Catalytic enantioselective oxidation of sulfides and disulfides by a chiral complex of bis-hydroxamic acid and molybdenum

Article abstract of DOI:10.1016/j.tetasy.2005.12.031

A chiral bis-hydroxamic acid (BHA)-molybdenum complex was used for the catalytic asymmetric oxidation of sulfides and disulfides utilizing one equivalent of alkyl peroxide with yields up to 83% and ee up to 86%. An extension of our methodology combines the asymmetric oxidation with kinetic resolution providing excellent enantioselectivity (ee 92-99%).

Full text of DOI:10.1016/j.tetasy.2005.12.031

Tetrahedron: Asymmetry 17 (2006) 508–511
Catalytic enantioselective oxidation of sulfides and disulfides by
a chiral complex of bis-hydroxamic acid and molybdenum
Arindrajit Basak, Allan U. Barlan and Hisashi Yamamoto*
Department of Chemistry, University of Chicago, 5735 South Ellis Avenue, Chicago, IL 60637, USA
Received 14 November 2005; accepted 29 December 2005
Available online 20 February 2006
This work is dedicated to Jack Halpern on the occasion of his 80th birthday and his wonderful contributions to organic chemistry
Abstract—A chiral bis-hydroxamic acid (BHA)-molybdenum complex was used for the catalytic asymmetric oxidation of sulfides
and disulfides utilizing one equivalent of alkyl peroxide with yields up to 83% and ee up to 86%. An extension of our methodology
combines the asymmetric oxidation with kinetic resolution providing excellent enantioselectivity (ee 92–99%).
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
To this end, direct asymmetric oxidation of pro-chiral
sulfides is the most convenient and straightforward
method. However, to date, the application of molybde-
num as a catalyst for the asymmetric oxidation of sulfide
remains under-explored.7 Herein, we report the first suc-
cessful catalytic asymmetric oxidation of sulfides and
disulfides utilizing a catalytic amount of a chiral molyb-
denum complex in the presence of an achiral oxidant
under mild conditions (Scheme 1, Eq. 1).
Metal catalyzed asymmetric oxidation of sulfides, a
powerful strategy for the rapid preparation of enantio-
pure sulfoxides, has garnered extensive attention from
the synthetic community. Of particular value are those
compounds which contain chiral sulfoxides, a structural
class widely utilized in both the pharmaceutical industry
and academia.1 Although a number of methods for
achieving high enantioselectivity during sulfide oxida-
tion have emerged in the recent years, most notably
the tri-coordinated vanadium catalyst system,2,11 man-
ganese,3 iron-catalyzed oxidation,4 and titanium-based
reagents;5 low enantioselectivity and restrictive struc-
tural requirements are still serious obstacles for this
transformation.1
MoO2(acac)2(2 mol%)
R1
R2
R1
R2
S
(1)
S
2, THP
O
R2
R2
O
Vanadium (1 mol%)
R1
OH
R1
OH
(2)
1, aqueous TBHP
Specifically, the most extensively studied titanium
reagents (1) often require an inert atmosphere and suffi-
cient quantity of molecular sieves; (2) need an exact
amount of water (or alcohol) to generate the active cat-
alyst, and (3) demand high catalyst loading for conver-
sion.1,5 As an alternative, an indirect multi-step route
to access these molecules has also been developed
employing nucleophillic substitution of a chiral sulfinyl
derivative with an organometallic reagent. This method,
however, is limited by the availability of the appropriate
intermediates.6
R3
R3
CHPh2
OH
O
O
CR3
N
N
OH
2a, R = phenyl
2b, R = 4-isopropylphenyl
1
OH
OH
N
N
CR3
O
O
CHPh2
Scheme 1.
2. Results and discussion
*
Our continuous research in the area of asymmetric oxi-
dation revealed that the vanadium complex of the
Corresponding author. Tel.: +1 773 702 5059; fax: +1 773 702
0805; e-mail: yamamoto@uchicago.edu
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.12.031

A. Basak et al. / Tetrahedron: Asymmetry 17 (2006) 508–511
509
hydroxamic acid efficiently oxidizes allylic and homo-
allylic alcohols.8 More recently, we also reported a
vanadium-bis-hydroxamic acid catalyst system, which
induces excellent enantioselectivities during oxidation
of both cis-substituted and trans-substituted allylic
alcohols (Scheme 1, Eq. 2).9a The preparation of these
bis-hydroxamic acids has been described earlier.9b
estingly, the molybdenum complex of 2a also provided
higher enantioselectivity (ee 54%). At this stage, an
array of ligands, reaction conditions and oxidants were
surveyed. We found that 2 mol % molybdenum catalyst
in the presence of trityl hydroperoxide (THP) is optimal
for the high enantioselectivity (entry 3). Cumene hydro-
peroxide (CHP) also provided good enantioselectivity
(entry 2) under similar reaction conditions. The highest
enantioselectivity was obtained when the bulkier BHA
2b was utilized. To determine the general scope of the
sulfide oxidation, a number of substrates with differing
substitution patterns were tested under the optimized
conditions; the results of which are summarized in Table
1. It is important to note that, isopropyl phenyl sulfide
3e, which usually provides relatively low enantioselectiv-
ity,1a,2d also provided good selectivity (entry 8) and the
(R)-configuration due to the steric hindrance of the
isopropyl group. The oxidation of dialkyl sulfides such
as cyclohexyl methyl sulfide, however, exhibited low
selectivity, ee 20%. Efforts are being focused to optimize
the catalyst system for dialkyl sulfides.
To evaluate the general applicability of BHA as a ligand
for asymmetric synthesis, the oxidation of various sul-
fides was explored. Thus, methyl phenyl sulfide 3a was
treated with the vanadium-1 complex (and vanadium-
2a complex) at 0 °C for 17 h affording the desired sulfox-
ide 4a in a modest yield (17% and 20%, respectively)
with moderate enantioselectivity (ee 30% and 47%,
respectively). Despite the inefficiency of the oxidation,
we were encouraged by the selectivity and decided to
survey other metal complexes for the oxidation. Reason-
ing that a dioxo-molybdenum complex of the bis-
hydroxamic acid would be a stronger oxidizing agent,7a
we opted to study the oxidation of 3a under these new
conditions.10 As expected, the modified catalyst
produced methyl phenyl sulfide 4a in a significantly
improved yield (77%) after 17 h (Table 1, entry 1). Inter-
High enantioselectivity during sulfide oxidation is often
due to kinetic resolution of the newly formed sulfoxides
Table 1. Asymmetric oxidation of sulfides 3a
2, MoO2(acac)2
R1
R2
R1
R2
S
S
THP, CH2Cl2
O
3
4
Entry
Sulfide
Ligand
Time (h)
Yieldb (%)
ee (%),c configd
1
2
3
4
2ae
2af
2a
17
26
20
16
77
89
83
81
54 (S)
65 (S)
68 (S)
79 (S)
S
CH3
S
3a
2b
CH3
5
6
3b
3c
2b
2b
20
19
75
76
81 (S)
75 (S)
S
S
CH3
7
8
3d
3e
2b
2b
18
24
81
66
82 (S)
62 (R)
S
S
CH3
9
3f
2b
17
82
86 (S)
S
CH3
10
3g
2b
19
83
72 (S)
a All reactions were carried out in CH2Cl2 in the presence of 1.0 equiv of THP and 2 mol % of molybdenum catalyst at 0 °C, unless otherwise
indicated.
b Isolated yield after chromatographic purification.
c Ee values were determined by chiral HPLC.
d Configurations determined by comparison of specific rotation to literature.
e 1.0 equiv TBHP.
f 1.0 equiv CHP.

510
A. Basak et al. / Tetrahedron: Asymmetry 17 (2006) 508–511
by generating a significant amount of sulfones.2–6,11
However, by employing the molybdenum-2b catalyst
in the presence of 1.0 equiv of THP, it did not produce
any sulfone. A key question was raised by this result
as to whether our catalyst was capable of performing
selective oxidation of one of the enantiomer of a racemic
mixture of sulfoxides. Thus, we decided to explore
oxidations of sulfoxides (Scheme 2). We found that the
oxidation of phenyl methyl sulfoxide 4a was slow, but
molybdenum-2b complex selectively oxidized one of
the enantiomers. We were pleased to find that the (R)-
isomer of 4a, which the minor isomer produced during
oxidation of 3a, was oxidized in a faster rate.
2b, MoO2(acac)2
S
S
S
S
THP (1 equiv), CH2Cl2
(79%, 90% ee)
O
6
7
Scheme 3.
important to note here that pre-distillation of the disul-
fide is not necessary to achieve high enantioselectivity.12
3. Conclusion
In conclusion, this work represents the first successful
application of the molybdenum catalyzed asymmetric
oxidation of sulfides and disulfides. These mild oxidizing
conditions provides moderate to good enantioselectivity
for the isolated sulfoxides. A kinetic resolution was
further developed to enrich the enantioselectivity
of sulfoxides.
2b, MoO2(acac)2
Ph
CH3
Ph
CH3 Ph
+
CH3
S
S
S
THP, CH2Cl2
O
O
O
O
4a (Racemic)
4a*
5
0 oC, 41 h
rt, 24 h
45 (75% ee) :
46 (68% ee) :
55
54
Scheme 2.
Acknowledgements
In the next stage, the scope of the asymmetric oxidation
followed by kinetic resolution was examined. The results
of this study are listed in Table 2. Both oxidants CHP
and THP provided excellent selectivity during the pro-
cess (ee 92–99%). The key feature of our catalyst is that
after the initial oxidation of sulfides to sulfoxides the
extent of kinetic resolution can be controlled by choos-
ing the oxidant and also its amount. This absolute
control of the asymmetric oxidation and kinetic resolu-
tion makes our process more attractive than other
available methods.
Support for this research was provided by SORST pro-
ject of the Japan Science and Technology Agency (JST)
and GAANN.
References
1. For recent reviews see: (a) Fernandez, I.; Khiar, N. Chem.
Rev. 2003, 103, 3651–3705; (b) Volcho, K. P.; Kurbakova,
S. Y.; Korchagina, D. V.; Suslov, E. V.; Salakhutdinov, N.
F.; Toktarev, A. V.; Echevskii, G. V.; Barkhash, V. A.
J. Mol. Cat. A: Chem. 2003, 195, 263–274; (c) Compre-
hensive Asymmetric Catalysis I–III; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
(d) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-
VCH: New York, 2000; pp 327–356; (e) Modern Oxidation
Methods; Backvall, J.-E., Ed.; Wiley-VCH: Weinheim,
2004.
2. (a) Blum, S. A.; Bergman, R. G.; Ellmann, J. A. J. Org.
Chem. 2003, 68, 150–155; (b) Vetter, A.; Berkessel, A.
Tetrahedron Lett. 1998, 39, 1741–1744; (c) Drago, C.;
Caggiano, L.; Jackson, R. F. W. Angew. Chem., Int. Ed.
2005, 44, 7221–7223; (d) Bolm, C.; Bienewald, F. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2640.
3. Palucke, M.; Hanson, P.; Jacobson, E. N. Tetrahedron
Lett. 1992, 33, 7111–7114, See references cited therein.
4. (a) Legros, J.; Bolm, C. Angew. Chem., Int. Ed. 2004, 43,
4225–4228; (b) Legros, J.; Bolm, C. Chem. Eur. J. 2005,
11, 1086–1092, See references cited therein.
5. (a) Massa, A.; Francesca, R.; Siniscalchi, R.; Bugagtti, V.;
Lattanzi, A.; Scettri, A. Tetrahedron: Asymmetry 2002, 13,
1277–1283, See references cited therein; (b) See Ref. 1.
6. Capozzi, M. A. M.; Cardellicchio, C.; Naso, F.; Torto-
rella, P. J. Org. Chem. 2000, 65, 2843–2846.
Table 2. Asymmetric oxidation with kinetic resolutiona
Entry Sulfide Oxidant Sulfoxide: Yieldb (%) ee (%),c
Sulfone
config
1
2
3
4
3a
3b
3d
3g
THPd
CHPe
81:19
49:51
68
43
92 (S)
96 (S)
THP
CHPe
74:26
46:54
55
37
94 (S)
95 (S)
THP
CHPf
72:28
32:68
51
31
96 (S)
97 (S)
THP
CHPe
76:24
50:50
50
47
93 (S)
99 (S)
a All reactions were carried out in CH2Cl2 in the presence of 1.5 equiv
of THP and 2 mol % of molybdenum-2b catalyst at À40 °C, 19 h then
0 °C, 24 h unless otherwise indicated.
b Isolated yield of sulfoxide after chromatographic purification.
c Ee values were determined by chiral HPLC.
d
À40 °C, 44 h then 0 °C, 47 h.
e 1.55 equiv CHP.
f 1.75 equiv CHP.
7. (a) Bortolini, O.; Campestrini, S.; Furia, F. D.; Modena,
G. J. Org. Chem. 1987, 52, 5093–5095; (b) See reviews in
Ref. 1 and other references are cited therein; (c) Schurig,
V.; Hinzer, K.; Layer, A.; Mark, C. J. Organmet. Chem.
1989, 370, 81; (d) Ambroziak, K.; Peloch, R.; Milchert, E.;
Dziemboska, T.; Rozwadowski, Z. J. Mol. Cat. A: Chem.
2004, 211, 9–16; (e) Masteri-Farahani, M.; Farzaneh, F.;
Finally, to study whether the substrate scope could be
extended beyond sulfides; 2-tert-butyldisulfanyl-2-methyl-
propane, 6, was subjected to the same reaction condi-
tions (Scheme 3).12 Gratifyingly, simple aqueous work
up followed by chromatographic separation provided a
high yield of 7 with excellent selectivity (ee 90%). It is

A. Basak et al. / Tetrahedron: Asymmetry 17 (2006) 508–511
511
Ghandhi, M. J. Mol. Cat A: Chem. 2003, 192, 103–111; (f)
Kotov, S. V.; Kolev, T. M.; Georgrieva, M. G. J. Mol.
Cat. A: Chem. 2003, 195, 83–94; (g) Wahl, G.; Sunder-
meyer, J. Chem. Eur. J. 1999, 5, 3230; (h) Winter, W.;
Mark, C.; Shurig, V. Inorg. Chem. 1980, 19, 2045–2048; (i)
Bonchio, M.; Carofiglio, T.; Di Furia, F.; Fornasier, R. J.
Org. Chem. 1995, 60, 5986–5988; (j) Batigalhia, F.; zaldin-
Hernandez, M.; Ferreira, A. G.; Malvestiti, I.; Cass, Q. B.
Tetrahedron 2001, 57, 9669–9676.
FTIR (film) tmax 3126, 2958, 2870, 1616, 1507, 1457, 1418,
1240, 1173, 1057, 1019, 910, 828, 734, 584 cmÀ1; 1H NMR
(400 MHz, CDCl3) d 8.40 (s, 2 H), 7.14 (d, J = 7.5 Hz,
12H), 6.97 (d, J = 7.5 Hz, 12H), 4.07 (br d, J = 14.5 Hz,
2H), 3.80–3.78 (br m, 2H), 3.59 (br d, J = 14.5 Hz, 2H),
2.85–2.79 (m, 6H), 1.54–1.50 (m, 2H), 1.29–1.15 (m, 40H),
0.95–0.91 (m, 2H); 13C NMR (125 MHz, CDCl3) d 173.6,
146.3, 144.9, 129.6, 125.7, 55.8, 55.0, 42.2, 33.7, 27.4, 24.5,
24.3, 24.1.
8. (a) Hoshino, Y.; Yamamoto, H. J. Org. Chem. 2000, 122,
10452–10453; (b) Hoshino, Y.; Murase, N.; Oishi, M.;
Yamamoto, H. Bull. Chem. Soc. Jpn. 2000, 73, 1653–1658;
(c) Hoshino, Y.; Yamamoto, H. J. Am. Chem. Soc. 2000,
122, 10452–10453.
10. Typical procedure for oxidation of sulfide: To a solution of
BHA (0.03 mmol) in dichloromethane (3 mL) was added
MoO2(acac)2 (5 mg, 0.015 mmol), and the mixture stirred
for 1 h at room temperature. The resulting solution was
cooled to 0 °C, and then sulfide (0.75 mmol), and THP
(207 mg, 0.75 mmol) were added and stirring continued in
air at the same temperature for several hours. The
oxidation process was monitored by TLC. Saturated
aqueous Na2SO3 was added, and the mixture was stirred
for 30 min at 0 °C. The mixture was then allowed to warm
to room temperature, extracted with CH2Cl2, dried over
Na2SO4 and concentrated under reduced pressure. The
remaining residue was purified by flash column chromato-
graphy on silica gel to provide the sulfoxide.
9. (a) Zhang, W.; Basak, A.; Kosugi, Y.; Hoshino, Y.;
Yamamoto, H. Angew. Chem., Int. Ed. 2005, 44, 4389; (b)
General procedure for preparation of bis-hydroxamic acids:
To a stirred solution of 6 (1 mmol) and DIEA (1.04 mL,
6 mmol) in CH2Cl2 (20 mL) was added acid chloride
(3 mmol, dissolved in 5 mL CH2Cl2) under nitrogen. After
24–72 h, the reaction mixture was treated with 3 M HCl
(or 1 M HCl/MeOH). After stirring for 30 min the
reaction mixture was extracted with CH2Cl2, washed with
brine, dried over Na2SO4 and filtered. The filtrate was
concentrated under reduced pressure and the residue was
purified by flash column chromatography on silica gel 60
extra pure to provide the bis-hydroxamic acid. Compound
2b: Yield 64%, solid; Rf = 0.62 (EtOAc/hexanes, 1:3);
11. Sun, J.; Zhu, C.; Dai, Z.; Yang, M.; Pan, Y.; Hu, H. J.
Org. Chem. 2004, 69, 8500–8503.
12. Cogan, D. A.; Liu, G. C.; Kim, K. J.; Backes, B. J.;
Ellmann, J. A. J. Am. Chem. Soc. 1998, 120, 8011–
8019.