Formation of unsymmetrical 1,4-enediones via A focusing domino strategy: Cross-coupling of 1,3-dicarbonyl compounds and methyl ketones or terminal aryl alkenes

Article abstract of DOI:10.1021/ol100473f

A highly efficient synthesis of unsymmetrical 1,4-enediones from 1,3-dicarbonyl compounds and methyl ketones or terminal aryl alkenes has been developed via a focusing domino strategy. Simple and readily available starting materials, mild reaction conditions, and a very simple operation are advantages of the reaction, which allow straightforward synthesis of a variety of unsymmetrical 1,4-enediones.

Full text of DOI:10.1021/ol100473f

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1856-1859
Formation of Unsymmetrical
1,4-Enediones via A Focusing Domino
Strategy: Cross-Coupling of
1,3-Dicarbonyl Compounds and Methyl
Ketones or Terminal Aryl Alkenes
Meng Gao, Yan Yang, Yan-Dong Wu, Cong Deng, Li-Ping Cao, Xiang-Gao Meng,
and An-Xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal UniVersity, Hubei, Wuhan 430079, P. R. China
chwuax@mail.ccnu.edu.cn
Received February 25, 2010
ABSTRACT
A highly efficient synthesis of unsymmetrical 1,4-enediones from 1,3-dicarbonyl compounds and methyl ketones or terminal aryl alkenes has
been developed via a focusing domino strategy. Simple and readily available starting materials, mild reaction conditions, and a very simple
operation are advantages of the reaction, which allow straightforward synthesis of a variety of unsymmetrical 1,4-enediones.
Domino reactions that perform multiple reactions simulta-
neously in a single reaction vessel offer possibilities for the
efficient construction of complex molecules from readily
available starting materials.1
For example, nature utilizes a focusing domino approach that
consists of two or more distinct pathways focusing on one
final common pathway to afford the same product (Scheme
1, path V).3 This should be the most efficient design during
evolution, as the desired products could be obtained from
diverse substrates via a common pathway.3b Inspired by the
striking efficiency of this graceful strategy, we would like
to develop a focusing domino reaction in synthetic chemistry,
which would allow changes in substrates and help chemists
for their flexibility in synthetic plans.
Although several domino strategies have been developed
(Scheme 1, paths I-IV),2 the prevalence of diverse domino
approaches in nature continues to stimulate organic chemists
to develop novel domino strategies in synthetic chemistry.
(1) For reviews on domino reactions, see: (a) Tietze, L. F.; Brasche,
G.; Gericke, K. Domino Reactions in Organic Synthesis; Wiley-VCH:
Weinheim, Germany, 2006. (b) Tietze, L. F. Chem. ReV. 1996, 96, 115. (c)
Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003, 551.
(2) For selective examples of domino strategies: (a) Vilotijevic, I.;
Jamison, T. F. Science 2007, 317, 1189. (b) Yoder, R. A.; Johnston, J. N.
Chem. ReV. 2005, 105, 4730. (c) Ikeda, S. Acc. Chem. Res. 2000, 33, 511.
(d) Enders, D.; Hu¨ttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441,
861. (e) Tietze, L. F.; Modi, A. Med. Res. ReV. 2000, 20, 304. (f) Zhu,
J. P., Bienayme´, H., Eds.; Multicomponent Reactions; Wiley-VCH: Wein-
heim, 2005. (g) Yin, G. D.; Zhou, B. H.; Meng, X. G.; Wu, A. X.; Pan,
Y. J. Org. Lett. 2006, 8, 2245. (h) Yin, G. D.; Wang, Z. H.; Chen, A. H.;
Gao, M.; Wu, A. X.; Pan, Y. J. J. Org. Chem. 2008, 73, 3377. (i) Gao, M.;
Yin, G. D.; Wang, Z. H.; Wu, Y. D.; Guo, C.; Pan, Y. J.; Wu, A. X.
Tetrahedron 2009, 65, 6047.
(3) (a) Berg, J. M.; Tymoczko, J. L.; Stryer, L. Biochemistry, 5th ed.;
W. H. Freeman and Co.: New York, 2002; p 697. (b) Mele´ndez-Hevia, E.;
Waddell, T. G.; Cascante, M. J. Mol. EVol. 1996, 43, 293. (c) Tadokoro,
S.; Shattil, S. J.; Eto, K.; Tai, V.; Liddington, R. C.; de Pereda, J. M.;
Ginsberg, M. H.; Calderwood, D. A. Science 2003, 302, 103. (d) Melikyan,
G. B. RetroVirology 2008, 5, 111. (e) Ainscow, E. K.; Brand, M. D. BBA-
Bioenergetics 1998, 1366, 284. (f) Nagaoka, H.; Muramatsu, M.; Yamamura,
N.; Kinoshita, K.; Honjo, T. J. Exp. Med. 2002, 195, 529. (g) Riddel, J. P.;
Aouizerat, B. E.; Miaskowski, C.; Lillicrap, D. P. J. Pediatr. Oncol. Nurs.
2007, 24, 123. (h) Chen, S. Y.; Sarlis, N. J.; Simons, S. S. J. Biol. Chem.
2000, 275, 30106. (i) Hugouvieux-Cotte-Pattat, N.; Nasser, W.; Robert-
Baudouy, J. J. Bacteriol. 1994, 176, 2386.
10.1021/ol100473f  2010 American Chemical Society
Published on Web 03/22/2010

intermediates, which further reacted with 1,3-dicarbonyl
compounds to afford unsymmetrical 1,4-enediones via a
common pathway (Scheme 2).
Scheme 1.
Strategies of Domino Reactiona
Scheme 2. Proposal: Preparation of Unsymmetrical
1,4-Enediones via the Focusing Domino Strategy
a Intramolecular domino reaction (Path I); Intermolecular domino
reaction (Path II); multicomponent domino reaction (Path III); self-sorting
domino reaction (Path IV); focusing domino reaction (Path V).
On the basis of our previous studies,2g-i we initially
examined the feasibility of the strategy by reaction of
acetophenone 1a with ethyl benzoylacetate 3a. When 1a and
3a were in the presence of copper(II) oxide and iodine in
DMSO at 70 °C for 12 h, the desired 1,4-enedione 4aa was
obtained in 88% yield (Scheme 3). The efficient formation
The 1,4-enedione framework is frequently found in
bioactive natural products and medicinal compounds.4 In
addition, by virtue of their multifunctional composition,
1,4-enediones could serve as versatile precursors for
heterocycle synthesis,5 Diels-Alder cycloaddition,6 Michael
addition,7 as well as many other useful transformations.8
Although a variety of approaches have been developed
for the synthesis of this skeleton,9 a general and practical
methodology is still needed for chemists to construct 1,4-
enediones from simple and readily available starting
materials. In our recent reports, we proposed a novel self-
sorting domino strategy for the efficient construction of
R-methylthio-substituted 1,4-enediones from readily avail-
able methyl ketones, wherein R-ketoaldehydes were
generated in situ.2g-i However, the direct synthesis of
unsymmetrical 1,4-enediones from two different methyl
ketones has been proved extremely difficult.2h We wondered
whether it would be possible for simple methyl ketones or
terminal aryl alkenes to focus on the same R-ketoaldehyde
Scheme 3.
Scope of Methyl Ketonesa
(4) (a) Abou-Gazar, H.; Bedir, E.; Takamatsu, S.; Ferreira, D.; Khan,
I. A. Phytochemistry 2004, 65, 2499. (b) Dura´n, R.; Zub´ıa, E.; Ortega, M. J.;
Naranjo, S.; Salva´, J. Tetrahedron 1999, 55, 13225. (c) Binder, R. G.;
Benson, M. E.; Flath, R. A. Phytochemistry 1989, 28, 2799. (d) Fouad,
M.; Edrada, R. A.; Ebel, R.; Wray, V.; Mu¨ller, W. E. G.; Lin, W. H.;
Proksch, P. J. Nat. Prod. 2006, 69, 211. (e) Ballini, R.; Astolfi, P. Liebigs
Ann. 1996, 1879. (f) Nguyen, C.; Teo, J. L.; Matsuda, A.; Eguchi, M.; Chi,
E. Y.; Henderson, W. R.; Kahn, M. Proc. Natl. Acad. Sci. U.S.A. 2003,
100, 1169.
(5) (a) Eicher, T.; Hauptmann, S.; Speicher, A. The Chemistry of
Heterocycles; Wiley-VCH: Weinheim, 2003. (b) Rao, H. S. P.; Jothilingam,
S. J. Org. Chem. 2003, 68, 5392.
(6) (a) Allen, J. G.; Danishefsky, S. J. J. Am. Chem. Soc. 2000, 123,
351. (b) Danishefsky, S.; Kahn, M. Tetrahedron Lett. 1981, 22, 489. (c)
Lenz, G. R. J. Org. Chem. 1979, 44, 1597.
(7) (a) Ballini, R.; Bosica, G.; Fiorini, D.; Gil, M. V.; Petrini, M. Org.
Lett. 2001, 3, 1265. (b) Ballini, R.; Bosica, G. Tetrahedron 1995, 51, 4213.
(8) (a) D’auria, M.; Piancatelli, G.; Scettri, A. Synthesis 1980, 245. (b)
DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130,
11546.
(9) For selected examples, see: (a) Yu, J. Q.; Corey, E. J. J. Am. Chem.
Soc. 2003, 125, 3232. (b) Vassilikogiannakis, G.; Margaros, I.; Montagnon,
T. Org. Lett. 2004, 6, 2039. (c) Crone, B.; Kirsch, S. F. Chem. Commun.
2006, 764. (d) Runcie, K. A.; Taylor, R. J. K. Chem. Commun. 2002, 974.
(e) Echavarren, A. M.; Perez, M.; Castano, A. M.; Cuerva, J. M. J. Org.
Chem. 1994, 59, 4179. (f) Ballini, R.; Bosica, G. J. Org. Chem. 1994, 59,
5466. (g) Bonete, P.; Na´jera, C. Tetrahedron 1995, 51, 2763. (h) Prakash,
O.; Batra, A.; Chaudhri, V.; Prakash, R. Tetrahedron Lett. 2005, 46, 2877.
(i) Ronsheim, M. D.; Zercher, C. K. J. Org. Chem. 2003, 68, 4535. (j)
Wasnaire, P.; de Merode, T.; Marko´, I. E. Chem.Commun. 2007, 4755. (k)
Cecere, M.; Gozzo, F.; Malandra, A.; Mirenna, L. Chem. Abstr. 1984, 100,
139119x; Ger. Offen 3,319,990, 1983.
a The reaction was carried out with 1.0 equiv of 1, 1.0 equiv of 3a, 1.1
equiv of CuO and 1.1 equiv of I2 in DMSO at 70 °C. Isolated yield. E:Z
1
ratio determined by H NMR.
Org. Lett., Vol. 12, No. 8, 2010
1857

of cross-coupling product prompted us to study the reaction
scope further. Pleasingly, all methyl ketones, regardless of
their electronic or steric properties, proceed cleanly in good
yields to afford the expected 1,4-enediones (67-89%;
4aa-4sa). The conditions were mild enough to be compat-
ible with haologenated and hydroxylated substrates (72-85%;
4ea-4ia). Moreover, the desired 1,4-enediones could also
be obtained in good yields from R,ꢀ-unsaturated methyl
ketones (70-79%; 4pa-4sa).2i In most cases, the reaction
delivers a mixture of E/Z isomers, and the thermodynamically
stable E-isomers were the major products. Although the two
isomers could not be separated by column chromatography,
pure (E)-4 isomers were obtained by recrystallization from
ethanol/petroleum ether. Furthermore, the configuration of
(E)-4na was unambiguously determined by X-ray crystal-
lographic analysis,10 and other 1,4-enedione products were
Scheme 4.
Socpe of 1,3-Dicarbonyl Compoundsa
1
assigned by analogy on the basis of their similar H NMR
spectra.
Next, the substrates were extended to terminal aryl alkenes.
On the basis of previous reports,11 we found that a wide
range of terminal aryl alkenes in the presence of I2/IBX in
DMSO could be easily transformed to R-iodoketones, which
further reacted with ethyl benzoylacetate 3a to afford the
corresponding 1,4-enediones in one-pot. The steric and
electronic nature of the alkenes had little influence on the
reaction, and generally high yields were obtained (74-86%;
Table 1).
a The reaction was carried out with 1.0 equiv of 1a, 1.0 equiv of 3, 1.1
equiv of CuO and 1.1 equiv of I2 in DMSO at 70 °C. Isolated yield. E:Z
1
b
ratio determined by H NMR. Reaction time of 3 h.
delight, aliphatic acetylacetone and multifunctionalized cur-
cumin could also give their corresponding products in
moderate yields (61-63%; 4aj-4ak).
Scheme 5.
Proposed Mechanisma
Table 1. Scope of Terminal Aryl Alkenesa,b
entry
2 (R1)
4
yield (%)c
E:Zd
1
2
3
4
5
6
7
2a (C6H5)
4aa
4ba
4ca
4ea
4ga
4ha
4ka
84
83
80
78
79
74
86
86:14
88:12
75:25
82:18
87:13
80:20
77:23
2b (4-MeC6H4)
2c (4-MeOC6H4)
2d (4-ClC6H4)
2e (4-BrC6H4)
2f (4-FC6H4)
a IBA ) iodosobenzoic acid.
2g (ꢀ-naphthyl)
a Reaction was carried out with 1.0 equiv of 2, 1.1 equiv of I2, 1.2
equiv of IBX, 1.0 equiv of 3a, and 1.1 equiv of CuO. b IBX )
2-iodoxybenzoic acid. c Isolated yield. d E:Z ratio determined by 1H NMR.
As shown in Scheme 5, a possible reaction mechanism
for this domino reaction is as follows using acetophenone
1a, styrene 2a and ethyl benzoylacetate 3a as an example:
Because 1a was more reactive than 3a toward iodination
under this condition,10 the phenacyl iodine A was preferen-
tially generated either by iodination of 1a or by consecutive
iodination and oxidation of 2a. Then it was oxidized to give
phenylglyoxal B via Kornblum oxidation,12 which further
reacted with 3a by Knoevenagel condensation to afford the
desired product 4aa after loss of water. We speculated that
1,3-dicarbonyl compounds would trap out small equilibrium
quantities of R-ketoaldehydes generated in situ from R-io-
Using acetophenone, structural variations in the 1,3-
dicarbonyl compounds were then examined (Scheme 4). The
electronic nature of the phenyl ring of the 1,3-dicarbonyl
compounds has little effect on the reaction efficiency
(79-88%; 4ab-4ad). Significantly, halo, heterocycle con-
taining and sterically encumbered 1,3-diketones are readily
tolerated in this transformation (73-84%; 4ae-4ai). To our
(10) See the Supporting Information.
(11) (a) Moorthy, J. N.; Senapati, K.; Singhal, N. Tetrahedron Lett. 2009,
50, 2493. (b) Yadav, J. S.; Subba Reddy, B. V.; Singh, A. P.; Basak, A. K.
Tetrahedron Lett. 2008, 49, 5880.
(12) Kornblum, N.; Powers, J. W.; Anderson, G. J.; Jones, W. J.; Larson,
H. O.; Levand, O.; Weaver, W. M. J. Am. Chem. Soc. 1957, 79, 6562.
1858
Org. Lett., Vol. 12, No. 8, 2010

doketones, thus accelerating equilibrium toward the desired
products and preventing the pathway toward dimethyl (acyl)-
sulfonium iodide.2g-i To prove the intermediacy of phenacyl
iodine A and phenylglyoxal B in the proposed mechanism,
we used phenacyl iodine and phenylglyoxal hydrate as
substrates to react with 3a and the desired product 4aa was
obtained.10
Scheme 6
.
Focusing Domino Reaction of Methyl Ketone 1a and
Terminal Aryl Alkene 2a in One-Pota
With the success in obtaining 1,4-enediones from indi-
vidual substrate, we considered the possibility of using
diverse substrates in one-pot to focus on the same product.
If successful, this would be an excellent example of the
focusing domino reaction based on retrosynthetic design from
the same intermediates, which further verified the proposed
mechanism. Fortunately, these substrates were compatible
under this condition and smoothly converted to the desired
products. For example, a mixture of acetophenone 1a and
styrene 2a were successfully converted to the same product
4aa in 81% yield (Scheme 6). Meanwhile, substrates with
different substituents were also successfully converted to their
corresponding products.10 These facts imply the focusing
process of two parallel reactions in one-pot via self-sorting
behavior.
In conclusion, we have developed a novel focusing domino
reaction to prepare unsymmetrical 1,4-enediones from 1,3-
dicarbonyl compounds and methyl ketones or terminal aryl
alkenes. Owing to the simple and readily available starting
materials, mild reaction conditions, and a very simple
operation, this reaction should be of great utility in organic
chemistry. Particularly noteworthy is the high efficiency of
a The reaction was carried out with 1.0 equiv of 1a, 1.0 equiv of 2a,
2.2 equiv of I2, 1.2 equiv of IBX, 2.0 equiv of 3a, 2.2 equiv of CuO. Isolated
1
yield based on 3a. E:Z ratio determined by H NMR.
this focusing domino reaction, as diverse substrates could
be used to prepare their corresponding products via a
common pathway. Further studies on the applications of this
strategy will be reported in due course.
Acknowledgment. We thank the National Natural Science
Foundation of China (Grant 20672042, 20872042, and
20902035). We also thank Zhejiang University for perform-
ing the structural analysis.
Supporting Information Available: Experimental pro-
cedures and compound characterization data including X-ray
crystal data for (E)-4na. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL100473F
Org. Lett., Vol. 12, No. 8, 2010
1859