New type of azacyclization: Thermal preparation of 4,6-disubstituted 2-piperidinone from N-sulfonyldienamide and its substituent effect

Article abstract of DOI:10.1016/j.tetlet.2011.12.014

The thermal 6-endo cyclization of N-sulfonyl-2,4-dienamide compounds to produce 4,6-disubstituted 2-piperidinone is described. The observed remarkable substituent effect due to the N-sulfonyl and C3 ethoxycarbonyl groups for acceleration of this 6-endo cy

Full text of DOI:10.1016/j.tetlet.2011.12.014

Tetrahedron Letters 53 (2012) 837–841
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New type of azacyclization: thermal preparation of 4,6-disubstituted
2-piperidinone from N-sulfonyldienamide and its substituent effect
⇑
Yuya Maekawa, Taku Sakaguchi, Hiroshi Tsuchikawa , Shigeo Katsumura
Department of Chemistry, School of Science and Technology, Kwansei Gakuin University, Gakuen 2-1, Sanda, Hyogo 669-1337, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The thermal 6-endo cyclization of N-sulfonyl-2,4-dienamide compounds to produce 4,6-disubstituted 2-
piperidinone is described. The observed remarkable substituent effect due to the N-sulfonyl and C3 eth-
oxycarbonyl groups for acceleration of this 6-endo cyclization strongly suggests that the reaction would
proceed via the 6p-azaelectrocyclization of the intermediary imidic acid. On the contrary, the corre-
sponding 5-formyl and 5-acetyl derivatives rapidly cyclized at room temperature to produce the 5-exo
Received 10 October 2011
Revised 2 December 2011
Accepted 5 December 2011
Available online 9 December 2011
cyclized products.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Azacyclization
N-Sulfonyldienamide
2-Piperidinone
Substituent effect
6-Endo cyclization
The substituted piperidines can be found as a core structural
motif in many naturally occurring alkaloids, and have also been
paid much attention because of their attractive pharmacological
activities.1 2-Piperidinone is known as an effective synthon for
substituted piperidines, because the stereocontrolled introduction
of the desired functional groups into this cyclic amide is easily real-
ized and produces the desired polysubstituted piperidines.2,3a Thus
various kinds of methods for the synthesis of substituted 2-piperid-
inones have been reported.3–6 They are roughly classified into four
groups. The first one is the relatively classical and general method,
which is the cyclization of amino acids or esters including the meth-
od using chiral bicyclic lactams originally developed by A. I. Meyers
as chiral templates.3 The second method is utilizing the Ring-Clos-
ing-Methathesis,4 in which the stereochemistry of the substrate can
be maintained in the product. The amidation reaction using Pd cat-
alysts is classified as the third method.5 The fourth one is the Diels–
Alder reaction catalyzed by Lewis and Brønsted acids.6 Although
various kinds of methods for the synthesis of 2-piperidinone have
already been reported, no application of the azaelectrocyclization
of azatrienes and their equivalents has been reported. In this Letter,
we describe the thermal 6-endo cyclization of N-sulfonyldiena-
mides as a new method for the 2-piperidinone synthesis and also
the remarkable accelerating effect on the cyclization due to the
N-sulfonyl and the ester group at the C3 position. This method eas-
ily allowed us to obtain 4,6-disubstituted 2-piperidinones by only
heating.
We have already developed an efficient synthetic method for
multisubstituted chiral piperidine compounds based on the rapid
6p
-azaelectrocyclization from 1-azatrienes over the past 10 years.7
In this reaction, the key azaelectrocyclization step is dramatically
accelerated by the C4 ester substituent in the azatriene due to the
enhancement of the HOMO–LUMO interaction in the 6
system (Fig. 1A).7j We have also found that the N-sulfonyl group
of the 1-azatrienes accelerates the 6 -azaelectrocyclization to pro-
p electron
p
duce the stabilized dihydropyridine derivatives by the similar pro-
tocol. This method was applied to the one-pot substituted pyridine
synthesis in both the solution and solid phases.7b,e For further
development of our accumulating knowledge on the activation of
this system, we next focused on the more challenging variant, the
catalytic 6p-azaelectrocyclization. The catalytic asymmetric 6-
endo azacyclization of dienamide compounds possessing the ester
group at the C3 position was achieved with the aid of the chiral BIN-
AP–Pd complex catalyst to afford the corresponding chiral 2-pipe-
ridinone compounds (Fig. 1B).8 Inspired by these reactions
described above, we tried to realize the thermal 6-endo azacycliza-
tion of the N-sulfonyldienamide compounds that would include the
6p-azaelectrocyclization of the activated intermediary imidic acids,
that is, the azatrienes (Fig. 1C).
We first investigated the reaction conditions of the thermal
cyclization using the 3-ethoxycarbonyl-5-phenyl-N-sulfonyldie-
neamide derivative 1a as a substrate for the cyclization (Table 1).
It was synthesized by the Migita–Stille coupling of vinylstannane
4a with vinyl iodide 3, which was prepared from the acid 2 through
⇑
Corresponding author. Tel.: +81 79 565 8314; fax: +81 79 565 9077.
E-mail address: katsumura@kwansei.ac.jp (S. Katsumura).
Present address: Department of Chemistry, Graduate School of Science, Osaka
University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.014

838
Y. Maekawa et al. / Tetrahedron Letters 53 (2012) 837–841
Rapid
A
6 -Azaelectro-
π
R2NH2
R2
R1
R2
R1
cyclization
N
N
O
R1
CO2Et
CO2Et
CO2Et
Dihydropyridine
(Unstable)
Activation
B
O
OH
O
Pd2(dba)3 (5 mol%)
(S)-BINAP (10 mol%)
Ts
Ts
Pd*
Ts
N
Azacyclization
N
H
N
Toluene
Ph
CO2Et
Ph
CO2Et
Ph
CO2Et
100 oC, 1 h
86%
81% ee
Activation
C
6
π
-Azaelectro-
O
OH
O
cyclization ?
Ts
Ts
Δ
Ts
N
N
H
N
Ph
CO2Et
Ph
CO2Et
Ph
CO2Et
Figure 1. Azacyclization reaction accelerated by substituent effect.
Table 1
Thermal 6-endo cyclization of dienamides 1a, 6 and 8
O
O
R1
R1
1
N
H
N
3
R2
Ph
R2
Ph
4
Substrate
Product
Entry
1
Substrate
R1
Ts
R2
Solvent
Condition
Product
Result
OEt
1a
Toluene
100 °C, 16 h
5a
No reaction
O
2
3
1a
1a
Ts
Ts
As above
o-Xylene
130 °C, 4 h
130 °C, 4 h
5a
5a
Quant.
Trace
OH
As above
MeO
4
5
1a
6
Ts
Bn
As above
As above
DMSO
o-Xylene
130 °C, 4 h
130 °C, 4 h
5a
7
Trace
No reaction
OTBDPS
6
8
Ts
o-Xylene
130 °C, 4 h
9
40% (32% recovered)
a mixed anhydride of isobutyl chloroformate (IBCF) in the presence
of N-methylmorpholine (NMM) followed by sulfonamidation
(Scheme 1).
effect at the amide nitrogen and the C3 position. When the tosyl
group attached at the amide nitrogen was replaced by a benzyl
group, the thermal cyclization did not proceed at all (entry 5).
Meanwhile, compound 8 afforded the cyclized product 9 in a 40%
yield along with 32% of the starting material under the same
reaction conditions (entry 6). This compound 8 possessed the
bulky siloxymethyl group instead of the electron-withdrawing eth-
oxycarbonyl group in order to keep the s-cis conformation at the
C3–4 bond. Thus, we found that the N-sulfonyl group was very
important for this new thermal 6-endo cyclization reaction10 and
the ester group at the C3 position obviously accelerated this cycli-
zation reaction.
Although the dienamide 1a was stirred at 100 °C in toluene for
16 h only to give the starting material (entry 1), we admitted that
the reaction of 1a slightly proceeded at 110 °C in xylene after stir-
ring for 1 h, however, it was not completed after 3 h at the same
temperature. We then stirred the solution at 130 °C for 4 h. The
reaction went to completion and the expected cyclized product
5a was quantitatively obtained (entry 2).9 2-Methoxyethanol and
dimethyl sulfoxide as a polar solvent were not suitable for this
reaction (entries 3 and 4). Next, we investigated the substituent
SnBu3
Ph
O
I
O
O
1) NMM, IBCF
4a
Ts
Ts
THF, 0 oC, 20 min.
PdCl2(PPh3)2, CuI
HO
N
H
N
H
2) NaH, TsNH2
THF, rt, 2 h
89% for 2 steps
CO2Et
I
CO2Et
Ph
CO2Et
1,4-dioxane
80 oC, 1 h
97%
1a
3
2
Scheme 1. Synthesis of N-sulfonyldienamide.

Y. Maekawa et al. / Tetrahedron Letters 53 (2012) 837–841
839
Table 2
Generality of C5 substituent in thermal 6-endo cyclization
O
O
Ts
Ts
R
N
H
N
6
o-xylene
130 o
R
CO2Et
CO2Et
5
4
C
5
1
Entry
1
Substrate
R
Time (h)
4
Product
Yield (%)
1a
5a
Quant.
76
2
3
1b
1c
2.5
4
5b
5c
MeO
HO
56
O
H
4
5
1d
1e
4
4
5d
5e
76
96
6
7
1f
3
4
5f
66
69
1g
5g
S
8
1h
4
5h
74
N
Ts
O
9
1i
1j
4
4
5i
5j
33
16
O
MeO
10
Table 3
One-pot 5-exo cyclization of C5 carbonyl-substituted dienamide
O
O
O
PdCl2(PPh3)2
CuI
Ts
Ts
R
Ts
SnBu3
N
H
N
N
H
R
+
+
1,4-dioxane
5
R
CO2Et
80 oC, 1 h
CO2Et
I
3
CO2Et
4
4
1
10: 5-exo product
Entry
4
R
Result
1
10
O
1
2
4k
4l
—
10k: 60%
10l: 75%
H
O
—
Me
O
3
4
5
4m
4n
4o
1m: 51%
1n: 75%
1o: 65%
10m: 13%
OMe
HO
HO
—
—
Me

840
Y. Maekawa et al. / Tetrahedron Letters 53 (2012) 837–841
Table 4
5-Exo cyclization of C5 carbonyl-substituted dienamide
O
O
O
[O]
Ts
N
Ts
Ts
R2
N
H
N
H
R1
CO2Et
R2
CO2Et
CO2Et
Product
Substrate
Entry
1
Substrate
R1
Condition
Product
R2
Yield (%)
58
HO
O
1n
MnO2, CH2Cl2, rt, 30 min.
10k
10l
H
HO
Me
O
2
1o
DMP, CH2Cl2, 0 °C, 30 min.
96
Me
To investigate the generality of the thermal 2-piperidinone syn-
thesis resulting from the 6-endo cyclization, we next examined the
cyclization using dienamide substrates having various C-5 substit-
uents (Table 2). Substituted benzene derivatives, such as p-
methoxyphenyl, p-hydroxymethylphenyl, p-formylphenyl, and o-
tolyl derivatives (entries 2–5) allowed the cyclization to produce
the 2-piperidinone compounds in good yields. Furthermore, the
reaction of the various aromatic derivatives such as 2-naphthale-
nyl, 3-thiophenyl, and N-p-toluenesulfonyl-3-indolyl derivatives
(entries 6–8), also produced the cyclized products in moderate
yields. Additionally, alkyl derivatives, which were rather unstable
at the reaction conditions at 130 °C, also gave the cyclized products
in relatively lower yields (entries 9 and 10).
O
O
A
Bn
Bn
MnO2
N
H
N
H
CH2Cl2
rt, 30 min
40%
HO
O
CO2Et
CO2Et
11
12
H
O
O
B
DMP
Ts
Ts
N
N
H
CH2Cl2
0 oC, 1 h
78%
HO
OTBDPS
O
OTBDPS
H
13
14
Scheme 2. Substituent effect in 5-exo cyclization.
On the contrary, the coupling reaction of formyl vinylstannane
4k with vinyl iodide 3 under the same reaction conditions as that
of compound 3–1a (Scheme 1) directly produced the 5-exo cy-
clized product 10k in a 60% yield and not the corresponding diena-
mide and the 6-endo cyclized product (Table 3, entry 1). We then
attempted a similar coupling reaction using the corresponding ke-
tone 4l with the same vinyl iodide 3 under the same reaction con-
ditions, and also obtained the similar 5-exo cyclized product 10l in
a 75% yield (entry 2).9 Meanwhile, in the case of ester 4m, the cou-
pling reaction gave the cyclized product 10m and the uncyclized
dienamide derivative 1m in an 13% and a 51% yields, respectively,
(entry 3). The stereochemistry of the 5-exo cyclized products was
determined by the detailed NMR analysis (13C, COSY, HMQC,
HMBC, NOE). These results strongly suggested that the 5-exo cycli-
zation, namely the Michael-type addition at the C4 position by the
amide nitrogen, proceeded from the intermediary C5-formyl- and
C5-acyl-2,4-dienamide derivatives resulting from the Migita–Stille
coupling.
We then tried to confirm the possibility of a conjugated addi-
tion-type reaction. The corresponding allylic alcohols 1n and 1o
were prepared by the coupling of 3 with the hydroxyl stannanes,
4n and 4o, respectively (Table 3, entries 4 and 5). Oxidation of
the obtained primary alcohol 1n with MnO2 directly produced
the cyclized compound 10k at room temperature for 30 min in a
58% yield (Table 4, entry 1). Oxidation of the secondary alcohol
1o with DMP at 0 °C cleanly produced the corresponding cyclized
product 10l in a 96% yield (entry 2). In both cases, the intermediate
aldehyde and ketone were not admitted. Thus, the 6-endo and 5-
exo cyclizations were clearly distinguished by the C-5 substituent.
Since we encountered the pronounced effect of the cyclization
reaction due to the aldehyde and ketone groups at the C5 position,
we investigated this substituent effect. When the allylic alcohol 11
possessing a N-benzyl group instead of a N-sulfonyl group was oxi-
dized with MnO2, the corresponding aldehyde 12 was isolated
without cyclization (Scheme 2A). Meanwhile, for the compound
having a bulky siloxy group instead of an ester group at the C3 po-
sition similar to the reaction from 8 to 9 (Table 1, entry 6), oxida-
tion of the allylic alcohol 13 with DMP smoothly proceeded to
produce the cyclized 14 at 0 °C in a 78% yield (Scheme 2B). Thus,
the N-sufonyl group of the dienamide compounds was again essen-
tial for the 5-exo cyclization. On the other hand, the ester group at
the C3 position during the 5-exo cyclization would not play a sig-
nificant role.
As a plausible mechanism of this thermal 6-endo cyclization
reaction, two pathways would be possible. One is the 6p-azaelec-
trocyclization from the azatriene of the imidic acid form as shown
in Figure 1C, which would be present in a solution resulting from
the equilibrium of N-sulfonyldienamide. The N-sufonyl group must
assist the imidic acid form of the dienamide, and the C3 ester group
would activate the resulting azatriene equivalent leading to the
easy cyclization. The other is the conjugated addition of nitrogen
in the dienamide form or the imidic acid form to the diene. Consid-
ering the apparent contribution by the C3 ester group to the accel-
eration of the 6-endo cyclization reaction, the former mechanism is
favorable because a similar substituent effect has been clearly ob-
served in the previous 6
our obtained results would be the first example of the thermal
p
-azaelectrocyclization.7j We believe that
6p-azaelectrocyclization of a dienamide as shown in Figure 1C.
In conclusion, we found a new thermal cyclization reaction of
N-sulfonyldienamide, which would be the first example of the
-azaelectrocyclization of a dienamide. Meanwhile, for the com-
6p
pounds substituted by formyl and acetyl groups at the C5 position,
the rapid 5-exo cyclization reaction proceeded resulting from the
Michael type addition reaction. The application of this simple
and easy thermal cyclization providing 4,6-disubstituted-2-pipe-
ridinones to natural product synthesis is now under way in our
laboratory.
Acknowledgments
This work was financially supported by the Grant-in-Aid for Sci-
entific Research on Innovative Areas ‘Organic Synthesis Based on

Y. Maekawa et al. / Tetrahedron Letters 53 (2012) 837–841
841
Am. Chem. Soc. 2008, 130, 14058; (d) Rice, G. T.; White, M. C. J. Am. Chem. Soc.
2009, 131, 11707–11711; For a recent review on catalytic C-H amination, see:
(e) Collet, F.; Dauban, R. H.; Dodd, P. Chem. Commun. 2009, 5061–5074.
6. (a) Chen, Z.; Lin, L.; Chen, D.; Li, J.; Liu, X.; Feng, X. Tetrahedron Lett. 2010, 51,
3088; (b) Itoh, J.; Fuchibe, K.; Akiyama, T. Angew. Chem. Int. Ed. 2006, 45, 4796;
(c) Kipassa, N. T.; Okamura, H.; Kina, K.; Hamada, T.; Iwagawa, T. Org. Lett. 2008,
10, 815–816.
Reaction Integration’ (No.2105) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan. This work was also
supported by a Matching Fund Subsidy for a Private University.
A. Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.014.
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8. The paper describes the Pd catalyzed asymmetric 6-endo azacyclization of
dienamides that has been submitted and is currently under evaluation.
9. The structures of compound 5a and 10l were determined by the detailed
analyses of the corresponding NMR spectra (1H, 13C, COSY, HMQC, HMBC, NOE),
in particular based on HMBC as shown in the following figures.
O
O
Ts
Ts
H
N
N
O
CO2Et
CO2Et
H
H
H
5a
10l
10. We tried to synthesize the N-benzoyl derivative 15 to examine the thermal
cyclization reaction. However, compound 15 was relatively unstable and could
not be obtained in the pure form. The attempts of the thermal cyclization of the
crude 15 under the same reaction conditions to those of N-sulfonyl compound.
gave the cyclized product 16 in roughly 60% yield along with the starting 15 in
about 27% yield.
O
O
O
Bz
Bz
Ph
Bz
Ph
N
H
N
N
H
+
o-xylene
Ph
CO2Et
CO2Et
CO2Et
130 oC, 4 h
15 (crude)
16: 60%
15: 27%
5. (a) Honda, T.; Namiki, H.; Satoh, F. Org Lett. 2001, 3, 631; (b) Inamoto, K.; Saito,
T.; Hiroya, K.; Doi, T. J. Org. Chem. 2010, 75, 3900–3903; (c) Wasa, M.; Yu, J.-O. J.