Microwave-assisted rapid synthesis of neurotransmitter release enhancer linopiridine and its new analogues

Article abstract of DOI:10.1081/SCC-120023425

A neurotransmitter release enhancer linopiridine and its new analogues have been synthesized rapidly in yields from the 1:2 coupling of oxiindole with 4-picolyl chloride hydrochloride on the surface of basic alumina doped with 37% KF under microwave irradiation in solvent-free conditions.

Full text of DOI:10.1081/SCC-120023425

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Microwave-Assisted Rapid Synthesis of
Neurotransmitter Release Enhancer Linopiridine and Its
New Analogues
a
a
J. S. Yadav & B. V. S. Reddy
a
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad, India
Published online: 17 Aug 2006.
To cite this article: J. S. Yadav & B. V. S. Reddy (2003) Microwave-Assisted Rapid Synthesis of Neurotransmitter Release
Enhancer Linopiridine and Its New Analogues, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 33:18, 3115-3121, DOI: 10.1081/SCC-120023425
To link to this article: http://dx.doi.org/10.1081/SCC-120023425
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 18, pp. 3115–3121, 2003
Microwave-Assisted Rapid Synthesis
of Neurotransmitter Release Enhancer
Linopiridine and Its New Analogues
J. S. Yadav* and B. V. S. Reddy
Division ofOrganic Chemistry, Indian Institute of
Chemical Technology, Hyderabad, India
ABSTRACT
A neurotransmitter release enhancer linopiridine and its new analo-
gues have been synthesized rapidly in yields from the 1:2 coupling of
oxiindole with 4-picolyl chloride hydrochloride on the surface of
basic alumina doped with 37% KF under microwave irradiation in
solvent-free conditions.
Key Words: Linopiridine; Microwave; Solid supports.
*
Correspondence: J. S. Yadav, Division ofOrganic Chemistry, Indian Institute
ofChemical Technology, Hyderabad, India; Fax: 91-40-27160512; E-mail:
yadav@iict.ap.nic.in.
3
115
DOI: 10.1081/SCC-120023425
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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3
116
Yadav and Reddy
Alzheimer’s disease (AD) is the most common form of dementia in
[1]
the elderly. It is a fatal disorder that robs its victims of their most
precious organ, the brain by slowly destroying the complex web ofneu-
ronal connections that support cognitive processes such as thought and
memory. This dementia is characterized by the loss ofshort-term
memory, deterioration in intellectual performance, and behavioural pro-
blems. AD destroys its victim’s personalities, leaving them unable to
recall the past or process the present. In addition to memory loss, patients
may exhibit agitation, combativeness, hallucinations, depression, sleep-
lessness and wandering. The symptoms ofdementia seen in AD are asso-
[
2]
ciated with cholinergic loss. Linopiridine stimulates the central nervous
system and increases the level ofthe acetylcholine in the brain. It pos-
sesses the ability to enhance acetylcholine release, as the optimal site of
the pendant nitrogen is the 4-position ofthe pyridine ring. The release
enhancing effects oflinopiridine are not only limited to ACh, as it also
[
3]
stimulates the release ofdopamine, serotonin, and glutamate.
In con-
[
4]
sequence, a few methods have been developed for the synthesis of
linopiridine and its derivatives, which involve the use ofstoichiometric
amounts ofbases and large volumes ofsolvents and also the products are
obtained in moderate yields after a long reaction period. Furthermore,
the use ofharm uf l organic solvents is undesirable rfom the view of
today’s environmental consciousness. The use ofinorganic solid supports
as reaction media in organic synthesis is increasingly widespread due to
[
5]
improved efficiency ofmany sur af ce-bound reagents.
Microwave-assisted organic reactions have attracted considerable
importance in organic synthesis because ofthe simplicity in operation,
greater selectivity and rapid synthesis ofa variety oforganic com-
[6]
pounds. The notable features of the microwave approach are enhanced
reaction rates, formation of pure products in high yields and ease of
manipulation. In recent years, solvent-free microwave assisted reactions
have gained more popularity as they provide an opportunity to work
with open vessels. This avoids the risk ofdevelopment ofhigh pressure
and provides a possibility ofup-scaling the reaction and helps the
induction ofthe reaction under dry conditions. Thus, microwave irradia-
tion has become a powerful tool for the rapid synthesis of a variety of
[
7]
bioactive molecules under solvent-free conditions.
In this report, we wish to describe our results on the microwave-
assisted synthesis oflinopiridine and its new derivatives rf om oxyindole
and 4-picolyl chloride hydrochloride using KF–Al O . Thus, treatment
2
3
ofoxiindole with 4-picolyl chloride hydrochloride in the presence ofbasic
alumina impregnated with 37% KF under microwave irradiation
afforded linopiridine in 90% yield (Sch. 1).

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Neurotransmitter Release Enhancer Linopiridine
3117
N
KF-Al O
2
3
+
N
N
R
O
Cl
N
R
N
MW
O
1
2
3
R = Phenyl, 2,6-dichlorophenyl, benzyl, phenethyl, ethyl, methyl
Scheme 1.
a
Table 1. Microwave-assisted synthesis oflinopiridine and its analogues.
Microwave irradiation
b
Yield (%)
Entry
a
Oxiindole
Picolychloride
Time (min)
3.0
90
ClCH2
N HCl
N
Ph
O
O
b
c
d
e
f
3.0
3.0
4.0
4.0
5.0
87
85
90
88
92
ClCH2
NHCl
N
CH3
ClCH2
ClCH2
ClCH2
ClCH2
NHCl
N
O
CH Ph
2
N
HCl
N
O
CH CH
2
3
NHCl
N
O
CH CH Ph
2
2
N
HCl
N
O
Cl
Cl
a
1
All products were characterized by H NMR, IR, and mass spectra.
b
Pulsed irradiation (1 min with 20 s interval) using BPL, BMO-700T
microwave oven.
In a similar fashion, various substituted oxiindoles reacted smoothly
with 4-picolyl chloride in solvent-free conditions to afford the
corresponding linopiridine analogues in high yields. The scope and gen-
erality ofthis process is illustrated with respect to alkyl, aryl, and benzyl
substituted oxiindoles and 4-picolyl chloride and the results are presented
in the Table 1.

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Yadav and Reddy
Microwave irradiations were carried out using BPL, BMO-700T
domestic microwave oven operated at 2450 MHz (450 W). The reactions
were carried out both under microwave as well as thermal conditions.
The reaction rates and yields were dramatically enhanced by microwave
irradiation. The rate enhancement under microwave may be attributed to
the absorption ofmore microwave energy by polar media, which gener-
ates heat energy as required to promote the reaction. The reaction tem-
ꢀ
perature was reached to 110 C after 3 min pulsed irradiation (1 min with
20 s intervals) at the same power. The same reaction, under thermal
ꢀ
conditions, at 110 C took 8–12 h to afford yields comparable with
those that are obtained by microwave irradiation.
In summary, the article describes a convenient and rapid method for
the synthesis oflinopiridine and its analogues rf om oxiindoles and 4-
picolyl chloride using a solid supported reagent system KF–Al O . The
2
3
present method avoids high temperature reaction conditions, the use of
solvent and extended reaction times. The time saving ability together with
very short response times and the minimization ofthermal decomposition
ofproducts are the main advantages ofmicrowave heating and uf rther
improvement will be facilitated by the availability of a continuous
microwave reactor.
EXPERIMENTAL
Melting points were recorded on Buchi R-535 apparatus and are
uncorrected. IR spectra were recorded on a Perkin-Elmer FT-IR 240-c
1
spectrophotometer using KBr optics. H NMR spectra were recorded on
Gemini-200 spectrometer in CDCl using TMS as internal standard.
3
Mass spectra were recorded on a Finning MAT 1020 mass spectrometer
operating at 70 eV. CHN analyses were recorded on a Vario EL analyzer.
Microwave irradiation was carried out using BPL, BMO-700T, operated
at 450 W (2450 MHz). 37% KF–Al O was prepared using known
2
3
[8]
literature procedure.
General Procedure
Oxiindole derivative (5 mmol) and 4-picolyl chloride hydrochloride
10 mmol) were admixed with 2.0 g ofKF–Al O (37% KF absorbed on
(
2
3
basic alumina) and subjected to microwave irradiation for 3–5 min as
required to complete the reaction. After completion of the reaction as
indicated by TLC, the reaction mixture was filtered and washed with

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Neurotransmitter Release Enhancer Linopiridine
3119
dichloromethane (2 ꢁ 15 mL). The combined organic layers were concen-
trated in vacuo and purified by column chromatography on silica gel to
afford pure linopiridine derivative 1.
3
a. N-Phenyl-3,3-di(4-pyridylmethyl)-2-indolinone. Solid, m.p.
ꢀ
1
1
(
80–182 C; H NMR (CDCl , 200 MHz) ꢀ: 3.20 (d, 2H, J ¼ 13.8 Hz), 3.45
3
d, 2H, J ¼ 13.8 Hz), 6.25 (dd, 1H, J ¼ 8.0, 1.7 Hz), 6.55 (dd, 2H, J ¼ 8.0,
1
8
1
1
1
1
.7 Hz), 6.85 (d, 4H, J ¼ 8.4 Hz), 7.05–7.18 (m, 2H), 7.30–7.45 (m, 4H),
1
3
.30 (d, 4H, J ¼ 8.4 Hz). C NMR (CDCl ) ꢀ: 43.48, 55.83, 109.62,
3
23.15, 124.46, 125.53, 126.84, 128.68, 128.94, 128.98, 129.93, 134.34,
44.95, 149.57, 176.95. IR (KBr) ꢁ: 3070, 2921, 1714, 1602, 1563, 1493,
465, 1414, 1366, 1212, 992, 795. EIMS: m/z: 391, 299, 271, 220, 193, 152,
27, 98, 69, 43. Anal. calcd. for C H N O (391.47): C, 79.77; H, 5.41;
2
6
21
3
N, 10.73. Found: C, 80.0; H, 5.43; N, 10.81.
b. N-Methyl-3,3-di(4-pyridylmethyl)-2-indolinone. Solid, m.p.
3
ꢀ
9–90 C; H NMR (CDCl , 200 MHz) ꢀ: 2.80 (s, 3H), 3.18 (d, 2H,
3
1
8
J ¼ 14.5 Hz), 3.38 (d, 2H, J ¼ 14.5 Hz), 6.40 (d, 1H, J ¼ 8.2 Hz), 6.81 (d,
4
4
1
H, J ¼ 8.2 Hz), 7.10–7.21 (m, 2H), 7.30 (dd, 1H, J ¼ 8.2, 1.6 Hz), 8.30 (d,
H, J ¼ 8.2 Hz). IR (KBr) ꢁ: 3051, 2933, 1710, 1610, 1578, 1497, 1460,
þ
414, 1365, 1215, 978, 879, 795. EIMS: m/z: 329 [M ]. Anal. calcd. for
C H N O (329.4): C, 76.57; H, 5.81; N, 12.76. Found: C, 76.61; H, 5.83;
2
1
19
3
N, 12.8.
c. N-Benzyl-3,3-di(4-pyridylmethyl)-2-indolinone. Viscous liquid,
3
1
H NMR (CDCl , 200 MHz) ꢀ: 3.18 (d, 2H, J ¼ 14.5 Hz), 3.40 (d, 2H,
3
J ¼ 14.5 Hz), 4.48 (s, 2H), 6.20 (d, 1H, J ¼ 7.8 Hz), 6.35 (d, 2H,
J ¼ 8.1 Hz), 6.80 (d, 4H, J ¼ 8.3 Hz), 7.02–7.20 (m, 4H), 7.32–7.48 (m,
þ
2
H), 8.20–8.38 (d, 4H, J ¼ 8.3 Hz). EIMS: m/z: 405 [M ]. IR (KBr) ꢁ:
3067, 2929, 1712, 1607, 1568, 1490, 1465, 1440, 1365, 1212, 987, 877, 790.
Anal. calcd. for C H N O(405.49): C, 79.98; H, 5.72; N, 10.36. Found:
2
7
23
3
C, 8.01; H, 5.75; N, 10.35.
d. N-Ethyl-3,3-di(4-pyridylmethyl)-2-indolinone.
3
Solid,
m.p.
ꢀ
1
1
40–142 C; H NMR (CDCl , 200 MHz) ꢀ: 0.70 (t, 3H, J ¼ 6.5 Hz), 3.15
3
(
4
d, 2H, J ¼ 14.0 Hz), 3.30–3.45 (m, 4H), 6.40 (d, 1H, J ¼ 8.0 Hz), 6.80 (d,
H, J ¼ 8.5 Hz), 7.05–7.20 (m, 2H), 7.35 (d, 1H, J ¼ 8.0 Hz), 8.30 (d, 4H,
1
3
J ¼ 8.5 Hz). C NMR (CDCl ) ꢀ: 25.43, 42.49, 55.01, 108.04, 122.06,
3
123.41, 124.77, 128.23, 128.53, 143.30, 144.57, 148.86, 176.77. EIMS:
m/z: 343 [M ], 251, 223, 195, 149, 93, 71, 57. IR (KBr) ꢁ: 3055, 2920,
þ
1717, 1607, 1565, 1497, 1443, 1210, 1010, 793. Anal. calcd. for
C H N O (343.42): C, 76.94; H, 6.16; N, 12.24. Found: C, 77.0; H,
2
2
21
3
6.13; N, 12.31.
3
e. N-Phenethyl-3,3-di(4-pyridylmethyl)-2-indolinone. Solid, m.p.
ꢀ
1
1
3
22–123 C; H NMR (CDCl , 200 MHz) ꢀ: 2.35 (t, 2H, J ¼ 6.8 Hz),
3
.15 (d, 2H, J ¼ 14.6 Hz), 3.35 (d, 2H, J ¼ 14.6 Hz), 3.50 (t, 2H,

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Yadav and Reddy
J ¼ 6.8 Hz), 6.35 (dd, 1H, J ¼ 8.0, 1.6 Hz), 6.80 (d, 4H, J ¼ 8.3 Hz), 7.0
(
dd, 2H, J ¼ 8.0, 1.5 Hz), 7.15 (t, 2H, J ¼ 7.9 Hz), 7.25–7.40 (m, 4H),
1
3
8
5
1
1
9
.22–8.38 (d, 4H, J ¼ 8.3 Hz). C NMR (CDCl ) ꢀ: 33.06, 41.07, 42.67,
3
4.77, 108.32, 121.99, 123.66, 125.02, 126.41, 128.37, 128.56, 142.62,
44.26, 148.96, 176.67. EIMS: m/z: 419 [M ], 328, 237, 209, 181, 149,
23, 109, 80, 43. IR (KBr) ꢁ: 3029, 2937, 1708, 1615, 1469, 1365, 1167,
þ
90, 765. Anal. calcd. for C H N O (419.52): C, 80.16; H, 6.01; N, 10.0.
2
8
25
3
Found: C, 80.18; H, 6.05; N, 10.05.
f. N-(2,6-Dichlorophenyl)-3,3-di(4-pyridylmethyl)-2-indolinone. Solid,
3
m.p. 191–192 C; H NMR (CDCl , 200 MHz) ꢀ: 3.30 (m, 4H), 6.18
ꢀ
1
3
(
dd, 1H, J ¼ 8.0, 1.8 Hz), 6.88 (brs, 4H), 7.15–7.40 (m, 6H), 8.38 (brs,
1
H). C NMR (CDCl ) ꢀ: 43.01, 54.40, 109.59, 122.75, 123.41, 124.55,
3
4
1
1
3
25.93, 128.32, 128.78, 128.98, 130.58, 135.15, 143.06, 144.37, 149.34,
þ
75.64. EIMS: m/z: 460 [M ], 436, 365, 339, 163, 107, 69, 57. IR (KBr)
ꢁ
: 3058, 2921, 1714, 1602, 1563, 1493, 1465, 1439, 1414, 1366, 1212, 1112,
92, 879, 795. Anal. calcd. for C H Cl N O (460.36): C, 67.83; H, 4.16;
Cl, 15.4; N, 9.13. Found: C, 67.80; H, 4.18; Cl, 15.45; N, 9.11.
9
2
6
19
2
3
ACKNOWLEDGMENT
BVS thanks CSIR, New Delhi, for the award of fellowship.
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Neurotransmitter Release Enhancer Linopiridine
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