Modular Synthesis of Multisubstituted Furans through Palladium-Catalyzed Three-Component Condensation of Alkynylbenziodoxoles, Carboxylic Acids, and Imines

Article abstract of DOI:10.1002/anie.201504687

Mild and regiocontrolled synthesis of a multisubstituted furan is achieved through Pd(OAc)₂-catalyzed room-temperature condensation of an alkynylbenziodoxole, a carboxylic acid, and an enolizable ketimine, which contribute to C1, CO, and C2 fragments, respectively, to the furan skeleton. The reaction tolerates a broad range of functional groups in each of the reaction components, and enables highly modular and flexible synthesis of variously substituted furans. The reaction is particularly effective for the rapid generation of tri- and tetraarylfurans and furan-containing oligoarylenes without relying on conventional cross-coupling chemistry.

Full text of DOI:10.1002/anie.201504687

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201504687
German Edition: DOI: 10.1002/ange.201504687
Multicomponent Reactions
Modular Synthesis of Multisubstituted Furans through Palladium-
Catalyzed Three-Component Condensation of Alkynylbenziodoxoles,
Carboxylic Acids, and Imines
Junliang Wu and Naohiko Yoshikai*
Abstract: Mild and regiocontrolled synthesis of a multisubsti-
tuted furan is achieved through Pd(OAc) -catalyzed room-
2
temperature condensation of an alkynylbenziodoxole, a car-
boxylic acid, and an enolizable ketimine, which contribute to
C1, CO, and C2 fragments, respectively, to the furan skeleton.
The reaction tolerates a broad range of functional groups in
each of the reaction components, and enables highly modular
and flexible synthesis of variously substituted furans. The
reaction is particularly effective for the rapid generation of tri-
and tetraarylfurans and furan-containing oligoarylenes with-
out relying on conventional cross-coupling chemistry.
B
ecause of the frequent occurrence of substituted furans in
natural products, pharmaceuticals, and other functional
[
1]
[2]
molecules as well as their utility as synthetic intermediates,
the efficient and regioselective synthesis of furans has been
[
3]
among important subjects in heterocyclic chemistry.
II
Scheme 1. Pd -catalyzed furan synthesis from imines and
Although cyclocondensation and cycloisomerization of
single precursors represent established approaches to fur-
alkynyliodine(III) reagents (PMP=p-MeOC H ).
6
4
[
3b,c,4]
ans,
they usually require multistep preparation of each
II
precursor and hence are unsuitable for the rapid generation of
a library of substituted furans. As such, modular approaches
such as a [3+2]-type coupling of two simple starting materi-
als and a cycloisomerization–cross-coupling cascade have
recently gained a great deal of interest. Although a [2+2+1]-
type coupling of three distinct reactants, in which each of the
reactants contributes to the carbon skeleton of furan,
potentially allows even more modular synthesis of multi-
substituted furans, such reactions are rare and of limited
ylic acid, and an N-aryl imine under Pd catalysis (Sche-
me 1b). The reaction represents a new example of [2+2+1]-
type furan synthesis, enabling rapid construction of a diverse
set of highly substituted furans including furan-containing
[
5]
[6]
[12]
oligoarylenes.
The alkynylbenziodoxolone/imine condensation (Sche-
me 1a) involves independent incorporation of the alkynyl and
the 2-iodobenzoate moieties into the product.
[
8]
This
prompted us to explore the feasibility of a three-component
furan synthesis by replacing the alkynylbenziodoxolone with
a combination of a different alkynyliodine(III) compound
and a carboxylic acid. A proof-of-concept result was obtained
by the reaction of alkynyliodonium tosylate 1a-OTs
(0.4 mmol), benzoic acid 2a (0.3 mmol), and 4’-methoxyace-
tophenone imine 3a (0.2 mmol) in the presence of Pd(OAc)2
(10 mol%), which afforded a triarylfuran 4a in 45% NMR
yield (entry 1, Table 1). While replacement of the tosylate of
1a-OTs with trifluoroacetate or triflate only caused adverse
[
7]
scope.
II
We recently discovered a Pd -catalyzed condensation
reaction of an alkynylbenziodoxolone and an enolizable N-
aryl ketimine to afford a multisubstituted furan, which
involves cleavage of the CꢀC bond and elimination of N-
[
8]
arylformamide as a coproduct (Scheme 1a). A major
limitation of this reaction is the lack of structural variation
of the 2-iodobenzoate moiety, which ends up in the C5-
substituent of the furan. Here we have removed this
limitation by the development of a three-component con-
effects (entries 2 and 3), the use of an alkynylbenziodoxole 1a
bearing bis-trifluoromethyl groups
[9–11]
[10,11]
densation reaction of an alkynylbenziodoxole,
a carbox-
resulted in a signifi-
cant improvement of the yield (entry 4). An analogous
bridged alkynyliodine(III) reagent bearing dimethyl groups
was prone to decomposition during preparation, whereas the
[
*] Dr. J. Wu, Prof. N. Yoshikai
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
one containing a sulfate bridge (1a-SO ) showed poor
3
solubility in toluene and failed to participate in the reaction
(entry 5). Upon a brief survey of the reaction stoichiometry,
E-mail: nyoshikai@ntu.edu.sg
4a was isolated in near quantitative yield (92%) with a 2:2:1
ratio of the starting materials (entry 6). For this particular
reaction, we confirmed the formation of the expected
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201504687.
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[
a]
Table 1: Screening of reaction conditions.
[b]
Entry
Iodine(III) reagent
Pd cat
Yield [%]
1
2
3
4
5
1a-OTs
1a-TFA
1a-OTf
1a
1a-SO3
1a
1a
1a
1a
1a
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
45
28
0
85
0
[
c]
6
7
8
9
1
97 (92)
84
85
64
69
[
c,d]
[
c]
[
c]
0
Pd (dba)
2
3
Scheme 2. Scope of carboxylic acids. The reaction was performed on
a 0.2 mmol scale under the conditions given in Table 1, entry 5.
[a] Acetophenone-derived imine (1b) was used in place of 1a.
[
3
a] Reaction conditions: iodine(III) reagent (0.4 mmol), 2a (0.3 mmol),
a (0.2 mmol), Pd catalyst (10 mol%), toluene, rt, 24 h. [b] Determined
1
by H NMR spectroscopy using 1,1,2,2-tetrachloroethane as an internal
standard; yields of isolated products in parentheses. [c] 0.4 mmol of 2a
was used. [d] 5 mol% of Pd(OAc) was used. p-An=4-methoxyphenyl,
2
dba=dibenzylideneacetone, TFA=trifluoroacetate.
acid (2i) as the reaction partners (Scheme 3). (Hetero)aryl
methyl imines smoothly participated in the three-component
coupling to afford the corresponding 2,3,5-triarylfurans 5a–
5h in moderate to good yields with tolerance of bromo, iodo,
and nitro groups. Likewise, imines derived from propiophe-
none, tetralone, chromanone, and 2-phenylacetophenone
afforded the desired tetrasubstituted furans (5i–5l). Notably,
acyclic and cyclic dialkylimines also reacted with 1a and 2a at
an elevated temperature of 808C (5m–5o), despite their
coproducts, N-(4-methoxyphenyl)formamide (87%) and
1
,1,1,3,3,3-hexafluoro-2-(2-iodophenyl)propan-2-ol
(78%
based on 1a; see Scheme 1b). Note that reduction of the
loading of Pd(OAc) to 5 mol% led to a slight decrease in the
2
yield of 4a (entry 7). Other palladium sources such as
Pd(TFA) , PdCl , and Pd (dba) also promoted the three-
2
2
2
3
component coupling albeit in lower yields (entries 8–10).
With the optimized conditions in hand, we explored the
scope of the present three-component furan synthesis. First,
we focused on the variation of the most readily available
component, carboxylic acid (Scheme 2). Various aromatic
and heteroaromatic acids participated in the reaction with 1a
and 3a to afford the corresponding triarylfurans 4a–4j in
moderate to good yields. Whereas electron-poor acids
afforded the desired furans (4b and 4c) in high yields,
electron-rich 4-methoxybenzoic acid reacted sluggishly (4d).
The reaction of 4-vinylbenzoic acid was also sluggish (4e),
which may be ascribed to the interference of the Pd catalyst
by the coordination of the vinyl moiety. Sterically hindered
mesitoic acid was well tolerated (4h). Cinnamic acid and
phenylpropiolic acid also afforded the desired furan products
albeit in low yields (4k and 4l). Notably, the scope of
carboxylic acids could be extended to simple aliphatic acids
[8]
failure in the condensation with alkynylbenziodoxolones.
An enamine derived from a b-ketoester also served as a viable
reactant, affording a tetrasubstituted furan 5p in 26% yield.
As illustrated in Scheme 4a, alkynylbenziodoxoles
derived from a series of arylacetylenes participated in the
condensation with 2a and 3a, affording the triarylfurans 6a–
6g in moderate to good yields. Although both electron-
donating (OMe) and electron-withdrawing (CF , CN) groups
3
on the aryl ring could be tolerated, the reaction became
sluggish with an o-tolyl group (6g). 2-Ethynylthiophene- and
enyne-derived benziodoxoles were also amenable to the
three-component coupling (6h and 6i). As an additional
demonstration, hitherto unknown tetrathienylfuran 7 could
be prepared from appropriate thiophene-containing starting
materials (Scheme 5b). Note that alkynylbenziodoxoles
derived from alkyl- and silylacetylenes failed to afford the
desired products.
(
4m and 4n) as well as to protected amino acid and glucuronic
acid (4o and 4p). Note that a low-yielding reaction was
typically accompanied by complete decomposition of the rest
of 1a into intractable products whereas the unreacted acid
and 3a were recovered partially and largely, respectively.
We next examined various imines using 1a and benzoic
acid (2a), 4-nitrobenzoic acid (2c), or 2-thiophenecarboxylic
The present reaction further enables the construction of
[
12]
oligoarylenes containing 2,3,5-triarylfuran units.
Twofold
condensation reactions of bis-imines 3t and 3u using 1a and
2a as the reaction partners afforded 1,4-di(3-furyl)- and 1,3-
di(3-furyl)benzene derivatives 8 and 9, respectively, in modest
yields (Scheme 5a). Bis-alkynylbenziodoxole 1k also under-
1
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Scheme 4. Scope of alkynylbenziodoxoles. The reaction was performed
on a 0.2 mmol scale under the conditions in Table 1, entry 5. [a] 2-
Thiophenecarboxylic acid was used in place of 3a.
Scheme 3. Scope of imines. The reaction was performed on
a 0.2 mmol scale under the conditions given in Table 1, entry 5. [a] The
reaction was performed at 808C for 12 h. [b] The starting material was
in the enamine form.
went twofold furan formation with 2-thiophenecarboxylic
acid 2i and acetophenone imine 3b to furnish a heptaaryl 10
(
Scheme 5b), which exhibited absorption and emission
4
À1 À1
maxima at 392 nm (e = 6.25 ” 10 cm m ) and 451 nm (F =
.31 determined using quinine as a standard), respectively.
0
Note, however, that dicarboxylic acids such as terephthalic
acid and 2,5-thiophenedicarboxylic acid failed to undergo
twofold condensation.
As reported previously, the reaction of alkynylbenziodox-
olone 1a’ and 4-pyridyl imine 3r failed to give the desired
furan but afforded 2-oxo-2-phenylethyl 2-iodobenzoate 11
[
8]
(
2
Scheme 6). An attempted three-component coupling of 1a,
-iodobenzoic acid 2g, and 3r also afforded 11 without
18
formation of the desired furan. Interestingly, O-labeling
experiments on these reactions suggested that not only the
ester oxygens but also the keto oxygen of 11 are derived from
the 2-iodobenzoate oxygens (Scheme S1).
We speculate that the present three-component conden-
sation shares the same mechanistic features as the alkynyl-
[8]
Scheme 5. Synthesis of oligoarylene derivatives containing furan moi-
eties through twofold condensation. See the Supporting Information
for detailed reaction conditions.
benziodoxolone/imine condensation (Scheme 1a),
involves 1) Michael addition of a palladium carboxylate A
formed from Pd(OAc)2 and carboxylic acid 2) to the
and
(
alkynylbenziodoxole 1, 2) conversion of the adduct B into
a Pd-vinylidene species C with concomitant elimination of the
iodoarene coproduct, 3) addition of the imine nitrogen to C,
and 4) protodepalladation of the intermediate D to afford an
enamine derivative E and regenerate A (Scheme 7). The
enamine E would further collapses into the furan and N-(4-
methoxyphenyl)formamide through multiple steps.
[
9]
[
8]
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reaction is notable for the high level of modularity and the
broad scope of each reaction component, and is particularly
useful for the rapid generation of a library of oligoaryls
[12]
featuring 2,3,5-triarylfuran motifs.
Further synthetic and
mechanistic studies on this reaction and palladium catalysis of
[13]
imines and hypervalent iodine reagents are underway.
Acknowledgements
Scheme 6. Reaction using 1a, 2-iodobenzoic acid 2g, and 4-pyridyli-
mine 3r.
This work was supported by the Singapore National Research
Foundation (NRF-RF2009-05) and Nanyang Technological
University.
Keywords: furans · hypervalent iodine compounds · imines ·
multicomponent reactions · palladium
How to cite: Angew. Chem. Int. Ed. 2015, 54, 11107–11111
Angew. Chem. 2015, 127, 11259–11263
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Received: May 24, 2015
Published online: July 29, 2015
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11111