Diels-Alder reactions of trifluoromethyl alkenes with 5-ethoxyoxazoles: synthesis of trifluoromethylated pyridine derivatives

Article abstract of DOI:10.1016/j.jfluchem.2004.04.013

Cycloaddition reactions between 5-ethoxyoxazole derivatives [2,4-dimethyl 5-ethoxyoxazole and 4-methyl 5-ethoxyoxazole] and various trifluoromethyl alkenes [ethyl 4,4,4-trifluorocrotonate CF₃CH=CHCO₂Et, 3,3,3-trifluoro 1-(phenylsulfo

Full text of DOI:10.1016/j.jfluchem.2004.04.013

Journal of Fluorine Chemistry 125 (2004) 1425–1430
Diels–Alder reactions of trifluoromethyl alkenes with 5-ethoxyoxazoles:
synthesis of trifluoromethylated pyridine derivatives
Graham Sandforda,*, Ian Wilsona, Christopher M. Timperleyb
aDepartment of Chemistry, University of Durham, South Road, Durham DH13LE, UK
bChemistry Team, Dstl Porton Down, Salisbury, Wiltshire SP40JQ, UK
Received 9 February 2004; received in revised form 13 April 2004; accepted 14 April 2004
Available online 2 July 2004
Abstract
Cycloaddition reactions between 5-ethoxyoxazole derivatives [2,4-dimethyl 5-ethoxyoxazole and 4-methyl 5-ethoxyoxazole] and various
trifluoromethyl alkenes [ethyl 4,4,4-trifluorocrotonate CF3CH¼CHCO2Et, 3,3,3-trifluoro 1-(phenylsulfonyl)-1-propene CF3CH¼CHSO2Ph
and 2-(trifluoromethyl) propenoic acid CF3(HO2C)C¼CH2] gave several trifluoromethyl-substituted pyridine systems in moderate yield (20–
1
56%). Their structures were determined by multinuclear NMR techniques including H-13C HETCOR spectroscopy.
# 2004 Elsevier B.V. All rights reserved.
Keywords: Cycloaddition; Diels–Alder; Fluorinated pyridine; Fluoroalkene; Oxazole
1. Introduction
using cycloaddition methodology and, generally, these
involve reactions of trifluoromethyl diene substrates. Viehe
and co-workers [9] prepared a series of 2-trifluoromethyl-
pyridine derivatives by performing cycloaddition reactions
between trifluoromethyl oxazinone and a variety of electron-
poor alkynes whilst Schlosser reported that 1-ethoxy-3-
trifluoromethyl-1,3-butadiene [10] underwent cycloaddition
with a range of imines to give various trifluoromethyl-
pyridine products.
[4þ2]-Cycloaddition reactions between oxazoles and
electron poor alkenes are well established, typically yielding
functionalised 3-hydroxypyridine systems [11,12]. Most
commonly, symmetrical alkenes are utilised as dienophilic
substrates, for example, in the pyridoxine synthesis from a
maleate ester (Scheme 1) [13].
In contrast, there are fewer reported examples of cycload-
dition methodology that involve reactions of oxazoles with
mono-substituted [14,15] and unsymmetrical 1,2-disubsti-
tuted alkenes [16–18] as dienophiles. Generally, in these
cases, pyridine systems bearing the most electron-withdraw-
ing substituent of the dienophile at the 4-position are the
major products formed. This regioselectivity can be ratio-
nalised by Frontier Orbital theory [19]. The presence of an
electron withdrawing group attached to the alkene increases
the LUMO coefficient at the CH2 site, making overlap with
the C-2 oxazole position, which has a large HOMO coeffi-
cient due to the electron donating ethoxy group, very
favourable.
Development of efficient methodology for the synthesis
of trifluoromethylated aromatic heterocycles is an active
area of research and, in particular, routes to trifluoromethy-
lated pyridines have been developed for applications in the
preparation of a number of valuable medicinal [1] and plant
protection targets [2–5].
Trifluoromethyl groups may be introduced into a pyridine
ring system by reaction of an appropriately functionalised
pyridine substrate with either a fluorinating agent (synthesis
of carbon–fluorine bonds) or a trifluoromethylating reagent
(synthesis of carbon–carbon bonds) [6]. For example, halo-
gen exchange processes involving transformation of tri-
chloromethyl- to trifluoromethyl-groups upon reaction
with a source of fluoride ion [7] or copper catalysed coupling
processes between heteraryl iodides and trifluoromethyl
iodide [8] have been utilised recently to provide access to
these valuable products. In contrast, however, the construc-
tion of a trifluoromethylated pyridine ring from non-pyr-
idine precursors using cycloaddition methodology is an
approach that remains relatively undeveloped.
There are only a limited number of publications that
report the syntheses of trifluoromethyl pyridine systems
* Corresponding author. Tel.: þ44-191-334-2039;
fax: þ44-191-384-4737.
E-mail address: graham.sandford@dur.ac.uk (G. Sandford).
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.04.013

1426
G. Sandford et al. / Journal of Fluorine Chemistry 125 (2004) 1425–1430
CO2Et
CO Et
CO2Et
CO2Et
2
CH2OH
CH2OH
EtO
Me
EtO
CO2Et
HO
Me
O
N
HO
Me
CO Et
O
N
2
N
N
pyridoxine
Scheme 1.
Whilst trifluoromethylated alkenes are known to partici-
pate in various Diels–Alder reactions [20] and N-arylfluor-
oalkylamines give trifluoromethyl quinoline derivatives by
aza Diels–Alder processes [21], syntheses involving oxa-
zoles as the diene partner have not been described. In this
paper, we report our studies concerning reactions between
various oxazoles and trifluoromethyl alkenes with a view to
establishing the utility of cycloaddition methodology for the
synthesis of functionalised trifluoromethyl pyridine systems.
signals attributed to the trifluoromethyl resonances, indi-
cated that 4 and 5 were formed in a 3:1 ratio. Separation and
purification of pyridines 4 and 5 from the resinous crude
product by silica gel chromatography was very difficult but
an analytically pure sample of 4 was eventually obtained.
Structural assignments of 4 and 5 were made by a con-
sideration of the 1H NMR spectra. The resonance attributed
to the hydrogen atoms of the C(6)-CH3 methyl group of 4
was observed as a distinct quartet (5JHF 3 Hz), due to
coupling with the fluorine atoms of the neighbouring CF3
group, whilst this coupling was, of course, absent from the
1H NMR spectrum of minor isomer 5. The mechanism for
the formation of pyridines 4 and 5 is outlined in Scheme 3.
Heating oxazole 2 together with an excess of 3 at 120 8C
in the absence of solvent for 48 h was necessary for cycload-
dition to occur and two different trifluoromethylated pro-
ducts, pyridine 6 (25%) and pyrrole derivative 7 (8%), were
obtained after purification by column chromatography
(Scheme 4).
2. Results and discussion
5-Ethoxyoxazoles 1 and 2 were prepared in the usual
manner from DL-alanine ethyl ester hydrochloride by N-
acylation [22] and N-formylation [23], respectively, fol-
lowed by cyclodehydration using phosphorous pentoxide
[24].
Reaction of 2,4-dimethyl-5-ethoxyoxazole 1 with ethyl
4,4,4-trifluorocrotonate 3 in refluxing toluene for 60 h
yielded two trifluoromethylated pyridine derivatives 4 and
5 in 33% combined yield (Scheme 2). Analysis of the crude
material by 19F NMR spectroscopy and integration of the
The structure of 6 was deduced by 1H-13C HETCOR
spectroscopy, which allowed the unambiguous identification
of the resonance attributed to the C-6 carbon atom as
a multiplet with three-bond carbon–fluorine coupling
CO2Et
CF
CF
3
EtO
O
HO
HO
CO Et
2
3
toluene
reflux, 60 h
CF
3
+
+
CH3
CO Et
2
N
H3C
N
CH
3
H C
3
N
CH3
H C
3
1
3
4
5
33% combined yield
4 : 5, 3:1
CO Et
2
HO
CF3
5JHF = 3.0 Hz
H C
3
N
CH
3
4
Scheme 2.
OH
OEt
OEt
CO2Et
EtO OH
N
O
CO Et
CO Et
2
CO Et
2
2
-EtOH
O
H
N
N
N
CF
F C
3
CF3
3
CF3
4, major
OH
OEt
CF3
CF
3
O
N
N
EtO2C
CO Et
2
5, minor
Scheme 3.

G. Sandford et al. / Journal of Fluorine Chemistry 125 (2004) 1425–1430
1427
CO Et
EtO2C
CF3
2
EtO
HO
CF3
120oC, 48 h
O
N
CF3
+
+
CO2Et
N
H
H3C
N
H3C
O
2
3
7 (8%)
6(25%)
CO Et
2
CF3
HO
H C
CF
HO
H3C
CO2Et
3
4JCF not observed
3JCF = 8 Hz
N
N
3
6
8
Scheme 4.
H2O
N
OEt
OEt
OEt
OEt
CO2Et
H2O
HO
HN
CO Et
2
CO2Et
CO2Et
CF3
O
O
O
N
N
F3C
CF3
CF3
OEt
O
O
O
CO Et
2
CO2Et
CF3
- H2O
O
7
H2N
CF3
H
H2N
Scheme 5.
CN
EtO
EtO
CF
O
120oC, 48 h
O
3
PhSO
2
EtO
HO
H C
CF
3
o
+
O
N
CF3
120 C, 48 h
CF
3
+
N
CN
H3C
N
H
H3C
N
H C
3
3
11
2
9
2
10 (20%)
12 (21%)
Scheme 6.
Scheme 7.
Scheme 8.
(d 137.7, 3JCF 8 Hz), which is consistent with the presence of
the ortho-CF3 group. Alternative product isomer 8 would
give a resonance with four-bond carbon–fluorine coupling,
which is typically only 0–3 Hz in magnitude.
exchangeable proton and a characteristic sharp NH stretch-
ing band in the infrared spectrum (3422 cm-1). It appears that
7 was formed as a result of hydrolysis of the intermediate
Diels–Alder adduct in the work-up stage, analogous to
reported processes involving other non-fluorinated sub-
strates [15] and a mechanism for the formation of 7 is given
in Scheme 5.
Immediately distinctive of pyrrole derivative 7 was the
multiplet centred at 7.26 ppm attributed to the hydrogen
attached to the pyrrole ring. The possibility that 7 was a
pyridine derivative was excluded on the basis that reso-
nances for only four aromatic carbon atoms were visible in
the 13C spectrum. The signal at 123.4 ppm was identified as
1
C-5 from the H-13C HETCOR spectrum and the multi-
plicity of this signal (3JCF 5 Hz) confirmed that the ring
hydrogen and CF3 were ortho to each other. Furthermore,
the 13C signal of the carbonyl group was particularly notice-
able at 188.4 ppm. Compound 7 also exhibited a D2O-
Scheme 9.

1428
G. Sandford et al. / Journal of Fluorine Chemistry 125 (2004) 1425–1430
Scheme 10.
By comparing the two experiments already described, we
regioselectivity in the cycloaddition step proceeded to give
the pyridine product having the stronger electron group (i.e.
CO2Et, CN, SO2Ph) orientated para to the ring nitrogen.
see that alkene 3 reacted regiospecifically with oxazole 2,
the products 6 and 7 arising from a common cycloadduct
intermediate followed by elimination of ethanol or hydro-
lysis, respectively. Conversely, the modest regioselectivity
seen in reaction between 3 and oxazole 1 may be ascribed to
a steric clash of the oxazole C(2)CH3 and the CF3-group of 3
in the initial cycloaddition step.
4. Experimental
4.1. General
Oxazole 2 also reacted regiospecifically with 4,4,4-tri-
fluorocrotonitrile 9 in refluxing toluene (48 h) to furnish
pyridine 10 in modest yield after column chromatography
(Scheme 6). No other regioisomeric pyridines or fluorine
containing products were observed by NMR spectroscopy.
2,4-Dimethyl 5-ethoxyoxazole 1 and 4-methyl 5-ethox-
yoxazole 2 were prepared by literature procedures [22–24].
Other starting materials were obtained commercially
(Sigma–Aldrich) and solvents were dried using literature
procedures. NMR spectra were recorded in deuteriochloro-
form, unless otherwise stated, on a Varian VXR 400S
spectrometer with tetramethylsilane and trichlorofluoro-
methane as internal standards. Spectral assignments were
made with the aid of data collected by 1H-1H COSYand 1H-
13C HETCOR experiments and coupling constants are given
in hertz. Mass spectra were recorded on either a VG 7070E
spectrometer or a Fissons VG Trio 1000 spectrometer
coupled with a Hewlett Packard 5890 series II gas chroma-
tograph. Accurate mass measurements were performed by
the EPSRC National Mass Spectrometry service, Swansea,
UK. Elemental analyses were obtained on either a Perkin-
Elmer 240 or a Carlo Erba Elemental Analyser. Melting
points were recorded at atmospheric pressure and are uncor-
rected. Column chromatography was carried out on silica gel
(Merck No. 1-09385, 230-400 mesh) and TLC analysis was
performed on silica gel plates.
1
The structure of 10 was confirmed by H-13C HETCOR
spectroscopy, which identified C-6 as a broadened signal at
135.5 ppm due to coupling with the adjacent CF3 group.
Treatment of 2 with 3,3,3-trifluoro 1-(phenylsulfonyl)-1-
propene 11 in refluxing toluene gave pyridin-2-one 12 as the
only product in modest yield (Scheme 7). A mechanism for
the formation of 12, involving loss of the very good phe-
nylsulfonyl leaving group is outlined in Scheme 8.
In contrast to the sluggish reactivity of 1,2-disubstituted
alkenes 3, 9 and 11, 2-(trifluoromethyl)propenoic acid 13
reacted rapidly with oxazole 2 at room temperature. The
reaction was accompanied by a strong exotherm and evolu-
tion of a gas. Column chromatography afforded pyridine 14
as the sole product in good yield (Scheme 9). Here, the
presence of two electron withdrawing groups makes the
orbital coefficient at the CH2 site larger and overlap with the
C-2 oxazole site more favourable, allowing the reaction to
proceed very readily with high regioselectivity.
4.2. 2,6-Dimethyl-3-hydroxy- 5-trifluoromethyl
isonicotinic acid ethyl ester (4)
The ortho relationship of the ring hydrogens in 14 was
evident from the doublet located at d 7.34 ppm (J 5 Hz).
Meta-couplings in pyridines typically have much smaller J
values (<1 Hz). Formation of 14 can be explained by
regiospecific cycloaddition of oxazole 2 to alkene 13, fol-
lowed by ring opening and decarboxylation (Scheme 10).
An analogous result was reported by Matsuo from the
reaction between methacrylic acid CH2¼C(CH3)CO2H
and oxazole 2 [17].
5-Ethoxy-2,4-dimethyl oxazole (1 g, 7 mmol), ethyl 4,4,4
trifluorocrotonate (2.44 g, 14 mmol) and toluene (20 ml)
were heated together at reflux temperature for 72 h. After
cooling, volatile materials were removed at reduced pressure
to yield a brown oily solid. 19F NMR analysis indicated a
mixture of two trifluoromethylated products in ratio 3:1.
Purification by column chromatography on silica gel (eluent
10:1 hexane-ethyl acetate) gave 3-hydroxy-2,6-dimethyl-5-
trifluoromethyl isonicotinic acid ethyl ester 4 (0.34 g,
18.5%) as a yellow solid; mp 106–107 8C (found: C,
49.8; H, 4.6; N, 5.2, [M]þ, 263.076517. C11H12NO3F3
requires: C, 50.2; H, 4.6; N, 5.3%, [M]þ, 263.076928);
dH 1.38 (3H, t, J 8 Hz, CH2CH3), 2.53 (3H, s, C(2)-CH3),
3. Conclusions
The cycloaddition of trifluoromethyl alkenes with
5-ethoxyoxazoles provides routes to various trifluoromethy-
lated pyridines and pyridone derivatives depending upon
the nature of the substituent present on the alkene. The
5
2.62 (3H, q, JHF 3.0 Hz, C(6)-CH3), 4.42 (2H, q, J 7 Hz,

G. Sandford et al. / Journal of Fluorine Chemistry 125 (2004) 1425–1430
1429
CH2CH3), 8.23 (1H, br s, OH); dC 13.9 (s, CH2CH3), 19.9 (s,
C(2)-CH3), 23.7 (q, JCF 3.5, C(6)-CH3), 63.5 (s, OCH2),
solid; mp 156 8C (decomp.) (found [M]þ 202.035398.
[C8H5N2OF3]þ requires 202.034501); dH 2.61 (3H, s,
CH3), 4.2 (br m, OH), 8.48 (1H, s, H-6); dF –60.3 (s); dC
4
2
1
119.4 (q, JCF 31, C–CF3), 121.2 (m, C-4), 123.9 (q, JCF
273, CF3), 147.8 (s, C-2), 148.3 (s, C-3), 152.8 (s, C-6),
168.0 (s, C¼O); dF ꢀ56.4 (s); m/z (EI) 263 ([M]þ, 38%), 218
([M-OCH2CH3]þ, 26%), 217 ([M-OCH2CH3]Hþ, 100%),
189 ([M-CO2CH2CH3-H]þ, 66%), 120 ([M-CO2CH2CH3-
CF3-H]þ, 34%); and a mixture (ratio 4:5, 1:2) containing 3-
hydroxy-2,6-dimethyl-4-trifluoromethyl nicotinic acid ethyl
ester 5 (0.27 g); dH 1.37 (3H, t, J 7 Hz, CH2CH3), 2.45 (3H,
s, CH3), 2.53 (3H, s, CH3), 4.39 (2H, q, J 7Hz, CH2CH3); dF
ꢀ58.95 (m); m/z (EI) 263 ([M]þ, 58%), 218 ([M-
CH3CH2O]þ, 100%).
1
21.1 (s, CH3), 102.8 (s, C-4), 113 (s, CN), 123 (q, JCF
272 Hz, CF3), 123.6 (q, 2JCF 31.5 Hz, C-5), 135.5 (m, C-6),
155.6 (s, C-2), 156.2 (s, C-3); m/z (EI) 203 ([MH]þ, 8%),
202 ([M]þ, 100%), 183 ([M-F]þ, 10%).
4.5. 5-Ethoxy-6-methyl-3-trifluoromethyl
1H-pyridin-2-one (12)
4-Methyl-5-ethoxy-oxazole (0.25 g, 1.97 mmol), 3,3,3-
trifluoro 1-(phenylsulfonyl)-1-propene (0.93 g, 3.94 mmol)
and toluene were heated at reflux for 48 h. Volatile materials
were removed at reduced pressure to yield a black residue,
which after column chromatography on silica gel (eluent 3:1
hexane-ethyl acetate) and recrystallisation from hexane-
ethyl acetate, gave 5-ethoxy-6-methyl-3-trifluoromethyl
1H-pyridin-2-one 12 (90 mg, 21%) as a brown solid; mp
119–120 8C (found: C 48.9, H 4.6%, N 6.3, [M]þ,
221.066418. C9H10NO2F3 requires: C 48.9%, H 4.6%, N
6.3%, [M]þ, 221.066363); dH 1.28 (3H, t, J 7 Hz, CH2CH3),
2.45 (3H, s, C(6)CH3), 4.20 (2H, q, J 7 Hz, CH3CH2O), 7.26
(1H, s, H-4), 11.87 (1H, br s, NH); dF ꢀ55.2 (s); dC 13.9 (s),
C(6)CH3, 15.0 (s, CH2CH3), 60.1 (s, CH2), 108.8 (s, C-6),
4.3. 2-Methyl-3-hydroxy- 5-trifluoromethyl isonicotinic
acid ethyl ester (6)
4-Methyl-5-ethoxy-oxazole (0.5 g, 3.9 mmol) and ethyl
4,4,4 trifluorocrotonate (2.70 g, 16 mmol) were heated
together at 120 8C for 48 h. Volatile materials were removed
at reduced pressure to yield a brown oily solid, which after
purification by column chromatography on silica gel (eluent
5:1 hexane-ethyl acetate) gave 2-methyl-3-hydroxy-5-tri-
fluoromethyl isonicotinic acid ethyl ester 6 (0.24 g, 25%)
as a waxy solid; (found [M]þ 249.062180. [C10H10NO3F3]þ
requires 249.061278); dH 1.36 (3H, t, J 7 Hz, CH2CH3), 2.53
(3H, s, C(2)-CH3), 4.21 (2H, q, J 7 Hz, CH3CH2O), 8.35
(1H, s, H-6), 10.80 (br s, OH); dF ꢀ58.6 (s); dC 13.8 (s,
CH2CH3), 20.2 (s, C(2)-CH3), 63.7 (s, CH2), 115.3 (m, C-4),
2
3
113.5 (q, JCF 36 Hz, C-3), 120.3 (q, JCF 6.5 Hz, C-4),
1
124.5 (q, JCF 266 Hz, CF3), 139.2 (s, C-5), 164 (s, C¼O);
m/z (EI) 221 ([M]þ, 28%), 176 ([M-OEt]þ, 100%).
4.6. 2-Methyl 4-trifluoromethyl pyridin-3-ol (14)
2
1
121.3 (q, JCF 32 Hz, C-5), 123.4 (q, JCF 272 Hz, CF3),
3
137.7 (q, JCF 8 Hz, C-6), 154.3 (s, C-2), 156.5 (s, C-3),
168.5 (s, C¼O); m/z (EI) 249 ([M]þ, 6%), 203 ([M-OEt-
H]þ, 14%), 175 ([M-CO2Et-H]þ, 20%), 156 ([M-CO2Et-H-
F]þ, 26%); and, 2-(acetyl)-3-(carboethoxy)-4-trifluoro-
methyl pyrrole 7 (0.08 g, 8%) as an oily solid; (found
[M]þ 249.061537. [C10H10NO3F3]þ requires 249.061278);
dH 1.33 (3H, t, J 7.0, CH2CH3), 2.51 (3H, s, CH3C¼O), 4.34
(2H, q, J 7.0, CH3CH2O), 7.60 (1H, m, H-5), 12.8 (br m,
NH); dF –57.7 (s); dC 13.7 (s, CH2CH3), 27.7 (s, CH3C¼O),
2-(Trifluoromethyl)propenoic acid (1.1 g, 3.9 mmol) was
added to 4-methyl 5-ethoxyoxazole (0.5 g, 3.9 mmol). After
gas evolution had subsided the viscous red oil was adsorbed
onto silica gel and purification by column chromatography
(eluent 2:1 hexane-ethyl acetate) gave 2-methyl 4-trifluor-
omethyl pyridin-3-ol 14 (0.46 g, 56%) as a white solid; mp
175 8C (decomp.) (found:
C 47.4, H 3.4, N 7.6,
[M]þ177.040139. [C7H6NOF3]þ requires: C 47.5, H 3.5,
N 7.9%, [M]þ 177.040149); dH 2.46 (3H, s, CH3), 7.34 (1H,
d, J 5 Hz, H-5), 8.09 (1H, m, H-6), 9.97 (1H, br s, OH); dF
ꢀ62.0 (m); dC 20.9 (s, CH3), 118.9 (m, C-5), 124.0 (q, 2JCF
31 Hz, C-4), 124.1 (q, 1JCF 272 Hz, CF3), 141 (s, C-6), 149.5
(s, C-2), 150.4 (s, C-3); m/z (EI) 177 ([M]þ, 100%), 157 ([M-
H-F]þ, 34%).
2
61.3 (s, CH2), 113.2 (q, JCF 36.0, C-4), 117.5 (m, C-3),
122.8 (q, 1JCF 267.0, CF3), 123.4 (q, 3JCF 5.0, C-5), 131.8 (s,
C-2), 163.7 (s, OC¼O), 188.4 (s, CH3C¼O); m/z (EI) 249
([M]þ, 6%), 204 ([M-OEt]þ, 88%), 203 ([M-OEt-H]þ,
100%), 188 ([M-OEt-H-CH3]þ, 60%), 184 ([M-OEt-H-
F]þ, 90%), 175 ([M-CO2Et-H]þ, 26%).
4.4. 3-Hydroxy-2-methyl-5-
trifluoromethylisonicotinonitrile (10)
Acknowledgements
4-Methyl-5-ethoxy-oxazole (0.5 g, 3.9 mmol), 4,4,4 tri-
fluorocrotonitrile (0.94 g, 7.8 mmol, 2 eq) and toluene
(20 ml) were heated at reflux for 48 h. Volatile materials
were removed at reduced pressure to yield a brown residue,
which after column chromatography on silica gel (eluent 3:1
hexane-ethyl acetate) gave 3-hydroxy-2-methyl-5-trifluoro-
methyl-isonicotinonitrile 10 (0.16 g, 20%) as an orange
We thank Dstl Porton Down for funding this work.
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