A novel and facile synthesis of 3,4-diacyl-2H-pyran-2-ones. New C[Formula presented]C bond formation

Article abstract of DOI:10.1016/j.tetlet.2016.06.095

The two-step synthesis of 3,4-diacyl-2H-pyran-2-ones was achieved in good yields from dehydroacetic acid via transformation of the hydroxyl group into an acyl group (TROHIA). This transformation which was earlier explored using the benzene nucleus of seve

Full text of DOI:10.1016/j.tetlet.2016.06.095

Accepted Manuscript
A novel and facile synthesis of 3,4-diacyl-2H-pyran-2-ones. New C-C bond
formation
Antigoni Kotali, Despina A. Nasiopoulou, Philip A. Harris
PII:
S0040-4039(16)30764-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.095
TETL 47822
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 April 2016
17 June 2016
22 June 2016
Please cite this article as: Kotali, A., Nasiopoulou, D.A., Harris, P.A., A novel and facile synthesis of 3,4-
diacyl-2H-pyran-2-ones. New C-C bond formation, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.06.095
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Graphical Abstract
A novel and facile synthesis of 3,4-diacyl-2H-
pyran-2-ones. New C-C bond formation
Leave this area blank for abstract info.
Antigoni Kotali,a,∗ Despina A. Nasiopoulou,a and Philip A. Harrisb

1
Tetrahedron Letters
journal homepage: www.els evier.com
A novel and facile synthesis of 3,4-diacyl-2H-pyran-2-ones. New C-C bond
formation.
Antigoni Kotali,a,∗ Despina A. Nasiopoulou,a and Philip A. Harrisb
aLaboratory of Organic Chemistry, Department of Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
bGlaxoSmithKline, 1250 South Collegeville Road, PO Box 5089, Collegeville, PA 19426-0989, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
The two-step synthesis of 3,4-diacyl-2H-pyran-2-ones was achieved in good yields from
dehydroacetic acid via transformation of the hydroxyl group into an acyl group (TROHIA). This
transformation which was earlier explored using the benzene nucleus of several substrates as
well as the benzene and pyrone ring of coumarins has now been applied successfully to the
pyrone heterocyclic ring. The reaction involves the formation of a new C-C bond.
Received in revised form
Accepted
Available online
Keywords:
Dehydroacetic acid
Diacyl-pyranones
Transformation
Oxidation
2009 Elsevier Ltd. All rights reserved.
Iodobenzene diacetate
Lead tetraacetate
C-C bond formation
———
∗ Corresponding author. Tel.: +00-30-2310-996253; fax: +00-30-2310-996253; e-mail: kotali@eng.auth.gr

2
Tetrahedron Letters
1. Introduction
1,4-Diketones, appearing in the literature as γ-diketones, are
well known building blocks in synthetic chemistry and the
development of new methods for their synthesis is still an
interesting goal.1 Among these, o-diacyl heterocycles are
interesting members. The presence of two ortho carbonyl groups
on a heterocyclic ring allows the formation of novel multi-
condensed heterocycles. However, there are few reports in the
literature regarding their synthesis and in this sense there is
demand for new and effective syntheses. Representative
examples of synthesized o-diacyl heterocycles are 4,5-diaroyl-
1H-pyrrole-2,3-diones,2 3,4-dibenzoyl-1,2,5-thiadiazole,3 3,4-
diacyl-1,2,5-oxadiazoles,3,4 2,3-dibenzoylchromenes5 and 2,3-
dibenzoyl-pyrido-pyrazolo-pyrimidine6 (Figure 1). Previously,
we synthesized 3,4-diacylbenzopyran-2-ones (Figure 1), known
as 3,4-diacylcoumarins, via the transformation of a hydroxy into
an acyl group (TROHIA) on the non-aromatic ring of 3-acetyl-4-
hydroxy-coumarin N-carbonyl hydrazones.7
Figure 2. DHA structure
2. Results and Discussion
Based on the above information we chose DHA N-aryl
carbonyl hydrazones to serve as synthons for the preparation of
novel 3,4-diacylpyran-2-ones (Scheme 1). Pyran-2-ones are well
known oxygen heterocycles, appearing in the literature as 2H-
pyran-2-ones, α-pyrones or 2-pyrones. The importance of pyran-
2-one derivatives as building blocks in synthetic and medicinal
chemistry has been well established and is a consequence of their
interesting structural features and diverse pharmacological
properties.25-28
Following our earlier work,29 the first step involves the
preparation of the desired precursors, DHA N-acylhydrazones 3,
which would in the second step, be treated with either
(diacetoxyiodo)benzene (DIB) or lead tetraacetate (LTA) in order
to apply the TROHIA protocol. Interconversion of functional
groups has always played an important role in organic
synthesis.30 TROHIA has been applied to a variety of aromatic
ortho-hydroxyaryl ketone N-carbonyl hydrazones as well as the
non-aromatic ring of 3-acetyl-4-hydroxy-coumarin N-carbonyl
hydrazones, affording the corresponding 1,2-diacyl-, 1,2,3-
triacyl, 1,2,3,4- and 1,2,4,6-tetracyl- benzenes as well as o-
acylarylcarboxylic esters,31 o-acylbenzaldehydes,32 and 6,7- and
7,8- diacylcoumarins33 in very good yields. Thanks to the
TROHIA protocol, 1,2-diacyl derivatives, which were either
unavailable or difficult to synthesize have now been proved
valuable for the synthesis of interesting heterocycles.34-37 In a
continuation of our research we now present the application of
TROHIA to the non-aromatic heterocyclic ring of DHA.
DHA, the starting ketone 1, is commercially available and
DHA N-acylhydrazones 3 were synthesized according to the
literature17 via treatment of DHA 1 with the appropriate
hydrazide 2 in methanol (Scheme 1). A reactant molar ratio of
1:1 was used and the reaction was performed at reflux for 2 h to
yield hydrazones 3a–3f in excellent yields (Table 1, entries 1-6,
95–99%). Hydrazones 3 were subsequently treated with DIB in
dichloromethane at room temperature to give the desired
products 4 in good yields (Table 1, entries 7-12, 40-55%). DIB
belongs to the family of hypervalent iodine reagents which have
proven to be valuable in organic synthesis since they allow mild
and highly selective oxidative transformations in a facile and
environmentally friendly manner.38,39 Furthermore, it is known to
exhibit reactivity analogous to that of LTA while not being as
hazardous and toxic as lead(IV) compounds.
Figure 1. Examples of known diacyl heterocycles.
Dehydroacetic acid (DHA), a pyrone derivative also known as
3-acetyl-6-methyl-2H-pyran-2-one 1A, or 3-acetyl-6-methyl-2,3-
dihydro-pyran-2,4-dione 1B (Figure 2), is
a plant-derived
preservative in the tropical flowers of Solandra nitida and
grandiflora species (commonly called cup of gold or golden
chalice vine).8,9 DHA is used as a food additive (E265) and in
cosmetics.10-12 DHA was first prepared in 1866 from
acetoacetate8 and since then it has attracted the interest of a great
number of researchers. Recently, the reactivity of DHA has been
reviewed.8 Among the several reactions, our interest was focused
on the reactivity with amino compounds such as N-amino-
heterocycles13 or hydrazines14-16 and we recently investigated
their reaction with hydrazides to synthesize DHA N-aryl carbonyl
hydrazones as well as their silicon and boron derivatives.17,18
Hydrazones are well known synthons in organic synthesis19-20 as
well as molecules with diverse biological activities.21-24
Since the TROHIA protocol works well using LTA, despite its
toxicity, we also performed the above reactions with LTA in
order to compare the results. The reaction of hydrazones 3 with
LTA in THF at room temperature afforded the corresponding
3,4-diacylpyrones 4 in 43-63% yield which was slightly higher
than those obtained using DIB oxidation (Table 1, entries 7-12).
The reaction conditions, yields and melting points of literature
hydrazones 3a, 3b and 3d-3f as well as of the new compounds 3c
and 4a-4f are presented in Table 1.

3
In the 13C NMR spectrum, characteristic peaks appeared at
17.1 and 19.8 ppm which were assigned the methyls at C-6 and
the 3-C=N carbon, respectively. The signal at 181.6 ppm was
assigned to C-4, whereas those at 168.9 and 164.4 ppm were
assigned to the amide carbon (=NHCO-) and the hydrazono (3-
C=N) carbon, respectively. Furthermore, hydrazone 3c showed a
prominent ion corresponding to [M+H] in the mass spectrum.
3,4-Diacylpyranones 4 displayed characteristic IR peaks at
1748-1733, 1682-1660 and 1648-1605 cm-1 corresponding to the
carbonyl of the acetyl, aroyl and lactone group, respectively. In
their 1H NMR spectra, compound 4 showed singlets at ~2.35 and
2.45 ppm for the methyl protons at C-6 and the 3-C=O carbon,
respectively. The proton at C-5 appeared as a singlet at ~6.41-
6.49 ppm. The resonances of the methyl protons in
diacylpyranones 4 were at higher field values than in hydrazones
3 due to the relative anisotropy of the carbonyl (C=O) and
hydrazonic (C=N) bonds, respectively, by analogy to 3,4-
diacylcoumarins and their precursor hydrazone derivatives.7
Concerning the mechanism of the reaction, it is suggested that
it proceeds analogous to the mechanism proposed for the
transformation of o-hydroxyacetophenone N-benzoyl hydrazone
into 1-acetyl-2-benzoylbenzene.31e
Scheme 1. Preparation of 3,4-diacyl-2H-pyran-2-ones 4.
Hydrazones were purified via recrystallisation from
3
propanol whereas the desired 3,4-diacyl-2H-pyran-2-ones 4 were
isolated by column chromatography. DHA hydrazone 3c and
products 4a-4f are new compounds and their structures were
identified by 1H, 13C NMR and mass spectra as well as by either
elemental analysis or high resolution mass spectrometry.
3. Conclusion
DHA 1 was successfully converted to 3,4-diacylpyran-2-ones
4 via intermediate DHA N-acyl hydrazones 3 formation under
mild conditions and in good yield (Scheme 1). TROHIA has been
successfully applied for the first time to a heterocyclic system,
the pyrone ring, which is not condensed to a benzene ring. 3,4-
Diacylpyran-2-ones 4 could prove to be useful synthons in
heterocyclic synthesis as well as important scaffolds for
pharmaceuticals.
In the 1H NMR spectra, DHA hydrazone 3c showed
characteristic singlets at 2.14 and 2.61 ppm which were assigned
to the methyl protons at C-6 and the 3-C=N carbon, respectively.
The C-5 proton appeared as a singlet at 5.91 ppm whereas the
amide proton gave a singlet at 11.40 ppm and the hydroxyl
protons appeared as broad peaks at 12.05 and 16.12 ppm. All the
above data were in accordance with the literature data for known
DHA hydrazone derivatives.17,18
Table 1. DHA N-acylhydrazones 3a-3f and 3,4-diacyl-2H-pyran-2-ones 4a-4f produced via Scheme 1.
Temp.
Entry
Compound
R
Reagents
Method B
(Method C)
Ratio of
reactants
Time (h)
Solvent
Yield (%)
m.p (°C)
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
4-H3CC6H4
4-ClC6H4
2-HOC6H4
2-O2NC6H4
2-furyl
1+2a
1+2b
1+2c
1+2d
1+2e
1+2f
1/1
1/1
1/1
1/1
1/1
1/1
2
2
2
2
2
2
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
reflux
reflux
reflux
reflux
reflux
reflux
r.t.
95
98
99
96
97
98
225a
214a
237-238
200-201a
218-219a
170-171a
2-thienyl
4a
4-H3CC6H4
3a+DIP
(3a+LTA)
1/1.5
(1/1.5)
1
(1)
CH2Cl2
(THF)
55
(63)
133-134b
(135-136)
8
4b
4c
4d
4e
4f
4-ClC6H4
2-HOC6H4
2-O2NC6H4
2-furyl
3b+DIP
(3b+LTA)
1/1.5
(1/1.5)
1
(1)
CH2Cl2
(THF)
r.t.
r.t.
r.t.
r.t.
r.t.
45
(54)
151-152b
156-157b
152-153b
9
3c+DIP
(3c+LTA)
1/1.5
(1/1.5)
2
(2)
CH2Cl2
(THF)
40
(43)
10
11
3d+DIP
(3d+LTA)
1/1.5
(1/1.5)
1
(2)
CH2Cl2
(THF)
42
(55)
3e+DIP
(3e+LTA)
1/1.5
(1/1.1)
1
(24)
CH2Cl2
(THF)
45
(51)
123-124b
(124)
12
2-thienyl
3f+DIP
(3f+LTA)
1/1.5
(1/1.1)
1
(24)
CH2Cl2
(THF)
42
(56)
124-1251b
aLit. ref. 17.
bRecrystallised from EtOH.

4
Tetrahedron
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5
Graphical Abstract
A novel and facile synthesis of 3,4-diacyl-2H-
pyran-2-ones. New C-C bond formation
Leave this area blank for abstract info.
Antigoni Kotali,a,∗ Despina A. Nasiopoulou,a and Philip A. Harrisb

6
Tetrahedron
HIGHLIGHTS
“A novel and facile synthesis of 3,4-diacyl-2H-
pyran-2-ones. New C-C bond formation”
•
Two-step synthesis of 3,4-diacylpyranones
starting from commercially available
reagents.
•
•
Good yields and simple experimental
procedures add to the value of the method.
Synthesis of new heterocycles, unavailable
by other methods, bearing acyl groups at
neighbouring positions
•
Transformation of the hydroxyl group into
an acyl group was applied to the pyrone
heterocyclic ring.
•
New C-C bond formation is involved.