Synthesis of tacrine analogs derived from N-Aryl-5-amino-4-cyanopyrazoles

Article abstract of DOI:10.1080/00397910802331638

Synthesis of 11 tacrine analogs derived from N-aryl-5-amino-4- cyanopyrazoles, by a Friedlander type reaction, is described. Their structures were confirmed by 1H and 13C NMR spectroscopy, elemental analysis, and/or mass spectrometry. Copyright Taylor & Francis Group, LLC.

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Synthesis of Tacrine Analogs
Derived from N-Aryl-5-amino-4-
cyanopyrazoles
Lígia M. Rodrigues a , Carla S. Francisco a , Ana M. F.
Oliveira-Campos a & Abdellatif M. Salaheldin a
a Chemistry Center, University of Minho, Braga,
Portugal
Version of record first published: 07 Nov 2008.
To cite this article: Lígia M. Rodrigues , Carla S. Francisco , Ana M. F. Oliveira-Campos
& Abdellatif M. Salaheldin (2008): Synthesis of Tacrine Analogs Derived from N-Aryl-5-
amino-4-cyanopyrazoles, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 38:24, 4369-4378
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Synthetic Communications1, 38: 4369–4378, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802331638
Synthesis of Tacrine Analogs Derived from
N-Aryl-5-amino-4-cyanopyrazoles
´
Lıgia M. Rodrigues, Carla S. Francisco,
Ana M. F. Oliveira-Campos, and Abdellatif M. Salaheldin
Chemistry Center, University of Minho, Braga, Portugal
Abstract: Synthesis of 11 tacrine analogs derived from N-aryl-5-amino-
4-cyanopyrazoles, by a Friedla¨nder type reaction, is described. Their structures
1
were confirmed by H and 13C NMR spectroscopy, elemental analysis, and=or
mass spectrometry.
Keywords: Alzheimer’s disease, aminocyanopyrazole, Friedla¨nder reaction,
nitrogen heterocycles, tacrine analogs
INTRODUCTION
Alzheimer’s disease (AD) is very common nowadays in elderly indivi-
duals. The finding of acetylcholine deficiency in those patients is the basis
for research related to drugs that will inhibit acetylcholinesterase
(AChE). The first of these inhibitors that received regulatory approval
for AD treatment was tacrine (1).[1,2] Modifications have also been per-
formed within the structure, either by increasing the number of rings or
changing their size or introducing heteroatoms
Received May 27, 2008.
´
´
Address correspondence to Lıgia M. Rodrigues, Centro de Quımica, Univer-
sidade do Minho, Campus de Gualtar, 4710-415 Braga, Portugal. E-mail:
ligiar@quimica.uminho.pt
4369

4370
L. M. Rodrigues et al.
One group found out that compounds with four rings were less active
than tacrine against AchE; however, they were more selective and have
shown potential against b-amyloid protein aggregation in the brain.[3]
Tacrine analogs containing a furan ring have been known for some
time,[4] and recently, Thomae et al. synthesized analogs of tacrine and
velnacrine containing thiophene.[5] An analog of tacrine was also des-
cribed, in which the primary amino group was replaced by the azetidine
moiety.[6]
A Spanish–Portuguese group has described the synthesis of tacrine
analogs containing heterocyclic rings, such as pyridine, pyran, and oxa-
zole, and their inhibitory effects on AChE and butyrylcholinesterase.[7]
Other families of tacrine analogs containing pyrazolopyridine (e.g., 2)
or pyrazolonaphthyridine (e.g., 3) systems as isosteres of the quinoline
ring of tacrine have been described by Barreiro et al.[8] They concluded
that compounds 2 and 3 were the most potent inhibitors of AChE in
their class.
We report here the synthesis of new tacrine analogs from 5-amino-4-
cyano-1-arylpyrazoles by reaction of an ortho-aminonitrile with a cyclic
ketone in the presence of a Lewis acid.
RESULTS AND DISCUSSION
We have been interested for some time in ortho-aminocyanopyrazoles,
such as 4, or their derivatives, as dye precursors[9] or xanthine oxidase
inhibitors.[10] We decided to prepare derivatives of the type 5 or similar,
which would be positional isomers of tacrine analogs 2 (Scheme 1).
Most published works build the system using the Friedla¨nder synth-
esis of tetrahydroquinoline.[11]
In the first approach, we applied the common conditions[2,3] with
dichloroethane, AlCl3, and reflux for 6 h under argon (method A). One
slight modification that we also applied includes heating for 6 h at
150 ꢀC without solvent and AlCl3 as the catalyst (method B). Finally con-
ditions of heterogeneous or solid-phase catalysis12 were applied with mix-
tures of ZnCl2 and silica in proportions 2:1 and 4:1 and heating for 4 h at
150 ꢀC (methods C and D).

Synthesis of Tacrine Analogs
4371
Scheme 1. Structures of compounds 4, 5, and 6.
The compounds were obtained in low yields, except for compound 5d
either with AlCl3 (method B, 80%) or ZnCl2 (method C, 60%). For this
compound, the yield dropped to 33% when method D (4:1 ZnCl2 and
silica) was used.
We observed that a less polar intermediate was quickly formed, pos-
sibly the Schiff’s base, but the cyclization was difficult. If we think on the
mechanism it is possible to assume that the acid will accelerate the for-
mation of the imine. However, the closing step may be easier when basic
catalysis is applied.
One method reported by Kirsch[5] obtained the imine, from the
aminocyanothiophene and 1,3-dicyclohexanedione, in toluene and
p-toluenesulphonic acid and cyclized it to the tacrine analog in DMF
solution with sodium methoxide and CuCl. Our attempt to obtain the
imine from the aminocyanopyrazole and cyclohexanone by this method
was not successful.
1
The newly synthesized compounds were identified by H NMR, 13C
NMR, mass spectra, and=or elemental analysis (cf. the Experimental section)
EXPERIMENTAL
General
Melting points were determined on a Gallenkamp melting-point appa-
ratus and are uncorrected. IR spectra were registered on a Perkin-Elmer

4372
L. M. Rodrigues et al.
FTIR-1600. 1H NMR (300-MHz) and 13C NMR (75.4-MHz) spectra were
recorded on a Varian Unity Plus spectrometer. Double-resonance hetero-
nuclear multiple quantum coherence (HMQC) and heteronuclear multiple
bond coherence (HMBC) experiments were carried out for complete
assignment of proton and carbon signals in the NMR spectra, whenever
possible. Mass spectra were obtained on a AutoSpec E spectrometer.
Elemental analyses were obtained on a Leco CHNS-932 instrument.
Method A
A solution of the p-chlorophenylpyrazole (4d) (0.7 mmol) in dichloro-
ethane (25 mL), cyclohexanone (0.1 mL, 0.97 mmol), and AlCl3 (0.1 g,
0.75 mmol) were added and the mixture was refluxed for 6 h under argon.
After cooling, a mixture of THF=H2O (1:1, 25 mL) was added, and then
an aqueous solution of NaOH (10%) was added dropwise until the
aqueous solution was basic. After stirring for 30 min, the mixture was
extracted with dichloromethane (3 ꢁ 20 mL), and the combined extracts
were washed with brine (20 mL), dried (MgSO4), and filtered. The solvent
was evaporated to give a solid, which was purified by preparative layer
chromatography (PLC) (CH2Cl2-MeOH, 9:1) yield 32%.
Method B
The pyrazole derivative (0.3 mmol), cyclohexanone (2.0 mmol), and
AlCl3 (0.1 g) were added to a sealed tube (screw cap). The mixture
was heated for 6 h (external temperature 150 ꢀC), while a color change
occured. After cooling, a mixture of THF=H2O (1:1, 5 mL) was added,
and then an aqueous solution of NaOH (10%) was added dropwise
until the aqueous solution was basic. After stirring for 30 min, the mix-
ture was extracted with dichloromethane (4 ꢁ 10 mL), and the combined
extracts were washed with brine (20 mL) and dried (MgSO4). Concen-
tration of the extract followed by chromatography yielded the target
compound.
Methods C and D
Preparation of the Catalyst ZnCl2=Siliga Gel. A mixture of ZnCl2 (8 g),
siliga gel (4 g, silica gel 60, 0.063 mm, Merck), and water (3 mL) was stir-
red for 15 min and left in the oven for 3 h at 80 ꢀC and then 15 h at 150 ꢀC.
The catalyst (ZnCl2=siliga gel 2:1) was cooled and kept in the desiccator
(method C).[12,13] The catalyst (ZnCl2=siliga gel 4:1) was prepared in a
similar manner, using ZnCl2 (8 g) and silica (2 g) (method D).

Synthesis of Tacrine Analogs
4373
Reaction with the Catalyst ZnCl2=Siliga Gel. In a screw-cap tube,
the pyrazole (0.20 mmol), the catalyst 2:1 or 4:1 (0.55 g, and 0.31g, respec-
tively), and the cyclic ketone (cyclohexanone (0.1 mL, 0.97 mmol) were
added. The mixture was heated for 4 h at 150 ꢀC. After cooling, ethyl acetate
(50 mL) was added and the mixture was filtered. The filtrate was washed
with saturated sodium bicarbonate solution (2 ꢁ 20 mL), dried (MgSO4),
and evaporated to give an oil that was submitted to chromatography.
Data
1-Phenyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolin-4-amine (5a)
The title compound was obtained by method A as a beige solid (32%); mp
195–197 ꢀC; dH (DMSO-d6): 8.33 (s, 3H, H-3), 8.40–8.29 (m, 2H, H-20 and
60), 7.47 (t, 2H, J ¼ 7.2 Hz, H-30 and 50), 7.21 (t, 1H, J ¼ 7.5 Hz, H-40), 6.68
(br s, 2H, NH2), 2.85–2.74 (m, 2H, H-8), 2.52–2.40 (m, 2H, H-5), 1.85–
1.71 (m, 4H, H-7 and H-6); dC (DMSO-d6): 157.05 (C-8a), 150.07 (C-4),
146.99 (C-9a), 140.28 (C-10), 132.94 (C-3), 128.84 (C-30 and 50), 124.53
(C-40), 119.45 (C-20 and 60), 106.83 (C-4a), 105.05 (C-3a), 33.78 (C-8),
22.92 (C-5), 22.72 and 22.53 (C-7 and C-6). Anal. calcd. for C16H16N4:
C, 72.73; H, 6.06; N, 21.21. Found: C, 72.83; H, 6.16; N, 20.83.
1-p-Tolyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolin-4-amine (5b)
The compound was obtained by method B as an off-white solid in 40%
yield, mp 174–176 ꢀC; dH (DMSO-d6): 8.28 (s, 1H, H-3), 8.18 (d, 2H,
J ¼ 8.4 Hz, H-20 and 60 or H-30 and 50), 7.28 (d, 2H, J ¼ 8.7 Hz, H30
and 50 or H-20 and 60), 6.63 (br s 2H, NH2), 2.85–2.74 (m, 2H, H-8),
2.50–2.40 (m, 2H, H-5), 2.32 (s, 3H, Me), 1.85–1.70 (m, 4H, H-7 and
H-6). dC (DMSO-d6): 156.99 (C-8a), 149.89 (C-4), 146.93 (C-9a), 137.93
(C-10), 133.67 (C-3), 132.51 (C-40), 129.25 (C-30 and 50), 119.56 (C-20 and
60), 106.63 (C-4a), 104.95 (C-3a), 33.79 (C-8), 22.92 (C-5), 22.74 and
1
22.55 (C-7 and C-6), 20.53 (Me). Anal. calcd. for C17H18N4 /4H2O:
C, 72.18; H, 6.59; N, 19.80. Found: C, 72.19; H, 6.45; N, 19.58.
1-(4-Methoxyphenyl)-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolin-4-
amine (5c)
The compound was prepared by method B and obtained as an off-white solid
(44% A), mp 106–108 ꢀC; dH (400 MHz, CDCl3): 8.12 (d, 2H, J¼ 7.0 Hz, H-20
and 60), 7.97 (s, 1H, H-3), 7.01 (d, 2H, J¼ 6.8 Hz, H-30 and 50), 4.61 (br s, 2H,

4374
L. M. Rodrigues et al.
NH2), 2.98 (t, 2H, J ¼ 6.0Hz, H-8), 2.54 (t, 2H, J ¼ 6.0 Hz, H-5), 2.0–1.80 (m,
4H, H-7 and H-6); dC (CDCl3): 158.51 (C-8a), 157.40 (C-40), 149.76 (C-4),
144.85 (C-9a), 133.46 (C-10), 129.78 (C-3), 122.72 (C-20 and 60), 114.12 (C-
30 and 50), 107.40 (C-4a), 105.23 (C-3a), 55.51 (OMe), 34.16 (C-8), 22.93
(C-5), 22.88 and 22.87 (C-7 and C-6). The compound was left to crystallize
from the NMR solution, and it was used for mass analysis. HRMS calcd.
for C17H18N4O: 294.1481; found: (M)þ 294.1482.
1-(4-Chlorophenyl)-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolin-4-
amine (5d)
The compound was obtained by methods B, C, and D (80, 60, and 33%,
respectively) as a beige solid, mp 150–152 ꢀC; dH (DMSO-d6): 8.41 (d, 2H,
J ¼ 7.0 Hz, H-20 and 60), 8.34 (s, 1H, H-3), 7.52 (d, 2H, J ¼ 7.0 Hz, H-30
and 50), 6.72 (br s, 2H, NH2), 2.85–2.74 (m, 2H, H-8), 2.52–2.42 (m,
2H, H-5), 1.86–1.70 (m, 4H, H-7 and H-6). dC (DMSO-d6): 157.15 (C-
8a), 150.09 (C-4), 147.11 (C-9a), 139.12 (C-10), 133.45 (C-3), 128.79
(C-30 and 50), 128.34 (C-40), 120.61 (C-20 and 60), 107.08 (C-4a), 105.05
(C-3a), 33.73 (C-8), 22.89 (C-5), 22.65 and 22.45 (C-7 and C-6). m=z
(EI=TOF): 297 (43), 300 (Mþ, 37Cl, 22), 299 (16), 298 (Mþ, 35Cl, 100).
Anal. calcd. for C16H15N4Cl: C, 64.32; H, 5.06; N, 18.75. Found: C,
63.92; H, 4.92; N, 18.36.
1-(4-Bromophenyl)-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolin-4-
amine (5e)
The compound was prepared by method B yielding a light brown solid
(20%); mp 127–129 ꢀC; dH (DMSO-d6): 8.35 (d, 2H, J ¼ 9.0 Hz, H-20
and 60), 8.35 (s, 1H, H-3), 7.65 (d, 2H, J ¼ 9.0 Hz, H-30 and 50), 6.73
(br s, 2H, NH2), 2.87–2.74 (m, 2H, H-8), 2.50–2.40 (m, 2H, H-5), 1.90–
1.70 (m, 4H, H-7 and H-6); dC (DMSO-d6): 157.24 (C-8a), 150.17
(C-4), 147.19 (C-9a), 139.57 (C-10), 133.61 (C-3), 131.78 (C-30 and 50),
121.05 (C-20 and 60), 116.59 (C-40), 107.17 (C-4a), 105.12 (C-3a), 33.80
(C-8), 22.95 (C-5), 22.70 and 22.51 (C-7 and C-6). m=z (EI=TOF): 345
(7), 344 (Mþ, 81Br, 87), 343 (46), 342 (Mþ, 79Br, 100), 341 (37), 316
(17), 314 (17), 261 (9), 235 (7), 121 (11).
1-(4-Chlorophenyl)-6-methyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]-
quinolin-4-amine (5f)
The compound was prepared by method C (38%); mp 185–186 ꢀC; dH
(DMSO-d6): 8.41 (d, 2H, J ¼ 9.0 Hz, H-20 and 60), 8.33 (s, 1H, H-3),

Synthesis of Tacrine Analogs
4375
7.53 (d, 2H, J ¼ 9.0 Hz, H-30 and 50), 6.73 (br s, 2H, NH2), 2.84 (t, 2H,
J ¼ 4.2 Hz, H-8), 2.70–2.58 (m, 1H, H-5), 2.08–1.76 (m, 3H, H-5, H-6
and H-7), 1.50–1.30 (m, 1H, H-7), 1.09 (d, 3H, J ¼ 6.3 Hz, Me).
dC (DMSO-d6): 156.97 (C-8a), 150.23 (C-4), 147.07 (C-9a), 139.14
(C-10), 133.52 (C-3), 128.85 (C-30 and 50), 128.38 (C-40), 120.65 (C-20
and 60), 106.81 (C-4a), 105.04 (C-3a), 33.46 (C-8), 31.52 (C-5), 30.87
(C-7), 28.77 (C-6), 21.98 (Me). m=z (EI=TOF): 315 (4), 314 (Mþ, 37Cl,
22), 313 (18), 312 (Mþ, 35Cl, 100), 311 (17), 297 (12), 272 (15), 270
(79). HRMS: 312.1133 (Mþ, C17H17N435Cl; calc. 312.1142). 314.1114
(Mþ, C17H17N437Cl; calc. 314.1112).
1-(4-Trifluoromethylphenyl)-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]-
quinolin-4-amine (5g)
The compound was obtained by methods A (16%), mp 115–118 ꢀC; dH
(DMSO-d6): 8.65 (d, 2H, J ¼ 8.4 Hz, H-20 and 60), 8.40 (s, 3H, H-3),
7.85 (d, 2H, J ¼ 8.7 Hz, H-30 and 50), 6.78 (br s, 2H, NH2), 2.88–2.78
(m, 2H, H-8), 2.52–2.42 (m, 2H, H-5), 1.86–1.74 (m, 4H, H-7 and H-
6); dC (DMSO-d6): 157.35 (C-8a), 150.55 (C-4), 147.28 (C-9a), 143.30
(C10), 134.45 (C-3), 126.21 (C-30 and 50), 122.61, 126.17, 129.80 (the other
1
peak of the q is hidden under C-20 and C-60, J ¼ 272.9 Hz, CF3), 124.32
(q, 2J ¼ 31.9 Hz, C-40), 118.92 (C-20 and 60), 107.59 (C-4a), 105.21 (C-3a),
33.75 (C-8), 22.91 (C-6 or C-7), 22.63 (C-5), 22.43 (C-6 or C-7).
ESI: 333.25 (M þ 1)þ; EI=TOF: 333.13 (15, M þ 1þ), 332.13 (100, Mþ),
331.13 (64), 304 (32), 303 (16).
1-(3-Chlorophenyl)-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolin-4-
amine (5h)
The compound was obtained in 15% yield by method A as a beige solid;
mp 199–201 ꢀC; dH (CDCl3): 8.45 (t, 1H, J ¼ 2.6 Hz, H-20), 8.34 (ddd, 1H,
J ¼ 1.2, 2.5, 10.9 Hz, H-40), 7.99 (s, 1H, H-3), 7.20 (ddd, 1H, J ¼ 1.2, 2.4,
10.4 Hz, H-60), 7.41 (t, 1H, J ¼ 10.4 Hz, H-50), 4.62 (br s, 2H, NH2), 2.30
(t, 2H, J ¼ 8.0 Hz, H-8), 2.53 (t, 2H, J ¼ 7.6 Hz, H-5), 1.90–2.00 (m,
4H, H-6 and H-7); dC (CDCl3): 158.77 (C-8a), 150.22 (C-9a), 144.94
(C-4), 141.21 (C-30), 134.50 (C-10), 130.99 (C-3), 129.90 (C-50), 124.98
(C-60), 120.43 (C-20), 118.35 (C-40), 108.05 (C-4a), 105.54 (C-3a), 34.15
(C-8), 22.85 (C-6 and C-7), 22.79 (C-5). Anal. calcd. for C16H15ClN4:
C, 64.32; H, 5.06; N, 18.75. Found: C, 63.94; H, 5.00; N, 18.37. m=z
(EI=TOF): 300 (Mþ, 37Cl, 22), 298 (Mþ, 35Cl, 100).

4376
L. M. Rodrigues et al.
1-(4-Chlorophenyl)-1,5,6,7-tetrahydrocyclopenta[e]pyrazolo[3,4-b]-
pyridin-4-amine (6d)
The compound was prepared by methods A (15%) and B (27%), mp
289–290 ꢀC. dH (DMSO-d6): 8.37 (d, 2H, J ¼ 9.0 Hz, H-20 and 60), 8.30
(s, 1H, H-3), 7.54 (d, 2H, J ¼ 9.0 Hz, H-30 and 50), 6.80 (br s, 2H,
NH2), 2.88 (t, 2H, J ¼ 7.8 Hz, H-7), 2.71 (t, 2H, J ¼ 7.5 Hz, H-5), 2.03
(quintet, 2H, J ¼ 7.5 Hz, H-6); dC (DMSO-d6): 166.57 (C-7a), 152.47
(C-4), 144.91 (C-8a), 139.05 (C-10), 133.50 (C-3), 128.87 (C-30 and 50),
128.61 (C-40), 120.96 (C-20 and 60), 111.62 (C-4a), 105.66 (C-3a), 34.57
(C-7), 26.71 (C-5), 22.57 (C-6). m=z-EI=TOF: 286.06 (Mþ, 37Cl, 22),
285.09 (14), 284.07 (Mþ, 35Cl, 100), 283.06 (64), 265.98 (95), 189.99
(92), 121 (80). Anal. calcd. for C15H13ClN4: C, 63.27; H, 4.60; N,
19.68. Found: C, 63.09; H, 4.79; N, 19.10.
1-(4-Trifluoromethylphenyl)-1,5,6,7-tetrahydrocyclopenta[e]-
pyrazolo[3,4-b]pyridin-4-amine (6g)
The compound was prepared by method A (31%) as a light brown solid,
mp 265–268 ꢀC; dH (DMSO-d6): 8.62 (d, 2H, J ¼ 8.7 Hz, H-20 and 60),
8.37 (s, 1H, H-3), 7.85 (d, 2H, J ¼ 8.4 Hz, H-30 and 50), 6.84 (br s, 2H,
NH2), 2.90 (t, 2H, J ¼ 7.5 Hz, H-7), 2.73 (t, 2H, J ¼ 7.5 Hz, H-5), 2.07
(quintet, 2H, J ¼ 7.5 Hz, H-6); dC (DMSO-d6): 166.33 (C-7a), 152.89
(C-8a), 145.01 (C-4), 143.21 (C-10), 134.41 (C-3), 126.18 (C-30 and 50),
2
124.50 (q, J ¼ 31.8 Hz, C-40), 122.58, 126.18, 129.89 (the other peak of
1
the q is hidden under C20 and C-60, J ¼ 274.5 Hz, CF3), 119.19 (C-20
and 60), 112.05 (C-4a), 105.82 (C-3a), 34.57 (C-7), 26.70 (C-5), 22.52
(C-6). HRMS calcd. for C16H13F3N4: 318.1092; found: (M)þ 318.1096.
1-(3-Chlorophenyl)-1,5,6,7-tetrahydrocyclopenta[e]pyrazolo[3,4-b]-
pyridin-4-amine (6h)
The compound was prepared by method A (15%) as a light brown solid;
mp 233.5–235 ꢀC; dH (400 MHz, CDCl3): 8.38 (t, 1H, J ¼ 2.4 Hz, H-20),
8.29 (ddd, 1H, J ¼ 1.2, 1.8, 8.3 Hz, H-40), 8.01 (s, 1H, H-3), 7.22 (ddd,
1H, J ¼ 0.8, 2.2, 8.1 Hz, H-60), 7.41 (t, 1H, J ¼ 8.0 Hz, H-50), 4.54 (br s,
2H, NH2), 3.08 (t, 2H, J ¼ 7.6 Hz, H-7), 2.80 (t, 2H, J ¼ 7.6 Hz, H-5),
2.23 (quintet, 2H, J ¼ 7.6 Hz, H-6); dC (CDCl3): 168.11 (C-7a), 152.65
(C-8a), 142.71 (C-4), 141.10 (C-10), 134.58 (C-30), 131.03 (C-3), 129.96
(C-60), 125.32 (C-50), 120.93 (C-20), 118. 83 (C-40), 112.93 (C-4a), 106.07
(C-3a), 35.00 (C-7), 26.37 (C-5), 23.14 (C-6). Anal. calcd. for

Synthesis of Tacrine Analogs
4377
C15H13ClN4: C, 63.27; H, 4.60; N, 19.68. Found: C, 63.22; H, 4.62; N,
18.29. EI=TOF: 284.08 (Mþ, 35Cl, 100), 286.08 (Mþ, 37Cl, 26).
ACKNOWLEDGMENTS
ˆ
We thank Fundac¸a˜o para a Ciencia e Tecnologia (FCT) and Fundo Europeu
de Desenvolvimento Regional (FEDER) for project POCTI-SFA-3-686 and
postdoctoral grant for A. Salaheldin (SFRH=BPD=31490=2006).
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