Access to Tetronic Acids via Silver-Catalyzed CO2 Incorporation into Conjugated Ynones

Article abstract of DOI:10.1021/acs.orglett.7b01309

Facile and versatile access to highly functionalized tetronic acids has been successfully achieved through the reaction of conjugated ynones with carbon dioxide. In the presence of a base, the enolates generated from the ynones capture CO₂ via

Full text of DOI:10.1021/acs.orglett.7b01309

Letter
pubs.acs.org/OrgLett
Access to Tetronic Acids via Silver-Catalyzed CO2 Incorporation into
Conjugated Ynones
Yuta Sadamitsu, Keiichi Komatsuki, Kodai Saito, and Tohru Yamada*
Department of Chemistry, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
S
* Supporting Information
ABSTRACT: Facile and versatile access to highly functionalized tetronic acids has
been successfully achieved through the reaction of conjugated ynones with carbon
dioxide. In the presence of a base, the enolates generated from the ynones capture CO2
via a carbon−carbon bond-forming reaction, accompanied by a 5-exo-dig cyclization
reaction of the resulting carboxylate to the alkyne, activated by a silver catalyst. The
present method should be applicable to the synthesis of a wide variety of tetronic acids.
Scheme 1. Synthesis of Tetronic Acids Based on CO2
Fixation into Ynones
etronic acids, or 4-hydroxy-5H-furan-2-ones, are found in
1
Ta range of natural products
and are considered as
important scaffolds for the construction of bioactive and
pharmaceutical compounds.2 Although several methods for the
synthesis of their derivatives have been reported, multiple steps
are generally required, e.g., introduction of a substituent at the
3-position of the 2-furanone, protection and deprotection
sequences, halogenation or diazotization, and a transition-
metal-catalyzed coupling reaction.3 Also, for substitution at the
5-position, organolithium reagents are generally employed to
obtain the corresponding carbanion. Therefore, many limi-
tations involving availability of electrophiles and tolerance of
the functional groups are of concern.4 Recently, a silver-
catalyzed synthesis of tetronic acids from (E)-2-en-4-ynoic acid
was reported,5 though the preparation of the starting materials
was complex.
Carbon dioxide is an attractive carbon source, having no
toxicity in itself and availability at a low cost, as well as easy
handling.6 Since CO2 adducts are considered thermodynami-
cally unstable, after nucleophilic addition to CO2, decarbox-
ylation often occurs competitively to form the starting
compound. Therefore, in order to incorporate CO2 into
organic molecules, countermeasures are frequently needed to
suppress the decarboxylation process.7 The successive intra-
molecular cyclization of an activated alkyne by transition metal
catalysts8 is one of the most commonly used and reliable
methods, widely applied to the syntheses of various multi-
substituted heterocycles.9 A silver-catalyzed CO2 incorporation
reaction, based on the above-mentioned strategy, had been
reported by this group. It was revealed that propargyl alcohols10
and alkynyl anilines11 were applicable as heteroatom
nucleophiles for these reactions with activated alkynes by silver
catalysts. Recently, methods for CO2 incorporation with
carbon−carbon bond formation were developed using carbon
nucleophiles, such as alkynyl ketones12 and alkynyl allylsi-
lanes.13 In this paper, we report that a readily prepared
conjugated ynone has been employed as a carbon nucleophile
to synthesize tetronic acid derivatives using CO2 in the
presence of a silver catalyst (Scheme 1).
Various organic bases were examined first, since enolate
generation from the ynone would be crucial to capture the
CO2. Under 2.0 MPa pressure of CO2, the ynone 1a was
treated with organic bases in the presence of a catalytic amount
of silver acetate in DCM (Table 1). When triethylamine or N-
methylimidazole (MeIm) was employed, no reaction occurred,
and the ynone 1a was quantitatively recovered (entries 1 and
2). Using DMAP, the reaction proceeded slightly to afford the
corresponding cyclic compounds in 19% yield (entry 3).
Stronger bases were expected to generate the corresponding
enolate to effectively capture the CO2. The use of 1,1,3,3-
tetramethylguanidine (TMG) resulted in a 37% yield (entry 4),
whereas 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), DBU, and
7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) were
found effective against the 5-exo-dig cyclization to afford
tetronic acid 2a in 74%, 86%, and 90% yields, respectively
(entries 5−7). On the other hand, when this reaction was
carried out under a lower pressure of CO2, the yield of the
Received: May 2, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01309
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Table 1. Examination of Reaction Conditions
Table 2. Substrate Scope for Various Tetronic Acids
a
bc
,
b
d
entry
base
Et3N
recovery/%
yield 2 + 3 (2:3) /%
1
2
3
4
5
6
7
92
94
nd
N-MeIm
DMAP
TMG
trace
44
19 (79:21)
37 (>95:5)
77 (>95:5)
86 (>95:5)
90 (>95:5)
trace
41
TBD
1
DBU
trace
trace
trace
trace
MTBD
MTBD
MTBD
e
8
f
9
92 (>95:5)
a
b
The reaction was carried out with 0.10 mmol of substrate. Detected
c
by 1H NMR. After quenching by 4 M solution of HCl in 1,4-dioxane,
1a was converted to 4a. The yield was estimated from the yield of 4a.
d
e
f
Isolated yield. N2 (balloon) was used instead of CO2. The reaction
time was 24 h.
desired product decreased, but no starting material was
recovered. Even when this reaction was performed under a
nitrogen atmosphere, no starting material was recovered (entry
8), but quantitative formation of a byproduct was observed.
1
Based on the H NMR, 13C NMR, and MS analyses, the
byproduct was identified to be the corresponding 1,4-adduct of
MTBD on the starting ynone (see Supporting Information).
Therefore, in this reaction, it was assumed that a higher CO2
pressure was required to selectively promote the CO2
incorporation; thus, the reaction was carried out for 24 h
under 2.0 MPa of CO2 to afford the corresponding product 2a
in 92% yield (entry 9).
a
b
The reaction was carried out using 0.10 mmol of substrate. Isolated
c
d
yield. DBU was used instead of MTBD. 3.0 equiv of MTBD.
e
f
g
h
CH3CN was used as solvent at 40 °C. 48 h. 20 mol% AgOAc. 20
i
j
mol% AgOTf. The product was an 89:11 mixture of 2i and 3i. The
product was an 85:15 mixture of 2k and 3k.
The optimized conditions were applied to various ynones
(Table 2). Substituents on the alkyne termini (R1) were first
examined (entries 1−6). The substrates bearing phenyl (1a), o-
tolyl (1b), m-tolyl (1c), and p-tolyl (1d) groups were converted
to the corresponding tetronic acids (2a−d) in 92%, 88%, 74%,
and 87% yield, respectively (entries 1−4). When the substrate
bearing a p-methoxyphenyl group (1e) reacted, the desired
product 2e was obtained quantitatively (entry 5). When the
substrate bearing a p-benzonitrile group (1f) was employed, the
corresponding product 2f was obtained in 62% yield (entry 6).
These results suggested that an electron-withdrawing group on
the aryl group of the alkyne termini caused a decrease in the
nucleophilicity of the enolate, resulting in the lower yield.
Various of substituents on the α-position of the carbonyl (R2)
were next examined (entries 7−11). When substrates with no
substituent (1g) or bearing an n-hexyl group (1h) were
employed, the 5-exo-dig cyclization proceeded to afford the
corresponding tetronic acids 2g and 2h in 95% and 97% yield,
respectively (entries 7 and 8). On the other hand, when the
reactions of substrates bearing isopropyl (1i) and cyclohexyl
(1j) groups were examined, 6-endo-dig cyclization occurred
versus the 5-exo-dig cyclization to afford the tetronic acids 2 and
the hydroxypyrones 3 in 88% (2i:3i = 89:11) and 77% (2j:3j =
85:15) yield, respectively (entries 9 and 10). These results
suggested that a sterically demanding R2 substituent tends to
promote the 6-endo-dig cyclization (entries 7−10), though the
precise reason is still unclear. The effect of the substituent on
the aromatic groups R2 was examined. The substrate bearing a
phenyl group (1k) was converted to the corresponding tetronic
acid 2k in 75% yield with a high regioselectivity (entry 11).
Next, using this protocol, we conducted the synthesis of
aspulvinone E14 having various bioactivities (Scheme 2).15 The
internal alkyne 1l, which is a precursor for the CO2
incorporation reaction, was prepared from the reaction of
ethyl (4-methoxyphenyl)acetate with the lithium acetylide,
generated from (4-methoxyphenyl)acetylene with n-BuLi. The
silver-catalyzed intramolecular cyclization involving the CO2
B
DOI: 10.1021/acs.orglett.7b01309
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Scheme 2. Synthetic Application
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In conclusion, we have developed a highly efficient synthesis
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functionalized tetronic acid derivatives. Further application of
this reaction to the synthesis of various tetronic acids is
currently underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01309.
(3) (a) Willis, C.; Bodio, E.; Bourdreux, Y.; Billaud, C.; Gall, T. L.;
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yamada@chem.keio.ac.jp.
ORCID
́
Duong, N.-T.; Lion, C.; Wagner, A.; Chahine, J.-M. E. H. Inorg. Chim.
Acta 2013, 394, 45. (b) Le Roux, A.; Meunier, S.; Le Gall, T.; Denis, J.-
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W.; Liu, J.; Zhang, H. Tetrahedron Lett. 2010, 51, 4874. (d) Habrant,
Tohru Yamada: 0000-0002-4177-5019
Notes
D.; Poigny, S.; Seg
Strehle, A.; Saladin, R.; Meunier, S.; Mioskowski, C.; Wagner, A. J.
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Castro, A.; Gomez, G.; Fall, Y. Chem. Commun. 2009, 3252.
́
ur-Derai, M.; Brunel, Y.; Heurtaux, B.; Le Gall, T.;
The authors declare no competing financial interest.
́
́
́
ACKNOWLEDGMENTS
■
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This paper is dedicated to Professor Emeritus Teruaki
Mukaiyama of The University of Tokyo in celebration of his
90th birthday.
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