Palladium-catalyzed decarboxylative asymmetric allylic alkylation of enol carbonates

Article abstract of DOI:10.1021/ja9053948

Palladium-catalyzed decarboxylative asymmetric allylic alkylation (DAAA) of allyl enol carbonates as a highly chemo-, regio-, and enantioselective process for the synthesis of ketones bearing either a quaternary or a tertiary R-stereogenic center has been investigated in detail. Chiral ligand L4 was found to be optimal in the DAAA of a broad scope of cyclic and acyclic ketones including simple aliphatic ketones with more than one enolizable proton. The allyl moiety of the carbonates has been extended to a variety of cyclic or acyclic disubstituted allyl groups. Our mechanistic studies reveal that, similar to the direct allylation of lithium enolates, the DAAA reaction proceeds through an "outer sphere" S _N2 type of attack on the π-allylpalladium complex by the enolate. An important difference between the DAAA reaction and the direct allylation of lithium enolates is that in the DAAA reaction, the nucleophile and the electrophile were generated simultaneously. Since the π-allylpalladium cation must serve as the counterion for the enolate, the enolate probably exists as a tight-ion-pair. This largely prevents the common side reactions of enolates associated with the equilibrium between different enolates. The much milder reaction conditions as well as the much broader substrate scope also represent the advantages of the DAAA reaction over the direct allylation of preformed metal enolates.

Full text of DOI:10.1021/ja9053948

Published on Web 11/23/2009
Palladium-Catalyzed Decarboxylative Asymmetric Allylic
Alkylation of Enol Carbonates
Barry M. Trost,* Jiayi Xu, and Thomas Schmidt
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received July 6, 2009; E-mail: bmtrost@stanford.edu
Abstract: Palladium-catalyzed decarboxylative asymmetric allylic alkylation (DAAA) of allyl enol carbonates
as a highly chemo-, regio-, and enantioselective process for the synthesis of ketones bearing either a
quaternary or a tertiary R-stereogenic center has been investigated in detail. Chiral ligand L4 was found to
be optimal in the DAAA of a broad scope of cyclic and acyclic ketones including simple aliphatic ketones
with more than one enolizable proton. The allyl moiety of the carbonates has been extended to a variety
of cyclic or acyclic disubstituted allyl groups. Our mechanistic studies reveal that, similar to the direct allylation
of lithium enolates, the DAAA reaction proceeds through an “outer sphere” SN2 type of attack on the
π-allylpalladium complex by the enolate. An important difference between the DAAA reaction and the direct
allylation of lithium enolates is that in the DAAA reaction, the nucleophile and the electrophile were generated
simultaneously. Since the π-allylpalladium cation must serve as the counterion for the enolate, the enolate
probably exists as a tight-ion-pair. This largely prevents the common side reactions of enolates associated
with the equilibrium between different enolates. The much milder reaction conditions as well as the much
broader substrate scope also represent the advantages of the DAAA reaction over the direct allylation of
preformed metal enolates.
Introduction
complex and in the other, it interacts with the alkylating agent
to form a more electrophilic chiral complex. In the first category,
The formation of carbon-carbon bonds represents the most
fundamental process for the synthesis of complex molecules
from simple ones. Among carbon-carbon bond forming strate-
gies, enolate alkylation has received intensive attention for
decades partially because carbonyl groups, or functional groups
easily derived from carbonyl groups, are frequently found in
many synthetic targets and they are rich in transformations to
many other structural moieties.1 While significant advances in
asymmetric alkylation of enolates have been achieved by using
chiral auxiliary approaches,2 most notably SAMP/RAMP,3 it
is more attractive in terms of atom economy4 to develop catalytic
enantioselective approaches to meet the environmental and
economical requirements of modern chemistry. Many efforts
have been made over the past three decades.1b,5 Upon the basis
of the role of the chiral catalyst, most approaches can be
classified into two categories, in one of which the catalyst
interacts with the enolate to form a more nucleophilic chiral
one of the most well-studied methods is phase transfer catalysis.6
To achieve a high degree of enantioselective control it is
essential but difficult to form a well organized transition state
involving the enolate, the catalyst and the alkylating agent.5
Thus, the enantioselectivity is often found to be very sensitive
to a subtle structural change of the substrate and optimization
of the reaction conditions is often required for each substrate.5
Another straightforward method in this category has been
demonstrated by Koga et al., in which a chiral polydentate amine
was used to coordinate the metal countercation of the lithium
enolate to achieve enantioselectivity in a catalytic fashion, but
its scope remains untested.7 High enantioselectivities have also
been achieved in the recently emerging organocatalyst promoted
asymmetric R-alkylation of aldehydes, although by a strict
definition, it does not go though enolate intermediates but
enamines.8 Besides their own limitations, such as the restriction
to intramolecular reactions or the use of harsh oxidative reagents,
(1) (a) Otera, J. Modern Carbonyl Chemistry; Wiley-VCH: New York,
2000. (b) Caine, D. In ComprehensiVe Organic Synthesis: Carbon-
Carbon s-Bond Formation; Trost, B. M. , Fleming Ian, Ed.; Pergamon:
New York, 1991; Vol. 3.
(6) (a) Hashimoto, T.; Maruoka, K. Chem. ReV. 2007, 107, 5656. (b) Ooi,
T.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 4222. (c) Maruoka,
K. In Asymmetric Phase Transfer Catalysis; Wiley-VCH Verlag GmbH
& Co. KGaA: Weinheim, 2008.
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Commun. 1990, 1657. (b) Imai, M.; Hagihara, A.; Kawasaki, H.;
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Yamashita, Y.; Odashima, K.; Koga, K. Tetrahedron Lett. 1999, 40,
2803.
(2) Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; John Wiley & Sons, Inc.: New York, 1995.
(3) (a) Enders, D. In Asymmetric Synthesis: Stereodifferentiating Addition
Reactions, Part B; Morrison, J. D., Ed; Academic Press: Orlando, FL,
1984; Vol. 3, p 275. (b) Seyden-Penne, J. Chiral Auxiliaries and
Ligands in Asymmetric Synthesis; John Wiley & Sons, Inc.: New York,
1995. (c) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D.
Tetrahedron 2002, 58, 2253. (d) Enders, D.; Voith, M.; Ince, S. J.
Synthesis 2002, 1775.
(8) (a) Vignola, N.; List, B. J. Am. Chem. Soc. 2004, 126, 450. (b)
Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129, 11336. (c) Sato,
T.; Tomioka, K. Heterocycles 2009, 77, 587. (d) Beeson, T. D.;
Mastracchio, A.; Hong, J. B.; Ashton, K.; Macmillan, D. W. C. Science
2007, 316, 582. (e) Jang, H. Y.; Hong, J. B.; Macmillan, D. W. C.
J. Am. Chem. Soc. 2007, 129, 7004. (f) Kim, H.; Macmillan, D. W. C.
J. Am. Chem. Soc. 2008, 130, 398. (g) Nicewicz, D. A.; Macmillan,
D. W. C. Science 2008, 322, 77.
(4) Trost, B. M. Science 1991, 254, 1471.
(5) Hughes, D. L. In ComprehensiVe Asymmetric Catalysis I-III; Jacob-
sen, E. N., Pfaltz., A., Yamamoto, H., Ed.; Springer: Berlin, 1999;
Vol. III.
9
10.1021/ja9053948  2009 American Chemical Society
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A R T I C L E S
Trost et al.
Scheme 1. Mechanism of Palladium-Catalyzed Decarboxylative
extending these methods to ketones has not been succeeded. In
the second category, a chiral Cr(salen)Cl complex catalyzed
asymmetric alkylation of tin enolates with various alkylation
agents was developed by Jacobsen and Doyle.9 The reaction
was proposed to follow a SN2 type of pathway; the halide in
the catalyst served as a Lewis base to activate the tin enolate
by the formation of an “ate” complex while the chiral cationic
Cr moiety may assist the departure of the halide in the alkylating
agent. Transition metal catalyzed enantioselective alkylation of
safer and less expensive lithium enolates by activation of the
electrophile, however, has almost exclusively focused on a
special type of alkylating group - the allylic groups. They can
be activated toward nucleophilic substitution by coordinating
with a low valent metal complex to form a cationic π-allylmetal
complex.10-12 Although good yields and high enantioselectivi-
ties have been reported, the scope of these reactions was quite
narrow, at least partially due to the structural complexity of
lithium enolates in solution.13 In some cases, a small change of
the enolate structure can dramatically affect the yield or
enantioselectivity of the reaction.10 For substrates with more
than one enolizable proton, proton transfer between the initially
formed enolate and the newly formed product may lead to
problems such as loss of regioselectivity and di- or poly-
alkylation.14 These problems caused by the faster equilibration
between enolates compared to the alkylation were elegantly
avoided in the decarboxylative alkylation of allyl enol carbonates
or allyl ꢀ-ketoesters, as independently reported by Saegusa15
and Tsuji.16 The proposed mechanism includes the coordination
of the Pd (0) complex to the allyl moiety, ionization of the
carbonate or ester leaving group, Pd-promoted decarboxylation
to form the enolate in situ and recombination of the enolate
and the π-allylpalladium to form the allylated product and
regenerate the catalyst (Scheme 1).15,16e Tsuji and co-workers
have demonstrated that under these extremely mild and neutral
conditions, the reaction preceded with highly conserved
regioselectivity.16c
Allylic Alkylation of Enol Carbonates and R,R-Disubstituted
ꢀ-Ketoesters
generate γ,δ-unsaturated ketones with a ꢀ-tertiary chiral center.17
It should be pointed out that in this report the newly formed
asymmetric center is on the electrophile; the control of the
stereoselectivity on the allyl moiety is easier than that on the
prochiral nucleophile since the allyl moiety is directly attached
to the chiral metal complex. In addition, as proposed by Tsuji
et al., the reaction probably does not go through the ionization-
decarboxylation-alkylation sequence but an alternative ioniza-
tion-alkylation-decarboxylation pathway; that means that the
nucleophile is not an unstabilized ketone enolate but a stabilized
ꢀ-keto carboxylate.16f Stoltz et al.18 and our group19 indepen-
dently reported the first catalytic enantioselective DAAA
reactions of allyl enol carbonates to form simple ketones bearing
a quaternary stereogenic R-carbon center. Since then, many
expansions and applications of this robust reaction have been
reported.20 We were specifically interested in the family of
ligands derived from 2-diphenylphosphinobenzoic or 1-naph-
thoic acid and chiral scalemic diamines, which had been used
successfully in inducing excellent enantioselectivity in numerous
palladium-catalyzed AAA reactions (Figure 1).21 We reported
herein a full account in the optimization, scope and mechanistic
studies of the decarboxylative asymmetric allylic alkylation
(DAAA) of various unstabilized ketone enolates.
At the time we started to question if we could use a chiral
ligand to induce a good enantioselectivity of the reaction while
keeping its regiospecificity, there was no enantioselective version
of this reaction reported. As our research proceeded, Burger
and Tunge reported the first palladium-catalyzed asymmetric
DAAA of racemic 1,3-disubstituted allylic ꢀ-ketoesters to
(9) (a) Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 62.
(b) Doyle, A. G.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2007, 46,
3701.
Results and Discussion
(10) (a) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759.
(b) Trost, B. M.; Schroeder, G. M. Chem.sEur. J. 2005, 11, 174.
(11) (a) You, S. L.; Hou, X. L.; Dai, L. X.; Zhu, X. Z. Org. Lett. 2001, 3,
149. (b) Yan, X. X.; Liang, C. G.; Zhang, Y.; Hong, W.; Cao, B. X.;
Dai, L. X.; Hou, X. L. Angew. Chem., Int. Ed. 2005, 44, 6544. (c)
Zheng, W. H.; Zheng, B. H.; Zhang, Y.; Hou, X. L. J. Am. Chem.
Soc. 2007, 129, 7718. (d) Zhang, K.; Peng, Q.; Hou, X. L.; Wu, Y. D.
Angew. Chem., Int. Ed. 2008, 47, 1741.
Preparation of Allyl Enol Carbonates. An allyl enol carbonate
was typically prepared by quenching the enolate, generated from
the deprotonation of a ketone, with allyl chloroformate at low
temperature. The chemo- and regio-selective control of enolate
formation has been well documented.1b For ketones with two
enolizable centers, either kinetically or thermodynamically
(12) (a) Braun, M.; Laicher, F.; Meier, T. Angew. Chem., Int. Ed. 2000,
39, 3494. (b) Braun, M.; Meier, T. Synlett 2005, 2968. (c) Braun, M.;
Meier, T. Synlett 2006, 661. (d) Braun, M.; Meier, T.; Laicher, F.;
Meletis, P.; Fidan, M. AdV. Synth. Catal. 2008, 350, 303.
(13) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624.
(14) Trost, B. M.; Keinan, E. Tetrahedron Lett. 1980, 21, 2591.
(15) Tsuda, T.; Chujo, Y.; Nishi, S.; Tawara, K.; Saegusa, T. J. Am. Chem.
Soc. 1980, 102, 6381.
(17) Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 4113. For a review,
see: Tunge, J. A.; Burger, E. C. Eur. J. Org. Chem. 2005, 9, 1715.
(18) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044.
(19) Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 2846.
(20) For reviews in transition metal catalyzed decarboxylative asymmetric
allylic alkylation, see: (a) You, S.-L.; Dai, L.-X. Angew. Chem., Int.
Ed. 2006, 45, 5346. (b) Braun, M.; Meier, T. Angew. Chem., Int. Ed.
2006, 45, 6952. (c) Stoltz, B. M.; Mohr, J. T. Chem. Asian J. 2007,
2, 1476.
(16) (a) Shimizu, I.; Yamada, T.; Tsuji, J. Tetrahedron Lett. 1980, 21, 3199.
(b) Shimizu, I.; Ohashi, Y.; Tsuji, J. Tetrahedron Lett. 1983, 24, 3865.
(c) Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24, 1793.
(d) Shimizu, I.; Minami, I.; Tsuji, J. Tetrahedron Lett. 1983, 24, 1797.
(e) Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140. (f) Tsuji, J.;
Yamada, T.; Minami, I.; Yuhara, M.; Nisar, M.; Shimizu, I. J. Org.
Chem. 1987, 52, 2988.
(21) (a) Trost, B. M.; Vanvranken, D. L. Chem. ReV. 1996, 96, 395. (b)
Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1. (c) Trost, B. M.;
Crawley, M. L. Chem. ReV. 2003, 103, 2921. (d) Trost, B. M.;
Fandrick, D. R. Aldrichimica Acta 2007, 40, 59.
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Palladium-Catalyzed DAAA of Unstabilized Ketone Enolates
A R T I C L E S
carboxylates are easily prepared in high yields from the
corresponding alcohol and carbonyldiimidazole (CDI) under
mild conditions (eq 3). They can be purified by flash column
chromatography and most are stable for months when refriger-
ated. Compared with chloroformates, imidazolides are relatively
“softer” eletrophiles, and thus, the reaction of sodium enolates
with 5 gave exclusively the C-acylated product 6,23 even in a
coordinating solvent DME, which presumably can stabilize the
charge-separated ion-pairs, thus favoring the formation of the
O-acylated product (eq 4).24 However, by coordinating the more
basic nitrogen on the imidazole with an azaphilic Lewis acid,
such as BF3, to increase the polarity of the carbonyl group as
well as to facilitate the leaving of the imidazole group, we were
able to tune the complex to a “harder” electrophile, which
favored the O-acylation and enol carbonate 7 was obtained
exclusively (eq 5).25 As listed in Table 1, a variety of substituted
allyl enol carbonates were prepared in this manner in good to
excellent yields.
Figure 1. Ligands used in optimization.
controlled enolate formation can be obtained by adjustment of
base, solvent, reaction temperature, and, most importantly, the
order of addition of the base and the ketone substrate. Most
allyl enol carbonates of cyclic ketones were prepared by the
method described by Houminer et al.22 In a general procedure
(eq 1), 5 mmol of ketone in anhydrous tetrahydrofuran (THF)
was slowly added into the solution of 6 mmol of sodium
hexamethyldisilazane (NaHMDS) and 6.0 mmol of N,N,N′,N′-
tetramethyl-1,2-ethylenediamine (TMEDA) in anhydrous THF
at -78 °C. The reaction mixture was stirred for 1 h and
transferred through a cannula into a solution of 6 mmol of allyl
chloroformate in anhydrous THF at -78 °C and stirred for 5
min. The product was typically purified by flash column
chromatography on silica gel; and most enol carbonates are
stable for years at refrigerator temperature. Alternatively, the
thermodynamically more stable enolates were generated by
exposure to sodium hydride and TMEDA at higher temperature,
and sequentially quenched with allyl chloroformate at low
temperature (eq 2).
Besides intrinsic electronic and steric effects, the double bond
geometry of an acyclic ketone enolate is also controlled by the
choice of base, solvent and reaction temperature, etc.1b,26
Normally the preformed enolate is geometrically stable at low
temperature if there is no external proton source to allow the
equilibration between different enolate structures; and it can be
rapidly trapped by allyl chloroformate at low temperature. As
an example, deprotonation of cyclohexyl ethyl ketone by
(PhMe2Si)2NLi in THF at -78 °C followed by quenching the
produced lithium enolate with allylchloroformate gave Z-15 in
1
56% yield and greater than 49:1 Z/E selectivity (by HNMR),
with the formation of a small portion of ꢀ-ketoester (Table 2,
entry 1). The double bond configuration was assigned by the
difference between the chemical shifts of the vinyl proton on
The preparation of substituted allyl enol carbonates from the
corresponding substituted allylchloroformates is, however, less
convenient since substituted allylchloroformates are not com-
mercial available and their preparation involves the use of highly
toxic and strictly regulated phosgene. Besides, many chloro-
formates are not stable to heat and moisture; thus their
purification and storage are problematic. Strongly acidic hy-
drogen chloride generated in the process also limits the range
of compatible functional groups. Furthermore, a significant
amount of diallyl carbonate is often formed lowering the yield
of chloroformate, which is a disadvantage especially for precious
allylic alcohols. On the other hand, allyl 1H-imidazole-1-
(23) (a) Moyer, M. P.; Feldman, P. L.; Rapoport, H. J. Org. Chem. 1985,
50, 5223. (b) Shone, R. L.; Deason, J. R.; Miyano, M. J. Org. Chem.
1986, 51, 268. (c) Tanaka, T.; Okamura, N.; Bannai, K.; Hazato, A.;
Sugiura, S.; Tomimori, K.; Manabe, K.i; Kurozumi, S. Tetrahedron
1986, 42, 6747.
(24) (a) House, H. O.; Auerbach, R. A.; Gall, M.; Peet, N. P. J. Org. Chem.
1973, 38, 514. (b) Olofson, R. A.; Cuomo, J.; Bauman, B. A. J. Org.
Chem. 1978, 43, 2073. (c) Taylor, R. J. K. Synthesis 1985, 4, 364. (d)
Bairgrie, L. M.; Leung-Toung, R.; Tidwell, T. T. Tetrahedron Lett.
1988, 29, 1673. (e) Zhong, M.; Brauman, J. I. J. Am. Chem. Soc. 1996,
118, 636.
(25) Trost, B. M.; Xu, J. Y. J. Org. Chem. 2007, 72, 9372.
(26) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M. C.;
Sohn, J. E.; Lampe, J. J. Org. Chem. 1980, 45, 1066.
(22) Harwood, L. M.; Houminer, Y.; Manage, A.; Seeman, J. I. Tetrahedron
Lett. 1994, 35, 8027.
9
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A R T I C L E S
Trost et al.
Table 1. Preparation of Various Substituted Allyl Enol Carbonates
Table 2. Control of Double Bond Geometry by the Base in the
Formation of Enol Carbonate
entry
base
yield
Z/E
1
2
3
(PhMe2Si)2NLi
LDA, TMEDA
LiTMP-LiBr-TMEDA
56%
91%
87%
>49/1
1.6/1
1/3
Scheme 2. Preparation of E-Enol Carbonates
a KOt-Bu was used as base.
lithium or tin enolates,10 products obtained through the DAAA
of enol carbonates under the above optimized conditions (2.5
mol% 20, 5.5 mol% (R,R)-L4, toluene, 23 °C) have much higher
enantioselectivity in general (Table 4). For instance, only a poor
6% ee was obtained in the allylation of the preformed tin enolate
of 2-methylbenzosuberone. By the DAAA method, however,
the ee of 26 was dramatically improved to 91% (entry 2). More
interestingly, R-24 was the major enantiomer (88% ee) in the
allylation of the preformed lithium or tin enolate of 2-meth-
yltetralone catalyzed by (S,S)-L1, while the same enantiomer
was also found to be the major one in the DAAA reaction of
the enol carbonate 23 catalyzed, however, by the (R,R)-ligand
(entry 1). This means that completely opposite enantioselec-
tivities were obtained by these two approaches. A similar
observation was also found in the allylation of 2-methylindanone
(entry 3). However, this phenomenon was not observed in the
allylation of some other six-membered cyclic ketones, that is,
the same enantiomers of 30 and 32 were obtained by both
approaches (entry 4 and entry 5). While the chiral scaffold
differed in the DAAA (ie L4) vs the standard enolate process
(ie L1), we have shown that the sense of asymmetric induction
in each series is independent of the scaffold. The results are
given for the best selectivities observed in each case.
One obvious difference between these two methods is that
the DAAA reactions of enol carbonates are under neutral
conditions and the AAA reactions of preformed lithium or tin
enolates are under strong basic conditions. Since there are acidic
amide protons in these ligands, under strong basic conditions
the ligand must be deprotonated. Therefore, it might be the
deprotonation of the ligand that caused the switch of enanti-
oselectivity observed in some cases. To test this hypothesis,
we pretreated the Pd/L4 catalyst with LDA to fully deprotonate
the catalyst before it was subjected to the solution of 23 (eq 6).
The reaction did not go to completion after 10 h, and the product
24 was obtained in only 31% yield, compared with the 88%
yield in 5 min when the neutral catalyst was used. However,
almost the same enantioselectivity was obtained with or without
deprotonation of the ligand (eq 6). Therefore, it is not likely
the trisubstituted enol carbonate. As proposed by Pascual et al.,
the proton trans to the carbonate substitution (in the Z-isomer)
has a lower chemical shift (δ ) 5.06) than the one cis to the
carbonate (in the E-isomer, δ ) 5.17).27 In the presence of
lithium diisopropylamide (LDA)/TMEDA as base, the ratio of
E-15 to Z-15 increased to 1:1.6 (entry 2). Switching from LDA
to lithium 2,2,6,6-tetramethylpiperidinide-LiBr (LiTMP-LiBr),28
the E-15 was obtained as the major isomer with a 3:1 E/Z ratio
(entry 3). Several E-enol carbonates were prepared in this
manner in good yields and high E/Z selectivity (Scheme 2).
Palladium-Catalyzed DAAA of Allyl Enol Carbonates to
Generate Ketones Possessing an r-Quaternary Center. Using
2-methylcyclohexanone as a model we systematically investi-
gated the DAAA reaction of its allyl enol carbonate 19 by
screening chiral ligands, solvents, reaction temperature and
substrate concentration. Some results are summarized in Table
3. Among the four chiral ligands listed in Figure 1, L4 gave
the best ee and yield (entry 1-4). Solvent had a small effect
on the ee of the reaction when L4 was used; and the highest ee
(85%) was obtained in toluene (entry 4-8). The ee was slightly
increased to 87% (entry 9) when the reaction temperature
decreased from 23 to 4 °C, but it dropped to 83% at -10 °C
(entry 10). The concentration of the substrate did not have a
significant effect on the ee and yield of the product (entry 11
and 12). The reaction performed in the presence of 2 mol% Pd
gave essentially the same results as that catalyzed by 5 mol%
Pd (entry 13).
The asymmetric synthesis of 2-allyl-2-methylcyclohexan-1-
one through palladium-catalyzed DAAA reaction of enol
carbonate 19 selectively demonstrated the advantage of this
method: extremely mild reaction conditions, exclusive regiose-
lectivity, high catalyst efficiency and good enantioselectivity.
Compared with our previous results carried out using preformed
(27) Pascual, C.; Meier, J; Simon, W. HelV. Chim. Acta 1966, 49, 164.
(28) (a) Hall, P. L.; Gilchrist, J. H.; Collum, D. B. J. Am. Chem. Soc. 1991,
113, 9571. (b) Hall, P. L.; Gilchrist, J. H.; Harrison, A. T.; Fuller,
D. J.; Collum, D. B. J. Am. Chem. Soc. 1991, 113, 9575.
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Palladium-Catalyzed DAAA of Unstabilized Ketone Enolates
A R T I C L E S
Table 3. Selected Optimization Studies
entry
ligand
solvent
temp
conc.
eeb
yieldc of 21
yieldc of 22
1
2
3
4
5
6
7
8
(R,R)-L1
(R,R)-L2
(R,R)-L3
(R,R)-L4
(R,R)-L4
(R,R)-L4
(R,R)-L4
(R,R)-L4
(R,R)-L4
(R,R)-L4
(R,R)-L4
(R,R)-L4
(R,R)-L4
Toluene
Toluene
Toluene
Toluene
CH2Cl2
1,4-Dioxane
DME
23 °C
23 °C
23 °C
23 °C
23 °C
23 °C
23 °C
23 °C
4 °C
0.1 M
0.1 M
0.1 M
0.1 M
0.1 M
0.1 M
0.1 M
0.1 M
0.1 M
0.1 M
0.3 M
0.025 M
0.3 M
31%
61%
60%
85%
84%
80%
84%
81%
87%
83%
85%
87%
85%
73%
73%
85%
88%
64%
99%
87%
85%
91%
84%
94%
92%
88%
0
2%
1%
0
26%
0
7%
1%
2%
6%
4%
0%
5%
THF
9
Toluene
Toluene
Toluene
Toluene
Toluene
10
11
12
13d
-10 °C
4 °C
4 °C
4 °C
a Unless otherwise indicated, all reactions were performed on a 0.3 mmol scale at 23 °C employing 2.5 mol% 20 and 5.5 mol% ligand. b Ee values
were determined by chiral GC. c Yields were determined by quantitative GC analysis using decane as internal reference. d 20 (1.0 mol%) and L4 (5
mol%) were used.
Table 4. Reaction of Various Allyl Enol Carbonatesa
Similarly, our previous studies revealed that palladium-
catalyzed AAA of the preformed enolate of 1-methyl-2-tetralone
(33) was very sensitive to the choice of base. Actually, a
completely opposite enantioselectivity was obtained by switch-
ing the base from LDA to cesium carbonate (Scheme 3).29
Presumably, the palladium enolate generated in situ from the
decarboxylation of the enol carbonate should be more like the
intermediate in the reaction of less covalently bonded cesium
enolate than that in the reaction of more covalently bonded
lithium enolate. Indeed, the DAAA reaction of the allyl enol
carbonate of 1-methyl-2-tetralone (35) catalyzed by Pd-L4
complex (eq 7) gave the same sense of chirality and nearly the
same enantioselectivity as the AAA of the cesium enolate.
The observation that opposite enantioselectivity was obtained
in the allylation of the lithium enolate of 2-methyl-1-tetralone
and the DAAA reaction of its enol carbonate can be probably
explained by the structural difference of the nucleophiles. As
a All reactions were performed on a 0.3 mmol scale at 0.1 M in
shown by the cartoons30 in Figure 2, the “naked” enolate
toluene at 23 °C for 20 h using 2.5 mol% 20 and 5.5 mol% ligand
(R,R)-L4. b Isolated yields. c Ee values were determined by HPLC on a
chiral stationary phase. d Conditions used were 2.5 mol%
[(η3-C3H5)PdCl]2, 5.0 mol% (S,S)-L1, 2.0 equiv LDA, 1.0 equiv
Me3SnCl, DME, r.t.10 e Absolute configuration and the sign of the
optical rotation ([R]D) of the product.9a f Ee was determined by GC on a
chiral stationary phase.
approaches the π-allylpalladium-L4 complex by its Si face (A),
to avoid the disfavored steric interaction between the “wall” of
the ligand and the phenyl ring of the substrate (B). On the other
hand, we have disclosed that two equivalents of LDA were
necessary for good enantioselectivity in the AAA of lithium
enolate.10 It possibly implies the dimer of one lithium enolate
and one LDA is the nucleophile. The aggregation makes the O
terminal very bulky so that it prefers to be located at the flap
side of the catalyst and leaves its Re face exposed to the
electrophile (C). The fact that enantioselectivity of the allylation
that the deprotonation of the ligand is the reason causing the
observed opposite enantioselectivity in Table 4, entries 1 and
3.
(29) Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew. Chem., Int. Ed.
2002, 41, 3492.
(30) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545.
9
J. AM. CHEM. SOC. VOL. 131, NO. 51, 2009 18347

A R T I C L E S
Trost et al.
Scheme 3. Countercation Effect in Palladium-Catalyzed AAA of
1-Methyl-2-tetralone29
of preformed enolates is very sensitive to structural change of
the enolate may also be explained by the complexity of the
lithium enolate in solution, which normally exists as a mixture
of monomer, dimer and oligomers and the equilibria among
them may change with the variation of substrate structure.31
However, it is perhaps too simple to say that the DAAA of
an enol carbonate is equivalent to the AAA reaction of a charge-
separated enolate. For instance, the optimized conditions for
the AAA of 2-phenylcyclohexan-1-one (3) involved the use of
substoichiometric amount of NaHMDS as base and L3 as ligand
in a coordinating solvent 1,2-dimethoxyethane (DME, eq 8).29
The DAAA reaction of 4 in the presence of the same catalyst,
however, gave a nearly racemic product (eq 9). Switching from
L3 to L4 dramatically improved the ee of 37 to over 90% (eq
9).
Figure 2. Cartoon models for the alkylation of charge separated palladium
enolate.
much better than the 47% ee obtained by the AAA of the
preformed tin enolate. In another example, the reaction of
cinnamyl enol carbonate 10 gave cleanly the linear product 39
quantitatively with excellent ee (92.5%), while the yield from
the preformed enolate was only 11% (entry 2). The reaction of
cis-crotyl enol carbonate 12 gave a 4:1 mixture of the linear
product 40 and the branched product 41 (entry 3). The E isomer
of 40 was the major one in a ratio of 11.7:1 to the Z-isomer,
implying a fast π-σ-π equilibration compared to the decar-
boxylation and alkylation. Equally good enantioselectivities were
achieved for the major product isomer from both the Z- and
E-isomers of the allyl substrates (entry 3 and 4). Surprisingly,
prenyl enol carbonate 9 remained intact for 13 h at 23 °C, while
at the same temperature the prenylation of the preformed enolate
was obtained in good yield (64%), albeit in poor ee (entry 5).
It might be because the palladium-involved decarboxylation step
is retarded by the steric hindrance of the π-prenylpalladium
species. Increasing the reaction temperature to 60 °C did push
the reaction of 9 to completion, but the only product found in
the crude residue after concentration was 2-methyl-1-tetralone
(entry 6). It was formed presumably through the ꢀ-hydride
elimination of the π-prenylpalladium intermediate followed by
reductive elimination of the hydrido-palladium enolate. Elimina-
tion from the π-allylpalladium complex to form diene can also
occur via a base promoted process. Nevertheless, the palladium-
catalyzed decarboxylative prenylation has been successfully
applied in the synthesis of spirotryprostatin B, where the
corresponding enolate was more stabilized, so the decarboxy-
lation may be more facile.32 We cannot rule out a role for the
hardness/softness of the enolate in the two cases although we
favor the former explanation. In entry 7, 42 was isolated in 62%
yield, over 20:1 dr and over 99% ee. The diastereoselectivity
(5:1 dr) in the DAAA of 2-methyl-1-indanone (entry 8) was
somehow lower, compared with that of 2-methyl-1-tetralone
Palladium-Catalyzed DAAA of Substituted Allyl Enol
Carbonates. The palladium-catalyzed AAA of preformed lithium
or tin enolates of ketones has been investigated in our previous
work.10b In general, the yields and enantioselectivities were quite
sensitive to the substitution changes on the allyl moiety. As a
comparison, a variety of 1,1- or 1,2-disubstituted allyl enol
carbonates of 2-methyl-1-tetralone were subjected to the opti-
mized conditions (Table 5). The reaction of 2′-methallyl enol
carbonate 8 went to completion within 4 h at room temperature
to produce the desired product 38 in 89% yield and over 99%
ee (Table 5, entry 1), similar to the results of the DAAA of the
unsubstituted allyl enol carbonate 23 (Table 3, entry 1), but
(31) Seebach, D. Angew. Chem., Int. Ed. 1988, 27, 1624.
(32) Trost, B. M.; Stiles, D. T. Org. Lett. 2007, 9, 2763.
9
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Palladium-Catalyzed DAAA of Unstabilized Ketone Enolates
A R T I C L E S
Table 5. Palladium-Catalyzed Decarboxylative AAA of Substituted Allyl Enol Carbonatesa
a All reactions were performed on a 0.2 mmol scale at 0.1 M in dioxane at 23 °C for 20 h using 2.5 mol% 20 and 5.5 mol% ligand (R,R)-L4; yields
are Isolated yields; ee values were determined by HPLC on a chiral stationary phase. b Absolute and relative stereochemistry were assigned by analogy
c
with compound 24 and 111. Conditions used were 2.5 mol% [(η3-C3H5)PdCl]2, 5.0 mol% (S,S)-L1, 2.0 equiv LDA, 1.0 equiv Me3SnCl, DME, rt.10b
d Reaction was performed at 60 °C. Conversion of the starting material by HNMR.
e
1
(entry 7), but the ee of the major diastereomer 43 remained
high (98% ee).
Table 6. Selected Optimization Studies for DAAA of Tri-substituted
Enol Carbonatesa
To Generate Ketones Possessing an r-Tertiary Center. Since
the reaction conditions are mild, we attempted to extend the
reaction into the asymmetric syntheses of ketones bearing an
R-tertiary center anticipating that no racemization of the R-center
or dialkylation would happen. Under the optimized conditions
described above, the reaction of 44 went to completion to afford
entry
T (°C)
solvent
eeb
45
46
47
R-45 in over 85% ee, albeit in a moderate yield (62%).33
A
1
2
3
23
4
23
50
50
23
PhMe
PhMe
THF
THF
THF
95%
95%
94%
89%
89%
97%
(62)c
53(52)c
51(51)c
46(44)c
22(18)c
81(81)c
(29)c
36(39)c
25(35)c
13(20)c
7(10)c
6
9%
8%
5%
19%
38%
<2%
large portion of 1-tetralone (46, 29%) and a significant amount
of 2,2-diallyl-1-tetralone (47, 9%) were obtained as side products
(Table 6, entry 1). At lower temperature the yield of 46 increased
to 39% and correspondingly the yield of the product decreased
to 52% without change of the ee (entry 2). Raising the
temperature from 23 to 50 °C in THF decreased the ee and
the yield of the desired product and increased the yield of the
diallylated product (entry 3 and 4). In the presence of less
4
5d
6
dioxane
a All reactions were performed on a 0.3 mmol scale at 0.1 M for
20 h at 23 °C using 2.5 mol% 20 and 5.5 mol% (R,R)-L4; yields were
measured by quantitative GC analysis using decane as internal reference.
b Ee values were determined by chiral HPLC. c Isloated yields. d 20 (1.0
mol%) and (R,R)-L4 (5.0 mol%) were used.
(33) The absolute configuration of 45 was assigned by the comparison of
its optical rotation with that known in the literature. Imai, M.; Hagihara,
A.; Kawasaki, H.; Manabe, K.; Koga, K. Tetrahedron 2000, 56, 179.
catalyst (2 mol%), diallylation was more severe; 47 was isolated
in 38% yield and the yield of the desired product was only 22%
9
J. AM. CHEM. SOC. VOL. 131, NO. 51, 2009 18349

A R T I C L E S
Trost et al.
Table 7. Summary of the Scope of the Reactiona
containing a sulfur atom is compatible with the Pd catalyst and
product 52 was obtained in excellent yield and enantioselectivity
(entry 6). The positions of substituents on the aryl ring did not
have a significant effect on the reaction and excellent ee’s were
obtained (entry 8 and 9). The ring size of ketones, however,
has a significant impact on the enantioselectivity of the reaction.
For instance, 2-allylindanone 58 was obtained in lower ee (81%
ee, entry 7) than 2-allyl-1-tetralone 45 (97% ee) while 2-allyl-
benzosuberone 60 was obtained in better ee (99% ee, entry 9).
Surprisingly, the DAAA of 2-tetralone and 2-indanone gave
essentially racemic monoallylated products 62 and 64 (entry
10 and 11), in stark contrast with the 80% ee obtained in the
allylation of 1-methyl-2-tetralone under the same reaction
conditions (eq 10). This is hard to be explained by the slight
structural difference between 2-tetralone and 1-methyl-2-tetral-
one. Instead, racemization through the equilibration of enolates
is possibly a more plausible reason for the complete loss of ee
in the product. The equilibration of enolates, which was largely
avoided in the DAAA of 1-tetralone, was more severe for
2-tetralone, probably because the later was more acidic, thus
the ion-pair of its palladium enolate was much looser so that
the enolate can leak out more easily from the solvent cage to
equilibrate with the product.
Palladium-Catalyzed DAAA of Allyl Enol Carbonates of
Acyclic Ketones. The alkylation of five to seven-membered
cyclic ketones is simplified by the fact that the geometry of the
enolate is fixed due to the strain in the formation of the Z-cyclic
enolate. For acyclic enolates the influence of double bond
geometry on the stereochemistry of reactions needs to be
considered. Both E and Z isomers of 15 were prepared and
submitted to the optimized palladium-catalyzed DAAA condi-
tions. Interestingly, E-15 was more reactive than its isomer and
its reaction went to completion in 2 h with 65 being isolated in
94% yield (eq 11), while Z-15 remained mostly unchanged after
4 h as detected by GC analysis. The product was isolated in a
lower yield (72%) after 16 h (eq 12). In both cases 65 was the
only product, however, the sign of its optical rotation was
reversed. Similarly the DAAA of 66 with a 5/95 Z/E ratio went
to completion in 6 h to afford 67 in quantitative yield and 93%
ee (eq 13), while only a trace amount of product was detected
in 16 h in the reaction of 66 with a 94/6 Z/E ratio (eq 14).
These results indicated that the possible equilibrium between
the E-enolate and the Z-enolate in the presence of a proton
source (the product) was avoided and the π-allylpalladium
reacted with the enolate from the same face. The different
enantioselectivity may be interpreted by models as shown in
Figure 3. The E-enolate approaching the π-allylpalladium
complex from its Si face (transition state A), with both the
cyclohexyl and the methyl groups occupying the “flap” side of
the catalyst, should be more favored than that if it reacts from
its Re face (B). Thus, R-65 was the predominating enantiomer
a Unless otherwise indicated, all reactions were performed on a 0.3
mmol scale at 0.1 M for 20 h at 23 °C using 2.5 mol% 20 and 5.5
mol% ligand L4 or 10 mol% dppe; the ee values were determined by
chiral HPLC. b Yields were isolated yields. c Ee values was determined
by the analysis of its derivative by chiral GC. d [R]D has the same sign
as reported for the R configuration.35
(entry 5). The best results were achieved when the reaction was
conducted in dioxane at ambient temperature (entry 6).
The reaction scope has also been explored and the results
are listed in Table 7. For comparison of this asymmetric process
to one using an achiral ligand, the DAA of cyclohexanone with
dppe was explored (eq 10). To our surprise, this reaction did
not give the desired monoallylated product 50; instead, 2,2-
diallylcyclohexanone 49 was isolated as the major product.
However, when L4 was used as ligand there was little diallylated
product and the monoallylated products were isolated in good
yields and moderate enantioselectivities (entry 1).34 Generally,
better yield was obtained in dioxane than in toluene, but slightly
better enantioselectivity was achieved in toluene than in dioxane
(entry 1 vs 2; entry 3 vs 4 and entry 7 vs 8). Substrate 51
(34) The direct catalytic asymmetric mono-allylation of lithium enolate of
cyclohexanone was recently reported. See: Braun, M.; Meletis, P.;
Fidan, M. Synthesis 2009, 86, 47.
(35) Meyers, A. I.; Williams, D. R.; Erickson, G. W.; White, S.; Druelinger,
M. J. Am. Chem. Soc. 1981, 103, 3081.
9
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Palladium-Catalyzed DAAA of Unstabilized Ketone Enolates
A R T I C L E S
Table 8. DAAA of Allyl Enol Carbonates of Various Phenyl
Ketones
entry
R2
substrate (Z/E)
product
time (h)
yield
ee
1
2
3
4
5
Me
Et
n-Pent
Bn
i-Pr
68 (>98/2)
70 (>98/2)
72 (>98/2)
74 (>98/2)
76 (>98/2)
S-69
71
73
75
77
3
2
16
1
96%
94%
93%
75%
30%
94%
94%
92%
88%
32%
24
E/Z-selectivity. They were subjected to the palladium-catalyzed
DAAA reactions in the presence of L4 ligand in dioxane at
ambient temperature and the results are listed in Table 8.
Carbonates bearing a small R2 group such as CH3, C2H5, C5H11
and CH2Ph reacted smoothly to generate the corresponding
ketones in excellent yields and ee’s (entry 1-4). However, the
reaction of carbonate 76 with R2 ) i-Pr was sluggish and the
desired product 77 was isolated in poor yield and ee (30%, 32%
ee, entry 5). The absolute configuration of 69 was assigned to
be S- by the hydrogenation of 69 to compound 78, which had
an optical rotation of +25.7 (EtOH), opposite to the reported
optical rotation of R-78 [-15.8 (EtOH), eq 15].36
Figure 3. Cartoon models for the explanation of the reactivity and the
selectivity of E- and Z-15.
The reaction is compatible with halogen substitutions at either
ortho-, meta-, or para- position of the phenyl ring and no
significant difference was observed in these reactions compared
with that of the unsubstituted one (Table 9, entry 1-3).
Remarkably, sterically hindered ortho-substitution on the phenyl
ring was tolerable; 86 and 88 were isolated in high yields and
excellent ee’s (entry 4 and entry 5). Compound 88 was cleanly
converted to 99, an analogue of the antitumor compound
CRM-51006,37,38 by catalytic hydrogenation in methanol to
saturate the double bond as well as to remove the benzyl groups
(eq 16). Replacement of the electron-rich methoxyl group in
85 with an electron-deficient CF3 group,apparently shortened
the reaction time to 2 h, possibly by facilitating the decarboxy-
lation; the product 90 was obtained in a slightly lower ee (92%)
(entry 6). The substrates possessing a more electron-deficient
2′-pyridyl (91) or 3′-nitrophenyl group (93) were even more
reactive, but the corresponding products 90 and 92 were obtained
in lower ee’s (73% ee and 83% ee respectively, entry 7 and 8).
However, the reaction of substrate 95 bearing a more electron-
rich but smaller 2′-furyl ring did not give better enantioselec-
tivity (88% ee, entry 9) than that of 69 (94% ee, entry 1),
implying the electronic property of the enolate may not be the
only factor influencing the enantioselectivity of the reaction.
Beside aryl ketones, the DAAA reactions of alkenyl ketones
were also investigated. Enol carbonate Z-2 was prepared in the
same way as aryl ketone enol carbonates. Its DAAA reaction
in the reaction of E-15. In the allylation of the Z-enolate, no
matter which side the enolate approaches the π-allylpalladium
complex, either the methyl group (C) or the cyclohexyl group
(D) has to have some steric interaction with the catalyst.
Approach C should be more favored than D, but the energy
difference between C and D is smaller than that between A
and B, and thus a poorer ee was obtained in the DAAA of Z-15.
Z-Enol carbonates are easily accessible if one side of the
ketone is sterically bulky, such as phenyl ketones. Several such
enol carbonates were made by deprotonating ketones with
NaHMDS/TMEDA at -78 °C followed by the quenching with
allyl chloroformate. All carbonates were isolated with over 98/2
(36) Wagner, P. J.; Liu, K. C; Noguchi, Y. J. Am. Chem. Soc. 1981, 103,
3837–3841.
(37) Oh, W. K.; Oh, H.; Kim, B. Y.; Kim, B. S.; Ahn, J. S. J. Antibiot.
2004, 57, 808.
(38) Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2005, 44, 6924.
9
J. AM. CHEM. SOC. VOL. 131, NO. 51, 2009 18351

A R T I C L E S
Trost et al.
Table 10. DAAA of Allyl Enol Carbonates of Various Acyclic Alkyl,
Alkenyl and Alkynyl Ketones
under the standard conditions went to completion in 5 h to afford
ketone 100 in 94% yield and 88% ee (Table 10, entry 1).
Comparison of the enantioselectivity in the DAAA of 68 (94%
ee, Table 8, entry 1), Z-2 (88% ee) and Z-15 (60% ee, Scheme
4) may suggest that the enantio-recognition step involves not
only steric effects of R1 and R2, but also some electronic effects
such as π-stacking interactions between the substrate and the
Table 9. DAAA of Allyl Enol Carbonates of Various Acyclic Aryl
Ethyl Ketones
a Conversion based on GC analysis.
ligand. The higher reactivity of aryl enol carbonate and alkenyl
enol carbonate than alkyl enol carbonate indicates that the
decarboxylation step is probably the rate determining step since
the lower pKa of the aryl and alkenyl ketones (presumably the
inductive effect of sp2 substituents) should facilitate the decar-
boxylation. Similarly the reaction of enol carbonate 101,
obtained as a 25/1 Z/E isomer mixture, reached full conversion
in 15 min to form the corresponding product 102 in 93% yield
and 91% ee (entry 2). The DAAA of Z-enol carbonate of alkyl
ketones was less successful. The reaction of 16 (Z/E > 98:2)
went to completion in 16 h, detected by GC analysis; however,
the ee of the product 103 was only moderate (46% ee) (entry
3). Fortunately, this limitation was overcome by the use of the
E-isomer; the ee jumped to 94% (entry 4). Similarly, excellent
conversions and good ee’s of the E-enol isomers were obtained
when R1 was as simple as an ethyl group (17, entry 5), or when
R1 was a sterically unhindered linear alkynyl group (18, entry
6).
Mechanism Studies of Palladium-Catalyzed DAAA Reac-
tion of Enol Carbonates. The highly conserved regioselectivity
in the decarboxylative alkylation of enol carbonates suggests
that proton-shuffling between the product and the palladium
enolate intermediate is negligible. However, the crossover
experiment conducted by Stoltz et al. showed a complete
scrambling of the allyl and the ketone moieties.39 To rule out
that this is not specific to certain substrates, certain ligands or
certain solvents, we performed a similar crossover experiment
using deuterium labeled allyl enol carbonate of 2-methyltetralone
106 and 107 in the presence of L4, PHOX-i-Pr or dppe as ligand
in dioxane (Scheme 4). The reaction went to completion within
5 min in all cases. Mass spectral analysis of the products from
each reaction clearly showed that four peaks (m/z 200, 202, 203,
9
18352 J. AM. CHEM. SOC. VOL. 131, NO. 51, 2009

Palladium-Catalyzed DAAA of Unstabilized Ketone Enolates
A R T I C L E S
Scheme 4. Crossover Experiment Catalyzed by Pd/L4, PHOX-i-Pr or dppe Ligand
Table 11. Acidic Additive Effect in the Palladium-Catalyzed DAAA
Reaction
Scheme 5. “Inner Sphere” and “Outer Sphere” Nucleophilic
Addition to π-Allylpalladium
entry
solvent
additive
time (min) 69% (ee%) 108% 109%
1
2
3
4
5
6
dioxane none
120
30
15
15
10
<5
94 (94)
94 (94)
90 (93)
17 (81)
71 (87)
8 (83)
6
6
10
83
27
92
-
0
9
91
22
76
dioxane MeCH(CO2Me)2
dioxane CH2(CO2Me)2
dioxane CH2(COMe)2
THF
THF
CH2(CO2Me)2
CH2(COMe)2
and 205) of nearly equal intensity were found implying a
complete scrambling of the six possible products. This experi-
ment confirmed complete crossover occurred. Such scrambling
suggests that any ion-pair undergoes ion exchange faster than
collapse to form products.
ylmalonate (pKa ) 15.9), there was a slight increase in the
amount of the protonated product 108 together with the same
amount of 109 (entry 3). The addition of one equivalent of
acetoacetone (pKa ) 13.3), eventually produced a large amount
of proton transfer products; the yield of propiophenone was
increased to 83% and allyl acetoacetone was obtained in 91%
yield (entry 4). With the other conditions unchanged, the proton-
transfer process was more severe in THF than in dioxane (entry
5 vs 3 and entry 6 vs 4).
If the scrambling in the above crossover experiment occurred
at the stage of palladium enolate, which means that palladium
enolates are completely charge-separated, then, it is hard to
explain why the decarboxylative alkylation reactions of enol
carbonates are highly regioselective and the possible diallylation
is largely minimized compared with the alkylation of preformed
lithium enolates. If the palladium enolate is completely charge-
separated, in the presence of an acidic additive the basic “naked”
enolate should be protonated by the additive. To regenerate the
Pd(0) catalyst, the anion of the additive is required to react with
the π-allylpalladium and to simplify the reaction, the alkylation
of the additive is best if made irreversible. Taking into account
the convenience to tune the acidity of the additive, we decided
to use 1,3-dicarbonyl compounds as additives. The pKa of a
simple ketone such as propiophenone is about 24.4 in DMSO,
and the pKa of dimethyl methylmalonate is about 18 in DMSO,
so it is acidic enough to protonate the enolate of propiophenone.
We subjected enol carbonate 68 to the DAAA reaction in the
presence of one equivalent of dimethyl methylmalonate and
found no change of the reaction (Table 11, entry 2 vs entry 1).
In the presence of one equivalent of the more acidic dimeth-
There lacks pKa values of enol carbonates in DMSO, however,
the pKa of HCO3- is 10.3 in water, which is lower than that of
dimethyl malonate (pKa ) 12.9 in water) but higher than that
of acetoacetone (pKa ) 9.0 in water). Therefore, it is probable
that the protonation did not occur on the enolate but on the
carbonate. The carbonate anion is more stabilized than the
enolate anion due to the delocalization of the anion on two
oxygen atoms, so the palladium carbonate should be more
charge separated than that of the palladium enolate. It is probably
also the stage that scrambling of the electrophile and nucleophile
may occur.
There are two possible mechanistic pathways for the recom-
bination of the π-allylpalladium complex and the enolate. One
is an “inner sphere” mechanism: the nucleophile coordinates
to the metal followed by a bond-forming reductive elimination
(Scheme 5, A). The other mechanism is an “outer sphere” one:
the nucleophile directly adds to one of the carbons of the allyl
moiety and substitutes the Pd complex (Scheme 5, B). Arbi-
trarily, “soft nucleophiles” with pKa < 20 favored the “outer
sphere” pathway and “hard nucleophiles” with pKa > 20 favored
(39) (a) Trost, B. M.; Fullerton, T. J. J. Am. Chem. Soc. 1973, 95, 292. (b)
Trost, B. M.; Weber, L. J. Am. Chem. Soc. 1975, 97, 1611. (c) Trost,
B. M.; Verhoeven, T. R. J. Org. Chem. 1976, 41, 3215. (d) Trost,
B. M.; Weber, L.; Strege, P. E.; Fullerton, T. J.; Dietsche, T. J. J. Am.
Chem. Soc. 1978, 100, 3416. (e) Trost, B. M.; Verhoeven, T. R. In
ComprehensiVe Organometallic Chemistry; Wilkinson, G., Stone,
F. G. A., Abel, E. W., Eds.; Pergamon: Oxford, 1982; Vol. 8, p 799.
(f) Fiaud, J. C.; Legros, J. Y. J. Org. Chem. 1987, 52, 1907. (g) Suzuki,
T.; Fujimoto, H. Inorg. Chem. 1999, 38, 370.
9
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A R T I C L E S
Trost et al.
Scheme 6. Palladium-Catalyzed DAAA Reaction of cis-110
the “inner sphere” pathway.40 Previous stereochemistry studies
suggested that unstabilized ketone enolates, including potas-
sium,41 lithium,42 tin,43 zinc,44 and boron enolates,44 attack
π-allylpalladium complexes through the “outer sphere” mech-
anism. Recently, Braun et al. also proved that the palladium-
catalyzed allylic alkylation of unstabilized lithium enolate was
a net retention-of-configuration process favoring the “outer
sphere” mechanism.12 In the palladium-catalyzed DAAA of enol
carbonates, the palladium enolate species are formed in situ as
nucleophiles and presumably they may behave similarly as other
metal enolates to attack π-allylpalladium through an “outer
sphere” pathway. On the other hand, since there is no other
countercation, it is quite reasonable to believe that the palladium
enolate may covalently bond or at least form a contact ion-
pair, especially in nonpolar solvents such as toluene. This was
implied by Tsuji’s early work, which showed that the major
competitive pathway of the decarboxylative allylic alkylation
of enol carbonates was the formation of conjugated enone, which
was proposed involving a ꢀ-hydride elimination of the co-
valently bonded palladium enolate.45 Stoltz and Goddard et al.
recently reported a theoretical calculation on the mechanism of
palladium-catalyzed DAAA reaction in the presence of PHOX-
t-Bu ligand. The authors claimed that the penta-coordinated
π-allylpalladium enolate complex was as stable as the charge
separated palladium enolate and the product was formed by the
reductive elimination of the η1-allylpalladium enolate complex
through a seven-membered ring transition state.46
To shed some light on this question, we synthesized enol
carbonate 110 and subjected it to the “standard” conditions we
used in the palladium-catalyzed DAAA reactions
(Pd2dba3CHCl3, L4, dioxane, rt). A nearly perfect kinetic
resolution was observed; one enantiomer of 110 reacted rapidly
within 1 h to afford the single diastereomer 111 in 39% yield
(78% based on 50% theoretical yield) and 99% ee (Scheme 6).
The other enantiomer was not touched even after 12 h at rt and
it was recovered in 37% yield (74% based on 50% theoretical
yield) and 99.5% ee. A small amount of O-alkylation product
112 was also isolated (6%). The relative stereochemistry of 111
was assigned by 1HNMR and X-ray crystallography (Figure 4).
The tetralone moiety and the phenyl group were cis. Since the
ionization of 110 should most likely follow the same anti-
addition mechanism as other allyl carbonates, the retention of
configuration of the product strongly suggests that the alkylation
step should also be an anti-nucleophilic addition. Thus, the
alkylation is an “outer-sphere” process, not an “inner-sphere”
one.
Similar results were observed in the reaction of the trans-
isomer 114; only the trans- diastereomer 113 was obtained.
Compared with the reaction of 110, the reaction of 114 was
significantly slower and was stopped after 8 h. Besides, a
significant amount of the O-alkylation product 116, 2-methyl-
1-tetralone (115) was also isolated. The reaction rates of the
two enantiomers of 114 were also significantly different so that
only one reacted in the given reaction time (eq 17).
Although it is highly likely that the π-allylpalladium complex
is in some degree covalently bonded with the enolate, it does
not necessarily mean that the covalently bonded palladium
enolate is involved in the transition state of the alkylation step.
As a comparison, the preformed lithium enolate prepared by
the deprotonation of 2-methyl-1-tetralone (115) by LDA was
reacted with allyl acetate 117 in the presence of the same
(40) Akermark, B.; Jutand, A. J. Organomet. Chem. 1981, 217, C41.
(41) (a) Trost, B. M.; Keinan, E. Tetrahedron Lett. 1980, 21, 2591. (b)
Fiaud, J. C.; Malleron, J. L. J. Chem. Soc.-Chem. Commun. 1981,
1159.
(42) Trost, B. M.; Self, C. R. J. Org. Chem. 1984, 49, 468.
(43) (a) Negishi, E.; Matsushita, H.; Chatterjee, S.; John, R. A. J. Org.
Chem. 1982, 47, 3188. (b) Negishi, E. I.; John, R. A. J. Org. Chem.
1983, 48, 4098.
(44) Shimizu, I.; Tsuji, J. J. Am. Chem. Soc. 1982, 104, 5844.
(45) Keith, J. A.; Behenna, D. C.; Mohr, J. T.; Ma, S.; Marinescu, S. C.;
Oxgaard, J.; Stoltz, B. M.; Goddard, W. A. J. Am. Chem. Soc. 2007,
129, 11876.
(46) Hogen-Esch, T. E.; Smid, J. J. Am. Chem. Soc. 1965, 87, 669.
Figure 4. X-ray structure of 111.
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Palladium-Catalyzed DAAA of Unstabilized Ketone Enolates
A R T I C L E S
enantioselectivity were achieved in a broad range of substrates.
Our studies suggested that solvent plays important roles in this
reaction; for reactions to generate ketones bearing quaternary
chiral centers, the nonpolar solvent toluene is the solvent of
choice leading to the highest enantioselectivity. For reactions
to generate ketones with a tertiary chiral center, dioxane is the
best solvent to minimize the equilibrium between the product
and the enolate intermediate, and hence minimize the protonated
and the diallylated side products.
The DAAA of the enol carbonates of aromatic ketones is
faster than that of aliphatic ketones, presumably because the
pKa of aromatic ketones is 2 or 3 units lower than the aliphatic
ketones and thus decarboxylation of conjugated ketones is faster.
The opposite enantiomers were obtained in the reaction of the
E-enolate and the Z-enolate. This suggests that there is no
equilibrium between the E-enolate and the Z-enolate through
the C-bound palladium enolate. We have demonstrated that the
E-enolate is more reactive than the corresponding Z-enolate and
better enantioselectivity can be obtained in the allylation of the
E-enolate as well. For a ketone with a big R1 group and a small
R2 group, the Z-enol carbonate is more readily prepared. In this
case, good enantioselectivity can be obtained since most
important factor is the interaction between R1 and the chiral
catalyst. For a ketone possesses a small R1 group and a small
R2 group, the E enol carbonates can be readily synthesized by
the use of LiTMP-LiBr as base. Generally high enantioselec-
tivities were achieved for the allylation of those ketones via
their E-enol carbonates.
Mechanistic studies revealed that the palladium enolate forms
a tight ion pair in less polar solvents, such as toluene and
dioxane. The scrambling of the enolate moiety and the allyl
moiety before the alkylation step probably occurs at the
palladium carbonate stage, not at the palladium enolate stage.
The C-C bond formation is more likely an “outer sphere” SN2
substitution than the alternative “inner sphere” reductive
elimination of the palladium enolate.
palladium catalyst (eq 18). Only the cis-product 111 was
obtained in 78% yield and 87% ee. This is in agreement with
Braun’s observation that the addition of lithium enolate to
π-allylpalladium was an “outer sphere” anti-attack.11 Interest-
ingly, in contrast to the reaction of enol carbonate 110, the
opposite enantiomer (-)-111 was obtained employing the same
enantiomer of ligand L4.
On the basis of the above information, we proposed a
mechanism as shown in Scheme 7. After the initial ionization,
a Pd carbonate intermediate is formed. The decarboxylation step
is probably the rate-determining step especially for simple
unsubstituted allyl enol carbonates of sterically less hindered
ketones. Since the carbonate anion is stabilized by delocalization,
it is probably at this stage scrambling of the π-allylpalladium
cation and the carbonate anion as well as protonation of the
carbonate by an acidic proton source may occur. The decar-
boxylation must be assisted by the Pd complex;15 therefore, the
enolate is generated in the presence of a π-allylpalladium
complex very close to it. Since there is no other countercation
in the system, the unstabilized enolate anion and the cationic
π-allylpalladium complex probably form a tight ion-pair caged
by solvent molecules. This may explain why less proton-transfer
related byproduct were found in dioxane than in THF, since
dioxane is better at stabilizing caged ion-pairs.47 The palladium
enolate ion-pair probably also equilibrates with the covalently
bonded palladium enolate, but the alkylation occurs only through
an “outer sphere” SN2 attack of the enolate to the π-allylpal-
ladium complex.
Experimental Section
All reactions were carried out under an atmosphere of nitrogen
or argon in oven-dried glasswares with magnetic stirring, unless
otherwiseindicated.Tris(dibenzylideneacetone)palladium(0)monochlo-
roform complex, Pd2dba3 ·CHCl3 was prepared by the procedure
of Ibers.48 Ligands were prepared by literature procedures. All other
reagents were used as obtained unless otherwise noted. Flash
Chromatography was performed with EM Science silica gel
(0.040-0.063 µm grade).1,4-Dioxane for palladium-catalyzed reac-
tions were freshly distilled from sodium. Other solvents were dried
by J. C. Meyer’s Solvent Purification System. Proton nuclear
magnetic resonance (1H NMR) data were acquired on a Mercury
400 (400 MHz) or on a Varian Unity Inova-500 (500 MHz)
spectrometer. Chemical shifts are reported in delta (δ) units, in parts
per million (ppm) downfield from tetramethylsilane. Carbon-13
nuclear magnetic resonance (13C NMR) data were acquired at 100
MHz on a Mercury 400 or at 125 MHz on a Varian Unity Inova
500 spectrometer. Chemical shifts are reported in ppm relative to
the center line of a triplet at 77.1 ppm for chloroform-d. Infrared
(IR) data were recorded as films on sodium chloride plates on a
Perkin-Elmer Paragon 500 FT-IR spectrometer. Absorbance fre-
quencies are reported in reciprocal centimeters (cm-1). Elemental
analyses (Anal.) were performed by M.-H.-W. Laboratories of
Pheonix, AZ. Chiral HPLC analyses were performed on a Themo
Conclusion
In the presence of enantiopure chiral ligand L4, palladium-
catalyzed DAAA of enol carbonates is a quite general method
for the asymmetric synthesis of cyclic and acyclic ketones with
either a quaternary or a tertiary R-center. The reaction conditions
are extremely mild; thus, it has quite broad functional group
compatibility. Compared with the allylic alkylation of preformed
lithium enolates, the nucleophile is structurally much simpler
since there is no other counterion in the reaction. This makes
the DAAA reaction much more tolerant to the structural
diversity of the substrate. As a result, excellent yield and
(48) (a) Trost, B. M.; Vanvranken, D. L.; Bingel, C. J. Am. Chem. Soc.
1992, 114, 9327. (b) Trost, B. M.; Bunt, R. C.; Lemoine, R. C.;
Calkins, T. L. J. Am. Chem. Soc. 2000, 122, 5968.
(47) Ukai, T.; Kawazura, H.; Ishii, Y.; Bonnet, J. J.; Ibers, J. A. J.
Organomet. Chem. 1974, 65, 253.
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A R T I C L E S
Trost et al.
Scheme 7. Plausible Mechanism for Palladium-Catalyzed DAAA of Enol Carbonates
Separation Products Spectra Series P-100 or 200 and UV100 (254
nm) using Chiralcel columns (OD-H, AD-H, IA, IB or IC) eluting
with heptane/iso-propanol mixtures indicated. Optical rotations were
measured on a Jasco DIP-1000 digital polarimeter using 5 cm cells
and the sodium D line (589 nm) at ambient temperature in the
solvent and concentration indicated.
rapidly stirred suspension at 0 °C and under nitrogen was added a
2.4 M solution of n-BuLi/hexanes (1.70 mL, 4.15 mmol, 2.4 equiv)
dropwise over a 3-min period. After being stirred for additional 15
min, the resulting pale yellow solution was cooled to -78 °C and
a solution of 3-pentanone (153 mg, 1.78 mmol, 1 equiv) in 1.5 mL
of DME was added dropwise. After 15 min, TMEDA (0.62 mL,
4.15 mmol, 2.4 equiv) was added dropwise over a 3-min period.
After another 15 min, a precooled (-78 °C) solution of allylchlo-
roformate (241 mg, 2.00 mmol, 1.1 equiv) in 1.4 mL of DME was
added at -78 °C. After 30 min at -78 °C the reaction was removed
from the bath and was allowed to warm to room temperature. The
reaction was quenched with 5% KH2PO4 aqueous solution and
transferred into a separatory funnel. It was extracted twice with 25
mL of diethyl ether. The combined organic layer was washed with
brine, dried over anhydrous magnesium sulfate and concentrated
in Vacuo. The residue was purified by silica gel column chroma-
tography eluting with 2-3% diethyl ether in petroleum ether to
afford 265 mg of colorless oil (90%). The E/Z ratio was determined
by 1H NMR to be 18:1 [by the signal of the CH3 at δ) 1.64 (d, J
) 7.2 Hz, major) and 1.59 (dt, J ) 6.9, 1.4 Hz, minor)]. Rf ) 0.35
(diethyl ether/ petroleum ether 1:9); IR (film): V˜max ) 2977 (m),
1756 (s), 1694 (m), 1459 (m), 1386 (m), 1365 (m), 1276 (s), 1245
(s), 1167 (s), 1031 (w), 983 (m), 942 (m), 916 (m), 783 (w), 734
Typical Procedure for the Preparation of the Kinetically
Controlled Z-Allyl Enol Carbonates. (Z)-Allyl 1-Cyclohexenyl-
1-propenyl Carbonate (2). To a clean dry 100 mL flask with a
magnetic stirring bar was loaded sodium hexamethyldisilazane
(Aldrich, 97%, 0.86 g, 4.5 mmol) stored in a glovebox under
nitrogen. The flask was cooled in a dry ice-acetone bath for 5 min
and THF (20 mL) was transferred to this flask with a syringe. The
suspension was warmed to 0 °C with stirring to make a clear
solution and TMEDA (freshly distilled from calcium hydride, 0.68
mL, 4.5 mmol) was added. The mixture was cooled to -78 °C
again and a solution of 1-cyclohexenyl-1-propanone (1, 520 mg,
3.76 mmol) in 5 mL of THF was added slowly over 5 min. The
reaction mixture was stirred for 1 h, and it was transferred through
a cannula into a solution of allyl chloroformate (0.48 mL, 4.5 mmol)
in 5 mL of THF at -78 °C. The reaction was stirred for 5 min and
it was quenched with saturated aqueous ammonium chloride
solution (10 mL). The mixture was extracted with diethyl ether
(20 mL) twice. The combined organic layer was washed with brine
(20 mL), then it was dried over anhydrous magnesium sulfate. After
filtration and concentration in vacuo, the residue was purified by
column chromatography on silica gel to afford the title compound (0.70
g, 84%) after purification by flash column chromatography eluting with
5% diethyl ether in petroleum ether. Colorless oil; Rf ) 0.41 (Diethyl
ether/petroleum ether 1:9); IR (film): V˜max ) 3047 (w), 2931 (s), 2861
(s), 1760 (s), 1664 (m), 1448 (s), 1364 (s), 1304 (s), 1248 (s), 1216
1
cm-1 (m); H NMR (500 MHz, CDCl3): δ ) 5.95 (ddt, J1 ) 17.2
Hz, J2 ) 10.5 Hz, J3 ) 5.7 Hz, 1H), 5.37 (dq, J1 ) 17.2 Hz, J2 )
1.4 Hz, 1H), 5.28 (dq, J1 ) 10.5 Hz, J2 ) 1.1 Hz, 1H), 5.24 (q, J
) 7.2 Hz, 1H), 4.64 (m, 2H), 2.31 (q, J ) 7.6 Hz, 2H), 1.64 (d, J
) 7.2 Hz, 3H), 1.04 (d, J ) 7.6 Hz, 3H);13C NMR (125 MHz,
CDCl3): δ ) 153.8, 150.9, 131.5, 119.1, 111.8, 68.7, 21.8, 11.5,
11.4. The structure as further confirmed by NOE experiment.
Typical Procedure for the Preparation of the Thermody-
namically Controlled Allyl Enol Carbonates. Allyl 2-Phenyl-
cyclohex-1-enyl Carbonate (4). To a clean dry 50 mL three-neck
flask with a magnetic stirring bar and a refluxing condenser was
loaded a suspension of sodium hydride (60% in mineral oil, 0.44 g,
11.0 mmol) and was purged with nitrogen. The sodium hydride
was washed three times with anhydrous hexane under nitrogen.
Freshly distilled TMEDA (1.51 mL) and 5 mL of anhydrous THF
were added to the flask and the suspension was added to a solution
of 2-phenylcyclohexanone (1.74 g, 10.0 mmol) in 5 mL of THF at
room temperature. The mixture was heated to reflux for 1 h. After
the enolate solution was cooled by an ice-water bath for 5 min, it
was transferred through a cannula into a solution of allyl chloro-
formate (1.07 mL, 10 mmol) in 5 mL of THF at 0 °C. After stirring
1
(s), 977 (s), 928 (s), 805 (s), 781 cm-1 (s); H NMR (400 MHz,
CDCl3): δ) 5.97 (ddt, J1 ) 17.1 Hz, J2 ) 10.4 Hz, J3 ) 5.8 Hz, 1H),
5.87 (bs, 1H), 5.40 (dq, J1 ) 17.2 Hz, J2 ) 1.4 Hz, 1H), 5.35 (qd, J1
) 7.0 Hz, J2 ) 0.8 Hz, 1H), 5.30 (dq, J1 ) 10.5 Hz, J2 ) 1.2 Hz,
1H), 4.69 (dt, J1 ) 5.8 Hz, J2 ) 1.4 Hz, 2H), 2.13 (m, 4H), 1.71-1.54
(m, 4H), 1.64 (dd, J1 ) 7.2 Hz, J2 ) 0.6 Hz, 3H).13C NMR (100
MHz, CDCl3): δ) 153.1, 148.7, 131.7, 130.4, 123.7, 119.2, 110.2,
69.0, 25.4, 24.8, 22.6, 22.2, 11.2. Anal. calcd for C13H18O3: C, 70.24;
H, 8.16; Found: C, 70.50; H, 7.97.
Typical Procedure for the Preparation of the Kinetically
Controlled E-Allyl Enol Carbonates. Allyl (E)-Pent-2-en-3-yl
Carbonate (E-17). To a clean dry 100 mL flask was loaded TMP-
HBr (500 mg, 2.25 mmol, 1.3 equiv) and 25 mL of DME. To this
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Palladium-Catalyzed DAAA of Unstabilized Ketone Enolates
A R T I C L E S
for another 15 min, saturated aqueous ammonium chloride (10 mL)
was poured into the reaction flask. The mixture was extracted with
diethyl ether (20 mL) twice. The combined organic layers were
dried over anhydrous magnesium sulfate. After filtration and
concentration the residue was purified by column chromatography
eluting with 2% diethyl ether in petroleum ether to afford 1.87 g
of the title compound (72%). Colorless oil; Rf ) 0.37 (Diethyl ether/
petroleum ether 1:9); IR (film): V˜max ) 2938 (s), 1750 (s), 1444
5.08 (m, 1H), 4.99 (m, 1H), 4.64 (m, 2H), 2.86 (t, J ) 8.0 Hz,
2H), 2.39 (dt, J ) 8.1, 1.0 Hz, 2H), 1.83 (t, J ) 1.0 Hz, 3H), 1.80
(m, 3H); 13C NMR (100 MHz, CDCl3): δ ) 153.2, 140.7, 139.3,
135.3, 130.9, 127.4, 127.1, 126.5, 124.5, 120.0, 113.7, 71.7, 29.0,
27.5, 19.4, 16.6. Anal. calcd for C16H18O3: C, 74.39; H, 7.02; found:
C, 74.50; H, 7.12.
Typical Procedure for the Palladium-Catalyzed DAAA Reac-
tion of Allyl Enol Carbonates. 2-Methyl-2-(2-methylallyl)-3,4-
dihydronaphthalen-1(2H)-one (38). Two clean oven-dried test
tubes were individually charged with a magnetic stirring bar. One
test tube was loaded with Pd2(dba)3CHCl3 (5.2 mg, 0.0075 mmol)
and (R,R)-L4 ligand (9.2 mg, 0.0165 mmol); the other one was
loaded with 8(52 mg, 0.20 mmol). They are sealed and connected
with a double-end needle. The system was evacuated and flushed
with argon three times at which point 1.0 mL of degassed anhydrous
dioxane was added to both of the test tubes. After stirring for 20
min, the orange solution containing the catalyst was transferred
into the test tube containing the carbonate substrate. The color of
the reaction solution turned to light yellow immediately, and it
turned back to orange within 4 h. The reaction mixture was
concentrated in Vacuo and the residue was purified by column
chromatography to afford 38 mg of the title compound as a colorless
oil (89%). Chromatography on silica gel, eluent: 3% diethyl ether
in petroleum ether. Rf ) 0.44 (Diethyl ether/petroleum ether 1:9);
1
(m), 1367 (m), 1238 (s), 1178 (m), 1036 cm-1 (s); H NMR (400
MHz, CDCl3): δ ) 7.4-7.2 (m, 5H), 5.78 (ddt, J ) 17.2, 10.4,
5.5 Hz, 1H), 5.20 (ddd, J ) 11.3, 1.5, 1.5 Hz, 1H), 5.17 (ddd, J )
4.6, 1.5, 1.5 Hz, 1H), 4.51 (dt, J ) 5.7, 1.5 Hz, 2H), 2.42 (m, 2H),
2.33 (m, 2H), 1.84 (m, 2H), 1.76 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ ) 152.9, 143.5, 138.9, 131.4, 128.2, 127.7, 126.9, 126.0,
118.6, 68.5, 30.2, 27.2, 22.9, 22.6; HRMS (EI): [M]+ calcd for
C16H18O3, 258.1256; found: 258.1257.
Typical Procedure for the Preparation of the Substituted
Allyl Enol Carbonates. 2-Methylprop-2-en-1-yl 1H-Imidazole-
1-carboxylate. To a clean oven-dried 250 mL flask with a magnetic
stirring bar was charged with 1,1′-carbonyldiimidazole (4.86 g, 30.0
mmol) and 100 mL THF under nitrogen. The flask was cooled in
an ice-water bath. A solution of 2-methyl-prop-2-en-1-ol (1.44 g,
20.0 mmol) in 30 mL methylene chloride was added slowly and
stirred for 2 h. Most solvent was removed in Vacuo by a
rotaevaporator and the crude product was purified by silica gel
column chromatography eluted with 1:1 ethyl acetate/petroleum
ether to afford 3.23 g of the title compound as a white solid (97%).
Mp ) 36-38 °C; Rf ) 0.18 (30% ethyl acetate in petroleum ether);
IR(neat): V˜max) 1761 cm-1; 1H NMR (400 MHz, CDCl3): 8.17-8.11
(m, 1H), 7.43 (dd, J ) 3.5, 2.1 Hz, 1H), 7.07 (dd, J ) 1.5, 0.9 Hz,
1H), 5.08 (m, 1H), 5.04 (m, 1H), 4.80 (s, 2H), 1.82 (m, 3H);13C
NMR (100 MHz, CDCl3): δ ) 148.5, 138.3, 137.1, 130.7, 117.1,
114.9, 71.2, 19.4. HRMS (EI): M+ calcd for C8H10N2O2 166.0742,
found 166.0737.
2-Methyl-3,4-dihydronaphthalen-1-yl 2-Methylprop-2-en-1-
yl Carbonate (8). To the solution of NaHMDS (460 mg, 2.51
mmol) in 5 mL of DME at -78 °C was added 2-methyl-1-tetralone
(320 mg, 2.0 mmol) in 2 mL of DME. The solution was stirred at
-78 °C for 30 min. Meanwhile, another clean oven-dried 50 mL
flask was charged with 2-methylprop-2-en-1-yl 1H-imidazole-1-
carboxylate (399 mg, 2.0 mmol) and 5 mL DME. The solution
cooled to -78 °C was added boron trifluoride etherate (0.30 mL,
2.4 mmol). The solution was transferred into the solution of enolate
through a cannula under nitrogen and stirred for 30 min. One portion
of 10 mL saturated aqueous ammonium chloride was poured into
the reaction mixture followed by 10 mL diethyl ether. The mixture
was taken out from the bath and allowed to warm to ambient
temperature. The organic layer was separated and the aqueous layer
was extracted once with 10 mL diethyl ether. The organic layer
was combined and dried over magnesium sulfate. After filtration
and concentration in Vacuo the crude material was purified by silica
gel column chromatography eluted with 10% diethyl ether in
petroleum ether to afford the title compound as colorless oil (472
mg, 92%). Rf ) 0.34 (Diethyl ether/petroleum ether 1:9); IR (film):
1760 cm-1; 1H NMR (400 MHz, CDCl3): δ ) 7.20-7.07 (m, 4H),
Colorless oil; IR (film): 1682 cm-1; [R]D ) +45.3 (c ) 1.77,
25
CH2Cl2, >99% ee); HPLC (Chiralcel AD-H column; 2000:1
Heptane/Isopropanol; flow rate ) 1 mL of/min; t1 ) 15.1 min
(minor), t2 ) 17.6 min (major)); 1H NMR (400 MHz, CDCl3): δ )
8.04 (m, 1H), 7.46 (dt, J ) 7.5, 1.5 Hz, 1H), 7.30 (m, 1H), 7.24
(m, 1H), 4.83(m, 1H), 4.68 (m, 1H), 2.99 (t, J ) 6.5 Hz, 2H), 2.66
(dd, J ) 13.5, 0.7 Hz, 1H), 2.23 (dd, J ) 13.5, 0.7 Hz, 1H), 2.10
(ddd, J ) 13.9, 6.8, 6.8 Hz, 1H), 1.88 (ddd, J ) 13.9, 5.8, 5.8 Hz,
1H), 1.65 (m, 3H), 1.20 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
) 202.2, 143.2, 142.5, 133.0, 131.8, 128.6, 128.1, 126.7, 114.9,
45.0, 44.7, 33.6, 25.5, 24.5, 23.3. Anal. calcd for C15H18O: C, 84.07;
H, 8.47; found: C, 84.32; H, 8.55.
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health, General Medical Sciences
Grant GM13598, for their generous support of our programs. Mass
spectra was provided by the Mass Spectrometry Regional Center
of the University of California-San Francisco supported by the NIH
Division of Research Resources. We thank Chirotech (now Dow)
for their generous gifts of ligands and Johnson Matthey for gifts
of palladium salts.
Supporting Information Available: Crystallographic data for
compound 111 in cif format, experimental procedures, and
characterization data for all new compounds in pdf format. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JA9053948
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