Efficient synthesis of 6-aryl-4-trifluoromethyl/ethoxycarbonyl-2H-pyran-2-ones through self-condensation of penta-2,4-dienenitriles

Article abstract of DOI:10.1016/j.tetlet.2017.12.003

An efficient synthesis of two new series of 6-aryl-4-trifluoromethyl-2H-pyran-2-ones and 6-aryl-4-carboxyethyl-2H-pyran-2-ones, obtained through the self-condensation reaction of 5-aryl-5-methoxy-3-(trifluoromethyl)penta-2,4-dienenitriles 3 and ethyl 4-ar

Full text of DOI:10.1016/j.tetlet.2017.12.003

Tetrahedron Letters 59 (2018) 121–124
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Tetrahedron Letters
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Efficient synthesis of 6-aryl-4-trifluoromethyl/ethoxycarbonyl-2H-
pyran-2-ones through self-condensation of penta-2,4-dienenitriles
Mário A. Marangoni a, Carlos E. Bencke b, Helio G. Bonacorso a, Marcos A.P. Martins a, Nilo Zanatta a,
⇑
a Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, Brazil
b Laboratory of Chemistry, Instituto Federal Catarinense, 89240-000 São Francisco do Sul, SC, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of two new series of 6-aryl-4-trifluoromethyl-2H-pyran-2-ones and
6-aryl-4-carboxyethyl-2H-pyran-2-ones, obtained through the self-condensation reaction of 5-aryl-5-
methoxy-3-(trifluoromethyl)penta-2,4-dienenitriles 3 and ethyl 4-aryl-2-(cyanomethylene)-4-methoxy-
but-3-enoates 4 respectively, is reported. The self-condensation reaction of the enoates 4 was performed
in water in the presence of hydrochloric acid whereas the self-condensation reaction of the penta-2,4-
dienenitriles 3 required the use of zinc bromide and hydrochloric acid in order to give the respective
2H-pyran-2-ones. Products were obtained up to 97% yield.
Received 22 September 2017
Revised 20 November 2017
Accepted 1 December 2017
Available online 5 December 2017
Keywords:
Penta-2,4-dienenitriles
Enones
Ó 2017 Elsevier Ltd. All rights reserved.
Self-condensation reaction
Pyran-2-ones
2-Pyranones
Introduction
lysts.20,21 (ii) From the reaction of (phenylthio)acetic acids and
a,b-
unsaturated trifluoromethyl ketones, which was performed via a
one-pot isothiourea-mediated Michael addition/lactonization/thiol
elimination cascade sequence.22 (iii) Through the condensation
reaction of b-alkoxyvinyl trifluoroalkyl ketones with N-acyl-
glycines.23 (iv) Through the reaction of aryl-4,4,4-trifluorobutane-
1,3-diones, PCl5, and sodium diethyl malonate, which furnished a
series of 4-substituted 6-trifluoromethyl-2-pyranones.24
According to the literature, and to the best of our knowledge,
the synthesis of 6-substituted 4-trifluoromethyl-2-pyranones, as
well as 6-substituted 4-carboxyethyl-2-pyranones, has not yet
been reported. Thus, the development of an efficient synthetic
method that furnishes 4- and 6-substituted 2-pyranones under
mild conditions is highly desirable. In this study we disclose a
method that enables the obtainment of such compounds through
the self-condensation reaction of penta-2,4-dienenitriles that were
obtained from the olefination reaction of enones with diethyl
cyanomethylphosphonate, through the Horner-Wadsworth-
Emmons protocol, in accordance with a previously developed
method (Scheme 1).25
2-Pyranones are heterocyclic compounds with structure
derived of pyran, and they are found in numerous natural products
isolated from plants, animals, marine organisms, bacteria, fungi,
and insects.1 2-Pyranones are prevalent in many areas, especially
in pharmacology, and they have diverse biological properties
(e.g., antifungal, antibiotic, cytotoxic, neurotoxic, and phytotox-
ic—see Fig. 1).1,2 Some examples of 2-pyranones include: neury-
menolide A,3 which is isolated from the red algae of the
Neurymenia fraxinifolia genus and has appreciable cytotoxicity
against the coccus group bacteria; (+)-violapyrone C,4 which is
obtained by fermentation of Streptomyces violascens; and styryl-
2-pyrone,5 which is extracted from Polygala sabulosa—these last
two both show cytotoxic action against cancer cells.
Due to the importance of 2-pyranones, particularly in organic
and medicinal chemistry, many methods for their synthesis have
been developed. Some of the most important methods are the
following: (i) Through the electrophilic cyclization of (Z)-2-alken-
4-ynoates, which are prepared from the catalyzed palladium cou-
pling reaction of either (Z)-3-iodoacrilates6–8 or (Z)-3-iodoacrylic
acid9–12 with a terminal alkyne. 2-Pyranones synthesized through
the intramolecular cyclization of (Z)-2-alken-4-ynoates have also
been catalyzed by gold,3,4,13–16 ruthenium,17–19 and rhodium cata-
The general strategy for the synthesis of the series of 4-trifluo-
romethyl-2-pyranones and 4-carboxyethyl-2-pyranones is shown
in Scheme 1.
This study began with the preparation of the enones with the
general structures 1 and 2, which were obtained in accordance
with a previously developed method.26
⇑
Corresponding author.
E-mail address: nilo.zanatta@ufsm.br (N. Zanatta).
https://doi.org/10.1016/j.tetlet.2017.12.003
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.

122
M.A. Marangoni et al. / Tetrahedron Letters 59 (2018) 121–124
Table 2
OH
O
O
OH
Optimized reaction conditions and yields for the synthesis of products 5a–e.
O
H
O
O
O
O
CF3
HO
CF3 OMe
styryl-2-pyrone
(+)-violapyrone C
neurymenolide A
NC
Fig. 1. Examples of bioactive 2-pyranones.
O
5a-e
O
R
R
3a-e
O
NC
O
OMe
R
(EtO)2PCH2CN
OMe
R
Compd
R
Producta
Yield (%)b
1) NaH, THF, 0 ºC, 30 min.
2) reflux, 2 h
Y
3a
3b
3c
3d
3e
–H
–Me
–F
–Br
–MeO
5a
5b
5c
5d
5e
97
95
86
88
88
Y
1, 2
3, 4
Self-
condensation
1, 3, 5: Y = CF3
2, 4, 6: Y = CO2Et
R = Ar, HetAr
a
Reaction conditions: H2O, HCl (1.0 equiv.), ZnBr2 (1.0 equiv.), reflux, 1.5 h.
Yields of isolated products.
b
Y
expected product 5a in excellent yields, when kept under reflux
for 1.5 h (Entries 4 and 5, Table 1).
With the optimized reaction conditions ascertained, the scope
of the self-condensation reactions of penta-2,4-dienenitriles 3a–e
for furnishing the respective 6-aryl-4-trifluoromethyl-2H-pyran-
2-ones 5a–e was investigated—the results are reported in
Table 2.29
R
O
O
5, 6
Scheme 1.
The optimization of the reaction conditions for obtaining the 6-
aryl-4-carboxyethyl-2H-pyran-2-ones 6 was then done, using the
pent-2,4-dienenitrile 4b and reported in Table 3. It was observed
that the conversion of the penta-2,4-dienenitrile 4b to the respec-
tive 2-pyranone 6b was accomplished in the presence of
hydrochloric acid, under reflux of the solvent for over 1 h (Entries
4–8, Table 3). Increasing the amount of hydrochloric acid from 1 to
6 equivalents did not improve the yield. The reaction conducted
without hydrochloric acid or at a lower temperature did not fur-
nish the expected products (Entries 9 and 1–2, respectively—see
Table 3). A slightly better yield was achieved when water/HCl
was substituted by ethanol/HCl (Entry 12, Table 3); however, this
reaction took 6 h to be completed. The use of the catalyst zinc bro-
mide alone did not furnish the expected product, and when the
reaction was performed with zinc bromide in the presence of
hydrochloric acid, the product 6b was isolated in 56% yield. Thus,
we concluded that the most convenient condition for the self-con-
densation reaction of compound 4b–6b involved using water as
the solvent in the presence of 1 equivalent of hydrochloric acid,
under reflux for 1.5 h.
The corresponding penta-2,4-dienenitriles 3 and 4 were also
synthesized in accordance with a previously reported method.25
The geometry of the penta-2,4-dienenitriles was detailed described
in Ref. 25. Initially, the optimization of the reaction conditions for
obtaining the 6-aryl-4-trifluoromethyl-2H-pyran-2-ones 5 was
done using the penta-2,4-dienenitrile 3a as the substrate of our
model reaction (Table 1). The starting reaction conditions were
based on the literature study in which the hydrolysis of the nitrile
group was performed using aqueous acid solutions and reflux tem-
perature; catalysts were sometimes also used.27,28
It was observed that the reaction carried out without catalyst
(Entries 1 and 2, Table 1) did not convert the substrate 3a into
its product 5a. However, with the addition of zinc bromide and
1.0 equivalent of hydrochloric acid, the reaction furnished the
Table 1
Optimization of the reaction conditions for obtaining the product 5a.
One can see that the self-condensation reaction of the trifluoro-
substituted nitriles 3 was only done in the presence of the catalyst
zinc bromide, while the reaction of the ethyl 2-(cyanomethylene)-
4-methoxybut-3-enoate 4 did not need the use of this catalyst. The
presence of the carboxylic ester in compounds 4—which is a strong
electron-withdrawing group that acts through both inductive and
mesomeric effect—is probably responsible for the easier hydrolysis
of the nitrile group. For the CF3 group, the electron-withdrawing
effect can only operate through the inductive effect. The lower
yields of the 4-carboxyethyl-2H-pyran-2-ones 6 compared to the
4-trifluoromethyl-2H-pyran-2-ones 5 are probably due to the
hydrolysis and/or elimination of the carboxylic ester group either
the intermediates 4 or the products 6.
CF3
NC
H2O, HCl,
OMe
catalyst, reflux
F3C
O
O
5a
3a
Entry
Time (h)
HCl (equiv.)
Catalyst
Yield (%)a
b
1
2
3
4
5
20
20
1.0
1.5
20
–
–
–
b
1.0
1.0
1.0
1.0
A possible mechanism for the self-condensation reaction of the
penta-2,4 dienenitriles to the respective 2-pyranones begins with
the hydrolysis of the nitrile group to the carboxylic acid, assisted
by hydrochloric acid (Structure I, Scheme 2). In the next step, an
oxygen of the carboxylic group undergoes an intramolecular attack
ZnBr2
ZnBr2
ZnBr2
75
97
92
a
Yields of isolated products.
Starting material was recovered.
b

M.A. Marangoni et al. / Tetrahedron Letters 59 (2018) 121–124
123
Table 3
Table 4
Optimization of the reaction conditions for obtaining the product 6b.
Optimized reaction conditions and yields for the synthesis of products 6a–j.
CO2Et
O
OEt
NC
NC
EtO
OMe
R
OMe
H2O, HCl (1 equiv.)
reflux, 1.5 h.
EtO2C
O
O
R
O
O
O
Me
Me
(4a-j)
4b
(6a-j)
6b
Compd
R
Producta
Yield (%)b
Entry Time
(h)
Temp.
(°C)
HCl
(equiv.)
Catalyst Solvent Yield
(%)a
4a
4b
4c
4d
4e
4f
C6H5
4-Me-C4H4
4-F-C4H4
4-Br-C4H4
4-MeO-C4H4
4-NO2-C4H4
Fur-2-il
6a
64
57
55
66
51
15
43
53
b
6b
6c
6d
6e
6f
1
2
3
1.5
1.5
1
30
80
1
1
1
1
1
1
3
6
–
1
1
1
–
6
–
–
–
–
–
–
–
–
–
–
–
–
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
EtOH
EtOH
–
c
d
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
25
4
5
1.5
2
58
57
55
56
4g
4h
6g
6j
6
3
4-Cl-C4H4
7
2
8
2
56
a
Reaction conditions: H2O, HCl (1.0 equiv.), reflux, 1.5 h.
Yield of the isolated products.
d
9
2
b
10
11
12
13
14
20
1.5
6
2
2
20
–
60
e
ZnBr2
ZnBr2
121.5
95.7
25
–
56
163.1
CF3
98.6
a
b
c
(6H.70)
H
CO2Et
Yield of isolated compounds.
Starting material was recovered.
Starting material was observed in the 1H NMR spectrum together with other
(7H.13)
144.7 H(6.71)
145.3
(6.52)
4
110.9
H
5
6
114.3
4
3
2
H
5
6
3
2
160.6
163.3
1
160.8
non-identified signals.
160.5
H
1
H
The 1H NMR spectrum showed signals of the starting material and signals of the
d
9
O
10
11
127.8 O
8
11
12
13
O
O
127.9
10
142.8
intermediate acid.
141,4
The 1H NMR spectrum showed no signs of the starting material nor the
e
(7.75) 126.2
Me
H
(7.79) 125.4
Me
H
expected product.
(2.42)
21.7
(7.29) 130.0
(2.3)
20.9
H
H(7.34) 129.7
5b
6b
at the d-carbon (6-endo-trig),31 thereby closing a dihydropyran ring
(Structure II, Scheme 2), which, after elimination of a methanol
molecule, furnishes the expected products 5 and 6 (Scheme 2).
These optimized reaction conditions were applied to the syn-
thesis of all the other products of this series—see Table 4.30
The structure of the 2-pyranones 5 and 6 was unambiguously
elucidated by GC–MS and 1H and 13C NMR spectroscopy, as well
as by two-dimensional NMR experiments such as HSQC and HMBC
for representative compounds. The purity of the products was con-
firmed by CHN elemental analyses or by high-resolution mass
spectrometry. Fig. 2 shows the 1H and 13C NMR chemical shifts
for the model compounds 5b and 6b, in which NMR data can be
used to characterize all compounds of these two series. The correct
Fig. 2. Atom numbering, 1H (in blue in parentheses) and 13C (in red) NMR chemical
shifts for compound 5b and 6b.
chemical shifts and structure were assigned via the two-dimen-
sional NMR HMBC experiment.
The H3 and H5 are difficult to assign because their signals are
close in chemical shifts and both are doublets with a coupling con-
stant approx. 1 Hz; however, in the HMBC experiment they have
distinct cross-peaks.
The H3 of compound 5b has cross-peaks with C2 and C5;
whereas H5 has cross-peaks with C3, C6, and C8. The H3 of com-
pound 6b has cross-peaks with C2, C4, C5, and C7 (carbonyl of
the ester group); whereas H5 has cross-peaks with C3, C4, C6,
C7, and C10.
In conclusion, this study showed an efficient synthesis of two
new series of 2-pyranones—the 6-aryl-4-trifluoromethyl-2H-
pyran-2-ones 5 and 6-aryl-4-carboxyethyl-2H-pyran-2-ones 6—
that were obtained through the self-condensation reaction of 5-
methoxy-5-aryl-3-(trifluoromethyl)penta-2,4-dienenitriles 3 and
OH
NC
OMe
O
OMe
H3O+/ZnBr2
Y
Y
R
3, 4
R
I
ethyl 2-(cyanomethylene)-4-methoxy-4-arylbut-3-enoates
4,
Y
Y
respectively. It was observed that the self-condensation reaction
of the ethyl 2-(cyanomethylene)-4-methoxy-4-arylbut-3-enoates
4 was performed in water and in the presence of hydrochloric acid
in order to give the respective 6-aryl-4-carboxyethyl-2H-
pyran-2-ones 6; whereas the self-condensation reaction of the
(trifluoromethyl)penta-2,4-dienenitriles 3 required the use of zinc
bromide and the presence of HCl in order to give the 6-aryl-4-tri-
fluoromethyl-2H-pyran-2-ones 5. However, the yield of the
products 6 was much lower than that obtained for the compounds
MeO
H
-MeOH
O
O
O
O
R
5, 6
II
R
Y: 5 = CF3; 6 = CO2Et
Scheme 2.

124
M.A. Marangoni et al. / Tetrahedron Letters 59 (2018) 121–124
24. Usachev BI, Obydennov DL, Röschenthaler G-V, Sosnovskikh VY. Org Lett.
2008;10:2857–2859.
25. Bencke CE, Marangoni MA, Camargo AF, et al. Synthesis. 2017;49:5131–5142.
26. (a) Colla A, Martins MAP, Clar G, Krimmer S, Fischer P. Synthesis.
1991;1991:483–486;
5, probably due to the acid hydrolysis and/or decarboxylation of
the carboxyethyl group.
Acknowledgments
(b) Martins MAP, Bastos GP, Bonacorso HG, Zanatta N, Flores AFC, Siqueira GM.
Tetrahedron Lett. 1999;40:4309–4312.
27. Katritzky AR, Rees CW. Comprehensive Heterocyclic Chemistry, vol. 3. New
York: Pergamon Press; 1984.
28. Carey FA. Química Orgânica. 7ª ed, vol. 2. AMGH Editora Ltda.; 2011.
29. General procedure for synthesis of 6-aryl-4-trifluoromethyl-2H-pyran-2-
The authors are grateful for financial support from the Fun-
dação de Amparo a Pesquisa do Estado do Rio Grande do Sul
(FAPERGS/CNPq – PRONEX – Grant No. 16/2551-0000477-3) and
fellowships from CNPq (C.E.B.) and CAPES (M.A.M.).
ones 5a–e: In
a round bottom flask was added the 3-trifluoromethyl-5-
methoxypenta-2,4-dienonitriles 3a–e (0.5 mmol), water (2.5 mL), ZnBr2 (0.135
g, 0.5 mmol) and concentrated hydrochloric acid (0.3 mL). Then, the reaction
mixture was heated at reflux for 2 hours. The reaction mixture was cooled,
ethyl acetate (25 mL) was added and extracted with water (3 Â 25 mL). The
organic layer was dried under anhydrous sodium sulfate and the solvent was
removed under reduced pressure. The solids obtained were dissolved in hot
hexane and the impurities were filtered off. The solvent was removed under
reduced pressure to give the respective 6-subtituted 4-trifluoromethyl-2H-
pyran-2-one 5a–e.4-Trifluoromethyl-6-(p-methylphenyl)-2H-pyran-2-one
(5b): Yellow solid. Yield: 95%. Melting point: 104–106 C. 1H NMR 400 MHz
(CDCl3): d 7.75 (d, 2H, J = 8.4, AR), 7.29 (d, 2H, J = 8.0, AR), 6.70 (d, 1H, J = 1.4,
H5), 6.52 (d, 1H, J = 1.4, H3), 2.42 (s, 3H, Me). 13C NMR 100 MHz (CDCl3): d
163.3 (C6), 160.6 (C2), 145.3 (qua, 2JC-F = 35.0, C4), 142.8 (AR), 130.0 (AR), 127.7
(AR), 126.0 (AR), 121.5 (qua, 1JC-F = 274.0, CF3), 110.9 (qua, 3JC-F = 5.0, C3), 95.7
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2017.12.003.
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