Straightforward three-component synthesis of diarylmethylpiperazines and 1,2-diarylethylpiperazines

Article abstract of DOI:10.1016/j.tet.2007.02.086

Several functionalized diarylmethylpiperazines and 1,2-diarylethylpiperazines have been synthesized in moderate to high yield according to a one-step three-component coupling between an aromatic or a benzylic organozinc reagent, a piperazine derivative, and an aromatic aldehyde. The procedure can be extended to the synthesis of benzylpiperazine derivatives or β-arylethylpiperazines toward the use of paraformaldehyde or aliphatic aldehydes.

Full text of DOI:10.1016/j.tet.2007.02.086

Tetrahedron 63 (2007) 3672–3681
Straightforward three-component synthesis of
diarylmethylpiperazines and 1,2-diarylethylpiperazines
*
Stephane Sengmany, Erwan Le Gall, Cedric Le Jean, Michel Troupel and Jean-Yves Nedelec
ꢀ
ꢀ
ꢀ ꢀ
´
Laboratoire d’Electrochimie, Catalyse et Syntheꢁse Organique, LECSO, CNRS-Universite Paris 12 Val de Marne, UMR 7582,
2-8 rue Henri Dunant, 94320 Thiais, France
Received 19 January 2007; accepted 21 February 2007
Available online 24 February 2007
Abstract—Several functionalized diarylmethylpiperazines and 1,2-diarylethylpiperazines have been synthesized in moderate to high yield
according to a one-step three-component coupling between an aromatic or a benzylic organozinc reagent, a piperazine derivative, and an
aromatic aldehyde. The procedure can be extended to the synthesis of benzylpiperazine derivatives or b-arylethylpiperazines toward the
use of paraformaldehyde or aliphatic aldehydes.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
procedures related to the aromatic Mannich10 or the
Petasis11 reaction have not been employed for the synthesis
of functionalized diarylmethylpiperazines. We described
recently a versatile three-component coupling among sec-
ondary amines, aromatic aldehydes, and aromatic organo-
zinc reagents providing diarylmethylamines in high
yields.12 On the basis of an experiment featuring N-methyl-
piperazine as the amine,12b it was mentioned that this proce-
dure should be relevant for the preparation of functionalized
diarylmethylpiperazines. In the present paper, we describe
the extension of this reaction to the synthesis of several
diarylmethylpiperazines but we also explore other possibil-
ities provided by this methodology like synthesis of 1,2-
diarylethylpiperazines by using a benzylzinc reagent as the
nucleophile. We also mention herein the possible use of
paraformaldehyde for the synthesis of benzylpiperazines
and b-arylethylpiperazines.
Diarylmethylpiperazines constitute an important class of
compounds, which exhibit various biological activities rang-
ing from antiemetic to anxiolytic, opioid agonists, or brady-
kinin antagonists. However, they are more commonly known
for their activity as antihistamine agents and the synthesis of
third-generation histamine H1 antagonists like levocetiri-
zine has been particularly studied during the last years.1–3
Nevertheless, there was alongside a particular emphasis on
the synthesis of diarylmethylpiperazines for their activity
as opioid agonists, and even if numerous structures have
been thoroughly assessed,4 only few procedures allowing
the construction of the diarylmethylpiperazine core are
available. For instance, Delorme et al. employed Corey’s
reductive chromium-mediated procedure2 for the enantio-
selective synthesis of the opioid delta receptor ligand
4-((4-benzylpiperazin-1-yl)(phenyl)methyl)-N,N-diethyl-
benzamide5 whereas Bishop and McNutt6 or Rice et al.7
described the diastereoselective syntheses of the opioid ago-
nists BW373U86 or SNC-80 analogues toward nucleophilic
displacement of a-benzotriazoylamines8 using aromatic
Grignard reagents. Numerous diarylmethylpiperazines were
also synthesized using a multi-step reductive procedure
starting from carbonyl compounds and involving the final
displacement of benzhydryl halides by piperazines.9
2. Results and discussion
In the first part of our study, we turned our attention to the
synthesis of diarylmethylpiperazines starting either from 4-
methylpiperazine or 4-phenylpiperazine, aromatic aldehydes,
and functionalized arylzinc reagents, which were prepared
in acetonitrile according to a previously described proce-
dure.12b,13 These piperazine derivatives were chosen as
model compounds for their nitrogen substituent, which ap-
peared sufficiently simple and representative. In addition,
preliminary experiments showed that these substrates react
in a same manner, providing coupling products in similar
yields.
Surprisingly, despite the fact that multi-component pro-
cesses constitute a very attractive tool of organic synthesis,
Keywords: Diarylmethylpiperazines; 1,2-Diarylethylpiperazines; Three-
component reaction; Arylzinc reagents; Benzylzinc reagents.
* Corresponding author. Tel.: +33 (0) 149781135; fax: +33 (0) 149781148;
e-mail: legall@glvt-cnrs.fr
As described in previous papers,12 two procedures were used
for the coupling. The simplest protocol (coupling method A)
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.086

S. Sengmany et al. / Tetrahedron 63 (2007) 3672–3681
3673
consisted of the addition of the aldehyde and the piperazine
derivative to the solution of the organozinc reagent in aceto-
nitrile. This procedure was particularly adapted to reactions
involving stable electron-rich organozinc compounds. Sur-
prisingly, contrary to what we reported in our previous study,
cuprous iodide did not lead to significant improvements of
yields and reaction times. Thus, in a simplification aim, we
abandoned the addition of cuprous salts to the organozinc re-
agent before the introduction of both other substrates. Forthe
coupling of unstable electron-deficient organozinc reagents,
prone to dimerization during the course of time, the procedure
was modified according to method B in which theorganozinc-
containing acetonitrile solution was added dropwise into
a pre-heated mixture of aromatic aldehyde and piperazine
derivative in acetonitrile. These conditions were chosen in or-
der to favor the production of a presumed iminium ion equiv-
alent, which might instantly been trapped by the organozinc
reagent thus preventing possibilities of degradation.
In the first series of experiments, we undertook to scan the
arylzinc scope of the reaction. Functionalized aromatic orga-
nozinc reagents were then allowed to react with 4-methyl-
piperazine and benzaldehyde.
Results are presented in Table 1.
Yields are moderate but it appears that a good range of func-
tionalities are tolerated by the reaction. It is also noticeable
Table 1. Scope of arylzinc reagent
Me
N
Me
N
Ar ZnBr
CHO
N
+
+
MeCN
N
H
Ar
Entry
Organozinc reagent
Reaction time (h)
Product
Isolated yielda (%)
Me
N
ZnBr
O
O
1
18b
1a
1b
1c
1d
59
N
O
O
Me
N
ZnBr
2
3
4
18,b 18c
16,b 18c
16c
34, 28
21, 28
29
N
Cl
Cl
Me
N
OEt
ZnBr
EtO
OEt
N
EtO
Me
N
MeO2C
ZnBr
N
MeO2C
Me
N
ZnBr
N
5
2c
1e
48
F3C
F3C
Yields based on initial N-methylpiperazine and benzaldehyde amounts (10 mmol).
Coupling method A: addition of N-methylpiperazine (10 mmol) and benzaldehyde (10 mmol) to the filtered organozinc solution (>20 mmol) at room
a
b
temperature.
Coupling method B: the organozinc-containing solution (>20 mmol) was added dropwise into the pre-heated mixture (70 ꢀC) of N-methylpiperazine and
benzaldehyde in acetonitrile (15 mL).
c

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S. Sengmany et al. / Tetrahedron 63 (2007) 3672–3681
Table 2. Scope of aldehyde
that organozinc reagents bearing protected aldehyde func-
tions can be employed in the procedure (entry 3 of Table
1). In some cases, we postulated that yields might be en-
hanced by a simple exchange of functionalities between
the organozinc reagent and the benzaldehyde derivative.
This principle was applied to the synthesis of chlorcyclizine
1b in which the reaction yield was enhanced from approxi-
mately 30% (entry 2 of Table 1) to 54% by simply reacting
4-methylpiperazine with phenylzinc bromide and 4-chloro-
benzaldehyde instead of 4-chlorophenylzinc bromide and
benzaldehyde (Scheme 1).
Ph
N
Ph
N
MeO
ZnBr
Ar CHO
+
N
+
MeCN
N
H
Ar
OMe
Entry Aldehyde Reaction
time (h)
Product
Isolated
yielda (%)
Ph
N
O
Me
2b
2b
3b
3c
N
2a 86
2b 89
2c 67
Me
N
N
1
2
3
4
1b
Method A
MeCN
ZnBr
Cl
+
CHO
+
N
N
H
OMe
OMe
Ph
N
Cl
O
54 %
N
Scheme 1.
S
S
In a second series of experiments, we examined the behavior
of various aldehydes in the coupling procedure. Aromatic or
heteroaromatic aldehydes were reacted with 4-phenylpiper-
azine and 4-methoxyphenylzinc bromide, taken as model
reagents.
Ph
N
O
F
N
F
Results are displayed in Table 2.
OMe
Ph
N
Results are satisfactory with a good range of functionalized
aromatic or heteroaromatic aldehydes.
O
2d 55
N
A supplementary experiment was realized with a non-
aromatic aldehyde, paraformaldehyde, which was allowed
to react with 4-methoxyphenylzinc bromide and N-phenyl-
piperazine for 16 h at 45 ꢀC providing the coupling product
in 69% yield (Scheme 2).
NC
NC
OMe
Ph
N
O
5
2c
N
2e 61
O2N
This feature gives rise to the possible formation of numerous
substituted benzylamines by coupling amines with function-
alized arylzinc reagents and paraformaldehyde. Further de-
velopments of this quite interesting result may be envisaged.
O2N
OMe
a
Yields based on initial N-phenylpiperazine and aldehyde amounts
(10 mmol).
Coupling method A: addition of N-phenylpiperazine (10 mmol) and alde-
hyde (10 mmol) to the filtered 4-methoxyphenylzinc bromide solution
(>20 mmol) at room temperature.
Coupling method B: the 4-methoxyphenylzinc bromide-containing solu-
tion (>20 mmol) was added dropwise into the pre-heated mixture (70 ꢀC)
of N-phenylpiperazine and aldehyde in acetonitrile (15 mL).
In the second part of the study, we investigated the impact of
the nitrogen substituent of piperazine derivatives by means
of experiments featuring benzaldehyde, 4-substituted piper-
azines, and benzylzinc bromide. This reagent was used
instead of an arylzinc reagent because it gave the opportu-
nity to obtain a new structural unit in the form of 1,2-diaryl-
ethylamine core.14 For the synthesis of benzylzinc bromide,
performed in acetonitrile as the solvent, we employed a very
simple and efficient procedure derived from syntheses
previously reported with tetrahydrofuran.15
b
c
Ph
N
Results are presented in Table 3.
Ph
N
2f
Method A, 45 °C
MeCN
The reaction proceeds fairly well with piperazine derivatives
bearing either aromatic, heteroaromatic, or aliphatic substi-
tuents. The presence of an oxygenated side chain does not
prevent the coupling (entry 2 of Table 3). This feature ap-
pears rather interesting. Indeed, multi-purpose bioactive
compounds like hydroxyzine bear this substituent and might
MeO
ZnBr
(CH O)n
+
2
N
+
N
H
OMe
69%
Scheme 2.

S. Sengmany et al. / Tetrahedron 63 (2007) 3672–3681
3675
Table 3. Scope of piperazine derivative
Table 3. (continued)
R
N
Entry
Piperazine
Reaction
time (h)
Product
Isolated
yielda (%)
R
N
BOC
N
CHO
N
+
+
MeCN
BOC
N
ZnBr
N
H
4b
7
3g
78
N
N
H
Entry
Piperazine
Reaction
time (h)
Product
Isolated
yielda (%)
a
Yields based on initial piperazine derivative and benzaldehyde amounts
(10 mmol).
Coupling method A: addition of piperazine derivative (10 mmol) and
benzaldehyde (10 mmol) to the filtered benzylzinc bromide solution
(>20 mmol) at room temperature.
b
c
N
N
1
3b
4c
3c
4b
4b
4b
3a 79
N
Coupling method A was followed, but amounts of piperazine derivative
and benzaldehyde are 7.5 mmol.
N
H
be easily synthesized starting from 4-chlorobenzaldehyde,
phenylzinc bromide, and commercial 2-(2-(piperazine-1-yl)-
ethoxy)ethanol.
OH
O
N
OH
O
N
2
3
4
5
6
3b 80
The result presented in entry 7 of Table 3 shows that the
N-Boc protected piperazine also undergoes the reaction
whereas preliminary experiments had revealed that, as a pos-
sible consequence of its very low solubility in acetonitrile,
piperazine itself does not provide coupling products, even
under thermal activation.
N
N
H
Cl
It is worth noting that for the coupling of piperazine deriva-
tives bearing one acidic hydrogen (entries 2 and 3 of Table
3), at least 3 equiv of the organozinc reagent was required
for the coupling reaction to proceed. This result is consistent
with the fact that in the absence of additional acidic hydro-
gens on substrates, 2 equiv of the organozinc reagent is
necessary, as mentioned in our previous study.12
Cl
N
N
N
3c 55
3d 76
3e 78
3f 84
. HCl
N
H
Me
N
In a general manner, it can be noted that benzylzinc bromide,
prepared by stirring benzyl bromide and zinc dust in aceto-
nitrile for several minutes at room temperature, reacts as
well as aromatic organozinc reagents.16 In addition to
what we had mentioned in a previous paper,12b this ob-
servation constitutes a further indication that cobalt salts,
which are still present in the reaction medium when
arylzinc compounds are employed in the three-component
coupling,17 are not required for the reaction to proceed. In
our preceding study,12b we mentioned that commercial tetra-
hydrofuran solutions of aromatic organozinc reagents18 are
inefficient in the three-component coupling. In order to ver-
ify that arylzinc reagents are particularly ineffective when
used as tetrahydrofuran solutions, we prepared 4-methoxy-
phenylzinc bromide in tetrahydrofuran, starting from 4-bro-
moanisole, by a metal–halogen exchange using butyllithium
and a transmetalation by means of zinc chloride.19 This or-
ganozinc reagent did not lead to satisfactory results, only
traces of its coupling product with benzaldehyde and piper-
idine being detected in the reaction mixture, even after
several hours stirring at room temperature. Thus, in order
to verify the hypothesis that the choice of the solvent is of
crucial importance for the reaction, and particularly that tet-
rahydrofuran is able to minimize the coupling, we prepared
benzylzinc bromide in tetrahydrofuran instead of acetoni-
trile. Surprisingly, this reagent gave rise to the coupling
Me
N
N
N
H
N
N
N
N
N
N
H
N
N
N
N
N
N
N
N
H
(continued)

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S. Sengmany et al. / Tetrahedron 63 (2007) 3672–3681
Table 4. Coupling of benzylzinc bromide with some aldehydes and piperazine derivatives
R1
N
R1
N
R2 CHO
N
+
+
MeCN
ZnBr
N
H
R2
Entry
1
Piperazine
Aldehyde
Reaction time (h)
Product
Isolated yield (%)a
Ph
N
Ph
N
O
3b
4a
94
N
N
H
Me
N
Me
N
O
2
3c
4b
60
89
NO2
N
N
H
NO2
Ph
N
Ph
N
3
(CH2O)n
3d
4c
N
N
H
a
Yields based on initial piperazine derivative and aldehyde amounts (10 mmol).
Coupling method A: addition of piperazine derivative (10 mmol) and aldehyde (10 mmol) to the filtered benzylzinc bromide solution (>20 mmol) at room
temperature.
Coupling method B: the benzylzinc bromide-containing solution (>20 mmol) was added dropwise into the pre-heated mixture (70 ꢀC) of piperazine deriv-
ative and aldehyde in acetonitrile (15 mL).
Coupling method A was followed, but heating at 45 ꢀC.
b
c
d
product in a similar GC yield to that observed in acetonitrile.
These quite singular results are not explained to date.
can imagine that numerous functionalized b-arylethyl-
amines could be easily accessible by reacting functionalized
benzylzinc reagents and amines in the presence of
paraformaldehyde.
In a further will to demonstrate that aldehydes other than
benzaldehyde, especially enolisable aldehydes, undergo the
coupling when allowed to react with benzylzinc bromide
and piperazine derivatives, we realized another series of
experiments.
3. Conclusion
In conclusion, results reported in this study show that orga-
nozinc reagents are very convenient nucleophiles in the
three-component Mannich-type synthesis of piperazine de-
rivatives. Arylzinc and benzylzinc reagents are efficient in
the process. Their reaction with aromatic aldehydes as
well as enolisable aldehydes or paraformaldehyde allows
the formation of several subunits like the diarylmethyl-
amine, the 1,2-diarylethylamine, the b-arylethylamine, and
the benzylamine core. Considering that last-generation
piperazine-based drugs are generally available as a single
enantiomer, many efforts are now directed toward enantio-
selective syntheses of diarylmethylamines, which may
likely be realized by means of chiral mediators.
Results are shown in Table 4.
As attested by entry 1 of Table 4, an enolisable aldehyde like
heptanal can be very efficient in the process. This result is
rather interesting when the introduction of a saturated side
chain at the a position to the nitrogen is expected. Numerous
a-alkyl-b-arylethylamines might thus be prepared starting
from aliphatic aldehydes, amines, and functionalized benzyl-
zinc reagents.
The association of a benzylzinc reagent and paraformalde-
hyde allows the formation of the b-arylethylpiperazine sub-
unit (entry 3 of Table 4). It should be noted that a two-step
one-pot procedure relying on the addition of benzylzinc bro-
mides to iminium salts preformed by the reaction of amine
salts with paraformaldehyde had already been employed
by Ku et al. for the efficient synthesis of several b-arylethyl-
amines.20 In comparison, our procedure appears more attrac-
tive by the fact that the reaction occurs more quickly and
does not require to preform iminium ions since they are
presumably evolved in situ without further handling. One
4. Experimental
4.1. General
Solvents (acetonitrile and tetrahydrofuran in analytical
grades) and starting materials were purchased from com-
mercial suppliers and used without further purification. All
reactions were monitored by gas chromatography (GC) using

S. Sengmany et al. / Tetrahedron 63 (2007) 3672–3681
3677
a Varian 3400 chromatograph equipped with a 5 m SGE BP1
column. Melting points (mp) were determined on a Kofler
apparatus and were not corrected. Infrared spectra were
recorded in CHCl3 on a Perkin–Elmer Spectrum BX FTIR.
NMR spectra were recorded in CDCl3 at 400 MHz (1H),
100 MHz (13C), and 376 MHz (19F) on a Bruker Avance II
400 spectrometer. Data are presented as follows: chemical
shift (multiplicity, coupling constants, integration). Mass
spectra were recorded on a Finnigan GC/MS GCQ spectro-
meter. Elemental analyses were realized at the ‘Service
central d’analyses’, Vernaison, France. Compounds labeled
by asterisk (*) are, to the best of our knowledge, new
compounds.
the aldehyde (10 mmol) and the piperazine derivative
(10 mmol) in acetonitrile (15 mL). Stirring was continued
for additional 2 h at 70 ꢀC.
4.6. Typical acid–base work-upy
The reaction mixture was poured into a 150 mL of a 5%
sodium hydroxide aqueous solution and extracted with di-
chloromethane (2ꢁ100 mL). The combined organic frac-
tions were dried over sodium sulfate and concentrated to
dryness. Diethyl ether (150 mL) was added to the residue
and after complete dissolution, concentrated sulfuric acid
(w1 mL) was added carefully to the vigorously stirred solu-
tion and allowed to react for 5 min. The resulting ammonium
salt was filtered and washed with diethyl ether (2ꢁ50 mL).
The solid was then poured, under stirring, into a mixture
of a 5% sodium hydroxide aqueous solution (100 mL) and
dichloromethane (100 mL). After complete dissolution, the
aqueous phase was extracted with additional 100 mL of di-
chloromethane. The combined organic fractions were dried
over sodium sulfate and concentrated to dryness. In the
case of liquid crude products, an additional chromatographic
purification was performed over silica gel (SDS 70–200 mm)
using a solvent gradient from pentane/diethyl ether: 90/10 to
diethyl ether/methanol: 90/10 whereas solids were recrystal-
lized using pentane/diethyl ether mixtures.
4.2. Typical experimental procedure for the synthesis
of organozinc reagents
A dried 100 mL flask was flushed with argon and charged
with acetonitrile (40 mL). Dodecane (0.2 mL, used as
internal standard), cobalt bromide (0.66 g, 3 mmol), zinc
bromide (0.68 g, 3 mmol), phenyl bromide (0.32 mL,
3 mmol), and zinc dust (6 g, 92 mmol) were added to the so-
lution. Trifluoromethanesulfonic acid (0.2 mL) was added to
the mixture under vigorous stirring. After ca. 15 min, the
aryl bromide (30 mmol) was added to the solution and as
soon as the exothermic reaction had begun (ca. 5 min), a
water bath at room temperature was used to moderate the
temperature of the medium. The reaction time, which was
monitored using gas chromatography, did not exceed
30 min in most cases. Yields of organozinc compounds
thus obtained were estimated as follows: a sample of the
reaction medium was exposed to iodine crystals and then
to sodium thiosulfate, and extracted with diethyl ether. The
amount of iodinated product was compared to the amount
of the starting aryl bromide via the internal standard using
gas chromatography (GC). After completion of the reaction,
the acetonitrile solution was taken up using a syringe fitted
with a 25 mm glass fiber filter.
4.7. Synthesis of N-Boc piperazine
In a 500 mL flask were added 250 mL dichloromethane and
8.6 g (100 mmol) piperazine. To the resulting solution,
maintained at 0 ꢀC using an ice bath, was added drop-
wise (20 min) a di-tert-butyldicarbonate solution (10.91 g,
50 mmol in 100 mL dichloromethane). The mixture was
stirred for additional 1 h, filtered, and the filtrate concen-
trated to dryness. Water (150 mL) was added to the resulting
oil and the mixture filtered. The filtrate was saturated
with potassium carbonate and extracted with diethyl ether
(3ꢁ75 mL). The solvent was dried over sodium sulfate
and concentrated to dryness yielding 7.67 g tert-butyl piper-
azine-1-carboxylate (82%), which was sufficiently pure
(>98% GC) for our purpose.
4.3. Synthesis of benzylzinc bromide
A dried 100 mL flask was flushed with argon and charged
with acetonitrile or tetrahydrofuran (40 mL). Dodecane
(0.2 mL, used as internal standard) and zinc dust (6 g,
92 mmol) were added to the solution. Trifluoromethanesul-
fonic acid (0.2 mL) was added to the mixture under vigorous
stirring. After ca. 5 min, benzyl bromide (3.6 mL, 30 mmol)
was added carefully (ca. 30 s) to the solution, maintained at
room temperature using a water bath, and kept for additional
10 min at room temperature. The solution was taken up
using a syringe fitted with a 25 mm glass fiber filter.
4.8. Analytical data
4.8.1. 1-(Benzo[1,3]dioxol-5-yl(phenyl)methyl)-4-methyl-
1
piperazine (1a)*. Pale yellow solid, mp: 89 ꢀC; H NMR,
d (ppm): 2.30 (s, 3H), 2.46 (br s, 8H), 4.15 (s, 1H), 5.89
(d, J¼10.0 Hz, 2H), 6.71 (d, J¼8.0 Hz, 1H), 6.87 (d,
J¼8.0 Hz, 1H), 6.98 (s, 1H), 7.19 (t, J¼7.4 Hz, 1H), 7.29
(t, J¼7.5 Hz, 2H), 7.42 (d, J¼7.6 Hz, 2H); 13C NMR,
d (ppm): 46.00, 51.93, 55.46, 75.86, 100.85, 107.91,
108.04, 121.11, 126.90, 127.73, 128.50, 137.01, 142.99,
146.43, 147.81; MS, m/z (relative intensity): 311 (8), 310
(33), 253 (9), 252 (44), 251 (100), 250 (21), 239 (13), 238
(38), 224 (7), 212 (9), 211 (45), 194 (10), 181 (28), 153
(29), 152 (20), 135 (5), 99 (9), 70 (6), 56 (7). Anal. Calcd
for C19H22N2O2: C, 75.52; H, 7.14; N, 9.03. Found: C,
75.59; H, 7.13; N, 8.90.
4.4. Typical coupling method A
To the solution of the organozinc reagent were added the
aldehyde (10 mmol) and the piperazine derivative
(10 mmol). Stirring was continued for additional 4 h at
room temperature.
4.5. Typical coupling method B
y
Note: due to a predictable sensitivity, a careful neutral aqueous work-up
followed by silica gel chromatography was applied for compounds 1a
and 1c.
The solution of the organozinc reagent was added dropwise
(2 h) under stirring to a pre-heated mixture (ca. 70 ꢀC) of

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S. Sengmany et al. / Tetrahedron 63 (2007) 3672–3681
4.8.2. 1-((4-Chlorophenyl)(phenyl)methyl)-4-methyl-
piperazine (1b). Yellow oil; H NMR, d (ppm): 2.19 (s,
(ppm): 2.70 (t, J¼4.7 Hz, 4H), 3.33 (t, J¼4.7 Hz, 4H), 3.86
(s, 3H), 4.39 (s, 1H), 6.97–7.01 (m, 3H), 7.05 (d, J¼8.0 Hz,
2H), 7.31–7.46 (m, 5H), 7.51 (d, J¼8.6 Hz, 2H), 7.61 (d,
J¼7.4 Hz, 2H); 13C NMR, d (ppm): 49.34, 52.08, 55.30,
75.65, 114.10, 115.92, 119.58, 127.06, 127.96, 128.70,
129.12, 129.24, 134.91, 143.22, 151.50, 158.77; MS, m/z
(relative intensity): 359 (14), 358 (71), 331 (9), 330 (49),
239 (12), 238 (71), 226 (15), 225 (66), 224 (72), 199 (6),
198 (23), 197 (100), 182 (23), 167 (12), 166 (16), 165
(23), 162 (13), 161 (34), 159 (5), 154 (11), 153 (20), 152
(11), 134 (29), 133 (36), 132 (20), 121 (21), 120 (38), 119
(5), 106 (8), 105 (8), 104 (10), 91 (8), 77 (9), 56 (23).
Anal. Calcd for C24H26N2O: C, 80.41; H, 7.31; N, 7.81.
Found: C, 80.44; H, 7.36; N, 7.71.
1
3H), 2.34 (br s, 8H), 4.11 (s, 1H), 7.09 (t, J¼7.5 Hz, 1H),
7.11–7.20 (m, 4H), 7.26–7.29 (m, 4H); 13C NMR, d
(ppm): 45.98, 51.88, 55.38, 75.51, 127.14, 127.84, 128.59,
128.66, 129.19, 132.53, 141.48, 142.27; MS, m/z (relative
intensity): 302 (10), 301 (7), 300 (35), 245 (12), 244 (32),
243 (41), 242 (100), 241 (67), 240 (33), 231 (8), 230 (21),
229 (29), 228 (80), 206 (18), 201 (22), 179 (6), 167 (6),
166 (42), 165 (53), 164 (7), 163 (5), 99 (17), 72 (7), 70
(9), 58 (8), 56 (10). Anal. Calcd for C18H21ClN2: C, 71.87;
H, 7.04; N, 9.31. Found: C, 71.85; H, 7.11; N, 9.07.
4.8.3. 1-((3-(Diethoxymethyl)phenyl)(phenyl)methyl)-4-
methylpiperazine (1c)*. Yellow oil; H NMR, d (ppm):
1
1.22–1.25 (m, 6H), 1.29 (s, 3H), 2.45 (br s, 8H), 3.48–3.64
(m, 4H), 4.26 (s, 1H), 5.48 (s, 1H), 7.18 (t, J¼7.5 Hz, 1H),
7.25–7.33 (m, 4H), 7.39 (d, J¼7.3 Hz, 1H), 7.43 (d,
J¼7.7 Hz, 2H), 7.53 (s, 1H); 13C NMR, d (ppm): 15.19,
45.98, 51.91, 55.42, 60.99, 76.14, 101.54, 125.29, 125.52,
126.28, 126.86, 127.96, 128.14, 128.32, 128.81, 139.25,
142.76; MS, m/z (relative intensity): 369 (8), 368 (21), 324
(6), 323 (8), 322 (13), 312 (6), 311 (17), 310 (50), 297
(14), 296 (52), 294 (8), 293 (15), 266 (17), 265 (100), 263
(8), 250 (9), 237 (5), 236 (25), 234 (11), 226 (11), 225
(62), 223 (8), 222 (13), 195 (13), 194 (24), 179 (9), 167
(22), 166 (8), 165 (15), 152 (7), 105 (5), 103 (9), 99 (13),
91 (5), 70 (5), 56 (5). Anal. Calcd for C23H32N2O2: C,
74.96; H, 8.75; N, 7.60. Found: C, 74.51; H, 8.79; N, 7.35.
4.8.7. 1-((4-Methoxyphenyl)(thiophen-3-yl)methyl)-4-
phenylpiperazine (2b)*. White solid, mp: 136 ꢀC; 1H
NMR, d (ppm): 2.46 (br s, 4H), 3.10 (t, J¼4.3 Hz, 4H),
3.70 (s, 3H), 4.34 (s, 1H), 6.72–6.78 (m, 3H), 6.81 (d,
J¼7.9 Hz, 2H), 7.02 (d, J¼4.7 Hz, 1H), 7.08 (br s, 1H),
7.12–7.19 (m, 3H), 7.26 (d, J¼8.4 Hz, 2H); 13C NMR,
d (ppm): 49.30, 51.61, 55.26, 70.62, 113.86, 115.86,
119.49, 121.67, 125.75, 127.25, 129.09, 129.17, 133.90,
143.95, 151.38, 158.70; MS, m/z (relative intensity): 365
(27), 364 (84), 336 (28), 244 (35), 231 (60), 230 (32), 204
(19), 203 (100), 161 (34), 134 (23), 133 (26), 132 (13),
121 (15), 120 (16), 77 (10), 56 (18). Anal. Calcd for
C22H24N2OS: C, 72.49; H, 6.64; N, 7.69. Found: C, 72.31;
H, 6.64; N, 7.61.
4.8.4. Methyl 3-((4-methylpiperazin-1-yl)(phenyl)-
methyl)benzoate (1d)*. Yellow oil; IR, n (cmꢂ1): 1719;
1H NMR, d (ppm): 2.28 (s, 3H), 2.45 (br s, 8H), 3.89 (s,
3H), 4.30 (s, 1H), 7.18 (t, J¼7.3 Hz, 1H), 7.27 (t,
J¼7.7 Hz, 2H), 7.35 (t, J¼7.3 Hz, 1H), 7.43 (d, J¼7.7 Hz,
2H), 7.66 (d, J¼7.7 Hz, 1H), 7.86 (d, J¼7.7 Hz, 1H), 8.11
(s, 1H); 13C NMR, d (ppm): 45.94, 51.90, 52.05, 55.33,
75.94, 127.15, 127.90, 128.24, 128.61, 128.63, 129.07,
130.41, 132.39, 142.22, 143.45, 167.04; MS, m/z (relative
intensity): 325 (6), 324 (23), 293 (10), 267 (33), 266 (67),
265 (48), 264 (22), 225 (6), 206 (14), 195 (6), 194 (6), 193
(14), 167 (6), 166 (13), 165 (36), 99 (8), 72 (8), 70 (8), 56
(7). Anal. Calcd for C20H24N2O2: C, 74.04; H, 7.46; N,
8.64. Found: C, 73.03; H, 7.40; N, 8.45.
4.8.8. 1-((3-Fluorophenyl)(4-methoxyphenyl)methyl)-4-
phenylpiperazine (2c)*. White solid, mp: 116 ꢀC; 1H
NMR, d (ppm): 2.62 (t, J¼4.5 Hz, 4H), 3.27 (t, J¼4.6 Hz,
4H), 3.83 (s, 3H), 4.3 (s, 1H), 6.86–7.00 (m, 6H), 7.25–
7.35 (m, 5H), 7.40 (d, J¼8.5 Hz, 2H); 13C NMR, d (ppm):
49.26, 51.91, 55.26, 75.02, 113.85 (d, J¼21.0 Hz), 114.10,
114.47 (d, J¼22.0 Hz), 115.89, 119.59, 123.47 (d,
J¼2.0 Hz), 129.07, 129.15, 130.05 (d, J¼8.0 Hz), 134.03,
145.99 (d, J¼6.0 Hz), 151.34, 158.88, 163.13 (d,
J¼245.0 Hz); 19F NMR, d (ppm): ꢂ112.85; MS, m/z (rela-
tive intensity): 377 (22), 376 (80), 349 (12), 348 (33), 270
(6), 257 (5), 256 (26), 244 (8), 243 (86), 242 (100), 216 (14),
215 (67), 200 (14), 184 (10), 183 (20), 172 (12), 171 (17),
165 (8), 162 (6), 161 (27), 135 (5), 134 (35), 133 (30), 132
(13), 122 (5), 121 (43), 120 (7), 106 (12), 104 (8), 77 (6),
56 (25). Anal. Calcd for C24H25FN2O: C, 76.57; H, 6.69;
N, 7.44. Found: C, 76.30; H, 6.75; N, 7.47.
4.8.5. 1-Methyl-4-((phenyl(4-trifluoromethyl)phenyl)-
methyl)piperazine (1e). Yellow oil; H NMR, d (ppm):
1
2.31 (s, 3H), 2.46 (br s, 8H), 4.31 (s, 1H), 7.22 (t,
J¼7.4 Hz, 1H), 7.30 (t, J¼7.4 Hz, 2H), 7.41 (d, J¼7.6 Hz,
2H), 7.54 (d, J¼8.4 Hz, 2H), 7.58 (d, J¼8.4 Hz, 2H); 13C
NMR, d (ppm): 45.94, 51.87, 55.33, 75.84, 125.54 (q, J¼
272.0 Hz), 125.48 (q, J¼3.8 Hz), 127.34, 127.92, 128.10,
128.67, 129.14 (q, J¼32.3 Hz), 141.76, 147.05; 19F NMR,
d (ppm): ꢂ62.41; MS, m/z (relative intensity): 335 (9), 334
(37), 315 (8), 290 (7), 277 (35), 276 (100), 275 (64), 274
(23), 264 (8), 263 (50), 262 (91), 235 (20), 233 (6), 216
(7), 215 (15), 214 (7), 206 (7), 179 (5), 166 (21), 165 (34),
99 (9), 70 (10), 58 (16), 56 (11). Anal. Calcd for
C19H21F3N2: C, 68.25; H, 6.33; N, 8.38. Found: C, 68.32;
H, 6.58; N, 8.22.
4.8.9. 4-((4-Methoxyphenyl)(4-phenylpiperazin-1-yl)-
methyl)benzonitrile (2d)*. Orange oil; IR, n (cmꢂ1):
2230; 1H NMR, d (ppm): 2.55–2.67 (m, 4H), 3.26 (t,
J¼4.8 Hz, 4H), 3.81 (s, 3H), 4.35 (s, 1H), 6.88–6.98 (m,
5H), 7.26–7.38 (m, 4H), 7.57–7.77 (m, 4H); 13C NMR,
d (ppm): 49.21, 51.86, 55.31, 75.12, 110.71, 114.32,
115.95, 118.96, 119.75, 128.47, 129.14, 129.20, 132.53,
133.10, 148.86, 151.22, 159.12; MS, m/z (relative intensity):
384 (21), 383 (66), 356 (10), 355 (24), 277 (6), 263 (10), 251
(23), 250 (100), 249 (86), 223 (12), 222 (58), 207 (14),
191 (6), 190 (23), 178 (11), 162 (5), 161 (20), 134 (19),
133 (13), 132 (18), 121 (40), 120 (8), 106 (19), 105 (6),
104 (7), 91 (7), 77 (7), 56 (18). Anal. Calcd for
C25H25N3O: C, 78.30; H, 6.57; N, 10.96. Found: C, 78.27;
H, 6.60; N, 10.90.
4.8.6. 1-((4-Methoxyphenyl)(phenyl)methyl)-4-phenyl-
1
piperazine (2a)*. White solid, mp: 164 ꢀC; H NMR, d

S. Sengmany et al. / Tetrahedron 63 (2007) 3672–3681
3679
4.8.10. 1-((4-Methoxyphenyl)(3-nitrophenyl)methyl)-4-
phenylpiperazine (2e)*. Yellow solid, mp: 146 ꢀC; IR,
(dd, J¼5.2, 9.3 Hz, 1H), 7.00 (td, J¼7.6, 1.4 Hz, 1H),
7.04–7.06 (m, 2H), 7.10 (dd, J¼8.1, 1.4 Hz, 1H), 7.14–
7.33 (m, 9H), 7.40 (dd, J¼7.9, 1.4 Hz, 1H); 13C NMR,
d (ppm): 39.50, 50.79, 51.56, 72.18, 120.35, 123.59,
125.84, 127.16, 127.60, 127.98, 128.01, 128.19, 128.76,
128.86, 129.47, 130.68, 139.52, 149.39; MS, m/z (relative
intensity): 288 (5), 287 (32), 286 (15), 285 (100), 195
(5), 194 (16), 193 (7), 168 (9), 166 (28), 165 (5), 146
(10), 138 (8), 105 (6), 91 (58). Anal. Calcd for
C24H25ClN2: C, 76.48; H, 6.69; N, 7.43. Found: C, 76.18;
H, 6.69; N, 7.37.
1
n (cmꢂ1): 1530, 1352; H NMR, d (ppm): 2.54–2.62 (m,
4H), 3.25–3.23 (m, 4H), 3.80 (s, 3H), 4.40 (s, 1H), 6.86–
6.90 (m, 3H), 6.93 (d, J¼8.8 Hz, 2H), 7.28 (t, J¼8.0 Hz,
2H), 7.35 (d, J¼8.6 Hz, 2H), 7.49 (t, J¼8.0 Hz, 1H), 7.83
(d, J¼7.7 Hz, 1H), 8.07 (d, J¼8.2 Hz, 1H), 8.36 (s, 1H);
13C NMR, d (ppm): 49.21, 51.84, 55.27, 74.71, 114.29,
115.92, 119.70, 122.04, 122.62, 129.06, 129.12, 129.55,
133.04, 133.86, 145.61, 148.58, 151.19, 159.08; MS, m/z
(relative intensity): 404 (13), 403 (48), 386 (11), 375 (11),
297 (6), 270 (100), 269 (50), 253 (13), 242 (27), 226 (6),
225 (12), 195 (7), 196 (13), 161 (17), 153 (13), 152 (7), 134
(11), 132 (8), 191 (22), 120 (6), 56 (11). Anal. Calcd for
C24H25N3O3: C, 71.44; H, 6.25; N, 10.41. Found: C,
71.32; H, 6.30; N, 10.28.
4.8.15. 1-(1,2-Diphenylethyl)-4-methylpiperazine (3d).
Yellow-orange oil; H NMR, d (ppm): 2.15 (s, 3H), 2.33
1
(br s, 4H), 2.43 (br s, 4H), 2.82 (dd, J¼13.2, 9.4 Hz, 1H),
3.22 (dd, J¼13.2, 5.2 Hz, 1H), 3.43 (dd, J¼9.4, 5.2 Hz,
1H), 6.83–6.86 (m, 2H), 6.93–7.12 (m, 8H); 13C NMR,
d (ppm): 39.45, 46.01, 50.42, 55.48, 72.02, 125.77, 127.65,
128.12, 128.56, 129.18, 129.69, 139.49, 139.80; MS, m/z
(relative intensity): 190 (14), 189 (100), 165 (6.37),
146 (18), 98 (7), 91 (23), 70 (24). Anal. Calcd for
C19H24N2: C, 81.38; H, 8.63; N, 9.99. Found: C, 81.31; H,
8.63; N, 9.84.
4.8.11. 1-(4-Methoxybenzyl)-4-phenylpiperazine (2f).
White solid, mp: 107 ꢀC; 1H NMR, d (ppm): 2.64 (t,
J¼4.9 Hz, 4H), 3.23 (t, J¼4.9 Hz, 4H), 3.55 (s, 2H), 3.84
(s, 3H), 6.86–6.96 (m, 5H), 7.29–7.31 (m, 4H); 13C NMR,
d (ppm): 49.11, 53.00, 55.28, 62.44, 113.68, 116.06,
119.60, 129.09, 129.35, 130.44, 151.40, 158.86; MS, m/z
(relative intensity): 283 (25), 282 (99), 281 (7), 254 (17),
176 (18), 175 (10), 164 (6), 162 (10), 161 (26), 150 (14),
149 (100), 148 (78), 135 (6), 134 (24), 133 (9), 132 (16),
122 (6), 121 (64), 120 (8), 118 (10), 119 (6), 106 (11), 105
(7), 104 (8), 91 (9), 77 (11), 56 (13). Anal. Calcd for
C18H22N2O: C, 76.56; H, 7.85; N, 9.92. Found: C, 76.47;
H, 7.88; N, 9.71.
4.8.16. 1-(1,2-Diphenylethyl)-4-(pyridin-2-yl)piperazine
1
(3e)*. White solid, mp: 94 ꢀC; H NMR, d (ppm): 2.61–
2.73 (m, 4H), 3.02 (dd, J¼13.2, 9.2 Hz, 1H), 3.43 (dd,
J¼13.3, 5.4 Hz, 1H), 3.58 (t, J¼5.0 Hz, 4H), 3.66 (dd,
J¼9.1, 5.4 Hz, 1H), 6.61–6.67 (m, 2H), 7.03 (d, J¼6.9 Hz,
2H), 7.12–7.22 (m, 5H), 7.23–7.32 (m, 3H), 7.45–7.49 (m,
1H), 8.22 (dd, J¼5.1, 1.5 Hz, 1H); 13C NMR, d (ppm):
39.44, 45.50, 50.34, 72.01, 106.99, 113.17, 125.85,
127.17, 127.96, 128.81, 129.44, 137.37, 139.42, 147.98,
159.58; MS, m/z (relative intensity): 253 (18), 252 (100),
149 (6), 149 (6), 148 (56), 147 (53), 121 (28), 119 (5), 107
(6), 78 (7). Anal. Calcd for C23H25N3: C, 80.45; H, 7.34;
N, 12.23. Found: C, 80.20; H, 7.32; N, 12.29.
4.8.12. 1-(1,2-Diphenylethyl)-4-phenylpiperazine (3a).
1
White solid, mp: 108 ꢀC; H NMR, d (ppm): 2.53–2.65
(m, 4H), 2.89 (dd, J¼13.1, 9.4 Hz, 1H), 3.10 (t, J¼4.8 Hz,
4H), 3.30 (dd, J¼13.2, 5.1 Hz, 1H), 3.52 (dd, J¼9.0,
5.4 Hz, 1H), 6.75 (t, J¼7.3 Hz, 1H), 6.81 (d, J¼7.9 Hz,
2H), 6.87–6.92 (m, 2H), 6.98–7.09 (m, 5H), 7.11–7.19 (m,
5H); 13C NMR, d (ppm): 39.47, 49.42, 50.57, 72.03,
116.00, 119.63, 125.85, 127.18, 127.96, 128.83, 129.09,
129.45, 139.41, 151.40; MS, m/z (relative intensity): 342
(3), 252 (20), 251 (100), 160 (16), 159 (8), 146 (15), 132
(25), 117 (5), 105 (8), 104 (10), 91 (34), 77 (5). Anal. Calcd
for C24H26N2: C, 84.17; H, 7.65; N, 8.18. Found: C, 84.01;
H, 7.65; N, 8.18.
4.8.17. 2-(4-(1,2-Diphenylethyl)piperazin-1-yl)pyrimi-
1
dine (3f)*. White solid, mp: 154 ꢀC; H NMR, d (ppm):
2.60 (br s, 4H); 3.03 (dd, J¼13.0, 9.3 Hz, 1H), 3.40 (dd,
J¼13.1, 5.0 Hz, 1H), 3.66 (dd, J¼8.6, 5.6 Hz, 1H), 3.85
(br s, 4H), 6.46 (t, J¼4.7 Hz, 1H), 7.02–7.04 (m, 2H),
7.11–7.21 (m, 5H), 7.22–7.29 (m, 3H), 8.29 (d, J¼4.7 Hz,
2H); 13C NMR, d (ppm): 39.29, 43.93, 50.31, 71.96,
109.67, 125.84, 127.16, 127.96, 128.81, 129.39, 139.45,
157.67, 161.60; MS, m/z (relative intensity): 254 (16), 253
(100), 162 (7), 150 (6), 149 (73), 148 (26), 122 (13). Anal.
Calcd for C22H24N4: C, 76.71; H, 7.02; N, 16.27. Found:
C, 76.92; H, 6.91; N, 16.00.
4.8.13. 2-(2-(4-(1,2-Diphenylethyl)piperazin-1-yl)eth-
oxy)ethanol (3b)*. Yellow oil; IR, n (cmꢂ1): 3250 (br); 1H
NMR, d (ppm): 2.59 (t, J¼5.4 Hz, 2H), 2.61 (br s, 8H),
2.90 (dd, J¼13.2, 9.6 Hz, 1H), 3.35 (dd, J¼9.5, 4.9 Hz,
1H), 3.52 (dd, J¼9.5, 5.0 Hz, 1H), 3.57–3.60 (m, 2H),
3.64 (t, J¼5.4 Hz, 2H), 3.66–3.69 (m, 2H), 6.90–6.95 (m,
2H), 7.05–7.25 (m, 10H); 13C NMR, d (ppm): 39.58,
50.33, 53.60, 57.90, 61.92, 67.52, 72.13, 72.46, 125.74,
127.04, 127.87, 128.33, 128.71, 129.39, 139.30, 140.07;
MS, m/z (relative intensity): 264 (16), 263 (100), 181 (12),
177 (10), 173 (9), 172 (76), 166 (8), 165 (5), 97 (23), 91
(13). Anal. Calcd for C22H30N2O2: C, 74.54; H, 8.53; N,
7.90. Found: C, 73.74; H, 8.69; N, 7.79.
4.8.18. tert-Butyl 4-(1,2-diphenylethyl)piperazine-1-
carboxylate (3g)*. Yellow oil; IR, n (cmꢂ1): 1683; 1H
NMR, d (ppm): 1.50 (s, 9H), 2.49 (br s, 4H), 3.00 (dd,
J¼13.5, 9.1 Hz, 1H), 3.36 (dd, J¼13.4, 5.5 Hz, 1H), 3.41–
3.50 (m, 4H), 3.63 (dd, J¼9.0, 5.6 Hz, 4H), 7.00–7.04 (m,
2H), 7.11–7.21 (m, 4H), 7.23–7.32 (m, 3H), 7.36–7.43 (m,
1H); 13C NMR, d (ppm): 28.48, 39.24, 50.24, 64.98,
71.87, 79.51, 125.89, 127.22, 127.99, 128.46, 129.03,
129.38, 139.38, 154.72; MS, m/z (relative intensity): 276
(14), 275 (64), 220 (16), 219 (100), 181 (5), 176 (8), 175
(52), 91 (17). Anal. Calcd for C23H30N2O2: C, 75.37; H,
8.25; N, 7.64. Found: C, 75.49; H, 8.34; N, 7.71.
4.8.14. 1-(2-Chlorophenyl)-4-(1,2-diphenylethyl)piper-
1
azine (3c)*. White solid, mp: 122 ꢀC; H NMR, d (ppm):
2.71–2.88 (m, 4H), 3.04 (dd, J¼13.2, 9.3 Hz, 1H),
3.11–3.19 (m, 4H), 3.46 (dd, J¼5.2, 13.2 Hz, 1H), 3.69

3680
S. Sengmany et al. / Tetrahedron 63 (2007) 3672–3681
8. The displacement of benzotriazole derivatives using organo-
metallic reagents has been first described by Katritzky. For
representative examples, see: (a) Katritzky, A. R.; Yao, G.;
Lan, X.; Zhao, X. J. Org. Chem. 1993, 58, 2086–2093; (b)
Katritzky, A. R.; Jurczyk, S.; Rachwal, B.; Rachwal, S.;
Shcherbakova, I.; Yannakopoulou, K. Synthesis 1992,
1295–1298; (c) Katritzky, A. R.; Yannakopoulou, K.; Lue,
P.; Rasala, D.; Urogdi, L. J. Chem. Soc., Perkin Trans. 1
1989, 225–233; (d) Katritzky, A. R.; Drewniak, M.; Lue,
P. J. Org. Chem. 1988, 53, 5854–5856; (e) Katritzky,
A. R.; Strah, S.; Belyakov, S. A. Tetrahedron 1998, 54,
7167–7178.
9. (a) Plobeck, N.; Delorme, D.; Wei, Z. Y.; Yang, H.; Zhou, F.;
Schwarz, P.; Gawell, L.; Gagnon, H.; Pelcman, B.; Schmidt,
R.; Yue, S. Y.; Walpole, C.; Brown, W.; Zhou, E.; Labarre,
M.; Payza, K.; St-Onge, S.; Kamassah, A.; Morin, P. E.;
Projean, D.; Ducharme, J.; Roberts, E. J. Med. Chem. 2000,
43, 3878–3894; (b) Barn, D. R.; Bom, A.; Cottney, J.;
Caulfield, W. L.; Morphy, J. R. Bioorg. Med. Chem. Lett.
1999, 9, 1329–1334; (c) Calderon, S. N.; Rice, K. C.;
Rothman, R. B.; Porreca, F.; Flippen-Anderson, J. L.;
Kayakiri, H.; Xu, H.; Becketts, K.; Smith, L. E.; Bilsky,
E. J.; Davis, P.; Horvath, R. J. Med. Chem. 1997, 40, 695–
704; (d) Katsura, Y.; Zhang, X.; Homma, K.; Rice, K. C.;
Calderon, S. N.; Rothman, R. B.; Yamamura, H. I.; Davis,
P.; Flippen-Anderson, J. L.; Xu, H.; Becketts, K.; Foltz,
E. J.; Porreca, F. J. Med. Chem. 1997, 40, 2936–2947; (e)
Zhang, X.; Rice, K. C.; Calderon, S. N.; Kayakiri, H.;
Smith, L.; Coop, A.; Jacobson, A. E.; Rothman, R. B.;
Davis, P.; Dersch, C. M.; Porreca, F. J. Med. Chem. 1999,
42, 5455–5463.
4.8.19. 1-Phenyl-4-(1-phenyloctan-2-yl)piperazine (4a)*.
White solid, mp: 50 ꢀC; 1H NMR, d (ppm): 1.94 (t,
J¼6.9 Hz, 3H), 1.25–1.65 (m, 10H), 2.46 (dd, J¼13.3,
8.3 Hz, 1H), 2.75–2.95 (m, 5H), 3.67 (dd, J¼13.3, 5.1 Hz,
1H), 3.2–3.4 (m, 4H), 6.95 (t, J¼7.3 Hz, 1H), 7.02
(d, J¼8.5 Hz, 2H), 7.24–7.27 (m, 3H), 7.31–7.37 (m,
4H); 13C NMR, d (ppm): 14.20, 22.73, 26.93, 29.41,
30.41, 31.93, 35.98, 48.42, 49.85, 66.25, 116.14,
119.59, 125.74, 128.27, 129.13, 129.32, 141.30, 151.75;
MS, m/z (relative intensity): 260 (19), 259 (100), 160 (13),
154 (5), 132 (28), 104 (7), 70 (14). Anal. Calcd for
C24H34N2: C, 82.23; H, 9.78; N, 7.99. Found: C, 82.18; H,
9.89; N, 7.48.
4.8.20. 1-Methyl-4-(1-(3-nitrophenyl)-2-phenylethyl)-
piperazine (4b)*. Brown oil; IR, n (cmꢂ1): 1531, 1350;
1H NMR, d (ppm): 2.28 (s, 3H), 2.35–2.65 (m, 8H), 2.88
(dd, J¼13.2, 9.9 Hz, 1H), 3.41 (dd, J¼13.2, 5.1 Hz, 1H),
3.68 (dd, J¼9.9, 5.1 Hz, 1H), 6.92 (d, J¼8.0 Hz, 2H),
7.10–7.16 (m, 3H), 7.33–7.41 (m, 3H), 8.02–8.05 (m, 1H);
13C NMR, d (ppm): 39.29, 45.90, 50.42, 55.27, 71.27,
122.09, 123.25, 126.19, 128.18, 128.67, 129.30, 134.84,
138.22, 142.74, 148.06; MS, m/z (relative intensity): 235
(14), 234 (100), 191 (43), 178 (8), 98 (9), 70 (22). Anal.
Calcd for C19H23N3O2: C, 70.13; H, 7.12; N, 12.91. Found:
C, 70.88; H, 7.18; N, 12.16.
4.8.21. 1-Phenethyl-4-phenylpiperazine (4c). White solid,
mp: 75 ꢀC; 1H NMR, d (ppm): 2.71–2.77 (m, 6H), 2.90–2.94
(m, 2H), 3.29–3.32 (m, 4H), 6.93 (t, J¼7.3 Hz, 1H), 7.01 (d,
J¼8.5 Hz, 2H), 7.28–7.39 (m, 7H); 13C NMR, d (ppm):
33.73, 49.23, 53.32, 60.57, 116.11, 119.74, 126.15,
128.48, 128.78, 129.17, 140.33, 151.40; MS, m/z (relative
intensity): 266 (9), 176 (14), 175 (100), 132 (33), 104 (12),
70 (31). Anal. Calcd for C18H22N2: C, 81.16; H, 8.32; N,
10.52. Found: C, 81.04; H, 8.24; N, 10.41.
10. (a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int.
Ed. 1998, 37, 1044–1070; (b) Heaney, H. Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 2, pp 953–973; (c) Overman,
L. E.; Ricca, D. J. Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2,
pp 1007–1046.
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handling. It can be noted that dialkylzinc reagents have also
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S. Sengmany et al. / Tetrahedron 63 (2007) 3672–3681
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phenylzinc iodide 0.5 M in tetrahydrofuran were supplied by
Aldrich.
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aldehyde and the amine are added.
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