Cationic palladium(II)-catalyzed synthesis of 2-substituted 3-hydroxymethylbenzo[b]furans

Article abstract of DOI:10.1055/s-0030-1289519

A tandem reaction involving an intramolecular oxypalladation of an alkyne and an addition to the carbonyl group to quench the carbon-palladium bond to complete the catalytic cycle was developed. The reaction was catalyzed with the cationic palladium(II) species without the necessity of a redox system. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1289519

2590
LETTER
Cationic Palladium(II)-Catalyzed Synthesis of 2-Substituted
3-Hydroxymethylbenzo[b]furans
2
-Substituted 3-H
y
u
droxymethy
a
lbenzo[
b
]fu
n
rans Wang, Xiuling Han,* Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Lu, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: xylu@mail.sioc.ac.cn
Received 29 July 2011
In an effort to expand the synthetic scope of previously re-
ported palladium(II)-catalyzed annulation reactions, we
explored here the reaction of 2-alkynylphenols with alde-
hydes to prepare substituted 3-hydroxymethylbenzo-
furans in one pot. In the literature, such compounds
usually can be obtained by the reaction of 3-metalated
benzofuran with aldehydes or ketones,9 or from benzo-
furans and aldehydes by a Friedel–Crafts reaction.10
Abstract: A tandem reaction involving an intramolecular oxypalla-
dation of an alkyne and an addition to the carbonyl group to quench
the carbon–palladium bond to complete the catalytic cycle was de-
veloped. The reaction was catalyzed with the cationic palladium(II)
species without the necessity of a redox system.
Key words: aldehyde, alkyne, cationic palladium(II) complex, 3-
hydroxymethylbenzofuran, oxypalladation
Initially, 2-phenylethynylphenol (1a) and p-nitrobenzal-
dehyde (2a) were chosen as the substrates to study the an-
nulation reaction. Different palladium catalysts were
firstly surveyed. When cationic palladium catalysts
[Pd(dppp)(H2O)2](BF4)2 and [Pd(dppp)(H2O)2](OTf)2
were used, the annulation product 3aa could be obtained
in moderate yield (Table 1, entries 1 and 2) together with
the byproduct 2-phenylbenzofuran (3aa¢). However,
when the catalyst such as [Pd(bpy)(H2O)2](OTf)2,
Pd(OAc)2/bpy or Pd(CO2CF3)2/dppp was used, no product
could be detected (Table 1, entries 3, 7, and 8). The cat-
ionic palladium(II) complexes took advantage in this re-
action, which maybe due to their stronger Lewis acidity
and vacant coordination.11 Then a binuclear cationic pal-
ladium catalyst [Pd(dppp)(m-OH)]2(BF4)2 was used, the
desired product 3aa could be obtained in 85% yield
(Table 1, entry 4). THF was the best solvent (Table 1, en-
tries 4–6). When 4 Å molecular sieve was added to the re-
action system catalyzed by [Pd(dppp)(H2O)2](BF4)2, the
yield of 3aa increased to 90% (Table 1, entry 9).12 Subse-
quently, the effect of temperature on the reaction was
studied. Higher temperature was not good for the reaction,
and lower temperature slowed the reaction progress (36 h,
Table 1, entries 10–12). Finally, [Pd(dppp)(H2O)2](BF4)2
and 4 Å MS in THF at 45 °C were used as the optimal con-
ditions. In the screening process above, the 2-phenylben-
zofuran was found to be the main byproduct.
The benzofuran moiety is popular in many biologically
active natural and therapeutic products.1 Some benzofu-
ran-containing products may serve as targets or precursors
for pharmaceutical researches and even as promising units
in material science.2 Many efforts have been made to
achieve an efficient synthesis of this skeleton.3 Among the
various approaches to benzofurans, the transition-metal-
catalyzed intramolecular cyclization would be straightfor-
ward and versatile.4 It is worth noting that palladium-cat-
alyzed heteroannulation reactions are now emerging as a
unique, powerful, and versatile synthetic approach toward
a variety of structural cores of heterocycles, especially for
indoles and benzofurans.4a,b,e Palladium(0)-catalyzed an-
nulation reactions of o-alkynyl-allyloxybenzenes or o-
alkynylphenols with allyl carbonates were reported.5
There were also some reports for the palladium(II)-cata-
lyzed synthesis of multiply substituted benzofurans from
2-alkynylphenols because of their availability. Some
groups reported the carboxylative annulation to synthe-
size benzofuran-3-carboxylic esters or acids.6 Papers re-
lated to the synthesis of 3-alkenylbenzofurans by an
oxypalladation–Heck-type coupling reaction were also re-
ported.7 In all of these tandem reactions, a redox system is
necessary for the regeneration of the catalytic palladi-
um(II) species.
In our previous work, we developed some tandem reac-
tions initiated by nucleopalladation of alkynes and
quenched by 1,2-addition to carbon–heteroatom multiple
bonds.8 The use of Pd(OAc)2/bpy or cationic palladium
complexes as catalysts is the key for the success of these
reactions. In all of these reactions, palladium(II) species
were regenerated in the final protonolysis step to complete
the catalytic cycle without the necessity of a redox system.
Under the optimized reaction conditions as shown in
Table 1 (entry 9) a series of substituted 2-alkynylphenol
and aromatic aldehydes were chosen to test this annula-
tion reaction as shown in Table 2. Aldehydes with a
strong electron-withdrawing group such as NO2, CN, or
CF3 on the benzene ring provided good results (Table 2,
entries 1–4, 10, and 11). When there are one or more halo-
gen atoms on the benzene ring of the aldehydes, the reac-
tions could proceed smoothly to provide the
corresponding products in moderate to excellent yields
(Table 2, entries 5–9 and 12). 4-Acetylbenzaldehyde
could also react with 1a in a yield of 52% (Table 2, entry
SYNLETT 2011, No. 17, pp 2590–2594
x
x
.x
x
.2
0
1
1
Advanced online publication: 06.10.2011
DOI: 10.1055/s-0030-1289519; Art ID: W16711ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
2-Substituted 3-Hydroxymethylbenzo[b]furans
2591
Table 1 Optimization of the Reaction Conditionsa
Ph
NO2
CHO
HO
catalyst
+
+
Ph
O
Ph
OH
O
NO2
1a
2a
3aa
3aa'
Entry
Catalyst
Solvent
THF
Time (h)
Yield of 3aa (%)b
1c
2
[Pd(dppp)(H2O)2](BF4)2
[Pd(dppp)(H2O)2](OTf)2
[Pd(bpy)(H2O)2](OTf)2
[Pd(dppp)(m-OH)]2(BF4)2
[Pd(dppp)(m-OH)]2(BF4)2
[Pd(dppp)(m-OH)]2(BF4)2
Pd(OAc)2/bpy
1.7
13
48
3
66
THF
54
3
THF
n.r.
85
4
THF
5
DME
dioxane
THF
8
trace
59
6
7
7
48
48
2.5
2
n.r.
n.r.
90
8
Pd(CO2CF3)2/dppp
THF
9d
10c,d
11d,e
12d,f
[Pd(dppp)(H2O)2](BF4)2
[Pd(dppp)(H2O)2](BF4)2
[Pd(dppp)(H2O)2](BF4)2
[Pd(dppp)(H2O)2](BF4)2
THF
THF
66
THF
2.8
36
85
THF
94
a A mixture of 1a (0.1 mmol), 2a (0.2 mmol, 2.0 equiv), and the catalyst (5 mol%) were stirred at 45 °C in solvent.
b Isolated yields.
c Reflux.
d 4 Å MS was used.
e 60 °C.
f At r.t.
13). It is worth noting that benzaldehyde or 1-naphthylal- Furthermore, the reaction hardly occurred for 2-methyl-
dehyde could also be used to react with 1a, even the yields benzaldehyde. For the substrates 2-alkynylphenols,
were low (Table 2, entries 15 and 24).
alkynes bearing aryl groups substituted with F, Br, Me, or
MeO reacted well with p-nitrobenzaldehyde to give the
desired products (Table 2, entries 16, 17, and 19–22).
However, when the phenyl (R2) group was replaced by n-
Bu or CH2OMe, no reactions occurred at all. Then, some
other activated aldehyde or ketone was used to examine
the annulation reaction. Both ethyl glyoxylate and 3,3,3-
trifluoropyruvate could react with substrate 1a in moder-
ate yields (Scheme 1). From the above-mentioned results,
it could be seen that strong electron-withdrawing groups
on the aldehydes were very important for this tandem re-
action, which might be due to the change of the electro-
philicity of the carbon atom of the aldehydes.
Ph
HO
CO2Et
OH
1a
[Pd(dppp)(H2O)2](BF4)2, 4 Å MS
+
THF
45 °C
O
O
3aq 56%
H
CO2Et
2q
Ph
Some control experiments were also run to gain further in-
sight into the mechanistic details of this sequential pro-
cess. From the literature, it is known that 2-alkynylphenol
derivatives could be easily transformed to benzofuran
through intramolecular cyclization reaction under transi-
tion-metal catalysts,13 and 3-unsubstituted benzofurans
were also the main byproducts in our reactions. So the
question aroused whether the intramolecular cyclization
of 2-alkynylphenol occurred first and the generated ben-
CF3
CO2Et
HO
OH
1a
[Pd(dppp)(H2O)2](BF4)2, 4 Å MS
+
THF
45 °C
O
O
3ar 44%
F3C
CO2Et
2r
Scheme 1 Tandem annulation reaction of 2-phenylethynylphenol
with activated aldehyde or ketone
Synlett 2011, No. 17, 2590–2594 © Thieme Stuttgart · New York

2592
H. Wang et al.
LETTER
Table 2 Tandem Annulation Reaction of 2-Arylethynylphenols
zofuran subsequently transferred to the final products
through palladium(II)-catalyzed Friedel–Crafts-type reac-
tion. However, when 2-phenylbenzofuran was employed
to react with p-nitrobenzaldehyde under standard reaction
conditions, no reaction occurred at all (Scheme 2). This
result indicated that our reaction was a tandem reaction,
not a one-pot, two-step process.
with Substituted Aldehydesa
R2
R1
OH
HO
1
R3
[Pd(dppp)(H2O)2](BF4)2, 4 Å MS
+
THF
45 °C
CHO
R1
R2
CHO
O
[Pd(dppp)(H2O)2](BF4)2, 4 Å MS
no reaction
+
Ph
3
THF
45 °C
O
R3
NO2
2
Scheme 2 Reaction of 2-phenylbenzo[b]furan with p-nitrobenzal-
dehyde
Entry
1
R1
2
R3
Yield (%)b
R2
A possible mechanism of this annulation reaction was
proposed as shown in Scheme 3. Initially, the active pal-
ladium species A, which came from the dissociation of the
cationic palladium complex, activated the triple bond of
the substrate 1 through coordination to form intermediate
B. Then intermediate C was generated by an intramolecu-
lar attack of hydroxyl group to the activated triple bond.
The carbon–palladium bond in intermediate C added to
the carbonyl group of the aldehyde through intermediate
D to produce intermediate E. The final product 3 was
formed via protonolysis of intermediate E with regenera-
tion of the palladium(II) species to make the catalytic cy-
cle possible. Concerning the generation of the byproduct
as shown in Scheme 3, the shift of the lone-pair electron
of the oxygen atom may promote the protonolysis of the
vinyl–Pd bond in the intermediate C.
1
2
H
1a Ph
2a 4-O2N
2b 2-O2N
2c 3-O2N
2d 4-CN
2e 2,4,5-F3
2f 4-Cl
3aa 90
3ab 98
3ac 83
3ad 93
3ae 85
3af 53
3ag 52
3ah 45
3ai 100
3aj 100
3ak 100
3al 82
3am 52
trace
H
1a Ph
3
H
1a Ph
4
H
1a Ph
5
H
1a Ph
6
H
1a Ph
7
H
1a Ph
2g 2,6-Cl2
2h 2,4-Cl2
2i 2,3-Cl2
8
H
1a Ph
9
H
1a Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
H
1a Ph
2j 2-Cl-3-F3C
2k 2-Cl-5-O2N
2l 2-Br
H
1a Ph
In conclusion, we developed a new process for the synthe-
sis of 2,3-disubstituted benzo[b]furans from readily ac-
cessible 2-alkynylphenols and aldehydes through cationic
palladium(II) complex catalyzed annulation reaction.14
This is a tandem reaction involving an oxypalladation of
the alkyne followed by an addition to the carbonyl group
of the aldehyde to quench the carbon–palladium bond by
protonolysis. This tandem reaction is catalyzed by cation-
ic Pd(II) species under relatively mild conditions and has
a good tolerance of substituents without the necessity of a
redox system. The asymmetric version of this reaction is
under way in our group.
H
1a Ph
H
1a Ph
2m 4-Ac
2n 2-Me
2o H
H
1a Ph
H
1a Ph
3ao 37
3ba 81
3ca 68
n.r.
H
1b 4-MeC6H4
1c 4-BrC6H4
1d n-Bu
1e Ph
2a 4-O2N
2a 4-O2N
2a 4-O2N
2a 4-O2N
2a 4-O2N
2a 4-O2N
2a 4-O2N
2a 4-O2N
2pc
H
H
4-Me
4-F
4-Br
3ea 64
3fa 58
3ga 44
3ha 66
n.r.
1f Ph
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
1g Ph
5-OMe 1h Ph
Acknowledgment
H
H
1i CH2OMe
1a Ph
The National Basic Research Program of China 2011CB808706 is
acknowledged. We also thank the National Natural Science Found-
ation of China (20732005, 20872158) and Chinese Academy of Sci-
ences for financial support.
3ap 51
a A mixture of 1 (0.1 mmol), 2 (0.2 mmol, 2.0 equiv), 4 Å MS (20 mg),
and [Pd(dppp)(H2O)2](BF4)2 (5 mol%) were stirred in THF at 45 °C
for 2–5 h.
b Isolated yields.
c Compound 2p is 1-naphthylaldehyde.
Synlett 2011, No. 17, 2590–2594 © Thieme Stuttgart · New York

LETTER
2-Substituted 3-Hydroxymethylbenzo[b]furans
2593
2+
P
P
OH2
OH2
Pd
2
2 –BF4
2
– 2HBF4
+
Pd
P
P
O
P
P+d
O
H
P
R2
2 –BF4
HO
R3
R2
R1
OH
1
OH
Pd
P
P
R1
–BF4
O
A
PdII
OH
R2
PdIIO
R1
R3
B
R2
R1
O
O
PdII
PdII
R3
H+
R1
R2
R1
R2
R1
R2
O
O
O
byproduct
C
D
Scheme 3 Possible mechanism for the annulation reaction of 2-alkynylphenols and aldehydes
(7) Martínez, C.; Álvarez, R.; Aurrecoechea, J. M. Org. Lett.
2009, 11, 1083.
References and Notes
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108, 3395. (e) Hosokawa, T.; Murahashi, S. In Handbook of
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(12) The paper reported that {Pd[(R)-Tol-BINAP](H2O)2}(BF4)2
could transform to {Pd[(R)-Tol-BINAP](m-OH)}2(BF4)2
with 4 Å MS. It is possible that [Pd(dppp)(m-OH)]2(BF4)2
formed in situ from [Pd(dppp)(H2O)2](BF4)2 and 4 Å MS is
more active for the reaction. See: Fujii, A.; Hagiwara, E.;
Sodeoka, M. J. Am. Chem. Soc. 1999, 121, 5450.
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(14) General Procedure for the Synthesis of 2-Substituted
3-Hydroxymethylbenzofuran Catalyzed by
[Pd(dppp)(H2O)2](BF4)2
A dried small tube with screw-cap was charged with
Synlett 2011, No. 17, 2590–2594 © Thieme Stuttgart · New York

2594
H. Wang et al.
LETTER
[Pd(dppp)(H2O)2](BF4)2 (1.2 mg, 0.002 mmol), 4 Å MS
(20 mg), THF (0.5 mL), then substrates 1 (0.1 mmol) and
aldehydes 2 (0.2 mmol, 2 equiv) were added to the mixture,
and the solution was stirred at 45 °C until complete
consumption of substrates 1 (monitored by TLC). Then,
the mixture was concentrated under reduced pressure and
purified by flash column chromatography on silica gel
using EtOAc and PE as the eluent to afford the product.
Compound 3aa: solid; mp 87–89 °C. 1H NMR (400 MHz,
CDCl3): d = 8.16 (d, J = 8.8 Hz, 2 H), 7.77 (d, J = 6.8 Hz, 2
H), 7.65 (d, J = 8.4 Hz, 2 H), 7.52–7.45 (m, 4 H), 7.28–7.23
(m, 1 H), 7.19 (d, J = 7.6 Hz, 1 H), 7.08 (t, J = 7.6 Hz, 1 H),
6.39 (s, 1 H), 2.61 (d, J = 3.6 Hz, 1 H). 13C NMR (75 MHz,
CDCl3): d = 154.3, 153.5, 149.1, 147.1, 129.7, 129.5, 129.0,
127.7, 126.9, 124.9, 123.0, 121.0, 116.2, 111.4, 67.7. IR
(KBr): n = 3349, 3065, 1600, 1518, 1453, 1344, 1027, 834,
746 cm–1. MS (EI): m/z (%) = 345 (100) [M+], 328, 223, 165,
105, 77, 57. HRMS (EI): m/z calcd for C21H15NO4:
345.1001; found: 345.1005.
Synlett 2011, No. 17, 2590–2594 © Thieme Stuttgart · New York

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