A novel synthesis of 1-aryl-3-piperidone derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.11.085

A novel method to construct the 1-aryl-3-piperidone scaffold is described here. Starting from 3,5-dichloroaniline, a seven-step synthesis, without the use of protecting groups, generates the desired 3-piperidone ring in an overall yield of 30% through a key Morita-Baylis-Hillman reaction and ring-closing metathesis, providing easy access to diverse and useful heterocycles.

Full text of DOI:10.1016/j.tetlet.2012.11.085

Tetrahedron Letters 54 (2013) 573–575
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Tetrahedron Letters
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A novel synthesis of 1-aryl-3-piperidone derivatives
⇑
Yinan Zhang, Richard B. Silverman
Department of Chemistry, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Design, Northwestern University, 2145 Sheridan Road, Evanston, Illinois
60208-3113, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A
novel method to construct the 1-aryl-3-piperidone scaffold is described here. Starting from
Received 19 October 2012
Revised 20 November 2012
Accepted 21 November 2012
Available online 29 November 2012
3,5-dichloroaniline, a seven-step synthesis, without the use of protecting groups, generates the desired
3-piperidone ring in an overall yield of 30% through a key Morita–Baylis–Hillman reaction and ring-
closing metathesis, providing an easy access to diverse and useful heterocycles.
Ó 2012 Elsevier Ltd. All rights reserved.
Key words:
3-Piperidone
Synthesis
Morita–Baylis–Hillman
Ring-closing metathesis
Heterocycles
The piperidine ring is an ubiquitous structure present in many
natural alkaloids1 and drug candidates;2 therefore, its synthesis at-
tracts much interest from organic chemists (Fig. 1). Of the piperi-
dine derivatives, 3-piperidone is an important intermediate
because of its easy conversion to other functional groups using var-
ious methods for the construction of bioactive heterocycles. For
example, the transformation of a 4-carboethoxy-3-piperidone to
the planar aniline structure (7) reduces the flexibility of the ester
chain and causes a loss of its ability to condense with the other ester.
Several other attempts, including the use of a strong lithium base,
intramolecular Claisen condensation between the corresponding
Weinreb amide and an ester and a Buchwald amination of the corre-
sponding phenyl bromide and 3-piperidone, also failed.
Since two possible bond-breaking positions around the
b-ketoester moiety (6, a and b, Fig. 2) were fruitless, our focus
shifted to position c. Given the wide utilization of Grubbs catalysts
to mediate ring closing metathesis reactions,8 we decided to re-
place the single bond at position c with a double bond. The double
bond might isomerize from position c to b, which would provide
the b-ketoester from the isomeric allylic alcohol in one step. Retro-
synthetically, 6 could be derived from 8, which could come from
another key synthon 9 through a Morita–Baylis–Hillman (MBH)
nucleophilic addition,9 and 9 could be made from commercially
available 10.
pyrimidinone RO3203546, a selective a
-1 antagonist,3 and the rear-
rangement of a 2-methyl-3-piperidone to a 2-acetylpyrrolidine4
proceed from 3-piperidone intermediates.
A typical procedure to 3-piperidones employs an intramolecular
Claisen condensation of two branched esters of a tertiary amine to
form a cyclic b-ketoester, followed by decarboxylation.5 However,
the extra deprotection step, as well as the moderate to low yield in
the Claisen condensation, limits its application. Herein we report a
novel route to construct 1-aryl-3-piperidone-4-carboxylate ana-
logues without the use of protecting groups.
As a part of an ongoing project in our group to discover a
therapeutic for amyotrophic lateral sclerosis (ALS),6 the synthesis
of the 3-piperidone, 1-(3,5-dichlorophenyl)-4-carboethoxy-
3-piperidone (6), was a high priority. Initially we tried diethyl
carbonate and Mander’s reagent,7 which was successful in our
synthesis of the isomeric 1-aryl-4-piperidone-3-carboxylate 2, but
those reagents gave no b-ketoester from 3-piperidone 5 (Scheme
1). A Dieckmann condensation of diester 3 was shown to be an effec-
tive alternative route, but that reaction also failed when applied to 7.
Possibly, the intramolecular enolate attack does not occur because
The selective reactions of ethyl bromoacetate and allyl bromide
with the aniline were performed under standard conditions
(Scheme 2) in good yields.
Subsequent conversion to 8 was achieved via DIBAL reduction
and then the MBH nucleophilic attack of acrylate mediated by DAB-
CO. Standard conditions for ring-closing metathesis with 5% Grubbs
II catalyst produced cyclic allyl alcohol 12 in near quantitative
yields; the product yield decreased if the loading amount of Grubbs
catalyst was reduced (see Supplementary data). With 12 on hand,
several redox isomerization reactions of allyl alcohols to carbonyl
compounds were explored, including Pd/C, Ru(PPh3)2Cl2,10 and
Cp⁄Ru(CH3CN)3PF6.11 However, no desired isomeric product was
observed. Therefore, 12 was converted to 6 by hydrogenolysis of
⇑
Corresponding author. Tel.: +1 847 491 5653; fax: +1 847 491 7713.
E-mail address: Agman@chem.northwestern.edu (R.B. Silverman).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.085

574
Y. Zhang, R. B. Silverman / Tetrahedron Letters 54 (2013) 573–575
F
N
OH
O
O
H
O
N
H
OH
N
O
OH
OH
N
N
H
Quinine
Phencyclidine
Swainsonine
Paroxetine
Figure 1. Examples of piperidine-containing alkaloids and drugs.
O
N
OH
COOEt
OH
COOEt
EtOOC
b
a
N
COOEt
N
N
Cl
Cl
Cl
Cl
4
3
2
1
COOEt
O
OH
EtOOC
b
a
Cl
N
COOEt
N
N
Cl
Cl
Cl
Cl
Cl
7
5
6
Scheme 1. Reagents and conditions: (a) (EtO)2CO or CNCOOMe, NaH, MeOH, toluene, 80 °C, 3 h, 24%; (b) NaH, toluene, reflux, 4 h, 52%.3
O
O
a
b
c
O
O
NH2
N
N
N
O
OH
Cl
O
Cl
Cl
Cl
Cl
Cl
Cl
Cl
10
9
6
8
Figure 2. Retrosynthetic analysis of 3-piperidone analogue.
OH
Cl
Cl
NH2
Cl
N
COOEt
Cl
N
COOMe
c-d
e
a-b
Cl
10
Cl
Cl
8
11
O
COOMe
OH
COOMe
OH
f/g/h
i-j
NH
k
N
Cl
N
Cl
N
N
H
13
12
Cl
Cl
6
Cl
Scheme 2. Reagents and conditions: (a) BrCH2COOEt, DIPEA, 90 °C, 24 h, 88%; (b) K2CO3, NaI, allyl bromide, CH3CN, reflux, 2 days, 83%; (c) DIBAL, DCM, À78 °C, 1 h, 86%; (d)
DABCO, methyl acrylate, room temp, 3 days, 71%; (e) 5 mol % Grubbs II, DCM, reflux, 5 h, 96%; (f) 5 mol % Pd/C, MeOH, reflux, 16 h; (g) 5 mol % Ru(PPh3)2Cl2 toluene, K2CO3,
100 °C, 16 h; (h) Cp⁄Ru(CH3CN)3PF6, K2CO3, CH3CN, 80 °C, 1 h; (i) Pd/C, EtOAc, 1 atm H2, room temp, 16 h; (j) Dess-Martin periodinane, DCM, room temp, 1 h, 70% for two
steps; (k) NH2NH2, EtOH, room temp, 16 h, 74%.

Y. Zhang, R. B. Silverman / Tetrahedron Letters 54 (2013) 573–575
575
the double bond followed by Dess–Martin periodinane oxidation of
References and notes
the alcohol in good yields, giving 6 in an overall yield of 30% for the
seven steps. Compound 6 was readily converted to our desired pyr-
azolone analogue 13 with hydrazine.
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The 3-piperidinone analogue (6) is a useful intermediate for the
synthesis of a variety of heterocycles, such as pyrimidinones,3
quinuclidinones,12 cyclohexanediamines13 and benzomorphans.14
Furthermore, medium size ring derivatives, such as azepanone
and azocanone analogues, could be attainable from homoallylic
or
c
-propionate anilines using standard RCM conditions.15
In conclusion,
a
novel synthesis of 1-aryl-3-piperidone-
4-carboxylates has been accomplished without the need for
protecting groups. This method should be highly applicable for
the synthesis of a variety of diverse heterocyclic compounds.
Acknowledgments
We thank the National Institutes of Health (Grant
1R43NS057849), the ALS Association (TREAT program) and the
Department of Defense (AL093052), for their generous support of
this research project.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
11.085.