Base-Mediated One-pot Synthesis of Oxygen-Based Heterocycles from 2-Hydroxyphenyl-Substituted para-Quinone Methides

Article abstract of DOI:10.1021/acs.joc.9b02455

One-pot synthesis of oxygen-containing heterocycles has been achieved through alkylation/acylation of 2-hydroxyphenyl-substituted para-quinone methides followed by an intramolecular 1,6-conjugate addition/cyclization and oxidation sequence. This protocol provides access to a wide range of oxygen-based heterocycles, such as 2,3-disubstituted benzo[b]furans, 2,3-dihydrobenzofurans and diaryl-substituted coumarin derivatives in moderate to good yields.

Full text of DOI:10.1021/acs.joc.9b02455

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Article
Base Mediated One-pot Synthesis of Oxygen Based Heterocycles
from 2-Hydroxyphenyl-substituted para-Quinone Methides
Gurdeep Singh, Suresh Kumar, Arjun Chowdhury, and Ramasamy Vijaya Anand
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02455 • Publication Date (Web): 26 Nov 2019
Downloaded from pubs.acs.org on November 26, 2019
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Base Mediated One-pot Synthesis of Oxygen Based Heterocycles from 2-
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Hydroxyphenyl-substituted para-Quinone Methides
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Gurdeep Singh, Suresh Kumar, Arjun Chowdhury and Ramasamy Vijaya Anand*
Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER)
Mohali, Sector 81, Knowledge City, S. A. S. Nagar, Manauli (PO), Punjab –140306. India.
E-mail: rvijayan@iisermohali.ac.in
OH
tBu
tBu
Cl
AArr
AArr
O
R1
OH
R
O
base then [O]
O
O
R
R
R
O
Coumarins
up to 84% yield
14 examples
Br
AArr
one-pot
O
R1
base
O
R1
X
OH
tBu
AArr
Br
OH
R = tBu, iPr
tBu
AArr
2,3-Dihydrobenzofurans
up to 80% yield
dr = 3:1 to > 20:1
21 examples
base then [O]
O
R1
O
AArr
Benzo[b]furans
up to 81% yield
12 examples
Abstract: A one-pot synthesis of oxygen-containing heterocycles has been achieved through
alkylation/acylation of 2-hydroxyphenyl-substituted para-quinone methides followed by an
intramolecular 1,6-conjugate addition/cyclization and oxidation sequence. This protocol provides
access to a wide range of oxygen based heterocycles, such as 2,3-disubstituted benzo[b]furans,
2,3-dihydrobenzofurans and diaryl-substituted coumarin derivatives in moderate to good yields.
Introduction:
Oxygen based heterocycles such as 2,3-dihydrobenzofurans, benzo[b]furans and
coumarins are privileged moieties found in various class of natural products and other biologically
active unnatural molecules (Fig. 1).1 For example, pterocarpan derivatives, a second largest group
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of natural isoflavanoids, are found to display impressive antiproliferative activities in various
human cancer cell lines.2a One of the dihydrobenzofuran derivatives, (+)-obtusafuran exhibits
remarkable biological properties ranging from anti-carcinogenic to insect antifeedant activities.2b
The naturally occurring 2,3-diaryl-substituted benzo[b]furan, amurensin H is being used in the
treatment of allergic airway inflammation.2c Similarly, one of the resveratrol aneuploids,
diptoindonesin G shows potent immunosuppressive activity.2d Warfarin, a well-known coumarin
derivative, is being used as a drug for the treatment of thromboembolic diseases.2e
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O
H
O
Me
OH
O
O
HO
Ph
O
H
MeO
O
Pterocarpan
Warfarin
(+)-Obtusafuran
OH
HO
HO
O
OH
OH
OH
OH
O
O
HO
HO
Amurensin H
Diptoindonesin G
Figure 1. Oxygen-containing Biologically Significant Heterocycles
Owing to their wide range of pharmaceutical applications, the synthesis of oxygen-
containing heterocycles3 has gained interest over the last several years. In fact, the chemical
syntheses of benzo[b]furan,4a 2,3-dihydrobenzofuran4b and coumarin1b,4c based natural products
through various approaches have been reviewed recently. The major ways in which the substituted
benzo[b]furan core could be constructed involve the metal catalyzed intramolecular O-arylation
of enolates,5 intramolecular annulation of 2-alkynyl phenols/anisoles under metal-catalyzed or
metal-free conditions,6,7 and metal-catalyzed oxidative annulation of phenols with unactivated
internal alkynes/alkenes.8 Similarly, the 2,3-dihydrobenzofuran core could be majorly accessed
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either through a formal [4+1]-annulation of o-quinone methides9 or by metal catalyzed intra- or
intermolecular C–O/C–C bond forming reactions.10 Apart from the traditional ways, such as
Knoevenagal11 and Pechmann12 condensations, the coumarin derivatives could be obtained
through many different synthetic strategies,4c including metal catalyzed intramolecular cyclization
of alkynoates,13 carbonylative annulation,14 carbonylative cyclization of o-alkenylphenols,15 etc.
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Recently, the synthetic utility of 2-hydroxyphenyl-substituted p-quinone methides has been
revealed in the preparation of many heterocycles16 including 2,3-dihydrobenzofurans17 and
dihydrocoumarin derivatives.18 In line with this, we have recently reported a one-pot protocol to
access 2,3-diaryl-substituted benzo[b]furan derivatives through N-heterocyclic carbene (NHC)
catalyzed 1,6-conjugate addition of aryl aldehydes to 2-hydroxyphenyl-substituted p-quinone
methides followed by acid mediated dehydrative cyclization.19 In continuation with our ongoing
research in the area of p-QMs,20 herein, we disclose an efficient one-pot method for the synthesis
2,3-dihydrobenzofurans through a base mediated O-alkylation of 2-hydroxyphenyl-substituted p-
quinone methides with a-halo ketones followed by intramolecular 1,6-conjugate addition strategy
(Scheme 1). This method was also elaborated for the synthesis of 2,3-disubstituted benzo[b]furan
derivatives through the in situ oxidation of 2,3-dihydrobenzofurans. Similar protocol was also
developed for the one-pot synthesis of 3,4-diaryl-substituted coumarin derivatives through O-
acylation of 2-hydroxyphenyl-substituted p-quinone methides with arylacetyl halides followed by
intramolecular 1,6-conjugate addition/oxidation strategy (Scheme 1). Although a few reports are
available for the synthesis of 2,3-dihydrobenzofurans either through a formal [4+1]-annulation of
2-hydroxyphenyl-substituted p-QMs with sulfur ylides17a-c and allenoates17d or through the
reaction of 2-hydroxyphenyl-substituted p-QMs with a-halo carbonyl compounds,17e,f the direct
one-pot synthesis of 2,3-disubstituted benzo[b]furans and 3,4-diaryl-substituted coumarin
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derivatives from 2-hydroxyphenyl-substituted p-QMs through O-alkylation followed by
cyclization and oxidation strategy (Scheme 1) has not been reported yet. Therefore, we have
decided to explore these transformations.
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O
tBu
tBu
O
Ar
O
Ar
Ar
Br
Ar
O
O
Ar
Cl
base
then DDQ
(one-pot)
base
then DDQ
(one-pot)
O
Ar
O
benzo[b]furans
coumarins
OH
O
Br
Ar
base
Ar
O
O
Ar
2,3-dihydrobenzofurans
Scheme 1. One-pot Synthesis of 2,3-Dihydrobenzofurans, Benzo[b]furans and Coumarins
Results and Discussion:
Since the proposed strategy to synthesize benzo[b]furans involves 2,3-dihydrobenzofurans
as intermediates, we thought of identifying the best conditions for the synthesis of 2,3-
dihydrobenzofurans before exploring the one-pot synthesis of benzo[b]furans. In this regard, the
optimization studies were initiated using a 2-hydroxyphenyl-substituted p-QM 1a and 2-
bromoacetophenone (phenacyl bromide) 2a under various conditions (Table 1). Initially, the
reaction between 1a and 2a was performed under basic conditions using 1.5 equivalents of K2CO3
in chlorinated solvents. However, the desired product 3a was obtained only in trace quantities even
after 24 h (entries 1 & 2). Interestingly, when the same reaction was performed in acetonitrile, the
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Table 1. Optimization Studiesa
OH
tBu
5
6
7
8
9
tBu
OH
O
tBu
O
O
base (1.5 equiv.)
+
solvent
Br
O
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tBu
1a
2a
3a
dr
isolated yield
entry
base
solvent
time [h]
(trans:cis)e
of trans-3a [%]
1
2
3
4
5
6
7
8
9b
10c
11d
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3 Acetone
NEt3
DBU
CH2Cl2
CHCl3
CH3CN
Acetone
CH3CN
24
24
12
8
1.5
1.5
24
24
24
1
-
-
trace
trace
67
73
73
80
40
46
71
6:1
9:1
9:1
10:1
3:1
7:1
9:1
9:1
9:1
Acetone
Acetone
Acetone
Acetone
Acetone
Cs2CO3
Cs2CO3
Cs2CO3
80
30
24
a All reactions were carried out with 1a (0.097 mmol), 2a (0.088 mmol) and 1.5 equivalent of base in 1.5 mL of
solvent. b 1.0 equivalent of base was used. c 2.0 equivalent of base was used. d Reaction was carried at 0 oC and 1.5
equivalent of base was used. e The diastereomeric ratio (dr) was calculated based on the 1H NMR analysis of crude
reaction mixture. The structure and the relative stereochemistry of the product 3a was assigned by comparing the 1H
NMR data with the previous reports.17
2,3-dihydrobenzofuran 3a was obtained as a diastereomeric pair [dr = 6:1 (trans:cis)] and the pure
trans-3a was isolated in 67% chemical yield (entry 3). It was found that the reaction worked well
in acetone as the product trans-3a was obtained in 73% isolated yield (entry 4). When the reaction
was carried out in acetonitrile, there was no change in the yield and diastereomeric ratio though
the reaction time was reduced to 1.5 h (entry 5). Further optimization studies were carried out in
acetone using other organic and inorganic bases. By using 1.5 equivalents of Cs2CO3 as a base,
the 2,3-dihydrobenzofuran 3a was obtained as a diastereomeric pair (dr = 10:1) and the pure trans-
3a was isolated in the maximum of 80% yield within 1.5 h (entry 6). Organic bases, such as
triethylamine and DBU were found to be less effective for this transformation (entries 7 & 8). The
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yield of 3a was relatively low (71%) when the reaction was carried out with 1 equivalent of Cs2CO3
(entry 9) and, there was no change in the yield and diastereoselectivity of 3a when 2 equivalents
of Cs2CO3 was used (entry 10). Since some decomposition was observed in most of the
optimization experiments at room temperature, an experiment was conducted at lower temperature
(0 oC) using 1.5 equivalents of Cs2CO3. However, in that case, although the reaction was found to
be clean, the rate of the reaction was low and, the product 3a was obtained only in 30% isolated
yield after 24 h (entry 11).
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After finding the optimal reactions conditions (entry 6, Table 1), the substrate scope was
investigated by employing a wide range of 2-hydroxyphenyl-substituted p-QMs (1a-j) and
bromomethyl aryl ketones (2a-l), and the results are summarized in Table 2. In general, most of
the bromomethyl aryl ketones (2b-l) reacted with 1a and provided the respective trans-2,3-
dihydrobenzofuran derivatives (3b-l) in moderate to good isolated yields. For example, the
reaction of 1a with bromomethyl aryl ketones 2a-k (containing alkyl-, alkoxy- and halo-
substitution at aryl ring) provided the corresponding trans-2,3-dihydrobenzofuran derivatives 3a-
k in 66-80% isolated yields. In the case of bromomethyl 1-naphthyl ketone (2l), the product 3l was
obtained in 66% yield. In the cases of reaction between 2a and 2-hydroxyphenyl-substituted p-
QMs 1b-h (derived from the respective alkyl-, halo- and alkoxy-substituted salicylaldehydes), the
trans-2,3-dihydrobenzofuran derivatives 3m-s were obtained in the rage of 53-77% chemical
yields. In the case of 2-hydroxyphenyl-substituted p-QM 1i (derived from 2-hydroxy-1-
naphthaldehyde), the respective product trans-3t was obtained in 73% yield. When the p-QM 1j
(derived from 2,6-diisopropylphenol), the product 3u was isolated as a diastereomeric mixture in
53% yield.
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Table 2. Substrate scope for the synthesis of trans-2,3-dihydrobenzofuransa
5
6
7
8
O
OH
tBu
tBu
tBu
tBu
O
R
Br
R1
R1
Cs2CO3 (1.5 equiv.)
acetone, rt, 1.5 h
O
9
O
OH
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1a-j (1.1 equiv.)
2a-l (1.0 equiv.)
3b-u
R
-----------------------------------------------------------------------------------------------------------------------
OH
OH
3b, R = 3-Me, 80%, dr = 10:1
3c, R = 4-Et, 72%, dr = 7:1
3d, R = 4-OMe, 79%, dr = 9:1
3e, R = 3-OMe, 72%, dr = 10:1
tBu
tBu
tBu
tBu
3f, R = 4-OCF3, 70%, dr = 7:1
3h, R = 4-Cl, 70% dr = 5:1
3i, R = 2-Cl, 73%, dr = 7:1
3j, R = 2-F, 66%, dr = 3:1
3k, R = 4-CF3, 69%, dr = 4:1
O
O
OMe
OMe
O
O
R
3g, 68%, dr = 6:1
OH
tBu
OH
tBu
OH
tBu
tBu
tBu
tBu
R1
O
O
O
O
O
O
MeO
3m, R1 = Me, 77%, dr = 8:1
3n, R1 = OMe, 71%, dr = 9:1
3o, 73%, dr = 6:1
3l, 66%, dr = >20:1
OH
tBu
tBu
OH
tBu
OH
tBu
R1
O
O
O
O
R2
O
O
3p, R1 = F, R2 = H, 70%, dr = 6:1
3q, R1 = Cl, R2 = H, 71%, dr = 4:1
3r, R1 = Br, R2 = H, 72%, dr = 7:1
3s, R1, R2 = Cl, 53%, dr = 3:1
3u, 53%, dr = 5:1
3t, 73%, dr = >20:1
-----------------------------------------------------------------------------------------------------------------------
a All reactions were carried out in ~ 0.1 mmol scale of 1(a-j) in 1.5 mL of acetone. Yields represented are isolated
yields of the pure trans-isomer (major isomer). The diastereomeric ratios (dr) were calculated based on the 1H NMR
analysis of crude reaction mixtures.
To show the importance of this methodology, this concept was also elaborated to the one-
pot synthesis of 2,3-disubstituted benzo[b]furans, directly from the 2-hydroxyphenyl-substituted
p-QMs through the in situ dehydrogenative oxidation of 2,3-dihydrobenzofurans by DDQ, and the
results are summarized in Table 3. It was found that the one-pot conversion of 1a to the
corresponding 2,3-disubstituted benzo[b]furan 4a worked well using 2 equivalents of DDQ in
acetonitrile and, in this case, 4a was obtained in 81% yield. However, the same transformation in
acetone provided the product 4a only in 73% yield even after 24 h. Since acetonitrile was found
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to be better solvent than acetone for this transformation, further elaboration of the substrate scope
had been performed in acetonitrile. As shown in Table 3, most of the reactions between 1a and
various bromomethyl aryl ketones (2b-g) worked well, and the respective products 4b-g were
obtained in the range of 44-79% yields. In the cases of reaction between 2a and 2-hydroxyphenyl-
substituted p-QMs 1b-e, the benzo[b]furan derivatives 4h-k were obtained in the rage of 73-78%
yields. In the case of 2-hydroxyphenyl-substituted p-QM 1i, the respective product 4l was obtained
in 69% yield.
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Table 3. Substrate scope for the synthesis of benzo[b]furansa
OH
O
tBu
tBu
tBu
tBu
O
(i) Cs2CO3 (1.5 equiv.)
CH3CN, rt,1.5 h
R2
R1
R1
O
+
(ii) DDQ (2.0 equiv.)
50 oC, 8 h
Br
R2
O
OH
2a-g
4a-l
1a-e & 1i
(1.1 equiv.)
(1.0 equiv.)
-----------------------------------------------------------------------------------------------------------------
OH
tBu
OH
tBu
4a, R2 = H, 81%
tBu
tBu
4b, R2 = 3-Me, 79%
4c, R2 = 4-OMe, 68%
4d, R2 = 2-F, 78%
O
O
4f, R2 = 3-CF3, 67%
4g, R2 = 3-NO2, 47%
Cl
O
O
4e, 44%
R2
Cl
OH
OH
tBu
OH
tBu
tBu
tBu
tBu
tBu
R1
O
O
O
O
O
MeO
O
4h, R1 = Cl, 75%
4i, R1 = Me, 76%
4k, 73%
4l, 69%
4j, R1 = OMe, 78%
-----------------------------------------------------------------------------------------------------------------
a All reactions were carried out in ~ 0.1 mmol scale of 1(a-e) & 1i in 1.5 mL of MeCN. Yields reported are isolated
yields.
After exploring the application potential of this methodology in the synthesis of various
2,3-dihydrobenzofuran and benzo[b]furan derivatives, our attention was shifted to further
elaborate this concept for the synthesis of other oxygen based heterocycles. We envisioned that it
could be a possible to access 3,4-diaryl-substituted coumarin derivatives by treating 2-
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hydroxyphenyl-substituted p-QMs with arylacetyl halides followed by one-pot dehydrogenative
oxidation with DDQ. In this regard, an initial experiment was carried out by treating 1a with
phenylacetyl chloride (5a) [1.2 equiv.] and Cs2CO3 (2.2 equiv.) in acetone for 1.5 h followed by
addition of DDQ (1.5 equiv.). As expected, in that case, the desired coumarin derivative 6a was
obtained in 84% isolated yield (Table 4). Encouraged by this result, the scope and limitations of
this transformation were examined using various 2-hydroxyphenyl-substituted p-QMs (1a-e) and
arylacetyl halides (5a-j), and the results are summarized in Table 4. Most of the arylacetyl halides
(5b-j) reacted smoothly with 1a and the respective products, after oxidation with DDQ, gave the
corresponding diaryl-substituted coumarin derivatives 6b-j in the range of 69-79% isolated yields.
In addition, other 2-hydroxyphenyl-substituted p-QMs (1b-e) also reacted with phenylacetyl
chloride (5a) and provided the desired products 6k-n in good yields (73-76%).
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Table 4. Substrate scope for the synthesis of coumarin derivativesa
O
OH
tBu
tBu
tBu
tBu
(i) Cs2CO3 (2.2 equiv.)
acetone, rt, 1.5 h
R2
R2
Cl
R1
R1
(ii) DDQ (1.5 equiv.)
6 h
O
OH
1a-e (1.0 equiv.)
O
O
5a-j(1.2 equiv.)
6a-n
--------------------------------------------------------------------------------------------------------------------
6a, R2 = H, 84%
OH
OH
6b, R2 = 3-OMe, 77%
6c, R2 = 4-OMe, 71%
6e, R2 = 4-F, 81%
6f, R2 = 3-F, 79%
6g, R2 = 4-Cl, 79%
6h, R2 = 3-Cl, 76%
6i, R2 = 4-Br, 78%
6j, R2 = 4-Ph, 73%
tBu
tBu
tBu
tBu
R2
OMe
OMe
O
O
O
O
6d, 69%
OH
OH
tBu
tBu
tBu
tBu
6k, R1 = Cl, 75%
6l, R1 = Br, 76%
6m, R1 = Me, 73%
R1
MeO
O
6n, 75%
O
O
O
--------------------------------------------------------------------------------------------------------------------
a All reactions were carried out in ~ 0.1 mmol scale of 1(a-e) in 1.5 mL of acetone. Yields reported are isolated yields.
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To show a practical application of this transformation, we thought of elaborating one of
the coumarin derivatives to a biologically active 3,4-diaryl-substituted coumarin derivative 8,
which was found to act as an immunomodulating agent.21 It has been reported that the coumarin
derivative 8 could be easily accessed in a couple of steps from 7 through O-alkylation followed by
amination with morpholine.21 In fact, the coumarin derivative 7 could be prepared in one step from
6a by removal of t-Bu groups. In this regard, the de-tert-butylation reaction of 6a was carried out
by treating it with excess of AlCl3 (10 equiv.) in toluene at 60 oC, and the expected product 7 was
obtained in 85% yield (Scheme 2).
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O
N
OH
O
2 steps
ref 21
AlCl3 (10 equiv.)
PhMe, 60 oC, 1 h
6a
O
O
O
O
7, 85% yield
8
Scheme 2. Formal Synthesis of Immunomodulating Agent 8
Later, we turned our attention to understand the mechanism of these transformations. There
are two different pathways possible for both the transformations [benzofuran as well as coumarin
formation] (Scheme 3); (i) O-alkylation followed by intramolecular cyclization (path A) or 1,6-
conjugate addition followed by intramolecular O-alkylation (path B) in the case of 2,3-
dihydrobenzofuran/benzo[b]furan formation and, (ii) O-acylation followed by intramolecular
cyclization (path C) or 1,6-conjugate addition followed by intramolecular O-acylation (path D) in
the case of coumarin formation.
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O
O
Coumarin
synthesis
Benzofuran
synthesis
R
R
R
R
O
O-acylation
O-alkylation
intramolecular
cyclization
intramolecular
cyclization
R
R
path A
path C
Ar
O
Ar
Ar
O
Ar
O
O
O
O
Ar
O
O
Ar
Br
Ar
OH
OH
Cl
O
Ar
R
R
OH
O
R
R
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1,6-addition
1,6-addition
path B
intramolecular
O-acylation
intramolecular
O-alkylation
Ar
path D
COAr
COCl
OH
Br
OH
Scheme 3. Possible Reaction Pathways
During the optimization studies, we thought of isolating the intermediate(s) in the reaction
between 2-hydroxyphenyl-substituted p-QM (1a) and 2-bromoacetophenone (2a) [entry 6, Table
1]. However, we were not able to isolate any of the intermediates as we could not notice any other
spot in the TLC except the starting materials (1a & 2a) and the product (3a). Most probably, the
transformation of the intermediate to the product 3a could be spontaneous. In fact, the 1H NMR
analysis of the crude reaction mixture before completion of the reaction did not help much in
identifying the intermediate(s). Therefore, to understand the actual reaction pathway(s), a few
control experiments have been performed (Scheme 4). Initially, a couple of experiments had been
carried out by treating phenyl-substituted p-QM 9 (instead of 1a) with phenacyl bromide (2a) and
phenylacetyl chloride (5a), individually under standard conditions. However, in both the cases, the
corresponding 1,6-adducts 10 and 11 were not observed even after 24 h (Scheme 4). In fact, the
starting material 9 was recovered unreacted in both the experiments.
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OH
OH
O
tBu
tBu
Ph
tBu
tBu
O
tBu
tBu
O
Cl
Ph
5
6
7
8
Br
Ph
2a
O
5a
standard
conditions
standard
conditions
Ph
COCl
11
not detected
Br
10
not detected
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O
O
O
tBu
tBu
tBu
tBu
tBu
tBu
Ph
O
Cl
Ph
Br
Ph
2a
O
5a
O
O
HO
standard
conditions
standard
conditions
O
Ph
O
14
70% yield
12
13
73% yield
Scheme 4. Control Experiments
In another set of experiments, 3-hydroxyphenyl-substituted p-QM 1223 (instead of 1a) was
treated with 2a and 5a, individually under the standard conditions (Scheme 4). Interestingly, in
those cases, the corresponding O-alkylated product 13 and O-acylated product 14 were obtained
in 73% and 70% yields, respectively within an hour. Moreover, the corresponding 1,6-adducts
were not at all observed in both the cases. The above-mentioned control experiments clearly
indicate that the reaction is proceeding through O-alkylation followed by intramolecular
cyclization17e in the case of 2,3-dihydrobenzofuran/benzo[b]furan formation (path A, Scheme 3).
Similarly, in the case of coumarin formation, one can conclude that the reaction is proceeding
through O-acylation followed by intramolecular cyclization (path C, Scheme 3).
In summary, an effective one-pot protocol has been developed for the diastereoselective
synthesis of trans-2,3-dihydrobenzofurans from 2-hydroxyaryl-substituted p-quinone methides
through O-alkylation followed by 1,6-conjugate addition/cyclization strategy. This methodology
has been elaborated for the one-pot synthesis of benzo[b]furans through the in situ
dehydrogenative oxidation of the trans-2,3-dihydrobenzofuran intermediates. Similar
methodology was also developed for the one-pot synthesis of 3,4-diaryl-substituted coumarin
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derivatives through the reaction between 2-hydroxyaryl-substituted p-quinone methides and
arylacetyl chlorides followed by oxidation. Under the optimal conditions, the above-mentioned
oxygen-containing heterocycles could be accessed in moderate to good yields.
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Experimental Section:
General Information. All reactions were carried out under an argon atmosphere in an oven dried
round bottom flask. All the solvents were distilled before use and stored under argon atmosphere.
Most of the reagents and starting materials were purchased from commercial sources and used as
such. The substituted 2-bromoacetophenones were prepared according to the literature
procedure.22 All 2-hydroxyphenyl-subsituted p-quinone methides (1a-j)16a and 3-hydroxy phenyl-
substituted p-quinone methide (12)23 were prepared by following literature procedures. Melting
1
13
19
points were recorded on SMP20 melting point apparatus and are uncorrected. H, C and F
spectra were recorded in CDCl3 (400, 100 and 376 MHz respectively) on Bruker FT–NMR
spectrometer. Chemical shift (d) values are reported in parts per million relative to TMS or CDCl3
(7.26 ppm for 1H and 77.16 ppm for 13C NMR) and the coupling constants (J) are reported in Hz.
High resolution mass spectra were recorded on Waters Q–TOF Premier–HAB213 spectrometer.
FT-IR spectra were recorded on a Perkin-Elmer FTIR spectrometer. Thin layer chromatography
was performed on Merck silica gel 60 F254 TLC pellets and visualized by UV irradiation and
KMnO4 stain. Column chromatography was carried out through silica gel (100–200 mesh) using
EtOAc/hexane as an eluent.
General procedure for the synthesis of 2,3-dihydrobenzofuran derivatives (3a-s):
Bromomethyl aryl ketone [2a-l] (0.1 mmol, 1.0 equiv.) was added to a mixture of 2-
hydroxyphenyl-subsituted p-QM [1a-j] (0.11 mmol, 1.1 equiv.) and Cs2CO3 (0.15 mmol, 1.5
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equiv.) in acetone (1.5 mL, 0.06 M) and, the resulting suspension was stirred at room temperature
until the bromomethyl aryl ketone was completely consumed (based on TLC analysis). The
reaction mixture was concentrated under reduced pressure and, the residue [a mixture of cis- and
trans-2,3-dihydrobenzofurans along with some amounts of the starting material(s)] was then
purified through a silica gel column using EtOAc/Hexane mixture as an eluent to get the trans-
2,3-dihydrobenzofuran derivatives (3a-u).
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trans-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydrobenzofuran-2-yl](phenyl)methanone
(3a):17b The reaction was performed at 0.097 mmol scale of 1a; white solid (31.0 mg, 80% yield);
1H NMR (400 MHz, CDCl3) δ 7.95 – 7.93 (m, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.8 Hz,
2H), 7.22 (t, J = 7.9 Hz, 1H), 7.06 (d, J = 7.4 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.96 (s, 2H), 6.91
(t, J = 7.4 Hz, 1H), 5.80 (d, J = 6.6 Hz, 1H), 5.20 (s, 1H), 4.86 (d, J = 6.6 Hz, 1H), 1.40 (s, 18H);
13C{1H} NMR (100 MHz, CDCl3) δ 195.3, 159.3, 153.2, 136.3, 134.7, 133.8, 132.7, 129.5, 129.4,
128.8, 128.7, 125.6, 124.9, 121.6, 109.9, 90.9, 51.4, 34.5, 30.4; FT-IR (thin film, neat): 3636, 2959,
1694, 1261, 750 cm-1; HRMS (ESI): m/z calcd for C29H31O3 [M–H]– : 427.2273; found : 427.2288.
trans-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydrobenzofuran-2-yl](m-tolyl)methanone
(3b):17c The reaction was performed at 0.097 mmol scale of 1a; white solid (31.6 mg, 80% yield);
1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.7 Hz, 1H), 7.66 (s, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.33
(t, J = 7.6 Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.04 (d, J = 7.4 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.95
(s, 2H), 6.90 (t, J = 7.4 Hz, 1H), 5.80 (d, J = 6.8 Hz, 1H), 5.18 (s, 1H), 4.81 (d, J = 6.8 Hz, 1H),
2.36 (s, 3H), 1.38 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.5, 159.4, 153.2, 138.5, 136.4,
134.8, 134.6, 132.6, 129.9, 129.5, 128.8, 128.6, 126.6, 125.5, 124.9, 121.5, 110.0, 90.9, 51.7, 34.5,
30.4, 21.5; FT-IR (thin film, neat): 3636, 2958, 1695, 1479, 1267, 759 cm-1; HRMS (ESI): m/z
calcd for C30H33O3 [M–H]– : 441.2430; found : 441.2448.
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trans-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydrobenzofuran-2-yl](4-ethylphenyl)-
methanone (3c): The reaction was performed at 0.097 mmol scale of 1a; white solid (29 mg, 72%
yield); m. p. = 151–153 ºC; Rf = 0.2 (5% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 7.85
(d, J = 7.4 Hz, 2H), 7.28 – 7.26 (m, 2H), 7.21 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 6.99
(d, J = 8.1 Hz, 1H), 6.95 (s, 2H), 6.90 (t, J = 7.5 Hz, 1H), 5.77 (d, J = 6.6 Hz, 1H), 5.18 (s, 1H),
4.84 (d, J = 6.6 Hz, 1H), 2.72 (q, J = 7.5 Hz, 2H) 1.38 (s, 18H), 1.27 (t, J = 7.5 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 195.0, 159.4, 153.1, 150.9, 136.3, 132.8, 132.4, 129.7, 129.5, 128.8,
128.3, 125.6, 124.9, 121.5, 109.9, 90.8, 51.5, 34.5, 30.4, 29.2, 15.3; FT-IR (thin film, neat): 3636,
2963, 1689, 1461, 1275, 750 cm-1; HRMS (ESI): m/z calcd for C31H35O3 [M–H]– : 455.2586; found
: 455.2599.
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trans-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydrobenzofuran-2-yl](4-methoxyphenyl)-
methanone (3d):17b The reaction was performed at 0.097 mmol scale of 1a; white solid (31.6 mg,
79% yield); 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.6 Hz, 2H), 7.20 (t, J = 7.7 Hz, 1H), 7.05
(d, J = 7.4 Hz, 1H), 6.98 – 6.96 (m, 3H), 6.92 – 6.88 (m, 3H), 5.74 (d, J = 6.8 Hz, 1H), 5.18 (s,
13
1H), 4.86 (d, J = 6.8 Hz, 1H), 3.87 (s, 3H), 1.38 (s, 18H); C{1H} NMR (100 MHz, CDCl3) δ
193.8, 164.0, 159.3, 153.1, 136.3, 132.7, 131.8, 129.6, 128.7, 127.7, 125.6, 125.0, 121.5, 113.9,
109.9, 90.8, 55.6, 51.5, 34.5, 30.4; FT-IR (thin film, neat): 3636, 2959, 1674, 1456, 1262, 750 cm-
1; HRMS (ESI): m/z calcd for C30H33O4 [M–H]– : 457.2379; found : 457.2397.
trans-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydrobenzofuran-2-yl](3-methoxyphenyl)-
methanone (3e):17c The reaction was performed at 0.097 mmol scale of 1n; white solid (28.8 mg,
72% yield); 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.6 Hz, 1H), 7.38 (s, 1H), 7.35 (t, J = 8.0
Hz, 1H), 7.21 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 7.00 (d, J =
8.1 Hz, 1H), 6.94 (s, 2H), 6.90 (t, J = 7.4 Hz, 1H), 5.79 (d, J = 6.7 Hz, 1H), 5.19 (s, 1H), 4.79 (d,
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J = 6.7 Hz, 1H), 3.74 (s, 3H), 1.38 (s, 18H); C{1H} NMR (100 MHz, CDCl3) δ 195.2, 159.8,
5
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7
8
159.3, 153.2, 136.4, 135.9, 132.7, 129.7, 129.4, 128.8, 125.6, 124.9, 122.0, 121.6, 120.5, 113.4,
110.0, 90.9, 55.4, 51.8, 34.5, 30.3; FT-IR (thin film, neat): 3632, 2958, 1699, 1480, 1263, 750 cm-
1; HRMS (ESI): m/z calcd for C30H33O4 [M–H]– : 457.2379; found : 457.2399.
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trans-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydrobenzofuran-2-yl](4-(trifluoromethoxy)-
phenyl)methanone (3f): The reaction was performed at 0.097 mmol scale of 1a; white solid (31.7
mg, 70% yield); m. p. = 127–129 ºC; Rf = 0.3 (5% EtOAc in hexane); 1H NMR (400 MHz, CDCl3)
δ 8.01 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.21 (t, J = 7.7 Hz, 1H) 7.06 (d, J = 7.3 Hz,
1H), 6.98 – 6.96 (m, 3H), 6.91 (t, J = 7.4 Hz, 1H), 5.71 (d, J = 6.8 Hz, 1H), 5.20 (s, 1H), 4.90 (d,
J = 6.8 Hz, 1H), 1.38 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.9, 159.0, 153.3, 153.1 (q,
JC-F = 1.6 Hz), 136.5, 132.9, 132.4, 131.6, 129.3, 128.9, 125.7, 124.9, 121.8, 120.4, 120.39 (q, JC-
19
F = 257.4 Hz), 110.0, 91.0, 51.1, 34.5, 30.4; F{1H} NMR (376 MHz, CDCl3) δ –57.54; FT-IR
(thin film, neat): 3639, 2960, 1696, 1479, 1268, 750 cm-1; HRMS (ESI): m/z calcd for C30H30F3O4
[M–H]– : 511.2096; found : 511.2119.
trans-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydrobenzofuran-2-yl](2,3-dimethoxyphenyl)-
methanone (3g): The reaction was performed at 0.097 mmol scale of 1a; white solid (29.5 mg,
68% yield); m. p. = 153–155 ºC; Rf = 0.1 (5% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ
7.18 (d, J = 7.6 Hz, 1H), 7.11 – 7.07 (m, 2H), 7.06 – 7.04 (m, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.94
(d, J = 8.1 Hz, 1H), 6.87 (t, J = 7.4 Hz, 1H), 6.80 (s, 2H), 5.77 (d, J = 6.5 Hz, 1H), 5.10 (s, 1H),
13
4.70 (d, J = 6.4 Hz, 1H), 3.85 (s, 3H), 3.68 (s, 3H), 1.33 (s, 18H); C{1H} NMR (100 MHz,
CDCl3) δ 200.0, 159.5, 152.9, 152.8, 148.0, 136.0, 133.1, 131.9, 129.2, 128.7, 125.6, 124.7, 124.1,
121.3, 121.2, 116.1, 109.9, 93.3, 61.5, 56.0, 51.6, 34.4, 30.3; FT-IR (thin film, neat): 3627, 2956,
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trans-(4-chlorophenyl)[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydrobenzofuran-2-yl]-
methanone (3h):17b The reaction was performed at 0.097 mmol scale of 1a; white solid (29.2 mg,
70% yield); 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.21
(t, J = 7.7 Hz, 1H), 7.06 (d, J = 7.4 Hz, 1H), 6.98 – 6.96 (m, 3H), 6.92 (t, J = 7.4 Hz, 1H), 5.71 (d,
J = 6.9 Hz, 1H), 5.20 (s, 1H), 4.89 (d, J = 6.9 Hz, 1H), 1.39 (s, 18H); 13C{1H} NMR (100 MHz,
CDCl3) δ 194.3, 159.1, 153.2, 140.3, 136.5, 133.1, 132.4, 130.9, 129.4, 129.0, 128.8, 125.6, 124.9,
121.7, 110.0, 91.0, 51.2, 34.5, 30.4; FT-IR (thin film, neat): 3636, 2959, 1695, 1479, 1261, 750
cm-1; HRMS (ESI): m/z calcd for C29H30ClO3 [M–H]– : 461.1883; found : 461.1904.
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trans-(2-chlorophenyl)[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydrobenzofuran-2-yl]-
methanone (3i): The reaction was performed at 0.097 mmol scale of 1a; white solid (30.4 mg, 73%
yield); m. p. = 133–135 ºC; Rf = 0.2 (5% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 7.42 –
7.37 (m, 3H), 7.30 – 7.28 (m, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 7.4 Hz, 1H), 6.91 – 6.90
(m, 2H), 6.84 (s, 2H), 5.69 (d, J = 6.5 Hz, 1H), 5.13 (s, 1H), 4.82 (d, J = 6.7 Hz, 1H), 1.34 (s,
18H); 13C{1H} NMR (100 MHz, CDCl3) δ 200.1, 159.1, 153.1, 137.1, 136.2, 132.5, 132.2, 131.7,
130.5, 129.6, 129.0, 128.9, 126.8, 125.7, 124.6, 121.7, 110.0, 92.9, 51.5, 34.4, 30.3; FT-IR (thin
film, neat): 3633, 2958, 1716, 1478, 1232, 751 cm-1; HRMS (ESI): m/z calcd for C29H30ClO3 [M–
H]– : 461.1883; found : 461.1894.
trans-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydrobenzofuran-2-yl](2-fluorophenyl)-
methanone (3j): The reaction was performed at 0.097 mmol scale of 1a; white solid (25.8 mg, 66%
yield); m. p. = 129–131 ºC; Rf = 0.2 (5% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 7.77
(t, J = 7.4 Hz, 1H), 7.54 (q, J = 7.1, 1H), 7.26 – 7.23 (m, 1H), 7.18 (t, J = 7.7 Hz, 1H), 7.12 – 7.07
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(m, 1H), 7.04 (d, J = 7.4 Hz. 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.91 (s, 2H), 6.88 (d, J = 7.5 Hz, 1H),
5.73 (d, J = 6.1 Hz, 1H), 5.14 (s, 1H), 4.82 (d, J = 6.0 Hz, 1H), 1.37 (s, 18H); 13C{1H} NMR (100
MHz, CDCl3) δ 195.5 (d, JC-F = 3.6 Hz), 161.4 (d, JC-F = 253.9 Hz), 159.2, 153.0, 136.1, 135.0 (d,
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C-F = 8.9 Hz), 132.7, 131.3 (d, JC-F = 2.8 Hz), 129.3, 128.8, 125.6, 124.72, 124.68, 124.4 (d, JC-F
= 13.5 Hz), 121.6, 116.6 (d, JC-F = 22.9 Hz), 109.9, 93.1 (d, JC-F = 5.8 Hz), 51.0, 34.5, 30.4; 19F{1H}
NMR (376 MHz, CDCl3) δ –108.95; FT-IR (thin film, neat): 3637, 2958, 1694, 1480, 1233, 751
cm-1; HRMS (ESI): m/z calcd for C29H30FO3 [M–H]– : 445.2179; found : 445.2189.
trans-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydrobenzofuran-2-yl]{4-(trifluoromethyl)-
phenyl}methanone (3k):17c The reaction was performed at 0.097 mmol scale of 1a; pale yellow
solid (30.8 mg, 69% yield); m. p. = 110–114 ºC; 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.0
Hz, 2H), 7.74 (d, J = 8.1 Hz, 2H), 7.24 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 7.4 Hz, 1H), 6.99 – 6.93
(m, 4H), 5.76 (d, J = 6.9 Hz, 1H), 5.23 (s, 1H), 4.94 (d, J = 6.9 Hz, 1H), 1.41 (s, 18H); 13C{1H}
NMR (100 MHz, CDCl3) δ 194.7, 159.0, 153.3, 137.6, 136.6, 135.0 (q, JC-F = 32.5 Hz ), 132.4,
129.9, 129.3, 128.9, 125.72 (q, JC-F = 3.7 Hz), 125.67, 124.9, 123.6 (q, JC-F = 271.2 Hz), 121.8,
110.0, 91.2, 51.1, 34.5, 30.4; 19F{1H} NMR (376 MHz, CDCl3) δ –63.20; FT-IR (thin film, neat):
3639, 2960, 1699, 1479, 1325, 750 cm-1; HRMS (ESI): m/z calcd for C30H30F3O3 [M–H]– :
495.2147; found : 495.2161.
trans-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydrobenzofuran-2-yl](phenyl)methanone
(3l): The reaction was performed at 0.097 mmol scale of 1a; white solid (27.9 mg, 66% yield); m.
p. = 145–147 ºC; Rf = 0.2 (5% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 8.4
Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.63 – 7.54
(m, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 7.00 (d, J = 8.0
Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 6.76 (s, 2H), 5.88 (d, J = 7.0 Hz, 1H), 5.12 (s, 1H), 4.81 (d, J =
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7.0 Hz, 1H), 1.30 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.2, 159.5, 153.0, 136.2, 134.0,
133.4, 133.1, 132.6, 130.9, 129.05, 129.01, 128.9, 128.7, 128.5, 126.8, 125.7 (2C), 124.7, 124.3,
121.6, 110.0, 92.4, 51.8, 34.4, 30.3; FT-IR (thin film, neat): 3627, 2958, 1683, 1479, 1261, 750
cm-1; HRMS (ESI): m/z calcd for C33H33CO3 [M–H]– : 477.2430; found : 477.2450.
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trans-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methyl-2,3-dihydrobenzofuran-2-yl](phenyl)-
methanone (3m):17b The reaction was performed at 0.092 mmol scale of 1b; white solid (29.1 mg,
77% yield); 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 7.8 Hz, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.44
(t, J = 7.4 Hz, 2H), 7.00 (d, J = 8.2 Hz, 1H), 6.96 (s, 2H), 6.88 – 6.86 (m, 2H), 5.77 (d, J = 6.4 Hz,
1H), 5.19 (s, 1H), 4.80 (d, J = 6.4 Hz, 1H), 2.25 (s, 3H), 1.40 (s, 18H); 13C{1H} NMR (100 MHz,
CDCl3) δ 195.4, 157.3, 153.1, 136.3, 134.7, 133.7, 132.9, 130.9, 129.44, 129.40, 129.3, 128.7,
126.0, 124.9, 109.4, 91.1, 51.5, 34.5, 30.4, 20.9; FT-IR (thin film, neat): 3636, 2958, 1699, 1489,
1275, 750 cm-1; HRMS (ESI): m/z calcd for C30H33O3 [M–H]– : 441.2430; found : 441.2444.
trans-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methoxy-2,3-dihydrobenzofuran-2-yl](phenyl)-
methanone (3n):17b The reaction was performed at 0.088 mmol scale of 1c; white solid (26.2 mg,
71% yield); 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J= 7.8 Hz, 2H), 7.59 (t, J= 7.4 Hz, 1H), 7.44
(t, J = 7.5 Hz, 2H), 6.98 (s, 2H), 6.89 (d, J= 8.7 Hz, 1H), 6.76 (d, J= 8.8 Hz, 1H), 6.62 (s, 1H),
5.76 (d, J= 6.6 Hz, 1H), 5.20 (s, 1H), 4.85 (d, J = 6.6 Hz, 1H), 3.71 (s, 3H), 1.40 (s, 18H); 13C{1H}
NMR (100 MHz, CDCl3) δ 195.4, 154.9, 153.4, 153.2, 136.4, 134.7, 133.8, 132.4, 130.3, 129.4,
128.7, 124.9, 114.4, 111.1, 110.0, 91.2, 56.2, 51.7, 34.5, 30.4; FT-IR (thin film, neat): 3627, 2957,
1695, 1486, 1234, 750 cm-1; HRMS (ESI): m/z calcd for C30H33O4 [M–H]– : 457.2379; found :
457.2398.
trans-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methoxy-2,3-dihydrobenzofuran-2-yl](phenyl)-
methanone (3o):17b The reaction was performed at 0.088 mmol scale of 1d; white solid (26.9 mg,
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73% yield); 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.7 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 7.45
(t, J = 7.4 Hz, 2H), 6.94 – 6.91 (m, 3H), 6.59 (s, 1H), 6.46 (d, J = 8.2 Hz, 1H), 5.79 (d, J = 6.2 Hz,
1H), 5.18 (s, 1H), 4.75 (d, J = 6.2 Hz, 1H), 3.81 (s, 3H), 1.39 (s, 18H); 13C{1H} NMR (100 MHz,
CDCl3) δ 195.4, 160.9, 160.7, 153.1, 136.3, 134.6, 133.8, 133.0, 129.4, 128.7, 125.7, 124.8, 121.3,
107.7, 96.2, 91.8, 55.6, 51.0, 34.5, 30.4; FT-IR (thin film, neat): 3632, 2958, 1699, 1503, 1275,
750 cm-1; HRMS (ESI): m/z calcd for C30H33O4 [M–H]– : 457.2379; found : 457.2397.
trans-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-fluoro-2,3-dihydrobenzofuran-2-yl](phenyl)-
methanone (3p):17b The reaction was performed at 0.091 mmol scale of 1e; white solid (25.1 mg,
70% yield); 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.9 Hz, 2H), 7.60 (t, J = 7.2 Hz, 1H), 7.45
(t, J = 7.5 Hz, 2H), 6.94 (s, 2H), 6.89 (d, J = 6.3 Hz, 2H), 6.75 (d, J = 7.8 Hz, 1H), 5.81 (d, J = 6.6
Hz, 1H), 5.21 (s, 1H), 4.84 (d, J = 6.5 Hz, 1H), 1.39 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3)
δ 195.0, 158.2 (d, JC-F = 236.5 Hz), 155.2 (d, JC-F = 1.3 Hz), 153.3, 136.5, 134.5, 133.9, 132.0,
131.0 (d, JC-F = 8.5 Hz), 129.5, 128.8, 124.8, 115.2 (d, JC-F = 24.3 Hz), 112.5 (d, JC-F = 24.7 Hz),
110.2 (d, JC-F = 8.4 Hz), 91.4, 51.4, 34.5, 30.4; 19F{1H} NMR (376 MHz, CDCl3) δ –123.14; FT-
IR (thin film, neat): 3636, 2959, 1699, 1483, 1233, 751 cm-1; HRMS (ESI): m/z calcd for
C29H30FO3 [M–H]– : 445.2179; found : 445.2201.
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trans-[5-chloro-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydrobenzofuran-2-yl](phenyl)-
methanone (3q):17b The reaction was performed at 0.087 mmol scale of 1f; white solid (26.4 mg,
71% yield); 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.0 Hz, 2H), 7.61 (t, J = 7.2 Hz, 1H), 7.45
(t, J = 7.5 Hz, 2H), 7.16 (d, J = 8.6 Hz, 1H), 7.01 (s, 1H), 6.94 (s, 2H), 6.91 (d, J = 8.6 Hz, 1H),
5.83 (d, J = 6.4 Hz, 1H), 5.22 (s, 1H), 4.81 (d, J = 6.4 Hz, 1H), 1.40 (s, 18H); 13C{1H} NMR (100
MHz, CDCl3) δ 194.7, 157.9, 153.4, 136.6, 134.4, 134.0, 132.0, 131.6, 129.4, 128.81, 128.78,
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126.3, 125.6, 124.8, 111.0, 91.4, 51.3, 34.5, 30.4; FT-IR (thin film, neat): 3633, 2959, 1699, 1475,
1261, 749 cm-1; HRMS (ESI): m/z calcd for C29H30ClO3 [M–H]– : 461.1883; found : 461.1902.
trans-[5-bromo-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydrobenzofuran-2-yl](phenyl)-
methanone (3r):17b The reaction was performed at 0.077 mmol scale of 1g; white solid (25.7 mg,
72% yield); 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.6 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.45
(t, J = 7.6 Hz, 2H), 7.30 (d, J = 8.5 Hz, 1H), 7.15 (s, 1H), 6.94 (s, 2H), 6.87 (d, J = 8.5 Hz, 1H),
5.82 (d, J = 6.4 Hz, 1H), 5.23 (s, 1H), 4.81 (d, J = 6.4 Hz, 1H), 1.40 (s, 18H); 13C{1H} NMR (100
MHz, CDCl3) δ 194.6, 158.4, 153.4, 136.6, 134.4, 134.0, 132.1, 132.0, 131.7, 129.4, 128.8, 128.5,
124.8, 113.4, 111.6, 91.3, 51.2, 34.5, 30.4; FT-IR (thin film, neat): 3633, 2958, 1699, 1471, 1262,
749 cm-1; HRMS (ESI): m/z calcd for C29H30BrO3 [M–H]– : 505.1378; found : 505.1397.
trans-[5,7-dichloro-3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydrobenzofuran-2-
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yl](phenyl)methanone (3s) : The reaction was performed at 0.079 mmol scale of 1h; pale yellow
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gummy solid (21.0 mg, 53% yield); H NMR (400 MHz, CDCl3) δ 7.95 – 7.93 (m, 2H), 7.63 –
7.59 (m, 1H), 7.48 – 7.44 (m, 2H), 7.22 (dd, J = 2.0, 0.7 Hz, 1H), 6.93 (s, 2H), 6.92 (dd, J = 2.0,
1.1 Hz, 1H), 5.88 (d, J = 6.8 Hz, 1H), 5.24 (s, 1H), 4.91 (d, J = 6.8 Hz, 1H), 1.40 (s, 18H); 13C{1H}
NMR (100 MHz, CDCl3) δ 193.9, 154.1, 153.6, 136.7, 134.3, 134.1, 132.8, 131.2, 129.5, 128.9
(2C), 126.7, 124.8, 124.1, 116.0, 91.5, 51.9, 34.5, 30.3; FT-IR (thin film, neat): 3638, 2959, 1699,
1456, 1238, 735 cm-1; HRMS (ESI): m/z calcd for C29H29Cl2O3 [M–H]– : 495.1494; found :
495.1475.
trans-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydronaphtho[2,3-b]furan-2-yl](phenyl)-
methanone (3t): The reaction was performed at 0.083 mmol scale of 1i; pale yellow solid (26.3
mg, 73% yield); m. p. = 171–173 ºC; Rf = 0.2 (5% EtOAc in hexane); 1H NMR (400 MHz, CDCl3)
δ 7.99 (d, J = 7.8 Hz, 2H), 7.81 – 7.77 (m, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.4 Hz, 2H),
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91.9, 51.2, 34.5, 30.4; FT-IR (thin film, neat): 3627, 2958, 1699, 1435, 1233, 750 cm-1; HRMS
(ESI): m/z calcd for C33H33O3 [M–H]– : 477.2430; found : 477.2451.
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(3-(4-hydroxy-3,5-diisopropylphenyl)-2,3-dihydrobenzofuran-2-yl)(phenyl)methanone (3u): The
reaction was performed at 0.11 mmol scale of 1j and the product 3u was obtained as an inseparable
diastereomeric mixture; pale yellow gummy solid (22.6 mg, 53% yield); Rf = 0.1 (5% EtOAc in
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hexane); H NMR (400 MHz, CDCl3) [major isomer] δ 7.95 (t, J = 7.6 Hz, 4H), 7.63 – 7.58 (m,
2H), 7.51 – 7.43 (m, 4H), 7.25 – 7.21 (m, 1H), 7.04 – 6.99 (m, 2H), 6.93 (s, 2H), 5.79 (d, J = 6.8
Hz, 1H), 5.09 (s, 1H), 4.91 (d, J = 6.8 Hz, 1H), 3.33 – 3.23 (m, 2H), 1.20 (d, J = 6.6 Hz, 6H), 1.12
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(d, J = 6.8 Hz, 6H); C{1H} NMR (100 MHz, CDCl3) [diastereomers] δ 195.1, 193.9, 159.3,
152.5, 142.3, 138.6, 134.7, 134.6, 133.9, 129.4, 129.2, 129.0, 128.8, 128.0, 125.5, 124.2, 121.7,
110.1, 90.7, 51.3, 26.8, 24.2, 24.1; FT-IR (thin film, neat): 3505, 2961, 1694, 1471, 1226, 750 cm-
1; HRMS (ESI): m/z calcd for C27H27O3 [M–H]– : 399.1960; found : 399.1942.
General procedure for the synthesis of Benzofuran derivatives (4a-l)
Bromomethyl aryl ketone [2a-g] (1.0 equiv.) was added to the suspension of 2-hydroxyphenyl-
subsituted p-QM [1a-e & 1i] (1.1 equiv.) and Cs2CO3 (1.5 equiv.) in acetonitrile (0.06 M) and the
resulting suspension was stirred at room temperature. After the reaction was complete (based on
TLC analysis), DDQ (2.0 equiv.) was added and the reaction mixture was stirred at 50 oC until the
former reaction product was completely consumed (based on TLC analysis). The residue was
filtered through a pad of celite and the filtrate was then concentrated under reduced pressure. The
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residue was purified through a silica gel column, using EtOAc/Hexane mixture as an eluent, to get
the pure product (4a-l).
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[3-(3,5-di-tert-butyl-4-hydroxyphenyl)benzofuran-2-yl](phenyl)methanone (4a):17b The reaction
was performed at 0.097 mmol scale of 1a; white solid (31.2 mg, 81% yield); 1H NMR (400 MHz,
CDCl3), δ 7.75 (d, J = 7.9 Hz, 1H), 7.67 (t, J = 7.7 Hz, 3H), 7.55 – 7.51 (m, 1H), 7.39 -7.34 (m,
2H) 7.20 – 7.17 (m, 4H), 5.25 (s, 1H), 1.35 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.7,
155.0, 154.1, 146.8, 137.4, 136.1, 132.4, 130.8, 129.9, 128.3 (2C), 127.9, 127.3, 123.9, 122.8,
121.9, 112.6, 34.4, 30.3; FT-IR (thin film, neat): 3631, 2958, 1649, 1448, 1161, 728 cm-1; HRMS
(ESI): m/z calcd for C29H31O3 [M+H]– : 427.2273; found : 427.2257.
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[3-(3,5-di-tert-butyl-4-hydroxyphenyl)benzofuran-2-yl](m-tolyl)methanone (4b): The reaction
was performed at 0.097 mmol scale of 1a; white solid (31 mg, 79% yield); m. p. = 180–182 ºC; Rf
= 0.6 (5% EtOAc in hexane); 1H NMR (400 MHz, CDCl3), δ 7.75 (d, J = 7.9 Hz, 1H), 7.67 (d, J
= 8.4 Hz, 1H), 7.54 – 7.51 (m, 2H), 7.42 (s, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H),
7.14 (s, 2H), 7.09 (t, J = 7.6 Hz, 1H), 5.25 (s, 1H), 2.16 (s, 3H), 1.34 (s, 18H); 13C{1H} NMR (100
MHz, CDCl3) δ 186.9, 155.1, 154.1, 146.8, 137.5, 137.3, 136.0, 133.2, 130.7, 130.6, 128.31,
128.28, 127.9, 127.2, 127.0, 123.8, 122.8, 122.1, 112.6, 34.3, 30.2, 21.2; FT-IR (thin film, neat):
3627, 2958, 1645, 1436, 1238, 1144, 744 cm-1; HRMS (ESI): m/z calcd for C30H33O3 [M+H]+ :
441.2430; found : 441.2415.
[3-(3,5-di-tert-butyl-4-hydroxyphenyl)benzofuran-2-yl](4-methoxyphenyl)methanone (4c): The
reaction was performed at 0.097 mmol scale of 1a; white solid (27.1 mg, 68% yield); m. p. = 182–
184 ºC; Rf = 0.4 (5% EtOAc in hexane); 1H NMR (400 MHz, CDCl3), δ 7.75 (d, J = 7.9 Hz, 1H),
7.70 – 7.65 (m, 3H), 7.51 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.17 (s, 2H), 6.66 (d, J = 8.6
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Hz, 2H), 5.26 (s, 1H), 3.76 (s, 3H), 1.36 (s, 18H); C{1H} NMR (100 MHz, CDCl3) δ 185.3,
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163.1, 154.9, 154.0, 147.1, 136.1, 132.3, 130.0, 129.8, 128.3, 128.0, 127.3, 123.8, 122.6, 122.1,
113.1, 112.5, 55.4, 34.4, 30.3; FT-IR (thin film, neat): 3627, 2958, 1639, 1435, 1258, 1160, 750
cm-1; HRMS (ESI): m/z calcd for C30H33O4 [M+H]+ : 457.2379; found : 457.2399.
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[3-(3,5-di-tert-butyl-4-hydroxyphenyl)benzofuran-2-yl](2-fluorophenyl)methanone (4d): The
reaction was performed at 0.097 mmol scale of 1a; white solid (30.3 mg, 78% yield); m. p. = 166–
168 ºC; Rf = 0.6 (5% EtOAc in hexane); 1H NMR (400 MHz, CDCl3), δ 7.68 – 7.63 (m, 2H), 7.55
– 7.46 (m, 2H), 7.33 (t, J = 7.5 Hz, 1H), 7.30 – 7.26 (m, 1H), 7.17 (s, 2H), 7.02 (t, J = 7.5 Hz, 1H),
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6.79 (t, J = 9.1 Hz, 1H), 5.26 (s, 1H), 1.37 (s, 18H); C{1H} NMR (100 MHz, CDCl3) δ 182.9,
160.1 (d, JC-F = 252.0 Hz), 155.1, 154.1, 147.1, 135.7, 133.2 (d, JC-F = 8.4 Hz), 132.2 (d, JC-F = 0.9
Hz), 130.8 (d, JC-F = 2.4 Hz), 128.9, 128.8, 127.4 (d, JC-F = 13.8 Hz), 127.1, 123.94 (d, JC-F = 3.6
Hz), 123.90, 123.1, 121.4, 115.9 (d, JC-F = 21.6 Hz), 112.6, 34.3, 30.3; 19F{1H} NMR (376 MHz,
CDCl3) δ –111.80; FT-IR (thin film, neat): 3632, 2959, 1652, 1454, 1153, 750 cm-1; HRMS (ESI):
m/z calcd for C29H30FO3 [M+H]+ : 445.2165; found : 445.2179.
[3-(3,5-di-tert-butyl-4-hydroxyphenyl)benzofuran-2-yl](2,4-dichlorophenyl)methanone (4e): The
reaction was performed at 0.097 mmol scale of 1a; white solid (19.5 mg, 44% yield); m. p. = 167–
169 ºC; Rf = 0.6 (5% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 7.65 – 7.60 (m, 2H), 7.54
(t, J = 7.3 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.18 (s, 1H), 7.10 (s, 2H),
7.01 (d, J = 8.2 Hz, 1H), 5.30 (s, 1H), 1.40 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 183.7,
155.3, 154.3, 146.6, 136.7, 136.5, 135.8, 133.3, 132.9, 131.0, 129.8, 129.3, 129.0, 126.73, 126.71,
124.1, 123.3, 121.2, 112.7, 34.4, 30.3; FT-IR (thin film, neat): 3632, 2959, 1652, 1434, 1238, 1144,
967 cm-1; HRMS (ESI): m/z calcd for C29H29Cl2O3 [M+H]+ : 495.1494; found : 495.1516.
[3-(3,5-di-tert-butyl-4-hydroxyphenyl)benzofuran-2-yl](3-(trifluoromethyl)phenyl)methanone
(4f): The reaction was performed at 0.097 mmol scale of 1a; white solid (28.5 mg, 67% yield); m.
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p. = 155–157 ºC; Rf = 0.7 (5% EtOAc in hexane); 1H NMR (400 MHz, CDCl3), δ 7.78 – 7.73 (m,
3H), 7.67 (d, J = 8.4 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 7.6
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Hz, 1H), 7.15 (s, 2H), 5.29 (s, 1H), 1.35 (s, 18H); C{1H} NMR (100 MHz, CDCl3) δ 185.4,
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155.2, 154.5, 146.4, 140.6 (q, JC-F = 0.9 Hz), 136.3, 133.6, 133.3, 132.1, 130.0 (2C), 128.9, 128.2,
127.2, 124.8 (q, JC-F = 3.6 Hz), 124.1, 123.6 (q, JC-F = 270.9 Hz), 123.0, 121.6, 112.7, 34.4, 30.2;
19F NMR (376 MHz, CDCl3) δ –63.17; FT-IR (thin film, neat): 3632, 2959, 1651, 1436, 1168, 762
cm-1; HRMS (ESI): m/z calcd for C30H30F3O3 [M+H]+ : 495.2147; found : 495.2125.
[3-(3,5-di-tert-butyl-4-hydroxyphenyl)benzofuran-2-yl](3-nitrophenyl)methanone (4g): The
reaction was performed at 0.097 mmol scale of 1a; pale yellow solid (19.1 mg, 47% yield); m. p.
= 189–191 ºC; Rf = 0.4 (5% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.20
(d, J = 8.0 Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H)
7.58 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.12 (s, 2H), 5.29 (s,
1H), 1.32 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 184.0, 155.4, 154.4, 147.3, 145.9, 138.8,
136.4, 135.0, 132.6, 129.3, 129.2, 128.2, 127.3, 126.5, 125.4, 124.3, 123.1, 121.4, 112.7, 34.3,
30.1; FT-IR (thin film, neat): 3626, 2959, 1652, 1435, 1275, 750 cm-1; HRMS (ESI): m/z calcd for
C29H30NO5 [M+H]+ : 472.2124; found : 472.2144.
[5-chloro-3-(3,5-di-tert-butyl-4-hydroxyphenyl)benzofuran-2-yl](phenyl)methanone (4h): The
reaction was performed at 0.087 mmol scale of 1f; pale yellow gummy solid (27.8 mg, 75% yield);
Rf = 0.5 (5% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 7.68 – 7.66 (m, 3H), 7.59 (d, J =
8.8 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.38 (t, J = 7.4 Hz, 1H), 7.19 (t, J = 7.5 Hz, 2H), 7.12 (s,
2H), 5.28 (s, 1H), 1.35 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.4, 154.3, 153.3, 147.8,
137.1, 136.3, 132.6, 130.0, 129.9, 129.7, 129.6, 128.6, 127.9, 127.1, 122.2, 121.3, 113.7, 34.4,
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30.3; FT-IR (thin film, neat): 3632, 2958, 1645, 1430, 1160, 733 cm-1; HRMS (ESI): m/z calcd for
C29H30ClO3 [M+H]+ : 461.1883; found : 461.1868.
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[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methylbenzofuran-2-yl](phenyl)methanone (4i): The
reaction was performed at 0.092 mmol scale of 1b; white solid (28.6 mg, 76% yield); m. p. = 142–
144 ºC; Rf = 0.5 (5% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.7 Hz, 2H),
7.54 (d, J = 8.5 Hz, 1H), 7.51 (s, 1H), 7.38 – 7.33 (m, 2H), 7.19 (d, J = 7.5 Hz, 2H), 7.15 (s, 2H),
5.25 (s, 1H), 2.47 (s, 3H), 1.35 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.6, 154.1, 153.5,
147.0, 137.5, 136.0, 133.5, 132.3, 130.6, 129.92, 129.88, 128.4, 127.8, 127.2, 122.2, 122.1, 112.1,
34.3, 30.3, 21.6; FT-IR (thin film, neat): 3627, 2958, 1645, 1431, 1239, 749 cm-1; HRMS (ESI):
m/z calcd for C30H33O3 [M+H]+ : 441.2430; found : 441.2408.
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[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-6-methoxybenzofuran-2-yl](phenyl)methanone (4j): The
reaction was performed at 0.088 mmol scale of 1d; white solid (28.6 mg, 78% yield); m. p. = 181–
183 ºC; Rf = 0.4 (5% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.8 Hz, 2H),
7.59 (d, J = 8.7 Hz, 1H), 7.34 (t, J = 7.3 Hz, 1H), 7.18 – 7.13 (m, 5H), 6.98 (d, J = 8.7 Hz, 1H),
5.25 (s, 1H), 3.91 (s, 3H), 1.34 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.1, 161.3, 156.5,
154.1, 146.5, 137.8, 136.0, 132.1, 131.6, 129.8, 127.8, 127.2, 123.3, 122.1, 121.7, 114.3, 95.6,
55.9, 34.3, 30.3; FT-IR (thin film, neat): 3627, 2959, 1634, 1267, 1156, 750 cm-1; HRMS (ESI):
m/z calcd for C30H33O4 [M+H]+ : 457.2379; found : 457.2361.
[3-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methoxybenzofuran-2-yl](phenyl)methanone (4k): The
reaction was performed at 0.088 mmol scale of 1c; pale yellow gummy solid (26.8 mg, 73% yield);
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Rf = 0.3 (5% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.7 Hz, 2H), 7.56 –
7.54 (m, 1H), 7.37 (t, J = 7.3 Hz, 1H), 7.21 – 7.18 (m, 4H), 7.15 – 7.13 (m, 2H), 5.26 (s, 1H), 3.84
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(s, 3H), 1.36 (s, 18H); C{1H} NMR (100 MHz, CDCl3) δ 186.5, 156.7, 154.1, 150.2, 147.6,
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137.5, 136.1, 132.4, 130.7, 129.9, 128.7, 127.9, 127.2, 122.0, 118.4, 113.3, 103.5, 56.0, 34.4, 30.3;
FT-IR (thin film, neat): 3627, 2957, 1645, 1481, 1275, 750 cm-1; HRMS (ESI): m/z calcd for
C30H33O4 [M+H]+ : 457.2379; found : 457.2365.
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[3-(3,5-di-tert-butyl-4-hydroxyphenyl)naphtho[2,3-b]furan-2-yl](phenyl)methanone (4l): The
reaction was performed at 0.083 mmol scale of 1i; yellow gummy solid (24.8 mg, 69% yield); Rf
= 0.2 (5% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 8.00 – 7.93 (m, 3H), 7.79 (d, J = 9.0
Hz, 1H), 7.60 (d, J = 7.9 Hz, 2H), 7.48 (t, J = 7.2 Hz, 1H), 7.39 – 7.31 (m, 2H), 7.16 – 7.13 (m,
4H), 5.24 (s, 1H), 1.35 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.4, 154.0, 153.7, 147.7,
137.8, 135.9, 132.7, 131.9, 131.2, 130.5, 129.51, 129.46, 129.3, 127.71, 127.68, 126.8, 125.2,
123.4, 122.9, 121.8, 113.1, 34.4, 30.4; FT-IR (thin film, neat): 3618, 2924, 1644, 1433, 1233, 709
cm-1; HRMS (ESI): m/z calcd for C33H33O3 [M+H]+ : 477.2430; found : 477.2412.
General procedure for the synthesis of coumarin derivatives
Arylacetyl halide [5a-j] (1.2 equiv.) was added to a mixture of 2-hydroxyphenyl-subsituted p-QM
[1a-e] (1.0 equiv.) and Cs2CO3 (2.2 equiv.) in acetone (0.06 M) and, the resulting suspension was
stirred at room temperature for 1.5 h. Then DDQ (1.5 equiv.) was added to the reaction mixture
and the resultant mixture was stirred at room temperature for additional 6 h. The reaction mixture
was filtered through a pad celite and the filtrate was concentrated under reduced pressure. The
crude was purified through a silica gel column using EtOAc/Hexane mixture as an eluent to get
the pure coumarin derivative (6a-n).
4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-phenyl-2H-chromen-2-one (6a): The reaction was
performed at 0.097 mmol scale of 1a; white solid (34.6 mg, 84% yield); m. p. = 197–199 ºC; Rf =
0.3 (10% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.52 (m, 2H), 7.44 (d, J = 8.3
Hz, 1H), 7.26 – 7.22 (m, 1H), 7.20 – 7.14 (m, 3H), 7.05 (d, J = 7.6 Hz, 2H), 6.87 (s, 2H), 5.28 (s,
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1H), 1.29 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.6, 154.0, 153.6, 152.8, 135.8, 134.9,
131.3, 130.7, 128.2, 127.8, 127.3, 127.2, 126.6, 125.0, 124.1, 120.7, 117.0, 34.3, 30.3; FT-IR (thin
film, neat): 3633, 2957, 1717, 1451, 763 cm-1; HRMS (ESI): m/z calcd for C29H31O3 [M+H]+ :
427.2273; found : 427.2260.
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4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(3-methoxyphenyl)-2H-chromen-2-one (6b): The reaction
was performed at 0.097 mmol scale of 1a; white solid (34 mg, 77% yield); m. p. = 197–199 ºC; Rf
= 0.2 (10% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.53 (m, 2H), 7.43 (d, J = 8.5
Hz, 1H), 7.26 – 7.22 (m, 1H), 7.15 (t, J = 7.9 Hz, 1H), 6.89 (s, 2H), 6.82 (d, J = 7.5 Hz, 1H), 6.72
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(d, J = 8.3 Hz, 1H), 6.42 (s, 1H), 5.30 (s, 1H), 3.52 (s, 3H), 1.29 (s, 18H); C{1H} NMR (100
MHz, CDCl3) δ 161.5, 159.1, 154.0, 153.6, 152.7, 136.0, 135.9, 131.4, 128.9, 128.1, 127.1, 126.4,
125.1, 124.1, 123.3, 120.6, 117.0, 115.4, 114.3, 55.1, 34.4, 30.2; FT-IR (thin film, neat): 3625,
2957, 1716, 1601, 758 cm-1; HRMS (ESI): m/z calcd for C30H33O4 [M+H]+ : 457.2379; found :
457.2360.
4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(4-methoxyphenyl)-2H-chromen-2-one (6c): The reaction
was performed at 0.097 mmol scale of 1a; white solid (31.3 mg, 71% yield); m. p. = 224–226 ºC;
Rf = 0.2 (10% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 7.55 – 7.51 (m, 2H), 7.42 (d, J =
8.5 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 8.4 Hz, 2H), 6.87 (s, 2H), 6.72 (d, J = 8.4 Hz,
2H), 5.28 (s, 1H), 3.74 (s, 3H), 1.30 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.8, 153.9,
153.7, 153.5, 152.3, 135.8, 131.9, 131.2, 128.1, 127.2, 127.1, 126.2, 125.2, 124.1, 116.9, 113.4,
110.9, 55.4, 34.4, 30.3; FT-IR (thin film, neat): 3604, 2923, 1717, 1608, 763 cm-1; HRMS (ESI):
m/z calcd for C30H33O4 [M+H]+ : 457.2379; found : 457.2374.
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4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(3,4-dimethoxyphenyl)-2H-chromen-2-one (6d): The
reaction was performed at 0.097 mmol scale of 1a; white solid (32.4 mg, 69% yield); m. p. = 256–
258 ºC; Rf = 0.2 (20% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 7.55 – 7.51 (m, 2H), 7.43
(d, J = 8.5 Hz, 1H), 7.26 – 7.22 (m, 1H), 6.90 – 6.88 (m, 3H), 6.79 (d, J = 8.3 Hz, 1H), 6.33 (s,
1H), 5.32 (s, 1H), 3.83 (s, 3H), 3.50 (s, 3H), 1.30 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ
161.7, 153.9, 153.4, 152.1, 148.3, 148.2, 136.0, 131.2, 128.0, 127.2, 127.1, 126.0, 125.4, 124.1,
123.6, 120.6, 116.9, 114.2, 110.6, 56.1, 55.6, 34.4, 30.3; FT-IR (thin film, neat): 3632, 2957, 1716,
1603, 1251, 764 cm-1; HRMS (ESI): m/z calcd for C31H35O5 [M+H]+ : 487.2484; found : 487.2466.
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4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(4-fluorophenyl)-2H-chromen-2-one (6e): The reaction
was performed at 0.097 mmol scale of 1a; white solid (34.8 mg, 81% yield); m. p. = 204–206 ºC;
Rf = 0.3 (10% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 7.57 – 7.50 (m, 2H), 7.43 (d, J =
8.2 Hz, 1H), 7.26 – 7.22 (m, 1H), 7.05 – 7.02 (m, 2H), 6.90 – 6.86 (m, 4H), 5.32 (s, 1H), 1.30 (s,
18H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.0 (d, JC-F = 245.6 Hz), 161.6, 154.1, 153.5, 153.1,
136.0, 132.5 (d, JC-F = 8.0 Hz ), 131.5, 130.9 (d, JC-F = 3.5 Hz ), 128.2, 127.1, 125.5, 124.8, 124.2,
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120.5, 117.0, 114.8 (d, JC-F = 21.5 Hz ), 34.4, 30.3; F{1H} NMR (376 MHz, CDCl3) δ –114.7;
FT-IR (thin film, neat): 3611, 2960, 1713, 1450, 803 cm-1; HRMS (ESI): m/z calcd for C29H30FO3
[M+H]+ : 445.2179; found : 445.2163.
4-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-(3-fluorophenyl)-2H-chromen-2-one (6f): The reaction
was performed at 0.097 mmol scale of 1a; white solid (33.9 mg, 79% yield); m. p. = 229–231 ºC;
Rf = 0.3 (10% EtOAc in hexane); 1H NMR (400 MHz, CDCl3) δ 7.59 – 7.52 (m, 2H), 7.44 (d, J =
8.2 Hz, 1H), 7.28 – 7.24 (m, 1H), 7.20 – 7.14 (m, 1H), 6.90 – 6.86 (m, 2H), 6. 88 (s, 2H), 6.77 –
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244.1 Hz), 161.2, 154.2, 153.6, 153.5, 137.1(d, JC-F = 8.3 Hz), 136.0, 131.7, 129.2 (d, JC-F = 8.2
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