Elemental sulfur-promoted one-pot synthesis of 2-(2,2,2-trifluoroethyl)benzoxazoles and their derivatives

Article abstract of DOI:10.1039/c9cc06822h

A novel and direct strategy has been developed for the synthesis of 2-(2,2,2-trifluoroethyl)benzoxazoles by reaction of o-aminophenols and 2-bromo-3,3,3-trifluoropropene in the presence of elemental sulfur under metal-free conditions. The scope of this me

Full text of DOI:10.1039/c9cc06822h

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Elemental sulfur-promoted one-pot synthesis of
-(2,2,2-trifluoroethyl)benzoxazoles and their
derivatives†
2
Cite this: Chem. Commun., 2019,
5, 13132
5
Received 2nd September 2019,
Accepted 8th October 2019
a
a
a
b
Zhengyu Li, Jingnan Dong, Junwen Wang, Ding-Yah Yang * and
a
Zhiqiang Weng
*
DOI: 10.1039/c9cc06822h
rsc.li/chemcomm
A novel and direct strategy has been developed for the synthesis of Quite a number of benzoxazole-containing compounds were
-(2,2,2-trifluoroethyl)benzoxazoles by reaction of o-aminophenols documented to exhibit valuable biological activities including
and 2-bromo-3,3,3-trifluoropropene in the presence of elemental antitumor, antiviral, antimicrobial, anticonvulsant, antiallergic,
2
40
sulfur under metal-free conditions. The scope of this methodology anthelmintic, antioxidant, antidepressant, and analgesic effects.
was further extended to the synthesis of the trifluoroethylated Owing to these exceptional properties, further functionalization of
benzothiazole and benzoimidazole derivatives. A plausible mechanism benzoxazole derivatives such as the introduction of a trifluoro-
was proposed on the basis of isolation and characterization of a ethyl group may be beneficial towards their future pharmaceutical
thioamide intermediate.
applications. Indeed, several patented bioactive benzoxazole
41
derivatives such as isothiazolylaminoacylbenzazole A, benzo
42
43
The occurrence of the fluorinated molecules in pharmaceuticals, fused heterocycle B, and substituted 2-amidobenzoxazole C
agrochemicals, and advanced materials has led to unceasing all contain a trifluoroethyl benzoxazole moiety as the key func-
research efforts toward the preparation of organofluorine tionality (Fig. 1). Thus, in consideration of the prevalence of
1–4
compounds. The appropriate introduction of fluorinated func- trifluoroethyl-substituted compounds in pharmaceuticals, as well
tional groups into lead molecules might change their affinity for as the occurrence of benzoxazole scaffolds in several biologically
biological receptors and modify their metabolic stability and active molecules, the development of a facile, general, and
5–8
lipophilicity. One of the most important organofluorine func- efficient synthesis of 2-trifluoroethylated benzoxazoles is highly
tionalities is the trifluoroethyl group (–CH CF ), which exhibits desirable.
2
3
intriguing physical and biological properties. As a consequence,
Recently, the elemental sulfur-promoted synthesis of
numerous elegant methodologies have been developed for direct benzoxazole derivatives from the reaction of o-aminophenols
9–11
44
45
46
trifluoroethyl functionalization.
These developments originated and cinnamic acids, ketones, or phenylglyoxylic acid has
in 1969, when McLoughlin and Thrower reported Cu(0)-mediated been reported. Inspired by these studies along with our
12
reductive coupling of iodoarenes with CF
flourish of activity in the development of transition-metal-catalyzed, compounds,
metal-free, or photoinduced trifluoroethylation of arylboronic addition and elimination of 2-hydroxyphenyl propanethioamide
3 2
CH I. In recent years, a recent experiences on the synthesis of fluorinated heterocyclic
47–52
we surmised that an intramolecular nucleophilic
1
3–15
16
17
18–25
26–30
acids
or esters, aryl iodides, arenes,
alkenes,
aryl Grignard forward pathway to the preparation of 2-trifluoroethylated
reagents, and others has been witnessed in the literature. benzoxazoles (Scheme 1). Herein, we reported a novel approach
On the other hand, the benzoxazole structural motif is found for accessing 2-trifluoroethylated benzoxazoles via elemental
via a radical anion intermediate would be a distinct and straight-
3
1,32
33,34
35,36
alkynes,
carboxylic acids,
amines,
3
7
38
3
9
in many natural products and synthetic bioactive molecules.
sulfur-promoted cyclization between 2-bromo-3,3,3-trifluoropropene
1) and o-aminophenols (2).
(
a
State Key Laboratory of Photocatalysis on Energy and Environment, and Key
Laboratory of Molecule Synthesis and Function Discovery, College of Chemistry,
Fuzhou University, Fuzhou, 350108, China. E-mail: zweng@fzu.edu.cn;
Fax: +86 591 22866247; Tel: +86 591 22866247
b
Department of Chemistry, Tunghai University, No. 1727, Sec. 4, Taiwan
Boulevard, Xitun District, Taichung City 40704, Taiwan
†
Electronic supplementary information (ESI) available. CCDC 1921974 and 1922077.
For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c9cc06822h
Fig. 1 Patented 2,2,2-trifluoroethyl-containg bioactive benzoxazole
derivatives.
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or bis(pinacolato)diboron (B
2
Pin
2
) as an additive (entries 17
and 18). The best result was obtained when ADVN and B
2 2
Pin
(0.090 mmol : 0.070 mmol = 9 : 7) were introduced, where the
product 3q was generated in 87% yield from 2-bromo-3,3,3-
trifluoropropene (1, 7 equiv.), o-aminophenol 2q (1 equiv.),
NaHCO
The role of ADVN/B
3
(3 equiv.), and S
8
(8 equiv.) at 100 1C for 15 h (entry 19).
2
in the cyclization might be to facilitate
2
Pin
the formation of reactive radical intermediates.
With the optimization conditions in hand, the substrate
scope of the reaction was then examined with different
o-aminophenols (Table 2). It was found that a variety of
o-aminophenols with electron-donating and electron-withdrawing
groups substituted on the aromatic ring were tolerable, and
moderate to good yields of trifluoroethylated products
were obtained. For instance, the reaction of unsubstituted
o-aminophenol (2a) with 1 afforded the corresponding product
Scheme 1 Elemental sulfur-promoted synthesis of benzoxazole
derivatives.
To test the reaction feasibility, we first examined the cycliza-
tion of 2-amino-4-chlorophenol (2q) with 2-bromo-3,3,3-
trifluoropropene (1) under a variety of reaction conditions
3
a in 70% yield. Numerous electron-donating (i.e., methyl,
tert-butyl, phenyl, and methoxy) and electron-withdrawing
i.e., acetyl, ester, carboxyl, cyano, and nitro) substituents at
(
(
Table 1). The major challenge was to identify an activator
entries 1–6) and elemental sulfur (8 equiv.) was found to be a
(
the positions ortho, meta, and para to the hydroxyl on the aryl
good promoter to afford the desired product 5-chloro-2-(2,2,2-
ring were well tolerated, rendering the corresponding products
trifluoroethyl)benzoxazole (3q) in promising 54% yield (entry 6).
3b–3n in 38–83% yields. The structure of 3i was verified by the
The use of less than 8 equiv. of S
product yield (entries 4 and 5). Among the bases evaluated
entries 5–11), NaHCO was superior and provided the best
8
resulted in a decrease in
a
Table 2 Scope of the reaction with o-aminophenols
(
3
yield of the product 3q at 100 1C for 15 h (entries 5 and 6).
A variety of solvents such as DMF, DMSO, NMP, DMAc, MeCN,
and THF were also screened for optimized conditions
(entries 12–16), and it was observed that DMF afforded a better
yield than other solvents. The reaction efficiency could be further
0
improved by using 2,2 -azobis-(2,4-dimethylvaleronitrile) (ADVN)
a
Table 1 Optimization of the reaction conditions
b
Entry Promoter (equiv.) Base
Additive
Solvent Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
I
2
(5)
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
NaOH
3
3
3
3
3
3
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
NMP
DMAc 41
MeCN
THF
DMF
DMF
DMF
0
0
0
KI (5)
O
2
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
8
(3)
(5)
(8)
(5)
(5)
(5)
(5)
(5)
(5)
(5)
(5)
(5)
(5)
(8)
(8)
(8)
19
51
54
45
8
35
16
30
0
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
Na CO
2 3
KOH
CsF
DBU
0
1
2
3
4
5
6
7
8
9
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
3
3
3
3
3
3
3
3
46
0
0
67
76
87
ADVN
B
2
Pin
2
ADVN/B
2
Pin
2
a
a
Reaction conditions: 1 (0.70 mmol), 2q (0.10 mmol), base (0.30 mmol),
8
Reaction conditions: 1 (2.10 mmol), 2 (0.30 mmol), S (2.40 mmol),
b
solvent (1.0 mL), under a N
2
atmosphere. The yield was determined by NaHCO
F NMR spectroscopy with PhOCF as an internal standard. (3.0 mL), under N
3
(0.90 mmol), ADVN (0.27 mmol), B
2 2
Pin (0.21 mmol), DMF
19
3
2
atmosphere; isolated yields.
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single-crystal X-ray analysis. Likewise, the o-aminophenols
bearing halogen substitutions such as fluoro (2o, 2p), chloro
(2n, 2q–2s), and bromo (2t, 2u) groups were all compatible with
this transformation and gave the desired products 3n–3u
in moderate to good yields. Similar to those disubstituted
o-aminophenols (2n and 2s), 3-amino-2-naphthol 2v also gave
the corresponding product 3v in a lower yield (36%). Notably,
heterocyclic substrates could also participate in the reaction,
even with a lower yield, to provide the corresponding products
Scheme 3 Proposed mechanism.
3w and 3x in 39% and 28% yield, respectively. Next, the bis-
(
o-aminophenol) derivatives were also tested, and the respective nucleophilic addition pathway may be infeasible. Interestingly,
bis-trifluoroethylated products 3y and 3z were obtained in 61% in addition to the desired product 5c which was generated
and 70% yield. It is noteworthy that when the hydroxyl group (79% yield) during the cyclization of 4-bromobenzene-1,2-
of o-aminophenol was switched to a hydroxymethyl moiety as in diamine with 1, a sulfurated product 7c (X-ray) was also isolated
o-aminophenylcarbinol, the corresponding cyclization product in ca. 5% yield (Scheme 2d). The intermediacy of thioamide 7c
3
aa was produced without difficulties in 53% yield.
To demonstrate the generality of the methodology, we CDCl
further extended the substrates to other o-substituted anilines, 5c was obtained in a yield of 40% (Scheme 2e).
was independently proven by intramolecular cyclization of 7c in
at room temperature for 72 h, where the desired product
3
and the results are summarized in Table 2. To our delight, a
Based on the aforementioned controlled experiments, a
variety of o-aminobenzenethiols and benzene-1,2-diamines were putative mechanism is depicted in Scheme 3. Initially, the
smoothly transformed to the corresponding trifluoroethylated reaction of elemental sulfur with the base in the presence of
ꢀ
ꢁ
53
benzothiazoles 4a–4c and benzoimidazoles 5a–5c in good yields ADVN/B
79–87%).
in situ generated 3,3,3-trifluoropropyne I (resulting from a
To explore the mechanism of this transformation, some dehydrobromination reaction of 1 under basic conditions)
2
Pin
2
would generate the S
3
radical anion. The
(
5
4
ꢀ
ꢁ
control experiments were carried out. The cyclization of 2q could react with S
to form the radical anion intermediate II.
group
3
with 1 in the presence of a radical scavenger such as TEMPO The generated radical anion II then reacted with the NH
2
halted the formation of product 3q, indicating a possible of the substrate, producing an alkyl radical intermediate III.
radical-mediated pathway (Scheme 2a). However, we did not Subsequent base dissociation of III generated IV, which under-
observe any TEMPO-adduct products. In the absence of went oxidation by sulfur species to give the carbocation inter-
elemental sulfur, the uncyclized O-trifluoroallylated product 6q mediate V. Deprotonation of V would furnish VI, which
was obtained instead of the desired product 3q (Scheme 2b), subsequently underwent protonation to form a thioamide VII.
suggesting that elemental sulfur plays a significant role in the Intramolecular nucleophilic addition of the XH
cyclization. The isolated compound 6q may presumably undergo the nearby CQS double bond afforded the cyclized VIII. Final
intramolecular nucleophilic addition of the amino group to the elimination of H S from VIII furnished the desired products 3–5.
double bond, followed by oxidation to afford the cyclized product
To conclude, we have described a novel and direct approach
q. However, treatment of 6q under the standard conditions failed toward the preparation of 2-(2,2,2-trifluoroethyl)benzoxazole
group of VII to
n
2
3
to give the expected 3q, and most of the starting material 6q was derivatives based on readily available o-aminophenols/o-
recovered (Scheme 2c). These results imply that 6q is not the aminobenzenethiols/benzene-1,2-diamines and 2-bromo-3,3,3-
putative intermediate involved in the cyclization and the proposed trifluoropropene with the latter as the source of the trifluoroethyl
group. Moreover, the isolation and characterization of a sulfurated
compound confirmed the involvement of a thioamide intermediate.
We acknowledge the financial support from the National
Natural Science Foundation of China (21772022), and Fuzhou
University.
Conflicts of interest
There are no conflicts to declare.
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