Selective synthesis of oxazoles and pyrazines from α-bromo-1-phenylethanone using a by-product-promoted strategy

Article abstract of DOI:10.1016/j.tet.2018.10.071

Oxazoles and pyrazines are fundamental heterocycles that widely found in natural products or drugs. In this work, a selective strategy for oxazoles and pyrazines synthesis using α-bromo-1-phenylethanone and ammonium acetate as starting materials was reported. This methodology features mild reaction conditions, readily accessible starting materials and good chemoselectivity. Mechanistic study indicates that this reaction involves a by-product-promoted (BPP) process for the formation of oxazole, that is, the in-situ formed hydrogen bromide (HBr) during the reaction promotes the whole tandem process.

Full text of DOI:10.1016/j.tet.2018.10.071

Accepted Manuscript
Selective synthesis of oxazoles and pyrazines from α-bromo-1-phenylethanone using
a by-product-promoted strategy
Changhui Liu, Jiateng Zhao, Yu Qiao, Wenbo Huang, Zhonghao Rao, Yanlong Gu
PII:
S0040-4020(18)31308-5
https://doi.org/10.1016/j.tet.2018.10.071
TET 29904
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 August 2018
Revised Date: 21 October 2018
Accepted Date: 26 October 2018
Please cite this article as: Liu C, Zhao J, Qiao Y, Huang W, Rao Z, Gu Y, Selective synthesis of
oxazoles and pyrazines from α-bromo-1-phenylethanone using a by-product-promoted strategy,
Tetrahedron (2018), doi: https://doi.org/10.1016/j.tet.2018.10.071.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphic abstract

ACCEPTED MANUSCRIPT
Selective synthesis of oxazoles and pyrazines from ˩-bromo-1-phenylethanone using a
by-product-promoted strategy
Changhui Liu a, Jiateng Zhao a, Yu Qiao a, Wenbo Huang b, Zhonghao Rao a*, Yanlong Gub*
a: School of Electrical and Power Engineering, China University of Mining and Technology,
Xuzhou, 221116, China. E-mail: raozhonghao@cumt.edu.cn; Tel: (0)86-(0)516-83592000.
b: Key Laboratory of Material Chemistry for Energy Conversion and Storage, Ministry of
Education, School of Chemistry and Chemical Engineering, Hubei Key Laboratory of Material
Chemistry and Service Failure, Huazhong University of Science and Technology, Wuhan,
430074, China, Tel: (0)86-(0)27-87543732. Fax: (0)86-(0)27-87544532.
Abstract: Oxazoles and pyrazines are fundamental heterocycles that widely found in natural
products or drugs. In this work, a selective strategy for oxazoles and pyrazines synthesis using
α-bromo-1-phenylethanone and ammonium acetate as starting materials was reported. This
methodology features mild reaction conditions, readily accessible starting materials and good
chemoselectivity. Mechanistic study indicates that this reaction involves a by-product-promoted
(BPP) process for the formation of oxazole, that is, the in-situ formed hydrogen bromide (HBr)
during the reaction promotes the whole tandem process.
Key words: tandem reaction, heterocyclic compounds synthesis, by-product-promoted, reactivity,
hydrogen bromide, chemoselectivity
Introduction
Waste prevention or utilization is at the core of Green Chemistry. By-product-promoted (BPP)
strategy means a by-product generated in the upstream process could facilitate the downstream
conversions, which has emerged as a new field in efficient synthesizing organic molecular in a
tandem manner in terms of environmental and labor saving considerations.1 Hydrogen bromide
(HBr), which is widely generated as a by-product, especially in nucleophillic substitution or
bromide involved C-C cross coupling reaction thanks to the good leaving ability of bromide.
However, in most scenarios, HBr is captured by a strong base aiming to complete the reaction,
whereas application of HBr as a by-product-promoter has been rarely reported.2 Previously, we
dedicated ourselves into developing new tandem reactions by using simple starting material and
commercially available catalysts target to synthesizing biological active heterocyclic compounds.3
1

ACCEPTED MANUSCRIPT
In most cases, water is the sole by-product, which generally displays a limited impact on the
whole process. To explore new molecular diversities and reactivity, we were attracted by HBr
liberation tandem reactions. Herein, a success outcome was demonstrated in our study by using
α-bromo-1-phenylethanone as starting material.
Oxazole is a sort of fundamental nitrogen occurring heterocycles, which was widely found in
natural products, pharmaceuticals and agrochemicals (Figure 1). Conventional routes to the
oxazole motif include the cyclodehydration of (α-acylamino) ketones under an acidic condition
(Robinson Gabriel Synthesis) (Scheme 1, eq. 1) and the annulation of enamide by the catalysis of
transition metals (Scheme 1, eq. 2 and 3). Condensation of α-halogenated ketones and
carboxamides, firstly reported by Blümlein and Lewy in the 1880s, is used as a more practical
method to oxazoles because a more accessible starting material was used compared with
intramolecular cases (Scheme 1, eq. 4).4 Recently, Wu et al. developed an iodine mediated method
for constructing oxazole motif. The key of this strategy is trapping the unstable α-ketoaldehyde
intermediate which was presumably formed in-situ during the reaction process in the presence of
iodine and DMSO system (Scheme 1, eq. 5).5 Though numerous strategies have gotten success in
forging oxazole motif, either the harsh reaction conditions (transition metals or strong acids) or
poor efficiency has limited their practical utilization. Considering the importance of oxazole
derivatives, a practical and economical methodology is also highly in demand. Herein, a
catalyst-free pathway was demonstrated by us to access oxazole motif through using
α-bromo-1-phenylethanone and ammonium acetate as starting materials. Intriguingly, a pyrazine
derivative can be selectively obtained when by-product HBr was neutralized by NaOH.
Figure 1. Some oxazole-containing biologically active compounds.
2

ACCEPTED MANUSCRIPT
Scheme 1. Previous work concerning oxazoles synthesis.
Results and discussion
Initially, α-bromo-1-phenylethanone 1a was treated with ammonium acetate 2a in acetonitrile at
60 oC. No reaction was observed in the absence of catalyst (entry 1). Some Lewis acids were then
tested. AlCl3 cannot promote this conversion that only trace amount of target compound was
observed (entry 2). FeCl3 and Sc(OTf)3 exhibited better efficiency than AlCl3, but those are still
far from satisfactory (entries 3 and 4). LiBr·H2O cannot work either in this reaction system (entry
5). Brönsted acid, HBr, did not work well for the reaction that no desired product was examined
(entry 6). To our surprise, the yield of 3a jumped to 18% when DMSO was used instead of
CH3CN (entry 7). Encouraged by this result, an elevated reaction temperature was then tested.
55% of desired product was obtained when reaction temperature was increased to 80 oC (entry 8).
However, the reaction yield did not show a linear relationship with reaction temperature since 100
oC only led to a lightly yield increase accompanied by consuming the rest of starting materials
(entry 9). Further investigation demonstrated that the reaction proceeded smoothly without adding
any catalyst (entry 10). To our great delight, the yield of desired product increased to 89% when
o
the reaction temperature rose to 130 C (entry 11). DMF was not a suitable solvent for this
3

ACCEPTED MANUSCRIPT
reaction as no reaction was examined under the same reaction conditions (entry 12). The reaction
proceeded sluggishly in nitrogen atmosphere, which indicated molecular oxygen also plays an
important role in this conversion (entry 13). From the viewpoint of economical and practical issue,
o
the optimized reaction condition was finally determined as follows: DMSO as solvent at 130 C
under air. Additionally, the structure of desired product 3a was unambiguously confirmed by
single X-ray crystal analysis.6
Table 1. Optimization of the reaction conditions for oxazole synthesis.a
O
N
Br
+
NH4OAc
2a
O
O
1a
3a
entry
1
catalystb
--
solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
temperature / oC
yield of 3ac / %
60
NR
trace
2
2
AlCl3
FeCl3
Sc(OTf)3
LiBr.H2O
HBr
60
3
60
4
60
5
5
60
NR
NR
18
6
60
7
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
--
60
8
80
55
9
100
100
130
130
130
58
10
11
12
13d
51
--
89
--
NR
35
--
DMSO
aUnless otherwise noted the reaction conditions are 1a (0.2 mmol), 2a (0.24 mmol), solvent (1
b
c
d
mL), 1 h, under air. Catalyst loading: 10 mol %. Isolated yield. The reaction was performed
under the protection of an argon balloon.
With the optimized reaction conditions in hand, substrates with respect to phenylethanone were
then surveyed. Firstly, substrates bearing electron donating group at para position were tested. As
shown in Table 2, 4-OMe substituted phenylethanone delivered target molecular in an over 91%
t
i
yield (3b). Other aliphatic chain substituted derivatives, such as propyl, Amyl, Bu and Bu, can
also participate in this reaction to produce the oxazole derivatives uneventfully (3c-3f), but bulky
4

ACCEPTED MANUSCRIPT
group led to inferior yield compared with less bulky substituents (3e and 3f). Thiomethyl and
trifluoromethyloxyl substituted phenylethanones readily yielded their corresponding oxazole motif
in good yields, which opened a new way to construct sulfur or trifluoro containing oxazole
derivatives (3g and 3h). Further study revealed that electron withdrawing group showed a negative
effect on this transformation as halide substituted phenylethanones afforded their corresponding
products in moderate yields (3i-3k). When basic NH2 substituted phenylethanone used as starting
material, desired product did not form and only unreacted starting material was recovered (3l).
The reason might ascribe to the turbulence to the in-situ generated HBr in the reaction system
which given by NH2. Furthermore, 3,4-disubstituted phenylethanone can also work well to afford
the target compound in a good yield (3m). Ortho-substituent substrate was also considered in this
reaction system that 2-Br substituted phenylethanone could afford its corresponding oxazole
derivative (3o), but the yield was inferior to that of para-substituted substrates, we ascribe the
reason to the steric-hinderance.
Table 2. Optimization of the reaction conditions for oxazole synthesis.a
entry
1
R
product
3a
isolated yield / %
4-H
89
91
83
78
72
71
89
85
55
45
49
0
2
4-OMe
4-propyl
4-nAmyl
4-tBu
3b
3c
3
4
3d
3e
5
6
4-iBu
3f
7
4-SMe
4-OCF3
4-F
3g
8
3h
3i
9
10
11
12
13
14
4-Cl
3j
4-Br
3k
3l
4-NH2
3,4-dimethoxy
2-Br
3m
3o
69
36
5

ACCEPTED MANUSCRIPT
aReaction conditions: phenylethanone 1a (0.2 mmol), ammonium acetate 2a (0.24 mmol), DMSO
(1 mL), 130 oC, 1 h.
To shed light on the mechanism behind this reaction, some control experiments were conducted.
To our surprised, the desired oxazole product cannot be detected when NaOH was used to
neutralize the HBr, whereas a symmetrical pyrazine derivative was obtained selectively in a 78%
yield after careful structure analysis (Scheme 2, eq. 1). Weaker base, K2CO3 could also promote
the formation of pyrazine derivative 4a in a 41% yield along with 38% of 3a. γ-Butyrolactone, a
neutral HBr scavenger, afforded only 8% of 4a along with 51% of 3a. It demonstrated that a
strong base is necessary to ensure the pyrazine selectivity, which indicated a rapid HBr adsorption
could reduce the impact of HBr on the downstream conversion, thus facilitate the formation of
pyrazine derivative. 3a could be detected in a moderate yield even in the presence of
γ-butyrolactone, it presumably due to its relatively slower HBr neutralization speed compared
with inorganic bases, it also demonstrated that the basicity of scavenger plays a key role to
manipulate the selectivity. Air also plays an important role as the reaction is suppressed to some
degree when the reaction was protected by argon, which reveals a molecular oxygen promoted
aromatization to be involved in (Scheme 2, eq. 2). However, still 35% of 3a was formed even in
nitrogen atmosphere, we ascribe the reason to twofold; firstly, it might come from the slight
contamination of molecular of oxygen in the reaction system; secondly, the oxidation ability was
responsible for this phenomenon.5b In order to know the exact role of by-product, aqueous HBr
and HOAc were adopted to examine the reaction. As shown in Scheme 2, eq. 3, desired product
was obtained readily in the presence of HBr, but HOAc can not promote the conversion at all,
which indicated that HBr was the key to promote the downstream conversion rather than HOAc.
The yield of 3a dropped significantly, but still 38% of desired product was obtained when
γ-butyrolactone was used along with HBr, it might due to the relatively slower neutralization
speed of γ-butyrolactone than that of inorganic base, which rendered the unreacted HBr acting as a
catalyst to promote the oxazole formation. 3a was yielded in 65% when the other ammonium
source, aqueous ammonia, was subjected to examination, which further excluded the impact of
HOAc on this conversion (Scheme 2, eq. 4). What’s more, the oxidation product of
2-bromo-1-phenylethanone, α-ketoaldehyde can not afford the pyrazine product in the presence of
6

ACCEPTED MANUSCRIPT
either stoichiometric amount of NaOH or NaBr (in order to create an identical reaction condition
system with that of model reaction) which indicated that 1ab was not the intermediate of the
reaction towards pyrazine derivative (Scheme 2, eq. 5). Based on these findings, a plausible
mechanism that was similar with Xue’s report for the formation of oxazole product was proposed
(Scheme 3).5c Firstly, phenylglyoxal 1ab was formed from 2-bromo-1-phenylethanone in the
presence of DMSO, then intermediate I was generated from 1ab and NH4OAc. Subsequently,
intermediate I reacted with the other molecular 1ab to afford intermediate II, which underwent an
intermolecular nucleophilic reaction to deliver intermediate III, notably, according to Xue’s
result,5c the intermolecular nucleophilic reaction step can not occur in the absence of acidic
catalysts, which further proved the importance of HBr in this whole conversion. Finally, the final
product was obtained via an intramolecular dehydration reaction. The mechanism for pyrazine
formation was also proposed in Scheme 3 based on previous reports with regard to pyrazine
derivative synthesis by using 2-bromo-1-phenylethanone analogues as starting materials.7
Intermediate IV, which generated from an electrophilic substitution of 2-bromo-1-phenylethanone
to NH4OAc, underwent a nucleophilic addition to NH4OAc to form intermediate V in the presence
of ammonium acetate with the aid of externally added base.8 Subsequently, the intramolecular
nucleophilic addition and aerobic oxidation occurred to deliver the final pyrazine derivative. It
should be noted that mechanism responsible for oxazole and pyrazine synthesis and their
selectivity was quite complicated in the reaction system, owing to so many by-products and
considerable factors were involved in, we just provided here the most reasonable mechanism as
we can.
7

ACCEPTED MANUSCRIPT
O
N
HBr scavenger(1.0
equiv)
N
Br
+
NH4OAc
2a
+
O
N
DMSO, 130 oC, 1 h
under air
(1)
O
3a 0%
1a
4a 78%
HBr scavenger: NaOH, 3a: 0%, 4a: 78%
K2CO3, 3a: 38%, 4a: 41%
butyrolactone,
3a: 51%, 4a: 8%
O
N
O
Br
NaOH (1.0 equiv)
+
NH4OAc
2a
(2)
DMSO, 130 oC, 1 h
under Ar
O
1a
3a 35%
O
N
O
OH
(3)
catalyst (100 mol %)
NH4OAc
+
O
DMSO, 130 o
C
OH
3a
1aa
Catalyst: HOAc, yield of 3a:0 %
Catalyst: HBr, yield of 3a: 85%
Catalyst: HBr in the presence of 1.0 eq.
yield of 3a: 38%
butyrolactone,
O
N
Br
NaOH (1.0 equiv)
NH3.H2
O
+
(4)
O
O
DMSO, 130 oC, 1 h
under air
3a 65%
1a
N
O
OH
N
catalyst (100 mol %)
(5)
NH4OAc
+
OH
DMSO, 110 o
C
4a
1aa
catalyst: NaOH: 0%
NaBr: 0%
Scheme 2. Some control experiments.
Mechanism for the formation of oxazole derivatives
O
O
O
O
O
Br
H
H
NH4OAc
1ab
DMSO
N
NH
(I)
O
OH
1a
1ab
HBr
By-product HBr promoted process
O
OH
O
O
N
Intramolecular
electrophilic addition
N
dehydration reaction
N
H
OH
O
O
OH
(II)
3a
(III)
Mechanism for the formation of pyrazine derivatives
NaOH
mediated
NH
O
O
O
O
H
N
Nucleophilic
substitution
H
NH4OAc, NaOH
Br
N
+
NH4OAc
1b
(IV)
(V)
1a
H
N
Intramolecular
electrophilic addition
/ elimination
N
N
NH2
O
H
Aerobic oxidation
N
N
H
- H2O
4a
(VII)
(VI)
Scheme 3. Plausible mechanism for the formation of oxazole and pyrazine derivatives.
Pyrazine is one of the fundamental nitrogen occurring heterocycles, which have attracted
intensive attention due to its promising applicability in argo-chemistry,9 fragrance10 and metal
coordination chemistry.11 Conventionally, pyrazine motif was constructed by the self-condensation
of α-amino carbonyl compounds and the combination of α-diketones with vicinal diamines
followed by dehydrogenation12. Recently, in order to forge pyrazine motif efficiently, some
8

ACCEPTED MANUSCRIPT
building blocks were described able to access pyrazine, such as 2-hydroxy-1,2-diarylethanone,7a
(Z)-β-haloenol acetates,7b N-alkyl piperazines,13 and β-keto-α-oximino ester.14 Besides these
methods, some alternatives were also reported. However, most of synthetic methods inevitably
suffer from the using of costly transition metals,15 harsh reaction condition,16 and poor selectivity
or yield.17 Consequently, a more practical protocol for synthesizing pyrazine is still desirable.
During the study process of synthesizing oxazole, it was found that a pyrazine motif can be
selectively obtained when the reaction was conducted in the presence of 1.0 equiv. of NaOH. This
result stimulated us to further study the reaction condition in terms of high efficiency and practical
issue. After a careful reaction condition optimization, it was determined that the suitable condition
for synthesizing pyrazine was NaOH (1 eq.) as additive, DMSO/H2O = 100/1 as solvent, at 110 oC
for 1 hour. (Detail parameters screening can be found in Table S1)
To realize the compatibility of this pyrazine synthesis protocol, various
α-bromo-1-phenylethanone were studied. As shown in Table 3, α-bromo-1-phenylethanone
bearing electron donating groups participated in the reaction readily produced the desired products
in excellent yields (entries 2 to 5). Notably, bulky groups at para position displayed a weak impact
on this transformation, which might offer a chance to use this protocol into pyrazine containing
ligand and coordination material synthesis18. A hydroxyl-functionalized substrate can also work
well without damaging the product structure (4f). Electron withdrawing groups at para position
were also tolerated in this transformation (entries 8 and 9), but a strong electron withdrawing
group, SO2Me, was reluctant to participate into this transformation (entry 10). Further study
revealed that substrate possessing a substitute at 2-position exhibited inactivity towards this
reaction, which might be caused by a steric-hindrance of substituent in the self-condensation step
(entry 11).
Table 3. Substrate scope of pyrazine synthesis.a
entry
1
R
product
isolated yield / %
93
4-H
4a
9

ACCEPTED MANUSCRIPT
2
4-Me
93
95
92
90
85
86
82
84
0
4b
3
4-OMe
4-tBu
4-nAmyl
4-OH
4-Ph
4c
4d
4e
4f
4
5
6
7
4g
4h
4i
8
4-Br
9
4-I
10
11
4-SO2Me
2-Br
4j
0
4k
aReaction conditions: phenylethanone 1a (0.2 mmol), ammonium acetate 2a (0.24 mmol), NaOH
(0.2 mmol), DMSO/H2O = 50/1 (1 mL), 110 oC, 1 h.
Conclusions
Oxazoles and pyrazines were selectively obtained from α-bromo-1-phenylethanone by tuning
the reaction conditions. This method exhibits good efficiency, selectivity and broad substrate
scope. Mechanism study revealed that the in-situ formed HBr plays a vital role in the formation of
oxazole. This work gives a new way to forge oxazoles and pyrazines from the same starting
material. Moreover, it offered a supplement for BPP application. Examination of further
challenging applications and developments of oxazole and pyrazine derivatives and analogues is
underway in our laboratory.
Experimental Sections
General information
Chemical shifts were expressed in ppm relative to Me4Si in solvent. All chemicals used were of
reagent grade and were used as received without further purification. All reactions were conducted
in a 10 mL of V-type flask equipped with triangle magnetic stirring.
10

ACCEPTED MANUSCRIPT
A typical reaction procedure for the synthesis of oxazole derivatives.
The reactions were conducted in a 10 mL of V-type flask equipped with triangle magnetic stirring.
In a typical reaction, 1a (0.20 mmol) was mixed with 2a (0.24 mmol) in dimethyl sulfoxide
o
(DMSO) (1.0 mL). The mixture was then stirred at 130 C for one hour. After reaction, the
reaction was quenched by water (5 mL), solution was subsequently extracted by ethyl acetate (3×5
mL). After extraction, organic phase was combined, removed solvent by rotate evaporation. The
final product was obtained by column chromatography. Tests for substrate scope were all
performed with an analogous procedure.
A typical reaction procedure for the synthesis of pyrazine derivatives.
The reactions were conducted in a 10 mL of V-type flask equipped with triangle magnetic stirring.
In a typical reaction, 1a (0.20 mmol) was mixed with 2a (0.24 mmol) and NaOH (0.2 mmol) in
DMSO (V) / H2O (V) = 50/1, . The mixture was then stirred at 110 oC for one hour. After reaction,
the reaction was quenched by water (5 mL), solution was subsequently extracted by ethyl acetate
(3×5 mL). After extraction, organic phase was combined, removed solvent by rotate evaporation.
The final product was obtained by column chromatography. Tests for substrate scope were all
performed with an analogous procedure.
Characterization data of new compounds
(4-Propylphenyl)(5-(4-propylphenyl)oxazol-2-yl)methanone (3c): white solid, melting point:
145-147 oC, 1H NMR (400 MHz, DMSO, 25 oC) δ = 8.32 (d, J = 8.2 Hz, 2H), 8.05 (s, 1H), 7.80 (d,
J = 8.1 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H), 2.62 (t,
J = 7.6 Hz, 2H), 1.70 – 1.55 (m, 4H), 0.91 ppm (td, J = 7.3, 4.2 Hz, 6H). 13C NMR (101 MHz,
DMSO) δ = 177.5, 156.5, 153.5, 149.0, 144.5, 132.8, 130.6, 129.3, 128.6, 125.1, 124.4, 123.9,
37.3, 37.0, 23.8, 23.7, 13.6, 13.6 ppm. IR (KBr) v: 2925, 2853, 1659, 1615, 1499, 1451, 1279,
1250, 1224, 1022, 954, 803, 753, 694 cm-1. HRMS-ESI (m/z) calcd for C22H23NNaO2, [M+Na]+
356.1626, found 356.1621.
(4-Pentylphenyl)(5-(4-pentylphenyl)oxazol-2-yl)methanone (3d): white solid, melting point:
178-180 oC, 1H NMR (400 MHz, DMSO, 25 oC) δ = 8.31 (d, J = 8.1 Hz, 2H), 8.05 (s, 1H), 7.79 (d,
J = 8.0 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 2.67 (t, J = 7.6 Hz, 2H), 2.62 (t,
J = 7.6 Hz, 2H), 1.68 – 1.53 (m, 4H), 1.29 (s, 8H), 0.86 ppm (t, J = 6.6 Hz, 6H). 13C NMR (101
o
MHz, DMSO, 25 C) δ = 177.5, 156.4, 153.5, 149.2, 144.8, 132.7, 130.6, 129.2, 128.5, 125.1,
11

ACCEPTED MANUSCRIPT
124.3, 123.9, 35.2, 34.9, 30.8, 30.3, 30.2, 21.9, 13.9 ppm. IR (KBr) v: 2923, 2868, 1678, 1615,
1491, 1279, 1250, 1224, 937, 803, 753, 725, 694 cm-1. HRMS-ESI (m/z) calcd for C26H31NNaO2,
[M+Na]+ 412.2252, found 412.2254.
(4-Isobutylphenyl)(5-(4-isobutylphenyl)oxazol-2-yl)methanone (3f): white solid, melting point:
151-153 oC, 1H NMR (400 MHz, DMSO, 25 oC) δ = 8.32 (d, J = 8.1 Hz, 2H), 8.05 (s, 1H), 7.80 (d,
J = 8.1 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 2.56 (d, J = 7.1 Hz, 2H), 2.51
(d, J = 7.5 Hz, 2H), 1.89 (dq, J = 20.6, 6.8 Hz, 2H), 0.88 ppm (dd, J = 6.4, 4.1 Hz, 12H). 13C
NMR (101 MHz, DMSO, 25 oC) δ = 177.5, 156.4, 153.5, 148.0, 143.5, 132.8, 130.4, 129.9, 129.1,
125.0, 124.4, 124.0, 44.5, 44.3, 29.6, 29.5, 22.1, 22.1 ppm. IR (KBr) v: 2928, 2871, 1690, 1621,
1491, 1287, 1252, 1222, 936, 753, 747, 725, 694 cm-1. HRMS-ESI (m/z) calcd for C24H27NNaO2,
[M+Na]+ 384.1939, found 384.1941.
(4-(Methylthio)phenyl)(5-(4-(methylthio)phenyl)oxazol-2-yl)methanone (3g): white solid, melting
point: 160-162 oC, 1H NMR (400 MHz, DMSO, 25 oC) δ = 8.35 (d, J = 8.5 Hz, 2H), 8.07 (s, 1H),
7.81 (d, J = 8.4 Hz, 2H) 7.43 (dd, J = 11.9, 8.6 Hz, 4H), 2.57 (s, 3H), 2.54 ppm (s, 3H). 13C NMR
(101 MHz, DMSO, 25 oC) δ = 176.6, 156.4, 153.1, 146.9, 141.2, 131.0, 130.9, 126.1, 125.5, 124.7,
124.4, 122.6, 14.2, 13.9 ppm. IR (KBr) v: 2931, 2875, 1692, 1627, 1489, 1285, 1250, 1220, 1080,
936, 753, 737, 725, 691 cm-1. HRMS-ESI (m/z) calcd for C18H15NNaO2S2, [M+Na]+ 364.0442,
found 364.0440.
(4-(Trifluoromethoxy)phenyl)(5-(4-(trifluoromethoxy)phenyl)oxazol-2-yl)methanone (3h): white
solid, melting point: 172-174 oC, 1H NMR (400 MHz, DMSO, 25 oC) δ = 9.08 (s, 1H), 8.58 (d, J =
8.9 Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.51 ppm (d, J = 8.1 Hz, 2H). 13
C
NMR (101 MHz, DMSO, 25 oC) δ = 176.8, 157.0, 152.1, 148.4, 140.4, 139.2, 133.6, 133.2, 129.1,
127.5, 121.7, 121.3, 120.5, 118.8 ppm. 19F NMR (377 MHz, DMSO, 25 oC) δ = -56.5, -56.8 ppm.
IR (KBr) v: 2935, 2871, 1691, 1619, 1490, 1285, 1250, 1220, 1080, 753, 737, 725, 688 cm-1.
HRMS-ESI (m/z) calcd for C18H9F6NNaO4, [M+Na]+ 440.0333, found 440.0336.
(2-Bromophenyl)(5-(2-bromophenyl)oxazol-2-yl)methanone (3o) (0.07 mmol, 29.1 mg, 36 %): white
o
o
solid, melting point: 162-164 C, 1H NMR (400 MHz, DMSO, 25 C) δ = 8.38 (d, J = 7.6 Hz, 2H),
8.13 (s, 1H), 7.90 (d, J = 7.1 Hz, 2H), 7.74 (t, J = 7.4 Hz, 1H), 7.65 – 7.52 ppm (m, 3H). 13C NMR
o
(101 MHz, DMSO, 25 C) δ = 178.1, 156. 6, 153.4, 135.0, 133. 9, 130.6, 130.4, 130.1, 129.4, 129.0,
128.7, 128.5, 126.3, 125.5, 125.1, 125.0 ppm. IR (KBr) v: 2938, 2870, 1698, 1625, 1492, 1287, 1248,
12

ACCEPTED MANUSCRIPT
1222, 1081, 729, 725, 681 cm-1. HRMS-ESI (m/z) calcd for C16H9Br2NNaO2, [M+Na]+ 427.8898,
found 427.8896.
2,6-Bis(4-pentylphenyl)pyrazine (4e): white solid, melting point: 189-191 oC, 1H NMR (400 MHz,
DMSO, 25 oC) δ = 9.14 (s, 2H), 8.15 (d, J = 8.1 Hz, 4H), 7.37 (d, J = 8.1 Hz, 4H), 2.63 (t, J = 7.6
Hz, 4H), 1.66 – 1.52 (m, 4H), 1.34 – 1.25 (m, 8H), 0.85 ppm (t, J = 6.8 Hz, 6H). 13C NMR (101
o
MHz, DMSO, 25 C) δ = 150.4, 144.6, 139.7, 133.5, 129.0, 126.8, 34.9, 30.9, 30.5, 22.0, 13.9
ppm. IR (KBr) v: 2999, 2890, 1690, 1498, 1250, 1080, 748, 730, 699 cm-1. HRMS-ESI (m/z)
calcd for C26H32N2Na, [M+Na]+ 395.2463, found 395.2461.
o
1
2,6-Di([1,1'-biphenyl]-4-yl)pyrazine (4g): white solid, melting point: 178-180 C, H NMR (400
MHz, DMSO, 25 oC) δ = 9.29 (s, 2H), 8.39 (d, J = 8.4 Hz, 4H), 7.90 (d, J = 8.4 Hz, 4H), 7.78 (d, J
= 7.4 Hz, 4H), 7.52 (t, J = 7.6 Hz, 4H), 7.42 ppm (t, J = 7.3 Hz, 2H). 13C NMR (101 MHz, DMSO,
o
25 C) δ = 150.0, 141.6, 140.2, 139.3, 134.9, 129.1, 128.0, 127.4, 127.3, 126.8 ppm. IR (KBr) v:
3015, 2988, 1678, 1490, 1370, 1078, 735, 728, 699 cm-1. HRMS-ESI (m/z) calcd for C28H20N2Na,
[M+Na]+ 407.1524, found 407.1525.
o
2,6-Bis(4-bromophenyl)pyrazine (4h): white solid, melting point: 156-158 C, 1H NMR (400
MHz, DMSO, 25 oC) δ = 9.26 (s, 2H), 8.22 (d, J = 8.0 Hz, 4H), 7.77 ppm (d, J = 8.0 Hz, 4H). 13
C
o
NMR (101 MHz, DMSO, 25 C) δ = 149.3, 140.5, 134.9, 132.0, 128.9, 123.9 ppm. IR (KBr) v:
2999, 2983, 1649, 1485, 1075, 899, 728, 697 cm-1. HRMS-ESI (m/z) calcd for C16H10Br2N2Na,
[M+Na]+ 410.9108, found 410.9110.
o
1
2,6-Bis(4-iodophenyl)pyrazine (4i): white solid, melting point: 165-167 C, H NMR (400 MHz,
DMSO, 25 oC) δ = 9.23 (s, 2H), 8.04 (d, J = 8.1 Hz, 4H), 7.93 ppm (d, J = 8.0 Hz, 4H). 13C NMR
o
(101 MHz, DMSO, 25 C) δ = 149.5, 140.5, 137.9, 135.3, 128.8, 97.4 ppm. IR (KBr) v: 3009,
2987, 1656, 1487, 1078, 737, 724, 698 cm-1. HRMS-ESI (m/z) calcd for C16H10I2N2Na, [M+Na]+
506.8831, found 506.8828.
Acknowledgements
The authors thank the China Postdoctoral Science Foundation (2017M612433). National Natural
Science Foundation of China for the financial support (21173089 and 21373093) is also
acknowledged.
1
Supporting Information: Supplementary data (copy of H and 13C NMR spectra of the products
13

ACCEPTED MANUSCRIPT
and X-ray crystallographic data for compound 3a. This material is available free of charge in the
website of the journal.) associated with this article can be found in the online version, at
http://dx.doi.org
References
(1) (a) J. Zhou, Multicatalyst System in Asymmetric Catalysis; John Wiley & Sons: New York, 2014, Chapter 9.
(b) L. Chen, Y. Du, X. –P. Zeng, T. –Da Shi, F. Zhou, J. Zhou, Org. Lett., 2015, 17, 1557−1560; (c) Y. –P. Zhu,
Q. –H. Gao, M. Lian, J. –J. Yuan, M. –C. Liu, Q. Zhao, Y. Yang, A. –X. Wu, Chem. Commun., 2011, 47, 12700–
12702; (d) J. –J. Cao, F. Zhou, J. Zhou, Angew. Chem., Int. Ed., 2010. 49, 4976–4980. (e) Z. Sun, H. Cao, Y. Xiao,
J. Sietsma, W. Jin, H. Agterhuis, Y. Yang, ACS Sus. Chem. Eng. 2017, 5, 21–40.
(2) Ma, X.; Yu, L.; Su, C.; Yang, Y.; Li, H.; Xu, Q. Adv. Synth. Catal. 2017, 359, 1649–1655.
(3) (a) Huang, W.; Liu, C.; Gu, Y. Adv. Synth. Catal. 2017, 359, 1811–1818. (b) Liu, C.; Huang, W.; Wang, M.;
Gu, Y. Adv. Synth. Catal. 2016, 358, 2260-2266. (c) Liu, C.; Zhou, L.; Huang, W.; Wang, M.; Gu, Y. Adv. Synth.
Catal. 2016, 358, 900–918. (d) Liu, C.; Shen, M.; Lai, B.; Taheri, A.; Gu, Y. ACS Comb. Sci. 2014, 16, 652−660.
(e) Liu, C.; Zhou, L.; Jiang, D.; Gu, Y. Asian J. Org. Chem. 2016, 5, 367–372. (f) Liu, C.; Taheri, A.; Lai, B.; Gu,
Y. Catal. Sci. Technol. 2015, 5, 234–245.
(4) (a) Blümlein, F. O. Chem. Ges. 1884, 17, 2578−2581. (b) Lewy, M. Ber. Dtsch. Chem. Ges. 1887, 20,
2576−2580.
(5) (a) Xue, W. –J.; Li, Q.; Zhu, Y. –P.; Wang, J. –G.; Wu, A. –X. Chem. Commun. 2012, 48, 3485–3487. (b) Gao,
Q. –H.; Fei, Z.; Zhu, Y. –P.; Lian, M.; Jia, F. –C.; Liu, M. –C.; She, N. –F.; Wu, A. –X. Tetrahedron 2013, 69,
22-28. (c) Xue, W. –J.; Zhang, W.; Zheng, K. –L.; Dai, Y.; Guo, Y. –Q.; Li, H. –Z.; Gao, F. –F.; Wu, A. –X. Asian
J. Org. Chem. 2013, 2, 638–641.
(6) CCDC number of 3a is 1516683.
(7) (a) Tamaddon, F.; Tafti, A. D.; Pooramini, F. Synthesis 2016, 48, 4295-4299. (b) Chen, Z.; Ye, D.; Xu, G.; Ye,
M.; Liu, L. Org. Biomol. Chem. 2013, 11, 6699–6702.
(8) Some selected examples for base catalyzed amination: (a) Song, J.; Zhang, Z. –J.; Chen, S. –S.; Fan, T.; Gong,
L. –Z. J. Am. Chem. Soc. 2018, 140, 3177–3180; (b) Devi, E. S.; Alanthadka, A.; Nagarajan, S.; Sridharan, V.;
Maheswari, C. U. Tetrahedron Lett. 2018, 59, 3485-3489; (c) Cai, L.; Qian, X.; Song, W.; Liu, T.; Tao, X.; Li,
W.; Xie, X. Tetrahedron 2014, 70, 4754-4759.
14

ACCEPTED MANUSCRIPT
(9) (a) Fales, H. M.; Blum, M. S.; Southwick, E. W.; Williams, D. L.; Roller, P. P.; Don, A. W. Tetrahedron 1998,
44, 5045–5050. (b) Wheeler, J. W.; Avery, J.; Olubajo, O.; Shamin, M. T.; Storm, C. B.; Duffield, R. M.
Tetrahedron 1982, 38, 1939–1948.
(10) (a) Maga, J. A.; Sizer, C. E. J. Agric. Food Chem. 1973, 21, 22–30. (b) Koehler, P. E.; Odell, G. V. J. Agric.
Food Chem. 1970, 18, 895–898. (c) Leunissen, M.; Davidson, V. J.; Kakuda, Y. J. Agric. Food Chem. 1996, 44,
2694–2699. (d) Wailzer, B.; Klocker, J.; Buchbauer, G.; Ecker, G.; Wolschann, P. J. Med. Chem. 2001, 44, 2805–
2813.
(11) (a) Mikuriya, M.; Yoshioka, D.; Handa, M. Coord. Chem. Rev., 2006, 250, 2194–2211. (b) Crutchley, R. J.
Angew. Chem., Int. Ed. 2005, 44, 6452–6454. (c) Caradoc-Davies, P. L.; Hanton, L. R.; Henderson, W. Dalton
Trans. 2001, 2749–2755. (d) Takamizawa, S.; Kohbara, M. Dalton Trans. 2007, 3640–3645.
(12) Cheeseman, G. W. H.; Werstiuk, E. S. G. Adv. Heter. Chem. 1972, 14, 99-209.
(13) Liu, R.; Wang, Y.; Weng, Y.; Yao, C.; Zhang, Y.; Zhu, G.; He, X.; Xu, K.; Tan, G. Synlett 2017, 28, 1083–
1086.
(14) Mo, K.; Park, J. H.; Kang, S. B.; Kim, Y.; Lee, Y. S.; Lee, J. W.; Keum, G. J.Mol. Catal.B: Enzymatic 2016,
123, 29–34.
(15) (a) Shan, Y.; Lai, M.; Li, R.; Wu, Z.; Zhao, M. Asian J. Org. Chem. 2017, 6, 1715–1718. (b) Lu, H.; Wang,
S.; Li, J.; Zou, D.; Wu, Y.; Wu, Y. Tetrahedron Lett. 2017, 58, 839–842.
(16) (a) Baleeva, N. S.; Levina, E. A.; Baranov, M. S. Chem. Heter. Comp. 2017, 53, 930–933. (b) Jadhav, S. A.;
Sarkate, A. P.; Shioorkar, M. G.; Shinde, D. B. Synth. Commun. 2017, 47, 1661–1667.
(17) Hoffert, K.; Durand, R. J.; Gauthier, S.; Guen, F. R. –l.; Achelle, S. Eur. J. Org. Chem. 2017, 523–529.
(18) (a) Li, W.; Tian, J.; Qi, X.; Wang, K.; Jin, Y.; Wang, B.; Zhang, Q. ChemistrySelect 2018, 3, 849–854. (b) Ju,
X.; Kong, L.; Zhao, J.; Bai, G. Electrochimica Acta 2017, 238, 36–48. (c) Echegaray, P. d.; Mancheño, M. J.;
Arrechea-Marcos, I.; Juárez, R.; López-Espejo, G.; Navarrete, J. T. L.; Ramos, M. M.; Seoane, C.; Ortiz, R. P.;
Segura, J. L. J. Org. Chem. 2016, 81, 11256-11267.
15