A One-Pot Approach to 2,3-Diarylbenzo[ b]furans through N-Heterocyclic Carbene-Catalyzed 1,6-Conjugate Addition Followed by Acid Mediated Dehydrative Annulation

Article abstract of DOI:10.1021/acs.joc.8b01358

A one-pot protocol for the synthesis of 2,3-diarylbenzo[b]furan derivatives through an N-heterocyclic carbene catalyzed 1,6-conjugate addition of aromatic aldehydes to 2-hydroxyphenyl-substituted para-quinone methides followed by acid-mediated dehydrative annulation has been developed. This protocol allowed us to access a wide range of 2,3-diarylbenzo[b]furan derivatives in moderate to good yields.

Full text of DOI:10.1021/acs.joc.8b01358

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Note
A One-pot Approach to 2,3-Diarylbenzo[b]furans through
N-Heterocyclic Carbene Catalyzed 1,6-Conjugate Addition
Followed by Acid Mediated Dehydrative Annulation
Gurdeep Singh, Prithwish Goswami, Sonam Sharma, and Ramasamy Vijaya Anand
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01358 • Publication Date (Web): 20 Jul 2018
Downloaded from http://pubs.acs.org on July 20, 2018
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A One-pot Approach to 2,3-Diarylbenzo[b]furans through N-Heterocyclic Carbene
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Catalyzed 1,6-Conjugate Addition Followed by Acid Mediated Dehydrative Annulation
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Gurdeep Singh, Prithwish Goswami, Sonam Sharma 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
O
(i)
OH
tBu
Cl
Bn
OH
tBu
tBu
tBu
S
N
(20 mol %)
O
R2
NaH (50 mol %)
MeCN, rt
R1
R1
H
+
R2
TsOH (2 equiv.), rt
(ii)
R2 = alkyl, aryl, halo, etc.
O
OH
29 examples
up to 91% yield
R1 = alkyl, alkoxy, halo
ABSTRACT: A one-pot protocol for the synthesis of 2,3-diarylbenzo[b]furan derivatives
through an N-heterocyclic carbene (NHC) catalyzed 1,6-conjugate addition of aromatic
aldehydes to 2-hydroxyphenyl-substituted para-quinone methides followed by acid-mediated
dehydrative annulation has been developed. This protocol allowed us to access a wide range of
2,3-diarylbenzo[b]furan derivatives in moderate to good yields.
The 2,3-diarylbenzo[b]furan scaffold is widely found in many natural products1 (Fig.
1) and several of them, including a few unnatural molecules,2 display a variety of
pharmacological activities. Apart from therapeutic applications, some of the 2,3-
diarylbenzo[b]furan derivatives have found remarkable applications in the area of materials
chemistry as electroluminescence molecules.3
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OH
HO
OH
4
5
HO
OH
OH
OH
6
O
7
8
9
OH
HO
O
HO
Anigopreissin A
Amurensin H
HO OH
O
HO
HO
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OH
HO
OH
OH
O
O
HO
HO
Diptoindonesin G
Malibatol A
Figure 1. Biologically active 2,3-diarylbenzo[b]furan based natural products
Due to their diverse range of applications, numerous synthetic approaches to construct
the 2,3-diarylbenzo[b]furan core have been developed.4 Among those methods, the metal-
catalyzed cyclization of 2-alkynyl phenols followed by coupling with suitable aryl coupling
partners is widely explored for the synthesis of 2,3-diarylbenzo[b]furan derivatives.5 A few
other protocols based on metal-catalyzed direct C-3 arylation of 2-arylbenzo[b]furan
derivatives with aryl halides have been reported.6 In addition, other metal-catalyzed approaches
such as, dehydrative C-H alkenylation and cyclization of phenols,7 dehydrative cyclization of
aryloxyketones followed by arylation,8 oxidative annulation of phenolsor their derivatives with
internal alkynes,9 Heck oxyarylation of o-hydroxystyrenes,10 one-pot decarbonylative
diarylation of coumarins,11 and intramolecular aryl-etherification of alkoxy alkynes12 have also
been developed to access 2,3-diarylbenzo[b]furans. Very recently, Rh-catalyzed
carboacylation/aromatization of benzo-cyclobutenones was also demonstrated.13
Apart from the metal-catalyzed reactions, a few metal-free approaches have also been
established for the synthesis of 2,3-diarylbenzo[b]furans.14 Although all the above-mentioned
approaches are elegant, most of them involve either the use of expensive metal catalysts or
harsh reaction conditions, which make those processes practically less attractive. Therefore,
developing a practical method, especially, under organocatalytic conditions would be highly
desirable.
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Recently, our group developed a bis(amino)-cyclopropenylidene (BAC) catalyzed 1,6-
conjugate addition of aromatic aldehydes to p-quinone methides (p-QMs) to access ,’-diaryl
acetophenone derivatives.15a Later, Zhang, Jiang and co-workers reported the same
methodology, where NHC was as a catalyst.15b While working in this particular transformation,
we envisioned that if a hydroxyl group is introduced at the 2-position of the aryl group of p-
QM 1, then it is possible to elaborate the 1,6-adduct 2 to the corresponding 2,3-
diarylbenzo[b]furan derivative 3 in a one-pot manner through acid mediated dehydrative
annulation reaction (Scheme 1). Based on this concept, we have developed a one-pot approach
to access 2,3-diarylbenzo[b]furan derivatives through N-heterocyclic carbene (NHC)catalyzed
1,6-conjugate addition of aromatic aldehydes to 2-hydroxyphenyl-substituted p-quinone
methides followed by acid mediated dehydrative annulation reaction, and the results are
exemplified herein. Although 2-hydroxyphenyl-substituted p-quinone methides16 have already
been utilized as electrophiles in few other synthetic transformations, to the best of our
knowledge, these synthons have not been utilized in combination with NHC catalysis17 for the
synthesis of 2,3-diarylbenzo[b]furan derivatives so far. Thus, we have decided to explore this
transformation in detail.
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O
R
R
OH
O
R
R
Ar
HO
N
N
O
1
OH
H
Ar
N
N
Ar
N
O
Breslow
Intermediate
H
N
OH
OH
OH
R
R
H
R
R
R
R
[H+]
Ar
-H2O
Ar
Ar
OH2
O
O
3
O
OH
H+
2
Scheme 1. Our hypothesis for the one-pot synthesis of 2,3-diarylbenzo[b]furans
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The 2-hydroxyphenyl-substituted p-QMs (1a-f) used in this study were prepared
4
5
6
according to the literature procedure (Scheme 2).16a
7
8
9
1. piperidine, PhMe,
OH
OH
o
CHO
140 C, 12 h
tBu
tBu
tBu
o
OTBS
then Ac2O, 110 C, 0.5 h
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R
+
R
2. TBAF, THF, 0 oC, 10 min.
O
tBu
R = H, alkyl, halo etc.
1a-f
Scheme 2. Synthesis of 2-hydroxyphenyl-substituted p-QMs (1a-f)
The optimization studies were carried out with 1a and 4-chloro benzaldehyde (4a) in
the presence of a wide range of carbene precursors (5-9) under different conditions, and the
results are summarized in Table 1. Our initial attempts were highly disappointing, by using
carbene precursors 5-7 and K2CO3 as a base in THF, as even the formation of intermediate 2a
did not take place under these reaction conditions (entries 1-3). However, delightfully, in the
presence of thiazolium based carbene precursor 8 and 50 mol% K2CO3, complete conversion
of 1a to 2a was observed within 12 h, and the expected diarylbenzo[b]furan 3a was obtained
in 50% yield in 12 h, after treating the reaction mixture with 2 equivalents of TsOH at rt (entry
4).
When the reaction was carried out with another thiazolium precatalyst 9, the product
3a was obtained only in 10% yield (entry 5). Unfortunately, when Cs2CO3 was used as a base,
the 1,6-addition reaction did not take place even after 24 h (entry 6). However, the reaction
worked well when KOtBu was used as a base, and 3a was obtained in 72% yield in that case
(entry 7). Interestingly, when NaH was used as a base and 8 was used as a precatalyst in THF,
the diarylbenzo[b]furan 3a was obtained in 78% isolated yield.
Encouraged by this result, the optimization studies were elaborated with other solvents
such as, CH2Cl2 and acetonitrile (entries 9 & 10). Although both the solvents were found to be
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very effective to drive this transformation with a considerable reduction in the reaction times,
acetonitrile was found to be a bit superior than CH2Cl2 in driving the TsOH mediated
annulation step and, as a result, the product 3a was obtained in 91% yield in that case (entry
10). Other acids such as, camphorsulfonic acid (CSA), methanesulfonic acid and trifluoroacetic
acid (TFA) were found to be less effective or ineffective for the annulation step (entries 11-
13).
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Table 1. Catalyst screen and optimizationa
O
OH
tBu
tBu
OH
tBu
tBu
tBu
CHO
precatalyst
(20 mol %)
tBu
base (50 mol %)
acid (2 equiv.)
+
solvent, rt
rt
t2
t1
Cl
Cl
OH
1a (1 equiv.)
O
O
OH
2a
4a (1.2 equiv.)
3a
Ph
N
I
OH
Cl
ClO4
Ph
Cl
Mes
Cl
Mes
S
N
N
N
N
N
S
N
N
N
Mes
Ph
Mes
Bn
5
6
7
8
9
entry precatalyst
base
acid
solvent
time
(t1+t2) [h]
24+0
Yield of
3a [%]
nr
1
2
5
6
7
8
9
8
8
8
8
8
8
8
8
8
8
8
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
KOtBu
NaH
-
-
-
THF
THF
24+0
24+0
12+12
12+12
24+0
12+12
12+12
4+2
nr
nr
3
THF
4
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
TsOH
CSA
THF
50
10
nr
5
THF
6
THF
7
THF
72
78
85
91
80
60
nr
8
THF
9
NaH
CH2Cl2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
10
11
12
13
14b
15c
16d
NaH
4+1
NaH
4+6
NaH
MsOH
TFA
4+20
4+20
24+1
4+10
6+1
NaH
NaH
TsOH
TsOH
TsOH
65
60
86
NaH
NaH
a All reactions were carried out with 30 mg of 1a in 1.5 mL of solvent. b 20 mol% of sodium hydride was used.
c 1 equiv. of TsOH was used. d Reaction was carried out with 3.22 mmol (1.0 g) of 1a and 3.87 mmol of 4a. nr =
No reaction. Yields reported are isolated yields.
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When the amount of NaH was reduced to 20 mol%, the 1,6-conjugate addition step was
found to be very slow and, in fact, the reaction was not complete even after 24 h; so 3a was
obtained only in 65% yield (entry 14). Similarly, when one equivalent of TsOH was used
instead of two equivalents, the annulation reaction was not complete even after 10 h, and the
yield of 3a was considerably reduced to 60% (entry 15). To show the practical applicability of
this one-pot transformation, an experiment was carried out in gram scale, in which 1.0 g (3.22
mmol) of 1a was treated with 4a (3.87 mmol) under the best conditions (entry 10), and in this
case, 3a was obtained in 1.20 g (86% yield) [entry 16].
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With the optimized conditions (entry 10, Table 1) in hand, the scope and limitation of
this transformation were examined (Table 2). This one-pot protocol worked well with electron-
poor aromatic aldehydes (4b-e), and in those cases, the respective 2,3-diarylbenzo[b]furans 3b-
e were obtained in moderate to good yields (66-75%). This protocol was found to be very
effective in the cases of benzaldehyde (4f) and methoxy- or trifluoromethoxy benzaldehydes
(4g & 4h) as the desired products (3f-h) were obtained in very good yields (75-84%). However,
surprisingly in the cases of alkyl substituted aldehydes (4i-k), the reaction was found to be very
sluggish, and the respective products 3i-k were isolated in poor yields (23-28%); because in
those cases, the 1,6-conjugate addition step was found to be very slow, and also the complete
conversion of 1a to the respective 1,6-adducts were not realized even after stirring the reaction
mixture for a prolonged period (24 h). The halo-substituted aromatic aldehydes (4l-t) reacted
efficiently with 1a to afford the desired annulated products 3l-t in moderate to good yields (35-
85%). Sterically hindered aldehydes such as, biphenyl-4-carboxaldehyde (4u) and 1-
naphthaldehyde (4v) also underwent smooth conversion to the desired 2,3-
diarylbenzo[b]furans (3u-v) in 72% and 69% yields, respectively. Under the standard
conditions, heteroaromatic aldehydes (4w-y) provided the corresponding 2,3-
diarylbenzo[b]furans 3w-y in good yields (72-75%).
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Table 2. Substrate scope with different aromatic aldehydesa
O
OH
tBu
tBu
tBu
tBu
6
7
8
9
CHO
(i) 8 (20 mol %)
NaH (50 mol %)
X
MeCN, rt
(ii) TsOH (2 equiv.), rt
X
O
OH
(1.0 equiv.)
3b-y
1a
4b-y (1.2 equiv.)
10
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------------------------------------------------------------------------------------------------------------------------------
OH OH
OH
tBu
tBu
tBu
tBu
tBu
tBu
X
X
X
O
O
O
3i, X = tBu, (11+1) h, 28%
3j, X = Et, (11+1) h, 23%
3k, X = Me, (11+1) h, 25%
3f, X = H, (5+1) h, 78%
3c, X = 3-NO2, (5+1) h, 75% 3g, X= 3,5-dimethoxy, (7+1) h, 75%
3b, X = 4-CN, (4+1) h, 70%
3d, X = 4-CF3, (6+1) h, 72%
3e, X = 3-CF3, (6+1) h, 66%
3h, X = 4-OCF3, (5+1) h, 84%
OH
tBu
OH
tBu
OH
tBu
tBu
tBu
tBu
X
X
X
O
O
O
Br
3l, X = 4-Br, (7+1.5) h, 81%b
3m, X = 2-Cl, (4+1) h, 81%
3n, X = 2-Br, (4+1) h, 82%
3o, X = 2-F, (4+1) h, 85%
3p, X = 2,4-dichloro, (4+1) h, 70%
3q, X = 2,4-difluoro, (4+1) h, 78%
3r, X = 5-F, (4+1) h, 58%
3s, X = 5-OMe, (7+1) h, 51%
3t, X = 4-Me, (11+1) h, 35%
OH
tBu
OH
tBu
tBu
OH
tBu
tBu
tBu
R1
X
O
O
Ph
3w, X = S, R1 = H, (9+1) h, 72%
3x, X = S, R1 = Br, (9+1) h, 75%
3y, X = O, R1 = H, (9+1) h, 75%
O
3v, (7+1) h, 69%
3u, (7+1) h, 72%
aAll reactions were carried out in 30 mg (0.097 mmol) scale of 1a in 1.5 mL of MeCN. b Reaction was carried out
with 2.0 g (6.45 mmol) of 1a in 30 mL of MeCN. Yields reported are isolated yields.
After exploring the substrate scope with different aromatic aldehydes, we investigated
the generality of this protocol using different 2-hydroxyphenyl-substituted para-quinone
methides (1b-f) and 4-chlorobenzaldehyde (4a) under optimized reaction conditions, and the
results are summarized in Table 3. To our delight, this method worked very well with 2-
hydroxy substituted para-quinone methides (1b & 1c), derived from electron-rich
salicylaldehydes, and the desired products 10a & 10b were obtained in 80% and 83% isolated
yields, respectively. Similarly, when 4a was treated with halo-substituted 2-hydroxyphenyl-
substituted para-quinone methides (1d-f), the desired 2,3-diarylbenzo[b]furans 10c-e were
obtained in the range of 75-82% yields.
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Table 3. Substrate scope with different 2-hydroxy para-quinone methidesa
O
OH
tBu
tBu
tBu
tBu
CHO
(i) 8 (20 mol %)
NaH (50 mol %)
MeCN, rt, 4 h
+
X
X
(ii) TsOH (2 equiv.)
rt, 1 h
Cl
Cl
O
OH
1b-f (1.0 equiv.)
10
11
12
13
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4a (1.2 equiv.)
10a-e
-----------------------------------------------------------------------------------------------------------------------------------
OH
OH
OH
tBu
tBu
tBu
tBu
tBu
tBu
X
X
F
Cl
Cl
Cl
O
O
O
10c, X = Cl, 81%
10d, X = Br, 75%b
10e, 82%
10a, X = OMe, 80%
10b, X = Me, 83%
aAll reactions were carried out with 30 mg scale of 1b-f in 1.5 mL of MeCN. b Reaction was carried out with 2.0
g (5.11 mmol) of 1e in 30 mL of MeCN. Yields reported are isolated yields.
Toward the further expansion of the substrate scope, we attempted the de-tert-
butylation reaction of one of the diarylbenzo[b]furans. In this context, 3n was treated with
excess of AlCl3 in benzene at 60 oC and, as expected, the corresponding de-tert-butylated 2,3-
diarylbenzo[b]furan 11 was obtained in 80% yield within 1 h (Scheme 3).
OH
OH
tBu
tBu
benzene
60 oC, 1 h
AlCl3
+
(10 equiv.)
O
O
Br
Br
3n
11, 80%
Scheme 3. De-tert-butylation of 3n
In summary, we have successfully demonstrated a one-pot approach for the synthesis
of 2,3-diarylbenzo[b]furans through N-heterocyclic carbene catalyzed 1,6-conjugate addition
of aromatic aldehydes to 2-hydroxyphenyl-substituted para-quinone methides followed by
TsOH mediated dehydrative aromatic annulation. This transformation occurs at mild conditions
and is tolerant to a variety of functional groups. Moreover, this protocol provides an easy and
straight-forward access to a new set of 2,3-diarylbenzo[b]furans in moderate to good yields.
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Experimental Section
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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 and NHC precursors (6 to 9) were
purchased from commercial sources and used as such. All 2-hydroxyphenyl-substituted p-
quinone methides were prepared by following a literature procedure.16a NHC precursor 5 was
prepared according to the literature procedure.18 Melting points were recorded on SMP20
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1
melting point apparatus and are uncorrected. H, 13C and 19F spectra were recorded in CDCl3
(400, 100 and 376 MHz respectively) on Bruker FT–NMR spectrometer. Chemical shift ()
values are reported in parts per million relative to TMS 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-diarylbenzo[b]furans:
A mixture of 2-hydroxyphenyl-substituted p-quinone methide (0.097 mmol), aromatic
aldehyde (0.116 mmol), precatalyst 8 (0.0194 mmol) and NaH (0.0485 mmol) in anhydrous
MeCN (1.5 mL) was stirred at room temperature under Ar atmosphere. After the reaction was
complete (based on TLC analysis), TsOH (0.194 mmol) was added to the reaction mixture and
the resultant mixture was further stirred at room temperature until most of the intermediate
(1,6-adduct) was completely consumed (based on TLC analysis). The reaction mixture was
concentrated under reduced pressure and the crude was directly loaded on to a silica gel column
and purified using EtOAc/Hexane mixture as an eluent to get the pure product.
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2,6-di-tert-butyl-4-(2-(4-chlorophenyl)benzofuran-3-yl)phenol (3a): The reaction was
performed at 0.097 mmol scale of 1a; Rf = 0.5 (5% EtOAc in hexane); white solid (37.7 mg,
91% yield); m. p. = 209–211 ºC; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.6 Hz, 2H), 7.59
(d, J = 7.6 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.36 (dd, J = 7.4, 1.2 Hz, 1H), 7.33 (s, 2H), 7.31
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(d, J = 8.7 Hz, 2H), 7.27 – 7.25 (m, 1H), 5.34 (s, 1H), 1.46 (s, 18H); C NMR (100 MHz,
CDCl3) δ 154.1, 153.7, 148.9, 136.6, 133.9, 130.3, 129.7, 128.6, 128.2, 126.4, 124.9, 123.1,
123.05, 120.5, 118.9, 111.2, 34.6, 30.5; FT-IR (thin film, neat): 3633, 2659, 750 cm-1; HRMS
(ESI): m/z calcd for C28H28ClO2 [M–H]– : 431.1778; found : 431.1759.
4-(3-(3,5-di-tert-butyl-4-hydroxyphenyl)benzofuran-2-yl)benzonitrile (3b): The reaction was
performed at 0.097 mmol scale of 1a; Rf = 0.4 (5% EtOAc in hexane); white solid (28.7 mg,
70% yield); m. p. = 235–237 ºC; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.4 Hz, 2H), 7.60
– 7.55 (m, 4H), 7.41 – 7.36 (m, 1H), 7.29 (s, 2H), 7.26 (s, 1H), 5.38 (s, 1H), 1.44 (s, 18H); 13C
NMR (100 MHz, CDCl3) δ 154.4, 154.1, 147.7, 136.8, 135.5, 132.1, 130.1, 127.1, 126.3, 125.8,
123.4, 122.6, 121.7, 121.0, 119.1, 111.4, 111.0, 34.7, 30.5; FT-IR (thin film, neat): 3615, 2960,
2856, 2220, 751 cm-1; HRMS (ESI): m/z calcd for C29H28NO2 [M–H]–: 422.2120; found :
422.2105.
2,6-di-tert-butyl-4-(2-(3-nitrophenyl)benzofuran-3-yl)phenol (3c): The reaction was
performed at 0.097 mmol scale of 1a; Rf = 0.4 (5% EtOAc in hexane); pale yellow solid (32.2
mg, 75% yield); m. p. = 197–199 ºC; 1H NMR (400 MHz, CDCl3) δ 8.64 (t, J = 1.9 Hz, 1H),
8.14 (ddd, J = 3.2, 2.2, 0.9 Hz, 1H), 8.07 – 8.04 (m, 1H), 7.59 – 7.57 (m, 2H), 7.48 (t, J = 8.0
Hz, 1H), 7.41 – 7.37 (m, 1H), 7.32 (s, 2H), 7.31 – 7.27 (m, 1H), 5.39 (s, 1H),1.45 (s, 18H); 13C
NMR (100 MHz, CDCl3) δ 154.3, 154.1, 148.5, 147.2, 136.9, 132.9, 132.2, 130.2, 129.3, 126.3,
125.7, 123.4, 122.5, 122.4, 121.4, 121.0, 120.9, 111.4, 34.6, 30.5; FT-IR (thin film, neat): 3630,
2961, 1531, 1265, 753 cm-1; HRMS (ESI): m/z calcd for C28H28NO4 [M–H]– : 442.2018; found
: 442.2001.
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2,6-di-tert-butyl-4-(2-(4-(trifluoromethyl)phenyl)benzofuran-3-yl)phenol (3d): The reaction
was performed at 0.097 mmol scale of 1a; Rf = 0.5 (5% EtOAc in hexane); white solid (32.5
mg, 72% yield); m. p. = 205–207 ºC; 1H NMR (400 MHz, CDCl3), δ 7.85 (d, J = 8.2 Hz, 2H),
7.57 (d, J = 8.2 Hz, 4H), 7.37 (t, J = 7.4 Hz, 1H), 7.31 (s, 2H), 7.29 (d, J = 7.8 Hz, 1H), 5.36
(s, 1H), 1.45 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 154.3, 153.9, 148.4, 136.7, 134.6 (q, JC-
F = 1.2 Hz), 130.3, 129.7 (q, JC-F = 32.4 Hz), 127.0, 126.4, 125.4, 125.3 (q, JC-F = 3.8 Hz), 124.2
(q, JC-F = 270.5 Hz), 123.2, 122.9, 120.8, 120.5, 111.4, 34.6, 30.5; 19F NMR (376 MHz, CDCl3)
δ –62.65; FT-IR (thin film, neat): 3631, 2960, 743 cm-1; HRMS (ESI): m/z calcd for C29H28F3O2
[M–H]– : 465.2041; found : 465.2029.
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2,6-di-tert-butyl-4-(2-(3-(trifluoromethyl)phenyl)benzofuran-3-yl)phenol (3e): The reaction
was performed at 0.097 mmol scale of 1a; Rf = 0.5 (5% EtOAc in hexane); white solid (29.8
mg, 66% yield); m. p. = 138–140 ºC; 1H NMR (400 MHz, CDCl3) δ 7.95 – 7.93 (m, 2H), 7.58
– 7.55 (m, 2H), 7.52 (d, J = 7.8 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.36 (t, J = 7.3 Hz, 1H), 7.30
(s, 2H), 7.26 (s, 1H), 5.34 (s, 1H), 1.44 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 154.2, 153.9,
148.3, 136.8, 132.0, 130.9 (q, JC-F = 32.0 Hz), 130.3, 129.8, 128.9, 126.3, 125.3, 124.6 (q, JC-F
= 3.7 Hz), 124.1 (q, JC-F = 270.9 Hz), 123.6 (q, JC-F = 4.0 Hz), 123.2, 122.8, 120.8, 120.0, 111.3,
34.6, 30.4; 19F NMR (376 MHz, CDCl3) δ –62.85; FT-IR (thin film, neat): 3642, 2965, 751 cm-
1; HRMS (ESI): m/z calcd for C29H28F3O2 [M–H]– : 465.2041; found : 465.2026.
2,6-di-tert-butyl-4-(2-phenylbenzofuran-3-yl)phenol (3f): The reaction was performed at 0.097
mmol scale of 1a; Rf = 0.5 (5% EtOAc in hexane); pale yellow solid (30.0 mg, 78% yield); m.
p. = 151–153 ºC; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.1 Hz, 2H), 7.59 (d, J = 7.6 Hz,
1H), 7.55 (d, J = 8.1 Hz, 1H), 7.33 (s, 3H), 7.31 – 7.25 (m, 4H), 5.29 (s, 1H), 1.43 (s, 18H);
13C NMR (100 MHz, CDCl3) δ 154.2, 153.5, 150.2, 136.4, 131.2, 130.4, 128.33, 128.27, 127.2,
126.5, 124.6, 123.4, 122.9, 120.4, 118.4, 111.2, 34.6, 30.5; FT-IR (thin film, neat): 3642, 2966,
762 cm-1; HRMS (ESI): m/z calcd for C28H29O2 [M–H]– : 397.2168; found : 397.2152.
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2,6-di-tert-butyl-4-(2-(3,5-dimethoxyphenyl)benzofuran-3-yl)phenol (3g): The reaction was
performed at 0.097 mmol scale of 1a; Rf = 0.3 (5% EtOAc in hexane); white solid (34.2 mg,
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77% yield); m. p. = 174–176 ºC; H NMR (400 MHz, CDCl3) δ 7.57 – 7.53 (m, 2H), 7.36 –
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7.34 (m, 1H), 7.32 (s, 2H), 7.27 – 7.24 (m, 1H), 6.88 (d, J = 2.3 Hz, 2H), 6.41 (t, J = 2.3 Hz,
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1H), 5.31 (s, 1H), 3.69 (s, 6H), 1.45 (s, 18H); C NMR (100 MHz, CDCl3) δ 160.6, 153.9,
153.5, 150.0, 136.5, 132.7, 130.7, 126.6, 124.8, 123.6, 122.9, 120.4, 119.0, 111.2, 104.7, 101.3,
55.3, 34.6, 30.5; FT-IR (thin film, neat): 3631, 2958, 749 cm-1; HRMS (ESI): m/z calcd for
C30H33O4 [M–H]– : 457.2379; found : 457.2391.
2,6-di-tert-butyl-4-(2-(4-(trifluoromethoxy)phenyl)benzofuran-3-yl)phenol (3h): The reaction
was performed at 0.097 mmol scale of 1a; Rf = 0.4 (5% EtOAc in hexane); white solid (38.8
mg, 83% yield); m. p. = 174–176 ºC; 1H NMR (400 MHz, CDCl3), δ 7.75 (d, J = 8.8 Hz, 2H),
7.60 (d, J = 7.7, Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.37 – 7.33 (m, 1H), 7.31 (s, 2H), 7.29 (d, J
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= 7.5 Hz, 1H), 7.18 (d, J = 8.5 Hz, 2H), 5.34 (s, 1H), 1.44 (s, 18H); C NMR (100 MHz,
CDCl3) δ 154.2, 153.7, 148.9 (q, JC-F = 1.7 Hz), 148.8, 136.6, 130.2, 130.0, 128.6, 126.4, 125.0,
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123.1, 123.0, 120.8, 120.59 (q, JC-F = 255.7 Hz), 120.57, 119.1, 111.3, 34.6, 30.5; F NMR
(376 MHz, CDCl3) δ –57.80; FT-IR (thin film, neat): 3631, 2961, 746 cm-1; HRMS (ESI): m/z
calcd for C29H28F3O3 [M–H]– : 481.1991; found : 481.2009.
2,6-di-tert-butyl-4-(2-(4-(tert-butyl)phenyl)benzofuran-3-yl)phenol (3i): The reaction was
performed at 0.097 mmol scale of 1a; Rf = 0.5 (5% EtOAc in hexane); white solid; (12.3 mg,
28% yield); m. p. = 178–180 ºC; 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.6 Hz, 2H), 7.58
– 7.56 (m, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 8.7 Hz, 2H), 7.31 (s, 2H), 7.30 – 7.29 (m,
1H), 7.26 – 7.23 (m, 1H), 5.28 (s, 1H), 1.43 (s, 18H), 1.32 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 154.1, 153.4, 151.4, 150.6, 136.2, 130.5, 128.3, 126.9, 126.5, 125.3, 124.4, 123.6, 122.8,
120.3, 117.8, 111.2, 34.8, 34.6, 31.4, 30.5; FT-IR (thin film, neat): 3636, 2959, 748 cm-1;
HRMS (ESI): m/z calcd for C32H37O2 [M–H]– : 453.2794; found : 453.2813.
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2,6-di-tert-butyl-4-(2-(4-ethylphenyl)benzofuran-3-yl)phenol (3j): The reaction was performed
at 0.097 mmol scale of 1a; Rf = 0.5 (5% EtOAc in hexane); pale yellow gummy solid; (9.5 mg,
23% yield); 1H NMR (400 MHz, CDCl3), δ 7.64 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 7.5 Hz, 1H),
7.53 (d, J = 8.1 Hz, 1H), 7.32 (s, 2H), 7.30 (dd, J = 8.1, 1.1 Hz, 1H), 7.26 – 7.22 (m, 1H), 7.15
(d, J = 8.2 Hz, 2H), 5.28 (s, 1H), 2.65 (q, J = 7.6 Hz, 2H), 1.43 (s, 18H), 1.24 (t, J = 7.4 Hz,
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3H); C NMR (100 MHz, CDCl3) δ 154.1, 153.4, 150.5, 144.6, 136.3, 130.5, 128.6, 127.8,
127.1, 126.5, 124.4, 123.6, 122.8, 120.3, 117.7, 111.2, 34.6, 30.5, 28.9, 15.7; FT-IR (thin film,
neat): 3637, 2960, 748 cm-1; HRMS (ESI): m/z calcd for C30H33O2 [M–H]– : 425.2481; found
: 425.2477.
2,6-di-tert-butyl-4-(2-(p-tolyl)benzofuran-3-yl)phenol (3k): The reaction was performed at
0.082 mmol scale of 1a; Rf = 0.5 (5% EtOAc in hexane); pale yellow solid (10.0 mg, 25%
yield); m. p. = 182–184 ºC; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 7.8 Hz, 2H), 7.56 (d, J
= 7.7 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.32 (s, 2H), 7.30 (d, J = 7.8 Hz, 1H), 7.26 – 7.22 (m,
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1H), 7.13 (d, J = 7.9 Hz, 2H), 5.28 (s, 1H), 2.36 (s, 3H), 1.44 (s, 18H); C NMR (100 MHz,
CDCl3) δ 154.1, 153.4, 150.4, 138.2, 136.3, 130.6, 129.0, 128.3, 127.0, 126.5, 124.4, 123.6,
122.8, 120.3, 117.7, 111.1, 34.6, 30.6, 21.5; FT-IR (thin film, neat): 3637, 2961, 759 cm-1;
HRMS (ESI): m/z calcd for C29H31O2 [M–H]– : 411.2324; found : 411.2307.
4-(2-(4-bromophenyl)benzofuran-3-yl)-2,6-di-tert-butylphenol (3l): The reaction was
performed at 6.45 mmol scale of 1a in 30 mL of MeCN; Rf = 0.5 (5% EtOAc in hexane); white
solid (2.50 g, 81% yield); m. p. = 229–231 ºC; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.7
Hz, 2H), 7.58 – 7.53 (m, 2H) 7.45 (d, J = 8.7 Hz, 2H), 7.36 – 7.32 (m, 1H), 7.32 (s, 2H), 7.28
– 7.24 (m, 1H), 5.33 (s, 1H) 1.45 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 154.1, 153.7, 148.9,
136.6, 131.5, 130.4, 130.1, 128.4, 126.4, 125.0, 123.08, 123.06, 122.2, 120.5, 119.1, 111.2,
34.6, 30.5; FT IR (thin film, neat): 3632, 2965, 752 cm-1; HRMS (ESI): m/z calcd for
C28H28BrO2 [M–H]– : 475.1273; found : 475.1252.
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2,6-di-tert-butyl-4-(2-(2-chlorophenyl)benzofuran-3-yl)phenol (3m): The reaction was
performed at 0.097 mmol scale of 1a; Rf = 0.5 (5% EtOAc in hexane); white solid (33.9 mg,
81% yield); m. p. = 177–179 ºC; 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.81 (m, 1H), 7.58 (d,
J = 7.8 Hz, 1H), 7.49 (dd, J = 8.0, 1.2 Hz, 1H), 7.44 (dd, J = 7.6, 1.7 Hz, 1H), 7.40 – 7.38 (m,
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1H), 7.36 – 7.32 (m, 2H), 7.31 – 7.28 (m, 1H), 7.22 (s, 2H), 5.20 (s, 1H), 1.35 (s, 18H); C
NMR (100 MHz, CDCl3) δ 154.9, 153.1, 148.6, 136.1, 135.0, 132.9, 131.0, 130.4, 130.1, 128.3,
126.7, 125.6, 124.7, 123.1, 123.0, 120.7, 120.4, 111.6, 34.5, 30.4; FT-IR (thin film, neat): 3633,
2958, 753 cm-1; HRMS (ESI): m/z calcd for C28H28ClO2 [M–H]– : 431.1778; found : 431.1767.
4-(2-(2-bromophenyl)benzofuran-3-yl)-2,6-di-tert-butylphenol (3n): The reaction was
performed at 0.097 mmol scale of 1a; Rf = 0.5 (5% EtOAc in hexane); pale yellow solid (37.9
mg, 82% yield); m. p. = 204–206 ºC; 1H NMR (400 MHz, CDCl3) δ 7.85 – 7.83 (m, 1H), 7.70
(dd, J = 7.7, 1.2 Hz, 1H), 7.60 – 7.57 (m, 1H), 7.44 – 7.41(m, 1H), 7.39 (dd, J = 7.3, 1.4 Hz,
1H), 7.36 (dd, J = 4.2, 1.6 Hz 1H), 7.34 – 7.31 (m, 1H), 7.309 – 7.27 (m, 1H), 7.23 (s, 2H);
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5.20 (s, 1H) 1.36 (s, 18H); C NMR (100 MHz, CDCl3) δ 154.8, 153.1, 150.0, 136.0, 133.2,
133.1, 130.7, 128.2, 127.3, 125.6 (2C), 124.9, 124.7, 123.05, 123.02, 120.8, 120.0, 111.7, 34.5,
30.4; FT-IR (thin film, neat): 3633, 2958, 752 cm-1; HRMS (ESI): m/z calcd for C28H28BrO2
[M–H]– : 475.1273; found : 475.1251.
2,6-di-tert-butyl-4-(2-(2-fluorophenyl)benzofuran-3-yl)phenol (3o): The reaction was
performed at 0.097 mmol scale of 1a; Rf = 0.5 (5% EtOAc in hexane); white solid (33.8 mg,
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84% yield); m. p. = 155–157 ºC; H NMR (400 MHz, CDCl3) δ 7.77 – 7.75 (m, 1H), 7.58 –
7.56 (m, 1H), 7.52 (td, J = 7.3, 1.7 Hz, 1H), 7.39 – 7.34 (m, 2H), 7.30 (td, J = 7.7, 1.2 Hz, 1H),
7.26 (s, 2H), 7.17 – 7.15 (m, 1H), 7.14 – 7.10 (m, 1H), 5.24 (s, 1H), 1.38 (s, 18H); 13C NMR
(100 MHz, CDCl3) δ 160.2 (d, JC-F = 251.2 Hz), 154.9, 153.3, 145.9 (d, JC-F = 1.5 Hz), 136.1,
131.7 (d, JC-F = 2.8 Hz), 130.7 (d, JC-F = 8.1 Hz ), 128.8, 125.6, 124.8, 124.0 (d, JC-F = 3.6 Hz),
123.3 (d, JC-F = 0.7 Hz), 123.0, 120.6, 119.6, 119.5, 116.3 (d, JC-F = 21.4 Hz), 111.5, 34.5, 30.4;
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19F NMR (376 MHz, CDCl3) δ –111.04; FT-IR (thin film, neat): 3634, 2958, 753 cm-1 HRMS
(ESI): m/z calcd for C28H28FO2 [M–H]– : 415.2073; found : 415.2054.
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performed at 0.097 mmol scale of 1a; Rf = 0.5 (5% EtOAc in hexane); white solid (31.6 mg,
70% yield); m. p. = 147–149 ºC; 1H NMR (400 MHz, CDCl3) δ 7.81 – 7.79 (m, 1H), 7.57 (d,
J = 7.9 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.40 – 7.38 (m, 2H), 7.34 (ddd, J = 8.8, 7.6, 1.5 Hz,
1H), 7.28 – 7.26 (m, 1H), 7.19 (s, 2H), 5.24 (s, 1H), 1.37 (s, 18H); 13C NMR (100 MHz, CDCl3)
δ 154.9, 153.3, 147.4, 136.2, 135.7, 135.6, 133.7, 130.0, 129.6, 128.3, 127.1, 125.6, 125.0,
123.1, 122.9, 121.0, 120.8, 111.6, 34.5, 30.4; FT-IR (thin film, neat): 3635, 2959, 750 cm-1
HRMS (ESI): m/z calcd for C28H27Cl2O2 [M–H]– : 465.1388; found : 465.1374.
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2,6-di-tert-butyl-4-(2-(2,4-difluorophenyl)benzofuran-3-yl)phenol (3q): The reaction was
performed at 0.097 mmol scale of 1a; Rf = 0.5 (5% EtOAc in hexane); white solid (33.2 mg,
79% yield); m. p. = 144–146 ºC; 1H NMR (400 MHz, CDCl3) δ 7.75 – 7.73 (m, 1H), 7.56 (d,
J = 8.0 Hz, 1H), 7.53 – 7.47 (m, 1H), 7.37 (td, J = 7.3, 1.3 Hz, 1H), 7.30 (td, J = 7.7, 1.1 Hz,
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1H), 7.24 (s, 2H), 6.93 – 6.90 (m, 1H), 6.89 – 6.86 (m, 1H), 5.25 (s, 1H), 1.39 (s, 18H); C
NMR (100 MHz, CDCl3) δ 160.6 (d, JC-F = 254.2 Hz), 160.5 (d, JC-F = 253.9 Hz), 154.9, 153.4,
145.0 (d, JC-F = 1.7 Hz), 136.2, 132.7 (dd, JC-F = 9.6, 4.3 Hz), 128.7, 125.6, 124.9, 123.1, 120.7,
120.6, 116.0 (dd, JC-F = 141.0, 3.8 Hz), 111.53, 111.50 (dd, JC-F = 21.2, 3.6 Hz), 104.7 (t, JC-F
= 25.4 Hz), 104.5, 34.5, 30.4; 19F NMR (376 MHz, CDCl3) δ –106.38 (d, J = 8.7 Hz), –108.24
(d, J = 8.8 Hz); FT-IR (thin film, neat): 3636, 2959, 2877, 1451, 1267, 1147, 753 cm-1; HRMS
(ESI): m/z calcd for C28H27F2O2 [M–H]– : 433.1979; found : 433.1958.
4-(2-(2-bromo-5-fluorophenyl)benzofuran-3-yl)-2,6-di-tert-butylphenol (3r): The reaction was
performed at 0.097 mmol scale of 1a; Rf = 0.5 (5% EtOAc in hexane); white solid (28.3 mg,
59% yield); m. p. = 193–195 ºC; 1H NMR (400 MHz, CDCl3) δ 7.84 – 7.82 (m, 1H), 7.64 (dd,
J = 8.8, 5.2 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.40 (td, J = 7.3, 1.3 Hz, 1H), 7.35 (td, J = 7.6,
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5.24(s, 1H), 1.38 (s, 18H); C NMR (100 MHz, CDCl3) δ 161.6 (d, JC-F = 246.7 Hz), 154.8,
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153.4, 148.4 (d, JC-F = 1.8 Hz), 136.2, 134.8 (d, JC-F = 8.5 Hz), 134.6 (d, JC-F = 8.1 Hz), 128.1,
125.6, 125.1, 123.2, 122.7, 120.9, 120.7, 120.1 (d, JC-F = 23.0 Hz), 119.2 (d, JC-F = 3.3 Hz),
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117.9 (d, JC-F = 22.3 Hz), 111.7, 34.5, 30.4; F NMR (376 MHz, CDCl3) δ –114.82; FT-IR
(thin film, neat): 3635, 2957, 752 cm-1; HRMS (ESI): m/z calcd for C28H27BrFO2 [M–H]– :
493.1178; found : 493.1159.
4-(2-(2-bromo-5-methoxyphenyl)benzofuran-3-yl)-2,6-di-tert-butylphenol (3s): The reaction
was performed at 0.097 mmol scale of 1a; Rf = 0.3 (5% EtOAc in hexane); pale yellow gummy
solid (25.0 mg, 51% yield); 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.6 Hz, 1H), 7.59 – 7.54
(m, 2H), 7.40 – 7.31 (m, 2H), 7.24 (s, 2H), 6.93 (d, J = 2.6 Hz, 1H), 6.85 (dd, J = 8.8, 2.8 Hz,
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1H), 5.21 (s, 1H), 3.70 (s, 3H), 1.36 (s, 18H); C NMR (100 MHz, CDCl3) δ 158.7, 154.7,
153.2, 149.8, 136.1, 133.9, 133.7, 128.3, 125.7, 124.8, 123.1, 123.0, 120.8, 120.1, 118.0, 117.1,
115.2, 111.7, 55.7, 34.5, 30.4; FT-IR (thin film, neat): 3642, 2970, 753 cm-1; HRMS (ESI): m/z
calcd for C29H30BrO3 [M+Na]+ : 505.1378; found : 505.1394.
4-(2-(2-bromo-4-methylphenyl)benzofuran-3-yl)-2,6-di-tert-butylphenol (3t): The reaction
was performed at 0.097 mmol scale of 1a; Rf = 0.5 (10% EtOAc in hexane); pale solid (16.6mg,
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35% yield); m. p. = 145–147 ºC; H NMR (400 MHz, CDCl3) δ 7.83 – 7.81 (m, 1H), 7.58 –
7.56 (m, 1H), 7.53 – 7.52 (m, 1H), 7.37 (td, J = 7.2, 1.4 Hz, 1H), 7.33 (dd, J = 7.6, 1.4 Hz, 1H),
7.29 (d, J = 7.8 Hz, 1H), 7.23 (s, 2H), 7.14 – 7.12 (m, 1H), 5.19 (s, 1H), 2.39 (s, 3H), 1.36 (s,
18H); 13C NMR (100 MHz, CDCl3) δ 154.7, 153.0, 150.1, 141.1, 136.0, 133.6, 132.8, 130.1,
128.3, 128.1, 125.6, 124.7, 124.6, 123.2, 122.9, 120.7, 119.8, 111.6, 34.5, 30.4, 21.2; FT-IR
(thin film, neat): 3633, 2958, 753 cm-1; HRMS (ESI): m/z calcd for C29H30BrO2 [M–H]– :
489.1429; found : 489.1443.
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4-(2-([1,1'-biphenyl]-4-yl)benzofuran-3-yl)-2,6-di-tert-butylphenol (3u): The reaction was
performed at 0.097 mmol scale of 1a; Rf = 0.3 (5% EtOAc in hexane); pale yellow solid (33.0
mg, 72% yield); m. p. = 207–209 ºC; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.1 Hz, 2H),
7.62 (d, J = 7.8 Hz, 2H), 7.59 – 7.55 (m, 4H), 7.45 (t, J = 7.6 Hz, 2H), 7.36 (s, 2H), 7.33 (d, J
= 8.0 Hz 1H), 7.28 – 7.24 (m, 2H), 5.31 (s, 1H), 1.45 (s, 18H); 13C NMR (100 MHz, CDCl3) δ
154.2, 153.6, 149.9, 140.8, 140.7, 136.5, 130.5, 130.2, 129.0, 127.6, 127.4, 127.1, 127.0, 126.5,
124.7, 123.5, 122.9, 120.4, 118.6, 111.2, 34.6, 30.6; FT-IR (thin film, neat): 3632, 2965, 744
cm-1; HRMS (ESI): m/z calcd for C34H33O2 [M–H]– : 473.2481; found : 473.2461.
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2,6-di-tert-butyl-4-(2-(naphthalen-1-yl)benzofuran-3-yl)phenol (3v): The reaction was
performed at 0.097 mmol scale of 1a; Rf = 0.4 (20% EtOAc in hexane); pale yellow gummy
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solid (30.0 mg, 69 % yield); H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.2 Hz, 1H), 7.89 –
7.87 (m, 2H), 7.80 (d, J = 8.4 Hz, 1H), 7.68 (dd, J = 7.1, 1.0 Hz, 1H), 7.63 – 7.60 (m, 1H), 7.53
– 7.49 (m, 1H), 7.47 – 7.42 (m, 1H), 7.38 (td, J = 7.8, 1.5 Hz, 2H), 7.35 – 7.28 (m, 1H), 7.16
(s, 2H), 5.11 (s, 1H), 1.21 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 155.0, 152.9, 150.5, 136.0,
133.9, 131.8, 129.7, 129.4, 129.0, 128.7, 128.2, 126.4, 126.1, 125.7 (2C), 125.3, 124.5, 123.3,
123.0, 120.6, 120.1, 111.6, 34.3, 30.2; FT-IR (thin film, neat): 3633, 2957, 750 cm-1; HRMS
(ESI): m/z calcd for C32H31O2 [M–H]– : 447.2324; found : 447.2311.
2,6-di-tert-butyl-4-(2-(thiophen-2-yl)benzofuran-3-yl)phenol (3w): The reaction was
performed at 0.097 mmol scale of 1a; Rf = 0.5 (5% EtOAc in hexane); pale yellow solid (28.2
mg, 72 % yield); m. p. = 188–190 ºC; 1H NMR (400 MHz, CDCl3) δ 7.51 (t, J = 7.7 Hz, 2H),
7.44 – 7.43 (m, 1H), 7.37 (s, 2H), 7.31 (t, J = 7.9 Hz, 1H), 7.26 – 7.21 (m, 2H), 7.02 – 7.00 (m,
1H), 5.33 (s, 1H), 1.47 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 153.93, 153.87, 146.4, 136.4,
133.2, 130.5, 127.3, 126.7, 125.8, 125.5, 124.7, 123.1, 122.6, 120.3, 117.8, 111.1, 34.6, 30.5;
FT-IR (thin film, neat): 3642, 2961, 762 cm-1; HRMS (ESI): m/z calcd for C26H27O2S [M–H]–
: 403.1732; found : 403.1746.
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4-(2-(3-bromothiophen-2-yl)benzofuran-3-yl)-2,6-di-tert-butylphenol (3x): The reaction was
performed at 0.097 mmol scale of 1a; Rf = 0.5 (5% EtOAc in hexane); pale yellow solid (35.0
mg, 75 % yield); m. p. = 180–182 ºC; 1H NMR (400 MHz, CDCl3), δ 7.75 (d, J = 7.8 Hz, 1H),
7.56 (d, J = 8.1 Hz, 1H), 7.40 – 7.36 (m, 2H), 7.31 (d, J = 7.5 Hz, 1H), 7.28 (s, 2H), 7.04 (d, J
= 5.3 Hz, 1H), 5.25 (s, 1H), 1.40 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 156.9, 154.9, 153.5,
136.2, 131.1, 128.6, 128.5, 128.1, 125.9, 125.3, 123.2, 122.8, 122.2, 120.8, 112.6, 111.6, 34.5,
30.4; FT-IR (thin film, neat): 3632, 2958, 749 cm-1; HRMS (ESI): m/z calcd for C26H26BrO2S
[M–H]– : 481.0837; found : 481.0827.
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2,6-di-tert-butyl-4-(2-(furan-2-yl)benzofuran-3-yl)phenol (3y): The reaction was performed at
0.097 mmol scale of 1a; Rf = 0.4 (5% EtOAc in hexane); pale yellow solid (27.8 mg, 74 %
yield); m. p. = 165–167 ºC; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.7 Hz, 1H), 7.54 (d, J
= 8.1 Hz, 1H), 7.46 (d, J = 1.0 Hz, 1H), 7.45 (s, 2H), 7.35 –7.31 (m, 1H), 7.28 – 7.24 (m, 2H),
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6.71 (d, J = 3.4 Hz, 1H), 5.33 (s, 1H), 1.49 (s, 18H); C NMR (100 MHz, CDCl3) δ 154.2,
153.6, 146.4, 142.7, 142.4, 136.0, 129.7, 126.5, 124.9, 123.2, 122.4, 120.5, 118.0, 111.6, 111.3,
108.9, 34.6, 30.6; FT-IR (thin film, neat): 3628, 2961, 739 cm-1; HRMS (ESI): m/z calcd for
C26H27O3 [M–H]– : 387.1960; found : 387.1977.
2,6-di-tert-butyl-4-(2-(4-chlorophenyl)-5-methoxybenzofuran-3-yl)phenol (10a): The reaction
was performed at 0.088 mmol scale of 1b; Rf = 0.3 (5% EtOAc in hexane); orange solid (32.6
mg, 80% yield); m. p. = 189–191 ºC; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.7 Hz, 2H),
7.42 (d, J = 8.8 Hz, 1H), 7.30 (s, 2H), 7.27 (d, J = 8.7 Hz, 2H), 7.01 (d, J = 2.5 Hz, 1H), 6.94
(dd, J = 8.9, 2.6 Hz, 1H), 5.33 (s, 1H), 3.83 (s, 3H), 1.44 (s, 18H); 13C NMR (100 MHz, CDCl3)
δ 156.3, 153.7, 149.8, 149.1, 136.6, 133.9, 130.8, 129.7, 128.5, 128.2, 126.3, 123.2, 119.1,
113.8, 111.7, 102.7, 56.0, 34.6, 30.6; FT-IR (thin film, neat): 3637, 2965, 754 cm-1; HRMS
(ESI): m/z calcd for C29H30ClO3 [M–H]– : 461.1883; found : 461.1866.
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2,6-di-tert-butyl-4-(2-(4-chlorophenyl)-5-methylbenzofuran-3-yl)phenol (10b): The reaction
was performed at 0.092 mmol scale of 1c; Rf = 0.5 (5% EtOAc in hexane); white solid (34.3
mg, 83% yield); m. p. = 222–224 ºC; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.8 Hz, 2H),
7.43 (d, J = 8.4 Hz, 1H ), 7.36 – 7.35 (m, 1H) 7.32 (s, 2H), 7.29 (d, J = 8.8 Hz, 2H), 7.16 (dd,
J = 8.4, 1.3 Hz, 1H), 5.34 (s, 1H), 2.46 (s, 3H), 1.47 (s, 18H); 13C NMR (100 MHz, CDCl3) δ
153.6, 152.5, 149.1, 136.6, 133.8, 132.5, 130.4, 129.8, 128.5, 128.1, 126.4, 126.2, 123.3, 120.2,
118.8, 110.7, 34.6, 30.5, 21.6; FT-IR (thin film, neat): 3633, 2957, 757 cm-1; HRMS (ESI): m/z
calcd for C29H30ClO2 [M–H]– : 445.1934; found : 445.1915.
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2,6-di-tert-butyl-4-(5-chloro-2-(4-chlorophenyl)benzofuran-3-yl)phenol (10c): The reaction
was performed at 0.087 mmol scale of 1d; Rf = 0.5 (5% EtOAc in hexane); white solid (33.0
mg, 81% yield); m. p. = 226–228 ºC; 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.8 Hz, 2H),
7.49 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.31 – 7.30 (m, 1H), 7.29 – 7.27 (m, 2H),
7.26 (s, 2H), 5.36 (s, 1H), 1.45 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 153.9, 152.5, 150.3,
136.8, 134.4, 131.8, 129.2, 128.7, 128.6, 128.2, 126.3, 125.1, 122.5, 120.1, 118.6, 112.2, 34.6,
30.5; FT-IR (thin film, neat): 3632, 2961, 754 cm-1; HRMS (ESI): m/z calcd for C28H27Cl2O2
[M–H]– : 465.1388; found : 465.1378.
4-(5-bromo-2-(4-chlorophenyl)benzofuran-3-yl)-2,6-di-tert-butylphenol (10d): The reaction
was performed at 5.11 mmol scale of 1e in 30 mL MeCN; Rf = 0.5 (5% EtOAc in hexane);
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orange solid (1.96 g, 75% yield); m. p. = 211–213 ºC; H NMR (400 MHz, CDCl3) δ 7.64 –
7.63 (m, 2H), 7.62 – 7.61 (m, 1H), 7.41 – 7.40 (m, 2H), 7.29 (d, J = 8.8 Hz, 2H), 7.24 (s, 2H),
5.36 (s, 1H), 1.44 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 153.9, 152.8, 150.2, 136.8, 134.4,
132.5, 129.1, 128.7, 128.2, 127.8, 126.3, 123.2, 122.4, 118.5, 116.2, 112.7, 34.6, 30.5; FT-IR
(thin film, neat): 3633, 2959, 754 cm-1; HRMS (ESI): m/z calcd for C28H27BrClO2 [M–H]– :
509.0883; found : 509.0905.
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2,6-di-tert-butyl-4-(2-(4-chlorophenyl)-5-fluorobenzofuran-3-yl)phenol (10e): The reaction
was performed at 0.091 mmol scale of 1f; Rf = 0.5 (5% EtOAc in hexane); white solid (33.6
mg, 82% yield); m. p. = 234–236 ºC; 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.5 Hz, 2H),
7.45 (dd, J = 8.8, 4.0 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 7.26 (s, 2H), 7.19 (dd, J = 8.6, 2.4 Hz,
1H), 7.04 (td, J = 9.0, 2.4 Hz, 1H), 5.34 (s, 1H) 1.44 (s, 18H); 13C NMR (100 MHz, CDCl3) δ
159.6 (d, JC-F = 236.9 Hz), 153.8, 150.5 (d, JC-F = 37.8 Hz), 136.7, 134.3, 131.3 (d, JC-F = 10.3
Hz), 129.3, 128.6, 128.3, 126.2, 122.6, 119.2 (d, JC-F = 4.0 Hz), 112.6 (d, JC-F = 26.3 Hz), 111.9
(d, JC-F = 9.5 Hz) 106.1, 105.9, 34.6, 30.5; 19F NMR (376 MHz, CDCl3) δ –120.54; FT-IR (thin
film, neat): 3637, 2956, 795 cm-1; HRMS (ESI): m/z calcd for C28H27ClFO2 [M–H]– : 449.1684;
found : 449.1698.
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Procedure for the de-tert-butylation of 3n
AlCl3 (84 mg, 0.63 mmol) was added to a solution of 3n (30 mg, 0.063 mmol) in dry benzene
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(3 mL) under argon atmosphere and the resulting mixture was stirred at 60 C for 1 h. The
reaction mixture was then quenched with 10 mL of cold ice water. It was extracted with EtOAc
(3 x 10 mL) and the combined organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was then purified through a silica gel column
using EtOAc/Hexane mixture as an eluent to get the pure product 11 (18.4 mg, 80%) as pale
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yellow gummy solid; Rf = 0.3 (15% EtOAc in hexane); H NMR (400 MHz, CDCl3) δ 7.74
(dd, J = 7.7, 0.5 Hz, 1H), 7.67 (dd, J = 7.7, 1.4 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.41 – 7.38
(m, 2H), 7.36 – 7.33 (m, 1H), 7.31 (s, 1H), 7.30 – 7.29 (m, 1H), 7.273 – 7.268 (m, 1H), 7.26 –
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7.25 (m, 1H), 6.83 (d, J = 8.5 Hz, 2H ), 4.94 (s, 1H); C NMR (100 MHz, CDCl3) δ 154.9,
154.7, 150.1, 133.5, 133.0, 132.5, 130.8, 130.4, 128.5, 127.4, 124.93, 124.89, 124.3, 123.1,
120.5, 119.2, 115.8, 111.6; FT-IR (thin film, neat): 3394, 2923, 753 cm-1; HRMS (ESI): m/z
calcd for C20H12BrO2 [M–H] – : 363.0021; found : 363.0039.
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A mixture of 2-hydroxy p-quinone methide 1a (1.0 g, 3.22 mmol), 4-chlorobenzaldehyde 4a
(544 mg, 3.87 mmol), precatalyst 8 (17.8 mg, 0.066 mmol) and NaH (64.4 mg, 1.61 mmol) in
anhydrous MeCN (40 mL) was stirred under argon atmosphere at room temperature. After the
reaction was complete (based on TLC analysis), TsOH (1.11 g, 6.44 mmol) was added to the
reaction mixture and the resultant mixture was stirred at room temperature until the
intermediate (1,6-adduct) was completely consumed (based on TLC analysis). The residue was
then concentrated under reduced pressure and the residue was then purified through a silica gel
column using EtOAc/Hexane mixture as an eluent to get the pure product 3a (1.2 g, 86%).
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Supporting Information
1H, 13C and 19F spectra of all new compounds
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors gratefully acknowledge DST-SERB (EMR/2015/001759) for the financial support
and IISER Mohali for the infrastructure. GS, PG and SS thank IISER Mohali for a research
fellowship. The NMR and HRMS facilities at IISER Mohali are gratefully acknowledged.
REFERENCES
1) For selected reviews and recent examples: (a) “Furans and Their Benzo Derivatives”:
Donelly, D. M. X.; Meegan, M. J. Comprehensive Heterocyclic Chemistry Vol. 4 (Ed.:
Katritzky, A. R.), Pergamon, New York, 1984, pp. 657–712; (b) Ito, J.; Takaya, Y.; Oshima,
Y.; Niwa, M. New Oligostilbenes Having a Benzofuran from Vitis vinifera 'Kyohou'.
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Tetrahedron 1999, 55, 2529–2544. (c) Li, Y.; Yao, C.; Bai, J.; Lin, M.; Cheng, G. Anti-
inflammatory Effect of Amurensin H on Asthma-like Reaction Induced by Allergen in
Sensitized Mice1. Acta Pharmacol. Sinica. 2006, 27, 735–740. (d) Convertini, P.;
Tramutola, F.; Iacobazzi, V.; Lupattelli, P.; Chiummiento, L.; Infantino, V. Permethylated
Anigopreissin A Inhibits Human Hepatoma Cell Proliferation by Mitochondria-induced
Apoptosis. Chem. Biol. Interact. 2015, 237, 1–8. (e) Yang, W.; Chen, X.; Pan, J.; Ge, H.;
Yin, K.; Wu, Z.; Li, X.; Sha, D.; Xu, Y. Malibatol A Protects Against Brain Injury through
Reversing Mitochondrial Dysfunction in Experimental Stroke. Neurochemistry
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3) Tsuji, H.; Mitsui, C.; Ilies, L.; Sato, Y.; Nakamura, E. Synthesis and Properties of 2,3,6,7-
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4) For selected reviews: (a) Cagniant, P.; Cagniant, D. Recent Advances in the Chemistry of
Benzo[b]furan and Its Derivatives. Part I: Occurrence and Synthesis. Adv. Heterocycl.
Chem. 1975, 18, 337–482. (b) Kwiecien, H.; Smist, M.; Kowalewska, M. Recent
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Synth. 2012, 9, 529–560. (c) Heravi, M. M., Zadsirjan, V. Chapter Five - Recent Advances
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5) (a) Hu, Y.; Nawoschik, K. J.; Liao, Y.; Ma, J.; Fathi, R.; Yang, Z. Synthesis of
Conformationally Restricted 2,3-Diarylbenzo[b]furan by the Pd-Catalyzed Annulation of
o-Alkynylphenols: Exploring a Combinatorial Approach. J. Org. Chem. 2004, 69, 2235-
2239. (b) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. 3-Zinciobenzofuran and 3-
Zincioindole: Versatile Tools for the Construction of Conjugated Structures Containing
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(b) Larbi, K. S.; Djebbar, S.; Soulé, J. –F.; Doucet, H. Reactivity of Benzofuran and
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7) Lee, D. –H.; Kwon, K. –H.; Yi, C. S. Dehydrative C−H Alkylation and Alkenylation of
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8) (a) Kim, I.; Choi, J. A. Versatile Approach to Oligostilbenoid Natural Products – Synthesis
of Permethylated analogues of Viniferifuran, Malibatol A, and Shoreaphenol. Org. Biomol.
Chem. 2009, 7, 2788–2795. (b) Kim, K.; Kim, I. Total Synthesis of Diptoindonesin G via
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Highly Efficient Domino Cyclodehydration/Intramolecular Friedel-Crafts
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Synthesis of 2,3-Disubstituted Benzofurans. J. Org. Chem. 2014, 79, 6153–6163.
9) (a) Kuram, M. R.; Bhanuchandra, M.; Sahoo, A. K. Direct Access to Benzo[b]furans
through Palladium-Catalyzed Oxidative Annulation of Phenols and Unactivated Internal
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Alkynes. Angew. Chem., Int. Ed. 2013, 52, 4607–4612. (b) Zhu, R.; Wei, J.; Shi, Z.
Benzofuran Synthesis via Copper-mediated Oxidative Annulation of Phenols and
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H.; Huang, L.; Sun, Y.; Chen, Z.; Li, X. Facile Synthesis of Benzofurans via Copper-
Catalyzed Aerobic Oxidative Cyclization of Phenols and Alkynes. Chem. Commun. 2013,
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Neutral Coupling of N-Phenoxyacetamides and Alkynes with Tunable Selectivity. Angew.
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10) (a) Rao, V. K.; Shelke, G. M.; Tiwari, R.; Parang, K.; Kumar, A. A Simple and Efficient
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13) (a) Liu, J.; Simmons, C. J.; Xie, H.; Yang, F.; Zhao, X. –L.; Tang, Y.; Tang, W. Synthesis of
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15) (a) Ramanjaneyulu, B. T.; Mahesh, S.; Anand, R. V. "Bis-(amino)cyclopropenylidene-
Catalyzed 1,6-Conjugate Addition of Aromatic Aldehydes to p-Quinone Methides:
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G.; Jiang, L.; Shi, W.; Zhou, M.; Qiu, F.; Sun, S.; Wang, J.; Guo, H. Direct Access to α,α’-
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16) For selected recent examples, where 2-hydroxyphenyl-substituted para–Quinone Methides
have been used as electrophiles: (a) Zhao, K.; Zhi, Y.; Shu, T.; Valkonen, A.; Rissanen, K.;
Enders, D. Organocatalytic Domino Oxa-Michael/1,6-Addition Reactions: Asymmetric
Synthesis of Chromans Bearing Oxindole Scaffolds. Angew. Chem., Int. Ed. 2016, 55,
12104–12108. (b) Liu, S.; Lan, X. –C.; Chen, K.; Hao, W. –J.; Li, G.; Tu S. –J.; Jiang, B.
Ag/Brønsted Acid Co-Catalyzed Spiroketalization of β-Alkynyl Ketones toward
Spiro[chromane-2,1′-isochromene] Derivatives. Org. Lett. 2017, 19, 3831–3834. (c) Chen,
K.; Liu, S.; Wang, D.; Hao, W. –J.; Zhou, P.; Tu, S. –J.; Jiang, B. Silver/Scandium-
Cocatalyzed Bicyclization of β-Alkynyl Ketones Leading to Benzo[c]xanthenes and
Naphtho[1,2-b]benzofurans J. Org. Chem. 2017, 82, 11524–11530. (d) Zhang, Z. –P.; Xie,
K. –X.; Yang, C.; Li, M.; Li, X. Asymmetric Synthesis of Dihydrocoumarins through Chiral
Phosphoric Acid-Catalyzed Cycloannulation of para-Quinone Methides and Azlactones J.
Org. Chem. 2018, 83, 364–373. (e) Mei, G. –J.; Xu, S. –L.; Zheng, W. –Q.; Bian, C. –Y.;
Shi, F. [4+2] Cyclization of para-Quinone Methide Derivatives with Alkynes. J. Org.
Chem. 2018, 83, 1414–1421. (f) Zhang, Z. –P.; Chen, L.; Li, X.; Cheng, J. –P.
Organocatalytic Asymmetric Sequential 1,6-Addition/Acetalization of 1-Oxotetralin-2-
carbaldehyde to ortho-Hydroxyphenyl-Substituted para-Quinone Methides for Synthesis
of Spiro-3,4- dihydrocoumarins J. Org. Chem. 2018, 83, 2714–2724. (g) Liu, L.; Yuan, Z.;
Pan, R.; Zeng, Y.; Lin, A.; Yao, H.; Huang, Y. 1,6-Conjugated Addition-Mediated [4+1]
Annulation:An Approach to 2,3-Dihydrobenzofurans Org. Chem. Front. 2018, 5, 623–628.
(h) Zhi, Y.; Zhao, K.; Essen, C. V.; Rissanen, K.; Enders, D. Synthesis of Trans-
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disubstituted-2,3-Dihydrobenzofurans by a formal [4+1] Annulation between para-
Quinone Methides and Sulfonium salts Org. Chem. Front. 2018, 5, 1348–1351.
17) For selected recent reviews on organocatalytic applications of N-heterocyclic carbenes: (a)
Enders, D.; Niemeier, O.; Henseler, A. Organocatalysis by N-Heterocyclic Carbenes.
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