Synthesis of constrained arylpiperidines using intramolecular Heck or radical reactions

Article abstract of DOI:10.1016/S0040-4039(01)01191-1

Two intramolecular routes were experimented to reach the hexahydrobenzofuro[2,3-c]pyridine platform: a Heck and a radical reaction. The radical route was applicable to all substrates, whereas the Heck route was of limited use. The key adducts were obtained via a Mitsunobu condensation between halogenated phenols and an allylic alcohol, the 3-hydroxy-tetrahydropyridine.

Full text of DOI:10.1016/S0040-4039(01)01191-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6499–6502
Synthesis of constrained arylpiperidines using intramolecular
Heck or radical reactions
Christophe Morice,a Mathias Domostoj,a Karin Briner,b Andre´ Mann,a,* Jean Sufferta and
Camille-Georges Wermutha
aLaboratoire de Pharmacochimie de la Communication Cellulaire, Universite´ Louis Pasteur, Faculte´ de Pharmacie,
UMR 7081 du CNRS/ULP, 74, route du Rhin, BP 24, 67401 Illkirch Cedex, France
bLilly Research Laboratories, Eli-Lilly and Company, Indianapolis, IN 46285, USA
Received 23 May 2001; revised 2 July 2001; accepted 4 July 2001
Abstract—Two intramolecular routes were experimented to reach the hexahydrobenzofuro[2,3-c]pyridine platform: a Heck and a
radical reaction. The radical route was applicable to all substrates, whereas the Heck route was of limited use. The key adducts
were obtained via a Mitsunobu condensation between halogenated phenols and an allylic alcohol, the 3-hydroxy-tetra-
hydropyridine. © 2001 Elsevier Science Ltd. All rights reserved.
The examination of medicinal chemistry reports
revealed that the structures of a great deal of pharma-
cological tools and/or drugs are constituted of an
arylpiperazine (AP) core 1.1 This is not really surprising
if one considers that the AP moiety is isosteric to
dopamine or serotonine which are among the most
targeted endogenous neurotransmitters in medicinal
chemistry. Furthermore conformational restriction is a
powerful device for the identification of a bioactive
conformation,2 several constricted AP were designed
such as 2 or 3.3,4 In our current work for the design of
new selective agents acting in the central nervous sys-
tem (CNS), we decided to prepare tricyclic adducts such
as 4, hexahydrobenzofuro[2,3-c]pyridines. The design
of this platform was motivated by the following points
(i) piperidines and AP have generally comparable
bioactivity, therefore the less basic nitrogen was
skipped; (ii) the oxygen atom link between the rings is
a potential hydrogen bond acceptor;5,6 (iii) the distance
of the basic nitrogen and the phenyl ring is fixed by the
cis junction of the structure; (iv) few operative methods
for the preparation of 4 are available in the literature.
With all these considerations, we embarked on the
synthesis of 4, in the quest of new leads for the CNS
receptors (Scheme 1). The reported routes to 4 are
linear, requiring tedious transformations and lacking
N
N
X
N
NH
NH
O
NH
R
NH
1 (AP)
2
R
3
4
+
NPG
4
X
X
HO
O
OH
NPG
B
C
A
Scheme 1. Structures of some conformational restricted phenylpiperazines, and retrosynthesis analysis towards 4.
Keywords: Heck reaction; radical reaction; benzofuropyridine; conformational restriction.
* Corresponding author. Tel.: +(33) 33 90 24 42 27; fax: +(33) 3 90 24 43 10; e-mail: andre.mann@pharma.u-strasbg.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01191-1

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C. Morice et al. / Tetrahedron Letters 42 (2001) 6499–6502
flexibility,7 we designed a short and versatile synthesis
of these compounds in order to reach diversity (Scheme
1). This paper describes our findings during the prepa-
ration of 4.
Pd(PPh3)4, triethylamine as base in a refluxing THF/
CH3CN mixture.9,10 In our hands when performed on
compounds 7c–e the expected Heck adducts 8c–e could
be isolated in good to modest yields (75 and 30%). The
cyclic carbopalladation was effective and furthermore,
the dehydropalladation was regioselective, installing the
double bond so as to produce an enamide function in
8c–e. Interestingly this acyl-enamide function could be
exploited for the introduction of various groups next to
the nitrogen atom. Unfortunately the other substrates
7a–b and 7f–h, under the same conditions gave no trace
of cyclization: the starting material disappeared, only
phenol and dihydropyridine were recovered. We believe
that in the case of the bromides 7a–b, and the more
sterically crowded iodide 7f–h the oxidative palladium
insertion did not occur. The reaction follows an other
pathway: a p-allyl complex is formed and the phenol
behaves as a leaving group. Owing to these disappoint-
ing results no other catalytic mixture was tried. We
experimented directly the second alternative which
makes use of a radical pathway. The ethers 7a–h were
submitted to the conditions recommended by
Snieckus:14 Bu3SnH (2.5 equiv.) and a catalytic amount
of AIBN. As expected the intramolecular 5-exo radical
cyclization proceeds cleanly and, we were pleased to
observe a complete consumption of the starting mate-
rial, after 3 h refluxing in benzene.15 The reaction was
productive either with bromine (7a–b) or with iodine
(7c–h), irrespective of the substituents present on the
aromatic ring. To facilitate the work-up of these reac-
tions we used the procedure of Curran.16 The com-
pounds were purified by column chromatography on
silica gel and excellent yields of the tricyclic adducts
9a–h were obtained (from 79 to 90%). As expected and
confirmed by extensive NMR studies, the stereochem-
istry of the ring junction was cis. A single X-ray
analysis performed on the corresponding t-Boc ana-
logue 9a% of 9a confirmed the assigned structure.17
Similarly catalytic hydrogenation of compounds 8c–d
provided also the adducts 9c–d. Finally the carbamate
protection on the nitrogen was cleaved under basic
hydrolytic conditions to give rise to the expected final
compounds 10a–h, as crystalline hydrochlorides in sat-
isfying yields (Scheme 3).
Our retrosynthesis relies on a disconnection crossing
the furano ring between the two six-membered cycles.
In fact the phenolic ether link is rather easy to con-
struct from phenols B and allylic alcohol C. If now an
halide is attached ortho to the oxygen atom on the
aromatic ring, an intramolecular Heck type coupling8
or alternatively a radical drived process may produce
the ring junction via the formation of a CꢀC bond,
provided that an acceptor such as a double bond is
properly set as it will be in the 3-OH-tetra-
hydropyridine C. With synthon A, where X stands for
I or Br, we have identified the desired structure, which
is accessible by coupling of fragments B (phenols) and
C (piperidinol). Indeed several ortho halogenated phe-
nols are commercially available, or accessible in few
known steps, and the synthesis of tetrahydropyridinol
C has been described. Such tricyclic constructions have
already been made in the past but only in an all carbon
version.9,10 Here we have experimented the intramolec-
ular cyclization with an heterocyclic partner.
The key intermediates A were obtained in the following
way. The phenols 6a–c are commercially available,
whereas the phenols 6d–h were prepared by ortho-
metallation using a three-step sequence starting from
the phenols 5d–h: the phenolic oxygen was protected as
a MOM ether (methoxymethylether), then the adjacent
proton was abstracted with BuLi in Et2O, and the
subsequent stabilized anion, quenched with I2 as solu-
tion in ether.11 The non optimized yields were moderate
to good over the three steps (Scheme 2).
The piperidinol fragment C was obtained uneventfully
as reported from 4-oxopiperidine.12 Then the
halogenophenols 6a–e were coupled to compound C
under classical Mitsunobu conditions to reach the phe-
nolic ethers 7a–e in good yields.13 The intramolecular
Heck reaction was performed on 7a–h using classical
conditions reported by Negishi:10 a catalytic amount of
yield %**
a
b
c
d
e
R1 = H; R2 = H;
R1 = Br; R2 =H;
R1 = H; R2 = H;
X = Br
X = Br
X = I
*
*
X
i, i i , i i i
*
R2
OH
R2
R1 = H; R2 = Me; X = I
R1 = H; R2 = OMe; X = I
OH
70
45
R1
R1
6a-h
5a-h
f
R1 = H; R2 = CF3; X = I
74
79
75
R1 = H; R2 = F;
X = I
*The compounds are commercial
** Isolated overall yields
g
h
R1 = Me; R2 = Me; X = I
Scheme 2. Reagents and conditions: (i) NaH, MeOCH2Cl, THF; (ii) BuLi, then I2 as solution in ether; (iii) TMSCl, NaI, CH3CN.

C. Morice et al. / Tetrahedron Letters 42 (2001) 6499–6502
6501
R2
R1
R2
R1
R2
R1
i
i i
X
O
O
O
N
N
N
CO2Et
7a-h
CO2Et
CO2Et
9a-h
8c-e
i i i
i v
R2
R1
i v
O
9c-e
N
O
CO2tBoc
NH
9a'
10a-h
X-ray
10a,b
R1
8a
9a
R2
X
a
b
H
H
H
Br
Br
0
0
86
80
88
80
Br
c
d
e
81
90
90
75
30
90
50
60
44
H
H
H
I
I
Me
H
OMe
I
30
0
87
79
79
f
H
I
I
I
CF3
F
g
H
58
53
h
Me
Me
a) yield in %; b) yield as the hydrochloride.
Scheme 3. Reagents and conditions: (i) Pd(PPh3)4, triethylamine, CH3CN/THF, reflux 20 h (see Ref. 18); (ii) Bu3SnH, AIBN,
C6H6, reflux (see Ref. 19); (iii) H2 Pd(OH)2/C in methanol, 30 psi; (iv) KOH, EtOH, reflux, then HCl (gas) in Et2O.
Finally we have prepared a series of benzofuropiperidi-
nes 10a–h from rapidly accessible precursors using
intramolecular pathways, either a Heck or a radical
reaction, the last route being the most reliable from a
preparative point of view. Compounds 10a–h will be
submitted to a biological trial, and the obtained results
will be reported on another forum.
4. Bo¨s, M.; Jenck, F.; Martin, J. R.; Moreau, J. L.; Mutel,
V.; Sleight, A. J.; Widmer, U. Eur. J. Med. Chem. 1997,
32, 253–261.
5. Monte, A. P.; Marona-Lewicka, D.; Parker, M. A.;
Wainscott, D. R.; Nelson, L. D.; Nichols, D. E. J. Med.
Chem. 1996, 39, 2953–2961 and references cited therein.
6. Parker, M. A.; Maron-Lewick, D.; Lucaites, V. L.; Nel-
son, D. L.; Nichols, D. E. J. Med. Chem. 1998, 41,
5148–5149.
7. Hutchinson, A. J.; de Jesus, R.; Williams, M.; Simke, J.
P.; Neale, F. R.; Jakson, R. H.; Ambrose, F.; Barbaz, B.
J.; Sills, M. A. J. Med. Chem. 1989, 32, 2221–2226.
8. For excellent reviews on the Heck-Tsuji reaction, see: (a)
Bra¨se, S.; de Meijere, A. In Metal-catalyzed Cross-cou-
pling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-
CH: Weinheim; 1997, pp. 99–166; (b) Tsuji, J. In
Palladium Reagents and Catalysts; Wiley & Sons: New
York, 1995.
Acknowledgements
One of us (C.M.) thanks Eli Lilly (Indianapolis, USA)
for funding.
References
9. Larock, R. C.; Stinn, D. E. Tetrahedron Lett. 1988, 29,
4687–4690.
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Silveira, A. Heterocycles 1989, 28, 55–58.
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1. Elks, J.; Ganellin, C. R. Dictionary of Drugs, Chemical
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2. For an excellent discussion, see: Wermuth, C. G. The
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York, 1996.
12. Imanishi, T.; Shin, H.; Hanaoka, M.; Imanishi, I. Chem.
Pharm. Bull. 1982, 10, 3617–3623. We found that if, in
the reported Shapiro reaction, potassium tert-butoxide is
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C. Morice et al. / Tetrahedron Letters 42 (2001) 6499–6502
replaced by sodium hydride, the yield was substantially
improved.
13. Mistsunobu, O. Synthesis 1981, 1–28.
200 MHz) l (ppm): 1.29 (brs, 3H), 3.72 (dd, J 13.7 and
3.5 Hz, 1H), 3.91 (br d, J 4.4 Hz, 1H), 4.02 (m, 1H), 4.22
(m, 2H), 5.05 (m, 2H), 6.81 (d, J 7.8 Hz, 1H), 6.96 (br s,
1H), 7.14 (q, J 7.8 Hz, 1H), 7.17 (d, J 7.5 Hz, 1H).
19. Experimental for the preparation of 9h: A 0.02 N
degazed benzene solution (150 ml) of 7h (1.17 g, 3 mmol)
under argon was treated with Bu3SnH (1.245 ml, 4.5
mmol), and AIBN (50 mg) and refluxed for 2 h. Solvents
were removed in vacuo and the resulting residue was
dissolved in ether (150 ml) and treated with DBU (670 ml,
4.5 mmol). Excess of DBU was neutralized with a 1 M
Br2 solution, the precipitate filtered and the solution
concentrated in vacuo. The residue was purified by flash
chromatography on silica gel eluting with ether/hexane:
40/60. Compound 9h was obtained as a colorless oil (711
14. Skankaran, K.; Sloan, C. P.; Sniekus, V. Tetrahedron
Lett. 1985, 26, 6001–6004.
15. Curran, D. P.; Porter, N. P.; Giese, B. Sterochemistry of
Radical Reactions: Concepts, Guidelines, and Synthetic
Applications; VCH: Weinheim, 1996; p. 31.
16. Curran, D. P.; Chang, C. T. J. Org. Chem. 1989, 54,
3140–3157.
17. The X ray structure coordinates for 9a% are on deposit at
the Cambridge Crystallographic Database under the fol-
lowing code: CCDC 158871. Copies of the data can be
obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB1EZ, UK (fax (+44) 1223-
336-033.
18. Experimental for the preparation of 8c: A solution of 7c
(950 mg, 2.6 mmol) in a mixture of CH3CN/THF (30
ml/10 ml) under argon was treated with Pd(PPh3)4 (294
mg, 0.195 mmol), and Et3N (530 ml, 3.8 mmol) and
refluxed for 15 h. The solvent was removed in vacuo and
the resulting residue was purified by flash chromatogra-
phy on silica gel eluting with ether/hexane: 20/80. Com-
pound 8c was obtained as a colorless oil (475 mg, 75%).
1H NMR (8c as a mixture of rotamers): (CDCl3, 330 K,
1
mg, 90%). H NMR: (CDCl3, 200 MHz, 300 K) l (ppm):
1.27 (br s, 3H), 1.86 (m, 1H), 2.10 (m, 1H), 2.21 (s, 1H),
3.25 (br m, 1H), 3.40 (m, 1H), 3.59 (dt, J 8.7 and 5.6 Hz,
1H), 3.67 (br d, J 12.9 Hz, 1H), 3.91 (dd, J 14.3 and 5
Hz), 4.15 (q, J 6.8 Hz, 2H), 4.90 (br s, 1H), 6.79 (t, J 7.2
Hz), 6.96 (d, J 7.5 Hz, 1H), 6.97 (d, J 7.2 Hz). 13C NMR:
(CDCl3, 50 MHz, 300°K) l (ppm): 14.6, 15.1, 26.2, 38.8,
39.9, 42.7, 61.2, 79.4, 119.8, 120.6, 121.4, 128.5, 129.7,
156.2, 157.8.