J. T. Repine et al. / Tetrahedron Letters 48 (2007) 5539–5541
5541
In summary, a collection of monofluorinated 1-(naph-
thalen-1-yl)piperazines 2–8 were prepared as templates
for drug discovery from a variety of routes and starting
materials.
F
F
Br
F
a
26
27
b or c
OH
OH
O
F
F
24
25
Supplementary data
Supplementary data associated with this article can be
F
e, f
d
26
N
F
7
28
OTf
References and notes
N
H
HCl
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Scheme 5. Reagents and conditions: (a) Mg/THF, furan, 2 h, 65 °C,
15 h, 97%; (b) concentrated HCl/ethanol, reflux, 2 h, 68%; (c)
BF3ÆOEt2, CH2Cl2, 0 °C to rt, 1.5 h, 60%; (d) Et3N, Tf2O CH2Cl2,
rt, 1 h, 99%; (e) 0.1 equiv Pd(OAc)2, 1.5 equiv NaOtBu, 0.12 equiv 2-
(dicyclophosphino)biphenyl, 1.5 equiv Boc-piperazine, toluene, 85 °C,
3 h, 80%; (f) HCl (gas), CH2Cl2, rt, 3 h, 96%.
4. Manetti, F.; Corelli, F.; Strappaghetti, G.; Botta, M. Curr.
Med. Chem. 2002, 9, 1303–1321.
b
a
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HO2C
Br
NH2 Br
F
Br
29
30
31
c
d
F
N
N
F
N
TFA
32
8
N
Boc
H
Scheme 6. Reagents and conditions: (a) H2SO4, NaN3, CHCl3, 40 °C,
96%; (b) 48% HBF4, NaNO2, THF; NaBF4, 69%; (c) Pd(OAc)2,
NaOtBu, 2-(dicyclohexylphosphino)biphenyl, Boc-piperazine, toluene,
80 °C, 38%; (d) TFA, CH2Cl2, 0 °C, 89%.
coupled to Boc-piperazine under Buchwald–Hartwig–
Migita conditions to give 7 after deprotection of the
Boc group.
The synthesis of 1-(8-fluoronaphthalen-1-yl)piperazine
(8) (Scheme 6) was analogous to the synthesis of 5
(Scheme 4), except that the starting 1-bromo-8-naph-
thoic acid (29),ꢀ was commercially available. Carboxylic
acid 29 was converted to amine 30 via a Curtius rear-
rangement using sodium azide and sulfuric acid. Diazo-
tization followed by fluorination of the diazonium salt
with fluoroboric acid provided the requisite 1-bromo-
8-fluoronaphthalene (31), which was coupled with
Boc-piperazine under Buchwald–Hartwig–Migita condi-
tions to give 32. Finally acidic deprotection with trifluo-
roacetic acid afforded 1-(8-fluoronaphthalen-1-yl)-
piperazine (8).
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Castagnetti, E. Eur. J. Org. Chem. 2001, 3991–3997.
ꢀ 1-Bromo-8-naphthoic acid, CO-0063, Carbocore Research Chemicals
and Intermediates.