Tandem reaction of 3-hydroxyhexa-4,5-allenic esters: A novel access to diversely substituted 2H-pyran-2-ones and indenes

Article abstract of DOI:10.1039/c2cc30247k

A highly efficient synthesis of diversely substituted 2H-pyran-2-ones and indenes through Bronsted acid promoted tandem reaction of the readily obtainable 3-hydroxyhexa-4,5-allenic esters under extremely mild conditions has been developed. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc30247k

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COMMUNICATION
Tandem reaction of 3-hydroxyhexa-4,5-allenic esters: a novel access to
diversely substituted 2H-pyran-2-ones and indenesw
Haiyun Xu, Xinying Zhang,* Yan He, Shenghai Guo and Xuesen Fan*
Received 12th January 2012, Accepted 30th January 2012
DOI: 10.1039/c2cc30247k
A highly efficient synthesis of diversely substituted 2H-pyran-
2-ones and indenes through Brønsted acid promoted tandem
reaction of the readily obtainable 3-hydroxyhexa-4,5-allenic
esters under extremely mild conditions has been developed.
Table 1 Optimization studies for the formation of 3aa
Allene derivatives are powerful synthetic intermediates
toward a plethora of important organic compounds and
frequent building blocks of natural products.1 In this regard,
2,4,5-trienoates are the core substructure of some sex pheromones
of male dried bean beetles.2 As a continuation of our research in
allene chemistry,3 we envisioned a synthetic pathway toward
2,4,5-trienoate through dehydration of 3-hydroxyhexa-4,5-
dienoate. For this purpose, 3-hydroxy-3-phenylhexa-4,5-dienoate
(2a), prepared from 1-phenylbuta-2,3-dien-1-one (1a) and methyl
2-bromoacetate, was treated with H2SO4 (10 mol%) in CH3CN
until a complete consumption of 2a (0.5 h). From the resulting
mixture, three products were isolated but none of them was
the desired 2,4,5-trienoate (I). Instead, they were identified
as 6-methyl-4-phenyl-2H-pyran-2-one (3a), methyl 3-phenyl
hex-2-en-5-ynoate (A) and methyl 5-oxo-3-phenylhex-2-enoate
(B) with yields of 52%, 15% and 21%, respectively (Scheme 1).
Although the desired 2,4,5-trienoate was not obtained, the
result is interesting since it offers a novel approach toward
2H-pyran-2-ones. 2H-Pyran-2-ones are versatile synthetic
Yieldb (%)
t/h 3a
Entry Acid
Solvent
T/1C
A
B
1
2
3
4
5
6
7
8
H2SO4c
CH3CN 40
CH3CN 40
CH3CN 60
CH3CN 40
CH3CN 40
0.5 52 15
0.5 56 12
0.5 61 10
21
23
19
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
TsOH
1
2
1
1
72 Trace 15
73 Trace 13
30 10
26 23
THF
CH3OH 40
40
35
25
CH2Cl2 Reflux 0.5 86 Trace Trace
9
CH2Cl2 rt
CH2Cl2 rt
CH2Cl2 rt
0.5 85 Trace Trace
10
11
12
13
1
1
1
1
36 Trace 35
BF3ÁEt2O
32 31
21 10
32 20
26
10
35
RuCl3ÁnH2O CH2Cl2 rt
FeCl3Á6H2O CH2Cl2 rt
a
Reaction conditions: 2a (1 mmol), acid catalyst (0.1 mmol).
c
Isolated yields. 0.2 mmol of acid were used.
b
building blocks and frequent backbones of compounds found
in bacteria, fungi, plants, and animals. Many compounds with
the a-pyrone moiety have shown antimicrobial, antineoplastic,
and anti-HIV effects.4,5 As a result, synthetic approaches to
a-pyrones have been extensively investigated.6–11 However, efficient
protocols without using sophisticated catalysts/reagents and
accomplished under mild conditions are still highly desirable.
Thus, exhaustive studies on reaction conditions for the
formation of 3a were conducted (Table 1). After some trial
and error, the optimal conditions were identified as follows:
10 mol% of H2SO4 in dichloromethane at rt for 0.5 h. Under
such conditions, 3a was obtained in 85% yield.
Scheme 1 Unexpected formation of a-pyrone 3a.
With the optimized conditions in hand, we screened a range
of 3-hydroxyhexa-4,5-dienoates to probe the scope of this
reaction. It turns out that substrates prepared from aryl
substituted allenic ketones with various substituents on the
aryl ring undergo this reaction smoothly with good to excellent
yields (Table 2, entries 1–13). The presence of an electron-
withdrawing or electron-donating group on the aryl ring
slightly affects the reactivity. The reaction is found to be also
compatible with substrates prepared from diaryl or alkyl, aryl
School of Chemistry and Environmental Science, Key Laboratory of
Green Chemical Media and Reactions, Ministry of Education,
Henan Key Laboratory for Environmental Pollution Control,
Henan Normal University, Henan 453007, P. R. China.
E-mail: xuesen.fan@htu.cn, xinyingzhang@htu.cn;
Fax: +86-373-3326336; Tel: +86-373-3329261
w Electronic supplementary information (ESI) available: Experimental
procedures, characterisation data and NMR spectra. See DOI:
10.1039/c2cc30247k
c
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Chem. Commun., 2012, 48, 3121–3123 3121

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Table 2 Synthesis of 4,6-disubstituted 2H-pyran-2-onesa
Scheme 3 Abarbri’s synthesis of a-pyrones via a hexa-2,4,5-trienoic
acid intermediate.
Entry
R1
R2
3
Yieldb (%)
1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
85
86
88
78
81
84
82
83
81
80
75
76
90
82
86
80
79
80
82
81
p-Cl–C6H4
p-Br–C6H4
o-Cl–C6H4
o-Br–C6H4
p-CH3–C6H4
m-CH3–C6H4
o-F–C6H4
m-F–C6H4
p-CH3O–C6H4
o-CH3O–C6H4
m,p-di-CH3O–C6H3
p-NC–C6H4
Ph
Scheme 4 Preparation of 3,4,6-trisubstituted a-pyrone 3u–3x.
9
10
11
12
13
14
15
16
17
18
19
20
3j
3k
3l
H
Ph
p-F–C6H4
Ph
p-F–C6H4
Ph
Ph
3m
3n
3o
3p
3q
3r
3s
3t
Ph
Scheme 5 Reaction of 2y and unexpected formation of 4a.
p-CH3–C6H4
p-CH3–C6H4
p-Cl–C6H4
CH3
two protocols are remarkably different in terms of substrates
starting from, catalysts and reagents employed, as well as
mechanistic pathways that involved.
CH3
p-F–C6H4
a
Reaction conditions: 2 (1 mmol), H2SO4 (0.1 mmol), CH2Cl2 (5 mL),
b
rt, 0.5 h. Isolated yields.
Having established an efficient and mild protocol toward
4,6-disubstituted 2H-pyran-2-ones, we moved forward to
study the possibility of preparing 2H-pyran-2-ones with
other substitution patterns. Firstly, reactions of 2u–2x were
studied (Scheme 4). From these reactions, 3,4,6-trisubstituted
2H-pyran-2-ones (3u–3x) were obtained in good yields.
Next, from substrates with a methyl group on the internal
position of the allene moiety (2y), 4,5,6-trisubstituted 2H-pyran-
2-one (3y) was obtained but in low yield (Scheme 5). Interestingly,
methyl 2-(2-methyl-1-methylene-1H-inden-3-yl)acetate (4a) was
isolated along with 3y in a yield of 61%. The structure of 4a
was established based on its MS and NMR spectra (1H, 13C and
HMQC). A possible mechanism leading to 3y and 4a is described
in Scheme 6. While acid promoted domino process via the
initially formed carbocation C affords 3y, the formation of 4a is
most likely through an intramolecular Friedel–Crafts reaction of
carbocation D.13 The presence of a methyl group makes this
alternative route possible since it can stabilize D with the
formation of a tetrasubstituted C–C double bond. Alternatively,
a Nazarov pathway leading to 4a cannot be eliminated.14
The unexpected formation of 4a turns out to be very
attractive since compounds with an indene core have been
widely used as drug candidates and functional materials.15 The
generality of the above process was demonstrated with
disubstituted allenic ketones (entries 14–20). Various func-
tional groups such as methyl, methoxy, halides and cyano
are well tolerated with the reaction conditions.
Based on the above observations, a plausible pathway for
the formation of 3a is depicted in Scheme 2. Acid promoted
dehydration of 2a affords 2,4,5-trienoate I or alkyne A.
Subsequent hydration of I or A gives an enol intermediate
(II) or its ketone isomer B. Intramolecular transesterification
of II affords a-pyrone 3a. The proposal that 3a could be
formed through the separable alkyne A is confirmed by a
separate experiment, in which A was treated with H2O in
CH2Cl2 at rt for 0.5 h in the presence of H2SO4 (10 mol%) to
give 3a in 88% yield.12
We noticed that Abarbri et al. have reported an efficient
synthesis of a-pyrones by treating (Z)-a-iodovinylic acids with
allenyl tributyltin (Scheme 3).11 Although the key intermediates
in Abarbri’s process and our method are structurally similar, the
Scheme 2 Plausible pathway for the formation of 3a.
3122 Chem. Commun., 2012, 48, 3121–3123
Scheme 6 Plausible pathway for the formation of 4a.
c
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Scheme 7 Preparation of 4,5,6-trisubstituted a-pyrones 3y–3ac and
indenes 4a–4e.
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Scheme 8 Preparation of 3,4,5,6-tetrasubstituted a-pyrone 3ad and
indene 4f.
substrates 2y–2ac, from which, indenes (4a–4e) were obtained
in reasonably good yields (Scheme 7). From these reactions,
the corresponding 4,5,6-trisubstituted pyran-2-ones (3y–3ac)
could also be obtained. As a further aspect, we were able to
obtain a 3,4,5,6-tetrasubstituted 2H-pyran-2-one (3ad) together
with indene 4f from substrate 2ad (Scheme 8).
In summary, we have developed a novel and easy-to-perform
protocol for the preparation of 2H-pyran-2-ones through an
acid-catalyzed domino reaction of 3-hydroxyhexa-4,5-dienoates.
By tuning the substitution patterns of the substrates, 4,6-
disubstituted and 3,4,6-trisubstituted a-pyrones can be synthesized
with high efficiency. More interestingly, from substrates with
a methyl group on the internal position of the allene moiety,
indene derivatives could also be prepared together with 4,5,6-
trisubstituted or 3,4,5,6-tetrasubstituted a-pyrones. With advan-
tages such as readily available substrates, diversely substituted
products, free of sophisticated catalysts or reagents, and extremely
mild reaction conditions, this finding should be an important
implication in heterocyclic chemistry and related areas. Further
studies to expand substrate scope and have a possible deeper
insight into the reaction mechanism are currently underway.
We are grateful to the National Natural Science Foundation of
China (20972042, 21172057), Innovation Scientists and Technicians
Troop Construction Projects (104100510019), PCSIRT (IRT1061)
and 2012IRTSTHN006 for financial support.
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Notes and references
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 3121–3123 3123