Palladium-catalyzed oxidative C-H bond coupling of indoles and benzaldehydes: A new approach to the synthesis of 3-benzoylindoles

Article abstract of DOI:10.1016/j.tet.2013.11.051

A palladium-catalyzed dehydrogenative acylation of indoles using easily accessible aldehydes as the acyl source is described. This reaction provides a new approach for the synthesis of 3-acylindoles.

Full text of DOI:10.1016/j.tet.2013.11.051

Tetrahedron 70 (2014) 349e354
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-catalyzed oxidative CeH bond coupling of indoles
and benzaldehydes: a new approach to the synthesis of
3-benzoylindoles
,
a
b
Ebrahim Kianmehr a , Shahrzad Kazemi , Alireza Foroumadi
*
a School of Chemistry, College of Science, University of Tehran, Tehran 1417614411, Iran
b Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 June 2013
Received in revised form 4 November 2013
Accepted 18 November 2013
Available online 3 December 2013
A palladium-catalyzed dehydrogenative acylation of indoles using easily accessible aldehydes as the acyl
source is described. This reaction provides a new approach for the synthesis of 3-acylindoles.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Cross-coupling
Homogeneous catalysis
Indole
Aldehyde
Palladium
Heterocycles
1. Introduction
Due to the need for efficient ways to synthesize more elaborate
structures possessing biological activity, the development of novel
Indole derivatives exhibit a broad range of useful pharmaco-
logical effects, including antibiotic, anti-inflammatory, antihyper-
tensive, and antitumor activities.1
and convenient methods for the preparation of indole derivatives,
among, which 3-acylindoles with valuable pharmaceutical activi-
ties, is of considerable importance in organic chemistry.
3-Acylindoles have been found to exhibit various pharmaceutical
activities like anticancer and antidiabetic effects and inhibition of
HIV-1 integrase and antinociceptive (Fig. 1). In 1991, it was reported
that an indole derivative, 1, unexpectedly inhibited contractions of
the electrically stimulated mouse vas deferens.2 Later work revealed
that 1, and a number of related compounds are antinociceptive and
interact with the cannabinoid CB1 receptor and exhibit typical
cannabinoid pharmacology in vivo.3 Aminoalkylindole 2 is not only
potent in vivo, but has high affinity for both the cannabinoid CB1 and
CB2 receptors. Since then various indole derivatives with similar
structural skeleton have been synthesized and their pharmacolog-
ical activities have been investigated. For example compound 3
was identified as a potent inhibitor of tubulin polymerization and
also as a cytotoxic agent against B16 melanoma cells.4
Numerous synthetic methodologies for the construction of 3-
acylindoles have been developed in the past decades.5 The Frie-
deleCrafts reaction is the classic method for the preparation of 3-
acylindoles and most of the other reported methods are also
based on the use of acid chlorides and modification of this process.6
Therefore, development of new methods using alternant acylating
agents is of considerable importance.
Classical methods have several drawbacks, notably Manich-type
indole oligomerization in the presence of Lewis acids and genera-
tion of side products caused by addition of indole to 3-acylindole.
Toxicity, commercial nonavailability and handling difficulty of the
reagents are some of the other disadvantages.
Direct CeH functionalization has emerged over the past
few years as an attractive strategy, from both scientific and envi-
ronmental points of view to install many different types of bonds,
including carboneoxygen, carbonehalogen, carbonenitrogen, car-
bonesulfur and carbonecarbon linkages.7
In recent years, building a carbonecarbon linkage directly from
two simple carbonehydrogen (CeH) bonds has emerged as an
* Corresponding author. E-mail addresses: kianmehr@khayam.ut.ac.ir (E. Kian-
mehr), aforoumadi@yahoo.com (A. Foroumadi).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.051

350
MeO
E. Kianmehr et al. / Tetrahedron 70 (2014) 349e354
Different organic solvents were screened. Chlorobenzene gave
the best yield while solvents, such as 1,4-dioxane, tert-amyl alcohol,
diglyme and DME afforded moderate yields of the product and
DCE, DMAc, DMF, DMSO, NMP, and CH3CN afforded poor results
(Table 1, entries 1e13). The effectiveness of the oxidant was also
examined. TBHP was the most suitable oxidant in this reaction.
Other peroxides such as DTBP (di-tert-butylperoxide), (PhCOO)2
and PhC(CH3)2OOH were less effective (Table 1, entries 14e16), and
no desired product was observed when oxygen was used as the sole
oxidant. The optimal TBHP added to the reaction was 3 equiv. A
screening of catalysts showed that Pd(OAc)2 gave the best results
while PdCl2, Pd(COD)Cl2 and Pd(PPh3)2Cl2 were found to be inferior
(Table 1, entries 17e19). The best activity was shown at 140 ꢀC and
the reaction provided a lower conversion at lower temperature
(Table 1, entries 20 and 21).
OMe
MeO
MeO
O
O
O
Me
Me
N
N
N
O
N
H
MeO
OH
1
2
N
3
O
O
Fig. 1. Some bioactive compounds with a benzoylindole core structure.
With the optimized reaction conditions in hand, we next tested
the scope of the reaction (Scheme 1). Aldehydes with electron
withdrawing groups and 1-naphthylaldehyde gave good yields of
the corresponding products. The presence of bromine on the ben-
zene ring did not change the reaction pathway, and moderate yields
of the product were obtained using this moderately electron poor
aldehyde. Aldehydes with electron-donating groups gave a slightly
lower yield of the product presumably due to the difficult CeH
bond cleavage of aldehyde.
attractive and challenging goal in catalysis.8 This reaction is more
atom economical and environmentally friendly than other cross-
coupling reactions, and can be considered as a complementary
strategy to the existing direct CeH bonds activations. Considerable
advances in this field have recently been achieved.
2. Results and discussion
Although the reaction mechanism is not clear at this stage, but
on the basis of the previous chemistry,9 it is believed that this
With an interest to develop catalytic CeH bond cross-coupling
reactions, here we describe a versatile 3-acylindole synthesis by
Pd catalyzed cross-coupling of indoles with aldehydes. N-methyl-
indole (4a) and 4-methylbenzaldehyde (5a) were used as the
substrates in the model reaction. In the initial trial, we were de-
lighted that the desired product 6a was obtained in 55% yield in the
presence of oxidant TBHP (Table 1, entry 7).
Table 1
Optimization of the reaction conditions.a
Entry
Pd catalyst
Oxidant
Solventa
Yield (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
(PhCOO)2
PhC(CH3)2OOH
TBHP
NMP
0
0
0
0
CH3CN
DMSO
DMF
DMAc
DCE
Toluene
DME
Diglyme
Neat
tert-Amyl alcohol
1,4-Dioxane
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
Trace
8
55
58
60
64
61
67
78
0
17
34
22
31
36
0
9
10
11
12
13
14
15
16
17
18
19
20b
21c
22d
Pd(COD)Cl2
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
TBHP
TBHP
TBHP
TBHP
59
38
TBHP
a
NMP: N-methyl-2-pyrrolidinone; DMSO: dimethylsulfoxide; DMF: N,N-dime-
thylformamide; DMAc: N,N-dimethylacetamide; DCE: 1,1-dichloroethane; DME:
1,2-dimethoxyethane; COD: cyclooctadiene.
b
The reaction was performed at 25 ꢀC.
Scheme 1. Scope of direct 3-acylation indoles with aldehydes. Indole derivatives
(1 mmol), aldehyde derivatives (3 mmol), TBHP 70% aq (3 mmol), Pd(OAc)2 (5 mol %) in
chlorobenzene at 140 ꢀC for 24 h.
c
The reaction was performed at 120 ꢀC.
d
The reaction was performed under air.

E. Kianmehr et al. / Tetrahedron 70 (2014) 349e354
351
transformation begins with the 3-palladation of indole with
Pd(OAc)2. At the same time, the aldehyde is transferred to an acyl
radical by TBHP. The Pd(II) intermediate A would react with the acyl
radicals to afford the Pd(IV) intermediate D. The Pd(IV) in-
termediate D would undergo reductive elimination to produce the
desired product and regenerate the Pd(II) species (Scheme 2).
charged with indole derivatives (1 mmol), aldehyde derivatives
(3 mmol), TBHP 70% aq (3 mmol, 0.4 ml) and Pd(OAc)2
(0.05 mmol, 11 mg). The vial was sealed and flushed with argon
for 2 min. Chlorobenzene (4 ml) was added via syringe. The re-
action vessel was then immersed in an oil bath, which was pre-
heated at 140 ꢀC, for 24 h. After this time the reaction mixture was
cooled to room temperature and diluted with ethyl acetate
(15 ml). The mixture was washed with 10% NaOH solution (15 ml),
and the organic extract was dried over sodium sulfate and filtered.
Concentration of the solution by rotary evaporation under re-
duced pressure gave a residue, which was purified by using col-
umn chromatography.
4.2.1. (1-Methyl-1H-indol-3-yl)(p-tolyl)methanone (6a). The gen-
eral procedure was followed using 1-methyl-1H-indole (1 mmol,
131 mg), 4-methylbenzaldehyde (3 mmol, 0.35 ml). Purification by
column chromatography (20% Et2O/hexane) gave the final product
6a (177 mg, 71%) as a white solid, mp¼136e137 ꢀC; Rf (20% Et2O/
hexane)¼0.18; IR (KBr) vmax 2920, 1609, 1521, 1461, 1368, 1228,
1121, 753 cmꢁ1; 1H NMR (500.1 MHz, DMSO-d6)
1H, ]CH), 8.00 (s, 1H, ]CHN), 7.70 (d, J¼7.8 Hz, 2H, ]CH), 7.58 (d,
J¼8.0 Hz, 1H, ]CH), 7.35 (d, J¼7.8 Hz, 2H, ]CH), 7.28e7.33 (m, 2H,
]CH), 3.88 (s, 3H, NMe), 2.41 (s, 3H, PhMe) ppm; 13C NMR
d
8.26 (d, J¼7.7 Hz,
(125.7 MHz, DMSO-d6)
d 189.2, 141.0, 139.2, 137.3, 131.6, 128.9,
128.5, 126.7, 123.1, 122.2, 121.6, 113.9, 110.6, 33.1, 21.0 ppm; MS (EI,
70 eV): m/z (%)¼249 (Mþ, 61), 234 (5), 220 (5), 158 (100), 130 (12),
115 (5), 91 (19), 77 (19), 72 (29); Anal. Calcd for C17H15NO: C, 81.90;
H, 6.06; N, 5.62; Found: C, 81.67; H, 6.02; N, 5.65.
Scheme 2. Tentative mechanism proposed for the 3-acylation of indoles (note: not all
the neutral/anionic ligands around the Pd centers are shown).
4.2.2. p-Tolyl(1-p-tolyl-1H-indol-3-yl)methanone (6b). The general
procedure was followed using 1-p-tolyl-1H-indole (1 mmol,
207 mg), 4-methylbenzaldehyde (3 mmol, 0.35 ml). Purification by
column chromatography (5% Et2O/hexane) gave the final product
6b (208 mg, 64%) as a yellow oil; Rf (10% Et2O/hexane)¼0.24; IR
3. Conclusion
In conclusion, we have developed a Pd-catalyzed protocol for
a selective 3-acylation of indoles by oxidative coupling with alde-
hydes. This new methodology enabled cross-coupling with aro-
matic aldehydes in high yield and high regioselectivity. Investi
gations into the Pd(II)/(IV) catalytic cycle along with characteriza-
tion of postulated intermediates and extension of the scope are
ongoing and will be reported in due course.
(KBr) vmax 2922, 1606, 1517, 1454, 1358, 1217, 1177, 744 cmꢁ1 1H
;
NMR (500.1 MHz, CDCl3)
d
8.50 (d, J¼7.3 Hz, 1H, ]CH), 7.81 (d,
J¼8.0 Hz, 2H, ]CH), 7.77 (s,1H, ]CHN), 7.51 (d, J¼8.0 Hz,1H, ]CH),
7.34e7.41 (m, 6H, ]CH), 7.31 (d, J¼8.0 Hz, 2H, ]CH), 2.47 (s, 3H,
Me), 2.45 (s, 3H, Me) ppm; 13C NMR (125.7 MHz, CDCl3)
d 190.9,
141.8, 138.0,137.9, 137.1, 136.5, 135.8, 130.4,129.0, 127.5, 124.7, 124.0,
123.0, 122.8, 117.1, 110.8, 21.5, 21.1 ppm; MS (EI, 70 eV): m/z (%)¼325
(Mþ, 61), 310 (3), 234 (68), 219 (5), 191 (13), 167 (55), 149 (100), 119
(43), 91 (39), 57 (53), 43 (63); Anal. Calcd for C23H19NO: C, 84.89; H,
5.89; N, 4.30; Found: C, 84.61; H, 5.92; N, 4.32.
4. Experimental section
4.1. General
All reactions were performed under anhydrous conditions.
Glassware was flame-dried and reactions were performed under an
argon atmosphere. Catalytic reactions were performed employing
microwave vials. Solvents were distilled before use. Chemicals were
purchased from commercial sources and were used as received.
Substituted indoles were prepared according to the literature.10
Thin layer chromatography (TLC) analysis was performed using
Silicycle precoated TLC plates (silica gel 60 F254). The products were
purified by preparative column chromatography on silica gel
(0.063e0.200 mm; Merck). IR Spectra: Bruker Equinox 55 spec-
4.2.3. (1-Isobutyl-1H-indol-3-yl)(p-tolyl)methanone (6c). The gen-
eral procedure was followed using 1-isobutyl-1H-indole (1 mmol,
173 mg), 4-methylbenzaldehyde (3 mmol, 0.35 ml). Purification by
column chromatography (10% Et2O/hexane) gave the final product
6c (227 mg, 78%) as a white solid, mp¼104e106 ꢀC, Rf (20% Et2O/
hexane)¼0.34; IR (KBr) vmax 2958, 1612, 1520, 1461, 1382, 1212,
748 cmꢁ1 1H NMR (500.1 MHz, CDCl3)
; d 8.41e8.43 (m, 1H, ]CH),
7.75 (d, J¼8.0 Hz, 2H, ]CH), 7.56 (s, 1H, ]CHN), 7.38e7.40 (m, 1H,
]CH), 7.32e7.35 (m, 2H, ]CH), 7.31 (d, J¼8.0 Hz, 2H, ]CH), 3.97 (d,
J¼7.3 Hz, 2H, NCH2), 2.46 (s, 3H, PhMe), 2.22e2.28 (m, 1H, CHMe2),
0.96 (d, J¼6.6 Hz, 6H, CHMe2) ppm; 13C NMR (125.7 MHz, CDCl3)
trometer; in cmꢁ1
Bruker DRX-500-Advance instrument; in CDCl3 at 500.1 and
125.7 MHz, resp.; in parts per million, J in Hertz. EI-MS (70 eV): HP
.
1H and 13C NMR Spectra: were recorded on
d
190.7, 141.5, 138.2, 137.1, 128.9, 127.4, 123.4, 122.8, 122.5, 121.4,
d
115.5, 110.0, 54.7, 29.2, 21.5, 20.2 ppm; MS (EI, 70 eV): m/z (%)¼291
(Mþ, 64), 248 (100), 234 (2), 220 (4), 200 (17), 144 (11), 119 (28), 91
(20), 57 (3). Anal. Calcd for C20H21NO: C, 82.44; H, 7.26; N, 4.81;
Found: C, 82.26; H, 7.30; N, 4.78.
5973 GCeMS instrument; in m/z. Melting points: Electrothermal
9200 apparatus.
4.2. General procedure for cyanoalkenylation of indoles
4.2.4. (1-Isobutyl-1H-indol-3-yl)(naphthalen-1-yl)methanone
(6d). The general procedure was followed using 1-isobutyl-1H-
indole (1 mmol, 173 mg), 1-naphthaldehyde (3 mmol, 0.41 ml).
Purification by column chromatography (5% Et2O/hexane) gave the
A 10 ml microwave vial equipped with a magnetic stirring bar
and septum was flame-dried and then cooled under a stream of
argon by venting through a needle in the septum. The vial was

352
E. Kianmehr et al. / Tetrahedron 70 (2014) 349e354
final product 6d (262 mg, 80%) as an orange oil; Rf (10% Et2O/
hexane)¼0.19; IR (KBr) vmax 2926, 1613, 1518, 1462, 1378, 1197, 1131,
C21H23NO: C, 82.58; H, 7.59; N, 4.59; Found: C, 82.41; H, 7.55;
N, 4.57.
747 cmꢁ1 1H NMR (500.1 MHz, CDCl3)
; d 8.50e8.51 (m, 1H, ]CH),
8.21 (d, J¼8.4 Hz, 1H, ]CH), 7.98 (d, J¼8.2 Hz, 1H, ]CH), 7.93 (d,
J¼7.9 Hz, 1H, ]CH), 7.68 (d, J¼7.0 Hz, 1H, ]CH), 7.46e7.56 (m, 3H,
]CH), 7.36e7.41 (m, 3H, ]CH), 7.34 (s, 1H, ]CHN), 3.88 (d,
J¼7.3 Hz, 2H, NCH2), 2.16e2.22 (m, 1H, CHMe2), 0.91 (d, J¼6.7 Hz,
4.2.8. (1-Butyl-5-methoxy-1H-indol-3-yl)(4-isopropylphenyl)meth-
anone (6h). The general procedure was followed using 1-butyl-5-
methoxy-1H-indole (1 mmol, 203 mg), 4-isopropylbenzaldehyde
(3 mmol, 0.45 ml). Purification by column chromatography (10%
Et2O/hexane) gave the final product 6h (294 mg, 84%) as a white
solid, mp¼72e73 ꢀC; Rf (20% Et2O/hexane)¼0.44; IR (KBr) vmax
6H, CHMe2) ppm; 13C NMR (125.7 MHz, CDCl3)
d 192.1, 139.1, 138.4,
137.3, 133.7, 130.8, 130.0, 128.1, 126.9, 126.7, 126.3, 126.0, 125.9,
124.5, 123.6, 122.9, 122.8, 117.4, 110.2, 54.7, 29.1, 20.1 ppm; MS (EI,
70 eV): m/z (%)¼327 (Mþ, 65), 298 (2), 284 (88), 270 (14), 200 (38),
167 (47), 149 (60), 127 (33), 71 (33), 57 (57), 43 (100). Anal.
Calcd for C23H21NO: C, 84.37; H, 6.46; N, 4.28; Found: C, 84.16; H,
6.49; N, 4.30.
3103, 2962, 1618, 1518, 1457, 1382, 1270, 1211, 1041, 843 cmꢁ1 1H
;
NMR (500.1 MHz, CDCl3)
d
7.99 (d, J¼2.5 Hz, 1H, ]CH), 7.77 (d,
J¼8.1 Hz, 2H, ]CH), 7.55 (s, 1H, ]CHN), 7.36 (d, J¼8.1 Hz, 2H, ]CH),
7.28 (d, J¼8.9 Hz, 1H, ]CH), 6.98 (dd, J¼2.5 Hz, J¼8.9 Hz, 1H, ]CH),
4.13 (t, J¼7.2 Hz, 2H, NCH2), 3.93 (s, 3H, OMe), 3.01 (septet, J¼6.9 Hz,
1H, CHMe2), 1.85 (quintet, J¼7.4 Hz, 2H, NCH2CH2), 1.37 (sextet,
J¼7.6 Hz, 2H, CH2Me), 1.33 (d, J¼6.9 Hz, 6H CHMe2), 0.95 (t,
4.2.5. (1-Isobutyl-1H-indol-3-yl)(3-nitrophenyl)
methanone
(6e). The general procedure was followed using 1-isobutyl-1H-in-
dole (1 mmol, 173 mg), 3-nitrobenzaldehyde (3 mmol, 453 mg).
Purification by column chromatography (10% Et2O/hexane) gave
J¼7.3 Hz, 3H, CH2Me) ppm; 13C NMR (125.7 MHz, CDCl3)
d 190.7,
156.4, 152.2, 138.7, 136.8, 131.7, 128.9, 128.3, 126.4, 115.2, 114.1, 110.6,
103.9, 55.8, 47.1, 34.2, 32.0, 23.9, 20.1, 13.6 ppm; MS (EI, 70 eV): m/z
(%)¼349 (Mþ, 68), 334 (2), 306 (26), 291 (3), 279 (29), 262 (2), 230
(21), 202 (2), 167 (66), 159 (5), 149 (100), 132 (6), 104 (14), 71 (35),
57 (51), 43 (33); Anal. Calcd for C23H27NO2: C, 79.05; H, 7.79; N,
4.01; Found: C, 79.11; H, 7.81; N, 3.99.
the final product 6e (267 mg, 83%) as
a white solid,
mp¼105e106 ꢀC, Rf (20% Et2O/hexane)¼0.32; IR (KBr) vmax 3058,
2962, 1614, 1520, 1464, 1381, 1346, 1210, 1134, 713 cmꢁ1 1H NMR
;
(500.1 MHz, CDCl3)
d 8.66 (s, 1H, ]CH), 8.41e8.42 (m, 2H, ]CH),
8.17 (d, J¼7.6 Hz, 1H, ]CH), 7.71 (t, J¼7.9 Hz, 1H, ]CH), 7.53 (s, 1H,
]CHN), 7.37e7.44 (m, 3H, ]CH), 4.00 (d, J¼7.3 Hz, 2H, NCH2),
4.2.9. (5-Methoxy-1-pentyl-1H-indol-3-yl)(4-methoxyphenyl)meth-
anone (6i). The general procedure was followed using 5-methoxy-
1-pentyl-1H-indole (1 mmol, 217 mg), 4-methoxybenzaldehyde
(3 mmol, 0.36 ml). Purification by column chromatography (20%
Et2O/hexane) gave the final product 6i (285 mg, 81%) as an orange
oil; Rf (20% Et2O/hexane)¼0.22; IR (KBr) vmax 2928, 1601, 1514, 1457,
1382, 1250, 1213, 1167, 1026, 842 cmꢁ1. 1H NMR (500.1 MHz, CDCl3)
2.23e2.30 (m, 1H, CHMe2), 0.98 (d, J¼6.6 Hz, 6H, CHMe2) ppm; 13
C
NMR (125.7 MHz, CDCl3)
d 187.8, 148.0, 142.3, 137.4, 137.3, 134.5,
129.6, 127.1, 125.6, 124.0, 123.6, 123.1, 122.7, 114.8, 110.3, 54.9, 29.2,
20.2 ppm; MS (EI, 70 eV): m/z (%)¼322 (Mþ, 55), 307 (3), 279 (100),
248 (16), 233 (9), 219 (3), 200 (20), 157 (3), 149 (27), 129 (13), 116
(8), 104 (8), 76 (8), 57 (21). Anal. Calcd for C19H18N2O3: C, 70.79; H,
5.63; N, 8.69; Found: C, 70.67; H, 5.61; N, 8.74.
d
7.95 (d, J¼2.2 Hz, 1H, ]CH), 7.85 (d, J¼8.6 Hz, 2H, ]CH),
7.54 (s, 1H, ]CHN), 7.28 (d, J¼9.0 Hz, 1H, ]CH), 7.00 (d, J¼8.6 Hz,
2H, ]CH), 6.98 (dd, J¼2.2 Hz, J¼9.0 Hz, 1H, ]CH), 4.13 (t, J¼7.1 Hz,
2H, NCH2), 3.92 (s, 3H, OMe), 3.90 (s, 3H, OMe), 1.88 (quintet,
J¼7.2 Hz, 2H NCH2CH2), 1.31e1.36 (m, 4H, CH2CH2Me), 0.89 (t,
4.2.6. Phenyl(1-propyl-1H-indol-3-yl)methanone (6f). The general
procedure was followed using 1-propyl-1H-indole (1 mmol,
159 mg), benzaldehyde (3 mmol, 0.31 ml). Purification by column
chromatography (10% Et2O/hexane) gave the final product 6f
(160 mg, 61%) as an orange solid, mp¼69e71 ꢀC; Rf (20% Et2O/
hexane)¼0.34; IR (KBr) vmax 3051, 2928, 1609, 1516, 1461, 1385,
J¼7.1 Hz, 3H, CH2Me) ppm; 13C NMR (125.7 MHz, CDCl3)
d 189.8,
162.1, 156.3, 136.3, 133.6, 131.7, 130.8, 128.3, 115.1, 114.0, 113.5, 110.6,
103.7, 55.8, 55.4, 47.3, 29.6, 29.0, 22.2, 13.9 ppm; MS (EI, 70 eV): m/z
(%)¼351 (Mþ, 12), 294 (6), 279 (51), 248 (7), 218 (5), 167 (88), 157
(3), 149 (100), 135 (20), 128 (4), 121 (18), 104 (16), 71 (49), 57 (71),
43 (47); Anal. Calcd for C22H25NO3: C, 75.19; H, 7.17; N, 3.99; Found:
C, 75.38; H, 7.15; N, 4.02.
1211, 1129, 721 cmꢁ1; 1H NMR (500.1 MHz, CDCl3)
d 8.44e8.45 (m,
1H, ]CH), 7.84 (d, J¼7.2 Hz, 2H, ]CH), 7.49e7.58 (m, 4H, ]CH),
7.41e7.42 (m, 1H, ]CH), 7.34e7.36 (m, 2H, ]CH), 4.14 (t, J¼7.0 Hz,
2H, NCH2), 1.93 (sextet, J¼7.2 Hz, 2H, CH2Me), 0.97 (t, J¼7.3 Hz, 3H,
Me) ppm; 13C NMR (125.7 MHz, CDCl3)
d 190.9, 141.0, 137.0, 136.8,
131.0, 128.7, 128.3, 127.4, 123.5, 122.8, 122.6, 115.5, 109.8, 48.8, 23.2,
11.4 ppm; MS (EI, 70 eV): m/z (%)¼263 (Mþ, 98), 234 (59), 220 (5),
186 (100), 167 (27), 158 (2), 149 (72), 144 (25), 116 (13), 105 (29), 77
(29), 43 (16); Anal. Calcd for C18H17NO: C, 82.10; H, 6.51; N, 5.32;
Found: C, 82.26; H, 6.54; N, 5.30.
4.2.10. (4-Bromophenyl)(7-ethyl-1-propyl-1H-indol-3-yl)methanone
(6j). The general procedure was followed using 7-ethyl-1-propyl-
1H-indole (1 mmol, 187 mg), 4-bromobenzaldehyde (3 mmol,
550 mg). Purification by column chromatography (5% Et2O/hexane)
gave the final product 6j (281 mg, 76%) as a white solid,
mp¼126e127 ꢀC; Rf (20% Et2O/hexane)¼0.45; IR (KBr) vmax 3027,
4.2.7. (4-Isopropylphenyl)(1-propyl-1H-indol-3-yl)methanone
(6g). The general procedure was followed using 1-propyl-1H-in-
dole (1 mmol, 159 mg), 4-isopropylbenzaldehyde (3 mmol,
0.45 ml). Purification by column chromatography (10% Et2O/hex-
ane) gave the final product 6g (208 mg, 68%) as an orange solid,
mp¼108e110 ꢀC; Rf (20% Et2O/hexane)¼0.36; IR (KBr) vmax 3107,
2924, 1607, 1527, 1467, 1384, 1255, 1210, 1112, 1065, 837 cmꢁ1
;
1H NMR (500.1 MHz, CDCl3)
d
8.33 (d, J¼7.7 Hz, 1H, ]CH),
7.69 (d, J¼8.5 Hz, 2H, ]CH), 7.63 (d, J¼8.5 Hz, 2H, ]CH), 7.47 (s, 1H,
]CHN), 7.28 (t, J¼7.5 Hz,1H, ]CH), 7.15 (d, J¼7.1 Hz,1H, ]CH), 4.27
(t, J¼7.3 Hz, 2H, NCH2), 3.05 (quartet, J¼7.5 Hz, 2H, CH2Me), 1.87
(sextet, J¼7.4 Hz, 2H, NCH2CH2), 1.37 (t, J¼7.5 Hz, 3H, CH2CH2Me),
0.97 (t, J¼7.5 Hz, 3H, CH2Me) ppm; 13C NMR (125.7 MHz, CDCl3)
2961, 1616, 1520, 1463, 1382, 1214, 1130, 758 cmꢁ1 1H NMR
;
(500.1 MHz, CDCl3)
d
8.45e8.47 (m, 1H, ]CH), 7.79 (d, J¼8.1 Hz, 2H,
d 189.5, 139.8, 138.8, 134.6, 131.5, 130.3, 128.6, 127.8, 125.7, 125.0,
]CH), 7.61 (s, 1H, ]CHN), 7.40e7.42 (m, 1H, ]CH), 7.32e7.36 (m,
4H, ]CH), 4.14 (t, J¼7.1 Hz, 2H, NCH2), 3.01 (septet, J¼6.9 Hz, 1H,
CHMe2), 1.93 (sextet, J¼7.2 Hz, 2H, CH2Me), 1.33 (d, J¼6.9 Hz, 6H,
CHMe2), 0.97 (t, J¼7.4 Hz, 3H, CH2Me) ppm; 13C NMR (125.7 MHz,
123.1, 120.6, 115.2, 51.5, 25.4, 25.2, 16.2, 11.1 ppm; MS (EI, 70 eV): m/
z (%)¼371 [(Mþ2)þ, 13], 369 (Mþ, 13), 340 (8), 291 (8), 246 (100),
214 (12), 202 (65), 183 (43),167 (33), 157 (23),149 (85),115 (20),105
(12), 71 (38), 57 (59), 43 (47); Anal. Calcd for C20H20BrNO: C, 64.87;
H, 5.44; N, 3.78; Found: C, 65.02; H, 5.43; N, 3.80.
CDCl3)
d 190.7, 152.3, 138.6, 136.8, 129.3, 129.0, 127.4, 126.3, 123.4,
122.8, 122.5, 115.5, 109.8, 48.7, 34.1, 23.8, 23.2, 11.4 ppm; MS (EI,
70 eV): m/z (%)¼305 (Mþ, 100), 276 (50), 262 (11), 186 (82), 157 (2),
144 (22), 129 (7), 116 (9), 104 (9), 77 (5), 43 (9); Anal. Calcd for
4.2.11. (1,7-Diethyl-1H-indol-3-yl)(4-methoxyphenyl)methanone
(6k). The general procedure was followed using 1,7-diethyl-1H-

E. Kianmehr et al. / Tetrahedron 70 (2014) 349e354
353
indole (1 mmol, 173 mg), 4-methoxybenzaldehyde (3 mmol,
0.36 ml). Purification by column chromatography (15% Et2O/hex-
ane) gave the final product 6k (234 mg, 76%) as a white solid,
mp¼146e147 ꢀC; Rf (20% Et2O/hexane)¼0.22; IR (KBr) vmax 2970,
123.5, 122.8, 122.6, 121.2, 117.3, 115.4, 113.4, 109.8, 55.4, 46.9, 31.9,
20.1, 13.6 ppm; MS (EI, 70 eV): m/z (%)¼307 (Mþ, 94), 279 (20), 264
(42), 248 (7), 220 (4), 200 (83), 189 (47), 167 (42), 149 (100), 143 (5),
135 (55), 129 (9), 118 (85), 105 (24), 77 (43), 57 (31), 43 (30); Anal.
Calcd for C20H21NO2: C, 78.15; H, 6.89; N, 4.56; Found: C, 78.08; H,
6.93; N, 4.53.
1602, 1525, 1417,1376, 1247, 1180, 1101, 1026, 825 cmꢁ1 1H NMR
;
(500.1 MHz, CDCl3)
d
8.31 (d, J¼7.6 Hz, 1H, ]CH), 7.85 (d, J¼8.6 Hz,
2H, ]CH), 7.54 (s, 1H, ]CHN), 7.25 (t, J¼7.6 Hz, 1H, ]CH), 7.13 (d,
J¼7.1 Hz, 1H, ]CH), 7.00 (d, J¼8.6 Hz, 2H, ]CH), 4.40 (quartet,
J¼7.2 Hz, 2H, NCH2Me), 3.90 (s, 3H, OMe), 3.07 (quartet, J¼7.5 Hz,
2H, CH2Me), 1.50 (t, J¼7.2 Hz, 3H, NCH2Me), 1.38 (t, J¼7.5 Hz, 3H,
4.2.15. (3-Chlorophenyl)(1-pentyl-1H-indol-3-yl)methanone
(6o). The general procedure was followed using 1-pentyl-1H-in-
dole (1 mmol, 187 mg), 3-chlorobenzaldehyde (3 mmol, 0.34 ml).
Purification by column chromatography (10% Et2O/hexane) gave
the final product 6o (238 mg, 73%) as an orange oil; Rf (20% Et2O/
hexane)¼0.50; IR (KBr) vmax 2929, 1620, 1519, 1462, 1380, 1226,
CH2Me) ppm; 13C NMR (125.7 MHz, CDCl3)
d 189.7, 162.1, 137.3,
134.4, 133.6, 131.0, 128.8, 127.6, 124.5, 122.7, 120.6, 115.8, 113.5, 55.4,
44.4, 25.5,17.3, 16.2 ppm; MS (EI, 70 eV): m/z (%)¼307 (Mþ, 39), 292
(9), 279 (16), 263 (5), 250 (2), 200 (25), 167 (38), 156 (4), 149 (100),
143 (3), 135 (21), 104 (9), 77 (10), 71 (20), 57 (33), 43 (24); Anal.
Calcd for C20H21NO2: C, 78.15; H, 6.89; N, 4.56; Found: C, 78.44; H,
6.86; N, 4.55.
1189, 1130, 743 cmꢁ1; 1H NMR (500.1 MHz, CDCl3)
d 8.42e8.43 (m,
1H, ]CH), 7.80 (m, 1H, ]CH), 7.70 (d, J¼7.6 Hz, 1H, ]CH), 7.56 (s,
1H, ]CHN), 7.52e7.54 (m, 1H, ]CH), 7.41e7.45 (m, 2H, ]CH),
7.34e7.38 (m, 2H, ]CH), 4.17 (t, J¼7.2 Hz, 2H, NCH2), 1.89 (quintet,
J¼7.3 Hz, 2H, NCH2CH2), 1.32e1.39 (m, 4H, CH2CH2Me), 0.91 (t,
4.2.12. Methyl-4-[(1-ethyl-1H-indol-3-yl)carbonyl]benzoate
(6l). The general procedure was followed using 1-ethyl-1H-indole
(1 mmol, 145 mg), methyl 4-formylbenzoate (3 mmol, 492 mg).
Purification by column chromatography (15% Et2O/hexane) gave the
final product 6l (264 mg, 86%) as a white solid, mp¼144e145 ꢀC; Rf
(20% Et2O/hexane)¼0.21; IR (KBr) vmax 3120, 2978, 1708,1604,1516,
1461,1383, 1278, 1218, 1107, 734 cmꢁ1; 1H NMR (500.1 MHz, CDCl3)
J¼7.1 Hz, 3H, CH2Me) ppm; 13C NMR (125.7 MHz, CDCl3)
d 189.0,
142.5, 136.9, 136.8, 134.3, 130.9, 129.6, 128.7, 127.2, 126.7, 123.7,
122.8, 122.7, 115.1, 109.9, 47.2, 29.5, 28.9, 22.2, 13.9 ppm; MS (EI,
70 eV): m/z (%)¼327 [(Mþ2)þ,47], 325 (Mþ, 89), 310 (6), 284 (18),
268 (56), 254 (9), 214 (100), 200 (9), 186 (16), 149 (35), 139 (39), 130
(25), 111 (25), 57 (15), 43 (27); Anal. Calcd for C20H20ClNO: C, 73.72;
H, 6.19; N, 4.30; Found: C, 73.75; H, 6.18; N, 4.28.
d
8.41e8.43 (m, 1H, ]CH), 8.17 (d, J¼8.2 Hz, 2H, ]CH), 7.86 (d,
J¼8.2 Hz, 2H, ]CH), 7.57 (s, 1H, ]CHN), 7.42e7.44 (m, 1H, ]CH),
7.34e7.39 (m, 2H, ]CH), 4.24 (quartet, J¼7.3 Hz, 2H, NCH2), 3.98 (s,
3H, OMe), 1.53 (t, J¼7.3 Hz, 3H, CH2Me) ppm; 13C NMR (125.7 MHz,
Acknowledgements
We gratefully acknowledge the financial support from the Iran
National Science Foundation (INSF) and the Research Council of the
University of Tehran. We thank Dr. Karol Gajewski, Canadian In-
tellectual Property Office, for helpful comments on this work.
CDCl3)
d 189.9, 166.6, 144.8, 136.7, 136.4, 132.1, 129.6, 128.5, 127.2,
123.7, 122.9, 122.8, 115.6, 109.8, 52.4, 41.9, 15.2 ppm; MS (EI, 70 eV):
m/z (%)¼307 (Mþ, 49), 292 (5), 279 (10), 248 (4), 172 (100), 163 (12),
157 (4),149 (70),143 (6),135 (13),129 (10),104 (12), 69 (66), 57 (51),
43 (49); Anal. Calcd for C19H17NO3: C, 74.25; H, 5.58; N, 4.56; Found:
C, 74.12; H, 5.59; N, 4.59.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.11.051.
4.2.13. (1-Ethyl-1H-indol-3-yl)(3,4-dimethoxyphenyl)methanone
(6m). The general procedure was followed using 1-ethyl-1H-indole
(1 mmol, 145 mg), 3,4-dimethoxybenzaldehyde (3 mmol, 500 mg).
Purification by column chromatography (25% Et2O/hexane) gave
the final product 6m (201 mg, 65%) as an orange solid,
mp¼106e109 ꢀC; Rf (30% Et2O/hexane)¼0.16; IR (KBr) vmax 3109,
References and notes
1. (a) Hegedus, L. S. Angew. Chem. 1988, 100, 1147; (b) Gribble, G. W.; Berthel, S. J.
In Studies in Natural Products Chemistry; Attaur-Rahman, Ed.; Elsevier: New
York, 1993; Vol. 12, p 365; (c) Pindur, U.; Kim, Y. S.; Mehrabani, F. Curr. Med.
Chem. 1999, 6, 29; Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045; (d)
Bergman, J.; Janosik, T.; Wahlstrom, N. Adv. Heterocycl. Chem. 2001, 80, 1; (e) Ito,
S. Pigment Cell Res. 2003, 16, 230; (f) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105,
2873; (g) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875; (h) Crich, D.;
Banerjee, A. Acc. Chem. Res. 2007, 40, 151; (i) Dischia, M.; Napolitano, A.; Pez-
zella, A.; Meredith, P.; Sarna, T. Angew. Chem., Int. Ed. 2009, 48, 2; (j) France-
schin, M.; Ginnari-Satriani, L.; Alvino, A.; Ortaggi, G.; Bianco, A. Eur. J. Org. Chem.
2010, 134.
2929, 1575, 1510, 1457, 1374, 1262, 1207, 1168, 1019, 744 cmꢁ1 1H
;
NMR (500.1 MHz, CDCl3)
d 8.38 (m, 1H, ]CH), 7.66 (s, 1H, ]CHN),
7.47e7.48 (m, 2H, ]CH), 7.42 (m, 1H, ]CH), 7.31e7.36 (m, 2H, ]
CH), 6.94 (d, J¼8.7 Hz, 1H, ]CH), 4.25 (quartet, J¼7.2 Hz, 2H NCH2),
3.98 (s, 3H, OMe), 3.96 (s, 3H, OMe), 1.54 (t, J¼7.2 Hz, 3H, CH2Me)
ppm; 13C NMR (125.7 MHz, CDCl3)
d 189.7, 151.8, 149.0, 136.6, 135.4,
133.6, 127.5, 123.4, 122.9, 122.8, 122.4, 115.7, 111.7, 109.9, 109.7, 56.0,
41.7, 15.2 ppm; MS (EI, 70 eV): m/z (%)¼309 (Mþ, 48), 291 (21), 279
(40), 248 (32),167 (83),149 (100),135 (6),129 (13), 104 (15), 77 (10),
71 (43), 57 (64), 43 (49); Anal. Calcd for C19H19NO3: C, 73.77; H,
6.19; N, 4.53; Found: C, 73.93; H, 6.16; N, 4.51.
2. Bell, M. R.; D’Ambra, T. E.; Kumar, V.; Eissanstat, M. A.; Herrmann, J. L.; Wetzel,
J. R.; Rosi, D.; Philion, R. E.; Daum, S. J.; Hlasta, D. J.; Kullnig, R. K.; Ackerman, J.
H.; Haubrich, D. R.; Luttinger, D. A.; Baizman, E. R.; Miller, M. S.; Ward, S. J. J.
Med. Chem. 1991, 34, 1099.
3. (a) D’Ambra, T. E.; Estep, K. G.; Bell, M. R.; Eissenstat, M. A.; Josef, K. A.; Ward, J.;
Haycock, D. A.; Baizman, E. R.; Casiano, F. M.; Beglin, N. C.; Chippari, S. M.;
Grego, J. D.; Kullnig, R. K.; Daley, G. T. J. Med. Chem. 1992, 35, 124; (b) Compton,
D. R.; Gold, L. H.; Ward, S. J.; Balster, R. L.; Martin, B. R. J. Pharmacol. Exp. Ther.
1992, 263, 1118.
4. Nancy, T. N.; Dupeyre, G.; Chabot, G. G.; Seguin, J.; Tillequin, F.; Scherman, D.;
Michel, S.; Cachet, X. Bioorg. Med. Chem. 2008, 16, 7494.
5. (a) Anthony, W. J. Org. Chem. 1960, 25, 2049; (b) Bergman, J.; Venemalm, L.
Tetrahedron Lett. 1987, 28, 3741; (c) Faul, M. M.; Winneroski, L. L. Tetrahedron
Lett. 1997, 38, 4749; (d) Eyley, S. C.; Giles, R. G.; Heaney, H. Tetrahedron Lett.
1985, 26, 4649.
6. (a) Okauchi, T.; Itonaga, M.; Minami, T.; Owa, T.; Kitoh, K.; Yoshino, H. Org. Lett.
2000, 2, 1485; (b) Wynne, J. H.; Lloyd, C. T.; Jensen, S. D.; Boson, S.; Stalick, W.
M. Synthesis 2004, 2277; (c) Ottoni, O.; Neder, A. D. F.; Dias, A. K. B.; Cruz, R. P.
A.; Aquino, L. B. Org. Lett. 2001, 3, 1005; (d) Ketcha, D. M.; Gribble, G. W. J. Org.
Chem. 1985, 50, 5451; (e) Yeung, K.-S.; Qiu, Z.; Farkas, M. E.; Xue, Q.; Regueiro-
Ren, A.; Yang, Z.; Bender, J. A.; Good, A. C.; Kadow, J. F. Tetrahedron Lett. 2008, 49,
6250; (f) Watanabe, T.; Kobayashi, A.; Nishiura, M.; Takahashi, H.; Usui, T.;
Kamiyama, I.; Mochizuki, N.; Noritake, K.; Yokoyama, Y.; Murakami, Y. Chem.
4.2.14. (1-Butyl-1H-indol-3-yl)(3-methoxyphenyl)methanone
(6n). The general procedure was followed using 1-butyl-1H-indole
(1 mmol, 173 mg), 3-methoxybenzaldehyde (3 mmol, 0.36 ml).
Purification by column chromatography (5% Et2O/hexane)
gave the final product 6n (227 mg, 74%) as an orange oil; Rf
(20% Et2O/hexane)¼0.38, IR (KBr) vmax 2957, 1578, 1518, 1461,
1379, 1268, 1248, 1196, 1035, 745 cmꢁ1 1H NMR (500.1 MHz,
;
CDCl3) d 8.44e8.46 (m, 1H, ]CH), 7.60 (s, 1H, ]CHN), 7.33e7.42 (m,
6H, ]CH), 7.14 (m, 1H, ]CH), 4.17 (t, J¼7.5 Hz, 2H, NCH2), 3.88 (s,
3H, OMe), 1.87 (quintet, J¼7.5 Hz, 2H, NCH2CH2), 1.38 (sextet,
J¼7.5 Hz, 2H, CH2Me), 0.96 (t, J¼7.5 Hz, 3H, CH2Me) ppm; 13C NMR
(125.7 MHz, CDCl3)
d 190.5, 159.5, 142.3, 137.0, 136.8, 129.2, 127.3,

354
E. Kianmehr et al. / Tetrahedron 70 (2014) 349e354
Pharm. Bull. 1991, 39, 1152; (g) Bergman, J.; Backvall, J. E.; Lindstron, J. O. Tet-
rahedron 1973, 29, 971.
9. (a) Sehnal, P.; Taylor, R. J. K.; Fairlamb, I. J. S. Chem. Rev. 2010, 110, 824; (b) Basle,
O.; Bidange, J.; Shuai, Q.; Li, C.-J. Adv. Synth. Catal. 2010, 352, 1145; (c) Chan, C.-
W.; Zhou, Z.; Chan, A. S. C.; Yu, W.-Y. Org. Lett. 2010, 12, 3926; (d) Wu, Y.; Li, B.;
Mao, F.; Li, X.; Kwong, F. Y. Org. Lett. 2011, 13, 3258; (e) Xiao, F.; Shuai, Q.; Zhao,
F.; Basle, O.; Deng, G.; Li, C.-J. Org. Lett. 2011, 13, 1614; (f) Chan, C.-W.; Zhou, Z.;
Yu, W.-Y. Adv. Synth. Catal. 2011, 353, 2999; (g) Yuan, Y.; Chen, D.; Wang, X. Org.
Lett. 2011, 353, 3373.
7. (a) Seregin, I. Y.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173; (b) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174; (c) McGlacken, G. P.; Bateman,
L. M. Chem. Soc. Rev. 2009, 38, 2447; (d) Xu, L.-M.; Li, B.-J.; Yang, Z.; Shi, Z.-J.
Chem. Soc. Rev. 2010, 39, 712; (e) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010,
110, 1147.
8. (a) Bras, J. L.; Muzart, J. Chem. Rev. 2011, 111, 1170; (b) Yeung, C. S.; Dong, V. M.
Chem. Rev. 2011, 111, 1215; (c) Wu, Y.; Choy, P. Y.; Mao, F.; Kwong, F. Y. Chem.
Commun. 2013, 689; (d) Min, M.; Kim, Y.; Hong, S. Chem. Commun. 2013, 196; (e)
Chidipudi, S. R.; Wieczysty, M. D.; Khan, I.; Lam, H. W. Org. Lett. 2013, 15, 570.
10. (a) Aidi, K.; Xiuling, H.; Xiyan, L. Org. Lett. 2006, 1339; (b) Roy, S.; Eastman, A.;
Gribble, G. W. Tetrahedron 2006, 62, 7838; (c) Guida, W. C.; Mathre, D. J. J. Org.
Chem. 1980, 45, 3172; (d) Huang, Y. Z.; Miao, H.; Zhang, Q. H.; Chen, C.; Xu, J.
Catal. Lett. 2008, 122, 344.