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Transition Metal-Catalyzed
Benzofuran Synthesis
Transition Metal-Catalyzed
Benzofuran Synthesis
Transition Metal-Catalyzed
Heterocycle Synthesis Series

Xiao-Feng Wu and Yahui Li

Leibniz-Institut für Katalyse e.V.
an der Universität Rostock (LIKAT),
Rostock, Germany
Elsevier
Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
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CHAPTER
Introduction
1
Benzofurans is a class of heterocyclic compound consisting of fused
benzene and furan rings. As naturally occurring compounds, benzo-
furans have been used in pharmaceuticals, etc. as well (Scheme 1.1).
Due to their potential applications, numerous methodologies have
been developed during the past few decades for their selective and
effective preparation [1].

In this volume, the progress of transition metal-catalyzed furan

synthesis is discussed. Based on the catalysts applied, this text is
organized by Pd, Cu, Ru, Rh, Pt, etc., i.e., the catalyzed reactions for
the synthesis of benzofuran. Some traditional procedures have been
included and discussed here as well to ensure readability.

CH3 HO
O HO
iPr HO
I OH
N HO
H
C 5H 11
O O
O OH
H 3C
I O
Cannabifuran Amiodarone Malibatol A

MeO OMe OMe

N
HO
R1 OMe OH
O
N O
R2
O O Ailanthoidol Antituberculosis agent

R 1=NH2 or N(Me) 2
R 2=H, Me or OMe
R 1= NH2 , R 2=6-OCH 3
R 1=N(CH3 )2 , R 2 =6-OCH 3
Tubulin polymerization inhibitors

Scheme 1.1 Selected examples of benzofuran derivatives.

Transition Metal-Catalyzed Benzofuran Synthesis. DOI: http://dx.doi.org/10.1016/B978-0-12-809377-1.00001-2

Copyright © 2017 Elsevier Inc. All rights reserved.
2 Transition Metal-Catalyzed Benzofuran Synthesis

REFERENCES
[1] a) Hayta, S. A.; Arisoy, M.; Arpaci, O. T.; Yildiz, I.; Aki, E.; Ozkan, S., et al. Eur. J. Med.
Chem. 2008, 43, 2568 2578.
b) Yeung, K.-S. Heterocycl. Chem. 2012, 29, 47 76.
c) Kamal, M.; Shakya, A. K.; Jawaid, T. Int. J. Med. Pharm. Sci. 2011, 1, 1 15.
d) Verma, A.; Pandeya, S. N.; Sinha, S. Int. J. Res. Ayurveda Pharm. 2011, 2, 1110 1116.
e) Deshpande, R.; Bhagawan Raju, M.; Parameshwar, S.; Shanth Kumar, S. M.;
Appalaraju, S.; Yelagatti, M. S. Am. J. Chem. 2012, 115 120.
f) Lin, S.-Y.; Chen, C.-L.; Lee, Y.-J. J. Org. Chem. 2003, 68, 2968 2971.
g) Zhu, R.; Wei, J.; Shi, Z. Chem. Sci. 2013, 4, 3706 3711.
h) Li, B.; Yue, Z.; Xiang, H.; Lv, L.; Song, S.; Miao, Z., et al. RSC Adv. 2014, 4, 358 364.
CHAPTER 2
Pd-Catalyzed Benzofuran Synthesis

In 1986, Marinelli and coworkers developed a palladium-catalyzed

reaction of o-iodophenols with 1-alkynes. This method represents a
very useful procedure for the synthesis of substituted-benzo[b]furan
(Scheme 2.1) [1]. In this procedure, good yields of the benzo[b]furan
can be obtained in the presence of Pd(OAc)2(PPh3)2 (2 mol%), CuI
(4 mol%), and piperidine at room temperature, or 60 C. This method
also has two main advantages. One is mild reaction conditions, and
the other is compatibility with a variety of functional groups, both in
the phenolic and the alkyne moiety.

Later, Kundu and coworkers reported palladium-catalyzed hetero-

annulation of acetylenic compounds for synthesis of benzo[b]furan
(Scheme 2.2) [2]. They synthesized a number of 2-substituted benzofur-
ans from readily accessible starting materials under relatively mild con-
ditions and with fair to excellent yields. Some of the synthesized
compounds were easily converted to known natural products or com-
pounds of biological interest.

Y Pd(OAc) 2 (PPh3 )2 Y
X CuI, piperidine
+ R R
DMF, 25–60 o C O
OH
X = Br, I

Scheme 2.1 Palladium-catalyzed synthesis of benzo[b]furan from alkynes.

I
PdCl2(PPh)3 , CuI
+ R R
OH Triethylamine, DMF O

Scheme 2.2 Palladium-catalyzed synthesis of benzo[b]furan from alkynes.

Transition Metal-Catalyzed Benzofuran Synthesis. DOI: http://dx.doi.org/10.1016/B978-0-12-809377-1.00002-4

Copyright © 2017 Elsevier Inc. All rights reserved.
4 Transition Metal-Catalyzed Benzofuran Synthesis

Scheme 2.2
Synthesis of benzofuran-2-ylmethanol. A mixture of o-iodophenol
(2 mmol), PdC12(PPh3)2 (0.07 mmol), CuI (0.26 mmol), and triethylamine
(4 mmol) was stirred in dimethylformamide (5 mL) under nitrogen for 1 h.
Prop-2-ynyl alcohol (4 mmol) was added, and the mixture was stirred
at room temperature for 1 h more and heated at 60 C for 16 h. The
mixture was then cooled, poured into water (100 mL), and extracted with
dichloromethane (3 3 50 mL). The combined organic extracts were washed
with 5 mol dm23 sodium hydroxide (3 3 100 mL) and water, dried
(MgSO4), and purified by chromatography on neutral alumina.

R' COOMe
R R
PdI 2 -thiourea
R'
CBr 4, Cs 2 CO 3 O
OH
CO, MeOH, 40 ºC

Scheme 2.3 Palladium 2 thiourea catalyzed carbonylative annulation of o-hydroxylarylacetylenes.

Yang and coworkers developed an effective cocatalysis system

(PdI2-thiourea and CBr4) for carbonylative cyclization of both
electron-rich and electron-deficient o-hydroxylarylacetylenes to the cor-
responding methyl benzo[b]furan-3-carboxylates (Scheme 2.3) [3]. The
application of this cocatalyst system to a silyl linker-based solid-phase
benzo[b]furan-3-carboxylate synthesis proved to be as effective as in
solution phase.

In 2003, the same group reported synthesis of conformationally

restricted 2,3-diarylbenzo[b]furan by the Pd-catalyzed annulation of
o-alkynylphenols (Scheme 2.4) [4]. The reaction used Pd2(dba)3 as the
catalyst, bipyridine as the ligand, and gave the desired results in good
yield. The aryl iodides with electron-withdrawing groups gave the best
results, presumably due to their favorable effect on the oxidative addi-
tion to the Pd0 complex.

Scheme 2.4
General Procedure for the Palladium-Catalyzed Formation of
2,3-Biarylbenzo[b]furans. Pd2(dba)3 (46 mg, 0.05 mmol, 5 mol%) was
added to a solution of acetonitrile (3.0 mL), ArI (2.0 mmol, 200 mol%),
 Pd-Catalyzed Benzofuran Synthesis 5

bpy (16 mg, 0.1 mmol, 10 mol%), and K2CO3 (552 mg, 4.0 mmol) and
the mixture was stirred at 50 C for 1 h. To this solution a solution of
o-alkylnylphenol (1.0 mmol, 100 mol%) in acetonitrile (2 mL) was added,
and the reaction mixture was stirred at 50 C for 5 h under Ar2
atmosphere. The reaction mixture was then concentrated, and the residue
was filtered through a silica gel pad and eluted with EtOAc. The filtrate
was concentrated, and the residue was purified by flash chromatography
on silica gel to give the corresponding cyclization product.

R' Ar
R
R
Pd 2(dba) 3 (5 mol%) R'
+ ArI O
bpy (10 mol%)
OH
K2CO 3 , CH 3CN, 50 o C

NO 2
OMe

Ph Ph Ph
O O O
64 % 87 % 74 %
O

Ph Ph
O O 52 %
85 %

Scheme 2.4 Synthesis of 2,3-diarylbenzo[b]furan by the Pd-catalyzed.

The key step of the previous three approaches is attack of a nucleo-

philic phenol oxygen atom onto an activated C C multiple bond. In
2004, Willis et al. reported alternative palladium-catalyzed cyclization
in which the nucleophilic oxygen atom of an enolate was coupled with
a halo-substituted arene ring (Scheme 2.5) [5]. In the presence of
Pd2(dba)3 and the ligand DPEphos, the corresponding benzofurans
were obtained by intramolecular C 2 O bond formation between
1-(2-haloaryl)ketones and aryl halides. Both cyclic and acyclic ketones
are efficient substrates.
6 Transition Metal-Catalyzed Benzofuran Synthesis

R' O R''
R
R Pd 2(dba) 3 (2.5 mol%)
R'' R'
DPEphos(6 mol%) O
Br base(2.2 equiv.), toluene, 110°C

Substrate Product Yield

O O
95%
Br

O
O
94%
Cl

O O
95%
Cl

O O
81%
Br

O O
80%

Br

O O
F 68%

Br
F
O
O N
N
86%
Cl

Scheme 2.5 Palladium-catalyzed intramolecular o-arylation of enolates.

Scheme 2.5
Synthesis of 1,2,3,4-tetrahydro-dibenzofuran. Cesium carbonate (0.18 g,
0.56 mmol) was added to a flask charged with Pd2(dba)3 (9 mg,
0.01 mmol) and DPEphos (13 mg, 0.02 mmol) under nitrogen. The
reagents were suspended in anhydrous toluene (1 mL), 2-(2-bromophenyl)
 Pd-Catalyzed Benzofuran Synthesis 7

cyclohexanone (0.10 g, 0.40 mmol) was added, and the reaction was
heated to 100 C for 20 h. After cooling the reaction mixture was filtered
through a plug of celite and the filtrate reduced in vacuo. The residue
was purified via flash chromatography (petroleum ether) to yield the title
compound (64 mg, 95%) as a colorless oil.

In 2004, Pan and coworkers reported the synthesis of

benzofurans in ionic liquid by a PdCl2-catalyzed intramolecular Heck
reaction (Scheme 2.6) [6]. The reaction was carried out in ionic liquid

PdCl2 (5 mol%), (n-Bu) 3N

O R''' O
NH 4O 2CH, (BMIm)BF 4
R' R' R''
R'' R'''' 60ºC, 24 h
I
R''''
R'''
1 2

1 2 Yield

O O
71%

O O
87%

O O
85%

O n-C 7 H 15 O
n-C 7H 15 78%

I
O O
45%

I I
O O
43%

Cl I Cl

Scheme 2.6 Synthesis of benzo[b]furans in ionic liquid by a PdCl2-catalyzed intramolecular Heck reaction.
8 Transition Metal-Catalyzed Benzofuran Synthesis

(1-n-butyl-3-methylimidazolium tetraborate) and substituted-benzo[b]

furans were obtained in modest to satisfactory yields. Interestingly, the
ionic liquid containing Pd catalyst can be used four times with little loss
of activity.
In 2002, Li and coworkers developed palladium-mediated reactions
for the synthesis of all four possible benzo[4,5]-furopyridine tricyclic
heterocycles, benzo[4,5]furo[2,3-b]pyridine, benzo[4,5]furo[2,3-c]pyri-
dine, benzo[4,5]furo[3,2-c]pyridine, and benzo[4,5]-furo[3,2-b]pyridine,
from the simple substances 2-chloro-3-iodopyridine, 3-chloro-4-stannyl-
pyridine, 4-chloro-3-iodopyridine, and 2-chloro-3-hydroxypyridine, respec-
tively (Scheme 2.7) [7].
In 2005, Yamamoto and coworkers developed platinum-olefin-
catalyzed carbo-alkoxylation of alkynylphenyl acetals for the synthesis
of benzo[b]furan (Scheme 2.8) [8]. The reaction was carried out in the
presence of 2 mol% of PtCl2 and 8 mol% of 1,5-cyclooctadiene (COD)
in toluene at 30 C. They also applied the reaction for the synthesis of
vibsanol, which was isolated from Viburnum awabuki. It is well known
that vibsanol works as an inhibitor of lipid peroxidation. They also
provided a possible mechanism for the reaction (Scheme 2.9).
In 2006, Li and coworkers reported a novel and selective
palladium-catalyzed annulation of 2-alkynylphenols method for the
synthesis of 2-substituted 3-halobenzo [b]furans. The method affords
products with a halide (Cl or Br) at the 3 position. Adding a halide at
the 3 position provides a way to introduce new groups for the synthesis
of new products (Scheme 2.10) [9]. Also, under optimized reaction con-
ditions, most halobenzo [b]furans can be obtained in good yield.
More recently, the same group reported PdCl2-promoted electro-
philic annulation of 2-alkynylphenol derivatives with disulfides or dise-
lenides in the presence of iodine (Scheme 2.11) [10]. This method
allows the reactions between 2-alkynylphenol derivatives and disulfides

I
I I
I
N OH N Me 3 Sn-SnMe 3 N
NaH, DMF, reflus, 89% PdCl2 (Ph 3P)2
Cl O O
xylene,reflux,92%

Scheme 2.7 Synthesis of benzo[4,5]furopyridines via palladium-mediated reactions.

 R''
R'''
R' 2 mol% PtCl2 O

R''' 8 mol% 1,5-cyclooctadiene

Toluene, 30ºC R'
R'' O
O O

Et Et Et
O O O

(CH 2) 4Cl (CH 2) 5CH 3

O O O

92% 91% 94%

Et Et Et
O O O

O
O O O
trace 90% 88%
Bn
Et Et
O
O O

CF3
O
O O
61% 73% 83%

Scheme 2.8 Synthesis of 2,3-disubstituted benzofurans by platinum-olefin-catalyzed arboalkoxylation of alkynyl-

phenyl acetals.

R'''
OR'' R'
PtCl2
R'
O
O

R''' OR''

Cl2 Pt R'
R'''
Cl2Pt –
OR''
R' O
O
R''' OR''

–
PtCl2

R'
O+
OR''
R'''

Scheme 2.9 Possible mechanism.

10 Transition Metal-Catalyzed Benzofuran Synthesis

R X H
PdX 2/CuX 2
R' R' R + R' R
HEt 3NX
OH O O
DCE, rt
Major Minor
X = Cl, Br

Scheme 2.10 Palladium-catalyzed annulations of 2-alkynylphenols to form 2-substituted 3-halobenzo[b]furans.

R' YR'''
R'''
PdCl 2, I 2
R + Y Y R' R'
R''' MeCN; 80ºC
OR'' O
Y = S, Se

Substrate 1 Disulfide 2 Yield

S 92%
S
OMe

CF 3 S
65%
S
OMe

MeO S
93%
S OMe
OMe

F S
S F 87%
OMe

F
S 60%
S
OMe F

Cl S 77%
S Cl
OMe

Scheme 2.11 PdCl2-catalyzed electrophilic annulation of 2-alkynylphenol derivatives with disulfides or diselenides.
 Pd-Catalyzed Benzofuran Synthesis 11

(or diselenides) for the synthesis of 3-chalcogen-benzo[b]furans. The

key step of the reaction is generation of RYI (Y 5 S, Se) in situ from
the reaction of RYYR with I2. PdCl2 can improve the reaction. In the
presence of PdCl2 and I2, a variety of 2-alkynylphenol derivatives
underwent annulation reactions with disulfides or diselenides to
successfully result in corresponding 3-sulfenylbenzofurans and 3-selene-
nylbenzofurans in moderate to excellent yields.

Scheme 2.11
A mixture of 2-alkynylphenol derivative 1 (0.2 mmol), disulfide or disele-
nide 2 (0.1 mmol), I2 (2 equiv.), and PdCl2 (10 mol%) in MeCN (2 mL)
was stirred at 80 C for the indicated time until complete consumption of
starting material as monitored by TLC and GC MS analysis. After the
reaction was finished, the mixture was poured into ethyl acetate, which
was washed with saturated NaS2O3 and extracted with diethyl ether.
The organic layers were dried over anhydrous Na2SO4 and evaporated
under vacuum. The residue was purified by flash column chromatography
(hexane/ethyl acetate) to create the products.

In 2008, Aurrecoechea and coworkers developed a new

Pd-catalyzed tandem intramolecular oxypalladation/Heck-type cou-
pling between 2-alkynylphenols and alkenes, leading to 3-(1-alkenyl)
benzofurans (Scheme 2.12) [11]. In the presence of PdCl2 and KI,
2-alkynylphenols reacted with alkenes, resulting in the desired benzo-
furan with excellent to good yields. The reaction has some features
including (1) a high degree of structural diversity, (2) effective partici-
pation of ketone derivatives without unwanted hydroarylation-type
side reactions, and (3) tolerance of substitution at the electron-deficient
olefin β position.

Scheme 2.12
To a solution of 2-alkynylphenols (0.24 mmol) in DMF (2 mL) was added
PdCl2 (0.003 g, 0.012 mmol), KI (0.020 g, 0.120 mmol) and alkenes
(1.44 mmol) and the mixture was stirred at 80 C for 20 h. The mixture was
allowed to cool to 25 C and water was added. The mixture was extracted
with EtOAc (three times), the combined organic layers were dried
(Na2SO4), and the solvent was removed. The residue was purified by chro-
matography (silica gel, 95:5 hexane/EtOAc) to afford the desired product.
12 Transition Metal-Catalyzed Benzofuran Synthesis

R1 R2

+ alkene PdCl2, KI
DMF, air, 80 oC O
OH

Entry Alkene Product Yield

CO2nBu
O
1 91
O
O
CO2Me
O
2 71
O
O
COMe
O
3 91

O
COMe
O
4 56

O
O
O
5 31

O
O
O
6 36

O
CONH2
O
7 50
NH2
O
Ph

8 57

Scheme 2.12 Palladium-catalyzed cyclization of 2-alkynylphenols and alkenes.

 Pd-Catalyzed Benzofuran Synthesis 13

More recently, Sridhar Reddy and coworkers palladium-catalyzed

tandem intramolecular oxy/amino-palladation/isocyanide insertion for
the synthesis of α-benzofuranyl/indolyl-acetamides (Scheme 2.13) [12].
The reaction does not need oxidant or ligand to promote the cascade
and can be carried out in open air. The reaction also includes isocya-
nide insertion.

In 2015, Chen and coworkers reported one-pot synthesis of

2,3-disubstituted dihydro-benzofurans and benzofurans via rhodium,
palladium-catalyzed intramolecular C H insertion reaction
(Scheme 2.14) [13]. The reactions proceeded via rhodium-catalyzed
ring-opening of N-sulfonyl-1,2,3-triazles, the intramolecular Csp3 H
insertion reaction of a-imino rhodium carbene, and subsequent
palladium-catalyzed dehydrogenation. 2,3-Disubstituted hydrobenzo-
furans and benzofurans can be obtained in good to excellent yields in
a one-pot manner.
The formation of 4 appears to proceed via the insertion of a-imino
rhodium carbene toward a C H bond adjacent to oxygen and
subsequent isomerization of the double bond in the presence of a Pd/C
catalyst. However, when the reaction was carried out under N2 atmo-
sphere instead of H2, the isolated 2 was transformed into benzofuranyl
imine 3 rather than 4 in the presence of Pd/C in CH2Cl2 or EtOH.
This indicates that the transformation of 2 4 is not a simple isomeri-
zation process. Similarly, 3 could also be obtained from 1 via the one-
pot, two-step process in N2 atmosphere (Scheme 2.15).

In 2015, Valdes and coworkers reported Pd-catalyzed synthesis of

benzo[b] fused carbo- and heterocycles through carbine migratory
insertion (Scheme 2.16) [14]. This method is an original approach to
substituted benzofurans, which are constructed by the formation of
two C C bonds on the same carbon atom. However, the yield of this
reaction is low.
In 2016, Jiang and coworkers developed palladium-catalyzed
cascade annulation/arylthiolation reaction in order to create functiona-
lized 3-sulfenylbenzofuran derivatives in moderate to good yields
from readily available 2-alkynylphenols and 2-alkynylamines in ionic
liquids (Scheme 2.17) [15]. This protocol provides a valuable synthetic
tool for the assembly of a wide range of 3-sulfenylbenzofuran deriva-
tives. Another feature of this method is the employment of ionic
liquids under mild reaction conditions.
14 Transition Metal-Catalyzed Benzofuran Synthesis

HO R R O R'''
5 mol% PdCl2
2 equiv. Na2 CO3 NH
R'' R''
2 equiv. R'''NC, MeCN
OH O
open air, rt

Entry Product Yield

t
O Bu
1 NH 85%

t
O Bu
2 NH 82%

t
O Bu
Br NH
3 74%

O
t
O Bu
O 2N NH
4 82%

t
O Bu
5 NH 52%

MeO O

Ph O tBu

6 NH 78%

t
Ph O Bu
7 NH 75%

t
O Bu
O 2N NH
8 81%

Scheme 2.13 Synthesis of α-benzofuranylacetamides via oxypalladation and isocyanide insertion.

 N N
N Ts 1) Rh2 (S-PTV) 4 (1 mol%) NHTs
R''
CH2 Cl2, 90 o C, 2h R''
R'
O R' 2) Pd/C (5 mol%), H 2 (1 atm) O
45ºC.3 h

Entry Product Yield

NHTs

1 90%
O

NHTs

2 91%
O

NHTs

3 88%
O

NHTs
4 68%
Cl
O

NHTs Cl

5 76%
O

NHTs F

6 81%
O

NHTs CF3

7 82%
O

NHTs OMe
8 70%

NHTs

9 OMe 57%
O

Scheme 2.14 One-pot synthesis of benzofurans.

16 Transition Metal-Catalyzed Benzofuran Synthesis

N N TsN NTs
N Ts Rh
Rh 2(L) 4 H - Rh 1,3 H shift
R
O R O R O
H
1 A B

Ts
NHTs N NTs N
H
Pd H -H2 Ts
Pd/C, H2
R R R
R O
O O O

C 3 4
2

Scheme 2.15 Possible mechanism.

Ar
R I NNHTs R
Pd 2(dba) 3 , Sphos
+
Ar H t-BuOLi , 5 equiv. H2 O
O O
CH3 CN, 85ºC

R Ar Yield

H 4-Me 2N-C 6 H4 50%

H 4-MeO-C 6H 4 77%
H Ph 60%
H 4-F-C 6 H 4 57%
H 4-Me-C 6H 4 59%
H 3-Cl-C 6H 4 58%
H 4-CF3 -C 6 H4 68%
H 4-CN-C 6H 4 73%
H 2-Furyl 40%
MeO Ph 68%

Scheme 2.16 Palladium-catalyzed synthesis of benzofurans.

Scheme 2.17
Pd(TFA)2 (5 mol%) and [Bmim]Cl (1 mL) were combined in an Schlenk
tube equipped with a stir-bar and stirred at room temperature for 10 min.
A balloon filled with N2 was connected to the Schlenk tube via the
side tube and purged three times. Then, 2-alkynylphenols (0.20 mmol),
arylboronic acid (0.4 mmol), S8 (0.60 mmol), CuI (0.40 mmol), Phen
 Pd-Catalyzed Benzofuran Synthesis 17

(0.44 mmol), Ag2CO3 (0.4 mmol), and K3PO4 (0.4 mmol) were quickly
added to the tube under N2 atmosphere and stirred at 80 C for 8 h. After
the reaction was completed, the N2 gas was released carefully, and the
reaction was quenched by water and extracted with CH2Cl2 three times.
The combined organic layers were dried over anhydrous Na2SO4 and
evaporated under vacuum. The desired products were obtained in the cor-
responding yields after purification by flash chromatography on silica gel
with hexanes/ethyl acetate.

R'' Pd(TFA) 2 (5 mol%), CuI (1 equiv.) S Ar

Phen (1.1 equiv.)
R' + ArB(OH) 2 + S8 R''
K3 PO4 (2 equiv.), Ag2CO3 (2 equiv.) R'
OH O
(Bmim)Cl (1 mL), N 2 , 80ºC

Entry Product Yield

SPh
1 78%
n
Pr
O

SPh
2 75%
Et
O

SPh
3 S 68%
O
SPh

4 74%
O
Cl

SPh
5 93%
O

SPh
6 80%

F O

Scheme 2.17 Palladium-catalyzed synthesis of 3-sulfenylbenzofurans.

18 Transition Metal-Catalyzed Benzofuran Synthesis

R'' R''
R'''
Pd/C (5 mol% Pd)
R' R' R''' + H 2
H N 2 , DMA, 140ºC
OH O
1 2
D
Pd(0) HPd(II)H
A H2 C

R'' R''
PdH
R''' B R'''
R' R'
O PdH O H
3 4

Scheme 2.18 Palladium-catalyzed synthesis of benzofurans and proposed mechanism.

In 2016, Liu and coworkers reported palladium-catalyzed C H

functionalization of ortho-alkenylphenols for the synthesis of substi-
tuted benzofurans. The reaction used palladium on carbon (Pd/C) as
the catalyst and did not require any oxidants or sacrifice of hydrogen
acceptors (Scheme 2.18) [16]. The reaction also has good tolerance of
different functional groups under optimized coupling conditions.
Ethers, aryl fluorides, carboxylic esters, trifluoromethylbenzenes,
nitriles, and naphthalene also proved compatible. The researchers also
provided an overall mechanism for this catalytic dehydrogenative cou-
pling reaction. In their opinion, the reaction mechanism is formally
similar to a Heck reaction mechanism. The reaction begins with an
oxidative addition in which palladium inserts itself in the O H bond
to form the organopalladium intermediate 3. A similar process in
which palladium (0) inserts itself into O H bonds has been observed
in oxidant- and acceptor-free dehydrogenation of alcohols. Then the
double bond inserts itself in the palladium-oxygen bond in a syn addi-
tion step to generate 4. The intermediate 4 is then converted into the
target compound by a β-hydride elimination step with the formation of
HPdH. The palladium(0) compound is regenerated by reductive elimi-
nation of the HPd(II)H with H2.

In 2016, Zhou and coworkers reported the synthesis of (Z)-α-tri-

fluoromethyl alkenyl triflates and their applications in a straightfor-
ward synthesis of trifluoromethylated benzofurans (Scheme 2.19) [17].
 Pd-Catalyzed Benzofuran Synthesis 19

CF3
CF3 1) KHCO3 (2.0 equiv.), DMF, 30ºC
R
OTf 2) 2-IC 6 H 4OH (1.2 equiv.), Pd 2(dba)3 (10 mol%), R
O
(t-Bu) 3 P (0.8 equiv.), K 2 CO3 (5.0 equiv.), DMF,

140ºC
Entry Product Yield

CF3

1 60%
O

CF3

2 61%
O
Cl
CF3
3 50%
O
OMe
CF3
4 61%
Ph
O

Scheme 2.19 Synthesis of 3-trifluoromethylbenzofuran.

The reaction used Pd(OAc)2 as the catalyst, X-Phos as the ligand, and
Cs2CO3 as the base. Their method can also be used for the synthesis of
3-trifluoromethylbenzofuran, which is an essential structural motif in
biologically active compounds.

In 2011, Li and coworkers reported palladium-catalyzed selective

heck-type diarylation of allylic esters with aryl halides. This methodology
can also be applied in constructing the indole and benzofuran skeletons
(Scheme 2.20) [18]. Both 2-iodophenol and 2-bromophenol are
also suitable substrates, providing the desired benzofuran in satisfactory
yields.

In 1998, Bumagin and coworkers developed Pd21-catalyzed

oxidative cyclization of 2-allylphenols for synthesis of benzofurans
(Scheme 2.21) [19]. Oxidative cyclization of 2-allylphenols can be
performed easily and under mild conditions using palladium dichloride
as a catalyst, Cu(OAc)2 LiCl as a reoxidant, and aqueous
20 Transition Metal-Catalyzed Benzofuran Synthesis

OH O
R PdCl2
OY +
X n-Bu 4 NCl, K 2 CO3 R
R' R'
X = I, Br DMA, 100ºC
1 2
1 2 Product

OH
OAc
I O 71%
OH
OAc
Br O
52%

Scheme 2.20 Palladium-catalyzed synthesis of benzofuran.

2 mol% PdCl 2, Cu(OAc) 2, LiCl

R R
OH DMF-H 2O, RT O

Scheme 2.21 Synthesis of benzofurans via Pd21-catalyzed oxidative cyclization of 2-allylphenols.

dimetyl-formamide as a solvent. A number of functionalized 2-methyl-

bezofurans were obtained in high yields.
In 2010, Correia and coworkers developed an intramolecular
Heck Matsuda reaction and applied it in the syntheses of benzofurans
and indoles (Scheme 2.22) [20]. The reaction has a wide scope of sub-
strates. Both electron-donating and/or electron-withdrawing groups at
the aromatic position can be tolerated. However, electron-rich, -poor
and -neutral substituents resulted in Heck adducts in lower yields,
compared to those obtained for an unsubstituted benzofuran.
In 2011, Lu and coworkers reported the synthesis of 1-benzoxepine
derivatives via cationic palladium-catalyzed [5 1 2] annulation reaction
of 2-acylmethoxyarylboronic acids with allenoates (Scheme 2.23) [21].
This annulation involves the intramolecular nucleophilic addition to
ketones without the formation of π-allylpalladium species.

In 2015, Stahl and coworkers reported a palladium-catalyzed

aerobic oxidative dehydrogenation system that can be used for synthe-
sis of benzofurans (Scheme 2.24) [22]. The reaction used O2 as the
 Pd-Catalyzed Benzofuran Synthesis 21

O Pd(OAc) 2 (5 mol%) O
R
N 2BF4 MeOH, 50ºC

Entry Substrate Product

O O
1

N 2BF4
30%

O O
2

MeO N 2BF4 MeO

31%

O O
3

Cl N 2BF4 Cl
trace

Scheme 2.22 Synthesis of benzofurans via Pd21-catalyzed cyclization of the aryl o-allylether.

B(OH) 2
(Pd(dppp)(H 2 O) 2) 2+(TfO -) 2
+
O CO2Et dioxane, 0.5h, 80ºC O
O 73%

Scheme 2.23 Synthesis of benzofurans via annulation reaction of the 2-formylphenylboronic acids with substituted
allenoates.

oxidant, which enables efficient synthesis of substituted arene deriva-

tives and shows good functional group tolerance.

In 2011, Sanz and coworkers reported a Pd-catalyzed Buchwald

protocol in an attempt to synthesize the desired dimethoxybenzo[b]
furan derivatives (Scheme 2.25) [23]. The reaction of the previously
prepared o-haloaryl alkynes with KOH, in the presence of catalytic
amounts of Pd2(dba)3 and t-BuXPhos at 100 C in a 1:1 mixture of
H2O:1,4-dioxane, gave rise to the corresponding benzo[b]furan deriva-
tives in moderate to good yields.

In 2013, Chen and coworkers developed a new synthesis of 2-aryl-

benzofurans by palladium-catalyzed reaction of arylboronic acid with
22 Transition Metal-Catalyzed Benzofuran Synthesis

5% Pd(OAc) 2 /25 % pTsOH

20% AMS
MgSO 4, PhCl 1M
24h, 110ºC, O2

Substrate Product Yield(conv.)

31(34)

53(61)

62(100)
O O

Scheme 2.24 Synthesis of benzofurans via annulation reaction of the 2-formylphenylboronic acids with substituted
allenoates.

OMe R OMe
Pd2 (dba) 3 (2 mol%)
t-BuXPhos (8 mol%)
+ KOH R
X H 2 O/1,4-dioxane(1/1) O
MeO MeO
C: 100ºC, 12–24 h
D: MW (150ºC), 12 min 50–81%

Scheme 2.25 Synthesis of benzofurans.

aliphatic nitriles (Scheme 2.26) [24]. The reactions used Pd(OAc)2

(5 mol%) as the catalyst, bpy (10 mol%) as the ligand, TFA as the
additive, and THF-H2O as the solvent. The electronic properties of the
groups on the phenyl ring of the benzoboronic acid had some effect on
the yield of the reaction. Arylboronic acids, which have electron-
donating groups at the para position, have higher yield.
In 2013, the same group also developed a new method for synthesis
of benzofurans from potassium aryltrifluoroborates and hydroxyphe-
nylacetonitriles (Scheme 2.27) [25]. The reaction used Pd(CF3CO2)2 as
the catalyst, bpy (10 mol%) as the ligand, TFA (10 equiv.) as the addi-
tive, and THF-H2O as the solvent.
 Pd-Catalyzed Benzofuran Synthesis 23

CN Pd(OAc) 2 (5 mol%)
ArB(OH) 2 + R R Ar
OH bpy,TFA, THF-H 2O, O
N 2, 80 o C

Entry R Ar Yield[b] (%)

1 H Ph 94

2 H 4-MeC6H4 91

3 H 4-MeOC6H4 92

4 H 4-FC6H4 86

5 H 4-ClC6H4 84

6 H 4-BrC6H4 81
H
7 4-PhC6H4 85
4-Me
8 Ph 91
3-MeO
9 Ph 89
4-Cl
10 Ph 81
4-Br
11 Ph 80

Scheme 2.26 Palladium-catalyzed synthesis of 2-arylbenzofurans.

In 2010, Manabe and coworkers reported palladium-catalyzed synthesis

of bentofuran from 2-chlorophenols (Scheme 2.28) [26]. This method used
a bifunctional ligand L1 for cross-coupling of chloroarenes, and provided a
new example of benzofuran synthesis from 2-chlorophenol.
In 2008, Burch and coworkers developed a palladium-catalyzed
one-pot synthesis of benzofuran from o-bromophenols (Scheme 2.29) [27].
The reaction used Pd(OAc)2 as the catalyst, rac-DTBPB as the ligand,
and NaOtBu as the additive. Then, treatment of the reaction mixture
with a 1:1 mixture of CH2Cl2 and trifluoroacetic acid provided the
benzofurans.
In 2008, Li and coworkers developed a palladium/copper cocata-
lyzed cross-coupling reaction of terminal alkynes with (E)-2,3-diio-
doalkenes for the synthesis of benzofuran (Scheme 2.30) [28]. The
reaction used Pd(OAc)2 and CuI as the catalyst, Et3N as the base, and
THF as the solvent.
 CN Pd(OAc) 2 (5 mol%)
ArBF 3K + R R Ar
OH bpy,TFA, THF-H 2O, O
N 2, 80ºC

t-Bu
O O O
97% 92% 95%

OMe Ph
O O O
79% 89% 96%
Cl

F Cl
O O O
88% 75% 85%

Cl
Br I
O O O
76% 68% 73%
Cl Br Br
t-Bu t-Bu
O O O
72% 67% 64%

t-Bu Cl
O O O
91% 91% 81%

Scheme 2.27 Synthesis of benzofurans from the potassium aryltrifluoroborates to 2-hydroxyphenylacetonitriles.

Cl PdCl2(CH 3CN)2 (2 mol%)

R' + R R Ar
L (4 mol%), t-BuOLi (3.6 equiv.),
OH O
t-BuOH, 110ºC

MeO Ph F N
C 10H21 OMe
O O O
42% 78% 79%
Cl
Cl
C10H 21 C 10H21 OMe
O O O
61% 88% 34%

PCy 2 HO

L1

Scheme 2.28 Benzofuran synthesis from 2-chlorophenols and alkyne.

 Pd-Catalyzed Benzofuran Synthesis 25

1. Pd(OAc) 2 (5 mol%)
Ligand (10 mol%)
NaO tBu (2.7 equiv.) R1
O
Br
toluene, 80ºC
+ R1 R2
OH 2. TFA/CH 2Cl 2, 23ºC O
R2

Entry Substrate Product Yield [%]

O
1 76
O

2 59
O

O
3 73
O

O O
O
4 65
O
O O

5 84
O

S O S
6 70
O

7 41
O

O
8 75
O

9 84
O

Scheme 2.29 One-pot synthesis of benzofurans.

26 Transition Metal-Catalyzed Benzofuran Synthesis

THF as the solvent.

Pd(OAc) 2 (1 mol%)
OH I R1 O
CuI (5 mol%)
R + R R1
I THF/Et3 N (4:1)
r.t., 18 h, reflux, 18 - 36 h
1 2
R 1 = Ar, Alkyl, CO2 Et

Entry 1 2 Yield (%)

I CO 2Et
1 33
OH I

I Ph
2 63
OH I

I
3 OH 58
OH I

O 2N I Ph
4 91
OH I

OHC
I Ph
5 36
OH I
OMe
Cl nC
I 8H 17
6 57
OH I
Cl

Scheme 2.30 One-pot synthesis of 2-ethynylbenzofurans.

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Another random document with
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 Myyminen ja ostaminen on ohitse.

Kaikki aartehistot ovat kasatut kokoon molemmin puolin, ja minun

on aika mennä kotiin.

Mutta, ovenvartija, kysytkö tulliasi?

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Hoi, lauttamies, sinä odotat palkkaasi!

Kyllä, veljeni, minulla on vielä jotakin jäljellä. Kohtaloni ei ole

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Tien varrella, puun varjossa, istuu kerjäläinen. Ah, hän katsoo

kasvoihini arasti toivoen!

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Kyllä, veljeni, minulla on vielä jotakin jäljellä. Kohtaloni ei ole

kaikessa vetänyt nenästä minua.

Yö pimenee ja katu yksinäistyy.

 Tulenkipinät hiiluvat läpi lehtien.

Ken olet sinä, joka seuraat minua hiipivin, hiljaisin askelin?

Ah, tiedän, että toivosi on ryöstää kaikki säästöni. En tahdo tuottaa

sinulle mielipahaa.

Sillä minulla on vielä jotakin jäljellä. Kohtaloni ei ole kaikessa

vetänyt nenästä minua.

Tulen kotiin keskiyöksi. Käteni ovat tyhjät.

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Kuin uupunut lintu lennät povelleni kiihkeässä rakkaudessa.

Oi, oi Jumalani, paljon on vielä jäljellä. Kohtaloni ei ole kaikessa

vetänyt nenästä minua.

59

Et mitään loppumatonta hyvää anna, suvaitsevainen ja sumuinen

äiti, tomu!

Kulutat voimasi täyttääksesi lastesi suut, mutta ravintosi on niukka.

Ilosi lahja, jonka suot meille, ei ole koskaan täydellinen.

Leikkikalut, joita laitat lapsillesi, ovat hauraita.

 Et voi täyttää kaikkia nälkäisiä toiveitamme, mutta miksi sinut sen
vuoksi hylkäisin?

Hymysi, tuskan varjostama, on suloinen nähdä silmilleni.

Rakkautesi, joka ei tunne täyttymystä, on kallis sydämelleni.

Povesi on ruokkinut meitä elämällä, mutta ei kuolemattomuudella;

siksi valvovat silmäsi ainiaan.

Aikakausia olet värein ja lauluin työskennellyt, mutta vieläkään ei

taivaasi ole valmis, ainoastaan sen heikko mielikuva.

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Tahdon tyhjentää lauluni mykkään sydämeesi ja lempeni sinun

lempeesi.

Tahdon turvata sinut työllä.

Olen nähnyt vienot kasvosi ja rakastan murheellista tomuasi, Äiti

Maa.

60

Maailman vastaanottosaleissa viihtyvät yksinkertaiset heinänkorret

samalla nurmikolla päivänsäteiden ja keskiyön tähtien kanssa.

Niinpä jakavat lauluni tyyssijansa maailman sydämessä pilvien ja

metsien sävelten kanssa.
 Mutta, rikas mies, sinun hyvinvoinnillasi ei ole mitään osaa
auringon iloisen kullan ja mietiskelevän, kimmeltävän kuun
yksinkertaisesta suuruudesta.

Kaikkisyleilevän taivaan siunaus ei ole langennut sen yli.

Kun kuolema tulee, se kalpenee, kuihtuu ja hajoaa tomuksi.

61

Keskiyöllä sanoi askeetiksi aikovainen:

"Nyt on aikani jättää kotini ja etsiä Jumalaa. Ah, kuka on niin

kauan pitänyt minua tässä harhaluulossa?"

Jumala kuiskasi: "Minä." Mutta miehen korvat olivat suljetut.

Nukkuva lapsonen rinnoillaan makasi hänen vaimonsa

rauhallisessa levossaan vuoteen toisella puolen.

Mies sanoi: "Kuka olet sinä, joka olet minua niin kauan
hulluttanut?"

Ääni sanoi jälleen: "Jumala." Mutta mies ei kuullut sitä.

Lapsi nyyhki unissaan ja puristautui lähemmä äitiään.

Jumala käski: "Seis, hullu, älä jätä kotiasi!" Mutta mies ei kuullut
vieläkään.
 Jumala huokasi valittaen: "Miksi vaeltaa palvelijani minua
etsimään ja samalla jättää minut?"

62

Oli toukokuu. Tukahduttava iltapäivä tuntui äärettömän pitkältä.

Kuiva maa ammotteli janoisena helteessään.

Silloin kuulin joelta äänen, joka sanoi: "Tule, armahaiseni!"

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vedessä ja pyytävänä sitä uimaan.

Hymyilin huvittuneena ja tunsin suloisen henkäyksen

sydämessäni.

63

Miksi kuiskit niin hiljaa korviini, oi Kuolema, minun Kuolemani?

Kun kukkaset putoavat illan suussa ja karjat palajavat

omettoihinsa, hiivit hiljaa minun vierelleni ja puhut sanoja, joita en
tajua.
 Näinkö sinun täytyy etsiä ja saavuttaa minut uneliaan muminan ja
kylmien suuteloiden oopiumilla, oi Kuolema, minun Kuolemani?

Eikö häitämme seuraa mitkään komeat juhlamenot?

Etkö tahdo kiinnittää seppeltä ruskeihin, kihariin kutreihisi?

Eikö ole ketään, joka kantaisi lippua sinun edessäsi ja eikö yö ole
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Kuolemani?

Tule rauskuvine raakunkuorinesi, tule unettomassa yössä!

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Kuolemani!

64

Tulemme leikkimään tänä yönä kuoleman leikkiä, morsiameni ja

minä.

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 Olemme jättäneet untemme vuoteen, sysänneet auki oven ja
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Me seisomme silmä silmää, sydän sydäntä vasten, morsiameni ja

minä.
 65

Viheliäisten ja keltaisten riisivainioiden yli luovat syksyn varjot

pilviään, joita nopsa-askelinen päivä ajelee. Mehiläiset unohtavat
imeä hunajaansa; valon juovuttamina ne liehuvat ja surisevat kuin
hullut

Sorsat joen saarissa hälisevät ilosta tyhjän takia.

Älkää antako kenenkään palata kotiinsa tänä aamuna, veljet,

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Valloittakaamme hyökkäyksellä sininen taivas ja työstäkäämme

aarteet avaruuden!

Nauru kulkee ilmassa kuin vaahto virralla.

Veljet, tuhlatkaamme aamumme arvottomiin lauleloihin!

66

Ken olet, lukija, joka luet laulujani vuosisatoja tämän jälkeen?

En voi lähettää sinulle yksinäistä kukkaa tämän keväämme

runsaudesta, en yksinäistä kultajuovaa pilvien korkeudesta.

Avaa ovesi ja katso ympärillesi!

Kokoa tuoksuvia muistoja kukkivasta tarhastasi, vuosisatoja sitten

kuihtuneiden kukkien muistoja!
 Tunteos sydämesi ilossa elävä riemu, joka lauloi eräänä kevään
aamuna kaiuttaen hilpeät sävelensä halki vuosisatojen.
 *** END OF THE PROJECT GUTENBERG EBOOK PUUTARHURI
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