A one-pot domino synthesis and discovery of highly functionalized dihydrobenzo[b]thiophenes as AChE inhibitors

Article abstract of DOI:10.1016/j.bmcl.2013.01.122

A library of novel 5-amino-2,7-diaryl-2,3-dihydrobenzo[b]thiophene-4,6- dicarbonitriles have been synthesized regioselectively in good yields through the one-pot domino reactions of 5-aryldihydro-3(2H)-thiophenones, malononitrile and aromatic aldehydes in the presence of morpholine. This transformation presumably involves Knoevenagel condensation-Michael addition-intramolecular Thorpe-Ziegler cyclization-Tautomerization-Elimination sequence of reactions. These compounds were evaluated for their acetylcholinesterase (AChE) inhibitory activity and 5-amino-2,7-bis(4-methoxyphenyl)-2,3-dihydrobenzo[b]thiophene-4,6- dicarbonitrile was found to be the most potent against AChE with IC₅₀ 4.16 μmol/L.

Full text of DOI:10.1016/j.bmcl.2013.01.122

Accepted Manuscript
A one-pot domino synthesis and discovery of highly functionalized dihydro‐
benzo[b]thiophenes as AChE inhibitors
Veerappan Jeyachandran, Raju Ranjith Kumar, Mohamed Ashraf Ali, Tan Soo
Choon
PII:
S0960-894X(13)00155-8
DOI:
http://dx.doi.org/10.1016/j.bmcl.2013.01.122
BMCL 20110
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
28 November 2012
25 January 2013
28 January 2013
Please cite this article as: Jeyachandran, V., Kumar, R.R., Ali, M.A., Choon, T.S., A one-pot domino synthesis and
discovery of highly functionalized dihydrobenzo[b]thiophenes as AChE inhibitors, Bioorganic & Medicinal
Chemistry Letters (2013), doi: http://dx.doi.org/10.1016/j.bmcl.2013.01.122
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A one-pot domino synthesis and discovery of highly functionalized
dihydrobenzo[b]thiophenes as AChE inhibitors
Veerappan Jeyachandran,a Raju Ranjith Kumar,a,∗ Mohamed Ashraf Ali,b,c,d, Tan Soo Choon b
aDepartment of Organic Chemistry, School of Chemistry, Madurai Kamaraj University,
Madurai – 625021, Tamil Nadu, India
bInstitute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800,
Penang, Malaysia
cNew Drug Discovery Research, Department of Medicinal Chemistry, Alwar Pharmacy
College, Alwar, Rajasthan – 301030, India
dNew Drug Discovery Research, Department of Medicinal Chemistry, Sunrise University,
Alwar, Rajasthan – 301030, India
Abstract-
A
library of novel 5-amino-2,7-diaryl-2,3-dihydrobenzo[b]thiophene-4,6-
dicarbonitriles have been synthesized regioselectively in good yields through the one-pot
domino reactions of 5-aryldihydro-3(2H)-thiophenones, malononitrile and aromatic
aldehydes in the presence of morpholine. This transformation presumably involves
Knoevenagel condensation–Michael addition–intramolecular Thorpe-Ziegler cyclization–
Tautomerization–Elimination sequence of reactions. These compounds were evaluated for
their acetylcholinesterase (AChE) inhibitory activity and 5-amino-2,7-bis(4-methoxyphenyl)-
2,3-dihydrobenzo[b]thiophene-4,6-dicarbonitrile was found to be the most potent against
AChE with IC50 4.16 μmol/L.
Keywords: Domino, Thiophenone, Malononitrile, Acetylcholinesterase, Alzheimer’s disease
∗
Corresponding author: Tel.: 0091-9655591445; e-mail: raju.ranjithkumar@gmail.com
1

Dementia is a brain disorder that badly affects a person’s ability to carry out daily activities.
Alzheimer’s disease (AD) is one form of dementia among old people that gradually worsens
over time. It affects the parts of brain that control thought, memory and language and lead to
trouble in speaking, reading or writing.1,2 For the past few decades, treatment for AD has
been based on the ‘cholinergic hypothesis’.1 Acetylcholine (ACh) is the principal
neurotransmitter which arbitrate cognitive function. The attenuation of this cholinergic
neurotransmission is the main reason for AD. The enzyme, AChE (acetyl cholinesterase
enzyme), catalyzes the hydrolysis of ACh to choline and acetic acid which results in the
decrease in hippocampal and cortical levels of ACh. AChE inhibitors are compounds that
inhibit the cholinesterase enzyme from breaking down ACh thereby increasing both the level
and duration of action of the neurotransmitter. The AChE inhibitors recommended by the
United Kingdom’s National Institute for Health and Clinical Excellence (NICE) are
donepezil 1,3 galantamine 2,4 rivastigmine 35 and memantine 46 (Figure 1). These drugs have
side effects which include nausea, diarrhea, constipation, vomiting, weight loss, headache,
loss of appetite etc. The complexity of the disease and limited option of drugs for the
treatment requires discovery of fast-acting efficient new drugs to effectively combat AD with
minimal or no side effects.
In this context, herein we report a domino protocol for the regioselective synthesis of
a library of highly functionalized dihydrobenzo[b]thiophene derivatives 8 (Scheme 1 and
Table 1) and their AChE inhibition studies. It is pertinent to note that this is the first report on
the AChE inhibition studies of dihydrobenzo[b]thiophene derivatives. Incidentally, domino
reactions comprise transformation of two or more bond-forming reactions under identical
conditions, in which the latter transformations take place at the functional groups obtained in
the former bond forming reactions, without the isolation of the intermediates or addition of
any further reagents/catalysts.7 In contrast to classical multi-step linear synthetic protocols,
2

domino reactions enable expedient and efficient assembly of molecules of structural
complexity and diversity in one-pot operations with facile execution, high atom-economy and
selectivity.7,8 These reactions obviate waste generation, thereby enhance the greenness of the
transformations. Consequently, one pot, multi-component domino reactions have emerged as
a powerful tool for the synthesis of complex organic heterocycles and natural products.9
Initially, to identify the optimum reaction condition, a representative reaction
affording 5-amino-2,7-bis(4-chlorophenyl)-2,3-dihydrobenzo[b]thiophene-4,6-dicarbonitriles
8u was investigated in the presence of different bases in refluxing ethanol. To begin with, the
reaction of 5-(4-chlorophenyl)dihydro-3(2H)-thiophenones 5 with two equivalents of
malononitrile 6 and one equivalent of 4-chlorobenzaldehyde 7, in the presence of
triethylamine as base in 6 h, afforded 60% isolated yield of 8u (Table 2, entry 1). This
reaction was then carried out in the presence of piperidine and pyrrolidine, which led to a
slight decrease in the isolated yield of 8u to 53% and 55% respectively (Table 2, entries 2 and
3). The representative reaction was then performed in the presence of morpholine which led
to noticeable enhancement in the yield (78%) within 4 h. Further increment in time did not
lead to significant increase in the yield of the product. The reaction completely failed to occur
when pyridine or picoline was used as base (Table 2, entries 5–7). Potassium carbonate
afforded moderate yield of 48%, whereas no reaction was observed with sodium hydroxide or
solid sodium ethoxide (Table 2, entries 8–10). From these results, morpholine emerged as the
best choice of base for these domino reactions. Having determined the optimum base for the
reaction, investigation pertaining to the choice of an appropriate solvent was performed. The
above reaction was examined in polar non-protic solvents such as acetonitrile,
dimethylformamide and other protic solvents like methanol and 2-propanol. From the data in
Table 2, ethanol was found to be the ideal solvent which afforded maximum yield of the
product (78%).
3

The optimal conditions thus established were then applied to the synthesis of a library
of novel 5-amino-2,7-diaryl-2,3-dihydrobenzo[b]thiophene-4,6-dicarbonitriles 8a–ad via the
one-pot four component domino reactions of 5-aryldihydro-3(2H)-thiophenones 5,
malononitrile 6 and aromatic aldehydes 7 (Scheme 1).10 A total of thirty novel
dihydrobenzo[b]thiophenes 8 were synthesized in excellent yields (70–78%). It is to be noted
that the compounds 8a–ad obtained are racemic mixtures.
The structure of all the dihydrobenzo[b]thiophenes 8 were elucidated unambiguously
with the help of one and two-dimensional NMR spectroscopy. As a representative case, the
1H and 13C NMR chemical shift assignment of 8r are discussed.
In the 1H NMR spectra of 8r, the 2-CH and the 5-NH2 protons overlap and appear as a
multiplet at 5.01–5.08 ppm. The D2O exchange experiment reveals that the H-2 appears as a
triplet at 5.04 ppm (J = 8.4 Hz) and the latter appears as a broad singlet at 5.08 ppm. From
the H,H-COSY correlation of 2-CH, it is evident that the two doublets of doublets at 3.84 and
3.70 ppm (J = 17.1 and 7.8 Hz) are due to 3-CH2 protons. The carbon signals at 52.8 and 45.3
ppm were assigned to 2-CH and 3-CH2 protons on the basis of their C,H-COSY correlations.
The CH proton of the two isopropyl groups in the aryl rings appeared as multiplet at 2.84–
2.99 ppm whereas the doublets at 1.23 and 1.27 ppm (J = 7.2 and 6.9 Hz respectively) can be
assigned to the methyl groups. The C,H-COSY spectrum assigns the signals at (i) 23.7 and
23.8 ppm to the methyl carbons and (ii) 33.8 and 34.0 ppm to the CH carbons of the
isopropyl groups respectively. That the carbon signals at 93.7 and 96.7 ppm are due to C-4
and C-6 respectively is evident from the fact that the 3-CH2 protons show HMBC correlation
with the carbon signal at 93.7 ppm and not with the other. Further, the 3-CH2 protons show
HMBC correlation with carbon signals at 52.8 ppm due to 2-CH and the signals of C-2, C-7a
and C-3a appearing at 131.2, 136.8 and 148.4 ppm respectively. The aryl ring protons appear
4

as multiplet at 7.16–7.43 ppm whereas the two nitrile carbons appear at 114.9 and 115.8 ppm.
The selected H,H-COSY and HMBC correlations of 8r are shown in Figure 2 whereas the 1H
and 13C chemical shifts of 8r are shown in Figure 3. Similarly, the structure of all the
dihydrobenzo[b]thiophenes 8 were assigned unambiguously. The structure of 8 assigned from
NMR spectroscopy was further confirmed from the single crystal X-ray studies.11 The
ORTEP diagram of 8f is shown in Figure 4. The structure of 8 assigned from NMR
spectroscopy and X-ray studies agree well.
This transformation probably occurs via domino mechanism as shown in Scheme 2.
Initially, the Knoevenagel condensation of 5-aryldihydro-3(2H)-thiophenone 5 with one mole
of malononitrile 6 affords 2-(5-aryltetrahydro-3-thiophenylidene)malononitrile 9, whereas the
condensation of second mole of
6
with aromatic aldehyde
7
affords 2-
(arylmethylene)malononitrile 10. The intermediate 9 presumably undergoes Michael addition
to 10 furnishing 11, which upon Thorpe–Ziegler cyclization yields 5-imino-2,7-diphenyl-
2,3,5,6,7,7a-hexahydrobenzo[b]thiophene-4,6,6-tricarbonitrile 12. The imine 12 then
undergoes tautomerization to afford the amine 13 followed by elimination to form the
product 5-amino-2,7-diaryl-2,3-dihydrobenzo[b]thiophene-4,6-dicarbonitrile 8. That the
formation of 8 is regioselective is evident from the fact that the other regioisomer 8′ (Figure
6) is not obtained even in traces in the course of the reaction. Further, it is confirmed from 1H
NMR spectroscopy wherein a triplet and doublet of doublets were observed in all the cases
due to 2-CH and 3-CH2 protons of 8 respectively. For the other regioisomer 8′, a singlet and
doublet of doublets would be obtained. The regioselectivity observed in the formation of 8
can be attributed to (i) the steric effect due to the interaction between the aryl rings at C-1 and
C-7 of the benzothiophene ring in 8′ (Figure 5) and/or (ii) the anion next to the sulfur of
compound 9 may be thermodynamically preferred over the other possible anion due
stabilization by the sulfur resulting in the formation of 11.
5

Twenty of the newly synthesized dihydrobenzo[b]thiophenes 8 were evaluated for
their AChE inhibitory activity according to Ellmann’s method12 on AChE from electric eel
using commercial Donepezil HCl as the reference standard.13 The results given in Table 3
clearly show that most of the dihydrobenzo[b]thiophenes 8 exhibit moderate to low inhibitory
activity towards AChE. Four compounds 8a, 8b, 8g and 8z show IC50 values of less than
10µM whereas five compounds 8h–j, 8s and 8y show IC50 values of less than 20µM. Other
compounds in this series show a remarkably low AChE inhibitory activity. Compounds 8b,
8g, and 8z show maximum potency with IC50 values of 5.11µM, 4.24µM and 4.16µM
respectively and in particular, compound 8z was found to be the most active AChE inhibitor
of all the dihydrobenzo[b]thiophene derivatives screened. When compared to the standard
drug all the compounds were less potent.
A simple structure-activity relationship analysis discloses that the AChE inhibitory
potency is closely related to the substitution in the phenyl rings of dihydrobenzo[b]thiophenes
8. From the series of compounds screened, 4-methyl- or 4-methoxy- phenyl group
substitution at C-2 or C-7 in the dihydrobenzo[b]thiophene ring displayed the most potent
AChE inhibitory activity. On the contrary, 4-chloro-, 4-bromo, 4-fluoro- or 4-isopropyl-
phenyl substituted dihydrobenzo[b]thiophene derivatives show relatively lower inhibitory
activity than the other compounds.
The present investigation reports a one-pot domino protocol for the regioselective
synthesis of novel 5-amino-2,7-diaryl-2,3-dihydrobenzo[b]thiophene-4,6-dicarbonitriles via
Knoevenagel condensation–Michael addition–intramolecular Thorpe-Ziegler cyclization–
Tautomerization–Elimination sequence of reactions. These compounds were evaluated for
their AChE inhibitory activity. Among the compounds screened, it is conceivable that
derivatives showing moderate AChE inhibitory activity can be further modified to maximize
6

the potency. Further studies to acquire more information about Quantitative Structure-
Activity Relationships (QSAR) are in progress in our laboratory. The
dihydrobenzo[b]thiophene ring containing derivatives discovered in this study may provide
valuable therapeutic intervention for the treatment of AD.
Acknowledgements
RRK thanks the Department of Science and Technology, New Delhi for the funds
under (i) DST-SERC Fast Track scheme no. SR/FT/CS-073/2009 and (ii) IRHPA program
for the high resolution NMR facility in the Department. VJ thanks the University Grants
Commission, New Delhi for the fellowship under UGC-BSR meritorious scheme. RRK
thanks Dr. S. Perumal, Senior Professor and Head, Department of Organic Chemistry,
Madurai Kamaraj University for his valuable discussions.
References and notes
1. (a) Bartus, R, T.; Dean, R. L.; Beer, B.; Lippa, A. S. Science 1982, 217, 408–414; (b)
Whitehouse, P. J.; Price, D. L.; Clark, A. W.; Coyle, J. T.; DeLong, M. R. Ann.
Neurol. 1981, 10, 122–126; (c) Smith, C. M.; Swash, M. Lancet 1979, 313, 42; (d)
Smith, C. M.; Swash, M.; Exton-Smith, A. N.; Phillips, M. J.; Overstall, P. W.; Piper,
M. E.; Bailey, M. R. Lancet 1978, 312, 318; (e) McGleenon, B. M.; Dynan, K. B.;
Passmore, A. P. Br. J. Clin. Pharmacol. 1999, 48, 471.
2. http://www.alz.co.uk/research/world-report-2011
3. Birks, J.; Harver, R. J. Cochrane Database Syst. Rev. 2009; (1): CD001190.
4. Loy, C.; Schneider, L. Cochrane Database Syst. Rev. 2009; (1): CD0011747.
5. Birkis, J.; Grimley, E. J.; Lakovidou, V.; Tsolaki, M. Holt, F. E. Cochrane Database
Syst. Rev. 2009; (2): CD001191.
7

6. McShane, R.; Areosa, S. A.; Minakaran, N. Cochrane Database Syst. Rev. 2009; (2):
CD003154.
7. Tietze, L. F.; Brasche, G.; Gericke, K. M. In Domino Reactions in Organic Synthesis
Wiley-VCH: Weinheim, 2006.
8. (a) Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967–1983; (b)
Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem. Int. Ed. 2006, 45,
7134–7186.
9. (a) Tietze, L. F. Chem. Rev. 1996, 96, 115.; (b) Toure, B. B.; Hall, D. G. Chem. Rev.
2009, 109, 4439; (c) Indumathi, S.; Perumal, S.; Menendez, J. C. J. Org. Chem. 2010,
75, 472; (d) Harikrishnan, P. S.; Michael Rajesh, S. Perumal, S. Tetrahedron Lett.
2012, 53, 3880; (e) Muthusaravanan, S.; Perumal, S.; Almansour, A. I. Tetrahedron
Lett. 2012, 53, 1144; (f) Vinosha, B.; Perumal, S.; Renuga, S.; Almansour, A. I.
Tetrahedron Lett. 2012, 53, 96; (g) Indumathi, S.; Perumal, S.; Anbananthan, N.;
Green Chem. 2012, 14, 3361.
10. Synthesis of 5-amino-2,7-diaryl-2,3-dihydrobenzo[b]thiophene-4,6-dicarbonitriles 8.
General procedure: A mixture of 5-aryldihydro-3(2H)-thiophenone (5, 1 mmol),
malononitrile (6, 2.1 mmol), appropriate aromatic aldehyde (7, 1 mmol) and
morpholine (2 equiv.) was refluxed in ethanol (10 mL) for 4–5 h. After completion of
the reaction as monitored by TLC, the reaction mixture was concentrated under
vacuum and the residue subjected to silica gel column chromatography using
petroleum ether: ethyl acetate mixture (4:1) as eluent to afford the pure product 8.
5-Amino-2,7-bis(4-isopropylphenyl)-2,3-dihydrobenzo[b]thiophene-4,6-dicarbonitrile
(8r): Isolated as pale yellow solid. Yield: 75%; m.p. 137-139 oC; 1H NMR (300 MHz,
CDCl3) δH: 1.23 (d, 6H, 7.2 Hz), 1.27 (d, 6H, 6.9 Hz), 2.84–2.99 (m, 2H), 3.70 (dd,
1H, J = 17.1, 7.8 Hz), 3.84 (dd, 1H, J = 17.1, 7.8 Hz), 5.04 (t, 1H, J = 8.4 Hz), 5.08
8

(s, 2H, NH2), 7.18–7.42 (m, 8H, Ar-H); 13C NMR (75 MHz, CDCl3) δC: 23.7, 23.8,
33.8, 34.0, 45.3, 52.8, 93.7, 96.7, 114.9, 115.8, 126.9, 127.0, 128.1, 131.1, 133.8,
136.8, 142.7, 148.4, 149.0, 150.2, 150.7. Anal. Calcd for C28H27N3S: C, 76.85; H,
6.22; N, 9.60%. Found C, 76.71; H, 6.14; N, 9.51%.
11. Crystallographic data (excluding structure factors) for compound 8f has been
deposited with the Cambridge Crystallographic Data Center as supplementary
publication number CCDC 911687. Copy of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0)
1223 762911 or e-mail: deposit@ccdc.cam.ac.uk].
12. Ellman, G. L.; Courtney, K. D.; Andres, B.; Featherstone, R. M. Biochem.
Pharmacol. 1961, 7, 88. Acetylcholinesterase (AChE) inhibition
activity:
Cholinesterase enzymes inhibitory potential of the test samples were determined by
Ellman’s microplate assay with slight modification. Donepenzil HCl was used as
positive control. Test samples and Donepenzil HCl were prepared in DMSO at the
initial concentration of 1mg/mL, followed by serial dilutions to prepare five sets of
concentrations to determine the 50% inhibitory concentration (IC50). The final DMSO
concentration in reaction mixture was 1%. At this concentration, DMSO has no
inhibitory effect on acetyl cholinesterase (AChE). For acetyl cholinesterase (AChE)
inhibitory assay, 140 µL of 0.1 M sodium phosphate buffer (pH 8) was added to a 96
wells microplate followed by 20 µL of test samples and 20 µL of 0.09 units/mL
AChE enzyme. Then 10 µL of 10 mM 5,5’-dithiobis(2-nitrobenzoic acid) (DTNB)
was added into each well followed by 10 µL of 14 mM of acetylthiocholine iodide. At
30 minutes after initiation of enzymatic reaction, absorbance of the coloured end
product was measured at 412 nm. Each test was conducted in triplicate. Absorbencies
9

of the test samples were corrected by subtracting the absorbance of their respective
blank. Percentage inhibition was calculated using the following formula:
Percentage inhibition= Absorbance of control - Absorbance of inhibitor X 100%
Absorbance of control
13. Acetylthiocholine iodide (ATCI), acetyl cholinesterase from electric eel (AChE), and
5,5’-dithiobis[2-nitrobenzoic acid] (DTNB) were purchased from Sigma Chemicals
(St. Louis, MO, USA). Donepenzil HCl was received from Ranbaxy Research Lab as
a gift sample. HPLC grade methanol was obtained from Fisher Scientific (Penang,
Malaysia). All the other reagents used were of analytical grade. Spectrophotometric
measurements were performed on Tecan Infinite 200 Pro Microplate Spectrometer.
10

2
Figure 1. AChE inhibitors recommended by NICE guidelines
4
3a
3
2
5
7a
2
6
1
7
Scheme 1 Synthesis of 2,3-dihydrobenzo[b]thiophene-4,6-dicarbonitriles 8
11

Table 1. Yield and melting point of 2,3-dihydrobenzo[b]thiophene-4,6-dicarbonitriles 8
Entry
1
Comp
8a
Ar
Ar′
Yield of 8 (%)
mp (oC)
165-167
172-173
170-173
159-162
164-165
140-142
164-167
166-168
169-171
168-170
170-172
165-168
151-153
165-167
157-159
162-164
159-161
137-139
179-181
199-201
174-176
194-196
179-181
182-184
181-183
204-206
198-200
197-199
198-201
188-190
C6H5
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
70
73
72
73
71
72
74
73
74
71
72
73
74
76
75
74
73
75
76
74
78
73
76
75
74
73
73
73
73
74
2
8b
8c
C6H5
3
C6H5
4
8d
8e
C6H5
5
C6H5
4-BrC6H4
4-PriC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
6
8f
C6H5
7
8g
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-PriC6H4
4-PriC6H4
4-PriC6H4
4-PriC6H4
4-PriC6H4
4-PriC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
8
8h
8i
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
8j
8k
8l
4-BrC6H4
4-PriC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
8m
8n
8o
8p
8q
8r
4-BrC6H4
4-PriC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
8s
8t
8u
8v
8w
8x
4-BrC6H4
4-PriC6H4
4-MeC6H4
8y
8z
4-MeOC6H4 4-MeOC6H4
8aa
8ab
8ac
8ad
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-FC6H4
4-BrC6H4
4-PriC6H4
a Isolated yield after purification by column chromatography
12

Table 2. Base- and solvent- screening
Entry
1
Base (equiv)
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Time (h) Yield of 8ua (%)
Et3N (2)
6
6
6
4
60
53
55
78
0b
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Piperidine (2)
Pyrrolidine (2)
Morpholine (2)
Pyridine (2)
α-Picoline (2)
β-Picoline (2)
K2CO3 (2)
10
10
10
6
10
10
10
10
10
10
10
10
10
10
0b
0b
48
NaOH (2)
NaOEt (2)
EtOH
EtOH
0b
0b
Morpholine (2)
Morpholine (2)
Morpholine (2)
Morpholine (2)
Morpholine (2)
Morpholine (2)
Morpholine (2)
Morpholine (2)
MeOH
2-Propanol
CH3CN
CH2Cl2
THF
DMF
DMSO
1,4-Dioxane
55
30
20
0b
25
0b
0b
20
a Isolated yield after purification by column chromatography
b No reaction took place
Figure 2. Selected H,H-COSY and HMBC correlations of 8r
13

J
J
J
114.9
93.7
J
148.4
2
149.0
96.7
136.8
131.2
115.8
150.2
142.7
J
J
133.8
150.7
3
3
J
J
3
3
J
Figure 3. 1H and 13C chemical shifts of 8r
Figure 4. ORTEP diagram of 8f
14

2
2
2
2
Scheme 2. Probable mechanism for the formation of 8
2
Figure 5. The regioisomer of 8 not formed in the reaction
15

Table 3. AChE inhibitory activity of 8
AChE Inhibition
Comp
(IC50 SD)aµmol/L)
8a
8b
8c
8d
8e
8f
9.62 0.1
5.11 0.1
29.16 0.1
32.30 0.01
37.86 0.1
37.11 0.1
4.24 0.1
8g
8h
8i
11.28 0.1
13.60 0.1
18.11 0.1
24.16 0.1
48.28 0.1
44.24 0.1
17.34 0.01
26.62 0.1
34.11 0.1
39.16 0.1
8j
8k
8o
8p
8s
8t
8u
8v
8w
8y
8z
41.30 0.01
11.60 0.1
4.16 0.1
Donepezil HCl
0.12 0.01
a Data are mean standard deviations of duplicate
independent experiments.
16

A one-pot domino synthesis and discovery of highly functionalized
dihydrobenzo[b]thiophenes as AChE inhibitors
Veerappan Jeyachandran, Raju Ranjith Kumar,* Mohamed Ashraf Ali, Tan Soo Choon
4
3a
7a
2
3
5
2
6
1
7
17