One pot synthesis of acridine analogues from 1,2-diols as key reagents

Article abstract of DOI:10.1039/c5ra19595k

Lead tetraacetate have been demonstrated to be efficient, low cost and mild reagents for the one pot synthesis of acridine derivatives from a variety of 1,2-diols. 1,2-Diols are oxidised in situ to aldehydes, which in turn undergo reaction with dimedone and ammonium acetate to yield acridine derivatives. The attractive features of this process are mild reaction conditions, short reaction times, broad functional group tolerance, easy isolation of products and excellent yields. Thus, the current method utilises 1,2-diols instead of benzaldehydes to synthesise acridines derivatives.

Full text of DOI:10.1039/c5ra19595k

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Page 1 of 18
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DOI: 10.1039/C5RA19595K
One pot synthesis of acridine analogues from 1,2-diols
as key reagents
.
Narasashetty Jagadishbabu and Kalegowda Shivashankar*
P.G. Department of Chemistry, Central College Campus, Bangalore University,
Bangalore ꢀ 560 001, Karnataka, India.
*Corresponding author. Tel: +91ꢀ80ꢀ22961249, Eꢀmail addresses:
shivashankark@gmail.com (K. Shivashankar)
Abstract: Lead tetraacetate have been demonstrated to be an efficient, low cost
and mild reagent for the one pot synthesis of acridine derivatives from a variety of
1,2ꢀdiols. 1,2ꢀDiols are oxidised in situ to aldehydes, which in turn undergo
reaction with dimedone and ammonium acetate to yield acridine derivatives. The
attractive features of this process are mild reaction conditions, short reaction times,
broad functional group tolerance, easy isolation of products and excellent yields.
Thus, the current method is utilizing 1,2ꢀdiols instead of benzaldehydes to
synthesis acridines derivatives
Keywords: Acridine, lead tetraacetate, multicomponent reaction, 1,2ꢀdiols,
dimedone, acetic acid, ammonium acetate.
Introduction
The multiꢀcomponent reaction (MCR) is one pot process in which at least
three or more different reactants react for the synthesis of target molecule. MCRs
tactics are proclaimed to be economic, cost and time effective attributing its
properties such as reducing the number of synthetic steps, isolation and
purification process, energy consumption and waste production. Hence, developing
new MCRs and improvement of existing MCRs are still important areas of
research in the current synthetic and medicinal organic chemistry.1ꢀ4
1

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The synthesis of acridine derivatives, which contain 1,4ꢀdihydropyridines
parent nucleus is an important reaction, as these scaffolds are found to be a very
important core in numerous synthetic, pharmaceutical and a wide variety of
biologically active compounds.5ꢀ13 A large number of compounds bearing 1,4ꢀ
dihydropyridines have entered preclinical and clinical trials over the last few years.
Many commercially available drugs (Figure 1) including Nifedipine, Clevidipine,
Lacidipine and Nisoldipine (calcium channel blocker), Nicardipine, Manidipine
and Felodipine (antihypertensive compounds), Amlodipine (used in coronary
artery disease) are derived from 1,4ꢀdihydropyridines core entities.14
1,4ꢀDihydropyridines moieties are also important as antiꢀinflammatory,15
antimicrobial,16 anticancer,17 antimalarial,18 antituberculosis,19 antiherpes,20
antiprotozoal activity,21 antiprion,22 antiviral23 and antileishmanial agents.24
Hence, the synthesis of acridine which contain 1,4ꢀDHP’s has evoked much
attention, as a result of which a variety of synthetic methodologies have been
reported. The most important approaches are: (i) one pot cyclocondensation of
aldehydes with dicarbonyls and ammonium acetate,25 (ii) one pot
cyclocondensation of aldehydes with dicarbonyls and methyl amine,26 (iii) one pot
cyclocondensation of aldehydes with dicarbonyls and ammonium bicarbonate.27 In
the past years, a few methods have described the oneꢀpot multicomponent
synthesis of acridine derivatives based on catalysts such as DBSA,28 Lꢀproline,29
amberlystꢀ15,30 under microwave,31 TMSClꢀNaI,32 I2,33 CeCl3ꢀ7H2O,34 SiO2ꢀPrꢀ
SO3H,35 Fe3O4 Nanoparticles,36 MCMꢀ41ꢀSO3H,37 and ionic liquid.38 However,
these methods have limitations in terms of the use of excess amounts of expensive
catalysts, product diversity and yields. Hence, the development of a simple and
high yielding protocol for the oneꢀpot multicomponent synthesis of acridine
scaffolds is still warranted.
2

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In continuation of our work on the development of useful synthetic
methodologies,39,40 in this study we report the use of lead tetraacetate as an
oxidizing agent for the oneꢀpot synthesis of acridine derivatives under mild
conditions. Lead tetraacetate function as oxidizing agent offering several
advantages such as high yields and purity, broad functional group tolerance and
easy work up when compared to traditional reagents. The byproduct lead acetate
can be removed by oxidation with chlorine gas to give PbCl2. The PbCl2 salt
formed may be separated by filtration making use of its lower solubility. The lead
acetate can also be removed by many advanced methods.41ꢀ47
Though, lead tetraacetate has been identified as an oxidizing agent,48 the
wider scope and synthetic utility of this reagent in multicomponent reactions has
not been explored. Here, we report a one pot approach for synthesis of acridine
derivatives starting from various 1,2ꢀdiols, dimedone and ammonium acetate
without the need for an additional catalyst. The tandem process involves oxidation,
condensation, cyclisation and dehydration under mild condition at 70 oC.
Results and discussion
First, the reaction of 1,2ꢀdiphenylꢀ1,2ꢀethanediol with dimedone and
ammonium acetate was selected as the model reaction for the optimization of the
reaction conditions (Scheme 1). It was hypothesized that the careful judgment of
lead tetraacetate might efficiently oxidizes 1,2ꢀdiols into the benzaldehyde
followed by condensation with dimedone and cyclisation and dehydration with
ammonium acetate in one pot. A preliminary examination showed that lead
tetraacetate in dry ethanol, among several other solvents, effectively oxidized
followed by acetic acid catalysed condensation, cyclisation and dehydration. Upon
o
varying the temperature of the reaction from 40 to 70 C, the best yield of 4a was
3

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o
obtained at 70 C. Further increase of the temperature neither increased the yield
nor shortened the reaction time. The time taken to achieve complete conversions
(monitored by TLC) and the isolated yields are recorded in Table 2. Of all the
reactions using different quantities of reactant, the best results were obtained using
a 1: 4: 2.2: 1 ratios of 1,2ꢀdiols, dimedone, ammonium acetate and lead tetraacetate
respectively. When a mixture of 1,2ꢀdiphenylꢀ1,2ꢀethanediol, dimedone,
ammonium acetate and lead tetraacetate respectively in dry ethanol were stirred at
o
room temperature and then refluxed at 70 C for 2 h, the fused heterocyclic
product,
3,3,6,6ꢀteteramethylꢀ9ꢀphenylꢀ3,4,6,7ꢀtetrahydroacridineꢀ
1,8(2H,5H,9H,10H)ꢀdione (4a) was obtained in excellent yield (95%).
The role of the solvent in the synthesis of acridine derivatives was then
studied and the results are depicted in Table 1. Replacing ethanol by acetonitrile
gave the product in high yield (entry 3) albeit lower than that obtained in ethanol
(entry 4). The use of other solvents such as dioxane, acetone, THF and methanol
afforded the desired product in average yields (70–80%, entries 2, 5, 6 and 7),
while DCM, DMF and DMSO produced lower yields (entries 1, 8 and 9). The
o
optimized conditions were established with a reaction temperature of 70 C and
time of 2 h in ethanol solvent.
This remarkable activation in the reaction rate prompted us to explore the
potential of this protocol for the synthesis of a variety of acridine derivatives and
the results are summarized in Table 2. All the aforementioned reaction proceeded
expeditiously and delivered good to excellent product yields. The overall yield
ranged from 95% for 3,3,6,6ꢀteteramethylꢀ9ꢀphenylꢀ3,4,6,7ꢀtetrahydroacridineꢀ
1,8(2H,5H,9H,10H)ꢀdione (4a) (entry 1) to 82% for 9ꢀ(2,6ꢀdichlorophenyl)ꢀ
3,3,6,6ꢀteteramethylꢀ3,4,6,7ꢀtetrahydroacridineꢀ1,8(2H,5H,9H,10H)ꢀdione
(4n)
(entry 14).
4

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A probable mechanistic pathway for the formation of acridine derivatives is
analogous to the established mechanism reported in the literature.49 The lead
tetraacetate oxidizes 1,2ꢀdiol to benzaldehyde giving acetic acid which in turn
would able to acid catalyse condensation between benzaldehyde and dimedone
gives the chalcone. The chalcone undergoes Michael addition with enamine which
is formed in situ by the reaction of dimedone with ammonium acetate that yields
the corresponding acridine via the cyclisation followed by the dehydration.
Conclusion
We have developed an efficient, one pot strategy for the synthesis of
acridine derivatives by in situ oxidation of 1,2ꢀdiols into benzaldehyde followed by
the reaction with dimedone and ammonium acetate in excellent yields. Tandem
nature, mild conditions, simple and convenient workꢀup are the main advantage of
this reaction. This protocol is also applicable to the broad range of substrates. The
current strategy reduces the number of steps in total synthesis.
Experimental
General information.
The melting points were determined by the open capillary method using an
electric melting point apparatus and are uncorrected. The IR spectra were recorded
1
13
on a Agilent Cary 630 FTꢀIR Spectrophotometer. H NMR and C NMR spectra
were recorded on a Bruker 400 MHz spectrometer using CDCl3 as a solvents and
TMS as an internal standard. The chemical shifts are expressed in δ ppm. The mass
spectrum was recorded on Thermo LCQ Fleet. The purity of the compounds was
checked by TLC. The elemental analyses were carried out using an Elemental
Vario Micro Cube CHNS Rapid Analyzer. All the compounds gave satisfactory
5

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elemental analysis. All reagents were purchased from SigmaꢀAldrich. Lead
tetraacetate is a solid compound. The purity of lead tetraacetate is ≥ 99.99%.
Typical procedure for the synthesis of 3,3,6,6-teteramethyl-9-phenyl-3,4,6,7-
tetrahydroacridine-1,8(2H,5H,9H,10H)-dione(4a).
Lead tetraacetate (0.44g, 1mmol) was added to a solution of 1,2ꢀ
diphenylethaneꢀ1,2ꢀdiol (0.21g, 1mmol), dimedone (0.56g, 4mmol) and
ammonium acetate (0.16g, 2.2mmol) in dry ethanol (10 mL) in a roundꢀbottomed
flask fitted with a reflux condenser and a guard tube. The resulting reaction
mixture was stirred at room temperature for 5 minutes and heated at 70 oC in an oil
bath for 2 h. The progress of the reaction was monitored by TLC. After completion
of the reaction, water (10 mL) was added and the reaction mixture was allowed to
cool to room temperature. The solid was collected by filtration at pump, washed
with cold ethanol and recrystallised from ethanol to obtain pure product.
2-(3,3,6,6-Teteramethyl-1,8-dioxo-1,2,3,4,5,6,7,8,9,10-decahydroacridin-9-
yl)benzonitrile (4d)
A pale brown solid, 329 mg (88% yield). IR (ATR, cmꢀ1): 3320 (NH), 2230 (CN),
o
1
1740 (C=O), 1715 (C=O); mp 235ꢀ237 C. H NMR (CDCl3, 400 MHz): δ 11.80
(s, 1H, NH), 7.48ꢀ7.26 (m, 4H, ArꢀH), 5.49 (s, 1H, CH), 2.50ꢀ2.29 (m, 8H, 4CH2),
13
1.23 (s, 6H, 2CH3), 1.10 (s, 6H, 2CH3) ppm. C NMR (CDCl3, 400 MHz): δ
196.8, 168.7, 161.7, 157.7, 138.0, 136.7, 136.4, 134.6, 131.7, 130.0, 117.1, 80.0,
51.2, 41.0, 32.4, 30.5, 29.1, 28.5, 21.6, 21.2, 19.6, 14.6 ppm. ESIꢀMS: [M+H[
375.7. Anal. Calcd for C24H26N2O2: C, 76.98; H, 7.00; N, 7.48; found: C, 76.92; H,
6.95; N, 7.36%.
6

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9-(4-(Benzyloxy)phenyl)-3,3,6,6-teteramethyl-3,4,6,7-tetrahydroacridine-1,8-
(2H,5H,9H,10H)-dione (4h)
A white solid, 391 mg (86% yield). IR (ATR, cmꢀ1): 3396 (NH), 1731 (C=O),
o
1
1720 (C=O); mp 283ꢀ285 C. H NMR (CDCl3, 400 MHz): δ 7.36 (s, 1H, NH),
7.34ꢀ6.78 (m, 9H, ArꢀH), 5.01 (s, 1H, CH), 4.92 (s, 2H, OCH2), 2.42ꢀ2.14 (m, 8H,
4CH2), 1.07 (s, 6H, 2CH3), 0.96 (s, 6H, 2CH3) ppm. 13C NMR (CDCl3, 400 MHz):
δ 195.6, 157.0, 149.3, 137.9, 132.2, 128.4, 128.2, 127.9, 127.2, 120.4, 111.9, 70.4,
50.9, 40.5, 32.3, 31.9, 29.5, 27.3 ppm. Anal. Calcd for C30H33NO3: C, 79.09; H,
7.30; N, 3.07; found: C, 78.99; H, 7.20; N, 3.01%.
9-(4-Bromo-2-fluorophenyl)-3,3,6,6-teteramethyl-3,4,6,7-tetrahydroacridine-
1,8-(2H,5H,9H,10H)-dione (4k)
A white solid, 374 mg (84% yield). IR (ATR, cmꢀ1): 3298 (NH), 1734 (C=O), 1713
o
1
(C=O); mp 275ꢀ277 C. H NMR (CDCl3, 400 MHz): δ 8.14 (s, 1H, NH), 7.30ꢀ
6.93 (m, 3H, ArꢀH), 5.01 (s, 1H, CH), 2.43ꢀ2.16 (m, 8H, 4CH2), 1.17 (s, 6H,
13
2CH3), 0.98 (s, 6H, 2CH3) ppm. C NMR (CDCl3, 400 MHz): δ 196.2, 157.6,
155.2, 150.0, 143.9, 130.1, 127.8, 120.3, 120.1, 116.1, 115.9, 112.5, 50.8, 40.6,
33.3, 32.7, 29.5, 27.1 ppm. Anal. Calcd for C23H25BrFNO2: C, 61.89; H, 5.65; N,
3.14; found: C, 61.79; H, 5.55; N, 3.11%.
9-(2-Bromo-6-chlorophenyl)-3,3,6,6-teteramethyl-3,4,6,7-tetrahydroacridine-
1,8-(2H,5H,9H,10H)-dione (4o)
A white solid, 299 mg (83% yield). IR (ATR, cmꢀ1): 3283 (NH), 1739 (C=O), 1721
o
1
(C=O); mp 256ꢀ258 C. H NMR (CDCl3, 400 MHz): δ 8.14 (s, 1H, NH), 7.36ꢀ
6.95 (m, 3H, ArꢀH), 5.05 (s, 1H, CH), 2.33ꢀ2.05 (m, 8H, 4CH2), 1.08 (s, 6H,
13
2CH3), 0.97 (s, 6H, 2CH3) ppm. C NMR (CDCl3, 400 MHz): δ 195.8, 193.1,
149.2, 133.4, 132.9, 131.9, 128.7, 116.0, 115.7, 112.7, 108.3, 105.0, 63.6, 51.6,
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50.7, 50.5, 42.6, 40.8, 33.2, 32.7, 29.6, 28.8, 28.6, 27.2 ppm. Anal. Calcd for
C23H25BrClNO2: C, 59.69; H, 5.44; N, 3.03; found: C, 59.64; H, 5.39; N, 2.95%
Acknowledgements
One of the authors (KS) is thankful to the Science and Engineering Research Board
(SERB), the Department of Science and Technology, India for financial assistance
(Grant No. SB/FT/CSꢀ028/2013).
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O2N
NO2
Cl
O
O
O
H3CO2C
CO2CH3
H3CO2C
H3CO2C
N
O
O
N
N
NH2
N
H
H
H
Nifedipine
Nicardipine
Amlodipine
Cl
Cl
O
O
NO2
CO2
CO2CH3
H3CH2CO2C
CO2CH2CH3
H3CO2C
CO2CH2CH3
N
H
N
N
H
H
Nisoidipine
Lacidipine
Felodipine
Figure 1: Commercially available drugs.
O
O
O
OH
Pb(OAc)4 , dry EtOH, Reflux
NH4OAc
+
+
OH
1a
N
H
O
Pb(OAc)2
+
3H2O
+
3AcOH
3
2
4a
Scheme 1. Synthesis of 3,3,6,6-teteramethyl-9-phenyl-3,4,6,7-tetrahydroacridine-
1,8(2H,5H,9H,10H)-dione (4a) using lead tetra acetate reagent.

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DOI: 10.1039/C5RA19595K
Table 1. Optimization of solvents for the synthesis (4a).
Entry
Solvents (Dry) Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
Dioxane
Acetonitrile
Ethanol
Acetone
THF
5.5
6.5
4
41
72
90
95
70
77
80
45
52
2
4.5
5
Methanol
DMF
3.5
5.5
5.5
DMSO
Table 2. Synthesis of acridine derivatives (4a–o).
Entry
1
1,2-diols
Products
Time (h)
Yield (%)
95
OH
O
O
2
OH
1a
N
H
4a
Cl
Cl
2
OH
O
O
2.5
89
OH
Cl
1b
N
H
4b

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DOI: 10.1039/C5RA19595K
OH
3
O
O
2
94
88
OH
N
H
1c
4c
CN
O
CN OH
O
4
5
2.5
OH CN
N
H
1d
4d
O
O
OH
O
O
3
93
87
OH
1e
O
N
H
4e
NO2
NO2
6
7
3.5
OH
O
O
OH
O2N
1f
N
H
4f
O
Br
Br
O
O
OH
2
92
O
OH
O
Br
N
H
1g
4g

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DOI: 10.1039/C5RA19595K
OCH2Ph
OCH2Ph
8
9
OH
O
O
3
86
OH
1h
PhH2CO
N
H
4h
Br
Br
OH
O
O
2.5
85
85
OH
Br
N
H
1i
4i
F
F
10
OH
2.5
O
O
OH
F
N
H
1j
4j
Br
Br
11
F
OH
F
O
O
3
84
OH
1k
F
Br
N
H
4k

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OH
12
OH
OH
O
O
2
90
88
OH
HO
1l
N
H
4l
F
F
OH
O
13
OH OH
O
2.5
OH OH
N
H
F
4m
1m
Cl
OH
Cl
O
Cl
O
Cl
14
15
3
82
83
OH Cl
Cl
N
H
1n
4n
Br
OH
Cl
O
Br
O
Cl
3.5
OH Cl
Br
N
H
1o
4o

RSC Advances
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DOI: 10.1039/C5RA19595K
Graphical abstract:
Lead tetraacetate is an efficient, low cost and mild reagent for the one pot
synthesis of acridine derivatives from a variety of 1,2-diols. 1,2-Diols are
oxidised in situ to aldehydes, which in turn undergo reaction with dimedone and
ammonium acetate to yield acridine derivatives.
OH
O
O
O
Pb(OAc)4
+
NH4OAc
+
dry EtOH, Reflux
OH
O
N
H