A versatile protocol for the preparation of substituted 1- and 2-naphthyl piperazines from aminonaphthols

Article abstract of DOI:10.1016/j.tetlet.2005.09.052

Aminonaphthols are easily transformed into a variety of 1- and 2-naphthyl piperazines using a sequence of diazotization, iodide substitution and Pd(0) catalyzed coupling reactions.

Full text of DOI:10.1016/j.tetlet.2005.09.052

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7769–7771
A versatile protocol for the preparation of substituted
1- and 2-naphthyl piperazines from aminonaphthols
Ana B. Bueno,a,* Claire J. Flynn,b Jeremy Gilmore,b Alicia Marcos,a Carlos Montero,a
Warren Porterc and Andrew C. Williamsb
aLilly SA, Avda. de la Industria, 30, 28108 Alcobendas, Madrid, Spain
bEli Lilly & Co. Ltd, Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK
cLilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
Received 15 July 2005; revised 6 September 2005; accepted 7 September 2005
Available online 27 September 2005
Abstract—Aminonaphthols are easily transformed into a variety of 1- and 2-naphthyl piperazines using a sequence of diazotization,
iodide substitution and Pd(0) catalyzed coupling reactions.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
and subsequent conversion of the amine to a piper-
azine.5 Alternative approaches from tetralones have also
been reported (Scheme 1).6,7
Naphthyl piperazines are known ligands for several
CNS targets, including serotonin (5-HT)1 and dopamine
receptors.2 During the course of our studies of naphthyl
piperazines as inhibitors of the 5-HT transporter,3 we
became interested in the evaluation of 5-, 6-, 7- and 8-
substituted 1- and 2-naphthyl piperazines of general for-
mula I and II (Fig. 1).
Despite the low yields reported, this is a valuable meth-
od; but it is restricted by the limited number of commer-
cially available tetralones. However we recognized
that many regioisomeric aminonaphthols could be
purchased, or could be accessed in a single step from
commercially available naphthalenes,8 though to date
they had not been used as starting materials for the
synthesis of substituted naphthyl piperazines. We rea-
soned that the use of two powerful reactions, the diazo-
tization of amines9 and the transition metal catalyzed
coupling of halogens/triflates with piperazines,10 could
give us the versatility needed for the incorporation of
a variety of substituents on the naphthalene moiety.
A general method to obtain these systems is not avail-
able. The most widely used approach is the Semmel–
Wolff reaction4 that relies on the formation of an oxime
from a tetralone, oxidation to the aminonaphthalene
H
N
In this paper we disclose the results obtained with
this versatile synthetic route to 5- and 6-substituted 1-
naphthyl piperazines, and 5- and 8-substituted 2-naph-
thyl piperazines, using aminonaphthols as starting
materials.
NH
N
N
R
R
II
I
2. Results and discussion
Figure 1.
The generation of diazonium salts from aromatic amines
and their subsequent decomposition to aromatic iod-
ides, chlorides, fluorides, alcohols, sulfonyl chlorides,
nitriles, azides and aldehydes is well documented in the
Keywords: Diazotization, Palladium coupling.
*
Corresponding author. Tel.: +34 9166 33402; fax: +34 9166 33411;
e-mail: Bueno_Ana_Belen@lilly.com
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.052

7770
A. B. Bueno et al. / Tetrahedron Letters 46 (2005) 7769–7771
H
N
O
NH2
N
c
a or b
R
R
R
d
Scheme 1. Reagents and conditions: (a) i. NH2OH, ii. HCl, AcOH, Ac2O, 100 ꢁC, 26–68% overall yield (Ref. 4); (b) i. BnNH2, ii. Pd–C 31–42%
overall yield (Ref. 6); (c) (ClCH2CH2)2NH, base; (d) i. piperazine, p-TsOH, ii. Pd–C. Overall yield not reported (Ref. 7).
literature.9 For the synthesis of I and II, we envisioned a
retrosynthetic scheme based on the diazotization of an
amine for the installation of the substituent R in replace-
ment of the nitrogen, and a Pd(0) catalyzed coupling for
the installation of the piperazine in replacement of the
alcohol (Scheme 2).
40% and 65% yield, respectively. Cyanation of 3b with
NaCN catalyzed by palladium (0) provided the nitrile
derivative 3d in 45% yield. Copper catalyzed reaction
of 3b with FSO2CF2CO2Me provided compound 3e in
52% yield. Although the direct decomposition of the dia-
zonium salt with suitable reagents could give rise to
compounds 3c–f from 2a in a single step, the two-step
procedure via the halide proved more suitable for our
needs (Scheme 3).
The reaction of 6-amino-1-naphthol with NaNO2/H+,
followed by controlled decomposition of the diazonium
salt with CuCl under standard conditions11 provided the
chloro derivative in only 21% yield, with dimers being
obtained as side products. Although such diazotization
reactions have been described for phenols,12 we decided
to protect the alcohol. Thus the reaction of 6-amino-1-
naphthol with N-phenyl trifluoromethanesulfonimide
provided the corresponding triflate 2a in good yield.
Subsequent reaction with NaNO2/H+, followed by
treatment with CuCl or KI, provided the corresponding
6-chloro and 6-iodo naphthyl triflates 3a and 3b, respec-
tively (Scheme 3).
It is worth noting how the triflate can act as a protecting
group in a variety of reactions (diazotization, metal–halo-
gen exchange, palladium catalyzed cyanation) without
decomposition or side reactions.
The results obtained for the synthesis of other naphthyl
triflates are collected in Table 1.
The naphthyl triflates were subsequently coupled with
(R)-2-methylpiperazine under standard palladium-cata-
lyzed conditions,13 providing the naphthyl piperazines
in variable yields, depending on the reaction conditions
and the nature of the starting material.14 When a
monoprotected piperazine was used instead in the cou-
pling step, yields were moderate but more reliable,
Compound 3b could then be further elaborated to other
functional groups. Thus lithium–halogen exchange of
the iodide, followed by treatment with FN(SO2Ph)2 or
with MeSSO2Me, provided compounds 3c and 3f in
H
N
R
N
R
H2N
OTf
OH
Scheme 2.
OTf
OH
OTf
OTf
for X = I
a
b or c
d or e
or f or g
Y
H2N
H2N
X
1a
Y = F
Y = CN
Y = CF3
2a
X = Cl 3a
X = I 3b
3c
3d
3e
Y = SMe 3f
Scheme 3. Reagents and conditions: (a) PhN(SO2CF3)2, NaOt-Bu, THF, 0 ꢁC (94%); (b) i. HCl, H2O, NaNO2, ii. CuCl, H2O (52%); (c) i. HCl, H2O,
NaNO2, ii. KI, H2O (74%); (d) t-BuLi (2·), FN(SO2Ph)2, THF, ꢀ78 ꢁC to rt (40%); (e) CuI, Pd(PPh3)4, NaCN, THF, reflux (41%); (f)
FSO2CF2CO2Me, CuI, DMF (52%); (g) t-BuLi (2·), MeSSO2Me, THF, ꢀ78 ꢁC to rt (65%).

A. B. Bueno et al. / Tetrahedron Letters 46 (2005) 7769–7771
Table 1. Synthesis of substituted naphthyl triflates from aminonaphtholsa
7771
X
OTf
OTf
OTf
OTf
X
X
X
3a-e
4a-d
6a-e
5a-d
I
Cl
F
CN
CF3
70%
49%
28%
31%
36%
70%
70%
28%
28%
77%
65%
30%
56%
77%
55%
63%
72%
45%
b
b
—
—
a Overall yield from the aminonaphthol.
b Not synthesized.
Moore, N. A.; Pullar, I.; Sanger, G. J.; Tomlinson, R.;
Tree, B.; Wedley, S. Bioorg. Med. Chem. Lett. 2004, 14,
2469–2472; Torrado, A.; Lamas, C.; Agejas, J.; Jimenez,
R'
N
H
N
´
A.; Dıaz, N.; Gilmore, J.; Boot, J.; Findlay, J.; Hayhurst,
R
R
N
OTf
N
H
L.; Wallace, L.; Broadmore, R.; Tomlinson, R. Bioorg.
Med. Chem. 2004, 12, 5277–5295.
4. Semmler, W. Chem. Ber. 1892, 25, 3352; Wolff, L. Liebigs
Ann. Chem. 1902, 322, 351.
5. Glennon, R. A.; Naimar, N. A.; Edward Pearson, M.;
Doyle Smith, J.; Ismaiel, A. M.; Titeler, M.; Lyon, R. A.
J. Med. Chem. 1989, 32, 1921–1926.
6. Janin, Y. L.; Bisagni, E. Synthesis 1993, 57–59.
7. Chenard, B. L.; Howard, H. R.; Macor, J.; Shenk, K. D.
Patent application WO9600720, 1996.
8. 7-Amino-1-naphthol: Mueller, Hamilton J. Am. Chem.
Soc. 1944, 66, 860; 8-Amino-1-naphthol: Fichter, Gageur
Chem. Ber. 1906, 39, 3337; 2-Amino-7-naphthol: Edwards,
B.; Sparks, A.; Voyta, J. C.; Strong, R.; Murphy, O.;
Bronstein, I. J. Org. Chem. 1990, 55, 6225–6229. 2-Amino-
6-naphthol: Seifert, H. Patent DE701902, 1941.
9. Zollinger, H. Azo and Diazo Chemistry; Wiley-Inter-
science: New York, 1961; The Chemistry of Diazonium
and Diazo groups; Patai, S., Ed.; Wiley: New York, 1978;
Chapters 8, 11 and 14; Saunders, H.; Allen, R. L. M.
Aromatic Diazo Compounds, 3rd ed.; Edward Arnold:
London, 1985.
a or b
Scheme 4. Reagents and conditions: (a) for R0 = H: Pd(OAc)2,
BINAP, NaOt-Bu, toluene, 100 ꢁC (30–95%); (b) for R0 = COCF3:
i. Pd(OAc)2, BINAP, Cs2CO3, toluene, 100 ꢁC, ii. NaBH4, EtOH (60–
65%).
although an extra deprotection step had to be per-
formed (Scheme 4).
In summary, substituted naphthyl piperazines can be
easily accessed by a four step process that relies on the
diazotization of aromatic amines; the versatility of aryl
iodides for incorporation of varied functionality; and
the Pd(0) catalyzed coupling of triflates.
Acknowledgement
10. For Pd(0) catalyzed coupling of bromonaphthalenes with
piperazines see: Kerrigan, F.; Martin, C.; Thomas, G. H.
Tetrahedron Lett. 1998, 39, 2219–2222; for Pd(0) cata-
lyzed coupling of chloronaphthalenes with piperazines see:
Reddy, N. P.; Tanaka, M. Tetrahedron Lett. 1997, 38,
4807–4810; for Ni(0) catalyzed coupling of chloronaph-
thalenes with piperazines see: Brenner, E.; Schneider, R.;
Fort, Y. Tetrahedron 1999, 55, 12829–12842.
This research was supported by the Spanish Profarma II
´
Program (Ministerio de Ciencia y Tecnologıa).
References and notes
´
´
1. Oru´s, L.; Perez-Silanes, S.; Oficialdegui, A.-M.; Martınez-
Esparza, J.; Del Castillo, J.-C.; Mourelle, M.; Langer, T.;
Guccione, S.; Donzella, G.; Krovat, E. M.; Poptodorov,
´
11. Sami, S. M.; Dorr, R. T.; Alberts, D. S.; Solyom, A. M.;
Remers, W. A. J. Med. Chem. 1996, 39, 4978–4983.
12. Kuhn, R.; Hensel, H. R. Chem. Ber. 1951, 84, 557.
13. Ahman, J.; Buchwald, S. L. Tetrahedron Lett. 1997, 38,
6363–6366.
´
K.; Lasheras, B.; Ballaz, S.; Hervıas, I.; Tordera, R.;
´
Del Rıo, J.; Monge, A. J. Med. Chem. 2002, 45, 4128–
4139.
2. Lowe, J. A., III; Seeger, T. F.; Nagel, A. A.; Howard, H.
R.; Seymour, P. A.; Heym, J. H.; Ewing, F. E.; Newman,
M. E.; Schmidt, A. W.; Furman, J. S.; Vincent, L. A.;
Maloney, P. R.; Robinson, G. L.; Reynolds, L. S.; Vinick,
F. J. J. Med. Chem. 1991, 34, 1860–1866.
14. Best yields were obtained using the following conditions:
1 M triflate concentration in reaction mixture, 1.2 equiv of
2-methyl piperazine, 1.4 equiv of sodium tert-butoxide,
5 mol % palladium catalyst, 1.4 equiv of racemic BINAP
relative to palladium, 48 h at 100 ꢁC stirring under N2
atmosphere, using thoroughly degassed anhydrous toluene
as solvent.
3. Timms, G. H.; Boot, J. R.; Broadmore, R. J.; Carney, S.
L.; Cooper, J.; Findlay, J. D.; Gilmore, J.; Mitchell, S.;