Metallation reactions. Part 35: A change of the regiochemistry in the metallation of (alkylthio)arenes

Article abstract of DOI:10.1016/j.tet.2004.02.069

The metallation reaction of bromo(alkylthio)benzenes is described. The results show the complementarity of these reactions with the metal-hydrogen exchange reaction. In fact, monometallation of bromo(methylthio)benzenes afforded products substituted in para or meta or ortho to the thioethereal function while bimetallation led to αS,para, αS,meta and αS,ortho disubstituted products. Analogously, the monometallation of 4-bromo-(isopropylthio)benzene afforded para-monosubstituted and ortho,para-disubstituted products.

Full text of DOI:10.1016/j.tet.2004.02.069

Tetrahedron 60 (2004) 3915–3920
Metallation reactions. Part 35: A change of the regiochemistry in
the metallation of (alkylthio)arenes
*
Maria G. Cabiddu, Salvatore Cabiddu, Enzo Cadoni, Stefania De Montis, Claudia Fattuoni
*
and Stefana Melis
`
Dipartimento di Scienze Chimiche, Universita di Cagliari, Cittadella Universitaria di Monserrato, S.S. 554 Bivio per Sestu,
I-09042 Monserrato, Italy
Received 6 November 2003; revised 2 February 2004; accepted 25 February 2004
Abstract—The metallation reaction of bromo(alkylthio)benzenes is described. The results show the complementarity of these reactions with
the metal–hydrogen exchange reaction. In fact, monometallation of bromo(methylthio)benzenes afforded products substituted in para or
meta or ortho to the thioethereal function while bimetallation led to aS,para, aS,meta and aS,ortho disubstituted products. Analogously, the
monometallation of 4-bromo-(isopropylthio)benzene afforded para-monosubstituted and ortho,para-disubstituted products.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
In our synthetic studies we sometimes needed
(methylthio)arenes bearing a substitutent para and meta to
the thioethereal group, retaining this function unaltered, or
in alpha and para or meta to this group. We decided to
attempt the metal–halogen exchange reaction for the first
set of products, and for the other products a one-step metal–
halogen/metal–hydrogen exchange using 4-bromo-(1a),
and 3-bromo-1-(methylthio)benzene (1b). For a full
analysis of the synthetic potential of this reaction we also
examined 2-bromo-1-(methylthio)benzene (1c).
The use of organolithium compounds as reaction inter-
mediates is of great interest in synthesis.1–6 They can be
prepared by hydrogen–lithium (this field includes the
directed ortho-lithiation of aromatic compounds),1 – 6
halogen–lithium,4,6 calcogen–lithium,7–10 tin–lithium11
and phosphorus–lithium exchange.12
The metallation reaction of aromatic compounds leads to
1,2-disubstituted derivatives: whenever organolithiums with
the metal atom meta or para to the substituent are needed,
the method of choice is mainly the halogen–lithium
exchange.13–19
2. Results and Discussion
All reactions were performed by treating ethereal solutions
of 1a–c with 2 or 3 M equiv. of n-butyllithium in hexane.
The results presented in Scheme 2 shows that 2 M equiv. of
organolithium effect the metal–halogen exchange with
subsequent functionalization, after electrophilic quenching
of the aromatic carbon previously bonded to the halogen. In
this way, products 2a–h were obtained in 75–85% yields.
In our previous work we showed how (methylthio)benzene
can be monometallated at the methylthio carbon by
butyllithium or by superbases.20,21 When the reaction was
performed with 2 M equiv. of the same reagents, the
thioether (Scheme 1) underwent bimetallation on the
methylthio carbon and in the ortho position.20,21
When the reaction was performed with 3 M equiv. of the
same organolithium, we functionalized this aromatic carbon
and the methylthio one with the same electrophile in one
step. Thus, products 3a–h were isolated in 63–73% yields.
It is also possible to introduce two different electrophiles at
these same sites by performing two sequential mono-
metallations/electrophilic quenching. In contrast, the
attempt to substitute in one-step the halogen and both
hydrogens alpha and ortho to the methylthio group was
unsuccessful. In fact, even using a large excess of
organolithium (10–12 M equiv.) the only products isolated
Scheme 1.
Keywords: Metallation; Lithiation; Bromo(alkylthio)arenes; Thioethers.
*
Corresponding authors. Tel.: þ39-70-6758625; fax: þ39-70-6758605;
tel.: þ39-70-6754387; fax: þ39-70-6754388;
e-mail address: scabiddu@unica.it
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.069

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M. G. Cabiddu et al. / Tetrahedron 60 (2004) 3915–3920
were the ones derived by bromine and alpha substitution.
The trisubstitution reaction can, however, be achieved
through two iterative one-pot metallations (Scheme 3): the
first substitutes the halogen atom by a monometallation/
electrophilic quenching and the second effects a bimetalla-
tion/electrophilic quenching.
With the aim of testing the behaviour of other thioalkyl
groups (SR where R–Me), analogous reactions were
performed on 4-bromo-1-(isopropylthio)benzene (6)
(Scheme 4). The results showed that every molar ratio of
organolithium (from two to eight) leads exclusively to the
metal–halogen exchange to give a 4-monolithiated inter-
mediate: this was proved by the attainment of 7 alone after
carboxylation. Furthermore it is possible to introduce a
second electrophile ortho to the thioethereal function by a
subsequent ‘one-pot’ metallation, as proved by the attain-
ment of compound 8. The results obtained are entirely
complementary with those obtained with (isopropylthio)-
benzene.22 In fact it is possible to prepare from this
compound 2-substituted-(alkylthio)benzenes by mono-
metallation and 2,6-disubstituted derivatives by two
iterative ‘one-pot’ monometallations.
In conclusion, from the results obtained, the difference with
analogous oxygen or nitrogen compounds is evident:6
(methylthio)bromobenzenes can successfully undergo a
direct bimetallation reaction. This is a further confirmation
of the thioether group’s capability to promote both annular
and side-chain metallations. Moreover, the above results
emphasize the synthetic potential both of dilithiation in the
preparation of polyfunctionalized aromatics, either in a
single or in two successive ‘one-pot’ monolithiations, and of
trilithiations through a combination of ‘one-step’ and ‘one-
pot’ processes. In particular, comparing the results here
obtained with those previously reported,20–22 it can be
deduced that:
Scheme 2.
(a) starting from (methylthio)benzene it is possible to
prepare:22
–
aS-substituted benzene derivatives through a direct
monometallation/electrophilic quenching;
aS,ortho-substituted benzene derivatives through a
‘one-step’ direct bimetallation/electrophilic quench-
ing;
–
(b) starting from 2-bromo-1-(methylthio)benzene it is
possible to obtain 2-substituted (methylthio)benzenes
through metal–halogen exchange/electrophilic
quenching. This result demonstrates that the mono-
metallations performed on (methylthio)benzene and on
Scheme 3.
Scheme 4.

M. G. Cabiddu et al. / Tetrahedron 60 (2004) 3915–3920
3917
2-bromo-1-(methylthio)benzene give complementary
results as they allow selective preparation of aS-
substituted or ortho-substituted products;
in anhydrous diethyl ether (25 mL) was treated with a 1.4 M
solution of n-butyllithium in hexane (7.9 mL, 11 mmol) at
0 8C under argon. After 2 h, a solution of the appropriate
electrophile (5 mmol) in anhydrous diethyl ether (10 mL)
was added, the cooling bath removed and the reaction
completed by stirring overnight at room temperature.
The reaction mixture was poured into water and the pH
adjusted to 4–5 by addition of 10% aqueous hydrochloric
acid. The organic layer was separated and the aqueous layer
extracted with diethyl ether (3£20 mL). The combined
organic extracts were dried (Na2SO4), filtered and
evaporated.
(c) starting from 3- and 4-bromo-substituted (methylthio)-
benzenes it is possible to obtain:
–
meta- and para-substituted (methylthio)benzenes
through metal–halogen exchange/electrophilic
quenching;
meta- or para,aS-disubstituted benzenes through a
simultaneous ‘one-step’ metal–halogen and metal–
hydrogen exchange followed by electrophilic quench-
ing;
–
(d) starting from 4-bromo-1-(isopropylthio)benzene it is
possible to obtain:
In this manner, the following compounds were prepared:
–
4-substituted-(alkylthio)benzenes derived by substi-
tution of the halogen with the electrophile;
2,4-disubstituted-(alkylthio)benzenes through two sub-
sequent ‘one-pot’ metallation/electrophilic quenching
procedures.
3.2.1. 4-Methyl-1-(methylthio)benzene (2a). This com-
pound was obtained from the reaction of the monometal-
lated 1a and iodomethane and was identified by comparison
of its NMR and mass spectra with those of an authentic
sample obtained from the reaction of sodium 4-methyl-
benzenethiolate with iodomethane. The crude product was
purified by distillation to give the title compound 2a (0.55 g,
4.0 mmol, 80%) as a pale yellow oil, bp 91–92 8C/
10 mm Hg (Lit.25 bp 104–105 8C/20 mm Hg).
–
3. Experimental
3.1. General
3.2.2. 4-Ethyl-1-(methylthio)benzene (2b). This com-
pound was obtained from the reaction of the mono-
metallated 1a and iodoethane and was identified by
comparison of its NMR and mass spectra with those of an
authentic sample obtained from the reaction of sodium
4-ethylbenzenethiolate with iodomethane. The crude
product was purified by distillation to give the title
compound 2b (0.59 g, 3.87 mmol, 78%) as a pale yellow
oil, bp 100–102 8C/10 mm Hg (Lit.26 bp 212 8C).
NMR spectra were recorded on a Varian VXR-300
spectrometer with tetramethylsilane as internal reference.
IR spectra were recorded on a Perkin–Elmer 1310 grating
spectrophotometer. The GC–MS analyses were performed
with a Hewlett Packard 5989A GC–MS system with HP
5890 GC fitted with a capillary column (50 m£0.2 mm)
packed with DH 50.2 Petrocol (0.50 mm film thickness). All
flash chromatographies were performed on silica G60
(Merck) columns. Microanalyses were carried out with a
Carlo Erba 1106 elemental analyser. Melting points were
obtained on a Kofler hot stage microscope and are
uncorrected. All yields reported are mass yields of purified
products.
3.2.3. 4-(Methylthio)benzoic acid (2c). The monometal-
lated mixture of 1a was poured onto ca. 100 g of crushed
solid carbon dioxide. After 24 h the residue was treated with
10% aqueous sodium bicarbonate (20 mL) and then with
diethyl ether (20 mL). The alkaline layer was separated,
washed with diethyl ether (3£10 mL), and then acidified
with cold concentrated hydrochloric acid, extracted with
diethyl ether (3£10 mL), dried (Na2SO4), and concentrated.
The crude product was crystallised from 1:1 aqueous
ethanol to give the title compound 2c (0.71 g, 4.23 mmol,
85%) as pale yellow crystals, mp 195–196 8C (Lit.27 mp
196–197 8C). This compound was identical to the
commercial product 2c.
Commercially available reagent-grade starting materials
and solvents were used. Solutions of butyllithium in hexane
were obtained from Aldrich Chemical Company and were
analysed by the Gilman double titration method before
use.23 4-Bromobenzenethiol, 4-bromo-(1a)-, 3-bromo-(1b)
and 2-bromo-1-(methylthio)benzene (1c) were purchased
(Aldrich).
3.1.1. 4-Bromo-1-(isopropylthio)benzene (6). A mixture
of 4-bromobenzenethiol (12.5 g, 66.0 mmol), 2-bromo-
propane (6.15 mL, 66.0 mmol) anhydrous potassium
carbonate (13.0 g, 94.0 mmol) and dry acetone (60 mL)
was heated under reflux for 10 h and then added to water.
The organic product was extracted with diethyl ether, the
ethereal layer was separated, dried (CaCl2) and the solvent
evaporated. The crude product was purified by distillation to
give the title compound 6 (13.90 g, 60.16 mmol, 91%) as a
pale yellow oil, bp 108–109 8C/5 mm Hg (Lit.24 bp 125–
126 8C/18 mm Hg). Spectroscopic data identical to those
reported in the literature.24
3.2.4. Phenyl(trimethylsilyl)methyl sulfide(2d). This
compound was obtained from the reaction of the mono-
metallated 1a and trimethylchlorosilane. The crude product
was flash-chromatographed on silica gel using light
petroleum as eluent to give the title compound 2d (0.73 g,
3.73 mmol, 75%). Spectroscopic data identical to those
reported in the literature.28
3.2.5. 3-Methyl-1-(methylthio)benzene (2e). This com-
pound was obtained from the reaction of the monometal-
lated 1b and iodomethane and was identified by comparison
of its NMR and mass spectra with those of an authentic
sample obtained from the reaction of sodium 3-methyl-
benzenethiolate with iodomethane. The crude product was
3.2. General procedure for monometallation
A vigorously stirred solution of starting material (5 mmol)

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M. G. Cabiddu et al. / Tetrahedron 60 (2004) 3915–3920
purified by distillation to give the title compound 2d (0.53 g,
3.83 mmol, 77%) as a pale yellow oil, bp 91–94 8C/
15 mm Hg (Lit.29 bp 101–103 8C/28 mm Hg).
thiolate with iodoethane. The crude product was purified by
distillation to give the title compound 3a (0.51 g,
3.38 mmol, 68%) as a pale yellow oil, bp 115–117 8C/
10 mm Hg (Lit.34 bp 101–103 8C/2 mm Hg).
3.2.6. 3-(Methylthio)benzoic acid (2f). This compound
was obtained from the reaction of the monometallated 1b
and carbon dioxide. The crude product was crystallised
from 1:1 aqueous ethanol to give the title compound 2f
(0.68 g, 4.03 mmol, 81%) as pale yellow crystals, mp 123–
124 8C (Lit.30 mp 122–123 8C). This compound was
identical to the commercial product 2f.
3.3.2. 4-Ethyl-1-(propylthio)benzene (3b). This com-
pound was obtained from the reaction of the bimetallated
1a and iodoethane and was identified by comparison of its
NMR and mass spectra with those of an authentic sample
obtained from the reaction of potassium 4-ethylbenzene-
thiolate with 1-bromopropane. The crude product was
purified by distillation to give the title compound 3b
(0.58 g, 3.23 mmol, 65%) as a pale yellow oil, bp 118–
120 8C/10 mm Hg (Lit.35 bp 105–106/3 mm Hg).
3.2.7. 2-Methyl-1-(methylthio)benzene (2g). This com-
pound was obtained from the reaction of the monometal-
lated 1c and iodomethane and was identified by comparison
of its NMR and mass spectra with those of an authentic
sample obtained from the reaction of sodium 2-methyl-
benzenethiolate with iodomethane. The crude product was
purified by distillation to give the title compound 2g (0.57 g,
4.12 mmol, 82%) as a pale yellow oil, bp 104–105 8C/
25 mm Hg (Lit.31 bp 96 8C/16 mm Hg).
3.3.3. 4-[(Carboxymethyl)thio]benzoic acid (3c). This
compound was obtained from the reaction of the bimetal-
lated 1a and carbon dioxide; the crude product was
crystallised from 1:1 aqueous ethanol to give the title
compound 3c (0.74 g, 3.48 mmol, 70%) as pale yellow
crystals, mp .250 8C (Lit.36 mp .250 8C); [Found: C,
50.81; H, 3.71; S, 14.99. C9H8O4S requires: C, 50.94; H,
3.80; S, 15.11%]; nmax (KBr) 3400, 3100, 2990, 1690, 1590,
1500, 1420, 1325, 1300, 1280, 1190, 1120, 1090, 1015, 900,
850, 810, 760 cm21; dH (300 MHz, DMSO) 13.00 (2H,
broad, CO2H, D2O exchangeable), 7.95 (2H, d, J¼8.2 Hz,
ArH), 7.50 (2H, d, J¼8.2 Hz, ArH), 4.04 (2H, s, CH2); dC
(75.4 MHz, DMSO) 170.2, 167.0, 142.5, 129.8, 127.6,
126.1, 33.9; m/z (EI) 212 (100, Mþ), 195 (8), 167 (76), 149
(14), 137 (24), 123 (14.5), 105 (1), 77 (2%).
3.2.8. 2-(Methylthio)benzoic acid (2h). This compound
was obtained from the reaction of the monometallated 1c
and carbon dioxide. The crude product was crystallised
from 1:1 aqueous ethanol to give the title compound 2h
(0.71 g, 4.19 mmol, 84%) as pale yellow crystals, mp 125–
126 8C (Lit.32 mp 126–127 8C). This compound was
identical to the commercial product 2h.
3.2.9. 4-(Isopropylthio)benzoic acid (7). This compound
was obtained from the reaction of the monometallated 6 and
carbon dioxide. The crude product was crystallised from
methanol to give the title compound 7 (0.86 g, 4.40 mmol,
88%) as pale yellow crystals, mp 154–155 8C (Lit.33 mp
155–156 8C); [Found: C, 61.09; H, 6.10; S, 16.21.
C10H12O2S requires: C, 61.20; H, 6.16; S, 16.34%]; nmax
(KBr) 3100, 2990, 1675, 1595, 1430, 1300, 1195, 1140, 1100,
1055, 960, 850, 770 cm21; dH (300 MHz, CDCl3) 8.01 (2H, d,
J¼8.4 Hz, ArH), 7.39 (2H, d, J¼8.4 Hz, ArH), 3.59 (1H, m,
CHMe), 1.40 (6H, d, J¼6.7 Hz, CHMe); dC (75.4 MHz,
CDCl3) 171.9, 144.8, 130.5, 128.1, 126.1, 36.6, 22.9; m/z (EI)
196 (41, Mþ), 154 (24), 136 (100), 108 (23), 97 (7), 69 (15%).
3.3.4. (Trimethylsilyl)methyl 4-(trimethylsilyl)phenyl
sulfide (3d). This compound was obtained from the reaction
of the bimetallated 1a and chlorotrimethylsilane. The crude
product was purified by flash-chromatography (light
petroleum) to give the title compound 3d (0.96 g,
3.58 mmol, 72%) as a pale yellow oil, n2D5¼1.540; [Found:
C, 58.05; H, 8.93; S, 11.83. C13H24SSi2 requires: C, 58.14;
H, 9.01; S, 11.94%]; nmax (neat) 2970, 2940, 2875, 1580,
1480, 1440, 1255, 1180, 850, 745, 700 cm21; dH (300 MHz,
CDCl3) 7.43 (2H, d, J¼8.1 Hz, ArH), 7.28 (2H, d,
J¼8.1 Hz, ArH), 2.20 (2H, s, SCH2), 0.27 (9H, s, MeSiAr),
0.20 (9H, s, MeSiCH2); dC (75.4 MHz, CDCl3) 141.4, 135.9,
133.5, 128.6, 29.7, 21.1, 21.6; m/z (EI) 268 (17, Mþ), 253
(9), 180 (8), 165 (11), 151 (2), 135 (2), 73 (100%).
3.3. General procedure for bimetallation
A vigorously stirred solution of starting material (5 mmol)
in anhydrous diethyl ether (25 mL) was treated with a 1.4 M
solution of n-butyllithium in hexane (12 mL, 16.5 mmol) at
0 8C under argon. After 2 h, a solution of the appropriate
electrophile (10 mmol) in anhydrous diethyl ether (15 mL)
was added, the cooling bath removed and the reaction
completed by stirring overnight at room temperature. The
resulting mixture was worked up in the same manner above
described.
3.3.5. 1-(Ethylthio)-3-methylbenzene (3e). This com-
pound was obtained from the reaction of the bimetallated
1b and iodomethane and was identified by comparison of its
NMR and mass spectra with those of an authentic sample
obtained from the reaction of sodium 3-methylbenzene-
thiolate with iodoethane. The crude product was purified by
distillation to give the title compound 3e (0.52 g,
2.91 mmol, 69%) as a pale yellow oil, bp 112–113 8C/
10 mm Hg (Lit.37 bp 80–82 8C/1 mm Hg).
In this manner the following products were prepared:
3.3.6. 3-[(Carboxymethyl)thio]benzoic acid (3f). This
compound was obtained from the reaction of the bimetal-
lated 1b and carbon dioxide and was identified by
comparison of its NMR and mass spectra with those of an
authentic sample obtained from the reaction of 3-mercapto-
benzoic acid and chloroacetic acid in potassium carbonate/
acetone. The crude product was crystallised from aqueous
3.3.1. 1-(Ethylthio)-4-methylbenzene (3a). This com-
pound was obtained from the reaction of the bimetallated
1a and iodomethane and was identified by comparison of its
NMR and mass spectra with those of an authentic sample
obtained from the reaction of sodium 4-methylbenzene-

M. G. Cabiddu et al. / Tetrahedron 60 (2004) 3915–3920
3919
ethanol to give the title compound 3f (0.77 g, 3.62 mmol,
73%) as white crystals, mp 196–197 8C (Lit.36 mp 198 8C).
3.4.3. 2-[(3-Methylphenyl)thio]acetic acid (4c). This
compound was obtained from 1b using iodomethane as
first electrophile and was identified by comparison of its
NMR and mass spectra with those of an authentic sample
obtained from the reaction of sodium 3-methylbenzene-
thiolate with monochloroacetic acid. The crude product
was crystallised from aqueous ethanol to give the title
compound 4c (0.59 g, 3.23 mmol, 65%) as white crystals,
mp 67–68 8C (Lit.38 mp 66.8–67.4 8C).
3.3.7. 1-(Ethylthio)-2-methylbenzene (3g). This com-
pound was obtained from the reaction of the bimetallated
1c and iodomethane and was identified by comparison of
its NMR and mass spectra with those of an authentic
sample obtained from the reaction of sodium 2-
methylbenzenethiolate with iodoethane. The crude
product was purified by distillation to give the title
compound 3g (0.48 g, 3.14 mmol, 63%) as a pale yellow
oil, bp 115–117 8C/10 mm Hg (Lit.22 bp 120–
122 8C/15 mm Hg).
3.5. Sequential, one-pot, introduction of three
electrophiles on 1a
A vigorously stirred solution of 1a (1.0 g, 5 mmol) in
anhydrous diethyl ether (25 mL) was treated with a 1.4 M
solution of n-butyllithium in hexane (7.5 mL, 11 mmol) at
0 8C under argon. After 2 h, a solution of iodomethane
(0.3 mL, 5 mmol) in anhydrous diethyl ether (15 mL) was
added, the cooling bath removed and the reaction completed
by stirring overnight at room temperature. The resulting
mixture was then cooled to 0 8C and treated dropwise with
n-butyllithium in hexane (7.5 mL, 11 mmol). After 2 h, the
solution was treated either with iodomethane (0.6 mL,
10 mmol) in anhydrous diethyl ether (15 mL) or poured
onto ca. 100 g of carbon dioxide and worked up in the same
manner above described.
3.3.8. 2-[(Carboxymethyl)thio]benzoic acid (3h). This
compound was obtained from the reaction of the bimetal-
lated 1c and carbon dioxide and was identified by
comparison of its NMR and mass spectra with those of an
authentic sample obtained from bimetallation/treatment with
carbon dioxide of (methylthio)benzene.20 The crude product
was crystallised from aqueous ethanol to give the title
compound 3h (0.72 g, 3.38 mmol, 68%) as pale yellow
crystals, mp 119–120 8C (Lit.20 mp 118–120 8C).
3.4. Sequential, one-pot, introduction of two different
electrophiles on 1a–b
A vigorously stirred solution of starting material (5 mmol)
in anhydrous diethyl ether (25 mL) was treated with a 1.4 M
solution of n-butyllithium in hexane (7.9 mL, 11 mmol) at
0 8C under argon. After 2 h, a solution of the appropriate
electrophile (5 mmol) in anhydrous diethyl ether (15 mL)
was added, the cooling bath removed and the reaction
completed by stirring overnight at room temperature. The
resulting mixture was then cooled to 0 8C and treated
dropwise with n-butyllithium in hexane (3.9 mL,
5.5 mmol). After the usual work-up, the resulting
solution was poured onto ca. 100 g of crushed solid
carbon dioxide and worked up in the same manner above
described.
In this manner the following products were prepared:
3.5.1. 2,4-Dimethyl-1-(ethylthio)benzene (5a). This com-
pound was obtained using iodomethane as second electro-
phile and was identified by comparison of its NMR and
mass spectra with those of an authentic sample obtained
from the reaction of sodium 2,4-dimethylbenzenethiolate
with iodoethane. The crude product was purified by
distillation to give the title compound 5a (0.53 g,
3.18 mmol, 64%) as a pale yellow oil, bp 73–74 8C/
2 mm Hg (Lit.20 68–70 8C/1 mm Hg).
3.5.2. 2-[(Carboxymethyl)thio]-5-methylbenzoic acid
(5b). This compound was obtained using carbon dioxide
as second electrophile and was identified by comparison of
its NMR and mass spectra with those of an authentic sample
obtained from bimetallation/treatment with carbon dioxide
of 4-methyl-1-(methylthio)benzene.20 The crude product
was crystallised from chloroform to give the title compound
5b (0.75 g, 3.33 mmol, 67%) as white crystals, mp 198–
199 8C (Lit.20 mp 197–198 8C).
In this manner, the following compounds were prepared:
3.4.1. 2-[(4-Methylphenyl)thio]acetic acid (4a). This
compound was obtained from 1a using iodomethane as
first electrophile and was identified by comparison of its
NMR and mass spectra with those of an authentic sample
obtained from the reaction of sodium 4-methylbenzene-
thiolate with monochloroacetic acid. The crude product was
crystallised from 1:1 chloroform/petroleum ether to give the
title compound 4a (0.55 g, 3.03 mmol, 61%) as white
crystals, mp 93–95 8C (Lit.38 mp 94–94.4 8C).
3.6. Sequential, one-pot, introduction of two
electrophiles on 6
Following the above procedure, when 6 was treated with
2.2 M equiv. of n-butyllithium followed by treatment with
iodomethane and then with 1.1 M equiv. of the same
organolithium followed by quenching with carbon dioxide,
the following compound was obtained:
3.4.2. 2-[(4-Ethylphenyl)thio]acetic acid (4b). This
compound was obtained from 1a and iodoethane as
first electrophile and was identified by comparison of its
NMR and mass spectra with those of an authentic
sample obtained from the reaction of sodium 4-ethyl-
benzenethiolate with monochloroacetic acid. The crude
product was crystallised from 1:1 chloroform/petroleum
ether to give the title compound 4b (0.61 g, 3.13 mmol,
63%) as white crystals, mp 60–62 8C (Lit.39 mp 62–
63 8C).
3.6.1. 2-(Isopropylthio)-5-methylbenzoic acid (8). This
compound was identified by comparison of its NMR and
mass spectra with those of an authentic sample obtained
from metallation/treatment with carbon dioxide of
1-(isopropylthio)-4-methylbenzene.22 The crude product

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M. G. Cabiddu et al. / Tetrahedron 60 (2004) 3915–3920
´ ´
A.; Trecourt, F.; Queguiner, G. Tetrahedron Lett. 1995, 36,
was crystallised from aqueous ethanol to give the title
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