Electrophilic cyclisation of bis(4-methoxybenzylthio)acetylene - Competition between Ar2-6 and Ar1-5 routes, yielding 1H-2-benzothiopyrans or spiro derivatives of cyclohexadienone

Article abstract of DOI:10.1002/1099-0690(200301)2003:1<47::AID-EJOC47>3.0.CO;2-B

Treatment of bis(4-methoxybenzylthio)acetylene (1) with iodine monochloride yields different products in the presence or absence of nucleophiles such as water or alcohols. Normally, the electrophilic cyclisation of bis(benzylthio)acetylenes produces 1H-2-benzothiopyrans 2 by intramolecular ortho attack on the aromatic ring by a vinyl cation formed in situ (Ar₂-6 cyclisation). In the case of 1, however, the high electron density in the ipso position of the aromatic ring favours ipso attack (Ar₁-5 route). The fate of the ipso σ complex is determined by the presence or absence of nucleophiles in the reaction medium. When nucleophiles are excluded, the σ complex is stabilised by 1,2-migration and formation of 1H-2-benzothiopyran 2a. In the presence of water, the σ complex yields spirocyclohexadienone dihydrothiophenes 3a and 3d. In the presence of 3-methylbenzyl alcohol, the methoxy substituent of the 2-benzothiopyran ring is exchanged by the 3-methylbenzyloxy group in product 2d. These findings are consistent with the formation of 2a, 2c, 2d and 2f by ipso and not ortho - attack on the 4-methoxyphenyl ring. Similar results were obtained both with ICl and from a proton-induced cyclisation. In one-pot syntheses, 3a and 3d were transformed into 2-benzothiopyrylium salts 4a and 4b by tritylium tetrafluoroborate, and 3a and 3b were rearranged into the 6-hydroxy-substituted 2-benzothiopyrans 2b and 2g by proton catalysis. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/1099-0690(200301)2003:1<47::AID-EJOC47>3.0.CO;2-B

FULL PAPER
Electrophilic Cyclisation of Bis(4-methoxybenzylthio)acetylene ؊ Competition
Between Ar -6 and Ar -5 Routes, Yielding 1H-2-Benzothiopyrans or Spiro
2
1
Derivatives of Cyclohexadienone
[
a]
[b]
[b]
[b]
Thomas R. Appel, Nasser A. M. Yehia, Ute Baumeister, Helmut Hartung,
[b]
[b]
[b]
Ralph Kluge, Dieter Ströhl, and Egon Fanghänel*
Keywords: Aromatic substitution / Carbocations / Cyclohexadienones / Rearrangement / Spiro compounds
Treatment of bis(4-methoxybenzylthio)acetylene (1) with
iodine monochloride yields different products in the presence
or absence of nucleophiles such as water or alcohols. Norm-
ally, the electrophilic cyclisation of bis(benzylthio)acetylenes
In the presence of 3-methylbenzyl alcohol, the methoxy sub-
stituent of the 2-benzothiopyran ring is exchanged by the 3-
methylbenzyloxy group in product 2d. These findings are
consistent with the formation of 2a, 2c, 2d and 2f by ipso −
produces 1H-2-benzothiopyrans 2 by intramolecular ortho at- and not ortho − attack on the 4-methoxyphenyl ring. Similar
tack on the aromatic ring by a vinyl cation formed in situ results were obtained both with ICl and from a proton-in-
Ar -6 cyclisation). In the case of 1, however, the high elec- duced cyclisation. In one-pot syntheses, 3a and 3d were
tron density in the ipso position of the aromatic ring favours
ipso attack (Ar -5 route). The fate of the ipso σ complex is
(
2
transformed into 2-benzothiopyrylium salts 4a and 4b by tri-
tylium tetrafluoroborate, and 3a and 3b were rearranged into
the 6-hydroxy-substituted 2-benzothiopyrans 2b and 2g by
proton catalysis.
1
determined by the presence or absence of nucleophiles in
the reaction medium. When nucleophiles are excluded, the
σ complex is stabilised by 1,2-migration and formation of 1H-
2-benzothiopyran 2a. In the presence of water, the σ complex
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
yields spirocyclohexadienone dihydrothiophenes 3a and 3d.
Germany, 2003)
Introduction
tramolecular ipso attack on the 4-methoxyphenyl ring in 1
by the intermediate vinyl cation (Ar -5 pathway), which
1
yields spiro derivatives 3. For this ipso pathway, the pres-
ence of nucleophiles such as water in the reaction medium
is necessary. In order to obtain an insight into the mechan-
ism of the cyclisation in the presence of iodine monochlor-
ide, methanol from the reaction medium was replaced by 3-
methylbenzyl alcohol. In this case the nucleophilic alcohol
was introduced into the 1H-2-benzothiopyran 2d as a
benzyloxy substituent, identified by a NOESY experiment.
Conclusions regarding the mechanism have been drawn.
The spiro derivatives 3 are valuable synthons. Their re-
arrangement into 1H-2-benzothiopyran derivatives with
new substitution patterns is described.
We recently described an efficient synthesis of 1H-2-
benzo- and 1H-2-naphthothiopyrans involving a ring-clos-
ure of symmetrical bis(arylmethylthio)acetylenes in the
presence of iodine monochloride or bromine, with meth-
anol/chloroform as reaction medium.[1] In a related cyclis-
ation of dialkynyl sulfides, 2H-benzothiopyran derivatives
[
2]
were obtained. These Ar -6 cyclisations were regarded as
2
intramolecular electrophilic substitutions of the aromatic
ring by a vinyl cation formed in situ from the acetylenes
and halonium ions. In agreement with this, when bis(4-me-
thoxybenzylthio)acetylene (1) was treated with iodine mon-
ochloride, 3-iodo-6-methoxy-4-(4-methoxybenzylthio)-1H-
benzothiopyran (2a) was produced in good yield.[ In view
of the known Ar -6/Ar -5 (ortho/ipso) competition in elec-
1]
2
1
trophilic cyclisation and substitution reactions of electron- Results
rich aromatic ring systems,[
of 1 in the presence either of iodine monochloride or of
protons in more detail. It was found that Ϫ as well as the conditions that had resulted in electrophilic Ar -6 cyclis-
3Ϫ5]
we studied the cyclisation
Bis(4-methoxybenzylthio)acetylene (1) was subjected to
2
1
H-2-benzothiopyran pathway Ϫ there is indeed also an in- ation of other symmetrically substituted bis(arylmethyl-
[
1]
thio)acetylenes. However, depending on the conditions,
different products or mixtures were observed (Scheme 1).
Only with strict exclusion of water (i) was the expected
benzothiopyran 2a obtained in high yield (84%). As a by-
product, traces of 1H-2-benzothiopyran 2aЈ were formed by
[
[
a]
Institute for Molecular Biotechnology,
Beutenbergstrasse 11, 07745 Jena, Germany
Department of Chemistry, Martin Luther University Halle-
Wittenberg,
b]
0
6099 Halle, Germany
Eur. J. Org. Chem. 2003, 47Ϫ53  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0101Ϫ0047 $ 20.00ϩ.50/0
47

E. Fanghänel et al.
FULL PAPER
proton-induced cyclisation of 1. Compound 2aЈ was identi-
1
fied by H NMR spectroscopy by comparison of its spec-
trum with that of an authentic specimen. In the presence of
small amounts of water (ii), the spiro compound 3a became
the main product. By-products were 2a and the 6-hydroxy-
3-iodo-substituted 1H-2-benzothiopyran 2b. The 1H-2-
benzothiopyran 2b was formed (iii) from 3a by a proton-
catalysed rearrangement (see cyclohexadienone/phenol re-
[
4,6,7]
arrangement),
as verified by an independent experi-
ment (treatment of 3a with trifluoroacetic acid in acetonitr-
ile). Use of sodium bicarbonate together with water (iv)
shifted the product relation in favour of 3a.
Scheme 2. Electrophilic cyclisation of 1 in the presence of ICl in
1
C
2
H
5
OH/CH
2
Cl
2
; * yields according to H NMR analysis
The structure of 3a was deduced from its H and 13C
1
NMR spectroscopic data and the precise molecular struc-
ture was established by an X-ray analysis (Figure 1). The
bond angles around the spiro atom are weakly distorted
tetrahedral [range 105.3(3)Ϫ112.1(3)°]. Within the crystal,
the molecules are connected by I1···O1 contacts of 2.949(4)
˚
A, considerably shorter than the sum of the corresponding
˚
[8]
van der Waals radii (3.50 A) and arranged in chains run-
ning parallel to the crystallographic y axis (Figure 2). The
chains are stacked in the x direction and neighbouring
stacks of chains are interlocked by the methoxybenzyl frag-
ments of the molecules.
Scheme 1. Electrophilic cyclisation of bis(4-methoxybenzyl-
3 2 2
thio)acetylene (1) in the presence of ICl in CH OH/CH Cl with
or without water in the reaction medium
Figure 3. Molecular structure of 3a (displacement ellipsoids at the
5
0% probability level, H atoms as small circles of arbitrary size);
In dry ethanol/dichloromethane, the spirocyclic ketone 3a
˚
selected bond lengths [A]: C1ϪC2 1.536(5), C1ϪC4 1.550(5),
was formed as intermediate and rearranged into the isolated C1ϪC5 1.491 (5), C1ϪC9 1.510 (5), C3ϪI1 2.074(4), C7ϪO1
1.216(5)
product 2b (Scheme 2). In addition, the 6-ethoxy-substi-
tuted 1H-2-benzothiopyran 2c was obtained and its struc-
ture was elucidated by NOESY experiments. An NOE was
To elucidate the mechanism of the cyclisation reaction of
found between 5-H and the methylene protons of the 6- 1 in the presence of ICl, the methanol of the reaction me-
ethoxy group.
dium was replaced by 3-methylbenzyl alcohol (Scheme 3).
48
Eur. J. Org. Chem. 2003, 47Ϫ53

Electrophilic Cyclisation of Bis(4-methoxybenzylthio)acetylene
FULL PAPER
Figure 2. Molecular packing in the crystals of 3a; I···O interactions are denoted by broken lines
This alcohol was chosen in order to avoid β-elimination
from an expected ipso σ complex and to use the methyl and/
or methylene group as indicators in the NMR spectroscopic
product analysis. Under the standard conditions for the
formation of 1H-2-benzothiopyrans a mixture of products
was obtained. Separation of the individual compounds by
column chromatography on silica gel was only partially suc-
1
cessful. By comparison of the H NMR spectra of separ-
ated fractions containing enriched components with the
spectra of 2a and 3a, it was possible to rule out that the
latter compounds had been formed in this experiment.
From some fractions the 6-(3-methylbenzyloxy)-1H-2-
benzothiopyran 2d was separated and identified by NOESY
experiments. An NOE was found between the proton in the
5-position of the 1H-2-benzothiopyran ring and the methyl-
ene protons of the 3-methylbenzyloxy substituent, as well as
between the protons of the methoxy group and the adjacent
aromatic protons of the 4-(4-methoxybenzylthio) side chain
of 2d. No indication of the formation of 2e as an isomer of
2d was found. A prepurified sample of the reaction mixture
(
the 3-methylbenzyl alcohol was separated by distillation Scheme 3. Electrophilic cyclisation of 1 in the presence of ICl in 3-
methylbenzyl alcohol
and chromatography) was treated with tritylium tetra-
fluoroborate (solvent: MeCN) in order to convert 1H-2-
benzothiopyrans and products of type 3 into the corres-
ponding thiopyrylium salts. The products were analysed by the intermediate 3b by the proton-catalysed rearrangement
ESI mass spectrometry. Besides the molecular ion peak of described above. As a second reaction product, the 6-
the pyrylium cation derived from 2d (m/z ϭ 545), other ethoxy-1H-2-benzothiopyran 2f was chromatographically
1
peaks were also observed. These corresponded to the pyryl- separated and identified by H NMR spectroscopy. NOEs
ium cations of 2a (traces), a derivative of 2a in which both were again found by NOESY experiments, between 5-H of
methoxy groups are displaced by 3-methylbenzyloxy groups the 2-benzothiopyran ring and the methylene protons of the
(m/z ϭ 635) and further derivatives of 2a, 2d, and the com- ethoxy group, as well as between the methoxy substituent
pound with m/z ϭ 635, in which one hydrogen atom is sub- of the side chain and the neighbouring aromatic protons.
stituted by the C H O (3-methylbenzyloxy) group. These
side-products are not considered in further discussions.
To trap the spirocyclic intermediate 3b formed from 1,
the cyclisation was performed in a solution of 2,4-dinitro-
8
9
[
9]
The electrophilic cyclisation of 1 could also be achieved phenylhydrazine in ethanol/sulfuric acid (Scheme 5). The
in ethanol by high proton concentrations (Scheme 4). Here, low solubility of the hydrazone of 3b in the reaction me-
no spiro derivative 3b was isolated, but 2g was formed from dium and the high water concentration influence the com-
Eur. J. Org. Chem. 2003, 47Ϫ53
49

E. Fanghänel et al.
FULL PAPER
Scheme 4. Electrophilic cyclisation of 1 in the presence of H
in C H OH/H O
2 5 2
2
SO
4
Scheme 6. 2-Benzothiopyrylium salts through rearrangement and
hydride abstraction
petition between Ar -5 and Ar -6 cyclisation in favour of formation of 1H-2-benzothiopyrans 2 from 1 in the absence
1
2
the former. The hydrazone 3d was obtained in high yield of nucleophiles in the reaction medium.
(
90%). From 3a and 2,4-dinitrophenylhydrazine, the hy-
Reaction Mechanism of the Formation of 2 or 3 from 1
drazone 3c was synthesised (Scheme 3).
Aromatic ipso substitution is normally observed for rings
containing strongly electron-withdrawing groups para to
[
5,10,11]
another substituent.
Our results are analogous, but in
the special context of an intramolecular reaction proceeding
through a stabilised electrophilic intermediate (vinyl cat-
ion). Products of intramolecular ipso substitution have been
[
12]
described in the literature, but the mechanism giving rise
to their formation was not provided. Scheme 7 therefore
presents mechanistic details. Compound 3 is formed from 1
through the vinyl cation 5 and the σ complex 6. By addition
of water or alcohols the σ complex 6 is transformed into
the hemiketal 7a, which upon acid-induced elimination of
methanol yields the spirocyclic ketone 3a via 9. This mech-
[
3,7,13]
anism agrees with literature results.
A radical pathway
Scheme 5. 2,4-Dinitrophenylhydrazones of 2-thiaspiro[4.5]deca-
[
14,15]
(see refs.
) is less probable under the reaction conditions
3,6,9-trien-8-ones from different starting materials
employed here.
From the σ complex 6, the thermodynamically favoured
H-2-benzothiopyran 2a is formed either by a 1,2-migration
The 2-benzothiopyrylium salts 4a and 4b were obtained
from the spiro derivatives 3a or 3d and tritylium tetra-
1
or, less probably, by an equilibrium reaction through the
stabilised vinyl cation 5. In methanol it is not possible to
distinguish between these two pathways. On the creation of
competition between the methoxy-substituted σ complex 6
and a high concentration of 3-methylbenzyl alcohol, the
methoxy substituent would be expected to be exchanged by
fluoroborate in one-pot reactions by Lewis acid induced re-
[
3]
arrangement and hydride abstraction (Scheme 6).
Discussion
Spiro derivatives 3 were formed in good yields by elec- this alcohol if the exchange reaction is fast in comparison
trophilic cyclisation of 1 in the presence of ICl or protons to the product-forming steps. Since 2a was formed only in
and of nucleophiles in the reaction medium. Ar -5 cyclis- traces (determined by ESI mass spectrometry) from 1 in
1
ation competes successfully with the Ar -6 cyclisation under the presence of 3-methylbenzyl alcohol, and the benzyloxy-
2
these reaction conditions. The formation of 3-methyl- substituted 1H-2-benzothiopyran 2d was the main product,
benzyloxy-substituted 1H-2-benzothiopyran 2d by replace- a fast exchange reaction can be assumed. Furthermore, the
ment of the methanol used for the Ar -6 pathway by 3- exclusive formation of 2d rather than a mixture of 2d and
2
methylbenzyl alcohol, or the formation of the ethoxy-sub- 2e strongly argues for the 1,2-migration in the σ complexes
stituted products 2c and 2g in ethanol, are clear indications 6 and 9 Ϫ and not an equilibrium with a vinyl cation of
of a σ complex formed by ipso substitution (Ar -5 path- type 5 followed by an ortho attack Ϫ as the product-deter-
1
way). This σ complex is also the first intermediate in the mining step.
50
Eur. J. Org. Chem. 2003, 47Ϫ53

Electrophilic Cyclisation of Bis(4-methoxybenzylthio)acetylene
FULL PAPER
aromatic ring and therefore on the free activation enthalpy
of the transition states of the intermediates. In the case of
bis(4-methoxybenzylthio)acetylene (1), ipso attack of the vi-
nyl cation 5 on the 4-methoxyphenyl ring is kinetically fa-
voured. The isolated and/or identified 1H-2-benzothiopyr-
ans 2aϪ2d, 2f and 2g (some with exchanged alkoxy substitu-
ents), as well as the spirocyclic ketones 3a and 3c, substanti-
ate this mechanistic proposal. As far as we know, no other
reaction in which the spiro derivatives 3 are obtained in
good yields has been described. The synthetic potential of 3
is high, due to their conversion into 1H-2-benzothiopyrans
2
or the corresponding thiopyrylium salts 4.
Experimental Section
General Remarks: Melting points were determined with a micro
1
13
melting point apparatus and are corrected. H and C NMR spec-
tra were recorded with Varian spectrometers (Gemini 300, Unity
500). Chemical shifts are reported as values in ppm from internal
TMS. Standard Varian software was employed for all NMR experi-
ments. The NOEs were measured by 2D NOESY; the mixing time
was 200Ϫ800 ms. The samples were degassed by at least two freeze-
thaw cycles. The ESI mass spectra were performed with a Finnigan
MAT LCQ spectrometer (solvent: MeCN; flow: 8 L/min; ESI spray
voltage 4.6 kV; cap. temp. 200 °C; cap. voltage 34 V). UV/Vis ab-
sorptions are given as λ in nm (ε in L/mol·cm). All reported ele-
mental analyses were averaged from two independent determina-
tions. Prefabricated silica gel sheets (Sigma-Aldrich) were used for
TLC. Reagents were obtained from commercial sources. The syn-
thesis of bis(4-methoxybenzylthio)acetylene (1) and 3-iodo-6-me-
thoxy-4-(4-methoxybenzylthio)-1H-2-benzothiopyran (2a) has al-
ready been described.[
1]
3
-Iodo-4-(4-methoxybenzylthio)-1H-2-benzothiopyran-6-ol
Compound 3a (90 mg, 0.2 mmol) was dissolved in dry CH
3 mL), and CF COOH (0.3 mL) was added. The mixture was
stirred at room temperature for 10 h and then concentrated in va-
cuo to 1 mL. After neutralization with saturated NaHCO solution
5 mL), diethyl ether (10 mL) was added. The organic phase was
(2b):
3
CN
(
3
3
Scheme 7. Proposed mechanism for product formation
(
separated and the water phase was extracted five times with diethyl
ether (3 mL each). The combined organic phases were washed twice
Further experiments support the decisive role of the ipso with water and dried with MgSO . The solvent was evaporated in
4
σ complexes for product formation. An exchange of the me- vacuo and the residue was dissolved in CH
2
Cl
53 mg, 59%) precipitated upon addition of a fivefold volume of n-
hexane. TLC (cyclohexane/ethyl acetate, 4:1): R (3a) ϭ 0.25,
(2b) ϭ 0.40; slightly yellow crystals, m.p. 118Ϫ120 °C. H NMR
300 MHz, CDCl , 25 °C): δ ϭ 3.47 (s, 2 H, CH ), 3.75 (s, 3 H,
OCH ), 3.79 (s, 2 H, CH ), 6.72Ϫ6.77 (m, 3 H), 6.92 (d, J ϭ 8.1 Hz,
H), 6.98 (d, J ϭ 8.5 Hz, 2 H), 7.40 (d, J ϭ 2.4 Hz, 1 H) ppm.
2
. Compound 2b
(
thoxy group by an ethoxy group in the 1H-2-benzothiopy-
ran ring when using 1 and ICl in dry ethanol/dichlorome-
thane or protons in ethanol/water is a clear argument for
an ipso complex as the product-determining intermediate in
electrophilic cyclisation reactions of 1. This mechanism is
further substantiated by the formation of 3a through an
assumed β-elimination from 9.
f
1
R
(
f
3
2
3
2
1
13
C NMR (300 MHz, CDCl
CH ), 55.29 (OCH ), 98.39, 113.59, 114.40, 115.17, 122.79, 127.76,
28.91, 130.24, 133.67, 134.70, 155.34, 158.62 ppm. UV/Vis
CN): λmax ϭ 227 (26900), 250 (sh, 14300), 319 (5660), 339
3
2
, 25 °C): δ ϭ 35.35 (CH ), 39.22
(
1
2
3
(
CH
(sh, 5180) nm. IR (KBr): ν˜ ϭ 3355 cm (broad). C17
442.34): calcd. C 46.16, H 3.42, S 14.50; found C 46.53, H 3.59,
3
Ϫ1
Conclusion
2 2
H15IO S
(
The mechanism of the electrophilic cyclisation of bis(aryl- S 14.36.
methylthio)acetylenes is described in a special case. Norm-
6
-Ethoxy-3-iodo-4-(4-methoxybenzylthio)-1H-2-benzothiopyran (2c)
and 2b: Compound 1 (100 mg, 0.3 mmol) was dissolved in dry
CH Cl (1.5 mL), and absolute ethanol (4 mL) was added. The so-
ally, 1H-2-benzothiopyrans are formed from these acetyl-
enes, through intramolecular ortho attack of vinyl cations on
2
2
the aromatic ring (Ar -6 ring closure). However, the regiose- lution was cooled to Ϫ70 °C with stirring and under exclusion of
2
lectivity of this reaction depends on the substituents on the water. ICl (54 mg, 0.34 mmol) in CH
2
Cl
2
(1.5 mL) was added drop-
Eur. J. Org. Chem. 2003, 47Ϫ53
51

E. Fanghänel et al.
FULL PAPER
wise to the suspension formed. The mixture was stirred for 30 min
(CH
3
O), 112.60, 113.76, 115.22, 121.79, 127.97, 128.40, 129.38,
at Ϫ70 °C and the solution was then allowed to warm to room 129.54, 130.11, 134.20, 155.53, 158.61 ppm. UV/Vis (CH
3
CN):
temperature for 10 min. The solvent was evaporated in vacuo (tem-
λ
max ϭ 226 (10353), 280 (3817), 426 (959) nm. IR (KBr): ν˜ ϭ 3436
Ϫ1
perature of the bath 25 °C, p ϭ 150Ϫ20 mbar) and the obtained cm (broad).
residue was separated chromatographically on silica gel with cyclo-
3
-Iodo-4-(4-methoxybenzylthio)-2-thiaspiro[4.5]-deca-3,6,9-trien-8-
hexane/ethyl acetate, 4:1. Compound 2c (1st Fraction): 19 mg (14%),
1
one (3a): Compound 1 (248 mg, 0.75 mmol) was dissolved in
R
7
OCH
f
ϭ 0.64. H NMR (300 MHz, CDCl
3
, 25 °C): δ ϭ 1.41 (t, J ϭ
-ethoxy), 3.48 (s, 2 H, CH -benzyl), 3.77 (s, 3 H,
-thiopyran), 4.04 (q, J ϭ 7 Hz, 2 H, CH
CH
630 mg, 7.5 mmol) was added to the solution in order to neutralise
HCl formed by the reaction in situ. The mixture was cooled to Ϫ78
C with solid CO /acetone. ICl (134 mg, 0.84 mmol) in CH Cl
2 mL) was added dropwise over 10 min. The reaction was com-
plete after a further 10 min at Ϫ78 °C [monitoring by TLC with
cyclohexane/ethyl acetate, 4:1; R (1) ϭ 0.55, R (3a) ϭ 0.22Ϫ0.25.
The solvent was removed in vacuo (bath temperature 25 °C, p ϭ
50Ϫ50 mbar). The remaining solid was extracted with CH Cl
3 mL), the solution was filtered, and 3a was precipitated with
2 2 2 3
Cl (4 mL), methanol (6 mL) and H O (1 mL). NaHCO
Hz, 3 H, CH
3
2
(
3
), 3.80 (s, 2 H, CH
2
2
-
ethoxy), 6.73 (d, J ϭ 8.7 Hz, 2 H), 6.80 (m, 2 H), 6.95 (dd, J ϭ
°
(
2
2
2
8
2
.3, 3.1 Hz, 2 H), 7.48 (d, J ϭ 2.4 Hz, 1 H) ppm. 2b (2nd Fraction):
8 mg (21%), R ϭ 0.40.
f
f
f
3-Iodo-4-(4-methoxybenzylthio)-6-(3-methylbenzyloxy)-1H-2-benzo-
thiopyran (2d): Compound 1 (100 mg, 0.3 mmol) was dissolved in
CH Cl (1.5 mL), and 3-methylbenzyl alcohol (4 mL) was added.
The solution was stirred under argon and cooled to Ϫ10 °C. A
solution of ICl (54 mg, 0.3 mmol) in CH Cl (1.5 mL) was added
1
(
2
2
2
2
cyclohexane (10 mL). Light, voluminous crystals were formed after
some minutes. Yield 240 mg (72%); m.p. 111Ϫ112 °C. H NMR
2
2
1
dropwise to the suspension formed. After 1 h of stirring at Ϫ5 °C
and 30 min at room temperature, the solvent was removed in vacuo
(
300 MHz, CDCl
OCH ), 3.80 (s, 2 H, CH
0 Hz, 2 H), 6.81 (d, J ϭ 8.5 Hz, 2 H), 7.10 (d, J ϭ 8.5 Hz, 2 H)
3
2
, 25 °C): δ ϭ 3.35 (s, 2 H, CH ), 3.78 (s, 3 H,
3
2
), 6.19 (d, J ϭ 10 Hz, 2 H), 6.55 (d, J ϭ
(bath temperature 85 °C, p ϭ 0.1 mbar) and the residue was separ-
1
ated chromatographically on silica gel with cyclohexane/ethyl acet-
ate, 9:1. Fractions of eluate (10 mL) were analysed by TCL. The
fractions containing pure 2d (R ϭ 0.63) were collected and the
f
solvent was evaporated in vacuo. The oily residue of 2d crystallised
after some hours. Compound 2d: 30 mg (18%), m.p. 123Ϫ124 °C.
1
3
ppm. C NMR (300 MHz, CDCl
CH ), 55.32 (OCH ), 57.52, 102.58, 113.61, 128.74, 129.95, 130.57,
31.00, 147.20, 159.12, 185.25 (CϭO) ppm. UV/Vis (CH CN):
3
2
, 25 °C): δ ϭ 39.75 (CH ), 43.86
(
1
λ
2
3
3
Ϫ1
max ϭ 280 (8100), 301 (sh) nm. IR (KBr): ν˜ ϭ 1660 cm . MS
ϩ
ϩ
1
EI: m/z (%) ϭ 442 (14) [M ], 316 (3) [C17
H
15
S
2
O
2
], 253 (6)
H NMR (300 MHz, CDCl
.45 (s, 2 H, CH -thiopyran), 3.65 (s, 2 H, CH
H, OCH ), 5.05 (s, 2 H, CH -tolyl), 6.71 (d, J ϭ 8.6 Hz, 2 H),
.86Ϫ6.91 (m, 2 H), 6.96 (d, J ϭ 8.3 Hz, 1 H), 7.11Ϫ7.27 (m, 4
3
, 25 °C): δ ϭ 2.35 (s, 3 H, CH
3
-tolyl),
ϩ
ϩ
ϩ
[
[
C
C
5
H
H
2
IS
2
], 227 (6) [C15
H
15
ϩ
S
2
], 215 (3) [C
2
IS
2
], 149 (4)
3
2
2
-benzyl), 3.74 (s, 3
ϩ
ϩ
ϩ
8
5
SO ], 135 (3) [C
7
H
3
SO ], 127 (5) [I ], 121 (100) [C
8
H
9
O ],
3
2
ϩ
ϩ
5
2 2 3 7 2 2
8 (15) [C H S ], 43 (33) [C H ]. C17H15IO S (442.34): calcd. C
6
13
46.16, H 3.42, S 14.50; found C 46.38, H 3.48, S 14.69.
H), 7.52 (d, J ϭ 2.3 Hz, 1 H) ppm. C NMR (300 MHz, CDCl
5 °C): δ ϭ 22.32 (CH -tolyl), 36.28 (CH -thiopyran), 39.99 (CH
benzyl), 56.22 (CH O), 71.25 (CH O), 98.74 (CϪI), 114.65, 114.89,
15.10, 116.30, 124.11, 125.65, 128.60, 129.30, 129.67, 129.89,
30.08, 130.50, 131.32, 134.54, 136.28, 137.96, 139.48, 159.68,
3
,
2
3
2
2
-
2 2
Crystal Data and X-ray Structure Analysis of 3a: C17H15IO S ,
M ϭ 442.34, yellow plates from diethyl ether, X-ray diffraction
r
data collected with a Stoe STADI-4 four-circle diffractometer with
graphite-monochromatized Mo-K
3
2
1
1
1
4
˚
α
radiation (λ ϭ 0.71073 A) in ω/
ϩ
3 4
59.81 ppm. MS ESI (2d ϩ Ph CBF ): m/z (%) ϭ 545 (100) [M] ,
2
θ scanning mode at T ϭ 293 K, crystal size 0.49 ϫ 0.34 ϫ 0.30
ϩ
18 (15) [M Ϫ I].
mm, orthorhombic, space group P2
9
1
F(000) ϭ 872, 5833 measured reflections in the range 1.22° Յ θ
Յ 30.00°, 5028 unique reflections (Rint ϭ 0.0156), 3537 observed
reflections [I Ͼ 2σ(I)]. Structure solved by direct methods
1
2
1
2
1
, a ϭ 5.7013(6), b ϭ
˚
˚
3
.1416(10), c ϭ 33.280(4) A, V ϭ 1734.5(3) A , Z ϭ 4, Dcalcd.
.694 g cm , µ ϭ 2.090 mm (empirical absorption correction),
ϭ
6-Ethoxy-4-(4-methoxybenzylthio)-1H-2-benzothiopyran (2f) and 4-
Ϫ3
Ϫ1
(
4-Methoxybenzylthio)-1H-2-benzothiopyran-6-ol (2g): Compound
(198 mg, 0.6 mmol) was dissolved in ethanol (10 mL), and a mix-
ture of ethanol (5 mL), H O (1.5 mL) and concd. H SO (1.5 mL)
was added. After the mixture had been kept for 19 h at room tem-
perature, H O (5 mL) was added to the dark solution, and the mix-
ture was extracted six times with CH Cl (5 mL each). The organic
phases were pooled and washed twice with NaHCO solution and
O, and then dried with MgSO . After evaporation of the solvent,
the residue obtained was separated on silica gel with cyclohexane/
ethyl acetate, 4:1. Compound 2f (1st Fraction): 36 mg (17%); R
1
2
2
4
[16]
(
SHELXS-86)
and refined by full-matrix least-squares tech-
2
2
[17]
niques against
F
(SHELXL-93),
hydrogen atoms placed
2
2
at calculated positions and treated according to the riding
model, 199 parameters, w ϭ 1/[σ (F
3
2
2
2
o
)
ϩ (0.0451P) ϩ 0.16P]
) ]/3}, R1obsd. ϭ 0.034, wR2obsd.
.078, R1all ϭ 0.066, wR2all ϭ 0.087, GOF ϭ 1.039, Flack
H
2
4
2
2
{with P ϭ [(F
o
)
ϩ 2(F
c
ϭ
0
f
ϭ
parameter ϭ Ϫ0.01(2), max./min. electron density 1.052/Ϫ0.613 e
1
0
(
3
.82, colourless oil. H NMR (300 MHz, CDCl
3
, 25 °C): δ ϭ 1.41
-ethoxy), 3.63 (s, 2 H, CH -benzyl), 3.76 (s,
-thiopyran), 4.04 (q, J ϭ 7 Hz. 2 H,
Ϫ3
[18]
˚
A
. Figures 1 and 2 were plotted using the program XP/PC.
t, J ϭ 7 Hz, 3 H, CH
3
2
CCDC-127357 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK [Fax: (internat.) ϩ 44-1223/336-033; E-mail:
deposit@ccdc.cam.ac.uk].
H, OCH
3
), 3.79 (s, 2 H, CH
2
CH
2
-ethoxy), 6.63 (s, 1 H), 6.76Ϫ6.82 (m, 3 H), 7.02 (t, J ϭ 8.0 Hz,
1
H), 7.04 (d, J ϭ 8.2 Hz, 2 H), 7.44 (d, J ϭ 2.4 Hz, 1 H) ppm.
13
C NMR (300 MHz, CDCl
0.31 (CH -benzyl), 38.37 (CH
-ethoxy), 111.74, 113.70, 114.51, 121.77, 127.67, 128.92,
3
, 25 °C): δ ϭ 14.82 (CH
2
-ethoxy),
3
(
2
2
-thiopyran), 55.21 (OCH
3
), 63.59
CH
2
1
29.51, 130.06, 130.46, 133.87, 158.57, 158.73 ppm. Compound 2g 2,4-Dinitrophenylhydrazone of 3-Iodo-4-(4-methoxybenzylthio)-2-
ϭ 0.61, colourless crystals, m.p. thiaspiro[4.5]deca-3,6,9-trien-8-one (3c): Compound 3a (85 mg,
3Ϫ95 °C. H NMR (300 MHz, CDCl , 25 °C): δ ϭ 3.62 (s, 2 H, 0.2 mmol), dissolved in ethanol (25 mL), was poured into a solu-
), 3.76 (s, 3 H, OCH ), 3.77 (s, 2 H, CH ), 6.63 (s, 1 H), 6.73 tion of 2,4-dinitrophenylhydrazine (400 mg, 2 mmol) in H SO
m, 1 H), 6.75 (d, J ϭ 8.2 Hz, 2 H), 6.98 (d, J ϭ 8.1 Hz, 1 H), 7.04 (2 mL), H O (3 mL) and ethanol (10 mL), and the mixture was
stirred for 1 h at room temperature. Red crystals started to precipit-
(2nd Fraction): 8 mg (13%), R
f
1
9
CH
3
2
3
2
2
4
(
(
(
2
d, J ϭ 8.4 Hz, 2 H), 7.36 (d, J ϭ 2.4 Hz, 1 H) ppm. 1 C NMR
300 MHz, CDCl
3
3
, 25 °C): δ ϭ 30.29 (CH
2
), 38.43 (CH
2
), 55.27 ate almost instantaneously. Finally, they were suction-filtered,
52
Eur. J. Org. Chem. 2003, 47Ϫ53

Electrophilic Cyclisation of Bis(4-methoxybenzylthio)acetylene
FULL PAPER
washed twice with ethanol and recrystallised from ethanol (91 mg,
6-(2,4-Dinitrophenylhydrazino)-4-(4-methoxybenzylthio)benzo-
1
7
3
1
1
5%); m.p. 154Ϫ156 °C. H NMR (300 MHz, CDCl
3
, 25 °C): δ ϭ thiopyrylium Tetrafluoroborate (4b): 110 mg (95%) from 3d (100 mg,
1
.34 (d, J ϭ 3.0 Hz, 2 H, CH
2.4 Hz, 2 H, CH ), 6.01 (d, J ϭ 9.4 Hz, 1 H), 6.21 (d, J ϭ 9.8 Hz, °C): δ ϭ 3.76 (s, 3 H, OCH
H), 6.45 (d, J ϭ 9.7 Hz, 1 H), 6.59 (d, J ϭ 10.0 Hz, 1 H), 6.82 8.4 Hz, 2 H), 7.28 (d, J ϭ 8.0 Hz, 2 H), 7.36 (d, J ϭ 9.5 Hz, 1 H),
2
), 3.78 (s, 3 H, OCH
3
), 3.84 (q, J ϭ
0.2 mmol); m.p. Ͼ 145 °C (dec.). H NMR (300 MHz, CD
3
CN, 25
2
3
), 4.33 (s, 2 H, CH ), 6.86 (d, J ϭ
2
(d, J ϭ 8.1 Hz, 2 H), 7.14 (d, J ϭ 8.1 Hz, 2 H), 8.03 (d, J ϭ 9.5 Hz,
7.69 (d, J ϭ 9.2 Hz, 1 H), 7.78 (s, 1 H), 8.30 (m, 3 H), 8.99 (s,
1
H), 8.34 (d, J ϭ 9.2 Hz, 1 H), 9.13 (s, 1 H), 11.59 (s, 1 H, NH) NH), 9.03 (d, J ϭ 2.3 Hz, 1 H), 9.79 (s, NH), 9.85 (d, J ϭ 2.6 Hz,
13
13
ppm. C NMR (300 MHz, CDCl
CH ), 55.31 (OCH ), 58.21, 101.26, 113.86, 114.96, 116.56, 123.40,
27.27, 129.15 129.73, 130.03, 130.49, 132.97, 135.96, 138.32, 127.43, 128.08, 128.81, 128.95, 129.46, 129.69, 130.31, 131.50 (2 C),
3
, 25 °C): δ ϭ 39.70 (CH
2
), 45.13
1 H) ppm. C NMR (300 MHz, CD
3
2
CN, 25 °C): δ ϭ 38.20 (CH ),
(
2
3
56.17 (OCH ), 99.18, 115.41, 116.30, 117.65, 118.24, 124.32,
3
1
1
41.81, 144.42, 144.92, 159.11 ppm. UV/Vis (CH
(622.46): calcd. C 44.38, H 3.08, N 9.03, S
0.30; found C 43.94, H 3.20, N 8.64, S 10.07.
2 2
Cl ): λmax ϭ 392 131.57 (2 C), 138.37, 144.27, 148.75, 156.89, 160.36, 160.77 ppm.
Ϫ1
Ϫ
Ϫ1
nm. C23
1
H19IN
4
O
5
S
2
IR (KBr): ν˜ ϭ 1062 cm (BF
4
), 3311 cm (NH). MS EI: m/z
ϩ
Ϫ
ϩ
4 6 4 3 4
(%) ϭ 493 (20) [M Ϫ BF ], 183 (18) [C H N O ], 121 (100)
[C H O ]. UV/Vis (DMSO): λmax ϭ 271 (22800), 369 (8040), 538
8 9
28700) nm. C23H N O S BF (582.36): calcd. C 47.44, H 3.29,
19 4 5 2 4
ϩ
2,4-Dinitrophenylhydrazone of 4-(4-Methoxybenzylthio)-2-thiaspiro-
ϩ
(
[
4.5]deca-3,6,9-trien-8-one (3d): Compound 1 (33 mg, 0.1 mmol),
dissolved in ethanol (10 mL), was poured into a solution of 2,4-
dinitrophenylhydrazine (200 mg, 1 mmol) in H SO (1 mL), H
1.5 mL) and ethanol (5 mL), and the mixture was stirred for 1 h at
N 9.62, S 11.01; found C 47.56, H 3.46, N 9.34, S 11.90.
2
4
2
O
(
Acknowledgments
room temperature. Red-orange crystals started to precipitate after 1
min. Finally, they were suction-filtered, washed twice with ethanol
T. R. A. thanks the Studienstiftung des Deutschen Volkes and N.
A. M. Y. the Deutscher Akademischer Austauschdienst (DAAD)
and the Graduiertenförderung des Landes Sachsen-Anhalt for fin-
ancial support.
and recrystallised from ethanol (44 mg, 89%); m.p. 153Ϫ154 °C.
1
H NMR (300 MHz, CDCl
3
, 25 °C): δ ϭ 3.29 (d, J ϭ 4.9 Hz, 2
), 3.83 (s, 2 H, CH ), 6.01 (s, 1 H),
H, CH
2
), 3.76 (s, 3 H, OCH
3
2
6
1
8
1
3
1
1
.24 (d, J ϭ 9.8 Hz, 1 H), 6.52 (d, J ϭ 10.0 Hz, 2 H), 6.74 (d, J ϭ
0.2 Hz, 1 H), 6.81 (d, J ϭ 8.6 Hz, 2 H), 7.16 (d, J ϭ 8.6 Hz, 2 H),
.01 (d, J ϭ 9.6 Hz, 1 H), 8.31 (d, J ϭ 9.5 Hz, 1 H), 9.12 (s, 1 H),
[1]
T. R. Klein, M. Bergemann, N. A. M. Yehia, E. Fanghänel, J.
Org. Chem. 1998, 63, 4626Ϫ4631.
13
[2]
1.62 (s, 1 H, NH) ppm. C NMR (300 MHz, CDCl
3
, 25 °C): δ ϭ
J. Barluenga, G. P. Romanelli, L. J. Alvarez-Garcia, I. Llorente,
8.68 (CH ), 42.99 (CH ), 55.22 (OCH ), 58.63, 113.91, 115.04,
2
2
3
J. M. Gonz a´ lez, S. Garc ´ı a-Grande, Angew. Chem. 1998, 110,
3332Ϫ3334; Angew. Chem. Int. Ed. 1998, 37, 3136Ϫ3139.
16.51, 123.32, 124.15, 127.32, 128.29, 129.42, 129.63, 129.94,
36.52, 138.21, 142.70, 144.42, 145.05, 158.95 ppm. UV/Vis
[
[
3]
4]
I. A. Blair, L. N. Mander, P. H. C. Mundill, Aust. J. Chem.
981, 34, 1235Ϫ1242.
1
2 2 20 4 5 2
(CH Cl ): λmax ϭ 392 nm. C23H N O S (496.56): calcd. C 55.63,
N. Boden, R. J. Bushby, A. N. Cammidge, G. Headdock, Syn-
thesis 1995, 31Ϫ32.
H 4.06, N 11.29, O 16.10, S 12.91; found C 55.27, H 4.26, N 10.90,
O 16.45, S 12.92.
[5]
C. L. Perrin, G. A. Skinner, J. Am. Chem. Soc. 1971, 93,
3389Ϫ3394.
General Procedure for the Synthesis of the 2-Benzothiopyrylium
Salts 4 by Hydride Abstraction with Tritylium Tetrafluoroborate
from 3: All steps were carried out under argon and exclusion of
[6]
H. Plieninger, G. Ege, M. I. Ullah, Chem. Ber. 1963, 96,
1
610Ϫ1617.
[
1]
[7]
[8]
H. J. Lewis, R. Robinson, J. Chem. Soc. 1934, 1253Ϫ1255.
A. Bondi, J. Phys. Chem. 1964, 8, 441Ϫ451.
moisture. Compound 3 (0.2 mmol) was dissolved in dry CH
2
Cl
1.5 mL) and added in one portion to an ice-cold solution of TrBF
185 mg; 0.56 mmol) in CH Cl
2
[9]
(
(
4
Further investigations are planned for the structure elucidation
of the side products and the mechanism of their formation.
The formation of the product with m/z ϭ 635 should be con-
nected with an equilibrium between the ipso complex 9 and a
corresponding vinyl cation. For treatment of 1 with ICl in
CH OH/CH Cl , tris(methoxy)-substituted 1H-2-benzothiopy-
3 2 2
rylium salts were not found by ESI MS.
J. G. Traynham, J. Chem. Educ. 1983, 60, 937Ϫ941.
R. B. Moodie, K. Schofield, Acc. Chem. Res. 1976, 9, 287Ϫ292.
R. A. Haack, K. R. Beck, Tetrahedron Lett. 1989, 30,
2
2
(1.5 mL). The resulting dark liquid
was stirred for 30 min at 0 °C and for a further 30 min at room
temperature. The solution was concentrated to 1 mL in vacuo, and
poured into dry diethyl ether (10 mL) with vigorous stirring. The
solid formed was collected, washed twice with diethyl ether and
dried in a vacuum desiccator. If necessary, recrystallisation was
possible in acetic anhydride with some loss of material (incom-
plete precipitation).
[10]
[11]
[12]
1
605Ϫ1608.
6
-Hydroxy-4-iodo-4-(4-methoxybenzylthio)-2-benzothiopyrylium
[13]
[14]
B. A. Collins, K.E. Richards, G. J. Wright, J. Chem. Soc.,
Chem. Commun. 1972, 1216.
P. C. Montevecchi, M. L. Navacchia, Tetrahedron Lett. 1996,
37, 6583Ϫ6586.
Tetrafluoroborate (4a): 35 mg (66%) of 4a was obtained from 44 mg
1
(
(
0.1 mmol) of 3a; yellow crystals, m.p. 154Ϫ155 °C. H NMR
300 MHz, CD CN, 25 °C): δ ϭ 3.68 (s, 3 H, OCH ), 4.16 (s, 2 H,
), 6.68 (d, J ϭ 8.5 Hz, 2 H), 6.96 (d, J ϭ 8.5 Hz, 2 H), 7.57
dd, J ϭ 9.0, 2.19 Hz, 1 H), 8.29 (d, J ϭ 2.0 Hz, 1 H), 8.35 (d, J ϭ
3
3
[15]
CH
(
2
S. P. Green, D. A. Whiting, J. Chem. Soc., Perkin Trans. 1
1998, 193Ϫ202.
[
[
16]
17]
ϩ
13
G. M. Sheldrick, Acta Crystallogr., Sect. A 1990, 46, 467Ϫ473.
G. M. Sheldrick, SHELXL-93, Program for the refinement of
crystal structures, Univ. Göttingen, Germany, 1986.
XP/PC, Molecular graphics program package for display and
analysis of stereochemical data, version 4.2, MS-DOS, Siemens
Analytical X-ray Instruments, Inc., Madison, Wisconsin,
U.S.A., 1990.
9
CD
1
1
.0 Hz, 1 H), 10.03 (s, 1 H, S ϭCH) ppm. C NMR (300 MHz,
CN, 25 °C): δ ϭ 41.53 (CH ), 55.98 (OCH ), 113.20 (CϪI),
14.89, 115.99, 118.31, 124.86, 128.81, 130.31, 131.47, 139.92,
45.16, 160.40, 168.43, 173.21 ppm. UV/Vis (CH CN): λmax ϭ 282
3
2
3
[18]
3
Ϫ1
(
(
(
18800), 371 (8100), 422 (7100) nm. IR (KBr): ν˜ ϭ 1061 cm
BF
528.13): calcd. C 38.66, H 2.67, S 12.14; found C 38.98, H 2.84,
Ϫ
ϩ
ϩ
Ϫ
4 14 2 2 4
). MS ESI: m/z (%) ϭ 441 (100) [M ]. C17H S O I BF
Received May 30, 2002
S 12.06.
[O02291]
Eur. J. Org. Chem. 2003, 47Ϫ53
53