Palladium-catalyzed S-benzylation of unprotected mercaptobenzoic acid with benzyl alcohols in water

Article abstract of DOI:10.1039/c2ob25091h

Palladium-catalyzed S-benzylation of unprotected mercaptobenzoic acids with benzyl alcohols gave only S-benzylated mercaptobenzoic acids in good yields. Water may play an important role for the smooth generation of the (η³-benzyl)palladium spec

Full text of DOI:10.1039/c2ob25091h

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Palladium-catalyzed S-benzylation of unprotected mercaptobenzoic acid with
benzyl alcohols in water†
Hidemasa Hikawa* and Yuusaku Yokoyama*
Received 13th January 2012, Accepted 21st February 2012
DOI: 10.1039/c2ob25091h
acids with benzylic alcohols in water, which is chemoselective
and leaves the carboxyl group intact. To the best of our knowl-
edge, the palladium-catalyzed S-benzylation with benzyl alco-
hols has not been described before.
Palladium-catalyzed S-benzylation of unprotected mercapto-
benzoic acids with benzyl alcohols gave only S-benzylated
mercaptobenzoic acids in good yields. Water may play an
important role for the smooth generation of the (η3-benzyl)
palladium species by activation of the hydroxyl group of the
benzyl alcohol.
The mixture of 4-mercaptobenzoic acid 1a and benzyl alcohol
(2a: 5 equiv.) in the presence of Pd(OAc)2 (5 mol%) and sodium
diphenylphosphinobenzene-3-sulfonate (TPPMS, 10 mol%) in
water was heated at 120 °C for 24 h in a sealed tube proceeded
to give the desired product 3a in 88% yield (Table 1, entry 1).
When the reaction carried out at 100 °C in open vessel, desired
3a was not obtained. Since the reaction did not proceed in the
absence of the palladium catalyst (entry 2), a SN2 reaction mech-
anism was excluded in the formation of the S-benzylated
product. The use of zero- or divalent palladium as the catalyst,
Pd2(dba)3 or PdCl2, gave the product in moderate to good yields
(entry 3, 61%; entry 4, 87%). To our surprise, the use of
PdCl2(PPh3)2 and Pd(PPh3)4 instead of a water-soluble ligand
also resulted in the formation of 3a in good yields (entry 5,
86%; entry 6, 87%). Since S-benzylated 3a was not obtained in
DMSO, EtOH, AcOH or DMSO–H2O (1 : 1) (entry 7) but in
water as the solvent, water must play an important role in the S-
benzylation with benzyl alcohols. NaOH as an additive sup-
pressed the benzylation (entry 8). In contrast, the reaction pro-
ceeded with addition of AcOH (4 equiv.) in good yield (entry 9,
86%). Basset and co-workers reported that the π-allyl palladium
intermediate is unstable under strong basic conditions.11 In con-
trast, Manabe and Kobayashi12 and Yang et al.13 reported that
carboxylic acids enhance the formation of the π-allyl complex in
aqueous media. Since our results are consistent with these
reports on the palladium-catalyzed allylation with allylic alco-
hols, (η3-benzyl)palladium may be an intermediate here in
analogy to the allylic substitution reaction.
Palladium-catalyzed benzylations with benzylic alcohols are
especially challenging because the reactivity of benzylic alcohols
towards Pd(0) is poor compared with benzylic halides, carboxy-
lates, carbonates and phosphates.1 However, we discovered a
direct catalytic substitution of benzylic alcohols with unprotected
anthranilic acids without additives for activation of benzylic
alcohols in water,2 which was analogous to the palladium-cata-
lyzed allylation of allyl alcohols.3 Water may play an important
role in the smooth generation of the (η3-benzyl)palladium
species by hydration of the hydroxyl group due to the structural
similarity to allylic alcohols (Scheme 1).
Based on this work, we became interested in further expand-
ing the substrate scope of this methodology to S-benzylation. S-
Benzylated thiophenyl structures are key units in a wide range of
relevant pharmacophores with a broad spectrum of activities.4
The most traditional S-benzylation method is the reaction of thio-
late anions with benzyl halides.4b,c,5 However, the use of excess
benzyl halides leads to over reaction of reactive functional
groups. For example, the reaction of 2-mercaptobenzoic acid
with 4-methylbenzyl chloride (2 equiv.) gives benzyl esters as
the undesired products (Scheme 2).6
Therefore, the development of a direct catalytic substitution of
benzylic alcohols, which produces the desired products along
with water as the sole coproduct, is also highly desired. S-Benzy-
lation with benzyl alcohols, which are activated by boron trifl-
9
10
uoride etherates,7 yttrium triflates,8 ZnI2 and ZrCl4 in organic
solvents, have been reported. Herein, we report a palladium-cata-
lyzed selective S-benzylation of unprotected mercaptobenzoic
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama,
Funabashi, Chiba 274-8510, Japan. E-mail: hidemasa.hikawa@phar.
toho-u.ac.jp, yokoyama@phar.toho-u.ac.jp; Fax: +81-47-472-1595; Tel:
+81-47-472-1591
†Electronic supplementary information (ESI) available: Experimental
procedures and characterization data. Copies of 1H and 13C NMR
spectra of the new compounds. See DOI: 10.1039/c2ob25091h
Scheme 1 Hydration of the hydroxyl group.
2942 | Org. Biomol. Chem., 2012, 10, 2942–2945
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Table 2 S-Benzylation of several mercaptobenzoic acids 1a
Scheme 2 Reaction of 2-mercaptobenzoic acid with 4-methylbenzyl
chloride.
Entry
1
Time (h)
24
Product 3
Yield (%)
90
3b
Table 1 Effects of catalysts and solventsa
2
3
4
48
48
48
3c
3d
3e
60
69
71
Entry
Catalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
7
Pd(OAc)2–TPPMS
TPPMS
H2O
H2O
H2O
H2O
H2O
H2O
88 (trace)c
0
61
87
86
87
Trace
Pd2(dba)3d–TPPMS
PdCl2–TPPMS
PdCl2(PPh3)2
Pd(PPh3)4
Pd(OAc)2–TPPMS
DMSO, EtOH, AcOH
or DMSO–H2O (1 : 1)
a Reaction conditions: 1 (1 mmol), Pd(OAc)2 (5 mol%), TPPMS
(10 mol%), benzyl alcohols 2 (5 equiv.), H2O (4 mL), 120 °C, 24–48 h
in sealed tube. Yield of isolated product.
e
8
9
Pd(OAc)2–TPPMS
Pd(OAc)2–TPPMS
1 N NaOHaq.
0
86
H2O–AcOHe
a Pd catalyst (5 mol%), ligand (10 mol%), benzyl alcohol 2 (5 equiv.),
solvent (0.25 M), 120 °C, 24 h in sealed tube. b Yield of isolated
product. c The reaction carried out at 100 °C in open vessel. d 2.5 mol%.
e 4 equiv. was used.
Table 3 S-Benzylation with substituted benzyl alcohols 2a
Results for the S-benzylation of several mercaptobenzoic acids
using Pd(OAc)2 and TPPMS in water are summarized in
Table 2. 3-Mercaptobenzoic acid smoothly underwent S-benzyla-
tion with benzyl alcohol 2a to give the corresponding S-benzy-
lated mercaptobenzoic acid in 90% yield (entry 1). The reaction
of 2-mercaptobenzoic acids also proceeded to give S-benzylated
3c–e in overall yields ranging from 60 to 71% despite the steric
effect of the carboxyl group at the ortho-position (entries 2–4).
Results for the S-benzylation of 4-mercaptobenzoic acid 1a
with a number of benzyl alcohols substituted by electron-with-
drawing and electron-donating groups using Pd(OAc)2 and
TPPMS are summarized in Table 3. The benzyl alcohols with
electron-donating methyl, ethyl and methoxy groups resulted in
good yields (entry 1, 80%; entry 2, 77%; entry 3, 94%). A steri-
cally demanding methyl group at the ortho position was tolerated
in the S-benzylation (entry 4, 70%). The use of 4-fluorobenzyl
alcohol also resulted in good yield (entry 5, 85%). The benzyl
alcohols with bromo and chloro groups produced S-benzylated
3k–m in good yields with the carbon–halogen moiety left intact,
which could be employed for further manipulation (entry 6,
88%; entry 7, 76%; entry 8, 87%).
Entry
R =
Product 3
Yield (%)
1
2
3
4
5
6
7
8
4-Me
4-Et
4-OMe
2-Me
4-F
4-Br
3-Br
4-Cl
3f
80
77
94
70
85
88
76
87
3g
3h
3i
3j
3k
3l
3m
a Reaction conditions: 1 (1 mmol), Pd(OAc)2 (5 mol%), TPPMS
(10 mol%), benzyl alcohols 2 (5 equiv.), H2O (4 mL), 120 °C, 24 h in
sealed tube. Yield of isolated product.
spite of the possible formation of a vinylarene through β-hydride
elimination from the benzylpalladium intermediate (entry 1,
74%; entry 2, 77%).14 The sterically demanding cyclic benzyl
alcohols also gave good yields (entry 3, 75%; entry 4, 74%).
Surprisingly, a hydrophobic benzyl alcohol such as diphenyl-
methanol, which is not soluble in water, gave the S-benzylated
We next investigated the scope of different benzylic alcohols 2
(Table 4). S-Benzylation with α-alkyl benzyl alcohols proceeded
smoothly to give the desired products 3n–o in good yields in
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Table 4 Scope of alcohols 2a
Scheme 3 Effect of carboxyl group of mercaptobenzoic acid.
Entry
1
Alcohol 2
Product 3
Yield (%)
74
3n
3o
3p
We are also interested in the development of unprotected
syntheses and selective reactions towards various reactive func-
tional groups in aqueous media.16 Protection of reactive func-
tional groups such as amino, hydroxyl, or carboxyl groups is
often required in organic synthesis, not only for suppressing side
reactions, but also for easy handling by decreased polarity.
However, protection sometimes causes serious problems, e.g.,
increasing the number of synthetic steps and difficulty in depro-
tecting unstable compounds. Therefore, the development of
unprotected syntheses should lead to a breakthrough in organic
synthesis.
2
3
77
75
4
3q
74
Conclusions
5
6
3r
3s
83 (76)b
87
In summary, we have developed a new synthetic methodology
for achieving a palladium-catalyzed S-benzylation of unprotected
mercaptobenzoic acids 1 with benzylic alcohols 2 in water
without additives. In our catalytic system, the key is the use of
water as a solvent. Water plays an important role in the activation
of the benzylic alcohols to form the corresponding palladium
complexes. Recently, organic reactions in water have attracted
attention not only for their environmental and economical advan-
tages, but also for their unique reactivity. Therefore, develop-
ment of reactions in water is an important goal of synthetic
methodology. We are currently investigating the scope of various
nucleophiles on the benzylation, and are developing new reac-
tions using (η3-benzyl)palladium species from benzyl alcohols
in aqueous media.
a Reaction conditions: 1 (1 mmol), Pd(OAc)2 (5 mol%), TPPMS
(10 mol%), benzyl alcohols 2 (5 equiv.), H2O (4 mL), 120 °C, 24 h in
sealed tube. Yield of isolated product. b Pd(PPh3)4 was used instead of
TPPMS.
product 3r in 83% yield (entry 5). In addition, the use of Pd
(PPh3)4 as a non water soluble catalyst instead of TPPMS also
resulted in good yield (76%). Thus, the reaction may proceed
“on water” in our catalytic system. 2-Thiophenemethanol also
resulted in good yield (entry 6, 87%), although palladium-cata-
lyzed reactions with heteroaryl methyl alcohol derivatives are
extremely rare.15
Finally, to evaluate the effect of the carboxyl group of mer-
captobenzoic acids in our catalytic system, S-benzylation of
2-mercaptobenzoic acid methyl ester and benzenethiol was
carried out (Scheme 3). The reaction with benzyl alcohol 2a
using Pd(OAc)2 and TPPMS in water did not afford the S-benzy-
lated products 3. S-benzylated 3 was also not obtained with
addition of AcOH (4 equiv.). These results suggested that the
carboxyl group of the mercaptobenzoic acid plays a key role as
an activator in our catalytic system. Our method also succeeds
under neutral conditions in good yields. NaOH suppressed the S-
benzylation. Therefore, pH plays a critical role in the palladium-
catalyzed S-benzylation and the outcome of the S-benzylation
can be controlled simply by changing the basicity of the reaction
media.
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