Exploring the Reactivity of 2-Trichloromethylbenzoxazoles for Access to Substituted Benzoxazoles

Article abstract of DOI:10.1021/acs.joc.6b02315

The reactivity of 2-trichloromethylbenzoxazoles toward various nucleophiles, under metal-free or iron-catalyzed conditions, for the synthesis of substituted benzoxazoles is described. These methods allow for selective substitution at either the 2- or 2′-position of the benzoxazoles using the same starting materials/reagents. This approach allows for the controlled synthesis of a variety of key derivatives from a single 2-trichloromethylbenzoxazole starting material.

Full text of DOI:10.1021/acs.joc.6b02315

Note
pubs.acs.org/joc
Exploring the Reactivity of 2‑Trichloromethylbenzoxazoles for
Access to Substituted Benzoxazoles
Roy P. Lester,† Travis Bham,‡ Thomas W. Bousfield,‡ William Lewis,† and Jason E. Camp*,†,‡
†School of Chemistry, University of Nottingham, Nottingham NG7 2RD, United Kingdom
‡Department of Chemical Sciences, University of Huddersfield, Queensgate, Huddersfield, HD1 3DH, United Kingdom
S
* Supporting Information
ABSTRACT: The reactivity of 2-trichloromethylbenzoxazoles
toward various nucleophiles, under metal-free or iron-catalyzed
conditions, for the synthesis of substituted benzoxazoles is
described. These methods allow for selective substitution at
either the 2- or 2′-position of the benzoxazoles using the same
starting materials/reagents. This approach allows for the
controlled synthesis of a variety of key derivatives from a
single 2-trichloromethylbenzoxazole starting material.
of the methods used for their synthesis, either 2-amino- or 2-
amidobenzoxazoles can be accessed, but generally not both,
from the same starting materials using the same reagents.
Additionally, to mitigate the negative environmental and cost
implication of noble metal catalysts, there has been a recent
push to develop metal-free or base metal-catalyzed methods.8,9
Thus, an opportunity exists to develop selective synthetic
methods for the derivatization of this important scaffold.
Previously, we showed that 2-trichloromethylbenzoxazoles 1
could be synthesized via a mild metal-free reaction between
trichloroacetonitrile10 and 2-aminophenols 4 in methanol at 40
°C (see Scheme 2).11,12 Although the reactivity of some 2-
trichloromethylazoles has been investigated,13 little work on the
reactivity of 2-trichloromethylbenzoxazoles has been re-
ported.14 Herein, we report our findings into controlling the
reactivity of 2-trichloromethylbenzoxazoles for the selective
synthesis of 2-amino- or 2-amidobenzoxazoles as well as other
derivatives in which the carbon of the trichloromethyl moiety is
either extruded or retained (Scheme 1c).
he benzoxazole motif has been incorporated into a
Tnumber of pharmaceuticals, agrochemicals, and materials
that are vital to our everyday lives.1 Because of the importance
of benzoxazoles, widespread research has been conducted on
their synthesis2 and subsequent functionalization.3 The
selective synthesis of 2-amino- or 2-amidobenzoxazoles from
both activated substrates4,5 and via C−H6,7 activation has been
extensively developed (Scheme 1a,b).4a,5b Because of the nature
Scheme 1. Methods of Benzoxazole Functionalization
Because of the importance of 2-aminobenzoxazoles, the
study began with the direct displacement of the 2-
trichloromethyl moiety from 2-(trichloromethyl)benzo[d]-
oxazole 1 with an amine nucleophile.15 Initial reactions resulted
in a mixture of 2-amino- and 2-amidobenzoxazoles. After
screening a variety of Lewis acids, which were hoped to activate
the C-2 position toward nucleophilic aromatic substitution, as
well as solvents, temperatures, and times, it was found that the
key parameters for controlling the product distribution between
amine 2 and amide 5 were the molarity of the system and water
content.16 Thus, reaction of 2-trichloromethylbenzoxazole 1
with pyrrolidine (1.1 equiv) in dry acetonitrile (1 M relative to
the benzoxazole) at 60 °C for 4 h afforded the desired 2-
(pyrrolidin-1-yl)benzo[d]oxazole (2) in excellent yield. The
Received: September 21, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b02315
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Note
Scheme 2. DOS Approach to the Functionalization of 2-(Trichloromethyl)benzo[d]oxazole (1)
reaction could also be run at rt, though it required 13 h to go to
completion, or in the presence of the nucleophilic catalysts
DABCO,17 which led to slightly improved yields (see Scheme
3). Interestingly, on the basis of the pKaH values, the reaction
reported that strong bases can be used in the addition of
alcohols to related trichloromethylazoles.13 Unfortunately,
these conditions did not lead to an improved yield of the
desired addition adducts.
Having established methods for the direct C-2 substitution of
2-trichloromethylbenzoxazoles, the selective C-2′ substitution
processes were investigated.21 After screening a variety of
conditions,16 it was found that reaction of 2-(trichloromethyl)-
benzo[d]oxazole (1) with pyrrolidine (0.9 equiv) in wet
acetonitrile (0.01 M, relative to the benzoxazole) at rt for 76 h
afforded the desired benzo[d]oxazol-2-yl(pyrrolidin-1-yl)-
methanone (5) in 66% yield. Reducing the reaction time to
19 h gave the product in 35% yield. These mild conditions are
in contrast to related amide forming processes from
heterocyclic trichloromethyl groups that use strong bases,
high reaction temperatures, or toxic solvents to achieve similar
transformations.20 They therefore should be particularly
applicable to substrates that are base or thermally unstable. It
was also possible to reduce the reaction time via the addition of
FeCl3 (1.0 equiv), which resulted in the formation of
benzo[d]oxazol-2-yl(pyrrolidin-1-yl)methanone (5) after 19 h
in 57% yield.
Scheme 3. Addition of Pyrrolidine to Substituted 2-
Trichloromethylbenzoxazoles
As part of a substrate scope study (vide infra), it was found
that the reaction of 2-(trichloromethyl)benzo[d]oxazole (1)
with pyrrolidine (1.1 equiv) in acetonitrile (1 M relative to the
pyrrolidine) at 60 °C for 4 h afforded 7-chloro-2,3-
di(pyrrolidin-1-yl)-2H-benzo[b][1,4]oxazine (6e), the struc-
ture of which was confirmed by X-ray analysis.22 Gauß and
Heitzer previously reported a related ring expansion process,
though they started from 2-dichloromethylbenzoxazoles rather
than 2-trichloromethylbenzoxazole 1.23 Also, Molinski et al.
found that 2-substituted oxazolines could be converted to
dihydrooxazinones in the presence of SeO2.24 Interestingly,
compound 6e could only be formed if a reduction was taking
place under the reaction conditions, though at which point in
the process the reduction is taking place is unclear. In related
work, it was also shown that 2-dichloromethylbenzoxazoles can
undergo hydrogen/deuterium exchange in the presence of
triethylamine.
a
b
At rt for 13 h. With DABCO (10 mol %) at 60 °C for 4 h.
should not proceed (see Scheme S1).18 It is believed that the
liberated chloroform decomposes under the reaction conditions
to form a reactive carbene intermediate, which then
decomposes and thus shifts the reaction equilibrium toward
the 2-amino product 2.19
Building upon the selective C-2 substitution of an amine
nucleophile, the addition of an alkoxide,20 generated in situ, to
the 2-position of the trichloromethylbenzoxazole was inves-
tigated. It was found that methanol and benzyl alcohol could
add effectively to 2-(trichloromethyl)benzo[d]oxazole (1) in
the presence of DBU in acetonitrile to form either 2-
methoxybenzo[d]oxazole (3a) or 2-(benzyloxy)benzo-[d]-
oxazole (3b), albeit in moderate yields. It was previously
Furthermore, hydrolysis of 2-trichloromethylbenzoxazole 1
was examined (Scheme 2). It was found that upon treatment of
2-(trichloromethyl)benzo[d]oxazole (1) with FeCl2 (2 mol %)
and H2O (2.5 equiv)25 that ring-opened 2,2,2-trichloro-N-(2-
B
DOI: 10.1021/acs.joc.6b02315
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The Journal of Organic Chemistry
Note
microwave reaction vessel and heated using an aluminum block on a
hot plate.
hydroxyphenyl) acetamide (7) was formed in good yield. The
connectivity of acetamide 7 was confirmed by X-ray analysis.22
Acetamide 7 and related analogues have previously been shown
2-(Pyrrolidin-1-yl)benzo[d]oxazole (2a).28 Method A. To a
stirred solution of 2-(trichloromethyl)benzo[d]oxazole (1a, 200 mg,
0.8 mmol) in dry acetonitrile (1 M) at rt was added pyrrolidine (79
μL, 0.9 mmol). The resultant solution was stirred at 60 °C for 4 h. The
solvent was removed in vacuo, and the residue was purified by flash
column chromatography on silica gel (5% ethyl acetate in petroleum
ether) to afford 2-(pyrrolidin-1-yl)benzo[d]oxazole (2a, 146 mg, 92%
yield) as a yellow solid.
to have germination inhibition activity against lettuce seeds.26
A
screen of hydrolysis conditions was undertaken to investigate
this process further. It was found that the best nonmetal-
containing process for the hydrolysis was to heat 2-
trichloromethylbenzoxazole 1 in H2O at 150 °C for 2 h. This
method gave the desired 2,2,2-trichloro-N-(2-hydroxyphenyl)
acetamide (7) in a moderate 37% yield.22
Method B. To a stirred solution of 2-(trichloromethyl)benzo[d]-
oxazole (1a, 200 mg, 0.8 mmol) in dry acetonitrile (1 M) at rt was
added pyrrolidine (79 μL, 0.9 mmol). The resultant solution was
stirred at rt for 13 h. The solvent was removed in vacuo, and the
residue was purified by flash column chromatography on silica gel (5%
ethyl acetate in petroleum ether) to afford 2-(pyrrolidin-1-yl)benzo-
[d]oxazole (2a, 143 mg, 90% yield) as a yellow solid.
In efforts to optimize the addition reactions and control the
C-2 vs C-2′ selectivity, a variety of Lewis acids were screened.22
During the course of this study, it was found that the reaction
of 2-trichloromethylbenzoxazole (1) with pyrrolidine (1.1
equiv) in the presence of FeCl3 afforded bisbenzoxazole 8 in
moderate yield. The structure of this novel compound was
confirmed by 2D NMR analysis and X-ray crystallography.22
With the optimized conditions in hand for the synthesis of 2-
aminobenzoxazoles, the effect of substitution on the benzox-
azole ring was investigated to assess the effect of electronic
factors on the formation of 2-aminobenzoxazoles 2 from 2-
trichloromethylbenzoxazoles 1 (Scheme 3). Thus, reaction of
2-(trichloromethyl)benzo[d]oxazole (1a) with pyrrolidine (1.1
equiv) at either 60 °C or rt afforded 2-(pyrrolidin-1-
yl)benzo[d]oxazole (2a) in excellent yield. The addition of
the nucleophilic catalyst DABCO (10 mol %) led to a slight
increase in the yield of 2-aminobenzoxazole 2a.17 The
annulation of an aromatic ring to the starting material led to
an increased yield of 2-(pyrrolidin-1-yl)naphtho[2,3-d]oxazole
(2b). Interestingly, having an electron-rich methoxy moiety in
the system resulted in a decrease in yield of 2c relative to that
of the electron-deficient 5- and 6-chloro derivatives 2d and 2e.
As mentioned previously, the mass balance in the reaction of
the chloro-substituted benzoxazoles 1d/1e are the ring-opened
species 6d/6e (see Scheme 2).
Method C. To a stirred solution of 2-(trichloromethyl)benzo[d]-
oxazole (1a, 100 mg, 0.42 mmol) in dry acetonitrile (1 M) at rt were
added pyrrolidine (40 μL, 0.47 mmol) and DABCO (4.7 mg, 0.042
mmol). The resultant solution was stirred at 60 °C for 4 h. The solvent
was removed in vacuo, and the residue was purified by flash column
chromatography on silica gel (5% ethyl acetate in petroleum ether) to
afford 2-(pyrrolidin-1-yl)benzo[d]oxazole (2a, 75 mg, 95% yield) as a
yellow solid. Mp 133−135 °C (lit. mp 136−137 °C); Rf = 0.25 (1:9
ethyl acetate/petroleum ether); IR (CHCl3, cm−1) 3011, 2978, 2880,
1
1648; H NMR (300 MHz, CDCl3, 298 K) δH 7.36 (1H, d, J = 7.8
Hz), 7.26 (1H, d, J = 7.8 Hz), 7.15 (1H, apparent td, J = 7.7, 1.2 Hz),
6.99 (1H, apparent td, J = 7.7, 1.2 Hz), 3.69−3.62 (4H, m), 2.07−2.01
(4H, m); 13C{1H} NMR (75 MHz, CDCl3, 298 K) δc 160.9, 148.9,
143.5, 123.6, 119.9, 115.8, 108.4, 47.2 (2C), 25.4 (2C); HRMS (ESI)
m/z calcd for [M + H]+ C11H13N2O+ 189.1023, found 189.1030.
2-(Pyrrolidin-1-yl)naphtho[2,3-d]oxazole (2b). To a stirred
solution of 2-(trichloromethyl)naphtho[2,3-d]oxazole (1b, 158 mg,
0.55 mmol) in dry acetonitrile (1 M) at rt was added pyrrolidine (51
μL, 0.6 mmol). The resultant solution was stirred at 60 °C for 4 h. The
solvent was removed in vacuo, and the residue was purified by flash
column chromatography on silica gel (5% ethyl acetate in petroleum
ether) to afford 2-(pyrrolidin-1-yl)naphtho[2,3-d]oxazole (2b, 130 mg,
1
99% yield) as a yellow oil. IR (CHCl3, cm−1) 2969, 2881, 1656; H
In conclusion, an investigation into the reactivity of 2-
trichloromethylbenzoxazole toward various nucleophiles under
metal-free or iron-catalyzed conditions was conducted. The
newly developed methods allow for the controlled synthesis of
a variety of benzoxazole derivatives starting from the same
starting material. Importantly, these methods allow for
substitution at either the 2- or 2′- position of the benzoxazoles
by simply altering the reactant concentration and water
content. Thus, a variety of derivatives can be synthesized
from a simple 2-trichloromethylbenzoxazole starting material
via this diversity-oriented synthesis (DOS)27 type approach.
NMR (300 MHz, CDCl3, 298 K) δH 7.86−7.80 (2H, m), 7.68 (1H, s),
7.58 (1H, s), 7.37 (2H, quint, J = 6.9, 1.3 Hz), 3.66 (4H, t, J = 6.7 Hz),
2.05−1.97 (4H, m); 13C{1H} NMR (75 MHz, CDCl3, 298 K) δc
161.9, 149.3, 144.1, 131.9, 129.2, 127.6, 127.5, 124.2, 123.5, 111.4,
104.3, 47.5 (2C), 25.5 (2C); HRMS (ESI) m/z calcd for [M + H]+
C15H15N2O+ 239.1179, found 239.1189.
5-Methoxy-2-(pyrrolidin-1-yl)benzo[d]oxazole (2c).29 To a
stirred solution of 5-methoxy-2-(trichloromethyl)benzo[d]oxazole (1c,
147 mg, 0.55 mmol) in dry acetonitrile (1 M) at rt was added
pyrrolidine (51 μL, 0.6 mmol). The resultant solution was stirred at 60
°C for 4 h. The solvent was removed in vacuo, and the residue was
purified by flash column chromatography on silica gel (5% ethyl
acetate in petroleum ether) to afford 5-methoxy-2-(pyrrolidin-1-
yl)benzo[d]oxazole (2c, 83 mg, 69% yield) as light brown crystals. IR
EXPERIMENTAL SECTION
1
(CHCl3, cm−1) 2957, 2880, 1650; H NMR (300 MHz, CDCl3, 298
■
General Remarks. Unless otherwise indicated, all commercially
available reagents and solvents were used directly from the supplier
without further purification. Solvents used for column chromatography
were of technical grade. Column chromatography was performed on
silica gel (60−120) mesh. Visualization was accomplished with UV
light and a potassium permanganate solution. 1H NMR and 13C NMR
were recorded at ambient temperature using CDCl3 (7.26 ppm).
Chemical shift values are expressed as parts per million (ppm), and J
values are in hertz. Splitting patterns are indicated as s, singlet; d,
doublet; t, triplet; q, quartet; or combination br.s, broad singlet; or m,
multiplet. The melting points reported are uncorrected. Infrared
spectra were recorded as diluted solutions in spectroscopic grade
chloroform unless otherwise stated. Absorption maxima (λ max) of
major peaks are reported in wavenumbers (cm-1) quoted to the
nearest integral wavenumber. Reactions were run in a sealed
K) δH 7.10 (1H, d, J = 8.6 Hz), 6.92 (1H, d, J = 2.5 Hz), 6.53 (1H, dd,
J = 8.6, 2.5 Hz), 3.79 (3H, s), 3.64−3.60 (4H, m), 2.04−1.99 (4H, m);
13C{1H} NMR (75 MHz, CDCl3, 298 K) δc 161.8, 156.9, 144.7, 143.6,
108.3, 106.3, 101.2, 55.8, 47.3 (2C), 25.6 (2C); HRMS (ESI) m/z
+
calcd for [M + H]+ C12H15N2O2 219.1129, found 219.1134.
5-Chloro-2-(pyrrolidin-1-yl)benzo[d]oxazole (2d).29 To a
stirred solution of 5-chloro-2-(trichloromethyl)benzo[d]oxazole (1d,
150 mg, 0.55 mmol) in dry acetonitrile (1 M) at rt was added
pyrrolidine (51 μL, 0.6 mmol). The resultant solution was stirred at 60
°C for 4 h. The solvent was removed in vacuo, and the residue was
purified by flash column chromatography on silica gel (5% ethyl
acetate in petroleum ether) to afford 5-chloro-2-(pyrrolidin-1-
yl)benzo[d]oxazole (2d, 100 mg, 81% yield) as a white solid. Mp
1
121−123 °C; IR (CHCl3, cm−1) 2979, 2882, 1650; H NMR (300
MHz, CDCl3, 298 K) δH 7.28 (1H, d, J = 2.1 Hz), 7.10 (1H, d, J = 8.4
C
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Hz), 6.90 (1H, dd, J = 8.4, 2.1 Hz), 3.60 (4H, t, J = 6.7 Hz), 2.05−1.96
(4H, m); 13C{1H} NMR (75 MHz, CDCl3, 298 K) δc 161.6, 147.5,
145.0, 128.9, 119.6, 115.8, 108.9, 47.3 (2C), 25.4 (2C); HRMS (ESI)
m/z calcd for [M + H]+ C11H12ClN2O+ 223.0633, found 223.0637.
6-Chloro-2-(pyrrolidin-1-yl)benzo[d]oxazole (2e). To a stirred
solution of 6-chloro-2-(trichloromethyl) benzo[d]oxazole (1e, 150 mg,
0.55 mmol) in dry acetonitrile (1 M) at rt was added pyrrolidine (51
μL, 0.6 mmol). The resultant solution was stirred at 60 °C for 4 h. The
solvent was removed in vacuo, and the residue was purified by flash
column chromatography on silica gel (5% ethyl acetate in petroleum
ether) to afford 6-chloro-2-(pyrrolidin-1-yl)benzo[d]oxazole (2e, 93
mg, 75% yield) as a white solid. Mp 126−128 °C; IR (CHCl3, cm−1)
2979, 2881, 1651; 1H NMR (300 MHz, CDCl3, 298 K) δH 7.22−7.19
(2H, m), 7.08−7.00 (1H, m), 3.62−3.58 (4H, m), 2.05−1.96 (4H, m);
13C{1H} NMR (75 MHz, CDCl3, 298 K) δc 161.2, 149.1, 142.6, 125.0,
124.0, 116.1, 109.3, 47.4 (2C), 25.5 (2C); HRMS (ESI) m/z calcd for
[M + H]+ C11H12ClN2O+ 223.0633, found 223.0639.
ambient temperature for 19 h. The solvent was removed in vacuo, and
the residue was purified by flash column chromatography on silica gel
(5% ethyl acetate in diethyl ether) to afford benzo[d]oxazol-2-
yl(pyrrolidin-1-yl)methanone (5, 52 mg, 57%) as a yellow solid. Mp
126−128 °C; Rf = 0.20 (1:9 ethyl acetate/petroleum ether); IR
1
(CHCl3, cm−1) 3006, 2886, 1640; H NMR (300 MHz, CDCl3, 298
K) δH 7.83 (1H, d, J = 7.5 Hz) 7.66 (1H, d, J = 7.6 Hz) 7.48−7.42
(2H, m), 4.14 (2H, t, J = 6.8 Hz), 3.76 (2H, t, J = 6.8 Hz), 2.11−1.93
(4H, m); 13C{1H} NMR (75 MHz, CDCl3, 298 K) δc 155.8, 155.3,
150.1, 140.6, 127.2, 125.2, 121.4, 111.7, 49.3, 47.5, 26.5, 23.9; HRMS
+
(ESI) m/z calcd for [M + H]+ C12H13N2O2 217.0972, found
217.0970.
6-Chloro-2,3-di(pyrrolidin-1-yl)-2H-benzo[b][1,4]oxazine
(6d). To a stirred solution of 5-chloro-2-(trichloromethyl) benzo[d]-
oxazole (1d, 150 mg, 0.55 mmol) in dry acetonitrile (1 M) at rt was
added pyrrolidine (51 μL, 0.6 mmol). The resultant solution was
stirred at 60 °C for 4 h. The solvent was removed in vacuo, and the
residue was purified by flash column chromatography on silica gel (5%
ethyl acetate in petroleum ether) to afford 6-chloro-2,3-di(pyrrolidin-
1-yl)-2H-benzo[b][1,4]oxazine (6d, 24 mg, 14% yield) as a yellow
2-Methoxybenzo[d]oxazole (3a).30 To a stirred solution of 2-
(trichloromethyl)benzo[d]oxazole (1a, 150 mg, 0.6 mmol, 1 equiv) in
acetonitrile (0.6 mL, 1 M) at ambient temperature were added
methanol (28 μL, 0.7 mmol, 1.1 equiv) and DBU (104 μL, 0.7 mmol,
1.1 equiv). The resultant solution was stirred at 60 °C for 16 h. The
mixture was allowed to cool to rt and filtered through silica
(dichloromethane). The solvent was removed in vacuo, and the
residue was purified by flash column chromatography on base-washed
silica gel (3% ethyl acetate in petroleum ether) to afford 2-
methoxybenzo[d]oxazole (3a, 24 mg, 25%) as a clear oil. Rf = 0.50
(1:2 ethyl acetate/petroleum); IR (CHCl3, cm−1) 3156, 2927, 2254,
1792, 1747, 1552; 1H NMR (300 MHz, CDCl3, 298 K) δH 7.90 (1H, d
J = 7.9 Hz) 7.67 (1H, d J = 8.1 Hz), 7.56−7.44 (2H, m), 4.10 (3H, s);
13C{1H} NMR (75 MHz, CDCl3, 298 K) δc 156.9, 150.9, 140.5, 128.3,
125.9, 122.2, 111.8, 53.7; HRMS (ESI) m/z calcd for [M + H]+
1
gummy solid. IR (CHCl3, cm−1) 3690, 2929, 2876, 1610; H NMR
(300 MHz, CDCl3, 298 K) δH 7.08 (1H, d, J = 2.1 Hz), 6.80−6.72
(2H, m), 5.45 (1H, s), 3.65 (3H, br.s), 3.36 (1H, br.s) 2.96−2.89 (2H,
m) 2.68−2.61 (2H, m) 1.97 (4H, br.s) 1.72−1.60 (4H, m); 13C{1H}
NMR (75 MHz, CDCl3, 298 K) δc 152.3, 144.7, 136.0, 125.8, 123.3,
121.9, 115.0, 80.2, 46.7 (4C), 24.4 (4C); HRMS (ESI) m/z calcd for
[M + H]+ C16H21ClN3O+ 306.1368, found 306.1373.
7-Chloro-2,3-di(pyrrolidin-1-yl)-2H-benzo[b][1,4]oxazine
(6e). To a stirred solution of 6-chloro-2-(trichloromethyl) benzo[d]-
oxazole (1e, 150 mg, 0.55 mmol) in dry acetonitrile (1 M) at rt was
added pyrrolidine (51 μL, 0.6 mmol). The resultant solution was
stirred at 60 °C for 4 h. The solvent was removed in vacuo, and the
residue was purified by flash column chromatography on silica gel (5%
ethyl acetate in petroleum ether) to afford 7-chloro-2,3-di(pyrrolidin-
1-yl)-2H-benzo[b][1,4]oxazine (6e, 42 mg, 25% yield) as a yellow
+
C8H8NO2 150.0550, found 150.0540.
2-(Benzyloxy)benzo[d]oxazole (3b).31 To a stirred solution of
2-(trichloromethyl)benzo[d]oxazole (1a, 150 mg, 0.6 mmol, 1 equiv)
in acetonitrile (0.6 mL, 1 M) were added benzyl alcohol (73 μL, 0.7
mmol, 1.1 equiv) and DBU (104 μL, 0.7 mmol, 1.1 equiv). The
resultant solution was stirred at 60 °C for 16 h. The mixture was
allowed to cool to rt and filtered through silica (dichloromethane).
The solvent was removed in vacuo, and the residue was purified by
flash column chromatography on base-washed silica gel (1% ethyl
acetate in petroleum ether) to afford 2-(benzyloxy)benzo[d]oxazole
(3b, 37 mg, 26%) as a clear oil. IR (CHCl3, cm−1) 3009, 2928, 2855,
1741, 1613, 1568; 1H NMR (300 MHz, CDCl3, 298 K) δH 7.81−7.79
(2H, m) 7.64−7.62 (2H, m), 7.47 (2H, apparent td, J = 7.7, 1.4 Hz),
7.42−7.35 (3H, m), 6.87 (2H s); 13C{1H} NMR (75 MHz, CDCl3,
298 K) δc 159.6, 151.0, 140.1, 128.6, 128.3, 126.9 (2C), 125.3 (2C),
121.2 (2C), 119.4, 111.3, 61.0; HRMS (ESI) m/z calcd for [M + H]+
1
gummy solid. IR (CHCl3, cm−1) 3667, 2974, 2876, 1607; H NMR
(300 MHz, CDCl3, 298 K) δH 7.01 (1H, dd, J = 7.9, 0.7 Hz), 6.84−
6.80 (2H, m), 5.46 (1H, s), 3.63 (3H, br.s), 3.37 (1H, br.s) 2.96−2.88
(2H, m) 2.68−261 (2H, m) 2.01−1.94 (4H, m) 1.69−1.60 (4H, m);
13C{1H} NMR (75 MHz, CDCl3, 298 K) δc 151.8, 146.5, 133.5, 126.6,
124.1, 121.3, 114.6, 80.2, 46.6 (4C), 24.4 (4C); HRMS (ESI) m/z
calcd for [M + H]+ C16H21ClN3O+ 306.1368, found 306.1360.
2,2,2-Trichloro-N-(2-hydroxyphenyl) acetamide (7).32 Meth-
od A. To a stirred solution of 2-(trichloromethyl)benzo[d]oxazole (1a,
237 mg, 1 mmol, 1 equiv) and iron(III) chloride (3.0 mg, 0.02 mmol,
2 mol %) in acetonitrile (0.2 mL, 5 M) at rt was added water (18 μL, 1
mmol, 1.0 equiv). The resultant mixture was stirred at rt for 5 h. Water
(27 μL, 1.5 mmol, 1.5 equiv) was added. The mixture was stirred at rt
for 3 h. The solvent was removed in vacuo, and the residue was
purified by flash column chromatography on silica gel (5% ethyl
acetate in petroleum ether) to afford 2,2,2-trichloro-N-(2-hydrox-
yphenyl) acetamide (7, 148 mg, 58%) as a yellow solid.
+
C14H12NO2 226.0863, found 226.0873.
Benzo[d]oxazol-2-yl(pyrrolidin-1-yl)methanone (5). Method
A. To a stirred solution of 2-(trichloromethyl)benzo[d]oxazole (1a,
100 mg, 0.42 mmol) in acetonitrile (0.01 M) at ambient temperature
was added pyrrolidine (40 μL, 0.47 mmol). The resultant solution was
stirred at ambient temperature for 76 h. The solvent was removed in
vacuo, and the residue was purified by flash column chromatography
on silica gel (5% ethyl acetate in diethyl ether) to afford
benzo[d]oxazol-2-yl(pyrrolidin-1-yl)methanone (5, 60 mg, 66%) as a
yellow solid.
Method B. To a stirred solution of 2-(trichloromethyl)benzo[d]-
oxazole (1a, 100 mg, 0.42 mmol) in acetonitrile (0.01 M) at ambient
temperature was added pyrrolidine (40 μL, 0.47 mmol). The resultant
solution was stirred at ambient temperature for 19 h. The solvent was
removed in vacuo, and the residue was purified by flash column
chromatography on silica gel (5% ethyl acetate in diethyl ether) to
afford benzo[d]oxazol-2-yl(pyrrolidin-1-yl)methanone (5, 32 mg,
35%) as a yellow solid.
Method B. 2-(Trichloromethyl)-benzo[d]oxazole (1a, 61 mg, 0.26
mmol) in H2O (1.0 mL) was stirred at 150 °C for 2 h. The solution
was allowed to cool to rt, and dichloromethane (10 mL) was added.
The resultant solution was washed with water (3 × 5 mL). The
organic layer was dried over magnesium sulfate, and the solvent was
removed in vacuo to afford 2,2,2-trichloro-N-(2-hydroxyphenyl)
acetamide (7, 24 mg, 37%) as a yellow solid. Mp 160−161 °C (lit.
1
mp 160 °C); IR (CHCl3, cm−1) 3594, 3397, 1720, 1615; H NMR
(300 MHz, CDCl3, 298 K) δH 8.98 (1H, br.s) 7.95 (1H, d, J = 8.0 Hz),
7.13−7.09 (1H, m), 7.02−6.93 (2H, m) 5.99 (1H br.s); 13C{1H}
NMR (75 MHz, CDCl3, 298 K) δc 159.7, 146.1, 126.6, 124.5, 121.7,
121.2, 116.5, 92.5; HRMS (ESI) m/z calcd for [M + H]+
+
C8H7Cl3NO2 253.9537, found 253.9534.
(Z)-2,2′-(1-Chloro-2-(pyrrolidin-1-yl)ethene-1,2-diyl)bis-
(benzo[d]-oxazole) (8). To a stirred suspension of 2-
(trichloromethyl)benzo[d]oxazole (1a, 150 mg, 0.6 mmol, 1.0
equiv) and iron(III) chloride (97 mg, 0.6 mmol, 1.0 equiv) in
acetonitrile (6 mL, 0.1 M) at rt was added pyrrolidine (260 μL, 3.17
Method C. To a stirred solution of 2-(trichloromethyl)benzo[d]-
oxazole (1a, 100 mg, 0.42 mmol) in acetonitrile (0.01 M) at ambient
temperature were added iron(III) chloride (68 mg, 0.42 mmol) and
pyrrolidine (40 μL, 0.47 mmol). The resultant solution was stirred at
D
DOI: 10.1021/acs.joc.6b02315
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
mmol, 5.0 equiv). The resultant mixture was stirred at rt for 19 h and
then filtered through base-washed silica. The solvent was removed in
vacuo, and the residue was purified by flash column chromatography
on silica gel (5% diethyl ether in petroleum ether) to afford (Z)-2,2′-
(1-chloro-2-(pyrrolidin-1-yl)ethene-1,2-diyl)bis(benzo[d]oxazole) (8,
58 mg, 26%) as a yellow solid. Rf = 0.40 (1:9 ethyl acetate/petroleum);
IR (CHCl3, cm−1) 2982, 2882, 1607, 1578, 1549; 1H NMR (300 MHz,
CDCl3, 298 K) δH 7.80−7.77 (1H, m), 7.56−7.54 (1H, m), 7.44−7.39
(3H, m), 7.13 (1H, apparent td, J = 7.7, 1.1 Hz), 7.05 (1H, apparent
td, J = 7.8, 1.3 Hz), 6.87 (1H, d, J = 7.8 Hz), 3.66−3.62 (4H, m),
2.00−1.97 (4H, m); 13C{1H} NMR (75 MHz, CDCl3, 298 K) δc
161.8, 158.1, 150.5, 150.4, 141.9, 141.2, 138.6, 126.1, 124.8, 124.1,
124.0, 120.9, 119.3, 111.1, 109.5, 94.7, 51.3 (2C), 25.6 (2C); HRMS
P.; Gao, P.; Liu, X.-Y.; Liang, Y.-M. J. Org. Chem. 2015, 80, 2263−
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+
(ESI) m/z calcd for [M + H]+ C20H17ClN3O2 366.1004, found
366.1000.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b02315.
■
(4) For the synthesis of 2-aminobenzoxazoles from activated starting
materials, see: (a) Kumar, R. U.; Reddy, H. V.; Kumar, B. S. P. A.;
Satish, G.; Reddy, V. P.; Nageswar, Y. V. D. Tetrahedron Lett. 2016, 57,
637−640. (b) Manolikakes, G.; Gavryushin, A.; Knochel, P. J. Org.
S
Tables of reaction parameters examined and copies of 1H
and 13C NMR spectra of all newly synthesized products
(PDF)
X-ray details of compound 6e (CIF)
X-ray details of compound 7 (CIF)
X-ray details of compound 8 (CIF)
Chem. 2008, 73, 1429−1434. (c) Cioffi, C. L.; Lansing, J. L.; Yuksel,
̈
H. J. Org. Chem. 2010, 75, 7942−7945.
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materials, see: (a) Zhang, Z.; Yin, Z.; Kadow, J. F.; Meanwell, N. A.;
Wang, T. J. Org. Chem. 2004, 69, 1360−1363. (b) Boger, D. L.;
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6654−6661. (c) Stover, J. S.; Shi, J.; Jin, W.; Vogt, P. K.; Boger, D. L. J.
Am. Chem. Soc. 2009, 131, 3342−3348. (d) Shin, S.; Kim, Y.; Kim, K.;
Hong, S. Org. Biomol. Chem. 2014, 12, 5719−5726.
AUTHOR INFORMATION
Corresponding Author
*E-mail: j.e.camp@hud.ac.uk.
■
(6) For the synthesis of 2-aminobenzoxazoles from unactivated
starting materials via C-H activation, see: (A) Froehr, T.; Sindlinger,
C. P.; Kloeckner, U.; Finkbeiner, P.; Nachtsheim, B. J. Org. Lett. 2011,
13, 3754−3757. (b) Joseph, J.; Kim, J. Y.; Chang, S. Chem. - Eur. J.
2011, 17, 8294−8298. (c) Wang, J.; Hou, J.-T.; Wen, J.; Zhang, J.; Yu,
X.-Q. Chem. Commun. 2011, 47, 3652−3654. (d) Chen, S.; Zheng, K.;
Chen, F. Tetrahedron Lett. 2012, 53, 6297−6299. (e) Xie, Y.; Qian, Bo;
Xie, P.; Huang, H. Adv. Synth. Catal. 2013, 355, 1315−1322. (f) Wertz,
S.; Kodama, S.; Studer, A. Angew. Chem., Int. Ed. 2011, 50, 11511−
11515. (g) Xu, D.; Wang, W.; Miao, C.; Zhang, Q.; Xia, C.; Sun, W.
Green Chem. 2013, 15, 2975−2980. (h) Armstrong, A.; Collins, J. C.
Angew. Chem., Int. Ed. 2010, 49, 2282−2285.
ORCID
William Lewis: 0000-0001-7103-6981
Jason E. Camp: 0000-0001-7394-2101
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The School of Chemistry at the University of Nottingham, the
Department of Chemical Sciences at the University of
Huddersfield, and a Royal Society Research Grant
(RG130535) supported this work.
(7) For the synthesis of 2-amidobenzoxazoles from unactivated
starting materials via C-H activation, see: He, Y.; Li, H.; Li, P.; Wang,
L. Chem. Commun. 2011, 47, 8946−8948.
(8) (a) Zuo, W.; Lough, A. J.; Li, Y. F.; Morris, R. H. Science 2013,
342, 1080−1083. (b) Friedfeld, M. R.; Shevlin, M.; Hoyt, J. M.; Krska,
S. W.; Tudge, M. T.; Chirik, P. J. Science 2013, 342, 1076−1080.
(c) Bullock, R. M. Science 2013, 342, 1054−1055.
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