An oxidative approach to a hydroxypiperidinone utilizing a Rh-catalyzed C-H activation process

Article abstract of DOI:10.1002/jhet.1718

C-H activation and isomerization using a Rh-catalyst provided quick access to dehydropiperidine derivatives that could be further oxidized to hydroxypiperidinone derivatives.

Full text of DOI:10.1002/jhet.1718

Month 2013
An Oxidative Approach to a Hydroxypiperidinone Utilizing a
Rh-Catalyzed C-H Activation Process
*
Timothy A. Ayers
Research and Development, Sanofi US, P.O. Box 5925, 55 Corporate Drive, Bridgewater, New Jersey 08807, USA
*
E-mail: timothy.ayers@sanofi.com
Additional Supporting Information may be found in the online version of this article.
Received March 22, 2012
DOI 10.1002/jhet.1718
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
NHAc
NHAc
OH
NHAc
N
O
N
O
N
O
H
C-H activation and isomerization using a Rh-catalyst provided quick access to dehydropiperidine
derivatives that could be further oxidized to hydroxypiperidinone derivatives.
J Hetercycl Chem, 00, 00 (2013).
INTRODUCTION
chloride 5 was available by LDA alkylation of ethyl isobu-
tyrate with bromochloroethane [9]. Initial direct thermal
elimination attempts to olefinic ester 6 by heating chloride
5 in the presence of NaI at 60ꢀC gave a,a-dimethyl-g-
butyrolactone as the only significant product. However,
when the chloride was heated in DBU in the presence of
NaI at 75ꢀC for 12 h, olefinic ester 6 was produced as the
major product and isolated in 31% yield after work-up
and simple distillation. Simple saponification of the ester
provided the required olefinic acid 4 in high yield for the
subsequent synthesis (Scheme 3).
Initial model studies for the C-H activation process were
performed on the simple 4-phenylpiperidine analog 7 that
was prepared from commercially available 4-phenylpiperi-
dine and olefinic acid 4 using EDC. Often, a limitation for
organic chemists pursuing organometallic transformations
is the commercial unavailability of the air sensitive cata-
lysts necessitating an in house synthesis. Simple protocols
that do not require the synthesis of a catalyst to explore the
viability of these very selective organometallic processes
without focusing on turnovers and yields would facilitate
greater application of these transformations. Thus, instead
of preparing the Brookhart catalyst [2,3], attempts to
produce the active catalyst in situ were explored by treating
[Cp*RhCl]2 with Zn powder. When cyclohexane, a
noncoordinating solvent [10], was used as the solvent,
<0.1% conversion of the starting material was observed
even with heating for 24 h. The lack of conversion was
postulated to arise from the low solubility of the Rh-com-
plex and Zn metal. However, using NMP as the solvent
with heating to 100ꢀC, conversion to new products was
observed by GC–MS that strongly indicated that the isom-
erization was successful as the fragmentation pattern of
two of the new products had 186 fragments (cleavage
alpha to keto group with loss of alkyl residue), whereas
the starting material had 188 fragments. The other product
The rapid synthesis of proposed metabolites of drug candi-
dates often requires innovative solutions to synthetically
challenging problems. Indeed, during the development of
saredutant [1], hydroxypiperidinone 1 (Scheme 1) was
isolated from metabolism studies, and an authentic sample
was needed for confirmation of the structural assignment.
Many de novo approaches were considered and attempted
without success.
The emergence of organometallicmediated C-H activation
to catalyze the cleavage of a strong C-H bond for the forma-
tion of new C-C, CO, and C-X bonds has become a key
synthetic transformation [2]. However, the utility of C-H
activation as an isomerization or olefin migration method
has not been fully exploited. Sames [3] described a C-H
activation process that resulted in the isomerization of a
simple pyrrolidine amide derivative 2a (X = CH2, n = 0) to
the corresponding enamide 3a (X = CH2, n = 0) in 54%
isolated yield using a Rh-catalyst [4] (Scheme 2), providing
the impetus for further development of C-C bond forming
processes. The adaptation of this isomerization/olefin migra-
tion process to the synthesis of other nitrogen heterocycle
derivatives was subsequently reported by Brookhart [5] using
both Rh- and Co-catalysts (Scheme 1) using vinylsilylamines
2b. [6] We now describe the application of the C-H activation
approach using an in situ generated Rh-catalyst to produce a
dehydropiperidine derivative [7] for an expedient synthesis
of hydroxypiperidinone 1 (Scheme 2).
RESULTS AND DISCUSSION
In order to pursue the C-H activation approach, the
noncommercial olefinic acid 4 was required. Even though
there are literature procedures [8] to synthesize acid 4, we
decided to pursue a new approach to this compound as
© 2013 HeteroCorporation

T. A. Ayers
Vol 000
Scheme 1. Metabolite of saredutant.
had a mass of M + 2 and was assigned as the simple reduc-
tion product. Indeed, upon isolation of the crude mixture,
1H NMR confirmed the formation of isomers 8 and 9 along
with reduction product 10 (Scheme 4).
NHAc
As methyl 3,3-dimethyl-4-pentanoate with one addi-
tional carbon on the tether is commercially available,
simple saponification to acid 11 and coupling with
4-phenylpiperidine provided the corresponding model
substrate 12 for the C-H activation chemistry (Scheme 4).
Not surprisingly, upon treatment of 12 under the Rh-
catalyst conditions, <0.1% of the enamide was observed
with slow conversion to the reduction by-product 13 being
the major product.
N
NHAc
metabolism
O
OH
Cl
others
H
N
+
Cl
N
H
O
Saredutant
1
Scheme 2. C-H activation/isomerization of pyrrolidine.
Having demonstrated the feasibility of the C-H
activation on a model piperidine system, attention was
turned to applying this approach toward the synthesis of
hydroxypiperidinone 1. Coupling of the available
piperidine 14 with olefinic acid 4 using EDC provided
the desired olefinic amide 15 in 90% yield (Scheme 5).
Subjecting olefinic amide 15 to the C-H activation/
isomerization conditions ([Cp*RhCl]2, Zn powder,
NMP,100ꢀC) provided the desired dehydropiperidine 16
and reduction product 17 as an approximately 3:1 mixture
from which 16 was isolated in 52% yield after chromatog-
raphy. In this instance, compared with the model piperi-
dine 7, further isomerization of the olefin is not possible
X
X
a. R =
Cp*M(vinylsilane)2
M = Co, Rh
O
( )n
( )n
N
R
N
R
3
b. R =
Si
2
Scheme 3. Synthesis of olefinic acid 4.
OEt
OH
OEt
OEt
Cl
LiOH
LDA
NaI
O
O
O
O
DBU
MeOH
Water
95%
Br(CH2)2Cl
31%
5
6
4
Scheme 4. C-H activation using model systems.
OH
Ph
N
Ph
N
Ph
N
Ph
O
2.75
Ph
4.97
7.17
6.09
[Cp*RhCl]2
4
+
+
N
Zn
NMP
100 °C
EDC
N
H
O
O
O
O
7
8
9
10
Ph
N
Ph
N
OH
O
[Cp*RhCl]2
11
EDC
Zn
NMP
100 °C
slow
O
O
12
13
Scheme 5. C-H activation for synthesis of dehydropiperidine 16.
NHAc
NHAc
NHAc
[Cp*RhCl]2
Zn
NHAc
4
+
N
O
EDC
90%
NMP
100 °C
52%
N
O
N
O
N
H
14
15
16
17
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
An Oxidative Approach to a Hydroxypiperidinone Utilizing a Rh-Catalyzed
C-H Activation Process
as the 4-position is quaternary. To drive the reaction to
completion, additional catalyst was added. Even though
further optimization of this process is clearly needed to
lower the catalyst loading (up to 33% catalyst used),
we achieved our objective of demonstrating the C-H
activation process on a 5-g scale and prepared ample
quantities of dehydropiperidine 16 for oxidation studies.
Epoxidation of dehydropiperidine 16 with further
oxidation to the desired hydroxyl imide 18 using mCPBA
was explored. However, oxidative cleavage to produce
aldehyde formamide 19 was the major pathway with a
small amount (<10%) of the desired hydroxyl imide 18
being formed (Scheme 6) [11]. Quite nicely, simple
oxidation with KMnO4 [12] in aqueous acetonitrile or
aqueous acetone as the solvent provided the desired
hydroxyl imide 18 as a single isomer with the acetamide
and hydroxyl group in a cis-relationship. Overoxidation
was also observed with cleavage to phenyl ketones 20
being significant side products. Simple slurrying of the
crude product in heptane provided pure hydroxyimide 18
in 18% isolated yield.
difficult owing to the sterically hindered neopentyl tether.
Thus, screening of several conditions was undertaken to
find suitable conditions to provide a reasonable amount
of the desired hydroxypiperidinone 1. The use of NaHCO3
in aqueous MeOH at room temperature provided a fairly
clean reaction profile with 68% of desired hydroxypiperidi-
none 1 and 13.7% of ring-opened methyl ester 21 being
formed. Interestingly, the selectivity for the desired
hydrolysis to hydroxypiperidinone 1 compared with the
ring-opened methyl ester 21 decreased significantly when
the reaction was performed at 45ꢀC with only 21% of the
hydroxypiperidinone 1 formed. Other bases such as LiOH
and K2CO3 provided a lower amount of the desired product
plus additional side products, such as the ring-opened acid
22. Acid hydrolysis with HCl also seems viable but, with
the time constraints, was not further pursued [13]. The final
selective hydrolysis of imide 18 was performed using the
NaHCO3 in aqueous MeOH at room temperature for 2 days
(80% conversion) with warming to 45ꢀC for completion of
the reaction. Slurrying the crude mixture in CH2Cl2 and
heptane provided 22 mg (30%) of hydroxypiperidinone 1
to complete the synthesis.
The selective hydrolysis of hydroxyl imide 18 to the
desired hydroxypiperidinone 1 without ring opening to
the undesired amides (Scheme 7) was anticipated to be
In conclusion, we have demonstrated an easy method
for C-H activation/isomerization using an in situ generated
Rh-catalyst for rapid access to dehydropiperidine deriva-
tives. These intermediates are suitable precursors toward
the preparation of functionalized piperidine derivatives
such as the oxidation product hydroxypiperidinone 1.
Scheme 6. Oxidation of dehydropiperidine 16.
NHAc
NHAc
O
SUPPLEMENTARY MATERIAL AVAILABLE
mCPBA
CDCl3
+
trace 18
NMR spectra and other supporting data are provided.
N
O
N
O
O
Acknowledgment. The author would like to acknowledge the
extensive NMR experiments performed by Dirk Friedrich for
structure elucidation and the samples of chloride 5 and
piperidine 14 provided by Greory Kubiak and Isaac Chekroun,
respectively. The author also acknowledges the extraordinarily
stimulating discussions with John Herbert, Guy Rossey, and
David Lythgoe.
16
19
NHAc
OH
KMnO4
O
ACN / Water
18%
N
O
O
+
Y
N
X
REFERENCES AND NOTES
cis-only
20
[1] Saredutant, a neurokinin 2(NK2) antagonist, was in develop-
ment for the treatment of major depressive disorder, see Rogacki, N.;
Lopez-Grancha, M.; Naimoli, V.; Potestio, L.; Stevens, R. J.; Pichat, P.;
Bergis, O. E.; Cohen, C.; Varty, G. B.; Griebelb, G. Pharmacol Biochem
Behav. 2011, 98, 405.
18
Scheme 7. Hydrolysis of imide 18 to hydroxypiperidinone 1.
[2] For leading references for C-H activation, see (a) Seregin, I.
V.; Gevorgyan, V. Chem Soc Rev 2007, 36, 1173. (b) Campeau, L.-C.;
Stuart, D. R.; Fagnou, K. Aldrichim. Acta 2007, 40, 35. (c) Alberico,
D.; Scott, M. E.; Lautens, M. Chem Rev 2007, 107, 174. (d) Satoh, T.;
Miura, M. Chem. Lett. 2007, 36, 200. (e) Godula, K.; Sames, D. Science
2006, 312, 67. (f) Pastine, S.J.; Gribov, D.V.; Sames, D. J Am Chem Soc
2006, 128, 14220. (g) Wang, D-H.; Hao, X-S.; Wu, D-F.; Yu, J-Q. Org
Lett 2006, 8, 3387. (h) Lyons, T. W.; Sanford, M. S. Chem Rev 2010,
110, 1147.
NHAc
OH
NHAc
OH
NHAc
OH
conditions
18
OH
O
H
N
H
N
+
+
O
O
N
H
O
O
O
1
21
22
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DOI 10.1002/jhet

T. A. Ayers
Vol 000
[3] Deboef, B.; Pastine, S.J.; Sames, D. J Am Chem Soc 2004, 126,
[4] Lenges, C. R.; White, P. S.; Brookhart, M. J Am Chem Soc
R.; Shin, S.I.; Park, H.J.; Jeon, D.J.; Ryu, E.K. Synlett 1998, 7, 789.
Hayashi, Y.; Orikasa, S.; Tanaka, K.; Kanoh, K.; Kiso, Y. J Org Chem.
2000, 65, 8402.
6556.
1999, 121, 4385.
[5] Bolig, A. D.; Brookhart, M. J Am Chem Soc 2007, 129,
14544.
[6] The chemistry described in this report began in October 2007
and finished several months later, so the Brookhart publication (reference
5) in November 2007 was unknown.
[7] For leading references for traditional synthesis of dehydropi-
peridines, see Magnus, P; Hulme, C.; Weber, W. J Am Chem Soc 1994,
116, 4501. Coldham, I.; Leonori, D. J Org Chem 2010, 75, 4069. Flick,
A. C.; Padwa, A. Tetrahedron Lett 2008, 49, 5739.
[8] Gu, Z.; Zakarin, A. Org Lett 2010, 13, 1080. Aurell, M.J.; Gil,
S.; Mestres, R.; Parra, M.; Parra, L. Tetrahedron 1998, 54, 4357. Kim, H.
[9] D’hooghe, M.; Van Driessche, B.; De Kimpe, N.; Hetero-
cycles 2009, 77, 255. Also, chloride 5 was available in kg quantities from
scale-up of an unrelated project.
[10] See references 3–5 for discussions on importance of non-
coordinating solvents.
[11] Adam, W.; Reinhardt, D. Tetrahedron 1995, 45, 12257.
[12] Oxidation of 2,3-dehydropiperidines has not been reported; for
oxidation of 4,5-dihydropiperidines, see Soldatenkov, A.T.; Temesgen, A.
V.; Bekro, I.A. Chemistry of Heterocyclic Compounds 2001, 37, 1216.
[13] It should be noted that hydroxypiperidinone 1 has limited
solubility in organic solvents such as CH2Cl2, so inadvertent losses may
have occurred.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet