Copper-catalyzed, C-C coupling-based one-pot tandem reactions for the synthesis of benzofurans using o-iodophenols, acyl chlorides, and phosphorus ylides

Article abstract of DOI:10.1021/jo5017508

One-pot reactions involving acyl chlorides, phosphorus ylides, and o-iodophenols with copper catalysis have been established for the rapid synthesis of functionalized benzofurans. With all of these easily available and stable reactants, the construction o

Full text of DOI:10.1021/jo5017508

Note
pubs.acs.org/joc
Copper-Catalyzed, C−C Coupling-Based One-Pot Tandem Reactions
for the Synthesis of Benzofurans Using o‑Iodophenols, Acyl
Chlorides, and Phosphorus Ylides
Yunyun Liu,* Hang Wang, and Jie-Ping Wan*
Key Laboratory of Functional Small Organic Molecules, Ministry of Education and College of Chemistry and Chemical Engineering,
Jiangxi Normal University, Nanchang 330022, P. R. China
S
* Supporting Information
ABSTRACT: One-pot reactions involving acyl chlorides, phosphorus
ylides, and o-iodophenols with copper catalysis have been established
for the rapid synthesis of functionalized benzofurans. With all of these
easily available and stable reactants, the construction of the target
products has been accomplished via tandem transformations involving
a key C−C coupling, leading to the formation of one C(sp2)−C bond,
one C(sp2)−O bond, and one CC bond.
he formation of C−C and C−heteroatom single bonds is
Tthe central and basic transformation in a tremendous
number of organic syntheses. Thanks to the rapid advances of
modern synthetic organic chemistry, there are presently a vast
number of methods available for achieving these bond
formations. In the synthetic toolbox, C−C and C−heteroatom
coupling reactions that enable the transformation of C(sp2)−X
(X = halide) bonds such as Ar−X and vinyl−X bonds into new
C−C/C−heteroatom bonds are of particular significance. One
typical example of the category is the Ullmann reaction, which
involves the copper-catalyzed coupling of aryl/vinyl halides and
corresponding C- or heteroatom-based nucleophiles.1 Among
the versatile utilities of Ullmann couplings in organic synthesis,
the direct synthesis of various N-, O-, and/or S-containing
heterocyclic products constitutes a major frontier.2,3
Benzofuran is a motif of prevalent presence in natural
products and biologically relevant organic molecules. The
investigation of benzofuran-based scaffolds has led to the
Figure 1. Benzofuran-based lead compounds and natural products.
discovery of many promising lead compounds. For instance,
SKF-64346 (1) (Figure 1) has been identified as a potent
catalyzed intramolecular C−H arylation/alkene isomerization
reactions of o-bromoaryl allyl ethers 4 for the synthesis of
benzofurans (eq 1 in Scheme 1). Maiti and co-workers13
achieved benzofuran synthesis using simple phenols and
alkenes via palladium/copper-cocatalyzed intermolecular C−
H annulation (eq 2 in Scheme 1). In another work, Yi and co-
workers14 employed a ruthenium-catalyzed tandem intermo-
lecular C−H dehydration/intramolecular dehydration trans-
formation to assemble benzofurans from phenols 5 and 1,2-
diols 7 (eq 3 in Scheme 1). Alternatively, by utilization of
Ullmann C−C coupling as a key transformation, Ma and co-
workers15 accomplished the construction of benzofurans with
copper-catalyzed tandem reactions of 2-bromophenyl iodides 8
inhibitor of β-amyloid aggregation and shown therapeutic
potential toward Alzheimer’s disease,4 and amiodarone (2) is a
widely utilized clinical drug in the treatment of intractable
cardiac arrhythmias.5 Daphnodorin B (3) is one of the natural
products of the Daphnodorin family and possesses a broad
spectrum of biological functions such as antifungal activity,6
antitumor activity,7 and cytotoxic activity8 as well as inhibition
activity against α-glucosidase,9 12-lipoxygenase,10 and human
chymase-dependent angiotensin II.11 The long-lasting and
extensive efforts toward the synthesis of benzofurans have
inspired the establishment of numerous elegant synthetic
methodologies targeting this heterocyclic scaffold. Some
particularly interesting and novel ones are those employing
transition-metal-catalyzed versions based on the conversion of
stable chemical bonds such as C(sp2)−H and C(sp2)−X bonds.
For example, Willis and co-workers12 developed the palladium-
Received: July 31, 2014
© XXXX American Chemical Society
A
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Note
readily available reactants such as acyl chlorides and different
Wittig reagents.
Scheme 1. Different Routes To Access Functionalized
Benzofurans
Originally, the reaction of o-iodophenol (10a), phosphorus
ylide 11a, and acetyl chloride (12a) was employed to probe the
expected transformation, wherein 11a and 12a were first
reacted following a literature procedure to prepare the
corresponding allene 14a.19 Subsequent employment of 10a,
a copper catalyst, ligand, base, etc., was discovered to be capable
of producing 13a. Therefore, the initial efforts focused on
optimizing the conditions for the assembly of allene 14a and o-
iodophenol 10a. As shown in Table 1, comparison of a series of
Table 1. Different Conditions for the Synthesis of
a
Benzofuran 13a
b
entry
ligand
cat.
CuBr
base
solvent
DMSO
yield (%)
1
2
L1
L2
L3
L4
L5
L6
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Et3N
53
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuI
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
32
3
36
4
41
5
72
6
51
7
trace
trace
29
8
NaOAc
K2CO3
9
10
11
12
13
t-BuOK
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
33
61
CuO
47
CuBr2
Cu(OAc)2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
26
c
and β-keto esters 9 (eq 4 in Scheme 1). In addition, on the
basis of classical routes such as the palladium-catalyzed Larock-
type annulation using o-halophenols and alkynes,16 a variety of
other practical protocols are also available to enable the
synthesis of benzofurans by catalysis with palladium, silver,
14
45
15
16
17
18
21
toluene
dioxane
acetonitrile
DMSO
DMSO
trace
trace
25
17
d
copper, or a Pd/Cu cocatalyst. While each of these known
19
e
65
protocols for benzofuran synthesis has specific features and/or
advantages, the design of new tandem reactions using simpler
starting materials to expand the structural diversity of the
products is still highly desirable. Herein we report a new
copper-catalyzed tandem approach for the synthesis of
benzofurans involving the assembly of allenes 14 and o-
iodophenols 10, wherein 14 are generated in situ by the direct
use of the corresponding Wittig reagents 11 and acyl chlorides
12 in one pot (eq 5 in Scheme 1). To the best of our
knowledge, no allene-based coupling reactions with copper
catalysis have been hitherto known for benzofuran synthesis,
and a palladium-catalyzed coupling protocol involving
allenylphosphonates and o-iodophenol proceeds via a different
selectivity to produce benzofurans by incorporating a β,γ-CC
bond (eq 6).18 Besides involving a novel selective reaction
20
56
a
General conditions: 10a (0.5 mmol), 11a (0.75 mmol), 12a (0.75
mmol), copper catalyst (0.075 mmol), ligand (0.2 mmol), base (2.0
mmol), and 5 Å molecular sieves (150 mg) in solvent (2 mL), stirred
b
c
at 90 °C for 12 h (TLC). Yield of isolated products. Commercial
Cu(OAc)2·H2O was used. The temperature was 110 °C. The
temperature was 70 °C.
d
e
different typical ligands such as 8-hydroxyquinoline (L1), D-
glucose (L2), L-proline (L3), ethyl 2-oxocyclohexanecarbox-
ylate (L4), 1,10-phenanthroline (L5), and bipyridine (L6)
revealed that L5 was the optimal ligand (Table 1, entries 1−6).
Subsequent comparison of different organic and inorganic
bases, including Et3N, K2CO3, NaOAc, t-BuOK, etc., did not
provide a better result than the entry with Cs2CO3, which had
also been previously known as a favorable base additive for
pathway, the present method is also advantageous for avoiding
the tedious prior isolation of unstable allenes and allowing the
generation of high product diversity by employing simple and
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other C−O coupling process (Table 1, entries 7−10).20 Later
on, as the catalysts, various Cu(I) and Cu(II) salts were also
employed for the reaction. In these experiments, CuBr turned
out to be evidently better than all of the other copper catalysts
tested (Table 1, entries 11−14). The subsequent examination
of reaction media of different polarity, including toluene, 1,4-
dioxane, DMF, and acetonitrile, demonstrated that a polar
solvent was better favored by the model reaction, and DMSO
was among the best ones (Table 1, entries 15−18). Finally,
variation of the reaction temperature proved that 90 °C was the
favored temperature (Table 1, entries 19 and 20).
our studies demonstrated that linear acyl chlorides were
generally good reaction partners, while acyl chlorides bearing
an aryl fragment, such as 2-phenylacetyl chloride, could not
undergo the expect transformation to give the corresponding
product. On the other hand, the reactions of ketone- and
nitrile-based ylides were also smoothly run to afford the
corresponding benzofurans 13n−t, which assured the broader
scope of application of the present protocol toward benzofuran
synthesis. In addition, an entry using o-bromophenol as an
alternative substrate for synthesizing 13a gave a yield of 36%
(Scheme 2).
Under the optimized conditions, various phosphorus ylides,
acyl chlorides, and o-iodophenols were employed for the
synthesis of different benzofurans, and the corresponding
results are outlined in Scheme 2. According to the obtained
After the examination of the scope of application, we also
compared the efficiency of the model reaction with that of the
stepwise operation using isolated allene 14a. As shown in
Scheme 3, the reaction of 11a and 12a in identical amounts
a
Scheme 2. Synthesis of Different Benzofurans
Scheme 3. Results for the Synthesis of Benzofuran 13a Using
Allene 14a
(0.75 mmol) as shown in the model reaction in Table 1 was
conducted following a literature procedure17 to provide allene
14a in 48% yield (eq 1 in Scheme 3). The obtained 14a (40
mg) was then reacted with 0.5 mmol of 1a under the standard
reaction conditions (eq 2 in Scheme 3) and provided
benzofuran 13a in 68% isolated yield (50 mg), which was
apparently lower than the total yield of the one-pot version (73
mg). With the further consideration of the consumption of
chemicals for the isolation of the allene, the one-pot method is
inarguably superior to the equivalent stepwise version in terms
of both efficiency and atom economy.
Being aware of the fact that the benzofuran products were
assembled from allene and o-iodophenol, we then attempted to
isolate possible intermediates from the reaction to explore the
reaction mechanism. When the model reaction was run under
modified conditions, ethyl 3-(2-iodophenoxy)but-2-enoate
(15a) was observed (eq 3 in Scheme 3), and in addition,
subjecting 15a to the standard copper-catalyzed conditions
efficiently yielded benzofuran 13a (eq 4 in Scheme 3). With
these results and related literature reports of indole synthesis
involving the allene intermediate,21 we postulated the reaction
mechanism shown in Scheme 4. At first, after the in situ
formation, allene 14 undergoes the oxa-Michael addition with
o-iodophenol 10 to provide intermediate 16, which quickly
isomerizes to give 15. Subsequently, the insertion of Cu(I) into
the Ar−I bond in 15 leads to the formation of intermediate 17,
a
Yields of isolated products based on 10 are shown.
results, the present protocol tolerated different functional
groups well. For example, the electron-withdrawing group
(EWG) in the ylide component could be an ester, carbonyl
(ketone), or cyano group, while different functional groups in
the o-iodophenol and acyl chloride components were also
found to be compatible. Generally, benzofurans could be
obtained in moderate to good yields via this tandem reaction,
and products provided by ester-based phosphorus ylides
displayed excellent tolerance, yielding 3-alkylate-functionalized
benzofurans with broad diversity. No systematic impact of the
functional groups in any of the components was observed,
probably because complex factors such as the efficiency of
allene synthesis and the C-arylative coupling between
nucleophilic allene intermediates and iodophenols, etc., were
involved in the process. While substituents with different
properties in the iodophenol component could also be
tolerated, the present transformation was found to be sensitive
to the structure of the acyl chloride component. Specifically,
C
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Note
(q, 2H, J = 7.6 Hz), 1.46 (t, 3H, J = 7.2 Hz), 1.36 (t, 3H, J = 7.6 Hz);
13C NMR (CDCl3, 100 MHz) δ 168.4, 164.5, 153.6, 126.3, 124.2,
123.7, 121.9, 110.8, 108.0, 60.2, 21.7, 14.2, 11.9; IR (KBr, cm−1) 2968,
1721, 1449, 1369, 1290, 1221, 1031, 756; ESI-HRMS calcd for
C13H15O3 [M + H]+ 219.1021, found 219.1024.
Scheme 4. General Mechanism for the Copper-Catalyzed,
One-Pot Cascade Synthesis of Benzofurans
Ethyl 2-Propylbenzofuran-3-carboxylate (13c). Yield 80 mg, 69%;
1
colorless liquid; H NMR (CDCl3, 400 MHz) δ 7.90−7.88 (m, 1H),
7.35−7.33 (m, 1H), 7.22−7.17 (m, 2H), 4.32 (q, 2H, J = 7.2 Hz), 3.08
(t, 2H, J = 7.6 Hz), 1.76−1.71 (m, 2H), 1.36 (t, 3H, J = 7.2 Hz), 0.93
(t, 3H, J = 7.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 167.4, 164.5,
153.6, 126.3, 124.3, 123.7, 121.9, 110.8, 108.7, 60.2, 30.0, 21.4, 14.4,
13.9; IR (KBr, cm−1) 2962, 1716, 1466, 1377, 1284, 1210, 1074, 751;
ESI-HRMS calcd for C14H17O3 [M + H]+ 233.1178, found 233.1184.
Methyl 2-Ethylbenzofuran-3-carboxylate (13d). Yield 71 mg,
1
70%; colorless liquid; H NMR (CDCl3, 400 MHz) δ 7.89−7.87 (m,
1H), 7.37−7.36 (m, 1H), 7.22−7.20 (m, 2H), 3.87 (s, 3H), 3.13 (q,
2H, J = 7.2 Hz), 1.28 (t, 3H, J = 7.2 Hz); 13C NMR (CDCl3, 100
MHz) δ 168.6, 164.9, 153.7, 126.2, 124.3, 123.7, 121.9, 110.9, 107.9,
51.4, 21.7, 11.9; IR (KBr, cm−1) 2971, 1725, 1452, 1389, 1227, 1109,
813; ESI-HRMS calcd for C12H12NaO3 [M + Na]+ 227.0684, found
227.0686.
Methyl 2-Propylbenzofuran-3-carboxylate (13e). Yield 73 mg,
1
67%; colorless liquid; H NMR (CDCl3, 400 MHz) δ 7.97−7.96 (m,
1H), 7.45−7.43 (m, 1H), 7.30−7.28 (m, 2H), 3.95 (s, 3H), 3.17 (t,
2H, J = 7.6 Hz), 1.84−1.79 (m, 2H), 1.01 (t, 3H, J = 7.6 Hz); 13C
NMR (CDCl3, 100 MHz) δ 167.5, 165.1, 153.6, 126.1, 124.3, 123.7,
121.8, 110.9, 108.5, 51.4, 30.0, 21.3, 13.8; IR (KBr, cm−1) 2973, 1731,
1438, 1381, 1231, 1106, 827; ESI-HRMS calcd for C13H15O3 [M +
H]+ 219.1021, found 219.1030.
which affords intermediate 18 via an intramolecular annulation.
Finally, a typical reductive elimination on 18 leads to the
production of benzofuran 13.
tert-Butyl 2-Ethylbenzofuran-3-carboxylate (13f). Yield 85 mg,
1
In summary, by employing copper-catalyzed C-arylation as a
key transformation, we have established a new synthetic
protocol for benzofurans. The synthesis employs simple
phosphorus ylides, acyl chlorides, and o-iodophenols as starting
materials to assemble target products with high diversity and
efficiency. In addition to providing a new practical and useful
method for the synthesis of 2,3-disubstituted benzofurans, the
present work can also guide the design of new reactions using
allene-based C−C coupling.
69%; colorless liquid; H NMR (CDCl3, 400 MHz) δ 7.96−7.94 (m,
1H), 7.43−7.41 (m, 1H), 7.28−7.26 (m, 2H), 3.18 (q, 2H, J = 7.6
Hz), 1.64, (s, 9H), 1.35 (t, 3H, J = 7.6 Hz); 13C NMR (CDCl3, 100
MHz) δ 167.9, 163.8, 153.5, 126.5, 124.1, 123.6, 121.8, 110.8, 109.2,
81.0, 28.4, 21.7, 12.2; IR (KBr, cm−1) 2976, 1675, 1439, 1326, 1209,
1108, 786; ESI-HRMS calcd for C15H19O3 [M + H]+ 247.1334, found
247.1331.
tert-Butyl 2-Propylbenzofuran-3-carboxylate (13g). Yield 105 mg,
1
81%; colorless liquid; H NMR (CDCl3, 400 MHz) δ 7.97−7.95 (m,
1H), 7.43−7.41 (m, 1H), 7.28−7.26 (m, 2H), 3.13 (t, 2H, J = 7.6 Hz),
1.86−1.76 (m, 2H), 1.64 (s, 9H), 1.01 (t, 3H, J = 7.6 Hz); 13C NMR
(CDCl3, 100 MHz) δ 166.9, 163.8, 153.5, 126.5, 124.1, 123.5, 121.9,
110.8, 109.9, 81.0, 30.0, 28.5, 21.3, 13.7; IR (KBr, cm−1) 2981, 1673,
1424, 1306, 1247, 1121, 785; ESI-HRMS calcd for C16H20NaO3 [M +
Na]+ 283.1310, found 283.1304.
EXPERIMENTAL SECTION
■
General Procedure for the One-Pot Synthesis of Benzofur-
ans 13. A 25 mL round-bottom flask was charged with phosphorus
ylide 11 (0.75 mmol), CH2Cl2 (5 mL), and Et3N (0.5 mmol). A
solution of acyl chloride 12 (0.75 mmol) in CH2Cl2 (1 mL) was added
dropwise with stirring. After an additional 1.5 h of stirring, the CH2Cl2
was completely evaporated under reduced pressure. To the residue
was added n-hexane (3 mL), and the resulting mixture was stirred at rt
for an additional 2 h. Subsequently, o-iodophenol 10 (0.5 mmol),
CuBr (0.075 mmol), 1,10-phenanthroline (0.2 mmol), Cs2CO3 (2.0
mmol), 5 Å MS (150 mg), and DMSO (2 mL) were added. The
resulting mixture was heated at 90 °C in the presence of a water
condenser (sealed with a 1 atm air balloon) for 12 h (TLC). Upon
completion (TLC), the reaction mixture was allowed to cool to rt, and
H2O (5 mL) was added. The resulting suspension was extracted with
ethyl acetate (3 × 8 mL). The organic phases were combined and
dried over Na2SO4. After filtration and removal of the solvent at
reduced pressure, the residue was subjected to silica gel column
chromatography using 60:1 (v/v) petroleum ether/ethyl acetate as the
eluent to give the pure product 13.
Ethyl 5-tert-Butyl-2-propylbenzofuran-3-carboxylate (13h). Yield
103 mg, 72%; colorless liquid; 1H NMR (CDCl3, 400 MHz) δ 8.02 (s,
1H), 7.35 (s, 2H), 4.41 (q, 2H, J = 7.2 Hz), 3.14 (t, 2H, J = 7.6 Hz),
1.85−1.75 (m, 2H), 1.45 (t, 3H, J = 7.6 Hz), 1.39 (s, 9H), 0.99 (t, 3H,
J = 7.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 167.4, 164.6, 151.9,
146.9, 126.1, 122.1, 118.1, 110.1, 108.7, 60.1, 34.8, 31.8, 30.1, 21.4,
14.1, 13.7; IR (KBr, cm−1) 2923, 1717, 1453, 1362, 1279, 1203, 1069,
768; ESI-HRMS calcd for C18H25O3 [M + H]+ 289.1804, found
289.1807.
Methyl 5-(tert-Butyl)-2-propylbenzofuran-3-carboxylate (13i).
1
Yield 101 mg, 74%; colorless liquid; H NMR (CDCl3, 400 MHz) δ
7.98 (s, 1H), 7.35 (s, 2H), 3.95 (s, 3H), 3.14 (t, 2H, J = 7.2 Hz), 1.82−
1.77 (m, 2H), 1.39 (s, 9H), 0.99 (t, 3H, J = 7.2 Hz); 13C NMR
(CDCl3, 100 MHz) δ 167.7, 165.3, 151.9, 146.9, 125.8, 122.2, 118.0,
110.1, 108.6, 51.4, 34.8, 31.8, 30.1, 21.4, 13.8; IR (KBr, cm−1) 2963,
1714, 1447, 1367, 1231, 1113, 813; ESI-HRMS calcd for C17H23O3 [M
+ H]+ 275.1647, found 275.1652.
Ethyl 2-Methylbenzofuran-3-carboxylate (13a).15 Yield 73 mg,
1
Ethyl 2-Ethyl-5-methylbenzofuran-3-carboxylate (13j). Yield 79
72%; colorless liquid; H NMR (CDCl3, 400 MHz) δ 7.96−7.95 (m,
1
mg, 68%; colorless liquid; H NMR (CDCl3, 400 MHz) δ 7.76 (s,
1H), 7.42−7.39 (m, 1H), 7.27−7.25 (m, 2H), 4.41 (q, 2H, J = 7.2
Hz), 2.76 (s, 3H), 1.44 (t, 3H, J = 7.2 Hz); 13C NMR (CDCl3, 100
MHz) δ 164.7, 163.6, 153.6, 126.2, 124.3, 123.7, 121.7, 110.7, 109.1,
60.2, 14.4 (2C).
1H), 7.31 (d, 1H, J = 8.4 Hz), 7.08 (d, 1H, J = 8.4 Hz), 4.41 (q, 2H, J
= 7.2 Hz), 3.18 (q, 2H, J = 7.2 Hz), 2.46 (s, 3H), 1.44 (t, 3H, J = 7.2
Hz), 1.34 (t, 3H, J = 7.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 168.4,
164.6, 152.0, 133.2, 126.4, 125.4, 121.7, 110.3, 107.8, 60.2, 21.8, 21.5,
14.4, 12.1; IR (KBr, cm−1) 2953, 1732, 1445, 1378, 1229, 1106, 787;
ESI-HRMS calcd for C14H17O3 [M + H]+ 233.1178, found 233.1180.
Ethyl 2-Ethylbenzofuran-3-carboxylate (13b). Yield 71 mg, 65%;
1
colorless liquid; H NMR (CDCl3, 400 MHz) δ 7.99−7.96 (m, 1H),
7.46−7.43 (m, 1H), 7.30−7.28 (m, 2H), 4.42 (q, 2H, J = 7.6 Hz), 3.21
D
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Ethyl 5-Methyl-2-propylbenzofuran-3-carboxylate (13k). Yield 85
mg, 69%; colorless liquid; H NMR (CDCl3, 400 MHz) δ 7.76 (s,
2H, J = 8.4 Hz), 7.47 (t, 3H, J = 8.8 Hz), 7.34−7.25 (m, 2H), 7.18 (t,
1H, J = 7.6 Hz), 2.92 (q, 2H, J = 7.6 Hz), 1.34 (t, 3H, J = 7.6 Hz); 13
C
1
1H), 7.31 (d, 1H, J = 8.4 Hz), 7.08 (dd, 1H, J = 1.2 Hz, J = 8.4 Hz),
4.41 (q, 2H, J = 7.2 Hz), 3.14 (t, 2H, J = 7.6 Hz), 2.46 (s, 3H), 1.85−
1.76 (m, 2H), 1.45 (t, 3H, J = 7.2 Hz), 1.0 (t, 3H, J = 7.2 Hz); 13C
NMR (CDCl3, 100 MHz) δ 167.5, 164.7, 152.1, 133.2, 126.3, 125.4,
121.7, 110.4, 108.4, 60.0, 30.1, 21.5, 21.4, 14.4, 13.8; IR (KBr, cm−1)
2963, 1714, 1463, 1378, 1279, 1075, 763; ESI-HRMS calcd for
C15H19O3 [M + H]+ 247.1334, found 247.1338.
Methyl 5-Methyl-2-propylbenzofuran-3-carboxylate (13l). Yield
88 mg, 76%; colorless liquid; 1H NMR (CDCl3, 400 MHz) δ 7.74 (s,
1H), 7.30 (d, 1H, J = 8.4 Hz), 7.07 (d, 1H, J = 8.0 Hz), 3.94 (s, 3H),
3.14 (t, 2H, J = 7.6 Hz), 2.45 (s, 3H), 1.83−1.77 (m, 2H), 1.00 (t, 3H,
J = 7.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 167.8, 165.3, 152.3,
133.5, 126.4, 125.7, 121.9, 110.6, 108.5, 51.5, 30.3, 21.6, 21.5, 14.0; IR
(KBr, cm−1) 2962, 1716, 1443, 1374, 1243, 1115, 812; ESI-HRMS
calcd for C14H17O3 [M + H]+ 233.1178, found 233.1179.
NMR (CDCl3, 100 MHz) δ 190.5, 166.6, 153.7, 139.0, 137.8, 130.5,
128.8, 126.7, 124.4, 123.5, 121.2, 115.7, 111.0, 21.7, 12.1; IR (KBr,
cm−1) 3423, 2926, 1644, 1439, 1271, 1063, 781; ESI-HRMS calcd for
C17H14ClO2 [M + H]+ 285.0682, found 285.0673.
(4-Chlorophenyl)(2-propylbenzofuran-3-yl)methanone (13t).
1
Yield 106 mg, 71%; colorless liquid; H NMR (CDCl3, 400 MHz) δ
7.70 (d, 2H, J = 8.4 Hz), 7.40 (t, 3H, J = 8.8 Hz), 7.22 (t, 2H, J = 7.6
Hz), 7.12 (t, 1H, J = 7.2 Hz), 2.82 (t, 2H, J = 7.6 Hz), 1.73 (m, 2H),
0.87 (t, 3H, J = 7.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 190.7, 165.6,
153.7, 139.1, 137.6, 130.6, 128.8, 126.7, 124.4, 123.6, 121.1, 116.5,
111.1, 30.1, 21.2, 13.5; IR (KBr, cm−1) 3428, 2931, 1662, 1424, 1217,
1103, 789, 717; ESI-HRMS calcd for C18H16ClO2 [M + H]+ 299.0839,
found 299.0836.
Ethyl 3-(2-Iodophenoxy)but-2-enoate (15a). Yield 65 mg, 39%;
pale-yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, 1H, J = 8.0
Hz), 7.34 (t, 1H, J = 8.0 Hz), 7.04 (d, 1H, J = 8.0 Hz), 6.94 (t, 1H, J =
8.0 Hz), 4.74 (s, 1H), 4.09 (q, 2H, J = 6.8 Hz), 2.54 (s, 3H), 1.19 (t,
3H, J = 6.0 Hz); 13C NMR (100 MHz, CDCl3): δ 171.1, 167.2, 153.2,
140.0, 129.9, 127.4, 122.7, 96.4, 90.4, 59.6, 18.3, 14.3; ESI-HRMS
calcd for C12H14IO3 [M + H]+ 332.9988, found 332.9980.
Methyl 5-Chloro-2-propylbenzofuran-3-carboxylate (13m). Yield
1
104 mg, 83%; colorless liquid; H NMR (CDCl3, 400 MHz) δ 7.83−
7.82 (m, 1H), 7.25 (d, 1H, J = 8.4 Hz), 7.16−7.15 (m, 1H), 3.86 (s,
3H), 3.06 (t, 2H, J = 7.6 Hz), 1.75−1.69 (m, 2H), 0.92 (t, 3H, J = 7.2
Hz); 13C NMR (CDCl3, 100 MHz) δ 168.8, 164.3, 152.0, 129.5, 127.5,
124.5, 121.6, 111.8, 108.4, 51.5, 30.0, 21.2, 13.8; IR (KBr, cm−1) 2963,
1719, 1448, 1374, 1241, 1110, 804, 712; ESI-HRMS calcd for
C13H14ClO3 [M + H]+ 253.0631, found 253.0640.
ASSOCIATED CONTENT
■
S
* Supporting Information
2-Propylbenzofuran-3-carbonitrile (13n). Yield 63 mg, 68%;
colorless liquid; 1H NMR (CDCl3, 400 MHz) δ 7.63−7.61 (m,
1H), 7.48 (d, 1H, J = 7.6 Hz), 7.36−7.34 (m, 2H), 2.96 (t, 2H, J = 7.6
Hz), 1.90−1.83 (m, 2H), 1.04 (t, 3H, J = 7.6 Hz); 13C NMR (CDCl3,
100 MHz) δ 168.4, 153.7, 126.0, 125.5, 124.3, 120.0, 113.3, 111.5,
91.0, 30.0, 20.9, 13.5; IR (KBr, cm−1) 2977, 2227, 1736, 1433, 1367,
1279, 1201, 753; EI-HRMS calcd for C12H11NO [M]+ 185.0841,
found 185.0838.
General experimental information and 1H and 13C NMR
spectra of all products. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: chemliuyunyun@jxnu.edu.cn.
*E-mail: wanjieping@jxnu.edu.cn.
■
5-tert-Butyl-2-isobutylbenzofuran-3-carbonitrile (13o). Yield 75
1
mg, 59%; colorless liquid; H NMR (CDCl3, 400 MHz) δ 7.61 (s,
1H), 7.40 (s, 2H), 2.83 (d, 2H, J = 6.8 Hz), 2.25−2.18 (m, 1H), 1.38
(s, 9H), 1.02 (d, 6H, J = 6.8 Hz); 13C NMR (CDCl3, 100 MHz) δ
168.0, 152.0, 147.8, 125.6, 123.4, 115.9, 113.8, 110.9, 91.5, 37.0, 34.9,
31.7, 28.2, 22.2; IR (KBr, cm−1) IR (KBr, cm−1) 3423, 2926, 2227,
1637, 1429, 1207, 1109, 779; ESI-HRMS calcd for C17H22NO [M +
H]+ 256.1701, found 256.1705.
(2-Ethylbenzofuran-3-yl)(phenyl)methanone (13p). Yield 86 mg,
69%; colorless liquid; 1H NMR (CDCl3, 400 MHz) δ 7.85 (d, 2H, J =
7.6 Hz), 7.63 (t, 1H, J = 7.2 Hz), 7.53−7.50 (m, 3H), 7.40 (d, 1H, J =
7.6 Hz), 7.33−7.28 (m, 1H), 7.21 (t, 1H, J = 7.6 Hz), 2.92 (q, 2H, J =
7.6 Hz), 1.34 (t, 3H, J = 7.6 Hz); 13C NMR (CDCl3, 100 MHz) δ
192.1, 166.5, 153.6, 139.4, 132.7, 129.2, 128.4, 127.0, 124.2, 123.7,
121.4, 116.1, 110.8, 21.9, 12.4; IR (KBr, cm−1) 3423, 2926, 1644,
1439, 1271, 1063, 781; ESI-HRMS calcd for C17H15O2 [M + H]+
251.1072, found 251.1077.
Phenyl(2-propylbenzofuran-3-yl)methanone (13q). Yield 98 mg,
74%; colorless liquid; 1H NMR (CDCl3, 400 MHz) δ 7.82 (d, 2H, J =
7.2 Hz), 7.61 (t, 1H, J = 7.2 Hz), 7.48 (t, 3H, J = 6.8 Hz), 7.34 (d, 1H,
J = 8.0 Hz), 7.26 (d, 1H, J = 8.0 Hz), 7.17 (t, 1H, J = 7.6 Hz), 2.87 (t,
2H, J = 7.6 Hz), 1.83−1.75 (m, 2H), 0.94 (t, 3H, J = 7.2 Hz); 13C
NMR (CDCl3, 100 MHz) δ 191.9, 165.5, 153.6, 139.6, 132.6, 129.6,
128.5, 126.9, 124.3, 123.4, 121.3, 116.8, 110.9, 30.0, 21.5, 13.8; IR
(KBr, cm−1) 3426, 2924, 1659, 1453, 1276, 1079, 763; ESI-HRMS
calcd for C18H17O2 [M + H]+ 265.1229, found 265.1233.
(2-Isobutylbenzofuran-3-yl)(phenyl)methanone (13r). Yield 87
mg, 63%; colorless liquid; 1H NMR (CDCl3, 400 MHz) δ 7.84 (d, 2H,
J = 6.8 Hz), 7.62 (t, 1H, J = 7.2 Hz), 7.50 (t, 3H, J = 7.2 Hz), 7.30 (t,
2H, J = 6.8 Hz), 7.19 (t, 1H, J = 8.0 Hz), 2.85 (d, 2H, J = 7.2 Hz),
2.29−2.18 (m, 1H), 0.96 (d, 6H, J = 6.4 Hz); 13C NMR (CDCl3, 100
MHz) δ 192.1, 164.9, 153.6, 139.4, 132.6, 129.2, 128.5, 126.8, 124.3,
123.4, 121.3, 117.4, 111.0, 36.7, 28.4, 22.4; IR (KBr, cm−1) 3429, 2923,
1639, 1476, 1231, 1096, 796; ESI-HRMS calcd for C19H19O2 [M +
H]+ 279.1385, found 279.1381.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (21202064 and 21102059), the
Natural Science Foundation of Jiangxi Province
(20142BAB213007), and a Sponsored Program for Cultivating
Youths of Outstanding Ability in Jiangxi Normal University
(Y.L.).
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