Allylic oxidation of alkenes catalyzed by a copper-aluminum mixed oxide

Article abstract of DOI:10.1021/ol500198c

A strategy for the allylic oxidation of cyclic alkenes with a copper-aluminum mixed oxide as catalyst is presented. The reaction involves the treatment of an alkene with a carboxylic acid employing tert-butyl hydroperoxide as the oxidant. In all cases, the corresponding allylic esters are obtained. When l-proline is employed, the allylic alcohol or ketone is obtained. The oxidation of cyclohexene and valencene has been optimized by design of experiments (DoE) statistical methodology.

Full text of DOI:10.1021/ol500198c

Letter
pubs.acs.org/OrgLett
Allylic Oxidation of Alkenes Catalyzed by a Copper−Aluminum
Mixed Oxide
Ana Leticia García-Cabeza, Ruben Marín-Barrios, F. Javier Moreno-Dorado, María J. Ortega,
́
Guillermo M. Massanet, and Francisco M. Guerra*
́ ́ ́
Departamento de Química Organica, Facultad de Ciencias, Universidad de Cadiz, 11510 Puerto Real, Cadiz, Spain
S
* Supporting Information
ABSTRACT: A strategy for the allylic oxidation of cyclic alkenes
with a copper−aluminum mixed oxide as catalyst is presented. The
reaction involves the treatment of an alkene with a carboxylic acid
employing tert-butyl hydroperoxide as the oxidant. In all cases, the
corresponding allylic esters are obtained. When L-proline is
employed, the allylic alcohol or ketone is obtained. The oxidation
of cyclohexene and valencene has been optimized by design of experiments (DoE) statistical methodology.
he allylic oxidation of an alkene is one of the simplest cases
1
Tof C−H bond activation. This transformation lacks a
general methodology due to problems such as regio- and
stereoselectivity, poor compatibility with other functional
groups, overoxidation issues, etc. It is not common to find a
total synthesis in which the key step lies in the allylic oxidation of
an alkene, despite the fact that in many cases this sort of
transformation could streamline a given route substantially.2
Classically, this transformation has been based mainly on the
chemistry of Se, Cr, Pd, and Cu species.3 Toxicity and cost are the
main drawbacks of some of them, especially when the reagent has
to be used in stoichiometric amounts. Additionally, remarkable
efforts have been made by the White4 and Doyle5 groups based
on Pd and Rh, respectively, leading to commercial versions of
their catalysts.
A lesser known approach employs a copper source and a
stoichiometric amount of an oxidant, usually a perester. This
reaction is known as the Kharasch−Sosnovsky reaction.6 First
described in the later years of the 1950s, the reaction involves the
oxidation of an alkene by tert-butyl peroxybenzoate in the
presence of a copper or cobalt source, providing the
corresponding benzoate ester (Figure 1a). An alternative is the
employment of a carboxylic acid as the donor of acyloxy radicals,
providing directly the corresponding allylic esters.7
Figure 1. (a) Kharasch−Sosnovsky reaction; (b) use of Cu−Al Ox for
the allylic oxidation of electron-deficient alkenes; (c) use of Cu−Al Ox
for the allylic oxidation of electron-rich alkenes.
°C, 24 h) and then at open atmosphere (3 days), a fine powder is
obtained. It consists of well-rounded grains in which copper and
aluminum can be detected in all zones measured in a constant
composition (Cu 63.3%, Al 9.1%, EDS measures).9
The optimal performance of Cu−Al Ox in the oxidation of
alkenones prompted us to investigate its use in the allylic
oxidation of electron-rich alkenes. To this end, we first carried
out an exploratory screening employing cyclohexene 1 and
benzoic acid 3a. After some experimentation, good yields of
cyclohexenyl benzoate 2 were obtained employing tert-butyl
hydroperoxide (TBHP) as the oxidant.
It was also observed that the reaction was highly sensitive to
the nature of the solvent, being quantitative when acetonitrile
was employed (Table 1).
The Kharasch−Sosnovsky reaction is an interesting option
that has not been fully exploited.8 Recently, we have reported the
preparation of a new copper−aluminum mixed oxide (Cu−Al Ox
henceforth) that catalyzes the allylic hydroxylation of enones.9
The electron-deficient double bond of the enone was oxidized
with moderate to good yields employing Cu−Al Ox, t-BuOK,
and molecular oxygen from the air as the oxidant (Figure 1b). In
this work, we describe the allylic oxidation of cyclic alkenes
catalyzed by Cu−Al Ox using tert-butyl hydroperoxide as the
oxidant (Figure 1c).
Cu−Al Ox is prepared from CuCl2 and AlCl3·6H2O by co-
precipitation with Na2CO3 and NaOH in water. After heating at
70 °C for 22 h, removal of water, and drying first in an oven (105
Received: January 20, 2014
Published: March 5, 2014
© 2014 American Chemical Society
1598
dx.doi.org/10.1021/ol500198c | Org. Lett. 2014, 16, 1598−1601

Organic Letters
Letter
a
Table 1. Oxidation of Cyclohexene with TBHP
Scheme 1. Oxidation of Simple Cycloalkenes with TBHP in
the Presence of Cu−Al Ox
a b
,
b
entry
catalyst
Cu−Al Ox
Cu−Al Ox
Cu−Al Ox
Cu−Al Ox
Cu−Al Ox
solvent
temp (°C)
yield (%)
1
2
3
4
hexane
69
40
20
82
37
100
9
CH2Cl2
pyridine
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
115
82
c
5
82
6
7
8
82
6
CuCl2
82
25
4
AlCl3·6H2O
CuCl2, AlCl3·6H2O
82
d
9
82
51
a
All reaction were carried out using cyclohexene 1 (4.0 mmol),
benzoic acid 3a (1.0 mmol), TBHP (1.5 mmol), catalyst (60 mg),
b
c
solvent (4 mL), 24 h. Determined by GC. Without TBHP, oxygen
from air as oxidant(1 atm, vigorous stirring). CuCl2 (33 mg), AlCl3·
6H2O (27 mg).
d
Several blank tests were run to evaluate the necessity of the use
of Cu−Al Ox and the behavior of its parent precursors (entries
6−9). The presence of Cu−Al Ox was essential since the yield of
the corresponding ester dropped to only 6% in its absence (entry
6). TBHP was needed for the reaction to proceed, and the
oxygen from the air did not work as the oxygen source (entry 5).
It was also observed that the use of any Cu−Al Ox precursors led
lower yields, demonstrating the superior catalytic activity of Cu−
Al Ox.
We next turned to the substrate scope of simple cycloalkenes
and carboxylic acids (Scheme 1). The yields ranged from
moderate to excellent. Several aromatic carboxylic acids bearing
different groups were employed. The presence of either an
electron-withdrawing or an electron-releasing group in the
aromatic ring of the carboxylic acids seemed not to affect the
outcome of the reaction. In the case of cyclohexene, the results
were excellent with all tested acids. There was more disparity
when cyclopentene 4 and cyclooctene 5 were used. In the case of
cyclopentene, the presence of a methoxyl group in the p-position
of the aromatic ring led to a 85% yield of the ester 13. The same
acid led to a moderate 36% yield of 18 when cyclooctene was
employed.
More complex alkenes were also evaluated (Scheme 2). In the
case of the monoterpene β-pinene 20, the yields ranged from
moderate to good. It is remarkable that no allylic transposition of
the double bond was observed in contrast to other oxidation
methods. In the case of the sesquiterpene valencene 21, the yields
were higher than those obtained in β-pinene, except in the case of
acetate 33 (only 46%). The nature of the group located in the
aromatic ring did not affect the outcome of the reaction. The
inertness shown by the exocyclic double bond of valencene under
the reaction conditions was also remarkable.
Finally, the benzylic oxidation of indane 22 was studied. The
reactions proceeded in a wide range of yields, from moderate in
the case of acetate 39 (26%) to good in the case of p-
methoxybenzoate 37 (88%).
a
All reactions were carried out using the cycloalkene (4.0 mmol),
carboxylic acids 3a−f (1.0 mmol), TBHP (1.5 mmol), Cu−Al Ox (60
mg), refluxing CH3CN (4 mL), 24 h. GC yields (isolated yield).
b
According to the mechanisms proposed by Beckwith and
Savitzas11 and Mayoral et al.12 for the Kharasch−Sosnovsky
reaction, a plausible mechanism for the present allylic oxidation is
outlined in Scheme 3. In this mechanism, the solid Cu−Al Ox
provides a surface in which coordination with the Cu or Al atoms
may diminish the activation energy needed for the homolytic
cleavage of the O−O or the C−H bonds of the TBHP or the
cyclohexene, respectively. The presence of a second metallic
atom in the close vicinity to the Cu atom would help to lock the
reacting species. After formation of the cyclohexenyl radical, the
carboxylic acid would be locked by the Cu or Al atoms. Finally, a
pericyclic rearrangement would take place, providing the
corresponding ester.
The use of amino acids as the carboxylic acid partner was also
investigated. When we employed L-proline and cyclohexene as
the olefin (Scheme 4), it was found that, contrary to the expected
esterification process described above, only cyclohexenol 40 and
cyclohexenone 41 were detected, although in low yield (12% and
11%, respectively).
Given that the reaction led to the formation of a free hydroxyl
group or a ketone, a different mechanism should be considered. A
possible explanation would involve the formation of a complex
between the L-proline ligand and the copper atom of Cu−Al Ox
as reported by the Ding13 and Stahl14 groups.
Most reports regarding the Kharasch−Sosnovsky reaction
employ an excess of the olefin, with the oxidant being the limiting
reagent.10 This fact restricts the use of this reaction in the case of
valuable alkenes. In our case, except when the volatility is an
issue, the reactions were carried out employing a 1:1 alkene−
oxidant ratio.
Since the mechanism of the latter transformation was unclear,
its optimization was troublesome. This fact and the low yields
obtained prompted us to employ a statistical approach, the
design of experiments (DoE), to increase the yield. DoE is a
statistical method that defines a domain for every variable
involved in a reaction. Instead of changing one variable at a time
1599
dx.doi.org/10.1021/ol500198c | Org. Lett. 2014, 16, 1598−1601

Organic Letters
Letter
Scheme 2. Oxidation of More Complex Alkenes with TBHP in
the Presence of Cu−Al Ox
Scheme 4. Synthesis of Cyclohexenol and Cyclohexenone
with TBHP in the Presence of Cu−Al Ox and L-Proline
ab
,
the yield of a given reaction under certain conditions or to
optimize the conditions in order to obtain the highest possible
yield.
Three variables were considered for the study: (i) the amount
of Cu−Al Ox, (ii) the equivalents of TBHP, and (iii) the
temperature. The election of acetonitrile as the solvent set the
temperature at 82 °C, enabling the cleavage of the O−O bond of
the TBHP. With only two variables, it was possible to perform a
32 full-factorial design with two central points, which resulted in
11 experiments (see the Supporting Information for the
experimental matrix).
This design increased the yield to 40% for cyclohexenol and
48% for cyclohexenone, which represents a 88% of overall
oxidation yield, employing 15 mg/mmol of Cu−Al Ox and 6.0
equiv of TBHP at 82 °C. The curved shape of the attained
response surface (Figure 2) revealed that higher amounts of Cu−
Al Ox and TBHP would not result in significant higher yields.
Figure 2. Calculated response surface for the synthesis of cyclohexenol
40.
a
All reactions were carried out using alkene (1.0 mmol), carboxylic
acids 3a−f (1.0 mmol), TBHP (1.5 mmol for valencene 21, 3.0 mmol
for β-pinene 20, and indane 22), Cu−Al Ox (60 mg), refluxing
The allylic oxidation of valencene employing Cu−Al Ox,
TBHP, and L-proline was studied next. We first carried out an
experiment employing 1.5 equiv of TBHP and 60 mg/mmol of
Cu−Al Ox. In contrast to the results of cyclohexene, the reaction
produced only nootkatone 42 (40% yield), a valuable
sesquiterpene commonly used in perfumery and cosmetics.16
Following the same methodology described above, a 32 full-
factorial design, with 9 experiments and 2 extra central points,
was conducted. The statistical analysis of the model thus
obtained (see the Supporting Information) displayed that the
main factor involved was the amount of Cu−Al Ox employed in
the reaction. The amount of oxidant resulted irrelevant in the
experimental domain. The response surface is displayed in Figure
3.
b
CH3CN (4 mL), 24 h. GC yields (isolated yield).
Scheme 3. Plausible Mechanism for the Allylic Oxidation of
Alkenes with TBHP in the Presence of Cu−Al Ox
The best result corresponded to 60 mg/mmol substrate of
Cu−Al Ox and 4.5 equiv of TBHP, which proceeded in 64%
yield. The reaction yield was thus improved from 40 to 64%.
(an OVAT approach), this technique allows several variables to
be changed at the same time.15 The experiments are run under
the conditions determined by a chosen algorithm, and different
yields are obtained. With these data in hand, a model that
accounts for the dependence of the yield with regard to every
variable studied can be calculated. It is then possible to predict
Figure 3. Response surface for the synthesis of nootkatone 42.
1600
dx.doi.org/10.1021/ol500198c | Org. Lett. 2014, 16, 1598−1601

Organic Letters
Letter
514. (h) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698−1712.
(i) Shilov, A. E.; Shul’pin, G. B. Chem. Rev. 1997, 97, 2879−2932.
(2) (a) Nakamura, A.; Nakada, M. Synthesis 2013, 45, 1421−1251.
(b) Fraunhoffer, K. J.; Prabagaran, N.; Sirois, L. E.; White, M. C. J. Am.
Chem. Soc. 2006, 128, 9032−9033. (c) Covell, D. J.; Vermeulen, N. A.;
Labenz, N. A.; White, M. C. Angew. Chem., Int. Ed. 2006, 118, 8397−
8400. (d) Ginotra, S. K.; Singh, V. K. Org. Biomol. Chem. 2006, 4, 4370−
4374. (e) Fraunhoffer, K. J.; Bachovchin, D. A.; White, M. C. Org. Lett.
2005, 7, 223−226. (f) Zhou, J.; Tang, Y. Chem. Soc. Rev. 2005, 34, 664−
676. (g) Andrus, M. B.; Asgari, D. Tetrahedron 2000, 56, 5775−5780.
(3) Weidmann, V.; Maison, W. Synthesis 2013, 45, 2201−2221.
(4) (a) Delcamp, J. H.; White, M. C. J. Am. Chem. Soc. 2006, 128,
15076−15077. (b) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White,
M. C. J. Am. Chem. Soc. 2005, 127, 6970−6971. (c) Chen, M. S.; White,
M. C. J. Am. Chem. Soc. 2004, 126, 1346−1347.
Extension of the study to the allylic oxidation of of β-pinene
and indane (Scheme 5) provided alcohol 43 and ketone 44,
respectively, with excellent yields.
Scheme 5. Oxidation of Alkenes in the Presence of L-
a b
,
Proline
(5) (a) McLaughlin, E. C.; Choi, H.; Wang, K.; Chiou, G.; Doyle, M. P.
J. Org. Chem. 2009, 74, 730−738. (b) Choi, H.; Doyle, M. P. Org. Lett.
2007, 9, 5349−5352. (c) Catino, A. J.; Forslund, R. E.; Doyle, M. P. J.
Am. Chem. Soc. 2004, 126, 13622−13623.
a
All reactions were carried out using cyclohexene 1 (4.0 mmol) and β-
pinene 20, (+)-valencene 21, and indane 22 (1.0 mmol), L-proline 3g
(1.0 mmol), TBHP (6.0 mmol for 1 and 20 and 4.5 mmol for 21 and
22), Cu−Al Ox (60 mg; 15 mol % [Cu] for 1, 60 mol % [Cu] for 20,
(6) (a) Kharasch, M. S.; Sosnovsky, G.; Yang, N. C. J. Am. Chem. Soc.
1959, 81, 5819−5824. (b) Kharasch, M. S.; Sosnovsky, G. J. Am. Chem.
Soc. 1958, 80, 756.
b
21, and 22), refluxing CH3CN (4 mL), 82 °C, 24 h. GC yields
(isolated yield).
(7) (a) Shi, E.; Shao, Y.; Chen, S.; Hu, H.; Liu, Z.; Zhang, J.; Wan, X.
Org. Lett. 2012, 14, 3384−3387. (b) Akermark, B.; Magnus Larsson, E.;
Oslob, J. D. J. Org. Chem. 1994, 59, 5729−5733.
To verify the uniqueness of L-proline in this context, an amino
acid and amine series were also tested, leading to poorer results
compared to L-proline (see the Supporting Information).
In summary, we have demonstrated the capacity of Cu−Al Ox
to catalyze the allylic oxidation of cyclic alkenes. The reactions
are technically easy to perform and provide synthetically useful
yields. In addition, DoE has revealed itself as a valuable tool for
the optimization of these processes. The use of Cu−Al Ox
discloses a promising route to the allylic oxidation of valuable
alkenes. Its preparation is amenable to fine-tuning, and its
chemical properties can thus be modulated. Its catalytic behavior
in other reactions is currently under study.
(8) (a) Marín-Barrios, R.; Guerra, F. M.; García-Cabeza, A. L.;
Moreno-Dorado, F. J.; Massanet, G. M. Tetrahedron 2012, 68, 1105−
1108. (b) Andrus, M. B.; Lashley, J. C. Tetrahedron 2002, 58, 845−866.
(c) Eames, J.; Watkinson, W. Angew. Chem., Int. Ed. 2001, 40, 3567−
3571.
(9) García-Cabeza, A. L.; Marín-Barrios, R.; Azarken, R.; Moreno-
Dorado, F. J.; Ortega, M. J.; Vidal, H.; Gatica, J. M.; Massanet, G. M.;
Guerra, F. M. Eur. J. Org. Chem. 2013, 8307−8314.
(10) Le Bras, J.; Muzart, J. Tetrahedron: Asymetry 2003, 14, 1911−
1915.
(11) Beckwith, A. L. J.; Zavitsas, A. A. J. Am. Chem. Soc. 1986, 108,
8230−8234.
(12) Mayoral, J. A.; Rodríguez-Rodríguez, S.; Salvatella, L. Chem.
Eur. J. 2008, 14, 9274−9285.
ASSOCIATED CONTENT
* Supporting Information
(13) Zhang, G.; Han, X.; Luan, Y.; Wang, Y.; Wen, X.; Ding, C. Chem.
Commun. 2013, 72, 7908−7910.
■
S
(14) Hoover, J. M.; Ryland, B. L.; Stahl, S. S. J. Am. Chem. Soc. 2013,
135, 2357−2367.
Experimental procedures, DoE optimization details, compound
1
characterization, and H/13C NMR reprints. This material is
(15) For a general introduction to experimental design in chemistry,
see: (a) Leardy, R. Anal. Quim. Acta 2009, 652, 161−172. (b) Carlson,
R.; Carlson, J. E. Design and Optimization in Organic Synthesis, in Data
Handling in Science and Technology, Elsevier, Amsterdam, 2005.
(c) Bezerra, M. A.; Santelli, R. E.; Oliveira, E. P.; Villar, L. S.;
Escaleira, L. A. Talanta 2008, 76, 965−977. (d) Araujo, P. W.; Brereton,
R. G. TrAC, Trends Anal. Chem. 1996, 15, 26−31. (e) Araujo, P. W.;
Brereton, R. G. TrAC, Trends Anal. Chem. 1996, 15, 63−70.
(16) (a) Neuenschwander, U.; Jensen, K. F. Ind. Eng. Chem. Res. 2014,
53, 601−608. (b) Wilson, C. W.; Shaw, P. E. J. Agric. Food. Chem. 1978,
26, 1430−1432.
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: francisco.guerra@uca.es.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by Junta de Andalucıa (FQM-169).
The authors are thankful to the Servicios Centrales de Ciencia y
■
́
́
́
Tecnologıa (SCCYT) of the University of Cadiz. A.L.G.-C. and
R.M.-B. thank the Spanish Ministry of Education, Culture and
Sport for a fellowship.
REFERENCES
■
(1) (a) White, M. C. Synlett 2012, 23, 2746−2748. (b) Wencel-Delord,
J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740−4761.
̈
(c) Baran, P. S.; Newhouse, T. Angew. Chem., Int. Ed. 2011, 50, 3362−
3374. (d) Bergman, R. G. Nature 2007, 446, 391−393. (e) Kalyani, D.;
Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127,
7330−7331. (f) Kakiuchi, F.; Chatani, N. Adv. Synth. Catal. 2003, 345,
1077−1101. (g) Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507−
1601
dx.doi.org/10.1021/ol500198c | Org. Lett. 2014, 16, 1598−1601