Palladium-catalyzed cascade reactions of 1-(3-arylprop-2-ynyloxy)-2-bromo benzene derivatives with organoboron compounds

Article abstract of DOI:10.1021/jo400503f

Applications of the cascade cyclocarbopalladation reaction followed by Suzuki-Miyaura coupling reactions of the readily available aryl-substituted propargylic aryl ethers with arylboronic acid and potassium trans-β- styryltrifluoroborate accomplish a new versatile entry in the synthesis of benzofuran derivatives. Notably, a new approach to the challenging synthesis of C3 functionalized 2-unsubstituted benzofurans has been developed by a cyclocarbopalladation/cross-coupling/aromatization process.

Full text of DOI:10.1021/jo400503f

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Article
PALLADIUM- CATALYZED CASCADE REACTIONS OF
1-(3-ARYLPROP-2-YNYLOXY)-2-BROMO BENZENE
DERIVATIVES WITH ORGANOBORON COMPOUNDS
Antonio Arcadi, Federico Blesi, Sandro Cacchi, Giancarlo Fabrizi, Antonella Goggiamani, and Fabio Marinelli
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400503f • Publication Date (Web): 11 Apr 2013
Downloaded from http://pubs.acs.org on April 13, 2013
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PALLADIUMꢀ CATALYZED CASCADE
REACTIONS OF 1ꢀ(3ꢀARYLPROPꢀ2ꢀYNYLOXY)ꢀ2ꢀ
BROMO BENZENE DERIVATIVES WITH
ORGANOBORON COMPOUNDS
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Antonio Arcadi,*a Federico Blesi,a Sandro Cacchi,b Giancarlo Fabrizi,*b Antonella Goggiamani,b Fabio
Marinelli.a
aDipartimento di Scienze Fisiche e Chimiche, Università di L’Aquila, Via Vetoio- 67010
Coppito(AQ)- Italy. E-mail: antonio.arcadi@univaq.it
b Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza, Università di Roma, P.le A. Moro 5,
00185, Rome, Italy. E-mail: giancarlo.fabrizi@uniroma1.it
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
• To whom correspondence should be addressed.
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ABSTRACT. Applications of the cascade cyclocarbopalladation reaction followed by SuzukiꢀMiyaura
coupling reactions of the ready available arylꢀsubstituted propargylic aryl ethers with arylboronic acid
and potassium transꢀβꢀstyryltrifluoroborate accomplish a new versatile entry in the synthesis of
benzofurans derivatives. Notably, a new approach to the challenging synthesis of C3 functionalized 2ꢀ
unsubstituted benzofurans has been developed by a cyclocarbopalladation/crossꢀcoupling/aromatization
process.
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Introduction
The synthesis of highly functionalized polycyclic compounds has been greatly advanced by the
development of cascade reactions catalyzed by transition metals.1 By triggering such cascade events
with wellꢀdefined functionalities in the structure of the starting material, these reactions have become a
major tool for organic chemists to build up more complex molecules in a minimum number of steps.
The main challenge in organic synthesis is the preparation of target products in a more efficient and
economical manner, which will enable the use of more sophisticated structures in industry and
academia. In this respect especially step economy is an important factor, since accessibility highly
depends on the amount of steps required to reach the desired compounds.2 The generally well
understood reactivity of palladium has allowed the discovery of many intriguing novel cascade
processes achieving relevant developments in this field, particularly on the generation of diverse polyꢀ
and heterocyclic scaffolds.3 Carbometalations of alkynes constitute an unconventional way to create,
often in a regioꢀ and stereoselective manner, carbonꢀcarbon bonds.4 Intramolecular palladiumꢀcatalyzed
versions are particularly attractive, for they afford (poly)carboꢀ and heterocyclic systems that can be
further functionalized from the intermediate vinylpalladium.5 In this field, a variety of palladiumꢀ
catalyzed domino sequences consisting of addition of in situ generated arylpalladium complexes over a
proximate carbonꢀcarbon triple bond/cross coupling reactions giving final products via regioꢀ and
stereselective 5-exo-dig and 6-exo-dig cyclization processes have been reported.6 Cascade
cyclocarbopalladation reaction followed by SuzukiꢀMiyaura coupling, also, achieved the synthesis of
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sevenꢀmembered dibenzoxapine derivatives with a stereodefined exocyclic double bond.7 Moreover, 4ꢀ
exo-dig cyclocarbopalladation reactions followed by a SuzukiꢀMiyaura or Sonogashira crossꢀcoupling
have been explored.8 Our continuing interest9 on the palladiumꢀcatalyzed reaction of alkynes with
boronic acids directed towards the development of new synthetic approaches to the construction of fused
heterocycles prompts us to explore the palladiumꢀcatalyzed reaction of 1ꢀ(3ꢀarylpropꢀ2ꢀynyloxy)ꢀ2ꢀ
bromo benzene derivatives 1 with organoboron compounds 2 as viable route to the synthesis of C3
functionalized benzofurans (Scheme 1).
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Scheme 1.
R1
R1
Ar
Ar
Ar
B(OH)2
R
R
[Pd]
R
Br
O
1
R1
O
O
3
2
4
The generality, scope and limitations, as well as the product selectivity in the cascade
cyclocarbopalladation reaction followed by SuzukiꢀMiyaura coupling or cyclocarbopalladation/cross
coupling/aromatization reactions of readily available of arylꢀsubstituted propargylic aryl ethers 1 has
not been previously investigated. Applications of this key reaction can be relevant in the synthesis of
new Oꢀheterocycles. Usually, different types of substitution patterns in these heterocycles provide new
opportunities for drug discoveries and by a fine tuning of their physical properties for applications in
material science.10 For their potential applications, development of novel synthetic strategies is in
strong demand.
Results and Discussion
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Ethers 1a-i were prepared in moderate to high yields through a selective Sonogashira crossꢀcoupling of
1ꢀbromoꢀ2ꢀpropꢀ2ꢀynyloxy)benzene derivatives with a range of aryl iodides (Table 1).11 We
hypothesized that the presence of the CꢀBr bond would be an invaluable handle for directing site
selectivity and greatly expanding the breadth of potential target compounds that might be accessible by
palladiumꢀcatalyzed crossꢀcoupling reactions.12
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Table 1. Synthesis of 1ꢀ(3ꢀarylpropꢀ2ꢀynyloxy)ꢀ2ꢀbromo benzene derivatives 1
1
R
Me
Me
Me
Ph
Ph
Ph
F
Ar
% yielda,b
1a
1b
1c
1d
1e
1f
4ꢀMeOꢀC6H4
4ꢀMeCOꢀC6H4
Ph
82
80
75
50
67
60
55
80
50
4ꢀMeOC6H4
4ꢀMeCOC6H4
Ph
1g
1h
1i
4ꢀMeOC6H4
4ꢀMeCOC6H4
Ph
F
F
a Reactions were carried out on 4.44 mmol scale in DMF (3
mL)/diꢀisopropylamine (6 mL) at r.t., using 1.equiv. of 2ꢀ
bromoꢀ1ꢀ(propꢀ2ꢀynyloxy)benzene derivative, 0.02 equiv. of
PdCl2(PPh3)2, 0.04 equiv. of CuI and 1.3 equiv. of aryl
iodide. b If not otherwise stated, yields refer to single run and
are for pure isolated products.
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Subsequent studies were directed toward searching for the best conditions for their
cyclocarbopalladation/SuzukiꢀMiyaura couplings.3a Interestingly, the simple commercial available
PdCl2(PPh3)2 achieved the high stereoselective synthesis of 3a in good yield. The choice of
PdCl2(PPh3)2 as the most suitable catalyst was shown by comparison with Pd2(dba)3/SꢀPhos catalytic
system which was previously reported as very effective in promoting SuzukiꢀMiyaura crossꢀcoupling of
the less reactive heteroaryl halides (Scheme 2).12 The formation of undesired direct coupling products
was not observed.
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Scheme 2
Entrya
Catalyst (mol %)
Pd2(dba)3/S-Phos
PdCl2(PPh3)2
Time (h)
Yield(%)b,c
3a/4a ratio
9/1
1
2
15
2
76
77
> 99/1
The formation of the stereoisomer 3a would be derived by the intramolecular syn addition over the Cꢀ
Cꢀtriple bond of the in situ generated arylpalladium(II) A which provides alkenylpalladium complex B.
Next, transmetallation with the arylboronic acid in the presence of K3PO4 would lead to intermediate C.
The reductive elimination of palladium from species C affords 3a and regenerates the palladium(0)
species (Scheme 3).
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Scheme 3
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Subsequently, this method was applied to the stereoselective synthesis of a variety of 2,3ꢀdihydroꢀ3ꢀ
(diarylmethylene)benzofurans 3. We explored the scope and the generality of the tandem palladiumꢀ
catalyzed cyclocarbopalladation reaction/SuzukiꢀMiyaura reaction in terms of rings substitution on both
substrates 1 and arylboronic acids 2. Both electronꢀwithdrawing and ꢀdonating groups did not have
much influence on the yield of the reaction. Table 2 shows our results. By using the PdCl2(PPh3)2 (2
mol %) in 1,4ꢀdioxane in the presence of K3PO4 (3 equiv.), the tandem palladiumꢀcatalyzed
cyclocarbopalladation reaction/SuzukiꢀMiyaura reaction of derivatives 1a-i was quite general and
proceeded smoothly at 100 °C to give exclusively the corresponding disubstituted 3ꢀmethyleneꢀ2,3ꢀ
dihydrobenzofurans 3a-z in moderate to excellent yields. The presence of the methyl, the phenyl and
the F group as a substituent onto the aromatic ring attached to the oxygen moiety was compatible with
the procedure. The stereochemistry of compounds 3 was unambiguously confirmed by NMR
spectroscopy.13 Boron mediated cleaving of aryl propargyl ethers was, also, not observed.14
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Table 2. Synthesis of disubstituted 3ꢀmethyleneꢀ2,3ꢀdihydrobenzofurans 3
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3
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Entrya
R1
Me
Me
Ar
R2
Time (h)
3 (yield %)b
3a (77)
1
2
4ꢀMeOꢀC6H4ꢀ
4ꢀMeOꢀC6H4ꢀ
H (2a)
2
1
4ꢀMeO (2b)
3b (74)
3
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
F
4ꢀMeOꢀC6H4ꢀ
4ꢀMeOꢀC6H4ꢀ
4ꢀMeOꢀC6H4ꢀ
4ꢀMeCOꢀC6H4ꢀ
4ꢀMeCOꢀC6H4ꢀ
4ꢀMeCOꢀC6H4ꢀ
4ꢀMeCOꢀC6H4ꢀ
4ꢀMeCOꢀC6H4ꢀ
Ph
4ꢀMeO2C (2c)
3ꢀMeO2C (2d)
3ꢀCHO (2e)
H
1
1
1
1
2
2
2
2
2
1
3
1
2
2
2
2
2
2
3
3c (55)
3d (70)
3e (45)
3f (83)
3g (88)
3h (80)
3i (83)
3j (72)
3k (99)
3l (82)
3m (52)
3n (81)
3o (86)
3p (85)
3q (82)
3r (90)
3s (76)
3t (79)
3u (55)
4
5
6
7
4ꢀMeO
4ꢀMeO2C
3ꢀMeO2C
3ꢀCHO
H
8
9
10
11
12
13
14
15
16
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18
19
22
23
Ph
4ꢀMeO
3ꢀMeO2C
4ꢀMeO2C
3ꢀMeO2C
4ꢀMeO
4ꢀMeO2C
H
Ph
Ph
F
Ph
F
Ph
F
4ꢀMeCOꢀC6H4ꢀ
4ꢀMeCOꢀC6H4ꢀ
4ꢀMeOꢀC6H4ꢀ
4ꢀMeOꢀC6H4ꢀ
4ꢀMeCOꢀC6H4ꢀ
F
F
4ꢀMeO2C
H
F
Ph
H
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Ph
Ph
Ph
Ph
Ph
4ꢀMeCOꢀC6H4ꢀ
Ph
4ꢀMeO2C
H
2
8
2
2
5
3v (75)
3w (67)
3x (64)
3y (53)
3z (45)
1
2
3
4
5
6
7
8
Ph
4ꢀMeO2C
4ꢀMeO2C
H
4ꢀMeOꢀC6H4ꢀ
4ꢀMeOꢀC6H4ꢀ
9
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a
Reactions were carried out on 0.30 mmol scale in1,4ꢀdioxane (2 mL) at 100 °C, using 1.equiv. of 1, 0.02 equiv. of
PdCl2(PPh3)2, 3 equiv. K3PO4 and 1,5 equiv. of 2. b If not otherwise stated, yields refer to single run and are for pure
isolated products.
In absolute agreement with previous results, 4ꢀfluoroꢀ3ꢀmethylboronic acid 2f was exclusively
converted to the corresponding 3ꢀ((4ꢀfluoroꢀ3ꢀmethyl)ꢀphenyl)ꢀ2,3ꢀdihydrobenzofurn derivatives 5a-e
(Table 3). The inclusion of fluorine into a host of organic substrates has been shown to affect the
activity of the drug in vivo and has resulted in a large number of viable drug candidates.15 In that
respect, there is a growing demand for synthetic methods for the preparation of selectively fluorinated
heterocyclic compounds for use in pharmaceutical and agrochemical industry.16
Table 3. Synthesis of 3ꢀ((4ꢀfluoroꢀ3ꢀmethyl)(aryl)ꢀ2,3ꢀdihydrobenzofurn derivatives 5
Entry
R1
Ph
Ph
Ph
F
Ar
Time (h)
5 (yield %)
5a (44)
1
2
3
4
5
4ꢀMeOꢀC6H4
4MeCOꢀC6H4
Ph
4
4
2
1
2
5b (60)
5c (74)
4ꢀMeOꢀC6H4
4MeCOꢀC6H4
5d (72)
5e (82)
F
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a
Reactions were carried out on 0.30 mmol scale in1,4ꢀdioxane (2 mL) at 100 °c, using 1.equiv. of 1, 0.02 equiv. of
PdCl2(PPh3)2, 3 equiv. K3PO4 and 1,5 equiv. of 2f. b If not otherwise stated, yields refer to single run and are for pure isolated
products.
1
2
3
4
5
6
7
8
The extension of the procedure to vinyl organoboron derivatives was briefly explored. The palladium
catalyzed reaction of 1b with the potassium transꢀβꢀstyryltrifluoroborate 2g resulted, also, highly
stereoselective leading to the formation of the 1ꢀ(4ꢀ((1E,2E)ꢀ1ꢀ(5ꢀmethylbenzofuranꢀ3(2H)ꢀylideneꢀ3ꢀ
phenylallyl)phenyl) ethanone 6 albeit in lower yield (Scheme 4).
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Scheme 4
It is worth underlying that many examples of isomerization of the primary synꢀadduct to the antiꢀadduct
in the carbopalladation step of alkynes have been reported and the observed stereochemistry deviated
from the expected Pdꢀmediated synꢀinsertion of triple bonds.5,17 Moreover, the substituents on the
arylpropargyl ethers have been reported to exhibit a great influence on the stereocontrol of the
intramolecular carbometallation18 and with the phenylꢀsubstituted substrate 7 a postꢀcarbometallation
isomerization was reported to occur (Scheme 5).19
Scheme 5
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1
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5
i or ii
I
+
6
7
O
O
O
8
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7
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i = NiBr2Bipy, Mn(0), DMF, rt;
54%
(Z/E = 83 : 17)
60-65% (Z/E = 10:90 at -100 °C)
(Z/E =31: 69 at - 40 °C)
ii = n-Buli (1 equiv), THF;
The 3ꢀmethyleneꢀ2,3ꢀdihydrobenzofurans have been reported to tend to aromatize into the
corresponding 2ꢀunsubstituted benzofurans.19,20 Our screening for the best reaction conditions for the
aromatization of compounds 3 to the corresponding C3 functionalized 2ꢀunsubstituted benzofurans 8
showed that the process can occur under basic conditions (Table 4). While the aromatization reaction
failed in 1,4ꢀdioxane under the presence of potassium phosphate tribasic even at higher temperature
(Table 4, entries 4.5), significant increase in the yield of 8a was observed with highly polar solvents
other than 1,4ꢀdioxane, such as N,Nꢀdimethylformamide (Table 4, entry 6). Interestingly the
aromatization was also observed in the ionic liquid [bmim]BF4 as the reaction medium (Table 4, entry
7).21 Ionic liquids represent a class of alternative solvents which are currently receiving serious
consideration because of their environmental and technological benefits.22
Table 4. Optimization conditions for the aromatization reaction of 3a
MeO
Ph
Me
i
3a
O
8a
Entry
Solvent
Acid or Base
Temperature °C
Time h
8a (yield %)a
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1
2
3
4
5
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7
EtOH
EtOH
HCl 2N
HCl 2N
TsOH
60
80
24
24
24
24
24
7
.
.
1
2
3
4
5
6
7
8
CH3CN
60
.
9
10
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20
21
22
1,4ꢀDioxane
1,4ꢀDioxane
DMF
K3PO4
K3PO4
K3PO4
K3PO4
100
120
100
100
.
.
73
65
[bmim]BF4
24
a Yields refer to single run and are for pure isolated compound 8a.
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Having successfully established the suitable conditions for the aromatization of derivative 3a, we
examined the versatility of the preparation of the target C3 funtionalizedꢀ2ꢀunsubstituted benzofurans
8a through a one pot procedure. We explored the oneꢀpot cyclocarbopalladation/cross
coupling/aromatization reactions of 1 as a suitable tool for the synthesis of C3 functionalized 2ꢀ
unsubstituted benzofurans. Procedures for the synthesis of these derivatives remained scarcely
described in the literature and the development of simple and general methods for their preparation is a
subject of great interest.23 Subsequently, we found that 8a (Table 5, entry 1) could be conveniently
prepared through a process in which, after extraction and evaporation of the of the mixture resulting
from the reaction of 1a with 2a carried out for 7 h in 1,4ꢀdioxane at 100°C in the presence of K3PO4
and Pd(Cl2)(PPh3)2, DMF was added to the crude which was heated at 100 °C for further 2 h. Using this
procedure (procedure A), 8a was isolated in a slightly higher overall yield (65%) than that obtained via
the stepwise protocol (56%). To simplify further the synthetic protocol by avoiding the workꢀup step,
we attempted to optimize reaction conditions for a domino process by using the same substrates as a
model system. The screening of solvents and temperature reaction showed that best results were
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observed in dimethyl sulfoxide at 100 °C (Table 5, entry 2) (Procedure B). No improvements were
observed with our model system even with prolonged reaction times or increasing the temperature
(Table 5, entry 3). The two different procedures A and B were extended to include other substrates.
While the procedure A appeared of general application, the procedure B was find to give satisfactory
results in some cases (Table 5, entries 2,4, 8) but to be ineffective in others (Table 6, entries 6,10).
Very likely, under the presence of the palladium catalyst, the in situ generation of a palladium(II) πꢀ
allyl complex20a from 3 should cause the formation of side products determining the ineffectiveness of
the aromatization process.
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Table 5. Synthesis of 2ꢀunsubstituted benzofurans 8
Entry
R1
Ar
R2
Procedur
e
time
8 (yield %)a
1
2
3
3
4
Me
Me
Me
Me
Me
4ꢀMeOꢀC6H4
4ꢀMeOꢀC6H4
4ꢀMeOꢀC6H4
C6H5
H
H
H
H
H
A
B
9
9
8a (65)
8a (51)
8a (48)
8b (73)
8b (51)
Bb
A
B
24
6
C6H5
3
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5
6
Me
Me
Me
Me
F
4ꢀMeCOꢀC6H4
H
A
B
A
B
A
B
3
2
8c (72)
8c (ꢀ)
1
2
3
4
5
6
7
8
4ꢀMeCOꢀC6H4
4ꢀMeOꢀC6H4
4ꢀMeOꢀC6H4
4ꢀMeOꢀC6H4
4ꢀMeOꢀC6H4
H
7
3ꢀMeOCOꢀC6H4
4.5
2.5
6
8d (55)
8d (30)
8e (90)
8e (ꢀ)
9
10
11
12
13
14
15
16
17
18
19
8
3ꢀMeOCOꢀC6H4
9
H
H
10
F
5
a Yields refer to single run and are for pure isolated compounds 8. b Reaction temperature = 120 °C.
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Conclusions
The generality, scope and limitations, as well as the product selectivity in the palladiumꢀcatalyzed
tandem carbocyclization/Suzuki coupling of the ready available 1ꢀ(3ꢀarylpropꢀ2ꢀynyloxy)ꢀ2ꢀbromo
benzene derivatives has been investigated. The reactions take place in the presence of PdCl2(PPh3)2 and
potassium phosphate in 1,4ꢀdioxane as the solvent at 100 °C. Various 1ꢀ(3ꢀarylpropꢀ2ꢀynyloxy)ꢀ2ꢀ
bromo benzene derivatives underwent the palladiumꢀcatalyzed cascade reaction with several
arylboronic acids to afford highly stereoselectively the corresponding 2,3ꢀdihydroꢀ3ꢀ(diarylmethylene)ꢀ
benzofurans in moderate to excellent yields. The stereochemistry of these products derives from the
exclusive Pdꢀmediated synꢀinsertion of triple bond. The application of the procedure to the potassium
transꢀβꢀstyryltrifluoroborate has been, also, shown. An efficient method for the synthesis of the
scarcely described C3 functionalized 2ꢀunsubstituted benzofurans has been developed providing a
versatile tool for further expansion of their utility such as the random screening in the search for drug
candidates.
Experimental Section
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General Methods. H and 13C NMR spectra were recorded at 400 and 100.6 MHz, respectively. IR
spectra were recorded in KBr pellets or neat in NaCl on a FTꢀIR spectrometer. Only the most
significant IR absorptions are given. Melting points were determined on a microscopes apparatus and
were uncorrected. High resolution mass spectra were recorded on QꢀTOF. Unless otherwise stated, all
starting materials, catalysts, and solvents were commercially available and were used as purchased.
Reaction products were purified by flash chromatography on silica gel by elution with nꢀhexane/EtOAc
mixtures.
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General Experimental Procedure for the Synthesis of 2-bromo-O-aryl-prop-2-ynyl)phenols (1):
Synthesis of -2-bromo-1-(3-(4-methoxyphenyl)prop-2-ynyloxy)-4-methylbenzene (1a). A solution of
2ꢀbromoꢀ4ꢀmethylꢀ1ꢀ(propꢀ2ꢀynyloxy)benzene (1 g, 4.44 mmol, 1 equiv.), PdCl2(PPh3)2 (0.062 g, 0.09
mmol, 0.02 equiv.) and CuI (0.034 g, 0.18 mmol, 0.04 equiv.) in DMF (3 mL) /diꢀisopropylamine (6
mL) was treated with 4ꢀiodoanisole (1.350 g, 5.77 mmol, 1.3 equiv.). The resulting solution was stirred
at room temperature for 1 h until determined to be complete by TLC. The crude reaction mixture was
poured into NH4Cl/H2O and extracted with ether. The combined organic extracts were washed with
NaCl/H2O, dried over Na2SO4 and finally concentrated under reduced pressure. The product was
subjected to flash column chromatography (SiO2 100 g), eluting with nꢀhexane/ethyl acetate 85:15 v/v
to afford the product 1a (1.205 g, 3.64 mmol, 82%): yellow solid; Mp: 56ꢀ57 °C; HRMS (ESI) m/z
Calcd for C17H16BrO2 [M+H]+ 331.0328; found: 331.0342; IR (KBr): 2240, 1604, 1257, 1029, 831 (cmꢀ
1
1); H NMR (CDCl3): δ 7.39ꢀ7.38 (m, 3H), 7.09ꢀ7.06 (m, 2H), 6.84 (d, J= 8.0 Hz, 2H), 4.97 (s, 2H),
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3.83 (s, 3H), 2.31 (s, 3H); C NMR (CDCl3): δ 159.9, 152.2, 133.9, 133.3, 132.5, 128.8, 114.6, 114.3,
113.9, 112.3, 87.6, 82.3, 58.1, 55.3, 20.2; Anal Calcd for C17H15BrO2, C, 61.65; H, 4.56; Br, 24.13
found C, 61.58; H, 4.57; Br, 24.19.
1-(4-(3-(2-bromo-4-methylphenoxy)prop-1-ynyl)phenyl)ethanone (1b): (1.218 g, 80%); yellow
solid;. Mp: 60ꢀ61 °C; HRMS (ESI) m/z Calcd for C18H15BrO2Na [M+Na]+: 365.0153; found: 365.0144;
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IR (KBr): 2954, 2372, 1670, 1261, 1022, 796 (cmꢀ1); Hꢀ NMR (CDCl3): δ 7.90 (d, J= 8.4 Hz, 2H),
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2
3
13
7.51 (d, J= 8.4 Hz, 2H), 7.41 (s, 1H), 7.11ꢀ7.03 (m, 2H), 4.99 (s, 2H), 2.60 (s, 3H), 2.30 (s, 3H); Cꢀ
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5
6
7
8
NMR (CDCl3): δ 197.2, 152.1, 136.7, 133.9, 132.9, 131.9, 128.8, 128.2, 127.0, 114.7, 112.4, 86.9,
86.7, 58.0, 26.6, 20.2; Anal Calcd for C18H15BrO2, C, 62.99; H, 4.41; Br, 23.28 found C, 62.90; H,
4.42; Br, 23.22.
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2-bromo-4-methyl-1-(3-phenylprop-2-ynyloxy)benzene) (1c): (1.002 g, 75%); white oil; HRMS (ESI)
m/z Calcd for C16H13BrONa [M+Na]+: 323.0047; found: 323.0037; IR (KBr): 3033, 2921, 1600, 1442,
1
1230, 916, 730 (cmꢀ1); HꢀNMR (CDCl3): δ 7.46ꢀ7.44 (m, 3H), 7.41ꢀ7.28 (m, 3H), 7.12ꢀ7.07 (m, 2H),
13
4.99 (s, 2H), 2.31 (s, 3H); CꢀNMR (CDCl3): δ 152.2, 133.9, 132.6, 131.8, 128.8, 128.7, 128.3, 122.3,
114.8, 112.4, 87.6, 83.6, 58.1, 20,2; Anal Calcd for C16H13BrO, C, 63.81; H, 4.35; Br, 26.53 found C,
63.75; H, 4.36; Br, 26.45.
3-bromo-4-(3-(4-methoxyphenyl)prop-2-ynyloxy)biphenyl (1d): (0.870 g, 50%); white solid; Mp:
116ꢀ117 °C; HRMS (ESI) m/z Calcd for C22H17BrO2Na [M+Na]+: 415.0310; found: 415.0329; IR
1
(KBr): 2240, 1604, 1278, 1029, 831, 754 (cmꢀ1); HꢀNMR (CDCl3): δ 7.83 (s, 1H), 7.57ꢀ7.24 (m, 9H),
6.85 (d, J= 8.4 Hz, 2H), 5.05 (s, 2H), 3.83 (s, 3H); 13CꢀNMR (CDCl3): δ 160.0, 153.7, 136.0, 133.4,
132.0, 128.9, 127.3, 126.9, 126.8, 113.9, 87.9, 82.0, 58.0, 55.3. Anal Calcd for C22H17BrO2, C, 67.19;
H, 4.36; Br, 20.32 found C, 67.10; H, 4.37; Br, 20.25.
1-(4-(3-(3-bromobiphenyl-4-yloxy)prop-1-ynyl)phenyl)ethanone (1e): (1.205 g; 67%); yellow solid;
Mp: 125ꢀ126 °C; HRMS (ESI) m/z Calcd for C23H17BrO2Na [M+Na]+: 427.0310; found: 427.0311; IR
1
(KBr): 2902, 2358, 1679, 1598, 1261, 838, 769 (cmꢀ1); Hꢀ NMR (CDCl3): δ 7.92 (d, J= 8.4 Hz, 2H),
7.84 (s, 1H), 7.57ꢀ7.53 (m, 5H), 7.47ꢀ7.43 (m, 2H), 7.38ꢀ7.36 (m, 1H), 7.22 (d, J= 8.4 Hz, 1H), 5.08 (s,
13
2H), 2.61 (s, 3H); CꢀNMR (CDCl3): δ 197.2, 153.6, 139.3, 136.7, 136.3, 132.2, 131.9, 128.9, 128.7,
128.2, 127.4, 126.9, 126.8, 114.5, 112.9, 87.0, 86.6, 57.8, 26.6; Anal Calcd for C23H17BrO2, C, 68.16;
H, 4.23; Br, 19.72 found C, 68.10; H, 4.24; Br, 19.65.
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3-bromo-4-(3-phenylprop-2-ynyloxy)biphenyl (1f): (0.970 g, 60%); yellow solid. Mp: 70ꢀ71 °C;
1
2
3
HRMS (ESI) m/z Calcd for C21H15BrONa [M+Na]+: 385.0204; found: 385.0215; IR (KBr): 1484, 1278,
4
5
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8
9
1
13
754 (cmꢀ1); HꢀNMR (CDCl3): δ 7.84 (s, 1H), 7.57ꢀ7.43 (m, 6H), 7.38ꢀ7.25 (m, 6H), 5.07 (s, 2H); Cꢀ
NMR (CDCl3): δ 153.7, 139.4, 136.1, 132.1, 131.8, 128.9, 128.8, 128.3, 127.3, 126.9, 126.8, 122.1,
114.6, 112.9, 87.0, 83.3, 57.9. Anal Calcd for C21H15BrO, C, 69.44; H, 4.16; Br, 22.00 found C, 69.53;
H, 4.17; Br, 22.05.
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2-bromo-4-fluoro-1-(3-(4-methoxyphenyl)prop-2-ynyloxy)benzene (1g): (0.818 g, 55%); yellow
solid; Mp: 79ꢀ80 °C; HRMS (ESI) m/z Calcd for C16H12BrFO2Na [M+Na]+: 356.9902; found:
356.9918; IR (KBr): 2967, 2235, 1604, 1509, 1261, 836, 734, 603 (cmꢀ1); HꢀNMR (CDCl3): δ 7.39ꢀ
1
13
7.33 (m, 3H), 7.16ꢀ7.13 (m, 1H), 7.06ꢀ6.98 (m, 1H), 6.87ꢀ6.84 (m, 2H), 4.97 (s, 2H), 3.83 (s, 3H); Cꢀ
NMR (CDCl3): δ 160.0, 157.2 (d, JCꢀF = 243.0 Hz), 150.9, 133.3, 121.1, 120.4 (d, JCꢀF = 25.6 Hz), 115.5
(d, JCꢀF = 8.5 Hz), 114.6 (d, JCꢀF = 22.5 Hz), 114.0 (d, JCꢀF = 11.3 Hz), 112.8 (d, JCꢀF = 10.0 Hz), 87.9,
81.8, 58.7, 55.3; Anal Calcd for C16H12BrFO2, C, 57.34; H, 3.61; Br, 23.84 found C, 57.26; H, 3.62;
Br, 23.79.
1-(4-(3-(2-bromo-4-fluorophenoxy)prop-1-ynyl)phenyl)ethanone (1h): (1.233 g; 80%); yellow solid;
Mp: 73ꢀ74 °C; HRMS (ESI) m/z Calcd for C17H12BrFO2Na [M+Na]+: 368.9902; found: 368.9900; IR
(KBr): 1687, 1600, 1488, 1403, 1292, 732 (cmꢀ1); 1HꢀNMR (CDCl3): δ 7.91 (d, J=8.0 Hz, 2H), 7.51 (d,
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J=8.4 Hz, 2H), 7.36ꢀ7.38 (m, 1H), 7.14ꢀ7.02 (m, 2H), 5.00 (s, 2H), 2.61 (s, 3H); CꢀNMR (CDCl3): δ
197.2, 157.3 (d, JCꢀF = 243.0 Hz), 150.8, 136.8, 131.9, 128.2, 126.8, 120.6 (d, JCꢀF = 25.6 Hz), 115.7 (d,
JCꢀF = 8.5 Hz), 114.7 (d, JCꢀF = 22.5 Hz), 113.1 (d, JCꢀF = 8.7 Hz), 87.1, 86.4, 58.5, 26.6; Anal Calcd for
C17H12BrFO2, C, 58.81; H, 3.48; Br, 23.02 found C, 58.73; H, 3.49; Br, 23.07.
2-bromo-4-fluoro-1-(3-phenylprop-2-ynyloxy)benzene (1i): (0.678 g, 50%); white oil; HRMS (ESI)
m/z Calcd for C15H10BrFONa [M+Na]+: 326.9797; found: 326.9810; IR (KBr): 2240, 1450, 1384, 873
(cmꢀ1); HꢀNMR (CDCl3): δ 7.45ꢀ7.43 (m, 2H), 7.53ꢀ7.51 (m, 1H), 7.36ꢀ7.32 (m, 4H), 7.12ꢀ7.15 (m,
1
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1H), 7.06ꢀ7.02 (m, 1H), 4.99 (s, 2H); CꢀNMR (CDCl3): δ 157.2 (d, JCꢀF = 243.0 Hz), 150.9, 131.8,
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128.8, 128.3, 122.0, 120.5 (d, JCꢀF = 25.6 Hz), 115.6 (d, JCꢀF = 8.5 Hz), 114.6 (d, JCꢀF = 22.5 Hz), 113.0
(d, JCꢀF = 9.6 Hz), 87.9, 83.2, 58.6; Anal Calcd for C15H10BrFO, C, 59.04; H, 3.30; Br, 26.19 found C,
59.12; H, 3.31; Br, 26.26.
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General Procedure for the Palladium-catalyzed cross-coupling of 2-bromo-O-aryl-prop-2-
ynyl)phenols with arylboronic acids: Synthesis of (Z)-3-((4-methoxyphenyl)(phenyl)methylene)-5-
methyl-2,3-dihydrobenzofuran (3a). A solution of 2ꢀbromoꢀ1ꢀ(3ꢀ(4ꢀmethoxyphenyl)propꢀ2ꢀynyloxy)ꢀ
4ꢀmethylbenzene (1a) (0.1 g, 0.30 mmol, 1 equiv.), PdCl2(PPh3)2 (0.004 g, 0.006 mmol, 0.02 equiv.)
and K3PO4 (0.191 g, 0.90 mmol, 3 equiv.) in 1,4ꢀdioxane (2 mL) was treated with phenylboronic acid
(2a) (0.055 g, 0.45 mmol, 1.5 equiv.). The resulting solution was stirred at 100 °C for 2 h until
determined to be complete by TLC. The crude reaction mixture was extracted with ether/H2O. The
combined organic extracts were washed with NaCl/H2O, dried over Na2SO4 and finally concentrated
under reduced pressure. The crude was subjected to flash column chromatography (SiO2 50 g), eluting
with nꢀhexane/ethyl acetate 90:10 v/v to afford the product 3a (0.076 g, 0.23 mmol, 77 %): yellow
solid; Mp: 100ꢀ101 °C; HRMS (ESI) m/z Calcd for C23H21O2 [M+H]+ 329.1536; found: 329.1550; IR
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(KBr): 1606, 1251, 1155, 754 (cmꢀ1); HꢀNMR (CDCl3): δ 7.45ꢀ7.39 (m, 3H), 7.31ꢀ7.28 (m, 2H), 7.13
(d, J= 8.4 Hz, 2H), 6.91ꢀ6.88 (m, 3H), 6.73 (d, J= 8.4 Hz, 2H), 6.06 (s, 1H), 5.30 (s, 2H), 3.83 (s, 3H),
2.03 (s, 3H); 13CꢀNMR (CDCl3): δ 162.3, 159.1, 142.6, 134.0, 133.7, 132.1, 130.8, 130.5, 129.2, 128.5,
128.2, 127.2, 125.9, 124.7, 114.3, 109.9, 75.7, 55.4, 21.0; Anal Calcd for C23H20O2, C, 84.12; H, 6.14
found C, 84.20; H, 6.15.
3-(bis(4-methoxyphenyl)methylene)-5-methyl-2,3-dihydrobenzofuran (3b): (0.080 g; 74%); yellow
solid; Mp: 149ꢀ150 °C; HRMS (ESI) m/z Calcd for C24H23O3 [M+H]+: 359.1642; found: 359.1637; IR
1
(KBr): 1604, 1508, 1240, 833 (cmꢀ1); HꢀNMR (CDCl3): δ 7.22 (d, J= 8.0 Hz, 2H), 7.12 (d, J=8.4 Hz,
2H), 6.98ꢀ6.88 (m, 5H), 6.74 (d, J= 8.0 Hz, 1H), 6.26 (s, 1H), 5.28 (s, 2H), 3.89 (s, 3H), 3.84 (s, 3H),
2.08 (s, 3H); 13CꢀNMR (CDCl3): δ 162.0, 159.0, 158.6, 135.0, 133.9, 132.9, 131.8, 130.8, 130.1, 129.5,
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129.1, 126.1, 124.6, 114.2, 113.7, 109.7, 75.8, 55.4, 55.3, 20.9; Anal Calcd for C24H22O3, C, 80.42; H,
6.19 found C, 80.50; H, 6.20.
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(Z)-methyl 4-((4-methoxyphenyl)(5-methylbenzofuran-3(2H)-ylidene)methyl)benzoate (3c): (0.064
g, 55%); white solid; Mp: 167ꢀ168 °C; HRMS (ESI) m/z Calcd for C25H23O4 [M+H]+: 387.1591; found:
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387.1580; IR (KBr): 1718, 1604, 1276, 823 (cmꢀ1); HꢀNMR (CDCl3): δ 8.10 (d, J= 8.4 Hz, 2H), 7.41
(d, J= 8.0 Hz, 2H), 7.10 (d, J= 8.4 Hz, 2H), 6.99ꢀ6.88 (m, 3H), 6.75 (d, J= 8.4 Hz, 1H), 6.19 (s, 1H),
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5.28 (s, 2H), 3.98 (s, 3H), 3.84 (s, 3H), 2.05 (s, 3H); CꢀNMR (CDCl3): δ 166.9, 162.4, 158.8, 146.5,
134.1, 134.0, 130.8, 130.7, 130.2, 129.8, 129.5, 129.4, 129.1, 125.3, 124.4, 113.9, 109.9, 75.8, 55.3,
52.2, 20.9; Anal Calcd for C25H22O4, C, 77.70; H, 5.74 found C, 77.62; H, 5.75.
(E)-Methyl 3-((4-methoxyphenyl)(5-methylbenzofuran-3(2H)-ylidene)methyl)benzoate (3d): (0.081
g, 70%); yellow solid; Mp: 162ꢀ163 °C; HRMS (ESI) m/z Calcd for C25H23O4 [M+H]+: 387.1591;
found: 387.1579; IR (KBr): 1718, 1604, 1508, 1276, 823, 744 (cmꢀ1); 1HꢀNMR (CDCl3): δ 8.11 (d, J=
7.2 Hz, 1H), 8.00 (s, 1H), 7.57ꢀ7.51 (m, 2H), 7.12 (d, J= 8.4 Hz, 2H), 6.93ꢀ6.89 (m, 3H), 6.76 (d, J=
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8.0 Hz, 1H), 6.06 (s, 1H), 5.31 (s, 2H), 3.93 (s, 3H), 3.84 (s, 3H), 2.03 (s, 3H); CꢀNMR (CDCl3): δ
166.9, 162.2, 158.8, 141.9, 134.4, 134.1, 134.0, 130.9, 130.8, 130.7, 130.5, 129.5, 129.3, 129.0, 128.7,
125.5, 124.4, 113.9, 109.9, 75.7, 55.3, 52.1, 20.9; Anal Calcd for C25H22O4, C, 77.70; H, 5.74 found C,
77.62; H, 5.75.
(E)-3-((4-Methoxyphenyl)(5-methylbenzofuran-3(2H)-ylidene)methyl)benzaldehyde (3e): (0.048 g,
45%); yellow solid; Mp: 125ꢀ126 °C; HRMS (ESI) m/z Calcd for C24H21O3 [M+H]+: 357.1485; found:
357.1484; IR (KBr): 1698, 1508, 1251, 1008, 835, 690 (cmꢀ1); 1HꢀNMR (CDCl3): δ 10.04 (s, 1H), 6.94
(d, J= 6.8 Hz, 1H), 7.83 (s, 1H), 7.80ꢀ7.50 (m, 2H), 7.24 (d, J= 8.8 Hz, 2H), 7.00ꢀ6.76 (m, 4H), 6.32 (d,
J= 8.0 Hz, 1H), 6.05 (s, 1H), 5.31 (s, 2H), 3.84 (s, 3H), 2.09 (s, 3H); 13CꢀNMR (CDCl3): δ 192.1,
162.3, 158.9, 142.6, 137.2, 136.0, 134.4, 133.9, 131.5, 130.7, 130.3, 129.6, 129.5, 129.3, 128.3, 125.3,
124.2, 114.5, 114.0, 110.1, 75.7, 55.3, 20.9; Anal Calcd for C24H20O3, C, 80.88; H, 5.66 found C,
80.80; H, 5.67.
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(Z)-1-(4-((5-methylbenzofuran-3(2H)-ylidene)(phenyl)methyl)phenyl)ethanone (3f): (0.085 g,
83%); yellow solid; Mp: 175ꢀ176 °C; HRMS (ESI) m/z Calcd for C24H21O2 [M+H]+: 341.1536; found:
341.1528; IR (KBr): 1673, 1600, 1481, 1268, 987, 719 (cmꢀ1); 1HꢀNMR (CDCl3): δ 7.95 (d, J= 8.0 Hz,
1H), 7.48ꢀ7.46 (m, 3H), 7.33ꢀ7.21 (m, 4H), 6.96 (d, J= 6.0 Hz, 1H), 6.77 (d, J= 8.0 Hz, 1H), 6.10 (s,
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1H), 5.31 (s, 2H), 2.61 (s, 3H), 2.06 (s, 3H); CꢀNMR (CDCl3): δ 197.4, 162.5, 146.7, 140.7, 136.2,
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135.6, 131.2, 131.1, 129.6, 129.4, 129.2, 128.6, 128.3, 127.9, 125.3, 125.1, 110.0, 75.4, 26.6, 20.9;
Anal Calcd for C24H20O2, C, 84.68; H, 5.92 found C, 84.60; H, 5.91.
(E)-1-(4-((4-Methoxyphenyl)(5-methylbenzofuran-3(2H)-ylidene)methyl)phenyl)ethanone
(3g):
(0.097 g, 88%); brown solid; Mp: 150ꢀ151 °C; HRMS (ESI) m/z Calcd for C25H23O3 [M+H]+:
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371.1642; found: 371.1631; IR (KBr): 1677, 1509, 1243, 815 (cmꢀ1); H NMR (CDCl3): δ 7.94 (d, J=
8.0 Hz, 2H), 7.29 (d, J= 7.6 Hz, 2H), 7.22 (d, J= 8.0 Hz, 2H), 7.00ꢀ6.95 (m, 3H), 6.76 (d, J= 8.0 Hz,
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1H), 6.29 (s, 1H), 5.27 (s, 2H), 3.89 (s, 3H), 2.62 (s, 3H), 2.09 (s, 3H); C NMR (CDCl3): δ 197.5,
162.5, 159.4, 147.2, 135.9, 135.5, 132.9, 131.1, 130.8, 130.0, 129.4, 128.6, 128.4, 125.5, 124.9, 114.5,
110.0, 75.5, 55.4, 26.6, 21.0; Anal Calcd for C25H22O3, C, 81.06; H, 5.99 found C, 81.14; H, 5.98.
(E)-Methyl-4-((4-acetylphenyl)(5-methylbenzofuran-3(2H)-ylidene)methyl)benzoate (3h): (0.096 g,
80%); yellow solid; Mp: 156ꢀ157 °C; HRMS (ESI) m/z Calcd for C26H23O4 [M+H]+: 399.1591; found:
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399.1587; IR (KBr): 1722, 1681, 727 (cmꢀ1); HꢀNMR (CDCl3): δ 8.13 (d, J= 8.0 Hz, 2H), 7.94 (d, J=
8.4 Hz, 2H), 7.41 (d, J= 8.0 Hz, 2H), 7.26 (d, J= 8.0 Hz, 2H), 6.97 (d, J= 7.6 Hz, 1H), 6.77 (d, J= 8.0
Hz, 1H), 6.21 (s, 1H), 5.28 (s, 2H), 3.99 (s, 3H), 2.61 (s, 3H), 2.05 (s, 3H); 13CꢀNMR (CDCl3): δ
197.3, 166.8, 162.8, 146.2, 145.5, 136.9, 135.9, 131.7, 130.4, 129.8, 129.7, 129.5, 128.7, 128.4, 128.3,
124.74, 124.69, 110.3, 75.5, 52.2, 26.5, 20.9. Anal Calcd for C26H22O4, C, 78.37; H, 5.57 found C,
78.45; H, 5.58.
(E)-methyl-3-((4-acetylphenyl)(5-methylbenzofuran-3(2H)-ylidene)methyl)benzoate (3i): (0.099 g,
83%); yellow solid; Mp: 150ꢀ151 °C; HRMS (ESI) m/z Calcd for C26H23O4 [M+H]+: 399.1591; found:
399.1578; IR (KBr): 1720, 1685, 725, 619 (cmꢀ1); 1HꢀNMR (CDCl3): δ 8.13 (s, 1H), 7.99ꢀ7.94 (m, 3H),
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7.55 (d, J= 8.0 Hz, 2H), 7.29 (d, J= 7.6 Hz, 2H), 6.95 (d, J= 8.0 Hz, 1H), 6.76 (d, J= 8.0 Hz, 1H), 6.06
(s, 1H), 5.29 (s, 2H), 3.99 (s, 3H), 2.60 (s, 3H), 2.02 (s, 3H); 13CꢀNMR (CDCl3): δ 197.4, 166.8, 162.7,
146.2, 141.0, 137.0, 135.7, 134.4, 131.5, 131.2, 130.8, 129.8, 129.5, 129.2, 129.0, 124.9, 124.8, 110.2,
75.4, 52.2, 26.5, 20.9; Anal Calcd for C26H22O4, C, 78.37; H, 5.57 found C, 78.46; H, 5.58.
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(E)-3-((4-acetylphenyl)(5-methylbenzofuran-3(2H)-ylidene)methyl)benzaldehyde (3j): (0.080 g,
72%); yellow solid; Mp: 128ꢀ130 °C. HRMS (ESI) m/z Calcd for C25H20O3Na [M+Na]+: 391.1305;
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found: 391.1302; IR (KBr): 2358, 1677,1481, 1265, 811 (cmꢀ1); HꢀNMR (CDCl3): δ 10.01 (s, 1H),
7.97ꢀ7.95 (m, 3H), 7.84 (d, J= 13.6 Hz, 1H), 7.64 (s, 1H), 7.28 (d, J= 7.6 Hz, 2H), 6.96 (d, J= 8.0 Hz,
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1H), 6.77 (d, J= 8.0 Hz, 1H), 6.06 (s, 1H), 5.29 (s, 2H), 2.62 (s, 3H), 2.01 (s, 3H); CꢀNMR (CDCl3):
δ 197.5, 192.1, 162.7, 146.1, 141.7, 137.3, 137.2, 136.0, 135.8, 131.8, 131.3, 129.9, 129.6, 129.3,
129.0, 128.8, 128.4, 124.8, 124.6, 110.4, 75.5, 26.6, 20.9; Anal Calcd for C25H20O3, C, 81.50; H, 5.47
found C, 81.59; H, 5.48.
3-(Diphenylmethylene)-5-methyl-2,3-dihydrobenzofuran (3k): (0.089 g, 99%); yellow wax; HRMS
(ESI) m/z Calcd for C22H19O [M+H]+: 299.1436; found: 299.1441; IR (KBr): 1590,1481, 1220, 813
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(cmꢀ1); Hꢀ NMR (CDCl3): δ 7.52ꢀ7.13 (m, 10H), 6.98 (d, J= 8.0 Hz, 1H), 6.82 (d, J= 8.0 Hz, 1H),
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6.19 (s, 1H), 5.36 (s, 2H), 2.11 (s, 3H); CꢀNMR (CDCl3): δ 162.3, 142.1, 141.4, 134.4, 132.4, 131.9,
130.6, 129.0, 128.8, 128.5, 128.2, 127.6, 127.2, 126.7, 124.9, 109.9, 75.7, 20.9; Anal Calcd for
C22H18O, C, 88.56; H, 6.08 found C, 88.64; H, 6.07.
(E)-3-((4-Methoxyphenyl)(phenyl)methylene)-5-methyl-2,3-dihydrobenzofuran (3l): (0.081 g,
82%); yellow solid; Mp: 103ꢀ104 °C; HRMS (ESI) m/z Calcd for C23H21O2 [M+H]+: 329.1542; found:
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329.1545; IR (KBr): 1606, 1482, 1288, 981 (cmꢀ1); HꢀNMR (CDCl3): δ 7.44ꢀ7.42 (m, 3H), 7.32ꢀ7.29
(m, 2H), 7.14 (d, J= 8.8 Hz, 2H), 6.90ꢀ6.87 (m, 3H), 6.74 (d, J= 8.4 Hz, 2H), 6.06 (s, 1H), 5.31 (s,
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2H), 3.84 (s, 3H), 2.04 (s, 3H); CꢀNMR (CDCl3): δ 162.3, 159.1, 142.6, 134.0, 133.7, 132.1, 130.8,
130.5, 129.2, 128.5, 128.2, 127.2, 125.9, 124.7, 114.3, 109.9, 75.7, 55.4, 21.0; Anal Calcd for
C23H20O2, C, 84.12; H, 6.14 found C, 84.21; H, 6.15.
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(E)ꢀMethyl 3-((5-methylbenzofuran-3(2H)-ylidene)(phenyl)methyl)benzoate (3m): (0.056 g, 52%);
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yellow solid; Mp: 132ꢀ133 °C; HRMS (ESI) m/z Calcd for C24H20O3Na [M+Na]+: 379.1310; found:
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(s, 1H), 7.59ꢀ7.52 (m, 7H), 6.94 (d, J= 8.0 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.09 (s, 1H), 5.30 (s, 2H),
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3.93 (s, 3H), 2.04 (s, 3H); CꢀNMR (CDCl3): δ 166.9, 162.4, 141.7, 141.6, 135.2, 134.3, 131.0, 130.9,
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130.8, 129.4, 129.0, 128.8, 128.6, 128.2, 127.4, 125.2, 124.6, 110.0, 75.6, 52.2, 20.9; Anal Calcd for
C24H20O3, C, 80.88; H, 5.66 found C, 80.80; H, 5.67.
(E)-Methyl 4-((5-fluorobenzofuran-3(2H)-ylidene)(phenyl)methyl)benzoate (3n): (0.088 g, 81%);
yellow solid; Mp: 116ꢀ117 °C; HRMS (ESI) m/z Calcd for C23H17FO3Na [M+Na]+: 383.1059; found:
383.1052; IR (KBr): 1714, 1477, 1272, 817 (cmꢀ1); 1HꢀNMR (CDCl3): δ 7.95 (d, J= 8.4 Hz, 2H), 7.48ꢀ
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7.46 (m, 3H), 7.32ꢀ7.28 (m, 4H), 6.84ꢀ6.76 (m, 2H), 5.97ꢀ5.95 (m, 1H), 5.34 (s, 2H), 2.62 (s, 3H); Cꢀ
NMR (CDCl3): δ 166.7, 160.4, 156.9 (d, JCꢀF = 235.0 Hz), 145.4, 141.0, 134.3 (d, JCꢀF = 3.5 Hz), 132.7,
130.5, 129.6, 129.5, 128.7, 128.1, 127.8, 126.2 (d, JCꢀF = 9.3 Hz), 116.8 (d, JCꢀF = 25.0 Hz), 110.7 (d, JCꢀ
F = 12.5 Hz), 110.6 (d, JCꢀF = 22.5 Hz), 76.2, 52.2; Anal Calcd for C23H17FO3, C, 76.65; H, 4.75 found
C, 76.73; H, 4.76.
(E)-methyl 3-((5-fluorobenzofuran-3(2H)-ylidene)(phenyl)methyl)benzoate (3o): (0.093 g, 86%);
white solid; Mp: 117ꢀ118 °C; HRMS (ESI) m/z Calcd for C23H17FO3Na [M+Na]+: 383.1059; found:
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383.1070; IR (KBr): 1718, 1432, 1259, 754 (cmꢀ1); HꢀNMR (CDCl3): δ 8.11ꢀ8.00 (m, 2H), 7.53ꢀ7.19
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(m, 7H), 6.81ꢀ6.77 (m, 2H), 5.92 (d, J= 8.4 Hz, 1H), 5.32 (s, 2H), 3.91 (s, 3H); CꢀNMR (CDCl3): δ
166.7, 160.3, 156.9 (d, JCꢀF = 237.3 Hz), 141.0 (d, JCꢀF = 15.1 Hz), 134.4, 134.0, 132.7, 131.8, 131.3,
130.5, 129.4, 129.1, 128.7, 128.1, 127.7, 126.4 (d, JCꢀF = 9.1 Hz), 116.7 (d, JCꢀF = 25.6 Hz), 110.7 (d, JCꢀ
F = 11.8 Hz), 110.6 (d, JCꢀF = 23.3 Hz), 76.1, 52.2; Anal Calcd for C23H17FO3, C, 76.65; H, 4.75 found
C, 76.72; H, 4.76.
(E)-5-Fluoro-3-((4-methoxyphenyl)(phenyl)methylene)-2,3-dihydrobenzofuran (3p): (0.084 g,
85%); yellow wax; HRMS (ESI) m/z Calcd for C22H17FO2Na [M+Na]+: 355.1110; found: 355.1098; IR
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(KBr): 1604, 1475, 1247, 779 (cmꢀ1); 1Hꢀ NMR (CDCl3): δ 7.48ꢀ7.44 (m, 3H), 7.32ꢀ7.30 (m, 2H), 7.15
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3H); CꢀNMR (CDCl3): δ 159.9, 158.9, 156.9 (d, JCꢀF = 235.9 Hz), 140.9, 134.9, 133.7, 132.4, 129.4,
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129.3, 129.2, 127.9, 127.1 (d, JCꢀF = 10.3 Hz), 115.9 (d, JCꢀF = 25.1 Hz), 113.9 (d, JCꢀF = 10.3 Hz),
110.8 (d, JCꢀF = 26.3 Hz), 110.2 (d, JCꢀF = 8.7 Hz), 76.3, 55.3; Anal Calcd for C22H17FO2, C, 79.50; H,
5.16 found C, 79.59; H, 5.15.
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(E)-Methyl 4-((4-acetylphenyl)(5-fluorobenzofuran-3(3H)-ylidene)methyl)benzoate (3q): (0.099 g;
82%); brown solid; Mp: 135ꢀ137 °C; HRMS (ESI) m/z Calcd for C25H19FO4Na [M+Na]+: 425.1165;
found: 425.1151; IR (KBr): 1729, 1479, 1274, 813 (cmꢀ1); 1HꢀNMR (CDCl3): δ 8.14 (d, J= 8.0 Hz, 2H),
7.94 (d, J= 7.6 Hz, 2H), 7.38 (d, J= 8.0 Hz, 2H), 7.26 (d, J= 8.0 Hz, 2H), 6.86ꢀ6.76 (m, 2H), 6.01 (d,
J= 8.8 Hz, 1H), 5.31 (s, 2H), 3.94 (s, 3H), 2.61 (s, 3H); 13CꢀNMR (CDCl3): δ 197.4, 166.7, 160.6,
156.9 (d, JCꢀF = 237.7 Hz), 145.6, 144.7, 136.1 (d, JCꢀF= 3.0 Hz), 131.4, 130.6, 129.4, 129.6, 129.1,
128.8, 128.3, 125.8 (d, JCꢀF = 10.0 Hz), 117.5 (d, JCꢀF= 25.4 Hz), 110.9 (d, JCꢀF = 10.0 Hz), 110.8 (d, JCꢀF
= 26.4 Hz), 76.0, 52.3, 26.6; Anal Calcd for C25H19FO4, C, 74.62; H, 4.76 found C, 74.70; H, 4.75.
(Z)-1-(4-((5-Fluorobenzofuran-3(2H)-ylidene)(phenyl)methyl)phenyl)ethanone (3r): (0.093 g,
90%); yellow solid; Mp: 153ꢀ155 °C; HRMS (ESI) m/z Calcd for C23H17FO2Na [M+Na]+: 367.1110;
found: 367.1098; IR (KBr): 1681, 1484, 1267, 715 (cmꢀ1); 1HꢀNMR (CDCl3): δ 7.95 (d, J= 8.4 Hz, 2H),
7.48ꢀ7.46 (m, 3H), 7.32ꢀ7.29 (m, 4H), 6.84ꢀ6.77 (m, 2H), 5.95 (dd, J1= 9.6 Hz, J2= 2.4 Hz, 1H), 5.34 (s,
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2H), 2.62 (s, 3H); CꢀNMR (CDCl3): δ 197.3, 160.4, 156.9 (d, JCꢀF = 236.4 Hz), 146.2, 140.0, 135.9,
135.3 (d, JCꢀF = 3.6 Hz), 132.7, 129.4, 129.3, 128.6, 128.3, 128.2, 126.5 (d, JCꢀF = 9.1 Hz), 116.9 (d, JCꢀ
F = 25.0 Hz), 111.0 (d, JCꢀF = 26.1 Hz), 110.6 (d, JCꢀF = 8.5 Hz), 76.0, 26.6; Anal Calcd for C23H17FO2,
C, 80.22; H, 4.98 found C, 80.31; H, 4.99.
(Z)-Methyl 4-((5-fluorobenzofuran-3(2H)-ylidene)(4-methoxyphenyl)methyl)benzoate (3s): (0.090
g, 76%); yellow solid; Mp: 129ꢀ130 °C; HRMS (ESI) m/z Calcd for C24H20FO4 [M+H]+ 391.1340;
found: 391.1343; IR (KBr): 1710, 1604, 1247, 823 (cmꢀ1); 1H NMR (CDCl3): δ 8.12 (d, J= 8.0 Hz, 2H),
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7.68 (d, J= 8.0 Hz, 2H), 6.89 (d, J= 8.4 Hz, 2H), 6.90ꢀ6.74 (m, 4H), 5.99 (dd, J1= 9.6 Hz, J2= 2.4 Hz,
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1H), 5.33 (s, 2H), 3.93 (s, 3H), 3.83 (s, 3H); CꢀNMR (CDCl3): δ 166.8, 160.2, 159.0, 156.9 (d, JCꢀF
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235.9 Hz), 145.7, 133.2 (d, JCꢀF = 2.5 Hz), 132.5, 130.4, 130.2, 129.6, 129.4, 127.2, 126.5 (d, JCꢀF = 9.0
Hz), 116.4 (d, JCꢀF = 25.0 Hz), 114.0, 110.6 (d, JCꢀF = 15.0 Hz), 110.5 (d, JCꢀF = 20.1 Hz), 76.3, 55.3,
52.2; Anal Calcd for C24H19FO4, C, 73.84; H, 4.91 found C, 73.90; H, 4.90.
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(Z)-5-fluoro-3-((4-methoxyphenyl)(phenyl)methylene)-2,3-dihydrobenzofuran (3t): (0.079 g, 79%);
yellow wax; HRMS (ESI) m/z Calcd for C22H17FO2Na [M+Na]+: 355.1110; found: 355.1108; IR
(KBr): 1631, 1457, 1247, 823 (cmꢀ1); 1HꢀNMR (CDCl3): δ 7.40ꢀ7.22 (m, 6H), 7.02ꢀ7.00 (m, 3H), 6.83ꢀ
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6.78 (m, 2H), 6.20 (d, J= 8.4 Hz, 1H), 5.33 (s, 2H), 3.91 (s, 3H); CꢀNMR (CDCl3): δ 160.2, 159.3,
156.9 (d, JCꢀF = 235.7 Hz), 142.1, 133.8, 132.9, 130.5, 128.6, 128.1, 127.5, 127.3 (d, JCꢀF = 8.4 Hz),
116.2 (d, JCꢀF = 24.8 Hz), 114.5, 114.0 (d, JCꢀF = 7.9 Hz), 110.8 (d, JCꢀF = 26.3 Hz), 110.4 (d, JCꢀF = 8.8
Hz), 76.3, 55.3; Anal Calcd for C22H17FO2, C, 79.50; H, 5.16 found C, 79.59; H, 5.17.
(Z)-1-(4-(Phenyl(5-phenylbenzofuran-3(2H)-ylidene)methyl)phenyl)ethanone (3u): (0.076 g; 55%);
brown solid; Mp: 174ꢀ175 °C; HRMS (ESI) m/z Calcd for C29H23O2 [M+H]+: 403.1698; found:
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403.1687; IR (KBr): 1644, 1457, 1261, 981 (cmꢀ1); HꢀNMR (CDCl3): δ 7.61ꢀ7.56 (m, 2H), 7.52ꢀ7.12
(m, 14H), 6.95 (d, J= 8.4 Hz, 1H), 6.54 (s, 1H), 5.41 (s, 2H), 2.63 (s, 3H); 13CꢀNMR (CDCl3): δ 197.4,
164.0, 146.3, 140.7, 135.9, 135.7, 133.4, 131.9, 130.0, 129.6, 129.44, 129.41, 129.2, 128.6, 128.3,
128.0, 126.6, 126.4, 126.1, 123.4, 110.6, 75.8, 26.6; Anal Calcd for C29H22O2, C, 86.54; H, 5.51 found
C, 86.60; H, 5.52.
(E)-Methyl 4-((4-acetylphenyl)(5-phenylbenzofuran-3(2H)-ylidene)methyl)benzoate (3v): (0.076 g;
55%); brown solid; Mp: 130ꢀ132 °C; HRMS (ESI) m/z Calcd for C31H25O4 [M+H]+: 461.1753; found:
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461.1775; IR (KBr): 1710, 1604, 1261, 757 (cmꢀ1); HꢀNMR (CDCl3): δ 8.20ꢀ7.98 (m, 4H), 7.48ꢀ6.95
(m, 11H), 6.51 (s, 1H), 5.38 (s, 2H), 4.00 (s, 3H), 2.63 (s, 3H); 13CꢀNMR (CDCl3): δ 197.5, 166.7,
164.2, 153.3, 145.7, 145.5, 140.5, 136.7, 135.9, 133.7, 130.7, 129.9, 129.8, 128.8, 128.8, 128.3, 126.8,
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126.4, 125.534, 123.2, 129.3, 110.9, 75.8, 52.3, 26.6; Anal Calcd for C31H24O4, C, 80.85; H, 5.25
found C, 80.79; H, 5.26.
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3-(Diphenylmethylene)-5-phenyl-2,3-dihydrobenzofuran (3w): (0.072 g, 67%); white solid; Mp:
160ꢀ161 °C; HRMS (ESI) m/z Calcd for C27H21O [M+H]+ 361.1587; found: 361.1582; IR (KBr): 1656,
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1471, 836 (cmꢀ1); HꢀNMR (CDCl3): δ 7.53ꢀ7.26 (m, 16H), 6.94 (d, J= 8.4 Hz, 1H), 6.47 (s, 1H), 5.41
(s, 2H); 13CꢀNMR (CDCl3): δ 163.8, 141.8, 141.3, 140.8, 133.9, 133.3, 133.2, 129.6, 129.2, 128.8,
128.6, 128.5, 128.1, 127.7, 127.3, 126.50, 126.48, 126.4, 123.2, 110.4, 75.9; Anal Calcd for C27H20O,
C, 89.97; H, 5.59 found C, 89.90; H, 5.58.
(E)-Methyl 4-(phenyl(5-phenylbenzofuran-3(2H)-ylidene)methyl)benzoate (3x): (0.080 g; 64%);
yellow solid; Mp: 153ꢀ154 °C; HRMS (ESI) m/z Calcd for C29H23O3 [M+H]+: 419.1647; found:
419.1652; IR (KBr): 2358,1656, 1471, 863 (cmꢀ1); HꢀNMR (CDCl3): δ 8.19 (d, J= 8.0 Hz, 2H),7.52ꢀ
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7.25 (m, 13H), 6.96 (d, J= 8.4 Hz, 1H), 6.58 (s, 1H), 5.40 (s, 2H), 4.02 (s, 3H); CꢀNMR (CDCl3): δ
166.8, 164.0, 146.2, 141.1, 140.7, 134.8, 133.5, 131.9, 130.5, 129.9, 129.5, 129.3, 128.7, 128.2, 127.7,
126.7, 126.5, 125.9, 123.0, 110.7, 76.0, 52.2; Anal Calcd for C29H22O3, C, 83.23; H, 5.30 found C,
83.30; H, 5.31.
(Z)-Methyl 4-((4-methoxyphenyl)(5-phenylbenzofuran-3(2H)-ylidene)methyl)benzoate (3y): (0.071
g, 53%); white solid; Mp: 163ꢀ164 °C. HRMS (ESI) m/z Calcd for C30H25O4 [M+H]+: 449.1753; found:
449.1766; IR (KBr): 1710, 1471, 1286, 771 (cmꢀ1); HꢀNMR (CDCl3): δ 8.16 (s, 2H), 7.47ꢀ6.92 (m,
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13H), 6.49 (s, 1H), 5.39 (s, 2H), 3.99 (s, 3H), 3.84 (s, 3H); CꢀNMR (CDCl3): δ 166.9, 163.8, 159.0,
146.4, 140.7, 133.6, 133.5, 131.7, 130.5, 130.3, 129.9, 129.5, 129.4, 129.0, 128.7, 126.6, 126.5, 126.2,
122.9, 114.0, 110.6, 76.1, 55.3, 52.2; Anal Calcd for C30H24O4, C, 80.34; H, 5.39 found C, 80.42; H,
5.40.
3-((4-methoxyphenyl)(phenyl)methylene)-5-phenyl-2,3-dihydrobenzofuran (3z): (0.053 g, 45%);
yellow solid; Mp: 158ꢀ159 °C; HRMS (ESI) m/z Calcd for C28H22O2Na [M+Na]+: 413.1517; found:
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413.1498; IR (KBr): 1590, 1261, 1035, 935 (cmꢀ1); HꢀNMR (CDCl3): δ 6.52ꢀ6.94 (m, 16H), 6.53 (s,
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1H), 5.44 (s, 2H), 3.86 (s, 3H); CꢀNMR (CDCl3): δ 163.6, 158.8, 141.5, 140.9, 134.2, 133.2, 132.9,
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132.7, 129.7, 129.5, 129.2, 128.6, 128.5, 127.657, 126.8, 126.5 , 123.0, 113.9, 110.4, 76.1, 55.3. Anal
Calcd for C28H22O2, C, 86.13; H, 5.68 found C, 86.20; H, 5.69.
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(E)-3-((4-Fluoro-3-methylphenyl)(4-methoxyphenyl)methylene)-5-phenyl-2,3-dihydrobenzofuran
(5a): (0.056 g, 44%); yellow solid; Mp: 140ꢀ141 °C; HRMS (ESI) m/z Calcd for C29H24FO2 [M+H]+
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423.1755; found: 423.1741; IR (KBr): 1631, 1484, 1247, 981 (cmꢀ1); HꢀNMR (CDCl3): δ 7.39ꢀ7.17
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(m, 11H), 6.95ꢀ6.93 (m, 3H), 6.63 (s, 1H), 5.40 (s, 2H), 3.87 (s, 3H), 2.35 (s, 3H); CꢀNMR (CDCl3):
δ 163.6, 161.0 (d, JCꢀF = 246.2 Hz), 158.8, 140.9, 137.1, 134.2, 133.3, 132.9, 132.9, 132.72, 132.67,
132.0, 129.4, 128.7, 128.6, 126.4, 125.6 (d, JCꢀF = 17.5 Hz), 123.0, 115.7 (d, JCꢀF = 21.9 Hz), 114.7,
113.9, 110.4, 76.1, 55.3, 14.6; Anal Calcd for C29H23FO2, C, 82.44; H, 5.49 found C, 82.50; H, 5.50.
(E)-1-(4-((4-Fluoro-3-methylphenyl)(5-phenylbenzofuran3(2H)ylidene)methyl)phenyl)ethanone
(5b): (0.078 g, 60%); yellow solid; Mp: 175ꢀ176 °C; HRMS (ESI) m/z Calcd for C30H24FO2 [M+H]+:
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435.1760; found: 435.1758; IR (KBr): 1683, 1590, 1161, 744 (cmꢀ1); HꢀNMR (CDCl3): δ 7.97 (d, J=
8.0 Hz, 2H), 7.43ꢀ7.13 (m, 11H), 6.93 (d, J= 9.6 Hz, 1H), 6.63 (s, 1H), 5.36 (s, 2H), 2.62 (s, 3H), ),
2.33 (s, 3H); 13CꢀNMR (CDCl3): δ 197.4, 164.0, 161.1 (d, JCꢀF = 247.1 Hz), 146.4, 140.7, 136.2 (d, JCꢀF
= 3.8 Hz), 135.9 (d, JCꢀF = 24.0 Hz), 135.8, 133.6, 132.6 (d, JCꢀF = 5.1 Hz), 130.9, 129.73, 128.65,
128.3, 126.7, 126.4, 126.1, 125.95, 125.89, 123.3, 115.9 (d, JCꢀF = 22.0 Hz), 110.7, 75.8, 26.6, 14.59,
14.55; Anal Calcd for C30H23FO2, C, 82.93; H, 5.34 found C, 82.85; H, 5.34.
(E)-3-((4-Fluoro-3-methylphenyl)(phenyl)methylene)-5-phenyl-2,3-dihydrobenzofuran(5c): (0.087
g, 74%); white solid; Mp: 157ꢀ158 °C. HRMS (ESI) m/z Calcd for C28H22FO [M+H]+: 393.1655;
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found: 393.1668; IR (KBr): 1631, 1484, 1247, 981 (cmꢀ1); HꢀNMR (CDCl3): δ 7.38ꢀ7.10 (m, 15H),
6.93 (d, J= 8.4 Hz, 1H), 6.65 (s, 1H), 5.37 (s, 2H), 2.34 (s, 3H); 13CꢀNMR (CDCl3): δ 163.8, 160.9 (d,
JCꢀF = 245.8 Hz), 141.8, 140.9, 136.8 (d, JCꢀF = 3.8 Hz), 134.1, 133.4, 132.6 (d, JCꢀF = 4.9 Hz), 132.2,
129.0, 128.71, 128.66, 128.59, 128.09, 127.4, 126.6, 126.4, 126.3, 125.7 (d, JCꢀF = 17.4 Hz), 123.08,
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115.7 (d, JCꢀF = 22.1 Hz), 110.5, 76.0, 14.61 (d, JCꢀF = 3.0 Hz); Anal Calcd for C28H21FO, C, 85.69; H,
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5.39 found C, 85.75; H, 5.40.
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(E)-5-fluoro-3-((4-fluoro-3-methylphenyl)(4-mthoxyphenyl)methylene)-2,3dihydrobenzofuran
(5d): (0.079 g, 72%); yellow solid; Mp: 146ꢀ147 °C; HRMS (ESI) m/z Calcd for C23H19F2O2 [M+H]+:
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365.1353; found: 365.1348; IR (KBr): 1594, 1477, 1251, 831 (cmꢀ1); H NMR (CDCl3): δ 7.14ꢀ7.09
(m, 5H), 6.92ꢀ6.76 (m, 4H), 6.04 (d, J=8.8 Hz, 1H), 5.34 (s, 2H), 3.85 (s, 3H), 2.32 (s, 3H); 13CꢀNMR
(CDCl3): δ 160,9 (d, JCꢀF = 246.0 Hz), 159.9, 158.9, 156.9 (d, JCꢀF = 235.9 Hz), 136.5 (d, JCꢀF = 3.7 Hz),
134.1, 132.9, 132.3 (d, JCꢀF = 5.0 Hz), 129.4, 128.3 (d, JCꢀF = 7.9 Hz), 127.1, 125.8 (d, JCꢀF = 17.2 Hz),
116.0 (d, JCꢀF = 25.1 Hz), 115.7 (d, JCꢀF = 22.6 Hz), 113.9, 113.9, 110.7 (d, JCꢀF = 26.4 Hz), 110.4 (d,
JCꢀF = 8.75 Hz), 76.3, 55.3, 14.6 (d, JCꢀF = 2.8 Hz); Anal Calcd for C23H18F2O2, C, 80.22; H, 4.98 found
C, 80.30; H, 4.99.
(E)-1-(4-((4-Fluoro-3-methylphenyl)(5-fluorobenzofuran3(3H)ylidene)methyl)phenyl)ethanone
(5e): (0.093 g, 82%); yellow wax; IR HRMS (ESI) m/z Calcd for C24H18F2O2 [M+Na]+: 399.1173;
found: 399.1192; (KBr): 1683, 1479, 1265, 821 (cmꢀ1); HꢀNMR (CDCl3): δ 7.96 (d, J= 8.4 Hz, 2H),
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7.29 (d, J= 8.4 Hz, 2H), 6.95ꢀ6.79 (m, 5H), 6.07 (dd, J1= 7.6 Hz, J2= 2.8 Hz, 1H), 5.31 (s, 2H), 2.62 (s,
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3H), 2.32 (s, 3H); CꢀNMR (CDCl3): δ 197.5, 161.1 (d, JCꢀF = 246.1 Hz), 156.9 (d, JCꢀF = 266.6 Hz),
146.2, 135.9, 135.6, 132.4 (d, JCꢀF = 5.3 Hz), 131.9 (d, JCꢀF = 3.9 Hz), 128.7, 128.4, 128.3, 128.2,
126.4 (d, JCꢀF = 9.3 Hz), 126.2 (d, JCꢀF = 17.6 Hz), 117.1 (d, JCꢀF = 22.1 Hz), 115.9 (d, JCꢀF = 22.6 Hz),
110.9 (d, JCꢀF = 23.8 Hz), 110.8 (d, JCꢀF = 6.3 Hz), 75.9, 26.6, 14.6 (d, JCꢀF = 3.8 Hz); Anal Calcd for
C24H18F2O2, C, 76.58; H, 4.82 found C, 76.67; H, 4.83.
Synthesis of 1-(4-(1E,2E)-1-(5-methylbenzofuran-3(2H)-ylidene)-3-phenylallyl)phenyl)ethanone
(6). A solution of 1ꢀ(4ꢀ(3ꢀ(2ꢀbromoꢀ4ꢀmethylphenoxy)propꢀ1ꢀynyl)phenyl)ethanone (1a) (0.1 g, 0.29
mmol, 1 equiv.), PdCl2(PPh3)2 (0.004 g, 0.006 mmol, 0.02 equiv.) and K3PO4 (0.184 g, 0.87 mmol, 3
equiv.) in 1,4ꢀdioxane (2 mL) was treated with potassium transꢀβꢀstyryltrifluoroborate (0.092 g, 0.44
mmol, 1.5 equiv.). The resulting solution was stirred at 100 °C for 4 h until determined to be complete
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by TLC. The crude reaction mixture was extracted with ether/H2O. The combined organic extracts were
washed with NaCl/H2O, dried over Na2SO4 and finally concentrated under reduced pressure. The
product was subjected to flash column chromatography (SiO2 50 g), eluting with nꢀhexane/ethyl acetate
85:15 v/v to afford the product 6 (0.048 g, 0.13 mmol, 45 %): yellow oil; HRMS (ESI) m/z Calcd for
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C26H23O2 [M+H]+: 367.1690; found: 367.1690; IR (KBr): 2921, 2360, 1683, 1265, 956 (cmꢀ1); Hꢀ
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NMR (CDCl3): δ 8.07 (d, J= 8.0 Hz, 2H), 7.83 (d, J= 16.0 Hz, 1H), 7.60 (s, 1H), 7.43ꢀ7.09 (m, 7H),
7.01 (d, J= 8.4 Hz, 1H), 6.82 (d, J= 8.4 Hz, 1H), 6.14 (d, J= 16.0 Hz, 1H), 4.87 (s, 2H), 2.70 (s, 3H),
2.44 (s, 3H); 13CꢀNMR (CDCl3): δ 197.7, 163.5, 145.1, 137.4, 136.4, 132.5, 131.3, 130.5, 130.4, 129.5,
129.1, 128.8, 127.8, 126.8, 126.5, 126.4, 125.2, 110.4, 75.8, 26.6, 21.3. Anal Calcd for C26H22O2, C,
85.22; H, 6.05 found C, 85.30; H, 6.06.
General Procedure for the aromatization reaction of 3-methylene-2,3-dihydrobenzofurans 3:
Synthesis of 3-((4-methoxyphenyl)(phenyl)methyl)-5-methylbenzofuran (8a). A solution of 3ꢀ((4ꢀ
methoxyphenyl)(phenyl)methylene)ꢀ5ꢀmethylꢀ2,3ꢀdihydrobenzofuran (3a) (0.05 g, 0.15 mmol, 1
equiv.) in DMF (1 mL) was added K3PO4 (0.318 g, 0.15 mmol, 1 equiv.) . The resulting solution was
stirred at 100 °C for 7 h until determined to be complete by TLC. After cooling, the reaction mixture
was dried under reduced pressure and the residue was purified by flash column chromatography (SiO2
50 g), eluting with nꢀhexane/ethyl acetate 90:10 v/v to afford the product (0.036 g, 0.11 mmol, 73 %) as
a yellow solid. Mp: 115ꢀ116 °C; HRMS (ESI) m/z Calcd for C23H21O2 [M+H]+ 329.1536; found:
329.1527; IR (KBr): 1617, 1511, 1087, 1022, 796 (cmꢀ1); 1HꢀNMR (CDCl3): δ 7.37ꢀ7.28 (m, 6H), 7.24
(d, J= 6.8 Hz, 2H), 7.16 (d, J= 8.4 Hz, 1H), 6.97 (s, 1H), 6.94 (s, 1H), 6.86 (d, J= 8.8 Hz, 2H), 5.47 (s,
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1H), 3.82 (s, 3H), 2.34 (s, 3H); CꢀNMR (CDCl3): δ 158.3, 154.3, 144.2, 142.7, 134.6, 131.8, 129.8,
128.8, 128.5, 127.7, 126.6, 125.6, 124.0, 120.4, 113.9, 110.9, 55.2, 46.8, 21.3; Anal Calcd for
C23H20O2, C, 84.12; H, 6.14 found C, 84.20; H, 6.15.
Typical Procedure A for the Synthesis of 3,5 disubstituted-benzo[b]furans (8): Synthesis of 3-((4-
methoxyphenyl)(phenyl)methyl)-5-methylbenzofuran (8a).
A
solution of 2ꢀbromoꢀ1ꢀ(3ꢀ(4ꢀ
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methoxyphenyl)propꢀ2ꢀynyloxy)ꢀ4ꢀmethylbenzene (1a) (0.1 g, 0.30 mmol, 1 equiv.), PdCl2(PPh3)2
(0.004 g, 0.006 mmol, 0.02 equiv.) and K3PO4 (0.191 g, 0.90 mmol, 3 equiv.) in 1,4ꢀdioxane (2 mL)
was treated with phenylboronic acid 2a (0.055 g, 0.45 mmol, 1.5 equiv.). The resulting solution was
stirred at 100 °C for 2 h until determined to be complete by TLC. The crude reaction mixture was
extracted with ether/H2O. The combined organic extracts were washed with NaCl/H2O, dried over
Na2SO4 and finally concentrated under reduced pressure. The residue was dissolved in DMF (2 ml) and
K3PO4 (0.631 g, 0.30 mmol, 1 equiv.) was added. The resulting solution was stirred at 100 °C for 2 h
until determined to be complete by TLC. After cooling, the reaction mixture was dried under reduced
pressure and the residue was purified by flash column chromatography (SiO2 50 g), eluting with nꢀ
hexane/ethyl acetate 90:10 v/v to afford the product 8a (0.064 g, 0.19 mmol, 65 %).
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Typical Procedure B for the Synthesis of 3,5 disubstituted benzo[b]furans (8): Synthesis of 3-((4-
methoxyphenyl)(phenyl)methyl)-5-methylbenzofuran (8a).
A
solution of 2ꢀbromoꢀ1ꢀ(3ꢀ(4ꢀ
methoxyphenyl)propꢀ2ꢀynyloxy)ꢀ4ꢀmethylbenzene (1a) (0.1 g, 0.30 mmol, 1 equiv.), PdCl2(PPh3)2
(0.004 g, 0.006 mmol, 0.02 equiv.) and K3PO4 (0.318 g, 1.50 mmol, 5 equiv.) in DMSO (2 mL) was
treated with phenylboronic acid (2a) (0.055 g, 0.45 mmol, 1.5 equiv.). The resulting solution was
stirred at 100 °C for 9 h until determined to be complete by TLC. The crude reaction mixture was
extracted with ether/H2O. The combined organic extracts were washed with NaCl/H2O, dried over
Na2SO4 and finally concentrated under reduced pressure. After cooling, the reaction mixture was dried
under reduced pressure and the residue was purified by flash column chromatography (SiO2 50 g),
eluting with nꢀhexane/ethyl acetate 90:10 v/v to afford the product 8a (0.050 g, 0.15 mmol, 51 %).
3-Benzhydryl-5-methylbenzofuran (8b): (0.065 g, 73% [procedure A]; 0.046 g, 51% [procedure B]);
yellow solid; Mp: 83ꢀ84 °C; HRMS (ESI) m/z Calcd for C22H19O [M+H]+ 299.1430; found: 299.1424;
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1H), 7.06 (s, 1H), 7.02 (s, 1H), 5.59 (s, 1H), 2.40 (s, 3H); CꢀNMR (CDCl3): δ 154.3, 144.3, 142.4,
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131.9, 128.8, 128.5, 127.7, 126,7, 125.6, 123.7, 120.4, 111.0, 47.6, 21.4; Anal Calcd for C22H18O, C,
88.56; H, 6.08 found C, 88.65; H, 6.09.
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1-(4-((5-Methylbenzofuran-3-yl)(phenyl)methyl)ethanone (8c): (0.074 g, 72% [procedure A]);
yellow solid; Mp: 90ꢀ91 °C; HRMS (ESI) m/z Calcd for C24H21O2 [M+H]+: 341.1542; found:
341.1555; IR (KBr): 1644, 1272, 1087, 703 (cmꢀ1); 1HꢀNMR (CDCl3): δ 7.94 (d, J= 8.4 Hz, 2H), 7.41ꢀ
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6.95 (m, 9H), 7.01 (s, 1H), 6.95 (s, 1H) 6.00 (s, 1H), 2.62 (s, 3H), 2.36 (s, 3H); CꢀNMR (CDCl3): δ
197.8, 154.3, 147.9,144.2, 141.5, 135.8, 132.1, 129.1, 128.8, 128.7, 127.4, 127.1, 125.8, 122.9, 120.2,
111.1, 47.6, 26.6, 21.4. Anal Calcd for C24H20O2, C, 84.68; H, 5.92 found C, 84.60; H, 5.93.
Methyl 3-((4-methoxyphenyl)(5-methylbenzofuran-3-yl)methyl)benzoate (8d): (0.064 g, 55%
[procedure A]; 0.035 g, 30% [procedure B]); yellow wax; HRMS (ESI) m/z Calcd for C25H23O4
1
[M+H]+: 387.1596; found: 387.1614; IR (KBr): 1722, 1604, 1284, 800 (cmꢀ1); HꢀNMR (CDCl3): δ
8.00 (s, 1H), 7.96 (d, J= 7.2 Hz, 1H), 7.46ꢀ7.37 (m, 3H), 7.19ꢀ7.09 (m, 3H), 6.96 (s, 1H), 6.91 (s, 1H),
13
6.89ꢀ6.87 (m, 2H), 5.51 (s, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 2.35 (s, 3H); CꢀNMR (CDCl3): δ 167.1,
158.5, 154.3, 144.2, 143.2, 133.8, 133.2, 131.9, 130.5, 129.9, 129.7, 128.6, 127.9, 127.5, 125.7, 123.6,
120.2, 114.0, 111.0, 55.2, 52.1, 46.7, 21.3; Anal Calcd for C25H22O4, C, 77.70; H, 5.74 found C, 77.61;
H, 5.75.
5-Fluoro-3-((4-methoxyphenyl)(phenyl)methyl)benzofuran (8e): (0.090 g, 90% [procedure A]);
yellow oil; HRMS (ESI) m/z Calcd for C22H18FO2 [M+H]+: C22H18FO2Na [M+Na]+: 333.1291; found:
333.1290; IR (KBr): 1610, 1469, 1249, 1099, 852 (cmꢀ1); HꢀNMR (CDCl3): δ 7.43ꢀ6.79 (m, 13H),
1
13
5.46 (s, 1H), 3.81 (s, 3H); CꢀNMR (CDCl3): δ 158.6 (d, JCꢀF = 237.0 Hz), 158.5, 152.1, 145.7, 142.2,
134.0, 129.8, 128.4, 128.6, 128.2, 126.8, 124.7 (d, JCꢀF = 3.8 Hz), 114.0, 112.2 (d, JCꢀF = 26.0 Hz),
112.0, 106.3 (d, JCꢀF = 25.0 Hz), 55.3, 46.8; Anal Calcd for C22H17FO2, C, 79.50; H, 5.72 found C,
79.42; H, 5.73.
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