Direct Use of Benzylic Alcohols for Gold(III)-Catalyzed S-Benzylation of Mercaptobenzoic Acids in Water

Article abstract of DOI:10.1002/adsc.201500839

We demonstrate the gold(III)-catalyzed direct substitution of benzylic alcohols in water. These atom economic and environmentally benign protocols afford S-benzylated products in moderate to excellent yields. In contrast, common Lewis or Br?nsted acids as

Full text of DOI:10.1002/adsc.201500839

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DOI: 10.1002/adsc.201500839
Direct Use of Benzylic Alcohols for Gold(III)-Catalyzed
S-Benzylation of Mercaptobenzoic Acids in Water
Hidemasa Hikawa,a,* Ayaka Tada,a Shoko Kikkawa,a and Isao Azumayaa,*
a
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
Fax: (+81)-47-472-1595; phone: (+81)-47-472-1591; e-mail: hidemasa.hikawa@phar.toho-u.ac.jp or
isao.azumaya@phar.toho-u.ac.jp
Received: September 8, 2015; Revised: November 5, 2015; Published online: January 26, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500839.
Abstract: We demonstrate the gold(III)-catalyzed tained, suggesting that there is a build-up of positive
direct substitution of benzylic alcohols in water. charge in the transition state. Our catalytic system
These atom economic and environmentally benign can be performed with the use of only 2 mol% of
protocols afford S-benzylated products in moderate gold(III) catalyst without any other additives in
to excellent yields. In contrast, common Lewis or water, and scaled up to 10 mmol scale (85% isolated
Brønsted acids as catalyst, and organic solvents such yield). Notably, the present method can accomplish
as dichloromethane or toluene were ineffective for the S-benzylation of unprotected mercaptobenzoic
the S-benzylation of mercaptobenzoic acids. Water acids, which is chemoselective and leaves the carbox-
can be an attractive tool for new transition metal- yl group intact. Furthermore, the direct substitution
catalyzed reactions. A Hammett study for the rate of allylic and propargylic alcohols also proceeded
constants with various substituted alcohols shows smoothly in good yields.
a good correlation (R2 =0.97) between the log(kX/
kH) and the s+ value of the respective substituents. Keywords: benzhydryl alcohol; benzylation; gold;
From the slope negative 1 values of 2.35 are ob- mercaptobenzoic acid; water
Introduction
further progress is needed to develop more environ-
mentally friendly conditions. Water can be an attrac-
Gold(III)-catalyzed direct substitution of hydroxy tive tool for new transition metal-catalyzed reactions.
groups affords a powerful methodology for the forma- However, most gold-catalyzed reactions are usually
[1]
tion of C C, C S or C N bonds. These reactions conducted in organic solvents.[5] Furthermore, the de-
occur through an attractive salt-free and atom-eco- hydration reaction in water is one of the most chal-
nomic process, which affords the desired products lenging research topics.
À
À
À
along with water as the sole co-product. Such an effi-
We have been developing a unique strategy for the
ciency is mainly due to the Lewis acidic character of direct substitution of benzyl alcohols using a water-
the gold(III) catalyst for the activation of several sp3 soluble gold catalyst Au(III)/TPPMS (sodium diphe-
À
C O bonds. It is worth noting that these efficient
atom-economical transformations have been devel-
oped utilizing AuCl4Na·2H2O in CH2Cl2 as a standard
protocol (Scheme 1). Campagne et al. reported the
nucleophilic substitution of propargylic alcohols by
a gold(III) catalyst, which acted as a propargylic alco-
hol-activating agent through coordination to a p-
bond.[2] Campagne and Prim developed the direct
amination of benzhydryl alcohols.[3] Ohshima and Ma-
shima reported the direct substitution of allylic alco-
hols with Boc-, Bus-, and Dios-protected amine nucle-
ophiles.[4] Although the direct substitution of benzylic
Scheme 1. Gold(III)-catalyzed direct substitution of hydroxy
alcohols benefits from high atom and step economies, groups.
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Hidemasa Hikawa et al.
nylphosphinobenzene-3-sulfonate) in water.[6] Nota- much interest due to their fascinating size-dependent
3
À
bly, water activates the sp C O bond by hydrogen electronic properties. Recently, Kornberg and co-
bonds between water and the hydroxy group of the workers reported the crystallization and X-ray struc-
alcohols. Theoretical calculations by Shinokubo and ture determination of p-mercaptobenzoic acid-pro-
Oshima have elucidated the importance of hydration tected gold nanoparticles.[12] Therefore, investigation
of the hydroxy group for the smooth generation of into reactions using our catalytic system would pro-
the p-allylpalladium species.[7] Cozzi et al. proposed vide new insights for biological chemistry and gold
that the direct generation of carbocations in water nanoclusters.
from alcohols is driven by the formation of hydrogen
bonds between water and the hydroxy group of the
alcohol.[8] Furthermore, the hydrophobic effect would Results and Discussion
also accelerate the benzylation in our catalytic
system. Since water molecules have unusual chemical Effects of Catalysts and Solvents
and physical properties compared to organic solvents,
water should play an important role in the develop- First, we heated a mixture of 2-mercaptobenzoic acid
ment of new and efficient reactions.
(1a) and benzhydrol (2a) (1.2 equiv.) in the presence
In light of our ongoing efforts to develop efficient of AuCl4Na·2H2O (2 mol%) in CH2Cl2 at 808C for
methods for direct substitution reactions of benzylic 16 h in a sealed tube. S-Benzylated 3a was obtained in
alcohols, we hypothesize that the Lewis acidic only 18% yield (Table 1, entry 1). As expected, the
gold(III) catalyst performs dual activation of the sp3 use of water as a solvent selectively afforded the de-
À
C O bond of alcohols and thiols as nucleophiles, gen- sired 3a in 70% yield, despite the possibility of form-
erating the corresponding S-benzylated products, ing the benzyl ester or disulfide (entry 2).[13] Using the
which have the potential to be powerful tools for water-soluble phosphine ligand TPPMS did not en-
direct transformations in water (Scheme 2). Conse- hance the reaction (entry 3). In the absence of cata-
quently, we herein report an efficient method for the lyst, no reaction occurred (entry 4). With regard to
gold(III)-catalyzed direct substitution reaction of ben- the gold catalyst, the use of AuBr3 also gave the prod-
zylic alcohols with unprotected mercaptobenzoic uct 3a in good yield (entry 5, 64%). In contrast, using
acids in water.[9] Notably, organic solvents such as AuCl3 or Au(III)-picolinate complex resulted in lower
CH2Cl2 or toluene were ineffective. Furthermore, yields (entries 6 and 7). A less Lewis acidic gold(I)
when using protocols based on traditional methods catalyst, AuCl, was ineffective (entry 8). Recently,
such as using Lewis or Brønsted acids, the substrate Morita and Tamura reported that the use of oxophilic
scope was difficult to extend to strong nucleophilic (hard) gold(III) and p-philic (soft) gold(I) catalysts
thiols. Thus, the key to the success of this strategy is provided access to two types of cyclic ethers from
to avoid the deactivation of catalysts in the presence propargylic alcohols, and these observations can be
of strong nucleophiles.[10]
explained by the hard and soft acids and bases
Additionally, gold complexes with thiolate ligands (HSAB) principle.[14] Thus, we decided to use more
have been investigated not only for the development stable and easier to handle AuCl4Na·2H2O as the cat-
of synthetic methods but also as antiarthritic and can- alyst for further investigations. To compare the
cerostatic drugs. For example, Auranofin is a well- gold(III) catalyst with other efficient catalysts, we
known drug used to treat rheumatoid arthritis. Fur- tested the reaction using Brønsted acids such as HCl
thermore, Henderson et al. reported that gold(III) and TsOH·H2O, and Lewis acids such as Sc(OTf)3
complexes containing a chelated thiosalicylate di- and CuBr2. However, the reactions resulted in low
anionic ligand showed high antitumor activity.[11] Thi- yields (entries 9–11), clearly showing the superiority
olate-protected gold nanoclusters have also attracted of AuCl4Na·2H2O for the S-benzylation. Furthermore,
Scheme 2. Our strategy for dual activation of alcohols and thiols by Lewis acidic gold(III) catalyst in water.
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Direct Use of Benzylic Alcohols for Gold(III)-Catalyzed S-Benzylation
Table 1. Effects of catalysts and solvents.[a]
benzylated products in moderate to excellent yields
(3h, 88%; 3i, 95%; 3j, 58%; 3k, 88%). This reaction
afforded 3i with the carbon-bromine moiety left
intact, which could be employed for further manipula-
tion.[16] Furthermore, S-benzylation with a-methylben-
zyl alcohol afforded the desired product 3l in 68%
yield. In contrast, no reaction occurred when using
simple benzyl alcohol. Not only mercaptobenzoic
acids but also benzenethiol with an aliphatic carboxyl-
ic acid, 4-mercaptohydrocinnamic acid, gave the de-
sired 3m in 78% yield. Allylic and propargylic alco-
hols also resulted in good yields (3n, 78%; 3o, 82%;
3p, 75%).
Entry Catalyst
Solvent
Conv.
[%][b]
1
2
AuCl4Na·2H2O
AuCl4Na·2H2O
CH2Cl2
H2O
18
70
70
trace
64
3
AuCl4Na·2H2O/TPPMS H2O
4
none
H2O
5
AuBr3
H2O
6
7
8
9
10
11
12
13
14
15
AuCl3
H2O
H2O
H2O
H2O
H2O
H2O
EtOH or DMF
toluene
dioxane
DMF/H2O (1:1)
42
28
37
25–26
25
26
0
11
13
Hammett Studies
Au(III)-picolinate[c]
AuCl
To demonstrate the electronic effect of substituents
HCl or TsOH·H2O
Sc(OTf)3
CuBr2
AuCl4Na·2H2O
AuCl4Na·2H2O
AuCl4Na·2H2O
AuCl4Na·2H2O
À
À
on the rates of the C O bond cleavage and C S bond
formation reactions, a Hammett study was conducted
for the gold-catalyzed S-benzylation (see the Support-
ing Information). From these studies, summarized in
Figure 1, the ratio of rate constants can be obtained.
The relative rates of coupling of 2-mercaptobenzoic
acid (1a) with para-substituted benzhydryl alcohols 2
(X=diOMe, Me, diF, and Cl groups) were examined.
Figure 1A shows a good correlation (R2 =0.97) be-
tween the log(kX/kH) and the s+ value of the respec-
tive substituents that resulted in a 1 value of À2.35,
0
[a]
[b]
[c]
Reaction conditions: 2-mercaptobenzoic acid 1a
(1 mmol), catalyst (2 mol%), benzhydrole 2a (1.2 equiv.),
solvent (4 mL), 808C, 16 h in sealed tube, air.
The conversion was determined by H NMR analysis of
the crude product using p-nitroanisole as an internal
standard.
1
À
which suggested that the C O bond cleavage process
involved a build-up of positive charge in the transition
state. Thus, this pathway should be favored by elec-
Dichloro(2-pyridinecarboxylato)gold.
no reaction or low yields occurred when using organic tron-donating groups on the long-lived benzyl cation,
solvents such as EtOH, DMF, toluene, or 1,4-dioxane since these will stabilize the positive charge on the ap-
instead of water (entries 12–14). The reaction also did propriate electrophilic carbon. Furthermore, the rela-
not proceed in DMF/H2O (entry 15). Thus, the hydro- tive rates of coupling of 5-substituted thiosalicylic
phobic effect in water could be observed in our cata- acid 1 (X=F and Cl groups) with benzhydrol (2a)
lytic system.[15]
showed that the reaction was decelerated by electron-
withdrawing groups on the benzene ring of 1 (Fig-
ure 1B, 1 value of À1.20, R2 =0.98).
Reaction Scope
Results for the S-benzylation reactions of several mer- Mechanistic Considerations
captobenzoic acids 1 with benzylic alcohols 2 using
AuCl4Na·2H2O in water are summarized in Scheme 3. These results and our previous report suggest the fol-
The reaction of 3-mercaptobenzoic acid gave almost lowing mechanism for the S-benzylation of mercapto-
the same result as 3a (3b, 74% vs. 3a, 70% NMR benzoic acids 1 with benzhydryl alcohols 2 using
yield). In contrast, 4-mercaptobenzoic acid resulted in AuCl4Na·2H2O in water (Scheme 4). First, thiol-
lower yield (3c, 50%). The 2-mercaptobenzoic acids Au(III) complex A ligates with alcohol 2 to form in-
with fluoro and chloro groups produced S-benzylated termediate B.[12,17] Lewis acidic Au(III) cation B and
3
À
products in moderate to good yields (3d, 71%; 3e, water activate the sp C O bond of alcohol 2 for the
61%). As expected, the benzhydryl alcohols with elec- smooth generation of benzylic cation D. Indeed the
tron-donating methoxy and methyl groups resulted in reaction does not occur in organic solvents (see
good yields (3f, 80%; 3g, 84%), and these observa- Table 1). These processes should be favored by elec-
tions can be explained by the stabilization of the tron-donating R groups of intermediate B, since these
benzyl cation intermediates. The benzhydryl alcohols could stabilize the positive charge on benzylic carbo-
with fluoro, bromo and chloro groups produced S- cation D. A negative Hammett 1 value in the reaction
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Hidemasa Hikawa et al.
Scheme 3. Scope of benzhydryl alcohols 3. Reaction conditions: mercaptobenzoic acids 1 (1 mmol), benzhydryl alcohols 2
(1.2 equiv.), AuCl4Na·2H2O (2 mol%), H2O (4 mL), 80–1208C, 16 h in sealed tube, air. Yield of isolated product.
of p-substituted benzhydryl alcohols 2 with thiols zoic acid (1a) with benzhydrol (2a) could be per-
1 clearly shows the formation of a positive charge on formed on the 10 mmol scale. After 10 min, an insolu-
the benzylic position in the transition state (see Fig- ble gum-like substance of a yellowish brown color
ure 1A). Indeed the benzylation using 3-trifluorome- formed in water, which slowly turned into a white sus-
thylbenzhydrol or decafluorobenzhydryl alcohol does pension. After 16 h, the reaction mixture was extract-
not occur, since these alcohols cannot form cationic ed with AcOEt, then crude 3a could be purified
intermediates D. The strong nucleophilic thiolate simply by recrystallization from hexanes and AcOEt
anion ligand C attacks the electrophilically active to give the desired product 3a in 85% isolated yield.
benzyl cation D to afford the desired product 3. The Notably, the developed process avoids using column
negative 1 value in the Hammett analysis (B) is con- chromatography.
sistent with the activation of thiol by cationic
Thiolate anions and benzyl halides with base are
gold(III) being the rate-limiting step in our catalytic generally used for S-benzylation. However, benzyl
system (see Figure 1B).
halides are chemically unstable and their synthesis
from benzyl alcohols is achieved by halogenation,
which is undesirable from an environmental point of
view. Furthermore, the use of excess benzyl halides
leads to over-reaction of reactive functional groups.
Scale-Up Experiment
Finally, we examined the scalability of our catalytic For example, the reaction of 2-mercaptobenzoic acid
system (Scheme 5). S-Benzylation of 2-mercaptoben- with 4-methylbenzyl chloride (2 equiv.) affords benzyl
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Direct Use of Benzylic Alcohols for Gold(III)-Catalyzed S-Benzylation
Conclusions
We have demonstrated an efficient and environmen-
tally benign procedure for direct substitution of ben-
zylic alcohols using a gold(III) catalyst in water. A
negative Hammett 1 value indicated a build-up of
positive charge on the benzylic carbon in the transi-
tion state. Our proposed strategy provided a scope for
the development of gold(III)-catalyzed reactions for
the direct modification of unprotected mercaptoben-
zoic acids, which would be utilized for pharmaceuti-
cals[20] and materials.
Experimental Section
General Procedure
A
mixture of mercaptobenzoic acids
1
(1 mmol),
AuCl4Na·2H2O (8 mg, 0.02 mmol), and benzylic alcohols 2
(1.2 mmol) in H2O (4 mL) was heated at 80 or 1208C for
16 h in a sealed tube under air. After cooling, the reaction
mixture was poured into water and extracted with EtOAc.
The organic layer was washed with brine, dried over MgSO4
and concentrated under vacuum. The residue was washed
with hexanes, then purified by flash column chromatography
(silica gel, hexanes/EtOAc) to give the desired product 4.
2-(Benzhydrylthio)benzoic acid (3a):[9a] Following the
scale-up experiment (see the Supporting Information), 3a
was obtained as a white solid; mp 210–2128C; IR (KBr): n=
1
3437, 1681 cmÀ1; H NMR (400 MHz, DMSO-d6): d=5.60 (s,
1H), 7.14 (dd, J=7.2 Hz, 2H), 7.17 (dt, J=7.6, 0.8 Hz 1H),
7.27–7.33 (m, 6H), 7.40 (dt, J=8.8, 2.0 Hz, 2H), 7.43 (dd,
J=6.4, 2.0 Hz, 2H), 8.01 (dd, J=8.0, 1.6 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6): d=52.9, 124.2, 126.8, 127.2, 128.2,
128.7, 130.8, 132.0, 140.2, 140.8, 167.5; MS (FAB): m/z=321
[M+H]+.
3-(Benzhydrylthio)benzoic acid (3b):[9a] Following the
general procedure, 3a was obtained as a white solid; yield:
196 mg (61%); mp 127–1298C; IR (KBr): n=2559,
Figure 1. Hammett plot for the rate constants of benzylation
by various substituted benzhydryl alcohols 2 (X=diOMe,
Me, diF and Cl groups) (A), and in the benzylation of 5-sub-
stituted thiosalicylic acid 1 (X=F and Cl groups) (B).
1
1693 cmÀ1; H NMR (400 MHz, DMSO-d6): d=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): d=54.5, 127.2, 127.3, 128.0, 128.6, 129.1, 129.9,
131.4, 133.5, 136.3, 140.7, 166.7; MS (FAB): m/z=321 [M+
H]+.
esters as undesired products.[18] In contrast, our pres-
ent method can accomplish the S-benzylation of un-
protected mercaptobenzoic acids with benzylic alco-
4-(Benzhydrylthio)benzoic acid (3c):[9a] Following the gen-
eral procedure, 3c was obtained as a pale yellow solid;
hols in water, which is chemoselective and leaves the yield: 159 mg (50%); mp 188–1908C; IR (KBr): n=3081,
1
1682 cmÀ1; H NMR (400 MHz, DMSO-d6): d=5.72 (s, 1H),
carboxyl group intact. Additionally, protection of re-
active functional groups such as amino, hydroxy, or
carboxyl groups is essential in organic synthesis, not
only for suppressing side reactions, but also for easy
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): d=53.8, 126.6, 127.9, 128.5, 129.2, 130.1, 130.9,
handling by decreased polarity. However, protection
141.1, 142.8, 167.3; FAB-MS: m/z=321 [M+H]+.
sometimes causes serious problems, e.g., increasing
the number of synthetic steps and difficulty in depro-
tecting unstable compounds. Therefore, the develop-
ment of syntheses without protecting groups should
lead to breakthroughs in organic synthesis.[19]
2-(Benzhydrylthio)-5-fluorobenzoic acid (3d):[9a] Follow-
ing the general procedure, 3d was obtained as a pale yellow
solid; yield: 239 mg (71%); mp 163–1668C; IR (KBr): n=
3067, 1692 cmÀ1 1H NMR (400 MHz, CDCl3): d=5.60 (s,
;
1H), 6.99 (ddd, J=8.8, 7.6, 2.8 Hz, 1H), 7.14 (dd, J=8.8,
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Hidemasa Hikawa et al.
Scheme 4. Plausible mechanism.
1684 cmÀ1
;
1H NMR (400 MHz, CDCl3): d=2.31 (s, 3H),
5.61 (s, 1H), 7.10–7.33 (m, 10H), 7.42 (dd, J=8.8, 7.2 Hz,
2H), 8.06 (dd, J=8.0, 1.6 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6): d=21.1, 53.5, 124.8, 127.6, 128.7, 129.2, 129.7,
131.2, 132.4, 136.9, 140.5, 141.6, 168.0; MS (FAB): m/z=335
[M+H]+; anal. calcd. for C21H18O2S: C 75.42, H 5.43, N 0;
found: C 75.44, H 5.38, N 0.
2-{[Bis(4-fluorophenyl)methyl]thio}benzoic acid (3h): Fol-
lowing the general procedure, 3h was obtained as a white
solid; yield: 313 mg (88%); mp 197–2008C; IR (KBr): n=
Scheme 5. Scale-up experiment.
1
3081, 1684 cmÀ1; H NMR (400 MHz, DMSO-d6): d=6.05 (s,
5.2 Hz, 1H), 7.23–7.27 (m, 2H), 7.30 (dd, J=7.2, 7.2 Hz,
4H), 7.41 (dd, J=7.2, 1.6 Hz, 4H), 7.76 (dd, J=9.2, 2.8 Hz,
1H); 13C NMR (100 MHz, DMSO-d6): d=53.9, 117.6 (d, J=
23.9), 119.7 (d, J=21.9 Hz), 127.9, 128.7, 129.2, 130.1 (d, J=
7.7 Hz), 131.4 (d, J=7.7 Hz), 135.5, 141.1, 159.6 (d, J=
242.2), 167.1; MS (FAB): m/z=339 [M+H]+.
1H), 7.13 (dd, J=8.8, 2.4 Hz, 5H), 7.25 (dd, J=7.2 Hz, 1H),
7.31 (dt, J=7.2, 1.6 Hz, 1H), 7.48 (dd, J=8.4, 5.2 Hz, 4H),
7.81 (dd, J=7.2, 1.6 Hz, 1H); 13C NMR (100 MHz, DMSO-
d6): d=51.9, 116.0 (d, J=22.0 Hz), 125.1, 127.8, 129.3, 130.7
(d, J=7.6 Hz), 131.2, 132.5, 137.4 (d, J=2.8 Hz), 139.8, 161.8
(d, J=243.1 Hz), 168.0; MS (FAB): m/z=357 [M+H]+;
anal. calcd. for C20H14F2O2S: C 67.40, H 3.96, N 0; found: C
67.03, H 4.15, N 0.
2-(Benzhydrylthio)-5-chlorobenzoic acid (3e): Following
the general procedure, 3e was obtained as a white solid;
yield: 218 mg (61%); mp 166–1688C; IR (KBr): n=3082,
1
1683 cmÀ1; H NMR (400 MHz, DMSO-d6): d=6.04 (s, 1H),
2-{[(4-Bromophenyl)(phenyl)methyl]thio}benzoic
acid
7.23–7.49 (m, 13H), 7.80 (d, J=2.4 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6): d=53.4, 127.9, 128.8, 129.2, 129.4,
130.6, 132.2, 139.6, 140.9, 166.9; FAB-MS: m/z=355 [M+
H]+, 357 [M+H+2]+.
(3i):[1] Following the general procedure (1/2 scale), 3i was
obtained as a white solid; yield: 191 mg (95%); mp 206–
1
2088C; IR (KBr): n=3080, 1683 cmÀ1; H NMR (400 MHz,
CDCl3): d=5.60 (s, 1H), 7.13–7.19 (m, 2H), 7.27–7.33 (m,
6H), 7.39–7.45 (m, 4H), 8.07 (dd, J=7.6, 2.4 Hz, 1H);
13C NMR (100 MHz, DMSO-d6): d=52.9, 120.9, 125.0,
126.5, 127.7, 129.2, 131.0, 132.1, 133.7, 140.9, 168.1; FAB-
MS: m/z=399 [M+H]+, 401 [M+H+2]+.
2-{[(4-Methoxyphenyl)(phenyl)methyl]thio}benzoic acid
(3f): Following the general procedure, 3f was obtained as
a white solid; yield: 283 mg (80%); mp 184–1878C; IR
1
(KBr): n=3080, 1683 cmÀ1; H NMR (400 MHz, CDCl3): d=
3.78 (s, 3H), 5.61 (s, 1H), 6.83 (dd, J=6.8, 2.4 Hz, 2H),
7.13–7.35 (m, 8H), 7.42 (s, 1H), 7.44 (s, 1H), 8.06 (dd, J=
8.0, 2.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): d=53.1,
55.6, 114.6, 124.8, 127.6, 127.7, 128.7, 129.1, 129.9, 140.6,
141.7, 158.9, 168.0; MS (FAB): m/z=351 [M+H]+; anal.
calcd. for C21H18O3S: C 71.98, H 5.18, N 0; found: C 71.87,
H 5.13, N 0.
2-{[Phenyl(p-tolyl)methyl]thio}benzoic acid (3g): Follow-
ing the general procedure, 3g was obtained as a white solid;
yield: 283 mg (84%); mp 176–1798C; IR (KBr): n=3080,
2-{[(4-Chlorophenyl)(phenyl)methyl]thio}benzoic
acid
(3j): Following the general procedure, 3j was obtained as
a white solid; yield: 207 mg (58%); mp 204–2078C; IR
1
(KBr): n=3081, 1684 cmÀ1; H NMR (400 MHz, CDCl3): d=
5.62 (s, 1H), 7.14 (dd, 2H), 7.25–7.34 (m, 5H), 7.37–7.42 (m,
4H), 8.06 (dd, J=7.6, 1.6 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6): d=52.8, 125.0, 127.8, 128.8, 129.2, 130.6, 132.4,
140.0, 140.4, 140.9, 168.0; MS (FAB): m/z=355 [M+H]+,
357 [M+H+2]+.
400
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Direct Use of Benzylic Alcohols for Gold(III)-Catalyzed S-Benzylation
2-{[Bis(4-chlorophenyl)methyl]thio}benzoic acid (3k): Fol-
lowing the general procedure, 3k was obtained as a yellow
solid; yield: 344 mg (88%); mp 190–1928C; IR (KBr): n=
3H), 7.84 (d, J=8.0 Hz, 1H), 7.91 (dd, J=8.0, 1.6 Hz, 1H);
13C NMR (100 MHz, DMSO-d6): d=5.4, 88.7, 122.5, 125.6,
128.3, 128.7, 128.9, 129.2, 129.3, 129.4, 131.3, 131.9, 132.7,
137.4, 139.9, 168.1; HR-MS-EI: m/z=344.0871 (M+), calcd.
for C22H16O2S: 344.0871.
1
3072, 1674, 1672 cmÀ1; H NMR (400 MHz, CDCl3): d=5.60
(s, 1H), 7.16 (dt, J=8.4, 1.2 Hz 1H), 7.27 (d, J=8.4 Hz,
2H), 7.33 (d, J=8.4 Hz, 4H), 8.06 (dd, J=7.6, 1.6 Hz, 1H);
13C NMR (100 MHz, DMSO-d6): d=51.6, 125.0, 127.4,
129.3, 130.6, 131.4, 132.7, 140.1, 168.0; MS (FAB): m/z=389
[M+H]+, 391 [M+H+2]+; anal. calcd. for C20H14Cl2O2S: C
61.71, H 3.63, N 0; found: C 61.71, H 4.08, N 0.
References
2-{[1-(4-Methoxyphenyl)ethyl]thio}benzoic acid (3l): Fol-
lowing the general procedure, 3l was obtained as a white
solid; yield: 195 mg (68%); mp 168–1718C; IR (KBr): n=
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2966, 1675 cmÀ1 1H NMR (400 MHz, CDCl3): d=1.66 (d,
;
J=6.8 Hz 3H), 3.78 (s, 3H), 4.39 (q, J=6.8 Hz, 4H), 6.80
(dd, J=6.8, 2.0 Hz 4H), 7.22 (dd, J=24, 8.4 Hz, 1H), 7.33
(dd, J=6.0, 1.2 Hz, 1H), 7.37 (dt, J=7.2, 1.6 Hz, 1H), 8.15
(dd, J=7.6, 1.2 Hz, 1H); 13C NMR(100 MHz, DMSO-d6):
d=23.0, 40.4, 55.6, 114.4, 124.9, 128.2, 128.9, 132.3, 135.2,
140.0, 158.8, 168.1; MS (FAB): m/z=289 [M+H]+; anal.
calcd. for C16H16O3S: C 66.64, H 5.59, N 0; found: C 66.53,
H 5.43, N 0.
3-[4-(Benzhydrylthio)phenyl]propanoic acid (3m): Follow-
ing the general procedure, 3f was obtained as a white solid;
yield: 264 mg (78%); mp 108–1108C; IR (KBr): n=3025,
1
1707 cmÀ1; H NMR (400 MHz, DMSO-d6): d=2.61 (t, J=
6.8 Hz, 2H), 2.87 (t, J=3.6 Hz, 2H), 5.49 (s, 1H), 7.02 (d,
J=4.6 Hz, 2H), 7.14–7.42 (m, 14H); 13C NMR (100 MHz,
DMSO-d6): d=30.3, 35.4, 55.6, 127.7, 128.5, 129.1, 129.3,
130.2, 133.2, 139.8, 141.8, 174.2; FAB-MS: m/z=349 [M+
H]+.
2-(Cinnamylthio)benzoic acid (3n): Following the general
procedure, 3n was obtained as a white solid; yield: 211 mg
(78%); mp 208–2108C; IR (KBr): n=3031, 1672 cmÀ1
;
1H NMR (400 MHz, DMSO-d6): d=3.82 (d, J=6.8 Hz, 1H),
6.36 (dt, J=15.6, 7.6 Hz, 1H), 6.70 (d, J=15.6 Hz, 1H),
7.18–7.27 (m, 2H), 7.32 (t, J=7.6 Hz, 2H), 7.41 (d, J=
7.6 Hz, 2H), 7.47–7.56 (m, 2H), 7.87 (dd, J=8.0, 1.6 Hz
1H); 13C NMR (100 MHz, DMSO-d6): d=34.2, 124.5, 125.1,
126.6, 126.7, 128.2, 128.9, 129.2, 131.4, 132.7, 133.5, 136.9,
140.9, 168.0; FAB-MS: m/z=271 [M+H]+; anal. calcd. for
C16H14O2S: C 71.09, H 5.22, N 0; found: C 70.91, H 5.19, N
0.
[7] H. Kinoshita, H. Shinokubo, K. Oshima, Org. Lett.
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Org. Biomol. Chem. 2014, 12, 5964–5972; b) H.
Hikawa, Y. Yokoyama, Org. Biomol. Chem. 2012, 10,
2942–2945.
[10] Hf(OTf)4-catalyzed Friedel–Crafts reaction of 1,3-dime-
thoxybenzene with benzhydrol did not proceed in the
presence of 1-methylindole, since the strong p nucleo-
phile 1-methylindole suppressed the acidity of
Hf(OTf)4.
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(E)-2-[(1,3-Diphenylallyl)thio]benzoic acid (3o): Follow-
ing the general procedure, 3n was obtained as a white solid;
yield: 284 mg (82%); mp 164–1668C; IR (KBr): n=3056,
1
1677 cmÀ1; H NMR (400 MHz, DMSO-d6): d=5.46 (d, J=
7.2 Hz, 1H), 6.58 (dd, J=15.6, 6.4 Hz, 1H), 6.63 (d, J=
15.6 Hz, 1H), 7.19 (dt, J=7.2, 0.8 Hz, 1H), 7.20–7.25 (m,
1H), 7.26–7.33 (m, 3H), 7.33–7.47 (m, 5H), 7.52–7.59 (m,
3H), 7.80 (dd, J=8.0, 2.0 Hz 1H); 13C NMR (100 MHz,
DMSO-d6): d=52.4, 125.3, 126.9, 128.0, 128.3, 128.7, 128.9,
129.1, 129.3, 129.5, 130.3, 131.0, 132.1, 132.3, 136.7, 139.3,
140.5, 168.2; FAB-MS: m/z=347 [M+H]+; anal. calcd. for
C22H18O2S·0.2H2O: C 75.49, H 5.30, N 0; found: C 75.26, H
5.19, N 0.
2-[(1,3-Diphenylprop-2-yn-1-yl)thio]benzoic acid (3p):
Following the general procedure, 3o was obtained as
a yellow solid; yield: 258 mg (75%); mp 170–1728C; IR
(KBr): n=3078, 3021, 1683 cmÀ1
;
1H NMR (400 MHz,
DMSO-d6): d=5.89 (s, 1H), 7.30 (dt, J=7.6, 0.8 Hz, 1H),
7.34–7.40 (m, 6H), 7.45 (t, J=8.0 Hz, 2H), 7.60–7.70 (m,
[13] A. Corma, T. Rodenas, M. J. Sabater, Chem. Sci. 2012,
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Adv. Synth. Catal. 2016, 358, 395 – 402
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401

FULL PAPERS
Hidemasa Hikawa et al.
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402
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Adv. Synth. Catal. 2016, 358, 395 – 402