Au(III)/TPPMS-catalyzed benzylation of indoles with benzylic alcohols in water

Article abstract of DOI:10.1021/jo402151g

A novel and efficient method for the Au(III)/TPPMS-catalyzed direct substitution reaction of benzhydryl and benzylic alcohols with indoles in water is developed. Au(III)/TPPMS is an effective catalyst for the benzylation of the strong π nucleophile 1-methylindole, while common Bronsted or Lewis acids are ineffective.

Full text of DOI:10.1021/jo402151g

Article
pubs.acs.org/joc
Au(III)/TPPMS-Catalyzed Benzylation of Indoles with Benzylic
Alcohols in Water
Hidemasa Hikawa,* Hideharu Suzuki, and Isao Azumaya*
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan
S
* Supporting Information
ABSTRACT: A novel and efficient method for the Au(III)/TPPMS-catalyzed direct substitution reaction of benzhydryl and
benzylic alcohols with indoles in water is developed. Au(III)/TPPMS is an effective catalyst for the benzylation of the strong π
nucleophile 1-methylindole, while common Brønsted or Lewis acids are ineffective.
altered depending on temperature and pressure. To achieve the
benzylation of 1-methylindole (1a) under mild conditions,
several effective catalysts have been developed (Scheme 1).7b−e
INTRODUCTION
■
The reaction of benzylic alcohols as benzylating agents has
attracted attention as an environmentally benign process,
whereas benzylic halides are toxic and their use in benzylation
produces large amounts of inorganic waste, which is undesirable
from the standpoint of green chemistry. Therefore, the
development of a direct substitution of benzylic alcohols,
which generates only H2O as the byproduct, is highly
important.1
Scheme 1. Benzylation of the Strong π Nucleophile 1-
Methylindole (1a)
The gold-catalyzed direct substitution of benzylic alcohols
with various nucleophiles provides a powerful methodology for
the formation of carbon−carbon and carbon−nitrogen bonds.2
Such efficiency is due to the σ-electrophilic Lewis acidic
character and allows for the activation of several hydroxyl
groups, thus promoting an environmentally benign chemical
process.
We have been investigating benzylation using the (η3-benzyl)
palladium system from benzyl alcohol in water,3 which activates
the benzyl alcohol via hydration of the hydroxyl group.
Recently, we reported the Au(III)/TPPMS-catalyzed chemo-
selective benzylation of unprotected anthranilic acids with
benzhydryl alcohols in water,4,5 which promises to generate
further innovative direct transformation reactions. In our
continuing effort to develop gold-catalyzed benzylation, we
began to investigate indoles as nucleophiles.
The nucleophilic substitution of alcohols without added
catalysts “on water” has been reported.6 However, the reaction
between the strong π nucleophile 1-methylindole (1a) and
benzhydrol (2a) did not afford the benzylated product 3a in
water at 80 °C, and common Brønsted acids (AcOH or TFA)
were also ineffective catalysts for this reaction in water.7d In
high-temperature water (220 °C) the reaction proceeds without
added catalysts since its physical properties are dramatically
In those papers, surfactant-type Brønsted acids have been
employed as nucleophilic partners. Liu and Wang reported
calix[n]arene sulfonic acids.7b Kobayashi and co-workers
reported DBSA-catalyzed dehydrative nucleophilic substitutions
of alcohols in water.7d Although various efficient catalytic
systems in water have been developed, the dehydration reaction
in water is one of the most challenging research topics. Herein,
we report the development of a water-soluble gold(III)-
catalyzed direct substitution reaction of benzhydryl or benzylic
alcohols with indoles in water. Notably, the protocol using
2,8
NaAuCl4·2H2O in CH2Cl2 was ineffective for benzylation of
the strong π nucleophile 1-methylindole (1a).9
Received: September 27, 2013
© XXXX American Chemical Society
A
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other efficient catalysts, we tested the reaction using Brønsted
acids such as HCl and MsOH and effective Lewis acids in water
such as Sc(OTf)3 and Hf(OTf)4. However, the reaction did not
proceed (entries 8−11), clearly showing the superiority of
water-soluble Au(III)/TPPMS for the benzylation of indole 1a
with benzhydrol (2a). Furthermore, using AuCl4Na·2H2O in
organic solvents such as CH2Cl2, 1,4-dioxane, and toluene also
resulted in no reaction (entries 12−14).1 In a biphasic system
such as toluene/H2O or 1,4-dioxane/H2O, the reaction also did
not proceed (entries 15 and 16). In contrast, using EtOH
resulted in good yield (entry 17).
RESULTS AND DISCUSSION
■
First, we heated a mixture of 1-methylindole (1a) and 2a (1.2
equiv) in the presence of AuCl4Na·2H2O (2 mol %) and
sodium diphenylphosphinobenzene-3-sulfonate (TPPMS, 2
mol %) in water at 80 °C for 16 h under air. Benzylated 3a
was obtained in 73% yield (Table 1, entry 1). When AuCl4Na·
a
Table 1. Effect of Catalysts and Solvents
Results for the direct substitution reaction of several
benzhydryl alcohols 2 with 1-methylindole (1a) using
AuCl4Na·2H2O and TPPMS in water are summarized in
Figure 1. The benzhydryl alcohols with electron-donating
methoxy and methyl groups afforded products in excellent
yields (3b, 95%; 3c, 95%; 3d, 84%). The reaction of benzhydryl
alcohols with electron-withdrawing chloro, bromo, and fluoro
groups proceeded to give benzylated products in moderate to
good yields (3e, 54%; 3f, 40%; 3g, 83%). In contrast,
trifluoromethyl and pentafluoro groups resulted in no reaction.
Since electron-poor diarylmethanols 2c,d failed to react with
indole 1a under the same conditions, the stability of the diaryl
carbocation must be critical to the success of these reactions.
The scope of the reaction with respect to indoles 1 was
further examined (Figure 2), and the reactions of 4,4′-
dimethoxybenzhydrol (2d) and indoles 1 with cyano, fluoro,
chloro, methyl carboxylate, and methoxy groups using
AuCl4Na·2H2O (0.5 mol %) and TPPMS (0.5 mol %) resulted
in excellent yields (3h, 93%; 3i, 90%; 3j, 95%; 3k, 95%; 3l,
66%). No isomers through N- or 2-benzylation were obtained.
The unsubstituted indole 1b also afforded benzylated 3m in
95% yield. Furthermore, the sterically demanding 2-substituted
indoles gave moderate to good yields (3n, 71%; 3o, 70%; 3p,
51%). 3-Methylindole (1c) afforded 2-benzylated 3q in 86%
yield. In contrast, N-tosylindole (1d) resulted in no reaction.
We became interested in further expanding the substrate
scope of the Au(III)/TPPMS system to water-soluble
unprotected indolecarboxylic acids 1, since we have been
studying the development of unprotected syntheses and
selective reactions toward various reactive functional groups.10
In general, unprotected syntheses represent a distinct challenge
and have been met with a number of difficulties such as
chemoselectivity. One of the most effective ways for achieving
unprotected syntheses is the development of selective reactions
toward various reactive functional groups.11 Interestingly, the
benzylation of indole-5-carboxylic acid afforded only C3-
benzylated 4a in 82% yield with the carboxyl group left intact
(Figure 3). Furthermore, indole-2-carboxylic acids with several
entry
1
catalyst
ligand
solvent
yield (%)
d
AuCl4Na·2H2O
AuCl4Na·2H2O
AuCl4Na·2H2O
HAuCl4·3H2O
AuBr3
TPPMS H2O
TPPMS H2O
73 (74)
b
2
18
c
3
4
5
6
none
H2O
trace
TPPMS H2O
TPPMS H2O
73
73
c
Au(III)-picolinate
none
H2O
trace
LI
c
7
AuCl
TPPMS H2O
trace
e
c
8
HCl
none
none
none
none
none
none
none
H2O
trace
e
c
9
MsOH
H2O
trace
c
10
11
12
13
14
15
Sc(OTf)3
H2O
trace
c
d
Hf(OTf)4
H2O
trace (4)
c
f
AuCl4Na·2H2O
AuCl4Na·2H2O
AuCl4Na·2H2O
AuCl4Na·2H2O
CH2Cl2
trace
c
1,4-dioxane
toluene
trace
c
trace
c
TPPMS 1,4-dioxane/H2O
(1/1)
trace
c
16
17
AuCl4Na·2H2O
AuCl4Na·2H2O
TPPMS toluene/H2O (1/1)
TPPMS EtOH
trace
d
(73)
a
Reaction conditions: 1a (131 mg, 1 mmol), catalyst (2 mol %),
TPPMS (7.3 mg, 2 mol %), benzhydrol (2a; 221 mg, 1.2 mmol),
b
solvent (4 mL), 80 °C, 16 h, in air. AuCl4Na·2H2O (0.5 mol %) and
c
d
TPPMS (0.5 mol %) were used. By TLC analysis. Conversion yield.
e
f
10 mol %. At 40 °C (bp).
2H2O (0.5 mol %) and TPPMS (0.5 mol %) were used, the
reaction afforded the desired 3a in only 18% yield (entry 2).
Using only AuCl4Na·2H2O resulted in no reaction, and
recovery of the starting material 1a was detected by TLC
analysis (entry 3). With regard to the gold catalyst, the use of
HAuCl4·3H2O or AuBr3 also gave the product 3a in good yield
(entry 4, 73%; entry 5, 73%). In contrast, when the Au(III)-
picolinate complex LI or AuCl was used, the reaction did not
proceed (entries 6 and 7). To compare AuCl4Na·2H2O with
Figure 1. Scope of benzhydryl alcohols 2. Reaction conditions: 1-methylindole 1a (1 mmol), AuCl4Na·2H2O (2 mol %), TPPMS (2 mol %),
benzhydryl alcohol 2 (1.2 equiv), H2O (4 mL), 80 °C, 16 h.
B
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Figure 2. Scope of indole 1. Reaction conditions: 1 (1.1 mmol), AuCl4Na·2H2O (0.5 mol %), TPPMS (0.5 mol %), 4,4′-dimethoxybenzhydrol (2d;
1 mmol), H2O (4 mL), 80 °C, 16 h.
Figure 3. C3-Benzylation of indolecarboxylic acids 1. Reaction conditions except where noted: 1 (1 mmol), AuCl4Na·2H2O (2 mol %), TPPMS (2
mol %), benzhydryl alcohol 2 (1.2 equiv), H2O (4 mL), 80 °C, 16 h in a sealed tube. The superscript b indicates that AuCl4Na·2H2O (0.5 mol %)
and TPPMS (0.5 mol %) were used.
benzhydryl alcohols 2 also resulted in moderate to excellent
yields (4b, 95%; 4c, 84%; 4d, 73%; 4e, 90%; 4f, 76%; 4g, 64%;
4h, 62%).
Furthermore, direct substitution of 1-phenylethyl alcohols 2
also afforded the desired 5 in moderate to excellent yield (5a,
95%; 5b, 55%; 5c, 91% in Figure 4). Interestingly, simple
AuCl4Na·2H2O and TPPMS resulted in no reaction or low
yield, the use of Hf(OTf)4 afforded benzylated 8a,b in
moderate yield. To our surprise, in the presence of 1-
methylindole (1a), the Hf(OTf)4-catalyzed Friedel−Crafts
reaction did not proceed, suggesting that the strong π
nucleophile 1-methylindole (1a) might suppress the acidity of
Hf(OTf)4. Thus, Au(III)/TPPMS is an effective catalyst for
benzylation of indoles in water.
On the basis of our results and literature reports, the
following mechanism can be suggested (Scheme 2). First, the
water-soluble Au−benzhydryl alcohol complex 9 forms from
benzhydryl alcohol 2 in the presence of AuCl4Na·2H2O and
TPPMS. Next, the benzyl cation species 11 forms, followed by
nucleophilic attack of the indole 1a, to give benzylated 3. In
aqueous solution, carbocations tend to have very short
lifetimes.12 However, the lifetimes of carbocations can be
increased by the introduction of electron-donating substituents
on the aryl ring.13 Figure 5 shows a good correlation between
the log(kX/kH) vs the σ+ value of the respective substituents.
From the slope a negative ρ value of 2.74 is obtained,
suggesting that there is a buildup of positive charge in the
transition state. Indeed, benzylation using benzhydryl alcohol
with the electron-withdrawing trifluoromethyl group 2c or
unsubstituted benzyl alcohol 2e did not proceed, since alcohols
2c,e could not form carbocationic intermediates in our catalytic
system (see Figures 1 and 4).
Figure 4. Scope of alcohols 2. Reaction conditions: 1 (1 mmol),
AuCl4Na·2H2O (2 mol %), TPPMS (2 mol %), benzhydryl alcohol 2
(1.2 equiv), H2O (4 mL), 80 °C, 16 h in a sealed tube.
benzyl alcohols 2 with a methoxy group also resulted in
moderate to good yield (6a, 74%; 6b, 50%). In contrast, the
reaction of the unsubstituted benzyl alcohol (2e) did not
proceed.
We investigated the classical Friedel−Crafts reaction of 1,3-
dimethoxybenzene (7) with benzhydrol (2a) (see Table S1 in
the Supporting Information). While the use of HCl or
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Scheme 2. Plausible Mechanism
Figure 5. Brown−Okamoto plot for the rate constants of benzylation by various substituted alcohols. Reaction conditions: 1-methylindole 1a (1
mmol), AuCl4Na·2H2O (2 mol %), TPPMS (2 mol %), benzhydrol 2a (1 mmol) and benzhydryl alcohols 2 (1 mmol), H2O (4 mL), 80 °C, 30 min
in a sealed tube (see Table S2 in the Supporting Information)
Scheme 3. Competition Experiment
Furthermore, a competition experiment using an equimolar
amount of benzhydryl alcohols 2f (R = OMe) and 2a (R = H)
gave only the OMe species 3c in 92% yield (Scheme 3).
Water might play an important role in the smooth generation
of intermediates 9−11, which are stabilized by hydration.6
Indeed, the reaction did not occur without water and water-
soluble phosphine ligands, TPPMS (see Table 1). In addition,
while the strong π nucleophile 1-methylindole (1a) might
suppress the acidity of naked Au(III) catalyst in organic
solvents, the water-soluble Au(III)/TPPMS active catalyst
could form in water.
EXPERIMENTAL SECTION
■
General Considerations. All reagents and solvents were obtained
commercially and used as received unless otherwise indicated. All
melting points were determined on a Yanagimoto micromelting hot
stage apparatus and are uncorrected. IR spectra were recorded as KBr
tablets (unless otherwise stated). NMR spectra were recorded at 400
MHz for 1H and 100 MHz for 13C NMR with tetramethylsilane as the
internal reference. The following abbreviations were used: s, singlet; d,
doublet; dd, doublet of doublets; t, triplet; q, quartet; m, multiplet. EI
mass spectra and high-resolution mass spectra were measured using a
direct inlet system. The mass analyzer type was a double-focusing
magnetic sector mass spectrometer for the HRMS measurements.
General Procedure. A mixture of indoles 1 (1 mmol), AuCl4Na·
2H2O (0.5−2 mol %), sodium diphenylphosphinobenzene-3-sulfonate
(TPPMS, 0.5−2 mol %), and alcohols 2 (1.2 mmol) in H2O (4 mL)
was heated at 80 °C for 16 h in a sealed tube. After it was cooled, 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, hexanes/EtOAc) to give the desired
products 3−6.
CONCLUSIONS
■
In summary, we developed the first direct substitution reaction
of benzhydryl and benzylic alcohols with indoles using a water-
soluble gold(III)/TPPMS catalyst system in water, one of the
most efficient and environmentally friendly synthetic strategies
for benzylation.
3-Benzhydryl-1-methyl-1H-indole (3a; Table 1, Entry 1).7c
Following the general procedure, 3a was obtained as a white solid:
D
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yield 217 mg (73%); mp 142−144 °C; IR (KBr) (cm−1) 3056, 1482;
1H NMR (400 MHz, CDCl3): δ 3.68 (s, 3H), 5.66 (s, 1H), 6.40 (s,
13C NMR (100 MHz, CDCl3): δ 47.0, 55.3, 102.4, 112.1, 113.6, 113.9,
121.8, 125.1, 125.8, 126.0, 126.9, 129.7, 132.4, 135.6, 138.6, 158.3; MS
(EI) m/z 368 (M+, 100); HRMS (EI) m/z calcd for C24H20N2O2 [M+]
368.1525, found 368.1527.
3-[Bis(4-methoxyphenyl)methyl]-6-fluoro-1H-indole (3i; Figure
2). Following the general procedure, 3i was obtained as a brown
amorphous solid: yield 325 mg (90%); IR (KBr) (cm−1) 3417, 1603,
1507; 1H NMR (400 MHz, CDCl3): δ 3.78 (s, 6H), 5.52 (s, 1H), 6.52
(dd, J = 2.1, 0.9 Hz, 1H), 6.73 (dt, J = 8.7, 2.5 Hz, 1H), 6.82 (d, J = 8.7
Hz, 4H), 7.01 (dd, J = 9.6, 2.1 Hz, 1H), 7.06−7.15 (m, 5H), 7.92 (br s,
1H); 13C NMR (100 MHz, CDCl3): δ 47.2, 55.3, 97.4 (d, J = 25.7
Hz), 108.1 (d, J = 24.8 Hz), 113.6, 113.7, 120.8 (d, J = 10.5 Hz),
120.9, 123.8, 124.2, 129.8, 132.4, 136.3, 136.8 (d, J = 12.4 Hz), 158.1,
160.0 (d, J = 236.5 Hz); MS (EI) m/z 361 (M+, 100); HRMS (EI) m/
z calcd for C23H20NO2F [M+] 361.1478, found 361.1479.
1H), 6.97 (dd, J = 7.8, 7.8 Hz, 1H), 7.10−7.40 (m, 13H); 13C NMR
(100 MHz, CDCl3): δ 32.8, 48.9, 109.2, 118.4, 118.9, 120.1, 121.7,
126.3, 127.5, 128.4, 128.8, 129.1, 137.5, 144.2; MS (EI) m/z 297 (M+,
100).
3-[Bis(4-methoxyphenyl)methyl]-1-methyl-1H-indole (3b; Figure
1).7d Following the general procedure, 3b was obtained as an off-white
solid: yield 339 mg (95%); mp 107−109 °C; IR (KBr) (cm−1) 2939,
1509; 1H NMR (400 MHz, CDCl3): δ 3.68 (s, 3H), 3.77 (s, 6H), 5.56
(s, 1H), 6.39 (s, 1H), 6.81 (d, J = 8.7 Hz, 4H), 6.97 (dd, J = 7.1, 7.1
Hz, 1H), 7.12 (d, J = 8.7 Hz, 4H), 7.15−7.30 (m, 3H); 13C NMR (100
MHz, CDCl3): δ 32.8, 47.2, 55.3, 109.2, 113.7, 118.8, 119.1, 120.2,
121.7, 127.4, 128.7, 129.9, 136.8, 137.6, 158.0; MS (EI) m/z (%) 357
(M+, 100).
3-[Bis(4-methoxyphenyl)methyl]-5-chloro-1H-indole (3j; Figure
2).7d Following the general procedure, 3j was obtained as a brown
amorphous solid: yield 359 mg (95%); IR (KBr) (cm−1) 3355, 1587;
1H NMR (400 MHz, CDCl3): δ 3.77 (s, 6H), 5.50 (s, 1H), 6.58 (dd, J
3-[(4-Methoxyphenyl)(phenyl)methyl]-1-methyl-1H-indole (3c;
Figure 1).14 Following the general procedure, 3c was obtained as a
white solid: yield 311 mg (95%); mp 116−118 °C; IR (KBr) (cm−1)
1
3017, 1506; H NMR (400 MHz, CDCl3): δ 3.68 (s, 3H), 3.78 (s,
3H), 5.61 (s, 1H), 6.40 (s, 1H), 6.81 (dt, J = 8.5, 1.8 Hz, 2H), 6.97
(dd, J = 6.9, 6.9 Hz, 1H), 7.13 (dt, J = 8.7, 2.1 Hz, 2H), 7.16−7.30 (m,
8H); 13C NMR (100 MHz, CDCl3): δ 32.8, 48.0, 55.3, 109.2, 113.7,
118.9, 120.1, 121.7, 126.2, 128.3, 128.8, 129.0, 130.0, 136.4, 144.6,
158.0; MS (EI) m/z 327 (M+, 100).
1-Methyl-3-[phenyl(p-tolyl)methyl]-1H-indole (3d; Figure 1).
Following the general procedure, 3d was obtained as a white solid:
yield 263 mg (84%); mp 114−116 °C; IR (KBr) (cm−1) 3023, 2930,
1470; 1H NMR (400 MHz, CDCl3): δ 2.31 (s, 3H), 3.67 (s, 3H), 5.62
(s, 1H), 6.40 (d, J = 0.9 Hz, 1H), 6.96 (ddd, J = 8.7, 7.1, 0.9 Hz, 1H),
7.07 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.15−7.30 (m, 8H);
13C NMR (100 MHz, CDCl3): δ 21.0, 32.6, 48.4, 109.1, 118.4, 118.8,
120.0, 121.6, 126.1, 127.4, 128.2, 128.7, 128.8, 128.9, 135.6, 137.4,
141.1, 144.3; MS (EI) m/z (%) 311 (M+, 100). Anal. Calcd for
C23H21N: C, 88.71; H, 6.80; N, 4.50. Found: C, 88.58; H, 6.85; N,
4.46.
3-[(4-Chlorophenyl)(phenyl)methyl]-1-methyl-1H-indole (3e; Fig-
ure 1). Following the general procedure, 3e was obtained as a white
solid: yield 180 mg (54%); mp 140−142 °C; IR (KBr) (cm−1) 3052,
1478; 1H NMR (400 MHz, CDCl3): δ 3.70 (s, 3H), 5.63 (s, 1H), 6.38
(s, 1H), 6.98 (ddd, J = 8.9, 8.0, 0.9 Hz, 1H), 7.10−7.32 (m, 12H); 13C
NMR (100 MHz, CDCl3): δ 32.7, 48.1, 109.2, 117.8, 118.9, 119.8,
121.8, 126.4, 127.1, 128.4, 128.7, 128.9, 130.3, 131.9, 137.4, 142.6,
143.6; MS (EI) m/z (%) 333 (M+ + 2, 35), 331 (M+, 100). Anal.
Calcd for C22H18ClN: C, 79.63; H, 5.47; N, 4.22. Found: C, 79.74; H,
5.52; N, 4.26.
= 2.6, 1.3 Hz, 1H), 6.82 (d, J = 8.7 Hz, 4H), 7.05−7.15 (m, 5H), 7.19
(d, J = 2.1 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 7.98 (s, 1H); 13C NMR
(100 MHz, CDCl3): δ 46.9, 55.2, 112.1, 113.7, 119.3, 120.4, 122.4,
125.0, 125.2, 128.0, 129.7, 135.1, 136.1, 158.0; MS (EI) m/z (%) 379
(M++2, 36), 377 (M+, 100); HRMS (EI) m/z calcd for C23H20NO2Cl
[M+] 377.1183, found 377.1183.
Methyl 3-[bis(4-methoxyphenyl)methyl]-1H-indole-5-carboxylate
(3k; Figure 2).7d Following the general procedure, 3k was obtained as
an off-white solid: yield 381 mg (95%); mp 151−153 °C; IR (KBr)
(cm−1) 3394, 1704; 1H NMR (400 MHz, CDCl3): δ 3.76 (s, 6H), 3.85
(s, 3H), 5.62 (s, 1H), 6.63 (d, J = 1.2 Hz, 1H), 6.81 (d, J = 8.7 Hz,
4H), 7.10 (d, J = 8.7 Hz, 4H), 7.34 (d, J = 8.5 Hz, 1H), 7.87 (dd, J =
8.5, 1.6 Hz, 1H), 8.05 (s, 1H), 8.18 (br s, 1H); 13C NMR (100 MHz,
CDCl3): δ 46.7, 51.8, 55.2, 110.8, 113.7, 121.5, 122.1, 122.7, 123.5,
125.1, 126.7, 129.7, 136.2, 139.3, 158.0, 168.2; MS (EI) m/z 401 (M+,
100). Anal. Calcd for C25H23NO4: C, 74.79; H, 5.77; N, 3.49. Found:
C, 74.89; H, 5.83; N, 3.45.
3-[Bis(4-methoxyphenyl)methyl]-5-methoxy-1H-indole (3l; Fig-
ure 2). Following the general procedure, 3l was obtained as a white
solid: yield 248 mg (66%); mp 118−120 °C; IR (KBr) (cm−1) 3369,
1503; 1H NMR (400 MHz, CDCl3): δ 3.67 (s, 3H), 3.77 (s, 6H), 5.51
(s, 1H), 6.52−6.56 (m, 1H), 6.64 (d, J = 2.1 Hz, 1H), 6.81 (d, J = 8.5
Hz, 5H), 7.13 (d, J = 8.5 Hz, 4H), 7.22 (d, J = 8.7 Hz, 1H), 7.82 (br s,
1H); 13C NMR (100 MHz, CDCl3): δ 47.1, 55.2, 55.8, 102.1, 111.6,
112.0, 113.6, 120.3, 124.6, 127.4, 129.8, 131.9, 136.4, 153.7, 157.9; MS
(EI) m/z (%) 373 (M+, 100). Anal. Calcd for C24H23NO3: C, 77.19;
H, 6.21; N, 3.75. Found: C, 77.14; H, 6.28; N, 3.62.
3-[(4-Bromophenyl)(phenyl)methyl]-1-methyl-1H-indole (3f; Fig-
ure 1). Following the general procedure, 3f was obtained as a white
solid: yield 150 mg (40%); mp 138−140 °C; IR (KBr) (cm−1) 3054,
3-[Bis(4-methoxyphenyl)methyl]-1H-indole (3m; Figure 2).6a
Following the general procedure, 3m was obtained as a pink solid:
yield 326 mg (95%); mp 121−123 °C; IR (KBr) (cm−1) 3419, 1509;
1H NMR (400 MHz, CDCl3): δ 3.77 (s, 6H), 5.56 (s, 1H), 6.54 (dd, J
= 2.3, 1.1 Hz, 1H), 6.81 (d, J = 8.7 Hz, 4H), 6.98 (ddd, J = 8.0, 7.1, 0.9
Hz, 1H), 7.10−7.18 (m, 5H), 7.21 (d, J = 8.7 Hz, 1H), 7.33 (dt, J =
8.3, 0.7 Hz, 1H), 7.91 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ
47.1, 55.2, 111.0, 113.6, 119.3, 120.0, 120.7, 122.0, 123.9, 127.0, 129.8,
136.5, 136.7, 157.9; MS (EI) m/z (%) 343 (M+, 100).
1
1478; H NMR (400 MHz, DMSO-d6): δ 3.71 (s, 3H), 5.68 (s, 1H),
6.71 (s, 1H), 6.90 (dd, J = 8.0, 8.0 Hz, 1H), 7.09−7.14 (m, 2H), 7.18
(d, J = 8.5 Hz, 1H), 7.20−7.26 (m, 4H), 7.30 (dd, J = 7.3, 7.3 Hz, 2H),
7.38 (d, J = 8.0 Hz, 1H), 7.48 (dt, J = 8.5, 2.5 Hz, 2H); 13C NMR (100
MHz, DMSO-d6): δ 32.8, 47.8, 110.0, 117.1, 119.1, 119.7, 119.8,
121.8, 126.8, 127.2, 128.9, 129.1, 131.3, 131.7, 137.6, 144.2; MS (EI)
m/z (%) 377 (M+ + 2, 99), 375 (M+, 100); HRMS (EI) m/z calcd for
C22H18NBr [M+ + 2] 377.0602, found 377.0599.
3-[Bis(4-fluorophenyl)methyl]-1-methyl-1H-indole (3g; Figure
1).7d Following the general procedure, 3g was obtained as a colorless
oil: yield 277 mg (83%); IR (neat) (cm−1) 3054, 1504; 1H NMR (400
MHz, CDCl3): δ 3.66 (s, 3H), 5.61 (s, 1H), 6.35 (s, 1H), 6.90−7.00
(m, 5H), 7.10−7.22 (m, 6H), 7.27 (d, J = 8.3 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ 32.0, 46.6, 108.6, 114.5 (d, J = 21.0 Hz), 117.4, 118.4,
119.2, 121.2, 126.4, 128.0, 129.6 (d, J = 7.6 Hz), 136.9, 139.0, 160.8
(d, J = 243.1 Hz); MS (EI) m/z (%) 333 (M+, 100).
3-[Bis(4-methoxyphenyl)methyl]-2-methyl-1H-indole (3n; Figure
2).15 Following the general procedure, 3n was obtained as a white
solid: yield 253 mg (71%); mp 165−167 °C; IR (KBr) (cm−1) 3416,
1
1505; H NMR (400 MHz, DMSO-d6): δ 2.18 (s, 3H), 3.70 (s, 6H),
5.60 (s, 1H), 6.73 (dd, J = 7.6, 7.6 Hz, 1H), 6.82 (d, J = 8.7 Hz, 4H),
6.88−6.93 (m, 2H), 7.04 (d, J = 8.7 Hz, 4H), 7.21 (d, J = 8.3 Hz, 1H),
10.8 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 12.4, 45.8, 55.5,
110.9, 113.7, 113.9, 118.6, 119.2, 120.2, 128.2, 130.1, 132.7, 135.8,
136.9, 157.8; MS (EI) m/z (%) 357 (M+, 100).
3-[Bis(4-methoxyphenyl)methyl]-1H-indole-5-carbonitrile (3h;
Figure 2). Following the general procedure, 3h was obtained as a
brown amorphous solid: yield 343 mg (93%); IR (KBr) (cm−1) 3330,
2222, 1608, 1507, 1251; 1H NMR (400 MHz, CDCl3): δ 3.79 (s, 3H),
5.53 (s, 1H), 6.69 (dd, J = 2.3, 1.2 Hz, 1H), 6.82 (d, J = 8.7 Hz, 4H),
7.10 (d, J = 8.7 Hz, 4H), 7.39 (s, 2H), 7.56 (s, 1H), 8.30 (br s, 1H);
Ethyl 3-[Bis(4-methoxyphenyl)methyl]-1H-indole-2-carboxylate
(3o; Figure 2). Following the general procedure, 3o was obtained as
a white solid: yield 291 mg (70%); mp 213−125 °C; IR (KBr) (cm−1)
3365, 1674, 1512; 1H NMR (400 MHz, CDCl3): δ 1.39 (t, J = 7.1 Hz,
3H), 3.74 (s, 6H), 4.38 (q, J = 7.1 Hz, 2H), 6.56 (s, 1H), 6.79 (d, J =
8.5 Hz, 4H), 6.89 (dd, J = 7.3, 7.3 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H),
E
dx.doi.org/10.1021/jo402151g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
7.12 (d, J = 8.7 Hz, 4H), 7.23 (dd, J = 7.6, 7.6 Hz, 1H), 7.35 (d, J = 8.5
Hz, 1H), 8.82 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 14.4, 45.6,
55.2, 61.0, 111.7, 113.5, 120.1, 123.6, 125.1, 126.7, 127.3, 130.1, 136.0,
136.1, 157.9, 162.1; MS (EI) m/z (%) 415 (M+, 57), 369 (100). Anal.
Calcd for C26H25NO4: C, 75.16; H, 6.07; N, 3.37. Found: C, 74.87; H,
6.13; N, 3.39.
Hz), 137.0, 140.0, 161.2 (d, J = 241.2 Hz), 163.7; MS (EI) m/z (%)
363 (M+, 68), 252 (100). Anal. Calcd for C22H15F2NO2: C, 72.72; H,
4.16; N, 3.85. Found: C, 72.72; H, 4.35; N, 3.94.
3-[(4-Methoxyphenyl)(phenyl)methyl]-1H-indole-2-carboxylic
Acid (4e; Figure 3). Following the general procedure, 4e was obtained
as a white solid: yield 322 mg (90%); mp 234−236 °C; IR (KBr)
(cm−1) 3457, 3005, 1664; 1H NMR (400 MHz, DMSO-d6): δ 3.71 (s,
3H), 6.83 (s, 1H), 6.77−6.88 (m, 3H), 6.93 (d, J = 8.0 Hz, 1H), 7.05
(d, J = 8.7 Hz, 2H), 7.10−7.22 (m, 4H), 7.27 (dd, J = 7.3, 7.3 Hz, 2H),
7.41 (d, J = 8.3 Hz, 1H), 11.6 (s, 1H); 13C NMR (100 MHz, DMSO-
d6): δ 45.3, 55.0, 112.7, 113.6, 119.4, 122.2, 124.1, 124.2, 124.3, 126.0,
126.3, 128.1, 128.7, 129.7, 135.4, 136.4, 143.9, 157.5, 163.4; MS (EI)
m/z (%) 357 (M+, 87), 339 (100). Anal. Calcd for C23H19NO3·
0.1H2O: C, 76.91; H, 5.39; N, 3.90. Found: C, 76.85; H, 5.53; N, 3.78.
3-[Phenyl(p-tolyl)methyl]-1H-indole-2-carboxylic Acid (4f; Figure
3). Following the general procedure, 4f was obtained as a white solid:
yield 258 mg (76%); mp 242−244 °C; IR (KBr) (cm−1) 3415, 3023,
3-[Bis(4-methoxyphenyl)methyl]-1-methyl-2-phenyl-1H-indole
(3p; Figure 2). Following the general procedure, 3p was obtained as a
white solid: yield 221 mg (51%); mp 203−205 °C; IR (KBr) (cm−1)
1
2956, 1505; H NMR (400 MHz, CDCl3): δ 3.58 (s, 3H), 3.76 (s,
6H), 5.42 (s, 1H), 6.75 (d, J = 8.7 Hz, 4H), 6.93 (ddd, J = 8.0, 7.1, 0.9
Hz, 1H), 7.06 (d, J = 8.3 Hz, 4H), 7.13 (d, J = 7.8 Hz, 1H), 7.18 (ddd,
J = 8.3, 7.1, 1.1 Hz, 1H), 7.25−7.29 (m, 2H), 7.33 (d, J = 8.3 Hz, 1H),
7.40−7.44 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 30.9, 46.5, 55.2,
109.3, 113.4, 115.7, 119.2, 121.3, 126.9, 128.2, 128.3, 130.0, 130.8,
136.9, 157.6; MS (EI) m/z (%) 433 (M+, 100). Anal. Calcd for
C30H27NO2: C, 83.11; H, 6.28; N, 3.23. Found: C, 82.89; H, 6.35; N,
3.22.
1
1666; H NMR (400 MHz, DMSO-d6): δ 2.25 (s, 3H), 6.70 (s, 1H),
6.80 (dd, J = 7.3, 7.3 Hz, 1H), 6.93 (dd, J = 8.0, 8.0 Hz, 1H), 7.02 (d, J
= 7.6 Hz, 2H), 7.07 (d, J = 7.6 Hz, 2H), 7.10−7.22 (m, 4H), 7.26 (dd,
J = 7.3, 7.3 Hz, 2H), 7.41 (d, J = 8.3 Hz, 1H), 11.6 (s, 1H); 13C NMR
(100 MHz, DMSO-d6): δ 21.1, 46.2, 113.2, 119.9, 122.7, 124.5, 124.6,
124.9, 126.5, 126.8, 128.7, 129.2, 129.3, 135.5, 136.9, 141.0, 144.2,
163.9; MS (EI) m/z (%) 341 (M+, 85), 323 (100). Anal. Calcd for
C23H19NO2·0.2H2O: C, 80.07; H, 5.67; N, 4.06. Found: C, 80.09; H,
5.82; N, 3.98.
2-[Bis(4-methoxyphenyl)methyl]-3-methyl-1H-indole (3q; Figure
2). Following the general procedure, 3q was obtained as an off-white
solid: yield 308 mg (86%); mp 119−121 °C; IR (KBr) (cm−1) 3433,
1
1508; H NMR (400 MHz, DMSO-d6): δ 2.13 (s, 3H), 3.72 (s, 6H),
5.67 (s, 1H), 6.87 (d, J = 8.5 Hz, 4H), 6.93 (dd, J = 8.5, 8.5 Hz, 1H),
6.99 (dd, J = 8.5, 8.5 Hz, 1H), 7.09 (d, J = 8.5 Hz, 4H), 7.25 (d, J = 7.8
Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 10.4 (br s, 1H); 13C NMR (100
MHz, DMSO-d6): δ 9.1, 46.7, 55.5, 106.4, 111.4, 114.2, 118.2, 118.6,
120.9, 129.1, 130.2, 135.3, 136.2, 137.3, 158.2; MS (EI) m/z (%) 357
(M+, 100). Anal. Calcd for C24H23NO2: C, 80.64; H, 6.49; N, 3.92.
Found: C, 80.62; H, 6.50; N, 3.91.
3-[Bis(4-methoxyphenyl)methyl]-1H-indole-5-carboxylic Acid
(4a; Figure 3). Following the general procedure, 4a was obtained as
a pink solid: yield 318 mg (82%); mp 260−262 °C; IR (KBr) (cm−1)
3391, 1687; 1H NMR (400 MHz, DMSO-d6): δ 3.71 (s, 6H), 5.62 (s,
1H), 6.74 (dd, J = 2.3, 0.7 Hz, 1H), 6.85 (d, J = 8.8 Hz, 4H), 7.12 (d, J
= 8.8 Hz, 4H), 7.40 (dd, J = 8.5, 0.7 Hz, 1H), 7.68 (dd, J = 8.5, 1.6 Hz,
1H), 7.85 (d, J = 1.6 Hz, 1H), 11.2 (s, 1H), 12.3 (s, 1H); 13C NMR
(100 MHz, DMSO-d6): δ 46.6, 55.5, 100.0, 114.2, 120.5, 121.4, 122.4,
126.6, 129.9, 136.9, 139.8, 158.0, 168.8; MS (EI) m/z (%) 387 (M+,
100). Anal. Calcd for C24H21NO4·0.1H2O: C, 74.06; H, 5.49; N, 3.60.
Found: C, 73.94; H, 5.62; N, 3.51.
3-Benzhydryl-1H-indole-2-carboxylic Acid (4g; Figure 3).16
Following the general procedure, 4g was obtained as a white solid:
yield 208 mg (64%); mp 146−148 °C; IR (KBr) (cm−1) 3452, 3049,
1
1665; H NMR (400 MHz, DMSO-d6): δ 6.71 (s, 1H), 6.76 (dt, J =
8.0, 0.7 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 7.07−7.18 (m, 8H), 7.23
(dd, J = 7.1, 7.1 Hz, 4H), 7.38 (d, J = 8.3 Hz, 1H), 11.6 (s, 1H); 13C
NMR (100 MHz, DMSO-d6): δ 46.7, 113.3, 119.9, 122.7, 124.3, 124.6,
125.0, 126.6, 126.9, 128.7, 129.3, 137.0, 144.0, 163.9; MS (EI) m/z
(%) 327 (M+, 100).
3-[(4-Chlorophenyl)(phenyl)methyl]-1H-indole-2-carboxylic Acid
(4h; Figure 3). Following the general procedure, 4h was obtained as a
white solid: yield 225 mg (62%); mp 231−233 °C; IR (KBr) (cm−1)
1
3431, 3053, 1667; H NMR (400 MHz, DMSO-d6): δ 6.68 (s, 1H),
6.92 (dd, J = 7.7, 7.7 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 7.10−7.32 (m,
11H), 7.38 (d, J = 8.3 Hz, 1H), 8.89 (s, 1H); 13C NMR (100 MHz,
DMSO-d6): δ 46.1, 113.3, 120.1, 122.4, 123.7, 124.7, 125.0, 126.8,
128.7, 128.8, 129.2, 131.1, 131.2, 136.9, 143.1, 143.5, 163.8; MS (EI)
m/z (%) 363 (M++2, 34), 361 (M+, 100). Anal. Calcd for
C22H16ClNO2: C, 73.03; H, 4.46; N, 3.87. Found: C, 73.01; H,
4.62; N, 3.87.
3-[1-(4-Methoxyphenyl)ethyl]-1-methyl-1H-indole (5a; Figure
4).7d Following the general procedure, 5a was obtained as a colorless
oil: yield 252 mg (95%); IR (neat) (cm−1) 2960, 1471; 1H NMR (400
MHz, CDCl3): δ 1.63 (d, J = 7.1 Hz, 3H), 3.59 (s, 3H), 3.67 (s, 3H),
4.28 (q, J = 7.1 Hz, 1H), 6.70−6.82 (m, 3H), 6.96 (dt, J = 8.0, 1.1 Hz,
1H), 7.10−7.23 (m, 4H), 7.35 (d, J = 7.8 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ 22.0, 31.8, 35.3, 54.4, 108.4, 112.9, 117.9, 119.1,
119.6, 120.8, 125.1, 127.6, 136.6, 138.4, 157.0; MS (EI) m/z (%) 265
(M+, 42), 250 (100).
3-[Bis(4-methoxyphenyl)methyl]-1H-indole-2-carboxylic Acid
(4b; Figure 3). Following the general procedure, 4b was obtained as
a white solid: yield 325 mg (84%); mp 248−250 °C; IR (KBr) (cm−1)
1
3457, 2939, 1664; H NMR (400 MHz, DMSO-d6): δ 3.70 (s, 6H),
6.61 (s, 1H), 6.79−6.88 (m, 5H), 6.95 (d, J = 8.3 Hz, 1H), 7.05 (d, J =
8.3 Hz, 4H), 7.14 (ddd, J = 8.3, 6.9, 1.1 Hz, 1H), 7.41 (d, J = 8.3 Hz,
1H), 11.6 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 45.0, 55.5,
113.2, 114.0, 119.8, 122.8, 124.6, 124.7, 125.2, 126.8, 130.2, 136.4,
137.0, 157.9, 163.9; MS (EI) m/z (%) 387 (M+, 92), 369 (100). Anal.
Calcd for C24H21NO4: C, 74.40; H, 5.46; N, 3.62. Found: C, 74.28; H,
5.65; N, 3.64.
3-[Bis(4-methoxyphenyl)methyl]-1-methyl-1H-indole-2-carbox-
ylic Acid (4c; Figure 3). Following the general procedure, 4c was
obtained as a white solid: yield 337 mg (84%); mp 227−229 °C; IR
(KBr) (cm−1) 2952, 1661; 1H NMR (400 MHz, DMSO-d6): δ 3.66 (s,
6H), 3.94 (s, 3H), 6.50 (s, 1H), 6.83 (d, J = 8.7 Hz, 4H), 6.87 (d, J =
8.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 8.5 Hz, 4H), 7.23
(dd, J = 7.3, 7.3 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H); 13C NMR (100
MHz, DMSO-d6): δ 32.6, 45.5, 55.5, 111.4, 114.0, 120.2, 122.9, 124.7,
125.3, 125.8, 127.0, 130.0, 130.1, 136.3, 139.0, 157.9, 164.1; MS (EI)
m/z (%) 401 (M+, 87), 383 (100). Anal. Calcd for C25H23NO4: C,
74.80; H, 5.77; N, 3.49. Found: C, 74.72; H, 5.71; N, 3.47.
1-Methyl-3-(1-phenylethyl)-1H-indole (5b; Figure 4).17 Following
the general procedure, 5b was obtained as a colorless oil: yield 130 mg
(55%); IR (neat) (cm−1) 2964, 1477; 1H NMR (400 MHz, CDCl3): δ
1.68 (d, J = 7.1 Hz, 3H), 3.69 (s, 3H), 4.35 (q, J = 7.1 Hz, 1H), 6.81
(s, 1H), 6.98 (ddd, J = 8.0, 7.1, 1.2 Hz, 1H), 7.10−7.32 (m, 7H), 7.35
(d, J = 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 22.7, 32.8, 37.1,
109.3, 118.8, 119.9, 120.1, 121.7, 126.0, 126.1, 127.4, 127.6, 127.8,
128.5, 137.5, 147.1; MS (EI) m/z (%) 235 (M+, 78), 220 (100).
3-(1-Phenylethyl)-1H-indole-2-carboxylic Acid (5c; Figure 4).
Following the general procedure, 5c was obtained as a white solid:
yield 282 mg (91%); mp 178−180 °C; IR (KBr) (cm−1) 2967, 1666;
1H NMR (400 MHz, DMSO-d6): δ 1.70 (d, J = 7.3 Hz, 3H), 3.69 (s,
3-[Bis(4-fluorophenyl)methyl]-1H-indole-2-carboxylic Acid (4d;
Figure 3). Following the general procedure, 4d was obtained as a
white solid: yield 267 mg (73%); mp 233−235 °C; IR (KBr) (cm−1)
1
3448, 3067, 1667; H NMR (400 MHz, DMSO-d6): δ 6.65 (s, 3H),
6.90−7.00 (m, 6H), 7.16 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H),
7.29 (ddd, J = 8.0, 6.4, 1.4 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 8.89 (s,
1H); 13C NMR (100 MHz, DMSO-d6): δ 45.3, 113.4, 115.5 (d, J =
21.0 Hz), 120.2, 122.3, 123.8, 124.7, 125.0, 126.6, 130.9 (d, J = 7.6
3H), 3.93 (s, 3H), 5.21 (q, J = 7.3 Hz, 1H), 6.81 (d, J = 8.7 Hz, 2H),
6.91 (dd, J = 7.6, 7.6 Hz, 1H), 7.20−7.30 (m, 3H), 7.33 (d, J = 8.4 Hz,
1H), 7.48 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ
F
dx.doi.org/10.1021/jo402151g | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
19.8, 31.9, 33.4, 54.8, 110.7, 113.3, 119.2, 121.9, 124.1, 124.2, 125.5,
127.0, 127.9, 137.1, 138.4, 157.0, 163.7; MS (EI) m/z (%) 309 (M+,
57), 294 (100); HRMS (EI) m/z calcd for C19H19NO3 [M+],
309.1365 found 309.1364.
AUTHOR INFORMATION
Corresponding Authors
*E-mail for H.H.: hidemasa.hikawa@phar.toho-u.ac.jp.
*E-mail for I.A.: isao.azumaya@phar.toho-u.ac.jp.
Notes
■
3-(4-Methoxybenzyl)-1-methyl-1H-indole (6a; Figure 4).18 Fol-
lowing the general procedure, 6a was obtained as a colorless oil: yield
1
186 mg (74%); IR (neat) (cm−1) 2905, 1471; H NMR (400 MHz,
The authors declare no competing financial interest.
CHCl3): δ 3.63 (s, 3H), 3.70 (s, 3H), 4.00 (s, 2H), 6.65 (d, J = 2.3 Hz,
1H), 6.73−6.82 (m, 2H), 7.00−7.08 (m, 1H), 7.12−7.25 (m, 4H),
7.48 (dd, J = 7.8, 2.3 Hz, 1H); 13C NMR (100 MHz, CHCl3): δ 30.9,
32.7, 55.4, 109.4, 114.0, 114.1, 115.0, 119.0, 119.5, 121.8, 127.3, 128.1,
129.8, 133.8, 137.4, 158.1; MS (EI) m/z (%) 251 (M+, 100).
ACKNOWLEDGMENTS
■
This work was supported in part by a Grant for Basic Science
Research Projects from The Sumitomo Foundation.
3-(3,4-Dimethoxybenzyl)-1-methyl-1H-indole (6b; Figure 4).
Following the general procedure, 6b was obtained as a colorless oil:
REFERENCES
■
1
yield 141 mg (50%); IR (neat) (cm−1) 2938, 1512; H NMR (400
(1) For a review see: Emer, E.; Sinisi, R.; Capdevila, M. G.;
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MHz, CHCl3): δ 3.64 (s, 3H), 3.78 (s, 3H), 3.80 (s, 3H), 4.02 (s, 2H),
6.65−6.90 (m, 4H), 7.05 (dd, J = 6.9, 6.9 Hz, 1H), 7.12−7.30 (m,
2H), 7.51 (d, J = 7.8 Hz, 1H); 13C NMR (100 MHz, CHCl3): δ 30.5,
31.9, 55.1, 55.2, 108.5, 110.4, 111.4, 113.9, 118.1, 118.5, 119.9, 120.9,
126.4, 133.3, 146.5, 148.1; MS (EI) m/z (%) 281 (M+, 100); HRMS
(EI) m/z calcd for C18H19NO2 [M+], 281.1416 found 281.1413.
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reaction mixture, which was extracted with CDCl3 (8 mL), and then
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1
the organic layer was analyzed by H NMR spectroscopy.
Preparation of 8a,b. A mixture of 1,3-dimethoxybenzene (7;
138.2 mg, 1.0 mmol), Hf(OTf)4 (77 mg, 0.1 mmol), and benzhydrol
(2a; 221 mg, 1.2 mmol) in H2O (4 mL) was heated to 120 °C for 3 h.
After it was cooled, 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, hexanes/EtOAc) to give 8a
(75 mg, 0.25 mmol) and 8b (60 mg, 0.13 mmol).
[(2,4-Dimethoxyphenyl)methylene]dibenzene (8a): white solid;
yield 75 mg (25%); mp 126−127 °C (lit.18 mp 120−121 °C); IR
(KBr) (cm−1) 2945, 1587, 1496, 1458; 1H NMR (400 MHz, CDCl3):
δ 3.69 (s, 3H), 3.78 (s, 3H), 5.83 (s, 1H), 6.39 (dd, J = 8.5, 2.5 Hz,
1H), 6.46 (d, J = 2.5 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 7.06−7.12 (m,
4H), 7.18 (tt, J = 7.3, 1.4 Hz, 2H), 7.22−7.30 (m, 5H); 13C NMR
(100 MHz, CDCl3): δ 49.1, 55.3, 55.6, 98.6, 103.7, 125.2, 125.9, 128.1,
129.4, 130.7, 144.2, 158.0, 159.4; MS (EI) m/z (%) 304 (M+, 100).
[(4,6-Dimethoxy-1,3-phenylene)bis(methanetriyl)]tetrabenzene
(8b): white solid, 60 mg (13%); mp 139−141 °C (lit.19 mp 154−155
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1
°C); IR (KBr) (cm−1) 3026, 1603, 1499, 1456; H NMR (400 MHz,
CDCl3): δ 3.70 (s, 6H), 5.75 (s, 2H), 6.39 (s, 1H), 6.44 (s, 1H), 6.90−
6.96 (m, 8H), 7.07−7.18 (m, 12H); 13C NMR (100 MHz, CDCl3): δ
49.1, 55.9, 95.5, 124.0, 125.9, 128.0, 129.3, 132.8, 144.2, 156.4; MS
(EI) m/z (%) 470 (M+, 100).
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General Procedure for Figure 1 and Table S2 (Supporting
Information). A mixture of 1-methylindole (1a; 131 mg, 1.0 mmol),
AuCl4Na·2H2O (8.0 mg, 2 mol %), sodium diphenylphosphinoben-
zene-3-sulfonate (TPPMS, 7.3 mg, 2 mol %), benzhydrol (2a; 184 mg,
1 mmol) and alcohols 2x (1 mmol) in H2O (4 mL) was heated to 80
°C for 30 min in a sealed tube. After it was cooled, the reaction
mixture was extracted with CDCl3 (8 mL) and then the organic layer
1
was determined by H NMR.
ASSOCIATED CONTENT
■
S
* Supporting Information
Tables giving data for the Friedel-Crafts reaction of 1,3-
dimethoxybenzene (7) and for the Brown−Okamoto plot for
the rate constants of benzylation by various substituted alcohols
1
and figures giving H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
G
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