Synthesis of new tacrine analogues from 4-amino-1H-pyrrole-3-carbonitrile

Article abstract of DOI:10.1002/hlca.200900190

An easy preparation of 4-amino-1H-pyrrole-3-carbonitrile derivatives and their transformation into new substituted pyrrolo[3,2-b]pyridines is described. The one-step transformation was carried out via Friedlaender reaction under microwave irradiation and

Full text of DOI:10.1002/hlca.200900190

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Synthesis of New Tacrine Analogues from 4-Amino-1H-pyrrole-3-carbonitrile
by Abdellatif M. Salaheldina), Ana M. F. Oliveira-Campos*a), Pier Parpota), Lꢀgia M. Rodriguesa),
M. Manuel Oliveirab), and Francisco P. Feixotoc)
a) Centro de Quꢀmica, Universidade do Minho, Campus de Gualtar, PT-4710-057 Braga
(fax: þ 351253604382; e-mail: amcampos@quimica.uminho.pt)
b) Centro de Quꢀmica-Vila Real, Departamento de Quꢀmica, UTAD, PT-5001-801 Vila Real
c
ˆ
´
) Centro de Ciencia Animal e Veterinaria, Departamento de Quꢀmica, UTAD, PT-5001-801 Vila Real
An easy preparation of 4-amino-1H-pyrrole-3-carbonitrile derivatives and their transformation into
new substituted pyrrolo[3,2-b]pyridines is described. The one-step transformation was carried out via
Friedlꢀnder reaction under microwave irradiation and by classical heating methods. The use of
microwave irradiation led to high conversion and shorter reaction times.
1. Introduction. – The Alzheimerꢁs disease (AD) is recognized as one of the most
severe conditions affecting the aged, and it is life-threatening for this group of people.
The disease is characterized by neuronal loss, synaptic damage, vascular plaques, and a
deficit in neurotransmitter acetylcholine (ACh) that leads to a progressive impairment
in memory, cognitive functions, and behavioral disturbances. To increase the ACh level
in the synapse, the inhibition of acetylcholinesterase (AChE) represents the currently
employed approach for the treatment of AD. Tacrine (Fig.) was the first AChE
inhibitor (AChEI) introduced in therapy, sold under the name Cognexꢂ since 1993, but
the poor selectivity of this drug for AChE resulted in side effects, especially
hepatotoxicity. Currently, the AChEIs used to treat AD patients are donepezil,
rivastigmine, and galantamine, but even those present some peripheral side effects [1 –
5]. Therefore, many efforts have been made by different research groups on the
synthesis of several tacrine analogues.
Figure. Structure of tacrine
Modifications on the tacrine structure have been performed, either by increasing
the number of rings or changing their size or introducing heteroatoms [5 – 11].
During the course of this work, we found only one report on the synthesis of tacrine
analogues of the ꢃpyrrolotetrahydroquinolineꢁ type [9], i.e., derivatives with a pyrrole
ring instead of the benzene ring of tacrine.
ꢄ 2010 Verlag Helvetica Chimica Acta AG, Zꢅrich

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2. Results and Discussion. – In continuation of our interest in the chemistry of b,b-
enamino nitriles, the results aimed at exploring the potential utility of 3-anilino-2-
cyanoacrylonitrile in the synthesis of heterocycles are reported here. The b,b-enamino
nitriles 2, which were synthesized by known methods [12], are converted into the
corresponding 3-amino-1H-pyrrole derivatives 3 by reaction with a-halogenated
ketones, nitriles, or esters under basic conditions, a Thorpe – Ziegler cyclization
(Scheme 1) [13][14].
Scheme 1. Synthesis and Structure of Compounds 3
The preparation of 2-substituted 3-amino-1H-pyrrole-4-carbonitriles 3 by using a-
halo ketones (or a-halo nitriles or esters) in anhydrous DMF in the presence of K2CO3
as the base has been well described in the literature [13]. Here, we report the
preparation of compounds 3 by a modification of the method described previously
using Et3N (TEA) as the base [14]. When the reaction was carried out in a solution with
an excess of Et3N, the desired 3-amino-1H-pyrrole derivatives 3a – 3f were obtained in
good yields (74 – 91%). Compounds 3g and 3h have already been described by us [14].
The new tacrine analogues 4 could be obtained by applying the Friedlꢀnder reaction
on 1H-pyrroles 3. As we have recently shown in the pyrazole series [11], the
Friedlꢀnder reaction can be performed under classical heating for 5 – 7 h. Here, we
decided to compare the reaction time and the yields of 4 by using the classical heating
under reflux and the microwave irradiation.
Pyrroles 3a, 3b, 3d, and 3g were dissolved in CH2Cl2, cyclic ketones and AlCl3 were
added, and the mixture was refluxed for 7 – 10 h, whereupon compounds 4a – 4f were
obtained in satisfactory yields (Scheme 2 and Table). Under microwave irradiation, the
time of reaction was reduced from 7 – 10 h to ca. 30 min, and compounds 4 were
obtained in high yields (80 – 90%); only the regioisomers 4 are formed. When Y was an
ester or ketone group, i.e., 3c and 3h, the cyclization occurred exclusively with the CN
group at C(4) of the pyrrole, thus affording regioisomers 6 and 5, respectively.

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Scheme 2. Synthesis and Structures of Compounds 4a – 4g, 5, and 6
a) AlCl3 in CH2Cl2 and reflux, or microwave irradiation. b) BBr3 in CH2Cl2.
Table. Friedlꢆnder Cyclization Reaction under Classical Heating and Microwave (MW) Irradiation
Starting material
Product
Classical heating
MW Irradiation
Time [min]
Time [h]
Yield [%]
Yield [%]a)
3a
3a
3g
3g
3d
3d
3h
3c
4a
4b
4c
4d
4e
4f
5
8
8
7
67
70
74
66
55
48
69
62
2 ꢀ 15
2 ꢀ 15
2 ꢀ 12
2 ꢀ 12
2 ꢀ 16
2 ꢀ 16
2 ꢀ 15
2 ꢀ 15
85
82
89
81
90
88
84
80
7
10
10
8
6
8
a) Yield of pure compounds.
The reaction of 3c with cyclohexanone and 3h with cyclopentanone under the
classical heating and microwave irradiation afforded compounds 6 and 5, respectively.
The structures of the new compounds were determined by 1H- and 13C-NMR
spectroscopy, and mass spectrometry. For example, the 1H-NMR spectrum of

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compound 5 showed the presence of a t at 1.13 ppm and a q at 4.21 ppm for the ester
function, and the absence of a CN absorption band in the IR spectrum. The 13C-NMR
and mass spectra of compound 5 are in agreement with the proposed structure.
Attempted cyclization of 2d to the corresponding pyrrole gave a complex mixture,
probably due to N- or/and O-alkylation. The required p-hydroxy derivative 4g was
obtained in 71% yield by demethylation of its precursor 4c.
3. Conclusions. – The 3-amino-4-cyano-1H-pyrrole derivatives reacted with cyclo-
pentanone and cyclohexanone to afford the corresponding tacrine analogues through
the Friedlꢀnder reaction under classical heating and microwave irradiation. Shorter
reaction times and higher yields were obtained by microwave irradiation.
Experimental Part
General. M.p.: Gallenkamp apparatus; uncorrected. IR Spectra: Perkin-Elmer FTIR-1600, with
Nujol emulsions between NaCl plates. UV/VIS Spectra: Cary 50 spectrophotometer. 1H- (300 or
400 MHz) and 13C-NMR (75.4 or 100.62 MHz) spectra: in (D6)DMSO or CDCl3 on a Varian Unity Plus
or Bruker Avance II 400 Spectrometer, with TMS as an internal reference, results as d values. Double
1
resonance, HMQC and HMBC experiments were carried out for complete assignment of H and 13C in
the NMR spectra, whenever possible. MS: Shimadzu GC/MS QP 1000 Ex mass spectrometer at 70 eV.
Electrospray-ionization (ESI) MS: ThermoFinnigan LCQ Deca XP Plus quadrupole ion-trap instrument
on samples diluted in MeCN. Elemental analyses: Leco CHNS-932 instrument. A CEM MARS oven was
used for Friedlꢀnderꢁs reaction under microwave irradiation. Compounds 2 were prepared according to
the literature [12][14].
General Procedure for Preparation of 3-Amino-1H-pyrrole Derivatives 3a – 3f (see [14]). To a soln.
of 2 (0.01 mol), the a-halo compound (chloroacetonitrile, chloroacetone, and ethyl bromoacetate;
0.011 mol) and Et3N (4 ml) were added with external cooling. The mixture was refluxed for 10 – 15 min.
After cooling, H2O (50 ml) was added, the solid product was filtered off, washed thoroughly with cold
H2O, and crystallized from EtOH. Compounds 3g and 3h were previously reported by us [14].
3-Amino-1-phenyl-1H-pyrrole-2,4-dicarbonitrile (3a). Yield 88%. White solid. M.p. 204 – 2068
1
(EtOH) ([13]: 187 – 1888). IR (Nujol): 3456, 3360 (NH2), 2205, 2227 (CN). H-NMR (CDCl3): 4.29 (s,
NH2); 7.22 (s, HꢁC(5)); 7.39 – 7.42 (m, 2 arom. H); 7.47 – 7.56 (m, 3 arom. H). Anal. calc. for C12H8N4
(208.22): C 69.22, H 3.87, N 26.91; found: C 69.12, H 4.07, N 26.81.
Ethyl 3-Amino-4-cyano-1-phenyl-1H-pyrrole-2-carboxylate (3b). Yield 74%. White solid. M.p. 154 –
1558 (EtOH) ([13]: 153 – 1548). IR (Nujol): 3453, 3342 (NH2), 2225 (CN), 1655 (CO). 1H-NMR
(CDCl3): 1.04 (t, J ¼ 7.2, Me); 4.09 (q, J ¼ 7.2, CH2); 5.05 (s, NH2); 7.06 (s, HꢁC(5)); 7.23 – 7.27 (m, 2 arom.
H); 7.41 – 7.44 (m, 3 arom. H). Anal. calc. for C14H13N3O2 (255.27): C 65.87, H 5.13, N 16.46; found: C
65.82, H 5.32, N 16.50.
5-Acetyl-4-amino-1-phenyl-1H-pyrrole-3-carbonitrile (3c). Yield 91%. White solid. M.p. 233 – 2358
(EtOH). IR (Nujol): 3413, 3349 (NH2), 2219 (CN), 1640 (CO). 1H-NMR (CDCl3): 1.74 (s, Me); 5.83 (s,
NH2); 7.06 (s, HꢁC(2)); 7.32 – 7.35 (m, HꢁC(2’), HꢁC(6’)); 7.50 – 7.52 (m, HꢁC(3’), HꢁC(4’),
HꢁC(5’)). 13C-NMR (CDCl3): 28.72 (Me); 83.67 (C(3)); 113.84 (CN); 119.05 (C(5)); 126.27 (C(2’);
C(6’)); 129.35 (C(4’)); 129.76 (C(3’); C(5’)); 132.80 (C(2)); 139.49 (C(1’)); 147.43 (C(4)); 187.61 (CO).
Anal. calc. for C13H11N4O (225.25): C 69.32, H 4.92, N 18.66; found: C 69.31, H 4.95, N 18.73.
3-Amino-1-(4-chlorophenyl)-1H-pyrrole-2,4-dicarbonitrile (3d). Yield 84%. Pale yellow solid. M.p.
1
243 – 2458 (EtOH). IR (Nujol): 3468, 3363 (NH2), 2232, 2200 (CN). H-NMR (CDCl3): 4.30 (s, NH2);
7.19 (s, HꢁC(5)); 7.35 (d, J ¼ 9.0, HꢁC(2’), HꢁC(6’)); 7.51 (d, J ¼ 9.0, HꢁC(3’), HꢁC(5’)). Anal. calc.
for C12H7ClN4 (242.66): C 59.39, H 2.91, N 23.09; found: C 59.32, H 2.88, N 23.10.
Ethyl 3-Amino-1-(4-chlorophenyl)-4-cyano-1H-pyrrole-2-carboxylate (3e). Yield 74%. White solid.
M.p. 153 – 1548 (EtOH) ([13]: 152 – 1548). IR (Nujol): 3445, 3343 (NH2), 2216 (CN), 1661 (CO).
1H-NMR ((D6)DMSO): 1.00 (t, J ¼ 7.2, Me); 4.02 (q, J ¼ 7.2, CH2); 6.00 (s, NH2); 7.35 (d, J ¼ 9.0,

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HꢁC(2’), HꢁC(6’)); 7.48 (d, J ¼ 9.0, HꢁC(3’), HꢁC(5’)); 7.76 (s, HꢁC(5)). MS-EI: 289 (75, [M, 35Cl]þ),
291 (21, [M, 37Cl]þ). Anal. calc. for C14H12ClN3O2 (289.72): C 58.04, H 4.17, N 14.50; found: C 57.92, H
4.45, N 14.43.
5-Acetyl-4-amino-1-(4-chlorophenyl)-1H-pyrrole-3-carbonitrile (3f). Yield 91%. White solid. M.p.
1
233 – 2358 (EtOH). IR (Nujol): 3443, 3337 (NH2), 2222 (CN), 1612 (CO). H-NMR (CDCl3): 1.78 (s,
Me); 5.83 (s, NH2); 7.02 (s, HꢁC(2)); 7.28 (d, J ¼ 9.0, HꢁC(2’), HꢁC(6’)); 7.50 (d, J ¼ 9.0, HꢁC(3’),
HꢁC(5’)). Anal. calc. for C13H10ClN3O (259.69): C 60.12, H 3.88, N 16.18; found: C 60.13, H 3.96, N 16.17.
Friedlꢆnder Reaction: General Procedure for the Preparation of Tacrine Analogues 4a – 4f, 5, and 6.
a) By Thermal Heating. A mixture of 2-substituted-3-aminopyrrole-4-carbonitrile 3 (0.3 mmol),
cyclohexanone or cyclopentanone (3.1 mmol), and AlCl3 (anh., 3.1 mmol) in dist. ClCH2CH2Cl (20 ml)
was heated to reflux for 7 – 10 h (TLC control). After cooling to r.t., a mixture of THF/H2O 1:1 (25 ml)
was added, and then an aq. soln. of NaOH (10%) was added dropwise until basic. After stirring for
30 min, the mixture was extracted with CH2Cl2 (3 ꢀ 20 ml), and the combined extracts were washed with
brine (20 ml), dried (MgSO4), and filtered, and the solvent was evaporated to give a solid, which was
purified by PLC (CH2Cl2/MeOH 9 :1) or crystallized from EtOH.
b) Under Microwave Irradiation. In a 100-ml round-bottom flask equipped with a condenser,
cyclohexanone or cyclopentanone (1.4 mmol) was added to a soln. of 3 (1 mmol) in 40 ml of dist.
ClCH2CH2Cl. AlCl3 (4 mmol) was added, and the mixture was heated at reflux during 30 and 32 min
(Table) under microwave irradiation (at a constant power of 400 W). After cooling to r.t., a mixture of
THF/H2O 1:1 (25 ml) was added, and then an aq. soln. of NaOH (10%) was added dropwise until basic.
After stirring for 30 min, the mixture was extracted with CH2Cl2 (3 ꢀ 20 ml), and the combined extracts
were washed with brine (20 ml), dried (MgSO4), and filtered, and the solvent was evaporated to give a
solid, which was identical in all respects with that obtained from the above reaction (TLC, m.p., NMR).
8-Amino-1,5,6,7-tetrahydro-1-phenylcyclopenta[e]pyrrolo[3,2-b]pyridine-3-carbonitrile (4a). Yield
75%. Yellow solid. M.p. 242 – 2448. IR (Nujol): 3465, 3360 (NH2), 2224 (CN). 1H-NMR ((D6)DMSO):
2.16 – 2.26 (m, CH2(6)), 2.71 (t, J ¼ 7.7, CH2(7)); 2.91 (t, J ¼ 7.8, CH2(5)); 4.85 (s, NH2); 7.55 – 7.66 (m, 5
arom. H); 8.28 (s, HꢁC(2)). 13C-NMR ((D6)DMSO): 22.82 (C(6)); 27.30 (C(7)); 34.18 (C(5)); 86.75
(C(3)); 115.46 (CN); 116.15 (C(8a)); 119.23 (C(3a)); 124.54 (C(4’)); 126.52 (C(2’); C(6’)); 129.61 (C(3’),
C(5’)); 129.97 (C(7a)); 137.17 (C(2)); 138.21 (C(1’)); 145.76 (C(8)); 162.19 (C(4a)). ESI-MS: 275.17
([M þ 1]þ). Anal. calc. for C17H14N4 (274.32): C 74.43, H 5.14, N 20.42; found: C 74.34, H 4.96, N 20.54.
9-Amino-5,6,7,8-tetrahydro-1-phenyl-1H-pyrrolo[3,2-b]quinoline-3-carbonitrile (4b). Yield 79%.
Yellow solid. M.p. 222 – 2248. IR (Nujol): 3467, 3356 (NH2), 2219 (CN). 1H-NMR ((D6)DMSO):
1.70 – 1.84 (m, CH2(6), CH2(7)); 2.40 – 2.52 (m, CH2(8)); 2.74 – 2.86 (m, CH2(5)); 4.74 (s, NH2); 7.53 – 7.65
(m, 5 arom. H); 8.29 (s, HꢁC(2)). 13C-NMR ((D6)DMSO): 22.40 (C(6)); 22.61 (C(7)); 23.28 (C(8));
33.06 (C(5)); 86.52 (C(3)); 110.56 (C(9a)); 115.75 (CN); 118.48 (C(3a)); 124.49 (C(4’)); 126.62 (C(2’),
C(6’)); 129.64 (C(3’), C(5’)); 138.28 (C(2)); 138.69 (C(1’)); 143.49 (C(8a)); 145.93 (C(9)); 153.41
(C(4a)). ESI-MS: 289.33 ([M þ 1]þ). Anal. calc. for C18H16N4 (288.35): C 74.98, H 5.59, N 19.43; found: C
74.86, H 5.38, N 19.25.
8-Amino-1,5,6,7-tetrahydro-1-(4-methoxyphenyl)cyclopenta[e]pyrrolo[3,2-b]pyridine-3-carbonitrile
(4c). Yield 81%. Yellow solid. M.p. 221 – 2228. IR (Nujol): 3393, 3299 (NH2), 2218 (CN). 1H-NMR
(CDCl3): 2.15 – 2.23 (m, CH2(6)); 2.74 (t, J ¼ 7.8, CH2(7)); 3.01 (t, J ¼ 7.8, CH2(5)); 3.78 (s, NH2); 3.90 (s,
OMe); 7.07 (d, J ¼ 9.2, HꢁC(3’), HꢁC(5’)); 7.38 (d, J ¼ 9.2, HꢁC(2’), HꢁC(6’)); 7.55 (s, HꢁC(2)).
13C-NMR (CDCl3): 23.26 (C(6)); 26.97 (C(7)); 34.50 (C(5)); 55.71 (OMe); 88.30 (C(3)); 114.70 (CN);
114.82 (C(3’), C(5’)); 116.26 (C(7a)); 117.29 (C(8a)); 125.05 (C(3a)); 128.05 (C(2’), C(6’)); 131.14
(C(1’)); 136.15 (C(2)); 145.93 (C(8)); 160.32 (C(4’)); 163.49 (C(4a)). ESI-MS: 305.17 ([M þ 1]þ). Anal.
calc. for C18H16N4O (304.35): C 71.04, H 5.30, N 18.41; found: C 71.15, H 4.94, N 18.20.
9-Amino-5,6,7,8-tetrahydro-1-(4-methoxyphenyl)-1H-pyrrolo[3,2-b]quinoline-3-carbonitrile (4d).
Yield 72%. Yellow solid. M.p. 214 – 2158. IR (Nujol): 3485, 3360 (NH2), 2223 (CN). 1H-NMR
((D6)DMSO): 1.85 – 1.88 (m, CH2(6), CH2(7)); 2.43 – 2.47 (m, CH2(8)); 2.98 – 3.02 (m, CH2(5)); 6.34 (br.
s, NH2); 7.03 (d, J ¼ 8.8, HꢁC(3’), HꢁC(5’)); 7.38 (d, J ¼ 8.8, HꢁC(2’), HꢁC(6’)); 7.53 (s, HꢁC(2)).
13C-NMR ((D6)DMSO): 22.69 (C(6)); 22.80 (C(7)); 23.19 (C(8)); 33.48 (C(5)); 87.88 (C(3)); 110.97
(C(9a)); 114.78 (C(3’), C(5’)); 114.84 (CN); 116.80 (C(3a)); 128.08 (C(2’), C(6’)); 131.02 (C(1’)); 136.76

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(C(2)); 137.81 (C(7a)); 143.53 (C(9)); 154.70 (C(4a)); 160.27 (C(4’)). ESI-MS: 319.25 ([M þ 1]þ). Anal.
calc. for C19H18N4O (318.37): C 71.68, H 5.70, N 17.60; found: C 71.62, H 5.79, N 17.41.
8-Amino-1,5,6,7-tetrahydro-1-(4-chlorophenyl)cyclopenta[e]pyrrolo[3,2-b]pyridine-3-carbonitrile
(4e). Yield 68%. Yellow solid. M.p. 304 – 3068. IR (Nujol): 3446, 3325 (NH2), 2226 (CN). 1H-NMR
((D6)DMSO): 2.14 – 2.24 (m, CH2(6)); 2.81 (t, J ¼ 7.7, CH2(7)); 3.11 (t, J ¼ 7.7, CH2(5)); 6.75 (br. s, NH2);
7.59 (d, J ¼ 9.0, HꢁC(2’), HꢁC(6’)); 7.71 (d, J ¼ 9.0, HꢁC(3’), HꢁC(5’)); 8.64 (s, HꢁC(2)). ESI-MS:
309.17 ([M þ 1, 35Cl]þ), 311.17 ([M þ 1, 37Cl]þ). Anal. calc. for C17H13ClN4 (308.76): C 66.13, H 4.24, N
18.15; found: C 66.09, H 4.20, N 17.95.
9-Amino-5,6,7,8-tetrahydro-1-(4-chlorophenyl)-1H-pyrrolo[3,2-b]quinoline-3-carbonitrile (4f).
Yield 62%. Pale yellow solid. M.p. 260 – 2628. IR (Nujol): 3412, 3335 (NH2), 2229 (CN). 1H-NMR
(CDCl3): 1.85 – 1.92 (m, CH2(6), CH2(7)); 2.40 – 2.60 (m, CH2(8)); 3.01 – 3.06 (m, CH2(5)); 3.86 (s, NH2);
7.42 (d, J ¼ 9.0, HꢁC(2’), HꢁC(6’)); 7.57 (d, J ¼ 9.0, HꢁC(3’), HꢁC(5’)); 7.54 (s, HꢁC(2)). 13C-NMR
(CDCl3): 22.70 (C(7)); 23.29 (C(6)); 26.81 (C(8)); 33.59 (C(5)); 89.41 (C(3)); 111.45 (C(8a)); 114.42
(CN); 116.39 (C(9a)); 127.79 (C(2’), C(6’)); 130.02 (C(3’), C(5’)); 135.49 (C(4’)); 136.46 (C(3a)); 136.92
(C(2)); 137.49 (C(1’)); 143.93 (C(9)); 155.19 (C(4a)). ESI-MS: 323.25 ([M þ 1, 35Cl]þ); 325.25 ([M þ 1,
37Cl]þ). Anal. calc. for C18H15ClN4 (322.79): C 66.98, H 4.68, N 17.36; found: C 66.94, H 4.72, N 17.12.
Ethyl 8-Amino-2,5,6,7-tetrahydro-2-(4-methoxyphenyl)cyclopenta[e]pyrrolo[3,4-b]pyridine-3-car-
boxylate (5). Yield 75%. Yellow solid. M.p. 208 – 2108. IR (Nujol): 3478, 3339 (NH2), 1710 (CO).
1H-NMR (CDCl3): 1.13 (t, J ¼ 7.5, Me); 2.04 – 2.14 (m, CH2(6)); 2.78 (t, J ¼ 8.0, CH2(7)); 3.03 (t, J ¼ 8.1,
CH2(5)); 4.21 (q, J ¼ 7.5, CH2); 6.31 (s, NH2); 6.89 (d, J ¼ 9.0, HꢁC(3’), HꢁC(5’)); 7.20 (d, J ¼ 9.0,
HꢁC(2’), HꢁC(6’)); 7.93 (s, HꢁC(1)). 13C-NMR (CDCl3): 14.24 (Me); 22.73 (C(6)); 26.93 (C(7)); 34.31
(C(5)); 55.48 (OMe); 60.09 (CH2); 109.59 (C(8a)); 110.04 (C(3a)); 111.48 (C(7a)); 113.61 (C(3’), C(5’));
121.47 (C(1)); 127.15 (C(2’), C(6’)); 133.39 (C(1’)); 141.39 (C(3)); 145.94 (C(8)); 159.44 (C(4’)); 160.48
(CO); 165.68 (C(4a)). ESI-MS: 352.25 ([M þ 1]þ). Anal. calc. for C20H21N3O3 (351.40): C 68.36, H 6.02,
N 11.96; found: C 68.53, H 5.87, N 11.91.
1-(9-Amino-5,6,7,8-tetrahydro-2-phenyl-2H-pyrrolo[3,4-b]quinolin-3-yl)ethanone (6). Yield 75%.
Yellow solid. M.p. 292 – 2948. IR (Nujol): 3458, 3342 (NH2), 1657 (CO). 1H-NMR ((D6)DMSO): 1.78 –
1.82 (m, CH2(6), CH2(7)); 2.40 – 2.52 (m, CH2(8)); 2.73 (s, Me); 2.76 – 2.85 (m, CH2(5)); 6.42 (s, NH2);
7.31 – 7.35 (m, 2 arom. H); 7.41 – 7.46 (m, 3 arom. H); 7.85 (s, HꢁC(1)). 13C-NMR ((D6)DMSO): 22.67
(C(7)); 22.91 (C(6)); 26.17 (C(8)); 28.94 (Me); 34.59 (C(5)); 104.63 (C(8a)); 109.97 (C(9a)); 119.47
(C(3)); 122.37 (C(1)); 125.78 (C(2’), C(6’)); 127.60 (C(4’)), 128.53 (C(3’), C(5’)), 131.42 (C(3a)), 141.66
(C(1’)), 145.81 (C(9)), 159.41 (C(9a)); 184.56 (CO). ESI-MS: 306.25 ([M þ 1]þ). Anal. calc. for
C19H19N3O (305.37): C 74.73, H 6.27, N 13.76; found: C 74.62, H 6.31, N 13.65.
8-Amino-1,5,6,7-tetrahydro-1-(4-hydroxyphenyl)cyclopenta[e]pyrrolo[3,2-b]pyridine-3-carbonitrile
(4g). To a stirred cold soln. of 4c (1.0 mmol) in dry CH2Cl2 (15 ml) at ꢁ 808 and under Ar, a soln. of BBr3
(1.0m in CH2Cl2; 3 ml) was added dropwise. The mixture was left stirring overnight at r.t., and then H2O
(20 ml) was added. After stirring for 30 min, the mixture was extracted with CH2Cl2 (3 ꢀ 20 ml), and the
combined extracts were washed with brine (20 ml), dried (MgSO4), filtered, and the solvent was
evaporated to give a solid. Yield 71%. Greenish solid. M.p. 320 – 3228. IR (Nujol): 3486 (OH), 3387
(NH2), 2219 (CN). 1H-NMR ((D6)DMSO): 2.02 – 2.07 (m, CH2(6)); 2.69 (t, J ¼ 7.8, CH2(7)); 2.88 (t, J ¼
7.8, CH2(5)); 4.81 (s, NH2); 6.92 (d, J ¼ 8.7, HꢁC(3’), HꢁC(5’)); 7.36 (d, J ¼ 8.7, HꢁC(2’), HꢁC(6’));
8.16 (s, HꢁC(2)); 10.07 (s, OH). 13C-NMR ((D6)DMSO): 22.86 (C(6)); 27.23 (C(7)); 33.80 (C(5)); 85.85
(C(3)); 115.19 (C(3a)); 115.61 (CN); 115.85 (C(3’), C(5’)); 116.64 (C(8a)); 128.21 (C(2’), C(6’)); 129.46
(C(1’)); 137.25 (C(7a)); 137.69 (C(2)); 145.31 (C(8)); 158.22 (C(4’)); 162.04 (C(4a)). ESI-MS: 291.33
([M þ 1]þ). Anal. calc. for C17H14N4O (290.32): C 70.33, H 4.86, N 19.30; found: C 70.17, H 4.60, N 19.07.
ˆ
We acknowledge the financial support from FundaÅa˜o para a Ciencia e Tecnologia (FCT) and
FEDER, for National NMR Network (Bruker Avance II 400) and REEQ/ 630/QUI/2005 (LC/MS
instrument), and also post-doctoral grant for A. M. Salaheldin (SFRH/BPD/31490/2006). We thank Ms.
E. Pinto for obtaining NMR spectra and elemental analyses, and Ms. N. Nunes for LC/MS
determinations.

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Helvetica Chimica Acta – Vol. 93 (2010)
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Received May 20, 2009