Benzonitrile oxide cycloadditions with exocyclic methylene benzothiazepine dioxides

Article abstract of DOI:10.1071/CH13444

N-substituted 5-methylene-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxides underwent 1,3-dipolar cycloaddition with benzonitrile oxide, generated in situ, to give isoxazoline spiro adducts. The cycloadditions were completely regioselective to give the hitherto unreported 3,4-dihydro-2H, 4′ H-spiro[benzo[f][1,2]thiazepine-5, 5′-isoxazole] 1,1-dioxide cycloadduct. Where the N-substituent on the sulfonamide cycloaddition precursor was a 2-substituted arene, the resulting atropisomerism along the N-aryl bond led to facial selectivity in the cycloaddition reaction, with greater than 90% diastereoselectivity. CSIRO 2014.

Full text of DOI:10.1071/CH13444

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2014, 67, 381–388
Full Paper
http://dx.doi.org/10.1071/CH13444
Benzonitrile Oxide Cycloadditions with Exocyclic
Methylene Benzothiazepine Dioxides
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-substituted 5-methylene-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxides underwent 1,3-dipolar cycloaddition
with benzonitrile oxide, generated in situ, to give isoxazoline spiro adducts. The cycloadditions were completely
regioselective to give the hitherto unreported 3,4-dihydro-2H,40H-spiro[benzo[f][1,2]thiazepine-5,50-isoxazole]
1,1-dioxide cycloadduct. Where the N-substituent on the sulfonamide cycloaddition precursor was a 2-substituted arene,
the resulting atropisomerism along the N-aryl bond led to facial selectivity in the cycloaddition reaction, with greater than
90 % diastereoselectivity.
Manuscript received: 26 August 2013.
Manuscript accepted: 23 September 2013.
Published online: 14 October 2013.
R
Introduction
RCNO
As part of a library enrichment program for our drug discovery
endeavours,[1,2] we are interested in preparing structurally novel
heterocycles. Many commercial drug-screening libraries con-
tain an abundance of planar, aromatic heterocycles and an
underrepresentation of three-dimensional structures. In contrast,
the bioactive ligands typically found in nature tend to have more
architectural complexity, with core structures containing a
higher proportion of sp3 centres. Screening libraries that are rich
in three-dimensional compounds, with high molecular shape
diversity, might be expected to display a broader range of bio-
logical activities.[3,4] ‘Flatness’ parameters such as the fraction
of sp3carbons as a proportion of total carbon (sp3/C), chiral atom
counts, and the difference between aromatic and sp3 atom counts
(Ar – sp3) have all been suggested as metrics to analyse the
quality of drug screening libraries.[5–7] It should be noted that
these measures are somewhat simplistic in that they value the
contribution of all sp3 centres equally. In reality, the molecular
three-dimensionality contribution of, for example, an sp3 methyl
substituent on a benzene ring is insignificant compared with that
of an sp3 bridgehead carbon. A more sophisticated metric for
compound shape is the principal moments of inertia (PMI),
which describes the shape of a molecule normalized to the
molecule’s longest dimension.[8]
N
O
Scheme 1.
Benzo-fused cyclic sulfonamide (sultam) ring systems have
been described as ‘privileged structures’ in medicinal chemis-
try.[26,27] Following the discovery of the antibacterial sulfon-
amide dye Prontosil,[28] this functionality has been incorporated
into a wide range of biologically active compounds as carbo-
xylic acid and amide isosteres.[29] The benzo-fused seven-
membered sultam partial structure has appeared in HIV-1
protease inhibitors,[30] hypolipidemic agents,[31] antiprolifera-
tive[32,33] and proapoptotic[34] anticancer compounds, and in
the antidepressant drug tianeptine.[35] Hanson and coworkers
recently described[36] the synthesis of 5-methylene-2,3,4,5-
tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxides 4, and these
compounds caught our attention as potential dipolarophiles for
1,3-dipolar NOC reactions. These exocyclic methylene seven-
membered sultams bear some resemblance to our previously
reported NOC reactions with five-membered sultams,[37] and
we were particularly interested to see if the pattern of reactivity
and facial selectivity was maintained.
One convenient method for introducing three-dimensionality
into molecules is with spiro linkages, and to that end, we have
pursued the construction of spiro heterocycles using 1,3-dipolar
nitrile oxide cycloaddition (NOC) reactions[9,10] with exocyclic
methylene compounds.[11–17] These reactions are highly regio-
selective, with the resulting spiro linkage appearing at the
5-position of the newly formed isoxazoline ring (Scheme 1).[18]
The steric sensitivity of the NOC process has been extensively
exploited to control the regiochemical outcomes of these reac-
tions.[19–23] The resulting spiro-isoxazoline substructure is itself
a structural motif that is found in several biologically active
natural products.[24,25]
Herein, we describe the NOC of N-substituted 5-methylene-
2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxides 4 to gen-
erate the previously unreported ring system 3,4-dihydro-2H,
40H-spiro[benzo[f][1,2]thiazepine-5,50-isoxazole] 1,1-dioxide 5.
Results and Discussion
The 5-methylene benzothiazepines 4 were prepared by a
procedure adapted from that of Hanson and coworkers
(Scheme 2).[36] Commercially available 2-bromobenzenesulfonyl
chloride 1 was reacted with the appropriate amine in pyridine
and dichloromethane (DCM) at room temperature to give the
Journal compilation Ó CSIRO 2014
www.publish.csiro.au/journals/ajc

382
S. J. Ryan, C. L. Francis, and G. P. Savage
OH
DAID, PPh3, rt
Br
S
Br
S
Br
N
RNH2
H
N
Cl
Et3N, DCM,
DMAP, rt
R
S
R
O
O
O
O
O O
2a–h
3a–h
1
Pd(OAc)2, PPh3
Et3N, MeCN
100°C, MW
Entry
N-Substituent (R)
phenyl
a
b
c
d
e
f
4-chlorophenyl
2-methoxyphenyl
2-morpholinophenyl
2-isopropylphenyl
1-naphthyl
N
S
R
O
g
h
2-nitrophenyl
benzyl
O
4a–h
Scheme 2.
2-bromosulfonamides 2, generally in high yields.[37,38] The
2-bromosulfonamides 2 thus obtained were subjected to a
Mitsunobu reaction with3-butenol, using triphenylphosphineand
diisopropyl azodicarboxylate (DIAD), to give the N-homoallyl
sulfonamides 3. In turn, the N-homoallyl sulfonamides 3
underwent an intramolecular Heck cyclization at 1008C under
microwave irradiation, using palladium acetate and triphenyl
phosphine in acetonitrile, to give 5-methylene benzothiazepines
4. For three of these compounds (the 2-morpholinophenyl
derivative 4d, the isopropylphenyl derivative 4e, and the
1-naphthyl derivative 4f), additional resonances in the 1H NMR
spectra were observed, which appeared to be consistent with
diastereomeric isomers. These may be due to atropisomerism
around the N-aryl bond or slow interconversion (on the NMR
time-scale) of pseudo-boat conformations of the seven-
membered ring,[39–43] or a combination of both. A variable-
temperature 1H NMR analysis of the N-(2-isopropyl)phenyl
benzothiazepine 4e, with spectra recorded at 20, 45, 85, 105, and
1258C in deuterated trichloroethane, revealed that the reso-
nances of the isomers fully coalesced by 1258C (see Supple-
mentary Material). Seven-membered rings are known to be
more flexible than five- and six-membered rings. They can exist
in complex pseudorotational equilibria, characterized by
numerous conformations of similar energy with low pseudor-
otational barriers. However, these conformational interconver-
sions can be significantly impeded by fused benzene rings and
sp2 centres in the ring.[43,44]
that this phenomenon is purely due to restricted conformational
interconversion of the ring cannot be discounted. However, the
N-phenyl derivative 4a, and the N-4-chlorophenyl derivative 4b,
with no asymmetry along the N-aryl axis, do not display such
1
diastereotopic separation in the H NMR. These observations
are consistent with N-aryl restricted rotation playing some part
in the conformational rigidity of these compounds. The chemi-
cal shift of one of the methylene protons on C(1) (Fig. 1) appears
at 3.53 ppm, which is not unusual for a methylene adjacent to the
nitrogen of an N-aryl sulfonamide. The other proton on C(1),
however, is appreciably downfield at 4.68 ppm, which is pre-
sumably caused by significant through-space deshielding due to
the proximity of the sulfonamide oxygen atom O(2) (Fig. 1).[45]
In the X-ray structure, the distances between O(2) and these two
˚
˚
methylene protons are 3.748 A and 2.497 A respectively.
Molecular simulation and conformational searching were
carried out using a constrained optimization along the rotation of
the N-naphthyl bond of compound 4f, to give the rotational
surface (see Supplementary Material). The calculations were
of the isolated molecules in a vacuum state, carried out at the
M06-2X/6-31G(d) level using the Gaussian package. The
barrier to N-aryl rotation was determined to be ,160 kJ molꢀ1
.
Nitrile oxides are reactive intermediates that readily dimer-
ize to give furoxans unless sterically hindered.[21,23] Hence, they
are almost always generated in situ and trapped with olefinic
dipolarophiles. Alkyl nitrile oxides are normally prepared by
formal dehydration of the corresponding primary nitroalkane
using the Mukaiyama procedure,[46] or one of its many var-
iants.[10] Aryl nitrile oxides are more conveniently prepared by
the base-catalyzed dehydrohalogenation of the corresponding
hydroximoyl chlorides, which in turn are prepared by chlorina-
tion of aldoximes.[47] The chlorination and dehydrohalogena-
tion steps for aryl nitrile oxides can be combined in a one-pot
process where water-insoluble aldoximes are reacted under
biphasic conditions with 5 % sodium hypochlorite solution as
both chlorinating agent and base.[48]
A single-crystal X-ray structure of 5-methylene-2-(naphthalen-
1-yl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide 4f
was obtained (Fig. 1). It can be seen that the seven-membered
ring resides in a chair conformation in the solid state,[44] and the
sulfonamide nitrogen is relatively flat. The exocyclic methylene
group protrudes below the plane of the fused benzene ring
such that one face is somewhat shielded by the axial hydrogen
on C(1) and one of the sulfonamide oxygen atoms O(2). The
other face is relatively unhindered.
It is interesting to note that the four protons on the seven-
membered ring of 4f are diastereotopic. They are clearly
resolved at room temperature and coupled to each other in the
1H NMR spectrum. This is additional evidence of restricted
N-aryl rotation in combination with restricted conformational
interconversion of the seven-membered ring. The possibility
Using this method, benzonitrile oxide was generated in situ
by mixing commercially available benzaldehyde oxime in
CH2Cl2 with a 5 % aqueous NaOCl solution at 08C, in the
presence of the 5-methylene benzothiazepines 4. The nitrile
oxide that formed was immediately trapped by the exocyclic
methylene dipolarophile to give the corresponding spiro

Spiro Isoxazolines by 1,3-Dipolar Cycloaddition
383
N(2)
C(14)
C(13)
C(16)
C(17)
O(3)
C(2)
C(12)
C(11)
C(10)
C(1)
S(1)
C(15)
C(16)
C(7)
C(4)
C(15)
C(14)
C(20)
C(21)
C(22)
C(3)
C(4)
C(9)
C(19)
C(12)
C(8)
C(23)
C(5)
C(13)
C(6)
C(18)
C(27)
C(20)
O(1)
N(1)
C(9)
C(11)
C(24)
C(17)
C(18)
C(26)
C(25)
C(6)
C(5)
S(1)
N(1)
C(7)
C(2)
O(2)
C(8)
C(19)
C(3)
O(1)
C(1)
Fig. 2. Molecular diagram of 2-(naphthalen-1-yl)-30-phenyl-3,4-dihydro-
2H,40H-spiro[benzo[f][1,2]thiazepine-5,50-isoxazole] 1,1-dioxide 5f with
non-hydrogen atoms represented by 50 % thermal ellipsoids and hydrogen
atoms as spheres of arbitrary size. The molecule has chirality, being R at
C(3); the opposite enantiomer is generated by crystallographic inversion in
the centrosymmetric space group.
O(2)
C(10)
Fig. 1. Molecular diagram of 5-methylene-2-(naphthalen-1-yl)-2,3,4,5-
tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide 4f with non-hydrogen atoms
represented by 50 % thermal ellipsoids and hydrogen atoms as spheres of
arbitrary size.
be clearly ascertained by examination of the 1H NMR spectra of
the products. The chemical shifts for the characteristic AB
system of the diastereotopic methylene protons on the newly
formed isoxazoline rings appeared at 3.6–4.0 ppm. This chemi-
cal shift range is indicative of protons on C-4 of the isoxazoline
ring. For the alternative possible regioisomer, the newly
formed isoxazoline methylene protons would be at C-5, and
would be expected to fall in the range of 4.5–5.0 ppm.[11] Hence,
the regiochemistry of cycloaddition is as shown in Scheme 3.
The X-ray crystal structure of a representative product 5f (Fig. 2)
was consistent with this assignment.
OH
ϩ
Ϫ
N
H2O
Ph
NaOCl
Ph
C
N
O
N
Ph
H
O
Biphasic
N
S
CH2Cl2
R
O
O
N
S
5a–h
R
O
O
4a–h
Scheme 3.
The methylene benzothiazepines 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 with respect to the substituent on the N-aryl
group. We have observed this behaviour previously with a range
of exocyclic methylene heterocycles, where the facial selecti-
vity ranged from complete to as little as 2 : 1.[15–17] In the present
study, however, only the resonances corresponding to a single
diastereomer, or at most a trace of the other diastereomer, were
Table 1. Yields for synthesis of homoallylsulfonamides 3, methylene
benzothiazepines 4, and spiro isoxazolines 5
Entry
N-Substituent
Yield [%]
3
4
5
a
b
c
d
e
f
phenyl
68
91
68
46
61
66
71
75
31
54
58
66
57
87
72
71
66
71
4-chlorophenyl
2-methoxyphenyl
2-morpholinophenyl
2-isopropylphenyl
1-naphthyl
100
100
80
1
observed in the H and 13C NMR spectra of the cycloadducts
(see Supplementary Material). This could be the result of either a
high degree of facial selectivity for the cycloaddition, or a
conformational change in the products leading to free rotation
around the N-aryl bond. To test for the latter, a 1H NMR
spectrum of the isopropyl derivative 5e was recorded at
ꢀ508C and compared with the room-temperature spectrum.
No change was observed at the lower temperature, which
indicates that the room-temperature spectrum does not represent
a time-averaged, freely interconverting mixture of diastereo-
mers. Hence, the products are most likely single diastereomers
due to a high degree of facial selectivity. An X-ray structure for
the spiro adduct 5f was obtained (Fig. 2) and the nitrile oxide
appears to have added to the more exposed face of 4f (see Fig. 1),
as would be expected.
A sample of the cycloadduct 5f was subjected to analytical
chiral HPLC. Two equal peaks corresponding to the major
diastereomeric enantiomer pair, and two equal peaks due to
the minor diastereomeric enantiomer pair, were clearly
resolved. The minor diastereomeric compounds were present
in ,5 % each (see Supplementary Material).
96
g
h
2-nitrophenyl
2-benzyl
100
52
cycloadducts 5 (Scheme 3). The reactions were generally
sluggish compared with more activated carbon–carbon dou-
ble-bond dipolarophiles, and a three-fold excess of nitrile oxide
was required to complete the reaction. The isolated yields for the
cycloadducts 5, the dipolarophiles 4, and the homoallylsulfo-
namide precursors 3 are collected in Table 1.
Nitrile oxide dipolar reactions with alkenes have been
characterized as Type II cycloadditions under the Stusmann
classification, which means nitrile oxides are ambiphilic dipoles
capable of reacting under either HOMO or LUMO control.[49] In
such cases, it is common for steric considerations to become the
overriding factor in the regiochemical outcome of the reac-
tion.[50] The dipolar cycloaddition reactions with 5-methylene
benzothiazepines 4 were completely regioselective in all cases,
with the oxygen of the nitrile oxide adding to the thiazepine ring
end of the dipolarophile double bond. This regiochemical
outcome is consistent with previous observations,[18] and could
As with the olefinic dipolarophiles 4, the four methylene
protons of the seven-membered ring of cycloadducts 5 were all
1
clearly resolved at room temperature in the H NMR spectra.

384
S. J. Ryan, C. L. Francis, and G. P. Savage
The protons on the methylene carbon adjacent to the spiro
linkage appeared between 2 and 3 ppm. One of the methylene
protons adjacent to the sulfonamide nitrogen appeared at ,3.5–
3.7 ppm while the other appeared considerably downfield at
4.6–4.8 ppm. As with the dipolarophile precursor, this is pre-
sumably caused by through-space deshielding by one of the
proximate sulfonamide oxygen atoms. In the X-ray structure of
cycloadduct 5f (Fig. 2), one of the methylene protons on C(1) is
almost syn-periplanar with sulfonamide oxygen O(2) and at a
140000 mass resolution. The probe was used with 0.6 mL minꢀ1
flow of solvent (usually methanol), and a solution of reserpine
was also introduced into the probe during the experiments to
serve as a lock mass in both positive- and negative-ion modes.
The nitrogen nebulising, desolvation gas used for vaporization
was heated to 1008C in these experiments. The sheath-gas flow
rate was set to 25 and the auxiliary gas flow rate to 7 (both
arbitrary units). The spray voltage was 3.8 kV and the capillary
temperature was 3008C. The Cambridge Crystallographic Data
Centre (CCDC) contains the supplementary crystallographic
data for this paper. The data for 5-methylene-2-(naphthalen-
1-yl)-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxide 4f
(deposition number CCDC954979) and 2-(naphthalen-1-yl)-
30-phenyl-3,4-dihydro-2H,40H-spiro[benzo[f][1,2]thiazepine-
5,50-isoxazole]1,1-dioxide5f(depositionnumber CCDC954980)
can be obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; email:
deposit@ccdc.cam.ac.uk.
˚
distance of ,2.47 A. The other methylene proton on C(1)
(Fig. 2) points away from the sulfonamide group and is 3.73 A
˚
away, which accounts for the large observed difference in
chemical shifts.
All of this evidence is consistent with a constrained dipolar-
ophile having an exposed face that leads to diastereofacial
selectivity of benzonitrile oxide 1,3-dipolar cycloaddition.
Given the remoteness of the N-aryl substituent from the dipo-
larophile, it is unlikely that steric hindrance from that group
alone is responsible for the diastereofacial selectivity of the
cycloaddition reactions. Based on the X-ray structure and NMR
evidence, it appears that in addition to the N-aryl restricted
rotation, an additional constrained, non-planar conformation of
the seven-membered ring leads to one face of the exocyclic
methylene dipolarophile being more exposed than the other,
which results in a high degree of diastereofacial selectivity in the
NOC reactions.
General Synthesis Procedure for Homoallylsulfonamides 3
Homoallylsulfonamides 3 were prepared according to the pro-
cedure of Hanson.[36] The appropriate sulfonamide 2 (10 mmol)
was dissolved in anhydrous CH2Cl2 (50 mL) in an oven-dried
round-bottom flask. Triphenylphosphine (2.89 g, 11 mmol) and
but-3-en-1-ol (0.95 mL, 11 mmol) were then added, and the
reaction mixture was stirred for 5 min. After this time, DIAD
(2.17 mL, 11 mmol) was slowly added over a period of 10 min.
The reaction mixture was stirred at room temperature for 3 h,
then concentrated under vacuum. The residue was purified by
flash column chromatography over silica to afford the title
compounds. Benzyl homoallyl sulfonamide 3h has been previ-
ously reported.[36]
Conclusion
N-Aryl-5-methylene-2,3,4,5-tetrahydrobenzo[f][1,2]thiazepine
1,1-dioxides participate in 1,3-dipolar cycloaddition reactions
with benzonitrile oxide at the exocyclic methylene function. The
5-spiro isoxazoline adducts are formed with complete regios-
electivity, and high diastereofacial selectivity in those cases
where unsymmetrical N-aryl substituents engender atropi-
somerism around the N-aryl axis.
2-Bromo-N-(but-3-en-1-yl)-N-
phenylbenzenesulfonamide (3a)
Experimental
The title compound was isolated as a white solid. Mp 89.2–
91.28C. Rf 0.3 (1 : 9 v/v EtOAc/light petroleum). nmax/cmꢀ1 1488
(m), 1447 (m), 1330 (s), 1146 (s), 1085 (s), 895 (s), 760 (s), 697
(s). dH 7.80 (dd, J 7.6, 1.6, 1H), 7.69 (dd, J 7.6, 1.6, 1H), 7.31–
7.18 (m, 7H), 5.80–5.70 (m, 1H), 5.05–5.01 (m, 2H), 3.93 (t, J
7.2, 2H), 2.26 (q, J 7.2, 2H). dC 138.3, 138.1, 135.3, 134.4, 133.6,
132.9, 129.2, 129.1, 128.0, 127.3, 120.2, 117.3, 51.9, 33.3. m/z
(HR-MS ESI) 387.9977; [M þ Na]þ requires 387.9983.
General
Melting points were determined on a Bu¨chi 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, Kie-
selgel; 90 active neutral) using the appropriate combination of
ethyl acetate and light petroleum as eluent, with compressed air.
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 visualized using a
254-nm UV lamp. Starting materials and reagents were pur-
chased from Sigma–Aldrich, Oakwood Chemicals, and Merck,
2-Bromo-N-(but-3-en-1-yl)-N-(4-chlorophenyl)
benzenesulfonamide (3b)
The title compound was isolated as a yellow solid. Mp 75.3–
75.68C. Rf 0.3 (1 : 9 v/v EtOAc/light petroleum). nmax/cmꢀ1
1487 (m), 1334 (s), 1150 (s), 1081 (s), 914 (s), 743 (s), 718 (s).
dH 7.82 (dd, J 7.6, 2.0, 1H), 7.70 (dd, J 7.6, 2.0, 1H), 7.33–7.14
(m, 6H), 5.78–5.68 (m, 1H), 5.06–5.01 (m, 2H), 3.90 (t, J 7.2,
2H), 2.24 (q, J 7.2, 2H). dC 138.2, 136.9, 135.6, 134.3, 133.9,
133.1, 130.7, 129.5, 127.6, 120.3, 117.6, 52.1, 33.4 (one
aromatic signal overlapping). m/z (HR-MS ESI) 421.9588;
[M þ Na]þ requires 421.9593.
and were used as supplied. H and 13C NMR spectra were
1
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
either CDCl3 or CD3CCl3 as solvent. Infrared spectra were
recorded neat using a Smart iTR accessory on a Thermo Nicolet
6700 Fourier-transform (FT)IR spectrometer. Electrospray
ionization (ESI) high-resolution mass spectrometric (HR-MS)
analyses were performed on a Thermo Scientific Q Exactive
mass spectrometer fitted with a HESI ion source. Positive and
negative ions were recorded in an appropriate mass range at
2-Bromo-N-(but-3-en-1-yl)-N-(2-methoxyphenyl)
benzenesulfonamide (3c)
The title compound was isolated as a yellow solid. Mp 68.9–
70.98C. Rf 0.2 (1 : 9 v/v EtOAc/light petroleum). nmax/cmꢀ1
2978 (w), 1494 (m), 1343 (s), 1259 (m), 1168 (s), 1023 (s),

Spiro Isoxazolines by 1,3-Dipolar Cycloaddition
385
903 (m), 758 (s). dH 7.68 (dd, J 8.0, 1.6, 1H), 7.65 (dd, J 8.0, 1.6,
1H), 7.31 (dd, J 8.0, 1.6, 1H), 7.23–7.15 (m, 3H), 6.86 (td, J 8.0,
1.6, 1H), 6.65 (dd, J 8.0, 1.6, 1H), 5.78–5.68 (m, 1H), 5.02–4.97
(m, 2H), 3.90 (br s, 2H), 3.31 (s, 3H), 2.18 (q, J 7.2, 2H).
dC 156.6, 140.0, 135.0, 134.9, 134.1, 132.8, 132.3, 130.0, 126.7,
125.3, 120.5, 120.4, 116.9, 111.4, 54.7, 50.3, 33.4. m/z (HR-MS
ESI) 418.0083; [M þ Na]þ requires 418.0089.
General Synthesis Procedure for Methylene
Benzothiazepines 4
Methylene benzothiazepines 4 were prepared according to the
method of Hanson.[36] The appropriate homoallylsulfonamide 3
(4.4 mmol) was weighed into a 20-mL microwave vial, to which
was added MeCN (15 mL), triethylamine (1.8 mL, 13 mmol),
PPh3 (230 mg, 0.88 mmol), and Pd(OAc)2 (98 mg, 0.44 mmol).
The vial was sealed and stirred at room temperature for 5 min,
followed by heating to 1008C in a microwave reactor for 1.5 h.
The reaction mixture was cooled to room temperature, then
filtered through a plug of Celite, rinsing with CH2Cl2. The fil-
trate was concentrated under vacuum and the residue was
purified via flash column chromatography to afford the title
compounds. The N-benzyl 5-methylene benzothiazepine 4h has
been previously reported.[36]
2-Bromo-N-(but-3-en-1-yl)-N-(2-morpholinophenyl)
benzenesulfonamide (3d)
The title compound was isolated as a yellow solid. Mp 67.2–
71.88C. Rf 0.3 (1 : 4 v/v EtOAc/light petroleum). nmax/cmꢀ1
2956 (w), 1490 (m), 1447 (m), 1343 (s), 1255 (m), 1162 (s), 1111
(s), 1024 (m), 901 (m), 754 (s). dH 7.94–7.91 (m, 1H), 7.74–7.72
(m, 1H), 7.36–7.32 (m, 2H), 7.28 (td, J 7.2, 1.6, 1H), 7.17 (dd,
J 8.0, 1.6, 1H), 7.11 (dd, J 8.0 1.6, 1H), 7.02 (td, J 7.2, 1.6, 1H),
5.67–5.56 (m, 1H), 4.97–4.89 (m, 2H), 4.09–4.04 (m, 2H), 3.74
(t, J 4.4, 4H), 2.78 (br s, 4H), 2.07 (t, J 7.2, 2H). dC 151.1, 141.0,
135.9, 134.6, 133.7, 133.4, 132.5, 132.3, 129.5, 127.6, 125.0,
123.5, 120.2, 117.1, 70.1, 67.4, 53.2, 49.9, 33.1, 22.1. m/z
(HR-MS ESI) 473.0505; [M þ Na]þ requires 473.0510.
5-Methylene-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,2]
thiazepine 1,1-Dioxide (4a)
The title compound was isolated as a waxy yellow solid. Rf
0.3 (1 : 4 v/v EtOAc/light petroleum). nmax/cmꢀ1 1595 (m), 1491
(m), 1335 (s), 1158 (s), 911 (s), 728 (s), 694 (s). dH 7.88 (dd, J
7.6, 1.2, 1H), 7.53 (td, J 7.6, 1.2, 1H), 7.44 (dd, J 7.6, 1.2, 1H),
7.37 (td, J 7.6, 1.2, 1H), 7.26–7.21 (m, 3H), 7.09–7.03 (m, 2H),
5.39 (d, J 0.8, 1H), 5.33 (d, J 0.8, 1H), 4.09–4.07 (m, 2H), 2.66 (t,
J 5.6, 2H). dC 147.3, 141.2, 140.2, 132.8, 130.8, 129.4, 127.8,
127.7, 127.5, 127.2, 121.3, 120.2, 54.6, 34.5. m/z (HR-MS ESI)
308.0716; [M þ Na]þ requires 308.0721.
2-Bromo-N-(but-3-en-1-yl)-N-(2-isopropylphenyl)
benzenesulfonamide (3e)
The title compound was isolated as a yellow waxy solid. Rf
0.3 (1 : 9 v/v EtOAc/light petroleum). nmax/cmꢀ1 2965 (w), 1487
(m), 1447 (m), 1342 (s), 1161 (s), 1100 (m), 1067 (m), 1025 (m),
906 (m), 751 (s). dH 7.73 (dd, J 7.6, 1.6, 2H), 7.30 (td, J 7.6, 1.6,
1H), 7.26–7.23 (m, 3H), 7.06–7.02 (m, 1H), 6.97 (d, J 7.6, 1H),
5.78–5.68 (m, 1H), 5.07–5.02 (m, 2H), 4.09–4.01 (m, 1H), 3.97–
3.72 (m, 1H), 3.26 (sept., J 6.8, 1H), 2.25 (q, J 7.2, 2H), 1.12 (d, J
6.8, 3H), 0.84 (d, J 6.8, 3H). dC 149.8, 139.5, 135.8, 135.0,
134.5, 133.5, 133.2, 131.3, 129.2, 127.5, 127.4, 126.2, 120.4,
117.3, 53.0, 33.5, 27.5, 24.9, 23.5. m/z (HR-MS ESI) 430.0445;
[M þ Na]þ requires 430.0452.
2-(4-Chlorophenyl)-5-methylene-2,3,4,5-
tetrahydrobenzo[f][1,2]thiazepine 1,1-Dioxide (4b)
The title compound was isolated as a yellow oil. Rf 0.35 (1 : 4
v/v EtOAc/light petroleum). nmax/cmꢀ1 1488 (s), 1342 (s), 1160
(s), 1089 (m), 906 (s), 739 (s). dH 7.84 (dd, J 7.6, 0.8, 1H), 7.53
(td, J 7.6, 1.2, 1H), 7.43 (dd, J 7.6, 0.8, 1H), 7.38 (td, J 7.6, 1.2,
1H), 7.19 (d, J 8.8, 2H), 6.98 (d, J 8.8, 2H), 5.39 (s, 1H), 5.33
(s, 1H), 4.04 (br s, 2H), 2.65 (t, J 5.6, 2H). dC 147.0, 140.2, 139.9,
139.5, 133.4, 133.0, 130.9, 129.5, 128.8, 127.9, 127.2, 120.4,
54.4, 34.6. m/z (HR-MS ESI) 342.0327; [M þ Na]þ requires
342.0331.
2-Bromo-N-(but-3-en-1-yl)-N-(naphthalene-1-yl)
benzenesulfonamide (3f)
The title compound was isolated as a yellow waxy solid. Rf
0.3 (1 : 9 v/v EtOAc/light petroleum). nmax/cmꢀ1 2936 (w), 1572
(m), 1445 (m), 1393 (m), 1333 (s), 1158 (s), 1101 (m), 1067 (m),
1027 (m), 1006 (m), 898 (m), 758 (s). dH 8.06–8.03 (m, 1H),
7.81–7.78 (m, 2H), 7.69 (td, J 8.0, 1.2, 1H), 7.45–7.39 (m, 2H),
7.34 (t, J 8.0, 1H), 7.83–7.23 (m, 2H), 7.14 (td J 8.0, 1.2, 1H),
5.75–5.65 (m, 1H), 5.02–4.97 (m, 2H), 4.14–4.00 (m, 2H), 2.31–
2.26 (m, 1H), 1.26–1.22 (m, 1H). dC 138.9, 135.6, 134.7, 134.4,
133.5, 132.9, 132.3, 129.4, 129.1, 128.3, 127.4, 126.8, 126.4,
125.2, 123.7, 120.2, 117.3, 52.9, 33.8 (one aromatic signal
overlapping). m/z (HR-MS ESI) 438.0132; [M þ Na]þ requires
438.0139.
2-(2-Methoxyphenyl)-5-methylene-2,3,4,5-
tetrahydrobenzo[f][1,2]thiazepine 1,1-Dioxide (4c)
The title compound was isolated as a yellow solid. Mp 118.0–
120.28C(dec.). Rf 0.3 (1 : 4 v/v EtOAc/light petroleum). nmax/cmꢀ1
2903 (w), 1497 (m), 1465 (m), 1339 (s), 1255 (m), 1159 (s), 1114
(m), 1099 (m), 1024 (m), 919 (m), 752 (s). dH 7.91 (dd, J 7.6, 1.2,
1H), 7.52 (td, J 7.6, 1.2, 1H), 7.44 (dd, J 7.6, 1.2, 1H), 7.40
(td, J 7.6, 1.2, 1H), 7.26–7.21 (m, 1H), 6.90–6.87 (m, 2H), 6.79
(td, J 7.6, 1.2, 1H), 5.37 (s, 1H), 5.34 (d, J 1.2, 1H), 3.99
(br s, 2H), 3.63 (s, 3H), 2.67 (t, J 5.6, 2H). dC 156.3, 148.1, 141.3,
140.2, 132.3, 130.7, 130.2, 129.5, 129.4, 127.6, 126.6, 120.8,
119.9, 112.5, 55.6, 53.9, 35.2. m/z (HR-MS ESI) 338.0821;
[M þ Na]þ requires 338.0827.
2-Bromo-N-(but-3-en-1-yl)-N-(2-nitrophenyl)
benzenesulfonamide (3g)
5-Methylene-2-(2-morpholinophenyl)-2,3,4,5-
tetrahydrobenzo[f][1,2]thiazepine 1,1-Dioxide (4d)
The title compound was isolated as a yellow solid. Mp 94.5–
95.68C. Rf 0.3 (1 : 4 v/v EtOAc/light petroleum). nmax/cmꢀ1
1447 (m), 1333 (s), 1160 (s), 911 (m), 759 (s), 692 (s). dH 7.82–
7.71 (m, 3H), 7.58–7.46 (m, 2H), 7.40–7.29 (m, 3H), 5.79–5.69
(m, 1H), 5.09–5.03 (m, 2H), 3.99 (br s, 2H), 2.43 (q, J 7.2, 2H).
dC 149.3, 138.6, 136.0, 134.3, 134.1, 134.0, 133.1, 132.3, 131.5,
129.7, 127.6, 125.5, 120.4, 117.6, 52.4, 33.5. m/z (HR-MS ESI)
432.9828; [M þ Na]þ requires 432.9834.
The title compound was isolated as a yellow solid. Mp 136.7–
138.08C. Rf 0.3 (1 : 4 v/v EtOAc/light petroleum). nmax/cmꢀ1
3245 (w), 2964 (w), 1687 (m), 1490 (m), 1441 (m), 1341 (s),
1254 (m), 1227 (m), 1162 (s), 1112 (s), 923 (m), 758 (s). dH 7.99
(d, J 7.2, 1H), 7.58 (td, J 7.2, 0.8, 1H), 7.49–7.46 (m, 2H), 7.21
(td, J 7.2, 0.8, 1H), 7.03 (d, J 7.2, 1H), 6.81 (td, J 7.2, 0.8, 1H),
6.64 (dd, J 7.2, 0.8, 1H), 5.38 (s, 1H), 5.34 (s, 1H), 4.98 (quint.,

386
S. J. Ryan, C. L. Francis, and G. P. Savage
J 6.4, 1H), 4.42–4.38 (m, 1H), 3.89–3.86 (m, 4H), 3.55–3.48
(m, 2H), 2.86–2.79 (m, 2H), 2.59–2.56 (m, 2H). dC 148.7, 147.6,
141.1, 140.2, 134.6, 132.8, 131.0, 128.5, 128.0, 127.7, 126.6,
123.0, 120.3, 120.0, 69.9, 67.6, 52.5, 51.8, 34.2, 22.0. m/z
(HR-MS ESI) 393.1244; [M þ Na]þ requires 392.1249.
purified via flash column chromatography (EtOAc/light petro-
leum) over neutral alumina to afford the title compounds.
2,30-Diphenyl-3,4-dihydro-2H,40H-spiro[benzo[f][1,2]
thiazepine-5,50-isoxazole] 1,1-Dioxide (5a)
The title compound was isolated as a white solid. Mp 204.9–
206.68C. Rf 0.3 (1 : 9 v/v EtOAc/light petroleum). nmax/cmꢀ1
1489 (m), 1443 (m), 1330 (s), 1165 (s), 1125 (m), 923 (m), 885
(m), 758 (s), 686 (s). dH 8.04 (d, J 7.6, 1H), 8.00 (d, J 7.6, 1H),
7.69–7.61 (m, 3H), 7.41–7.26 (m, 7H), 6.99 (br s, 2H), 4.74
(t, J 14.0, 2.4, 1H), 3.93 (d, J 17.6, 1H), 3.85 (d, J 17.6, 1H), 3.62
(d, J 14.8, 1H), 2.63 (t, J 14.0, 1H), 2.15 (d, J 14.0, 1H). dC 157.1,
140.8, 140.7, 138.6, 133.5, 130.5, 129.7, 129.2, 128.9, 128.6,
128.3, 128.2, 127.7, 126.9, 91.0, 49.2, 46.6, 36.0. m/z (HR-MS
ESI) 427.1087; [M þ Na]þ requires 427.1092.
2-(2-Isopropylphenyl)-5-methylene-2,3,4,5-
tetrahydrobenzo[f][1,2]thiazepine 1,1-Dioxide (4e)
The title compound was isolated as a yellow waxy solid. Rf
0.25 (1 : 9 v/v EtOAc/light petroleum). nmax/cmꢀ1 2958 (w),
1486 (m), 1445 (m), 1344 (s), 1165 (s), 1129 (m), 1101 (m),
1087 (m), 1045 (m), 906 (s), 842 (m), 758 (s). dH 7.87 (dd, J 8.0,
1.2, 1H), 7.56 (td, J 8.0, 1.2, 1H), 7.48 (dd, J 8.0, 1.2, 1H), 7.42–
7.38 (m, 2H), 7.28 (td, J 8.0, 1.2, 1H), 6.95 (td, J 8.0, 1.2, 1H),
6.59 (dd, J 8.0, 1.2, 1H), 5.42 (s, 1H), 5.38 (s, 1H), 4.52 (ddd,
J 14.4, 11.6, 2.8, 1H), 3.54 (sept., J 6.8, 1H), 3.39 (dt, J 14.4, 4.0,
1H), 2.76 (tdd, J 14.4, 4.0, 0.8, 1H), 2.64 (dt, J 14.4, 4.0, 1H) 1.30
(d, J 6.8, 3H), 1.24 (d, J 6.8, 3H). dC 148.9, 147.6, 140.3, 140.1,
138.5, 132.8, 130.9, 129.1, 127.8, 127.6, 127.5, 127.3, 126.2,
120.3, 54.3, 34.4, 27.8, 24.1, 24.0. m/z (HR-MS ESI) 350.1185;
[M þ Na]þ requires 350.1191.
2-(4-Chlorophenyl)-30-phenyl-3,4-dihydro-2H,
40H-spiro[benzo[f][1,2]thiazepine-5,50-isoxazole]
1,1-Dioxide (5b)
The title compound was isolated as a white solid. Mp 178.9–
180.28C. Rf 0.3 (1 : 9 v/v EtOAc/light petroleum). nmax/cmꢀ1
1490 (m), 1342 (s), 1167 (s), 865 (m), 837 (m), 750 (s). dH 8.06
(d, J 8.0, 1H), 8.00 (dd, J 7.6, 1.2, 1H), 7.71–7.69 (m, 2H), 7.64
(td, J 7.6, 1.2, 1H), 7.46–7.39 (m, 4H), 7.25 (d, J 8.8, 2H), 6.95
(d, J 8.8, 2H), 4.74 (td, J 14.0, 2.4, 1H), 3.95 (d, J 18.0, 1H), 3.85
(d, J 18.0, 1H), 3.60 (dt, J 15.6, 3.6, 1H), 2.61 (td, J 14.0, 3.6,
1H), 2.19 (dt, J 15.6, 2.4, 1H). dC 157.1, 140.8, 139.1, 138.1,
134.2, 133.7, 130.6, 129.9, 129.3, 129.1, 128.9, 128.7, 128.3,
126.9, 90.9, 49.2, 46.7, 36.1 (one aromatic signal overlapping).
m/z (HR-MS ESI) 461.0697; [M þ Na]þ requires 461.0703.
5-Methylene-2-(naphthalen-1-yl)-2,3,4,5-
tetrahydrobenzo[f][1,2]thiazepine 1,1-Dioxide (4f)
The title compound was isolated as a yellow waxy solid. Rf
0.2 (1 : 9 v/v EtOAc/light petroleum). nmax/cmꢀ1 2980 (w), 1706
(m), 1466 (m), 1339 (s), 1159 (s), 1107 (m), 914 (m), 757 (s). dH
8.31 (d, J 8.0, 1H), 7.91 (dd, J 7.6, 1.2, 1H), 7.86 (d, J 8.0, 1H),
7.80 (d, J 8.0, 1H), 7.65–7.51 (m, 4H), 7.44 (td, J 7.6, 1.2, 1H),
7.22 (t, J 8.0, 1H), 6.81 (dd, J 7.6, 1.2, 1H), 5.45 (s, 1H), 5.42 (d,
J 1.2, 1H), 4.68 (ddd, J 14.4, 11.6, 2.8, 1H), 3.53 (dt, J 14.4, 4.0,
1H), 2.76 (tdd, J 14.4, 4.0, 1.2, 1H), 2.65 (dt, J 14.4, 4.0, 1H). dC
147.6, 140.4, 140.2, 137.3, 135.0, 133.0, 131.9, 131.1, 130.0,
128.4, 127.9, 127.5, 127.4, 126.9, 125.0, 124.8, 123.5, 120.5,
53.9, 34.7. m/z (HR-MS ESI) 358.0871; [M þ Na]þ requires
358.0878.
2-(2-Methoxyphenyl)-30-phenyl-3,4-dihydro-2H,40H-
spiro[benzo[f][1,2]thiazepine-5,50-isoxazole]
1,1-Dioxide (5c)
The title compound was isolated as a white solid. Mp 146.8–
152.18C. Rf 0.2 (1 : 9 v/v EtOAc/light petroleum). nmax/cmꢀ1
2947 (w), 1500 (m), 1343 (s), 1254 (m), 1159 (s), 1055 (m), 1024
(m), 903 (m), 756 (s). dH 8.00 (d, J 8.0, 2H), 7.70–7.68 (m, 2H),
7.58 (td, J 8.0, 0.8, 1H), 7.42–7.37 (m, 4H), 7.24 (td, J 8.0, 0.8,
1H), 6.89–6.78 (m, 3H), 4.66 (td, J 13.6, 0.4, 1H), 3.92 (d, J 18.0,
1H), 3.83 (d, J 18.0, 1H), 3.57–3.51 (m, 4H), 2.66 (td, J 13.6, 3.2,
1H), 2.11 (dt, J 13.6, 1.2, 1H). dC 157.1, 156.2, 140.6, 140.0,
132.9, 130.5, 129.8, 129.7, 129.6, 129.5, 129.3, 128.9, 128.2,
127.9, 126.9, 120.9, 112.4, 91.3, 55.6, 48.4, 46.6, 36.6. m/z
(HR-MS ESI) 457.1192; [M þ Na]þ requires 457.1198.
5-Methylene-2-(2-nitrophenyl)-2,3,4,5-tetrahydrobenzo
[f][1,2]thiazepine 1,1-Dioxide (4g)
The title compound was isolated as a white solid. Mp 189.3–
190.98C (dec.). Rf 0.3 (3 : 7, v/v EtOAc/light petroleum). nmax
/
cmꢀ1 1526 (m), 1351 (s), 1166 (s), 923 (m), 766 (m), 724 (s).
dH 7.85 (dd, J 7.6, 1.6, 1H), 7.81 (d, J 7.6, 1H), 7.57 (td, J 7.6,
1.6, 1H), 7.50–7.38 (m, 4H), 6.94 (dd, J 7.6, 1.6, 1H), 5.45
(s, 1H), 5.41 (s, 1H), 4.38–3.80 (m, 2H), 2.77 (t, J 5.6, 2H).
dC 149.5, 146.8, 140.1, 139.6, 134.1, 133.2, 133.1, 130.9, 130.1,
129.5, 128.0, 127.0, 125.3, 120.6, 54.4, 35.1. m/z (HR-MS ESI)
353.0566; [M þ Na]þ requires 353.0572.
2-(2-Morpholinophenyl)-30-phenyl-3,4-dihydro-2H,
40H-spiro[benzo[f][1,2]thiazepine-5,50-isoxazole]
1,1-Dioxide (5d)
The title compound was isolated as a white solid. Mp 199.3–
General Procedure for Nitrile Oxide
Cycloaddition Reactions
200.08C (dec.). Rf 0.3 (1 : 4 v/v EtOAc/light petroleum). nmax
/
cmꢀ1 2957 (w), 1737 (m), 1596 (m), 1494 (m), 1444 (m), 1338
(s), 1232 (m), 1166 (m), 1115 (s), 935 (m), 909 (m), 761 (s).
dH 8.10 (dd, J 7.6, 1.2, 1H), 8.03 (dd, J 7.6, 1.2, 1H), 7.70–7.68
(m, 2H), 7.63 (td, J 7.6, 1.2, 1H), 7.49 (td, J 7.6, 1.2, 1H), 7.40–
7.36 (m, 3H), 7.21 (td, J 7.6, 1.2, 1H), 7.01 (dd, J 7.6, 1.2, 1H),
6.78 (td, J 7.6, 1.2, 1H), 6.45–6.32 (m, 1H), 4.60 (t, J 14.4, 1H),
3.95–3.80 (m, 5H), 3.93 (d, J 18.0, 1H), 3.83 (d, J 18.0, 1H),
3.54–3.51 (m, 2H), 2.84–2.79 (m, 2H), 2.46 (t, J 15.6, 1H), 2.08
(d, J 15.6, 1H). dC 157.0, 148.8, 140.7, 139.8, 133.9, 133.5,
130.5, 129.2, 129.0, 128.9, 128.8, 128.5, 128.3, 127.6, 126.9,
123.3, 120.6, 91.1, 67.8, 60.5, 52.0, 46.9, 46.5, 35.5, 22.5. m/z
(HR-MS ESI) 512.1618; [M þ Na]þ requires 512.1620.
Nitrile oxide cycloaddition reactions were carried out using our
previously reported method.[16] The appropriate methylene
benzothiazepine 4 (1 mmol) was dissolved in CH2Cl2 (5 mL).
Benzaldehyde oxime (363 mg, 3 mmol) was added and the
vigorously stirred solution was cooled to 08C in an ice bath.
NaOCl (5.5 mL of an 5 % aqueous solution, 6 mmol) was added
slowly over a period of 30 min. The reaction mixture was stirred
vigorously overnight, then diluted with CH2Cl2 (5 mL) and
brine (5 mL). 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

Spiro Isoxazolines by 1,3-Dipolar Cycloaddition
387
2-(2-Isopropylphenyl)-30-phenyl-3,4-dihydro-2H,
40H-spiro[benzo[f][1,2]thiazepine-5,50-isoxazole]
1,1-Dioxide (5e)
130.3, 129.2, 128.9, 128.8, 128.5, 128.4, 128.3, 128.0, 126.9,
90.7, 50.0, 46.5, 42.3, 32.7. m/z (HR-MS ESI) 441.1244;
[M þ Na]þ requires 441.1249.
The title compound was isolated as a white solid. Mp 204.5–
205.68C. Rf 0.15 (1 : 9 v/v EtOAc/light petroleum). nmax/cmꢀ1
2961 (w), 1488 (m), 1446 (m), 1341 (s), 1305 (m), 1174 (s), 1129
(m), 924 (m), 753 (s). dH 8.07 (d, J 8.0, 1H), 7.98 (d, J 8.0, 1H),
7.72–7.70 (m, 2H), 7.64 (t, J 8.0, 1H), 7.44–7.40 (m, 5H), 7.30
(t, J 8.0, 1H), 6.92 (td, J 8.0, 1.6, 1H), 6.41 (d, J 8.0, 1H), 4.75
(td, J 14.4, 1.6, 1H), 3.97 (d, J 18.0, 1H), 3.89 (d, J 18.0, 1H),
3.56 (sept., J 6.8, 1H), 3.38 (dt, J 15.6, 3.6, 1H), 2.69 (td, J 14.4,
3.6, 1H), 2.14 (dd, 15.6, 3.6, 1H), 1.34 (d, J 6.8, 3H), 1.26
(d, J 6.8, 3H). dC 157.1, 148.7, 140.5, 138.8, 137.7, 133.4, 130.5,
129.4, 129.2, 128.9, 128.8, 128.5, 128.2, 127.7, 127.1, 126.9,
126.3, 91.1, 48.8, 46.6, 35.5, 27.9, 24.1, 23.9. m/z (HR-MS ESI)
469.1559; [M þ Na]þ requires 469.1562.
Supplementary Material
Variable-temperature 1H NMR experiments of the N-(2-
isopropyl)phenyl benzothiazepine 4e, a plot of the of N-aryl
rotational energy for compound 4f (molecular simulation),
chiral HPLC chromatogram for 5f, and the H and 13C NMR
1
spectra of cycloadducts are available on the Journal’s website.
Acknowledgements
The authors wish to thank Dr Roger Mulder of CSIRO for assistance with
NMR spectroscopy, Dr Leaf Lin and Professor Michelle Coote of The
Australian National University for rotational barrier calculations, Professor
James De Voss of the University of Queensland for chiral HPLC, and
Dr Craig Forsyth of Monash University for the X-ray crystallographic
structure determination.
2-(Naphthalen-1-yl)-30-phenyl-3,4-dihydro-2H,
40H-spiro[benzo[f][1,2]thiazepine-5,50-isoxazole]
1,1-Dioxide (5f)
References
The title compound was isolated as a white solid. Mp 260.3–
262.18C. Rf 0.25 (1 : 9 v/v EtOAc/light petroleum). nmax/cmꢀ1
2961 (w), 1488 (m), 1446 (m), 1341 (s), 1305 (m), 1174 (s), 1129
(m), 924 (m), 753 (s). dH 8.33 (d, J 8.0, 1H), 8.12 (dd, J 8.0, 1.2,
1H), 8.03 (dd, J 8.0, 1.2, 1H), 7.87 (d, J 8.0, 1H), 7.81 (d, J 8.0,
1H), 7.75–7.72 (m, 2H), 7.69 (dd, J 8.0, 1.2, 1H), 7.65 (dd, J 8.0,
1.2, 1H), 7.57 (td, J 8.0, 1.2, 1H), 7.46 (td, J 8.0, 1.2, 1H), 7.44–
7.41 (m, 3H), 7.20 (t, J 8.0, 1H), 6.65 (dd, J 8.0, 1.2, 1H), 4.90
(ddd, J 15.6, 13.6, 2.0, 1H), 4.03 (d, J 18.0, 1H), 3.95 (d, J 18.0,
1H), 3.54 (td, J 15.6, 3.2, 1H), 2.72 (td, J 13.6, 2.0, 1H), 2.17
(ddd, J 15.6, 3.2, 2.0, 1H). dC 157.1, 140.8, 138.8, 136.4, 135.1,
133.5, 132.1, 130.6, 129.3, 128.9, 128.7, 128.6, 128.5, 128.4,
128.3, 127.7, 127.0, 126.9, 125.1, 124.6, 123.2, 91.1, 48.4, 46.7,
35.8. m/z (HR-MS ESI) 477.1243; [M þ Na]þ requires
477.1249.
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1,1-Dioxide (5g)
The title compound was isolated as a white solid. Mp 208.7–
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1524 (s), 1341 (s), 1170 (m), 1158 (m), 910 (m), 847 (m), 762
(s), 740 (s), 695 (s). dH 8.10 (d, J 8.0, 1H), 7.93 (dd, J 7.6, 1.2,
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