Synthesis of Sulfoxides by the Hydrogen Peroxide Induced Oxidation of Sulfides Catalyzed by Iron Tetrakis(pentafluorophenyl)porphyrin: Scope and Chemoselectivity

Article abstract of DOI:10.1021/jo049879h

The oxidation of sulfides with H₂O₂ catalyzed by iron tetrakis(pentafluorophenyl)porphyrin in EtOH is an efficient and chemoselective process. With a catalyst concentration 0.03-0.09% of that of the substrate, sulfoxides are obtained with yields generally around 90-95% of isolated product. With vinyl and allyl sulfides, no epoxidation is observed. With a catalyst concentration between 0.09% and 0.25% of that of the substrate, sulfones are obtained in almost quantitative yield and with the same high chemoselectivity observed in the synthesis of sulfoxides.

Full text of DOI:10.1021/jo049879h

SCHEME 1
Syn th esis of Su lfoxid es by th e Hyd r ogen
P er oxid e In d u ced Oxid a tion of Su lfid es
Ca ta lyzed by Ir on
Tetr a k is(p en ta flu or op h en yl)p or p h yr in :
Scop e a n d Ch em oselectivity
considered and the actual merit of this system for the
synthesis of sulfoxides remains therefore unassessed.
In view of the general and continuous interest for the
oxidation of sulfides6 and particularly for the develop-
ment of synthetic methods for the selective conversion
of sulfides into sulfoxides7 and the use of H2O2 as an
environmental benign oxidant, we have considered it
worthwhile to carry out a detailed investigation on the
oxidation of sulfides by H2O2 in ethanol catalyzed by
F20TPPFe, with the aim of acquiring information on the
scope and chemoselectivity of the process. The com-
mercially available F20TPPFe was the iron porphyrin of
choice on the basis of the Ruasse’s results5 and also
because a recent study by Nam and co-workers8 estab-
lished that this iron porphyrin is the most effective also
in the H2O2-induced epoxidation of alkenes in protic
solvents. The results of this investigation are reported
herewith.
For the synthesis of sulfoxides, sulfoxidations were
carried out by using equimolar concentrations of H2O2
(6 mL of a 1 M solution in ethanol) and substrate (6.0
mmol in 20 mL of ethanol) at room temperature. The
concentration of F20TPPFe was extremely small ranging
from 0.03% to 0.09% with respect to that of the substrate.
The H2O2 solution was slowly added to that of the
substrate during 1 min with a syringe and the mixture
was stirred for 3 min, then sodium dithionite was added.
After the solvent was removed, chromatography of the
residue on silica gel provided excellent yields of isolated
pure sulfoxide which were close to those determined by
GC or 1H NMR on the crude reaction mixture. The
sulfides investigated and the sulfoxide yields are reported
in Table 1.
Enrico Baciocchi,* Maria Francesca Gerini, and
Andrea Lapi
Dipartimento di Chimica, Universita` degli Studi di Roma
“La Sapienza”, Piazzale Aldo Moro 5, 00185 Rome, Italy
enrico.baciocchi@uniroma1.it
Received J anuary 21, 2004
Abstr a ct: The oxidation of sulfides with H2O2 catalyzed by
iron tetrakis(pentafluorophenyl)porphyrin in EtOH is an
efficient and chemoselective process. With a catalyst con-
centration 0.03-0.09% of that of the substrate, sulfoxides
are obtained with yields generally around 90-95% of
isolated product. With vinyl and allyl sulfides, no epoxidation
is observed. With a catalyst concentration between 0.09%
and 0.25% of that of the substrate, sulfones are obtained in
almost quantitative yield and with the same high chemose-
lectivity observed in the synthesis of sulfoxides.
The capacity of iron tetraarylporphyrins to catalyze the
oxidation of sulfides by H2O2, presumably through the
formation of the iron oxo complex P•+Fe(IV)dO as the
active species (Scheme 1, P ) tetraarylporphyrin), has
been long known.1
However, the pioneering study by Oae and co-workers3
and the few other studies that dealt later with this
oxidizing system4 were mainly focused on its mechanistic
aspects (e.g., oxygen vs electron-transfer mechanisms)
with little or no concern about its possible practical
application in organic synthesis. Very recently, Ruasse’s
group reported interesting results on the exploitation of
Looking at the results reported in Table 1, the first
observation is that the reaction is very efficient affording
yields of sulfoxide generally around 90% with a very low
catalyst/substrate ratio (from 1/3300 to 1/1100) and with
a reaction time as short as 4 min. The selectivity with
respect to the formation of sulfone is also very high as
this catalytic system for mustard decontamination.5
A
number of iron tetraarylporphyrins were examined as
catalysts for the H2O2-induced oxidation of mustard
models to the corresponding sulfones. A high catalytic
efficiency was observed, particularly with iron tetrakis-
(pentafluorophenyl)porphyrin (F20TPPFe). However, given
the aim of the study, very few (specific) substrates were
1
the yields of sulfone, determined by GC or H NMR, are
only between 1% and 4%. More importantly, such small
amounts of sulfone did not cause significant problems in
preparative experiments, where high yields of pure
sulfoxide were obtained.
Going more into detail, it can be observed that in the
series of aryl methyl sulfides (Table 1, entries 1-4), high
yields of the sulfoxide are also found when the strong
electron-withdrawing group (EWG) CN is present in the
* Address correspondence to this author. Phone: +39-06-49913711.
Fax: +39-06-490421..
(1) However, there is a lively debate about the structure of the active
species in oxidation catalyzed by iron porphyrins. Another possibility
is that, when the oxidant is H2O2, the active species structure would
be P-Fe(III)-O-OH.2
(2) Wang, S. H.; Mandimutsira, B. S.; Todd, R.; Ramdhanie, B.; Fox,
J . P.; Goldberg, D. P. J . Am. Chem. Soc. 2004, 126, 18-19.
(3) Oae, S.; Watanabe, Y.; Fujimori, K. Tetrahedron Lett. 1982, 23,
1189-1192.
(4) (a) Baciocchi, E.; Lanzalunga, O.; Marconi, F. Tetrahedron Lett.
1994, 35, 9771-9774. (b) Baciocchi, E.; Lanzalunga, O.; Pirozzi, B.
Tetrahedron 1997, 53, 12287-12298. (c) Baciocchi, E.; Gerini, M. F.;
Lanzalunga, O.; Lapi, A.; Lo Piparo, M. G. Org. Biomol. Chem. 2003,
1, 422-426.
(5) (a) Marques, A.; Di Matteo, M.; Ruasse, M.-F. Can. J . Chem.
1998, 16, 770-775. (b) Marques, A.; Marin, M.; Ruasse, M.-F. J . Org.
Chem. 2001, 66, 7588-7595.
(6) Chu, J .-W.; Trou, B. L. J . Am. Chem. Soc. 2004, 126, 900-908.
(7) (a) Choi, S.; Yang, J .-D.; J i, M.; Choi, H.; Kee, M.; Ahn, K.-H.;
Byeon, S.-H.; Baik, W.; Koo, S. J . Org. Chem. 2001, 66, 8192-8198.
(b) Gelalcha, F. G.; Schulze, B. J . Org. Chem. 2002, 67, 8400-8406.
(c) Matteucci, M.; Bhalay, G.; Bradley, M. Org. Lett. 2003, 5, 235-
237. (d) Linde´n, A. A.; Kru¨ger, L.; Ba¨ckvall, J .-E. J . Org. Chem. 2003,
68, 5890-5896.
(8) Nam, W.; Oh, S.-Y.; Sun, Y. J .; Kim, J .; Kim, W.-K.; Woo, S. K.;
Shin, W. J . Org. Chem. 2003, 68, 7903-7906.
10.1021/jo049879h CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/20/2004
3586
J . Org. Chem. 2004, 69, 3586-3589

TABLE 1. Isola ted Yield s of Su lfoxid es in th e Oxid a tion
of Ar om a tic a n d Alip h a tic Su lfid es by H2O2 (1/1)
benzene ring (entry 2). However, passing from methyl
phenyl sulfide (entry 1) to phenyl trifluoromethyl sulfide
(entry 9), the sulfoxide yield significantly decreases.
Clearly, the catalytic activity of this system is strongly
reduced when the EWG is directly bonded to the sulfur
atom. However, it should be noted that a very good yield
of sulfoxide is obtained with monochloromethyl phenyl
sulfide (Table 1, entry 8). Interestingly, the reaction does
not appear to be significantly affected by steric effects
as comparable yields of sulfoxide are found with methyl
phenyl sulfide and tert-butyl phenyl sulfide (entries 1 and
5). The same behavior holds also with aliphatic sulfides
since yields around 90% of isolated product are obtained
with dibutyl sulfide, butyl tert-butyl sulfide, and bis(1-
methylpropyl) sulfide (Table 1, entries 15-17). Another
notation is that when other oxidizable groups (hydroxyl,
dimethylamino) are present in the substrate, these are
unaffected under the reaction conditions and the sulfox-
ide is the only reaction product (Table 1, entries 3, 4, 6,
7, and 18). Moreover, in the case of the â-hydroxy sulfide
reported in entry 7, a system that is very prone to
oxidative fragmentation,9 only sulfoxidation was found.
It should also be noted that no diastereoselectivity was
observed with this substrate.
Ca ta lyzed by F 20TP P F e in EtOH, a t Room Tem p er a tu r ea
Since there is considerable interest in the chemoselec-
tive sulfoxidation of sulfides containing double bonds,7
we tested our catalytic system also in the oxidation of
vinyl and allyl sulfides. As shown in Table 1 (entries 11-
14 and 19) high chemoselectivity was found in all cases,
as the sulfoxide was obtained in high yield without any
detectable epoxidation of the double bond. Particularly
remarkable in this respect is the oxidation of 1-phenyl-
2-(thiophenyl)ethene (mixture of E and Z isomers) where
a highly activated double bond is present (Table 1, entry
14).
Cyclic sulfides (Table 1, entries 20-22) are also ef-
ficiently sulfoxidated and it is interesting to note that
with 1,3-dithiane and 1,3-dithiolane exclusive monosul-
foxidation was observed (entries 21 and 22).
Few experiments were carried out with solvents dif-
ferent from ethanol. In MeOH and 3:1 MeOH/CH2Cl2 the
results were similar to those in EtOH, but the reaction
was much less efficient when the solvent was MeCN
(Table 1S, Supporting Information).
Finally, we also attempted sulfoxidation using
F20TPPFe covalently linked to silica gel.10 However, this
system, when tested with thioanisole, was unsatisfactory
since a drastic drop in sulfoxide yield (from 95% to 60%)
was observed when the catalyst was reused after the first
run. Probably, since the heterogeneous reaction is sig-
nificantly slower than the homogeneous one, the catalyst
is progressively destroyed in the oxidizing medium
(indeed, a bleaching is observed).
For the synthesis of sulfones it was considered of
interest to carry out several experiments with a 2:1 H2O2:
substrate molar ratio to check whether sulfones could be
efficiently obtained by using just a stoichiometric amount
of oxidant11 and whether also in this case the high
a
b
Reaction time ) 4 min. Yields of isolated product referred
to the initial amount of substrate. In parentheses are reported
the yields determined by GC and 1H NMR analysis on the crude
reaction mixture. Average of at least 2 determinations. The error
(9) Gravel, D.; Farmer, L.; Ayotte, C. Tetrahedron Lett. 1990, 31,
63-66.
is <(1%. c 4:1 mixture of the two diastereoisomers. Due to the
d
(10) Battioni, P.; Bartoli, J . F.; Mansuy, D.; Byun, Y. S.; Traylor, T.
G. Chem. Commun. 1992, 1051-1053.
low solubility of the substrate in EtOH, the reaction was carried
out in EtOH/CH2Cl2 1/1. e A Z/E 6/4 mixture. f Mixture of Z and
E sulfoxide.
(11) In the Ruasse’s works,5 oxidations were carried out with a 5:1
H2O2:substrate molar ratio.
J . Org. Chem, Vol. 69, No. 10, 2004 3587

aromatic and aliphatic sulfides.12 With only 1 equiv of
H2O2 and a very low concentration of catalyst (from
0.03% to 0.09% with respect to that of the substrate)
sulfoxides can be obtained in yields of isolated product
generally larger than 90% at room temperature in a very
short reaction time (4 min). The chemoselectivity is also
very high as sulfoxides are isolated as pure products
without any contamination by sulfones. Moreover, in sul-
fides containing a hydroxyl group or a double bond, sul-
foxidation to sulfoxide takes place in very high yield
without any formation of aldehydes (or ketones) or
epoxides, respectively.
TABLE 2. Isola ted Yield s of Su lfon es in th e Oxid a tion
of Ar om a tic Su lfid es by H2O2 (1/2) Ca ta lyzed by
F
20TP P F e in EtOH, a t Room Tem p er a tu r ea
By using just 2 equiv of H2O2, sulfones can be obtained
with almost quantitative yields of isolated products. The
chemoselectivity of this process is similar to that of the
synthesis of sulfoxides.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. See Supporting Information.
Gen er a l P r oced u r e for t h e Oxid a t ion of Su lfid es t o
Su lfoxid es. To a stirred solution of the sulfide (6.0 mmol) and
the catalyst F20TPPFe (0.03-0.09%) in ethanol (20 mL) at room
temperature was added in small amounts a solution of H2O2 (6.0
mmol) in ethanol with a syringe over 1 min. The resulting
mixture was stirred at room temperature for 3 min; after the
addition of sodium dithionite and then water, the mixture was
extracted with dichloromethane and the organic layers were
dried over Na2SO4 and filtered. The solvent was removed in
vacuo and the residue was chromatographed on silica gel to
afford the pure product.
a
b
Reaction time ) 15 min. Yields of isolated product re-
Gen er a l P r oced u r e for t h e Oxid a t ion of Su lfid es t o
Su lfon es. To a stirred solution of the sulfide (6.0 mmol) and
the catalyst F20TPPFe (0.09-0.25%) in ethanol (20 mL) at room
temperature was added in small amounts a solution of H2O2
(12.0 mmol) in ethanol with a syringe over 5 min. The resulting
mixture was stirred at room temperature for 10 min; after the
addition of sodium dithionite and then water, the mixture was
extracted with dichloromethane and the organic layers were
dried over Na2SO4 and filtered. The solvent was removed in
vacuo and the residue was chromatographed on silica gel to
afford the pure product.
Gen er a l P r oced u r e for t h e Oxid a t ion of 1,3-Dit h ia n e
a n d 1,3-Dith iola n e to th e Cor r esp on d in g 1,3-Disu lfoxid es.
To a stirred solution of the sulfide (6.0 mmol) and the catalyst
F20TPPFe (0.15%) in ethanol (20 mL) at room temperature was
added in small amounts a solution of H2O2 (12.0 mmol) in
ethanol with a syringe over 5 min. The resulting mixture was
stirred at room temperature for 10 min; after the addition of
sodium dithionite and then water, the mixture was extracted
with dichloromethane and the organic layers were dried over
Na2SO4 and filtered. The solvent was removed in vacuo and the
residue was chromatographed on silica gel to afford the pure
product.
ferred to the initial amount of substrate. In parentheses are
reported the yields determined by GC and 1H NMR analysis on
the crude reaction mixture. Average of at least 2 determinations.
The error is <(1%. c Due to the low solubility of the substrate in
d
EtOH, the reaction was carried out in EtOH/CH2Cl2 1/1. A Z/E
6/4 mixture.
chemoselectivity found in the synthesis of sulfoxides
could be observed. Indeed, it was found (Table 2) that
with 2 equiv of oxidant a very efficient synthesis of
sulfones is possible using a slightly higher concentration
of catalyst (0.09-0.25% with respect to that of the
substrate) and slightly longer reaction times (15 min)
than those used in the synthesis of sulfoxides. In all cases
the sulfones were isolated in almost quantitative yields.
The results displayed in Table 2 also show clearly that
these reactions exhibit a high chemoselectivity, with both
aromatic and aliphatic sulfides. Thus, sulfones can be
conveniently synthesized from sulfides containing an
hydroxyl group without any contamination by the cor-
responding aldehydes (Table 2, entries 1, 2, and 7). High
selectivity is also observed with allyl and vinyl sulfides.
Accordingly, sulfones are obtained in the oxidations
reported in entries 3-6 and 8 without any detectable
formation of the corresponding epoxides.
Finally, also 1,3-dithiane and 1,3-dithiolane were
reacted with 2 equiv of H2O2. In this case no sulfone was
obtained, but (as expected) we observed the exclusive
formation of the corresponding 1,3-disulfoxides (1,3-
dithiane-1,3-dioxide and 1,3-dithiolane-1,3-dioxide, re-
spectively), both in 70% yield.
In conclusion, the results reported in this paper clearly
indicate that F20TPPFe/H2O2 in EtOH is certainly one of
the best oxidizing systems for a mild, fast, and selective
catalytic laboratory synthesis of sulfoxides from both
The identity of the isolated products (sulfoxides, sulfones, or
disulfoxides) was established by comparing their spectral and
physical properties with those of commercial samples or with
those reported in the literature (details are in the Supporting
Information). The only exception was 4-methanesulfonylbenzyl
alcohol, which was identified on the basis of the melting point,
mp 82 °C (lit.13 mp 82-84 °C). For this compound the spectral
properties were as follows. MS (EI) m/z (rel intensity): 186 (M+,
(12) The numerous problems encountered in the sulfoxidation of
phenyl prenyl sulfide by a large variety of conventional oxidants have
been recently illustrated.7a The most selective conditions for sulfoxide
formation were H2O2/AcOH (90% yield in 24 h) and NaIO4/MeOH (82%
yield in 6 h), using in both cases 3 equiv of oxidant. Under our
conditions, the yield of isolated sulfoxide is 96% (Table 1, entry 12) in
4 min with only 1 equiv of oxidant. From the economical point of view,
our method is comparable to that where NaIO4 is used.
(13) Kidd, D. A. A.; Wright, D. E. J . Chem. Soc 1962, 1420-1427.
3588 J . Org. Chem., Vol. 69, No. 10, 2004

37%), 157 (100), 107 (67), 89 (58), 79 (40), 77 (62). 1H NMR
(CDCl3): δ 2.18 (s, OH), 3.04 (s, 3H), 4.80 (s, 2H), 7.54 (d, J )
8.8 Hz, 2H), 7.88 (d, J ) 8.5 Hz, 2H). 13C NMR (CDCl3): δ 44.5,
64.0, 127.2, 127.3, 139.2, 147.6.
Bou n d in g F 20TP P F e on Silica Gel. F20TPPFe was co-
valently linked to propylamino silica gel as reported in the
literature.10 This heterogeneous catalyst was tested in the
oxidation of thioanisole with H2O2. To a stirred solution of
thioanisole (6.0 mmol) and 100 mg of the catalyst (about 10%
vs the substrate) in EtOH (10 mL) at room temperature was
added a solution of H2O2 (12.0 mmol) in EtOH over a period of
5 min. The mixture was stirred for 30 min after which it was
filtered an washed three times with CH2Cl2. GC analysis showed
the formation of the corresponding sulfoxide (95%). The filtrated
catalyst was then reused, but a drop in efficiency was observed
(sulfoxide yield 60%).
Ack n ow led gm en t. The authors thank the Minis-
tero dell’Istruzione, dell’Universita` e della Ricerca (MIUR)
and the University “La Sapienza” for financial support.
Su p p or tin g In for m a tion Ava ila ble: Reaction yields of
sulfoxides in the oxidation of aromatic sulfides by H2O2
catalyzed by F20TPPFe in different solvents and experimental
details (General Methods and Materials). This material is
available free of charge via the Internet at http://pubs.acs.org.
J O049879H
J . Org. Chem, Vol. 69, No. 10, 2004 3589