Pd(ii)-catalyzed ligand controlled synthesis of methyl 1-benzyl-1H-indole- 3-carboxylates and bis(1-benzyl-1H-indol-3-yl)methanones

Article abstract of DOI:10.1039/c4ob00714j

A simple change of ligand and solvent allows controlled, effective switching between cyclization-carbonylation and cyclization-carbonylation- cyclization-coupling (CCC-coupling) reactions of 2-alkynylanilines catalyzed by palladium(ii). The use of a [Pd(tfa)₂(box)] catalyst in iPrOH afforded symmetrical ketones bearing two indoles in good yields; replacing the catalyst and solvent with Pd(tfa)₂ and DMSO-MeOH led to the formation of methyl 1-benzyl-1H-indole-3-carboxylates in good yields. This journal is

Full text of DOI:10.1039/c4ob00714j

Volume 12 Number 26 14 July 2014 Pages 4533–4764
Organic &
Biomolecular
Chemistry
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ISSN 1477-0520
PAPER
Keisuke Kato et al.
Pd(II)-catalyzed ligand controlled synthesis of methyl 1-benzyl-1H-indole-3-
carboxylates and bis(1-benzyl-1H-indol-3-yl)methanones

Organic &
Biomolecular Chemistry
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PAPER
Pd(II)-catalyzed ligand controlled synthesis of
methyl 1-benzyl-1H-indole-3-carboxylates and
bis(1-benzyl-1H-indol-3-yl)methanones†
Cite this: Org. Biomol. Chem., 2014,
12, 4602
Rong Shen, Taichi Kusakabe, Keisuke Takahashi and Keisuke Kato*
A simple change of ligand and solvent allows controlled, effective switching between cyclization–
carbonylation and cyclization–carbonylation–cyclization-coupling (CCC-coupling) reactions of 2-alkynyl-
anilines catalyzed by palladium(II). The use of a [Pd(tfa)2(box)] catalyst in iPrOH afforded symmetrical
ketones bearing two indoles in good yields; replacing the catalyst and solvent with Pd(tfa)2 and
DMSO–MeOH led to the formation of methyl 1-benzyl-1H-indole-3-carboxylates in good yields.
Received 4th April 2014,
Accepted 29th April 2014
DOI: 10.1039/c4ob00714j
www.rsc.org/obc
Introduction
Indoles are recognized as an important class of N-heterocycles
in pharmaceutical science.1 They constitute the core frame-
work of a large variety of drugs and important biologically
active compounds that occur in nature, such as vincristine
(anti-cancer), panobinostat (anti-leukemic), tropisetron (anti-
emetic), vincamine (vasodilator), pindolol (antihypertensive),
indomethacin (anti-inflammatory), atevirdine (anti-HIV),
arbidol (antiviral), melatonin, tryptamine, serotonin (mono-
amine neurotransmitters), indole-3-acetic acid (auxin) and
lysergic acid (Fig. 1).2 Diarylketones are also frequently found
in natural products and pharmaceuticals,3 e.g., 3-aroyl indoles
(anti-cancer),3f raloxifene (selective estrogen receptor modu-
lator used for treatment of osteoporosis), benzbromarone
(antipodagric) and amiodarone (antiarrhythmic). A variety of
heterocycles can be synthesized by transition-metal-catalyzed
cyclization of unsaturated systems.4 2-Alkynylanilines are good
precursors for the synthesis of 3-substituted indoles.5 Among
these, indole-3-carboxylates are also an important class of
heterocyclic compounds which display a wide range of biologi-
cal activities.5b Gabriele et al. reported PdI2-KI-catalyzed cycli-
zation–carbonylation of N-benzyl 2-alkynylanilines, with
indole-3-carboxylates obtained in 69–84% yields.5b
Fig. 1 Structures of biologically active indoles and diarylketones.
coupling reaction (CCC-coupling reaction) of propargyl acetate,
amides,6a γ-propynyl-1,3-diketones,6b N-propargylanilines,
o-alkynylphenols,6c propargyl ureas,6d α,β-alkynic hydrazones6e
and (o-alkynylphenyl) (methoxymethyl) sulfides6f catalyzed by
palladium(II)-bisoxazoline (box) complexes (Scheme 1). Sym-
metrical ketones bearing two oxazoles, cyclic orthoesters, oxa-
bicyclic groups, quinolines, benzofurans, oxazolines, pyrazoles
and benzo[b]thiophenes were obtained in one-step reactions.
In this transformation, the triple bond of the substrate coordi-
nates to palladium(II) and undergoes nucleophilic attack by
the intramolecular nucleophile X followed by CO insertion to
produce the acyl palladium intermediate A. Coordination of
the triple bond of a second molecule induces the second cycli-
zation,7 and reductive elimination then leads to the formation
of a ketone bearing two heterocyclic groups. Meanwhile,
methanolysis of the acyl palladium intermediate A gives the
ester product as a result of cyclization–carbonylation. If the
course of the reaction is switched by a simple change of ligand
(or solvent), heterocycle-3-carboxylates and symmetrical
ketones bearing two indole groups (dimeric ketones) are selec-
tively synthesized. In this work, we investigated Pd(II)-catalyzed
ligand-controlled switching between cyclization–carbonylation
and CCC-coupling reactions of 2-alkynylanilines.
If these intramolecular cyclization–carbonylation reactions
could be expanded to include carbonylative coupling reactions,
the process would be a synthetically valuable method for
direct preparation of ketones bearing two indole groups.
Recently, we reported a cyclization–carbonylation–cyclization-
Toho University, Funabashi, Japan. E-mail: kkk@phar.toho-u.ac.jp
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ob00714j
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Fig. 2 Ligands for Table 1.
although the yields were low (Table 1, entries 4–6). Next, an
attempt was made to use the box-PdII complexes according to
our previous results (Table 1, entries 7–10).6,7 As expected, the
reaction occurred smoothly in the presence of the [Pd(tfa)2L2],
and the yield of dimeric ketone 2a improved to 79% (Table 1,
entry 8). The nature of the counteranion of the palladium com-
plexes had some influence on the catalytic activity (Table 1,
entries 8 and 10). When the carbonylation reaction was
started, substrate 1a did not completely dissolve in methanol
due to its high lipophilicity. Therefore, various solvents were
tested in the carbonylation reaction. DMF and CH2Cl2 were
Scheme 1 Reaction courses of cyclization–carbonylation and cycliza-
tion–carbonylation–cyclization-coupling (CCC-coupling) in propargylic
compounds.
Results and discussion
Synthesis of the 2-alkynyl-N-benzylaniline substrates 1 was not suitable as solvents, as the reaction did not proceed when
carried out from the appropriate 2-iodoanilines, which were they were used (Table 1, entries 11 and 12). Finally, 2-propanol
converted to their N-benzyl derivatives using a reductive amin-
was found to be the best solvent, affording the dimeric ketone
ation protocol. Sonogashira coupling of the N-benzyl-2-iodo- 2a in 91% yield (Table 1, entries 13–15). Next, we turned our
anilines with terminal acetylenes, according to the literature, attention to the synthesis of indole-3-carboxylate derivative 3a
gave 1.8 Initially, we selected 1a as a standard substrate to
(Table 2). A palladium(II)/DMSO catalytic system has been used
search for potential catalysts (Table 1, Fig. 2). The reaction of in a variety of oxidative transformations, and DMSO has been
1a with Pd(tfa)2 (5 mol%) and p-benzoquinone (1.5 equiv.) in proposed as a ligand.9 Lee et al. reported Pd(II)-catalyzed con-
methanol under a carbon monoxide atmosphere (balloon) trolled switching between oxidative Heck reaction and conju-
afforded the indole-3-carboxylate derivative 3a in 41% yield gate addition to enones.10 In this reaction, DMSO plays a vital
along with an unidentified mixture (Table 1, entry 1). The use role in switching between two reaction pathways. Inspired by
of [PdCl2(PPh3)2] and [PdCl2(CH3CN)2] also gave the ester 3a in these studies, several different solvent mixtures at various
yields of 34–57% as a major product (Table 1, entries 2 and 3). ratios (DMSO–MeOH) were tested in the carbonylation reaction
The desired ketone 2a was obtained using palladium com- of 1a (Table 2, entries 1–5). Although a large amount of DMSO
plexes bearing 2,2′-bipyridine and the sulfoxide ligand L1, (DMSO–MeOH = 5/1) led to decreased product yield (Table 2,
Table 1 Optimization of CCC-coupling reaction of 1a
Temp (°C),
time (h)
Yield of
2a (%)
Yield of
3a (%)
Yield of
4a (%)
Entry
Catalyst
Solvent
1
Pd(tfa)2
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DMF
0 ∼ rt, 48
0 ∼ rt, 48
0, 47
0 ∼ rt, 51
0, 72
0 ∼ rt, 72
0, 72
−10, 69
0, 58
0, 72
0, 72
0, 72
0 ∼ rt, 48
0, 47
0 ∼ rt, 51
—
—
15
33
40
18
20
79
42
49
41
34
57
5
—
17
—
53
27
20
—
15
—
31
2a
3
[PdCl2(Ph3P)2]
[PdCl2(CH3CN)2]
[PdCl2(2,2′-bipy)]
[Pd(tfa)2(2,2′-bipy)]b
[Pd(OAc)2(L1)]
[Pd(tfa)2(L1)]c
[Pd(tfa)2(L2)]b
[Pd(tfa)2(L3)]b
[PdCl2(L2)]b
4
5
3
6
24
13
8
58
8
NR
NR
4
Trace
—
7d
8
9
10
11
12
13
14
15
[Pd(tfa)2(L2)]b
[Pd(tfa)2(L2)]b
[Pd(tfa)2(L2)]b
[Pd(tfa)2(L2)]b
[Pd(tfa)2(L2)]b
CH2Cl2
EtOH
iPrOH
iBuOH
81
91
52
16
Trace
40
a Recovery 54%. b Isolated complex was employed. c Pd(tfa)2 5 mol%/L1 10 mol%. d Recovery 54%.
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Table 2 Optimization of cyclization–carbonylation reaction of 1a
Table 3 Substrate scope of CCC-coupling (condition A) and cycliza-
tion–carbonylation reactions (condition B)
Temp (°C), Yield of Yield of Recovery
Entry Solvent
time (h)
2a (%) 3a (%) of 1a (%)
Temp (°C),
time (h)
Entry R1
R2
R3
R4
Yield (%)
1
DMSO–MeOH = 5/1 0 ∼ rt, 48
DMSO–MeOH = 1/1 0, 72
DMSO–MeOH = 1/1 0, 72
DMSO–MeOH = 1/2 0 ∼ 5, 72
DMSO–MeOH = 1/5 0, 72
DMSO–MeOH = 1/10 0 ∼ 5, 72
DMSO–MeOH = 1/21 0, 48
—
—
14
—
—
—
—
—
—
—
5
71
34
74
86
83
82
57
51
52
78
21
40
12
5
7
4
37
33
21
2
3a
4
1
2
3
4
Ph(CH2)2
H
H
H
H
H
H
H
H
H
H
H
Br
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
MeO
MeO
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
0, 47
0, 72
0, 72
0 ∼ rt, 72
−5 ∼ 5, 72
0 ∼ rt, 72
15, 48
15, 72
0 ∼ rt, 72
15, 48
0 ∼ 15, 72
0, 72
2a: 91
2b: 89
2c: 90
2d: 86
2e: 89
2f: 83
2g: 87
2h: 84
2i: 92
2j: 82
2k: 89
2l: 74
2m: 89
2n: 86
2o: 76
2p: 76
2q: 73
2r: 76
3a: 86
3b: 79
3c: 79
3d: 82
3e: 74
3f: 85
3g: 89
3h: 87
3i: 83
3j: 90
3k: 84
3m: 85
3n: 78
3s: 80
Me(CH2)3
Me(CH2)7
Ph
5
6
7
8
9
10
5
6
7
4-MeOPh
4-CF3Ph
4-FPh
THF–MeOH = 1/1
CH2Cl2–MeOH = 1/1 0, 72
DMF–MeOH = 1/1 0, 72
0, 72
8
9
4-ClPh
4-BrPh
4-MePh
4-tBuPh
Ph(CH2)2
Ph
Ph
Ph(CH2)2
Ph
3,5-(MeO)2Ph
3,4,5-(MeO)3Ph
Ph(CH2)2
Me(CH2)3
Me(CH2)7
Ph
4-MeOPh
4-CF3Ph
4-FPh
4-ClPh
4-BrPh
4-MePh
4-tBuPh
Ph
a PdCl2 was employed as a catalyst.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
5 ∼ 10, 72
entry 1), the best results were obtained by using the ratio
DMSO–MeOH = 1/5 or 1/10 with Pd(tfa)2, affording 3a in
83–86% yields (Table 2, entries 4–7). In addition, the use of
other mixed solvents (THF–MeOH, CH2Cl2–MeOH and DMF–
MeOH) did not give good results (Table 2, entries 8–10).
Having elucidated the optimum conditions for both reac-
tions, we then employed a variety of 2-alkynylanilines 1 in the
CCC-coupling reaction (Table 3, entries 1–18, condition A).
Substrates 1a–1d, bearing alkyl and phenyl substituents at the
alkyne terminus, gave good results which were similar to that
of the parent substrate 1a (Table 3, entries 1–4). Substrates 1e
and 1f, bearing both electron-donating and electron-withdraw-
ing substituents on an aromatic moiety in the alkyne termi-
nus, afforded the products 2e and 2f in 83–89% yields
(Table 3, entries 5 and 6). The three kinds of halogen substitu-
ent (F, Cl, Br) and alkyl groups on the phenyl ring in the
Me 0, 48
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5, 72
0 ∼ rt, 72
5 ∼ 15, 72
0 ∼ 15, 72
0, 72
0, 72
0, 72
0, 72
0, 48
0 ∼ rt, 120
0 ∼ rt, 72
0 ∼ rt, 72
0 ∼ 15, 48
15, 48
0 ∼ 10, 72
0, 72
Ph
H
Me 0, 48
H 0, 48
alkyne terminus were tolerated under the reaction conditions bearing methyl groups on the aniline ring, were transformed
used (Table 3, entries 7–11). Substrates 1l–1n, bearing Br and to the corresponding esters 2m and 2n in 85 and 78% yield,
methyl groups on the aniline ring, were transformed to the respectively (Table 3, entries 30 and 31). It is noteworthy that
corresponding ketones 2l–2n in 74–89% yields (Table 3, the terminal acetylene 1s was transformed to 3s in 80% yield
entries 12–14). The introduction of methoxy groups on the (Table 3, entry 32).
aniline ring led to a slightly lowered yield (Table 3, entries
A plausible mechanism for the CCC-coupling and cycliza-
15–16). Substrates 1q–1r, bearing two or three methoxy groups tion–carbonylation reactions of 1 is shown in Scheme 2.
on the phenyl ring at the alkyne terminus, afforded the pro- Nucleophilic attack by the nitrogen atom at the electrophili-
ducts 2q–2r in 73–76% yields (Table 3, entries 17–18). The cally activated triple bond is followed by CO insertion to
reaction pathways were switched by using condition produce the acyl palladium intermediate I-1. Under condition
B. Substrates 1a–1d, bearing alkyl and phenyl substituents at A (L = box), coordination of the triple bond of a second mole-
the alkyne terminus, were transformed to the corresponding cule (I-2) induces the second cyclization, and reductive elimi-
methyl indole-3-carboxylates 3a–3d in good yields (Table 3, nation then leads to the formation of a ketone bearing two
entries 19–22). Substrates 1e and 1f, bearing both electron- indole groups. We believe that the box ligand enhances the
donating and electron-withdrawing substituents on an aro- π-electrophilicity of palladium(II),7 and thus promotes coordi-
matic moiety in the alkyne terminus, gave moderate to good nation of the second triple bond to the acyl palladium inter-
results (Table 3, entries 23 and 24). The three kinds of halogen mediate I-1, leading to the dimerization reaction. Under
substituent (F, Cl, Br) and alkyl groups on the phenyl ring in condition B, DMSO acts as a neutral ligand instead of a box.11
the alkyne terminus were tolerated under the reaction con- Methanolysis of the acyl palladium intermediate I-1 should be
ditions used (Table 3, entries 25–29). Substrates 1m and 1n, facilitated, giving indole-3-carboxylates 3 in good yields.
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three-way stopcock connected to a balloon filled with carbon
monoxide. The apparatus was purged with carbon monoxide
by pump-filling via the three-way stopcock. A iPrOH (1 mL)
solution (or suspension) of catalyst was added to the stirred
solution via syringe at 0 °C. The remaining catalyst was
washed in iPrOH (1 mL) twice, and stirred for 47 h at the same
temperature. In most cases, the dimeric ketones precipitated
from the reaction mixture. The resulting precipitate was col-
lected by filtration and washed with cold iPrOH (1.5 mL × 2) to
yield dimeric ketone 2a. As small amounts of 2a (and 3a, see
Table 1) still remained in the filtrate, the filtrate was diluted
with CH2Cl2 (50 mL) and washed with 5% NaOH (40 mL). The
aqueous layer was extracted with CH2Cl2 (25 mL) and the com-
bined organic layers were dried over MgSO4 and concentrated
in vacuo. The crude product was purified by column chromato-
graphy on silica gel. The fraction eluted with hexane–ethyl
acetate (20/1) afforded small amounts of dimeric ketone 2a
(monomeric ester 3a, hexane–ethyl acetate = 50/1).
Scheme 2 Plausible mechanism for the CCC-coupling and cycliza-
tion–carbonylation reactions of 1.
Bis(1-benzyl-2-phenethyl-1H-indol-3-yl)methanone (2a). 91%
yield (93.9 mg), white solid, mp 139–141 °C, 1H NMR
(400 MHz, CDCl3) δ 2.83–2.90 (4H, m), 3.16–3.28 (4H, m), 5.25
(4H, s), 6.97–7.03 (10H, m), 7.10–7.28 (16H, m), 7.41 (2H, br-d,
J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 28.2 (2C), 36.7 (2C),
46.5 (2C), 109.8 (2C), 116.9 (2C), 120.9 (2C), 121.3 (2C), 122.2
(2C), 125.9 (4C), 126.1 (2C), 126.8 (2C), 127.6 (2C), 128.4 (4C),
128.4 (4C), 128.9 (4C), 136.4 (2C), 136.9 (2C), 141.0 (2C), 145.2
Conclusions
In conclusion, we developed an efficient way of switching
between CCC-coupling and cyclization–carbonylation reactions
of 2-alkynylanilines (1) catalyzed by PdII. The use of [Pd-
(tfa)2(box)] as a catalyst in iPrOH afforded symmetrical ketones
bearing two indoles in good to excellent yields, while replacing
the catalyst and solvent with Pd(tfa)2 and DMSO–MeOH led to
the formation of methyl 1-benzyl-1H-indole-3-carboxylates in
good yields. These reactions were general for a wide range of
2-alkynylanilines. We are currently investigating additional
cascade reactions based on the reaction strategy of CCC-coup-
ling and cyclization–carbonylation presented here for the syn-
thesis of the other types of ketone containing two heterocyclic
groups and heterocycles-carboxylates.
(2C), 188.3; IR (KBr) 1614, 1604, 1523, 1455, 1410 cm−1
;
HRMS-EI: m/z [M+] calcd for C47H40N2O 648.3141, found
648.3141.
Bis(1-benzyl-2-butyl-1H-indol-3-yl)methanone (2b). 89%
yield (93.5 mg) from 1b (100 mg, 0.38 mmol), white solid, mp
1H NMR (400 MHz, CDCl3) δ 0.78 (6H, t, J = 7.2 Hz), 1.26–1.32
(4H, m), 1.50–1.56 (4H, m), 2.92–2.98 (4H, m), 5.42 (4H, s),
6.97 (2H, t, J = 7.6 Hz), 7.05–7.11 (6H, m), 7.20–7.33 (8H, m),
7.37 (2H, br-d, J = 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ 13.7
(2C), 22.8 (2C), 25.3 (2C), 32.5 (2C), 46.7 (2C), 109.7 (2C), 116.8
(2C), 120.8 (2C), 121.1 (2C), 121.9 (2C), 126.0 (4C), 127.1 (2C),
127.6 (2C), 128.9 (4C), 136.3 (2C), 137.0 (2C), 146.3 (2C), 188.5;
IR (KBr) 2956, 1603, 1522, 1463, 1410 cm−1; HRMS-EI: m/z [M+]
calcd for C39H40N2O 552.3141, found 552.3142.
Experimental section
General information
Bis(1-benzyl-2-octyl-1H-indol-3-yl)methanone (2c). 90%
yield (92.6 mg) from 1c (100 mg, 0.31 mmol), white solid, mp
1H NMR (400 MHz, CDCl3) δ 0.83 (6H, t, J = 6.8 Hz), 1.13–1.25
(20H, m), 1.50–1.58 (4H, m), 2.90–2.98 (4H, m), 5.42 (4H, s),
6.97 (2H, br-t, J = 8.0 Hz), 7.04–7.11 (6H, m), 7.20–7.32 (8H,
m), 7.38 (2H, br-d, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ
14.1 (2C), 22.6 (2C), 25.6 (2C), 29.2 (2C), 29.2 (2C), 29.7 (2C),
30.5 (2C), 31.8 (2C), 46.7 (2C), 109.7 (2C), 116.8 (2C), 120.8
(2C), 121.1 (2C), 121.9 (2C), 125.9 (4C), 127.1 (2C), 127.6 (2C),
128.9 (4C), 136.3 (2C), 137.0 (2C), 146.4 (2C), 188.5; IR (KBr)
2924, 1604, 1523, 1464, 1410 cm−1; HRMS-EI: m/z [M+] calcd
for C47H56N2O 664.4393, found 664.4392.
See ESI† for general experimental details as well as procedures
for the preparation and characterization of all precursors and
products.
Preparation of box-palladium complexes
The box ligands L1–L3 and palladium complexes [Pd(tfa)2(2,2′-
bipy)], [Pd(tfa)2(L2)], [Pd(tfa)2(L3)] and [PdCl2(L3)] were pre-
pared according to the literature.6a,d,12
Typical procedure for CCC-coupling reaction of N-benzyl-2-
(4-phenylbut-1-yn-1-yl)aniline (1a): condition A
A 30 mL two-necked round-bottom flask containing a mag-
Bis(1-benzyl-2-phenyl-1H-indol-3-yl)methanone (2d). 86%
netic stirring bar, N-benzyl-2-(4-phenylbut-1-yn-1-yl)aniline (1a) yield (89.0 mg) from 1d (100 mg, 0.35 mmol), yellow solid, mp
(100 mg, 0.32 mmol), p-benzoquinone (51.9 mg, 0.48 mmol) 295–297 °C, 1H NMR (400 MHz, CDCl3) δ 5.04 (4H, s),
and iPrOH (3 mL) was fitted with a rubber septum and a 6.64–6.67 (4H, m), 6.96–7.03 (10H, m), 7.11–7.27 (12H, m),
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8.06 (2H, br-d, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 47.7 solid, mp 254–255 °C, H NMR (400 MHz, CDCl3) δ 5.02 (4H,
(2C), 110.3 (2C), 118.3 (2C), 121.1 (2C), 121.9 (2C), 122.9 (2C), br-s), 6.50 (4H, br-d, J = 7.2 Hz), 6.84–6.87 (4H, m), 7.04 (2H,
125.7 (4C), 127.2 (2C), 127.4 (4C), 128.0 (2C), 128.2 (2C), 128.6 br-d, J = 8.0 Hz), 7.13–7.28 (10H, m), 7.35–7.39 (4H, m), 8.02
(4C), 130.1 (2C), 130.5 (4C), 136.9 (2C), 137.3 (2C), 143.9 (2C), (2H, br-d, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 47.9 (2C),
189.2; IR (KBr) 1604, 1484, 1461, 1450, 1418, 1143 cm−1
HRMS-EI: m/z [M+] calcd for C43H32N2O 592.2515, found (2C), 125.4 (4C), 127.4 (2C), 127.8 (2C), 129.0 (2C), 129.0 (4C),
;
110.4 (2C), 118.5 (2C), 121.1 (2C), 122.2 (2C), 122.9 (2C), 123.5
592.2513.
130.6 (4C), 131.7 (4C), 137.0 (2C), 137.3 (2C), 142.7 (2C), 188.7;
Bis(1-benzyl-2-(4-methoxyphenyl)-1H-indol-3-yl)methanone IR (KBr) 1604, 1459, 1417, 1141, 1011 cm−1; HRMS-EI: m/z [M+]
(2e). 89% yield (93.0 mg) from 1e (100 mg, 0.32 mmol), yellow calcd for C43H30N2OBr2 748.0725, found 748.0720.
1
solid, mp 220–223 °C, H NMR (400 MHz, CDCl3) δ 3.64 (6H,
Bis(1-benzyl-2-(4-methylphenyl)-1H-indol-3-yl)methanone
s), 5.02 (4H, s), 6.50 (4H, d, J = 8.8 Hz), 6.68 (4H, d, J = 6.8 Hz), (2j). 82% yield (86.8 mg) from 1j (100 mg, 0.34 mmol), yellow
1
6.89–6.94 (6H, m), 7.10–7.32 (10H, m), 8.10 (2H, d, J = 8.0 Hz); solid, mp 137–138 °C, H NMR (400 MHz, CDCl3) δ 2.26 (6H,
13C NMR (100 MHz, CDCl3) δ 47.8 (2C), 55.2 (2C), 110.2 (4C), s), 5.03 (4H, s), 6.72–6.74 (4H, m), 6.84 (4H, d, J = 8.4 Hz),
112.9 (4C), 117.8 (2C), 121.0 (2C), 121.8 (2C), 122.3 (2C), 122.7 6.93–6.95 (6H, m), 7.08–7.28 (10H, m), 8.01 (2H, br-d, J = 7.6
(2C), 125.6 (4C), 127.2 (2C), 128.3 (2C), 128.7 (4C), 131.8 (2C), Hz); 13C NMR (100 MHz, CDCl3, one quaternary carbon peak
137.1 (2C), 137.4 (2C), 144.0 (2C), 159.7 (2C), 189.6; IR (KBr) (2C) was overlapped) δ 21.3 (2C), 47.8 (2C), 110.2 (2C), 118.2
1609, 1496, 1460, 1251, 1177, 1030 cm−1; HRMS-EI: m/z [M+] (2C), 121.1 (2C), 121.7 (2C), 122.7 (2C), 125.7 (4C), 127.1 (2C),
calcd for C45H36N2O3 652.2726, found 652.2726.
127.3 (2C), 128.1 (4C), 128.6 (4C), 130.3 (4C), 137.0 (2C), 137.5
Bis(1-benzyl-2-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)- (2C), 138.1 (2C), 144.3 (2C), 189.3; IR (KBr) 1603, 1454, 1412,
methanone (2f). 83% yield (84.7 mg) from 1f (100 mg, 1141, 1059 cm−1; HRMS-EI: m/z [M+] calcd for C45H36N2O
1
0.28 mmol), yellow solid, mp 221–223 °C, H NMR (400 MHz, 620.2828, found 620.2829.
CDCl3) δ 5.05 (4H, br-s), 6.72–6.75 (4H, m), 7.06–7.08 (2H, m),
Bis(1-benzyl-2-(4-(tert-butyl)phenyl)-1H-indol-3-yl)metha-
7.16–7.26 (14H, m), 7.33 (4H, d, J = 8.0 Hz), 7.88–7.91 (2H, m); none (2k). 89% yield (91.2 mg) from 1k (100 mg, 0.29 mmol),
13C NMR (100 MHz, CDCl3) δ 47.9 (2C), 110.6 (2C), 119.1 (2C), yellow solid, mp 264–265 °C, 1H NMR (400 MHz, CDCl3) δ 1.19
1
121.2 (2C), 122.3 (2C), 123.7 (2C), 123.8 (2C, q, JC–F = 270.8 (18H, s), 5.09 (4H, s), 6.84 (4H, br-d, J = 8.0 Hz), 6.95 (2H, d, J =
3
Hz), 124.3 (4C, q, JC–F = 3.8 Hz), 125.5 (4C), 127.4 (2C), 127.6 8.0 Hz), 7.04–7.13 (12H, m), 7.20–7.24 (6H, m), 7.84 (2H, br-d,
(2C), 128.9 (4C), 130.3 (2C, q, 2JC–F = 32.4 Hz), 130.6 (4C), 133.9 J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 31.2 (6C), 34.5 (2C),
(2C), 136.7 (2C), 137.1 (2C), 142.2 (2C), 188.1; IR (KBr) 1616, 47.7 (2C), 110.2 (2C), 118.7 (2C), 121.1 (2C), 121.5 (2C), 122.5
1603, 1497, 1414, 1322, 1133 cm−1; HRMS-EI: m/z [M+] calcd (2C), 124.2 (4C), 125.9 (4C), 127.2 (2C), 127.3 (2C), 127.8 (2C),
for C45H30N2OF6 728.2262, found 728.2263.
128.6 (4C), 130.0 (4C), 136.6 (2C), 137.4 (2C), 144.4 (2C), 151.2
Bis(1-benzyl-2-(4-fluorophenyl)-1H-indol-3-yl)methanone (2C), 189.3; IR (KBr) 2963, 1619, 1608, 1496, 1460, 1410,
(2g). 87% yield (90.5 mg) from 1g (100 mg, 0.33 mmol), white 732 cm−1; HRMS-EI: m/z [M+] calcd for C51H48N2O 704.3767,
1
solid, mp 108–110 °C, H NMR (400 MHz, CDCl3) δ 5.03 (4H, found 704.3769.
br-s), 6.67–6.72 (8H, m), 6.93–6.97 (4H, m), 7.03 (2H, d, J = 8.2
Bis(1-benzyl-5-bromo-2-phenethyl-1H-indol-3-yl)methanone
Hz), 7.15–7.32 (10H, m), 8.04 (2H, d, J = 8.2 Hz); 13C NMR (2l). 74% yield (77.6 mg) from 1l (100 mg, 0.26 mmol), yellow
2
(100 MHz, CDCl3) δ 47.7 (2C), 110.3 (2C), 114.5 (4C, d, JC–F
=
solid, mp 78–80 °C, 1H NMR (400 MHz, CDCl3) δ 2.84–2.89
21.9 Hz), 118.2 (2C), 121.1 (2C), 122.1 (2C), 123.3 (2C), 125.5 (4H, m), 3.16–3.22 (4H, m), 5.20 (4H, s), 6.91–7.00 (8H, m),
4
(4C), 126.1 (2C, d, JC–F = 3.9 Hz), 127.4 (2C), 127.7 (2C), 128.8 7.08 (2H, d, J = 8.4 Hz), 7.12–7.34 (14H, m), 7.52 (2H, d, J = 1.6
3
(4C), 132.2 (4C, d, JC–F = 8.6 Hz), 137.0 (2C), 137.0 (2C), 142.7 Hz); 13C NMR (100 MHz, CDCl3) δ 28.1 (2C), 36.5 (2C), 46.7
(2C), 162.7 (2C, d, 1JC–F = 247.9 Hz), 188.7; IR (KBr) 1605, 1495, (2C), 111.5 (2C), 115.1 (2C), 116.1 (2C), 123.2 (2C), 125.3 (2C),
1460, 1454, 1415, 1225 cm−1; HRMS-EI: m/z [M+] calcd for 125.7 (4C), 126.3 (2C), 127.8 (2C), 128.4 (6C), 128.5 (4C), 129.2
C43H30F2N2O 628.2326, found 628.2324.
(4C), 135.0 (2C), 136.2 (2C), 140.5 (2C), 146.1 (2C), 187.1; IR
Bis(1-benzyl-2-(4-chlorophenyl)-1H-indol-3-yl)methanone (KBr) 1601, 1522, 1508, 1457, 1437, 1411 cm−1; HRMS-ESI+ m/z
(2h). 84% yield (86.3 mg) from 1h (100 mg, 0.31 mmol), [M + Na]+ calcd for C47H38Br2N2NaO 827.1249 found 827.1278.
yellow solid, mp 140–144 °C, 1H NMR (400 MHz, CDCl3) δ 5.03
Bis(1-benzyl-5-methyl-2-phenyl-1H-indol-3-yl)methanone
(4H, br-s), 6.69 (4H, br-d, J = 7.2 Hz), 6.90–6.92 (4H, m), (2m). 89% yield (94.0 mg) from 1m (100 mg, 0.34 mmol),
6.97–7.00 (4H, m), 7.03 (2H, br-d, J = 8.0 Hz), 7.17–7.21 (2H, yellow solid, mp >300 °C, 1H NMR (400 MHz, CDCl3) δ 2.45
m), 7.23–7.28 (4H, m), 7.33–7.37 (4H, m), 8.04 (2H, br-d, J = 7.2 (6H, s), 5.02 (4H, s), 6.69–6.71 (4H, m), 6.85 (2H, d, J = 8.4 Hz),
Hz); 13C NMR (100 MHz, CDCl3) δ 47.9 (2C), 110.4 (2C), 118.5 6.94 (2H, dd, J = 8.4, 1.6 Hz), 7.02–7.04 (8H, m), 7.19–7.26 (8H,
(2C), 121.1 (2C), 122.2 (2C), 123.5 (2C), 125.4 (4C), 127.4 (2C), m), 7.85 (2H, br-s); 13C NMR (100 MHz, CDCl3) δ 21.6 (2C),
127.7 (4C), 127.8 (2C), 128.5 (2C), 129.0 (4C), 131.5 (4C), 134.6 47.7 (2C), 109.9 (2C), 117.9 (2C), 121.0 (2C), 124.4 (2C), 125.8
(2C), 137.0 (2C), 137.2 (2C), 142.6 (2C), 188.7; IR (KBr) 1603, (4C), 127.2 (2C), 127.3 (4C), 128.1 (2C), 128.2 (2C), 128.6 (4C),
1482, 1459, 1454, 1417 cm−1; HRMS-EI: m/z [M+] calcd for 130.4 (2C), 130.5 (4C), 131.2 (2C), 135.3 (2C), 137.5 (2C), 144.0
C43H30N2OCl2 660.1735, found 660.1739.
(2C), 188.9; IR (KBr) 1604, 1476, 1410, 1351, 1055 cm−1
;
Bis(1-benzyl-2-(4-bromophenyl)-1H-indol-3-yl)methanone HRMS-EI: m/z [M+] calcd for C45H36N2O 620.2828, found
(2i). 92% yield (96.6 mg) from 1i (100 mg, 0.28 mmol), yellow 620.2827.
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Bis(1-benzyl-5,7-dimethyl-2-phenyl-1H-indol-3-yl)methanone 1454, 1418, 1240, 1126 cm−1; HRMS-ESI+ m/z [M + Na]+ calcd
(2n). 86% yield (89.3 mg) from 1n (100 mg, 0.32 mmol), for C49H44N2NaO7 795.3046 found 795.3065.
yellow solid, mp 127–129 °C, 1H NMR (400 MHz, CDCl3) δ 2.28
Typical procedure for cyclization–carbonylation reaction of
(6H, s), 2.38 (6H, s), 5.20 (4H, br-s), 6.58 (4H, br-d, J = 6.0 Hz),
N-benzyl-2-(4-phenylbut-1-yn-1-yl)aniline (1a): condition B
6.70 (2H, br-s), 7.03–7.07 (8H, m), 7.19–7.25 (8H, m), 7.67 (2H,
br-s); 13C NMR (100 MHz, CDCl3) δ 19.4 (2C), 21.2 (2C), 48.9 A 30 mL two-necked round-bottom flask containing a mag-
(2C), 118.3 (2C), 119.0 (2C), 120.3 (2C), 125.1 (4C), 126.9 (4C), netic stirring bar, N-benzyl-2-(4-phenylbut-1-yn-1-yl)aniline (1a)
127.2 (4C), 127.7 (2C), 128.0 (2C), 128.7 (4C), 128.9 (2C), 130.5 (100 mg, 0.32 mmol), p-benzoquinone (51.9 mg, 0.48 mmol)
(2C), 130.8 (2C), 131.0 (2C), 133.9 (2C), 139.8 (2C), 144.6 (2C), and MeOH (8 mL) was fitted with a rubber septum and a
189.0; IR (KBr) 1600, 1484, 1421, 1396, 703 cm−1; HRMS-EI: three-way stopcock connected to a balloon filled with carbon
m/z [M+] calcd for C47H40N2O 648.3141, found 648.3139.
monoxide. The apparatus was purged with carbon monoxide
Bis(1-benzyl-6-methoxy-2-phenethyl-1H-indol-3-yl)metha- by pump-filling via the three-way stopcock. A DMSO (1 mL)
none (2o). 76% yield (78.1 mg) from 1o (100 mg, 0.29 mmol), solution of catalyst was added to the stirred solution via
yellow solid, mp 156–157 °C, 1H NMR (400 MHz, CDCl3) δ syringe at 0 °C. The remaining catalyst was washed in DMSO
2.81–2.88 (4H, m), 3.15–3.22 (4H, m), 3.75 (6H, s), 5.20 (4H, s), (1 mL) and MeOH (2 mL) and stirred for 72 h at the same
6.65–6.70 (4H, m), 6.98–7.04 (8H, m), 7.11–7.30 (14H, m); 13C temperature. The mixture was diluted with CH2Cl2 (70 mL)
NMR (100 MHz, CDCl3) δ 28.2 (2C), 36.9 (2C), 46.5 (2C), 55.6 and washed with 5% NaOH (40 mL). The aqueous layer was
(2C), 93.8 (2C), 110.4 (2C), 116.8 (2C), 121.1 (2C), 121.7 (2C), extracted with CH2Cl2 (25 mL) and the combined organic
126.0 (4C), 126.1 (2C), 127.6 (2C), 128.4 (8C), 129.0 (4C), 136.9 layers were dried over MgSO4 and concentrated in vacuo. The
(2C), 137.2 (2C), 141.1 (2C), 144.2 (2C), 156.4 (2C), 188.2; IR crude product was purified by column chromatography on
(KBr) 1598, 1523, 1453, 1404, 1150 cm−1; HRMS-EI: m/z [M+] silica gel. The fraction eluted with hexane–ethyl acetate (50/1)
calcd for C49H44N2O3 708.3352, found 708.3353.
afforded monomeric ester 3a.
Bis(1-benzyl-6-methoxy-2-phenyl-1H-indol-3-yl)methanone
Methyl 1-benzyl-2-phenethyl-1H-indole-3-carboxylate (3a). 86%
(2p). 76% yield (79.4 mg) from 1p (100 mg, 0.32 mmol), yield (102.0 mg) from 1a (100 mg, 0.32 mmol), yellow solid,
1
yellow solid, mp 126–128 °C, 1H NMR (400 MHz, CDCl3) δ 3.72 mp 90–91 °C, H NMR (400 MHz, CDCl3) δ 2.82–2.86 (2H, m),
(6H, s), 4.97 (4H, s), 6.40 (2H, d, J = 2.4 Hz), 6.64–6.66 (4H, m), 3.37–3.41 (2H, m), 3.97 (3H, s), 5.11 (2H, s), 6.91–6.94 (2H, m),
6.88 (2H, dd, J = 2.4, 8.8 Hz), 6.95–7.03 (8H, m), 7.18–7.26 (8H, 7.10–7.12 (2H, m), 7.18–7.27 (9H, m), 8.20 (1H, br-d, J = 1.2,
m) 7.95 (2H, d, J = 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ 47.8 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 28.5, 35.8, 46.3, 50.8,
(2C), 55.6 (2C), 94.1 (2C), 111.0 (2C), 118.3 (2C), 121.9 (2C), 104.2, 109.8, 121.6, 122.0, 122.5, 125.9 (2C), 126.3, 126.6,
122.4 (2C), 125.8 (4C), 127.2 (2C), 127.4 (4C), 128.0 (2C), 128.7 127.7, 128.5 (2C), 128.5 (2C), 128.9 (2C), 136.3, 136.6, 141.1,
(4C), 130.2 (2C), 130.4 (4C), 137.2 (2C), 137.9 (2C), 143.1 (2C), 148.6, 166.1; IR (KBr) 1685, 1530, 1443, 1235, 1113 cm−1
156.8 (2C), 189.4; IR (KBr) 1606, 1491, 1049, 818 cm−1 HRMS-EI: m/z [M+] calcd for C25H23NO2 369.1729, found
HRMS-EI: m/z [M+] calcd for C45H36N2O3 652.2726 found 369.1731.
652.2725.
Methyl 1-benzyl-2-butyl-1H-indole-3-carboxylate (3b).13a 79%
Bis(1-benzyl-2-(3,5-dimethoxyphenyl)-1H-indol-3-yl)metha- yield (96.8 mg) from 1b (100 mg, 0.38 mmol).
;
;
none (2q). 73% yield (75.5 mg) from 1q (100 mg, 0.29 mmol),
Methyl 1-benzyl-2-octyl-1H-indole-3-carboxylate (3c). 79%
yellow solid, mp 132–134 °C, 1H NMR (400 MHz, CDCl3) δ 3.22 yield (92.7 mg) from 1c (100 mg, 0.31 mmol), yellow oil; 1H
(12H, s), 5.10 (4H, br-s), 6.10 (4H, d, J = 2.4 Hz), 6.31 (2H, t, J = NMR (400 MHz, CDCl3) δ 0.86 (3H, t, J = 6.8 Hz), 1.23–1.59
2.4 Hz), 6.76 (4H, d, J = 7.6 Hz), 7.04 (2H, d, J = 8.0 Hz), (12H, m), 3.12–3.16 (2H, m), 3.94 (3H, s), 5.37 (2H, s),
7.17–7.31 (10H, m), 8.15 (2H, t, J = 7.6 Hz); 13C NMR 6.95–6.98 (2H, m), 7.16–7.27 (6H, m), 8.16 (1H, br-d, J =
(100 MHz, CDCl3) δ 48.1 (2C), 54.8 (4C), 102.6 (2C), 108.1 (4C), 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 14.1, 22.6, 25.8, 29.2, 29.3,
110.4 (2C), 118.1 (2C), 121.3 (2C), 122.0 (2C), 123.3 (2C), 125.5 29.6, 29.8, 31.8, 46.6, 50.7, 103.9, 109.9, 121.6, 121.9, 122.3,
(4C), 127.1 (2C), 128.2 (2C), 128.8 (4C), 131.5 (2C), 137.3 (2C), 125.8 (2C), 126.8, 127.6, 128.9 (2C), 136.3, 136.6, 149.9, 166.2;
137.5 (2C), 143.9 (2C), 159.4 (4C), 189.3; IR (KBr): 1596, 1464, IR (KBr) 2925, 1698, 1535, 1464, 1139, 1114 cm−1; HRMS-EI:
1455, 1419, 1206, 1155 cm−1; HRMS-ESI+ m/z [M + H]+ calcd m/z [M+] calcd for C25H31NO2 377.2355, found 377.2356.
for C47H41N2O5 713.3015 found 713.3019.
Bis(1-benzyl-2-(3,4,5-trimethoxyphenyl)-1H-indol-3-yl)metha- yield (98.4 mg) from 1d (100 mg, 0.35 mmol).
Methyl 1-benzyl-2-phenyl-1H-indole-3-carboxylate (3d).13a 82%
none (2r). 76% yield (79.3 mg) from 1r (100 mg, 0.27 mmol),
Methyl 1-benzyl-2-(4-methoxyphenyl)-1H-indole-3-carboxy-
yellow solid, mp 227–230 °C, 1H NMR (400 MHz, CDCl3) δ 3.07 late (3e). 74% yield (88.0 mg) from 1e (100 mg, 0.32 mmol),
1
(12H, s), 3.74 (6H, s), 5.10 (4H, br-s), 6.13 (4H, s), 6.74 (4H, d, J yellow oil, H NMR (400 MHz, CDCl3) δ 3.79 (3H, s), 3.83 (3H,
= 7.6 Hz), 7.05 (2H, d, J = 8.0 Hz), 7.16–7.29 (6H, m), 7.37 (4H, s), 5.20 (2H, s), 6.90–6.94 (4H, m), 7.20–7.31 (8H, m), 8.25 (1H,
t, J = 7.6 Hz), 8.24 (2H, d, J = 7.6 Hz); 13C NMR (100 MHz, br-d, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 47.5, 50.8, 55.2,
CDCl3) δ 48.4 (2C), 55.3 (4C), 60.7 (2C), 108.1 (4C), 110.4 (2C), 105.4, 110.7, 113.6 (2C), 122.0, 122.2, 123.0, 123.1, 126.0 (2C),
117.8 (2C), 121.2 (2C), 122.2 (2C), 123.5 (2C), 124.9 (2C), 125.1 126.8, 127.4, 128.7 (2C), 131.5 (2C), 136.3, 137.0, 147.2, 160.1,
(4C), 127.3 (2C), 128.4 (2C), 129.2 (4C), 137.5 (2C), 137.7 (2C), 165.7; IR (KBr) 1701, 1686, 1459, 1250, 1149 cm−1; HRMS-EI:
138.2 (2C), 144.0 (2C), 151.9 (4C), 189.5; IR (KBr) 1583, 1496, m/z [M+] calcd for C24H21NO3: 371.1521; found: 371.1521.
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Methyl 1-benzyl-2-(4-(trifluoromethyl)phenyl)-1H-indole-3- 165.7; IR (KBr) 1699, 1542, 1398, 1146, 1108 cm−1; HRMS-EI:
carboxylate (3f). 85% yield (97.4 mg) from 1f (100 mg, m/z [M+] calcd for C25H23NO2: 369.1729; found: 369.1729.
1
0.28 mmol), yellow solid, mp 122–124 °C, H NMR (400. MHz,
Methyl 1-benzyl-1H-indole-3-carboxylate (3s).13b 80% yield
CDCl3) δ 3.78 (3H, s), 5.18 (2H, s), 6.87–6.89 (2H, m), 7.23–7.35 (102.2 mg) from 1s (100 mg, 0.48 mmol).
(6H, m), 7.46 (2H, d, J = 8.0 Hz), 7.66 (2H, d, J = 8.0 Hz), 8.27
(1H, br-d, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 47.6, 51.0,
1
106.2, 110.8, 122.2, 122.6, 123.6, 123.9 (q, JC–F = 270.8 Hz),
Acknowledgements
3
125.0 (2C, q, JC–F = 3.8 Hz), 125.8 (2C), 126.4, 127.7, 128.9
2
(2C), 130.7 (2C), 131.1 (q, JC–F = 32.4 Hz), 135.0, 136.5, 136.6, This work was supported by a JSPS KAKENHI grant (no.
145.1, 165.4; IR (KBr) 1710, 1324, 1149, 1115, 1109 cm−1
;
24590026).
HRMS-EI: m/z [M+] calcd for C24H18 F3NO2: 409.1290; found:
409.1289.
Methyl 1-benzyl-2-(4-fluorophenyl)-1H-indole-3-carboxylate
(3g). 89% yield (105.6 mg) from 1g (100 mg, 0.33 mmol),
yellow solid, mp 106–107 °C, 1H NMR (400 MHz, CDCl3) δ 3.77
(3H, s), 5.17 (2H, s), 6.87–6.89 (2H, m), 7.06–7.10 (2H, m),
7.19–7.32 (8H, m), 8.26 (1H, br-d, J = 8.0 Hz); 13C NMR
Notes and references
1 (a) R. J. Sundberg, Indoles, Academic Press, London, 1996;
(b) A. J. Kochanowska-Karamyan and M. T. Hamann, Chem.
Rev., 2010, 110, 4489; (c) V. Sharma, P. Kumar and
D. Pathak, J. Heterocycl. Chem., 2010, 47, 491; (d) D. F. Taber
and P. K. Tirunahari, Tetrahedron, 2011, 67, 7195.
2 For review, see: N. K. Kaushik, N. Kaushik, P. Attri,
N. Kumar, C. H. Kim, A. K. Verma and E. H. Choi, Mole-
cules, 2013, 18, 6620, and references cited therein.
3 (a) M. Ehrlich and T. Carell, Eur. J. Org. Chem., 2013, 77;
(b) K. Grossmann and T. Ehrhardt, Pest Manage. Sci., 2007,
63, 429; (c) H. Neumann, A. Brennführer and M. Beller,
Chem. – Eur. J., 2008, 14, 3645; (d) F. Jafarpour, P. Rashidi-
Ranjbar and A. O. Kashani, Eur. J. Org. Chem., 2011, 2128;
(e) M. J. Lo Fiego, G. F. Silbestri, A. B. Chopa and
M. T. Lockhart, J. Org. Chem., 2011, 76, 1707; (f) Y.-S. Wu,
M. S. Coumar, J.-Y. Chang, H.-Y. Sun, F.-M. Kuo, C.-C. Kuo,
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2
(100 MHz, CDCl3) δ 47.5, 50.8, 105.9, 110.7, 115.3 (2C, d, JC–F
= 21.0 Hz), 122.1, 122.4, 123.3, 125.9 (2C), 126.6, 127.1 (d, 4JC–F
= 3.9 Hz), 127.6, 128.4 (2C), 128.8 (2C), 132.1 (2C, d, 3JC–F = 8.5
1
Hz), 136.4, 136.7, 145.9, 163.1 (d, JC–F = 247.9 Hz) 165.4; IR
(KBr) 1712, 1227, 1217, 1149, 1121 cm−1; HRMS-EI: m/z [M+]
calcd for C23H18FNO2: 359.1322; found: 359.1320.
Methyl 1-benzyl-2-(4-chlorophenyl)-1H-indole-3-carboxylate
(3h). 87% yield (101.4 mg) from 1h (100 mg, 0.31 mmol), Col-
1
orless solid, mp 126–128 °C, H NMR (400 MHz, CDCl3) δ 3.78
(3H, s), 5.18 (2H, s), 6.87–6.89 (2H, m), 7.22–7.38 (10H, m),
8.26 (1H, br-d, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3) δ 47.5,
50.9, 105.9, 110.7, 122.1, 122.4, 123.3, 125.9 (2C), 126.6, 127.6,
128.4 (2C), 128.8 (2C), 129.6, 131.6 (2C), 135.3, 136.5, 136.7,
145.6, 165.4; IR (KBr) 1709, 1401, 1230, 1149 cm−1; HRMS-EI:
m/z [M+] calcd for C23H18NO2Cl: 375.1026; found: 375.1025.
Methyl 1-benzyl-2-(4-bromophenyl)-1H-indole-3-carboxylate
(3i).13a 83% yield (97.7 mg) from 1i (100 mg, 0.28 mmol).
Methyl 1-benzyl-2-(p-tolyl)-1H-indole-3-carboxylate (3j).13a 90%
yield (108.5 mg) from 1j (100 mg, 0.34 mmol).
Methyl 1-benzyl-2-(4-(tert-butyl)phenyl)-1H-indole-3-carboxy-
late (3k). 84% yield (96.8 mg) from 1k (100 mg, 0.29 mmol),
yellow solid, mp 118–120 °C, 1H NMR (400 MHz, CDCl3) δ 1.35
(9H, s), 3.80 (3H, s), 5.20 (2H, s), 6.92–6.94 (2H, m), 7.19–7.31
(8H, m), 7.41–7.44 (2H, m), 8.24 (1H, br-d, J = 8.0 Hz); 13C
NMR (100 MHz, CDCl3) δ 31.3 (3C), 34.8, 47.6, 50.8, 105.4,
110.8, 122.0, 122.2, 122.9, 125.1 (2C), 126.1 (2C), 126.8, 127.4,
128.0, 128.7 (2C), 129.8 (2C), 136.3, 137.0, 147.6, 152.0, 165.7;
IR (KBr) 2963, 1702, 1687, 1460, 1164, 1149 cm−1; HRMS-EI:
m/z [M+] calcd for C27H27NO2: 397.2042; found: 397.2041.
Methyl 1-benzyl-5-methyl-2-phenyl-1H-indole-3-carboxylate
(3m).13a 85% yield (102.7 mg) from 1m (100 mg, 0.34 mmol).
Methyl 1-benzyl-5,7-dimethyl-2-phenyl-1H-indole-3-carboxy-
late (3n). 78% yield (92.4 mg) from 1n (100 mg, 0.32 mmol),
yellow solid, mp 127–130 °C, 1H NMR (400 MHz, CDCl3) δ 2.42
(3H, br-s), 2.45 (3H, s), 3.71 (3H, s), 5.34 (2H, s), 6.72–6.74 (2H,
m), 6.81 (1H, s), 7.19–7.26 (5H, m), 7.32–7.39 (3H, m), 7.99
(1H, br-s); 13C NMR (100 MHz, CDCl3) δ 19.6, 21.3, 49.1, 50.7,
105.6, 119.6, 121.0, 124.9 (2C), 127.1, 127.9, 127.9 (2C), 128.1,
128.8 (2C), 128.8, 130.0 (2C), 131.7, 131.8, 133.5, 139.1, 147.9,
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