Direct synthesis of γ-pyrones by electrophilic condensation of β-ketoesters

Article abstract of DOI:10.1039/c6ob01884j

Triflic anhydride is a versatile electrophile that is able to activate poor nucleophiles. Herein, we show that readily available β-keto esters are activated by Tf₂O furnishing γ-pyrones. Mechanistic studies suggest that this transformation proceeds via a double triflation, formation of an oxocarbenium intermediate and dealkylation promoted by a crucial nitrile additive.

Full text of DOI:10.1039/c6ob01884j

Organic &
Biomolecular Chemistry
View Article Online
View Journal
PAPER
Direct synthesis of γ-pyrones by electrophilic
condensation of β-ketoesters†
Catarina A. B. Rodrigues,a,b Antonio Misale,a Florian Schiela and Nuno Maulide*a
Cite this: DOI: 10.1039/c6ob01884j
Received 26th August 2016,
Accepted 2nd December 2016
Triflic anhydride is a versatile electrophile that is able to activate poor nucleophiles. Herein, we show that
readily available β-keto esters are activated by Tf2O furnishing γ-pyrones. Mechanistic studies suggest that
this transformation proceeds via a double triflation, formation of an oxocarbenium intermediate and deal-
kylation promoted by a crucial nitrile additive.
DOI: 10.1039/c6ob01884j
www.rsc.org/obc
Introduction
Triflic anhydride (Tf2O) is
a versatile electrophile in
organic chemistry, commonly used to generate triflate
moieties with exceptional leaving group ability.1 Its electron-poor
character makes it prone to react with relatively weak nucleo-
philes such as carbonyl groups, non-activated arenes and
unsaturated compounds, ethers or nitriles, and thus initiate a
series of interesting transformations.1 Our group and
others are well aware of the peculiar reactivity of Tf2O
and reported several examples of Tf2O-mediated domino
electrophilic rearrangements for the construction of diverse
scaffolds.2–14
Fig. 1 (a) General structure of γ-pyrones, (b) natural products with a
γ-pyrone scafold and application, (c) synthetic methods to access γ-pyrones.
γ-Pyrones have the general structure depicted in Fig. 1(a)
and form the basic skeleton of various biologically relevant
substances.15 These compounds are also key intermediates in
the synthesis of pyridinone derivatives (Fig. 1(b)) that present
relevant pharmaceutical activity16 and are used as fluorescent
probes.17,18 These scaffolds are usually synthesized by three
general pathways (Fig. 1(c)): cyclocondensation of 1,3,5-tri-
carbonyl compounds under acidic conditions,19,20 hetero
Diels–Alder reaction between a ketoketene and an alkyne21 or
recyclisation of α-pyrones.22 All these strategies imply some
synthetic effort for the synthesis of the non-commercially avail-
able starting materials.
Results and discussion
During our studies on the chemistry of sulfur ylides,23 we
required access to an ylide (3) containing a specific substi-
tution pattern on sulfur (Scheme 1(a)). An attempt to syn-
thesize this ylide by combination of the corresponding
β-ketoester (1a) and the sulfoxide (2) unexpectedly afforded a
new product that was identified as γ-pyrone (4a). Spectroscopic
features include a well-defined singlet peak in 1H NMR spectra
at 6–7 ppm, but ultimately an unambiguous structural assign-
ment was made possible by single crystal X-ray analysis
(Scheme 1(b)).
Herein we report a triflic anhydride-mediated condensation
of β-ketoesters resulting in the direct synthesis of γ-pyrones.
aUniversity of Vienna, Institute of Organic Chemistry, Währinger Strasse 38,
1090 Vienna, Austria. E-mail: nuno.maulide@univie.ac.at
bInstituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia,
Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c6ob01884j
Scheme 1 (a) Original observation on the Tf2O-mediated condensation
of β-ketoesters. (b) X-ray analysis of the side product γ-pyrone (4a).
This journal is © The Royal Society of Chemistry 2016
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 1 Optimization of the reaction conditions
Tf2O Temp. Conc.
Time
(h)
Entry (eq.) (°C)
(M)
Additive (eq.)
NMR yield
1
2
3
4
1
1
1
1
23
40
40
40
0.22
0.22
0.22
0.22
None
None
48
48
48
48
No product
37%
59%
CH3CN (2.2)
CH3CN (2.2)
TfOH (0.2)
TfOH (0.2).
CH3CN (2.2)
CH3CN (2.2)
49%
5
6
7
8
1
1
1
1
1
1
1
2
2
40
40
40
40
40
40
40
40
40
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
48
18
23%
42%
7 days 59%
CH3CN (2.2) (air) 48
58%
53%
55%
25%
47%
37%
9
EtCN (2.2)
t-BuCN (2.2)
CCl3CN (2.2)
CH3CN (3)
CH3CN (4)
48
48
48
48
48
10
11
12
13
Scheme 2 Substrate scope of the Tf2O-mediated condensation of
β-ketoesters (in brackets are the yields determined by NMR).
This unanticipated result compelled us to explore and opti-
mize the conditions for the synthesis of γ-pyrones from
β-ketoesters.
Early control experiments (not depicted) revealed that the
sulfoxide component is not needed for the successful reaction
The γ-pyrone products were obtained in yields up to 100%
described above. As depicted in Table 1, we set to investigate using different substrates. Alkyl β-ketoesters appear to be more
the condensation of model β-ketoester (1b) in the presence of reactive under these conditions (up to 68% yield) than the
triflic anhydride, and first studied the influence of tempera- corresponding aryl derivatives (up to 28% yield). Substrates
ture. At 23 °C no product was observed after 48 hours (Table 1, carrying electron-withdrawing groups are not reactive under
entry 1). However, increasing the temperature to 40 °C resulted this protocol resulting in the recovery of the starting material
in a 37% yield (NMR analysis) of γ-pyrone (Table 1, entry 2).
(Scheme 2, 4m and 4n). An interesting result was obtained
Subsequently, the influence of additives was screened. when a β-ketoacid (benzoylacetoacetic acid) was used instead
While with DMSO no product was observed (see ESI†), 59% of the ester, affording the disubstituted γ-pyrone in quanti-
yield was obtained by adding 2.2 eq. of MeCN (Table 1, entry tative yield (Scheme 2, 4l).
3). This observation is in accordance with what was previously
At this juncture, some preliminary mechanistic studies
were carried out and the results thereof are compiled in
observed by Martinez et al.24
The impact of triflic acid was also studied. The yield Table 2. We initially hypothesized that this transformation
decreased when only 0.2 eq. of this reagent was added, both in might proceed via the intermediacy of an enol triflate (5)
the presence and absence of MeCN (Table 1, entries 4 and 5). derivative. Such an enol triflate could be prepared indepen-
When the reaction was quenched after 18 hours only 42% dently.25 When this substrate was subjected to the reaction
yield was observed, but on extending the reaction time up to 7 conditions without Tf2O, in both the presence and absence of
days no improvement was observed (59%) (Table 1, entries 6 MeCN, no product was observed (Table 2, entries 2–4).
and 7). This reaction could also be run in an open vessel with Hypothesizing an equilibrium scenario, we employed
a
virtually no change in yield (Table 1, entry 8). 1 : 1 mixture of enol triflate and β-ketoester, but even in the
The influence of the nitrile was also studied and it became presence of 1 eq. of Tf2O this resulted in only 5% of γ-pyrone
clear that electron-poor nitriles are less reactive than electron- (4b) (Table 2, entry 5). When the same substrate mixture was
rich ones, suggesting a possible nucleophilic role in the mech- treated under the optimized conditions (with MeCN) the
anism (Table 1, entries 9–11).
γ-pyrone (4b) was obtained in 21% yield (Table 2, entry 6).
An extensive screening of the Tf2O : MeCN ratio was finally Albeit a positive outcome, this is a rather low yield compared
carried out (summarised in Table 1, entries 12 and 13), and to the standard reaction (vide supra). To clarify this strange
the best overall conditions for this transformation comprise result, the same experiment was repeated but using a different
the use of 1 eq. of Tf2O and 2.2 eq. of MeCN at 40 °C over β-ketoester (ethyl benzoylacetate (1a)) with the same enol tri-
48 hours.
flate (5) previously employed. In fact this experiment resulted
With improved conditions in hand, we examined the sub- in 20% yield of 4a, showing that the enol triflate is not the
strate scope of this transformation (Scheme 2).
active intermediate in this transformation.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2016

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 2 Mechanistic studies with enol triflate
Scheme 3 Tf2O-mediated condensation of β-ketoester (1a) using
2-phenylpropanenitrile (7).
Entry
(5)
(1)
MeCN
Tf2O
NMR yield
1
2
3
4
5
6
7
None
1 eq.
1 eq.
0.5 eq.
0.5 eq.
0.5 eq.
0.5 eq.
(1b)
—
—
(1b) 0.5 eq.
(1b) 0.5 eq.
(1b) 0.5 eq.
(1a) 0.5 eq.
2.2 eq.
—
2.2 eq.
—
—
2.2 eq.
2.2 eq.
1 eq.
—
—
59%
No product
No product
No product
(4b) 5%
(4b) 21%
(4a) 20%
—
the same γ-pyrone (4a) is obtained if a mixture of (6a) and (1a)
is used (Table 2, entry 3). This last experiment provides a
higher yield of 4a than that using only the corresponding
β-ketoester (1a) (Scheme 2, 4a), indicating that a second tri-
flation must be present in the mechanism which is faster for
the carboxylic acid substrate. This conclusion is also supported
by another experiment when 6a was subjected to the optimized
conditions but without MeCN resulting in a quantitative yield
of the corresponding 2,6-diphenyl-4H-pyran-4-one 4l, which
also supports the hypothesis of the nucleophilic role of MeCN
in this transformation, mentioned above.
To verify the role of the nitrile in the reaction under study,
we performed an experiment using the optimized conditions
and the model β-ketoester (1b) but replacing acetonitrile by
2-phenylpropanenitrile (7) (Scheme 3). In fact, after work-up
we were able to identify amide (8) in the crude by high resolu-
tion mass spectrometry. This confirms the nucleophilic role of
the nitrile as the ultimate destiny of the ethyl group from the
β-ketoester.
1 eq.
1 eq.
1 eq.
Table 3 Mechanistic studies using β-ketoacids
Entry
β-Ketoacid
β-Ketoester
Product
NMR yield
44%
1
2
3
4
(6b) 0.5 eq.
(6b) 0.5 eq.
(6a) 0.5 eq.
(6a) 1 eq.
(1b) 0.5 eq.
(1a) 0.5 eq.
(1a) 0.5 eq.
—
(4b)
(4a)
(4a)
(4l)
16%
50% (49%)a
No MeCN, 100%
a Isolated yield.
Along with the surprising result previously obtained with a
β-ketoacid substrate (Scheme 2, 4l), additional experiments
were triggered by these observations. When a mixture of aceto-
acetic acid (6b) and the corresponding ethyl ester (1b) is sub-
jected to the optimized conditions, a 44% yield of γ-pyrone
(4b) (Table 3, entry 1) ensues. Conversely, a mixture of (6b) and
(1a) gave 16% of (4a) (Table 2, entry 2) whilst a 50% yield of
Taking into account the results described above, we can
postulate the mechanism depicted in Scheme 4.
In solution, the β-ketoester A is in equilibrium with the
corresponding enol B which can afford the enol triflate C in
the presence of Tf2O. At high temperature, this species can
undergo a second triflation resulting in oxocarbenium D
Scheme 4 Proposed mechanism for the synthesis of γ-pyrones by electrophilic condensation of β-ketoesters.
This journal is © The Royal Society of Chemistry 2016
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
which is prone to nucleophilic dealkylation (promoted by
MeCN). This step gives the nitrilium ion F – which following
aqueous work up leads to the corresponding amide H – and
intermediate E, which is now a strong acylating agent.
Acylation of another molecule of enol B with E generates
species G, primed for intermolecular cyclization (Michael
addition/elimination) finally affording the γ-pyrone.
7 B. Peng, D. Geerdink, C. Farès and N. Maulide, Angew.
Chem., Int. Ed., 2014, 53, 5462–5466.
8 D. Kaiser and N. Maulide, J. Org. Chem., 2016, 81, 4421–
4428.
9 O. K. Ahmad, J. W. Medley, A. Coste and M. Movassaghi,
Org. Synth., 2012, 89, 549–561.
10 G. Pelletier, W. S. Bechara and A. B. Charette, J. Am. Chem.
Soc., 2010, 132, 12817–12819.
11 K.-J. Xiao, J.-M. Luo, K.-Y. Ye, Y. Wang and P.-Q. Huang,
Angew. Chem., Int. Ed., 2010, 49, 3037–3040.
12 K.-J. Xiao, Y. Wang, K.-Y. Ye and P.-Q. Huang, Chem. – Eur.
J., 2010, 16, 12792–12796.
13 W. S. Bechara, G. Pelletier and A. B. Charette, Nat. Chem.,
2012, 4, 228–234.
14 P.-Q. Huang, Y.-H. Huang, K.-J. Xiao, Y. Wang and X.-E. Xia,
J. Org. Chem., 2015, 80, 2861–2868.
15 Y.-L. Yan and S. M. Cohen, Org. Lett., 2007, 9, 2517–
2520.
Conclusions
In summary, we have reported a triflic-anhydride-mediated
direct condensation of β-ketoesters to afford γ-pyrones. This
transformation allows expedient and simple access to the
γ-pyrone framework, delivering the products in moderate
yields. Mechanistic experiments suggest the formation of a
bis-electrophilic species.
16 C. V. Credille, Y. Chen and S. M. Cohen, J. Med. Chem.,
2016, 59, 6444–6454.
Acknowledgements
17 Y. Lei, D. Yang, H. Hua, C. Dai, L. Wang, M. Liu, X. Huang,
Y. Guo, Y. Cheng and H. Wu, Dyes Pigm., 2016, 133, 261–
272.
18 Y. Ma, W. Luo, P. J. Quinn, Z. Liu and R. C. Hider, J. Med.
Chem., 2004, 47, 6349–6362.
We are grateful to the University of Vienna for continued
support of our research. C. A. B. R. was supported by the
Fundação para a Ciência e Tecnologia (SFRH/BPD/100677/
2014).
19 R. J. Light and C. R. Hauser, J. Org. Chem., 1960, 25, 538–
546.
20 D. Hobuß, S. Laschat and A. Baro, Synlett, 2005, 123–124.
Notes and references
1 I. L. Baraznenok, V. G. Nenajdenko and E. S. Balenkova, 21 A. Stadler, K. Zangger, F. Belaj and G. Kollenz, Tetrahedron,
Tetrahedron, 2000, 56, 3077–3119. 2001, 57, 6757–6763.
2 V. Tona, A. de la Torre, M. Padmanaban, S. Ruider, 22 M. Sato, T. Oda, K.-I. Iwamoto and E. Murakami,
L. González and N. Maulide, J. Am. Chem. Soc., 2016, 138,
8348–8351.
3 C. Madelaine, V. Valerio and N. Maulide, Angew. Chem., Int.
Ed., 2010, 49, 1583–1586.
4 V. Valerio, C. Madelaine and N. Maulide, Chem. – Eur. J.,
2011, 17, 4742–4745.
5 X. Huang, M. Patil, C. Farès, W. Thiel and N. Maulide,
J. Am. Chem. Soc., 2013, 135, 7312–7323.
Tetrahedron, 2003, 59, 2651–2655.
23 I. Klose, A. Misale and N. Maulide, J. Org. Chem., 2016, 81,
7201–7210.
24 A. G. Martinez, A. H. Fernandez, D. M. Vilchez,
A. H. Ubeda, M. Hanack and L. R. Subramanian, An. Quim.,
1995, 91, 121–123. For a recent related report, see: S. Dong,
C. Fang, W. Tang, T. Lu and D. Du, Org. Lett., 2016, 18,
3882–3885.
6 V. Valerio, D. Petkova, C. Madelaine and N. Maulide, Chem. 25 D. Babinski, O. Soltani and D. E. Frantz, Org. Lett., 2008,
– Eur. J., 2013, 19, 2606–2610.
10, 2901–2904.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2016