Dibenzothiepins, phthalans and phthalides from 4-heterosubstituted dibenzothiins

Article abstract of DOI:10.1016/S0040-4020(03)00210-2

The lithiation of 4-heterosubstituted dibenzothiins 1 (phenoxathiin, phenothiazine and thianthrene) with lithium and a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB, 7.5% molar) in THF at temperatures ranging from -90 to -78°C gives the corresponding functionalised organolithium intermediate I, which by reaction with different electrophiles [H₂O, D₂O, Bu^tCHO, PhCHO, Ph(CH₂)₂CHO, Me₂CO, Et₂CO, (CH₂)₅CO, (CH₂)₇CO] at the same temperature, followed by hydrolysis, gives the expected functionalised thiols 2. Cyclisation of some thiols 2 under acidic conditions leads to the corresponding seven-membered dibenzo heterocycles 5. In the case of thianthrene 1c, after addition of a carbonyl compound as the first electrophile [MeCHO, Bu^tCHO, Me₂CO, Et₂CO, (CH₂)₅CO], the corresponding intermediate II can be lithiated again and react with a second electrophile. Diols 3 are obtained after hydrolysis when a carbonyl compound [Bu^tCHO, PhCHO, Ph(CH₂)₂CHO, Me₂CO, Et₂CO, (CH₂)₅CO] is used as the second electrophile. Acidic cyclisation of diols 3 gives substituted phthalans 6 in almost quantitative yields. Finally, in the case of using carbon dioxide as the second electrophile, phthalides 4 are obtained after acidic hydrolysis.

Full text of DOI:10.1016/S0040-4020(03)00210-2

Tetrahedron 59 (2003) 2083–2092
Dibenzothiepins, phthalans and phthalides from
4-heterosubstituted dibenzothiins
*
Miguel Yus, Francisco Foubelo and Jose V. Ferrandez
´
´
´ ´
Departamento de Quımica Organica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, E-03080 Alicante, Spain
Received 19 November 2002; revised 13 January 2003; accepted 5 February 2003
Abstract—The lithiation of 4-heterosubstituted dibenzothiins 1 (phenoxathiin, phenothiazine and thianthrene) with lithium and a catalytic
amount of 4,40-di-tert-butylbiphenyl (DTBB, 7.5% molar) in THF at temperatures ranging from 290 to 2788C gives the corresponding
functionalised organolithium intermediate I, which by reaction with different electrophiles [H2O, D2O, ButCHO, PhCHO, Ph(CH2)2CHO,
Me2CO, Et2CO, (CH2)5CO, (CH2)7CO] at the same temperature, followed by hydrolysis, gives the expected functionalised thiols 2.
Cyclisation of some thiols 2 under acidic conditions leads to the corresponding seven-membered dibenzo heterocycles 5. In the case of
thianthrene 1c, after addition of a carbonyl compound as the first electrophile [MeCHO, ButCHO, Me2CO, Et2CO, (CH2)5CO], the
corresponding intermediate II can be lithiated again and react with a second electrophile. Diols 3 are obtained after hydrolysis when a
carbonyl compound [ButCHO, PhCHO, Ph(CH2)2CHO, Me2CO, Et2CO, (CH2)5CO] is used as the second electrophile. Acidic cyclisation of
diols 3 gives substituted phthalans 6 in almost quantitative yields. Finally, in the case of using carbon dioxide as the second electrophile,
phthalides 4 are obtained after acidic hydrolysis. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
(mainly naphthalene or DTBB).7,8 More recently, polymer
supported naphthalene, biphenyl9 and also polyphenylene10
have been used as electron transfer reagents in these
processes.11 Heterocycles can be reductively opened due to
a release of strain energy2 (three and four membered-rings),
or due to the presence of activated bonds that can be
reductively broken, as in the case of allylic12 and benzylic13
carbon-heteroatom bonds, as well as aryl ethers14 and
thioethers.15 The application of the arene-catalysed version
to some sulfur-containing heterocycles with benzylic
carbon–sulfur bonds such as thietanes,16 tetrahydrothio-
phenes,16,17 tetrahydrothiopyrans,16 and 2,7-dihydro-
dibenzoazepine18 allows the direct preparation of
functionalised organolithium compounds. On the other
hand, the stoichiometric arene-mediated lithiation has
been used in the reductive opening of different cyclic
arylthioethers such as dihydrobenzothiophene,19 3,4-dihydro-
2H-benzothiane,19 and trimethylbenzo-1,3-thiazolidine.19b,20
In this paper we report on the application of the mentioned
arene-catalysed lithiation methodology to the reductive ring
opening of 4-hetero-substituted dibenzothiins and the study of
the synthetic utility of the resulting functionalised organo-
lithium compounds.
Probably the most elegant and direct strategy for the
preparation of functionalised organolithium compounds1
consists in the reductive opening of different appropriate
oxygen, nitrogen and sulfur-containing heterocycles.2 In
addition, these highly reactive intermediates have also been
prepared by halogen–lithium exchange, metal–lithium
exchange, direct deprotonation, as well as by addition of
organolithium compounds to unsaturated systems.1,3 The
interest of these systems lies in their utility in synthetic
organic chemistry because polyfunctionalised molecules are
obtained in only one step by their reaction with electrophilic
reagents.4 Polyfunctionalised molecules are also obtained
by reaction of polylithium organic compounds5 with
electrophiles, however more interestingly in this case
would be to introduce different electrophilic fragments in
the polyanionic unit, the iterative sequential lithiation-
reaction with the electrophile being the only way to achieve
this goal, acting always functionalised organolithium
compounds as intermediates. Since most functionalised
organolithium compounds are very unstable molecules, they
have to be prepared at low temperature in order to avoid
their decomposition.6 In the last few years a methodology
was developed using, as lithiating agent, an excess of
lithium in the presence of a catalytic amount of an arene
2. Results and discussion
Keywords: lithiation; heterocycle reductive opening; cyclisation; dianionic
synthon.
The reaction of 4-heterosubstituted 0 dibenzothiins 1 with
lithium and a catalytic amount of 4,4 -di-tert-butylbiphenyl
(DTBB, 7.5 mol%) in THF at 2788C in the case of
*
Corresponding author. Tel.: þ34-965-909672; fax: þ34-965-903549;
e-mail: foubelo@ua.es
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00210-2

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M. Yus et al. / Tetrahedron 59 (2003) 2083–2092
Scheme 1. Reagents and conditions: (i) Li, DTBB cat. (7.5%), THF, 278 (for 1a) or 2908C (for 1b,c), 45 min; (ii) E1¼H2O, D2O, ButCHO, PhCHO,
Ph(CH2)2CHO, Me2CO, Et2CO, (CH2)5CO, (CH2)7CO, 278 (for 1a) or 2908C (for 1b,c); (iii) H2O, 278 (for 1a) or 2908C (for 1b,c) to 208C, then 3 M HCl;
(iv) 2908C, 45 min; (v) E2¼ButCHO, PhCHO, Ph(CH2)2CHO, Me2CO, Et2CO, (CH2)5CO, 290 to 2788C, 30 min; (vi) H2O, 278 to 208C.
Table 1. Preparation of compounds 2
Entry
Starting material 1
Electrophile E1
Product 2a
No.
X1
Yield (%)b
Rfc
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
H2O
D2O
H
D
2aa
2abd
2ac
2ad
2ae
2af
2ag
2ah
2ai
2ba
2bb
2bc
2bd
2ca
2cb
2cc
50
53
63
49
36
82
44
41
31
95
25
64
48
98
39
52
0.54
0.54
0.29
0.15
0.14
0.16
0.11
0.22
0.13
0.59
0.24
0.31
0.16
0.57
0.20
0.18
ButCHO
PhCHO
Ph(CH2)2CHO
Me2CO
Et2CO
ButCHOH
PhCHOH
Ph(CH2)2CHOH
Me2COH
Et2COH
(CH2)5CO
(CH2)7CO
H2O
(CH2)5COH
(CH2)7COH
H
9
10
11
12
13
14
15
16
ButCHO
PhCHO
Ph(CH2)2CHO
H2O
ButCHOH
PhCHOH
Ph(CH2)2CHOH
H
ButCHO
PhCHO
ButCHOH
PhCHOH
a
All products 2 were .95% pure (300 MHz 1H NMR and/or GLC).
Isolated yield after column chromatography (silica gel, hexane/ethyl acetate) based on the starting material 1.
Silica gel, hexane/ethyl acetate: 10:1.
.90% Deuterium incorporation (MS).
b
c
d
phenoxathiin (1a) or 2908C for phenothiazine (1b) and
thianthrene (1c) for 45 min gave the corresponding
intermediate I, which after reacting with different electro-
philes [H2O, D2O, ButCHO, PhCHO, Ph(CH2)2CHO,
Me2CO, Et2CO, (CH2)5CO, (CH2)7CO], followed by
hydrolysis with hydrochloric acid, led to the expected
functionalised thiols 2 (Scheme 1 and Table 1).21 In the case
of phenothiazine (1b) and thianthrene (1c), the process
should be performed at 2908C because at higher
temperature (2788C) complex mixtures of reaction
products were obtained. Also for thianthrene (1c) the final
acidic hydrolysis has to be carried out immediately after the
addition of the electrophile in order to avoid further
lithiation.
compound [ButCHO, Me2CO, Et2CO, (CH2)5CO] at
2908C, the resulting intermediate II (Scheme 1, Y¼S,
X1¼R1R2COLi) was stirred for 45 min at the same
temperature, a second lithiation occurred by reductive
cleavage of one of the aryl–sulfur bonds of intermediate II
to give intermediate III and dithiolate IV (Chart 1), because
of the excess of lithium still present in the reaction medium.
When this second lithiation was carried out at higher
temperature (2788C), the other possible aryl–sulfur bond
reductive cleavage also took place leading to intermediates
V and VI (Chart 1), so a complex mixture of products was
obtained. The reaction of intermediate III with a second
carbonyl compound [ButCHO, PhCHO, Ph(CH2)2CHO,
Due to this latest reason, we found especially interesting
thianthrene (1c), because it is possible to develop a
sequential double lithiation-reaction with electrophiles to
prepare polyfunctionalised molecules. Thus, when after
reductive opening of 1c and reaction with a carbonyl
Chart 1. Intermediates IV–VII.

M. Yus et al. / Tetrahedron 59 (2003) 2083–2092
2085
Table 2. Preparation of diols 3 from thianthrene 1c
Entry
Electrophile E1
Electrophile E2
Product 3a
R1
R2
R3
R4
No.
Yield (%)b
Rfc
1
2
3
4
5
6
7
8
9
ButCHO
Me2CO
Me2CO
Me2CO
Me2CO
Me2CO
Me2CO
Et2CO
ButCHO
ButCHO
PhCHO
Ph(CH2)2CHO
Me2CO
Et2CO
(CH2)5CO
Et2CO
(CH2)5CO
H
But
Me
Me
Me
Me
Me
Me
Et
H
H
H
H
Me
Et
(CH2)5
Et
(CH2)5
But
But
Ph
Ph(CH2)2
Me
Et
3a
3b
3c
3d
3e
3f
3g
3h
3i
68d
81
76
58
64
55
71
47
60
0.47þ0.46e
0.36
0.31
Me
Me
Me
Me
Me
Me
Et
0.27
0.28
0.43
0.51
0.51
0.72
Et
(CH2)5CO
(CH2)5
a
All products 3 were .95% pure (300 MHz 1H NMR and/or GLC).
Isolated yield after column chromatography (silica gel, hexane/ethyl acetate) based on the starting material 1c.
b
c
d
Silica gel, hexane/ethyl acetate: 3:1.
A ca. 1:1 mixture of diastereomers was obtained (GLC), which was separated by column chromatography (silica gel, hexane/ethyl acetate) giving 35þ33%
of both diastereomers.
Rf value for each diastereomer.
e
Me2CO, Et2CO, (CH2)5CO] at temperatures ranging
between 290 and 2788C for 10 min followed by final
hydrolysis with water at 278 to 208C led to the formation of
diols 3 (Scheme 1, Table 2).22 A 1:1 mixture of
diastereomers was obtained when a prochiral carbonyl
compound such as pivaldehyde was used in both steps,
which could be separated by column chromatography
(Table 2, entry 1). Through this methodology, thianthrene
1c acts as a 1,2-dianionic synthon of benzene of type VII
(Chart 1), allowing the introduction of two different
electrophiles in a sequential manner at both carbanionic
centres.
the second electrophile, allowed the preparation of 3-substi-
tuted phthalides 4 in a one-pot process.23 Thus, the DTBB-
catalysed reductive opening lithiation of 1c and reaction
with a carbonyl compound [MeCHO, BunCHO, Me(CH2)7-
CHO, PhCHO, Me2CO, MeCOEt, (CH2)5CO] at 2908C
gave intermediates II, which after a new lithiation at the
same temperature afforded intermediates of type III.
Treatment of these dianions by bubbling carbon dioxide at
2708C for 15 min and final acidic hydrolysis, led to the
formation of 3-substituted phthalides 4 (Scheme 2 and Table
3). Many of these phthalides are natural occurring products
with important biological activities. For instance,
3-methylphthalide (4a, Table 3, entry 1) shows anti-
aggregatory and anti-inflammatory activity by inhibition
of prostaglandin synthesis in platelets.24 Meanwhile 3-n-
butylphthalide (4b, Table 3, entry 2), which is a constituent
of celery oil,25 increases the duration of anaesthesia,26 and
exhibits cerebral antiischemic action.27
From a synthetic point of view, the use of carbonyl
compounds as the first electrophile and carbon dioxide as
Finally, some functionalised hydroxythiols 2, and diols 3
were cyclised under acidic conditions (85% phosphoric acid
under toluene at reflux)18 to give the corresponding seven-
membered dibenzo compounds 528,29 (Scheme 3 and Table
4) and substituted phthalans 630 in almost quantitative yield
(Scheme 3 and Table 5), respectively. The whole process
1!5 could be considered a homologation of the starting
4-heterosubstituted dibenzothiins 1. A benzylic carbenium
ion is probably involved in these reactions, which after
intramolecular nucleophilic attack by the sulfur atom or the
oxygen atom gives the final heterocycles 5 and 6,
respectively.
Scheme 2. Reagents and conditions: (i) Li, DTBB cat. (7.5%), THF,
2908C, 45 min; (ii) E1¼MeCHO, BunCHO, Me(CH2)7CHO, PhCHO,
Me2CO, MeCOEt, (CH2)5CO, 2908C, 45 min; (iii) CO2, 2708C, 15 min;
(iv) H2O, 270 to 208C, then 3 M HCl.
Table 3. Preparation of phthalides 4 from thianthrene 1c
Entry Electrophile E1
Product 4a
R1
R2
No. Yield (%)b
Rfc
1
2
3
4
5
6
7
MeCHO
H
H
H
H
Me
Bun
4a
4b
58
78
38
58
59
78
39
0.54
0.54
0.29
0.15
0.14
0.16
0.18
BunCHO
Me(CH2)7CHO
PhCHO
3. Conclusions
Me(CH2)7 4c
Ph
4d
4e
4f
We report here that the reductive opening lithiation of
4-heterosubstituted dibenzothiins 1 at low temperature led
to functionalised organolithium compounds I, which by
reaction with electrophiles and final hydrolysis gave thiols
2. In the case of thianthrene 1c it is possible to perform a
sequential double lithiation-reaction with electrophiles, 1c
behaving as a dianionic synthon of benzene of type VII.
Me2CO
MeCOEt
(CH2)5CO
Me Me
Me Et
(CH2)5
4g
a
All products 4 were .95% pure (300 MHz 1H NMR and/or GLC).
Isolated yield after column chromatography (silica gel, hexane/ethyl
acetate) based on the starting material 1c.
Silica gel, hexane/ethyl acetate: 10:1.
b
c

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M. Yus et al. / Tetrahedron 59 (2003) 2083–2092
respectively. The purity of volatile products and the
chromatographic analyses (GLC) were determined with a
Hewlett–Packard HP-5890 instrument equipped with a
flame ionisation detector and a 12 m capillary column
(0.2 mm diam, 0.33 mm film thickness), using nitrogen
(2 mL/min) as carrier gas, Tinjector¼2758C, Tdetector¼3008C,
Tcolumn¼808C (3 min) and 80–2708C (158C/min),
P¼40 kPa. Elemental analyses were performed by the
Mycroanalyses Service at the University of Alicante.
4.2. Reductive lithiation of 4-hetero-substituted
dibenzothiins 1 and reaction with electrophiles
Isolation of compounds 2. General procedure. To a blue
suspension of lithium powder (100 mg, 14 mmol) and a
catalytic amount of DTBB (40 mg, 0.15 mmol; 7.5 mol%)
in THF (4 mL) was added the corresponding 4-hetero-
substituted dibenzothiin 1 (2.0 mmol) at 2788C for 1a and
2908C for 1b,c, and the resulting mixture was stirred for
45 min at the same temperature. Then, the corresponding
electrophile (2.4 mmol; 0.5 ml in the case of H2O and D2O)
was added dropwise and stirring was continued for 5 min.
After that the reaction mixture was hydrolysed with water,
extracted with ether (3£20 mL) and the aqueous layer was
acidified with 3 M HCl and extracted with ethyl acetate
(3£20 mL), dried over anhydrous Na2SO4 and evaporated
(15 Torr). The residue was purified by column chromato-
graphy (silica gel, hexane/ethyl acetate) to yield pure
products. Yields and Rf values are given in Table 1,
physical, analytical and spectroscopic data follow.
Scheme 3. Reagents and conditions: (i) H3PO4 (85%), PhCH3, 1108C.
Table 4. Preparation of compounds 5
Entry Starting material 2
Product 5a
Y
R1
H
Et Et
H
H
R2
Ph
No. Yield (%)b
Rfc
1
2
3
4
2ad
2ag
2cb
2cc
O
O
S
5a
5b
78
85
74
97
0.57
0.61
0.64
0.54
But 5c
Ph
S
5d
a
All products 5 were .95% pure (300 MHz 1H NMR and/or GLC).
Isolated yield after column chromatography (silica gel, hexane/ethyl
acetate) based on the starting material 2.
Silica gel, hexane/ethyl acetate: 10:1.
b
4.2.1. 2-Phenoxythiophenol (2aa).31 Colorless liquid; n
(film) 3063, 3052, 3037, 3011 (ArH), 2576 cm21 (SH); dH
3.79 (1H, s, SH), 6.86 (1H, d, J¼7.9 Hz, ArH), 6.95–7.11
(4H, m, ArH), 7.29–7.36 (4H, m, ArH); dC 118.1, 119.3,
123.3, 124.1, 126.4, 129.75, 129.8, 152.5, 156.7 (ArC); m/z
202 (Mþ, 100%), 201 (22), 169 (13), 141 (13), 97 (15), 96
(80), 77 (17), 69 (17), 65 (14), 63 (12), 51 (41), 50 (15), 45
(31); HMRS: Mþ, found 202.0457. C12H10OS requires
202.0452.
c
Table 5. Preparation of compounds 6
Entry Starting material 3
Product 6a
R1 R2 R3
R4
No. Yield Rfc
(%)b
1
2
3
4
5
3d
3e
3g
3h
3i
Me Me
H
Ph(CH2)2 6a
.95 0.11
6b .95 0.20
Me Me Me Me
Me Me (CH2)5
Et Et Et Et
4.2.2. 2-(2-Deuteriophenoxy)thiophenol (2ab). Colorless
liquid; n (film) 3063, 3052, 3037, 3011 (ArH), 2576 cm21
(SH); dH 3.80 (1H, s, SH), 6.87 (1H, dd, J¼7.9, 1.8 Hz,
ArH), 6.96–7.13 (4H, m, ArH), 7.30–7.35 (3H, m, ArH);
dC 117.9 (t, J¼24.4 Hz, CD), 118.1, 119.3, 123.4, 124.1,
126.5, 129.7, 129.8, 129.9, 152.5, 156.6 (ArC); m/z 203
(Mþ, 100%), 202 (23), 170 (12), 97 (12), 96 (77), 78 (14), 69
(15), 52 (22), 51 (23), 45 (32), 40 (13); HMRS: Mþ, found
203.0507. C12H9DOS requires 203.0515.
6c
6d .95 0.16
6e .95 0.54
.95 0.24
(CH2)5
(CH2)5
a
b
c
All products 6 were .95% pure (300 MHz 1H NMR and/or GLC).
Isolated yield based on the starting material 3.
Silica gel, hexane.
4. Experimental
4.2.3. 2,2-Dimethyl-1-[2-(2-sulfanylphenoxy)phenyl]-1-
propanol (2ac). Colorless liquid; n (film) 3460–3320
(OH), 3064, 3033 (ArH), 2587 cm21 (SH); dH 1.02 [9H, s,
C(CH3)3], 1.95 (1H, br s, OH), 3.77 (1H, s, SH), 4.89 (1H, s,
CHOH), 6.72–6.79 (2H, m, ArH), 6.97–7.22 (4H, m, ArH),
7.32–7.36 (1H, m, ArH), 7.52–7.55 (1H, m, ArH); dC 26.0
[C(CH3)3], 36.6 [C(CH3)3], 75.6 (CHOH), 117.6, 118.3,
123.3, 123.7, 123.9, 126.5, 128.3, 129.4, 129.9, 132.8,
152.6, 153.6 (ArC); m/z 270 [Mþ–(H2O), 8%], 231 (13),
214 (18), 213 (100), 181 (22), 77 (16), 65 (15), 57 (17), 51
(13), 45 (13), 41 (32); HMRS: Mþ–(H2O), found 270.1072.
C17H18OS requires 270.1078.
4.1. General
All reactions were carried out under an atmosphere of
nitrogen in oven-dried glassware. All reagents were
commercially available and were used as received. THF
was distilled from sodium benzophenone ketyl. Melting
points were recorded in a Reichert Thermovar and are
uncorrected. IR spectra were measured (neat) with a Nicolet
Impact 400 D-FT Spectrometer. NMR spectra were
recorded with a Bruker AC-300 using CDCl3 as the solvent.
LRMS and HRMS were measured with Shimadzu GC/HS
QP-5000 and Finingan MAT95
S spectrometers,

M. Yus et al. / Tetrahedron 59 (2003) 2083–2092
2087
4.2.4. Phenyl-[2-(2-sulfanylphenoxy)phenyl]methanol
(2ad). Colorless oil; n (film) 3520–3370 (OH), 3062,
3030 (ArH), 2569 cm21 (SH); dH 3.05 (1H, br s, OH), 3.48
(1H, s, SH), 6.14 (1H, s, CHOH), 6.67 (2H, d, J¼7.3 Hz,
ArH), 6.97–7.00 (2H, m, ArH), 7.13–7.30 (6H, m, ArH),
7.39–7.41 (2H, m, ArH), 7.60 (1H, d, J¼7.3 Hz, ArH); dC
71.6 (CHOH), 117.0, 119.1, 123.6, 124.0, 124.3, 126.5,
126.7, 127.5, 127.8, 128.4, 128.7, 129.9, 133.8, 143.1,
151.8, 153.4 (ArC); m/z 290 [Mþ–(H2O), 100%], 289 (26),
273 (11), 261 (14), 247 (10), 234 (11), 213 (25), 211 (14),
210 (87), 197 (28), 185 (31), 184 (22), 181 (14), 165 (30),
164 (11), 163 (10), 152 (20), 139 (11), 77 (13), 69 (12), 63
(17), 51 (20); HMRS: Mþ–(H2O), found 290.0762.
C19H14OS requires 290.0765.
3565, 3435 (OH), 3064 (ArH), 2583 cm21 (SH); dH 1.22–
1.31 (2H, m, CH2), 1.59–1.88 (4H, m, 2£CH2), 2.03 (4H, t,
J¼4.3 Hz, 2£CH2), 2.67 (1H, br s, OH), 3.68 (1H, s, SH),
6.68 (1H, d, J¼7.9 Hz, ArH), 6.89 (1H, d, J¼7.9 Hz, ArH),
7.03–7.17 (4H, m, ArH), 7.36 (1H, dd, J¼7.3, 1.8 Hz,
ArH), 7.53 (1H, dd, J¼7.3, 1.8 Hz, ArH); dC 21.8, 25.5, 36.7
(CH2), 73.2 (COH), 117.7, 119.6, 123.4, 124.6, 126.6,
126.8, 128.0, 129.7, 130.3, 138.2, 152.0, 154.4 (ArC); m/z
282 [Mþ–(H2O), 79%], 240 (26), 239 (100), 227 (11), 213
(16), 189 (22), 181 (24), 161 (10), 160 (15), 152 (11), 148
(16), 147 (39), 141 (12), 134 (11), 129 (20), 128 (24), 127
(11), 115 (32), 107 (15), 91 (30), 79 (13), 77 (24), 65 (17),
63 (11), 53 (16), 51 (16), 45 (16), 41 (22); HMRS: Mþ,
found 300.1175. C18H20O2S requires 300.1184.
4.2.5. 3-Phenyl-1-[2-(2-sulfanylphenoxy)phenyl]-1-pro-
panol (2ae). Colorless oil; n (film) 3520–3370 (OH),
3045, 3023 (ArH), 2563 cm21 (SH); dH 2.26–2.46 (2H, m,
PhCH2), 2.59–2.65 (2H, m, PhCH2CH2), 3.13 (1H, br s,
OH), 3.61 (1H, s, SH), 4.30 (1H, dd, J¼8.8, 6.4 Hz, CHOH),
6.72–6.89 (5H, m, ArH), 6.92–7.28 (8H, m, ArH); dC 33.7,
35.5 (CH2), 77.2 (CHOH), 114.7, 116.2, 120.3, 121.1,
126.0, 128.2, 128.3, 128.4, 128.7, 131.5, 133.3, 136.2,
136.9, 141.0, 153.4, 157.5 (ArC); m/z 336 (Mþ, 1%), 318
(46), 229 (20), 228 (16), 227 (93), 224 (12), 223 (32), 213
(46), 197 (12), 194 (11), 193 (12), 181 (27), 165 (14), 147
(12), 137 (10), 134 (11), 115 (19), 92 (12), 91 (100), 77 (22),
65 (27), 51 (17), 45 (15), 44 (16), 40 (11); HMRS: Mþ,
found 336.1149. C21H20O2S requires 336.1184.
4.2.9. 1-[2-(2-Sulfanylphenoxy)phenyl]cyclooctanol
(2ai). Colorless oil; n (film) 3520–3325 (OH), 3054, 3028
(ArH), 2555 cm21 (SH); dH 1.26–1.87 (14H, m, CH2), 2.55
(1H, br s, OH), 3.09 (1H, s, SH), 6.80–7.54 (8H, m, ArH);
dC 27.3, 31.3, 34.5, 41.9 (CH2), 72.4 (COH), 115.0, 118.1,
119.3, 120.8, 123.3, 124.2, 126.4, 129.75, 129.8, 129.9,
134.7, 155.6 (ArC); m/z 310 [Mþ–(H2O), 81%], 241 (14),
240 (27), 239 (92), 228 (19), 227 (100), 226 (24), 217 (14),
213 (34), 203 (13), 187 (10), 182 (16), 181 (45), 165 (13),
161 (23), 149 (17), 148 (33), 147 (58), 141 (16), 135 (20),
134 (18), 131 (11), 129 (22), 128 (25), 127 (12), 115 (30),
107 (23), 97 (11), 91 (28), 81 (13), 79 (12), 77 (21), 67 (36),
65 (21), 55 (38), 53 (21), 51 (17), 45 (20), 43 (13), 41 (70);
HMRS: Mþ–(H2O), found 310.1405. C20H22OS requires
310.1391.
4.2.6. 2-[2-(2-Sulfanylphenoxy)phenyl]-2-propanol (2af).
Colorless oil; n (film) 3550–3415 (OH), 3065 (ArH),
2569 cm21 (SH); dH 1.72 [6H, s, C(CH3)2], 3.25 (1H, br s,
OH), 3.67 (1H, s, SH), 6.69 (1H, dd, J¼7.9, 1.2 Hz, ArH),
6.91 (1H, dd, J¼7.9, 1.2 Hz, ArH), 7.03–7.20 (4H, m,
ArH), 7.38 (1H, dd, J¼7.3, 1.8 Hz, ArH), 7.55 (1H, dd,
J¼7.3, 1.8 Hz, ArH); dC 30.1 (CH3), 72.3 (COH), 117.5,
119.5, 123.4, 124.3, 124.6, 126.5, 126.8, 128.2, 130.3,
137.8, 152.0, 153.9 (ArC); m/z 242 [Mþ–(H2O), 48%], 228
(16), 227 (100), 194 (18), 165 (13), 149 (52), 148 (12), 147
(11), 135 (19), 134 (20), 115 (16), 107 (10), 91 (21), 77 (14),
65 (17), 59 (22), 51 (15), 43 (71); HMRS: Mþ, found
260.0866. C15H16O2S requires 260.0871.
4.2.10. 2-(N-Methylanilino)thiophenol (2ba). Colorless
oil; n (film) 3055 (ArH), 2550 cm21 (SH); dH 3.19 (3H, s,
NCH3), 3.88 (1H, s, SH), 6.62 (2H, d, J¼7.9 Hz, ArH), 6.78
(1H, t, J¼7.0 Hz, ArH), 7.12–7.22 (5H, m, ArH), 7.37–
7.40 (1H, m, ArH); dC 38.6 (CH3), 113.9, 118.2, 126.7,
127.0, 128.6, 129.0, 129.2, 133.4, 145.2, 148.6 (ArC); m/z
215 (Mþ, 100%), 214 (18), 199 (13), 182 (16), 181 (16), 180
(24), 167 (35), 136 (21), 109 (14), 104 (16), 91 (65), 84 (11),
78 (15), 77 (51), 69 (11), 65 (19), 51 (23), 45 (13); HMRS:
Mþ, found 215.0761. C13H13NS requires 215.0769.
4.2.11. 2,2-Dimethyl-1-[2-(N-methyl-2-sulfanylanilino)-
phenyl]-1-propanol (2bb). Colorless oil; n (film) 3470–
3290 (OH), 3055 (ArH), 2539 cm21 (SH); dH 0.93 [9H, s,
C(CH3)3], 2.89 (1H, br s, OH), 3.11 (3H, s, NCH3), 3.93
(1H, s, SH), 4.55 (1H, s, CHOH), 6.60 (1H, dd, J¼6.1,
3.7 Hz, ArH), 6.92–6.96 (2H, m, ArH), 7.17 (1H, t,
J¼7.3 Hz, ArH), 7.29–7.39 (3H, m, ArH), 7.48 (1H, d,
J¼7.9 Hz, ArH); dC 26.0 [C(CH3)3], 26.7 [C(CH3)3], 40.1
(NCH3), 74.9 (COH), 121.5, 123.8, 124.7, 124.9, 126.3,
127.1, 127.7, 129.2, 130.1, 137.2, 148.3, 149.6 (ArC); m/z
283 [Mþ–(H2O), 15%], 227 (13), 226 (100), 194 (86), 179
(17), 77 (14), 44 (34), 41 (19); HMRS: Mþ, found 301.1477.
C18H23NOS requires 301.1500.
4.2.7. 3-[2-(2-Sulfanylphenoxy)phenyl]-3-pentanol (2ag).
Colorless oil; n (film) 3540–3320 (OH), 3058 (ArH),
2579 cm21 (SH); dH 0.83 (6H, t, J¼7.3 Hz, 2£CH2CH3),
1.82–1.94 (2H, m, CH2CH3), 2.14–2.26 (2H, m, CH2CH3),
2.58 (1H, br s, OH), 3.68 (1H, s, SH), 6.69 (1H, d, J¼7.9 Hz,
ArH), 6.81–7.30 (4H, m, ArH), 7.33–7.42 (2H, m, ArH),
7.56 (1H, dd, J¼7.3, 1.8 Hz, ArH); dC 8.2 (CH3), 33.2
(CH2), 77.9 (COH), 117.8, 118.9, 123.2, 124.2, 126.7,
127.9, 128.8, 129.8, 130.1, 134.7, 152.2, 153.4 (ArC);
m/z 270 [Mþ–(H2O), 15%], 242 (17), 241 (100), 209 (13),
208 (39), 207 (22), 177 (10), 115 (12), 107 (11), 91 (11),
77 (14), 65 (13), 57 (49), 45 (24), 43 (13), 41 (14);
HMRS: Mþ–(H2O), found 270.1866. C17H18OS requires
270.1878.
4.2.12. Phenyl-[2-(N-methyl-2-sulfanylanilino)phenyl]-
methanol (2bc). Colorless oil; n (film) 3440–3310 (OH),
3055 (ArH), 2526 cm21 (SH); dH 2.65 (1H, br s, OH), 3.15
(3H, s, NCH3), 3.81 (1H, s, SH), 6.02 (1H, s, CHOH), 6.82
(1H, dd, J¼7.6, 1.5 Hz, ArH), 6.89–7.01 (2H, m, ArH),
7.10 (1H, t, J¼7.3 Hz, ArH), 7.18–7.33 (9H, m, ArH); dC
41.5 (NCH3), 70.6 (COH), 121.7, 124.2, 124.4, 124.8,
4.2.8. 1-[2-(2-Sulfanylphenoxy)phenyl]cyclohexanol
(2ah). White solid, mp 166–1678C (dichloro-
methane/hexane); [Found: C, 71.58; H, 6.59; S, 9.93.
C18H20O2S requires C, 71.97; H, 6.71; S, 10.67]; n (KBr)

2088
M. Yus et al. / Tetrahedron 59 (2003) 2083–2092
126.5, 126.7, 127.0, 128.0, 128.5, 129.8, 130.5, 138.2,
142.8, 148.3, 148.8 (ArC); m/z 303 [Mþ–(H2O), 62%], 302
(20), 288 (33), 273 (28), 271 (27), 270 (100), 255 (14), 254
(21), 227 (13), 226 (75), 224 (19), 207 (14), 197 (19), 194
(51), 193 (11), 165 (30), 152 (26), 151 (10), 143 (10), 139
(15), 136 (13), 135 (33), 134 (11), 133 (12), 128 (24), 127
(36), 126 (12), 121 (14), 115 (17), 109 (15), 91 (20), 77 (24),
69 (11), 65 (20), 63 (17), 51 (19), 45 (15), 44 (12); HMRS:
Mþ–(H2O), found 303.1089. C20H17NS requires 303.1082.
HMRS: Mþ–(H2O), found 306.0533. C19H14S2 requires
306.0537.
4.3. Sequential double lithiation of thianthrene (1c) and
reaction with carbonyl compounds
Isolation of compounds 3. General procedure. To a blue
suspension of lithium powder (100 mg, 14 mmol) and a
catalytic amount of DTBB (40 mg, 0.15 mmol; 7.5 mol%)
in THF (4 mL) thianthrene (1c, 430 mg, 2.0 mmol) was
added at 2908C, and the resulting mixture was stirred for
45 min at the same temperature. Then, the corresponding
carbonyl compound (2.1 mmol) was added dropwise and
stirring was continued for 45 min at 2908C. After that, a
second carbonyl compound was added (2.4 mmol) allowing
the reaction temperature to rise to 2788C for 30 min and the
resulting mixture was hydrolysed with water (10 mL),
extracted with ethyl acetate (3£20 mL), dried over
anhydrous Na2SO4 and evaporated (15 Torr). The residue
was purified by column chromatography (silica gel,
hexane/ethyl acetate) to yield pure products. Yields and Rf
values are given in Table 2, physical, analytical and
spectroscopic data follow.
4.2.13. 3-Phenyl-1-[2-(N-methyl-2-sulfanylanilino)phe-
nyl]-1-propanol (2bd). Colorless oil; n (film) 3470–3360
(OH), 3055 (ArH), 2533 cm21 (SH); dH 1.35–1.46 (1H, m,
CHHCHOH), 1.69–1.84 (1H, m, CHHCHOH), 2.32–2.42
(1H, m, CHHPh), 2.58–2.68 (1H, m, CHHPh), 2.98 (1H, br
s, OH), 3.01 (3H, s, NCH3), 3.79 (1H, s, SH), 4.76 (1H, dd,
J¼9.2, 3.7 Hz, CHOH), 6.65–6.68 (1H, m, ArH), 6.89–
6.98 (4H, m, ArH), 7.05–7.24 (7H, m, ArH), 7.41 (1H, d,
J¼7.9 Hz, ArH); dC 33.0, 39.3 (CH2), 41.0 (NCH3), 68.3
(COH), 121.0, 124.3, 124.9, 125.0, 125.6, 126.3, 127.6,
128.1, 128.2, 128.4, 129.1, 130.1, 139.0, 142.2, 147.5, 149.1
(ArC); m/z 331 [Mþ–(H2O), 57%], 298 (11), 241 (10), 240
(59), 227 (18), 226 (79), 225 (18), 224 (30), 223 (21), 208
(13), 207 (38), 206 (11), 195 (15), 194 (100), 193 (19), 192
(11), 180 (18), 179 (16), 166 (10), 147 (11), 115 (17), 109
(12), 107 (41), 91 (63), 78 (10), 77 (33), 65 (38), 63 (11), 51
(25), 45 (18); HMRS: Mþ–(H2O), found 331.1405.
C22H21NS requires 331.1395.
4.3.1. 1-[2-(1-Hydroxy-2,2-dimethylpropyl)phenyl]-2,2-
dimethyl-1-propanol (3a). First isomer: colorless liquid;
n (film) 3485–3360 (OH), 3065 (ArH), 1246 cm21 (CO);
dH 0.99 [18H, s, C(CH3)3], 2.07 (2H, br s, OH), 4.93 (2H, s,
CHOH), 7.22 (2H, dd, J¼5.9, 3.4 Hz, ArH), 7.42 (2H, dd,
J¼5.9, 3.4 Hz, ArH); dC 27.1 [C(CH3)3], 36.3 [C(CH3)3],
78.6 (CHOH), 126.6, 128.8, 140.6 (ArC); m/z 232 [Mþ–
(H2O), 0.1%], 193 (11), 176 (12), 175 (84), 158 (14), 157
(100), 142 (31), 129 (16), 118 (12), 91 (13), 57 (19); HMRS:
Mþ, found 250.1933. C16H26O2 requires 250.1933. Second
isomer: colorless liquid; n (film) 3455–3340 (OH), 3063
(ArH), 1242 cm21 (CO); dH 0.88 [18H, s, C(CH3)3], 1.57
(2H, br s, OH), 4.87 (2H, s, CHOH), 7.25 (2H, dd, J¼5.8,
3.4 Hz, ArH), 7.42 (2H, dd, J¼5.8, 3.4 Hz, ArH); dC 26.0
[C(CH3)3], 35.1 [C(CH3)3], 76.5 (CHOH), 126.6, 126.7,
139.8 (ArC); m/z 232 [Mþ–(H2O), 0.4%], 193 (21), 175
(64), 158 (21), 157 (100), 142 (26), 129 (15), 91 (22), 57
(18); HMRS: Mþ, found 250.1910. C16H26O2 requires
250.1933.
4.2.14. 2-Phenylsulfanylthiophenyl (2ca).32 Colorless oil;
n (film) 3055 (ArH), 2555 cm21 (SH); dH 4.23 (1H, s, SH),
7.06–7.11 (1H, m, ArH), 7.15–7.30 (6H, m, ArH), 7.37
(2H, d, J¼7.9 Hz, ArH); dC 126.1, 126.7, 128.8, 129.2,
129.4, 131.7, 134.6, 135.2, 137.2 (ArC); m/z 218 (Mþ,
70%), 185 (28), 184 (39), 141 (11), 140 (100), 109 (16), 108
(11), 96 (15), 92 (19), 77 (22), 69 (24), 65 (16), 51 (20), 45
(11); HMRS: Mþ, found 218.0228. C12H10S2 requires
218.0224.
4.2.15. 2,2-Dimethyl-1-[2-(2-sulfanylphenylsulfanyl)phe-
nyl]-1-propanol (2cb). Colorless oil; n (film) 3480–3310
(OH), 3055 (ArH), 2539 cm21 (SH); dH 1.01 [9H, s,
C(CH3)3], 2.86 (1H, br s, OH), 4.05 (1H, s, SH), 5.13 (1H, s,
CHOH), 6.98–7.27 (6H, m, ArH), 7.34 (1H, d, J¼7.9 Hz,
ArH), 7.57 (1H, d, J¼7.3 Hz, ArH); dC 26.0 [C(CH3)3], 36.8
[C(CH3)3], 77.1 (CHOH), 126.2, 126.7, 128.0, 128.3, 128.6,
129.6, 130.3, 133.0, 133.7, 133.9, 136.1, 142.5 (ArC); m/z
304 (Mþ, 1.3%), 231 (11), 230 (21), 229 (100), 197 (24),
184 (11), 137 (21), 109 (16), 77 (15), 57 (15), 41 (30);
HMRS: Mþ, found 304.0944. C17H20OS2 requires
304.0956.
4.3.2. 1-[2-(1-Hydroxy-1-methylethyl)phenyl]-2,2-
dimethyl-1-propanol (3b). Colorless liquid; n (film)
3453–3335 (OH), 3055 (ArH), 1265 cm21 (CO); dH 0.96
[9H, s, C(CH3)3], 1.57 (3H, s, CH3), 1.65 (3H, s, CH3), 2.12
(2H, br s, OH), 5.54 (1H, s, CHOH), 7.10–7.19 (2H, m,
ArH), 7.26 (1H, dd, J¼7.3, 1.8 Hz, ArH), 7.57 (1H, dd,
J¼7.3, 1.8 Hz, ArH); dC 27.5 [C(CH3)3], 32.9, 33.4 (CH3),
36.3 [C(CH3)3], 74.1 (COH), 75.9 (CHOH), 125.6, 126.6,
126.9, 129.3, 141.6, 145.5 (ArC); m/z 204 [Mþ–(H2O),
0.5%], 148 (11), 147 (100), 129 (59), 91 (14), 77 (12), 57
(15), 43 (38), 41 (32); HMRS: Mþ–(H), found 221.1525.
C14H21O2 requires 221.15442.
4.2.16. Phenyl-[2-(2-sulfanylphenylsulfanyl)phenyl]-
methanol (2cc). Colorless oil; n (film) 3420–3290 (OH),
3052 (ArH), 2531 cm21 (SH); dH 2.39 (1H, br s, OH), 3.89
(1H, s, SH), 6.25 (1H, s, CHOH), 6.91–7.32 (12H, m, ArH),
7.52 (1H, d, J¼7.3 Hz, ArH); dC 73.2 (CHOH), 126.3,
127.0, 127.6, 127.7, 128.3, 128.4, 128.5, 129.8, 131.3,
132.5, 132.7, 133.4, 135.5, 142.5, 143.7 (ArC); m/z 306
[Mþ–(H2O), 59%], 274 (20), 273 (100), 272 (13), 271 (33),
229 (40), 198 (15), 197 (85), 184 (11), 165 (50), 164 (14),
163 (12), 153 (14), 152 (23), 139 (12), 137 (15), 136 (36),
91 (16), 77 (13), 69 (16), 63 (17), 51 (17), 45 (18);
4.3.3. 2-[2-(Hydroxyphenylmethyl)phenyl]-2-propanol
(3c). Colorless liquid; n (film) 3410–3295 (OH), 3062,
3030 (ArH), 1247 cm21 (CO); dH 1.65 (3H, s, CH3), 1.66
(3H, s, CH3), 3.43 (2H, br s, OH), 6.56 (1H, s, CH), 7.13–
7.32 (9H, m, ArH); dC 32.7, 32.8 (CH3), 73.1 (CHOH), 74.6
(COH), 126.2, 126.5, 126.7, 127.2, 127.5, 128.1, 131.0,

M. Yus et al. / Tetrahedron 59 (2003) 2083–2092
2089
141.6, 144.4, 145.5 (ArC); m/z 224 [Mþ–(H2O), 62%],
223 (32), 210 (16), 209 (100), 208 (17), 195 (13), 194 (46),
191 (12), 166 (10), 165 (31), 105 (17), 91 (11), 77 (26);
HMRS: Mþ–(H2O), found 224.1202. C16H16O requires
224.1201.
(CH2), 80.0 (COH), 125.4, 129.4, 143.9 (ArC); m/z 221
[Mþ–(CH2CH3), 3%], 204 (15), 203 (100), 157 (23), 145
(18), 143 (27), 131 (12), 129 (19), 117 (24), 115 (15), 91 (21),
59 (10), 57 (38), 45 (10), 43 (44), 41 (21); HMRS: Mþ–
(CH2CH3), found 221.1525. C14H21O2 requires 221.1542.
4.3.4. 1-[2-(1-Hydroxy-1-methylethyl)phenyl]-3-phenyl-
1-propanol (3d). Colorless oil; n (film) 3390–3255 (OH),
3062, 3026 (ArH), 1247 cm21 (CO); dH 1.49 (3H, s, CH3),
1.60 (3H, s, CH3), 1.96–2.10 (1H, m, CHCHH), 2.16–2.29
(1H, m, CHCHH), 2.62–2.72 (1H, m, PhCHH), 2.83–2.93
(1H, m, PhCHH), 3.09 (2H, br s, OH), 5.46 (1H, dd, J¼9.0,
4.3 Hz, CHOH), 7.12–7.28 (8H, m, ArH), 7.48–7.51 (1H,
m, ArH); dC 32.45, 32.5 (CH3), 33.0 (CH2), 39.2 (PhCH2),
69.9 (CHOH), 73.9 (COH), 125.6, 125.7, 127.1, 127.4,
127.9, 128.3, 128.4, 142.1, 142.6, 144.7 (ArC); m/z 252
[Mþ–(H2O), 5%], 148 (14), 147 (100), 129 (44), 105 (10),
103 (11), 91 (51), 77 (21), 65 (16), 51 (10), 43 (40), 41 (15);
HMRS: Mþ–(H2O), found 252.1510. C18H20O requires
252.1514.
4.3.9. 1-[2-(1-Hydroxycyclohexyl)phenyl]cyclohexanol
(3i). White solid, mp 170–1718C (dichloromethane/
hexane); [Found: C, 78.57; H, 9.27. C18H26O2 requires C,
78.79; H, 9.55]; n (KBr) 3415 (OH), 3055 (ArH),
1264 cm21 (CO); dH 1.28–1.35 (2H, m, CH2), 1.64–1.87
(14H, m, 7£CH2), 2.05–2.24 (4H, m, 2£CH2), 4.58 (2H, br
s, OH), 7.08–7.25 (2H, m, ArH), 7.36–7.44 (2H, m, ArH);
dC 22.2, 25.6, 40.3 (CH2), 75.6 (COH), 126.1, 127.9, 147.0
(ArC); m/z 256 [Mþ–(H2O), 14%], 214 (17), 213 (100), 195
(11), 157 (32), 145 (14), 129 (22), 128 (11), 115 (14), 91
(13), 55 (29), 43 (23), 41 (37).
4.4. Sequential double lithiation of thianthrene (1c) and
reaction with carbonyl compounds and carbon dioxide,
respectively
4.3.5. 2-[2-(1-Hydroxy-1-methylethyl)phenyl]-2-pro-
panol (3e).32 White solid, mp 169–1708C (dichloro-
methane/hexane); [Found: C, 74.34; H, 9.14. C12H18O2
requires C, 74.19; H, 9.34]; n (KBr) 3340–3260 (OH), 3055
(Ar-H), 1264 cm21 (CO); dH 1.64 (12H, s, CH3), 7.09 (2H,
dd, J¼6.1, 3.7 Hz, ArH), 7.25 (2H, dd, J¼6.1, 3.7 Hz, ArH);
dC 33.5 (CH3), 74.9 (COH), 126.3, 128.1, 145.6 (ArC); m/z
179 [Mþ–(CH3), 11%], 162 (12), 161 (95), 143 (46), 128
(25), 118 (12), 117 (19), 115 (12), 91 (16), 77 (13), 59 (13),
51 (14), 43 (100).
Isolation of compounds 4. General procedure. To a blue
suspension of lithium powder (100 mg, 14 mmol) and a
catalytic amount of DTBB (40 mg, 0.15 mmol; 7.5 mol%)
in THF (4 mL) thianthrene (1c, 430 mg, 2.0 mmol) was
added at 2908C, and the resulting mixture was stirred for
45 min at the same temperature. Then, the corresponding
carbonyl compound (2.1 mmol) was added dropwise and
stirring was continued for 45 min at 2908C. After that
carbon dioxide was bubbled for 15 min at 2708C, and the
reaction mixture was hydrolysed with water, extracted with
ether (3£20 mL) and the aqueous layer was acidified with
3 M HCl and extracted with ethyl acetate (3£20 mL), dried
over anhydrous Na2SO4 and evaporated (15 Torr). The
residue was purified by column chromatography (silica gel,
hexane/ethyl acetate) to yield pure products. Yields and Rf
values are given in Table 3, physical, analytical and
spectroscopic data follow.
4.3.6. 3-[2-(1-Hydroxy-1-methylethyl)phenyl]-3-penta-
nol (3f). White solid, mp 131–1328C (dichloromethane/
hexane); [Found: C, 75.62; H, 10.09. C14H22O2 requires C,
75.63; H, 9.97]; n (KBr) 3310–3190 (OH), 3058 (ArH),
1266 cm21 (CO); dH 0.81 (6H, t, J¼7.3 Hz, 2£CH2CH3),
1.75 (6H, s, 2£CH3), 1.80–1.91 (2H, m, CH2), 1.96–2.08
(2H, m, CH2), 5.08 (2H, br s, OH), 7.11–7.19 (3H, m, ArH),
7.36 (1H, d, J¼7.3 Hz, ArH); dC 8.4, 33.1 (CH3), 37.5
(CH2), 74.7, 80.4 (COH), 125.6, 126.4, 127.2, 129.4, 143.5,
146.5 (ArC); m/z 204 [Mþ–(H2O), 0.5%], 189 (8), 176 (13),
175 (100), 157 (26), 145 (11), 142 (22), 131 (11), 129 (14),
117 (14), 115 (13), 91 (11).
4.4.1. 3-Methyl-1,3-dihydro-1-isobenzofuranone (4a).34
Colorless liquid; n (film) 3057 (ArH), 1758 (CvO),
1267 cm21 (CO); dH 1.57 (3H, d, J¼6.7 Hz, CHCH3),
5.50 (1H, q, J¼6.7 Hz, CHCH3), 7.37 (1H, d, J¼7.6 Hz,
ArH), 7.46 (1H, t, J¼7.6 Hz, ArH), 7.61 (1H, td, J¼7.6,
1.0 Hz, ArH), 7.83 (1H, d, J¼7.6 Hz, ArH); dC 20.4 (CH3),
77.7 (CHO), 121.5, 125.7, 126.5, 129.0, 134.0, 151.2 (ArC),
170.4 (CvO); m/z 148 (Mþ, 19%), 133 (66), 105 (100), 77
(30), 51 (16); HMRS: Mþ, found 148.0502. C9H8O2
requires 148.0524.
4.3.7. 1-[2-(1-Hydroxy-1-methylethyl)phenyl]cyclo-
hexanol (3g).33 White solid, mp 156–1578C (dichloro-
methane/hexane); [Found: C, 75.98; H, 9.44. C15H22O2
requires C, 76.88; H, 9.46]; n (KBr) 3305–3210 (OH), 3055
(ArH), 1266 cm21 (CO); dH 1.58–1.88 (14H, m, 4£CH2,
2£CH3), 2.13–2.16 (2H, m, CH2), 5.17 (2H, br s, OH),
7.14–7.17 (2H, m, ArH), 7.30–7.33 (1H, m, ArH), 7.37–
7.40 (1H, m, ArH); dC 22.1, 25.6 (CH2), 34.1 (CH3), 39.8
(CH2), 74.9, 75.3 (COH), 126.1, 126.2, 127.4, 128.5, 146.2,
146.4 (ArC); m/z 234 (Mþ, 0.5%), 216 (12), 201 (25), 183
(11), 174 (13), 173 (100), 145 (38), 115 (14), 91 (13), 55
(15), 43 (60), 41 (21).
4.4.2. 3-Butyl-1,3-dihydro-1-isobenzofuranone (4b).35
Colorless liquid; n (film) 3056 (ArH), 1760 (CvO),
1267 cm21 (CO); dH 0.84 (3H, t, J¼7.1 Hz, CH3), 1.24–
1.44 (3H, m, CH2, CHH), 1.63–1.75 (2H, m, CH2),
1.92–2.03 (1H, m, CHH), 5.40 (1H, q, J¼4.1 Hz, CH),
7.36 (1H, d, J¼7.6 Hz, ArH), 7.45 (1H, t, J¼7.6 Hz, ArH),
7.60 (1H, t, J¼7.6 Hz, ArH), 7.82 (1H, d, J¼7.6 Hz, ArH);
dC 13.8 (CH3), 22.4, 26.8, 34.4 (CH2), 81.4 (CHO), 121.7,
125.7, 126.2, 129.0, 133.9, 150.1 (ArC), 170.6 (CvO);
m/z 190 (Mþ, 2%), 134 (11), 133 (100), 105 (29), 77
(12); HMRS: Mþ, found 190.0983. C12H14O2 requires
190.0994.
4.3.8. 3-[2-(1-Ethyl-1-hydroxypropyl)phenyl]-3-pentanol
(3h). Colorless liquid; n (film) 3330–3225 (OH), 3056
(ArH), 1265 cm21 (CO); dH 0.80 (12H, t, J¼7.0 Hz,
4£CH2CH3), 1.91–2.11 (8H, m, 4£CH2CH3), 5.77 (2H,
br s, OH), 7.11–7.26 (4H, m, ArH); dC 8.4 (CH3), 36.0

2090
M. Yus et al. / Tetrahedron 59 (2003) 2083–2092
4.4.3. 3-Octyl-1,3-dihydro-1-isobenzofuranone (4c).36
Colorless oil; n (film) 3055 (ArH), 1763 (CvO),
1285 cm21 (CO); dH 0.80 (3H, t, J¼6.5 Hz, CH3), 1.12–
1.24 (11H, m, 5£CH2, CHH), 1.36–1.41 (1H, m, CHH),
1.62–1.74 (1H, m, CHH), 1.91–2.00 (1H, m, CHH), 5.40
(1H, dd, J¼7.8, 4.1 Hz, CHH), 7.36 (1H, d, J¼7.7 Hz,
ArH), 7.44 (1H, t, J¼7.4 Hz, ArH), 7.59 (1H, t, J¼7.4 Hz,
ArH), 7.82 (1H, d, J¼7.7 Hz, ArH); dC 14.0 (CH3), 22.6,
24.8, 29.1, 29.3, 31.7, 34.7 (CH2), 81.5 (CHO), 121.7,
125.6, 126.1, 129.0, 133.9, 150.1 (ArC), 170.7 (CvO); m/z
246 (Mþ, 6%), 176 (12), 134 (15), 133 (100), 105 (21), 77
(11); HMRS: Mþ, found 246.1609. C16H22O2 requires
246.1620.
(0.5 mmol) in toluene (3 mL) 85% phosphoric acid
(0.2 mL) was added. The reaction mixture was heated at
1108C for 12 h in the case of hydroxythiols 2 and for 2 h in
the case of diols 3, then toluene was removed by distillation
and the resulting residue was hydrolysed with water and
extracted with ethyl acetate (3£20 mL), the organic layer
dried over anhydrous Na2SO4 and evaporated (15 Torr).
The residue was purified by column chromatography (silica
gel, hexane/ethyl acetate) to yield pure products 5 and 6.
Yields and Rf values are given in Tables 4 and 5, analytical
and spectroscopic data follow.
4.5.1. 11-Phenyl-11H-dibenzo[b, f ][1,4]oxathiepin (5a).
Colorless oil; n (film) 3048, 3017 (ArH) 1233 cm21 (CO);
dH 6.20 (1H, s, ArCH), 6.95 (2H, t, J¼7.6 Hz, ArH), 7.04–
7.09 (3H, m, ArH), 7.22–7.44 (8H, m, ArH); dC 47.9
(ArCH), 122.0, 122.4, 124.8, 125.3, 126.7, 127.75, 127.8,
127.9, 128.55, 128.6, 129.1, 129.2, 135.0, 138.5, 153.6,
156.2 (ArC); m/z 290 (Mþ, 100%), 289 (26), 273 (13), 261
(14), 213 (23), 211 (14), 210 (83), 197 (30), 185 (32), 184
(20), 181 (15), 165 (29), 152 (18), 139 (11), 77 (11), 69 (11),
63 (15), 51 (16); HMRS: Mþ, found 290.0756. C19H14OS
requires 290.0765.
4.4.4. 3-Phenyl-1,3-dihydro-1-isobenzofuranone (4d).37
White solid, mp 113–1148C (dichloromethane/hexane);
[Found: C, 79.68; H, 4.68. C14H10O2 requires C, 79.98; H,
4.79]; n (KBr) 3056 (ArH), 1765 (CvO), 1281 cm21 (CO);
dH 6.33 (1H, s, CHO), 7.18–7.31 (6H, m, ArH), 7.48 (1H, t,
J¼7.3 Hz, ArH), 7.55–7.60 (1H, m, ArH), 7.89 (1H, t,
J¼7.3 Hz, ArH); dC 82.7 (CHO), 122.8, 125.6, 126.9, 128.4,
128.9, 129.3, 129.35, 134.3, 136.4, 149.7 (ArC), 170.5
(CvO); m/z 210 (Mþ, 42%), 209 (10), 165 (18), 133 (10),
105 (100), 104 (30), 77 (36), 76 (19), 51 (31), 50 (19).
4.5.2. 11,11-Diethyl-11H-dibenzo[b, f ][1,4]oxathiepin
(5b). Colorless oil; n (film) 3060, 3026 (ArH) 1245 cm21
(CO); dH 0.96 (6H, t, J¼7.3 Hz, 2£CH2CH3), 2.03–2.15
(2H, m, CH2CH3), 2.26–2.38 (2H, m, CH2CH3), 6.98–7.26
(8H, m, ArH); dC 9.1 (CH3), 32.3 (CH2), 55.6 (CS), 121.6,
123.2, 124.7, 124.9, 127.1, 127.4, 128.3, 130.9, 136.3,
139.4, 151.7, 155.8 (ArC); m/z 270 (Mþ, 23%), 255 (13),
243 (12), 242 (19), 241 (100), 209 (23), 208 (11), 207 (15),
181 (14), 177 (18), 163 (11), 149 (13), 115 (17), 107 (16), 91
(11), 77 (11), 51 (11), 45 (13), 44 (29), 41 (15), 40 (36);
HMRS: Mþ, found 270.1048. C17H18OS requires 270.1078.
4.4.5. 3,3-Dimethyl-1,3-dihydro-1-isobenzofuranone
(4e).38 Colorless liquid; n (film) 3056 (ArH), 1759
(CvO), 1266 cm21 (CO); dH 1.65 (6H, s, 2£CH3), 7.40
(1H, d, J¼7.3 Hz, ArH), 7.49 (1H, t, J¼7.3 Hz, ArH), 7.65
(1H, t, J¼7.3 Hz, ArH), 7.85 (1H, d, J¼7.3 Hz, ArH); dC
27.3 (CH3), 85.4 (CO), 120.6, 125.2, 125.7, 128.9, 134.1,
154.9 (ArC), 169.8 (CvO); m/z 162 (Mþ, 5%), 148 (12),
147 (100), 91 (27), 51 (14), 50 (18), 43 (30); HMRS: Mþ,
found 162.0675. C10H10O2 requires 162.0681.
4.4.6. 3-Ethyl-3-methyl-1,3-dihydro-1-isobenzofuranone
(4f).39 Colorless liquid; n (film) 3056 (ArH), 1758 (CvO),
1267 cm21 (CO); dH 0.67 (3H, t, J¼7.4 Hz, CH2CH3), 1.56
(3H, s, COCH3), 1.75–1.90 (1H, m, CHHCH3), 1.93–2.09
(1H, m, CHHCH3), 7.29 (1H, d, J¼7.7 Hz, ArH), 7.42 (1H,
t, J¼7.6 Hz, ArH), 7.59 (1H, t, J¼7.6 Hz, ArH), 7.79 (1H, d,
J¼7.7 Hz, ArH); dC 7.7, 25.6 (CH3), 32.8 (CH2), 87.9 (CO),
120.8, 125.6, 128.0, 128.8, 134.0, 153.6 (ArC), 170.1
(CvO); m/z 176 (Mþ, 2%), 148 (10), 147 (100), 91
(16); HMRS: Mþ, found 176.0818. C11H12O2 requires
176.0837.
4.5.3. 11-(tert-Butyl)-11H-dibenzo[b,e][1,4]dithiepin
(5c). Pale yellow oil; n (film) 3055 (ArH), 739 cm21
(CS); dH 1.21 [9H, s, C(CH3)3], 5.68 (1H, s, SCH), 6.88–
6.98 (2H, m, ArH), 7.07–7.25 (3H, m, ArH), 7.31 (1H, d,
J¼7.3 Hz, ArH), 7.41 (1H, d, J¼7.3 Hz, ArH), 7.56 (1H, d,
J¼7.9 Hz, ArH); dC 28.8 [C(CH3)3], 29.7 [C(CH3)3], 56.1
(SCH), 125.9, 126.0, 126.9, 127.4, 127.7, 127.9, 129.1,
130.7, 132.5, 134.7, 136.3, 137.3 (ArC); m/z 286
(Mþ, 13%), 231 (12), 230 (27), 229 (100), 197 (48), 41
(18); HMRS: Mþ, found 286.0835. C17H18S2 requires
286.0850.
4.4.7. Spirocyclohexane-3-[1,3-dihydro-1-isobenzofura-
none] (4g).40 Colorless oil; n (film) 3055 (ArH), 1756
(CvO), 1266 cm21 (CO); dH 1.72–1.85 (10H, m, 5£CH2),
7.38 (1H, d, J¼7.3 Hz, ArH), 7.48 (1H, t, J¼7.3 Hz, ArH),
7.63 (1H, t, J¼7.3 Hz, ArH), 7.85 (1H, d, J¼7.3 Hz, ArH);
dC 22.3, 24.7, 36.3 (CH2), 86.9 (CO), 120.9, 125.4, 125.7,
128.9, 133.9, 154.9 (ArC), 170.1 (CvO); m/z 202 (Mþ,
41%), 160 (15), 159 (94), 147 (15), 146 (100), 131 (24), 105
(13), 104 (24), 103 (11), 77 (15), 76 (27), 55 (11), 51 (17),
50 (20), 41 (19); HMRS: Mþ, found 202.0999. C13H14O2
requires 202.0994.
4.5.4. 11-Phenyl-11H-dibenzo[b,e][1,4]dithiepin (5d).
Pale yellow oil; n (film) 3056 (ArH), 745 cm21 (CS); dH
6.66 (1H, s, SCH), 6.87–6.99 (4H, m, ArH), 7.08–7.22 (7H,
m, ArH), 7.40–7.43 (1H, m, ArH), 7.51–7.54 (1H, m,
ArH); dC 51.8 (SCH), 126.6, 127.5, 127.9, 128.2, 128.4,
128.8, 128.9, 129.1, 131.3, 132.8, 133.1, 134.4, 134.8,
138.4, 139.6, 142.1 (ArC); m/z 306 (Mþ, 64%), 274 (22),
273 (100), 272 (12), 271 (33), 229 (44), 198 (12), 197 (84),
184 (12), 165 (48), 164 (14), 163 (12), 153 (15), 152 (25),
139 (14), 137 (16), 136 (43), 91 (18), 77 (14), 69 (17), 63
(18), 51 (18), 45 (19); HMRS: Mþ, found 306.0561.
C19H14S2 requires 306.0537.
4.5. Cyclisation of hydroxythiols 2 and diols 3
Isolation of compounds 5 and 6. General procedure. To a
solution of the corresponding hydroxythiol 2 or diol 3
4.5.5. 3-(2-Phenylethyl)-1,1-dimethyl-1,3-dihydroiso-
benzofuran (6a). Colorless oil; n (film) 3061, 3026

M. Yus et al. / Tetrahedron 59 (2003) 2083–2092
2091
(ArH), 1257 cm21 (CO); dH 1.48 (3H, s, CH3), 1.58 (3H, s,
CH3), 1.94–2.06 (1H, m, CHCHH), 2.15–2.27 (1H, m,
CHCHH), 2.67–2.85 (2H, m, PhCH2), 5.27 (1H, dd, J¼5.3,
3.8 Hz, CHO), 7.10–7.30 (9H, m, ArH); dC 29.0 (CH3),
29.7 (CH2), 31.4 (CH3), 38.5 (CH2), 80.7 (CHO), 84.8 (CO),
120.6, 121.0, 125.7, 127.3, 127.6, 128.3, 128.4, 141.2,
142.4, 147.4 (ArC); m/z 252 (Mþ, 10%), 237 (11), 174 (13),
148 (11), 147 (100), 131 (11), 129 (30), 91 (43); HMRS:
Mþ, found 252.1490. C18H20O requires 252.1514.
´
1991, 2, 155–181. (b) Najera, C.; Yus, M. Org. Prep. Proc.
´
1995, 27, 383–457. (c) Najera, C.; Yus, M. Recent Res. Dev.
´
Org. Chem. 1997, 1, 67–96. (d) Najera, C.; Yus, M. Curr. Org.
Chem., in press.
2. For a review, see: Yus, M.; Foubelo, F. Rev. Heteroatom
Chem. 1997, 17, 73–107.
3. For a review on the generation of organolithium reagents from
non-halogenated materials, see: Guijarro, D.; Yus, M. Recent
Res. Dev. Org. Chem. 1998, 2, 713–744.
4. Wakefield, B. Organolithium Methods; Academic: London,
1988.
4.5.6. 1,1,3,3-Tetramethyl-1,3-dihydroisobenzofuran
(6b).41 Colorless oil; n (film) 3055 (ArH), 1261 cm21
(CO); dH 1.52 (12H, s, 4£CH3), 7.09 (2H, dd, J¼5.5,
3.1 Hz, ArH), 7.27 (2H, dd, J¼5.5, 3.1 Hz, ArH); dC 30.8
(CH3), 84.1 (CO), 120.7, 127.4, 146.1 (ArC); m/z 161
[Mþ–(CH3), 100%], 143 (29), 128 (16), 115 (10), 51 (11),
43 (58); HMRS: Mþ, found 176.1196. C12H16O requires
176.1201.
5. For a review, see: Foubelo, F.; Yus, M. Trends Org. Chem.
1998, 7, 1–26.
´
6. Barluenga, J.; Yus, M.; Concellon, J. M.; Bernad, P. J. Org.
Chem. 1981, 46, 2721–2726, and references cited therein.
7. For the first account on this reaction, see: Yus, M.; Ramon,
´
D. J. J. Chem. Soc., Chem. Commun. 1991, 398–400.
8. For reviews, see: (a) Yus, M. Chem. Soc. Rev. 1996, 155–161.
´
(b) Ramon, D. J.; Yus, M. Eur. J. Org. Chem. 2000, 225–237.
´
(c) Yus, M. Synlett 2001, 1197–1205. (d) Yus, M.; Ramon,
´
D. J. Lat. J. Chem. 2002, 79–92. (e) Ramon, D. J.; Yus, M.
4.5.7. Spirocyclohexane-1-[3,3-dimethyl-1,3-dihydroiso-
benzofuran] (6c).42 Colorless oil; n (film) 3070, 3024
(ArH), 1263 cm21 (CO); dH 1.50 (6H, s, 2£CH3), 1.61–
1.85 (10H, m, 5£CH2), 7.07–7.11 (2H, m, ArH), 7.24–7.27
(2H, m, ArH); dC 22.4, 25.3 (CH2), 31.1 (CH3), 39.5 (CH2),
83.8, 85.2 (CO), 120.8, 121.0, 127.2, 127.5, 146.3, 146.7
(ArC); m/z 216 (Mþ, 25%), 201 (19), 174 (13), 173 (100),
145 (37), 115 (14); HMRS: Mþ, found 216.1505. C15H20O
requires 216.1514.
Rev. Cubana Quim. 2002, 14, 75–115.
9. (a) van den Ancker, T. R.; Hanson, G. R.; Lee, F.-C.; Raston,
´
C. L. Chem. Commun. 1997, 125–126. (b) Gomez, C.; Ruiz,
S.; Yus, M. Tetrahedron Lett. 1998, 39, 1397–1400.
´
(c) Gomez, C.; Ruiz, S.; Yus, M. Tetrahedron 1999, 55,
7017–7026. (d) Arnauld, T.; Barret, A. G. M.; Hopkins, B. T.
Tetrahedron Lett. 2002, 43, 1081–1083.
´
10. Yus, M.; Gomez, C.; Candela, P. Tetrahedron 2002, 58,
6207–6210.
4.5.8. 1,1,3,3-Tetraethyl-1,3-dihydroisobenzofuran (6d).
Colorless oil; n (film) 3070, 3027 (ArH), 1242 cm21 (CO);
dH 0.92 (12H, t, J¼7.6 Hz, 4£CH2CH3), 1.69–1.89 (8H, m,
4£CH2CH3), 7.06 (2H, dd, J¼5.5, 3.1 Hz, ArH), 7.24 (2H,
dd, J¼5.5, 3.1 Hz, ArH); dC 8.6 (CH3), 32.6 (CH2), 88.9
(CO), 121.5, 127.0, 145.5 (ArC); m/z 203 [Mþ–(CH2CH3),
100%], 159 (14), 157 (18), 145 (11), 143 (22), 129 (15), 115
(13), 91 (15), 57 (21), 43 (29), 41 (16); HMRS: Mþ–
(CH2CH3), found 203.1428. C14H19O requires 203.1436.
11. For studies on the mechanism of this reaction, see: (a) Yus, M.;
Herrera, R. P.; Guijarro, D. Tetrahedron Lett. 2001, 42,
3455–3458. (b) Yus, M.; Herrera, R. P.; Guijarro, D. Chem.
Eur. J. 2002, 8, 2574–2584.
12. (a) Sabes, S. F.; Urbanek, R. A.; Forsyth, C. J. J. Am. Chem.
Soc. 1998, 120, 2534–2542. (b) Alonso, F.; Lorenzo, E.; Yus,
M. Tetrahedron Lett. 1998, 39, 3303–3306. (c) Lorenzo, E.;
Alonso, F.; Yus, M. Tetrahedron 2000, 56, 1745–1757.
(d) Lorenzo, E.; Alonso, F.; Yus, M. Tetrahedron Lett. 2000,
41, 1661–1665. (e) Alonso, F.; Falvello, L. R.; Fanwick, P. E.;
Lorenzo, E.; Yus, M. Synthesis 2000, 949–952. (f) Alonso, F.;
4.5.9. Spirocyclohexane-1-{spirocyclohexane-3-[-1,3-
dihydroisobenzofuran]} (6e). Colorless oil; n (film)
3047, 3029 (ArH), 1266 cm21 (CO); dH 1.26–1.36 (2H,
m, CH2), 1.62–1.89 (18H, m, 9£CH2), 7.08 (2H, dd, J¼5.5,
3.1 Hz, ArH), 7.24 (2H, dd, J¼5.5, 3.1 Hz, ArH); dC 22.6,
25.5, 39.7 (CH2), 84.5 (CO), 121.0, 127.2, 146.9 (ArC); m/z
256 (Mþ, 21%), 214 (18), 213 (100), 157 (28), 145 (12), 129
(15), 128 (12), 115 (14), 55 (20), 43 (12), 41 (29); HMRS:
Mþ, found 256.1926. C18H24O requires 256.1827.
´
Melendez, J.; Yus, M. Helv. Chim. Acta 2002, 85, 3262–3271.
13. (a) Azzena, U.; Demartis, S.; Fiori, M. G.; Melloni, G.; Pisano,
L. Tetrahedron Lett. 1995, 36, 5641–5644. For a review, see:
(b) Azzena, U. Trends Org. Chem. 1997, 6, 55–65. (c) Azzena,
U.; Carta, S.; Melloni, G.; Sechi, A. Tetrahedron 1997, 53,
16205–16212.
14. (a) Maercker, A. Angew. Chem. Int. Ed. Engl. 1987, 26,
972–989. (b) Lazana, M. C. L. R. L.; Franco, M. L. T. M. B.;
Herold, B. J. J. Am. Chem. Soc. 1989, 111, 8640–8646.
(c) Azzena, U.; Denurra, T.; Melloni, G.; Piroddi, A. M. J. Org.
Chem. 1990, 55, 5386–5390. (d) Azzena, U.; Denurra, T.;
Melloni, G.; Fenude, E.; Rassu, G. J. Org. Chem. 1992, 57,
1444–1448. (e) Casado, F.; Pisano, L.; Farriol, M.; Gallardo,
I.; Marquet, J.; Melloni, G. J. Org. Chem. 2000, 65, 322–331.
15. (a) Screttas, C. G.; Micha-Screttas, M. J. Org. Chem. 1978, 43,
1064–1071. (b) Screttas, C. G.; Micha-Screttas, M. J. Org.
Chem. 1979, 44, 713–719. (c) Cohen, T.; Bhupathy, M. Acc.
Chem. Res. 1989, 22, 152–161.
Acknowledgements
This work was financially supported by the DGES from the
´
Spanish Ministerio de Educacion y Cultura (MEC) (project
no. PB-97-0133) and by the Generalitat Valenciana (projects
no. GV01-443 and CTIDIB/2002/318). J. V. F. thanks the
Generalitat Valenciana for a predoctoral fellowship.
16. Almena, J.; Foubelo, F.; Yus, M. Tetrahedron 1997, 53,
5563–5572.
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