Halogen-lithium exchange versus deprotonation: regioselective mono- and dilithiation of aryl benzyl sulfides. A simple approach to α,2-dilithiotoluene equivalents

Article abstract of DOI:10.1016/j.tetlet.2010.01.074

Halogen-lithium exchange and deprotonation reactions between aryl benzyl sulfides and alkyllithiums were investigated. The resultant mono- and dilithiated intermediates were converted into the corresponding aldehydes and boronic, or carboxylic acids in good yields. It was found that diethyl ether stabilizes the ortho-lithiated compounds toward isomerisation to the benzylic derivatives. The process occurs easily in THF at low temperature and is a facile route to the α,2-dilithiotoluene derivative which can be transformed into a dicarboxylic acid on treatment with CO₂.

Full text of DOI:10.1016/j.tetlet.2010.01.074

Tetrahedron Letters 51 (2010) 1685–1689
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Halogen–lithium exchange versus deprotonation: regioselective mono- and
dilithiation of aryl benzyl sulfides. A simple approach to
equivalents
a,2-dilithiotoluene
*
_
´
Tomasz Klis , Janusz Serwatowski, Grzegorz Wesela-Bauman, Magdalena Zadrozna
Physical Chemistry Department, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Halogen–lithium exchange and deprotonation reactions between aryl benzyl sulfides and alkyllithiums
were investigated. The resultant mono- and dilithiated intermediates were converted into the corre-
sponding aldehydes and boronic, or carboxylic acids in good yields. It was found that diethyl ether sta-
bilizes the ortho-lithiated compounds toward isomerisation to the benzylic derivatives. The process
Received 2 December 2009
Revised 23 December 2009
Accepted 22 January 2010
Available online 28 January 2010
occurs easily in THF at low temperature and is a facile route to the
a,2-dilithiotoluene derivative which
can be transformed into a dicarboxylic acid on treatment with CO2.
Keywords:
Lithiation
Sulfides
Ó 2010 Elsevier Ltd. All rights reserved.
Boronic acids
Aldehydes
Directed metalation of substituted arenes has been studied over
many years and has become a powerful method for the functional-
ization of aromatic systems. However, many reports on the lithia-
tion of sulfides are concerned only with the deprotonation
mechanism. We report an investigation in which the competition
between two mechanisms (halogen–lithium exchange and depro-
tonation) has been studied for the first time.1 Compared with our
previous studies on lithiation of aryl benzyl ethers where the ben-
zylic position was rather unreactive, here it becomes the important
factor influencing the reaction selectivity.2 Sulfur is an element
halogen–lithium exchange (HLE) or a deprotonation mechanism.
We have demonstrated that a careful choice of the reagents and
reaction conditions is required to obtain the desired product selec-
tively. The new functionalized organolithium compounds can react
with various electrophilic compounds such as CH3I, DMF, B(OEt)3,
B(OMe)3, and CO2 to give, after hydrolysis, the functionalized ABSs.
We were interested in comparing the selectivity of the lithiation
of substrates 1–3 with respect to the solvent (Table 1). The reaction
of 1 or 2 with n-BuLi proceeds cleanly in THF as well as in diethyl
ether to give the monolithiated species which were next reacted
with B(OMe)3 to give the respective arylboronic acids 1a and 2a
after hydrolysis (entries 1 and 2). However, lithiation of 3 with
n-BuLi in THF gave exclusively 3a (entry 3) as a result of the rear-
rangement of ortho-lithiated 3 to the more stable benzylic deriva-
tive which reacts with butyl bromide. In a competition experiment
where 3 was treated with 3 equiv of t-BuLi we isolated 3b exclu-
sively (entry 4) after a CH3I quench of the formed organolithium
compound. These results revealed that isomerisation of ortho-lith-
iated 3 to the benzylic derivative is preferred over deprotonation
with t-BuLi. The use of diethyl ether as a solvent stabilizes ortho-
lithiated 3 at À78 °C, however, it rearranges to the benzylic deriv-
ative on heating to À20 °C. The reaction with B(OMe)3 at À78 °C
and its subsequent hydrolysis gave the respective boronic acid 3c
(entry 5). The molecular structure of 3c was determined using X-
ray analysis (Fig. 1). Koh has patented the ortho lithiation of 2-
bromophenyl 2,4,6-trimethoxyphenylbenzyl sulfide which pro-
ceeds in moderate yield (46%) at À78 °C using THF as the solvent.7
This result shows that the stability of the ortho-lithiated ABSs to-
known to promote both
a and ortho lithiation. In a lithiation the
effect is generally considered to be a result of sulfur polarizability
3
*
and of hyperconjugation with the anitperiplanar S–C
r
orbital.
This fact has led to interesting applications in the synthesis of var-
ious benzo- and naphthothiophenes via intramolecular ring clo-
sure of
species can be a problem in the synthesis of ortho-lithiated sulfides
because they can isomerize to the more stable -lithiated deriva-
a a-lithiated
-lithiated sulfides.4 However, the stability of
a
tives.5 The ortho-directing power of sulfur is relatively weak.
Whereas thiophene can be lithiated to give 2-lithiothiophene, dia-
ryl sulfides undergo lithiation less efficiently than diaryl ethers.6
Molecules containing both sulfur and oxygen atoms are lithiated
ortho to oxygen.1d The present Letter is concerned with the
lithiation of aryl benzyl sulfides (ABSs) containing halogen substit-
uents. Lithiation of these compounds can proceed either via
* Corresponding author. Tel.: +48 22 2347575; fax: +48 22 6282741.
E-mail address: ktom@ch.pw.edu.pl (T. Klis´).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.074

´
T. Klis et al. / Tetrahedron Letters 51 (2010) 1685–1689
1686
Table 1
Preparation of functionalized ABSs via halogen–lithium exchange or deprotonation and subsequent treatment with various electrophiles
Entry
Starting material
RLi, solvent, temperature, electrophile
Product
S
S
1. n-BuLi, THF, À78 °C
2. B(OEt)3
1
3. H2O, HCl
Br
(HO)2B
(HO)2B
1a
90%
1
S
S
1. n-BuLi, THF, À78 °C
2. B(OEt)3
3. H2O, HCl
Br
2
3
4
2a
2
94%
Br
Br
S
S
C4H9
S
1. n-BuLi, THF, À78 °C
3
3a 87%
CH3
1. 3 t-BuLi, THF, À78 °C
S
2. CH3I
3
3b 85%
Br
S
(HO)2B
S
1. n-BuLi, Et2O, À78 °C
2. B(OMe)3
3. H2O, HCl
5
6
3
3c
88%
Br
CH3
1. 2 t-BuLi, THF, À78 °C
2. CH3I
SCH3
SCH3
4a 96% a
SCH2CH3
4b 4% a
4
Br
CHO
Br
OHC
1. 2 n-BuLi, THF, À78 °C
2.DMF
3.H2O, HCl
S
S
S
S
S
7
8
5
5a 85%
CH3
S
1. 3 t-BuLi, THF, À78 °C
2. CH3I
3. H2O
Br
1
H3C
1b
79%
S
CH3
S
1. 3 t-BuLi, THF, À78 °C
2. CH3I
3. H2O
Br
Br
9
H3C
2
2b
S
79%
CHO
S
Br
OHC
1. 4 t-BuLi, Et2O, À78 °C
2. DMF
10
3. H2O, HCl
6
81%
6a

´
1687
T. Klis et al. / Tetrahedron Letters 51 (2010) 1685–1689
Table 1 (continued)
Entry
Starting material
RLi, solvent, temperature, electrophile
Product
Br
S
Br
CO2H
S
CO2H
1. 4 t-BuLi, THF, À78 °C
2. CO2
11
3. H2O,HCl
6
6f 82%
F
F
CH3 Br
CH3 Br
Br
1. 2 LTMP, THF, À78 °C
12
13
F
F
S
2. CH3I
S
S
CH3
8
8a 15% a
8b 85% a
S
Br
S
B(OH)2
1. 2 t-BuLi, THF, À78 °C
2. B(OEt)3
3. H2O, HCl
F
8
8c 79%
a
Yields calculated from the 1H NMR spectra.
ward isomerisation also depends on the stability of the benzylic
carbanion which can be moderated by the substituents on the phe-
nyl ring. A detailed study on this effect is in progress and will be
published elsewhere.
and 4b (4%) (entry 6). The stability of ortho-lithiated anisole en-
abled dilithiation of 5 using n-BuLi in THF. The reaction afforded
5a after treatment of the formed organolithium compound with
DMF (entry 7). The above results suggest that rearrangement of
ortho-lithiated ABSs to the benzylic derivatives is kinetically
driven.
It was interesting to compare the reactivity of the
a-hydrogen
atoms in ABSs with anisole. In the lithiation of 2-bromothioanisole
4 with 2 equiv of t-BuLi in THF at À78 °C we found that the rear-
Dilithiated compounds are valuable reagents which have found
many applications in the synthesis of complex molecules.8 The
presence of two types of reactive centers in ABSs opens the possi-
bility to synthesize the respective dilithiated derivatives. Com-
pounds 1 and 2 can be lithiated according to the HLE and
deprotonation mechanism. The use of n-BuLi is not a good method
to form dilithiated derivatives because butyl bromide formed in
the process reacts at the benzylic carbon atom at À78 °C. However,
1 and 2 can be dilithiated selectively using t-BuLi in THF. The ob-
tained dilithiated derivatives are stable in THF at low temperature.
They were kept at À78 °C for two hours and then reacted with CH3I
to give 1b and 2b, respectively (entries 8 and 9). However, the use
of CO2 as the electrophile resulted in significant amounts of 2e and
2f apart from the expected bis-carboxylic acid 2d (Scheme 1).9 An
explanation relies on the activation of the benzylic hydrogen in 2c
toward deprotonation as a result of CO2 adduct formation.
In continuation of our studies we tried to replace selectively
two bromine atoms with lithium in compound 6. The lithiation
was carried out using 2 equiv of n-BuLi in diethyl ether at
À60 °C. However, this temperature was too low to exchange the
bromine atom in the benzylic part of the molecule and a compli-
cated mixture of products formed after treatment of the organo-
lithium derivatives with DMF. The use of t-BuLi as the base
enabled selective formation of the respective aldehyde 6a (entry
10). We have already revealed that THF destabilizes ortho-lithiated
3. Hence, the dilithiation of 6 in THF afforded 6b (Scheme 2) which
was quenched with CH3I to give 6c. This reaction proceeds
rangement of the ortho-lithioanisole to the
a-lithio derivative
was very slow. After quenching with CH3I we obtained 4a (96%)
B1
O2
O1
O1
O2
C6
B1
C7
C13
S1
C8
smoothly and can be used as a general route to synthesize
a,2-
dilithiotoluene derivatives. Contrary to this result, di-lithiation of
7 with t-BuLi proceeds sluggishly and gives a 1:1 mixture of 6c
and 6d. These results suggest that intramolecular benzylic lithia-
tion is preferred over the intermolecular process. Compared with
the reaction with 1 and 2, quenching of the dilithiated 6 with
Figure 1. ORTEP drawing of 3c (dimer) with thermal ellipsoid plot (50% probabil-
ity). Selected bond lengths (Å) and angles (°): B1–O1 1.370(2), B1–C13 1.575(2),
O1–H2–O2 171.28(2), O1–B1–C13–C8 30.95(2). Crystallographic data for this
structure have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 746938.

´
T. Klis et al. / Tetrahedron Letters 51 (2010) 1685–1689
1688
CO2Li
CO2Li
LiCO2
+
S
Li
S
LiCO2
H
S
S
+
LiO2C
1. CO2
2. HClaq
HClaq
Li
2c
CO2Li
HClaq
CO2H
CO2H
CO2H
CO2H
S
S
S
HO2C
HO2C
2d 35%
2e 35%
2f 30%
Scheme 1. The possible lithiation sequence providing the mixture of 2d, 2e, and 2f.
Br
Br
Li
Li
CH3
S
CH3
a)
b)
S
S
6
6b
6c 95%
Br
CH3
CH3
CH3
c)
+
S
S
S
6c 50%
6d 50%
7
Scheme 2. Reagents and conditions: (a) 4 t-BuLi, THF, À78 °C; (b) CH3I; (c) 3 t-BuLi, THF, À78 °C then CH3I.
CO2 afforded diacid 6f (entry 11) in high yield and we observed
only small amounts (less than 5 mol %) of side products. This result
suggests that the benzylic hydrogen atom gains some protection
from the ortho-carboxylithium group.
Typical procedure for lithiation of ABSs: In a typical lithiation, t-
BuLi (1.7 M solution in pentane, 24 mL, 40 mmol) was added at
À78 °C to a solution of 2-bromobenzyl-2-bromophenyl sulfide
(3.58 g, 10 mmol) in Et2O (40 mL). The resultant slurry was stirred
for 2.5 h followed by slow addition of DMF (1.46 g, 20 mmol). The
mixture was stirred overnight and then hydrolyzed with dilute aq
H2SO4. The organic phase was separated and the aq phase was ex-
tracted with Et2O (20 mL). Evaporation of the combined organic
solutions left a solid which was washed with H2O and recrystal-
lized from hexane (20 mL) to give 6a as yellow crystals, mp 98–
99 °C. Yield: 2.07 g, 81%; 1H NMR (400 MHz, CDCl3): d 10.17 (1H,
s, CHO), 10.14 (1H, s, CHO), 7.80 (2H, m, Ph), 7.46 (4H, m, Ph),
7.34 (1H, m, Ph), 7.20 (1H, m, Ph), 4.55 (2H, s, CH2); 13C{1H} NMR
(100.6 MHz, CDCl3): d 192.23, 191.42, 140.10, 138.10, 135.11,
134.00, 133.94, 133.62, 133.50, 131.24, 131.20, 131.13, 128.15,
126.72, 35.93. Anal. Calcd for C15H12SO2: C, 70.29; H, 4.72. Found:
C, 70.34; H, 4.75.
It was interesting to study the lithiation ability of a hydrogen
atom flanked by sulfur and fluorine atoms and to compare it with
the reactivity of the benzylic hydrogen atom. For this purpose,
compound 8 was reacted with 2 equiv of lithium 2,2,6,6-tetra-
methylpiperidine (LTMP) in THF and the organolithium compound
obtained was quenched with CH3I. Analysis of the reaction mixture
revealed that the conversion into the corresponding dilithiated
compound was not quantitative, as apart from 8a, a substantial
amount of 8b was detected (entry 12). However, the lithiation of
8 with n-BuLi in THF proceeded selectively according to the HLE
mechanism to give 8c after reaction with B(OEt)3 (entry 13).
In conclusion, the lithiation of ABSs occurs easily both on the
aromatic ring and at the benzylic position, hence the reaction re-
quires careful choice of the organolithium reagent, solvent, and
temperature to introduce the lithium atom selectively. The ob-
tained organolithium reagents are stable at low temperature, how-
ever, when the lithium atom is ortho to sulfur, isomerisation to a
benzylic derivative can take place. This process occurs easily in
THF at À78 °C, but it can be avoided using diethyl ether as the sol-
vent. On the other hand, the isomerisation gives access to the
Compound 1a: mp 148–149 °C. Yield: 2.20 g, 90%; 1H NMR
(400 MHz, acetone-d6): d 7.76 (2H, d, J= 8.0 Hz, Ph), 7.39 (2H, d,
J = 8.0 Hz, Ph), 7.29 (4H, m, Ph), 7.22 (1H, m, Ph), 7.17 (2H, s, –
OH), 4.24 (2H, s, CH2); 13C{1H} NMR (100.6 MHz, acetone-d6): d
140.38, 138.43, 135.44, 129.69, 129.21, 127.89, 127.79, 37.63. Anal.
Calcd for C13H13BSO2: C, 63.96; H, 5.37. Found: C, 63.98; H, 5.40.
Compound 2a: mp 137–138 °C. Yield: 2.29 g, 94%; 1H NMR
(400 MHz, acetone-d6): d 7.85 (1H, br s, Ph), 7.65 (1H, m, Ph),
7.36–7.17 (7H, m, Ph), 4.18 (2H, s, CH2), 3.50 (2H, s, –OH);
13C{1H} NMR (100.6 MHz, acetone-d6): d 138.63, 136.37, 135.71,
respective
a,2-dilithiotoluene derivatives. The synthetic potential
of these compounds was demonstrated in the reaction with CO2
leading to the respective dicarboxylic acid.

´
1689
T. Klis et al. / Tetrahedron Letters 51 (2010) 1685–1689
132.73, 131.76, 129.61, 129.10, 128.85, 127.77, 38.66. Anal. Calcd
Acknowledgments
for C13H13BSO2: C, 63.96; H, 5.37. Found: C, 63.99; H, 5.43.
Compound 3c: mp 115–117 °C. Yield: 2.14 g, 88%; 1H
NMR (400 MHz, acetone-d6): d 7.71 (1H, m, Ph), 7.37 (1H, m,
Ph), 7.31–7.17 (7H, m, Ph), 4.13 (2H, s, CH2), 3.42 (2H, s, –OH);
This work was supported by the Warsaw University of Technol-
ogy and the Polish Ministry of Science and Higher Education (Grant
No. N N205 055633). The X-ray measurements of compound 3c
were undertaken at the Crystallographic Unit of the Physical
Chemistry Laboratory, Chemistry Department, University of War-
saw. Support from Aldrich Chemical Company, Milwaukee, WI,
USA, through the donation of chemicals and equipment is grate-
fully acknowledged.
13C{1H} NMR (100.6 MHz, acetone-d6):
d
140.08, 138.36,
135.75, 133.24, 130.87, 129.67, 129.10, 127.85, 127.47, 41.32.
Anal. Calcd for C13H13BSO2: C, 63.96; H, 5.37. Found: C, 63.97;
H, 5.38.
Compound 5a: mp 135–136 °C. Yield: 2.55 g, 85%; 1H NMR
(400 MHz, CDCl3): d 10.37 (2H, s, CHO), 7.87 (2H, m, Ph), 7.51
(2H, m, Ph), 7.36 (4H, m, Ph), 3.19 (4H, s, CH2); 13C{1H} NMR
(100.6 MHz, CDCl3): d 191.43, 139.75, 134.47, 134.13, 132.40,
128.67, 126.21, 32.10. Anal. Calcd for C16H14S2O2: C, 63.55; H,
4.67. Found: C, 63.90; H, 4.71.
References and notes
1. (a) Gilman, H.; Webb, F. J. J. Am. Chem. Soc. 1949, 71, 4062; (b) Corey, E. J.;
Seebach, D. J. J. Org. Chem. 1966, 31, 4097; (c) Mallan, J. M.; Bebb, R. L. Chem. Rev.
1969, 69, 693; (d) Cabiddu, S.; Fattuoni, C.; Floris, C.; Gelli, G.; Melis, S.; Sotgiu, F.
Tetrahedron 1990, 46, 861; (e) Manka, J. S.; Guo, F.; Huang, J.; Yin, H.; Farrar, J.
M.; Sienkowska, M.; Benin, V.; Kaszynski, P. J. Org. Chem. 2003, 68, 9574; (f)
Schlosser, M.; Marzi, E.; Cottet, F.; Büker, H. H.; Nibbering, N. M. M. Chem. Eur. J.
2001, 7, 3511; (g) Schlosser, M.; Marzi, E. Chem. Eur. J. 2005, 11, 3449; (h) Klis, T.;
Lulinski, S.; Serwatowski, J. Curr. Org. Chem. 2008, 12, 1479.
2. (a) Chodakowski, J.; Klis, T.; Serwatowski, J. Tetrahedron Lett. 2005, 46, 1963; (b)
Klis, T.; Serwatowski, J.; Wojcik, D. Appl. Organomet. Chem. 2006, 20, 677; (c) Klis,
T.; Serwatowski, J. Tetrahedron Lett. 2007, 48, 1169.
3. (a) Epiotis, N. D.; Yates, R. L.; Bernardi, F.; Wolfe, S. J. Am. Chem. Soc. 1976, 98,
5435; (b) Borden, W. T.; Davidson, E. R.; Andersen, N. H.; Denniston, A. D.;
Epiotis, N. D. J. Am. Chem. Soc. 1978, 100, 1604.
4. (a) Mukherjee, C.; Kamila, S.; De, A. Tetrahedron 2003, 59, 4767; (b) Pradhan, T.
K.; De, A. Tetrahedron Lett. 2005, 46, 1493.
5. Shirley, D. A.; Reeves, B. J. J. Organomet. Chem. 1969, 16, 1.
6. (a) Carpita, A.; Rossi, R.; Veracini, C. A. Tetrahedron 1985, 41, 1919; (b) Gilman,
H.; Morton, J. W. Org. React. 1954, 8, 258.
7. Koh, J.T.-T. U.S. Patent 60,832,897, 2008; Chem. Abstr. 2008, 148, 1286.
Compound 6f: mp 148–149 °C. Yield: 2.36 g, 82%; 1H NMR
(400 MHz, acetone-d6): d 8.00 (1H, m, Ph), 7.77 (1H, m, Ph), 7.59
(1H, m, Ph), 7.40 (3H, m, Ph), 7.32–7.23 (3H, m, Ph), 6.52 (1H, s,
CH); 13C{1H} NMR (100.6 MHz, acetone-d6): d 171.46, 168.64,
139.04, 135.58, 133.17, 132.18, 131.69, 130.82, 130.20, 129.74,
128.69, 128.18, 51.91. Anal. Calcd for C15H12SO4: C, 62.49; H,
4.20. Found: C, 62.55; H, 4.23.
Compound 8c: mp 135–136 °C. Yield: 2.07 g, 79%; 1H NMR
(400 MHz, acetone-d6): d 7.66 (1H, m, Ph), 7.30–7.23 (3H, m, Ph),
7.18 (1H, m, Ph), 7.13 (1H, m, Ph), 7.08 (1H, m, Ph), 6.89 (1H, s,
Ph), 4.55 (2H, s, CH2), 3.17 (s, 2H, OH)
;
13C{1H} NMR
(100.6 MHz, acetone-d6): d 163.53 (d, J = 244 Hz), 142.55, 141.02
(d, J = 8.3 Hz), 135.44, 131.15 (d, J = 9.1 Hz), 130.12 (d, J = 6.9 Hz),
127.12, 125.00, 124.98, 115.50 (d, J = 13.8 Hz), 113.07 (d,
J = 21.2 Hz), 38.09. Anal. Calcd for C13H12BFSO2: C, 59.57; H, 4.61.
Found: C, 59.64; H, 4.65.
8. Foubelo, F.; Yus, M. Curr. Org. Chem. 2005, 9, 459.
9. Formation of compounds 2d–f was confirmed by GC/MS analysis after silylation
with bis(trimethylsilyl)acetamide.