Asymmetric Allylic Alkylation of Alkanoic-Acid Ester Enolates

Article abstract of DOI:10.1002/ejoc.201900822

A protocol for the direct palladium-catalyzed asymmetric allylic alkylation of simple alkanoic-acid esters through their lithium enolates has been developed. The method permits to create stereogenic centers in the homo-allylic or allylic position. The configuration of the allylation products has been elucidated.

Full text of DOI:10.1002/ejoc.201900822

A Journal of
Accepted Article
Title: Asymmetric Allylic Alkylation of Alkanoic-Acid Ester Enolates
Authors: Robin Visse, Martin-Alexander Möllemann, and Manfred
Braun
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900822
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Supported by

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Asymmetric Allylic Alkylation of Alkanoic-Acid Ester Enolates
[
a]
[a]
[a]
Robin Visse, Martin-Alexander Möllemann, and Manfred Braun*
th
Dedicated to Professor Hans-Ulrich Reißig on the occasion of his 70 birthday
Abstract: A protocol for the direct palladium-catalyzed asymmetric
allylic alkylation of simple alkanoic-acid esters through their lithium
enolates has been developed. The method permits to create
stereogenic centers in the homo-allylic or allylic position. The
configuration of the allylation products has been elucidated.
nonchelated enolates of simple alkanoic-acid esters has not
been disclosed so far. In this article, we describe our studies
aimed at palladium-catalyzed enantioselective allylic alkylations
of lithium enolates of carboxylic esters (Figure 1).
Introduction
The palladium-catalyzed asymmetric allylic alkylation, known as
‘
Tsuji–Trost reaction’ has developed into a highly efficient and
versatile method for enantioselective carbon–carbon bond
[1]
formation. For a long period, the reaction suffered however
from a limitation: It was restricted to stabilizes carbanions that
function as “soft” carbon nucleophiles. Guided by the idea that
the scope of the Tsuji-Trost reaction will be enhanced
considerably if it can be extended to nonstabilized, preformed
[
2]
enolates as nucleophiles, protocols for palladium- and iridium-
catalyzed asymmetric allylic alkylations of ketones through their
tin, silicon, magnesium and lithium enolates were elaborated
[3]
since the beginning of the 2000s. These procedures were
completed by decarboxylative variants that started from enol
carbonates or -keto-esters and permitted enantioselective
[4]
allylic alkylations as well. Several carboxylic-acid derivatives
[5]
[6]
like amides and lactones were successfully submitted to
asymmetric allylic alkylations through their preformed enolates,
and lactams were allylated using the asymmetric
Figure 1. Asymmetric allylic alkylations of esters and ester surrogates..
[7]
decarboxylative protocol. Even doubly deprotonated carboxylic
acids have been shown to function as suitable nucleophiles for Results and Discussion
[8]
stereoselective palladium-catalyzed allylic alkylations.
Prerequisite to any stereoselective -functionalization of
Among all the preformed enolates, those derived from carboxylic
esters are known as the most fragile and sensitive ones,
particularly due to their inherent tendency to decompose under
formation of ketene and alkoxide. Therefore, it is not surprising
that ester enolates were used as nucleophiles in Tsuji-Trost
reactions only reluctantly. So far, the only broadly applicable
protocols are based on chelated zinc enolates derived from -
alkanoic esters is the formation of the enolate in the desired
[
11]
configuration: cis and trans.
Fortunately, the seminal
contributions of Ireland and co-workers opened controlled routes
to generate either diastereomer by means of suitable reaction
.
[12]
conditions
The selectivity in enolate formation depends
[2]
however on the particular -substituent. For evaluating the
asymmetric allylic alkylation of ester enolates, we have chosen
methyl 3,3-dimethylbutyrate (1a) that is known to form the trans-
enolate in a highly selective manner (trans-2a:cis-2b = 97:3). In
previous studies on palladium-catalyzed reactions of allylic
carbonates with “hard” nucleophiles, we noticed that the
presence of lithium chloride was crucial to both reactivity and
enantioselectivity. Therefore, we had used the salt as an
additive to the reaction mixture. Feeling that using the salt in
over-stoichiometric amounts is rather uneconomical, we turned
to allylic chlorides 3 as a source for lithium chloride that forms
gradually as the reaction proceeds.
[9]
amino acids or peptides (‘Kazmaier enolates’). Whereas
several ester enolate equivalents like N-acyloxazolinones and 2-
acylimidazoles were applied in decarboxylative asymmetric
[
10]
allylic alkylations, the direct stereoselective allylic alkylation of
[
a]
Prof. Dr. M. Braun; Dr. R. Visse; M.-A. Möllemann
Institute of Organic and Macromolecular Chemistry
Heinrich-Heine-University Düsseldorf
Universitätsstr. 1, D-40225 Düsseldorf, Germany
E-mail: braunm@hhu.de
Homepage: http://www.ak-braun.hhu.de/
Thus, carboxylic ester 1a was deprotonated with LDA in THF
and the enolate mixture of trans-2a and cis-2b (97:3) was
allowed to react with allyl chloride (3a) in the presence of the
Supporting information for this article is given via a link at the end of
the document.
catalyst
precursor
tris(dibenzylideneacetone)dipalladium-
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European Journal of Organic Chemistry
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[
13b]
chloroform adduct and the ligands 4a-j (Scheme 1). We had
noticed previously that, in asymmetric allylation reactions of
ketone and lactone enolates, only axially-chiral biaryl-derived
4j developed recently by us.
With these ligands,
enantioselectivity reached 80% ee (entries 9 and 10) that could
further enhanced by lowering the reaction temperature to –
100 °C, without loss in the chemical yield.
bisphosphanes
provided
a
significant
degree
of
enantioselectivity. As a consequence, this type of ligands was
used for optimizing the allylation of ester 1a. The palladium-
catalyzed reaction was performed at –78 °C. In control
experiments, we had proved that in the absence of the noble
metal no reaction between the enolate and allyl chloride
occurred. The results of the optimization study, yields of the
allylated ester 5a, isolated by column chromatography, and
enantiomeric excess determined by chiral GC are shown in
Table 1.
Table 1. Optimization of the reaction conditions
Entry
Ligand
Allylation product 5a
a)
Configuration
Yield [%]
ee [%]
70
1
2
3
4
5
6
7
8
9
(R)-4a
(R)-5a
(R)-5a
(R)-5a
(R)-5a
(S)-5a
(S)-5a
(S)-5a
(S)-5a
(R)-5a
(S)-5a
54
(R)-4b
(R)-4c
(R)-4d
(S)-4e
(S)-4f
(S)-4g
(S)-4h
(R)-4i
(S)-4j
(R)-4i
(S)-4j
67
43
78
73
54
67
68
69
66
75
57
30
76
68
73
79
10
11
12
83
80
b)
(R)-5a
85
88
b)
(S)-5a
83
85
[
a] Isolated yield. [b] Reaction temperature: –100 °C.
Having evaluated the ether-bridged TUNEPHOS-type ligands 4i
and 4j as the most efficient ones for catalyzing the allylic
alkylation of methyl 3,3,-dimethybutyrate (1a), alkanoic esters
1
b-d were submitted to the same protocol. The results are
shown in Table 2. Under those deprotonation conditions, a high
preference for the formation of trans-enolates has been proved
[14]
or assumed based upon analogy.
The -isopropyl- and -
cyclohexyl-substituted esters 1b and 1c led to the formation of
allylation products 5b and 5c, respectively in remarkable
enantiomeric excess. On the other hand, the result with methyl
butyrate 1d is poor and the alkene 5d was formed in 30% ee
only. The protocol was also extended to cinnamyl chloride (3b)
Scheme 1. Enantioselective palladium-catalyzed allylic alkylation of carboxylic
ester 1a mediated by ligands 4a-j.
as allylic component. In this case,
a fair degree of
enantioselectivity in the formation of products (S)-5e and (R)-5e
was reached by using the ligands (S)-4j or (R)-4i, respectively.
The low isolated chemical yields of allylation products 5b and 5d
are caused mainly by their volatility that led to loss of material
upon the isolation.
The standard ligand (R)-BINAP (4a) (entry 1), the Cl-MeO-
BIPHEP-type ligands 4c and 4d (entries 3 and 4) as well as the
PHOS-type ligands 4e and 4f (entries 5 and 6) and SYNPHOS
[
12]
(4h) (entry 8) led to substantial, but not satisfying
We did not use cis-enolates for two reasons: Ireland’s studies
had shown that the selectivity for them is only moderate (2a:2b =
:91, and even lower for other alkanoic ester enolates).
enantioselectivities in the range of 70% ee. Remarkably, the
extension of the aryl groups at the phosphorus atom, realized by
tolyl-BINAP (4b) and xylyl-GARPHOS (4g) proved itself to be
deleterious and resulted in very moderate ee-values (entries 2
and 7). Optimum results however were obtained with Zhang’s
9
Furthermore, the formation of cis-ester enolates requires HMPA
or DMPU. Both are deleterious to the selectivity in our allylation
protocol, as they disrupt the aggregate of lithium enolate, lithium
chloride and allylpalladium, an arrangement that was postulated
[
13a]
C
3
-TUNEPHOS (4i)
and the bis-chloro-substituted analogue
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European Journal of Organic Chemistry
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FULL PAPER
to be responsible for high stereoselectivity in the allylation
[6]
step.
Table 2. Scope of the enantioselective allylic alkylation of -substituted
carboxylic esters 1.
Alkanoic Ester 1
Ligand
Allylation Product 5
Yield
ee
[%]
a)
[
%]
(
(
R)-4i
R)-4i
50
81
91
Scheme 2. Enantioselective formation of ,-disubstituted carboxylic esters 7.
90
As the absolute configuration of the allylation products 5a-5e
was unknown, it was determined unambiguously by chemical
correlation. First, pentenoic ester 5a, obtained in 70% ee by
allylic alkylation with the ligand (S)-4j, was submitted to an
ozonolysis, followed by oxidation with sodium chlorate and
subsequent esterification. The comparison of the optical rotation
(
R)-4i
50
30
[15]
of succinate (+)-8 with the data described in the literature
revealed the compound (+)-8 and, consequently, the allylation
product (+)-5a to be (S)-configured (Scheme 3).
[
b]
(
(
S)-4j
R)-4i
86
79
75
[
b]
79
)
[
a] Isolated yield. [b] Allylation reagent: (E)-PhCH=CHCH
2
Cl (4b)
After the protocol reported has been found to be appropriate for
introducing a stereogenic center in the homoallylic position, we
were interested whether the procedure is also suitable to create
an allylic stereocenter in an enantioselective manner. For this
purpose, we submitted ,-disubstituted carboxylic esters 6a-c
to the palladium catalyzed reaction with dimethylallyl chloride
(3c). When, however, catalyzed by TUNEPHOS ligands 4i or 4j,
the reaction occurred in an unsatisfying manner in terms of
chemical yield and enantioselectivity, indicating that this type of
ligands is unsuitable for 1,3-disubstituted allyl palladium
complexes. Fortunately, (S)-xylyl-GARPHOS (4g) proved itself
as much more efficient and catalyzed the formation of the
allylation products 7 in fair to high enantioselectivity, as shown in
Scheme 2.
Scheme 3. Conversion of carboxylic esters 5 into succinate 8 and lactones 9
for determination of the absolute configuration.
Furthermore, all the carboxylic esters 5a-5e, obtained by the
allylation protocol with (R)-configured ligands 4 were converted
into -butyrolactones 9a-d by ozonolysis followed by reduction
and cyclization under acidic conditions. Lactones (S)-()-9b and
[16]
(
R)-(–)-9d have been described in the literature. Positive sign
of optical rotation was observed for lactones 9b and 9d that
resulted from allylation products 5b and 5d, both prepared with
ligand (R)-3i (see Table 1) Thus, the configurations were
assigned as (R)-(+)-9b and (S)-(+)-9d to the lactones and,
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European Journal of Organic Chemistry
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based thereupon, (R)-(–)-5b and (S)-(–)-5d to the allylated
the preparation of succinate 8 and lactones 9 are given in the Supporting
Information.
[17]
esters (Scheme 3).
In order to confirm the homo-chirality of
all the carboxylic esters obtained with (R)-configured ligands 4,
the CD spectra of the corresponding lactones were measured
and displayed the same sign of Cotton effects (see Supporting Acknowledgments
Information). The configuration of carboxylic esters 7a-7c
carrying the stereogenic center in the allylic position was
This
work
was
supported
by
the
Deutsche
assigned to be R by analogy to the stereochemical outcome
observed with lactone enolates.
Forschungsgemeinschaft (Br 604/16-1/16-2/16-3).
[6a]
.
Conclusions
Keywords: Catalysis • Enantioselectivity • Lithium •Palladium •
Synthetic methods.
In summary, we have elaborated a protocol that enables a
palladium-catalyzed asymmetric allylic alkylation of lithium
enolates derived from simple alkanoic-acid esters. This direct
method can be considered an alternative to detours that are
based on ester surrogates. The protocol permits to create
stereogenic centers in the homo-allylic or allylic position,
depending on the substrates chosen. The configuration of the
allylation products was elucidated.
[
1]
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A dry 100-mL two-necked flask, equipped with a magnetic stirrer, was
charged with [Pd (dba) ] CHCl (12.5 mg; 12.4 µmol) and 50 µmol of the
2 3 3
.
corresponding ligand 4. The flask was closed with a septum, connected
to a combined nitrogen/vacuum line, evacuated and filled with nitrogen.
Then, dry THF (20 mL) was added by syringe. After chloride 3 (5.5 mmol)
had been injected, the resulting solution rapidly turned yellow and was
cooled down to –78 ºC.
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A second 100 mL two-necked flask with a connection to the combined
nitrogen/vacuum line was equipped with a magnetic stirrer and a
resistance low-temperature thermometer (introduced through a septum).
The flask was three times evacuated and refilled with nitrogen. Into this
flask, diisopropylamine (0.71 mL, 5.0 mmol) and dry THF (5 mL) were
injected. After cooling to –78 °C, n-butyllithium (1.6 M in n-hexane, 3.1
mL, 5.0 mmol) was added dropwise by syringe; at such a rate that the
temperature did not exceed –70 °C. After stirring at 0 °C for 30 min, the
mixture was cooled to -78 °C and the corresponding ester 1 or 6 (5.0
mmol) was injected by syringe. Stirring was continued at –78 °C for 1 h.
2
2
6
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means of a cannula while maintaining a slight nitrogen overpressure in
the first flask, whereas the second one was slightly evacuated. After the
combination of the two mixtures had been completed at –78 °C, stirring
was continued at the same temperature for 24. Then, the mixture was
poured into a saturated aqueous solution of ammonium chloride and
extracted with diethyl ether (three 20-mL portions). The combined
organic layers were dried with magnesium sulfate, and the solvent was
removed in a rotary evaporator. The crude product was purified by
column chromatography or fractional distillation.
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[
[
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cf. ref.12].
[
[
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5d and 9d is a formal one, due to priority change of the substituents at
the stereogenic center.
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European Journal of Organic Chemistry
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Entry for the Table of Contents
FULL PAPER
Lithium - Palladium
Robin Visse, Martin-Alexander
Möllemann, Manfred Braun*
Page No. – Page No.
Asymmetric Allylic Alkylation of
Alkanoic-Acid Ester Enolates
The palladium-catalyzed enantioselective allylic alkylation of nonstabilized lithium
enolates is a long-standing problem in asymmetric syntheses. A protocol based
upon suitable reaction conditions and appropriate ligands enables the asymmetric
allylation of alkanoic-acid esters through their lithium enolates in a direct manner
that does not require detours via ester surrogates. Thus, stereogenic centers can
be created either in allylic or homo-allylic position.
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