Microwave assisted synthesis of melatonin

Article abstract of DOI:10.1081/SCC-120016317

Melatonin was prepared from phthalimide by N- and C-alkylation, cyclization, hydrolytic, decarboxylation, and acetylation. The four-pot reactions were carried out on microwave irradiation in good yield with short time.

Full text of DOI:10.1081/SCC-120016317

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Microwave Assisted Synthesis of Melatonin
a
a
b
a
a
Ling He , Ju-Lian Li , Jian-Jun Zhang , Pu Su & Shi-Long Zheng
a
West China School of Pharmacy , Sichuan University , Chengdu, Sichuan, P.R. China
Kangyi Fine Chemical Works , Changzhou, Zhejiang, P.R. China
b
Published online: 17 Aug 2006.
To cite this article: Ling He , Ju-Lian Li , Jian-Jun Zhang , Pu Su & Shi-Long Zheng (2003) Microwave Assisted Synthesis of
Melatonin, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
33:5, 741-747, DOI: 10.1081/SCC-120016317
To link to this article: http://dx.doi.org/10.1081/SCC-120016317
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 5, pp. 741–747, 2003
Microwave Assisted Synthesis of Melatonin
1
,
1
2
1
Ling He, * Ju-Lian Li, Jian-Jun Zhang, Pu Su,
1
and Shi-Long Zheng
1
West China School of Pharmacy, Sichuan University,
Chengdu, Sichuan, P.R. China
2
Kangyi Fine Chemical Works, Changzhou,
Zhejiang, P.R. China
ABSTRACT
Melatonin was prepared from phthalimide by N- and C-alkylation,
cyclization, hydrolytic, decarboxylation, andacetylation. The four-pot
reactions were carried out on microwave irradiation in good yield
withs ho rt time.
Key Words: Melatonin; Microwave assisted organic synthesis;
Phase-transfer catalytic condensation.
*
Correspondence: Ling He, West China School of Pharmacy, Sichuan University,
Chengdu, Sichuan, 610041, P.R. China; E-mail: zshilong@yahoo.com.
7
41
DOI: 10.1081/SCC-120016317
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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7
42
He et al.
1
. INTRODUCTION
Melatonin (N-acetyl-5-methoxytryptamine) was primarily isolated
[
1]
from pineal body of cattle in 1958. It possesses of abroad bioactivities
of increasing evidence suggests that melatonin may somehow delay the
aging process and/or the progression of age-related disease processes,
[
2]
perhaps owing to its ability to eliminate free radicals. The total
synthesis of melatonin has been reported by Szmuszkovicz et al. using
[
-methoxyindole as starting material. Flaughet al. took nine steps for
3]
5
synthesis.
[4,5]
The method of Franschini et al. showed not facility in
[
7]
reaction condition control. This article reported a convenient green
chemical synthesis method of melatonin by means of a four-pot reaction
route using phthalimide as starting material. N-Alkylation of phthalimide
with1,3-dibromo-propane in t he presence of potassium carbonate and
phase-transfer catalysts under the condition of microwave irradiation for
just only 6 min, then C-alkylation of ethyl acetacetate with the resulting
bromide at another 6 min gave compound (2) in 81% yield. It condensed
and cyclized with 4-methoxyphenyl hydrazine at same microwave
irradiation condition for 15 min to get the desired 2-ethoxycarbonyl-3-
(
2-phthalimidoethyl)-5-methoxylindole (3) in 80% yield through the
Fischer indole synthesis. Then through saponification and treatment
witht he solution of sulfuric acid under microwave irradiation afforded
5-methoxytryptamine (4) in 70% yield. The resulting product was
acetylated under microwave irradiation for 2 min to give melatonin in
85% yield. The synthetic route is shown in Sch. 1.
This synthesis proceeds much faster with higher yield under
microwave irradiation in comparison withconventional e ha ting
conditions, under which normally reactions would require many hours
at reflux for completion, but only several minutes or less than 20 min
required under microwave irradiation. It yielded purer reaction product,
as well as it needed less solvent. Therefore, the reactions promoted by
microwave irradiation produced less pollutant withlow cost.
2. RESULTS AND DISCUSSION
Herein we also report a catalytic condensation method promoted
by microwave irradiation using a phase-transfer catalyst. While exploring
interest on triethylbenzenylamine chloride (TEBA) as an effective
catalyst for condensation from 1 to 2, not only TEBA as a solid–liquid
phase-transfer catalyst for the condensation was very effective, but also
microwave-absorbing rate was high for the reaction system. Alkylation of

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Synthesis of Melatonin
743

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He et al.
Scheme 2.
phthalimide with 1,3-dibromo-propane in the presence of phase-transfer
catalysts TEBA under microwave irradiation just took 6 min, but the
alkylation reaction could not be completed in 50 min without TEBA.
It is also important to choose the solvent for the alkylation.
We experimented acetonitrile, phenyl methyl ether, chloroform, and
1,3-dibromo-propane. But acetonitrile was found to be the optimal solvent
for the purpose. Bisubstituent product would be produced if 1,3-di-
bromo-propane is used as solvent in excess for the alkylation (Sch. 2).
Comparison with the traditional heating method (Table 1).
3. EXPERIMENTAL
Melting points (uncorrected) were determined by electro thermal
1
melting point apparatus. H NMR spectra in CDCl on Bruker AC-E200
3
(
200 MHz) using TMS as an internal standard. Microwave irradiation
was carried out using a MCL-T domestic oven withmaximum power
output of 850 W.
3.1. The Synthesis of 3-(3-Phthalimidopropyl)
Ethyl Acetacetate (2)
The mixture of phthalimide (5 g, 0.034 mol); 1,3-dibromo-propane
6.8 mL, 0.068 mol); potassium carbonate (6.9 g, 0.05 mol); TEBA
0.77 g, 0.0034 mol), and acetonitrile (8 mL) was refluxed under micro-
(
(
wave irradiation for 6 min. Then the reaction mixture was charged with
potassium carbonate (0.05 mol) and ethyl acetacetate (5.3 g, 0.041 mol),
to the resulting mixture refluxed at same condition for another 6 min.

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Synthesis of Melatonin
Table 1. Reaction time and yields in different preparing methods.
745
From
to 2
From
2 to 3
From
3 to 4
From
Yield 4 to 5 Yield
a
1
Yield
Yield
Traditional
heating
method
6 h85%;
10–20 h74%
8 h
66% 1–2 h 85%
77%;
72%
81%
Microwave
irradiation
6 þ 6 min
15 min
80% 5 þ 10 min 70% 2 min 85%
a
Note: Traditional heating method.
Microwave irradiation method.
After cooling, acetone was added and then the mixture was filtered, the
filtrate was concentrated in vacuo, the residue was recrystallized from
ethyl acetate-ligroin to give 2 in 81% yield.
3.2. The Synthesis of 2-Ethoxycarbonyl-3-phthalimido-
ethyl-5-methoxylindole (3)
To a solution of 4-methoxyphenyl hydrazine (4 g, 0.03 mol) and
-(3-phthalimidopropyl) ethyl acetacetate (2) (9.5 g, 0.03 mol) in 10 mL
of n-butanol was added dropwise with a solution of hydrochloride acid
3
(
0.2 mol) in 70 mL of butanol (0.2 mol acetochloride þ n-butanol).
The mixture was refluxed under microwave irradiation for 15 min, then
cooled and put in refrigerator overnight. The resulting yellow solid was
collected by filtration. The solid was recrystallized from ethanol to give 3
ꢀ
in 80% yield, m.p. 239–241 C.
3.3. The Synthesis of 5-Methoxytryptamine (4)
A
mixture of 2-ethoxycarbonyl-3-phthalimido-ethyl-5-methoxy-
lindole (3) (11 g, 0.03 mol) and sodium hydroxide (10%, 30 mL) was

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7
46
He et al.
refluxed under microwave irradiation for 5 min, and then sulfuric acid
20%, 130 mL) was added dropwise slowly over 10 min. After that, the
mixture was refluxed in microwave oven for 10 min. It was then extracted
(
withet hy l acetate (3 Â 50 mL). The pH of aqueous layer was adjusted to
8–9 with 40% sodium hydroxide and extracted with ethyl acetate.
The combined extract was washed with saturated brine and dried with
sodium sulfate anhydrous. The solvent was removed in vacuo and the
residue was recrystallized from benzene to give light yellow crystals sub-
ꢀ
1
stance, in 70% yield, m.p. 119–121 C. H NMR (CDCl ): 7.90 (s, bs, 1H),
3
6
.83–7.27 (m, 4H), 3.86 (s, 3H), 2.87 (t, 2H, J ¼ 3.1 Hz, CH ; J ¼ 9.0 Hz,
2
CH CH ), 3.02 (t, 2H, J ¼ 3.1 Hz, CH ), 1.41 (s, bs, 2H).
2
2
2
3.4. The Synthesis of Melatonin (5)
A mixture of 5-methoxytryptamine (4) (5.7 g, 0.03 mol), pyridine
0.2 g, 0.003 mol), and acetic anhydride (20 mL) was warmed in the
presence of N under microwave irradiation for 2 min, and then the
(
2
resulting reaction mixture was poured into ice-water (300 mL), the solid
ꢀ
was collected, to give melatonin (5) in 85% yield, m.p. 117–118 C.
The spectral data of the synthesized melatonin were identical with
[4]
those in literature or of an authentic sample.
ACKNOWLEDGMENT
The authors thank Prof. Han-Bao Jiang in the department of
Radio Engineering, Sichuan University, for reconstructing the
microwave oven.
REFERENCES
1
. Lemer, A.B.; Case, J.D.; Takahashi, Y. J. Am. Chem. Soc. 1958, 80,
587.
2
2
. (a) Reiter, R. J. Bioassays 1992, 14, 169; (b) Reiter Braz, R.J. J. Med.
Biol. Res. 1993, 26 (11), 1141; (c) Pierpaoli, W.; Regelson, W. Proc.
Natl. Acad. Sci. USA 1994, 91, 787.
3. Szmuszkovicz, J.; Anthoony, W.C.; Heinzelman, R.V. J. Org. Chem.
1960, 25 (5), 857–859.

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Synthesis of Melatonin
747
4. Michael E. Flaugh; Thomas A. Crowell; James A. Clemens, et al.
J. Med. Chem. 1979, 22 (1), 63–69.
5
6
. Chuan-foung Duan; Yi-jun Yong. J. Phar. 1996, 31 (3), 182–185.
. Szantay, Cs.; Szabo, L.; Kalaaus, Gy., et al. Synthesis 1974, (5),
3
54–356.
. Franschini Franco; Bella, D.I.; Luigi Durant, et al. EP: 330 625
1989, 8.30).
7
(
Received in Japan September 14, 2001

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