A mild copper catalyzed method for the selective deprotection of aryl allyl ethers

Article abstract of DOI:10.1016/j.tetlet.2016.11.084

Copper boryl reagents enable the selective cleavage of aryl allyl ethers to the corresponding phenols in good to moderate yields.

Full text of DOI:10.1016/j.tetlet.2016.11.084

Accepted Manuscript
A mild copper catalyzed method for the selective deprotection of aryl allyl ethers
David S. Hemming, Eric P. Talbot, Patrick G. Steel
PII:
S0040-4039(16)31563-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.11.084
TETL 48370
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 October 2016
15 November 2016
18 November 2016
Please cite this article as: Hemming, D.S., Talbot, E.P., Steel, P.G., A mild copper catalyzed method for the selective
deprotection of aryl allyl ethers, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.11.084
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A mild copper catalyzed method for the
selective deprotection of aryl allyl ethers
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David S. Hemming, Eric P. Talbot, Patrick G. Steel

1
Tetrahedron Letters
A mild copper catalyzed method for the selective deprotection of aryl allyl ethers
David S. Hemming,a Eric P. Talbotb and Patrick G. Steela
aDepartment of Chemistry, University of Durham, South Road, Durham, DH1 3LE, United Kingdom
bGlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, United Kingdom
ARTICLE INFO
ABSTRACT
Article history:
Received
Copper boryl reagents enable the selective cleavage of aryl allyl ethers to the corresponding
phenols in good to moderate yields.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Borylation
Deallylation
Bis(pinacolato)diboron
Copper
Protecting group
 Corresponding author. Tel.: +44-191-334-2131; fax: +44-191-384-4737; e-mail: p.g.steel@durham.ac.uk

2
1. Introduction
reaction mixture had no adverse effect on the yield. In keeping
with C-X borylation processes using similar reagent
combinations, DMF was found to be the optimal solvent (Entries
20 and 21).
Allyl ethers serve as useful protecting groups for alcohols,
owing to their stability under a wide pH range and a variety of
reaction conditions. This allows them to be used in orthogonal
protecting group strategies and many procedures have been
established for their removal.1-5 Whilst these methods give the
corresponding alcohols in high yields and show good functional
group tolerance, the vast majority employ catalysts based on
palladium and rhodium. Due to ever increasing cost and
diminishing availability, there is considerable current interest in
efforts to substitute processes mediated by palladium group
metals (such as cross couplings) with more readily available
transition metals.6-10 In this paper we describe a new copper
mediated process for the selective deprotection of aryl allyl ethers
that is orthogonal to classic palladium-mediated methods,
operationally simple and occurs under mild conditions with good
functional group tolerance.
Having determined optimal conditions, we then examined the
substrate scope (Table 2). Initial exploration of a set of phenyl
allyl ethers revealed that electron deficient phenols were
deprotected most readily whilst very electron rich substrates were
only cleaved slowly and in low yields (1c and 1d). In these cases
a complex reaction mixture resulted with hydroboration of the
alkene being one minor isolable product. These results suggested
that the pKa of the alkoxide/phenoxide was critical. Consistent
with this hypothesis, alkyl allyl ethers did not perform well in the
reaction (1h and 1r) and allyl amines were stable to the reaction
conditions (1l). Steric bulk on the aromatic ring is well tolerated
but the presence of a terminal methyl group on the alkene (1g)
prevents the reaction from occurring.
Table 1. Screening Conditions
2. Results and discussion
As a component of a study into the C-X borylation of aryl and
alkyl halides,11 we attempted the borylation of allyl protected
bromophenol 1 (Scheme 1). In this reaction, a solution of the
Entry
Change from standard
conditions
None
% yield after 1.5 h
(GC)
80
0
76
1
2
3
4
5
No B2pin2
1 eq. B2pin2 (glove box)
LiOtBu
Scheme 1. Attempted borylation resulting in cleavage of the allyl ether
62
substrate in DMF was added to a mixture of CuI, LiOMe, PPh3
and B2pin2. The reaction rapidly darkened and after ~2 h
complete consumption of the starting material was observed by
TLC. Surprisingly, no evidence for the expected borylated
product could be obtained but rather formation of 2-bromophenol
was observed. This suggested that this reagent combination
might represent a simple and convenient alternative to the
commonly used methods for cleavage of allyl ethers based on
palladium complexes. Pleasingly, applying the same conditions
to 4-fluorophenylallyl ether (1a) afforded the parent phenol (2a)
in good yield (71%) after only 1 h at room temperature. Further
examination of the reaction variables (Table 1) revealed that the
presence of the diboron reagent is essential (Entry 2), with no
reaction occurring in the absence of this component. The reaction
can be run using just stoichiometric amounts of B2pin2 but this
requires rigorous exclusion of air and moisture (reaction was run
in a glove–box), thus it proves more pragmatic to use 1.5
equivalents B2pin2. Under these conditions the reaction can be
run open to air with minimal / no loss in yield suggesting that the
excess diboron reagent may serve to sequester trace oxygen and
preserve the catalytically active species. Similarly, the base is
important, with LiOMe proving to be the most effective (Entries
4-9). This suggests that the formation of a Bpin-OMe adduct may
be necessary for the reaction to proceed. In the absence of the
metal catalyst the reaction progresses very slowly (Entry 10).
This effect was not due to presence of trace precious metal in the
copper source as control reactions using Pd(0) and Pd(II) (Entries
13 and 14) only gave limited conversion, comparable to
background reactivity. The role of the phosphine remains unclear
but the presence of this component is important (Entry 17). It is
possible that the ligand helps to stabilise the metal catalyst,
potentially, given the heterogeneous nature of the reaction
mixture, as nanoparticles. However, addition of mercury to the
KOtBu
s.m isomerisma
6
NaOtBu
55
7
8
9
K2CO3
CsF
No base
No metal
CuCl
CuCl2
Pd(PPh3)4
PdCl2(PPh3)2
ZnCl2
65
59
0
15
10
11
12
13
14
15
16
17
18
19
20
21
62
61
35b
12b
14
MgCl2
5
trace
78
72
trace
No ligand
Xantphos ligand
P(nBu)3 ligand
THF solvent
MeCN solvent
20
GC-MS yields calculated using mesitylene as an internal standard; a) to the
corresponding vinyl ether; b) 5 mol% Pd catalyst was used
Surprisingly, in view of the pKa correlation for phenoxides,
whilst allyl esters are viable substrates the rate of reaction is
significantly slower than for simple phenols. Alloc ethers are
cleaved (1p) as are alloc carbamates of anilines (1n). Given these
results, it was surprising to discover that N-alloc phenylalanine
was resistant to this cleavage protocol (1q). This observation
suggested that this new copper mediated deallylation may have
use in selective deprotection strategies for peptide chemistry. As
proof of concept, dipeptide 4 bearing both an N-terminal alloc
group and an O-allyl tyrosine residue was subjected to the
cleavage conditions (Scheme 2). Whilst the cleavage reaction
requires further optimisation, it was pleasing to observe that
treatment with the CuI-B2pin2 combination selectively cleaved

3
22-28
Table 2. Substrate scope
boronates.11,
Of these, the current reaction has closest
parallels with the last of these transformations for which an SN2’
type displacement is commonly invoked.29 In line with this,
GCMS analysis of the crude reaction mixture reveals the
presence of a signal with m/z = 168 corresponding to the
formation of allyl-Bpin as a by-product. In a series of elegant
studies,24, 29-33 Ito has provided compelling evidence for Cu-Bpin
complexes adding to alkenes to afford η1-Cu alkyl complexes
which in this case would then undergo fragmentation to generate
the observed phenoxide and allyl-Bpin. Alternatively, McQuade
and co-workers using electron poor allyl aryl ethers as the
leaving group in combination with a chiral copper-NHC/B2pin2
system
to
generate
chiral
allyl
boronates
proposed formation of an η3-complex between copper and the
allylic system.34 In all these possibilities the observed
regiochemistry of copper-boryl addition differs to that of copper
catalysed hydroboration18 and it may be that the heteroatom co-
ordinates to the copper directing it towards the carbon closest to
the oxygen thus facilitating elimination.35 In some cases, small
amounts of the alternative ‘hydroboration’ regiochemistry could
be detected, presumably arising from protodemetallation of the
corresponding B-boryl copper which cannot undergo
fragmentation. However, the possibility of competing
hydroboration using HBpin generated during the reaction cannot
be completely discounted.16 Whilst these pathways are consistent
with the observation of higher reactivity of electron deficient aryl
arenes compared with their more electron rich analogues, the
lower reactivity of other allyl derivatives with better leaving
groups (lower pKa), notably carboxylate, would suggest
otherwise.
A final possibility is that the reaction occurs by a single electron
transfer (SET) process. The observed selectivities are paralleled
by those obtained for the reductive cleavage of allyl ethers using
a SmI2/water/amine reagent combination36 in which alkyl allyl
ethers reacted more slowly than their aryl counterparts and N-
allyl amines were not cleaved. Moreover, as with 1g (Table 2), a
terminal methyl substituent prevented the reaction from
occurring. However, counter to this proposal, our attempts to
inhibit the reaction by the addition of radical scavengers
(cyclohexadiene or dihydroanthracene) had no effect on the
reaction of fluorophenyl ether 1a.
Yields quoted represent that of purified isolated products; d.n.r. = did not react; a) after
26 h with coelution of PPh3; b) after 5 h; c) after oxidation to remove boron impurities
the tyrosine allyl ether. In contrast, treatment of the same
dipeptide with Pd resulted in cleavage of the N-alloc group after
30 minutes, followed by subsequent deprotection of the O-allyl
ether after 2 h reaction time.
3. Conclusions
Mechanistic considerations
Scheme 2. Selective removal of an allyl ether in the presence of an alloc protected amine
The mechanism of this transformation remains an ongoing
question. Similar copper boryl reagent combinations to those
described in this report have been shown to promote a diverse
array of transformations, including the hydroboration of alkenes
Copper boryl complexes provide a new approach for the
cleavage of allyl ethers and related functional groups. The
reaction proceeds under mild conditions, giving the deprotected
products in good to moderate yields and presents a simple
alternative to existing methods, avoiding the use of expensive
palladium group metal catalysts. Furthermore, aryl allyl ethers
can be selectively cleaved in the presence of N-alloc protected
and alkynes,12-16 the borylation of aldehydes and imines, β-
17-21
borylation of α,β-unsaturated carbonyl compounds13,
and a
variety of C-X borylations to generate aryl, alkyl and allyl

4
25. E. Yamamoto, K. Izumi, Y. Horita, S. Ukigai and H. Ito,
Top. Catal. 2014, 57, 940-945.
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deprotection strategies.
26. E. Yamamoto, Y. Takenouchi, K. Kubota and H. Ito, J.
Synth. Org. Chem. Jpn. 2014, 72, 758-769.
4. Acknowledgments
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We wish to thank Allychem for a donation of B2pin2 and
GSK/EPSRC for funding.
5. Notes and references
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37. Typical procedure for deallylation experiments: To a round
bottomed flask/microwave vial containing a magnetic stirrer bar
was added CuI (0.1 eq.), PPh3 (0.13 eq.), LiOMe (2 eq.) and
B2pin2 (1.5 eq.). The vessel was capped and via syringe was
added a solution of the allyl ether (1 mmol, 1 eq.) in anhydrous
DMF (0.5 M). The reaction mixture was left to stir at room
temperature (1.5 – 6 h). After completion, the crude mixture was
diluted with EtOAc and filtered through Celite®, washing with
EtOAc. The filtrate was washed 3 times with water and once with
brine then dried over magnesium sulfate and concentrated in
vacuo. The crude mixture was purified by column
chromatography (ethyl acetate:hexanes) to give the desired
product, spectroscopically identical in all respects with an
authentic sample. In some cases, coelution of boron containing
impurities with the products was observed; in these cases
oxidation of the crude reaction mixture with oxone facilitated
purification.
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5
A mild copper catalyzed method for the
selective deprotection of aryl allyl ethers
David S. Hemming,a Eric P. Talbotb and Patrick G.
Steela
aDepartment of Chemistry, University of Durham, South Road, Durham, DH1
3LE, United Kingdom
bGlaxoSmithKline Medicines Research Centre, Gunnels Wood Road,
Stevenage, SG1 2NY, United Kingdom
Highlights





Copper boryl complexes promote
deallylation of aryl allyl ethers
Selective deprotection of aryl allyl ethers in
the presence of an Alloc group
Reaction can be run in air if needed with
minimal loss of yield
Allyl amines are stable to the reaction
conditions
Allyl esters may be cleaved under the same
conditions
 Corresponding author. Tel.: +44-191-334-2131; fax: +44-191-384-
4737; e-mail: p.g.steel@durham.ac.uk