Aza-Annulation of β-aminovinyl trifluoromethyl ketones with acryloyl chloride: An efficient synthesis of 5-(trifluoroacetyl)-3,4-dihydro-2(1H)- pyridinones

Article abstract of DOI:10.1016/j.tetlet.2013.05.108

The first example of aza-annulation of β-aminovinyl trifluoromethyl ketones with acryloyl chloride has been studied. 5-Trifluoroacetyl-containing 3,4-dihydro-2(1H)-pyridinones 3a-j were obtained from β-substituted enaminones 2a-j, whereas β-unsubstituted enaminone 4 gave a mixture of cyclic and acyclic products.

Full text of DOI:10.1016/j.tetlet.2013.05.108

Accepted Manuscript
Aza-annulation of β-aminovinyl trifluoromethyl ketones with acryloyl chloride:
an efficient synthesis of 5-(trifluoroacetyl)-3,4-dihydro-2(1H)-pyridinones
Nataliya V. Lyutenko, Igor I. Gerus
PII:
S0040-4039(13)00887-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.05.108
TETL 43008
Reference:
To appear in:
Tetrahedron Letters
Please cite this article as: Lyutenko, N.V., Gerus, I.I., Aza-annulation of β-aminovinyl trifluoromethyl ketones with
acryloyl chloride: an efficient synthesis of 5-(trifluoroacetyl)-3,4-dihydro-2(1H)-pyridinones, Tetrahedron Letters
(2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.05.108
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1
Tetrahedron Letters
journal homepage: www.elsevier.com
Aza-annulation of β-aminovinyl trifluoromethyl ketones with acryloyl chloride: an
efficient synthesis of 5-(trifluoroacetyl)-3,4-dihydro-2(1H)-pyridinones
Nataliya V. Lyutenko, Igor I. Gerus
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Murmanska 1, Kyiv-94, 02094, Ukraine
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The first example of aza-annulation of β-aminovinyl trifluoromethyl ketones with acryloyl
chloride has been studied. 5-Trifluoroacetyl-containing 3,4-dihydro-2(1H)-pyridinones 3a-j
were obtained from β-substituted enaminones 2a-j, whereas β-unsubstituted enaminone 4 gave a
mixture of cyclic and acyclic products.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Enaminones;
Aza-annulation;
Pyridinones;
Heterocycles;
Fluorinated building blocks.
Substituted six-membered lactams and their dihydro- and
tetrahydro- analogs have received significant attention from
synthetic organic chemists since they are found in numerous
naturally occurring alkaloids1 and other compounds with
synthons for various fluorinated heterocycles, and can be easily
synthesized via amination of readily accessible β-alkoxyvinyl
trifluoromethyl ketones 1 (Scheme 1).9 In continuation of our
research on electrophilic reactions of β-aminovinyl
polyfluoroalkyl ketones 2,10 we describe herein the synthesis of
new 3,4-dihydro-5-trifluoroacetyl-2(1H)-pyridinones via aza-
annulation of β-aminovinyl trifluoromethyl ketones 2 with
acryloyl chloride.
interesting
biological
activity.2
They
also
exhibit
antihypertensive, cardiac stimulating and antiviral activity,3 and
some can be used as central nervous system depressants.4
Therefore, the development of synthetic routes toward novel
analogs of this class of nitrogen-containing heterocycles is a
highly rewarding challenge for bioorganic chemists. Several
general and efficient methods have been reported in the literature
for the synthesis of 3,4-dihydro-2(1H)-pyridinones.5 Among
them, the aza-annulation of substituted enamines (i.e. enamino-
ketones, -esters, -nitriles, and -amides) with activated acrylates is
a useful and versatile method for the synthesis of functionalized
3,4-dihydro-2(1H)-pyridinones and their derivatives.6
(CF3CO)2O , py
AlkO
AlkO
COCF3
R1
R1
1
R2NH2
R1 = H, Alk, Ar
R2 = Alk, Ar, Het
The growing interest in fluorine-containing compounds as
pharmaceuticals, agrochemicals and reagents for biochemistry
has led to the synthesis of new fluorinated analogs, especially
fluorine-containing heterocycles.7 In the latter case, synthetic
methods based on readily available fluorine-containing building
blocks are often more useful than direct introduction of fluorine
atoms into the molecule.8 Due to the high polarity at its C=C
bond β-aminovinyl trifluoromethyl ketones 2 are attractive
R2HN
COCF3
R1
2
Scheme 1. General method of the synthesis the β-aminovinyl
trifluoromethyl ketones 2.
———
Corresponding author. Tel.: +380 44 573 2598; fax: +380 44 573 2552; e-mail: igerus@hotmail.com (I. I. Gerus).

2
Tetrahedron
We found that β-substituted enaminoketones 2a-j react
This indicates that there is strong steric hindrance between the
regiospecifically with acryloyl chloride to give N-substituted 5-
(trifluoroacetyl)-3,4-dihydro-2(1H)-pyridinones 3a-j in high
yields (Scheme 2).
methyl and trifluoromethyl groups in the s-E conformation.
The aza-annulation of enamines is mechanistically interesting
since they are ambident nucleophiles which can undergo
reactions at position 1 or 3, whilst α,β-unsaturated acid chlorides
are ambident electrophiles which can react at positions 1' or 3'
(Scheme 3).
O
R2
R1
H
O
R2
R1
N
CHCl3, 65 °C
N
Cl
+
8-15 h
-HCl
O
R1
THF, Δ
O
CF3
N
O
CF3
R2
R4
R4 = H, Me
2a-j
R1 = Ph (a), Me (b-j)
R2 = Me (a,b), Ph (c), 4-MeC6H4 (d), 4-MeOC6H4 (e),
2-MeOC6H4 (f), 4-NO2C6H4 (g), c-Hept (h), (R,S)-CH(Me)Ph (i),
(S)-CH(COOMe)CH2Ph (j)
3a-j
60-78%
1
R1
R2
R3
R4
O
1'
NH
I
Cl
+
3
3'
R4
R3
R1
R2
xylene,
Et3N, Δ
N
O
Scheme 2. Synthesis of 3,4-dihydro-5-trifluoroacetyl-2(1H)-
pyridinones 3a-j.
R1, R2 = Alk, Ar, Het
R3 = Alk, COAlk, COAr, COOAlk,
COOAr, CONHAr
4 = Alk
R3
R
II
The aza-annulation was carried out in a screw-cap pressure
vessel in dry chloroform, and was monitored by 19F NMR
spectroscopy. Complete conversion was observed after heating
for 8 hours at 65 °C in the presence of a slight excess (20%) of
acryloyl chloride. In the case of N-aryl and N-cycloheptyl
substituted enaminones 2c-h extended heating (15 h) was
required to complete the reaction. A higher excess of acryloyl
chloride led to a decrease in the reaction time, but an increase in
the quantity of the unwanted by-product, β-chloropropionic acid,
which is formed upon addition of HCl to acryloyl chloride and
further hydrolysis. Purification of pyridinones 3a-j by column
chromatography was unsatisfactory. In order to minimize the
formation of β-chloropropionic acid we tried to optimize the
reaction conditions by varying the solvent and adding a base to
the reaction mixture. However, after heating enaminone 2b for
24 hours with acryloyl chloride in the presence of an equimolar
quantity of triethylamine or pyridine, only 20% of the desired
dihydropyridinone 3b was observed by 19F NMR spectroscopy.
Prolonging the reaction time (up to 72 h) proved ineffective. A
better result was obtained using THF, 1,4-dioxane or 1,2-
dimethoxyethane as the solvent. Complete formation of
dihydropyridinone 3b was observed by 19F NMR spectroscopy of
the reaction mixture after 15 hours of heating. At the same time
however, significant amounts of by-products were also obtained.
Based on the above studies, 3,4-dihydro-2(1H)-pyridinones 3a-j
were prepared in dry chloroform followed by thorough washing
with aqueous NaHCO3 (рН~9-10) and brine, drying (MgSO4),
concentration and crystallization from ethanol.11
Scheme 3. Two possible synthetic pathways for the aza-
annulation reaction.
In fact, two cyclic regioisomeric products I and II can be
obtained in this reaction, and both regioselective aza-annulation
routes have been reported.6,12 The formation of product I is
possible via an initial Michael addition of an imine-enamine
tautomer to the α,β-unsaturated acid derivative, followed by an
intramolecular N-acylation.6e,12 The R4 substituent at the β-
position of the acrylate derivative hinders the addition process
and increases the formation of by-products during the N-
acylation reaction. Acyclic N-acylation products also
predominate when pyridine or triethylamine are used as the
base.12 The formation of product II (in some cases an acyclic C-
acylation intermediate was detected) was reported by Murphy et
al. as a result of regio-reversed aza-annulation of enaminones
with crotonyl and 2-hexenoyl chlorides in the presence of
triethylamine in high-boiling solvents.6a
We did not observe the formation of N-acylation products, or
any other intermediate, upon aza-annulation of β-substituted
1
enaminoketones 2a-j with acryloyl chloride, by H or 19F NMR
spectroscopy. However, we found that unsubstituted
enaminoketone 4 reacts with acryloyl chloride to produce a
mixture of products: 3,4-dihydro-2(1H)-pyridinone 5 (30%), and
the acyclic N-acylated products 6 (15%) and 7 (55%) (Scheme
4).
O
O
O
O
Me
H
N
Me
Me
Me
CHCl3, 65 °C
N
N
N
Cl
The structures of dihydropyridinones 3a-j were confirmed
from 1H, 13C, 19F NMR and IR spectroscopic data.
Characteristically, the 19F NMR spectra of dihydropyridinones 3
showed a resonance signal due to the CF3 group shifted
downfield by 4 ppm ( ~ –73.7) in comparison with starting
enaminones 2 ( ~ –77.0). The 1H NMR spectra showed
resonances for the two CH2 groups at δ 2.3-2.8 (broad multiplet);
in some cases the signal for the methyl group at position 6 of the
pyridinone ring appeared as a triplet (5JHH = 1.2 Hz), probably
due to a long-range spin-spin interaction between these methyl
protons and the protons of the CH2 group found in non-
flourinated dihydropyridinones.6c It is interesting that the 13C
NMR signal for the carbon at position 4 in dihydropyridinones 3
appeared as a quartet (4JCF ~ 3.5-4.0 Hz) which establishes the s-
Z conformation of the C–C bond of the С=С–С=О fragment.
+
+
+
8 h
Cl
-HCl
O
CF3
F3C
O
F3C
O
F3C
O
4
5 (30%)
6 (15%)
7 (55%)
Scheme 4. Aza-annulation of 1,1,1-trifluoro-4-(methylamino)-3-
buten-2-one (4) with acryloyl chloride (CHCl3, 65 °C, 8 h).
The ratio of products in the reaction mixture was estimated by
19F and 1H NMR spectroscopy. The pure pyridinone 5 was
separated by column chromatography, whereas the products 6
and 7 were isolated as a mixture in the ratio 1:2 (see
Supplementary data). The structures of compounds 5-7 were
supported by the spectroscopic data. In the 1H NMR spectrum of
pyridinone 5 the olefinic proton at position 6 of the ring appeared

3
as a broad quartet (5JHF ~ 1.0 Hz) due to spin-spin interactions
with the fluorine atoms of the CF3 group. This suggests that the
C–C bond in the fragment С=С–С=О in the compound 5 exists in
Scheme 5. Mechanistic pathways for the aza-annulation of
enaminoketones with acryloyl chloride.
In conclusion, we have developed a facile and versatile
method for the synthesis of 5-trifluoroacetyl-3,4-dihydro-2(1H)-
pyridinones, which are potentially biologically active
compounds, and which could be potentially used in the design of
novel analogues for structure-activity research. They are also
precursors for fluorine-containing piperidines, pyridines, natural
alkaloids and other compounds.
1
s-E conformation. The H NMR spectrum of the mixture 6 and 7
showed three characteristic doublets of doublets at 6.0 (2JНН
=
1.6 Hz, 3JНН = 10.5 Hz), 6.5 (2JНН = 1.6 Hz, 3JНН = 16.8 Hz) and
6.8 (3JНН = 10.5, 16.8 Hz) which were assigned to the vinyl
protons of compound 6. The methylene groups of 7 appeared as
two triplets at 3.1 and 3.9 (3JНН = 6.5 Hz). The С=С double
bond of compounds 6 and 7 has the E-configuration (3JНН
~
13 Hz), which is characteristic of N,N-disubstituted fluorinated
enaminones.13 The structures of dihydropyridinones 3a-j and 5
were also confirmed by X-ray analysis of 6-methyl-1-(4-
methylphenyl)-5-(trifluoroacetyl)-3,4-dihydro-2(1H)-pyridinone
(3d) (Figure 1).14
Acknowledgments
We are grateful to ENAMINE Ltd, Kyiv, for providing NMR
spectra and to Dr. O. V. Shishkin, STC ‘Institute for Single
Crystals’, Kharkiv, for performing the X-ray diffraction study.
References and notes
1.
(a) Jones, T. H.; Blum, M. S. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York,
1983; Vol. 1, Chap. 2. (b) Fodor, G. B.; Colaamti, B. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Wiley: New York, 1985; Vol. 31, Chapter 1. (c) Daly, J. W. J.
Nat. Prod. 1998, 61, 162. (d) Rubiralta, M.; Giralt, E.; Diez, A. In
Piperidine: Structure, Preparation, Reactivity and Synthetic
Applications of Piperidine and its Derivatives; Elsevier:
Amsterdam, 1991.
2.
(a) Karpov, A. S.; Oeser, T.; Muller, T. J. Chem. Commun. 2004,
1502; (b) Karpov, A. S.; Rominger, F.; Muller, T. J. J. Org.
Biomol. Chem. 2005, 3, 4382; (c) Eles, J.; Kalaus, G.; Greiner, I.;
Kajtar-Peredy, M.; Szabo, P.; Szabo, L.; Szantay, C. Tetrahedron
2002, 58, 8921.
Figure 1. X-ray structure of 6-methyl-1-(4-methylphenyl)-5-
(trifluoroacetyl)-3,4-dihydro-2(1H)-pyridinone (3d).
3.
4.
5.
Lesher, G. Y., Singh, B., Carabateas, Ph. M. US Patent 4,431,651,
1984; Chem. Abstr. 1984, 100, 174679.
Winters, G., Sala, A. EP 90275 A2, 1983; Chem. Abstr. 1984, 100,
85678.
Extended heating of the mixture 6 and 7 in pure chloroform or
in the presence of an equimolar quantity of pyridine did not yield
the pyridinone 5. This fact confirms the general view of the aza-
annulation reaction mechanism. We believe that electron-
donating substituents at the β-position in compounds 2a-j play an
important role in decreasing the activation barrier in the Michael
addition to acryloyl chloride, whereas for the less electron-rich
enaminone 4 the N-acylation reaction becomes competitive
(Scheme 5).
(a) Corriu, R. J. P., Perz, R. Tetrahedron Lett. 1985, 26, 1311; (b)
Barluenga, J.; Jardon, J.; Gotor, V. Synthesis 1988, 146; (c)
Marugen, M. M.; Martin, N.; Seoane, C.; Soto J. L. Liebigs Ann.
Chem. 1989, 2, 145; (d) Barluenga, J.; Tomas, M.; Suarez-
Sorbrino, A.; Gotor, V. Tetrahedron Lett. 1988, 29, 4855; (e)
Iwao, O.; Anna, K. Tetrahedron Lett. 1989, 30, 6283; (f) Meyers,
A. I.; Garcia-Munoz, G. J. Org. Chem. 1964, 29, 1435; (g) Duran,
F.; Ghosez, L. Tetrahedron Lett. 1970, 3, 245; (h) Sain, B;
Baruah, J. N.; Sandhu, J. J. Chem. Soc., Perkin Trans. 1 1985, 4,
773.
(a) Murphy, J. P.; Hadden, M.; Stevenson, P. J. Tetrahedron 1997,
53, 11827; (b) Chowdhury, S. K. D.; Sarkar, M.; Chowdhury, S.
R.; Mahalanabis, K. K. Synth. Commun. 1996, 26, 4233; (c)
Paulvannan, K.; Stille, J. R. J. Org. Chem. 1994, 59, 1613; (d)
Beholz, L. G., Benovsky, P., Ward, D. L., Barta, N. S., Stille, J. R.
J. Org. Chem. 1997, 62, 1033; (e) Chakrabarti, S.; Panda, K.;
Misra, N. C.; Ila, H.; Junjappa, H. Synlett 2005, 1437; (f)
Lyubchanskaya, V. M.; Sarkisova, L. S.; Alekseev, L. M.; Granik
V. G. Pharm. Chem. J. 1994, 28, 70. (g) Schirok, H.; Alonso-
Alija, C.; Michels, M. Synthesis 2005, 3085. (h) Benovsky, P.;
Stille, J.R. Tetrahedron Lett. 1997, 38, 8475;
(a) Welch, J. T.; Eswarakrishnan, S., Ed. In Fluorine in
Bioorganic Chemistry; Wiley: New York, 1991; (b) Filler, R.;
Kobayashi, Y.; Yagupolskii, L. M., Ed. In Organofluorine
Compounds in Medicinal Chemistry and Biochemical
Applications; Elsevier: Amsterdam, 2000; (c) Hiyama, T. In
Organofluorine compounds; Springer: Berlin, 2000; (d) Pondee,
R.; Liu, H. Bioorg. Chem. 2004, 32, 393; (e) Begue, J.-P.; Bonnet-
Delpon, D. J. Fluorine Chem. 2006, 127, 992; (f) Kirk, K. L. J.
Fluorine Chem. 2006, 127, 1013.
H3C
H
6.
O
N
Cl
+
R
O
CF3
R = H, Alk, Ar
R = H
Cl
H
H3C
N
O
Cl
N
O
H
H3C
7.
R
O
CF3
O
CF3
-HCl
-HCl
O
O
H3C
H3C
R
8.
9.
(a) Kacharova, L. M.; Gerus, I. I.; Kacharov, A. D. J. Fluorine
Chem. 2002, 117, 193; (b) Nenaidenko, V. G.; Sanin, A. V.;
Balenkova, E. S. Russ. Chem. Rev. 1999, 68, 483.
For typical procedures for the preparation of enaminones 2a-j and
4, see: (a) Hojo, M.; Masuda, R.; Okada, E.; Sakaguchi, S.;
Narumiya, H.; Morimoto, K. Tetrahedron Lett. 1989, 30, 6173; (b)
Gerus I.I., Gorbunova M.G., Vdovenko S.I., Yagupolskii Y.L.,
Kukhar V.P. Zh. Org. Khim., 1990, 26, 1877; (c) Lyutenko N.V.,
N
O
N
O
CF3
CF3
6
3

4
Tetrahedron
Gerus I.I., Vdovenko S.I., Bzhezovsky V.M., Iksanova S.V.,
Kudryavcev A.A., Kukhar V.P. Proc. Acad. Sci. Ukr. 2002, 10,
141-146.
10. (a) Gerus I.I., Lyutenko N.V., Kacharov A.D., Kukhar V.P.
Tetrahedron Lett. 2000, 41, 10141; (b) Lyutenko N.V., Gerus I.I.,
Kacharov A.D., Kukhar V.P. Tetrahedron 2003, 59, 1731.
11. A typical procedure for the preparation of 5-(trifluoroacetyl)-3,4-
dihydro-2(1H)-pyridinones 3a-j and 5: a mixture of
enaminoketone 2a-j, 4 (~3.00 mmol) and acryloyl chloride
(3.6 mmol) in dry CHCl3 (10 mL) was heated in a screw cap
pressure vessel at 65 oC for 8-15 h. After cooling to room
temperature, additional CHCl3 (50 mL) was added and the organic
phase was washed thoroughly with 5% NaHCO3 (3×30 mL) and
brine (1×30 mL), dried (MgSO4) and then evaporated. The
products were purified by crystallization from EtOH (3a-j) or by
column chromatography (5) (silica gel, hexane/CH2Cl2, 1:2). Data
for 1-methyl-6-phenyl-5-(trifluoroacetyl)-3,4-dihydro-2(1H)-
pyridinone (3a): Yellow solid, 70%, mp 98-100 °C (EtOH); 1H
NMR (500 MHz, CDCl3) δ: 2.68-2.75 (m, 2H), 2.76-2.87 (m, 2H),
2.82 (s, 3H), 7.14 (m, 2H), 7.45 (m, 3H); 19F NMR (470.5 MHz,
CDCl3) δ: - 73.9 (s); 13C NMR (125 MHz, CDCl3) δ: 20.5 (q, JCF
=
3.5 Hz), 31.0, 32.0, 111.0, 116.2 (q, JCF = 292.8 Hz), 127.9, 129.1,
129.7, 133.5, 156.2, 170.6, 179.9 (q, JCF = 34.1 Hz); IR (CHCl3,
cm-1): ν = 1580, 1705; Anal. Calcd for C14H12F3NO2: С, 59.37;
H, 4.27; N, 4.94. Found: C, 59.50; H, 4.55; N, 5.34.
12. Paulvannan, K.; Stille, J. R. J. Org. Chem. 1992, 57, 5319.
13. (a) Vdovenko, S. I.; Gerus, I. I.; Gorbunova, M. G. J. Chem. Soc.,
Perkin Trans. 2 1993, 559. (b) Wojcik, J.; Domalewski, W.;
Kamienska-Trela, K.; Stefaniak, L.; Vdovenko, S. I.; Gerus, I. I.;
Gorbunova, M. G. Magn. Reson. Chem. 1993, 31, 808.
14. Crystal data for 3d (ref. CCDC 923297) are available free of
charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
(+44) 1223-336-033; or deposit@ccdc.cam.ac.uk.
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at

Graphical Abstract (for review)
Graphical Abstract
Aza-annulation of β-aminovinyl trifluoromethyl
Leave this area blank for abstract info.
ketones with acryloyl chloride: an efficient synthesis of
5-(trifluoroacetyl)-3,4-dihydro-2(1H)-pyridinones
Nataliya V. Lyutenko, Igor I. Gerus*