Ruthenium(II)-Catalyzed C3 Arylation of 2-Aroylbenzofurans with Arylboronic Acids/Aryltrifluoroborates via Carbonyl-Directed C-H Bond Activation

Article abstract of DOI:10.1021/acs.joc.5b01932

The Ru(II)-catalyzed carbonyl-directed C-H activation with (hetero)arylboron reagents has been executed for the synthesis of 2-aroyl-3-(hetero)arylbenzofurans. A hypothesis founded upon the involvement of an active carbonatoruthenium(II) complex for a coo

Full text of DOI:10.1021/acs.joc.5b01932

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Note
Ruthenium(II)-Catalyzed C3 Arylation of 2-Aroylbenzofurans with Arylboronic
Acids/Aryltrifluoroborates via Carbonyl Directed C–H Bond Activation
Dinesh J Paymode, and Chepuri V. Ramana
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01932 • Publication Date (Web): 13 Oct 2015
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Ruthenium(II)-Catalyzed C3 Arylation of 2-Aroylbenzofurans with
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Arylboronic Acids/Aryltrifluoroborates via Carbonyl Directed C–H Bond
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Activation
Dinesh J. Paymode and Chepuri V. Ramana*
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Division of Organic Chemistry, CSIRꢀNational Chemical Laboratory, Dr. Homi Bhabha
Road, Pune, Maharashtra, Indiaꢀ 411008.
*Corresponding author: Tel.: +91 20 25902577; Fax: +91 20 25902629
Eꢀmail: vr.chepuri@ncl.res.in
Abstract: The Ru(II)ꢀcatalyzed carbonyl directed C–H activation with (hetero)arylboron
reagents has been executed for the synthesis of 2ꢀaroylꢀ3ꢀ(hetero)arylbenzofurans. A
hypothesis founded upon the involvement of an active carbonatoruthenium(II) complex for a
coordinative insertion and the aerobic oxidation of the in situ generated Ru(0) to Ru(II), to
continue the catalytic cycle, has been extended.
The direct and directed catalytic activation of aryl C−H bonds and their
functionalization with various electrophiles is one of the contemporary approaches for the
construction of various types of C–C and C–heteroatom bonds.1 The step and atom
economies associated with this C–H activation approach has led to a revolution in synthetic
methodologies and a plethora of new methods that can competitively replace several classical
catalytic crossꢀcoupling reactions have been documented and a wideꢀrange of metal
complexes have been explored in this pursuit.2 Arguably, the rutheniumꢀcomplexes, because
of their cost, compatibility with many oxidants, stability and ready suitability at least for
some of the complexes to carry the reactions even in water, have emerged as powerful
catalysts in this “C–H activation and functionalization” domain.3
Benzofuran is one of the commonly encountered structural units in natural products.4
In recent years, benzofuran derivatives have seen applications in the development of
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pharmaceutical agents and functionalized materials.5 Particularly, the 2ꢀaroylꢀ3ꢀ
arylbenzofuran structural motifs are present in many natural products and have been shown to
display a range of biological activities.6 General approaches reported for the synthesis of
these 2ꢀaroylꢀ3ꢀarylbenzofuran substrates involve the use of classical acid/baseꢀmediated
condensations and subsequent aroylation or arylation.7 Despite the fact that the core of 2ꢀ
aroylbenzofuran is integrated with a readily required carbonyl directing group, the utilization
of this handle for the directed alkylation or arylation has not been used until recently.8ꢀ10
Recently, the Bertounesque and Doucet groups documented the Pdꢀcatalyzed C3ꢀarylation of
C2ꢀsubstituted benzofurans using aryl bromides9 and alkylation with acrylates was
documented by our group using Ruꢀcomplexes.10 Given their significant biological activities
and also considering the fact that the ruthenium complexes are cheaper and stable with air
and moisture, the possibility of Ruꢀcatalyzed C3ꢀarylation of C2ꢀaroylbenzofurans has been
undertaken.10–13 There was only a single report on the carbonyl directed arylation with the
Ruꢀcomplexes. In 2003, Kakiuchi described the Ru(0)ꢀcatalyzed carbonyl directed ortho
arylation of acetophenones with arylboronates (eq 1).14 Apart from, to the best of our
knowledge, there has been no reports so far on this aspect. Herein we describe the Ru(II)ꢀ
catalyzed carbonyl directed C3ꢀarylation of 2ꢀaroylbenzofurans either with arylboronic acids
or with arylꢀBF3K salts (eq 2).15,16
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Initially, the feasibility of arylation of benzofuran 1a with 4ꢀacetylphenylboronic acid
2a was examined in the presence of the RuCl2(PPh3)3/AgOAc catalyst system under the
conditions that have been earlier established for the alkylation of 1a with acrylates.10 The
reaction was conducted by heating a mixture of substrates 1a and 2a in the presence of
catalyst RuCl2(PPh3)3 (10 mol%), K2CO3 (3.0 eq.) and coꢀcatalyst AgOAc (30 mol%) in
toluene at 140 °C for 24 h in a screwꢀcapped sealed tube under the argon atmosphere.
However, the reaction was incomplete and afforded the required 3aa in 13% yield (Table 1,
entry 1). With this initial optimistic result, the reaction was explored by varying the coꢀ
oxidants like Cu(OAc)2.2H2O/AgSbF6 and AdꢀCO2H (Table 1, entries 2 and 3). With the
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former, the yield of 3aa was improved up to 37%. Surprisingly, the reaction in the presence
of AdꢀCO2H was sluggish and no product formation was noticed. Quite interestingly, when
the reaction was conducted only in the presence of catalyst/K2CO3 and without any other
additive, the complete consumption of starting 1a was noticed and provided 3aa in 87%
isolated yield. With these promising results in hand, we next examined the compatibility of
other solvents like 1,2ꢀdichloroethane (DCE), 1,4ꢀdioxane, NMP and DMF (Table 1, entries
4–8) as well as other bases. It was found that toluene was the best solvent for the present
arylation reaction. Coming to the other bases examined, Na2CO3 and Cs2CO3 gave 78% and
68% yield respectively (Table1, entries 9 and 10).
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Table 1.Optimization of C3ꢀarylation of benzofuran 1a with boronic acid 2aa
entry
1b
2b
3b
additive
AgOAc
AdꢀCO2H
Cu(OAc)2.2H2O, K2CO3 Toluene
AgSbF6
base
solvent
yield [%]c
13(71)d
K2CO3 Toluene
K2CO3 Toluene
ꢀꢀ
31(78)d
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
4
5
6
7
8
9
10
K2CO3 Toluene
K2CO3 DCE
K2CO3 1,4 Dioxane 42(83)d
K2CO3 NMP
K2CO3 DMF
Na2CO3 Toluene
Cs2CO3 Toluene
87
81
53(84)d
11(58)d
78
68(79)d
aReaction conditions: 1a (0.2 mmol), 2a (0.22 mmol),
RuCl2(PPh3)3 (0.02 mmol), base (0.6 mmol) and additive (0.06
mmol); 140 °C, 24 h, solvent (2 mL). bUnder Argon
atmosphere, cIsolated yields. dYields (based on recovered 1a).
Next, the scope and limitations of the ruthenium catalyzed arylation reaction has been
examined by employing variously substituted benzofurans and arylboronic acids. Functional
groups like acetyl, bromo, chloro, fluoro and methoxy on the phenylboronic acid unit were
found to be tolerated under these conditions and gave the corresponding products in excellent
yields. These results indicated that the reaction is not sensitive to the electronic properties of
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the substituents present on the any boronic acids. Coming to the effect of the substituents on
the benzofuran reactivity, 5,7ꢀdichloro substituted benzofuran 3c delivered the arylation
products in excellent yields (Table 2, entries 3ca–3ch). It has been observed that the yields
are moderate when the benzofuran ring contains electron donating substituents like the
methoxy group (Table 2, entries 3ea, 3eb, 3fa, 3fg), which is expected as the C3–H bond
should be less acidic, and more difficult to deprotonate. The successful reaction of 4ꢀ
bromophenylboronic acid (2c) with benzofuran 1a is noteworthy, since the reaction
specifically worked with the boronic acid counterpart and not with the bromide (Table 2,
entry 3ac).
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Table 2. Reaction scope of C3ꢀarylation with boronic acids 2
H
Ar'
2y
( , 1.1 eq.)
RuCl2(PPh3)3 (10 mol%)
Ar'B(OH)2
O
O
R
R
O
O
Ar
Ar
K2CO3 (3.0 eq.), air
toluene, 140 °C, 24 h
1x
3xy
R
O
R
O
O
PMP
O
Ph
3bb
3bd
3be
, 89% (R = 3-OMe)
, 79% (R = 4-F)
, 58% (R = 3-NO2)
3aa
3ab
3ac
, 87% (R = 4-Ac)
, 89% (R = 3-OMe)
, 71% (R = 4-Br)
3bf
, 93% (R = 3,4-dichloro)
3bg
, 85% (R = 3-Ac)
(PMP = 4-methoxyphenyl)
R
O
Cl
R
O
Ph
Br
O
Cl
, 96% (R = 4-Ac)
, 93% (R = 3-OMe)
, 81% (R = 4-F)
, 92% (R = 3-Ac)
, 92% (R = 3,4-dimethoxy)
3ca
3cb
3cd
3cg
3ch
O
Ph
3df
, 83% (R = 3,4-dichloro)
3dh
,86% (R = 3,4-dimethoxy)
R
O
R
MeO
O
O
PClP
O
PClP
OMe
3fa
3fg
, 68% (R = 4-Ac)
, 75% (R = 3-Ac)
3ea
3eb
, 64% (R = 4-Ac)
, 53% (R = 3-OMe)
(PClP = p-chlorophenyl)
Having established the arylation with various arylboronic acids, we next focused our
attention on the arylation with potassium aryltrifluoroborates considering the superior air–
and moisture stability and the better nucleophilicity over the corresponding aryl boronic acid
derivatives.16c In the first instance, the reaction was carried under the conditions optimized
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with the arylboronic acids (3.0 eq. K2CO3 in toluene at 140 °C for 24 h). The reaction
proceeded smoothly and afforded the required 3ai in moderate yield (Table 3, entry 1). Like
with the boronic acids, the presence of carboxylic acid additives has a negative effect (Table
3, entries 2–6). Among the various solvents screened, in DCE the yield has been further
improved (Table 3, entries 7–10). The variation in base did not show any promising effect on
the reaction (Table 3, entry 11 and 12). To this end, when we employed 3.0 eq. of 2i, the
yield was improved from 67% to 83% (Table 3, entry 13). The requirement of excess of 2i
may be due to its lower solubility as has been seen earlier.16a
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Table 3. Optimization of C3 arylation of benzofuran 1a with aryltrifluroborate salt 2ia
entry
1
additive
base
solvent
yield [%]c
58
ꢀ
K2CO3 toluene
K2CO3 toluene
K2CO3 toluene
K2CO3 1,4ꢀdioxane 9(63) d
2b
AgOAc
AgOTf
AdꢀCO2H
Cu(OAc)2.2H2O, K2CO3 toluene
AgSbF6
KPF6
35(76)d
28(68) d
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5b
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K2CO3 DCE
K2CO3 1,4ꢀdioxane 32
K2CO3 NMP
K2CO3 DMF
Na2CO3 DCE
Cs2CO3 DCE
K2CO3 DCE
15(64) d
67
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
-
42
ꢀꢀ
44
51
83e
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11
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13
aReaction conditions: 1a (0.2 mmol), 2i (0.24 mmol),
RuCl2(PPh3)3 (0.02 mmol), base (0.6 mmol) and additive (0.06
b
mmol); 140 °C, 24 h, solvent (2 mL). Under air atmosphere,
d
e
cIsolated yields. Yields (based on recovered 1a). 2i 0.6 mmol
was used.
Table 4 reveals the scope of the C2 arylation of various 2ꢀaroylbenzofurans 1 with
potassium (hetero)aryltrifluoroborates 2. As has been seen earlier, the nature of the
substituents on the aryl ring does not have much influence on the reaction outcome.
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Impressively, the reaction with 3ꢀfuryltrifluoroborate 2k also proceeded smoothly and
provided the corresponding products in very good yields.
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Table 4: Reaction scope of C3ꢀarylation with potassium aryltrifluorolborates 2
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Next we proceeded further to understand the course of the reaction mechanism. As
mentioned earlier, the only available reports on the Ru(0)ꢀcatalyzed carbonyl directed C–H
arylation are from Kakiuchi’s group where arylboronates were employed as the
electrophiles.14 The in situ generation of a Ru(0) complex from the employed
RuH2(CO)(PPh3)3 complex and the subsequent carbonyl directed oxidative insertion across
the Ar–H bond has been proposed as the key step. It has been proposed that the reduction of
one molecule of either of the acetophenone substrates or an added aliphatic ketone to the
corresponding alcohol is inevitable for the hydride transfer from the initially generated Ar–
Ru–H species and the resulting alcohol assists the transfer of the aryl group from the boronate
to the Ruꢀcenter. A final reductive elimination results in the formation of product and the
regeneration of initial Ru(0)ꢀcomplex to continue the catalytic cycle. Coming to the current
conditions for the carbonyl directed arylation, both the substrate and boronic acid were
employed in equal molar proportions and the yields were excellent. An examination of the
course of the reaction with HPLC revealed that there is no formation of the corresponding
alcohol 4a which is expected if the Ru–H intermediate is involved. In addition, we examined
the arylation of 4a with 2a under established reaction conditions (Scheme 1). The reaction
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was sluggish and the arylation product 5aa was obtained 40% yield along with portion of 4a
being recovered. The HPLC analysis of this reaction mixture revealed that there were no
traces of 3aa or 1a resulting from the oxidation of either product 5aa or starting 4a. When
simple 2ꢀphenylbenzofuran 4b was used as a substrate, there was no arylation under these
conditions. This revealed that the current arylation needs a carbonyl as a directing group.
Now, the important question is about the oxidation of the resulting Ru(0)ꢀspecies after the
final reductive elimination, thus completing the catalytic cycle. At this stage, some reports on
aerobic oxidation by palladium17 and rhodium18 catalysts and also a recent report on
ruthenium from Ackermann’s group19 revealing the reoxidation of Ru(0) by molecular
oxygen in a Ru(II)ꢀcatalyzed oxidative alkyne annulation has rescued our hypothesis.
Considering this, the arylation of 1a with 2a was examined under the established conditions,
albeit purging the reaction mixture with oxygen prior to heating. Under these conditions, the
reaction proceeded smoothly and provided the expected arylation product 3aa in 85% yield.
This, suggests the aerobic oxidation of the intermediate Ru(0)ꢀcomplex in the presence of
bi/carbonate to regenerate the carbonatoruthenium(II) complex (I), to continue the catalytic
cycle.
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Scheme 1: control experiments.
With this available information in hand, and based upon the earlier studies, we
propose the following tentative mechanism (Scheme 2).20 First, the catalyst RuCl2(PPh3)3
reacts with K2CO3 to form the active carbonatoruthenium(II) complex I.21 Then the Ruꢀmetal
reversibly coordinates with carbonyl to form the intermediate II. Next, the ruthenium
interacts with the orthoꢀcarbon atom to favour the concerted metallation deprotonation
(CMD) by the coordinated carbonate to deliver the cyclometallated intermediate III.22
Subsequently, the transmetalation of III takes place with the arylboronic reagents to yield the
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Ru–Ar species IV. Poor yields were obtained when AgOAc was employed and the complete
lack of reactivity when AdꢀCO2H was employed as an additive reveals that the steric
crowding around the Ruꢀcenter in the intermediate metallacycle III is detrimental in the
transmetalation with the arylboron reagents 2, leading to the [Ru]–Ar species IV. Finally, the
intermediate species IV undergoes a reductive elimination reaction resulting in the arylation
product 3 and a Ru(0)ꢀcomplex, which was subsequently oxidized by molecular oxygen to
Ru(II)ꢀcomplex (I) that continues the catalytic cycle.
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Scheme 2. Plausible reaction mechanism.
In conclusion, a carbonyl directed ruthenium(II)ꢀcatalyzed C3–H activation and
(hetero)arylation of 2ꢀaroylbenzofurans employing either (hetero)arylꢀboronic acids or their
corresponding trifluoroborate salts, has been documented. The reactions proceed smoothly in
the presence of K2CO3 and added carboxylates were found to be detrimental to the reactivity.
This has been attributed to the steric crowding caused by the corresponding carboxylate
during the transmetalation step. The control experiments revealed that the directing group is
essential and that crucial reoxidation of Ru(0) with molecular oxygen assists to continue the
catalytic cycle.
EXPERIMENTAL SECTION
General information:
Reactions were carried out in anhydrous solvents in ovenꢀdried glassware. NMR spectra were
recorded on 200 MHz, 400 MHz and 500 MHz spectrometers. TMS was used as an internal
standard and chemical shifts were reported in parts per million (δ) relative to internal
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standard TMS (0 ppm) and for CDCl3, 25 °C (7.25 ppm for 1H NMR; and central peak is 77.0
ppm in CDCl3 for 13C NMR). Mass spectroscopy was carried out on Hybrid QuadrupoleꢀTOF
LC/MS/MS. Melting points are uncorrected.
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General procedure: 2ꢀaroylbenzofuran (0.2 mmol) was placed in a screw cap pressure tube
and dissolved in anhydrous solvent (2 ml). To the reaction vessel arylboronic acid (0.42
mmol) or potassium aryltrifluoroborate (0.6 mmol), K2CO3 (0.6 mmol), RuCl2(PPh3)3 (10
mol%) were added. The solution was then stirred at 140 °C (bath temperature) for 24 h. The
reaction mixture was cooled to room temperature. The solvent was evaporated and the crude
mixture was purified by silica gel (230–400 mesh) column chromatography (0→15% pet.
ether/EtOAc).
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1ꢀ(4ꢀ(2ꢀBenzoylbenzofuranꢀ3ꢀyl)phenyl)ethanꢀ1ꢀone (3aa):9b Pale yellow solid; 87% yield
1
(60 mg); mp 87–89 °C; Rf = 0.2 (pet. ether/EtOAc = 9:1); H NMR (500 MHz, CDCl3):
δ
2.62 (s, 3H), 7.36–7.41 (m, 3H), 7.51–7.56 (m, 2H), 7.62–7.67 (m, 4H), 7.94 (d, J = 7.6 Hz,
2H), 7.99 (d, J = 8.2 Hz, 2H); 13C NMR (125 MHz, CDCl3):
26.7 (q), 112.5 (d), 122.0 (d),
δ
124.3 (d), 127.6 (s), 128.2 (s), 128.3 (d, 2C), 128.3 (d, 2C), 128.5 (d), 129.9 (d, 2C), 130.2 (d,
2C), 133.0 (d), 136.0 (s), 136.6 (s), 137.0 (s), 147.5 (s), 154.5 (s), 185.4 (s), 197.6 (s) ppm; IR
(CHCl3) 3022, 1681, 1649, 1606, 1567, 1367, 1265, 1008, 766 cm−1; HRMS (ESI) calcd. for
C23H17O3 (M+H)+ 341.1172, found 341.1173.
(3ꢀ(3ꢀMethoxyphenyl)benzofuranꢀ2ꢀyl)(phenyl)methanone (3ab): White solid; 89% yield (59
1
mg); mp 84–86 °C; Rf = 0.4 9 (pet. ether/EtOAc = 9:1; H NMR (400 MHz, CDCl3):
δ 3.74
(s, 3H), 6.87 (ddd, J = 0.9, 2.3, 8.2 Hz, 1H), 6.98 (dd, J = 1.3, 2.3 Hz, 1H), 7.07(dt, J = 1.1,
7.6 Hz, 1H), 7.27(t, J = 7.9 Hz, 1H), 7.31–7.37 (m, 3H), 7.47 (tt, J = 1.4, 7.5 Hz, 1H), 7.53
(ddd, J = 1.4, 7.3, 8.3 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.84–7.86
(m, 2H); 13C NMR (125 MHz, CDCl3):
δ 55.3 (q), 112.4 (d), 114.3 (d), 115.4 (d), 122.4 (d),
122.4 (d), 123.9 (d), 128.0 (s), 128.1 (d, 2C), 128.2 (d), 129.2 (s), 129.4 (d), 129.8 (d, 2C),
132.1 (s), 132.7 (d), 137.3 (s), 147.1 (s), 154.6 (s), 159.5 (s), 185.9 (s) ppm; IR (CHCl3)
3021, 1646, 1597, 1481, 1436, 1217, 1170, 1021, 760 cm−1; HRMS (ESI) calcd. for C22H17O3
(M+H)+ 329.1172, found 329.1170.
(3ꢀ(4ꢀBromophenyl)benzofuranꢀ2ꢀyl)(phenyl)methanone (3ac): White solid; 71% yield (54
1
mg); mp 115–117 °C; Rf = 0.4 (pet. ether/EtOAc = 9.5:0.5); H NMR (400 MHz, CDCl3):
δ
7.34–7.45 (m, 5H), 7.52–7.55 (m, 4H), 7.64 (t, J = 7.9 Hz, 2H), 7.91 (d, J = 7.8 Hz, 2H); 13C
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NMR (100 MHz, CDCl3):
δ
112.5 (d), 122.0 (d), 122.6 (s), 124.1 (d), 127.8 (s), 128.2 (d,
2C), 128.4 (d), 128.4 (s), 129.7 (s), 129.9 (d, 2C), 131.5 (d, 2C), 131.6 (d, 2C), 132.9 (d),
137.1 (s), 147.2 (s), 154.5 (s), 185.4 (s) ppm; IR (CHCl3) 3022, 1648, 1596, 1485, 1432,
1216, 1116, 764, 672 cm−1; HRMS (ESI) calcd. for C21H14BrO2 (M+H)+ 377.0172, found
377.0168.
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(4ꢀMethoxyphenyl)(3ꢀ(3ꢀmethoxyphenyl)benzofuranꢀ2ꢀyl)methanone (3bb): Yellow oil; 89%
yield (63 mg); Rf = 0.4 (pet. ether/EtOAc = 9:1); 1H NMR (500 MHz, CDCl3):
δ 3.76 (s, 3H),
3.84 (s, 3H), 6.84 (d, J = 8.8 Hz, 2H), 6.89 (dd, J = 2.2, 8.1 Hz, 1H), 7.03 (s, 1H), 7.10 (d, J =
7.5 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.4 Hz, 1H), 7.63
(d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.8 Hz, 2H); 13C NMR (125 MHz,
CDCl3):
δ 55.3 (q), 55.5 (q), 112.3 (d), 113.5 (d, 2C), 114.1 (d), 115.4 (d), 122.2 (d), 122.4
(d), 123.8 (d), 127.8 (d), 128.0 (s), 128.1 (s), 129.4 (d), 130.0 (s), 132.3 (d, 2C), 132.3 (s),
147.5 (s), 154.4 (s), 159.5 (s), 163.5 (s), 184.3 (s) ppm; IR (CHCl3) 3022, 1639, 1598, 1425,
1254, 1216, 1119, 765 cm−1; HRMS (ESI) calcd. for C23H19O4 (M+H)+ 359.1278, found
359.1274.
(3ꢀ(4ꢀFluorophenyl)benzofuranꢀ2ꢀyl)(4ꢀmethoxyphenyl)methanone (3bd): White solid; 79%
1
yield (54 mg); mp 114–116 °C; Rf = 0.5 (pet. ether/EtOAc = 9:1); H NMR (500 MHz,
CDCl3):
1H), 7.52 (t, J = 6.4 Hz, 3H), 7.63(d, J = 8.5 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.96 (d, J =
8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3):
55.5 (q), 112.4 (d), 113.6 (d, 2C), 115.5 (d, J =
δ 3.86 (s, 3H), 6.88 (d, J = 8.7 Hz, 2H), 7.10 (t, J = 8.6 Hz, 2H), 7.35 (t, J = 7.5 Hz,
δ
21.9 Hz, 2C), 122.0 (d), 124.0 (d), 127.1 (d, J = 2.9 Hz), 127.5 (s), 128.0 (d), 128.0 (s), 129.8
(s), 131.8 (d, J = 8.6 Hz, 2C), 132.4 (d, 2C), 147.6 (s), 154.4 (s), 162.6 (d, J = 248.0 Hz),
163.6 (s), 184.0 (s) ppm; IR (CHCl3) 3021, 1643, 1601, 1568, 1423, 1221, 1025, 765 cm−1;
HRMS (ESI) calcd. for C22H16FO3 (M+H)+ 347.1078, found 347.1078.
(4ꢀMethoxyphenyl)(3ꢀ(3ꢀnitrophenyl)benzofuranꢀ2ꢀyl)methanone (3be): Pale yellow solid;
58% yield (43 mg); mp 131–133 °C; Rf = 0.3 (pet. ether/EtOAc = 9:1); 1H NMR (500 MHz,
CDCl3):
1H), 7.60–7.68 (m, 3H), 7.93 (d, J = 7.6 Hz, 1H), 8.03 (d, J = 8.8 Hz, 2H), 8.25 (d, J = 8.2
Hz, 1H), 8.45 (s, 1H); 13C NMR (125 MHz, CDCl3):
55.5 (q), 112.6 (d), 113.7 (d, 2C),
δ 3.87 (s, 3H), 6.93 (d, J = 8.8 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.5 Hz,
δ
121.5 (d), 123.1 (d), 124.4 (d), 124.9 (d), 126.2 (s), 127.4 (s), 128.4 (d), 129.3 (d), 129.6 (s),
132.5 (d, 2C), 133.1 (s), 136.2 (d), 148.2 (s), 148.3 (s), 154.3 (s), 163.8 (s), 183.5 (s) ppm; IR
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(CHCl3) 3022, 1642, 1597, 1527, 1425, 1217, 1027, 766 cm−1; HRMS (ESI) calcd. for
C22H16NO5 (M+H)+ 374.1023, found 374.1022.
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(3ꢀ(3,4ꢀDichlorophenyl)benzofuranꢀ2ꢀyl)(4ꢀmethoxyphenyl)methanone (3bf): White solid;
93% yield (73 mg); mp 119–121 °C; Rf = 0.4 (pet. ether/EtOAc = 9:1); 1H NMR (500 MHz,
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CDCl3):
δ
3.88 (s, 3H), 6.92 (d, J = 8.7 Hz, 2H), 7.36–7.41 (m, 2H), 7.49 (d, J = 8.3 Hz, 1H),
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7.53 (t, J = 7.3 Hz, 1H), 7.63–7.66 (m, 3H), 8.00 (d, J = 8.6 Hz, 2H); C NMR (125 MHz,
CDCl3):
δ 55.5 (q), 112.5 (d), 113.7 (d, 2C), 121.7 (d), 124.2 (d), 126.1 (s), 127.6 (s), 128.2
(d), 129.4 (d), 129.7 (s), 130.4 (d), 131.2 (s), 131.6 (d), 132.4 (d , 2C), 132.4 (s), 132.6 (s),
147.9 (s), 154.3 (s), 163.8 (s), 183.6 (s) ppm; IR (CHCl3) 3021, 1639, 1597, 1469, 1421,
1217, 1027, 762 cm−1; HRMS (ESI) calcd. for C22H15Cl2O3 (M+H)+ 397.0393, found
397.0394.
1ꢀ(3ꢀ(2ꢀ(4ꢀMethoxybenzoyl)benzofuranꢀ3ꢀyl)phenyl)ethanꢀ1ꢀone (3bg): White solid; 85%
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yield (62 mg); mp 81–83 °C; Rf = 0.5 (pet. ether/EtOAc = 8.5:1.5); H NMR (200 MHz,
CDCl3):
2H), 7.63–7.68 (m, 2H), 7.77 (dt, J = 1.5, 7.6 Hz, 1H), 7.96 (d, J = 8.8 Hz, 3H), 8.12 (t, J =
1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3):
26.7 (q), 55.5 (q), 112.4 (d), 113.6 (d, 2C),
δ 2.59 (s, 3H), 3.85 (s, 3H), 6.85–6.89 (m, 2H), 7.32–7.40 (m, 1H), 7.48–7.58 (m,
δ
121.9 (d), 124.1 (d), 127.6 (s), 127.8 (s), 128.0 (d), 128.1 (d), 128.7 (d), 129.8 (s), 130.0 (d),
131.7 (s), 132.4 (d, 2C), 134.6 (d), 137.2 (s), 147.8 (s), 154.4 (s), 163.6 (s), 183.9 (s), 197.7
(s) ppm; IR (CHCl3) 3022, 1684, 1600, 1426, 1298, 1218, 1026, 767 cm−1; HRMS (ESI)
calcd. for C24H19O4 (M+H)+ 371.1278, found 371.1278.
1ꢀ(4ꢀ(2ꢀBenzoylꢀ5,7ꢀdichlorobenzofuranꢀ3ꢀyl)phenyl)ethanꢀ1ꢀone (3ca): White solid; 96%
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yield (81 mg); mp 168–170 °C; Rf = 0.2 (pet. ether/EtOAc = 9:1); H NMR (500 MHz,
CDCl3):
δ
2.63 (s, 3H), 7.45 (t, J = 7.8 Hz, 2H), 7.52–7.59 (m, 3H), 7.61 (d, J = 8.2 Hz, 2H),
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8.01–8.03 (m, 4H); C NMR (125 MHz, CDCl3):
δ 26.7 (q), 118.8 (s), 120.0 (d), 127.7 (s),
128.3 (d), 128.5 (d, 2C), 128.6 (d, 2C), 129.9 (s), 130.0 (d, 4C), 130.3 (s), 133.6 (d), 134.7
(s), 136.3 (s), 137.0 (s), 148.9 (s), 149.0 (s), 184.3 (s), 197.5 (s) ppm; IR (CHCl3) 3024, 1678,
1592, 1418, 1217, 1119, 761 cm−1; HRMS (ESI) calcd. for C23H14Cl2O3Na (M+Na)+
431.0212, found 431.0214.
(5,7ꢀDichloroꢀ3ꢀ(3ꢀmethoxyphenyl)benzofuranꢀ2ꢀyl)(phenyl)methanone (3cb): Brown solid;
93% yield (76 mg); mp 113–115 °C; Rf = 0.4 (pet. ether/EtOAc = 9:1); 1H NMR (400 MHz,
CDCl3):
δ
3.77 (s, 3H), 6.92 (dd, J = 2.3, 8.3 Hz, 1H), 6.97 (t, J = 2.2 Hz, 1H), 7.04 (d, J =
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7.7 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.39 (t, J = 7.8 Hz, 2H), 7.51–7.55 (m, 2H), 7.58 (d, J =
13
1.9 Hz, 1H), 7.92–7.94 (m, 2H); C NMR (100 MHz, CDCl3):
δ 55.3 (q), 114.5 (d), 115.4
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(d), 118.6 (s), 120.4 (d), 122.1 (d), 128.0 (d), 128.3 (d, 2C), 128.5 (s), 129.7 (d), 129.9 (s),
129.9 (d, 2C), 130.3 (s), 131.0 (s), 133.2 (d), 136.6 (s), 148.7 (s), 149.0 (s), 159.6 (s), 184.7
(s) ppm; IR (CHCl3) 3021, 1718, 1595, 1571, 1457, 1217, 1168, 1045, 764 cm−1; HRMS
(ESI) calcd. for C22H15Cl2O3 (M+H)+ 397.0393, found 397.0396.
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(5,7ꢀDichloroꢀ3ꢀ(4ꢀfluorophenyl)benzofuranꢀ2ꢀyl)(phenyl)methanone (3cd): Pale yellow
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solid; 81% yield (64 mg); mp 140–142 °C; Rf = 0.3 (pet. ether/EtOAc = 9.5:0.5); H NMR
(200 MHz, CDCl3):
δ
7.12 (tt, J = 2.1, 8.5 Hz, 2H), 7.38–7.42 (m, 1H), 7.43–7.47 (m, 2H),
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7.48–7.61 (m, 4H), 7.94–7.99 (m, 2H); C NMR (125 MHz, CDCl3):
δ 115.8 (d, J = 21.9
Hz, 2C), 118.7 (s), 120.1 (d), 125.7 (d, J = 2.9 Hz), 127.8 (s), 128.1 (d), 128.4 (d, 2C), 130.0
(d, 2C), 130.0 (s), 130.3 (s), 131.7 (d, J = 7.6 Hz, 2C), 133.4 (d), 136.5 (s), 148.7 (s), 148.9
(s), 162.9 (d, J = 243.2 Hz), 184.5 (s) ppm; IR (CHCl3) 3022, 1717, 1654, 1595, 1449, 1218,
1088, 762 cm−1; HRMS (ESI) calcd. for C21H12Cl2FO2 (M+H)+ 385.0193, found 385.0189.
1ꢀ(3ꢀ(2ꢀBenzoylꢀ5,7ꢀdichlorobenzofuranꢀ3ꢀyl)phenyl)ethanꢀ1ꢀone (3cg): White solid; 92%
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yield (78 mg); mp 164–166 °C: Rf = 0.2 (pet. ether/EtOAc = 9:1); H NMR (500 MHz,
CDCl3):
δ
2.60 (s, 3H), 7.42 (t, J = 7.7 Hz, 2H), 7.51 (d, J = 1.8 Hz, 1H), 7.54–7.57 (m, 3H),
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7.71(d, J = 7.6 Hz, 1H), 7.97–7.99 (m, 3H), 8.07 (s, 1H); C NMR (125 MHz, CDCl3):
δ
26.7 (q), 118.8 (s), 120.0 (d), 127.9 (s), 128.3 (d), 128.4 (d, 2C), 128.7(d), 129.0 (d), 129.8
(d), 130.0 (d, 2C), 130.0 (s), 130.1 (s), 130.2 (s), 130.4 (s), 133.4 (d), 134.2 (d), 136.4 (s),
137.4 (s), 148.9 (s), 184.4 (s), 197.4 (s) ppm; IR (CHCl3) 3020, 1687, 1599, 1424, 1216,
1017, 771 cm−1; HRMS (ESI) calcd. for C23H15Cl2O3 (M+H)+ 409.0393, found 409.0392.
(5,7ꢀDichloroꢀ3ꢀ(3,4ꢀdimethoxyphenyl)benzofuranꢀ2yl)(phenyl)methanone (3ch): Yellow
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solid; 92% yield (81 mg); mp 145–147 °C; Rf = 0.3 (pet. ether/EtOAc = 9:1); H NMR (500
MHz, CDCl3):
δ 3.81 (s, 3H), 3.91 (s, 3H), 6.92 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 1.9 Hz, 1H),
7.09 (dd, J = 1.9, 8.2 Hz, 1H), 7.39 (t, J = 7.9 Hz, 2H), 7.51–7.54 (m, 2H), 7.59 (d, J = 1.8
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Hz, 1H), 7.93 (d, J = 8.0 Hz, 2H); C NMR (125 MHz, CDCl3):
δ 56.0 (q), 56.0 (q), 111.2
(d), 113.3 (d), 118.6 (s), 120.5 (d), 122.1 (s), 122.5 (d), 128.0 (d), 128.3 (d, 2C), 128.7 (s),
129.8 (s), 129.9 (d, 2C), 130.5 (s), 133.2 (d), 136.8 (s), 148.4 (s), 148.9 (s), 149.0 (s), 149.6
(s), 184.8 (s) ppm; IR (CHCl3) 3022, 1651, 1592, 1456, 1252, 1218, 1154, 764 cm−1; HRMS
(ESI) calcd. for C23H17Cl2O4 (M+H)+ 427.0498, found 427.0499.
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(5ꢀBromoꢀ3ꢀ(3,4ꢀdichlorophenyl)benzofuranꢀ2ꢀyl)(phenyl)methanone (3df): White solid;
83% yield (74 mg); mp 118–120 °C: Rf = 0.4 (pet. ether/EtOAc = 9:1); 1H NMR (500 MHz,
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CDCl3):
7.64 (m, 3H), 7.76 (d, J = 1.5 Hz, 1H), 7.91 (d, J = 7.7 Hz, 2H); 13C NMR (125 MHz, CDCl3)
114.1 (d), 117.5 (s), 124.3 (d), 126.0 (s), 128.4 (d, 2C), 129.1 (d), 129.4 (s), 129.8 (d, 2C),
δ 7.35 (dd, J = 1.7, 8.4 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 7.48–7.53(m, 2H), 7.55–
δ
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130.2 (s), 130.5 (d), 131.6 (d, 2C), 132.8 (s), 133.0 (s), 133.3 (d), 136.6 (s), 148.3 (s), 153.0
(s), 1884.9 (s) ppm; IR (CHCl3) 3022, 1678, 1594, 1425, 1216, 1122, 1024, 766, 670 cm−1;
HRMS (ESI) calcd. for C21H12BrCl2O2 (M+H)+ 444.9397, found 444.9405.
(5ꢀBromoꢀ3ꢀ(3,4ꢀdimethoxyphenyl)benzofuranꢀ2ꢀyl)(phenyl)methanone (3dh): White solid;
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86% yield (75 mg); mp 118–120 °C; Rf = 0.4 (pet. ether/EtOAc = 9:1); HNMR (400 MHz,
CDCl3):
1H), 7.34 (t, J = 7.8 Hz, 2H), 7.46–7.52 (m, 2H), 7.60 (dd, J = 2.0, 8.8 Hz, 1H), 7.82–7.85
(m, 3H); 13C NMR (100 MHz, CDCl3):
56.0 (q, 2C), 111.2 (d), 113.4 (d), 114.0 (d), 117.1
δ 3.77 (s, 3H), 3.90 (s, 3H), 6.90 (dd, J = 2.9, 4.8 Hz, 2H), 7.08 (dd, J = 2.0, 8.3 Hz,
δ
(s), 122.5 (d), 122.6 (s), 125.0 (d), 128.2 (d, 2C), 128.3 (s), 129.8 (d, 2C), 130.1 (s), 131.2
(d), 132.9 (d), 137.1 (s), 147.7 (s), 148.9 (s), 149.5 (s), 153.3 (s), 185.6 (s) ppm; IR (CHCl3)
3021, 1646, 1594, 1452, 1255, 1217, 1153, 758 cm−1; HRMS (ESI) calcd. for C23H18BrO4
(M+H)+ 437.0383, found 437.0384.
1ꢀ(4ꢀ(2ꢀ(4ꢀChlorobenzoyl)ꢀ7ꢀmethoxybenzofuranꢀ3ꢀyl)phenyl)ethanꢀ1ꢀone (3ea): Brown
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solid; 64% yield (50 mg); mp 151–153 °C; Rf = 0.3 (pet. ether/EtOAc = 8:2); H NMR (500
MHz, CDCl3):
δ 2.64 (s, 3H), 4.04 (s, 3H), 7.02 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H),
7.29 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.99 (d, J = 8.5
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Hz, 2H), 8.01 (d, J = 8.3 Hz, 2H); C NMR (125 MHz, CDCl3):
δ 26.7 (q), 56.2 (q), 109.7
(d), 113.7 (d), 125.1 (d), 128.4 (d, 2C), 128.7 (d, 2C), 129.3 (s), 130.2 (d, 2C), 130.3 (s),
131.4 (d, 2C), 135.3 (s), 135.9 (s), 136.7 (s), 139.6 (s), 144.2 (s), 146.1 (s), 147.3 (s), 183.5
(s), 197.6 (s) ppm; IR (CHCl3) 3021, 1678, 1592, 1492, 1437, 1217, 1095, 766 cm−1; HRMS
(ESI) calcd. for C24H18ClO4 (M+H)+ 405.0888, found 405.0880.
(4ꢀChlorophenyl)(7ꢀmethoxyꢀ3ꢀ(3ꢀmethoxyphenyl)benzofuranꢀ2ꢀyl)methanone (3eb): Yellow
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oil; 53% yield (40 mg); Rf = 0.5 (pet. ether/EtOAc = 8:2); H NMR (500 MHz, CDCl3):
δ
3.80 (s, 3H), 4.05 (s, 3H), 6.93 (ddd, J = 8.4, 2.7, 0.9 Hz, 1H), 7.01 (dd, J = 7.0, 1.8 Hz, 1H),
7.05 (m, 1H), 7.10 (dd, J = 7.6, 1.2 Hz, 1H), 7.27 (d, J = 3.9 Hz, 1H), 7.28 (d, J = 1.8 Hz,
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1H), 7.32 (t, J = 7.9 Hz, 1H), 7.33–7.37 (m, 2H), 7.88–7.90 (m, 2H); C NMR (125 MHz,
CDCl3):
δ
55.3 (q), 56.2 (q), 109.6 (d), 114.2 (d, 2 C), 115.6 (d), 122.4 (d), 124.7 (d), 128.5
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(d, 2C), 129.5 (d), 129.6 (s), 131.3 (d, 2C), 131.4 (s), 132.0 (s), 135.6 (s), 139.2 (s), 144.3 (s),
146.1 (s), 147.0 (s), 159.5 (s), 183.9 (s) ppm; IR (CHCl3) 3020, 1649, 1591, 1491, 1386,
1218, 1095, 918, 764 cm−1; HRMS (ESI) calcd. for C23H18ClO4 (M+H)+ 393.0888, found
393.0882.
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1ꢀ(4ꢀ(2ꢀ(4ꢀChlorobenzoyl)ꢀ5ꢀmethoxybenzofuranꢀ3ꢀyl)phenyl)ethanꢀ1ꢀone (3fa): Brown oil;
68% yield (53 mg); Rf = 0.4 (pet. ether/EtOAc = 8:2); 1H NMR (500 MHz, CDCl3):
δ 2.64 (s,
3H), 3.82 (s, 3H), 6.98 (d, J = 2.2 Hz, 1H), 7.17 (dd, J = 8.9, 2.5 Hz, 1H), 7.39 (d, J = 8.4 Hz,
2H), 7.53 (d, J = 9.1 Hz, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 8.03 (d, J =
13
8.0 Hz, 2H); C NMR (125 MHz, CDCl3):
δ 26.7 (q), 56.9 (q), 102.4 (d), 113.2 (d), 119.0
(d), 128.1 (s), 128.4 (d, 2C), 128.6 (d, 2C), 128.7 (s), 130.1 (d, 2C), 131.3 (d, 2C), 135.4 (s),
136.0 (s), 136.7 (s), 139.4 (s), 147.9 (s), 149.7 (s), 157.1 (s), 183.6 (s), 197.6 (s) ppm; IR
(CHCl3) 3021, 1681, 1599, 1488, 1219, 1095, 1016, 767 cm−1; HRMS (ESI) calcd. for
C24H18ClO4 (M+H)+ 405.0888, found 405.0879.
1ꢀ(3ꢀ(2ꢀ(4ꢀChlorobenzoyl)ꢀ5ꢀmethoxybenzofuranꢀ3ꢀyl)phenyl)ethanꢀ1ꢀone (3fg): Brown
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solid; 75% yield (58 mg); mp 139–141 °C; Rf = 0.4 (pet. ether/EtOAc = 8:2); H NMR (400
MHz, CDCl3):
δ 2.61 (s, 3H), 3.82 (s, 3H), 6.98 (d, J = 2.6 Hz, 1H), 7.17 (dd, J = 9.2, 2.7 Hz,
1H), 7.37 (br d, J = 8.6 Hz, 2H), 7.53 (d, J = 9.0 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.75 (td, J
= 7.6, 1.4 Hz, 1H), 7.89 (br d, J = 8.6 Hz, 2H), 8.00 (td, J = 7.8, 1.6 Hz, 1H), 8.11 (t, J = 1.8
Hz, 1H); 13C NMR (125 MHz, CDCl3):
δ 26.7 (q), 55.9 (q), 102.5 (d), 113.2 (d), 119.0 (d),
128.1 (s), 128.3 (d), 128.5 (d, 2C), 128.8 (d), 128.9 (s), 129.9 (d), 131.3 (d, 2C), 131.6 (s),
134.4 (d), 135.5 (s), 137.3 (s), 139.2 (s), 147.9 (s), 149.7 (s), 157.1 (s), 183.7 (s), 197.6 (s)
ppm; IR (CHCl3) 3019, 1685, 1588, 1485, 1436, 1216, 1177, 755 cm−1; HRMS (ESI)
calcd.for C24H18ClO4 (M+H)+ 405.0888, found 405.0880.
(3ꢀ(4ꢀ(tertꢀButyl)phenyl)benzofuranꢀ2ꢀyl)(phenyl)methanone (3ai): Yellow oil; 83% yield
1
(60 mg); Rf = 0.5 (pet. ether/EtOAc = 9.5:0.5); H NMR (500 MHz, CDCl3):
δ 1.32 (s, 9H),
7.30 (t, J = 7.7 Hz, 2H), 7.34–7.36 (m, 3H), 7.40–7.45 (m, 3H), 7.52 (t, J = 7.3 Hz, 1H), 7.63
(d, J = 8.4 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 7.6 Hz, 2H); 13C NMR (125 MHz,
CDCl3):
δ 31.2 (q, 3C), 34.6 (s), 112.4 (d), 122.6 (d), 123.8 (d), 125.2 (d, 2C), 127.8 (s),
128.0 (d, 2C), 128.1 (s), 128.2 (d), 129.6 (s), 129.7 (d, 2C), 129.8 (d, 2C), 132.4 (d), 137.3
(s), 147.1 (s), 151.3 (s), 154.6 (s), 185.9 (s) ppm; IR (CHCl3) 3021, 1717, 1646, 1565, 1457,
1218, 1004, 764 cm−1; HRMS (ESI) calcd. for C25H23O2 (M+H)+ 355.1693, found 355.1693.
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(3ꢀ(3ꢀFluorophenyl)benzofuranꢀ2ꢀyl)(phenyl)methanone (3aj):9b Yellow oil; 68% yield (43
mg); Rf = 0.4 (pet. ether/EtOAc = 9.5:0.5); 1H NMR (400 MHz, CDCl3):
δ 7.05 (ddt, J = 1.4,
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2.8, 8.5 Hz, 1H), 7.23 (dt, J = 1.7, 9.6 Hz, 1H), 7.27 (dt, J = 1.0, 7.7 Hz, 1H), 7.31–7.40 (m,
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4H), 7.49–7.56 (m, 2H) 7.65 (d, J = 8.3 Hz, 1H), 7.69 (dd, J = 1.1, 8.7 Hz, 1H), 7.88–7.90
(m, 2H); 13C NMR (100 MHz, CDCl3):
δ 112.5 (s), 115.3 (d, J = 21.1 Hz), 116.9 (d, J = 23.0
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Hz), 122.1 (d), 124.1 (d), 125.8 (d, J = 2.9 Hz), 127.7 (s), 128.0 (d, J = 1.9 Hz), 128.2 (d,
2C), 128.4 (d), 129.8 (d, 2C), 129.9 (d, J = 8.6 Hz), 132.9 (d), 133.0 (d, J = 7.7 Hz), 137.1
(s), 147.3 (s), 154.5 (s), 162.6 (d, J = 246.3 Hz), 185.6 (s) ppm; IR (CHCl3) 3068, 1650,
1614, 1563, 1448, 1292, 1262, 1233, 1168, 1021 cm−1; HRMS (ESI) Calcd. for C21H14FO2
(M+H)+ 317.0972, found 317.0971.
(3ꢀ(Furanꢀ3ꢀyl)benzofuranꢀ2ꢀyl)(phenyl)methanone (3ak): Pale yellow oil; 70% yield (41
mg); Rf = 0.6 (pet. ether/EtOAc = 9.5:0.5); 1H NMR (200 MHz, CDCl3):
δ 6.87 (dd, J = 0.8,
1.9 Hz, 1H), 7.38 (ddd, J = 1.5, 6.8, 8.1 Hz, 1H), 7.43–7.51 (m, 2H), 7.51–7.63 (m, 4H), 7.84
(br d, J = 7.8 Hz, 1H), 8.00 (br d, J = 6.8 Hz, 2H), 8.13 (dd, J = 0.8, 1.5 Hz, 1H); 13C NMR
(125 MHz, CDCl3):
δ 111.4 (d), 112.4 (d), 115.4 (s), 120.5 (s), 122.4 (d), 123.9 (d), 127.6 (s),
128.2 (d), 128.3 (d, 2C), 129.9 (d, 2C), 132.8 (d), 137.5 (s), 143.0 (d), 143.2 (d), 147.4 (s),
154.5 (s), 185.4 (s) ppm; IR (CHCl3) 3023, 1717, 1601, 1541, 1433, 1216, 1023, 1116, 767
cm−1; HRMS (ESI) calcd. for C19H13O3 (M+H)+ 289.0859, found 289.0857.
(3ꢀ(3ꢀFluorophenyl)benzofuranꢀ2ꢀyl)(4ꢀmethoxyphenyl)methanone (3bj): White solid; 69%
1
yield (47 mg); mp 124–126 °C; Rf = 0.5 (pet. ether/EtOAc = 9:1); H NMR (400 MHz,
CDCl3):
δ 3.85 (s, 3H), 6.88 (br d, J = 8.9 2H), 7.06 (ddt, J = 1.2, 2.7, 8.6 Hz, 1H), 7.26 (dt, J
= 2.1, 9.3 Hz, 1H), 7.30 (dt, J = 1.2, 7.7 Hz, 1H), 7.33–7.39 (m, 2H), 7.52 (ddd, J = 1.2, 7.0,
8.1 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.96 (br d, J = 8.8 Hz, 2H);
13C NMR (100 MHz, CDCl3):
δ 55.5 (q), 112.3 (d), 113.5 (d, 2C), 115.1 (d, J = 21.1 Hz),
116.8 (d, J = 23.0 Hz), 121.9 (d), 124.0 (d), 125.8 (d, J = 2.9 Hz), 127.1 (s), 127.7 (s), 128.0
(d), 129.7 (s), 129.9 (d, J = 8.6 Hz), 132.4 (d, 2C), 133.2 (d, J = 8.6 Hz), 147.7 (s), 154.3 (s),
162.6 (d, J = 246.3 Hz), 163.6 (s), 183.9 (s) ppm; IR (CHCl3) 3021, 1717, 1643, 1501, 1479,
1434, 1220, 1168, 1028, 762 cm−1; HRMS (ESI) calcd. for C22H16FO3 (M+H)+ 347.1078,
found 347.1077.
(3ꢀ(Furanꢀ3ꢀyl)benzofuranꢀ2ꢀyl)(4ꢀmethoxyphenyl)methanone (3bk): Brown oil; 83% yield
1
(52 mg); Rf = 0.4 (pet. ether/EtOAc = 9.5:0.5); H NMR (500 MHz, CDCl3):
δ 3.89 (s, 3H),
6.86 (s, 1H), 6.96 (d, J = 8.6 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.50–7.53 (m, 2H), 7.59 (d, J
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= 8.4 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.7 Hz, 2H), 8.11 (s, 1H); 13C NMR (125
MHz, CDCl3):
δ 55.5 (q), 111.4 (d), 112.3 (d), 113.6 (d, 2C), 115.5 (s), 119.7 (s), 122.3 (d),
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123.8 (d), 127.6 (s), 127.9 (d), 130.2 (s), 132.4 (d, 2C), 142.9 (d), 143.0 (d), 147.8 (s), 154.3
(s), 163.5 (s), 183.9 (s) ppm; IR (CHCl3) 3021, 1718, 1599, 1456, 1429, 1219, 1117, 761
cm−1; HRMS (ESI) calcd. for C20H15O4 (M+H)+ 319.0965, found 319.0966.
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(3ꢀ(4ꢀ(tertꢀButyl)phenyl)ꢀ5,7ꢀdichlorobenzofuranꢀ2ꢀyl)ꢀ(phenyl)methanone (3ci): White
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solid; 83% yield (66 mg); mp 121–123 °C; Rf = 0.3 (pet. ether/EtOAc = 9.5:0.5); H NMR
(400 MHz, CDCl3):
δ
1.33 (s, 9H), 7.37 (t, J = 7.8 Hz, 2H), 7.41 (m, 4H), 7.49–7.52 (m, 2H),
31.2 (q,
7.60(d, J = 1.9 Hz, 1H), 7.92 (br d, J = 7.9 Hz, 2H); 13C NMR (100 MHz, CDCl3):
δ
3C), 34.7 (s), 118.5 (s), 120.6 (d), 125.5 (d, 2C), 126.6 (s), 128.0 (d), 128.2 (d, 2C), 129.0 (s),
129.5 (d, 2C), 129.7 (s), 129.9 (d, 2C), 130.4 (s), 133.0 (d), 136.7 (s), 148.6 (s), 149.0 (s),
152.0 (s), 184.8 (s) ppm; IR (CHCl3) 3022, 1678, 1592, 1420, 1216, 1120, 766 cm−1; HRMS
(ESI) calcd. for C25H21Cl2O2 (M+H)+ 423.0913, found 423.0913.
(5ꢀBromoꢀ3ꢀ(4ꢀ(tertꢀbutyl)phenyl)benzofuranꢀ2ꢀyl)(phenyl)methanone (3di): White solid;
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74% yield (64 mg); mp 133–135 °C; Rf = 0.5 (pet. ether/EtOAc = 9.5:0.5); H NMR (400
MHz, CDCl3):
δ 1.32 (s, 9H), 7.31 (t, J = 7.7 Hz, 2H), 7.37–7.38 (m, 4H), 7.45 (t, J = 7.5 Hz,
1H), 7.51 (d, J = 8.8 Hz, 1H), 7.60 (dd, J = 2.0, 8.8 Hz, 1H), 7.81 (br d, J = 7.6 Hz, 2 H), 7.85
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(d, J = 1.8 Hz, 1H); C NMR (100 MHz, CDCl3):
δ 31.2 (q, 3C), 34.7 (s), 113.9 (d), 117.0
(s), 125.1 (d), 125.4 (d, 2C), 127.1 (s), 128.1 (d, 2C), 128.7 (s), 129.6 (d, 2C), 129.8 (d, 2C),
130.1 (s), 131.1 (d), 132.7 (d), 137.0 (s), 147.9 (s), 151.7 (s), 153.3 (s), 185.6 (s) ppm; IR
(CHCl3) 3022, 1648, 1590, 1495, 1433, 1216, 1118, 766, 672 cm−1; HRMS (ESI) calcd. for
C25H22BrO2 (M+H)+ 433.0803, found 433.0805.
(5ꢀBromoꢀ3ꢀ(furanꢀ3ꢀyl)benzofuranꢀ2ꢀyl)(phenyl)methanone (3dk): Yellow oil; 81% yield
1
(59 mg); Rf = 0.3 (pet. ether/EtOAc = 9.5:0.5); H NMR (500 MHz, CDCl3):
δ 6.82 (s, 1H),
7.48 (t, J = 7.3 Hz, 3H), 7.54 (s, 1H), 7.60 (t, J = 9.7 Hz, 2H), 7.96–7.98 (m, 3H), 8.09 (s,
1H); 13C NMR (125 MHz, CDCl3):
111.2 (d), 113.9 (d), 114.8 (s), 117.1 (s), 119.7 (s),
δ
125.0 (d), 128.4 (d, 2C), 129.5 (s), 129.9 (d, 2C), 131.2 (d), 133.1 (d), 137.1 (s), 143.2 (d,
2C), 148.3 (s), 153.1 (s), 185.1 (s) ppm; IR (CHCl3) 3020, 1710, 1656, 1423, 1216, 1120,
1022, 769 cm−1; HRMS (ESI) calcd. for C19H10BrO3 (M–H)+ 364.9811, found 364.9777.
(4ꢀChlorophenyl)(3ꢀ(furanꢀ3ꢀyl)ꢀ5ꢀmethoxybenzofuranꢀ2ꢀyl)methanone (3fk): Yellow solid;
73% yield (49 mg); mp 123–125 °C; Rf = 0.5 (pet. ether/EtOAc = 9:1); 1H NMR (400 MHz,
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CDCl3):
δ
3.94 (s, 3H), 6.91 (s, 1H), 7.19–7.31 (m, 2H), 7.49–755 (m, 3H), 7.61 (s, 1H),
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8.00–8.03 (m, 2H), 8.16 (s, 1H); C NMR (100 MHz, CDCl3):
δ 56.0 (q), 103.3 (d), 111.4
(d), 113.1 (d), 115.4 (s), 118.6 (d), 121.1 (s), 128.1 (s), 128.6 (d, 3C), 131.4 (d, 2C), 135.8
(s), 139.2 (s), 143.1 (d), 147.9 (s), 149.6 (s), 156.9 (s), 183.7 (s) ppm; IR (CHCl3) 3019,
1646, 1591, 1493, 1391, 1234, 1092, 761 cm−1; HRMS (ESI) calcd. for C20H14ClO4 (M+H)+
353.0575, found 353.0571.
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(3ꢀ(4ꢀ(tertꢀButyl)phenyl)benzofuranꢀ2ꢀyl)(4ꢀfluorophenyl)methanone (3gi): Pale yellow oil;
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79% yield (61 mg); Rf = 0.4 (pet. ether/EtOAc = 9.5:0.5); H NMR (400 MHz, CDCl3):
δ
1.33 (s, 9H), 6.97 (t, J = 8.7 Hz, 2H), 7.33–7.37 (m, 2H), 7.38 (d, J = 2.0 Hz, 3H), 7.53 (dt, J
= 1.1, 8.3 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.83–7.87 (m, 2 H); 13C
NMR (100 MHz, CDCl3):
δ 31.2 (q, 3C), 34.7 (s), 112.4 (d), 115.1 (d, J = 22.4 Hz, 2C),
122.6 (d), 123.9 (d), 125.3 (d, 2C), 127.7 (s), 128.1 (s), 128.3 (d), 129.7 (d, 2C), 129.9 (s),
132.4 (d, J = 9.3 Hz, 2C), 133.6 (d, J = 3.1 Hz), 146.9 (s), 151.6 (s), 154.7 (s), 165.3 (d, J =
254.3 Hz), 184.3 (s) ppm; IR (CHCl3) 3020, 1728, 1648, 1599, 1465, 1225, 1160, 758 cm−1;
HRMS (ESI) calcd. for C25H22FO2 (M+H)+ 373.1598, found 373.1602.
(4ꢀFluorophenyl)(3ꢀ(3ꢀfluorophenyl)benzofuranꢀ2ꢀyl)methanone (3gj): Yellow solid; 73%
1
yield (51 mg); mp 56–58 °C; Rf = 0.4 (pet. ether/EtOAc = 9.5:0.5); H NMR (200 MHz,
CDCl3):
δ
7.02–7.13 (m, 3H), 7.20–7.22 (m, 1H), 7.26–7.30 (m, 1H), 7.32–7.42 (m, 2H),
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7.55 (dt, J = 1.3, 7.0 Hz, 1H), 7.62–7.70 (m, 2H), 7.93–8.00 (m, 2H); C NMR (100 MHz,
CDCl3):
δ 112.4 (d), 115.4 (d, J = 22.0 Hz, 3C), 116.8 (d, J = 22.1 Hz), 122.1 (d), 124.2 (d),
125.8 (d, J = 2.9 Hz), 127.7 (s), 128.1 (s), 128.5 (d), 130.0 (d, J = 8.6 Hz), 132.5 (d, J = 9.6
Hz, 2C), 132.9 (d, J = 7.7 Hz), 133.3 (d, J = 2.9 Hz), 147.1 (s), 154.5 (s), 162.6 (d, J = 246.3
Hz), 165.6 (d, J = 255.9 Hz), 183.8 (s) ppm; IR (CHCl3) 3022, 1650, 1599, 1494, 1438, 1295,
1221, 1159, 764 cm−1; HRMS (ESI) calcd. for C21H13F2O2 (M+H)+ 335.0878, found
335.0878.
(5ꢀBromoꢀ3ꢀ(4ꢀ(tertꢀbutyl)phenyl)benzofuranꢀ2ꢀyl)(4ꢀmethoxyphenyl)methanone
White solid; 77% yield (70 mg); mp 137–139 °C; Rf = 0.4 (pet. ether/EtOAc = 9:1); 1H NMR
(3hi):
(500 MHz, CDCl3):
δ
1.33 (s, 9H), 3.82 (s, 3H), 6.82 (d, J = 8.7 Hz, 2H), 7.39 (m, 4H), 7.50
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(d, J = 8.7 Hz, 1H), 7.58 (dd, J = 1.8, 8.8 Hz, 1H), 7.88–7.87 (m, 3H); C NMR (125 MHz,
CDCl3):
δ 31.2 (q, 3C), 34.7 (s), 55.4 (q), 113.4 (d, 2C), 113.8 (d), 116.9 (s), 124.9 (d), 125.4
(d, 2C), 127.3 (s), 127.7 (s), 129.6 (d, 2C), 129.7 (s), 130.1 (s), 130.8 (d), 132.3 (d, 2C),
148.3 (s), 151.6 (s), 153.1 (s), 163.5 (s), 184.1 (s) ppm; IR (CHCl3) 3021, 1715, 1643, 1509,
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1431, 1217, 1115, 766, 672 cm−1; HRMS (ESI) calcd. for C26H24BrO3 (M+H)+ 463.0903,
found 463.0902.
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Benzofuranꢀ2ꢀyl(phenyl)methanol (4a): A solution of benzofuran 1a (250 mg, 1.12 mmol) in
methanol was treated with NaBH4 (1.24 mmol) at 0 °C and then it was stirred at room
temperature for one hour. The reaction mixture was quenched with cold water and portioned
between water and EtOAc. The organic phase was separated and the aqueous phase was
extracted with EtOAc (2×50 mL). The combined organic phase was washed with brine, dried
(Na2SO4) and concentrated under reduced pressure. The crude product was purified by silica
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gel column (pet. ether/EtOAc as eluent) to afford colorless solid; 92% yield (232 mg); H
NMR (400 MHz, CDCl3):
(dt, J = 1.4, 7.3 Hz, 1H), 7.34–7.42 (m, 3H), 7.46–7.50 (m, 3H), 7.52–7.54 (m, 2H); 13C
NMR (50 MHz, CDCl3): 70.5 (d), 103.9 (d), 111.2 (d), 121.0 (d), 122.7 (d), 124.2 (d),
δ 5.91 (br s, 1H), 6.52 (s, 1H), 7.24 (dt, J = 0.9, 7.3 Hz, 1H), 7.29
δ
126.7 (d, 2C), 127.9 (s), 128.2 (d), 128.5 (d, 2C), 140.2 (s), 155.0 (s), 158.5 (s) ppm.
1ꢀ(4ꢀ(2ꢀ(Hydroxy(phenyl)methyl)benzofuranꢀ3ꢀyl)phenyl)ethanꢀ1ꢀone (5aa): Brown oil; 40%
yield (27 mg); Rf = 0.2 (pet. ether/EtOAc = 7:3); 1H NMR (500 MHz, CDCl3):
δ 2.65 (s, 3H),
6.03 (s, 1H), 7.26–7.68 (m, 5H), 7.48 (d, J = 7.3 Hz, 2H), 7.51 (d, J = 8.2 Hz, 1H), 7.59 (d, J
= 7.6 Hz, 1H), 7.64 (d, J = 7.9 Hz, 2H), 8.08 (d, J = 7.9 Hz, 2H); 13C NMR (125 MHz,
CDCl3):
δ 26.7 (q), 68.6 (d), 111.8 (d), 118.6 (s), 120.1 (d), 123.3 (d), 125.2 (d), 126.6 (d,
2C), 127.6 (s), 128.2 (d), 128.7 (d, 2C), 128.9 (d, 2C), 129.4 (d, 2C), 136.3 (s), 136.7 (s),
140.5 (s), 152.9 (s), 154.4 (s), 197.6 (s) ppm; IR (CHCl3) 3355, 3021, 1678, 1606, 1451,
1448, 1266, 1217, 760 cm−1; HRMS (ESI) calcd. for C23H18O3Na (M+Na)+ 365.1148, found
365.1138.
HPLC Method
The HPLC was equipped with a SupelgoꢀCꢀ18, RP 10 x 250 mm, 10 ꢁm column maintained
at a temperature of 20 °C. The mobile phase used for was found to be 85% methanol, 15%
water with a flow rate of 2.0 mL/min. Note that all solvents were HPLC grade. The volume
of sample injected was set at 20 ꢁL and runtime for each sample was 30 minute. The
retention time of benzofuran 1a was 11.822, benzofuran alcohol 4a was 9.421,
arylbenzofuran 3aa was 14.890 and arylbenzofuran 3aa in crude reaction mixture was
14.812. In reaction of 4a with 2a, retention time of arylbenzofuran 5aa was 11.045,
benzofuran alcohol 4a was 9.405 and arylbenzofuran 5aa was 11.191 in crude reaction
mixture.
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Supporting Information
HPLC plots of control experiments and NMR and HRMS spectra of all new compounds. This
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material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
* Eꢀmail: vr.chepuri@ncl.res.in
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
We thank the CSIR for funding this project under 12 FYP ORIGIN Program (CSC0108) and
UGC (New Delhi) for a research fellowship to DJP.
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