Novel chemoselective reduction of the tetrahydro-4-pyridyl versus indole moiety governed by electron donation: First X-ray evidence for indolopiperidyl-borane complexation

Article abstract of DOI:10.1016/S0040-4039(02)01927-5

A series of amino-borane complexes of structure type 2 are the key intermediates in the preparation of 3-(piperidyl) indole derivatives. The selective reduction of the tetrahydro-4-pyridyl double bond via 2 under strongly acidic conditions is feasible only when the pyridyl double bond is conjugated with electron rich substituents, such as indoles. This reduction methodology allows the presence of reducible and hydrogenolizable functional groups. An improved process to prepare 2 by treatment of the 3-(tetrahydro-4-pyridyl) indole derivatives with NaBH₄ in THF under acidic conditions (AcOH or CF₃COOH) is also described.

Full text of DOI:10.1016/S0040-4039(02)01927-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8087–8090
Novel chemoselective reduction of the tetrahydro-4-pyridyl versus
indole moiety governed by electron donation: first X-ray
evidence for indolopiperidyl–borane complexation
a,
a
b
Alfio Borghese, * Luc Antoine and Gregory Stephenson
a
Chemical Process Research and Development, Lilly Development Centre SA, 1348 Mont-Saint-Guibert, Belgium
b
Material Science and Physical Characterization, Eli Lilly & Co, Indianapolis, IN, USA
Received 2 September 2002; accepted 9 September 2002
Abstract—A series of amino–borane complexes of structure type 2 are the key intermediates in the preparation of 3-(piperidyl)
indole derivatives. The selective reduction of the tetrahydro-4-pyridyl double bond via 2 under strongly acidic conditions is
feasible only when the pyridyl double bond is conjugated with electron rich substituents, such as indoles. This reduction
methodology allows the presence of reducible and hydrogenolizable functional groups. An improved process to prepare 2 by
treatment of the 3-(tetrahydro-4-pyridyl) indole derivatives with NaBH in THF under acidic conditions (AcOH or CF COOH)
4
3
is also described. © 2002 Elsevier Science Ltd. All rights reserved.
The 3-(piperidyl) indole derivative 3 are common build-
treated with NaBH or NaBH CN in acidic media as
4 3
ing blocks found in many pharmaceutical compounds
well as BH –THF in TFA, indolines are formed. In
3
1
having interesting serotoninergic activity. These phar-
neat AcOH, the corresponding indolines are further
7
macophores are usually prepared by catalytic hydro-
1-N alkylated. Also, borane reduction of indole deriva-
genation of 3-(tetrahydro-4-pyridyl) indole derivatives 1
tives bearing amino substituents yields the correspond-
ing indoline derivatives.
2
8
(
Scheme 1). Silane reduction (Et SiH/CF COOH) in
3
3
acidic media is preferred when substituents susceptible3
to hydrogenolysis are present. Bonjoch et al. reported
one example on the reduction of 3-(tetrahydro-4-
pyridyl) indole to the corresponding 3-(piperidyl)
derivative by using NaBH /BF –Et O in THF, specu-
In this paper, we report that the synthesis of 3-(pipe-
ridyl) derivatives 3, via the formation of the isolable
key amino–borane intermediate 2 from 3-(tetrahydro-4-
pyridyl) derivatives 1 (Scheme 1) is feasible when the
pyridyl double bond is conjugated to an electron rich
indole. Strong acid treatment of 2 yields the desired
3-(piperidyl) indole derivative 3 in excellent yields
(Table 1). Indeed, when we replaced the indole sub-
4
3
2
lating the tetrahydropyridine–borane complex as an
intermediate. The same reduction reaction applied to
the 3-(tetrahydro-2-pyridyl) indoles lead only to the
5
,6
indolines derivatives. In general, when indoles are
Scheme 1.
*
0
Corresponding author. Tel.: +32(0)10 476309; fax: +32(0)10 476315; e-mail: a.borghese@lilly.com
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01927-5

8
088
A. Borghese et al. / Tetrahedron Letters 43 (2002) 8087–8090
Table 1. Reduction of 3-(tetrahydro-4-pyridyl) indoles
double bond with NaBH under neutral conditions was
4
also attempted in THF, as the tetrahydropyridine dou-
ble bond might be considered activated through conju-
gation with the indole ring. Under these conditions,
only starting materials were recovered unchanged.
Entry
R1
R2
Salt
Yieldb
1
2
3
4
5
6
7
8
9
5-Br
Me
Me
Me
H
4
5
Me
Me
H
4
5
96
83
66
93
78
63
92
88
98
93
5-NH2
5-NO2
6-F
6-F
6-F
This novel operating procedure was applied successfully
to several 3-(tetrahydro-4-pyridyl) indole derivatives
bearing hydrogenolizable or easily reducible (catalytic
hydrogenation) functional groups (Table 1, entries 1–7),
demonstrating the generality and the high chemoselec-
tivity of the reaction. In each case the key amino–
borane complex 2 was formed as an intermediate in the
course of the reduction reaction. More highly function-
alized molecules (Table 1, entries 5, 6, Scheme 2) also
bearing uniquely reducible functional groups were
selectively transformed to the corresponding piperidine
derivatives in high yield.
5-BnO
5-NO2
Acetate
Hydrochloride
Phosphate
6-F
6-F
6-F
1
1
0
1
a
L
-Tartrate
\99
a
Isolated as hydrochloride salt.
Isolated crude yields with 1H NMR analysis.
b
stituent with 2-naphthyl or 5-benzothiophene moieties,
the reaction failed to furnish the reduced compound4
Table 1 contains several examples performed with the
despite the formation of the amino–borane complex.
NaBH /AcOH protocol to illustrate the selectivity of
In this case, strong acid treatment of the amino–borane
complex restored the starting material.
4
the operating procedure. AcOH was selected for conve-
nience, as it was found equally effective to CF COOH.
3
The last four entries are examples of the reduction
using preformed salts of the 3-(tetrahydro-4-pyridyl)
indole derivatives. More interesting, when various salts
of 1 (Table 1, entries 8, 9, 10, 11) were used, the
An improved process to prepare the amino–boranes 2
by treating 1 with NaBH in THF under mildly acidic
4
conditions (AcOH or TFA) is also reported. BH –THF
3
could be employed without hydroboration of the tetra-
hydro-4-pyridyl double bond under these conditions.
reaction with NaBH afforded the amino–borane com-
4
However, use of the NaBH –RCOOH couple over-
plex 2 directly without the need for addition of an
external acid, leading to 3 after strong acid treatment of
the reaction mixture. It is noteworthy that in general, a
better yield was obtained when the salts of 1 were used
4
comes significant scale up and equipment issues associ-
ated with the use of BF –Et O, BH –THF or
3
2
3
Et SiH/CF COOH, and was thus the method of choice.
3
3
(
compare entries 3 with 8, 5 with 10, 6 with 11, Table
Most significantly, no reduction of the tetrahydro-4-
1). Moreover, the detrimental effect of the strong elec-
pyridyl double bond occurred prior to strong acid
tron withdrawing group NO (entries 3 and 8, Table 1)
2
9
(
HCl) treatment of the reaction mixture. This complex
on the yield should be noted, indicating the importance
of the electronic effect on the efficiency of that reaction.
2
could be isolated in almost quantitative yield as a
crystalline, stable solid and was characterized by
1
0
1
XRD (Fig. 1), H NMR and mass spectral analysis.
The reduction of the 3-(tetrahydro-4-pyridyl) indole
The observation that the amine–borane derivative was
formed in almost quantitative yield demonstrated that a
Figure 1. ORTEP view of 2 (entry 3, Table 1).

A. Borghese et al. / Tetrahedron Letters 43 (2002) 8087–8090
8089
Scheme 2.
borane surrogate was generated in situ. Indeed, the
BH hydride, forming a six-membered ring transition
state (cf. 7), although definitive evidence is not
available.
3
NaBH /RCO H mixture was previously used by Hach
4
2
1
1
and by Marshall to perform the hydroboration of
olefins. Masamune also reported the in situ generation
1
2
of borane by reaction of NaBH with HCl, MeSO H or
In conclusion, these results demonstrated the generality
4
3
H SO . These results might explain the formation of 2
of NaBH /organic acid in reducing the 3-(tetrahydro-4-
4
2
4
when salts of 1 are used with NaBH . The salt positions
pyridyl) indole derivatives to the corresponding pipe-
ridyl derivatives and the selective application to indole
substituted derivatives. The amino–borane complex is
the key intermediate in these reduction reactions. The
fact that no indoline is formed during the reduction
process in acidic media demonstrated the high chemose-
lectivity of this reaction. Moreover, this reduction pro-
tocol can be extended to 3-(tetrahydro-4-pyridyl)
indoles bearing hydrogenolizable substituents on the
indole ring. The same experimental protocol has also
been successfully extended to other 3-(tetrahydro-3-
pyridyl) indole derivatives. In addition, from a large-
scale synthesis perspective, this reduction procedure is
very attractive as it can be performed without the need
of highly corrosive or reactive reagents.
4
the requisite acid at the site of complexation. When
carboxylic acids (RCOOH) are used in combination
with NaBH4, sodium acyloxyborohydrides species
(
NaBH (OCOR) or NaBH (OCOR) are formed, and
x y 3
13
these are thought to be the reactive species. In our
case, we believe that if NaBH (OCOCH ) forms, it
1
4
3
3
reacts rapidly with the amine to form the amine–borane
before further reaction with AcOH to form the triacet-
2
oxy species. We have demonstrated that the reduction
of 1 with NaBH(OCOCH ) failed to give the desired 3.
3
3
Under our experimental conditions, no indoline deriva-
tives have been formed, indicating that the selectivity of
the reduction process is in favor of the formation of the
(
piperidyl) indole derivatives. This reactivity is very
likely due to the vinylogous nature of the tetrahydro-4-
pyridyl double bond, conjugated through the indole
moiety. The fact that strong acid treatment of 2 is
needed to perform the reduction supports a mechanistic
notion that a tertiary carbocation is generated by dou-
ble bond protonation in 2. This is in agreement with
Acknowledgements
We thank Dr. Michael Martinelli, Lilly Research Fel-
low (Eli Lilly & Company, Indianapolis, IN, USA) for
revising the manuscript and Dr. Pieter Delbeke (Lilly
Development Centre SA, Mont-Saint-Guibert, Bel-
3
previous reported observations. Indirect evidence for
1
gium) for the H NMR analysis.
the proposed protonation of the double bond is given
by the formation of compound 6 when HCl is added to
a THF solution of 1. The formation of 6 also demon-
strates the acid sensitivity of this conjugated species.
The cation could react intramolecularly with amine–
References
1
. Hoyer, D.; Clarke, D. E.; Fozard, J. R.; Hartig, P. R.;
Martin, G. R.; Mylecharane, E. J.; Saxena, P. R.;
Humphrey, P. P. A. Pharmacol. Rev. 1994, 46, 157.
. (a) Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthe-
sis 1974, 633–651; (b) Lanzilotti, A. E.; Little, R.; Fan-
shawe, W. J.; Mackenzie, T. C.; Lovell, F. M. J. Org.
Chem. 1979, 44, 4809.
2
3
. (a) Bonjoch, J.; Boncompte, F.; Casamitjana, N.; Bosch,
J. Tetrahedron 1986, 42, 6693; (b) Bonjoch reported that
no reaction was observed when NaBH4 was used in
AcOH or TFA.

8
090
A. Borghese et al. / Tetrahedron Letters 43 (2002) 8087–8090
4. In these examples the N-methyl, 2-methyl pyridyl deriva-
1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
tives were used.
11. (a) Hach, V. Synthesis 1974, 340; (b) Marshall, J. A.;
Johnson, W. S. J. Org. Chem. 1963, 28, 421.
12. Abiki, A.; Masamune, S. Tetrahedron Lett. 1992, 33,
5517.
5
6
. Gribble, G. W.; Hoffman, J. H. Synthesis 1977, 859.
. Maryanoff, B. E.; McComsey, D. F.; Nortey, S. O. J.
Org. Chem. 1981, 46, 355–360.
7
8
9
. Gribble, G. W.; Lord, P. D.; Skotnicki, J.; Stephen, F.;
Eaton, J. T.; Johnson, J. L. J. Am. Chem. Soc. 1974, 96,
13. Gribble, G. W. Chem. Soc. Rev. 1998, 27, 395.
14. Experimental procedure: To a suspension of NaBH (2.6
4
7
812.
g, 68.7 mmol; 2.0 equiv.) and 6-fluoro-3-(1,2,3,6-tetra-
hydro-pyridin-4-yl)-1H-indole (7.4 g, 34.3 mmol, 1.0
equiv.) in THF (100 ml) is slowly added glacial
. (a) Berger, J. G.; Teller, S. R.; Adams, C. D.; Guggen-
berger, L. J. Tetrahedron Lett. 1975, 16, 1807; (b) Elliot,
A. J.; Guzik, H. Tetrahedron Lett. 1982, 23, 1983.
CH COOH (6.0 ml, 104.8 mol; 3.0 equiv.), while keeping
3
1
.
H NMR of the isolated 2 (entry 4) confirmed the
the temperature below 30°C. Stirring of the reaction
mixture was continued at room temperature for 0.5 h. A
37% HCl solution (10 ml) was slowly added to the
reaction mixture, and the mixture stirred for 0.5 h at
1
presence of the piperidyl double bond. H NMR (400
MHz, DMSO-d ): l ppm 1.46 (s (br), 3 H), 2.61 (m, 3 H),
6
3
6
.19 (m, 2 H), 3.51 (dm, J=17.72 Hz, 1 H), 6.10 (s, 1 H),
.24 (s (br), 1 H), 6.90 (td, J=9.23, 2.21 Hz, 1 H), 7.17
room temperature. H O (100 ml) was added and the THF
2
(
dd, J=10.09, 2.22 Hz, 1 H), 7.43 (s, 1 H), 7.79 (dd,
J=8.61, 5.66 Hz, 1 H), 11.39 (s, 1 H).
0. Crystallographic data (excluding structure factors) for 2
entry 3) have been deposited with the Cambridge Crys-
removed from the reaction mixture by distillation under
atmospheric pressure. The reaction mixture is cooled to
room temperature and neutralized with a 30% NaOH
solution (20 ml) until pH>12. The resulting suspension
was stirred for 1 h at room temperature. The precipitate
1
(
tallographic Data Centre as supplementary publication
number CCDC 182427. Copies of the data can be
obtained free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0)
was filtered, washed with H O (50 ml) and dried under
2
reduced pressure at 50°C to yield 6.97 g (93.3%) of
6-fluoro-3-piperidin-4-yl-1H-indole.