Development of a tandem base-catalyzed, triphenylphosphine-mediated disulfide reduction-Michael addition

Article abstract of DOI:10.1055/s-2008-1067102

A tandem disulfide reduction-Michael addition was developed using both free and polymer-bound triphenylphosphine as the reducing agent. The procedure was applied to intermolecular systems for the synthesis of arylsulfanyl- and alkylsulfanyl-substi-tuted p

Full text of DOI:10.1055/s-2008-1067102

PAPER
2023
Development of a Tandem Base-Catalyzed, Triphenylphosphine-Mediated
Disulfide Reduction–Michael Addition
A
T
andem Base-C
l
a
talyze
e
d,
T
ripheny
s
lphosphin
s
e-Mediate
a
d Disulfide
n
Reduction–
d
Michael
A
dd
r
ition a Bartolozzi,* Hope M. Foudoulakis, Bridget M. Cole
Surface Logix, Inc., 50 Soldiers Field Place, Brighton, MA 02135, USA
Fax +1(617)7838877; E-mail: abartolozzi@surfacelogix.com
Received 20 February 2008; revised 1 April 2008
This article is dedicated to the memory of Professor Giuseppe Capozzi.
R2
R1
R3
R2
O
R1
R3
S
Abstract: A tandem disulfide reduction–Michael addition was de-
[Red]
R
X
veloped using both free and polymer-bound triphenylphosphine as
the reducing agent. The procedure was applied to intermolecular
systems for the synthesis of arylsulfanyl- and alkylsulfanyl-substi-
tuted propanoates and related ketones, and to an intramolecular sys-
tem for the synthesis of a benzothiazepinone derivative.
R
S
+
2
S
R
X
R4
R4
O
X = O, NH, CH
Scheme 1 Generic representation of the Michael addition under re-
ductive conditions
Key words: Michael additions, reductions, thiols, triphenylphos-
phine, benzothiazepinones
fide formation needs to be taken into account as it may
occur either during the isolation of the free thiol or during
the following reaction under typical Michael addition
conditions. Furthermore, the typically unpleasant smell of
thiols is often a discouraging factor for their use, especial-
ly in a scaled-up synthesis. Disulfides, typically not odor-
ous, offer a simple circumvention of such issues.
Carbon–sulfur bond formation is a common transforma-
tion used in organic synthesis to prepare compounds for
various applications. For example, many products of
biological1 and medical2 relevance, including ligands3 as
well as commercial drugs,4 are sulfur-containing com-
pounds. Several carbon–sulfur bond forming methods are
known, including the reactions of disulfides with
trialkylboranes5 and organometallic compounds,6 the
hetero-Diels–Alder reaction,7 the Friedel–Crafts reac-
tion,8 and the Kindler modification of the Willgerodt reac-
tion.9 Thiol Michael addition to a,b-unsaturated systems
is one of the most valuable and commonly employed tools
used to introduce sulfur-containing functionalities into or-
ganic molecules. Despite the close scrutiny paid to this
system by researchers over the years, many synthetic ap-
plications are yet to be realized and continue to motivate
new investigations.10
In this context, we developed a tandem disulfide reduc-
tion–Michael addition to (i) overcome the need for thiol-
protecting groups by using the disulfide itself as masked
form of the thiol and (ii) guarantee complete Michael ad-
dition of the thiol via the in situ disulfide reduction
(Scheme 1).
Disulfide-based Michael additions have not been exten-
sively reported in the literature11 and, to the best of our
knowledge, very few are carried out under one-pot reduc-
tive conditions.12 Specifically, we report herein a tandem
disulfide reduction–Michael addition to synthesize alkyl-
sulfanyl- and arylsulfanyl-substituted propanoates and ke-
tones, including arylsulfanyl compounds derived from
disulfides containing amino, hydroxy, and carbonyl sub-
stituents on the phenyl ring. The reaction is performed by
heating a disulfide and an a,b-unsaturated molecule in
isopropyl alcohol in the presence of triphenylphosphine
and base to afford the desired Michael addition product.
Thiols are generally very reactive species that easily un-
dergo addition to electrophiles. In a traditional convergent
synthetic strategy, chemical modifications of groups
present on the thiol moiety would occur prior to the
Michael addition, and the high reactivity of the thiol
would impose the use of protection/deprotection schemes
to avoid undesired side reactions. Michael addition be-
tween the thiol and an acceptor would follow under acidic
or basic conditions to afford the desired compound. This
strategy presents several drawbacks. First, while synthetic
chemists routinely rely on protecting groups in designing
syntheses, protection/deprotection steps increase the
length of those syntheses with a potential negative impact
on the final yield. Additionally, when designing a synthe-
sis involving a free thiol, its high tendency toward disul-
Among the several methods known for disulfide reduc-
tion,13 the triphenylphosphine/alcohol14 system was the
most suitable for our purpose: first, the phosphine-based
reduction is a very efficient reaction that is usually com-
plete in minutes; second, the reagents used and the
byproducts formed are compatible with the presence of a
wide variety of functional groups and do not interfere with
the Michael addition; and finally, the triphenylphosphine-
mediated reduction is not adversely affected by the base
present in the system to promote the Michael addition
step.
SYNTHESIS 2008, No. 13, pp 2023–2032
x
x.
x
x
.
2
0
0
8
Advanced online publication: 21.05.2008
DOI: 10.1055/s-2008-1067102; Art ID: M00908SS
© Georg Thieme Verlag Stuttgart · New York

2024
A. Bartolozzi et al.
PAPER
Br
OMe
OMe
O
AcHN
O
N
S
DIAD, Ph3P
THF, 77%
Br
O
O
O
7
8
9
S
O
HO
+
OH
2
2
1a
2
O
OPh
O
EtOOC
COOEt
O
10
11
12
13
N
morpholine
K2CO3, DMF, quant.
Figure 1 Michael acceptors tested in the tandem procedure
S
O
chemical transformation and have one or multiple hydro-
gen bond donors/acceptors for binding to a target protein.
2
3
The one-pot Michael addition was performed by heating
the disulfide and acceptor in the presence of 1.5 equiva-
lents of triphenylphosphine in a solution of isopropyl al-
cohol and aqueous potassium carbonate (10:1 or 5:1)
(Table 1). The reaction between disulfide 1a and various
Michael acceptors (entries 1–6) was usually complete
within an hour, affording products 14–19 in good to high
yield. The reduction of 1a occurred over a few minutes to
afford 4-sulfanylphenol, a highly reactive nucleophile that
easily undergoes addition to a,b-unsaturated systems. The
tandem procedure could also be successfully applied to
nonterminal a,b-unsaturated systems (entries 5 and 6);
predictably, a longer reaction time was required when a
more-hindered double bond was involved (entry 6).15
O
S
1) (COCl)2, CH2Cl2,
DMF (cat.)
N
O
S
2) morpholine,
CH2Cl2, Et3N,
quant.
COOH
NEt3
2
1b
4
2
NH2
O
Et3N, CH2Cl2
53%
S
HN
+
Cl
2
O
S
S
1c
2
The reactions of disulfides 3, 4, and 1d afforded com-
pounds 20–25 in moderate to good yields (entries 7–13).
The tandem reactions involving disulfide 4 took longer to
go to completion than those involving the other disulfides
and the same Michael acceptors (e.g., entries 9 and 10).
Upon closer examination, we determined that the disul-
fide reduction was complete in about 15 minutes, but that
the coupling of the derived thiol was much slower than in
those other cases. Evidently, the electronic effect of the
meta amide substituent decreases the nucleophilicity of
the thiol. We next explored the reaction of disulfide 4 with
Michael acceptor 10 in the presence of varying amounts
of base to test the effect on the reaction rate. The reaction
of compound 4 with acceptor 10 in the presence of a 10:1
and 5:1 ratio of isopropyl alcohol and aqueous potassium
carbonate was complete in one hour (entry 11) and 15
minutes (entry 12), respectively, suggesting that the rate-
determining step (the thiol addition) is dependent upon the
base concentration.
OH
5
S
S
6
2
1d
Scheme 2 Synthesis of disulfides used in the tandem procedure
This one-pot disulfide reduction–Michael addition is of
general application and has been successfully carried out
on both aliphatic and aromatic disulfides (Table 1). The
procedure is straightforward and the reaction rate is main-
ly dependent on the reactivity of the nucleophile/electro-
phile pair and the amount of base used. The reaction
conversion is generally very high with triphenylphos-
phine oxide being the only major byproduct. Scheme 2
shows the synthesis of the disulfides and Figure 1 lists the
commercially available Michael acceptors that were test-
ed in the tandem procedure. Disulfides 1a–d were synthe-
sized from the corresponding thiols under mild oxidative
conditions, and disulfides 3–5 were derived from 1a–c, re-
spectively, via standard organic chemistry transforma-
tions. While aiming to synthesize generic disulfides to
demonstrate the breadth of application of the tandem re-
duction–addition methodology, we chose disulfides that
could be precursors to molecules of relevance to general
medicinal chemistry. Specifically, the selected disulfides
carry a variety of polar groups that are amenable to further
This tandem procedure was also successfully applied to
the addition of aliphatic disulfide 6 to acceptor 10 to af-
ford product 26 in good yield (entry 14). Similarly, the re-
action between diethyl disulfide (6) and compound 13
afforded adduct 27 (entry 15). In the latter example, the
conversion was quantitative, but the moderate yield re-
flects the difficulties that were encountered during the iso-
lation of the compound by preparative thin-layer
chromatography because of the lack of strong chro-
mophores in product 27. Further work will focus on ex-
tending this procedure to substituted aliphatic disulfides.
Synthesis 2008, No. 13, 2023–2032 © Thieme Stuttgart · New York

PAPER
Tandem Base-Catalyzed, Triphenylphosphine-Mediated Disulfide Reduction–Michael Addition
2025
Table 1 Tandem Disulfide Reduction–Michael Addition
R2
R1
R3
R2
O
R1
R3
S
O
S
Ph3P, i-PrOH
R
X
R
S
+
2
S
R
X
K2CO3 (aq), 80 °C
R4
R4
Entry
1
Disulfide
Acceptor
Product
Time
1 hb
Yielda (%)
OMe
OMe
1a
7
83
80
90
HO
O
O
O
14
S
2
3
1a
1a
8
9
7 minb
HO
AcN
H
15
S
50 minc
O
HO
N
16
OH
O
4
1a
10
30 minb
90
S
17
OH
5
6
1a
1a
11
12
30 minc
2.5 hb
82
73
S
S
O
18
OH
EtOOC
COOEt
19
S
O
N
OMe
7
8
3
3
8
3 hb
70
73
O
AcN
H
O
20
21
O
O
N
O
10
40 minb
S
O
S
N
9
4
7
5.5 hc
63
O
OMe
O
22
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A. Bartolozzi et al.
PAPER
Table 1 Tandem Disulfide Reduction–Michael Addition (continued)
R2
R1
R3
R2
R1
R3
S
Ph3P, i-PrOH
R
X
R
S
+
2
S
R
X
K2CO3 (aq), 80 °C
R4
R4
O
O
Entry
10
Disulfide
Acceptor
Product
Time
12 hb
Yielda (%)
O
S
N
4
9
50
O
O
N
O
23
O
O
N
11
12
4
4
10
10
1 hb
65
60
S
O
24
24
15 minc
O
O
13
14
15
1d
6
10
10
13
2 hb
36
75
52
S
S
OH
25
26
2.5 hb
S
O
6
3 hb
O
27
a Isolated yield.
b Using 0.2 M disulfide in i-PrOH–aq K2CO3 (10:1).
c Using 0.2 M disulfide in i-PrOH–aq K2CO3 (5:1).
After successfully applying this methodology to intermo-
lecular Michael additions, we next examined the suitabil-
ity of the one-pot procedure for the intramolecular
Michael addition of a disulfide carrying an a,b-unsaturat-
ed functional group to synthesize heterocyclic com-
pounds. In particular, we were interested in the synthesis
of benzothiazepinones, which are common scaffolds in bi-
ologically active compounds16 and optimal precursors to
the pharmaceutically valuable benzothiazepines.17 To this
end, disulfide 5 was synthesized and treated using the one-
pot reaction conditions to afford compound 28 in 40%
yield (Scheme 3).
O
O
O
H
N
Ph3P, i-PrOH
HN
HN
K2CO3 (aq),
80°C, 40%
S
HS
S
2
5
28
Scheme 3 Intramolecular application of the tandem disulfide reduc-
tion–Michael addition
rigidity and lower reactivity as the Michael acceptor are
the main reasons for the significant increase in the reac-
tion time required for the formation of compound 28 com-
pared with that of the previously discussed intermolecular
addition products. Our future work will focus on extend-
ing this protocol to disulfides bearing various Michael
acceptors, possibly with additional C-3 substituents that
The disulfide reduction of 5 occurred in less than one
hour, and although the intermediate thiol was not isolated,
it was clearly identified by liquid chromatography–mass
spectrometry analysis. The ring closure of the intermedi-
ate thiol was the rate-determining step, requiring 31 hours
to go to completion. We believe that the amide’s structural
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Tandem Base-Catalyzed, Triphenylphosphine-Mediated Disulfide Reduction–Michael Addition
2027
dure with resin-supported triphenylphosphine to aliphatic
disulfide reduction–additions and the further development
of the intramolecular disulfide reduction–addition toward
the synthesis of heterocyclic compounds.
Table 2 Tandem Disulfide Reduction–Michael Addition with
Resin-Supported Triphenylphosphine
Entry Disulfide Acceptor Product Reaction Yielda Purityb
time
(%)
(%)
1
2
3
1a
1a
1a
7
14
15
17
3.5 hc
71
98
Reactions were monitored by analytical HPLC or TLC; for visual-
ization, UV, Pd, and ceric ammonium molybdate (CAM) stain were
employed. The HPLC analyses were performed using an Agilent
1100 instrument; LC-MS analyses were performed using a Waters
ZQ2000 instrument. The 1H and 13C NMR spectra were acquired on
a Varian 400 MHz instrument using CDCl3 (reference set at 7.26
and 77.0 ppm, respectively) or CD3OD (reference set at 3.34 and
49.0 ppm, respectively) as solvent. The final products were purified
by silica gel column chromatography using a Combiflash Compan-
ion purification system, silica gel preparative TLC using Uniplate
TLC Plates, or preparative HPLC on a Waters Delta 600 instrument
8
25 mind 60
30 minc 60
92
10
85
a Isolated yield.
b Purity estimated by HPLC at l = 254 nm.
c Using 0.07 M disulfide in i-PrOH–aq K2CO3 (60:1).
d Using 0.07 M disulfide in i-PrOH–aq K2CO3 (30:1).
could function as ‘handles’ for creating further deriva- [buffers: A: H2O, 0.100% HCO2H; B: MeCN, 0.085% HCO2H; re-
verse-phase column: YMC Pack Pro C18 (150 × 20 mm i.d.)]. Di-
tives.
ethyl disulfide (6) was purchased from Sigma–Aldrich; Ph3P–
After demonstrating the application of the tandem reac-
NovaGel resin was purchased from Novabiochem.
tion with aliphatic and aromatic disulfides to intermolec-
ular and intramolecular systems, we examined strategies
to simplify the purification of the final products. Overall,
the reported one-pot reaction is very clean: the experimen-
tal conditions are mild, and the disulfide reduction and thi-
ol addition, in general, proceed smoothly with complete
conversion and no significant side reactions. Triphe-
nylphosphine oxide is the only other major product that is
formed during the disulfide reduction. Reaction mixtures
containing triphenylphosphine oxide are often difficult to
purify with commonly employed techniques, resulting in
the compromised purity and/or yield of the isolated com-
pounds. To address this issue, we tested the compatibility
of the one-pot disulfide reduction–Michael addition with
resin-supported triphenylphosphine,18 to enable the re-
moval of triphenylphosphine oxide by simple filtration af-
ter completion of the reaction (Table 2).
4,4¢-Disulfanediyldiphenol (1a); Typical Procedure
A solution of 4-sulfanylphenol (100 mg, 0.79 mmol) in Et3N (0.44
mL, 3.16 mmol) and DMF (0.79 mL) was stirred at r.t. for 5 min.
Air was bubbled through the solution for a few min, and then the so-
lution was heated at 105 °C for 12 h. The solvent was removed un-
der reduced pressure and the crude product was purified by silica
gel preparative TLC (hexanes–EtOAc, 1:1) to afford compound 1a
as a pale-yellow solid. Yield: 51 mg (51%); mp 130–133 °C.
1H NMR (400 MHz, CDCl3): d = 7.36–7.34 (A part of AB system,
J = 8.4 Hz, 4 H), 6.77–6.75 (B part of AB system, J = 8.4 Hz, 4 H),
4.92 (br s, 2 H).
1H NMR (400 MHz, DMSO):19 d = 9.88 (s, 2 H), 7.28–7.25 (A part
of AB system, J = 8.8 Hz, 4 H), 6.76–6.74 (B part of AB system,
J = 8.8 Hz, 4 H).
13C NMR (100 MHz, CDCl3): d = 155.94, 132.86, 121.56, 116.09.
ESI-MS: m/z = 249.03 (M – H).
Triethylammonium Hemi(3,3¢-disulfanediyldibenzoate) (1b)
Compound 1b was synthesized according to the above typical pro-
cedure from 3-sulfanylbenzoic acid (600 mg, 3.89 mmol) in Et3N
(2.70 mL, 19.5 mmol) and THF (12.0 mL). In this case, the solution
was heated at 50 °C for 12 h. The solvent was removed under re-
duced pressure to afford product 1b as a pale-yellow oil. Yield: 995
mg (100%).
1H NMR (400 MHz, CDCl3): d = 8.18 (br t, J = 1.6 Hz, 2 H), 7.90–
7.89 (m, 2 H), 7.58–7.56 (m, 2 H), 7.29 (t, J = 7.2 Hz, 2 H), 3.07 (q,
J = 7.6 Hz, 12 H), 1.28 (t, J = 7.6 Hz, 18 H).
Given that the reaction solvent was isopropyl alcohol, a
pre-swollen resin was selected that was compatible with a
protic solvent. The syntheses of compounds 14, 15, and 17
were repeated, slightly adapting the procedure to the pres-
ence of the resin. The syntheses proceeded smoothly with
longer reaction times than those required when soluble
triphenylphosphine was used. After completion of the re-
action, simple filtration of the resin removed the byprod-
uct triphenylphosphine oxide to afford the desired
products in high purity.
13C NMR (100 MHz, CDCl3): d = 171.54, 137.22, 136.64, 129.33,
128.67, 128.61, 128.26, 44.89, 8.68.
In conclusion, we have developed a tandem disulfide re-
duction–Michael addition with specific application to the
synthesis of alkylsulfanyl- and arylsulfanyl-substituted
propanoates and related ketones. Of special interest is the
use of the methodology for the synthesis of benzothiaze-
pinones via an intramolecular Michael addition starting
from a disulfide bearing an a,b-unsaturated moiety. The
procedure is of simple application and is amenable to the
use of resin-supported reagents. In addition to the devel-
opment of a synthetic method, the herein reported investi-
gation led to the synthesis of novel compounds that, to the
best of our knowledge, have not been previously reported.
Our future work will focus on applying the tandem proce-
ESI-MS: m/z = 305.07 (M – H).
2,2¢-Disulfanediyldianiline (1c)
Compound 1c was synthesized according to the above typical pro-
cedure from 2-aminobenzenethiol (143 mg, 1.14 mmol). Purifica-
tion by silica gel preparative TLC (hexanes–EtOAc, 1:1) afforded
product 1c as a brown solid. Yield: 121 mg (86%); mp 76–81 °C.
1H NMR (400 MHz, CDCl3):20 d = 7.17–7.13 (m, 4 H), 6.72–6.69
(B part of ABX system, J = 8.0, 1.2 Hz, 2 H), 6.58 (td, J = 7.6, 1.2
Hz, 2 H), 4.02 (br s, 4 H).
13C NMR (100 MHz, CDCl3): d = 148.57, 136.81, 131.58, 118.77,
118.25, 115.24.
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2028
A. Bartolozzi et al.
PAPER
ESI-MS: m/z = 247.08 (M – H).
A solution of the above crude product in anhyd CH2Cl2 (4.0 mL)
was added to a solution of morpholine (0.17 mL, 1.96 mmol) and
Et3N (0.54 mL, 3.92 mmol) in anhyd CH2Cl2 (3.0 mL). After stir-
ring at r.t. for 30 min, the mixture was diluted with CH2Cl2 (30 mL)
and then washed with H2O (30 mL) and sat. NaHCO3 soln (30 mL).
The organic phase was dried (anhyd Na2SO4), and the solvent was
removed under reduced pressure to afford product 4 as a dark-
orange oil, which was used in the next step without further purifica-
tion. Yield: 173 mg (100%).
1H NMR (400 MHz, CDCl3): d = 7.54–7.50 (m, 4 H), 7.36 (t, J =
7.6 Hz, 2 H), 7.27–7.25 (m, 2 H), 3.87–3.33 (m, 16 H).
13C NMR (100 MHz, CDCl3): d = 168.98, 136.89, 136.13, 129.21,
128.05, 125.69, 125.16, 66.52, 47.94, 42.37.
2,2¢-Disulfanediyldi-o-phenylenedimethanol (1d)
Compound 1d was synthesized according to the above typical pro-
cedure from 2-sulfanylbenzyl alcohol (171 mg, 1.22 mmol). Crys-
tallization (CH2Cl2–MeOH) afforded product 1d as a beige solid.
Yield: 90 mg (54%); mp 132–138 °C.
1H NMR (400 MHz, CD3OD): d = 7.56 (dd, J = 7.6, 1.6 Hz, 2 H),
7.49 (br d, J = 7.2 Hz, 2 H), 7.32 (td, J = 7.2, 1.6 Hz, 2 H), 7.25 (td,
J = 7.2, 1.6 Hz, 2 H), 4.73 (s, 4 H).
1H NMR (400 MHz, DMSO):21 d = 7.54–7.52 (m, 2 H), 7.46–7.44
(m, 2 H), 7.30–7.27 (m, 4 H), 5.39 (t, J = 5.2 Hz, 2 H), 4.60 (d, J =
5.2 Hz, 4 H).
13C NMR (100 MHz, CD3OD): d = 142.74, 135.93, 131.75–131.64,
129.30–129.13, 129.00–128.91, 62.91.
ESI-MS: m/z = 445.28 (M + H).
N,N¢-(2,2¢-Disulfanediyldi-o-phenylene)bis(2-methylacryl-
amide) (5)
ESI-MS: m/z = 277.04 (M – H).
A solution of 2,2¢-disulfanediyldianiline (1c) (100 mg, 0.40 mmol),
methacryloyl chloride (78 mL, 0.80 mmol), and Et3N (0.14 mL, 1.00
mmol) in anhyd CH2Cl2 (2.0 mL) was stirred at r.t. for 8 h. Then,
Et3N (83 mL, 0.60 mmol) and methacryloyl chloride (39 mL, 0.40
mmol) were added. The reaction was complete after 15 min. The
mixture was diluted with CH2Cl2 (10 mL) and then washed with
H2O (10 mL). The organic phase was dried (anhyd Na2SO4), the sol-
vent was removed under reduced pressure, and the crude product
was purified by silica gel column chromatography (hexanes–
EtOAc, 3:1) to afford compound 5 as a yellow oil. Yield: 80 mg
(53%).
1H NMR (400 MHz, CDCl3): d = 8.60 (br s, 2 H), 8.49 (dd, J = 8.4,
1.2 Hz, 2 H), 7.40 (td, J = 8.8, 1.6 Hz, 2 H), 7.32 (dd, J = 8.0, 1.6
Hz, 2 H), 6.98 (td, J = 7.2, 1.2 Hz, 2 H), 5.69 (s, 2 H), 5.41 (br s, 2
H), 1.97 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 165.78, 140.16, 139.81, 136.58,
132.30, 124.17, 123.02, 120.89, 120.47, 18.45.
1,2-Bis[4-(2-bromoethoxy)phenyl]disulfane (2)
Diisopropyl azodicarboxylate (0.97 mL, 5.00 mmol) was added
dropwise to a solution of 4,4¢-disulfanediyldiphenol (1a) (500 mg,
2.00 mmol), 2-bromoethanol (0.31 mL, 4.4 mmol), and Ph3P (1.30
g, 4.96 mmol) in anhyd THF (10 mL). After stirring the solution at
r.t. overnight, 2-bromoethanol (71 mL, 1.00 mmol), Ph3P (263 mg,
1.00 mmol), and DIAD (0.19 mL, 1.00 mmol) were added, and the
solution was stirred for an additional 3 h. The solvent was removed
under reduced pressure, and the crude product was purified by silica
gel column chromatography (hexanes–EtOAc, 3:1) to afford the
byproduct 4-{2-[4-(2-bromoethoxy)phenyl]disulfanyl}phenol (46
mg, 6%) and compound 2. Yield: 712 mg (77%); mp 84–87 °C.
1H NMR (400 MHz, CDCl3): d = 7.41–7.39 (A part of AB system,
J = 8.8 Hz, 4 H), 6.86–6.83 (B part of AB system, J = 8.8 Hz, 4 H),
4.28 (t, J = 6.0 Hz, 4 H), 3.63 (t, J = 6.0 Hz, 4 H).
13C NMR (100 MHz, CDCl3): d = 158.34, 132.34, 129.51, 115.42,
67.97, 28.81.
ESI-MS: m/z = 385.17 (M + H).
1,2-Bis[4-(2-morpholinoethoxy)phenyl]disulfane (3)
A mixture of 1,2-bis[4-(2-bromoethoxy)phenyl]disulfane (2) (100
mg, 0.21 mmol), morpholine (56 mL, 0.64 mmol), and K2CO3 (119
mg, 0.86 mmol) in anhyd DMF (1.0 mL) was stirred at r.t. overnight
and then heated at 60 °C for 6 h. The solvent was removed under
reduced pressure, and the crude product was diluted with EtOAc (15
mL) and then washed with H2O (15 mL) and brine (15 mL). The or-
ganic phase was dried (anhyd Na2SO4), and the solvent was re-
moved under reduced pressure to afford product 3, which was used
without further purification. Yield: 98 mg (100%).
One-Pot Disulfide Reduction–Michael Addition; General Pro-
cedure
A mixture of the Michael acceptor (2.0 equiv), Ph3P (1.5 equiv), 0.2
M disulfide in i-PrOH and 1.9 M aq K2CO3 (Method A: i-PrOH/1.9
M aq K2CO3, 10:1; Method B: i-PrOH/1.9 M aq K2CO3, 5:1) was
heated at 80 °C for a specified amount of time. The solvent was re-
moved under reduced pressure, and the crude product was purified
to afford the desired compound.
Methyl 3-[(4-Hydroxyphenyl)sulfanyl]-2-methylpropanoate
(14)
Compound 14 was synthesized according to the above general pro-
cedure (Method A) from disulfide 1a (30 mg, 0.12 mmol) and
Michael acceptor 7 by heating the mixture for 1 h. Silica gel prepar-
ative TLC (hexanes–EtOAc, 1:1) afforded product 14 as a colorless
oil. Yield: 45 mg (83%).
1H NMR (400 MHz, CDCl3): d = 7.38–7.36 (A part of AB system,
J = 8.8 Hz, 4 H), 6.83–6.81 (B part of AB system, J = 8.8 Hz, 4 H),
4.08 (t, J = 5.6 Hz, 4 H), 3.72 (br t, J = 4.8 Hz, 8 H), 2.78 (t, J = 5.6
Hz, 4 H), 2.55 (br t, J = 4.8 Hz, 8 H).
13C NMR (100 MHz, CDCl3): d = 158.96, 132.44, 128.58, 115.20,
66.85, 65.90, 57.50, 54.04.
1H NMR (400 MHz, CDCl3): d = 7.31–7.29 (m, 2 H), 6.78–6.76 (m,
2 H), 5.90 (br s, 1 H), 3.66 (s, 3 H), 3.14–3.10 (A part of ABX sys-
tem, J = 13.2, 7.2 Hz, 1 H), 2.84–2.79 (B part of ABX system, J =
13.2, 6.8 Hz, 1 H), 2.65 (sext, J = 7.2 Hz, 1 H), 1.24 (d, J = 7.2 Hz,
3 H).
13C NMR (100 MHz, CDCl3): d = 176.09, 155.61, 134.28, 125.30,
116.12, 51.96, 39.88, 39.49, 16.67.
ESI-MS: m/z = 477.30 (M + H).
3,3¢-Disulfanediyldi-m-phenylenebis(morpholinomethanone)
(4)
A catalytic amount of DMF (40 mL) was added to a solution of tri-
ethylammonium hemi(3,3¢-disulfanediyldibenzoate) (1b) (200 mg,
0.39 mmol) and oxalyl chloride (136 mL, 1.56 mmol) in anhyd
CH2Cl2 (6.0 mL). After stirring the solution at r.t. for 5 h, the solvent
was removed under reduced pressure to afford 3,3¢-disul-
fanediyldibenzoyl dichloride, which was used without further puri-
fication after drying the compound overnight under high vacuum.
ESI-MS: m/z = 225.06 (M – H).
Synthesis 2008, No. 13, 2023–2032 © Thieme Stuttgart · New York

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Tandem Base-Catalyzed, Triphenylphosphine-Mediated Disulfide Reduction–Michael Addition
2029
Methyl2-Acetamido-3-[(4-hydroxyphenyl)sulfanyl]propanoate
(15)
Compound 15 was synthesized according to the above general pro-
cedure (Method A) from disulfide 1a (42 mg, 0.17 mmol) and
Michael acceptor 8 by heating the mixture for 7 min. Silica gel pre-
parative TLC (toluene–EtOAc, 3:1) afforded product 15 as a color-
less oil. Yield: 72 mg (80%).
Diethyl 2-{2-[(4-Hydroxyphenyl)sulfanyl]propan-2-yl}mal-
onate (19)
Compound 19 was synthesized according to the above general pro-
cedure (Method A) from disulfide 1a (50 mg, 0.20 mmol) and
Michael acceptor 12 by heating the mixture for 2.5 h. Silica gel col-
umn chromatography (hexanes–EtOAc, 5:1) afforded product 19 as
a yellow oil. Yield: 95 mg (73%).
1H NMR (400 MHz, CDCl3): d = 7.96 (br s, 1 H), 7.34–7.32 (m, 2
H), 6.79–6.77 (m, 2 H), 6.35 (br d, J = 7.6 Hz, 1 H), 4.78 (dt, J =
7.2, 4.8 Hz, 1 H), 3.64 (s, 3 H), 3.38–3.33 (A part of ABX system,
J = 14.8, 4.8 Hz, 1 H), 3.18–3.13 (B part of ABX system, J = 14.8,
5.6 Hz, 1 H), 1.89 (s, 3 H).
13C NMR (100 MHz, CD3OD): d = 173.23, 172.54, 158.97, 136.11,
124.30, 117.12, 53.67, 52.77, 38.70, 22.32.
1H NMR (400 MHz, CDCl3): d = 7.44–7.42 (A part of AB system,
J = 8.4 Hz, 2 H), 6.84–6.82 (B part of AB system, J = 8.4 Hz, 2 H),
6.55 (s, 1 H), 4.21 (q, J = 7.6 Hz, 4 H), 3.53 (s, 1 H), 1.45 (s, 6 H),
1.27 (t, J = 7.6 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 167.60, 157.37, 139.29, 121.08,
115.85, 61.54, 60.15, 48.51, 26.46, 13.97.
ESI-MS: m/z = 325.14 (M – H).
ESI-MS: m/z = 268.10 (M – H).
Methyl 2-Acetamido-3-{[4-(2-morpholinoethoxy)phenyl]sulfa-
nyl}propanoate (20)
Compound 20 was synthesized according to the above general pro-
cedure (Method A) from disulfide 3 (40 mg, 0.084 mmol) and
Michael acceptor 8 by heating the mixture for 3 h. Preparative
HPLC (using 0–20% B/90 min) afforded product 20 as a colorless
oil. Yield: 45 mg (70%).
1H NMR (400 MHz, CD3OD): d = 7.41–7.40 (A part of AB system,
J = 8.8 Hz, 2 H), 6.94–6.92 (B part of AB system, J = 8.8 Hz, 2 H),
4.47 (dd, J = 8.4, 5.2 Hz, 1 H), 4.19 (br t, J = 4.8 Hz, 2 H), 3.76 (br
t, J = 4.4 Hz, 4 H), 3.62 (s, 3 H), 3.28–3.23 (A part of ABX system,
J = 14.0, 5.2 Hz, 1 H), 3.11–3.05 (B part of ABX system, J = 14.0,
8.0 Hz, 1 H), 3.00 (br t, J = 5.2 Hz, 2 H), 2.79 (m, 4 H), 1.94 (s, 3 H).
13C NMR (100 MHz, CD3OD): d = 173.21, 172.45, 159.82, 135.53,
126.71, 116.44, 66.92, 66.68, 58.32, 54.74, 53.53, 52.84, 38.27,
22.29.
2-(Dimethylamino)ethyl 3-[4-Hydroxyphenyl)sulfanyl]-2-meth-
ylpropanoate (16)
Compound 16 was synthesized according to the above general pro-
cedure (Method B) from disulfide 1a (50 mg, 0.20 mmol) and
Michael acceptor 9 by heating the mixture for 50 min. Preparative
HPLC (using 0–40% B/90 min) afforded product 16 as a colorless
oil. Yield: 102 mg (90%).
1H NMR (400 MHz, CDCl3): d = 7.26–7.22 (m, 2 H), 6.72–6.68 (m,
2 H), 4.25–4.18 (m, 2 H), 3.10–3.04 (A part of ABX system, J =
13.6, 8.0 Hz, 1 H), 2.78–2.70 (m, 3 H), 2.62–2.57 (m, 1 H), 2.37 (s,
6 H), 1.18 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 175.23, 156.74, 134.39, 124.19,
116.38, 61.33, 57.22, 45.04, 39.72, 39.56, 16.62.
ESI-MS: m/z = 284.2 (M + H).
3-{[(4-Hydroxyphenyl)sulfanyl]methyl}bicyclo[2.2.1]heptan-2-
one (17)
Compound 17 was synthesized according to the above general pro-
cedure (Method A) from disulfide 1a (56 mg, 0.22 mmol) and
Michael acceptor 10 by heating the mixture for 30 min. Silica gel
column chromatography (hexanes–EtOAc, 2:1) afforded product
17 as a white solid. Yield: 100 mg (90%); mp 71–73 °C.
1H NMR (400 MHz, CDCl3): d = 7.32–7.30 (A part of AB system,
J = 8.0 Hz, 2 H), 6.79–6.76 (B part of AB system, J = 8.0 Hz, 2 H),
5.07 (br s, 1 H), 3.28 (dd, J = 13.2, 3.6 Hz, 1 H), 2.79 (br s, 1 H),
2.63 (br d, J = 4.8 Hz, 1 H), 2.57 (dd, J = 13.2, 11.6 Hz, 1 H), 2.34
(br dt, J = 11.6, 4.0 Hz, 1 H), 1.89–1.80 (m, 1 H), 1.66–1.53 (m, 4
H), 1.43–1.36 (m, 1 H).
ESI-MS: m/z = 383.2 (M + H).
3-({[4-(2-Morpholinoethoxy)phenyl]sulfanyl}methyl)bi-
cyclo[2.2.1]heptan-2-one (21)
Compound 21 was synthesized according to the above general pro-
cedure (Method A) from disulfide 3 (27 mg, 0.057 mmol) and
Michael acceptor 10 by heating the mixture for 40 min. Preparative
HPLC (using 10–35% B/90 min) afforded product 21 as a yellow
oil. Yield: 30 mg (73%).
1H NMR (400 MHz, CDCl3): d = 7.35–7.32 (A part of AB system,
J = 8.8 Hz, 2 H), 6.84–6.82 (B part of AB system, J = 8.8 Hz, 2 H),
4.09 (t, J = 5.2 Hz, 2 H), 3.74–3.72 (m, 4 H), 3.28 (dd, J = 14.0, 4.4
Hz, 1 H), 3.16 (br s, 1 H), 2.81 (t, J = 5.6 Hz, 2 H), 2.78 (br s, 1 H),
2.63–2.54 (m, 6 H), 2.22 (br td, J = 11.6, 4.0 Hz, 1 H), 1.87–1.79
(m, 1 H), 1.66–1.53 (m, 3 H), 1.42–1.35 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 217.68, 158.10, 133.18, 125.93,
115.30, 66.71, 65.71, 57.44, 53.93, 53.08, 50.42, 37.84, 36.48,
32.70, 25.33, 20.99.
13C NMR (100 MHz, CDCl3): d = 219.60, 155.62, 133.58, 124.92,
116.21, 53.14, 50.56, 37.82, 36.48, 32.77, 25.33, 20.93.
ESI-MS: m/z = 247.14 (M – H).
3-[(4-Hydroxyphenyl)sulfanyl]cyclopentanone (18)10j
Compound 18 was synthesized according to the above general pro-
cedure (Method B) from disulfide 1a (51 mg, 0.20 mmol) and
Michael acceptor 11 by heating the mixture for 30 min. Silica gel
column chromatography (hexanes–EtOAc, 3:1) afforded product
18 as a white solid. Yield: 68 mg (82%); mp 96–99 °C.
1H NMR (400 MHz, CDCl3): d = 7.33–7.31 (A part of AB system,
J = 8.8 Hz, 2 H), 6.82–6.79 (B part of AB system, J = 8.8 Hz, 2 H),
6.42 (br s, 1 H), 3.74–3.68 (m, 1 H), 2.58–2.44 (m, 2 H), 2.32–2.18
(m, 3 H), 2.02–1.95 (m, 1 H).
ESI-MS: m/z = 362.3 (M + H).
Methyl 2-Methyl-3-{[3-(morpholinocarbonyl)phenyl]sulfa-
nyl}propanoate (22)
Compound 22 was synthesized according to the above general pro-
cedure (Method B) from disulfide 4 (30 mg, 0.067 mmol) and
Michael acceptor 7 by heating the mixture for 5.5 h. Silica gel pre-
parative TLC (hexanes–EtOAc, 2:1) afforded product 22 as a yel-
low oil. Yield: 27 mg (63%).
1H NMR (400 MHz, CDCl3): d = 7.41–7.36 (m, 2 H), 7.32 (t, J =
8.0 Hz, 1 H), 7.21 (dt, J = 7.6, 1.2 Hz, 1 H), 3.72–3.44 (m, 11 H),
3.30–3.24 (A part of ABX system, J = 13.6, 7.6 Hz, 1 H), 2.98–2.93
(B part of ABX system, J = 13.6, 6.8 Hz, 1 H), 2.69 (sext, J = 7.2
Hz, 1 H), 1.27 (d, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 218.75, 156.42, 136.01, 123.38,
116.23, 45.20, 44.66, 36.87, 29.05.
ESI-MS: m/z = 207.1 (M – H).
Synthesis 2008, No. 13, 2023–2032 © Thieme Stuttgart · New York

2030
A. Bartolozzi et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 175.07, 169.62, 136.92–136.14,
130.79–130.77, 129.14–129.11, 127.91–127.82, 124.87–124.85,
66.84, 51.94, 51.85, 48.16, 42.56, 39.60, 37.00, 16.78.
(s, 3 H), 1.91–1.82 (m, 1 H), 1.69–1.56 (m, 4 H), 1.45–1.38 (m, 1
H).
13C NMR (100 MHz, CDCl3): d = 217.22, 170.78, 135.85, 135.44,
130.02, 129.57, 129.02, 126.62, 64.56, 52.84, 50.30, 37.99, 36.51,
31.14, 25.39, 20.98, 20.95.
ESI-MS: m/z = 324.2 (M + H).
2-(Dimethylamino)ethyl 2-Methyl-3-{[3-(morpholinocarbon-
yl)phenyl]sulfanyl}propanoate (23)
ESI-MS: m/z = 327.15 (M + Na).
Compound 23 was synthesized according to the above general pro-
cedure (Method A) from disulfide 4 (30 mg, 0.067 mmol) and
Michael acceptor 9 by heating the mixture for 12 h. Silica gel pre-
parative TLC (CH2Cl2–MeOH, 10:1) afforded traces of 2-methyl-
3-{[(3-(morpholinocarbonyl)phenyl]sulfanyl}propanoic acid and
product 23 as a yellow oil. Yield: 26 mg (50%).
1H NMR (400 MHz, CDCl3): d = 7.40–7.37 (m, 2 H), 7.32 (t, J =
7.6 Hz, 1 H), 7.21–7.19 (m, 1 H), 4.22 (t, J = 5.2 Hz, 2 H), 3.76–
3.43 (m, 8 H), 3.30–3.25 (A part of ABX system, J = 13.6, 7.2 Hz,
1 H), 3.00–2.95 (B part of ABX system, J = 13.2, 6.8 Hz, 1 H), 2.73
(sext, J = 7.2 Hz, 1 H), 2.65 (t, J = 5.2 Hz, 2 H), 2.34 (s, 6 H), 1.27
(d, J = 7.2 Hz, 3 H).
3-[(Ethylsulfanyl)methyl]bicyclo[2.2.1]heptan-2-one (26)
Compound 26 was synthesized according to the above general pro-
cedure (Method A) from diethyl disulfide (6) (59 mL, 0.48 mmol)
and Michael acceptor 10 (1.0 equiv) by heating the mixture for 2.5
h. Silica gel preparative TLC (hexanes–EtOAc, 3:1) afforded prod-
uct 26 as a yellow oil. Yield: 67 mg (75%).
1H NMR (400 MHz, CDCl3): d = 2.91 (dd, J = 12.4, 3.6 Hz, 1 H),
2.74 (br s, 1 H), 2.61 (br d, J = 5.2 Hz, 1 H), 2.52 (q, J = 5.2 Hz, 2
H), 2.29 (q, J = 12.0 Hz, 1 H), 2.23 (dt, J = 11.6, 3.6 Hz, 1 H), 1.86–
1.76 (m, 1 H), 1.68–1.53 (m, 4 H), 1.41–1.34 (m, 1 H), 1.23 (t, J =
6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 217.60, 53.42, 50.31, 38.05,
36.51, 28.40, 26.23, 25.33, 20.88, 14.62.
13C NMR (100 MHz, CDCl3): d = 174.57, 169.61, 136.98, 136.14,
130.75, 129.11, 127.88–127.82, 124.80, 66.84, 62.05, 57.42, 48.13,
45.39, 42.51, 39.61, 36.94, 16.80.
ESI-MS: m/z = 185.14 (M + H).
ESI-MS: m/z = 381.26 (M + H).
Phenyl 3-(Ethylsulfanyl)-2-methylpropanoate (27)
Compound 27 was synthesized according to the above general pro-
cedure (Method A) from diethyl disulfide (6) (70 mL, 0.58 mmol)
and Michael acceptor 13 (1.0 equiv) by heating the mixture for 3 h.
Silica gel preparative TLC (hexanes–EtOAc, 6:1) afforded product
27 as a yellow oil. Yield: 68 mg (52%).
1H NMR (400 MHz, CDCl3): d = 7.41–7.36 (m, 2 H), 7.23 (tt, J =
7.2, 1.6 Hz, 1 H), 7.12–7.09 (m, 2 H), 3.00–2.89 (m, 2 H), 2.76–2.72
(m, 1 H), 2.63 (q, J = 7.6 Hz, 2 H), 1.41 (d, J = 7.2 Hz, 3 H), 1.29
(t, J = 7.6 Hz, 3 H).
3-({[3-(Morpholinocarbonyl)phenyl]sulfanyl}methyl)bi-
cyclo[2.2.1]heptan-2-one (24)
Compound 24 was synthesized according to the above general pro-
cedure (Method A) from disulfide 4 (20 mg, 0.045 mmol) and
Michael acceptor 10 by heating the mixture for 1 h. Silica gel pre-
parative TLC (CH2Cl2–MeOH, 19:1) afforded product 24 as a yel-
low oil. Yield: 10 mg (65%).
1H NMR (400 MHz, CDCl3): d = 7.40–7.31 (m, 3 H), 7.19 (dt, J =
7.6, 1.2 Hz, 1 H), 3.76–3.66 (m, 8 H), 3.42 (dd, J = 13.2, 4.4 Hz, 2
H), 2.78 (br s, 1 H), 2.68–2.66 (m, 2 H), 2.31 (dt, J = 11.2, 4.0 Hz,
1 H), 1.90–1.83 (m, 1 H), 1.70–1.56 (m, 3 H), 1.46–1.39 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 173.63, 150.68, 129.30, 125.71,
121.43, 40.33, 34.98, 26.42, 16.79, 14.68.
13C NMR (100 MHz, CDCl3): d = 217.01, 169.58, 137.03, 136.13,
129.87, 129.10, 127.05, 124.51, 66.79, 52.66, 50.22, 48.09, 42.60,
37.98, 36.49, 30.28, 25.38, 20.96.
ESI-MS: m/z = 223.11 (M – H).
3-Methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (28)16d
A mixture of disulfide 5 (35 mg, 0.091 mmol), Ph3P (36 mg, 0.140
mmol), and 1.9 M aq K2CO3 (160 mL) in i-PrOH (0.8 mL) was heat-
ed at 80 °C for 32 h. The solvent was removed under reduced pres-
sure, and the crude product was purified by silica gel preparative
TLC (hexanes–EtOAc, 1:1) to afford product 28 as a colorless oil.
Yield: 14 mg (40%).
1H NMR (400 MHz, CDCl3): d = 7.83 (br s, 1 H), 7.59 (dd, J = 8.0,
1.2 Hz, 1 H), 7.35 (td, J = 8.0, 1.6 Hz, 1 H), 7.16 (td, J = 7.6, 1.6 Hz,
1 H), 7.09 (dd, J = 7.6, 0.8 Hz, 1 H), 3.50–3.46 (A part of ABX sys-
tem, J = 11.2, 5.6 Hz, 1 H), 3.00 (t, J = 11.2 Hz, 1 H), 2.81–2.75 (m,
1 H), 1.18 (d, J = 6.4 Hz, 3 H).
ESI-MS: m/z = 346.19 (M + H).
3-({[2-(Hydroxymethyl)phenyl]sulfanyl}methyl)bi-
cyclo[2.2.1]heptan-2-one (25)
Compound 25 was synthesized according to the above general pro-
cedure (Method A) from disulfide 1d (30 mg, 0.11 mmol) and
Michael acceptor 10 by heating the mixture for 2 h. Silica gel pre-
parative TLC (toluene–EtOAc) afforded product 25 as a yellow oil.
Yield: 20 mg (36%).
For the purpose of characterization, compound 25 was converted
into 2-{[(3-oxobicyclo[2.2.1]heptan-2-yl)methyl]sulfanyl}benzyl
acetate: A solution of the above product (20 mg, 0.076 mmol) in
CH2Cl2 (1.5 mL), pyridine (12 mL, 0.15 mmol), Ac2O (14 mL, 0.15
mmol), and DMAP (cat.) was stirred at r.t. for 30 min. The solvent
was removed under reduced pressure, and the crude product was pu-
rified by silica gel preparative TLC (toluene–EtOAc, 8:1) to afford
the corresponding benzyl acetate as a colorless oil. Yield: 18 mg
(78%).
1H NMR (400 MHz, CDCl3): d = 7.45–7.43 (A part of ABX system,
J = 8.0, 1.2 Hz, 1 H), 7.39–7.37 (B part of ABX system, J = 7.2, 1.2
Hz, 1 H), 7.30 (td, J = 7.6, 1.6 Hz, 1 H), 7.22 (td, J = 7.6, 1.2 Hz, 1
H), 5.24 (d, J = 1.2 Hz, 2 H), 3.40 (dd, J = 13.6, 4.0 Hz, 1 H), 2.78
(br s, 1 H), 2.69–2.62 (m, 2 H), 2.30 (dt, J = 11.2, 4.0 Hz, 1 H), 2.11
13C NMR (100 MHz, CDCl3): d = 175.70, 141.10, 135.12, 129.68,
127.67, 126.42, 123.42, 41.48, 36.28, 15.43.
ESI-MS: m/z = 194.13 (M + H).
One-Pot Disufide Reduction–Michael Addition Using Resin-
Supported Triphenylphosphine: Methyl 2-Acetamido-3-[(4-hy-
droxyphenyl)sulfanyl]propanoate (15); Typical Procedure
A mixture of disulfide 1a (50 mg, 0.20 mmol), Michael acceptor 8
(57 mg, 0.40 mmol), Ph3P–NovaGel resin (678 mg, 0.40 mmol) in
i-PrOH (3.0 mL), and 1.9 M aq K2CO3 (0.1 mL) was heated at 80
°C for 25 min. After cooling to r.t., the solution was filtered, and the
resin was washed successively with CH2Cl2 (5 mL) and MeOH (5
mL). The washing procedure was repeated 3 times. Removal of the
solvents afforded product 15. Yield: 64 mg (60%).
Synthesis 2008, No. 13, 2023–2032 © Thieme Stuttgart · New York

PAPER
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