Allylic oxidation: Easy synthesis of alkenones from activated alkenes with TEMPO

Article abstract of DOI:10.1016/j.tetlet.2005.02.032

Activated alkenes and dienes are converted into the corresponding alkenone in excellent yields (>90%). In aqueous acetonitrile, the transformations are catalyzed by 2,2,6,6-tetramethyl-1-oxopiperidinium (TEMPO⁺) in the presence of water and 2,6-lutidine. TEMPO⁺ cations were regenerated electrochemically from the radical parent (TEMPO^.) at a vitreous carbon anode.

Full text of DOI:10.1016/j.tetlet.2005.02.032

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2487–2490
Allylic oxidation: easy synthesis of alkenones from
activated alkenes with TEMPO
Tony Breton,a Denis Liaigrea and El Mustapha Belgsir*
aLaboratoire de Catalyse en Chimie Organique, BioCydex, UMR 6503 CNRS, 40 avenue du Recteur Pineau,
86022 Poitiers Cedex, France
Received 2 December 2004;revised 4 February 2005;accepted 7 February 2005
Abstract—Activated alkenes and dienes are converted into the corresponding alkenone in excellent yields (>90%). In aqueous ace-
tonitrile, the transformations are catalyzed by 2,2,6,6-tetramethyl-1-oxopiperidinium (TEMPO+) in the presence of water and 2,6-
lutidine. TEMPO+ cations were regenerated electrochemically from the radical parent (TEMPOÅ) at a vitreous carbon anode.
Ó 2005 Elsevier Ltd. All rights reserved.
Oxoammonium ions 1, obtained by oxidation of persis-
tent nitroxyl radicals 2, are successfully used principally
for the regioselective alcohol oxidation.1,2 The focus of
our work has been the evaluation of synthetic utility
of 1 in the functionalization of unsaturated compounds.
To our knowledge the oxidation of alkenes with 1 has
never been described moreover it is admitted that 1 does
not react with non-activated alkenes. Conversely, conju-
gated alkenes or 1,4-dienes were found to undergo rela-
tively easily allylic oxidation in the presence of water
leading to the corresponding alkenones.3
An important aspect of our synthetic approach will be
the use of the commercially available 2,2,6,6-tetrameth-
ylpiperidinyl-1-oxy (TEMPO) 2 in catalytic amount.
The regeneration of 1 is achieved electrochemically5 at
controlled potential in the presence of lutidine (Scheme
2). All electrolyses were carried out at 0.55 V (Ag/
AgNO3) in aqueous acetonitrile AcCN/H2O (95:5), the
substrate (2 mmol) and the TEMPO (0.15 equiv) were
dissolved in the presence of 2 equiv of 2,6-lutidine
(4 mmol). At the end of electrolysis, acetonitrile was
evaporated and 20 mL of aqueous HCl (5%) was added.
Then, the products were extracted with diethylether,
dried and chromatographied.
To assess the reactivity of 1 in the allylic oxidation of
activated alkenes, a sample experiment between 1-phen-
ylcyclohexene 3 and 2.1 equiv of tetrafluoroborate salt
14 in acetonitrile/water (95/5) was performed as outlined
in Scheme 1. The reaction has led exclusively to the
1-phenylcyclohexene-3-one 4 in 96% yield.
In alkaline medium (2,6-lutidine) a rapid syn-propor-
tionation between 1 and the corresponding hydroxyl-
amine 5 yields two molecules of 2, which undergo
electrochemical oxidation at the anode into 1. Such
regeneration process is carried out under controlled
potential at 0.55 V (Ag/AgNO3), which corresponds to
the diffusion limited current observable under stirred
conditions (Fig. 1).
In the absence of water, no conversion was observed.
Tetrafluoroborate salt 1
O
2.1 equiv.
We were able to oxidize various activated alkenes into
the corresponding a-carbonyl compounds under stan-
dard conditions using 0.05 equiv of 2 as catalyst (Table
1). The electrochemical regeneration of 1 allowed to oxi-
dize 3 into 4 with the same yields as obtained during the
preliminary essay under stoichiometric conditions. We
therefore decided to carry out the allylic oxidation of
cycloheptatriene 5. It arose from the results an improved
route to tropone 6 with the consumption of 4 F molÀ1
corresponding to 2 equiv of 1.8 The reaction rate
AcCN/H2O
96%
Scheme 1.
Keywords: Oxidation;TEMPO;Electrosynthesis.
*
Corresponding author. Tel.: +33 549 454881, fax: +33 549 470876;
e-mail: mbelgsir@biocydex.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.032

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T. Breton et al. / Tetrahedron Letters 46 (2005) 2487–2490
(0.5 mmol LÀ1 minÀ1) and the chemical yield (96%) were
excellent and no traces of alkenol were detected indicat-
ing that the alkenol intermediates are more reactive than
the corresponding alkene.
2.0
1.5
1.0
In our research programme concerned with the allylic
oxidation we have also investigated the functionali-
zation of fatty esters. Linoleic acid methyl ester 7
was converted into the corresponding conjugated
dienone isomers 8a (47%), b (6%), c (43%) and d (4%)
0.5
0.0
with
a good Faradaic yield and reaction rate
(0.2 mmol LÀ1 minÀ1). As far as oxidation of the 9-
and 13-positions is concerned, it is clear that the allylic
functionalization proceeds via a conjugation step lead-
ing to an inversion of configuration (Scheme 3). The
compounds 8a–d were characterized by 1H and 13C
NMR.9
-0.5
-1.0
-0.3
-0.2
-0.1
0.0
0.1
0.2
0.3
0.4
0.5
0.6
E / V(Ag/AgNO3)
Figure 1. Electrocatalytic oxido-reduction of 1 on a vitreous carbon
anode. Voltammograms recorded at 50 mV sÀ1 in 50 mL of
0.2 mol LÀ1 NaClO4 AcCN/water (95:5) solution: (Á Á Á) unstirred, (—)
stirred.
More explicitly, in the case of non-conjugated diene, the
hydride abstraction (step A) leads to a delocalized carbo-
cation. The nucleophilic attack of the hydroxyl displayed
Table 1. Electromediated oxidation of activated olefin by TEMPO at controlled potential
Substrate
Product
Yielda/%
95
Q/F molÀ1
O
4.2
3
4
O
96b
4.1
6
5
O
OMe
OMe
OMe
OMe
8a
8b
8c
8d
7
4
O
O
O
7
4
OMe
7
4
7
93c
3.8
O
O
7
4
O
O
4
7
O
O
O
O
O
7
35
5.8
OCH3
OCH3
7
10
9
96d, 63a
2.1
2.1
13
11
94d, 60a
13
12
a Isolated.
b At 5 °C in order to avoid the formation of benzaldehyde (Refs. 6 and 7).
c Mixture of 8a–d.
d By GC.

T. Breton et al. / Tetrahedron Letters 46 (2005) 2487–2490
2489
N
O
N
OH
5
N
product
N
H
N
O
2
N
O
activated
alkene
anode
1e-
N
O
1
Scheme 2. Electrochemical regeneration of 1 via the syn-proportionation route in the presence of 2,6-lutidine.
N
O
HH
HH
H
H
H
H
A
B
H
H
H
HH
H
N
OH
H
H
H
OH-
C
N
O
HH
H
H
O
HH
H
D
H
OH
H
H
H
H
H+
N
OH
Scheme 3.
a penchant for the conjugated diene carbocation (step C).
The resulting alkenol is finally oxidized by a second mole-
cule of 1 (step D). This mechanism requires the transfer of
four electrons.
We were intrigued by the effect of the double bond posi-
tion and this prompted an investigation of the oxidation
of 1,3 and 1,4-dienes: a-11 and c-terpinene 12, respec-
tively. Noteworthy results are the aromatization of both
`
terpinenes giving p-cymene 13 with excellent chemical
The proposed mechanism holds true for the oxidation of
linolenic acid methylester 9 under aqueous acetonitrile
conditions: unfortunately the reaction was not found
to be selective and a complex mixture of different iso-
mers containing carbonyl or hydroxyl groups was
obtained. However, 9,16-dioxo-(10-trans,12-cis,14-trans)-
octadecatrienoic acid methylester 10 was isolated in
35% yield.10
yields (96%). Only 2 Faradays per mole were consumed
before the current reached its lower value (capacitive
current). As the experiments were carried out in aqueous
acetonitrile the reaction was expected to proceed via a
rapid intramolecular dehydration reaction of the hydr-
oxyl substituted 11 and 12. However, in dry acetonitrile
the reaction exhibited the same selectivity towards 13.
Analysis of these results suggests that the hypothesis

2490
T. Breton et al. / Tetrahedron Letters 46 (2005) 2487–2490
(C5);29.1 (C );29.0 (C );28.2 (C );24.8 (C );24.0 (C 15);
6
of the hydroxyl substituted intermediates is rejected in
favour of a direct aromatization of the carbocation
derivatives.
8
4
3
22.5 (C17);13.9 (C 18). Compound 8b: 1H NMR (300 MHz,
CDCl3), d: 7.13 (dd, 1H, J 15.6, H11);6.17 (m, 2H, H ,
9
H10);6.07 (d, 1H, J 15.52, H12);3.63 (s, 3H, OMe);2.53 (t,
2H, J 7.35, H14);2.30 (t, 2H, J 7.37, H2);2.17 (q, 2H, H 8);
1.61 (m, 4H, H3, H15);1.43 (m, 2H, H 16);1.31 (m, 10H,
H17, H7, H6, H5, H4);0.89 (t, 3H, J 6.21, H18). 13C NMR
In conclusion this study has outlined the synthetic po-
tential of 1 in allylic oxidation reactions of activated
dienes and the extension of the methodology to the aro-
matization of cyclohexadienes.
(300 MHz, CDCl3), d: 201.1 (C13);174.2 (C );145.4 (C
)
11
1
142.8 (C9);128.9 (C 12);127.9 (C 10);51.4 (OMe);40.4 (C 14);
34.0 (C2);33.0 (C 16);31.5 (C );29.1 (C );29.0 (C );28.9
(C8);28.8 (C 4);28.4 (C 3);24.8 (C 15);22.4 (C 17);13.9 (C 18).
7
5
6
1
References and notes
Compound 8c: H NMR (300 MHz, CDCl3), d: 7.44 (dd,
1H, J 15.8, J 11.6, H11);6.12 (d, 1H, J 15.30, H10);6.07
(dd, 1H, J 10.67, H12);5.90–5.80 (m, 1H, H 13);3.63 (s, 3H,
OMe);2.52 (t, 2H, J 7.31, H8);2.29 (t, 2H, J 6.43, H2);
2.29 (q, 2H, H14);1.59 (m, 4H, H 3, H7);1.39 (m, 2H, H 6);
1.29 (m, 10H, H5, H15, H16, H17, H4);0.86 (t, 3H, J 6.19,
H18). 13C NMR (300 MHz, CDCl3), d: 201.0 (C9);174.3
(C1);142.7 (C 11);137.0 (C 13);129.3 (C 10);126.9 (C 12);
51.4 (OMe);41.0 (C 8);34.0 (C 16);31.4 (C 2);29.3 (C 15);
29.2 (C6);29.1 (C );29.0 (C 14);28.2 (C );24.8 (C );24.2
1. De Nooy, A. E. J.;Besemer, A. C.;Van Bekkum, H.
Synthesis 1996, 1153.
2. Sheldon, R. A.;Arends, I. W. C. E. Adv. Synth. Catal.
2004, 346, 1051–1071.
3. Breton, T.;Liaigre, D.;Belgsir, E. M. French Patent No.
402619, 03/12/2004.
4. Preparation of 1-tetrafluoroborate: Bobbit, J. M.;Flores,
M. C.;Zhenkum, M.;Huitong, T. Heterocycles 1990, 30,
1131.
5. Schnatbaum, K.;Scha¨fer, H. J. Synthesis 1999, 5, 864–
872.
6. Trahanovsky, W. S.;Young, L. B.;Robbins, M. D. J. Am.
Chem. Soc. 1969, 91, 7084.
7. Doering, W. von E.;Knox, L. H. J. Am. Chem. Soc. 1954,
101, 352.
4
5
3
(C7);22.5 (C 17);13.9 (C 18). Compound 8d: 1H NMR
(300 MHz, CDCl3), d: 7.13 (dd, 1H, J 15.6, H11);6.17 (m,
2H, H12, H13);6.07 (d, 1H, J 15.52, H10);3.63 (s, 3H,
OMe);2.53 (t, 2H, J 7.35, H8);2.30 (t, 2H, J 7.37, H2);
2.17 (q, 2H, H14);1.61 (m, 4H, H 3, H7);1.43 (m, 2H, H 6);
1.31 (m, 10H, H5, H15, H16, H17, H4);0.89 (t, 3H, J 6.21,
H18). 13C NMR (300 MHz, CDCl3), d: 201.1 (C9);174.2
(C1);145.4 (C 11) 142.8 (C13);128.9 (C 10);127.9 (C 12);51.4
(OMe);40.4 (C 8);34.0 (C 16);33.0 (C 2);31.5 (C 15);29.1
(C6);29.0 (C );28.9 (C );28.8 (C 14);28.4 (C ). 28.2 (C5);
8. Compound 6 was previously obtained via a multistep
synthesis using direct anodic oxidation of cycloheptatriene
in methanol in 35% yield: Shono, T.;Nozoe, T.;Maek-
awa, H.;Kashimura, S. Tetrahedron Lett. 1988, 29,
555.
4
8
3
24.8 (C7);22.4 (C 17);13.9 (C 18).
1
10. Compound 10: H NMR (300 MHz, CDCl3), d: 7.22 (m,
2H, J 15, H11, H14);6.68 (dd, 2H, J 7, H12, H13);6.32 (dd,
1
9. Compound 8a: H NMR (300 MHz, CDCl3), d: 7.44 (dd,
1H, J 15.8, J 11.6, H11);6.12 (d, 1H, J 15.30, H12);6.07
(dd, 1H, J 10.67, H10);5.90–5.80 (m, 1H, H 9);3.63 (s, 3H,
OMe);2.52 (t, 2H, J 7.31, H14);2.29 (t, 2H, J 6.43, H2);
2.29 (q, 2H, H8);1.59 (m, 4H, H 3, H15);1.39 (m, 2H, H 16);
1.29 (m, 10H, H17, H7, H6, H5, H4);0.86 (t, 3H, J 6.19,
H18). 13C NMR (300 MHz, CDCl3), d: 201.0 (C13), 174.3
(C1);142.7 (C 11) 137.0 (C9);129.3 (C 12);126.9 (C 10);51.4
(OMe);41.1 (C 14);34.0 (C 2);31.5 (C 16);29.4 (C 7);29.2
2H, J 15.1, H10, H15);3.66 (s, 3H, OMe);2.62 (q, 2H,
7.3, H17);2.57 (t, 2H, J 6.5, H8);2.30 (t, 2H, J 6.6, H2);
J
1.61 (m, 2H, H5);1.32 (m, 8H, H , H4, H6, H7);1.01 (t,
3
3H, J 7.3, H18). 13C NMR (300 MHz, CDCl3), d: 200.9
(C9), 200.6 (C16);174.4 (C 1);140.4 (C 11);140.3 (C 14);138.3
(C12);138.2 (C 11);132.2 (C 10);132.0 (C 15);51.5 (OMe);
41.1 (C8);34.3 (C 17);34.0 (C );29.0 (C );29.0 (C );28.9
2
7
5
(C6);24.4 (C );14.1 (C );8.1 (C 18).
4
3