Synthesis of 2,6-bis(1H-indole-6-yl)-4H-pyran-4-ones via leimgruber-batcho indole synthesis

Article abstract of DOI:10.1002/jhet.80

2,6-Bis(1H-indole-6-yl)-4H-pyran-4-one 4 was synthesized via Leimgruber-Batcho methodology starting from 2,6-bis(4-methyl-3-nitrophenyl)-4H- pyran-4-one 2. Enamine intermediate in this reaction, 3, reacts with aroyl chlorides in the presence of 1,4-diazab

Full text of DOI:10.1002/jhet.80

March 2009
Synthesis of 2,6-Bis(1H-indole-6-yl)-4H-pyran-4-ones
via Leimgruber–Batcho Indole Synthesis
273
Aziz Shahrisa,* Zarrin Ghasemi, and Mahnaz Saraei
Department of Organic Chemistry, Faculty of Chemistry, University of Tabriz, Tabriz 51664, Iran
*E-mail: ashahrisa@yahoo.com
Received August 6, 2008
DOI 10.1002/jhet.80
Published online 13 April 2009 in Wiley InterScience (www.interscience.wiley.com).
2,6-Bis(1H-indole-6-yl)-4H-pyran-4-one 4 was synthesized via Leimgruber–Batcho methodology start-
ing from 2,6-bis(4-methyl-3-nitrophenyl)-4H-pyran-4-one 2. Enamine intermediate in this reaction, 3,
reacts with aroyl chlorides in the presence of 1,4-diazabicyclo[2.2.2]octane in dioxane to give the sub-
stituted enamines 8(a-c). Enamines 8a,b undergo reductive cyclization with Fe/AcOH to the correspond-
ing 3-aroylindoles 10a,b.
J. Heterocyclic Chem., 46, 273 (2009).
INTRODUCTION
variety of biologically important alkaloids [6]. 3-Aroy-
lindoles represent significant biological activities, for
example, some of these have potential as promising
anticancer agents [7]. For the synthesis of 3-aroylin-
doles, electrophilic substitution at C-3 position of indole
ring through reaction of indoles with aroyl chlorides in
the presence of Grignard reagents as base and/or metal
chlorides as Lewis acid is well known [7]. Another
appropriate method for synthesis of 3-substituted
indoles, which include functionalization of enamine
intermediates in Leimgruber–Batcho procedure, has
rarely been reported [8]. This modification, in which
reaction of the enamine intermediate with aroyl chlor-
ides carried out in the presence of a tertiary amine, can
be considerable for its potential regiochemical control in
the synthesis of 3-substituted indoles.
The indole ring system is one of the most ubiquitous
heterocycles in nature and an important structural com-
ponent in many pharmaceutical agents [1]. Therefore
synthesis and functionalization of indoles has been a
major area of focus for synthetic organic chemists, and
numerous methods for the preparation of indoles have
been developed [2]. One powerful procedure is the
Leimgruber–Batcho indole synthesis [3]. The classical
sequence of this reaction that has been used for the
preparation of 2,3-unsubstituted indoles, involves the
condensation of methyl group positioned adjacent to an
aromatic nitro group (as 2, Scheme 1) with N,N-di-
methyl formamide-dimethyl acetal (DMFDMA) to give
the enamine intermediate such as 3. Subsequent reduc-
tion of the nitro group leads to spontaneous cyclization
and formation of the corresponding indole derivative (as
4). Modifications of Leimgruber–Batcho procedure to
accelerate products formation [4] or to the production of
N-substituted indoles [5] have also been described.
Polycyclic aryl and heteroaryl substituted 4-pyrones
have also been found in a variety of natural and syn-
thetic biologically active compounds [9]. They have
been shown to be anticoagulant [10a], anti-HIV [10b],
and antitumor [10c] agents. Through our attempts to
prepare various azaaryl substituted 4-pyrones, we turned
Synthesis of 3-substituted indoles has also received
continued attention. 3-Acylindoles are precursors to a
C
V
2009 HeteroCorporation

274
A. Shahrisa, Z. Ghasemi, and M. Saraei
Vol 46
Scheme 1
Scheme 2
We then examined the incorporation of aroyl substitu-
ents onto the enamine intermediate 3. The reactivity of
enamine 3 toward aroyl chlorides such as benzoylchlor-
ide, 4-methylbenzoylchloride, and 4-nitrobenzoylchloride
was explored initially using triethylamine in dry dioxane
at 90ꢁC. Under these conditions no reactivity was
observed. Then, we used 2 equiv. of DABCO instead of
triethylamine, and the substitution was successfully
achieved as shown in Scheme 3. The structures of prod-
ucts 8a-c were characterized by spectroscopic data and
elemental analysis.
our attention to the 4-pyrone derivatives that would
allow for the construction of the indole moiety. Herein,
we report synthesis of two (1H-indole-6-yl)-4-pyrones
via the Leimgruber–Batcho methodology and then reac-
tion of enamine intermediate 3 with aroylchlorides in
the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO)
as tertiary amine and the results of reductive cyclization
of obtained enaminones for synthesis of 3-aroyl substi-
tuted indole derivatives.
In the final step, a few reagents and conditions were
evaluated to optimize the reductive cyclization of enami-
nones 8a-c to form the 3-aroyl substituted indole deriva-
tives. When the compound 8a was treated with Zn or Fe
in 1:1 mixture of EtOH–AcOH at 90–100ꢁC for 24 h, the
major product that was formed and separated, showed a
singlet at 3.0 ppm for 12 protons in 1H NMR spectrum (in
DMSO-d6), which indicated the presence of AN(CH3)2
groups in molecule and established that the cyclization
has not been accomplished. Spectroscopic data confirmed
the symmetrical structure of 9, which was obtained in
32% yield under these conditions (Fig. 1).
RESULTS AND DISCUSSION
Scheme 1 shows the synthetic sequences for prepara-
tion of product 4. The starting compound 1 was syn-
thesized through cyclization of related 1,3,5-triketone
derivative under acidic conditions, which is an important
method for the synthesis of a variety of 4-pyrone struc-
tures [11]. Nitration of 1 with HNO3/H2SO4 at ꢀ5ꢁC for
0.5 h afforded the dinitro 2 in quantitative yield. These
nitration conditions were different from those reported
for nitration of diphenyl-4-pyrones [12]. Treatment of 2
with 8 equiv. of DMFDMA at 90ꢁC for 24 h gave stable
dienamine 3 in 86% yield. Reductive cyclization of 3
was carried out using Fe or Zn in EtOH/HOAc at 80ꢁC,
that provided the 2,6-bis(1H-indole-6-yl)-4H-pyran-4-
one 4 after 5 and 24 h, respectively. Therefore the con-
ditions using Fe/EtOH/AcOH were optimal resulting in
a faster and also a cleaner reaction.
Treatment of enaminones 8a and 8b with Fe/AcOH at
100ꢁC for 24 h, gave the desired bis(indole) derivatives
Scheme 3
We also used 2-(4-methylphenyl)-6-methyl-4H-pyran-
4-one 5 in the same synthetic sequence. This compound
was synthesized according to reported procedure [13].
Nitration of 5 gave the ortho-nitrotolyl derivative 6.
Treatment of 6 with DMFDMA at 80ꢁC and subsequent
reduction of nitro group resulted the indole 7 in 33%
yield. The enamine intermediate in this reaction that
was not isolated was readily converted to indole 7, by
stirring with the Zn/EtOH/AcOH mixture at room tem-
perature for 4 h. This result indicated that oxidation of
the methyl ortho- to nitro-group in compound 6 has pre-
dominantly been achieved (Scheme 2).
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Synthesis of 2,6-Bis(1H-indole-6-yl)-4H-pyran-4-ones
via Leimgruber–Batcho Indole Synthesis
275
ric acid (95–98%) cooled to ꢀ5ꢁC using ice-salt bath. To this
solution, 7 mL of fuming nitric acid was added dropwise over
15 min. The reaction mixture was stirred at ꢀ5ꢁC for a further
0.5 h and then poured to 100 g ice. The produced precipitate
was collected by filtration and washed with water and dried in
vacuo to give 2 (4.7 g, 98% yield) as a white solid, mp
254ꢁC; FTIR (KBr): m 3065, 2977, 1663 (pyrone C¼¼O), 1614,
1528, 1444, 1355 cmꢀ1 1H NMR(CDCl3): d 2.703 (s, 6H,
;
CH3), 6.861 (s, 2H, pyrone H-3), 7.564 (d, 2H, J ¼ 8.1 Hz,
phenyl H-5), 7.948 (dd, 2H, J ¼ 8.0, 1.9 Hz, phenyl H-6),
8.438 (d, 2H, J ¼ 1.9 Hz, phenyl H-2) ppm; 13C NMR
(CDCl3): d 19.5 (CH3), 111.4, 121.1, 128.6, 129.3, 133.0,
136.1, 148.7, 160.0, 178.0 (pyrone CO) ppm. MS (m/z, %):
366 (Mþ, 30), 338 (100). Anal. Calcd. for C19H14N2O6: C,
62.32; H, 3.82; N, 7.65. Found: C, 61.94; H, 3.89; N, 7.39.
2,6-Bis{4-[trans-2-(N,N-dimethylamino)ethenyl]-3-nitro-
phenyl}-4H-pyran-4-one (3). A mixture of (2) (4.70 g, 0.013
mol) and DMFDMA(12.4 g, 0.104 mol) in 100 mL DMF was
heated at 90ꢁC under Ar for 24 h. After cooling, the precipi-
tated product was filtered, washed several times with H2O, and
dried in vacuo to provide 5.3 g (86.5 %) of 3 as a deep red
solid, mp 250ꢁC; FTIR(KBr): m 3075, 2900, 2802, 1640 (py-
Figure 1. Structure of compound 9 obtained from reduction of the
enaminone 8a with Zn in EtOH–AcOH (1:1).
10a and 10b as major products, respectively (Scheme 4).
These compounds were separated and characterized by
spectroscopic methods. The Fe/AcOH system has been
described previously for reduction-cyclization of nitro
group for construction of a variety of indole structures
[14].
We also found that using Fe in 1M aqueous HCl solu-
tion/MeOH with heating resulted in a complex mixture
with unidentified residues.
rone C¼¼O), 1591, 1516, 1375, 1209, 1098 cmꢀ1
;
1H NMR
(DMSO-d6): d 2.975 (s, 12H, AN(CH3)2), 5.713 (d, 2H, J ¼
13.2 Hz, PhCH¼¼), 6.961 (s, 2H, pyrone H-3), 7.777 (d, 2H, J
¼ 13.2 Hz, ¼¼CHAN(Me)2), 7.859 (d, 2H, J ¼ 8.9 Hz, phenyl
H-5), 7.935 (dd, 2H, J ¼ 8.8, 1.9 Hz, phenyl H-6), 8.364 (d,
2H, J ¼ 2.0 Hz, phenyl H-2) ppm; 13C NMR (CDCl3): d 39.9
(CH3-N), 89.5, 109.2, 122.4, 123.0, 123.2, 127.6, 137.8, 143.2,
145.7, 160.4, 178.6 (pyrone CO) ppm; MS (m/z, %): 476 (Mþ,
65), 459 (40), 386 (50), 42 (100); Anal. Calcd. for
C25H24N4O6: C, 63.02; H, 5.04; N, 11.76. Found: C, 62.86; H,
5.27; N, 11.90.
2,6-Bis(1H-indole-6-yl)-4H-pyran-4-one (4). A suspension
of (3) (0.476 g, 1 mmol), AcOH (6 mL), EtOH (6 mL), and Fe
(2.24 g, 40 mmol) was heated with stirring at 80ꢁC. After 5 h,
the dark color of the reaction mixture disappeared and a brown
suspension was obtained, indicating the completion of reaction.
The reaction mixture was cooled, concentrated by rotary evapo-
rator to remove EtOH, neutralized by saturated NaHCO3 solu-
tion, and then extracted by EtOAc. The extract was dried over
anhydrous Na2SO4, concentrated and purified by thin-layer chro-
matography (silica gel, 1:1 acetone:n-hexane) to give 0.114 g
(35% yield) of 4, mp 280ꢁC (decomp.); FTIR (KBr): m 3367
(NH), 3161, 2918, 1637 (pyrone C¼¼O), 1575, 1554, 1456,
1395, 1181 cmꢀ1; 1H NMR (DMSO-d6): d 6.557 (t, br., 2H, J ¼
1.8 Hz, indole H-3), 6.891 (s, 2H, pyrone H-3), 7.568 (t, 2H, J ¼
2.7 Hz, indole H-2), 7.674 (dd, 2H, J ¼ 8.4, 1.5 Hz, indole H-5),
7.739 (d, 2H, J ¼ 8.4 Hz, indole H-4), 8.091 (s, 2H, indole H-7),
11.506 (s, 2H, NH) ppm; 13C NMR (DMSO-d6): d 101.6, 109.4,
In conclusion, we have reported the synthesis of two
Leimgruber–Batcho
(1H-indole-6-yl)-4-pyrones
via
indole synthesis, starting from the corresponding ortho-
methylnitrophenyl derivatives. Aroyl substituents at C-3
of the bis(indole) derivative were installed via reaction
of the enamine intermediate with aroylchlorides before
the final reductive cyclization. Among the different con-
ditions and reagents that were examined for reductive
cyclization of enaminoketones, the Fe/AcOH at 100ꢁC
was the appropriate method for this purpose. This modi-
fied Leimgruber–Batcho procedure is attractive because
of the regioselectivity of substitution, which may be
observed less in the direct C-3 aroylation of indole
nucleus.
EXPERIMENTAL
Melting points were determined on a 1202D model Electro-
thermal MEL-TEMP apparatus and are uncorrected. FTIR
spectra were obtained with a Bruker Tensor 27 spectrometer.
1H NMR and 13C NMR spectra were recorded with a Bruker
Spectrospin Avance 400 spectrometer operating at 400 and
100 MHz, respectively; chemical shifts are given in parts per
million (ppm, d) relative to solvent peaks as internal standards
(d: CDCl3: 7.26 ppm (1H), 76 ppm (13C); DMSO-d6: 2.50 ppm
(1H), 39.5 ppm (13C)). Mass spectra (MS) were measured by a
Shimadzo (70 ev) spectrometer and elemental analyses were
measured by Vario EL III apparatus (Elementar Co.). Column
chromatography was done using silica gel (Merk Kieselgel 60,
no. 9385, 230-400 mesh ASTM). Thin-layer chromatography
was done with prepared glass-backed plates (20 ꢂ 20 cm2,
500 l) using silica gel (Merk Kieselgel 60 HF254, no. 7739).
Scheme 4
2,6-Bis(4-methyl-3-nitrophenyl)-4H-pyran-4-one
stirred solution of 3.66 g (0.013 mol) of 2,6-bis(4-methyl-
(2). A
phenyl)-4H-pyran-4-one (1) in 11.5 mL of concentrated sulfu-
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A. Shahrisa, Z. Ghasemi, and M. Saraei
Vol 46
109.6, 116.6, 120.6, 123.7, 128.6, 130.1, 135.7, 163.9, 178.8
(pyrone CO) ppm; MS (m/z, %): 326 (Mþ, 80), 298 (100), 269
(20), 141 (45); Anal. Calcd. for C21H14N2O2: C, 77.30; H, 4.29;
N, 8.59. Found: C, 77.0; H, 4.55; N, 8.53.
obtained as a red solid in 67% yield, mp 160–162ꢁC; FTIR
(KBr): m 3062, 2921, 1702 (benzoyl C¼¼O), 1649 (pyrone
C¼¼O), 1579, 1534, 1382, 1312 cmꢀ1
;
1H NMR (CDCl3): d
2.832 (s, 12H, AN(CH3)2), 6.887 (s, 2H, pyrone H-3), 7.262
(d, 2H, J ¼ 1.9 Hz, ¼¼CHAN(Me)2), 7.470–7.362 (m, 10H,
benzoyl-H), 7.519 (d, 2H, J ¼ 6.9 Hz, phenyl H-5), 8.006 (d,
2H, J ¼ 6.5 Hz, phenyl H-6), 8.392 (s, 2H, phenyl H-2) ppm;
13C NMR (CDCl3): d 42.8 (CH3-N), 106.5, 111.4, 120.5,
127.0, 127.4, 127.6, 129.0, 129.5, 134.2, 134.7, 139.6, 149.8,
154.3, 160.1, 178.2 (pyrone CO), 192.3 (benzoyl CO) ppm;
Anal. Calcd. for C39H32N4O8: C, 68.35; H, 4.67; N, 8.18.
Found: C, 68.63; H, 5.00; N, 8.05.
2-(4-Methyl-3-nitrophenyl)-6-methyl-4H-pyran-4-one
(6). A stirred solution of 0.4 g (2 mmol) of 2-(4-methyl-
phenyl)-6-methyl-4H-pyran-4-one (5) in 1 mL of concentrated
sulfuric acid (95–98 %) cooled to ꢀ5ꢁC using ice-salt bath. To
this solution, 0.6 mL of fuming nitric acid was added dropwise
over 15 min. The reaction mixture was stirred at ꢀ5ꢁC for a
further 0.5 h and then poured to 100 g ice. The precipitate was
collected by filtration, washed with water, and dried in vacuo
to give 6 (0.45 g, 92% yield) as a white solid, mp 160ꢁC;
FTIR (KBr): m 3066, 2970, 1660 (pyrone C¼¼O), 1612, 1531,
2,6-Bis{4-[(Z)-2-(N,N-dimethylamino)-1-(4-methylbenzoyl)
ethenyl]-3-nitrophenyl}-4H-pyran-4-one (8b). This compound
was obtained as a red solid in 65% yield, mp 165–168ꢁC; FTIR
(KBr): m 3021, 2918, 1702 (aroyl C¼¼O), 1649 (pyrone C¼¼O),
1579, 1531, 1382, 1308, 1096 cmꢀ1; 1H NMR (CDCl3): d 2.383
(s, 6H, p-CH3-benzoyl), 2.844 (s, 12H, N(CH3)2), 6.911 (s, 2H,
pyrone H-3), 7.187 (d, 4H, J ¼ 7.8 Hz, aroyl H-3), 7.298 (s, 2H,
¼¼CHAN(Me)2), 7.439 (d, 4H, J ¼ 7.9 Hz, aroyl H-2), 7.476 (s,
2H, phenyl H-5), 8.005 (s, br, 2H, phenyl H-6), 8.391 (s, 2H,
phenyl H-2) ppm; 13C NMR (CDCl3): 28.2 (p-CH3-benzoyl),
42.9 (CH3-N), 106.5, 111.5, 120.6, 127.0, 127.5, 127.6, 129.0,
129.6, 134.2, 134.7, 139.6, 149.8, 154.2, 160.1, 178.1 (pyrone
CO), 192.3 (aroyl CO) ppm; Anal. Calcd. for C41H36N4O8: C,
69.03; H, 5.05; N, 7.85. Found: C, 68.98; H, 5.09; N, 7.78.
2,6-Bis{4-[(Z)-2-(N,N-dimethylamino)-1-(4-nitrobenzoyl)-
ethenyl]-3–nitrophenyl}-4H-pyran-4-one (8c). This compound
was obtained as an orange solid in 54% yield, mp 172–174ꢁC;
FTIR (KBr): m 3070, 2921, 1711 (aroyl C¼¼O), 1648 (pyrone
1
1402, 1350, 1168, 920, 796 cmꢀ1; H NMR (CDCl3): d 2.378
(s, 3H, CH3), 2.627 (s, 3H, CH3), 6.172 (d, 1H, J ¼ 1.1 Hz,
pyrone H-5), 6.695 (d, 1H, J ¼ 1.9 Hz, pyrone H-3), 7.457 (d,
1H, J ¼ 8.1 Hz, phenyl H-5), 7.828 (dd, 1H, J ¼ 8.4, 1.7 Hz,
phenyl H-6), 8.324 (d, 1H, J ¼ 1.6 Hz, phenyl H-2) ppm; 13C
NMR (CDCl3): d 18.8, 19.3, 110.3, 113.5, 120.7, 128.3, 129.4,
132.6, 135.4, 148.4, 159.7, 164.5, 178.4 (pyrone CO) ppm;
MS (m/z, %): 245 (Mþ, 89), 228 (42), 217 (32), 172 (100), 89
(46); Anal. Calcd. for C13H11NO4; C, 63.67; H, 4.49; N, 5.71.
Found: C, 63.30; H, 4.52; N, 5.47.
2-(1H-indole-6-yl)-6-methyl-4H-pyran-4-one (7). A mix-
ture of (6) (0.4 g, 1.63 mmol) and DMFDMA (0.78 g, 6.53
mmol) in 1 mL DMF was heated at 80ꢁC under Ar for 24 h.
After cooling, 30 mL H2O was added to the reaction mixture
and the precipitated product was filtered, washed with H2O,
and dried in vacuo. The red solid was mixed with Zn (2.12 g,
32.6 mmol), EtOH (4 mL), and AcOH (4 mL). The mixture
was stirred at r.t. for 4 h and then concentrated by rotary evap-
orator. The residue was neutralized by saturated NaHCO3 solu-
tion and the precipitate was filtered. This solid was purified by
thin-layer chromatography (silica gel, 1:1 acetone:n-hexane) to
give 7 (0.12 g, 33% yield). mp 228ꢁC; FTIR (KBr): m
3331(NH), 3002, 2976, 1650 (pyrone C¼¼O), 1590, 1406,
C¼¼O), 1571, 1524, 1389, 1347, 1313, 1097 cmꢀ1
;
1H NMR
(CDCl3): d 2.881 (s, 12H, N(CH3)2), 6.920 (s, 2H, pyrone H-
3), 7.184 (s, 2H, ¼¼CHAN(Me)2), 7.490 (d, 2H, J ¼ 8.0 Hz,
phenyl H-5), 7.666 (d, 4H, J ¼ 8.5 Hz, aroyl H-3), 8.028 (d,
2H, J ¼ 7.8 Hz, phenyl H-6), 8.252 (d, 4H, J ¼ 8.5 Hz, aroyl
H-2), 8.429 (d, 2H, J ¼ 1.4 Hz, phenyl H-2) ppm; 13C NMR
(CDCl3): d 45.9 (CH3-N), 111.7, 120.8, 122.4, 122.5, 127.7,
128.1, 130.1, 133.7, 134.2, 145.6, 147.4, 149.8, 154.3, 178.1
(pyrone CO), 189.9 (aroyl CO) ppm; Anal. Calcd. for
C39H30N6O12: C, 60.41; H, 3.87; N, 10.84. Found: C, 60.09;
H, 4.13, N, 10.71.
1324, 1159, 916, 676 cmꢀ1 1H NMR (CDCl3): d 2.393 (s,
;
3H, CH3), 6.185 (d, 1H, J ¼ 1.0 Hz, pyrone H-5), 6.608 (s,
1H, pyrone H-3), 6.768 (d, 1H, J ¼ 2.2 Hz, indole H-3), 7.380
(t, 1H, J ¼ 2.8 Hz, indole H-2), 7.516 (dd, 1H, J ¼ 8.4, 1.5
Hz, indole H-5), 7.710 (d, 1H, J ¼ 8.4 Hz, indole H-4), 7.869
(s, 1H, indole H-7), 8.896 (s, 1H, NH) ppm; 13C NMR
(CDCl3): d 18.9 (CH3), 102.0, 108.1, 108.7, 113.1, 116.4,
120.1, 123.8, 126.2, 129.4, 134.6, 164.1, 164.2, 179.5 (pyrone
CO) ppm; MS (m/z, %): 225 (Mþ, 28); Anal. Calcd. for
C14H11NO2: C, 74.67; H, 4.89; N, 6.22. Found: C, 74.29; H,
5.00; N, 6.51.
General procedure for the synthesis of enaminoketones
(8a-c). A mixture of enamine (3) (0.952 g, 2 mmol), DABCO
(0.448 g, 4 mmol), and aroylchlorides (9a-c) (12 mmol) in 20
mL dioxane (dry) was heated at 90ꢁC for 20 h. The resulting
suspension was cooled to r.t. and water (120 mL) was added.
The resulting mixture was stirred for 5 min and then extracted
with chloroform (4 ꢂ 50 mL). The combined chloroform
extract was washed with 150 mL of H2O, dried over Na2SO4,
and concentrated to dryness. The residue was purified by col-
umn chromatography (silica gel, 6:4 acetone:n-hexane) to give
the products 9a-c.
2,6-Bis{3-amino-4-[(Z)-1-benzoyl-2-(N,N-dimethyl-
amino)ethenyl]phenyl}-4H-pyran-4-one (9). A suspension of
8a (0.342 g, 0.5 mmol), AcOH (3 mL), EtOH (3 mL), and Zn
(1.30 g, 20 mmol) was heated with stirring at 90ꢁC for 24 h.
The hot reaction mixture was then filtered and washed with an
appropriate amount of warm methanol. The combined filtrate
was then concentrated by rotary evaporator to remove the alco-
hols (EtOH, MeOH), neutralized by saturated NaHCO3 solu-
tion and extracted by EtOAc. The extract was dried over anhy-
drous Na2SO4, concentrated, and purified by thin-layer chro-
matography (silica gel, 1:1 acetone:chloroform) to give 0.099
g (32% yield) of 9 as brown solid, mp 300ꢁC (decomp.), FTIR
(KBr): m 3383, 3217 (NH2), 3067, 2920, 1737 (benzoyl C¼¼O),
1635 (pyrone C¼¼O), 1562, 1460, 1406 cmꢀ1
;
1H NMR
(DMSO-d6): d 3.024 (s, 12H, AN(CH3)2), 6.713 (s, 2H, pyrone
H-3), 6.777 (d, 2H, J ¼ 8.5 Hz, phenyl H-5), 7.419 (dd, 2H,
J ¼ 8.5, 1.5 Hz, phenyl H-6), 7.493–7.530 (m, 6H: 2H,
¼¼CHAN(Me)2, 4H, benzoyl H-3), 7.586 (t, 2H, J ¼ 7.3 Hz,
benzoyl H-4), 7.670 (d, 4H, J ¼ 7.6 Hz, benzoyl H-2), 7.957
(d, 2H, J ¼ 1.2 Hz, phenyl H-2), 11.686 (br., NH2) ppm; 13C
2,6-Bis{4-[(Z)-1-benzoyl-2-(N,N-dimethylamino) ethenyl]-3-
nitrophenyl}-4H-pyran-4-one (8a). This compound was
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Synthesis of 2,6-Bis(1H-indole-6-yl)-4H-pyran-4-ones
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277
[2] Humphrey, G. R.; Kuethe, J. T. Chem Rev 2006, 106,
NMR (DMSO-d6): d 41.7 (CH3-N), 97.3, 107.3, 108.0, 117.5,
118.3, 121.6, 128.4, 128.5, 131.2, 131.9, 133.1, 141.9, 155.5,
163.0, 178.9 (pyrone CO), 188.2 (benzoyl CO) ppm; Anal.
Calcd. for C39H36N4O4: C, 75.00; H, 5.77; N, 8.97. Found C,
74.88; H, 5.59; N, 9.16.
2875.
[3] (a) Ponticello, G. S.; Baldwin, J. J. J Org Chem 1979, 44,
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General procedure for the synthesis of 3-aroylindoles
(10a-b). A mixture of the enaminone 8a or 8b (0.3 mmol),
iron powder (0.5 g), and glacial HOAc (4 mL) was refluxed at
100ꢁC. After 24 h, the dark color of the reaction mixture dis-
appeared and a brown suspension was obtained. The reaction
mixture was cooled, neutralized by saturated NaHCO3 solu-
tion, and then extracted by EtOAc. The extract was dried over
anhydrous Na2SO4, concentrated and purified by thin-layer
chromatography (silica gel, EtOAc) to give the products 10a
or 10b in 25 and 22% yield, respectively.
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5-fluoroindole: Bentley, J. M.; Davidson, J. E.; Duncton, M. A. J.;
Giles, P. R. Synth Commun 2004, 34, 2295; (e) For a modified Leim-
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K.; Singh, S. K. J Org Chem 2003, 68, 5720; (c) Ottoni, O.; Neder, A.
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2,6-Bis(3-benzoyl-1H-indole-6-yl)-4H-pyran-4-one (10a).
This compound was obtained as a pale-yellow solid in 25%
yield, mp 270ꢁC (decomp.); FTIR (KBr): m 3416 (NH), 3122,
2923, 1736 (benzoyl C¼¼O), 1637 (pyrone C¼¼O), 1576, 1502,
1
1451 cmꢀ1; H NMR (DMSO-d6): d 7.011 (s, 2H, pyrone H-3),
7.550–7.586 (m, 4H, benzoyl H-3), 7.639 (t, 2H, J ¼ 7.0 Hz,
benzoyl H-4), 7.828 (d, 4H, J ¼ 7.1 Hz, benzoyl H-2), 7.954 (d,
2H, J ¼ 8.0 Hz, indole H-4), 8.140 (s, 2H, indole H-7), 8.234 (s,
2H, indole H-2), 8.404 (d, 2H, J ¼ 8.5 Hz, indole H-5), 8.879 (s,
2H, NH, deuterium oxide-exchangeable) ppm; 13C NMR
(DMSO-d6): d 110.3, 110.6, 115.2, 119.8, 122.1, 125.9, 128.5,
128.6, 128.7, 131.5, 136.8, 138.2, 140.1, 163.4, 179.1 (pyrone
CO), 190.0 (benzoyl CO) ppm; Anal. Calcd. for C35H22N2O4: C,
78.65; H, 4.12; N, 5.24. Found: C, 78.60; H, 4.23; N, 5.01.
2,6-Bis[1H-indole-3-(4-methylbenzoyl)-6-yl]-4H-pyran-4-one
(10b). This compound was obtained as a pale-yellow solid, mp
240ꢁC (decomp.); FTIR (KBr): m 3398 (NH), 3100, 2925,
1737 (aroyl C¼¼O), 1641 (pyrone C¼¼O), 1600, 1517, 1452,
[8] (a) Zhu, J.; Wong, H.; Zhang, Z.; Yin, Z. Tetrahedron Lett
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1
1423, 1383 cmꢀ1; H NMR (DMSO-d6): d 2.422 (s, 6H, CH3),
7.011 (s, 2H, pyrone H-3), 7.376 (d, 4H, J ¼ 7.9 Hz, aroyl H-
3), 7.751 (d, 4H, J ¼ 7.9 Hz, aroyl H-2), 7.946 (d, 2H, J ¼
8.6 Hz, indole H-4), 8.147 (s, 2H, indole H-7), 8.225 (s, 2H,
indole H-2), 8.302 (s, 2H, NH, deuterium oxide-exchangeable)
8.389 (d, 2H, J ¼ 8.5 Hz, indole H-5) ppm; 13C NMR
(DMSO-d6): d 28.4, 109.6, 110.8, 115.3, 119.3, 121.9, 125.3,
128.7, 128.9, 129.1, 131.2, 137.6, 138.2, 141.4, 162.9, 179.0
(pyrone CO), 189.6 (aroyl CO) ppm; Anal. Calcd. for
C37H26N2O4: C, 79.00; H, 4.62; N, 4.98. Found: C, 78.77; H,
4.45; N, 4.77.
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Acknowledgment. The authors thank research affairs of Univer-
sity of Tabriz for financial support.
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REFERENCES AND NOTES
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet