Pd(0) amination of benzimidazoles as an efficient method towards new (benzimidazolyl)piperazines with high affinity for the 5-HT(1A) receptor

Article abstract of DOI:10.1016/S0040-4020(00)00225-8

New (benzimidazolyl)amines have been synthesized from 4- and 6- bromobenzimidazole derivatives via palladium-mediated amination reactions. Among them, (benzimidazol-4(7)-yl)piperazine derivatives have been shown to be a new family of high affinity 5-HT(1A) receptor ligands. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00225-8

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3245±3253
Pd(0) Amination of Benzimidazoles as an Ef®cient Method
towards New (Benzimidazolyl)piperazines with High Af®nity for
the 5-HT1A Receptor
a,
Marõa L. Lopez-Rodrõguez, Bellinda Benhamu, David Ayala, J. Luis Rominguera,
a
a
a
*
Â
Â
Â
Marta Murcia, Jose A. Ramos and Alma Viso
Â
a
b
a
Â
a
  Â
Departamento de Quõmica Organica I, Facultad de Ciencias Quõmicas, Universidad Complutense, E-28040 Madrid, Spain
Â
b
Departamento de Bioquõmica, Facultad de Medicina, Universidad Complutense, E-28040 Madrid, Spain
Received 4 January 2000; revised 24 February 2000; accepted 9 March 2000
AbstractÐNew (benzimidazolyl)amines have been synthesized from 4- and 6-bromobenzimidazole derivatives via palladium-mediated
amination reactions. Among them, (benzimidazol-4(7)-yl)piperazine derivatives have been shown to be a new family of high af®nity 5-HT1A
receptor ligands. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
temperature resistive polymers.6 Nevertheless, there are
few methods available to prepare benzimidazole derivatives
bearing substituents attached to the homocycle, since most
of the known routes are directed to functionalize carbon-2
and nitrogens (N-1, N-3).7 On the other hand, most
methods to obtain arylpiperazines involve cyclization of
aromatic amines and bis(haloethyl)amines.8 However,
these procedures present some problems such as the use
of toxic reagents and the dif®cult isolation of the products.
Moreover, in our hands treatment of 4-amino-1-tritylbenz-
imidazole with bis(chloroethyl)amine under a number of
different conditions did not yield the expected 1-(1-trityl-
benzimidazol-4-yl)piperazine, but complex crude mixtures
with extensive decomposition. These disappointing results
prompted us to explore alternative routes to reach our target
compounds.
Serotonin 5-HT1A receptors have been intensively studied1
because of their implication in several physiological
processes and psychiatric disorders such as anxiety and
depression. In addition to these therapeutic uses, serotoner-
gic 5-HT1A agonists have been proposed recently to be
employed as neuroprotective agents2 and the effect of
these drugs may be therapeutically relevant. For these
reasons, the discovery of new 5-HT1A receptor ligands is
an area of active research in Medicinal Chemistry. Within
this ®eld, we have found that arylpiperazines I (Scheme 1)
are potent 5-HT1A ligands.3 3D-QSAR studies4 suggested
that increasing the size of the substituent of the aromatic
ring could enhance the af®nity for 5-HT1A receptors. These
results led us to design a new family of arylpiperazines
where the substituted phenyl ring (Ar) has been replaced
by a bicyclic aromatic ring. Among the considered
moieties, we found particularly interesting arylpiperazines
II (Scheme 1), which include a benzimidazole ring
attached to the piperazine through carbon 4(7) or 5(6) and
this required an ef®cient entry to 1-(benzimidazol-4(7)- and
-5(6)-yl)piperazines.
The metal-mediated coupling of aromatic halides and tri¯ates
with amines has become a powerful tool to synthesize
Benzimidazole derivatives are becoming increasingly
important since they are present in naturally occurring
cyanocobalamine, serine protease inhibitors and a number
of different therapeutic agents.5 They are also applied as
cyanine dyes in photographic emulsions and as high
Keywords: Pd(0) amination; arylpiperazines; 5-HT1A receptor.
* Corresponding author. Fax: 134-1-3944103;
e-mail: mluzlr@eucmax.sim.ucm.es
Scheme 1.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00225-8

 Â
M. L. Lopez-Rodrõguez et al. / Tetrahedron 56 (2000) 3245±3253
3246
Scheme 2. (a) NaH, BnCl, Bu4Ni, THF, 48% for 2a; 20% for 2b; (b) NaH, TrCl, Bu4Ni, 90% for 3; 45% for 7a; 40% for 7b; 46% for 8a.
aromatic amines, especially since Buchwald and Hartwig
independently studied the process from a synthetic and
mechanistic standpoint.9 Because of the broad scope of
the amination reaction, we considered it suitable for our
purposes.10 In this paper, we would like to report our results
on the coupling of 4(7)- and 5(6)-halobenzimidazoles with
different aliphatic and aromatic amines. Among the coupled
compounds, (benzimidazol-4(7)-yl)piperazine derivatives
have shown to be a new family of high af®nity 5-HT1A
receptor ligands.
1-trityl- and 6-halo-1-tritylbenzimidazoles, subsequently
separated by column chromatography.
The following step in our synthetic plan was the amination
of the protected halobenzimidazoles (Scheme 3). Starting
from 3, a wide variety of amine/catalyst/ligand systems
have been tested to optimize this procedure for our
substrates. Treatment of 3 with morpholine (1.4 equiv.) in
the presence of Pd2dba3´CHCl3 (2±10%), dppp (4±10%)
and NaOtBu (1.4 equiv.) in toluene rendered 4-(benzimida-
zol-4-yl)morpholine 4a in 65% yield, and we did not
observe the corresponding reduction product (Scheme 3,
Table 1, entry 1). In a similar way, 1-methylpiperazine
reacted with 3 giving an excellent yield of 4b even when
Pd2dba3´CHCl3 was changed to Pd(OAc)2 as the palladium
source (Scheme 3, Table 1, entries 2±3).
Results and Discussion
The synthesis of 4(7)-bromobenzimidazole 1 was carried
out starting from 4-bromoaniline following a described
procedure in ®ve steps.11 5(6)-Bromobenzimidazole 6a
was obtained by treating benzimidazole with N-bromosuc-
cinimide in the presence of silica gel.12 This reaction,
employing N-iodosuccinimide instead of the bromine ana-
logue, did not allow us the attainment of 5(6)-iodobenz-
imidazole 6b, ®nally obtained by iodation, reduction and
cyclization of o-nitroaniline.13
When piperazine was used as amine, a higher excess
(4 equiv.) was employed to avoid an undesired double
coupling. Formation of the corresponding (benzimidazolyl)-
piperazine 4c was carried out under slightly different condi-
tions than used for morpholine and 1-methylpiperazine,
because the use of Pd2dba3´CHCl3/dppp did not yield the
expected product but a 75/25 mixture of starting material
3 and reduction product 5 after 24 h under these reaction
conditions, probably due to a competitive b-elimination
process. Moreover, changing the catalyst system to
Pd(OAc)2/dppp gave a small amount of 4c in the crude
mixture (25/50/25, 3/4c/5). The best result was obtained
with Pd2dba3´CHCl3/(^)-BINAP, with 87% yield of 4c
(Scheme 3, Table 1, entries 5±7). Under these conditions,
neither the corresponding dimer nor the reduction product 5
were observed, even in the presence of an excess of 3 and
after prolonged reaction times (48 h).
Substrates 1, 6a and 6b were N-protected before the amina-
tion procedure (Scheme 2), because no amination reaction
was observed for the unprotected halobenzimidazoles
(Scheme 3, Table 1, entry 4). Initially, a benzyl group was
selected as the protective group, but the treatment of 1 with
benzyl chloride yielded an 80/20 mixture of the anti/syn
isomers (2a, 2b) (the relative percentage was determined
by integration of the 1H NMR spectrum of the crude
mixture, and the identi®cation of each isomer, using steady
state 1D-NOE experiments).14 In order to avoid this lack of
regioselectivity, we considered the introduction of a bulkier
trityl group, obtaining then a single anti N-alkylated
product, identi®ed as 4-bromo-1-tritylbenzimidazole 3. In
contrast, reaction of 6a and 6b with trityl chloride was a
non-selective process, producing a 50/50 mixture of 5-halo-
Other amines submitted to the coupling reaction showed a
lower reactivity.15 Thus, hexylamine (Scheme 3, Table 1,
entry 8) led to only 28% conversion after 48 h. In contrast,
PhNH2 afforded N-(benzimidazol-4-yl)aniline 4e, which
was isolated pure in 54% yield (Scheme 3, Table 1, entry 9).

 Â
M. L. Lopez-Rodrõguez et al. / Tetrahedron 56 (2000) 3245±3253
3247
Scheme 3.
Table 1. Pd(0) amination of bromobenzimidazoles
Entry
Substrate
RR0NH
Catalyst/Ligand
Product (yield %)a
1
2
3
4
5
6
7
8
3
3
3
1
3
3
3
3
3
7a
8a
7b
7b
7b
Morpholine
Pd2dba3´CHCl3/dppp
Pd2dba3´CHCl3/dppp
Pd(OAc)2/dppp
Pd(OAc)2/dppp
Pd2dba3´CHCl3/dppp
Pd(OAc)2/dppp
Pd2dba3´CHCl3/(^)-BINAP
Pd2dba3´CHCl3/(^)-BINAP
Pd2dba3´CHCl3/(^)-BINAP
Pd2dba3´CHCl3/(^)-BINAP
Pd2dba3´CHCl3/dppp
Pd(OAc)2/(^)-BINAP
Pd(OAc)2/(^)-BINAP
Pd(OAc)2/(^)-BINAP
4a (65)
4b (97)
4b (97)
1-Methylpiperazine
1-Methylpiperazine
1-Methylpiperazine
Piperazine
Piperazine
Piperazine
Hexylamine
Aniline
Piperazine
1-Methylpiperazine
Piperazine
Piperazine
b
±
±
c
4cd
4c (87)
4de
9
4ef (54)
g
10
11
12
13
14
±
±
±
g
h
9a (60)i
9b (55)i
1-Methylpiperazine
a Yield of isolated pure compounds.
b No reaction was observed.
c A 75/25 mixture of 3 and 5 was observed in the reaction crude (1H NMR, 300 MHz).
d A 25/50/25 mixture of 3, 4c and 5 was observed in the reaction crude (1H NMR, 300 MHz).
e A 72/28 mixture of 3 and 4d was observed in the reaction crude (1H NMR, 300 MHz); 4d was not isolated from this mixture.
f 60% conversion after 20 h of reaction.
g A 50/50 mixture of starting material and 5 was observed in the reaction crude (1H NMR, 300 MHz).
h A 30/40/30 mixture of 7b, 5 and 9a was observed in the reaction crude (1H NMR, 300 MHz).
i A 15% of 5 was also obtained; Cs2CO3 instead of NaOtBu was employed.
With regard to N-trityl derivatives 7a and 7b, an unexpectedly
very different reactivity of these regioisomers was found
towards the Pd(0) catalyzed amination. Thus, 5-bromo-1-
tritylbenzimidazole 7a was not a suitable substrate for the
coupling process, yielding the starting material along with
variable amounts of reduction product 5, independently of
the reaction conditions employed, Pd2dba3´CHCl3/(^)-
BINAP/NaOtBu/toluene (Scheme 3, Table 1, entry 10),
Pd2dba3´CHCl3/(^)-BINAP/Cs2CO3/toluene or Pd(OAc)2/
(^)-BINAP/NaOtBu/toluene. Even when aniline was used
to prevent b-elimination, the coupling product could not be
detected upon examination of the crude reaction mixture.
The use of 5-iodo-1-tritylbenzimidazole 8a gave again a
mixture of the starting material and reduction product
(Table 1, entry 11). On the other hand, 6-bromo-1-trityl-
benzimidazole 7b reacted more readily than its isomer 7a
(Table 1, entries 12±13), although a low conversion to the
corresponding (benzimidazolyl)piperazine 9a (30%) along
with an important amount of reduction product 5 (40%)
were produced after treatment of 7b with an excess of piper-
azine and Pd(OAc)2/(^)-BINAP/NaOtBu. The use of
Cs2CO3 instead of NaOtBu allowed the isolation of the
desired product 9a in a moderate yield (60%). Following
the same procedure, the N-methyl analogue 9b was obtained
from 7b (Table 1, entry 14).
Once afforded 1-(1-tritylbenzimidazol-4-yl)piperazine 4c
and 1-(1-tritylbenzimidazol-6-yl)piperazine 9a, the next
step was the incorporation of a bicyclohydantoin moiety.
Reaction of 4c or 9a with bromoderivative (^)-103a gave,
in good yields, the mixed hydantoin±arylpiperazine deriva-
tives (^)-11 and (^)-12, susceptible to be tested as new
ligands for serotonin 5-HT1A receptors (Scheme 4).
Finally, standard acidic conditions16 (AcOH/H2O/THF)
allowed for the smooth removal of the trityl group for
(^)-11 and (^)-12 derivatives, obtaining (^)-17 and
(^)-18, respectively. Similarly, simple arylpiperazines 4b,
4c, 9a and 9b were converted into 13, 14, 15 and 16, respec-
tively. All these compounds were obtained in very good
yields (Scheme 4).
Target compounds were evaluated for in vitro af®nity at
central 5-HT1A receptors by radioligand binding assays,
using [3H]-8-OH-DPAT in rat cerebral cortex membranes.17
The binding data of the tested compounds are presented in

 Â
M. L. Lopez-Rodrõguez et al. / Tetrahedron 56 (2000) 3245±3253
3248
Scheme 4.
Table 2, as the inhibition constant Ki, de®ned from the IC50
using the Cheng±Prusoff equation.18
readily accessible pharmacophoric moiety in the research
for new potent 5-HT1A ligands.
Interestingly, benzimidazol-4(7)-yl derivatives exhibit high
af®nity (nanomolar range) for the 5-HT1A receptor (i.e. Ki
(13)ˆ4.72^0.50 nM, Ki (17)ˆ1.21^0.02 nM), whereas
benzimidazol-5(6)-yl analogues are inactive (Ki.1000
nM). These results indicate that these arylpiperazines are
new potent 5-HT1A receptor ligands. Thus, the fragment
1-(benzimidazol-4-yl)piperazine represents a novel and
Conclusion
The synthesis of target (benzimidazolyl)piperazines
exempli®es a new approach to (benzimidazolyl)amines via
Pd(0) amination of bromobenzimidazole derivatives.
Among the prepared compounds, we have identi®ed some
Table 2. In vitro binding af®nity of (benzimidazolyl)piperazines at 5-HT1A receptors (Ki values are means ^ SEM of two to four assays, performed in triplicate.
Inhibition curves were analyzed by a computer-assisted-curve-®tting program (Prism GraphPad) and Ki values were determined from Cheng±Prusoff equation)
Compound
R
Position of piperazine
R0
Ki (nM)^SEM
4b
4c
13
14
9a
9b
15
16
CH3
H
CH3
H
H
CH3
H
4
4
4(7)
4(7)
6
6
5(6)
5(6)
Tr
Tr
H
.1000
.1000
4.72^0.50
27.0^1.7
.1000
.1000
.1000
.1000
H
Tr
Tr
H
CH3
H
(^)-11
(^)-12
(^)-17
(^)-18
4
6
4(7)
5(6)
Tr
Tr
H
36.7^4.6
.1000
1.21^0.02
.1000
H

 Â
M. L. Lopez-Rodrõguez et al. / Tetrahedron 56 (2000) 3245±3253
3249
(benzimidazol-4(7)-yl)piperazines as novel and potent
5-HT1A receptor ligands. The synthesis of new analogues
bearing this innovative pharmacophoric moiety, assessment
for 5-HT1A receptor af®nity and further pharmacological
characterization of selected products are in progress in our
laboratory, and the results will be published in due course.
and a catalytic amount of n-Bu4NI were added, and the
mixture was re¯uxed for 5 h. The mixture was then cooled
down, hydrolyzed with H2O (2 mL/mmol) and extracted
with CHCl3 (3£50 mL). The extracts were dried over
Na2SO4 and evaporated to dryness in vacuo. Puri®cation
of the crude by column chromatography on silica gel
rendered 3 (90%) as a white solid. Rfˆ0.2 (CHCl3). mp:
225±2278C (EtOAc). IR (CHCl3, cm21): 3030±3080,
1
1440, 1420, 1300, 1210, 700. H NMR (CDCl3-d): 7.94
Experimental
Synthesis
(s, 1H, H2), 7.36±7.28 (m, 10H, trityl), 7.19±7.13 (m, 6H,
trityl, H5), 6.76 (t, 1H, H6, Jˆ8.1 Hz), 6,42 (d, 1H, H7,
Jˆ8.1 Hz). 13C NMR (CDCl3-d): 144.5 (C2), 143.2 (C3a),
140.9 (trityl), 135.3 (C7a), 130.0 (trityl), 128.3 (trityl), 128.2
(trityl), 125.2 (C5/C6), 123.3 (C6/C5), 114.8 (C7), 113.6 (C4),
75.9 (trityl). MS (m/z): 243 (100%), 228, 215, 198, 165, 117,
90, 63.
All reagents were the commercial products purchased from
Aldrich, Fluka or Strem Chemicals. All solvents were
distilled prior to use. Anhydrous toluene was obtained by
distillation over CaH2. Analytical TLC was carried out on
Merck (Kieselgel 60F-254) silica gel plates with detection
by UV light, iodine and acidic vanillin solution. Melting
points were determined on a Gallenkamp apparatus and
are uncorrected. Infrared spectra (IR) were obtained on an
FTIR-8300 Shimadzu spectrophotometer. Nuclear magnetic
resonance spectra were recorded on a Varian VXR-300S,
Bruker AM-300 and Bruker AM-200. Low resolution mass
spectra were recorded by direct injection on an HP5989A EI
(70 eV). Elemental analyses were carried out on a Perkin±
Elmer 2400 apparatus at the Facultad de Farmacia, UCM.
5-Bromo-1-tritylbenzimidazole, 7a and 6-bromo-1-trityl-
benzimidazole, 7b. From 6a (6 g, 30 mmol), NaH (1.4 g,
36 mmol) and TrCl (11.2 g, 39 mmol), following the pro-
cedure reported for 3, a 50/50 mixture of 7a and 7b (white
solids) was obtained. Separation was performed by column
chromatography (silica gel) using mixtures of hexane/
EtOAc as eluent. Yield: 7a (45%), 7b (40%). Data of 7a;
Rfˆ0.6 (hexane/EtOAc, 1/1). mp: 232±2348C (toluene/
hexane). IR (KBr, cm21): 3440, 1490, 1475, 1450, 1220,
700. 1H NMR (CDCl3-d): 7.93 (d, 1H, H4, Jˆ1.8 Hz),
7.88 (s, 1H, H2), 7.36±7.28 (m, 10H, trityl), 7.22±7.12
(m, 5H, trityl), 7.00 (dd, 1H, H6, Jˆ8.8, 1.8 Hz), 6.34 (d,
1H, H7, Jˆ8.8 Hz). 13C RMN (CDCl3-d): 146.0 (C3a), 145.1
(C2), 141.0 (trityl), 133.8 (C7a), 129.9 (trityl), 128.3 (trityl),
128.2 (trityl), 125.5 (C4/C6), 123.1 (C6/C4), 116.5 (C7),
115.3 (C5), 75.5 (trityl). Data of 7b; Rfˆ0.4 (hexane/
EtOAc, 1/1). mp: 234±2368C (toluene/hexane). IR (KBr,
cm21): 3060, 1600, 1490, 1450, 1280, 700. 1H NMR
(CDCl3-d): 7.87 (s, 1H, H2), 7.60 (d, 1H, H4, Jˆ8.8 Hz),
7.37±7.31 (m, 10H, trityl), 7.25 (dd, 1H, H5, Jˆ8.8, 2.5 Hz),
7.19±7.11 (m, 5H, trityl), 6.58 (d, 1H, H7, Jˆ2.5 Hz). 13C
NMR (CDCl3-d): 144.7 (C2), 143.6 (C3a), 140.9 (trityl),
135.8 (C7a), 129.9 (trityl), 128.3 (trityl), 128.2 (trityl),
125.6 (C4/C5), 121.5 (C5/C4), 118.0 (C7), 115.7 (C6), 75.7
(trityl). MS (m/z): 243 (100%), 228, 215, 198, 165, 120, 90,
63.
1-Benzyl-4-bromobenzimidazole, 2a and 1-benzyl-1-
bromobenzimidazole, 2b. To a solution of 1 (175 mg,
0.9 mmol) in anhydrous THF (2.6 mL) at 08C, 60% NaH
in mineral oil (40.5 mg, 0.99 mmol) was added under an
argon atmosphere. After 30 min stirring, benzyl chloride
(0.11 mL, 0.99 mmol) and a catalytic amount of n-Bu4NI
were added, and the mixture was re¯uxed for 5 h. The
mixture was then cooled down, hydrolyzed with H2O
(2 mL/mmol) and extracted with CHCl3 (3£50 mL). The
extracts were dried over Na2SO4 and evaporated to dryness
in vacuo. Puri®cation of the crude by column chromato-
graphy on silica gel, using mixtures of CH2Cl2/EtOAc as
eluent, rendered an 80/20 mixture of 2a (white solid, yield:
48%) and 2b (white solid, yield: 20%). Data of 2a; Rfˆ0.6
(CH2Cl2/EtOAc, 8/1). mp: 114±1168C (CHCl3/hexane). IR
(KBr, cm21): 3060±3000, 1495, 1450, 1430, 1270, 1195,
780. 1H NMR (CDCl3-d): 7.91 (s, 1H, H2), 7.38 (d, 1H, H5,
Jˆ7.5 Hz), 7.26±7.23 (m, 3H, benzyl), 7.12 (d, 1H, H7,
Jˆ7.5 Hz), 7.09±7.06 (m, 2H, benzyl), 7.05 (t, 1H, H6,
Jˆ7.5 Hz), 5.23 (s, 2H, CH2). 13C NMR (CDCl3-d): 143.6
(C2), 142.5 (C3a), 134.9 (benzyl/C7a), 134.4 (C7a/benzyl),
128.8 (benzyl), 128.2 (benzyl), 126.8 (benzyl), 125.3 (C5/
C6), 124.0 (C6/C5), 113.8 (C4), 109.6 (C7), 49.2 (CH2). Data
of 2b; Rfˆ0.5 (CH2Cl2/EtOAc, 8/1). IR (KBr, cm21): 2990±
2910, 1560, 1500, 1440, 1280, 1170, 725. 1H NMR (CDCl3-
d): 7.83 (s, 1H, H2), 7.72 (d, 1H, H4, Jˆ7.8 Hz), 7.36 (d, 1H,
H6, Jˆ7.8 Hz), 7.31±7.27 (m, 3H, benzyl), 7.08 (t, 1H, H5,
Jˆ7.8 Hz), 7.08±7.02 (m, 2H, benzyl), 5.72 (s, 2H, CH2).
13C NMR (CDCl3-d): 145.7 (C2), 142.9 (C3a), 137.5 (C7a),
128.8 (benzyl), 127.9 (C6), 126.9 (benzyl), 126.4 (benzyl),
123.5 (C5), 120.0 (C4), 109.3 (C7), 49.8 (CH2).
5-Iodo-1-tritylbenzimidazole, 8a. From 6b (470 mg,
1.9 mmol), NaH (95 mg, 2,3 mmol) and TrCl (663 mg,
2.3 mmol), following the procedure reported for 3, a 50/50
mixture of 8a (46%, white solid) and its isomer 6-iodo-1-
tritylbenzimidazole (8b) was obtained. Separation was
performed by column chromatography (silica gel) using
mixtures of hexane/EtOAc as eluent. Data of 8a; Rfˆ0.4
(hexane/EtOAc, 3/1). mp: 242±2448C (MeOH/Et2O). IR
(CHCl3, cm21): 3020, 2400, 1605, 1490, 1480, 1450,
1
1280, 1035, 865, 850, 650, 630. H NMR (CDCl3-d): 8.14
(s, 1H, H2), 7.84 (s, 1H, H4), 7.35±7.27 (m, 10H, trityl),
7.18±7.14 (m, 6H, trityl, H6), 6.23 (d, 1H, H7, Jˆ8.7 Hz).
13C NMR (CDCl3-d): 146.4 (C3a), 144.6 (C2), 140.9 (trityl),
134.3 (C7a), 130.9 (C4/C6), 129.8 (trityl), 129.3 (C6/C4),
128.2 (trityl), 128.1 (trityl), 117.0 (C7), 85.7 (C5), 75.6
(trityl). MS (m/z): 243 (100%), 228, 215, 198, 165, 139,
115, 91, 63, 51. Partial data of 8b (from crude mixture):19
Rfˆ0.3 (hexane/EtOAc, 3/1).1H NMR (CDCl3-d): 7.82 (s,
1H, H2), 7.53 (d, 1H, H4, Jˆ8.5 Hz), 7.44 (dd, 1H, H5,
4-Bromo-1-tritylbenzimidazole, 3. To a solution of 1 (1 g,
5.1 mmol) in anhydrous THF (25 mL) at 08C, 60% NaH in
mineral oil (252 mg, 6.1 mmol) was added under an argon
atmosphere. After 30 min stirring, TrCl (1.9 g, 6.6 mmol)

 Â
M. L. Lopez-Rodrõguez et al. / Tetrahedron 56 (2000) 3245±3253
3250
Jˆ8.5, 1.2 Hz), 7.37±7.32. (m, 10H, trityl), 7.17±7.13
(m, 5H, trityl), 6.76 (d, 1H, H7, Jˆ1.2 Hz). 13C NMR
(CDCl3-d): 141.0 (C2), 131.2 (C3a/C7a), 129.9 (trityl),
129.3 (C7a/C3a), 128.3 (trityl), 128.2 (trityl), 127.3 (C5/C7),
124.1 (C7/C5), 122.0 (C4), 86.3 (C6), 75.7 (trityl).
obtained 4c (yield: 87%, pale yellow solid) after chromato-
graphy using mixtures of toluene/EtOH as eluent. Rfˆ0.3
(toluene/EtOH/NH3, 9/1/0.1). mp: 104±1088C. IR (KBr,
cm21): 3650±3340, 1590, 1490, 1445, 1235, 1090. 1H
NMR (CDCl3-d): 7.79 (s, 1H, H2), 7.34±7.25 (m, 10H,
trityl), 7.21±7.17 (m, 5H, trityl), 6.77 (t, 1H, H6,
Jˆ7.8 Hz), 6.51 (d, 1H, H5, Jˆ7.8 Hz), 6.08 (d, 1H, H7,
Jˆ8.4 Hz), 3.50 (m, 4H, 2CH2-N), 3.14 (m, 4H, 2CH2-N).
13C NMR (CDCl3-d): 143.8 (C4), 141.2 (C2), 141.0 (trityl),
136.5 (C3a/C7a), 135.7 (C7a/C3a), 129.7 (trityl), 127.7 (trityl),
127.6 (trityl), 122.5 (C6), 108.3 (C5/C7), 107.0 (C7/C5), 75.0
(trityl), 51.1 (2CH2-N), 46.0 (2CH2-N). Anal. calculated for
C30H28N4: C, 81.05%; H, 6.35%; N, 12.60%. Found: C,
81.31%; H, 6.68%; N, 12.40%.
General procedure for the palladium catalyzed amina-
tion of halobenzimidazoles
To a solution of 1 equiv. of the corresponding bromobenz-
imidazole in toluene (10 mL£mmol), under an argon
atmosphere, amine (1.2±6 equiv.), base (1.4±2 equiv.),
palladium catalyst (0.02±0.1 equiv.) and phosphine (0.04±
0.15 equiv.) were added. The mixture was heated at 858C
(2±10 h), and when TLC showed complete disappearance
of the starting material the mixture was cooled down and
®ltered through a short column of Celite. The resulting solu-
tion was evaporated to dryness under vacuum. The crude
mixture was puri®ed by column chromatography on silica
gel using the appropriate eluent.
N-(1-Tritylbenzimidazol-4-yl)aniline, 4e. From 3 (44 mg,
0.1 mmol), aniline (53 mg, 0.12 mmol), NaOtBu (13.4 mg,
0.14 mmol), Pd2dba3´CHCl3 (2 mg, 0.002 mmol), (^)-
BINAP (4 mg, 0.006 mmol) and toluene (1 mL) was
obtained 4e (yield: 54%, yellow oil) after chromatography
using mixtures of CHCl3/EtOAc as eluent. Rfˆ0.4 (CHCl3/
EtOAc, 9.5/1). IR (KBr, cm21): 3410, 3020, 2925, 1615,
1-(1-Tritylbenzimidazol-4-yl)morpholine, 4a. From 3
(50 mg, 0.12 mmol), morpholine (0.012 mL, 0.14 mmol),
NaOtBu (15.8 mg, 0.16 mmol), Pd2dba3´CHCl3 (2.4 mg,
0.0023 mmol), dppp (2 mg, 0.0046 mmol) and toluene
(1.2 mL) was obtained 4a (yield: 65%, white solid) after
chromatography using mixtures of hexane/EtOAc as eluent.
Rfˆ0.3 (hexane/EtOAc, 3/1). mp: 196±1988C (CHCl3/
hexane). IR (KBr, cm21): 3060±3010, 1590, 1495, 1445,
1
1590, 1495, 1370, 1215, 755. H NMR (CDCl3-d): 7.71
(s, 1H, H2), 7.34±7.27 (m, 10H, trityl), 7.25±7.19 (m, 7H,
0
trityl, 2H3 ), 7.02 (d, 1H, H5, Jˆ7.3 Hz), 6.93±6.86 (m, 3H,
13
0
0
2H2 , H4 ), 6.75 (t, 1H, H6, Jˆ8.1 Hz), 5.93 (d, 1H, H7,
0
Jˆ8.1 Hz). C NMR (CDCl3-d): 142.1 (C1 , C4), 142.0
(C2), 141.4 (trityl), 135.4 (C3a/C7a), 135.0 (C7a/C3a), 130.4
0
(C3 ), 129.2 (trityl), 128.1 (trityl), 128.0 (trityl), 123.1 (C6),
1
0
0
121.4 (C4 ), 119.0 (C2 ), 106.8 (C5/C7), 104.1 (C7/C5), 75.6
(trityl). MS (m/z): 451 (M), 351, 282, 243 (100%), 228, 209,
165, 141, 119, 84, 57.
1250, 1200. H NMR (CDCl3-d): 7.79 (s, 1H, H2), 7.25±
7.19 (m, 10H, trityl), 7.13±7.08 (m, 5H, trityl), 6.80 (t, 1H,
H6, Jˆ8.0 Hz), 6.52 (d, 1H, H5, Jˆ8.4 Hz), 6.08 (d, 1H, H7,
Jˆ7.5 Hz), 3.98 (m, 4H, 2CH2-O), 3.54 (m, 4H, 2CH2-N).
13C NMR (CDCl3-d): 143.5 (C4), 141.7 (C2), 141.2 (trityl),
136.7 (C3a/C7a), 136.0 (C7a/C3a), 129.9 (trityl), 128.0 (trityl),
127.9 (trityl), 122.8 (C6), 108.9 (C5/C7), 107.1 (C7/C5), 75.4
(trityl), 67.2 (2CH2-O), 50.6 (2CH2-N). MS (m/z): 445 (M),
243 (100%), 228, 203, 172, 165, 145, 118, 105, 91, 63.
1-(1-Tritylbenzimidazol-6-yl)piperazine, 9a. From 7b
(550 mg, 1.25 mmol), piperazine (441 mg, 5.01 mmol),
Cs2CO3 (572 mg, 1.75 mmol), Pd(OAc)2 (28 mg, 0.12
mmol), (^)-BINAP (241 mg, 0.38 mmol) and toluene
(12 mL) was obtained 9a (yield: 60%, white solid) after
chromatography using mixtures of toluene/EtOH/NH3 as
eluent. Rfˆ0.3 (toluene/EtOH/NH3, 9/1/0.1). mp: 136±
1398C. IR (CHCl3, cm21): 3400±3200, 3060, 2950, 1670,
1-(1-Tritylbenzimidazol-4-yl)-4-methylpiperazine, 4b. From
3 (150 mg, 0.34 mmol), 1-methylpiperazine (0.05 mL,
0.41 mmol), NaOtBu (47.5 mg, 0.48 mmol), Pd2dba3´CHCl3
(36 mg, 0.034 mmol) or Pd(OAc)2 (7.63 mg, 0.034 mmol),
dppp (22 mg, 0.05 mmol) and toluene (4 mL) was obtained
4b (yield: 97%, pale yellow solid) after chromatography
using mixtures of CHCl3/EtOH as eluent. Rfˆ0.3 (CHCl3).
mp: 217±2198C (CH2Cl2/hexane). IR (KBr, cm21): 3050±
3000, 1590, 1500, 1485, 1240, 1000, 700. 1H NMR (CDCl3-
d): 7.71 (s, 1H, H2), 7.23±7.19 (m, 10H, trityl), 7.12±7.09
(m, 5H, trityl), 6.70 (t, 1H, H6, Jˆ8.0 Hz), 6.46 (d, 1H, H5,
Jˆ7.8 Hz), 5.99 (d, 1H, H7, Jˆ8.3 Hz), 3.51 (m, 4H, 2CH2-
N), 2.63 (m, 4H, 2CH2-N), 2.26 (s, 3H, CH3-N). 13C NMR
(CDCl3-d): 143.5 (C4), 141.5 (C2), 141.2 (trityl), 136.5 (C3a/
C7a), 135.9 (C7a/C3a), 129.9 (trityl), 127.9 (trityl), 127.8
(trityl), 122.7 (C6), 108.6 (C5/C7), 107.3 (C7/C5), 75.2
(trityl), 55.3 (2CH2-N), 50.0 (2CH2-N), 46.2 (CH3-N).
Anal. calculated for C31H30N4: C, 81.19%; H, 6.59%; N,
12.22%. Found: C, 80.92%; H, 6.75%; N, 12.08%.
1
1600, 1490, 1230. H NMR (CDCl3-d): 7.74 (s, 1H, H2),
7.61 (d, 1H, H4, Jˆ8.7 Hz), 7.29±7.26 (m, 10H, trityl),
7.16±7.13 (m, 5H, trityl), 6.85 (dd, 1H, H5, Jˆ8.7,
1.8 Hz), 5.83 (d, 1H, H7, Jˆ1.8 Hz), 3.67 (br s, 1H, NH),
2.89 (m, 4H, 2CH2-N), 2.72 (m, 4H, 2CH2-N). 13C NMR
(CDCl3-d): 147.5 (C6), 143.2 (C2), 141.3 (trityl), 139.1
(C3a), 135.4 (C7a), 130.1 (trityl), 128.1 (trityl), 128.0 (trityl),
120.1 (C4), 116.2 (C5/C7), 114.6 (C7/C5), 77.2 (trityl), 50.8
(2CH2-N), 45.3 (2CH2-N). MS (m/z): 444 (M), 243 (100%),
228, 202, 165, 146, 120, 85, 71, 57.
1-(1-Tritylbenzimidazol-6-yl)-4-methylpiperazine, 9b. From
7b (300 mg, 0.68 mmol), 1-methylpiperazine (82 mg,
0.82 mmol), Cs2CO3 (312 mg, 0.95 mmol), Pd(OAc)2
(2 mg, 0.01 mmol), (^)-BINAP (25 mg, 0.04 mmol) and
toluene (4 mL) was obtained 9b (yield: 55%, white solid)
after chromatography using mixtures of toluene/EtOH/NH3
as eluent. Rfˆ0.3 (toluene/EtOH/NH3, 10/1/0.1). mp: 228±
2308C. IR (CHCl3, cm21): 3020, 2940, 2810, 1620, 1600,
1-(1-Tritylbenzimidazol-4-yl)piperazine, 4c. From
3
1
(1.0 g, 2.28 mmol), piperazine (1.2 g, 13.7 mmol), NaOtBu
(316 mg, 3.2 mmol), Pd2dba3´CHCl3 (47 mg, 0.046 mmol),
(^)-BINAP (82 mg, 0.136 mmol) and toluene (22 mL) was
1490, 1480, 1290, 1260. H NMR (CDCl3-d): 7.72 (s, 1H,
H2), 7.60 (d, 1H, H4, Jˆ9.0 Hz), 7.30±7.26 (m, 10H, trityl),
7.17±7.14 (m, 5H, trityl), 6.86 (dd, 1H, H5, Jˆ9.0, 2.1 Hz),

 Â
M. L. Lopez-Rodrõguez et al. / Tetrahedron 56 (2000) 3245±3253
3251
0 0 0
147.4 (C6 ), 143.1 (C2 ), 141.3 (trityl), 139.0 (C3 a), 135.4
5.83 (d, 1H, H7, Jˆ2.1 Hz), 3.20 (t, 4H, 2CH2-N,
Jˆ5.1 Hz), 2.57 (t, 4H, 2CH2-N, Jˆ5.1 Hz), 2.34 (s, 3H,
CH3-N). 13C NMR (CDCl3-d): 147.3 (C6), 143.1 (C2),
141.3 (trityl), 138.9 (C3a), 135.3 (C7a), 130.0 (trityl), 129.8
(trityl), 128.0 (trityl), 120.0 (C4), 114.6 (C7), 77.2 (trityl),
54.7 (2CH2-N), 50.2 (2CH2-N), 45.8 (CH3-N).
0
(C7 a), 130.2 (trityl), 129.0 (trityl), 127.9 (trityl), 120.1 (C4 ),
0
0
0
0
0
116.0 (C5 /C7 ), 114.6 (C7 /C5 ), 75.2 (trityl), 63.3 (C7a), 57.9
(CH2-N), 53.1 (2CH2-pip), 50.3 (2CH2-pip), 45.5 (C5), 38.8
(CH2-N), 27.5 (C7), 26.9 (C6), 26.0 (CH2), 23.9 (CH2). MS
(m/z): 639 (M), 396, 243 (100%), 215, 175, 165, 125, 86, 70,
56. Anal. calculated for C40H42N6O2: C, 75.21%; H, 6.63%;
N, 13.16%. Found: C, 75.47%; H, 6.89%; N, 13.02%.
2-[4-[4-(1-Tritylbenzimidazol-4-yl)piperazin-1-yl]butyl]-
1,3-dioxoperhydropyrrolo[1,2-c]imidazole, (^)-11. To a
solution of (^)-10 (62 mg, 0.23 mmol) and NEt3 (0.2 mL)
in acetonitrile (2 mL, 10 mL£mmol) was added 100 mg of
4c (0.23 mmol). The mixture was stirred at 608C during
24 h, and when TLC (toluene/EtOH/NH3, 9/1/0.1) showed
complete disappearance of the starting materials the solvent
was removed under vacuum. The resulting crude mixture
was dissolved in CH2Cl2 and washed with H2O. The organic
layer was dried over anhydrous Na2SO4, ®ltered and the
solvent was evaporated. (^)-11 (white solid) was obtained
in 80% yield after puri®cation by chromatography on silica
gel using mixtures of CHCl3/MeOH as eluent. Rfˆ0.3
(CHCl3/MeOH, 9/1). mp: 98±1008C. IR (KBr, cm21):
General procedure for trityl group removal
A solution of the corresponding (1-tritylbenzimidazolyl)-
piperazine (1 equiv.) in THF (7.5 mL£mmol), H2O
(7.5 mL£mmol) and AcOH (7.5 mL£mmol) was re¯uxed
for 3 h (TLC). After cooling, the mixture was brought to
pHˆ1±2 by addition of 1 M HCl, and then extracted with
EtOAc. The aqueous layer was basi®ed to pHˆ9±10 by
addition of solid K2CO3 and extracted with CH2Cl2. The
organic extracts were dried (Na2SO4) and the solvent was
evaporated under vacuum. Puri®cation of the crude was
performed by column chromatography using the appropriate
eluent.
3600±3400, 1775, 1710, 1590, 1490, 1440, 1410, 1235.
0
H NMR (CDCl3-d): 7.71 (s, 1H, H2 ), 7.25±7.13 (m,
1
0
10H, trityl), 7.12±7.08 (m, 5H, trityl), 6.70 (t, 1H, H6 ,
1-(Benzimidazol-4(7)-yl)-4-methylpiperazine, 13. From
4b (155 mg, 0.34 mmol) in THF (2.5 mL), H2O (2.5 mL)
and AcOH (2.5 mL) was obtained 13 (yield: 86%, yellow
solid) after chromatography using MeOH as eluent. Rfˆ0.3
(MeOH). mp: 71±738C (EtOAc/hexane). IR (CHCl3, cm21):
3500±3100, 1610, 1590, 1450, 1250, 1140, 1000. 1H NMR
(CDCl3-d): 10.20 (br s, NH), 7.95 (s, 1H, H2), 7.20±6.90 (m,
2H, H5, H7), 6.67 (d, 1H, H6, Jˆ7.4 Hz), 3.51 (s, 4H, 2CH2-
N), 2.62 (s, 4H, 2CH2-N), 2.31 (s, 3H, CH3-N). 13C NMR
(CDCl3-d): 142.9 (C4), 138.9 (C2), 135.9 (C3a/C7a), 134.1
(C7a/C3a), 123.5 (C6), 55.0 (2CH2-N), 50.1 (2CH2-N), 45.9
(CH3-N). MS (m/z): 216 (M, 100%), 201, 173, 160, 146,
132, 118, 90, 85, 70, 56. Anal. calculated for C12H16N4: C,
66.64%; H, 7.46%; N, 25.90%; Found: C, 66.46%; H, 7.34
%; N, 25.79%.
0
0
Jˆ8.0 Hz), 6.45 (d, 1H, H5 , Jˆ7.6 Hz), 5.99 (d, 1H, H7 ,
Jˆ8.0 Hz), 4.01 (dd, 1H, H7a, Jˆ9.0, 7.4 Hz), 3.8±3.5 (m,
7H, 1H5, CH2-N, 2CH2-pip), 3.24±3.11 (m, 1H, 1H5), 2.65
(br s, 4H, 2CH2-pip), 2.38 (t, 2H, CH2-N, Jˆ7.4 Hz), 2.20±
2.11 (m, 1H, 1H7), 2.07±1.98 (m, 2H, 2H6), 1.71±1.56 (m,
5H, 1H7, 2CH2). 13C NMR (CDCl3-d): 173.3 (C1), 160.2
0
0
0
(C3), 143.0 (C4 ), 141.0 (C2 ), 140.7 (trityl), 136.1 (C3 a/
0
C7 a), 135.3 (C7 a/C3 a), 129.4 (trityl), 127.4 (trityl), 127.3
0
0
0
0
0
0
0
(trityl), 122.3 (C6 ), 108.1 (C5 /C7 ), 106.8 (C7 /C5 ), 76.4
(trityl), 62.7 (C7a), 57.5 (CH2-N), 52.8 (2CH2-pip), 44.9
(2CH2-pip), 44.9 (C5), 38.2 (CH2-N), 27.0 (C7), 26.4 (C6),
25.5 (CH2), 23.3 (CH2). Anal. calculated for C40H42N6O2: C,
75.21%; H, 6.63%; N, 13.16%. Found: C, 75.47%; H,
6.62%; N, 13.32%.
2-[4-[4-(1-Tritylbenzimidazol-6-yl)piperazin-1-yl]butyl]-
1,3-dioxoperhydropyrrolo[1,2-c]imidazole, (^)-12. To a
solution of (^)-10 (160 mg, 0.56 mmol) and NEt3 (0.6 mL)
in acetonitrile (5 mL, 10 mL£mmol) was added 100 mg of
9c (0.23 mmol). The mixture was stirred at 608C during
19 h, and when TLC (EtOH) showed complete disappear-
ance of the starting materials the solvent was removed under
vacuum. The resulting crude mixture was dissolved in
CH2Cl2 and washed with H2O. The organic layer was
dried over anhydrous Na2SO4, ®ltered and the solvent was
evaporated. (^)-12 (white solid) was obtained in 63% yield
after puri®cation by chromatography on silica gel using
mixtures of EtOH/EtOAc as eluent. Rfˆ0.3 (CHCl3/
MeOH, 9/1). mp: 126±1288C (toluene). IR (CHCl3,
1-(Benzimidazol-4(7)-yl)piperazine, 14. From 4c (200 mg,
0.45 mmol) in THF (3.5 mL), H2O (3.5 mL) and AcOH
(3.5 mL) was obtained 14 (yield: 66%, yellow solid) after
chromatography using MeOH as eluent. Rfˆ0.2 (CHCl3/
MeOH/NH3, 3/3/0.1). mp: 132±1358C (EtOH/Et2O). IR
(KBr, cm21): 3600±3300, 3080, 2920, 1590, 1510, 1450,
1300. 1H NMR (CDCl3-d): 7.94 (s, 1H, H2), 7.18±7.08 (m,
2H, H5, H7), 6.66±6.60 (m, 1H, H6), 3.34 (m, 4H, 2CH2-N),
2.98 (m, 4H 2CH2-N). 13C NMR (CDCl3-d): 142.8 (C4),
138.8 (C2), 136.0 (C3a/C7a), 133.3 (C7a/C3a), 123.4 (C6),
108.2 (C5/C7), 106.5 (C7/C5), 51.3 (2CH2-N), 45.7 (2CH2-
N). Anal. calculated for C11H14N4: C, 65.32%; H, 6.98%; N,
27.70%; Found: C, 65.02%; H, 7.05 %; N, 27.62%.
cm21): 3670±3500, 3060, 2950, 1770, 1710, 1600, 1495,
1-(Benzimidazol-5(6)-yl)piperazine, 15. From 9a (138 mg,
0.31 mmol) in THF (2.3 mL), H2O (2.3 mL) and AcOH
(2.3 mL) was obtained 15 (yield: 58%, white solid) after
chromatography using mixtures of CHCl3/MeOH/NH3 as
eluent. Rfˆ0.2 (CHCl3/MeOH/NH3, 5/5/0.1). mp: 126±
1288C. IR (KBr, cm21): 3020±2960, 1710, 1640, 1600,
1
1450, 1275. H NMR (CDCl3-d): 7.72 (s, 1H, H2 ), 7.59
0
0
(d, 1H, H4 , Jˆ8.8 Hz), 7.24±7.17 (m, 10H, trityl), 7.12±
0
7.07 (m, 5H, trityl), 6.82 (dd, 1H, H5 , Jˆ8.8, 2.0 Hz), 5.82
0
(d, 1H, H7 , Jˆ2.0 Hz), 4.03 (dd, 1H, H7a, Jˆ9.1, 7.3 Hz),
3.70±3.56 (m, 1H, 1H5), 3.50±3.40 (m, 2H, CH2-N), 3.24±
3.11 (m, 1H, 1H5), 2.76±2.71 (m, 4H, 2CH2-pip), 2.43±2.40
(m, 4H, 2CH2-pip), 2.35±2.26 (m, 2H, CH2-N), 2.22±2.12
(m, 1H, 1H7), 2.10±1.98 (m, 2H, 2H6), 1.70±1.40 (m, 5H,
1H7, 2CH2). 13C NMR (CDCl3-d): 173.9 (C1), 160.8 (C3),
1
1570, 1520, 1450, 1260, 1220. H NMR (CDCl3-d): 7.92
(s, 1H, H2), 7.55 (d, 1H, H4, Jˆ9.2 Hz), 7.04 (d, 1H, H7,
Jˆ2.4 Hz), 6.98 (dd, 1H, H5, Jˆ9.2, 2.4 Hz), 3.15 (m, 4H,
2CH2-N), 2.99 (m, 4H, 2CH2-N), 1.64 (br s, 1H, NH). 13C

 Â
M. L. Lopez-Rodrõguez et al. / Tetrahedron 56 (2000) 3245±3253
3252
NMR (CDCl3-d): 146.5 (C6), 144.8 (C2), 141.4 (C3a), 134.8
(C7a), 116.1 (C5/C7), 113.1 (C7/C5), 100.8 (C4), 56.3 (2CH2-
N), 50.5 (2CH2-N). Anal. calculated for C11H14N4: C,
65.32%; H, 6.98%; N, 27.70%; Found: C, 65.30%; H,
7.16 %; N, 27.66%.
(CH2-N), 53.2 (2CH2-pip), 50.7 (2CH2-pip), 45.5 (C5),
38.7 (CH2-N), 27.5 (C7), 27.0 (C6), 25.9 (CH2), 23.7
(CH2). MS (m/z): 396 (M), 381, 250 (100%), 200, 172,
160, 145, 117, 98, 83, 70, 56. Anal. calculated for
C21H28N6O2: C, 63.62%; H, 7.12%; N, 21.20%; Found: C,
63.75%; H, 7.03%; N, 21.22%.
1-(Benzimidazol-5(6)-yl)-4-methylpiperazine, 16. From
9b (90 mg, 0.20 mmol) in THF (1.5 mL), H2O (1.5 mL)
and AcOH (1.5 mL) was obtained 16 (yield: 65%, white
solid) after chromatography using mixtures of CHCl3/
MeOH as eluent. Rfˆ0.2 (CHCl3/MeOH, 1/1). mp: 82±
848C. IR (KBr, cm21): 3020±2950, 1710, 1670, 1630,
Radioligand binding assays at 5-HT1A receptor
Male Sprague-Dawley rats (Rattus norvegicus albinus),
weighing 180±200 g, were killed by decapitation and the
brains rapidly removed and dissected. Tissues were stored at
2808C for subsequent use. Membrane suspensions were
centrifugated on a Beckman XL-90.
1
1590, 1510, 1450, 1220. H NMR (CDCl3-d): 7.92 (s, 1H,
H2), 7.53 (d, 1H, H4, Jˆ8.8 Hz), 7.05 (d, 1H, H7, Jˆ2.1 Hz),
7.01 (dd, 1H, H5, Jˆ8.8, 2.1 Hz), 3.17 (m, 4H, 2CH2-N),
2.61 (m, 4H, 2CH2-N), 2.35 (s, 3H, CH3-N). 13C NMR
(CDCl3-d): 148.5 (C6), 146.1 (C2), 140.1 (C3a), 135.1
(C7a), 116.3 (C5/C7), 115.3 (C7/C5), 103.1 (C4), 55.1
(2CH2-N), 50.7 (2CH2-N), 45.9 (CH3-N). Anal. calculated
for C12H16N4: C, 66.64%; H, 7.46%; N, 25.90%; Found: C,
66.81%; H, 7.28 %; N, 26.00%.
Binding assays were performed by a modi®cation of the
procedure previously described by Clark et al.17 The cere-
bral cortex was homogenized in 10 volumes of ice-cold
50 mM Tris±HCl buffer (pH 7.7 at 258C) and centrifuged
at 28000 g for 15 min. The membrane pellet was washed
once by resuspension and centrifugation. The resuspended
pellet was incubated at 378C for 10 min. Membranes were
then collected by centrifugation, and the ®nal pellet was
resuspended in 50 mM Tris±HCl, 5 mM MgSO4, and
0.5 mM EDTA buffer (pH 7.4 at 258C). Fractions of
100 mL of the ®nal membrane suspension (about 5 mg/mL
of protein) were incubated at 378C for 15 min with 0.6 nM
[3H]-8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetra-
lin) (133 Ci/mmol), in the presence or absence of several
concentrations (1025±10210 M) of the competing drug, in
a ®nal volume of 1.1 mL of assay buffer (50 mM Tris±HCl,
10 nM clonidine, 30 nM prazosin, pH 7.4 at 258C). Non-
speci®c binding was determined with 10 mM 5-HT and
represented less than 15% of the total binding. Competing
drug, nonspeci®c, total and radioligand bindings were
de®ned in triplicate. Incubation was terminated by rapid
vacuum ®ltration through Whatman GF/C ®lters, using a
Brandel harvester, and the ®lters were washed twice with
4 mL of ice-cold 50 mM Tris±HCl (pH 7.4 at 258C). The
®lters were placed in poly(ethylene) vials to which were
added 4 mL of a scintillation cocktail (Ecolite), and the
radioactivity bound to the ®lters was measured by liquid
scintillation spectrometry on a Packard 2500 TR instrument.
The data were analyzed by using an iterative curve-®tting
procedure (program Prism, Graphpad), which provided
IC50, Ki and r2 values for test compounds, Ki values
being calculated from the Cheng and Prusoff equation.18
The protein concentrations of the rat cerebral cortex were
determined by the method of Lowry20 with bovine serum
albumin as the standard.
2-[4-[4-(Benzimidazol-4(7)-yl)piperazin-1-yl]butyl]-1,3-
dioxoperhydropyrrolo[1,2-c]imidazole, (^)-17. From
(^)-11 (110 mg, 0.24 mmol) in THF (1.8 mL), H2O
(1.8 mL) and AcOH (1.8 mL) was obtained (^)-17 (yield:
85%, white solid) after chromatography using mixtures of
CHCl3/MeOH as eluent. Rfˆ0.2 (CHCl3/EtOH, 9/1). mp:
160±1638C (acetone/hexane). IR (CHCl3, cm21): 3450±
3100, 1770, 1705, 1610, 1485, 1350, 1300. 1H NMR
0
0
(CDCl3-d): 7.96 (s, 1H, H2 ), 7.20±7.08 (m, 2H, H5 , H7 ),
0
0
6.66 (d, 1H, H6 , Jˆ6.9 Hz), 4.05 (t, 1H, H7a, Jˆ8.4 Hz),
3.70±3.61 (m, 1H, 1H5), 3.47 (m, 6H, CH2-N, 2CH2-pip),
3.24±3.18 (m, 1H, 1H5), 2.70 (br s, 4H, 2CH2-pip), 2.44 (t,
2H, CH2-N, Jˆ7.5 Hz), 2.24±2.19 (m, 1H, 1H7), 2.10±2.01
(m, 2H, 2H6), 1.70±1.50 (m, 5H, 1H7, 2CH2). 13C NMR
0
(CDCl3-d): 174.0 (C1), 160.8 (C3), 142.6 (C4 ), 138.5
0
(C2 ), 135.9 (C3 a/C7 a), 133.5 (C7 a/C3 a), 120.6 (C6 ), 108.7
0
0
0
0
0
0
0
0
0
(C5 /C7 ), 106.5 (C7 /C5 ), 63.3 (C7a), 57.9 (CH2-N), 53.1
(2CH2-pip), 50.0 (2CH2-pip), 45.5 (C5), 38.8 (CH2-N),
27.5 (C7), 27.0 (C6), 26.0 (CH2), 23.6 (CH2). MS (m/z):
396 (M), 379, 250, 237, 215, 200, 187, 173, 146, 132,
118, 98, 83, 70, 55. Anal. calculated for C21H28N6O2: C,
63.62%; H, 7.12%; N, 21.20%; Found: C, 63.59%; H,
7.15%; N, 21.10%.
2-[4-[4-(Benzimidazol-5(6)-yl)piperazin-1-yl]butyl]-1,3-
dioxoperhydropyrrolo[1,2-c]imidazole, (^)-18. From
(^)-12 (54 mg, 0.086 mmol) in THF (0.7 mL), H2O
(0.7 mL) and AcOH (0.7 mL) was obtained (^)-18 (yield:
65%, white solid) after chromatography using mixtures of
CHCl3/EtOH as eluent. Rfˆ0.2 (CHCl3/EtOH, 9/1). mp:
138±1408C (toluene). IR (KBr, cm21): 3400±3200, 1770,
Acknowledgements
1
1710, 1590, 1450, 1420. H NMR (CDCl3-d): 7.94 (s, 1H,
0
0
0
H2 ) 7.51 (d, 1H, H4 , Jˆ8.7 Hz), 7.00 (m, 1H, H5 ), 6.95 (d,
This work was supported by DGICYT (Grant No. PB97-
0282) and by CAM (Grant No. 08.5/0046/98). We also
thank CAM for a postdoctoral grant to David Ayala, and
UCM for a predoctoral grant to Marta Murcia.
0
1H, H7 , Jˆ1.8 Hz), 4.12±4.02 (m, 1H, H7a), 3.69±3.58 (m,
1H, 1H5), 3.50±3.46 (m, 2H, CH2-N), 3.27±3.17 (m, 1H,
1H5), 3.16±3.10 (m, 4H, 2CH2-pip), 2.60±2.55 (m, 4H,
2CH2-pip), 2.43±2.37 (m, 2H, CH2-N), 2.28±2.17 (m, 1H,
1H7), 2.09±2.00 (m, 2H, 2H6), 1.68±1.48 (m, 5H, 1H7,
2CH2). 13C NMR (CDCl3-d): 174.0 (C1), 160.8 (C3),
References
0
148.4 (C6 ), 140.1 (C2 ), 139.5 (C3 a), 135.5 (C7 a), 116.8
0
0
0
0
(C5 /C7 ), 115.3 (C7 /C5 ), 101.3 (C4 ), 63.3 (C7a), 57.8
0
0
0
0
È
1. (a) Baumgarten, H. G., Gothert, M., Eds. Serotoninergic

 Â
M. L. Lopez-Rodrõguez et al. / Tetrahedron 56 (2000) 3245±3253
3253
Neurons and 5-HT Receptors in the CNS; Springer-Verlag: Berlin,
1997. (b) Winjgaarden, I. V.; Soudijn, W.; Tulp, M. Th. M. 5-HT1A
Receptor Ligands. In Serotonin Receptors and their Ligands;
Olivier, B., van Wijngaarden, I., Soudijn, W., Eds.; Elsevier:
Amsterdam, 1997.
E.; Dence, C. S.; McCarthy, T. J.; Welch, M. J. Tetrahedron Lett.
1996, 37, 319.
9. For some representative papers in this ®eld, see: (a) Guram,
A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1348. (b) Sadighi, J. P.; Singer, R. A.; Buchwald,
S. L. J. Am. Chem. Soc. 1998, 120, 4960. (c) Singer, R. A.;
Buchwald, S. L. Tetrahedron Lett. 1999, 40, 1095. (d) Louie, J.;
Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609. (e) Hamann, B. C.;
Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369. (f) Ward, Y. D.;
Farina, V. Tetrahedron Lett. 1996, 37, 6993. For recent reviews in
this area, see: (g) Hartwig, J. F. Angew. Chem., Int. Ed. Engl. 1998,
37, 2046. (h) Frost, C. G.; MendoncËa, P. J. Chem. Soc., Perkin
Trans. 1 1998, 2615. (i) Bel®eld, A. J.; Brown, G. R.; Foubister,
A. J. Tetrahedron 1999, 55, 11399. (j) Harris, M. C.; Geis, O.;
Buchwald, S. L. J. Org. Chem. 1999, 64, 6019.
2. (a) Semkova, I.; Wolz, P.; Krieglstein, J. Eur. J. Pharmacol.
1998, 359, 251. (b) Suchanek, B.; Struppeck, H.; Fahring, T. Eur.
J. Pharmacol. 1998, 355, 95.
Â
Â
Â
3. (a) Lopez-Rodrõguez, M. L.; Rosado, M. L.; Benhamu, B.;
Morcillo, M. J.; Sanz, A. M.; Orensanz, L.; Beneytez, M. E.;
Fuentes, J. A.; Manzanares, J. J. Med. Chem. 1996, 39, 4439.
  Â
(b) Lopez-Rodrõguez, M. L.; Morcillo, M. J.; Fernandez, E.;
Porras, E.; Murcia, M.; Sanz, A. M.; Orensanz, L. J. Med. Chem.
Â
1997, 40, 2653. (c) Lopez-Rodrõguez, M. L.; Morcillo, M. J.;
Â
Â
Rovat, T. K.; Fernandez, E.; Sanz, A. M.; Orensanz, L. Bioorg.
Â
Med. Chem. Lett. 1998, 8, 581. (d) Lopez-Rodrõguez, M. L.;
Â
10. Other arylpiperazines have been obtained by this method
recently, see: (a) Morita, S.; Kitano, K.; Matsubara, J.; Ohtani,
T.; Kawano, Y.; Otsubo, K.; Uchida, M. Tetrahedron 1998, 54,
4811. (b) Hong, Y.; Tanoury, G. J.; Wilkinson, H. S.; Bakale, R. P.;
Wald, S. A.; Senanakaye, C. H. Tetrahedron Lett. 1997, 38, 5607.
(c) Zhao, S.-H.; Miller, A. K.; Berger, J.; Flippin, L. A. Tetrahedron
Lett. 1996, 37, 4463. (d) Nishiyama, M.; Yamamoto, T.; Koie, Y.
Tetrahedron Lett. 1998, 39, 617. (e) Kerrigan, F.; Martin, C.;
Thomas, G. H. Tetrahedron Lett. 1998, 39, 2219. (f) Tanoury,
G. J.; Senanayake, C. H.; Hett, R.; Kuhn, A. M.; Kessler, D. W.;
Wald, S. A. Tetrahedron Lett. 1998, 39, 6845. (g) Wolfe, J. P.;
Buchwald, S. L. J. Org. Chem. 1997, 62, 1264.
Â
Morcillo, M. J.; Rovat, T. K.; Fernandez, E.; Vicente, B.; Sanz,
Â
A. M.; Hernandez, M.; Orensanz, L. J. Med. Chem. 1999, 42, 36.
Â
Â
Â
(e) Lopez-Rodrõguez, M. L.; Morcillo, M. J.; Fernandez, E.;
Rosado, M. L.; Orensanz, L.; Beneytez, M. E.; Manzanares, J.;
Fuentes, J. A.; Schaper, K. J. Bioorg. Med. Chem. Lett. 1999, 9,
1679.
 Â
4. Lopez-Rodrõguez, M. L.; Rosado, M. L.; Benhamu, B.;
Â
Â
Morcillo, M. J.; Fernandez, E.; Schaper, K. J. J. Med. Chem.
1997, 40, 1648.
5. (a) Lehninger, A. D.; Nelson, D. L.; Cox, M. M. Principios de
Â
Bioquõmica; Omega, 1995. (b) Katz, B. A.; Clark, J. M.; Finer-
Moore, J. S.; Jenkins, T. E.; Johnson, C. R.; Ross, M. J.; Luong, C.;
Moore, W. R.; Stroud, R. M. Nature 1998, 391, 608. (c) Hansch,
C.; Sammes, P. G.; Taylor, J. B. Comprehensive Medicinal
Chemistry; Pergamon: Oxford, 1990; Vol. 6. (d) Im, W. B.; Sih,
J. C.; Blakeman, D. P.; McGrath, J. P. J. Biol. Chem. 1985, 260,
4591. (e) Yamada, S.; Goto, T.; Shimanuki, E.; Narita, S. Chem.
Pharm. Bull. 1994, 42, 718.
11. (a) Dandegaonker, S. H.; Revankar, G. R. Chem. Abstr. 1965,
59, 10023e. (b) Tallec, A. Ann. Chim. 1968, 3, 164. (c) Montanari,
F.; Passerini, R. Boll. Fac. Chim. Ind. Bolog. 1953, 11, 42.
12. 5-(6)-Bromobenzimidazole was obtained in a single step:
Mistry, A. G.; Smith, K.; Bye, M. R. Tetrahedron Lett. 1986, 27,
1051.
13. Wilson, J. G.; Hunt, F. C. Aust. J. Chem. 1983, 36, 2317.
14. For isomer 2a irradiation of the benzyl CH2 signal caused
NOE enhancement of three signals, assigned to H2 (1.9%), H7
(2.5%) and phenyl (2.5%). In the case of isomer 2b, irradiation
of the same signal caused NOE enhancement of only two signals,
assigned to H2 (1.1%) and phenyl (2.0%), and no effect on any
other benzimidazole proton was observed.
6. (a) Peng, Z.; Geise, H. J.; Zhou, X.; Peng, B.; Carleer, R.;
Dommisse, R. Liebigs Ann. Recueil 1997, 27. (b) Cassidy, P. E.
In Thermally Stable Polymers Synthesis and Properties; Dekker,
M., Ed.; Academic: New York, 1980. (c) Tant, M. R.; Connell,
J. W. In High Temperature Properties and Applications of Poly-
meric Materials; McManus, H. L., Ed.; ACS Symposium Series
603, American Chemical Society: Washington, 1994.
15. (a) Ma, D.; Yao, J. Tetrahedron: Asymmetry 1996, 7, 3075.
(b) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc.
1998, 120, 12459.
7. For a recent review of the synthetic methods to obtain benz-
imidazoles, see: (a) Grimmett, M. R. In Imidazole and Benz-
imidazole Synthesis; Meth-Cohn, O., Ed.; Academic: New York,
1997. For recent papers on the synthesis of functionalized benz-
imidazole rings, see: (b) Edlin, C. D.; Parker, D. Tetrahedron Lett.
16. Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991.
17. Clark, R. D.; Weinhardt, K. K.; Berger, J.; Fisher, L. E.;
Brown, C. M.; MacKinnon, A. C.; Kilpatrick, A. T.; Spedding,
M. J. Med. Chem. 1990, 33, 633.
È
1998, 39, 2797. (c) Langer, P., Doring, M. Synlett 1998, 399.
(d) Meziane, M. A. A.; Rahmouni, M.; Bazureau, J. P.; Hamelin,
J. Synthesis 1998, 967. (e) Konstantinova, L. S.; Rakitin, O. A.;
Rees, C. W.; Sivadasan, S.; Torroba, T. Tetrahedron 1998, 54,
9639. (f) Mayer, J. P.; Lewis, G. S.; McGee, C.; Bankaitis-
Davis, D. Tetrahedron Lett. 1998, 39, 6655. (g) Blettner, C. G.;
18. Cheng, Y. C.; Prusoff, W. H. Biochem. Pharmacol. 1973, 22,
3099.
19. 6-Iodo-1-tritylbenzimidazole (8b) was partially characterized
but not isolated from the crude mixture because it was not
necessary to obtain the target benzimidazolylpiperazines.
20. Lowry, O. H.; Rosebrough, N. J.; Farr, A. L.; Randall, R. J.
J. Biol. Chem. 1951, 193, 265.
È
Konig, W. A.; Ruhter, G.; Stenzel, W.; Schotten, T. Synlett 1999,
307.
È
8. (a) Parcell, R. F. Chem. Abstr. 1960, 54, 9967b±9967i.
(b) Parke, Davis & Co. Chem. Abstr. 1961, 55, 8444h. (c) Mishani,