Palladium(0)-catalyzed rearrangement of allyl enol ethers to form chiral quaternary carbon centers via asymmetric allylic alkylation

Article abstract of DOI:10.1016/j.tetlet.2018.07.065

Herein we report the first palladium(0)-catalyzed asymmetric allylic alkylation (AAA) of allyl enol ether via π-allylpalladium intermediate using Trost chiral diphosphine. This unprecedented reaction produced very rare α-aryl quaternary aldehydes with multi-functional groups. The main novelty in the chemistry demonstrates that enol ethers can be used as precursors for π-allylpalladium intermediates, an observation that is certainly rare and to the best of our knowledge, perhaps without prior precedent. Chiral ligand (R,R)-L3 was found to be optimal in this Pd-AAA reaction and provided good to excellent yield (80–95%) and enantioselectivity (70–90%) with a range of analogs.

Full text of DOI:10.1016/j.tetlet.2018.07.065

Accepted Manuscript
Palladium(0)-Catalyzed Rearrangement of Allyl Enol Ethers to Form Chiral
Quaternary Carbon Centers via Asymmetric Allylic Alkylation
Nazim Uddin, Mizzanoor Rahaman, Eduardo Alberch, Sharif A. Asad, M.
Mahmun Hossain
PII:
S0040-4039(18)30953-5
https://doi.org/10.1016/j.tetlet.2018.07.065
TETL 50174
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 July 2018
25 July 2018
28 July 2018
Please cite this article as: Uddin, N., Rahaman, M., Alberch, E., Asad, S.A., Mahmun Hossain, M., Palladium(0)-
Catalyzed Rearrangement of Allyl Enol Ethers to Form Chiral Quaternary Carbon Centers via Asymmetric Allylic
Alkylation, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.07.065
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Tetrahedron Letters
jo u r n a l h o m e p a g e : w w w . e ls e v ie r . c o m
Palladium(0)-Catalyzed Rearrangement of Allyl Enol Ethers to Form Chiral
Quaternary Carbon Centers via Asymmetric Allylic Alkylation
Nazim Uddin, Mizzanoor Rahaman, Eduardo Alberch, Sharif A. Asad, M. Mahmun Hossain
Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 N Cramer Street, Milwaukee, Wisconsin, 53211, USA.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein we report the first palladium(0)-catalyzed asymmetric allylic alkylation (AAA) of allyl
enol ether via π-allylpalladium intermediate using Trost chiral diphosphine. This unprecedented
reaction produced very rare α-aryl quaternary aldehydes with multi-functional groups. The main
novelty in the chemistry demonstrates that enol ethers can be used as precursors for π-
allylpalladium intermediates, an observation that is certainly rare and to the best of our
knowledge, perhaps without prior precedent. Chiral ligand (R,R)-L3 was found to be optimal in
this Pd-AAA reaction and provided good to excellent yield (80-95%) and enantioselectivity (70-
90%) with a range of analogs.
Available online
Keywords:
Acrylate
Enantioselectivity
Allylic alkylation
Asymmetric catalysis
All-carbon quaternary aldehydes
2009 Elsevier Ltd. All rights reserved.
Introduction
We developed
a
new procedure of synthesizing
arylhydroxyacrylates from simple aromatic aldehydes and ethyl
diazoacetate (EDA) in the presence of a Brønsted acid or iron
Lewis acid. We also found out that these substrates are very
useful precursors for the synthesis of indoles8 and furans9. Most
importantly, the presence of prochiral carbon centers in these
compounds allow us to synthesize chiral all-carbon quaternary
stereocenters.10
Ever since the first example of [3,3]-sigmatropic
rearrangement of an allyl enol ether was reported by Claisen in
1912,1 this reaction has been developed into one of the most
powerful C-C bond forming methods (Scheme 1).2 There are
numerous methods to carry out the Claisen rearrangement and
related [3,3]-sigmatropic rearrangements enantioselectively by
using chiral reagents.3 Overman et al. reported the first catalytic
enantioselective [3,3]-sigmatropic rearrangement for allyl-
imidates using a Pd(II) asymmetric catalyst.4 Yamamoto et al.
used chiral Lewis acids based on Al(III) for the enantioselective
Claisen rearrangement of acyclic, aliphatic allyl vinyl ethers.5
However, 1-2 equivalents of the chiral Lewis acid are required
and the scope of the reactions are limited to selective substrates.
Recently the Kozlowski group described Cu(II)- and Pd(II)-
catalyzed enantioselective Claisen rearrangement of allyloxy-
and propargyloxy-indoles to quaternary oxindoles and spirocyclic
lactones with excellent yield and enatioselectivity.6
Scheme 2. Phase transfer catalyzed reaction of ethyl 2-aryl-3-
hydroxyacrylates 1 provided mostly O-allylated product 2.
In order to synthesize all-carbon quaternary centers first we
investigated the allylation reactions of hydroxyacrylates with
allyl halides, as electrophilic counterparts, in bases such as solid
or aqueous KOH and NaOH using achiral Bu4NI or Bu4NBr as
the phase transfer catalyst (PTC). All of the reactions provided
exclusively O-allylation product 2 (Scheme 2).11 Reactions
carried out in the absence of a PTC resulted in very low yields of
product. The NMR studies (NOESY experiment) showed E-
stereochemistry of the double bond of O-allylated product,
presumably due to minimization of dipoles in an approximate
anti-parallel orientation between the oxygen of the allyl vinyl
Scheme 1. The Claisen rearrangement of an allyl enol ether
subsrates
———
 Corresponding author. Tel.: +1-414-229-6698; fax: +0-000-000-0000; e-mail: mahmun@uwm.edu

2
ether and the carbonyl oxygen of the ester. The O-allylation is
more favored because of the high degree of conjugation present
in the acrylate 1 is preserved during O-allylation, and it is
disrupted in C-allylation. Later, we observed the O-allylated
compound, allyl enol ether 2 undergoes the thermal Claisen
rearrangement reactions to provide all carbon quaternary
aldehydes in good yields.11
Pd(0) generated both the decarbonylated product 5 and the
quaternary aldehyde 6 in 75% and 15% yields, respectively
(Scheme 4). However, when the reaction was refluxed in DMF,
the compound 4 exclusively produced Claisen product 6. Based
on these observations whereas both 5 and 6 were detected as
products, it is likely that the Pd(0)-catalyzed reaction of 4 is
proceeding through
rearrangement.
a mechanism other than a Claisen
Results and discussion
Encouraged by the results from the thermal Claisen
rearrangement, we then turned our attention to the asymmetric
variant using chiral catalysts. In order to identify the desired
catalyst, allyl enol ether 2a as a test substrate, different chiral
Lewis acids3-6 along with some achiral Lewis acids have been
investigated. The results are summarized in Table 1. In this
study, we found that our catalytic rearrangement reaction resulted
either in no product being formed or, for stronger achiral Lewis
acids (entries 4 and 6), cleavage of the bond between the enolic
oxygen and the allylic carbon was occurred. Only low yields of
product have been observed (29% C-alkylated) for the Claisen
rearrangement with the [Cu(box)](SbF6)2 metal complex at
elevated temperature (60 °C) (entry 11).
Scheme 3. Pd(0) catalyzed rearrangement of allyl enol ether 2a.
In this palladium-catalyzed mechanism, we believe that the
strong nucleophilicity of Pd(0) and the stability of aryl acrylate
anion 8 are the driving forces for the formation of Pd-allyl
complex 7 from 4 (Scheme 4). The nucleophilic attack by the
acrylate anion 8 to π-allyl complex 7 could occur at symmetrical
and asymmetrical ends,12 providing compounds 9 and 6.
Compound 9 subsequently undergoes decarbonylation under the
reaction condition to form compound 5. A similar process such
as an allylic alkylation rather than a Claisen rearrangement is
occurring in Pd(0)-catalyzed reaction of compound 2 in the
formation of 3.
Table 1. Attempted Claisen rearrangement with Lewis acids.
entry
1
catalyst
Zn(OTf)2
ligand
BOX
BOX
BINAP
-
product
T (C)
-
-
rt
rt
rt
rt
2
3
4
5
Zn(SbF6)2
Ni(SbF6)2
-
PdCl2(CH3CN)2
1+2
Pd(dppf)Cl2
.CH2Cl2
-
-
rt to 50
6
7
BF3·OEt2
Fe(SbF6)2
-
PyBox
(R,R)-L3
-
1+2
rt
rt
-
8
[Rh(COD)Cl]2
(Cp*RhCl2)2
Cu(SbF6)2
-
50
9
-
rt to 50
rt
10
11
BOX
BOX
-
Scheme 4. Proposed mechanism of Pd(0) catalyzed reaction of
(Z)-ethyl 3-((E)-but-2-en-1-yloxy)-2-phenylacrylate 4.
Cu(SbF6)2
3a (29%)
60
Later, we directed our study to the asymmetric variant of this
Pd(0)-catalyzed allylic alkylation. To optimize the reaction
conditions for high asymmetric induction, we first attempted
investigating the effects of systematic variations of the ligand,
solvent, and temperature on enantiodiscrimination. For our ligand
screening, we selected C2 symmetric Trost diphenylphosphino
benzoic acid (DPPBA) ligands and phosphinooxazolines (PHOX)
ligands, which are well known for Pd(0)-catalyzed asymmetric
allylic alkylation reactions (Figure 1). It was demonstrated from
our studies that C2 symmetric Trost ligands (R,R)-L3, (R,R)-L4
are more effective in enantiodiscrimination than the PHOX type
ligand (S)-L2.
To our surprise, during investigation, we observed that allyl
enol ether 2a did go through a Pd(0)-catalyzed rearrangement to
give quantitative yield of the α-aryl quaternary aldehyde 3a
(Scheme 3). As a Pd(0) source both Pd(PPh3)4 and Pd2(dba)3.
CHCl3 were equally found to be effective in the catalytic
transformation. To understand the mechanism of this
arrangement, we investigated the reaction of the O-crotylated
compound 4 in the presence of Pd(0) (Scheme 4). The compound
4 was synthesized from arylhydroxyacrylate 1 and crotyl bromide
using the same procedure which was used for the preparation of
compound 2. Reaction of the O-crotyl compound 4 catalyzed by

Table 2. Selected optimization studiesa
entry
ligand
solvent
Tb
(°C)
conv.c
(%)
eed
(%)
1
2
3
4
5
6
7
8
9
(R,R)-L1
(R,R)-L1
(S)-L2
CH2Cl2
Tol:Hex (1:1)
Tol:Hex (1:1)
Tol:Hex (1:1)
Tol:Hex (1:1)
Toluene
rt
0
0
-20
rt
0
0
>99
>99
>99
90
20
0
Figure 1. Chiral ligands used for the optimization
(S)-L2
-20
rt
(R,R)-L3
(R,R)-L3
(R,R)-L3
(R,R)-L3
(R,R)-L3
30
50
33
65
83
Among the Trost ligands, DACH-napthyl Trost ligand, (R,R)-
L3 is the most effective. The highest level of enantioselectivity
were observed with the use of (R,R)-L3 (Table 2, entry 9 and 10)
and ANDEN-phenyl Trost (R,R)-L4 gave only 30% ee (Table 2,
entry 16) whereas with DACH-pyridyl ligand (R,R)-L1 there was
no reaction at all (Table 2, entry 1, and 2). Other ligands such as
phosphinooxazoline (PHOX), bis(oxaziline) (BOX), and (2,2'-
bis(diphenylphosphino)-1,1'-binaphthyl) (BINAP) did not yield
product at all and sometimes they were found less active in the
transformation, and in all cases they failed to induce any
enantioselectivity. After ligand screening, the effect of
temperature on reaction rate and enantioselectivity was
investigated. We did reaction by varying temperature from room
temperature to -78 °C. Our results showed that temperature also
has a profound effect in both yield and %ee. The reaction was
found to work best between -10 °C and -20 °C. We observed that
reaction at room temperature or at 0 °C, rate of the reaction were
faster but resulted in reduced enantioselectivity (Table 2, entries
3, 5, 13, and 15). At lower temperature (i.e., -40 °C or -78 °C)
there were no reactions at all (Table 2, entries 11 and 12). We
investigated the best yield as well as best enantiomeric excess at -
20 °C (Table 2, entry 9).
-20
-20
-20
-20
THF
90
Tol:Hex (1:1)
90
Tol : MeOH
(20:1)
95
10
11
12
(R,R)-L3
(R,R)-L3
(R,R)-L3
Tol : EtOH
(30:1)
-20
-40
-78
80
0
75
0
Tol : MeOH
(30:1)
Tol : MeOH
(30:1)
0
0
13
14
15
16
17
(R,R)-L3
(R,R)-L3
(R,R)-L3
(R,R)-L4
(R,R)-L4
CH2Cl2
ACN
rt
0
>99
>99
>99
70
Rac.
Rac.
20
Finally, we explored the reaction in different solvents. It was
mentioned that nonpolar aprotic solvents gave higher yields and
%ee of the product.13 During our observation of solvent screening
it was also revealed that nonpolar aprotic solvents gave higher
yields and % ee of the product (Table 2, entry 6) and at lower
temperature it was more effective (Table 2, entry 8). But with the
help of polar protic solvent such as methanol, it provided higher
yield and higher enantiomeric excess. Experimental results
showed solvent polarity played a major role in the reaction rate
and enantioselectivity; for instance, under similar reaction
condition the %ee in mixed solvent toluene:hexane (1:1) was
65% (Table 2, entry 8), whereas in the toluene:methanol (20:1),
the %ee jumped to 83% (Table 2, entry 9). The ideal solvent
polarity, toluene:methanol (20:1), afforded us with maximum
yield and enantioselectivity for our parent system comes from
mixed solvent. We believe a plausible explanation for this lies in
the solubility and complex formation of ligand and metal. In our
reaction pathway acrylate and palladium complex ion were
formed, so nonpolar solvents help to dissolve the ligand slowly to
form the metal complex, and the polar solvents has better
interaction with the substrate enolate in a ‘tight ion pair’
formation for a longer period of time over the course of the
reaction which were found in the reaction mechanism.
DMSO
rt
Tol:Hex (1:1)
CH2Cl2
-20
rt
0
>99
30
aThe reaction was performed with 2a (0.25 mmol) in solvent (5.0 mL). bOptimized
temperature for the best ee value and conversion. cDetermined by analysis of the
reaction mixture by 1H NMR spectroscopy. dDetermined by HPLC analysis by
using a chiral stationary phase.
In order to determine the scope of this rearrangement reaction,
a number of analogs were subjected to the newly optimized
reaction conditions (Table 3). In general, good to excellent yields
(80%-95%) and enantioselectivities (70-90%) were obtained.
Studies showed that electron donating substituents (3f, 3h)
appreciably affect the yields and enantioselectivities. These
groups make the acrylate ion electron rich and help to attack π-
allyl complex 7 to get higher yields and enantioselectivities (with
an exception of 3b) compare with electron withdrawing
substituents (3c-e). Surprisingly, the sterically bulky and hence
theoretically more challenging napthyl analog (3g) provided high
yield (90%) and good enantioselectivity (75% ee) as well.

4
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aAll reactions were performed on 0.25 mmol scale in solvent (5.0 mL). The yields
shown are those of the isolated products, and the %ee values were determined by
HPLC analysis using a chiral stationary phase.
Conclusion
In summary, we have developed palladium(0)-catalyzed
asymmetric allylic alkylation (AAA) of allyl enol ethers via π-
allylpalladium intermediate using Trost chiral diphosphine
ligand. In this process, syntheses of α-aryl quaternary aldehydes14
were achieved in high yields and moderate to high
enantioselectivies. To the best of our knowledge, we believe this
is the first example of allyl enol ethers rearrangement to create
chiral α-aryl quaternary aldehydes via AAA catalyzed by Pd(0).
Synthetic methodologies to access compounds containing α-aryl
groups to the quaternary carbon stereocenters are still rare. The
increasing appearance of these all-carbon α-aryl quaternary
stereocenters14,15,16 in a growing number of biologically active
natural products and pharmaceutical agents17 make this important
motif very demanding.
A. Supplementary data
Supplementary data associated with this article can be found,
in the online version, at
References and Notes
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2933. (c) Uozumi, Y.; Kato, K.; Hayashi, T. Tetrahedron: Asymmetry
1998, 9, 1065. (d) Cohen, F.; Overman, L. E. Tetrahedron:
Asymmetry 1998, 9, 3213. (e) Hollis, T. K.; Overman, L. E.
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Maruoka, K.; Banno, H.; Yamamoto, H. Tetrahedron: Asymmetry
1991, 2, 647.

6
Highlights



The first palladium(0)-catalyzed allylic
alkylation of enol ether.
Development of catalytic and enantioselective
reaction via π-allyl complex.
Quaternary aldehydes with multiple functional
groups were enantioselectively prepared.