2
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.