A highly tunable stereoselective dimerization of methyl ketone: Efficient synthesis of e - And Z-1,4-enediones

Article abstract of DOI:10.1021/ol4006344

A new method for the tunable synthesis of 1,4-enedione directly from aromatic methyl ketone is described. This tandem reaction enables the construction of symmetric and unsymmetric 1,4-enediones with complete E-selectivity. Moreover, the resulting E-1,4-enedione could be transformed into a Z-isomer by irradiation with 23 W of white light.

Full text of DOI:10.1021/ol4006344

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Highly Tunable Stereoselective
Dimerization of Methyl Ketone: Efficient
Synthesis of E- and Z‑1,4-Enediones
Kun Xu,† Yang Fang,† Zicong Yan, Zhenggen Zha, and Zhiyong Wang*
Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of
Soft Matter Chemistry and Department of Chemistry, University of Science and
Technology of China, Hefei, Anhui, 230026, P. R. China
zwang3@ustc.edu.cn
Received March 10, 2013
ABSTRACT
A new method for the tunable synthesis of 1,4-enedione directly from aromatic methyl ketone is described. This tandem reaction enables the
construction of symmetric and unsymmetric 1,4-enediones with complete E-selectivity. Moreover, the resulting E-1,4-enedione could be
transformed into a Z-isomer by irradiation with 23 W of white light.
The construction of a carbonÀcarbon double bond, a
principal functionality in organic chemistry, plays a central
role in chemical synthesis.1 Therefore, various olefination
methodologies have been developed over the past decades.2
Among these versatile protocols, direct functionalization of
inert C;H bonds, involving coupling reactions of Caryl;H
bonds with Cvinyl;H bonds3 and double Cvinyl;H bond
activation,4 has emerged as a step-economic and powerful
tool for carbonÀcarbon double bond formation. However,
owing to the general low reactivity of C(sp3);H bonds,
direct functionalization of two sp3 C;H bonds to generate
aCdC bond with high selectivity remains a great challenge.5
As an important class of olefins, the 1,4-enedione
(R1COCHdCHCOR2) compound has attracted note-
worthy attention in recent years since it constitutes a key
component of many bioactive compounds including
steroids, antitumor agents, and marine natural products.6
† These authors contributed equally.
(1) Takeda, T. Modern Carbonyl Olefination; Wiley-VCH, Weinheim,
Germany, 2004.
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2005, 7, 4281. (c) Huang, J.; Wu, C.; Wulff, W. D. J. Am. Chem. Soc.
2007, 129, 13366. (d) Trost, B. M. Angew. Chem., Int. Ed. 1995, 34, 259.
(e) Alcaide, B.; Almendros, P.; Luna, A. Chem. Rev. 2009, 109, 3817. (f)
Vehlow, K.; Wang, D.; Buchmeiser, M. R.; Blechert, S. Angew. Chem.,
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Rev. 2011, 111, 1315. (b) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius,
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D. H.; Engle, K. M.; Shi, B. F.; Yu, J. Q. Science 2010, 327, 315. (f)
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8872. (g) Patureau, F. W.; Besset, T.; Glorius, F. Angew. Chem., Int. Ed.
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(5) For selected examples on sp3 CÀH activation, see: (a) Colby,
D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (b)
Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (c) Wang,
D. H.; Wasa, M.; Giri, R.; Yu, J. Q. J. Am. Chem. Soc. 2008, 130, 7190.
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2005, 127, 13154. (f) Barder, T. E.; Walker, S. D.; Martinelli, J. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685. (g) Baudoin, O.
Chem. Soc. Rev. 2011, 40, 4902. (h) Zhang, S. Y.; Zhang, F. M.; Tu, Y. Q.
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W.; Pidacs, C.; Lancaster, J. E. J. Am. Chem. Soc. 1962, 84, 3185. (b)
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2009, 11, 2639. (c) Xu, Y. H.; Chok, Y. K.; Loh, T. P. Chem. Sci. 2011, 2,
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2012, 3647.
r
10.1021/ol4006344
XXXX American Chemical Society

Conventional synthetic routes to 1,4-enedione units in-
volve ring opening of furan and thiophene derivatives,7 the
oxidation of an enone subunit,8 and decomposition of
R-diazo carbonyl compounds.9 Recently, Kirsch reported
a useful oxidative rearrangement of 2-alkynyl alcohols to
yield 1,4-enediones in 33À65% yield.10 Although consid-
erable progress has been made in 1,4-enedione synthesis,
the limited availability of starting materials restricts the
substitution pattern of the product, and the low yield also
limits its synthetic application. In addition to these prob-
lems, great challenges remain in the synthesis of symmetric
and unsymmetric 1,4-diaryl-substituted 1,4-enedione, and
there is no single method providing a universal solution to
the stereoselective tunable synthesis. We envisioned that
construction of a 1,4-diaryl substituted 1,4-enedione unit
directly from aromatic methyl ketone would be a more
appreciable synthetic route, since the direct transformation
of two simple C(sp3);H bonds into the CdC bond elim-
inates prefunctionalization steps for substrate activation.
Herein, we first report an efficient synthesis of symmetric
and unsymmetric 1,4-enediones directly from commercially
available aromatic methyl ketones in a complete E-selective
manner. Moreover, the resulting E-1,4-enedione could be
transformed into a Z-isomer by irradiation with white light
(23 W) at rt with high to excellent E/Z photoconversions.
(Table 1). In a continuing effort to develop iodine-mediated
tandem reactions,11 a preliminary study revealed that iodine
could promote the homodimerization of acetophenone 1a to
yield the product 2a in 43% yield (Table 1, entry 1). Then,
experiments were performed to investigate the effect of Lewis
acids on the reaction, and CuBr2 was identified to be the
suitable Lewis acid to give the best chemical yield (see Table
S1 in the Supporting Information for details). Further study
showed that iodine was essential for this transformation
(Table 1, entry 3). Increasing the temperature to 90 °C led
to a slight decrease in the yield (Table 1, entry 7). Subse-
quently, different polar and nonpolar solvents were examined
(Table 1, entries 8À11), and the results revealed the super-
iority of N,N-dimethylformamide (DMF) as solvent with
respect to the chemical yield (Table 1, entry 2 vs entries
8À11). Further assessment of the reaction conditions indi-
cated that an oxygen atmosphere had little effect on the
reaction activity; however, a nitrogen atmosphere would lead
to a decrease in the chemical yield (Table 1, entries 12 and 13).
Table 2. Scope of the Homodimerization Reactiona
Table 1. Optimization of the Reaction Conditionsa
entry
R1
product
yield (%)b
1
C6H5
2a
2b
2c
2d
2e
2f
77
78
82
90
89
91
75
70
29
72
74
68
65
61
83
61
2
4-MeC6H4
4-tBuC6H4
4-nBuC6H4
4-iBuC6H4
4-MeOC6H4
4-FC6H4
3
4
5
6
entry
solvent
yield (%)b
7
2g
2h
2i
1c
2
3d
4e
5f
6g
7h
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
DMSO
CH3NO2
Tol
43
8
4-ClC6H4
76
9
4-CF3C6H4
3-MeC6H4
3-MeOC6H4
3-FC6H4
0
10
11
12
13
14
15
16
2j
76
2k
2l
72
31
2-MeC6H4
2-FC6H4
2m
2n
2o
2p
74
45
2,5-di-MeOC6H3
2-thio
9
trace
trace
trace
77
10
11
12i
13j
a The reactions were carried out with 1a (0.5 mmol), I2 (2 equiv),
CuBr2 (0.2 equiv), and DMF (dry, 0.5 mL) at 80 °C for 20 h. b Isolated
yield.
DMF
DMF
56
a The reactions were carried out in a sealed tube with 1a (0.5 mmol),
I2 (2 equiv), CuBr2 (0.2 equiv), and solvent (dry, 0.5 mL) at 80 °C for
20 h. b Isolated yield. c No copper salt was added. d No iodine was added.
e Using 3 equiv of iodine. f 1 equiv of water was added. g 10 equiv of water
were added. h The reaction temperature was 90 °C. i The reaction was
performed under 1 atm of oxygen. j The reaction was performed under
1 atm of nitrogen.
With the optimized reaction conditions in hand, the
substrate scope and limitations of the homodimerization
reaction were investigated by evaluating a variety of aro-
matic methyl ketones. As illustrated in Table 2, the reac-
tionproceededsmoothlywithdifferent substratestoafford
a wide range of 1,4-diaryl-substituted 1,4-enediones in
complete E-selectivity. The electronic properties of a series
of aromatic methyl ketones were found to greatly influence
With the homodimerization of acetophenone 1a as a
model reaction, a series of reaction conditions were optimized
(11) (a) Wan, C. F.; Gao, L. F.; Wang, Q.; Zhang, J. T.; Wang, Z. Y.
Org. Lett. 2010, 12, 3902. (b) Zhang, J. T.; Zhu, D. P.; Yu, C. M.; Wan,
C. F.; Wang, Z. Y. Org. Lett. 2010, 12, 2841. (c) Xu, K.; Hu, Y. B.;
Zhang, S.; Zha, Z. G.; Wang, Z. Y. Chem.;Eur. J. 2012, 18, 9793.
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(9) Baratta, W.; Del Zotto, A.; Rigo, P. Chem. Commun. 1997, 2163.
(10) Crone, B.; Kirsch, S. F. Chem. Commun. 2006, 764.
B
Org. Lett., Vol. XX, No. XX, XXXX

the reaction (Table 2, entries 1À9). In general, the electron-
donating group has a positive effect on the yield (Table 2,
entries 1À6 vs 7À9). On the other hand, the steric effects of
substituents on the aromatic rings also had some influence on
the reaction. A heteroaryl substrate was also efficiently trans-
formed, affording the product 2p in moderate yield (Table 2,
entry 15). The absolute configuration of 2a was determined by
single-crystal X-ray diffraction analysis (CCDC 918566).
As shown in Table 2, the homodimerization of aromatic
methyl ketone has been demonstrated as a step-economic
method for symmetric 1,4-enedione synthesis. It would be
more valuable if the present reaction system could be
applied to unsymmetric 1,4-diaryl substituted 1,4-ene-
dione synthesis, since an unsymmetric 1,4-enedione moiety
is an important structural feature found in many biologi-
cally relevant compounds.12 However, the rapid and
stereoselective synthesis of these units remain an ongoing
syntheticchallenge. Itwas found thata minor modification
of the standard reaction conditions led to the formation of
heterodimerized products 5aÀ5l in synthetically useful
yields, in which a 2-fold excess of one ketone over the other
was employed to facilitate heterodimerization. As presented
in Table 3, both electron-withdrawing and -donating func-
tionalities on the aromatic ring of methyl ketones were
compatible with this heterodimerization reaction, yielding
5aÀ5l in 58À83% yields.
reveals that high pressure mercury (200 W) and degassed
Et2O are needed.13 Herein, we described a photoisomeriza-
tion of E-1,4-enedione into the Z-isomer by irradiation with
white light (23 W) at rt. As illustrated in Table 4, a series of
symmetric and unsymmetric E-1,4-enediones with different
substituents on the aromatic ring underwent the photoisome-
rization smoothly, yielding Z-1,4-enediones 6aÀ6i with high
to excellent E/Z photoconversions. The absolute configura-
tion of 6a was determined by single-crystal X-ray diffraction
analysis (CCDC 918565). Compared to the previously re-
ported method, the present protocol may be more appealing
for laboratory applications due to its operational simplicity.14
Table 4. Scope of the Photoisomerization Reactiona
entry
R1
C6H5
R2
C6H5
product
yield (%)b
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
99
93
97
81
88
87
90
89
81
4-MeC6H4
4-iBuC6H4
4-MeOC6H4
3-MeOC6H4
3-FC6H4
4-MeC6H4
4-iBuC6H4
4-MeOC6H4
3-MeOC6H4
3-FC6H4
C6H5
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
6g
6h
6i
4-nBuC6H4
4-FC6H4
Table 3. Scope of the Heterodimerization Reactiona
a The reactions were carried out with 5 (0.3 mmol), solvent (2.1 mL,
EtOAc/Hex = 1:6) by irradiation with 23 W of white light at rt for 5 h.
b Isolated yield.
entry
R1
C6H5
R2
product
yield (%)b
To gain insight into the mechanism of this dimerization re-
action, a series of control experiments were set up (see eqs 1À
3 in the Supporting Information for details). The control
1
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-nBuC6H4
4-nBuC6H4
2-thio
5a
5b
5c
5d
5e
5f
83
65
62
58
72
65
61
74
70
58
70
63
2
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-FC6H4
3-FC6H4
2-FC6H4
4-nBuC6H4
4-iBuC6H4
C6H5
3
4
€
(13) (a) Zirnmerrnan, H. E.; Durr, H. G.; Givens, R. S.; Lewis, R. G.
5
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P. T.; Parameswaran, P. S.; Tilve, S. G. Chem.;Eur. J. 2012, 18, 5460.
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(e) Do, H. Q.; Daugulis, O. J. Am. Chem. Soc. 2011, 133, 13577. (f) Gao,
M.; Yang, Y.; Wu, Y. D.; Deng, C.; Cao, L. P.; Meng, X. G.; Wu, A. X.
Org. Lett. 2010, 12, 1856. (g) Yin, G. D.; Zhou, B. H.; Meng, X. G.; Wu,
A. X.; Pan, Y. J. Org. Lett. 2006, 8, 2245. For selected examples of
hypervalent iodine catalysis, see: (h) Cho, S. H.; Yoon, J.; Chang, S.
J. Am. Chem. Soc. 2011, 133, 5996. (i) Antonchick, A. P.; Samanta, R.;
Kulikov, K.; Lategahn, J. Angew. Chem., Int. Ed. 2011, 50, 8605. (j)
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6
7
5g
5h
5i
8
9
10
11
12
5j
4-FC6H4
4-FC6H4
5k
5l
a The reactions were carried out with 3 (0.5 mmol), 4 (0.25 mmol), I2
(2 equiv), CuBr2 (0.2 equiv), and DMF (dry, 0.5 mL) at 80 °C for 20 h.
b Isolated yield.
As shown above, the symmetric and unsymmetric 1,4-
enediones can be synthesized in complete E-selectivity under
the I2/CuBr2 reaction system. We wondered whether the
E-1,4- enedione could be transformed into the Z-isomer with
a rapid and practical protocol. Careful inspection of the
literature describing E/Z isomerization of 1,4-enedione
(12) (a) Seto, H.; Cary, L. W.; Tanabe, M. J. Chem. Soc., Chem.
Commun. 1973, 867. (b) Ballini, R.; Astolfi, P. Liebigs Ann. 1996, 1879.
Org. Lett., Vol. XX, No. XX, XXXX
C

molecule of HI. Then, copper(II) is inserted into the CÀI
bond to yield intermediate 11, which subsequently undergoes
a β-H elimination to yield corresponding product 2a with
complete E-selectivity. Molecular iodine plays two important
roles in the tandem reaction: iodination and induction of the
phenacyl radical 8 formation. However, the molecular iodine
can be recovered after inducing the phenacyl radical forma-
tion; therefore, only 2 equiv of iodine compared to acetophe-
none 1a are needed in the dimerization reaction. The high
selectivity in the heterodimerization reaction could be ex-
plained by the persistent-radical effect (PRE).17 Since the
reaction is not a radical chain reaction, the concentration of
the radicals in the mixture should be high enough to obtain
efficient radical/radical coupling. The excess of one ketone
compared to the other will lead to an increase of the relative
concentration of one phenacyl radical with respect to the
other, and hence the concentration difference would then be
the reason for the selective cross-coupling.
In conclusion, a new and facile method for the tunable
synthesis of 1,4-enedione directly from aromatic methyl
ketone was described. Thepresenttandem reaction enables
the construction of symmetric and unsymmetric 1,4-en-
edione withcompleteE-selectivity. Moreover, the resulting
E-1,4-enedione could be transformed into a Z-isomer by
irradiation with 23 W of white light with good to excellent
photoconversions. Further studies to clearly understand
the mechanism are ongoing in our laboratory.
Scheme 1. Possible Mechanism for the Formation of 2a
experiments show that this tandem reaction involves a radical
process and compounds 7 and 9 are key intermediates of this
reaction. On the basis of the control experiments and pre-
vious studies,15 a possible pathway of the present dimeriza-
tion reaction was shown in Scheme 1. Initially, iodination of
acetophenone 1a yields phenacyl iodine 7, accompanied by
the liberation of one molecule of HI. Then, phenacyl radical
8 is generated from R-iodo ketone 7 with the participation
of iodine. Subsequent radical coupling leads to the formation
of 1,4-dione 9.16 Iodination of dibenzoylethane 9 affords
compound 10, accompanied by the generation of another
Acknowledgment. The authors are grateful to National
Nature Science Foundation of China (20932002, 20972144,
90813008, 21172205, 21272222, J1030412 and 973 program
2010CB912103).
(16) For selected examples of radical coupling, see: (a) Davin, L. B.;
Wang, H. B.; Crowell, A. L.; Bedgar, D. L.; Martin, D. M.; Sarkanen, S.;
Lewis, N. G. Science 1997, 275, 362. (b) Suga, S.; Suzuki, S.; Yoshida, J.
J. Am. Chem. Soc. 2002, 124, 30. (c) Anderson, T. J.; Jones, G. D.; Vicic,
D. A. J. Am. Chem. Soc. 2004, 126, 8100. (d) Liu, W. P.; Li, Y. M.; Liu,
K. S.; Li, Z. P. J. Am. Chem. Soc. 2011, 133, 10756. (e) Liu, Z. J.; Zhang,
J.; Chen, S. L.; Shi, E. B.; Xu, Y.; Wan, X. B. Angew. Chem., Int. Ed.
2012, 51, 3231. (f) Reference 11c.
(17) For reviews on the PRE, see: (a) Fischer, H. Chem. Rev. 2001,
101, 3581. (b) Studer, A. Chem.;Eur. J. 2001, 7, 1159. (c) Studer, A.
Chem. Soc. Rev. 2004, 33, 267. (d) Studer, A.; Schulte, T. Chem. Rec.
2005, 5, 27.
Supporting Information Available. Detailed experimen-
tal procedures and spectroscopic data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX