Synthesis of 2-Keto(hetero)aryl Benzox(thio)azoles through Base Promoted Cyclization of 2-Amino(thio)phenols with α,α-Dihaloketones

Article abstract of DOI:10.1021/acs.joc.5b02093

An interesting base-promoted protocol for the synthesis of 2-keto(hetero)aryl benzox(thi)azoles has been developed. Starting from commercially available 2-amino(thio)phenols and α,α-dihaloketones, moderate to good yields of the corresponding heterocycles can be achieved. Notably, only EtNH₂ was required as the promoter here, and the reaction can be easily performed on a large scale.

Full text of DOI:10.1021/acs.joc.5b02093

Article
pubs.acs.org/joc
Synthesis of 2‑Keto(hetero)aryl Benzox(thio)azoles through
Base Promoted Cyclization of 2‑Amino(thio)phenols with
α,α-Dihaloketones
Jun Jiang, Huaxu Zou, Qizhi Dong, Ruijia Wang, Linghui Lu, Yonggang Zhu, and Weimin He*
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, P.R. China
S
* Supporting Information
ABSTRACT: An interesting base-promoted protocol for the
synthesis of 2-keto(hetero)aryl benzox(thi)azoles has been
developed. Starting from commercially available 2-amino(thio)-
phenols and α,α-dihaloketones, moderate to good yields of the
corresponding heterocycles can be achieved. Notably, only
EtNH2 was required as the promoter here, and the reaction can
be easily performed on a large scale.
Scheme 1. Synthesis of 2-Keto(hetero)aryl
Benzox(thi)azoles via Cyclization Reaction
INTRODUCTION
■
Heterocyclic compounds are the most important class of
compounds in the pharmaceutical and agrochemical industries,
with heterocycles comprising around 60% of all drug sub-
stances.1 The bis-heteroaryl ketone ring system, in particular, is
a very common structural motif and is found in numerous
biologically active natural products and pharmacologically
relevant therapeutic agents, such as FAAH inhibitors, cysteine
protease inhibitors, and channel activating protease inhibitors.2
Furthermore, they are versatile synthetic intermediates with a
carbonyl group that can easily be functionalized for further syn-
thetic applications. As a result, the development of an efficient
method to prepare 2-keto(hetero)aryl benzox(thi)azoles is
currently a main topic in organic synthesis.
Most current processes for accessing bis-heteroaryl ketone
molecules are performed by acylation of benzoxazole-
(benzothiophene) with a carbonyl compound under organo-3
or metal catalysis,4 either sequentially or in a one-step process.
A common drawback to these methods is the requirement of
expensive organic catalysts or heavy transition metals, and limited
by the availability of the properly substituted benzoxazole-
(benzothiophene). To overcome such drawbacks, cyclization
reactions between 2-amino(thio)phenols and 1,1-dibromoe-
thenes5 (Scheme 1a) or phenacyl bromide6 (Scheme 1b)
recently received much attention. However, approach (a)
requires a prefunctionalization process of benzoxazole-
(benzothiophene) partners, resulting in the inevitable formation
of large amounts of side products during the preactivation
steps. The drawback to approach (b), is the requirement for
corrosive and moisture-sensitive RuCl3 in the catalytic
oxidation reaction. Thus, it is challenging to update these
traditional methods for a more concise and environmentally
friendly method for the synthesis of 2-keto(hetero)aryl
benzox(thi)azoles. It is extremely worthwhile to develop highly
efficient methods to prepare 2-keto(hetero)aryl benzox(thi)-
azoles from α,α-dihaloketones as starting materials because
α,α-dihaloketones are important and readily available building
blocks, which can be conveniently prepared from alkynes.7
Herein, we disclose a novel methodology for preparation of
q2-keto(hetero)aryl benzox(thi)azoles through base-mediated8
cyclization with the advantages of operational simplicity of the
procedure, moderate to good yields and broad substrate
applicability (Scheme 1c).
RESULTS AND DISCUSSION
■
Our investigation began with the cyclization reaction of between
the readily available 2-aminophenol 1a and 2,2-dibromoaceto-
phenone 2a with Na2CO3(2 equiv) as a base in DMF at 100 °C
(Table 1, entry 1). Gratifyingly, the desired product 3a was
obtained in 31% NMR yield. Encouraged by this promising
result, various bases were further investigated (entries 2−8).
It was found that a strong base like t-BuOK afforded 3a in a
lower yield of 20% (entry 3), but when some weak bases such as
DIPA and Et2NH were used, the yield could increase to 41% and
49% NMR yields, respectively (entries 6 and 7). The investiga-
tion on the optimal amount of Et2NH (entries 7 and 9−11)
Received: September 7, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02093
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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a
a,b
Table 1. Optimization of the Reaction Conditions
Table 2. Reaction Scope
b
entry
base
equiv of base
solvent
temperature yield %
1
2
Na2CO3
NaOH
t-BuOK
CsCO3
Et3N
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
3 equiv
4 equiv
5 equiv
4 equiv
4 equiv
4 equiv
4 equiv
4 equiv
4 equiv
4 equiv
4 equiv
4 equiv
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
MeOH
MeCN
PhCl
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
90 °C
31
17
20
12
31
41
49
35
71
83
82
78
80
60
38
30
55
83
83
75
3
4
5
6
DIPA
7
Et2NH
pyridine
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
Et2NH
8
9
10
11
12
13
14
15
16
17
Toluene
DCE
c
18
DMF
DMF
DMF
19
20
80 °C
a
All reactions were performed with 2,2-dibromoacetophenone
(1a, 0.25 mol), 2-aminophenol (2a, 0.3 mol), base and solvent (0.5 mL),
b
5 h. Estimated by 1H NMR spectroscopy using diethyl phthalate as an
c
internal reference. 2.5 mL DMF was used as the solvent.
indicated that 4 equiv of Et2NH was an appropriate amount.
Subsequently, various solvents were surveyed (entries 12−17).
While the use of the polar solvents DMSO and MeOH (entries
12 and 13) as well as DMF (entry 10) provided comparable
yields, the nonpolar solvents resulted in low yields (entries
15−17). Ultimately, the higher boiling solvent DMF was
selected for further reaction optimization because it allowed
reactions to be conducted at higher temperatures. Conducting
the reaction at a concentration of 0.1 M of the substrate did not
affect the reaction yield (entries 18 vs 10); however, the higher
concentration of 0.5 M was selected to provide conditions that
minimize solvent waste. Lowering the reaction temperature to
90 °C was feasible without compromising reaction efficiency;
however, further reduction to 80 °C led to a lower yield
(entries 19−20). On the basis of all of the acquired test results,
the optimized conditions to obtain the 2-keto(hetero)aryl
benzox(thi)azoles were concluded to be that of entry 19 in
Table 1, namely, treatment of compound 1a with 1.2 equiv of
2a, 4 equiv of Et2NH in DMF (0.5 M) at 90 °C.
Having identified the optimized reaction conditions, we
turned our attention to the scope of this transformation. A wide
array of substituted α,α-dibromoacetophenones were first
explored with reactions being analyzed at different reaction
time points and occasionally 5 h depending on the substrate.
As shown in Table 2, it is clear that ring electronics do not
affect the reaction yield. Under identical reaction conditions,
use of electrondeficient, -neutral or -rich α,α-dibromoaceto-
phenones gave moderate to good yields of 2-keto(hetero)aryl
benzox(thi)azoles, although the reaction proceeded faster for
electron-rich substrates (3aa−3al). The low yields observed
a
Conditions: 1 (0.25 mol), 2 (0.3 mol), Et2NH (1 mol) and solvent
b
(0.5 ml), 90 °C, 5 h. After column chromatography.
with ortho-substituted substrates, such as 3am and 3an, are
likely due to the steric hindrance. Nonetheless, the reaction is
tolerant of a wide range of α,α-dibromoacetophenones
containing reactive functional groups, such as methyl, methoxy,
phenyl, halo, trifluoromethyl, acetyl, and acetylamino groups.
Polycyclic and heteroaromatic substituted α,α-dibromoaceto-
phenones could also be transformed into the corresponding
products in good yields (3ao − 3ar). Switching the substrates
to diiodoacetophenone or dichloroacetophenone, did not
influence the reaction efficiency (3ao−3ar). 2-Aminophenols
derivatives, which bear substituted groups, such as methyl,
methoxy, fluoro, chloro and bromo at different positions, all
reacted smoothly with 2a to afford the desired corresponding
products (3ao−3ar). Notably, this reaction was not limited to
2-aminophenols; 2-aminothiols were also effective substrates
and provided desired products 3ha−3ha in moderate yields.
To demonstrate the reaction efficiency of this Et2NH pro-
moted cyclization system, we tried to expand the reaction to a
10 mmol scale. In the case of 3aa, the loading of Et2NH and
DMF could be reduced to 3.5 equiv and 1 mL, respectively, by
increasing the reaction time to ensure completion (Scheme 2).
Furthermore, a one-pot, sequential oxybromination of alkynes
with NBS followed by Et2NH/DMF mediated cyclization to
provide 2-keto(hetero)aryl benzox(thi)azoles have been
demonstrated (Scheme 3). Inspite of moderate yields in most
B
DOI: 10.1021/acs.joc.5b02093
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Article
Scheme 2. Gram Scale Synthesis
Scheme 5. Controlled Experiments
Scheme 3. One-Pot Protocol: Sequential Process
moderate to good yields under metal-free conditions. Various
functional groups are accepted, resulting in a wide range of
substituted 2-keto(hetero)aryl benzox(thi)azoles. Additionally,
this methodology can be performed on a large scale without any
problems. A sequential synthesis of dibromoketones, starting from
corresponding substituted phenylacetylene and NBS, followed by
Et2NH promoted cyclization has also been demonstrated.
EXPERIMENTAL SECTION
■
General Information. Commercially available reagents were of
reagent grade (AR grade) and were used without further purification.
Reactions were monitored by thin layer chromatography (TLC) using
silicycle precoated silica gel plates. Flash column chromatography was
cases were obtained, nevertheless, the one-pot methodology is
expected to be of high synthetic utility.
performed over silicycle silica gel (200−300 mesh). 1H NMR and 13
C
Finally, the utility of our method was demonstrated by
performing a series of chemical modifications of 2-keto-
(hetero)aryl benzox(thi)azoles 3aa (Scheme 4). As shown
in Scheme 3, the carbonyl group of 2aa can be reduced
exhaustively via ionic hydrogenation to give 4, or partially with
NaBH4, to produce alcohol 5. On treatment of 2aa with
phenylmagnesium bromide, tertiary alcohol 6 was obtained.
Finally, a controlled reaction was conducted to better
understand the possible reaction mechanism (Scheme 5) As
anticipated, when 2,3-diaminophenol and 2,2-dibromoaceto-
phenone were subjected to the standard reaction system, only
3-phenylquinoxalin-5-ol 7 was obtained. The result demon-
strated that amine nucleophile was added before the hydroxylic
nucleophile in the intermolecular cyclization process.
On the basis of the above-mentioned controlled experiment,
a plausible mechanism for the base promoted cyclization of
2-amino(thio)phenols and α,α-dihaloketones is proposed in
Scheme 6. First, Et2NH would undergo the interaction with
dibromoketone to generate the intermediate A. Then the
nucleophile NH2 attacked intermediate A to give intermediate
B and eliminate HBr. The intermediate B followed by base-
mediated intramolecular nucleophilic substitution with the OH
group as the nucleophile to form the intermediate C. Finally,
intermediate C could undergo deprotonation/aromatization to
give the 3.
NMR spectra were recorded on 400 MHz NMR plus spectrometer
using residue solvent peaks as internal standards. Infrared spectra
were recorded with IR spectrometer and are reported in reciprocal
centimeter (cm−1). High resolution mass spectra were obtained using
GCT-TOF instrument with EI or ESI source.
General Procedure of 3. A mixture of 2-amino(thio)phenols
(0.25 mmol), α,α-dihaloketones (0.3 mmol), Et2NH (1 mmol, 74 mg),
and DMF (0.5 mL) was stirred at 90 °C for 5 h. After cooling to room
temperature, water (20 mL) was added, and the aqueous phase was
extracted by EtOAc (5 × 20 mL). The combined organic phases were
dried over Na2SO4, and concentrated in vacuum. The residue was
purified by chromatography on silica gel with petroleum ether/ethyl
acetate as eluent to afford the corresponding product.
Benzo[d]oxazol-2-yl(phenyl)methanone (3aa). White solid
1
(46.27 mg, 83% yield); mp 65−68 °C; H NMR (400 MHz, CDCl3):
δ 8.58−8.49 (m, 2H), 7.94−7.85 (m, 1H), 7.71−7.62 (m, 2H), 7.60−
7.50 (m, 3H), 7.50−7.38 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 179.5 (CO), 156.1 (Cquat), 149.4 (Cquat), 139.7 (Cquat),
134.0 (Cquat), 133.3 (CH), 130.0 (CH × 2), 127.6 (CH × 2), 127.4
(CH), 124.7 (CH), 121.4 (CH), 110.8 (CH). The data meet the
literature report.4a
Benzo[d]oxazol-2-yl(p-tolyl)methanone (3ab). White solid
(35.55 mg, 60% yield); mp 80−82 °C; 1H NMR (400 MHz,
CDCl3): δ 8.46 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.0 Hz, 1H), 7.71 (d,
J = 8.4 Hz, 1H), 7.58−7.50 (m, 1H), 7.48−7.42 (m,1H), 7.20−7.16
(d, J = 8.0 Hz, 2H), 2.47 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3):
δ 180.2 (CO), 157.3 (Cquat), 150.4 (Cquat), 145.5 (Cquat), 140.8 (Cquat),
132.5 (Cquat), 131.1 (CH × 2), 129.4 (CH × 2), 128.3 (CH), 125.6
(CH), 122.3 (CH), 110.8 (CH), 21.9 (CH3). The data meet the
literature report.4a
Benzo[d]oxazol-2-yl(4-methoxyphenyl)methanone (2ac):
White solid (56.48 mg, 64% yield); mp 78−80 °C; 1H NMR
(400 MHz, CDCl3): δ 8.61 (d, J = 8.8 Hz, 2H), 7.95−7.88 (m, 1H),
7.68−7.62 (m, 1H), 7.59−7.37 (m, 2H), 7.04 (d, J = 8.8 Hz, 2H),
CONCLUSIONS
■
In conclusion, a practical and efficient methodology for the
synthesis of 2-keto(hetero)aryl benzox(thi)azoles has been
developed. With 2-amino(thio)phenols and α,α-dihaloketones
as the substrates, the corresponding products can be isolated in
Scheme 4. Examples of Synthetic Utility of 3aa
C
DOI: 10.1021/acs.joc.5b02093
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The Journal of Organic Chemistry
Article
Scheme 6. Possible Mechanism for Cyclization Reaction
3.92(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 179.0 (CO), 164.9
(Cquat), 157.6 (Cquat), 150.5 (Cquat), 140.9 (CH × 2), 133.8 (CH),
128.3 (CH), 128.2 (CH), 125.7 (CH), 122.4 (CH), 114.1 (CH × 2),
112.0 (CH), 55.8 (OCH3). The data meet the literature report.4a
[1,1′-Biphenyl]-4-yl(benzo[d]oxazol-2-yl)methanone (3ad).
White solid (34.39 mg, 46% yield); mp 132−134 °C; 1H NMR
(400 MHz, CDCl3): δ 8.64 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 8.4 Hz,
1H), 7.79 (d, J = 8.4 Hz, 2H), 7.79−7.68 (m, 3H), 7.56 (t, J = 7.6 Hz,
1H), 7.50 (m, 3H), 7.42 (t, J = 7.4 Hz, 1H); 13C{1H} NMR
(100 MHz, CDCl3): δ 180.2 (CO), 157.4 (Cquat), 150.6 (Cquat), 147.1
(Cquat), 140.9 (Cquat), 139.9 (Cquat), 133.9 (Cquat), 131.8 (CH × 2),
129.2 (CH × 2), 128.6 (CH), 128.5 (CH), 127.5 (CH × 2), 127.4
(CH × 2), 125.9 (CH), 122.5 (CH), 112.0 (CH). IR (neat) 3022,
1645, 1582, 1322, 966 cm−1; GC-MS (EI, 70 eV): m/z (%) = 299
(M+, 12), 271 (11), 181 (100), 153 (19). HRMS (EI) m/z calcd. for
C20H13NO2: 299.0941; found: 299.0939.
(Cquat), 131.4 (CH × 2), 129.0 (CH × 2), 128.4 (CH), 126.1 (CH),
122.7 (CH), 112.1 (CH), 27.1 (CH3); IR (neat): 3022, 1666, 1522,
1155, 922 cm−1; GC-MS (EI, 70 eV): m/z (%) = 265 (M+, 13), 237
(24), 147 (100), 119 (16), 91 (17). HRMS (EI) m/z calcd for
C16H11NO3: 265.0733; found: 265.0730.
Benzo[d]oxazol-2-yl(m-tolyl)methanone (3aj). White solid (34.37
mg, 58% yield); mp 86−88 °C; 1H NMR (400 MHz, CDCl3): δ 8.38
(d, J = 7.6, 1H), 8.28 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.70 (d, J =
8.0 Hz, 1H), 7.58−7.50 (m, 1H), 7.49−7.42 (m, 3H), 2.47 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 180.9 (CO), 157.3 (Cquat),
150.5 (Cquat), 140.9 (Cquat), 138.6 (Cquat), 135.3 (Cquat), 135.1 (CH),
131.3 (CH), 128.6 (CH), 128.5 (CH), 128.4 (CH), 125.8 (CH),
122.5 (CH), 111.9 (CH), 21.5 (CH3). The data meet the literature
report.4c
Benzo[d]oxazol-2-yl(3-bromophenyl)methanone (3ak). Yellow
1
solid (52.67 mg, 70% yield); mp 107−109 °C; H NMR (400 MHz,
Benzo[d]oxazol-2-yl(4-fluorophenyl)methanone (3ae). Yellow
CDCl3): δ 8.70 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz,
1H), 7.82−7.75 (m, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.57 (t, J = 7.8 Hz,
1H), 7.51−7.45 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 179.1
(CO), 156.8 (Cquat), 150.6 (Cquat), 140.8 (Cquat), 137.2 (Cquat), 136.8
(CH), 133.9 (CH), 130.3 (CH), 129.8 (CH), 128.9 (CH), 126.1
(CH), 123.0 (Cquat), 122.7 (CH), 112.0 (CH). The data meet the
literature report.6
1
solid (42.18 mg, 70% yield); mp 107−109 °C; H NMR (400 MHz,
CDCl3): δ 8.65−8.52 (m, 2H), 7.86 (d, J = 7.6 Hz, 1H), 7.63 (d, J =
8.0 Hz,1H), 7.51−7.42 (m, 1H), 7.41−7.36 (m, 1H), 7.15 (t, J =
8.6 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 178.9 (CO), 166.7
(d, JC,F = 252 Hz, Cquat), 157.1 (Cquat), 150.5 (Cquat), 140.8 (Cquat),
134.1 (d, JC,F = 9.5 Hz, CH × 2), 131.5 (d, JC,F = 2.9 Hz, Cquat), 128.7
(CH), 125.9 (CH), 122.5 (CH), 116.0 (d, JC,F = 21.9, CH × 2), 112.0
(CH). The data meet the literature report.4a
N-(3-(Benzo[d]oxazole-2-carbonyl)phenyl)acetamide (3al).
White solid (31.50 mg, 45% yield); mp 125−127 °C; 1H NMR
(400 MHz, DMSO-d6): δ 10.27 (s, 1H), 8.54 (s, 1H), 8.18 (d, J =
7.6 Hz, 1H), 8.09−7.97 (m, 2H), 7.97−7.90 (m, 1H), 7.66 (t, J =
7.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 2H), 2.09 (s, 3H); 13C{1H} NMR
(100 MHz, DMSO-d6): δ 179.9 (CO), 168.7 (CO), 156.9 (Cquat),
149.8 (Cquat), 140.1 (Cquat), 139.6 (Cquat), 135.2 (Cquat), 129.0 (Cquat),
128.7 (CH), 126.0 (CH), 125.7 (CH), 124.6 (CH), 122.1 (CH),
120.4 (CH), 112.0 (CH), 24.0 (CH3); IR (neat): 3389, 1687, 1544,
1205, 658; GC-MS (EI, 70 eV): m/z (%) = 280 (M+, 30), 238 (25),
162 (100), 120 (52), 92 (24). HRMS (EI) m/z calcd. for C16H12N2O3:
280.0848; found: 280.0851.
Benzo[d]oxazol-2-yl(4-chlorophenyl)methanone (3af). Beige
1
solid (41.76 mg, 65% yield); mp 92−94 °C; H NMR (400 MHz,
CDCl3): δ 8.61−8.51 (m, 2H), 7.96−7.92 (m, 1H), 7.76−7.71
(m, 1H), 7.63−7.50 (m, 3H), 7.50−7.41 (m, 1H); 13C{1H} NMR
(100 MHz, CDCl3): δ 179.2 (CO), 157.0 (Cquat), 150.5 (Cquat), 141.2
(Cquat), 140.8 (Cquat), 133.4 (Cquat), 132.6 (CH × 2), 129.1 (CH × 2),
128.8 (CH), 126.0 (CH), 122.6 (CH), 112.0 (CH). The data meet the
literature report.9
Benzo[d]oxazol-2-yl(4-bromophenyl)methanone (3ag). White
1
solid (40.63 mg, 54% yield); mp 140−142 °C; H NMR (400 MHz,
Benzo[d]oxazol-2-yl(o-tolyl)methanone (3am). White solid
(17.78 mg, 30% yield); mp 96−98 °C; 1H NMR (400 MHz,
CDCl3): δ 8.04 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.71 (d,
J = 8.4 Hz, 1H), 7.60−7.40 (m, 3H), 7.39−7.31 (m, 2H), 2.55 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 183.9 (CO), 158.0 (Cquat),
150.8 (Cquat), 140.9 (Cquat), 139.7 (Cquat), 135.1 (CH), 132.7 (CH),
131.9 (CH), 131.5 (CH), 128.6 (Cquat), 125.9 (CH), 125.6 (CH),
122.6 (CH), 112.0 (CH), 20.8 (CH3). The data meet the literature
report.4a
CDCl3): δ 9.77 (d, J = 2.0 Hz, 1H), 8.95−8.85 (m, 2H), 7.96 (d, J =
8.4 Hz, 1H), 7.69−7.62 (m, 1H), 7.61−7.53 (m, 1H), 7.52−7.43 (m,
2H); 13C{1H} NMR (100 MHz, CDCl3): δ 179.5 (CO), 157.0 (Cquat),
150.5 (Cquat), 140.8 (Cquat), 133.8 (Cquat), 132.6 (CH × 2), 132.1
(CH × 2), 130.1 (Cquat), 128.8 (CH), 126.0 (CH), 122.6 (CH), 112.0
(CH). The data meet the literature report.4a
Benzo[d]oxazol-2-yl(3-(trifluoromethyl)phenyl)methanone
(3ah). White solid (36.38 mg, 50% yield); mp 122−124 °C; 1H NMR
(400 MHz, CDCl3): δ 8.68 (d, J = 9.2 Hz, 2H), 7.96 (d, J = 8.0 Hz,
1H), 7.84 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.65−7.57
(m, 1H), 7.54−7.47 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ
179.7 (CO), 156.8 (Cquat), 150.7 (Cquat), 140.8 (Cquat), 137.9 (Cquat),
135.6 (d, JC,F = 32.1 Hz, Cquat), 131.5 (CH × 2), 129.1 (CH × 2),
126.2 (CH), 125.7 (d, JC,F = 4.7 Hz, CF3), 125.0 (CH), 122.7 (CH),
112.1 (CH). The data meet the literature report. The data meet the
literature report.4a
Benzo[d]oxazol-2-yl(2-bromophenyl)methanone (3an). White
1
solid (31.60 mg, 42% yield); mp 106−108 °C; H NMR (400 MHz,
CDCl3): δ 7.90 (d, J = 8.0 Hz, 1H), 7.78−7.67 (m, 3H), 7.60−7.55
(m,1H), 7.64−7.42 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
183.1 (CO), 157.1 (Cquat), 151.0 (Cquat), 141.0 (Cquat), 137.8 (Cquat),
133.9 (CH), 133.1 (CH), 130.8 (CH), 129.0 (CH), 127.5 (CH),
126.1 (CH), 122.8 (Cquat), 120.9 (CH), 112.1 (CH); IR (neat): 3088,
1682, 1544, 1422, 1122, 978 cm−1; GC-MS (EI, 70 eV): m/z (%) =
303 (M+, 18), 301 (M+, 18), 273 (12), 185 (96), 183 (100), 157 (20),
155 (20). HRMS (EI) m/z calcd. for C13H8N2O2: 300.9733; found:
300.9729.
1-(4-(Benzo[d]oxazole-2-carbonyl)phenyl)ethanone (3ai). White
1
solid (42.40 mg, 64% yield); mp 127−129 °C; H NMR (400 MHz,
CDCl3): δ 8.64 (d, J = 8.4 Hz, 2H), 8.23−8.15 (m, 2H), 7.97−7.92
(m, 1H), 7.55−7.66 (m, 1H), 7.62−7.57 (m, 1H), 7.55−7.48 (m, 1H),
2.69 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 197.6 (CO), 180.1
(CO), 157.0 (Cquat), 150.7 (Cquat), 140.9 (Cquat), 140.8 (Cquat), 138.4
Benzo[d]oxazol-2-yl(thiophen-3-yl)methanone (3ao). Yellow
1
solid (29.20 mg, 51% yield); mp 102−104 °C; H NMR (400 MHz,
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CDCl3): δ 9.22 (d, J = 3.2 Hz, 1H), 7.99 (d, J = 5.2 Hz, 1H), 7.92 (d,
J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.41
(t, J = 8.8 Hz, 1H), 7.41−7.36 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 173.6 (CO), 157.4 (Cquat), 150.6 (Cquat), 140.9 (Cquat),
139.0 (Cquat), 138.3 (CH), 128.6 (CH), 128.5 (CH), 126.3 (CH),
125.8 (CH), 122.4 (CH), 112.0 (CH). The data meet the literature
report.4a
Benzo[d]oxazol-2-yl(pyridin-2-yl)methanone (3ap). White solid
(37.52 mg, 67% yield); mp 114−116 °C; 1H NMR (400 MHz,
CDCl3): δ 9.77 (d, J = 2.0 Hz, 1H), 8.91−8.82 (m, 2H), 7.96 (d, J =
8.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.68−7.64 (m, 1H), 7.63−7.57
(m, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 179.4 (CO), 156.7
(Cquat), 154.4 (Cquat), 152.3 (Cquat), 150.7 (CH), 140.8 (Cquat), 138.3
(CH), 130.9 (CH), 129.1 (CH), 126.2 (CH), 123.6 (CH), 122.8
(CH), 112.1 (CH); IR (neat): 3066, 1655, 1522, 1125, 988 cm−1;
GC-MS (EI, 70 eV): m/z (%) = 224 (M+, 5), 196 (100), 106 (81),
78 (42). HRMS (EI) m/z calcd. for C13H8N2O2: 224.0580; found:
224.0576.
Benzo[d][1,3]dioxol-5-yl(benzo[d]oxazol-2-yl)methanone (3aq).
White solid (31.37 mg, 47% yield); mp 116−118 °C; 1H NMR
(400 MHz, CDCl3): δ 8.42−8.35 (m, 1H), 8.01 (d, J = 2.0 Hz, 1H),
7.93 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.58−7.50 (m, 1H),
7.49−7.43 (m, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.10 (s, 2H); 13C{1H}
NMR (100 MHz, CDCl3): δ 178.5 (CO), 157.4 (Cquat), 153.3 (Cquat),
150.5 (Cquat), 148.3 (Cquat), 140.8 (Cquat), 129.7 (Cquat), 128.8 (CH),
128.4 (CH), 125.8 (CH), 122.4 (CH), 111.9 (CH), 110.4 (CH),
108.4 (CH), 102.3 (CH2); IR (neat): 3022, 1694, 1522, 1483, 1271,
918 cm−1; GC-MS (EI, 70 eV): m/z (%) = 267 (M+, 25), 149 (100),
147 (100), 121 (15), 63 (9). HRMS (EI) m/z calcd. for C15H9NO4:
267.0532, found 267.0536.
(6-fluorobenzo[d]oxazol-2-yl) (phenyl)methanone (3ea). White
solid (29.52 mg, 49% yield); mp 88−90 °C; H NMR (400 MHz,
1
CDCl3): δ 8.56−8.51 (m, 2H), 7.73−7.65 (m, 2H), 7.64−7.55
(m, 3H), 7.34−7.26 (m, 1H) ; 13C{1H} NMR (100 MHz, CDCl3): δ
180.4 (CO), 161.9 (Cquat), 159.5 (d, JC,F = 80.3 Hz, Cquat), 147.0
(Cquat), 141.5 (d, JC,F = 13.8 Hz, Cquat), 134.6 (d, JC,F = 31.4 Hz, Cquat),
131.2 (CH × 2), 128.8 (CH × 2), 117.0 (d, JC,F = 26.2 Hz, CH), 112.6
(d, JC,F = 10.2 Hz, CH), 108.5 (d, JC,F = 25.5 Hz, CH) ; IR (neat):
3091, 1674, 1521, 1228, 968 cm−1; GC-MS (EI, 70 eV): m/z (%) =
241 (M+, 22), 213 (17), 105 (100), 77 (26). HRMS (EI) m/z calcd.
for C14H8FNO2: 241.0534; found: 241.0538.
(5-Chlorobenzo[d]oxazol-2-yl) (phenyl)methanone (3fa). White
1
solid (35.34 mg, 55% yield); mp 98−100 °C; H NMR (400 MHz,
CDCl3): δ 8.53 (d, J = 7.2, 2H), 7.92 (d, J = 2.0, 1H), 7.73−7.67
(m, 1H), 7.66−7.62 (m, 1H), 7.60−7.51 (m, 2H), 7.51−7.49 (m, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 180.3 (CO), 158.2 (Cquat),
149.1 (Cquat), 141.8 (Cquat), 134.8 (Cquat), 134.7 (CH), 131.4
(CH × 2), 131.1 (CH × 2), 129.0 (Cquat), 128.9 (CH), 122.2
(CH), 112.8 (CH). The data meet the literature report.5
(5-Bromobenzo[d]oxazol-2-yl) (phenyl)methanone (3ga). White
1
solid (38.38 mg, 51% yield); mp 112−114 °C; H NMR (400 MHz,
CDCl3): δ 8.53 (d, J = 7.2 Hz, 2H), 8.07 (d, J = 1.6 Hz, 1H), 7.73−
7.63 (m, 2H), 7.62−7.54 (m, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 180.3 (CO), 158.0 (Cquat), 149.5 (Cquat), 142.3 (Cquat),
134.9 (Cquat), 134.7 (CH), 131.7 (CH × 2), 131.2 (CH × 2), 128.8
(CH), 125.3 (CH), 118.6 (Cquat), 113.3 (CH). The data meet the
literature report.4c
Benzo[d]thiazol-2-yl(phenyl)methanone (3ha). Pale yellow solid
(31.07 mg, 52% yield); mp 102−104 °C; 1H NMR (400 MHz,
CDCl3): δ 8.57 (d, J = 8.0 Hz, 2H), 8.26 (d, J = 8.0 Hz, 1H), 8.03 (d,
J = 7.6 Hz, 1H), 7.71−7.64 (m, 1H), 7.62−7.52 (m, 4H); 13C{1H}
NMR (100 MHz, CDCl3): δ 185.5 (CO), 167.3 (Cquat), 154.0 (Cquat),
137.2 (Cquat), 135.1 (Cquat), 134.0 (CH), 131.4 (CH × 2), 128.6
(CH × 2), 127.8 (CH), 127.0 (CH), 125.9 (CH), 122.3 (CH). The
data meet the literature report.10
Benzo[d]thiazol-2-yl(4-methoxyphenyl)methanone (3ia). Color-
less solid (37.66 mg, 56% yield); mp 111−113 °C; 1H NMR
(400 MHz, CDCl3): δ 8.67−8.62 (m, 2H), 8.24 (d, J = 8.0 Hz, 1H),
8.02 (d, J = 8.0 Hz, 1H), 7.61−7.50 (m, 2H), 7.07−7.01 (m, 2H), 3.92
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 183.6 (CO), 168.0
(Cquat), 164.6 (Cquat), 154.0 (Cquat), 137.0 (Cquat), 134.0 (CH × 2),
127.9 (Cquat), 127.5 (CH), 126.9 (CH), 125.7 (CH), 122.3 (CH),
114.0 (CH × 2), 55.7 (CH3). The data meet the literature report.10
Benzo[d]thiazol-2-yl(4-bromophenyl)methanone (3ja). Pale yel-
low solid (38.04 mg, 48% yield); mp 121−123 °C; 1H NMR
(400 MHz, CDCl3): δ 8.49−8.45 (m, 2H), 8.25−8.22 (m, 1H), 8.04−
8.00 (m, 1H), 7.73−7.68 (m, 2H), 7.65−7.53 (m, 2H); 13C{1H} NMR
(100 MHz, CDCl3): δ 184.4 (CO), 166.9 (Cquat), 154.0 (Cquat), 137.2
(Cquat), 133.8 (CH × 2), 132.9 (Cquat), 132.0 (CH × 2), 129.0 (Cquat),
127.9 (CH), 127.2 (CH), 125.9 (CH), 122.3 (CH). The data meet the
literature report.10
Benzo[d]oxazol-2-yl(naphthalen-2-yl)methanone (3ar). White
1
solid (43.00 mg, 63% yield); mp 110−112 °C; H NMR (400 MHz,
CDCl3): δ 9.32 (s, 1H), 8.48−8.41 (m, 1H), 8.08 (d, J = 8.4 Hz, 1H),
8.02−8.43 (m, 2H), 7.91 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H),
7.71−7.65 (m, 1H), 7.64−7.53 (m, 2H), 7.52−7.48 (m, 1H); 13C{1H}
NMR (100 MHz, CDCl3): δ 180.4 (CO), 157.4 (Cquat), 150.6 (Cquat),
141.0 (Cquat), 136.3 (Cquat), 134.4 (Cquat), 132.5 (Cquat), 132.4 (CH),
130.4 (CH), 129.4 (CH), 128.6 (CH), 128.5 (CH), 127.9 (CH),
127.0 (CH), 125.9 (CH), 125.5 (CH), 122.6 (CH), 112.0 (CH). The
data meet the literature report.5
(4-Methylbenzo[d]oxazol-2-yl) (phenyl)methanone (3ba). White
1
solid (33.77 mg, 57% yield); mp 86−88 °C; H NMR (400 MHz,
CDCl3): δ 8.63−8.57 (m, 2H), 7.74−7.66 (m, 1H), 7.62−7.55 (m,
2H), 7.54−7.50 (m, 1H), 7.47−7.40 (m, 1H), 7.29−7.24 (m, 1H),
2.73 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 180.7 (CO), 156.6
(Cquat), 150.4 (Cquat), 140.4 (Cquat), 135.2 (Cquat), 134.4 (Cquat), 133.4
(CH), 131.3 (CH × 2), 128.7 (CH × 2), 128.3 (CH), 126.1 (CH),
109.1 (CH), 16.7 (CH3); IR (neat): 3066, 1639, 1521, 1191, 1116,
916 cm−1; GC-MS (EI, 70 eV): m/z (%) = 237 (M+, 22), 209 (11),
105 (100), 77 (34). HRMS (EI) m/z calcd. for C15H11NO2: 237.0784;
found: 237.0786.
(5-Methylbenzo[d]oxazol-2-yl) (phenyl)methanone (3ca). White
solid (37.11 mg, 66% yield); mp 91−93 °C; H NMR (400 MHz,
General Procedure for One-Pot Protocol. To a stirred solution
of alkynes (3 mmol) and NBS (1.78 g, 10 mmol) in H2O (5 mL),
taken in a round bottomed flask under N2. The reaction was stirred at
80 °C for 3 h. After consumption of starting material (followed by
TLC analysis), the solvent was removed under reduced pressure.
To this reaction mixture, DMF (2 mL), Et2NH (1 mL) and
2-amino(thio)phenols (2 mmol) was added. The reaction was stirred
at 90 °C under N2 for 5 h. After being cooled to room temperature,
water (40 mL) was added, and the aqueous phase was extracted by
EtOAc (5 × 40 mL). The combined organic phases were dried over
Na2SO4, and concentrated in vacuum. The residue was purified by
chromatography on silica gel with petroleum ether/ethyl acetate as
eluent to afford the corresponding product and obtain the yields.
Reactions of 3aa. 2-Benzylbenzo[d]oxazole(4). At room temper-
ature, to ketone 3aa (112 mg, 0.5 mmol) in CF3CO2H (1 mL) under
argon, was added dropwise at agitation triethylsilane (199 mg,
1.7 mmol). The mixture was stirred at room temperature under argon
for 3 h, after which full conversion of 3aa was observed (TLC).
Diethyl ether (15 mL) and water (30 mL) were added to the dark
1
CDCl3): δ 8.54 (d, J = 7.6 Hz, 2H), 7.73−7.65 (m, 2H), 7.60−7.54
(m, 3H), 7.36 (d, J = 8.4 Hz, 1H), 2.53 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 180.9 (CO), 157.5 (Cquat), 148.9 (Cquat), 141.2
(Cquat), 136.0 (Cquat), 135.3 (Cquat), 134.4 (CH), 131.2 (CH × 2),
130.1 (CH × 2), 128.8 (CH), 122.1 (CH), 111.4 (CH), 21.7 (CH3).
The data meet the literature report.4c
(5-Methoxybenzo[d]oxazol-2-yl) (phenyl)methanone (3da).
White solid (46.81 mg, 74% yield); mp 102−104 °C; 1H NMR
(400 MHz, CDCl3): δ 8.55−8.50 (m, 2H), 7.71−7.64 (m, 1H), 7.61−
7.52 (m, 3H), 7.35 (d, J = 2.4 Hz, 1H), 7.18−7.12 (m, 1H), 3.88
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 180.5 (CO), 158.3
(Cquat), 158.0 (Cquat), 145.4 (Cquat), 141.8 (Cquat), 135.2 (Cquat), 134.3
(CH), 131.1 (CH × 2), 128.7 (CH × 2), 118.6 (CH), 112.3 (CH),
103.7 (CH), 56.1 (CH3); IR (neat): 3046, 1665, 1532, 1122,
957 cm−1; GC-MS (EI, 70 eV): m/z (%) = 253 (M+, 22), 225 (13),
105 (100), 77 (24). HRMS (EI) m/z calcd. for C15H11NO3: 253.0739;
found: 253.0735.
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reaction mixture. After agitation, the organic layer was separated and
the aqueous layer washed with diethyl ether (2 × 25 mL). The
combined diethyl ether solutions were dried over MgSO4, filtered, and
evaporated. Column chromatography of the residue on silica gel
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
1
■
(hexanes) produced 4 as a pure white solid (69 mg; 66%). H NMR
(CDCl3, 400 MHz):13C NMR (CDCl3, 100 MHz): δ 7.71−7.67
(m, 1H), 7.48−7.44 (m, 1H), 7.41−7.32 (m, 4H), 7.31−7.27 (m, 3H),
4.28 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ 165.3 (Cquat),
151.2 (Cquat), 141.5 (Cquat), 134.9 (Cquat), 129.2 (CH × 2), 129.0
(CH × 2), 127.5 (CH), 124.8 (CH), 124.3 (CH), 120.0 (CH), 110.6
(CH), 35.4 (CH2). The data meet the literature report.11
This work was supported by the National Natural Science
Foundation of China (No. 21302048), Specialized Research
Fund for the Doctoral Program of Higher Education (No.
20130161120035), China Postdoctoral Science Foundation
(No. 2013M540625), Hunan Provincial Natural Science
Foundation of China (No. 13JJ5018 and 14JJ7028), and
Department of Science and Technology Foundation of
Changsha (No. K1403243-31).
Benzo[d]oxazol-2-yl(phenyl)methano(5). To ketone 3aa (112 mg,
0.5 mmol) in MeOH (4 mL) at 0 °C was added sodium borohydride
(38 mg, 1 mmol) over a period of 15 min and stirred at RT for 12 h.
After the reaction finished, the reaction mass was quenched with
NH4Cl solution and extracted into EtOAc. The combined organic
layer was washed with brine solution and dried, evaporated in vacuo.
The resulted crude passed through a Flash column chromatography on
silica gel provided the compound 5 (92 mg, 82%) as pale-yellow
solid.1H NMR (CDCl3, 400 MHz): δ 7.70−7.66 (m, 1H), 7.55−7.52
(m, 2H), 7.48−7.44 (m, 1H), 7.41−7.30 (m, 5H), 6.05 (s, 1H), 4.21
(s, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 166.6 (Cquat), 151.1
(Cquat), 140.3 (Cquat), 138.9 (Cquat), 128.9 (CH × 2), 128.8 (CH),
126.9 (CH × 2), 125.3 (CH), 124.6 (CH), 120.2 (CH), 110.9 (CH),
70.6 (CH). The data meet the literature report.3a
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Benzo[d]oxazol-2-yldiphenylmethanol(6). To ketone 3aa
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stirred for 2 h. The reaction mixture was quenched with NH4Cl (4 mL,
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gel and provided the title compound (143 mg, 95%) as a white solid.
1H NMR (CDCl3, 400 MHz): δ 7.64−7.60 (m, 1H), 7.52−7.45
(m, 5H), 7.40−7.30 (m, 8H), 4.96 (s, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 168.7 (Cquat), 151.5 (Cquat), 143.1 (Cquat × 2), 140.2
(Cquat), 128.4 (CH × 4), 127.5 (CH × 4), 125.4 (CH × 2), 124.8
(CH), 120.5 (CH), 115.5 (CH), 111.2 (CH), 78.8 (Cquat). The data
meet the literature report.12
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of 2,3-diaminophenol (31 mg, 0.25 mmol), 2,2-dibromo-1-phenyl-
ethanone (83.4 mg, 0.3 mmol), Et2NH (1 mmol, 74 mg), and DMF
(0.5 mL) was stirred at 90 °C for 5 h. After cooling to room tem-
perature, water (20 mL) was added, and the aqueous phase was
extracted by EtOAc (5 × 20 mL). The combined organic phases were
dried over Na2SO4, and concentrated in vacuum. The residue was
purified by chromatography on silica gel with petroleum ether/ethyl
acetate as eluent to afford 7 (44.5 mg, 80%) as a brown solid. 1H NMR
(CDCl3, 400 MHz): δ 9.37 (s, 1H), 8.19−8.15 (d, J = 8.0 Hz, 2H),
7.94 (s, 1H), 7.67−7.64 (d, J = 4.4 Hz, 2H), 7.61−7.52 (m, 3H),
7.25−7.21 (d, J = 3.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ
151.1 (Cquat), 148.5 (CH), 146.2 (Cquat), 143.0 (Cquat), 140.9 (Cquat),
135.1 (Cquat), 129.7 (CH), 129.5 (CH), 128.2 (CH × 2), 126.4
(CH × 2), 118.6 (CH), 110.3 (CH); IR (neat):3210, 3020, 1539,
1491, 1303, 841 cm−1; GC-MS (EI, 70 eV): m/z (%) = 222 (M+, 100),
196 (13), 104 (15), 92 (37). HRMS (EI) m/z calcd. for C14H10N2O:
222.0788; found: 222.0785.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02093.
■
S
1H and 13C NMR spectra of compounds 3aa − 3ja, 4−7
(PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: wmhe@hnu.edu.cn (W.H.).
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F
DOI: 10.1021/acs.joc.5b02093
J. Org. Chem. XXXX, XXX, XXX−XXX