An expedient in situ preparation of symmetrical 1,4-dibenzylpiperazines from benzyl bromides and 2-bromoethylamine hydrobromide

Article abstract of DOI:10.1016/j.tetlet.2010.08.071

A straightforward synthesis of a variety of 1,4-bis-benzylpiperazines from benzyl halides and 2-bromoethylamine hydrobromide is described.

Full text of DOI:10.1016/j.tetlet.2010.08.071

Tetrahedron Letters 51 (2010) 5613–5614
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Tetrahedron Letters
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An expedient in situ preparation of symmetrical 1,4-dibenzylpiperazines
from benzyl bromides and 2-bromoethylamine hydrobromide
⇑
Lynn M. Bradley , Michael J. Nardone, David A. Hunt
Department of Chemistry, The College of New Jersey, PO Box 7718 Ewing, NJ 08628-7718, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A straightforward synthesis of a variety of 1,4-bis-benzylpiperazines from benzyl halides and 2-bromo-
ethylamine hydrobromide is described.
Received 3 August 2010
Accepted 19 August 2010
Available online 24 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
During the course of an investigation requiring a variety of ben-
zyl aziridines, we sought to generate these compounds through the
reduction of N-(2-haloalkyl) imines as described by De Kimpe and
De Smaele.1 However, this method proved problematic in our
hands and typically led to overreduced product mixtures that were
difficult to purify. In an effort to overcome these difficulties, we at-
tempted to form the desired benzyl aziridines 3 via the reaction of
benzyl bromides 2 with 2-bromoethylamine hydrobromide 1 fol-
lowed by an intramolecular ring closure under basic conditions.
However, while the desired aziridines were formed as observed
by GC/MS analysis, the major product isolated was symmetrical
bis-benzyl piperazine dimers 4 (Scheme 1).
of the type 5 have been reported to show high affinity for r-1
receptors, thus acting as a competitive ligand versus cocaine and
attenuating cocaine-induced convulsions. Among the derivatives
studied by Coop and co-workers (Fig. 1), the 3-chloro- and 3-meth-
oxy-analogs have shown the most promise in attenuating
cocaine-induced convulsions in mice.2 More recently, a variety of
1,4-dibenzylpiperazines have been observed to inhibit the growth
of colon tumors in mice.3
This novel dimerization reaction is believed to occur through a
simple bimolecular nucleophilic substitution reaction. The 2-bro-
moethylamine was generated in situ by converting the free base
from the corresponding hydrobromide salt 1 with triethylamine.
To this cloudy solution, the benzyl bromide 2 was added and the
solution was allowed to stir at room temperature for one week.
The importance of N,N-dibenzylpiperazines has been well doc-
umented in the literature. For example, 1,4-dibenzylpiperazines
Br
2
N
Br
4 NEt3
THF
H3N
X
+
Br
X
Br
+ 3 Et3NH
1
2
3
dimerize
N
X
X
N
4
Scheme 1.
⇑
Corresponding author. Tel.: +1 609 771 3013; fax: +1 609 637 5157.
E-mail address: bradley@tcnj.edu (L.M. Bradley).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.071

5614
L. M. Bradley et al. / Tetrahedron Letters 51 (2010) 5613–5614
zines for biological screening studies from relatively abundant and
N
X
inexpensive starting materials. A survey of the literature revealed
that only one method of forming the symmetrically substituted
1,4-dibenzyl-piperazines has been reported; that of Yamaguchi
and co-workers in 2009 in which N-benzylethanol-amines were
coupled via a Cp*Ir complex-catalyzed reaction.5
The inverse addition of substituted benzyl bromides to 2-bro-
moethylamine produces substituted 1,4-dibenzylpiperazines in
moderate to good yields when left to react over one week. This
clean dimerization reaction of aziridines as characterized through
GC/MS studies constitutes a new and straightforward synthetic
method for the preparation of these compounds. Future work will
include kinetic studies regarding the conversion of 3 to 4 and stud-
ies to better understand the conditions necessary to isolate the
benzyl aziridine intermediates prior to subsequent dimerization.
N
5
X
H
3-OMe
4-OMe
2-Cl
3-Cl
4-Cl
3, 4-diCl
2,4-diCl
Figure 1.
Acknowledgments
Table 1
The authors would like to express their gratitude to The College
of New Jersey for support of this work, and the Mass Spectrometry
Facility at Michigan State University for providing high resolution
mass spectral data.
Y
X
Z
Y
N
N
Z
X
Compound
X
Y
Z
Yield (%)
References and notes
4a
4b
4c
4d
4e
4f
H
H
H
H
H
CF3
H
H
H
H
Cl
H
OCH3
74
83
80
38
81
66
Br
CN
H
H
Br
1. De Kimpe, N.; De Smaele, D. Tetrahedron Lett. 1994, 35, 8023–8026.
2. Foster, A.; Wu, H.; Chen, W.; Williams, W.; Bowen, W. D.; Matsumoto, R. R.;
Coop, A. Bioorg. Med. Chem. Lett. 2003, 13, 749–751.
3. Putt, K. S.; Chen, G. W.; Pearson, J. M.; Sandhorst, J. S.; Hoagland, M. S.; Kwon, J.-
T.; Hwang, S.-K.; Jin, H.; Churchwell, M. I.; Cho, M.-H.; Doerge, D. R.; Helferich,
W. G.; Hergenrother, P. J. Nat. Chem. Biol. 2006, 2, 543–550.
4. General procedure illustrated by the preparation of 4e: To a suspension of 2-
bromoethyl- amine hydrobromide (2.40 g, 11.7 mmol) in THF (20 mL) was
added triethylamine (3.4 mL, 23.40 mmol). The mixture was stirred for 10 min
at rt. To this cloudy solution 4-trifluoromethylbenzyl bromide (0.70 mL,
5.85 mmol) was added dropwise and the solution was allowed to stir for one
By monitoring aliquots of the reaction over time by GC/MS, initial
formation of the aziridine was observed. With continued reaction
time, the aziridine intermediate 3 was converted to the observed
benzyl piperazine product 4 quite cleanly.
week, at which time
a solid precipitate was observed. The mixture was
transferred to a separatory funnel with ethyl acetate (25 mL), distilled water
(25 mL), and a 5% solution of NaHCO3 (25 mL). After separation of the layers, the
organic layer was subsequently washed with distilled water. The organic phase
was dried (MgSO4), filtered, and concentrated under reduced pressure. The
crude product was purified by recrystallization from isopropanol and water,
yielding 1,4-bis-[4-(trifluoromethyl)phenylmethyl] piperazine (4e) as a white
solid (0.95 g; 81% yield); mp determined by DSC: endotherm at 133.39 °C; IR
(KBr): 2963, 2823, 1618, 1420, 1326, 1167, 1130, 1108, 1065, 1017, 933, 859,
In order to test the versatility of our method, five mono-substi-
tuted (including ortho, meta and para) benzyl bromides were stud-
ied, as well as one disubstituted example. In all cases, initial
formation of the aziridine intermediate was observed, and the
piperazine products were formed in relatively good yields (Table
1). In most cases, the isolated piperazines were converted to their
HCl salts in order to purify them and were characterized in the salt
form or converted to the free base form prior to characterization.4
A major advantage to this method is the ability to rapidly and
cleanly prepare a wide variety of symmetrical 1,4-dibenzylpipera-
851, 809, 639 cmÀ1 1H NMR (CDCl3, 300 MHz): d (ppm) 7.54 (d, J = 8.1 Hz, 4H);
;
7.42 (d, J = 7.8 Hz, 4H); 3.54 (s, 4H); 2.46 (br s, 8H); 13C NMR (CDCl3, 75 MHz): d
(ppm) 142.7, 129.4, 125.4, 125.3, 124.5 (q, JCF = 266 Hz); 62.6, 53.3; 19F NMR
(CDCl3), 300 MHz): d (ppm) À63.12 (s); HRMS (EI) calcd for C20H20N2F6 [M]+: m/
z = 402.1531, found m/z = 402.1524.
5. Fujita, K.; Kida, Y.; Yamaguchi, R. Heterocycles 2009, 77, 1371–1377.