Multisubstituted benzo[b]furans through a copper- and/or palladium-catalyzed assembly and functionalization process

Article abstract of DOI:10.1016/j.tet.2012.12.058

Full details as well as the study of the scope, limitations, and further elaboration of a straightforward approach to the synthesis of 2,5,7-trisubstituted benzo[b]furans from 2-bromo- and 2-chloro-6-iodo-4- substituted phenols through a consecutive copper- and/or palladium-catalyzed assembly and functionalization process is described. Functionalization at the C(7) position is carried out by Suzuki-Miyaura cross-coupling, alkynylation, alkenylation, and C-N bond forming reactions. A one-pot protocol for the synthesis of 2,5,7-trisubstituted benzo[b]furans is also reported.

Full text of DOI:10.1016/j.tet.2012.12.058

Tetrahedron 69 (2013) 1857e1871
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Multisubstituted benzo[b]furans through a copper- and/or
palladium-catalyzed assembly and functionalization process
,
a
b
b,
Antonio Arcadi a , Federico Blesi , Sandro Cacchi , Giancarlo Fabrizi
*
*
,
Antonella Goggiamani b, Fabio Marinelli a
Dipartimento di Scienze Fisiche e Chimiche, Universita di L’Aquila, Via Vetoio, 67010 L’Aquila, Italy
a
ꢀ
b
ꢀ
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza, Universita di Roma, P.le A. Moro 5, 00185 Rome, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 October 2012
Received in revised form 12 December 2012
Accepted 21 December 2012
Available online 2 January 2013
Full details as well as the study of the scope, limitations, and further elaboration of a straightforward
approach to the synthesis of 2,5,7-trisubstituted benzo[b]furans from 2-bromo- and 2-chloro-6-iodo-4-
substituted phenols through a consecutive copper- and/or palladium-catalyzed assembly and function-
alization process is described. Functionalization at the C(7) position is carried out by SuzukieMiyaura
cross-coupling, alkynylation, alkenylation, and CeN bond forming reactions. A one-pot protocol for the
synthesis of 2,5,7-trisubstituted benzo[b]furans is also reported.
Keywords:
Copper
Ó 2012 Elsevier Ltd. All rights reserved.
Palladium
Cross-couplings
Benzo[b]furans
One-pot process
1. Introduction
trisubstituted benzofuran AChE inhibitors with significant in-
hibitory effects on A
b aggregation was identified. The structur-
The development of methods for the construction of fused furan
ring systems is of current interest.1 This interest is stimulated by the
identification of the benzofuran scaffold as a ‘privileged structure’
in medicinal chemistry.2 Benzo[b]furans have been isolated from
different medicinal plants and they were the subject of various
investigations related to their therapeutic potential.3 Members of
this class of compounds have shown biological activities ranging
from anti-inflammatory, anti-arrhythmic, hemostatic, antifungal,
and antimicrobial, to anti-viral, anti-tumor, and anti-oxidant ac-
tivities and antagonists for the H3 receptor and angiotensin II.4
Some of them are promising drugs against Parkinson’s5 and Alz-
heimer’s disease.6 Thus, these compounds are promising for dis-
covery of new leads via pharmacophore modeling and QSAR
analysis.7 A variety of methods have been developed to prepare
specific structures characterized by given pharmacological quali-
ties. A sulfated benzofuran library of 15 sulfated monomers and 13
sulfated dimers with different charged, polar, and hydrophobic
substituents was studied as the first examples of potent, small al-
eeactivity relationships provide a suitable template whose key
structural features will contribute by optimization to the inhibitory
potency of the benzofuran derivatives against AChE.9 Usually, dif-
ferent types of substitution patterns in these heterocycles provide
new opportunities for drug discoveries and a fine tuning of their
physical properties for other applications in material science. Some
benzofuran derivatives are attractive as organic materials, due to
their optical and electronic properties.10 For their potential appli-
cations, development of novel synthetic strategies is in strong
demand.
In recent years, transition metal-catalyzed reactions have played
a remarkable role in this area.1lem Particularly, palladium-11 and
copper12-catalyzed reactions have been widely employed in the
construction of the benzo[b]furan core providing functional group
tolerance, simplified procedures, and improved yields.
However, procedures for the synthesis of 2,5,7-trisubstituted
benzo[b]furans remain scarcely described in the literature9,13 and
the development of simple and general methods for their prepa-
ration is a subject of great interest.
losteric inhibitors of thrombin.8
A novel series of 2,5,7-
As part of our studies devoted to the construction of the benzo
[b]furan skeleton through tandem Sonagashira coupling/5-endo-
dig cyclization starting from alkynes and o-halophenols,14 we ob-
served and previously communicated15 that readily available 2-
bromo- and 2-chloro-6-iodo-4-substituted phenols can be used
* Corresponding authors. Tel.: þ39 (0)862 433774; fax: þ39 (0)882 433033
(A.A.); tel.: þ39 (0)6 4991 2795; fax: þ39 (0)6 4991 2780 (G.F.); e-mail addresses:
antonio.arcadi@univaq.it (A. Arcadi), giancarlo.fabrizi@uniroma1.it (G. Fabrizi).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.058

1858
A. Arcadi et al. / Tetrahedron 69 (2013) 1857e1871
as suitable building blocks for the target 2,5,7-trisubstituted benzo
[b]furans through a consecutive process that involves the assembly
of the benzo[b]furan ring followed by the functionalization at the
C(7) position via SuzukieMiyaura cross-coupling and CeN bond
forming reactions (Scheme 1A).
Scheme 3. Synthesis of 7-chloro-2,5-diphenylbenzo[b]furan 5a.
Some results of our screening summarized in Table 1 show that
benzo[b]furan formation was not observed by using PdCl2(PPh3)2,
CuI, and Et2NH in DMF at room temperature (entry 1). Increasing
the reaction temperature to 50 ꢀC gave 5a only in moderate yield
(entry 2). A similar result was obtained with NH(Pr-i)2 as the base
Table 1
Optimization of the reaction conditions for the synthesis of 5a from 3aa
Entry Catalytic system
(equiv)
Solvent Base
Et2NH
Et2NH
Temperature Time Yield
(ꢀC)
(h)
% of 5ab
1
2
3
4
PdCl2(PPh3)2 (0.02)/ DMF
CuI (0.04)
PdCl2(PPh3)2 (0.02)/ DMF
CuI (0.04)
PdCl2(PPh3)2 (0.02)/ DMF
CuI (0.04)
Pd2(dba)3 (0.025),
BF4HP(Bu-t)3
(0.05)
rt
24
d
50
48
48
48
53
50
68
NH(Pr-i)2 50
DMSO
Cs2CO3
60
Scheme 1. Synthesis of 2,5,7-trisubstituted benzo[b]furans from 2-halo-6-iodo-4-
substituted phenols.
5
Cu(phen)(PPh3)2]NO3 Toluene K2CO3
(0.10)
Cu(phen)(PPh3)2]NO3 Toluene Cs2CO3
(0.10)
Cu(phen)(PPh3)2]NO3 Toluene K3PO4
(0.10)
110
110
110
120
120
120
120
120
120
2
2
2
1
1
1
2
2
1
73
74
73
75
68
69
70
73
75
6
Now, we wish to report full details of the results we have ob-
tained as well as the study of the scope, limitations, and further
elaboration of this approach (Scheme 1B,C) to highly functionalized
benzo[b]furans. Moreover, a one-pot double-coupling procedure to
afford a convergent synthesis of the target polysubstituted de-
rivatives will be described.
7
8
CuI (0.10)/
(0.20)
CuI (0.10)/
(0.20)
CuI (0.10)/
(0.20)
CuI (0.10)/
(0.20)
CuI (0.10)/
(0.20)
CuI (0.10)/
(0.20)
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
Toluene K3PO4
9
DMF
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
10
11
12
13
DMSO
2. Results and discussion
1,4-
Dioxane
1,4-
Dioxane
1,4-
The starting building blocks 2-bromo- and 2-chloro-6-iodo-4-
substituted phenols 3aeg were prepared in high yields from
commercially available 4-substituted phenols 1aed according to
the sequence outlined in Scheme 2.16
Dioxane
a
Reactions were carried out on a 2 mmol scale of 3a using 6 mL of solvent,
1.5 equiv of phenylacetylene, and 2 equiv of base.
b
Yields refer to single run and are for pure isolated products.
(entry 3). Interestingly, 5a was isolated in good yield when
Pd2(dba)3 was used as the Pd(0) source in the presence of the bulky
P(Bu-t)3 ligand generated in situ from the robust BF4HP(Bu-t)3
salt17 under copper-free conditions (entry 4). Best results were
observed by using copper catalysis. Recently, copper-catalyzed
alkynylation of aryl halides has gained a growing attention due to
the lower toxicity and cost of copper catalysts. A number of ligands
have been examined for this type of reaction.18 We initially used the
Cu(I) complex Cu(phen)(PPh3)2]NO3 developed by Venkataraman
et al. and applied to the synthesis of 2-arylbenzo[b]furans.18j,19
Under their conditions 5a was isolated in good yields (entries
5e7). Nevertheless, we subsequently found that similar results
Scheme 2. Synthesis of 2-bromo- and 2-chloro-6-iodo-4-substituted phenols 3.
could be obtained by using the simpler CuI/L-proline combination
developed by Ma et al. and successfully employed in the N-aryla-
tion of aryl bromides20 and in the synthesis of 2-arylindoles from
terminal alkynes and 2-bromoalkynyltrifluoroacetanilides.21 1,4-
Dioxane, toluene, and DMF were suitable solvents (entries 8e10)
with this catalyst system and K2CO3 or K3PO4 or Cs2CO3 were ef-
fective as bases (entries 11e13).
Subsequent studies were directed toward searching for the best
conditions for their conversion into the corresponding benzo[b]
furan derivatives 5 by the reaction with terminal alkynes. 2-Chloro-
6-iodo-4-phenylphenol 3a and phenylacetylene 4 were selected as
the model system (Scheme 3).

A. Arcadi et al. / Tetrahedron 69 (2013) 1857e1871
1859
The CuI/
L
-proline catalytic system was then used when we ex-
To overcome such drawbacks and extend the cross-coupling
approach to 7-chlorobenzo[b]furans, our studies were directed
toward the use of derivatives 5a,c,e,gei as coupling partners of
boronic acids (Scheme 6).
plored of 2-halo-6-iodo-4-substituted phenols 3aeg with a variety
of terminal alkynes (Scheme 4).
Scheme 4. Synthesis of Synthesis of 7-halo-2-phenyl-5-substituted benzo[b]furans 5.
Scheme 6. Palladium-catalyzed cross-coupling of 7-chlorobenzo[b]furan derivatives
with arylboronic acids.
We found that 2-halo-6-iodo phenols bearing at C(4) position
either an electron-releasing group or an electron-withdrawing
group reacted with terminal alkynes to give the corresponding
benzo[b]furans 5aeg in good yield (Table 2). Notably, the extension
of this copper-catalyzed procedure to alkyl acetylenes, also, pro-
vided the expected 2-alkyl substituted benzofurans under our
conditions overcoming some previous described limitations (Table
2, entries 7 and 8).12g
After a brief optimization study, we found that under the same
conditions used for the preparation of 2-arylhydroxytyrosol de-
rivatives,16 7-chlorobenzo[b]furans 5a,c,e,gei could give the cor-
responding 7-arylbenzo[b]furans 6 in almost quantitative yields.
As shown by Table 3, the reaction can be applied to a variety of
neutral, electron-rich, and electron-poor arylboronic acids. Heter-
oarylboronic acids can also be successfully used.
Table 2
Synthesis of 7-halo-2-phenyl-5-substituted benzo[b]furans 5aeja
Table 3
Synthesis of 7-aryl-2-phenyl-5-substituted benzo[b]benzofurans
6 from 7-
Entry
R1
R2
X
t (h)
Yield % of 5b
chlorobenzo[b]furans 5 and arylboronic acidsa
1
2
3
4
5
6
7
8
Ph
Ph
Me
Me
F
F
Ph
Me
Ph
Ph
Ph
Ph
Ph
Ph
Cl
Br
Cl
Br
Cl
Br
Cl
Cl
Cl
Br
Br
2
2
1
1
2
8
3
7
4
8
2
5a (73)
5b (73)
5c (75)
5d (70)
5e (65)
5f (65)
5g (73)
5h (60)
5i (65)
5j (65)
5k (85)
Entry
R1
R2
Ar
t (h)
Yield % of 6b
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
F
F
F
F
F
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
Ph
3-CH3O2CC6H4
4-CH3OC6H4
4-C6H5C6H4
3-CH3,4-FC6H3
3-Thienyl
3-CH3O2CC6H4
4-CH3OC6H4
4-C6H5C6H4
3-CH3,4-FC6H3
3-Thienyl
3-CH3O2CC6H4
4-CH3OC6H4
4-C6H5C6H4
3-CH3,4-FC6H3
3-Thienyl
4-CH3COOC6H4
3-CH3,4-FC6H3
4-C6H5C6H4
3-Thienyl
2
3
2
3
4
2
3
2
3
3
2
3
2
2
3
4
4
2
5
3
1.5
3
2
3
1.5
3
3
6aa (99)
6ab (99)
6ac (99)
6ad (99)
6ae (99)
6ca (95)
6cb (95)
6cc (99)
6cd (95)
6ce (99)
6ea(99)
6eb (95)
6ec (99)
6ed (95)
6ee (98)
6ga (99)
6gb (99)
6gc (99)
6gd (99)
6ge (99)
6ha (94)
6hb (99)
6hc (99)
6hd (99)
6he (97)
6ia (99)
6ib (99)c
6ic (99)
6id (99)
6ie (99)
n-C5H11
(CH2)2Ph
Ph
4-CH3OeC6H4
MeC(OH)Ph
9
10
11
Me(CH2)2CO2
Me
Ph
9
a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Reactions were carried out on a 2 mmol scale of 3 using 6 mL of toluene at
120 ꢀC, 1.5 equiv of alkyne, 0.10 equiv of CuI, 0.20 equiv of
L-proline, and 2 equiv of
K3PO4.
b
Yields refer to single run and are for pure isolated products.
The potential of the functionalization at C(7) position of de-
rivatives 5aeg was next studied. Firstly, it appeared of interest to us
to investigate the scope and generality of a route to 2,5,7-
trisustituted benzo[b]furans bearing an aryl substituent at the
C(7) position based on the SuzukieMiyaura cross-coupling. To the
best of our knowledge, only one example of this chemistry was
reported by Moody et al.22 who showed that 2,7-diphenylbenzo[b]
furan could be prepared either directly by the reaction of phenyl
boronic acid with 2-phenyl-7-bromobenzo[b]furan or indirectly by
conversion of 2-phenyl-7-bromobenzo[b]furan into the corre-
sponding boronic acid followed by reaction with bromobenzene
(Scheme 5). The preparation of 7-benzo[b]furan-7-yl boronic acids
involves the utilization of butyllithium, a synthetic approach that
has important deficiencies in terms of flexibility and functional
group tolerance when a high degree of functionalization on the
benzo[b]furan ring is required.
C6H5
4-CH3COOC6H4
3-CH3,4-FC6H3
4-C6H5C6H4
3-Thienyl
Me
C6H5
Me(CH2)2CO2
Me(CH2)2CO2
Me(CH2)2CO2
Me(CH2)2CO2
Me(CH2)2CO2
3-CH3COOC6H4
4-CH3OC6H4
4-C6H5C6H4
3-CH3,4-FC6H3
3-Thienyl
Ph
Ph
Ph
Ph
24
8
12
a
Reactions were carried out on a 0.4 mmol scale of 5 using 2 mL of 1,4-dioxane at
100 ꢀC, 1.5 equiv of arylboronic acids, 0.04 equiv of Pd2(dba)3, 0.04 equiv of SPhos,
and 3 equiv of K3PO4.
b
Yields refer to single run and are for isolated products.
Reaction temperature¼120 ꢀC.
c
Secondly, the palladium-catalyzed functionalization of 7-
bromobenzo[b]furans was applied to the synthesis of alkynyl/
alkenyl C(7) functionalized benzo[b]furans through Sonogashira/
Heck reactions. Sonogashira-type cross-coupling of 2,3-
dibromobenzofuran and 2,3,5-tribromobenzofuran was reported
to smoothly proceed only at C(2) position.23
Scheme 5. Synthesis of 2,7-diphenylbenzo[b]furan.

1860
A. Arcadi et al. / Tetrahedron 69 (2013) 1857e1871
One current challenge associated with the Sonogashira coupling
electrocyclization
reactions
of
2,3-di-and
2,3,5-
reaction is its inefficiency when ‘unreactive’ aryl halides are
employed.24 As illustrated in Table 4, we failed to obtained the
alkynyl derivative 7 under copper catalysis (entry 1) and un-
satisfactory results from synthetic point of view were observed
tribromobenzofuran,27 to the best of our knowledge the alkeny-
lation reaction at the C(7) position has not been previously
reported.
The Heck coupling of the deactivated bromide derivative 5d
with various alkenes 8 was then performed (Scheme 7).
Table 4
Synthesis of 5-methyl-2-phenyl-7-(phenylethynyl)benzo[b]furan 7a
Scheme 7. Palladium-catalyzed cross-coupling of 7-bromobenzo[b]furan 5c with
alkenes.
Entry Catalytic system
Base
Solvent/T (ꢀC)
t (h) Yield % of 7b
The Heck coupled derivative 9a was obtained in 63% yield by
reacting 5c with styrene in 1,4-dioxane at 110 Cꢀ in the presence
of Pd2(dba)3/[(t-Bu)3HP]3BF4 as the catalytic system and Cs2O3
as the base. The use of the Hermann catalyst and MeCOOK as
a base gave inferior results under the same conditions (Table 6,
entry 1). It has been recognized that palladium complexes de-
rived from sterically bulky electron-rich phosphines,28 N-het-
erocyclic carbenes,29 and carbocyclic carbenes30 facilitate the
Heck reaction of deactivated aryl/heteroaryl halides. Surpris-
ingly, we failed to obtain efficiently the desired cross-coupling
derivatives with ethyl or butyl acrylate (Table 6, entry 3e8).
An unusual propensity of substrate 5d to protodebrominate in
the presence of acrylates caused the failure of the Heck
coupling.
1
2
3
4
CuI/
L
-proline
Cs2CO3
1,4-Dioxane/110 24
d
PdCl2(PPh3)2/CuI
Pd2(dba)3/P(c-C6H11
Pd2(dba)3/[(t-Bu)3HP]3BF4 Cs2CO3
i-Pr2eNH 1,4-Dioxane/100 24 35
Cs2CO3 1,4-Dioxane/100 24 20
1,4-Dioxane/60 99
)
3
6
a
Reactions were carried out on a 0.34 mmol of 5c scale using 1 mL of 1,4-dioxane
at 60 ꢀC.
b
Yields refer to single run and are for isolated products.
both in standard Sonogashira conditions (Table 4, entry 2) and
under copper-free conditions by using Pd2(dba)3/P(c-C6H11)3 as
catalyst.25 The steric bulk and electron-rich Pt-Bu3 had a pro-
nounced impact on the process accomplishing the formation of the
expected alkynyl derivative in very high yield (entry 4).26 The most
effective base among those surveyed was Cs2CO3.
Table 6
Having optimized the reaction conditions for the Sonogashira
reaction of 5d, we determined the substrate scope of the process. As
shown in Table 5, in general the desired products 7 were obtained
in good to excellent yields with both aryl and alkyl acetylenes.
Relative lower yields occurred in the cross-coupling reactions of
5j,f,d with the tertiary propargylic alcohol 2-methylbut-3-yn-2-ol
(Table 5, entries 5e7).
Optimization of the reaction conditions for the Heck reaction of 5-methyl-2-phenyl-
7-bromobenzofuran 5da
Entry
R
Catalytic system (equiv)
Yield % of 9b
1c
Ph
Ph
Hermann catalyst
Pd2(dba)3/[(t-Bu)3HP]3BF4
Hermann catalyst
PdEnCat
9a (34)
9a (63)
9b (e)
9c (e)
9c (e)
9c (e)
9b (12)
9b (e)
2d,e
3c,f
4c,f
5f,g
6c,f
7c,f
8d,e
MeCOO
BuCOO
BuCOO
BuCOO
MeCOO
MeCOO
Pd(OAc)2/Lh
Although 2,3-dialkenylbenzofurans and functionalized di-
benzofurans were prepared based on domino twofold Heck/6p-
Pd(OAc)2/Lh
Hermann catalyst
Pd2(dba)3/[(t-Bu)3HP]3BF4
a
Reactions were carried out in 24 h on a 0.34 mmol scale of 5 in 1 mL of DMF at
110 ꢀC, using 1.5 equiv of alkene, 1.1 equiv of base, 0.02 equiv of catalyst.
b
Table 5
Yields refer to single run and are for isolated products.
Using AcOK as base.
In 1,4-dioxane.
Using Cs2CO3 as base.
At 120 ꢀC.
Using K2CO3/Cs2CO3 as combination of bases.
Synthesis of 2,5-disubstituted-7-alkynylbenzo[b]furan 7a
c
d
Entry
1
5
Alkyne
t (h)
Yield % of 7b
e
f
5d
6
7a (99)
7b (82)
g
2
3
5f
3
3
5d
7c (83)
e L =
h
L¼
.
4
5
5j
5j
2
2
7d (80)
7e (50)
6
7
8
5f
6
6
7f (50)
7g (60)
7h (99)
7i (79)
5d
5k
5k
Results of further investigations demonstrated that all sub-
strates tested were tolerated in this Heck coupling with good yields
(Table 7).
1
9
24
The potential of our strategy for the preparation of 2,5,7-
trisubstituted benzo[b]furans is further demonstrated by the for-
mation of 7-amino derivatives 10. The results of a brief screening
aimed to the optimization of the reaction conditions for CeN bond
a
Reactions were carried out on a 0.34 mmol scale of 5 using 1 mL of 1,4-dioxane
at 60 ꢀC, using 1.5 equiv of alkyne, 0.02 equiv of Pd2(dba)3, 0.08 equiv of [(t-
Bu)3HP]3BF4, 1.1 equiv of Cs2CO3.
b
Yields refer to single run and are for isolated products.

A. Arcadi et al. / Tetrahedron 69 (2013) 1857e1871
1861
Table 7
Table 9
Synthesis of 2,5-disubstituted-7-styrylbenzo[b]furan 9a
Synthesis of 7-aminobenzo[b]benzofurans 10 from 7-chlorobenzo[b]furans 5 and
secondary amines/hydrazinesa
Entry
5
t (h)
Yield % of 9b
Entry
1
5
R2NH or R2NeNH2
Time (h)
12
Yield % of 10b
10a (71)
1
2
3
5d
5f
5j
49
24
48
9a (63)
9b (70)
9c (72)
5b
a
Reactions were carried out in 24 h on a 0.34 mmol scale of 5 in 1 mL of 1,4-
dioxane at 110 ꢀC, using 1.5 equiv of styrene, 1.1 equiv of Cs2CO3, 0.02 equiv of
Pd2(dba)3, 0.08 equiv of [(t-Bu)3HP]3BF4.
2
3
4
5
5c
5c
5c
5c
3
10b (60)
10c (86)
10d (76)
10e (56)
1.3
1
b
Yields refer to single run and are for isolated products.
formation by reacting 7-bromo[b]furans 5b, d, e with piperidine are
summarized in Table 8.
2.5
The best results were obtained using the Pd2(dba)3/X-Phos
catalytic system.31 Copper based protocols32 resulted less efficient
in promoting the CeN bond formation at the C-7 position.
6
5c
H2NNMe2
3.5
10f (61)
7
5c
5d
5d
5e
5g
5f
1.5
24
40
12
5
10g (99)
10b (99)
10h (60)
10i (86)
10j (55)
10i (71)
10k (70)
Table 8
8
Optimization of the reaction conditions for the synthesis of 7-amino-2,5-
disubstituted-benzo[b]furans 10a
9
10
11
12
13
12
3
5g
14
5g
H2NNMe2
2
10l (90)
Entry
5
Catalytic system (equiv)
CuI/ -proline
Pd2(dba)3/X-Phos
Time (h)
Yield % of 10b
1c
5b
5b
5d
5d
5d
5d
5d
5d
5e
L
72
24
72
36
72
36
72
12
12
10a (55)
10a (71)
10b (46)
10b (56)
10b (27)
10b (55)
10b (39)
10b (99)
10c (72)
15
16
17
5g
5g
5j
2
3
1
10m (91)
10n (65)
10o (83)
2d,e,f,g
3c,h
4c
CuI/
CuI/
CuI/
L-proline
L-proline
L-proline
5h
6c
CuI/N-methylglycine
CuI/N,N-dimethylglycine
Pd2(dba)3/X-Phos
7i
8d,e,f,g
9d,e,f,g
Pd2(dba)3/X-Phos
18
5k
H2NNMe2
7
10p (67)
a
Reactions were carried out on a 0.34 mmol scale of 5 in 1 mL of toluene at 80 ꢀC,
10 equiv of nitrogen compound, 0.025 equiv of Pd2(dba)3, 0.10 equiv of X-Phos, and
2 equiv of NaOBu-t.
a
Reactions were carried out in 24 h on a 0.34 mmol scale using 1 mL of solvent at
120 ꢀC, using 10 equiv of piperidine, 2 equiv of K2CO3, 0.10 equiv of CuI, and
0.20 equiv of N-ligand catalyst.
b
b
Yields refer to single run and are for isolated products.
Yields refer to single run and are for isolated products.
In DMSO.
In toluene.
Using NaOBu-t.
At 80 ꢀC.
c
d
e
piperazine in the presence of Pd(dba)2, P(o-tol)3, and NaOBu-t in
toluene at 100 ꢀC followed by a deprotection step with trifluoro-
acetic acid (Scheme 8).
Having successfully established a protocol to produce 2,5,7-
trisubstituted benzo[b]furans through the consecutive process
f
g
With 0.025 equiv of Pd2(dba)3 and 0.10 equiv of X-Phos.
h
At 100 ꢀC in 1,4-dioxane.
i
At 120 ꢀC in 1,4-dioxane.
Using the ‘optimal’ condition found, we next examined the re-
action using 7-chlorobenzo[b]furan derivatives in order to de-
termine the scope and limitations of the palladium-catalyzed CeN
bond formation process. The results are listed in Table 9. To our
delight, the cross-coupling reaction of the less reactive chlorides
with secondary amines proceeds as well as with the corresponding
7-bromoderivatives.
Moreover, the reaction of the 7-chloro-2,5-disubstituted benzo
[b]furans with N,N-dialkylhydrazines occurs in high to excellent
yields.
Interestingly, unprotected piperazine can be used in the cou-
pling reaction with 5d to give 10h in 60% yield although mono-Boc
derivatives have been suggested to be required to circumvent bis-
arylation reactions.33 Compound 10h was reported to form only
in 20% yield upon treatment of 7-bromobenzo[b]furan with N-Boc-
Scheme 8. Palladium-catalyzed amination of 7-bromobenzo[b]furans 5d with
piperazine.

1862
A. Arcadi et al. / Tetrahedron 69 (2013) 1857e1871
involving the assembly of the benzo[b]furan ring followed by the
functionalization at the C(7) position via SuzukieMiyaura cross-
coupling and CeN bond forming reactions, we examined the ver-
satility of a one-pot preparation. One-pot multistep processes are
economically advantageous considering the outlays for the catalyst,
solvent, purification materials, and time. We used the same cata-
lytic system for the two successive reaction steps in which at first
the terminal alkyne would react selectively with 2-chloro-6-iodo-
4-substituted phenols 3a,c,e at the more reactive C-6 position to
give the corresponding 7-chloro-2,5-disubstituted benzo[b]furan
derivative 5. Then the boronic acid would be added to react at the
C-7 position (Scheme 9).
Scheme 10. One-pot palladium-catalyzed synthesis the tyrosol derivative 6ha.
One-pot two-step cross-coupling of compound 5d, with phe-
nylacetylene and piperidine to give the 7-amino derivative 10b
was also studied. For the optimization of this process, we
screened a variety of reaction conditions to compare copper
versus palladium catalysis for the one-pot protocol (Table 11).
Under the best conditions developed the product 10b was isolated
in 33% overall yield by using the same copper catalyst and 50%
overall yield whith the same palladium catalyst in both the re-
action steps. Analogously 10b could be conveniently prepared
Scheme 9. Palladium-catalyzed one-pot assembly of 2,5,7-trisubstituted benzo[b]
furans.
The best reaction conditions were the following: the starting 2-
chloro-6-iodo-4-substituted phenol was treated with phenyl-
acetylene in the presence of Pd2(dba)3, SPhos as the catalytic sys-
tem, and K3PO4 as the base in 1,4-dioxane at 110 ꢀC. After the end of
the reaction, an extraction was made and the boronic acid de-
rivative (1.5 equiv) was added together with Pd2(dba)3, SPhos/
K3PO4 to the residue and the reaction mixture was then heated at
100 ꢀC. These sequences afforded the target 2,5,7- tri-substituted
benzo[b]furan in satisfactory overall yield (Table 10).
through a process in which the first step was catalyzed by CuI/L-
proline. Subsequently, the palladium-catalyzed C-N bond forma-
tion step was carried out on the resulting crude mixture after
extraction and evaporation of the solvent. Using this procedure,
10b was isolated in the same overall yield (50%) than that ob-
tained via the one-pot palladium-catalyzed double cross-coupling
protocol.
3. Conclusion
Table 10
In summary, this paper describes a straightforward general
protocol for the synthesis of 2,5,7-trisubstituted benzo[b]furans
from readily available 2-bromo- and/or 2-chloro-6-iodo-4-
substituted phenols.
One-pot palladium-catalyzed synthesis of 2,5,7-trisubstituted benzo[b]furans 6a,b
Entry
3
Time
Time
Yield % of 6c
(step 1, h)
(step 2, h)
1
2
3
3a
3c
3e
3
3
3
4
4
6
6aa (50)
6ca (60)
6ea (50)
A comparison of the copper and palladium catalysis shows that
both transition metals are suitable catalysts for the site selective
sequential alkynylation/cyclization process.
Pd2(dba)3/SPhos and Pd2(dba)3/X-Phos catalysts achieve very
efficiently the consecutive functionalization at the C(7) position of
both bromo- and chloro-benzo[b]furans through cross-coupling
with boronic acids and secondary amines/N,N-dialkylhydrazines,
respectively.
The use of Pd2(dba)3/[(t-Bu)3HP]3BF4 as the catalyst and Cs2O3
as the base achieves the alkynylation of 7-bromo-benzo[b]furan
derivative under copper-free conditions in 1,4-dioxane. Under
these latter conditions the Heck coupling of the 7-heroaryl bro-
mides could be, also, performed.
One-pot double cross-coupling protocols for the synthesis of
polysubstituted benzo[b]furans from 2-bromo- and/or 2-chloro-6-
iodo-4-substituted phenols can accomplish the formation of the
target products in about the same overall yield than that obtained
through the stepwise procedure.
a
Reactions were carried out on a 0.37 mmol scale of 3. Reaction condition for step
1: 1.5 equiv of phenylacetylene, 0.025 equiv of Pd2(dba)3 and 0.10 equiv of SPhos,
2 equiv of K3PO4 in 2 mL of 1,4-dioxane at 110 ꢀC. Reaction condition for step 2:
1.5 equiv of boronic acid, 0.02 equiv of Pd2(dba)3 and 0.04 equiv of SPhos, 1.1 equiv
of K3PO4 in 2 mL of 1,4-dioxane at 100 ꢀC.
b
Between step 1 and step 2 an extraction was performed.
Yields refer to single run and are for isolated products.
c
As part of a program devoted to the chemical valorization of
widespread diffused molecules in renewable sources,16 we ex-
tended the one-pot process to the preparation of the poly-
substituted benzo[b]furan derivative 6ha by starting from the 4-(2-
hydroxyethyl)phenol (tyrosol), a naturally occurring bioactive
molecule found in extra virgin olive oil and agricultural wastewa-
ters.34 The described one-pot double cross-coupling procedure was
applied on substrate 3h derived by halogenation reaction of the
selectively protected tyrosol. The expected product 6ha was iso-
lated in 50% overall yield (Scheme 10).
Extension of the one-pot protocol can allow the preparation of
one polysubstituted benzo[b]furans from tyrosol.

A. Arcadi et al. / Tetrahedron 69 (2013) 1857e1871
1863
Table 11
Optimization of the reaction conditions for one-pot synthesis of 10ba
Entry
Catalytic system 1 (equiv)
Catalytic system 2 [molar ratio]
Solvent
Base
T1/T2 (ꢀC)
t1/t2 (h)
Yield % of 10db
1
2
3
4
CuI/
CuI/
CuI/
L
L
L
-proline (0.10:0.20)
-proline (0.10:0.20)
-proline (0.10:0.20)
DMSO
DMSO
1,4-Dioxane
1,4-Dioxane
K2CO3
K2CO3
K2CO3
K3PO4
100:100
120:100
120:100
120:110
4:24
2:24
6:24
6:24
14
18
33
Cu[(phen)(PPh3)2]NO3 (0.10)
d
O
5
1,4-Dioxane
K2CO3
120:120
12:24
15
15
CuI/
(0.10)
COOEt
O
6
1,4-Dioxane
K2CO3
120:120
12:24
COOEt
CuBr/
(0.10/0.20)
7
8
9
CuI/
L
-proline (0.10:0.20)
-proline (0.10:0.20)
Pd2(dba)3/X-Phos (0.025:0.10)
Pd2(dba)3/X-Phos(0.025:0.10)
Pd2(dba)3/X-Phos (0.025:0.10)
Toluene
Toluene
Toluene
NaOBu-t
NaOBu-t
NaOBu-t
120:80
120:80
100:80
2:24
2:24
3:24
27
50c
50c
CuI/
L
Pd2(dba)3/X-Phos (0.025:0.10)
a
Reactions were carried out on a 0.37 mmol scale of 3. Reaction condition for step 1: 1.5 equiv of phenylacetylene, 2 equiv of base in 2 mL of solvent. Reaction condition for
step 2: 10 equiv of piperidine.
b
Yields refer to single run and are for isolated products.
Between step 1 and step 2 an extraction was made before the addition of palladium catalyst and base.
c
4. Experimental section
4.1. General conditions
solution of 2-phenyl-5-methyl-7-chlorobenzo[b]furan 5c (0.100 g,
0.41 mmol), 3-carbomethoxyphenyl boronic acid (0.112 g,
0.62 mmol), Pd2(dba)3 (0.0075 g, 0.0082 mmol), SPhos (0.0067 g,
0.0164 mmol), and K3PO4 (0.261 g,1.23 mmol) in 1,4-dioxane (2 mL)
was stirred at 100 ꢀC for 2 h. After cooling, the reaction mixture was
dried under reduced pressure and the residue was purified by flash
chromatography (SiO2, 50 g; n-hexane/ethyl acetate 90:10 v/v) to
give 6ca (0.133 g, 95%) as a white solid. Mp: 130e131 ꢀC. MS: m/z 365
All the starting materials, catalysts, bases, solvents, and eluents
are commercially available and were used as purchased, without
further purification. 1H NMR (400.13 MHz) and 13C NMR
(100.6 MHz) were recorded with a Bruker Avance 400 spectrome-
ter. Infrared spectra were recorded on a Jasco FT/IR-430 spectro-
(MNaþ); IR (KBr): 3100,1708, 761, 690 cmꢁ1; 1H NMR (CDCl3):
d 8.69
€
photometer. Melting points were determined with a Buchi B-545
(s, 1H), 8.21 (d, J¼8.0 Hz,1H), 8.11 (d, J¼7.6 Hz,1H), 7.89 (d, J¼7.6 Hz,
apparatus and are uncorrected. GCeMS spectra were recorded with
Shimadzu (QP 2010S), LCeMS were recorded with Thermo Fin-
ningan Analyzer Ion Trap LXQ with ESI source.
2H), 7.63 (t, J¼7.6 Hz,1H), 7.47e7.29 (m, 5H), 7.04 (s,1H), 4.02 (s, 3H),
2.54 (s, 3H); 13C NMR (CDCl3):
d 194.3, 167.1, 156.2, 150.4, 136.9,
133.0, 132.8, 130.6, 130.4, 130.3, 129.6, 128.8, 128.7, 128.61, 128.57,
124.9, 123.5, 120.6, 101.2, 52.2, 21.4. Anal. Calcd for C23H18O3: C,
80.68; H, 5.30. Found: C, 80.60; H, 5.31.
4.2. General procedures and methods
4.2.1. General procedure for the copper-catalyzed synthesis of 7-
halobenzo[b]furans (5): synthesis of 7-bromobromo-5-methyl-2-
phenylbenzo[b]furan (5d). A solution of 2-bromo-4-methyl-6-
4.2.3. Procedure for the palladium-catalyzed amination reaction of 7-
halobenzo[b]furans (5b,c,d,e,f,g,j): synthesis of 1-(5-methyl-2-
phenylbenzo[b]furan-7-yl)piperidine (10b). A solution of 2-phenyl-
5-methyl-7-bromobenzo[b]furan 5d (0.100 g, 0.34 mmol),
Pd2(dba)3 (0.0078 g, 0.0085 mmol), X-Phos (0.0162 g, 0.034 mmol),
NaOBu-t (0.065 g, 0.68 mmol), and piperidine (0.337 mL, 3.4 mmol)
in toluene (1 mL) was stirred at 80 ꢀC for 24 h. After cooling, the
reaction mixture was dried under reduced pressure and the residue
was purified by flash chromatography (SiO2, 50 g; n-hexane/ethyl
acetate 85:15 v/v) to give 10b (0.133 g, 99%) as aþyellow solid. Mp
139e140 ꢀC; MS (relative intensity): m/z 291 (M , 100), 235 (13),
207 (17); IR (KBr) 3100, 2921,1596, 765, 690 cmꢁ1; 1H NMR (CDCl3):
iodophenol 3d (0.600 g, 1.92 mmol), CuI (0.036 g, 0.192 mmol), L-
proline (0.044 g, 0.384 mmol), and K3PO4 (0.815 g, 3.84 mmol) in
toluene (6 mL) was added phenylacetylene 4 (0.309 mL, 2.88 mmol)
and the mixture was stirred at 120 ꢀC for 1 h. After cooling, the
reaction mixture was dried under reduced pressure and the residue
was purified by flash chromatography (SiO2, 50 g; n-hexane/ethyl
acetate 98:2 v/v) to give 5d (0.387 g, 70%) as a white soliþd. Mp:
70e71 ꢀC. MS (relative intensity): m/z 288 (Mþ, 100), 286 (M , 100),
207 (52), 178 (46); IR (KBr): 3112, 3033, 2927, 1459, 761 cmꢁ1 1H
;
NMR (CDCl3):
d
7.91 (d, J¼7.6 Hz, 2H), 7.48e7.41 (m, 2H), 7.39 (t,
d
7.87 (d, J¼8.4 Hz, 2H), 7.46 (t, J¼7.6 Hz, 2H), 7.36 (d, J¼7.2 Hz, 1H),
6.98 (s,1H), 6.95 (s,1H), 6.62 (s,1H), 3.37 (br t, J¼5.2 Hz, 4H), 2.43 (s,
3H), 1.91e1.85 (m, 4H), 1.72e1.65 (m, 2H); C NMR (CDCl3): 155.0,
J¼7.2 Hz, 1H), 7.38 (s, 1H), 7.31 (s, 1H), 7.02 (s, 1H), 2.45 (s, 3H); 13C
NMR (CDCl3):
d
156.7, 150.4, 134.1, 130.5, 130.0, 128.9, 128.8, 128.3,
d
125.1, 120.0, 130.2, 101.6, 21.1. Anal. Calcd for C15H11BrO: C, 62.74; H,
3.86; Br, 27.83. Found: C, 62.66; H, 3.87; Br, 27.88.
145.2, 137.8, 133.2, 130.8, 130.3, 128.7, 128.2, 124.8, 113.3, 113.1, 101.5,
51.4, 26.2, 24.6, 21.8. Anal. Calcd for C20H21NO3: C, 82.44; H, 7.26; N,
4.81. Found: C, 82.36; H, 7.27; N, 4.80.
4.2.2. Procedure for the palladium-catalyzed cross-coupling of 7-
chlorobenzo[b]furans (5a,c,e) with arylboronic acids: synthesis of 7-
(3-carbomethoxyphenyl)-5-methyl-2-phenylbenzo[b]furan (6ca). A
4.2.4. Procedure for the palladium-catalyzed cross-coupling of 7-
bromobenzo[b]furans (5d,f,j) with alkynes: synthesis of 5-methyl-2-

1864
A. Arcadi et al. / Tetrahedron 69 (2013) 1857e1871
phenyl-7-(phenylethynyl)benzo[b]furan (7a). A solution of 2-
phenyl-5-methyl-7-bromo[b]furan 5d (0.100 g, 0.34 mmol), phe-
nylacetylene 4 (0.058 mL, 0.53 mmol), Pd2(dba)3 (0.0064 g,
0.007 mmol), [(t-Bu)3PH]BF4 (0.0081 g, 0.028 mmol), and Cs2CO3
(0.125 g, 0.39 mmol) in 1,4-dioxane (1 mL) was stirred at 60 ꢀC for
6 h. After cooling, the reaction mixture was dried under reduced
pressure and the residue was purified by flash chromatography
(SiO2, 50 g; n-hexane/ethyl acetate 95:5 v/v) to give 7a (0.107 g,
99%) as a white solid. Mp: 133e134 ꢀC; MS: m/z 331 (MNaþ); IR
(0.0148 g, 0.031 mmol), phenylacetylene (0.04 mL, 0.37 mmol), and
NaOBu-t (0.089 g, 0.93 mmol) in toluene (1 mL) was stirred at 100 ꢀC
for 3 h. After cooling, the reaction mixture was diluted with Et2O and
washed with water and with brine. The organic layer was dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was dissolved in toluene (2 mL) and piperidine (0.337 mL,
3.4 mmol), Pd2(dba)3 (0.007 g, 0.0078 mmol), X-Phos (0.0148 g,
0.031 mmol), and NaOBu-t (0.059 g, 0.62 mmol) were added. The
mixture was then stirred at 80 ꢀC for 24 h. After cooling, the reaction
mixture was dried under reduced pressure and the residue was
purified by flash chromatography (SiO2, 50 g; n-hexane/ethyl ace-
tate 85:15 v/v) to give 10b (0.045 g, 50%) asþa yellow solid. Mp
139e140 ꢀC; MS (relative intensity): m/z 291 (M ,100), 235 (13), 207
(KBr): 2924, 2362, 1599, 1568, 1489, 1466, 1442 cmꢁ1
(CDCl3):
7.96 (d, J¼7.2 Hz, 2H), 7.76e7.74 (m, 2H), 7.53e7.28 (m,
8H), 6.99 (s, 1H), 2.49 (s, 3H); 13C NMR (CDCl3):
156.5, 153.2, 132.5,
;
1H NMR
d
d
131.9, 130.3, 129.6, 128.9, 128.7, 128.4, 125.1, 123.5, 121.5, 106.9,
101.3, 93.6, 84.3, 21.2. Anal. Calcd for C23H16O: C, 89.58; H, 5.23.
Found: C, 89.65; H, 5.22.
(17); IR (KBr) 3100, 2921, 1596, 765, 690 cmꢁ1
7.87 (d, J¼8.4 Hz, 2H), 7.46 (t, J¼7.6 Hz, 2H), 7.36 (d, J¼7.2 Hz, 1H),
6.98 (s,1H), 6.95 (s,1H), 6.62 (s,1H), 3.37 (br t, J¼5.2 Hz, 4H), 2.43 (s,
3H), 1.91e1.85 (m, 4H), 1.72e1.65 (m, 2H); C NMR (CDCl3): 155.0,
;
1H NMR (CDCl3):
d
4.2.5. Procedure for the palladium-catalyzed Heck reaction of 7-
bromobenzo[b]furans 5d with alkenes: synthesis of 5-methyl-2-
phenyl-7-(2-phenylethenyl)benzo[b]furan (9a). A solution of 2-
phenyl-5-methyl-7-bromo[b]furan 5d (0.100 g, 0.34 mmol), sty-
rene (0.060 mL, 0.53 mmol), Pd2(dba)3 (0.0064 g, 0.007 mmol), [(t-
Bu)3PH]BF4 (0.0081 g, 0.028 mmol), and Cs2CO3 (0.125 g,
0.39 mmol) in 1,4-dioxane (1 mL) was stirred at 110 ꢀC for 48 h.
After cooling, the reaction mixture was dried under reduced pres-
sure and the residue was purified by flash chromatography (SiO2,
50 g; n-hexane/ethyl acetate 90:10 v/v) to give 9a (0.068 g, 63%) as
white solid. Mp: 118e120 ꢀC. MS: m/z 333 (MNaþ); IR (KBr): 2922,
d
145.2, 137.8, 133.2, 130.8, 130.3, 128.7, 128.2, 124.8, 113.3,113.1, 101.5,
51.4, 26.2, 24.6, 21.8. Anal. Calcd for C20H21NO3: C, 82.44; H, 7.26; N,
4.81. Found: C, 81.95; H, 7.28; N, 4.78.
4.3. Characterization
4.3.1. 2-Chloro-4-phenylphenol (2a). White solid. Mp: 80e81 ꢀC.
MS (relative intensity): m/z 206 (Mþ, 32), 204 (Mþ, 100), 128 (22),
91 (26); IR (KBr): 3288, 3030, 1515, 1450, 1278, 761 cmꢁ1; 1H NMR
(CDCl3):
3H), 7.37e7.34 (m, 1H), 7.11 (d, 1H), 5.58 (s, 1H); 13C NMR (CDCl3):
150.7, 139.6, 135.0, 128.9, 127.5, 127.3, 127.1, 126.7, 120.3, 116.5.
d
7.59 (d, J¼2.0 Hz, 1H), 7.55e7.53 (m, 2H), 7.47e7.43 (m,
1597, 1564, 1493, 1444 cmꢁ1
2H), 7.69 (d, J¼7.6 Hz, 3H), 7.53e7.27 (m, 9H), 7.01 (s, 1H), 2.51 (s,
3H); 13C NMR (CDCl3):
156.0, 150.9, 137.9, 132.7, 131.6, 130.6, 129.9,
;
1H NMR (CDCl3):
d
7.95 (d, J¼7.6 Hz,
d
d
Anal. Calcd for C12H9ClO: C, 70.43; H, 4.43; Cl, 17.32. Found: C,
70.48; H, 4.42; Cl, 17.39.
128.8, 128.7, 128.5, 127.7, 126.7, 124.9, 124.6, 123.7, 121.5, 120.1, 101.3,
21.4. Anal. Calcd for C23H18O: C, 89.00; H, 5.85. Found: C, 88.92; H,
5.86.
4.3.2. 2-Bromo-4-phenylphenol (2b). White solid. Mp: 94e96 ꢀC.
MS (relative intensity): m/z 250 (Mþ, 92), 248 (Mþ, 90), 77 (21); IR
4.2.6. One-pot procedure for palladium-catalyzed alkynylation/cy-
clization reaction and functionalization at C(7) position via Suzu-
kieMiyaura cross-coupling: synthesis of 7-(3-carbomethoxyphenyl)-
5-methyl-2-phenylbenzo[b]furan (6ca). A solution of 2-bromo-4-
methyl-6-iodophenol 3d (0.100 g, 0.37 mmol), Pd2(dba)3
(0.0085 g, 0.0093 mmol), SPhos (0.015 g, 0.037 mmol), phenyl-
acetylene (0.047 mL, 0.44 mmol), and K3PO4 (0.157 g, 0.74 mmol) in
1,4-dioxane (2 mL) was stirred at 110 ꢀC for 3 h. After cooling, the
reaction mixture was diluted with Et2O and washed with water and
with brine. The organic layer was dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was dissolved in
1,4-dioxane (2 mL) and 3-carbomethoxyphenyl boronic acid
(0.099 g, 0.55 mmol), Pd2(dba)3 (0.007 g, 0.0074 mmol), SPhos
(0.0061 g, 0.0148 mmol), and K3PO4 (0.235 g, 1.10 mmol) were
added and the obtained solution was stirred at 100 ꢀC for 4 h. After
cooling, the reaction mixture was dried under reduced pressure
and the residue was purified by flash chromatography (SiO2, 50 g;
n-hexane/ethyl acetate 90:10 v/v) to give 6ca (0.076 g, 60%) as
a white solid. Mp: 130e131 ꢀC. MS: m/z 365 (MNaþ); IR (KBr): 3100,
(KBr) 3293, 3039, 1450, 761 cmꢁ1; 1H NMR (CDCl3):
d
7.73 (d, J¼2 Hz,
1H), 7.54e7.52 (m, 2H), 7.46e7.41 (m, 3H), 7.36 (t, J¼7.2 Hz, 1H), 7.12
(d, J¼8.4 Hz, 1H), 5.56 (s, 1H); 13C NMR (CDCl3):
d 151.7, 139.4, 135.4,
130.5, 128.9,128.0, 127.2, 126.7,116.3,110.7. Anal. Calcd for C12H9BrO:
C, 57.86; H, 3.64; Br, 32.08. Found: C, 57.94; H, 3.63, Br, 32.01.
4.3.3. 2-Chloro-6-iodo-4-methylphenol (3c). Yellow oil. MS (relative
intensity): m/z 270 (Mþ, 32), 268 (Mþ, 100), 233 (23), 142 (10), 77
(89); IR (KBr): 3488, 2921, 2360, 1471, 1160, 779 cmꢁ1 1H NMR
;
(CDCl3):
d
7.46 (d, J¼1.2 Hz,1H), 7.15 (d, J¼1.2 Hz,1H), 5.78 (br s,1H),
2.26 (s, 3H); 13C NMR (CDCl3):
d
163.6, 148.6, 138.0, 132.7, 130.1, 83.1,
19.9. Anal. Calcd for C7H6ClIO: C, 31.32; H, 2.25; Cl, 13.21. Found: C,
31.25; H, 2.24; Cl, 13.16.
4.3.4. 2-Chloro-4-fluorophenol (2e). Yellow oil. MS (relative in-
tensity): m/z 148 (Mþ, 32), 146 (Mþ, 100), 111 (20), 83 (35); IR (KBr):
3430, 2927, 1114 cmꢁ1
;
1H NMR (CDCl3):
d
7.1 (dd, J1¼7.6 Hz,
J2¼2.8 Hz, 1H), 6.99e6.90 (m, 2H), 5.46 (s, 1H); 13C NMR (CDCl3):
d
156.9 (d, JCeF¼248 Hz), 149.0, 125.9, 118.9, 118.2 (d, JCeF¼22 Hz),
1708, 761, 690 cmꢁ1
;
1H NMR (CDCl3):
d
8.69 (s, 1H), 8.21 (d,
115.0 (d, JCeF¼20 Hz). Anal. Calcd for C6H4ClFO: C, 76.57; H, 6.43; Cl,
J¼8.0 Hz, 1H), 8.11 (d, J¼7.6 Hz, 1H), 7.89 (d, J¼7.6 Hz, 2H), 7.63 (t,
24.19. Found: C, 76.65; H, 6.42; Cl, 24.26.
J¼7.6 Hz, 1H), 7.47e7.29 (m, 5H), 7.04 (s, 1H), 4.02 (s, 3H), 2.54 (s,
3H); 13C NMR (CDCl3):
d
194.3, 167.1, 156.2, 150.4, 136.9, 133.0, 132.8,
4.3.5. 2-Bromo-4-fluorophenol (2f). White solid. Mp: 43e45 ꢀC. MS
(relative intensity): m/z 191 (Mþ, 100), 189 (Mþ, 100), 111 (13); IR
130.6, 130.4, 130.3, 129.6, 128.8, 128.7, 128.61, 128.57, 124.9, 123.5,
120.6, 101.2, 52.2, 21.4. Anal. Calcd for C23H18O3: C, 80.68; H, 5.30.
Found: C, 80.60; H, 5.31.
(KBr): 3519, 3076, 1198, 768 cmꢁ1 1H NMR (CDCl3):
; d 7.23 (dd,
J1¼7.6 Hz, J2¼2.8 Hz, 1H), 7.00e6.97 (m, 2H), 5.37 (s, OH); 13C NMR
(CDCl3):
d
155.7 (d, JCeF¼248 Hz), 149.2, 122.1 (d, JCeF¼22.0 Hz),
4.2.7. One-pot for palladium-catalyzed alkynylation/cyclization re-
action and functionalization at C(7) position via CeN bond forming
reactions: synthesis of 1-(5-methyl-2-phenylbenzo[b]furan-7-yl)pi-
peridine (10b). A solution of 2-bromo-4-methyl-6-iodophenol 3d
(0.100 g, 0.31 mmol), Pd2(dba)3 (0.007 g, 0.0078 mmol), X-Phos
117.4, 116.0 (d, JCeF¼20.0 Hz), 114.8. Anal. Calcd for C6H4BrFO: C,
37.73; H, 2.11; Br, 41.84. Found: C, 37.65; H, 2.12; Br, 41.91.
4.3.6. 3-Chloro-4-hydroxyphenethyl methyl carbonaþte (2g). White
solid. Mp: 79e80 ꢀC. MS: m/z 255 (MþNa), 253 (M Na); IR (KBr):

A. Arcadi et al. / Tetrahedron 69 (2013) 1857e1871
1865
3370, 3079, 2954,1718, 1278, 792; 1H NMR (CDCl3):
d
7.18 (d, J¼2 Hz
C20H13ClO4: C, 78.82; H, 4.30; Cl, 11.63. Found: C, 78.74; H, 4.31; Cl,
11.58.
1H), 7.02 (dd, J1¼8 Hz, J2¼2 Hz, 1H), 6.93 (d, J¼8 Hz, 1H), 5.99 (br s,
OH), 4.30 (t, J¼7.2 Hz, 2H), 3.77 (s, 3H), 2.88 (t, J¼7.2 Hz, 2H); 13C
NMR (CDCl3):
d
155.8, 150.3, 130.4, 129.4, 128.8, 119.8, 116.4, 68.2,
4.3.14. 7-Bromo-2,5-diphenylbenzo[b]furan (5b). White solid. Mp:
123e125 ꢀC. MS (relative intensity): m/z 350 (Mþ, 100), 348 (Mþ,
54.8, 34.0. Anal. Calcd for C10H11ClO4: C, 52.07; H, 4.81; Cl, 15.37.
Found: C, 76.15; H, 4.80; Cl, 15.29.
100), 77 (43); IR (KBr): 3060, 2930, 1577, 1457, 1234,1141, 761 cmꢁ1
;
1H NMR (CDCl3):
7.63e7.61 (m, 2H), 7.50e7.47 (m, 4H), 7.41e7.39 (m, 2H), 7.11 (s,1H);
13C NMR (CDCl3):
157.3, 151.5, 140.4, 138.3, 130.8, 129.8, 129.1,
d
7.94 (d, J¼8.0 Hz, 2H), 7.71e7.69 (m, 2H),
4.3.7. 3-Chloro-5-iodobiphenyl-4-ol
(3a). Wþhite
solid.
Mp:
90e91 ꢀC. MS (relative intensity): m/z 332 (M , 16), 330 (Mþ, 42),
d
253 (25), 205 (100), 207 (83), 73 (100); IR (KBr): 3480, 1552, 1471,
128.9, 127.4, 127.3, 126.8, 125.2, 118.5, 104.0, 102.0, 29.8. Anal. Calcd
for C20H13BrO: C, 68.79; H, 3.75; Br, 22.88. Found: C, 68.88; H, 3.74;
Br, 22.80.
1286, 1166, 757 cmꢁ1; 1H NMR (CDCl3):
d
7.87 (d, J¼2 Hz, 1H), 7.57
(d, J¼2 Hz, 1H), 7.50e7.48 (m, 2H), 7.45e7.43 (m, 2H), 7.37e7.35 (m,
1H), 5.96 (br s, 1H); 13C NMR (CDCl3):
150.2, 138.1, 136.5, 136.3,
d
129.0, 128.3, 127.7, 126.7, 119.3, 83.9. Anal. Calcd for C12H8ClIO: C,
43.60; H, 2.44; Cl, 10.73. Found: C, 43.51; H, 2.43; Cl, 10.68.
4.3.15. 7-Chloro-5-methyl-2-phenylbenzo[b]furan (5c). White solid.
Mp: 123e124 ꢀC. MS (relative intensity): m/z 244 (Mþ, 32), 242
(Mþ, 100), 207 (36), 77 (14); IR (KBr): 3112, 2927, 1463, 763 cmꢁ1
;
4.3.8. 3-Bromo-5-iodobiphenyl-4-ol
(3b). White
solid. þ Mp:
1H NMR (CDCl3):
d
7.91 (d, J¼8.0 Hz, 2H), 7.48e7.45 (m, 2H), 7.39 (t,
80e81 ꢀC. MS (relative intensity): m/z 376 (Mþ, 100), 375 (M , 100),
J¼7.2 Hz, 1H), 7.27 (s, 1H), 7.13 (s, 1H), 6.98 (s, 1H), 2.45 (s, 3H); 13C
168 (26); IR (KBr): 3438, 3060, 2970, 1459, 1284, 767 cmꢁ1; 1H NMR
NMR (CDCl3): d 194.3, 156.9, 149.0, 133.7, 130.8, 130.0, 128.8, 125.5,
(CDCl3):
d
7.91 (d, J¼2 Hz, 1H), 7.72 (d, J¼2 Hz, 1H), 7.52e7.35 (m,
125.1, 119.3, 115.9, 101.5, 21.2. Anal. Calcd for C15H11ClO: C, 74.23; H,
4.57; Cl, 14.61. Found: C, 74.15; H, 4.58; Cl, 14.55.
5H), 5.9 (s, 1H); 13C NMR (CDCl3):
d
150.8, 139.3, 137.98, 137.0, 131.3,
128.9, 127.7, 126.8, 109.0, 83.5. Anal. Calcd for C12H8BrIO: C, 38.43;
H, 2.15; Br, 21.31. Found: C, 38.35; H, 2.16; Br, 21.25.
4.3.16. 7-Chloro-5-fluoro-2-phenylbþenzo[b]furan (5e). White solid.
Mp: 74e75 ꢀC. MS: m/z 269 (MNa ), 267 (MNaþ); IR (KBr): 1631,
4.3.9. 2-Bromo-6-iodo-4-methylphenol (3d). þYellow solid.þ Mp:
52e53 ꢀC. MS (relative intensity): m/z 311 (M , 100), 313 (M , 98),
1471, 1193, 728 cmꢁ1
;
1H NMR (CDCl3):
d
7.91 (d, J¼8 Hz, 2H),
7.50e7.47 (m, 2H), 7.43e7.40 (m, 1H), 7.17 (dd, J1¼8.4 Hz, J2¼2.4 Hz,
233 (38), 185 (30), 106 (29); IR (KBr): 3400, 2940, 1467, 721 cmꢁ1
;
1H), 7.10 (dd, J1¼8.4 Hz, J2¼2.4 Hz, 1H), 7.03 (s, 1H); 13C NMR
1H NMR (CDCl3):
(br s, 1H), 2.26 (s, 3H); 13C NMR (CDCl3):
d
7.50 (d, J¼1.2 Hz, 1H), 7.30 (d, J¼1.2 Hz, 1H), 5.78
(CDCl3):
d
158.0 (d, JCeF¼240 Hz), 157.5, 146.3, 129.8, 128.5, 128.4,
d
149.3, 138.8, 134.1, 133.1,
127, 124.3, 115.8 (d, JCeF¼12 Hz), 111.5 (d, JCeF¼29 Hz), 104.1 (d,
JCeF¼25 Hz), 100.9. Anal. Calcd for C14H8ClFO: C, 68.17; H, 3.27; Cl,
14.37. Found: C, 68.09; H, 3.28; Cl, 14.30.
108.0, 82.8, 19.7. Anal. Calcd for C7H6BrIO: C, 26.87; H, 1.93; Br,
25.83. Found: C, 26.80; H, 1.94; Br, 25.78.
4.3.10. 2-Chloro-4-fluoro-6-iodophenol (3e). Brown oil. MS (relative
intensity): m/z 273 (Mþ, 34), 271 (Mþ, 100), 145 (13), 127 (38), 91
4.3.17. 7-Bromo-5-fluoro-2-phenylbþenzo[b]furan (5f). White solid.
Mp: 59e60 ꢀC. MS: m/z 313 (MNa ), 311 (MNaþ); IR (KBr): 3087,
(10); IR (KBr): 3519, 3081, 1594, 1467, 1197, 784 cmꢁ1
;
1H NMR
2927, 1631, 1577, 1469, 1193, 755 cmꢁ1
;
1H NMR (CDCl3):
d
7.90 (d,
J¼7.2 Hz, 2H), 7.50e7.47 (m, 2H), 7.42e7.40 (m, 1H), 7.23 (m, 2H),
7.06 (s, 1H); 13C NMR (CDCl3):
(CDCl3):
d
7.40 (dd, J1¼7.6 Hz, J2¼2.8 Hz, 1H), 7.15 (dd, J1¼7.6 Hz,
J2¼2.8 Hz, 1H), 5.67 (br s, 1H); 13C NMR (CDCl3):
d
155.8 (d,
d
162.0 (d, JCeF¼240 Hz), 161.3, 151.6,
JCeF¼247 Hz), 147.9, 124.5 (d, 24 Hz), 118.6, 116.9 (d, 26 Hz), 82.3.
Anal. Calcd for C6H3ClFIO: C, 26.45; H, 1.11; Cl, 13.01. Found: C,
26.54; H, 1.12, Cl, 13.07.
133.2, 132.4, 132.2, 131.8, 128.1, 118.1 (d, JCeF¼29 Hz), 108.6 (d,
JCeF¼25 Hz), 106.4 (d, JCeF¼12 Hz), 104.8 (d, JCeF¼4 Hz). Anal. Calcd
for C14H8BrO: C, 57.76; H, 2.77; Br, 27.45. Found: C, 57.82; H, 2.78; Br,
27.51.
4.3.11. 2-Bromo-4-fluoro-6-iodophenol (3f). Brown solid. þ Mp:
48e50 ꢀC. MS (relative intensity): m/z 315 (Mþ, 100), 317 (M , 99),
4.3.18. 7-Chloro-2-pentyl-5-phenylbenzo[b]furan þ(5g). White solid.
Mp: 58e59 ꢀC. MS: m/z 321 (MNaþ), 319 (MNa ); IR (KBr): 2929,
110 (29); IR (KBr): 3461, 1637, 1463, 727 cmꢁ1 1H NMR (CDCl3):
;
d
7.45 (dd, J1¼7.6 Hz, J2¼2.8 Hz, 1H), 7.29 (dd, J1¼7.6 Hz, J2¼2.8 Hz,
1597, 1572, 1462, 1444 cmꢁ1; 1H NMR (CDCl3):
d 7.63e7.59 (m, 3H),
1H), 5.74 (br s, 1H); 13C NMR (CDCl3):
d
155.9 (d, JCeF¼248 Hz),
7.50e7.46 (m, 3H), 7.41e7.37 (m, 1H), 6.49 (s, 1H), 2.85 (t, J¼7.6 Hz,
148.6, 125.1 (d, JCeF¼22 Hz), 119.7 (d, JCeF¼20 Hz), 107.5, 83.9. Anal.
Calcd for C6H3BrFIO: C, 22.74; H, 0.95; Br, 25.21. Found: C, 22.82; H,
0.94; Br, 25.16.
2H), 1.85e1.79 (m, 2H), 1.47e1.43 (m, 4H), 0.97 (t, J¼8 Hz, 3H); 13C
NMR (CDCl3):
d 161.6, 149.9, 140.7, 137.4, 131.1, 128.8, 127.4, 127.2,
122.8, 117.3, 116.2, 102.7, 31.4, 28.5, 27.3, 22.4, 14.0. Anal. Calcd for
C19H19ClO: C, 76.37; H, 6.41; Cl, 11.86. Found: C, 76.45; H, 6.42; Cl,
11.80.
4.3.12. 3-Chloro-4-hydroxy-5-iodophenethyl
(3g). White solid. Mp: 80e81 ꢀC. MS: m/z 381 (MNaþ), 379 (MNaþ);
IR (KBr): 3400, 3006, 2954, 1741, 1457, 1282, 956 cmꢁ1 1H NMR
methyl
carbonate
;
4.3.19. 7-Chloro-5-methyl-2-phenethylbenzo[b]furan (5h). Yellow
oil. MS: m/z 293 (MNaþ), 291 (MNaþ); IR (KBr): 2924, 1601, 1473,
(CDCl3):
d
7.51 (d, J¼2.0 Hz, 1H), 7.22 (d, J¼2.0 Hz, 1H), 6.01 (br s,
1H), 4.29 (t, J¼7.2 Hz, 2H), 3.79 (s, 3H), 2.86 (t, J¼7.2 Hz, 2H); 13C
1456 cmꢁ1; 1H NMR (CDCl3):
d
7.34e7.24 (m, 5H), 7.16 (s, 1H), 7.07
(s, 1H), 6.33 (s, 1H), 3.13e3.11 (m, 4H), 2.42 (s, 3H); 13C NMR
(CDCl3): 159.6, 148.7, 140.7, 133.2, 130.5, 128.5, 128.4, 126.2, 124.5,
NMR (CDCl3):
d 155.6, 149.7, 138.0, 123.2, 130.1, 119.0, 83.6, 67.8,
54.9, 33.5. Anal. Calcd for C10H10ClIO4: C, 33.69; H, 2.83; Cl, 9.94.
Found: C, 33.60; H, 2.84; Cl, 9.89.
d
118.9, 115.5, 102.8, 33.8, 30.2, 21.1. Anal. Calcd for C17H15ClO: C,
75.41; H, 5.58; Cl, 13.09. Found: C, 75.50; H, 5.59; Cl, 13.02.
4.3.13. 7-Chloro-2,5-diphenylbeþnzo[b]furan (5a). White solid. Mp:
120e122 ꢀC. MS: m/z 327 (MNa ), 325 (MNaþ); IR (KBr): 3112, 2913,
4.3.20. 2-(7-Chloro-2-phenylbenzo[b]furan-5-yl)ethyl
acetate
2848, 1461, 1145, 763 cmꢁ1
;
1H NMR (CDCl3):
d
7.95 (d, J¼7.2 Hz,
(5i). White solid. Mp: 103e104 ꢀC. MS (relative intensity): m/z
2H), 7.68 (d, J¼1.2 Hz, 1H), 7.63 (d, J¼7.2 Hz, 2H), 7.54 (d, J¼1.2 Hz,
256 (Mþ, 27), 254 (100), 78 (26); IR (KBr): 3073, 2954, 1747, 1467,
1H), 7.50e7.47 (m, 4H), 7.40e7.38 (m, 2H), 7.11 (s, 1H); 13C NMR
1265, 734 cmꢁ1; 1H NMR (CDCl3):
d
7.90 (d, J¼7.2 Hz, 2H), 7.48 (m,
(CDCl3):
d
157.4, 150.1, 140.5, 137.9, 131.2, 129.8, 129.7, 128.9, 128.7,
2H), 7.4 (t, J¼7.6 Hz, 1H), 7.34 (s, 1H), 7.18 (s, 1H), 7.00 (s, 1H), 4.40
128.5, 127.4, 125.2, 124.0, 117.9, 116.7, 101.9. Anal. Calcd for
(t, J¼6.8 Hz, 2H), 3.8 (s, 3H), 3.06 (t, J¼6.8 Hz, 2H); 13C NMR

1866
A. Arcadi et al. / Tetrahedron 69 (2013) 1857e1871
(CDCl3):
d
157.2, 155.7, 149.7, 139.7, 133.3, 131.0, 129.8, 129.0,
2927, 1600, 1467, 1228, 786, 762 cmꢁ1 1H NMR (CDCl3):
; d 8.15
128.8, 125.1, 119.5, 116.4, 101.5, 68.4, 54.8, 34.9. Anal. Calcd for
C18H15ClO3: C, 68.68; H, 4.80; Cl, 11.26. Found: C, 68.59; H, 4.79;
Cl, 11.19.
(dd, J1¼2.8 Hz, J2¼1.2 Hz, 1H), 7.96e7.94 (m, 2H), 7.86 (dd,
J1¼4.0 Hz, J2¼1.2 Hz, 1H), 7.81 (d, J¼1.6 Hz, 1H), 7.73e7.71 (m,
3H), 7.55e7.51 (m, 5H), 7.45e7.41 (m, 2H), 7.12 (s, 1H); 13C NMR
(CDCl3):
d 156.6, 151.3, 141.7, 137.2, 136.8, 130.6, 130.3, 128.9,
4.3.21. 7-Bromo-2-(4-methoxyphenyl)-5-methylbenzo[b]furan
(5j). White solid. Mp: 133e135 ꢀC. MS: m/z 339 (MNaþ), 337
(MNaþ); IR (KBr): 2960, 1610, 1577, 1504, 1464, 1254, 1036 cmꢁ1; 1H
128.8, 128.7, 127.6, 127.1, 125.6, 125.1, 123.3, 122.1, 120.1, 118.3,
101.8. Anal. Calcd for C24H16OS: C, 81.79; H, 4.58. Found: C, 81.70;
H, 4.59.
NMR (CDCl3):
d
7.84 (d, J¼8.8 Hz, 2H), 7.27e7.25 (m, 2H), 7.01 (d,
J¼8.8 Hz, 2H), 6.87 (s, 1H), 3.89 (s, 3H), 2.44 (s, 3H); 13C NMR
4.3.28. 7-(4-Methoxyphenyl)-5-methyl-2-phenylbenzo[b]furan
(6cb). White solid. Mp: 127e128 ꢀC. MS: m/z 337 (MNaþ); IR (KBr):
3060, 2941, 1608, 1513, 1384, 1245, 833, 746 cmꢁ1; 1H NMR (CDCl3):
(CDCl3):
d 160.3, 156.9, 150.2, 134.0, 129.8, 127.7, 122.8, 119.7, 115.7,
114.3, 103.1, 100.0, 55.4, 21.1. Anal. Calcd for C16H13BrO2: C, 60.59; H,
4.13; Br, 25.19. Found: C, 60.50; H, 4.14; Br, 25.12.
d
7.95e7.87 (m, 4H), 7.50e7.35 (m, 5H), 7.13e7.04 (m, 3H), 3.94 (s,
3H), 2.53 (s, 3H); 13C NMR (CDCl3):
d
159.2,156.0,150.4,132.8,130.6,
4.3.22. 1-(7-Bromo-5-phenylbenzo[b]furan-2-yl)-1-phenylethanol
(5k). White-yellow. Mp: 45e47 ꢀC. MS: m/z 417 (MNaþ), 415
(MNaþ); IR (KBr): 3408, 2925,1572,1493, 1460, 1444 cmꢁ1; 1H NMR
130.1, 129.6, 129.5, 129.1, 128.7, 128.4, 124.9, 124.7, 119.4, 114.1, 101.2,
55.3, 21.4. Anal. Calcd for C22H18O2: C, 84.05; H, 5.77. Found: C,
84.14; H, 5.78.
(CDCl3):
d
7.69e7.66 (m, 2H), 7.62e7.36 (m, 10H), 6.73 (s, 1H), 3.65
163.1, 151.6, 144.7, 140.4,
(br s, 1H), 2.06 (s, 3H); 13C NMR (CDCl3):
d
4.3.29. 7-(4-Methoxyphenyl)-5-methyl-2-phenylbenzo[b]furan
(6cb). White solid. Mp: 127e128 ꢀC. MS: m/z 337 (MNaþ); IR (KBr):
3060, 2941, 1608, 1513, 1384, 1245, 833, 746 cmꢁ1; 1H NMR (CDCl3):
138.3, 129.8, 128.9, 128.4, 127.8, 127.5, 126.9, 125.4, 118.9, 110.1,
104.2, 104.1, 73.5, 29.1. Anal. Calcd for C22H17BrO2: C, 67.19; H, 4.36;
Br, 20.32. Found: C, 67.10; H, 4.37; Br, 20.25.
d
7.95e7.87 (m, 4H), 7.50e7.35 (m, 5H), 7.13e7.04 (m, 3H), 3.94 (s,
3H), 2.53 (s, 3H); 13C NMR (CDCl3):
d
159.2,156.0,150.4,132.8,130.6,
4.3.23. Methyl 3-(2,5-diphenylbenzo[b]furaþn-7-yl)benzoate (6aa). White
solid. Mp: 143e145 ꢀC. MS: m/z 427 (MNa ); IR (KBr): 3112, 2954, 1712,
130.1, 129.6, 129.5, 129.1, 128.7, 128.4, 124.9, 124.7, 119.4, 114.1, 101.2,
55.3, 21.4. Anal. Calcd for C22H18O2: C, 84.05; H, 5.77. Found: C,
84.14; H, 5.78.
1297, 1218, 756 cmꢁ1; 1H NMR (CDCl3):
d
8.74 (s, 1H), 8.25 (d, J¼7.6 Hz,
1H), 8.16 (d, J¼8.0 Hz, 1H), 7.93e7.91 (m, 2H), 7.80 (d, J¼2 Hz, 1H),
7.75e7.65 (m, 4H), 7.54e7.48 (m, 4H), 7.43e7.40 (m, 2H), 7.153 (s, 1H),
4.3.30. 7-(4-Fluoro-3-methylphenyl)-5-methyl-2-phenylbenzoþ[b]fu-
4.02 (s, 3H); 13C NMR (CDCl3):
d
167.1, 156.8, 151.6, 141.5, 137.4, 136.7,
ran (6cd). White solid. Mp: 81e82 ꢀC. MS: m/z 334 (MNa ); IR
132.9, 130.7, 130.2, 129.7, 128.9, 128.83, 128.81, 128.77, 127.5, 127.1, 125.0,
124.1, 124.1, 123.5, 123.4, 119.1, 101.6, 52.2. Anal. Calcd for C28H20O3: C,
83.15; H, 4.98. Found: C, 83.23; H, 4.99.
(KBr): 3033, 2927, 1617, 1508, 1238, 746 cmꢁ1 1H NMR (CDCl3):
;
d
7.89 (d, J¼7.6 Hz, 2H), 7.79 (d, J¼6.8 Hz, 2H), 7.51e7.48 (m, 2H),
7.42e7.37 (m, 2H), 7.27e7.21 (m, 2H), 7.03 (s, 1H), 2.55 (s, 3H),
2.48 (s, 3H); 13C NMR (CDCl3):
d
161.3 (d, JCeF¼245 Hz), 156.1,
4.3.24. 7-(4-Methoxyphenyl)-2,5-diphenylbenzo[b]furan
150.4, 132.9, 132.4, 131.6, 130.5, 130.1, 128.8, 128.5, 127.6, 127.5,
125.0, 124.9, 123.9, 119.9, 115.1 (d, JCeF¼22 Hz), 101.3, 21.4, 14.8.
Anal. Calcd for C22H17FO: C, 83.52; H, 5.42. Found: C, 83.45; H,
5.41.
(6ab). White solid. Mp: 137e138 ꢀC. MS: m/z 399 (MNaþ); IR (KBr):
3006, 2821, 1606, 1513, 1461, 1243, 1180, 752 cmꢁ1 1H NMR
;
(CDCl3):
7.53e7.48 (m, 4H), 7.42e7.37 (m, 2H), 7.16e7.13 (m, 3H), 3.95 (s,
3H); 13C NMR (CDCl3):
159.4, 156.6, 151.6, 141.8, 137.3, 130.6, 130.4,
d
7.97 (d, J¼8 Hz, 2H), 7.93e7.91 (m, 2H), 7.74e7.68 (m, 4H),
d
4.3.31. 5-Methyl-2-phenyl-7-(thiophen-3-yl)benzo[b]furan (6ce). White
solid. Mp: 107.5e108.5 ꢀC. MS: m/z 313 (MNaþ); IR (KBr): 2921, 1606,
128.9, 128,82, 128.79, 128.6, 127.5, 126.9, 125.0, 123.2, 117.98, 114.2,
101.6, 55.4. Anal. Calcd for C27H20O2: C, 86.14; H, 5.36. Found: C,
86.23; H, 5.37.
1384, 1203, 783, 762 cmꢁ1
;
1H NMR (CDCl3):
d
8.11e8.10 (m, 1H),
7.94e7.92 (m, 2H), 7.82e7.81 (m, 1H), 7.54e7.34 (m, 6H), 7.03 (s,
1H), 2.54 (s, 3H); 13C NMR (CDCl3):
156.1, 150.2, 148.2, 132.8,
d
4.3.25. 7-(Biphenyl-4-yl)-2,5-diphenylbenzo[b]furan (6ac). White
solid. Mp: 181e183 ꢀC. MS: m/z 445 (MNaþ); IR (KBr): 3033, 2940,
130.5, 128.8, 128.5, 127.0, 125.4, 124.9, 123.9, 122.9, 119.7, 119.4,
101.4, 21.5. Anal. Calcd for C19H14OS: C, 78.59; H, 4.86. Found: C, 78.50;
H, 4.87.
2861, 1604. 1446, 1218, 762 cmꢁ1 1H NMR (CDCl3):
; d 8.4 (d,
J¼8.0 Hz, 2H), 7.95 (d, J¼7.2 Hz, 2H), 7.85 (d, J¼8.0 Hz, 2H),
7.80e7.74 (m, 8H), 7.54e7.42 (m, 9H), 7.17 (s, 1H); 13C NMR (CDCl3):
4.3.32. Methyl 3-(5-fluoro-2-phenylbenzo[b]furan-7-yl)benzoate (6ea).
White solid. Mp: 111e112 ꢀC. MS: m/z 369 (MNaþ); IR (KBr):
d
159.7, 151.8, 141.7, 140.8, 140.6, 137.4, 135.5, 130.7, 130.3, 129.0,
128.89, 128.86, 128.85, 128.76, 128.5, 127.5, 127.4, 127.2, 127.1, 125.0,
123.9, 123.6, 118.7, 101.7. Anal. Calcd for C32H22O: C, 90.97; H, 5.25.
Found: C, 90.89; H, 5.26.
3060, 2940, 1730, 1606, 1473, 1448, 1400, 1294, 752 cmꢁ1 1H
;
NMR (CDCl3):
J¼7.2 Hz, 2H), 7.65 (t, J¼7.6 Hz, 1H), 7.50e7.38 (m, 3H), 7.27e7.25
(m, 2H), 7.07 (s, 1H), 4.02 (s, 3H); 13C NMR (CDCl3):
166.9,
d
8.68 (s, 1H), 8.15 (t, J¼7.6 Hz, 2H), 7.87 (d,
d
4.3.26. 7-(4-Fluoro-3-methylphenyl)-2,5-diphenylbenzo[b]furan
(6ad). White solid. Mp: 126e127 ꢀC. MS (relative intensity): m/z
378 (Mþ, 100), 364 (19), 301 (23), 108 (16), 77 (17); IR (KBr): 3046,
159.5 (d, JCeF¼237 Hz), 157.8, 148.2, 138.8, 136.8, 135.7, 132.7,
129.9, 129.2, 129.0, 128.9, 128.8, 128.5, 125.0, 111.1 (d,
JCeF¼26 Hz), 105.9 (d, JCeF¼25 Hz), 101.6 (d, JCeF¼4 Hz), 52.3.
Anal. Calcd for C22H15FO: C, 76.29; H, 4.37. Found: C, 76.20; H,
4.38.
2927, 1504, 1465, 1234, 756 cmꢁ1
;
1H NMR (CDCl3):
d
9.32e9.07
(m, 8H), 8.93e8.83 (m, 6H), 8.69e8.63 (m, 1H), 8.55 (s, 1H), 3.88
(s, 3H); 13C NMR (CDCl3):
d
160.4 (d, JCeF¼245 Hz), 156.6, 151.5,
141.6, 137.2, 132.2, 131.7, 130.6, 130.3, 128.8, 128.7, 127.7, 127.6,
127.5, 127.0, 125.1, 125.0, 124.5, 123.4, 118.4, 115.2 (d, JCeF¼22 Hz),
101.7, 14.8. Anal. Calcd for C27H19FO: C, 85.69; H, 5.06. Found: C,
85.78; H, 5.07.
4.3.33. 5-Fluoro-7-(4-methoxyphenyl)-2-phenylbenzo[b]furan
(6eb). White solid. Mp: 90e92 ꢀC. MS: m/z 341 (MNaþ); IR (KBr):
2923,1600,1517,1469,1390,1290,1180, 761 cmꢁ1; 1H NMR (CDCl3):
d
7.93e7.86 (m, J1¼4 Hz), 7.51e7.39 (m, 3H), 7.21e7.12 (m, 4H), 7.04
(s, 1H), 3.94 (s, 3H); 13C NMR (CDCl3):
d
160.0 (d, JCeF¼237 Hz),
4.3.27. 2,5-Diphenyl-7-(thiophen-3-yl)benzo[b]fþuran (6ae). White
solid. Mp: 136e137 ꢀC. MS: m/z 375 (MNa ); IR (KBr): 3033,
159.7, 157.5, 148.2, 130.7, 130.1, 129.7, 128.8, 128.0, 127.5, 127.4, 125.1,
114.3, 110.5 (d, JCeF¼26 Hz), 104.6 (d, JCeF¼25 Hz), 101.6 (d,

A. Arcadi et al. / Tetrahedron 69 (2013) 1857e1871
1867
JCeF¼4 Hz), 55.4. Anal. Calcd for C21H15FO2: C, 79.23; H, 4.75. Found:
120.3, 101.3, 68.8, 54.8, 35.2. Anal. Calcd for C30H24O4: C, 80.34; H,
5.39. Found: C, 80.43; H, 5.40.
C, 79.15; H, 4.76.
4.3.34. 7-(Biphenyl-4-yl)-5-fluoro-2-phenylbenzo[b]furan (6ec). White
solid. Mp: 173e175 ꢀC. MS: m/z 387 (MNaþ); IR (KBr): 3033, 2930,
4.3.40. 2-(7-(4-Fluoro-3-methylphenyl)-2-phenylbenzo[b]furan-5-
yl)ethylmethyl carbonate (6id). Brown wax. MS: m/z 427 (MNaþ);
1604, 1471, 1390, 761 cmꢁ1; 1H NMR (CDCl3):
d
8.05 (d, J¼8.4 Hz, 2H),
IR (KBr): 2950, 1749, 1617, 1508, 1444, 1272, 760 cmꢁ1 1H NMR
;
7.90 (d, J¼7.2 Hz, 2H), 7.82 (d, J¼8.4 Hz, 2H), 7.74 (d, J¼7.2 Hz, 2H),
(CDCl3):
d
7.87 (d, J¼7.2 Hz, 2H), 7.76 (d, J¼6.4 Hz, 2H), 7.48 (t,
7.55e7.41 (m, 6H), 7.29e7.24 (m, 2H), 7.09 (s, 1H); 13C NMR (CDCl3):
J¼7.6 Hz, 2H), 7.43e7.37 (m, 2H), 7.29 (s, 1H), 7.21e7.19 (m, 1H),
d
159.2 (d, JCeF¼237 Hz), 157.7, 148.6, 148.4, 141.0, 140.6, 134.5, 130.9,
7.05 (s, 1H), 4.47 (t, J¼7.2 Hz, 2H), 3.82 (s, 3H), 3.16 (t, J¼7.2 Hz, 2H),
130.7, 130.0, 129.0, 128.9, 128.8, 127.6, 127.5, 126.1, 125.1, 110.9 (d,
JCeF¼27 Hz), 105.3 (d, JCeF¼25 Hz), 101.5 (d, JCeF¼4 Hz). Anal. Calcd for
C26H17FO: C, 85.69; H, 4.70. Found: C, 85.60; H, 4.71.
2.45 (s, 3H); 13C NMR (CDCl3):
d
160.4 (d, JCeF¼237 Hz), 156.5,
155.8, 151.0, 132.5, 131.7, 131.6, 130.4, 130.3, 128.8, 128.7, 127.6,
127.5, 124.9, 124.7, 124.4, 120.1, 115.2 (d, JCeF¼22 Hz), 101.3, 68.8,
54.8, 35.2, 14.8. Anal. Calcd for C25H21FO4: C, 74.24; H, 5.23. Found:
C, 74.33; H, 5.24.
4.3.35. 5-Fluoro-7-(4-fluoro-3-methylphenyl)-2-phenylbenzo[b]fu-
ran (6ed). White solid. Mp: 106e107 ꢀC. MS: m/z 343 (MNaþ); IR
(KBr): 3079, 2923, 1604, 1469, 1234, 759 cmꢁ1
;
1H NMR (CDCl3):
4.3.41. Methyl-2-(2-phenyl-7-(thiophen-3-yl)benzo[b]furan-5-yl)
d
7.85 (d, J¼7.2 Hz, 2H), 7.74 (d, J¼6.8 Hz, 2H), 7.50 (t, J¼7.2 Hz, 2H),
ethyl carbonate (6ie). Brown solid. Mp: 93e94 ꢀC. MS: m/z 401
7.42 (t, J¼7.2 Hz, 1H), 7.24e7.14 (m, 3H), 7.02 (s, 1H), 2.45 (d,
(MNaþ); IR (KBr): 3099, 2940, 1745, 1444, 1263, 786 cmꢁ1 1H
;
J¼1.6 Hz, 3H); 13C NMR (CDCl3):
d
161.3 (d, JCeF¼245 Hz), 159.6 (d,
NMR (CDCl3):
d
8.08 (s, 1H), 7.91 (d, J¼8.4 Hz, 2H), 7.79 (d,
JCeF¼237 Hz), 158.4 (d, JCeF¼237 Hz), 157.6, 148.2, 131.7, 131.6, 130.8,
130.7,130.0, 129.0, 128.9, 127.5, 125.0, 115.3 (d, JCeF¼22 Hz),110.9 (d,
JCeF¼27 Hz), 105.2 (d, JCeF¼25 Hz), 101.5 (d, JCeF¼4 Hz), 14.7 (d,
JCeF¼3 Hz). Anal. Calcd for C21H14F2O: C, 78.74; H, 4.41. Found: C,
78.67; H, 4.40.
J¼4.8 Hz, 1H), 7.51e7.48 (m, 3H), 7.44e7.38 (m, 3H), 7.04 (s, 1H),
4.46 (t, J¼7.2 Hz, 2H), 3.81 (s, 3H), 3.14 (t, J¼7.2 Hz, 2H); 13C NMR
(CDCl3):
d 156.4, 155.8, 150.7, 136.7, 132.6, 130.4, 130.3, 128.9,
128.7, 127.0, 125.3, 125.1, 125.0, 123.6, 123.2, 119.9, 101.4, 68.8,
54.8, 35.2. Anal. Calcd for C22H18O4S: C, 69.82; H, 4.79. Found: C,
69.74; H, 4.80.
4.3.36. 5-Fluoro-2-phenyl-7-(thiophen-3-þyl)benzo[b]furan (6ee). White
solid. Mp: 114e115 ꢀC. MS: m/z 317 (MNa ); IR (KBr): 3093, 2921, 1604,
4.3.42. Methyl
(6ga). White solid. Mp: 83e85 ꢀC. MS: m/z 421 (MNaþ); IR
(KBr): 2935, 1712, 1606, 1564, 1514, 1466, 1281, 1020 cmꢁ1 1H
NMR (CDCl3):
4-(2-pentyl-5-phenylbenzo[b]furan-7-yl)benzoate
1471, 1384, 1137, 761 cmꢁ1; 1H NMR (CDCl3):
d 8.10e8.09 (m, 1H), 7.89
(d, J¼7.6 Hz, 2H), 7.74 (dd, J¼5.2, 1.2 Hz, 1H), 7.53e7.49 (m, 3H),
;
7.44e7.40 (m, 1H), 7.30e7.27 (m, 1H), 7.18 (dd, J¼8.0 Hz, J¼2.4 Hz, 1H),
d
8.26 (d, J¼8.4 Hz, 2H), 8.07 (d, J¼8.4 Hz, 2H),
7.03 (s, 1H); 13C NMR (CDCl3):
135.9, 130.6, 130.0, 128.9, 126.8, 125.5, 123.9, 120.8, 120.7, 110.0 (d,
JCeF¼27 Hz), 105.0 (d, JCeF¼25 Hz), 101.7 (d, JCeF¼4 Hz). Anal. Calcd for
C18H11FOS: C, 73.45; H, 3.77. Found: C, 73.38; H, 3.78.
d
159.5 (d, JCeF¼237 Hz), 157.6, 147.9,
7.74e7.70 (m, 4H), 7.52 (t, J¼7.6 Hz, 2H), 7.44e7.40 (m, 1H), 6.53
(s, 1H), 4.02 (s, 3H), 2.88e2.84 (m, 2H), 1.86e1.82 (m, 2H),
1.48e1.46 (m, 4H), 1.01 (t, J¼6.8 Hz, 3H); 13C NMR (CDCl3):
d
167.0, 161.0, 151.5, 141.7, 141.4, 136.9, 130.7, 129.9, 129.1, 128.8,
128.6, 127.5, 127.0, 123.7, 122.5, 119.0, 102.3, 52.1, 31.4, 28.5, 27.4,
22.5, 14.1. Anal. Calcd for C27H26O3: C, 81.38; H, 6.58. Found: C,
81.47; H, 6.59.
4.3.37. 3-(5-(2-(Methoxycarbonyloxy)ethyl)-2-phenylbenzo[b]furan-
7-yl)benzoate (6ia). White solid. Mp: 103e104 ꢀC. MS: m/z 453
(MNaþ); IR (KBr): 2954, 1737, 1714, 1604, 1440, 1384, 1274,
759 cmꢁ1; 1H NMR (CDCl3):
d
8.68 (s, 1H), 8.19 (d, J¼7.6 Hz,1H), 8.13
4.3.43. 7-(4-fluoro-3-methylphenyl)-2-pentyl-5-phenylbenzo[b]fu-
ran (6gb). Yellow oil. MS: m/z 395 (MNaþ); IR (KBr): 2929, 1603,
(d, J¼7.6 Hz, 1H), 7.88 (d, J¼7.2 Hz, 2H), 7.64 (t, J¼8 Hz, 1H),
7.49e7.45 (m, 3H), 7.40e7.36 (m, 2H), 7.06 (s, 1H), 4.47 (t, J¼7.2 Hz,
2H), 4.02 (s, 3H), 3.81 (s, 3H), 3.16 (t, J¼7.2 Hz, 2H); 13C NMR
1504, 1466, 1444 cmꢁ1 1H NMR (CDCl3):
; d 7.82 (m, 2H), 7.75 (m,
3H), 7.66 (s, 1H), 7.56 (t, J¼7.6 Hz, 2H), 7.45e7.43 (m, 1H), 7.25e7.22
(CDCl3):
d 172.8, 167.1, 156.6, 155.8, 151.1, 136.6, 132.9, 132.6, 130.7,
(m,1H), 6.56 (s, 1H), 2.91 (t, J¼7.2 Hz, 2H), 2.50 (s, 3H),1.91e1.85 (m,
130.5, 130.2, 129.7, 128.8, 128.7, 125.0, 124.9, 124.6, 123.9, 120.7,
101.3, 68.7, 54.8, 52.2, 35.2. Anal. Calcd for C26H22O6: C, 72.55; H,
5.15. Found: C, 72.48; H, 5.16.
2H), 1.53 (m, 4H), 1.06 (t, J¼6.8 Hz, 3H); 13C NMR (CDCl3):
d 161.5 (d,
JCeF¼244 Hz), 160.8, 151.5, 142.0, 136.8, 132.5, 130.5, 128.8, 127.8,
127.7, 127.6, 126.9, 125.1, 124.2, 122.4, 118.0, 115.1 (d, JCeF¼22 Hz),
102.3, 31.5, 28.5, 27.5, 22.5, 14.1. Anal. Calcd for C26H25FO: C, 83.84;
H, 6.77. Found: C, 83.90; H, 6.78.
4.3.38. 2-(7-(4-Methoxyphenyl)-2-phenylbenzo[b]furan-5-yl)ethyl-
methyl carbonate (6ib). Brown solid. Mp: 112e113 ꢀC. MS: m/z 425
(MNaþ); IR (KBr): 2950, 1749, 1270, 748 cmꢁ1
;
1H NMR (CDCl3):
4.3.44. 7-(Biphenyl-4-yl)-2-pentyl-5-phenylbenþzo[b]furan
d
7.93e7.88 (m, 4H), 7.47 (t, J¼7.6 Hz, 2H), 7.41e7.36 (m, 2H), 7.29 (d,
(6gc). White solid. Mp: 100e102 ꢀC. MS: m/z 439 (MNa ); IR (KBr):
J¼7.6 Hz, 1H), 7.11 (d, J¼8.8 Hz, 2H), 7.06 (s, 1H), 4.46 (t, J¼7.2 Hz,
2931, 1606, 1577, 1518, 1464 cmꢁ1 1H NMR (CDCl3):
; d 8.15 (d,
2H), 3.93 (s, 3H), 3.81 (s, 3H), 3.15 (t, J¼7.2 Hz, 2H); 13C NMR
J¼8.4 Hz, 2H), 7.89 (d, J¼8.4 Hz, 2H), 7.82e7.78 (m, 6H), 7.59e7.55
(m, 4H), 7.50e7.49 (m, 2H), 6.60 (s, 1H), 2.95 (t, J¼7.2 Hz, 2H),
1.95e1.89 (m, 2H), 1.55 (m, 4H), 1.08 (t, J¼7.2 Hz, 3H); 13C NMR
(CDCl3):
d 159.3, 156.3, 155.8, 151.1, 132.4, 130.4, 130.3, 129.7, 128.8,
128.78, 128.6, 125.0, 124.9, 124.4, 119.5, 114.2, 101.3, 68.9, 55.4, 54.7,
35.2. Anal. Calcd for C25H22O5: C, 74.61; H, 5.51. Found: C, 74.53; H,
5.52.
(CDCl3):
d 160.9, 151.7, 142.0, 141.0, 140.5, 136.9, 135.8, 130.6, 129.1,
129.0, 128.9, 127.6, 127.5, 127.4, 127.2, 127.0, 124.5, 122.5, 118.2,
102.3, 31.5, 28.6, 27.5, 22.6, 14.2. Anal. Calcd for C31H28O, 89.38; H,
6.78. Found: C, 89.30; H, 6.79.
4.3.39. 2-(7-(Biphenyl-4-yl)-2-phenylbenzo[b]furan-5-yl)ethyl-
methyl carbonate (6ic). White solid. Mp: 200 ꢀC dec. MS: m/z 471
(MNaþ); IR (KBr): 2956, 1741, 1604, 1439, 1269, 1024 cmꢁ1; 1H NMR
4.3.45. 2-Pentyl-5-phenyl-7-(thiophen-3-yl)benþzo[b]furan
(CDCl3):
d
8.07 (d, J¼7.6 Hz, 2H), 7.91 (d, J¼7.2 Hz, 2H), 7.82 (d,
(6gd). White solid. Mp: 77e79 ꢀC. MS: m/z 369 (MNa ); IR (KBr):
J¼8.0 Hz, 2H), 7.75 (d, J¼7.2 Hz, 2H), 7.55e7.37 (m, 8H), 7.08 (s, 1H),
2925, 1606, 1574, 1466 cmꢁ1 1H NMR (CDCl3):
; d 8.12 (s, 1H),
4.49 (t, J¼7.2 Hz, 2H), 3.82 (s, 3H), 3.18 (t, J¼7.2 Hz, 2H); 13C NMR
7.85e7.43 (m, 9H), 6.54 (s, 1H), 2.92 (t, J¼7.2 Hz, 2H), 1.92e1.86 (m,
(CDCl3):
d
156.5, 155.8, 151.2, 140.8, 140.5, 135.4, 132.5, 130.5, 130.4,
2H), 1.51 (m, 4H), 1.04 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3):
d 160.6,
124.9, 128.9, 128.86, 128.82, 127.5, 127.4, 127.1, 125.0, 124.8, 124.7,
151.2, 142.0, 137.1, 136.7, 130.5, 128.8, 127.6, 127.1, 126.9, 125.5, 123.2,

1868
A. Arcadi et al. / Tetrahedron 69 (2013) 1857e1871
121.3, 119.7, 117.8, 102.3, 31.5, 28.6, 27.5, 22.5, 14.1. Anal. Calcd for
C23H22OS: C, 79.73; H, 6.40. Found: C, 79.64; H, 6.41.
JCeF¼25 Hz), 101.6 (d, JCeF¼4 Hz), 94.9, 81.8, 55.3. Anal. Calcd for
C23H15FO2: C, 80.69; H, 4.42. Found: C, 80.78; H, 4.43.
4.3.46. 2-Pentyl-5,7-diphenylbenzo[b]furan (6ge). Yellow oil. MS:
4.3.53. 7-((4-Methoxyphenyl)ethynyl)-5-methyl-2-phenylbenzo[b]
furan (7c). Yellow solid. Mp: 102e104 ꢀC. MS: m/z 361 (MNaþ); IR
(KBr): 2920, 2359,1595,1568,1508,1444,1246,1020 cmꢁ1; 1H NMR
m/z 363 (MNaþ); IR (KBr): 2927, 1603, 1577, 1498, 1464 cmꢁ1 1H
;
NMR (CDCl3):
d 8.05e8.02 (m, 2H), 7.80e7.75 (m, 4H), 7.66e7.44
(m, 6H), 6.60 (s, 1H), 2.92 (t, J¼7.2 Hz, 2H), 1.92e1.87 (m, 2H),
(CDCl3):
J¼7.6 Hz, 2H), 7.42e7.38 (m, 1H), 7.34 (d, J¼6.4 Hz, 2H), 6.99e6.97
(m, 3H), 3.88 (s, 3H), 2.48 (s, 3H); 13C NMR (CDCl3):
159.8, 156.4,
153.1, 133.3, 132.5, 130.4, 129.5, 128.8, 128.7, 125.1, 121.2, 115.6, 114.1,
107.2, 101.3, 93.7, 83.0, 55.3, 21.2. Anal. Calcd for C24H18O: C, 85.18;
H, 5.36. Found: C, 85.25; H, 5.37.
d
7.95 (d, J¼7.2 Hz, 2H), 7.66 (d, J¼8.8 Hz, 2H), 7.50 (t,
1.55e1.49 (m, 4H), 1.06 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3):
d 160.8,
151.6, 142.0, 136.9, 136.8, 130.6, 128.9, 128.8, 128.7, 127.7, 127.6,
126.9, 125.0, 122.6, 118.1,102.3, 31.5, 28.6, 27.5, 22.5,14.1. Anal. Calcd
for C25H24O: C, 88.20; H, 7.11. Found: C, 88.29; H, 7.12.
d
4.3.47. Methyl 4-(5-methyl-2-phenethylbenzo[b]furan-7-yl)benzoate
(6ha). White solid. Mp: 114e115 ꢀC. MS: m/z 393 (MNaþ); IR (KBr):
4.3.54. 2-(4-Methoxyphenyl)-5-methyl-7-(phenylethynyl)benzo[b]
furan (7d). White solid. Mp: 142e144 ꢀC. MS: m/z 361 (MNaþ); IR
(KBr): 2918, 2214, 1614, 1589, 1508, 1444, 1254, 1039 cmꢁ1; 1H NMR
2947, 1711, 1604, 1564, 1496, 1437, 1277, 1018 cmꢁ1 1H NMR
;
(CDCl3):
(m, 7H), 6.42 (s, 1H), 4.02 (s, 3H), 3.19e3.12 (m, 4H), 2.54 (s, 3H); 13C
NMR (CDCl3): 167.1, 159.1, 150.3, 141.5, 140.8, 132.5, 130.1, 129.9,
d
8.22 (d, J¼8.4 Hz, 2H), 7.97 (d, J¼8.4 Hz, 2H), 7.38e7.27
(CDCl3):
(m, 3H), 7.34 (s, 1H), 7.30 (s, 1H), 7.01 (d, J¼8.8 Hz, 2H), 6.84 (s, 1H),
3.88 (s, 3H), 2.47 (s, 3H); 13C NMR (CDCl3):
160.1, 156.6, 152.9,
d
7.87 (d, J¼8.4 Hz, 2H), 7.71 (d, J¼6.4 Hz, 2H), 7.44e7.41
d
128.9, 128.6, 128.5, 128.4, 126.3, 124.2, 123.2, 120.6, 102.4, 52.1, 34.1,
30.3, 21.4. Anal. Calcd for C25H22O3: C, 81.06; H, 5.99. Found: C,
81.15; H, 5.98.
d
132.4, 131.8, 129.8, 128.4, 128.3, 125.5, 126.6, 123.5, 123.2, 121.2,
114.2, 106.6, 99.6, 93.4, 84.4, 55.4, 21.2. Anal. Calcd for C24H18O2: C,
85.18; H, 5.36. Found: C, 85.27; H, 5.37.
4.3.48. 7-(4-Fluoro-3-methylphenyl)-5-methyl-2-phenethylbenzo[b]
furan (6hb). Yellow oil. MS: m/z 367 (MNaþ); IR (KBr): 3046,
4.3.55. 4-(2-(4-Methoxyphenyl)-5-methylbenzo[b]furan-7-yl)-2-
methylbut-3-yn-2-ol (7e). Yellow solid. Mp: 102e103 ꢀC. MS: m/z
343 (MNaþ); IR (KBr): 3448, 2924, 2360, 1614, 1587, 1508, 1464,
2924, 1603, 1508, 1234, 756 cmꢁ1
;
1H NMR (CDCl3):
d
7.72e7.66
(m, 2H), 7.38e7.11 (m, 8H), 6.42 (s, 1H), 3.17e3.14 (m, 4H), 2.54 (s,
3H), 2.45 (s, 3H); 13C NMR (CDCl3):
d
160.9 (d, JCeF¼244 Hz),
1250, 1024 cmꢁ1; 1H NMR (CDCl3):
d
7.82 (d, J¼8.8 Hz, 2H), 7.29 (s,
1H), 7.16 (s, 1H), 7.00 (d, J¼8.4 Hz, 2H), 6.82 (s, 1H), 3.88 (s, 3H), 2.42
(s, 3H), 2.29 (s, 1H), 1.74 (s, 6H); 13C NMR (CDCl3):
160.1, 156.5,
158.9, 150.2, 140.9, 132.4, 131.7, 131.6, 129.9, 128.5, 127.7, 126.2,
124.9, 124.8, 124.0, 123.6, 119.5, 115.0 (d, JCeF¼22 Hz), 102.4, 34.1,
30.3, 21.4, 14.8. Anal. Calcd for C24H21FO: C, 83.69; H, 6.15. Found:
C, 83.78; H, 6.16.
d
153.0, 132.2, 129.7, 128.4, 126.7, 123.1, 121.1, 115.6, 114.2, 105.9, 99.5,
65.8, 55.4, 31.6, 21.1. Anal. Calcd for C26H22O3: C, 78.73; H, 6.29.
Found: C, 78.65; H, 6.28.
4.3.49. 7-(Biphenyl-4-yl)-5-methyl-2-phenethylbenzo[b]furan
(6hc). White solid. Mp: 85e87 ꢀC. MS: m/z 411 (MNaþ); IR (KBr):
4.3.56. 4-(5-Fluoro-2-phenylbenzo[b]furan-7-yl)-2-methylbut-3-yn-
þ
2924, 1603, 1577, 1491, 1452 cmꢁ1
;
1H NMR (CDCl3):
d
8.03 (d,
J¼8 Hz, 2H), 7.84e7.78 (m, 4H), 7.59e7.32 (m,10H), 6.46 (s,1H), 3.21
(s, 4H), 2.60 (s, 3H); 13C NMR (CDCl3):
158.9, 150.5, 141.0, 140.3,
2-ol (7f). Yellow solid. Mp: 93e95 C. MS: m/z 317 (MNa ); IR
ꢀ
(KBr): 3354, 2927, 1599, 1473, 1444 cmꢁ1 1H NMR (CDCl3):
;
d
7.88
d
(d, J¼7.6 Hz, 2H), 7.49 (t, J¼7.6 Hz, 2H), 7.42 (d, J¼6.8 Hz,1H), 7.21 (d,
135.9, 132.5, 130.1, 129.0, 128.9, 128.6, 128.5, 127.4, 127.3, 127.2,
126.3, 124.1, 124.0, 119.7, 111.1, 102.4, 34.2, 30.4, 21.5. Anal. Calcd for
C29H24O: C, 89.66; H, 6.23. Found: C, 89.75; H, 6.24.
J¼8.4 Hz, 1H), 7.07 (d, J¼9.6 Hz, 1H), 6.98 (s, 1H), 2.35 (br s, 1H), 1.75
(s, 6H); 13C NMR (CDCl3):
140.3, 130.0, 129.1, 128.9, 125.1, 114.9 (d, JCeF¼27 Hz), 107.4 (d,
JCeF¼27 Hz), 107.3, 101.6 (d, JCeF¼4 Hz), 99.3, 75.9, 65.8, 31.4. Anal.
Calcd for C24H17FO2: C, 77.54; H, 5.14. Found: C, 77.62; H, 5.15.
d
158.6 (d, JCeF¼237 Hz), 157.9, 151.2,
4.3.50. 5-Methyl-2-phenethyl-7-(thiophen-3-yl)benzo[b]furan
(6hd). White solid. Mp: 68e69. MS: m/z 341 (MNaþ); IR (KBr):
3101, 2925, 1601, 1495, 1450 cmꢁ1
;
1H NMR (CDCl3):
d
7.93 (s, 1H),
7.72 (d, J¼4.8 Hz, 1H), 7.48e7.46 (m, 1H), 7.38e7.26 (m, 7H), 6.40 (s,
1H), 3.23e3.15 (m, 4H), 2.52 (s, 3H); 13C NMR (CDCl3):
158.7,150.0,
4.3.57. 2-Methyl-4-(5-methyl-2-phenylbenzo[b]furan-7-yl)bþut-3-
yn-2-ol (7g). Yellow solid. Mp: 102e103 ꢀC. MS: m/z 313 (MNa ); IR
d
(KBr): 3440, 2924, 2364, 1597, 1564, 1491, 1444 cmꢁ1 1H NMR
;
141.0, 137.1, 132.2, 129.8, 128.5, 128.4, 127.0, 126.3, 125.3, 122.9,
119.3, 119.1, 102.4, 34.2, 30.3, 21.4. Anal. Calcd for C21H18OS: C,
79.21; H, 5.70. Found: C, 79.15; H, 5.71.
(CDCl3):
(s, 1H), 2.42 (s, 3H), 1.76 (s, 6H), 1.31 (br s, 1H); 13C NMR (CDCl3):
156.4, 153.2, 132.4, 131.1, 130.3, 129.4, 128.9, 128.8, 128.7, 125.0,
d
7.89 (d, J¼7.6 Hz, 2H), 7.49e7.32 (m, 4H), 7.19 (s, 1H), 6.94
d
121.4, 106.2, 101.2, 98.2, 65.9, 31.6, 21.1. Anal. Calcd for C25H18O2: C,
82.73; H, 6.25. Found: C, 85.65; H, 6.24.
4.3.51. 5-Methyl-2-phenethyl-7-phenylbenzo[b]furan (6he). Yellow
oil. MS: m/z 335 (MNaþ); IR (KBr): 2922, 1603, 1577, 1496,
1471 cmꢁ1
;
1H NMR (CDCl3):
d
7.96 (d, J¼7.2 Hz, 2H), 7.60 (t,
J¼7.6 Hz, 2H), 7.49 (m, 1H), 7.42e7.28 (m, 7H), 6.45 (s, 1H),
3.24e3.15 (m, 4H), 2.59 (s, 3H); 13C NMR (CDCl3):
158.9, 150.4,
4.3.58. 1-Phenyl-1-(5-phenyl-7-(phenylethynyl)benzo[b]furan-2-yl)
ethanol (7h). Brown wax. MS: m/z 437 (MNaþ); IR (KBr): 3417,
d
2924, 2216, 1599, 1574, 1491, 1444 cmꢁ1 1H NMR (CDCl3):
;
141.0, 137.0, 132.4, 130.0, 128.7, 128.6, 128.5, 128.4, 127.5, 126.2,
124.4, 124.2, 119.6, 102.4, 34.2, 30.4, 21.5. Anal. Calcd for C23H20O: C,
88.43; H, 6.45. Found: C, 88.50; H, 6.46.
d
7.75e7.74 (m, 2H), 7.68e7.37 (m, 15H), 6.69 (s, 1H), 3.01 (br s, 1H),
2.09 (s, 3H); 13C NMR (CDCl3):
d 162.9, 154.1, 145.0, 140.9, 136.8,
131.8, 129.0, 128.9, 128.6, 128.4, 128.3, 127.8, 127.6, 127.4, 127.2,
125.5, 123.1, 120.2, 107.7, 103.6, 94.0, 84.0, 73.5, 29.2. Anal. Calcd for
C30H22O2: C, 86.93; H, 5.35. Found: C, 86.85; H, 5.36.
4.3.52. 5-Fluoro-7-((4-methoxyphenyl)ethynyl)-2-phenylbenzoþ[b]fu-
ran (7b). Yellow solid. Mp: 131e133 ꢀC. MS: m/z 365 (MNa ); IR
(KBr): 2937, 2212, 1597, 1568, 1510, 1462, 1250, 1026 cmꢁ1; 1H NMR
4.3.59. 1-(7-(Hept-1-ynyl)-5-phenylbenzo[b]furan-2-yl)-1-phenylethanol
(CDCl3):
3H), 7.23e7.18 (m, 2H), 7.00e6.96 (m, 3H), 3.88 (s, 3H); 13C NMR
(CDCl3):
160.1, 158.8 (d, JCeF¼237 Hz), 157.6, 151.0, 133.4, 129.8,
129.1, 128.8, 125.2, 114.9, 114.8, 114.5, 114.1, 108.5, 106.7 (d,
d
7.92 (d, J¼7.6 Hz, 2H), 7.64 (d, J¼8.4 Hz, 2H), 7.51e7.39 (m,
(7i). Brown wax. MS: m/z 431 (MNaþ); IR (KBr): 3433, 2929, 2235,
1599, 1493, 1444 cmꢁ1 1H NMR (CDCl3):
; d 7.68e7.35 (m, 12H),
d
6.66 (s, 1H), 3.03 (s, 1H), 2.52 (t, J¼6.8 Hz, 2H), 2.06 (s, 3H),
1.71e1.66 (m, 2H), 1.54e1.49 (m, 2H), 1.45e1.39 (m, 2H), 0.98

A. Arcadi et al. / Tetrahedron 69 (2013) 1857e1871
1869
(t, J¼6.8 Hz, 3H); 13C NMR (CDCl3):
d
162.5, 154.4, 145.1,
C21H24N2O: C, 78.71; H, 7.55; N, 8.74. Found: C, 78.63; H, 7.56; N,
8.75.
141.1, 136.7, 128.8, 128.7, 128.3, 128.1, 127.6, 127.4, 127.1, 125.5,
119.3, 108.5, 103.5, 95.6, 75.1, 73.5, 31.1, 29.2, 28.4, 22.3, 19.8, 14.1.
Anal. Calcd for C29H28O2: C, 85.26; H, 6.91. Found: C, 85.19; H,
6.92.
4.3.66. 1,1-Dimethyl-2-(5-methyl-2-phenylbenzo[b]furan-7-yl)hy-
drazine (10f). Yellow solid. Mp: 112e114 ꢀC. MS: m/z 267 (MHþ); IR
(KBr): 2949, 2771, 1603, 1498, 1471, 1444 cmꢁ1 1H NMR (CDCl3):
;
4.3.60. (E)-2-(4-Methoxyphenyl)-5-methyl-7-styrylbeþnzo[b]furan
d
7.89 (d, J¼7.6 Hz, 2H), 7.48 (t, J¼7.6 Hz, 2H), 7.38 (t, J¼7.6 Hz, 1H),
6.99 (s,1H), 6.96 (s,1H), 6.88 (s,1H), 4.86 (s,1H), 2.71 (s, 6H), 2.48 (s,
3H); 13C NMR (CDCl3):
155.4, 141.6,133.8, 132.2, 130.8, 129.4, 128.7,
(9b). Yellow solid. Mp: 127e129 ꢀC. MS: m/z 363 (MNa ); IR (KBr):
2918, 1610, 1570, 1506, 1462, 1250, 1026 cmꢁ1
;
1H NMR (CDCl3):
d
d
7.87 (d, J¼8.8 Hz, 2H), 7.69 (d, J¼8.4 Hz, 2H), 7.49e7.45 (m, 3H),
7.41e7.34 (m, 2H), 7.28e7.24 (m, 2H), 7.05e7.02 (m, 2H), 6.86e6.84
(m, 1H), 3.90 (s, 3H), 2.50 (s, 3H); 13C NMR (CDCl3):
160.0, 156.1,
128.3, 124.8, 111.1, 109.8, 101.8, 48.1, 21.8. Anal. Calcd for C17H18N2O:
C, 76.66; H, 6.81; N, 10.52. Found: C, 76.58; H, 6.82; N, 10.53.
d
150.7, 137.9, 132.5, 131.4, 130.2, 128.8, 127.7, 126.7,126.4, 124.1, 123.8,
123.5,121.3,119.9,114.3, 99.6, 55.4, 21.4. Anal. Calcd for C24H20O2: C,
84.68; H, 5.92. Found: C, 84.60; H, 5.93.
4.3.67. N-(5-Methyl-2-phenylbenzo[b]furan-7-yl)piperidin-1-amine
(10g). Yellow solid. Mp: 108e109 ꢀC. MS: m/z 307 (MHþ); IR (KBr):
2941, 1604, 1495, 1469 cmꢁ1
;
1H NMR (CDCl3):
d
7.92 (d, J¼7.6 Hz,
2H), 7.52e7.40 (m, 3H), 7.04 (s, 1H), 6.97 (s, 1H), 6.88 (s, 1H), 5.02 (s,
4.3.61. (E)-5-Fluoro-2-phenyl-7-styrylbenzoþ[b]furan
(9c). Yellow
1H), 2.86 (s, 4H), 2.51 (s, 3H), 1.86e1.80 (m, 4H), 1.53 (s, 2H); 13C
solid. Mp: 103e105 ꢀC. MS: m/z 337 (MNa ); IR (KBr): 1595, 1495,
NMR (CDCl3): d 155.3, 141.6, 133.7, 132.3, 130.9, 129.4, 128.7, 128.2,
124.8, 110.9, 109.6, 101.9, 57.7, 26.2, 23.8, 21.9.
1471, 1446 cmꢁ1
7.67e7.63 (m, 3H), 7.54e7.37 (m, 7H), 7.17e7.14 (m, 2H), 7.00 (s,
1H); 13C NMR (CDCl3):
;
1H NMR (CDCl3):
d
7.91 (d, J¼7.6 Hz, 2H),
d
159.5 (d, JCeF¼237 Hz), 157.4, 148.7, 137.2,
4.3.68. 1-(5-Methyl-2-phenylbenzo[b]furan-7-yl)piperazine (10h).
Yellow solid. Mp: 120e122 ꢀC. MS: m/z 293 (MHþ); IR (KBr): 3315,
132.8, 130.4, 130.1, 128.9, 128.2, 126.9, 125.0, 122.9, 122.8, 122.3,
110.0, 109.8 (d, JCeF¼26 Hz), 105.3 (d, JCF¼25 Hz), 101.5 (d,
JCeF¼4 Hz). Anal. Calcd for C22H15FO: C, 84.06; H, 4.81. Found: C,
84.15; H, 4.82.
3102, 2946, 2834, 1598, 767 cmꢁ1 1H NMR (CDCl3):
; d 7.85 (d,
J¼8 Hz, 2H), 7.46 (t, J¼7.6 Hz, 2H), 7.36 (d, J¼7.6 Hz, 1H), 7.0 (s, 1H),
6.94 (s, 1H), 6.61 (s. 1H), 3.39 (t, J¼4.8 Hz, 4H), 3.19 (t, J¼4.8 Hz, 4H),
2.45 (s, 3H), 1.95 (br s, NH); 13C NMR (CDCl3):
d 155.1, 145.1, 137.2,
4.3.62. 1-(2,5-Diphenylbenzo[b]furan-7-yl)piperidine (10a). Yellow
solid. Mp: 173e175 ꢀC. MS (relative intensity): m/z 354 (Mþ,100); IR
133.2, 130.7, 130.5, 128.7, 128.3, 124.8, 113.7, 112.8, 101.5, 51.3, 46.3,
21.7. Anal. Calcd for C19H20N2O: C, 78.05; H, 6.89; N, 9.58. Found: C,
78.13; H, 6.90; N, 9.59.
(KBr): 2944, 2931, 2811, 1637 cmꢁ1 1H NMR (CDCl3):
; d 7.93 (d,
J¼7.2 Hz, 2H), 7.70 (d, J¼7.2 Hz, 2H), 7.51e7.48 (m, 4H), 7.42e7.38
(m, 3H), 7.07e7.05 (m, 2H), 3.48 (t, J¼5.6 Hz, 4H), 1.95 (m, 4H), 1.75
4.3.69. 1-(5-Fluoro-2-phenylbenzo[b]furan-7-yl)piperidine (10i).
Yellow solid. Mp: 200 ꢀC (dec). MS (relative intensity): m/z 295 (Mþ,
(m, 2H); 13C NMR (CDCl3):
d 155.5, 146.3, 142.4, 138.3, 137.6, 130.8,
130.6, 128.8, 128.7, 128.5, 127.5, 126.8, 124.9, 112.3, 111.7, 102.0, 51.4,
27.0, 26.2, 24.6. Anal. Calcd for C25H23NO: C, 84.95; H, 6.56; N, 3.96.
Found: C, 84.86; H, 6.57; N, 3.97.
100), 212 (10), 77 (9); IR (KBr): 2933, 1614, 1495, 1475 cmꢁ1 1H
;
NMR (CDCl3):
d
7.86 (d, J¼7.6 Hz, 2H), 7.48 (t, J¼7.6 Hz, 2H), 7.39 (t,
J¼7.6 Hz,1H), 6.97 (s,1H), 6.81 (dd, J1¼8.0 Hz, J2¼2 Hz,1H), 6.53 (dd,
J1¼12.0 Hz, J2¼2.0 Hz, 1H), 3.40 (t, 4H), 1.88e1.85 (m, 4H), 1.72e1.68
4.3.63. 4-(5-Methyl-2-phenylbenzo[b]furan-7-yl)morpholine
(m, 2H); 13C NMR (CDCl3):
d
160.0 (d, JCeF¼236 Hz), 156.1, 142.7,
(10c). Yellow solid. Mp: 100e102 ꢀC. MS: m/z 316 (MNaþ); IR
138.8 (d, JCF¼104 Hz), 130.2, 130.0, 128.8, 128.6, 124.8, 101.9 (d,
JCeF¼5 Hz), 100.0 (d, JCeF¼29 Hz), 97.7 (d, JCeF¼25 Hz), 51.0, 26.0,
24.5. Anal. Calcd for C19H18FNO: C, 77.27; H, 6.14; N, 4.74. Found: C,
77.20; H, 6.15; N, 4.75.
(KBr): 3057, 2945, 2854, 1603, 1496, 1477, 1448 cmꢁ1 1H NMR
;
(CDCl3):
d
7.86 (d, J¼7.6 Hz, 2H), 7.49 (t, J¼7.6 Hz, 2H), 7.39 (t,
J¼7.2 Hz, 1H), 7.04 (s, 1H), 6.96 (s, 1H), 6.62 (s, 1H), 4.05 (t,
J¼4.4 Hz, 4H), 3.45 (t, J¼4.4 Hz, 4H), 2.48 (s, 3H); 13C NMR
(CDCl3):
d
155.3, 144.9, 136.6, 133.3, 130.6, 128.8, 128.4, 124.8,
4.3.70. 1-(2-Pentyl-5-phenylbenzo[b]furan-7-yl)piperidine (10j).
Yellow oil. MS: m/z 369 (MNaþ); IR (KBr): 2931, 1603, 1577,
114.0, 112.6, 103.3, 101.6, 67.1, 50.4, 21.8. Anal. Calcd for
C19H19NO2: C, 77.79; H, 6.53; N 4.77. Found: C, 77.86; H, 6.54; N,
4.78.
1466 cmꢁ1; 1H NMR (CDCl3):
d
7.66 (d, J¼7.6 Hz, 2H), 7.50e7.46 (m,
2H), 7.38e7.28 (m, 2H), 6.98 (s, 1H), 6.43 (s, 1H), 3.40e3.37 (m, 3H),
2.87e2.81 (m, 2H), 1.92e1.70 (m, 9H), 1.48e1.41 (m, 4H), 0.98 (t,
4.3.64. 1-(4-Fluorophenyl)-4-(5-methyl-2-phenylbenzo[b]furan-7-
J¼6.8 Hz, 3H); 13C NMR (CDCl3):
d 159.4, 146.1, 142.6, 138.0, 136.9,
yl)piperazine (10d). Yellow solid. Mp: 139e140 ꢀC. MS: m/z 409
130.5, 128.7, 127.5, 126.6, 111.7, 110.5, 102.3, 51.4, 31.4, 28.4, 27.5,
26.2, 24.6, 22.5, 14.0. Anal. Calcd for C24H29NO: C, 82.95; H, 8.41; N,
4.03. Found: C, 82.87; H, 8.42; N, 4.04.
(MNaþ); IR (KBr): 2825, 1601, 1512, 1475, 1448 cmꢁ1 1H NMR
;
(CDCl3):
d
7.87 (d, J¼7.6 Hz, 2H), 7.48 (t, J¼7.6 Hz, 2H), 7.38 (t,
J¼7.6 Hz, 1H), 7.08e6.98 (m, 6H), 6.66 (s, 1H), 3.60 (t, J¼4.8 Hz, 4H),
3.43 (t, J¼4.8 Hz, 4H), 2.47 (s, 3H); 13C NMR (CDCl3):
d
155.2, 145.0,
4.3.71. 4-(2-Pentyl-5-phenylbenzo[b]furan-7-yl)þmorpholine (10k).
Yellow solid. Mp: 55e57 ꢀC. MS: m/z 372 (MNa ); IR (KBr): 2924,
136.4, 133.3, 130.6, 130.5, 128.8, 128.4, 124.8, 118.2, 118.1, 115.6 (d,
JCeF¼22 Hz), 114.0, 113.0, 101.6, 50.6, 50.0, 21.7. Anal. Calcd for
C25H23FN2O: C, 77.70; H, 6.00; N, 7.25. Found: C, 77.78; H, 5.99; N,
7.26.
1597, 1574, 1475, 1448, 1273, 1026 cmꢁ1; 1H NMR (CDCl3):
d 7.66 (d,
J¼7.2 Hz, 2H), 7.49 (t, J¼7.6 Hz, 2H), 7.40e7.36 (m, 2H), 6.95 (s, 1H),
6.45 (s, 1H), 4.03 (t, J¼4.4 Hz, 4H), 3.45 (t, J¼4.4 Hz, 4H), 2.85 (t,
J¼7.2 Hz, 2H), 1.84e1.79 (m, 2H), 1.46e1.42 (m, 4H), 0.99 (t,
4.3.65. 1-Ethyl-4-(5-methyl-2-phenylbenzo[b]furan-7-yl)piperazine
J¼7.2 Hz, 3H); 13C NMR (CDCl3):
d 159.7, 145.8, 142.4, 137.1, 136.7,
(10e). Yellow solid. Mp: 83e84 ꢀC. MS: m/z 321 (MHþ); IR (KBr):
130.8, 128.7, 127.5, 126.8, 112.3, 109.9, 102.4, 67.1, 50.3, 31.4, 28.4,
27.5, 22.5, 14.1. Anal. Calcd for C23H27NO2: C, 79.05; H, 7.79; N, 4.01.
Found: C, 79.13; H, 7.80; N, 4.02.
2918, 2817, 1604, 1496, 1477, 1446 cmꢁ1; 1H NMR (CDCl3):
d 7.85 (d,
J¼7.6 Hz, 2H), 7.46e7.42 (m, 2H), 7.36 (t, J¼7.6 Hz, 1H), 7.00 (s, 1H),
6.94 (s, 1H), 6.61 (s, 1H), 3.50 (t, J¼4.4 Hz, 4H), 2.81 (t, J¼4.4 Hz, 4H),
2.60 (q, J¼7.2 Hz, 2H), 2.45 (s, 3H), 1.22 (t, J¼7.2 Hz, 3H); 13C NMR
4.3.72. N-Isopropyl-2-pentyl-5-phenylbenzo[b]furan-7-amine
(CDCl3):
d
155.1, 145.0, 136.6, 133.3, 130.7, 130.4, 128.7, 128.3, 124.7,
(10l). Yellow oil. MS: m/z 343 (MNaþ); IR (KBr): 2952, 1604, 1577,
113.7, 112.8, 101.5, 52.9, 52.5, 49.8, 21.7, 11.9. Anal. Calcd for
1468, 1448 cmꢁ1; 1H NMR (CDCl3):
d
7.74 (d, J¼7.2 Hz, 2H), 7.50 (t,

1870
A. Arcadi et al. / Tetrahedron 69 (2013) 1857e1871
Liu, L.; Liang, Y.-M. Tetrahedron 2012, 68, 1367e1370; (l) Sakiyama, N.; Noguchi,
K.; Tanaka, K. Angew. Chem., Int. Ed. 2012, 51, 5976e5980; (m) Fisher, E. L.;
Wilkerson-Hill, S. M.; Sarpong, R. J. Am. Chem. Soc. 2012, 134, 9946e9949.
2. (a) De Simone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow, J. W.; Pippin, D. A.
Comb. Chem. High Throughput Screening 2004, 7, 473e493; (b) Horton, D. A.;
Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893e930.
J¼7.6 Hz, 2H), 7.40e7.39 (m, 2H), 7.23 (s, 1H), 6.45 (s, 1H), 4.87 (s,
1H), 2.83 (t, J¼7.2 Hz, 2H), 2.71 (s, 6H), 1.85e1.82 (m, 2H), 1.49e1.46
(m, 4H),1.01 (t, J¼6.8 Hz, 3H); 13C NMR (CDCl3):
d 159.7,142.7,142.3,
137.4, 132.5, 129.6, 128.6, 127.6, 126.6, 109.3, 107.2, 102.6, 48.0, 31.5,
28.5, 27.5, 22.5, 14.1. Anal. Calcd for C22H27NO: C, 82.20; H, 8.47; N,
4.36. Found: C, 82.28; H, 8.46; N, 4.37.
3. (a) Lu, D.; Yang, L.; Li, Q.; Gao, X.; Wangn, F.; Zhang, G. Eur. J. Pharmacol. 2012,
ꢁ
691, 275e282; (b) Romano, E.; Raschi, A. B.; Gonzalez, A. M.; Jaime, G.; Fortuna,
ꢁ
M. A.; Hernandez, L. R.; Bach, H.; Benavente, A. M. Plant Physiol. Biochem. 2011,
49, 671e675; (c) Wu, S.-F.; Chang, F.-R.; Wang, S.-Y.; Hwang, T.-L.; Lee, C.-L.;
Chen, S.-L.; Wu, C.-C.; Wu, Y.-C. J. Nat. Prod. 2011, 74, 989e996.
4.3.73. N-(2-Pentyl-5-phenylbenzo[b]furan-7-yl)piperidin-1-amine
(10m). Yellow oil. MS: m/z 363 (MHþ); IR (KBr): 2933, 1604, 1577,
4. (a) Song, W.-J.; Yang, X.-D.; Zeng, X.-H.; Xu, X.-L.; Zhang, G.-L.; Zhang, H.-B. RSC
Adv. 2012, 2, 4612e4615; (b) Butini, S.; Gemma, S.; Campiani, G.; Franceschini,
S.; Trotta, F.; Borriello, M.; Ceres, N.; Ros, S.; Coccone, S. S.; Bernetti, M.; Angelis,
M. D.; Brindisi, M.; Nacci, V.; Fiorini, I.; Novellino, E.; Cagnotto, A.; Mennini, T.;
Sandager-Nielsen, K.; Andreasen, J. T.; Scheel-Kruger, J.; Mikkelsen, J. D.;
Fattorusso, C. J. Med. Chem. 2009, 52, 151e159; (c) Galal, S. A.; Abd El-All, A. S.;
Abdallah, M. M.; El Diwani, H. I. Bioorg. Med. Chem. Lett. 2009, 19, 2420e2428;
(d) Ando, K.; Kawamura, Y.; Akai, Y.; Kunitomo, J.; Yokomizo, T.; Yamashita, M.;
Ohta, S.; Ohishi, T. Org. Biomol. Chem. 2008, 6, 296e307; (e) Bakunova, S. M.;
Bakunov, S. A.; Wenzler, T.; Barszcz, T.; Werbovetz, K. A.; Brun, R.; Hall, J. E.;
Tidwell, R. R. J. Med. Chem. 2007, 50, 5807e5823; (f) Kozikowsky, A. E. WO
1469, 1442 cmꢁ1; 1H NMR (CDCl3)
d
: 7.75 (d, J¼7.6 Hz, 2H), 7.52 (t,
J¼7.6 Hz, 2H), 7.42e7.39 (m, 2H), 7.22 (s, 1H), 6.46 (s, 1H), 5.03 (s,
1H), 2.87e2.83 (m, 6H), 1.87e1.81 (m, 6H), 1.54e1.43 (m, 6H), 1.03
(t, J¼6.8 Hz, 3H); 13C NMR (CDCl3)
d: 159.6, 142.9, 142.4, 137.3, 132.5,
129.6, 128.6, 127.7, 126.6, 109.2, 107.1, 102.6, 57.6, 31.5, 28.6, 27.6,
26.2, 23.8, 22.5, 14.1. Anal. Calcd for C24H30N2O: C, 79.52; H, 8.34; N,
7.73. Found: C, 79.45; H, 8.35; N, 7.74.
€
010008, 2006. (Chem. Abstr. 2006, 144, 164278 ); (g) Ziegert, R. E.; Torang, J.;
4.3.74. 1-(4-Fluorophenyl)-4-(2-pentyl-5-phenylbenzo[b]furan-7-yl)
€
ꢁ
Knepper, K.; Brase, S. J. Comb. Chem. 2005, 7, 147e169; (i) Marugan, J. J.;
Manthey, C.; Anaclerio, B.; Lafrance, L.; Lu, T.; Markotan, T.; Leonard, K. A.;
Crysler, C.; Eisennagel, E.; Dasgupta, M.; Tomczuk, B. J. Med. Chem. 2005, 48,
926e934; (j) Hu, Y.; Xiang, J. S.; DiGrandi, M. J.; Du, X.; Ipek, M.; Laakso, L. M.;
Li, J.; Li, W.; Rush, T. S.; Schmid, J.; Skotnicki, J. S.; Tam, S.; Thomason, J. R.;
Wang, Q.; Levin, J. I. Bioorg. Med. Chem. 2005, 13, 6629e6644; (k) Gfesser, G. A.;
Faghih, R.; Bennani, Y. L.; Curtis, M. P.; Esbenshade, T. A.; Hancock, A. A.; Cowart,
M. D. Bioorg. Med. Chem. Lett. 2005, 15, 2559e2563; (l) Khan, M. W.; Alam, M. J.;
Rashid, M. A.; Chowdhury, R. Bioorg. Med. Chem. 2005, 13, 4796e4805; (m)
Cowart, M.; Pratt, J. K.; Stewart, A. O.; Bennani, Y. L.; Esbenshade, T. A.; Hancock,
A. A. Bioorg. Med. Chem. Lett. 2004, 14, 689e693; (n) Collini, M. D.; Kaufman, D.
H.; Manas, E. S.; Harris, H. A.; Henderson, R. A.; Xu, Z. B.; Unwalla, R. J.; Miller, C.
P. Bioorg. Med. Chem. Lett. 2004, 14, 4925e4929; (o) Kawasaki, K.; Masabuchi,
M.; Morikami, K.; Sogabe, S.; Aoyama, T.; Ebiike, H.; Niizuma, S.; Hayase, M.;
Fujii, T.; Sakata, K.; Shindoh, H.; Shiratori, Y.; Aoki, Y.; Ohtsuka, T.; Shimma, N.
Bioorg. Med. Chem. Lett. 2003, 13, 87e91; (p) Fleischer, R.; Wiese, M. J. Med.
piperazine (10n). Yellow wax. MS: m/z 465 (MNaþ); IR (KBr): 2929,
1603, 1508, 1473, 1450 cmꢁ1
;
1H NMR (CDCl3):
d
7.68 (d, J¼7.2 Hz,
2H), 7.50 (t, J¼7.6 Hz, 2H), 7.41e7.38 (m, 2H), 7.09e7.02 (m, 5H),
6.47 (s, 1H), 3.61 (t, J¼4.8 Hz, 4H), 3.42 (t, J¼4.8 Hz, 4H), 2.87 (t,
J¼7.2 Hz, 2H), 1.86e1.83 (m, 2H), 1.48e1.34 (m, 4H), 1.00 (t,
J¼6.8 Hz, 3H); 13C NMR (CDCl3):
d
159.7, 158.4 (d, JCeF¼237 Hz),
148.1, 145.9, 142.4, 137.1, 136.6, 128.8, 127.6, 126.8, 118.2, 118.1, 115.6
(d, JCeF¼22 Hz), 112.4, 110.3, 102.4, 50.5, 50.0, 31.4, 28.5, 27.5, 22.5,
14.1. Anal. Calcd for C29H31FN2O: C, 78.70; H, 7.06; N, 6.33. Found: C,
78.62; H, 7.05; N, 6.34.
4.3.75. 4-(2-(4-Methoxyphenyl)-5-methylbenzo[b]furan-7-yl)mor-
€
Chem. 2003, 46, 4988e5004; (q) Bettinetti, L.; Schlotter, K.; Hubner, H.;
pholine (10o). Yellow solid. Mp: 129e130 ꢀC. MS: m/z 346 (MNaþ);
Gmeiner, P. J. Med. Chem. 2002, 45, 4594e4597; (r) Peglion, J.-L.; Goument, B.;
Despaux, N.; Charlot, V.; Giraud, H.; Nisole, C.; Tancredi, A. N.; Dekeine, A.;
Bertrand, M.; Genissel, P.; Millan, M. J. J. Med. Chem. 2002, 45, 165e176; (s) Yoo,
S.; Kim, S.-H.; Lee, S.-H.; Kim, N.-J.; Lee, D.-W. Bioorg. Med. Chem. 2000, 8,
2311e2316.
IR (KBr): 2850, 1601, 1568, 1508, 1479, 1444, 1250, 1026 cmꢁ1 1H
;
NMR (CDCl3):
1H), 6.58 (s, 1H), 4.03 (s, 4H), 3.88 (s, 3H), 3.42 (s, 4H), 2.45 (s, 3H);
13C NMR (CDCl3):
159.9, 155.4, 144.6, 136.4, 133.2, 130.8, 126.2,
d
7.77 (d, J¼8.4 Hz, 2H), 7.00e6.98 (m, 3H), 6.81 (s,
d
5. Saku, O.; Saki, M.; Kurokawa, M.; Ikeda, K.; Takizawa, T.; Uesaka, N. Bioorg. Med.
Chem. Lett. 2010, 20, 1090e1093.
123.4, 114.2, 113.9, 112.1, 99.9, 67.1, 55.4, 50.4, 21.8. Anal. Calcd for
C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C, 74.36; H, 6.56; N,
4.34.
6. (a) Rizzo, S.; Riviare, C.; Piazzi, L.; Bisi, A.; Gobbi, S.; Bartolini, M.; Andrisano, V.;
Morroni, F.; Tarozzi, A.; Monti, J.-P.; Rampa, A. J. Med. Chem. 2008, 51,
2883e2886; (b) Lu, Z.; Ott, G. R.; Anand, R.; Liu, R.-Q.; Covington, M. B.; Vaddi,
K.; Qian, M.; Newton, R. C.; Christ, D. D.; Trzaskos, J.; Duan, J. J.-W. Bioorg. Med.
Chem. Lett. 2008, 18, 1958e1962.
7. Taha, M. O.; Qandil, A. M.; Al-Haraznah, T.; Abu Khalaf, R.; Zalloum, H.; Al-Bakri,
A. G. Chem. Biol. Drug Des. 2011, 78, 391e407.
8. Sidhu, P. S.; Liang, A.; Mehta, A. Y.; Abdel Aziz, M. H.; Zhou, Q.; Desai, U. R.
J. Med. Chem. 2011, 54, 5522e5531.
9. Liu, J.; Dumontet, V.; Simonin, A.-L.; Iorga, B. I.; Guerineau, V.; Litaudon, M.;
Nguyen, V. H.; Gueritte, F. J. Nat. Prod. 2011, 74, 2081e2088.
4.3.76. 1-(7-(2,2-Dimethylhydrazinyl)-5-phenylbenzo[b]furan-2-yl)-
1-phenylethanol (10p). Yellow wax. MS: m/z 373 (MHþ); IR (KBr):
3427, 2924, 1603, 1574, 1495, 1446 cmꢁ1; 1H NMR (CDCl3):
d
7.68 (d,
J¼7.6 Hz, 2H), 7.53e7.21 (m, 10H), 6.68 (s, 1H), 4.84 (s, 1H), 2.85 (br
s, 1H), 2.63 (s, 6H), 2.01 (s, 3H); 13C NMR (CDCl3):
161.2, 145.3,
d
142.6, 142.4, 137.9, 137.7, 132.8, 132.6, 128.6, 128.3, 127.6, 126.7,
125.4, 109.7, 108.0, 104.2, 73.5, 47.9, 29.7, 29.4. Anal. Calcd for
C24H24N2O2: C, 77.39; H, 6.49; N, 7.52. Found: C, 77.48; H, 6.50; N,
7.53.
10. (a) Mitsui, C.; Soeda, J.; Miwa, K.; Tsuji, H.; Takeya, J.; Nakamura, E. J. Am. Chem.
Soc. 2012, 134, 5448e5451; (b) Wang, T.; Li, Z.-Y.; Xie, A.-L.; Yao, X.-J.; Cao, X.-P.;
Kuck, D. J. Org. Chem. 2011, 76, 3231e3238; (c) Hwu, J. R.; Chuang, K.-S.; Chuang,
S. H.; Tsay, S.-C. Org. Lett. 2005, 7, 1545e1548.
11. (a) Liu, J.; Chen, W.; Ji, Y.; Wanga, L. Adv. Synth. Catal. 2012, 354, 1585e1592; (b)
€
Carrer, A.; Brinet, D.; Florent, J.-C.; Rousselle, P.; Bertounesque, E. J. Org. Chem.
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Lett. 2012, 14, 1098e1101; (d) Leibeling, M.; Pawliczek, M.; Kratzert, D.; Stalke,
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Larock, R. C. Comb. Chem. High Throughput Screening 2012, 15, 451e472; (f) Li, C.;
Zhang, Y.; Li, P.; Wang, L. J. Org. Chem. 2011, 76, 4692e4696; (g) Wang, S.; Li, P.;
Lin, Yu.; Wang, L. Org. Lett. 2011, 13, 5968e5971; (h) Luo, Y.; Wu, J. Org. Lett.
2011, 13, 5558e5561; (i) Wu, L.; Shi, X.; Xu, X.; Liang, F.; Huang, G. J. Chem. Sci.
Acknowledgements
The authors are grateful for financial support from the Consorzio
di Ricerca per l’Innovazione Tecnologica, la Qualita e la Sicurezza
degli Alimenti S.C.R.L. (grant number 28497/2006) and from Sapi-
ꢀ
ꢁ
2011, 123, 697e702; (j) Guilarte, V.; Castroviejo, M. P.; Alvarez, E.; Sanz, R.
ꢀ
enza, Universita di Roma.
ꢁ
Beilstein J. Org. Chem. 2011, 7, 1255e1260; (k) Treguier, B.; Rasolofonjatovo, E.;
Hamze, A.; Provot, O.; Joanna Wdzieczak-Bakala, J.; Dubois, J.; Brion, J.-D.;
Alami, M. Eur. J. Org. Chem. 2011, 4868e4876; (l) Cacchi, S.; Fabrizi, G.;
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