Selective β-oxidation of α-sulfanyl amides

Article abstract of DOI:10.1016/j.tet.2011.05.041

A selective β-oxidation of a series of α-sulfanyl amides to the corresponding β-oxo-α-sulfanyl amides is described. This selective efficient oxidation of an unfunctionalised methyl or methylene group occurs under mild conditions, involving three sequentia

Full text of DOI:10.1016/j.tet.2011.05.041

Tetrahedron 67 (2011) 5494e5499
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Selective b-oxidation of a-sulfanyl amides
,
Marie Kissane a, Maureen Murphy a, Lorraine M. Bateman a, Daniel G. McCarthy a, Anita R. Maguire b
*
a Department of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
b Department of Chemistry and School of Pharmacy, Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
A selective b-oxidation of a series of a-sulfanyl amides to the corresponding b-oxo-a-sulfanyl amides is
described. This selective efficient oxidation of an unfunctionalised methyl or methylene group occurs
under mild conditions, involving three sequential transformations conducted without isolation of the
Received 21 February 2011
Received in revised form 20 April 2011
Accepted 9 May 2011
intermediates. Critically neither the sulfur nor the reactive
a
-CH bond is affected in the overall process.
Available online 14 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Oxidation
Organosulfur chemistry
Stereoselective synthesis
1. Introduction
The preparation of
direct oxidation at the
b-oxo esters/amides does not usually involve
The selective oxygenation of unactivated CeH bonds is chal-
lenging and has attracted much attention. Alkane oxidation is
normally achieved using oxidants such as hydrogen peroxide or
molecular oxygen in the presence of a transition metal catalyst.1e4
For substrates, which contain a sulfide, selective oxidation at car-
bon over the sulfur centre is extremely difficult to achieve.
b-carbon. Oxidation of a nonactivated
methyl or methylene group is challenging,9 and almost invariably
involves attack by free radicals, resulting in regiocontrol and se-
lectivity problems. b-Keto amides and esters may be prepared by
various methods where the b-carbon is already at the same level of
oxidation as a carbonyl carbon.10,11
b
-Oxo esters and amides are very useful compounds having
widespread biological applications. For example, 5,6-dihydro-2H-
pyran-2-ones 1, which contain the -keto- -sulfanyl ester func-
We recently reported a highly efficient and stereoselective
transformation of
fanyl-
-chloroacrylamide derivatives on treatment with NCS.12
Chemoselective and stereoselective oxidations of the -chlor-
a-sulfanyl amides to the corresponding a-sul-
b
a
b
tionality, have been investigated as inhibitors of HIV protease,
b
which is essential for viral replication.5,6 Westwood et al. reported
oacrylamides to the sulfoxide and sulfone levels of oxidation have
extended the scope of this methodology,13,14 and the dipolarophilic
the activity of
hibitor of an enzyme that is involved in the de novo pyrimidine
biosynthesis.7 Antirheumatic oxindoles contain a
-ketoamide
a-cyano-b-oxoamide 2 and its derivatives as an in-
and dienophilic behaviour of the
b
-chloroacrylamides has also been
described.15e17 The synthetic potential of the
b-chloroacrylamides
b
functionality in which the acidic enolic OH group is essential for
cyclooxygenase inhibitory activity;8 Tenidap 3 is one of the most
potent oxindoles in the treatment of rheumatoid and osteoarthritis.
as Michael acceptors in nucleophilic addition/substitution re-
actions has also been investigated, including addition of morpho-
line to yield
hydrolysis was seen on purification of the morpholine adducts by
b
-enaminoamides.18 In early experiments, partial
chromatography on silica gel, hence showing that the
noamides could be hydrolysed (Scheme 1).
b-enami-
Scheme 1.
* Corresponding author. E-mail address: a.maguire@ucc.ie (A.R. Maguire).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.041

M. Kissane et al. / Tetrahedron 67 (2011) 5494e5499
5495
Herein, the optimisation of the hydrolysis of the
mides to the corresponding -hydroxyacrylamides is described.
Having established that the -enaminoamides could be efficiently
hydrolysed, a ‘one-pot’ oxidation from the -sulfanyl amides to the
-hydroxyacrylamides was subsequently developed (Scheme 2).
b
-enaminoa-
The b-hydroxyacrylamides 5d, 7a, 9ae9c were isolated, follow-
b
ing extraction into dichloromethane and concentration, as single
stereoisomers (tentatively assigned as E), while a second set of mi-
nor signals (w7%), which were present in the 1H NMR spectrum of
9c, and which persisted on recrystallisation, were tentatively
b
a
b
assigned as the other stereoisomer. The b-hydroxyacrylamides 5d,
7a, 9ae9b were clean by 1H and 13C NMR spectroscopy, and further
purification was not required.
The b-hydroxyacrylamides may exist as the E- or Z-isomers. It is
likely that the E-isomer is favoured due to a stabilising intra-
molecular hydrogen bond between the enol OH and the amide
carbonyl; however, at this stage there is no definitive structural
evidence for the stereochemistry. The enol form predominates in
Scheme 2.
2. Results and discussion
most instances as indicated by the signal for the b-hydrogen at
7.10e7.99 ppm and the signal for the OH group at 13.52e15.70 ppm
The nucleophilic addition of morpholine to a range of
oacrylamides has been described.18 The resulting
-morpholinoa-
crylamides contain an enamine functionality, and during
chromatographic purification with a number of these -morpholi-
noacrylamides, partial or complete hydrolysis of the acid labile
enamine group was observed (Scheme 3). For example, partial
hydrolysis of the b-morpholinoacrylamide 4a on silica gel led to
a 3:1 mixture of the keto and enol tautomers of 5a, while hydrolysis
of 4b and 4c led to the enol tautomers 5b and 5c exclusively.
b-chlor-
in the 1H NMR spectra.
b
In the room temperature 1H NMR spectra of 9ae9c, the signals
for the
the broadening of the
b
-hydrogens were evident as broad singlets. To establish if
-hydrogen signal arises from the in-
b
b
terconversion of the E and Z isomers on the NMR timescale or if
coupling to the adjacent hydroxyl group is responsible, the 1H
NMR spectrum of 9a was recorded at 220 K on a 500 MHz NMR
spectrometer in CDCl3; both signals for the b-hydrogen and the
Scheme 3.
As formation of
an interesting and potentially useful transformation, the condi-
tions were optimised using the -morpholinoacrylamide 4d. Use
b
-oxygenated acrylamides by hydrolysis was
hydroxyl proton split into clearly resolved doublets with a cou-
pling constant of 11.0 Hz. Thus, the broadening of the signal for
b
the b
-hydrogen when the 1H NMR spectrum is recorded at room
of silica gel in 1:1 ethanol/water or 0.1 M hydrochloric acid in
hexane, water or toluene led to partial hydrolysis on stirring at
room temperature for 16 h. However, the use of 0.1 M hydro-
chloric acid in acetone at room temperature resulted in complete
temperature is attributed to coupling to the exchanging hydroxyl
proton, and is not due to rapid EeZ interconversion.
Since the chlorination, nucleophilic substitution and hydrolysis
conditions are intrinsically compatible, we decided to explore the
possibility of a ‘one-pot’ oxidation sequence. To that end, the con-
hydrolysis of 4d within 30 min. Hydrolysis of the
b-morpholino-
sulfinylacrylamide 6a and a number of -morpholinosulfonyla-
b
ditions for the transformation of the
a-sulfanyl amide 10d to the
crylamides (8ae8c) was also achieved under these conditions
(Table 1), highlighting that the transformation can be achieved
equally efficiently at the sulfide, sulfoxide and sulfone levels of
corresponding -hydroxyacrylamide 5d without isolation of the
intermediates were subsequently developed; treatment of the sul-
fide 10d with 2.1 equiv of NCS in toluene under reflux for 2 h gave
b
oxidation. Notably, exposure of the
a
-sulfanyl-
b
-chlor-
quantitative transformation to the b-chloroacrylamide 11d. The oil
oacrylamides to aqueous HCl does not result in hydrolysis to form
the enol under the same reaction conditions; therefore the se-
quential morpholine addition followed by enamine hydrolysis is
necessary.
bath was removed and the reaction mixture was allowed to cool to
room temperature before 2.5 equiv morpholine was added to the
stirring solution. The morpholine substitution reaction was com-
plete within 5 min by TLC analysis and the product was cooled to
0 ꢀC, enabling most of the succinimide and morpholine hydrochlo-
ride by-products to be removed by filtration prior to evaporation of
the toluene. The sample was subsequently redissolved in acetone
and 1 equiv of 0.1 M hydrochloric acid was added. Following stirring
at roomtemperaturefor 5 min and extraction into dichloromethane,
Table 1
Hydrolysis of b-morpholinoacrylamides
the b-hydroxyacrylamide 5d was isolated. This simple, rapid pro-
cedure involving only filtration, evaporation and extraction gave
a very clean product within a total reaction time of 2.5 h in 84% yield
over three steps (Scheme 4). When the transformations were con-
ducted in
a
stepwise manner, the yields of the oxidative
Starting material
R
R1
n
Product
% Yield
4d
6a
8a
8b
8c
Ph
Bn
Bn
Bn
Bn
p-Tol
4-FeC6H4
Bn
4-FeC6H4
p-Tol
0
1
2
2
2
5d
7a
9a
9b
9c
86a
71a
95a
72a
54b
a
Crude yield, further purification was not required.
Isolated yield after recrystallisation from dichloromethane/hexane.
b
Scheme 4.

5496
M. Kissane et al. / Tetrahedron 67 (2011) 5494e5499
b
-chlorination, morpholine enamide formation and enamine hy-
was the only instance that there was evidence for the existence of
the keto tautomer. -Keto esters and amides normally adopt the
conformation that allows stabilising hydrogen bond formation be-
tween the -OH and the carbonyl oxygen. The hydrogen bond be-
drolysis are 80%, 67% and 86%, respectively, leading to an overall
yield of 46%, highlighting the advantage of the telescoped process.
Investigation of the efficiency of the sequential oxidation se-
b
b
quence with a range of thio, amide and
b-alkyl substituents was
tween the amide NH and sulfur holds the primary and secondary
undertaken to establish the scope of this synthetic method. Table 2
summarises the results of these experiments.
propanamides in a rigid s-cis conformation favouring hydrogen
bonding between the
b-OH and the carbonyl oxygen in these
b-hydroxyacrylamides. In the tertiary amides, there is no NHeS
hydrogen bond thereby allowing the b-chloroacrylamide to adopt
either the s-cis or s-trans conformation.12 In the s-trans conforma-
tion, hydrogen bonding between the carbonyl oxygen and the hy-
drogen of the OH group is not possible and therefore this compound
would exist in the keto form. However, in the s-cis conformation the
Table 2
b-Oxidation of a-sulfanyl amidesdtelescoped process without isolation of
intermediates
tertiary b-hydroxyacrylamide 5a could exist in the enol form (Fig.1).
Apparently, 5a exists in both s-cis and s-trans conformations (pos-
sibly in equilibrium) as evidence for both the keto and enol forms
was observed in the 1H NMR spectrum.
Sulfide R1
R2
R3 R4 t1
t2
Product % Yieldc
a
b
(h) (h)
10d
10e
10f
Ph
Ph
n-Bu
Ph
Ph
Tol
i-Pr
Tol
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
2
2
1.5
1.5
2
2
2
1.5
0.1 5d
0.1 5e
5f
0.1 5g
84d
88
2
60e
81
10g
10a
10b
10h
10i
Me
H
16
5a
5b
5h
41f
67
Ph
Ph
(S)-CH(CH3)Ph
Tol
Bn
Et
Ph
H
23
60g
<17
83
n-Bu
(CH2)2OH Ph
0.1 5i
11jh
Me dh 22
5j
24e
Fig. 1. Keto and enol tautomers of 5a.
a
Reaction with NCS was complete within this time.
Reaction with morpholine was complete within this time.
Yield of b-hydroxyacrylamide based on starting sulfide.
Isolated yield following trituration using water and hexane.
Isolated yield following chromatographic purification.
Isolated as a mixture of the enol and keto tautomers.
Heating at reflux was required for reaction completion.
b
c
d
e
f
3. Conclusion
The transformation of secondary propanamides into the corre-
sponding b-hydroxypropenamides in a telescoped process without
g
h
Compound 5j was prepared from the b-chloroacrylamide 11j and not the sul-
isolation of the intermediates proceeds under mild conditions,
without the use of metal catalysis, in good yields of 60e88% and in
a very short time (w2.5 h) for the overall three-step process. In
fide. Dichloromethane was used as the solvent in the reaction with morpholine.
effect, this transformation oxidises the unactivated
b-methyl group
As is evident from Table 2, the limiting step in the reaction se-
quence is nucleophilic substitution of the chloride with morpho-
line, with the reaction time for this step varying from 5 min for 10d
to 60 h for 10h. In most instances, the b-hydroxyacrylamides were
isolated in good yields as clean products, although purification by
trituration or chromatography was necessary for 5d, 5f and 5j. The
of the -sulfanyl amide to the aldehyde level, while the products
a
exist predominantly as the enol tautomer. In most instances,
product purification is not required. This ‘one-pot’ oxidation is also
possible for primary, tertiary and extended chain amides, albeit in
lower yields than those obtained for the secondary propanamides.
The synthetically powerful oxidative functionalisation of the
reactivity of the
philicity of the
and yield of
secondary
b-chloroacrylamide is dependant on the electro-
-carbon, with the rate of morpholine substitution
-hydroxyacrylamide highest for the primary and
-chloroacrylamides. The reduced yield observed for the
b-carbon without affecting the sulfur centre provides scope for
b
further reaction at this carbon, including olefination or asymmetric
1,2-addition.
b
b
b
-hydroxyacrylamide 5a derived from tertiary propanamide is
presumably due to conformational effects,12,19 while steric effects
account for the lower yields of the extended chain acrylamides 5b
and 5h.
4. Experimental
4.1. General
Furthermore, the rate of the nucleophilic addition is dependent
on the stereochemistry of the
of the tertiary propanamide 10a with NCS led to a mixture of the E
and Z isomers of the -chloroacrylamide 11a. Upon addition of
morpholine, both the E and Z isomers reacted to give the corre-
sponding -morpholinoacrylamide 4a, and subsequent hydrolysis
yielded the -hydroxyacrylamide 5a. Reaction of the extended chain
-thioamides 10b and 10h with NCSalso led to a mixture of the E and
-chloroacrylamides 11b and 11h. In both instances, the Z isomers
b-chloroacrylamide. Thus, treatment
All solvents were distilled prior to use as follows: dichloro-
methane was distilled from phosphorous pentoxide and ethyl ac-
etate was distilled from potassium carbonate, ethanol and
methanol were distilled from magnesium in the presence of iodine.
Acetone was distilled from potassium permanganate and toluene
b
b
b
ꢀ
was distilled from sodium and stored over 4 A molecular sieves.
a
Z
N,N-Dimethylformamide was stored overnight over calcium hy-
b
ꢀ
dride, then distilled and stored over 4 A molecular sieves. Organic
11b-Z and 11h-Z were found to react much more rapidly with mor-
pholine than the corresponding E isomers 11b-E and 11h-E. For the
phases were dried using anhydrous magnesium sulfate.
1H (500 MHz) and 13C (125.8 MHz) NMR spectra were recorded
on a Bruker (AV500) NMR spectrometer. 1H (300 MHz) and 13C
(75.5 MHz) NMR spectra were recorded on a Bruker AV300 NMR
spectrometer. 1H (270 MHz) and 13C (67.8 MHz) NMR spectra were
recorded on a Jeol GSX 270 NMR spectrometer. All spectra were
recorded at room temperature (w20 ꢀC) in deuterated chloroform
a
-sulfanyl amides 10de10g, 10i, treatment with NCS led to the ex-
clusive formation of the Z -chloroacrylamides 11de11g, 11i.
The -hydroxyacrylamides 5b, 5de5j wereisolatedexclusivelyas
theirenol tautomers, while theN,N-dimethyl- -oxopropanamide 5a
was isolated as a 3:1 mixture of the keto and enol tautomers; this
b
b
b

M. Kissane et al. / Tetrahedron 67 (2011) 5494e5499
5497
(CDCl3) unless otherwise stated using tetramethylsilane (TMS) as
an internal standard. Chemical shifts are expressed in parts per
million (ppm) and coupling constants in Hertz (Hz).
crystalline solid. The spectroscopic details were identical to those
outlined above.
Elemental analyses were performed by the Microanalysis Lab-
oratory, National University of Ireland, Cork, using a Exeter Ana-
lytical 240 elemental analyzer. Melting points were carried out on
a Uni-Melt Thomas Hoover Capillary melting point apparatus. Mass
spectra were recorded on a Kratos Profile HV-4 double focussing
high resolution mass spectrometer (EI), a Waters/Micromass LCT
Premier Time of Flight spectrometer (ESI) and a Waters/Micromass
Quattro Micro triple quadrupole spectrometer (ESI). Infrared
spectra were recorded as potassium bromide (KBr) discs for solids
or thin films on sodium chloride plates for oils on a PerkineElmer
Paragon 1000 FT-IR spectrometer.
Thin layer chromatography (TLC) was carried out on precoated
silica gel plates (Merck 60 PF254). Column chromatography was
performed using Merck silica gel 60. Visualisation was achieved by
UV (254 nm) light detection, iodine staining, vanillin staining and
ceric sulfate staining.
4.3. N-(4-Fluorophenyl)-3-hydroxy-2-(benzylsulfinyl)
propenamide 7a
Aqueous hydrochloric acid (8.0 mL, 0.1 M, 0.80 mmol) was
added to a solution of 6a (0.16 g, 0.40 mmol) in acetone (5 mL).
Following stirring at room temperature for 15 min, TLC analysis
indicated that the reaction was complete. CH2Cl2 (10 mL) was
added to the reaction mixture, the phases were separated and the
organic layer was washed with brine (2ꢁ5 mL), dried, filtered and
concentrated at reduced pressure to give the product 7a (0.09 g,
71%) as a sticky yellow solid, as a single isomer; nmax/cmꢂ1 (KBr)
3368 (br, OH and NH), 2924 (CH), 1620 (CO), 1572, 1508, 1371 (CN
stretch), 1013 (SO); dH (300 MHz, CDCl3) 4.30 (2H, s, SCH2),
6.99e7.07 (2H, m, ArH), 7.10 [1H, s, C(3)H]], 7.16e7.39 (5H, m,
ArH), 7.42e7.49 (2H, m, ArH), 10.14 (1H, br s, NH), 13.52 (1H, br s,
OH); dc (75.5 MHz, CDCl3) 60.9 (CH2, SCH2), 104.8 [C, C(2)S], 115.7
[CH, d, 2JCF 23, aromatic C(30)H], 122.5 [CH, d, 3JCF 8, aromatic C(20)
H], 128.88, 128.93, 129.1 (3ꢁCH, 3ꢁaromatic CH), 132.5, 132.6 (2ꢁC,
2ꢁaromatic C), 159.8 [C, d, 1JCF 245, aromatic C(40)], 165.7 [CH, C(3)
H]], 167.0 (C, CO); HRMS (ESþ): exact mass calculated for
C16H15NO3SF [MþH]þ 320.0757. Found 320.0764; m/z (ESꢂ) 318.0
{[(C16H14NO3SF)ꢂHꢂ], 100%}.
4.2. Z-3-Hydroxy-N-(4-methylphenyl)-2-(phenylsulfanyl)
propenamide 5d
4.2.1. Hydrolysis of
b-morpholinopropenamide. Aqueous HCl
(3.1 mL, 0.1 M, 0.31 mmol) was added to a stirred solution of N-
(4-methylphenyl)-3-morpholino-2-(phenylsulfanyl)propenamide
4d (0.10 g, 0.28 mmol) in acetone (4 mL). Further acetone (2-
3 mL) was added to redissolve the propenamide 4d if it came out
of solution. After stirring at room temperature for 5 min, the
reaction was complete (by TLC analysis). CH2Cl2 (10 mL) was
added, the phases were separated and the organic layer was
washed with brine (2ꢁ5 mL), dried and evaporated to give 5d
(76 mg, 86%) as a light pink, crystalline solid, which was essen-
4.4. N-Benzyl-Z-3-hydroxy-2-(benzylsulfonyl)propenamide
9a
The title compound was prepared as described for 7a using 8a
(0.14 g, 0.36 mmol) in acetone (10 mL) and hydrochloric acid
(7.1 mL, 0.1 M, 0.71 mmol). Following stirring at room temperature
for 60 min, TLC analysis indicated that the reaction had gone to
completion. Dichloromethane (15 mL) was added to the reaction
mixture, the phases were separated and the organic layer was
washed with brine (2ꢁ10 mL), dried, filtered and concentrated at
reduced pressure to give 9a (0.11 g, 95%) as an off-white solid, mp
113e114 ꢀC; nmax/cmꢂ1 (KBr) 3434 (OH), 3350 (NH), 2923 (CH),1619
(CO), 1552 (NH bend), 1453 (CN stretch), 1360 (asymmetric SO2
stretch), 1148 (symmetric SO2 stretch); dH (400 MHz, CDCl3) 4.24
(2H, s, SCH2), 4.28 (2H, d, J 6.0, NHCH2), 7.14e7.20 (2H, m, ArH),
7.23e7.41 (8H, m, ArH), 7.55 (1H, br s, NH), 7.88 [1H, br s, C(3)H]],
15.70 (1H, br s, OH); dH (500 MHz, CDCl3, 220 K) 4.23 (2H, d, J 4.7,
SCH2), 4.32 (2H, s, NHCH2), 7.19 (2H, d, J 7.2, ArH), 7.30e7.52 (9H, m,
NH and ArH), 7.93 [1H, d, J 11.0, C(3)H]], 15.88 (1H, d, J 11.0, OH); dc
(75.5 MHz, CDCl3) 43.2 (CH2, NHCH2), 63.9 (CH2, SCH2), 105.1 [C,
C(2)S], 127.6, 127.9 (2ꢁCH, 2ꢁaromatic CH), 128.0 (C, aromatic C),
128.9,129.0,129.3,130.9 (4ꢁCH, 4ꢁaromatic CH),136.5 (C, aromatic
C), 167.2 (C, CO), 176.1 [CH, C(3)H]]; HRMS (ESþ): exact mass cal-
culated for C17H18NO4S [MþH]þ 332.0957. Found 332.0947; m/z
(ESþ) 332.0 {[(C17H18NO3S)þHþ], 48%}.
1
tially pure by H NMR spectroscopy; mp 61e63 ꢀC. Found C,
67.47; H, 5.28; N, 5.01; S, 11.20. C16H15NO2S requires C, 67.34; H,
5.30; N, 4.91; S, 11.24; UV lmax/nm 274, 245, 207;
dmꢂ3 molꢂ1 cmꢂ1 16,180, 17,470, 25,770; nmax/cmꢂ1 (KBr) 3355
(br NH, OH), 1628, 1594 (CO -unsaturated amide); dH (270
3/
a,b
MHz, CDCl3) 2.29 (3H, s, ArCH3), 7.09e7.32 (9H, m, ArH), 7.74 (1H,
d, J 11, CHOH]), 8.30 (1H, br s, NH), 14.21 (1H, d, J 11, ]CHOH);
dC (67.8 MHz, CDCl3) 20.8 (ArCH3), 96.4 (SC]), 120.2, 125.4, 125.8,
129.3, 129.8 (aromatic CH), 133.9, 134.8, 136.5 (aromatic C), 169.0
(CO amide), 172.0 (CHOH]); MS m/z 285 (Mþ, 32%), 196 (89), 107
(100), 91 (100).
4.2.2. One pot synthesis. NCS (0.31 g, 2.3 mmol) was added in one
portion to a solution of 10d (0.30 g, 1.11 mmol) in toluene (6 mL)
and the reaction flask was submerged rapidly in an oil bath pre-
heated to 130 ꢀC. After 2 h the reaction was complete (by TLC
analysis) and the reaction mixture was removed from the oil bath
and cooled to room temperature. Morpholine (243 mL, 2.78 mmol)
was added generating fumes (probably hydrogen chloride gas). TLC
analysis after 5 min showed complete reaction. Filtration to remove
the by-products (succinimide and morpholine hydrochloride) fol-
4.5. N-(4-Fluorophenyl)-3-hydroxy-2-(benzylsulfonyl)
propenamide 9b
lowed by evaporation of the toluene gave the
b
-morpholinopro-
This was synthesised as outlined for 7a using 8b (0.10 g,
0.3 mmol) in acetone (5 mL) and hydrochloric acid (10.0 mL, 0.1 M,
10.0 mmol). TLC analysis showed the reaction to be complete after
40 min and following the work-up, 9b (0.06 g, 72%) was obtained as
a white solid and as a single isomer, mp 113e114 ꢀC; nmax/cmꢂ1
(KBr) 3429 (OH), 3320 (NH), 2923 (CH), 1618 (CO), 1567 (NH bend),
1507, 1367 (asymmetric SO2 stretch), 1143 (symmetric SO2 stretch);
dH (400 MHz, CDCl3) 4.34 (2H, s, SCH2), 6.95e7.03 (2H, m, ArH),
7.18e7.36 (7H, m, ArH), 7.99 [1H, br s, C(3)H]], 8.91 (1H, br s, NH),
15.16 (1H, br s, OH); dc (75.5 MHz, CDCl3) 64.4 (CH2, SCH2), 106.1 [C,
penamide 4d (436 mg, quant.), which was dissolved in acetone
(3 mL). HCl (0.1 M, 11 mL, 1.11 mmol) was added followed by ace-
tone (3 mL) to redissolve the reactants. After stirring for 10 min at
room temperature the reaction was complete (by TLC analysis) and
CH2Cl2 (10 mL) was added. The aqueous layer was washed with
CH2Cl2 (2ꢁ5 mL) and the combined organic layers were washed
with brine (2ꢁ10 mL), dried and evaporated to give 5d (0.30 mg,
94%) as a dark pink, crystalline solid. The compound was essentially
pure by 1H NMR spectroscopy at this stage, however trituration
with water/hexane (99:1) gave 5d (0.27 g, 84%) as a light pink,
2
3
C(2)S], 115.7 [CH, d, JCF 23, aromatic C(30)H], 122.9 [CH, d, JCF 8,

5498
M. Kissane et al. / Tetrahedron 67 (2011) 5494e5499
aromatic C(20)H], 127.8 (C, aromatic C), 129.1, 129.5, 130.9 (3ꢁCH,
3ꢁaromatic CH), 131.6 (C, aromatic C), 160.1 [C, d, 1JCF 245, aromatic
C(40)], 165.3 (C, CO), 175.9 [CH, C(3)H]]; HRMS (ESꢂ): exact mass
calculated for C16H13NO4SF [MꢂH]ꢂ 334.0549. Found 334.0560; m/z
(ESꢂ) 334.0 {[(C16H13NO4SF)ꢂHꢂ], 100%}.
(1H, br s, NH), 13.81 (1H, d, J 12, CHOH]); dC (67.8 MHz, CDCl3) 13.6
[C(40)H3], 20.9 (ArCH3), 21.7 [C(30)H2], 31.1 [C(20)H2], 36.9 [C(10)H2],
98.7 (SC]), 120.4, 129.6 (aromatic CH), 134.3, 134.7 (aromatic C),
169.5 (CO amide), 170.1 (CHOH]); MS m/z 265 (Mþ, 18%), 107 (100),
91 (8, [Tol]þ).
4.6. 3-Hydroxy-N-(4-methylphenyl)-2-(benzylsulfonyl)
propenamide 9c
4.9. Z-3-Hydroxy-2-(phenylsulfanyl)propenamide 5g
This was prepared following the procedure described for 5d
using 10g (0.30 g, 1.66 mmol), NCS (0.47 g, 3.5 mmol) and toluene
(6 mL) with a reaction time of 2 h, followed by morpholine
(0.36 mL, 4.15 mmol) with a reaction time of 10 min. Hydrolysis
using acetone (4 mL) and HCl (1 M, 2 mL, 2 mmol) gave 5g (0.21 g,
81%) as a light pink, crystalline solid; mp 58e60 ꢀC. Found C 55.65;
H, 4.84; N, 7.33; S, 16.08. C9H9NO2S requires C, 55.37; H, 4.65; N,
The title compound was prepared as described for 7a using 8c
(0.09 g, 0.2 mmol) in acetone (5 mL) and hydrochloric acid (9.0 mL,
0.1 M, 0.9 mmol). Following stirring for 30 min, TLC analysis in-
dicated that the reaction had gone to completion and the crude
product 9c was obtained as an off-white solid after the work-up.
After recrystallisation from dichloromethane/hexane, 9c was iso-
lated as a white solid (0.04 g, 54%), mp 126e127 ꢀC; nmax/cmꢂ1
(KBr) 3439 (OH), 3314 (NH), 2984 (CH), 1630 (CO), 1607, 1558 (NH
bend), 1509, 1408 (CN stretch), 1324 (asymmetric SO2 stretch), 1125
(symmetric SO2 stretch); dH (400 MHz, CDCl3) 2.33 (3H, s, ArCH3),
4.33 (2H, s, SCH2), 7.11 (2H, d, J 8.4, ArH), 7.16 (2H, d, J 8.4, ArH),
7.22e7.40 (5H, m, ArH), 7.94 [1H, s, C(3)H]], 8.92 (1H, br s, NH),
15.36 (1H, br s, OH); dc (75.5 MHz, CDCl3) 20.9 (CH3, ArCH3), 64.2
(CH2, SCH2), 105.9 [C, C(2)S], 121.2 (CH, aromatic CH), 127.8 (C, ar-
omatic C), 129.1, 129.5 (signal for 2ꢁCH), 130.9 (3ꢁCH, 3ꢁaromatic
CH), 133.0, 135.5 (2ꢁC, 2ꢁaromatic C), 165.3 (C, CO), 176.0 [CH, C(3)
H]]; HRMS (ESþ): exact mass calculated for C17H18NO4S [MþH]þ
332.0957. Found 332.0962; m/z (ESꢂ) 330.1 {[(C17H17NO3S)þHþ],
100%}.
7.17; S,16.42; nmax/cmꢂ1 (KBr) 3421 (br NH, OH),1654,1604 (CO
a,b-
unsaturated amide); dH (270 MHz, CDCl3) 6.11 (1H, br s, NH), 6.48
(1H, br s, NH), 7.14e7.48 (5H, m, ArH), 7.70 (1H, br s, CH]), (1H, br d,
COH]); dC (67.8 MHz, CDCl3) 95.2 (SC]), 124.7, 125.7, 129.4 (aro-
matic CH), 136.7 (aromatic C), 172.6 (aromatic CH), 173.7 (CO); MS
m/z 195 (Mþ, 80%), 178 (71, MþꢂOH), 121 (100, [PhS]C]þ).
4.10. N,N-Dimethyl-3-oxo-2-(phenylsulfanyl)propanamide 5a
Note: This compound is judged to be a mixture of keto and enol
tautomers.
This was prepared following the procedure described for 5d
using 10a (0.20 g, 1.0 mmol), NCS (0.28 mg, 2.06 mmol) and toluene
(4 mL) with a reaction time of 2 h, followed by morpholine
(0.22 mL, 2.5 mmol) with a reaction time of 16 h. Hydrolysis using
acetone (6 mL) and HCl (10 mL, 0.1 M, 1 mmol) gave a mixture of
products. Purification by chromatography using ethyl acetate/hex-
ane (25:75) as eluent gave N,N-dimethyl-3-oxo-2-(phenylthio)
propanamide 5a (0.90 g, 41%) as a colourless oil, which is unstable
at room temperature. The estimated ratio of keto to enol tautomeric
forms is 3:1; nmax/cmꢂ1 (film) 3272 (br NH), 1721 (CO aldehyde),
1645 (CO amide); dH (270 MHz, CDCl3) 3.00 (ArCH3), 3.13, 3.18 [6H,
3ꢁs, N(CH3)2 enol/keto forms], 4.33 (<1H, d, J 5, CHS keto form),
7.13e7.57 (5H, m, ArH), 7.71 (<1H, s, CHOH¼enol form), 9.62 (<1H,
d, J 5, CHO keto form); dC (67.8 MHz, CDCl3) 35.8, 37.2, 38.2
[N(CH3)2], 57.6 (CHS), 129.2, 129.3, 133.3 (aromatic CH), 136.0 (ar-
omatic C), 165.2, 175.7, 192.2 (CO amide, C-3 enol/keto forms); MS
m/z 223 (Mþ, 5%), 194 (8, MþꢂCHO), 72 (100, [CON(CH3)2]þ).
A second set of signals (w7%) were also present in the 1H NMR
spectrum and were tentatively assigned to the stereoisomer: dH
(400 MHz, CDCl3) 4.37 (2H, s), 7.88 (1H, br d), 9.45 (1H, br s).
4.7. 3-Hydroxy-N-i-propyl-2-(phenylsulfanyl)propenamide 5e
This was prepared following the procedure described for 5d
using 10e (0.30 g, 1.35 mmol), NCS (0.38 g, 2.83 mmol) and toluene
(6 mL) with a reaction time of 1.5 h, followed by morpholine
(0.29 mL, 3.36 mmol) with a reaction time of 5 min. Hydrolysis
using acetone (4 mL) and HCl (14 mL, 0.1 M, 1.4 mmol) gave 5e
(0.19 g, 60%) as a pink oil. The propenamide was judged to be an-
alytically pure; nmax/cmꢂ1 (film) 3380 (br NH, OH), 1613 (CO
a,b-
unsaturated amide); dH (270 MHz, CDCl3) 1.06 [6H, d, J 7,
NHCH(CH3)2], 4.07 (1H, symm m, J 7, NCH), 6.31e6.41 (1H, br m,
NH), 7.13e7.31 (5H, m, ArH), 7.65 (1H, d, J 7, CHOH]), 14.52 (1H, br
d, CHOH]); dC (67.8 MHz, CDCl3) 22.9 [NHCH(CH3)2], 41.8 (NCH),
96.4 (SC]), 125.7, 126.4, 129.3 (aromatic CH), 137.6 (quaternary
aromatic C), 170.2, 171.6 (CO amide and CHOH]); MS m/z 237 (Mþ,
78%), 208 (30, MþꢂCHO), 178 (68), 120 (100), 105 (49). Found
(HRMS, EI) Mþ 237.08249. C12H15NO2S requires m/z 237.08235.
4.11. Z-3-Hydroxy-(10S)-N-10-phenylethyl-2-(phenylsulfanyl)-
2-pentenamide 5b
This was prepared following the procedure described for 5d
using 10b (0.20 g, 0.64 mmol), NCS (0.18 g, 1.34 mmol) and toluene
(4 mL) with a reaction time of 2 h, followed by morpholine
(0.14 mL, 1.6 mmol) with a reaction time of 23 h. Acetone (6 mL)
and HCl (0.1 M, 6.5 mL, 0.65 mmol) were used for hydrolysis giving
a crude reaction mixture (190 mg). Purification by chromatography
using ethyl acetate/hexane (10:90) as eluent gave 5b (95 mg, 67%)
4.8. 3-Hydroxy-N-(4-methylphenyl)-2-(n-butylsulfanyl)
propenamide 5f
This was prepared following the procedure described for 5d
using 10f (0.25 g, 1.0 mmol), NCS (0.28 mg, 2.09 mmol) and toluene
(5 mL) with a reaction time of 2 h, followed by morpholine
(0.22 mL, 2.49 mmol) with a reaction time of 2 h. Hydrolysis using
acetone (5 mL) and HCl (0.1 M, 10 mL, 1 mmol) gave crude 3-
hydroxypropenamide 5f (0.22 mg, 82%) as a yellow oil. Purifica-
tion by chromatography using ethyl acetate/hexane (4:96) as eluent
gave 5f (0.16 g, 60%) as a light pink oil. Found C, 63.42; H, 7.31; N,
5.42; S, 12.17. C14H19NO2S requires C, 63.37; H, 7.22; N, 5.28; S,
12.09; nmax/cmꢂ1 (film) 3330 (br NH, OH), 1625, 1595 (CO amide);
dH (270 MHz, CDCl3) 0.91 [3H, t, J 7, C(40)H3], 1.34e1.45 [2H, m, C(30)
H2], 1.47e1.62 [2H, m, C(20)H2], 2.33 (3H, s, ArCH3), 2.52 (2H, t, J 7,
SCH2), 7.15e7.45 (4H, ABq, J 8, ArH), 7.60 (1H, d, J 12, CHOH]), 8.70
(Rf 0.6 using ethyl acetate/hexane (25:75) as eluent) as a colourless
20
D
oil; [
a]
13.48 (c 7, ethanol); nmax/cmꢂ1 (film) 3380 (br NH, OH),
1581, 1518 (CO
a,b-unsaturated amide); dH (270 MHz, CDCl3) 1.09
[3H, t, J 8, C(5)H3], 1.35 [3H, d, J 8, C(20)H3], 2.64 [1H, q, J 8, C(4)H2],
5.00e5.13 [1H, dq, J 8, 8, C(10)H], 7.09e7.30 (11H, m, ArH, NH),
enolic OH seen at d>10 ppm; dC (67.8 MHz, CDCl3) 11.0 [C(5)H3],
22.2 [C(20)H3], 27.2 [C(4)H2], 48.9 [C(10)H], 90.0 (SC]), 125.3, 125.8,
126.1, 127.2, 128.6, 129.2 (aromatic CH), 137.2, 143.1 (aromatic C),
171.3 (CO amide), 187.5 (COH]); MS m/z 327 (Mþ, 100%), 271 (5),
120 (15, [NHCHCH3Ph]þ), 105 (28, [CHCH3Ph]þ). Found (HRMS, EI)
M
þ 327.13609. C19H21NO2S requires m/z 327.12930.

M. Kissane et al. / Tetrahedron 67 (2011) 5494e5499
5499
4.12. 3-Hydroxy-N-(4-methylphenyl)-3-phenyl-2-
(phenylsulfanyl)propenamide 5h
(16 mg, 24%) as a red oil; nmax/cmꢂ1 (film) 3314 (br NH, OH), 1682,
1597 (CO -unsaturated amide); dH (270 MHz, CDCl3) 2.39 [3H, s,
a,b
C(4)H3], 2.74 (2H, dd, J 6, 6, CH2S), 3.80 (2H, dd, J 6, 6, CH2O),
7.13e7.59 (5H, m, ArH), 9.35 (1H, br s, NH). The enolic OH was seen
in one sample at >10 ppm; MS m/z 253 (Mþ, 17%), 209 (9), 107(48),
93 (100, [NH2Ph]þ).
This was prepared following the procedure described for 5d
using 10h (0.30 g, 0.86 mmol), NCS (0.24 g, 1.76 mmol) and toluene
(6 mL) with a reaction time of 2 h, followed by morpholine
(0.19 mL, 2.15 mmol) with a reaction time of 60 h (by TLC analysis),
including heating at reflux for 1 h. Hydrolysis using acetone (7 mL)
and HCl (0.1 M, 9 mL, 0.9 mmol) in a reaction time of 24 h gave
a crude reaction mixture (198 mg) as an oil. Purification by chro-
matography using ethyl acetate/hexane (5:95) as eluent gave 5h;
Acknowledgments
IRCSET, Forbairt and University College Cork are gratefully
acknowledged for funding of this work.
nmax/cmꢂ1 (film) 3339 (br NH, OH), 1678 (CO
a,b-unsaturated am-
ide), dH (270 MHz, CDCl3) 2.31 (3H, s, ArCH3), 7.09e7.62 (14H, m,
ArH), 8.85 (1H, br s, NH), the signal for the enolic proton was seen at
References and notes
1. Hudlicky, M. Oxidations in Organic Chemistry; American Chemical Society:
Washington, DC, 1990.
dH>11.
2. Thomas, J. M.; Raja, R.; Sankar, G.; Bell, R. G. Acc. Chem. Res. 2001, 34, 191e200.
3. Mizuno, N.; Nozaki, C.; Kiyoto, I.; Misono, M. J. Am. Chem. Soc. 1998, 120,
9267e9272.
4.13. N-Benzyl-3-hydroxy-2-(n-butylsulfanyl)propenamide 5i
4. Hayashi, T.; Kishida, A.; Mizuno, N. Chem. Commun. 2000, 381e382.
5. Hahn, H. G.; Nam, K. D.; Mah, H.; Lee, J. J. J. Org. Chem. 1996, 61, 3894e3896.
6. Hamilton, H. W.; Tait, B. D.; Gajda, C.; Hagen, S. E.; Ferguson, D.; Lunney, E. A.;
Pavlovsky, A.; Tummino, P. J. Bioorg. Med. Chem. Lett. 1996, 6, 719e724.
7. Kuo, E. A.; Hambleton, P. T.; Kay, D. P.; Evans, P. L.; Matharu, S. S.; Little, E.;
McDowall, N.; Jones, C. B.; Hedgecock, C. J.; Yea, C. M.; Chan, A. W.; Hairsine, P.
W.; Ager, I. R.; Tully, W. R.; Williamson, R. A.; Westwood, R. J. Med. Chem. 1996,
39, 4608e4621.
This was prepared following the procedure described for 5d
using 10i (0.28 g, 1.12 mmol), NCS (0.31 g, 2.34 mmol) and toluene
(6 mL) with a reaction time of 1.5 h, followed by morpholine
(0.25 mL, 2.8 mmol), with a reaction time of 5 min. Hydrolysis us-
ing acetone (6 mL) and HCl (0.1 M, 11 mL, 1.1 mmol) gave 5i (0.21 g,
83%), as a pink oil; nmax/cmꢂ1 (film) 3369 (br NH, OH), 1618 (CO
a,b-
8. Robinson, R. P.; Reiter, L. A.; Barth, W. E.; Campeta, A. M.; Cooper, K.; Cronin, B.
J.; Destito, R.; Donahue, K. M.; Falkner, F. C.; Fiese, E. F.; Johnson, D. L.; Kuper-
man, A. V.; Liston, T. E.; Malloy, D.; Martin, J. J.; Mitchell, D. Y.; Rusek, F. W.;
Shamblin, S. L.; Wright, C. F. J. Med. Chem. 1996, 39, 10e18.
9. Haines, A. H. Methods for the Oxidation of Organic Compounds; Academic Press:
London, 1985.
10. Kanner, C. B.; Pandit, U. K. Tetrahedron 1982, 38, 3597e3604.
11. Abram, T. S.; Boeshagen, H.; Butler, J. E.; Cuthbert, N. J.; Francis, H. P.; Gardiner,
P. J.; Hartwig, W.; Kluender, H. C.; Meier, H. Bioorg. Med. Chem. Lett. 1993, 3,
1517e1522.
unsaturated amide); dH (270 MHz, CDCl3) 0.86 [3H, t, J 7, C(40)H3],
1.27e1.38 [2H, m, C(30)H2],1.39e1.65 [2H, m, C(20)H2], 2.39e2.45
[2H, m, C(10)H2], 4.51 (2H, d, J 6, CH2Ph), 7.25e7.35 (5H, m, ArH),
7.52 (1H, d, J 10, CH]), 11.30 (1H, d, J 11, COH]); dC (67.8 MHz,
CDCl3) 14.0 [C(40)H3], 22.0 [C(30)H2], 31.6 [C(20)H2], 36.9 [C(10)H2],
44.2 (CH2Ph), 98.6 (SC]), 128.1, 128.8 (aromatic CH, 2 signals for 3
carbons), 138.1 (aromatic C), 169.8 (CH]), 171.5 (CO); MS m/z 265
(Mþ, 20%), 237 (22, MþꢂCO), 208 (12), 178 (18). Found (HRMS, EI),
Mþ 265.11326. C14H19NO2S requires m/z 265.11365.
12. Murphy, M.; Lynch, D.; Schaeffer, M.; Kissane, M.; Chopra, J.; O’Brien, E.; Ford,
A.; Ferguson, G.; Maguire, A. R. Org. Biomol. Chem. 2007, 5, 1228e1241.
13. Kissane, M.; Lynch, D.; Chopra, J.; Lawrence, S. E.; Maguire, A. R. Tetrahedron:
Asymmetry 2008, 19, 1256e1273.
4.14. N-Phenyl-2-[20-(hydroxyethyl)sulfanyl]-3-hydroxy-2-
butenamide 5j
14. Kissane, M.; Lawrence, S. E.; Maguire, A. R. Tetrahedron: Asymmetry 2010, 21,
871e884.
15. Kissane, M.; Lawrence, S. E.; Maguire, A. R. Org. Biomol. Chem. 2010, 8,
2735e2748.
16. Kissane, M.; Lawrence, S. E.; Maguire, A. R. Tetrahedron 2010, 66, 4564e4572.
17. Kissane, M.; Lynch, D.; Chopra, J.; Lawrence, S. E.; Maguire, A. R. Org. Biomol.
Chem. 2010, 8, 5602e5613.
18. Kissane, M.; Murphy, M.; O’Brien, E.; Chopra, J.; Murphy, L.; Collins, S. G.;
Lawrence, S. E.; Maguire, A. R. Org. Biomol. Chem. 2011, 9, 2452e2472.
19. Kissane, M.; Murphy, M.; Lynch, D.; Ford, A.; Maguire, A. R. Tetrahedron 2008,
64, 7639e7649.
This was prepared following the procedure described for 5d
using 11j-Z (85 mg, 0.31 mmol), morpholine (68 mL, 0.78 mmol)
and CH2Cl2 (2 mL) with a reaction time of 22 h. Acetone (4 mL) and
HCl (0.1 M, 3 mL, 3 mmol) were used for the hydrolysis giving
a crude mixture (50 mg). Purification by preparative thin layer
chromatography using ethyl acetate/DCM/hexane (25:5:70) gave 5j