Tandem Synthesis of 2-Carboxybenzofurans via Sequential Cu-Catalyzed C-O Coupling and Mo(CO)6-Mediated Carbonylation Reactions

Article abstract of DOI:10.1021/acs.joc.0c01620

A modular tandem synthesis of 2-carboxybenzofurans from 2-gem-dibromovinylphenols has been established based on a sequence of Cu-catalyzed intramolecular C-O coupling and Mo(CO)6-mediated intermolecular carbonylation reactions. This protocol allowed one-step access to a broad variety of functionalized benzofuran-2-carboxylic acids, esters, and amides in good to excellent yields under Pd- and CO gas-free conditions.

Full text of DOI:10.1021/acs.joc.0c01620

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Article
Tandem Synthesis of 2-Carboxybenzofurans via Sequential Cu-
Catalyzed C-O Coupling and Mo(CO)6-Mediated Carbonylation reactions
Qinliang Mo, Nan Sun, Liqun Jin, Baoxiang Hu, Zhenlu Shen, and Xinquan Hu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01620 • Publication Date (Web): 06 Aug 2020
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Page 1 of 12
The Journal of Organic Chemistry
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Tandem Synthesis of 2-Carboxybenzofurans via Sequential
Cu-Catalyzed C-O Coupling and Mo(CO)6-Mediated
Carbonylation reactions
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Qinliang Mo, Nan Sun,* Liqun Jin, Baoxiang Hu, Zhenlu Shen, and Xinquan Hu*
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310032, P. R. China.
Supporting Information Placeholder
Br
O
[Cu]



Pd and CO-gas free
Substoichiometric amount of Mo(CO)6
Broad substrate scope
CO HNu
Mo( ) +
6
+
Br
R
R
O
Nu
OH
Nu
: OH, OR' or NHR'
58 examples, 48-95% yields
ABSTRACT: A modular tandem synthesis of 2-carboxybenzofurans from 2-gem-dibromovinylphenols has been established, based
on a sequence of Cu-catalyzed intramolecular C-O coupling and Mo(CO)6-mediated intermolecular carbonylation reactions. This
protocol allowed one-step access to a broad variety of functionalized benzofuran-2-carboxylic acids, esters, and amides in good to
excellent yields under Pd- and CO- gas free conditions.
INTRODUCTION
Scheme 1. Tandem synthesis of 2-carbonyl functionalized
heterocycles and carboncycles from gem-dihaloolefins
2-Carboxybenzofurans are an important class of carbonyl-
containing heterocyclic compounds featuring an acid, ester or
amide group at 2-position of benzofuran ring. These
compounds have extensive utilization in medicinal chemistry
for the achievement of bioactive molecules.1 For example,
Vilazodone, a derivative of benzofuran-2-carboxamide, is an
important antidepressant drug launched in 2011 for the
treatment of major depressive disorder.2 Moreover, they can
also serve as building blocks in the construction of liquid
crystal molecules.3 Currently, there are several approaches
available to access 2-carboxybenzofurans, including
(A) Previous works:
Alper
, 2008, 2011
Br
O
"Pd", P-Ligand
+
HNu
Br
R
R
CO (10 atm), 110 o
C
X
Nu
XH
X: NR, S
HNu: alcohols, phenol and amines
Florent
, 2009
Br
Br
O
Pd(PPh3)4
Ar-B(OH)
R
+
2
CO (12 bar), 85-110 o
C
R
N
H
Ar
NH2
Wu
, 2011
intramolecular
Knoevenagel
condensation
of
2-
Br
Br
O
Pd(OAc)2, PPh3
formylphenoxyacetates,4 Perkin rearrangement of 3-
halocoumarins,5 carbonylation of 2-metalated benzofurans6 or
intramolecular cyclization of 3-aryloxy-4-dimethylamino-3-
buten-2-ones.7 All of these methods are incapable to
concurrently construct benzofuran-2-carboxylic acids, esters
and amides in one-step, thus leading to inefficiency. Therefore,
development of a novel direct and modular protocol for 2-
carboxybenzofurans synthesis from easily available reagents is
highly desirable.
+
HNu
R1
CO (ballon), 90 o
C
R1
Nu
R2
HNu: alcohols and phenol
R2
(B) This work:
Br
Br
O
"Cu" / Mo(CO)6
+
HNu
R
R
O
Nu
OH
HNu: alcohols, H2O and amines
Mo(CO)6, HNu
[Cu]
Br
Lauters and Wang
O
gem-Dihaloolefins are valuable synthons in synthetic
chemistry owing to their high reactivity and easy availability
from inexpensive aldehydes by Ramirez-Corey olefination
reaction.8 In particularly, the two halo functional groups of
gem-dihaloolefins have different reactivity allowing them to
undergo potentially selective di-functionalization. Over the
past years, the research groups of Alper,9 Florent10 and Wu11
have independently reported efficient protocols for the
12 13
and
References
gem-dihaloolefins (Scheme 1, A). These reactions involved
two orthogonal reactions: a) Pd-catalyzed C-N, C-S or C-C
coupling to form the 2-bomo-functionalized heterocycles or
carboncycles; b) Pd-catalyzed carbonylation reactions. These
nice achievements inspired us to extend this orthogonal
tandem strategy for the synthesis of 2-carboxybenzofurans
from 2-gem-dibromovinylphenols. Previously, Eustache,12
Lauterns,13 and others groups14 developed a series of elegant 2-
synthesis
of
2-carbonyl
functionalized
indoles,
benzothiophenes and indenes from corresponding
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Page 2 of 12
substituted
benzofunans
syntheses
from
2-gem-
Table 1. Optimization of the reaction conditionsa
1
2
3
4
5
6
7
8
dibromovinylphenols based on Cu- or Pd-catalyzed tandem C-
O and C-C/C-X/C-H doubling couplings. Lautens15 and
Wang16 also successively disclosed that copper can efficiently
CuBr2 (5 mol%)
Br
Br
2,2'-Bpy (5 mol%)
Et3N (3.0 equiv.)
O
catalyze
2-gem-dibromovinylphenols
to
form
2-
Mo(CO)6
+
+
C2H5OH
(1.5 mL)
90 oC, 8 h, N2
O
OC2H5
bromobenzofurans. Therefore, we reckon that the exploration
of a carbonylation process, which can be compatible with this
Cu-catalyzed intramolecular C-O coupling reaction (Ullman
reaction), is crucial for this novel protocol. In recent years, the
idea of combing two different metal catalysts in a single vessel
to promote tandem reactions has been received much
attentions.17 Mo(CO)6 is an intriguing solid carbonyl source
with wide applications in palladium and non-palladium-
catalyzed carbonyl reactions.18 More recently, we found that
Mo(CO)6 can act as efficient and easy-to-handling carbonyl
source for Pd-catalyzed carbonylative Suzuki coupling
reaction.19 As a continuation, we herein reported a Cu-
catalyzed and Mo(CO)6-mediated carbonylative tandem
protocol for the synthesis of 2-carboxybenzofurans under Pd-
and CO-gas free conditions (Scheme 1, B).
(0.6 equiv.)
OH
1a
2a
entry
variations from the standard conditions
Yield (%)b
9
1
2
none
Without CuBr2
89(85)
22
12
9
87
86
82
88
83
16
7
10
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3
4
Without 2,2’-Bpy
Without Et3N
5
6
CuCl2 instead of CuBr2
Cu(OTf)2 instead of CuBr2
7
8
CuSO4 instead of CuBr2
CuI instead of CuBr2
9
1,10-Phen instead of 2,2’-Bpy
L-Proline instead of 2,2’-Bpy
PPh3 instead of 2,2’-Bpy
DIPEA instead of Et3N
Na2CO3 instead of Et3N
K3PO4 instead of Et3N
Pd2(dba)3 instead of CuBr2
10
11
12
13
14
15
RESULTS AND DISCUSSION
87
16
21
15
We began our study by choosing the reaction of 2-(2,2-
dibromovinyl)phenol (1a) and Mo(CO)6 (0.6 equiv. as solid
CO source) in ethanol (both as external O-nucleophile and
solvent) as a template reaction to investigate the viability of
the strategy. Table 1 summarized the results of partial
optimization experiments. These results showed that the
reaction can efficiently proceed under Pd-free conditions.
When the reaction was carried out in the presence of 5 mol%
CuBr2 as catalyst, 5 mol% 2, 2’-Bpy as ligand and 3.0 equiv.
of Et3N as base at 90 oC for 8 hours, the desired product ethyl
benzofuran-2-carboxylate (2a) can be isolated in 85% yield
(entry 1, Table 1). Copper catalyst, ligand and base were
essential for the reaction (entries 2-4, Table 1). Other copper
salts, such as CuCl2, Cu(OTf)2, CuSO4 or CuI, were also
reactive on this transformation and afforded 2a in comparable
yields (entries 5-8, Table 1). By changing 2,2’-Bpy with 1,10-
Phen, good yield (83%) of 2a can still be obtained (entry 9,
Table 1). However, other types of ligands such as L-proline
and PPh3 were innocent in this transformation (entries 10 and
11, Table 1). In addition, base also played a crucial role on the
transformation. Similar yield can be obtained with organic
DIPEA as base, while with Na2CO3 and K3PO4 as base, only
16% and 21% yields of 2a were resulted, respectively (en-tries
12-14, Table 1). Noteworthy, in these two cases, a large
amount of 2-bromobenzofuran were observed by GC-MS
analyses. Varying the amount of Mo(CO)6, CuBr2 and 2,2’-
Bpy as well as the reaction temperatures cannot further
improve the yield (See supporting information, Table S1).
Finally, a comparative experiment showed that Pd catalyst was
much less efficient in this transformation (entries 15, Table 1).
a
Reaction conditions: 1a (0.5 mmol), Mo(CO)6 (0.6 equiv.),
catalyst (5 mol%), ligand (5 mol%), base (3.0 equiv.), C2H5OH
(1.5 mL), 90 oC, purged with N2 and 8 h. 2,2’-Bpy = 2,2'-
bipyridine, 1,10-Phen =1,10-phenanthroline, DIPEA = N,N-
Diisopropylethylamine. b Yields were determined by GC analysis.
with diphenyl as internal standard and the datum in parentheses
was isolated yield.
carboxylates 2b, 2c and 2d in 81%, 85% and 87% yields. The
sterically hindered secondary alcohol (iso-propanol) and
tertiary alcohol (tert-butanol) was less active. Nevertheless,
after increasing the reaction temperature to 130 oC, their
corresponding esters 2e and 2f can also be obtained in 82%
and 48% yields, respectively. Interestingly, when ethylene
glycol was employed, only mono-alkoxycarbonylative product
2g was exclusively generated. Then, the reaction activities of
various
substituted
2-gem-dibromovinylphenols
were
investigated. The results showed that neither the electron
character nor the position of the substituents attached on the
phenyl ring had obvious effect on the reactivity. Under the
identified reaction conditions, most of the tested substrates
worked well and gave the desirable products 2h-2s in good to
excellent yields. A number of functional groups such as Me,
OMe, t-Bu, Ph, F, Cl, Br and COOCH3 on the phenyl ring
were well tolerated, and some of them could be utilized for
further derivatization. Unfortunately, the reaction of 4-nitro-2-
gem-dibromovinylphenol could not generate its corresponding
ester. Some complex reductive by-products was observed by
GC-MS. This phenomenon was similar to that in Pd-catalyzed
Mo(CO)6-mediated carbonylative reactions.20 In addition, 1-
(gem-dibromovinyl)-2-naphthalenol can also undergo this
tandem transformation to afford corresponding ester 2t in
excellent yields (88%). To our delight, the developed catalytic
system can be directly applied for the synthesis of benzofuran-
2-carboxylic acids in aqueous t-butanol solution (1:5).21 Under
the same reaction conditions, a number of functionalized
With the optimal reaction conditions in hand, the generality
of the newly developed carbonylative tandem synthesis was
explored and the results were summarized in Scheme 2. First,
the activities of alcohols were investigated. Under the
identified reaction conditions, the reactions of 2-(2,2-
dibromovinyl)phenol (1a) with methanol, n-propanol, or n-
butanol generated the corresponding benzofuran-2-
2
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The Journal of Organic Chemistry
benzofuran-2-carboxylic acids 3a-3n were obtained in
moderate to good yields. Noteworthy, 5-
thiomorpholine,
phenylpiperidine,
1-methylpiperazine,
pyrrolidine, di(n-propyl)amine,
piperidine,
4-
n-
1
2
3
4
5
6
7
8
9
(methoxycarbonyl)benzofuran-2-carboxylic acid 3k was a key
intermediate for a patented cysteine protease inhibitor.22 In the
patent, it required 4 reaction steps for its synthesis starting
from 5-formylsalicylaldehyde with a 12% overall yield.
However, in this work, only 2 reaction steps was needed from
much cheaper 5-methoxycarbonylformylsalicylaldehyde and
the overall yield of 3k was reached to about 40% (based on 5-
propylamine, and benzylamine, to provide the corresponding
amides 4b-4i in good to excellent yields. For the reaction of 1a
and aniline, N-phenylbenzofuran-2-carboxamide 4j was
obtained in relative lower yield (50%), which maybe ascribe to
its weaker nucleophilicity. Other than organic amines,
ammonia (25-28%) could be also employed as external N-
nucleophile, and primary amide 4k was obtained in good yield
(81%). Similar to the esters and acids, a wide range of
functionalized groups, such as Me, OMe, t-Bu, Ph, F, Cl, Br
and COOCH3, can tolerate, and the electron character and
position of these substituents attached on the phenyl ring had
no obvious effect on the outcome of the reaction. A number of
functionalized benzofuran-2-carboxylic amides 4l-4w were
obtained in good to excellent yields (73-93%). 1-(gem-
dibromovinyl)-2-naphthalenol can also provide the
corresponding amide 4x in 73% yield. To further demonstrate
the practical utility of our newly developed method, selected
carbonylative tandem syntheses were carried out on gram-
scale (5 mmol of substrates). Delightedly, equivalent results
were obtained (2p, 3f, and 4a).
methoxycarbonylformylsalicylaldehyde
optimization).
and
without
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Scheme 2. Synthesis of benzofuan-2-carboxylic acids and
esters from 2-(gem-dibromovinyl)phenolsa
Br
O
CuBr2, 2,2'-Bpy, Et3N
90 oC , 8 h , N2
R2-OH
+
R1
R1
Mo(CO)6
+
Br
OH
OR2
O
(alcohols or water)
2 (esters), 3 (acids)
1
O
H3C
O
O
OR2
OR2
O
H3C
OR2
O
O
(R2 = C2H5), 85%
(R2 = CH3), 81%
2a
2b
2c
2d
2e
2f
(R2 = C2H5), 87%
(R2 = H), 80%c
(R2 = C2H5), 88%
(R2 = H), 79%c
2h
2i
3b
3c
(R2 = n-C3H7), 85%
(R2 = n-C4H9), 87%
(R2 = iso-C3H7), 82%b
(R2 = tert-C4H9), 48%b
(R2 =CH2CH2OH), 53%
(R2 = H), 76%c
O
H3CO
O
OR2
O
Scheme 3. Synthesis of benzofuan-2-carboxylic amides
OR2
O
CH3
from 2-gem-dibromovinylphenolsa
(R2 = C2H5), 87%
(R2 = H), 75%c
(R2 = C2H5), 84%
(R2 = H), 73%c
2j
2k
3e
2g
3a
3d
O
tBu
Ph
F
R2
Br
O
O
O
OR2
R1
CuCl2, 1,10-Phen
R1
+
Mo(CO)6
NH
+
O
N
R2
R3
100 oC , 8 h , N2
Br
OH
OR2
OR2
R3
O
O
O
(R2 = C2H5), 83%
(R2 = H), 74%c, 77%d
(R2 = C2H5), 85%
(R2 = C2H5), 84%
(R2 = H), 73%c
primary, second amines
or NH3.H2O
2l
3f
2m
2n
3h
1
4 (amides)
3g (R2 = H), 59%c
O
O
H3C
O
N
O
N
Cl
Br
O
O
O
H3CO
O
R
O
O
H3C
OR2
O
(R2 = C2H5), 82%
(R2 = H), 80%c
OR2
O
OR2
O
N
N
N
N
N
O, 92%, 91%d
4a
R =
R =
R =
R =
(R2 = C2H5), 81%, 80%d
(R2 = H), 72%c
(R2 = C2H5), 80%
93%
92%
2o
3i
2p
3j
2q
4l
4m
O
O
(R2 = H), 65%c
3k
H3CO
O
O
N
, 64%
4b
4c
4d
S
N
Br
Cl
O
O
O
N
O
, 95%
O
OR2
OR2
CH3
O
O
OR2
O
O
, 76%
4n
85%
4o
4q
78%
O
OCH3
Br
O
tBu
Ph
Cl
(R2 = C2H5), 65%
(R2 = H), 51%c
(R2 = C2H5), 73%
(R2 = H), 66%c
(R2 = C2H5), 88%
(R2 = H), 84%c
O
N
2r
3l
2s
2t
Ph
, 86%
4e
R =
R =
3m
3n
O
O
N
4f
N
, 85%
a Reaction conditions: 1 (0.5 mmol), alcohols (1.5 mL), CuBr2 (5
mol %), 2,2'-Bpy (5 mol %), Mo(CO)6 (0.6 equiv.), Et3N (3.0
equiv.), 90 oC, purged with N2 and 8 h, isolated yields. b 90 oC for
c
O
O
4g
4p
4r
81%
90%
R = N(n-C3H7)2, 83%
F
4h
4i
R = NH(n-C3H7), 80%
R = NHBn, 87%
O
O
N
O
O
N
o
c
4 h and then 130 C for 4 h. water (0.25 mL), t-BuOH (1.25
4j
R = NHPh, 50%
mL). d 5 mmol scale.
b
4k
R = NH2, 81%
O
O
O
4s
85%
88%
O
Br
Cl
O
O
N
O
N
H3CO
Having successfully developed a novel procedure for the
synthesis of benzofuran-2-carboxylic acids and esters, this
method was extended to the synthesis of benzofuran-2-
O
O
N
O
Br
O
4t
4u
4v
87%
84%
77%
O
carboxylic
amides.
Initial
study
using
2-(2,2-
Br
O
O
N
dibromovinyl)phenol 1a and morpholine as reaction partners
showed that the same catalytic system only afforded the
desired benzofuran-2-yl(morpholino)methanone (4a) in 33%
yield. After re-optimizing the reaction conditions, it was
delighted that a high isolated yield (92%) of 4a can be
obtained by using 10 mol% CuCl2, 10 mol% 1,10-
phenanthroline, 0.6 equiv. Mo(CO)6, 4.0 equiv. morpholine,
O
N
O
OCH3
4w
O
O
4x
89%
73%
a Reaction conditions: 1 (0.5 mmol), amine (4.0 equiv.), CuCl2 (10
mol %), 1,10-Phen (10 mol %), Mo(CO)6 (0.6 equiv.), n-PrOH
o
b
(1.5 mL), 100 C, purged with N2 and 8 h, isolated yields. 25%-
28% aqueous NH3H2O was used. c in t-BuOH. d 5 mmol scale.
o
and in n-PrOH at 100 C for 8 h.23 Also, the scope of this
catalytic system for benzofuran-2-carboxylic amides synthesis
was explored and the results were illustrated in Scheme 3.
Under the identified reaction conditions, 2-(2,2-
dibromovinyl)phenol (1a) could smoothly react with a wide
range of primary and secondary amines, including
To further explore the detailed reaction pathway for this
tandem reaction, a few control experiments were designed
(eqns. 1-4, Scheme 4). Firstly, in absence of Mo(CO)6 and
under the identified reaction conditions (5 mol% of CuBr2, 5
3
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mol% of 2, 2’-Bpy, 3.0 equiv. of Et3N, and in ethanol at 90 oC
catalyst. Depending on the external nucleophiles (alcohols,
1
2
3
4
5
6
7
8
for 8h), the reaction of 1a provided 2-bromobenzofuran (5) in
nearly quantitative yield (eqn. 1 Scheme 4). This result proved
an efficient copper-catalyzed intramolecular cyclization of 2-
gem-dibromovinylthiophenol, which was consistent with the
reports of Lautens12 and Wang13. To probe the feasibility that
the reaction proceeded with 2-bromobenzofuran as
intermediate, the isolated 5 was then subjected to the
carbonylative transformations in the presence of Mo(CO)6.
Without Cu catalyst and ligand, the carbonylation products 2a,
3a, and 4a were obtained in 86%, 79% and 89% yields,
respectively (eqns. 2 and 3, Scheme 4). Furthermore, it was
found that gaseous CO greatly restrained this carbonylative
water or amines), benzofuran-2-carboxylic esters 2, acids 3 or
amides 4 were finally obtained as the desired products,
respectively.
Scheme 5. Plausible reaction pathway for 2-
carboxybenzofurans formation
Mo(CO)6
amine
9
Br
O
Mo(CO)6-n(amine)n
HNu
Cu, Ligand
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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60
Br
Br
O
O
Nu
OH
Nu: OR, OH, NH2, NHR, NR1R2 etc
transformation.
When
the
Mo(CO)6-mediated
1
5
2
3
4
(esters), (acids), (amides)
alkoxycarbonylation of 2-bromobenzofuran was performed in
an CO atmosphere (1 atm in autoclave), the yield of 2a was
dramatically dropped to 10% (eqn. 4, Scheme 4). Recently,
similar “Pd-free” carbonylation of (hetero)aryl halides by
Mo(CO)6 to form organic carboxylic acids and derivatives
have been also described in several reports.24 Although the
actual mechanism was unclear, it was generally suggested that
in the presence of a suitable exchange ligand Mo(CO)6 can in
situ transform to Mo complex (Mo(CO)6-nLn), which acted not
only as the carbonyl donor, but also as the catalyst for the
carbonylative transformation. In current carbonylation of 2-
bromobenzofuran, such ligand was postulated as Et3N or
morpholine. Since the activation of Mo(CO)6 by exchanging
ligand is crucial, it could be also understandable that gaseous
CONCLUSIONS
In summary, we have successfully developed a novel
versatile and modular carbonylative tandem protocol for the
synthesis
of
2-carboxybenzofurans
from
2-gem-
dibromovinylphenols via
a
sequential Cu-catalyzed
intramolecular C-O coupling and Mo(CO)6-mediated
carbonylation reactions. With water, alcohols or amines as
simple external nucleophiles and 0.6 equiv. of Mo(CO)6 as
carbonyl source and under the catalysis of copper salts, a wide
range of functionalized bezofuran-2-carboxylic acids, esters
and amides can be conveniently obtained in good to excellent
yields. In addition, the reaction avoided the use of precious
Pd-catalyst as well as took place under true CO-gas free
conditions. Therefore, the newly developed methodology was
safe and easy-to-operate, which will be attractive to organic
and medicinal chemists.
CO has
a
detrimental effect on this carbonylative
transformation.
Scheme 4. Control experiments
Br
Br
CuBr2 (5 mol %)
2,2'-Bpy (5 mol %)
Et3N , 90 oC , 8 h , N2
Without Mo(CO)6
EXPERIMENTAL SECTION
eqn. 1
Br
+
C2H5OH
O
OH
1a
All chemicals and organic solvents were commercially
available and directly used without further purification. De-
ionized water was used in the synthesis of benzofuran-2-
carboxylic acids. All proton and 13C nuclear magnetic
resonance (NMR) spectra were recorded on a Bruker
AVANCE III 500 MHz or a Bruker Magnet System 400/600
5
(97%)
O
Mo(CO)6 (0.6 equiv.)
eqn. 2
Br
+ HNu
Et3N , 90 oC , 8 h , N2
O
O
Nu
Without Cu and Ligand
5
2a
3a
(86%), (79%)
HNu: C2H5OH or H2O
O
N
MHz
spectrometer
in
deuterated
solvents
with
Mo(CO)6 (0.6 equiv.)
100 oC , 8 h , N2
eqn. 3
Br
+
O
O
NH
tetramethylsilane (TMS) as internal standard. GC-MS analyses
were performed on a Thermo Scientific TRACE GC Ultra gas
chromatograph using a SHIMADZU SH-Rtx-5MS (30 m x
0.25 mm ID, 0.25 μm) coupled with a Thermo Scientific ISQ
single quadrupole mass spectrometer in EI mode (70 eV).
High resolution mass spectra were recorded in the EI mode on
Waters GCT Premier TOF mass spectrometer with an Agilent
6890 gas chromatography using a DB-XLB column (30 m x
0.25 mm (i.d.), 0.25 μ) or ESI mode on an Agilent 6210
LC/TOF mass spectrometer. Melting points (uncorrected)
were determined on a BUCHI M-565 apparatus. Gas
chromatography (GC) analyses were performed on Shimadzu
GC-2010 Plus instrument with FID detector using a Shimadzu
SH-Rtx-5 capillary column (30 m x 0.32 mm (i.d.), 0.25 μm).
Flash column chromatography was performed on silica gel
(200-300 mesh) with petroleum ether/ethyl acetate as eluent.
O
Without Cu and Ligand
O
4.0 equiv.
4a
(89%)
5
Mo(CO)6 (0.6 equiv.)
CO (1 atm)
O
eqn. 4
Br + C2H5OH
Et3N , 90 oC , 8 h , N2
OC2H5
O
O
5
2a
(10%)
Based on above experimental results and pervious reports, a
two-step mechanistic pathway for this carbonylative tandem
synthesis
of
2-carboxybenzofurans
from
2-gem-
dibromovinylphenols was proposed (Scheme 5). 2-gem-
dibromovinylphenols were firstly converted to 2-
bromobenzofuran intermediates through a copper-catalyzed
intramolecular Ullman cross-coupling, which then underwent
a carbonylative transformation by Mo(CO)6. Prior to the
carbonylations, Mo(CO)6 was in situ activated by amines
(Et3N, morpholine, or other amines) to form Mo complex
[Mo(CO)6-n(amine)n] which acted as both carbonyl donor and
The substrates 2-gem-dibromovinylphenols
1
were
synthesized from corresponding salicylaldehydes according to
the literature procedure.25
4
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The Journal of Organic Chemistry
1. General procedure for the synthesis of benzofuran-2-
carboxylic esters (2a-2t) and analytic data
(125 MHz, CDCl3): δ 159.4, 155.8, 146.2, 127.6, 127.2, 123.8,
122.9, 113.7, 112.5, 69.4, 22.0; HRMS(EI-TOF) m/z: [M+]
1
2
3
4
5
6
7
8
9
calculated for C12H12O3 204.0786, found 204.0790.
To a 15 mL of Young tube, 2-gem-dibromovinylphenols (0.5
mmol, 1.0 equiv.), CuBr2 (0.025 mmol, 5 mol%), 2,2’-Bpy
(0.025 mmol, 5 mol%), Mo(CO)6 (0.3 mmol, 0.6 equiv.), NEt3
(1.5 mmol, 3.0 equiv.), alcohols (1.5 mL) were successively
added. Then the tube was purged with N2, capped and stirred
tert-Butyl benzofuran-2-carboxylate 2f (CAS No.: 1447608-
46-9): The title compound was purified by flash
chromatography (PE/EA = 50/1) to afford the product as a
1
light yellow oil (52.2 mg, 48% yield); H NMR (600 MHz,
o
at 90 C (oil bath) for 8 h. After the reaction finished, the
CDCl3): δ 7.65 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H),
7.46-7.38 (m, 2H), 7.28 (t, J = 7.6 Hz, 1H), 1.63 (s, 9H);
13C{1H} NMR (150 MHz, CDCl3): δ 159.0, 155.7, 147.0,
127.3, 127.2, 123.7, 122.8, 113.1, 112.4, 82.7, 28.4;
HRMS(EI-TOF) m/z: [M+] calculated for C13H14O3 218.0943,
found 218.0942.
reaction mixture was concentrated under vacuum. The resulted
residual was purified by chromatography on silica gel eluting
with petroleum ether/ethyl acetate to afford the desired esters.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl benzofuran-2-carboxylate 2a (CAS No.: 3199-61-9):
The title compound was purified by flash chromatography
(PE/EA = 30/1) to afford the product as a white solid (80.6 mg,
2-Hydroxyethyl benzofuran-2-carboxylate 2g: The title
compound was purified by flash chromatography (PE/EA =
50/1) to afford the product as a white solid (54.6 mg, 53%
yield), M.p.: 69 oC; 1H NMR (500 MHz, CDCl3): δ 7.68 (d, J =
7.6 Hz, 1H), 7.62-7.55 (m, 2H), 7.46 (t, J = 7.9 Hz, 1H), 7.31
(t, J = 7.5 Hz, 1H), 4.54-4.50 (m, 2H), 3.99 (t, J = 4.6 Hz, 2H),
2.26-2.05 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 159.9,
156.0, 145.3, 128.0, 127.0, 124.0, 123.0, 114.6, 112.5, 67.1,
61.3; HRMS(EI-TOF) m/z: [M+] calculated for C11H10O4
206.0579, found 206.0581.
o
o
1
85% yield). M.p.: 30 C (lit.26 m.p.: 30 C); H NMR (500
MHz, CDCl3): δ 7.66 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 8.4 Hz,
1H), 7.52 (s, 1H), 7.45-7.40 (m, 1H), 7.29 (t, J = 7.9 Hz, 1H),
4.43 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (125 MHz, CDCl3): δ 159.8, 155.9, 145.9, 127.7, 127.1,
123.9, 122.9, 113.9, 112.5, 61.7, 14.5; HRMS(EI-TOF) m/z:
[M+] calculated for C11H10O3 190.0630, found 190.0638.
Methyl benzofuran-2-carboxylate 2b (CAS No.: 1646-27-1):
The title compound was purified by flash chromatography
(PE/EA = 30/1) to afford the product as a light yellow oil
(71.4 mg, 81% yield); 1H NMR (500 MHz, CDCl3): δ 7.67 (d,
J = 7.9 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.52 (s, 1H), 7.46-
7.42 (m, 1H), 7.30 (t, J = 7.9 Hz, 1H), 3.97 (s, 3H); 13C{1H}
NMR (125 MHz, CDCl3): δ 160.0, 155.7, 145.4, 127.6, 126.9,
123.8, 122.8, 114.0, 112.3, 52.3; HRMS(EI-TOF) m/z: [M+]
calculated for C10H8O3 176.0473, found 176.0474.
Ethyl 5-methylbenzofuran-2-carboxylate 2h (CAS No.:
53715-88-1): The title compound was purified by flash
chromatography (PE/EA = 30/1) to afford the product as a
o
white solid (88.8 mg, 87% yield). M.p.: 40 C (lit.27 m.p.: 41-
o
1
42 C); H NMR (500 MHz, CDCl3): δ 7.49-7.40 (m, 3H),
7.24 (d, J = 8.5 Hz, 1H), 4.43 (q, J = 7.2 Hz, 2H), 2.44 (s, 3H),
1.42 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ
159.8, 154.3, 145.9, 133.5, 129.2, 127.2, 122.4, 113.7, 112.0,
61.5, 21.4, 14.4; HRMS(EI-TOF) m/z: [M+] calculated for
C12H12O3 204.0786, found 204.0792.
Propyl benzofuran-2-carboxylate 2c (CAS No.: 91963-00-7):
The title compound was purified by flash chromatography
(PE/EA = 30/1) to afford the product as a white solid (86.7 mg,
o
1
85% yield). M.p.: 37 C; H NMR (500 MHz, CDCl3): δ 7.66
(d, J = 7.8 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.52 (s, 1H),
7.45-7.40 (m, 1H), 7.29 (t, J = 7.8 Hz, 1H), 4.34 (t, J = 6.8 Hz,
2H), 1.86-1.77 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H); 13C{1H}
NMR (125 MHz, CDCl3): δ 159.7, 155.7, 145.7, 127.5, 127.0,
123.7, 122.7, 113.7, 112.3, 67.0, 22.1, 10.3; HRMS(EI-TOF)
m/z: [M+] calculated for C12H12O3 204.0786, found 204.0789.
Ethyl 6-methylbenzofuran-2-carboxylate 2i (CAS No.:
53715-89-2): The title compound was purified by flash
chromatography (PE/EA = 30/1) to afford the product as a
o
1
white solid (89.7 mg, 88% yield). M.p.: 44 C; H NMR (500
MHz, CDCl3): δ 7.53 (d, J = 8.1 Hz, 1H), 7.48 (s, 1H), 7.37 (s,
1H), 7.53 (d, J = 7.4 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 2.49 (s,
3H), 1.42 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz,
CDCl3): δ 159.9, 156.4, 145.3, 138.5, 125.6, 124.6, 122.3,
113.9, 112.5, 61.5, 22.1, 14.5; HRMS(EI-TOF) m/z: [M+]
calculated for C12H12O3 204.0786, found 204.0787.
Butyl benzofuran-2-carboxylate 2d (CAS No.: 1025760-20-6):
The title compound was purified by flash chromatography
(PE/EA = 30/1) to afford the product as a light yellow oil
(94.8 mg, 87% yield); 1H NMR (500 MHz, CDCl3): δ 7.66 (d,
J = 7.9 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.50 (s, 1H), 7.45-
7.40 (m, 1H), 7.28 (t, J = 7.9 Hz, 1H), 4.37 (t, J = 6.7 Hz, 2H),
1.80-1.73 (m, 2H), 1.51-1.43 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H);
13C{1H} NMR (125 MHz, CDCl3): δ 159.7, 155.7, 145.7,
127.5, 127.0, 123.7, 122.8, 113.7, 112.4, 65.3, 30.7, 19.1, 13.7;
HRMS(EI-TOF) m/z: [M+] calculated for C13H14O3 218.0943,
found 218.0939.
Ethyl 7-methylbenzofuran-2-carboxylate 2j (CAS No.:
53715-90-5): The title compound was purified by flash
chromatography (PE/EA = 30/1) to afford the product as a
yellow oil (88.7 mg, 87% yield); 1H NMR (500 MHz, CDCl3):
δ 7.53-7.46 (m, 2H), 7.25-7.17 (m, 2H), 4.44 (q, J = 7.2 Hz,
2H), 2.58 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125
MHz, CDCl3): δ 159.9, 155.1, 145.7, 128.4, 126.7, 123.9,
122.8, 120.3, 114.2, 61.5, 15.3, 14.5; HRMS(EI-TOF) m/z:
[M+] calculated for C12H12O3 204.0786, found 204.0791.
iso-Propyl benzofuran-2-carboxylate 2e (CAS No.: 13257-
16-4): The title compound was purified by flash
chromatography (PE/EA = 40/1) to afford the product as a
Ethyl 5-methoxybenzofuran-2-carboxylate 2k (CAS No.:
50551-56-9): The title compound was purified by flash
chromatography (PE/EA = 20/1) to afford the product as a
1
light yellow oil (83.9 mg, 82% yield); H NMR (500 MHz,
o
CDCl3): δ 7.68 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H),
7.52 (s, 1H), 7.45 (t, J = 8.4 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H),
5.38-5.29 (m, 1H), 1.42 (d, J = 6.3 Hz, 6H); 13C{1H} NMR
white solid (92.2 mg, 84% yield). M.p.: 56 C (lit.28 m.p.: 62
1
oC); H NMR (500 MHz, CDCl3): δ 7.52-7.42 (m, 2H), 7.10-
7.03 (m, 2H), 4.44 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 1.42 (t, J
5
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Page 6 of 12
= 7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 159.7,
156.7, 151.0, 146.5, 127.6, 117.6, 114.0, 113.1, 103.9, 61.6,
56.0, 14.5; HRMS(EI-TOF) m/z: [M+] calculated for C12H12O4
220.0736, found 220.0746.
white solid (99.2 mg, 80% yield). M.p.: 93.5 C; H NMR
(400 MHz, CDCl3): δ 8.43 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H),
7.62 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H), 4.45 (q, J = 7.2 Hz, 2H),
3.95 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 166.8, 159.3, 158.1, 147.2, 129.1, 127.1,
126.4, 125.6, 114.1, 112.4, 61.9, 52.5, 14.5; HRMS(EI-TOF)
m/z: [M+] calculated for C13H12O5 248.0685, found 248.0692.
o
1
1
2
3
4
5
6
7
8
Ethyl 5-(tert-butyl)benzofuran-2-carboxylate 2l (CAS No.:
2097262-18-3): The title compound was purified by flash
chromatography (PE/EA = 30/1) to afford the product as a
1
light yellow oil (102.1 mg, 83% yield); H NMR (500 MHz,
Ethyl 7-bromo-5-chlorobenzofuran-2-carboxylate 2r (CAS
No.: 1823331-46-9): The title compound was purified by flash
chromatography (PE/EA = 30/1) to afford the product as a
CDCl3): δ 7.64 (s, 1H), 7.54-7.44 (m, 3H), 4.44 (q, J = 7.2 Hz,
2H), 1.42 (t, J = 7.2 Hz, 3H), 1.37 (s, 9H); 13C{1H} NMR (125
MHz, CDCl3): δ 159.8, 154.2, 147.0, 145.9, 126.8, 126.0,
118.7, 114.2, 111.8, 61.5, 34.9, 31.8, 14.4; HRMS(EI-TOF)
m/z: [M+] calculated for C15H18O3 246.1256, found 246.1248.
9
o
1
white solid (98.4 mg, 65% yield). M.p.: 110.5 C; H NMR
(500 MHz, CDCl3): δ 7.61 (s, 2H), 7.50 (s, 1H), 4.45 (q, J =
7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz,
CDCl3): δ 158.8, 151.7, 147.8, 130.5, 130.0, 128.9, 121.5,
113.7, 105.6, 62.1, 14.4; HRMS(EI-TOF) m/z: [M+] calculated
for C11H8BrClO3 301.9345, found 301.9352.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl 5-phenylbenzofuran-2-carboxylate 2m (CAS No.:
59962-90-2): The title compound was purified by flash
chromatography (PE/EA = 30/1) to afford the product as a
o
1
white solid (113.1 mg, 85% yield). M.p.: 78.5 C; H NMR
(500 MHz, CDCl3): δ 7.85 (s, 1H), 7.70-7.63 (m, 2H), 7.61 (d,
J = 7.1 Hz, 2H), 7.57 (s, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.37 (t,
J = 7.4 Hz, 1H), 4.47 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.1 Hz,
3H); 13C{1H} NMR (125 MHz, CDCl3): δ 159.7, 155.4, 146.5,
141.1, 137.7, 129.0, 128.9, 127.7, 127.6, 127.4, 121.2, 114.1,
112.7, 66.7, 14.5; HRMS(EI-TOF) m/z: [M+] calculated for
C17H14O3 266.0943, found 266.0937.
Ethyl 5-bromo-7-methoxybenzofuran-2-carboxylate 2s (CAS
No.: 150612-67-2): The title compound was purified by flash
chromatography (PE/EA = 30/1) to afford the product as a
white solid (109.1 mg, 73% yield). M.p.: 93 oC; 1H NMR (600
MHz, CDCl3): δ 7.44 (s, 1H), 7.40 (s, 1H), 7.02 (s, 1H), 4.44
(q, J = 7.1 Hz, 2H), 4.00 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (150 MHz, CDCl3): δ 159.1, 147.0, 146.4,
144.4, 129.8, 117.2, 117.0, 113.3, 112.7, 61.8, 56.5, 14.5;
HRMS(EI-TOF) m/z: [M+] calculated for C12H11BrO4
297.9841, found 297.9837.
Ethyl 5-fluorobenzofuran-2-carboxylate 2n (CAS No.:
93849-31-1): The title compound was purified by flash
chromatography (PE/EA = 30/1) to afford the product as a
Ethyl naphtho[2,1-b]furan-2-carboxylate 2t (CAS No.:
32730-03-3): The title compound was purified by flash
chromatography (PE/EA = 30/1) to afford the product as a
o
1
white solid (87.4 mg, 84% yield). M.p.: 59 C; H NMR (500
MHz, CDCl3): δ 7.55-7.50 (m, 1H), 7.48 (s, 1H), 7.34-7.29 (m,
1H), 7.20-7.12 (m, 1H), 4.44 (q, J = 7.2 Hz, 2H), 1.42 (t, J =
7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 159.5 (d, J
= 239.1 Hz), 159.3, 151.9, 147.3, 127.7 (d, J = 10.9 Hz), 115.8
(d, J = 26.6 Hz), 113.6 (d, J = 4.5 Hz), 113.3 (d, J = 9.6 Hz),
107.8 (d, J = 24.7 Hz), 61.7, 14.3; HRMS(EI-TOF) m/z: [M+]
calculated for C11H9FO3 208.0536, found 208.0540.
o
yellow solid (105.4 mg, 88% yield). M.p.: 96.5 C (lit.31 m.p.:
84-86 oC); 1H NMR (500 MHz, CDCl3): δ 8.17 (d, J = 8.1 Hz,
1H), 8.02 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 9.0 Hz,
1H), 7.71 (d, J = 9.0 Hz, 1H), 7.68-7.62 (m, 1H), 7.58-7.52 (m,
1H), 4.49 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (125 MHz, CDCl3): δ 159.7, 154.1, 145.2, 130.6, 129.2,
129.1, 128.2, 127.4, 125.5, 123.5, 122.9, 112.9, 61.6, 14.6;
HRMS(EI-TOF) m/z: [M+] calculated for C15H12O3 240.0786,
found 240.0791.
Ethyl 5-chlorobenzofuran-2-carboxylate 2o (CAS No.:
59962-89-9): The title compound was purified by flash
chromatography (PE/EA = 30/1) to afford the product as a
white solid (92.0 mg, 82% yield). M.p.: 49 oC (lit.29 m.p.: 49.5
2. General procedure for the synthesis of benzofuran-2-
carboxylic acids (3a-3n) and analytic data
1
oC); H NMR (500 MHz, CDCl3): δ 7.65 (d, J = 2.1 Hz, 1H),
7.51 (d, J = 8.9 Hz, 1H), 7.45 (s, 1H), 7.39 (d, J = 8.9 Hz, 1H),
4.44 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H); 13C{1H}
NMR (125 MHz, CDCl3): δ 159.3, 154.1, 147.1, 129.6, 128.4,
128.0, 122.3, 113.6, 113.1, 61.9, 14.4; HRMS(EI-TOF) m/z:
[M+] calculated for C11H9ClO3 224.0240, found 224.0244.
To a 15 mL of Young tube, 2-gem-dibromovinylphenols (0.5
mmol, 1.0 equiv.), CuBr2 (0.025 mmol, 5 mol%), 2,2’-Bpy
(0.025 mmol, 5 mol%), Mo(CO)6 (0.3 mmol, 0.6 equiv.), NEt3
(1.5 mmol, 3.0 equiv.), H2O (0.25 mL), t-BuOH (1.25 mL)
were successively added. Then the tube was purged with N2,
capped and stirred at 90 oC (oil bath) for 8 h. After the reaction
finished, the reaction mixture was poured over water, acidified
with HCl (1 mol/L) and then extracted with ethyl acetate (5
mL × 3). The extractions were combined, dried over
anhydrous Na2SO4, filtrated and concentrated under vacuum.
The resulted residual was purified by chromatography on
silica gel eluenting with petroleum ether/ethyl acetate to afford
the desired acids.
Ethyl 5-bromobenzofuran-2-carboxylate 2p (CAS No.:
84102-69-2): The title compound was purified by flash
chromatography (PE/EA = 30/1) to afford the product as a
o
light yellow solid (108.9 mg, 81% yield). M.p.: 58 C (lit.30
o
1
m.p.: 60-62 C); H NMR (500 MHz, CDCl3): δ 7.81 (s, 1H),
7.55-7.42 (m, 3H), 4.44 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (125 MHz, CDCl3): δ 159.3, 154.5, 147.0,
130.7, 129.0, 125.5, 117.0, 114.0, 113.0, 61.9, 14.4;
HRMS(EI-TOF) m/z: [M+] calculated for C11H9BrO3 267.9735,
found 267.9742.
Benzofuran-2-carboxylic acid 3a (CAS No.: 496-41-3): The
title compound was purified by flash chromatography (PE/EA
= 5/1, 5‰ AcOH) to afford the product as a white solid (61.2
2-Ethyl 5-methyl benzofuran-2,5-dicarboxylate 2q (CAS No.:
1652570-59-6): The title compound was purified by flash
chromatography (PE/EA = 20/1) to afford the product as a
o
o
1
mg, 76% yield). M.p.: 192 C (lit.27 m.p.: 193.0-193.5 C); H
NMR (500 MHz, DMSO-d6): δ 13.90-13.10 (br, 1H), 7.79 (d,
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o
J = 7.8 Hz, 1H), 7.73-7.64 (m, 2H), 7.50 (t, J = 7.8 Hz, 1H),
product as a white solid (70.7 mg, 59% yield). M.p.: 221 C;
1H NMR (600 MHz, DMSO-d6): δ 14.00-12.80 (br, 1H), 8.04
(s, 1H), 7.79 (s, 1H), 7.72-7.68 (m, 3H), 7.49 (t, J = 7.7 Hz,
2H), 7.39 (t, J = 7.4 Hz, 1H); 13C{1H} NMR (150 MHz,
DMSO-d6): δ 156.0, 154.6, 146.8, 140.0, 136.4, 128.9, 127.5,
127.3, 127.0, 126.8, 120.9, 113.7, 112.4; HRMS(ESI--TOF)
7.35 (t, J = 7.5 Hz, 1H); 13C{1H} NMR (125 MHz, DMSO-d6):
δ 160.1, 155.0, 146.2, 127.6, 126.9, 123.8, 123.1, 113.5, 112.1;
1
2
3
4
5
6
7
8
-
HRMS(ESI--TOF) m/z: [M-H]- calculated for C9H5O3
161.0244, found 161.0247.
5-Methylbenzofuran-2-carboxylic acid 3b (CAS No.: 10242-
09-8): The title compound was purified by flash
chromatography (PE/EA = 5/1, 5‰ AcOH) to afford the
m/z: [M-H]- calculated for C15H9O3 237.0557, found 237.0558.
-
5-Fluorobenzofuran-2-carboxylic acid 3h (CAS No.: 89197-
62-6): The title compound was purified by flash
chromatography (PE/EA = 5/1, 5‰ AcOH) to afford the
o
product as a white solid (70.0 mg, 80% yield). M.p.: 239 C
o
1
(lit.24 m.p.: 237-238 C); H NMR (500 MHz, DMSO-d6): δ
14.19-12.70 (br, 1H), 7.62-7.52 (m, 3H), 7.31 (d, J = 8.7 Hz,
1H), 2.41 (s, 3H); 13C{1H} NMR (125 MHz, DMSO-d6): δ
160.1, 153.5, 146.2, 132.9, 128.9, 126.9, 122.4, 113.2, 111.6,
9
o
product as a white solid (65.4 mg, 73% yield). M.p.: 255 C;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H NMR (500 MHz, DMSO-d6): δ 14.20-13.30 (br, 1H), 7.78-
7.73 (m, 1H), 7.64 (s, 1H), 7.62-7.55 (m, 1H), 7.40-7.33 (m,
1H); 13C{1H} NMR (125 MHz, DMSO-d6): δ 159.8, 158.8 (d,
J = 236.1Hz), 151.4, 147.9, 127.8 (d, J = 11.3 Hz), 115.6 (d, J
= 26.6 Hz), 113.55 (d, J = 7.7 Hz), 113.50 (d, J = 2.2 Hz),
108.2 (d, J = 24.9 Hz); HRMS(ESI--TOF) m/z: [M-H]-
-
20.8; HRMS (ESI--TOF) m/z: [M-H]- calculated for C10H7O3
175.0401, found 175.0405.
6-Methylbenzofuran-2-carboxylic acid 3c (CAS No.: 50779-
65-2): The title compound was purified by flash
chromatography (PE/EA = 5/1, 5‰ AcOH) to afford the
-
calculated for C9H4FO3 179.0150, found 179.0153.
o
product as a white solid (69.3 mg, 79% yield). m.p.: 202 C;
5-Chlorobenzofuran-2-carboxylic acid 3i (CAS No.: 10242-
10-1): The title compound was purified by flash
chromatography (PE/EA = 5/1, 5‰ AcOH) to afford the
product as a light yellow solid (79.9 mg, 80% yield). M.p.:
1H NMR (600 MHz, DMSO-d6): δ 14.03-12.67 (br, 1H), 7.65
(d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.50 (s, 1H), 7.18 (d, J = 8.0
Hz, 1H), 2.45 (s, 3H); 13C{1H} NMR (150 MHz, DMSO-d6): δ
160.2, 155.5, 145.7, 137.9, 125.4, 124.4, 122.5, 113.5, 111.9,
258 C (lit.33 m.p.: 259-262 C); H NMR (400 MHz, DMSO-
d6): δ 14.03-13.46 (br, 1H), 7.87 (s, 1H), 7.76 (d, J = 8.9 Hz,
1H), 7.63 (s, 1H), 7.53 (d, J = 8.9 Hz, 1H); 13C{1H} NMR
(100 MHz, DMSO-d6): δ 159.8, 153.5, 147.6, 128.5, 128.2,
127.6, 122.4, 113.9, 113.0; HRMS(ESI--TOF) m/z: [M-H]-
o
o
1
-
21.4; HRMS(ESI--TOF) m/z: [M-H]- calculated for C10H7O3
175.0401, found 175.0404.
7-Methylbenzofuran-2-carboxylic acid 3d (CAS No.: 17349-
64-3): The title compound was purified by flash
chromatography (PE/EA = 5/1, 5‰ AcOH) to afford the
-
calculated for C9H4ClO3 194.9854, found 194.9859.
o
product as a white solid (66.1 mg, 75% yield). M.p.: 217 C;
5-Bromobenzofuran-2-carboxylic acid 3j (CAS No.: 10242-
11-2): The title compound was purified by flash
chromatography (PE/EA = 5/1, 5‰ AcOH) to afford the
product as a light yellow solid (86.0 mg, 72% yield). M.p.:
1H NMR (500 MHz, DMSO-d6): δ 14.76-12.16 (br, 1H), 7.65
(s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.25
(t, J = 7.5 Hz, 1H), 2.50 (s, 3H); 13C{1H} NMR (125 MHz,
DMSO-d6): δ 160.2, 154.1, 145.9, 128.1, 126.4, 123.8, 121.8,
120.5, 113.8, 14.7; HRMS(ESI--TOF) m/z: [M-H]- calculated
o
1
258 C; H NMR (400 MHz, DMSO-d6): δ 14.12-13.40 (br,
1H), 8.01 (d, J = 1.9 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.67-
7.59 (m, 2H); 13C{1H} NMR (100 MHz, DMSO-d6): δ 159.8,
153.5, 147.6, 128.5, 128.2, 127.6, 122.4, 113.9, 113.0;
-
for C10H7O3 175.0401, found 175.0403.
5-Methoxybenzofuran-2-carboxylic acid 3e (CAS No.:
10242-08-7): The title compound was purified by flash
chromatography (PE/EA = 5/1, 5‰ AcOH) to afford the
HRMS(ESI--TOF) m/z: [M-H]- calculated for C9H4BrO3
-
238.9349, found 238.9348.
o
product as a white solid (70.3 mg, 73% yield). M.p.: 214 C
5-(Methoxycarbonyl)benzofuran-2-carboxylic acid 3k (CAS
No.: 251457-26-8): The title compound was purified by flash
chromatography (PE/EA = 5/1, 5‰ AcOH) to afford the
o
1
(lit.32 m.p.: 215-217 C); H NMR (500 MHz, DMSO-d6): δ
13.76-13.16 (br, 1H), 7.64-7.56 (m, 2H), 7.25 (s, 1H), 7.09 (d,
J = 9.0 Hz, 1H), 3.80 (s, 3H); 13C{1H} NMR (125 MHz,
DMSO-d6): δ 160.0, 156.1, 150.0, 146.7, 127.5, 117.2, 113.6,
112.8, 104.2, 55.6; HRMS(ESI--TOF) m/z: [M-H]- calculated
o
product as a white solid (71.2 mg, 65% yield). M.p.: 209 C;
1H NMR (500 MHz, DMSO-d6): δ 14.05-13.45 (br, 1H), 8.46
(s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.86-7.75 (m, 2H), 3.89 (s,
3H); 13C{1H} NMR (125 MHz, DMSO-d6): δ 166.0, 159.7,
157.3, 147.6, 128.3, 127.2, 125.6, 125.3, 114.0, 112.5, 52.3;
-
for C10H7O4 191.0350, found 191.0353.
5-(tert-Butyl)benzofuran-2-carboxylic acid 3f (CAS No.:
1210226-98-4): The title compound was purified by flash
chromatography (PE/EA = 5/1, 5‰ AcOH) to afford the
product as a light yellow solid (81.1 mg, 74% yield). M.p.:
HRMS(ESI--TOF) m/z: [M-H]- calculated for C11H7O5
-
219.0299, found 219.0303.
7-Bromo-5-chlorobenzofuran-2-carboxylic acid 3l (CAS No.:
190775-65-6): The title compound was purified by flash
chromatography (PE/EA = 5/1, 5‰ AcOH) to afford the
o
1
175 C; H NMR (500 MHz, DMSO-d6): δ 13.77-13.20 (br,
1H), 7.74 (s, 1H), 7.64-7.55 (m, 3H), 1.33 (s, 9H); 13C{1H}
NMR (125 MHz, DMSO-d6): δ 160.2, 153.3, 146.4, 146.3,
126.6, 125.7, 118.7, 113.8, 111.4, 34.5, 31.4; HRMS(ESI--
o
product as a white solid (69.7 mg, 51% yield). M.p.: 259 C;
1H NMR (600 MHz, DMSO-d6): δ 14.92-12.49 (br, 1H), 7.90
(s, 1H), 7.87 (s, 1H), 7.72 (s, 1H); 13C{1H} NMR (150 MHz,
DMSO-d6): δ 159.4, 150.8, 148.2, 129.5, 129.1, 128.7, 122.1,
113.6, 114.0, 104.7; HRMS(ESI--TOF) m/z: [M-H]- calculated
-
TOF) m/z: [M-H]- calculated for C13H13O3 217.0870, found
217.0878.
5-Phenylbenzofuran-2-carboxylic acid 3g (CAS No.: 59962-
93-5): The title compound was purified by flash
chromatography (PE/EA = 5/1, 5‰ AcOH) to afford the
-
for C9H3BrClO3 272.8960, found 272.8967.
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5-Bromo-7-methoxybenzofuran-2-carboxylic acid 3m (CAS 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.47-7.41 (m, 1H), 7.39 (s, 1H),
1
2
3
4
5
6
7
8
No.: 20037-37-0): The title compound was purified by flash
chromatography (PE/EA = 5/1, 5‰ AcOH) to afford the
product as a yellow solid (88.8 mg, 66% yield). M.p.: 246 oC;
1H NMR (600 MHz, DMSO-d6): δ 14.35-12.86 (br, 1H), 7.59
(s, 1H), 7.54 (s, 1H), 7.24 (s, 1H), 3.98 (s, 3H); 13C{1H} NMR
(150 MHz, DMSO-d6): δ 159.6, 147.1, 145.9, 143.5, 129.7,
117.0, 116.2, 113.0, 112.3, 56.4; HRMS(ESI--TOF) m/z: [M-H]-
7.33 (t, J = 7.5 Hz, 1H), 3.83-3.55 (m, 4H), 2.37 (t, J = 5.0 Hz,
4H), 2.20 (s, 3H); 13C{1H} NMR (125 MHz, DMSO-d6): δ
158.9, 153.9, 148.3, 126.7, 126.5, 123.7, 122.4, 111.8, 110.7,
54.5, 45.6; HRMS(EI-TOF) m/z: [M+] calculated for
C14H16N2O2 244.1212 , found 244.1219.
Benzofuran-2-yl(piperidin-1-yl)methanone 4d (CAS No.:
77509-75-2): The title compound was purified by flash
chromatography (PE/EA = 10/1) to afford the product as a
-
calculated for C10H6BrO4 268.9455, found 268.9461.
o
Naphtho[2,1-b]furan-2-carboxylic acid 3n (CAS No.: 5656-
67-7): The title compound was purified by flash
chromatography (PE/EA = 5/1, 5‰ AcOH) to afford the
white solid (86.9 mg, 76% yield). M.p.: 66 C (lit.35 m.p.: 65
9
1
oC); H NMR (500 MHz, DMSO-d6): δ 7.73 (d, J = 7.8 Hz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H), 7.65 (d, J = 8.3 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.36-
7.28 (m, 2H), 3.73-3.55 (m, 4H), 1.68-1.61 (m, 2H), 1.60-1.53
(m, 4H); 13C{1H} NMR (125 MHz, DMSO-d6): δ 158.8, 153.8,
148.7, 126.8, 126.2, 123.6, 122.3, 111.7, 109.9, 47.3, 43.1,
26.2, 25.4, 24.0; HRMS(EI-TOF) m/z: [M+] calculated for
C14H15NO2 229.1103 , found 229.1109.
o
product as a brown solid (88.9 mg, 84% yield). M.p.: 195 C
o
1
(lit.34 m.p.: 197-199 C); H NMR (500 MHz, DMSO-d6): δ
13.86-13.05 (br, 1H), 8.44 (d, J = 8.2 Hz, 1H), 8.37 (s, 1H),
8.08 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.86 (d, J =
9.1 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.59 (t, J = 7.5 Hz, 1H);
13C{1H} NMR (125 MHz, DMSO-d6): δ 160.0, 153.1, 145.5,
130.1, 128.9, 128.8, 127.6, 127.3, 125.5, 123.8, 122.5, 113.0,
Benzofuran-2-yl(4-phenylpiperidin-1-yl)methanone 4e (CAS
No.: 312511-61-8): The title compound was purified by flash
chromatography (PE/EA = 20/1) to afford the product as a
white solid (87.3 mg, 86% yield). M.p.: 140 oC; 1H NMR (500
MHz, CDCl3): δ 7.66 (d, J = 7.4 Hz, 1H), 7.54 (d, J = 8.4 Hz,
1H), 7.40 (t, J = 8.4 Hz, 1H), 7.36-7.27 (m, 4H), 7.26-7.20 (m,
3H), 5.00-4.50 (m, 2H), 3.43-2.80 (m, 3H), 1.99 (d, J = 12.5
Hz, 2H), 1.87-1.76 (m, 2H); 13C{1H} NMR (125 MHz,CDCl3):
δ 160.0, 154.6, 149.4, 145.1, 128.6, 127.1, 126.8, 126.6, 126.3,
123.5, 122.2, 111.9, 111.5, 42.9; HRMS(EI-TOF) m/z: [M+]
calculated for C20H19NO2 305.1416 , found 305.1420.
-
112.7; HRMS(ESI--TOF) m/z: [M-H]- calculated for C13H7O3
211.0401 , found 211.0404.
3. General procedure for the synthesis of benzofuran-2-
carboxylic amides (4a-4x) and analytic data
To a 15 mL of Young tube, 2-gem-dibromovinylphenols (0.5
mmol, 1.0 equiv.), CuCl2 (0.05 mmol, 10 mol%), 1,10-Phen
(0.05 mmol, 10 mol%), Mo(CO)6 (0.3 mmol, 0.6 equiv.),
amines (2.0 mmol, 4.0 equiv.), n-PrOH (1.5 mL) were
successively added. Then the tube was purged with N2, capped
o
and stirred for at 100 C (oil bath) for 8 h. After the reaction
Benzofuran-2-yl(pyrrolidin-1-yl)methanone 4f (CAS No.:
92028-90-5): The title compound was purified by flash
chromatography (PE/EA = 10/1) to afford the product as a
white solid (91.2 mg, 85% yield). M.p.: 101 oC; 1H NMR (500
MHz, DMSO-d6): δ 7.75 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 8.3
Hz, 1H), 7.49 (s, 1H), 7.46-7.42 (m, 1H), 7.32 (t, J = 7.5 Hz,
1H), 3.82 (t, J = 6.8 Hz, 2H), 3.51 (t, J = 6.8 Hz, 2H), 1.97-
1.88 (m, 2H), 1.86-1.80 (m, 2H); 13C{1H} NMR (125 MHz,
DMSO-d6): δ 157.5, 154.0, 149.3, 126.9, 126.6, 123.6, 122.5,
111.8, 110.9, 47.7, 46.8, 26.0, 23.3; HRMS(EI-TOF) m/z: [M+]
calculated for C13H13NO2 215.0946 , found 215.0951.
finished, the reaction mixture was concentrated under vacuum.
The resulted residual was purified by chromatography on
silica gel eluting with petroleum ether/ethyl acetate to afford
the desired amides.
Benzofuran-2-yl(morpholino)methanone 4a (CAS No.:
77509-76-3): The title compound was purified by flash
chromatography (PE/EA = 10/1) to afford the product as a
white solid (106.7 mg, 92% yield). M.p.: 97 oC (lit.35 m.p.: 95
1
oC); H NMR (500 MHz, DMSO-d6): δ 7.74 (d, J = 7.8 Hz,
1H), 7.66 (d, J = 8.4 Hz, 1H), 7.47-7.40 (m, 2H), 7.33 (t, J =
7.5 Hz, 1H), 3.85-3.60 (m, 8H); 13C{1H} NMR (125 MHz,
DMSO-d6): δ 158.9, 153.9, 148.1, 126.7, 126.5, 123.7, 122.4,
111.8, 111.0, 66.2, 47.3, 42.8; HRMS(EI-TOF) m/z: [M+]
calculated for C13H13NO3 231.0895 , found 231.0903.
N,N-dipropylbenzofuran-2-carboxamide 4g (CAS No.:
904081-20-5): The title compound was purified by flash
chromatography (PE/EA = 15/1) to afford the product as a
yellow oil (101.8 mg, 83% yield); 1H NMR (500 MHz,
DMSO-d6): δ 7.73 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 8.4 Hz,
1H), 7.46-7.39 (m, 1H), 7.35 (s, 1H), 7.31 (t, J = 7.5 Hz, 1H),
3.42-3.25 (m, 4H), 1.65-1.53 (m, 4H), 0.92-0.78 (m, 6H);
13C{1H} NMR (125 MHz, DMSO-d6): δ 159.8, 153.8, 149.3,
126.7, 126.3, 123.6, 122.3, 111.6, 110.1, 49.7, 47.5, 22.1, 20.3,
11.2, 10.9; HRMS(EI-TOF) m/z: [M+] calculated for
C15H19NO2 245.1416 , found 245.1419.
Benzofuran-2-yl(thiomorpholino)methanone 4b (CAS No.:
2327350-36-5): The title compound was purified by flash
chromatography (PE/EA = 10/1) to afford the product as a
o
1
white solid (79.1 mg, 64% yield). M.p.: 74 C; H NMR (500
MHz, DMSO-d6): δ 7.74 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 8.4
Hz, 1H), 7.47-7.41 (m, 1H), 7.39 (s, 1H), 7.33 (t, J = 7.5 Hz,
1H), 4.01-3.82 (m, 4H), 2.71 (t, J = 5.1 Hz, 4H); 13C{1H}
NMR (125 MHz, DMSO-d6): δ 159.2, 153.9, 148.1, 126.7,
126.5, 123.7, 122.4, 111.7, 110.6, 27.0; HRMS(EI-TOF) m/z:
[M+] calculated for C13H13NO2S 247.0667 , found 247.0675.
N-propylbenzofuran-2-carboxamide 4h (CAS No.: 24282-71-
1): The title compound was purified by flash chromatography
(PE/EA = 10/1) to afford the product as a colorless oil (81.4
mg, 80% yield); 1H NMR (500 MHz, DMSO-d6): δ 8.73 (t, J =
5.7 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H),
7.52 (s, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H),
3.24 (q, J = 6.8 Hz, 2H), 1.54 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H);
13C{1H} NMR (125 MHz, DMSO-d6): δ 158.1, 154.2, 149.4,
Benzofuran-2-yl(4-methylpiperazin-1-yl)methanone 4c (CAS
No.: 83820-17-1): The title compound was purified by flash
chromatography (PE/EA = 10/1) to afford the product as a
white solid (116.4 mg, 95% yield). M.p.: 69 oC (lit.36 m.p.: 65
1
oC); H NMR (500 MHz, DMSO-d6): δ 7.74 (d, J = 7.6 Hz,
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o
1
127.2, 126.6, 123.6, 122.7, 111.7, 109.1, 40.5, 22.4, 11.4;
white solid (104.0 mg, 85% yield). M.p.: 117 C; H NMR
(500 MHz, DMSO-d6): δ 7.55 (d, J = 7.5 Hz, 1H), 7.40 (s, 1H),
7.28-7.20 (m, 2H), 3.85-3.60 (m, 8H), 2.49 (s, 3H); 13C{1H}
NMR (125 MHz, DMSO-d6): δ 159.0, 153.0, 147.8, 127.1,
126.2, 123.7, 121.5, 119.8, 111.2, 66.2, 46.9, 42.6, 14.6;
HRMS(EI-TOF) m/z: [M+] calculated for C14H15NO3
245.1052 , found 245.1059.
HRMS(EI-TOF) m/z: [M+] calculated for C12H13NO2
1
2
3
4
5
6
7
8
203.0946 , found 203.0950.
N-benzylbenzofuran-2-carboxamide 4i (CAS No.: 21315-63-
9): The title compound was purified by flash chromatography
(PE/EA = 15/1) to afford the product as a white solid (109.3
mg, 87% yield). M.p.: 100 oC; 1H NMR (400 MHz, DMSO-d6):
δ 9.32 (t, J = 6.1 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.66 (d, J =
8.3 Hz, 1H), 7.60 (s, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.38-7.29
(m, 5H), 7.27-7.20 (m, 1H), 7.66 (d, J = 6.2 Hz, 2H); 13C{1H}
NMR (100 MHz, DMSO-d6): δ 158.2, 154.3, 149.1, 139.3,
128.3, 127.4, 127.2, 126.9, 126.8, 123.7, 122.8, 111.8, 109.6,
42.2; HRMS(EI-TOF) m/z: [M+] calculated for C16H13NO2
251.0946 , found 251.0949.
(5-Methoxybenzofuran-2-yl)(morpholino)methanone
4o
(CAS No.: 92249-04-2): The title compound was purified by
flash chromatography (PE/EA = 10/1) to afford the product as
9
o
1
a white solid (101.6 mg, 78% yield). M.p.: 83 C; H NMR
(500 MHz, DMSO-d6): δ 7.56 (d, J = 9.0 Hz, 1H), 7.35 (s, 1H),
7.22 (s, 1H), 7.04 (d, J = 9.0 Hz, 1H), 3.83-3.60 (m, 11H);
13C{1H} NMR (125 MHz, DMSO-d6): δ 158.8, 156.1, 148.9,
148.9, 127.3, 115.8, 112.4, 111.3, 103.9, 66.2, 55.6, 46.8, 42.7;
HRMS(EI-TOF) m/z: [M+] calculated for C14H15NO4
261.1001 , found 261.1009.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
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N-phenylbenzofuran-2-carboxamide 4j (CAS No.: 50635-12-
6): The title compound was purified by flash chromatography
(PE/EA = 15/1) to afford the product as a light yellow solid
o
o
1
(59.1 mg, 50% yield). M.p.: 155 C (lit.37 m.p.: 158 C); H
NMR (500 MHz, DMSO-d6): δ 10.53 (s, 1H), 7.86-7.79 (m,
3H), 7.78 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.51 (t, J1 = 7.8 Hz,
1H), 7.41-7.34 (m, 3H), 7.13 (t, J1 = 7.4 Hz, 1H); 13C{1H}
NMR (125 MHz, DMSO-d6): δ 156.7, 154.5, 148.8, 138.4,
128.7, 127.2, 127.1, 124.1, 123.9, 122.9, 120.5, 112.0, 110.7;
HRMS(EI-TOF) m/z: [M+] calculated for C15H11NO2
237.0790 , found 237.0783.
(5-(tert-Butyl)benzofuran-2-yl)(morpholino)methanone 4p:
The title compound was purified by flash chromatography
(PE/EA = 10/1) to afford the product as a white solid (116.6
mg, 81% yield). M.p.: 117 oC; 1H NMR (400 MHz, DMSO-d6):
δ 7.69 (s, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz,
1H), 7.38 (s, 1H), 3.87-3.52 (m, 8H), 1.33 (s, 1H); 13C{1H}
NMR (100 MHz, DMSO-d6): δ 159.0, 152.2, 148.2, 146.3,
126.4, 124.6, 118.2, 111.4, 111.1, 66.2, 47.0, 42.6, 34.5, 31.5;
HRMS(EI-TOF) m/z: [M+] calculated for C17H21NO3
287.1521 , found 287.1528.
Benzofuran-2-carboxamide 4k (CAS No.: 50342-50-2): The
title compound was purified by flash chromatography (PE/EA
= 5/1) to afford the product as a white solid (65.3 mg, 81%
Morpholino(5-phenylbenzofuran-2-yl)methanone 4q: The
title compound was purified by flash chromatography (PE/EA
= 10/1) to afford the product as a white solid (138.0 mg, 90%
yield). M.p.: 162 C; H NMR (500 MHz, DMSO-d6): δ 7.99
(s, 1H), 7.77-7.71 (m, 2H), 7.69 (d, J = 7.1 Hz, 2H), 7.51-7.45
(m, 3H), 7.38 (t, J = 7.4 Hz, 1H), 3.84-3.61 (m, 8H); 13C{1H}
NMR (125 MHz, DMSO-d6): δ 158.8, 153.5, 148.8, 140.2,
136.3, 129.0, 127.4, 127.2, 127.0, 125.8, 120.3, 112.1, 111.2,
67.2; HRMS(EI-TOF) m/z: [M+] calculated for C19H17NO3
307.1208 , found 307.1213.
o
o
1
yield). M.p.: 162 C (lit.38 m.p.: 158-159 C); H NMR (500
MHz, DMSO-d6): δ 8.21-8.05 (m, 1H), 7.76 (d, J = 7.5 Hz,
1H), 7.73-7.65 (m, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H),
7.48-7.40 (m, 1H), 7.31 (t, J = 7.5 Hz, 1H); 13C{1H} NMR
(125 MHz, DMSO-d6): δ 159.9, 154.3, 149.4, 127.3, 126.8,
123.7, 122.8, 111.8, 109.6; HRMS(EI-TOF) m/z: [M+]
calculated for C9H7NO2 161.0477 , found 161.0480.
o
1
(5-Methylbenzofuran-2-yl)(morpholino)methanone 4l (CAS
No.: 950255-28-4): The title compound was purified by flash
chromatography (PE/EA = 10/1) to afford the product as a
(5-Fluorobenzofuran-2-yl)(morpholino)methanone 4r: The
title compound was purified by flash chromatography (PE/EA
= 10/1) to afford the product as a white solid (105.6 mg, 85%
o
1
white solid (114.2 mg, 93% yield). M.p.: 120.5 C; H NMR
(500 MHz, DMSO-d6): δ 7.57-7.47 (m, 2H), 7.35 (s, 1H), 7.26
(d, J = 8.5 Hz, 1H), 3.87-3.57 (m, 8H), 2.40 (s, 3H); 13C{1H}
NMR (125 MHz, DMSO-d6): δ 159.0, 152.4, 148.2, 132.8,
127.9, 126.8, 121.9, 111.3, 110.9, 66.2, 46.9, 42.9, 20.8;
HRMS(EI-TOF) m/z: [M+] calculated for C14H15NO3
245.1052 , found 245.1060.
o
1
yield). M.p.: 88 C; H NMR (400 MHz, DMSO-d6): δ 7.75-
7.65 (m, 1H), 7.60-7.48 (m, 1H), 7.40 (s, 1H), 7.33-7.24 (m,
1H), 3.90-3.51 (m, 8H); 13C{1H} NMR (100 MHz, DMSO-d6):
δ 158.8 (d, J = 235.9 Hz), 158.6, 150.3, 149.8, 127.6 (d, J =
11.4 Hz), 114.4 (d, J = 26.7 Hz), 113.2 (d, J = 9.8 Hz), 111.1
(d, J = 4.1 Hz), 107.7 (d, J = 25.2 Hz), 66.2, 47.0, 42.6;
HRMS(EI-TOF) m/z: [M+] calculated for C13H12FNO3
249.0801, found 249.0804.
(6-Methylbenzofuran-2-yl)(morpholino)methanone 4m (CAS
No.: 1789659-35-3): The title compound was purified by flash
chromatography (PE/EA = 10/1) to afford the product as a
o
1
white solid (112.9 mg, 92% yield). M.p.: 118.5 C; H NMR
(600 MHz, DMSO-d6): δ 7.60 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H),
7.36 (s, 1H), 7.14 (d, J = 8.0 Hz, 1H), 3.85-3.57 (m, 8H), 2.42
(s, 3H); 13C{1H} NMR (150 MHz, DMSO-d6): δ 159.0, 154.4,
147.6, 136.7, 125.1, 124.2, 121.9, 111.7, 111.1, 66.2, 46.8,
42.8, 21.3; HRMS(EI-TOF) m/z: [M+] calculated for
C14H15NO3 245.1052 , found 245.1060.
(5-Chlorobenzofuran-2-yl)(morpholino)methanone 4s (CAS
No.: 882308-53-4): The title compound was purified by flash
chromatography (PE/EA = 10/1) to afford the product as a
light yellow solid (116.8 mg, 88% yield). M.p.: 99 C; H
NMR (400 MHz, DMSO-d6): δ 7.81 (s, 1H), 7.71 (d, J = 8.8
Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.39 (s, 1H), 3.88-3.51 (m,
8H); 13C{1H} NMR (100 MHz, DMSO-d6): δ 158.5, 152.4,
149.5, 128.3, 128.0, 126.5, 121.8, 113.5, 110.5, 66.2, 47.0,
42.6; HRMS(EI-TOF) m/z: [M+] calculated for C13H12ClNO3
265.0506, found 265.0513.
o
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(7-Methylbenzofuran-2-yl)(morpholino)methanone 4n (CAS
No.: 2215703-74-3): The title compound was purified by flash
chromatography (PE/EA = 10/1) to afford the product as a
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(5-Bromobenzofuran-2-yl)(morpholino)methanone 4t (CAS vacuum. The resulted residual was purified by
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2
3
4
5
6
7
8
No.: 838887-57-3): The title compound was purified by flash
chromatography (PE/EA = 10/1) to afford the product as a
chromatography on silica gel using petroleum ether/ethyl
acetate as eluent to afford the desired products 2p as a light
yellow solid (1.07 g, 80% yield).
o
1
white solid (135.1 mg, 87% yield). M.p.: 110 C; H NMR
(400 MHz, DMSO-d6): δ 7.96 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H),
7.58 (d, J = 8.8 Hz, 1H), 7.39 (s, 1H), 3.89-3.49 (m, 8H);
13C{1H} NMR (100 MHz, DMSO-d6): δ 158.5, 152.8, 149.3,
129.2, 128.9, 124.8, 115.9, 113.9, 110.4, 66.2, 46.8, 42.6;
HRMS(EI-TOF) m/z: [M+] calculated for C13H12BrNO3
309.0001, found 309.0006.
Similarly, 3f (0.838 g, 77% yield) was synthesized from 4-
(tert-butyl)-2-(2,2-dibromovinyl)phenol (5.0 mmol) as a light
yellow solid, and 4a (1.05 g, 91% yield) was synthesized from
2-(2,2-dibromovinyl)phenol (5.0 mmol) as a white solid.
9
Methyl 2-(morpholine-4-carbonyl)benzofuran-5-carboxylate
4u: The title compound was purified by flash chromatography
(PE/EA = 10/1) to afford the product as a white solid (121.3
mg, 84% yield). M.p.: 129 oC; 1H NMR (400 MHz, DMSO-d6):
δ 8.39 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.8 Hz,
1H), 7.54 (s, 1H), 3.88 (s, 1H), 3.83-3.56 (m, 8H); 13C{1H}
NMR (100 MHz, DMSO-d6): δ 166.0, 158.5, 156.3, 149.5,
127.5, 127.0, 125.4, 124.5, 112.2, 111.4, 66.2, 52.3, 47.0, 42.6;
HRMS(EI-TOF) m/z: [M+] calculated for C15H15NO5 289.0950,
found 289.0957.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/xx.xxxx/xxxxxxxx
Details of optimization of the reaction conditions.
1H and 13C NMR spectra for all products (PDF).
AUTHOR INFORMATION
Corresponding Author
(7-Bromo-5-chlorobenzofuran-2-yl)(morpholino)methanone
4v (CAS No.: 2334613-06-6): The title compound was
purified by flash chromatography (PE/EA = 10/1) to afford the
product as a white solid (131.8 mg, 77% yield). M.p.: 130 oC;
1H NMR (400 MHz, DMSO-d6): δ 7.85 (s, 1H), 7.80 (s, 1H),
7.48 (s, 1H), 3.81-3.57 (m, 8H); 13C{1H} NMR (100 MHz,
DMSO-d6): δ 158.1, 149.9, 149.8, 129.0, 128.6, 128.5, 121.5,
111.0, 104.4, 66.1, 47.0, 42.6; HRMS(EI-TOF) m/z: [M+]
calculated for C13H11BrClNO3 342.9611, found 342.9620.
* E-Mail: sunnan@zjut.edu.cn, xinquan@zjut.edu.cn
ACKNOWLEDGMENT
The project was supported by the National Natural Science
Foundation of China (21972125).
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(5-Bromo-7-methoxybenzofuran-2-
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(PE/EA = 10/1) to afford the product as a white solid (151.5
mg, 89% yield). M.p.: 152 oC; 1H NMR (600 MHz, DMSO-d6):
δ 7.51 (s, 1H), 7.36 (s, 1H), 7.21 (s, 1H), 3.97 (s, 3H), 3.79-
3.59 (m, 8H); 13C{1H} NMR (150 MHz, DMSO-d6): δ 158.4,
149.0, 145.8, 142.3, 129.6, 116.5, 116.1, 112.6, 110.5, 66.1,
56.4, 46.9, 42.5; HRMS(EI-TOF) m/z: [M+] calculated for
C14H14BrNO3 339.0106, found 339.0112.
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o
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white solid (102.5 mg, 73% yield). M.p.: 145 C; H NMR
(500 MHz, DMSO-d6): δ 8.41 (d, J = 8.2 Hz, 1H), 8.15 (s, 1H),
8.07 (d, J = 8.1 Hz, 1H), 7.97 (d, J = 9.0 Hz, 1H), 7.84 (d, J =
9.0 Hz, 1H), 7.68 (t, J = 8.2 Hz, 1H), 7.57 (t, J = 8.2 Hz, 1H),
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4. Procedure for the gram-scale syntheses of 2p, 3f and 4a.
To
a
50 mL of Young tube, 4-bromo-2-(2,2-
dibromovinyl)phenol (5.0 mmol, 1.0 equiv.), CuBr2 (0.25
mmol, 5 mol%), 2,2’-Bpy (0.25 mmol, 5 mol%), Mo(CO)6
(3.0 mmol, 0.6 equiv.), NEt3 (15 mmol, 3.0 equiv.), EtOH (15
mL) were successively added. Then the tube was purged with
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o
N2, capped and stirred at 90 C (oil bath) for 8 h. After the
reaction finished, the reaction mixture was concentrated under
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