Rapid access to 1-benzyl 2-substituted piperazines: Application to the synthesis of 1-benzyl-2-difluoromethyl-piperazine

Article abstract of DOI:10.1080/00397911.2010.491171

A rapid and efficient synthesis of 1-benzyl-2-difluoromethyl-piperazine is herein described. The new pathway has the advantage of avoiding orthogonal protection at the two piperazine nitrogen atoms; therefore it is suitable for access to several 1-benzyl

Full text of DOI:10.1080/00397911.2010.491171

Synthetic Communications1, 41: 2031–2035, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.491171
RAPID ACCESS TO 1-BENZYL 2-SUBSTITUTED
PIPERAZINES: APPLICATION TO THE SYNTHESIS
OF 1-BENZYL-2-DIFLUOROMETHYL-PIPERAZINE
Carmela Napolitano,1 Manuela Borriello,2
Francesca Cardullo,2 Daniele Donati,2 Alfredo Paio,2 and
Stefano Manfredini1
1Department of Pharmaceutical Sciences, University of Ferrara,
Ferrara, Italy
2GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery,
Medicine Research Centre, Verona, Italy
GRAPHICAL ABSTRACT
Abstract A rapid and efficient synthesis of 1-benzyl-2-difluoromethyl-piperazine is herein
described. The new pathway has the advantage of avoiding orthogonal protection at the
two piperazine nitrogen atoms; therefore it is suitable for access to several 1-benzyl
2-substituted piperazines starting from the simple commercially available N,N0-
dibenzylethylendiamine.
Keywords Chemoselective deprotection; piperazines; privileged structures
INTRODUCTION
The piperazine ring is found in a number of biologically active compounds,
including several marketed drugs,[1] and is considered to be a privileged structure
in drug discovery.[2,3] The main feature that confers druglike properties is the con-
straint of the two nitrogen atoms in the six-membered ring, which enhances favor-
able interactions with macromolecules.
Whereas the synthesis of simple 1,4-disubstituted piperazines has received
considerable attention, only a comparatively small number of C-substituted deriva-
tives have been prepared and evaluated for their pharmacological properties.[4]
C-Substituted piperazines are contained in several pharmacologically active
compounds such as platelet activating factor (PAF) inhibitors,[5] soluble epoxide
Received December 26, 2009.
Address correspondence to Stefano Manfredini, Department of Pharmaceutical Sciences,
University of Ferrara, via Fossato di Mortara, 17-19 I 44100, Ferrara, Italy. E-mail: mv9@unife.it
2031

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C. NAPOLITANO ET AL.
Figure 1. pKa2 values of benzyl piperazine and 1-benzyl-2-difluoromethyl piperazine (1) (predicted with
the ACD=labs software[9]).
hydrolase (sEH) inhibitors,[6] farnesyl transferase inhibitors (i.e., L-745631),[7] and
NK-1 antagonists (i.e., FK-355).[8]
As part of our efforts working toward the synthesis of novel scaffolds with high
potential as building blocks in medicinal chemistry, we became interested in 1-benzyl-2-
difluoromethyl-piperazine (1), hypothesizing that modulation of N-atom electronic as
well as steric hindrance properties could be valuable strategies to modulate activity at
the biological target and influence physicochemical properties (Fig. 1).
To the best of our knowledge, only one approach to the synthesis of
2-difluoromethyl-piperazine has been reported, and it involves the reaction of
pyrazine-carboxaldehyde and diethylaminosulfur trifluoride (DAST) followed by
catalytic reduction.[10] However, this synthetic pathway is unsuitable for a multigram
scale because of its low efficiency (5% overall yield), and moreover it gives access to
the full deprotected 2-difluoromethyl-piperazine, which can be converted into desired
1 only after protection=deprotection steps. Inspired by a paper of Gubert and colla-
borators in which regioselective debenzylation of (1,4-dibenzyl-piperazin-2-yl)-
acetonitrile was described,[11] we have explored a general and efficient route for the
preparation of 1 starting from commercially available N,N0-dibenzylethylendiamine
(Scheme 1).
Double alkylation of N,N0-dibenzylethylendiamine with ethyl 2,3-dibromopro-
penoate afforded excellent yields of ester 2, which was quantitatively converted into
difluoro derivative 4 through controlled reduction with diisobutylaluminumhydride
(DIBAL)–H at ꢀ78 ꢁC followed by double fluorine substitution with DAST (43%
yield over two steps). Both classical catalytic hydrogenation conditions and N-depro-
tection via carbamate [1-chloroethyl chloroformate (ACE-Cl), dimethylchloride
(DCM), 2 h, reflux; then MeOH at reflux] gave access in excellent yield to the desired
1 (four steps, 23% overall yield, Scheme 2).
In conclusion, a rapid and efficient synthesis of 1-benzyl-2-difluoromethyl-
piperazine is herein described. This pathway has the advantage of avoiding
Scheme 1. Retrosynthetic analysis.

BENZYL DIFLUOROMETHYL PIPERAZINE
2033
Scheme 2. Synthesis of 1-benzyl-2-difluoromethyl piperazine (1).
orthogonal protection at the two piperazine nitrogen atoms and allows us to directly
functionalize the piperazine ring at the less accessible N-position.
EXPERIMENTAL
All moisture-sensitive reactions were performed under an argon atmosphere
using oven-dried glassware. All chemicals and solvents were purchased from com-
mercial sources and used without purification. 1H NMR and 13C NMR spectra were
recorded on a Bruker 400-MHz instrument operating at 400 MHz and 100 MHz,
respectively. Chemical shifts are reported in ppm (d) using the residual solvent line
as internal standard. Reactions were monitored by thin-layer chromatography
(TLC) (precoated silica-gel plate F254, Merck). Chromatography was carried out
on silica gel (70–230 mesh) supplied by Merck AG Darmstadt, Germany. Combus-
tion analyses were performed using a CHNO analyzer.
Ethyl 1,4-Dibenzylpiperazine-2-carboxylate (2)
A solution of N,N-diisopropylethylamine (DIPEA) (4.73 mL, 27.2 mmol) and
N,N0-dibenzylethylendiamine (2 mL, 8.5 mmol) dissolved in 13.5 mL dry toluene
was added to a solution of ethyl 2,3-dibromopropionate (2.48 mL, 17.0 mmol) in
20 mL dry toluene warmed to 50 ꢁC. The mixture was heated to reflux for 21 h,
cooled to room temperature, and filtered from the solid. The organic layer was
evaporated under vacuum, and the crude residue was purified by chromatography
over silica gel (PE=Et2O ¼ 85:15) to afford the pure ester 2 (2.68 g, 93%) as a pale
1
yellow oil. H NMR (400 MHz, CDCl3) d 7.22–7.34 (m, 10H), 4.08–4.20 (m, 2H),
3.92 (d, J ¼ 13.6 Hz, 1H), 3.48–3.62 (m, 2H), 3.38 (d, J ¼ 13.2 Hz, 1H), 3.24–3.35
(m, 1H), 3.02–3.12 (m, 1H), 2.59–2.80 (m, 2H), 2.38–2.57 (m, 3H), 1.24 (t, J ¼ 7.2 Hz,
Hz, 3H). 13C NMR (100 MHz, CDCl3) d 14.6, 49.0, 53.4, 55.9, 60.0, 60.8, 63.0, 63.2,
127.1, 127.4, 127.6, 128.0, 128.6, 128.8, 138.3, 138.5, 172.5. Elemental analysis calcu-
lated for C21H26N2O2: C, 74.52; H, 7.74; N, 8.28; O, 9.45. Found: C, 74.49; H, 7.78;
N, 8.23; O, 9.50.

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C. NAPOLITANO ET AL.
1,4-Dibenzyl-2-(difluoromethyl)piperazine (4)
DIBAL-H solution (25% wt) in toluene (1.58mL, 2.36mmol) was added dropwise
at ꢀ78ꢁC to a solution of ester 2 (400mg, 1.18mmol) in 10mL dry toluene. The mixture
was stirred at ꢀ78ꢁC for 15min, and then saturated aqueous NH4Cl solution and
EtOAc were added. The layers were separated, and the organic phase was washed twice
with saturated aqueous NH4Cl solution, dried (Na2SO4), and filtered. Solvent removal
under reduced pressure afforded aldehyde 3 (340mg, 98%), which was used for the next
step without purification. DAST (365 mL, 2.76mmol) was added dropwise to a solution
of 3 (340mg, 1.15mmol) in 17mL dry toluene cooled to 0 ꢁC. The mixture was gently
warmed to reflux; after 3 h, the reaction was quenched with saturated aqueous NaHCO3
solution. EtOAc was added. The layers were separated, and the organic phase was
washed twice with brine, dried (Na2SO4), filtered, and concentrated under vacuum.
Chromatography of the crude residue over silica gel (PE=Et2O ¼ 9:1) gave the pure
difluoro derivative 4 (160mg, 44%) as a pale yellow oil. 1H NMR (400MHz, CDCl3)
d 7.21–7.36 (m, 10H), 6.32 (dt, J ¼ 6.0 Hz, J ¼ 56.4Hz, 1H), 3.91 (dd, J ¼ 2.8 Hz,
J ¼ 13.6 Hz, 1H), 3.78 (d, J ¼ 14.0Hz, 1H), 3.52 (d, J ¼ 13.2 Hz, 1H), 3.48 (d,
J ¼ 13.2 Hz, 1H), 2.80–2.98 (m, 2H), 2.67–2.78 (m, 1H), 2.44–2.60 (m, 3H), 2.34–2.40
(m, 1H). 13C NMR (100 MHz, CDCl3) d 51.6, 52.6, 52.9, 55.6, 56.7, 60.3, 121.0,
124.3, 127.1, 128.0, 128.6, 129.1, 130.4, 135.8, 139.7. Elemental analysis calculated for
C19H22F2N2: C, 72.13; H, 7.01; N, 8.85. Found: C, 72.24; H, 7.00; N, 8.83.
1-Benzyl-2-(difluoromethyl)piperazine (1)
ACE-Cl (6.25 mL, 57.4 mmol) was added dropwise to a solution of piperazine 4
(13.9 g, 44.1 mmol) in 50 mL dry 1,2-dichloroethane cooled to 0 ꢁC. The mixture was
gently heated to reflux. After 2 h, volatiles were evaporated under vacuum; the crude
residue was dissolved in 20 mL MeOH, and the resulting mixture was heated to
reflux for 1 h. After cooling to rt, filtration from the precipitate and volatile evapor-
ation afforded a brown oil. Crystallization from CHCl3=MeOH (9:1) afforded amine
1
1 as hydrochloride salt (white solid, 9.59 g, 83%). H NMR (400 MHz, CDCl3) d
10.03 (bs, 1H), 9.86 (bs, 1H), 7.26–7.41 (m, 5H), 6.41 (t, J ¼ 54.4 Hz, 1H), 4.10 (d,
J ¼ 13.2 Hz, 1H), 3.69 (d, J ¼ 13.2 Hz, 1H), 3.12–3.56 (m, 5H), 3.07 (bd, J ¼ 1.7 Hz,
1H), 2.82 (bs, 1H). 13C NMR (100 MHz, CDCl3) d 45.1, 48.1, 49.5, 51.6, 60.4, 119.9,
124.4, 128.0, 130.4, 139.7. Elemental analysis calculated for C12H16F2N2: C, 63.70;
H, 7.13; N, 12.38. Found: C, 63.65; H, 7.22; N, 12.33.
ACKNOWLEDGMENTS
The authors thank A. Casolari and E. Durini for careful assistance in NMR
experiments and structure assignments.
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