Unusual tandem sequence of oxa Diels-Alder reaction, retro Diels-Alder reaction, and oxa 6π-electrocyclic ring opening in the reaction of 6-amino-4-(4-methoxyphenyl)-2H-pyran-2-ones with benzaldehydes

Article abstract of DOI:10.1039/c4ra13374a

The oxa Diels-Alder reaction of 6-amino-4-(4-methoxyphenyl)-2H-pyran-2-ones with benzaldehydes took an unusual path whereby a tandem sequence of the oxa Diels-Alder reaction, retro Diels-Alder reaction, and 6π-electrocyclic ring opening of the pyran yielded 3-(4-methoxyphenyl)-5-phenyl-1-(piperidin-1-yl/pyrrolidin-1-yl)penta-2,4-dien-1-ones. The reaction took place in boiling toluene with a series of substituted benzaldehydes. An electron-donating group on benzaldehyde retarded the reaction, while an electron-withdrawing group favoured it, thus indicating the normal electron demand pathway. This journal is

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Unusual tandem sequence of oxa DielsꢀAlder reaction, retroꢀDielsꢀAlder
reaction and oxa 6ᴨꢀelectrocyclic ringꢀopening in the reaction of 6ꢀ
aminoꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ2Hꢀpyranꢀ2ꢀones with benzaldehydes†
Adil I. Khatri and Shriniwas D. Samanta
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
The DielsꢀAlder reactions of 2ꢀpyrones reported so far are mostly
carbocyclic. There are only a few reports of normal electron
50 demand hetero DielsꢀAlder reaction of 2ꢀpyrones (1) with nitrile
group of toluene sulfonyl cyanide13 (2a) or benzonitrile (2b),14 as
hetero dienophile, to afford pyridine derivatives (3aꢀb).
Interestingly, in an attempt to carry out the DielsꢀAlder reaction
of 3ꢀhydroxyꢀ2ꢀpyrone (4) with the carbonyl group of aromatic
55 aldehydes (5), a vinylogous aldol reaction took place and 6ꢀ
arylhydroxymethylꢀ3ꢀhydroxyꢀ2ꢀpyrones (6) was formed, instead
of the hetero DielsꢀAlder adduct (7) (Scheme 1).15
The
oxa
DielsꢀAlder
reaction
of
6ꢀaminoꢀ4ꢀ(4ꢀ
methoxyphenyl)ꢀ2Hꢀpyranꢀ2ꢀones with benzaldehydes took
an unusual path; and through a tandem sequence of oxa
10 DielsꢀAlder reaction, retro DielsꢀAlder reaction, and 6πꢀ
electrocyclic ring opening of the pyran yielded 3ꢀ(4ꢀ
methoxyphenyl)ꢀ5ꢀphenylꢀ1ꢀ(piperidinꢀ1ꢀyl/pyrollidenꢀ1ꢀ
yl)pentaꢀ2,4ꢀdienꢀ1ꢀones. The reaction took place in boiling
toluene with a series of substituted benzaldehydes. An
15 electron donating group on benzaldehyde retarded the
reaction, while an electron withdrawing group favoured it;
thus indicating the normal electron demand pathway.
R1
R1
R3
R2
R3
R
R2
R3
R
R2
R1
N
O
N
Heat
or
or
Tos
2ꢀPyrones are function as dienes in the DielsꢀAlder reaction. The
first DielsꢀAlder reaction of 2-pyrone was reported way back in
20 1931 by Otto Diels and Kurt Alder; only three years after the
discovery of DielsꢀAlder reaction.1 Subsequently, the reaction has
been applied in the synthesis of various natural and synthetic
products.2,3 The application in synthesis and the utility of 2ꢀ
pyrones has been described in reviews.4,5 The reaction is
25 interesting, as the intermediate bicyclic adduct undergoes rapid
expulsion of carbon dioxide, through retroꢀDielsꢀAlder reaction,
to form the carbocyclic product. There are a few reports in which
the unstable bicyclic adduct has been isolated.6–8 An electron
donating group on the 2ꢀpyrones ring favours the normal electron
30 demand DielsꢀAlder reaction. The DielsꢀAlder reaction of 3ꢀ
hydroxyꢀ2ꢀpyrones is accelerated in the presence of a base due to
the formation of better electron donating oxide anion.9,10 3,5ꢀ
dibromoꢀ2ꢀpyrone reacts with electron deficient as well as
electron rich dienophiles and give normal and inverse electron
35 demand DielsꢀAlder reactions, thus showing an ambident diene
characteristic.8 An electron donating group, like methyl or
methoxyl group, at the 6ꢀposition of the 2ꢀpyrones ring is highly
favorable and the corresponding DielsꢀAlder reaction has been
used to construct diverse skeletons.11,12
Ph
N
Tos
N
Ph
O
R
3b
3a
1
2b
2a
HO
Ph
O
O
Ph
O
5
O
Catalytic organic base
Solvent, rt
O
O
Ph
H
O
HO
O
OH
4
(not observed)
7
OH
6
60 Scheme 1 Previous attempts of hetero Diels-Alder reaction 2-pyrones
The normal electron demand DielsꢀAlder reaction of 2ꢀpyrones is
favored by an electron donating group in the 2ꢀpyrones ring,
particularly at 4ꢀ and 6ꢀpositions, and using an electron deficient
dienophile. The carbonyl group of benzaldehydes is known to
65 function as a dienophile in the hetero DielsꢀAlder reaction.16,17
Hence, we thought that if a 2ꢀpyrone is activated by an amino
group at the 6ꢀposition, the pyrone would undergo a normal
electron demand18 oxa DielsꢀAlder reaction with the carbonyl
group of an aryl aldehyde; the reaction would provide 2ꢀ
70 aminopyrans. With this objective we attempted the DielsꢀAlder
reaction of 6ꢀaminoꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ2Hꢀpyranꢀ2ꢀones (11)
with benzaldehydes (12). Unexpectedly, the DielsꢀAlder reaction
gave 3,5ꢀdiarylꢀ1ꢀaminopentaꢀ2,4ꢀdienꢀ1ꢀones (15 and 16),
through the expected DielsꢀAlder reaction followed by oxa 6πꢀ
75 electrocyclic ring opening of the initial adduct. This unusual
reaction is described herein.
40 ____________________________________________________
a Department of Chemistry, Institute of Chemical Technology, N. M.
Parekh Road, Matunga, 400019 (India). Fax: +91 22 2269 2102
; Tel: +91 22 3361 2606; E-mail: sd.samant@ictmumbai.edu.in
† Electronic Supplementary Information (ESI) available: Experimental
45 procedures, characterisation data of compounds, copies of NMR, HRMS
spectra. See DOI: 10.1039/b000000x/
Acetone dicarboxylic acid was prepared by treating citric acid
with conc. sulfuric acid and reacted with anisole in situ to obtain
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3ꢀ(4ꢀmethoxyphenyl)pentꢀ2ꢀenedioic acid (8).19 Conversion of 3ꢀ
initial adduct 13 (Scheme 3). However, the product 15a was
found to be different than 14a.
arylpentꢀ2ꢀenedioc acid directly to 6ꢀchloroꢀ4ꢀarylꢀ2ꢀpyrone is
known using PCl5 in chlorobenzene.20 We used the similar 45 In the IR spectrum of 15a there was a strong amide carbonyl peak
condition for the conversion of 8 to 9, but found that isolation of
9 from chlorobenzene solution was difficult and hence we
replaced chlorobenzene with DCM. We recorded the m.p. of 9 as
110ꢀ112oC. Synthesis of 9 by some other procedure is known,
at 1619 cmꢀ1, the lower frequency was due to conjugated carbonyl
group. In the 1H NMR spectrum of 15a, the piperidine ring
protons were intact along with the aromatic protons of both the
phenyl rings; one of the diene and the other of the dienophile.
5
interestingly the m.p. reported earlier is 216ꢀ217oC.21 9 on 50 Interestingly, a pair of doublets, with trans coupling, J2=16 Hz,
reaction with piperidine (10a) and pyrrolidine (10b) gave 6ꢀ
due to olefinic protons were obtained at δ 6.54 and δ 7.69.
10 aminoꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀpyrones 11a and 11b, respectively
A third olefinic proton was observed at δ 6.01 as a singlet. The
(Scheme 2).
magnetically nonꢀequivalent protons at δ 3.52(2H) and δ
3.68(2H) as two triplet hinted as piperidine amide moiety in the
O
1
55 product. The structure was further confirmed by Hꢀ1H COSY
O
spectrum, the two trans coupling protons were seen at 6.54 and
7.69 δ.
PCl5/DCM
0oC-rt
O
On the basis of the spectral analysis structure 14a was ruled out
and structure 15a was assigned to the product. Thus, it appeared
60 that the course of the reaction involved – formation of the initial
DielsꢀAlder adduct 13, which underwent decarboxylation to form
6ꢀaminopyran 14a; which in turn underwent 6πꢀelectrocyclic ring
opening to form the product (2E,4E)ꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀ
phenylꢀ1ꢀ(piperidinꢀ1ꢀyl)pentaꢀ2,4ꢀdienꢀ1ꢀone (15a).
OH
HO
O
8
O
O
9
Cl
O
O
65 This is in accord with the fact that 2Hꢀpyran ring is unstable, and
undergoes reversible ring opening to form open chain 1ꢀ
oxodienes, even at ambient temperature.22–31 Such 1ꢀoxodienes
find many synthetic applications.32–34
Et3N, DCM
0oC-rt
( ) x=1,2
4
4
5
N
H
3
5
6
3
2
2
6
( ) x=1,2
O
O
1
N
O
O
1
Cl
10a:x=1
10b:x=2
O
11a/11b
9
O
N
Scheme 2 Synthesis of 6-amino-2-pyrones 11a and 11b
piperine
O
17
O
15 The DielsꢀAlder reaction of 11a with benzaldehyde (12a) was
attempted in refluxing toluene. The reaction was very slow; after
50 h the diene was almost consumed, and product 15a was
obtained. The expected product of the heteroꢀDielsꢀAlder reaction
O
N
piperyline
O
18
70
O
O
20
O
O
O
CO2
Toluene
O
O
Reflux
O
75
N
N
N
O
O
25
30
35
40
14a
11a
12a
13
not observed
80
O
3
H
1
2
H
85
4
N
H
5
O
15a
observed product
90
Scheme 3 Hetero Diels-Alder reaction of 11a with benzaldehyde
The dienamides 15 and 16 are interesting dienoic acid amides
which are otherwise difficult to synthesize, as the respective
of 11a with benzaldehyde (12a) under thermal conditions would
be 2ꢀaminopyran (14a); after the expulsion of CO2 from the
dienoic
acids
are
not
available.
2
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Table 1: HeteroꢀDielsꢀAlder reaction of 6ꢀaminoꢀ2Hꢀpyrones (11) with benzaldehydes (12)a
O
O
H
H
R1
H
R1
H
R1
Toluene
Reflux
N
or
H
R2
O
N
or
11b
O
11a
H
O
X
R2
X
R2
X
12a-g
16a-c
15a-g
Benzaldehydes
X
Timeb
Entry
Pyrone
Product
Yield (%)
mp (oC)
12
R1
H
R2
H
CN
CF3
H
H
H
NO2
H
CN
CF3
(h)
50
48
32
60
38
80
40
46
42
42
80
1
2
3
4
5
6
7
8
9
11a
11a
11a
11a
11a
11a
11a
11b
11b
11b
11a
12a
12b
12c
12d
12e
12f
12g
12a
12b
12c
C
C
C
N
C
C
C
C
C
C
15a
15b
15c
15d
15e
15f
15g
16a
16b
16c
ꢀ
81
86
84
49
56
33
73
61
78
79
ꢀ
94ꢀ96
124ꢀ126
112ꢀ114
90ꢀ92
100ꢀ102
Gum
128ꢀ130
114ꢀ116
146ꢀ148
122ꢀ124
ꢀ
H
H
H
NO2
CH3
H
H
H
10
H
11c
piperonal
a: Reaction conditions: 11a/b: 0.5 mmol; 12: 1 mmol; solvent: toluene (5 mL), reflux; b: complete consumption of 11a/b c: no reaction
______________________________________________________________________________________________________________
5
Further, such compounds are present in natural products. For
example, piperine (17) and piperyline (18) are pentadienoic acid
amides, which are biologically active and are present in Piper
nigrum.37–39 Synthesis of these compounds often require multi
step and cumbersome processes. 35, 36
Acknowledgements
30
AIK is grateful to CSIR, Delhi (India), for a fellowship. The
authors are thankful to Institute for Intensive Research in Basic
Sciences (IIRBS), M. G. University, Kottayam, Kerala (India)
and Guru Jambheshwar University of Science and Technology
10 11a and 11b were reacted with
a series of substituted
benzaldehydes (12aꢀg) in refluxing toluene to obtain a series of 35 (GJUST), Harayana, (India) for providing NMR facility.
dienamides (15aꢀg and 16aꢀc) (Table 1).
An electron donating group on benzaldehyde retarded the
reaction; even methyl group gave poor yield (10f) and piperonal
15 fails to furnish the product. On the other hand, electron
266.
Notes and references
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Conclusions
In conclusion, we have discovered, for the first time, an unusual
20 reaction of 6ꢀaminoꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ2Hꢀpyranꢀ2ꢀones with
aromatic aldehydes involving a tandem sequence of normal
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