N-aryl atropisomerism induces facial selectivity in benzonitrile oxide cycloadditions with exocyclic methylene benzosultams

Article abstract of DOI:10.1071/CH13270

N-aryl methylene benzo-fused sultams (2,3-dihydrobenzo[d]isothiazole 1,1-dioxides) underwent [3+2] cycloaddition with benzonitrile oxide to give 5-spiro isoxazoline adducts with complete regioselectivity. Steric hindrance by atropisomerism around the N-ar

Full text of DOI:10.1071/CH13270

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2013, 66, 874–881
Full Paper
http://dx.doi.org/10.1071/CH13270
N-Aryl Atropisomerism Induces Facial Selectivity
in Benzonitrile Oxide Cycloadditions
with Exocyclic Methylene Benzosultams
A
A
A B
,
Sarah J. Ryan, Craig L. Francis, and G. Paul Savage
A
CSIRO Materials Science and Engineering, Private Bag 10,
Clayton South MDC, Vic. 3169, Australia.
B
Corresponding author. Email: paul.savage@csiro.au
N-aryl methylene benzo-fused sultams (2,3-dihydrobenzo[d]isothiazole 1,1-dioxides) underwent [3þ2] cycloaddition
with benzonitrile oxide to give 5-spiro isoxazoline adducts with complete regioselectivity. Steric hindrance by
atropisomerism around the N-aryl bond induced facial selectivity in these cycloadditions.
Manuscript received: 28 May 2013.
Manuscript accepted: 27 June 2013.
Published online: 19 July 2013.
O
R
Introduction
R
[H]
RLi
Cyclic sulfonamides, or sultams, are an important class of chiral
auxiliary for p-facial discrimination in asymmetric reactions.[1]
Benzosultam (2,3-dihydrobenzo[d]isothiazole 1,1-dioxide)
chiral auxiliaries 1 are readily prepared from saccharine
(Scheme 1) by the addition of organometallic reagents followed
by asymmetric hydrogenation.[2,3] Since the first discovery of
the antibacterial dye Prontosil,[4] sulfonamides and sultams[5–9]
have also been incorporated into a wide range of biologically
active compounds as carboxylic acid and amide isosteres.[10]
Hanson and coworkers recently described[11] the synthesis of
3-methylene benzosultams 5, and these compounds caught our
attention as potential dipolarophiles for 1,3-dipolar nitrile oxide
cycloaddition (NOC) reactions. We have previously reported
the construction of spiro heterocycles using NOC reactions with
exocyclic methylene compounds[12–18] as part of an ongoing
program to introduce novelty, diversity, and non-planar com-
pounds into our medicinal chemistry screening library.[19–21]
Nitrile oxides react readily with carbon-carbon double bonds to
give isoxazolines,[22,23] usually with high regioselectivity that is
dominated by steric influences. In the case of exocyclic methy-
lene dipolarophiles the resulting spiro linkage invariably ends
up at the 5-position of the newly formed isoxazoline ring.[24]
This characteristic of NOC reactions has been extensively
exploited to control regiochemical outcomes of these reac-
tions.[25–29] We recently reported that the steric sensitivity of
NOC reactions can induce facial selectivity in 1,3-dipolar
reactions with methylene pyrrolones,[16] methylene hydan-
toins,[17] and methylene oxazolidinones,[18] as controlled by
atropisomerism due to unsymmetrical N-aryl substituents
(Scheme 2).
N
NH
NH
S
S
S
O
O
O
O
O
O
Saccharine
1
Scheme 1.
O
Ph
N
O
N
O
O
N
N
ϩ
Ϫ
O
O
N
Ph
C
N
ϩ
R
R
R
Ph
Scheme 2.
would be influenced by atropisomeric diastereoselectivity. The
2H,40H-spiro[benzo[d]isothiazole-3,50-isoxazole] 1,1-dioxide
ring system expected from cycloaddition to benzosultams
5 has only been reported once previously, and that was
via condensation between dilithiated oximes and methyl
2-(aminosulfonyl)benzoate.[31]
Herein we describe the nitrile oxide cycloaddition of N-aryl
3-methylene benzosultams 5 to generate 2H,40H-spiro[benzo[d]
isothiazole-3,50-isoxazole] 1,1-dioxide systems, and the effect
on facial selectivity engendered by atropisomeric asymmetry.
Results and Discussion
The 3-methylene benzosultams 5 were prepared by a procedure
adapted from that of Hanson and coworkers (Scheme 3).[11]
Commercially available 2-bromobenzenesulfonyl chloride
2 was reacted with the appropriate aniline derivate in pyr-
idine and dichloromethane at room temperature to give the
2-bromosulfonamides 3, generally in high yields.[32] The reac-
tion with 2-nitroaniline did not proceed at room temperature
Atropisomerism is a relatively overlooked source of asym-
metry, with important implications in the pharmaceutical indus-
try.[30] Hence, in addition to our interest in the inherent novelty
of potential NOC adducts with the 3-methylene sultams, we
sought to determine if the facial selectivity of cycloaddition
Journal compilation Ó CSIRO 2013
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Spiroheterocycles via Regioselective Cycloaddition Reactions
875
TMS
Ar
Br
S
Br
TMS, CuI
ArNH2
H
N
H
N
NEt3, PdCl2(PPh3)2
DMF 80°C
Cl
pyridine
CH2CI2, rt
S
Ar
S
O
O
O
O
O
O
3a–g
4a–g
2
K2CO3
MeCN, 80°C
Entry
N-Substituent (Ar)
Phenyl
a
b
4-chlorophenyl
c
d
e
f
2-methoxyphenyl
2-morpholinophenyl
2-isopropylphenyl
1-naphthyl
R
N
ϩ
N
S
Ar
S
O
O
O
O
g
h
2-nitrophenyl
6
5a–h
2-aminophenyl
Scheme 3.
TMS
Table 1. Synthesis of methylene benzosultams 5
NH2
K2CO3
MeOH, rt
NO2
Entry
N-Substituent
Yield [%]
N
H
N
S
3
4
5
S
O
O
O
O
a
b
c
d
e
f
Phenyl
100
84
92
91
72
81
74
59
36
45
56
62
80
28
4g
5h
4-chlorophenyl
2-methoxyphenyl
2-morpholinophenyl
2-isopropylphenyl
1-naphthyl
100
86
Scheme 4.
56
76
41B
were unable to remove, were observed in the 1H NMR spectra of
the products in a ratio of around 1 : 4, favouring the desired
product. However, the side products did not undergo the
subsequent NOC reaction and were easily removed from
the cycloadducts.
g
2-nitrophenyl
49A
43C
AReflux in pyridine.
B2-Iodosulfonamide substrate used.
CAmino product.
Unfortunately the standard conditions, and alternative bases
such as pyridine, did not give 5g by cyclisation of the nitro-
substituted compound 4g. TMS alkynes are commonly depro-
tected by K2CO3 in methanol at room temperature,[33,34] and
treatment of 4g under these conditions led to the formation of a
5-membered, exocyclic methylene sultam. Analysis revealed
that the isolated product was however the 2-aminophenyl
derivative 5h (Scheme 4). The unexpected concomitant nitro
reduction is presumably the result of potassium carbonate
induced transfer hydrogenation with methanol in a similar
fashion to the Woodward modification[35] of the Meerwein-
Ponndorf-Verley reduction.[36] Similar transfer hydrogenation
reactions of nitro compounds have been reported using ammo-
nium formate as the hydrogen source.[37,38] The yield of 5h
could not be improved above 43 % with prolonged stirring at
room temperature. Heating at 608C for 2 h resulted in an increase
in the undesired 6-endo product 6 (Ar ¼ 2-aminophenyl).
Nitrile oxides are reactive intermediates that readily dimerise
to give furoxans unless sterically hindered.[27,29] To mitigate
dimerisation, nitrile oxides are usually generated in situ and
trapped in the presence of olefinic dipolarophiles. Aryl nitrile
oxides are typically prepared by the base-catalysed dehydroha-
logenation ofthe correspondinghydroximoyl chlorides, which in
turn are prepared by chlorination of aldoximes.[39] The chlo-
rination and dehydrohalogenation steps can conveniently be
combined in a one pot process where water-insoluble aldoximes
and required heating at reflux in pyridine. Since 2-nitroaniline
is no more sterically hindered than 2-isopropylaniline or
1-naphthylamine, it is likely that this sluggishness is due to
reduced nucleophilicity of the amine. The 2-bromosulfonamides
3a–g thus obtained were subjected to Sonogashira coupling with
trimethylsilylacetylene (TMS-acetylene) in the presence of tri-
ethylamine, PdCl2(PPh3)2, and CuI to furnish the TMS-acetylenic
sulfonamides 4a–g (Table 1). The only exception was the
2-nitrophenyl derivative 3g, which failed to give any coupling
product under a variety of conditions. We therefore resorted to
the more reactive 2-iodo-N-(2-nitrophenyl)benzenesulfonamide,
prepared via commercially available 2-iodobenzenesulfonyl
chloride, which underwent the desired TMS-acetylene
Sonogashira reaction to provide 4g in 41% yield.
Hanson reports cyclisation of the analogous N-methyl-
benzenesulfonamides with K2CO3 in acetonitrile at 508C, over
2 h[11] and we were able to replicate that result. However, the
N-arylbenzenesulfonamides in this work required higher tem-
peratures to induce cyclisation. Treatment of the sulfonamides 4
with K2CO3 in acetonitrile at 808C gave the methylene sultams 5
via a 5-exo intramolecular hydroamination-cyclisation of the
acetylene functional group. Possibly as a result of the more
forcing conditions, the exocyclic methylene products were
contaminated with side-products, which were identified as the
6-endo cyclisation products 6. These side-products, which we

876
S. J. Ryan, C. L. Francis, and G. P. Savage
OH
H
H2O
ϩ
N
Ϫ
O
Ph
C
N
N
Ph
N
Ph
R
O
Ph
O
Biphasic
R
N
ϩ
N
S
S
O
O
R
O
O
CH2Cl2
N
S
7a–h (anti)
7a–h (syn)
O
O
5a–h
Scheme 5.
Table 2. Diastereomeric product ratios for benzonitrile oxide cyclo-
adducts 7a h
]
Entry
N-Substituent
7 Yield [%]
anti : syn ratioA
a
b
c
d
e
f
Phenyl
68
61
66
51
69
52
68
N/A
N/A
4-chlorophenyl
2-methoxyphenyl
2-morpholinophenyl
2-isopropylphenyl
1-naphthyl
.50 : 1
.50 : 1
2 : 1
4 : 1
O(3)
h
2-aminophenyl
4 : 1
N(3)
ADetermined by 1H NMR.
N(2)
1
with respect to the substituent on the N-aryl group. H NMR
spectra of the crude reaction mixtures, before purification, were
recorded and the diastereomeric ratios determined (Table 2).
In three cases (7e, 7f, and 7h) diastereomers were evident in
the 1H NMR spectra and their ratios were measured (Table 2).
In the other two cases (7c and 7d) only a single diastereomer
could be detected by 1H NMR spectroscopy, which indicates a
high degree of diastereoselectivity in the cycloaddition reaction.
The cycloadducts were then purified on neutral alumina as they
were less stable on silica. We were unable to separate the
diastereomers using column chromatography.
O(4)
N(1)
S(1)
O(1)
O(2)
Fig. 1. Molecular diagram of 7d with non-hydrogen atoms represented by
50 % thermal ellipsoids and hydrogen atoms as spheres of arbitrary size.
It is conceivable that in the case of 7c and 7d, the observation
of a single set of resonances in the respective 1H NMR spectra is
due to free rotation around the N-aryl bond, leading to an
averaged spectrum on the NMR timescale. This is unlikely
given the evident diastereomers for the other cycloadducts,
but nevertheless to dispel this possibility the 1H NMR spectrum
of the 2-methoxyphenyl cycloadduct 7c was recorded at ꢀ208C
and ꢀ508C. The spectra at the two lower temperatures were
unchanged from that at room temperature. From this it can be
deduced that compound 7c, and by implication the more
hindered 7d, are single atropisomeric diastereomers that are
locked into a single conformation rather than a time-averaged
mixture of diastereomers.
are reacted under biphasic conditions with 5 % sodium hypo-
chlorite solution as both chlorinating agent and base.[40]
Using this method, benzonitrile oxide was generated in situ
by mixing commercially available benzaldehyde oxime in
dichloromethane with a 5 % aqueous NaOCl solution at 08C,
in the presence of the 3-methylene sultams 5a–h. The nitrile
oxide that formed was immediately trapped by the dipolarophile
to give the corresponding spiro cycloadducts 7 (Scheme 5). The
crudeproduct mixtures were examined by 1H NMR spectroscopy.
In each case the dipolar cycloaddition reaction was completely
regioselective in that the oxygen of the nitrile oxide became
attached to the sultam end of the dipolarophile double bond, as
expected.[24] The 1H NMR chemical shifts for the characteristic
AB system of the diastereotopic methylene protons on the newly
formed isoxazoline rings fell in the range of 3.5–4.0 ppm. This
chemical shift is indicative of protons on C-4 of the isoxazoline
ring rather than C-5 (4.5–5.0 ppm),[12] hence establishing the
regiochemistry of cycloaddition as shown in Scheme 5. X-ray
crystallography of one of the products (Fig. 1) was consistent
with this assignment.
Based on previous observations with analogoussystems,[17,18]
the anti cycloaddition product is likely to predominate because
1
the syn face is more sterically hindered. The H NMR data
supported this hypothesis. When there was a mixture of diaster-
eomers (7e, 7f, and 7h) the 1H resonance for the isoxazoline ring
methylene AB system of the major isomer always appeared
upfield from the corresponding AB system in the minor isomer.
This observation is consistent with the isoxazoline methylene
protons of the major cycloadducts being shielded by the substitu-
ent on the N-aryl group, in comparison to the corresponding
isoxazoline methylene protons of the minor isomer. In the case of
the morpholino derivative 7d, where only a single diastereomer
was observed, crystals grown from ethyl acetate were suitable to
The methylene sultams 5c–h bearing an ortho-substituted
N-aryl group, including 1-naphthyl, are potentially atropisomeric
via restricted rotation around the N-aryl bond. Hence, the faces
of the dipolarophile are non-equivalent leading to the possibility
of diastereomeric cycloadducts due to either syn or anti addition

Spiroheterocycles via Regioselective Cycloaddition Reactions
877
obtain a single crystal structure by X-ray crystallography (Fig. 1).
From this structure it can be seen that the nitrile oxide has added
to the dipolarophile from the face opposite the 2-morpholino
substituent on the N-aryl group. All of these data are consistent
with preferential cycloaddition to the anti face of the dipolar-
ophile, controlled by atropisomeric induction.
It is noteworthy that steric hindrance alone is insufficient
to account for the observed facial selectivity in the NOC
reactions with the atropisomeric methylene benzosultams 5.
The 2-isopropylphenyl (5e) and 1-naphthyl (5f) substituents
only induced modest facial selectivity compared with the
2-methoxyphenyl derivative 5c. We have previously noted that
a combination of steric hindrance and electrostatic repulsion
appears to influence the incoming nitrile oxide in NOC reac-
tions,[17,18] and this again appears to be the case with the
benzosultam ring system. Coulombic repulsive interactions of
this type have previously been postulated as a rationale for
diastereofacial differentiation in NOC reactions,[41,42] as a
generalised extension of the ‘inside alkoxy effect’.[43]
The Cambridge Crystallographic Data Centre contains the
supplementary crystallographic data for this paper. The data
for 2-(2-morpholinophenyl)-30-phenyl-2H,40H-spiro[benzo[d]
isothiazole-3,50-isoxazole] 1,1-dioxide 7d (deposition number
CCDC 939831) can be obtained free of charge at www.ccdc.
cam.ac.uk/conts/retrieving.html or from the Cambridge Crys-
tallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: þ44(0)1223–336033; email: deposit@ccdc.cam.ac.uk.
General Method for Benzenesulfonamides 3
Following the procedure of Park,[44] 2-bromobenzenesulfonyl
chloride 2 (25 mmol) was added to a stirred solution of the
appropriate aniline (25 mmol) and pyridine (8.1 mL, 100 mmol)
in CH2Cl2 (70 mL). The reaction mixture was stirred for 2 h at
room temperature. Following this time it was washed with a 5 %
aqueous solution of HCl (3 ꢁ 20 mL). The organic layer was
then dried (MgSO4), filtered, and concentrated under vacuum.
This method was used to prepare benzenesulfonamides 3a–d.
For compounds 3e and 3f the reaction was stirred overnight at
room temperature. 2-Bromo-N-(2-nitrophenyl)benzenesulfo-
namide 3g, and its iodo-analogue, were prepared following the
procedure of Njar,[45] whereby 2-iodo- or 2-bromobenzene-
sulfonyl chloride (20 mmol) was slowly added to a stirred
solution of 2-nitroaniline (2.68 g, 20 mmol) in pyridine (10 mL).
The reaction flask was fitted with a reflux condenser and the
reaction mixture was heated at reflux for 6 h. After this time the
solution was cooled to room temperature and diluted with
CH2Cl2 (50 mL). The organic material was washed with a 5 %
aqueous solution of HCl (3 ꢁ 10 mL). The organic layer was
then dried (MgSO4), filtered, and concentrated under vacuum.
The crude benzenesulfonamides were used immediately without
further purification.
Conclusion
N-aryl methylene benzo-fused sultams (2,3-dihydrobenzo[d]
isothiazole 1,1-dioxides) participate in 1,3-dipolar cycloaddi-
tion reactions with benzonitrile oxide to give 5-spiro isoxazoline
adducts with complete regioselectivity. In cases where unsym-
metrical N-aryl substituents engender atropisomerism around
the N-aryl bond, facial selectivity for the less hindered face vary
from a modest ratio of 2 : 1 to complete selectivity within the
limits of NMR detection. While steric hindrance certainly
carries some responsibility for this facial selectivity, it appears
that electrostatic repulsions are also involved.
Experimental
General Method for Synthesis of TMS Alkynes 4
General
TMS alkynes 4 were prepared according to the procedure of
Hanson,[11] from the corresponding 2-bromobenzenesulfonamide
3. Triethylamine (4.2 mL, 30 mmol), triphenylphosphine
(315 mg, 1.2 mmol), copper(I) iodide (95 mg, 0.5 mmol),
and PdCl2(PPh3)2 (211 mg, 0.3 mmol) were added to a stirred
solution of the appropriate 2-bromobenzenesulfonamide 3
(10 mmol) in DMF (50 mL). TMS acetylene (4.3 mL, 30 mmol)
was then added and the reaction vessel was fitted with a reflux
condenser and heated to 808C overnight. The mixture was
cooled to room temperature and concentrated under vacuum.
The residue was purified by flash column chromatography to
afford the title compounds. Compounds 4a and 4b have previ-
ously been reported.[32]
Melting points were determined on a Buchi B-545 instrument
and are uncorrected. Flash column chromatography was per-
formed on silica gel (Merck, 230–400 mesh ASTM, Kieselgel;
60) or aluminium oxide (Merck, 70–230 mesh ASTM,
Kieselgel; 90 active neutral) with the appropriate combination
of ethyl acetate and light petroleum as eluant, using compressed
air for elution. Thin layer chromatography was performed using
aluminium-backed plates coated with 0.2 mm silica (Merck,
DC-Platten, Kieselgel; 60 F254 plates). Eluted plates were
visualised using a 254 nm ultraviolet (UV) lamp. Starting
materials and reagents were purchased from Sigma-Aldrich,
Oakwood Chemicals, and Merck, and were used as supplied;
where specified dichloromethane and THF were dried through a
1
solvent purification system (SPS). H and 13C NMR spectra
N-(2-Methoxyphenyl)-2-((trimethylsilyl)ethynyl)
benzenesulfonamide (4c)
were recorded at room temperature on a Bruker Biospin AV400
spectrometer operating at 400 MHz for proton and 100 MHz for
carbon nuclei, using CDCl3 as solvent and internal reference.
Variable temperature 1H NMR spectra were recorded on a
Bruker DRX 500 spectrometer operating at 500 MHz, using
CDCl3 as solvent. Infrared spectra were recorded using a Smart
iTR accessory on a Thermo Nicolet 6700 Fourier transform
infrared (FTIR) spectrometer. FT-IR spectra were recorded on a
Bruker Equinox 55/S FT-IR spectrometer with neat samples in
KBr disks. Electron impact (EI) mass spectra were recorded on a
ThermoQuest MAT95XP mass spectrometer using ionisation
energy of 70 eV. Accurate mass measurements were obtained
on the same instrument with a resolution of 5000–10000
using perfluorokerosene (PFK) as the reference compound.
This compound was prepared from sulfonamide 3c and isolated
as a pale yellow oil. Rf 0.31 (1 : 9, v/v EtOAc : light petroleum).
n
max/cmꢀ1 2956 (w), 2161 (w), 1501 (m), 1345 (s), 1249 (s),
1161 (s), 1111 (m), 843 (s), 748 (s). 1H NMR (400 MHz, CDCl3)
d 7.94 (dd, J ¼ 8.0, 1.2 Hz, 1H), 7.74 (br s, 1H), 7.56 (dd, J ¼ 7.6,
1.2 Hz, 1H), 7.46 (dd, J ¼ 7.6, 1.2 Hz, 1H), 7.41 (td, J ¼ 7.6,
1.2 Hz, 1H), 7.31 (td, J ¼ 7.6, 1.2 Hz, 1H), 6.97 (td, J ¼ 8.0,
1.2 Hz, 1H), 6.82 (td, J ¼ 8.0, 1.2 Hz, 1H), 6.74 (dd, J ¼ 8.0,
1.2 Hz, 1H), 3.73 (s, 3H), ꢀ0.36 (s, 9H). 13C NMR (100 MHz,
CDCl3) d 149.2, 141.1, 134.5, 132.3, 129.5, 128.2, 126.0, 124.8,
121.3, 121.0, 120.1, 110.7, 104.2, 101.0, 55.7, 0.3. m/z (HR-MS
ESI) 382.0905; [MþNa]þ requires 382.0909.

878
S. J. Ryan, C. L. Francis, and G. P. Savage
N-(2-Morpholinophenyl)-2-((trimethylsilyl)ethynyl)
benzenesulfonamide (4d)
fitted with a reflux condenser and heated to 808C for 3 h. The
mixture was allowed to cool to room temperature then filtered
through a plug of silica, which was then rinsed with EtOAc. The
filtrate was concentrated under reduced pressure and the residue
was purified by flash column chromatography to afford the title
compounds. The products were isolated as a 4 : 1 mixture with
the corresponding 6-endo-dig isomer. We were unable to sep-
arate these materials but the unwanted side-product product did
not affect the subsequent nitrile oxide cycloaddition reaction.
This compound was prepared from sulfonamide 3d and isolated
as a brown oil. Rf 0.3 (1 : 4, v/v EtOAc : light petroleum). nmax
/
cmꢀ1 3148 (w), 2969 (w), 2161 (w), 1491 (m), 1383 (m), 1333
1
(m), 1253 (m), 1171 (s), 1115 (s), 840 (s), 755 (s). H NMR
(400 MHz, CDCl3) d 8.11 (br s, 1H), 7.96 (dd, J ¼ 7.6, 1.2 Hz,
1H), 7.59 (dd, J ¼ 7.6, 1.2 Hz, 1H), 7.47–7.42 (m, 2H), 7.36
(td, J ¼ 7.6, 1.2 Hz, 1H), 7.12–7.01 (m, 3H), 3.86 (t, J ¼ 4.8 Hz,
4H), 2.68 (t, J ¼ 4.8 Hz, 4H), 0.34 (s, 9H). 13C NMR (100 MHz,
CDCl3) d 142.1, 141.3, 135.2, 133.0, 132.4, 129.2, 128.5, 126.0,
124.6, 121.7, 121.4, 119.4, 104.8, 101.4, 67.4, 53.0, 0.0. m/z
(HR-MS ESI) 437.1325; [MþNa]þ requires 437.1331.
3-Methylene-2-phenyl-2,3-dihydrobenzo[d]isothiazole
1,1-dioxide (5a)
The title compound was isolated as a yellow waxy solid. Rf 0.2
(1 : 9, v/v EtOAc : light petroleum). nmax/cmꢀ1 1592 (m), 1490
(m), 1471 (m), 1301 (s), 1160 (s), 748 (s), 696 (s). H NMR
1
N-(2-Isopropylphenyl)-2-((trimethylsilyl)ethynyl)
benzenesulfonamide (4e)
(400 MHz, CDCl3) d 7.85 (dd, J ¼ 7.2, 1.2 Hz, 1H), 7.75
(dd, J ¼ 7.2, 1.2 Hz, 1H), 7.69–7.59 (m, 2H), 7.52–7.38 (m, 5H),
4.99 (d, J ¼ 2.8 Hz, 1H), 4.29 (d, J ¼ 2.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d 139.6, 133.2, 130.8, 130.3, 130.1, 129.7,
129.5, 128.4, 127.1, 121.7, 121.2, 86.7. m/z (HR-MS ESI)
280.0403; [MþNa]þ requires 280.0408.
This compound was prepared from sulfonamide 3e and isolated
as a yellow oil. Rf 0.3 (1 : 9, v/v EtOAc : light petroleum). nmax
/
cmꢀ1 2962 (w), 2157 (w), 1492 (w), 1387 (m), 1250 (m), 1168
1
(s), 909 (m), 860 (s), 842 (s), 755 (s). H NMR (400 MHz,
CDCl3) d 7.84 (d, J ¼ 7.6 Hz, 1H), 7.65 (dd, J ¼ 7.6, 0.4 Hz, 1H),
7.46 (td, J ¼ 7.6, 0.4 Hz, 1H), 7.34 (t, J ¼ 7.6 Hz, 1H), 7.21
(d, J ¼ 7.6 Hz, 1H), 7.13 (t, J ¼ 7.6 Hz, 1H), 7.08–6.98 (m, 3H),
3.36 (sept, J ¼ 6.8 Hz, 1H), 1.10 (d, J ¼ 6.8 Hz, 6H), 0.31
(s, 9H). 13C NMR (100 MHz, CDCl3) d 143.9, 141.9, 134.7,
132.8, 132.3, 129.3, 128.8, 127.2, 126.4, 125.3, 120.8, 104.7,
101.8, 27.5, 23.6, 0.2 (one aromatic signal overlapping). m/z
(HR-MS ESI) 394.1268; [MþNa]þ requires 394.1273.
2-(4-Chlorophenyl)-3-methylene-2,3-dihydrobenzo[d]
isothiazole 1,1-dioxide (5b)
The title compound was isolated as a yellow waxy solid. Rf 0.2
(1 : 9, v/v EtOAc : light petroleum). nmax/cmꢀ1 1489 (m), 1303
(s), 1175 (s), 1162 (s), 1091 (m), 749 (s). 1H NMR (400 MHz,
CDCl3) d 7.84 (dd, J ¼ 7.2, 0.8 Hz, 1H), 7.77 (d, J ¼ 7.2 Hz, 1H),
7.76–7.60 (m, 2H), 7.51–7.37 (m, 2H), 7.38 (d, J ¼ 8.8 Hz, 1H),
7.30 (d, J ¼ 8.8 Hz, 1H), 5.01 (d, J ¼ 2.8 Hz, 1H), 4.28
(d, J ¼ 2.8 Hz, 1H). m/z (HR-MS ESI) 314.0013; [MþNa]þ
requires 314.0018.
N-(Naphthalen-1-yl)-2-((trimethylsilyl)ethynyl)
benzenesulfonamide (4f)
This compound was prepared from sulfonamide 3f and isolated
as a yellow oil. Rf 0.3 (1 : 9, v/v EtOAc : light petroleum). nmax
/
cmꢀ1 2956 (w), 2156 (w), 1465 (w), 1351 (w), 1249 (m), 1164
2-(2-Methoxyphenyl)-3-methylene-2,3-dihydrobenzo[d]
isothiazole 1,1-dioxide (5c)
1
(s), 1126 (m), 1066 (m), 840 (s), 759 (s). H NMR (400 MHz,
The title compound was isolated as a yellow oil. Rf 0.2 (1 : 4, v/v
EtOAc : light petroleum). nmax/cmꢀ1 1595 (m), 1500 (s), 1474
(m), 1304 (s), 1282 (s), 1162 (s), 1023 (s), 763 (s). H NMR
(400MHz, CDCl3) d 7.86 (d, J ¼ 7.6 Hz, 1H), 7.76 (d, J ¼ 7.6 Hz,
1H), 7.65 (t, J ¼ 7.6 Hz, 1H), 7.60 (t, J ¼ 7.6 Hz, 1H), 7.52–7.44
(m, 2H), 7.09–7.05 (m, 2H), 4.93 (d, J ¼ 2.4 Hz, 1H), 4.10
(d, J ¼ 2.4 Hz, 1H), 3.81 (s, 3H). m/z (HR-MS ESI) 310.0508;
[MþNa]þ requires 310.0514.
CDCl3) d 8.29 (d, J ¼ 8.4 Hz, 1H), 7.82 (dd, J ¼ 8.4, 0.8 Hz, 1H),
7.79 (dd, J ¼ 8.4, 0.8 Hz, 1H), 7.68–7.65 (m, 2H), 7.55–7.46
(m, 4H), 7.45 (td, J ¼ 8.2, 0.8 Hz, 1H), 7.32–7.24 (m, 2H), 0.35
(s, 9H). 13C NMR (100 MHz, CDCl3) d 141.3, 134.7, 134.4,
132.4, 131.7, 129.4, 129.3, 128.8, 128.4, 127.3, 126.7, 126.5,
125.4, 122.4, 121.8, 120.8, 105.0, 102.1, 0.2. m/z (HR-MS ESI)
402.0955; [MþNa]þ requires 402.0960.
1
N-(2-Nitrophenyl)-2-((trimethylsilyl)ethynyl)
benzenesulfonamide (4g)
3-Methylene-2-(2-morpholinophenyl)-2,3-dihydrobenzo
[d]isothiazole 1,1-dioxide (5d)
This compound was prepared from 2-iodo-N-(2-nitrophenyl)
benzenesulfonamide and isolated as a brown waxy solid. Rf 0.25
(1 : 9, v/v EtOAc : light petroleum). nmax/cmꢀ1 3262 (w), 2956
(w), 2163 (w), 1531 (m), 1487 (m), 1350 (s), 1248 (s), 1174 (s),
814 (s), 758 (s). 1H NMR (400 MHz, CDCl3) d 10.44 (br s, 1H),
8.14–8.13 (m, 2H), 7.67 (dd, J ¼ 8.4, 1.2 Hz, 1H), 7.60
(dd, J ¼ 7.6, 1.2 Hz, 1H), 7.51 (td, J ¼ 7.6, 1.2 Hz, 1H),
7.49–7.43 (m, 2H), 7.07 (td, J ¼ 7.6, 1.2 Hz, 1H), ꢀ0.35 (s, 9H).
13C NMR (100 MHz, CDCl3) d 139.6, 136.2, 135.8, 135.7,
134.1, 133.2, 130.0, 128.4, 126.5, 122.9, 122.0, 118.7, 106.5,
99.4, 0.4. m/z (HR-MS ESI) 397.0649; [MþNa]þ requires
397.0654.
The title compound was isolated as a brown solid. Rf 0.3 (1 : 4,
v/v EtOAc : light petroleum). nmax/cmꢀ1 2820 (w), 1493 (m),
1448(m), 1310 (s), 1270(m), 1176 (s), 1159 (s), 1112(s), 919(m),
760 (s), 728 (s). 1H NMR (400 MHz, CDCl3) d 7.85
(d, J ¼ 7.6 Hz, 1H), 7.78 (d, J ¼ 7.6 Hz, 1H), 7.68 (td, J ¼ 7.6,
0.8 Hz, 1H), 7.62 (dd, J ¼ 7.6, 0.8 Hz, 1H), 7.52 (dd, J ¼ 7.6,
0.8 Hz, 1H), 7.48–7.41 (m, 1H), 7.16–7.11 (m, 2H), 5.03
(d, J ¼ 2.4 Hz, 1H), 4.18 (d, J ¼ 2.4 Hz, 1H), 3.63–3.61 (m, 4H),
3.20–3.15 (m, 2H), 2.96–2.91 (m, 2H). m/z (HR-MS ESI)
314.0013; [MþNa]þ requires 314.0018.
2-(2-Isopropylphenyl)-3-methylene-2,3-dihydrobenzo[d]
isothiazole 1,1-dioxide (5e)
General Synthesis Procedure for Methylene Sultams 5
In a modification of Hanson’s procedure,[11] K2CO3 (5.5 g,
40 mmol) was added to a stirred solution of the appropriate TMS
alkyne 4 (5 mmol) in MeCN (50 mL). The reaction vessel was
The title compound was isolated as a yellow solid. Rf 0.2 (1 : 9,
v/v EtOAc : light petroleum). nmax/cmꢀ1 2961 (w), 1487 (m),
1469(m), 1446 (m), 1306(s), 1181 (s), 1155 (s), 1028(m), 768 (s).

Spiroheterocycles via Regioselective Cycloaddition Reactions
879
1H NMR (400 MHz, CDCl3) d 7.87 (d, J ¼ 7.6 Hz, 1H), 7.77 (d,
J ¼ 7.6 Hz, 1H), 7.67 (td, J ¼ 7.6, 0.8 Hz, 1H), 7.63
(td, J ¼ 7.6, 0.8 Hz, 1H), 7.51–7.48 (m, 2H), 7.43–7.40 (m, 2H),
4.94 (d, J ¼ 2.4 Hz, 1H), 4.02 (d, J ¼ 2.4 Hz, 1H), 3.14 (sept,
J ¼ 6.8 Hz, 1H), 1.26 (d, J ¼ 6.8 Hz, 3H), 1.16 (d, J ¼ 6.8 Hz,
3H). 13C NMR (100 MHz, CDCl3) d 151.2, 140.4, 133.1, 131.8,
130.8, 130.7, 130.3, 128.1, 127.7, 127.3, 126.9, 121.8, 121.3,
86.2, 28.2, 24.4, 24.2. m/z (HR-MS ESI) 322.0873; [MþNa]þ
requires 322.0878.
(d, J ¼ 18.4 Hz, 1H), 3.70 (d, J ¼ 18.4 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d 156.6, 136.2, 134.8, 134.0, 132.0, 131.5,
130.8, 130.2, 130.0, 129.9, 128.9, 128.2, 126.6, 124.1, 121.5,
99.1, 43.3. m/z (HR-MS ESI) 399.0775; [MþNa]þ requires
399.0779.
2-(4-Chlorophenyl)-30-phenyl-2H,4’H-spiro[benzo[d]
isothiazole-3,50-isoxazole] 1,1-dioxide (7b)
Isolated as a white solid. Mp182.9–183.88C. Rf 0.15 (1 : 4, v/v
EtOAc : light petroleum). nmax/cmꢀ1 1488 (m), 1304 (s), 1171
(s), 759 (s). 1H NMR (400 MHz, CDCl3) d 7.93 (d, J ¼ 7.6 Hz,
1H), 7.77–7.72 (m, 2H), 7.66–7.60 (m, 3H), 7.49–7.37 (m, 7H),
3.88 (d, J ¼ 18.4 Hz, 1H), 3.66 (d, J ¼ 18.4 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d 156.7, 136.5, 136.2, 134.6, 134.2, 133.2,
131.6, 131.0, 130.2, 129.1, 128.6, 128.1, 126.6, 124.1, 121.6,
99.1, 43.5. m/z (HR-MS ESI) 433.0383; [MþNa]þ requires
433.0390.
3-Methylene-2-(naphthalen-1-yl)-2,3-dihydrobenzo[d]
isothiazole 1,1-dioxide (5f)
The title compound was isolated as a yellow waxy solid. Rf 0.3
(1 : 9, v/v EtOAc : light petroleum). nmax/cmꢀ1 3066 (w), 1635
(m), 1467 (m), 1393 (m), 1309 (s), 1175 (s), 1155 (s), 1030 (m),
768 (s). 1H NMR (400 MHz, CDCl3) d 8.00 (d, J ¼ 8.4 Hz, 1H),
7.93–7.91 (m, 2H), 7.82–7.58 (m, 5H), 7.53–7.50 (m, 3H), 4.94
(d, J ¼ 2.4 Hz, 1H), 3.97 (d, J ¼ 2.4 Hz, 1H). m/z (HR-MS ESI)
330.0559; [MþNa]þ requires 330.0565.
2-(2-Methoxyphenyl)-30-phenyl-2H,4’H-spiro[benzo[d]
isothiazole-3,50-isoxazole] 1,1-dioxide (7c)
2-(2-Aminophenyl)-3-methylene-2,3-dihydrobenzo[d]
isothiazole 1,1-dioxide (5h)
Isolated as a yellow waxy solid. Rf 0.2 (1 : 4, v/v EtOAc : light
petroleum). nmax/cmꢀ1 1497 (m), 1307 (s), 1168 (s), 1021 (m),
902 (m), 754 (s). 1H NMR (400 MHz, CDCl3) d 7.92 (d,
J ¼ 7.6Hz, 1H), 7.76–7.64 (m, 4H), 7.45–7.43(m, 2H), 7.40–7.32
(m, 4H), 7.04 (t, J ¼ 7.6 Hz, 1H), 6.91 (d, J ¼ 7.6 Hz, 1H), 4.07
(d, J ¼ 18.4 Hz, 1H), 3.81 (s, 3H), 3.80 (d, J ¼ 18.4 Hz, 1H).
13C-NMR (100 MHz, CDCl3) d 158.4, 156.7, 136.0, 135.5, 133.8,
131.9, 131.3, 130.7, 128.9, 128.5, 126.6, 124.2, 122.0, 121.6,
117.8, 112.9, 99.5, 56.4, 43.0 (one aromatic signal overlapping).
m/z (HR-MS ESI) 429.0879; [MþNa]þ requires 429.0885.
K2CO3 (3.96 g, 30 mmol) was added to a stirred solution of
the TMS-alkyne 4 g (1.12 g, 3 mmol) in methanol (6 mL). The
reaction mixture was stirred overnight at room temperature.
The mixture was diluted with diethyl ether and filtered through
a plug of silica. The filtrate was concentrated under vacuum and
the residue was purified by flash column chromatography
(1 : 4 v/v EtOAc : light petroleum) to afford the title compound
as a yellow solid. Rf 0.3 (1 : 4, v/v EtOAc : light petroleum).
n
max/cmꢀ1 3379 (w), 1620 (m), 1486 (m), 1469 (m), 1303 (s),
1
1256 (m), 1176 (s), 1159 (s), 726 (s). H NMR (400 MHz,
CDCl3) d 7.87 (d, J ¼ 7.6 Hz, 1H), 7.78 (d, J ¼ 7.6 Hz, 1H), 7.68
(td, J ¼ 7.6, 0.8 Hz, 1H), 7.62 (td, J ¼ 7.6, 0.8 Hz, 1H),
7.29–7.24 (m, 2H), 6.88–6.82 (m, 2H), 4.99 (d, J ¼ 2.4 Hz, 1H),
4.22 (d, J ¼ 2.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) d 144.4,
139.7, 134.3, 134.1, 133.8, 130.5, 125.7, 123.8, 122.6, 121.8,
118.1, 113.1, 87.6 (one signal overlapping). m/z (HR-MS ESI)
295.0511; [MþNa]þ requires 295.0517.
2-(2-Morpholinophenyl)-30-phenyl-2H,4’H-spiro[benzo[d]
isothiazole-3,50-isoxazole] 1,1-dioxide (7d)
Isolated as a white solid. Mp 204.5–208.18C (decomp.). Rf 0.2
(3 : 7, v/v EtOAc : light petroleum). nmax/cmꢀ1 2958 (w), 1491
(m), 1304 (s), 1172 (s), 1115 (m), 848 (m), 757 (s). H NMR
1
(400 MHz, CDCl3) d 7.92 (d, J ¼ 7.6 Hz, 1H), 7.84 (dd, J ¼ 7.6,
1.2 Hz, 1H), 7.77–7.67 (m, 3H), 7.36–7.27 (m, 6H), 7.19 (t,
J ¼ 7.6 Hz, 1H), 6.91 (d, J ¼ 7.6 Hz, 1H), 5.13 (d, J ¼ 17.6 Hz,
1H), 3.83 (d, J ¼ 17.6 Hz, 1H), 3.78–3.67 (m, 4H), 3.54–3.51
(m, 2H), 2.49–2.45 (m, 2H). 13C NMR (100 MHz, CDCl3)
d 156.9, 152.3, 136.1, 135.9, 135.2, 133.9, 131.5, 131.1, 130.8,
128.9, 128.6, 126.4, 125.3, 124.9, 124.4, 121.5, 121.0, 100.4,
67.5, 53.0, 43.3. m/z (HR-MS ESI) 484.1303; [MþNa]þ
requires 484.1307.
General Procedure for Nitrile Oxide Cycloaddition
Reactions
According to the procedure of Savage,[16] the appropriate
methylene sultam 5 (1 mmol) and benzaldehyde oxime (363 mg,
3 mmol) were dissolved in CH2Cl2 (5 mL). The solution was
cooled to 08C in an ice bath with vigorous stirring and NaOCl
(5.5 mL of an 8 % aqueous solution, 6 mmol) was then slowly
added over a period of 30 min. The reaction mixture was then
stirred vigorously overnight. After this time the mixture was
diluted with CH2Cl2 and brine was added. The layers were
separated and the aqueous phase was extracted with CH2Cl2
(3 ꢁ 10 mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated under vacuum. The residue was
purified by flash column chromatography (EtOAc : light petro-
leum) over neutral alumina to afford the title compounds.
2-(2-Isopropylphenyl)-30-phenyl-2H,4’H-spiro[benzo[d]
isothiazole-3,50-isoxazole] 1,1-dioxide (7e)
The title compound was formed as a 2 : 1 mixture of diaster-
eomers, as determined by integration of suitable peaks in the 1H
NMR spectrum of the crude product. These diastereomers could
not be separated by standard purification techniques. The mix-
ture of products was a white solid. Mp 197.1–199.98C. Rf 0.2
(1 : 4, v/v EtOAc : light petroleum). nmax/cmꢀ1 2962 (w), 1450
(m), 1363 (m), 1309 (s), 1164 (s), 895 (m), 753 (s). major dia-
1
stereomer H NMR (400 MHz, CDCl3) d 7.94 (d, J ¼ 7.6 Hz,
2,30-Diphenyl-2H,4’H-spiro[benzo[d]isothiazole-3,50-
isoxazole] 1,1-dioxide (7a)
1H), 7.82–7.64 (m, 4H), 7.47–7.30 (m, 8H), 3.89 (d, J ¼ 18.4Hz,
1H), 3.60 (d, J ¼ 18.4 Hz, 1H), 3.39 (sept, J ¼ 6.8 Hz, 1H),
1.30 (d, J ¼ 6.8 Hz, 3H), 1.21 (d, J ¼ 6.8 Hz, 3H); minor dia-
Isolated as a white solid. Mp 231.4–234.18C. Rf 0.25 (3 : 7, v/v
EtOAc : light petroleum); nmax/cmꢀ1 1362 (w), 1301 (s), 1173
(m), 1156 (s), 759 (s). H NMR (400 MHz, CDCl3) d 7.92
1
stereomer H NMR (400 MHz, CDCl3) d 7.92 (d, J ¼ 7.6 Hz,
1
1H), 7.82–7.64 (m, 3H), 7.47–7.30 (m, 8H), 7.15 (td, J ¼ 7.6,
1.6 Hz, 1H), 3.95 (d, J ¼ 18.0 Hz, 1H), 3.75 (d, J ¼ 18.0 Hz, 1H),
(d, J ¼ 7.6 Hz, 1H), 7.77–7.63 (m, 5H), 7.46–7.32 (m, 8H), 3.86

880
S. J. Ryan, C. L. Francis, and G. P. Savage
3.71 (sept, J ¼ 6.8 Hz, 1H), 1.32 (d, J ¼ 6.8 Hz, 3H), 1.24
(d, J ¼ 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 156.3, 156.2,
154.0, 151.1, 137.0, 136.3, 135.2, 135.0, 134.6, 134.0, 133.9,
132.7, 131.5, 131.0, 130.9, 130.8, 129.0, 128.9, 129.6, 128.4,
128.3, 127.3, 126.6, 126.5, 126.4, 126.1, 124.3, 123.0, 121.7,
121.4, 99.5, 99.4, 43.6, 42.4, 28.5, 28.1, 25.5, 25.4, 24.5, 23.9
(4 aromatic signals overlapping). m/z (HR-MS ESI) 441.1243;
[MþNa]þ requires 441.1249.
Acknowledgements
We thank Dr Roger Mulder of CSIRO for assistance with NMR spectros-
copy, and Dr Craig Forsyth of Monash University for the X-ray crystallo-
graphic structure determination.
References
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M. C. Harrison, T. C. Hohman, J. Sredy, D. Sullivan, J. Med. Chem.
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2-(2-Naphthalen-1-yl)-30-phenyl-2H,4’H-spiro[benzo[d]
isothiazole-3,50-isoxazole] 1,1-dioxide (7f)
The title compound was formed as a 4 : 1 mixture of diaster-
eomers, as determined by integration of suitable peaks in the 1H
NMR spectrum of the crude product. These diastereomers could
not be separated by standard purification techniques. The mix-
ture of products was a white solid. Mp 244.3–245.58C
(decomp.). Rf 0.2 (1 : 4, v/v EtOAc : light petroleum). nmax/cmꢀ1
2965 (w), 1363 (m), 1321 (s), 1179 (s), 1165 (s), 897 (m),
763 (s). major diastereomer 1H NMR (400 MHz, CDCl3) d 8.22
(d, J ¼ 7.6 Hz, 1H), 8.06 (d, J ¼ 7.6 Hz, 1H), 7.97 (d, J ¼ 7.6 Hz,
1H), 7.88 (d, J ¼ 7.6 Hz, 1H), 7.81 (d, J ¼ 7.6 Hz, 1H), 7.78–
7.70 (m, 2H), 7.63 (d, J ¼ 7.6 Hz, 1H), 7.57–7.46 (m, 3H), 7.29–
7.18 (m, 5H), 3.82 (d, J ¼ 18.4 Hz, 1H), 3.67 (d, J ¼ 18.4 Hz,
1H); minor diastereomer 1H NMR (400 MHz, CDCl3) d 8.57 (d,
J ¼ 7.6 Hz, 1H), 7.95 (d, J ¼ 7.6 Hz, 1H), 7.85–7.71 (m, 4H),
7.65–7.62 (m, 1H), 7.57–7.46 (m, 3H), 7.29 (t, J ¼ 7.6 Hz, 1H),
7.29–7.18(m, 5H), 4.01(d, J ¼ 18.0Hz, 1H), 3.78(d, J ¼ 18.0 Hz,
1H). 13C-NMR (100 MHz, CDCl3) d 156.6, 156.5, 136.5,
135.2, 135.1, 134.7, 134.3, 134.0, 133.9, 133.3, 131.6, 131.5,
131.2, 131.0, 130.7, 130.6, 128.6, 128.1, 128.0, 127.7, 127.6,
127.5, 127.1, 126.9, 126.5, 126.3, 125.7, 125.6, 124.9, 124.4,
123.9, 123.4, 121.7, 121.5, 99.9, 99.7, 43.7, 42.1 (8 aromatic
signals overlapping). m/z (HR-MS ESI) 449.0929; [MþNa]þ
requires 449.0936.
[7] L. Kiefer, T. Gorojankina, P. Dauban, H. Faure, M. Ruat, R. H. Dodd,
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2006, 3, 175.
2-(2-Aminophenyl)-30-phenyl-2H,4’H-spiro[benzo[d]
isothiazole-3,50-isoxazole] 1,1-dioxide (7h)
The title compound was formed as a 4 : 1 mixture of diaster-
eomers, as determined by integration of suitable peaks in the 1H
NMR spectrum of the crude product. These diastereomers could
not be separated by standard purification techniques. The mix-
ture of products was a white solid. Mp 136.2–138.98C Rf 0.2
(3 : 7, v/v EtOAc : light petroleum). nmax/cmꢀ1 3586 (w), 3415
(w), 1620 (m), 1498 (m), 1363 (m), 1299 (s), 1170 (s), 902 (m),
792 (m), 759 (s). major diastereomer 1H NMR (400 MHz,
CDCl3) d 7.92 (d, J ¼ 7.6 Hz, 1H), 7.78–7.58 (m, 4H), 7.46 (d,
J ¼ 7.6 Hz, 2H), 7.38–7.31 (m, 3H), 7.13 (t, J ¼ 7.6 Hz, 1H),
6.80 (t, J ¼ 7.6 Hz, 1H), 6.71 (d, J ¼ 7.6 Hz, 1H), 4.03 (d,
J ¼ 18.4 Hz, 1H), 3.80 (d, J ¼ 18.4 Hz, 1H); major diastereomer
1H NMR (400 MHz, CDCl3) d 7.92 (d, J ¼ 7.6 Hz, 1H), 7.78–
7.58 (m, 4H), 7.46 (d, J ¼ 7.6 Hz, 2H), 7.38–7.31 (m, 3H), 7.08
(t, J ¼ 7.6 Hz, 1H), 6.73 (d, J ¼ 7.6 Hz, 1H), 6.63 (t, J ¼ 7.6 Hz,
1H), 3.91 (d, J ¼ 18.4 Hz, 1H), 3.75 (d, J ¼ 18.4 Hz, 1H).
13C NMR (100 MHz, CDCl3) d 157.0, 156.9, 149.0, 147.4,
136.9, 136.1, 135.1, 135.0, 134.8, 134.0, 133.5, 131.7, 131.6,
131.4, 130.9, 130.7, 129.0, 128.9, 128.5, 128.3, 126.7, 124.2,
121.5, 121.4, 120.1, 118.1, 117.6, 117.1, 115.0, 114.1, 99.8,
99.3, 43.1, 42.7 (4 aromatic signals overlapping). m/z (HR-MS
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