Mercaptobenzoic acid-palladium(0) complexes as active catalysts for S-benzylation with benzylic alcohols via (η3-benzyl)palladium(II) cations in water

Article abstract of DOI:10.1039/c4ob00688g

Mercaptobenzoic acid-palladium(0) complexes show high catalytic activity for S-benzylation with benzylic alcohols via the (η³-benzyl) palladium(ii) cation in water. Notably, these palladium(0) complexes could play an important role in formation

Full text of DOI:10.1039/c4ob00688g

Organic &
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Mercaptobenzoic acid-palladium(0) complexes as
active catalysts for S-benzylation with benzylic
alcohols via (η3-benzyl)palladium(II) cations
in water†
Cite this: Org. Biomol. Chem., 2014,
12, 5964
Hidemasa Hikawa* and Isao Azumaya*
Mercaptobenzoic acid-palladium(0) complexes show high catalytic activity for S-benzylation with
benzylic alcohols via the (η3-benzyl)palladium(II) cation in water. Notably, these palladium(0) complexes
could play an important role in formation of active (η3-benzyl)palladium(II) cation complexes followed by
S-benzylation. Hammett studies on the rate constants of S-benzylation by various substituted alcohols
show good correlation between log(kX/kH) and the σ+ value of the respective substituents. From the
slope, negative ρ values are obtained, suggesting that there is a build-up of positive charge in the tran-
sition state. Water plays an important role in the catalytic system for sp3 C–O bond activation and stabiliz-
ation of the activated Pd(II) cation species. The catalytic system can be performed using only 2.5 mol%
Pd2(dba)3 without the phosphine ligand or other additives.
Received 1st April 2014,
Accepted 19th June 2014
DOI: 10.1039/c4ob00688g
www.rsc.org/obc
unprotected mercaptobenzoic acids with benzylic alcohols
using Pd(OAc)2/TPPMS (sodium diphenylphosphinobenzene-3-
1. Introduction
(η3-Benzyl)palladium catalysts are attracting increasing interest sulfonate) catalysts in water.4 Classical approaches for S-benzyl-
for the formation of carbon–carbon or carbon–nitrogen ation with benzyl alcohols, which are activated by Lewis acids
bonds.1 However, the potentiality of these complexes is still such as boron trifluoride etherates,5 yttrium triflates,6 ZnI2,7
unrealized compared to other well-established Tsuji–Trost and ZrCl4,8 have been reported.
reactions, merely due to their more recent development. Palla-
Although palladium-catalyzed reactions of organosulfur
dium-catalyzed benzylations with benzylic alcohols via the compounds, e.g. thiols, are expected to be efficient methods
(η3-benzyl)palladium(II) species are especially challenging, for the synthesis of organosulfur compounds including the
because the reactivity of benzylic alcohols towards Pd(0) is formation of new C–S bonds, the development of these
poor compared to benzylic halides, esters, carbonates, and methods is challenging due to poisoning of palladium cata-
phosphates. Therefore, the development of a direct substi- lysts by sulfur.9 Recently, there have been many reports on the
tution method for benzylic alcohols, which produces the stabilization of palladium nanoparticles by thiol ligands due
desired products along with water as the sole co-product, is to the strong interaction between palladium and sulfur
highly desired in organic chemistry. Only a few papers describe atoms.10 Fornasiero and co-workers reported the synthesis of
palladium-catalyzed benzylation with benzylic alcohols in variably functionalized thiol-protected palladium nanoparti-
aqueous media.2 We have been developing a unique strategy cles (Pd-NPs).10c Palladium(II) complexes with a thiosalicylic
for benzylation and C–H activation by the (η3-benzyl)palla- acid (HSC6H4CO2H) ligand have been synthesized and charac-
dium(II) system from a palladium catalyst and benzyl alcohol terized.10a,f–h
in water.3 Notably, water may activate the sp3 C–O bond, then
In light of our ongoing efforts to develop new methods for
stabilize the Pd(II) cation species by hydration, which can then direct substitution reactions of benzyl alcohols, this paper
undergo innovative direct transformation reactions. Recently describes new insights into the chemistry of thiol-protected
we reported a palladium-catalyzed selective S-benzylation of (η3-benzyl)palladium(II) cation complexes for S-benzylation.
Based on observations made in this investigation, we can now
provide support for the cationic (η3-benzyl)palladium(II)
system in water. Notably, water-soluble mercaptobenzoic acid-
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi,
Chiba 274-8510, Japan. E-mail: hidemasa.hikawa@phar.toho-u.ac.jp,
Pd(0) species could play an important role in formation of
isao.azumaya@phar.toho-u.ac.jp
active (η3-benzyl)palladium(II) cation complexes followed by
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
S-benzylation in our catalytic system, while benzenethiol is
NMR spectra for new compounds. See DOI: 10.1039/c4ob00688g
5964 | Org. Biomol. Chem., 2014, 12, 5964–5972
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Paper
groups is essential in organic synthesis, not only for suppres-
sing side reactions, but also for easy handling by decreased
polarity. However, protection sometimes causes serious pro-
blems, e.g. increasing the number of synthetic steps and
difficulty in deprotecting unstable compounds. Therefore, the
development of syntheses without protecting groups should
lead to a breakthrough in organic synthesis.14
2. Results and discussion
2.1. Effects of catalysts and solvents on S-benzylation
First, a mixture of 4-mercaptobenzoic acid 1a and benzyl
alcohol (2a, 5 equiv.) in the presence of Pd2(dba)3 (2.5 mol%)
in water was heated at 120 °C for 16 h in a sealed tube.
S-Benzylated product 4a was obtained in 81% conversion and
80% yield (Table 1, entry 1). The use of Pd(PPh3)4 also resulted
in good yield (entry 2). Reduction of Pd(II) complexes in the
presence of a phosphine ligand such as PPh3 or TPPMS gave a
Pd(0) species that could be used as a catalyst (entries 3 and 4).
Since Pd(OAc)2 instead of Pd(0) was ineffective (entry 5) and
the reaction did not proceed in the absence of the palladium
catalyst (entry 6), a SN2 reaction mechanism was excluded in
the formation of the S-benzylated product. The direct substi-
tution of benzhydrol 3a also afforded the desired 5a in good
yield (entries 7 and 8). Since using organic solvents such as
DMF, EtOH or 1,4-dioxane resulted in no reaction (entries
9–11), water must play an important role in our catalytic
system. To compare Pd2(dba)3 with other efficient catalysts, we
tested the reaction using Brønsted acids such as TsOH·H2O,
Scheme 1 Activation of the sp3 C–O bond for S-benzylation. Classical
approach and our approach.
ineffective due to poisoning of palladium catalysts by sulfur
(Scheme 1). To the best of our knowledge, the phosphine-free
palladium-catalyzed S-benzylation with benzyl alcohols via
(η3-benzyl)palladium(II) complexes in water was not described
before.
S-Benzylated thiophenyl structures are key units in a wide
range of relevant pharmacophores with a broad spectrum of
activities.11 The most traditional S-benzylation method is the
reaction of thiolate anions with benzyl halides.11b,c,12 However,
the use of excess benzyl halides leads to over-reaction of reac-
tive functional groups. For example, the reaction of 2-mercapto-
benzoic acid with 4-methylbenzyl chloride (2 equiv.) gives
benzyl esters as the undesired products.13 Protection of reac-
tive functional groups such as amino, hydroxyl, or carboxyl
Table 1 Effect of catalysts and solventsa
Entry
Catalyst (mol%)
Alcohols
Solvent
Temp. (°C)
Products
Conversionb (%)
1
2
3
4
5
6
7
8
Pd2(dba)3 (2.5)
Pd(PPh3)4 (5)
PdCl2(PPh3)2 (5)
Pd(OAc)2 (5)/TPPMS (10)
Pd(OAc)2 (5)
2a
2a
2a
2a
2a
2a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
DMF
EtOH
1,4-Dioxane
H2O
H2O
H2O
H2O
120
120
120
120
120
120
80
100
80
80
80
80
80
80
4a
4a
4a
4a
4a
4a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
81 (80% yield)c
(87% yield)c,d
(86% yield)c,d
(88% yield)c,d
27
0
72
none
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
TsOH·H2O (5)
Sc(OTf)3 (5)
Hf(OTf)4 (5)
CuCl2 (5)
Pd2(dba)3 (2.5)
85 (84% yield)c
9
0
10
11
12
13
14
15
16
Trace
Trace
0
Trace
40
43
0
80
80
NaOH aq. (1 equiv.)
a Reaction conditions: 4-mercaptobenzoic acid 1a (1 mmol), catalyst (2.5 or 5 mol%), benzylic alcohols (2a: 5 equiv. or 3a: 1.2 equiv.), solvent
(4 mL), 80–120 °C, 16 h in a sealed tube. b The conversion was determined by 1H NMR analysis of the crude product using p-nitroanisole as an
internal standard. c Yield of the isolated product in parenthesis. d 24 h.
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and effective Lewis acids such as Sc(OTf)3, Hf(OTf)4, or CuCl2. 2.3. Scope of benzhydryl alcohols 3
However, the reaction did not proceed or gave low yields
Results for the reaction of 4-mercaptobenzoic acid (1a) with a
(entries 12–15), clearly showing the superiority of Pd2(dba)3 for
the S-benzylation of mercaptobenzoic acid 1a with benzhydrol
3a in water. In the presence of a base such as NaOH (1 equiv.),
the reaction did not proceed (entry 16). Basset and co-workers
reported that the π-allyl palladium intermediate was unstable
under basic conditions.15 Since our results were consistent
with these reports on the palladium-catalyzed allylation with
allylic alcohols, (η3-benzyl)palladium was proposed to be an
intermediate here in analogy to the allylic substitution
reaction.
number of benzhydryl alcohols 3 using Pd2(dba)3 in water are
summarized in Table 3. The use of benzhydryl alcohols with
electron-donating methoxy and methyl groups resulted in
excellent yield (5b, 95%; 5c, 83%; 5d, 82%). In contrast, the
reaction using substrates with electron-withdrawing chloro
and fluoro groups proceeded slowly (5e, 62%; 5f, 78%), and
the strong electron-withdrawing decafluorophenyl group
resulted in no reaction.
2.4. Scope of mercaptobenzoic acids 1
The reaction of 2-mercaptobenzoic acids with benzyl alcohol
(2a) proceeded to give S-benzylated 4n–p in overall yields
ranging from 65 to 71% despite the steric effect of the carboxyl
group at the ortho-position (Table 4). 3-Mercaptobenzoic acid
smoothly underwent S-benzylation to give S-benzylated 4q in
80% yield. The use of benzhydryl alcohol (3a) also resulted in
good yields (5g, 65%; 5h, 78%; 5i, 68%). The reaction of
4-mercaptophenylcarboxylic acid or 4-mercaptohydrocinnamic
acid instead of mercaptobenzoic acids resulted in moderate
yields (5j, 50%; 5k, 51%).
2.2. Scope of benzyl alcohols 2
Results for the S-benzylation of 4-mercaptobenzoic acid (1a)
with a number of benzyl alcohols substituted by electron-
withdrawing and electron-donating groups using Pd2(dba)3 in
water are summarized in Table 2. The benzyl alcohols with
electron-donating methoxy, methyl, and ethyl groups resulted
in good yields (4b, 70%; 4c, 86%; 4d, 75%). The use of 4-fluoro-
benzyl alcohol also resulted in good yield (4e, 80%). The
benzyl alcohols with bromo and chloro groups produced
S-benzylated products in good yields with the carbon–halogen
moiety left intact, which could be employed for further
manipulation (4f, 79%; 4g, 78%). The use of 3-methoxybenzyl
2.5. Hammett studies
alcohol also resulted in good yield (4h, 84%). A sterically To demonstrate the electronic effect of substituents on the
demanding methyl group at the ortho position was tolerated in rates of the C–O bond cleavage and C–S bond formation reac-
the S-benzylation (4i, 65%). A heteroaryl methyl alcohol, tions, a Hammett study was conducted on the reaction of 2a or
thienyl methyl, also resulted in good yield (4j, 85%; 4k, 86%), 3a with substituted benzylic alcohols 2 or benzhydryl alcohols
although palladium-catalyzed reactions with heteroaryl methyl 3 in the presence of Pd2(dba)3 (2.5 mol%) to obtain the ratio of
alcohol derivatives are extremely rare.16 S-Benzylation with rate constants. The results are summarized in Fig. 1 (see
α-alkyl benzyl alcohols proceeded smoothly to give the desired Tables S1 and S2 in ESI†). The relative rates of coupling of
product in good yields in spite of the possible formation of a 4-mercaptobenzoic acid (1a) with para-substituted benzylic
vinylarene through β-hydride elimination from the benzylpalla- alcohols (OMe, Me, Br, F, and Cl groups) were examined.
dium intermediate (4l, 80%).17 A sterically demanding cyclic Hammett plots show a good correlation (A: R2 = 0.98; B: R2 =
benzyl alcohol also gave good yield (4m, 77%). In contrast, the 0.93) between the log(kX/kH) and the σ+ value of the respective
reaction using a substrate with a strong electron-withdrawing substituents that resulted in a negative ρ value of 2.7. These
nitro group resulted in no reaction.
results suggested that a
cationic (η3-benzyl)palladium(II)
Table 2 Scope of benzyl alcohols 2a
a Reaction conditions: 4-mercaptobenzoic acid 1a (1 mmol), Pd2(dba)3 (2.5 mol%), benzyl alcohols 2 (1.2 equiv.), H2O (4 mL), 100 or 120 °C, 16 h
in a sealed tube. Yield of the isolated product.
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Table 3 Scope of benzhydryl alcohols 3a
a Reaction conditions: 1 (1 mmol), Pd2(dba)3 (2.5 mol%), benzhydryl
alcohols 3 (1.2 equiv.), H2O (4 mL), 100–120 °C, 16 h in a sealed tube.
Yield of the isolated product.
Fig. 1 Hammett plots for the rate constants of benzylation by various
substituted benzylic alcohols (Tables S1–2 in ESI†).
Table 4 Scope of mercaptobenzoic acid 1a
the S-benzylated products 7 (entries 1 and 2). In the presence
of AcOH (1 equiv.), the reaction also did not proceed (entry 3).
In the presence of TPPMS, thiol 6a or 6c also did not afford
S-benzylated 7. In contrast, the use of benzenethiol with a
strong electron-withdrawing nitro group afforded the desired
7a in 69% yield (entry 6). These results suggested that the
electron-withdrawing properties at the para-position on
benzene rings causes an increase in the acidity of the
mercapto groups, followed by formation of thiolate-Pd(II)
species or thiolate anions as a nucleophile in our catalytic
system. Indeed, while the carboxyl groups at the ortho- or para-
position resulted in good yields (5a, 72%; 5g, 68%), those at
the meta-position resulted in low yield (5i, 48%) (Scheme 2).
Additionally, mercaptophenylcarboxylic acid (1c) or 4-mercapto-
hydrocinnamic acid (1b) resulted in no reaction. However,
4-mercaptobenzoic acid 1a (σp value: 0.45) resulted in good
yield (72%), while the reaction of ester 6a (σp value: 0.45) did
not proceed (see Scheme 2 and Table 5). Therefore, the carbox-
ylate anion 1a′ as a base would play an important role in
deprotonation of the mercapto group 9 in water (Scheme 3).
a Reaction conditions: 1 (1 mmol), Pd2(dba)3 (2.5 mol%), alcohol 2 or 3
(5 or 1.2 equiv.), H2O (4 mL), 80–120 °C, 16 h in a sealed tube. Yield of
the isolated product.
species was formed that played an important role in our cata-
lytic system.
2.7. Mechanism
2.6. Role of the carboxyl group
These results and our previous report suggest the following
To evaluate the role of the carboxyl group18 of the mercapto- mechanism for the S-benzylation of 4-mercaptobenzoic acid 1a
benzoic acids, S-benzylations of 2-mercaptobenzoic acid with benzylic alcohols 2 using Pd2(dba)3 in water (Scheme 3).
methyl ester (6a), 4-mercaptobenzoic acid methyl ester (6b), In the absence of a strong stabilizer such as a phosphine
benzenethiol (6c), and 4-nitrobenzenethiol (6d) were carried ligand for Pd(0), the low reactive precipitate of Pd black is
out (Table 5). The reaction of ester 6a or 6b with benzhydryl produced. In contrast, Pd2(dba)3 ligates with thiol 1a to form
alcohol (3a) using Pd2(dba)3 in water or toluene did not afford thiol-protected Pd(0) species 8.10 Next, oxidative addition of
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Table 5 Effect of carboxyl group
Hammett const.
σp values
Temp.
(°C)
Yield of 7
(%)
Entry
Catalysts (mol%)
R1
R2
Solvents
Additive (equiv.)
1
2
3
4
5
6
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd(OAc)2 (5)/TPPMS (10)
Pd(OAc)2 (5)/TPPMS (10)
Pd2(dba)3 (5)
2-CO2Me (6a)
4-CO2Me (6b)
2-CO2Me (6a)
2-CO2Me (6a)
H (6c)
—
0.45
—
—
0
Ph (3a)
Ph (3a)
Ph (3a)
H (2a)
H (2a)
Ph (3a)
H2O or toluene
80
80
80
120
120
80
None
None
AcOH (1)
None or AcOH (1)
None or AcOH (4)
None
0
0
0
0
H2O
H2O
H2O
H2O
H2O
0
NO2 (6d)
0.778
69 (7a)
since these will stabilize the positive charge on Pd(II).
Hammett studies show a negative ρ value of 2.7, suggesting
that there is a build-up of positive charge in the transition
state. Indeed the benzylation using 4-nitrobenzyl alcohol 2b or
decafluorobenzhydryl alcohol 3b does not proceed, since alco-
hols 2b or 3b cannot form cationic intermediates 9 (see
Table 3). The carboxyl group of mercaptobenzoic acid and
water activate the benzyl alcohol for the smooth generation of
the cationic Pd(II) species 9, which is stabilized by hydration.
Indeed the reaction does not occur in organic solvents (see
Table 1). Next, a thiolate-Pd(II) species is formed, then the
nucleophilic thiolate anion ligand attacks the electrophilically
active (η3-benzyl) ligand of the intermediate 9 to afford the
desired product 4 and regenerate Pd(0). Formation of the thio-
late-Pd(II) species should be favored by electron-withdrawing R
groups on the intermediate 9, since these will stabilize the
negative charge. Indeed, the use of benzene thiols with elec-
tron-withdrawing carboxyl groups at the ortho- or para-position
proceeded smoothly compared with the meta-position (see
Scheme 2).
Scheme 2 Effect of the position of carboxyl groups. Reaction con-
ditions: 1 (1 mmol), Pd2(dba)3 (2.5 mol%), 3a (1.2 equiv.), H2O (4 mL),
80 °C, 16 h.
Additionally, thiol-stabilized Pd nanoparticles featuring car-
boxylic functional end-groups at the edge of the self-assembled
monolayer have been conveniently prepared starting from
Pd(II) and 11-mercaptoundecanoic acid in aqueous media.11c
Therefore, mercaptobenzoic acids (1) might form a monolayer
in water, which is important in our catalytic system. Although
the characterization of thiol-protected (η3-benzyl)palladium(II)
cation complexes are very difficult, there have been many
reports on the stabilization of palladium nanoparticles by
thiol ligands due to the strong interaction between palladium
and sulfur atoms,10 and palladium(II)/thiosalicylic acid com-
plexes have been characterized.10a,f–h In addition, we could
propose the formation of thiol-protected (η3-benzyl)palladium(II)
cation complexes by Hammett studies.
In general, thiols undergo oxidative homocoupling to
produce disulfide byproducts. As shown in Scheme 4, disulfide
10 did not afford S-benzylated 5i, suggesting that disulfide 10
was not an intermediate and oxidative homocoupling did not
occur in our catalytic system. Additionally, although the direct
use of thiols has drawbacks due to their foul smell, the use of
mercaptobenzoic acid can solve this problem.19
Scheme 3 Plausible mechanism.
alcohol
2 to thiol-Pd(0) species 8 affords the cationic
(η3-benzyl)palladium(II) complex 9. These processes should be
favored by electron-donating R groups on the intermediate 9,
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4-(4-Methylbenzylthio)benzoic acid 4c (Table 2).4 288 mg
(86%); white solid; mp 210–212 °C; IR (KBr) (cm−1) 2916, 1681,
1588, 1418, 1288; 1H NMR (400 MHz, DMSO-d6): δ 2.26 (s, 3H),
4.30 (s, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H),
7.41 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 12.9 (brs, 1H);
13C NMR (400 MHz, DMSO-d6): δ 20.6, 35.1, 126.4, 127.3,
128.7, 129.0, 129.7, 133.6, 136.4, 143.1, 166.9; MS (EI): m/z (%)
258 (M+, 13.9), 105 (100).
Scheme 4 Pd-catalyzed reaction of disulphide 10.
4-(4-Ethylbenzylthio)benzoic acid 4d (Table 2).4 204 mg
(75%); white solid; mp 203–205 °C; IR (KBr) (cm−1) 2963, 1680,
3. Conclusions
1
1587, 1417, 1288; H NMR (400 MHz, DMSO-d6): δ 1.15 (t, J =
In summary, we have demonstrated a phosphine-free palla-
dium-catalyzed S-benzylation with benzylic alcohols in water.
The thiol-protected (η3-benzyl)palladium(II) cation complexes
are highly efficient catalysts for S-benzylation. Water-soluble
mercaptobenzoic acid-Pd(0) species could play an important
role in the formation of active (η3-benzyl)palladium(II) cation
complexes followed by S-benzylation in our catalytic system.
Hammett studies on the rate constants of benzylation by
various substituted alcohols show a good correlation. The
negative ρ values showed that there is a build-up of positive
charge in the transition state. Notably, our catalytic system and
the proposed mechanism provide a scope for the development
of palladium-catalyzed reactions for the direct modification of
thiols, which are pharmaceutically active compounds, and
electro materials.
8.0 Hz, 3H), 2.56 (q, J = 8.0 Hz, 2H), 4.31 (s, 2H), 7.15 (d, J =
8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.83
(d, J = 8.4 Hz, 2H), 12.9 (brs, 1H); 13C NMR (400 MHz, DMSO-
d6): δ 15.5, 27.8, 35.0, 126.3, 127.3, 127.9, 128.8, 129.7, 133.9,
142.8, 143.2, 167.0; MS (EI): m/z (%) 272 (M+, 12.4), 119 (100).
4-(4-Fluorobenzylthio)benzoic acid 4e (Table 2).4 210 mg
(80%); off-white solid; mp 197–199 °C; IR (KBr) (cm−1) 2821,
1675, 1589, 1503, 1415, 1286; 1H NMR (400 MHz, DMSO-d6):
δ 4.35 (s, 2H), 7.14 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H),
7.45 (dd, J = 8.8, 5.6 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 12.9 (brs,
1H); 13C NMR (400 MHz, DMSO-d6): δ 34.5, 115.1, 115.4, 126.5,
127.5, 129.7, 130.8, 133.0, 133.1, 142.7, 160.1, 162.5, 166.9; MS
(EI): m/z (%) 262 (M+, 48.7), 109 (100).
4-(4-Chlorobenzylthio)benzoic acid 4f (Table 2).4 220 mg
(79%); white solid; mp 210–212 °C; IR (KBr) (cm−1) 2842, 1685,
1589, 1419, 1295; 1H NMR (400 MHz, DMSO-d6): δ 4.36 (s, 2H),
7.34–7.46 (m, 6H), 7.83 (d, J = 8.0 Hz, 2H), 12.9 (brs, 1H);
13C NMR (400 MHz, DMSO-d6): δ 34.5, 126.6, 127.6, 128.4,
129.7, 130.7, 131.8, 136.1, 142.5, 166.9; MS (EI): m/z (%) 280
(M+ + 2, 6.6), 278 (M+, 17.2), 125 (100).
4. Experimental
4.1. General procedure
A mixture of mercaptobenzoic acids 1 (1 mmol), Pd2(dba)3
4-(4-Bromobenzylthio)benzoic acid 4g (Table 2).4 252 mg
(23 mg, 0.025 mmol) and benzylic alcohols (2a: 5 mmol or 3a: (78%); white solid; mp 222–224 °C; IR (KBr) (cm−1) 2879, 1684,
1.2 mmol) in H2O (4 mL) was heated at 80–120 °C for 16 h in a 1589, 1419, 1291; 1H NMR (400 MHz, DMSO-d6): δ 4.34 (s, 2H),
sealed tube. After cooling, the reaction mixture was poured 7.38 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.50 (d, J =
into water and extracted with EtOAc. The organic layer was 8.4 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 12.9 (brs, 1H); 13C NMR
washed with brine, dried over MgSO4 and concentrated (400 MHz, DMSO-d6): δ 34.5, 120.3, 126.6, 127.6, 129.7, 131.0,
in vacuo. The residue was purified by flash column chromato- 131.3, 136.5, 142.5, 166.9; MS (EI): m/z (%) 324 (M+ + 2, 17.8),
graphy (silica gel, hexanes–EtOAc) to give the desired product 322 (M+, 17.2), 169 (100).
4 or 5.
4-(3-Methoxybenzylthio)benzoic acid 4h (Table 2). 230 mg
4-Benzylthiobenzoic acid 4a (Table 1).4 195 mg (80%); white (84%); white solid; mp 145–147 °C; IR (KBr) (cm−1) 2834, 1675;
solid; mp 188–190 °C; IR (KBr) (cm−1) 3401, 2925, 1676, 1589, 1H NMR (400 MHz, DMSO-d6): δ 3.72 (s, 3H), 6.82 (ddd, J = 8.3,
1
1419, 1289; H NMR (400 MHz, DMSO-d6): δ 4.35 (s, 2H), 7.23 2.5, 0.9 Hz, 1H), 6.98–7.01 (m, 2H), 7.24 (dd, J = 4.8 Hz, 1H),
(t, J = 7.2 Hz, 1H), 7.32 (dd, J = 7.2, 7.2 Hz, 2H), 7.41 (d, J = 7.42 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 8.7 Hz, 2H); 13C NMR
7.2 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), (100 MHz, DMSO-d6): δ 35.8, 55.5, 113.2, 115.0, 121.6, 126.9,
12.9 (brs, 1H); 13C NMR (400 MHz, DMSO-d6): δ 35.3, 126.4, 127.9, 130.1, 130.2, 138.8, 143.6, 159.8, 167.5; MS (EI): m/z (%)
127.2, 127.4, 128.5, 128.8, 129.7, 136.8, 143.0, 166.9; MS (EI): 274 (M+, 26), 121 (100); Anal. Calcd for C15H14O3S: C, 65.67; H,
m/z (%) 244 (M+, 35.0), 91 (100).
5.14; N, 0. Found: C, 65.44; H, 4.83; N, 0.
4-(4-Methoxybenzylthio)benzoic acid 4b (Table 2).4 191 mg
4-(2-Methylbenzylthio)benzoic acid 4i (Table 2).4 168 mg
(70%); white solid; mp 200–202 °C; IR (KBr) (cm−1) 2955, 1683, (65%); white solid; mp 173–175 °C; IR (KBr) (cm−1) 2866, 1678,
1
1589, 1505, 1419, 1294; H NMR (400 MHz, DMSO-d6): δ 3.72 1587, 1415, 1286; 1H NMR (400 MHz, DMSO-d6): δ 2.38 (s, 3H),
(s, 3H), 4.29 (s, 2H), 6.87 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz, 4.33 (s, 2H), 7.10–7.25 (m, 3H), 7.32 (d, J = 7.2 Hz, 1H), 7.44
2H), 7.40 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 12.9 (brs, (d, J = 8.0 Hz, 2H), 7.86 (d, J = 8.0 Hz, 2H), 12.9 (brs, 1H);
1H); 13C NMR (400 MHz, DMSO-d6): δ 34.8, 55.0, 113.9, 126.4, 13C NMR (400 MHz, DMSO-d6): δ 18.7, 34.1, 126.0, 126.6,
127.3, 128.4, 129.7, 130.0, 143.3, 158.4, 166.9; MS (EI): m/z (%) 127.5, 127.6, 129.7, 130.4, 134.1, 136.7, 143.3, 167.0; MS (EI):
274 (M+, 9.4), 121 (100).
m/z (%) 258 (M+, 16.7), 105 (100).
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4-(Thiophen-3-ylmethylthio)benzoic acid 4j (Table 2). 7.2 Hz, 2H), 7.51 (d, J = 8.6 Hz, 1H), 7.58 (dd, J = 8.6, 2.4 Hz,
213 mg (85%); white solid; mp 188–190 °C; IR (KBr) (cm−1
2558, 1683; H NMR (400 MHz, DMSO-d6): δ 4.36 (s, 2H), 7.11 (400 MHz, DMSO-d6): δ 35.7, 127.3, 127.7, 128.5, 129.1, 130.1,
(dd, J = 5.0, 1.4 Hz, 1H), 7.41 (d, J = 8.7 Hz, 2H), 7.45 (s, 1H), 131.9, 136.3, 140.2, 166.2; MS (EI): m/z (%) 280 (M+ + 2, 13.3),
7.49 (dd, J = 5.0, 3.0 Hz, 1H), 7.83 (d, J = 8.5 Hz, 2H); 13C NMR 278 (M+, 35.8), 91 (100).
)
1H), 7.84 (d, J = 2.4 Hz, 1H), 13.4 (brs, 1H); 13C NMR
1
(100 MHz, DMSO-d6): δ 30.6, 124.0, 126.8, 127.1, 127.8, 128.8,
3-Benzylthiobenzoic acid 4q (Table 4).4 195 mg (80%); white
130.2, 137.6, 143.6, 167.5; MS (EI): m/z (%) 250 (M+, 19), 97 solid; mp 129–131 °C; IR (KBr) (cm−1) 2847, 1689, 1579, 1433,
1
(100); Anal. Calcd for C12H10O2S2: C, 57.58; H, 4.03; N, 1288; H NMR (400 MHz, DMSO-d6): δ 4.30 (s, 2H), 7.23 (t, J =
0. Found: C, 57.53; H, 3.79; N, 0.
7.2 Hz, 1H), 7.30 (t, J = 7.2 Hz, 2H), 7.35–7.39 (m, 2H), 7.42 (t,
4-(Thiophen-2-ylmethylthio)benzoic acid 4k (Table 2).4 J = 8.0 Hz, 1H), 7.55–7.60 (m, 1H), 7.73 (dt, J = 8.0, 1.2 Hz, 1H),
215 mg (85%); off-white solid; mp 136–138 °C; IR (KBr) (cm−1
)
7.84 (t, J = 1.6 Hz, 1H), 13.1 (brs, 1H); 13C NMR (400 MHz,
2838, 1678, 1589, 1417, 1290; 1H NMR (400 MHz, DMSO-d6): DMSO-d6): δ 36.4, 126.7, 127.1, 128.4, 128.6, 128.8, 129.2,
δ 4.60 (s, 2H), 6.93 (dd, J = 5.2, 3.6 Hz, 1H), 7.07 (d, J = 3.6 Hz, 131.5, 132.3, 136.9, 137.1, 166.8; MS (EI): m/z (%) 244
1H), 7.40 (dd, J = 5.2, 1.2 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.84 (M+, 67.1), 91 (100).
(d, J = 8.0 Hz, 2H), 12.9 (brs, 1H); 13C NMR (400 MHz, DMSO-
4-(Benzhydrylthio)benzoic acid 5a (Table 1).4 269 mg (84%);
d6): δ 30.1, 125.6, 126.8, 126.9, 127.7, 129.7, 140.1, 142.2, off-white solid; mp 179–181 °C; IR (KBr) (cm−1) 3021, 1685,
166.9; MS (EI): m/z (%) 250 (M+, 30.7), 97 (100).
1591, 1488, 1417, 1282; H NMR (400 MHz, DMSO-d6): δ 6.13
1
4-(1-Phenylethylthio)benzoic acid 4l (Table 2).4 207 mg (s, 1H), 7.23 (t, J = 7.2 Hz, 2H), 7.30–7.40 (m, 6H), 7.52 (d, J =
(80%); white solid; mp 172–174 °C; IR (KBr) (cm−1) 3430, 2974, 7.6 Hz, 4H), 7.75 (d, J = 8.4 Hz, 2H), 12.9 (brs, 1H); 13C NMR
2920, 1683, 1591, 1426, 1301; 1H NMR (400 MHz, DMSO-d6): (400 MHz, DMSO-d6): δ 53.3, 127.4, 127.8, 128.0, 128.7, 129.6,
δ 1.59 (d, J = 6.8 Hz, 3H), 4.81 (q, J = 6.8 Hz, 1H), 7.23 (t, J = 140.5, 142.2, 166.8; MS (EI): m/z (%) 320 (M+, 2.1), 167 (100).
7.2 Hz, 1H), 7.32 (t, J = 7.2 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H),
4-[Bis(4-methoxyphenyl)methylthio]benzoic
acid
5b
7.45 (d, J = 7.2 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 12.9 (brs, 1H); (Table 3). 293 mg (95%); white solid; mp 160–162 °C; IR (KBr)
1
13C NMR (400 MHz, DMSO-d6): δ 22.3, 44.6, 127.2, 127.3, (cm−1) 2830, 1686, 1600; H NMR (400 MHz, DMSO-d6): δ 3.71
127.9, 128.2, 128.5, 129.6, 142.0, 142.5, 166.9; MS (EI): m/z (%) (s, 6H), 6.04 (s, 1H), 6.88 (d, J = 8.9 Hz, 4H), 7.34 (d, J = 8.7 Hz,
258 (M+, 57.5), 105 (100).
2H), 7.39 (d, J = 8.9 Hz, 4H), 7.74 (d, J = 8.7 Hz, 2H); 13C NMR
4-(1,2,3,4-Tetrahydronaphthalen-1-ylthio)benzoic acid 4m (100 MHz, DMSO-d6): δ 52.6, 55.6, 114.5, 127.7, 128.1, 129.6,
(Table 2).4 218 mg (77%); off-white solid; mp 169–171 °C; 130.1, 133.2, 143.3, 158.8, 167.4; MS (FAB): m/z 381 [M + H]+;
IR (KBr) (cm−1) 2936, 1684, 1590, 1418, 1286; 1H NMR Anal. Calcd for C22H20O4S: C, 69.45; H, 5.30; N, 0. Found:
(400 MHz, DMSO-d6): δ 1.70–1.80 (m, 1H), 1.90–2.10 (m, 3H), C, 69.18; H, 5.00; N, 0.
2.65–2.85 (m, 2H), 4.98 (s, 1H), 7.10–7.20 (m, 3H), 7.38 (d, J =
4-[(4-Methoxyphenyl)phenylmethylthio]benzoic
acid
5c
7.2 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.90 (dd, J = 8.4, 1.2 Hz, (Table 3). 291 mg (83%); white solid; mp 183–185 °C; IR (KBr)
2H), 12.9 (brs, 1H); 13C NMR (400 MHz, DMSO-d6): δ 18.2, (cm−1) 2841, 1684; 1H NMR (400 MHz, DMSO-d6): δ 3.71 (s,
27.9, 28.3, 44.6, 125.7, 127.2, 128.0, 129.1, 129.9, 130.4, 134.3, 3H), 6.08 (s, 1H), 6.88 (d, J = 8.7 Hz, 2H), 7.23 (tt, J = 7.3,
137.5, 142.6, 166.9; MS (EI): m/z (%) 284 (M+, 6.0), 131 (100).
1.1 Hz, 1H), 7.32 (dd, J = 7.8, 7.8 Hz, 2H), 7.35 (d, J = 8.7 Hz,
2-Benzylthiobenzoic acid 4n (Table 4).4 159 mg (65%); white 2H), 7.42 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.75 (d, J =
solid; mp 187–189 °C; IR (KBr) (cm−1) 3413, 2920, 1674, 1459, 8.7 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): δ 52.6, 54.9, 113.9,
1411, 1262; 1H NMR (400 MHz, DMSO-d6): δ 4.21 (s, 2H), 127.2, 127.5, 127.8, 128.5, 129.1, 129.5, 132.2140.7, 142.4, 158.3,
7.18–7.23 (m, 1H), 7.27 (t, J = 6.0 Hz, 1H), 7.34 (t, J = 7.2 Hz, 166.7; MS (FAB): m/z 331 [M + H]+; Anal. Calcd for C21H18O3S:
2H), 7.40–7.60 (m, 2H), 7.48–7.52 (m, 2H), 7.89 (d, J = 7.6 Hz, C, 71.98; H, 5.18; N, 0. Found: C, 71.98; H, 4.92; N, 0.
1H), 13.0 (brs, 1H); 13C NMR (400 MHz, DMSO-d6): δ 35.7,
124.0, 125.7, 127.1, 127.6, 128.5, 129.2, 130.9, 132.3, 136.6, 274 mg (82%); white solid; mp 187–189 °C; IR (KBr) (cm−1
4-[Phenyl(p-tolyl)methylthio]benzoic acid 5d (Table 3).
)
141.2, 167.4; MS (EI): m/z (%) 244 (M+, 25.1), 91 (100).
3025, 1676; 1H NMR (400 MHz, DMSO-d6): δ 2.24 (s, 3H),
2-Benzylthio-5-fluorobenzoic acid 4o (Table 4).4 184 mg 6.09 (s, 1H), 7.13 (d, J = 7.8 Hz, 2H), 7.23 (dt, J = 7.3, 1.4 Hz,
(70%); white solid. mp 153–155 °C; IR (KBr) (cm−1) 3034, 2912, 1H), 7.28–7.42 (m, 6H), 7.49 (d, J = 7.1 Hz, 2H), 7.74 (d, J =
1
1690, 1465, 1424, 1246; H NMR (400 MHz, DMSO-d6): δ 4.21 8.7 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): δ 21.1, 53.5, 127.9,
(s, 2H), 7.27 (t, J = 7.2 Hz, 1H), 7.34 (t, J = 7.2 Hz, 2H), 128.3, 128.4, 128.5, 129.2, 129.8, 130.1, 137.2, 138.0,
7.38–7.44 (m, 3H), 7.51 (dd, J = 9.0, 5.2 Hz, 1H), 7.63 (dd, J = 141.2, 142.9, 167.4; MS (FAB): m/z 335 [M + H]+; Anal. Calcd
9.0, 2.8 Hz, 1H), 13.4 (brs, 1H); 13C NMR (400 MHz, DMSO-d6): for C21H18O2S: C, 75.42; H, 5.43; N, 0. Found: C, 75.28;
δ 36.1, 117.0, 117.3, 119.3, 119.5, 127.2, 128.3, 128.4, 128.5, H, 5.12; N, 0.
129.1, 129.9, 130.0, 136.2, 136.5, 157.8, 160.2, 166.4; MS (EI):
4-[(4-Chlorophenyl)phenylmethylthio]benzoic
(Table 3). 220 mg (62%); white solid; mp 173–175 °C; IR (KBr)
acid
5e
m/z (%) 262 (M+, 18.7), 91 (100).
2-Benzylthio-5-chlorobenzoic acid 4p (Table 4).4 198 mg (cm−1) 3004, 1685; 1H NMR (400 MHz, DMSO-d6): δ 6.19 (s,
(71%); white solid; mp 162–164 °C; IR (KBr) (cm−1) 2924, 1681, 1H), 7.25 (dd, J = 6.4, 6.4 Hz, 1H), 7.30–7.47 (m, 6H), 7.49 (d,
1462, 1317, 1250; 1H NMR (400 MHz, DMSO-d6): δ 4.23 (s, 2H), J = 8.5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.76 (d, J = 8.5 Hz, 2H);
7.27 (t, J = 7.2 Hz, 1H), 7.34 (t, J = 6.0 Hz, 2H), 7.43 (d, J = 13C NMR (100 MHz, DMSO-d6): δ 53.0, 128.1, 128.5, 129.2,
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129.3, 130.2, 130.4, 132.5, 140.1, 140.6, 142.3, 167.3; MS (FAB): 7.1 Hz, 4H), 7.40 (d, J = 6.9 Hz, 4H), 7.84 (dd, J = 8.0, 1.6 Hz,
m/z 357 [M + 2 + H]+, 355 [M + H]+; Anal. Calcd for 1H); 13C NMR (100 MHz, DMSO-d6): δ 30.3, 35.4, 55.5, 127.7,
C20H15ClO2S: C, 67.70; H, 4.26; N, 0. Found: C, 67.44; H, 4.11; 128.5, 129.1, 129.3, 130.2, 133.2, 139.8, 141.7, 174.2; MS (FAB):
N, 0.
m/z 348 [M]+; Anal. Calcd for C22H20O2S·0.6H2O: C, 73.55; H,
4-[Bis(4-fluorophenyl)methylthio]benzoic acid 5f (Table 3). 5.95; N, 0. Found: C, 73.52; H, 5.63; N, 0.
278 mg (78%); white solid; mp 179–181 °C; IR (KBr) (cm−1
)
1
2991, 1683; H NMR (400 MHz, DMSO-d6): δ 6.22 (s 1H), 7.17
(dd, J = 8.9, 8.9 Hz, 4H), 7.38 (d, J = 8.7 Hz, 2H), 7.52 (d, J =
8.7 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 8.7 Hz, 2H);
13C NMR (100 MHz, DMSO-d6): δ 52.1, 116.1 (d, J = 21.0 Hz),
128.2, 128.6, 130.2, 130.5 (d, J = 7.6 Hz), 137.1 (d, J = 2.9 Hz),
142.3, 161.8 (d, J = 243 Hz), 167.3; MS (FAB): m/z 337 [M + H]+;
Anal. Calcd for C20H14F2O2S: C, 67.40; H, 3.96; N, 0. Found: C,
67.37; H, 3.94; N, 0.
Acknowledgements
This work was supported by JSPS KAKENHI grant number
25460026.
2-(Benzhydrylthio)benzoic acid 5g (Table 4). 208 mg (65%);
white solid; mp 209–211 °C; IR (KBr) (cm−1) 3024, 1681;
1H NMR (400 MHz, DMSO-d6): δ 5.99 (s, 1H), 7.13 (dd, J = 6.9,
1.6 Hz, 1H), 7.24 (tt, J = 7.3, 1.1 Hz, 2H), 7.28–7.38 (m, 6H),
7.49 (dt, J = 8.0, 1.4 Hz, 4H), 7.84 (dd, J = 8.9, 1.4 Hz, 1H); 13C
NMR (100 MHz, DMSO-d6): δ 53.4, 124.7, 127.4, 127.8, 128.7,
128.8, 129.2, 131.3, 132.5, 140.7, 141.3, 168.0; MS (FAB): m/z
334 [M + H]+; Anal. Calcd for C20H16O2S: C, 74.97; H, 5.03; N,
0. Found: C, 74.61; H, 4.70; N, 0.
2-(Benzhydrylthio)-5-fluorobenzoic acid 5h (Table 4). 264 mg
(78%); white solid; mp 166–168 °C; IR (KBr) (cm−1) 3066, 1687;
1H NMR (400 MHz, DMSO-d6): δ 6.00 (s, 1H), 7.20–7.30 (m,
4H), 7.33 (dd, J = 7.3, 7.3 Hz, 4H), 7.47 (d, J = 7.1 Hz, 4H), 7.58
(dd, J = 9.4, 3.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 53.9,
117.5 (d, J = 22.9 Hz), 119.7 (d, J = 21.9 Hz), 127.9, 128.7, 129.2,
130.2 (d, J = 7.6 Hz), 131.4 (d, J = 6.7 Hz), 135.5 (d, J = 2.9 Hz),
141.1, 159.6 (d, J = 243 Hz), 167.1; MS (FAB): m/z 339 [M + H]+;
Anal. Calcd for C20H15FO2S: C, 70.99; H, 4.47; N, 0. Found: C,
70.80; H, 4.31; N, 0.
3-(Benzhydrylthio)benzoic acid 5i (Table 4). 218 mg (68%);
white solid; mp 127–129 °C; IR (KBr) (cm−1) 2559, 1693; 1H
NMR (400 MHz, DMSO-d6): δ 6.02 (s, 1H), 7.22 (dd, J = 7.3,
7.3 Hz, 2H), 7.28–7.38 (m, 5H), 7.50 (d, J = 7.3 Hz, 4H), 7.54
(dt, J = 8.7, 0.9 Hz, 1H), 7.69 (dt, J = 7.8, 1.1 Hz, 1H), 7.82 (t, J =
1.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 55.0, 127.7,
127.9, 128.6, 129.1, 129.6, 130.4, 131.9, 134.0, 136.8, 141.2,
167.2; MS (FAB): m/z 321 [M + H]+; Anal. Calcd for C20H16O2S:
C, 74.97; H, 5.03; N, 0. Found: C, 74.74; H, 4.76; N, 0.
2-[4-(Benzhydrylthio)phenyl]acetic acid 5j (Table 4). 167 mg
(50%); white solid; mp 99–101 °C; IR (KBr) (cm−1) 3026, 1695;
1H NMR (400 MHz, DMSO-d6): δ 3.48 (s, 2H), 5.91 (s, 1H), 7.10
(d, J = 8.5 Hz, 2H), 7.15–7.28 (m, 4H), 7.31 (dd, J = 7.1, 7.1 Hz,
4H), 7.49 (d, J = 7.1 Hz, 4H); 13C NMR (100 MHz, DMSO-d6):
δ 40.5, 55.3, 127.7, 128.6, 129.1, 129.8, 130.5, 133.8, 134.1,
141.7, 173.0; MS (FAB): m/z 334 [M]+; Anal. Calcd for
C21H18O2S·0.2H2O: C, 74.62; H, 5.49; N, 0. Found: C, 74.70; H,
5.31; N, 0.
Notes and references
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and L. C. Czabaniuk, J. Am. Chem. Soc., 2010, 132, 15534–
15536; (i) R. Kuwano, Synthesis, 2009, 1049–1061;
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I. Azumaya, Adv. Synth. Catal., 2013, 355, 2308–2320;
(b) H. Hikawa and Y. Yokoyama, RSC Adv., 2013, 3, 1061–
1064; (c) H. Hikawa, H. Suzuki, Y. Yokoyama and
I. Azumaya, Catalysts, 2013, 3, 486–500; (d) H. Hikawa,
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Chem., 1983, 48, 1357–1359.
3-[4-(Benzhydrylthio)phenyl]propanoic acid 5k (Table 4).
178 mg (51%); white solid; mp 97–99 °C; IR (KBr) (cm−1) 3026,
1
1707; H NMR (400 MHz, DMSO-d6): δ 2.61 (t, J = 8.0 Hz, 2H),
2.86 (t, J = 8.0 Hz, 2H), 5.49 (s, 1H), 7.01 (d, J = 8.2 Hz, 2H),
7.15 (d, J = 8.2 Hz, 2H), 7.18–7.24 (m, 2H), 7.29 (dd, J = 7.1,
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