Reinvestigatioan of base-induced skeletal conversion via a spirocyctic intermediate of dibenzodithiocinium derivatives and a computational study using the HF/6-31G* basis set

Article abstract of DOI:10.1039/b205588k

Treatment of 6-methyl-12-oxo-5H,7H-dibenzo[b,g][1,5]dithiocinium salt (1a) with methanolic KOH afforded a mixture of dibenzothiepin derivative 5 in 66% yield. The rearrangement was explained in terms of usual [2,3]-sigmatropic shift via a spirocyclic inte

Full text of DOI:10.1039/b205588k

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Reinvestigation of base-induced skeletal conversion via a
spirocyclic intermediate of dibenzodithiocinium derivatives and a
computational study using the HF/6-31G* basis set
1
Keiji Okada* and Masato Tanaka
Department of Chemistry, Graduate School of Science, Hiroshima University, Kagamiyama,
Higashi-Hiroshima 739-8526, Japan. E-mail: ohkata@sci.hiroshima-u.ac.jp
Received (in Cambridge, UK) 10th June 2002, Accepted 25th September 2002
First published as an Advance Article on the web 30th October 2002
Treatment of 6-methyl-12-oxo-5H,7H-dibenzo[b,g][1,5]dithiocinium salt (1a) with methanolic KOH afforded a
mixture of dibenzothiepin derivative 5 in 66% yield. The rearrangement was explained in terms of usual [2,3]-
sigmatropic shift via a spirocyclic intermediate. However, an unique rearrangement via an alternative spirocyclic
intermediate was observed in 6-methyl-5H,7H-dibenzo[b,g][1,5]dithiocinium salt (2) to give an unexpected
dibenzothiepin derivative 6 in 29% yield along with a small amount of a ring-opening product 7 in 5% yield under the
same reaction conditions. In order to clarify the origin of the different behaviour between the sulfoxide derivative 1a
and the sulfide derivative 2 in the rearrangements, 6-methyl-12-oxo-7,12-dihydro-5H-dibenzo[c,f]thiocinium salt (3)
as the reference compound with an electron withdrawing group (carbonyl group) was prepared and treated under the
same conditions to furnish a mixture of acid 8 and ester 9. It was considered that these products resulted from the
ring-opening of a spirocyclic intermediate analogous to the intermediate from the sulfoxide derivative 1a. On the
other hand, the rigid system, 10b-phenyl-10b,11-dihydro-6H-[1]benzothieno[2,1-a][2]benzothiophenium perchlorate
(4) afforded the compound 10 via the Stevens-type rearrangement. The ab initio MO calculations at HF/6-31G* basis
set was performed on the possible reaction intermediates and products.
Introduction
The Sommelet–Hauser rearrangement is a very attractive reac-
tion via [2,3]-sigmatropic dearomatization followed by [1,3]-
shift rearomatization processes1 and thus, the [2,3]-rearrange-
ments of sulfonium ylides can be highly exothermic with low
activation energies.2 Such a rearrangement of sulfonium or
ammonium ylides offers various interesting routes for prepar-
ation of substituted aromatic compounds.3
In the course of investigations of transannular interaction
Scheme 1
in heterocyclic dibenzocyclooctadiene systems (thiazocine,
dithiocin etc.),4,5 we encountered a skeletal contraction of these
systems into thiepin derivatives.6 This interesting rearrange-
ment was reinvestigated from the points of mechanistic view on
the basis of reactions of the reference compounds and stability
of the intermediates. This paper describes the novel base-
induced rearrangements in the title compounds 1–3 via spiro-
cyclic intermediates of the various spiro-intermediates.
as shown in Scheme 1 but the ratio of geometric isomers 5b–1
(35%) and 5b–2 (18%) was 1.9.
The products were characteristic as dibenzothiepin deriv-
atives 5a–1 and 5a–2 on the basis of their spectral data and
their chemical behaviour. For the purpose of further confirm-
ing their skeleton, treatment of a mixture of 5a–1 and 5a–2
with HSiCl3–LiAlH4 gave dibenzothiepin 11 in 41% as shown in
Scheme 2. Alternatively, deoxygenation of the pure sample 5a–1
with triphenylphosphine in carbon tetrachloride–acetonitrile
solution gave dibenzothiepin derivative 12 in 38% yield along
with its related alcohol 13 in 19% yield which might be hydro-
Results and discussion
Dithiocinium and related salts 1–4 were prepared by S-alkyl-
ation of the corresponding heterocycles containing sulfur
atom.5–7
Rearrangement of 6-methyl-12-oxo-5H,7H-
dibenzo[b,g][1,5]dithiocinium salt (1a) and the ethyl derivative 1b
Reaction of 6-methyl-12-oxo-5H,7H-dibenzo[b,g][1,5]dithio-
cinium tetrafluoroborate (1a) with methanolic KOH at room
temperature gave a mixture of geometric isomers 5 as shown in
Scheme 1. The cis/trans isomers, S O versus S–Me, existed in
the dibenzothiepin derivatives 5. TLC-separation on silica gel
furnished two kinds of pure samples (5a–1 in 41% and 5a–2 in
25% isolated yields). The same ring-contraction was observed
in the reaction of ethyl sulfonium salt 1b with methanolic KOH
Scheme 2 Reagents: (a) Cl3SiH ϩ LiAIH4; (b) Ph3P.
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This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b205588k

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lyzed during separation on silica gel. Analogous results were
observed for the isomer 5a–2 under the same conditions.
When a pure sample of 5a–1 or 5a–2 was allowed to stand
under the reaction conditions for 20 h, equilibration was
reached between 5a–1 and 5a–2, the ratio being the same value
(1.55) as that of the above products before purification. In the
IR spectra of both products, a characteristic absorption was
observed at νmax = 1025 cmϪ1 which is assignable to a stretching
vibration band for the sulfoxide group. In the 1H NMR spectra,
the CHSMe proton for 5a–1 is seen as a sharp singlet at δ 5.12
in CDCl3 solution. The slightly downfield shift relative to its
counterpart (δ 5.09) in 5a–2 is a consequence of its projection
into a region of the molecule where the deshielding anisotropies
of the sulfoxide group are exerting their effect. Therefore, the
major isomer 5a–1 is assigned to a trans geometry, which is
expected to have a comparatively strong anisotropic effect
if the model study is taken into consideration.
There are considered to be at least four types of stereo-
isomers of 5. Two are in the conformation (axial-like or
equatorial-like) of the methylthio- group in the seven-
membered ring (thiepin ring) and the other two are adopt the
relative stereochemistry (cis or trans) between the sulfoxide
group and the methylthio group. The orientation of the
S-methyl substituent can be described as axial-like or
equatorial-like in the seven-membered ring (subscript ax or eq)
as shown in Fig. 1. It is considered that cis/trans isomerization
Scheme 3
Fig. 1 The conformers of 5a–1 and 5a–2.
does not easily occur at room temperature but the axial/
equatorial interconversion via ring-inversion of the seven-
membered ring easily occurs at room temperature. Stereo-
chemistry of the major conformer indicated the difference of
chemical shifts of the CHSMe proton in 5a–1 and 5a–2.
The 1H NMR signals for the cis and trans isomers were
observed as the average values between those of the axial and
equatorial conformations at ambient temperature.
Rearrangement of 6-methyl-5H,7H-dibenzo[b,g][1,5]dithio-
cinium salt (2)
Treatment of 2 under the same conditions (methanolic KOH)
did not furnish 12, which had been expected from the
rearrangement of 1, but the structural isomer 6 in 29% yield
along with a small amount of 2-methoxymethylphenyl 2-methyl-
thiomethylphenyl sulfide (7) in 5% yield which was produced
by way of the ring-opening by nucleophilic substitution of 2
with methanol as shown in Scheme 3.
Since the structure of 6 could not be determined on the basis
of the spectral data, it was confirmed by comparing the spectra
with those of an authentic sample which was prepared by the
alternative route as shown in Scheme 4.
Scheme 4 Reagents: (a) LiAlH4 or LiAlD4; (b) SOCl2; (c) aq NaOH;
(d) MeSSMe ϩ LiAlH4; (e) LiAlH4 ϩ AlCl3; (f ) SO2Cl2; (g) methanolic
KOH.
15 in acetonitrile with methane thiolate prepared freshly from
dimethyl disulfide afforded thiepin derivative 12. No hydrogen
shift in the synthetic sequence was confirmed by preparation of
the α-deuterated derivatives (13-D, 15-D and 12-D) and
hydrolysis of 15 into 13. Furthermore 12 did not rearrange into
6 under the reaction conditions (in methanolic KOH at room
temperature for 4 h). On the other hand, 6 was prepared
independently by successive treatment of 14; reduction with
LiAlH4–AlCl3, chlorination with SO2Cl2 and substitution with
an MeS-anion. The spectral data of the compound, which was
Reduction of 11-oxo-dibenzothiepin derivative 14 with
LiAlH4 gave alcohol 13, followed by chlorination with SOCl2 to
give the corresponding chloride 15.8,9 Treatment of the chloride
J. Chem. Soc., Perkin Trans. 1, 2002, 2704–2711
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obtained by such an independent route, was perfectly consistent
with those of the rearranged product 6.
were synthesized by way of an alternative route as shown in
Scheme 6.
Reaction of o-tolualdehyde with 2-(2-bromophenyl)-4,4-
dimethyl-1,3-oxazole by means of Meyer’s procedure afforded
benzhydryl derivative 18 in excellent yield.10 Treatment of 18
with hydrochloric acid furnished phthalide derivatives 19,
which was ring-opened to give 8 by lithium methanethiolate in
HMPA solution. Methylation of 8 with diazomethane afforded
9. The spectral data of the compounds prepared by such an
alternative route were consistent with those of the rearranged
products 8 and 9.
Rearrangement of 6-methyl-12-oxo-7,12-dihydro-5H-dibenzo-
[c,f ]thiocinium salt (3)
The different rearrangement pattern between the sulfoxide
derivative 1 and the sulfide 2 can be attributed to the difference
of the electronic effect of these groups rather than the steric
effect in the starting materials 1 and 2. In order to clarify the
origin of the different rearrangements of 1 and 2, the related
derivative 3 containing a carbonyl group instead of a sulfoxide
group was prepared and treated under the same reaction condi-
tions. Reaction of 3 with methanolic KOH produced carboxylic
acid 8 in 45% yield along with the methyl ester 9 in 35% yield
instead of dibenzo[a,d]cycloheptene derivative 17 as shown
in Scheme 5. Methylation of 8 with diazomethane gave 9
Rearrangement of 10b-phenyl-10b,11-dihydro-6H-[1]benzo-
thieno[2,1-a][2]benzothiophenium perchlorate (4)
In order to clarify the importance of the transannular inter-
action in the flexible eight-membered ring systems such as 1–3,
the related rigid tetracyclic system 4 was prepared. There is a
possibility that a Stevens-type [1,2]rearrangement could occur
instead of the Sommelet–Hauser rearrangement from such a
rigid sulfonium ylide. In fact, the related system 4 was treated
under the same basic conditions (methanolic KOH) to afford 10
in high yield as shown in Scheme 7, while compound 20 which
Scheme 7
was expected from the Sommelet–Hauser rearrangement was
not observed.
Structural assignment of 10 is founded upon 1H NMR
spectral data. The benzyl protons appear as double doub-
lets (J = 15.0 and 1.5 Hz, 1H) at δ 3.10 and two doublets
(J = 15.0 Hz, 1H) at δ 3.21, and (J = 1.5 Hz, 1H) at δ 4.70. In the
1H NMR spectrum of 10 the following characteristic signals are
observed δ 2.45 (s, 3H), 3.80 (dd, J = 13.0 and 3.1 Hz, 1H) and
4.40 (d, J = 13.0 Hz, 1H) together with the other signals.
Due to the severe stereo-demand for a [2,3]sigmatropic
rearrangement in the ylide, the Stevens [1,2]rearrangement,
instead of the Sommelet–Hauser rearrangement, would occur
in the rigid tetracyclic derivative 4 (Scheme 8).11
Scheme 5
quantitatively. Structural assignments of products 8 and 9 were
founded upon the spectral data and the independent synthesis
(Scheme 6). In the H NMR spectrum of 9 in CDCl3 solution
the following characteristic signals are observed δ 1.94 (s, 3H),
2.25 (s, 3H), 3.74 (s, 3H) and 6.33 (s,1H) together with signals
for eight aromatic protons. The authentic compounds 8 and 9
1
Mechanistic considerations of the rearrangements
The rearrangements into the dibenzothiepin system of 1a and
1b are explained in terms of consecutive [2,3]- and [1,3]-
sigmatropic shifts (the Sommelet–Houser rearrangement) via
spirocyclic intermediates 23a,b as shown in Scheme 9.
In these rearrangements, the corresponding sulfonium ylides
21a and 21b were considered to be the first generated inter-
mediates for the process from 1a,b into 5a,b, respectively. The
anionic [2,3]sigmatropic shifts in 21a,b give spiro-23a,b by way
of a concerted process, followed by a [1,3] shift to afford the
final products 5a,b.
The rearrangement of dibenzothiepin 3 can also be explained
by assuming the same spirocyclic intermediate 24 formed via a
[2,3]sigmatropic shift of ylide 22. It is considered that the
[1,3]sigmatropic shift of the carbonyl group is a high-energy
Scheme
6
Reagents: (a) n-BuLi, o-CH3C6H5CHO; (b) HCl;
(c) MeSSMe ϩ LiAIH4, then HMPA; (d) CH2N2.
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Table 1 Calculated total energies of the spirocyclic intermediate 25 and the thiaspiro compound 26 along with relative energies
Compound
Ap.a
Eq.b
Total energy/a.u.
Relative energy/a.u.
Relative energy/kJ molϪ1
trans-25
cis-25
26
—
—
b,d
a,c
b,c
a,d
—
—
a,c
b,d
a,d
b,c
Ϫ1371.14931
Ϫ1371.14742
Ϫ1371.01863
Ϫ1371.02476
Ϫ1371.02675
Ϫ1371.02423
0.0 (std.)
0.0019
0.1307
0.1245
0.1225
0.1251
0.0 (std.)
4.97
342.89
326.63
321.36
328.17
a Apical positions of 26. b Equatorial positions of 26.
Scheme 8 A possible mechanism for the rearrangement of 4 into 10.
process compared with that of the sulfenyl group via a con-
certed process and that the carbonyl group is more reactive to
nucleophilic attack by methanol or hydroxide than the sulfenyl.
Therefore, the spirocyclic intermediate 24 resulted in the ring-
opening process via attack on the carbonyl carbon in the inter-
mediate 24 by a hydroxide anion and MeOH as shown in
Scheme 6, instead of a [1,3] shift of the carbonyl group.
On the other hand, a very strange and unique rearrangement
was observed in the sulfonium salt 2. The rearranged product
6 could not be explained by either a Sommelet–Houser
rearrangement or a Stevens rearrangement. Either the spiro-
cyclic intermediate 25 or the thiaspiro compound 26 as illus-
trated in Table 1 were assumed to explain the rearrangement of
2 into 6.6 We performed ab initio molecular orbital calculations
at the HF/6-31G* basis set. The calculated total energies and
relative energies from trans-25 are summarized in Table 1. The
HF methods predict the spirocyclic intermediate 25 to be
favoured by more than 320 kJ molϪ1
.
The difference in rearrangement reactions in these ring sys-
tems is understandable in terms of the electronic factor rather
than the steric factor. It is considered that the anionic carbon of
ylides 21 and 22 attacks transannularly the ipso carbon in the
aromatic ring which is substituted by an electron withrawing
group, in the sulfonium ion and 3, respectively. On the other
hand, the ipso carbon in sulfonium 2 is substituted by an elec-
tron donating group and is not reactive enough to be attacked
intramolecularly by the anionic carbon of the ylide. The form-
ation of the ring-opening (benzyl carbon) product 7 supports
this assumption. Furthermore there is a possibility that the
sulfide group in compound 2 assists heterolytic cleavage of the
benzyl carbon. In addition it can be assumed that this electron
deficient benzyl carbon attacks the ipso carbon to furnish the
spirocyclic intermediate 25 as shown in Scheme 10.
Scheme 9 A possible mechanism for the rearrangement of 1a,b and 3.
Theoretical considerations of the reaction intermediates by MO
calculations
We have performed molecular orbital calculations of these
various intermediates from the ylides 21a and 30 to the final
products 5 and 6, respectively. Ab initio calculations were
carried out at the Hartree–Fock (HF) level with the 6-31G*
basis set using the HONDO-2001 program package.12 The
geometry optimisation was performed for each of the inter-
mediates at the HF/6-31G*. Total energies for the most stable
conformer in each of the derivatives are shown in Tables 2 and
J. Chem. Soc., Perkin Trans. 1, 2002, 2704–2711
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Table 2 Calculated total energies of the intermediates 21a, 23a, 28,
product 5 and the possible product 29 along with the relative energies
with respect to 21a
Table 3 Calculated total energies of the intermediates 30, 31, 25, the
product 6 and the possible product 12 along with the relative energies
with respect to 30
Total
energy/a.u.
Relative
energy/a.u.
Relative energy/
kJ molϪ1
Compound
Total
energy/a.u.
Relative
energy/a.u.
Relative energy/
kJ molϪ1
Compound
30
31
25
12
6
Ϫ1371.09245
Ϫ1371.14445
Ϫ1371.14931
Ϫ1371.19484
Ϫ1371.19237
0.0 (std.)
Ϫ0.05200
Ϫ0.05686
Ϫ0.10239
Ϫ0.09992
0.0 (std.)
Ϫ136.54
Ϫ149.31
Ϫ268.86
Ϫ262.37
21a
23a
28
5
Ϫ1445.89676
Ϫ1445.94489
Ϫ1445.95349
Ϫ1445.99161
Ϫ1445.99779
0.0 (std.)
Ϫ0.04814
Ϫ0.05673
Ϫ0.09486
Ϫ0.10104
0.0 (std.)
Ϫ126.39
Ϫ148.97
Ϫ249.06
Ϫ265.29
29
the spirocyclic intermediate in spite of the dearomatization, fol-
lowed by the second step and the rearomatization to give the
final product 5. A similar calculation was carried out for the
rearrangement of the dithiocinium 2 (Table 3). In our previous
speculation of the rearrangement mechanism, we assumed that
the mechanism via [3,3]sigmatropic rearrangement from 31 into
25 gave 6.6 However, the energy difference between the spiro-
cyclic intermediate 31 and the previously postulated 25 was
only 13 kJ molϪ1 since the rearomatization did not occur in this
step. This difference is very small compared with that of the
stabilized energy (132 kJ molϪ1) in the [1,3]sigmatropic shift
from 31 to 12. Furthermore, the structural rigidity in the ring
system of of 31 might restrict the [3,3]sigmatropic rearrange-
ment.13 Therefore, it can be proposed that the reaction path
which rearranged directly from the sulfonium 2 into the spiro-
intermediate 25 gave the final product 6 as shown Scheme 10.
Experimental
All the melting points are uncorrected. IR spectra were
obtained with a Hitachi 215 grating IR spectrophotometer. 1H
NMR measurements were carried out on a Hitachi R-90H
instrument, using tetramethylsilane as the internal reference.
6-Methyl-12-oxo-5H,7H-dibenzo[b,g][1,5]dithiocinium
tetrafluoroborate (1a)
To a solution of 5H,7H-dibenzo[b,g][1,5]dithiocin 12-oxide4c,5
(114 mg, 0.44 mmol) in dichloromethane (5 mL) was added
excess methyl iodide (0.1 mL) and silver tetrafluoroborate (99.2
mg, 0.51 mmol) successively. The mixture was stirred at room
temperature for 8 h. After filtration and concentration, a col-
ourless solid (91.5 mg, 66%) of 1a was obtained. Recrystalliz-
ation from acetonitrile–dichloromethane gave a pure sample
1a: mp 243–246 ЊC; 1H NMR (δ CD3CN) 3.20 (s, 3H), 4.77, 5.35
(ABq, J = 14.1 Hz, 4H), 7.50–7.73 (m, 6H) and 8.03–8.18
(m, 2H). Found: C, 49.59; H, 3.94. Calcd for C15H15OS2BF4: C,
49.74; H, 4.17%.
Scheme 10 A possible mechanism for the rearrangement of 2 into 6.
3. The spirocyclic intermediate 23a would give the dibenzo-
thiepin derivative 5 through a [1,3]sigmatropic migration. The
[1,3]-sigmatropic migration in these systems gave the aromatic
dibenzo systems.
Because the constitutional elements of 21a, 23a, 28, 5a and
29 are the same as each other, it is possible to compare the
energy levels of these compounds as summarized in Table 2. In
the rearrangement from 21a into 5 the stabilized energy level
of the first step ([2,3]sigmatropic shift) was about 126 kJ molϪ1
and the second step ([1,3]-sigmatropic shift) was stabilized by
approximately 123 kJ molϪ1. It seems that the driving force of
the first step is caused by conversion of the unstable ylide into
6-Ethyl-12-oxo-5H,7H-dibenzo[b,g][1,5]dithiocinium
tetrafluoroborate (1b)
By means of the procedure described for 1a, 1b (19.5 mg, 26%)
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was obtained from 46.3 mg (0.24 mmol) of the corresponding
sulfoxide with excess ethyl iodide (0.1 mL) and silver tetrafluoro-
borate (46 mg, 0.24 mmol) in dichloromethane (3 mL). For 1b:
1H NMR (δ CD3CN) 1.66 (t, J = 7 Hz, 3H), 3.69 (q, J = 7 Hz,
2H), 4.75, 5.31 (ABq, J = 14.0 Hz, 4H), 7.4–7.7 (m, 6H) and
8.0–8.1 (m, 2H).
Rearrangement of 1a with methanolic potassium hydroxide
A mixture of 1a (137 mg, 0.399 mmol) and 1.25 g of potassium
hydroxide in 20 mL of methanol was stirred at room temper-
ature for 6 h. After solvent removal, the residue was dissolved in
dichloromethane and was washed with water before drying.
The organic solution was concentrated and thin layer chrom-
atographic separation on silica gel (n-hexane–ethyl acetate;
6 : 4) gave 45 mg (41%) of 5a–1 and 27 mg (25%) of 5a–2.
6-Methyl-5H,7H-dibenzo[b,g][1,5]dithiocinium
tetrafluoroborate (2)5
Physical data for 5a–1: colourless oil; νmax (neat) 1020 cmϪ1
;
1H NMR (δ CDCl3) 1.94 (s, 3H), 4.25, 4.94 (ABq, J = 14.5 Hz,
By means of the method described for 1a, 2 (140 mg, 86%) was
obtained from 139 mg (0.57 mmol) of 5H,7H-dibenzo-
[b,g][1,5]dithiocin2,4 in dichloromethane (3 mL). For 2: mp
2H), 5.12 (s, 1H), 7.15–7.60 (m, 7H) and 7.89–8.10 (m, 1H); 13
C
NMR (δ CDCl3) 16.5 (q), 57.4 (d), 58.5 (t), 127.5, 128.1, 128.3,
128.8, 129.3, 130.4, 131.1, 132.3 and 132.4; mass (m/z) 274
(Mϩ, 9%), 241 (Mϩ Ϫ 33, 16%), 228 (Mϩ Ϫ 46, 78%), 211
(Mϩ Ϫ 63, 44%) and 178 (Mϩ Ϫ 96, 100%). Found: C; 65.48, H;
5.22. Calcd for C15H14OS2: C, 65.66; H, 5.14.
1
212.5–214 ЊC; νmax (KBr) 1050 cmϪ1; H NMR (δ CDCl3) 3.19
(s, 3H), 4.56, 5.72 (ABq, J = 13.0 Hz, 4H), 7.33–7.65 (m, 6H),
and 7.85–8.06 (m, 2H). Found: C, 52.15; H, 4.49. Calcd for
C15H15S2BF4: C, 52.04; H, 4.37%.
Physical data for 5a–2: colourless oil; νmax (neat) 1020 cmϪ1
;
1H NMR (δ CDCl3) 1.96 (s, 3H), 4.37, 5.82 (ABq, J = 13.0 Hz,
2H), 5.09 (s, 1H), 7.20–7.60 (m, 7H) and 7.9–8.0 (m, 1H); mass
(m/z) 274 (Mϩ) and the same fragments as those of 5a–1.
Found: C, 65.60; H, 5.07. Calcd for C15H14OS2: C, 65.66; H,
5.14%.
6-Methyl-12-oxo-7,12-dihydro-5H-dibenzo[c,f ]thiocinium
hexachloroantimonate (3)
A solution of 2,2Ј-dimethylbenzophenone (5.31 g, 25.3 mmol),
N-bromosuccinimide (10.13 g, 59.6 mmol) and 0.1 g of benzoyl
peroxide in 250 mL of carbon tetrachloride was irradiated with
a sun-lump for 9 h at reflux. After filtration, the filtrate was
dissolved in a solution of 10.8 g of sodium sulfide nonahydrate
in 400 mL of methanol. The mixture was heated at reflux for
15 h, followed by concentration to give a yellow solid. The crude
product was dissolved in dichlormethane and washed with
water. After drying over sodium sulfate and evaporation 2.68 g
(44%) of 6-methyl-12-oxo-7,12-dihydro-5H-dibenzo[c,f]thiocin
was obtained. Recrystallization from n-hexane–dichloro-
methane gave the pure sample: mp 211.5–213 ЊC; νmax (KBr)
Rearrangement of 1b with methanolic potassiun hydroxide
By means of the above procedure, 1b (19 mg, 0.054 mmol) was
rearranged into a mixture of 5b–1 and 5b–2. The resultant oil
was subjected to preparative layer chromatography on silica gel
(n-hexane–ethyl acetate; 1 : 1). There were isolated 2.6 mg (18%)
1
of 5b–1 and 5.1 mg (35%) of 5b–2. Spectral data for 5b–1; H
NMR (δ CDCl3) 1.18 (t, J = 7.3 Hz, 3H), 2.35 (q, J = 7.3 Hz,
2H), 4.25, 4.97 (ABq, J = 14.5 Hz, 2H), 5.24 (s, 1H), 7.2–7.6 (m,
7H) and 7.9–8.0 (m, 1H); mass (m/z) 288 (Mϩ), 211 (Mϩ Ϫ 77,
100%). For 5b–2; 1H NMR (δ CDCl3) 1.19 ( t, J = 7.4 Hz, 3H),
2.36 (dq, J = 7.4 and 2.8 Hz, 2H), 4.38, 5.80 (ABq, J = 12.9 Hz,
2H), 5.21 (s, 1H), 7.2–7.6 (m, 7H) and 7.9–8.0 (m, 1H); Mass
(m/z) 288 (Mϩ) and the same fragments as those of 5b–1.
1
1625 and 1590 cmϪ1; H NMR (δ CDCl3) 3.49 (s, 4H), 7.2–7.7
(m, 6H) and 7.9–8.0 (m, 2H); 13C NMR (δ CDCl3) 31.2, 127.2,
129.7, 129.8, 133.3, 135.3, 138.9 and 193.6. Found: C, 75.23; H,
4.96. Calcd for C15H12OS: C, 74.97; H, 5.03%.
A mixture of the corresponding keto sulfide (56 mg, 0.23
mmol) and trimethyloxonium hexachloroantimonate (95 mg,
0.24 mmol) in dichloromethane (3 mL) was stirred at Ϫ78 ЊC
for 15 h under a nitrogen atmosphere. The mixture was filtered
and the solid was washed with dichloromethane. A pure sample
(60 mg, 43%) of 3 was obtained by recrystallization from aceto-
nitrile–dichloromethane: mp 155–160 ЊC (decomp.); νmax (KBr)
1640 cmϪ1; 1H NMR (δ CD3CN) 2.54 (s, 3H), 4.08, 4.46 (ABq,
J = 14.0 Hz, 4H), 7.4–7.6 (m, 2H), 7.7–7.9 (m, 4H) and 8.1–8.2
(m, 2H). Found: C, 32.75; H, 2.54. Calcd for C16H15OSSbCl6: C,
32.58; H, 2.56%.
Rearrangement of 2 with methanolic potassium hydroxide
By means of a similar procedure to 1a, treatment of 2 (135 mg,
0.468 mmol) with 0.7 g of potassium hydroxide in 5 mL of
methanol afforded 29.2 mg (29%) of 6 and 5.2 mg (5%) of
2-methoxymethylphenyl 2-methylthiomethylphenyl sulfide (7),
after thin layer chromatographic separation on silica gel
(n-hexane–ether; 9 : 1). For 6: mp 86–87 ЊC; 1H NMR (δ CDCl3)
2.16 (s, 3H), 4.10, 4.60 (ABq, J = 13.9 Hz, 2H), 5.42 (s, 1H) and
7.0–7.3 (m, 8H); mass (m/z) 258 (Mϩ, 7%), 211 (Mϩ Ϫ47,
100), 178 (Mϩ Ϫ-80, 68%). Found: C, 69.79; H, 5.23. Calcd
1
10b-Phenyl-10b,11-dihydro-6H-[1]benzothieno[2,1-a][2]benzo-
for C15H14S2: C, 69.72; H, 5.46%. For the sulfide 7: H NMR
thiophenium perchlorate (4)
(δ CDCl3) 2.05 (s, 3H), 3.41 (s, 3H), 3.86 (s, 2H), 4.57 (s, 2H)
and 7.1–7.6 (m, 8H); Mass (m/z) 290 (Mϩ, 46%), 211 (Mϩ Ϫ 79,
100%).
To a solution of Grignard reagent which was prepared from
0.52 mL of bromobenzene and 116 mg (4.8 mmol) of mag-
nesium in 4 mL of THF, the corresponding keto sulfide (1.0 g,
4.2 mmol) in 20 mL of THF was added at 0 ЊC. The mixture
was stirred at reflux for 1 h and poured into ice-water. The
product was extracted into dichloromethane. The organic phase
was washed with saturated ammonium chloride solution. Fol-
lowing drying and evaporation, 1.2 g (90%) of 7,12-dihydro-12-
hydroxy-12-phenyl-5H-dibenzo[c,f]thiocin was obtained: mp
Rearrangement of 3 with methanolic potassium hydroxide
A solution of 3 (280 mg, 0.477 mmol), 0.5 g of potassium
hydroxide in 30 mL of methanol was stirred at room temper-
ature overnight. The mixture was neutralized and extracted
with dichloromethane. After evaporation of the solvent, the
residue was dissolved in ether and carboxylic acid 9 was
extracted into aqueous sodium carbonate solution. The acid 9
was extracted again into ether after acidification. The organic
layers were dried and concentrated to give 8 (58.4 mg, 45%) and
9 (47.1 mg, 35%), respectively. For 8: 1H NMR (δ CDCl3)
1.94 (s, 3H), 2.25 (s, 3H), 6.40 (s, 1H), 7.0–7.8 (m, 7H), 7.96 (dd,
J = 7.3 and 1.3 Hz, 1H), and 10.3 (s, 1H). Found: C, 70.55; H,
148–150 ЊC; νmax (KBr) 3370, 1440 and 1000 cmϪ1; H NMR
1
(δ CDCl3 at Ϫ30 ЊC) 2.47 (s, 1H), [3.59, 3.91 (ABq, J = 13.0 Hz)
and 3.50, 3.60 (ABq, J = 13.3 Hz), 4H], 6.59 (d, J = 8.0 Hz, 1H)
and 6.9–7.6 (m, 12H). Found: C, 79.09; H, 5.82. Calcd for
C21H18OS: C, 79.21; H, 5.70%.
Treatment of the above alcohol in dichloromethane with 70%
aqueous HClO4 solution gave the sulfonium salt (4) in quanti-
tative yield: mp >300 ЊC; 1H NMR (δ CD3CN) 4.91, 5.21 (ABq,
J = 16.0 Hz, 4H) and 7.1–7.5 (m, 13H). Found: C, 63.22; H,
4.30. Calcd for C21H17O4SCl: C, 62.92; H, 4.27%.
1
5.96. Calcd for C16H16O2S: C, 70.57; H, 5.92. For 9: H NMR
(δ CDCl3) 1.94 (s, 3H), 2.25 (s, 3H), 3.74 (s, 3H), 6.33 (s, 1H),
7.0–7.6 (m, 7H) and 7.80 (dd, J = 7.3 and 1.3 Hz, 1H); mass
(m/z) 286 (Mϩ, 9%), 239 (Mϩ Ϫ 47, 100%).
J. Chem. Soc., Perkin Trans. 1, 2002, 2704–2711
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Treatment of 8 (58.4 mg, 0.215 mmol) with excess diazo-
methane in ether solution afforded 9 in quantitative yield.
(0.3 mL) was added excess thionyl chloride (0.3 mL). The reac-
tion mixture was stirred at room temperature for 30 min and
concentrated to give chloride 15.9 The crude sample of 15 was
dissolved 1 mL of DMF and the solution was treated with
methane thiolate prepared from dimethyl disulfide (0.1 mL) and
lithium aluminium hydride (35 mg, 0.92 mmol) in ether (2 mL).
The mixture was stirred at room temperature for 1 day and
poured into ice-water. Workup and TLC separation on silica gel
afforded 42 mg (72%) of an oily product 12. Found: C, 69.68;
H, 5.43. Calcd for C15H14S2: C, 69.72; H, 5.46%.
Rearrangement of 4 with methanolic potassium hydroxide
By means of a similar procedure to 1a, treatment of 4 (53 mg,
0.13 mmol) with 0.25 g of potassium hydroxide in 3 mL
methanol gave 37 mg of 10 (93%): 1H NMR (δ CDCl3) 3.10 (dd,
J = 15.0 and 1.5 Hz, 1H), 3.21 (d, J = 15.0 Hz, 1H), 4.70 (d,
J = 1.5 Hz, 1H) and 6.7–7.4 (m, 13H); mass (m/z) 300 (Mϩ), 267
(Mϩ Ϫ 33, 94%). Found: C, 84.25; H, 5.32. Calcd for C21H16S:
C, 84.00; H, 5.37%.
11-Deutero-11-methylthio-6,11-dihydrodibenzo[b,e]thiepin
(12-D)
Deoxygenation and demethylthiolation of 5a–1 and 5a–2
By the same methodology, 12-D was obtained in 86% yield:
1H NMR (δ CDCl3) 2.00 (s, 3H), 3.71, 5.35 (ABq, J = 14 Hz,
2H) and 6.93–7.35 (m, 8H); mass (m/z) 258 (Mϩ, 12%), 212
(Mϩ Ϫ 46, 95%), 211 (Mϩ Ϫ 47, 100%), 179 (Mϩ Ϫ 79, 74%).
(i) Treatment of a mixture of 5a–1 and 5a–2 (85 mg, 0.31 mmol)
with HSiCl3 (0.5 mL)–LiAlH4 (20 mg) in 3 mL of ether at room
temperature for 2 h afforded dibenzothiepin derivative (11, 27
mg, 41%) along with a small amount of 12 (3 mg, 3%). For 11;
1H NMR (δ CDCl3) 4.12 (s, 2H), 4.25 (s, 2H), 6.9–7.3 (m, 8H);
1
Mass (m/z) 212 (Mϩ, 78%), 178 (Mϩ Ϫ 34, 100%). For 12; H
Hydrolysis of the chloride 15 under basic conditions
NMR (δ CDCl3) 2.00 (s, 3H), 3.71, 5.35 (ABq, J = 14.0 Hz, 2H),
5.07 (s, 1H) and 6.93–7.35 (m, 8H); Mass (m/z) 258 (Mϩ, 10%),
211 (Mϩ Ϫ 47, 75%), 210 (Mϩ Ϫ 48, 80%), 178 (Mϩ Ϫ 80,
100%). The spectra were superimposable upon those of authen-
tic samples of 11 and 12 which were prepared by way of an
alternative procedure, respectively.
(ii) Reaction of 5a–1 (45 mg, 0.16 mmol) with triphenyl-
phosphine (100 mg)–carbon tetrachloride (2 mL) reagents in
acetonitrile (4 mL) in the presence of trifluoroacetic acid
(0.1 mL) afforded a mixture of deoxygenated products. Thin
layer chromatographic separation (n-hexane–ethyl acetate; 1 : 1)
gave 16 mg (38 %) of 12, 7 mg (19%) of 13 and the recovered
substrate 5a–1 (9 mg, 20%).
Treatment of 15, which was prepared from 13 (102 mg, 0.443
mmol), with 15% aqueous potassium hydroxide (0.5 mL) in
5 mL of acetonitrile gave 101 mg of 13.
6,11-Dihydrodibenzo[b,e]thiepin (11)
To a stirred suspension of LiAlH4 (390 mg, 10.3 mmol) and
anhydrous aluminium chloride (2.8 g, 21 mmol) in anhydrous
ether (5 mL) was added dropwise a solution of 14 (900 mg,
4.2 mmol) in the same solvent (1 mL). The mixture was stirred
at reflux for 1 h before the excess hydride was decomposed with
water. Workup in the predescribed manner gave 380 mg (45%)
of a colourless oil 11. Found: C, 69.69; H, 5.47. Calcd for
C15H14S2: C, 69.72; H, 5.46%.
(iii) By means of an analogous procedure, treatment of 5a–2
(27 mg, 0.099 mmol) with triphenylphosphine (60 mg)–carbon
tetrachloride (1 mL) afforded 8 mg (32%) of 12, 9 mg (41%) of
13 and the starting material 5a–2 (6 mg, 22%).
6-Methylthio-6,11-dihydrodibenzo[b,e]thiepin (6)
To a solution of 11 (109 mg, 0.51 mmol) in 3 mL of dichloro-
methane was added sulfonyl dichloride (0.045 mL, 0.56 mmol).
After being stirred for 2 h at reflux, the reaction mixture was
concentrated and the residue was dissolved in 4 mL of
acetonitrile. Without further purification, reaction of the crude
sample 16 with methane thiolate prepared as predescribed
manner afforded an oily product containing 6. Thin layer
chromatographic separation on silica gel (n-hexane–ether; 9 : 1)
gave 20 mg of a pure sample (6, 20 mg) in 15% yield based on
11.
Equilibration between 5a–1 and 5a–2
A solution of 5a–1 (51 mg, 0.19 mmol) in methanol (6 mL)
containing 0.3 g of potassium hydroxide was allowed to stand
at room temperature for 20 h to result in equilibrium between
5a–1 and 5a–2. After the predescribed workup, the ratio was
determined to be 5a–1 : 5a–2 = 1.54, evaluated from the integral
1
value of each methyl proton in the H NMR spectrum. By the
same methodology, treatment of 5a–2 (34 mg, 0.12 mmol) with
potassium hydroxide (0.4 g) in 5 mL methanol afforded a
mixture of 5a–1 and 5a–2, the ratio being 1.57.
2-Methyl-2Ј-(4,4-dimethyl-1,3-oxazol-2-yl)diphenylmethyl
alcohol (18)
11-Hydroxy-6,11-dihydrodibenzo[b,e]thiepin (13)
To a solution of 4,4-dimethyl-2-(2-bromophenyl)-1,3-oxazole10
(4.0 g, 15.3 mmol) in 20 mL of THF was added 13 mL (19.5
mmol) of 1.5 M n-butyllithium in hexane solution at Ϫ78 ЊC
under a nitrogen atmosphere. The mixture was stirred for
20 min at the same temperature and warmed to room temper-
ature. After being cooled again to Ϫ78 ЊC, 2.4 g (20 mmol) of
o-tolualdehyde in 20 mL THF was introduced into the anion
solution. The mixture was stirred at Ϫ78 ЊC for 30 min and then
at room temperature for 3 h. After workup, column chromato-
graphic separation on silica gel (ether–hexane; 3 : 10 and then
ethyl acetate) furnished a pure sample 18 (4.6 g, 99%): νmax
To a stirred suspension of LiAlH4 (0.7 g, 18.4 mmol) in
anhydrous THF (80 mL) was added dropwise a solution
of 6,12-dihydro-12-oxo-dibenzo[b,e]thiepin8 (14) (3.60 g, 15.8
mmol) in the same solvent (20 mL). The mixture was stirred at
0 C for 1 h and at reflux for 3 h before the excess hydride was
decomposed. Workup in the usual manner gave 3.55 mg (98%)
1
of a solid 13: mp 108–109 ЊC (lit.,8 107.5–109 ЊC); H NMR
(δ CDCl3) 2.6–3.2 (br s, 1H), 4.10, 4.34 (ABq, J = 13.6 Hz, 2H),
5.96 (s, 1H) and 6.9–7.5 (m, 8H).
(neat) 3300, 3000, 1650, 1470, 1360, 1320, 1230 and 1050 cmϪ1
;
11-Deutero-11-hydroxy-6,11-dihydrodibenzo[b,e]thiepin (13-D)
1H NMR (δ CDCl3) 1.39 (s, 3H), 1.43 (s, 3H), 1.97 (s, 3H), 4.15,
4.18 (ABq, J = 8.0 Hz, 2H), 6.20 (s, 1H) and 6.7–7.9 (m, 8H);
mass (m/z) 295 (Mϩ, 93%), 223 (Mϩ Ϫ 72, 100%).
Reduction of a 510 mg (2.24 mmol) sample of 14 with 52 mg
(1.37 mmol) of lithium aluminium deuteride in 5 mL of ether as
described above afforded 491 mg (95%) of 13-D: 1H NMR
(δ CDCl3) 2.1–3.2 (br s, 1H), 4.10, 4.34 (ABq, J = 14.4 Hz, 2H)
and 7.0–7.7 (m, 8H); mass (m/z) 231 (Mϩ).
3-(o-Tolyl)-1-oxy-(3H)-isobenzofuran (19)
A mixture of 18 (1.5 g, 5.1 mmol) and 30 mL of 3 M hydro-
chloric acid in 30 mL of methanol was heated at reflux for 1 h.
After concentration of the solution, the product was extracted
11-Methylthio-6,11-dihydrodibenzo[b,e]thiepin (12)
To a solution of 13 (55 mg, 0.24 mmol) in dichloromethane
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2 Y. D. Wu and K. N. Houk, J. Org. Chem., 1991, 56, 5657.
into ether. The organic phase was washed with water prior to
drying and evaporated. The residue was purified by preparative
thin layer chromatography to yield 1.1 g (96%) of 19: Mp 113
3 (a) E. Vedejs, Acc. Chem. Res., 1984, 17, 358; (b) I. E. Marko,
Comprehensive Organic Synthesis, eds B. M. Trost and I. Freming,
Pergamon Press, Oxford, 1991, vol. 3, p. 913; (c) R. Bruckner,
Comprehensive Organic Synthesis, eds B. M. Trost and I. Freming,
Pergamon Press, Oxford, 1991, vol. 6, p. 873; (d ) R. Berger,
J. W. Ziller and D. L. Van Vranken, J. Am. Chem. Soc., 1998, 120,
841; (e) M. Hori, T. Kataoka, H. Shimizu, O. Komatsu and
K. Hamada, J. Org. Chem., 1987, 52, 3668; ( f ) N. Shirai,
F. Sumiyama, Y. Sato and M. Hori, J. Org. Chem., 1989, 54, 83;
(g) F. Sumiya, N. Shirai and Y. Sato, Chem. Pharm. Bull., 1991, 39,
36; (h) T. Nishimura, C. Zhang, Y. Maeda, N. Shirai, S. Ikeda and
Y. Sato, Chem. Pharm. Bull., 1999, 47, 267; (i) K. Fujiwara,
Y. Maeda, N. Shirai and Y. Sato, J. Org. Chem., 2000, 65, 7055;
(j) M. G. Burdon and J. G. Moffatt, J. Am. Chem. Soc., 1965, 87,
4656; (k) R. A. Olofson and J. P. Marino, Tetrahedron, 1971, 4195.
4 (a) K. Ohkata, K. Takee and K.-y. Akiba, Tetrahedron Lett., 1983,
24, 4859; (b) K. Ohkata, K. Takee and K.-y. Akiba, Bull. Chem. Soc.
Jpn., 1985, 58, 1946; (c) K. Ohkata, K. Okada and K.-y. Akiba,
Tetrahedron Lett., 1985, 26, 4491; (d ) K.-y. Akiba, K. Takee,
Y. Shimizu and K. Ohkata, J. Am. Chem. Soc., 1986, 108, 6320.
5 K. Ohkata, K. Okada and K.-y. Akiba, Heteroat. Chem., 1995, 6,
145.
1
ЊC; νmax 300, 1770, 1470, 1300, 1220 and 1170 cmϪ1; H NMR
(δ CDCl3) 2.50 (s, 3H), 6.65 (s, 1H) and 6.8–8.0 (m, 8H); mass
(m/z) 224 (Mϩ, 100%) Found: C, 80.18; H, 5.50. Calcd for
C15H12O2: C, 80.34; H, 5.39%.
2-Carboxy-2Ј-methyldiphenylmethyl methylsulfide (8)
To a solution of methane thiolate prepared from dimethyl
disulfide (200 mg, 2.1 mmol) and LiAlH4 (20 mg, 0.53 mmol) in
THF by heating at reflux for 1 day, was added a solution of 22
(100 mg, 0.45 mmol) in 5 mL of hexamethylphosphoric tri-
amide (HMPA). The mixture was stirred at 100 ЊC for 6 h and
poured into ice-water. The product was taken up in ether. The
organic phase was washed with diluted hydrochloric acid and
the acid product was extracted into aqueous sodium carbonate
solution. After neutralization of the alkaline solution, the
aqueous phase was extracted with ether. The combined extracts
were dried over sodium sulfate and evaporated to yield 8 (37.4
mg, 29%). Treatment of 8 (30.4 mg, 0.112 mmol) with excess
diazomethane in ether solution afforded 9 in quantitative yield.
The spectral data were consistent with those of 8 and 9, which
were obtained from rearrangement of 3.
6 Preliminary report: K. Ohkata, K. Okada, K. Maruyama and
K.-y. Akiba, Tetrahedron Lett., 1986, 27, 3257.
7 R. P. Gellatly, W. D. Ollis and I. O. Sutherland, J. Chem. Soc.,
Perkin Trans.1, 1976, 913.
8 M. Hori, T. Kataoka, H. Shimizu and K. Onogi, Yakugaku Zasshi,
1978, 98, 1333 (Chem. Abstr., 1979, 90, 54797s).
9 V. Valenta, F. Kvis, J. Nemec and M. Protiva, Collect. Czech. Chem.
Commun., 1979, 44, 2689 (Chem. Abstr., 1980, 92, 128699b).
10 A. I. Meyers, D. L. Temple, D. Haidukewych and E. D. Mihelich,
J. Org. Chem., 1974, 39, 2787.
11 (a) B. M. Trost and L. S. Melvin, Jr, Sulfur Ylide: Emerging
Synthetic Intermediates, Academic Press, New York, 1975;
(b) E. Block, Reaction of Organosulfur Compounds, Academic Press,
New York, 1978; (c) A. Robert and M.-T. Lucas-Thomas, J. Chem.
Soc., Chem. Commun., 1980, 629; (d ) J. F. Biellmann, J. B. Ducep
and D. Schirlin, Tetrahedron, 1979, 36, 1249.
Acknowledgements
The authors are grateful to Professor M. Aida for her helpful
advice on MO calculations. The calculations were carried out
in part at the Research Center for Computational Science,
Okazaki National Research Institute.
12 M. Dupuis A. Marquez E. R. Davidson, HONDO 2001, based on
HONDO 95, available from the Quantum Chemistry Program
Exchange, Indiana University.
13 (a) H. Lange, P. Loeb, T. Herb and R. Gleiter, J. Chem. Soc.,
Perkin Trans. 2, 2000, 1155; (b) D. J. Tantilllo and R. Hoffmann,
J. Org. Chem., 2002, 67, 1421.
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