Tetrahedron Letters

j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m

Expanding the scope of the Babler-Daubin oxidation: 1,3-oxidative transposition of

secondary allylic alcohols
Patrick M. Killoran*, Steven B. Rossington, James A. Wilkinson and John A. Hadfield
Biomedical Research Centre, Kidscan Laboratories, University of Salford, Salford M5 4WT, UK
2 Tetrahedron

A RT I C L E I N F O ABSTRACT

Article history: We report the catalytic chromium-mediated oxidation of secondary allylic alcohols to give α,β-
Received unsaturated aldehydes with exclusive (E)-stereoselectivity. This facile procedure employs
Received in revised form catalytic PCC (5 mol%) and periodic acid (H 5IO6) as a co-oxidant. This transformation occurs
Accepted specifically with aromatic substituted allyl alcohols containing both electron withdrawing and
Available online electron donating substituents as well as a range of functional groups.
Keywords:
Allylic rearrangement
Oxidative transposition
Stereoselective
Chromium
Co-oxidant

Introduction
α,β-Unsaturated aldehydes are of great importance in several
areas of chemical research, ranging from medicinal chemistry
through to catalysis and materials science. This moiety is also
present 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
Scheme 1 Previously reported chromium-mediated oxidative
transpositions of tertiary allyl alcohols
*Corresponding author.
E-mail address: p.killoran@edu.salford.ac.uk
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
pyridinium chlorochromate (PCC). These reagents have also
been used in the oxidation of tertiary allylic alcohols to give α,β-
unsaturated carbonyls (1,3-oxidative transposition). 2a-e This
transformation allows strategic modification of a 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
reagents, followed by reaction with PCC to give an α,β-
unsaturated system (Scheme 1A).3 Daubin 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
The transformation has also been employed using both
oxoammonium salts and IBX as oxidants.7,8
Owing to the extraordinarily wide range of possible
applications for the enal functionality,9 it is surprising that so few
efforts have been directed at the development of a robust
synthetic strategy. The reported synthetic approaches to enals
include; the MnO2 oxidation of cinamyl alcohols, the Heck
coupling of aromatic halides with acrolein or acrylaldehyde
diethyl acetal10 as well as a rhenium-catalysed Meyer-Schuster
rearrangement of propargyl alcohols to aromatic enals. 11 These
methods require the use of expensive transition metal catalytic
systems and high temperature/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-funtionalised vinyl alcohol. 15
Aromatic allyl alcohols are easily accessible from inexpensive
and readily available benzaldehydes via reaction with a vinyl
Grignard reagent. We report herein the first catalytic chromium-
mediated 1,3-oxidative transposition of secondary allylic
alcohols resulting in the exclusive formation of trans α,β-
unsaturated aldehydes.
Results and discussion
Table 1 Preliminary screening of oxidants for the oxidation of
phenyl-2-propen-1-ol.
 quantities. Using H5IO6 as the co-oxidant gave 1c as the major
product with benzaldehyde 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
Oxidation 1b (%) 1c (%) 1d (%) using stoichiometric PCC (71%) was observed. Increasing the
Swern 70 0 0 catalytic loading above 5 mol% gave a similar yield but also an
Dess Martin 81 <5 0 increase in side-product 1d. The process was attempted in the
TPAP/NMO 85 0 0 absence of light and under an inert atmosphere with no
PIFA/TEMPO 42 <5 0 significant variation in yield.
Oxone/TEMPO 38 0 0
NaOCl/TEMPO 56 0 0 With optimized conditions in hand, we then screened a series of
PCC 0 71 24 substrates (Scheme 2). These compounds were easily prepared
CrO3/H2SO4 80 <5 <5 from the reaction of the appropriate aromatic aldehyde with vinyl
PDC 51 <5 <5 magnesium bromide. A range of molecules with varied functional
Detailed reaction procedures are in the ESI
groups and steric properties were selected. The method is general
in terms of functionality with little variation in overall yield but
1-Phenyl-2-propen-1-ol (1a) was chosen as a test substrate and compounds with electron donating substituents gave the highest
was easily accessed in excellent yield (95%) from the reaction of yields (Scheme 2, 2a -2g).
vinyl magnesium bromide with benzaldehyde. Table 1
summarizes the results from the oxidant screen. The reaction also proceeds with the sterically hindered mesityl
These oxidants were selected because Cr(VI) and oxoammonium compound 2j. 3-Naphthalen-2-ylpropenal 2l was also
reagents have previously been used for the 1,3 oxidative synthesized in moderate yield. For all of the allyl alcohols
transposition of tertiary allylic alcohols. 7 Most of the oxidants screened a small amount of aromatic aldehyde resulting from
produced the vinyl ketone product 1b. The Dess Martin reagent cleavage was observed for each reaction (~10-15%). The
and PIFA/TEMPO system produced only trace amounts of the procedure was also attempted with alkyl vinyl alcohols. 20
desired enal 1c, instead giving the expected vinyl ketone 1b. Unfortunately this exclusively generated the vinyl ketone
There have been reports of PCC induced transposition enal side- product.
products in benzylic and polyaromatic systems. 16, 17 Remarkably
PCC oxidation of 1a generated the desired product 1c in good The procedure (Scheme 2) is operationally simple with an
yield (71%) with no trace of the vinyl ketone 1b, instead giving improved workup compared to using stoichiometric PCC in
only benzaldehyde 1d (24%) as a side-product. Motivated by this dichloromethane. The reaction proceeds open to the air, and uses
result, attempts were made to optimize the conditions. In an acetonitrile as solvent.
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.
Table 2 summarises the optimisation of the PCC/co-oxidant
system. Initially DTBP was investigated with increasing PCC
loading (2.5-10 mol%). Unfortunately vinyl ketone 1b was the
major product with the desired product 1c present in small

Table 2 Screening of co-oxidants and PCC loading for the oxidation of 1a

Co-oxidant PCC mol% 1b (%) 1c (%) 1d (%)

Di-tert-butyl peroxide 2.5 23 <5 -

5 41 12 -
7.5 52 17 -
10 50 Scheme 16
2 Reaction scope -
Periodic acid 2.5 - 43 11
3 - 52 17
4 - 56 14
5 - 66 15
6 - 60 21
7 - 59 26
7.5 - 53 25
10 - 61 31
4 Tetrahedron

Product ratios were determined from crude 1H NMR. Aldehyde side-product in parenthesis.

Scheme 3 Proposed mechanistic pathways for the oxidative

transposition of secondary aryl allylic alcohols (Path A and Path
B)

The mechanism likely follows that of a tertiary allylic
transposition for which two routes have been proposed (Scheme
3). Path A involves ionisation 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.
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Conclusion

We have developed a robust system for the 1,3-oxidative

transposition of readily accessible aromatic allylic alcohols to
exclusively 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.

Acknowledgments

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.

References and notes

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