Synthesis of 1-benzyl-3-[4-(aryl-1-piperazinyl) carbonyl]-1h-indoles. novel ligands with potential D4 dopaminergic activity

Article abstract of DOI:10.4067/S0717-97072011000400009

The synthesis of a series of functionalized 1-Benzyl-3-[4-Aryl-1- piperazingl]carbonyl-1H-Indoles 6(a-f), as a potential new class of bioactive ligands at D₄ receptors is reported. The synthetic strategy took place through a five steps sequence

Full text of DOI:10.4067/S0717-97072011000400009

J. Chil. Chem. Soc., 56, Nº 4 (2011)
SYNTHESIS OF 1-BENZYL-3-[4-(ARYL-1-PIPERAZINYL) CARBONYL]-1H-INDOLES. NOVEL LIGANDS WITH
POTENTIAL D4 DOPAMINERGIC ACTIVITY
HERNÁN PESSOA-MAHANA1*, IGNACIO CUEVAS M.1, C. DAVID PESSOA-MAHANA2. RAMIRO ARAYA-
MATURANA1, IRIUX ALMODOVAR FAJARDO, AND CLAUDIO SAITZ BARRÍA1
1Department of Organic and Physical Chemistry , Faculty of Chemical and Pharmaceutical Sciences, University of Chile. Casilla 233. Santiago 1. Chile.
2 Department of Pharmacy, Faculty of Chemistry, Pontificia Universidad Católica de Chile. Casilla 306. Santiago 22 . Chile.
(Received: December 26, 2010 - Accepted: November 24, 2011)
ABSTRACT
The synthesis of a series of functionalized 1-Benzyl-3-[4-Aryl-1-piperazingl]carbonyl-1H-Indoles 6(a-f), as a potential new class of bioactive ligands at D4
receptors is reported. The synthetic strategy took place through a five steps sequence to provide indole amides 6(a-f) in 75-92% yield.
Keywords : Indole, Arylpiperazines, dopaminergic activity.
INTRODUCTION
The indole ring system is present in many biologically active medicinal
agents and natural products1-3. The first synthesis of substituted indoles was
conducted by Fischer and Jourdan as early as 1883, and since then the bicyclic
heteroaromatic core has been the target of many synthetic approaches and
reactivity studies.4-7 Indoles are also prominent structural elements in the
neurotransmitter serotonin, the antiinflammatory drug indomethacin and other
molecules showing promise in the treatment of cardiovascular disease, erectile
dysfunction, cancer and neurological conditions such as the Alzheimer’s
X= CH ; R= 2-OMe, 3-OMe, 4-F, 4-NO2, H.
X= N ; R =H.
disease8-10
.
Interesting investigations on the role of dopaminergic system in the
ethiology of neurological and psychiatric disorders such as Parkinson´s disease
and schizophrenia have been carried out in the last years11. In the course of
these studies, and in an attempt to improve the activity of 3-(4-phenylpiperazin-
1-yl-methyl) indole (I) on D4 receptors (Fig.1). Troschütz12 and Gmeiner13
have synthesized a series of new phenylpiperazinylmethyl indole derivatives.
The 2-arylpiperazinylindolecarboxylates (II) displayed high affinity and great
selectivity for the human dopamine D receptor over the other dopamine
receptor subtypes. For instance the Ki va4lue for compound (II), R=H was 1.9
nM (D4) over (D1,D2 and D3 > 2000 nM).
RESULT AND DISCUSSION
The N-benzyl-3-(4-aryl-1-piperazingl)carbonyl-1(H)-indoles (I) were
obtained as follows: commercially available, indole (1) was subjected to a
Vilsmeier-Haack formilation to provide 1H-Indole-3-carbaldehyde (2) in 85%
yield. The aldehyde function was clearly detected in IR by its strong absorption
band at 1634 cm-1 in accord with their aromatic and highly polar character,
1
the H-NMR displayed a singlet signal at δ: 9.9 ppm. With the purpose to
avoid secondary reactions such as N-oxidation, we decided to protect the
indolic N-H, using benzyl bromide in dry DMF at 5 °C, the reaction gave the
N-Benzyl derivative (3) as a crystalline solid in 75 % yield (Scheme 1). The
electron-withdrawing effect of the formyl group on the indole ring, enhanced
the acidity of the NH, facilitating the proton abstraction and N- substitution.
Considering the above results, and given our interest in the synthesis
of neurobioactive indoles, we carry out the preparation of a new series of
indolepiperazines (III) based on the incorporation of an amide function
between the arylpiperazine14 and the indole framework. Selectivity studies
respect to D4 binding affinity15, recognize the preference of compounds type
(I) bearing substituents with a large negative region (COOEt, CN, CHO,
CH=NOH), which are naturally not well tolerated by the other D-receptors.
In such sense, this new structural function may reinforce the stability of the
ligand-receptor D4-complex, acting both as a hydrogen bond acceptor and
providing the negative region required for D4 receptor selectivity as well.
Scheme 1. Preparation of 1-Benzyl-1H- indole-3-carbaldehyde(3).
Oxidation of (3) with KMnO in acetone-water (1:1) mixture, aforded the
indole carboxylic acid derivative4 (4), (Scheme 2) which exhibited in IR the
characteristic O-H absorption at 3420-2550cm-1, along with a strong signal at
1655 cm-1 for the carboxylic function. At this point, it is interesting to comment
that a first approach considered the preparation of 3-acyl halide indole (4-a),
which would react in a second step with appropriate series of arylpiperazines.
To the best of our knowledge, these are the first examples of indoles amide
connected to arylpiperazines, which will be pharmacologically evaluated in
a near future. In this article we report the synthesis in good yield of a series
of 1-benzyl-3-[4-Aryl-1-piperazingl]carbonyl-1H-Indoles, with potential
biological interest in D4 dopaminergic receptors.
e-mail: hpessoa@ciq.uchile.cl
866

J. Chil. Chem. Soc., 56, Nº 4 (2011)
The mass spectrum analysis for indoles 6(a-f) showed the presence of
a fragment (m/z) at 233.95 which can be explained assuming an α-cleavage
fragmentation pattern of an amide. The major fragment in this series involved
a fragment (m/z) at 90.97 which may arise from a N-debenzylation cleavage to
yield the base peaks (100%).
Finally, the N-debenzylation reaction of the indoles 6 (a-f) will be carried
out after the biological proofs, taking into account a possible favorable π- π
interaction of the N-benzylic aromatic ring with aromatic aminoacidic residues
with the receptor.
However, this reaction was unsuccessful giving a red-dark syrup displaying
many products on thin layer chromatography, even under different experimental
conditions. A probable explanation may arise of a policondensation reaction
between the indolic rings under the acidic medium.
CONCLUSION
In conclusion new arylpiperazine indole derivatives have been synthesized
in good yield, the utilized strategy provides an efficient method for the
preparation of potentially bioactive ligands. Further efforts focused on the
synthesis of new indole derivatives with potential biological relevance, along
with neurobiological screening of the synthesized compounds are in progress.
EXPERIMENTAL SECTION
Thus, we decided to utilize the reaction of (4) with N,N´-
dicyclohexylcarbodiimide (DCC). Treatment of (4) with DCC in anhydrous
CH2Cl2, gave the indole intermediate (5) in quantitative yield (Scheme 2), the
1H NMR signals at δ: 0.8-2.0 ppm for twenty protons, indicated the presence of
the cyclohexyl rings. The signals at δ: 3.51 ppm (m, 1H, CHNH), and δ: 4.30-
4.37 ppm (m,1H, CHN=) suported the methine protons.
Melting points were determined on a hot-stage apparatus and are
uncorrected. The IR spectra were recorded, on a FT-IR Bruker IFS 55
spectrophotometer for KBr disc and wave numbers are reported in cm-1.
1
The H NMR and 13C NMR spectra were performed on a Bruker DRX-300
spectrometer (300 and 75 MHz) in deuterochloroform, or DMSO-d . Chemical
shifts were recorded in ppm (δ) relative to TMS as an internal 6standard. J
values are given in Hz. Microanalyses were carried out on a Fisons EA 1108
analizer. High resolution mass spectrum were recorded on a Thermo Finnigan
model MAT 95XP Mass Spectrometer. Silica gel Merck 60 (70-230mesh)
and DC- alufolien 60 F254 were used for column and TLC chromatography
respectively.
6.1 1H-Indole-3-carbaldehyde (2).
To a solution of indole (1) at 0 °C, (500 mg, 4.27mmol) in DMF (2,5 mL),
was added drop by drop a solution of POCl3 (0,4 mL, 4.36 mmoles) in DMF (2,5
mL) recently prepared (1h) and the mixture stirred for 30 min. After stirring the
mixture was poured onto a water-ice mixture and basified with NaOH (0.5 M)
to pH : 12. The obtained white-yellow precipitate was filtered off and dried to
yield 526 mg , 85%) of pure indole (2). mp 181-182 ºC ; IRνmax (cm-1) : 3168(N-
Scheme 2. Synthesis of 2-(1-Benzyl-1H-indole-3-carbonyl)-1,3-
dicyclohexyl-isourea.
Finally, the indole (5) was cleanly converted to the corresponding
1-benzyl-3-[4-aryl-1-piperazingl]carbonyl-1H-indoles 6(a-f) in good yield 65-
92 % by reaction with a series of commercially available arylpiperazines.
1
H), 1634 (C=O), 1576(C=C) ; H NMR (300 MHz, CDCl3): 7.21(m,2H, 5-H
and 6-H), 7,49 (dd,1H, 7-H, Jo = 7.1 Hz, Jm =1.5 Hz), 8.1 (dd,1H,4-H, Jo = 6.7
Hz, J =1.9 Hz), 9.9(s,1H,CHO), 12.1 (s,1H, NH). 13C NMR (75 MHz, CDCl3)
: 112m.4, 118.2, 121.1, 122.1, 123.4, 124.1, 137.0, 138.4, 184.9. HRMS (EI)
Calcd for C9H7NO, : 145.05276. Found (M-1)+: 144.0445.
1-Benzyl-1H- indole-3-carbaldehyde. (3).
To a solution of indole (2) (500 mg, 3.44 mmol) in dry DMF (10 ml) NaH
(123 mg, 5.16 mmol, 60% suspension in mineral oil) was added slowly. The
reaction mixture was stirred and cooled to 5 °C, then benzyl bromide (816 mg,
4.8 mmol) was added dropwise.
After stirring for 30 min, the mixture was poured onto a water-ice mixture
and a white-pink precipitated was formed to yield pure indole (3) (607 mg
,75%). mp. 94-95 ºC. IRνmax(cm-1). 3108 (C-H Arom.), 2815 (C-H aliph.),
1661(C=O), 1536 (C=C). 1H NMR (300 MHz, CDCl3): 5.3(s,2H, Ar-CH2-),
7.14-7.35 (m,8H, 5-H, 6-H, 7-H, and Ar-CH2 ), 7.7(s,1H, 2-H ), 8.3(m,1H,
4-H), 9.97(s,1H,CHO).13C NMR (75 MHz, CDCl3) : 50.4, 109.9, 118.0, 121.7,
122.6, 123.7, 125.0, 126.8 (2C), 127.8, 128.7 (2C), 134.9, 137.0, 138.1, 184.2.
HRMS (EI) Calcd for C16H13NO,(M+) : 235.09971. Found : 235.09946.
Formation of series 6(a-f) was mainly supported in 1H NMR by the
presence of two bride singulets or two triplets assigned for the piperazine ring
protons at δ : 3.57 and 3.77 6(a), δ : 3.0 and 3.79 6(b), δ : 3.17 and 3.81 6(c),
δ : 3,21 and 3,78 6(d), δ : 3.58 and 3.82 6(e) and δ : 3.29 and 3.88 6(f) along
with the aromatic proton signals. The M+ obtained values in HRMS confirmed
the proposed structures. (Table 1.)
1-Benzyl-1H- indole-3-carboxylic acid (4).
To a solution of indole aldehyde (3) (420 mg , 1.78 mmol) in acetone
–water mixture ( 80 mL, 1:1 v/v) was added KMnO4 (1.120 mg, 7.12 mmol).
The mixture was stirred for 3h, filtered on celite and concetrated in vacuo to
remove the organic solvent. The resulting aqueous solution was cooled and
acidified with HCl (concd.) to afford a white precipitate, which was collected
by filtration and dried to provide pure carboxylic acid (4) (358 mg, 80%).
mp :183-184 ºC. IRνmax(cm-1): 3420-2550 (O-H), 3031 (C-H Arom.), 2931(C-H
Table 1. Physical constants for the 6(a-f) series.
HRMS (M+)
Calculated / Experimental
Products
m.p. ºC
Yield %
6-a
6-b
6-c
6-d
6-e
6-f
396.19501 / 396.19505.
114-116
130-131
140-141
107-109
157-159
124-125
65
92
78
82
87
89
425.21033
413.19034
/
425.20978.
413.19025
1
aliph.), 1655 (C=O), 1576(C=C),1220 (C-O). H NMR (300 MHz, CDCl3)
/
: 5.43(s,2H, Ar-CH2-), 7.1-7.29 (m, 7H, 5-H, 6-H, and Ar-CH2), 7.47 (m,
1H,4-H), 8.00 (m, 1H, 7-H), 8.18 (s,1H, 2-H), 12.1 (br.s.,1H,COOH). 13C
NMR (75 MHz, CDCl3): 50.0, 107.4, 111.6, 121.4, 121.9, 122.8, 127.1, 127.8
(2H), 128.1, 129.1(2H), 135.9, 136.8, 137.6, 166.0. HRMS (EI) Calcd for
C16H13NO2, (M+) : 251.09463. Found : 251.09446.
425.21033 / 425.20922
440.18484 / 440.18490
395.19976 / 395.19940
867

J. Chil. Chem. Soc., 56, Nº 4 (2011)
1
2-(1-Benzyl-1H-indole-3-carbonyl)-1,3-dicyclohexyl-isourea (5).
To a solution of 3-indole carboxylic acid (4) (500 mg, 1.99 mmol) in
CH2Cl2 (20 mL), was added N,N´-dicyclohexylcarbodiimide (490mg, 2.38
mmoles) and 4-dimethylaminopyridine (290 mg; 2.38 mmol). The mixture was
stirred at room temperature for 90 min. The solvent was removed in vacuo and
the residue purified by column chromatography (EtOAc: Hexane 1:1) to afford
(5) (880 mg, quantitative yield). mp : 169-171 ºC. IRνmax(cm-1) : 3327 (N-H),
3032 (C-H Arom.), 2927(C-H aliph.), 1752(C=O), 1696 (C=N), 1575(C=C).
1H NMR : 0.8-2.2 (m, 20 H), 3.43-3.51 (m, 1H, CHNH), 4.30-4.37 (m,1H,
CHN=), 5.29 (s,2H, CH -C6H5), 6.04 (d,1H,NH, J =5.7 Hz), 7.59 (s,1H, 2-H),
8.06 (dd, 1H, 4-H, Jo =24.8 Hz, Jm =2.1 Hz), 7.14-7.32 (m,8H, CH2-Ar and
5-H, 6-H, 7-H ). 13C NMR (75 MHz) : 24.6, 25.4, 25.5(2C), 26.4(2C), 31.2(2C),
32.5(2C), 49.7, 50.6, 57.1, 110.2, 111.9, 121.7, 121.9, 123.2, 127.1(2C), 127.4,
128.2(2C), 129.0, 131.1, 136.0, 136.5, 155.3, 166.8. HRMS (EI) Calcd for
C29H35N3O2, (M+) : 457.27293. Found: 457.27474.
(C=C). H NMR (300 MHz, DMSO-d ) : 3.21 (m,4H, 3’-H and 5’-H), 3.72
(s,3H, OMe), 3.78 (m,4H, 2’-H and 5’-6H), 6.40(d,1H, 6”-H, J = 8.0 Hz), 6.50
(s,1H, 2”-H), 6.56 (d,1H, 4”-H), 7.05-7.22 (m,3H, 5”-H and 2x Ar-CH ), 7.25
(m,5H, 5-H, 6-H and 3x Ar-CH2), 7.51 (d,1H, 7-H, J = 7.7 Hz), 7.742(d,1H,
4-H, J = 7.3 Hz), 7.98 (s, 1H, 2-H). 13C NMR ( 75 MHz, DMSO-d ) : 45.0(2C),
49.2, 49.8(2C), 55.3, 102.4, 105.0, 108.9, 109.7, 111.3, 121.1 6(2C), 122.6,
127.2, 127.7 (2C), 128.0, 129.1(2C), 130.1, 132.0, 136.0, 138.0, 152.7, 160.7,
165.6. HRMS (EI) Calcd for C27H27N3O2 (M+) : 425.21033. Found : 425.20922.
1-Benzyl-3-{[4-(4-nitrophenyl)-1-piperazinyl]carbonyl}-1H-Indole.
(6-e)
Prepared from 1-(4-nitrophenyl)-piperazine (468 mg; 2.1mmol) and
2-(1-Benzyl-1H-indole-3-carbonyl)-1,3-dicyclohexyl-isourea (5), (961 mg,
2.1 mmol), stirred for 6h to give crude ( 6-e) in quantitative yield. Purified by
column chromatography (EtOAc/ Hexane 1:3) to yield. 6-e (988 mg, 87 %).
mp : 157-159 ºC. IRνmax(cm-1) : 3029 (C-H arom.), 2927 (C-H aliph.), 1615
(C=O), 1592 (NO2 asym.), 1328 (NO2 sym.). 1H NMR (300 MHz, DMSO-d6)
: 3.58 (t,4H, 3’-H and 5’-H, J= 3.6 Hz), 3.82 (t,4H, 2’-H and 6’-H, J= 3.6
Hz), 5.49 (s,2H, CH2-Ar), 7.00 (d,2H, 2”-H and 6”-H, J= 9.4 Hz), 7.10-7.38
(m,7H, Ar-CH2 and 5-H, 6-H), 7.52 (d,1H, 7-H, J = 7.2 Hz), 7.81 (dd,1H, 4-H,
Jo =7.7 and Jm =1.5 Hz ), 8.02 (s,1H, 2-H), 8.08 (d,2H, 3”-H and 5”-H, J =
9.4 Hz). 13C NMR ( 75 MHz, DMSO-d ) : 44.5 (2C), 46.7, 49.9 (2C), 109.5,
111.3, 112.9 (2C), 122.7, 121.1, 121.2, 6126.2 (2C), 127.3, 127.7 (2C), 128.0,
129.1 (2C), 132.2, 136.0, 137.4, 138.0, 154.9, 165.7. HRMS (EI) Calcd for
C26H24N4O3 (M+) : 440.18484. Found : 440.18490.
General Procedure for the Synthesis of 1-Benzyl-3-[4-(aryl-1-
piperazinyl) carbonyl]-1H-Indoles 6(a-f).
1-Benzyl-3-[4-(2-pyridinyl-1-piperazinyl)carbonyl]-1H-Indole (6-a).
To a solution of 1-Pyridin-2-yl-piperazine (220 mg, 1.35 mmol) in CH2Cl2
(30 mL) was added 2-(1-Benzyl-1H-indole-3-carbonyl)-1,3-dicyclohexyl-
isourea (5), (618 mg,1.35 mmol) and the mixture stirred at room temperature
for 1h. The crude residue was concentrated in vacuo, and purified by column
chromatography (EtOAc/ Hexane 1:1) to give pure 6(a) (386 mg, 65%). mp
: 114-116 ºC. IRνmax(cm-1): 3027 (C-H Arom.), 1619 (C=O), 1542 (C=C). 1H
NMR (300 MHz, DMSO-d ): 3.57 (b.s. 4H, 2’-H, 6’-H), 3.77 (b.s., 4H, 3’-H,
5’-H), 5.40 (s,2H, CH -Ar)6, 6.59(t,1H, 5”’-H, J = 5.9 Hz) 6.71 (d,1H, 3”’-H,
J = 8.4 Hz), 7.05-7.252(m,7H, 5-H, 6-H and Ar-CH2), 7.37(m,1H, 7-H), 7.46
(t,1H, 4”’-H, J = 7.8 Hz), 7.74 (m,2H, 4-H y 2-H), 8.10 (d,1H, 6”’-H, J =
4.2 Hz). 13C RMN ( 75 MHz, DMSO-d ) : 44.8 (2C), 45.4 , 50.1(2C) , 107.5
, 109.9 , 110.8, 113.6, 120.9, 121.0, 1262.6, 127.0, 127.3 (2C), 127.9, 128,.8,
128.9(2C), 131.5, 136.0, 137.7, 147.9, 159.2, 166.0. HRMS (EI) Calcd for
C25H24N4O (M+): 396.19501. Found : 396.19505.
1 -Benzyl-3-[(4-phenyl-1-piperazinyl)carbonyl]-1H-Indole. (6-f)
Prepared from 1-Phenyl-piperazine (177 mg ,1.09 mmol) and 2-(1-Benzyl-
1H-indole-3-carbonyl)-1,3-dicyclohexyl-isourea (5), (499 mg, 1.09 mmoles ),
stirred for 1.5 h to give crude ( 6-f) in quantitative yield. Purified by column
chromatography (EtOAc / Hexane 1:1) to yield ( 6-f) (384 mg, 89%). mp :
124-125 ºC. IRνmax(cm-1) : 3033 (C-H arom.), 2927 (C-H aliph.), 1626 (C=O),
1576 (C=C Arom). 1H NMR (300 MHz, DMSO-d6) : 3.29 (t,4H, 3’-H and 5’-H,
J= 4.9), 3.88 (t,4H, 2’-H and 6’-H, J= 4,9 Hz), 5.38 (s,2H, CH -Ar) , 6.86 (t,1H,
4”-H, J= 7.3 Hz), 6.94 (d,2H, 2”-H, and 6”-H, J = 7.9 Hz), 72.15-7.38 (m,10H,
3”-H, 5”-H, Ar-CH2, 5-H, 6-H and 7-H ), 7.58 (s,1H,2-H), 7.76 (m,1H, 4-H).
13C NMR ( 75 MHz, DMSO-d6) : 44.9 (2C), 49.4, 50.0 (2C), 110.1, 110.2,
116.2 (2C), 119.9, 120.4, 120.8, 122.4, 126.3, 126.8 (2C), 127.6, 128.6 (2C),
128.9 (2C),130.6, 135.7, 136.3, 150.8, 165.9 HRMS (EI) Calcd for C26H25N3O,
(M+): 395.19976. Found : 395.19940.
1-Benzyl-3-{[4-(2-methoxyphenyl)-1-piperazinyl]carbonyl}-1H-
Indole.(6-b)
Prepared from 1-(2-methoxyphenyl)-piperazine (490 mg, 2.55 mmol) and
2-(1-Benzyl-1H-indole-3-carbonyl)-1,3-dicyclohexyl-isourea (5), (1167 mg,
2.55 mmol), to give crude 6(b) in quantitative yield. The residue was purified
by column chromatography (EtOAc/ Hexane 1:1) to yield 6(b) (307 mg, 92%).
mp : 130-131 ºC. IRνmax(cm-1) : 3015 (C-H Arom.), 1610 (C=O), 1541 (C=C).
1H NMR (300 MHz, DMSO-d ) : 3.0 (b.s.,4H, 3’-H and 5’-H), 3.79 (b.s., 7H,
2’-H, 6’-H and OMe), 5.47 (6s,2H, CH2-Ar), 6.92(m,4H, 3”-H, 4”-H, 5”-H
and 6”-H), 7.12-7.37 (m,7H, 5-H,6-H and 5x CH2-Ar), 7.49(m,1H, 7-H), 7.76
(m,1H, 4-H), 7.98 (s,1H, 2-H). 13C NMR ( 75 MHz, DMSO-d6) : 45.5 (2C),
49.8, 51.1 (2C), 55.8, 109.8, 111.3, 112.3, 118.8, 121.0, 121.1, 121.3, 122.6,
123.3, 127.2, 127.7(2C), 128.0, 129.1(2C), 132.0, 136.0, 138.0, 141.3, 152.5,
165.4. HRMS (EI) Calcd for C27H27N3O (M+) : 425.21033. Found : 425.20978.
ACKNOWLEDGEMENTS
We acknowledge with thanks to PROYECTO FONDECYT 1090169
for the financial support.
REFERENCES
1. I.Borza, S. Kolok, A. Gere, E. Àgai-Csongor, B.Ágai, G. Tárkányi, C.
Horváth, G. Barta-Szalai, E.Bozó, C. Kiss, A.Bielik, J. Nagy, S.Farkasa
and G. Dománya, Bioorg. Med. Chem. Lett. 13, 3859–3861, (2003).
2. S. Pedpradab, R.A. Edrada, R. Ebel, V. Wray, and P. Proksch. J. Nat.
Prod. 67, 2113-2116, (2004).
1-Benzyl-3-{[4-(4-fluorophenyl)-1-piperazinyl]carbonyl}-1H-Indole.
(6-c)
Prepared from 1-(4-fluorophenyl)-piperazine (330 mg, 1.83 mmol),
and 2-(1-Benzyl-1H-indole-3-carbonyl)-1,3-dicyclohexyl-isourea (5), (836
mg, 1.83.mmol) to give crude 6(c) in quantitative yield. Purified by column
chromatography (EtOAc/ Hexane 1:1), to yield (589 mg, 78%). mp : 140-
141 ºC. IRνmax(cm-1) : 3058 (C-H Arom.), 2927 (C-H aliph.), 1625 (C=O),
3. T. Heinrich, H. Bottcher, G. D. Bartoszyk, H. E. Greiner; Ch. A. Seyfried;
and Ch. van Ámsterdam. J. Med. Chem. 47, 4677-4683, (2004).
4. T. Opatz and D. Ferenc, Org. Lett. 8, 20,4473-4475, (2006).
5. G. W. Gribble, J. Chem. Soc., Perkin Trans. 1. 1045-1075 (2000).
6. G. R. Humphrey; J. T. Kuethe, Chem. Rev., 106, 2875-2911, (2006).
7. H. Pessoa-Mahana, M. González, M. González, C.David.Pessoa-Mahana,
R. Araya-Maturana, N. Ron, C.Saitz. Arkivoc (xi), 316-325, (2009).
8. I. Borza; E.A. Bozo´; G. Barta-Szalai, C. Kiss, G. Tárkányi, A. Demeter,
T. Gáti, V. Háda, S. Kolok, A. Gere, L. Fodor, J. Nagy, K. Galgóczy, I.
Magdo´, B. A. Agai, J. F. F. Bertha, G. M. Keseru, C. Horváth, S. Farkas,
I. Greiner, and G. Domány. J. Med. Chem. 50, 901-914, (2007).
9. T. Heinrich, H. Bottcher, K. Schiemann, G. Hölzemann, M. Schwarz, G.
D. Bartoszyk, Ch. van Ámsterdam, H. E. Greiner, and Ch. A. Seyfried.
Bioorg. Med. Chem. 12, 4843–4852, (2004).
10. P. Muñoz-Ruiz, L. Rubio, E. García-Palomero, I. Dorronsoro, M. del
Monte-Millán, R. Valenzuela, P. Usán, C. de Austria, M. Bartolini, V.
Andrisano, A. Bidon-Chanal, M. Orozco, F. J. Luque, M. Medina, and A.
Martínez.. J. Med. Chem. 48, 7223-7233, (2005).
11. S. Vangveravong, E. McElveen, M. Taylor, J. Xu, Z. Tu, R. R. Luedtkeb
and R. H. Macha, Bioorg. Med. Chem. 14, 815–825, (2006).
1
1580 (C=C). H NMR (300 MHz, DMSO-d6) : 3.17 (m,4H, 3’-H and 5’-H),
3.81(m,4H, 2’-H, 6’-H), 5.51 (s,2H, CH -Ar), 6.94-7.35 (m,11H, 5-H, 6-H,
2”-H, 3”-H, 5”-H 6”-H and CH2-Ar), 72.54 (d,1H, 7-H, Jo = 7.3 Hz), 7.77
(dd,1H, 4-H, Jo = 6,5 Hz, Jm =1.5 Hz), 8.01 (s,1H, 2-H). 13C NMR ( 75 MHz,
DMSO-d6) : 45.0 (2C), 49.8, 50.0 (2C), 109.8, 111.3, 115.8 (d,2C, 2J = 22 Hz),
118.2 (d, 2C,3J = 7.6 Hz ), 121.0, 121.1, 122.6, 127.1, 127.7 (2C), 128.0, 129.1
(2C), 132.1, 136.0, 138.0, 148.3 (d, 4J =2.0 Hz), 156.8 (d, 1J = 227 Hz), 165.5.
HRMS (EI) Calcd for C26H24FN3O (M+) : 413.19034. Found : 413.19025.
1-Benzyl-3-{[4-(3-methoxyphenyl)-1-piperazinyl]carbonyl}-1H-
Indole. (6-d)
Prepared from 1-(3-methoxy-phenyl)-piperazine (420 mg, 2.18 mmol)
and 2-(1-Benzyl-1H-indole-3-carbonyl)-1,3-dicyclohexyl-isourea (5), (1000
mg, 2.18 mmol), to give crude 6(d) in quantitative yield. Purified by column
chromatography (EtOAc/ Hexane 1:1) to yield (760 mg, 82%). mp : 107-109
ºC. IRνmax (cm-1): 3032 (C-H arom.), 2927 (C-H aliph.), 1626 (C=O), 1578
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J. Chil. Chem. Soc., 56, Nº 4 (2011)
12. A. Moll, H. Hübner, P. Gmeiner and R. Troschütz. Bioorg. Med. Chem.
14. H. Pessoa-Mahana, C. González L., R. Araya- Maturana, Claudio Saitz
B., C. David Pessoa-Mahana. J. Chil. Chem. Soc., 54, 2, 147-150 (2009).
15. S.Löber, Hübner, P. Gmeiner, Bioorg. Med. Chem. Lett. 9, 97-102, (1999).
10, 1671–1679, (2002).
13. H. Hübner, J. Kraxner, and P. Gmeiner, J. Med. Chem. 43, 4563-4569,
(2000).
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