Gold(III)-Catalyzed Decarboxylative C3-Benzylation of Indole-3-carboxylic Acids with Benzylic Alcohols in Water

Article abstract of DOI:10.1021/acs.joc.8b02947

A strategy for the gold(III)-catalyzed decarboxylative coupling reaction of indole-3-carboxylic acids with benzylic alcohols has been developed. This cascade reaction is devised as a straightforward and efficient synthetic route for 3-benzylindoles in moderate to excellent yields (50-93%). A Hammett study of the protodecarboxylation gives a negative ρ value, suggesting that there is a buildup of positive charge on the indole ring in the transition state. Furthermore, comparison of initial rates in H₂O and in D₂O reveals an observed kinetic solvent isotope effect (KSIE = 2.7). This simple protocol, which affords the desired products with CO₂ and water as the coproducts, can be achieved under mild conditions without the need for base or other additives in water.

Full text of DOI:10.1021/acs.joc.8b02947

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Article
Gold(III)-catalyzed decarboxylative C3-benzylation of
indole-3-carboxylic acids with benzylic alcohols in water
Hidemasa Hikawa, Fumiya Kotaki, Shoko Kikkawa, and Isao Azumaya
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02947 • Publication Date (Web): 23 Jan 2019
Downloaded from http://pubs.acs.org on January 26, 2019
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Gold(III)-catalyzed decarboxylative C3-benzylation of
indole-3-carboxylic acids with benzylic alcohols in water
Hidemasa Hikawa,* Fumiya Kotaki, Shoko Kikkawa, and Isao Azumaya*
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Faculty of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan
E-mail: hidemasa.hikawa@phar.toho-u.ac.jp and isao.azumaya@phar.toho-u.ac.jp
KEYWORDS. decarboxylation, gold, water, benzylic alcohol, indole-3-carboxylic acid
Abstract: A strategy for the gold(III)-catalyzed decarboxylative coupling reaction of indole-3-carboxylic
acids with benzylic alcohols has been developed. This cascade reaction is devised as a straightforward
and efficient synthetic route for 3-benzylindoles in moderate to excellent yields (50-93%). A Hammett
study of the protodecarboxylation gives a negative  value, suggesting that there is a build-up of positive
charge on the indole ring in the transition state. Furthermore, comparison of initial rates in H2O and in
D2O reveals an observed kinetic solvent isotope effect (KSIE = 2.7). This simple protocol, which affords
the desired products with CO2 and water as the co-products, can be achieved under mild conditions
without the need for base or other additives in water.
Introduction
Transition metal-catalyzed decarboxylative transformation affords a powerful methodology for C-C
bond formation. Carboxylic acids are recognized as atom-economic alternatives to traditional coupling
partners in synthetic organic chemistry. In 1930, Shepard et al. discovered the copper-promoted
decarboxylation reaction.1 However, this procedure required very high temperatures (260 oC) and the use
of stoichiometric amounts of copper salts. The first report of a catalytic protodecarboxylation of aromatic
carboxylic acids was described in 2007 by Gooen.2 Subsequently, various transition metals such as Cu,3
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Ag,4 Pd5 and Au6 were successfully utilized for catalytic decarboxylative activation. In 2011, Larrosa et
al. reported that gold(I)-salts mediated the decarboxylative activation of (hetero)aromatic carboxylic acids
at lower temperatures than did copper(I).6e In 2013, Nolan et al. reported the gold(I) complex,
[Au(Ipr)(OH)], promoted the decarboxylation of aromatic carboxylic acids without the use of a silver co-
catalyst under mild conditions.6c
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The indole scaffold is one of the most valuable synthetic targets since it is a common structural motif
found in pharmaceuticals and functional materials (Figure 1).7 Therefore, a dehydrative coupling reaction
for the direct introduction of diverse functionalities on indoles is gaining increasing interest.8 Recently,
we developed a green and sustainable strategy for catalytic dehydrative C-C bond formation of indoles
with benzylic alcohols.9 Continuing our studies in the dehydrative coupling strategy, we envisioned its
expansion to indole-3-carboxylic acids as a valuable coupling partner with its attractive features of low
toxicity, high stability, and easy use.10,11 Recently, Miura et al. reported the Pd-catalyzed decarboxylative
C3-arylation of 3-carboxyindoles with aryl bromides (Scheme 1A).10b We herein present a strategy for the
gold(III)-catalyzed decarboxylative and dehydrative coupling reaction of indole-3-carboxylic acids with
benzylic alcohols in water (Scheme 1B). This simple protocol has reduced waste generation, uses safer
solvent and reaction conditions, and increases energy efficiency, all of which contribute to the efficiency
of a chemical transformation.11 To the best of our knowledge, this is the first example of using a gold(III)
catalyst for the decarboxylative activation of carboxyindoles.
Figure 1. Representative biologically active 3-benzylindoles.
O2N
O
MeO
O
HO
O
O
O
S
S
N
H
H
Ph
H
N
N
Br
Cy
O
O
Me
N
N
N
H
Me
H
topoisomerase I inhibitor
anti-inflammatory agent
antibacterial agent
Cl
Cl
O
F
N
N
F
NH
Cl
N
Me
N
F
OH
O
Me
HO2C
CRTH2 antagonist
N
H
OH
OH
SGLT2 inhibitor
VDR-coactivator inhibitor
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Scheme 1. Decarboxylative coupling reactions.
Previous work
(ref. 10b)
CO2H
Ar
cat. Pd(OAc)2/PCy3
Cs2CO3, MS4A
+ Ar-Br
(A)
(B)
Ph
Ph
Ph
mesitylene
170 oC, 6 h
N
N
Me
Me
Present work
Ph
CO2H
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AuCl4Na·2H2O (5 mol%)
TPPMS (5 mol%)
Ph
+
N
H2O, 120 oC, 16 h
HO
1.2 equiv
Ph
N
Me
Me
91%
Results and Discussion
Initially, 1-methylindole-3-carboxylic acid (1a) and benzhydrol (2a) were chosen as the model
compounds to optimize the decarboxylative coupling reaction. The reaction of 1a with 2a (1.2 equiv)
using AuCl4Na·2H2O (1 mol%) and sodium diphenylphosphinobenzene-3-sulfonate (TPPMS, 1 mol%) in
o
water at 120 C for 16 h gave the corresponding C3-benzylated product 3a in 61% yield along with
protodecarboxylated 4a in 28% yield (Table 1, entry 1). The yield of 3a was increased to 91% by use of
AuCl4Na·2H2O (5 mol%) and TPPMS (5 mol%) (entry 2). In contrast, using only AuCl4Na·2H2O
resulted in low yield (entry 3). A control experiment using HCl indicated that the Au(III) catalyst was
essential in this system (entry 4). With regard to the gold catalysts, AuCl4Na·2H2O gave the best result
(entry 1 vs. entries 5-8). Other transition metals were less effective than AuCl4Na·2H2O (entries 9-16).
While Sc(OTf)3 generally works as a Lewis acid in water solutions, the desired product 3a was obtained
in only 25% yield (entry 17). Replacing water with organic solvents such as EtOH, DMF and toluene
resulted in low yields or no reaction (entries 18-21).
Table 1. Effect of catalysts and solventsa
Ph
CO2H
Catalyst (1 mol%)
TPPMS (1 mol%)
Ph
Ph
+
solvent
120 oC, 16 h
HO
Ph
N
N
2a
N
1a
4a
Me
Me
3a
(1.2 equiv)
Me
Entry Catalyst
ligand
Solvents
Yield (%)b
4a
28
9
3a
61
91
1
2 c
AuCl4Na·2H2O TPPMS
AuCl4Na·2H2O TPPMS
H2O
H2O
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AuCl4Na·2H2O none
H2O
18
14
2
55
62
4
4
HCl
none
H2O
5
HAuCl4·3H2O
AuBr3
TPPMS
TPPMS
TPPMS
TPPMS
TPPMS
TPPMS
TPPMS
TPPMS
TPPMS
TPPMS
TPPMS
TPPMS
none
H2O
6
H2O
6
9
d
7
PicAuCl2
H2O
25
17
28
6
21
33
24
58
6
8
AuCl
H2O
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9
PdCl2
H2O
10
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16
17
18
19
20
21
CuCl2
H2O
PtCl2
H2O
25
2
NiCl2·6H2O
FeCl3·6H2O
CoCl2·6H2O
RuCl3
H2O
63
40
63
16
28
53
7
H2O
18
3
H2O
H2O
16
24
25
16
0
IrCl3·H2O
Sc(OTf)3
H2O
H2O
AuCl4Na·2H2O TPPMS
AuCl4Na·2H2O TPPMS
AuCl4Na·2H2O TPPMS
AuCl4Na·2H2O TPPMS
EtOH
DMF
toluene
toluene/H2Oe
0
9
3
5
47
a Reaction conditions: 1a (1 mmol), catalyst (1 mol%), TPPMS (1 mol%), 2a (1.2 equiv), solvent (4 mL),
120 °C, 16 h in a sealed tube under air. b The conversion was determined by 1H NMR analysis of the
crude product using 4-nitroanisole as an internal standard. c AuCl4Na·2H2O (5 mol%) and TPPMS (5
mol%) were used. d Dichloro(2-pyridinecarboxylato)gold. e 1:1.
With the optimized conditions in hand, we examined the substrate scope of the decarboxylative
tandem reaction (Scheme 2). First, the scope of alcohols 2 as the coupling partner was examined. Both
electron-donating groups (OMe and Me) and electron-withdrawing groups (F and Cl) on the benzene ring
of substituted benzhydrols 2 were tolerated well to produce the corresponding C3-benzylated products
3b-g in moderate to excellent yields (64-93%). The carbon-bromine moiety in 3g was left intact, which
could be employed for further cross-coupling. We explored different benzylic alcohols such as 4-
methoxy-α-methylbenzyl alcohol, 4-methoxybenzylalcohol, veratryl Alcohol, trityl alcohol and trans-1,3-
diphenyl-2-propen-1-ol, which afforded the corresponding products 3h-l in moderate to excellent yields
(52-88%). In contrast, pentafluorobenzhydrol or isopropyl alcohol resulted in no reaction. Since electron-
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deficient diarylmethanol or aliphatic alcohol failed to react with 1a, stability of the diarylcarbocation
would be critical to the success of these reactions. Next, the scope of indole-3-carboxylic acids 1 was
examined. N-Benzylindole-3-carboxylic acid and indole-3-carboxylic acid also led to the desired products
3m-n in good yields (71-76%). The coupling reactions of indole-3-carboxylic acid with electron-
withdrawing (OMe and Me) groups and an electron-withdrawing bromo group on the benzene ring
afforded the desired products 3o-r in moderate to good yields (50-68%). A sterically demanding methyl
group at the C2 position was also tolerated in the C3-benzylation (3s, 81%). In previous work,9 we have
shown that the reaction of indole 2-carboxylic acids with several benzhydryl alcohols 2 afford the 3-
benzylated products with the carboxyl group left intact.
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Scheme 2. Scope of carboxylic acids 1 and alcohols 2.a
R3
Ar
CO2H
+
N
R2
R1
R1
AuCl4Na·2H2O (5 mol%)
TPPMS (5 mol%)
R3
H2O, 120 oC, 16 h
HO
Ar
N
R2
1
2
3
F
OMe
Me
Ph
Ph
F
N
N
Me
3b
Me
3c
: 82%
N
: 90%
3d
: 93%
Cl
Me
Cl
Cl
Br
Ph
Ph
N
N
N
Me
3e
Me
3f
Me
3g
: 71%
: 64%
: 70%
OMe
OMe
Me
OMe
OMe
N
N
N
Me
3i
Me
Me
b
: 56%
3h
: 71%
3j
: 52%
Ph
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
Me
Me
: 88%
Ph
Ph
3m
: 71%
c
3k
3l
: 85%
Ph
Ph
Ph
Ph
Ph
Ph
Me
MeO
N
N
N
H
H
H
3n
3o
3p
: 76%
: 50%
: 62%
Ph
Ph
Ph
Me
Ph
Ph
Ph
Br
N
N
Me
N
Me
: 81%
H
H
3q
3r
3s
: 68%
: 56%
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a Reaction conditions: 1 (1 mmol), AuCl4Na·2H2O (5 mol%), TPPMS (5 mol%), alcohols (2, 1.2 equiv),
H2O (4 mL), 120 oC under air in a seald tube. Yield of isolated product. b 4-Methoxybenzyl alcohol (1
equiv) was used. cAuCl4Na·2H2O (2 mol%) was used.
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To gain insight into the catalytic decarboxylative activation, several catalysts were investigated (Table
2). As expected, the reaction of 1a using AuCl4Na·2H2O (2 mol%) and TPPMS (2 mol%) in water was
o
extremely rapid at 120 C, affording the protodecarboxylated product 4a in 83% yield after only 1 h
(entry 1). The use of only AuCl4Na·2H2O resulted in decreased yield (entry 2). No reaction occurred
without the catalysts or when replacing water with an organic solvent such as DMF (entries 3-4). The use
of HCl instead of the Au(III)/TPPMS catalyst also resulted in low yield, since it excluded the Brønsted
acid-catalyzed decarboxylative activation pathway (entry 5). The reaction was suppressed by addition of
NaOH (1 equiv) (entry 6). The reactions were much slower when using other salts such as Cu(I), Cu(II),
Ag(I) Pd(II) and Fe(III) (entries 7-15). These results indicate that the gold(III)/TPPMS catalyst is highly
effective as a Lewis acid for the activation of indole-3-carboxylic acid in water.
Table 2. Catalytic decarboxylative activation.a
CO2H
H
catalyst (2 mol%)
TPPMS (2 mol%)
solvents, sealed tube
120 oC, 1 h, air
N
Me
N
Me
1a
4a
Entr Catalyst
ligand
Solvent
H2O
H2O
H2O
DMF
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
Yield (%)b
83
60
0
0
18
2
25
15
40
15
33
36
37
17
31
1
2
3
4
AuCl4Na·2H2O TPPMS
AuCl4Na·2H2O none
none
AuCl4Na·2H2O TPPMS
HCl none
AuCl4Na·2H2O TPPMS
Cu2O
CuCl2
Cu(OTf)2
Ag2CO3
AgOAc
Ag2O
none
5
6 c
7
TPPMS
TPPMS
TPPMS
TPPMS
TPPMS
TPPMS
TPPMS
TPPMS
TPPMS
8
9
10
11
12
13
14
15
AgOTf
Pd(OAc)2
FeCl3·4H2O
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a Reaction conditions: 1a (1 mmol), catalyst (2 mol%), TPPMS (2 mol%), solvent (4 mL), 120 oC, 1 h in a
4
5
sealed tube under air. b NMR yields. c NaOH (1 equiv) was added.
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To demonstrate the electronic effect of the substituents on the rates of the decarboxylative C3-
benzylation, Hammett studies were conducted. First, the relative rates in the protodecarboxylation of
various substituted indole-3-carboxylic acids (1X) show excellent correlation (R2 = 0.99) between the
log(kX/kH) and the p values of the respective substituents, resulting in a negative  value (–1.1) (Figure
2A). Furthermore, the C3-benzylation of 1-methylindole-3-carboxylic acid (1a) proceeded faster than that
of indole-3-carboxylic acid (1b) (Scheme 3). These results suggest that there is a build-up of positive
charge on the indole ring in the transition state. Next, the relative rates using the p-substituted
benzhydrols (2Y) also showed a negative slope  = –2.1, R2 = 0.997) (Figure 2B), indicating a positive
charge on the benzylic position in the transition state.
Figure 2. Hammett plot for the rate constants in the protodecarboxylation of substituted indole-3-
carboxylic acids 1X (A), and in the substitution of benzhydrols 2Y (B).
Y
Ph
CO2H
CO2H
AuCl4Na·2H2O (5 mol%)
TPPMS (5 mol%)
AuCl4Na·2H2O (5 mol%)
TPPMS (5 mol%)
X
Ph
X
(A)
+
H2O, 100 oC, 30 min
HO
N
H2O, 110 oC, 16 h
N
H
(B)
N
N
H
1X
Hammett  = -1.1
4X
Me
1a
2Y
Y
Hammett  = -2.1
Me
3Y
Scheme 3. Competition experiment.
CO2H
CO2H
cat. AuIII/TPPMS
+
+
N
N
N
H2O
100 oC, 30 min
H
N
Me
1-methylindole
H
Me
1b
(0.25 mmol)
indole
k(N-Me)/k(N-H) = 1.2
1a
(0.25 mmol)
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The rates for the decarboxylative activation of 1a “in H2O” and “in D2O” were compared (Scheme 4).
The initial rate of the protodecarboxylation was faster “in H2O” than “in D2O” with a kinetic solvent
isotope effect (KSIE) of 2.7, suggesting that the water molecules stabilized the transition state by
hydrogen-bonding interactions that accelerated the decarboxylation rate. Furthermore, a smaller KSIE
value of 1.2 was obtained in the dehydrative C-C bond formation step.
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Scheme 4. Deuterium isotope effects.
Ph
CO2H
cat. AuIII/TPPMS
Ph
2a
Benzhydrole
cat. AuIII/TPPMS
100 oC, 30 min
100 oC, 30 min
N
N
N
KSIE = 2.7
1a
Me KSIE = 1.2
4a
Me
3a
Me
On the basis of these experimental results and the literature,6 we propose a catalytic system for the
decarboxylative coupling reaction of 1-methylindole-3-carboxylic acid (1a) with benzhydrol (2a) in water
as illustrated in Scheme 5. Initially, AuCl4Na·2H2O and TPPMS catalysts react with carboxylic acid 1a to
form the gold(III) carboxylate A (step 1).13 Subsequent C3 electrophilic auration of complex A proceeds
to form zwitter ion B via a 4-membered transition state TS (step 2). This process should be favored by
electron-donating groups on B, since these will stabilize the positive charge on the indole ring (Hammett
 = –1.1). The intermediate B rearomatizes with release of CO2 to afford the arylgold complex C13 (step
3), which is in equilibrium with 1-methylindole (4a). Notably, the use of water as a reaction medium
would enhance the decarboxylation (KSIE = 2.7). The sp3 C-O bond of benzhydrol (2a) is activated by
the Lewis acidic Au(III) cation species A to form the benzylic cation D (step 4).15 The observed negative
 value of –2.1 is consistent with electrophilic C-O bond cleavage in the transition state which has a
build-up of positive charge. Furthermore, the direct substitution of trityl alcohol affords the corresponding
desired products 3h and 3l, which is in agreement with the reaction proceeding through an SN1 reaction.
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Finally, the C-C bond formation of intermediate C (or 4a) with carbocation D leads to the C3-benzylated
4
5
product 3a selectively (step 5).
6
7
8
9
Scheme 5. Proposed mechanism.
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CO2H
Ph
Ph
+ AuCl4Na·2H2O
TPPMS
N
1a
Me
CO2 [Au]
O
-
step 1
O
N
1a
step 5
3a
Me
[Au]
step 2
[Au]
step 4
Ph
H
+
O
N
N
A
O
Ph
[Au]
Me
D
TS
Me
O
Ph
Ph
2a
Hammett  = -1.1
Hammett  = -2.1
[Au]
KSIE = 2.7
KSIE = 1.2
N
C
N
B
H3O+
Me
step 3
-CO2
Me
N
+ [Au]
Me
4a
Control experiments were performed to exclude a radical pathway based on a single electron transfer
(SET). First, in the presence of a radical scavenger (BHA: 3-tert-butyl-4-hydroxyanisole, 1 equiv),
desired product 3a was obtained in 70% NMR yield (Scheme 6A). Next, a radical clock experiment using
-cyclopropylbenzyl alcohol (2b) was conducted to observe whether the rapid isomerization of the
cyclopropylmethyl radical to the allylmethyl radical occurred (Scheme 6B). As expected, corresponding
3t was obtained in 85% isolated yield via the cyclopropylmethyl cation and not the ring-opened product
3u.
Scheme 6. Control experiments.
Ph
CO2H
Ph
Ph
cat. AuIII/TPPMS
H2O, 120 oC, 16 h
BHA (1 equiv)
(A)
(B)
+
HO
Ph
N
Me
2a
N
1a
1a
(1.2 equiv)
Me
3a
: 70%
Ph
Ph
2b
(3 equiv)
HO
Ar
3u
cat. AuIII/TPPMS
H2O, 120 oC, 16 h
Ph
: not obtained
N
Me
3t
: 85%
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Our catalytic system can be applied to the synthesis of bis(indolyl)methanes 5 (Scheme 7). The
gold(III)-catalyzed decarboxylative and dehydrative coupling reaction of indole-3-carboxylic acids 1 with
benzaldehyde gave desired 5a-b in good to excellent yields. After 2 h, the reaction mixture was extracted
with AcOEt, then crude products were purified simply by recrystallization from n-hexane and AcOEt to
give desired products. The developed process avoids the use of column chromatography.
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Scheme 7. Synthesis of bis(indolyl)methanes 5.
(0.5 equiv)
AuCl4Na·2H2O (5 mol%)
TPPMS (5 mol%)
Ph CHO
Ph
CO2H
H2O, 120 oC, 2 h
sealed tube, air
N
R
N
R
N
R
1
5a
5b
(R = Me), 88%
(R = H), 84%
Finally, to demonstrate the utility of our catalytic system, a gram scale reaction of 1a (1.05 g, 6 mmol)
was carried out (Scheme 8). As expected, the desired 3a was obtained successfully in 72% isolated yield.
Scheme 8. Scale-up experiment.
Ph
2a
Benzhydrol
CO2H
Ph
AuCl4Na·2H2O (5 mol%)
TPPMS (5 mol%)
H2O, 110 oC, 16 h
N
N
Me
(1.1 g)
Me
1a
3a
, 72%
Conclusion
In summary, we have demonstrated a gold(III)/TPPMS-catalyzed decarboxylative C-C bond
formation of indole-3-carboxylic acids with benzhydryl alcohols in water. This simple protocol provides
rapid access to valuable 3-benzylindoles as a common structural motif found in pharmaceuticals in
moderate to excellent yields.
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The mass analyzer type is double-focusing magnetic sector mass spectrometer for the HRMS
measurements.
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General procedure: A mixture of indole-3-carboxylic acids 1 (1 mmol), AuCl4Na·2H2O (20 mg, 0.05
mmol), sodium diphenylphosphinobenzene-3-sulfonate (TPPMS) (18 mg, 0.05 mmol) and benzylic
o
alcohols 2 (1.2 mmol) in H2O (4 mL) was heated at 120 C 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 in vacuo. The residue was washed with hexanes,
then purified by flash column chromatography (silica gel, hexanes/EtOAc) to give desired product 3.
3-Benzhydryl-1-methyl-1H-indole 3a 1
Following the scale-up experiment procedure (Scheme 8), 3a was obtained as a pale yellow solid; mp
142−144 C; IR (KBr) (cm-1) 3056, 1482; 1H NMR (400 MHz, CDCl3):  3.69 (s, 3H), 5.66 (s, 1H), 6.41
(s, 1H), 6.97 (ddd, J=7.8, 6.9, 0.9 Hz, 1H), 7.16-7.31 (m, 13H); 13C{1H} NMR (100 MHz, CDCl3):  32.8,
49.0, 109.3, 118.4, 119.0, 120.1, 121.8, 126.3, 127.5, 128.4, 128.9, 129.2, 137.6, 144.3; MS(FAB): m/z
298 [M+H]+.
3-[(4-Methoxyphenyl)(phenyl)methyl]-1-methyl-1H-indole 3b 9
Following the general procedure, 3b was obtained as a white solid; 294 mg (90%); mp 98-105 C; IR
(KBr) (cm-1) 3012, 1506; 1H NMR (400 MHz, CDCl3):  3.69 (s, 3H), 3.78 (s, 3H), 5.61 (s, 1H), 6.40 (d,
J=0.8 Hz, 1H), 6.82 (d, J=8.8 Hz, 2H), 6.97 (ddd, J=8.0, 7.1, 1.0 Hz, 1H), 7.14 (d, J=8.4 Hz, 2H), 7.16-
13
7.30 (m, 8H); C{1H} NMR (100 MHz, CDCl3):  32.7, 47.9, 55.2, 109.1, 113.6, 118.6, 118.8, 120.0,
121.6, 126.1, 127.3, 128.2, 128.7, 128.9, 129.9, 136.3, 137.4, 144.5, 157.9; MS(EI): m/z 327 (M+, 100).
1-Methyl-3-[phenyl(p-tolyl)methyl]-1H-indole 3c 9
Following the general procedure, 3c was obtained as a white solid; 202 mg (65%); mp 117-120 C; IR
1
(KBr) (cm-1) 3024, 2921, 1473; H NMR (400 MHz, CDCl3):  2.32 (s, 3H), 3.69 (s, 3H), 5.62 (s, 1H),
6.41 (s, 1H), 6.97 (dd, J=7.9, 7.1 Hz, 1H), 7.08 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.1 Hz, 2H), 7.15-7.30 (m,
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8H); 13C{1H} NMR (100 MHz, CDCl3):  21.1, 32.7, 48.4, 109.1, 118.4, 118.8, 120.0, 121.6, 126.1,
127.4, 128.2, 128.7, 128.8, 128.9, 129.0, 135.6, 137.4, 141.1, 144.3; MS(EI): m/z (%) 311 (M+, 100).
3-[Bis(4-fluorophenyl)methyl]-1-methyl-1H-indole 3d 9
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9
Following the general procedure, 3d was obtained as a colorless oil; Yield 309 mg (93%); IR (neat) (cm-
1) 3054, 1504; 1H NMR (400 MHz, CDCl3):  3.67 (s, 3H), 5.56 (s, 1H), 6.36 (s, 1H), 6.85-7.05 (m, 5H),
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7.10-7.23 (m, 6H), 7.28 (d, J=8.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3):  32.8, 47.4, 109.4, 115.3
(d, JCF=22.0 Hz), 118.2, 119.1, 120.0, 122.0, 127.2, 128.8, 130.4 (d, JCF=7.8 Hz), 137.6, 139.8 (d, JCF=2.3
Hz), 161.6 (d, JCF=224.4 Hz); MS(FAB): m/z 334 [M+H]+.
3-[(4-Chlorophenyl)(phenyl)methyl]-1-methyl-1H-indole 3e 9
Following the general procedure, 3e was obtained as a white solid; Yield 236 mg (71%); mp 140-142 C;
1
IR (KBr) (cm-1) 3052, 1478; H NMR (400 MHz, DMSO-d6):  3.71 (s, 3H), 5.70 (s, 1H), 6.71 (s, 1H),
13
6.90 (t, J=7.2 Hz, 1H), 7.11 (d, J=7.7 Hz, 1H), 7.10-7.16 (m, 1H), 7.18-7.42 (m, 10H); C{1H} NMR
(100 MHz, CDCl3):  32.8, 47.7, 110.3, 117.2, 119.1, 119.7, 121.8, 126.8, 127.2, 128.8, 128.9, 129.1,
130.9, 131.2, 137.6, 143.8, 144.2; MS(FAB): m/z 332 [M+H]+, 334 [M+H+2]+.
3-[Bis(4-chlorophenyl)methyl]-1-methyl-1H-indole 3f
Following the general procedure, 3f was obtained as a white solid; Yield 236 mg (64%); mp 137-140 C;
IR (KBr) (cm-1) 3049, 1487; 1H NMR (400 MHz, CDCl3):  3.71 (s, 3H), 5.60 (s, 1H), 6.37 (s, 1H), 6.99
(dd, J=7.8, 7.1 Hz, 1H), 7.12-7.31 (m, 12H); 13C{1H} NMR (100 MHz, CDCl3):  32.8, 47.6, 76.8, 77.1,
77.3, 77.4, 109.4, 117.3, 119.1, 119.7, 122.0, 127.0, 128.5, 128.7, 130.2, 132.2, 137.5, 142.1; MS (EI):
m/z (%) 365 (M+, 83), 367 (M++2, 62), 369 (M++4, 11), 254 (100); Anal. Calcd for C22H17Cl2N: C, 72.14;
H, 4.68; N, 3.82. Found: C, 71.95; H, 4.80; N, 3.76.
3-[(4-Bromophenyl)(phenyl)methyl]-1-methyl-1H-indole 3g 9
Following the general procedure, 3g was obtained as a white solid. 132 mg (70%) from 198 mg (0.5
mmol) of 3a; mp 138-140 C; IR (KBr) (cm-1) 3050, 1613, 1596; 1H NMR (400 MHz, CDCl3):  3.71 (s,
3H), 5.61 (s, 1H), 6.39 (d, J=0.9 Hz, 1H), 6.99 (ddd, J=7.8, 6.9, 0.9 Hz, 1H), 7.10 (d, J=8.2 Hz, 2H),
13
7.16-7.25 (m, 5H), 7.26-7.31 (m, 3H), 7.39 (d, J=8.2 Hz, 2H); C NMR (100 MHz, DMSO-d6):  32.8,
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47.8, 110.3, 117.1, 119.1, 119.7, 119.8, 121.9, 126.8, 127.2, 128.9, 129.1, 131.3, 131.7, 137.6, 144.2; MS
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5
(FAB): m/z 378 [M+H+2]+, 376 [M+H]+.
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3-[1-(4-Methoxyphenyl)ethyl]-1-methyl-1H-indole 3h 9
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9
Following the general procedure, 3h was obtained as a colorless oil. 188 mg (71%); IR (KBr) (cm-1) 2962,
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1612, 1512; H NMR (400 MHz, CDCl3):  1.89 (d, J=7.3 Hz, 3H), 3.84 (s, 3H), 3.92 (s, 3H), 4.54 (q,
J=7.3 Hz, 1H), 6.99 (s, 1H), 7.02 (d, J=8.2 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.35-7.47 (m, 4H), 7.60 (d,
J=7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3):  23.0, 32.8, 36.3, 55.4, 109.4, 113.9, 118.9, 120.1, 120.6,
121.8, 126.1, 127.5, 128.6, 137.6, 139.4, 158.0; MS (FAB): m/z 266 [M+H]+.
3-(4-Methoxybenzyl)-1-methyl-1H-indole 3i 9
Following the general procedure, 3g was obtained as a colorless oil; Yield 140 mg (56%); IR (neat) (cm-1)
2905, 1471; 1H NMR (400 MHz, CHCl3):  3.72 (s, 3H), 3.78 (s, 3H), 4.04 (s, 2H), 6.73 (s, 1H), 6.82 (d,
J=8.2 Hz, 2H), 7.06 (dd, J=7.8, 6.9 Hz, 1H), 7.20 (d, J=8.2 Hz, 2H), 7.21-7.23 (m, 1H), 7.28 (d, J=8.2 Hz,
1H), 7.51 (d, J=7.8 Hz, 1H); 13C NMR (400 MHz, CDCl3):  30.9, 32.7, 55.5, 109.4, 114.0, 115.0, 119.0,
119.5, 121.8, 127.3, 128.1, 129.9, 133.8, 137.5, 158.1; MS(FAB): m/z 252 [M+H]+.
3-(3,4-Dimethoxybenzyl)-1-methyl-1H-indole 3j 9
Following the general procedure, 3j was obtained as a colorless oil. 145 mg (52%); IR (neat) (cm-1) 2935,
1
1513; H NMR (400 MHz, CHCl3):  3.68 (s, 3H), 3.79 (s, 3H), 3.82 (s, 3H), 4.03 (s, 2H), 6.70 (s, 1H),
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6.71-6.83 (m, 3H), 7.06 (dd, J=7.8, 6.9 Hz, 1H), 7.15-7.30 (m, 2H), 7.52 (dd, J=7.8, 0.9 Hz, 1H); C
NMR (100 MHz, CHCl3):  31.3, 32.7, 56.0, 77.5, 109.3, 111.3, 112.2, 114.7, 118.9, 119.3, 120.7, 121.7,
127.2, 127.9, 134.1, 137.3, 147.3, 149.0; MS (FAB): m/z 282 [M+H]+.
1-Methyl-3-trityl-1H-indole 3k 16
Following the general procedure, 3k was obtained as a white solid; Yield 329 mg (88%); mp 196-198 C;
IR (KBr) (cm-1) 3064, 3027, 1597, 1483; 1H NMR (400 MHz, CDCl3):  3.71 (s, 3H), 6.64 (d, J=8.2 Hz,
1H), 6.78 (ddd, J=8.2, 6.9, 0.9 Hz, 1H), 7.12 (d, J=7.8, 7.3, 0.9 Hz, 1H), 7.16-7.28 (m, 16H); C{1H}
13
NMR (100 MHz, CDCl3):  32.7, 59.4, 109.0, 118.6, 121.2, 122.9, 125.9, 127.3, 128.2, 130.2, 130.7,
137.7, 146.6; MS(FAB): m/z 374 [M+H]+.
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(E)-3-(1,3-Diphenylallyl)-1-methyl-1H-indole 3l 16
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Following the general procedure, 3l was obtained as a brown oil; Yield 275 mg (85%); IR (neat) (cm-1)
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7
1
3058, 3025, 1702, 1596; H NMR (400 MHz, CDCl3):  3.68 (s, 3H), 5.10 (d, J=7.3 Hz, 1H), 6.43 (d,
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J=15.8 Hz, 1H), 6.71 (dd, J=15.8, 7.3 Hz, 1H), 6.72 (s, 1H), 7.00 (t, J=7.6 Hz, 1H), 7.13-7.38 (m, 12H),
7.41 (d, J=8.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3):  32.6, 46.1, 109.2, 117.0, 118.8, 119.9, 121.6,
126.3, 127.1, 127.3, 128.4, 128.4, 130.4, 132.7, 137.4, 137.5, 143.5; MS (FAB): m/z 324 [M+H]+.
3-Benzhydryl-1-benzyl-1H-indole 3m
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Following the general procedure, 3m was obtained as a pale yellow oil; Yield 221 mg (71 %); IR (neat)
(cm-1) 3056, 3026, 1713, 1658; 1H NMR (400 MHz, CDCl3):  5.22 (s, 2H), 5.69 (brs, 1H), 6.54 (d, J=0.9
Hz, 1H), 6.96 (ddd, J=7.8, 6.9, 0.9 Hz, 1H), 7.04 (d, J=6.9 Hz, 2H), 7.11 (dt, J=7.3, 1.4 Hz, 1H), 7.17-
7.30 (m, 16H); 13C{1H} NMR (100 MHz, CDCl3):  48.8, 50.0, 109.7, 119.1, 120.1, 121.8, 126.2, 126.4,
128.3, 128.7, 129.0, 137.1, 137.8, 144.0; MS (FAB): m/z 373 (M+); HRMS-FAB: m/z (M+) calcd for
C28H23N 373.1830, found 373.1831.
3-Benzhydryl-1H-indole 3n 17
Following the general procedure, 3n was obtained as a white solid; Yield 215 mg (76%); mp 122-123 C;
IR (KBr) (cm-1) 3384, 3024, 1596, 1494; 1H NMR (400 MHz, CDCl3):  5.67 (s, 1H), 6.57 (d, J=1.3 Hz,
13
1H), 6.98 (t, J=7.8 Hz, 1H), 7.13-7.39 (m, 13H), 7.95 (brs, 1H); C{1H} NMR (100 MHz, CDCl3): 
48.8, 111.0, 119.4, 119.9, 122.1, 124.0, 126.2, 128.3, 129.0, 136.7, 143.9; MS (FAB): m/z 284 [M+H]+.
5-Methoxy-3-trityl-1H-indole 3o
Following the general procedure, 3o was obtained as a white solid; Yield 195 mg (50%); mp 269-270 C;
IR (KBr) (cm-1) 3450, 3058, 1623, 1581; 1H NMR (400 MHz, CDCl3):  3.37 (s, 3H), 6.04 (d, J=2.3 Hz,
13
1H), 6.74 (dd, J=9.2, 2.8 Hz, 1H), 6.82 (d, J=2.8 Hz, 1H), 7.16-7.27 (m, 16H), 7.87 (brs, 1H); C{1H}
NMR (100 MHz, CDCl3):  55.5, 59.5, 104.3, 111.6, 112.2, 123.8, 126.1, 126.2, 127.5, 128.4, 130.9,
132.1, 146.5, 155.3; MS(FAB): m/z 390 [M+H]+; HRMS-FAB: m/z [M+H]+ calcd for C28H24NO
390.1858, found 390.1857.
3-Benzhydryl-5-methyl-1H-indole 3p
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Following the general procedure, 3p was obtained as a white solid; Yield 185 mg (62%); mp 128-129 C;
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5
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IR (KBr) (cm-1) 3398, 1491, 1451; H NMR (400 MHz, CDCl3):  2.33 (s, 3H), 5.64 (s, 1H), 6.52 (d,
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7
8
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J=1.6 Hz, 1H), 6.99 (dd, J=8.2, 1.4 Hz, 1H), 7.03 (s, 1H), 7.17-7.31 (m, 11H), 7.84 (brs, 1H); C{1H}
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NMR (100 MHz, CDCl3):  21.5, 48.7, 110.7, 119.4, 123.7, 124.2, 126.1, 127.2, 128.2, 128.6, 129.0,
135.0, 144.1; MS(FAB): m/z 298 [M+H]+; Anal. Calcd for C22H19N: C, 88.85; H, 6.44; N, 4.71. Found: C,
88.80; H, 6.56; N, 4.69.
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3-Benzhydryl-6-methyl-1H-indole 3q
Following the general procedure, 3q was obtained as a white solid; Yield 202 mg (68%); mp 134-135 C;
IR (KBr) (cm-1) 3421, 3383, 3024, 1491, 1449; 1H NMR (400 MHz, CDCl3):  2.42 (s, 3H), 5.64 (s, 1H),
6.48 (dd, J=2.3, 0.9 Hz, 1H), 6.81 (dd, J=8.2, 0.9 Hz, 1H), 7.09 (d, J=7.8 Hz, 1H), 7.14 (s, 1H), 7.16-7.31
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(m, 10H), 7.80 (brs, 1H); C{1H} NMR (100 MHz, CDCl3):  21.8, 49.0, 111.1, 119.7, 119.9, 121.3,
123.6, 125.0, 126.3, 128.4, 129.1, 132.0, 137.3, 144.1; MS(FAB): m/z 298 [M+H]+; Anal. Calcd for
C22H19N: C, 88.85; H, 6.44; N, 4.71. Found: C, 88.83; H, 6.53; N, 4.62.
3-Benzhydryl-5-bromo-1H-indole 3r 18
Following the general procedure, 3r was obtained as a purple amorphous; Yield 203 mg (56%); IR (KBr)
(cm-1) 3418, 1493, 1451; 1H NMR (400 MHz, CDCl3):  5.56 (s, 1H), 6.45 (dd, J=2.3, 0.9 Hz, 1H), 7.08
(d, J=8.7 Hz, 1H), 7.12-7.28 (m, 11H), 7.34 (d, J=1.8 Hz, 1H), 7.78 (brs, 1H); 13C{1H} NMR (100 MHz,
CDCl3):  48.7, 112.8, 112.9, 120.0, 122.4, 125.2, 125.5, 126.6, 128.6, 128.9, 129.1, 135.4, 143.7; MS
(FAB): m/z 362 [M+H]+, 364 [M+H+2]+.
3-Benzhydryl-1,2-dimethyl-1H-indole 3s
Following the general procedure, 3s was obtained as a white solid; Yield 252 mg (0.81 mmol); mp 108-
1
109 C; IR (KBr) (cm-1) 3058, 3022, 1599, 1494; H NMR (400 MHz, CDCl3):  2.25 (s, 3H), 3.66 (s,
3H), 5.76 (s, 1H), 6.87 (ddd, J=7.8, 6.9, 0.9 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 7.09 (ddd, J=8.2, 6.9, 0.9 Hz,
1H), 7.15-7.30 (m, 11H); 13C{1H} NMR (100 MHz, CDCl3):  10.7, 29.5, 48.0, 108.5, 113.5, 118.7,
119.6, 120.3, 126.0, 127.4, 128.1, 129.1, 133.9, 136.7, 144.1; MS (FAB): m/z 312 [M+H]+; Anal. Calcd
for C23H21N: C, 88.71; H, 6.80; N, 4.50. Found: C, 88.68; H, 6.88; N, 4.44.
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Following the general procedure, 3t was obtained as a pale yellow oil; Yield 222 mg (0.85 mmol); IR
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(neat) (cm-1) 3056, 3029, 3000, 1724, 1615, 1470; H NMR (400 MHz, CDCl3):  0.30-0.40 (m, 2H),
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0.53-0.63 (m, 1H), 0.64-0.73 (m, 1H), 1.35-1.45 (m, 1H), 3.47 (d, J=9.2 Hz, 1H), 3.77 (s, 3H), 6.93 (ddd,
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J=8.2, 7.6, 0.9 Hz, 1H), 7.05 (s, 1H), 7.12-7.21 (m, 2H), 7.21-7.29 (m, 5H), 7.29-7.35 (m, 2H); C{1H}
NMR (100 MHz, CDCl3):  5.18, 6.11, 17.8, 32.9, 48.0, 109.5, 118.9, 119.0, 120.3, 121.8, 126.4, 127.1,
127.9, 128.5, 128.6, 137.7, 145.9; MS (FAB): m/z 261 (M+); HRMS-FAB: m/z (M+) calcd for C19H19N
261.1517, found 261.1517.
Effects of catalysts and solvents (Table 1): A mixture of 1-methylindole-3-carboxylic acid (1a) (175 mg,
1 mmol), AuCl4Na·2H2O (4.0 mg, 0.01 mmol), TPPMS (3.6 mg, 0.01 mmol) and benzhydrol (2a) (221
mg, 1.2 mmol) in H2O (4 mL) was heated at 120 oC for 16 h in a sealed tube under air. After the reaction
mixture was cooled, 4-nitroanisole (153 mg, 1 mmol, internal standard) was added to the reaction mixture,
which was extracted with CDCl3 (8 mL), then the organic layer was analyzed by 1H-NMR spectroscopy.
Catalytic decarboxylative activation (Table 2): A mixture of 1-methylindole-3-carboxylic acid (1a)
(175 mg, 1 mmol), AuCl4Na·2H2O (8.0 mg, 0.02 mmol), and TPPMS (7.2 mg, 0.02 mmol) in H2O (4
mL) was heated at 120 oC for 1 h in a sealed tube under air. After the reaction mixture was cooled, 1,3,5-
trimethoxybenzene (168.2 mg, 1 mmol, internal standard) was added to the reaction mixture, which was
extracted with CDCl3 (8 mL), then the organic layer was analyzed by 1H-NMR spectroscopy.
Hammett studies (Figure 2A): A mixture of indole-3-carboxylic acids 1X (0.25 mmol), indole-3-
carboxylic acid (1b) (40 mg, 0.25 mmol), AuCl4Na·2H2O (5 mg, 0.0125 mmol), and TPPMS (5 mg,
o
0.0125 mmol) in H2O (1 mL) was heated at 100 C for 30 min in a sealed tube under air. After the
reaction mixture was cooled, which was extracted with CDCl3 (8 mL), then the organic layer was
analyzed by 1H-NMR spectroscopy.
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Hammett studies (Figure 2B): A mixture of benzhydryl alcohols 2Y (1 mmol), benzhydrol (2a) (184 mg,
1 mmol), 1-methylindole-3-carboxylic acid (1a) (175 mg, 1 mmol), AuCl4Na·2H2O (8.0 mg, 0.02 mmol),
and TPPMS (7.2 mg, 0.02 mmol) in H2O (4 mL) was heated at 120 oC for 4 h in a sealed tube under air.
After the reaction mixture was cooled, which was extracted with CDCl3 (8 mL), then the organic layer
was analyzed by 1H-NMR spectroscopy.
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Competition experiment (Scheme 3): A mixture of 1-methylindole-3-carboxylic acid (1a) (44 mg, 0.25
mmol), indole-3-carboxylic acid (1b) (40 mg, 0.25 mmol), AuCl4Na·2H2O (5 mg, 0.0125 mmol), and
TPPMS (5 mg, 0.0125 mmol) in H2O (1 mL) was heated at 100 oC for 30 min in a sealed tube under air.
After the reaction mixture was cooled, which was extracted with CDCl3 (8 mL), then the organic layer
was analyzed by 1H-NMR spectroscopy.
Deuterium isotope effects (Scheme 4): A mixture of 1-methylindole-3-carboxylic acid (1a) (88 mg, 0.5
mmol), AuCl4Na·2H2O (10 mg, 0.025 mmol), and TPPMS (10 mg, 0.025 mmol) in H2O (2 mL) was
heated at 100 oC for 30 min or 1 h in a sealed tube under air. After the reaction mixture was cooled, 1,3,5-
trimethoxybenzene (168.2 mg, 1 mmol, internal standard) was added to the reaction mixture, which was
extracted with CDCl3 (8 mL), then the organic layer was analyzed by 1H-NMR spectroscopy.
Control experiments (Scheme 6A): A mixture of 1-methylindole-3-carboxylic acid (1a) (88 mg, 0.5
mmol), benzhydrol (2a) (110 mg, 0.5 mmol), 4-hydroxy-3-tert-butylanisole (BHA) (90 mg, 0.5 mmol),
AuCl4Na·2H2O (10 mg, 0.025 mmol), and TPPMS (10 mg, 0.025 mmol) in H2O (2 mL) was heated at
o
100 C for 30 min in a sealed tube under air. After the reaction mixture was cooled, 1,3,5-
trimethoxybenzene (168.2 mg, 1 mmol, internal standard) was added to the reaction mixture, which was
extracted with CDCl3 (8 mL), then the organic layer was analyzed by 1H-NMR spectroscopy.
Control experiments (Scheme 6B): A mixture of 1-methylindole-3-carboxylic acid (1a) (175 mg, 1
mmol), α -cyclopropylbenzyl alcohol (248 L, 3 mmol), AuCl4Na·2H2O (20 mg, 0.05 mmol), and
TPPMS (20 mg, 0.05 mmol) in H2O (4 mL) was heated at 120 oC for 16 h in a sealed tube under air. After
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cooling, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was
washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was washed with hexanes,
then purified by flash column chromatography (silica gel, hexanes/EtOAc) to give desired product 3q
(222 mg, 85%).
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Synthesis of bis(indolyl)methanes 5 (Scheme 7)
Bis(1-methylindol-3-yl)(phenyl)methane 5a19
A mixture of 1-methylindole-3-carboxylic acid (1a) (175 mg 1 mmol), AuCl4Na·2H2O (20 mg, 0.05
mmol), and TPPMS (20 mg, 0.05 mmol) and benzaldehyde (106 mg, 0.5 mmol) in H2O (4 mL) was
o
heated at 120 C for 5 h in a sealed tube. 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 in
vacuo. The residue was purified by flash column chromatography (silica gel, hexane/EtOAc) to give
desired product 5a as a pale brown solid. 155 mg (88%) from benzaldehyde (0.5 mmol); mp 199-201 C;
IR (KBr) (cm-1) 3023, 1476; 1H NMR (400 MHz, CDCl3):  3.67 (s, 6H), 5.88 (s, 1H), 6.52 (d, J=0.9 Hz,
2H), 6.99 (dd, J=8.2, 6.9, 0.9 Hz, 2H), 7.16-7.23 (m, 3H), 7.24-7.30 (m, 4H), 7.32-7.40 (m, 4H); 13C{1H}
NMR (100 MHz, DMSO-d6):  32.8, 40.0, 110.1, 117.8, 118.9, 119.7, 121.6, 126.4, 127.4, 128.4, 128.6,
128.8, 137.5, 145.3; MS (FAB): m/z 351 [M+H]+.
Bis(indol-3-yl)(phenyl)methane 5b19
Brown solid. 135 mg (84%) from benzaldehyde (0.5 mmol); mp 141-143 C; IR (KBr) (cm-1) 3395, 1600;
1H NMR (400 MHz, CDCl3):  5.88 (s, 1H), 6.65 (d, J=1.4 Hz, 2H), 7.00 (t, J=7.3 Hz, 2H), 7.16 (t, J=7.3
13
Hz, 2H), 7.18-7.40 (m, 9H), 7.88 (brs, 2H); C{1H} NMR (100 MHz, DMSO-d6):  40.0, 112.0, 118.6,
118.7, 119.6, 121.4, 124.1, 126.3, 127.1, 128.5, 128.8, 137.1, 145.5; MS (FAB): m/z 323 [M+H]+.
Scale-up experiment (Scheme 8): A mixture of 1-methylindole-3-carboxylic acid (1a) (1.05 g, 6.0
mmol), AuCl4Na·2H2O (119.0 mg, 0.3 mmol), TPPMS (109.3 mg, 0.3 mmol) and benzhydrol (2a) (1.33
g, 7.2 mmol) in H2O (24 mL) was heated at 110 oC for 16 h under air. After cooling, the reaction mixture
was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over
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MgSO4 and concentrated in vacuo. The residue was recrystallized from hexane and AcOEt to give desired
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product 3a (1.28 g, 72%) as a pale yellow solid.
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Supporting Information Available: Copies of H and 13C NMR spectra for all compounds. This
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material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: hidemasa.hikawa@phar.toho-u.ac.jp
*E-mail: isao.azumaya@phar.toho-u.ac.jp
ACKNOWLEDGMENT
This work was supported by JSPS KAKENHI Grant Number 16K08179.
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Table of Contents (TOC) graphic
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R3
Ar
CO2H
R1
R1
R3
cat. Au(III)/TPPMS
+
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H2O
HO
Ar
N
R2
N
R2
-CO2, -H2O
1
2
3
20 examples, 50-93% yield
Decarboxylative and dehydrative coupling reaction in water
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