A new route to heterocyclic compounds by the mercuric acetate oxidation of N-alkyl substituted 4-piperidones

Article abstract of DOI:10.1016/j.tetlet.2008.07.109

N-Alkyl substituted 4-piperidones readily undergo oxidation in high yield upon reaction with mercuric acetate. Application of the oxidation to the synthesis of the skeletal framework of several alkaloids is described.

Full text of DOI:10.1016/j.tetlet.2008.07.109

Tetrahedron Letters 49 (2008) 5739–5741
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Tetrahedron Letters
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A new route to heterocyclic compounds by the mercuric acetate
oxidation of N-alkyl substituted 4-piperidones
*
Andrew C. Flick, Albert Padwa
Department of Chemistry, Emory University, Atlanta, GA 30322, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Alkyl substituted 4-piperidones readily undergo oxidation in high yield upon reaction with mercuric
acetate. Application of the oxidation to the synthesis of the skeletal framework of several alkaloids is
described.
Received 5 June 2008
Accepted 18 July 2008
Available online 24 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
2,3-Dihydro-4-pyridones (2) are important synthetic intermedi-
ates, particularly for the preparation of alkaloids and medicinal
agents.1 The presence of the vinylogous amide found in six-mem-
bered azaheterocycles facilitates the introduction of other substit-
uents onto the piperidine ring in a regio- and stereocontrolled
manner.2 Due to A1,3 strain,3 the C2 group of the dihydropyridone
2 is forced into a pseudoaxial position providing a conformational
bias in the molecule. This effect allows for control of the stereo-
selectivity of 1,2- and 1,4-addition to the enone moiety, C3 enolate
alkylation, Luche reduction of the C4 carbonyl and intramolecular
radical cyclization.4,5 The C5 position can also be halogenated using
NBS and a subsequent palladium-mediated coupling provides
various 5-substituted derivatives (Scheme 1).6 A widely used
method for the synthesis of the dihydropyridone system involves
the reaction of carbon nucleophiles with various 1-acylpyridinium
salts (1).1,7 Because of the abundance of piperidine-containing
natural products,8 this method has been extensively utilized by Co-
mins et al. for the asymmetric synthesis of many quinolizidine,
indolizidine and perhydroquinoline alkaloids.4 Another approach
that has been occasionally employed for the preparation of 2,3-
dihydro-4-pyridones consists of an oxidation of the related 4-pip-
eridone system (i.e., 3?2).9 4-Piperidones are readily available
from the Dieckmann cyclization of aminodicarboxylate esters or
by the condensation of carbonyl compounds with ammonia via a
Mannich reaction.10,11 One general problem associated with this
method is that the oxidation only works well when an electron-
withdrawing group is attached to the nitrogen atom. In addition,
the reaction frequently leads to a mixture of 2,3-dihydro-4-pyri-
done isomers. Oxidation of these N-acylated 4-piperidones is
typically effected by using PhSeCl/H2O2, Saegusa or IBX methods
(carbonyl directed dehydrative protocols).9 In contrast, the few re-
ported examples of oxidation of N-alkyl substituted 4-piperidones
almost always involve the use of a peracid induced Polonovski
reaction12 and generally results in meager yields of the corre-
sponding vinylogous amide. Thus, a high yielding oxidation meth-
od for the preparation of substituted 2,3-dihydro-4-pyridones from
N-alkyl substituted 4-piperidones would be an advance in the area
of heterocyclic synthesis.
O
O
OMe
reduce
oxidize
R2M
+
+
H3O
N
R2
N
R2
N
CO2R1
CO2R1
CO2R1
3
2
1
1. NBS
NaBH4
(R3)2CuLi
2. ArZnBr, Pd
CeCl3
O
OH
N
O
As part of an ongoing synthetic program aimed at the develop-
ment of new approaches to functionalized piperidine ring systems,
we have explored the use of the tandem conjugate addition–dipo-
lar cycloaddition cascade of keto oximes 8 with 2,3-bis(phenylsul-
fonyl)-1,3-butadiene (7) as a route to various marine alkaloids.13
This reaction cascade is easy to perform and affords azaoxabicyclic
Ar
N
R2
R2
N
R2
R3
CO2R1
CO2R1
CO2R1
6
5
4
cycloadducts
9 in good to excellent yields with essentially
Scheme 1.
complete stereocontrol (Scheme 2).14 Raney-Ni reduction of
cycloadduct 9 triggers a sequential nitrogen–oxygen bond cleavage
followed by desulfonylation to furnish a 2,2-disubstituted 4-pip-
eridone of type 10. With an easy entry into 4-piperidones such
* Corresponding author. Tel.: +1 404 727 0283; fax: +1 404 727 6629.
E-mail address: chemap@emory.edu (A. Padwa).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.109

5740
A. C. Flick, A. Padwa / Tetrahedron Letters 49 (2008) 5739–5741
O
O
N
SO2Ph
H
SO2Ph
R1
N
+
MeO
MeO
OH
R1
1. K2CO3
Br
O
O
SO2Ph
MeO
MeO
R2
+
N
SO2Ph
+
2. H3O
R2
9
8
7
N
H
17
18 (87%)
Ra(Ni)
O
Hg(OAc)2
O
O
O
(R4)2CuLi
O
R1
R2
R1
R1
R2
steps
N
R3
N
R3
N
H
R4
1. 10% H2SO4
2. Hg(OAc)2
R2
MeO
MeO
MeO
MeO
N
N
10
12
11
Scheme 2.
20 (79%)
19 (88%)
Scheme 4.
as 10, our intention was to further oxidize the system in order to
produce the corresponding 2,3-dihydro-4-pyridone 11. This would
be followed by reaction with several cuprate reagents to afford
2,2,6-trisubstituted 4-piperidones 12 which are useful intermedi-
ates for alkaloid synthesis.13
Br
N
O
+
O
1. K2CO3
The ubiquity and utility of the dihydropyridone system coupled
with the difficulties that are associated with the oxidation of
N-alkyl substituted 4-piperidones suggested a more detailed inves-
tigation. The earlier success of the mercuric acetate oxidation of
piperidines by Leonard et al.15 led us to test the utility of this
oxidizing agent with various 4-piperidones. Scheme 3 outlines
several 2,3-dihydro-4-pyridones that were prepared in good yield
from the corresponding N-alkyl 4-piperidone precursor using
mercuric acetate conditions.16 It should be noted that only the
more substituted dihydropyridone (i.e., 13 and 15) was obtained
from the oxidation, thereby indicating a distinct preference for
the formation of the thermodynamically most stable product.
We then conducted a brief exploration of the synthetic utility of
the reaction to create the skeletal framework of various alkaloids.
Reaction of the commercially available bromide 17 with 1,4-di-
oxa-8-azaspiro[4.5]decane in the presence of K2CO3 followed by
a subsequent hydrolysis of the ketal provided 4-piperidone 18 in
87% yield. Mercuric acetate oxidation of 18 gave 19 in 88% yield.
Treatment of 19 with 10% H2SO4 at 90 °C induced initial enamide
protonation and this was followed by a Pictet–Spengler cyclization.
A subsequent mercuric acetate oxidation of the cyclized 4-piperi-
done intermediate afforded dihydropyridone 20 in 79% yield for
the two-step sequence (Scheme 4). Consistent with previous
+
2. H3O
N
H
O
N
N
H
H
22 (74%)
21
Hg(OAc)2
N
N
1. 10% H2SO4
2. Hg(OAc)2
N
N
H
O
O
H
23 (90%)
24 (76%)
Scheme 5.
observations (i.e., 13 and 15), only the more heavily substituted
enamide 20 was formed in the final oxidation step.
We also investigated a similar approach to the core skeleton of
the yohimbenone framework. Reaction of 3-(2-bromoethyl)-1H-in-
dole (21) with 1,4-dioxa-8-azaspiro[4.5]decane followed by ketal
hydrolysis furnished 4-piperidone 22 in 74% yield. Treatment of
22 with mercuric acetate provided a 90% yield of the corresponding
dihydropyridone 23. This heterocycle represents a useful inter-
mediate for alkaloid synthesis, as is shown by its sequential acid
cyclization/mercuric acetate oxidation to give tetrahydroindo-
lo[2,3-a]quinolizinone 24 in 76% yield for the two-step sequence
(Scheme 5).
In summary, we have demonstrated that N-alkyl substituted 4-
piperidones readily undergo oxidation in high yield upon reaction
with mercuric acetate. The resulting 2,3-dihydro-4-pyridones rep-
resent useful synthetic intermediates for a host of reactions. Stud-
ies concerning the application of the mercuric acetate oxidation to
various 4-piperidones prepared by a conjugate addition/dipolar
cycloaddition cascade of oximes with 2,3-bis(phenylsulfonyl)-1,3-
butadiene are in progress and will be reported in due course.
O
O
R1
R2
R1
R2
Hg(OAc)2/EDTA
H2O/EtOH
80 ºC
N
R3
N
R3
O
N
O
N
O
N
O
N
CO2Me
C6H13
Acknowledgment
16 (92%)
13 (88%)
14 (90%)
15 (76%)
We appreciate the financial support provided by the National
Science Foundation (Grant CHE-0742663).
Scheme 3.

A. C. Flick, A. Padwa / Tetrahedron Letters 49 (2008) 5739–5741
5741
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16. A typical mercuric acetate oxidation: To a round-bottomed flask charged with
0.25 g (0.88 mmol) of 1-benzyl-4-oxo-3-piperidinecarboxylate were
sequentially added 30 mL of a solution of H2O/EtOH (2:1), 0.3 g (0.92 mmol)
of Hg(OAc)2, and 0.34 g (0.92 mmol) of EDTA. The mixture was heated to 80 °C
for 2 h, cooled to rt and filtered through a pad of Celite. The filtrate was
partitioned between CH2Cl2 and aqueous NH4Cl. The organic layer was
extracted with CH2Cl2, washed with water, brine, then dried over anhydrous
Na2SO4. The ether layer was concentrated under reduced pressure to give
0.19 g (88%) of dihydropyridone 13 as a colorless oil which required no further
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purification: IR (CH2Cl2): 1719, 1658, 1601, 1436, 1337, 1155, and 1054 cmÀ1
1H NMR (600 MHz, CDCl3) d 2.56 (t, 2H, J = 7.2 Hz), 3.52 (t, 2H, J = 7.2 Hz), 3.84
(s, 3H), 4.62 (s, 2H), 7.34 (t, 2H, J = 6.6 Hz), 7.43–7.48 (m, 3H), 8.41 (s, 1H); 13
;
C
NMR (75 MHz, CDCl3) d 36.1, 46.3, 51.7, 61.3, 100.5, 128.0, 129.2, 129.5, 134.2,
160.0, 166.4, and 186.6; HRMS calcd for [C14H15NO3+H+]: 246.1052, found:
246.1125.