Synthesis of possible o-thioquinone methide precursors

Article abstract of DOI:10.1139/V07-142

Investigating the synthetic accessibility of o-thioquinone methide precursors containing electron donating groups, we prepared four methyl- and methoxy-substituted 2H-benzo[b]thiete derivatives by means of flash vacuum pyrolysis of the corresponding benzo

Full text of DOI:10.1139/V07-142

119
Synthesis of possible o-thioquinone methide
precursors
Kirill A. Kolmakov and A. Jerry Kresge
Abstract: Investigating the synthetic accessibility of o-thioquinone methide precursors containing electron donating
groups, we prepared four methyl- and methoxy-substituted 2H-benzo[b]thiete derivatives by means of flash vacuum py-
rolysis of the corresponding benzooxathiinone species. Methyl- and methoxy-substituted substrates proved to be com-
patible with the pyrolysis protocol. The pyrolysis can be performed at considerably lower temperatures and with higher
yields than in previously reported syntheses of nonsubstituted 2H-benzo[b]thiete. Under proper conditions the reaction
products can be isolated in excellent yields and with 100% purity, so the troublesome purification of temperature sensi-
tive and volatile 2H-benzo[b]thiete derivatives becomes unnecessary. The sulfur-containing compounds so obtained are
efficient o-thioquinone methide precursors and possible synthones for heterocyclic chemistry.
Key words: 2H-benzo[b]thietes, flash vacuum pyrolysis, methyl-substituted, methoxy-substituted, o-thioquinone methide
precursors.
Résumé : Dans le cadre de nos travaux sur l’accessibilité synthétique de précurseurs de méthides de o-thioquinone
contenant des groupes électrodonneurs, on a préparé quatre dérivés du 2H-benzo[b]thiète substitués par des groupes
méthyles et méthoxy en faisant appel à la pyrolyse éclair sous vide des espèces benzooxathiinones correspondantes. Il
est possible d’effectuer les pyrolyses à des températures beaucoup plus basses et avec de meilleurs rendements que
ceux rapportés antérieurement pour les 2H-benzo[b]thiètes non substitués. Dans les bonnes conditions, les produits de
la réaction peuvent être isolés avec d’excellents rendements et une pureté de 100, ce qui rend inutile la purification des
dérivés 2H-benzo[b]thiètes volatils et sensibles à la température. Les composés contenant du soufrant ainsi obtenus
sont des précurseurs efficaces de méthides de o-thioquinone et pourraient servir de synthons en chimie hétérocyclique.
Mots-clés : 2H-benzo[b]thiètes, pyrolyse éclair sous vide, substitué par un méthyle, substitué par un méthoxy, précur-
seurs de méthides de o-thioquinone
[Traduit par la Rédaction] Kolmakov and Kresge 123
Introduction
Scheme 1.
R
Quinone methides and their far less studied sulfur analogs
are interesting molecules with wide application in organic
synthesis (1). Extending our investigation of quinone
methides generated by flash photolysis to sulfur-containing
species, we synthesized some substituted 2H-benzo[b]thiete
derivatives (Scheme 1, structure 1) as possible precursors of
o-thioquinone methides (Scheme 1, structure 2). In our
previous research (2), we had established that 2H-
benzo[b]thiete (1a, R = H), containing a strained four-
membered ring, is a good precursor for clean and high-
yielding photo-generation of 2a (R = H), needed for accurate
kinetic measurements of its hydration in aqueous solution by
means of flash photolytic methods. o-Thioquinone methide
(2a, R = H) proved to be quite short-lived in aqueous solu-
o-
3
3
hν
or
S
p-
S
5
5
S
2a–2e
R
1a–1c
1d–1e
R
R = H, 3- or 5-Me, 3- or 5-MeO
tions (2). Expecting to obtain transients 2 with considerably
longer lifetimes, we were particularly interested in the prep-
aration of compounds 1 containing electron donating groups
at 3- or 5- positions, which would correspond to ortho and
para positions, respectively, in the “thioquinone” ring of 2,
relative to the methylene group.
Despite the merits of the 2H-benzo[b]thiete molecule, no
compounds of type 1 substituted in the benzene ring have
been described previously. The few known syntheses of 1a
made use of flash vacuum pyrolysis (FVP) at very high tem-
peratures (700–1200 °C (3a–3c)), and no mention was made
of substituted precursors (R = Me, MeO) that could be used
in the synthetic procedures.
Received 27 September 2007. Accepted 26 November 2007.
Published on the NRC Research Press Web site at
canjchem.nrc.ca on 21 December 2008.
This paper is dedicated to the memory of Keith Yates, a good
friend, wise editor, and father of modern physical organic
chemistry in Canada.
One could get the impression that because of the drastic
reaction conditions of FVP, the synthesis of substituted 2H-
benzo[b]thietes was unfeasible. Also, it is known that
methyl- and methoxy-substituted aromatic hydrocarbons, in-
cluding such simple derivatives as toluene and anisole,
K.A. Kolmakov1 and A.J. Kresge. Department of Chemistry,
University of Toronto, Toronto, ON M5S 3H6, Canada.
1Corresponding author (e-mail: kkolmako@chem.utoronto.ca).
Can. J. Chem. 86: 119–123 (2008)
doi:10.1139/V07-142
© 2008 NRC Canada

120
Can. J. Chem. Vol. 86, 2008
Scheme 2. (1 torr = 133.322 4 Pa)
O
O
LiAlH4
O
1) HNO2
Cl3COCOCl
Py
OH
OH
OH
O
1/2
OH
5b–5d
2) Na2S2
S
O
SH
6a–6d
NH2
4b–4d
S
S
R
R
R
R
3a–3e
Py
CCl3OCOCl
R
O
S
O
O
O
ClCSNMe2
DABCO
rearrangement
LiAlH4
H
O
OH
SH
H
S
H
mesithylene,
160oC
MeO
MeO
MeO
MeO
OH
8
9
7
6e
Me2N
Me2N
Flash vacuum pyrolysis
3
350oC / 0.01Torr
R = H (1a), 3-Me (1b), 3-MeO (1c), 5-Me (1d), 5-MeO (1e)
O
5
S
1a 1b 1c 1d 1e
-- CO2
Compound
S
O
3a–3e
R
R
Isolated yield (%) 82
88
83
92 84
1a–1e
undergo demethylation when exposed to high temperatures
(typically above 700 °C); soot and many other products are
formed depending on conditions of the gas-phase pyrolysis
(4). Finally, the existing syntheses of 1a leave much to be
improved.
LiAlH4, as described (6) for 5a (R = H). On the other hand,
the synthesis of 4-methoxy derivative (6e, R = 4-MeO) in-
volved a Newman–Kwart reaction (7) on the commercially
available 2-hydroxy-4-methoxybenzaldehyde (Scheme 2, 7)
followed by reduction (see the Experimental section for de-
tails).
According to H. Meier and A. Mayer (3d), 4H-
benzo[d][1,3]oxathiin-2-one (Scheme 2, compound 3a, R =
H) undergoes decarboxylation at 140 °C already and there-
fore can be used as a synthetic equivalent of 2H-
benzo[b]thiete (1a, R = H) in some reactions. Nonetheless,
in the course of the preparative synthesis of 1a via pyrolysis
of 3a, the authors maintained a rather high (550 °C) temper-
ature (3d). We decided to check if the pyrolysis temperature
could be considerably decreased. The lower the temperature,
the better the chances are to obtain the derivatives of 1 in
greater diversity, and, also importantly, utilize a pyrex appa-
ratus instead of the traditionally used quartz. We explored
the synthetic accessibility of o-thioquinone methide precur-
sors of structure 1 containing methyl and methoxy groups.
Now that the synthetic part of our research is complete, we
wish to report the properties of the novel 2H-benzo[b]thiete
derivatives and details of the syntheses.
Flash vacuum pyrolysis (FVP) generally involves con-
trolled vaporization of neat compounds in vacuo and vapor
passage through tube type reactors maintained at high tem-
peratures (3–6). The initial experiments on the compound 3a
as a substrate gave promising results. First, we established
that the flash vacuum pyrolysis does occur at considerably
lower temperatures (i.e., 250–300 °C) than H. Meier and A.
Mayer suggest (550 °C). Further, we found that the decar-
boxylation in this temperature range is selective. Apart from
1a, the unreacted starting material 3a was detected as the
only impurity in some experiments (at low pyrolysis temper-
atures and with high substrate sublimation rates). This
means that, under the right conditions, the reaction product
can be collected pure, which is a great advantage consider-
ing the instability and volatility of 2H-benzo[b]thiete. The
latter usually poses difficulties when solvents are being
evaporated from dilute compound solutions — for example,
after chromatographic separation in the final purification
stage.
Results and discussion
In our syntheses of compounds 1b–1e, we decided to fol-
low the route described by H. Meier and A. Mayer (5) for
1a, which involved the preparation of the 4H-
benzo[d][1,3]oxathiin-2-one (Scheme 2, 3a, R = H) followed
by decarboxylation performed under FVP conditions. As
seen in Scheme 2, compounds 3b–3e were obtained from the
corresponding 2-mercaptobenzyl alcohols (6a–6e) by the re-
action with trichloromethyl chloroformate (diphosgene). The
alcohols 6, of which all except 6a are new compounds, were
prepared from the commercially available substituted 2-
aminobenzoic acids (4a–4d). The first stage of the syntheses
involved a simplified Leukart reaction, which is known to
provide good yields for 2,2′-dithiosalicylic acid 5a and its
methyl and methoxy derivatives 5b–5d (5). The diazotiza-
tion of the amino groups in 4a–4d was followed by decom-
position in aqueous solutions of sodium disulfide, and the
disulfides 5a–5d were reduced with a large excess of
Besides the reaction temperature, another important pa-
rameter of the process is the so-called “contact time”, which
indicates how long the compound vapor is exposed to high
temperature in the reactor. This depends on the length of the
reaction tube and (or) substrate sublimation rate. Despite
100% selectivity achieved for the gas phase pyrolysis itself,
all the compounds 3, including the nonsubstituted 3a, proved
temperature sensitive and underwent polymerization to a no-
ticeable extent even at 30–40 °C. Therefore, there is a limit
to the sublimation temperature and consequently the process
output. When we switched to methyl and methoxy deriva-
tives 3b–3e as substrates, we found that their volatility was
3–5 times lower than that of 3a. As expected, the introduc-
tion of substituents into the small molecule 3a drastically
decreased the volatility. With the apparatus we had at our
disposal and under high vacuum (0.005–0.010 torr, 1 torr =
133.322 4 Pa), the process output was some 1–1.5 mg/h.
© 2008 NRC Canada

Kolmakov and Kresge
121
With lower substrate sublimation rates and consequently
longer contact times, temperature variations in the 300–
450 °C range did not affect either yield or purity of the
products. All the compounds were isolated in the pure state
(~99%, HPLC, NMR) and in excellent yields (82–92%, see
Scheme 2). The general procedure for flash vacuum pyrolysis
is described in the Experimental section. The four deriva-
verse-phase column (4.6/150 mm, 5 µ particle size, metha-
nol/water (50:50 vol.) as mobile phase) or by or TLC on sil-
ica gel SIL G/UV 254 plates developed in hexane. Mass
spectra were recorded on a Micromass 70S-250 sector mass
spectrometer and NMR spectra on a Varian spectrometer at
300 MHz (1H) and 75 MHz (13C). All the solvents, including
THF and pyridine, were freshly distilled and dried by con-
ventional methods.
1
tives 1b–1e were characterized by H and 13C NMR, high-
and low-resolution mass spectrometry, and by melting
points.
Flash vacuum pyrolysis — General procedure for the
preparation of 2H-benzo[b]thiete derivatives (1a–1e).
The apparatus for flash vacuum pyrolysis consisted of a
test tube for sublimation connected to a pyrex reactor
(2.5 cm × 35 cm) placed inside a tube furnace. The
oxathiinone precursors (30–50 mg) were dissolved in ~2 mL
of methylene chloride and the solutions were evaporated
inside the test tube under an argon purge to achieve better
coverage of its inner surface by the solids, which assisted
sublimation. The test tube was mainained at 30–35 °C by
means of external heating. The vacuum was maintained at
0.005–0.010 torr by means of a rotary pump. The products
were condensed in a trap, cooled with liquid nitrogen, and
handled uner inert atmosphere. In a typical experiment,
about 20 mg of a compound 1a–1e was isolated.
In the NMR spectra of 1b–1e at 4.30–4.40 ppm (1H) and
at 35.10–36.55 ppm (13C), signals were observed that could
be unmistakeably attributed to methylene groups (CH2) in
the four-membered ring. As expected, those signals were
markedly shifted upfield, compared with that of oxy-
methylene groups (OCH2) in oxathiinone precursors 3b–3e
(5.10–4.50 ppm (1H) and 66.60–72.60 ppm (13C), respec-
tively). The latter compounds also develop “carbonyl” sig-
nals resonating in the low-field area at 166–168 ppm (13C).
Also, in proton NMR spectra of compounds 1b and 1c, one
could observe the typical picture of meta-substituted ben-
zene rings with well-resolved singlets and doublets (see Ex-
perimental section for NMR spectroscopic data).
It should be noted that compounds 1b–1e proved much
more temperature sensitive, especially in solutions, than the
nonsubstituted compound 1a. Polymerization of 1a has been
described in the literature (4c), and polymerization of the de-
rivatives 1b–1e was evidenced in our research by the forma-
tion of insoluble precipitates upon storage (even at –10 °C).
In addition, chromatographic analyses showed a decrease in
compound concentration, while no other products were de-
tected (polymers could not pass through the column we have
used for the analysis of compounds 2 and 3; see Experimen-
tal section for details).
General procedure for the preparation of 4H-
benzo[d][1,3]oxathiin-2-one derivatives (3a–3e)
To a stirred solution of the thiol substrates (2 mmol) and
pyridine (470 mg,
6 mmol) in 40 mL of THF,
trichloromethylchlorocarbonate (260 mg, 1.30 mmol) in
5 mL of THF was added at –5 °C in 20 min under an argon
atmosphere. Further, 0.5 mL of concd. HCl in 50 mL of wa-
ter, 50 mL of saturated brine, 25 mL of hexane, and 5 mL of
methylene chloride was added successively upon stirring at
RT. The organic layer was separated, and the aqueous layer
was extracted with a mixture of hexane (25 mL) and methy-
lene chloride (5 mL). Combined extracts were washed with
15 mL of water and then with a solution of 28 mg
(0.5 mmol) KOH in 10 mL of water. The extracts were dried
over MgSO4, and the solvents were evaporated under re-
duced pressure. Crude products were purified by column
chromatography over a short column containing ~8 g of sil-
ica gel with methylene chloride/hexane (1:2 vol.) as liquid
phase.
Conclusions
Four methyl- and methoxy-substituted 2H-benzo[b]thietes
1b–1e were synthesized in excellent yields from the corre-
sponding 4H-benzo[d][1,3]oxathiin-2-ones 3b–3e via flash
vacuum pyrolysis. The process was a substantial improve-
ment on the previously reported syntheses of 3a. Particu-
larly, we showed that the pyrolysis can be performed at
considerably lower temperatures (300 °C), which allows the
use of pyrex instead of quartz in the apparatus. Our experi-
ments demonstrated that methyl- and methoxy-substituted
substrates are compatible with the pyrolysis protocol. Under
proper conditions, the reaction products can be isolated in
excellent yields and with a very high purity. The final purifi-
cation step is thus avoided, which is very important in dealing
with the temperature sensitive and volatile 2H-benzo-
[b]thiete derivatives.
2-Mercaptobenzyl alcohols (6b–6d)
The compounds 6b–6dwere obtained by reduction of the
corresponding dithiosalicylic acids 5b–5d (Scheme 2), them-
selves prepared via a simplified Leukart reaction on 2-
aminobenzoic acids (4b–4d) in good yields, according to
known procedures (5b and 5c). The identity of the products
identity was confirmed by melting point determination and
1
by H NMR spectroscopy. The most recent report on the
preparation of 2-mercaptobenzyl alcohol 6a (R = H) belongs
to A. Arnoldi and M. Carughi (6), who used it as an inter-
mediate without purification. Our recipe for the preparation
of 6b–6d is very simple and, more importantly, provides
very high purities (~99%, HPLC) for all the produts. In a
typical experiment, the reduction was carried out as follows:
To an ice-cooled solution of the dithiosalicylic acid substrate
5b–5d (0.004 mol) in THF (60 mL), LiAlH4 powder
Experimental section
General
Substituted 2-aminobenzoic acids (4b–4d) were pur-
chased from Peakdale Molecular (UK), and the rest of the
chemicals from Aldrich. Progress of the reactions was moni-
tored either by HPLC using
chromatograph equipped with Waters Symmetry C-18 re-
a 5500 Varian Vista
© 2008 NRC Canada

122
Can. J. Chem. Vol. 86, 2008
(0.800 g, 0.021 mol) was added in a few portions upon stir-
ring under an argon purge. The solution was slowly
(~30 min) warmed up to RT, stirred for 1 h at 55–60 °C,
cooled again, and carefully poured onto a mixture of ice
(100 g) and 30 mL of 10 wt% H2SO4 upon vigorous stirring.
Benzene (20 mL) was added immediately afterwards, and
the organic layer separated. Water phase was extracted with
benzene (20 mL × 2) and the combined organic extract was
washed with water (15 mL) and a saturated NaHCO3 solu-
tion (10 mL). From the benzene solution, the compounds
6b–6d were extracted with NaOH (0.400 g, 0.010 mol) in
15 mL of water. The alkaline extract was acidified with
concd. HCl (1.5 mL) and treated with CH2Cl2 (20 mL × 2).
The organic phase was washed with brine (10 mL), dried
and evaporated in vacuo. For the final purification, the alco-
hols were decolorized with silica gel (0.10 g) in methylene
chloride/pentane (~1:10 vol.) solutions at RT, and crystal-
lized upon cooling to (–20)–(+30) °C (because of their low
melting points; properties and yields are reported later). All
the compounds 6 are air-sensitive, and therefore all the ma-
nipulations were carried out under an argon atmosphere. The
identity and purity of the alcohols 6b–6d (all four are new
Dimethylthiocarbamic acid O-(2-formyl-5-
methoxyphenyl) ester (8)
A
solution of N,N-dimethylthiocarbamoyl chloride
(3.10 g, 0.025 mol), 2-hydrohy-4-methoxybenzaldehyde
(3.04 g, 0.02 mol), and DABCO (3.02g, 0.027 mol) in
20 mL of anhyd. DMF was stirred overnight at RT for 2 h at
35–40 °C, and then poured into 200 mL of ice cold water.
The yellow powder was collected, dried, and recrystallized
from a benzene/hexane mixture (1:3 vol.) to afford 3.32 g
(70%) of a colorless product whose melting point was 88 to
1
89 °C. H NMR and mass spectra agreed with the structure
1
8. H NMR (CDCl3, ppm) δ: 3.41, 3.47 (2s, 6H, NCH3),
3.88 (s, 3H, OCH3), 6.63 (s, 1HAr), 6.90 (d, J = 6Hz, 1HAr),
7.85 (d, J = 6Hz, 1HAr), 9.92 (s, 1H, CHO). MS (ESI) m/z
(%): 262 (100, M + Na+), 239 (15, M + H+), 212 (10, M+ –
CO). HRMS (ESI) calcd. for (M + Na+) C11H13O3NaS:
262.0508; found: 262.0501.
Dimethylcarbamic acid S-(2-formyl-5-methoxyphenyl)
ester (9)
The rearrangement of the O-ester 8 to the corresponding
S-ester 9 (see Scheme 2) was performed at 165 °C using
mesithylene as solvent instead of the commonly used
biphenyl ether (7b). Mesithylene proved much easier to re-
move and, more importantly, higher reaction temperatures
(190–200 °C) are unsuitable for 8 because of its thermal
sensitivity. Compound 8 (2.00 g, 0.008 mol) was refluxed in
20 mL of mesithylene for 25 h under an argon atmosphere.
The rearrangement was monitored by TLC on silica plates
using methylene chloride/acetone (10:1) as mobile phase.
The solution was evaporated in a Petrie plate at atmospheric
pressure, the residue dissolved in a methylene chloride/hexane
(1:2 vol.) mixture (180 mL), decolorized with 0.40 g of sil-
ica gel, and crystallized to afford 1.65 g (80%) of pale yel-
1
compounds) was confirmed by H and 13C NMR spectro-
scopic data and mass spectrometry (see following).
2-Mercapto-6-methylbenzyl alcohol (6b)
Yield 67%. Colorless needles, mp 74–76 °C (methylene
1
chloride/pentane). H NMR (CDCl3, ppm) δ: 1.84 (br s, 1H,
OH) 2.41 (s, 3H, CH3), 3.64 (s, 1H, SH), 4.88 (s, 2H, CH2)
6.99–7.25 (m, 3HAr). 13C NMR (CDCl3, ppm) δ: 19.72
(CH3), 60.57 (CH2OH), 128.52, 128.73, 129.39, 131.90,
136.72, 138.40. MS EI (70 eV) m/z (%): 154 (10, M+), 136
(100, M+ – H2O), 121 (12, M+ – H2O – CH3). HRMS (EI)
calcd. for (M+) C8H10O2S: 154.0452; found: 154.0456.
1
low needles with mp 78 °C. H NMR (CDCl3, ppm) δ: 3.04,
3.16 (2s, 6H, NCH3), 3.88 (s, 3H, OCH3), 7.02 (s, 1HAr),
7.05 (d, J = 6Hz, 1HAr), 8.01 (d, J = 6Hz, 1HAr), 10.27 (s,
1H, CHO). MS (ESI) m/z (%): 262 (100, M + Na+), 239
(30, M + H+), 212 (10, M+ – CO), 167 (20, M+ – CON(CH3)2).
HRMS (ESI) calcd. for (M + Na+) C11H13O3NaS: 262.0508;
found: 262.0504.
2-Mercapto-6-methoxybenzyl alcohol (6c)
Yield 62%. Colorless needles, mp 68 to 69 °C (methylene
1
chloride/pentane). H NMR (CDCl3, ppm) δ: 2.22 (br s, 1H,
OH), 3.64 (s, 1H, SH), 3.83 (s, 3H, OCH3), 4.66 (s, 2H,
CH2), 6.71–7.49 (m, 3HAr). 13C NMR (CDCl3, ppm) δ:
55.70 (OCH3), 58.26 (CH2OH), 108.52, 123.62, 127.20,
129.16, 132.77, 158.40. MS EI (70 eV) m/z (%): 170 (15,
M+), 152 (100, M+ – H2O), 121 (20, M+ – H2O – OCH3).
HRMS (EI) calcd. for (M+) C8H10O2S: 170.0402; found:
170.0407.
Compound 9 (0.956 g, 0.004 mol) in 5 mL of THF was
added to a stirred suspension of LiAlH4 (0.800 g, 0.021
mol) in 30 mL of THF at 0 °C during 10 min under an argon
purge, the reaction mixture was stirred for 4 h at 50°, and
then treated exactly as described for the alcohols 6b–6d (see
earlier) to furnish 6e (0.456 g, 67%) as colorless needles
2-Mercapto-4-methylbenzyl alcohol (6d)
1
with mp 26–28 °C (methylene chloride/pentane). H NMR
Yield 73%. Colorless needles, mp 42 to 43 °C (methylene
1
(CDCl3, ppm) δ: 1.84 (br s, 1H, OH) 3.78 (s, 3H, OCH3),
3.90 (s, 1H, SH), 4.66 (s, 2H, CH2) 6.64 (d, J = 7Hz, 1HAr),
6.87 (s, 1HAr), 7.22 (d, J = 7Hz, 1HAr). 13C NMR (CDCl3,
ppm) δ: 55.52 (OCH3), 64.09 (CH2OH), 111.81, 116.69,
130.45, 131.20, 132.14, 159.45. MS EI (70 eV) m/z (%): 170
(25, M+), 152 (100, M+ – H2O), 121 (15, M+ – H2O –
OCH3). HRMS (EI) calcd. for (M+) C8H10O2S: 170.0402;
found: 170.0401.
chloride/pentane). H NMR (CDCl3 ppm) δ: 1.85 (br s, 1H,
OH) 2.30 (s, 3H, CH3), 3.66 (s, 1H, SH), 4.69 (s, 2H, CH2)
6.98 (d, J = 7Hz, 1HAr), 7.19 (s, 1HAr), 7.24 (d, J = 7Hz,
1HAr). 13C NMR (CDCl3, ppm) δ: 20.91 (CH3), 64.29 (CH2OH),
127.19, 128.94, 130.13, 131.99, 135.89, 138.48. MS EI
(70 eV) m/z (%): 154 (12, M+), 136 (100, M+ – H2O), 121
(15, M+ – H2O – CH3). HRMS (EI) calcd. for (M+)
C8H10O2S: 154.0452; found: 154.0451.
2-Mercapto-4-methoxybenzyl
3-Methyl-2H-benzo[b]thiete (1b)
1
The alcohol (6e) was obtained via a Newman–Kwart reac-
tion (see Scheme 2) on the commercially available 2-
hydroxy-4-methoxybenzaldehyde (7) by the following steps.
Yield 88%. Colorless liquid, fp (–10)–(+)9 °C. H NMR
(CD3CN, ppm) δ: 2.27 (s, 3H, CH3), 4,33 (s, 2H, CH2),
6.91–6.98 (m, 2HAr), 7,18–7.24 (m, 1HAr). 13C NMR
© 2008 NRC Canada

Kolmakov and Kresge
123
(CD3CN, ppm) δ: 15.08 (CH3), 35.88 (CH2), 118.52, 125.42,
129.51, 133.12, 138.88, 142.46. MS EI (70 eV) m/z (%): 136
(100, M+), 121 (20, M+ – CH3), 91 (45, M+ – S – CH3).
HRMS (EI) calcd. for (M+) C8H8S: 136.0347; found:
136.0348.
5-Methoxy-2H-benzo[b]thiete (1e)
1
Yield 84%. Colorless prisms, mp 27 to 28 °C. H NMR
(CD3CN, ppm) δ: 3.79 (s, 3H, OCH3), 4,41 (s, 2H, CH2),
6.55 (d, J = 7Hz, 1HAr), 6.61 (s, 1HAr), 6.69 (d, J = 7Hz,
1HAr). 13C NMR (CD3CN, ppm) δ: 37.07 (CH2), 56.11
(OCH3), 108.18, 111.68, 118.80, 132.35, 143.91, 161.70
(C5). MS EI (70 eV) m/z (%): 152 (100, M+), 137 (5, M+ –
CH3), 121 (10, M+ – OCH3), 107 (25, M+ – CH2 – OCH3).
HRMS (EI) calcd. for (M+) C8H8OS: 152.0296; found:
152.0297.
5-Methyl-4H-benzo[d][1,3]oxathiin-2-one (3b)
Yield 55%. Colorless needles, mp 64–66 °C. H NMR
1
(CD3CN, ppm) δ: 2.44 (s, 3H, CH3), 5.47 (s, 2H, CH2),
7.23–7.27 (m, 2HAr), 7.33–7.38 (m, 1HAr). 13C NMR
(CD3CN, ppm) δ: 18.31 (CH3), 69.39 (CH2), 124.44, 128.18,
129.73, 130.09, 131.18, 136.47, 167.20 (C=O). MS EI
(70 eV) m/z (%): 180 (20, M+), 136 (100, M+ – CO2), 121
(45, M+ – CO2 – CH3). HRMS (EI) calcd. for (M+)
C9H8O2S: 180.0245; found: 180.0248.
7-Methoxy-4H-benzo[d][1,3]oxathiin-2-one (3e)
Yield 62%. Colorless needles, mp 76 to 77 °C. H NMR
1
(CD3CN, ppm) δ: 3.74 (s, 3H, CH3), 5.16 (s, 2H, CH2), 6.73
(d, J = 7.5Hz, 1HAr), 6.76 (s, 1HAr), 7.18 (d, J = 7.5 Hz,
1HAr). 13C NMR (CD3CN, ppm) δ: 56.43 (OCH3), 72.57
(CH2), 112.46, 114.26, 121.92, 128.99, 133.10, 161.44 (C5),
167.23 (C=O). MS EI (70 eV) m/z (%): 196 (25, M+), 152
(100, M+ – CO2), 121 (10, M+ – CO2 – OCH3). HRMS (EI)
calcd. for (M+) C9H8O3S: 196.0194; found: 196.0197.
3-Methoxy-2H-benzo[b]thiete (1c)
Yield 83%. Colorless liquid, fp 11–13 °C. 1H NMR
(CD3CN, ppm) δ: 3.95 (s, 3H, OCH3), 4.41 (s, 2H, CH2),
6.64–6.66 (m, 2HAr), 7.21–7.26 (m, 1HAr). 13C NMR
(CD3CN, ppm) δ: 35.10 (CH2), 56.05 (OCH3), 109.76,
114.41, 124.12, 130.67, 143.96, 153.01 (C3). MS EI (70 eV)
m/z (%): 152 (100, M+), 137 (10, M+ – CH3), 121 (40, M+ –
OCH3), 107 (15, M+ – CH2 – OCH3). HRMS (EI) calcd. for
(M+) C8H8OS: 152.0296; found: 152.0299.
Acknowledgement
We are grateful to the Natural Sciences and Engineering
Research Council of Canada for its generous financial sup-
port of our work.
5-Methoxy-4H-benzo[d][1,3]oxathiin-2-one (3c)
Yield 63%. Colorless needles, mp 68 to 69 °C. H NMR
References
1
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Y. Shi, and C. Yang. Can. J. Chem. 74, 465 (1996).
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Zhan. J. Org. Chem. 70, 1643 (2005).
3. For the preparation and properties of 2H-benzo[b]thiete see:
(a) K. Kanakarajan and H. Meier. J. Org. Chem. 48, 881
(1983); (b) R. Schulz and A. Schweig, Tetrahedron Lett. 21,
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ganic chemistry. Vol. 3. Wiley & Sons Inc., NY. 1965. pp. 1–
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Cummins, and S.J. Peacock. Trans. Faraday Soc. 67, 3265,
(1971); (c) S.J. Price. Can. J. Chem. 40, 1310 (1962); for the
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1047 (2001); (e) Y. Tsujino, C. Wakai, N. Matubayasi, and M.
Nakahara. Chem. Lett. 35, 1334 (2006).
(CD3CN, ppm) δ: 3.93 (s, 3H, CH3), 5.49 (s, 2H, CH2),
7.95–7.10 (m, 2HAr), 7.41–7.49 (m, 1HAr). 13C NMR
(CD3CN, ppm) δ: 56.25 (OCH3), 66.63 (CH2), 110.82,
117.42, 118.56, 131.17, 132.34, 156.61 (C3), 166.88 (C=O).
MS EI (70 eV) m/z (%): 196 (15, M+), 152 (100, M+ – CO2),
121 (40, M+ – CO2 – OCH3). HRMS (EI) calcd. for (M+)
C9H8O3S: 196.0194; found: 196.0193.
5-Methyl-2H-benzo[b]thiete (1d)
Yield 92%. Colorless prisms, mp 54 to 55 °C. H NMR
1
(CD3CN, ppm) δ: 2.35(s, 3H, CH3), 4.32 (s, 2H, CH2), 6.81
(d, J = 8Hz, 1HAr), 6.95 (s, 1HAr), 6.97 (d, J = 8Hz, 1HAr).
13C NMR (CD3CN, ppm) δ: 21.65 (CH3), 36.55 (CH2),
121.96, 123.13, 125.30, 137.23, 139.24, 142.53. MS EI
(70 eV) m/z (%): 136 (100, M+), 121 (15, M+ – CH3), 91
(25, M+ – S – CH3). HRMS (EI) calcd. for (M+) C8H8S:
136.0347; found: 136.0346.
5. For the preparation of dithiosalicylic acid, its 6-methoxy-, 6-
and 4-methyl derivatives, respectively, see: (a) Organic synthe-
sis, coll. Vol. 2. NY-L. p. 580. 1943; (b) K.C. Roberts, L.A.
Wiles, and B.A.S. Kent. J. Chem. Soc. 54, 1792 (1932); (c) R.
Ponci, V. Tullo, L. Amoretti, and F. Mossini. Farmaco, 22, 935
(1967).
6. A. Arnoldi and M. Carughi. Synthesis, 155 (1988).
7. For Newman–Kwart rearrangement see; (a) M.S. Newman and
H.A. Karnes. J. Org. Chem. 31, 3980 (1966); (b) A. Mayer, N.
Rumpf, and H. Meier. Liebigs Ann. 2221 (1995).
7-Methyl-4H-benzo[d][1,3]oxathiin-2-one (3d)
Yield 60%. Colorless needles, mp 71 to 72 °C. H NMR
1
(CD3CN, ppm) δ: 2.40 (s, 3H, CH3), 5.37 (s, 2H, CH2), 7.24
(d, J = 8Hz, 1HAr), 7.25 (s, 1HAr), 7.36 (d, J = 8Hz, 1HAr).
13C NMR (CD3CN, ppm) δ: 20.69 (CH3), 72.19 (CH2),
126.59, 126.87, 127.20, 128.81, 130.95, 140.57, 166.89
(C=O). MS EI (70 eV) m/z (%): 180 (25, M+), 136 (100,
M+ – CO2), 121 (8, M+ – CO2 – CH3). HRMS (EI) calcd. for
(M+) C9H8O2S: 180.0245; found: 180.0246.
© 2008 NRC Canada

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