[3+1+1] Annulation Reaction of Benzo-1,2-Quinones, Aldehydes and Hydroxylamine Hydrochloride: Access to Benzoxazoles with Inorganic Nitrogen Source

Article abstract of DOI:10.1002/adsc.202001521

A synthesis of benzoxazoles with an inorganic nitrogen source is reported. By employing large-tonnage industrial feedstock inorganic hydroxylamine hydrochloride as the nitrogen source, its [3+1+1] annulation reaction with benzo-1,2-quinones and aldehydes

Full text of DOI:10.1002/adsc.202001521

FULL PAPER
DOI: 10.1002/adsc.202001521
[3+1+1] Annulation Reaction of Benzo-1,2-Quinones, Aldehydes
and Hydroxylamine Hydrochloride: Access to Benzoxazoles with
Inorganic Nitrogen Source
Fulin Chen,a Chuanle Zhu,a and Huanfeng Jianga, b,*
a
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering,
South China University of Technology, Guangzhou 510640, People’s Republic of China
Fax: (+86) 20-87112906
E-mail: jianghf@scut.edu.cn
b
State Key Laboratory of Applied Organic Chemistry (Lanzhou University), Lanzhou 730000, People’s Republic of China
Manuscript received: December 6, 2020; Revised manuscript received: February 17, 2021;
Version of record online: March 9, 2021
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001521
Abstract: A synthesis of benzoxazoles with an inorganic nitrogen source is reported. By employing large-
tonnage industrial feedstock inorganic hydroxylamine hydrochloride as the nitrogen source, its [3+1+1]
annulation reaction with benzo-1,2-quinones and aldehydes delivers various useful benzoxazoles in high
yields. Preliminary mechanistic studies prove that the quinone oxime rather than the aldehyde oxime is the
reaction intermediate.
Keywords: multi-component reaction; benzoxazoles; inorganic nitrogen source; annulation
Introduction
Hydroxylamine hydrochloride is a well-known
inorganic reagent. As an inexpensive and abundant
Benzoxazole skeletons are extraordinarily valuable industry feedstock in the areas of chemistry and
structures existed in multidisciplinary fields, such as
natural products, materials, pharmaceuticals, and bio-
logically active molecules.[1–2] Therefore, the develop-
ment of efficient methods for the construction of
benzoxazoles becomes a more and more important
research topic in synthetic chemistry.[3–8] According to
nitrogen source for the construction of the benzoxazole
rings, these well documented methods could be
classified into four types: 1) condensation of 2-
hydroxyanilines with carbonyl-containing substrates
(Scheme 1, a),[3] 2) transition-metal-catalyzed annula-
tion reaction of alkyl amines with phenol derivatives
(Scheme 1, b),[4] 3) tandem cyclization reactions of
imines with phenol and their analogues (Scheme 1,
c),[5] and 4) intermolecular coupling reactions of
amides with 1,2-dihalogenated aromatic compounds
(Scheme 1, d).[6] Despite of this progress, however,
these reported synthetic methods generally require the
organic amine compounds as the nitrogen source to
construct the benzoxazole ring. However, the method
for the construction of these useful compounds with an
inorganic amino source has not been reported.
Scheme 1. Nitrogen Source in the Synthesis of Benzoxazoles.
Adv. Synth. Catal. 2021, 363, 2124–2132
2124
© 2021 Wiley-VCH GmbH

FULL PAPER
asc.wiley-vch.de
chemical industry, it has been used to construct various desired product 4a in reasonable yields (entries 2–5),
high value-added N-heterocycles.[9] To the best of our while nonprotic nonpolar solvent seemed to be fatal to
knowledge, the utilizatioin of hydroxylamine this transformation, because only trace amount of
hydrochloride as the inorganic nitrogen source for the product 4a was detected under these conditions
synthesis of benzoxazoles has not been reported. (entries 6–8). Gratifyingly, a protic polar solvent of
Benzo-1,2-quinones, as a class of stable and readily CH3CH2OH improved the yield of 4a to 65% (entry 9).
available raw materials, have been employed as Moreover, changing the reaction temperature in either
oxidants in many oxidative transformations,[10] and direction eroded the yield of 4a slightly (entries 10–
served as fundamental building blocks inmaterial 11). Prolonging the reaction time to 24 h, the NMR
science,[11] ligand design,[12] catalyst engineering,[13] yield of 4a was further enhanced to 73% (entries 12–
and the construction of complexmolecules.[14] As our 13).
recent interest for the construction of heterocyclic
With the established reaction conditions in hand
compounds with benzo-1,2-quinones,[15] we herein (Table 1, entry 13), the scope of the aldehydes was
describe a highly chemoselective [3+1+1] annulation explored firstly for this cyclization reaction, and the
of benzo-1,2-quinones, aldehydes and hydroxylamine results were summarized in Table 2. In general, a series
hydrochloride for the direct synthesis of benzoxazoles of aldehydes with both electron-donating and electron-
under transition-metal-free conditions. This protocol withdrawing substituents at the para-, meta-, and
features operationally simple, a broad substrate scope, ortho- position of the phenyl ring has no influence on
high yields, valuable functional group tolerance, and the conversion, the corresponding products 4a–w were
gram-scalable.
isolated in highly yields. Functional groups such as
alkoxy, methylthio, amino, halo, nitro, cyano and
trifluoromethyl groups were well tolerated under this
reaction system, providing ample potential for further
Results and Discussion
We commenced our exploration with optimization synthetic utilities. Moreover, the structure of 4s was
studies by screening the reaction parameters of unambiguously confirmed by single-crystal X-ray
aldehyde 1a, benzo-1,2-quinone 2a and hydroxyl- crystallography.[16] 1-Naphthaldehyde and 2-naphthal-
amine hydrochloride 3a. The desired product 4a was dehyde gave the corresponding products 4x and 4y in
detected by NMR in 22% yield, when CH3CN was 60% and 62% yields, respectively. Different heteroar-
°
used as the solvent at 110 C under N2 for 12 h omatic aldehydes such as pyridyl, thienyl, and furanyl
(Table 1, entry 1). Then different types of solvents aldehydes were well tolerated, and the desired products
were screened. Nonprotic polar solvent such as 4z–4ac were obtained in moderate to good yields.
DMSO, DMF, DMA, and NMP could afford the Cinnamaldehyde was also found to be good substrate
Table 1. Optimization of the reaction conditions.[a]
Table 2. Substrate Scope of Aldehydes.[a]
[b]
°
Entry Solvent
Time (h) Temp ( C) Yield of 4a (%)
1
2
3
CH3CN
DMSO
DMF
12
12
12
12
12
12
12
12
110
110
110
110
110
110
110
110
110
100
120
110
110
22
25
45
45
4
5
DMA
NMP
10
6
DCE
trace
trace
trace
65
7
THF
8
toluene
9
CH3CH2OH 12
CH3CH2OH 12
CH3CH2OH 12
CH3CH2OH 18
CH3CH2OH 24
10
11
12
13
53
60
70
73(70)
[a] Reaction conditions: 1 (0.4 mmol), 2a (0.2 mmol), 3a
[a] Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), 3a
(0.4 mmol), CH3CH2OH (2.0 mL), 110 C, N2, 24 h. Isolated
°
(0.4 mmol), solvent (2.0 mL) under N2 for 12 h.
yield.
[b] Determined by H NMR using BrCH2CH2Br as the internal
[b] ORTEP representation with 50% probability thermal ellip-
soids of a crystal structure of 4s.
1
standard. The value in parentheses is the isolated yield.
Adv. Synth. Catal. 2021, 363, 2124–2132
2125
© 2021 Wiley-VCH GmbH

FULL PAPER
asc.wiley-vch.de
to give product 4ad in 45% yield. In addition, aliphatic benzo-1,2-quinones also afforded product 4aq in 51%
3-phenylpropanal also delivered the desired product yield.
4ae in acceptable yield.
To demonstrate the potential utility of this reaction,
To further define the generality of our method, the a 5 mmol scale reaction was performed under the
substrate scope was extended to different benzo-1,2- standard reaction to give product 4a in 60% yield
quinones (Table 3). Pleasingly, diverse di-substituted (Scheme 2).
benzo-1,2-quinones derivatives could undergo reaction
A series of mechanistic experiments were per-
smoothly with 1a and 3a to give the corresponding formed to further clarify the reaction pathway as
products in moderate to good isolated yields. Benzo- shown in Scheme 3. Quinone oxime 5 was synthesized,
1,2-quinones with both electron-donating substitutents which could give the desired product 4a in 88% yield
such as methyl, and methylthio groups, and electron- under the standard reaction conditions (Scheme 3,
withdrawing substitutents such as fluoro, chloro, and eq 1), however the aldehyde oxime 6 could not afford
cyano groups, were well tolerated, the obtained the desired product 4a under the standard reaction
products 4af–4au might be beneficial for further conditions (Scheme 3, eq 2). These results indicated
coupling reactions. It is worth mentioning that that the quinone oxime 5 rather than aldehyde oxime 6
unprotected hydroxyl group could also be tolerated was the reaction intermediate. 3,5-Di-tert-butylben-
under the standard reaction conditions, delivering the zene-1,2-diol 7 was used instead of 3,5-Di-tert-butyl-
desired product 4aj in 76% yield. Heteroaromatic o-benzoquinone 2a, product 4a was detected in <2%
yield, which also ruled out compound 7 as an
intermediate in this reaction (Scheme 3, eq 3). Impor-
Table 3. Substrate Scope of Benzo-1,2-quinones.[a]
tantly, the oxidation of 3,5-di-tert-butylbenzene-1,2-
diol 7 to 3,5-di-tert-butyl-o-benzoquinone 2a was
difficult under this copper-free reaction system,[4c]
because only a trace amount of 4a was detected
(Scheme 3, eq 4). It is noted that when air instead of
N2 was tested, the corresponding product 4a was
obtained in 26% yield (Scheme 3, eq 5).
Furthermore, compared with aldehyde oxime 6 the
kinetic dynamic analysis showed that quinone oxime 5
was generated more efficiently by the condensation of
benzo-1,2-quinone
2a
and
hydroxylamine
hydrochloride 3a under our standard reaction con-
[a] Reaction conditions: 1a (0.4 mmol), 2 (0.2 mmol), 3a
°
(0.4 mmol), CH3CH2OH (2.0 mL), 110 C, N2, 24 h. Isolated
yield.
[b] CH3OH as solvent.
Scheme 2. Gram-Scale Synthesis.
Scheme 3. Control Experiments.
Adv. Synth. Catal. 2021, 363, 2124–2132
2126
© 2021 Wiley-VCH GmbH

FULL PAPER
asc.wiley-vch.de
ditions (Figure 1). Significantly, the structure of inter- to construct nitrogen-containing heterocycles are in
mediate 5 was also characterized by X-ray diffraction progress in our laboratory.
analysis.[16]
Based on above investigations and previous
Experimental Section
reports,[3–14] we tentatively proposed the reaction
mechanism in Scheme 4. Initially, the condensation of General Procedure for the Synthesis of Benzoxa-
the hydroxylamine hydrochloride 3a with benzo-1,2- zoles 4
quinone 2a gave the quinone oxime intermediate 5,
which reacted with 1a to form intermediate A. The
A 25 mL oven-dried Schlenk tube equipped with a magnetic
stirring bar, aldehydes 1 (0.4 mmol), benzo-1,2-quinonnes 2
(0.2 mmol), NH2OH·HCl 3a (0.4 mmol), and CH3CH2OH
subsequent intramolecular cyclization of A afforded
intermediate B,[4b] which then gave the desired product
°
(2.0 mL) was vigorously stirred at 110 C for 24 h under N2.
4a by dehydration.
Then the mixture was cooled to room temperature, added water
(15 mL), extracted with EtOAc (15 mL×3). The combined
organic phases were dried over anhydrous Na2SO4, filtered and
concentrated in vacuo. Further purification by flash column
chromatography on silica gel (eluting with petroleum ether/
ethyl acetate) provided the product 4.
Conclusion
In summary, we have developed a novel strategy to
synthesize benzoxazoles through a [3+1+1] annula-
tion protocol of benzo-1,2-quinones, aldehydes and
hydroxylamine hydrochloride. Remarkably, useful ben-
zoxazoles could be directly synthesized with an
inorganic amino source. This protocol features opera-
tionally simple, a broad substrate scope, high yields,
valuable functional group tolerance, and gram-scalable.
Further explorations of hydroxylamine hydrochloride
Procedure for the Synthesis of Benzoxazole 4a on a
Preparative Scale
A 250 mL oven-dried round-bottom flask equipped with a
magnetic stirring bar, aldehydes 1a (10.0 mmol), benzo-1,2-
quinonnes 2a (5.0 mmol), NH2OH·HCl 3a (10.0 mmol), and
°
CH3CH2OH (50.0 mL) was vigorously stirred at 110 C for 24 h
under N2. Then the mixture was cooled to room temperature,
added water (150 mL), extracted with EtOAc (150 mL×3). The
combined organic phases were dried over anhydrous Na2SO4,
filtered and concentrated in vacuo. Further purification by flash
column chromatography on silica gel (eluting with petroleum
ether/ethyl acetate) provided the product 4a in 60% yield
(0.921 g).
5,7-Di-tert-butyl-2-phenylbenzo[d]oxazole (4a). 43.1 mg,
1
70% yield; yellow oil; H NMR (400 MHz, CDCl3) δ 8.27 (d,
J=4.0 Hz, 2H), 7.67 (s, 1H), 7.53 (s, 3H), 7.32 (s, 1H), 1.57 (s,
9H), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 162.5, 147.8,
146.9, 142.2, 133.7, 131.2, 128.9, 127.6, 127.4, 119.6, 114.2,
35.1, 34.5, 31.8, 30.0; IR (KBr): 2955, 1558, 1471, 1379, 1179,
1056 cmÀ 1; HRMS (ESI, m/z): [M+H]+ Calcd. for C21H25NO
+H, 308.2009; found, 308.2012.
5,7-Di-tert-butyl-2-(p-tolyl)benzo[d]oxazole (4b). 39.8 mg,
1
°
62% yield; yellow soild, mp: 90–91 C; H NMR (400 MHz,
CDCl3) δ 8.16 (d, J=7.6 Hz, 2H), 7.67 (s, 1H), 7.32–7.34 (m,
3H), 2.44 (s, 3H), 1.57 (s, 9H), 1.41 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 162.7, 147.6, 146.8, 142.3, 141.6, 133.6,
129.6, 127.4, 124.8, 119.3, 114.1, 35.0, 34.5, 31.8, 30.0, 21.6;
IR (KBr): 2958, 1589, 1472, 1387, 1182, 1067 cmÀ 1; HRMS
(ESI, m/z): [M+H]+ Calcd. for C22H27NO+H, 322.2165;
found, 322.2167.
Figure 1. Diagram of Yields with Time Variation.
5,7-Di-tert-butyl-2-(m-tolyl)benzo[d]oxazole (4c). 39.2 mg,
61% yield; yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.05–8.09
(m, 2H), 7.67 (s, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.32–7.35 (m,
2H), 2.47 (s, 3H), 1.57 (s, 9H), 1.41 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 162.7, 147.7, 146.9, 142.3, 138.7, 133.7,
132.0, 128.8, 127.9, 127.4, 124.5, 119.5, 114.1, 35.1, 34.5, 31.8,
30.0, 21.4; IR (KBr): 2957, 1558, 1472, 1384, 1171, 1069 cmÀ 1;
HRMS (ESI, m/z): [M+H]+ Calcd. for C22H27NO+H,
322.2165; found, 322.2163.
Scheme 4. Proposed mechanism.
Adv. Synth. Catal. 2021, 363, 2124–2132
2127
© 2021 Wiley-VCH GmbH

FULL PAPER
asc.wiley-vch.de
5,7-Di-tert-butyl-2-(o-tolyl)benzo[d]oxazole (4d). 34.7 mg,
54% yield; yellow oil; H NMR (400 MHz, CDCl3) δ 8.19 (d,
NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 8.11 (s, 1H), 7.61 (s,
1H), 7.24 (s, 1H), 6.80 (s, 1H), 6.78 (s, 1H), 3.06 (s, 6H), 1.55
(s, 9H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 163.6,
152.2, 147.3, 146.6, 142.5, 133.2, 128.9, 118.4, 114.7, 113.5,
111.6, 40.1, 35.0, 34.4, 31.9, 30.0; IR (KBr): 2955, 1609, 1508,
1360, 1179, 1065 cmÀ 1; HRMS (ESI, m/z): [M+H]+ Calcd. for
C23H30N2O+H, 351.2431; found, 351.2433.
1
J=7.6 Hz, 1H), 7.71 (s, 1H), 7.33–7.42 (m, 4H), 2.83 (s, 3H),
1.56 (s, 9H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
163.0, 147.6, 146.6, 142.1, 138.4, 133.7, 131.7, 130.7, 130.0,
126.6, 126.1, 119.5, 114.3, 35.1, 34.4, 31.9, 30.0, 22.3; IR
(KBr): 2955, 1681, 1554, 1470, 1383, 1041 cmÀ 1; HRMS (ESI,
m/z): [M+Na]+ Calcd. for C22H27NO+Na, 344.1985; found,
344.1986.
5,7-Di-tert-butyl-2-(4-fluorophenyl)benzo[d]oxazole
(4k).
46.8 mg, 72% yield; orange solid, mp: 98–99 C; 1H NMR
(400 MHz, CDCl3) δ 8.24–8.27 (m, 2H), 7.65 (s, 1H), 7.32 (s,
1H), 7.20–7.32 (m, 2H), 1.55 (s, 9H), 1.40 (s, 9H); 13C NMR
°
5,7-Di-tert-butyl-2-(4-methoxyphenyl)benzo[d]oxazole (4e).
1
43.8 mg, 65% yield; yellow oil; H NMR (400 MHz, CDCl3) δ
1
8.20 (d, J=8.4 Hz, 2H), 7.63 (s, 1H), 7.28 (s, 1H), 7.04 (d, J=
8.4 Hz, 2H), 3.89 (s, 3H), 1.55 (s, 9H), 1.40 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 162.6, 162.1, 147.6, 146.8, 142.2, 133.5,
131.6, 129.2, 120.0, 119.1, 114.3, 113.9, 55.4, 35.1, 34.5, 31.8,
30.0; IR (KBr): 2957, 1607, 1492, 1256, 1172, 1038 cmÀ 1;
HRMS (ESI, m/z): [M+H]+ Calcd. for C22H27NO2 +H,
338.2115; found, 338.2114.
(100 MHz, CDCl3) δ 164.6 (d, JC-F =250.8 Hz), 161.6, 147.9,
3
4
146.9, 142.2, 133.7, 129.6 (d, JC-F =8.8 Hz), 123.8 (d, JC-F
=
3.2 Hz), 119.6, 116.1 (d, 2JC-F =22.0 Hz), 114.2, 35.1, 34.5,
31.8, 30.0; 19F NMR (376 MHz, CDCl3) δ À 108.0 (s, 1F); IR
(KBr): 2957, 1601, 1489, 1306, 1062 cmÀ 1; HRMS (ESI, m/z):
[M+H]+ Calcd. for C21H24FNO+H, 326.1915; found,
326.1914.
5,7-Di-tert-butyl-2-(3,4-dimethoxyphenyl)benzo[d]oxazole
5,7-Di-tert-butyl-2-(3-fluorophenyl)benzo[d]oxazole
(4l).
1
(4f). 44.0 mg, 60% yield; white soild, mp: 101–102 C; 1H
42.3 mg, 65% yield; orange solid, mp: 115–116 C; H NMR
(400 MHz, CDCl3) δ 8.11 (d, J=7.6 Hz, 1H), 7.99 (d, J=
9.6 Hz, 1H), 7.72 (s, 1H), 7.53–7.59 (m, 1H), 7.39 (s, 1H),
7.28–7.32 (m, 1H), 1.61 (s, 9H), 1.46 (s, 9H); 13C NMR
°
°
NMR (400 MHz, CDCl3) δ 7.84 (d, J=8.4 Hz, 1H), 7.80 (s,
1H), 7.64 (s, 1H), 7.29 (s, 1H), 6.99 (d, J=8.0 Hz, 1H), 4.02 (s,
3H), 3.96 (s, 3H), 1.55 (s, 9H), 1.39 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 162.5, 151.8, 149.3, 147.7, 146.8, 142.2,
133.5, 120.8, 120.1, 119.2, 113.8, 111.0, 110.0, 56.1, 56.0, 35.1,
34.4, 31.8, 30.0; IR (KBr): 2953, 1601, 1495, 1262, 1147,
1025 cmÀ 1; HRMS (ESI,m/z): [M+H]+ Calcd. for C23H29O3 +
H, 368.2220; found, 368.2223.
(100 MHz, CDCl3)
δ
162.9 (d, 1JC-F =245.3 Hz), 161.2,
3
148.1,147.0, 142.0, 133.9, 130.6 (d, JC-F =8.1 Hz), 129.5 (d,
3JC-F =8.5 Hz), 123.1 (d, JC-F =3.1 Hz), 120.1, 118.2 (d, JC-F
=
4
2
21.2 Hz), 114.3, 114.3 (d, 2JC-F =23.8 Hz), 35.1, 34.5, 31.8,
30.0; 19F NMR (376 MHz, CDCl3) δ À 111.9 (s, 1F); IR (KBr):
2958, 1568, 1471, 1204, 1063 cmÀ 1; HRMS (ESI, m/z): [M+
H]+ Calcd. for C21H24FNO+H, 326.1915; found, 326.1917.
5,7-Di-tert-butyl-2-(3-methoxyphenyl)benzo[d]oxazole (4g).
1
41.1 mg, 61% yield; yellow oil; H NMR (400 MHz, CDCl3) δ
7.85 (d, J=7.6 Hz, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 7.44 (t, J=
8.0 Hz, 1H), 7.32 (s, 1H), 7.08 (d, J=8.4 Hz, 1H), 3.93 (s, 3H),
1.56 (s, 9H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
162.4, 159.9, 147.8, 146.9, 142.1, 133.8, 130.0, 128.6, 119.9,
119.7, 117.7, 114.2, 112.1, 55.5, 35.1, 34.5, 31.8, 30.0; IR
(KBr): 2954, 1565, 1470, 1309, 1231, 1048 cmÀ 1; HRMS (ESI,
m/z): [M+H]+ Calcd. for C22H27NO2 +H, 338.2115; found,
388.2118.
5,7-Di-tert-butyl-2-(4-chlorophenyl)benzo[d]oxazole
(4m).
1
°
44.3 mg, 65% yield; yellow solid, mp: 114–115 C; H NMR
(400 MHz, CDCl3) δ 8.19 (d, J=8.0 Hz, 2H), 7.66 (s, 1H), 7.50
(d, J=7.6 Hz, 2H), 7.33 (s, 1H), 1.56 (s, 9H), 1.41 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 161.5, 148.0, 146.9, 142.2, 137.4,
133.8, 129.2, 128.6, 126.0, 119.8, 114.3, 35.1, 34.5, 31.8, 30.0;
IR (KBr): 2957, 1590, 1476, 1386, 1180, 1079 cmÀ 1; HRMS
(ESI, m/z): [M+H]+ Calcd. for C21H24ClNO+H, 342.1619;
found, 342.1618.
5,7-Di-tert-butyl-2-(2-methoxyphenyl)benzo[d]oxazole (4h).
1
39.1 mg, 58% yield; yellow oil; H NMR (400 MHz, CDCl3) δ
5,7-Di-tert-butyl-2-(3,4-dichlorophenyl)benzo[d]oxazole
(4n). 40.5 mg, 54% yield; orange solid, mp: 133–134 C; H
1
°
8.13 (d, J=8.0 Hz, 1H), 7.71 (s, 1H), 7.49 (t, J=8.0 Hz, 1H),
7.30 (s, 1H), 7.07–7.12 (m, 2H), 4.01 (s, 3H), 1.55 (s, 9H), 1.40
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 161.0, 158.5, 147.4,
146.5, 142.1, 133.5, 132.4, 131.0, 120.7, 119.2, 116.6, 114.4,
112.1, 56.1, 35.1, 34.4, 31.8, 29.9; IR (KBr): 2954, 1594, 1471,
1258, 1036 cmÀ 1; HRMS (ESI, m/z): [M+Na]+ Calcd. for
C22H27NO2 +Na, 360.1934; found, 360.1932.
NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.07 (d, J=8.4 Hz,
1H), 7.65 (s, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 1.55 (s,
9H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 160.3, 148.2,
147.0, 142.1, 135.5, 133.9, 133.4, 131.0, 129.0, 127.4, 126.3,
120.3, 114.4, 35.1, 34.5, 31.8, 30.1; IR (KBr): 2955, 1553,
1465, 1377, 1253, 1063 cmÀ 1; HRMS (ESI, m/z): [M+H]+
Calcd. for C21H23Cl2NO+H, 376.1229; found, 376.1226.
5,7-Di-tert-butyl-2-(4-(methylthio)phenyl)benzo[d]oxazole
1
°
(4i). 43.8 mg, 62% yield; yellow soild, mp: 119–120 C; H
5,7-Di-tert-butyl-2-(3-chlorophenyl)benzo[d]oxazole
(4o).
1
°
NMR (400 MHz, CDCl3) δ 8.16 (d, J=8.0 Hz, 2H), 7.65 (s,
1H), 7.36 (d, J=8.0 Hz, 2H), 7.31 (s, 1H), 2.54 (s, 3H), 1.56 (s,
9H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 162.3, 147.7,
146.8, 143.2, 142.3, 133.6, 127.6, 125.8, 123.8, 119.4, 114.0,
35.0, 34.4, 31.8, 30.0, 15.1; IR (KBr): 2956, 1598, 1477, 1394,
1182, 1085 cmÀ 1; HRMS (ESI, m/z): [M+Na]+ Calcd. for
C22H27NOS+Na, 376.1706; found, 376.1708.
40.9 mg, 60% yield; yellow solid, mp: 112–113 C; H NMR
(400 MHz, CDCl3) δ 8.23 (s, 1H), 8.14 (d, J=7.2 Hz, 1H), 7.66
(s, 1H), 7.44–7.50 (m, 2H), 7.34 (s, 1H), 1.56 (s, 9H), 1.40 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 161.1 148.1, 147.0, 142.1,
135.0, 133.9, 131.1, 130.2, 129.3, 127.3, 125.4, 120.0, 114.4,
35.1, 34.5, 31.8, 30.0; IR (KBr): 2957, 1557, 1469, 1304, 1184,
1070 cmÀ 1; HRMS (ESI, m/z): [M+H]+ Calcd. for
C21H24ClNO+H, 342.1619; found, 342.1619.
4-(5,7-Di-tert-butylbenzo[d]oxazol-2-yl)-N,N-Dimethylaniline
1
°
(4j). 39.2 mg, 56% yield; yellow solid, mp: 142–143 C; H
Adv. Synth. Catal. 2021, 363, 2124–2132
2128
© 2021 Wiley-VCH GmbH

FULL PAPER
asc.wiley-vch.de
5,7-Di-tert-butyl-2-(2-chlorophenyl)benzo[d]oxazole
(4p).
134.0, 132.7, 131.4, 127.7, 120.7, 118.2, 114.6, 114.3, 35.1,
36.1 mg, 53% yield; red solid, mp: 99–100 C; 1H NMR
(400 MHz, CDCl3) δ 8.19 (d, J=7.2 Hz, 1H), 7.73 (s, 1H), 7.57
(d, J=7.2 Hz, 1H), 7.42–7.44 (m, 2H), 7.36 (s, 1H), 1.55 (s,
9H), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 160.6, 147.9,
147.0, 141.7, 134.0, 133.3, 131.8, 131.7, 131.4, 126.9, 126.6,
120.0, 114.5, 35.1, 34.4, 31.8, 29.9; IR (KBr): 2954, 1563,
1464, 1249, 1187, 1034 cmÀ 1; HRMS (ESI, m/z): [M+H]+
Calcd. for C21H24ClNO+H, 342.1619; found, 342.1624.
34.5, 31.7, 30.0; IR (KBr): 2959, 1565, 1480, 1384, 1192,
1066 cmÀ 1; HRMS (ESI, m/z): [M+H]+ Calcd. for C22H24N2O
+H, 333.1961; found, 333.1969.
°
5,7-Di-tert-butyl-2-(4-(trifluoromethyl)phenyl)benzo[d]
°
oxazole (4w). 45.0 mg, 60% yield; yellow solid, mp: 80–81 C;
1H NMR (400 MHz, CDCl3) δ 7.79–7.80 (m, 2H), 7.66–7.68
(m, 2H), 6.83 (s, 1H), 6.82 (s, 1H), 2.01 (s, 3H), 1.43 (s, 9H),
1.31 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 160.9, 148.2,
2
2-(4-Bromophenyl)-5,7-Di-tert-butylbenzo[d]oxazole
(4q).
147.1, 142.1, 134.0, 132.7 (q, JC-F =32.3 Hz), 130.8, 127.6,
46.8 mg, 61% yield; red solid, mp: 99–100 C; 1H NMR
(400 MHz, CDCl3) δ 8.11 (d, J=8.0 Hz, 2H), 7.65–7.67 (m,
3H), 7.33 (s, 1H), 1.55 (s, 9H), 1.40 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 161.6, 148.0, 147.0, 142.2, 133.8, 132.2,
128.8, 126.5, 125.8, 119.9, 114.3, 35.1, 34.5, 31.8, 30.0; IR
(KBr): 2955, 1573, 1485, 1387, 1181, 1062 cmÀ 1; HRMS (ESI,
m/z): [M+H]+ Calcd. for C21H24BrNO+H, 386.1114; found,
386.1112.
125.9 (q, 3JC-F =3.7 Hz), 123.8 (q, 4JC-F =270.7 Hz), 120.3,
114.5, 35.1, 34.5, 31.7, 30.0; 19F NMR (376 MHz, CDCl3) δ
À 62.9 (s, 3F); IR (KBr): 2960, 1562, 1478, 1322, 1139,
1072 cmÀ 1; HRMS (ESI, m/z): [M+H]+ Calcd. for
C22H24F3NO+H, 376.1883; found, 376.1879.
°
5,7-Di-tert-butyl-2-(naphthalen-2-yl)benzo[d]oxazole
(4x).
1
42.8 mg, 60% yield; yellow oil; H NMR (400 MHz, CDCl3) δ
8.77 (s, 1H), 8.34 (d, J=8.8 Hz, 1H), 7.97–8.03 (m, 2H), 7.89–
7.90 (m, 1H), 7.73 (s, 1H), 7.56–7.58 (m, 2H), 7.36 (s, 1H),
1.63 (s, 9H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
162.6, 147.8, 147.1, 142.4, 134.6, 133.7, 133.0, 128.9, 128.7,
127.9, 127.6, 127.6, 126.8, 124.8, 123.9, 119.6, 114.2, 35.1,
34.5, 31.8, 30.1; IR (KBr): 2956, 1558, 1471, 1375, 1180,
1060 cmÀ 1; HRMS (ESI, m/z): [M+Na]+ Calcd. for C25H27NO
+Na, 380.1985; found, 380.1980.
2-(3-Bromophenyl)-5,7-Di-tert-butylbenzo[d]oxazole
(4r).
1
°
43.9 mg, 57% yield; yellow solid, mp: 101–102 C; H NMR
(400 MHz, CDCl3) δ 8.39 (s, 1H), 8.19 (d, J=7.6 Hz, 1H),
7.63–7.67 (m, 2H), 7.35–7.41 (m, 2H), 1.56 (s, 9H), 1.41 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 160.9, 148.0, 147.0, 142.1,
134.0, 133.9, 130.4, 130.2, 129.4, 125.9, 123.0, 120.0, 114.3,
35.1, 34.5, 31.8, 30.0; IR (KBr): 2959, 1554, 1470, 1395, 1184,
1067 cmÀ 1; HRMS (ESI, m/z): [M+H]+ Calcd. for
C21H24BrNO+H, 386.1114; found, 386.1119.
5,7-Di-tert-butyl-2-(naphthalen-1-yl)benzo[d]oxazole
(4y).
44.2 mg, 62% yield; white solid, mp: 110–111 C; 1H NMR
(400 MHz, CDCl3) δ 9.46 (d, J=8.4 Hz, 1H), 8.42 (d, J=
6.8 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H),
7.79 (s, 1H), 7.71 (t, J=7.2 Hz, 1H), 7.58–7.65 (m, 2H), 7.38
(s, 1H), 1.60 (s, 9H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 162.3, 147.8, 146.4, 142.4, 134.0, 133.7, 132.0, 130.7, 129.1,
128.6, 127.8, 126.4, 126.3, 125.0, 124.0, 119.8, 114.5, 35.1,
34.5, 31.9, 30.1; IR (KBr): 2955, 1546, 1469, 1382, 1195,
1114 cmÀ 1; HRMS (ESI, m/z): [M+H]+ Calcd. for C25H27NO
+H, 358.2165; found, 358.2161.
°
2-(2-Bromophenyl)-5,7-Di-tert-butylbenzo[d]oxazole
(4s).
42.3 mg, 55% yield; red solid, mp: 159–160 C; 1H NMR
(400 MHz, CDCl3) δ 8.12 (d, J=8.0 Hz, 1H), 7.77 (d, J=
8.0 Hz, 1H), 7.73 (s, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.34–7.37
(m, 2H), 1.56 (s, 9H), 1.42 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 161.1, 147.9, 147.0, 141.8, 134.6, 134.1, 132.2, 131.7,
128.8, 127.4, 121.6, 119.9, 114.5, 35.1, 34.4, 31.8, 30.0; IR
(KBr): 2956, 1563, 1463, 1312, 1185, 1025 cmÀ 1; HRMS (ESI,
m/z): [M+H]+ Calcd. for C21H24BrNO+H, 386.1114; found,
386.1116.
°
5,7-Di-tert-butyl-2-(pyridin-3-yl)benzo[d]oxazole
(4z).
1
°
5,7-Di-tert-butyl-2-(4-iodophenyl)benzo[d]oxazole
(4t).
25.9 mg, 42% yield; orange solid, mp: 100–101 C; H NMR
(400 MHz, CDCl3) δ 9.48 (s, 1H), 8.75 (s, 1H), 8.50 (d, J=
8.0 Hz, 1H), 7.67 (s, 1H), 7.45–7.48 (m, 1H), 7.35 (s, 1H), 1.55
(s, 9H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 160.0,
151.7, 148.5, 148.2, 147.0, 142.0, 134.5, 133.9, 123.7, 120.2,
114.4, 35.1, 34.5, 31.8, 30.0; IR (KBr): 2959, 1587, 1472, 1193,
1076, 1019 cmÀ 1; HRMS (ESI, m/z): [M+H]+ Calcd. for
C20H24N2O+H, 309.1961; found, 309.1958.
1
51.1 mg, 59% yield; yellow oil; H NMR (400 MHz, CDCl3) δ
7.96–7.98 (m, 2H), 7.86–7.88 (m, 2H), 7.66 (s, 1H), 7.33 (s,
1H), 1.55 (s, 9H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
161.7, 148.0, 146.9, 142.1, 138.1, 133.8, 128.8, 127.0, 119.9,
114.3, 97.9, 35.1, 34.5, 31.8, 30.0; IR (KBr): 2957, 1573, 1485,
1387, 1181, 1062 cmÀ 1; HRMS (ESI, m/z): [M+H]+ Calcd. for
C21H24INO+H, 434.0975; found, 434.0978.
5,7-Di-tert-butyl-2-(4-nitrophenyl)benzo[d]oxazole
(4u).
5,7-Di-tert-butyl-2-(thiophen-3-yl)benzo[d]oxazole
(4aa).
1
1
°
33.0 mg, 47% yield; orange solid, mp: 195–196 C; H NMR
(400 MHz, CDCl3) δ 8.36–8.42 (m, 4H), 7.68 (s, 1H), 7.39 (s,
1H), 1.56 (s, 9H), 1.41 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
160.1, 149.1, 148.5, 147.3, 142.2, 134.1, 133.1, 128.1, 124.2,
120.9, 114.7, 35.1, 34.5, 31.7, 30.0; IR (KBr): 2955, 1623,
1532, 1344, 1206, 1076 cmÀ 1; HRMS (ESI, m/z): [M+H]+
Calcd. for C21H24N2O3 +H, 353.1860; found, 353.1867.
36.3 mg, 58% yield; yellow oil; H NMR (400 MHz, CDCl3) δ
8.19 (s, 1H), 7.80 (d, J=4.8 Hz, 1H), 7.64 (s, 1H), 7.45 (s, 1H),
7.30 (s, 1H), 1.54 (s, 9H), 1.40 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 159.2, 147.8, 146.5, 142.0, 133.6, 129.6, 127.4, 126.9,
126.6, 119.5, 114.1, 35.1, 34.5, 31.8, 30.0; IR (KBr): 2958,
1585, 1477, 1388, 1275, 1071 cmÀ 1; HRMS (ESI, m/z): [M+
H]+ Calcd. for C19H23NOS+H, 314.1573; found, 314.1576.
4-(5,7-Di-tert-butylbenzo[d]oxazol-2-yl)benzonitrile
(4v).
5,7-Di-tert-butyl-2-(thiophen-2-yl)benzo[d]oxazole
(4ab).
1
1
°
35.9 mg, 54% yield; green solid, mp: 122–123 C; H NMR
(400 MHz, CDCl3) δ 8.35 (d, J=7.6 Hz, 2H), 7.81 (d, J=
7.6 Hz, 2H), 7.67 (s, 1H), 7.37 (s, 1H), 1.55 (s, 9H), 1.40 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 160.3, 148.4, 147.1, 142.1,
37.0 mg, 59% yield; yellow oil; H NMR (400 MHz, CDCl3) δ
7.91 (d, J=3.6 Hz, 1H), 7.62 (s, 1H), 7.53 (d, J=5.2 Hz, 1H),
7.30 (s, 1H), 7.18 (t, J=4.4 Hz, 1H), 1.54 (s, 9H), 1.39 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 158.5, 147.9, 146.6, 142.1,
Adv. Synth. Catal. 2021, 363, 2124–2132
2129
© 2021 Wiley-VCH GmbH

FULL PAPER
asc.wiley-vch.de
133.6, 130.1, 129.7, 129.4, 128.1, 119.6, 114.0, 35.1, 34.4, 31.8,
30.0; IR (KBr): 2956, 1580, 1480, 1384, 1226, 1042 cmÀ 1;
HRMS (ESI, m/z): [M+Na]+ Calcd. for C19H23NOS+Na,
336.1393; found, 336.1391.
5-(tert-butyl)-7-(4-(methylthio)phenyl)-2-Phenylbenzo[d]
oxazole (4ai). 44.0 mg, 59% yield; yellow solid, mp: 115–
1
°
116 C; H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J=6.8 Hz,
2H), 7.95 (d, J=7.6 Hz, 2H), 7.76 (s, 1H), 7.62–7.66 (m, 4H),
7.47 (d, J=8.0 Hz, 2H), 2.56 (s, 3H), 1.41 (s, 9H); 13C NMR
(100 MHz, DMSO-d6) δ 163.0, 148.9, 146.1, 142.8, 139.0,
132.4, 132.0, 129.8, 128.9, 127.7, 127.0, 126.7, 123.3, 121.7,
115.8, 35.3, 32.0, 15.0; IR (KBr): 2956, 1556, 1480, 1330,
1201, 1057 cmÀ 1; HRMS (ESI, m/z): [M+H]+ Calcd. for
C24H23NOS+H, 374.1573; found, 374.1571.
5,7-Di-tert-butyl-2-(furan-2-yl)benzo[d]oxazole
(4ac).
1
30.3 mg, 51% yield; black oil; H NMR (400 MHz, CDCl3) δ
7.65 (s, 1H), 7.62 (s, 1H), 7.30 (s, 1H), 7.24 (s, 1H), 6.60 (s,
1H), 1.53 (s, 9H), 1.39 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
154.9, 148.0, 146.3, 145.3, 143.0, 141.8, 133.7, 119.7, 114.3,
113.5, 112.0, 35.0, 34.4, 31.8, 30.0; IR (KBr): 2956, 1535,
1381, 1300, 1082, 1004 cmÀ 1; HRMS (ESI, m/z): [M+H]+
Calcd. for C19H23NO2 +H, 298.1802; found, 298.1804.
4-(5-(tert-butyl)-2-Phenylbenzo[d]oxazol-7-yl)phenol (4aj).
1
°
41.8 mg, 61% yield; colorless solid, mp: 245–246 C; H NMR
(400 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.21 (d, J=4.8 Hz, 2H),
7.83 (d, J=8.0 Hz, 2H), 7.70 (s, 1H), 7.59–7.64 (m, 4H), 6.98
(d, J=8.0 Hz, 2H), 1.41 (s, 9H); 13C NMR (100 MHz, DMSO-
d6) δ 162.9, 158.1, 148.8, 146.0, 142.7, 132.3, 129.8, 129.7,
127.7, 127.1, 126.3, 124.0, 121.4, 116.3, 114.9, 35.3, 32.0.; IR
(KBr): 2962, 1743, 1612, 1462, 1376, 1242, 1049 cmÀ 1; HRMS
(ESI, m/z): [M+H]+ Calcd. for C23H21NO2 +H, 344.1645;
found, 344.1640.
(E)-5,7-Di-tert-butyl-2-Styrylbenzo[d]oxazole (4ad). 30.0 mg,
1
45% yield; yellow oil; H NMR (400 MHz, CDCl3) δ 7.76 (d,
J=16.0 Hz, 1H), 7.60–7.63 (m, 3H), 7.37–7.44 (m, 3H), 7.31
(s, 1H), 7.11 (d, J=16.4 Hz, 1H), 1.55 (s, 9H), 1.40 (s, 9H); 13
C
NMR (100 MHz, CDCl3) δ 147.7, 146.6, 142.4, 138.5, 135.3,
133.5, 129.5, 128.9, 127.5, 119.7, 114.4, 114.1, 35.0, 34.4, 31.8,
30.0; IR (KBr): 2954, 1636, 1540, 1465, 1368, 1160 cmÀ 1;
HRMS (ESI, m/z): [M+H]+ Calcd. for C23H28NO+H,
334.2165; found, 334.2169.
5-(tert-butyl)-7-(4-fluorophenyl)-2-Phenylbenzo[d]oxazole
1
°
(4ak). 36.6 mg, 53% yield; colorless solid, mp: 130–131 C; H
5,7-Di-tert-butyl-2-Phenethylbenzo[d]oxazole (4ae). 32.2 mg,
NMR (400 MHz, CDCl3) δ 8.28–8.31 (m, 2H), 7.90–7.94 (m,
1
48% yield; yellow oil; H NMR (400 MHz, CDCl3) δ 7.55 (s,
2H), 7.83 (d, J=1.6 Hz, 1H), 7.55–7.57 (m, 4H), 7.28–7.30 (m,
1H), 7.27–7.29 (m, 5H), 7.24 (s, 1H), 3.22–3.26 (m, 4H), 1.45
(s, 9H), 1.37 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 147.4,
147.0, 141.3, 140.2, 133.6, 128.6, 128.3, 126.4, 119.0, 113.8,
35.0, 34.4, 33.0, 31.9, 30.4, 30.0; IR (KBr): 2953, 1578, 1472,
1380, 1146, 1011 cmÀ 1; HRMS (ESI, m/z): [M+H]+ Calcd. for
C23H29NO+H, 336.2322; found, 336.2321.
2H), 1.49 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 163.3, 162.6
4
(d, 1JC-F =246.3 Hz), 148.7, 146.2, 142.7, 131.5 (d, JC-F
=
3
3.1 Hz), 129.9 (d, JC-F =8.1 Hz), 129.8, 128.9, 127.6, 127.1,
2
123.1, 121.9, 115.8 (d, JC-F =21.4 Hz), 115.7, 35.1, 31.8; 19F
NMR (376 MHz, CDCl3) δ À 114.0 (s, 1F); IR (KBr): 2958,
1557, 1476, 1331, 1225, 1053 cmÀ 1; HRMS (ESI, m/z): [M+
H]+ Calcd. for C23H20FNO+H, 346.1599; found, 346.1602.
5-(tert-butyl)-2,7-Diphenylbenzo[d]oxazole (4af). 36.6 mg,
1
°
56% yield; orange solid, mp: 102–103 C; H NMR (400 MHz,
5-(tert-butyl)-7-(3-fluorophenyl)-2-Phenylbenzo[d]oxazole
DMSO-d6) δ 8.18–8.20 (m, 2H), 7.97–7.99 (m, 2H), 7.77 (s,
1H), 7.57–7.65 (m, 6H), 7.45–4.48 (m, 1H), 1.41 (s, 9H); 13C
NMR (100 MHz, DMSO-d6) δ 163.0, 148.9, 146.3, 142.8,
135.7, 132.3, 129.7, 129.5, 128.6, 128.5, 127.7, 127.0, 123.9,
122.2, 116.0, 35.3, 32.0; IR (KBr): 2959, 1556, 1478, 1393,
1331, 1203, 1057 cmÀ 1; HRMS (ESI, m/z): [M+H]+ Calcd. for
C23H21NO+H, 328.1696; found, 328.1692.
1
°
(4al). 33.1 mg, 48% yield; gray solid, mp: 83–84 C; H NMR
(400 MHz, DMSO-d6) δ 8.18 (d, J=7.2 Hz, 2H), 7.78–7.85 (m,
3H), 7.68 (s, 1H), 7.59–7.64 (m, 4H), 7.29 (t, J=8.4 Hz, 1H),
1.40 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 163.1, 163.0 (d,
1JC-F =241.9 Hz), 148.9, 146.2, 142.8, 138.0 (d, JC-F =8.2 Hz)
3
3
132.3, 131.4 (d, JC-F =8.5 Hz), 129.7, 127.7, 126.9, 124.6 (d,
4JC-F =2.8 Hz), 122.5, 122.3, 116.6, 115.4 (d, JC-F =20.6 Hz),
2
115.1 (d, 2JC-F =22.4 Hz), 35.3, 31.9; 19F NMR (376 MHz,
DMSO-d6) δ À 112.4 (s, 1F); IR (KBr): 2957, 1570, 1474, 1388,
1207, 1056 cmÀ 1; HRMS (ESI, m/z): [M+H]+ Calcd. for
C23H20FNO+H, 346.1599; found, 346.1602.
5-(tert-butyl)-2-Phenyl-7-(m-tolyl)benzo[d]oxazole
(4ag).
1
35.5 mg, 52% yield; red oil; H NMR (400 MHz, DMSO-d6) δ
8.17–8.19 (m, 2H), 7.76–7.78 (m, 3H), 7.61–7.64 (m, 4H),
7.44–7.48 (t, J=7.6 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 2.45 (s,
3H), 1.41 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 163.0,
148.8, 146.3, 142.8, 138.7, 135.7, 132.3, 129.8, 129.3, 129.2,
129.0, 127.7, 127.0, 125.7, 124.0, 122.2, 115.9, 35.3, 32.0,
21.6; IR (KBr): 2957, 1557, 1475, 1383, 1192, 1054 cmÀ 1;
HRMS (ESI, m/z): [M+H]+ Calcd. for C24H23NO+H,
342.1852; found, 342.1850.
5-(tert-butyl)-7-(2-fluorophenyl)-2-Phenylbenzo[d]oxazole
1
(4am). 30.4 mg, 44% yield; colorless oil; H NMR (400 MHz,
DMSO-d6) δ 8.13 (d, J=7.6 Hz, 2H), 7.85 (s, 1H), 7.77 (t, J=
7.6 Hz, 1H), 7.54–7.61 (m, 5H), 7.39–7.46 (m, 2H), 1.40 (s,
1
9H); 13C NMR (100 MHz, DMSO-d6) δ 163.0, 159.8 (d, JC-F
=
3
246.0 Hz) 148.6, 146.5, 142.3, 132.4, 131.9 (d, JC-F =3.2 Hz),
3
4
131.0 (d, JC-F =8.2 Hz), 129.8, 127.6, 126.9, 125.5 (d, JC-F
=
=
5-(tert-butyl)-2-Phenyl-7-(o-tolyl)benzo[d]oxazole
(4ah).
3.6 Hz), 123.5 (d, 2JC-F =14.7 Hz), 116.7, 116.6 (d, JC-F
2
32.1 mg, 47% yield; red oil; 1H NMR (400 MHz, CDCl3) δ 8.21
(d, J=7.2 Hz, 2H), 7.83 (s, 1H), 7.44–7.50 (m, 4H), 7.36–7.39
(m, 4H), 2.33 (s, 3H), 1.44 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 163.2, 148.2, 146.5, 141.8, 136.6, 136.2, 131.4, 130.4,
130.4, 128.8, 128.1, 127.6, 127.2, 125.9, 124.5, 124.5, 115.4,
35.0, 31.8, 20.4; IR (KBr): 2959, 1555, 1475, 1390, 1331, 1204,
1052 cmÀ 1; HRMS (ESI, m/z): [M+H]+ Calcd. for C24H23NO
+H, 342.1852; found, 342.1853.
21.9 Hz), 35.3, 31.9; 19F NMR (376 MHz, DMSO-d6) δ À 114.8
(s, 1F); IR (KBr): 2957, 1559, 1477, 1395, 1216, 1052 cmÀ 1;
HRMS (ESI, m/z): [M+H]+ Calcd. for C23H20FNO+H,
346.1597; found, 346.1602.
5-(tert-butyl)-7-(4-chlorophenyl)-2-Phenylbenzo[d]oxazole
1
°
(4an). 39.0 mg, 54% yield; yellow solid, mp: 115–116 C; H
NMR (400 MHz, CDCl3) δ 8.25–8.27 (m, 2H), 7.81–7.86 (m,
Adv. Synth. Catal. 2021, 363, 2124–2132
2130
© 2021 Wiley-VCH GmbH

FULL PAPER
asc.wiley-vch.de
3H), 7.52–7.56 (m, 6H), 1.46 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 163.3, 148.8, 146.2, 142.8, 134.6, 133.9, 131.5, 129.4,
129.0, 128.9, 127.6, 127.1, 122.8, 121.8, 116.1, 35.1, 31.8; IR
(KBr): 2958, 1557, 1482, 1379, 1203, 1092 cmÀ 1; HRMS (ESI,
m/z): [M+H]+ Calcd. for C23H20ClNO+H, 362.1306; found,
362.1304.
163.7, 141.9, 141.2, 139.6, 138.9, 137.2, 134.9, 132.6, 132.1,
130.8, 130.7, 130.3, 129.8, 128.4, 128.1, 127.8, 127.8, 127.7,
126.8, 126.8, 125.2, 120.3; IR (KBr): 3050, 2922, 1421, 1046,
697 cmÀ 1; HRMS (ESI, m/z): [M+H]+ Calcd. for C25H17NO+
H, 348.1383; found, 348.1382.
5-(tert-butyl)-6-methoxy-2-phenylbenzo[d]oxazole
(4au).
1
5-(tert-butyl)-7-(3-chlorophenyl)-2-Phenylbenzo[d]oxazole
27.0 mg, 48% yield; yellow oil; H NMR (400 MHz, CDCl3) δ
8.21–8.23 (m, 2H), 7.72 (s, 1H), 7.50–7.52 (m, 3H), 7.11 (s,
1H), 3.93 (s, 3H), 1.43 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
161.8, 157.7, 149.8, 136.7, 134.5, 131.1, 128.9, 127.3, 127.2,
117.1, 94.1, 55.6, 35.3, 29.9; IR (KBr): 2931, 1625, 1459, 1319,
1048 cmÀ 1; HRMS (ESI, m/z): [M+H]+ Calcd. for C18H19NO2
+H, 282.1489; found, 282.1484.
1
(4ao). 36.8 mg, 51% yield; yellow oil; H NMR (400 MHz,
DMSO-d6) δ 8.17–8.19 (m, 2H), 8.02 (s, 1H), 7.98 (d, J=
7.6 Hz, 1H), 7.81 (s, 1H), 7.70 (s, 1H), 7.60–7.64 (m, 4H),
7.52–7.54 (m, 1H), 1.42 (s, 9H); 13C NMR (100 MHz, DMSO-
d6) δ 163.1, 149.0, 146.2, 142.8, 137.8, 134.2, 132.4, 131.3,
129.8, 128.5, 128.1, 127.7, 127.3, 126.9, 122.4, 116.7, 35.4,
31.9; IR (KBr): 2956, 1559, 1473, 1382, 1204, 1059 cmÀ 1;
HRMS (ESI, m/z): [M+H]+ Calcd. for C23H20ClNO+H,
362.1306; found, 362.1303.
Acknowledgements
The authors thank the National Program on Key Research
Project (2016YFA0602900), and the Fundamental Research
Funds for the Central Universities (2019PY05) for financial
support.
4-(5-(tert-butyl)-2-Phenylbenzo[d]oxazol-7-yl)benzonitrile
1
°
(4ap). 39.4 mg, 56% yield; yellow solid, mp: 148–149 C; H
NMR (400 MHz, DMSO-d6) δ 8.21 (d, J=7.2 Hz, 4H), 8.03 (d,
J=8.0 Hz, 2H), 7.85 (s, 1H), 7.74 (s, 1H), 7.62–7.63 (m, 3H),
1.41 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 163.2, 149.1,
146.3, 143.0, 140.2, 133.3, 132.5, 129.7, 129.3, 127.8, 126.8,
122.5, 122.0, 119.2, 117.4, 111.1, 35.4, 31.9; IR (KBr): 2957,
2227, 1608, 1474, 1205, 1052 cmÀ 1; HRMS (ESI, m/z): [M+
H]+ Calcd. for C24H20N2O+H, 353.1648; found, 353.1650.
References
[1] a) S. K. Tipparaju, S. Joyasawal, M. Pieroni, M. Kaiser,
R. Brun, A. P. Kozikowski, J. Med. Chem. 2008, 51,
7344–7347; b) J. Easmon, G. Pürstinger, K.-S. Thies, G.
Heinisch, J. Hofmann, J. Med. Chem. 2006, 49, 6343–
6350; c) S. Aiello, G. Wells, E. L. Stone, H. Kadri, R.
Bazzi, D. R. Bell, M. F. G. Stevens, C. S. Matthews,
T. D. Bradshaw, A. D. Westwell, J. Med. Chem. 2008,
51, 5135–5139; d) A. D. Rodríguez, C. Ramírez, I. I.
Rodríguez, E. González, Org. Lett. 1999, 1, 527–530;
e) K. Seth, S. K. Garg, R. Kumar, P. Purohit, V. S.
Meena, R. Goyal, U. C. Banerjee, A. K. Chakraborti,
ACS Med. Chem. Lett. 2014, 5, 512–516; f) S. Singh, G.
Veeraswamy, D. Bhattarai, J.-l. Goo, K. Lee, Y. Choi,
Asian J. Org. Chem. 2015, 4, 1338–1361.
[2] a) C. Carayon, S. F. Forgues, Photochem. Photobiol. Sci.
2017, 16, 1020–1035; b) J. Jiang, X. Tang, W. Dou, H.
Zhang, W. Liu, C. Wang, J. Zheng, J. Inorg. Biochem.
2010, 104, 583–591; c) Y. Ooyama, Y. Kagawa, H.
Fukuoka, G. Ito, Y. Harima, Eur. J. Org. Chem. 2009, 31,
5321–5326.
5-(tert-butyl)-2-Phenyl-7-(thiophen-3-yl)benzo[d]oxazole
(4aq). 34.1 mg, 51% yield; orange solid, mp: 98–99 C; 1H
°
NMR (400 MHz, CDCl3) δ 8.29–8.30 (m, 2H), 7.98 (s, 1H),
7.74–7.75 (m, 2H), 7.67 (s, 1H), 7.55 (s, 3H), 7.50–7.51 (m,
1H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 163.2, 148.5,
145.9, 142.6, 136.5, 131.5, 128.9, 127.6, 127.2, 126.6, 126.0,
123.0, 120.9, 118.9, 115.4, 35.0, 31.8; IR (KBr): 2957, 1556,
1476, 1201, 1056 cmÀ 1; HRMS (ESI, m/z): [M+H]+ Calcd. for
C21H19NOS+H, 334.1260; found, 334.1256.
5-(tert-butyl)-7-(naphthalen-1-yl)-2-phenylbenzo[d]oxazole
1
(4ar). 56.0 mg, 74% yield; yellow oil; H NMR (400 MHz,
CDCl3) δ 8.12 (m, 2H), 7.98 (d, J=8.0 Hz, 2H), 7.91 (d, J=
1.6 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.61–7.69 (m, 2H), 7.53–
7.57 (m, 2H), 7.41–7.47 (m, 4H), 1.47 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 163.4, 148.3, 147.1, 142.1, 134.4, 133.8,
131.6, 131.4, 128.8, 128.5, 128.4, 127.8, 127.6, 127.1, 126.2,
126.0, 125.9, 125.4, 125.2, 123.3, 115.7, 35.1, 31.8; IR (KBr):
2954, 1556, 1475, 1201, 1057 cmÀ 1; HRMS (ESI, m/z): [M+
H]+ Calcd. for C27H23NO+H, 378.1852; found, 378.846.
[3] a) C. S. Cho, D. T. Kim, J. Q. Zhang, S.-L. Ho, T.-J.
Kim, S. C. Shim, J. Heterocycl. Chem. 2002, 39, 421–
423; b) Y. Kawashita, N. Nakamichi, H. Kawabata, M.
Hayashi, Org. Lett. 2003, 5, 3713–3715; c) W. Li, C.
Zeng, L. Hu, H. Tian, R. Little, Adv. Synth. Catal. 2013,
355, 2884–2890; d) M. Bala, P. Verma, U. Sharma, N.
Kumar, B. Singh, Green Chem. 2013, 15, 1687–1693;
e) A. Khalafi-Nezhad, F. Panahi, ACS Catal. 2014,
4,1686–1692; f) X. Shi, J. Guo, J. Liu, M. Ye, Q. Xu,
Chem. Eur. J. 2015, 21, 9988–9993; g) M. Wu, X. Hu, J.
Liu, Y. Liao, G.-J. Deng, Org. Lett. 2012, 14, 2722–
2725; h) N. Aljaar, C. C. Malakar, J. Conrad, W. Frey, U.
Beifuss, J. Org. Chem. 2013, 78, 154–166; i) S. S. K.
Boominathan, W.-P. Hu, G. C. Senadi, J. K. Vandavasia,
J.-J. Wang, Chem. Commun. 2014, 50, 6726–6728; j) L.
7-(tert-butyl)-5-(tert-pentyl)-2-phenylbenzo[d]oxazole (4as).
49.2 mg, 77% yield; yellow oil; H NMR (400 MHz, CDCl3) δ
1
8.33 (m, 2H), 7.68 (s, 1H), 7.58–7.60 (m, 3H), 7.31–7.38 (m,
1H), 1.78 (q, J=7.2 Hz, 2H), 1.62 (s, 9H), 1.43–1.47 (m, 6H),
0.78 (t, J=7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.4,
146.0, 142.3, 133.6, 131.1, 128.8, 127.5, 127.4, 120.1, 115.0,
38.3, 37.2, 34.4, 31.8, 30.1, 30.0, 28.9, 9.2; IR (KBr): 2960,
1557, 1473, 1178, 1063 cmÀ 1; HRMS (ESI, m/z): [M+H]+
Calcd. for C22H27NO+H, 322.2165; found, 322.2160.
2,5,7-triphenylbenzo[d]oxazole (4at). 49.4 mg, 71% yield;
1
°
white solid, mp: 195–196 C; H NMR (400 MHz, DMSO-d6) δ
8.09–8.11 (m, 2H), 7.77 (s, 1H), 7.59–7.61 (m, 2H), 7.26–7.27
(m, 4H), 7.16–7.18 (m, 2H), 7.10–7.12 (m, 2H), 7.00–7.02 (m,
2H), 6.87–6.89 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ
Adv. Synth. Catal. 2021, 363, 2124–2132
2131
© 2021 Wiley-VCH GmbH

FULL PAPER
asc.wiley-vch.de
Tang, X. Guo, Y. Yang, Z. Zha, Z. Wang, Chem.
Commun. 2014, 50, 6145–6148; k) Y. Kawashita, N.
Nakamichi, H. Kawabata, M. Hayashi, Org. Lett. 2003,
5, 3713–3715; l) Y.-X. Chen, L.-F. Qian, W. Zhang, B.
4759–4761; g) S. Royo, R. S. L. Chapman, A. M. Sim,
L. R. Peacock, S. D. Bull, Org. Lett. 2016, 18, 1146–
1149; h) H.-Y. Bi, M. Du, C.-X. Pan, Y. Xiao, G.-F. Su,
D.-L. Mo, J. Org. Chem. 2019, 84, 9859–9868.
Han, Angew. Chem. Int. Ed. 2008, 47, 9330–9333; [10] A. E. Wendlandt, S. S. Stahl, Angew. Chem. Int. Ed.
m) A. J. Blacker, M. M. Farah, M. I. Hall, S. P. Marsden, 2015, 54, 14638–14658.
O. Saidi, J. M. J. Williams, Org. Lett. 2009, 11, 2039– [11] a) K. Pirnat, G. Mali, M. Gaberscek, R. Dominko, J.
2042; n) Y. H. Cho, C.-Y. Lee, D.-C. Ha, C.-H. Cheon,
Adv. Synth. Catal. 2012, 354, 2992–2996.
[4] a) L. Liu, L. Qian, S. Wu, J. Dong, Q. Xu, Y. Zhou, Org.
Power Sources 2016, 315, 169–178; b) L. Sun, M. G.
Campbell, M. Dinca, Angew. Chem. Int. Ed. 2016, 55,
3566–3579.
Lett. 2017, 19, 2849–2852; b) K. V. N. Esguerra, W. Xu, [12] a) Y. Fujiwara, V. Domingo, I. B. Seiple, R. Gianatassio,
J.-P. Lumb, Chem 2017, 2, 533–549; c) X. Chen, F. Ji, Y.
Zhao, Y. Liu, Y. Zhou, T. Chen, S.-F. Yin, Adv. Synth.
Catal. 2015, 357, 2924–2930.
M. Del Bel, P. S. Baran, J. Am. Chem. Soc. 2011, 133,
3292–3295; b) Z. Huang, J.-P. Lumb, Angew. Chem. Int.
Ed. 2016, 55, 11543–11547.
[5] a) S. Gao, L. Gao, H. Meng, M. Luo, X. Zeng, Chem. [13] a) B. I. Kharisov, M. A. Medndez-Rojas, A. D. Garnov-
Commun. 2017, 53, 9886–9889; b) A. R. Tiwari, B. M.
Bhanage, Org. Biomol. Chem. 2016, 14, 7920–7926.
[6] R. D. Viirre, G. Evindar, R. A. Batey, J. Org. Chem.
2008, 73, 3452–3459.
[7] a) T. E. Müller, K. C. Hultzsch, M. Yus, F. Foubelo, M.
Tada, Chem. Rev. 2008, 108, 3795–3892; b) K. Oshimo-
to, H. Tsuji, M. Kawatsura, Org. Biomol. Chem. 2019,
skii, E. P. Ivakhnenko, U. Ortiz-Mendez, J. Coord.
Chem. 2002, 55, 745–770; b) M. Mure, Acc. Chem. Res.
2004, 37, 131–139; c) J. P. Klinmn, F. Bonnot, Chem.
Rev. 2014, 114, 4343–4365; d) Y. Qin, L. Zhang, J. Lv,
S. Luo, J.-P. Cheng, Org. Lett. 2015, 17, 1469–1472;
e) M. Largeron, Org. Biomol. Chem. 2017, 15, 4722–
4730.
17, 4225–4229; c) H.-Z. Xie, Q. Gao, Y. Liang, H.-S. [14] a) P. Li, D. Menche, Angew. Chem. Int. Ed. 2009, 48,
Wang, Y.-M. Pan, Green Chem. 2014, 16, 2132–2135;
d) Z. Luo, H. Wu, Y. Li, Y. Chen, J. Nie, S. Lu, Y. Zhu,
Z. Zeng, Adv. Synth. Catal. 2019, 361, 4117–4125.
[8] a) S. Ueda, H. Nagasawa, Angew. Chem. Int. Ed. 2008,
47, 6411–6413; b) S. Ueda, H. Nagasawa, J. Org. Chem.
2009, 74, 4272–4277; c) P. Saha, M. A. Ali, P. Ghosh, T.
Punniyamurthy, Org. Biomol. Chem. 2010, 8, 5692–
5699; d) S. K. Alla, P. Sadhu, T. Punniyamurthy, J. Org.
Chem. 2014, 79, 7502–7511; e) X. Cao, X. Cheng, Y.
Bai, S. Liu, G.-J. Deng, Green Chem. 2014, 16, 4644–
4648.
5078–5080; b) C. A. Ramsden, Adv. Heterocycl. Chem.
2010, 100, 1–51; c) I. Usui, D. W. Lin, T. Masuda, P. S.
Baran, Org. Lett. 2013, 15, 2080–2083; d) Y. Nishiyama,
Y. Han-ya, S. Yokoshima, T. Fukuyama, J. Am. Chem.
Soc. 2014, 136, 6598–6601; e) S. Sato, K. Sakata, Y.
Hashimoto, H. Takikawa, K. Suzuki, Angew. Chem. Int.
Ed. 2017, 56, 12608–12613; f) F. Wakita, Y. Ando, K.
Ohmori, K. Suzuki, Org. Lett. 2018, 20, 3928–3932;
g) M. Zhang, R. A. Barrow, Org. Lett. 2017, 19, 2302–
2305; h) K. V. N. Esguerra, J.-P. Lumb, Angew. Chem.
Int. Ed. 2018, 57, 1514–1518; i) H. Miyamura, F. Tobita,
A. Suzuki, S. Kobayashi, Angew. Chem. Int. Ed. 2019,
58, 9220–9224.
[9] a) L. Zheng, J. Ju, Y. Bin, R. Hua, J. Org. Chem.,2012,
77, 5794–5800; b) R. Harigae, K. Moriyama, H. Togo, J.
Org. Chem. 2014, 79, 2049–2058; c) L. Wang, X. Yu, X. [15] H. Jiang, F. Chen, C. Zhu, R. Zhu, H. Zeng, C. Liu, W.
Feng, M. Bao, Org. Lett. 2012, 14, 2418–2421; d) E. Y. Wu, Org. Lett. 2018, 20, 3166–3169.
Schmidt, I. V. Tatarinova, E. V. Ivanova, N. V. Zorina, [16] CCDC 2021608 (4s) and 2022337 (5) contain the
I. A. Ushakov, B. A. Trofimov, Org. Lett. 2013, 15, 104–
107; e) D. Xiang, X. Xin, X. Liu, R. Zhang, J. Yang, D.
Dong, Org. Lett. 2012, 14, 644–647; f) M. Ghorbani, B.
Mohammadi, M. Saraii, B. Masoumi, M. Abbasian, A.
Ramazani, K. Slepokura, T. Lis, Org. Lett. 2016, 18,
supplementary crystallographic data. These data can also
be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.a-
c.uk/data_request/cif.
Adv. Synth. Catal. 2021, 363, 2124–2132
2132
© 2021 Wiley-VCH GmbH