A concise and efficient way to synthesize polyenic diones directly from α,β-unsaturated methyl ketones

Article abstract of DOI:10.1016/j.tet.2009.05.050

A concise and efficient approach to polyenic compounds containing important diketone structural fragments is developed from readily available α,β-unsaturated methyl ketones in the presence of copper(II) oxide, iodine, and dimethyl sulfoxide. This is a new carbon-carbon double bond-forming reaction from two methyl sp³ C-H bonds and an attractive route to introduce the SMe group into the molecule from inexpensive dimethyl sulfoxide. The hypothetic self-sorting tandem reaction mechanism is also proposed in this paper.

Full text of DOI:10.1016/j.tet.2009.05.050

Tetrahedron 65 (2009) 6047–6049
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Tetrahedron
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A concise and efficient way to synthesize polyenic diones directly
from a,b-unsaturated methyl ketones
Meng Gao a, Guodong Yin a, Zihua Wang a, Yandong Wu a, Cheng Guo b,
,
Yuanjiang Pan b, Anxin Wu a
*
a Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, Central China Normal University, Wuhan 430079, PR China
b Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 April 2009
Received in revised form 15 May 2009
Accepted 22 May 2009
Available online 27 May 2009
A concise and efficient approach to polyenic compounds containing important diketone structural
fragments is developed from readily available a,b-unsaturated methyl ketones in the presence of cop-
per(II) oxide, iodine, and dimethyl sulfoxide. This is a new carbon–carbon double bond-forming reaction
from two methyl sp3 C–H bonds and an attractive route to introduce the SMe group into the molecule
from inexpensive dimethyl sulfoxide. The hypothetic self-sorting tandem reaction mechanism is also
proposed in this paper.
Keywords:
Polyenic diones
Self-sorting tandem
Ó 2009 Elsevier Ltd. All rights reserved.
a,b-Unsaturated methyl ketones
Dimethyl sulfoxide
1. Introduction
and cumbersome workup procedures. Therefore, there is a strong
driving force to design new and efficient strategies for synthesis of
Polyenic compounds containing diketone structural fragments
are important intermediates in the preparation of polyenes,1 nat-
ural products,2 (e.g., compounds 1 and 2, Fig. 1), and interesting
heterocyclic compounds.3 Although polyenic diones are useful in-
termediates to afford various products, an advance of its synthetic
method has not been performed to date. In particular, previous
methods can synthesize only a few derivatives. For instance, they
are usually prepared by copper-promoted dimerization of ketone
enolates4 or furan–diazoketone reaction.1 Problems in these re-
actions are the use of expensive reagents under harsh conditions
these compounds.
In our recent reports,5 we proposed a novel self-sorting tandem
reaction pattern and established a simple, efficient method for the
preparation of
a-methylthio-substituted a,b-unsaturated 1,4-
dicarbonyl compounds from readily available (hetero)aryl methyl
ketones as substrates. These products are facile substrates for the
synthesis of saturated 1,4-dicarbonyl compounds,6 substituted fu-
rans, pyrroles, and thiophenes.5b Compared with the previously
reported methods for synthesis of 1,4-enediones,7 this is a new
carbon–carbon double bond-forming reaction between the sp3 C–H
bonds of two methyl groups and an attractive way to introduce the
methylthio group into these molecules from inexpensive dimethyl
sulfoxide.8 The self-sorting tandem reaction mechanism shows that
OEt
O
the key step is the generation of a-iodinated ketone intermediate 3
O
O
from enol form 2. Probably copper(II) oxide could promote the
formation of highly reactive enol form from methyl ketone 1,9
which is stabilized by the aromatic ring through conjugation effect
(Scheme 1, n¼0). According to the proposed mechanism,5 we en-
vision that if there exists one or more carbon–carbon double bonds
between the aromatic ring and the carbonyl group, due to the
possible conjugation effect of the introduced carbon–carbon dou-
ble bonds and the enol form of ketones, the reaction could give the
O
O
O
OEt
2
1
Figure 1.
polyenic diones via methyl-iodinated
a,b-unsaturated ketone
intermediate9c (Scheme 1, n¼1, 2). Herein, the detailed research
* Corresponding author. Tel.: þ86 27 6786 7129; fax: þ86 27 6786 7954.
E-mail address: chwuax@mail.ccnu.edu.cn (A. Wu).
results were discussed.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.050

6048
M. Gao et al. / Tetrahedron 65 (2009) 6047–6049
Table 2
O
SMe
O
Formation of carbon–carbon double bonds via the coupling reaction of
a,b-un-
CuO, I2, DMSO
n=0,1,2
saturated methyl ketonesa
Ar
Ar
Ar
CH3
n
n
n
1
O
SMe
O
O
O
4
CuO, I2, DMSO
65 °C, 20 h
R
R
R
CH3
step 1
OH
step 3
1
4
O
Entry
Substrates (R¼)
C6H5
4-MeC6H4
4-MeOC6H4
4-EtOC6H4
4-ClC6H4
2,4-Cl2C6H3
4-BrC6H4
3-NO2C6H4
3-MeO-4–HOC6H3
3-MeO-4–AcOC6H3
2-Furyl
Products
Isolated yield (Z/E)
Ar
CH2
Ar
CH2 I
step 2
n
n
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
52 (55:45)
62 (55:45)
78 (62:38)
80 (62:38)
68 (62:38)
58 (52:48)
49 (57:43)
52 (65:35)
db
2
3
Scheme 1.
2. Results and discussion
9
10
11
12
4j
4k
4l
62 (88:12)
57 (52:48)
50 (60:40)c
To begin our study, benzalacetone (1a) was synthesized in 89%
yield via the aldol condensation of benzaldehyde with acetone cat-
alyzed by sodium hydroxide according to a modified procedure.10
Based on our previous studies,5 herein we only investigated the ef-
fect of reaction temperature and molar ratio of n(1a)/n(I2)/n(CuO) on
the yield of the coupling product 4a in freshly distilled dimethyl
sulfoxide for 20 h using benzalacetone as a model substrate. The
experimental results were summarized in Table 1.
(E)-C6H5–CH]CH–
a
Standard conditions: n(substrate)/n(I2)/n(CuO)¼1:2:3, T¼65 ꢀC, 20 h.
Complicated mixture.
b
c
Pure Z-isomer was not obtained, the ratio of Z/E isomers was estimated from 1
H
NMR analysis of the crude reaction mixture.
Table 1
Effect of reaction temperature and molar ratio of n(1a)/n(CuO)n(I2) on the yield of 4a
O
SMe
O
CuO, I2, DMSO
Temp., 20 h
Ph
Ph
Ph
CH3
O
1a
4a
Entry
n(1a)/n(CuO)/n(I2)
Temp (ꢀC)
Isolated yield
1
2
3
4
5
6
7
8
1:3:2
1:3:2
1:3:2
1:3:2
1:1:1
1:1:2
1:2:1
1:2:2
20
45
65
90
65
65
65
65
0
29
52
10
24
30
37
45
Figure 2. X-ray structures of compound (E)-4e.
When the molar ratio of n(1a)/n(CuO)/n(I2) was fixed at 1:3:2,
the expected product 4a was obtained in 52% yield (Z/E isomers)
at 65 ꢀC (entry 3). At the room temperature, no reaction was
observed (entry 1). When the temperature was 45 ꢀC or 90 ꢀC, 4a
was obtained in 29% and 10% yields, respectively (entries 2 and 4).11
Next we varied the molar ratio of n(1a)/n(CuO)/n(I2) from 1:1:1 to
1:2:2, the reaction afforded 4a in 24–45% yield (entries 5–8).
With the successful synthesis of polyenic diketone 4a, a series of
However, it was a pity that this reaction was not suitable for
the substrate (1i) containing a sensitive hydroxyl group (–OH)
probably due to the use of iodine and dimethyl sulfoxide as oxi-
dants (entry 9). Much to our satisfaction, when the hydroxyl
group was protected by acetyl group, substrate 1j gave the
product 4j in 62% yield (entry 10). It should be noted that the
coupling reaction did not occur between the methyl carbons of
acetoxy owing to the difficulty in the formation of enol form (see
Scheme 3 for the reaction mechanism). In addition, (E)-4-(furan-
2-yl)but-3-en-2-one delivered the corresponding product 4k in
57% yield. When using (3E,5E)-6-phenylhexa-3,5-dien-2-one as
a substrate, we only separated the pure (E)-4l from the Z/E
mixture.
In order to further expand the substrate scope, 4-phenyl-
but-3-yn-2-one (1m)13 was employed for this reaction, which
gave a complicated mixture, possibly because it was difficult
for the enolization of this substrate under these conditions
(Scheme 2).
As shown in Scheme 3, a possible reaction mechanism is as
follows using benzalacetone (1a) as a example: First, (E)-1-iodo-4-
phenylbut-3-en-2-one (A) obtained by the selective iodination of
1a in the presence of copper(II) oxide is sequentially oxidized by
dimethyl sulfoxide to give intermediate (E)-2-oxo-4-phenylbut-3-
enal (C).5 While A is reacted with dimethyl sulfide (DMS), which is
other a,b-unsaturated methyl ketones were prepared (see Supple-
mentary data for details) to investigate the generality of this re-
action under the above optimized conditions (Table 2). The
substrates bearing electron-donating groups (e.g., –Me, –OMe,
–OEt) on the phenyl rings afforded the products 4b–d in 62–80%
yields (entries 2–4). When the substrates bearing electron-with-
drawing groups (e.g., –Cl, –Br, –NO2), the corresponding products
4e–h were obtained with a slightly lower yields in 49–68% (entries
5–8). In all cases, the products were a mixture of Z/E isomers, and
the thermodynamically stable Z-isomers were the major products.
All these target molecules were characterized by 1H NMR, 13C NMR,
HRMS, and IR spectra. The structure of compound (E)-4e was fur-
ther determined by X-ray single diffraction analysis.12 The bond
distance of C10–C11 and the torsion angle of C(9)–C(10)–C(11)–
C(12) are 1.33 Å and 2.2ꢀ, respectively, which supports the E-con-
figuration of the olefin 4e (Fig. 2).

M. Gao et al. / Tetrahedron 65 (2009) 6047–6049
6049
O
m/z [MþNa]þ calcd for C21H18NaO2S: 357.0920; found: 357.0904.
Compound (E)-4a: 0.20 g, yield 23%; 1H NMR (CDCl3, 400 MHz):
CuO, I2, DMSO
65 °C, 20 h
Complicated mixture
CH3
d
(ppm) 7.62 (d, J¼16.0 Hz, 1H), 7.56–7.36 (m, 11H), 6.89 (d,
1m
J¼16.0 Hz, 1H), 6.83 (d, J¼16.0 Hz, 1H), 6.42 (s, 1H), 2.46 (s, 3H); 13C
Scheme 2.
NMR (CDCl3, 100 MHz):
d (ppm) 193.6, 183.8, 160.0, 144.5, 143.7,
134.3, 134.0, 130.5, 130.4, 128.7, 128.6, 128.3, 128.2, 125.6, 125.1,
118.2,14.8; IR (KBr, cmꢂ1): 1659, 1601, 1534, 1116; MS (EI, 70 eV) m/z
(%): 334 (53), 257 (12), 203 (41), 131 (100), 103 (99), 91 (8), 77 (55);
HRMS (ESI): m/z [MþNa]þ calcd for C21H18NaO2S: 357.0920; found:
357.0913.
HI
DMSO
O
DMS
I
Ph
O
B
HI
A
I
S
Ph
I2/CuO
Acknowledgements
O
SCH3
O
-MeI
Ph
Ph
Ph
CH3
1a
O
Z/E-4a
We thank the National Natural Science Foundation of China (Grant
No. 20672042 and No. 20872042) for generous financial support.
O
I2/CuO
Ph
CHO
O
HI
C
I
Ph
Supplementary data
DMSO
A
Scheme 3. The proposed self-sorting tandem reaction mechanism.
The general experimental methods and the characterizing data
for
a,b
-unsaturated methyl ketones, 1H NMR, 13C NMR, MS, and
HRMS data for compound 4 and X-ray crystallography data for (E)-
4e are available. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/j.tet.2009.05.050.
readily produced from reduction of dimethyl sulfoxide by HI formed
in the iodination step, to give (E)-dimethyl-(2-oxo-4-phenylbut-3-
enyl)sulfonium iodide (B). Furthermore, B condenses with C in an
aldol-type reaction to give target product Z/E-4a isomers after loss
of MeI and water. It can be seen from Scheme 3 that the starting
material benzalacetone displays a self-sorting property during the
reaction process.
References and notes
1. Wenkert, E.; Guo, M.; Lavilla, R.; Porter, B.; Ramachandran, K.; Sheu, J. H. J. Org.
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3. Conclusion
3. (a) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles; G. Thieme: Stuttgart,
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2008, 2317–2320; (c) Yu, J. Q.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 3232–3233;
(d) Runcie, K. A.; Taylor, R. J. K. Chem. Commun. 2002, 974–975; (e) Bonete, P.;
A concise and efficient approach to polyenic compounds con-
taining important diketone structural fragments from
a,b-un-
saturated methyl ketones in the presence of copper(II) oxide,
iodine, and DMSO has been developed. This is an efficient carbon–
carbon double bond-forming reaction from two methyl sp3 C–H
bonds and an attractive route to introduce the methylthio group
into these molecules from inexpensive dimethyl sulfoxide. The
hypothetic reaction mechanism shows the starting material ben-
zalacetone displays a self-sorting property during the reaction
process. Further application of this methodology for the synthesis
of various substituted heterocyclic compounds and polyenes is
under way in our laboratory.
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Najera, C. Tetrahedron 1995, 51, 2763–2776; (f) Ballini, R.; Bosica, G. J. Org. Chem.
4. Experimental
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8. General routes to introduce the methylthio group into molecules: (a) Wu, H. J.;
Yen, C. H.; Chuang, C. T. J. Org. Chem. 1998, 63, 5064–5070; (b) Padwa, A.; Ginn,
J. D.; Bur, S. K.; Eidell, C. K.; Lynch, S. M. J. Org. Chem. 2002, 67, 3412–3424; (c)
Padwa, A.; Ginn, J. D.; McClure, M. S. Org. Lett. 1999, 1, 1559–1561.
9. (a) Yin, G. D.; Gao, M.; She, N. F.; Hu, S. L.; Wu, A. X.; Pan, Y. J. Synthesis 2007,
3113–3116; (b) Yin, G. D.; Gao, M.; Wang, Z. H.; Wu, Y. D.; Wu, A. X. Bull. Chem.
Soc. Jpn. 2008, 81, 369–372; (c) Wang, Z. H.; Yin, G. D.; Qin, J.; Gao, M.; Cao, L. P.;
Wu, A. X. Synthesis 2008, 3675–3681.
4.1. General procedure for preparation of 4 (4a as an example)
A mixture of benzalacetone (0.73 g, 5 mmol), iodine (2.54 g,
10 mmol), and CuO (1.20 g, 15 mmol) in anhyd DMSO (30 mL) was
heated at 65 ꢀC for 20 h. The reaction mixture was poured into
brine (150 mL) after filtration and the aqueous layer was extracted
with CH2Cl2 (4ꢁ50 mL). The extract was washed with 10% Na2S2O3
then a small amount 5% NaOH solution, dried over anhyd Na2SO4
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel using petroleum ether/EtOAc (v/
v¼8:1) as the eluent to give the expected products (Z)-4a and (E)-
4a as yellow solids in 52% overall yield. Compound (Z)-4a: 0.24 g,
10. Drake, N. L.; Allen, P., Jr. Org. Synth. Coll. Vol. 1; John Wiely & Sons: London, 1941;
pp 77–78.
11. To ensure that the coupling reaction is carried out efficiently between in-
termediates B and C, the reaction rate from A to C should be close to that from A to
B. However, if the temperature was elevated to 90 ꢀC, the reaction rate for the
oxidation step from A to C might be much faster than that from A to B in the whole
system, and the corresponding aromatic acid would be the major product (see
Scheme 3 and Supplementary data for Org. Lett. 2006, 8, 2245–2248 ).
12. Crystal data for compound (E)-4e: C21H16Cl2O2S1, MW¼425.01, monoclinic,
yield 29%; 1H NMR (CDCl3, 400 MHz):
d
(ppm) 7.68 (d, J¼16.0 Hz,
a¼14.9253(10), b¼13.5170(10), c¼9.9867(7) Å,
a
¼90.00ꢀ,
b
¼104.2030(10)ꢀ,
g
¼90.00ꢀ, V¼1953.2(2) Å3, T¼295(2) K, space group Z¼4,
m
(Mo
K
a
)¼0.
1H), 7.65 (d, J¼16.0 Hz, 1H), 7.61–7.38 (m, 10H), 6.88 (d, J¼16.0 Hz,
094 mmꢂ1, 21,634 reflections measured, 4260 unique (Rint¼0.0908), which
were used in all calculations. The final wR2 (F2) was 0.1378. CCDC 725679
contains the supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
1H), 6.86 (d, J¼16.0 Hz, 1H), 6.65 (s, 1H), 2.28 (s, 3H); 13C NMR
(CDCl3, 100 MHz):
d (ppm) 191.6, 187.2, 159.2, 149.1, 142.8, 134.5,
133.6, 131.6, 130.3, 129.0, 128.8, 128.7, 128.2, 126.5, 125.1, 119.3, 15.5;
IR (KBr, cmꢂ1): 1652, 1603, 1531, 1510, 1245, 1116, 975; MS (EI,
70 eV) m/z (%): 334 (60), 203 (46), 131 (100), 103 (81); HRMS (ESI):
13. Dos Santos, A. A.; Castelani, P.; Bassora, B. K.; Fogo, J. C.; Costa, C. E.; Comasseto,
J. V. Tetrahedron 2005, 61, 9173–9179.