CaCl2- or MgCl2-catalyzed allylic oxidations of ionone-like dienes

Article abstract of DOI:10.1055/s-2006-951476

The allylic oxidation of ionone-like dienes catalyzed by CaCl₂ or MgCl₂ with TBHP is presented. The method provides a facile method to synthesize dienones derived from ionone-like dienes in good to moderate yields. A plausible mechan

Full text of DOI:10.1055/s-2006-951476

LETTER
2617
CaCl2- or MgCl2-Catalyzed Allylic Oxidations of Ionone-like Dienes
C
aCl
-
or MgCl
-
Catal
i
yzed
A
n
llylic
O
xidations Yang,a,c Qian-Rong Peng,b Jing-Bo Lan,a Guang-Fu Song,c Ru-Gang Xie*a
2
2
a
Department of Chemistry, Sichuan University, Chengdu, 610064, P. R. of China
Fax +86(28)85411684; E-mail: orgxie@scu.edu.cn; E-mail: schemorg@mail.sc.cninfo.net
b
c
Technology Center, Guizhou Huang Guo Shu Tobacco Group, Guiyang, 550003, P. R. of China
Department of Chemistry Technology, Guizhou University, Guiyang, 550003, P. R. of China
Received 16 April 2006
esters.7 It is interesting to note that in nature alkali-earth-
metal ions, such as Ca2+ and Mg2+, can act as Lewis acid
catalysts.8 Hence, we reasoned that such metal ions could
catalyze the allylic oxidation through Lewis acid cataly-
sis. As part of our continuing interests in exploring novel
uses of simple metal catalysts,9 herein we reported that
Ca2+ and Mg2+ ions exhibited good catalytic activity in the
allylic oxidation of a-ionone-like dienes.
Abstract: The allylic oxidation of ionone-like dienes catalyzed by
CaCl2 or MgCl2 with TBHP is presented. The method provides a
facile method to synthesize dienones derived from ionone-like
dienes in good to moderate yields. A plausible mechanism for the
oxidation is proposed.
Key words: allylic oxidation, ionone-like dienes, calcium chloride,
magnesium chloride, tert-butyl hydroperoxide
R2
R1
R2
R1
The allylic oxidation of alkenes to carbonyl compounds is
a useful transformation in organic synthesis. It is under-
going continual refinement with the aim to develop more
environmentally friendly, efficient, and selective process-
es. Some new strategies have been reported for such a
transformation, such as the protocols using tert-butyl
hydroperoxide (TBHP) catalyzed by transition metal ion
centers (Cr, Ru, Cu, Co, Pd),1 iodoxybenzene catalyzed
by fluorous seleninic acid,2 or TBHP catalyzed by dirhod-
ium(II) caprolactamate.3
CaCl2 or MgCl2 (20 mol%)
t-BuOOH (5 equiv)
O
MeCN
1a–c
2a–c
R1 R2
R2
R1
CaCl2 or MgCl2 (20 mol%)
t-BuOOH (5 equiv)
MeCN
O
1d–f
2d–f
a,d: R1 = R2 = O; b,e: R1 = OCOMe, R2 = H; c,f: R1 = OEt, R2 = H
Ionones and their derivatives are important synthetic
building blocks in the synthesis of many biologically
active compounds.4 The introduction of a carbonyl group
at their allylic C–H bond can result not only in more com-
plex molecules, but also yield more important intermedi-
ates for further transformations.5 However, the direct
synthesis of dienones through the allylic oxidation of ion-
ones and their derivatives required either a stoichiometric
amount of chromium reagents or a catalytic amount of
chromium trioxide with TBHP.5 Although the latter
protocol avoided the use of stoichiometric reagents, the
hazard arising from chromium trioxide remains an
environmental problem. Therefore, it is highly desirable
to develop practical, efficient, and safer reactions for the
allylic oxidation of ionones and their derivatives.
Scheme 1 The allylic oxidation of ionone-like dienes
Using a-ionone (1 mmol) as the substrate and TBHP (5
equiv) as the oxidant in acetonitrile at 60 °C, we initially
examined the catalytic effects of several simple calcium
or magnesium salts. Among them, both CaCl2 and
MgCl2·6H2O gave good product yields (66% and 65%,
respectively for 2a). Compound 2a was also obtained in
45% yield with MgSO4. However, only trace amounts
of 2a were found when CaSO4, Ca(OAc)2·H2O,
CaCO3,
CaHPO4·2H2O,
Mg(OAc)2·4H2O,
and
(MgCO3)4·Mg(OH)2·5H2O were employed. In the
presence of Ca(NO3)2·4H2O as well as Mg(ClO4)2·6H2O,
the allylic oxidation did not proceed and 1a could be
recovered.
It is well known that the most effective catalysts for oxi-
dation are transition-metal ions that readily undergo one
or more electron redox processes, for example Fe2+/Fe3+,
Cu+/Cu2+, Co2+/Co3+, Mn2+/Mn3+, Cr3+/Cr6+, V4+/V5+,
Rh4+/Rh5+.6 To date only a few reports were presented on
the use of Ca2+ as a catalyst in oxidation reactions, such as
the oxidation of alcohols and the functionalization of
saturated hydrocarbons with CO to carboxylic acids and
We then investigated the effect of the amount of CaCl2 or
MgCl2·6H2O had on the allylic oxidation. As shown in
Table 1, only trace amounts of the desired product were
observed in the absence of CaCl2 or MgCl2·6H2O. The
yields were poor, when less than 20 mol% of CaCl2 or
MgCl2·6H2O were used. However, good yields were
obtained (65–67%) with 20–30 mol% of the catalyst
(Table 1, entries 4, 5, 8, and 9). In addition, the yields of
2a could not increase further when using more than 30
mol% catalyst.
SYNLETT 2006, No. 16, pp 2617–2620
0
4
.1
0
.2
0
0
6
Advanced online publication: 22.09.2006
DOI: 10.1055/s-2006-951476; Art ID: W08206ST
© Georg Thieme Verlag Stuttgart · New York

2618
M. Yang et al.
LETTER
Table 1 Effect of Catalyst Loadinga
The effect of reaction temperature on the efficacy of the
oxidation was also examined. When the CaCl2-promoted
allylic oxidation of a-ionone 1a in acetonitrile was con-
ducted at 20 °C, 40 °C, and 50 °C, 3-oxo-a-ionone 2a was
obtained in 20%, 31%, and 45% yields, respectively.
Good yields (66% and 67%) were obtained when the
reaction was run at 60 °C and 70 °C. However, at 80 °C a
slight decrease in the yield of 2a (64%) was observed.
Similar results were obtained when MgCl2·6H2O was
employed. Thus, the optimum reaction temperature was
determined to be 60–70 °C.
Entry
Catalyst
Loading
(mol %)
Conversion Yield
(%)b
17
71
82
95
97
40
84
95
95
(%)c
trace
39
1
2
3
4
5
6
7
8
9
–
0
5
CaCl2
CaCl2
10
20
30
5
50
CaCl2
66
CaCl2
67
We also investigated the effect of other solvents on the
allylic oxidations at 60 °C or under reflux. It was found
that with 20 mol% of CaCl2 or MgCl2·6H2O, good yields
(65% and 63%, respectively) of 2a were obtained in ace-
tone and moderate yields (54% and 58%, respectively) of
2a were afforded in dichloromethane. Using chloroform,
hexane, benzene, toluene, tetrahydrofuran, diethyl ether,
and ethyl acetate as solvent, the allylic oxidation of a-ion-
one 1a could also produce 3-oxo-a-ionone 2a but in poor
yields. Moreover, we also found that under solvent-free
conditions 33% and 24% yields of 2a were afforded,
respectively, when 20 mol% of CaCl2 and MgCl2·6H2O
were employed.
MgCl2·6H2O
MgCl2·6H2O
MgCl2·6H2O
MgCl2·6H2O
17
10
20
30
50
65
66
a Conditions: a-ionone (1 mmol), TBHP (5 equiv), MeCN (6 mL),
60 °C, 4 h.
b Conversions of 1a.
c Isolated yields of 2a.
It was noted that the amount of TBHP used not only af-
fected the outcome of oxidation reactions, but also created
experimental hazards.1d We noted that a large amount of
TBHP (5–30 equiv) had been used in previous reports.1
Hence, we investigated the amount of TBHP required in
the oxidation reactions (Table 2). As shown in Table 2,
when the amount of TBHP reached three and five equiva-
lents, the desired product could be obtained in good yields
(64–66%; Table 2, entries 3, 4, 7, and 8). Further addition
of TBHP did not improve the product yield. It was thus
established that this catalytic system required a lower
amount of TBHP (3–5 equiv) than those required in
previous reports.1a–h
Utilizing optimized conditions, 20–30 mol% of CaCl2 or
MgCl2·6H2O, 3–5 equivalents of 70% aqueous TBHP in
acetonitrile at 60 °C, we examined the oxidation of other
ionone-like dienes including a/b-ionone (1a and 1d), a/b-
ionyl acetates (1b and 1e), and a/b-ionyl ether (1c and 1f)
(Table 3). a-Ionone and its acetate as well as ether deriv-
atives could be oxidized to the corresponding dienones in
better yields than that of b-ionone and its derivatives. This
was probably due to the increased steric hindrance of the
allylic methyl of b-ionone and its derivatives. It is also
noteworthy that the oxidation of b-ionyl acetate and a/b-
ionyl ether had to be conducted in a shorter reaction time
because prolonging the reaction time resulted in the oxi-
dative cleavage of the ester and ether bond to produce the
corresponding 4-oxo-b-ionone 2b or 3-oxo-a-ionone 2a.
Table 2 Effect of the Amount of Oxidanta
Entry
Catalyst
TBHP
Conversion Yield
(equiv)
(%)b
53
75
94
95
62
78
91
95
(%)c
36
50
64
66
34
50
65
65
Mechanistically, the evolution of oxygen was confirmed
by passing the evolved gas through aqueous potassium
pyrogallate and is consistent with the formation of tert-bu-
tyl peroxy radical t-BuOO·. Furthermore, the UV-visible
spectrum of the catalyst upon addition of TBHP revealed
a low-energy absorption at 269 nm, probably due to the
coordination of Ca2+ or Mg2+ to the oxygen atom of
TBHP. The resulting mixture was investigated by GCMS
after the reaction proceeded for 1 h, 2 h, and 3 h; in all
cases the existence of a-ionone-tert-butyl peroxyether 7
was confirmed. Based on the above observations, we
speculated a radical mechanism catalyzed by the Lewis
acid accounted for the reaction (Scheme 2). Hence, Ca2+
or Mg2+ was coordinated to the oxygen atom of TBHP and
promoted the homolysis of the O–O bond to produce rad-
icals HO· and t-BuO·. The t-BuO· then reacted with TBHP
to yield tert-butyl peroxy radical t-BuOO· (3), which
could then abstract a hydrogen atom from compound 1a to
yield an allylic radical 6. At the same time, HO· carried by
1
2
3
4
5
6
7
8
CaCl2
1
2
3
5
1
2
3
5
CaCl2
CaCl2
CaCl2
MgCl2·6H2O
MgCl2·6H2O
MgCl2·6H2O
MgCl2·6H2O
a Conditions: a-ionone (1 mmol), CaCl2 or MgCl2·6H2O (20 mol%),
MeCN (6 mL), 60 °C, 4 h.
b Conversions of 1a.
c Isolated yields of 2a.
Synlett 2006, No. 16, 2617–2620 © Thieme Stuttgart · New York

LETTER
CaCl2- or MgCl2-Catalyzed Allylic Oxidations
2619
Table 3 Allylic Oxidation of Six Substratesa,10
Acknowledgment
We thank the Science Research Program of Guizhou Huang Guo
Shu Tobacco Group for financial support.
Entry
Substrate Catalyst
Time
(h)
Product Yield
(%)b
1
2
1a
1b
1c
1d
1e
1f
CaCl2
4
2a
2b
2c
2d
2e
2f
66
References and Notes
CaCl2
5
65
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Tetrahedron Lett. 1984, 25, 1235. (b) Muzart, J.
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(2) Crich, D.; Zou, Y. Org. Lett. 2004, 6, 775.
3
CaCl2
2
55c
58
4
CaCl2
5
5
CaCl2
1.5
1
52c
45c
65
6
CaCl2
7
1a
1b
1c
1d
1e
1f
MgCl2·6H2O
MgCl2·6H2O
MgCl2·6H2O
MgCl2·6H2O
MgCl2·6H2O
MgCl2·6H2O
4
2a
2b
2c
2d
2e
2f
8
5
63
9
2
54c
60
10
11
12
5
1.5
1
53c
42c
(3) Catino, A. J.; Forslund, R. E.; Doyle, M. P. J. Am. Chem.
Soc. 2004, 126, 13622.
(4) (a) Anzaldi, M.; Sottofattori, E.; Dusatti, F.; Ferro, M.; Pani,
M.; Balbi, A. Eur. J. Med. Chem. 2000, 35, 797. (b) Zeng,
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Stepanenko, V.; Jarowicki, K.; Kocienski, P. J. J. Org.
Chem. 2003, 68, 4008.
a Conditions: substrate (1 mmol), CaCl2 or MgCl2·6H2O (20 mol%),
TBHP (5 equiv), MeCN (6 mL), 60 °C.
b Isolated yields.
c TBHP (3 equiv).
(5) (a) Aasen, A. J.; Kimland, B.; Enzell, C. R. Acta Chem.
Scand. 1973, 27, 2107. (b) Aasen, A. J.; Hlubucek, J. R.;
Enzell, C. R. Acta. Chem. Scand. 1974, 28, 285. (c) Davis,
D. L.; Stevens, K. L.; Jurd, L. J. Agric. Food. Chem. 1976,
24, 187. (d) Kaiser, R.; Lamparsky, D. Helv. Chim. Acta
1978, 61, 2328. (e) Becher, E.; Albrecht, R.; Bernhard, K.;
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J.; Jung, L. J.; Cheng, K. M. Tetrahedron Lett. 2000, 41,
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(6) (a) Sheldon, R. A.; Kochi, J. K. Metal-Catalyzed Oxidations
of Organic Compounds; Academic Press: New York, 1981.
(b) Metal-Catalyzed Selective Oxidations. In Peroxide
Chemistry – Mechanistic and Preparative Aspects of
Oxygen Transfer; Adam, W., Ed.; Wiley: Weinheim, 2000,
301.
complex 4 reacted with TBHP to produce water and com-
plex 5. The complex transferred t-BuOO· to the allylic
radical 6 to form tert-butyl peroxyether 7 and regenerate
the catalyst (Ca2+ or Mg2+). Finally, rapid decomposition
of 7 yielded oxidation product enone 2a.
In summary, we have developed a novel catalytic allylic
oxidation of ionone-like dienes based on CaCl2 or MgCl2,
which offers an efficient and facile way to synthesize
dienones in moderate to good yields. The use of the alkali-
earth-metal catalyst, which is inexpensive and non-toxic,
could open a new area in allylic oxidation reactions.
Efforts are currently underway in our laboratories to
elucidate the details of the reaction mechanism.
O
O
MeCN
O
OH2
t-BuOO
t-BuOOH
2+
M
t-BuOH
2a
7
t-BuOOH
t-BuOH
t-BuOO·
t-BuO·
O
O
M = Ca, Mg
3
3
t-BuOO·
.
.
.
OH
NCMe
t-BuOO
MeCN
1a
6
2+
M
2+
M
4
5
H2O
t-BuOOH
Scheme 2 Mechanistic proposal for the allylic oxidation catalyzed by Lewis acid CaCl2 or MgCl2·6H2O
Synlett 2006, No. 16, 2617–2620 © Thieme Stuttgart · New York

2620
M. Yang et al.
LETTER
(7) (a) Asadullah, M.; Kitamura, T.; Fujiwara, Y. J. Catal. 2000,
195, 180. (b) Suppes, G. J.; Roy, S.; Ruckman, J. AIChE J.
2001, 47, 2102.
(8) Dugas, H. Bioorganic Chemistry: A Chemical Approach to
Enzyme Action, 3rd ed.; Springer-Verlag: New York, 1996,
165.
particularly when the reaction was performed on >5 mmol
scale. Analytical data for compounds 2a, 2b, 2d, and 2e is
consistent with those previously reported.5a,c,f
Compound 2c: 1H NMR (400 MHz, CDCl3): d = 5.92 (br s,
1 H), 5.46–5.49 (m, 1 H), 5.46–5.49 (m, 1 H), 3.81–3.85 (m,
1 H), 3.29–3.50 (m, 2 H), 2.50–2.53 (m, 1 H), 2.31 (d,
J = 16.8 Hz, 1 H), 2.06 (d, J = 16.8 Hz, 1 H), 1.88 (d, J = 1.2
Hz, 3 H), 1.22 (d, J = 4 Hz, 3 H), 1.16 (t, J = 5.4 Hz, 3 H),
1.01 (s, 3 H), 0.98 (s, 3 H). 13C NMR (400 MHz): d = 198.75,
161.49, 137.07, 127.98, 125.69, 63.44, 55.46, 47.44, 35.88,
29.48, 27.27, 26.94, 23.45, 21.68, 15.22. HRMS (ESI): m/z
calcd for C15H24O2 [M + Na]+: 259.1674; found: 259.1669.
Compound 2f: 1H NMR (400 MHz, CDCl3): d = 6.16 (d,
J = 16.0 Hz, 1 H), 5.55 (q, J = 16.4 Hz, 1 H), 3.93–3.99 (m,
1 H), 3.40–3.60 (m, 2 H), 2.50 (t, J = 7.0 Hz, 2 H), 1.85 (t,
J = 6.8 Hz, 2 H), 1.81 (s, 3 H), 1.31 (d, J = 6.8 Hz, 3 H), 1.23
(t, J = 7.2 Hz, 3 H), 1.16 (s, 3 H), 1.15 (s, 3 H). 13C NMR
(200 MHz): d = 199.26, 160.45, 139.02, 129.92, 126.77,
63.68, 37.17, 35.33, 34.22, 27.27, 27.27, 26.50, 21.77,
15.36, 13.31. HRMS (ESI): m/z calcd for C15H24O2 [M +
Na]+: 259.1674; found: 259.1674.
(9) (a) Lan, J. B.; Chen, L.; Yu, X. Q.; You, J. S.; Xie, R. G.
Chem. Commun. 2004, 2, 188. (b) Lan, J. B.; Zhang, G. L.;
Yu, X. Q.; You, J. S.; Chen, L.; Yang, M.; Xie, R. G. Synlett
2004, 1095. (c) Zhang, S. Y.; Lan, J. B.; Su, X. Y.; Guo, S.
J.; Chen, L.; You, J. S.; Xie, R. G. J. Chem. Res. 2005, 7,
418.
(10) Allylic Oxidation of Ionone-Like Dienes; Typical
Procedure: To a mixture of ionone-like diene 1 (1 mmol)
and CaCl2 or MgCl2·6H2O (0.2 mmol) in MeCN (6 mL) was
addded aq TBHP (70%, 3–5 mmol) in one or two portions
under vigorous stirring at 60 °C for 1–5 h. The resulting
mixture was concentrated under reduced pressure to give a
residue (0.5 mL), which was purified by column chromatog-
raphy on silica gel (PE–EtOAc, 3:1) to give dienone 2 and
small amounts of 5,6-b-epoxides. Alternatively, the product
could be isolated by distillation under reduced pressure,
Synlett 2006, No. 16, 2617–2620 © Thieme Stuttgart · New York