First examples of oxidizing aldehydes to carboxylic acids in the presence of a tertiary disulfide functional group: Synthesis of novel diacid-disulfides

Article abstract of DOI:10.1055/s-2003-37518

The disulfide functionality exists in numerous organic compounds of interest in both chemistry and biology. In view of the fact that the disulfide function is highly susceptible to further oxidation by a broad range of agents, conducting a chemoselective

Full text of DOI:10.1055/s-2003-37518

LETTER
489
First Examples of Oxidizing Aldehydes to Carboxylic Acids in the Presence of
a Tertiary Disulfide Functional Group: Synthesis of Novel Diacid-disulfides
S
X
ynthesis of
N
ove
i
l
D
iacid
n
-disulfides qin Fang,* Upul K. Bandarage, Tiansheng Wang, Joseph D. Schroeder, David S. Garvey
NitroMed, Inc., 12 Oak Park Drive, Bedford, Massachusetts 01730, USA
Fax +1(781)2751127; E-mail: ffang@nitromed.com
Received 20 January 2003
was the preparation of dialdehyde-disulfides 1a–e by re-
Abstract: The disulfide functionality exists in numerous organic
compounds of interest in both chemistry and biology. In view of
the fact that the disulfide function is highly susceptible to further
4
action of their monoaldehyde precursors with S Cl .
2
2
Compounds 1a-d were prepared in a single step from the
oxidation by a broad range of agents, conducting a chemoselective commercially available monoaldehyde precursors using
oxidation without further oxidizing the disulfide group poses a syn- the published methods.4 The corresponding monoalde-
a–d
thetic challenge. Disclosed herein are the first examples of such an
oxidation in which a series of aldehyde disulfides (1a–e) were con-
verted to the corresponding symmetrical carboxylic acid disulfides
hyde precursor for compound 1e was synthesized in three
5
steps from ethyl piperidine-4-carboxylate. Treatment of
this precursor with S Cl in carbon tetrachloride afforded
2
2
(
2a–e), utilizing sodium chlorite as the oxidant, and dimethyl sulf-
1
e in nearly quantitative yield. In order to convert 1a–e
oxide as both a reaction solvent and an efficient hypochlorous acid
scavenger.
into 2a–e, we needed a method that would be capable of
oxidizing aldehydes into the corresponding carboxylic ac-
ids while leaving the disulfide functionality intact. To the
best of our knowledge, however, there have been no such
literature examples reported to date. We felt that this lack
of precedent would thus require a judicious choice of an
appropriate oxidant as well as suitable reaction condi-
tions. In this connection, it is noteworthy that the oxida-
tion chemistry of organic disulfides has been well studied
Key words: aldehydes, carboxylic Acids, oxidation, disulfides
Organic disulfides constitute a prominent class of com-
pounds in biological systems. The disulfide functional
group (-S-S-) exists not only in proteins, but also in nu-
merous natural products. Notable examples of disulfide-
containing natural products of pharmacological interest
3
and documented, by virtue of its importance in biological
1
a
1b
1c
include thiocoraline, BE-22179, triostin A, echino-
3a
3g,h
metabolism and its utility in organic synthesis. This
wealth of information has greatly facilitated our selection
of tentative oxidation methods for conversion of 1a–e to
1
d
1e,f
mycin, the thiarubrines,
and related 1,2-dithiins
which possess intriguing antibacterial, antifungal, anti-
1
g,h
cancer, and antiviral properties. On the other hand, the
oxidation of aldehydes into carboxylic acids represents
one of the fundamental transformations in synthetic or-
ganic chemistry, and a number of chemoselective oxida-
tion methods have been developed which tolerate a
2
a–e. It has allowed those methods that would be capable
of oxidizing both aldehydes and disulfides with compara-
ble ease to be precluded from our planned experiments.
2
diverse array of functional groups. However, this trans-
formation has not been reported for aldehyde substrates
which contain the disulfide moiety. The paucity of such
literature precedent is probably associated with the high
susceptibility of the disulfide function toward further oxi-
3
a
dation. In fact, it has been extensively documented that
organic disulfides can be readily oxidized by a wide range
of agents to produce thiosulfinates, thiosulfonates, sulfon-
Scheme 1 See Table 1 for the identities of R
3
a–j
ic acids, and a variety of other products. Despite this
conspicuous challenge, we have recently investigated the A set of experiments was carried out to search for a viable
feasibility of oxidizing aldehydes into the corresponding oxidizing agent, using dialdehyde-disulfide 1a as the test
carboxylic acids in the presence of the disulfide function- substrate. We first briefly examined some mild transition
ality, and we wish to report our results herein.
metal oxidizing systems, such as Masamune’s potassium
6a
permanganate protocol, and Corey’s pyridinium di-
During the course of our drug discovery research, dicar-
boxylic acid-disulfides 2a–e (see Table 1) were required
as versatile synthetic intermediates. Our general approach
to these molecules is outlined in Scheme 1. The first step
6
b
chromate procedure. However, applying these methods
to the oxidation of 1a resulted in a complex mixture,
which was not synthetically useful.
We subsequently focused on the use of sodium chlorite
(
NaClO ), which reacts with aldehydes under mild condi-
2
Synlett 2003, No. 4, Print: 12 03 2003.
Art Id.1437-2096,E;2003,0,04,0489,0492,ftx,en;S03803ST.pdf.
7a–i
tions to give carboxylic acids.
this reaction is the formation of hypochlorous acid
A major drawback of
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

4
90
X. Fang et al.
LETTER
Table 1 Oxidation of Dialdehyde-disulfides to Diacid-disulfides
Substrate
Product
NaH PO /NaClO
2
Conditions
Yield
2
4
Molar equiv
Time/Temp.
2
/5
5 h/r.t.
89%
1a
2a
2
.5/5
3 h/r.t.
82%
1
b
c
2b
2c
2
2
/2.5
/5
15 min/0 °C
2 h/r.t.
52%
77%
1
1d
2d
4
/10
6 h/r.t.
96%
1e
2e
(HOCl), which has to be intercepted in situ with a compe- taken place to generate several by-products, in which one
tent scavenger in order to prevent side reactions, owing to to four additional oxygen atoms were present. The forma-
–
the fact that the redox pair of HOCl/Cl possesses a great- tion of these species may be reasonably attributed to the
–
7j
er oxidation potential than does the pair of ClO /HOCl.
undesired further oxidation on the -S-S- moiety.
2
This requirement was particularly crucial for the conver-
In striking contrast to the preceding observations, dimeth-
yl sulfoxide proved to be efficient in preventing the dele-
terious oxidation on the disulfide function, especially
when it was employed as a reaction solvent. Indeed, treat-
ment of 1a with NaClO (5 molar equiv) and NaH PO (2
sion of 1a–e into 2a–e, because HOCl was known to oxi-
3
a
dize the -S-S- group in aqueous media. In the literature,
several reagents have been identified as HOCl scaven-
7
a–i
gers, including sulfamic acid, resorcinol, 2-methyl-2-
butene, hydrogen peroxide, dimethyl sulfide, and dimeth-
yl sulfoxide. In our attempts to oxidize 1a to 2a, we exam-
ined all these scavengers except dimethyl sulfide (a
notorious stench reagent). With the first four scavengers
2
2
4
molar equiv) in DMSO/H O at ambient temperature
2
cleanly generated the desired product 2a in 89% yield!
Moreover, this procedure has also been successfully uti-
lized for the oxidation of 1b–e to afford the desired prod-
ucts 2b–e in moderate to excellent yields (52–96%). It
in the foregoing list, oxidation of 1a by NaClO under a
2
variety of conditions provided very poor yields of the de-
sired product 2a (0–12% isolated yields) at complete con-
version of the substrate 1a. The reaction mixtures
contained a number of over-oxidized by-products which
were more polar than 2a by TLC. For instance, even when
a large excess of 2-methyl-2-butene (20 molar equiv.) was
employed as the scavenger, the Pinnick procedure7 (3
molar equiv of NaClO , 2 molar equiv of NaH PO , tert-
should be noted that an excess of NaClO (4–5 molar
2
equiv for substrates 1a, 1b, and 1d; 10 molar equiv for 1e)
was required for the complete conversion of these sub-
strates within a reasonable reaction time (2–6 hours). On
the other hand, the oxidation of 1c, a smaller and sterically
less congested substrate proceeded rapidly at 0 °C with
c
2
.5 molar equivalent of NaClO , and the reaction was
2
2
2
4
found to be complete in 15 minutes. Especially notewor-
thy is the fact that the products (2a–e) could be purified by
a simple recrystallization without resorting to tedious
BuOH/H O as solvents) gave only 12% of 2a at complete
2
conversion of 1a. An inspection of the mass spectra of the
reaction mixture revealed that further oxidation of 2a had
Synlett 2003, No. 4, 489–492 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Novel Diacid-disulfides
491
chromatography; thus the procedure would be well suited tion of dialdehyde-disulfide 1a (5.73 g, 20 mmol) in DMSO (120
mL) was added a solution of NaH PO (4.80 g, 40 mmol) in H O (40
mL); an exotherm was observed. The resulting mixture was allowed
for the practical synthesis of these compounds.
2
4
2
Some additional points are worth mentioning. First of all,
to cool to room temperature, and a solution of NaClO (tech. 80%,
2
a high concentration of DMSO was required for the suc- 11.3 g, 100 mmol) in H O (60 mL) was added dropwise over a pe-
2
cess of the reaction, only when DMSO was used as a re- riod of 45 min. The resulting slurry was stirred rapidly at room tem-
perature for 5 hours; TLC indicated complete conversion of the
action solvent, could the desired product be obtained in
substrate. The mixture was poured into ice-cold 2 N hydrochloric
good yields. Secondly, the inherent steric hindrance of
acid (100 mL), and extracted with EtOAc (4 × 100 mL). The com-
these tertiary disulfides (1a–e) may also contribute to the
bined organic extracts were thoroughly washed with brine (3 × 100
success of this reaction. In fact, application of this proce-
dure to the oxidation of dialdehyde 3, which contains a
mL), dried over Na SO , filtered, and concentrated by rotary evap-
2
4
8
oration to give a solid material. Recrystallization from EtOAc/THF
primary disulfide group, did not give the expected product (1:1) afforded the desired product 2a (5.65 g, 89%) as white nee-
1
4
(Scheme 2); a complex mixture of over-oxidized species dles: mp 120–121 °C; H NMR (DMSO-d
6
) δ 2.2–2.0 (m, 4 H), 1.7–
1
3
1
.2 (m, 16 H); C NMR (DMSO-d ) δ 174.1, 57.1, 34.4, 25.5, 24.4;
LRMS (APTIS, negative ions) m/z 317 [(M – H) ]; Anal. Calcd for
was generated instead.
6
–
C H O S : C, 52.80; H, 6.96; S, 20.14. Found: C, 52.72; H, 7.05;
1
4
22
4 2
S, 19.90.
2
-[(1-Carboxy-l-ethylpropyl)disulfanyl]-2-ethylbutonic Acid
1
(
2b). A white solid (2.3 g, 82%): mp 110 °C; H NMR (DMSO-d )
6
1
3
δ 0.85 (t, J = 7.2 Hz, 6 H), 1.66–1.84 (m, 4 H); C NMR (DMSO-
d ) δ 9.8, 27.2, 62.9, 174.7; LRMS (APTIS) m/z 295 [(M + H) ], 312
+
6
+
[(M + NH ) ]; Anal Calcd for C H O S : C, 48.95; H 7.53; S.
4
12 22
4 2
2
1.78. Found: C, 48.87; H 7.42; S. 22.14.
2
-[(1-Carboxy-isopropyl)disulfanyl]-2-methylpropanoic Acid
Scheme 2
1
(2c). A white solid (1.2 g, 52%): mp 163 °C; H NMR (DMSO-d )
6
1
3
δ 1.48 (s, 12 H); C NMR (DMSO-d ) δ 26.1, 52.9, 175.4; LRMS
6
+
+
(
APTIS) m/z 238 [(M + H) ], 256 [(M + NH ) ]; Anal Calcd for
4
In conclusion, dicarboxylic acid-disulfides 2a–e have
been synthesized by reaction of the corresponding alde-
hyde-disulfide precursors 1a–e with sodium chlorite, us-
ing DMSO as both a reaction solvent and an efficient
HOCl scavenger. This work has disclosed the first exam-
ples of oxidizing aldehydes into carboxylic acids without
detriment to the tertiary disulfide functionality.
C H O S : C, 40.33; H 5.93; S. 26.86. Found: C, 40.48; H, 5.87; S,
2
8
14
4 2
6.45.
2
-[(Carboxydiphenylmethyl)disulfanyl]-2,2-diphenylacetic
1
Acid (2d). A white solid (0.831 g, 77%): mp 104–105 °C; H NMR
13
(
(
DMSO-d ) δ 6.32 (d, J = 6.9 Hz, 8 H), 6.1–5.9 (m, 12 H); C NMR
DMSO-d ) δ 176.7, 146.9, 130.3, 129.9, 129.7, 81.2; LRMS (AP-
6
6
–
TIS, negative ions) m/z 485 [(M – H) ]; Anal Calcd for C H O S :
2
8
22
4 2
C, 69.11; H, 4.56; S, 13.18. Found: C, 69.03; H, 4.72; S, 12.89.
Melting points are uncorrected. H NMR (at 300 MHz) and 13C
1
4-({4-Carboxy-1-[(4-methylphenyl)sulfanyl](4-piperidyl)}dis-
NMR (at 75 MHz) were recorded in CDCl or DMSO-d . Low-res-
ulfanyl)-1-[(4-methyl-phenyl)sulfonyl]piperidine-4-carboxylic
3
6
1
olution mass spectra were determined with atmospheric pressure
turbo ion spray (APTIS). Elemental analyses were obtained from
Robertson Microlit Laboratories, Madison, NJ. Compounds 1a–d
were prepared according to the methods previously reported by
us and by others. All commercial reagents and solvents were
used as received.
Acid (2e). White rods (6.40 g, 96%): mp 185–186 °C; H NMR
(CDCl
) δ 7.61 (d, J = 8.2 Hz, 4 H), 7.33 (d, J = 8.2 Hz, 4 H), 3.24
3
(m, 4 H), 2.88 (m, 4 H), 2.46 (s, 6 H), 2.25 (m, 4 H), 1.89 (m, 4 H);
1
3
C NMR (DMSO-d
44.5, 32.7, 22.0; LRMS (APTIS, negative ions) m/z 627 [(M–H) ];
Anal Calcd for C26 : C, 49.66; H, 5.13; N, 4.45; S, 20.40.
) δ 172.8, 144.7, 133.0, 130.8, 128.4, 54.6,
6
4
c,d
4a,b
–
H N O S
32 2 8 4
Found: C, 49.52; H, 5.18; N, 4.40; S, 20.17.
4
-({4-Formyl-1-[(4-methylphenyl)sulfonyl](4-piperidyl)}disul-
fanyl)-1-[(4-methyl-phenyl)sulfonyl]piperidine-4-carbalde-
hyde (1e). stirred solution of 1-[(4-methylphenyl)-
sulfonyl]piperidine-4-carbaldehyde (14.22 g, 53 mmol) and sulfur
monochloride (3.40 g, 25.2 mmol) in carbon tetrachloride (25 mL)
was heated at 90–100 °C for 90 min, at which point the evolution of
the HCl gas had ceased. The mixture was dissolved in CH Cl (300
mL) and washed with 2 M aqueous K CO and water, dried over
Na SO , filtered, and concentrated. The resulting material was trit-
urated with EtOAc to afford the title compound as a white solid
A
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1
(
(
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3
1
3
4
C
3
+
2
2
6
32
2
6 4
H, 5.27; N, 4.64; S 21.20.
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yl)disulfanyl]cyclo-hexanecarboxylic acid (2a). To a stirred solu-
Synlett 2003, No. 4, 489–492 ISSN 0936-5214 © Thieme Stuttgart · New York

4
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LETTER
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Synlett 2003, No. 4, 489–492 ISSN 0936-5214 © Thieme Stuttgart · New York