Tetrasubstituted furans by PdII/CuI-cocatalyzed three-component domino reactions of 2-(1-alkynyl)-2-alken-1-ones, nucleophiles and diaryliodonium salts

Article abstract of DOI:10.1039/c0cc03450a

A novel Pd(OAc)₂/CuI-cocatalyzed three-component reaction of 2-(1-alkynyl)-2-alken-1-ones, nucleophiles and diaryliodonium salts has been developed. The procedure allows the synthesis of tetrasubstituted furans in good to high yields under mild

Full text of DOI:10.1039/c0cc03450a

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Tetrasubstituted furans by PdII/CuI-cocatalyzed three-component domino
reactions of 2-(1-alkynyl)-2-alken-1-ones, nucleophiles and
diaryliodonium saltsw
Wenbo Li and Junliang Zhang*
Received 24th August 2010, Accepted 21st September 2010
DOI: 10.1039/c0cc03450a
A novel Pd(OAc)2/CuI-cocatalyzed three-component reaction of
2-(1-alkynyl)-2-alken-1-ones, nucleophiles and diaryliodonium salts
has been developed. The procedure allows the synthesis of tetra-
substituted furans in good to high yields under mild conditions.
Hypervalent iodine reagents have recently received consider-
able attention as mild, selective and non-toxic reagents in
many areas of synthesis.1 Diaryliodonium salts, which are
iodineIII compounds with two aryl ligands, are the most
well-known compounds in this class. They are often applied
in metal-catalyzed cross-coupling reactions,2 in a-arylations of
carbonyl compounds,3 as benzyne generators,4 and also as
photoinitiators in polymerizations.5 On the other hand, highly
substituted furans are frequently found as backbones in many
bioactive natural products and man-made drugs, and they are
also important building blocks in organic synthesis.6,7 In
this regard, transformations that utilize readily available
substrates to provide access to tetrasubstituted furans are in
high demand.8 Recently, Larock and Liu have independently
reported electrophiles mediated cyclization of 2-(1-alkynyl)-2-
alken-1-ones (yne-enones) 19,10 with various nucleophiles
leading to highly substituted 3-halofurans. These halofurans
readily undergo further transformations to afford tetrasubstituted
furans (Scheme 1a). In our ongoing efforts to develop multi-
component domino reactions11 in the synthesis of tetrasubstituted
furans,10c–f we became interested in synthesis of tetrasubstituted
Scheme 1 (a) Larock’s and Liu’s work, (b) our previous work,
(c) proposed working hypothesis.
3-arylated furans. We have recently tried to address this issue
by application of Pd0 species to catalyze three component
domino reactions of ketones 1, nucleophiles 2 and aryl iodides,
but the reaction afforded the 1,2-allenyl ketones rather than
the expected 3-arylated furans (Scheme 1b).10g Thus, we
turned to examine the PdII-catalyzed three component reactions
by using diaryliodonium salts as the cross-coupling reagent
(Scheme 1c). We envisaged that a PdII/IV catalytic cycle
consisting of two key intermediates A and B would take place
to promote multifunctionalized 3-arylated furan formation.12
PdII/IV sequences should tolerate important functional groups
(e.g., aryl halides) that can react with the low-valent Pd
intermediates. Herein, we report a novel PdII/CuI-cocatalyzed
three component domino reaction of yne-enones 1, nucleo-
philes and diaryliodonium salts to give the tetrasubstituted
3-arylated furans 5 in good yields under mild conditions.
Initially, we examined the three component reaction by
using yne-enone (1a), Ph2I+PF6ꢀ (4a) and methanol as model
substrates (Table 1). The reaction of 1a with 4a (1.1 equiv.)
was carried out with Pd(OAc)2 (5 mol%) in DMSO (3 mL)/
MeOH (0.3 mL) at 35 1C to give the desired three component
product 5aa in 38% NMR yield along with some two
component by-products (Table 1, entry 1). Further investigation
showed that copper salts are crucial to improve the yield
(Table 1, entries 2–5). The best result was obtained by using
0.1 equiv. of cuprous iodide as the cocatalyst (Table 1,
entry 5). Furthermore, [(p-allyl)PdCl]2 is also very effective to
provide satisfied results (Table 1, entry 6). The reaction cannot
occur in the absence of palladium catalyst (Table 1, entry 7).
Other additives and solvents failed to improve the yield (for
details see ESIw).
With the optimal conditions in hand (Table 1, entry 5), we
next turned our attention to the scope of this PdII/CuI-
cocatalyzed three-component reaction by variation of the
yne-enones 1 component. As shown in Table 2, in general,
moderate to good yields of three component cross-coupling
products 5 can be obtained for most substrates under standard
conditions (Table 2, entries 1–11). Not only electron-rich and
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry, East China Normal University,
3663 N. Zhongshan Road, Shanghai 200062, P.R. China.
E-mail: jlzhang@chem.ecnu.edu.cn; Fax: +86 21-6223-5039
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c0cc03450a
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 8839–8841 8839

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Table 1 Optimization of reaction conditionsa
Table 2 Variation of yne-enone 1 component
Catalyst
(5 mol%)
Additives
(equiv.)
NMR yield
of 5aa (%)
Yne-enone 1
R1/R2/R3
Entry
Isolated yield
Time/h of 5 (%)
Entry
1b
2
3
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
[(p-Allyl)PdCl]2
None
None
38
62
45
68
77
70
0
1
2
3
4
5
6
7
8
Me/Ph/Ph (1a)
16
40
11
60
14
27
5aa (72)
5ab (85)
5ac (75)
5ad (53)
5ae (69)
5af (54)
5ag (69)
5ah (65)
5ai (68)
5aj (53)
5ak (57)
5al (61)
CuCl2 (0.1)
Cu(OTf)2 (0.1)
CuCl (0.1)
CuI (0.1)
CuI (0.1)
CuI (0.1)
Me/1-naphthyl/Ph (1b)
Me/4-MeOC6H4/Ph (1c)
Me/4-NO2C6H4/Ph (1d)
Me/1-cyclohexenyl/Ph (1e)
Me/1-cyclopropyl/Ph (1f)
5
6c
7
Me/4-MeOC6H4/4-MeOC6H4 (1g) 10
a
Me/1-naphthyl /4-MeOC6H4 (1h)
Me/Ph/4-MeOC6H4 (1i)
Ph/Ph/Ph (1j)
Ph/4-MeOC6H4/Ph (1k)
Ph/Ph/4-MeOC6H4 (1l)
28
11
30
12
23
Reaction conditions: 1a (0.3 mmol), 4a (0.6 mmol) and catalyst
(5 mol%) in DMSO (3 mL)/MeOH (0.3 mL) at 35 1C for 10–20 h.
4a (0.33 mmol). 0.5 equiv. of Et3N was added.
9
10a
11
12a
b
c
electron-deficient aromatic but also aliphatic groups such as
cyclopropyl and cyclohexenyl can be compatible. Interestingly,
the reactions of 1j and 1l work much better under the catalysis
of 5 mol% [(p-allyl)PdCl]2 and 10 mol% CuI in the presence of
50 mol% Et3N than the standard conditions (Table 2, entries
10 and 12). Cyclic substrate 6 also afforded a bicyclic 2,3-fused
furan 7 in 69% yield catalyzed by 5 mol% Pd2(dba)3 in the
presence of 10 mol% CuI and K2CO3 (1.2 equiv.) (eqn (1)).
The reaction of the ketone 8 produced a tricyclic furan 913 in
47% isolated yield (eqn (2)).
a
Conditions: [(p-allyl)PdCl]2 (5 mol%), CuI (10 mol%) and 0.5 equiv.
of Et3N.
Table 3 Study of the scope by variation of nucleophile component
Isolated yield
of 5/10 (%)
ð1Þ
Entry
NuH (2)
Time/h
1
2
3
4
H2O (2b)
12
19
12
13
5ba (56)
5ca (57)
5da (53)
5ea (64)
BnOH (2c)
iPrOH (2d)
nC6H13OH (2e)
5
20
5fa (69)
6
7
20
20
5ga (57)
ð2Þ
Different nucleophiles were next tested and the results are
listed in Table 3. It is noteworthy that water (2 equiv.) can be
used as the nucleophile and the desired product alcohol 5ba
was obtained in 56% isolated yield (Table 3, entry 1). In many
cases, much excess of nucleophiles are necessary to obtain
good results since there are some other competing side reactions.
Primary alcohols, such as benzyl alcohol 2c, n-hexanol 2e,
cyclopropyl methanol 2f and (tetrahydrofuran-2-yl) methanol
2g, can act as nucleophiles to give the corresponding tetra-
substituted furans in moderate to good yields (Table 3, entries
2, 4–6). Secondary alcohols, such as isopropyl alcohol, allowed
for slightly lower yield (Table 2, entry 3). However, cinnamyl
alcohol as nucleophile afforded the trisubstituted furan 10ha in
75% yield (Table 3, entry 7), in which the diphenyliodonium
salt may be consumed by other competing reactions such as
the Heck-type reaction with cinnamyl alcohol.
10ha (75)
To further expand the utility of this methodology, we
explored different diaryliodonium salts (Table 4).14 It should
be noted that the tolerance of C–Br bond in iodine(III) reagents
made this reaction very attractive for further assembly
through the cross-coupling reactions (Table 4, entry 1).
Substituted [(4-MeC6H4)2I]OTf can also act as the cross-
coupling reagent to afford the corresponding tetrasubstituted
furan 5an in 74% yield (Table 4, entry 2). We next sought to
sterically differentiate the two Ar groups on iodine(III).
Gratifyingly, the smaller phenyl group of the mesityl/phenyl-
substituted reagents [Mes-I-Ph]OTf was selectively coupled
(Table 4, entry 3).
c
8840 Chem. Commun., 2010, 46, 8839–8841
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Table 4 Study the scope of this domino reaction by variation of
[Ar1-I-Ar2]OTf
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Isolated yield
of 5 (%)
Entry
Ar1
Ar2
Time/h
1
4-BrC6H4
4-MeC6H4
C6H5
4-BrC6H4
4-MeC6H4
Mesityl
18
10
20
5am (69)
5an (74)
5aa (53)
2a
3
a
Conditions: [(p-allyl)PdCl]2 (5 mol%), CuI (10 mol%) and 0.5 equiv.
of Et3N.
In conclusion, we have developed a novel PdII/CuI-cocatalyzed
three-component domino reactions of 2-(1-alkynyl)-2-alken-1-
ones, nucleophiles and diaryliodonium salts, which provide a
rapid, mild, efficient and general access to multi-functionalized
tetrasubstituted 3-arylated furans. It is noteworthy that the
steric differentiation between the two aryl groups on iodine(III)
allows for the selective transfer of the smaller substituent.
Further studies including the detailed mechanism, scope and
synthetic applications are in progress in our laboratory and
will be reported in due course.
We are grateful to National Natural Science Foundation of
China (20972054), the Ministry of Education of China
(NCET) and the Fundamental Research Funds for the Central
Universities.
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c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 8839–8841 8841