Formation of indole trimers in Vilsmeier type reactions

Article abstract of DOI:10.24820/ark.5550190.p011.012

The reaction of indole with the complex formed from 1,3-dimethylimidazolidin-2-one or N-methyloxindole with phosphorus oxychloride (phosphoryl chloride), was studied. In similar reactions of five-membered tertiary amide rings, 3-(1-alkyl-pyrrolidin-2-ylidene)-3H-indoles or ring opening products were obtained but in these cases, new products N¹,N²-dimethyl-N¹-[tri-(1H-indol-3-yl)methyl]ethane-1,2-diamine and N-methyl-2-(3,3,3-tri-(1H-indol-3-yl)propyl)aniline as trimers of indole were obtained. (Formula presented).

Full text of DOI:10.24820/ark.5550190.p011.012

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Formation of indole trimers in Vilsmeier type reactions
Masomeh Aghazadeha,b
a Department of Chemistry, Maku Branch, Islamic Azad University, Maku, 58619-93548, Iran
b Young Researchers and Elite Club, Maku Branch, Islamic Azad University, Maku, 58619-93548, Iran
Email: aghazadehchemist@gmail.com
Received 07-02-2019
Accepted 09-27-2019
Published on line 10-10-2019
Abstract
The reaction of indole with the complex formed from 1,3-dimethylimidazolidin-2-one or N-methyloxindole
with phosphorus oxychloride (phosphoryl chloride), was studied. In similar reactions of five-membered
tertiary amide rings, 3-(1-alkyl-pyrrolidin-2-ylidene)-3H-indoles or ring opening products were obtained but in
these cases, new products N1,N2-dimethyl-N1-[tri-(1H-indol-3-yl)methyl]ethane-1,2-diamine and N-methyl-2-
(3,3,3-tri-(1H-indol-3-yl)propyl)aniline as trimers of indole were obtained.
H
N
NH
N
O
N
N
HN
NH
NH
POCl3
+
-10 to 0 °C
N
H
HN
O
N
HN
N
H
Keywords: Indoles, Vilsmeier reactions, 1,3-dimethylimidazolidin-2-one, N-methyloxindole
DOI: https://doi.org/10.24820/ark.5550190.p011.012
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Introduction
The reaction of indole with the Vilsmeier reagent, followed by base, is the classic and very efficient method for
the 3-formylation of indoles.1 3-Acylindoles can be obtained from Vilsmeier reaction of indole and tertiary
amides in combination with phosphorus oxychloride.2 However, when 1-methylpyrrolidin-2-one is used as the
cyclic amide component, 3-(1-methylpyrrolidin-2-ylidene)-3H-indole (1) is the product, without formation of
an amino ketone product (2) (Scheme 1).3,4 Compound 1 contains an intriguing combination of enamine and
imine (as part of a 3H-indole) groups in conjugation.
O
N
N
POCl3
H
//
+
O
N
N
N
N
H
H
2
1
Scheme 1. The reaction of 1-methylpyrrolidin-2-one with indole under Vilsmeier conditions.
Usually the primary products, resulting from the Vilsmeier–Haack acylation, are hydrolyzed immediately
without isolation of the intermediate iminium salts.5 Iminium chemistry is the basis of an important
formylation reaction of aromatic and heteroaromatic ring systems. Iminium salts and their neutral relatives,
the imines, have found importance in the synthesis of heterocyclic ring systems.6 They react as electrophiles
with electron-rich systems such as indoles.7 The iminium ion has a short lifetime in water and it is known to
have an even shorter lifetime in the presence of a strong nucleophilic reagent.8
Indole derivatives are widely distributed in nature and are known as an important class of heterocyclic
compounds and bioactive intermediates in pharmaceutical industry.9 Various derivatives of indole have been
synthesized to study their bioactivity. Thus di- and tri- indolylmethanes are well known, and the electrophilic
substitution reaction of indoles with carbonyl compounds is an important method for their preparation.
Bis(indolyl)methanes promote beneficial estrogen metabolism and induce apoptosis in human cancer cells.10
Thus, there is great interest in the synthesis of these compounds.11-15 Many simple indoles and bisindoles have
been shown to have interesting biological activities.16,17 It is reported that triindolylmethane cations could be
used as the acceptors of hydride ions.18 However, there is no report on the biological activity of triindoles,
especially, triindolylmethanes.
Our continuing interest involves using alternatives to 1-methyl-2-pyrrolidinone in Vilsmeier-type reactions
with indole. The reactions of indole with the complex formed from different tertiary cyclic amides and
phosphorus oxychloride were studied in our group.19-24 In similar reactions of five-membered tertiary amide
rings, 3-(1-alkyl-pyrrolidin-2-ylidene)-3H-indoles or ring opening products were obtained. The 3-(2-pyrrolidin-
ylidene)-3H-indoles are stable compounds and they resist hydrolysis to the corresponding amino ketones.
Finally, we came to try 1,3-dimethylimidazolidin-2-one (3) and N-methyloxindole (4) as tertiary cyclic amides in
reaction with indole and phosphorus oxychloride.
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N
N
O
O
N
4
3
Results and Discussion
Our interest in this type of reaction promoted us to test the use of 1,3-dimethylimidazolidin-2-one (3) and
N-methyloxindole (4). When 1,3-dimethylimidazolidin-2-one, instead of 1-methylpyrrolidin-2-one, was reacted
with phosphorus oxychloride at –10 to 0 °C, an active complex was obtained that took a different path in its
reaction with indole. The expected products (5) or (6) by analogy were not formed, but instead reaction
proceeded to a trimer of indole with structure 7 (Scheme 2).
N
N
N
5
O
N
N
N
POCl3
+
H
O
-10 to 0 °C
N
N
N
H
H
6
3
H
N
NH
N
HN
NH
7
Scheme 2. The expected and found products of reaction of 1,3-dimethylimidazolidin-2-one (3) and indole
under Vilsmeier conditions.
Identification and confirmation of the product structure (7) was carried out using various spectroscopic
methods. In the 1H-NMR spectrum, the –NH signals of indole rings and secondary amine, in a 3 to 1 ratio, were
observed as single peaks at δ 10.77 ppm and δ 9.72 ppm respectively, which disappeared on addition a few
drops of D2O. The UV absorption spectrum of the compound was similar to that of indole. The base peak in its
mass spectrum was observed at m/z 447. A peak at m/z 331.13 belongs to the stable fragment ion (8), which
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results by loss of an indole unit and is stabilized by conjugation with two indole rings on one side and a
nitrogen atom on the other.
H
N
HN
+
N
HN
8
The mechanism by which we believe the reaction of 1,3-dimethylimidazolidin-2-one with phosphorus
oxychloride and indole proceeds is shown in Scheme 3.
N
N
N
N
N
POCl3
+
+ indole
O
+
+ H
NH
-10 to 0 °C
N
N
H
N+
H
N
H
H
N
NH
NH
N
+HN
N
N
HN
HN
+ indole
NH
N+
N
H
7
H
N
H
m/z = 447
Scheme 3. The proposed mechanism for the synthesis of compound 7 from 1,3-dimethylimidazolidin-2-one
(3) and phosphorus oxychloride and indole.
We also studied the reaction of N-methyloxindole (4) as a tertiary cyclic amide with phosphorus
oxychloride and indole. Although it is commercially available, we prepared it from isatin.25 In this method,
isatin was first N-methylated using methyl iodide and then N-methyloxindole (4) was obtained in high yield by
reduction with a Wolff-Kishner procedure.26
Treatment of N-methyloxindole with indole under Vilsmeier reaction conditions produced N-methyl-2-
[3,3,3-tri-(1H-indol-3-yl)ethyl]aniline (9) in 48% yield.
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HN
NH
HN
N
H
9
1
In the H-NMR spectrum of 9, signals for the N-methyl, methylene and the NH of the indole rings were
observed at δ 2.18, δ 3.71 and δ 4.47 ppm respectively. The main peak in the mass spectrum was observed at
m/z 480. A suggested mechanism of this reaction is shown in Scheme 4.
N
N
POCl3
+
+
+ indole
O
+ H
NH
-10 to 0 °C
N
N
+
N
H
N
H
H
H
N
NH
H+
N
HN
HN
+ indole
NH
NH
+
N
N
9
H
H
N
H
Scheme 4. Proposed mechanism for the synthesis of compound 9 from the reaction of N-methyloxindole (4)
with phosphorus oxychloride and indole.
Conclusions
In conclusion, we have reported a simple and convenient method for the synthesis of tri-(1H-indol-3-yl)
derivatives by Vilsmeier-type reactions of indole with 1,3-dimethylimidazolidin-2-one and N-methyloxindole.
Experimental Section
General. Melting points were taken on a Philip Harris C4954718 apparatus. Infrared spectra were recorded on
a Thermo Nicolet (Nexus 670) Fourier transform (FT) infrared spectrometer, using sodium chloride cells and
1
13
measured in KBr pellets. H (300 MHz) and C (75.5 MHz) NMR spectra were recorded on a Bruker 300
spectrometer using TMS as the internal reference. Mass spectra were recorded on Agilent 6890-N-Network-
GC-system. Analytical thin-layer chromatography’s (TLC) were carried out on Merck silica gel 60 F254 aluminum
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sheets and detection was made with the help of a UV lamp (λ 254 nm). The ultraviolet spectra were recorded
with a Perkin Elmer Lambda 25 UV device. Microanalyses were performed on a Leco Analyzer 932.
N1,N2-Dimethyl-N1-[tri-(1H-indol-3-yl)methyl]ethane-1,2-diamine (7). To 1,3-dimethylimidazolidin-2-one (3)
(4 mL, 0.04 mol) cooled in an ice bath was added POCl3 (4.08 g, 0.026 mol) with stirring during 30 min. The
temperature was maintained at –10-0 °C. The mixture was stirred an additional 10 min, and then a solution of
indole (2.80 g, 0.024 mol) in 1,3-dimethylimidazolidine-2-one (4 mL, 0.04 mol) was added slowly during 2 h.
The temperature rose to 45 °C. The mixture was heated at 80 °C for 3 h, and then mixed with water (100 mL).
Some sediment began to form on dropwise addition of H2O. The solid was filtered off and washed with water.
Recrystallization from EtOH-H2O afford the product 7 (5.6 g, 53%), mp 221-222 °C. 1H-NMR (DMSO-d6) δ (ppm)
2.39 (3H, s, CH3-N), 3.32-3.45 (4H, m, CH2CH2), 3.62 (3H, s, CH3-NH), 6.85-7.58 (15H, m, Ar), 9.72 (1H, bs, NH),
13
10.77 (3H, bs, three NH of indoles). C-NMR (DMSO-d6) δ (ppm) 19.00, 34.11, 34.90, 36.33, 48.91, 111.82,
118.23, 118.39, 119.48, 121.11, 122.87, 126.75, 126.95, 127.46, 127.9, 131.1, 134.6, 137.0, 137.8, 155.8. FT-IR
(KBr, cm-1) νmax 3213, 2915, 1625, 1455, 1300, 745. UV (EtOH, nm) λmax 223, 282, 291. MS (EI, 70 eV): m/z
202.00, 300.33, 331.13, 447. Anal. Calcd for C29H29N5: C, 77.82; H, 6.53; N, 15.65. Found: C, 77.91; H, 6.27; N,
15.82%.
N-Methylisatin.25 A mixture of isatin (1.48 g, 10 mmol), K2CO3 (1.82 mg, 13 mmol), MeI (1.56 g, 11mmol) and
DMF (50mL) was heated on an oil bath. After one hour the reaction mixture was poured into ice-H2O and
extracted with CH2Cl2. The organic layer was washed with H2O, and then dried and concentrated in vacuum.
Recrystallization from n-hexane/acetone afford the product as orange needle crystals (1.42 g, 88%), mp 125-
1
13
126 °C (lit.17 mp 130-133 °C). H-NMR (CDCl3) δ (ppm) 3.27 (3H, s, CH3N), 6.89-7.63 (4H, m, Ar). C-NMR
(CDCl3) δ 26.2, 109.9, 115.9, 123.8, 125.3, 130.2, 138.3, 183.3, 186.6. FT-IR (KBr, cm-1) νmax 1728, 1608, 1468,
757, 474.
N-Methyloxindole (4).26 N-Methylisatin (10 mmol) was dissolved in hydrazine hydrate (98%; 10 mL) and the
mixture heated at reflux for 30 min. The reaction mixture was then poured in cold H2O, extracted in EtOAc and
the extract dried over Na2SO4. Evaporation of the solvent and subsequent recrystallization from hexane/EtOAc
afforded the desired product (1.25 g, 85%), mp 86-87 °C (lit.33 mp 85-88 °C). 1H-NMR (CDCl3) δ (ppm) 3.21 (3H,
13
s, CH3N), 3.52 (2H, s, CH2), 6.80-7.31 (4H, m, Ar). C-NMR (CDCl3) δ 26.1, 35.7, 108.1, 122.3, 124.3, 124.5,
127.9, 145.2, 175.1. FT-IR (KBr, cm-1) νmax 1707, 1610, 1466, 747.
N-Methyl-2-[3,3,3-tri-(1H-indol-3-yl)ethyl]aniline (9). N-Methyloxindole (0.2 g, 1.4 mmol) was dissolved in a
minimum quantity of 1,4-dioxane and cooled in an ice bath. Then POCl3 (0.135 g, 0.88 mmol) was added with
stirring during 30 min. The temperature was maintained at –10 to 0 °C. The mixture was stirred an additional
10 min, and then a solution of indole (0.098 g, 0.84 mmol) in the minimum or 1,4-dioxane was added slowly
during 2 h. The temperature rose to 45 °C for 1 hour. The mixture was heated at 80 °C for 2.5 h, and then
mixed with H2O (10 mL). Some sediment began to form by dropwise addition of H2O. The brown solid was
filtered off and washed with H2O. Recrystallization from EtOH-H2O afforded the desired product (0.19 g, 48%),
mp 159-160 °C. 1H-NMR (CDCl3) δ (ppm) 2.18 (3H, s, CH3), 3.71 (2H, s, CH2), 4.13 (1H, s, NH), 6.63-8.48 (22H, m,
13
Ar). C-NMR (CDCl3) δ (ppm) 36.0, 53.3, 58.5, 109.2, 109.7, 118.9, 119.7, 121.7, 123.0, 124.0, 124.4, 125.5,
128.8, 139.2, 141.9, 142.1. FT-IR (KBr, cm-1) νmax 3382, 2924, 1609, 1465, 1323, 742. UV (EtOH, nm) λmax 209,
219, 248, 293. MS (EI, 70 ev): m/z 480, 375, 246, 117. Anal. Calcd for C33H24N4: C, 82.47; H, 5.87; N, 11.66
Found: C, 81.67; H, 5.28; N, 13.05.
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