Anticancer prodrug studies: DielsAlder chemistry of 1-methylthio-1-(p- tolylsulfonyl)ethene

Article abstract of DOI:10.1071/CH10450

The reactivity of 1-methylthio-1-(p-tolylsulfonyl)ethene (1) as a dienophile in DielsAlder chemistry is investigated. Cycloaddition reactions were carried out with a range of pyran-2-ones and isobenzofurans. The initial DielsAlder adducts have the potenti

Full text of DOI:10.1071/CH10450

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2011, 64, 945–950
Anticancer Prodrug Studies: Diels Alder Chemistry
]
of 1-Methylthio-1-(p-tolylsulfonyl)ethene
A B
,
A
A
Andrew J. Pratt,
Phillip M. Rendle, and Peter J. Steel
A
Department of Chemistry, University of Canterbury, Christchurch, PB4800,
New Zealand.
B
Corresponding author. Email: andy.pratt@canterbury.ac.nz
The reactivity of 1-methylthio-1-(p-tolylsulfonyl)ethene (1) as a dienophile in Diels–Alder chemistry is investigated.
Cycloaddition reactions were carried out with a range of pyran-2-ones and isobenzofurans. The initial Diels–Alder adducts
have the potential of undergoing fragmentation in chemistry that is relevant to the design of anticancer intercalator
prodrugs. The nature of the final products of the reactions provided insights into both the cycloaddition reactions and
fragmentation pathways of the adducts. By comparison with a thioether group, the sulfonyl substituent of the dienophile
was found to decrease the reactivity and regioselectivity of the cycloaddition chemistry and to facilitate fragmentation of
the initial adducts by the elimination of p-toluenesulfinic acid.
Manuscript received: 9 December 2010.
Manuscript accepted: 12 April 2011.
Introduction
hydrogen chloride from 1-chloro-1-methylthio-1-(p-toluene-
sulfonyl)ethane was accomplished more efficiently by heating
at 908C neat rather than refluxing in chloroform. Compound 1
was reacted with a series of pyranones and isobenzofurans to
ascertain its potential as a Diels–Alder dienophile.
The targeting and activation of anticancer prodrugs is an active
field of cancer chemotherapy research. As part of a program to
develop ‘prodrugs’ of intercalating agents suitable for antibody-
directed enzyme prodrug therapy (ADEPT)[1] we have been
exploring the chemistry of sulfur-substituted bridged Diels–
Alder adducts.[2] The aim of this program is to generate non-
planar precursors to aromatic systems that can be fragmented to
planar aromatic derivatives under controlled conditions by a
carbon–sulfur bond cleavage process (Scheme 1). This con-
trolled change of molecular geometry is potentially applicable
to a wide range of activation processes involving recognition of
planar aromatic species, including nucleic acids. The investi-
gation of cycloaddition and fragmentation chemistry is aimed at
optimizing the synthesis of fragmentable adducts, and hence the
development of anticancer prodrugs.
We have demonstrated that 1,1-bis(methylthio)ethene (2) is a
dienophile of modest reactivity in cycloadditions with pyran-
2-ones[3] and provides both non-planar Diels–Alder adducts and
aromatic fragmentation products depending on the substitution
pattern of the diene. In an effort to produce a more reactive
dienophile and adducts of different reactivity we have investi-
gated the Diels–Alder chemistry of an analogous hemi-sulfone,
1 (Fig. 1). Vinyl sulfones have received much attention as useful
intermediates in organic synthesis, both as Michael acceptors
and in cycloaddition reactions.[4] Sulfonyl substituents have
proved to be suitable electron-withdrawing groups for the
activation of Diels–Alder reactions and there have been occa-
sional reports of the reaction of vinyl sulfones with electron-rich
pyranones and pyridones.[5]
Diels-Alder Reactions of 1 with Pyran-2-ones
1-Methylthio-1-(p-tolylsulfonyl)ethene (1) was reacted with
methyl coumalate (3) and methyl 4,6-dimethylcoumalate (4).
These reactions bore similarities with the corresponding
reactions employing 1,1-bis(methylthio)ethene as dienophile.
Cycloaddition reactions took place in refluxing toluene but the
sulfonyl-substituted alkene 1 required longer reaction times and
the yield of products was much lower (less than 10%). The
regiochemistry of all the cycloadditions were the same. In
the reactions of 1 with these coumalates only aromatized pro-
ducts 5 and 6, arising from decarboxylation, were isolated. This
mirrors the situation when alkene 2 reacts with diene 4 but
contrasts the reaction of 2 with 3 where the bridged adduct is the
sole product under these conditions (Scheme 2).
The cycloaddition between 1 and a more reactive pyran-
2-one, 4-methyl-1-phenylbenzopyran-3-one (7) was investigat-
ed. In this case the rate of reaction of 1 was comparable to the
analogous reaction of 2. This Diels–Alder reaction occurred in
more reasonable yield (38%) but contrasted in two ways with the
analogous chemistry observed for 2: no bridged adduct was
obtained, and the high regioselectivity observed when 2 reacts
with this diene was not mirrored in the reaction of 1. The two
regioisomers 8 and 9 were obtained in a ratio of 2:5, respectively
(Scheme 3).
The exclusive generation of aromatic products in these three
cycloaddition reactions presumably reflects the ease of elimina-
tion of p-toluenesulfinic acid from this type of adduct. This
elimination would induce decarboxylation because of the
Results and Discussion
1-Methylthio-1-(p-toluenesulfonyl)ethene (1) was prepared by
a variation of the method of Ogura and Fujina.[6] Elimination of
Ó CSIRO 2011
10.1071/CH10450
0004-9425/11/070945

946
A. J. Pratt, P. M. Rendle, and P. J. Steel
X
R
O
Cleave
S–R
SH
S–R
MeS
SO2Tol
O
O
O
MeO2C
–HX
R
3 R ϭ H
4 R ϭ Me
1
Aromatization
R
SMe
SH
MeO2C
R
Scheme 1. Schematic illustration of prodrug activation by S–R bond
cleavage and spontaneous fragmentation of a bridged Diels–Alder adduct
to a planar derivative.
5 R ϭ H
6 R ϭ Me
Scheme 2.
MeS
SO2Tol
MeS
SMe
Me
Ph
1
2
O
MeS
SO2Tol
Fig. 1. Structures of compounds 1 and 2.
O
unstable nature of bridged cyclohexadienes. It was hoped that
this elimination–fragmentation chemistry could be exploited in
prodrug development, provided the system could be modified
to allow access to the initial bridged Diels–Alder adduct. The
lower reactivity of 1 than 2 in reaction with coumalates is not
surprising since it involves the reaction of a less electron-rich
dienophile with electron-deficient dienes. For this reason
cycloadditions of 1 with a more electron-rich pyranone was
evaluated.
7
1
Me
Me
SMe
Compound 1 was reacted with 1-methylpyrano-[3,4-b]indol-
3-one (10), a polycyclic intercalator precursor. The Diels–Alder
reaction was successful and produced two aromatic regioi-
somers, 11 and 12, albeit in low yield (Scheme 4). Unfortunately
no bridged adducts were observed and so, although 1 appeared
to be more reactive with 10 than 2, this was not further
investigated as a synthetic route.
SMe
Ph
Ph
8
9
Scheme 3.
The reaction of 13 with 1 was comparatively slow and a
major product of the reaction did not involve reaction with
the vinyl sulfone. This product was found to be thioester 16, the
structure of which was confirmed by X-ray crystallography
(Fig. 3). The formation of this type of compound has been
observed before in Diels–Alder reactions of isobenzofurans
with poor dienophiles[7] and as the product of prolonged expo-
sure of isobenzofuran solutions to the atmosphere.[8]
For the anticipated prodrugs a hydrogen is preferable to a
phenyl group at the bridgehead position to allow subsequent
controlled aromatization by elimination chemistry. Con-
sequently, the Diels–Alder reaction of 1[6] with 1-(methylthio)
isobenzofuran (17),[2] was investigated to determine whether
stable bridged adducts could be prepared by this cycloaddition
chemistry. This reaction gave all of the four possible regio- and
stereo-isomeric bridged adducts 18a, 18b, 19a, and 19b in the
ratio 12:49:13:26, respectively (as judged by 1H NMR spectros-
copy) (Scheme 6). The slight preference for the formation of
the isomers 18b and 19b can be attributed to steric effects.
Three of these isomers were isolated by chromatography in a
combined yield of 85%; the other, 18a, decomposed on the
silica. The regio- and stereo-chemistries of the other isomers
Diels–Alder Reactions of 1 with Isobenzofurans
It is clear that 1 is not a synthetically useful dienophile for
the formation of bridged Diels–Alder adducts from electron-
deficient pyran-2-ones. To complement these studies we
investigated the Diels–Alder reactivity of this alkene with two
reactive, electron-rich isobenzofuran dienes.
The initial investigation utilized a phenyl-substituted
isobenzofuran as a model, because of its ease of preparation.
When 1-methylthio-3-phenylisobenzofuran (13), generated
in situ by deprotonation and methylation of 3-phenyl-1,3-
dihydroisobenzofuran-1-thione,[2] was reacted with 1, only
one of the four possible isomeric adducts, 14, was observed
(Scheme 5). This compound decomposed rapidly in most
solvents making elucidation of its regio- and stereo-chemistry
by NMR spectroscopy problematic. The product of this decom-
position was shown to be 15 by X-ray crystallography (Fig. 2).
The position of the thiomethyl substituent in 15 implies that the
two thiomethyl groups of the initial adduct were meta-orientat-
ed. On steric grounds, and by analogy with the stereoselectivity
of cycloaddition between 1 and 17 (see below) the p-tolylsulfo-
nyl group is tentatively assumed to be exo in adduct 14.

Diels–Alder Chemistry of 1-Methylthio-1-(p-tolylsulfonyl)ethene
947
O
O(1)
C(1)
MeS
SO2Tol
O
N
H
C(8)
C(2)
C(3)
Me
C(3Љ)
10
1
C(8a)
C(4a)
C(7)
C(6)
SMe
C(4)
S(3)
11
C(2Ј)
N
H
C(5)
Me
Me
O(4)
C(1Ј)
C(3Ј)
12
C(6Ј)
C(4Ј)
SMe
N
H
C(5Ј)
Scheme 4.
Fig. 2. The X-ray crystal structure of 15.
SMe
S
(i) LDA
(ii) MeI
SMe
O
O
O
O
H
Ph
Ph
13
1
Ph
16
SMe
SO2Tol
C(12)
SMe
O
S(1)
O(1)
O
SMe
SO2Tol
C(11)
C(1)
SMe
O(2)
C(21)
C(26)
Ph
Ph OH
14
15
C(20)
C(25)
C(24)
Scheme 5. LDA: lithium diisopropylamide.
C(2)
C(6)
C(22)
C(23)
were determined by analysis of 1H NMR chemical shifts,
coupling constants, and nuclear Overhauser effects (the effect
of irradiating each of the three methyl singlet resonances was
evaluated).
C(5)
C(3)
C4
Isomer 18b underwent elimination of p-toluenesulfinic acid
and bridge opening within a few hours in chloroform to give a
naphthol 20. This product slowly oxidized in air to give the
known naphthaquinone 21 (Fig. 4). This chemistry is analogous
to the aromatization anticipated for prodrug activation. The
adducts with an ortho regiochemistry (19a and 19b) are
of greater stability and so bridged adducts of this class are of
potential as prodrug precursors to intercalators.
Fig. 3. The X-ray crystal structure of 16.
reactions with isobenzofurans proved more successful and
allowed the preparation and study of bridged Diels–Alder
adducts. The sulfonyl group labilized some of the initial adducts
and provided insights into the fragmentation chemistry required
for prodrug activation and structural features that are important
in producing stable bridged adducts.
Conclusion
1-Methylthio-1-(p-tolylsulfonyl)ethene (1) shows modified
reactivity as a dienophile compared with the bis-thioether
analogue. With a lower electron density it is of limited utility as a
dienophile with electron-deficient pyranones. Cycloaddition
Experimental
All solvents and reagents were dried rigorously before use and
all reactions were carried out under dry nitrogen. Radial

948
A. J. Pratt, P. M. Rendle, and P. J. Steel
SMe
O
of the setting angles of reflections from a Siemens P4 diffrac-
tometer. A unique dataset was measured (v scans). The unique
reflections obtained were used in the full-matrix least-squares
refinement (SHELXL-93).[9] The intensities of three standard
reflections were measured every 97 reflections throughout the
data collection to check for decay. The structure was solved by
direct methods (SHELXS-86).[10] Hydrogen atoms were fixed in
idealized positions. All non-hydrogen atom parameters were
refined using anisotropic atomic displacement parameters.
Neutral scattering factors and anomalous dispersion corrections
for non-hydrogen atoms were taken from Ibers and Hamilton.[11]
MeS
SO2Tol
1
17
SMe
O
SMe
O
1-Methylthio-1-(p-tolylsulfonyl)ethene (1)
SO2Tol
1-Chloro-1-(methylthio)ethyl p-tolyl sulfone[6] (6.34 g, 23.9 mmol)
was heated neat at 908C for 5 h. The resulting crude product
was purified by vacuum distillation (1558C/0.5 mmHg). Ether
(7 mL) was added to the distillate and the solution kept in a
freezer overnight. The resulting white platelets of the title
compound 1, were isolated by vacuum filtration (1.1 g, 20%);
mp 82–858C Anal. Calc. for C10H12O2S2: C 52.6, H 5.30, S 28.1,
Mþꢁ 228.0279. Found: C 52.4, H 5.4, S 27.8, Mþꢁ 228.0277.
dH (CDCl3) 2.27 (s, 3H), 2.41 (s, 3H), 5.64 (d, J 1.9, 1H), 6.53
(d, J 1.9, 1H), 7.31 (d, J 7.8, 2H), 7.80 (d, J 7.8, 2H). dC (CDCl3)
17.04, 21.61, 121.24, 128.44, 129.65, 135.76, 144.80, 150.06.
nmax 1917w, 1597m, 1319s, 1157s. m/z 228 (M), 139, 91, 73
(100%).
18a
SMe
SMe
19a
SO2Tol
SMe
SMe
O
SMe
18b
SO2Tol
O
SO2Tol
19b
SMe
Scheme 6.
Methyl 4-(Methylthio)benzoate (5)
SMe
OH
O
Methyl-2-oxo-2H-pyrano-5-carboxylate (46 mg, 0.30 mmol,
1.0 equiv.) and 1 (137 mg, 0.60 mmol, 2.0 equiv.) were
dissolved in toluene (12 mL). The solution was refluxed under
nitrogen for 5.5 days and then concentrated under vacuum.
Purification by radial chromatography gave the title compound 5
(4 mg, 7%), identical to a previously prepared sample.[12]
SMe
SMe
O
20
21
Methyl 2,6-Dimethyl-4-(methylthio)benzoate (6)
Fig. 4. Structures of compounds 20 and 21.
Methyl 4,6-dimethyl-2-oxo-2H-pyrano-5-carboxylate (55 mg,
0.30 mmol, 1.0 equiv.) and 1 (137 mg, 0.60 mmol, 2.0 equiv.)
were refluxed in toluene (12 mL) under nitrogen for 9 days and
then concentrated under vacuum. Purification by radial chro-
matography gave the title compound 6 (0.6 mg, 1%), identical to
a previously prepared sample.[3]
chromatography was performed using a 1 mm silica plate. The
plate was washed and reactivated using methanol. Melting
points (mp) were determined on a Reichert Hotstage microscope
and are uncorrected. Infrared spectra were scanned on a
Shimadzu FTIR-8201PC or a Perkin-Elmer 1600-FTIR spec-
trophotometer. The sample was presented as a CDCl3 solution in
a 0.1 or 1.0 mm NaCl solution cell. Positions of selected
absorptions (nmax) are recorded in wavenumbers (cmꢀ1) and
relative intensities denoted as weak (w), medium (m), or
strong (s). 1H NMR spectra were determined on a Varian Unity
300 MHz Fourier transform spectrophotometer. Peaks are
quoted in ppm relative to tetramethylsilane (TMS) and the
CHCl3 signal referenced to 7.24 ppm. Coupling constants (J)
are quoted in hertz (Hz). 13C NMR spectra were measured at
75 MHz on a Varian Unity 300 MHz or a Varian XL 300 MHz
Fourier transform spectrophotometer. Peaks are quoted in ppm
relative to TMS and the CDCl3 signal referenced to 77.0 ppm.
Electron ionization mass spectra (m/z) were determined on a
Kratos MS80RFA operating at 4 kV and electron impact at
70 eV. Elemental microanalyses of crystalline samples were
performed at the Chemistry Department, University of Otago,
New Zealand.
1-Methyl-2-methylthio-4-phenylnaphthalene (8)
and 1-Methyl-3-methylthio-4-phenylnaphthalene (9)
2-Benzoylphenylpropanoic acid (41 mg, 0.16 mmol, 1.0 equiv.)
was dissolved in conc. H2SO4 (0.16 mL) with gentle warming to
give an orange solution. Water (20 mL) was added to produce a
deep red precipitate which was extracted with ethyl acetate (2 ꢂ
15 mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated under vacuum to ,10 mL. Toluene
(15 mL) was added and the solution again concentrated to
,10 mL. This process was repeated to remove any remaining
ethyl acetate. The final volume was 12 mL. Compound 1
(110 mg, 0.48 mmol, 3.0 equiv.) was added and the red solution
was refluxed under nitrogen for 20 h. By this stage the solution
was pale yellow in colour and so was concentrated under vac-
uum and separated into its components by radial chromato-
graphy. Elution with 90% petroleum ether/10% ethyl acetate
gave title compound 8 (5 mg, 12%) identical to a previously
prepared sample.[12] Further elution gave title compound 9
(11 mg, 26%) as a pale yellow oil (Found: Mþꢁ 264.0971.
X-Ray crystallographic data was collected as follows: The
unit cell parameters were obtained by least-squares refinement

Diels–Alder Chemistry of 1-Methylthio-1-(p-tolylsulfonyl)ethene
949
C18H16S requires: 264.0973). dH (CDCl3) 2.45 (s, SCH3), 2.77
(s, Ar-CH3), 7.35 (s, 1H), 7.31–7.56 (m, 8H), 7.99 (d, J 8.3, 1H).
dC (CDCl3) 16.29, 19.68, 123.94, 124.05, 124.82, 126.13,
126.24, 127.57, 128.42, 130.38, 130.63, 132.92, 134.04, 134.49,
135.63, 138.72. nmax cmꢀ1 3062m, 2982m, 2926m, 1717w,
1601m, 1587s, 1556m, 1508m, 1443s. m/z 264 (M, 100%), 249
(M – CH3), 234 (M – 2 ꢂ CH3), 215 (M – SCH5), 202 (M –
CH3 – SCH3).
(Found: M – TolSO2(CH3S)C¼CHþ2 ꢁ 240.0611; C15H12OS
requires: Mþꢁ 240.0609 (the parent ion was not observed)).
dH (CDCl3) 1.32 (s, 3H), 2.23 (s, 3H), 2.35 (d, J 12.7, 1H), 2.38
(s, 3H), 2.87(d, J 12.7, 1H), 7.21–7.48 (8H, m), 7.61–7.67 (m, 3H),
8.15 (dd, J 8.3, 1.5, 2H). dC (CDCl3) 12.14, 14.91, 21.41, 46.42,
83.07, 92.53, 119.53, 122.86, 127.63, 127.70, 128.13, 128.21,
129.12, 129.76, 133.76, 135.84, 143.24, 143.91. nmax cmꢀ1
2978m, 2930m, 1761w, 1448m, 1439m, 1144s, 1113s. m/z 266
(M – SO2Tol – SCH3), 240 (M – TolSO2(CH3S)C¼CH2, 100%),
228 (TolSO2(CH3S)C¼CH2), 226 197, 165, 139, 91 77, 73.
1-Methyl-3-methylthiocarbazole (11) and 1-Methyl-
2-methylthiocarbazole (12)
Crystal Data and Structural Refinement for 16
1-Methylpyrano[3,4-b]indol-3-one (58 mg, 0.29 mmol, 1.0 equiv.)
and 1 (132 mg, 0.58 mmol, 2.0 equiv.) were dissolved in
bromobenzene (14 mL). The solution was heated at 1208C under
nitrogen. The reaction was monitored by 1H NMR spectroscopy.
After 4 h there was no remaining diene. The reaction mixture
was concentrated under vacuum and was separated into its
components by radial chromatography. Elution with 80%
petroleum ether/20% ethyl acetate gave title compound 11
(0.7 mg, 1%) identical to a previously prepared product. Further
elution gave title compound 12 which recrystallized from
methanol (2 mg, 3%) as white platelets (Found: Mþꢁ 227.0766.
C14H13NS requires: 227.0769). mp 158–1608C. dH (CDCl3)
2.52 (s, 3H), 2.59 (s, 3H), 7.19 (d, J 7.9, 2H), 7.35–7.44 (m, 2H),
7.87 (d, J 8.3, 1H), 7.91 (br s, 1H), 8.00 (d, J 8.3, 1H). m/z 227
(M, 100%), 212 (M – CH3), 180 (M – SCH3), 167 (M – C2H4S).
C15H12O2S, M 256.31, crystal dimensions 0.79 ꢂ 0.33 ꢂ
0.03 mm3; triclinic, a 7.9480(10), b 8.0680(10), c 11.0900
˚
(10) A; a 74.490(10)8, b 88.250(10)8, g 69.980(10)8; V 642.37
3
(13) A , space group P-1, Z 2, F(000) 268, Dcalc 1.325 Mg mꢀ3
,
˚
absorption coefficient 0.242 mmꢀ1, y range for data collection
2.73 to 25.00; maximum and minimum transmissions 0.85 and
0.89, data/restraints/parameters 2231/0/163, goodness of fit on
F2 was 0.797, final R indices [I . 2s(I)] R1 0.0353, wR2 0.0661,
R indices (all data) R1 0.0671, wR2ꢀ03.0733, largest difference
˚
peak and hole 0.171 and ꢀ0.293 eA
.
The unit cell parameters were obtained by least-squares
refinement of the setting angles of 37 reflections with 88 ,
2y , 148. A unique dataset was measured at 163(2) K within
2ymax ¼ 508 limit (v scans). Of the 2416 reflections obtained,
2235 were unique (Rint 0.0194) and were used in the full-matrix
least-squares refinement after being corrected for absorption by
using the psi-scan method. The intensities of three standard
reflections, measured every 97 reflections throughout the data
collection, showed only 8% decay.
S-Methyl 2-(Benzoyl)thiobenzoate (16) and 1,9-Bis
(methylthio)-11-oxa-8-phenyl-9-(p-tolylsulfonyl)tricyclo
[6.2.1.02,7]undeca-2,4,6-triene (14)
n-Butyl lithium (0.27 mL of a 1.6 mol Lꢀ1 solution in hexanes,
0.43 mmol, 1.25 equiv.) was added dropwise to a stirred solution
of diisopropylamine (58 mL, 0.41 mmol, 1.2 equiv.) in tetrahy-
drofuran (3.5 mL) under dry nitrogen in an ice-salt bath. The
solution was stirred for 35 min at this temperature and then
cooled further in an acetone/dry ice bath. A solution of 3-phenyl-
1,3-dihydroisobenzofuran-1-thione[2] (78 mg, 0.34 mmol,
1.0 equiv.) in tetrahydrofuran (3.5 mL) was added dropwise.
The bright red solution was stirred under nitrogen at ꢀ788C for
1 h. Iodomethane (28 mL, 0.45 mmol, 1.3 equiv.) was added
dropwise and the resulting mixture allowed to warm to room
temperature over 2 h. A solution of 1 (157 mg, 0.69 mmol,
2.0 equiv.) in tetrahydrofuran (0.7 mL) was added. The reaction
solution was left stirring overnight under nitrogen at room
temperature. The solution was then concentrated under vacuum
to remove excess tetrahydrofuran. The residue was partitioned
between water (6 mL) and ethyl acetate (6 mL). The aqueous
layer was further extracted with ethyl acetate (2 ꢂ 6 mL). The
combined organic layers where dried (MgSO4), filtered, and
concentrated under vacuum. Purification by radial chromato-
graphy, eluting with 90% petroleum ether/10% ethyl acetate,
gave S-Methyl 2-(benzoyl)thiobenzoate (16), which was
recrystallised from petroleum ether (30 mg, 41%) as white
needles, mp 60–61.58C. dH (CDCl3) 2.29 (s, 3H), 7.41 (t, J 7.3,
3H), 7.50–7.62 (m, 3H), 7.75 (dd, J 7.4, 1.4, 2H), 7.99 (dd, J 7.4,
1.9, 1H). dC (CDCl3) 11.95, 128.10, 128.33, 129.39, 129.70,
132.15, 132.99, 133.04, 136.71, 136.80, 139.30, 192.27, 196.87.
nmax cmꢀ1 3069w, 2932w, 1773m, 1668s, 1599m, 1450m,
1317m, 1279s, 1265s, 1211s. m/z 209 (M – SCH3, 100%), 180,
152, 105, 77.
4-Hydroxy-3-methylthio-4-phenyl-4H-naphthalen-1-one (15)
Compound 14 decomposed within a few hours in chloroform to
give the titled compound, 15, which recrystallized from meth-
anol as white prisms mp 2108C (sublimes). (Found: Mþꢁ
282.0716; C17H14O2S requires: Mþꢁ 282.0715). dH (CDCl3),
2.30 (s, 3H), 3.02 (br s, 1H), 6.24 (s, 1H), 7.22–7.31 (m, 3H),
7.36–7.49 (m, 5H), 8.12 (dd, J 6.9, 1.5, 1H). dC ((D6)DMSO)
2.37 (s, 3H), 6.33 (s, 1H), 7.22 (s, 1H), 7.26 (ddd, J 6.8, 4.4, 1.4,
1H), 7.35 (t, J 7.3, 2H), 7.42 (dd, J 8.8, 1.5, 2H), 7.49–7.53 (m,
2H), 7.62 (td, J 7.3, 1.5, 1H), 8.06 (dd, J 8.3, 1.5, 1H). dC ((D6)
DMSO) 13.70, 74.03, 118.19, 124.66, 125.24, 127.18, 127.77,
127.86, 128.44, 129.07, 132.84, 144.81, 149.25, 173.18, 180.62.
n
(s) 1256w, 1132w. m/z 282 (M, 21%), 266 (M – O), 235 (M –
SCH3, 100%), 209, 181, 177, 152, 105, 77.
max cmꢀ1 3580w, 1645s, 1601m, 1589w, 1564m, 1448w, 1321
Crystal Data and Structural Refinement for 15
C17H14O2S, M 282.34, crystal dimensions 0.76 ꢂ 0.33 ꢂ
3
0.13 mm ; monoclinic, a 7.216(2), b 22.708(5), c 8.544(2) A;
˚
3
˚
a 908, b 104.51(3)8, g 908; V 1355.4(6) A , space group P21/c, Z
4, F(000) 592, Dcalc 1.384 Mg mꢀ3, absorption coefficient
0.236 mmꢀ1, y range for data collection 2.62 to 25.00; data/
restraints/parameters 2369/0/185, goodness of fit on F2 was
0.877, final R indices [I . 2s(I)] R1 0.0720, wR2 0.1699, R
indices (all data) R1 0.1249, wR2 0.1999, largest difference peak
ꢀ3
˚
and hole 0.623 and ꢀ0.570 e A
.
The unit cell parameters were obtained by least-squares
refinement of the setting angles of 30 reflections with 138 .
2y . 78. A unique dataset was measured at 163(2) K within
2ymax 508 limit (v scans). Of the 2441 reflections obtained, 2372
Further elution with 80% petroleum ether/20% ethyl acetate,
gave the title compound 14, (80 mg, 50%) as a yellow oil.

950
A. J. Pratt, P. M. Rendle, and P. J. Steel
were unique (Rint 0.0640) and were used in the full-matrix least-
squares refinement. The intensities of three standard reflections,
measured every 97 reflections throughout the data collection,
showed only 2% decay.
petroleum ether, gave the titled compound 20[13] (6 mg, 43%) as
white needles, mp 57–588C. (Found: 236.0329; C12H12OS2
requires: 236.0329). dH (CDCl3) 2.36 (s, 3H), 2.48 (s, 3H), 7.24
(s, 1H), 7.54 (dd, J 8.3, 1.4, 1H), 7.58 (dd, J 8.3, 1.4, 1H), 7.62
(s, 1H), 8.28 (t, J 8.3, 2H). dC (CDCl3) 18.42, 19.98, 113.40,
123.51, 124.06, 125.03, 126.04, 126.11, 127.75, 132.87, 134.05,
152.88 nmax cmꢀ1 3398br m, 2926m, 1578s, 1499m, 1437m,
1418m, 1366s, 1333s, 1238s. m/z 236 (M, 100%), 221 (M –
CH3), 177.
1,9-Bis(methylthio)-11-oxa-9-(p-tolylsulfonyl)tricyclo
[6.2.1.02,7]undeca-2,4,6-triene (18) and 1,10-Bis
(methylthio)-11-oxa-10-(p-tolylsulfonyl)tricyclo-
[6.2.1.02,7]undeca-2,4,6-triene (19)
n-Butyl lithium (0.24 mL of a 1.6 mol Lꢀ1 solution in hexanes,
0.38 mmol, 1.2 equiv.) was added dropwise to a stirred solution
of diisopropylamine (49 mL, 0.35 mmol, 1.1 equiv.) in tetrahy-
drofuran (3.3 mL) cooled in an ice-salt bath. The solution
was stirred for 20 min at this temperature and then cooled further
in an acetone/dry ice bath. A solution of 1,3-dihydroisoben-
zofuran-1-thione[2] (48 mg, 0.32 mmol, 1.0 equiv.) in tetrahy-
drofuran (3.3 mL) was added dropwise. The solution was stirred
at ꢀ788C for 1 h. Iodomethane (24 mL, 0.38 mmol, 1.2 equiv.)
was added dropwise and the resulting mixture allowed to warm
to room temperature over 2 h. A solution of 1 (87 mg,
0.38 mmol, 1.2 equiv.) in tetrahydrofuran (0.9 mL) was added.
The reaction solution was left stirring overnight at room
temperature. The solution was then concentrated under vacuum
to remove excess tetrahydrofuran. The residue was partitioned
between water (8 mL) and dichloromethane (8 mL). The aque-
ous layer was further extracted with dichloromethane (2 ꢂ
8 mL). The combined organic layers where dried (MgSO4),
filtered, and concentrated under vacuum. Purification by radial
chromatography, eluting with 80% petroleum ether/20% ethyl
acetate gave 1,endo-9-bis(methylthio)-11-oxa-exo-9-(p-tolyl-
sulfonyl)tricyclo[6.2.1.02,7]-undeca-2,4,6-triene (18b) (75 mg,
60%) as a white solid, mp 67.5–698C. (Found: M – TolSO2Hþꢁ
236.0330; C12H12OS2 requires: Mþꢁ 236.0330 (the parent ion
was not observed)). dH (C6D6) 1.69 (d, J 13.1, endo H), 1.84
(s, CH3S–CO), 1.96 (s, CH3–Ø), 2.15 (s, CH3S–C–SO2), 3.13
(d, J 13.1, exo H), 6.01 (s, H–CO), 6.92 (d, J 7.8, 2H), 6.99–7.09
(m, 3H), 7.20 (d, J 5.9, 1H), 8.01 (d, J 8.3, 2H). m/z 236 (M –
TolSO2H, 100%), 221 (M – TolSO2H – CH3), 189 (M – Tol-
SO2H – SCH3), 177, 164, 139, 91, 73.
2-(Methylthio)naphthalen-1,4-dione (21)
Compound 20 slowly oxidized to naphthoquinone 21 upon
exposure to air. Purification by radial chromatography, eluting
with 90% petroleum ether/10% ethyl acetate, gave the titled
compound, 21,[14] which crystallized from ethanol as yellow
needles mp 161–1638C. dH (CDCl3) 2.37 (s, SCH3), 6.56
(s, CHCO), 7.69 (td, J 7.3, 1.5, ArH), 7.74 (td, J 7.3, 2.0, ArH),
8.08 (dd, J 7.3, 2.0, ArH), 8.10 (dd, J 7.3, 1.5, ArH).
Acknowledgement
The authors acknowledge the provision of funding by the University of
Canterbury and the Public Good Science Fund.
References
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Further elution gave 1,exo-10-bis(methylthio)-11-oxa-endo-
10-(p-tolylsulfonyl)tricyclo[6.2.1.02,7]-undeca-2,4,6-triene (19a)
(6 mg, 5%) as a white solid, mp 126–1288C. dH (CDCl3) 2.05
(s, CH3S–CO), 2.10 (s, CH3–Ø), 2.43 (s, CH3S–C–SO2), 2.60 (d,
J 12.7, endo H), 2.75, dd, J 12.7, 5.4, exo H), 5.52 (d, J 5.4, H–
CO), 7.29–7.38 (m, 5H), 7.54 (d, J 7.3, 1H), 7.78 (d, J 8.3, 2H).
Further elution gave 1,endo-10-bis(methylthio)-11-oxa-
exo-10-(p-tolylsulfonyl)tricyclo[6.2.1.02,7]-undeca-2,4,6-triene
(19b) (25 mg 20%), which recrystallized from ethanol as white
needles, mp 148–1528C. (Found: M – TolSO2Hþꢁ 236.0329;
C12H12OS2 requires: Mþꢁ 236.0330 (the parent ion was not
observed)). dH (CDCl3) 1.38 (d, J 13.2, endo H), 2.11 (s, CH3S–
CO), 2.42 (s, CH3–Ø), 2.48 (s, CH3S–C–SO2), 3.05 (dd, J 13.2,
5.4, exo H), 5.33 (d, J 4.9, H–CO), 7.22–7.32 (m, 5H), 7.49 (d,
J 6.4, 1H), 7.99 (d, J 8.3, 2H). dC (CDCl3) 13.94, 15.83, 21.66,
43.64, 77.12, 78.96, 101.20, 119.39, 121.86, 126.94, 128.24,
128.90, 131.52, 135.30, 141.69, 144.56, 145.41. nmax cmꢀ1
2932m, 1597m, 1302m, 1142s. m/z 236 (M – TolSO2H, 37%),
228, 221, 164, 139, 121 91, 73 (100%).
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1,3-Bis(methylthio)naphthalen-4-ol (20)
Compound 18a decomposed within hours upon standing in
chloroform. Purification by radial chromatography, eluting with