1,3-Dipolar cycloadditions of 2-thio-3-chloroacrylamides with nitrile oxides and nitrones

Article abstract of DOI:10.1016/j.tet.2010.04.057

1,3-Dipolar cycloadditions of 2-thio-3-chloroacrylamides with nitrile oxides and nitrones is described. A?series of novel isoxazolines are isolated from the nitrile oxide cycloadditions, whilst the isoxazolines generated from the nitrone cycloadditions undergo further ring opening to yield piperidines.

Full text of DOI:10.1016/j.tet.2010.04.057

Tetrahedron 66 (2010) 4564e4572
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Tetrahedron
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1,3-Dipolar cycloadditions of 2-thio-3-chloroacrylamides with nitrile oxides
and nitrones
,
Marie Kissane a, Simon E. Lawrence a, Anita R. Maguire b
*
a Department of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
b Department of Chemistry & 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:
1,3-Dipolar cycloadditions of 2-thio-3-chloroacrylamides with nitrile oxides and nitrones is described.
A series of novel isoxazolines are isolated from the nitrile oxide cycloadditions, whilst the isoxazolines
generated from the nitrone cycloadditions undergo further ring opening to yield piperidines.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 19 February 2010
Received in revised form 26 March 2010
Accepted 12 April 2010
Available online 24 April 2010
1. Introduction
to a novel series of isoxazolines and piperidines is discussed. While
the cycloadditions have been attempted at the sulfide and sulfoxide
The 1,3-dipolar cycloaddition is a powerful synthetic tool in or-
ganic synthesis due to the high degree of regio- and stereocontrol
which accompanies the reaction.1 The versatility of the cycloaddition
levels of oxidation, use of the sulfoxide derivatives is clearly ben-
eficial for stereoselective construction of dipolar cycloadducts. We
were particularly interested to establish the regio- and stereo-
chemical aspects of the cycloadditions, and also to investigate if
desulfinylation of the cycloadducts would occur.
is evident in the structural variety of the 4p and 2p components,
including functionality such as C^C, C]C, C^N, C]N, C]O and C]
S with both isolated or conjugated systems.
We have recently reported the highly efficient and stereoselective
2. Results and discussion
transformation of
chloroacrylamide derivatives on treatment with NCS.2 We have ex-
tended this work to include -bromoacrylamides, -chloroacrylates
and -thio- -chloroacrylamides can be
-chloroacrylonitriles.3 The
a-thioamides to the corresponding a-thio-b-
2.1. 1,3-Dipolar cycloadditions with nitrile oxides
b
b
b
a
b
Preliminary investigations of the 1,3-dipolar cycloaddition of
chemoselectively oxidised to either the racemic sulfoxide or sulfone
p-nitrobenzonitrile oxide with the benzenesulfinyl substituted
very efficiently, and furthermore enantioselective oxidation to the
b-chloroacrylamide
1
involved the generation of p-nitro-
sulfoxide derivatives of the
achieved.4 The
-chloroacrylamides, which can have a wide variety
of substituents on the basic acrylamide framework, have synthetic
potential as the 2 component in 1,3-dipolar cycloadditions.
a-thio-b-chloroacrylamides has been
benzonitrile oxide in situ from p-nitrobenzohydroximoyl chloride 2
in the presence of triethylamine. However, the expected isoxazo-
line cycloadduct was not formed; instead, nucleophilic addition of 2
b
p
or its oxyanion to the b-carbon of 1 occurred to afford 3 (Scheme 1).
The dipolarophilic behaviour of vinyl sulfides and in particular
vinyl sulfoxides in cycloadditions with nitrile oxides has been
reported, with desulfinylation of the resulting cycloadducts to
afford aromatic compounds commonly observed.5e7 Reports on
1,3-dipolar cycloadditions of nitrones with vinyl sulfoxides are
more limited, but in general the reactions proceed with a high
degree of regio- and stereoselectivity.8e12 The 1,3-dipolar cy-
cloaddition of vinyl sulfides with nitrones has also been
reported.13
Nucleophilic attack of 2 was much faster than dehydrohalogenation
with triethylamine, therefore in situ generation of the dipole was
not feasible.
O
N
S(O)Ph
CONHTol
Ar
O
PhS
O
Cl
Ar
Cl
C N OH
NHTol
+
NEt3
Cl
Herein, the reactivity of a range of b-chloroacrylamides with
benzonitrile oxide and 2,3,4,5-tetrahydropyridine N-oxide leading
Ar = p-NO2-C6H4
O
PhS
O
1
NHTol
2
N
Cl
O
3
Ar
* Corresponding author. Tel.: þ353 21 4901693; fax: þ353 21 4274097;
Scheme 1.
e-mail address: a.maguire@ucc.ie (A.R. Maguire).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.057

M. Kissane et al. / Tetrahedron 66 (2010) 4564e4572
4565
To eliminate the possibility of nucleophilic addition, benzonitrile
oxide 4 was pre-formed by reaction of benzohydroximoyl chloride 5
with a 1 M solution of sodium hydroxide in ether (Scheme 2). Fol-
lowing stirring at 0 ꢀC for 10 min, the ether layer was quickly dried
and added to a solution of the b-chloroacrylamide in ether. Under
these conditions, by minimising the time involved, dimerisation of
contain unreacted starting material and small amounts of the iso-
xazoline cycloadduct. For the reaction of the sulfoxides 1,10 (entries
6 and 7, Table 1) and 12 (entry 8, Table 1) and the sulfides 16 and 17
(entries 10 and 11, Table 1) with 4 the product did not precipitate
from the reaction mixture and accordingly, the reaction mixture
was concentrated to give a mixture of unreacted starting material
and the isoxazoline cycloadduct. Purification by chromatography on
silica gel afforded the isoxazoline cycloadducts 22, 23, 25, 27 and 28.
For the isoxazolines 25, 27 and 28, the isolated products also con-
the nitrile oxide did not prove to be a significant issue.
1M NaOH, ether
0 °C, 10 min
Ph
Cl
Ph C N O
C N OH
tained unreacted b-chloroacrylamides 12, 16 and 17 respectively.
Modest yields of the isoxazolines were obtained in most cases. For
the cycloaddition of 12 with 4, a fresh portion of 4 in ether was
added after 16 h; however, this did not succeed in driving the re-
action to completion.
5
4
Scheme 2.
2.2. Cycloadditions with benzonitrile oxide
The dipolarophilic behaviour of the -chloroacrylamides towards
benzonitrile oxide was explored first as summarised in Table 1.
A solution of pre-formed benzonitrile oxide in ether was added to
There is a characteristic singlet in the 1H NMR spectra of the iso-
xazoline cycloadducts 18e25 at dH 6.22e6.51 ppm due to the proton
of the heterocycle geminal to the chloride. A distinctive doublet of
doublets is also seen in the region dH 7.78e7.85 ppm, assigned to the
ortho-protons on the phenyl ring attached to the 3-position of the
heterocycle. This is presumably attributed to the magnetic anisotropy
of the C]N of the isoxazoline ring. In no instance were signals for
regioisomeric isoxazoline cycloadducts identified.
b
a solution of the b-chloroacrylamide (sulfoxide or sulfide) in ether
and the reaction mixture was then stirred overnight at room tem-
perature. The product was isolated either by concentration at re-
duced pressure followed by chromatographic purification or, in cases
where the product precipitated out of solution as the reaction pro-
gressed, by filtration of the reaction mixture. In each instance the
isoxazoline cycloadduct was isolated as a single regioisomer and di-
astereoisomer. Formation of a single regioisomer of these cyclo-
adducts, in contrast to the literature precedent,6,7 is particularly
significant.
All attempts to grow a single crystal of one of the isoxazolines for
X-ray crystallographic analysis to confirm the regiochemistry of the
cycloaddition were unsuccessful and therefore the isoxazoline 18
was transformed to the isoxazole 29 on treatment with morpholine
to effect base-induced elimination of the sulfoxide (Scheme 3).17e19
O
O
O
N
S(O)Bn
CONHTol
N
CONHTol
+
Table 1
Ph
N
H
Ph
Cl
29
Reaction of b-chloroacrylamides with benzonitrile oxide
Cl
18
O
N
O
S(O)nR1
CONHR2
O
R1S(O)n
Cl
N
ether
Scheme 3.
NHR2
C
rt, 16 h
Ph
Cl
Ph
It was possible to grow a single crystal of 29 from acetone, and
X-ray diffraction established the structure of 29 and hence the
regiochemistry of the cycloaddition to be that with the amide
group at the 5-position of the isoxazole ring (Fig. 1).
The regiochemistry of the isoxazoline cycloadducts was thus
assigned by analogy, with the sulfoxide and amide groups at the 5-
position of the isoxazoline ring. The observed regiochemistry agrees
with theoretical predictions;20 nitrile oxide cycloadditions are di-
pole-LUMO controlled for conjugated dipolarophiles, and the most
favourable direction of combination is that in which the carbon atom
Entry
b-Cl
R1
R2
n
Isoxazoline
% Yield
1
2
3
4
5
6
7
8
6
7
8
9
1
10
11
12
15
16
17
Bn
Bn
Bn
Ph
Ph
Ph
n-Bu
n-Bu
Bn
Tol
Bn
Me
Bn
Tol
Me
Tol
Bn
Tol
Bn
1
1
1
1
1
1
1
1
0
0
0
18
19
20
21
22
23
24
25
26
27
28
48a
72a
43a
32a
13b
12b
16a
33c
9
10
11
21a
11d
21b,e
of the nitrile oxide adds to the b-carbon of the b-chloroacrylamide
Bn
Bn
(Fig. 2). This combination is also very favourable on steric grounds, as
the less crowded end of the dipole adds to the more substituted end
of the dipolarophile.
n-Bu
a
Isolated yield after filtration of reaction mixture.
Isolated yield after chromatography.
Calculated yield. Isolated in 48% yield as a mixture with the precursor 12
b
c
As well as being highly regioselective, the cycloaddition proceeds
with excellent stereoselectivity, with the isoxazoline cycloadduct
isolated as a single diastereomer. As described earlier based on
(pure ratio 0.47:1 12/25).
d
Calculated yield. Isolated in 63% yield as a mixture with the precursor 16
(pure ratio 1:0.51 16/27).
crystallographic data,2,4 the
b-chloroacrylamides are conformation-
e
Calculated yield. Isolated in 79% yield as a mixture with the precursor 17
ally constrained due to the intramolecular hydrogen bond between
the amide proton and sulfoxide, adopting the s-cis conformation.
Complete diastereofacial control from the sulfoxide is envisaged,
(pure ratio 1:0.50 17/28).
Due to its rapid dimerisation, benzonitrile oxide has a lifetime of
approximately 1 h,14,15 and thus even though the reactions were left
overnight, in reality the cycloaddition probably took place within
the first hour. None of the reactions went to completion, with
unreacted dipolarophiles clearly visible by TLC and 1H NMR spec-
troscopic analysis. Notably, cycloadditions with diazoalkanes re-
quire longer reaction times to go to completion.16 On reaction of the
sulfoxides 6e9 (entries 1e4, Table 1) and 11 (entry 7, Table 1) and
the sulfide 15 (entry 9, Table 1) with benzonitrile oxide 4, a pre-
cipitate formed as the reaction progressed and the isoxazoline
cycloadducts 18e21, 24 and 26 were isolated by filtration of the
reaction mixture. The filtrate was concentrated and was found to
with the favoured approach of benzonitrile oxide to the b-chlor-
oacrylamides avoiding steric interactions with the R1 group, which
blocks the approach of the dipole from above (Fig. 3). It is reasonable
to assume that the stereochemistry of the dipolarophile is preserved
in the cycloaddition.
2.3. 1,3-Dipolar cycloadditions with nitrones
As it is not always possible to predict the stereochemical outcome
on employment of acyclic nitrones (E/Z isomerisation is possible),21
the cyclic nitrone 2,3,4,5-tetrahydropyridine N-oxide 30 was

4566
M. Kissane et al. / Tetrahedron 66 (2010) 4564e4572
Figure 1. Crystal structure of 29 (anisotropic displacement parameters are drawn at the 50% probability level).
major product. When the b-chloroacrylamide 8 was subjected to 1,3-
dipolar cycloaddition with the nitrone 30 in dichloromethane under
microwave conditions for 15 min, the substituted piperidine 32 was
detected as the minor product from the reaction (entry 5, Table 2).
The mechanism of the formation of the substituted piperidines
31e33 is believed to involve the initial formation of the isoxazolidine
cycloadduct, which subsequently eliminates the elements of R1S(O)
Cl to yield the isoxazoline. Hydride transfer from the bridgehead
carbon to the bridgehead nitrogen coupled with the generation of
the extensively conjugated orange product leads to ring opening of
the isoxazoline to yield the substituted piperidine (Scheme 4).
Figure 2.
Dipole approach from
above blocked by R1
R1
H
O
N R2
O
S
Cl
R1
S(O)R1
CONHR2
O
H
N R2
O
N
O
S
C
Cl
Ph
Cl
N
O
O N
Figure 3.
-R1S(O)Cl
H
CONHR2
employed for the investigation of the dipolarophilic reactivity of the
-chloroacrylamides with nitrones to simplify the stereochemical
outcome in the product mixture.
The -chloroacrylamide was added to a solution of 2,3,4,5-tet-
N
H
O
H
N
b
NR2
H
O
O
b
rahydropyridine N-oxide 30 (freshly prepared quantitatively each
time before use following the procedure described by Hootelé and
Louis)11 in dichloromethane, with the results summarised in Table 2.
Scheme 4.
The structure of the novel substituted piperidine products, and
thus the regioselectivity of the cycloaddition, was confirmed by
X-ray crystallographic analysis of a single crystal of 32 recrystallised
from chloroform (Fig. 4). The crystal structure confirms the Z-ste-
Table 2
Reaction of
b
-chloroacrylamides with nitrone 30
reochemistry of the b-aminoacrylamides; presumably this is the
H
thermodynamic isomer of these compounds, at least in the solid
state. NMR studies also indicated the presence of just a single iso-
mer in solution, presumably with the Z-stereochemistry.
O
O
N
O
CH2Cl2, 6 d, rt
R1S
NHR2
+
NR2
H
N
O
or
mw, 100 °C
Cl
O
Entry Sulfoxide R1 R2
Conditions
Product % Yielda
1
2
3
4
5
13
13
10
14
8
Ph Ph
Ph Ph
Ph Me
CH2Cl2, 6 d, rt
31
19
19
mw, 100 ꢀC, 20 min 31
mw, 100 ꢀC, 10 min 32
18
Bn 4-F-C6H4 mw, 100 ꢀC, 20 min 33
34b
dc
Bn Me
mw, 100 ꢀC, 15 min 32
a
Isolated yield after chromatography.
In the 1H NMR spectrum of 33 there was also evidence for another unidentified
b
product.
c
Detected as the minor product by 1H NMR spectroscopy.
The cycloaddition was explored under microwave22e26 and con-
ventional conditions; although similar yields were achieved under
both sets of conditions, conducting the cycloadditions in the micro-
wave was more advantageous due to the significantly shorter re-
action times (entries 1 and 2, Table 2). The cycloaddition of the
sulfoxides 13, 10 and 14 with the nitrone 30 yielded the unexpected
novel substituted piperidines 31e33 (entries 1e4, Table 2) as the
Figure 4. Crystal structure of 32 (anisotropic displacement parameters are drawn at
the 50% probability level).

M. Kissane et al. / Tetrahedron 66 (2010) 4564e4572
4567
The hydrogen bonding network present in 32 is highlighted in
4. Experimental
4.1. General
Figure 5; there are intramolecular hydrogen bonds from the piper-
ꢀ
idine NeH to the oxygen of the amide group (bond length 1.75 A)
and from the amide NeH to the oxygen of the aldehyde (bond length
ꢀ
2.15 A), making this a very rigid structure. An intermolecular hy-
Solvents were distilled prior to use as follows: dichloromethane
was distilled from phosphorous pentoxide and ethyl acetate was
distilled from potassium carbonate. Hexane was distilled prior to
use. Organic phases were dried using anhydrous magnesium sul-
fate. Diethyl ether is referred to as ether throughout.
drogen bond also exists from the amide NeH to the aldehyde group
with a bond length of 2.56 A.
ꢀ
Infrared spectra were recorded as thin films on sodium chloride
plates for oils or as potassium bromide (KBr) discs for solids on
a Perkin Elmer Paragon 1000 FT-IR spectrometer.
1H (300 MHz) and 13C (75.5 MHz) NMR spectra were recorded on
a Bruker Avance 300 MHz NMR spectrometer. 1H (400 MHz) NMR
spectra were recorded on a Bruker Avance 400 MHz NMR spec-
trometer. All spectra were recorded at room temperature (w20 ꢀC)
in deuterated chloroform (CDCl3) unless otherwise stated using
tetramethylsilane (TMS) as an internal standard. 1H NMR spectra
that were recorded in deuterated dimethylsulfoxide (DMSO-d6)
were assigned using the DMSO peak as the reference peak. Chemical
shifts (dH and dC) are reported in parts per million (ppm) relative to
TMS and coupling constants are expressed in hertz (Hz).
Low resolution mass spectra were recorded on a Waters Quattro
Micro triple quadrupole spectrometer in electrospray ionisation
(ESI) mode using 50% water/acetonitrile containing 0.1% formic acid
as eluent; samples were made up in acetonitrile. High resolution
mass spectra (HRMS) were recorded on a Waters LCT Premier Time
of Flight spectrometer in electrospray ionisation (ESI) mode using
50% water/acetonitrile containing 0.1% formic acid as eluent;
samples were made up in acetonitrile.
Elemental analyses were performed by the Microanalysis Lab-
oratory, National University of Ireland, Cork, using PerkineElmer
240 and Exeter Analytical CE440 elemental analysers.
Melting points were carried out on a uni-melt Thomas Hoover
Capillary melting point apparatus and are uncorrected.
Figure 5. Hydrogen bonding network in 32.
The observed regioselectivity is consistent with theoretical
predications for the cycloaddition of nitrones with conjugating and
electron-withdrawing dipolarophiles, which are dipole-HOMO con-
trolled, leading to the 4,4-disubstituted regioisomer (Fig. 6),27,28 and
even though the isoxazolidine cycloadduct was not isolated, the pi-
peridines 31e33 confirm the regiochemistry of the cycloaddition.
Wet Flash chromatography was performed using Kieselgel silica
gel 60, 0.040e0.063 mm (Merck). Thin layer chromatography (TLC)
was carried out on precoated silica gel plates (Merck 60 PF254).
Visualisation was achieved by UV (254 nm) light detection, iodine
staining, vanillin staining and ceric sulfate staining.
Microwave assisted synthesis was achieved using the CEM
Discover Labmate Synthesiser in conjunction with ChemDriver
software (Version 3.5.0) and the CEM Discover S-Class Synthesiser
in conjunction with Synergy software.
Benzohydroximoyl chloride was prepared by chlorination of the
commercially available benzaldoxime in chloroform.21 2,3,4,5-Tet-
rahydropyridine N-oxide was prepared by oxidation of 1-hydrox-
ypiperidine with yellow mercuric oxide.11 The synthesis of the
Figure 6.
The 1H NMR and 13C NMR spectra of 31 and 32 also aided in
confirming the structure. In the 1H NMR spectra, a singlet is evident
at dH 9.61 ppm for 31 and at dH 9.55 ppm for 32, characteristic of an
aldehyde proton. Two broad signals for the two NH protons are also
present, which is further evidence that the isoxazoline ring has
opened. In the 13C NMR spectra, signals at dC 184 ppm are consis-
tent with the conjugated aldehyde carbons.
a
-sulfinyl-
b-chloroacrylamides 1, 6e14 and the a-thio-b-chloro-
acrylamides 15e17 has already been described.2,4
Thus, nitrone cycloaddition is feasible with the sulfinyl
substituted b-chloroacrylamides, albeit to form labile cycloadducts,
Single crystal X-ray data for compound 30 was collected on
a Nonius MACH3 diffractometer and data for 63 was collected by
which undergo further reaction to generate unexpected products.
While the NeO bond of the isoxazolidines is known to be cleaved
under reducing conditions, the spontaneous cleavage in these re-
actions is rather unusual and presumably is driven by the high degree
of conjugation in the products. While the isolated yields are low,
there was no evidence for the formation of products derived from the
regioisomeric cycloadducts.
Rigaku on a Rigaku Saturn 724 CCD diffractometer using Mo-K
a
graphite monochromated radiation. The data was corrected for
Lorentz and polarisation effects. The structures were solved by di-
rect methods and refined by full-matrix least-squares using all F2
data. The SHELX-97,29 PLATON,30 Nonius31 and CrystalClear32 suite
of programs were used. Full structural data have been deposited at
the Cambridge Crystallographic Data Centre. CCDC reference
numbers 759494 and 759495.
3. Conclusion
4.2. (E)-4-Nitro-N-[(Z)-3-oxo-2-(phenylsulfinyl)-3-(p-
1,3-Dipolar cycloadditions of nitrile oxides and nitrones to
tolylamino)prop-1-enyloxy]benzimidoyl chloride 3
b
-chloroacrylamides leads to a range of novel isoxazolines and pi-
peridines. The cycloadditions proceed in a highly regioselective and
diastereoselective manner in all instances.
Triethylamine (0.14 mL, 1.03 mmol) was added to a solution of 1
(0.30 g, 0.94 mmol) in dichloromethane (10 mL). The resulting

4568
M. Kissane et al. / Tetrahedron 66 (2010) 4564e4572
solution was cooled to 0 ꢀC and compound 2 (0.19 g, 0.94 mmol) was
added. After 0.5 h a precipitate was seen to form in the reaction flask.
The reaction mixture was allowed to warm to room temperature and
was stirred at this temperature for 13 h. The precipitate was removed
by filtration through a bed of Celite. Following removal of the solvent
the crude product 3 was isolated as an off-white solid. The crude
product was purified by chromatography on silica gel using ethyl
acetate/hexane (20:80) to give 3 as an off-white solid (0.24 g, 52%);
mp 206e208 ꢀC; nmax/cmꢁ1(KBr) 1642 (CO), 1556. Found C, 56.68; H,
3.98, N, 8.48, S, 6.83, Cl, 7.09. C23H18N3ClO5S requires C, 57.08; H,
3.78; N, 8.68; S, 6.63; Cl; 7.33. dH 2.30 (3H, s, CH3 of Tol), 7.02e7.41
(13H, m, ArH), 8.03 (1H, s, ]CHO); dC 21.3 (CH3, CH3 of Tol), 115.7
(C, ]CS), 121.0, 124.4, 129.2, 129.9, 130.1, 131.9 (CH, ArCH), 134.7,
135.5, 136.3, 142.6, 145.2, 150.1 (C, ArC and N]CCl), 160.1
(CH, CHOH), 160.3 (C, CO); MS m/z (ESþ) 483 (Mþ, 10%).
(75.5 MHz, DMSO-d6) 43.0 (CH2, NHCH2), 55.1 (CH2, SCH2), 64.5
(CH, CHCl), 100.8 [C, C(5)], 125.0 (C, aromatic C), 126.9, 127.4, 127.7,
128.2, 128.4, 128.9, 129.2, 130.3 (8ꢂCH, 8ꢂaromatic CH), 130.7 (C,
aromatic C), 131.7 (CH, aromatic CH), 138.2 (C, aromatic C), 157.6 [C,
C(3)Ph], 163.1 (C, CO); HRMS (ESþ): exact mass calculated for
C24H22N2O3S35Cl [MþH]þ 453.1040. Found 453.1042; m/z (ESþ)
455.2 {[(C24H21N2O3S37Cl)þHþ], 44%}, 453.2 {[(C24H21N2O3S35Cl)þ
Hþ], 100%}.
The filtrate was concentrated to give a yellow oil (0.18 g), con-
taining the
b-chloroacrylamide 7 and the product 19 (ratio of 7/19
1:0.14 by 1H NMR spectroscopy).
4.5. (4R
*
,5R
*
*
,SS)-5-(Benzylsulfinyl)-4-chloro-4,5-dihydro-N-
methyl-3-phenylisoxazole-5-carboxamide 20
This was prepared following the procedure outlined for 18 using
benzohydroximoyl chloride (0.36 g, 2.5 mmol) and sodium hy-
droxide (1 M, 4.48 mL) in ether (9 mL) and N-methyl-Z-3-chloro-2-
(benzylsulfinyl)propenamide 8 (0.16 g, 0.6 mmol) in ether (6 mL). A
precipitate formed as the reaction progressed. The reaction prog-
ress was monitored by TLC, which indicated that some starting
material still remained after stirring at room temperature for 16 h
but it was decided to work up the reaction at this stage. The product
was collected by filtration through a sintered glass funnel (grade 4)
to give 20 as a white solid (0.10 g, 43%); mp 144e145 ꢀC. Found C,
56.75; H, 4.28; N, 7.07. C18H17ClN2O3S requires C, 57.37; H, 4.55; N,
7.43%. nmax/cmꢁ1 (KBr) 3368 (NH), 2986 (CH), 1665 (CO), 1532, 1074
(SO); dH (400 MHz, CDCl3) 2.98 (3H, d, J 4.8, NHCH3), 4.10 (1H, d, A of
AB system, J 12.8, SCH2), 4.53 (1H, d, B of AB system, J 12.8, SCH2),
6.36 (1H, s, CHCl), 6.89 (1H, br d, J 4.8, NH), 7.36e7.56 (8H, m, ArH),
7.79 (2H, dd, J 8.4, 1.6, ArH); dC (75.5 MHz, DMSO-d6) 26.3 (CH3,
NHCH3), 55.2 (CH2, SCH2), 64.7 (CH, CHCl), 100.8 [C, C(5)], 125.1 (C,
aromatic C), 127.7, 128.3, 128.8, 129.1, 130.4 (5ꢂCH, 5ꢂaromatic CH),
130.9 (C, aromatic C), 131.6 (CH, aromatic CH), 157.4 [C, C(3)Ph],
163.4 (C, CO); HRMS (ESþ): exact mass calculated for
C18H18N2O3S35Cl [MþH]þ 377.0727. Found 377.0720; m/z (ESþ)
379.2 {[(C18H17N2O3S37Cl)þHþ], 16%}, 377.2 {[(C18H17N2O3S35Cl)þ
Hþ], 42%}, 73.9 (100%).
4.3. (4R
*
,5R
*
,SS)-5-(Benzylsulfinyl)-4-chloro-4,5-dihydro-3-
*
phenyl-N-(4-methylphenyl)isoxazole-5-carboxamide 18
Benzohydroximoyl chloride (0.38 g, 2.4 mmol) was added por-
tionwise over 10 min to a stirring solution of sodium hydroxide
(1 M, 3.64 mL) and ether (7 mL) cooled to 0 ꢀC with an ice-bath. The
ether layer was separated, quickly dried over MgSO4 and added to
a
solution of N-(4-methylphenyl)-Z-3-chloro-2-(benzylsulfinyl)
propenamide 6 (0.17 g, 0.5 mmol) in ether (7 mL) and acetone
(2 mL). After stirring at room temperature for 3 h, a precipitate
formed. The reaction progress was monitored by TLC, which in-
dicated that some starting material still remained after stirring at
room temperature for 48 h. It was decided to stop the reaction at
this stage and the product was collected by filtration through
a sintered glass funnel (grade 4) to give 18 as a white solid (0.12 g,
48%); mp 179e180 ꢀC. Found C, 63.30; H, 4.47; N, 6.19; S, 7.86; Cl,
7.84. C24H21ClN2O3S requires C, 63.64; H, 4.67; N, 6.18; S, 7.08, Cl,
7.83%. nmax/cmꢁ1 (KBr) 3266 (NH), 3014 (CH), 1665 (CO), 1601, 1536,
1079 (SO); dH (400 MHz, CDCl3) 2.34 (3H, s, ArCH3), 4.11 (1H, d, A of
AB system, J 12.8, SCH2), 4.54 (1H, d, B of AB system, J 12.8, SCH2),
6.47 (1H, s, CHCl), 7.17 (2H, d, J 8.4, ArH), 7.35e7.39 (5H, m, ArH),
7.46e7.56 (5H, m, ArH), 7.82 (2H, dd, J 8.4, 1.6, ArH), 8.50 (1H, br s,
NH); dC (75.5 MHz, DMSO-d6) 20.5 (CH3, ArCH3), 55.1 (CH2, SCH2),
65.2 (CH, CHCl), 101.0 [C, C(5)], 121.4 (CH, aromatic CH), 125.1
(C, aromatic C), 127.8, 128.4, 128.85, 128.94, 129.1, 130.5 (6ꢂCH,
6ꢂaromatic CH), 130.7 (C, aromatic C), 131.6 (CH, aromatic CH),
134.2, 134.6 (2ꢂC, 2ꢂaromatic C), 157.5 [C, C(3)Ph], 162.0 (C, CO);
HRMS (ESþ): exact mass calculated for C24H22N2O3S35Cl [MþH]þ
453.1040. Found 453.1041; m/z (ESþ) 455.0 {[(C24H21N2O3S37Cl)þ
Hþ], 46%}, 453.0 {[(C24H21N2O3S35Cl)þHþ], 100%}.
The filtrate was concentrated to give a yellow oil (0.18 g), con-
taining the
1:0.66).
b-chloroacrylamide 8 and the product 20 (ratio of 8/20
4.6. (4R
*
,5R
*
*
,SS)-N-Benzyl-5-(phenylsulfinyl)-4-chloro-
4,5-dihydro-3-phenylisoxazole-5-carboxamide 21
The filtrate was concentrated to give a yellow solid (0.14 g),
This was prepared following the procedure outlined for 18 using
benzohydroximoyl chloride (0.33 g, 2.3 mmol) and sodium hy-
droxide (1 M, 4.14 mL) in ether (8 mL) and N-benzyl-Z-3-chloro-2-
(phenylsulfinyl)propenamide 9 (0.18 g, 0.6 mmol) in ether (10 mL).
A white solid was observed to precipitate out of solution as the re-
action progressed. After stirring at room temperature for 16 h, the
product was collected by filtration through a sintered glass funnel
(grade 4) to give 21 as a white solid (0.08 g, 32%); mp 129e131 ꢀC;
nmax/cmꢁ1 (KBr) 3264 (NH), 3061 (CH),1673 (CO),1538,1075 (SO); dH
(300 MHz, CDCl3) 3.96 (1H, dd, A of ABX, JAB 14.7, JAX 5.7, one of
NHCH2), 4.13 (1H, dd, B of ABX, JAB 14.7, JBX 5.4, one of NHCH2), 6.24
(1H, s, CHCl), 6.51 (1H, br s, NH), 6.87e6.95 (2H, m, ArH), 7.22e7.29
(2H, m, ArH), 7.42e7.61 (7H, m, ArH), 7.78 (2H, dd, J 8.4,1.8, ArH), 7.84
(2H, dd, J 8.1, 1.2, ArH); dC (75.5 MHz, DMSO-d6) 42.0 (CH2, NHCH2),
65.8 (CH, CHCl), 102.5 [C, C(5)], 125.5 (C, aromatic C), 126.7, 127.0,
127.2, 127.8,128.0, 128.8, 129.0, 131.4, 132.3 (9ꢂCH, 9ꢂaromatic CH),
137.8, 138.6 (2ꢂC, 2ꢂaromatic C), 156.7 [C, C(3)Ph], 164.0 (C, CO);
HRMS (ESþ): exact mass calculated for C23H20N2O3S35Cl [MþH]þ
439.0883. Found 439.0883; m/z (ESþ) 441.2 {[(C23H19N2O3S37Cl)þ
Hþ], 46%}, 439.2 {[(C23H19N2O3S35Cl)þHþ], 100%}.
containing the
b-chloroacrylamide 6 and the product 18 (ratio 6/18
1:0.10 by 1H NMR spectroscopy).
4.4. (4R
*
,5R
*
,SS)-N-Benzyl-5-(benzylsulfinyl)-4-chloro-4,5-
*
dihydro-3-phenylisoxazole-5-carboxamide 19
This was prepared following the procedure outlined for 18 using
benzohydroximoyl chloride (0.32 g, 2.2 mmol) and sodium hy-
droxide (1 M, 4.00 mL) in ether (8 mL) and benzyl-Z-3-chloro-2-
(benzylsulfinyl)propenamide 7 (0.19 g, 0.6 mmol) in ether (8 mL).
A precipitate formed as the reaction progressed. After stirring at
room temperature for 16 h, the product was collected by filtration
through a sintered glass funnel (grade 4) to give 19 as a white solid
(0.18 g, 72%); mp 151e152 ꢀC; nmax/cmꢁ1 (KBr) 3299 (NH), 3001
(CH), 1677 (CO), 1527, 1075 (SO); dH (300 MHz, CDCl3) 4.03 (1H, d, A
of AB system, J 13.2, SCH2), 4.46 (1H, d, B of AB system, J 12.9, SCH2),
4.50 (1H, dd, A of ABX, JAB 15.0, JAX 6.0, one of NHCH2), 4.67 (1H, dd,
B of ABX, JAB 15.0, JBX 6.3, one of NHCH2), 6.41 (1H, s, CHCl),
7.20e7.58 (14H, m, ArH and NH), 7.80 (2H, dd, J 8.4, 1.6, ArH); dC

M. Kissane et al. / Tetrahedron 66 (2010) 4564e4572
4569
The filtrate was concentrated to give a yellow oil (0.23 g), con-
ether (10 mL). A precipitate formed as the reaction progressed. The
reaction progress was monitored by TLC, which indicated that some
starting material still remained after stirring at room temperature
for 16 h. At this stage, the product was collected by filtration
through a sintered glass funnel (grade 4) to give 24 as a white solid
(0.05 g, 16%); mp 157e158 ꢀC; nmax/cmꢁ1 (KBr) 3348 (NH), 2919
(CH), 1664 (CO), 1599, 1528, 1078 (SO); dH (400 MHz, CDCl3) 0.98
[3H, t, J 7.6, C(40)H3], 1.44e1.65 [2H, m, C(30)H2], 1.78e1.95 [2H, m, C
(20)H2], 2.32 (3H, s, ArCH3), 3.01 (1H, ddd, J 12.8, 8.8, 5.6, one of
SCH2), 3.13 (1H, ddd, J 12.8, 8.8, 7.8, one of SCH2), 6.38 (1H, s, CHCl),
7.14 (2H, d, J 8.4, ArH), 7.41e7.56 (5H, m, ArH), 7.79 (2H, dd, J 8.0, 1.6,
ArH), 8.43 (1H, br s, NH); dC (75.5 MHz, DMSO-d6) 13.5 [CH3, C(40)
H3], 20.5 (CH3, ArCH3), 21.2 [CH2, C(30)H2], 24.3 [CH2, C(20)H2], 47.5
(CH2, SCH2), 65.4 (CH, CHCl),100.7 [C, C(5)],121.3 (CH, aromatic CH),
125.2 (C, aromatic C), 127.8, 128.9, 129.1, 131.5 (4ꢂCH, 4ꢂaromatic
CH), 134.1, 134.5 (2ꢂC, 2ꢂaromatic C), 157.4 [C, C(3)Ph], 162.2 (C,
CO); HRMS (ESþ): exact mass calculated for C21H24N2O3S35Cl
[MþH]þ 419.1196. Found 419.1208; m/z (ESþ) 436.0
{[(C21H23N2O3S35Cl)þH2Oþ], 14%}, 109.9 (100%).
taining the
1:0.06).
b-chloroacrylamide 9 and the product 21 (ratio of 9/21
4.7. (4R
*
,5R
*
*
,SS)-4-Chloro-4,5-dihydro-3-phenyl-5-
(phenylsulfinyl)-N-(4-methylphenyl)isoxazole-
5-carboxamide 22
This was prepared following the procedure outlined for 18 using
benzohydroximoyl chloride (0.33 g, 2.3 mmol) and sodium hydrox-
ide (1 M, 4.12 mL) in ether (10 mL) and N-(4-methylphenyl)-Z-3-
chloro-2-(phenylsulfinyl)propenamide 1 (0.18 g, 0.6 mmol) in ether
(8 mL) and acetone (3 mL). The reaction progress was monitored by
TLC, which indicated that some starting material still remained after
stirring at room temperature for 16 h but it was decided to work up
the reaction at this stage. The solvent was removed by concentration
at reduced pressure to give the crude product as an orange oil. Fol-
lowing purification by column chromatography in silica gel using
hexane/ethyl acetate (gradient elution 10e80% ethyl acetate), 22 was
obtained as a white solid (0.03 g, 13%); mp 94e96 ꢀC; nmax/cmꢁ1
(KBr) 3391 (NH), 1672 (CO), 1597, 1526, 1090 (SO); dH (300 MHz,
CDCl3) 2.28 (3H, s, ArCH3), 6.32 (1H, s, CHCl), 6.95e7.08 (4H, m),
7.35e7.62 (6H, m), 7.74e7.91 (5H, m) (ArH and NH); dC (75.5 MHz,
CDCl3) 20.9 (CH3, ArCH3), 63.7 (CH, CHCl), 102.3 [C, C(5)], 120.0 (CH,
aromatic CH), 125.2 (C, aromatic C), 126.4, 127.8, 128.3, 129.0, 129.5,
131.8, 132.8 (7ꢂCH, 7ꢂaromatic CH), 133.0, 135.4, 138.4 (3ꢂC,
3ꢂaromatic C), 157.9 [C, C(3)Ph], 161.8 (C, CO); HRMS (ESþ): exact
mass calculated for C23H20N2O3S35Cl [MþH]þ 439.0883. Found
439.0862; m/z (ESþ) 441.1 {[(C23H19N2O3S37Cl)þHþ], 44%}, 439.2
{[(C23H19N2O3S35Cl)þHþ], 100%}.
The filtrate was concentrated to give as a yellow solid (0.34 g),
containing the
b-chloroacrylamide 11 and the product 24 (ratio of
11/24 1:0.9 by 1H NMR spectroscopy).
4.10. (4R
*
,5R
*
*
,SS)-N-Benzyl-5-(n-butylsulfinyl)-4-chloro-4,5-
dihydro-3-phenylisoxazole-5-carboxamide 25
This was prepared following the procedure outlined for 18 using
benzohydroximoyl chloride (0.32 g, 2.2 mmol) and sodium hy-
droxide (1 M, 4.00 mL) in ether (10 mL) and N-benzyl-Z-3-chloro-
2-(n-butylsulfinyl)propanamide 12 (0.17 g, 0.6 mmol) in ether
(8 mL). The reaction progress was monitored by TLC, which in-
dicated that some starting material still remained after stirring at
room temperature for 16 h and a further 4 equiv of benzonitrile
oxide [freshly prepared as outlined above from benzohydroximoyl
chloride (0.32 g, 2.2 mmol)] was added to the reaction solution.
Following stirring for a further 16 h, TLC analysis indicated that
some starting material still remained and it was decided to work
up the reaction. Following concentration of the reaction mixture at
reduced pressure, the product was isolated as a yellow oil, con-
taining 25 and 12 in a ratio of 1:0.6. After purification by column
chromatography using hexane/ethyl acetate (gradient elution
5e40% ethyl acetate) as eluent, 25 was obtained as a pale yellow oil
(0.16 g, 48%), containing w 32 mol % 12; nmax/cmꢁ1 (KBr) 3338
(NH), 2956 (CH), 1661 (CO), 1533; dH (300 MHz, CDCl3) 0.97 [3H, t, J
7.2, C(40)H3], 1.41e1.93 [4H, m, C(30)H2 and C(20)H2], 2.82e3.16 (2H,
m, SCH2), 4.40e4.66 (2H, m, NHCH2), 6.30 (1H, s, CHCl), 7.18 (1H, br
t, NH), 7.23e8.23 (10H, m, ArH); dC (75.5 MHz, CDCl3)13.7 [CH3, C
(40)H3], 21.9 [CH2, C(30)H2], 25.2 [CH2, C(20)H2], 44.4, 50.0 (2ꢂCH2,
SCH2 and NHCH2), 62.0 (CH, CHCl), 100.3 [C, C(5)], 125.1 (C, aro-
matic C), 127.7, 127.8, 128.8, 129.2, 130.1, 131.8 (6ꢂCH, 6ꢂaromatic
CH), 136.5 (C, aromatic C), 157.8 [C, C(3)Ph], 162.7 (C, CO); HRMS
(ESþ): exact mass calculated for C21H24N2O3S35Cl [MþH]þ 419.1196.
Found 419.1191; m/z (ESþ) 421.1 {[(C21H23N2O3S37Cl)þHþ], 50%},
419.0 {[(C21H23N2O3S35Cl)þHþ], 100%}, 300.0 {[(C14H18NO2S35Cl)þ
Hþ], 58%}.
A fraction containing the
b-chloroacrylamide 1 was also re-
covered as a white solid (0.09 g).
4.8. (4R
*
,5R
*
,SS)-4-Chloro-4,5-dihydro-N-methyl-3-phenyl-5-
*
(phenylsulfinyl)isoxazole-5-carboxamide 23
This was prepared following the procedure outlined for 18 using
benzohydroximoyl chloride(0.45 g, 3.1 mmol)and sodiumhydroxide
(1 M, 5.56 mL) in ether (11 mL) and N-methyl-Z-3-chloro-2-(phe-
nylsulfinyl)propenamide 10 (0.19 g, 0.8 mmol) in ether (10 mL) and
acetone (1 mL). The reaction progress was monitored by TLC, which
indicated that some starting material still remained after stirring at
room temperature for 16 h but it was decided to work up the reaction
at this stage. Following concentration of the reaction mixture, the
crude product was obtained as a yellow oil (0.37 g), containing 10 and
23 in a ratio of 1:0.38 by 1H NMR spectroscopy. After purification by
columnchromatographyusinghexane/ethylacetate(gradientelution
10e80% ethyl acetate) as eluent, 23 was obtained as a white solid
(0.04 g,12%); mp 139e140 ꢀC; nmax/cmꢁ1 (KBr) 3350 (NH), 2995 (CH),
1667 (CO), 1518, 1086 (SO); dH (300 MHz, CDCl3) 2.46 (3H, d, J 5.1,
NHCH3),6.22(2H, overlappingsandbrs,CHClandNH), 7.41e7.63 (6H,
m, ArH), 7.77 (2H, dd, J 8.4, 1.2, ArH), 7.85 (2H, dd, J 8.1, 1.5, ArH); dC
(75.5 MHz, CDCl3) 26.1 (CH3, ArCH3), 63.7 (CH, CHCl), 102.4 [C, C(5)],
125.3 (C, aromatic C), 126.6, 127.8, 128.9, 129.1, 131.7, 132.6 (6ꢂCH,
6ꢂaromatic CH),138.7 (C, aromatic C), 157.6 [C, C(3)Ph],164.6 (C, CO);
HRMS (ESþ): exact mass calculated for C17H16N2O3S35Cl [MþH]þ
363.0570. Found 363.0554; m/z (ESþ) 365.2 {[(C17H15N2O3S37Cl)þ
Hþ], 44%}, 363.2 {[(C17H15N2O3S35Cl)þHþ], 100%}.
4.11. 4-Chloro-3-phenyl-N-(4-methylphenyl)isoxazole-5-
carboxamide 29
4.9. (4R
*
,5R
*
,SS
*
)-5-(n-Butylsulfinyl)-4-chloro-4,5-dihydro-3-
Morpholine (0.05 mL, 0.6 mmol) was added to a solution of
5-(benzylsulfinyl)-4-chloro-4,5-dihydro-3-phenyl-N-(4-methyl-
phenyl)isoxazole-5-carboxamide 18 (0.10 g, 0.2 mmol) in dichloro-
methane (20 mL). Following stirring at room temperature for 16 h,
TLC analysis indicated that some starting material remained and
a further 2.5 equiv of morpholine (0.05 mL, 0.6 mmol) was added.
Following stirring at room temperature for a further 24 h, saturated
phenyl-N-(4-methylphenyl)isoxazole-5-carboxamide 24
This was prepared following the procedure outlined for 18 using
benzohydroximoyl chloride (0.42 g, 2.9 mmol) and sodium hy-
droxide (1 M, 5.20 mL) in ether (10 mL) and N-(4-methylphenyl)-Z-
3-chloro-2-(n-butylsulfinyl)propenamide 11 (0.22 g, 0.7 mmol) in

4570
M. Kissane et al. / Tetrahedron 66 (2010) 4564e4572
ammonium chloride (20 mL) was added. The layers were separated
and the aqueous layer was washed with dichloromethane
(2ꢂ20 mL). The combined organic layers were washed with satu-
rated sodium bicarbonate (20 mL) and brine (20 mL), dried and
concentrated to give 29 as a white solid. Following purification by
column chromatography using hexane/ethyl acetate 95:5, 29 was
obtained as a white solid (0.06 g, 84%); nmax/cmꢁ1 (KBr) 3336 (NH),
2924 (CH), 1668 (CO), 1606, 1526; dH (400 MHz, CDCl3) 2.36 (3H, s,
ArCH3), 7.21 (2H, d, J 8.4, ArH), 7.50e7.61 (5H, m, ArH), 7.86e7.91
(2H, m, ArH), 8.18 (1H, br s, NH); dC (75.5 MHz, DMSO-d6) 21.0 (CH3,
ArCH3), 112.7 (C, aromatic C), 126.2, 128.3, 128.9, 129.8, 130.9, 130.5
(6ꢂCH, 6ꢂaromatic CH), 133.9, 135.4, 152.8, 156.9 (4ꢂC, 4ꢂaromatic
C, 4 signals for 5 carbons), 161.5 (C, CO); HRMS (ESþ): exact
mass calculated for C17H14N2O2S35Cl [MþH]þ 313.0744. Found
313.0735; m/z (ESþ) 315.0 {[(C17H13N2O2S37Cl)þHþ], 36%}, 313.0
{[(C17H13N2O2S35Cl)þHþ], 100%}.
4.13. (4R
*
,5R )-N-Benzyl-5-(benzylthio)-4-chloro-4,5-
*
dihydro-3-phenylisoxazole-5-carboxamide 27
This was prepared following the procedure outlined for 18 using
benzohydroximoyl chloride (0.27 g, 1.9 mmol) and sodium hy-
droxide (1 M, 3.40 mL) in ether (7 mL) and N-benzyl-Z-3-chloro-2-
(benzylthio)propenamide 16 (0.15 g, 0.5 mmol) in ether (8 mL). The
reaction progress was monitored by TLC, which indicated that some
starting material still remained after stirring at room temperature
for 16 h and a further 2 equiv of benzonitrile oxide [prepared as
described above from benzohydroximoyl chloride (0.14 g,
1.0 mmol)] was added. Following stirring at room temperature for
a further 24 h, the reaction mixture was concentrated to give the
product as a yellow oil (0.32 g), containing 16 and 27 in the ratio
1:0.38. Following purification using hexane/ethyl acetate (gradient
elution 5e10% ethyl acetate), 27 was obtained as a white solid
(0.11 g), containing w66 mol % 16; nmax/cmꢁ1 (of mixture) (KBr)
3310 (NH), 3029 (CH), 1664 (CO), 1518; dH (300 MHz, CDCl3) 3.90
(1H, d, A of AB system, JAB 12.0, one of SCH2), 4.02 (1H, d, B of AB
system, JAB 11.7, one of SCH2), 4.34 (1H, dd, A of ABX, JAB 14.7, JAX 5.7,
one of NHCH2), 4.47 (1H, dd, A of ABX, JAB 14.7, JBX 6.0, one of
NHCH2), 6.07 (1H, s, CHCl), 7.05e7.52 (14H, m, NH and ArH), 7.77
(2H, dd, J 8.1, 2.1, ArH); dC (75.5 MHz, DMSO-d6) 35.4 (CH2, SCH2),
44.1 (CH2, NHCH2), 66.0 (CH, CHCl), 98.2 [C, C(5)], 126.4 (C, aromatic
C), 127.8, 127.9, 128.15, 128.20, 128.9, 129.1, 129.3, 129.5, 131.8
(9ꢂCH, 9ꢂaromatic CH), 135.7, 137.2 (2ꢂC, 2ꢂaromatic C), 159.0 [C,
C(3)Ph], 167.5 (C, CO); HRMS (ESþ): exact mass calculated for
C24H22N2O2S35Cl [MþH]þ 437.1091. Found 437.1093; m/z (ESþ)
437.0 {[(C24H21N2O2S35Cl)þHþ], 12%}.
The regiochemistry was determined by single crystal X-ray
diffraction on a crystalline sample of 29 recrystallised from
acetone.
Crystals of 29 are monoclinic, space group P21/n, formula
ꢀ
ꢀ
3
ꢀ
C17H13ClN2O2, M¼312.74, a¼6.352(2) Aꢀ, b¼12.196(4) A, c¼18.983
ꢀ
(8) A,
648,
a
¼90.00ꢀ,
b
¼97.414(17)ꢀ,
¼90.00 , U¼1458.3(9) A , F(000)¼
g
m
(Mo K
a
)¼0.270 mmꢁ1, R(Fo)¼0.0781, for 2442 observed re-
flections with I>2
s
(I), wR2(F2)¼0.1738 for all 3071 unique re-
flections. Data in the
q
range 2.16e27.53ꢀ were collected at 125 K on
a Rigaku Saturn 724 CCD diffractometer using Mo K
a
graphite
ꢀ
monochromated radiation,
l¼0.7107 A, and corrected for Lorentz
and polarisation effects. The structure was solved by direct
methods and refined by full-matrix least-squares using all F2 data.
The methyl hydrogen atoms were found from a Fourier difference
map and allowed to ride on the parent atom; all other hydrogen
atoms were placed in calculated positions and allowed to ride on
the parent atom.
4.14. (4R
*
,5R )-5-(Benzylthio)-N-n-butyl-4-chloro-4,5-
*
dihydro-3-phenylisoxazole-5-carboxamide 28
This was prepared following the procedure outlined for 18 using
benzohydroximoyl chloride (0.35 g, 2.4 mmol) and sodium hy-
droxide (1 M, 3.40 mL) in ether (7 mL) and N-n-butyl-Z-3-chloro-2-
(benzylthio)propenamide 17 (0.16 g, 0.6 mmol) in ether (8 mL). The
reaction progress was monitored by TLC, which indicated that some
starting material still remained after stirring at room temperature
for 16 h and a further 2 equiv of benzonitrile oxide [prepared as
described above from benzohydroximoyl chloride (0.14 g,
1.0 mmol)] was added. Following stirring at room temperature for
a further 24 h, the reaction mixture was concentrated to give the
product as a yellow oil (0.32 g) containing 17 and 28 in the ratio
1:0.29. Following purification using hexane/ethyl acetate (gradient
elution 5e10% ethyl acetate), 28 was isolated as a yellow oil (0.15 g),
containing w66 mol % 17; nmax/cmꢁ1 (of mixture) (KBr) 3313 (NH),
3062 (CH), 2959 (CH), 1649 (CO), 1561, 1519; dH (300 MHz, CDCl3)
0.87 [3H, t, J 7.2, C(40)H3], 1.18e1.52 [4H, m, C(30)H2 and C(20)H2],
3.18e3.28 (2H, m, NHCH2), 3.96 (1H, d, A of AB system, JAB 11.7, one
of SCH2), 4.07 (1H, d, B of AB system, JAB 12.0, one of SCH2), 6.04 (1H,
s, CHCl), 6.86 (1H, br s, NH), 7.15e7.56 (8H, m, ArH), 7.77 (2H, dd, J
8.1, 2.1, ArH); dC (75.5 MHz, DMSO-d6) 13.6 [CH3, C(40)H3], 20.0 [CH2,
C(30)H2], 31.3 [CH2, C(20)H2], 35.2 (CH2, SCH2), 39.8 (CH2, NHCH2),
65.8 (CH, CHCl), 98.1 [C, C(5)], 126.2 (C, aromatic C), 127.5, 127.6,
128.7, 129.0, 129.2, 131.4 (6ꢂCH, 6ꢂaromatic CH), 135.6 (C, aromatic
C), 158.7 [C, C(3)Ph], 166.9 (C, CO); HRMS (ESþ): exact mass calcu-
lated for C21H24N2O2S35Cl [MþH]þ 403.1247. Found 403.1231; m/z
(ESþ) 403.1 {[(C21H23N2O2S35Cl)þHþ], 8%}.
4.12. (4R
*
,5R )-5-(Benzylthio)-4-chloro-4,5-dihydro-3-
*
phenyl-N-(4-methylphenyl)isoxazole-5-carboxamide 26
This was prepared following the procedure outlined for 18
using benzohydroximoyl chloride (0.27 g, 1.9 mmol) and sodium
hydroxide (1 M, 3.40 mL) in ether (7 mL) and N-(4-methylphenyl)-
Z-3-chloro-2-(benzylthio)propenamide 15 (0.15 g, 0.5 mmol) in
ether (8 mL). The reaction progress was monitored by TLC, which
indicated that some starting material still remained after stirring
at room temperature for 16 h and a further 2 equiv of benzonitrile
oxide [prepared as described above from benzohydroximoyl
chloride (0.14 g, 1.0 mmol)] was added. Following stirring at room
temperature for a further 24 h, a white solid precipitated out of
solution. The product was collected by filtration through a sintered
glass funnel (grade 4) to give 26 as a white solid (0.04 g, 21%); mp
177e178 ꢀC. Found C, 65.10; H, 4.54; N, 6.30. C24H21ClN2O2S re-
quires C, 65.97; H, 4.84; N, 6.41%. nmax/cmꢁ1 (KBr) 3272 (NH), 3015
(CH), 2919 (CH), 1667 (CO), 1597, 1531; dH (300 MHz, CDCl3) 2.32
(3H, s, ArCH3), 4.01 (1H, d, A of AB system, JAB 12.3, one of SCH2),
4.10 (1H, d, B of AB system, JAB 12.3, one of SCH2), 6.12 (1H, s,
CHCl), 7.14 (2H, d, J 8.4, ArH), 7.22e7.58 (8H, m, ArH), 7.77 (2H, dd,
J 8.1, 2.1, ArH), 8.47 (1H, br s, NH); dC (75.5 MHz, DMSO-d6) 20.4
(CH3, ArCH3), 34.1 (CH2, SCH2), 66.2 (CH, CHCl), 97.5 [C, C(5)], 121.1
(CH, aromatic CH), 125.7 (C, aromatic C), 127.6, 128.6, 128.9, 129.1,
131.5 (5ꢂCH, 5ꢂaromatic CH, 5 signals for 7 carbons), 133.9, 134.7,
135.6 (3ꢂC, 3ꢂaromatic C), 158.3 [C, C(3)Ph], 164.7 (C, CO); HRMS
(ESþ): exact mass calculated for C24H22N2O2S35Cl [MþH]þ
437.1091. Found 437.1086; m/z (ESþ) 437.0 {[(C24H21N2O2S35Cl)þ
Hþ], 78%}.
4.15. 2-Formyl-N-phenyl-2-(piperidin-2-ylidene)acetamide 31
4.15.1. Method A. N-Phenyl-Z-3-chloro-2-(phenylsulfinyl)prope-
namide 13 (0.40 g, 1.3 mmol) was added to a solution of 2,3,4,5-
tetrahydropyridine N-oxide 30 (0.16 g, 1.6 mmol) in dichloro-
methane (10 mL) and the reaction solution was stirred at room
The filtrate was concentrated to give an orange oil (0.24 g),
containing the
b-chloroacrylamide 15 and the product 26 (ratio of
15/26 1:0.16 by 1H NMR spectroscopy).

M. Kissane et al. / Tetrahedron 66 (2010) 4564e4572
4571
temperature for 6 days. The reaction solution was then concen-
4.17. N-(4-Fluorophenyl)-2-formyl-2-(piperidin-2-ylidene)
trated at reduced pressure to give the crude product as an orange
solid. The 1H NMR spectrum of the crude product was very com-
plex. Following purification by column chromatography using
hexane/ethyl acetate (gradient elution 20e40% ethyl acetate), 31
acetamide 33
N-(4-Fluorophenyl)-Z-3-chloro-2-(benzylsulfinyl)propena-
mide 14 (0.15 g, 0.4 mmol) was added to a solution of 2,3,4,5-
tetrahydropyridine N-oxide 30 (0.05 g, 0.6 mmol) in dichloro-
methane (1.2 mL) in a sealed microwave reaction vessel and the
reaction solution was subsequently heated in the microwave for
20 min at 300 W at 100 ꢀC. The reaction mixture was directly
applied to a silica column and the product was eluted with hex-
ane/ethyl acetate (gradient elution 40e60% ethyl acetate) to give
33 as an off-white solid (0.04 g, 34%); nmax/cmꢁ1 (KBr) 3434 (NH),
3308 (NH), 2924, 1721, 1665, 1635, 1602, 1578, 1552, 1506; dH
(400 MHz, CDCl3) 1.81e1.95 [4H, m, C(4)H2 & C(5)H2], 2.88e2.98
[2H, m, C(6)H2], 3.47e3.57 [2H, m, C(3)H2], 6.95e7.08 (2H, m,
ArH), 7.48e7.61 (2H, m, ArH), 9.60 [1H, s, CHO], 12.02 (1H, s, NH),
12.93 (1H, br s, NH); dC (75.5 MHz, CDCl3) 18.8, 21.0 [2ꢂCH2, C(4)
H2 and C(5)H2], 24.8 [CH2, C(6)H2], 42.0 [CH2, C(3)H2], 100.1 (C,
was obtained as a yellow solid (0.06 g, 19%); mp 140e141 ꢀC; nmax
/
cmꢁ1 (KBr) 3379 (NH), 3192 (NH), 2930, 1638, 1622, 1579, 1537; dH
(400 MHz, CDCl3) 1.84e1.92 [4H, m, C(4)H2 and C(5)H2], 2.89e2.95
[2H, m, C(6)H2], 3.49e3.55 [2H, m, C(3)H2], 7.03e7.10 (1H, m, ArH),
7.28e7.35 (2H, m, ArH), 7.55e7.61 (2H, m, ArH), 9.61 [1H, s, CHO],
12.04 (1H, s, NH), 12.98 (1H, br s, NH); dC (75.5 MHz, CDCl3) 18.8,
21.0 [2ꢂCH2, C(4)H2 & C(5)H2], 24.8 [CH2, C(6)H2], 42.0 [CH2, C(3)
H2], 100.2 (C, CCHO), 120.9, 123.2, 128.7 (3ꢂCH, 3ꢂaromatic CH),
138.7 (C, aromatic C), 168.3, 172.8 [2ꢂC, CO & C(2)], 184.2 [CH, CHO];
HRMS (ESþ): exact mass calculated for C14H17N2O2 [MþH]þ
245.1290. Found 245.1291; m/z (ESþ) 245.0 {[(C14H16N2O2)þHþ],
100%}, 489.2 {[(C28H32N4O4)þHþ], 4%}.
2
3
4.15.2. Method B. This was also synthesised by addition of N-phe-
nyl-Z-3-chloro-2-(phenylthio)propenamide 13 (0.12 g, 0.4 mmol)
to a solution of 2,3,4,5-tetrahydropyridine N-oxide 30 (0.09 g,
0.9 mmol) in dichloromethane (1 mL) in a sealed microwave re-
action vessel with stirring and subsequent heating for 20 min at
300 W at 100 ꢀC. Following concentration at reduced pressure, the
crude product was obtained as a brown oil. After purification by
column chromatography using hexane/ethyl acetate (gradient
elution 40e60% ethyl acetate) as eluent, 31 was isolated as a yellow
solid (0.02 g, 19%), with spectroscopic characteristics identical to
those outlined above.
CCHO), 115.3 [CH, d, JCF 22, aromatic C(30)H], 122.5 [CH, d, JCF 8,
1
aromatic C(20)H], 134.6 (C, aromatic C), 159.0 [C, d, JCF 242, aro-
matic C(40)], 168.2 (C, CO), 172.8 [C, C(2)], 184.3 [CH, CHO]; exact
mass calculated for C14H16N2O2 [MþH]þ 263.1196. Found
262.1202; m/z (ESþ) 263.1 {[(C14H15N2O2)þHþ], 100%}.
Acknowledgements
IRCSET are gratefully acknowledged for funding of this work. We
thank Rigaku for data collection and structural analysis of com-
pound 63. Jay Chopra is acknowledged for his input into some of
this work (Scheme 1).
4.16. 2-Formyl-N-methyl-2-(piperidin-2-ylidene)acetamide
32
Supplementary data
N-Methyl-Z-3-chloro-2-(phenylsulfinyl)propenamide 10 (0.13 g,
0.5 mmol) was added to a solution of 2,3,4,5-tetrahydropyridine N-
oxide 30 (0.06 g, 0.6 mmol) in dichloromethane (1 mL) in a sealed
microwave reaction vessel with stirring and the reaction solution
was subsequently heated in the microwave for 10 min at 300 W at
100 ꢀC. The reaction mixture was directly applied to a silica column
and the product was eluted with hexane/ethyl acetate (gradient
elution 40e80% ethyl acetate) to give 32 as an off-white solid
(0.02 g, 18%); mp 146e147 ꢀC; nmax/cmꢁ1 (KBr) 3436 (NH), 3227
(NH), 2917 (CH), 1630 (CO), 1609, 1539; dH (300 MHz, CDCl3)
1.78e1.92 [4H, m, C(4)H2 and C(5)H2], 2.78e2.96 [5H, m, C(6)H2 and
NHCH3; NHCH3 could be distinguished as a doublet at 2.83 ppm, J
4.8], 3.37e3.56 [2H, m, C(3)H2], 9.55 [1H, s, CHO], 9.77 (1H, br s,
NH), 13.03 (1H, br s, NH); dC (75.5 MHz, CDCl3) 18.9, 21.1 [2ꢂCH2, C
(4)H2 & C(5)H2], 24.5 [CH2, C(6)H2], 25.0 (CH3, NHCH3), 41.8 [CH2, C
(3)H2], 100.2 (C, CCHO), 170.6, 172.1 [2ꢂC, CO & C(2)], 183.9 [CH,
CHO]; HRMS (ESþ): exact mass calculated for C9H15N2O2 [MþH]þ
183.1134. Found 183.1137; m/z (ESþ) 183.0 {[(C9H14N2O2)þHþ],
100%}.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2010.04.057. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
References and notes
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The structure of 32 was determined by single crystal X-ray dif-
fraction on a crystalline sample of 32 recrystallised from chloroform.
Crystals of 32 are monoclinic, space group P21/c, formula
ꢀ
ꢀ
C9H14N2O2, M¼182.22, a¼6.8793(6) A, b¼8.6766(6) A, c¼15.5216
3
ꢀ
ꢀ
ꢀ
(13) A,
a
¼90.00ꢀ,
b
¼96.679(12)ꢀ,
g
¼90.00 , U¼920.18(13) A , F
(000)¼392,
m
(Mo K
a
)¼0.094 mmꢁ1, R(Fo)¼0.0668, for 906 ob-
served reflections with I>2
s
(I), wR2(F2)¼0.2180 for all 1720
unique reflections. Data in the
q
range 2.64e28.28ꢀ were collected
at 293 K on a Nonius MACH3 diffractometer using Mo K
a
graphite
ꢀ
monochromated radiation,
l
¼0.7107 A, and corrected for Lorentz
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The hydrogen atoms were placed in calculated positions and
allowed to ride on the parent atom.
22. Singh, M.; Singh, B.; Singal, K. K. Asian J. Chem. 2008, 20, 736e740.

4572
M. Kissane et al. / Tetrahedron 66 (2010) 4564e4572
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