Iron-Catalyzed Cycloaddition of Amides and 2,3-Diaryl-2 H-azirines to Access Oxazoles via C-N Bond Cleavage

Article abstract of DOI:10.1021/acs.joc.0c02843

A novel and efficient iron-catalyzed cycloaddition reaction using readily available 2,3-diaryl-2H-azirines and primary amides is reported. A wide range of trisubstituted oxazoles could be achieved in good yields with good functional group compatibility. In this transformation, two C-N bonds were cleaed and new C-N and C-O bonds were formed.

Full text of DOI:10.1021/acs.joc.0c02843

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Article
Iron-Catalyzed Cycloaddition of Amides and 2,3-Diaryl‑2H‑azirines
To Access Oxazoles via C−N Bond Cleavage
Mi-Na Zhao,* Gui-Wan Ning, De-Suo Yang, Ming-Jin Fan, Sheng Zhang, Peng Gao, and Li-Fang Zhao
Cite This: J. Org. Chem. 2021, 86, 2957−2964
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ABSTRACT: A novel and efficient iron-catalyzed cycloaddition
reaction using readily available 2,3-diaryl-2H-azirines and primary
amides is reported. A wide range of trisubstituted oxazoles could be
achieved in good yields with good functional group compatibility.
In this transformation, two C−N bonds were cleaed and new C−N
and C−O bonds were formed.
Scheme 1. Transformation of Amides by N−C(O) Bond
Cleavage To Construct New Chemical Bonds
INTRODUCTION
■
The oxazole skeleton is an important N-heterocyclic structural
unit widely found in natural products, biologically active
compounds, pharmaceuticals, and materials science.1 Examples
include siphonazole,2 aleglitazar,3 and ulapualide C.4 Owing to
their significant value, numerous strategies have been
developed to synthesize oxazole derivatives,5 mainly involving
oxidation of oxazoline,6 intramolecular cyclization of N-
propargylamide,7 or transition-metal-catalyzed intermolecular
cyclization.8 Despite these significant achievements on the
synthesis of oxazole derivatives, a concise and flexible method
for the synthesis of this type of skeleton remains highly
desirable.
Amides, which are key building blocks in organic synthesis,9
have been widely applied in transition-metal-free trans-
amidation via cleavage of an amide C−N bond to synthesize
widely valuable amides (Scheme 1a, left).10 Recently,
transition-metal-catalyzed cross-coupling reactions by selective
metal insertion into the inert N−C(O) bond have also been
developed for the synthesis of various ketones (Scheme 1a,
right).11 However, preactivated amides are generally required
for these reactions because N-substitution could facilitate
metal insertion. Meanwhile, the cyclization reaction of amides
via cleavage of C−N bond has rarely been reported12 and
remains a challenging task. 2H-Azirines are versatile synthetic
intermediates for the synthesis of various azaheterocycles by a
ring-opening reaction.13,14 Our interest in the transition-metal-
catalyzed transformation of 2H-azirines15 prompted us to study
the cycloaddition of 2H-azirines and primary amides. In this
paper, we describe a novel iron-catalyzed cycloaddition of 2,3-
diaryl-2H-azirines with primary amides (N-unsubstituted
amides) via cleavage of two C−N bonds for the synthesis of
trisubstituted oxazoles (Scheme 1b).
RESULTS AND DISCUSSION
■
We start our investigation by taking 2,3-diphenyl-2H-azirine 1a
and acetamide 2a in DCE at 80 °C (Table 1). Initially, a wide
range of different nickel and copper compounds were used as
catalysts. Disappointingly, there is no result (Table 1, entries 1
and 2). To our delight, when FeCl2 was used as catalyst, the 2-
methyl-4,5-diphenyloxazole 3aa was observed in 19% yield
Received: November 30, 2020
Published: January 14, 2021
https://dx.doi.org/10.1021/acs.joc.0c02843
© 2021 American Chemical Society
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a
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope with Respect to Ar1
entry
catalyst
[Ni]
[Cu]
solvent
DCE
DCE
T (°C)
yield (%)
b
1
80
80
0
0
c
2
3
4
5
6
7
8
9
FeCl2
FeCl3
Fe(acac)2
Fe(acac)3
Fe(OTf)2
Fe(OTf)3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
80
80
80
80
80
80
80
19
20
trace
trace
35
39
0
10
11
12
13
14
15
16
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
toluene
THF
CH3CN
1,4-dioxane
DMF
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
80
80
80
80
20
20
24
45
0
54
63
61
70
80
100
120
120
120
d
17
18
e
a
Reaction condition: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (5 mol
b
%), solvent (3 mL), 80 °C oil bath, 6 h. Ni(OAc)2, Ni(acac)2, or
c
NiCl2 was screened. Cu(OAc)2 or Cu(acac)2 was screened.
d
e
Fe(OTf)3 (10 mol %) was added. 2a (0.6 mmol) was added.
a
Reaction conditions: 1 (0.2 mmol), 2a (0.6 mmol), Fe(OTf)3 (5
mol %), 1,4-dioxane (3 mL), 120 °C oil bath, 6 h.
(Table 1, entry 3). Therefore, screening of Fe catalysts is
significant for this cycloaddition reaction. Gratifyingly, Fe-
(OTf)3 was found to be an effective catalyst by screening
different iron catalysts to give the desired oxazole 3aa in 39%
yield (Table 1, entries 4−8). Notably, iron catalyst plays a vital
role in the reaction. No reaction occurred in the absence of the
iron catalyst (Table 1, entry 9). For improving the reaction
efficiency, various solvents such as toluene, THF, CH3CN, 1,4-
dioxane, and DMF were also screened (Table 1, entries 10−
14). These results reveal that 1,4-dioxane was the best choice;
the yield of 3aa reached 45% (Table 1, entry 13). It was found
that increasing the reaction temperature to 120 °C could
improve the yield of 3aa to 63% (Table 1, entries 15 and 16).
However, increasing the amount of Fe(OTf)3 resulted in no
improvement (Table 1, entry 17). Pleasingly, the yield of the
desired product 3aa could be improved to 70% when a molar
ratio of [2a]/[1a] = 3/1 was employed (Table 1, entry 18).
Ultimately, the best conditions for the reaction were
determined as 1a (0.2 mmol), 2a (0.6 mmol), and Fe(OTf)3
(5 mol %) in 1,4-dioxane in a 120 °C oil bath.
fluoro, chloro, and bromo, were well tolerated in this reaction,
giving the desired oxazoles 3ia−3ka in good yields. In addition,
the desired oxazole 3la was also obtained in 48% yield when 2-
naphthyl-substituted 2H-azirine 1l was used as the substrate,
albeit in somewhat diminished yield. However, the alkyl-
substituted 2H-azirine, such as 3-methyl-2-phenyl-2H-azirine,
was incompatible under the reaction conditions.
Beyond variation of the substitution pattern at the Ar1
moiety, the changes on Ar2 were also tested (Scheme 3).
Substituents such as methyl, methoxyl, phenyl, or halogen
groups such as fluoro, chloro, and bromo at the Ar2 group of
2H-azirines have not much impacted this transformation. The
corresponding oxazoles 3ma−3ua were obtained in 53−66%
yields. From these results, the electronic nature effect of the
substituents on Ar2 is unconspicuous in this cycloaddition
reaction. Nevertheless, 2,5-dimethyl-substituted and 2,4,6-
trimethyl-substituted 2H-azirines 1o and 1p afforded the
desired oxazoles 3oa and 3pa in 55% and 53% yields. This
phenomenon indicates that the steric effect has a slight
influence on the reaction.
Encouraged by the above results, we were committed to
searching for other reactions with different substituents on Ar1
and Ar2 to further expand the range of substrates for the
transformation (Scheme 4). We were pleased to find that 2H-
azirines 1v−1y proceeded smoothly to give the corresponding
oxazoles 3va−3ya in 50−66% yields. The structure of 3wa was
clearly confirmed by X-ray crystallographic analysis (CCDC
2036963, see Supporting Information for details). At the same
With optimal reaction conditions in hand, we next turned
our attention to the scope of 2H-azirines that can participate in
this reaction (Scheme 2). Changing the Ar1 group on the C
N double bond moiety of the 2H-azirines was studied first. 2H-
Azirines bearing electron-donating groups on Ar1, such as
methyl, ethyl, tert-butyl, and methoxyl, all afforded the
corresponding trisubstituted oxazoles 3aa−3ha in 60−70%
yields.16 Of particular note, the required oxazoles 3ca and 3da
were successfully obtained in 68% and 63% yields when the Ar1
of 2H-azirines was ortho substituted, implying that the ring-
forming process was insensitive to the steric hindrance of Ar1.
2H-Azirines with an electron-withdrawing group, such as
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a
a
Scheme 3. Substrate Scope with Respect to Ar2
Scheme 5. Substrate Scope with Respect to Amides
a
Reaction conditions: 1a (0.2 mmol), 2 (0.6 mmol), Fe(OTf)3 (5
mol %), 1,4-dioxane (3 mL), 120 °C oil bath, 6 h.
Scheme 6. Investigation of the Reaction Mechanism
a
Reaction conditions: 1 (0.2 mmol), 2a (0.6 mmol), Fe(OTf)3 (5
mol %), 1,4-dioxane (3 mL), 120 °C oil bath, 6 h.
Scheme 4. Fe-Catalyzed Cycloaddition of Various 2H-
Azirines and Acetamide 2a
time, it was also confirmed that C−N single bond cleavage of
the 2H-azirine was involved in the reaction.
In addition, to further investigate the scope and limitation of
this cycloaddition reaction, a variety of amides with different
substituents were examined (Scheme 5). Expectedly, when we
replace the substrate acetamide (2a) with propamide (2b),
isobutyramide (2c), pivalamide (2d), and cyclopropanecarbox-
amide (2e), the corresponding oxazoles 3ab−3ae were
obtained in 50−75% yields. Meanwhile, the R group of
amide bearing phenyl 2f and benzyl 2g proceeded smoothly to
afford the desired oxazoles 3af and 3ag in 63% and 61% yields,
respectively. Strikingly, oxazole 3ah was also obtained in 40%
yield when R was substituted by an electron-withdrawing
group (−CH2Cl). However, no reaction occurred when the 5-
amino-3-(4-chlorophenyl)-5-oxopentanoic acid 2i was used as
the substrate.
the desired product 3aa in 66% or 65% yield, respectively
(Scheme 6, eq 1). These results indicate that a radical pathway
might not be involved in this transformation. Furthermore,
when N-methylacetamide 2j, N-phenylacetamide 2k, or N,N-
dimethylacetamide 2l was used instead of acetamide 2a, the
oxazole 3aa was obtained as well, albeit in low yield (Scheme
6, eq 2). This result confirmed that the nitrogen atom of the
oxazole ring should indeed come from 2H-azirines rather than
amides.
On the basis of the above experimental results and previous
reports,9−15 a plausible mechanism was postulated for the Fe-
catalyzed cycloaddition reaction (Scheme 7). Initially, C−N
bond cleavage of 2H-azirines 1 in the presence of Fe(III)
generated intermediate A. Then the oxygen of the amides 2
attacked the electrophilic carbon of intermediate A to form
intermediate B, which subsequently underwent intramolecular
cyclization to give intermediate C. Simultaneously, the Fe(III)
catalyst was released to facilitate the next catalytic cycle.
To achieve insights into the reaction mechanism, some
control experiments were conducted (Scheme 6). Addition of
a radical trapping reagent 2,2,6,6-tetramethylpiperidin-1-yl)-
oxyl (TEMPO) or butylated hydroxytoluene (BHT) produced
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2-Methyl-4,5-diphenyloxazole (3aa).8h Flash column chromatog-
raphy on silica gel (eluent: PE/EtOAc = 20/1, v/v) to afford 3aa.
Yield 70% (32.9 mg); yellow oil. H NMR (400 MHz, CDCl3) δ
Scheme 7. Proposed Mechanism for Fe-Catalyzed
Cycloaddition of 2H-Azirines and Amides
1
7.65−7.63 (m, 2H), 7.59−7.56 (m, 2H), 7.37−7.29 (m, 6H), 2.54 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.1, 145.2, 135.1, 132.4,
129.0, 128.5, 128.4, 128.3 127.9, 127.8, 126.3, 13.9. HRMS calcd
(ESI-TOF) m/z for C16H14NO: [M + H]+ 236.1099. Found:
236.1090.
2-Methyl-5-phenyl-4-(p-tolyl)oxazole (3ba).8h Flash column
chromatography on silica gel (eluent: PE/EtOAc = 20/1, v/v) to
1
afford 3ba. Yield 65% (32.4 mg); yellow oil. H NMR (400 MHz,
CDCl3) 7.59−7.56 (m, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.36−7.29 (m,
3H), 7.17−7.15 (m, 2H), 2.54 (s, 3H), 2.36 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 160.1, 144.9, 137.8, 135.2, 129.5, 129.2, 128.5,
128.2, 127.7, 126.3, 21.3, 13.9. HRMS calcd (ESI-TOF) m/z for
C17H16NO: [M + H]+ 250.1226. Found: 250.1231.
4-(2,5-Dimethylphenyl)-2-methyl-5-phenyloxazole (3ca). Flash
column chromatography on silica gel (eluent: PE/EtOAc = 20/1,
v/v) to afford 3ca. Yield 68% (35.9 mg); yellow solid; mp 50−51 °C.
1H NMR (400 MHz, CDCl3) δ 7.39−7.37 (m, 2H), 7.29−7.21 (m,
3H), 7.18−7.12 (m, 3H), 2.56 (s, 3H), 2.31 (s, 3H), 2.11 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 159.7, 145.5, 135.4, 135.0,
133.9, 132.2, 130.7, 130.3, 129.3, 129.0, 128.5, 127.6, 124.6, 20.8,
19.3, 14.0. HRMS calcd (ESI-TOF) m/z for C18H18NO: [M + H]+
264.1383. Found: 264.1390.
Finally, elimination of intermediate C by release of ammonia
gas (NH3) resulted in formation of the oxazole product 3.
CONCLUSION
■
In summary, we successfully developed a novel iron-catalyzed
cycloaddition reaction of 2,3-diaryl-2H-azirines with primary
amides, providing efficient access to valuable trisubstituted
oxazoles in moderate to good yields. This transformation
proceeds through cleavage of the C−N bond, followed by an
intermolecular nucleophilic addition/intramolecular cycliza-
tion in one pot. The readily available starting materials, low-
cost transition-metal catalysts, and good functional group
tolerance make this protocol attractive for organic synthesis.
Studies toward mechanistic investigations as well as on further
developments of the Fe-catalyzed transformations of 2H-
azirines are actively pursued in our laboratory.
4-(2,4-Dimethylphenyl)-2-methyl-5-phenyloxazole (3da).8h
Flash column chromatography on silica gel (eluent: PE/EtOAc =
1
20/1, v/v) to afford 3da. Yield 63% (33.2 mg); yellow oil. H NMR
(400 MHz, CDCl3) δ 7.39−7.37 (m, 2H), 7.28−7.20 (m, 4H), 7.09
(s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 2.55 (s, 3H), 2.36 (s, 3H), 2.14 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.6, 145.5, 138.3, 136.9,
135.0, 131.2, 130.1, 129.4, 129.0, 128.5, 127.6, 126.8, 124.7, 21.3,
19.7, 14.0. HRMS calcd (ESI-TOF) m/z for C18H18NO: [M + H]+
264.1383. Found: 264.1391.
4-(3,4-Dimethylphenyl)-2-methyl-5-phenyloxazole (3ea). Flash
column chromatography on silica gel (eluent: PE/EtOAc = 20/1, v/
1
EXPERIMENTAL SECTION
General Information. H NMR spectra were recorded at 400
v) to afford 3ea. Yield 64% (33.8 mg); yellow oil. H NMR (400
■
1
MHz, CDCl3) δ 7.59 (d, J = 8.0 Hz, 2H), 7.45 (s, 1H), 7.35−7.28 (m,
4H), 7.09 (d, J = 8.0 Hz, 1H), 2.54 (s, 3H), 2.27 (s, 3H), 2.25 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.0, 144.8, 136.8, 136.4,
135.3, 130.0, 129.7, 129.3, 129.0, 128.5, 128.1, 126.3, 125.2, 19.6,
19.6, 13.9. HRMS calcd (ESI-TOF) m/z for C18H18NO: [M + H]+
264.1383. Found: 264.1393.
MHz in CDCl3, and 13C NMR spectra were recorded at 100 MHz in
CDCl3. The following abbreviations (or combinations thereof) were
used to explain multiplicities: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, b = broad. Coupling constants, J, were
reported in Hertz (Hz). Melting points were determined with a digital
melting point measuring instrument. All products were characterized
by HRMS; copies of their 1H NMR and 13C NMR spectra are
provided in the Supporting Information. Unless otherwise stated, all
reagents and solvents were purchased from commercial suppliers and
used without further purification.
4-(4-Ethylphenyl)-2-methyl-5-phenyloxazole (3fa). Flash column
chromatography on silica gel (eluent: PE/EtOAc = 20/1, v/v) to
1
afford 3fa. Yield 67% (35.2 mg); yellow oil. H NMR (400 MHz,
CDCl3) δ 7.60−7.54 (m, 4H), 7.36−7.29 (m, 3H), 7.19 (d, J = 8.0
Hz, 2H), 2.69−2.63 (m, 2H), 2.54 (s, 3H), 1.25 (t, J = 8.0 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 160.0, 144.9, 144.1, 135.2,
129.8, 129.2, 128.5, 128.2, 128.0, 127.7, 126.4, 28.6, 15.3, 13.9.
HRMS calcd (ESI-TOF) m/z for C18H18NO: [M + H]+ 264.1383.
Found: 264.1390.
General Procedure. Synthesis of 2,3-Diaryl-2H-azirines 1
According to the Known Procedure.15 Compounds 1a−1y are
known and were identified by comparison of their NMR data with the
data reported in the literature.15c
4-(4-(tert-Butyl)phenyl)-2-methyl-5-phenyloxazole (3ga). Flash
column chromatography on silica gel (eluent: PE/EtOAc = 20/1, v/
Synthesis of Trisubstituted Oxazoles 3 According to the
Following Procedure. In a 25 mL round-bottom flask, the 2,3-
diaryl-2H-azirines 1 (0.2 mmol), amides 2 (0.6 mmol), and Fe(OTf)3
(0.01 mmol, 0.0050 g) were stirred in 1,4-dioxane (3 mL) at 120 °C
in an oil bath. After completion of the reaction (detected by TLC),
the reaction mixture was cooled to room temperature. The solvent
was evaporated under vacuum. The crude product was purified by
column chromatography on silica gel to afford the corresponding
oxazoles 3 with hexanes/ethyl acetate (v/v = 20:1) as the eluent.
Preparation of 3aa on Gram Scale. In a 25 mL round-bottom
flask, the 2,3-diphenyl-2H-azirine 1a (6 mmol, 1.16 g), acetamide 2a
(18 mmol, 1.06 g), and Fe(OTf)3 (0.3 mmol, 0.1509 g) were stirred
in 1,4-dioxane (15 mL) at 120 °C in an oil bath. After completion of
the reaction (detected by TLC), the reaction mixture was cooled to
room temperature. The solvent was evaporated under vacuum. The
crude product was purified by column chromatography on silica gel to
afford the oxazole 3aa in 64% yield (0.910 g) with hexanes/ethyl
acetate (v/v = 20:1) as the eluent.
1
v) to afford 3ga. Yield 60% (34.9 mg); yellow oil. H NMR (400
MHz, CDCl3) δ 7.62−7.56 (m, 4H), 7.38−7.30 (m, 5H), 2.53 (s,
3H), 1.33 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.0, 151.0,
144.9, 135.1, 129.5, 129.3, 128.6, 128.2, 127.4, 126.4, 125.4, 34.6,
31.3, 13.9. HRMS calcd (ESI-TOF) m/z for C20H22NO: [M + H]+
292.1696. Found: 292.1706.
4-(4-Methoxyphenyl)-2-methyl-5-phenyloxazole (3ha).8h Flash
column chromatography on silica gel (eluent: PE/EtOAc = 15/1, v/
1
v) to afford 3ha. Yield 62% (32.9 mg); yellow oil. H NMR (400
MHz, CDCl3) δ 7.58−7.54 (m, 4H), 7.36−7.29 (m, 3H), 6.90 (d, J =
8.0 Hz, 2H), 3.83 (s, 3H), 2.54 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 160.0, 159.4, 144.5, 134.9, 129.3, 129.1, 128.6, 128.1, 126.2,
124.9, 114.0, 55.2, 13.9. HRMS calcd (ESI-TOF) m/z for
C17H16NO2: [M + H]+ 266.1176. Found: 266.1183.
4-(4-Fluorophenyl)-2-methyl-5-phenyloxazole (3ia).8h Flash col-
umn chromatography on silica gel (eluent: PE/EtOAc = 20/1, v/v) to
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afford 3ia. Yield 62% (31.2 mg); yellow oil. H NMR (400 MHz,
CDCl3) δ 7.62−7.58 (m, 2H), 7.56−7.53 (m, 2H), 7.38−7.31 (m,
3H), 7.07−7.02 (m, 2H), 2.54 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 162.5 (C−F, d, JC−F = 246.0 Hz), 160.2, 145.2, 134.2, 129.6
(C−F, d, JC−F = 8.0 Hz), 128.9, 128.7, 128.6, 128.6, 128.4, 126.4,
115.5 (C−F, d, JC−F = 21.0 Hz), 13.9. HRMS calcd (ESI-TOF) m/z
for C16H13FNO: [M + H]+ 254.0976. Found: 254.0980.
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.6, 159.6, 145.3, 133.8,
132.6, 128.4, 128.0, 127.7, 127.5, 121.6, 114.0, 55.2, 13.9. HRMS
calcd (ESI-TOF) m/z for C17H16NO2: [M + H]+ 266.1176. Found:
266.1183.
5-([1,1′-Biphenyl]-4-yl)-2-methyl-4-phenyloxazole (3ra).8h Flash
column chromatography on silica gel (eluent: PE/EtOAc = 20/1, v/
v) to afford 3ra. Yield 62% (38.4 mg); yellow solid; mp 55−58 °C. 1H
NMR (400 MHz, CDCl3) δ 7.69−7.64 (m, 4H), 7.61−7.56 (m, 4H),
7.45−7.32 (m, 6H), 2.56 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ 160.2, 145.1, 141.0, 140.3, 135.3, 132.6, 128.8, 128.5, 128.0, 128.0,
127.9, 127.6, 127.2, 126.9, 126.7, 14.0. HRMS calcd (ESI-TOF) m/z
for C22H18NO: [M + H]+ 312.1383. Found: 312.1393.
4-(4-Chlorophenyl)-2-methyl-5-phenyloxazole (3ja).8h Flash col-
umn chromatography on silica gel (eluent: PE/EtOAc = 20/1, v/v) to
1
afford 3ja. Yield 61% (32.7 mg); yellow solid; mp 43−45 °C. H
NMR (400 MHz, CDCl3) δ 7.58−7.53 (m, 4H), 7.38−7.30 (m, 5H),
2.54 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.3, 145.6,
134.0, 133.7, 131.0, 129.0, 128.8, 128.7, 128.7, 128.6, 126.5, 13.9.
HRMS calcd (ESI-TOF) m/z for C16H13ClNO: [M + H]+ 270.0680.
Found: 270.0687.
5-(3-Fluorophenyl)-2-methyl-4-phenyloxazole (3sa). Flash col-
umn chromatography on silica gel (eluent: PE/EtOAc = 20/1, v/v) to
1
afford 3sa. Yield 61% (30.8 mg); yellow oil. H NMR (400 MHz,
4-(4-Bromophenyl)-2-methyl-5-phenyloxazole (3ka).8h Flash
column chromatography on silica gel (eluent: PE/EtOAc = 20/1,
v/v) to afford 3ka. Yield 60% (37.6 mg); yellow solid; mp 54−57 °C.
1H NMR (400 MHz, CDCl3) δ 7.56−7.46 (m, 6H), 7.38−7.32 (m,
3H), 2.53 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.3, 145.6,
134.0, 131.7, 131.4, 129.3, 128.8, 128.7, 128.6, 126.5, 121.9, 13.9.
HRMS calcd (ESI-TOF) m/z for C16H13BrNO: [M + H]+ 314.0175.
Found: 314.0185.
CDCl3) δ 7.63−7.60 (m, 2H), 7.41−7.34 (m, 4H), 7.32−7.26 (m,
2H), 7.01−7.69 (m, 1H), 2.55 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 162.8 (C−F, d, JC−F = 244.0 Hz), 160.5, 144.0, 136.2,
132.2, 131.0 (C−F, d, JC−F = 8.0 Hz), 130.2 (C−F, d, JC−F = 8.0 Hz),
128.6, 128.3, 128.0, 121.8, 115.1 (C−F, d, JC−F = 21.0 Hz), 113.1
(C−F, d, JC−F = 24.0 Hz), 13.9. HRMS calcd (ESI-TOF) m/z for
C16H13FNO: [M + H]+ 254.0976. Found: 254.0982.
5-(4-Chlorophenyl)-2-methyl-4-phenyloxazole (3ta).8h Flash col-
umn chromatography on silica gel (eluent: PE/EtOAc = 20/1, v/v) to
2-Methyl-4-(naphthalen-2-yl)-5-phenyloxazole (3la).8h Flash
column chromatography on silica gel (eluent: PE/EtOAc = 20/1,
v/v) to afford 3la. Yield 48% (27.3 mg); yellow oil. H NMR (400
1
afford 3ta. Yield 65% (35.0 mg); yellow solid; mp 33−35 °C. H
1
NMR (400 MHz, CDCl3) δ 7.61−7.59 (m, 2H), 7.52−7.49 (m, 2H),
7.39−7.30 (m, 5H), 2.54 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ 160.4, 144.2, 135.6, 134.1, 132.2, 128.9, 128.6, 128.2, 127.8, 127.5,
127.5, 13.9. HRMS calcd (ESI-TOF) m/z for C16H13ClNO: [M +
H]+ 270.0680. Found: 270.0679.
MHz, CDCl3) δ 8.18 (s, 1H), 7.83−7.79 (m, 3H), 7.70−7.67 (m,
1H), 7.62−7.59 (m, 2H), 7.47−7.45 (m, 2H), 7.36−7.31 (m, 3H),
2.58 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.3, 145.7,
135.1, 133.5, 133.0, 129.9, 129.1, 128.6, 128.4, 128.2, 128.0, 127.6,
126.9, 126.5, 126.2, 126.1, 125.6, 14.0. HRMS calcd (ESI-TOF) m/z
for C20H16NO: [M + H]+ 286.1226. Found: 286.1235.
5-(3-Bromophenyl)-2-methyl-4-phenyloxazole (3ua). Flash col-
umn chromatography on silica gel (eluent: PE/EtOAc = 20/1, v/v) to
2-Methyl-4-phenyl-5-(p-tolyl)oxazole (3ma).8h Flash column
chromatography on silica gel (eluent: PE/EtOAc = 20/1, v/v) to
1
afford 3ua. Yield 64% (40.1 mg); yellow solid; mp 66−69 °C. H
NMR (400 MHz, CDCl3) δ 7.76−7.75 (m, 1H), 7.62−7.60 (m, 2H),
7.50−7.47 (m, 1H), 7.44−7.34 (m, 4H), 7.18 (t, J = 8.0 Hz, 1H),
2.55 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.6, 143.7,
136.2, 132.1, 131.2, 131.0, 130.1, 129.0, 128.6, 128.4, 127.9, 124.7,
122.7, 14.0. HRMS calcd (ESI-TOF) m/z for C16H13BrNO: [M +
H]+ 314.0175. Found: 314.0180.
1
afford 3ma. Yield 66% (33.1 mg); yellow solid; mp 49−51 °C. H
NMR (400 MHz, CDCl3) δ 7.64−7.62 (m, 2H), 7.47−7.45 (m, 2H),
7.37−7.29 (m, 3H), 7.15 (d, J = 8.0 Hz, 2H), 2.53 (s, 3H), 2.36 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.9, 145.5, 138.4, 134.5,
132.6, 129.3, 128.4, 127.8, 127.7, 126.4, 126.2, 21.3, 13.9. HRMS
calcd (ESI-TOF) m/z for C17H16NO: [M + H]+ 250.1226. Found:
250.1228.
2-Methyl-4,5-di-p-tolyloxazole (3va).5i Flash column chromatog-
raphy on silica gel (eluent: PE/EtOAc = 20/1, v/v) to afford 3va.
2-Methyl-4-phenyl-5-(o-tolyl)oxazole (3na).8h Flash column
chromatography on silica gel (eluent: PE/EtOAc = 20/1, v/v) to
1
Yield 63% (33.2 mg); brown solid; mp 77−80 °C. H NMR (400
MHz, CDCl3) δ 7.52 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H),
7.16−7.13 (m, 4H), 2.52 (s, 3H), 2.35 (s, 6H). 13C{1H} NMR (100
MHz, CDCl3) δ 159.7, 145.1, 138.2, 137.6, 134.6, 129.7, 129.2, 129.1,
127.6, 126.4, 126.4, 21.3, 21.3, 13.9. HRMS calcd (ESI-TOF) m/z for
C18H18NO: [M + H]+ 264.1383. Found: 264.1391.
1
afford 3na. Yield 62% (30.8 mg); yellow oil. H NMR (400 MHz,
CDCl3) δ 7.52−7.49 (m, 2H), 7.38−7.33 (m, 2H), 7.30−7.21 (m,
5H), 2.54 (s, 3H), 2.18 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
160.4, 145.1, 137.9, 135.6, 132.1, 130.7, 130.5, 129.5, 129.0, 128.4,
127.4, 126.4, 126.0, 19.9, 14.0. HRMS calcd (ESI-TOF) m/z for
C17H16NO: [M + H]+ 250.1226. Found: 250.1235.
5-(2,5-Dimethylphenyl)-2-methyl-4-phenyloxazole (3oa). Flash
column chromatography on silica gel (eluent: PE/EtOAc = 20/1, v/
4-(4-Chlorophenyl)-2-methyl-5-(p-tolyl)oxazole (3wa). Flash col-
umn chromatography on silica gel (eluent: PE/EtOAc = 20/1, v/v) to
1
afford 3wa. Yield 66% (37.3 mg); yellow solid; mp 127−130 °C. H
NMR (400 MHz, CDCl3) δ 7.58−7.56 (m, 2H), 7.44 (d, J = 8.0 Hz,
2H), 7.33−7.30 (m, 2H), 7.17 (d, J = 8.0 Hz, 2H), 2.53 (s, 3H), 2.37
(s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 160.1, 145.7, 138.7,
133.5, 133.4, 131.1, 129.4, 128.9, 128.7, 126.5, 125.9, 21.4, 13.9.
HRMS calcd (ESI-TOF) m/z for C17H15ClNO: [M + H]+ 284.0837.
Found: 284.0838.
1
v) to afford 3oa. Yield 55% (28.9 mg); yellow oil. H NMR (400
MHz, CDCl3) δ 7.53−7.50 (m, 2H), 7.28−7.16 (m, 6H), 2.54 (s,
3H), 2.32 (s, 3H), 2.11 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
160.3, 145.2, 135.5, 135.4, 134.7, 132.1, 130.9, 130.6, 130.3, 128.8,
128.4, 127.4, 126.3, 20.8, 19.4, 14.0. HRMS calcd (ESI-TOF) m/z for
C18H18NO: [M + H]+ 264.1383. Found: 264.1386.
5-Mesityl-2-methyl-4-phenyloxazole (3pa). Flash column chro-
matography on silica gel (eluent: PE/EtOAc = 20/1, v/v) to afford
5-(4-Chlorophenyl)-4-(2,5-dimethylphenyl)-2-methyloxazole
(3xa). Flash column chromatography on silica gel (eluent: PE/EtOAc
= 20/1, v/v) to afford 3xa. Yield 62% (36.7 mg); yellow solid; mp
70−73 °C. 1H NMR (400 MHz, CDCl3) δ 7.32−7.29 (m, 2H),
7.25−7.22 (m, 2H), 7.17−7.11 (m, 3H), 2.55 (s, 3H), 2.31 (s, 3H),
2.10 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 159.9, 144.6,
135.6, 135.5, 133.8, 133.4, 131.9, 130.5, 130.4, 129.5, 128.8, 127.4,
125.8, 20.8, 19.2, 14.0. HRMS calcd (ESI-TOF) m/z for
C18H17ClNO: [M + H]+ 298.0993. Found: 298.0996.
4-(4-bromophenyl)-5-(4-chlorophenyl)-2-methyloxazole (3ya).
Flash column chromatography on silica gel (eluent: PE/EtOAc =
20/1, v/v) to afford 3ya. Yield 50% (34.6 mg); yellow solid; mp 156−
158 °C. 1H NMR (400 MHz, CDCl3) δ 7.49−7.46 (m, 6H), 7.33 (d,
J = 8.0 Hz, 2H), 2.54 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
1
3pa. Yield 53% (29.4 mg); brown solid; mp 51−54 °C. H NMR
(400 MHz, CDCl3) δ 7.48−7.45 (m, 2H), 7.26−7.18 (m, 3H), 6.96
(s, 2H), 2.54 (s, 3H), 2.35 (s, 3H), 2.06 (s, 6H). 13C{1H} NMR (100
MHz, CDCl3) δ 160.6, 144.0, 139.6, 138.8, 135.6, 132.1, 128.6, 128.5,
127.2, 125.8, 125.4, 21.3, 19.9, 14.0. HRMS calcd (ESI-TOF) m/z for
C19H20NO: [M + H]+ 278.1539. Found: 278.1548.
5-(4-Methoxyphenyl)-2-methyl-4-phenyloxazole (3qa).8h Flash
column chromatography on silica gel (eluent: PE/EtOAc = 15/1, v/
v) to afford 3qa. Yield 60% (31.7 mg); yellow solid; mp 51−53 °C.
1H NMR (400 MHz, CDCl3) δ 7.64−7.62 (m, 2H), 7.51−7.49 (m,
2H), 7.37−7.29 (m, 3H), 6.89−6.87 (m, 2H), 3.82 (s, 3H), 2.35 (s,
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160.6, 144.5, 134.6, 134.5, 131.8, 131.2, 129.3, 129.0, 127.7, 127.3,
122.2, 13.9. HRMS calcd (ESI-TOF) m/z for C16H12BrClNO: [M +
H]+ 347.9785. Found: 347.9790.
Accession Codes
CCDC 2036963 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
2-Ethyl-4,5-diphenyloxazole (3ab).8h Flash column chromatog-
raphy on silica gel (eluent: PE/EtOAc = 60/1, v/v) to afford 3ab.
1
Yield 67% (33.3 mg); yellow oil. H NMR (400 MHz, CDCl3) δ
7.66−7.63 (m, 2H), 7.60−7.57 (m, 2H), 7.39−7.30 (m, 6H), 2.91−
2.85 (m, 2H), 1.42 (t, J = 8.0 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 164.5, 145.0, 134.9, 132.6, 129.1, 128.6, 128.5, 128.2, 127.9,
127.9, 126.3, 21.7, 11.4. HRMS calcd (ESI-TOF) m/z for C17H16NO:
[M + H]+ 250.1226. Found: 250.1237.
AUTHOR INFORMATION
Corresponding Author
■
2-Isopropyl-4,5-diphenyloxazole (3ac).8h Flash column chroma-
tography on silica gel (eluent: PE/EtOAc = 70/1, v/v) to afford 3ac.
Mi-Na Zhao − Shaanxi Key Laboratory of Phytochemistry,
College of Chemistry and Chemical Engineering, Baoji
University of Arts and Sciences, Baoji 721013, P. R. China;
orcid.org/0000-0001-7937-9284; Email: zhaomina@
bjwlxy.edu.cn
1
Yield 71% (37.5 mg); yellow solid; mp 30−33 °C. H NMR (400
MHz, CDCl3) δ 7.65 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H),
7.38−7.27 (m, 6H), 3.21−3.14 (m, 1H), 1.44 (s, 3H), 1.43 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 167.6, 144.7, 134.8, 132.7,
129.2, 128.5, 128.5, 128.2, 127.9, 127.9, 126.3, 28.5, 20.5. HRMS
calcd (ESI-TOF) m/z for C18H18NO: [M + H]+ 264.1383. Found:
264.1390.
Authors
Gui-Wan Ning − Shaanxi Key Laboratory of Phytochemistry,
College of Chemistry and Chemical Engineering, Baoji
University of Arts and Sciences, Baoji 721013, P. R. China
De-Suo Yang − Shaanxi Key Laboratory of Phytochemistry,
College of Chemistry and Chemical Engineering, Baoji
University of Arts and Sciences, Baoji 721013, P. R. China;
orcid.org/0000-0002-7190-3122
Ming-Jin Fan − Shaanxi Key Laboratory of Phytochemistry,
College of Chemistry and Chemical Engineering, Baoji
University of Arts and Sciences, Baoji 721013, P. R. China;
orcid.org/0000-0003-4343-4514
Sheng Zhang − Shaanxi Key Laboratory of Phytochemistry,
College of Chemistry and Chemical Engineering, Baoji
University of Arts and Sciences, Baoji 721013, P. R. China;
orcid.org/0000-0001-9370-0548
Peng Gao − Shaanxi Key Laboratory of Phytochemistry,
College of Chemistry and Chemical Engineering, Baoji
University of Arts and Sciences, Baoji 721013, P. R. China;
orcid.org/0000-0003-1292-0691
2-(tert-Butyl)-4,5-diphenyloxazole (3ad).5h Flash column chro-
matography on silica gel (eluent: PE/EtOAc = 80/1, v/v) to afford
3ad. Yield 75% (41.6 mg); yellow oil. 1H NMR (400 MHz, CDCl3) δ
7.66−7.64 (m, 2H), 7.59−7.57 (m, 2H), 7.38−7.29 (m, 6H), 1.48 (s,
9H). 13C{1H} NMR (100 MHz, CDCl3) δ 169.8, 144.6, 134.8, 132.8,
129.3, 128.5, 128.5, 128.1, 128.1, 127.9, 126.3, 33.7, 28.7. HRMS
calcd (ESI-TOF) m/z for C19H20NO: [M + H]+ 278.1539. Found:
278.1547.
2-Cyclopropyl-4,5-diphenyloxazole (3ae).5i Flash column chro-
matography on silica gel (eluent: PE/EtOAc = 40/1, v/v) to afford
3ae. Yield 50% (26.2 mg); yellow solid; mp 61−63 °C. 1H NMR (400
MHz, CDCl3) δ 7.64−7.61 (m, 2H), 7.56−7.53 (m, 2H), 7.38−7.29
(m, 6H), 2.18−2.12 (m, 1H), 1.19−1.17 (m, 2H), 1.11−1.06 (m,
2H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.7, 144.3, 135.1, 132.6,
129.1, 128.5, 128.5, 128.1, 127.9, 127.9, 126.2, 8.95, 8.25. HRMS
calcd (ESI-TOF) m/z for C18H16NO: [M + H]+ 262.1226. Found:
262.1234.
2,4,5-Triphenyloxazole (3af).5i Flash column chromatography on
silica gel (eluent: PE/EtOAc = 70/1, v/v) to afford 3af. Yield 63%
(37.3 mg); yellow solid; mp 100−103 °C. 1H NMR (400 MHz,
CDCl3) δ 8.17−8.14 (m, 2H), 7.74−7.72 (m, 2H), 7.69−7.66 (m,
2H), 7.49−7.45 (m, 3H), 7.42−7.33 (m, 6H). 13C{1H} NMR (100
MHz, CDCl3) δ 160.1, 145.5, 136.8, 132.6, 130.3, 129.0, 128.7, 128.7,
128.6, 128.5, 128.2, 128.1, 127.4, 126.5, 126.4. HRMS calcd (ESI-
TOF) m/z for C21H16NO: [M + H]+ 298.1226. Found: 298.1224.
2-Benzyl-4,5-diphenyloxazole (3ag).8e Flash column chromatog-
raphy on silica gel (eluent: PE/EtOAc = 40/1, v/v) to afford 3ag.
Li-Fang Zhao − Shaanxi Key Laboratory of Phytochemistry,
College of Chemistry and Chemical Engineering, Baoji
University of Arts and Sciences, Baoji 721013, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02843
1
Notes
Yield 61% (37.8 mg); yellow solid; mp 75−77 °C. H NMR (400
The authors declare no competing financial interest.
MHz, CDCl3) δ 7.65−7.63 (m, 2H), 7.56−7.53 (m, 2H), 7.42−7.26
(m, 11H), 4.20 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 161.6,
145.7, 135.5, 135.3, 132.5, 129.0, 128.9, 128.7, 128.6, 128.5, 128.4,
128.0, 127.9, 127.0, 126.5, 34.8. HRMS calcd (ESI-TOF) m/z for
C22H18NO: [M + H]+ 312.1383. Found: 312.1379.
ACKNOWLEDGMENTS
■
This work was supported by generous grants from the Natural
Science Foundation of Shaanxi Province (No. 2018JQ2031),
Scientific Research Foundation of Shaanxi Provincial Key
Laboratory (No. 19JS006), the Baoji University of Arts and
Sciences (No. ZK2018057), and the China Postdoctoral
Science Foundation (No. 2019T120936).
2-(Chloromethyl)-4,5-diphenyloxazole (3ah).5j Flash column
chromatography on silica gel (eluent: PE/EtOAc = 40/1, v/v) to
1
afford 3ah. Yield 40% (21.4 mg); yellow solid; mp 35−38 °C. H
NMR (400 MHz, CDCl3) δ 7.65−7.60 (m, 4H), 7.40−7.35 (m, 6H),
4.70 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 157.6, 147.0,
135.8, 131.8, 129.0, 128.7, 128.6, 128.4, 128.3, 127.9, 126.7, 36.0.
HRMS calcd (ESI-TOF) m/z for C16H13ClNO: [M + H]+ 270.0680.
Found: 270.0685.
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sı
* Supporting Information
The Supporting Information is available free of charge at
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1H and 13C NMR spectra for products (PDF)
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