Expanding the scope of the Babler–Dauben oxidation: 1,3-oxidative transposition of secondary allylic alcohols

Article abstract of DOI:10.1016/j.tetlet.2016.07.076

We report the catalytic chromium-mediated oxidation of secondary allylic alcohols to give α,β-unsaturated aldehydes with exclusive (E)-stereoselectivity. This facile procedure employs catalytic PCC (5?mol?%) and periodic acid (H₅IO₆) as a co-oxidant. This transformation occurs specifically with aromatic substituted allyl alcohols containing both electron withdrawing and electron donating substituents as well as a range of functional groups.

Full text of DOI:10.1016/j.tetlet.2016.07.076

Tetrahedron Letters 57 (2016) 3954–3957
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Tetrahedron Letters
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Expanding the scope of the Babler–Dauben oxidation: 1,3-oxidative
transposition of secondary allylic alcohols
⇑
Patrick M. Killoran , Steven B. Rossington, James A. Wilkinson, John A. Hadfield
Biomedical Research Centre, Kidscan Laboratories, University of Salford, Salford M5 4WT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the catalytic chromium-mediated oxidation of secondary allylic alcohols to give
a,b-unsatu-
Received 8 July 2016
Revised 19 July 2016
Accepted 25 July 2016
Available online 26 July 2016
rated aldehydes with exclusive (E)-stereoselectivity. This facile procedure employs catalytic PCC
(5 mol %) and periodic acid (H5IO6) as a co-oxidant. This transformation occurs specifically with aromatic
substituted allyl alcohols containing both electron withdrawing and electron donating substituents as
well as a range of functional groups.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Allylic rearrangement
Oxidative transposition
Stereoselective
Chromium
Co-oxidant
Introduction
The transformation has also been employed using both oxoammo-
nium salts and IBX as oxidants.7,8
a
,b-Unsaturated aldehydes are of great importance in several
Owing to the extraordinarily wide range of possible applica-
tions for the enal functionality,9 it is surprising that so few efforts
have been directed at the development of a robust synthetic strat-
egy. The reported synthetic approaches to enals include; the MnO2
oxidation of cinnamyl alcohols, the Heck coupling of aromatic
halides with acrolein or acrylaldehyde diethyl acetal10 as well as
a rhenium-catalyzed Meyer–Schuster rearrangement of propargyl
alcohols to aromatic enals.11 These methods can require the use
of expensive transition metal catalytic systems and high tempera-
ture/air-free conditions. Deng and co-workers recently developed
an organoselenium-catalyzed route to cinnamaldehydes.12 An iron
catalyzed C–H oxidation of allyl arenes to enals has also been
reported.13 Kakiuchi reported a single example of the BnN3/TsOH
induced formation of an aromatic enal from an allylic alcohol in
poor yield.14 Reddy and co-workers reported an acid catalyzed
variation of this transformation using a cyano-functionalized vinyl
alcohol.15 Aromatic allyl alcohols are easily accessible from inex-
pensive and readily available benzaldehydes via reaction with a
vinyl Grignard reagent. Herein, we report the first catalytic chro-
mium-mediated 1,3-oxidative transposition of secondary allylic
areas of chemical research, ranging from medicinal chemistry
through to catalysis and materials science. This moiety is also pre-
sent in many natural products and the synthetic utility of these
compounds is extensive as they can react as excellent electrophiles
and Michael acceptors, taking part in a vast array of processes
including cycloadditions and nucleophilic reactions.1
Since the 1940s chromium(VI)–amine complexes have been
used for the oxidation of alcohols.2a Typical systems include Jones
reagent (CrO3/aq H2SO4), pyridinium dichromate (PDC) and pyri-
dinium chlorochromate (PCC). These reagents have also been used
in the oxidation of tertiary allylic alcohols to give
carbonyls (1,3-oxidative transposition).2a–e This transformation
allows strategic modification of compound’s functionality
without altering the basic carbon skeleton. Babler and co-
workers carried out this process by first forming a tertiary
alcohol via alkylation or vinylation of a ketone using Grignard
a,b-unsaturated
a
reagents, followed by reaction with PCC to give an
a,b-
unsaturated system (Scheme 1A).3 Dauben and co-workers
extended the transformation to cyclic systems, thus greatly
expanding its utility (Scheme 1B).4 The method has been used in
several total syntheses, notably, that of morphine (Scheme 1C).5,6
alcohols resulting in the exclusive formation of trans
a,b-unsatu-
rated aldehydes.
⇑
Corresponding author.
E-mail address: p.killoran@edu.salford.ac.uk (P.M. Killoran).
http://dx.doi.org/10.1016/j.tetlet.2016.07.076
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

P. M. Killoran et al. / Tetrahedron Letters 57 (2016) 3954–3957
3955
3
A.
Babler's approach to allyl alcohols and subsequent PCC mediated oxidation
Results and discussion
MgBr, Et2O,
0oC, 2 hr
1.
1-Phenyl-2-propen-1-ol (1a) was chosen as a test substrate and
was easily accessed in excellent yield (95%) from the reaction of
vinyl magnesium bromide with benzaldehyde. Table 1 summarizes
the results from the oxidant screen.
PCC, DCM
rt, 2 hr
O
OH
H
O
2. H2O
87%
4
B.
Dauben's approach to allyl alcohols and subsequent PCC mediated oxidation
These oxidants were selected because Cr(VI) and oxoammo-
nium reagents have previously been used for the 1,3-oxidative
transposition of tertiary allylic alcohols.7 Most of the oxidants pro-
duced the vinyl ketone product 1b. The Dess Martin reagent and
PIFA/TEMPO system produced only trace amounts of the desired
enal 1c, instead giving the expected vinyl ketone 1b. There have
been reports of PCC induced transposition enal side-products in
benzylic and polyaromatic systems.16,17 Remarkably PCC oxidation
of 1a generated the desired product 1c in good yield (71%) with no
trace of the vinyl ketone 1b, instead giving only benzaldehyde 1d
(24%) as a side-product. Motivated by this result, attempts were
made to optimize the conditions. In an effort to reduce the amount
of toxic chromium to catalytic levels we were inspired by the work
of Musart18 and Hunsen,19 who employed di-tert-butyl peroxide
(DTBP) and periodic acid (H5IO6), respectively, as co-oxidants,
allowing the use of catalytic PCC for the oxidation of alcohols to
carbonyls.
Ph
Ph
O
1.PhLi, Et2O,
0oC, 2 hr
OH
PCC, DCM
rt, 2 hr
2. H2O
O
90%
C.
1,3-oxidative transpositionof an allyl alcoholin the synthesis of
morphine6
Aryl = 2,3-dimethoxyphenyl
Aryl
O
PCC,
DCM
morphine
OH
OMOM
Aryl
OMOM
81%
2 hr, rt
Scheme 1. Previously reported chromium-mediated oxidative transpositions of
tertiary allyl alcohols.
Table 2 summarizes the optimization of the PCC/co-oxidant sys-
tem. Initially DTBP was investigated with increasing PCC loading
(2.5–10 mol %). Unfortunately vinyl ketone 1b was the major pro-
duct with the desired product 1c present in small quantities. Using
H5IO6 as the co-oxidant gave 1c as the major product with ben-
zaldehyde 1d as a minor impurity. A more detailed screening of
PCC loading allowed us to identify 5 mol % as optimum, giving
the best yield of 66% with minimum formation of 1d (15%). A small
decrease in yield compared to using stoichiometric PCC (71%) was
observed. Increasing the catalytic loading above 5 mol % gave a
similar yield but also an increase in side-product 1d. The process
was attempted in the absence of light and under an inert atmo-
sphere with no significant variation in yield.
With the optimized conditions in hand, we then screened a ser-
ies of substrates (Scheme 2). These compounds were easily pre-
pared from the reaction of the appropriate aromatic aldehyde
with vinyl magnesium bromide. A range of molecules with varied
functional groups and steric properties were selected. The method
is general in terms of functionality with little variation in overall
Table 1
Preliminary screening of oxidants for the oxidation of phenyl-2-propen-1-ol
OH
O
H
O
[O]
Ph
Ph
Ph
O
Ph
H
1a
1b
1c
1d
Oxidation method
1b (%)
1c (%)
1d (%)
Swern
70
81
85
42
38
56
0
0
<5
0
<5
0
0
71
<5
<5
0
0
0
0
0
0
24
<5
<5
Dess Martin
TPAP/NMO
PIFA/TEMPO
Oxone/TEMPO
NaOCl/TEMPO
PCC
CrO3/H2SO4
PDC
80
51
a Detailed reaction procedures are in the ESI.
Table 2
Screening of co-oxidants and PCC loading for the oxidation of 1a
OH
O
H
H
[O]
Ph
Ph
Ph
O
Ph
O
1a
1b
1c
1d
Co-oxidant
PCC (mol %)
1b (%)
1c (%)
1d (%)
Di-tert-butyl peroxide
2.5
5
7.5
10
23
41
52
50
<5
12
17
16
—
—
—
—
Periodic acid
2.5
3
4
5
6
7
7.5
10
—
—
—
—
—
—
—
—
43
52
56
66
60
59
53
61
11
17
14
15
21
26
25
31
a To a flask containing 1a (5 mmol) and co-oxidant (5 mmol) in MeCN (5 mL) at 0 °C, PCC in MeCN (1 mL) was added dropwise and the reaction monitored by TLC. Product
ratios were determined from crude proton NMR.

3956
P. M. Killoran et al. / Tetrahedron Letters 57 (2016) 3954–3957
OH
OH
H
The reported procedure (Scheme 2) is operationally simple with
an improved workup compared to using stoichiometric PCC in
dichloromethane. The reaction proceeds open to the air, and uses
acetonitrile as solvent.
O
O
H5IO6 (1 eq.),
PCC (5 mol%)
R
R
MeCN , 0 °C - RT
Air, 2 h
H
The mechanism likely follows that of a tertiary allylic transpo-
sition for which two routes have been proposed (Scheme 3). Path
A involves ionization of the allylic alcohol 3a via the formation of
a chromate ester 3b, resulting in benzylic carbocation 3c. This
combines with a chromate anion to give intermediate 3e that is
common to both routes. The second route (Path B) involves a
[3,3]-sigmatropic rearrangement to give common intermediate
3e from which the final oxidation gives the enal product. The acidic
nature of PCC /H5IO6 favors the non-sigmatropic path A, which is
supported by the fact that the process only works with benzylic
substrates and not aliphatic substrates.
Alkyl
Alkyl
H
H
H
O
O
O
MeO
Me
2b 72% (< 10%), E > 99%
1c 66% (11%), E > 99%
Me
2a 78% (< 10%), E > 99%
H
H
H
MeO
O
O
O
O
O
MeO
OMe
Me
Me
Conclusion
2d 79% (< 10%), E > 99%
2e 85% (< 10%), E > 99%
2c 64% (12%), E > 99%
OH
H
We have developed a robust system for the 1,3-oxidative trans-
position of readily accessible aromatic allylic alcohols to exclu-
sively yield (E)-cinnamaldehydes in average to excellent yields.
The process can be performed open to air and is tolerant of a range
of functional groups. By employing a co-oxidant the procedure
avoids the use of both stoichiometric PCC and chlorinated solvents.
H
H
O
O
O
O2N
2f 64% (15%), E > 99%
2g 51% (12%), E > 99%
2h 70% (16%), E > 99%
H
H
H
O
O
O
Acknowledgments
F3C
F
NC
2j 60% (15%), E > 99%
2k 58% (13%), E > 99%
2i 63% (14%), E > 99%
We acknowledge the people who have supported our work.
Thanks to Kirit Amin for analytical support and Dr Timothy
Wallace for helpful advice. Dr Killoran was supported by Kidscan.
H
Br
H
H
O
O
O
O
Cl
Supplementary data
2l 54% (13%), E > 99%
2m 56% (29%), E > 99%
2n 68% (< 10%), E > 99%
Scheme 2. Reaction scope. (aProduct ratios were determined from crude 1H NMR.
Aldehyde side-product in parenthesis.)
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.07.
076.
Ar
OH
O-
Cr O-
O
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Path B
H
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Cr
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