Evidence for a non-concerted, dissoziative mechanism of the palladium-catalyzed enolate Claisen rearrangement of allylic esters

Article abstract of DOI:10.1002/ejoc.201000874

In an enolate Claisen rearrangement, deprotonated allyl phenylacetate undergoes a smooth conversion at -78 °C to 2-phenyl-4-pentenoic acid under palladium(O) catalysis. By using labelled starting materials in crossover experiments, the reaction is shown to follow a dissoziative, non-concerted, non-[3,3]-sigmatropic mechanism that involves palladium complexes and carboxylic-acid dianions as intermediates.

Full text of DOI:10.1002/ejoc.201000874

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000874
Evidence for a Non-Concerted, Dissoziative Mechanism of the Palladium-
Catalyzed “Enolate Claisen Rearrangement” of Allylic Esters
Manfred Braun,*[a] Panos Meletis,[a] and Wolfgang Schrader[b]
Keywords: Allylation / Enantioselectivity / Ion pairs / Lithium / Homogeneous catalysis
In an enolate Claisen rearrangement, deprotonated allyl
phenylacetate undergoes a smooth conversion at –78 °C to
2-phenyl-4-pentenoic acid under palladium(0) catalysis. By
using labelled starting materials in crossover experiments,
the reaction is shown to follow a dissoziative, non-concerted,
non-[3,3]-sigmatropic mechanism that involves palladium
complexes and carboxylic-acid dianions as intermediates.
postulated intermediate 2, the [3,3]-sigmatropic, intramo-
lecular course is maintained. When, however, allylic acet-
ates are rearranged in the presence of palladium(0) cata-
lysts, a dissociation occurs with formation of a cationic al-
lylpalladium complex 3.[10] taking advantage of the readily
replaced leaving group acetate. This mechanism has been
assumed for various palladium(0)-mediated Claisen-type re-
arrangements of allyl phosphoro and phosphonothiona-
tes[11a] and allyllic esters of N-alkylidene glycine[11b] as well
as the allylic allylation through allyl enol carbonates,[12]
originally reported by Tsuji.[12a]
Introduction
The Claisen rearrangement, diversified in various vari-
ants, is one of the most versatile and powerful reactions that
permit carbon-carbon bond formations.[1] The questions of
the mechanism and the exact nature of the transition state
with its stereochemical implications have been studied thor-
oughly, and it is generally accepted that the Claisen re-
arrangement of allyl vinyl ethers as well as the Ireland–
Claisen and the enolate Claisen rearrangement follow a
concerted, albeit asynchronous, [3,3]-sigmatropic path.[2] It
is not surprising that intense efforts have been directed
towards a metal catalysis for these reactions.[3] This ap-
proach has become particularly efficient when chiral metal
complexes were used to bring about enantioselective
Claisen-type rearrangements starting form prochiral pre-
cursors.[4] Aside from main group metal based Lewis-acidic
salts and complexes, copper and, in particular, palladium
catalysts enjoyed manifold applications.[5] The activation by
the late transition metals has been attributed to a coordina-
tion of the carbon-carbon π-bonds in the transition state
model 1,[4,5c] illustrated for palladium(II) in Scheme 1.
However, the concerted course of palladium(II)-mediated
Claisen rearrangements is challenged by the cyclization-in-
duced rearrangement mechanism[5a] (Scheme 1) that was
first proposed by Winstein[6] and supported by Henry[7]
when explaining the palladium(II)-induced rearrangement
of allylic acetates. This mechanism postulates a σ-palladium
intermediate 2,[3a,5a] an idea that has not only been adopted
to the palladium(II)-mediated rearrangement of allyl vinyl
ethers[3a,5a] and allyl imidates,[8] but also to the Ireland–
Claisen rearrangement of silyl ketene acetals.[9] Despite the
Scheme 1. Mechanisms of palladium-catalyzed Claisen rearrange-
ments.
The so-called simple-enolate Claisen rearrangement
(Scheme 2) differs from the Ireland–Claisen rearrangement
and is defined as the reaction of enolates derived from al-
lylic esters, wherein the enolate-counterion is an alkali or
an earth alkali metal.[13a] A concerted course has been pos-
tulated for this reaction as well as for the related chelate-
enolate Claisen rearrangement.[13b] When, however, the lat-
[a] Institut für Organische Chemie und Makromolekulare Chemie,
Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf,
Germany
Fax: +49-211-8115079
E-mail: braunm@uni-duesseldorf.de
[b] Max-Planck-Institut für Kohlenforschung,
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany ter reaction was mediated by palladium, an intermolecular
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M. Braun, P. Meletis, W. Schrader
SHORT COMMUNICATION
course was shown to occur.[14] To the best of our knowl- Ireland–Claisen version, the palladium-mediated simple-
edge, the influence of palladium(0) complexes on the enolate rearrangement is not a [3,3]-sigmatropic shift.
Claisen rearrangement of simple, non-stabilized enolates
Then, the question of an intramolecular vs. intermo-
has not been reported. Therefore, we have studied the re- lecular mechanism was investigated by a crossover experi-
arrangement of lithium enolates generated by deproton- ment that started from equal molar amounts of dideuter-
ation allyl phenylacetate in the presence of palladium(0) ated ester 4-d2 of phenylacetic acid and non-deuterated allyl
catalysts.
(4-chlorophenyl)acetate 8. The mixture was deprotonated to
give the corresponding lithium enolates and treated with
[Pd2(dba)3]·CHCl3 (0.5 mol-%), (S)-6a (2 mol-%) and lith-
ium chloride (2.4 equiv.) following the protocol described
above. Prior to the mass spectrometric analysis, whose re-
sult is shown in Scheme 4, the crude mixture of carboxylic
acids was transferred into the methyl esters 9 and 10 by
treatment with trimethylsilyl diazomethane. GC–MS analy-
sis of the crude methyl esters revealed the formation of a
mixture of 9a–c and 10a–c. In the rearranged products 9a–
c with the 4-chlorophenyl substituent, the distribution of
deuterated 9a/9b to non-deuterated 9c was found to be
50Ϯ4:50Ϯ4. Correspondingly, the deuterated and non-
deuterated esters 10a/10b and 10c, respectively, were ob-
tained in essentially the same ratio of 45Ϯ4:55Ϯ4 The
scrambling of the labels, deuterium and the para-chloro
substituent, in the products clearly excludes an intramolecu-
lar mechanism for the palladium(0)-catalyzed simple-enol-
ate Claisen-rearrangement.
Scheme 2. The simple-enolate Claisen rearrangement of allylic
esters: M = Li, Na, MgX.
Results and Discussion
The [3,3]-sigmatropic character of the rearrangement was
studied first. For this purpose, dideuterated allyl phenyl-
acetate 4-d2 (Scheme 3) was deprotonated with lithium di-
isopropylamide in THF in the presence of lithium chloride
to give the lithium enolate 5-d2. When left at room tempera-
ture overnight, no reaction took place and unchanged ester
4-d2 was re-isolated in quantitative yield.[15] However, when
the lithium enolate was treated with [Pd2(dba)3]·CHCl3
(0.5 mol-%) and (S)-BINAP (6a) (2 mol-%), again in the
presence of lithium chloride, the formation of 2-phenyl-4-
pentenoic acid occurred at –78 °C. NMR analysis revealed
a scrambling of the deuterium labels: Thus, 3,3-dideuterated
and 5,5-dideuterated acids 7a and 7b, respectively, resulted
as a 1:1 mixture in 73% combined yield. In addition, minor
amounts of phenylacetic acid and tetradeuterated allyl 2-
phenyl-4-pentenoate were detected by GC analysis. For
reasons of comparison, the Ireland–Claisen variant was ap-
plied to the lithium enolate 5-d2 as well. Addition of chloro-
trimethylsilane and warming to room temperature led, as
expected, to 5,5-dideuterated acid 7a exclusively after acidic
work up. Thus it was concluded that, in contrast to the
Scheme 4. Crossover experiment of the palladium-catalyzed re-
arrangement of lithium enolates of allylesters 4-d2 and 8. Reagents
and conditions: a) LiN(iPr)2, THF, –78 °C; b) [Pd2(dba)3]·CHCl3
(0.5 mol-%), (S)-6a (2 mol-%), LiCl (2.4 equiv.), THF, –78 °C; then:
NH4Cl, H2O; c) Me3SiCHN2.
The stereochemical outcome of the palladium-mediated
enolate Claisen rearrangement was studied with allyl phen-
ylacetate (4) through the lithium enolate 5 and mediated
with (S)-Cl-MeO-BIPHEP (6b) as chiral ligand. As shown
in Scheme 5, (S)-2-penyl-4-pentenoic acid (7) was obtained
in 25% ee, determined by comparison of the optical rota-
tion with that described in the literature[16] and chiral GC
of the methyl ester, generated from acid 7 by treatment with
trimethylsilyl diazomethane. In addition to the rearranged
Scheme 3. Palladium-catalyzed enolate Claisen rearrangement of
deuterated allyl phenylacetate 4-d2. Reagents and conditions: a) Li-
N(iPr)2, THF, –78 °C; b) [Pd2(dba)3]·CHCl3 (0.5 mol-%), 6a
(2 mol-%), LiCl (2.4 equiv.), THF, –78 °C; then: NH4Cl, H2O.
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Pd-Catalyzed “Enolate Claisen Rearrangement” of Allylic Esters
product 7 obtained in 75% yield, phenylacetic acid 11 and
ester 12 were formed in 12.5% yield each, according to GC–
MS analysis.
Scheme 5. Enantioselective formation of carboxylic acid 7 by palla-
dium-catalyzed enolate Claisen rearrangement. Formation of by-
products 11 and 12. Reagents and conditions: a) LiN(iPr)2, THF,
–78 °C; b) [Pd2(dba)3]·CHCl3 (0.5 mol-%), (S)-6b (2 mol-%), LiCl
(2.4 equiv.), THF, –78 °C; then: NH4Cl, H2O.
Scheme 6. Proposed mechanism of the palladium-catalyzed lithium
enolate Claisen rearrangement of allyl phenylacetate (4).
A mechanism that is suitable to explain the results de-
scribed above is proposed in Scheme 6. It is assumed that
the ester enolate 5, upon exposure to palladium(0), dissoci-
ates into an allylpalladium complex 13 and the “dianion”
14. It has been shown that in the presence of lithium chlo-
ride, cationic η3-palladium complexes 13 are converted into
neutral η1 complexes 15.[17] Based thereupon, we postulate
an equilibrium between the palladium complexes 13 and
15 to lie on the side of the latter. Concomitantly with the
formation of the neutral complex 15, the dilitiated carbox-
ylic acid 16 is generated. The species of carboxylic-acid di-
anions is well know to result from double deprotonation of
carboxylic acids.[18] Palladium complex 15 and dilithiated
phenylacetic acid 16 will combine under carbon-carbon-
Conclusions
In summary, we have shown for the first time that lith-
ium-enolate Claisen rearrangements can be successfully me-
diated by palladium catalysis so that they smoothly occur
even at –78 °C. The reaction has been shown not to follow
a concerted, [3,3]-sigmatropic route. Instead, a non-con-
certed, dissoziative mechanism applies. Stereoselective ap-
plications of this novel variant of the enolate Claisen re-
arrangement are going to be developed.
bond formation to give the lithium carboxylate 17 that Experimental Section
yields 2-phenyl-4-pentenoic acid (7) as the major product
Procedure for the Palladium-Catalyzed Enolate Claisen Rearrange-
upon aqueous acidic workup. In the η3-η1-equilibrium of
13 and 15, neither terminus of the allyl moiety is preferred,
so that the observed scrambling of the deuterium labels be-
tween 7a and 7b becomes evident. The result of the cross-
ment of Allyl Phenylacetate 4: A 100-mL two-necked flask was
equipped with a magnetic stirrer and charged with [Pd2(dba)3]·
CHCl3 (25.9 mg; 25 µmol), (S)-Cl-MeO-BIPHEP [(S)-6b]
(65.8 mg; 101 µmol) and LiCl (0.51 g; 12 mmol). The flask was
over experiment (Scheme 4) is explained by a dissociation of closed with a septum, connected to a combined nitrogen/vacuum
line, evacuated for 4 h at 25 °C in order to remove traces of water
from the lithium salt, and filled with nitrogen. To this flask was
added dry THF (30 mL) and the resulting solution was cooled
down to –78 °C. A 100-mL two-necked flask was equipped with a
magnetic stirrer, a connection to the combined nitrogen/vacuum
line and a resistance low-temperature thermometer that was intro-
duced through the septum. The flask was evacuated and refilled
with nitrogen three times. Into this flask diisopropylamine (0.7 mL;
5.0 mmol) and 40 mL of dry THF were injected. After cooling to
–78 °C, a 1.6  solution of butyllithium in n-hexane (3.1 mL;
the ion pair 13 and 14 or neutral complex 15 and dilithiated
species 16, where the individual partners escape from the
solvent cage. The postulated palladium complex 15 can –
to a minor extent – combine with the ester enolate 5 – an
assumption that explains not only the formation of the ester
12 containing two allyl moieties, but also the formation of
phenylacetic acid: as a part the palladium complexes
switched to ester enolate 5, the forsaken original partner,
the dianion 14, is finally hydrolyzed to phenylacetic acid.
The presence of lithium chloride may also enhance the reac- 5.0 mmol) was added dropwise by syringe, while keeping the tem-
perature below –70 °C. After stirring at 0 °C for 30 min, the mix-
ture was cooled again to –78 °C and a solution of allyl phenylacet-
ate 4 (0.85 mL; 5.0 mmol) in 5 mL of dry THF was injected by
syringe. In the course of the addition, the internal temperature of
the solution was not allowed to exceed –70 °C. This solution was
stirred for 1 h at –78 °C and then transferred through a cannula
into the first flask, which was cooled also to –78 °C. After stirring
at –78 °C for 40 h, the mixture was poured into a saturated solution
of ammonium chloride (100 mL) and acidified with 2  sulfuric
acid. The aqueous layer was extracted three times with 50-mL por-
tions of diethyl ether. Then the combined organic layers were ex-
tivity of the doubly deprotonated carboxylic acid due to the
known influence on the aggregation of lithium halides on
lithium enolates.[19] Indeed, the palladium-mediated re-
arrangement of the lithium enolate 5 does not occur in the
absence of lithium chloride at –78 °C but requires enhance-
ment of the temperature to 0 °C conditions that lead to an
almost complete loss of enantioselectivity. These results are
in accordance with the crucial role, lithium chloride was
found to play in the enantioselective palladium-catalyzed
allylic alkylation of ketone enolates.[20,21]
Eur. J. Org. Chem. 2010, 5369–5372
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M. Braun, P. Meletis, W. Schrader
SHORT COMMUNICATION
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tracted with 75 mL of a 20% aqueous solution of potassium car-
bonate. Thereafter, the aqueous layer was acidified with 6  sulfuric
acid to pH = 1–2 and re-extracted with diethyl ether (3ϫ50 mL).
The resulting combined organic layer was dried with magnesium
sulfate, filtered, and concentrated under reduce pressure. The re-
sulting yellow crude product, which contained the acid 7 in 75%
yield according to GC analysis, was purified by chromatography
on silica gel to afford an analytically pure sample of (S)-2-phenyl-
4-pentenoic 7 acid as white solid. Rf = 0.42 (n-hexane/ethyl acetate,
3:1 and a few drops acetic acid). [α]2D5 = +24 (c = 1, acetone) [Lit.[16]
1
+ 102.5 for (S)-7]. H NMR (500 MHz, CDCl3): δ = 2.5–2.6 (m, 1
3
H, 3-H), 2.8–2.9 (m, 1 H, 3-H), 3.6 (t, JH,H = 7.7 Hz, 1 H, 2-H),
3
3
5.0 (d, JH,H = 10.4 Hz, 1 H, cis 5-H), 5.1 (d, JH,H = 17.0 Hz, 1
H, trans 5-H), 5.7–5.8 (m, 1 H, 4-H), 7.3–7.4 (m, 5 H, Ph) ppm.
13C NMR (125 MHz. CDCl3): δ = 37.5, 51.7, 117.7, 128.0, 128.5,
129.1, 135.3, 138.2, 179.6 ppm. GC column: DN-GAMMA
25 mϫ0.25 mmϫ0.25 µ, column temperature 85 °C, flow 1.5 mL/
min [(S)-7 tR = 52.03 min, (R)-7 tR = 53.29 min].
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Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG) (Br-604/16, 1-2).
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Received: June 17, 2010
Published Online: August 24, 2010
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Eur. J. Org. Chem. 2010, 5369–5372