N-acylation of 5-substituted indoles with carboxylic acids via DCC coupling

Article abstract of DOI:10.1055/s-2004-831228

A method for the N-acylation of 5-substituted indoles with carboxylic acids using DCC and DMAP is presented. High yields were obtained when an electron-withdrawing group was present at C-5, however the method was less effective with a C-5 electron-donating group.

Full text of DOI:10.1055/s-2004-831228

PAPER
2653
N-Acylation of 5-Substituted Indoles with Carboxylic Acids via DCC Coupling
N-Acylati
o
on of 5-Subs
h
tituted Indole
n
s
w
ith Carboxylic
B
A
cids via
D
CC
C
.
oupling Bremner,* Siritron Samosorn, Joseph I. Ambrus
Institute for Biomolecular Science and Department of Chemistry, University of Wollongong, N.S.W. 2522, Australia
Fax +61(2)42214287; E-mail: john_bremner@uow.edu.au
Received 28 June 2004
To avoid the use of acid chlorides, direct coupling of car-
Abstract: A method for the N-acylation of 5-substituted indoles
with carboxylic acids using DCC and DMAP is presented. High
yields were obtained when an electron-withdrawing group was
present at C-5, however the method was less effective with a C-5
electron-donating group.
boxylic acids to the indoles was also investigated. The re-
action was trialled with 5-nitro-1H-indole (3), phenyl
acetic acid and boric acid in mesitylene at 185 °C for two
days, based on the method11 of Terashima and Fujioka.
The N-acylated product was only obtained in very low
yield (4%). The second method used a coupling agent12 to
acylate the indoles with carboxylic acids. In this paper the
results of this new direct acylation of indoles with aromat-
ic carboxylic acids using DCC13,14 as the coupling agent
are described.
Key words: N-acylation, indoles, carboxylic acids, DCC coupling,
DMAP
The N-acylation of indoles is a well established reaction
which is used to protect the indolic nitrogen with an acyl
group1,2 which can then be easily removed by base hydro-
lysis,3 and also to provide precursors for intramolecular
cyclization.4 The most common N-acylation method re-
quires the generation of an indole anion (by addition of a
Reaction of the indole 3 with benzoic acid, DCC and
DMAP15 in CH2Cl2 at room temperature for three hours
(Scheme 1) afforded the N-acylated product 13 in high
yield (91%). Previously, 13, a selective cyclooxygenase-2
inhibitor, had been prepared in moderate yield (43%)8
from 3 using benzoyl chloride and K2CO3. A series of oth-
er acylation reactions with indole (1) itself and with 5-
substituted indoles 2–5 were attempted and the results are
shown in Table 1. The N-acylated products of indoles
bearing an electron-withdrawing group at C-5 were ob-
tained in good yields under mild conditions. In the case of
the N-acylated products with benzyloxy substituents
ortho to the acyl group, an increased susceptibility to
cleavage of the amide was noted, however, if the reaction
time was prolonged for more than 8 hours.
8
base, e.g. BuLi,5 NaH,6,7 KOH,7 and K2CO3 ) followed by
nucleophilic attack on an acyl halide. As part of a project
to make 2-arylindole derivatives via intramolecular ring
closure of N-aroylindoles with palladium acetate,9 we in-
vestigated the common acylation method with acid chlo-
rides and strong bases (n-BuLi or NaH) at low
temperature. The desired acid chlorides were not commer-
cially available and hence were synthesized from their ac-
ids using oxalyl chloride under anhydrous conditions.10
The acid chlorides were found to be unstable due to mois-
ture sensitivity and could not be chromatographed, and
thus the yields of the subsequent acylated indolic products
were low.
R
COOH
R1
R
DCC, DMAP
CH2Cl2, r.t.
N
O
+
N
H
2–72 h, 0–95%
R2
R1
R2
(1–5)
(6)
(7–21)
1 R = H
6a R1 = H, R2 = H
7 R = H, R1 = H, R2 = H
15 R = NO2, R1 = OCH3, R2 = H
16 R = F, R1 = H, R2 = H
6b R1 = H, R2 = OCH3
6c R1 = OCH3, R2 = H
6d R1 = OBn, R2 = H
8 R = H, R1 = H, R2 = OCH3
9 R = H, R1 =OCH3, R2 = H
10 R = OCH3, R1 = H, R2 = H
2 R = OCH3
3 R = NO2
4 R = F
17 R = F, R
1 = H, R2 = OCH3
18 R = F, R1 = OCH3, R2 = H
19 R = CN, R1 = OBn, R2 = H
20 R = CN, R1 = OBn-o-OCH3, R2 = H
21 R = CN, R1 = OBn-m-OCH3, R2 = H
6e R1 = OBn-o-OCH3, R2 = H
6f R1 = OBn-m-OCH3, R2 = H
11 R = OCH3, R1 = H, R2 = OCH3
12 R = OCH3, R1 = OCH3, R2 = H
13 R = NO2, R1 = H, R2 = H
5 R = CN
14 R = NO2, R1 = H, R2 = OCH3
Scheme 1 N-acylation of indoles with various carboxylic acids using DCC and DMAP.
SYNTHESIS 2004, No. 16, pp 2653–2658
x
x.
x
x
.
2
0
0
4
Advanced online publication: 22.09.2004
DOI: 10.1055/s-2004-831228; Art ID: P06904SS
© Georg Thieme Verlag Stuttgart · New York

2654
J. B. Bremner et al.
PAPER
Table 1 N-Acylation of Indoles 1–5 with Carboxylic Acids 6a–f
Table 1 N-Acylation of Indoles 1–5 with Carboxylic Acids 6a–f
(continued)
Indole Carboxylic
acid
Product
Yield
(%)
Indole Carboxylic
acid
Product
Yield
(%)
321
3
6a
918
1
6a
O2N
N
O
N
O
(7)
(13)
1
6b
461
3
6b
95
O2N
N
N
O
O
OCH3
OCH3
(8)
(14)
1
6c
34
3
6c
80
O2N
N
N
O
O
H3CO
H3CO
(9)
(15)
2
6a
151
4
4
6a
89
F
H3CO
N
O
N
O
(16)
(10)
6b
87
F
2
6b
9
H3CO
N
N
O
O
OCH3
OCH3
(17)
(11)
4
6c
85
F
2
6c
0
H3CO
N
O
N
O
H3CO
H3CO
(18)
(12)
5
6d
76
NC
N
O
O
(19)
Synthesis 2004, No. 16, 2653–2658 © Thieme Stuttgart · New York

PAPER
N-Acylation of 5-Substituted Indoles with Carboxylic Acids via DCC Coupling
2655
Table 1 N-Acylation of Indoles 1–5 with Carboxylic Acids 6a–f
(continued)
of 15 though the signal for H-7 was overlapped with that
of H-4), whereas it was a sharp doublet signal for products
without the ortho alkoxy substituents in the aryl-acyl moi-
ety. While the reason for this is not clear, it appears to be
associated with partial conformational restriction in the
acylated region of the molecules.
Indole Carboxylic
acid
Product
Yield
(%)
5
5
6e
73
75
NC
OCH3
Thus, reaction of 5-electron withdrawing group substitut-
ed indoles with various aromatic carboxylic acids in the
presence of DCC and DMAP is a viable new approach to
N-acylated indoles. Other advantages of this new method
include mild reaction conditions and convenience as it
avoids the problems associated with the synthesis, isola-
tion and yields that may be encountered using non-com-
mercially available acid chlorides.
N
O
O
(20)
6f
NC
N
O
O
All melting points were determined using a Reichert hot-stage melt-
ing point apparatus and are uncorrected. The 1H and 13C NMR spec-
tra were determined at 300.73 MHz and 75.63 MHz, respectively,
with a Varian Unity-300 spectrometer. Unless otherwise stated, all
spectra were obtained in CDCl3 and referenced to TMS (1H) and
CHCl3 mid-line (77 ppm) (13C). Chemical shifts of the outer peaks
OCH3
(21)
In an attempt to explore the effects of DMAP, DCC and
carboxylic acid concentrations on the reaction outcome,
the nitro indole 3 and 4-methoxybenzoic acid (6b) were
reacted using varying amounts of DMAP (0.1 equivalent
and one equivalent), DCC (1.3 equivalents and two equiv-
alents) and the carboxylic acid (1.3 equivalents and two
equivalents). All reactions gave the product 14 in high
yields (91–97%). However, the N-acylation reaction oc-
curred most rapidly (four hours) when one equivalent of
DMAP was used together with two equivalents each of
DCC and the carboxylic acid. When a catalytic amount of
DMAP (0.1 equiv) was used, together with 1.3 equiva-
lents each of DCC and the carboxylic acid, only a very
slow reaction ensued (72 hours). However, when 0.1
equivalent of DMAP and an excess of DCC and acid (two
equivalents each) were used, the reaction time was re-
duced to six hours.
1
are given for specified multiplet patterns in the H NMR spectra.
Superscript letters in the 1H and 13C NMR data indicate interchange-
able assignments. All assignments were based on standard gradient
correlation spectroscopy (gCOSY), gradient heteronuclear single
quantum correlation (gHSQC) and gradient heteronuclear multiple
bond correlation (gHMBC) spectroscopy. High resolution (EI) MS
(for M+) and High resolution (CI) MS (for MH+) were run using a
VG Autospec spectrometer operating at 70 eV and a source temper-
ature of 250 °C with PFK reference and CH4 as ionising gas in CI
mode. Column chromatography was performed using Merck Kie-
selgel 60 silica gel under medium pressure. All chromatographic
solvent proportions are volume for volume. Reactions were moni-
tored by TLC on Merck silica gel 60 F254 on aluminium sheets and
the compounds were detected by examination under UV light and
by adsorbing with I2 vapour. Solvents were removed under reduced
pressure by rotary evaporation.
Synthesis of the Methyl Benzoate Precursors of Carboxylic Ac-
ids 6d–f; Typical Procedure
Without an electron-withdrawing group at C-5 in the in-
dole, product formation proceeded generally in low
yields, and was not successful in the attempted synthesis
of 12 from 5-methoxy-1H-indole (2) and 2-methoxyben-
zoic acid (6c). Since the methoxy substituent is an elec-
tron-donating group, it would increase electron density
adjacent to the indole nitrogen in the para position, which
reduces the acidity of the indole 2 and hence retards in-
dolide anion formation via reaction with DMAP.
To a solution of methyl salicylate (1.0 mL, 7.7 mmol), cesium car-
bonate (2.61 g, 8.0 mmol) and a catalytic amount of tetrabutylam-
monium iodide in anhyd DMF (30 mL) was added the benzyl halide
(benzyl bromide, 2-methoxybenzyl chloride or 3-methoxybenzyl
bromide) (8.0 mmol). The reaction mixture was heated at 80 °C
with stirring for 5 h. After cooling and filtration, the solvent was re-
moved from the filtrate under reduced pressure to afford a crude
oily residue. Column chromatography (silica gel) using 5% EtOAc
in hexane as eluant gave the methyl ester products.
Methyl 2-Benzyloxybenzoate
The N-acylation reaction was also extended to the prepa-
ration, in moderate yields, of the more hindered benzyl-
oxy substituted derivatives 19–21. The substituted
benzoic acids 6d–f required for the N-acylation reaction
in these cases were prepared in turn from O-alkylation of
the cesium salt of methyl salicylate, followed by methyl
ester hydrolysis in aqueous KOH and subsequent acidifi-
cation.
In the 1H NMR spectra of the ortho alkoxy substituted N-
acylated indoles (9, 15, 18–21) the signal assigned to the
H-7 proton appeared as a broadened multiplet (in the case
Yield: 1.52 g (81%); colourless oil.16
HRMS (CI): m/z [MH+] calcd for C15H15O3: 243.1021; found:
243.1026.
Methyl 2-(2-Methoxybenzyloxy)benzoate
Yield: 2.04 g (97%); mp 69–71 °C.
1H NMR (CDCl3): d = 3.86 (s, 3 H, OCH3), 3.92 (s, 3 H, COOCH3),
5.23 (s, 2 H, CH2), 6.89 (d, J = 8.2 Hz, 1 H, H-3¢), 6.99 (dt, J = 8.1,
1.5 Hz, 1 H, H-5¢), 7.00 (dt, J = 7.5, 0.9 Hz, 1 H, H-4), 7.06 (d, J =
8.4 Hz, 1 H, H-6), 7.28 (dt, J = 8.1, 1.8 Hz, 1 H, H-4¢), 7.44 (ddd,
J = 9.0, 7.5, 1.8 Hz, 1 H, H-5), 7.67 (dd, J = 7.2, 0.9 Hz, 1 H, H-6¢)
7.84 (dd, J = 7.8, 1.8 Hz, 1 H, H-3).
Synthesis 2004, No. 16, 2653–2658 © Thieme Stuttgart · New York

2656
J. B. Bremner et al.
PAPER
Synthesis of N-Acylated Products 7–21; Typical Procedure
13C NMR (CDCl3): d = 51.9 (OCH3), 55.2 (COOCH3), 65.6 (CH2),
109.8 (C3´), 113.7 (C6), 120.3 (C5¢), 120.4 (C2), 120.7 (C4), 125.2
(C1¢), 127.6 (C6¢), 128.4 (C4¢), 131.7 (C3), 133.4 (C5), 156.1 (C2¢),
158.3 (C1), 166.9 (C=O).
HRMS (CI): m/z [MH+] calcd for C16H17O4: 273.1127; found:
273.1131.
To a solution of indoles 1–5 (0.2 mmol), DMAP (0.2 mmol) and
carboxylic acids 6a–f (0.4 mmol) in CH2Cl2 (2 mL) at 0 °C under a
N2 atmosphere, was added a stirred solution of DCC (0.4 mmol) in
CH2Cl2 (1 mL). The solution was then warmed to r.t. and stirred for
2–24 h, except for indoles 1 and 2 with carboxylic acid 6c which
took 72 h each, and was monitored by TLC until no starting material
remained or there was no change in the concentration of acylated
product. The resulting suspension was concentrated in vacuo and
chromatographed on silica gel [5–20% EtOAc in petroleum spirit
(bp 40–60 °C)] to give the N-acylated products (7–11, 16–21). In
the case of indole 3, a different work up procedure was used. After
evaporation of the solvent the residue was treated with MeOH (20
mL), the mixture filtered, and the precipitate then washed with
MeOH and dried to give the desired product (13–15). The filtrate
was concentrated and the residue was recrystallised from MeOH.
Methyl 2-(3-Methoxybenzyloxy)benzoate
Yield: 1.79 g (85%); mp 73–75 °C.
1H NMR (CDCl3): d = 3.82 (s, 3 H OCH3), 3.91 (s, 3 H, COOCH3),
5.16 (s, 2 H, CH2), 6.85 (dd, J = 8.4, 2.4 Hz, 1 H, H-4¢), 6.98 (td,
J = 7.2, 1.5 Hz, 1 H, H-4), 6.99 (d, J = 7.7 Hz, 1 H, H-6¢), 7.06 (d,
J = 7.8, 1 H, H-6), 7.12 (s, 1 H, H-2¢), 7.29 (td, J = 7.5, 2.1 Hz, 1 H,
H-5¢), 7.42 (td, J = 8.1, 1.8 Hz, 1 H, H-5), 7.84 (dd, J = 8.1, 1.8 Hz,
1 H, H-3).
13C NMR (CDCl3): d = 51.9 (COOCH3), 55.1 (OCH3), 70.2 (CH2),
112.1 (C2¢), 113.2 (C4¢), 113.7 (C6¢), 118.7 (C6), 120.4 (C4), 120.6
(C2), 129.4 (C5´), 131.6 (C3), 133.3 (C5), 138.3 (C1´), 157.7
(C3¢)a, 159.9 (C1¢)a, 166.6 (COOCH3).
HRMS (CI): m/z [MH+] calcd for C16H17O4: 273.1127; found:
273.1135.
1-Benzoyl-1H-indole (7)
Yield: 14.0 mg (32%); mp 63–64 °C (Lit.1 59–60 °C).
1-(4-Methoxybenzoyl)-1H-indole (8)
Yield: 23.1 mg (46%); mp 138–139 °C (Lit.1 137–139 °C).
1-(2-Methoxybenzoyl)-1H-indole (9)
Yield: 17.1 mg (34%); pinkish-red glassy solid.
Synthesis of the Carboxylic Acids 6d–f; Typical Procedure
The methyl esters were hydrolyzed using 30% (w/v) aq KOH (2.5
mL) solution in MeOH (40 mL) which was heated at 80 °C for 10
h. After completion of the reaction, the solvent was evaporated to
give a crude residue. Water (40 mL) was added to the residue and 5
M HCl was slowly added to give a pH of 1. The precipitate that
formed was removed by suction filtration and washed with water to
afford the carboxylic acids 6d–f as white powders.
1H NMR (CDCl3): d = 3.79 (s, 3 H, OCH3), 6.55 (dd, J = 3.8, 0.9
Hz, 1 H, H-3), 7.03 (d, J = 8.5 Hz, 1 H, H-3¢), 7.07 (d, J = 3.3 Hz, 1
H, H-2), 7.09 (td, J = 7.3, 0.9 Hz, 1 H, H-5¢), 7.33 (td, J = 7.6, 1.5
Hz, 1 H, H-5), 7.37 (td, J = 7.3, 1.5 Hz, 1 H, H-6), 7.45 (dd, J = 7.6,
1.8 Hz, 1 H, H-6¢), 7.51 (ddd, J = 8.5, 7.3, 1.8 Hz, 1 H, H-4¢), 7.57
(ddd, J = 7.6, 1.5, 0.6 Hz, 1 H, H-4), 8.44 (br d, J = 8.2 Hz, 1 H,
H-7).
13C NMR (CDCl3): d = 55.7 (OCH3), 108.6 (C3), 111.4 (C3¢), 116.5
(C7), 120.7 (C5¢)a, 120.8 (C4)a, 123.9 (C5), 124.8 (C1¢), 124.9 (C6),
127.4 (C2), 129.0 (C6¢), 131.0 (C3a), 132.1 (C4¢), 135.6 (C7a),
156.3 (C2¢), 167.2 (C=O).
HRMS (EI): m/z [M]+ calcd for C16H13NO2: 251.0946; found:
251.0955.
2-Benzyloxybenzoic Acid (6d)
Yield: 1.28 g (73%); mp 78–80 °C (Lit.17 76–78 °C).
2-(2-Methoxybenzyloxy)benzoic Acid (6e)
Yield: 1.73 g (87%); mp 72–74 °C.
1H NMR (CDCl3): d = 3.88 (s, 3 H, OCH3), 5.33 (s, 2 H, CH2), 6.96
(d, J = 8.4 Hz, 1 H, H-3¢), 6.97 (td, J = 8.0, 0.9 Hz, 1 H, H-5¢), 7.13
(td, J = 7.8, 1.2 Hz, 1 H, H-4), 7.19 (d, J = 7.8 Hz, 1 H, H-6), 7.36
(ddd, J = 10.2, 7.8, 1.2 Hz, 1 H, H-4¢), 7.40 (dd, J = 7.8, 1.8 Hz, 1
H, H-6¢), 7.55 (ddd, J = 10.2, 7.2, 1.8 Hz, 1 H, H-5), 8.18 (dd, J =
8.1, 1.8 Hz, 1 H, H-3).
1-Benzoyl-5-methoxy-1H-indole (10)
Yield: 7.7 mg (15%); mp 106–107 °C (Lit.1 109–111 °C).
5-Methoxy-1-(4-methoxybenzoyl)-1H-indole (11)
13C NMR (CDCl3): d = 55.3 (OCH3), 68.4 (CH2), 110.7 (C3¢), 113.4
(C6), 118.2 (C2), 120.6 (C5¢), 122.1 (C4), 122.2 (C1¢), 130.3 (C4¢),
130.8 (C6¢), 133.6 (C3), 134.8 (C5), 157.4 (C2¢), 157.7 (C1), 165.7
(COOH).
Yield: 5.1 mg (9%); mp 105–106 °C.
1H NMR (CDCl3): d = 3.81 (s, 3 H, OCH3), 3.83 (s, 3 H, OCH3),
6.47 (dd, J = 3.8, 0.6 Hz, 1 H, H-3), 6.89–7.00 (m, 4 H, H-4, H-6,
H-3¢), 7.26 (d, J = 3.8 Hz, 1 H, H-2), 7.66 (tt, J = 9.7, 2.7 Hz, 2 H,
H-2¢), 8.18 (d, J = 9.1 Hz, 1 H, H-7).
HRMS (CI): m/z [MH+] calcd for C15H15O4: 259.0971; found:
13C NMR (CDCl3): d = 55.5 (OCH3), 55.7 (OCH3), 103.4 (C6),
108.0 (C3), 113.3 (C4), 113.8 (C3¢), 117.0 (C7), 126.6 (C1¢), 128.4
(C2), 130.8 (C3a), 131.6 (C2¢), 131.6 (C7a), 156.5 (C5), 162.6
(C4¢), 167.9 (C=O).
259.0970.
2-(3-Methoxybenzyloxy)benzoic Acid (6f)
Yield: 1.52 g (76%); mp 52–54 °C.
1H NMR (CDCl3): d = 3.83 (s, 3 H, OCH3), 5.27 (s, 2 H, CH2), 6.91–
6.97 (m, 2 H, H-2¢, H-4¢), 7.01 (d, J = 7.2 Hz, 1 H, H-6¢), 7.12 (d,
J = 8.1 Hz, 1 H, H-6), 7.16 (td, J = 8.7, 0.9 Hz, 1 H, H-4), 7.34 (t,
J = 7.8 Hz, 1 H, H-5¢), 7.56 (ddd, J = 9.3, 7.2, 1.8 Hz, 1 H, H-5),
8.22 (dd, J = 8.1, 1.8 Hz, 1 H, H-3).
HRMS (EI): m/z [M]+ calcd for C17H15NO3: 281.1052; found:
281.1053.
1-Benzoyl-5-nitro-1H-indole (13)
Yield: 48.4 mg (91%); mp 158–159 °C.
13C NMR (CDCl3): d = 55.3 (CH2), 72.0 (OCH3), 113.1 (C6), 113.2
(C4¢)a, 114.6 (C2¢)a, 118.0 (C2), 120.0 (C6¢), 122.4 (C4), 130.3
(C5¢), 133.9 (C3), 135.0 (C5), 135.8 (C1¢), 157.3 (C3¢)b, 160.1
(C1)b, 165.4 (COOH).
HRMS (CI): m/z [MH+] calcd for C15H15O4: 259.0970; found:
259.0970.
1-(4-Methoxybenzoyl)-5-nitro-1H-indole (14)
Yield: 56.1 mg (95%); mp 199–200 °C.
1H NMR (CDCl3): d = 3.92 (s, 3 H, OCH3), 6.76 (d, J = 3.8 Hz, 1 H,
H-3), 7.05 (d, J = 8.8 Hz, 2 H, H-3¢), 7.55 (d, J = 3.8 Hz, 1 H, H-2),
7.77 (dd, J = 7.0, 1.8 Hz, 2 H, H-2¢), 8.25 (dd, J = 9.1, 2.1 Hz, 1 H,
H-6), 8.41 (d, J = 9.1 Hz, 1 H, H-7), 8.54 (d, J = 2.1 Hz, 1 H, H-4).
Synthesis 2004, No. 16, 2653–2658 © Thieme Stuttgart · New York

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N-Acylation of 5-Substituted Indoles with Carboxylic Acids via DCC Coupling
2657
13C NMR (CDCl3): d = 55.6 (OCH3), 108.3 (C3), 114.2 (C3¢), 116.2
(C7), 117.2 (C4), 119.9 (C6), 125.1 (C1¢), 130.4 (C3a), 130.6 (C2),
132.0 (C2¢), 139.1 (C7a), 144.1 (C5), 163.4 (C4¢), 167.9 (C=O).
HRMS (EI): m/z calcd for C16H12N2O4 [M]+: 296.0797; found:
296.0796.
HRMS (EI): m/z [M]+ calcd for C16H12NO2F: 269.0852; found:
269.0854.
1-(2-Benzyloxybenzoyl)-1H-indole-5-carbonitrile (19)
Yield: 53.5 mg (76%); mp 108–109 °C.
1H NMR (CDCl3): d = 5.07 (s, 2 H, CH2), 6.60 (dd, J = 3.8, 0.6 Hz,
1 H, H-3), 7.06–7.10 (m, 3 H, H-3¢¢, H-3¢), 7.13 (td, J = 7.6, 0.9 Hz,
1 H, H-5¢), 7.15–7.22 (m, 3 H, H-2¢¢, H-4¢¢), 7.27 (d, J = 4.1 Hz, 1
H, H-2), 7.51 (d, J = 7.6 Hz, 1 H, H-6¢), 7.52 (td, J = 7.1, 1.8 Hz, 1
H, H-4¢), 7.61 (dd, J = 8.5, 1.5 Hz, 1 H, H-6), 7.90 (d, J = 0.9 Hz, 1
H, H-4), 8.46 (br d, J = 8.8 Hz, 1 H, H-7).
13C NMR (CDCl3): d = 70.4 (CH2), 101.1 (C5), 108.0 (C3), 113.1
(C3¢), 117.0 (C7), 119.6 (CN), 121.4 (C5¢), 124.4 (C1¢), 125.5 (C4),
126.7 (C3¢¢), 128.0 (C2¢¢), 128.0 (C6), 128.4 (C4¢¢), 129.4 (C6¢),
129.6 (C2), 131.0 (C3a), 132.9 (C4¢), 135.8 (C7a)a, 137.3 (C1¢¢)a,
155.5 (C2¢), 167.2 (C=O).
1-(2-Methoxybenzoyl)-5-nitro-1H-indole (15)
Yield: 47.3 mg (80%); mp 144–145 °C.
1H NMR (CDCl3): d = 3.71 (s, 3 H, OCH3), 6.61 (d, J = 3.5 Hz, 1 H,
H-3), 6.98 (d, J = 8.5 Hz, 1 H, H-3¢), 7.05 (t, J = 7.5 Hz, 1 H, H-5¢),
7.17 (d, J = 3.5 Hz, 1 H, H-2), 7.41 (d, J = 7.3 Hz, 1 H, H-6¢), 7.49
(t, J = 7.6 Hz, 1 H, H-4¢), 8.17 (t, J = 9.1 Hz, 1 H, H-6), 8.41–8.46
(m, 2 H, H-4, H-7).
13C NMR (CDCl3): d = 55.7 (OCH3), 108.7 (C3), 111.5 (C3´), 116.5
(C7), 116.9 (C4), 120.1 (C6), 121.0 (C5¢), 123.5 (C1¢), 129.4 (C6¢),
130.3 (C2), 130.9 (C3a), 133.0 (C4¢), 138.5 (C7a), 144.3 (C5),
156.4 (C2¢), 167.2 (C=O).
HRMS (EI): m/z [M]+ calcd for C23H16N2O2: 322.1212; found:
352.1213.
HRMS (EI): m/z [M]+ calcd for C16H12N2O4: 296.0797; found:
296.0804.
1-[2-(2-Methoxybenzyloxy)benzoyl]-1H-indole-5-carbonitrile
(20)
5-Fluoro-1-benzoyl-1H-indole (16)
Yield: 55.8 mg (73%); mp 135–136 °C.
Yield: 42.7 mg (89%); mp 65–66 °C.
1H NMR (CDCl3): d = 3.76 (s, 3 H, OCH3), 5.11 (s, 2 H, CH2), 6.57
(d, J = 3.8 Hz, 1 H, H-3), 6.65 (td, J = 7.6, 0.6 Hz, 1 H, H-5¢¢), 6.97
(d, J = 8.2 Hz, 1 H, H-3¢¢), 6.86 (dd, J = 7.0, 0.9 Hz, 1 H, H-6¢¢), 7.12
(t, J = 7.0 Hz, 1 H, H-5¢), 7.13 (d, J = 7.9 Hz, 1 H, H-3¢), 7.18 (td,
J = 7.9, 1.5 Hz, 1 H, H-4¢¢), 7.27 (d, J = 3.8 Hz, 1 H, H-2), 7.51 (d,
J = 7.6 Hz, 1 H, H-6¢), 7.52 (td, J = 7.6, 1.8 Hz, 1 H, H-4¢), 7.60 (dd,
J = 8.8, 1.8 Hz, 1 H, H-6), 7.88 (d, J = 0.6 Hz, 1 H, H-4), 8.48 (br
d, J = 8.5 Hz, 1 H, H-7).
13C NMR (CDCl3): d = 55.2 (OCH3), 65.5 (CH2), 107.0 (C5), 107.7
(C3), 109.9 (C3¢¢), 113.2 (C3¢), 117.0 (C7), 119.7 (CN), 120.3
(C5¢¢), 121.2 (C5¢), 124.2 (C1¢)a, 124.2 (C1¢¢), 125.4 (C4), 127.5
(C6¢¢), 127.9 (C6), 128.8 (C4¢¢), 129.4 (C6¢), 129.7 (C2), 131.9
(C3a), 132.9 (C4¢), 137.3 (C7a), 155.6 (C2¢¢)b, 156.2 (C2¢)b, 167.2
(C=O).
1H NMR (CDCl3): d = 6.50 (d, J = 3.8 Hz, 1 H, H-3), 7.03 (td, J =
9.1, 2.3 Hz, 1 H, H-6), 7.18 (dd, J = 8.8, 2.6 Hz, 1 H, H-4), 7.25 (d,
J = 3.8 Hz, 1 H, H-2), 7.46 (tt, J = 8.5, 1.5 Hz, 2 H, H-3¢), 7.54 (tt,
J = 6.2, 1.2 Hz, 1 H, H-4¢), 7.65 (dd, J = 8.8, 1.8 Hz, 2 H, H-2¢), 8.31
(dd, J = 9.1, 5.3 Hz, 1 H, H-7).
13C NMR (CDCl3): d = 106.4 (d, J = 23.9 Hz, C4), 108.2 (d, J = 4.0
Hz, C3), 112.7 (d, J = 24.8 Hz, C6), 117.4 (d, J = 9.2 Hz, C7), 128.6
(C3¢), 129.1 (C2), 129.1 (C2¢), 131.7 (d, J = 10.1 Hz, C3a), 132.0
(C4¢), 132.4 (C1¢), 134.2 (C7a), 159.8 (d, J = 240.4 Hz, C5), 168.5
(C=O).
HRMS (EI): m/z [M]+ calcd for C15H10NOF: 239.0746; found:
239.0738.
5-Fluoro-1-(4-methoxybenzoyl)-1H-indole (17)
Yield: 47.0 mg (87%); mp 133–135 °C.
HRMS (EI): m/z [M]+ calcd for C24H18N2O3: 382.1317; found:
382.1315.
1H NMR (CDCl3): d = 3.91 (s, 3 H, OCH3), 6.57 (d, J = 3.8, 0.9 Hz,
1 H, H-3), 7.02 (dt, J = 9.4, 2.6 Hz, 2 H, H-3¢), 7.09 (td, J = 9.1, 2.6
Hz, 1 H, H-6), 7.25 (dd, J = 8.5, 2.3 Hz, 1 H, H-4), 7.40 (d, J = 3.8
Hz, 1 H, H-2), 7.74 (dt, J = 9.7, 2.9 Hz, 2 H, H-2¢), 8.32 (ddd, J =
9.3, 4.8, 0.6 Hz, 1 H, H-7).
13C NMR (CDCl3): d = 55.5 (OCH3), 106.3 (d, J = 23.9 Hz, C4),
107.7 (d, J = 3.7 Hz, C3), 112.5 (d, J = 25.0 Hz, C6), 113.9 (C3¢),
117.2 (d, J = 9.2 Hz, C7), 126.2 (C1¢), 129.2 (C2), 131.5 (C3a),
131.7 (C2¢), 132.5 (C7a), 159.7 (d, J = 239.9 Hz, C5), 162.8 (C4¢),
168.0 (C=O).
1-[2-(3-Methoxybenzyloxy)benzoyl]-1H-indole-5-carbonitrile
(21)
Yield: 57.3 mg (75%); mp 117–118 °C.
1H NMR (CDCl3): d = 3.58 (s, 3 H, CH3), 5.05 (s, 2 H, CH2), 6.59
(dd, J = 3.8, 0.9 Hz, 1 H, H-3), 6.61 (s, 1 H, H-2¢¢), 6.68 (d, J = 7.3
Hz, 1 H, H-6¢¢), 6.74 (dd, J = 8.2, 2.6 Hz, 1 H, H-4¢¢), 7.01–7.15 (m,
3 H, H-3¢, H-5¢, H-5¢¢), 7.27 (d, J = 3.8 Hz, 1 H, H-2), 7.50 (dd, J =
7.6, 1.8 Hz, 1 H, H-6¢), 7.52 (td, J = 7.3, 1.8 Hz, 1 H, H-4¢), 7.60
(dd, J = 8.5, 1.5 Hz, 1 H, H-6), 7.88 (dd, J = 1.8, 0.6 Hz, 1 H, H-4),
8.49 (br d, J = 8.8 Hz, 1 H, H-7).
HRMS (EI): m/z [M]+ calcd for C16H12NO2F: 269.0852; found:
13C NMR (CDCl3): d = 54.9 (OCH3), 70.2 (CH2), 107.1 (C5), 108.0
(C3), 111.8 (C2¢¢), 113.1 (C3¢), 113.5 (C4¢¢), 117.0 (C7), 118.7
(C6¢¢), 119.6 (CN), 121.4 (C5¢), 124.3 (C1¢), 125.5 (C4), 128.0 (C6),
129.3 (C5¢¢)a, 129.4 (C6¢)a, 129.6 (C2), 130.9 (C3a), 132.8 (C4¢),
137.2 (C1¢¢)b, 137.4 (C7a)b, 155.4 (C2¢), 159.7 (C3¢¢), 167.2 (C=O).
HRMS (EI): m/z [M]+ calcd for C24H18N2O3: 382.1317; found:
382.1305.
269.0854.
5-Fluoro-1-(2-methoxybenzoyl)-1H-indole (18)
Yield: 45.7 mg (85%); mp 100–101 °C.
1H NMR (CDCl3): d = 3.79 (s, 3 H, CH3), 6.50 (d, J = 3.8 Hz, 1 H,
H-3), 7.01–7.12 (m, 4 H, H-3¢, H-5¢, H-2, H-6), 7.22 (dd, J = 8.2,
2.1 Hz, 1 H, H-4), 7.44 (dd, J = 7.3, 2.3 Hz, 1 H, H-6¢), 7.51 (td,
J = 8.5, 1.8 Hz, 1 H, H-4¢), 8.44 (bdd, J = 8.8, 4.7 Hz, 1 H, H-7).
13C NMR (CDCl3): d = 55.6 (OCH3), 106.3 (d, J = 23.9 Hz, C4),
108.2 (d, J = 4.0 Hz, C3), 111.4 (C3¢), 112.4 (d, J = 24.8 Hz, C6),
117.5 (d, J = 9.2 Hz, C7), 120.8 (C5¢), 124.4 (C1¢), 128.9 (C6¢)a,
129.1 (C2)a, 131.9 (C3a)b, 132.0 (C7a)b, 132.3 (C4¢), 156.3 (C2¢),
159.8 (d, J = 240.1 Hz, C5), 167.0 (C=O).
Acknowledgement
We wish to thank the University of Wollongong, Australia and Sri-
nakharinwirot University, Thailand for supporting this work. The
award of an APA scholarship (Joseph Ambrus) and UPA/IPRS
scholarships (Siritron Samosorn) are also gratefully acknowledged.
Synthesis 2004, No. 16, 2653–2658 © Thieme Stuttgart · New York

2658
J. B. Bremner et al.
PAPER
(10) Okumura, M.; Maekawa, Y.; Mizuno, H.; Yagiyu, O. EP
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Synthesis 2004, No. 16, 2653–2658 © Thieme Stuttgart · New York