A novel synthesis of N-(piperidin-4-yl)-1,3-dihydroindol-2-one via an intramolecular Pd-catalyzed amination

Article abstract of DOI:10.1016/j.tetlet.2004.09.121

A novel efficient synthetic route to the pharmaceutical key intermediate N-(piperidin-4-yl)-1,3-dihydroindol-2-one is described. The key step involves a high-yielding intramolecular palladium-catalyzed amination reaction using Buchwald's X-Phos ligand und

Full text of DOI:10.1016/j.tetlet.2004.09.121

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8535–8537
A novel synthesis of N-(piperidin-4-yl)-1,3-dihydroindol-2-one
via an intramolecular Pd-catalyzed amination
*
Adri van den Hoogenband, Jack A. J. den Hartog, Jos H. M. Lange and
Jan Willem Terpstra
Solvay Pharmaceuticals, Research Laboratories, C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands
Received 20 July 2004; revised 7 September 2004; accepted 16 September 2004
Available online 1 October 2004
Dedicated to Professor Victor Snieckus for his stimulating work in the area of organometallic chemistry
Abstract—A novel efficient synthetic route to the pharmaceutical key intermediate N-(piperidin-4-yl)-1,3-dihydroindol-2-one is
described. The key step involves a high-yielding intramolecular palladium-catalyzed amination reaction using BuchwaldÕs X-Phos
ligand under mild reaction conditions.
Ó 2004 Elsevier Ltd. All rights reserved.
1,3-Dihydroindol-2-one (oxindole) derivatives are of
great pharmaceutical interest as growth hormone secret-
O
O
1
agogues, P-glycoprotein-mediated multiple drug resist-
3
a)
N
N
Bn
Br
2
ance inhibitors,
4
anti-inflammatory agents,
and
N
H
N
Bn
serotonergics. In addition, the oxindole moiety consti-
tutes a key structural element in several natural prod-
5
2
ucts. The 1,3-dihydroindol-2-one derivative 6 (Scheme
3
1
) is of current pharmaceutical interest as a key interme-
6
Scheme 1. (a) Conditions described in Table 1.
diate in the synthesis of ORL-1 receptor ligands. As a
consequence, the development of novel synthetic strate-
gies leading to substituted oxindole derivatives is of
great importance. Hitherto, two different synthetic ap-
proaches to the 3-unsubstituted 1-(piperidinyl-4-yl)oxin-
dole 6 have been described. Unfortunately, these routes
the Pd-catalyzed intramolecular amination of the aryl
bromide 1, thereby leading to the N-protected oxindole
derivative 2 as schematically depicted in Scheme 1. Such
reactions proceed under relatively mild basic conditions.
In particular, the effect of different phosphine ligands on
the efficiency and yield of this conversion is highlighted
herein.
7
either consist of a lengthy five-step synthesis or a three-
step synthesis from N-benzylpiperidin-4-one, which suf-
6
fers from harsh reaction conditions (AlCl , 160°C) in
3
the last intramolecular Friedel–Crafts acylation step. It
is clear that such harsh conditions do not comply with
the presence of vulnerable substituents on the oxindole
aromatic ring.
9
The starting material 1 is known but we slightly im-
proved its preparation, resulting in a considerably
higher yield (Scheme 2). Thus the acid chloride 3 was
amidated with amine 4 (both commercially available)
8
Our interest in N-arylations prompted us to devise an
efficient route for the synthesis of the pharmaceutical
key intermediate 6. The resulting approach is based on
1
to afford compound 1 in high yield. Its H NMR data
were in full accordance with the literature data.
The resulting amide 1 was subjected to several reaction
1
0
conditions, based on the earlier work of Buchwald in
order to find the optimal combination of parameters
leading to the oxindole 2 (Scheme 1 and Table 1).
*
0
Corresponding author. Tel.: +31 (0)294 479605; fax: +31 (0)294
77138; e-mail: adri.vandenhoogenband@solvay.com
4
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.121

8536
A. van den Hoogenband et al. / Tetrahedron Letters 45 (2004) 8535–8537
O
O
a)
Cl
+
H N
N CH Ph
2
2
N
H
N CH Ph
2
Br
Br
3
4
1
Y = 78%
2 3 3
Scheme 2. Reagents and conditions: (a) 1equiv 3; 1.2equiv K CO ; 1.1equiv 4, CH CN, room temperature.
Table 1. Reaction conditions in the intramolecular Pd-catalyzed formation of compound 1
Entry
1
Conditions
Time (h)
40
Yield (%)
Trace
1equiv compound 1, 1.4equiv K
a
2
CO , 1.5mol% Pd
3
2
dba
3
,
4
1equiv compound 1, 5equiv K
.5mol% Xantphos , toluene, 100°C
2
3
4
2
CO , 1.5mol% Pd
3
2
2
dba
3
,
,
40
64
3
15
58
90
4.5mol% Xantphos, toluene, 100°C
1equiv compound 1, 5equiv K
2
CO , 7.5mol% Pd
3
dba
3
3
0mol% P(o-tolyl)
3
, toluene, 100°C
CO
, 7.5mol% X-Phos , t-BuOH, 85°C
1equiv compound 1, 2.5equiv K
2
3 2
, 3mol% Pd(OAc) ,
a
7
.5mol% PhB(OH)
2
a
PCy2
O
Pr-i
i-Pr
PPh2
PPh2
Xantphos
X-Phos
i-Pr
1
1
Van LeeuwenÕs Xantphos ligand has been reported to
assist in the arylation of amides and a number of aza-
The discovery by Buchwald and co-workers of the X-
1
3
Phos ligand prompted the use of this exciting catalyst
in the conversion of 1 into 2 (Table 1, entry 4). We
found that the X-Phos ligand effected an amazingly effi-
cient formation of 2 in a high yielding and clean
1
2
containing heterocycles. The application of this ligand
in the conversion of 1 to 2 initially gave only a trace of
desired product. Although slightly better yields could be
obtained by increasing the amount of base (K CO ) in
1
4
reaction.
2
3
this Xantphos-mediated conversion, the yields still re-
mained unsatisfactory.
The resulting N-benzyl protected oxindole 2 was
subsequently debenzylated to the target oxindole 6 by
a catalytic hydrogenation reaction via the isolated corres-
ponding hydrochloric acid salt 5 in quantitative yield
(Scheme 3).
It was envisioned that the use of the monodentate tris-
tolylphosphine in the intramolecular Pd-catalyzed ami-
1
5
1
0
nation of 1 into 2 would lead to better results. As
can be seen in Table 1 (entry 3) use of the P(o-tolyl)3
ligand led to an isolated yield of the desired oxindole 2
of 58%. However, the reaction required relatively large
amounts of Pd (dba) and P(o-tolyl) ligand and pro-
Conclusion
2
3
3
ceeded very slowly. Furthermore, a problematic chro-
matographic purification was required in the work-up.
A novel synthetic approach has been devised for the
pharmaceutically important N-piperidin-4-yloxindole 6.
O
O
O
N
N
N
N
b
a
N
H
N
.
HCl
.HCl
Bn
2
Bn
5
6
2 2
Scheme 3. Reagents and conditions: (a) 2 equiv acetyl chloride/EtOH; (b) Pd(OH) /C, H , MeOH, 50psi (quant.).

A. van den Hoogenband et al. / Tetrahedron Letters 45 (2004) 8535–8537
8537
The key step comprises an intramolecular Pd-catalyzed
amination reaction. The X-Phos ligand was found to
be superior in this conversion, leading to both a high
reaction rate and an excellent yield. The prospects of
the X-Phos ligand for the synthesis of structurally re-
lated oxindole derivatives, having vulnerable aromatic
substituents, are promising as the applied reaction con-
ditions are very mild. Furthermore, due to the specific
Pd-mediated cyclisation at the bromo-substituted ortho
position of 1, this approach will produce exclusively
one regioisomer in the case of the presence of additional
substitutent(s) on the aryl ring.
12. (a) Lovely, C. J.; Browning, R. G.; Badarinarayana, V.;
Mahmud, H. Tetrahedron 2004, 60, 359–365; (b) Wallace,
D. J.; Kluber, D. J.; Chen, C.; Volante, P. Org. Lett. 2003,
5, 4749–4752; (c) Buchwald, S. L.; Yin, J. J. Am. Chem.
Soc. 2002, 124, 6043–6048; (d) Buchwald, S. J.; Yin, J.
Org. Lett. 2000, 2, 1101–1104.
3. (a) Buchwald, S. L.; Gelman, D. Angew. Chem., Int. Ed.
1
2
003, 42, 5993–5996; (b) Buchwald, S. L.; Huang, X.;
Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A. J. Am.
Chem. Soc. 2003, 125, 6653–6655; (c) Blackmond, D. G.;
Buchwald, S. L.; Strieter, E. R. J. Am. Chem. Soc. 2003,
125, 13978–13980; (d) Buchwald, S. L.; Nguyen, H. N.;
Huang, X. J. Am. Chem. Soc. 2003, 125, 11818–11819.
4. Procedure for the intramolecular Pd-catalyzed amination
of compound 1: A dried 100mL three-necked reaction
vessel was charged with 35mL dry and degassed t-BuOH.
At a temperature of 35°C, compound 1 (0.97g, 2.5mmol)
was added. The temperature was raised to 80°C, until a
clear solution was obtained. After cooling down to 35°C,
1
Acknowledgements
We wish to thank Mrs. Alice Borst and Mr. Pieter Spa-
ans for analytical support, and Mr. Peter Koelman for
screening the literature.
Pd(OAc)
.1875mmol), X-Phos (89.4mg, 0.1875mmol) and
K CO (0.86g, 6.25mmol) were successively added. Under
2 2
(16.8mg, 0.075mmol), PhB(OH) (22.8mg,
0
2
3
stirring and nitrogen atmosphere, the reaction mixture was
heated at 85°C. After 3h, the starting compound 1 had
disappeared (TLC: CH Cl /MeOH/NH OH 96:3.75:0.25).
References and notes
2
2
4
1
. Nagata, R.; Tokunaga, T.; Hume, W.; Umezone, T.;
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1
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3
6
in the literature. HRMS ES+: calculated for C H N O
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3
4
2
0
23
2
. Mokrosz, M. J.; Duszynska, B.; Misztal, S.; Klodinska,
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15. Procedure for the debenzylation of compound 2 to
compound 6: Compound 2 (0.55g, 1.8mmol) was dis-
solved in 15mL EtOH. To the magnetically stirred
solution was added 3.6mmol HCl in EtOH (from
3.6mmol AcCl in 10mL EtOH). The solution obtained
was evaporated under reduced pressure and the crude
residue was treated with diethyl ether. The obtained solid
substance was isolated and dissolved in 25mL MeOH.
1
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2
reaction mixture was hydrogenated at 50psi for 24h. After
filtration of the Pd/C, and evaporation of the filtrate under
reduced pressure, compound 6 was isolated in quantitative
yield. Analytical data for compound 6 (as free base): H
1
9
NMR d ppm (CDCl , 400MHz): 1.68–1.82 (m, 3H), 2.28–
3
4
1, 2361–2370.
2.40 (m, 2H), 2.72–2.82 (m, 2H), 3.22–3.28 (m, 2H), 3.52
(s, 2H), 4.32–4.42 (m, 1H), 7.02 (t, J = 8Hz, 1H), 7.15 (d,
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1
3
17
2