Synthesis of tacrine derivatives under solventless conditions

Article abstract of DOI:10.1002/jhet.5570440305

(Chemical Equation Presented) Effects of microwave irradiation on the solid-phase synthesis of tacrine and its derivatives have been evaluated. Preparation of tacrine analogues under conventional conditions suffers from poor synthetic efficiency and usually gives low yield. Reaction of substituted anthranilonitrile with cyclohexanone under microwave irradiation gave a good to excellent yield of the corresponding substituted 9-amino-1,2,3,4- tetrahydroacridines.

Full text of DOI:10.1002/jhet.5570440305

May-Jun 2007
535
Synthesis of Tacrine Derivatives Under Solventless Conditions
Mohammad A. Khalilzadeh*, Abolfazl Hosseini and Mahmoud Tajbakhsh,
Department of Chemistry, Islamic Azad University, Qaemshahr, Iran
E-mail: mkkalagar@yahoo.com
Received March 3, 2006
O
NH2
R1
R2
CN
R1
R2
Silica gel/P-toluensulfonic acid
+
MW
NH2
N
R1= CH3, H, NH2, NO2, Cl, OCH3
R2= CH3, H, NH2, NO2, Cl, OCH3, F
Effects of microwave irradiation on the solid-phase synthesis of tacrine and its derivatives have been
evaluated. Preparation of tacrine analogues under conventional conditions suffers from poor synthetic
efficiency and usually gives low yield. Reaction of substituted anthranilonitrile with cyclohexanone under
microwave irradiation gave a good to excellent yield of the corresponding substituted 9-amino-1,2,3,4-
tetrahydroacridines.
J. Heterocyclic Chem., 44, 535 (2007).
INTRODUCTION
family of enzymes [11]. More recently, tacrine has been
shown to possess a much broader pharmacological profile
than cholinesterase inhibition: blockage of potassium
channels [12], inhibition of the neuronal monoamine
uptake processes [13], and inhibition of monamine
oxidase [14] have all been reported.
Dementia is the most common psychiatric disorder of
old age, and Alzheimer’s disease [1] is its most common
cause. Alzheimer’s disease involves the degeneration of
cholinergic neurones in the cerebral cortex and
hippocampus, areas of the brain particularly associated
with memory, higher intellectual functioning, and
consciousness [2]. The biochemical deficits also extend
into other neurochemical systems, affecting the levels of
monoamine transmitters for example [3], but the most
The study of tacrine analogues is still of interest to
medicinal chemists involved in AD research. In this
regard, we have studied the synthesis of tacrine
derivatives under very mild and efficient conditions.
O
NH2
NH2
CH3
CH3
N
CH3NH
O
CH3
O
O
H
N
N
N
N
CH3
CH3
(1)
(2)
(3)
Scheme1
(4)
profound and consistent loss is that of cholinergic
transmission. Consequently, much research concerns
enhancing the cholinergic system in some way [4],
ranging from the use of acetylcholine-releasing agents
such as 4-aminopyridine (1) [5]; the acetylcholine
precursor, choline [6]; cholinergic agonists, e.g. arecoline
(2); and anticholinesterase drugs, e.g. physostigmine (3).
However, one drug in particular has become the subject of
intense pharmacological scrutiny for its efficacy in
alleviating the symptoms of Alzheimer’s disease, namely
9-amino-1,2,3,4-tetrahydroacridine, commonly referred to
as tacrine (4) [7].
Synthesis of tacrine analogues was generally reported by
condensing of substituted anthranilonitrile (5) with
cyclohexanone (6) in the presence of a Lewis acid. ZnCl2
[15a], P-toluensolfunic acid (PTSA) [15b, 15c], BF3/Et2O
[15d], and P2O5 [15e] were used as Lewis acid. Tacrine
analogues were also prepared by condensing 2-amino-3-
cyano-4H-pyrans with cyclohexanone [15f]. Amongst
above procedures, the use of P-toluensolfunic acid is
preferred because of its lower toxicity than other acids.
However, all these methods suffer from low yield and
long reaction time. The use of microwave irradiation to
simplify and improve classical organic reactions has
become a very popular technique because it often results
in shorter reaction times, higher yields and cleaner
reaction [16].
Tacrine (4) [8] was found to be a potent acetyl-
cholinesterase inhibitor [9,10] in 1953 and, subsequently,
an even stronger inhibitor of the butyrylcholinesterase

536
M. A. Khalilzadeh, A. Hosseini and M. Tajbakhsh
Vol 44
O
In order to find optimum condition for this synthesis we
have treated 2-aminobenzonitrile (anthranilonitrile) with
cyclohexanone using PTSA under microwave irradiation
as a model experiment. As indicated in Table 1, when the
reaction was conducted on acidic alumina or zeolite HY a
moderate yield of tacrine was obtained after 12 minutes
irradiation at 440 or 600W (Table 1, entries 1-4). When
montmorillonite K10 clay was employed only low yield
of tacrine was formed (Table 1, entries 5,6).
R1
R2
CN
R1
R2
CN
N
+
NH2
(5)
(6)
(7)
NH
N
NH2
N
R1
R1
R2
R2
1-12
A quantitative yield of tacrine was gained when silica
gel used as a solid support in this reaction (Table 1,
entries 7, 8). No evidence of by-product formation was
found in any case.
R1= CH3, H, NH2, NO2, Cl, OCH3
R2= CH3, H, NH2, NO2, Cl, OCH3, F
Scheme 2
It is noteworthy from a mechanistic view point that an
intermediate probably 2-cyclohexylideneamino-benzonitrile
(7) [10d] was first formed which then converted to tacrine.
To continue our systematic study of the cyclization
reaction and to further appraise the influence of the silica
gel on the outcome of the reaction, we have modified the
relative ratios of reagents and catalyst. While maintaining
a 1.5 molar excess of PTSA (0.26 g, 1.5 mmol) to
anthranilonitrile (1 mmol) and cyclohexanone (1.2 mmol),
the amount of silica gel was varied between 0.1 and 0.6 g.
The results are clear-cut: the rate of tacrine formation
steadily increases with the quantity of silica gel used. A
2:1 silica gel:PTSA weight ratio was required in order to
achieve a quantitative conversion of anthranilonitrile
within a few minutes.
On the other hand solvent-free chemical synthesis has
received much attention recently [17]. Solvent-free
processes are not only environmentally benign but also
economical [18]. Since solvent is not required, toxic
wastes can be minimized or eliminated and so the cost of
solvent and waste treatment is reduced. Furthermore,
operational simplicity is an attractive feature. Recent
advances in this area include, for example, Aldol [19a,b]
and related reactions [19c], asymmetric-catalyzed
addition [19d] and catalyzed cross-coupling reactions
[19e-h]. We now report here a simple and efficient
method for preparation of tacrineanalogues via treatment
of substituted anthranilonitrile (5) with cyclohexanone (6)
using PTSA supported on silica gel under microwave
irradiation (Scheme 2).
In order to investigate the generality and applicability
of this procedure we have carried out the reaction of
substituted anthranilonitrile with cyclohexanone under
RESULTS AND DISCUSSION
optimum conditions. As
a comparison, the PTSA
The reaction of substituted anthranilonitrile (5) with
mediated cyclodehydration reaction between anthranilo-
nitrile with cyclohexanone which gave tacrine (4) [15b]
was adopted to produce the ranges of compounds by
substituting anthranilonitrile (5) (Scheme 2). The results
are presented in the Table 2.
As indicated in this Table reaction of substituted
anthranilonitrile with cyclohexanone using PTSA under
conventional conditions usually gives low yield of
corresponding tacrine derivatives in long reaction time
(Table 2, entries 1-12). On the other hand these reactions
cyclohexanone (6) was performed in
a domestic
microwave oven in sealed heavy-walled Teflon tubes
(Scheme 2). When compounds (5), cyclohexanone and
PTSA without silica gel were subjected to microwave
irradiation, very low yield of corresponding tacrine was
obtained. This result implies that silica gel plays an
important role in this reaction. This was further confirmed
when other solid supports such as montmorillonite K10,
alumina and zeolite were employed. The results are
shown in Table 1.
Table 1
Comparison of various solid supports for tacrine synthesis
Solid support
Entry
Power (W)
yielda %
8min
4min
12min
Alumina (acidic)
Zeolite HY
1
2
3
4
5
6
7
440
600
440
600
440
600
440
15
20
20
20
30
65
70
75
75
70
80
40
70
70
75
75
85
85
95
Montmorillonite (K-10)
Silica gel
Trace
Trace
8
600
50
95
>95
a) Isolated yield.

May-Jun 2007
Synthesis of Tacrine Derivatives Under Solventless Conditions
537
B: Under microwave irradiation. PTSA (0.26 g, 1.5 mmoles),
substituted anthranilonitrile (1 mmoles), cyclohexanone (0.12 g,
1.2 mmoles) and solid supports (0.5-0.55 g) were thoroughly mixed
in a mortar and exposed to microwave irradiation (600 W) in 2
minute intervals. After completion of the reaction (TLC), methanol
(10 ml) was added and the mixture filtered. The resulting solution
was dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure to afford pure products. All the
products were characterized by their m.p, IR and H NMR spectra
and comparison with authentic samples.
Acknowledgement. Financial support of this work from the
Research Council of Qaemshahr Azad University is gratefully
acknowledged.
under microwave irradiation using PTSA supported on
silica gel gives moderate to high yield of products in a
much shorter reaction time (Table 2, entries 1-12).
In conclusion, we have described a rapid, novel and
efficient method for condensation of substituted
anthranilonitrile and using the solid catalyst PTSA/silica
gel under microwave irradiation which forms tacrine
analogues exclusively in moderate to high yield and high
purity. Also, the unfavourable use of the aromatic
solvents such as xylene was avoided. Several advantages
like inexpensive and nontoxic catalyst; very short reaction
1
Table 2
Synthesis of tacrine analogues under conventional heating and microwave irradiation
Entry
R1
R2
Isolated yield%a
Isolated yield%a
m.p. ºCb
Ref.
Thermal heating
Microwave
1
2
3
4
5
6
7
8
CH3
H
Cl
H
NO2
H
H
NH2
H
Cl
OCH3
H
CH3
H
Cl
H
NO2
OCH3
H
F
Cl
35
35
50
45
40
30
55
60
40
40
45
70
65
60
70
78
65
70
68
75
65
65
80
95
223-225
220-222
254-256
296-298
264-266
260-262
181-183
118-120
210-212
265-267
275-277
120-122
20
21
22
22
23
21
24
25
25
21
24
15b
9
10
11
12
OCH3
H
H
a) Yields refer to isolated products. b) All the products are known compounds were characterized by IR, 1HNMR spectra and
comparison with authentic samples.
REFERENCES AND NOTES
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EXPRIMENTAL
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General Procedure for Preparation of Tacrine
Derivatives. A: Under conventional conditions [15b,15c]. To
a 25 ml, round-bottom flask equipped with Dean-Stark trap was
charged PTSA (0.52 g, 3 mmoles), substituted anthranilonitrile
(2 mmoles), cyclohexanone (0.24 g, 2.4 mmoles). The stirred
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