Oxidation of α-Alkoxy allenes into α′-alkoxy enones

Article abstract of DOI:10.1002/chem.201000914

Rearrangement enablers: α-Alkoxy allenes undergo regioselective oxidative migration to give α′-alkoxy enones in good to excellent yields (see scheme; Bn=benzyl, mCPBA=m-chloroperbenzoic acid). The influence of substituents on the allene, at C1, and at the

Full text of DOI:10.1002/chem.201000914

COMMUNICATION
DOI: 10.1002/chem.201000914
Oxidation of a-Alkoxy Allenes into ACTHNUTRGNEaNUG ’-Alkoxy Enones
Pierre Cordier,[a] Corinne Aubert,[a] Max Malacria,*[a] Vincent Gandon,*[a, b] and
Emmanuel Lacꢀte*[a]
Oxygenation of allenes leads to the formation of reactive
(Scheme 2), which gives the oxacycles after prototropy. We
allene oxides (Scheme 1, A). This oxygenation reaction was
reasoned that a suitably modified enolate (as in E) might
Scheme 1. Oxygenation of allenes.
first reported in 1934,[1] and has since then elicited consider-
able attention,[2] mostly because the high reactivity of allene
oxides allows the selective insertion of oxygen atoms into
carbon backbones, an endeavor that is undergoing a renais-
sance in recent years.[3] Nature has devised enzymes to har-
ness the synthetic potential of allene oxides.[4] Depending on
the conditions, they can open to oxyallyl cations (B)[5] or be
oxidized again into spirodiepoxides (C).[6] Both routes have
been used to access cyclic oxygenated compounds.[7]
Scheme 2. Access to a’-alkoxy ketones.
undergo a retro-Michael reaction to deliver a’-alkoxy ke-
tones.[9] Such a pathway has been suggested only once,[10]
but has never been thoroughly investigated. Herein, we
report efficient conditions for the oxidative migration and
evaluate its scope and limitations.
As part of our research program devoted to the design of
new reactions involving allenes,[8] we decided to re-investi-
gate the oxacyclization of allenols to oxa-cyclopentanones.
The reaction presumably occurs via zwitterionic enolate D
We selected peracids and dimethyldioxirane (DMDO) as
representative oxidizing systems employed for allene oxy-
genation.[7,11] Peracids generate nucleophilic carboxylic acids
upon reduction, whereas DMDO does not, and we anticipat-
ed this might modulate the reactivity. Also, we expected
that added steric hindrance at C1 could be a way to orient
the reaction toward migration, because of the steric strain
generated in the ring.
DMDO oxidation of dimethyl-substituted a-hydroxy
allene 1a, which has two isopropyl substituents at C1 led to
dihydrofuran-3(2H)-one 3a (Table 1, entry 1, conditions A),
that is it did not lead to the migration. On the other hand,
substrate 1b—exhibiting a less sterically demanding cyclo-
pentyl ring at C1—led exclusively to 4-hydroxydihydrofu-
[a] P. Cordier, Dr. C. Aubert, Prof. Dr. M. Malacria,
Prof. Dr. V. Gandon, Dr. E. Lacꢀte
UPMC Univ Paris 06
IPCM UMR CNRS 7201
4 place Jussieu, 75005 Paris (France)
Fax : (+33)1-44-27-73-60
E-mail: max.malacria@upmc.fr
vincent.gandon@u-psud.fr
emmanuel.lacote@upmc.fr
[b] Prof. Dr. V. Gandon
Present address: ꢁquipe de Catalyse Molꢂculaire
ICMMO, UMR CNRS 8182, Universitꢂ Paris-Sud 11
91405 Orsay cedex (France)
AHCTUNGTREGrNNNU an-3(2H)-one 4b (Table 1, entry 2) as a result of double ep-
oxidation of the starting allene (see Scheme 1). We imagined
that formation of a diepoxide might be limited by switching
to the less reactive m-chloroperbenzoic acid (mCPBA, con-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000914.
Chem. Eur. J. 2010, 16, 9973 – 9976
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9973

Table 1. Initial screening of substrates and reaction conditions.
Table 2. Oxidation of tertiary a-alkoxy allenes with a quaternary center
at C1.
Entry Substrate R1
R2
Y
Conditions[a] Yield [%] (2/3/4)[b]
Entry Allene R1
R2
Y
Yield [%] (E/Z)
1
2
3
4
5
6
7
8
9
1a
1b
1b
1c
1c
1c
1c
1d
1d
iPr
A
Me
H
H
H
H
H
H
H
A
67 (0:1:0)
74 (0:0:1)
A
1
2
3
4
5
6
7
1e
1 f
1g
1h
1i
1j
1k
1l
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
Ph
Ph
Ph
Ph
Ph
Me
Bn
allyl
propargyl
CH2CH
SiMe3
93
78
68
N
B[c]
A
93 (1:5.6:5)[d]
50 (2.6:1:0)[d]
74 (2:1:0)[d]
83 (2.5:1:0)[d]
81 (2.1:1:0)[d]
55 (1:0:0)
Ph
Ph
Ph
Ph
Ph
Ph
Et
Et
Et
Et
Me Me
Me Me
B
ACHTUNGTRNE(NUNG OCH2)2 86
B[e]
B[f]
A
94
0
87
95
Si
Bn
(iPr)3
B
91 (1:0:0)
8
N
(CH2)2 Bn
[a] Conditions A: DMDO, acetone, À308C, 20 min; Conditions B:
mCPBA (1.1 equiv), CH2Cl2, 08C, 5 h. [b] Isolated yield. [c] Using
1.5 equiv of mCPBA. [d] Separated. [e] 10% aq NaHCO3 added.
[f] TsOH (1 equiv) added.
9
10
11
1m
1n
1o
Me
Me
Ph
iPr
Bn
Bn
Bn
85 (5.7:1)
89 (1:0)
76 (1:0)
(E)-styryl Ph
ditions B). Besides, the preparation and manipulation of
DMDO are both hazardous. Nonetheless, mCPBA led to a
roughly equimolar mixture of oxacycles 3b and 4b. Yet, we
were pleased to observe the desired enone 2b as a minor
product of the reaction (Table 1, entry 3).
Notably, when several oxidizable groups were present on
the molecules, oxidation occurred exclusively at the allene
framework, and not on the allyl, styryl, or propargyl moiet-
ies. Lastly, the facile transformation of substrates containing
protecting groups, such as benzyl (Bn, Table 2, entries 1, 7–
11), and, above all, trimethylsilyl (Table 2, entry 5), provided
an access to synthetically useful a’-hydroxy enones.
Smooth double migration was achieved from oxidation of
the bis-allene 1p (Scheme 3). Using 2 equiv of mCPBA, the
reaction proceeded within 2 h at 08C to deliver diketone 2p
in 77% yield. No traces of over oxidation product could be
detected.
We have shown in a previous report that aromatic groups
at C1 provide an entry to new reactivities.[12] In the present
case, introduction of a gem-diphenyl group blocked the bis-
oxidation (Table 1, entries 4 and 5). Also, enone 2c was now
the major product, but it was still accompanied by a large
amount of cyclic ketone 3c. The use of additives such as
sodium hydrogen carbonate (Table 1, entry 6) or p-toluene
sulfonic acid (TsOH, Table 1, entry 7) did not markedly
change the ratios. Overall, these combined results suggest
that the formation of spirodiepoxides is delayed by steric
factors at C1, but it appears that the prototropy leading to
products 3 is too fast to be avoided even in sterically de-
manding cases.
We therefore decided to protect the alcohol functionality.
Gratifyingly, enone 2d was then isolated as the only product
under both experimental conditions, albeit the yield was
better when mCPBA was used (Table 1, entries 8 and 9). A
typical reaction is thus carried out with the allene in the
presence of mCPBA (1.1 equiv) in dichloromethane at 08C.
The conditions B were chosen to illustrate the scope and
limitations of the methodology (Table 2). Both alkyl and
silyl ethers underwent efficient migration to C4. However,
the sterically demanding triisopropylsilyloxy group prevent-
ed any reaction occurring (Table 2, entry 6). In addition, var-
ious combinations of alkyl and aryl groups at C1 could be
used (only achiral or racemic allenes were used). This shows
that i) the prototropy is the major obstacle to the migration
in a-alkoxy allenes, and ii) that the other factor steering the
reactivity away from oxacyclization is the steric hindrance at
C1.
Scheme 3. Oxidation of a bis-allene derivative.
More in-depth analysis also showed that the substitution
pattern at C1 plays an important role. Diphenyl-substituted
a-alkoxy allene 1e led exclusively to enone 2e in 93% yield
(Table 2, entry 1). When one phenyl ring was removed, as in
1q, ketoester 5q was formed as a byproduct (Table 3). This
byproduct is the result of intermolecular attack of m-chloro-
benzoic acid onto the intermediate allene oxide. Decreasing
the temperature to À788C (Table 3, entries 2 and 3), slightly
modified the ratio in favor of the enone. The ratio remained
unchanged even when commercial mCPBA was purified to
remove traces of the acid (Table 3, entry 4). We could sup-
press the byproduct by carrying out the reaction under bi-
phasic conditions (CH2Cl2/water) in the presence of sodium
Interestingly, the migration is stereoconvergent and gener-
ally selective. Except in one case (Table 2, entry 9), the E
isomer was the only product (Table 2, entries 10 and 11).[13]
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Chem. Eur. J. 2010, 16, 9973 – 9976

Oxidation of a-Alkoxy Allenes into a’-Alkoxy Enones
COMMUNICATION
Table 3. Case of a tertiary center at C1.
Entry Conditions
Yield [%] (2q/5q)[a]
1
2
3
4
5
6
CH2Cl2, 08C, 2 h
55 (3:1)
62 (4:1)
58 (4:1)
45 (4:1)
53 (1:0)
CH2Cl2, À108C, 2 h
CH2Cl2, À788C to RT, 5 h
Purified mCPBA, CH2Cl2, À108C, 2 h
CH2Cl2/H2O (biphasic), NaHCO3, RT, 2 h
Scheme 5. Double oxidation leading to a’-alkoxy oxiranyl ketones.
Xylenes/H2O (biphasic), NaHCO3, RT, 2 h 77 (1:0)
[a] Isolated, not separated.
tolerates various substitution patterns. Further work will
focus on b-alkoxy allenes and higher homologues, amino al-
lenes, as well as the asymmetric version of the migration.
hydrogen carbonate, which ushered the carboxylate out of
the organic phase (Table 3, entry 5). Using xylenes as the or-
ganic phase resulted in a significant improvement of the
yield (77%, Table 3, entry 6), which considerably broadened
the scope of the migration.
The influence of the allene substitution was investigated
next (Scheme 4). Monosubstituted allene derivative 1r was
not nucleophilic enough to react with mCPBA (1.1 equiv) in
Experimental Section
Oxidative rearrangements of the allenyl ethers (Table 2): The allenic
ether was dissolved in CH2Cl2 (0.1m) and mCPBA (77 wt%) was added
in one portion at RT. The resulting mixture was stirred at RT until disap-
pearance of the starting material (TLC monitoring, usually within 2 h).
The mixture was then added to a 10% aq solution of Na2CO3. The aque-
ous phase was extracted twice with CH2Cl2 (15 mL each time). The com-
bined organic extracts were dried over MgSO4, filtered, and concentrated
in vacuo. The desired ketones were purified by flash chromatography
over silica gel. See the Supporting Information for the product descrip-
tions.
Acknowledgements
We thank UPMC, le Ministꢄre de la Recherche, CNRS, IUF and ANR
(grant BLAN 06-2 159258, allene) for financial support of this work.
Technical assistance (MS, elemental analyses) was generously offered by
ICSN (Gif sur Yvette, France) and FR 2769.
Keywords: allenes · epoxidation · ketones · oxidation ·
rearrangement
Scheme 4. Influence of the allene substitution pattern. Compound 1u was
used as a single diastereomer.
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Chem. Eur. J. 2010, 16, 9973 – 9976
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9975

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ways to prepare them have been described. For recent synthetic ap-
Received: April 12, 2010
Published online: July 19, 2010
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