Synthesis of new 2-aryl-4-chloro-3-hydroxy-1H-indole-5,7-dicarbaldehydes via Vilsmeier-Haack reaction

Article abstract of DOI:10.1002/jhet.338

(Chemical Equation Presented) New 2-aryl-4-chloro-3-hydroxy-1H-indole-5,7- dicarbaldehydes were synthesized in three steps from acetophenone derivatives. By oxidation of acetophenones to aryl glyoxals using selenium dioxide and condensation with acetylacetone in the presence of ammonium acetate in water 3-acetyl-5-aryl-4-hydroxy-2-methyl-1H-pyrrols were obtained. 2-Aryl-4-chloro-3-hydroxy-1H-indole-5,7-dicarbaldehydes were synthesized via Vilsmeier-Haack reaction of pyrrole derivatives in moderate yields.

Full text of DOI:10.1002/jhet.338

March 2010
Synthesis of New 2-Aryl-4-chloro-3-hydroxy-1H-indole-5,7-
dicarbaldehydes via Vilsmeier-Haack Reaction
463
Bagher Eftekhari-Sis,a* Maryam Zirak,b Ali Akbari,a
and Mohammed M. Hashemic
aDepartment of Chemistry, Faculty of Science, University of Maragheh, Maragheh, Iran
bDepartment of Organic Chemistry, Faculty of Chemistry, Tabriz University, Tabriz, Iran
cDepartment of Chemistry, Sharif University of Technology, Tehran, Iran
*E-mail: eftekharisis@mhec.ac.ir
Received August 12, 2009
DOI 10.1002/jhet.338
Published online 4 March 2010 in Wiley InterScience (www.interscience.wiley.com).
New 2-aryl-4-chloro-3-hydroxy-1H-indole-5,7-dicarbaldehydes were synthesized in three steps from
acetophenone derivatives. By oxidation of acetophenones to aryl glyoxals using selenium dioxide and
condensation with acetylacetone in the presence of ammonium acetate in water 3-acetyl-5-aryl-4-
hydroxy-2-methyl-1H-pyrrols were obtained. 2-Aryl-4-chloro-3-hydroxy-1H-indole-5,7-dicarbaldehydes
were synthesized via Vilsmeier-Haack reaction of pyrrole derivatives in moderate yields.
J. Heterocyclic Chem., 47, 463 (2010).
INTRODUCTION
ring, the majority of which involve the elaboration of
the heterocyclic system from aniline, o-halo aniline, or
other 2-substituted aniline derivatives. In contrast, few
existing methods provide efficient and regiocontrolled
access to indoles that are highly substituted on the ben-
zenoid ring. Herein we disclose a method, based on
Vilsmeier-Haack reaction of 3-acetyl-4-hydroxy-2-
methyl-5-phenyl-1H-pyrrols 3, to provide new highly
substituted indoles 4 with substituted on both five-mem-
bered and benzenoid ring of indole (Scheme 1).
The synthesis of indoles has occupied organic chem-
ists for well over a century [1]. And the invention of
new synthetic routes to substituted indoles continues to
command wide interest due to the numerous natural
products [2], physiologically active natural products and
important pharmaceuticals [3] whose structures incorpo-
rate this heterocyclic system. Indole derivatives are used
as neuroprotective agents affecting oxidative stress [3f],
potent opioid receptor agonists [3g], highly functional-
ized pharmacophores [3h], potent PPAR-c binding
agents with potential application for the treatment of
osteoporosis [3i], drugs for the treatment of peripheral
neuropathy and neurodegenerative diseases [3j,k], gluco-
kinase activators [3l,m], the cytotoxic antibiotic CC-
1065 and prodrugs [3n], PPAR-delta activators for the
treatment of cardiovascular diseases [3o] and dyestuffs
[4]. The combination of traditional and modern methods
has provided accessibility to a wide variety of structural
variations of this important class of heterocycles [3e,5].
A number of useful strategies are now available for the
synthesis of indoles substituted on the five-membered
The Vilsmeier–Haack reaction is a widely used
method for the formylation of activated aromatic and
heteroaromatic compounds [8]. The reactions of aliphatic
substrates [9], particularly carbonyl compounds [10] with
chloromethylene iminium salts are highly versatile. They
lead to multiple iminoalkylations in the presence of
excess reagent and the resulting intermediates undergo
cyclization to afford aromatic or heterocyclic compounds
[11]. Multifunctional intermediates derived from these
reactions (e.g., b-chloroenaldehydes) are subsequently
exploited for the synthesis of functionalized heterocycles
or other valuable target molecules [12].
C
V
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464
B. Eftekhari-Sis, M. Zirak, A. Akbari, and M. M. Hashemi
Vol 47
Scheme 1. Three steps synthesis of 2-aryl-4-chloro-3-hydroxy-1H-
indole-5,7-dicarbaldehydes.
In conclusion, we have reported the synthesis of new
2-aryl-4-chloro-3-hydroxy-1H-indole-5,7-dicarbaldehydes
via Vilsmeier-Haack reaction starting from acetophenone
derivatives.
EXPERIMENTAL
General methods. Chemical shifts of the 1H NMR spectra
are reported in d (ppm) from tetramethylsilane with the solvent
as the internal standard (deuteriodimethyl sulfoxide, d ¼ 2.5
ppm), and coupling constants J were measured in Hz. Data are
reported as follows: chemical shifts, multiplicity (s ¼ singlet,
d ¼ doublet, t ¼ triplet, q ¼ quartet, dd ¼ doublet of doublets,
m ¼ multiplet, br ¼ broad). 13C NMR spectra were recorded
with complete proton decoupling. Chemical shifts are reported
in ppm from tetramethylsilane with the solvent as the internal
standard (deuteriodimethyl sulfoxide, d ¼ 39.0 ppm). Elemen-
tal analyses were carried out by using a CHN analyzer. IR
analyses were performed with an FT-IR spectrophotometer. IR
spectra of compounds are expressed by wavenumber (cmꢀ1).
General procedure for synthesis of 2-aryl-4-chloro-3-
hydroxy-1H-indole-5,7-dicarbaldehydes 4. POCl3 (3 mmol)
was added dropwise to dimethylformamide (DMF) (1.5 mL)
RESULTS AND DISCUSSION
The reaction of 2-hydroxyacetophenones with Vilsme-
ier-Haack reagent also involves an iminoalkylation-cycli-
zation sequence, leading to the formation of 3-formyl
chromones 5 [13]. Similarly we expected to synthesis the
5-methyl-4-oxo-7-phenyl-4,6-dihydro-pyrano[2,3-c]pyr-
role-3-carbaldehyde 6a from the reaction of 3-acetyl-4-
hydroxy-2-methyl-5-phenyl-1H-pyrrol 3 with Vilsmeier-
Haack reagent, but we did not obtained the expected
compound 6a instead the reaction gave compound 4. In
the case of 4-bromoacetophenone 1c, not only 4c was
formed but also 6b was obtained in low yield.
Table 1
Synthesis of 2-aryl-4-chloro-3-hydroxy-1H-indole-5,7-dicarbaldehydes
4 via Vilsmeier-Haack reaction.
Acetophenone 1
Indole 4
Yield (%)a
31
42
53
35
Four examples of the conversion of acetophenones
1a–1d to various 2-aryl-4-chloro-3-hydroxy-1H-indole-
5,7-dicarbaldehydes 4a–4d are listed in Table 1.
As shown in Scheme 2, the proposed mechanism
involves the addition of enol 7 to the 2 equiv. chlorome-
thyleneiminium salt 8, then bis-iminium salt 9 under-
goes iminoalkylation to result enamine 10, that undergo
cyclization and elimination of dimethylamine to afford
the bis-iminium salt 12 which on hydrolysis leads to the
formation of 2-aryl-4-chloro-3-hydroxy-1H-indole-5,7-
dicarbaldehydes 4 [14].
4-Chloro-2-phenyl-5,7-bis-phenyliminomethyl-1H-indol-
3-ol 14 and 4-chloro-5,7-bis[(2,4-dinitrophenyl)-hydra-
zonomethyl]-2-phenyl-1H-indol-3-ol 16 were synthe-
sized from the reaction of 4a with aniline 13 and 2,4-
dinitrophenylhydrazine 15 in the presence of catalytic
amount of H2SO4 respectively (Scheme 3).
a Yield of indole from pyrrole (3).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2010
Synthesis of New 2-Aryl-4-chloro-3-hydroxy-1H-indole-5,7-dicarbaldehydes via
Vilsmeier-Haack Reaction
465
Scheme 2. Proposed mechanism for conversion of pyrroles 3 to indoles 4.
with stirring at 30–35ꢁC, after the addition, the mixture was
stirred at 50ꢁC for 1 h. Then the solution of 3-acetyl-5-aryl-4-
hydroxy-2-methyl-1H-pyrrol 3 (0.5 mmol) at least amount of
DMF was added dropwise with stirring to the above mixture.
After that the mixture was stirred at 45–55ꢁC for 2 h, kept
over the night at room temperature and poured over mixture of
ice and water (10 g). Product was stirred for 0.5 h, then fil-
tered off and recrystallized from ethanol.
4-Chloro-3-hydroxy-2-phenyl-1H-indole-5,7-dicarbaldehyde
(4a). A yellow solid, mp: decomposed at 258.2–261.2ꢁC; IR
(KBr) 3553, 3343, 3053, 2853, 1671, 1580, 1425, 1025, 902,
812, 683 cmꢀ1 1H NMR (500 MHz, DMSO-d6): d 11.55 (s,
;
1H, NH, Exchanged with D2O), 10.49 (s, 1H, CHO), 10.39 (s,
1H, CHO), 8.75 (s, 1H, OH, Exchanged with D2O), 8.17 (s,
1H, CH), 8.01 (d, J ¼ 7.5 Hz, 2H, CH), 7.51 (t, J ¼ 7.45 Hz,
2H, CH), 7.37 (t, J ¼ 7.3 Hz, 1H, CH) ppm; 13C NMR (125
MHz, DMSO-d6): d 192.6, 189.5, 136.6, 134.6, 134.4, 130.9,
130.7, 129.3, 128.4, 127.7, 127.3, 124.8, 122.1, 119.8 ppm;
Anal. Calcd. for C16H10ClNO3: C, 64.12; H, 3.36; N, 4.67.
Found: C, 63.98; H, 3.50; N, 4.72.
C16H9BrClNO3: C, 50.76; H, 2.40; N, 3.70. Found: C, 50.82;
H, 2.53; N, 3.66.
2-Biphenyl-4-yl-4-chloro-3-hydroxy-1H-indole-5,7-dicarbal-
dehyde (4d). A yellow solid, mp: decomposed at 204.1–
205.9ꢁC; IR (KBr) 3561, 3419, 3033, 2922, 2857, 1670, 1598,
1468, 1427, 1029, 901, 840, 766, 697 cmꢀ1 1H NMR (500
;
MHz, DMSO-d6): d 11.60 (s, 1H, NH, Exchanged with D2O),
10.49 (s, 1H, CHO), 10.40 (s, 1H, CHO), 8.82 (s, 1H, OH,
Exchanged with D2O), 8.17 (s, 1H, CH), 8.12 (d, J ¼ 7.1 Hz,
2H, CH), 7.83 (d, J ¼ 7.0 Hz, 2H, CH), 7.76 (d, J ¼ 5.8 Hz,
2H, CH), 7.49 (m, 2H, CH), 7.39 (m, 1H, CH) ppm; 13C NMR
(125 MHz, DMSO-d6): d 192.6, 189.4, 140.5, 140.0, 136.6,
134.6, 134.4, 132.3, 130.9, 130.7, 129.7, 129.3, 128.4, 127.7,
127.3, 124.8, 122.1, 119.8 ppm; Anal. Calcd. for
C22H14ClNO3: C, 70.31; H, 3.75; N, 3.73. Found: C, 70.51; H,
3.68; N, 3.75.
7-(4-Bromophenyl)-5-methyl-4-oxo-4,6-dihydro-pyrano [2,3-
c]pyrrole-3-carbaldehyde (6b). In addition to 2-(4-bromo-
phenyl)-4-chloro-3-hydroxy-1H-indole-5,7-dicarbalde-hyde 4c,
5-methyl-4-oxo-7-phenyl-4,6-dihydro-pyrano[2,3-c]pyrrole-3-
carbaldehyde 6b was obtained in the case of 4-bromoaceto-
4-Chloro-2-(4-fluorophenyl)-3-hydroxy-1H-indole-5,7-dicar-
baldehyde (4b). A yellow solid, mp: decomposed at 286.2–
289.3ꢁC; IR (KBr) 3553, 3360, 3058, 2843, 1670, 1584, 1471,
1
phenone. Ratio of 4c/6a was obtained 68/32, according to H
NMR spectrum of the mixture of 4c and 6a. This product
1
1030, 901, 834, 634 cmꢀ1; H NMR (500 MHz, DMSO-d6): d
11.60 (s, 1H, NH, Exchanged with D2O), 10.48 (s, 1H, CHO),
10.37 (s, 1H, CHO), 8.74 (s, 1H, OH, Exchanged with D2O),
8.16 (s, 1H, CH), 8.04 (dd, JH,F ¼ 8.07 Hz, JH,H ¼ 5.75 Hz,
2H, CH), 7.35 (t, J ¼ 8.75 Hz, 2H, CH) ppm; 13C NMR (125
MHz, DMSO-d6): d 192.5, 189.6, 161.3, 136.6, 134.5, 134.4,
129.9, 127.5, 127.1, 124.8, 122.0, 119.9, 116.4, 116.2 ppm;
Anal. Calcd. for C16H9ClFNO3: C, 60.49; H, 2.86; N, 4.41.
Found: C, 60.60; H, 2.73; N, 4.16.
Scheme 3
2-(4-Bromophenyl)-4-chloro-3-hydroxy-1H-indole-5,7-dicar-
baldehyde (4c). A yellow solid, mp: decomposed at 268.9–
272.5ꢁC; IR (KBr) 3540, 3352, 3030, 2839, 1670, 1585, 1465,
1
1030, 902, 814, 633 cmꢀ1; H NMR (500 MHz, DMSO-d6): d
11.63 (s, 1H, NH, Exchanged with D2O), 10.47 (s, 1H, CHO),
10.38 (s, 1H, CHO), 8.74 (s, broad, 1H, OH, Exchanged with
D2O), 8.18 (s, 1H, CH), 7.97 (d, J ¼ 8.4 Hz, 2H, CH), 7.35
(d, J ¼ 8.35 Hz, 2H, CH) ppm; 13C NMR (125 MHz, DMSO-
d6): d 192.5, 189.5, 136.7, 135.4, 134.7, 132.2, 130.2, 129.6,
127.7, 126.7, 124.9, 122.0, 121.4, 119.9 ppm; Anal. Calcd. for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

466
B. Eftekhari-Sis, M. Zirak, A. Akbari, and M. M. Hashemi
Vol 47
was characterized only in mixture with 4c using 1H NMR
spectrum and eliminate from mixture with washing of solid
with warm 85% ethanol. 1H NMR (500 MHz, DMSO-d6): d
11.75 (s, 1H, NH, Exchanged with D2O), 10.43 (s, 1H,
CHO), 8.63 (s, 1H, CH), 7.57 (d, J ¼ 8.2 Hz, 2H, CH), 7.36
(d, J ¼ 8.2 Hz, 2H, CH), 2.5 (s, 3H, CH3) ppm.
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4-Chloro-2-phenyl-5,7-bis-phenyliminomethyl-1H-indol-3-ol
(14). To mixture of 4-chloro-3-hydroxy-2-phenyl-1H-indole-
5,7-dicarbaldehyde 4a. (0.2 mmol) and 3 drops of concentrate
H2SO4 in boiling ethanol (5 mL), was added Aniline 13 (0.4
mmol), and stirred at the same temperature for the 5 min.
Then the heat was removed and solution was cooled to room
temperature and product was obtained as pale yellow crystals
in 85% yield by filtration and washing with 5 mL of ethanol.
mp: decomposed at 173.6–175.1ꢁC; IR (KBr) 3559, 3053,
2849, 2585, 2060, 1677, 1557, 1497, 1321, 1015, 741, 685,
606 cmꢀ1 1H NMR (500 MHz, DMSO-d6): d 11.34 (s, 1H,
;
NH, Exchanged with D2O), 9.20 (s, 1H, HC¼¼NPh), 9.05 (s,
1H, HC¼¼NPh), 8.52 (s, 1H, OH, Exchanged with D2O), 8.00
(d, J ¼ 7.55 Hz, 1H, CH), 7.5–7.04 (m, 15H, CH) ppm; Anal.
Calcd. for C28H20ClN3O: C, 74.74; H, 4.48; N, 9.34. Found:
C, 74.68; H, 4.47; N, 9.21.
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4-Chloro-5,7-bis-[(2,4-dinitrophenyl)hydrazonomethyl]-2-
phenyl-1H-indol-3-ol (16). To the solution of 2,4-dinitrophe-
nylhydrazine 15 (0.6 mmol) and 3 drops of concentrate H2SO4
in mixture of ethanol/water (3/2 mL), was added the hot solu-
tion of 4-chloro-3-hydroxy-2-phenyl-1H-indole-5,7-dicarbalde-
hyde 4a (0.2 mmol) in ethanol (5 mL), and stirred for the 5
min. Then solution was cooled to room temperature and prod-
uct was obtained as dark purple solid in 83% yield by filtration
and washing with 5 mL of mixture of ethanol/water (3/2 mL).
mp: 326.8–328.5ꢁC. Don’t soluble in solvents such as DMSO-
d6, Aceton-d6 and etc. for taking NMR spectra. IR (KBr)
3539, 3428, 3270, 3087, 1613, 1508, 1422, 1329, 1208, 1131,
920, 827, 734, 597 cmꢀ1; Anal. Calcd. for C28H18ClN9O9: C,
50.96; H, 2.75; N, 19.10. Found: C, 51.09; H, 2.64; N, 18.93.
In comparing of IR spectrum of 16 with IR spectrum of 4a,
peak of the CAH of the aldehyde group at 2850 cmꢀ1 for 4a
was eliminated in 16 IR spectrum, and the C¼¼O peak of 4a at
1673 cmꢀ1 was replaced with C¼¼N peak of 16 at 1613 cmꢀ1
.
Acknowledgments. The authors thank the research council of
the University of Maragheh and Mr. S. Taheri (Sharif University
of Technology) for taking NMR Spectra.
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DOI 10.1002/jhet

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Synthesis of New 2-Aryl-4-chloro-3-hydroxy-1H-indole-5,7-dicarbaldehydes via
Vilsmeier-Haack Reaction
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet