Practical and phase transfer-catalyzed synthesis of 6-methoxytryptamine

Article abstract of DOI:10.1080/00397910600588504

A convenient and cost-effective synthesis of 6-methoxytryptamine (1), starting from commercially available phthalimide and 1-bromo-3-chloropropane via PTC N-alkylation, PTC C-alkylation, Japp-Klingemann reaction, hydrolysis, and decarboxylation, has been accomplished with a 44% overall yield. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600588504

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Practical and Phase Transfer–Catalyzed
Synthesis of 6‐Methoxytryptamine
Yunyan Kuang a , Jian Huang a & Fener Chen a
a Department of Chemistry, Fudan University, Shanghai, China
Published online: 21 Aug 2006.
To cite this article: Yunyan Kuang , Jian Huang & Fener Chen (2006) Practical and Phase Transfer–Catalyzed
Synthesis of 6‐Methoxytryptamine, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 36:11, 1515-1519
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Synthetic Communicationsw, 36: 1515–1519, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600588504
Practical and Phase Transfer–Catalyzed
Synthesis of 6-Methoxytryptamine
Yunyan Kuang, Jian Huang, and Fener Chen
Department of Chemistry, Fudan University, Shanghai, China
Abstract: A convenient and cost-effective synthesis of 6-methoxytryptamine (1),
starting from commercially available phthalimide and 1-bromo-3-chloropropane via
PTC N-alkylation, PTC C-alkylation, Japp–Klingemann reaction, hydrolysis, and
decarboxylation, has been accomplished with a 44% overall yield.
Keywords: Japp–Klingemann reaction, 6-methoxytryptamine, PTC alkylation,
reserpine
INTRODUCTION
6-Methoxytryptamine (1) is an important intermediate for the total synthesis
of pentacyclic indole alkaloid reserpine.[1] Although several reported
approaches to 1 have been developed with varying degrees of success,[1,2]
Received in Japan September 20, 2005
Address correspondence to Fener Chen, Department of Chemistry, Fudan
University, 220 Handan Road, Shanghai 200433, China. E-mail: rfchen@fudan.edu.cn
1515

1516
Y. Kuang, J. Huang, and F. Chen
none of them is attractive enough for the scale-up synthesis of 1 because
of drawbacks such as the use of expensive materials (6-methoxyindole or
3-methoxycarbonyl-6-methoxyindole), tedious workup, low reaction tempera-
ture (2788C), poor overall yield, and so forth. Therefore, a simple and
economical preparation of 1 that is amenable to large-scale synthesis and
that delivers consistently high levels of purity is required.
As part of a development project on the total synthesis of reserpine in
our laboratory,[3] herein we describe the practical and efficient preparation
of 1 starting from commercially available phthalimide and 1-bromo-3
chloropropane.
The synthetic route to 1 is depicted in Scheme 1. Treatment of phtha-
limide and 1-bromo-3-chloropropane using a catalytic amount of PEG-600
and K2CO3 under reflux for 7 h afforded the chloropropylphthalimide 2 in
90% yield,which was recrystallized from CH3OH to remove formed impu-
rities such as 1,3-diphthalimidopropane and bromopropylphthalimide. The
phase transfer–catalyzed (PTC) alkylation of ethyl acetoacetate with 2 in
the presence of a catalytic amount of triethylbenzylammoniun chloride
(TEBAC) and KOH was carried out in refluxing toluene to provide
the phthalimidopentanoate 3 in 72% yield. Treatment of 3 with the
diazonium salt of m-anisidine in CH3OH via a Japp–Klingemann
reaction[4] led to the 5-methoxyindole 4 in 76% yield. Hydrolysis of ester
group in 4 with 15% aqueous KOH, without isolation, followed by acid
treatment with 15% HCl at reflux temperature gave 6-methoxytryptamine
(1) in 90% yield.
Scheme 1.

6-Methoxytryptamine Synthesis
1517
In summary, we have developed a simple and practical protocol for the
synthesis of 1 in an overall yield of 44%, starting from commercially
available phthalimide and 1-bromo-3-chloropropane. The notable advantages
of the present method are its mild experimental conditions, short reaction
time, simple operation, and high overall yield compared to those literature
procedures.
EXPERIMENTAL
Melting points were measured on a WRS-1B digital melting-point apparatus
and are uncorrected. Elemental analyses were performed on a Carlo-Erba
1006 elemental analyzer. IR spectra were recorded on a Nicolet FI-IR 360
1
spectrophotometer. H NMR spectra were obtained on a Bruker DMX500
using TMS as an internal standard. Chemical shifts (d) are expressed in
ppm. Mass spectra were determined on a HP5988A instrument by direct
inlet at 70 ev. All reagents and solvents were purchased from commercial
sources and used as received without further purification.
N-(3-Chloropropyl)phthalimide (2)
1-Bromo-3-chloropropane (51 g, 0.32 mol) was added dropwise to a well-
stirred mixture of phthalimide (40 g, 0.27 mol), K2CO3 (75.8 g, 0.55 mol),
and PEG-600 (1.0 g) in toluene (500 mL) under stirring at room temperature.
The reaction mixture was stirred under reflux for 7 h, and then cooled to room
temperature and filtered. The filtrate was evaporated in vacuo to give the crude
product, which was recrystallized from CH3OH to afford pure 2 (54.2 g, 90%)
1
as a white crystal, mp 70–728C. H NMR (CDCl3): d 7.85 (d, 2H), 7.7
(m, 2H), 3.86 (t, 2H), 3.58 (t, 2H), 2.2 (m, 2H); EI-MS (m/z): 223 (Mþ); IR
(KBr) y (cm21): 1773, 1710, 1395, 1111, 1033, 871, 724.
Ethyl 2-Acetyl-5-phthalimidopentanoate (3)
The mixture of ethyl acetoacetate (22 g, 0.17 mol), KOH (12 g, 0.21 mol), and
TEBAC (1.1 g, 48 mmol) in toluene (200 mL) was stirred under reflux for
30 min. Then 2 (35.7 g, 0.16 mol) was added, and the reaction mixture was
refluxed with stirring for an additional 5 h, cooled to room temperature,
and filtered. The filtrate was evaporated under reduced pressure. Water
(75 mL) was added to the residue and acidified to pH 4 with 10% HCl. The
mixture was extracted with CH2Cl2 (3 ꢀ 100 mL). The combined organic
layer was washed several times with water and dried over Na2SO4. The
solvent was evaporated in vacuo to give the crude product, which was recrys-
tallized from CH3OH to afford pure 3 (36.5 g, 72%) as a white powder, mp

1518
Y. Kuang, J. Huang, and F. Chen
1
59–608C. H NMR (CDCl3): d 7.70–7.86 (m, 4H), 4.15–4.23 (q, 2H), 3.70
(t, 2H), 3.50 (t, 1H), 2.23 (s, 3H), 1.68–1.92 (m, 4H), 1.27 (t, 3H); EI-MS
(m/z): 317 (Mþ); IR (KBr) y (cm21): 1737, 1711, 1402, 1244, 1190, 1141.
2-Carboxyethyl-3-(2-phthalimidoethyl)-6-methoxy Indole (4)
Conc. HCl (200 mL) was added dropwise to a well-stirred mixture of
m-anisidine (60 g, 0.56 mol), methanol (200 mL), and H2O (30 mL) at 08C
over a period of 45 min. Stirring was continued at the same temperature for
20 min. A solution of NaNO2 (38.4 g, 0.56 mol) in H2O (140 mL) was added
dropwise to the reaction mixture at 08C over a period of 45 min. Stirring
was continued at the same temperature for 45 min to give a solution of the
diazonium salt of m-anisidine.
Sodium acetate (330 g, 4.2 mol) was added to a stirred mixture of 3 (160 g,
0.5 mol) in methanol (3.0 L) and the reaction mixture was stirred at room
temperature for 1 h and cooled to 08C. The solution of the diazonium salt
of m-anisidine as prepared previously was added dropwise at 08C over a
period of 1.5 h. The reaction mixture was stirred at room temperature for an
additional 4 h. Then CH2Cl2 (1.2 L) was added to the reaction mixture. The
organic layer was washed several times with water and dried over Na2SO4.
The solvent was evaporated in vacuo, and 10% HCl in EtOH (750 mL) was
added to the residue and stirred under reflux for 2.5 h. After cooling to
108C, the precipitated product was collected by filtration and recrystallized
1
from glacial HOAc to give pure 4 (154 g, 76%), mp 231.3–231.88C. H
NMR (CDCl3): d 11.3 (br s, 1H), 7.8 (m, 4H), 7.5 (d, 1H), 6.8 (s, 1H), 6.7
(d, 1H), 4.2 (q, 2H), 4.0 (t, 2H), 3.8 (s, 3H), 3.4 (q, 2H), 1.4–1.5 (t, 3H).
EI-MS (m/z): 392 (Mþ); IR (KBr) y (cm21): 3352, 1768, 1711, 1666, 1396,
1254, 1012, 719.
6-Methoxytryptamine (1)
Compound 4 (8.6 g, 21.9 mmol), was added to a stirred solution of 15% aq.
KOH (37 mL) and the reaction mixture was stirred under reflux for 3 h.
Then 15% HCl (250 mL) was added, and the reaction mixture was stirred
under reflux for 10 h, then cooled to 08C, and filtered. The filtrate was
extracted with CH2Cl2 (3 ꢀ 30 mL). The aqueous phase was basified with
50% aq. NaOH and extracted with CH2Cl2 (3 ꢀ 50 mL). The combined
organic extracts were washed several times with water and dried over
Na2SO4. The solvent was evaporated under reduced pressure to give the
crude product, which was recrystallized from CH3OH to afford the pure 1
1
(3.7 g, 90%) as white crystal, mp 140–1428C. H NMR (CDCl3): d 8.26
(br s, 1H), 7.46 (d, 1H), 6.89 (s, 1H), 6.82 (s, 1H), 6.78 (d, 1H), 3.83

6-Methoxytryptamine Synthesis
1519
(s, 3H), 3.01 (t, 1H), 2.86 (t, 2H), 1.24 (d, 2H). EI-MS (m/z): 190 (Mþ); IR
(KBr) y (cm21): 3408, 3344, 1626, 1460, 1204, 1105, 1026, 807, 773.
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