Palladium-catalyzed anti-markovnikov oxidation of allylic amides to protected β-amino aldehydes

Article abstract of DOI:10.1021/ja510163w

A general method for the preparation of N-protected β-amino aldehydes from allylic amines or linear allylic alcohols is described. Here the Pd(II)-catalyzed oxidation of N-protected allylic amines with benzoquinone is achieved in tBuOH under ambient conditions with excellent selectivity toward the anti-Markovnikov aldehyde products and full retention of configuration at the allylic carbon. The method shows a wide substrate scope and is tolerant of a range of protecting groups. Furthermore, β-amino aldehydes can be obtained directly from protected allylic alcohols via palladium-catalyzed autotandem reactions, and the application of this method to the synthesis of β-peptide aldehydes is described. From a mechanistic perspective, we demonstrate that tBuOH acts as a nucleophile in the reaction and that the initially formed tert-butyl ether undergoes spontaneous loss of isobutene to yield the aldehyde product. Furthermore, tBuOH can be used stoichiometrically, thereby broadening the solvent scope of the reaction. Primary and secondary alcohols do not undergo elimination, allowing the isolation of acetals, which subsequently can be hydrolyzed to their corresponding aldehyde products.

Full text of DOI:10.1021/ja510163w

Article
pubs.acs.org/JACS
Palladium-Catalyzed Anti-Markovnikov Oxidation of Allylic Amides
to Protected β‑Amino Aldehydes
Jia Jia Dong, Emma C. Harvey, Martín Fananas-Mastral, Wesley R. Browne,* and Ben L. Feringa*
́
̃
Stratingh Institute for Chemistry, Faculty of Mathematics and Natural Sciences, University of Groningen, 9747 AG Groningen, The
Netherlands
S
* Supporting Information
ABSTRACT: A general method for the preparation of N-protected β-amino aldehydes
from allylic amines or linear allylic alcohols is described. Here the Pd(II)-catalyzed
oxidation of N-protected allylic amines with benzoquinone is achieved in tBuOH under
ambient conditions with excellent selectivity toward the anti-Markovnikov aldehyde
products and full retention of configuration at the allylic carbon. The method shows a
wide substrate scope and is tolerant of a range of protecting groups. Furthermore, β-
amino aldehydes can be obtained directly from protected allylic alcohols via palladium-
catalyzed autotandem reactions, and the application of this method to the synthesis of β-
peptide aldehydes is described. From a mechanistic perspective, we demonstrate that
tBuOH acts as a nucleophile in the reaction and that the initially formed tert-butyl ether
undergoes spontaneous loss of isobutene to yield the aldehyde product. Furthermore,
tBuOH can be used stoichiometrically, thereby broadening the solvent scope of the reaction. Primary and secondary alcohols do
not undergo elimination, allowing the isolation of acetals, which subsequently can be hydrolyzed to their corresponding aldehyde
products.
Scheme 1. Catalytic Oxidative Synthesis of Phthalimide-
Protected β-Amino Aldehydes from Branched Allylic
Amines12
INTRODUCTION
■
β-Amino acids, in particular unnatural variants, are of increasing
importance, not least in the preparation of protease-resistant β-
peptides and α/β-peptides.1,2 Furthermore, β-amino aldehydes,
the direct precursors of β-amino acids,2 are crucial building
blocks for the preparation of peptide aldehydes,3 which enable
ligation of unprotected peptides in aqueous solution, show
potent bioactivity,4 and are key intermediates in the synthesis of
natural products and pharmaceutical derivatives.5
Catalytic approaches for the preparation of β-amino
aldehydes rely primarily on the Mannich reaction,6 Michael
additions,7 hydroformylation,8 and methodologies such as anti-
Markovnikov (AM) hydration of alkynes and the aza-Petasis−
Ferrier rearrangement.9 A highly attractive direct route to
protected β-amino aldehydes is through the AM oxidation of
N-protected terminal allylic amines under mild and neutral
conditions.10
Recent progress in the palladium-catalyzed AM oxidation of
alkenes made by both our group and Grubbs and co-workers
has enabled the realization of selective oxidation of a range of
terminal alkenes to aldehydes.11 Indeed, we recently demon-
strated that allylic esters can be oxidized readily to the
corresponding aldehydes selectively using a catalyst such as
[(PhCN)2PdCl2] and the oxidant p-benzoquinone in tert-butyl
alcohol (tBuOH) under ambient conditions.11c
method to any other protecting group resulted in loss of AM
selectivity, severely limiting its utility (Scheme 1). Hence,
despite its obvious synthetic importance, a general method for
the synthesis of protected β-amino aldehydes through AM
oxidation of the corresponding allylic amines has, until the
present report, not been achieved.
Herein we show highly selective AM oxidation of branched
allylic amines bearing a range of protecting groups to give the
corresponding aldehydes under ambient conditions (Scheme
2). The fact that various protecting groups and solvents can be
used makes this approach general and flexible in both organic
synthesis and peptide chemistry. The key to the success of our
method lies in the combination of p-benzoquinone (BQ) as the
oxidant and tBuOH as the solvent/reagent (in place of the
conventional Wacker−Tsuji conditions employing O2, CuCl,
and DMF/H2O, respectively). Importantly, the method allows
for full retention of the stereochemistry of enantioenriched
The new opportunities arising from Wacker−Tsuji AM
oxidations of allylic amines were demonstrated recently by
Feringa and co-workers in the AM-selective oxidation of
phthalimide-protected allylic amines to their corresponding β3-
amino aldehydes (Scheme 1).12 However, extension of this
Received: October 2, 2014
© XXXX American Chemical Society
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enable ready displacement of a ligand by the substrate (i.e., the
alkene).13
Scheme 2. Catalytic Oxidative Synthesis of Protected β-
Amino Aldehydes Described in the Present Report
Substrate Scope and Tolerance of Protecting Groups.
The scope of the reaction with regard to protecting groups and
substituents was investigated with the readily available catalyst
[(CH3CN)2PdCl2] and BQ as the oxidant in tBuOH (Scheme
3). When the catalyst loading was varied from 2.5 to 10 mol %,
a
Scheme 3. Pd(II)-Catalyzed Oxidation of Allylic Amides
allylic amides, providing a new route for the catalytic
asymmetric synthesis of amino aldehydes (Scheme 2).
Furthermore, the Pd(II) catalysts used also enable protected
β-amino aldehydes to be obtained directly from protected
linear allylic alcohols via an autotandem approach. Finally, in
earlier studies by both our group and the group of Grubbs, the
use of tBuOH as the solvent was perceived to be essential to
achieving AM selectivity. Here we demonstrate that the role
played by the alcohol, either as a solvent or stoichiometrically,
is as a nucleophile and the source of the oxygen atom in the
final product. However, although all of the linear and tertiary
alcohols employed give full conversion, only tBuOH provides
excellent AM selectivity in the oxidation of allylic amides.
a
Isolated yields and (in parentheses) aldehyde:ketone ratios are
shown.
RESULTS AND DISCUSSION
■
The method introduced recently by our group for the oxidation
of allylic esters, i.e., with [(RCN)2PdCl2] (R = CH3, Ph) as the
catalyst and BQ as the oxidant in tBuOH under ambient
conditions,11c was applied here in the oxidation of trichlor-
oacetyl-protected phenylallylamine to yield the aldehyde
product exclusively (>99:1; Table 1, entry 1). Several related
only the reaction rate was affected (it increased), and no change
in AM selectivity was observed (typically >99:1 aldehyde:ke-
tone). Notably, the addition of excess BQ oxidant did not
increase the reaction rate. Further studies employed a catalyst
loading of 5 mol % and stoichiometric BQ with a substrate
concentration at 0.5 M in tBuOH.
Table 1. Catalyst Screening
Phthalimide-protected allylic amines were oxidized to
aldehydes 2a and 2b with excellent selectivity (>99:1; Scheme
3) using a reduced reaction time of 16 h compared with those
required under Wacker−Tsuji conditions (Scheme 1), where
72 h was required together with 10 mol % catalyst.12 N-Boc-
protected 1-phenylallylamine (1d) was converted to 2d in high
yield and selectivity, which contrasts with the formation of the
corresponding ketone product under Wacker−Tsuji conditions
as reported earlier.12 Mono- or bis-N-protected 1-phenylallyl-
amines with a series of protecting groups were also converted
to the corresponding aldehydes selectively, including pivalic
(2c), benzoyl (2e), 2-furoyl (2g), and trichloroacetyl (2h)
monoprotected substrates and benzoyl/phenyl (2k) and
trifluoroacetyl/p-methoxyphenyl (2l) bisprotected ones. In
addition, 4-methoxyphenyl (2f), methyl (2i), pentyl (2j), and
ethyl (2m) substituted allylic amines with various protecting
groups were converted selectively in good isolated yields
(Scheme 3). The relatively lower yields of 2c, 2e, and 2f are
mainly due to lower conversion of the substrate and formation
of enamine side products.
a
a
entry
catalyst
conversion
A:M
1
2
3
4
5
6
[(CH3CN)2PdCl2]
[(iPrCN)2PdCl2]
[(PhCN)2PdCl2]
[PdCl2]
full
99:1
99:1
99:1
99:1
99:1
−
full
full
30%
40%
0%
[(MeCN)2PdCl(NO2)]
[Pd(OAc)2]
a
1
Determined by H NMR spectroscopy.
catalysts were tested under the same conditions (Table 1).
Complexes of the type [(RCN)2PdCl2] (entries 2 and 3) were
similarly effective with full conversion and excellent AM
selectivity, whereas lower conversion was obtained using
[PdCl2] or [(MeCN)2PdCl(NO2)], albeit with full retention
of the AM selectivity (entries 4 and 5). Conversion was not
observed with [Pd(OAc)2] (entry 6). The activity observed
with [PdCl2] is less than that when nitrile ligands are present,
but the observation that the AM selectivity is retained with all
of the catalysts that showed activity suggests that the role of the
nitrile ligand is to increase the solubility of the catalyst and to
Synthesis of Protected β-Amino Aldehydes from
Linear Allylic Alcohols. It should be noted that the synthesis
of allylic amine precursors is often challenging.15 The wide
tolerance to protecting groups shown by the present catalytic
system, however, allows for protected β-amino aldehydes to be
prepared directly from protected linear allylic alcohols in high
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yield and atom economy. Protection of linear allylic alcohols
with several imidoyl groups was followed by in situ Pd(II)-
catalyzed rearrangement16 to the protected branched allylic
amines and subsequent oxidation to the corresponding
aldehydes in good yields (Scheme 4) with the same selectivities
amine was protected with N-trifluoroacetyl-L-proline and
subsequently converted to the corresponding β-amino
aldehyde-containing peptide in 83% yield with excellent AM
selectivity (Scheme 6). The corresponding dipeptide aldehyde
Scheme 6. Synthesis of β-Peptide Aldehydes via Palladium-
Catalyzed Oxidation
a
Scheme 4. Synthesis of β-Amino Aldehydes from Allylic
a
Imidates via an Autotandem14 Reaction
a
Catalyst loading 5 mol %. Isolated yields and diastereomeric ratios
1
determined by H NMR spectroscopy are shown.
a
Conditions: total reaction time 36−72 h; 10 mol % catalyst loading
added in the first step. Isolated yields and (in parentheses)
is obtained with the expected 1:1 ratio of diastereomers.
Furthermore, phthalylglycine was coupled to 1-phenylallyl-
amine, and upon oxidation the corresponding aldehyde
derivative was obtained in high yield (81%; Scheme 6). The
peptide bond here helps the selective oxidation to the β-peptide
aldehyde, which circumvents the need for N-deprotection in
conventional peptide synthesis.
Role of the Solvent. A key feature of AM oxidations of
alkenes with Pd(II) is the requirement that tBuOH be used as
solvent.11 The attack of a nucleophile, i.e., water or alcohol, is
viewed as being a key step in the Pd(II)-catalyzed oxidation of
alkenes. Indeed, Grubbs and co-workers proposed that tBuOH
reacted with an η2-styrene complex to form an enol ether as an
intermediate, followed by hydrolysis with water to release
phenylacetaldehyde.11b,f The importance of stoichiometric
water in the oxidation of styrene was exemplified by the 38%
yield of aldehyde achieved when only adventitious water (i.e.,
from atmospheric moisture) was present.11b
In sharp contrast, in both the oxidation of allylic esters
reported by our group earlier11c and in the oxidation of allylic
amines reported here, reduced selectivity was observed with
water present, and indeed, water is not needed in order to
achieve both full conversion and AM selectivity. The data
support a mechanism for the oxidation of these substrates in
which water and tBuOH compete as nucleophiles, with the
former providing the methyl ketone product and the latter the
desired aldehyde product.
aldehyde:ketone ratios are shown.
as obtained in the one-step protocol (Scheme 3). Trifluor-
oacetyl/4-methoxyphenyl-protected but-3-en-2-amine (2o) was
converted with excellent selectivity (99:1), while trichloroace-
tyl-protected but-3-en-2-amine (2i) provided the same
selectivity as in the one-step protocol (7:1 aldehyde:ketone).
It should be noted that for product 2p, the lower yield obtained
was due to low conversion in the oxidation of the allylic amide.
Furthermore, the slightly lower yields in the tandem reactions
(Scheme 4) compared with those for oxidation of isolated
allylic amides (Scheme 3) were due to the formation of small
amounts of decomposition products, which has been noted
earlier as being due to the formation of acetamides and allylic
cations.16a Notably, the palladium-catalyzed [3,3]-rearrange-
ment of the allylic imidate to the allylic amide was not observed
in the case of 3-phenylallyl trichloroacetimidates.16b
Importantly, in contrast to the oxidation of allylic esters,
where the reversibility of the Pd(II)-catalyzed rearrangement
between branched and linear isomers resulted in erosion of the
enantiomeric excess in enantioenriched branched allylic
esters,11c the enantioselectivity is fully retained in the case of
allylic amines (Scheme 5). The palladium-catalyzed enantiose-
Scheme 5. Asymmetric Overman Rearrangement Followed
by Pd(II)-Catalyzed Oxidation to the Aldehyde with
Retention of Enantiomeric Excess
In the present study, when methanol or ethanol was used as
the solvent, a decrease in AM selectivity (dialkoxy acetal:ketone
ca. 2:1) was observed. The formation of dialkoxy acetals is
notable and consistent with earlier reports on the oxidation of
α-olefins bearing electron-withdrawing substituents in the
presence of, in particular, diols.17 Furthermore, when aldehyde
2h was added at the start of a reaction, together with an
oxidizable allylic amide, it did not form an acetal (Scheme 7).
Hence, the formation of the acetal must occur during the
catalytic cycle and not subsequent to oxidation of the alkene.
These data confirm the role of the alcohol as a nucleophile.
However, the direct formation of the aldehyde product when
tBuOH is used as the solvent, even under anhydrous
conditions, suggested that an elimination reaction takes place
subsequent to the oxidation (Scheme 8). The elimination was
lective Overman rearrangement16 proceeds with excellent
enantiomeric excess in tBuOH, and the subsequent Pd(II)-
catalyzed oxidation provides the corresponding aldehyde in
95% ee. Hence the synthesis of an optically active β-amino
aldehyde can be readily achieved starting from the achiral allylic
alcohol.
Synthesis of Protected β-Amino Aldehyde Dipep-
tides. In view of the substrate scope of the reaction, its
application to dipeptide synthesis was examined. 1-Phenylallyl-
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was not observed with either 1a or 1h (Scheme 10). It should
be noted that in both cases full conversion was achieved after 5
h while excellent selectivity was retained (A:M > 99:1).
Scheme 7. Oxidation of 1h in the Presence of 2h in
Methanol
Scheme 10. AM-Selective Oxidations with tBuOH-d10
Scheme 8. Oxidation of Allylic Amine or Allylic Ester in the
Presence of tBuOH
confirmed by headspace GC analysis with the detection of 2-
methylprop-1-ene during the oxidations of both allylic amides
and allylic esters. As expected, although other alcohols could be
used for the reaction, butene isomers were not detected in the
gas phase in those cases. Indeed, neither was 2-methylprop-1-
ene observed when the substrate was omitted. Furthermore,
when stoichiometric tBuOH was used with acetone as the
solvent, full conversion and selectivity were achieved. When
tBuOH was omitted from the reaction, conversion was not
observed, confirming its role as reagent.
Quantification of the transformation of a tertiary alcohol to
its corresponding alkene during the oxidation of allylic amides
was obtained using the tertiary alcohol 2-phenyl-2-propanol
stoichiometrically in the oxidation of allylic amides in acetone
(Scheme 9). 2-Phenyl-1-propene was formed stoichiometrically
These data further indicate that hydrolysis of an enol ether,
which would involve deuterium incorporation at the β-carbon
of the terminal alkene, is unlikely to be involved in the reaction
under the conditions employed here. Hence, the mechanism is
distinct from that proposed by Grubbs and co-workers in the
oxidation of styrene in the presence of stoichiometric water.11b
Furthermore, the absence of deuterium incorporation when
tBuOH-d10 was used as the solvent excludes the occurrence of
enol tautomerization under the reaction conditions. The
absence of deuterium incorporation is consistent with a
model in which intramolecular hydrogen transfer from C1 to
C2 occurs together with acetal formation.17b,19
On the basis of the experimental data, a number of possible
nucleophilic pathways can be excluded already (Scheme 11).
Scheme 9. Oxidation of Allylic Amide in the Presence of 2-
Phenyl-2-propanol
Scheme 11. Proposed Mechanism for Aldehyde and Acetal
Formation
together with full conversion of the allylic amide, albeit notably
with a loss in selectivity (aldehyde to ketone ratio of 1.5:1).
The decrease in AM selectivity is likely due to water,18 which
competes with sterically hindered tertiary alcohols more
effectively than with tBuOH. Indeed, although full AM
selectivity was observed when tBuOH was used stoichiometri-
cally in acetone, the addition of 10 equiv of water resulted in a
substantial decrease in selectivity to 3:1 (aldehyde:ketone).
Similar results were obtained with 3-methylpentan-3-ol and 2,3-
dimethylpentan-3-ol (see the Supporting Information for
further details).
These data confirm the role of the alcohol in the reaction as a
nucleophile and that the direct formation of aldehyde is due to
elimination in the case of tertiary alcohols. However, the fact
that AM selectivity is achieved only with tBuOH indicates that
the selectivity is not solely dependent on either steric factors or
the occurrence of the elimination itself.
Mechanistic Considerations. The observation of stoi-
chiometric isobutene formation with tertiary alcohols as well as
alkoxy acetals with other alcohols precludes mechanisms in
which hydrolysis of an alkyl enol ether intermediate is involved
in the catalytic cycle. It is notable that when tBuOH-d10 was
employed either stoichiometrically with acetone as the solvent
and stoichiometric palladium catalyst or as the solvent with
Pd(II) (20 mol %), deuterium incorporation into the product
When primary alcohols are used (i.e., EtOH, MeOH), the
corresponding dialkoxy acetals are obtained from allylic amides;
however, these acetals are not formed after oxidation from
aldehyde products (vide supra, Scheme 7). Hence, although
aldehydes are obtained directly when tertiary alcohols are used,
in all other cases it is clear that alkoxy acetals are the primary
product of the oxidation by palladium. The absence of
deuterium incorporation from the solvent excludes enol
intermediates in the reaction pathway, and the full retention
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of enantioselectivity excludes the formation of intermediate η3-
allylpalladium complexes.
ACKNOWLEDGMENTS
■
The authors acknowledge the financial support of the
SMARTMIX CatchBio Program (J.J.D.), the European
Research Council (Consolidator Investigator Grant 279549 to
W.R.B.), and The Netherlands Ministry of Education, Culture
and Science (Gravitation Program 024.001.035 to W.R.B. and
B.L.F.).
CONCLUSION
■
We have demonstrated that protected β-amino aldehydes, from
the corresponding protected allylic amines and even from linear
allylic alcohols, can be obtained under ambient conditions with
a wide range of protecting groups. Furthermore, we
demonstrate that tBuOH acts as a nucleophile and provides
the aldehyde product directly by means of an elimination to
give isobutene. Crucially, the retention of stereochemistry in
chiral protected allylic amines and the applicability of this
method to peptide synthesis present considerable opportunities
in synthesis and chemical biology.
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EXPERIMENTAL SECTION
■
Reagents and Characterization Methods. Reagents were of
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General Procedure for the Oxidation of Allylic Amides.
Unless stated otherwise, [PdCl2(CH3CN)2] (0.05 mmol) and p-
benzoquinone (1 mmol) were dissolved in tBuOH (2 mL). The allylic
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aldehyde. For characterization data, see the Supporting Information.
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Aldehydes. [PdCl2(CH3CN)2] (0.05 mmol) and allylic imidate
(0.5 mmol, 0.5 M) were dissolved in tBuOH (1 mL). After 6 h of
stirring, p-benzoquinone (0.5 mmol) was added to the solution. The
reaction mixture was stirred at room temperature until the reaction
was complete. The combined organic layers were washed with water,
dried over Na2SO4, and concentrated in vacuo. Purification by silica gel
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* Supporting Information
Experimental details and spectral characterization of products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Authors
w.r.browne@rug.nl
b.l.feringa@rug.nl
Notes
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The authors declare no competing financial interest.
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(18) It should be noted that in the absence of substrate under
otherwise catalytic conditions, spontaneous partial dehydration (20−
50%) of tertiary alcohols other than tBuOH was observed over a 72 h
1
period by H NMR spectroscopy. The dehydration, in addition to
releasing water into the reaction mixture that can potentially increase
the amount of ketone formed, reduces the amount of alcohol available
for AM oxidation.
(19) Keith, J. A.; Henry, P. M. Angew. Chem., Int. Ed. 2009, 48,
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