Synthesis of 5-acylindoles via regioselective acylation of 3-trifluoroacetylindole

Article abstract of DOI:10.1055/s-2003-40864

5-Acylindoles were synthesized by regioselective acylation of 3-trifluoroacetylindole with acyl chloride under the catalysis of Lewis acids, followed by hydrolysis of trifluoroacetyl and decarboxylation. Polar solvents were beneficial to the acylation and most of the Lewis acids tested showed good catalytic activities.

Full text of DOI:10.1055/s-2003-40864

LETTER
1447
Synthesis of 5-Acylindoles via Regioselective Acylation of
3-Trifluoroacetylindole
Synthesis
u
of 5-Acylind
n
ole
s
via
R
egioselec
L
tive
A
cylationiof 3-T a,b
r
ifluoroacetylindole Bogang Li,a Xiaozhen Chen,a Guolin Zhang*a
a
Chengdu Institute of Biology, the Chinese Academy of Sciences, Chengdu 610041, P. R. China
b
Chengdu Institute of Organic Chemistry, the Chinese Academy of Sciences, Chengdu 610041, P. R. China
Fax +86(28)85225401; E-mail: zhanggl@cib.ac.cn
Received 4 June 2003
It was reported that trifluoroacetyl group was easy to be
introduced onto C-3 of indole13 and easy to be re-
moved.14,15 Considering the easy deprotection of trifluoro-
acetyl group and its strong electron-withdrawing ability,
the Friedel–Crafts acylation of 3-trifluoroacetylindole
was investigated in this communication and highly selec-
tive C-5 acylation was realized (Scheme 1).
Abstract: 5-Acylindoles were synthesized by regioselective acyla-
tion of 3-trifluoroacetylindole with acyl chloride under the catalysis
of Lewis acids, followed by hydrolysis of trifluoroacetyl and decar-
boxylation. Polar solvents were beneficial to the acylation and most
of the Lewis acids tested showed good catalytic activities.
Key words: regioselectivity, acylation, 3-trifluoroacetylindole, 5-
acylindole-3-carboxylic acid, 5-acylindole
COCF3
ROC
Indole and its derivatives have been a topic of research in
organic synthesis for over a century because of their im-
portant biological activities.1–3 The presence of functional
groups at C-5 was necessary for the bioactivities of many
indole compounds.4,5 Friedel–Crafts acylation is one of
the most outstanding methods to introduce functional
groups onto indole. C-3 is the normal attack site for acy-
lation, when it is unsubstituted.6 So, in order to selectively
introduce acyl groups to benzene moiety of indole, C-3
should be protected or its reactivity should be decreased.
3a–g
N
COCF3
RCOCl (2a–g)
H
+
+
COCF3
Lewis acids
N
H
Solvents, r.t.
4a, 4b, 4g
N
H
1
ROC
COCF3
a: R=CH3
b: R=ClCH2
c: R=CH3CH2CH2 d: R=(CH3)2CH
5a
e: R=C6H5
f: R=p-CH3C6H4
N
H
g: R=p-NO2C6H4
The acylation of 1-acylindoles was firstly reported to give
C-3 and/or C-6 acylated derivatives according to the acy-
lating agents.7,8 When ethoxycarbonyl or other relative
groups were introduced to C-2 of indole, C-5 could be
acylated, but in many cases, 3-acylindoles were the major
products. Only chloroacetic chloride could give relatively
higher C-5 selectivity, but the yield was not satisfactory
(yieldtotal = 63%, C-3/C-5/C-7 = 1:86:13).9,10 3-Acetylin-
dole and ethyl 3-indolecarboxylate were reported to be
acetylated to give C-5, C-6 and C-7 acetylated products.
The C-5 selectivity and total yield were not adequate.
During the process of deprotection of acetyl group at C-3,
the acetyl group on phenyl ring was also turned into car-
boxyl group. In most cases, the acyl group on phenyl ring
was usually expected to be kept.11 When C-3 was protect-
ed by formyl group, acylation could give C-5 isomer as
main product, but the selectivity was still not significant
(C-5/C-6 = 73:27 to 80:20) and the deprotection of the
formyl group involved reduction catalyzed by Pd/C,
which may reduce some groups on indole ring.12 Because
of the low C-5 selectivity and the difficulty in separating
C-5 and C-6 acylated isomers in some cases, highly regio-
selective acylation at C-5 of indole is still a challenge.
COR
Scheme 1 Friedel–Crafts acylation of 3-trifluoroacetylindole (1)
Firstly, we investigated the effects of solvents on this
Friedel–Crafts acetylation and found that polar solvents,
such as nitrobenzene and nitromethane, benefited the re-
action, whereas non-polar solvents are unsuitable for the
acylation. It seems that nitromethane is a much better sol-
vent in terms of conversion, C-5 selectivity and total
yield. It could be explained that the stabilization of polar
solvent on transition states and reaction intermediates
(carbonyl cation) played an important role on these reac-
tions. On the other hand, the acetylation of 1 with 2a could
be catalyzed at room temperature by many Lewis acids,
such as AlCl3, FeCl3, SnCl4, ZnCl2, TiCl4 and so on.
Among them, AlCl3 gave the highest C-5 selectivity and
total yields (3a: 62%, 4a: 24%, and 5a: 11%).16
In view of the best effect of AlCl3/CH3NO2, this system
was adapted in the acylation of 1 with different acyl chlo-
ride (2b–g) and the results were listed in Table 1.17 When
1 was acylated by 2b, only 3b was produced, but its yield
was not satisfactory (28%, entry 1). In our screening of
bioactivities, 3b showed strong cytotoxic activities
against Bre-04, N-04 and Lu-04 cell lines with GI50 values
1.04, 0.80 and 2.57 mgmL–1 successively. Compound
3b was also a very important intermediate to synthesize
5-hydroxylindoles,18 or the analogues of bisindolylmeth-
Synlett 2003, No. 10, Print: 05 08 2003.
Art Id.1437-2096,E;2003,0,10,1447,1450,ftx,en;U10303ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1448
J. Li et al.
LETTER
Table 1 The Acylation of 1 with Different Acyl Chlorides at Room
Temperature
Table 2 The Results of Deprotection of 5-Acyl-3-trifluoroacetylin-
dole 3a–g
Entry Acylating chloride Conversion (%)d
No. R
3 (%)e 4 (%)e
Entry
Compounds 6/Yield
Decarboxylation con- 7/Yield
(%)a
ditionsb
(%)a
86
–
a
1
2
3
4
5
6
7
2b ClCH2
2b ClCH2
30 (25 h)
100 (3 h)
83 (17 h)
53 (17 h)
58 (16 h)
50 (16 h)
56 (16 h)
28
86
63
26
58
50
43
0
4
0
0
0
0
6
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
98
–
155 °C, 120 min
–
b
a
2c CH3CH2CH2
2d (CH3)2CH a
97
74
98
99
–
150 °C, 45 min
160 °C, 90 min
155 °C, 60 min
150 °C, 45 min
–
93
95
93
79
–
a
2e C6H5
a
2f p-CH3C6H4
c
2g p-O2NC6H4
3g
a Carried out in AlCl3/MeNO2.
a Isolated yields.
b 4 Mol% of cupric salt of 6 was used as catalyst.
b Carried out in ionic liquid [MeBuIm]Cl–AlCl3.
c Carried out in FeCl3/MeNO2.
d Based on the recovery of 1.
e Isolated yields.
In conclusion, regioselective Friedel–Crafts acylation at
C-5 of indole was succeeded under the catalysis of Lewis
acids by protecting C-3 with trifluoroacetyl group, which
could be removed by hydrolysis, followed by decarboxy-
lation. Ionic liquid, MeBuImCl–AlCl3 (molar fraction
anone which could inhibit autophosphorylation of plate-
let-derived growth factor (PDGF) receptor tyrosine kinase
in intact cells.19 When the acylation of 1 with 2b was
carried out in ionic liquid 1-methyl-3-butylimidazolium
chloride-aluminium chloride (MeBuImCl–AlCl3, molar
fraction XAlCl3 = 0.67), the yield of 3b could reach up to
86% and only 4% of 4b was isolated (entry 2).20 The se-
lectivity and yield of C-5 were much better than the previ-
ously reported.11,12 However, this ionic liquid showed no
advantages over AlCl3/CH3NO2 for acylation of 1 with
other acyl chlorides investigated. Compound 1 could be
selectively acylated at C-5 by 2c–f under the catalysis of
AlCl3 in nitromethane (entries 3–6). However, AlCl3 gave
complex products when 1 reacted with 2g. FeCl3 could
overcome the drawback and gave high C-5 selectivity (en-
try 7, 3g: 43%, 4g: 6%). Except the acetylation, all other
acylation of 1 did not produce 7-acylated isomers.
X
AlCl3 = 0.67), as solvent and catalyst, is favorable to the
acylation of 3-trifluoroacetylindole by chloroacetic chlor-
ide with respect to conversion, total yield and C-5 selec-
tivity.
Acknowledgment
The authors thank Di-Ao Pharmaceutical Group for partial analyti-
cal support.
References
(1) Hibino, S.; Choshi, T. Nat. Prod. Rep. 2002, 19, 148.
(2) Steele, J. C. P.; Veitch, N. C.; Kite, C. G.; Simmonds, M. S.
J.; Warhurst, D. C. J. Nat. Prod. 2002, 65, 85.
(3) Austin, J. F.; Macmillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 1172.
(4) Szmuszkovicz, J.; Anthony, W. C. J. Org. Chem. 1960, 25,
857.
(5) Nicolaou, I.; Zaher, N.; Demopoulos, V. J. Org. Prep.
Proced. Int. 2002, 34, 501.
(6) Sundberg, R. J. Indoles; Academic Press: London, 1996.
(7) Nakatsuka, S.; Teranishi, K.; Goto, T. Tetrahedron Lett.
1994, 35, 2699.
(8) Cruz, R. P. A.; Ottoni, O.; Abella, C. A. M.; Aquino, L. B.
Tetrahedron Lett. 2001, 42, 1467.
Deprotection of trifluoroacetyl group in 3 was carried out
as shown in Scheme 2. Except 3b and 3g, all acylated 3-
trifluoroacetylindole (3a, 3c–f) were converted into their
corresponding carboxylic acids 6 by treating 3 with 4.4 M
KOH (aq) at reflux, followed by adjusting pH value to
5–6 with 5.5 M HCl (aq).21 In fact, the chloroacetyl group
on 3b and nitro group on 3g could firstly be converted into
other expected groups and then trifluoroacetyl group may
be removed as Scheme 2.22 When 6 and 4 mol% of its
cupric(II) salt were heated in quinoline at certain tempare-
ture (150–160 °C), decarboxylation could take place to
give 7 with high yields (Table 2).15
(9) Murakami, Y.; Tani, M.; Tanaka, K.; Yokoyama, Y. Chem.
Pharm. Bull. 1988, 36, 2023.
COCF3
COOH
ROC
ROC
H+
ROC
4 mol% of cupric (II)
salt of 6 in quinoline
4.4 M KOH (aq)
reflux
pH 5–6
N
H
N
H
N
H
3a, 3c–f
7a, 7c–7f
6a, 6c–6f
Scheme 2 Deprotection of 5-acyl-3-trifluoroacetylindole (3a–3g)
Synlett 2003, No. 10, 1447–1450 © Thieme Stuttgart · New York

LETTER
Synthesis of 5-Acylindoles via Regioselective Acylation of 3-Trifluoroacetylindole
1449
(10) Tani, M.; Aoki, T.; Ito, S.; Matsumoto, S.; Hideshima, M.;
Fukushima, K.; Nozawa, R.; Maeda, T.; Tashiro, M.;
Yokoyama, Y.; Murakami, Y. Chem. Pharm. Bull. 1990, 38,
3261.
(11) Hino, T.; Torisawa, Y.; Nakagawa, M. Chem. Pharm. Bull.
1982, 30, 2349.
(12) Demopoulos, V. J.; Nicolaou, I. Synthesis 1998, 1519.
(13) Heidi, L. H.; Richard, M. S.; Gordon, W. G. Tetrahedron
Lett. 1998, 39, 3095.
(14) Barduhn, A. J.; Kobe, K. A. J. Chem. Soc. 1954, 1651.
(15) Piers, E.; Brown, R. K. Can. J. Chem. 1962, 40, 559.
(16) Friedel–Crafts Acylation of 3-Trifluoroacetylindole (1);
General Procedure: To an ice cold solution of 1 (0.107 g,
0.5 mmol) in nitromethane (4 mL) was added acyl chloride
(2, 1.5 mmol) under a N2 atmosphere, and the mixture was
stirred for 15 min. Then AlCl3 (0.2 g, 1.5 mmol) was rapidly
added and the reaction proceeded 4 h at r.t. To the reaction
mixture H2O (5 mL) was added to quench the reaction.
Nitromethane was removed under reduced pressure. The
residue was resolved in EtOAc (30 mL) and washed with sat.
aq NaHCO3 solution (three times) and NaCl solution(twice).
The organic layer was dried over Na2SO4 and evaporated
under reduced pressure to give a solid residue, which was
purified by silica gel column chromatography with
petroleum ether/acetone or petroleum ether/EtOAc as eluent
to afford the acylated products.
5-(n-Butyryl)-3-trifluoroacetylindole (3c): Mp 185–186
°C (petroleum ether:acetone = 7:1). ESI-MS (negative
mode): m/z = 282 [(M – 1)–], 283 [(M)–]. IR (KBr): 3230,
2966, 1664, 1638, 1524, 1439, 1380, 1205, 1139, 1077, 897
cm–1. 1H NMR (400 MHz, CD3COCD3): d = 11.85 (br s, 1
H, N-H), 8.98 (dd, 1 H, J = 1.6 Hz, 0.8 Hz, H-4), 8.54 (br s,
1 H, H-2), 8.03 (dd, 1 H, J = 8.4 Hz, 1.6 Hz, H-6), 7.72 (dd,
1 H, J = 8.4 Hz, 0.8 Hz, H-7), 3.10 (t, 2 H, J = 7.2 Hz, CH2),
1.77 (m, 2 H, J = 7.6 Hz, 7.2 Hz, CH2), 1.02 (t, 3 H, J = 7.6
Hz, CH3).
5-(iso-Butyryl)-3-trifluoroacetylindole (3d): Mp 169–170
°C (petroleum ether:EtOAc = 6:1). ESI-MS (negative
mode): m/z = 282 [(M – 1)–], 283 [(M)–]. IR (KBr): 3249,
2975, 1659, 1615, 1525, 1465, 1385, 1345, 1276, 1138,
1075, 897 cm–1. 1H NMR (400 MHz, CD3COCD3): d = 11.86
(br s, 1 H, N-H), 8.98 (dd, 1 H, J = 1.6 Hz, 0.8 Hz, H-4), 8.55
(m, 1 H, H-2), 8.03 (dd, 1 H, J = 8.4 Hz, 1.6 Hz, H-6), 7.74
(dd, 1 H, J = 8.4 Hz, 0.8 Hz, H-7), 3.78 (m, 1 H, CH), 1.21
(d, 6 H, J = 7.2 Hz, CH3).
5-Benzoyl-3-trifluoroacetylindole (3e): Mp 207–208 °C
(petroleum ether:EtOAc = 6:1). ESI-MS (negative mode):
m/z = 316 [(M – 1)–], 317 [(M)–]. IR (KBr): 3219, 3056,
2941, 1645, 896, 712 cm–1. 1H NMR (500 MHz,
CD3COCD3): d = 11.91 (br s, 1 H, N-H), 8.76 (d, 1 H, J = 1.5
Hz, H-4), 8.56 (br d, 1 H, J = 1.5 Hz, H-2), 7.87 (dd, 1 H,
J = 8.0 Hz, 1.5 Hz, H-6), 7.82 (d, 2 H, J = 7.5 Hz, H-2¢ and
H-6¢ in phenyl), 7.79 (d, 1 H, J = 8.5 Hz, H-7), 7.67 (td, 1 H,
J = 7.5, 1.5 Hz, H-4¢ in phenyl), 7.57 (t, 2 H, J = 7.5 Hz, H-
3¢ and H-5¢ in phenyl).
(17) Acylated Indole Compounds:
A mixture of 5-acetyl-3-trifluoroacetylindole (3a) and 6-
acetyl-3-trifluoroacetylindole (4a) (72:28) was obtained by
chromatography in total yield 85%. Recrystallization of the
mixture from EtOAc resulted in pure 3a, but pure 4a could
not be obtained.
Compound 3a: Mp 195–196 °C (EtOAc). ESI-MS (negative
mode): m/z = 254 [(M – 1)–], 255 [(M)–]. IR (KBr): 3222,
1676, 1642, 1439, 1376, 1276, 1190, 1142, 896 cm–1. 1H
NMR (400 MHz, CD3COCD3): d = 11.86 (br s, 1 H, N-H),
8.97 (dd, 1 H, J = 2.0 Hz, 0.8 Hz, H-4), 8.54 (m, 1 H, H-2),
8.02 (dd, 1 H, J = 8.8 Hz, 2.0 Hz, H-6), 7.73 (dd, 1 H, J = 8.8
Hz, 0.8 Hz, H-7), 2.68 (s, 3 H, CH3).
5-(4¢-Methylbenzoyl)-3-trifluoroacetylindole (3f): Mp
225 °C (petroleum ether:acetone = 6:1). ESI-MS (negative
mode): m/z = 330 [(M – 1)–], 331 [(M)–]. IR (KBr): 3363,
2925, 1679, 1642, 1604, 1525, 1437, 1312, 1288, 1192,
1142, 891, 758 cm–1. 1H NMR (500 MHz, CD3COCD3): d =
11.90 (br s, 1 H, N-H), 8.74 (d, 1 H, J = 1.5 Hz, H-4), 8.55
(m, 1 H, H-2), 7.85 (dd, 1 H, J = 8.5 Hz, 1.5 Hz, H-6), 7.78
(d, 1 H, J = 8.5 Hz, H-7), 7.73 (dd, 2 H, J = 7.5 Hz, 1.5 Hz,
H-2¢ and H-6¢ in phenyl), 7.38 (dd, 2 H, J = 7.5 Hz, 1.5 Hz,
H-3¢ and H-5¢ in phenyl), 3.45 (s, 3 H, CH3).
Compound 4a: The 1H NMR data of 4a came from the 1H
NMR spectra of the mixture of 3a and 4a. 1H NMR (400
MHz, CD3COCD3): d = 11.92 (br s, 1 H, N-H), 8.61 (m, 1 H,
H-2); 8.37 (dd, 1 H, J = 8.8 Hz, 0.8 Hz, H-4), 8.29 (dd, 1 H,
J = 2.0 Hz, 0.8 Hz, H-7), 8.02 (dd, 1 H, J = 8.8 Hz, 2.0 Hz,
H-5), 2.66 (s, 3 H, CH3).
7-Acetyl-3-trifluoroacetylindole (5a): Mp 173–174 °C
(petroleum ether:EtOAc = 6:1). ESI-MS (negative mode):
m/z = 254 [(M – 1)–], 255 [(M)–]. IR (KBr): 3312, 2924,
1674, 1658, 1521, 1431, 1364, 1269, 1198, 895 cm–1. 1H
NMR (400 MHz, CD3COCD3): d = 12.03 (br s, 1 H, N-H),
8.56 (dd, 1 H, J = 8.0 Hz, 0.8 Hz, H-4), 8.41 (m, 1 H, H-2),
8.09 (dd, 1 H, J = 8.0 Hz, 0.8 Hz, H-6), 7.49 (t, 1 H, J = 8.0
Hz, H-5), 2.73 (s, 3 H, CH3).
5-Chloroacetyl-3-trifluoroacetylindole (3b): Mp 231–232
°C (petroleum ether:acetone = 5:1); ESI-MS (negative
mode): m/z = 288 [(M – 1)–], 290 [(M + 1)–]. IR (KBr): 3238,
2924, 1684, 1667, 1139, 895 cm–1. 1H NMR (500 MHz,
CD3COCD3): d = 11.92 (br s, 1 H, N-H), 8.98 (s, 1 H, H-4),
8.56 (s, 1 H, H-2), 8.03 (dd, 1 H, J = 8.5 Hz, 2.0 Hz, H-6),
7.77 (d, 1 H, J = 8.5 Hz, H-7), 5.10 (s, 2 H, CH2).
6-Chloroacetyl-3-trifluoroacetylindole (4b): Mp 198–199
°C (petroleum ether:acetone = 5:1). ESI-MS (negative
mode: m/z = 288 [(M – 1)–], 290 [(M + 1)–]. IR (KBr): 3315,
2925, 1674, 1446, 1269, 1147, 892, 728 cm–1. 1H NMR (400
MHz, CD3COCD3): d = 12.02 (br s, 1 H, N-H), 8.63 (m, 1 H,
H-2), 8.40 (dd, 1 H, J = 8.4 Hz, 0.4 Hz, H-4), 8.34 (dd, 1 H,
J = 1.6 Hz, 0.4 Hz, H-7), 8.04 (dd, 1 H, J = 8.4 Hz, 1.6 Hz,
H-5), 5.09 (s, 2 H, CH2).
5-(4¢-Nitrobenzoyl)-3-trifluoroacetylindole (3g): The
acylation of 1 with p-nitrobenzoyl chloride was catalyzed by
FeCl3 in nitromethane. The operation was the same as the
acetylation catalyzed by AlCl3.
Compound 3g: Mp 237–238 °C (petroleum
ether:acetone = 6:1). ESI-MS (negative mode): m/z = 361
[(M – 1)–], 362 [(M)–]. IR: 3222, 3055, 1651, 1619, 1521,
1435, 1193, 900, 849, 729, 687 cm–1. 1H NMR (500 MHz,
CD3COCD3): d = 11.97 (br s, 1 H, N-H), 8.75 (d, 1 H, J = 1.5
Hz, H-4), 8.59 (br d, 1 H, J = 1.0 Hz, H-2), 8.43 (dt, 2 H,
J = 9.0 Hz, 2.0 Hz, H-3¢ and H-5¢ in phenyl), 8.05 (dt, 2 H,
J = 9.0 Hz, 2.0 Hz, H-2¢ and H-6¢ in phenyl), 7.91 (dd, 1 H,
J = 9.0 Hz, 1.5 Hz, H-6), 7.82 (d, 1 H, J = 9.0 Hz, H-7).
6-(4¢-Nitrobenzoyl)-3-trifluoroacetylindole (4g): Mp 250
°C (petroleum ether:acetone = 6:1). ESI-MS (negative
mode): m/z = 361 [(M – 1)–], 362 [(M)–]. IR (KBr): 3358,
3129, 1656, 1617, 1521, 1350, 1283, 1193, 885, 848, 719
cm–1. 1H NMR (500 MHz, CD3COCD3): d = 11.92 (br s, 1
H, N-H), 8.64 (br d, 1 H, J = 1.5 Hz, H-2), 8.43 (d, 1 H,
J = 8.5 Hz, H-4), 8.42 (dt, 2 H, J = 8.5 Hz, 2.0 Hz, H-3¢ and
H-5¢ in phenyl), 8.14 (d, J = 1.5 Hz, H-7), 8.05 (dt, 2 H,
J = 8.5 Hz, 2.0 Hz, H-2¢ and H-6¢ in phenyl), 7.86 (dd, 1 H,
J = 8.5 Hz, 1.5 Hz, H-5).
(18) Nakatsuka, S.; Asano, O.; Uea, K.; Goto, T. J. Heterocycles
1987, 26, 1471.
(19) Mahboobi, S.; Teller, S.; Pongratz, H.; Hufsky, H.; Sellmer,
A.; Botzki, A.; Uecker, A.; Beckers, T.; Baasner, S.;
Schachtele, C.; Uberall, F.; Kassack, M. U.; Dove, S.;
Bohmer, F.-D. J. Med. Chem. 2002, 45, 1002.
Synlett 2003, No. 10, 1447–1450 © Thieme Stuttgart · New York

1450
J. Li et al.
LETTER
(20) The acylation of 1 with chloroacetyl chloride catalyzed by
ionic liquid produced not only 5-acylated product 3b but also
6-acylated isomer 4b. The procedure was as follows: The
mixture of 1-methyimidazole (5 mL, 0.062 mol) and excess
n-butyl chloride (15 mL) was stirred at reflux for 24 h under
a N2 atmosphere. Superfluous n-butyl chloride was
evaporated under reduced pressure to give 8.96 g of
1-methyl-3-butylimidazolium chloride (MeBuImCl),
yield = 82%. A dry flask was charged with 2.62 g of
MeBuImCl (15 mmol). With vigorous stirring AlCl3 (4 g, 30
mmol) was added to the flask in four portions under a N2
atmosphere and a liquid formed (MeBuImCl–AlCl3). When
the ionic liquid was cooled to r.t., 1 (0.107 g, 0.5 mmol) was
then dissolved in the ionic liquid, followed by adding
chloroacetyl chloride (2b, 1.5 mmol). Stirring was continued
for another 3 h and H2O was added slowly to quench the
reaction. The mixture was extracted by EtOAc. The
following work-up was the same as that of acetylation of 1
catalyzed by AlCl3. The residue was chromatographed on a
silica gel colum with 5:1 petroleum ether:acetone to result in
3b (yield = 86%) and 4b (yield = 4%).
(negative mode): m/z = 278 [(M – 1)–], 279 [(M)–]. IR (KBr):
3423, 3187, 2924, 1662, 1530, 1454, 1292, 1198, 1130, 759
cm–1. 1H NMR (600 MHz, DMSO-d6): d = 12.21 (s, 1 H, -
COOH), 12.08 (br s, 1 H, N-H), 8.42 (br s, 1 H, H-4), 8.16
(d, 1 H, J = 2.4 Hz, H-2), 7.65 (d, 3 H, J = 7.8 Hz, H-6 and
H-2¢ and H-6¢ in phenyl), 7.61 (d, 1 H, J = 8.4 Hz, H-7), 7.38
(d, 2 H, J = 7.8 Hz, H-3¢ and H-5¢ in phenyl), 2.42 (s, 3 H,
CH3).
(22) Decarboxylation; General Procedure:
Quinoline (0.5 mL), 6 (0.5 mmol) and its cupric salt (0.02
mmol) were added to a flask fitted with a magnetic bar and
a reflux condenser connected to an oil bubbler. The mixture
was heated until gas evolution (CO2) occurred and kept at
this temperature until gas evolution ceased (45–120 min).
The reaction mixture was cooled to r.t. To the mixture was
added 20 mL EtOAc and washed with 1 N HCl(aq) (three
times). The organic layer was washed with sat. aq NaHCO3
solution (three times), brine(once) and dried over Na2SO4.
Removal of the solvent gave a solid residue, which was
purified by silica gel column chromatography (petroleum
ether:acetone = 8:1 to 2:1).
(21) Hydrolysis of 3a, 3c–f; General Procedure: To a aq 4.4 M
KOH solution was added 5-acyl-3-trifluoroacetylindole (3a,
3c–f, 1 mmol). The mixture was refluxed until 3 disappeared
(0.5–2 h). The mixture was adjusted to pH = 5–6 with 5.5 M
HCl(aq) to precipitate carboxylic acid, which was extracted
with EtOAc or n-butanol (3 × 20 mL). The combined
extracts were washed with brine and dried (Na2SO4).
Removal of the solvent in vacuum gave a solid residue,
which was purified by silica gel column chromatography
(petroleum ether:acetone = 2:1).
5-Acetylindole (7a): Mp 69–71 °C (petroleum
ether:acetone = 8:1). ESI-MS (negative mode): m/z = 158
[(M – 1)–], 159 [(M)–]. IR (KBr): 3271, 1661, 1600, 1429,
1351, 1273, 914, 771, 731 cm–1. 1H NMR (600 MHz,
CDCl3): d = 10.65 (br s, 1 H, N-H), 8.35 (s, 1 H, H-4), 7.83
(dd, 1 H, J = 8.4 Hz, 1.5 Hz, H-6), 7.52 (d, 1 H, J = 8.4 Hz,
H-7), 7.48 (t, 1 H, J = 2.2 Hz, H-2), 6.66 (br d, 1 H, J = 2.2
Hz, H-3), 2.62 (s, 3 H, CH3).
5-n-Butyrylindole (7c): Mp 104–105 °C (petroleum
ether:acetone = 8:1). ESI-MS (negative mode): m/z = 186
[(M – 1)–]. IR (KBr): 3269, 2963, 1664, 1605, 1380, 1367,
1329, 1223, 1154, 892, 759 cm–1. 1H NMR (600 MHz,
CDCl3): d = 10.48 (br s, 1 H, N-H), 8.37 (br d, 1 H, J = 0.8
Hz, H-4), 7.84 (dd, 1 H, J = 8.4 Hz, 1.0 Hz, H-6), 7.52 (d, 1
H, J = 8.4 Hz, H-7), 7.47 (t, 1 H, J = 2.8 Hz, 2.4 Hz, H-2),
6.66 (br d, 1 H, J = 2.0 Hz, H-3), 3.06 (t, 2 H, J = 7.2 Hz,
CH2), 1.77 (m, 2 H, J = 7.2 Hz, CH2), 1.01 (t, 3 H, J = 7.2
Hz, CH3).
5-Acetylindole-3-carboxylic Acid (6a): Mp 198–200 °C
(petroleum ether:acetone = 2:1). ESI-MS (negative mode):
m/z = 202 [(M – 1)–], 203 [(M)–]. IR (KBr): 3210, 2925,
1681, 1646, 1449, 1311, 1176, 700 cm–1. 1H NMR (600
MHz, DMSO-d6): d = 12.25 (s, 1 H, -COOH), 12.16 (s, 1 H,
N-H), 8.66 (br s, 1 H, H-4), 8.14 (d, 1 H, J = 2.4 Hz, H-2),
7.82 (dd, 1 H, J = 8.4 Hz, 1.2 Hz, H-6), 7.55 (d, 1 H, J = 8.4
Hz, H-7), 2.62 (s, 3 H, CH3).
5-n-Butyrylindole-3-carboxylic Acid (6c): Mp 174–175
°C (petroleum ether:acetone = 2:1). ESI-MS (negative
mode): m/z = 230 [(M – 1)–], 231 [(M)–]. IR (KBr): 3237,
2961, 1669, 1533, 1444, 1169 cm–1. 1H NMR (600 MHz,
DMSO-d6): d = 12.24 (s, 1 H, -COOH), 12.14 (br s, 1 H, N-
H), 8.68 (br s, 1 H, H-4), 8.14 (d, 1 H, J = 2.9 Hz, H-2), 7.83
(dd, 1 H, J = 8.4 Hz, 1.6 Hz, H-6), 7.55 (d, 1 H, J = 8.4 Hz,
H-7), 3.05 (t, 2 H, J = 7.2 Hz, CH2), 1.67 (m, 2 H, J = 7.2 Hz,
CH2), 0.95 (t, 3 H, J = 7.2 Hz, CH3).
5-iso-Butyrylindole (7d): Mp 65-66 °C (petroleum
ether:acetone = 8:1). ESI-MS (negative mode): m/z = 186
[(M – 1)–]. IR (KBr): 3300, 2975, 1663, 1603, 1430, 1383,
1346, 1228, 1139, 1097, 1007, 749 cm–1. 1H NMR (600
MHz, CDCl3): d = 10.65 (br s, 1 H, N-H), 8.38 (s, 1 H, H-4),
7.85 (dd, 1 H, J = 8.4 Hz, 1.5 Hz, H-6), 7.54 (d, 1 H, J = 8.4
Hz, H-7), 7.48 (t, 1 H, J = 2.4 Hz, H-2), 6.66 (d, 1 H, J = 2.4
Hz, H-3), 3.78 (m, 1 H, J = 7.2 Hz, CH), 1.20 (d, 6 H, J = 7.2
Hz, CH3).
5-iso-Butyrylindole-3-carboxylic Acid (6d): Mp 171–172
°C (petroleum ether:acetone = 2:1). ESI-MS (negative
mode): m/z = 230 [(M)–]. IR (KBr): 3281, 2973, 1657, 1537,
1446, 1186, 1128, 759 cm–1. 1H NMR (600 MHz, DMSO-
d6): d = 12.10 (s, 2 H, -COOH and N-H), 8.67 (br s, 1 H, H-
4), 8.12 (d, 1 H, J = 2.7 Hz, H-2), 7.83 (dd, 1 H, J = 8.4 Hz,
0.9 Hz, H-6), 7.55 (d, 1 H, J = 8.4 Hz, H-7), 3.70 (t, 2 H,
J = 6.6 Hz, CH), 1.14 (d, 6 H, J = 6.6 Hz, CH3).
5-Benzoylindole (7e): Mp 148–149 °C (petroleum
ether:acetone = 5:1). ESI-MS (negative mode): m/z = 220
[(M – 1)–]. IR (KBr): 3292, 1623, 1607, 1571, 1322, 880,
737 cm–1. 1H NMR (600 MHz, CDCl3): d = 10.72 (br s, 1 H,
N-H), 8.10 (br s, 1 H, H-4), 7.80 (dd, 2 H, J = 7.4 Hz, 1.2 Hz,
H-2¢ and H-6¢ in phenyl), 7.71 (dd, 1 H, J = 8.4 Hz, 1.5 Hz,
H-6), 7.66 (t, 1 H, J = 7.4 Hz, H-4¢ in phenyl), 7.59 (t, 2 H,
J = 7.4 Hz, H-3¢ and H-5¢ in phenyl), 7.57 (d, 1 H, J = 8.4
Hz, H-7), 7.51 (t, 1 H, J = 2.4 Hz, H-2), 6.67 (br d, 1 H,
J = 2.4 Hz, H-3).
5-(4¢-Methylbenzoyl)indole (7f): Mp 168-169 °C
(petroleum ether:acetone = 8:1). ESI-MS (negative mode):
m/z = 234 [(M – 1)–]. ESI-MS (positive mode): m/z = 258
[(M + Na)+], 274 [(M + K)+]. IR (KBr): 3235, 1631, 1606,
1329, 1316, 1177, 754 cm–1. 1H NMR (600 MHz, CDCl3): d
= 10.70 (br s, 1 H, N-H), 8.08 (br s, 1 H, H-4), 7.71 (d, 2 H,
J = 7.8 Hz, H-2¢ and H-6¢ in phenyl), 7.69 (dd, 1 H, J = 8.4
Hz, 1.2 Hz, H-6), 7.59 (d, 1 H, J = 8.4 Hz, H-7), 7.51 (t, 1 H,
J = 2.2 Hz, H-2), 7.38 (d, 2 H, J = 7.8 Hz, H-3¢ and H-5¢ in
phenyl), 6.66 (br d, 1 H, J = 2.2 Hz, H-3), 2.47 (s, 3 H, CH3).
5-Benzoylindole-3-carboxylic Acid (6e): Mp 178–179 °C
(petroleum ether:acetone = 2:1). ESI-MS (negative mode):
–
m/z = 264 [(M)–], 220 [(M – 1 – CO2 )]. IR (KBr): 3184,
2925, 1668, 1639, 1499, 1201, 1138, 705 cm–1. 1H NMR
(600 MHz, DMSO-d6): d = 12.23 (s, 1 H, -COOH), 12.10 (br
s, 1 H, N-H), 8.44 (br s, 1 H, H-4), 8.17 (d, 1 H, J = 3.3 Hz,
H-2), 7.73 (d, 2 H, J = 7.8 Hz, H-2¢ and H-6¢ in phenyl), 7.67
(d, 1 H, J = 8.4 Hz, H-6), 7.66 (t, 1 H, J = 7.8 Hz, H-4¢ in
phenyl), 7.62 (d, 1 H, J = 8.4 Hz, H-7), 7.57 (t, 2 H, J = 7.8
Hz, H-3¢ and H-5¢ in phenyl).
5-(4¢-Methylbenzoyl)indole-3-carboxylic Acid (6f): Mp
193–194 °C (petroleum ether:acetone = 2:1). ESI-MS
Synlett 2003, No. 10, 1447–1450 © Thieme Stuttgart · New York