Diverse trifluoromethyl heterocycles from a single precursor

Article abstract of DOI:10.1021/jo202201w

Ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate is a highly versatile intermediate for the synthesis of a wide range of trifluoromethyl heterocycles. With the use of rhodium(II) or copper(II) catalyzed carbene X-H insertion reactions as key steps, a diverse

Full text of DOI:10.1021/jo202201w

Article
pubs.acs.org/joc
Diverse Trifluoromethyl Heterocycles from a Single Precursor
Mark A. Honey, Raffaele Pasceri, William Lewis, and Christopher J. Moody*
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U. K.
S
* Supporting Information
ABSTRACT: Ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate is a highly
versatile intermediate for the synthesis of a wide range of trifluoromethyl
heterocycles. With the use of rhodium(II) or copper(II) catalyzed carbene
X−H insertion reactions as key steps, a diverse set of trifluoromethyl-
oxazoles, -thiazoles, -imidazoles, -1,2,4-triazines, and -pyridines are available
from the diazoketoester, either directly in a single step or with just one
additional step.
preformed heterocyclic rings (Scheme 1A) using, for example,
INTRODUCTION
■
one of the methods developed recently.5−9 Alternatively, in a
Fluorine-containing compounds rarely occur in nature, but an
increasing number of synthetic bioactive pharmaceuticals and
agrochemicals contain fluorine.1 At present, ca. 20% of
marketed medicines and ca. 30% of agrochemicals contain at
least one fluorine atom. In many such compounds, the fluorine
is incorporated in the form of a trifluoromethyl group, and
examples include well-known pharmaceuticals such as fluox-
etine (Prozac), celecoxib (Celebrex), and mefloquin (Lariam)
Scheme 1. Possible Routes to a Diverse Set of
Trifluoromethyl-Substituted Heterocyclic Rings
and a recently developed 5-trifluoromethyl oxazole,2
a
diacylglycerol acyltransferase-1 (DGAT-1) inhibitor (Figure 1).
Figure 1. Some trifluoromethyl-containing pharmaceuticals.
complementary approach, one could access a carefully chosen
single CF3-containing precursor that can be subsequently
converted into a range of different heterocycles (Scheme 1B).
In certain circumstances, we believe that the second approach
might be more efficient and versatile, and we therefore have
investigated the metal-catalyzed reactions of a trifluoroacetyl diazo
compound, ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate (1),
As a consequence, a number of methods have been developed for
the introduction of trifluoromethyl groups into molecules.3,4
Given the importance of trifluoromethyl groups in bioactive
compounds and the fact that a large majority of modern
medicines and agrochemicals contain one or more heterocyclic
rings, it is not surprising that the synthesis of trifluoromethyl
heterocycles is a topic of current interest to the chemical
community. There are two main options for the construction of
trifluoromethyl heterocycles. First is the trifluoromethylation of
Received: October 29, 2011
Published: January 4, 2012
© 2012 American Chemical Society
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Scheme 2. Formation of 5- and 4-Trifluoromethyloxazoles
in heterocycle construction. We now report the use of this versa-
tile reagent in the synthesis of a wide range of trifluoromethyl-
oxazoles, -thiazoles, -imidazoles, -1,2,4-triazines, and -pyridines.
derivative 2d was confirmed by X-ray crystallography (see the
Supporting Information). The remaining material was largely made
up by the product of carbene O−H insertion and cyclization, the
oxazolines 3 (Scheme 2), with the structures of the 2-bromo- and
4-methoxy-phenyl derivatives 3b and 3c being confirmed by X-ray
crystallography (see the Supporting Information). Hence, the
trifluoroacetyl diazoketoester 1 behaves somewhat differently to its
nonfluorinated counterpart, presumably the enhanced oxophilicity
of the rhodium carbene intermediate derived from 1 causing the
competing O−H insertion process. We have only previously
observed significant amounts of products derived from competing
O−H insertion when using perfluorinated ligands on rhodium,
where the ligands also influence the electrophilicity of the
intermediate rhodium carbene.16
As expected, both compounds 2 and 3 could be dehydrated
to the corresponding oxazoles. Thus, the hydrated ketoamide
2b underwent cyclodehydration to the 5-trifluoromethyloxazole
4b in 75% yield using the Wipf protocol (Scheme 2).28
Likewise, the 4-hydroxyoxazolines 3 underwent dehydration to
the corresponding 4-trifluoromethyloxazoles 5 upon treatment
with phosphorus oxychloride (Scheme 2). The intermediates 2
and 3 need not be isolated; repeating the rhodium(II)-acetate-
catalyzed reaction of 1 with carboxamides, but with subsequent
addition of phosphorus oxychloride to the reaction mixture,
leads directly to a separable mixture of the 5-trifluoromethyl
and 4-trifluoromethyl oxazoles 4 and 5 in modest yields
(Scheme 2), with the 4-isomer, the product of initial O−H
insertion, predominating (Table 1). Although in general, the
RESULTS AND DISCUSSION
■
In continuation of our work on metal carbene N−H insertion
reactions in synthesis,10−17 we were keen to explore the potential
of similar reactions using trifluoroacetyl diazo compounds as
starting materials. Although ethyl 2-diazo-4,4,4-trifluoro-3-oxobu-
tanoate (1) is a known diazo-β-ketoester, it has been sparingly
used in synthesis and has only seen use in a limited number of
heterocycle-forming reactions. Thus, as early as 1968, Dworschak
and Weygard reported its photochemical reaction with acetonitrile
to give ethyl 2-methyl-4-trifluoromethyloxazole-2-carboxylate in
60% yield,18 while Hoffmann and Wenkert reported the first
rhodium(II)-acetate-catalyzed reaction of the diazo compound.19
Thus, reaction with ethyl vinyl ether gave a dihydrofuran, which
upon reaction with amines gave 2-trifluoromethylpyrroles. Non-
metal-catalyzed reactions with ynamines or with phosphoranes
followed by Ph3P gave pyrazoles and pyridazines, respectively,20−22
before Wang and Zhu reinvestigated the reaction with nitriles but
under rhodium(II) acetate catalysis.23 Wang and Zhu also
reinvestigated the reaction with vinyl ethers24 as a route to
dihydrofurans and furans. Trifluoromethylfurans are also obtained
from reaction of the diazo compound 1 with alkynes.25 Hence, the
conversion of diazo β-ketoester 1 into trifluoromethyl heterocycles
has been exemplified in a few cases, although none of this work
has involved the N−H insertion chemistry that has proved so
versatile in the synthesis of a series of nonfluorinated N-containing
heterocycles.
Table 1. Formation of 5- and 4-Trifluoromethyloxazoles 4
and 5
Ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate 1 is readily
prepared either by diazo transfer to ethyl trifluoroacetoacetate22
or by trifluoroacetylation of commercially available ethyl
diazoacetate with trifluoroacetic anhydride.23 We preferred
the latter method and routinely prepared the compound in 5-g
batches. Initially, we investigated oxazole formation by reaction
of diazocarbonyl compound 1 with carboxamides under our
previously reported rhodium(II)-acetate-catalyzed conditions,16
expecting to isolate the N−H insertion products, β-ketoamides.
In this event, these were isolated in modest yields but as their
hydrates 2,26,27 presumably because of the enhanced electro-
philicity of the trifluoromethyl ketone toward adventitious water
during chromatography. The structure of the 4-bromophenyl
2
3
3 → 5
1 → 4
yield/%
1 → 5
yield/%
Ar
yield/% yield/% yield/%
a
b
c
Ph
43
32
40
38
35
40
38
33
73
69
72
67
13
14
28
23
30
35
33
31
2-BrC6H4
4-MeOC6H4
4-BrC6H4
d
oxazole-4- and -5-carboxylates 4 and 5 were distinguishable
by 13C NMR spectroscopy (the CF3-bearing ring carbon
occurring at δ 141.4−142.5 and δ 135.9−136.7, respectively),
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the structures of oxazoles 4b, 5b, and 5c were confirmed by
crystallography (see the Supporting Information). Oxazole 4a
was also obtained in 50% yield by rhodium(II)-acetate-
catalyzed reaction of 1 with benzonitrile, in confirmation of
earlier findings.23
With N−H insertion products 2 in hand, albeit in modest
yield, we were able to prepare 5-trifluoromethyl imidazoles 6
simply by treatment with ammonium acetate in acetic acid/
toluene (Scheme 3).29
initial N−H insertion product, or in this case its hydrate, with
Lawesson’s reagent.29 This was exemplified by the conversion of
ketoamide hydrate 2d into thiazole 9 in modest yield (Scheme 4).
In order to explore further the utility of diazoketoester 1 in the
synthesis of trifluoromethyl heterocycles, we next investigated its
reaction with aryl hydrazides (Scheme 5). Despite the wide range
a
Scheme 5. Synthesis of 2-Trifluoromethylnicotinates
a
Scheme 3. Formation of 5-Trifluoromethylimidazoles
a
10a, Ar = Ph (28%); 10b, Ar = 3-MeOC6H4 (35%); 10c, Ar = 4-
BrC6H4 (31%); 11a, Ar = Ph (89%); 11b, Ar = 3-MeOC6H4 (86%);
11c, Ar = 4-BrC6H4 (91%).
a
2a, Ar = Ph; 2c, Ar = 4-MeOC6H4; 2d, Ar = 4-BrC6H4; 6a, Ar = Ph
(42%); 6b, Ar = 4-MeOC6H4 (45%); 6c, Ar = 4-BrC6H4 (40%).
of N−H compounds that have been reported to undergo metal
carbene N−H insertion reactions, the reaction of hydrazides has
only recently been reported from our laboratory.30 Microwave-
assisted reaction of 1 with benzhydrazide in the presence of
copper(II) acetate, followed by reaction with ammonium acetate in
acetic acid as previously described,30 gave after chromatography
the 1,2,4-triazines 10 in modest yield (Scheme 5). The structure of
the 5-trifluoromethyl-1,2,4-triazine 10a was confirmed by X-ray
crystallography (see the Supporting Information). 1,2,4-Triazines
are known to act as electron-deficient dienes in aza Diels−Alder
reactions,31−33 and therefore we investigated their conversion into
pyridines by Diels−Alder reaction with norbornadiene as an
ethyne equivalent.34−37 Thus, heating triazines 10 with an excess of
norbornadiene in chlorobenzene gave 6-aryl-2-trifluoromethylni-
cotinates 11 in excellent yield (Scheme 5).
Finally, within the 1,3-azole series, we investigated the
preparation of trifluoromethylthiazoles by reaction of diazo-
ketoester 1 with thiocarboxamides. Although the reaction of
diazocarbonyl compounds with thioamides is less well-known
than the corresponding reaction with amides, we have recently
shown that with the right choice of rhodium catalyst, it
proceeds readily.16 Thus, rhodium(II)-heptafluorobutyramide-
catalyzed reaction of diazocarbonyl compound 1 with a range of
thiocarboxamides under microwave irradiation followed by
addition of DBU to the reaction mixture gave the 4-trifluoromethyl
thiazoles 7 in good yield (Scheme 4). As expected, the reaction
a
Scheme 4. Formation of Trifluoromethylthiazoles
In conclusion, the present work not only further confirms the
utility of carbene X−H insertion reactions as a key step in the
synthesis of heterocycles, but also establishes ethyl 2-diazo-
4,4,4-trifluoro-3-oxobutanoate as a highly versatile intermediate
for the synthesis of a wide range of trifluoromethyl heterocycles
as summarized in Scheme 6. Oxazoles, thiazoles, imidazoles, 1,2,
4-triazines, and pyridines are available directly from diazoketoester
1, either directly in a single step or with just one additional
step. In the case of oxazoles and thiazoles, the same diazoketo-
ester precursor can give rise to 4- or 5-trifluoromethyl d
erivatives depending on the reaction conditions, adding to the
versatility.
EXPERIMENTAL SECTION
■
General Information. Commercially available reagents were used
throughout without purification unless otherwise stated. Anhydrous
solvents were used as supplied. Tetrahydrofuran was distilled from
sodium benzophenone ketyl under nitrogen atmosphere. Dichloro-
methane was distilled from calcium hydride under a nitrogen atmo-
sphere. Light petroleum refers to the fraction with bp 40−60 °C. Ether
refers to diethyl ether. Reactions were routinely carried out under a
nitrogen or argon atmosphere. Analytical thin layer chromato-
graphy was carried out on aluminum-backed plates coated with silica
gel and visualized under UV light at 254 and/or 360 nm and/or
potassium permanganate or ethanolic vanillin dip. Chromato-
graphy was carried out on silica gel. Fully characterized compounds
were chromatographically homogeneous. Infrared spectra were
recorded on an FT-IR spectrometer in the range 4000−600 cm−1
as solutions in chloroform. NMR spectra were recorded at 400 or
a
7a, Ar = Ph (64%); 7b, Ar = 4-BrC6H4 (63%); 7c, Ar = 4-CF3C6H4
(65%); 7d, Ar = 2-quinolinyl (68%).
proceeds by C−S bond formation to the carbene intermediate
(S−H insertion into the thiocarboxamide imino tautomer),
although the thiazole 4c was subjected to X-ray crystallographic
analysis to confirm its structure (see the Supporting Information).
If DBU is not added, the reaction stops at the 4-hydroxy-thiazoline
stage. In the case of thiobenzamide, the intermediate thiazoline 8
was isolated in 54% yield, and its structure was confirmed by X-ray
crystallography (see the Supporting Information). The regioiso-
meric 5-trilfluoromethylthiazoles are also available by treating the
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a
Scheme 6. Ethyl 2-Diazo-4,4,4-trifluoro-3-oxobutanoate
Ethyl 4-Hydroxy-2-phenyl-4-trifluoromethyl-4,5-dihydrooxazole-
5-carboxylate 3a and Ethyl 2-Benzamido-4,4,4-trifluoro-3,3-dihy-
droxybutanoate 2a. According to General Method A, ethyl 2-diazo-
4,4,4-trifluoro-3-oxobutanoate 1 (200 mg, 0.95 mmol), benzamide
(152 mg, 1.26 mmol), and rhodium(II) acetate (8.4 mg, 2 mol %)
gave (i) ethyl 4-hydroxy-2-phenyl-4-trifluoromethyl-4,5-dihydrooxazo-
le-5-carboxylate 3a as a colorless solid (100 mg, 35%): mp 92−95 °C
(lit.,38 no data); (Found: M + Na+, 326.0598. C13H12F3NO4 + Na+
requires 326.0611); νmax (CHCl3)/cm−1 3569, 2987, 1759, 1645, 1582,
1496, 1452, 1376, 1355, 1301, 1256, 1192, 1159; δH (400 MHz;
CDCl3) 8.45 (2 H, d, J 8.0 Hz), 7.62 (1 H, t, J 8.0 Hz), 7.48 (2 H, t,
J 8.0 Hz), 6.57 (1H, s), 5.23 (1 H, s), 4.35 (2 H, m), 1.35 (3 H, t, J 7.2
Hz); δC (100 MHz; CDCl3) 169.9 (C), 165.0 (C), 133.5 (CH), 129.5
(CH), 128.8 (C), 124.6 (CH), 122.8 (q, J 283.0 Hz, CF3), 98.4 (q,
J 35.0 Hz, C), 80.2 (CH), 62.2 (CH2), 14.0 (Me); δF (377 MHz;
CDCl3) −82.05 (s, CF3). (ii) Ethyl 2-benzamido-4,4,4-trifluoro-3,3-
dihydroxybutanoate 2a was also given as a colorless crystalline solid (115
mg, 38%): mp 69−71 °C; (Found: M + Na+, 344.0700. C13H14F3NO5 +
Na+ requires 344.0716); νmax (CHCl3)/cm−1 3569, 3437, 2987, 1738,
1676, 1640, 1580, 1517, 1446, 1375, 1301, 1259, 1191, 1144; δH (400
MHz; (CD3)2SO) 8.24 (1 H, d, J 8.8 Hz), 7.85 (2 H, d, J 8.4 Hz), 7.58−
7.64 (2 H, m), 7.50−7.57 (3 H, m), 4.94 (1 H, d, J 8.8 Hz), 4.15 (2 H, q,
J 7.2 Hz), 1.21 (3 H, t, J 7.2 Hz); δC (100 MHz; CDCl3) 169.4 (C), 166.6
(C), 133.7 (C), 132.3 (CH), 129.0 (CH), 127.8 (CH), 123.5 (q, J 288.0
Hz, CF3), 92.8 (q, J 31.0 Hz, C), 61.4 (CH2), 56.4 (CH), 14.5 (Me); δF
(377 MHz; CDCl3) −81.6 (s, CF3).
a
A highly versatile precursor to a wide range of heterocyclic products
via carbene insertion reactions (the carbon that originates from the
carbene is indicated).
500 MHz (1H frequency, 100 or 125 MHz 13C frequency, 377 MHz
19F frequency). Chemical shifts are quoted in ppm and J-values in Hz.
Chemical shift values are referenced against residual proton in the
deuterated solvents. In the 13C NMR spectra, signals correspond-
ing to CH, CH2, or CH3 are assigned from DEPT-90 and -135
spectra; all others are quaternary C. Mass spectra were recorded
on a time-of-flight mass spectrometer using electrospray ioniza-
tion (ESI). Microwave reactions were carried out in a CEM
Discover TM S-class microwave reactor at 300 W with IR temper-
ature sensor.
Ethyl 2-(2-Bromophenyl)-4-hydroxy-4-trifluoromethyl-4,5-dihy-
drooxazole-5-carboxylate 3b and Ethyl 2-(2-Bromobenzamido)-
4,4,4-trifluoro-3,3-dihydroxybutanoate 2b. According to General
Method A, ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate 1 (200 mg,
0.95 mmol), 2-bromobenzamide (252 mg, 1.26 mmol), and
rhodium(II) acetate (8.4 mg, 2 mol %) gave (i) ethyl 4-hydroxy-2-
(2-bromophenyl)-4-trifluoromethyl-4,5-dihydrooxazole-5-carboxylate
3b as a colorless solid (144 mg, 40%): mp 139−141 °C; (Found: M +
Na+, 403.9716. C13H1179BrF3NO4 + Na+ requires 403.9721); νmax
(CHCl3)/cm−1 3688, 3566, 3008, 1758, 1652, 1601, 1567, 1439, 1395,
1376, 1351, 1303, 1246, 1191, 1161; δH (400 MHz; (CD3)2SO) 8.27
(1 H, s), 7.84 (2 H, m), 7.58 (2 H, m), 5.47 (1 H, s), 4.23 (2 H, m),
1.25 (3 H, t, J 7.2 Hz); δC (126 MHz; CDCl3) 167.1 (C), 165.4 (C),
134.7 (C), 134.2 (CH), 132.1 (CH), 127.5 (CH), 126.9 (CH), 123.5 (q,
J 283.7 Hz, CF3), 121.5 (C), 98.8 (q, J 32.5 Hz, C), 80.2 (CH), 61.8
(CH2), 14.5 (Me); δF (377 MHz; CDCl3) −82.0 (s, CF3). (ii) Ethyl 2-(2-
bromobenzamido)-4,4,4-trifluoro-3,3-dihydroxybutanoate 2b was also given
as a colorless crystalline solid (120 mg, 32%): mp 111−114 °C; (Found:
M + Na+, 421.9822. C13H1379BrF3NO5 + Na+ requires 421.9827); δH (400
MHz; (CD3)2SO) 8.46 (1 H, d, J 9.2 Hz), 7.68 (1 H, d, J 8.0 Hz), 7.58−
7.64 (2 H, m), 7.50−7.57 (3 H, m), 4.89 (1 H, d, J 9.2 Hz), 4.17 (2 H, q,
J 7.2 Hz), 1.23 (3 H, t, J 7.2 Hz); δC (126 MHz; CDCl3) 169.1 (C), 167.3
(C), 138.6 (C), 133.8 (CH), 131.8 (CH), 129.5 (CH), 128.4 (CH), 123.3
(q, J 292.3 Hz, CF3), 119.3 (C), 92.6 (q, J 30.2 Hz, C), 61.4 (CH2), 56.2
(CH), 14.4 (Me); δF (377 MHz; CDCl3) −81.6 (s, CF3).
Ethyl 2-Diazo-4,4,4-trifluoro-3-oxobutanoate 1. To a solution
of ethyl diazoacetate (3.1 mL, 30.0 mmol) in dichloromethane
(33 mL) at 0 °C was added dropwise pyridine (2.7 mL, 33.0 mmol).
The mixture was stirred for 15 min. A solution of trifluoroacetic
anhydride (4.7 mL, 33.0 mmol) in dichloromethane (8.0 mL) was
added dropwise and stirred for 30 min. The reaction mixture was
poured into water (30 mL) and neutralized with NaHCO3. The
organic layer was isolated, and the solvent was removed under reduced
pressure, yielding a dark yellow oil. The crude product was purified
over a silica cartridge (100 g) using a gradient of 0−50% ethyl acetate
in cyclohexane over a period of 40 min. The appropriate fractions were
combined to give the title compound as a yellow oil (5.3 g, 84%): νmax
(CHCl3)/cm−1 2990, 2164, 1740, 1711, 1671, 1377, 1360, 1305, 1279,
1203, 1164, 1014; δH (400 MHz; CDCl3) 4.37 (2 H, q, J 7.1 Hz), 1.36
(3 H, t, J 7.1 Hz); δC (100 MHz; CDCl3) 172.1 (q, J 39 Hz, C), 158.3
(C), 115.7 (q, J 287 Hz, CF3), 71.9 (C), 62.6 (CH2), 13.9 (Me).
Oxazoles. General Method A. To a solution of ethyl 2-diazo-
4,4,4-trifluoro-3-oxobutanoate 1 (200 mg, 0.95 mmol) and the
benzamide (1.26 mmol) in dichloromethane (5 mL) was added
rhodium(II) acetate (8.4 mg, 2 mol %). The reaction vessel was sealed,
and the solution was heated in a microwave reactor to 80 °C for 20
min. The reaction mixture was cooled to room temperature, and the
solvent was removed under reduced pressure. The residue was purified
over silica using a solvent system of 30% ethyl acetate in light
petroleum to give (i) the ethyl 4-hydroxy-2-aryl-4-trifluoromethyl-4,5-
dihydrooxazole-5-carboxylate 3 and (ii) the ethyl 2-benzamido-4,4,4-
trifluoro-3,3-dihydroxybutanoate 2.
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Ethyl 4-Hydroxy-2-(4-methoxyphenyl)-4-trifluoromethyl-4,5-dihy-
drooxazole-5-carboxylate 3c and Ethyl 2-(4-Methoxybenzamido)-
4,4,4-trifluoro-3,3-dihydroxybutanoate 2c. According to General
Method A, ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate 1 (200 mg,
0.95 mmol), 4-methoxybenzamide (190 mg, 1.26 mmol), and
rhodium(II) acetate (8.4 mg, 2 mol %) gave (i) ethyl 4-hydroxy-2-(4-
methoxyphenyl)-4-trifluoromethyl-4,5-dihydrooxazole-5-carboxylate 3c
as a colorless solid (120 mg, 38%): mp 125−127 °C; (Found: M +
Na+, 356.0700. C14H14F3NO5 + Na+ requires 356.0716); νmax (CHCl3)/
cm−1 3689, 3568, 3011, 1758, 1639, 1610, 1513, 1464, 1425, 1377, 1356,
1307, 1259, 1192, 1173, 1096; δH (400 MHz; CDCl3) 8.02 (2 H, d, J
8.8 Hz), 6.97 (2 H, d, J 8.8 Hz), 5.20 (1 H, s), 4.36 (2 H, m), 4.19 (1 H,
br), 3.90 (3 H, s), 1.36 (3 H, t, J 7.0 Hz); δC (126 MHz; CDCl3) 169.6
(C), 165.3 (C), 163.7 (C), 131.5 (CH), 122.6 (q, J 284.8 Hz, CF3),
117.1 (C), 114,0 (CH), 98.5 (q, J 32.7 Hz, C), 79.9 (CH), 62.2 (CH2),
55.5 (Me), 14.0 (Me); δF (377 MHz; CDCl3) −81.6 (s, CF3). (ii) Ethyl
4,4,4-trifluoro-3,3-dihydroxy2-(4-methoxybenzamido)butanoate 2c was
also given as a colorless crystalline solid (133 mg, 40%): mp 71−74 °C;
(Found: M + Na+, 374.0815. C14H16F3NO6 + Na+ requires 374.0822);
νmax (CHCl3)/cm−1 3690, 3571, 3007, 1738, 1668, 1606, 1577, 1496,
1442, 1375, 1343, 1311, 1259, 1182, 1096, 1030; δH (400 MHz;
(CD3)2SO) 8.10 (1 H, d, J 9.0 Hz), 7.83 (2 H, d, J 8.7 Hz), 7.59
(1 H, s), 7.52 (1 H, s), 7.05 (2 H, d, J 8.7 Hz), 4.93 (1 H, d, J 9.0 Hz),
4.13 (2 H, q, J 7.1 Hz), 3.83 (3 H, s), 1.20 (3 H, t, J 7.1 Hz); δC (100
MHz; CDCl3) 168.6 (C), 166.0 (C), 162.5 (C), 129.7 (CH), 125.8
(CH), 122.0 (q, J 287.8 Hz, CF3), 114.2 (C), 93.0 (q, J 32.2 Hz, C),
61.4 (CH2), 56.3 (Me), 55.9 (CH), 13.8 (Me); δF (377 MHz; CDCl3)
−81.6 (s, CF3).
(152 mg, 0.60 mmol), and anhydrous dichloromethane (15 mL).
Once the solids had dissolved completely, triethylamine (173 μL,
1.24 mmol) and a solution of ethyl 2-(2-bromobenzamido)-4,4,4-tri-
fluoro-3,3-dihydroxybutanoate 2b (119.7 mg, 0.30 mmol) in dichloro-
methane (5 mL) were added. The mixture was allowed to stir under
argon overnight at room temperature and then concentrated in vacuo.
The product was purified by chromatography over silica using 20%
ethyl acetate in light petroleum to give the title compound 4b as
colorless solid (25.7 mg, 75%): mp 52−55 °C; (Found: M + H+,
363.9807. C13H979BrF3NO3 + H+ requires 363.9791); νmax (CHCl3)/
cm−1 3684, 3409, 2986, 2854, 1740, 1605, 1571, 1459, 1398, 1379,
1361, 1317, 1246, 1153, 1028; δH (400 MHz, CDCl3) 8.04 (1 H, d, J
8.0 Hz), 7.78 (1 H, d, J 8.0 Hz), 7.49 (1 H, t, J 8.0 Hz), 7.42 (1 H, t, J
8.0 Hz), 4.50 (2 H, q, J 7.2 Hz), 1.46 (3 H, t, J 7.2 Hz); δC (100 MHz;
CDCl3) 160.5 (C), 159.2 (C), 142.5 (q, J 44.0 Hz, C), 134.6 (CH),
133.2 (C), 133.1 (CH), 133.2 (CH), 127.5 (C), 126.3 (C), 121.7
(CH), 118.3 (q, J 269.0 Hz, CF3), 62.3 (CH2), 13.9 (Me); δF (377
MHz; CDCl3) −61.01 (s, CF3).
General Method B. Phosphoryl chloride (20 μL, 0.21 mmol) was
added to a solution of the ethyl 4-hydroxy-2-aryl-4-trifluoromethyl-4,5-
dihydrooxazole-5-carboxylate 3 (0.09 mmol) in DMF (300 μL) at
0 °C. The mixture was stirred at room temperature for 16 h, poured
into ice-water (1 mL), and then extracted with EtOAc (3 × 2 mL).
The organic layers were dried over MgSO4 and concentrated under
reduced pressure. The residue was purified over silica using 10% ethyl
acetate in light petroleum to give the ethyl 2-aryl-4-trifluoromethylox-
azole-5-carboxylate 5.
Ethyl 2-Phenyl-4-trifluoromethyloxazole-5-carboxylate 5a. Ac-
cording to General Method B, ethyl 4-hydroxy-2-phenyl-4-trifluor-
omethyl-4,5-dihydrooxazole-5-carboxylate 3a (28.5 mg, 0.09 mmol)
gave ethyl 2-phenyl-4-trifluoromethyloxazole-5-carboxylate 5a as a
colorless solid (19.5 mg, 73%): mp 44−47 °C (lit.,38 no data);
(Found: M + H+, 286.0687. C13H10F3NO3 + H+ requires 286.0686);
νmax (CHCl3)/cm−1 2987, 2929, 1739, 1609, 1560, 1488, 1451, 1398,
1379, 1362, 1329, 1315, 1276, 1151, 1037; δH (400 MHz, CDCl3) 8.17
(2 H, d, J 8.0 Hz), 7.50−7.60 (3 H, m), 4.48 (2 H, q, J 7.2 Hz), 1.44 (3
H, t, J 7.2 Hz); δC (100 MHz; CDCl3) 162.7 (C), 156.1 (C), 139.9
(C), 136.7 (q, J 44.0 Hz, C), 132.4 (CH), 129.2 (CH), 127.7 (CH),
125.2 (C), 119.8 (q, J 268.0 Hz, CF3), 62.7 (CH2), 14.0 (Me); δF (377
MHz; CDCl3) −61.84 (s, CF3).
Ethyl 2-(4-bromophenyl)-4-hydroxy-4-trifluoromethyl-4,5-dihy-
drooxazole-5-carboxylate 3d and Ethyl 2-(4-Bromobenzamido)-
4,4,4-trifluoro-3,3-dihydroxybutanoate 2d. According to General
Method A, ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate 1 (200 mg,
0.95 mmol), 4-bromobenzamide (252 mg, 1.26 mmol), and
rhodium(II) acetate (8.4 mg, 2 mol %) gave (i) ethyl 4-hydroxy-2-
(4-bromophenyl)-4-trifluoromethyl-4,5-dihydrooxazole-5-carboxylate
3d as a colorless solid (119 mg, 33%): mp 103−105 °C; (Found: M +
Na+, 403.9716. C13H1179BrF3NO4 + Na+ requires 403.9721); νmax
(CHCl3)/cm−1 3690, 3011, 1759, 1646, 1584, 1569, 1489, 1403, 1377,
1354, 1300, 1256, 1182, 1160; δH (400 MHz; (CD3)2SO) 8.18
(1 H, s), 7.90 (2 H, d, J 8.7 Hz), 7.80 (2 H, d, J 8.7 Hz), 5.50 (1 H, s),
4.22 (2 H, q, J 7.1 Hz), 1.22 (3 H, t, J 7.1 Hz); δC (126 MHz; CDCl3)
169.1 (C), 164.9 (C), 132.1 (CH), 131.0 (CH), 128.8 (C), 123.6 (C),
122.6 (q, J 284.8 Hz, CF3), 98.5 (q, J 33.0 Hz, C), 80.2 (CH), 62.4
(CH2), 14.0 (Me); δF (377 MHz; CDCl3) −81.9 (s, CF3). (ii) Ethyl 2-
(4-bromobenzamido)-4,4,4-trifluoro-3,3-dihydroxybutanoate 2d was
also given as a colorless crystalline solid (162 mg, 43%): mp 111−
114 °C; (Found: M + Na+, 421.9822. C13H1379BrF3NO5 + Na+ requires
421.9827); νmax (CHCl3)/cm−1 3690, 3568, 3011, 1740, 1716, 1645,
1593, 1568, 1516, 1480, 1398, 1341, 1314, 1258, 1145, 1070; δH (400
MHz; (CD3)2SO) 8.37 (1 H, d, J 9.0 Hz), 7.80 (2 H, d, J 8.7 Hz), 7.72 (2
H, d, J 8.7 Hz), 7.59 (1 H, s), 7.52 (1 H, s), 4.93 (1 H, d, J 9.0 Hz), 4.13
(2 H, q, J 7.1 Hz), 1.20 (3 H, t, J 7.1 Hz); δC (126 MHz; CDCl3) 169.1
(C), 167.6 (C), 132.1 (CH), 131.3 (C), 128.9 (CH), 127.5 (C), 122.0 (q,
J 287.8 Hz, CF3), 93.8 (q, J 32.2 Hz, C), 63.5 (CH2), 55.3 (CH), 13.8
(Me); δF (377 MHz; CDCl3) −81.6 (s, CF3).
Ethyl 2-(2-Bromophenyl)-4-trifluoromethyloxazole-5-carboxylate
5b. According to General Method B, ethyl 2-(2-bromophenyl)-4-
hydroxy-4-trifluoromethyl-4,5-dihydrooxazole-5-carboxylate 3b (36.1
mg, 0.09 mnmol) gave ethyl 2-(2-bromophenyl)-4-trifluoromethylox-
azole-5-carboxylate 5b as colorless solid (23.7 mg, 69%): mp 62−63
°C; (Found: M + H+, 363.9807. C13H979BrF3NO3 + H+ requires
363.9791); νmax (CHCl3)/cm−1 3689, 3606, 3053, 2988, 1737, 1602,
1549, 1523, 1472, 1455, 1398, 1382, 1322, 1296, 1255, 1175, 1157,
1012; δH (400 MHz, CDCl3) 8.06 (1 H, d, J 8.0 Hz), 7.78 (1 H, d, J
8.0 Hz), 7.39−7.52 (2 H, m), 4.50 (2 H, q, J 7.2 Hz), 1.46 (3 H, t, J
7.2 Hz); δC (126 MHz; CDCl3) 161.2 (C), 155.9 (C), 140.4 (C),
135.9 (q, J 41.0 Hz, C), 134.8 (CH), 133.2 (CH), 132.1 (CH), 127.6
(C), 126.4 (CH), 120.7 (C), 119.7 (q, J 268.0 Hz, CF3), 62.5 (CH2),
14.0 (Me); δF (377 MHz; CDCl3) −61.71 (s, CF3).
Conversion of 2 and 3 into Oxazoles 4 and 5. Ethyl 2-(2-
Bromophenyl)-5-trifluoromethyloxazole-4-carboxylate 4b. To a dry
flask were added triphenylphosphine (157 mg, 0.60 mmol), iodine
1400
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Ethyl 2-(4-Methoxyphenyl)-4-trifluoromethyloxazole-5-carboxy-
late 5c. According to General Method B, ethyl 4-hydroxy-2-(4-
methoxyphenyl)-4-trifluoromethyl-4,5-dihydrooxazole-5-carboxylate
3c (33 mg, 0.09 mmol) gave ethyl 2-(4-methoxyphenyl)-4-trifluo-
romethyloxazole-5-carboxylate 5c as a colorless solid (22 mg, 72%):
mp 104−106 °C; (Found: M + H+, 316.0813. C14H13F3NO4 + H+
requires 316.0791); νmax (CHCl3)/cm−1 3011, 2932 2842, 1738, 1613,
1564, 1500, 1464, 1442, 1425, 1397, 1378, 1361, 1322, 1258, 1150,
1079, 1036, 840; δH (400 MHz, CDCl3) 8.12 (2 H, d, J 9.2 Hz), 7.02
(2 H, d, J 9.2 Hz), 4.46 (2 H, q, J 7.2 Hz), 3.90 (3 H, s), 1.43 (3 H, t, J
7.2 Hz); δC (100 MHz; CDCl3) 162.8 (C), 156.2 (C), 139.4 (C),
136.5 (q, J 43.0 Hz, C), 133.4 (C), 129.2 (CH), 119.7 (q, J 268.0 Hz,
CF3), 117.6 (C), 114.5 (CH) 62.3 (CH2), 55.5 (Me), 14.0 (Me); δF
(377 MHz; CDCl3) −61.85 (s, CF3).
Ethyl 2-Phenyl-5-trifluoromethyloxazole-4-carboxylate 4a from
Benzonitrile. A solution of 2-diazo-4,4,4-trifluoro-3-oxobutanoate 1
(420 mg, 2.0 mmol) in benzonitrile (1.5 mL) was added dropwise
over a 6 h period to a stirred mixture of rhodium(II) acetate (44 mg,
5 mol %) and benzonitrile (1.5 mL) at 80 °C, and the stirring continued
at this temperature for 2 h. The solvent was evaporated under vacuum
and purified by chromatography using 10% ethyl acetate in petroleum
ether to give ethyl 2-phenyl-5-trifluoromethyloxazole-4-carboxylate
4a as a colorless solid (285 mg, 50%), data given in the previous
experiment.
Ethyl 2-(4-Bromophenyl)-4-trifluoromethyloxazole-5-carboxylate
5d. According to General Method B, ethyl 2-(4-bromophenyl)-4-
hydroxy-4-trifluoromethyl-4,5-dihydrooxazole-5-carboxylate 3d (36.1 mg,
0.09 mmol) gave ethyl 2-(4-bromophenyl)-4-trifluoromethyloxazole-
5-carboxylate 5d as a colorless solid (23.0 mg, 67%): mp 58−61 °C;
(Found: M + Na+, 385.9611. C13H979BrF3NO3 + Na+ requires 385.9616);
νmax (CHCl3)/cm−1 3687, 3012, 2415, 1737, 1603, 1544, 1479, 1407,
1382, 1323, 1306, 1288, 1176, 1158; δH (400 MHz; CDCl3) 8.06−8.02
(2 H, m), 7.69−7.66 (2 H, m), 4.48 (2 H, q, J 7.2 Hz), 1.44 (3 H, t,
J 7.2 Hz); δC (126 MHz; CDCl3) 161.8 (C), 156.0 (C), 140.1 (q, J 2.8
Hz, C), 136.7 (q, J 41.1 Hz, C), 132.5 (CH), 128.9 (CH), 127.4
(C), 124.1 (C), 119.6 (q, J 269.8 Hz, CF3), 62.6 (CH2), 14.0 (Me);
δF (377 MHz; CDCl3) −61.85 (s, CF3).
Ethyl 2-(2-Bromophenyl)-4-trifluoromethyloxazole-5-carboxylate
5b and Ethyl 2-(2-Bromophenyl)-5-trifluoromethyloxazole-4-car-
boxylate 4b. According to General Method C, 2-bromobenzamide
(64 mg, 0.32 mmol), ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate 1
(73 mg, 0.35 mmol), and rhodium(II) acetate (3.1 mg, 2 mol %) gave
(i) ethyl 2-(2-bromophenyl)-4-trifluoromethyloxazole-5-carboxylate
5b as colorless solid (40 mg, 35%), data given above, and (ii) ethyl
2-(2-bromophenyl)-5-trifluoromethyloxazole-4-carboxylate 4b as a
colorless solid (16 mg, 14%), data given above.
Direct Preparation of Oxazoles 4 and 5. General Method C. To
a solution of the benzamide (0.32 mmol) and ethyl 2-diazo-4,4,4-
trifluoro-3-oxobutanoate 1 (73 mg, 0.35 mmol) in dichloromethane (1
mL) was added rhodium(II) acetate (3.1 mg, 2 mol %). The reaction
vessel was sealed and heated in a microwave reactor to 80 °C for 15
min. The solution was cooled to room temperature, and phosphorus
oxychloride (98 mg, 60 μL, 0.64 mmol) was added. The reaction
mixture was resealed and heated in a microwave reactor to 105 °C for
20 min. The solution was again cooled to room temperature, and
Amberlyst 15 (100 mg) was added. The reaction vessel was resealed
and heated in a microwave reactor at 105 °C for 15 min. The solution
was cooled to room temperature and filtered, and the filtrate was
concentrated under reduced pressure. The residue was purified over
silica using a solvent system of 10−20% ethyl acetate in light
petroleum to give (i) the ethyl 2-aryl-4-trifluoromethyloxazole-5-
carboxylate 5 and (ii) the ethyl 2-aryl-5-trifluoromethyloxazole-4-
carboxylate 4.
Ethyl 2-(4-Methoxyphenyl)-4-trifluoromethyloxazole-5-carboxy-
late 5c and Ethyl 2-(4-Methoxyphenyl)-5-trifluoromethyloxazole-
4-carboxylate 4c. According to General Method C, 4-methoxybenza-
mide (48 mg, 0.32 mmol), ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate
1 (73 mg, 0.35 mmol), and rhodium(II) acetate (3.1 mg, 2 mol %)
gave (i) ethyl 2-(4-methoxyphenyl)-4-trifluoromethyloxazole-5-car-
boxylate 5c as a colorless solid (33 mg, 33%), data given above, and
(ii) ethyl 2-(4-methoxyphenyl)-5-trifluoromethyloxazole-4-carboxylate
4c as a colorless solid (28 mg, 28%): mp 53−55 °C; (Found: M + H+,
316.0813. C14H13F3NO4 + H+ requires 316.0791); νmax (CHCl3)/cm−1
2986, 2931 2842, 1734, 1612, 1558, 1495, 1465, 1442, 1426, 1397,
1381, 1362, 1326, 1309, 1036; δH (400 MHz, CDCl3) 8.10 (2 H, d, J
8.8 Hz), 7.02 (2 H, d, J 8.8 Hz), 4.46 (2 H, q, J 7.2 Hz), 3.90 (3 H, s),
1.43 (3 H, t, J 7.2 Hz); δC (126 MHz; CDCl3) 162.8 (C), 162.0 (C),
159.5 (C), 141.4 (q, J 41.1 Hz, C), 133.4 (CH), 129.4 (CH), 120.3 (q,
J 269.9 Hz, CF3), 117.6 (C), 114.7 (CH), 62.3 (CH2), 55.5 (Me), 13.9
(Me); δF (377 MHz; CDCl3) −60.84 (s, CF3).
Ethyl 2-Phenyl-4-trifluoromethyloxazole-5-carboxylate 5a and
Ethyl 2-Phenyl-5-trifluoromethyloxazole-4-carboxylate 4a. Accord-
ing to General Method C, benzamide (38 mg, 0.32 mmol), ethyl 2-
diazo-4,4,4-trifluoro-3-oxobutanoate 1 (73 mg, 0.35 mmol), and
rhodium(II) acetate (3.1 mg, 2 mol %) gave (i) ethyl 2-phenyl-4-
trifluoromethyloxazole-5-carboxylate 5a as a colorless solid (27 mg,
30%), data given above, and (ii) ethyl 2-phenyl-5-trifluoromethyloxazole-
4-carboxylate 4a as a colorless solid (16 mg, 13%): mp 59−61 °C; (lit.,23
mp 57−58 °C); (Found: M + H+, 286.0687. C13H10F3NO3 + H+ requires
286.0686); νmax (CHCl3)/cm−1 3011, 2929, 1735, 1608, 1549, 1486,
1450, 1399, 1382, 1363, 1329, 1315, 1299, 1177, 1157, 1013; δH (400
MHz, CDCl3) 8.17 (2 H, d, J 8.0 Hz), 7.51−7.61 (3 H, m), 4.49 (2 H, q,
J 7.2 Hz), 1.45 (3 H, t, J 7.2 Hz); δC (100 MHz; CDCl3) 161.8 (C), 159.4
(C), 141.8 (q, J 41.1 Hz, C), 133.5 (CH), 132.2 (CH), 129.0 (CH), 127.4
(C), 125.9 (C), 118.3 (q, J 267.0 Hz, CF3), 62.3 (CH2), 13.9 (Me); δF
(377 MHz; CDCl3) −60.93 (s, CF3).
Ethyl 2-(4-Bromophenyl)-4-trifluoromethyloxazole-5-carboxylate
5d and Ethyl 2-(4-Bromophenyl)-5-trifluoromethyloxazole-4-car-
boxylate 4d. According to General Method C, 4-bromobenzamide
(63 mg, 0.32 mmol), ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate 1
(73 mg, 0.35 mmol), and rhodium(II) acetate (3.1 mg, 2 mol %) gave
(i) ethyl 2-(4-bromophenyl)-4-trifluoromethyloxazole-5-carboxylate
5d as a colorless solid (36 mg, 31%), data given above, and (ii)
ethyl 2-(4-bromophenyl)-5-trifluoromethyloxazole-4-carboxylate 4d as
a colorless solid (26 mg, 23%): mp 47−49 °C; (Found: M + Na+,
385.9611. C13H9BrF3NO3 + Na+ requires 385.9616); νmax (CHCl3)/
cm−1 3691, 3606, 3011, 2928, 2855, 2360, 1740, 1603, 1571, 1459,
1398, 1379, 1361, 1317, 1239, 1153, 1047, 1027; δH (400 MHz,
CDCl3) 8.04 (2 H, d, J 8.0 Hz), 7.68 (2 H, d, J 8.0 Hz), 4.49 (2 H, q, J
7.2 Hz), 1.44 (3 H, t, J 7.2 Hz); δC (100 MHz; CDCl3) 161.0 (C),
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159.2 (C), 141.8 (q, J 41.1 Hz, C), 133.6 (C), 132.4 (CH), 128.7
(CH), 127.2 (C), 123.9 (C), 118.3 (q, J 269.9 Hz, CF3), 62.3 (CH2),
13.9 (Me); δF (377 MHz; CDCl3) −60.91 (s, CF3).
The reaction vessel was allowed to cool to room temperature, and
DBU (100 mg, 0.66 mmol) was added. The reaction mixture was
resealed and stirred at room temperature for 20 min. The solvent was
removed under reduced pressure, and the residue was purified over
silica using a solvent system of 15% diethyl ether in light petroleum to
give the ethyl 2-aryl-4-trifluoromethylthiazole-5-carboxylate 7.
Imidazoles. Ethyl 2-Phenyl-5-trifluoromethyl-1H-imidazole-4-
carboxylate 6a. Ethyl 2-benzamido-4,4,4-trifluoro-3,3-dihydroxy-
butanoate 2a (120 mg, 0.51 mmol), ammonium acetate (51 mg,
0.70 mmol), and glacial acetic acid (180 μL) were dissolved in toluene
(4.5 mL), and the solution was heated under reflux for 3 h. The
mixture was cooled, washed with brine (3 mL), dried (MgSO4), and
concentrated in vacuo, and the residue was purified over silica using a
solvent system of 30% ethyl acetate in light petroleum to yield the title
compound 6a as a colorless solid (61 mg, 42%): mp 168−171 °C;
(Found: M + Na+, 307.0659. C13H11F3N2O2 + Na+ requires
307.0665); νmax (CHCl3)/cm−1 3418, 3011, 1703, 1602, 1581, 1535,
1478, 1437, 1415, 1368, 1285, 1264, 1174, 1146, 1050; δH (400 MHz;
CDCl3) 14.06 (1 H, br), 8.14 (2 H, d, J 7.8 Hz), 7.50−7.52 (3 H, m),
4.34 (2 H, q, J 7.2 Hz), 1.33 (3 H, t, J 7.2 Hz); δC (126 MHz; CDCl3)
158.4 (C), 148.3 (C), 134.1−135.2 (m, C), 130.5 (CH), 129.3 (CH),
128.7 (CH), 127.0 (C), 122.8 (C), 121.5 (q, J 272.8 Hz, CF3), 61.8
(CH2), 14.3 (Me); δF (377 MHz; CDCl3) −59.45 (s, CF3).
Ethyl 2-Phenyl-4-trifluoromethylthiazole-5-carboxylate 7a. Ac-
cording to General Method D, thiobenzamide (30 mg, 0.22 mmol),
ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate 1 (51 mg, 0.24 mmol),
and rhodium(II) heptafluorobutyramide (5.0 mg, 2 mol %) gave the
title compound 7a as a colorless solid (43 mg, 64%): mp 109−111 °C
(lit.,39 no data); (Found: M + Na+, 324.0274. C13H10F3NO2S + Na+
requires 324.0282); νmax (CHCl3)/cm−1 3689, 3012, 1733, 1602, 1531,
1458, 1432, 1372, 1355, 1302, 1271, 1170; δH (400 MHz; CDCl3)
8.02−7.99 (2 H, m), 7.56−7.47 (3 H, m), 4.43 (2 H, q, J 7.2 Hz), 1.42
(3 H, t, J 7.2 Hz); δC (126 MHz; CDCl3) 170.6 (C), 159.1 (C), 146.8
(q, J 37.9 Hz, C), 131.9 (CH), 131.8 (C), 129.4 (C), 129.2 (CH),
126.9 (CH), 119.8 (q, J 272.8 Hz, CF3), 62.6 (CH2), 14.0 (Me); δF
(377 MHz; CDCl3) −60.97 (s, CF3).
Ethyl 2-(4-Bromophenyl)-4-trifluoromethylthiazole-5-carboxy-
late 7b. According to General Method D, 4-bromothiobenzamide
(60 mg, 0.28 mmol), ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate 1
(70 mg, 0.34 mmol), and rhodium(II) heptafluorobutyramide (7.2 mg,
2 mol %) gave the title compound 7b as a colorless solid (67 mg,
63%): mp 94−96 °C; (Found: M + Na+, 401.9383. C13H979BrF3NO2S
+ Na+ requires 401.9387); νmax (CHCl3)/cm−1 3011, 1735, 1591,
1533, 1443, 1396, 1371, 1299, 1271, 1240, 1169, 1091, 1073, 1013; δH
(400 MHz; CDCl3) 7.88−7.85 (2 H, m), 7.65−7.62 (2 H, m), 4.43 (2
H, q, J 7.2 Hz), 1.42 (3 H, t, J 7.2 Hz); δC (126 MHz; CDCl3) 169.2
(C), 158.9 (C), 146.9 (q, J 38.0 Hz, C), 132.5 (CH), 130.7 (C),
129.8−129.8 (m, C), 128.3 (CH), 126.5 (C), 119.7 (q, J 272.8 Hz,
CF3), 62.7 (CH2), 14.0 (Me); δF (377 MHz; CDCl3) −60.98 (s, CF3).
Ethyl 2-(4-Methoxyphenyl)-5-trifluoromethyl-1H-imidazole-4-
carboxylate 6b. Ethyl 2-(4-methoxybenzamido)-4,4,4-trifluoro-3,3-
dihydroxybutanoate 2c (63 mg, 0.19 mmol), ammonium acetate
(22 mg, 0.29 mmol), and glacial acetic acid (86 μL) were dissolved in
toluene (2.2 mL), and the solution was heated under reflux for 2 h.
Work up as for compound 6a gave the title compound 6b as a color-
less solid (27 mg, 45%): mp 175−177 °C; (Found: M + H+, 315.0938.
C14H14F3N2O3 + H+ requires 315.0951); νmax (CHCl3)/cm−1 3419,
2989, 1704, 1602, 1581, 1535, 1478, 1437, 1415, 1368, 1285, 1264,
1174, 1146, 1050; δH (400 MHz; CDCl3) 13.86 (1H, br), 8.09 (2 H, d,
J 8.0 Hz), 7.07 (2 H, d, J 8.0 Hz), 4.36 (2 H, q, J 7.2 Hz), 3.82 (3 H, s),
1.33 (3 H, t, J 7.2 Hz); δC (126 MHz; CDCl3) 161.1 (C), 158.4 (C),
148.4 (C), 134.0−135.0 (m, C), 129.3 (CH), 126.9 (C), 122.2 (C),
121.5 (q, J 272.8 Hz, CF3), 114.7 (CH), 61.7 (CH2), 55.8 (Me), 14.3
(Me); δF (377 MHz; CDCl3) −59.41 (s, CF3).
Ethyl 4-Trifluoromethyl-2-(4-(trifluoromethyl)phenyl)thiazole-5-
carboxylate 7c. According to General Method D, 4-trifluoromethy-
thiobenzamide (60 mg, 0.29 mmol), ethyl 2-diazo-4,4,4-trifluoro-3-
oxobutanoate 1 (74 mg, 0.31 mmol), and rhodium(II) heptafluor-
obutyramide (6.5 mg, 2 mol %) gave the title compound 7c as a
colorless solid (70 mg, 65%): mp 80−82 °C (lit.,40 no data); (Found:
M + Na+, 392.0149. C14H9F6NO2S + Na+ requires 392.0156); νmax
(CHCl3)/cm−1 3012, 1736, 1523, 1447, 1409, 1372, 1325, 1302, 1272,
1172, 1112, 1091, 1069, 1018; δH (400 MHz; CDCl3) 8.12 (2 H, d, J
8.0 Hz), 7.76 (2 H, d, J 8.0 Hz), 4.45 (2 H, q, J 7.2 Hz), 1.43 (3 H, t, J
7.2 Hz); δC (126 MHz; CDCl3) 168.4 (C), 158.8 (C), 147.1 (q, J 38.1
Hz, C), 134.8 (C), 133.3 (q, J 33.0 Hz, C), 130.7−130.7 (m, C), 127.2
(CH), 126.3 (q, J 3.6 Hz, CH), 123.5 (q, J 272.5 Hz, CF3), 119.7 (q, J
272.9 Hz, CF3), 62.9 (CH2), 14.0 (Me); δF (376 MHz; CDCl3) −60.99
(s, CF3), −63.08 (s, CF3).
Ethyl 2-(4-Bromophenyl)-5-trifluoromethyl-1H-imidazole-4-car-
boxylate 6c. Ethyl 2-(4-bromobenzamido)-4,4,4-trifluoro-3,3-dihy-
droxybutanoate 2d (150 mg, 0.54 mmol), ammonium acetate (54
mg, 0.70 mmol), and glacial acetic acid (210 μL) were dissolved in
toluene (5.3 mL), and the solution was heated under reflux for 2 h.
Work up as for compound 6a gave the title compound 6c as a colorless
solid (78 mg, 40%), mp 184−186 °C; (Found: M + H+, 362.9950.
C13H1179BrF3N2O2 + H+ requires 362.9951); νmax (CHCl3)/cm−1
3420, 3012, 1704, 1601, 1581, 1535, 1478, 1437, 1415, 1368, 1285,
1265, 1174, 1146, 1071, 1050; δH (400 MHz; CDCl3) 14.18 (1H, br),
8.09 (2 H, d, J 8.0 Hz), 7.73 (2 H, d, J 8.0 Hz), 4.37 (2 H, q, J 7.2 Hz),
1.33 (3 H, t, J 7.2 Hz); δC (126 MHz; CDCl3) 158.3 (C), 147.3 (C),
133.8−135.1 (m, C), 132.3 (CH), 128.9 (CH), 128.4 (C), 128.1 (C),
124.0 (C), 123.2 (C), 121.5 (q, J 272.8 Hz, CF3), 61.8 (CH2), 14.3
(Me); δF (377 MHz; CDCl3) −59.49 (s, CF3).
Thiazoles. General Method D. To the thiobenzamide (0.22
mmol) and ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate 1 (51 mg, 0.24
mmol) in 1,2-dichloroethane (1 mL) was added rhodium(II)
heptafluorobutyramide (5.0 mg, 2 mol %). The reaction vessel
was sealed and heated in a microwave reactor to 125 °C for 30 min.
Ethyl 2-(Quinolin-2-yl)-4-trifluoromethylthiazole-5-carboxylate
7d. According to General Method D, quinoline-2-thiocarboxamide
(52.6 mg, 0.28 mmol), ethyl 2-diazo-4,4,4-trifluoro-3-oxobutanoate 1
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(70 mg, 0.34 mmol), and rhodium(II) heptafluorobutyramide (7.2 mg,
2 mol %) gave the title compound 7d as a colorless solid (67 mg, 68%):
mp 143−147 °C; (Found: M + H+, 353.0578. C16H12F3N2O2S + H+
requires 353.0566); νmax (CHCl3)/cm−1 2987, 1735, 1594, 1484, 1409,
1372, 1352, 1302, 1298, 1260, 1171, 1152, 1092, 1013; δH (400 MHz;
CDCl3) 8.39 (1 H, d, J 8.0 Hz), 8.33 (1 H, d, J 8.0 Hz), 8.16 (1 H, d, J 8.0
Hz), 7.90 (1 H, d, J 8.0 Hz), 7.81 (1 H, t, J 8.0 Hz), 7.65 (1 H, t, J 8.0
Hz), 4.45 (2 H, q, J 7.2 Hz); 1.43 (3 H, t, J 7.2 Hz); δC (126 MHz;
CDCl3) 171.7 (C), 159.2 (C), 149.6 (C), 147.7 (C), 146.7 (q, J 38.1 Hz,
C), 137.4 (CH), 132.1 (CH), 130.5 (CH), 129.6 (C), 129.2 (C), 128.0
(CH), 127.8 (CH), 120.5 (q, J 272.5 Hz, CF3), 117.5 (CH), 62.9 (CH2),
14.0 (Me); δF (376 MHz; CDCl3) −61.11 (s, CF3).
purified over silica using 10% ethyl acetate in light petroleum to give
the ethyl 3-aryl-5-trifluoromethyl-1,2,4-triazine-6-carboxylate 10.
Ethyl 3-Phenyl-5-trifluoromethyl-1,2,4-triazine-6-carboxylate
10a. According to General Method E, ethyl 2-diazo-4,4,4-trifluoro-3-
oxobutanoate 1 (108 mg, 0.51 mmol), benzhydrazide (100 mg, 0.73
mmol), and anhydrous copper(II) acetate (2.8 mg, 3 mol %) gave the title
compound 10a as a yellow solid (45 mg, 28%): mp 114−116 °C (lit.,41
no data); (Found: M + Na+, 320.0614. C13H10F3N3O2 + Na+ requires
320.0622); νmax (CHCl3)/cm−1 3066, 1746, 1602, 1537, 1474, 1406, 1395,
1316, 1286, 1174, 1081; δH (400 MHz; CDCl3) 8.67−8.64 (2 H, m),
7.69−7.59 (3 H, m), 4.60 (2 H, t, J 7.2 Hz), 1.49 (3 H, q, J 7.2 Hz); δC (126
MHz; CDCl3) 163.9 (C), 162.3 (C), 147.0 (C), 145.9 (q, J 38.8 Hz, C),
133.6 (CH), 132.5 (C), 129.3 (CH), 129.3 (CH), 119.8 (q, J 276.9, CF3),
63.7 (CH2), 13.9 (Me); δF (377 MHz; CDCl3) −67.12 (s, CF3).
Ethyl 4-Hydroxy-2-phenyl-4-trifluoromethyl-4,5-dihydrothiazole-
5-carboxylate 8. To thiobenzamide (30 mg, 0.22 mmol) and ethyl 2-
diazo-4,4,4-trifluoro-3-oxobutanoate 1 (51 mg, 0.24 mmol) in 1,2-
dichloroethane (1 mL) was added rhodium(II) heptafluorobutyramide
(5.1 mg, 2 mol %). The reaction vessel was sealed and heated in a
microwave reactor to 125 °C for 30 min. The reaction vessel was
allowed to cool to room temperature, and the solvent was removed
under reduced pressure. The residue was purified over silica using a
solvent system of 8% ethyl acetate in light petroleum. The title
compound 8 was isolated as a colorless solid (38 mg, 54%): mp 109−
111 °C; (Found: M + Na+, 342.0377. C13H12F3NO3S + Na+ requires
342.0388); νmax (CHCl3)/cm−1 3566, 3011, 2360, 1740, 1606, 1578,
1493, 1449, 1372, 1312, 1192, 1138; δH (400 MHz; CDCl3) 7.91−
7.88 (2 H, m), 7.60−7.55 (1 H, m), 7.48−7.44 (2 H, m), 4.84 (1 H, s),
4.72 (1 H, s), 4.38−4.26 (2 H, m), 1.34 (3 H, t, J 7.2 Hz); δC
(126 MHz; CDCl3) 174.8 (C), 167.8 (C), 133.1 (CH), 131.0 (C),
128.9 (CH), 128.8 (CH), 123.0 (q, J 286.3 Hz, CF3), 106.4 (q, J 31.1
Hz, C), 63.0 (CH2), 53.1 (CH), 13.9 (Me); δF (377 MHz; CDCl3) −83.08
(s, CF3).
Ethyl 3-(3-Methoxyphenyl)-5-trifluoromethyl-1,2,4-triazine-6-car-
boxylate 10b. According to General Method E, ethyl 2-diazo-4,4,4-
trifluoro-3-oxobutanoate 1 (108 mg, 0.51 mmol), 3-methoxybenzhy-
drazide (121 mg, 0.75 mmol), and anhydrous copper(II) acetate
(2.8 mg, 3 mol %) gave the title compound 10b as a yellow solid
(57 mg, 35%): mp 78−82 °C; (Found: M + Na+, 350.0731.
C14H12F3N3O3 + Na+ requires 350.0723); νmax (CHCl3)/cm−1 3682,
3011, 1746, 1601, 1533, 1494, 1458, 1406, 1393, 1374, 1287, 1174,
1080; δH (400 MHz; CDCl3) 8.25 (1 H, d, J 8.0 Hz), 8.18 (1 H, s),
7.52 (1 H, t, J 8.0 Hz), 7.22 (1 H, d, J 8.0 Hz), 4.60 (2 H, q, J 7.2 Hz),
3.96 (3 H, s), 1.50 (3 H, t, J 7.2 Hz); δC (100 MHz; CDCl3) 163.7 (C),
162.2 (C), 160.3 (C), 147.1 (C), 146.1 (q, J 38.0 Hz, C), 133.8 (C),
130.3 (CH), 123.9 (CH), 121.8 (CH), 120.1 (CH), 119.6 (q, J 275.0,
CF3), 113.5 (CH), 63.7 (CH2), 55.5 (Me), 13.9 (Me); δF (377 MHz;
CDCl3) −67.11 (s, CF3).
Ethyl 2-(4-Bromophenyl)-5-trifluoromethylthiazole-4-carboxy-
late 9. A solution of ethyl 2-(4-bromobenzamido)-4,4,4-trifluoro-3,3-
dihydroxybutanoate 2d (150 mg, 0.46 mmol) and Lawesson’s reagent
(282 mg, 0.70 mmol) in dry THF (2.5 mL) was heated to reflux for
4 h. The reaction mixture was then evaporated in vacuo, and the residue
was purified over silica gel eluting with ethyl acetate−light petroleum
(3:7) to yield the title compound 9 as a colorless solid (78 mg, 45%):
mp 108−110 °C; (Found: M + Na+, 401.9383. C13H979BrF3NO2S +
Na+ requires 401.9387); νmax (CHCl3)/cm−1 3007, 2941 1734, 1590,
1569, 1454, 1335, 1288, 1248, 1165, 1072, 1031; δH (400 MHz; CDCl3)
7.88 (2 H, d, J 8.0 Hz), 7.65 (2 H, d, J 8.0 Hz), 4.50 (2 H, q, J 7.2 Hz),
1.45 (3 H, t, J 7.2 Hz); δC (126 MHz; CDCl3) 167.5 (C), 160.0 (C),
146.6 (C), 132.5 (CH), 130.6 (q, J 3.6 Hz, CH), 130.5 (C), 128.4
(CH), 126.4 (C), 121.0 (q, J 272.8 Hz, CF3), 62.5 (CH2), 13.9 (Me); δF
(377 MHz; CDCl3) −52.47 (s, CF3).
1,2,4-Triazines. General Method E. To ethyl 2-diazo-4,4,4-
trifluoro-3-oxobutanoate 1 (108 mg, 0.51 mmol) and the benzhy-
drazide (0.73 mmol) in dichloromethane (1 mL) was added
anhydrous copper(II) acetate (2.8 mg, 3 mol %). The reaction vessel
was sealed and heated in a microwave reactor to 80 °C for 10 min. The
solvent was removed under reduced pressure, and acetic acid (0.5 mL)
was added. To the acetic acid solution was added ammonium acetate
(198 mg, 2.57 mmol), and the reaction mixture was heated in a
microwave reactor to 110 °C for 5 min. The reaction mixture was
allowed to cool to room temperature and was neutralized with
saturated sodium hydrogen carbonate solution (5 mL). The organic
material was extracted with ethyl acetate (3 × 10 mL), washed with
brine (10 mL), and dried over MgSO4. The mixture was filtered, and
the filtrate was concentrated under reduced pressure. The residue was
Ethyl 3-(4-Bromophenyl)-5-trifluoromethyl-1,2,4-triazine-6-car-
boxylate 10c. According to General Method E, ethyl 2-diazo-4,4,4-
trifluoro-3-oxobutanoate 1 (108 mg, 0.51 mmol), 4-bromobenzohy-
drazide (155 mg, 0.75 mmol), and anhydrous copper(II) acetate
(2.8 mg, 3 mol %) gave the title compound 10c as a yellow solid
(59 mg, 31%): mp 88−93 °C; (Found: M + Na+, 397.9710.
C13H979BrF3N3O2 + Na+ requires 397.9722); νmax (CHCl3)/cm−1
3691, 2988, 1746, 1592, 1534, 1446, 1412, 1391, 1303, 1288, 1175,
1076; δH (400 MHz; CDCl3) 8.53 (2 H, d, J 8.0 Hz), 7.77 (2 H, d, J
8.0 Hz), 4.60 (2 H, q, J 7.2 Hz), 1.49 (3 H, t, J 7.2 Hz); δC (100 MHz;
CDCl3) 163.2 (C), 162.1 (C), 147.2 (C), 146.1 (q, J 39.0 Hz, C),
132.7 (CH), 131.4 (C), 130.6 (CH), 128.9 (C), 119.5 (q, J 275.0,
CF3), 63.7 (CH2), 13.9 (Me); δF (377 MHz; CDCl3) −67.09 (s, CF3).
Pyridines. General Method F. The ethyl 3-aryl-5-trifluoromethyl-
1,2,4-triazine-6-carboxylate 10 (0.044 mmol) was dissolved in
chlorobenzene (0.5 mL), and norbornadiene (40.0 mg, 0.437 mmol,
44.5 μL) was added. The reaction vessel was sealed and heated to
131 °C for 5 h. The reaction mixture was allowed to cool to room
temperature, and the solvent was removed under reduced pressure.
The residue was purified over silica using a solvent system of 10%
ethyl acetate in light petroleum to give the ethyl 6-aryl-2-
trifluoromethylnicotinate 11.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: c.j.moody@nottingham.ac.uk.
ACKNOWLEDGMENTS
Ethyl 6-Phenyl-2-trifluoromethylnicotinate 11a. According to
General Method F, ethyl 3-phenyl-5-trifluoromethyl-1,2,4-triazine-6-
carboxylate 10a (13.0 mg, 0.044 mmol) and norbornadiene (40.0 mg,
0.437 mmol, 44.5 μL) gave the title compound 11a as a colorless
solid (11.5 mg, 89%): mp 32−35 °C; (Found: M + Na+, 318.0707.
C15H12F3NO2 + Na+ requires 318.0718); νmax (CHCl3)/cm−1 2987, 1729,
1595, 1462, 1451, 1397, 1370, 1223, 1302, 1283, 1192, 1154, 1074, 1057,
1015; δH (400 MHz; CDCl3) 8.19 (1 H, d, J 8.3 Hz), 8.13−8.10 (2 H,
m), 7.98 (1 H, d, J 8.3 Hz), 7.55−7.48 (3 H, m), 4.45 (2 H, q, J 7.2 Hz),
1.43 (3 H, t, J 7.2 Hz); δC (126 MHz; CDCl3) 165.6 (C), 158.4 (C),
145.6 (q, J 35.2 Hz, C), 139.4 (CH), 136.8 (C), 130.5 (CH),
129.0 (CH), 127.3 (CH), 125.8 (C), 121.8 (CH), 120.9 (q, J 275.4
Hz, CF3), 62.5 (CH2), 13.9 (Me); δF (377 MHz; CDCl3) −64.38
(s, CF3).
■
We thank the EPSRC and GlaxoSmithKline for support of this
work under the Array Chemistry Programme (Ph.D. student-
ship to M.A.H.).
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1594, 1495, 1466, 1393, 1369, 1292, 1192, 1153, 1074, 1057, 1015; δH
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for all compounds, X-ray
figures (ORTEP), and X-ray CIF files. This material is available
free of charge via the Internet at http://pubs.acs.org.
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