First examples of oxidizing secondary alcohols to ketones in presence of the disulfide functional group: Synthesis of novel diketone disulfides

Article abstract of DOI:10.1021/jo0101813

The disulfide functionality is present in a number of organic compounds of interest in the fields of both chemistry and biology. Because the disulfide group is known to be highly susceptible to further oxidation by a wide range of agents, performing a chemoselective oxidation without further oxidizing the disulfide moiety poses a synthetic challenge. Reported herein are the first examples of such a chemoselective oxidation in which a series of novel secondary alcohol disulfides 2a-f have been converted to the corresponding symmetrical diketones 3a-f utilizing a modified Swern oxidation.

Full text of DOI:10.1021/jo0101813

J . Org. Chem. 2001, 66, 4019-4021
4019
F ir st Exa m p les of Oxid izin g Secon d a r y Alcoh ols to Keton es in th e
P r esen ce of th e Disu lfid e F u n ction a l Gr ou p : Syn th esis of Novel
Dik eton e Disu lfid es
Xinqin Fang,* Upul K. Bandarage, Tiansheng Wang, J oseph D. Schroeder, and
David S. Garvey
NitroMed, Inc., 12 Oak Park Drive, Bedford, Massachusetts 01730
ffang@nitromed.com
Received February 16, 2001
The disulfide functionality is present in a number of organic compounds of interest in the fields of
both chemistry and biology. Because the disulfide group is known to be highly susceptible to further
oxidation by a wide range of agents, performing a chemoselective oxidation without further oxidizing
the disulfide moiety poses a synthetic challenge. Reported herein are the first examples of such a
chemoselective oxidation in which a series of novel secondary alcohol disulfides 2a -f have been
converted to the corresponding symmetrical diketones 3a -f utilizing a modified Swern oxidation.
In tr od u ction
sponding ketones in the presence of the disulfide func-
tional group, and we wish to report our results herein.
Organic disulfides are a class of compounds of wide-
spread occurrence in biological systems. The disulfide
functional group (-SS-) exists not only in proteins but
also in numerous natural products. Notable examples of
natural disulfides of pharmacological interest include
thiocoraline,1a BE-22179,1b triostin A,1c echinomycin,1d the
thiarubrines,1e,1f and related 1,2-dithiin-type antibiotic
pigments.1g In the synthetic transformations of organic
disulfides, it may be desirable to perform an oxidation
reaction on a particular functional group without dis-
turbing the disulfide moiety. However, the realization of
this type of chemoselective oxidation may present a
challenge because organic disulfides are highly suscep-
tible toward further oxidation. Indeed, it has been well
documented that organic disulfides can be readily oxi-
dized by a broad range of agents to produce thiosulfi-
nates, thiosulfonates, sulfonic acids, and a variety of
other products.2a-j We have recently investigated the
feasibility of oxidizing secondary alcohols into the corre-
Resu lts a n d Discu ssion
During the course of our drug-discovery research,
diketone disulfides 3a -f (see Table 1) were desired as
versatile synthetic intermediates. Our general approach
to these compounds is outlined in Scheme 1. The first
step was the preparation of dialdehyde disulfides (1a -
d ) from their monoaldehyde precursors. Disulfides 1a -c
were prepared by using the published procedures,3a-c and
the new compound 1d was obtained by treatment of
diphenylacetaldehyde with S2Cl2 in CCl4. The second step
was the conversion of dialdehyde disulfides 1a -d into
diols 2a -f via a Grignard reaction with methylmagne-
sium bromide, vinylmagnesium bromide, or phenylmag-
nesium chloride. It is noteworthy that Grignard reagents
are known to cleave the S-S bond in organic disulfides
to give the corresponding thioethers and thiols.4 To
minimize this side reaction and to maximize the yields
of diol disulfides 2a -f, we have taken the following
measures: (1) nearly a stoichiometric quantity of the
Grignard reagent was used and added dropwise to the
stirred solution of the dialdehyde disulfide 1; (2) RMgCl
or RMgBr was the choice of reagents, because they
consistently gave higher yields of 2 than did RMgI; (3)
tert-butyl methyl ether was found to be a more appropri-
ate reaction solvent relative to tetrahydrofuran in some
cases in terms of the yield of the desired product (see the
Supporting Information). Gratifyingly, moderate to good
yields (61-89%) of diols 2a -f were produced under those
* To whom correspondence should be addressed. Phone:
(781) 685-9726. Fax (781) 275-1127.
(1) (a) Perez Baz, J .; Canedo, L. M.; Fernandez-Puentes, J . L. J .
Antibiot. 1997, 50, 738. (b) Okada, H.; Suzuki, H.; Yoshinari, T.;
Arakawa, H.; Okura, A.; Suda, H. J . Antibiot. 1994, 47, 129. (c) Otsuka,
H.; Shoji, J .; Kawano, K.; Kyogoku, Y. J . Antibiot. 1976, 29, 107. (d)
Martin, D. G.; Mizsak, S. A.; Biles, C.; Stewart, J . C.; Baczynskyj, L.;
Meulman, P. A. J . Antibiot. 1975, 28, 332. (e) Norton, R. A.; Finlayson,
A. J .; Towers, G. H. N. Phytochemistry 1985, 24, 356. (f) Freeman, F.;
Aregullin, M.; Rodriguez, E. Rev. Heteroat. Chem. 1993, 9, 1. (g) Block,
E.; Birringer, M.; DeOrazio, R.; Fabian, J .; Glass, R. S.; Guo, C.; He,
C.; Lorance, E.; Qian, Q.; Schroeder, T. B.; Shan, Z.; Thiruvazhi, M.;
Wilson, G. S.; Zhang X. J . Am. Chem. Soc. 2000, 122, 5052-5064 and
references therein.
(2) (a) Oae, S. Organic Sulfur Chemistry: Structure and Mechanism;
CRC Press: Boca Raton, FL, 1991; Vol.1, Chapter 4. (b) Bhattacharya,
A. K.; Hortman, A. G. J . Org. Chem. 1978, 43, 2728. (c) Allen, P., J r.;
Brook, J . W. J . Org. Chem. 1962, 27, 1019. (d) Gu, D.; Harpp, D. N.
Tetrahedron Lett. 1993, 34, 67. (e) Folkins, P. L.; Harpp, D. N. J . Am.
Chem. Soc. 1993, 115, 3066. (f) Freeman, F. Chem. Rev. 1984, 84, 117-
135. (g) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J .; Ellman, J . A. J .
Am. Chem. Soc. 1998, 120, 8011. (h) Trost, B. M. Chem. Rev. 1978,
78, 8. (i) Benassi, R.; Fiandri, L. G.; Taddei, F. J . Org. Chem. 1997,
62, 8018-8023 and references therein. (j) Field, L. In Organic
Chemistry of Sulfur; Oae, S., Ed.; Plenum Press: New York and
London, 1977; pp 303-382.
(3) (a) Stec, W. J .; Karwowski, B.; Boczkowska, M.; Guga, P.;
Koziolkiewicz, M.; Sochacki, M.; Roy, B.; du Moulinet d’Hardemare,
A.; Fontecave, M. J . Org. Chem. 1994, 59, 7019. (b) Wieczorek, M. W.;
Blaszyk, J . J . Am. Chem. Soc. 1998, 120, 7156. (c) Bandarage, U. K.;
Chen, L.; Fang, X.; Garvey, D. S.; Glavin, A.; J anero, D. R.; Letts, L.
G.; Mercer, G. J .; Saha, J . K.; Schroeder, J . D.; Shumway, M. J .; Tam,
S. W. J . Med. Chem. 2000, 43, 4005.
(4) (a) Smith, M. B.; March, J . March’s Advanced Organic Chemistry,
5th ed.; J ohn Wiley & Sons: New York, 2001; pp 797-798 and
references therein. (b) Li, X.; Xie, R. Tetrahedron: Asymmetry 1997, 8,
2283-2285.
10.1021/jo0101813 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/21/2001

4020 J . Org. Chem., Vol. 66, No. 11, 2001
Ta ble 1. Sta r tin g Ma ter ia l, In ter m ed ia tes, a n d P r od u cts
Fang et al.
pyridinium dichromate,5a,b and tetrapropylammonium
perruthenate/N-methylmorpholine N-oxide,5c,5d using 2a
as the test substrate. However, treatment of 2a with
these oxidants under standard conditions5 resulted in a
complex mixture, which was not synthetically useful.
Next, we focused on the use of activated dimethyl
sulfoxide-based methods,6 such as the Swern oxidation.
Since it was known that DMSO was capable of oxidizing
thiols to disulfides without overoxidation,7 we anticipated
that the disulfide function would tolerate activated
DMSO.
Sch em e 1a
In the first runs of Swern oxidation with substrate 2a ,
we initially adopted the standard protocol,8 which recom-
mends that once the addition of triethylamine is com-
plete, the reaction mixture is allowed to warm from -78
to 0 °C or room temperature, prior to quenching with
water. Although this procedure led to complete conver-
sion of the substrate and did furnish the desired product
3a (ca. 60% yield), it also generated a significant amount
a
See Table 1 for the identities of R1 and R2.
carefully controlled conditions despite the reported vul-
nerability of the S-S bond to attack by Grignard rea-
gents. Diols 2a -f thus obtained existed as an inseparable
mixture of two diastereomers. However, the formation
of diastereomeric diols was inconsequential since the two
diastereomers would be converted to the same diketone-
disulfide after the ensuing oxidation step.
For the conversion of 2a -f to 3a -f, we needed a
method that would be capable of oxidizing secondary
alcohols to ketones while leaving the disulfide function
intact. To the best of our knowledge, there have been no
such literature examples reported to date. We felt that
this lack of precedent would thus require a judicious
choice of appropriate oxidant as well as reaction condi-
tions. We first examined some mild transition metal
oxidizing agents, such as pyridinium chlorochromate,5a,b
(5) (a) Corey, E. J .; Schmidt, G. Tetrahedron Lett. 1979, 20, 399-
402. (b) Corey, E. J .; Suggs, J . W. Tetrahedron Lett. 1975, 16, 2647-
2650. (c) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J .
Chem. Soc., Chem. Commun. 1987, 1625-1627. (d) Ley, S. V.; Norman,
J .; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639.
(6) Tidwell, T. T. Synthesis 1990, 857.
(7) (a) Yiannios, C. N.; Karabinos, J . V. J . Org. Chem. 1963, 28,
3246. (b) Wallace, T. J .; Mahon, J . J . J . Org. Chem. 1965, 30, 1502.
(8) (a) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480-2482. (b) Mancuso, A. J .; Swern, D. Synthesis 1981, 165-
185. (c) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651-1660. (d)
Mancuso, A. J .; Brownfain, D. S.; Swern, D. J . Org. Chem. 1979, 44,
4148-4150.

Synthesis of Novel Diketone Disulfides
J . Org. Chem., Vol. 66, No. 11, 2001 4021
solid (23.9 g, 83%): mp 95-96 °C; 1H NMR δ 9.20 (s, 2 H),
7.4-7.2 (m, 20 H); 13C NMR δ 190.8, 136.1, 129.8, 128.7, 128.6,
72.8; LRMS (APTIS) m/z 472 [(M + NH4)+]. Anal. Calcd for
of cyclohexyl methyl ketone. After some experimentation,
we discovered that the yield of 3a could be greatly
enhanced if the reaction was quenched with water at low
temperature. Thus, after addition of NEt3, the reaction
was maintained at -78 °C for 2 h to ensure complete
consumption of the substrate, and then a mixture of
water and THF was added dropwise while maintaining
the temperature of the reaction below -60 °C. This
simple yet important modification provided the desired
product 3a in excellent yield (96%). This modified pro-
cedure of Swern oxidation has also been utilized in the
conversion of diols 2b, 2c, and 2e into diketone disulfides
3b, 3c, and 3e in 81-98% yields. On the other hand, the
conventional Swern oxidation protocol was also found to
be appropriate for the conversion of diols 2d and 2f to
the corresponding diketones 3d and 3f.
In conclusion, diketone disulfides (3a -f) have been
synthesized from dialdehyde disulfides (1a -d ) through
a carefully controlled Grignard reaction, followed by a
Swern oxidation. This work has established the first
examples of oxidizing secondary alcohols into the corre-
sponding ketones without detriment to the disulfide
functional group. This information should be useful in
the synthetic transformations of organic disulfides, which
constitute an important class of compounds in both
chemistry and biology.
C
28H22O2S2: C, 73.98; H, 4.88; S, 14.11. Found: C, 73.77; H,
5.02; S, 14.18.
1-[[[(Hyd r oxyeth yl)cycloh exyl]d isu lfa n yl]cycloh exyl]-
eth a n -1-ol (2a ). To a stirred solution of dialdehyde disulfide
1a (12.5 g, 43.7 mmol) in THF (200 mL) at 0 °C under a
nitrogen atmosphere was added methylmagnesium bromide
(1.4 M in THF/toluene, 63 mL, 88 mmol) dropwise over a
period of 30 min. After the addition, the mixture was stirred
at 0 °C for an additional 15 min, quenched by 2 M aqueous
HCl (80 mL), and extracted with EtOAc. The combined organic
extracts were dried over Na2SO4, filtered, concentrated on a
rotary evaporator. The resulting oil was purified by flash
chromatography (silica gel, 2:1 CH2Cl2/EtOAc) to afford the
desired diol disulfide (a mixture of two diastereomers, 12.3 g,
88%) as a white foam: 1H NMR δ 3.9-3.7 (m, 2 H), 2.18 (br,
2 H), 1.9-1.5 (m, 20 H), 1.3-1.2 (2 doublets, J ) 6.3 Hz for
both, 6H); 13C NMR δ 72.4, 72.2, 60.5, 60.3, 31.2, 30.8, 30.1,
29.6, 25.9, 25.8, 21.95, 21.92, 21.82, 21.76, 17.1, 17.0; LRMS
(APTIS) m/z 319.2 [(M + H)+]. Anal. Calcd for C16H30O2S2: C,
66.33; H, 9.49; S, 20.13. Found: C, 66.48; H, 9.55; S, 20.11.
1-[[(Acet ylcycloh exyl)d isu lfa n yl]cycloh exyl]et h a n -1-
on e (3a ). Th e Mod ified Sw er n Oxid a tion P r oced u r e. To
a stirred solution of oxalyl chloride (12.6 mL, 144 mmol) in
CH2Cl2 (150 mL) at -78 °C under a nitrogen atmosphere was
added dimethyl sulfoxide (20.5 mL, 289 mmol, in 20 mL of
CH2Cl2) dropwise over a period of 20 min. After 15 min, the
diol disulfide 2a (15.3 g, 48.0 mmol) in CH2Cl2 (60 mL) was
added dropwise over 30 min, and the dropping funnel was
rinsed with 5 mL of CH2Cl2. The mixture was stirred at -78
°C for 90 min. Triethylamine (50 mL, 360 mmol) was added
dropwise over 15 min, and the stirred mixture was maintained
at -78 °C for 2 h. Aqueous THF (100 mL, 1:1 H2O/THF) was
added at such a rate that the internal temperature was kept
below -60 °C while the reaction mixture was agitated vigor-
ously. Upon complete addition, the dry ice-acetone bath was
removed, and the stirred mixture was allowed to warm to 0
°C. The mixture was then taken up with additional CH2Cl2,
washed with 2 M aqueous HCl, dried over Na2SO4, filtered,
and concentrated under reduced pressure to give a foam.
Crystallization from CH2Cl2/hexanes (1:1) afforded the desired
diketone disulfide 3a (14.5 g, 96%) as a white crystalline
Exp er im en ta l Section
Melting points are uncorrected. 1H and 13C NMR spectra,
taken in CDCl3, were recorded at 300 and 75 MHz, respec-
tively. Low-resolution mass spectra were obtained using
atmospheric pressure-turbo ion spray ionization. High-resolu-
tion mass spectra were obtained from the Auburn Mass
Spectra Center, Auburn, AL. Elemental analyses were per-
formed by Robertson Microlit Laboratories, Inc., Madison, NJ .
Triethylamine was purified by distillation over CaH2 prior to
use. All other commercial reagents and anhydrous solvents
were used as received. Dialdehyde-disulfides 1a -c were
synthesized according to the literature procedures.3a-c
2-[(2-Oxo-1,1-d ip h en ylet h yl)d isu lfa n yl]-2,2-d ip h en yl-
eth a n a l (1d ). A stirred solution of diphenylacetaldehyde (25.0
g, 127 mmol) and S2Cl2 (5.10 mL, 64 mmol) in CCl4 (30 mL)
was heated to 40 °C. After 5 min, the formation of HCl gas
started. The reaction mixture was stirred at the same tem-
perature for 2 h, and TLC indicated the complete conversion
of the substrate. The solvent was evaporated; the residue was
dissolved in EtOAc and washed with 1 M aqueous K2CO3 and
brine. The organic layer was dried over Na2SO4, filtered, and
concentrated to give a solid. Recrystallization from CH2Cl2/
hexanes (1:4) afforded the title compound as a white crystalline
1
solid: mp 80-81 °C; H NMR δ 2.25 (s, 6 H), 2.1-2.0 (m, 4
H), 1.7-1.3 (m, 16 H); 13C NMR δ 204.6, 61.7, 32.4, 25.0, 24.5,
23.0; LRMS (APTIS) m/z 315 [(M + H)+]. Anal. Calcd for
C
16H26O2S2: C, 61.10; H, 8.33; S, 20.39. Found: C, 61.22; H,
8.18; S, 20.42.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 1d , 2a -f, and 3a -f. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O0101813