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TsujiЦTrost Allylic Alkylation with Ketone Enolates.

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DOI: 10.1002/anie.200602169
Asymmetric Synthesis
Tsuji–Trost Allylic Alkylation with Ketone Enolates
Manfred Braun* and Thorsten Meier
chirality · homogeneous catalysis · palladium ·
stereoselectivity · substitutions
The palladium-catalyzed allylic substitution with carbon nucleophiles, first
discovered by Tsuji and thoroughly
developed by the research group of
Trost, turns out to be a very fruitful
and versatile method for carbon–carbon
bond formations. In general, the reaction starts with an allylic substrate 1
(usually an acetate or carbonate) that,
upon treatment with a suitable palladium(0) compound, forms a p-allyl complex 2 (Scheme 1). Thereby, the transi-
Scheme 1. “Standard” enantioselective version
of the Tsuji–Trost allylation.
tion metal adopts the + 2 oxidation
state, and the allyl moiety becomes a
strong carbon electrophile. In the subsequent reaction with the carbon nucle-
[*] Prof. Dr. M. Braun, Dr. T. Meier
Institut f5r Organische Chemie und
Makromolekulare Chemie I
Universit8t D5sseldorf
Universit8tsstrasse 1
40225 D5sseldorf (Germany)
Fax: (+ 49) 211-81-15079
ophile, the allylation products 3 are
obtained under concomitant liberation
of the noble metal in the oxidation
state 0, thus closing the catalytic cycle.[1]
Various chiral ligands L* have been
developed which direct the attack of the
nucleophile to one of the diastereotopic
termini in the p-allyl complex 2, so that
the alkenes 3 and ent-3 can be obtained
from racemic starting material 1 in an
enantioselective manner. Moreover, solutions to the problem of regioisomer
formation arising from substrates 1 with
nonidentical residues R have been reported more recently.[2]
Despite the impressive progress this
reaction has made since the 1970s, it has
continued to suffer from a significant
drawback: the limitation in the type of
carbon nucleophile. Thus, “soft” carbanions derived from carbon acids with
pKa values lower than 20 were used
almost exclusively, and the combination
of malonates with diphenylallyl acetate
1 (R = Ph) became a kind of standard
procedure in palladium-catalyzed allylations, particularly for evaluating the
performance of chiral ligands L*. It is
obvious that, in this combination, just
one stereogenic center is formed in the
allylic position. If, however, the formation of stereogenic centers in the homoallylic position (R2 ¼
6 R3, R4 = H) or in
both the allylic and the homoallylic
position (R2 ¼
6 R3 , R 4 ¼
6 H) is the target,
as outlined in the retrosynthetic synthesis for alkenyl ketones 4 (Scheme 2),
the nucleophilic reagents of choice are
preformed “hard” metal enolates 5.
The chemistry of preformed enolates on the one hand and the TsujiTrost reaction on the other hand
emerged and evolved at the same time,
since the 1970s.[3] Surprisingly, however,
only very few attempts were made to
combine both concepts. It seems that,
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Scheme 2. Retrosynthesis of alkenyl ketones 4
based on preformed enolates 5 and allylpalladium complexes. R1 = alkyl, aryl; R2–R5 = H,
alkyl, aryl.
owing to early disappointing results,
organic chemists avoided attempts to
carry out palladium-catalyzed allylation
reactions with preformed “hard” enolates. The few approaches did not have
much success[4a] or remained unnoticed.[4b,c] Stereoselective variants of this
transformation, in particular, had not
been developed until the beginning of
this decade.[5]
In 1999, the first enantioselective
allylic alkylation of a nonstabilized ketone enolate was reported by Trost and
Schroeder.[6a] Thus, the tin enolate 7 b,
generated from 2-methyl tetralone (6),
was submitted to a palladium-catalyzed
allylation that was mediated by the C2symmetric ligand 8 (Scheme 3). Thereby, ketone (R)-9 was obtained in 88 % ee
and 99 % yield when the ligand (S,S)-8,
which causes the allylpalladium intermediate to attack the enolate from its
Si face, was used.
This stereochemical outcome is
plausibly explained by the simplified
“mnemonic” illustration of the C2-symmetric ligand (S,S)-8 in the lower portion of Scheme 3. It is quite clear that
the disfavored topicity involves substantial steric hindrance. The protocol has
been applied to different allylic subAngew. Chem. Int. Ed. 2006, 45, 6952 – 6955
enolate gave the optimum results when
the reaction with diphenylallyl acetate
1 a was mediated by the binap–palladium complex, as shown in Scheme 4. The
syn diastereomer 10 a formed predominantly, and an enantiomeric excess of
99 % ee resulted.
Scheme 3. Enantioselective allylation of 2methyl tetralone (6) mediated by the C2-symmetric ligand 8.
Scheme 4. Diastereo- and enantioselective
allylation of cyclohexanone enolates.
strates as well as various six- and fivemembered ketone rings.[6] In all cases,
the carbonyl compounds featured an amethyl substituent, thus avoiding a later
racemization that would inevitably occur as a result of the excess of base
(lithium diisopropylamide). Moreover,
the ketones that were used did not
contain hydrogen substituents in the
a’ position so that double allylation
was excluded. The research groups of
Trost[6] as well as Hou and Dai[7a] were
able to demonstrate that the enantioselective allylation of methyl tetralone 6 is
also feasible through the lithium enolate
7 a by using different chiral ligands at
the palladium center.
The first diastereoselective and
enantioselective allylic alkylation of cyclohexanone was reported by us in
2000.[8] It turned out that the magnesium
The reaction could be extended to
the dimethyl-substituted analogue 1 b.
In this case, a more reactive enolate was
necessary because of the more sluggish
electrophile. Thus, the combination of
the lithium enolate and lithium chloride
turned out to be the suitable reagent,
thus leading to the formation of the
allylation product 10 b in a syn/anti
diastereomeric ratio of 97:3, whereby
the predominant diastereomer formed
in 96 % ee.[9a] Lithium enolates of acyclic
ketones have been found to be suitable
nucleophiles for palladium-catalyzed allylic substitution reactions as well.[8] To
obtain high stereoselectivity in the allylation process, control of the enolate
geometry is necessary, and addition of
silver salts is advantageous.[7b]
The research group of Hartwig recently presented a solution to the prob-
Angew. Chem. Int. Ed. 2006, 45, 6952 – 6955
lem of regio- and enantioselective allylation of nonstabilized ketone enolates.[10] If the formation of the branched
product 14 instead of the thermodynamically more stable linear product 15 is
the target in nucleophilic substitutions
on nonsymmetrically substituted allylic
substrates like 12, iridium rather than
palladium complexes are preferential.
Thus, enolsilanes 11 derived from aryl
methylketones were allowed to react
with carbonates 12 in the presence of
catalysts that were generated from [{Ir(cod)Cl}2] and several phosphoramidites, of which the C2-symmetric ligand
13 gave optimum results. The reactive
enolate was generated from the enolsilanes 11 by treatment with a mixture of
cesium fluoride and zinc fluoride
(Scheme 5). The branched products 14
Scheme 5. Regio- and enantioselective iridium-catalyzed allylation of fluoride-activated
enolsilanes 11.
were obtained predominantly, and their
enantiomeric excesses ranged from 91 to
96 % ee (ratio of regioisomers 14/15
between 85:15 and 99:1). Concerning
the reactive nucleophile, it remains uncertain whether a cesium, zinc, or hypervalent silicon enolate plays that role.
An elegant solution to the problem
of the enantioselective allylic alkylation
of nonstabilized enolates relies on their
in situ generation. Thus, the research
groups of Stoltz[11] and Trost[12] have
independently shown that allyl enol
carbonates can serve as suitable enolate
precursors. The method, which has been
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
applied to various cyclic[11, 12a,b] and acyclic[12c] ketones, is illustrated for the
enantioselective allylation of 2-methylcyclohexanone in Scheme 6. Thus, treatment of the enol carbonate 16 with a
chiral catalyst, generated from [Pd2(dba)3]·CHCl3 and phosphanes such as
8, 20, or 21, leads to the formation of the
allylated ketone 18 (up to 88 % ee).
Obviously, the allylpalladium complex
is formed initially under liberation of
the enol carbonate anion, which spontaneously undergoes decarboxylation.
Through the advantage of CO2 formation as a driving force of the reaction,
the ion pair 17 is formed. The combination of the enolate anion and allylpalladium complex in 17 leads to the allylation product 18. Crossover experiments
have shown the intramolecular course of
the reaction, so that only minor leakage
from the caged contact ion pair occurs.[12a] On the other hand, a scrambling of
the deuterium label was observed when
selectively deuterated allyl enol carbonates were submitted to the palladiummediated reaction, a result that led the
authors to postulate a “discrete ketone
Another kind of precursor for the
in situ generation of enolates are allyl b-
keto esters, whereby the formation of
carbon dioxide again serves as the driving force.[12b, 13] As a representative of
recently developed enantioselective variants,[11b, 12b, 13] the allylation of allyl bketoester 19[12b] is outlined in Scheme 6.
A remarkable insight into the nature
of the enolate species comes from the
stereochemical outcome of the different
allylation protocols. As shown in
Scheme 3, the tin (and also the lithium)
enolates 7 are attacked predominantly
from the Si face when the reaction is
mediated by the ligand (S,S)-8. This
lk topicity is, however, reversed when
the corresponding enol carbonate is
used as a substrate. In this case, the
allylpalladium species approaches the
enolate in a ul manner from the Si face,
provided that the R,R-configured ligands 8 or 20 are used. The opposite
stereochemical outcome implies that
different mechanisms are operating: on
the one hand, a lithium or tin enolate
reacts with an allylpalladium complex
or, on the other hand, an enolate anion
and allylpalladium cation combine in a
caged pair 17. For the allylation through
b-ketoesters, a reductive elimination of
the palladium center bound to the allyl
moiety and the enolate oxygen atom has
Scheme 6. Enantioselective allylation through in situ generation of enolates from enol carbonates and allyl b-keto esters. L* = (R,R)-8, (R,R)-20, (R)-21, or (S)-21.
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
been proposed as the carbon–carbon
bond-forming step.[12b]
At a glance, the enantioselective
allylation of simple ketones[14] such as
cyclohexanone appears to be rather
facile. As there is no restriction, however, that prevents double allylation and
particularly subsequent racemization of
the product, the simplicity of the cyclohexanone substrate makes it the most
challenging. Nevertheless, the allylation
through the enol carbonate 22 yields
allylcyclohexanone (R)-23 in 78 % ee
when mediated by the ligand (R,R)-20.
Moreover, we have recently been able
to show that the simple lithium enolate
of cyclohexanone can be allylated to
give the ketone (S)-23 in up to 98 % ee
(Scheme 7).[9b] A prerequisite to this
reaction, which is mediated by the
ligand (S)-24, is the presence of lithium
These results clearly demonstrate
that the combination of allylpalladium
and preformed enolate chemistry provides a new tool for synthetic chemists.
The elaboration of this concept will be
followed by applications in the syntheses of drugs and natural products. Thus,
students in advanced chemistry courses
should no longer be taught that the
Scheme 7. Enantioselective allylations of
cyclohexanone through enol carbonate
and lithium enolate.
Angew. Chem. Int. Ed. 2006, 45, 6952 – 6955
Tsuji–Trost method is limited to stabilized carbanions.
Published online: October 9, 2006
[1] a) B. M. Trost, Pure Appl. Chem. 1981,
53, 2357; b) J. Tsuji, Pure Appl. Chem.
1982, 54, 197; c) B. M. Trost, T. R. Verhoeven in Comprehensive Organometallic Chemistry, Vol. 8 (Eds.: G. Wilkinson,
F. G. A. Stone, E. W. Abel), Pergamon,
Oxford, 1982, p. 799; d) J. A. Davies in
Comprehensive Organometallic Chemistry II, Vol. 9 (Eds.: E. W. Abel, F. G. A.
Stone, G. Wilkinson), Pergamon, Oxford, 1995, p. 323.
[2] Reviews: a) O. Reiser, Angew. Chem.
1993, 105, 576; Angew. Chem. Int. Ed.
Engl. 1993, 32, 547; b) J. M. J. Williams,
Synlett 1996, 705; c) B. M. Trost, D. L.
Van Vranken, Chem. Rev. 1996, 96, 395;
d) G. Helmchen, J. Organomet. Chem.
1999, 576, 203; e) G. Helmchen, A.
Pfaltz, Acc. Chem. Res. 2000, 33, 336;
f) B. M. Trost, M. L. Crawley, Chem.
Rev. 2003, 103, 2921; g) U. Kazmaier,
Curr. Org. Chem. 2003, 7, 317.
Angew. Chem. Int. Ed. 2006, 45, 6952 – 6955
[3] C. H. Heathcock in Modern Synthetic
Methods (Ed.: R. Scheffold), VHCA/
VCH, Basel, Weinheim, 1992, p. 1, and
references therein.
[4] a) B. M. Trost, E. Keinan, Tetrahedron
Lett. 1980, 21, 2591; b) J.-C. Fiaud, J.-L.
Malleron, J. Chem. Soc. Chem. Commun. 1981, 1159; c) B. Mkermark, A.
Jutand, J. Organomet. Chem. 1981, 217,
[5] M. Braun, T. Meier, Synlett 2006, 661.
[6] a) B. M. Trost, G. M. Schroeder, J. Am.
Chem. Soc. 1999, 121, 6759; b) B. M.
Trost, G. M. Schroeder, Chem. Eur. J.
2005, 11, 174.
[7] a) S.-L. You, X.-L. Hou, L.-X. Dai, X.-Z.
Zhu, Org. Lett. 2001, 3, 149; b) X.-X.
Yan, C.-G. Liang, Y. Zhang, W. Hong,
B.-X. Cao, L.-X. Dai, X.-L. Hou, Angew.
Chem. 2005, 117, 6702; Angew. Chem.
Int. Ed. 2005, 44, 6544.
[8] M. Braun, F. Laicher, T. Meier, Angew.
Chem. 2000, 112, 3637; Angew. Chem.
Int. Ed. 2000, 39, 3494.
[9] a) M. Braun, T. Meier, Synlett 2005,
2968; b) M. Braun, P. Meletis, M. Fidan,
unpublished results.
[10] T. Graening, J. F. Hartwig, J. Am. Chem.
Soc. 2005, 127, 17 192.
[11] a) D. C. Behenna, B. M. Stoltz, J. Am.
Chem. Soc. 2004, 126, 15 044; b) J. T.
Mohr, D. C. Behenna, A. M. Harned,
B. M. Stoltz, Angew. Chem. 2005, 117,
7084; Angew. Chem. Int. Ed. 2005, 44,
[12] a) B. M. Trost, J. Xu, J. Am. Chem. Soc.
2005, 127, 2846; b) B. M. Trost, R. N.
Bream, J. Xu, Angew. Chem. 2006, 118,
3181; Angew. Chem. Int. Ed. 2006, 45,
3109; c) B. M. Trost, J. Xu, J. Am. Chem.
Soc. 2005, 127, 17 180.
[13] a) E. C. Burger, J. A. Tunge, Org. Lett.
2004, 6, 4113; b) J. A. Tunge, E. C.
Burger, Eur. J. Org. Chem. 2005, 1715.
[14] Promising, however not enantioselective, allylations of aldehyde enolates
have been reported recently: M. Kimura, Y. Horino, R. Mukai, S. Tanaka,
Y. Tamaru, J. Am. Chem. Soc. 2001, 123,
10 401; I. Ibrahem, A. CQrdova, Angew.
Chem. 2006, 118, 1986; Angew. Chem.
Int. Ed. 2006, 45, 1952.
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enolate, alkylation, ketone, allylic, tsujiцtrost
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