Unexpected formation of diethyl 2-ethoxy-6-CF3-2H-pyran-3,5-dicarboxylate from the condensation of ethyl 4,4,4-trifluoroacetoacetate with CH(OEt)3

Article abstract of DOI:10.1016/j.tetlet.2017.01.026

The one-step preparation of diethyl 2-ethoxy-6-CF₃-2H-pyran-3,5-dicarboxylate via the condensation of ethyl 4,4,4-trifluoroacetoacetate with CH(OEt)₃ has been reported and a plausible mechanism for this transformation is discussed. T

Full text of DOI:10.1016/j.tetlet.2017.01.026

Accepted Manuscript
Unexpected formation of diethyl 2-ethoxy-6-CF -2H-pyran-3,5-dicarboxylate
3
from the condensation of ethyl 4,4,4-trifluoroacetoacetate with CH(OEt)3
Yulia S. Kudyakova, Denis N. Bazhin, Pavel A. Slepukhin, Yanina V. Burgart,
Victor I. Saloutin, Valery N. Charushin
PII:
S0040-4039(17)30048-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.026
TETL 48529
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
7 November 2016
26 December 2016
10 January 2017
Please cite this article as: Kudyakova, Y.S., Bazhin, D.N., Slepukhin, P.A., Burgart, Y.V., Saloutin, V.I., Charushin,
V.N., Unexpected formation of diethyl 2-ethoxy-6-CF -2H-pyran-3,5-dicarboxylate from the condensation of ethyl
3
4,4,4-trifluoroacetoacetate with CH(OEt) , Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
3
2
017.01.026
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Unexpected formation of diethyl 2-ethoxy-6-CF -2H-pyran-3,5-dicarboxylate from the
3
condensation of ethyl 4,4,4-trifluoroacetoacetate with CH(OEt)3
a
a,
a,b
a
Yulia S. Kudyakova, Denis N. Bazhin, Pavel A. Slepukhin, Yanina V. Burgart, Victor I.
a
a,b
Saloutin, Valery N. Charushin
a
Postovsky Institute of Organic Synthesis, the Ural Branch of the Russian Academy of Sciences,
2 S. Kovalevskoy str., 620990, Ekaterinburg, Russian Federation
2
b
Ural Federal University, Ekaterinburg, Russian Federation
Abstract
The one-step preparation of diethyl 2-ethoxy-6-CF -2H-pyran-3,5-dicarboxylate via the
3
condensation of ethyl 4,4,4-trifluoroacetoacetate with CH(OEt) has been reported and a
3
plausible mechanism for this transformation is discussed. To demonstrate the synthetic potential
of the obtained pyran, the reactions with ammonia and aromatic amines to give
trifluoromethylated pyridine derivatives are presented.
Keywords: Pyran, Detrifluoroacetylation, Ethyl trifluoroacetoacetate, Condensation, Pyridines
Introduction
Ethyl 4,4,4-trifluoroacetoacetate (β-keto ester 1) is an attractive building block in organic
synthesis due to its readily availability and ease of handling in various condensation reactions to
1
,2
produce compounds of biological interest. Three non-equivalent carbon centers in the structure
of β-keto ester 1 open the possibility for highly chemo- and regioselective modification, thereby
2
providing numerous heterocyclic, aromatic and multi-functional frameworks. This diversity can
be achieved by varying the reagents in two- or three-component condensations with β-keto ester
1
, for example, a number of trifluoromethylated pyrazoles and pyrimidines have been obtained
(Fig. 1). In most cases the target product skeleton is based on the β-dicarbonyl fragment of β-
keto ester 1 and only a few reports describe C-C bond cleavage resulting in trifluoroacetyl group
3
elimination.

Corresponding author. Tel.: +7-343-362-3425; fax: +7-343-374-5954; e-mail: dnbazhin@gmail.com

Figure 1. Representative examples of the applications of β-keto ester 1
The reaction between β-keto ester 1 and CH(OEt) was described more than 60 years ago
3
2
b
and nowadays the condensation product (2) is commercially available (Scheme 1). In the initial
report, Jones and co-workers obtained ethyl 2-ethoxymethylene trifluoroacetoacetate 2 in 67-
4
a
7
0% isolated yield after distillation, with recovery of the starting reagents. Later, it was shown
4
b-e
that minor changes in the reagent ratio resulted in increased yields of the target compound 2
(Table 1). Previously, our research group described a more economical method for this
4
f
condensation without the use of toxic Ac O. The proposed two-component synthesis from β-
2
keto ester 1 and CH(OEt) seemed reasonable due to the high α-CH-activity of fluorinated β-
3
ketoesters, however, the drawback was a lower yield of compound 2 compared to Ac O-based
2
5
procedures. In general, the α-functionalization of trifluorinated 1,3-dicarbonyl derivatives leads
to enhanced reactivity of the trifluoroacetyl moiety which can be a reason for unpredictable
6
reaction routes. Taking this into account, we focused on investigating the reaction between β-
keto ester 1 and CH(OEt) in detail.
3
Herein, we report a novel method for the construction of a trifluoromethylated pyran
derivative from the condensation of β-keto ester 1 with CH(OEt)3.

Scheme 1. Two possible pathways for the reaction of β-keto ester 1 with CH(OEt)3
Table 1. Reaction of β-keto ester 1 with CH(OEt) under different conditions
3
Entry
Reactant ratio
Reaction
conditions
120-140 °C
Yield, Yield,
(%) 3 (%)
2
Ref
4a
4b
4c
4d
4e
4f
1
: CH(OEt) : Ac O, (mol)
3
2
1
2
3
4
5
6
7
8
9
0.5 : 0.75 : 1.5
0.25 : 0.5 : 0.75
0.54 : 0.81 : 1.62
0.548 : 1.106 : 1.118
0.54 : 0.81 : 1.62
0.1 : 0.4 : 0
67-70
98
-
-
120-140 °C, 7 h, N2
reflux, 5 h
79
-
120-140 °C, 1.5 h
120-140 °C, 7 h
reflux, 1 h
75
-
63
-
59
-
0.1 : 0.4 : 0
reflux, 24 h
56
30
21
-
0.1 : 0.4 : 0.1
reflux, 24 h
65
0.1 : 0.4 : 0.4
reflux, 10 h
84
To begin, the condensation reaction between β-keto ester 1 and CH(OEt) without Ac O
3
2
was studied. In contrast to the previous report, the reaction time was increased from 1 to 24
hours to increase the conversion of β-keto ester 1 (Table 1, entry 7). Distillation of the reaction
mixture gave two main fractions. The first fraction (colorless liquid) was collected under reduced
pressure (10 Torr) at 130-132 °C and contained compound 2 while the second fraction (yellow-
colored liquid) was collected at 157-159 °C/10 Torr. To our surprise, the second distillation
fraction contained diethyl 2-ethoxy-6-CF -2H-pyran-3,5-dicarboxylate (3). The structure of
3
1
compound 3 was confirmed by NMR, GS-MS and HRMS. In the H NMR spectrum, besides the

signals for ethyl groups, singlets for the 2H- and 4H-pyran protons at δ = 6.17 and 7.61 ppm,
H
1
9
respectively, were observed. The F NMR spectrum also contained a characteristic singlet for
the CF group at δ = 95.17 ppm (C F as an internal standard).
3
F
6 6
1
9
19
The reaction process could easily be monitored by F NMR. According to the F NMR
in CDCl , there are two main peaks (δ 87.12 and 83.54 ppm) in β-keto ester 1 attributed to the
3
F
enol and keto forms, respectively. As 2-ethoxymethylene 2 started to form in the reaction
mixture, two signals corresponding to the geometric isomers of 2 appeared at δ = 89.22 and
F
8
6.17 ppm. Additional signals at δ = 79.65, 86.54 and 95.17 ppm were also observed, indicating
F
7
the formation of a new species. According to literature data, the signal at δ = 79 ppm
F
corresponded to hemiketal formation as a result of the reaction of β-keto ester 1 with ethanol
generated in situ from CH(OEt) . Also the signal at δ = 86.54 ppm could be attributed to the
3
F
appearance of ethyl trifluoroacetate during the condensation reaction.
To understand this process, an extensive screening of reaction parameters was carried
out. Acidic and basic agents (H SO , PTSA, DBU), and the Lewis acid BF •Et O were
2
4
3
2
investigated in the reaction between β-keto ester 1 and CH(OEt) . In most cases low conversion
3
along with the formation of a mixture of by-products was observed. We also verified the effect
of Ac O on the outcome of the condensation reaction. The use of equal equivalents of β-keto
2
ester 1 and Ac O along with an excess of CH(OEt) resulted in the high conversion of 3-oxo
2
3
ester 1 to give compounds 2 and 3 in 65% and 21% yield, respectively (Table 1, entry 8).
From these experiments, a plausible mechanism for product 3 formation from β-keto
ester 1 and CH(OEt) was proposed (Scheme 2). It is well known that CH(OEt) generates both
3
3
+
-
(
EtO) CH and EtO , which in the reaction with β-keto ester 1 can initiate two possible pathways
2
(
A and B). Discussing pathway A, the crucial role of Ac O can be explained as a scavenger of
2
-
EtO and EtOH, thereby preventing by-product formation. To provide an irreversible reaction
between 1 and CH(OEt) , a major factor is either the removal of EtOH from the reaction media
3
by distillation or its acylation by Ac O. In accordance with pathway B, the electron-withdrawing
2
properties of the CF group accelerate the nucleophilic addition of ethanol to the trifluoroacetyl
3
moiety of β-keto ester 1, producing intermediate hemiketal B. This suggestion is reasonable in
19
view of the F NMR data described above. After the detrifluoroacetylation of B, the highly
reactive intermediate formed then interacts with excess CH(OEt) to give C. Intermediate C acts
3
as a C-nucleophile in the Michael addition on the activated C=C bond of 2, with subsequent
intermolecular cyclization resulting in pyran 3 formation.

Scheme 2. Plausible mechanism for 6-(trifluoromethyl)-2H-pyran (3) formation
CF -containing pyrans are well known scaffolds for the construction of different
3
8
heterocyclic compounds. To demonstrate the synthetic potential of novel pyran 3, the reactions
with ammonia, aniline and o-aminophenol were performed. The reaction of 3 with ammonia in
ethanol under ambient conditions afforded diethyl 2-(trifluoromethyl)pyridine-3,5-dicarboxylate
(4) in 83% yield (Scheme 3). Initially, the reaction of 3 with aromatic amines was carried out at
reflux, resulting in the formation of 2-hydroxy-1,2-dihydropyridine (5) and benzopyrido-1,3-
oxazole (7). To the best of our knowledge, compounds similar to 5 and 7 were recently
synthesized from the three-component reaction of β-keto ester 1 with 3-formylchromones and
9
aromatic amines. In contrast, we found that the formation of benzopyrido-1,3-oxazole derivative
7
proceeds via formation of the corresponding 2-hydroxy-1,2-dihydropyridine 6 at room
temperature. The structures of compounds 4-7 were confirmed by NMR, LCMS analysis and
1
0
19
single crystal X-ray diffraction (Fig. 2, 3). In the F NMR spectra of 2-CF -2-hydroxy-1,2-
3
dihydropyridines 5, 6 and benzopyrido-1,3-oxazole 7, characteristic signals of the CF -group
3
appeared in the range of 75-78 ppm.

Scheme 3. Reagents and conditions: (i) 3 (3 mmol), NH (gas, excess), EtOH, rt, 1 h, 83%; (ii) 3 (30
3
mmol), aniline (3 mmol), EtOH, reflux, 2 h, 72%; (iii) 3 (3 mmol), o-aminophenol (30 mmol), EtOH, rt, 4
h, 75%; (iv) 3 (3 mmol), o-aminophenol (3 mmol), EtOH, reflux, 4 h, 82%; (v) EtOH, reflux, 2 h, 95%.
Figure 2. ORTEP view of molecule 6 (thermal ellipsoids at the 50% probability at 150K)

Figure 3. ORTEP view of molecule 7 (thermal ellipsoids at the 50% probability at 150K)
Notably, in contrast to compounds 4-6, heterocycle 7 gave bright-yellow crystals that
were luminescent under visible light (see ESI).
In summary, we describe the unexpected synthesis of a novel (trifluoromethyl)pyran from
ethyl trifluoroacetoacetate and CH(OEt) . The remarkable feature of this condensation is the
3
construction of a pyran core from two molecules of both starting reactants in a one-step reaction.
The obtained CF -pyran is of interest as a precursor for the synthesis of heterocyclic compounds.
3
Further studies on the improved preparation of fluorinated pyran derivatives and their reactivity
are in progress.
Acknowledgments
This work was financially supported by the Russian Foundation for Basic Research (grant no.
1
6-33-60048 mol_a_dk). BDN is thankful for scholarship of the President of the Russian
Federation (1895.2016.4).
Supplementary data
1
19
13
Supplementary data with experimental procedure, spectral data and copies of H, F, C spectra
associated with this article can be found, in the online version, at http://dx.doi.org/
References and notes
1
. (a) Schiffler, M.A.; Antonysamy, S.; Bhattachar, S.N.; Campanale, K.M.;
Chandrasekhar, S.; Condon, B.; Desai, P.V.; Fisher, M.J.; Groshong, C.; Harvey, A.;
Hickey, M.J.; Hughes, N.E.; Jones, S.A.; Kim, E.J.; Kuklish, S.L.; Luz, J.G.; Norman,

B.H.; Rathmell, R.E.; Rizzo, J.R.; Seng, T.W.; Thibodeaux, S.J.; Woods, T.A.; York,
J.S.; Yu, X.-P. J. Med. Chem. 2016, 59, 194; (b) Wityak, J.; McGee, K.F.; Conlon, M.P.;
Song, R.H.; Duffy, B.C.; Clayton, B.; Lynch, M.; Wang, G.; Freeman, E.; Haber, J.;
Kitchen, D.B.; Manning, D.D.; Ismail, J.; Khmelnitsky, Y.; Michels, P.; Webster, J.;
Irigoyen, M.; Luche, M.; Hultman, M.; Bai, M.; Kuok, I.D.; Newell, R.; Lamers, M.;
Leonard, P.; Yates, D.; Matthews, K.; Ongeri, L.; Clifton, S.; Mead, T.; Deupree, S.;
Wheelan, P.; Lyons, K.; Wilson, C.; Kiselyov, A.; Toledo-Sherman, L.; Beconi, M.;
Muñoz-Sanjuan, I.; Bard, J.; Dominguez, C. J. Med. Chem. 2015, 58, 2967; (c) Bach, P.;
Boström, J.; Brickmann, K.; Giezen, J.J.J.; Hovland, R.; Petersson, A.U.; Ray, A.;
Zetterberg, F. Bioorg. Med. Chem. Lett. 2011, 21, 2877; (d) Ladzik, S.; Lubbe, M.;
Kelzhanova, N.K.; Abilov, Z.A.; Feist, H.; Langer, P. J. Fluorine Chem. 2012, 136, 38.
. (a) Gerus, I.I.; Tolmachova, N.A.; Vdovenko, S.I.; Fröhlich, R.; Haufe, G. Synthesis
2
2
005, 1269; (b) Kudyakova, Yu.S.; Bazhin, D.N.; Goryaeva, M.V.; Burgart, Ya.V.;
Saloutin,V.I. Russ. Chem. Rev. 2014, 83, 120; (c) Liu, J.; Li, J.; Zhang, L.; Song, L.;
Zhang, M.; Cao, W.; Zhu, S.; Deng, H.; Shao, M. Tetrahedron Lett. 2012, 53, 2469; (d)
Rozin, Y.A.; Leban, J.; Dehaen, W.; Nenajdenko, V.G.; Muzalevskiy, V.M.; Eltsov,
O.S.; Bakulev, V.A. Tetrahedron 2012, 68, 614; (e) Volochnyuk, D.M.; Kostyuk, A.N.;
Sibgatulin, D.A.; Chernega, A.N.; Pinchuk, A.M.; Tolmachev, A.A. Tetrahedron 2004,
6
0, 2361; (f) Schmitt, E.; Rugeri, B.; Panossian, A.; Vors, J.-P.; Pazenok, S.; Leroux,
F.R. Org. Lett. 2015, 4510; (g) Goryaeva, M.V.; Burgart, Y.V.; Kudyakova, Y.S.;
Ezhikova, M.A.; Kodess, M.I.; Slepukhin, P.A.; Saloutin, V.I. Eur J. Org. Chem. 2015,
6
306; (h) Chizhov, D.L.; Sosnovskikh, V.Ya.; Pryadeina, M.V.; Burgart, Y.V.; Saloutin,
V.I.; Charushin, V.N. Synlett 2008, 281.
3
4
. (a) Bazhin, D.N.; Kudyakova, Y.S.; Nemytova, N.A.; Burgart, Y.V.; Saloutin, V.I. J.
Fluorine Chem. 2016, 186, 28; (b) Raju, B.C.; Suman, P. Chem. Eur. J. 2010, 16, 11840.
. (a) Jones, R.G. J. Am. Chem. Soc. 1951, 73, 3684; (b) Palanki, M.S.S.; Erdman, P.E.;
Gayo-Fung, L.M.; Shevlin, G.I.; Sullivan, R.W.; Suto, M.J.; Goldman, M.E.; Ransone,
L.J.; Bennet, B.L.; Manning, A.M.. J. Med. Chem. 2000, 43, 3995; (c) I.I. Gerus, R.X.
Mironetz, I.S. Kondratov, A.V. Bezdudny, Y.V. Dmytriv, O.V. Shishkin, V.S. Starova,
O.A. Zaporozhets, A.A. Tolmachev, P.K. Mykhailiuk. J. Org. Chem. 77, 47 (2012); d)
P.J. Sanfilippo, M.J. Urbanski, K.N. Beers, A. Eckardt, R. Falotico, M.H. Ginsberg, S.
Offord, J.B. Press, J. Tighe, K. Tomko, P. Andrade-Gordon. J. Med. Chem. 38, 34
(
2
1995); e) Kim, R.M.; Parmee, E.R.; Sinz, C.J.; Ziouzina, O.A. Patent US
010/0216764; f) M.V. Pryadeina, Ya.V. Burgart, V.I. Saloutin, P.A. Slepukhin, O.N.
Kazheva, G.V. Shilov, O.A. D’yachenko, O.N. Chupakhin. Russ. J. Org. Chem. 2007,
3, 945.
4
5
6
. Reactions of various (non)fluorinated 1,3-dicarbonyl compounds with CH(OEt)3
proceeds without by-product formation. See, for example: (a) Kudyakova, Yu.S.;
Bazhin, D.N.; Burgart, Ya.V.; Saloutin, V.I. Mendeleev Commun. 2016, 26, 54; (b)
Bazhin, D.N.; Kudyakova, Yu.S.; Gorbunova, T.I.; Kozhevnikova, N.S.; Suntsov,
A.Yu.; Burgart, Ya.V.; Rempel’, A.A.; Saloutin, V.I.; Chupakhin, O.N. Russ. J. Org.
Chem. 2013, 49, 315; (c) Bazhin, D.N.; Kudyakova, Yu.S.; Gorbunova, T.I.; Burgart,
Ya.V.; Zapevalov, A.Ya.; Saloutin, V.I. Russ. J. Gen. Chem. 2013, 87, 1330.
. (a) Mei, H.; Xie, C.; Aceña, J.L.; Soloshonok, V.A.; Röschenthaler, G.-V.; Han, J. Eur.
J. Org. Chem. 2015, 6401; (b) Barkov, A.Yu.; Korotaev, V.Yu.; Sosnovskikh, V.Ya.
Tetrahedron Lett. 2013, 54 6819; (c) Danheiser, R.L.; Miller, R.F.; Brisbois, R.G.; Park,
S.Z. J. Org. Chem. 1990, 55, 1959; (d) Fioravanti, S.; Pellacani, L.; Ramadori, F.;
Tardella, P.A. Tetrahedron Lett. 2007, 48, 7821; (e) Ruddraraju, K.V.; Parsons, Z.D.;
Llufrio, E.M.; Frost, N.L.; Gates, K.S. J. Org. Chem. 2015, 80, 12015; (f) Riofski, M.V.;
John, J.P.; Zheng, M.M.; Kirshner, J.; Colby, D.A. J. Org. Chem. 2011, 76 3676; (g)
Shchegolkov, E.V.; Khudina, O.G.; Burgart, Ya.V.; Saloutin, V.I.; Chupakhin, O.N.
Russ. J. Org. Chem. 2004, 40, 813.

7
8
. (a) Camps, F.; Coli, J.; Messenguer, A.; Roca, A. Tetrahedron, 1977, 33, 1637; (b)
Jagodzinska, M.; Huguenot, F.; Zanda, M. Tetrahedron 2007, 63, 2042; (c) Von Arx,
M.; Mallet, T.; Baiker, A. Angew. Chem. Int. Ed. 2001, 40, 2302.
. Usachev, B.I. J. Fluorine Chem. 2015, 175, 36; Usachev, B.I. J. Fluorine Chem. 2015,
1
72, 80.
9
1
. Rajkumar, K.; Suman, P.; Raju, B.C. RSC Adv. 2015, 5, 73850.
0. Crystallographic data (excluding structure factors) for the structures in this paper have
been deposited with the Cambridge Crystallographic Data Centre as supplementary
publication CCDC 1515308 (compound 6), 1515307 (compound 7). Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.Uk).

Graphical Abstract

Highlights



Novel route for the condensation of β-oxo ester with CH(OEt)3.
One-step formation of a novel CF -pyran was described.
3
Synthesis of CF -pyridine derivatives was elaborated.
3