Asymmetric synthesis of 2-arylpiperazines

Article abstract of DOI:10.1016/j.bmcl.2014.10.047

An asymmetric synthesis of 2-arylpiperazines starting from phenacyl bromides, a variety of which are easily available, has been established. The synthesis features a CBS reduction of phenacyl bromide to provide optically enriched compounds, an S_N2 reaction of 1,2,3-oxathiazolidine 2-oxides with an azide anion with invert of configuration, and construction of the piperazine ring via reduction of piperazine-2,3-diones.

Full text of DOI:10.1016/j.bmcl.2014.10.047

Bioorganic & Medicinal Chemistry Letters xxx (2014) xxx–xxx
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Asymmetric synthesis of 2-arylpiperazines
,
Satoshi Yokoshima , Kazutoshi Watanabe ,à, Fumiaki Uehara, Yoshihiro Usui §, Hiroshi Tanaka
⇑
⇑
Research Division, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric synthesis of 2-arylpiperazines starting from phenacyl bromides, a variety of which are
easily available, has been established. The synthesis features a CBS reduction of phenacyl bromide to
provide optically enriched compounds, an SN2 reaction of 1,2,3-oxathiazolidine 2-oxides with an azide
anion with invert of configuration, and construction of the piperazine ring via reduction of piperazine-
2,3-diones.
Received 22 September 2014
Revised 14 October 2014
Accepted 15 October 2014
Available online xxxx
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric synthesis
Heterocycles
Piperazines
2-Arylpiperazines (Fig. 1) are fascinating moieties in the devel-
opment of novel drugs because the aryl groups can be arranged on
the molecules with restricted conformations, while the nitrogen
atoms can be used to connect to other units.1 A variety of synthetic
methods for 2-arylpiperazines have been reported to date. While
asymmetric preparations of 2-arylpiperazines, which include
separation of diastereomers,1c resolution of racemic materials,2,3
enantioselective addition of Grignard reagents to pyrazine N-
oxides,4 and diastereoselective reduction at the benzylic position,5
have also been reported,6 methods that can be used to synthesize a
variety of derivatives are relatively limited.
Figure 1. 2-Arylpiperazines.
During the optimization of lead compound in our GSK-3b inhib-
itor project,7 we have been interested in introducing an optically
active 2-phenylpiperazine moiety as the analog of promising
compound possessing 2-phenylmorpholine substructure.8 To
supply optically active 2-arylpiperazines, we developed an asym-
metric preparation method applicable to various derivatives.
Our first attempt was based on the reduction of diketopipera-
zine, which can be easily derived from amino acids. Condensation
of (S)-phenylglycine methyl ester (1) with N-Boc-glycine yielded
dipeptide 2 (Scheme 1). After cleaving the Boc group, the resulting
amine was treated under basic conditions to provide diketopiper-
azine 3. Subsequent reduction of 3 with lithium aluminum hydride
Scheme 1. Reagents and conditions: (a) N-Boc-glycine, EDCI, Et3N, CH2Cl2, quant;
(b) HCl in AcOEt; aq NaHCO3, 36%; (c) LiAlH4, THF, reflux, quant.
furnished phenylpiperazine 4. Then the two nitrogen atoms were
protected with Boc groups, and the optical purity was determined
by HPLC, revealing that partial racemization occurred (73% ee). In
addition to this result, the limited availability of phenylglycines
derivatives made us turn our attention to development of other
methods.
⇑
Corresponding authors.
E-mail addresses: yokosima@ps.nagoya-u.ac.jp (S. Yokoshima), Watanabe.
Kazutoshi@mb.mt-pharma.co.jp (K. Watanabe).
Present address: Graduate School of Pharmaceutical Sciences, Nagoya University,
Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8601, Japan.
à
Present address: Research Division, Mitsubishi Tanabe Pharma Corporation,
2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan.
From the viewpoint of the availability, we decided to employ
1,2-aminoalcohols as substrates. Asymmetric aminohydroxylation
§
Present address: Synthetic Chemistry Department, Tanabe R&D Service Co., Ltd,
2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan.
http://dx.doi.org/10.1016/j.bmcl.2014.10.047
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Yokoshima, S.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.10.047

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S. Yokoshima et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
Scheme 2. Reagents and conditions: (a) MsCl, Et3N, CH2Cl2; (b) BnNH2, K2CO3, DMF,
11% (2 steps).
(AA) of styrenes may provide optically enriched 2-amino-2-pheny-
lethanols. Fortunately, examples of AAs employing chloroacet-
amide (6) as a reagent have been reported.9 Because resulting
product 7 (Scheme 2) seems to possess suitable functional groups
to synthesize 2-arylpiperazine, and we tried to convert 7. After
introducing a mesyl group onto the hydroxy group, resulting
mesylate 8 was treated with benzylamine. However, desired piper-
azine 10 was not obtained. Instead, oxazoline 9 was isolated,
indicating that the intramolecular SN2 reaction of the mesylate
with the carbonyl oxygen is faster than the intermolecular one
with benzylamine.
Scheme 4. Reagents and conditions: (a) (S)-CBS catalyst, BH3ÁTHF, THF, À40 °C; (b)
aq KOH, ether; (c) BnNH2, 80 °C, 75% (3 steps); (d) SOCl2, Et3N, CH2Cl2, –78 °C, 88%;
(e) NaN3, DMF, 70 °C, 92%; (f) Ph3P, THF–H2O, 60 °C; (g) diethyl oxalate, 120 °C, 80%
(2 steps); (h) BH3ÁTHF, THF, 96%; (i) Boc2O, Et3N, CH2Cl2, 80%; (j) ClCO2CHClCH3,
ClCH2CH2Cl; MeOH, reflux; (k) Boc2O, Et3N, CH2Cl2; recrystallization from hexane,
65% (2 steps), 99.7% ee.
We then attempted using a regioisomeric 1,2-aminoalcohol, 2-
amino-1-arylethanol, which was prepared via epoxide cleavage of
styrene oxide with amine (Scheme 3). Commercially available ( )-
4-bromostyrene oxide was reacted with
a-phenethylamine to
furnish 11, which was condensed with N-Boc-glycine to give 12.
After introducing a mesyl group onto the hydroxy group, the Boc
group was cleaved with TFA. The resulting mixture was treated
with aqueous sodium bicarbonate to liberate the amine for the
intramolecular SN2 reaction. However, the only detectable product
was aminoalcohol 11 because the reaction likely proceeds via an
undesired intramolecular reaction of the mesylate with the car-
bonyl oxygen and subsequent hydrolysis of resulting oxazolinium
intermediate 14.
group resulted in undesired intramolecular reactions of the
carbonyl oxygen. To avoid these undesired reactions, we attempted
to employ a cyclic sulfamidite (1,2,3-oxathiazolidine 2-oxide)10 as a
substrate with the vision that activation of the hydroxy group and
protection of the amino group would be realized simultaneously.
The synthesis began by preparing an optically active styrene
oxide. CBS reduction11,12 of 4-bromophenacyl bromide (15) gave
bromohydrin 16 (Scheme 4). Treatment of 16 with aqueous potas-
sium hydroxide afforded styrene oxide 17, which was subsequently
reacted with benzylamine to produce 2-amino-1-phenylethanol 18.
Treating 18 with thionyl chloride in the presence of triethylamine
furnished 1,2,3-oxathiazolidine 2-oxide 19 as a mixture of diaste-
reomers.13 Upon heating 19 with sodium azide, the SN2 reaction
proceeded smoothly at the benzylic position with inversion of
configuration to afford azide 20, stereoselectively introducing the
nitrogen atoms for the piperazine synthesis.
As mentioned above, activation of the hydroxy group in 1,2-ami-
noalcohols, in which the amino group is substituted with an acyl
Next, we tried to form the piperazine ring. Reduction of azide 20
with triphenylphosphine, and subsequent condensation of result-
ing 1,2-diamine 21 with diethyl oxalate furnished lactam 22 as a
highly crystalline solid.14 Reducing the carbonyl groups with
borane gave piperazine 23. After protecting the secondary amine
with a Boc group, the benzyl group was removed by treatment
with ACE-Cl,15 yielding a mixture of mono Boc-protected pipera-
zine 24 and deprotected piperazine 25. The mixture was treated
Scheme 3. Reagents and conditions: (a) 80 °C, 61%; (b) N-Boc-glycine, EDCI, CH2Cl2,
83%; (c) MsCl, Et3N, CH2Cl2; (d) TFA, CH2Cl2; aq NaHCO3.
Figure 2. Other synthesized 2-arylpiperazines.
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S. Yokoshima et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
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with Boc2O to afford, after recrystallization from hexane, the
product 26 as white crystals in 65% yield (2 steps) and 99.7% ee.
We have also used this procedure to synthesize other 2-arylpip-
erazines starting from the corresponding phenacyl bromides
(Fig. 2).16
In conclusion, we have achieved the asymmetric syntheses of 2-
arylpiperazines. CBS reduction of phenacyl bromides furnishes
optically enriched substrates. The nitrogen atom at the benzylic
position can be installed via an SN2 reaction of an azide anion with
1,2,3-oxathiazolidine 2-oxide, giving optically active 1,2-diamines.
The piperazine ring is constructed via the reduction of piperazine-
2,3-diones. Currently, we are preparing other 2-arylpiperazines for
potential applications in new drugs. The results will be reported in
due course.
Acknowledgments
We gratefully thank Sanofi-Aventis R&D CNS Research
Department (formerly Sanofi-Synthelabo R&D, Bagneux, France)
for the fruitful collaboration.
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13. Compound 19 has two stereogenic centers at the benzylic position and the
sulfur atom.
References and notes
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Please cite this article in press as: Yokoshima, S.; et al. Bioorg. Med. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.bmcl.2014.10.047