. (e) Kagan, H.; Luukas,
T. In Transition Metals for Organic Synthesis; Beller, M., Bolm, C.,
Eds.; Wiley-VCH: Weinheim, 1998; Vol. 2, Chapter 2, pp 361-373. (f)
Murahashi, S.-I.; Imada, Y. In Transition Metals for Organic Synthesis;
Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998; Vol. 2,
Chapter 2, pp 373-383. (g) Kagan, H. B. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; pp
327-356.
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cycles 2000, 52, 365-382. (b) Gollnick, K.; Fries, S. Angew. Chem. 1980,
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and references therein.
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Y.-X.; Rodriguez, A. J . Heterocycl. Chem. 1996, 33, 1399-1402. (f)
Larsen, J .; J orgensen, K. A. J . Chem. Soc., Perkin Trans. 2 1992, 1213-
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(7) Davis, A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703-5742.
10.1021/jo0202841 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/01/2002
8400
J . Org. Chem. 2002, 67, 8400-8406

Chemoselective Electrophilic Oxidation of Heteroatoms
SCHEME 1
SCHEME 2
and peroxy acids.9,10 R-Hydroperoxyamines are implicated
as intermediates in the camphorsulfonylimine mediated
enantioselective oxidation of sulfides by hydrogen per-
oxide.11
Recently, we have introduced a new class of chiral
sultams of the type 1 (Scheme 1) that are characterized
by a hydroperoxy group at the 3-position as stable
crystalline compounds at room temperature and higher
that are easily accessible in a few steps12 and with a
potential application as heteroatom oxidants (eq 1).
or heavy metal catalysts are needed; (8) the hydroperoxy
sultams 1 are potential asymmetric oxidants.
Herein, we report (a) the syntheses of 1b-d , 2c,d , and
3c,d 13 and the single-crystal X-ray structure of 1c, (b)
the use of these new class of oxidants as efficient reagents
for the chemoselective electrophilic oxidation of a wide
range of nitrogen, sulfur and phosphorus heteroatoms (eq
1), (c) the factors that are important in their application
as selective oxidants, (d) comparison of their reactivity
with those of the more common oxidants based on kinetic
data, and (e) the scope and limitations of their use as
selective oxidants together with a possible reaction
mechanism.
By inspecting structure of 1, one may expect the
peroxide oxygen atom to be electron deficient due to the
strongly electron-withdrawing effect of the sulfone amide
function adjacent to the hydroperoxy group. Furthermore,
the electronic properties of the peroxide oxygen may be
tuned by judicious variation of the substituents at the
aromatic ring, thus potentially allowing one to predict
the reactivity and selectivity of these reagents. In addi-
tion, this system offers even more important practical
advantages: (1) high thermal stability; (2) in the solid-
state lesser sensitivity to impact and to metals compared
to H2O2, peracids, peresters, or TBHP, consequently safer
to handle; (3) solubility in polar (MeOH) and nonpolar
(CH2Cl2) solvents, thus more flexibility in solvent choice;
(4) reactions are carried out under essentially neutral
conditions; hence applicable to acid-sensitive substrates;
(5) products may be separated directly by chromatogra-
phy without the need of cumbersome workup procedures;
(6) 1 may be regenerated by treatment of 3-hydroxysul-
tam 2 with H2O2/HOAc mixture (vide infra); (7) no acid
Resu lts a n d Discu ssion
The synthesis of some stable hydroperoxy sultams has
been described previously.12 Briefly, the commercially
available ketones such as 4 are treated with the Vils-
meier reagent14 in DMF and POCl3 to give the â-chlo-
rovinylaldehydes 5 in high yields. Subsequent reaction
with NH4SCN furnishes the thiocyanates 6 (Scheme 2).
The thiocyanates 6 react with suitably substituted
anilines 7 in the presence of stoichiometric mounts of
perchloric acid in glacial acetic acid by intramolecular
cyclocondensation of the intermediate imines to the
bicyclic isothiazolium salts 8 in a one-pot reaction at room
temperature. Treatment of these salts with excess 30%
H2O2 in glacial acetic acid gives 1 in high yields as
crystalline products that are ready to use as oxidants.15
The choice of these oxidants for an oxidation reaction
depends among other things on their yields, stability,
solubility, and reactivity under the experimental condi-
(8) Majetich, G.; Hicks, R.; Sun, G.-r.; McGill, P. J . Org. Chem. 1998,
63, 2564-2573.
(9) Plesnicar, B. In The Chemistry of Functional Groups, Peroxides;
Patai, S., Ed.; Wiley: New York, 1983; Chapter 17, pp 521-584.
(10) Sawaki, Y. In Organic Peroxides; Ando, W., Ed.; Wiley: Chich-
ester, 1992; Chapter 9, pp 425-477.
(11) Page, P. C. B.; Heer, J . P.; Bethell, D.; Collington, E. W.;
Andrews, D. M. Synlett 1995, 7, 773-775.
(12) (a) Schulze, B.; Kirrbach, S.; Illgen, K.; Fuhrmann, P. Tetra-
hedron 1996, 52, 783-790. (b) Schulze, B. Obst, U.; Zahn, G.; Friedrich,
B.; Cimiraglia, R.; Hoffman, H.-J . J . Prakt. Chem. Chem. Ztg. 1995,
337, 175-183.
(13) For 1a , 2a , and 3a , see ref 12a.
(14) Arnold, Z.; Zemlicka, J . Collect. Czech. Chem. Commun. 1959,
24, 2385-2388.
(15) At lower temperatures (10-20 °C) and in shorter reaction times
(1-2 h), the cis- or trans-configured cyclic hydroperoxy sulfin amides
(sultims) 9 are isolated as solid products.
J . Org. Chem, Vol. 67, No. 24, 2002 8401

Gelalcha and Schulze
TABLE 1. Com p a r ison of Bon d Dista n ces in Som e
O-Don or s
TABLE 2. Oxid a tion of Secon d a r y a n d Ter tia r y Am in es
10a -g w ith Hyd r op er oxy Su lta m s 1b,c
compd
HO-OH
t-BuO-OH
CH3COO-OH
CF3COO-OH
1
d(O-O) (Å)
1.464a
1.480a
1.400a
1.400a
1.474
a
Data from ref 17.
tions. For example, donor substituents at the aromatic
ring reduce the hydroperoxide stability, whereas hydro-
peroxides with strongly electron-withdrawing groups may
be prepared in good yields, but are virtually insoluble in
common organic solvents. Therefore, we screened the
hydroperoxides taking these problems into consideration
and selected the hydroperoxides 1b-d as oxidants and
dichloromethane and chloroform as model organic sol-
vents. Most reactions were run with 1c since the yield
of this compound was found to be the most satisfactory.
The electrophilic character of the peroxy oxygen is further
increased by the inductive effect of the chlorine atoms;
the bulky isopropyloxy group would enhance the solubil-
ity in organic solvents. It must also be noted that in the
absence of acid or metal catalysts divalent sulfur and
trivalent nitrogen nucleophiles do not react readily with
conventional alkyl hydroperoxides.16
The remarkable stability also allowed us to obtain a
single-crystal X-ray structure of this compound 1c (Fig-
ure S1, Supporting Information). Selected bond distances
and angles are presented in the Supporting Information.
Interestingly, the solid-state stability arises at least
partly from the hydrogen bonding between the OH group
of one molecule with a sulfone oxygen of a neighboring
molecule leading to a polymer chain. Furthermore, the
torsional angle between the aromatic ring and the
approximate plane defined by the isothiazole ring is 85°.
This leaves the peroxidic oxygen easily accessible to a
potential nucleophilic substrate. The O-O bond distance
of 1.474 Å (Table 1) is similar to that calculated for H2O2
and tert-butyl hydroperoxide, t-BuOOH, but significantly
longer than that in peracetic acid, CH3CO3H, and tri-
fluoroperacetic acid, CF3CO3H.17
Ch em oselective Oxid a tion of Secon d a r y a n d Ter -
tia r y Am in es. The oxidation of tertiary amines to amine
oxides is important since amine oxides themselves are
often employed as selective O-transfer reagents. The
results of oxidation of various secondary and tertiary
amines 10 to amine oxides 11 is summarized in Table 2.
The high yields of oxidation products is very unusual for
hydroperoxy sultams 1 as secondary hydroperoxides
because the normal reaction of a secondary hydroperoxide
and dialkyl peroxides with R-hydrogen atoms with amines
is base-catalyzed decomposition to form carbonyl com-
pounds (see discussion below).
a
Unless stated otherwise, calculated from NMR spectra using
b
an internal standard (error ) (5% the stated values). No
conversion. c 25% 3c was also detected. Yield of isolated products
d
based on conversion.
readily with hydroperoxides 1b,c to the respective N-
oxides 11 and the 3-hydroxysultams 2 in high yields. The
fact that 10d can be oxidized to 11d whereas the similar
compound 10e (entry 6) does not react at all suggests
that the hydroperoxide is acting as an electrophile: the
electron density at this nitrogen atom is reduced due the
electron-withdrawing CHO group at the 4-position of 10e.
Instead, the reaction of 1c is diverted to the more
favorable decomposition to give 2c and 3c in a 4:1 ratio,
respectively, leaving 10e virtually intact. On the other
hand, the lack of any reaction between 1c and tribenzy-
lamine (not in Table 2) after 24 h reflects the high
sensitivity of the reaction to steric hindrance since this
amine is not electron deficient. The reaction of a second-
ary amine with at least H-atom at R-C-atom, e.g.,
dibenzylamine 10f (entry 7), normally gives the respec-
tive hydroxylamine with 1 equiv of an oxygen donor.
Compound 10f reacted to a mixture of the nitrone 11f
and the corresponding hydroxylamine with 1 equiv of 1c
while 2 equiv of oxidant reacted with 10f to furnish 11f
in quantitative yield. The situation is different with the
secondary amine that lacks a hydrogen atom on R-C.
Thus, the NMR spectrum of the reaction mixture of the
sterically hindered secondary amine 10g, 4-hydroxy-
It is also clear from Table 2 that the reaction is
sensitive to both steric and electronic factors. Sterically
unhindered tertiary amines 10a -c (entries 1-4) react
(16) Sheldon, R. A. In The Chemistry of Functional Groups, Perox-
ides; Patai, S., Ed.; Wiley: New York, 1983; Chapter 16, pp 161-200.
(17) Yamaguchi, K.; Kazuhiro, K.; Takada, K.; Otsuji, Y.; Mizuno,
K. In Organic Peroxides; Ando, W., Ed.; Wiley: Chichester, 1992;
Chapter 1, pp 1-100.
8402 J . Org. Chem., Vol. 67, No. 24, 2002

Chemoselective Electrophilic Oxidation of Heteroatoms
TABLE 3. Oxid a tion of Su lfid es 12a -g w ith 1.0 Equ iv of
Hyd r op er oxy Su lta m s 1c,d
SCHEME 3
2,2,6,6-tetramethylpiperidine (TEMPOL-H), with 1c after
24 h was too broad for quantitative analysis suggesting
the formation of a radical. In fact, the EPR spectrum of
this solution revealed a triplet signal with aN ) 15.7 G
at g ) 2.007, characteristic of the known nitroxide radi-
cal 11g, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oyl
(TEMPOL,)18 that could be isolated by column chroma-
tography in pure form and characterized by comparing
the melting point with the literature values (entry 8). Its
formation may be explained by further oxidation of the
intermediate hydroxylamine to the corresponding amine
oxide which reacts to form the resonance stabilized
radical, similar to the corresponding reactions of hydro-
gen peroxide, peracids, and dimethyldioxirane with hin-
dered amines.19 Primary amines are very sluggish in
their reaction with 1c, while the reaction of pyridine with
1d led to rapid base-catalyzed dehydration of the hydro-
peroxide to furnish the carbonyl compound 3d in quan-
titative yield. This Kornblum-DeLaMare reaction20 is
not unexpected since it is well established that secondary
hydroperoxides and dialkyl peroxides with hydrogen
atoms attached to R- carbon are known to undergo similar
base-catalyzed decomposition (Scheme 3) and may also
explain why tertiary amines in Table 2 needed more than
1 equiv of oxidant for complete consumption.
a
b
Yields refer to those of isolated, pure compounds. Estimated
from the 1H NMR spectrum by using s-trioxane as the internal
standard. c Sum of diastereomeric S-oxides.
Ch em oselective Oxid a tion of Su lfid es to Su lfox-
id es. The results of the oxidation of various sulfides to
sulfoxides are summarized in Table 3.
In the case of 12h , electrophilic attack at S would
dramatically reduce the aromaticity (and thus the stabil-
ity) of the 5-ring system. However, dimethyldioxirane is
known to oxidize substituted thiophenes to the very
unstable 1,1-dioxide products.21 Similarly, the presence
of the aldehyde group at position 2 in 12i places a partial
positive charge on S by resonance; again electrophilic
attack is impeded. No oxidation of the aldehyde group is
observed either. 1,4-Thioxane 12f was quantitatively
oxidized to the sulfoxide 13f in methanol, suggesting
solvent polarity is less important to the outcome and
product yield.22 Therefore, we became interested to know
if substrates with low solubility in most organic solvents
could also be oxidized under this system.
Thus, the oxidation of L-methionine 12g in a mix-
ture of water/methanol with hydroperoxide 1c gave
selectively a 1:1 diastereomeric mixture of S-oxides 13g
and the reduction product 2c within 4 h in excellent
yields. Oxidation took place exclusively at sulfur. All
those products can be easily separated by column chro-
matography in pure form (see the Experimental Sec-
tion).
The reaction of various sulfides 12 with 1c is very
smooth and is cleaner than that of amines 10 in Table 2.
Also in this case, steric and electronic factors play a major
role in determining the rate and the outcome of the
reaction. Sterically unhindered aliphatic and aromatic
sulfides 12a ,b,d -g are oxidized readily at 0-20 °C in
excellent yields to the respective sulfoxides 13 in short
reaction times. Allylphenyl sulfide 12b (entry 3) and
diallyl sufide 12e (entry 6) were chemoselectively oxi-
dized at S, and no traces of epoxides were detected by
1H NMR spectroscopy. Further oxidation to sulfones was
also not observed with all of the substrates in Table 3
even with more than 1 equiv of oxidant showing that the
reaction is highly selective. However, when excess DMSO-
d6 was added to the hydroperoxide 1c, rapid oxidation
1
to sulfone took place as evidenced by H and 13C NMR
spectroscopy. Interestingly, 12b failed to react with 1c
in ethyl acetate even after 3 h at room temperature while
reaction was complete within 2 h in dichloromethane. The
relatively slow reaction of diphenyl sulfide 12c is clearly
due to steric grounds, while the absence of any reaction
between the thiophene derivatives 12h ,i is almost cer-
tainly due to electronic reasons (eq 2).
(18) Baracu, I.; Dobre, V.; Niculescu-Duvaz, I. J . Prakt. Chem. 1985,
327, 667-674.
(19) (a) Toda, T.; Mori, E.; Murayama, K. Bull Chem. Soc. J pn. 1972,
45, 1904-1908. (b) Toda, T.; Mori, E.; Higashida, S.; Murayama, K.
Bull Chem. Soc. J pn. 1972, 45, 636-638. (c) Murray, R.; Singh, M.
Tetrahedron Lett. 1988, 29, 4677-4680.
(20) Kornblum, N.; DeLaMare, H. E.J . Am. Chem. Soc. 1951, 73,
880-881.
(21) Nagasawa, H.; Sugihara, Y.; Ishii, A.; Nakayama, J . Bull. Chem.
Soc. J pn. 1999, 72, 1919-1926.
(22) However, see Dankleff, M. A. P.; Curci, R.; Edwards, J . O.;
Pyun, H.-Y. J . Am. Chem. Soc. 1968, 90, 3209-3218.
J . Org. Chem, Vol. 67, No. 24, 2002 8403

Gelalcha and Schulze
TABLE 4. Oxid a tion a t P h osp h or u s 14a -c w ith 1.0
TABLE 5. Com p a r ison of Secon d Or d er Ra te Con sta n ts
for th e Rea ction of 12f to 13f w ith Som e Oxid a n ts in
Meth a n ol a t 30 °C
Equ iv of Hyd r op er oxy Su lta m 1c
yield (%)a
solvent, T (°C),
oxidant
t-BuOOH
k/M-1s-1 (krel
)
substrate
time (h)
product
15
2
3.75 × 10-6 (1)a
((H3C)2N)3P CH2Cl2, 0, 0.75
((H3C)2N)3P f O
98
98
H2O2
9.38 × 10-5 (24)a
14a
15a
4a-FlCD3OOHb
6.60 × 10-1 (1.8 × 105)a
3.6 × 10-2 (9.6 × 103)c
Ph3P
14b
CH2Cl2, 0, 0.75
Ph3P f O
15b
98
98
1c
Data from ref 25. 4a-Hydroperoxyflavin. c Determined by
Ph3P f S
14c
acetone-d6, 40, 24 15b
a
b
50
50
iodometric titration of the reaction mixture of 12f and 1c.
a
Calculated from 1H NMR spectra using an internal standard
(error ) (5% of the stated values.
SCHEME 4
Ch em oselective Oxidation of P h osph in es to P h os-
p h in e Oxid es. Although reduction of hydroperoxides
with tertiary phosphines is no novelty,23 phosphorus tris-
(dimethylamido)phosphine 14a and triphenylphosphine
14b were oxidized quantitatively even faster and at a
lower temperature than the sulfur compounds 12 and the
amines 10 to the respective phosphine oxides 15a and
15b in dichloromethane, whereas triphenylphosphine
sulfide 14c, a phosphine with a pentavalent phosphorus,
reacted only slowly and at a higher temperature to 15a
in low yield (Table 4). The faster rate of oxidation of 14a ,b
than 12 is in line with the greater nucleophilicity of
phosphorus than sulfur.
measure by iodometric titration. A linear relationship
was established when the reaction was conducted in a
thermostated flask at 30 °C using [12f]: [1c] of 3.01, 3.50,
5.06, and 7.58 molar ratios with the pseudo-first-order
rate constants kobs of 7.19 × 10-4, 7.42 × 10-4, 10.00 ×
10-4, and 14.60 × 10-4 s-1, respectively. The linearity of
the plot establishes that the reaction of 1c with 12f is
first order in 1c and first order in 12f.
Table 5 shows comparison of published second-order
rates for the reaction of 12f with various oxidants.
Obviously, the rate of oxidation of 12f with 1c is nearly
4 orders of magnitude faster than that with tert-butyl
hydroperoxide and more than 2 orders of magnitude than
H2O2 under comparable experimental conditions.
Mech a n ism of Heter oa tom Oxid a tion s by Hyd r o-
p er oxy Su lta m s. From the above results, it is possible
to propose that heteroatom oxidation by hydroperoxy
sultams may involve a polar transition state involving
the typical SN2 displacement by the incoming nucleophile
at peroxide oxygen (Scheme 4) accompanied by rapid
proton transfer to the oxygen atom adjacent to carbon.
In addition to the sulfone amide functionality, intramo-
lecular hydrogen bonding between the nitrogen atom and
the peroxide hydrogen may account for the enhanced
reactivity, as suggested for electrophilic nature of other
R-hetero substituted hydroperoxides1b,3d-f,4d,8 as well as
organic peracids.9,10 The mechanism and kinetic data
presented here are closest to those reported for the cyclic
R-azohydroperoxides. Although more mechanistic studies
are necessary a similar mechanism may apply to the
oxidation of phosphines and amines with hydroperoxy
sultams as well.
Lim ita tion s. It has been shown that the reactions of
hydroperoxy sultams with various N, S, and P nucleo-
philes give high yields of the oxidation products in short
reaction times without any added catalyst or additives.
However, these reactions are sensitive to steric as well
as electronic factors. In reaction with amines, highly basic
amines catalyzed decomposition of hydroperoxides com-
petes with oxygen transfer to substrates. Reactions with
pyridines lead to decomposition while primary amines
were least reactive. Furthermore, the active oxygen
content is lower than that of the more conventional
oxidants, although this may not be limiting given the
Com p etitive Heter oa tom Oxid a tion s. To determine
the relative nucleophilicities of sulfur and nitrogen
centers toward the hydroperoxide 1c, competitive experi-
ments were carried out on equivalent amounts of diben-
zylamine 10f and dibenzyl sulfide 12d by treatment with
0.5 equiv of the oxidant in deuterated chloroform at room
1
temperature. After the end of the reaction, the H NMR
was recorded. Integration of the signals revealed that
nearly all (> 99%) of the half equivalents of oxygen has
been transferred to sulfur while virtually no reaction took
place with 10f. This finding is in a very good accord with
the result observed with 2-sulfonyoxaziridines (Davis
reagent) with 10f and dibenzyl sulfide 12d under the
same experimental condition.24 However, the spectrum
of our reaction mixture did not show even traces of
dibenzylhydroxylamine or dibenzyl sulfone.
Kin etic Stu d ies. To gain more insight into the reac-
tion mechanism, we carried out preliminary kinetic
studies using oxidant 1c and 1,4-thioxane 12f based on
the reported kinetic data for the oxidation of this sulfide
with H2O2, t-BuOOH, and the hydroperoxyflavins in
methanol.25 The progress of the reaction was followed by
iodometric titration. With [12f] ) [1c], the plot of [1c]-1
versus time is a straight line which means the reaction
follows a second-order rate law (eq 3).
rate ) d[ROOH]/dt ) d[sulfide]/dt )
-k [sulfide][ROOH] (3)
The second-order rate constant k2 of 3.6 × 10-2 M-1
s-1 was obtained from the slope of this plot (see Figure
S2, Supporting Information). Under strictly pseudo-first-
order conditions, [12f] g 20 [1c], the rate was too fast to
(23) Horner, L.; Lurgeleit, W.; J ustus Liebigs Ann. Chem. 1955,591,
138-152. Poppas, J . J .; Keaveney, W. P.; Berger, M.; Rusch, R. V. J .
Org. Chem. 1968, 33, 787-792.
(24) Zajac, J r., W. W.; Walters, T. R.; Darcy, M. G. J . Org. Chem.
1988, 53, 5856-5860.
(25) Kemal, C.; Chan, T. W.; Bruice, T. C. Proc. Natl. Acad. Sci.
U.S.A. 1977, 74, 405-409.
8404 J . Org. Chem., Vol. 67, No. 24, 2002

Chemoselective Electrophilic Oxidation of Heteroatoms
CAUTION: Although we have not encountered a single
incident over the years, peroxides should always be considered
potentially explosive and thus hazardous. In fact, more care
should be exercised in handling perchlorates and 30% H2O2
than any of the new hydroperoxides reported here.
possibility to recycle the hydroxy sultam 2c in one step
to the active oxidant 1c in good yield (see the Experi-
mental Section).
Con clu sion
Gen er a l P r oced u r e for th e P r ep a r a tion of Hyd r op er -
oxy Su lta m s 1. The hydroperoxy sultams 1b-d were pre-
pared by treatment of the respective isothiazolium salts 8 (0.5
mmol) with excess 30% H2O2 (2.5 mL) in glacial acetic (3 mL)
at room temperature (1b, 2 h) or at 45 °C (1c,d , 4 h) following
the general procedure developed for the synthesis of 1a .12a
2(4-ter t-Bu tylph en yl)-3-h ydr oper oxy-2,3,4,5,6,7-h exah y-
d r o-1,2-ben zisoth ia zole 1,1-d ioxid e (1b): yield 0.23 mmol,
46%;37 mp 132-135 °C; FT-IR (KBr) 1516, 1363, 1270, 1220,
1155, 1070 cm-1; UV (EtOH) λmax (log ꢀ) 224 (3.90), 267.0
(2.87); MS (EI) m/z 319.3 (M - H2O); 1H NMR (200 MHz,
CDCl3) δ 1.32 (s, 9H), 1.82 (m, 4H), 2.51 (m, 4H), 5.84 (s, 1H),
7.36-7.43 (m, 4H); 13C NMR (50 MHz, CDCl3) δ 19.1, 21.4,
21.5, 23.4, 31.8, 35.0, 92.5, 123.5, 127.2, 132.1, 137.2, 140.1,
150.2.
In summary, we have shown that stable hydroperoxy
sultams possess an attractive monooxygen donation
capacity as recyclable mild reagents for a wider range of
heteroatom oxidations without the need to employ acid
or heavy metal catalysts in non aqueous media. The base-
catalyzed decomposition of hydroperoxides observed with
some amines may be minimized by lowering the reaction
temperature and is completely absent in the reaction
with the nonbasic nucleophiles sulfides and phosphines.
The kinetic studies in methanol of the oxidation of 12f
with 1c showed that the reaction is first order in both
the oxidant and the substrate and the rate is much faster
than oxidation of 12f with H2O2 or t-BuOOH under com-
parable experimental conditions. The use of the sultam
skeleton holds several advantages. The hydroxysultam
byproducts 2c,d can be recycled to 1c,d . Furthermore,
the sultam skeleton can in principle be modified to afford
an effective chiral oxidant. Extensive efforts are currently
underway in our laboratory to better understand the
mechanism and to extend applications of these com-
pounds to other substrates.
2(2,5-Dich lor o-4-isop r op yloxyp h e n yl)-3-h yd r op e r -
oxy-2,3,4,5,6,7-h exa h yd r o-1,2-ben zisoth ia zole 1,1-d ioxid e
(1c): yield 0.38 mmol, 75%; mp 195-197 °C; FT-IR (KBr,
cm-1) 3413, 1483, 1376, 1294, 1221, 1159, 1091 cm-1; UV
(EtOH) λmax (log ꢀ) 239 (4.09), 285 (3.31), 290 (3.31); MS (EI)
1
m/z 407.1 (M - 1); H NMR (200 MHz, CDCl3) δ 1.40 (d, J )
5.8.0 Hz, 6H), 1.80-1.90 (m, br, 4H), 2.20-2.60 (m, br, 4H),
4.56 (m, 1H), 5.67 (s, br, 1H), 7.04 (s, 1H), 7.64 (s, 1H); 13C
NMR (50 MHz, CDCl3) δ 19.2, 21.3, 22.1, 23.2, 73.0, 94.3,
116.1, 123.2, 123.4, 134.1, 134.8, 137.1, 140.1, 155.3. Anal.
Calcd for C16H19Cl2NO5S (408.29): C, 47.09; H, 4.66; N, 3.43;
Cl, 17.38; O, 19.61. Found: C: 46.60; H, 4.67; N, 3.33; Cl,
17.31; O, 19.70.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were corrected. Mi-
croanalyses were performed by the Microanalysis Service of
the University of Leipzig. 1H and 13C NMR spectra were
recorded on the δ scale (ppm) in CDCl3, acetone-d6, or D2O
solvents at 200 or 300 MHz (1H) and at 50 or 75 MHz (13C)
against residual solvent signals as references. An FTIR
spectrophotometer was used for the IR spectra (KBr pellets).
UV/vis spectra were recorded on a spectrometer. A 70 eV
equipment was used for the MS spectra. TLC analyses were
conducted on precoated plates (silica gel 60 F 254), and the pots
were visualized either by UV irradiation at 254 nm or by
spraying with a saturated solution of KI in acetic acid. Silica
gel (0.063-0.200 mm) was used for flash chromatography. All
starting amines, phosphines, and sulfides and the ketones 4
are commercial products and were used without further
purification. Compounds 5,14,26 6,27 and 8b-d 12 were prepared
analogous to the reported procedure. A sample of the aniline
7c was kindly supplied by the Bayer AG. Solvents were dried
by standard methods and purified by distillation before use.
All oxidation products 11a ,28 11b-d ,29 11f,30 11g,31 13a -c,f 32
13d ,33 13e,34 13g,35 15a ,28 and 15b36 are known and gave the
reported spectral data.
2(2,5-Dich lor o-4-isop r op yloxyp h en yl)-3-h yd r op er oxy-
2,3,5,6,7,8-h exa h yd r o-4H -cycloh ep t a [d ]-isot h ia zole 1,1-
d ioxid e (1d ): yield 0.4 mmol, 80%; mp 200-203 °C; FT-IR
(KBr, cm-1) 1484, 1377, 1292, 1224, 1157, 1080 cm-1; 1H (200
MHz, CDCl3) δ 1.41 (d, J ) 6.0 Hz, 6H), 1.70-1.90 (m, 6H),
2.40-2.72 (m, 4H), 4.58 (m, 1H), 5.58 (s, 1H), 7.05 (s, 1H), 7.58
(s, 1H); 13C (75 MHz, CDCl3) δ 22.0, 23.9, 25.9, 26.7, 28.3, 30.3,
73.0, 94.5, 116, 123.5, 134.0, 134.7, 139.3, 142.5, 155.3.
Ch em oselective Oxid a tion of Secon d a r y a n d Ter tia r y
Am in es 10a -g w ith Hyd r op er oxy Su lta m s 1b,c. Gen er a l
P r oced u r e. A 1.1-2.5 equiv portion of the hydroperoxides
1b,c (97-98% pure by iodometric assay) was dissolved in the
appropriate solvent (Table 1) and treated with the amine at 0
°C (ice cooling). The temperature was raised, and the mixture
was stirred for the specified times. The progress of the reaction
was monitored by TLC (ethyl acetate/n-hexane 4:5; saturated
KI in acetic acid): When the reaction was finished, the crude
mixture was analyzed by 1H NMR spectroscopy after addition
of an internal standard. All amine oxide products are known
1
and gave satisfactory H and 13C NMR analyses. Compounds
2b,c were characterized in the crude mixture by comparison
of their NMR spectra with those of independently prepared
compounds (see below and the Supporting Information). In
case of the reaction of 0.127 mmol of 10g with 0.142 mmol of
1c, the reaction was incomplete after 24 h. The crude product
was purified by silica gel chromatography (ethyl acetate/n-hex-
ane 4/5 (vol/vol) and then ethyl acetate/methanol 1/1 (vol/vol))
to yield 11g (0.047 mmol, 74%) and 2c (0.061 mmol, 65%),
respectively. In cases where significant decomposition occurred
in competition with oxygen transfer from 1c at room temper-
ature, the corresponding compound 3c was identified by
comparison of TLC and NMR data with those of independently
prepared 3c (Supporting Information). When the amine was
pyridine, base-catalyzed dehydration of 1d (0.112 mmol) to the
carbonyl compound 3d had occurred at 70 °C within 6h while
(26) Reddy, C. P.; Tanimoto, S. Synthesis 1987, 575-577.
(27) (a) Mu¨hlsta¨dt, M.; Bra¨mer; R.; Schulze, B. Z. Chem. 1976, 16,
49-51. (b) Schulze, B.; Bra¨mer; R.; Kleinpeter, E.; Mu¨hlsta¨dt, M. J .
Prakt. Chem. 1976, 318, 795-800.
(28) Bravo, R.; Laurent, J .-P. J . Chem. Res., Synop. 1983, 61.
(29) Ferrer, M.; Sanchez-Baeza, F.; Messeguer, A. Tetrahedron 1997,
53, 15877-15888.
(30) Murray, R.; Singh, M. J . Org. Chem. 1990, 55, 2954-2957.
Murray, R.; Singh, M. Tetrahedron Lett. 1988, 29, 4677-4680.
(31) Kluge, R.; Schulz, M.; Liebsch, S. Tetrahedron 1996, 52, 5773-
5782.
(32) Hashmat Ali, M.; Stevens, W. C. Synthesis 1997, 764-765.
(33) Yang, R.-Y.; Dai, L.-X. Synth. Commun. 1994, 24, 229-236.
(34) Block, E.; Zhao, S. H. Tetrahedron Lett. 1990, 31, 5003-5006.
(35) (a) Holland, H. L.; Andreana, P. R.; Brown, F. M. Tetrahedron:
Asymmetry 1999, 10, 2833-2843. (b) Holland, H. L.; Brown, F. M.
Tetrahedron: Asymmetry 1998, 9, 535-538.
(36) (a) Cantrill, A. A.; Osborn, H. M. I.; Sweeney, J . Tetrahedron
1998, 54, 2181-2208. (b) Aitken, R. A.; Karodia, N. Eur. J . Org. Chem.
1999, 251-254.
(37) Unlike 1c,d which require almost no further purification, this
product is usually contaminated with its hydroxy derivative 2b and/
or the keto compound 3b that need to be separated by column
chromatography.
J . Org. Chem, Vol. 67, No. 24, 2002 8405

Gelalcha and Schulze
1
no reaction was observed at room temperature. Compound 3d
was isolated in quantitative yield (0.111 mmol, 99%) by
removal of the unreacted pyridine and the water under
reduced pressure.
The H NMR spectrum showed no resolution of the signals of
diastereoisomers of 13g. Baseline resolution of some signals
could be achieved by 13C NMR, which revealed that the product
is approximately a 1:1 mixture of diastereoisomers. 1H and
13C NMR data are in full accord with the literature. The ether
phase was washed with brine (2 × 5 mL) and dried over
MgSO4. The solvent was removed under reduced pressure to
give 165 mg (98%) of pure hydroxysultam 2c. Spectral data
are as above.
2-(2,5-Dich lor o-4-isop r op yloxyp h en yl)-5,6,7,8-t et r a -
h yd r o-4H-cycloh ep ta [d ]isoth ia zol-3(2H)-on e 1,1-d ioxid e
(3d ): mp 130-134 °C; FT-IR (KBr) 1734, 1483, 1377, 1331,
1230, 1170, 1099 cm-1; UV (EtOH) λmax (log ꢀ) 230 (4.16), 232
1
(4.15), 284 (3.37), 291 (3.35); MS (EI) m/z 403.1 (M - 1); H
NMR (300 MHz, CDCl3): δ 1.44 (d, J ) 6.0 Hz, 6H); 1.78 (m,
2H), 1.90 (m, 4H), 2.75 (m, 2H), 2.85 (m, 2H), 4.62 (m, 1H),
7.11 (s, 1H), 7.37 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 22.1,
24.3, 24.9, 25.8, 26.5, 30.0, 73.0, 116.0, 118.0, 123.2, 132.9,
134.3, 138.5, 148.9, 156.1, 159.0.
Ch em oselective Oxid a tion of P h osp h in es 14a -c to
P h osp h in e Oxid es 15a ,b. The hydroperoxide 1c (1 equiv),
dissolved in the appropriate solvent (Table 5), was dropped
via a syringe to a solution of the phosphines 14 at 0 °C (ice
cooling) under N2. The cooling was removed, the temperature
was raised as indicated, and the mixture was stirred for the
specified time. The progress of the reaction was monitored by
TLC. When the reaction was finished, the crude mixture was
analyzed by 1H NMR spectroscopy after addition of an internal
standard.
Gen er a l P r oced u r e for th e Regen er a tion of 1c fr om
2c. A 65 mg (0.166 mmol) portion of 2c was suspended in a
mixture of 2 mL of glacial acetic acid and 2 mL of 30%
hydrogen peroxide, and the suspension was stirred at 50 °C
for 8 h. After the end of the reaction (monitored by TLC), the
mixture was cooled to 5 °C, and the solid material was filtered
over a sintered glass filter, washed with cold water (3 × 5 mL),
and air dried to give 50 mg (0.122 mmol, 73% yield) of 1c that
has identical analytical data as above.
Ch em oselect ive Oxid a t ion of Su lfid es12a -f t o Su l-
foxid es 13f-g. Gen er a l P r oced u r e. A 0.1-1.0 mmol portion
of 1c,d dissolved in the appropriate solvent (Table 2) was
dropped via a syringe to a solution of 1.0 equiv of the respective
sulfides 12a -f at 0 °C (ice cooling) under N2. The cooling was
removed, the temperature raised as indicated, and the mixture
was stirred for the specified time. The progress of the reaction
was monitored by TLC. When the reaction was finished, the
crude mixture was analyzed by 1H NMR spectroscopy after
addition of an internal standard. Isolation of the pure sulfox-
ides 13 and the hydroxy compounds 2 was achieved by silica
gel chromatography (ethyl acetate/n-hexane 4/5 (v/v); saturated
KI in acetic acid) following solvent removal from the mixture
under reduced pressure.
2-(2,5-Dich lor o-4-isop r op yloxyp h e n yl)-3-h yd r oxy-
2,3,4,5,6,7-h exa h yd r o-1,2-ben zisoth ia zole 1,1-d ioxid e (2c):
mp 148-150 °C; FT-IR (KBr) 3430, 1485, 1375, 1296, 1223,
1159, 1093 cm-1; UV (EtOH) λmax (log ꢀ) 238 (4.00), 285 (3.21),
291 (3.21); MS (EI) m/z 391.1 (M - 1); 1H NMR (200 MHz,
CDCl3) δ 1.41 (d, J ) 6.0 Hz, 6H), 1.80-1.90 (m, br, 4H), 2.15-
2.60 (m, br, 4H), 4.58 (m, 1H), 5.49 (s, br, 1H), 7.05 (s, 1H),
7.53 (s, 1H); 13C NMR (50 MHz, CDCl3) δ 19.0, 21.4, 22.2, 23.4,
73.1, 84.4, 116.5, 122.6, 123.1, 134.98, 135.03, 143.1, 155.2.
2-(2,5-Dich lor o-4-isop r op yloxyp h e n yl)-3-h yd r oxy-
2,3,5,6,7,8-h exa h yd r o-4H -cycloh ep t a [d ]isot h ia zole 1,1-
d ioxid e (2d ): mp 204-207 °C; FT-IR (KBr) 3372, 1485, 1375,
1280, 1223, 1155, 1057 cm-1; UV (EtOH) λmax (log ꢀ) 238 (3.56),
284 (2.92), 316 (2.29); MS (EI) m/z 405.1 (M - 1); 1H NMR
(200 MHz, CDCl3) δ 1.40 (d, J ) 6.0 Hz, 6H), 1.70-1.90 (m,
6H), 2.5-2.70 (m, 4H), 3.21 (d, J ) 10.6 Hz, 1H), 4.57 (m, 1H),
5.42 (d, J ) 10.6 Hz,1H), 7.05 (s, 1H), 7.54 (s, 1H); 13C NMR
(50 MHz, CDCl3) δ 22.0, 23.7, 26.4, 26.8, 28.8, 30.3, 73.0, 84.3,
116.0, 122.9, 123.1, 134.7, 134.8,137.3, 145.5, 155.1. Anal.
Calcd for C17H21Cl2NO4S (406.32): C, 50.25; H, 5.21; N, 3.45.
Found: C, 50.30; H, 5.30; N, 3.40.
Ch em oselective Oxid a tion of Meth ion in e 12g to Me-
th ion in e S-Oxid e 13g. A 165 mg (0.404 mmol) portion of
hydroperoxide 1c dissolved in 10 mL of methanol was dropped
within 20 min via a syringe to a solution of the 60 mg (0.403
mmol) of L-methionine 12g in distilled water at 0 °C (ice-
cooling) under N2. An additional 10 mL of methanol was added,
and the mixture was stirred at room temperature by which
time the initially heterogeneous mixture became homogeneous
as the reaction proceeded. The progress of the reaction was
monitored by TLC (ethyl acetate/n-hexane 4/5; saturated KI
in acetic acid; ninhydrin). When the reaction was complete,
the solvent was removed under reduced pressure to dryness
and replaced by 10 mL of distilled water. This mixture was
extracted with ether (5 × 10 mL) until no trace of the hydroxy
compound could be detected in the aqueous phase by TLC
(silicagel 60, Rf 0.15, n-butanol/acetic acid/water 4/1/1 (v/v/v);
ninhydrin). The combined ether phases were washed with 2
mL of water. The water phases were united and the water
removed under reduced pressure until the weight of the flask
remained constant to give 67 mg (99%) of white solid product.
Com p etitive Oxid a tion of 10f a n d 12d . A 10.5 mg (0.049
mmol) portion of dibenzylamine 10f, 9.7 mg (0.049 mmol) of
dibenzyl sulfide 12d , and 10 mg (0.025 mmol) 1c were
dissolved in deuteriochloroform at room temperature. After the
end of the reaction (monitored by TLC), the 1H NMR was
recorded. Integration of the signals at δ 3.65, 3.83, 3.93, and
5.45 ppm that are, respectively, due to 12d , 10f, 13d , and 2c
protons revealed that these products are present in the
mixture nearly in 1:2:1:1 molar ratios in that order.
Kin etic Mea su r em en ts. The oxidation of 1,4-thioxane 12f
to 1,4-thioxane oxide 13f (Table 4, eq 3) was monitored by a
modified iodometric titration38 method of Kokatnur and J elling
on four samples containing 30.6 mg of hydroperoxide 1c (0.073
mmol) in 10 mL of methanol and were thermostated at 30 °C
after the addition of 1.00, 3.01, 3.50, 5.06, and 7.58 equiv of
1,4-thioxane. Reactions were followed to 75% completion. The
corresponding rate constant of the 1:1 mixture was determined
from the second-order plot while the apparent rate constants
were determined from the pseudo-first-order plots. The preci-
sion of the constants is given in terms of the 95% confidence
limit calculated with the “student t” test using the computer
program ORIGIN.
Ack n ow led gm en t. We gratefully acknowledge the
financial support by the Deutsche Forschungsgemein-
schaft and the Graduiertenkolleg: Mechanistische und
Anwendungsaspekte nichtkonvetioneller Oxidation-
sreaktionen.
Su p p or tin g In for m a tion Ava ila ble: Detailed character-
ization data (1H and 13C NMR, IR, MS) of 2b, 3c, and 8b-d ,
1H and 13C NMR spectra of 1b-d , 2c,d , 3c,d , and 8c,d .
Figures S1,2. Complete X-ray crystallographic data for 1c. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J O0202841
(38) Kokatnur, V. R.; J elling, M. J . Am. Chem. Soc. 1941, 63, 1432-
1433.
8406 J . Org. Chem., Vol. 67, No. 24, 2002