Syntheses of 2-Aroyl Benzofurans through Cascade Annulation on Arynes

Article abstract of DOI:10.1021/acs.joc.8b00360

The highly efficient and expedient route for the syntheses of 2-aroyl benzofurans has been developed via the cascade [2+2] followed by a [4+1] annulation on arynes. The overall transformation proceeded through the formation of ortho-quinone methide by the

Full text of DOI:10.1021/acs.joc.8b00360

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Article
Syntheses of 2-aroyl benzofurans through cascade annulation on arynes
Pashikanti Gouthami, Lahu N Chavan, Rambabu Chegondi, and Srivari Chandrasekhar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00360 • Publication Date (Web): 23 Feb 2018
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Syntheses of 2-aroyl benzofurans through cascade annulation on arynes
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Pashikanti Gouthami,a Lahu N. Chavan,a,c Rambabu Chegondib,c and Srivari Chandrasekhar*,a,c
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aNatural Products Chemistry Division, bOrganic & Biomolecular Chemistry Division, CSIRꢀIndian
Institute of Chemical Technology (CSIRꢀIICT), Hyderabad 500007, India
cAcademy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India.
*E-mail: srivaric@iict.res.in
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RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
ABSTRACT: The highly efficient, and expedient route for the syntheses of 2ꢀaroyl benzofurans has
been developed via the cascade [2+2] followed by a [4+1] annulation on arynes. The overall
transformation proceeded through the formation of orthoꢀquinone methide by the insertion of transient
aryne into N,Nꢀdimethylformamide and subsequent trapping with sulfur ylide. Moreover, this
transformation has broad range of substrate scope with high functionalꢀgroup tolerance. This new
reaction was successfully utilized in the synthesis of potent CYP19 Aromatase inhibitor and lateꢀstage
functionalization on the bioactive complex estrone.
KEYWORDS: domino reaction, ketenimine, copperꢀcatalysis, cycloaddition
INTRODUCTION
The transient reactive intermediates have a pivotal role in organic synthesis to create diverse
skeletons of relevance. orthoꢀQuinone methides (oꢀQMs) have gained much importance due to the easy
access from phenol derivatives through oxidation, acid promoted βꢀelimination, base promoted βꢀ
elimination, tautomerization, thermolysis, and photolysis.1 In addition, the insertion of highly reactive
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aryne into carbonyl bond via [2 + 2] cycloaddition followed by isomerization gave oꢀQMs which further
subjected to nucleophiles to produce multifunctional building blocks in single operation.2 The recent
reviews in this area indicate the volume of contributions to these important functionalities.3 In 1965,
Yaroslavsky et al. reported the synthesis of salicylaldehyde from benzyne in 32% yield via oꢀQM,
generated from transient benzyne and N,Nꢀdimethylformamide (DMF) as carbonyl source.4 Recently,
Miyabe and coꢀworkers described the trapping of these oꢀQMs with active methylene compounds to give
2Hꢀchromene derivatives in good yields.5
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Figure 1. Benzofuran as structural motif in natural products and bioactives.
We have recently taken advantage of the Stolz’s contributions in benzyne chemistry6 for the total
synthesis of natural products.7 Also, we were successful in adding imidate functionality to benzynes to
generate disubstituted aryl systems with minimal effort.8 We were exploring to develop a strategy for
easy entry to 2ꢀsubstituted benzofurans enroute the total synthesis of natural products and bioactive
molecules (Figure 1).9 In 2017, Miyabe et al. have recently reported the synthesis of dihydrobenzofurans
and benzofurans from arynes wherein oꢀQM reacts with diethyl 2ꢀchloromalonate and diethylzinc at ꢀ40
to ꢀ60 °C in DMF as a solvent.10 This method offers advantages in diversity, however it requires low
temperature, αꢀchlorinated methines and use of a highly pyrophoric Et2Zn in the reaction. Herein, we
envisioned that sulfur yilide would be suitable one carbon unit for [4+1] cycloaddition on the oꢀQM for
the synthesis of 2ꢀaroyl benzofuran. Sulfur ylides are versatile reagents which can be generated from
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easily accessible αꢀhalo carbonyls and dialkyl sulfides. Many research groups elegantly demonstrated
the utility of these ylides in cycloaddition reactions.11 Recently, Xiao et al. reported the synthesis of
substituted indoles via [4+1] annulation reaction.12
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Scheme 1. Previous and present approaches
RESULTS AND DISCUSSION
We initiated our studies with the domino cyclization of in situ generated benzyne from 1a13
with sulfonium bromide salt 2a in DMF solvent by applying different fluoride sources at various
temperatures (Table 1). To our delight, CsF as base at room temperature led to the formation desired
product 3a in 87% yield. Increasing the reaction temperature did not show any significant variation on
yields. Other fluorides, TBAF and KF afforded 3a in lower yields when compared to CsF. The addition
of 18ꢀcrownꢀ6 to KF and CsF did not lead to an improvement in the reaction yield. In the case of CsF,
decrease in the reaction time was found to have high impact on the efficiency of the reaction.
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Table 1. Screening for Optimal Reaction Conditionsa
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O
Me
F source
DMF
OTf
S
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Me
+
Br
O
O
TMS
t
oC
time (h)
1a
2a
3a
entry
time (h)
t (oC)
yieldb
F source
1
CsF
CsF
CsF
TBAF
KF
12
12
12
12
12
12
12
1
rt
50
80
rt
87
87
88
52
68
87
63
0
2
3
4c
5
rt
6c
7c
8
CsF/18-C-6
KF/18-C-6
NaF
rt
rt
rt
9
CsF
5
rt
30
58
10c
CsF
12
rt
aStandard reaction conditions: The reaction was carried out with 1a (1.2 mmol), 2a (1 mmol), and
fluoride source (4 mmol) in solvent (0.1 M). Yield of the isolated product. 18ꢀCrownꢀ6 (0.25 mmol)
was used.
b
c
With the optimal reaction conditions in hand (Table 1, entry 1; 4 equiv of CsF in DMF at rt), the
scope of various sulfonium bromide salts 2 were investigated. As summarized in table 2, sulfonium salts
having electronꢀdonating or electronꢀwithdrawing substituents on the aromatic ring were well tolerated
in this reaction to provide corresponding benzofurans 3a−3k in high yields (66ꢀ87%). However,
substituents at metaꢀposition gave slightly lower yields (Table 2, entries 3gꢀh). With other sulfonium salts
bearing aryl groups such as furan thiophene and naphthyl rings, the reactions proceeded smoothly with
good yields (Table 2, entries 3l−3n).
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Table 2. Substrate scope for sulphur ylidesa,b
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O
Me
S
CsF
DMF
OTf
Ar
O
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+
Ar
Me
O
rt, 12h
TMS
Br
1a
3
2
O
O
O
O
O
O
O
3b; 71%
3c; 75 %
3a; 87%
F
Cl
O
O
O
O
O
3e; 81%
3f; 70%
3d; 79%
Br
Ph
NO2
O
O
O
O
O
O
3g; 66%
3h; 68%
3i; 79%
Br
Me
O2N
O
O
O
O
O
O
O
O
3j; 76%
3k; 81%
3l; 72%
OMe
N Me
Me
O
O
O
S
3m; 74%
3n; 78%
aReaction conditions: The reaction was carried out with 1a (1.2 mmol), 2 (1 mmol), and fluoride source
(4 mmol) in DMF (0.1 M). bYields of products isolated after column chromatography
We next investigated the [2+2] followed by [4+1] cycloaddition reaction of symmetrical and
unsymmetrical arynes (Table 3, entries 3o−3v). Regardless of electronꢀdonating or ꢀwithdrawing nature
of the substituent on the symmetrical aryne precursor 1, corresponding benzofurans were obtained in
good yields (69−83%). It is also noted that the electronꢀpoor aryne gave slightly lower yield (Table 3,
entry 3s). In case of unsymmetrical arynes, 3ꢀmethoxytriflate reacted with sulfonium salt 2a to give 3u
exclusively in 83% yield with complete regiocontrol, which is consistent with previous reports.14 The
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regioselectivity of 3u was also established single crystal Xꢀray analysis.15 However, the annulation of 4ꢀ
methoxytriflate with 2a afforded two regioisomers 3v (45%) and 3v' (35%) in a 9:7 ratio (isolated by
column chromatography).
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Table 3. Substrate scope for benzynea,b
aReaction conditions: The reaction was carried out with
source (4 mmol) in DMF (0.1 M). bYields of products isolated after column chromatography
1 (1.2 mmol), 2 (1 mmol), and fluoride
To gain further insights into the mechanism of annulation reaction, a series of competition and
labelled experiments were conducted (Scheme 2). The intermolecular competition experiment revealed
the formation of product being favored from electronꢀrich sulfonium salt 2j than electronꢀpoor substrate
2f. Next, the reaction between 1a and 2a under standard conditions in deuterated DMFꢀd7 afforded 3aꢀ
d1 in 81% yield with exclusive deuterium incorporation at 3 position of benzofuran. This result clearly
indicates that the formation of oꢀQM proceeded via [2+2] cycloaddition of aryne with DMF solvent. The
same reaction in equimolar ratio of DMF/DMFꢀd7 solvent afforded ~1:1 ratio of 3a and 3aꢀd1 in 38%
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yield. Similarly, two parallel reactions were conducted separately with the nonꢀdeuterated substrate 2a
and the deuterated substrate 2aꢀd2 using standard conditions for 2 h, which afforded 3a in similar yields.
Based on these experiments (Scheme 2c & 2d), [2+2] and [4+1] cycloaddition steps as well as
aromatization didn’t influence the rate of reaction.
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Scheme 2. Mechanistic experiments
a. Intermolecular competition between ylides
OTf
R
O
Me
S
O
Me
S
TMS
(3 equiv)
Me
Me
Br
Br
O2N
MeO
O
CsF, DMF
rt, 12 h
O
2f
(1 equiv)
R = NO2; 3f
R = OMe; 3j
2j
(1 equiv)
3f:3j
= 1:7.8
crude 1H NMR analysis
b. Labelled experiment
O
O
Me
CD3
D
D
N
OTf
S
Me
CD3
+
Br
CsF, rt
12 h, 81 %
O
O
TMS
3a d
-
1a
2a
1
c. Kinetic Isotope Effect form an inter molecular competition of solvent
O
Me
S
H/D
DMF/DMF-d7
OTf
Me
(1 : 1)
+
Br
2a
CsF, rt
2 h, 38 %
O
O
TMS
3a 3a d
/
-
1a
1
~1:1 ratio
d. Kinetic Isotope Effect form two parallel reactions
O
Me
S
O
Me
S
Br
Me
Br
Me
OTf
H H
D
D
2a
2a d
-
2
3a
3a
DMF, CsF, rt
2 h, 37 %
DMF, CsF, rt
2 h, 34 %
TMS
1a
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Based on the above experimental outcome and previous reports3,12, a possible mechanism was proposed
in scheme 3. The strained four membered ring intermediate B is produced through the C=O group
insertion of N,Nꢀdemethylformamide (DMF) onto transient benzyne A, generated in situ from aryl triflate
1a via [2+2] cycloaddition. The ring opening of intermediate B gives orthoꢀquinone methide C, which
would further undergo [4+1] cycloaddition with sulfur yilide D to afford 2,3ꢀdihydrobenzofuran F
followed by aromatization leads to the 2ꢀaroyl benzofuran 3a
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Scheme 3. Plausible mechanism
To demonstrate the synthetic utility of this method, 2ꢀaroyl benzofuran 3v' was treated with pyridineꢀ3ꢀ
magnesium bromide to generate potent CYP19 Aromatase inhibitor 416 in 62% yield (Scheme 4). The
C1ꢀWittig olefination of 3a afforded 2ꢀvinylbenzofuran 5 in 87% yield which was further subjected to
DielsꢀAlder reaction17 using methyl acrylate in the presence of Sc(OTf)3 at 110 oC gave
tetrahydrodibenzofuran 6 in 92 % yield with 13:1 ratio of diastereoselectivity. Finally, the present
cascade reaction was employed for lateꢀstage functionalization on the complex bioactive steroid estrone.
The sterically crowded aryne precursor 7 synthesized from estrone in 5 steps,18 was subjected to
sulfonium salt 2n under standard reaction conditions at 60 oC to afford the corresponding product as 7:3
ratio of inseparable regiomers 8a & 8b.
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Scheme 4: Synthetic utilitya,b
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In summary, we have developed a highly practical synthesis of 2ꢀaroyl benzofurans using aryne
insertion reaction via the formation of orthoꢀquinone methide followed by [4+1] cycloaddition with
stable sulfur ylides and subsequent aromatization sequence. Owing the mild reaction conditions and
broad range of substrate scope, this method has excellent potential in the natural product synthesis and
lateꢀstage functionalization on the complex bioactive molecules.
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EXPERIMENTAL SECTION
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General information: Unless otherwise noted, all reagents were used as received from commercial
suppliers. All reactions were performed under nitrogen atmosphere and in a flameꢀdried or ovenꢀdried
glassware with magnetic stirring. All solvents were dried before use following the standard procedures.
Reactions were monitored using thinꢀlayer chromatography (SiO2). TLC plates were visualized with UV
light (254 nm), iodine treatment or using ninhydrin stain. Column chromatography was carried out using
silica gel (60ꢀ120 mesh & 100ꢀ200 mesh) packed in glass columns. NMR spectra were recorded at 300,
400, 500 MHz (H) and at 75, 100, 125 MHz (C), respectively. Chemical shifts (δ) are reported in ppm,
using the residual solvent peak in CDCl3 (H: δ = 7.26 and C: δ = 77.16 ppm) as internal standard, and
coupling constants (J) are given in Hz. HRMS were recorded using ESIꢀTOF techniques.
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General procedure for the syntheses of 2-aroyl benzofurans through cascade annulation on arynes:
To a stirred solution of triflate 1 (1.2 mmol, 1.2 equiv) in DMF (0.1 M) at room temperature was added
CsF (4 mmol, 4 equiv) under N2 atmosphere and stirred for 10 minutes to generate oꢀQM (ortho quinone
methide). Then, sulfonium bromide salt 2 (1 mmol, 1.0 equiv) was added to the reaction mixture and
stirred for 12 h. After completion of the reaction, the mixture was poured into ice cold water (10 mL)
then extracted with EtOAc (15 mL X 2). The combine organic layer was dried over Na2SO4 and the
solvent was removed under reduced pressure. The residue was purified by column chromatography on
silical gel (EtOAc/Hexanes) to afford 2ꢀaroyl benzofurans 3.
Benzofuran-2-yl(phenyl)methanone (3a): White solid (74 mg, 87% yield) Rf = 0.4 (hexanes:EtOAc
= 19:1); mp = 88–90 °C; 1H NMR (400 MHz, CDCl3) δ 8.07 – 8.02 (m, 2H), 7.75 – 7.71 (m, 1H), 7.67
– 7.61 (m, 2H), 7.57 – 7.48 (m, 4H), 7.36 – 7.31 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 184.4, 156.0,
152.2, 137.3, 133.0, 129.5, 128.6, 128.4, 127.0, 124.0, 123.3, 116.6, 112.6; IR (neat): υmax 3063, 1648,
1547, 1299, 972, 749, 722 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C15H11O2 223.0759; found:
223.0761.
Benzofuran-2-yl(4-fluorophenyl)methanone (3b): White solid (61 mg, 71% yield); Rf = 0.5
(hexanes:EtOAc = 19:1); mp = 133–135 °C; 1H NMR (400 MHz, CDCl3) δ 8.17 – 8.09 (m, 2H), 7.73
(d, J = 7.9 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.53 – 7.48 (m, 1H), 7.34 (t, J = 7.5 Hz, 1H),
7.25 – 7.18 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 182.81, 165.8 (d, JCF = 255.2 Hz), 156.1, 152.3,
133.5 (d, JCF = 2.6 Hz), 132.3 (d, JCF = 9.2 Hz), 128.6, 127.1, 124.2, 123.4, 116.4, 115.9 (d, JCF = 21.9
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Hz), 112.7. IR (neat): υmax 3127, 3075, 2929, 1646, 1597, 1502, 1299, 1223, 974, 749 cmꢀ1; HRMS (ESIꢀ
TOF) m/z: [M+H]+ Calcd for C15H10FO2 241.0665; found: 241.0676.
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Benzofuran-2-yl(4-chlorophenyl)methanone (3c): White solid (89 mg, 75% yield); Rf = 0.5
1
(hexanes:EtOAc = 19:1); mp = 150–152 °C; H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 8.5 Hz, 2H),
7.74 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.51 (t, J = 7.3 Hz, 3H), 7.35 (t, J = 7.5
Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 183.0, 156.0, 152.1, 139.5, 135.4, 131.0, 128.9, 128.6, 126.9,
124.1, 123.4, 116.5, 112.6; IR (neat): υmax 3123, 2928, 1644, 1550, 1302, 1090, 973, 6983 cmꢀ1; HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C15H10ClO2 257.0369; found: 257.0380.
Benzofuran-2-yl4-bromophenyl)methanone (3d): White solid (69 mg, 79% yield); Rf = 0.5
(hexanes:EtOAc = 19:1); mp = 170–172 °C; 1H NMR (400 MHz, CDCl3) δ 7.98 – 7.92 (m, 2H), 7.74
(d, J = 7.9 Hz, 1H), 7.71 – 7.66 (m, 2H), 7.64 (dd, J = 8.4, 0.7 Hz, 1H), 7.55 (d, J = 0.8 Hz, 1H), 7.54 –
7.48 (m, 1H), 7.38 – 7.32 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 183.1, 156.1, 152.1, 135.9, 131.9,
131.0, 128.6, 128.1, 126.9, 124.2, 123.4, 116.6, 112.6; IR (neat): υmax 2925, 2855, 1643, 1549, 1463,
973, 744 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C15H10O2Br 300.9864; found: 300.9865.
[1,1'-Biphenyl]-4-yl(benzofuran-2-yl)methanone (3e): White solid (71 mg, 81% yield); Rf = 0.5
(hexanes:EtOAc = 19:1); mp = 148–150 °C; 1H NMR (500 MHz, CDCl3) δ 8.19 – 8.13 (m, 2H), 7.80 –
7.73 (m, 3H), 7.70 – 7.64 (m, 3H), 7.59 (d, J = 0.9 Hz, 1H), 7.54 – 7.47 (m, 3H), 7.45 – 7.40 (m, 1H),
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7.35 (ddt, J = 7.3, 3.0, 1.9 Hz, 1H); C NMR (75 MHz, CDCl3) δ 183.9, 156.0, 152.4, 145.8, 139.9,
135.9, 130.2, 129.0, 128.4, 128.3, 127.3, 127.2, 127.1, 124.0, 123.3, 116.3, 112.6; IR (neat): υmax 3056,
2925, 1639, 1551, 1403, 1301, 975, 741 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C21H15O2
299.1072; found: 299.1084.
Benzofuran-2-yl(4-nitrophenyl)methanone (3f): Pale yellow solid (61 mg, 70% yield); Rf = 0.5
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(hexanes:EtOAc = 19:1); mp = 200–202 °C; H NMR (300 MHz, CDCl3) δ 8.41 (d, J = 8.7 Hz, 2H),
8.23 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 7.9 Hz, 1H), 7.71 – 7.60 (m, 2H), 7.56 (t, J = 7.7 Hz, 1H), 7.38 (t,
J = 7.5 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 182.3, 156.3, 151.7, 150.2, 142.1, 130.5, 129.2, 126.8,
124.4, 123.7, 123.6, 117.4, 112.7; IR (neat): υmax 3084, 2934, 1651, 1543, 1351, 1172, 975, 717 cmꢀ1;
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C15H10NO4 268.0610; found: 268.0620.
Benzofuran-2-yl(3-bromophenyl)methanone (3g): White solid (58 mg, 66% yield); Rf = 0.5
(hexanes:EtOAc = 19:1); mp = 125–127 °C; 1H NMR (400 MHz, CDCl3) δ 8.18 (t, J = 1.7 Hz, 1H), 8.03
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– 7.95 (m, 1H), 7.81 – 7.72 (m, 2H), 7.65 (d, J = 8.4 Hz, 1H), 7.58 – 7.50 (m, 2H), 7.43 (t, J = 7.9 Hz,
1H), 7.39 – 7.32 (m, 1H);13C NMR (101 MHz, CDCl3) δ 182.75, 156.14, 151.81, 138.93, 135.80, 132.35,
130.15, 128.75, 128.04, 126.90, 124.19, 123.47, 122.79, 116.96, 112.65; IR (neat): υmax 3142, 3060,
1644, 1589, 1550, 1300, 1189, 984, 745 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C15H10O2Br
300.9864; found: 300.9865.
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Benzofuran-2-yl(3-nitrophenyl)methanone (3h): Pale yellow solid 59 mg, 68% yield); Rf = 0.5
(hexanes:EtOAc = 19:1); mp = 134–136 °C; 1H NMR (500 MHz, CDCl3) δ 8.96 (t, J = 1.9 Hz, 1H), 8.50
(ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 8.48 – 8.38 (m, 1H), 7.83 – 7.74 (m, 2H), 7.67 (d, J = 6.3 Hz, 2H), 7.60
– 7.52 (m, 1H), 7.44 – 7.35 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 181.6, 156.2, 151.6, 148.3, 138.3,
135.1, 129.9, 129.1, 127.2, 126.8, 124.5, 124.4, 123.6, 117.2, 112.7; IR (neat): υmax 3085, 2924, 1654,
1533, 1351, 1304, 1091, 717 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C15H10NO4 268.0610;
found: 268.0620.
Benzofuran-2-yl(p-tolyl)methanone (3i): White solid (67 mg, 79% yield); Rf = 0.5 (hexanes:EtOAc =
19:1); mp = 60–62 °C; 1H NMR (300 MHz, CDCl3) δ 7.97 (d, J = 8.1 Hz, 2H), 7.72 (d, J = 7.8 Hz, 1H),
7.64 (d, J = 8.4 Hz, 1H), 7.54 – 7.45 (m, 2H), 7.32 (t, J = 7.2 Hz, 3H), 2.46 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 184.1, 155.9, 152.5, 143.8, 134.6, 129.7, 129.3, 128.2, 127.1, 123.9, 123.3, 116.1, 112.6, 21.7;
IR (neat): υmax 2938, 2873, 1419, 1250, 1213, 1143, 918, 843 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C16H13O2 237.0916; found: 237.0923.
Benzofuran-2-yl(4-methoxyphenyl)methanone (3j): White solid (65 mg, 76% yield); Rf = 0.5
(hexanes:EtOAc = 9:1); mp = 97–99 °C; 1H NMR (500 MHz, CDCl3) δ 8.15 – 8.10 (m, 2H), 7.75 – 7.72
(m, 1H), 7.64 (dd, J = 8.4, 0.8 Hz, 1H), 7.53 (d, J = 0.9 Hz, 1H), 7.52 – 7.47 (m, 1H), 7.36 – 7.31 (m,
1H), 7.06 – 7.01 (m, 2H), 3.92 (s, 3H); 13C NMR (400 MHz, CDCl3) δ 182.9, 163.6, 155.8, 152.7, 132.0,
129.9, 128.0, 127.1, 123.9, 123.2, 115.5, 113.9, 112.5, 55.6; IR (neat): υmax 3076, 2936, 1643, 1602,
1260, 1171, 1029, 972, 753 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C16H13O3 253.0865; found:
253.0865.
Benzofuran-2-yl(4-(dimethylamino)phenyl)methanone (3k): Yellow solid (70 mg, 81% yield); Rf =
0.5 (hexanes:EtOAc = 9:1); mp = 107–109 °C; 1H NMR (400 MHz, CDCl3) δ 8.14 – 8.10 (m, 2H), 7.71
(d, J = 7.8 Hz, 1H), 7.63 (dd, J = 8.4, 0.8 Hz, 1H), 7.49 (d, J = 0.9 Hz, 1H), 7.46 (ddd, J = 8.4, 5.8, 1.3
Hz, 1H), 7.34 – 7.29 (m, 1H), 6.76 – 6.72 (m, 2H), 3.11 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 182.1,
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155.6, 153.6, 153.5, 132.2, 127.4, 127.3, 124.6, 123.6, 122.9, 114.2, 112.4, 110.8, 40.1; IR (neat): υmax
3509, 3149, 2922, 1631, 1594, 1328, 1173, 970, 754 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C17H16NO2 266.1181; found: 266.1191.
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Benzofuran-2-yl(furan-2-yl)methanone (3l): Pale yellow solid (60 mg, 72% yield); Rf = 0.5
(hexanes:EtOAc = 19:1); mp = 84ꢀ86 °C; 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 0.9 Hz, 1H), 7.79
– 7.73 (m, 2H), 7.70 (dd, J = 3.6, 0.6 Hz, 1H), 7.64 (dd, J = 8.4, 0.8 Hz, 1H), 7.50 (ddd, J = 8.4, 7.2, 1.2
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Hz, 1H), 7.38 – 7.31 (m, 1H), 6.67 (dd, J = 3.6, 1.7 Hz, 1H); C NMR (101 MHz, CDCl3) δ 170.1,
155.8, 151.6, 151.5, 147.2, 128.3, 127.2, 124.0, 123.4, 120.4, 115.5, 112.6, 112.4; IR (neat): υmax 3145,
1638, 1565, 1466, 1306, 1022, 983, 751cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C13H9O3
213.0552; found: 213.0561.
Benzofuran-2-yl(thiophen-2-yl)methanone (3m): White solid (63 mg, 72% yield); Rf = 0.5
(hexanes:EtOAc = 19:1); mp = 66–68 °C; 1H NMR (300 MHz, CDCl3) δ 8.33 (dd, J = 3.8, 0.8 Hz, 1H),
7.80 ꢀ7.70 (m, 3H), 7.78 ꢀ7.61 (m, 1H), 7.55 – 7.46 (m, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.29 – 7.22 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 199.4, 177.6, 175.0, 155.8, 155.4, 152.6, 142.3, 134.6, 134.5, 128.4,
128.2, 127.0, 124.0, 123.2, 114.6, 112.4; IR (neat): υmax 3019, 2979, 1744, 1687, 1389, 1216, 1156, 745,
666 667 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C13H9O2S 229.0323; found: 229.0333.
Benzofuran-2-yl(naphthalen-2-yl)methanone (3n): White solid (63 mg, 78% yield); Rf = 0.5
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(hexanes:EtOAc = 19:1); mp = 100–102 °C; H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 8.06 (dd, J =
8.5, 1.4 Hz, 1H), 8.01 – 7.86 (m, 3H), 7.72 (d, J = 7.8 Hz, 1H), 7.68 – 7.53 (m, 4H), 7.53 – 7.45 (m, 1H),
7.32 (t, J = 7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 184.3, 156.0, 152.4, 135.5, 134.5, 132.4, 131.2,
129.6, 128.6, 128.5, 128.4, 127.9, 127.1, 125.5, 125.2, 124.0, 123.4, 116.5, 112.6; IR (neat): υmax 3059,
1646, 1548, 1296, 1176, 907, 752 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C19H13O2 273.0916;
found: 273.0928.
(5,6-Dimethylbenzofuran-2-yl)(phenyl)methanone (3o): White solid (68 mg, 71% yield); Rf = 0.4
(hexanes:EtOAc = 20:1); mp = 77–79 °C; 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J = 7.2 Hz, 2H), 7.62
(t, J = 7.3 Hz, 1H), 7.53 (t, J = 7.4 Hz, 2H), 7.48ꢀ7.38 (m, 3H), 3.98 (s, 3H), 3.94 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 184.4, 154.0, 148.8, 138.7, 137.5, 133.1, 132.7, 129.4, 128.5, 125.0, 122.9, 116.7, 112.7,
21.0, 20.0; IR (neat): υmax 3064, 2925, 1648, 1545, 1320, 1235, 970, 721 cmꢀ1; HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C17H15O2 251.1072; found: 251.1082.
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(5,6-Dimethoxybenzofuran-2-yl)(phenyl)methanone (3p): Yellow solid (74 mg, 69% yield); Rf = 0.4
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(hexanes:EtOAc = 17:3); mp = 127–129 °C; H NMR (300 MHz, CDCl3) δ 8.00 (d, J = 7.2 Hz, 2H),
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7.61 (t, J = 7.3 Hz, 1H), 7.51 (t, J = 7.3 Hz, 2H), 7.45 (s, 1H), 7.10 (s, 1H), 7.06 (s, 1H), 3.96 (s, 3H),
3.93 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 183.6, 152.0, 147.9, 137.6, 132.6, 129.3, 128.5, 119.2,
117.4, 102.8, 95.2, 56.4; cmꢀ1; IR (neat): υmax 300+, 2934, 1642, 1541, 1467, 1298, 1119, 969, 700 cmꢀ1;
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17H15O4 283.0970; found : 283.0983.
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[1,3]Dioxolo[4,5-f]benzofuran-6-yl(phenyl)methanone (3q): Pale yellow solid (81 mg, 79% yield); Rf
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= 0.5 (hexanes:EtOAc = 17:3); mp = 152–154 °C; H NMR (400 MHz, CDCl3) δ 8.0 ꢀ 7.97 (m, 2H),
7.64 – 7.57 (m, 1H), 7.55 – 7.48 (m, 2H), 7.40 (s, 1H), 7.06 (s, 1H), 6.99 (d, J = 1.3 Hz, 1H), 6.04 (d, J
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= 1.3 Hz, 2H); C NMR (75 MHz, CDCl3) δ 183.5, 152.5, 152.3, 150.0, 145.9, 137.5, 132.6, 129.3,
128.5, 120.6, 117.6, 102.0, 100.2, 93.9; IR (neat): υmax 2905, 1618, 1458, 1236, 972, 795, 697 cmꢀ1;
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C16H11O4 267.0657; found: 267.0668.
[1,3]Dioxolo[4,5-f]benzofuran-6-yl(4-methoxyphenyl)methanone (3r) : Pale yellow solid (82 mg,
81% yield); Rf = 0.5 (hexanes:EtOAc = 8.5:1.5); mp = 164–166 °C; 1H NMR (400 MHz, CDCl3) δ 8.11
– 8.02 (m, 2H), 7.42 (d, J = 0.7 Hz, 1H), 7.07 (s, 1H), 7.04 – 6.98 (m, 3H), 6.05 (s, 2H), 3.91 (s, 3H; 13C
NMR (101 MHz, CDCl3) δ 182.0, 163.4, 152.8, 152.2, 149.7, 145.8, 131.7, 130.1, 120.7, 116.6, 113.8,
101.9, 100.2, 93.9, 55.5; IR (neat): υmax 2936, 2905, 1618, 1458, 1236, 1171, 972, 795, 697 cmꢀ1; HRMS
(ESIꢀTOF) m/z: [M+Na]+ Calcd for C17H12O5Na 319.0582; found: 319.0580.
(5,6-Difluorobenzofuran-2-yl)(phenyl)methanone (3s): White solid (68 mg, 69% yield); Rf = 0.4
(hexanes:EtOAc = 19:1); mp = 117–119 °C; 1H NMR (400 MHz, CDCl3) δ 8.08ꢀ8.01 (m, 2H), 7.70 –
7.64 (m, 1H), 7.62 (d, J = 0.6 Hz, 1H), 7.71ꢀ7.64 (m, 2H), 7.42 – 7.30 (m, 2H); 13C NMR (101 MHz,
CDCl3) δ 183.80, 170.41, 153.40, 152.3 (d, JCF = 6.4 Hz),, 136.63, 133.39, 129.50, 128.74, 117.8 (d,
JCF = 22.1 Hz),, 112.3 (d, JCF = 4.1 Hz),, 108.5 (d, JCF = 5.4 Hz),, 108.4 (d, JCF = 5.3 Hz). IR (neat): υmax
2925, 2825, 1658, 1549, 1332, 1122, 722 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C15H9F2O2
259.0571; found: 259.0577.
Naphtho[2,3-b]furan-2-yl(phenyl)methanone (3t): Pale yellow solid (77 mg, 74% yield); Rf = 0.5
(hexanes:EtOAc = 19:1); mp = 99–101 °C; 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 8.12 – 8.07 (m,
2H), 8.05 (s, 1H), 8.01 – 7.95 (m, 2H), 7.70 – 7.62 (m, 2H), 7.60 – 7.43 (m, 4H);13C NMR (101 MHz,
CDCl3) δ 184.7, 154.1, 154.0, 137.2, 133.6, 133.1, 130.8, 129.6, 128.6, 128.5, 128.1, 127.7, 126.3, 124.7,
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122.3, 116.2, 109.0; IR (neat): υmax 3058, 2924, 2855, 640, 1549, 1332, 1122, 972, 722 cmꢀ1; HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C19H13O2 273.0916; found: 273.0914.
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(4-Methoxybenzofuran-2-yl)(phenyl)methanone (3u): White solid (80 mg, 83% yield); Rf = 0.5
(hexanes:EtOAc = 9:1); mp = 99–101 °C; 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J = 7.3 Hz, 2H), 7.67
– 7.57 (m, 2H), 7.52 (t, J = 7.5 Hz, 2H), 7.42 (t, J = 8.2 Hz, 1H), 7.25 (t, J = 5.9 Hz, 1H), 6.69 (d, J = 8.0
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Hz, 1H), 3.95 (s, 3H); C NMR (75 MHz, CDCl3) δ 184.2, 157.2, 155.1, 151.0, 137.4, 132.7, 129.6,
129.4, 128.5, 118.1, 114.8, 105.3, 103.6, 55.7; IR (neat): υmax 2942, 2843, 1648, 1607, 1541, 1265, 1131,
1087, 972, 731 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C16H13O3 253.0865; found: 253.0871.
(5-Methoxybenzofuran-2-yl)(4-methoxyphenyl)methanone
(3v)
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(6-Methoxybenzofuran-2-yl)(4-methoxyphenyl)methanone (3v'): Following the general procedure 4ꢀ
methoxyꢀ2ꢀ(trimethylsilyl)phenyl trifluoromethanesulfonate (135 mg, 0.41 mmol) in DMF at room
temperature under N2 atmosphere, CsF (232.3 mg, 1.5 mmol) was added and the reaction mixture was
stirred for 10 minutes then (2ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀoxoethyl)dimethylsulfonium bromide (100 mg, 0.34
mmol) was added and stirred for 12 h. After completion, the residue was purified by column
chromatography on silical gel (8% EtOAc in petroleum ether) to afford product 3v (43 mg, 45% yield)
and 3v' (33 mg, 35% yield) as yellow solids.
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Data for compound 3v: Rf = 0.40 (hexanes:EtOAc = 17:3); mp = 91–93 °C; H NMR (300 MHz,
CDCl3) δ 8.11 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 9.9 Hz, 1H), 7.47 (s, 1H), 7.10 (dd, J = 7.4, 2.4 Hz, 2H),
7.02 (d, J = 8.8 Hz, 2H), 3.91 (s, 3H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 182.7, 163.6, 156.6,
153.5, 151.0, 132.0, 129.9, 127.6, 118.1, 115.5, 113.8, 113.1, 103.9, 55.9, 55.5; IR (neat): υmax 2929,
2844, 1643, 1600, 1547, 1262, 1174, 1030, 975, 763 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C17H15O4 283.0975; found: 283.0970.
Data for compound 3v'; Rf = 0.375 (hexanes:EtOAc = 17:3); mp = 136–140 °C; 1H NMR (400 MHz,
CDCl3) δ 8.10 – 8.05 (m, 2H), 7.58 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 0.9 Hz, 1H), 7.11 (d, J = 2.1 Hz,
1H), 7.04 – 6.99 (m, 2H), 6.96 (dd, J = 8.7, 2.2 Hz, 1H), 3.91 (s, 3H), 3.89 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 182.5, 163.4, 161.0, 157.4, 152.3, 131.8, 130.1, 123.5, 120.4, 116.3, 114.3, 113.8, 95.7, 55.8,
55.5; IR (neat): υmax 2961, 2929, 2846, 1734, 1639, 1601, 1263, 1170, 1028, 976, 765 cmꢀ1; HRMS (ESIꢀ
TOF) m/z: [M+H]+ Calcd for C17H15O4 283.0970; found: 283.0981.
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(6-Methoxybenzofuran-2-yl)(4-methoxyphenyl)(pyridin-3-yl)methanol (4): Compound 4 was
synthesized using reported procedure16 from benzofuran 3v' with 54% yield as a white solid (54%) ; mp
= 41–43 °C; 1H NMR (500 MHz, CDCl3) δ 8.54 (d, J = 1.7 Hz, 1H), 8.47 (dd, J = 4.7, 1.3 Hz, 1H), 7.69
– 7.66 (m, 1H), 7.30 – 7.27 (m, 1H), 7.22 – 7.15 (m, 4H), 6.89 (d, J = 2.1 Hz, 1H), 6.83 – 6.77 (m, 3H),
6.17 (d, J = 0.8 Hz, 1H), 3.75 (s, 3H), 3.74 (s, 3H);13C NMR (126 MHz, CDCl3) δ 167.9, 159.5, 158.5,
158.3, 156.3, 148.9, 148.8, 139.9, 136.0, 135.6, 135.0, 133.0, 128.7, 122.9, 121.5, 120.9, 113.7, 112.2,
106.5, 96.1, 55.7, 55.3; IR (neat): υmax 2958, 2927, 1510, 1492, 1252, 1030, 830, 756 cmꢀ1; HRMS (ESIꢀ
TOF) m/z: [M+H]+ Calcd for C22H20NO4 362.1392; found: 362.1402.
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2-(1-Phenylvinyl)benzofuran (5): To a solution of methyltriphenylphosphonium bromide (56.2 mg,
o
0.16 mmol) in anhydrous THF (1.5 mL), at 0 C, a solution of nꢀBuLi (64 µL of 2.5 M in hexane, 1.6
mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 h, afterwards a
solution of previously synthesized ketone 3a (25 mg, 0.11 mmol), in anhydrous THF (1.5 mL), was
added dropwise at 0 oC. The mixture was allowed to warm to room temperature and stirred for 1 h. The
solvent was evaporated in vacuo and the residue was purified by flash column chromatography (silica
gel, hexane) to afford the desired olefin 5 (21 mg, 87 %); 1H NMR (400 MHz, CDCl3) δ 7.52 – 7.46 (m,
4H), 7.45 – 7.37 (m, 3H), 7.32 – 7.26 (m, 1H), 7.22 – 7.17 (m, 1H), 6.53 (s, 1H), 6.04 (d, J = 1.0 Hz,
1H), 5.43 (d, J = 1.2 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 155.9, 155.0, 139.5, 139.3, 128.9, 128.5,
128.4, 128.2, 124.8, 122.8, 121.1, 115.1, 111.1, 105.9; IR (neat): υmax 2925, 2855, 1454, 1258, 1179,
1067, 971, 749, 702 cmꢀ1; This compound was analysed by GCꢀMS, observed only one peak in GCꢀ
chromatogram at 8.26 rt, this rétention time shows 220 [M+] peak in the mass spectrum.
Methyl 4-phenyl-1,2,3,4-tetrahydrodibenzo[b,d]furan-1-carboxylate (6): A screwꢀcap vial equipped
with stirred bar was charged with a mixture of 5 (10.0 mg, 0.04 mmol, 1 equiv) in toluene and Methyl
acrylate (4.5 µL, 0.05 mmol, 1.1 equiv) at room temperature under N2 atmosphere, Sc(oTf)3 (2.2 mg, 10
o
mol%) was added and the reaction mixture was stirred for 12 h at 100 C, after cooling to room
temperature solvent was evaporated. To the reaction mixture water was added and extracted with CH2Cl2.
The organic phase was dried over NaSO4 and the crude product was purified by column chromatography
(Hexane) to obtain 6 (12 mg, 92%) with 13 : 1 dr; 1H NMR (500 MHz, CDCl3) δ 7.56 – 7.52 (m, 1H),
7.38 – 7.35 (m, 1H), 7.33 (ddd, J = 13.0, 5.3, 2.3 Hz, 2H), 7.30 – 7.26 (m, 1H), 7.25 – 7.19 (m, 4H), 4.19
– 4.14 (m, 1H), 3.92 (dd, J = 7.6, 3.2 Hz, 1H), 3.77 (s, 3H), 2.36 – 2.25 (m, 2H), 2.23 – 2.12 (m, 1H),
2.08 – 1.98 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 174.1, 155.7, 154.7, 142.1, 128.6, 128.1, 127.7,
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126.9, 123.8, 122.6, 119.5, 112.6, 111.3, 52.1, 41.1, 38.4, 31.4, 24.7; IR (neat): υmax 3510, 3389, 2960,
1807, 1737, 1687, 1455, 1172,1068, 755 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd cd for C20H19O3
307.1334; found: 307.1343.
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o
Compond 8a & 8b: Prepared according to the general procedure as described above at 60 C in 63%
combined yield. It was purified by flash chromatography (12% EtOAc/hexanes; Rf = 0.4) to afford as an
1
inseparable mixture of 8a and 8b as a semi solid. H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 5.2 Hz,
1H), 8.07 (dt, J = 8.5, 2.1 Hz, 1H), 7.99 (dd, J = 14.5, 8.3 Hz, 2H), 7.93 (d, J = 8.1 Hz, 1H), 7.67 – 7.55
(m, 3H), 7.54 – 7.48 (m, 1H), 7.45 – 7.35 (m, 1H), 4.04 – 3.86 (m, 4H), 3.10 – 2.94 (m, 2H), 2.49 – 2.35
(m, 2H), 2.12 – 2.00 (m, 1H), 1.96 (dt, J = 9.9, 4.4 Hz, 1H), 1.90 – 1.77 (m, 3H), 1.69 – 1.53 (m, 4H),
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1.52 – 1.42 (m, 2H), 0.91 (s, 3H); C NMR (101 MHz, CDCl3) δ 184.3, 155.4, 154.9, 152.4, 152.1,
143.0, 139.3, 137.6, 135.4, 134.8, 133.5, 132.4, 131.1, 129.6, 128.4, 127.9, 126.9, 125.3, 124.8, 122.1,
119.3, 119.2, 117.0, 116.4, 111.6, 108.7, 65.3, 64.7, 49.8, 46.1, 44.6, 43.9, 38.8, 38.6, 34.3, 32.0, 30.7,
30.4, 26.9, 26.8, 26.3, 26.1, 22.7, 22.5, 14.3, 14.2; IR (neat): υmax 2228, 2865, 1742, 1646, 1544, 1309,
1108, 909, 766 cmꢀ1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C33H33O4 493.2379; found: 493.2381.
Acknowledgement
PG, LNC thanks the Council of Scientific and Industrial Research (CSIR), New Delhi, for a research
fellowship. SC thanks DST for J. C. Bose fellowship (SB/S2/JCBꢀ002/2015) for financial support. We
gratefully acknowledge Dr. Balasubramanian Sridhar, Laboratory of Xꢀray Crystallography, and CSIRꢀ
IICT for Xꢀray analysis.
Supporting Information
1
13
Copies of H and C spectra for all new compounds, deuteriumꢀlabelling experiments, and Xꢀray
crystallographic data (CIF file) of compound 3u. This material is available free of charge via the Internet
at http://pubs.acs.org.
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