The Construction of C-N, C-O, and C(sp2)-C(sp3) Bonds from Fluorine-Substituted 2-Aryl Benzazoles for Direct Synthesis of N-, O-, C-Functionalized 2-Aryl Benzazole Derivatives

Article abstract of DOI:10.1021/acs.joc.8b00587

Herein, a general and practical route to 2-(2-aminophenyl)- and 2-(2-alkoxyphenyl)-substituted benzazoles by nucleophilic aromatic substitution (S_NAr) is described. Upon treatment with Cs₂CO₃, the formation of C-N, C-O bonds occur between fluorine-substituted 2-aryl benzazoles and a diverse range of nitrogen, oxygen nucleophiles to provide the targets in good to excellent yields. Commercially available nucleophiles and high atom economy are notable features of the protocol. Meanwhile, the construction of C(sp²)-C(sp³) bond was also furnished in the presence of palladium catalyst.

Full text of DOI:10.1021/acs.joc.8b00587

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
The Construction of C−N, C−O, and C(sp2)−C(sp3) Bonds from
Fluorine-Substituted 2‑Aryl Benzazoles for Direct Synthesis of N‑, O‑,
C‑Functionalized 2-Aryl Benzazole Derivatives
Quan Zhou, Xi Hong, He-Zhen Cui, Shuang Huang, Ying Yi, and Xiu-Feng Hou*
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
S
* Supporting Information
ABSTRACT: Herein, a general and practical route to 2-(2-
aminophenyl)- and 2-(2-alkoxyphenyl)-substituted benzazoles
by nucleophilic aromatic substitution (SNAr) is described.
Upon treatment with Cs2CO3, the formation of C−N, C−O
bonds occur between fluorine-substituted 2-aryl benzazoles
and a diverse range of nitrogen, oxygen nucleophiles to
provide the targets in good to excellent yields. Commercially
available nucleophiles and high atom economy are notable
features of the protocol. Meanwhile, the construction of
C(sp2)−C(sp3) bond was also furnished in the presence of palladium catalyst.
Scheme 1. Transformations Involving 2-Aryl Benzazoles C−
N Construction
1. INTRODUCTION
2-Aryl benzazoles, an important structural motif for medicinal
chemistry, have been applied for the therapeutical agents for
Alzheimer’s disease1 and have potential applications in
fluorescent materials or light-activated catalysts.2 [11C]-2-(4-
(Methylamino)phenyl)-6-hydroxybenzothiazol (PIB)3 was the
most extensively studied positron emission tomography
radiolabeled imaging agent for Alzheimer’s disease β-amyloid
plaques. Furthermore, 2-(2-aminophenyl)-benzoxazoles deriva-
tives are special bidenated ligands for anion/cation fluorescence
chemosensors as well as solid-state luminescent dyes.4 Up to
now, extensive reports mainly focused on transition metal
catalyzed ortho C−H activation and functionalization, for
example, arylation,5 acylation,6 hydroxylation,7 fluorination,8
olefination.9 The construction of C−N/C−O bond for
benzoxazoles is rare. Chang10 reported an efficient Ir(III)/
Ag(I) catalytic system for C−H activation and amination of 2-
aryl benzoxazole with sulfonyl azides. Yao11 provided a copper
catalyzed formation of 2-(2-aminophenyl)-benzoxazoles, which
utilized diiodosubstituted N-phenyl benzamide as substrates.
Sequentially, similar halogen substituted N-phenyl benzamide
was also disclosed by Han12 (Scheme 1). However, these
protocols require loading high amounts of metal catalysts and/
or multihalogen substituted starting material. We speculated
that the formation of C−N bond for benzazoles may be
furnished via SNAr strategy. First, an abnormal product B
always accompanies with the aerobic oxidative cyclization for A
in our previous studies (Scheme 1),13 which is probably
associated with intramolecular nucleophilic attack from phenol
anion to fluorine atom at the aldehyde ring. Second,
benzimidazole-activated phenyl moieties SNAr reaction was
found in several special cases.14
protocol to obtain 2-(2-aminophenyl)-benzazoles and 2-(2-
alkoxyphenyl)-benzazoles by nucleophilic aromatic substitution
of fluorine-substituted 2-aryl benzazoles. Meanwhile, two
C(sp3)-functional 2-aryl benzazole derivatives were also
afforded in the presence of palladium (Scheme 1).
Considering the importance of N-, O-, C-functionalized 2-
aryl benzazoles, we reported a practical and high atom economy
Received: March 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b00587
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The Journal of Organic Chemistry
2. RESULTS AND DISCUSSION
Article
a
Table 2. Scope of Nitrogen Nucleophiles
Initially, as the imidazole was frequently found as fragment of
organic light emitting diodes15 and artificial pharmaceuticals,16
we attempted to anchor it on benzoxazole fragment. However,
the reported protocol is not quite efficient enough to synthesize
the target molecules.11 We took a primary test between 1a and
imidazole (Table 1, entry 1). To our delight, 3a was obtained in
a
Table 1. Optimization of Reaction Conditions
b
entry
substrate
base
solvent (temp.)
yield (%)
1
1a
1b
1c
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Cs2CO3
NaOH
DMF (120)
DMF (120)
DMF (120)
DMF (120)
DMF (120)
DMF (120)
DMF (120)
DMSO (120)
Toluene (120)
1,4-Dioxane (100)
THF (60)
95
2
N.R.
N.R.
3
c
4
70
d
5
60
6
N.R.
N.R.
60
7
TEA
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
N.R.
21
10
11
12
13
N.R.
71
a
CH3CN (80)
MeOH (60)
Standard condition: 1a (0.5 mmol), NuH (0.75 mmol, 1.5 equiv),
b c
solvent (3 mL), Cs2CO3 (1 mmol, 2.0 equiv). 10 mmol scale. 0.3
mmol.
N.R.
a
Standard condition: substrate (0.5 mmol), imidazole (0.75 mmol, 1.5
b
equiv), solvent (3 mL), base (1 mmol, 2.0 equiv), 12 h. Isolated yield.
c
d
24 h. 3 h.
However, all of them (2a, 2b, 2c) did not totally convert into
the corresponding products under standard condition.
Attempts to make modifications, such as changing other
aprotic solvent (DMSO), bases (NaH, K2CO3 or NaOH), have
all proven ineffectual. After all, we turned our attention to alkyl
amine. To our delight, not only primary (3h, 3i), but also
secondary amine (3j) present to be good nucleophiles.
However, diisopropylamine (2d) with large steric hindrance
was proved not feasible to undertake the SNAr reaction, which
was inconsistent with the previous reports.19 Furthermore,
cycloalkyl amine could fuse with 1a albeit with moderate to
excellent isolated yields, for example pyrrolidine (3k, 80%),
piperidine (3l, 86%), morpholine (3m, 91%), azetidine (3n,
43%).
After the C−N bond construction with first and second
amines, we focused our attention to C−O bond construction as
shown in Table 3. Initially, various kinds of oxygen nucleophiles
were checked with the 1a under the standard condition, for
example, alkyl alcohol, phenol and acid. To our surprised,
phenols with steric bulky group at para or ortho position are
both good nucleophilics (4ap, 91%; 4ao, 89%), while phenols
with halogen at para, meta or ortho position have distinct
difference: the para, meta iodo-substitued phenols could be
smoothly converted into the desired products (4bp, 91%; 4bm,
81%), however, the conversion of ortho-iodophenol (2e) was
not observed. Furthmore, considering the heterocyclic aromatic
rings in term of medical chemistry, we tried to fuse the pyridine
or quinoline into the 2-aryl benzoxazoles. Under the optimized
condition, pyridin-4-ol, pyridin-3-ol and quinolin-6-ol were
successfully converted into the desire products in good yields
(4cp, 61%; 4cm, 70%; 4d, 69%,); unfortunately, pyridin-2-ol
(2f), quinolin-8-ol (2g) were demonstrated not available
95% isolated yield. Then bromo-, chloro-substituted substrates
were tested to scrutinize element effect.17 (see Table 1, entries
2−3). Examination showed that chloro-, bromo-substituted 2-
aryl benzoxazoles (1b, 1c) did not convert into 3a with the
imidazole. This observation is important with respect to the
conversion mechanism, which is consistent with a typical
nucleophilic aromatic substitution (SNAr) where the leaving
ability of halogen commonly bear a clear trend (F ≫ Cl >
Br).18 Further optimization studies showed that Cs2CO3 is
crucial for this reaction, while other bases, like K2CO3, NaOH
or triethylamine (TEA), would result in significant decrease in
reaction efficiency and conversion. Different solvents were also
evaluated (Table 1, entries 8−13), MeOH, toluene, 1,4-
dioxane, THF did not give satisfactory yields, which might be
due to their poor solubility of Cs2CO3 and/or imidazole, polar
aprotic solvent, CH3CN, DMSO, comparatively, could also
express moderate conversion, however not better than DMF.
With the encouraging result of the reaction, the scope of
nitrogen nucleophiles was explored (Table 2). First, we tested
benzo[d]imidazole, 1,2,4-triazole, pyrazole and halogen sub-
stituted pyrazole derivatives, luckily all forging the desired
products albeit with quantitative isolated yields under optimal
condition. Notable, halogen substituted azoles were well
tolerated (3e, 86%; 3f, 83%). To further test the facility of
this reaction, a gram-scale reaction of 3a was conducted.
Pleasingly, no apparent yield decrease was observed; worthy to
note, no gel chromatography was necessary for the gram-scale
purification, only by simple extraction and crystallization, which
would result in good purity. Then the anilines with electron-
withdrawing groups or electron-donating groups were tested.
B
DOI: 10.1021/acs.joc.8b00587
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Table 3. Scope of Oxygen Nucleophiles
Scheme 2. Construction of C(sp2)−C(sp3) Bond Catalyzed
by Palladium
frequently used SNAr C−C bond construction, C(sp2)−
C(sp),20 C(sp2)−C(sp3)21 formation have been reported as
protocols to access various substrates. Selvakumar21a,d and
Shen21f developed C(sp2)−C(sp3) cross coupling method-
ologies under strong base (NaH, NaHMDS). So, we followed
these methods; however, no desired product was forged. We
rationalized that additional transition metal would stabilize in
situ generated carbon anion by the metal−carbon interaction,
which might facilitate the conversion.22 Actually, the 5 mol %
Pd(PPh3)4 addition into reaction (5a, 52%) could achieve
moderate yield. Comparable experiment showed that bromide
substrate (1b) instead of fluoride substrate could not have any
trace of desired product, which indicated the SNAr effect
assisted C−C bond formation. In the same way, the para
fluoride substrate could also take use of the strategy en route to
the desired C(sp2)−C(sp3) cross coupling product. Further-
more, taking into account the fact that aryl terminal alkyne
proton owns higher pKa value than methyl 2-cyanoacetate
C(sp3)−H bond, it would more likely undertake deprotonation
under the basic situation and trap by the palladium precursor,
However, some tries have proven ineffectual (see the SI for
details). Interestingly, the C(sp3)−H chemical shift of ortho-
substituted product 5a (7.00 ppm) moved to lower field
compared to that of para-substituted product 5b (4.83 ppm).
This is similarly observed in our previous study.9 Such
significant difference is likely due to shielding field and
hydrogen bonding resulted from benzoxazole ring.
After exploring the scope of O-, N- C-nucleophiles, we
turned our attention on the scope of 2-aryl benzazoles (Table
4). First, we evaluate whether fluorine atom located meta, para
to benzoxazolyl group could undertake SNAr conversion. As
expectation, para substrate (1d) worked well (3o, 90%; 3p,
84%), the desired SNAr products had the similar good yield
with 1a, while meta substrate (1e) was exclusively not reactive
and owned good starting material recycle, which is coincident
with other electron-withdrawing groups directed SNAr reac-
tion.17 Furthermore, two kinds of important benzoxazoles
derivatives, benzo[d]thiazole (1f), benzo[d]imidazole (1g),
were also screened, which demonstrated their feasibility of
utilizing this strategy for easy access to N-, O-derivatives at
ortho and para position (3q, 90%; 4t, 78%; 3r, 85%). Lastly, we
designed and screened two special substrates to evaluate the
electronic effect on the benzoxazole fragment (1h, 1i), which
demonstrated that neither electron-withdrawing nor electron-
donating group on benzo[d]oxazole ring would affect the SNAr
efficiency of this reaction, both smoothly converted into
substituted products (3s, 94%; 3t, 90%; 3u, 94%). Interesting,
3u was generated and fused with two imidazole molecules, one
imidazole molecule was fused the standard C−F bond, while
another is, determined by 19F NMR spectra, the C−F bond
a
Standard condition: 1a (0.5 mmol), 2 (0.75 mmol, 1.5 equiv), solvent
b
(3 mL), Cs2CO3 (1 mmol, 2.0 equiv). 2 (0.25 mmol).
nucleophiles. Moreover, phenols containing late-stage function-
alization functional groups were also tested, for example,
aldehyde- and acetyl-containing phenols, which could bear
good tolerance to this condition and afforded the correspond-
ing products in excellent yields (4e, 93%; 4f, 78%). However,
their positional isomers, 2-hydroxybenzaldehyde (2h) and 1-(2-
hydroxyphenyl)ethan-1-one (2i) failed to convert into the
desired products. The failed reactions (2e−2i) were possibly
due to the presence of the intramolecular hydrogen bond
between the hydroxyl and adjacent electron-withdrawing
groups. When hydroquinone worked as nucleophile, double
C−O bonds were formed en route to a symmetric molecule
with good yield (4g, 86%). In addition, different benzyl
alcohols (BnOHs) worked well, too. The BnOHs could range
from heteroaromatic rings (4h, 90%; 4i, 95%) to benzyl ring
with substitution at ortho-(4l, 65%), meta-(4m, 76%), para-(4n,
75%; 4o, 79%; 4p, 77%). The halogen atoms affiliated on the
nucleophile are well tolerated under such conversion and useful
for future transformation. Steric bulky alcohols have a slight
negative effect on this reaction, which could be observed by the
comparison between 4j (81%) and 4k (78%). More significant
steric effect could be learned from 4q (45%) and 4r (93%),
which was derived from large steric tetra-butyl alcohol and n-
hexanol. Lastly, we tried to take usage of benzyl acid as the
oxygen nucleophile. However, neither benzoate sodium nor
benzoic acid (2j) could work as the oxygen nucleophile for
SNAr transformation.
After the C−O, C−N bond construction, we addressed on
C−C bond construction (Scheme 2). As the most two
C
DOI: 10.1021/acs.joc.8b00587
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a
delocalization and stabilization of the bielectronic species in
Table 4. Scope of 2-Aryl Benzazoles
zwitterionic intermediate. (Scheme 3, D, benzOxa-Nu).18,24
3. CONCLUSIONS
In summary, benzazolyl groups were discovered to facilitate
SNAr reaction for C−O, C−N construction upon simple
deprotonation of N- or O-nucleophiles. Available nucleophiles
could range from azoles (benzo[d]imidazole, imidazole,
triazole, pyrazole derivatives), alkyl amines (primary and
secondary amines), alcohols to phenols. The facile protocol
presents good functional group tolerance for the nucleophiles,
especially to acetyl, aldehyde, halogen, which provides a
versatile platform for further transformation. Moreover, C-
(sp2)−C(sp3) bond was also constructed in the presence of
palladium catalyst. Worthy to note, the new benzoazoles-
imidazole backbones could be used as bidentate ligands in
coordination chemistry, an avenue that we will pursue in future
work.
4. EXPERIMENTAL SECTION
a
All commercially available compounds were purchased and used
without purification. Reaction temperatures are reported as the
temperature of the bath surrounding the reaction bottle unless
otherwise stated. Toluene, xylene (mixture of o, m, p-xylene), N,N-
dimethyl formaldehyde (DMF), ethanol, were purchased and used
without purification. Dry THF and dry DMF were purchased and used
under Schlenk line.
Standard condition: 1 (0.5 mmol), NuH (0.75 mmol, 1.5 equiv),
b
solvent (3 mL), Cs2CO3 (1 mmol, 2.0 equiv), 12 h. 10 mmol scale.
c
1i (0.2 mmol), NuH (0.6 mmol, 3 equiv), Cs2CO3 (0.8 mmol, 4
equiv).
ortho to oxygen atom of benzoxazole fragment (see Supporting
Information).
After all, we want to shed some light on the reaction
mechanism. First, 2-(2-fluorophenyl)-4-methyl-oxazoline (1j)
was tested (Scheme 3, A); however, no conversion was
Analytical thin layer chromatography was performed on GF 254
plates. Flash Chromatography was performed on silica gel (200−300
mesh) by standard technical eluting with solvents as indicated. 1H and
13C NMR were recorded at 295 K in CDCl3 or DMSO-d6; The
residual solvent signals were used as references and the chemical shifts
converted to the TMS scale (CDCl3: δH = 7.26 ppm, δC = 77.16 ppm;
DMSO-d6: δH = 2.50 ppm, δC = 39.52 ppm). For 19F NMR, chemical
shifts refer to an external calibration using CFCl3 (δ = 0.00 ppm). Data
Scheme 3. Mechanism Studies and Proposal
1
for H NMR are reported as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, dd = double doublet, m = multiplet),
coupling constants (J) in Hz and integration. Mass spectrometric data
were obtained using ESI (electrospray ionization, Q-Tof, positive ion)
mode. Melting points (mp) of the reported values are tested in
capillary auxiliary. Infrared spectra were recorded on a Nicolet 8700
Fourier Transform Infrared Spectrometer (FT-IR), and were reported
in wave numbers (cm−1).
Substrates (1b,13 1c,13 1d,13 1e13 1g,13 1i,9 1j,25 1k23) were
synthesized according to reported references.
1a was synthesized according to the according procedures13 on 10
mmol scale. Into a 50 mL round-bottom flask were added 5-methyl-2-
amino phenol (2.463g, 20 mmol) and 2-fluorobenzaldehyde (2.482g,
20 mmol), xylene (30 mL; mixture of o, m, p-xylene), the mixture was
allowed into preheated 120 °C oil-bath, stirred for half an hour, then
1,3-dimethyl-1H-benzo[d]imidazol-3-ium iodide (0.5 mmol, 136 mg)
and NaOH (2 mmol, 80 mg) were added into the reaction bottle,
continued to stir for 12 h under oxygen gas. After reaction, the mixture
was diluted with ethyl acetate, filtrated, the solution was concentrated
under vacuum, and the residue was applied on silica gel column
chromatography (PE/EA: 50/1), which afforded the corresponding
oxidative cyclization product 1a as light yellow solid (3.5 g, 77%).
Characterization Data of Newly Synthesized Substrates. 2-
(2-Fluorophenyl)benzo[d]thiazole (1f).26 Title compound was
synthesized by the same protocol for 1a on 10 mmol scale, which
observed, which demonstrated the importance of benzazoles for
this SNAr conversion. Second 2-(2-fluorophenyl)pyridine,23 was
synthesized and addressed whether undertake the SNAr
reaction with nucleophiles. Various nucleophiles were tested
(Scheme 3, B); however, we failed to observe more than trace
amounts of the desired substituted products. Compared to
benzazoles, pyridinyl- owns sole electron-withdrawing nitrogen
in the aromatic ring. We wondered whether one more nitrogen
atom on the aromatic ring could furnish this conversion.
Luckily, 2-(2-fluorophenyl)pyrimidine (1l) could give 20%
conversion under the optimized condition (Scheme 3, C).
Above all, we speculated the excellent SNAr mainly benefit from
the conjugation system and extra heteroatom (X) of 2-aryl
benzazoles, which may provide enough space for electron
1
afforded yellow solid 1.7 g (74%); mp 67.4−67.9 °C; H NMR (400
MHz, CDCl3) δ 8.46 (td, J = 7.7, 1.7 Hz, 1H), 8.16 (d, J = 8.1 Hz,
1H), 7.96 (d, J = 8.0 Hz, 1H), 7.57−7.52 (m, 1H), 7.47 (ddt, J = 18.3,
15.2, 4.8 Hz, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.30−7.20 (m, 1H); 13C
NMR (101 MHz, CDCl3) δ 161.2, 160.6 (d, J = 253.5 Hz), 152.5,
135.8 (d, J = 8.0 Hz), 132.2 (d, J = 8.6 Hz), 129.8, 126.4, 125.4, 124.8,
124.7, 123.4, 121.5, 116.6, 116.3; 19F NMR (376 MHz, CDCl3) δ
D
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−111.84 (tt, J = 11.1, 7.2 Hz); IR (neat/cm−1) 3061, 1620, 1581,
1504, 1453, 1437, 1312, 1280, 1203, 1101, 796, 966, 765, 729, 694,
653, 544, 457; HRMS (ESI) calcd for C13H9FNS+ [M + H+] 230.0434
, found 230.0432. Worthy to note, no benzo[b,f ][1,4]thiazepine was
isolated from this reaction.
Hz, 1H), 6.95 (s, 1H), 2.35 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
160.2, 149.0, 141.6, 137.9, 136.2, 134.7, 132.0, 131.4, 129.5, 129.1,
128.0, 126.9, 124.3, 120.8, 120.2, 110.2, 21.5; IR (neat/cm−1) 3109,
2962, 2923, 2853, 1601, 1585, 1504, 1267, 1203, 1111, 1066, 1034,
803, 774, 662, 598; HRMS (ESI) calcd for C17H14N3O [M + H+]
276.1131, found 276.1151.
2-(2-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-methylbenzo[d]-
oxazole (3b). According to the general procedure II, which afforded
3b in yellow solid (156 mg, 96%); Rf = 0.2 (DCM/MeOH = 50:1);
mp 134.3−137.4 °C;1H NMR (400 MHz, CDCl3) δ 8.41 (dd, J = 7.3,
2.1 Hz, 1H), 8.05 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.72−7.63 (m,
2H), 7.54 (dd, J = 7.2, 1.8 Hz, 1H), 7.37 (s, 1H), 7.26 (td, J = 8.1, 1.2
Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.07 (d, J =
8.3 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 2.37 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 160.0, 148.8, 143.7, 143.5, 141.5, 135.2, 134.6, 134.5,
132.2, 131.6, 129.5, 129.1, 126.9, 125.2, 123.6, 122.5, 120.3, 120.2,
109.98, 109.95, 21.4; IR (neat/cm−1) 3106, 3051, 2955, 2923, 1617,
1604, 1578, 1556, 1504, 1488, 1456, 1309, 1293, 1235, 1194, 1040,
813, 790, 777, 742, 704; HRMS (ESI) calcd for C21H16N3O [M + H+]
326.1288, found 326.1297.
5-(tert-Butyl)-2-(2-fluorophenyl)benzo[d]oxazole (1h). Into a 50
mL round-bottom flask were added 4-tert-butyl-2-amino-phenol (10
mmol, 2.69 g) and 2-fluorobenzaldehyde (10 mmol, 1.24 g), xylene
(15 mL; mixture of o, m, p-xylene), the mixture were lowered into
preheated 120 °C oil-bath, stirred for half an hour, monitored by TLC,
when the aldehyde point was disappeared, then 1-butyl-3-methyl-1H-
imidazol-3-ium iodide (1 mmol, 266 mg, 10% equiv) and K2CO3 (2
mmol, 276 mg, 20% equiv) were added into the reaction bottle,
continued to stir for 12 h under oxygen atmosphere. The reaction
mixture was filtered through Celite, the filtrate was concentrated under
reduced pressure to remove the versatile solution, the residue was
applied on silica gel chromatography (PE/EA: 100/1), which afforded
the desired product 1h as light yellow oil (1.5 g, 57% yield)]. Rf = 0.8
1
(PE/EA = 10:1); mp 29.5−30.3 °C; H NMR (500 MHz, CDCl3) δ
8.27−8.21 (m, 1H), 7.89 (t, J = 2.5 Hz, 1H), 7.53 (dt, J = 6.7, 5.1 Hz,
2H), 7.47 (dd, J = 8.6, 1.9 Hz, 1H), 7.37−7.30 (m, 1H), 7.28 (d, J =
8.7 Hz, 1H), 1.42 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 160.8 (d, J
= 258.8 Hz), 159.5, 159.5, 148.5, 148.3, 141.7, 132.9 (d, J = 8.6 Hz),
130.4 (d, J = 1.3 Hz), 124.5 (d, J = 3.8 Hz), 123.3, 117.1 (d, J = 21.5
Hz), 116.9, 115.7 (d, J = 10.4 Hz), 109.8, 35.0, 31.8; 19F NMR (471
MHz, CDCl3) δ −110.19 (d, J = 6.1 Hz); IR (neat/cm−1) 3077, 2962,
2907, 2869, 1623, 1613, 1588, 1546, 1482, 1460, 1341, 1274, 1223,
1203, 1111, 1024, 874, 829, 803, 777, 749, 704, 659; HRMS (ESI)
calcd for C17H17FNO [M + H+] 270.1289, found 270.1291.
2-(2-(1H-1,2,4-Triazol-1-yl)phenyl)-5-methylbenzo[d]oxazole
(3c). According to the general procedure I, which afforded 3c in white
solid (123 mg, 89%); Rf = 0.45 (DCM/MeOH= 50:1); mp 117.1−
1
118.5 °C; H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.30 (dd, J =
5.9, 3.4 Hz, 1H), 8.11 (s, 1H), 7.71−7.61 (m, 2H), 7.58 (dd, J = 5.8,
3.3 Hz, 1H), 7.47 (s, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.13 (d, J = 8.3 Hz,
1H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 159.7, 152.3,
148.9, 144.9, 141.7, 135.7, 134.7, 131.9, 131.1, 130.0, 128.0, 127.0,
124.1, 120.4, 110.1, 21.5; IR (neat/cm−1) 3132, 2917, 2850, 1510,
1453,1283, 1203, 1139, 1069, 1035, 979, 960, 867, 808, 772, 751, 697;
HRMS (ESI) calcd for C16H13N4O [M + H+] 277.1084, found
277.1083.
2-(2-Fluorophenyl)pyrimidine (1l). A suspension of 2-bromopyr-
imidine (1 mmol, 157 mg, 1.0 equiv) and (2-fluorophenyl)boronic
acid (1.1 mmol, 154 mg, 1.1 equiv), Pd(PPh3)4 (0.05 mmol, 57 mg, 5
mol %), Na2CO3 (2 mmol, 210 mg, 2.0 equiv), EtOH (3 mL), deionic
water (3 mL), N,N-dimethylacetamide (5 mL) was stirred at 120 °C
under nitrogen in a sealed Shlenck tube for 18 h. After finished, the
mixture was extracted with ethyl acetate (5 mL × 3), the combined
organic phase was dried over anhydrous sodium sulfate, concentrated
under reduced pressure, purified through Silica gel chromatography
(PE/EA = 10/1), which afforded the desired product 1l in colorless oil
2-(2-(1H-Pyrazol-1-yl)phenyl)-5-methylbenzo[d]oxazole (3d). Ac-
cording to the general procedure I, which afforded 3d in colorless oil
(124 mg, 90%); Rf = 0.1 (DCM/MeOH = 50:1); 1H NMR (400 MHz,
CDCl3) δ 8.13 (d, J = 7.6 Hz, 1H), 7.68−7.48 (m, 6H), 7.21 (d, J = 8.3
Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.38 (s, 1H), 2.43 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 161.2, 149.1, 141.8, 141.1, 139.6, 134.3,
131.8, 131.4, 130.9, 128.4, 127.0, 126.6, 123.5, 120.2, 110.1, 107.0,
21.5; IR (neat/cm−1) 3109, 3067, 2920, 2859, 1591, 1521, 1485, 1399,
1335, 1261, 1200, 1111, 1037, 941, 832, 803, 762, 621, 598; HRMS
(ESI) calcd for C17H14N3O [M + H+] 276.1131, found 276.1150.
2-(2-(4-Bromo-1H-pyrazol-1-yl)phenyl)-5-methylbenzo[d]oxazole
(3e). According to the general procedure I, which afforded 3e in
yellow solid (152 mg, 86%); Rf = 0.75 (DCM/MeOH= 50:1); mp
103.9−105.7 °C; 1H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 7.5, 1.4
Hz, 1H), 7.67 (s, 1H), 7.64−7.59 (m, 2H), 7.59−7.50 (m, 3H), 7.27
(d, J = 8.3 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 2.45 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 160.5, 149.0, 141.7, 141.4, 138.8, 134.4, 131.7,
131.3, 131.0, 129.0, 127.0, 126.7, 123.5, 120.2, 110.0, 94.7, 21.4; IR
(neat/cm−1) 3128, 3045, 2965, 2927, 2856, 1601, 1562, 1498, 1457,
1389, 1335, 1194, 1037, 960, 803, 768, 704, 611; HRMS (ESI) calcd
for C17H13N3BrO [M + H+] 354.0237, found 354.0241.
1
(150 mg, 86%); H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 4.9 Hz,
2H), 7.99 (td, J = 7.8, 1.7 Hz, 1H), 7.44−7.31 (m, 1H), 7.20 (d, J = 7.6
Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ
−115.53 to −115.68 (m); 13C NMR (101 MHz, CDCl3) δ 163.3,
161.0 (d, J = 255.0 Hz), 157.2 (2), 131.8 (2), 126.3(d, J = 9.4 Hz),
124.1, 116.8 (d, J = 22.5 Hz); IR (neat/cm−1) 3045, 2968, 1620, 1588,
1572, 1498, 1456, 1424, 1248, 1232, 1216, 1120, 1037, 838, 819, 768,
637; HRMS (ESI) calcd for C10H8FN2 [M + H+] 175.0666, found
175.0665.
General Protocol for the Construction of C−N Bond. General
Procedure I. Into a glass tube were added substrate 1a (0.5 mmol, 112
mg), Cs2CO3 (326 mg, 1 mmol, 2.0 equiv), nitrogen nucleophiles
(0.75 mmol), DMF (3 mL), sealed by rubber stopper. The glass tube
was stirred under preheated 120 °C oil bath for 12 h. After finished,
the reaction solution was diluted by NH4Cl solution (20 mL),
extracted by ethyl acetate (EA) (3 × 10 mL), combined the organic
phase, washed by brine (2 × 10 mL), dried by anhydrous sodium
sulfate, and concentrated under reduced pressure, and the residue was
applied on silica gel chromatography.
2-(2-(4-Chloro-1H-pyrazol-1-yl)phenyl)-5-methylbenzo[d]oxazole
(3f). According to the general procedure I, which afforded 3f in white
solid (128 mg, 83%); Rf = 0.85 (DCM/MeOH = 50:1); white solid;
1
mp 189.8−191.7 °C; H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H),
8.29 (dd, J = 5.8, 3.4 Hz, 1H), 8.22 (s, 1H), 7.76−7.65 (m, 2H), 7.63−
7.55 (m, 1H), 7.46 (s, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.14 (d, J = 8.1
Hz, 1H), 2.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 159.3, 148.8,
141.8, 137.7, 136.9, 136.6, 134.9, 132.0, 131.2, 131.1, 130.5, 127.8,
127.2, 124.0, 120.6, 110.1, 21.5; IR (neat/cm−1) 3112, 2920, 1537,
1507, 1498, 1483, 1405, 1320, 1280, 1197, 1043, 1002, 819, 805, 766,
754, 704, 598; HRMS (ESI) calcd for C17H13ClN3O [M + H+]
310.0742, found 310.0740.
General Procedure II. According to procedure I, the residue was set
overnight at ∼10 °C, until no more solid grew out. Then the
supernatant was decanted, the precipitate was washed three times with
PE/EA (10/1) mixture, and the resulting product was dried under
vacuum.
2-(2-(1H-Imidazol-1-yl)phenyl)-5-methylbenzo[d]oxazole (3a).
According to the general procedure II, which afforded 3a in a yellow
solid (131 mg, 95%); while 10 mmol scale forge 3a abeit with 92%
yield. Rf = 0.3 (PE/EA = 1:1) or = 0.1 (DCM/MeOH = 50:1); mp
5-Methyl-2-(2-(4-phenyl-1H-imidazol-1-yl)phenyl)benzo[d]-
oxazole (3g). According to the general procedure I, which afforded 3g
in white solid (145 mg, 80%); Rf = 0.6 (DCM/MeOH= 50:1); mp
1
51.7−53.2 °C; H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.8 Hz,
1
1H), 7.55 (s, 1H), 7.52 (t, J = 6.4 Hz, 2H), 7.40 (s, 1H), 7.35 (d, J =
7.3 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.08 (s, 1H), 7. 03 (d, J = 8.3
81.6−82.1 °C; H NMR (400 MHz, CDCl3) δ 8.26 (dd, J = 6.8, 1.3
Hz, 1H), 7.80 (d, J = 7.7 Hz, 2H), 7.65 (s, 1H), 7.58 (m, 2H), 7.44 (d,
E
DOI: 10.1021/acs.joc.8b00587
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
J = 8.4 Hz, 2H), 7.39−7.31 (m, 3H), 7.26−7.18 (m, 2H), 7.06 (d, J =
8.3 Hz, 1H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 160.1,
148.9, 142.3, 141.5, 138.2, 138.1, 135.9, 134.6, 134.0, 131.9, 131.3,
129.1, 128.6, 128.0, 126.9, 125.0, 124.0, 120.3, 120.2, 116.6, 116.5,
110.2, 21.4; IR (neat/cm−1) 3119, 3100, 2917, 1601, 1578, 1556, 1501,
1456, 1338, 1264, 1197, 1123, 1069, 1024, 931, 877, 803, 755, 707;
HRMS (ESI) calcd for C23H18N3O [M + H+] 352.1444, found
352.1455.
2-(5-Methylbenzo[d]oxazol-2-yl)-N-propylaniline (3h). According
to the general procedure I, which afforded 3h in slight yellow liquid
(80 mg, 60%); Rf = 0.85 (PE/EA = 10:1); 1H NMR (400 MHz,
CDCl3) δ 8.38 (s, 1H), 8.08 (dd, J = 7.9, 1.1 Hz, 1H), 7.50 (s, 1H),
7.42 (d, J = 8.2 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.12 (d, J = 7.8 Hz,
1H), 6.79 (d, J = 8.4 Hz, 1H), 6.71 (t, J = 7.4 Hz, 1H), 3.33 (dd, J =
12.3, 6.8 Hz, 2H), 2.48 (s, 3H), 1.83 (Sept, J = 7.2 Hz, 2H), 1.11 (t, J
= 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 163.6, 148.7, 147.5,
142.2, 134.0, 132.7, 129.1, 125.7, 119.4, 114.9, 111.0, 109.6, 108.2,
45.0, 22.6, 21.6, 12.0; IR (neat/cm−1) 3304, 2962, 2927, 2869, 1607,
1588, 1546, 1530, 1440, 1335, 1319, 1264, 1197, 1165, 1030, 800, 749,
701, 592; HRMS (ESI) calcd for C17H19N2O [M + H+] 267.1492,
found 267.1503.
601; HRMS (ESI) calcd for C19H21N2O [M + H+] 293.1648, found
293.1664.
5-Methyl-2-(2-morpholinophenyl)benzo[d]oxazole (3m). Accord-
ing to the general procedure I, which afforded 3m in yellow oil (133
1
mg, 91%); Rf = 0.2 (PE/EA = 10:1); H NMR (400 MHz, CDCl3) δ
8.05 (d, J = 7.7 Hz, 1H), 7.57 (s, 1H), 7.46 (m, 2H), 7.17 (d, J = 8.4
Hz, 1H), 7.12 (m, 2H), 3.88 (s, 4H), 3.04 (s, 4H), 2.50 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 163.2, 152.0, 148.8, 142.3, 134.4, 132.33,
132.32, 126.3, 122.4, 120.5, 120.1, 118.9, 109.9, 67.0(2), 52.6(2), 21.5;
IR (neat/cm−1) 2956, 2920, 2891, 2863, 2818, 1604, 1572,1549, 1489,
1450, 1380, 1338, 1300, 1268, 1223, 1197, 1117, 1037, 935, 925, 800,
762, 710, 601; HRMS (ESI) calcd for C18H19N2O2 [M + H+]
295.1441, found 295.1450.
2-(2-(Azetidin-1-yl)phenyl)-5-methylbenzo[d]oxazole (3n). Ac-
cording to the general procedure I on 0.3 mmol scale, with azetidine
hydrochloride (93.5 mg, 1 mmol, 3.3 equiv) as nucleophilic, Cs2CO3
(652 mg,2 mmol, 6.6 equiv) as base, which afforded 3n in white solid
(35 mg, 43%). mp 58.1−59.1 °C; Rf = 0.3 (PE/EA = 10:1); 1H NMR
(400 MHz, CDCl3) δ 7.77 (dd, J = 7.8, 1.4 Hz, 1H), 7.57 (s, 1H), 7.45
(d, J = 8.3 Hz, 1H), 7.37 (t, J = 7.0 Hz, 1H), 7.14 (dd, J = 8.2, 0.8 Hz,
1H), 6.87 (t, J = 7.5 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 3.86 (t, J = 7.4
Hz, 4H), 2.48 (s, 3H), 2.35−2.21 (m, 2H); 13C NMR (101 MHz,
CDCl3) δ 162.7, 151.5, 148.7, 142.4, 134.1, 131.6, 131.4, 125.8, 119.8,
117.8, 114.0, 112.3, 109.8, 54.2(2), 21.6, 16.7; IR (neat/cm−1) 3064,
2997, 2972, 2920, 2863, 1607, 1578, 1549, 1482, 1437, 1351, 1309,
1261, 1197, 1165, 1031, 925, 832, 803, 755, 710, 608; HRMS (ESI)
calcd for C17H17N2O [M + H+] 265.1335, found 265.1333.
N-Benzyl-2-(5-methylbenzo[d]oxazol-2-yl)aniline (3i). According
to the general procedure I, which afforded 3i in colorless crystal (115
mg, 73%); Rf = 0.8 (PE/EA = 10:1); mp 77.1−80.4 °C;1H NMR (400
MHz, CDCl3) δ 8.92 (s, 1H), 8.12 (dd, J = 7.9, 1.4 Hz, 1H), 7.48 (s,
1H), 7.43 (dd, J = 7.8, 3.7 Hz, 3H), 7.36 (t, J = 7.5 Hz, 2H), 7.31−7.26
(m, 2H), 7.14 (dd, J = 8.2, 0.9 Hz, 1H), 6.77−6.68 (m, 2H), 4.64 (d, J
= 5.8 Hz, 2H), 2.48 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 163.5,
148.3, 147.5, 142.0, 139.4, 134.2, 132.7, 129.0, 128.8 (2), 127.1, 127.0
(2), 125.8, 119.4, 115.5, 111.6, 109.7, 108.7, 47.2, 21.6; IR (neat/
cm−1) 3304, 3055, 3026, 2968, 2920, 2853, 1623, 1610, 1597, 1527,
1447, 1335, 1261, 1200, 1095, 1030, 925, 800, 736, 697, 464; HRMS
(ESI) calcd for C21H19N2O [M + H+] 315.1492, found 315.1501.
N-Butyl-N-methyl-2-(5-methylbenzo[d]oxazol-2-yl)aniline (3j).
According to the general procedure I, which afforded 3j in light
2-(4-(1H-Imidazol-1-yl)phenyl)-5-methylbenzo[d]oxazole (3o).
The reaction was conducted as general procedure II, after finished,
deionic water (10 mL) was added, then numerous white power
precipitate out, than ethyl acetate was used to remove nonconsumed
starting material, filtrated, the white solid was washed by PE/EA (1/1;
v/v), which afforded 3o in white solid (124 mg, 90%); Rf = 0.05
1
(DCM/MeOH = 50:1); mp 254.1−255.4 °C; H NMR (400 MHz,
MeOD) δ 8.36−8.27 (m, 2H), 8.21 (s, 1H), 7.77−7.68 (m, 2H), 7.62
(s, 1H), 7.54−7.48 (m, 2H), 7.25−7.18 (m, 2H), 2.49 (s, 3H); 13C
NMR (101 MHz, MeOD) δ 161.6, 148.4, 141.0, 138.9, 134.9, 134.5,
129.1, 128.5(2), 126.2, 125.3, 120.6, 118.7, 117.5 (2), 109.5, 20.1; IR
(neat/cm−1) 3087, 2989, 1605, 1542, 1504, 1474, 1452, 1433, 1344,
1308, 1295, 1258, 1187, 1062, 880, 845, 821, 796, 758, 738, 694, 630,
527; HRMS (ESI) calcd for C17H14N3O [M + H+] 276.1131, found
276.1150.
1
yellow oil (94 mg, 64%); Rf = 0.55 (PE/EA = 10:1); H NMR (400
MHz, CDCl3) δ 7.87 (d, J = 7.7 Hz, 1H), 7.57 (s, 1H), 7.44 (d, J = 8.2
Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 7.07 (d, J =
8.3 Hz, 1H), 6.99 (t, J = 7.7 Hz, 1H), 3.00−2.90 (m, 2H), 2.80 (s,
3H), 2.49 (s, 3H), 1.55−1.46 (m, 2H), 1.14 (q, J = 7.4 Hz, 2H), 0.77
(t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 164.3, 152.5,
149.0, 142.4, 134.2, 132.6, 131.8, 126.0, 120.3, 120.0, 119.1, 118.9,
110.0, 56.1, 40.4, 29.3, 21.6, 20.6, 13.9; IR (neat/cm−1) 2959, 2930,
2866, 2802, 1604, 1482, 1457, 1264, 1194, 1034, 797, 755, 605;
HRMS (ESI) calcd for C19H23N2O [M + H+] 295.180, found
295.1821.
5-Methyl-2-(2-(pyrrolidin-1-yl)phenyl)benzo[d]oxazole (3k). Ac-
cording to the general procedure I, which afforded 3k in yellow oil
(111 mg, 80%); Rf = 0.6 (PE/EA = 10:1); 1H NMR (400 MHz,
CDCl3) δ 7.70 (d, J = 7.7 Hz, 1H), 7.56 (s, 1H), 7.44 (d, J = 8.2 Hz,
1H), 7.36 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 8.5
Hz, 1H), 6.83 (t, J = 7.4 Hz, 1H), 3.16 (d, J = 5.5 Hz, 4H), 2.49 (s,
3H), 1.87 (s, 4H); 13C NMR (101 MHz, CDCl3) δ 164.6, 148.9,
148.8, 142.5, 134.2, 132.7, 131.6, 125.7, 119.9, 116.8, 114.4, 113.5,
110.0, 51.0 (2), 25.9 (2), 21.5; IR (neat/cm−1) 2965, 2917, 2869,
1604, 1572, 1485, 1450, 1354, 1261, 1191, 1024, 800, 752, 601;
HRMS (ESI) calcd for C18H19N2O [M + H+] 279.1492, found
279.1507.
5-Methyl-2-(2-(piperidin-1-yl)phenyl)benzo[d]oxazole (3l). Ac-
cording to the general procedure I, which afforded 3l in yellow oil
(125 mg, 86%); Rf = 0.2 (PE/EA = 10:1); 1H NMR (400 MHz,
CDCl3) δ 8.01 (d, J = 7.7 Hz, 1H), 7.58 (s, 1H), 7.46 (d, J = 8.1 Hz,
1H), 7.42 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 8.2
Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 3.03−2.88 (m, 4H), 2.50 (s, 4H),
1.71 (d, J = 4.6 Hz, 4H), 1.56 (d, J = 5.0 Hz, 2H); 13C NMR (101
MHz, CDCl3) δ 164.1, 153.3, 149.0, 142.3, 134.1, 132.3, 132.1, 126.0,
121.4, 120.2, 120.0, 118.9, 53.6 (2), 26.1 (2), 24.2, 21.5; IR (neat/
cm−1) 2936, 2853, 2795, 2744, 2706, 2674, 1597, 1572, 1485, 1450,
1386, 1267, 11232, 1200, 1127, 1104, 1034, 925, 829, 803, 761, 710,
2-(4-(1H-Benzo[d]imidazol-1-yl)phenyl)-5-methylbenzo[d]-
oxazole (3p). Similar procedure as 3o, addition of large amount
deionic water as well as filtration and washed with PE/EA (1/1; v/v,
20 mL), dried under reduced pressure, which afforded 3p in white
solid (136 mg, 84%); Rf = 0.1 (DCM/MeOH = 50:1); mp 213.5−
224.6 °C; 1H NMR (400 MHz, CDCl3) δ 8.48−8.41 (m, 2H), 8.20 (s,
1H), 7.94−7.87 (m, 1H), 7.72−7.66 (m, 2H), 7.66−7.60 (m, 1H),
7.59 (s, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.42−7.35 (m, 2H), 7.20 (dd, J
= 8.3, 1.1 Hz, 1H), 2.51 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
162.0, 149.2, 144.4, 142.4, 142.0, 138.9, 134.9 (2), 133.4, 129.4 (2),
126.9, 126.8, 124.2, 124.0, 123.3, 121.0, 120.2, 110.6, 110.2, 21.7; IR
(neat/cm−1) 3087, 3055, 3019, 2917, 2862, 1605, 1496, 1476, 1453,
1298, 1280, 1234, 1202, 1063, 842, 807, 779, 735, 696, 578, 526, 427;
HRMS (ESI) calcd for C21H16N3O [M + H+] 326.1288, found
326.1298.
2-(2-(1H-Imidazol-1-yl)phenyl)benzo[d]thiazole (3q). According
to the general procedure II, which afforded 3q in yellow-brown crystal
(124 mg, 90%); Rf = 0.1 (DCM/MeOH = 50:1); mp 85.7−88.1 °C;
1H NMR (400 MHz, CDCl3) δ 8.23 (dd, J = 6.6, 1.3 Hz, 1H), 8.04 (d,
J = 8.2 Hz, 1H), 7.76 (dd, J = 7.5, 0.5 Hz, 1H), 7.65−7.53 (m, 3H),
7.46 (ddd, J = 8.3, 7.3, 1.2 Hz, 1H), 7.41−7.31 (m, 2H), 7.18 (s, 1H),
7.01 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 163.1, 152.8, 137.9,
136.2, 135.6, 131.21, 131.16, 130.8, 130.1, 129.5, 128.0, 126.4, 125.7,
123.6, 121.6, 121.1; IR (neat/cm−1) 3112, 3071, 3061, 2968, 2930,
2846, 1504, 1453, 1428, 1319, 1300, 1287, 1245, 1101, 1043, 970, 957,
909, 765, 749, 736, 662, 624, 544, 464; HRMS (ESI) calcd for
C16H12N3S [M + H+] 278.0746, found 278.0768.
F
DOI: 10.1021/acs.joc.8b00587
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2-(4-(1H-Imidazol-1-yl)phenyl)-1-butyl-1H-benzo[d]imidazole
(3r). According to the general procedure II, which afforded 3r in
colorless crystal needles (134 mg, 85%); Rf = 0.2 (DCM/MeOH =
50:1); mp 67.3−70.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H),
7.84 (m, 3H), 7.56 (d, J = 8.0 Hz, 2H), 7.43 (m, 1H), 7.37 (s, 1H),
7.32 (m, 2H), 7.25 (s, 1H), 4.26 (t, J = 7.5 Hz, 2H), 1.88−1.77 (m,
2H), 1.30 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 152.3, 143.2, 138.3, 135.8, 135.5, 131.05 (2), 131.99, 129.96,
123.1, 122.7, 121.4(2), 120.2, 118.0, 110.3, 44.8, 32.0, 20.1, 13.7; IR
(neat/cm−1) 3359, 3301, 3119, 3100, 2962, 2875, 1681, 1614, 1543,
1495, 1469, 1425, 1399, 1309, 1261, 1117, 1069, 963, 842, 771, 749,
665, 531; HRMS (ESI) calcd for C20H21N4 [M + H+] 317.1761, found
317.1769.
2-(2-(1H-Imidazol-1-yl)phenyl)-5-(tert-butyl)benzo[d]oxazole
(3s). According to the general procedure II on 10 mmol scale, which
afforded 3s in slight yellow solid (3g, 94%); Rf = 0.2 (DCM/MeOH =
50:1); mp 49.6−52.5 °C; 1H NMR (400 MHz, CDCl3) δ 8.27 (dd, J =
7.2, 2.1 Hz, 1H), 7.74−7.68 (m, 2H), 7.67−7.59 (m, 2H), 7.46 (dd, J
= 7.2, 2.1 Hz, 1H), 7.40 (dd, J = 8.6, 1.8 Hz, 1H), 7.34 (d, J = 8.6 Hz,
1H), 7.21 (s, 1H), 7.06 (s, 1H), 1.37 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ 160.2, 148.9, 148.6, 141.5, 137.9, 136.2, 132.0, 131.5, 129.4,
129.2, 128.2, 124.6, 123.8, 121.1, 117.1, 110.1, 35.1, 31.9 (3); IR
(neat/cm−1) 3135, 3119, 2962, 2866, 1588, 1546, 1504, 1488, 1463,
1353, 1364, 1338, 1277, 1242, 1203, 1072, 1069, 1037, 816, 771, 707,
669; HRMS (ESI) calcd for C20H20N3O [M + H+] 318.1601, found
318.1607.
5-(tert-Butyl)-2-(2-morpholinophenyl)benzo[d]oxazole (3t). Ac-
cording to the general procedure I, which afforded 3t in slight yellow
liquid (151 mg, 91%); Rf = 0.4 (PE/EA = 10:1); 1H NMR (400 MHz,
CDCl3) δ 8.06 (dd, J = 8.1, 1.6 Hz, 1H), 7.81 (d, J = 1.5 Hz, 1H), 7.50
(d, J = 8.6 Hz, 1H), 7.47(dd, 7.8, 1.2 Hz, 1H), 7.43 (dd, J = 7.8, 1.9
Hz, 1H), 7.15−7.10 (m, 2H), 3.97−3.83 (m, 4H), 3.07−3.02 (m, 4H),
1.43 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 163.3, 152.0, 148.5,
148.0, 142.0, 132.3, 132.2, 122.9, 122.4, 120.5, 118.8, 116.6, 109.6,
67.1, 52.6, 35.0, 31.9; IR (neat/cm−1) 3068, 2968, 2907, 2863, 2818,
1601, 1578, 1546, 1482, 1453, 1271, 1229, 1117, 1037, 931, 925, 774,
717, 659; HRMS (ESI) calcd for C21H25N2O2 [M + H+] 337.1911,
found 337.1919.
1617, 1607, 1575, 1485, 1421, 1267, 1194, 1069; HRMS (ESI) calcd
for C13H11N4 [M + H+] 223.0978, found 223.0977.
General Protocol for the Construction of C−O Bond. Into a
glass tube were added fluoride 2-aryl benzazoles (0.5 mmol), oxygen
nucleophiles (0.75 mmol), Cs2CO3 (326 mg, 1 mmol), DMF (3 mL),
the mixture was stirred under 120 °C oil bath, after 12 h, the reaction
solution was diluted by saturated NH4Cl solution, extracted with ethyl
acetate (10 × 3 mL), combined the organic phase, dried over
anhydrous sodium sulfate, and concentrated under reduced pressure,
and the residue was applied on silica gel chromatography, which
afforded the corresponding the desired product.
2-(2-(4-(tert-Butyl)phenoxy)phenyl)-5-methylbenzo[d]oxazole
(4ap). White solid (162 mg, 91%); Rf = 0.8 (PE/EA = 10:1); mp 85.9−
87.9 °C; 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 7.8 Hz, 1H), 7.57
(s, 1H), 7.47−7.39 (m, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.23 (t, J = 7.6
Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 7.03 (dd, J = 8.6, 2.7 Hz, 3H), 2.47
(s, 3H), 1.32 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 161.6, 156.4,
154.7, 149.2, 146.6, 142.2, 134.2, 132.5, 131.5, 126.7(2), 126.2, 123.3,
120.1, 119.9, 119.1, 118.8(2), 110.1, 34.4, 31.6(3), 21.6; IR (neat/
cm−1) 2959, 2946, 2923, 2859, 1543, 1508, 1444, 1226, 1104, 1024,
829, 800, 707, 598, 547; HRMS (ESI) calcd for C24H24NO2 [M + H+]
358.1802, found 358.1818.
2-(2-(2-(tert-Butyl)phenoxy)phenyl)-5-methylbenzo[d]oxazole
(4ao). White solid (142 mg, 89%); Rf = 0.65 (PE/EA = 30:1); mp
143.3−145.1 °C; 1H NMR (400 MHz, CDCl3) δ 8.29 (dd, J = 7.9, 1.7
Hz, 1H), 7.57 (s, 1H), 7.47−7.40 (m, 2H), 7.35 (d, J = 8.3 Hz, 1H),
7.26−7.20 (m, 1H), 7.18−7.05 (m, 3H), 6.96 (d, J = 8.4 Hz, 1H), 6.85
(dd, J = 7.9, 1.3 Hz, 1H), 2.48 (s, 3H), 1.50 (s, 9H); 13C NMR (101
MHz, CDCl3) δ 162.0, 156.3, 155.6, 149.4, 142.1, 141.2, 134.2, 132.6,
131.6, 127.5, 127.3, 126.2, 123.6, 123.0, 120.02, 119.96, 119.4, 110.1,
34.9, 30.3(3), 21.6; IR (neat/cm−1) 3077, 2994, 2959, 2914, 2869,
1543, 1572, 1492, 1466, 1440, 1335, 1261, 1226, 1197, 1114, 1085,
1027, 883, 803, 749, 704, 604; HRMS (ESI) calcd for C24H24INO2 [M
+ H+] 358.1802, found 358.1797.
2-(2-(4-Iodophenoxy)phenyl)-5-methylbenzo[d]oxazole (4bp).
White solid (194 mg, 91%); Rf = 0.6 (PE/EA = 10:1); mp 161.7−
1
163.1 °C; H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 7.7 Hz, 1H),
7.60 (d, J = 7.9 Hz, 2H), 7.54 (s, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.37 (d,
J = 8.2 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.07
(d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 160.8, 157.7, 154.6, 148.9, 141.9, 138.6 (2),
134.3, 132.6, 131.4, 126.3, 124.5, 121.1, 120.4, 120.1(2), 119.9, 110.0,
86.0, 21.5; IR (neat/cm−1) 3051, 3023, 2955, 2923, 2859, 1604, 1575,
1482, 1440, 1248, 1200, 1165, 1037, 1005, 829, 803, 768, 707, 601,
496, 467; HRMS (ESI) calcd for C20H15INO2 [M + H+] 428.0142,
found 428.0157.
2-(2-(1H-Imidazol-1-yl)phenyl)-5-fluoro-7-(1H-imidazol-1-yl)-
benzo[d]oxazole (3u). Into a glass tube were added 5, 7-difluoro-2-(2-
fluorophenyl)benzo[d]oxazole (50 mg, 0.2 mmol), imidazole (20 mg,
0.6 mmol, 3 equiv), Cs2CO3 (254 mg, 0.8 mmol, 4.0 equiv), DMF (3
mL). The mixture was stirred under 120 °C for 12 h. Then the
reaction solution was diluted by saturated NH4Cl aq., extracted by
ethyl acetate (3 × 10 mL). The organic phase was collected, washed
with brine (5 mL), dried over anhydrous magnesium sulfate,
concentrated under reduced pressure to appear precipitation, and
light yellow precipitation increased with the extension of the setting
time (∼10 °C). Then the supernatant was decanted, the precipitate
was washed three times with PE/EA (5 mL × 2, 10/1, v/v), which
afforded the desired product in yellow solid (62 mg, 90% crystallized
2-(2-(3-Iodophenoxy)phenyl)-5-methylbenzo[d]oxazole (4bm).
Colorless oil (179 mg, 84%); mp 63.5−65.5 °C;Rf = 0.53 (PE/EA =
30:1); 1H NMR (400 MHz, CDCl3) δ 8.27 (dd, J = 7.8, 1.2 Hz, 1H),
7.55 (s, 1H), 7.53−7.46 (m, 1H), 7.44−7.35 (m, 3H), 7.31 (t, J = 7.6
Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 7.05−6.97
(m, 2H), 2.46 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.9, 158.2,
154.8, 149.1, 142.1, 134.4, 132.8, 132.4, 131.6, 131.1, 127.6, 126.4,
124.6, 121.2, 120.2, 120.0, 117.8, 110.1, 94.3, 21.6; IR (neat/cm−1)
3087, 3023, 2920, 2862, 1607, 1578, 1485, 1466, 1264, 1245, 1037,
893, 803, 742; HRMS (ESI) calcd for C20H15INO2 [M + H+]
428.0142, found 428.0135.
5-Methyl-2-(2-(pyridin-4-yloxy)phenyl)benzo[d]oxazole (4cp).
Yellow solid (92 mg, 61%), after simple slowing evaporating, it will
grow into yellow crystals. Rf = 0.15 (DCM/MeOH = 50:1); mp 86.1−
89.4 °C; 1H NMR (400 MHz, CDCl3) δ 8.32 (m, 1H), 7.65 (m, 2H),
7.45 (s, 2H), 7.35 (d, J = 6.6 Hz, 2H), 7.30 (d, J = 8.3 Hz, 1H), 7.13
(d, J = 8.3 Hz, 1H), 6.43 (d, J = 6.7 Hz, 2H), 2.42 (s, 4H); 13C NMR
(101 MHz, CDCl3) δ 179.3, 159.0, 148.8, 141.6, 141.5, 140.8(2),
135.0, 132.5, 131.3, 130.1, 128.1, 127.4, 124.0, 120.5, 118.4(2), 110.2,
21.5; IR (neat/cm−1) 3369, 3266, 3055, 3074, 3055, 3032, 1555, 1572,
1495, 1412, 1348, 1191, 1037, 854, 784, 710; 531; HRMS (ESI) calcd
for C19H15N2O2 [M + H+] 303.1128, found 303.1134.
1
yield); Rf = 0.05 (DCM/MeOH = 50:1); mp 223.5−225.1 °C; H
NMR (400 MHz, DMSO) δ 8.33 (d, J = 7.8 Hz, 1H), 8.15 (s, 1H),
7.93 (s, 1H), 7.87−7.78 (m, 2H), 7.75 (t, J = 7.6 Hz, 1H), 7.69 (dd, J
= 8.1, 2.2 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.62 (s, 1H), 7.48 (s, 1H),
7.16 (s, 1H), 7.09 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 162.7,
160.1 (d, J = 243.8 Hz), 144.1 (d, J = 14.2 Hz), 138.4, 137.9, 136.5,
136.5, 133.2, 131.9, 130.9, 130.3, 129.6, 128.4, 123.2, 122.1 (d, J = 12.2
Hz), 121.0, 118.4, 105.9 (d, J = 29.7 Hz), 105.3 (d, J = 25.6 Hz); 19F
NMR (376 MHz, CDCl3) δ −114.0 (dd, J = 9.7, 7.8 Hz); IR (neat/
cm−1) 3141, 3106, 3039, 1642, 1601, 1514, 1434, 1239, 1210, 1149,
1130, 1075, 1027, 995, 835, 765, 653; HRMS (ESI) calcd for
C19H13FN5O [M + H+] 346.1099, found 346.1094
2-(2-(1H-Imidazol-1-yl)phenyl)pyrimidine (3v). According to the
general procedure I, which afforded 3v in colorless oil (22 mg, 20%).
1
Rf = 0.2 (PE/EA = 1:1); H NMR (400 MHz, CDCl3) δ 8.68 (d, J =
4.9 Hz, 2H), 7.97−7.89 (m, 1H), 7.46 (s, 1H), 7.44−7.39 (m, 1H),
7.18 (t, J = 4.9 Hz, 1H), 7.04 (s, 1H), 6.93 (s, 1H); 13C NMR (101
MHz, CDCl3) δ 164.8, 157.2 (2), 137.9, 136.0, 135.3, 131.5, 130.6,
128.9, 128.8, 126.9, 120.8, 119.3; IR (neat/cm−1) 2965, 2933, 2862,
5-Methyl-2-(2-(pyridin-3-yloxy)phenyl)benzo[d]oxazole (4cm).
White solid (105 mg, 70%). Rf = 0.1 (DCM/MeOH = 50:1); mp
G
DOI: 10.1021/acs.joc.8b00587
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
108.5−109.5 °C; 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 2.6 Hz,
1H), 8.32 (dd, J = 4.6, 1.3 Hz, 1H), 8.28 (dd, J = 7.9, 1.6 Hz, 1H),
7.54−7.47 (m, 2H), 7.37−7.31 (m, 2H), 7.31−7.27 (m, 1H), 7.25−
7.22 (m, 1H), 7.13−7.07 (m, 2H), 2.44 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 160.7, 154.5, 154.4, 149.1, 144. 4, 142.1, 141.1, 134.5, 132.9,
131.7, 126.6, 125.4, 125.1, 124.8, 124.2, 121.4, 120.3, 110.1, 21.6; IR
(neat/cm−1) 3042, 2930, 2869, 1607, 1575, 1553, 1492, 1476, 1437,
1280, 1235, 1203, 1114, 1046, 1040, 928, 864, 809, 797, 777, 704, 601,
582; HRMS (ESI) calcd for C19H15N2O2 [M + H+] 303.1128, found
303.1125.
1H), 7.21−7.07 (m, 4H), 6.99 (dd, J = 5.0, 3.6 Hz, 1H), 5.41 (s, 2H),
2.49 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.0, 157.0, 149.1,
142.2, 139.2, 134.1, 132.5, 131.5, 126.7, 126.5, 126.11, 126.07, 121.8,
120.0, 117.9, 115.2, 110.0, 66.9, 21.6; IR (neat/cm−1) 3083, 2923,
2898, 1607, 1581, 1556, 1498, 1485, 1440, 1290, 1264, 1200, 1168,
1053, 1030, 800, 752, 701, 601, 476; HRMS (ESI) calcd for
C19H16NO2S [M + H+] 322.0896, found 322.0900.
5-Methyl-2-(2-(1-(naphthalen-1-yl)ethoxy)phenyl)benzo[d]-
oxazole (4j). White solid (149 mg, 78%); Rf = 0.6 (PE/EA = 10:1);
mp 75.8−78.5 °C; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 7.5 Hz,
1H), 7.87−7.81 (m, 3H), 7.77−7.62 (m, 2H), 7.62−7.45 (m, 3H),
7.35−7.27 (m, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.12−6.94 (m, 2H), 5.64
(q, J = 6.2 Hz, 1H), 2.56 (s, 3H), 1.83 (d, J = 6.2 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 162.7, 156.9, 149.3, 142.3, 140.5, 134.2, 133.4,
133.1, 132.4, 131.6, 128.6, 128.1, 127.8, 126.3, 126.1, 126.0, 124.8,
123.9, 121.2, 120.0, 118.0, 116.0, 110.0, 77.9, 24.4, 21.7; IR (neat/
cm−1) 3035, 2984, 2971, 2917, 2898, 1607, 1549, 1492, 1482, 1453,
1437, 1261,1072, 1027, 813, 742, 697, 598; HRMS (ESI) calcd for
C26H22NO2 [M + H+] 380.1645, found 380.1638.
5-Methyl-2-(2-(quinolin-6-yloxy)phenyl)benzo[d]oxazole (4d).
White solid (121 mg, 69%); Rf = 0.2 (DCM/MeOH = 50:1); mp
1
91.1−92.8 °C; H NMR (400 MHz, CDCl3) δ 8.83−8.75 (m, 1H),
8.31 (d, J = 7.8 Hz, 1H), 8.10 (d, J = 9.1 Hz, 1H), 7.93 (d, J = 8.3 Hz,
1H), 7.60 (d, J = 9.2 Hz, 1H), 7.53−7.46 (m, 2H), 7.37−7.25 (m,
3H), 7.17 (d, J = 6.6 Hz, 2H), 7.07 (d, J = 8.3 Hz, 1H), 2.41 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 160.8, 156.0,, 154.6, 149.04, 148.95,
145.1, 141.9, 135.3, 134.3, 132.8, 131.6, 131.4, 129.1, 126.4, 124.8,
123.2, 121.8, 121.5, 120.2, 120.1, 112.2, 110.0, 21.5; IR (neat/cm−1)
3071, 3035, 2920, 2856, 1629, 1585, 1543, 1501, 1453, 1325, 1232,
1197, 1155, 1030, 915, 838, 787, 755, 701, 624; HRMS (ESI) calcd for
C23H17N2O2 [M + H+] 353.1285, found 353.1294.
5-Methyl-2-(2-(naphthalen-1-ylmethoxy)phenyl)benzo[d]oxazole
(4k). White solid (147 mg, 81%); Rf = 0.55 (PE/EA= 10:1); mp
1
146.4−147.8 °C; H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 7.7 Hz,
1H), 8.09 (s, 1H), 7.92−7.83 (m, 3H), 7.64 (d, J = 11.8 Hz, 2H), 7.47
(m, 4H), 7.17 (t, J = 8.3 Hz, 2H), 7.13 (t, J = 7.9 Hz, 1H), 5.46 (s,
2H), 2.54 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.2, 157.5,
149.1, 142.4, 134.4, 134.3, 133.5, 133.1, 132.7, 131.6, 128.3, 128.1,
127.9, 126.3, 126.2, 126.1, 125.8, 124.8, 121.4, 120.1, 117.4, 114.2,
110.0, 71.0, 21.7; IR (neat/cm−1) 3045, 2917, 2856, 1604, 1585, 1549,
1498, 1485, 1437, 1399, 1290, 1271, 1258, 1242, 1203, 1171, 1127,
1034, 922, 742, 697, 601, 486; HRMS (ESI) calcd for C25H20NO2 [M
+ H+] 366.148, found 366.1489.
3-(2-(5-Methylbenzo[d]oxazol-2-yl)phenoxy)benzaldehyde (4e).
Yellow solid (153 mg, 93%); Rf = 0.35 (PE/EA= 10:1); mp 71.6−
1
74.3 °C; H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 8.29 (dd, J =
7.8, 1.3 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.55−7.45 (m, 4H), 7.35
(m, 3H), 7.14−7.10 (m, 2H), 2.44 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 191.7, 160.7, 158.7, 154.3, 149.0, 142.0, 138.1, 134.4, 132.9,
131.6, 130.5, 126.5, 125.0, 124.8, 124.3, 121.7, 120.2 117.7, 110.0,
21.4; IR (neat/cm−1) 3051, 2917, 2853, 2741, 1703, 1597, 1578, 1482,
1440, 1386, 1261, 1216, 1200, 1043, 797, 701; HRMS (ESI) calcd for
C21H16NO3 [M + H+] 330.1125, found 330.1134.
1-(4-(2-(5-Methylbenzo[d]oxazol-2-yl)phenoxy)phenyl)ethan-1-
one (4f). Yellow solid (133 mg, 78%); Rf = 0.3 (PE/EA= 10/1); eluent
= PE/EA 50:1−10:1; mp 159.1−160.3 °C; 1H NMR (400 MHz,
CDCl3) δ 8.30 (dd, J = 7.8, 1.2 Hz, 1H), 7.91 (d, J = 8.7 Hz, 2H), 7.54
(t, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.32 (d, J =
8.3 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 7.02
(d, J = 8.7 Hz, 2H), 2.53 (s, 3H), 2.43 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 196.8, 162.3, 160.6, 153.6, 149.0, 142.0, 134.4, 132.9, 132.0,
131.6, 130.7(2), 126.5, 125.5, 122.7, 120.7, 120.2, 116.9 (2), 110.0,
26.5, 21.6; IR (neat/cm−1) 3069, 3045, 2959, 2927, 2850, 1668, 1601,
1578, 1488, 1444, 1364, 1283, 1258, 1165, 1040, 960, 829, 797, 768,
701, 598; HRMS (ESI) calcd for C22H18NO3 [M + H+] 344.1281,
found 344.1289.
1,4-Bis(2-(5-methylbenzo[d]oxazol-2-yl)phenoxy)benzene (4g).
White solid (112.7 mg, 86%); Rf = 0.05 (PE/EA = 10:1) mp
226.1−227.6 °C; 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 7.8 Hz,
2H), 7.61 (s, 2H), 7.46 (dd, J = 12.8, 7.8 Hz, 4H), 7.29 (d, J = 7.9 Hz,
2H), 7.18 (d, J = 8.2 Hz, 2H), 7.10 (s, 4H), 7.01 (d, J = 8.3 Hz, 2H),
2.51 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 161.3(2), 156.2(2),
153.0(2), 149.1(2), 142.1(2), 134.3(2), 132.6(2), 131.5(2), 126.3(2),
123.6(2), 120.5(4), 120.2(2), 119.8(2), 119.1(2), 110.1(2), 21.6(2);
IR (neat/cm−1) 3035, 2930, 2862, 1607, 1549, 1504, 1485, 1248, 1191,
1034, 797, 765; HRMS (ESI) calcd for C34H25N2O4 [M + H+]
525.1809, found 525.1826.
2-(2-(Furan-2-ylmethoxy)phenyl)-5-methylbenzo[d]oxazole (4h).
White solid (137 mg, 90%); Rf = 0.25 (PE/EA = 10:1); mp 57.0−59.4
°C; 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 7.7 Hz, 1H), 7.58 (s,
1H), 7.52−7.38 (m, 3H), 7.21−7.10 (m, 3H), 6.48 (s, 1H), 6.37 (s,
1H), 5.20(s, 2H), 2.48 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 161.9,
157.2, 150.3, 149.0, 142.9, 142.2, 134.1, 132.5, 131.5, 126.1, 121.9,
120.0, 117.9, 115.4, 110.6, 110.0 (2), 64.3, 21.5; IR (neat/cm−1) 3039,
2955, 2920, 1677, 1649, 1610, 1553, 1498, 1460, 1296, 1248, 1200,
1171, 1143, 1056, 1040, 995, 912, 890, 742, 704, 601; HRMS (ESI)
calcd for C19H16NO3 [M + H+] 306.1125, found 306.1128.
5-Methyl-2-(2-((2-methylbenzyl)oxy)phenyl)benzo[d]oxazole (4l).
Colorless needle crystals (106 mg, 65%); Rf = 0.6 (PE/EA= 10:1); mp
1
71.1−74.3 °C; H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 7.7 Hz,
1H), 7.74 (s, 1H), 7.61 (s, 1H), 7.50 (dd, J = 14.8, 7.0 Hz, 1H), 7.45
(d, J = 8.2 Hz, 1H), 7.30−7.28 (m, 1H), 7.22 (m, 1H), 7.18 (d, J = 8.7
Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 5.28 (s, 2H), 2.52 (s, 3H), 2.43(s,
3H); 13C NMR (101 MHz, CDCl3) δ 162.2, 157.6, 149.1, 142.2,
135.9, 134.8, 134.2, 132.7, 131.6, 130.2, 128.0, 127.9, 126.1(2), 121.3,
120.0, 117.3, 114.0, 109.9, 69.4, 21.6, 19.0; IR (neat/cm−1) 3061,
3029, 2920, 2843, 1604, 1578, 1537, 1488, 1453, 1312, 1271, 1248,
1197, 1120, 1040, 1030, 793, 755, 701, 595; HRMS (ESI) calcd for
C22H20NO2 [M + H+] 330.1489, found 330.1487.
2-(2-((3-Chlorobenzyl)oxy)phenyl)-5-methylbenzo[d]oxazole
(4m). White solid (132 mg, 76%); Rf = 0.5 (PE/EA = 10:1); mp
1
106.2−107.3 °C; H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 7.6 Hz,
1H), 7.88 (s, 1H), 7.63 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.49−7.43
(m, 1H), 7.39 (s, 1H), 7.30 (s, 2H), 7.18 (d, J = 8.2 Hz, 1H), 7.16−
7.10 (m, 1H), 7.07 (d, J = 8.3 Hz, 1H), 5.23 (s, 2H), 2.51 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 161.9, 157.1, 149.0, 142.3, 139.0, 134.7,
134.3, 132.7, 131.5, 129.7, 127.9, 127.1, 126.2, 124.6, 121.5, 120.1,
117.1, 113.7, 110.0, 69.8, 21.7; IR (neat/cm−1) 3051, 2971, 2927,
2866, 1604, 1585, 1549, 1498, 1434, 1373, 1290, 1258, 1200, 1168,
1101, 1059, 1027, 816, 793, 777, 745, 697, 678, 604; HRMS (ESI)
calcd for C21H17ClNO2 [M + H+] 350.0942, found 350.0952.
2-(2-((4-Methoxybenzyl)oxy)phenyl)-5-methylbenzo[d]oxazole
(4n). White solid (129 mg, 75%); Rf = 0.5 (PE/EA = 10:1); mp
1
109.3−111.5 °C; H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 7.7 Hz,
1H), 7.60 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H),
7.16 (d, J = 8.3 Hz, 1H), 7.15−7.10 (m, 2H), 6.91 (d, J = 7.5 Hz, 2H),
5.25 (s, 2H), 3.81 (s, 3H), 2.50 (s, 3H); 13C NMR (101 MHz, CDCl3)
δ 162.2, 159.3, 157.5, 149.0, 142.2, 134.2, 132.6, 131.5, 128.9, 128.6
(2), 126.1, 121.2, 120.0, 117.4, 114.4, 113.9 (2), 109.9, 70.8, 55.4, 21.6;
IR (neat/cm−1) 3058, 2997, 2962, 2927, 2834, 1617, 1607, 1581, 1549,
1517, 1495, 1444, 1306, 1264, 1251, 1191, 1030, 822, 797, 749, 701,
595, 512; HRMS (ESI) calcd for C22H20NO3 [M + H+] 346.1438,
found 346.1424.
5-Methyl-2-(2-(thiophen-2-ylmethoxy)phenyl)benzo[d]oxazole
(4i). Yellow solid (152 mg, 95%); Rf = 0.25 (PE/EA = 10:1); mp
5-Methyl-2-(2-((4-methylbenzyl)oxy)phenyl)benzo[d]oxazole
1
96.3−97.8 °C; H NMR (400 MHz, CDCl3) δ 8.17 (dd, J = 8.0, 1.5
(4o). White solid (130 mg, 79%); Rf = 0.7 (PE/EA= 10:1); mp 126.7−
1
Hz, 1H), 7.61 (s, 1H), 7.48−7.43 (m, 2H), 7.31 (dd, J = 5.0, 1.0 Hz,
128.5 °C; H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.6 Hz, 1H),
H
DOI: 10.1021/acs.joc.8b00587
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The Journal of Organic Chemistry
Article
7.60 (s, 1H), 7.46 (d, J = 7.3 Hz, 4H), 7.19 (d, J = 8.2 Hz, 2H), 7.16−
7.08 (m, 3H), 5.27 (s, 2H), 2.50 (s, 3H), 2.36 (s, 3H); 13C NMR (101
MHz, CDCl3) δ 162.3, 157.6, 149.1, 142.3, 137.5, 134.2, 133.9, 132.6,
131.6, 129.3(2), 127.0 (2), 126.1, 121.2, 120.1, 117.3, 114.3, 110.0,
70.9, 21.7, 21.3; IR (neat/cm−1) 3045, 2917, 2859, 1604, 1578, 1553,
1504, 1444, 1383, 1293, 1267, 1261, 1200, 1175, 1059, 1030; HRMS
(ESI) calcd for C22H20NO2 [M + H+] 330.1489, found 330.1487.
2-(2-((4-Bromobenzyl)oxy)phenyl)-5-methylbenzo[d]oxazole
(4p). Light yellow solid (151 mg, 78%); Rf = 0.6 (PE/EA = 10:1); mp
124.7−125.7 °C; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.7 Hz,
1H), 7.60 (s, 1H), 7.47 (dd, J = 15.0, 7.8 Hz, 4H), 7.44 (d, J = 8.0 Hz,
1H), 7.17 (d, J = 8.2 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 8.3
Hz, 1H), 5.20 (s, 2H), 2.50 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
161.9, 157.1, 148.9, 142.2, 135.9, 134.3, 132.6, 131.6 (2), 131.5, 128.6
(2), 126.2, 121.7, 121.5, 120.0, 117.2, 114.0, 109.9, 70.0, 21.6; IR
(neat/cm−1) 3048, 3035, 2923, 2853, 1607, 1585, 1549, 1501, 1492,
1444, 1408, 1376, 1296, 1274, 1264, 1200, 1162, 1127, 1040, 1008,
835, 819, 806, 765, 752, 697, 601; HRMS (ESI) calcd for
C21H17BrNO2 [M + H+] 394.0437 (100.0%), 396.0417 (97.3%),
found 394.0433 (100%), 396.0412 (97%).
2-(2-(tert-Butoxy)phenyl)-5-methylbenzo[d]oxazole (4q). Yellow
solid (63.3 mg, 45%); Rf = 0.1 (PE/EA = 10:1); mp 156.2−158.4 °C;
1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H),
7.47 (d, J = 8.9 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 8.2 Hz,
1H), 7.16 (d, J = 8.3 Hz, 1H), 2.49 (s, 3H), 1.34 (s, 9H); 13C NMR
(101 MHz, CDCl3) δ 155.1, 149.1, 142.1, 134.3, 131.8, 131.4, 126.2,
124.9, 123.6, 123.3, 120.1, 110.0, 81.2, 29.0 (3), 21.7; IR (neat/cm−1)
3051, 2981, 2927, 2866, 1588, 1447, 1367,1335, 1303, 1165, 1117,
1062, 1030, 893, 809, 787, 601, 537; HRMS (ESI) calcd for
C18H20NO2 [M + H+] 282.1489, found 282.1461.
NMR (400 MHz, CDCl3) δ 8.32.(dd, J = 7.1, 1.9 Hz, 1H), 7.75 (dd, J
= 7.2, 1.4 Hz, 1H), 7.65−7.56 (m, 2H), 7.54 (s, 1H), 7.46 (d, J = 8.3
Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 6.98 (s, 1H,, CN−CH−COOMe),
3.82 (s, 3H,, CN−CH−COOMe), 2.49 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 165.7, 160.9, 148.1, 141.7, 134.7, 131.6, 130.3, 130.0, 129.8,
129.5, 127.0, 125.6, 120.2, 116.1, 110.0, 53.8, 40.8, 21.4; IR (neat/
cm−1) 2965, 2917, 2882, 2853, 1764, 1546, 1498, 1431, 1258, 1200,
1191, 1143, 1046, 992, 816, 784, 736, 704, 598; HRMS (ESI) calcd for
C18H15N2O3 [M + H+] 307.1077, found 307.1086.
Methyl 2-cyano-2-(4-(5-methylbenzo[d]oxazol-2-yl)phenyl)-
acetate (5b). Similar procedure as for 5a was conducted on 0.5
mmol scale, which afforded the 5b in white solid (49 mg, 32%); Rf =
0.1 (PE/EA = 10:1); mp 103.5−106.1 °C; 1H NMR (400 MHz,
CDCl3) δ 8.30 (t, J = 9.5 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.56 (s,
1H), 7.47 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 4.83 (s, 1H,
CN−CH−COOMe), 3.84 (s, 3H, CN−CH−COOMe), 2.49 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 165.1, 162.0, 149.2, 142.3, 134.9,
132.7, 128.7 (2), 128.59, 128.55 (2), 126.9, 120.3, 115.2, 110.2, 54.3,
43.6, 21.7; IR (neat/cm−1) 3055, 3016, 2965, 2930, 1754, 1501, 1440,
1418, 1300, 1258, 1239, 1059, 806, 704, 598; HRMS (ESI) calcd for
C18H15N2O3 [M + H+] 307.1077, found 307.1085.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b00587.
■
S
1H, 13C and 19F NMR spectra for all new compounds
(PDF)
2-(2-(Hexyloxy)phenyl)-5-methylbenzo[d]oxazole (4r). Light yel-
low liquid (143 mg, 93%); Rf = 0.8 (PE/EA= 10:1); H NMR (400
1
AUTHOR INFORMATION
Corresponding Author
*E-mail: xfhou@fudan.edu.cn.
ORCID
Xiu-Feng Hou: 0000-0001-7513-4650
Notes
The authors declare no competing financial interest.
■
MHz, CDCl3) δ 7.60 (d, J = 7.9 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.19
(t, J = 6.7 Hz, 2H), 7.05 (d, J = 8.9 Hz, 2H), 6.88 (d, J = 8.1 Hz, 1H),
4.42 (t, J = 6.6 Hz, 2H), 2.29 (s, 3H), 1.90−1.78 (m, 2H), 1.55−1.45
(m, 2H), 1.39 (m, 4H), 0.94 (t, J = 6.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 160.9, 160.4, 149.9, 138.1, 135.4, 133.3, 129.1, 127.9, 126.3,
124.9, 124.6, 120.6, 120.5, 66.7, 31.7, 28.8, 26.0, 22.8, 20.8, 14.2; IR
(neat/cm−1) 3026, 2955, 2933, 2856, 1645, 1604, 1492, 1450, 1309,
1283, 1258, 1200, 1162, 1095, 854, 819, 790, 681; HRMS (ESI) calcd
for C20H24NO2 [M + H+] 310.1808, found 310.1802.
ACKNOWLEDGMENTS
■
2-(2-(Quinolin-6-yloxy)phenyl)benzo[d]thiazole (4s). Light yellow
crystals (138 mg, 78%); Rf = 0.3 (DCM/MeOH= 50:1); mp 67.3−
Financial support by the National Science Foundation of China
(Grant Nos. 20971026, 21271047) and ShanXi Science and
Technology Department, China (Project No. MH2014-07) is
gratefully acknowledged.
1
70.1 °C; H NMR (400 MHz, CDCl3) δ 8.85 (dd, J = 4.2, 1.6 Hz,
1H), 8.66 (dd, J = 7.9, 1.6 Hz, 1H), 8.16 (d, J = 9.2 Hz, 1H), 8.10 (d, J
= 8.2 Hz, 1H), 8.01 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.63
(dd, J = 9.2, 2.7 Hz, 1H), 7.52−7.45 (m, 2H), 7.37 (dd, J = 8.2, 0.9 Hz,
1H), 7.35 (t, J = 4.2H, 1H), 7.34 (dd, J = 6.9, 1.0 Hz, 1H), 7.28 (d, J =
2.7 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ
162.2, 154.7, 154.1, 152.3, 149.5, 145.5, 136.1, 135.3, 132.0, 131.8,
130.1, 129.1, 126.2, 125.7, 125.2, 124.9, 123.1, 123.0, 121.8, 121.4,
120.5, 112.9; IR (neat/cm−1) 3055, 2962, 2927, 2850, 1523, 1498,
1447, 1437, 1383, 1322, 1219, 1197, 1157, 1117, 963, 918; 829, 758;
HRMS (ESI) calcd for C22H15N2OS [M + H+] 355.0900, found
355.0897.
General Protocol for Construction of C−C Bond. Methyl 2-
cyano-2-(2-(5-methylbenzo[d]oxazol-2-yl)phenyl)acetate (5a). Into
a 25 mL dried Schlenk tube were added 1a (227 mg, 0.5 mmol),
Cs2CO3 (326 mg, 1 mmol), Pd(PPh3)4 (28 mg, 0.025 mmol) under
N2 atmosphere, sealed by rubber, methyl 2-cyanoacetate (100 mg, 1
mmol) and DMF (3 mL) were added sequentially via syringe, and the
rubber was changed to glass topper and sealed. The mixture was
heated and stirred in 120 °C oil bath for 12 h. After finished, the
reaction mixture was quenched by saturated NH4Cl solution, extracted
by ethyl acetate (3 × 10 mL). The organic phase was combined,
washed by brine, dried with sodium sulfate, and concentrated under
reduced pressure. The residue was applied on silica gel chromatog-
raphy, afforded the desired product in yellow solid (80 mg, 52%).
Yellow crystals were obtained by slow evaporation in open-air vessel at
room temperature. Rf = 0.35 (PE/EA = 10:1); mp 114.2−118.1 °C;1H
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