Elemental tellurium mediated synthesis of 2-(trifluoromethyl)oxazoles using trifluoroacetic anhydride as reagent

Article abstract of DOI:10.1039/C8CC05670F

An elemental tellurium mediated synthesis of 2-(trifluoromethyl)oxazoles from the reaction of acetophenone oxime acetates with trifluoroacetic anhydride has been developed. This new tandem cyclization proceeds in good to excellent yields via a SET reduction followed by a 5-endo-trig pathway. Some of the title compounds showed fungicidal and insecticidal activities.

Full text of DOI:10.1039/C8CC05670F

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Elemental tellurium mediated synthesis 2-
(trifluoromethyl)oxazoles using trifluoroacetic anhydride as
reagent
Received 00th January 20xx,
Accepted 00th January 20xx
Beibei Luo, and Zhiqiang Weng*
DOI: 10.1039/x0xx00000x
www.rsc.org/
An elemental tellurium mediated synthesis of 2- convenient for product diversification. These procedures also
(trifluoromethyl)oxazoles from the reaction of acetophenone revealed some drawbacks such as limited availability of the
oxime acetates with trifluoroacetic anhydride has been developed. starting materials, or multistep reaction processes.
This new tandem cyclization proceeds in good to excellent yields
via a SET reduction followed by a 5-endo-trig pathway. Some of
the title compounds showed fungicidal and insecticidal activities.
The oxazole scaffold is a prominent and privileged chemical
entity that is found in a wide variety of natural products and
synthetic biologically active compounds.1-3 In fact, molecules
derived from oxazole exhibit excellent pharmacological
properties such as COX-2 inhibitory activity,4 antiinflammatory
7
activity,5 anticancer activity,6,
antidiabetic activity,8 and
antifungal activity9, 10 (Figure 1). Therefore, there is continuing
interest in the development of more general and versatile
synthetic methodologies for the construction and chemical
modification of oxazoles.11-13
Figure 1. Examples of biologically relevant oxazoles.
On the other hand, introduction of the trifluoromethyl (-CF3)
group onto heterocyclic rings often gives rise to significant
changes in the chemical and physical properties of a potential
drug candidate due to displaying increased bioavailability,
membrane and metabolic stability, etc.14-19 Therefore, the
development of efficient methods for the construction of 2-
trifluoromethylated oxazoles and their derivatives would be of
particular interest as the effect of trifluoromethyl introduction
on this motif.
In this context, several methods have been introduced in
recent years for the preparation of 2-(trifluoromethyl)oxazoles,
often based on multiple steps through trifluoroacetamide20-24
(Scheme 1a) or trifluoroacetate25-27 (Scheme 1b) intermediates
followed by coupling or cyclization, or rearrangement
reaction.28, 29 Although these previous contributions represent
important developments, these approaches are not
Scheme 1. Strategies for the preparation of 2-
(trifluoromethyl)oxazoles.
State Key Laboratory of Photocatalysis on Energy and Environment, College of
Chemistry, Fuzhou University, Fuzhou, 350108, China.
E-mail: zweng@fzu.edu.cn; Fax: +86 591 22866121; Tel: +86 591 22866121
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: CCDC 1835965. For ESI and
Tellurium is mainly used in metallurgy, electronics, chemical
industry, and glass. There are very rare examples of organic
synthesis that are mediated by elemental tellurium or
crystallographic
data
in
CIF
or
other
electronic
format
See
DOI: 10.1039/x0xx00000x
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organotellurium reagent.30-32 On the other hand, oxime In the absence of a promoter, complete recovery of the
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DOI: 10.1039/C8CC05670F
acetates have emerged as readily accessible and versatile starting material was observed after 4 hours at 120 C (entry
building blocks for the synthesis of nitrogen-containing 1). It was recognized that oxygen, sulfur, as well as selenium
heterocyclic compounds catalyzed by copper,33-38 cobalt,39 and do not show reactivity at 120

C (entries 2 4), whereas at the

iron complexes.40 Recognizing the semimetallic character of same temperature, tellurium do mediate the desired reaction
tellurium, we envisioned that tellurium could be utilized as a (entry 5). Since the addition of molecular iodine could promote
single electron transfer (SET) reagent to generate iminium oxidative cyclization reaction,45-47 0.20 equiv of I2 was used as
radical from oxime acetates, which subsequently may undergo additive for the reaction. Gratifyingly, the desired product 4-
cyclization to afford 2-(trifluoromethyl)oxazole products phenyl-2-(trifluoromethyl)oxazole 3a was generated in 98%
(Scheme 1c). We were interested in developing an efficient NMR yield (entry 6). The reaction could not be performed with
method for synthesis of trifluoromethylated heterocyclic I2 alone, thus implying that tellurium was essential (entry 7).
compounds that utilised only readily available and inexpensive The essential role of tellurium combining with iodine for the
fluorinating reagents.41-44 Here, we report a new method for reaction was further verified by lowering Te loading to 0.2
the synthesis of 2-(trifluoromethyl)oxazoles through elemental equiv or increasing I2 loading to 1 equiv and observing a
tellurium mediated reaction of oxime acetates with significant decrease in the yield of 3a (75% and 32% yield;
trifluoroacetic anhydride.
entries 8 and 9, respectively). Transition-metal catalysts were
also examined, and it was found that CuI, Ni(COD)2, Pd(PPh3)4,
and Zn were ineffective for this reaction (entries 10–13). A
solvent screen was then carried out and low conversions were
observed in diglyme, dioxane, DMSO, and DMF (entries 14–17).
Interestingly, product 3a was formed in slightly lower yield
when the reaction was carried out under an air atmosphere
(entry 18). It was also found a significant decrease in reactivity
Table 1. Optimization of the reaction conditions a
when the reaction temperature was reduced to 100
19).
C (entry
Entry Promoter (equiv)
Solvent
Tem. (°C) Yield (%) b
Additive (equiv)
Under the optimized reaction conditions, the scope and
limitation of the cyclization of oxime acetates with
trifluoroacetic anhydride were investigated (Table 2).
Acetophenone oxime acetate derivatives bearing electron-
donating groups such as methyl, tert-butyl, iso-butyl, methoxy,
and methylmercapto underwent successful cyclization in good


Toluene 120
Toluene 120
Toluene 120
Toluene 120
Toluene 120
Toluene 120
Toluene 120
Toluene 120
Toluene 120
Toluene 120
Toluene 120
Toluene 120
Toluene 120
Diglyme 120
Dioxane 120
0
1
2
O2

0
S8 (1)

0
3
Se (1)
Te (1)
Te (1)


2
4

38
98
1
5
to excellent yield (3b–3h, 62–98%). Moreover, product 3a was
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (1)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
6
isolated in 71% yield (1.52 g) upon performing the reaction on
a 10.0 mmol scale. Acetophenone oxime acetate derivatives
containing electron-withdrawing substituents including ester,
nitro, fluoro, chloro, and bromo also underwent successful
cyclization, giving the 2-(trifluoromethyl)oxazoles in moderate
7
Te (0.2)
Te (0.2)
CuI (1)
Ni(COD)2 (1)
Pd(PPh3)4 (1)
Zn (1)
Te (1)
Te (1)
Te (1)
Te (1)
Te (1)
Te (1)
75
32
5
8
9
10
11
12
13
14
15
16
17
18
19
yields, with no cleavage of aryl–halide bond observed (3i–3m,
0
40–63%). The structure of 3j was also unequivocally confirmed
by single-crystal X-ray analysis. Furthermore, 4-acetyl-biphenyl
oxime acetate and 2-acetylnaphthalene oxime acetate also
afforded good yields of products 3n (97%) and 3o (64%),
respectively. The cyclization worked fine for the disubstituted
acetophenone oxime acetate to furnish 3p in 56% yield. The
heteroaromatic substrates such as benzo[d][1,3]dioxole,
thiophene, and benzo[b]thiophene oxime acetates efficiently
0
0
9
8
DMSO
DMF
120
120
0
0
underwent cyclization with
2 to afford the corresponding
Toluene 120
Toluene 100
86 c
products 3q 3t in 62–89% yields.
–
73
In addition, oxime acetates derived from other aromatic
ketones such as propiophenone, butyrophenone, and 1-(4-
a Reaction conditions: 1a (0.10 mmol),
under N2 atmosphere; b The yield was determined by 19F NMR spectroscopy
2 (0.20 mmol), solvent (1.0 mL),
methoxyphenyl)-2-phenylethanone reacted smoothly with
under the standard conditions to afford the 4,5-disubstituted
2-(trifluoromethyl)oxazoles 3u 3af in 35–82% yields.
Importantly, a broad range of functional groups such as
methoxy (3w 3x, and 3af), benzyloxy (3y), and halo (3z 3ac
were well tolerated.
2
c
with PhOCF3 as internal standard; The reaction was conducted under an
–
air atmosphere.
,
–
)
To test the above hypothesis, we investigated the reaction of
acetophenone oxime acetate
(
1a
)
with trifluoroacetic
anhydride ( ) in the presence of various promoters (Table 1).
2
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Table 2. Synthesis of 2-(trifluoromethyl)oxazoles 3 a
again confirms that the reaction follows a radical mechanism
(Scheme 2c).
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DOI: 10.1039/C8CC05670F
Scheme 2. Mechanistic experiments.
Based on the above studies, a plausible reaction mechanism
of the present 2-(trifluoromethyl)oxazoles formation is
depicted in Scheme 3. The electrophilic trifluoroacetylation of
acetophenone oxime acetates
which smoothly underwent
1

with
2 gave intermediate I,
-H elimination to furnish
trifluoroacetylated enamide derivatives II. A SET reduction of
II by the reducing elemental tellurium and subsequent AcO-
elimination afforded a alkyl radical intermediate III. Upon
isomerization of III to an alkoxyl radical III
endo cyclization would generate the radical intermediate IV
Finally, the oxidation of IV with tellurium species or I2 gave the
carbocation intermediate , which upon deprotonation furnish
the desired product
, followed by a 5-
.
V
3
.
a
Reaction conditions:
1 (1.0 mmol), 2 (2.0 mmol, 2.0 equiv), Te (1.0 mmol,
2.0 equiv), I2 (0.20 mmol, 0.20 equiv), toluene (4.0 mL), 120
Isolated yields; b Performed on 10.0 mmol scale.
C, 4 h, N2;
In order to gain insight into the mechanism of the cyclization
of oxime acetates with trifluoroacetic anhydride, a series of
control experiments and radical trapping were rationally
designed and performed.
butyrophenone oxime 1ad and allyl p-tolyl ketone oxime 1ag
toward resulted in preferential reaction of 1ad (Scheme 2a). Scheme 3. Proposed mechanism for the formation of 3.
A
competition between
2
This observation implied that more stable allyl radical, which
suffers from a higher activation energy for further endo
To evaluate biological activities of the title compounds, a
general screening on their bactericidal and insecticidal
activities was performed (See Supporting Information). The
results revealed that some of 2-(trifluoromethyl)oxazoles
displayed potent fungicidal activities against wheat powdery
mildew (WPM) and corn rust (CSR), and insecticidal activities
against plutella xylostella.
In conclusion, we have demonstrated that elemental
tellurium can promote synthesis of 2-(trifluoromethyl)oxazoles
from the reaction of acetophenone oxime acetates with
trifluoroacetic anhydride. Mechanistic studies demonstrated
cyclization, may be generated during the reaction with 1ag
.
When the reaction of acetophenone oxime acetate (1a) was
carried out in the presence of a radical scavenger, 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO), none of the desired
product 3a was detected (Scheme 2b). Instead, the
trifluoroacetylated product
4 was formed in 85% yield. This
result indicates that the reaction might proceed via a radical
process. When BHT was used as a radical trap, low yield of
product 3a was observed. Trapping of the adduct
5 formed by
the combination of trifluoroacetylated imine and BHT once
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DOI: 10.1039/C8CC05670F
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DOI: 10.1039/C8CC05670F
An elemental tellurium mediated synthesis of 2-(trifluoromethyl)oxazoles from the
reaction of acetophenone oxime acetates with trifluoroacetic anhydride is described.