Synthesis of polysubstituted furans via copper-mediated annulation of alkyl ketones with α,β-unsaturated carboxylic acids

Article abstract of DOI:10.1021/ol400912v

A novel copper-mediated annulation of alkyl ketones with α,β-unsaturated carboxylic acids has been accomplished. This reaction provides a facile and regio-defined method for the synthesis of 2,3,5-trisubstituted furans from simple chemical reagents.

Full text of DOI:10.1021/ol400912v

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Synthesis of Polysubstituted Furans
via Copper-Mediated Annulation of
Alkyl Ketones with r,β-Unsaturated
Carboxylic Acids
Yuzhu Yang,† Jinzhong Yao,† and Yuhong Zhang*,†,‡
Department of Chemistry, ZJU-NHU United R&D Center, Zhejiang University,
Hangzhou 310027, P. R. China, and State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
yhzhang@zju.edu.cn
Received April 3, 2013
ABSTRACT
A novel copper-mediated annulation of alkyl ketones with R,β-unsaturated carboxylic acids has been accomplished. This reaction provides a
facile and regio-defined method for the synthesis of 2,3,5-trisubstituted furans from simple chemical reagents.
Furans, one of the most important classes of five-membered
heterocyclic compounds, can be found as key structural
units in many natural products and diverse therapeutic
agents.1 They are also served as useful intermediates in
synthetic chemistry.2 Accordingly, tremendous efforts
have been devoted to the development of versatile methods
for constructing this heteroaromatic core.3 Apart from the
classical cyclocondensation of dicarbonyl compounds,
strategies exploring transition-metal-catalyzed intramole-
cular cycloisomerization of alkyne- and allene-containing
compounds have been extensively studied during the past
decades.3c Although this intramolecular approach offers
an important method in furan synthesis, the preparation of
starting alkyne- and allene-containing compounds usually
requires a multistep synthesis which may possesses trou-
blesome operation. On the other hand, the intermolecular
approach would provide a more direct and regio-defined
route to furans with operational simplicity from simple
and readily available chemical reagents.4 Given the great
importance of furans in natural and synthetic substances,
the development of a more selective and straightforward
intermolecular approach to construct polysubstituted fur-
ans from simple and cheap chemical reagents isstill ingreat
demand.
† Zhejiang University.
‡ Lanzhou University.
(1) (a) Wong, H. N. C.; Hou, X. L.; Yeung, K. S.; Huang, H. In Five-
Membered Heterocycles: Furan, Vol. 1; Alvarez-Builla, J., Vaquero,
J. J., Barluenga, J., Eds.; Wiley-VCH: Weinheim, 2011; pp 533À692. (b)
Katritzky, A. R. Comprehensive Heterocyclic Chemistry III, 1st ed.;
Elsevier: Amsterdam; New York, 2008. (c) Fraga, B. M. Nat. Prod. Rep.
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r
10.1021/ol400912v
XXXX American Chemical Society

Carboxylic acids have been recognized as important
starting materials in synthetic chemistry due to their low
cost and ready availability.5 Decarboxylative coupling
represents a novel strategy to form carbonÀcarbon and
carbonÀheteroatom bonds by the extrusion of carbon
dioxide from carboxylic acids.6 During recent years, the
area of decarboxylative dehydrogenative cross-coupling has
receivedmuchattention, and significantprogressincluding
arylation,7 alkenylation,8 acylation,9 and etherification10
has been made. In particular, Liu et al have demonstrated
copper-catalzyed decarboxylation reactions via a free-radical
process involving C(sp3)ÀC(sp2) coupling and trifluoro-
methylation.11 In the course of our continuing efforts toward
reactions of R,β-unsaturated carboxylic acids involving both
CÀH functionalization and decarboxylation process,12 we
previously investigated a copper-catalyzed annulation of
2-alkylazaarenes with R,β-unsaturated carboxylic acids
leading to C-2 arylated indolizines.12b Herein, we wish
to report a copper-mediated reaction of alkyl ketones with
R,β-unsaturated carboxylic acids, illustrating a novel and
convenient access to 2,3,5-trisubstituted furans.
ployed in this reaction (Table 1, entries 2À9). The amount of
the two copper salts was also examined. Increasing or
decreasing the amount of both CuCl and Cu(OAc)2 H2O
3
resulted in lower yields (Table 1, entries 10À11). The yields
were also lowered when the ketone/acid ratio was changed
(Table 1, entries 12À14). Screening of other solvents such as
DMA, DMSO, NMP, and mesitylene (Table 1, entries 15À18)
indicated that only DMA delivered a comparable yield with
that in DMF (Table 1, entry 16). No product was detected in
the absence of copper salts (Table 1, entry 19). However,
employing a catalytic amount of copper salts with external
oxidants (such as K2S2O8, BQ, DDQ, BPO, DTBP, and
TBHP) and additives (such as LiOAc, NaOAc, KOAc,
CsOAc, and Et3N) did not yield better results (see Supporting
Information).
Table 1. Reaction Optimizationa
We selected propiophenone and cinnamic acid as the
model substrates for the optimization. It was found that the
combination of 1 equiv of CuCl and 1 equiv of Cu(OAc)2
H2O afforded the furan product 3a in the highest 72% yield
after stirring at 140 °C for 24 h (Table 1, entry 1). It is
important to note that the reaction is highly regioselective
with respect to both ketone and acid: we did not observe any
regioisomer of 3a. The reaction appeared to be more
change of the
yield
(%)b
3
entry
standard conditions
1
none
72
46
50
39
12
trace
0
2
1 equiv of CuCl
3
1 equiv of Cu(OAc)2 H2O
3
4
1 equiv of CuBr
1 equiv of CuI
5
effective in the presence of both CuCl and Cu(OAc)2 H2O
since the yields decreased when one copper source was em-
3
6
1 equiv of CuCl2
1 equiv of CuBr2
2 equiv of CuCl
7
8
51
56
55
67
35
53
67
69
45
57
31
0
9
2 equiv of Cu(OAc)2 H2O
3
(6) For pioneering examples of decarboxylative coupling reactions,
see: (a) Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc.
2002, 124, 11250. (b) Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am.
Chem. Soc. 2005, 127, 10323. (c) Goossen, L. J.; Deng, G.; Levy, L. M.
10
11
12
13
14
15
16
17
18
19
0.5 equiv of CuCl/Cu(OAc)2 H2O
3
3
1.5 equiv of CuCl/Cu(OAc)2 H2O
2.0 equiv of cinnamic acid
1.0 equiv of ketone
3.0 equiv of ketone
DMA
Science 2006, 313, 662. (d) Goossen, L. J.; Rodrıguez, N.; Melzer, B.;
´
Linder, C.; Deng, G.; Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824. (e)
Forgione, P.; Brochu, M.-C.; St-Onge, M.; Thesen, K. H.; Bailey, M. D.;
Bilodeau, F. J. Am. Chem. Soc. 2006, 128, 11350. (f) Voutchkova, A.;
Coplin, A.; Leadbeater, N. E.; Crabtree, R. H. Chem. Commun. 2008,
6312.
DMSO
NMP
(7) (a) Wang, C.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009, 131,
4194. (b) Yu, W.-Y.; Sit, W. N.; Zhou, Z.; Chan, A. S. C. Org. Lett. 2009,
11, 3174. (c) Cornella, J.; Lu, P.; Larrosa, I. Org. Lett. 2009, 11, 5506. (d)
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Kan, J.; Wang, M.; Su, W.; Hong, M. Chem. Commun. 2010, 46, 5455.
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(h) Hu, P.; Zhang, M.; Jie, X.; Su, W. Angew. Chem., Int. Ed. 2012, 51,
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Z.; Zhao, P. Angew. Chem., Int. Ed. 2009, 48, 6726. (d) Sun, Z.; Zhang, J.;
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Duan, X.-H. Org. Lett. 2012, 14, 4358.
mesitylene
no copper salts
a Reaction conditions: propiophenone (1.0 mmol), cinnamic acid
(0.5 mmol), CuCl (0.5 mmol), Cu(OAc)2 H2O (0.5 mmol), DMF (1 mL),
3
140 °C, air, 24 h. b Isolated yield.
With the optimized reaction conditions established, we
turned our attention toward examining the acid scope of this
furan synthesis process in Scheme 1. A variety of substituents
on the aryl moiety of cinnamic acids were tolerated to provide
the corresponding furans. Comparison of these results indi-
cated that the product yield is slightly affected by the position
of substituents on the aryl ring. The yields for the methyl and
chloro substituted products 3bÀd and 3iÀk follow the order
ortho < meta < para. The observed trend could be rationa-
lized by the steric effect of the substrates. It was also found
that substituted cinnamic acids with electron-donating groups
such as methyl and methoxyl delivered relatively lower yields
than those obtained with electron-withdrawing groups such
(10) Bhadra, S.; Dzik, W. I.; Goossen, L. J. J. Am. Chem. Soc. 2012,
134, 9938.
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B
Org. Lett., Vol. XX, No. XX, XXXX

as trifluoromethyl, fluoro, and chloro. The stucture of 3e was
comfirmed by single crystal X-ray analysis (Figure 1).
Naphthyl and thiophenyl substituted R,β-unsaturated car-
boxylic acids could also be employed in this reaction to afford
the products 3l and 3m in moderate yields. In addition, C-5
alkenylated furan product 3n was accessed by employing
5-phenylpenta-2,4-dienoic acid as the annulation partner.
Unfortunately alkyl substituted R,β-unsaturated carboxylic
acid such as crotonic acid was not suitable under the current
reaction conditions.
Scheme 1. Annulation of Propiophenones with Different
R,β-Unsaturated Carboxylic Acidsa
Figure 1. X-ray single crystal structure of 3e.
Scheme 2. Annulation of Different Alkyl Ketones with Cin-
namic Acidsa,b
a Reaction conditions: propiophenone (1.0 mmol), R,β-unsaturated
carboxylic acid (0.5 mmol), CuCl (0.5 mmol), Cu(OAc)2 H2O (0.5 mmol),
DMF (1 mL), 140 °C, air, 24 h. Isolated yield.
3
a Reaction conditions: alkyl ketone (1.0 mmol), cinnamic acid (0.5 mmol),
To further explore the substrate scope, various alkyl
ketones were then investigated as depicted in Scheme 2.
Propiophenonesbearingsubstituentssuchasphenylandn-
Bu delivered the corresponding furans 3o and 3p in mod-
erate yields. Particularly, 2,2-dimethyl-3-hexanone could
be readily employed, allowing the preparation of furan 3q
with alkyl substituents on both C-2 and C-3 positions. 2,5-
Disubstituted furan products 3r and 3s were synthesized
from methyl ketones such as acetophenone and napthphe-
none under modified reaction conditions, albeit in lowered
yields. 1-(2-Thienyl)-1-propanone was compatible in this
reaction to give the desired product 3t with double hetero-
cyclic structure. Propiophenones bearing a methoxy group
on the para position of the aryl ring furnished the product
3u in higher yield than the product 3v with a fluoro group.
It is noteworthy that replacing cinnamic acid with
styrene under the above reaction conditions in Table 1
could also deliver the same furan product 3a. After opti-
mization of this reaction, the furan product 3a was isolated
in 65% yield in the presence of 2 equiv of CuCl in DMF as
shown in Scheme 3. The effect of the substitution on the
CuCl (0.5 mmol), Cu(OAc)2 H2O (0.5 mmol), DMF (1 mL), 140 °C, air,
3
24 h. Isolated yield. b CuCl (1.0 mmol), KOAc (1.0 mmol), DMF (1 mL),
140 °C, air, 24 h.
Scheme 3. Annulation of Alkyl Ketones with Styrenesa
a Reaction conditions: ketone (1.0 mmol), styrene (0.5 mmol), CuCl
(1.0 mmol), DMF (1 mL), 140 °C, air, 24 h. Isolated yield.
ketone moiety was examined, and similar results were
obtained with the previous method using cinnamic acids
Org. Lett., Vol. XX, No. XX, XXXX
C

dical inhibitor blocked the formation of expected furan
product 3a (eqs 1 and 2), which may support a radical
initiation pathway. Based on the above experimental
results and previous reports,11,13 a plausible reaction me-
chanism could be proposed in Scheme 4. Under the
oxidative conditions, reaction of the acrylic acid with
copper salts would generate cupric cinnamate, and alkyl
ketone would produce the carbon-centered radical A.
Addition of radical A to the R-position of the double bond
in cupric cinnamate would give the adduct radical B.
Through further single electron oxidation, this adduct
radical B would be converted to intermediate C. The
subsequent intramolecular cyclization of intermediate C
resulted in the formation of intermediate D, which proceeds
via deprotonation and elimanation to generate the furan
product. In the case of employing styrene in the annulation
reaction, the reaction mechanism is similar except that this
process involves dehydrogenation and generates intermedi-
ates without the cupric carboxylate group.
Scheme 4. Plausible Mechanism
as the annulation partner. Comparing the yields of the same
furan products in Schemes 2 and 3 indicates that, except for
the furan product 3o in a higher yield, other products such as
3p, 3u, and 3v were isolated in lower yields in Scheme 3 than
the yields in Scheme 2. Although copper has been reported
to catalyze the protodecarboxylation reaction of cinnamic
acid to generate styrene,6d we did not detect the formation of
styrene in the annulaton reaction of cinnamic acids.
In summary, we have demonstrated the copper-mediated
annulation via an oxidative free-radical process from alkyl
ketones and R,β-unsaturated carboxylic acids in a wide
substrate scope. This reaction provides a novel synthetic
route to 2,3,5-trisubstituted furans.
Acknowledgment. Financial support from National
Basic Research Program of China (2011CB936003) and
Natural ScienceFoundationof China(21072169) isgreatly
acknowledged.
In the above two reactions, the addition of 2 equiv of
TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) as the ra-
Supporting Information Available. Experimental pro-
cedure, characterization of all compounds, and crystallo-
graphic information file for compound 3e. This material is
available free of charge via the Internet at http://pubs.acs.org.
(13) (a) Logan, A. W. J.; Parker, J. S.; Hallside, M. S.; Burton, J. W.
Org. Lett. 2012, 14, 2940. (b) Xiang, J.; Fuchs, P. L. J. Am. Soc. Chem.
1996, 118, 11986. (c) Russell, G. A.; Ngoviwatchai, P. J. Org. Chem.
1989, 54, 1836.
The authors declare no competing financial interest.
D
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