CAN-mediated highly regio- and stereoselective oxidation of vinylidenecyclopropanes: A novel method for the synthesis of unsymmetrical divinyl ketone and functional enone derivatives

Article abstract of DOI:10.1021/jo800829a

(Chemical Equation Presented) CAN-mediated oxidative rearrangement of various vinylidenecyclopropanes under mild conditions generates unsymmetrical divinyl ketone and functional enone derivatives in moderate to good yields with excellent regio- and stereoselectivities. The reaction mechanism was investigated on the basis of an oxygen-18 tracer experiment.

Full text of DOI:10.1021/jo800829a

employing metal catalysts or not, affording an efficient method
for the preparation of many compounds with synthetic and
biological importance.3
CAN-Mediated Highly Regio- and Stereoselective
Oxidation of Vinylidenecyclopropanes: A Novel
Method for the Synthesis of Unsymmetrical
Divinyl Ketone and Functional Enone Derivatives
The previous investigations have shown that CAN was a
useful reagent for oxidative single-electron transfer4 processes
leading to a number of novel carbon-carbon and carbon-
heteroatom bond-forming reactions.5,6 We, along with Nair, have
reported several examples of CAN-mediated oxidation of
methylenecyclopropanes (MCPs).7 Recently, much attention has
been paid to the radical reactions of VCPs.8 To the best of our
knowledge, reports on the metal salt mediated single-electron
oxidation of VCPs are limited, probably due to the regioselec-
tivity. Herein, we wish to report a CAN-mediated highly regio-
and stereoselective oxidation of VCPs leading to unsymmetrical
divinyl ketone and functional enone derivatives in moderate to
good yields.
Chenliang Su,† Xian Huang,*,†,‡ and Qingyang Liu†
Department of Chemistry, Zhejiang UniVersity (Xixi
Campus), Hangzhou 310028, People’s Republic of China,
and State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, Shanghai 200032, People’s Republic of China
huangx@mail.hz.zj.cn
ReceiVed April 15, 2008
Initially, we examined the reaction of VCP (1a) with a
solution of CAN (2.2 equiv) in methanol under an air atmo-
sphere. After the solution was stirred for 6 h at room temper-
ature, the unsymmetrical divinyl ketone (E)-2a was obtained
in 48% yield along with the functional enone 3a in 16% yield
(entry 2, Table 1). With this result in hand, we assumed that
the carbonyl oxygen might come from the oxygen in the air or
the H2O in the solvent. We then tried to confirm the origin of
the carbonyl oxygen and optimize the reaction conditions. The
experimental results showed that the oxygen was not necessary
in this reaction; nevertheless the presence of H2O in the solvent
sharply improved the yield (entries 4-6, Table 1). We next
found that the temperature effect was also important in improv-
ing the product yields. When the reaction was carried out under
CAN-mediated oxidative rearrangement of various vi-
nylidenecyclopropanes under mild conditions generates
unsymmetrical divinyl ketone and functional enone deriva-
tives in moderate to good yields with excellent regio- and
stereoselectivities. The reaction mechanism was investigated
on the basis of an oxygen-18 tracer experiment.
(3) (a) Sugita, H.; Mizuno, K.; Saito, T.; Isagawa, K.; Otsuji, Y. Tetrahedron
Lett. 1992, 33, 2539–2542. (b) Mizuno, K.; Sugit, H.; Kamada, T.; Otsuji, Y.
Chem. Lett. 1994, 449. (c) Mizuno, K.; Sugit, H.; Isagawa, K.; Goto, M.; Otsuji,
Y. Tetrahedron Lett. 1991, 34, 5737. (d) Mizuno, K.; Nire, K.; Sugit, H.; Otsuji,
Y. Tetrahedron Lett. 1993, 34, 6563. (e) Mizuno, K.; Maeda, H.; Sugita, H.;
Nishioka, S.; Hirai, T.; Sugimoto, A. Org. Lett. 2001, 3, 581. (f) Maeda, H.;
Hirai, T.; Sugimoto, A; Mizuno, K. J. Org. Chem. 2003, 68, 7700. (g) Xu, G. C.;
Ma, M.; Liu, L. P.; Shi, M. Synlett 2006, 1869. (h) Xu, G. C.; Liu, L. P.; Lu,
J. M. J. Am. Chem. Soc. 2005, 127, 14552. (i) Zhang, Y. P.; Lu, J. M.; Xu,
G. C.; Shi, M. J. Org. Chem. 2007, 72, 509. (j) Shao, L. X.; Zhang, Y. P.; Qi,
M. H.; Shi, M. Org. Lett. 2007, 9, 117. (k) Liu, L. P.; Lu, J. M. Org. Lett. 2007,
9, 1303. (l) Lu, J. M.; Shi, M. Org. Lett 2007, 9, 1805. (m) Huang, X.; Su,
C. L.; Liu, Q. Y.; Song, Y. T. Synlett 2008, 229.
Vinylidenecyclopropanes (VCPs)1 show unique reactivity in
organic synthesis due to the presence of the cumulated CdC
double bonds adjacent to the highly strained cyclopropyl ring,
which might lead to several possible reactive positions. There-
fore, controlling the regio- and stereoselective reactions of VCPs
is a formidable challenge in organic synthesis.2 Recently, much
attention has been paid to the study of their reactivity, especially
the control of the related selectivity and their potential synthetic
utilities. Researchers have found that VCPs can be utilized as
versatile starting materials to develop sequential reactions either
(4) (a) Heiba, E. I.; Dessau, R. M. J. Am. Chem. Soc. 1971, 93, 524. (b)
Baciocchi, E.; Civitarese, G.; Ruzziconi, R. Tetrahedron Lett. 1987, 28, 5357.
(5) For recent reviews, see: (a) Molander, G. A. Chem. ReV. 1992, 92, 29.
(b) Nair, V.; Rajan, R.; Mathew, J. Acc. Chem. Res. 2004, 37, 21. (c) Nair, V.;
Deepthi, A. Chem. ReV. 2007, 107, 1862.
(6) For some of the CAN-mediated carbon-carbon and carbon-heteroatom
bond-forming reactions, see: (a) Nair, V.; Mathew, J.; Kanakamma, P. P.;
Panicker, S. B.; Sheeba, V.; Zeena, S.; Eigendorf, G. K. Tetrahedron Lett. 1997,
38, 2191. (b) Nair, V.; Nair, L. G.; George, T. G.; Augustine, A. Tetrahedron
2001, 56, 7607. (c) Nair, V.; Panicker, S. B.; George, T. G.; Rajan, R.; Balagopal,
L.; Vairamani, M.; Prabhakar, S. Tetrahedron 2000, 56, 2461. (d) Nair, V.; Rajan,
R.; Rath, N. P. Org. Lett. 2002, 4, 1575. (e) Clark, A. J.; Dell, C. P.; McDonagh,
J. M.; Geden, J.; Mawdsley, P. Org. Lett. 2003, 5, 2063.
† Zhejiang University (Xixi Campus).
(7) (a) Nair, V.; Suja, T. D. Synthesis 2006, 2335. (b) Nair, V.; Suja, T. D.;
Mohanan, K. Synthesis 2006, 2531. (c) Chen, W. L.; Huang, X.; Zhou, H. W.;
Ren, L. J. Synthesis 2005, 609.
‡ Chinese Academy of Sciences.
(1) For synthesis of vinylidenecyclopropanes, see: (a) Isagawa, K.; Mizuno,
K.; Sugita, H.; Otsuji, Y. J. Chem. Soc., Perkin Trans. 1 1991, 2283, and
references therein. (b) Al-Dulayymi, J. R.; Baird, M. S. J. Chem. Soc., Perkin
Trans. 1 1994, 1547. (c) Maeda, H.; Hirai, T.; Sugimoto, A.; Mizuno, K. J.
Org. Chem. 2003, 68, 7700.
(8) For radical reactions related to VCPs, see: (a) Pasto, D. J.; Miles, M. F.
J. Org. Chem. 1976, 41, 2068. (b) Mizuno, K.; Nire, K.; Sugita, H.; Maeda, H.
Tetrahedron Lett. 2001, 42, 2689. (c) Mizuno, K.; Sugita, H.; Hirai, T.; Maeda,
H.; Otsuji, Y.; Yasuda, M.; Hashiguchi, M.; Shima, K. Tetrahedron Lett. 2001,
42, 3363. (d) Mizuno, K.; Maeda, H.; Sugita, H.; Nishioka, S.; Hirai, T.;
Sugimoto, A. Org. Lett. 2001, 3, 581. (e) Shi, M.; Lu, J. M.; Xu, G. C.
Tetrahedron Lett. 2005, 46, 4745. (f) Shi, M.; Lu, J. M. J. Org. Chem. 2006,
71, 1920.
(2) For some reviews related to VCPs, see: (a) Poutsma, M. L.; Ibarbia, P. A.
J. Am. Chem. Soc. 1971, 93, 440. (b) Smadja, W. Chem. ReV. 1983, 83, 263. (c)
Sydnes, L. K. Chem. ReV. 2003, 103, 1133. (d) Brandi, A.; Cicchi, S.; Cordero,
F. M.; Goti, A. Chem. ReV. 2003, 103, 1213.
10.1021/jo800829a CCC: $40.75
Published on Web 07/23/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6421–6424 6421

TABLE 1. Optimization of the Reaction Conditions for the Synthesis of Unsymmetrical Divinyl Ketone 2aa
entry
CAN (equiv)
solvent
T (°C)
time (h)
yield of 2a (%)b
yield of 3a (%)b
1
2
3
4
5
6
7
8
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
CH3OH
CH3OH
CH3OH
CH3OH/N2
CH3OHd/N2
CH3OHd/O2
CH3OH
0
25
50
50
50
50
reflux
reflux
reflux
reflux
reflux
6
6
5
5
5
5
1
5
5
5
5
31
48
66
67
17
15
58
72
69
72
71
26
16
8
9
4
3
12
trace
trace
trace
trace
c
c
CH3OH
9
10
11
CH3OHd/H2O(1.2 equiv)
CH3OHd/H2O(5.5 equiv)
CH3OHd/H2O(55.5 equiv)
a Unless otherwise specified, the reaction was carried out with 1a (0.5 mmol) and commercial CAN in MeOH under an air atmosphere. b Isolated
yield. c The reaction was carried out in glovebox: O2 e 10 ppm. d Anhydrous CH3OH was used: H2O e 0.05%, and CAN was dried over vacuo at 110
°C.
TABLE 2. Synthesis of Various Unsymmetrical Divinyl Ketones 2a
SCHEME 1. Configuration of 2g
entry
R1/R2
R3
R4
1
yield of 2 (%)b
1
2
3
4
5
6
7
Ph/Ph
Ph/Ph
Ph/Ph
Ph
p-ClC6H4
p-MeC6H4
H
H
H
H
H
1a
1b
1c
1d
1e
2a, 72
2b, 73
2c, 65
2d, 61
2e, 70
2f, 51
2g, 53c
NOESY studies (Scheme 1). These unsymmetrical divinyl
ketones are valuable building blocks for organic synthesis, which
have been utilized in Diels-Alder reactions,9 Michael reac-
tions,10 and conjugate addition reactions to prepare various ring
systems.11 The characteristic reaction of divinyl ketones is their
acid-catalyzed Nazarov cyclization leading to cyclopentenones.12
Interestingly, when bicyclic VCP (4b) was employed, no
divinyl ketone product was observed. Instead, the functional
enone 5b13 was obtained in 53% yield. After a variety of
reaction conditions were examined, we fortunately found the
yield of 5b could be improved to 71% when the reaction was
carried out in MeOH at 30 °C for 5 h (eq 2).
p-ClC6H4/p-ClC6H4 Ph
Ph/Ph
Ph/Ph
Ph/Me
n-C4H9
Ph
Ph
Me 1f
1g
H
a Unless otherwise specified, the reaction was carried out with 1 (0.5
mmol) and commercial CAN (1.1 mmol) in MeOH. b Isolated yields.
c 2g was not very stable, and the reaction was completed in 2 h.
reflux, the yield of product 2a was improved to 72% and 3a
was obtained in trace amount (entry 8, Table 1). Further
investigations disclosed that the reaction in the presence of an
excess amount of H2O had little effect on the yield of 2a (entries
8-11, Table 1).
We also found that 2a could be produced in 76% yield via
elimination of one MeOH molecule when 3a was heated for
5 h under reflux (eq 1).
Synthesis of functional enone compounds 5 with high
stereoselectivity is of high chemical and biochemical importance.
(9) (a) Winkler, J. D.; Kim, H. S.; Kim, S.; Ando, K.; Houk, K. N. J. Org.
Chem. 1997, 62, 2957. (b) Jung, M. E.; McCombs, C. A.; Takeda, Y.; Pan,
Y. G. J. Am. Chem. Soc. 1981, 103, 6677.
(10) (a) Britten-Kelly, M.; Willis, B. J.; Barton, D. H. R. Synthesis 1980,
27–29. (b) Hamanaka, N.; Nakai, H.; Kurono, M. Bull. Chem. Soc. Jpn. 1980,
53, 2327. (c) de Jongh, H. A. P.; Wynberg, H. Tetrahedron 1964, 20, 2553.
(11) (a) Dunn, P. J.; Graham, A. B.; Grigg, R.; Higginson, P.; Thornton-
Pett, M. Tetrahedron 2002, 58, 7727. (b) Kuehne, M. E.; Bornmann, W. G.;
Earley, W. G.; Marko, I. J. Org. Chem. 1986, 51, 2913. (c) Snider, B. B.; Harvey,
T. C. Tetrahedron Lett. 1995, 36, 4587. (d) Magomedov, N. A.; Ruggiero, P. L.;
Tang, Y. C. Org. Lett. 2004, 6, 3373.
With the optimized conditions in hand, we next examined
the reaction of various arylvinylidenecyclopropanes (ACPs)
under identical conditions. The results are summarized in Table
2. When R4 ) H, R1 ) R2 ) Ar, the reaction proceeded
smoothly to give the unsymmetrical divinyl ketones in good
yields (entries 1-5, Table 2). A slightly lower yield was
observed when R4 ) Me, R1 ) R2 ) Ph (entry 6, Table 2).
Moreover, when the unsymmetrical VCP 1g (Z:E ) 1:1) was
employed, only the thermodynamically stable product (1E,4E)-
1,5-diphenylhexa-1,4-dien-3-one, 2g, was observed in 53% yield
(entry 7, Table 2). The configuration was established by the
(12) (a) Nazarov, I. N.; Zaretskaya, I. I.; Sorkina, T. I. Zh. Obsh. Khim. 1960,
30, 746. (b) Habermas, K. L.; Denmark, S. E.; Jones, T. K. Org. React. 1994,
45, 1. (c) He, W.; Huang, J.; Sun, X. F.; Frontier, A. J. J. Am. Chem. Soc. 2003,
125, 14278. (d) He, W.; Sun, X. F.; Frontier, A. J. J. Am. Chem. Soc. 2007,
129, 498.
(13) The structure was confirmed by X-ray crystallographic analysis of the
(2,4-dinitrophenyl)hydrazine derivative of 5b (see the Supporting Information).
6422 J. Org. Chem. Vol. 73, No. 16, 2008

VCPs by CAN to furnish radical cation A.7 The following
nucleophilic attack of the solvent such as MeOH at the
cyclopropane moiety may cause the rearrangement to produce
the ring-opened radical intermediate B.15 B can be further
oxidized by a second equivalent of CAN to give cation C, which
is quenched by water in the solvent to produce D. For VCPs 1,
a subsequent enol arrangement of the corresponding intermediate
D and further elimination of MeOH may occur to furnish the
product 2. For bicyclic VCPs 4, the key point is that the
intermediate B is selectively attacked by the nucleophile from
the less sterically hindered position to afford C. In this case,
the trans isomer of functional enones 5 could not progress to
the corresponding divinyl ketones (Scheme 3).
TABLE 3. Synthesis of Various Functional Enones 5 with High
Stereoselectivitya
entry
Ar
n, 4
ROHb
MeOH
MeOH
EtOH
CH2dCHCH2OH
MeOH
MeOH
yield of 5 (%)c
1
2
3
4
5
6
Ph
Ph
Ph
Ph
1, 4a
2, 4b
2, 4b
2, 4b
2, 4c
3, 4d
5a, 59
5b, 71
5c, 68
5d, 55
5e, 61
d
p-ClC6H4
Moreover, when VCP (1h) with four methyl groups at the
cyclopropane moiety was employed, the interesting product 2h
was observed in 41% yield (eq 4).
Ph
a Unless otherwise specified, the reaction was carried out with 4 (0.5
mmol) and commercial CAN (1.1 mmol) in ROH. b ROH in the
reactions was also worked as solvent. c Isolated yields. d The reaction
was complex.
SCHEME 2. Reaction of 4b with the Nucleophiles from
CAN and Mn(OAc)3
In conclusion, we have disclosed the CAN-mediated oxidative
reactions of various VCPs with high regio- and stereoselectivity
and developed a convenient approach to the synthesis of
unsymmetrical divinyl ketone and functional enone derivatives.
These novel compounds bearing unsaturated ketone skeletons
would be useful in organic synthesis. On the basis of the oxygen-
18 tracer experiment, we clarified that the oxygen atom of the
products arises from the H2O in the reaction system, and a
plausible reaction mechanism was proposed. Hence, the reaction
may be of interest from both the mechanistic and synthetic
standpoints. Further studies to expand the scope and synthetic
utility of the method are underway.
In fact, these moieties are part of biologically important natural
and unnatural compounds.14 Therefore, under the optimized
conditions, a series of bicyclic VCPs were employed to give
the corresponding functional enone derivatives with high
stereoselectivity (entries 1-5, Table 3).
Experimental Section
General Procedure for Synthesis of Unsymmetrical Divinyl
Ketones via a CAN-Mediated Oxidation of VCPs. To a stirred
solution of VCP 1 (0.5 mmol) in MeOH (2 mL) was added a
solution of CAN (1.1 mmol) in MeOH (2 mL). Then the mixture
was refluxed. After being stirred for the specified time, the reaction
mixture was extracted with EtOAc (3 × 5 mL). The combined
organic layers were dried over anhydrous MgSO4. After filtration
and removal of the solvent in vacuo, the residue was purified with
flash chromatography (silica/petroleum ether-ethyl acetate 15:1 to
10:1 v/v) to afford 2. Spectral data for 2b: yellow solid, mp 84-86
°C; 1H NMR (400 MHz, CDCl3) δ 7.35-7.42 (m, 8H), 7.23-7.31
(m, 5H), 7.10-7.15 (m, 2H), 6.77 (s, 1H), 6.36 (d, J ) 16.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 126.7, 127.4, 128.3, 128.4,
128.6, 128.9, 129.0, 129.1, 129.5, 130.2, 133.4, 135.8, 139.0, 140.0,
140.4, 154.0, 191.1; IR (KBr) 3026, 1645, 1589, 1489, 1331, 1195,
When THF was employed as solvent, treatment of 4b with
CAN afforded 5f in 58% yield. Apparently, the NO3 group in
5f comes from CAN dissolving in the weakly nucleophilic
solvent THF. Moreover, when Mn(OAc)3 was employed instead
of CAN and AcOH was chosen as the solvent, the reaction could
smoothly proceed to produce the corresponding functional enone
5g in 73% yield as a result of trapping AcO- (Scheme 2).
To clarify the mechanism of this reaction, we carried out the
reaction of 1a with CAN in the presence of H2O18. As a result,
we found that 2a-O18 was formed in 71% yield with 87.5%
O18 content in the oxygen atom of carbonyl group. This result
clearly indicates that the oxygen atom of the carbonyl group in
product 2 comes from the H2O in the reaction system (eq 3).
1089, 1030, 818, 766, 697 cm-1; MS (70 eV, EI) m/z 346 (M+
+
2), 344 (M+); HRMS (EI) m/z calcd for C23H17ClO (M+) 344.0968,
found 344.0969.
General Procedure for the Synthesis of Functional Enone
Derivatives via a CAN-Mediated Oxidation of Bicyclic VCPs.
To a stirred solution of bicyclic VCP 4 (0.5 mmol) in the appropriate
solvent (2 mL) was added CAN (1.1 mmol) in the same solvent (2
mL). The reaction temperature was then increased to 30 °C. After
being stirred for the specified time, the reaction mixture was
extracted with EtOAc (3 × 5 mL). The combined organic layers
were dried over anhydrous MgSO4. After filtration and removal of
On the basis of the above results, a plausible mechanism of
the CAN-mediated oxidation reaction is shown in Scheme 3.
The initial event is likely to be a single-electron oxidation of
(14) (a) Smith, A. B.; Fukui, M. J. Acc. Chem. Res. 1987, 109, 1269. (b)
Gybin, A. S.; Smit, W. A.; Caple, R.; Veretenov, L.; Shashkov, A. S.; Vorontsova,
L. G.; Kurella, M. G.; Chertkov, V. S. J. Acc. Chem. Res. 1992, 11, 114–5555.
(c) Rubenstein, S. M.; Williams, R. M. J. Org. Chem. 1995, 60, 7215. (d)
Vazquez, A.; Williams, R. M. J. Org. Chem. 2000, 65, 7865.
(15) (a) Siriwardana, A. I.; Nakamura, I.; Yamamoto, Y. Tetrahedron Lett.
2003, 44, 985. (b) Huang, X.; Yang, Y. W. Org. Lett. 2007, 9, 1667.
J. Org. Chem. Vol. 73, No. 16, 2008 6423

SCHEME 3. Proposed Mechanistic Pathway for the Reaction
the solvent in vacuo, the residue was purified with flash chroma-
Acknowledgment. We are grateful to the National Natural
Science Foundation of China (Project Nos. 20672095 and
20732005) and CAS Academician Foundation of Zhejiang
Province for financial support.
tography (silica/petroleum ether-ethyl acetate 15:1 to 10:1 v/v) to
1
afford 5. Spectral data for 5b: yellow semisolid; H NMR (400
MHz, CDCl3) δ 7.29-7.37 (m, 8H), 7.19-7.23 (m, 2H), 6.67 (s,
1H), 3.31-3.39 (m, 1H), 3.29-3.31 (s, 3H), 2.46-2.55 (m, 1H),
2.10-2.17 (m, 1H), 1.69-1.80 (m, 2H), 1.60-1.68 (m, 1H),
1.28-1.39 (m, 1H), 1.00-1.24 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 24.1, 25.0, 28.6, 30.3, 56.5, 56.6, 80.8, 126.6, 128.0,
128.2, 128.3, 128.5, 129.2, 129.5, 139.1, 141.4, 153.5, 203.8; IR
Supporting Information Available: General experimental
procedures and spectroscopic data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(KBr) 2931, 1686, 1589, 1445, 1361, 1189, 1097, 766, 696 cm-1
;
MS (70 eV, EI) m/z 320 (M+); HRMS (EI) m/z calcd for C22H24O2
(M+) 320.1776, found 320.1770.
JO800829A
6424 J. Org. Chem. Vol. 73, No. 16, 2008