Palladium-catalyzed allylic alkylation of carboxylic acid derivatives: N-acyloxazolinones as ester enolate equivalents

Article abstract of DOI:10.1002/anie.201105801

Triple A: A general asymmetric allylic alkylation of ester enolate equivalents at the carboxylic acid oxidation state is reported. N-Acylbenzoxazolinone-derived enol carbonates were synthesized and employed in the palladium-catalyzed alkylation reaction. The imide products were readily converted into a series of carboxylic acid derivatives without loss of enantiopurity.

Full text of DOI:10.1002/anie.201105801

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Angewandte
Communications
DOI: 10.1002/anie.201105801
Ester Enolate Alkylations
Palladium-Catalyzed Allylic Alkylation of Carboxylic Acid
Derivatives: N-Acyloxazolinones as Ester Enolate Equivalents**
Barry M. Trost,* David J. Michaelis, Julie Charpentier, and Jiayi Xu
The asymmetric alkylation of carbonyl compounds is one of
the most important methods for generating stereocenters in
organic synthesis.[1] The alkylation of ester enolates is
particularly useful as the resulting products can be converted
into a variety of carboxylic acid derivatives or reduced to
alcohols without loss of enantioenrichment at the a center.[2]
The most common procedures for asymmetric ester enolate
alkylations, however, involve the use of stoichiometric chiral
auxiliaries.[3,4] Attempts to render this asymmetric trans-
formation catalytic have achieved only limited success. For
example, successful asymmetric alkylations of specialized
carboxylic acid derivatives including oxindoles,[5] azalac-
tones,[6] and zinc enolates of glycine esters[7] have been
reported. A recent example of an asymmetric Pd-catalyzed
Claisen rearrangement of allyl phenylacetate demonstrated
an alternative strategy for obtaining enantioenriched ester
derivatives.[8] While these reports demonstrate the continued
importance of developing asymmetric alkylations of ester
derivatives, a highly general and enantioselective alkylation
of simple ester derivatives is still elusive.[9]
derivatives under mild conditions without prior activation. In
addition, the modularity of our diamino bis(phosphine)
ligands allowed for a new strategy for catalyst design wherein
the steric properties of the diaryl phosphines was varied to
enable high enantioselectivity.
From the outset, our goal was to develop an enantiose-
lective ester enolate alkylation where the products could be
easily derivatized under mild conditions to a variety of
carboxylic acid derivatives. Thus, our initial studies focused
on employing ester surrogates at the carboxylic acid oxidation
state that are known to hydrolyze under mild conditions
(Table 1). One significant advantage of using these activated
Table 1: Auxiliary screen of ester enolate equivalents.[a]
As a solution to this unmet need, we and others have
recently reported the use of ester enolate surrogates in the
asymmetric allylic alkylation (AAA) reaction, including
2-acylimidazoles,[10] N,N-dialkyl amides,[11] and acylsilanes.[12]
However, there are several drawbacks to each of these
methods. First, the acylimidazoles and acylsilanes require
multiple steps to synthesize from carboxylic acids. Second,
subsequent transformations that take advantage of the
reactivity of the carboxylic acid functionality are not straight-
forward. Thus, a general enantioselective method for enolate
alkylations of simple ester derivatives that can function
directly in subsequent transformations is still elusive.[13] We
report herein the palladium-catalyzed asymmetric alkylation
of N-acylbenzoxazolinone-derived enol carbonates, which
represents a general asymmetric alkylation of ester enolate
equivalents at the carboxylic acid oxidation state.[14] Impor-
tantly, the resulting enantioenriched imide products are easily
converted into the acid, ester, thioester, amide, or alcohol
[a] Reactions performed on 1–2 mmol scale. Yields are of the isolated
products. Enantiomeric excess (ee) values determined by HPLC analysis
on a chiral stationary phase; absolute configuration of 2a–c not
determined. Reagents and conditions: a) NaHMDS, DME, À788C, then
allylchloroformate; b) [Pd2dba3]·CHCl3 (2.5 mol%), 4 (6 mol%), dioxane,
RT, 16 h. DME=1,2-dimethoxyethane, dba=dibenzylideneacetone,
NaHMDS=sodium bis(trimethylsilyl)amide. [b] Run in toluene.
esters over previously reported systems is the ability to
quickly access substrates in one step from any carboxylic acid
by amide bond formation. A major challenge in the alkylation
of ester derivatives is the propensity of the intermediate
enolate to undergo elimination to form a ketene. We believed
that the recently developed decarboxylative allylic alkylation
methodology[15,16] provided a unique way to avoid this
problem because the enolate could be trapped as an enol
carbonate at low temperature where competing ketene
formation would be minimized. The enol carbonate might
then be purified and employed in the AAA reaction. In our
initial studies, we found that a variety of enol carbonates
derived from ester equivalents could indeed be isolated,
including N-acyl imidazoles, indoles, and oxazolinones
(Table 1). In the ensuing decarboxylative asymmetric alkyla-
tion reaction using our anthracenediamine-derived bisphos-
phine ligand 4 (see below), the best yield and enantioselec-
[*] Prof. B. M. Trost, Dr. D. J. Michaelis, J. Charpentier, Dr. J. Xu
Department of Chemistry, Stanford University
Stanford, CA 94305-5080 (USA)
E-mail: bmtrost@stanford.edu
Homepage: http://www.stanford.edu/group/bmtrost/
[**] We thank the National Science Foundation and the National
Institutes of Health, General Medical Sciences (Grant GM33049),
for their generous support of our programs. D.J.M. also thanks the
National Institutes of Health for a postdoctoral fellowship
(F32GM093467-01).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105801.
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tivity was observed with N-acylbenzoxazolinone-derived
substrate 1d. Further optimization studies, therefore, focused
on the N-acyloxazolinone-derived enol carbonates as sub-
strates for the asymmetric alkylation reaction.
The major challenge with employing the benzoxazoli-
none-derived enol carbonates was the low yield of the enol-
forming reaction. Careful analysis of the crude reaction
mixture showed that the remainder of the yield was consumed
by side reactions resulting from ketene elimination, with
benzoxazolinone 3 as the major side product [Eq. (1); THF =
a variety of functional groups including primary alkyl
chlorides [Eq. (5)] could all be isolated in good yield. These
enol carbonates are relatively stable and can be stored at low
temperature for several months without decomposition.
Having established that imide-derived enol carbonates
could be synthesized in good yield, we then sought to improve
the enantioselectivity of the asymmetric alkylation process
(Table 2). By varying both the ligand (entries 1–4) and solvent
Table 2: Optimization of asymmetric alkylation reaction.
Entry[a]
Ligand
Solvent
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
4
5
6a
7
6a
6a
6a
6a
6b
6c
6d
8
dioxane
dioxane
dioxane
dioxane
toluene
CH2Cl2
THF
DME
THF
THF
THF
87
88
96
83
99
66
96
99
99
12
25
22
49
62
64
60
75
63
75
73
85
54
30
60
tetrahydrofuran]. As a solution to this problem, we found that
formation of the enolate in the presence of the chloroformate
provided the desired product 1d in much improved and
synthetically useful yields (65%). Our optimization studies
also demonstrated that the chloroformate acylating agent was
necessary for efficient generation of the enol carbonate. This
new procedure for enol carbonate formation proved excep-
tionally general. For instance, a wide range of chloroformate
electrophiles could be employed in the process, including
those substituted at the terminal [Eq. (2), (4)] and internal
positions of the olefin [Eq. (3), (5)]. The tolerance for
substitution on the N-acylbenzoxazolinone partner also
proved to be very general. Enol carbonates bearing longer
alkyl chains [Eq. (3)], b,b-disubstituted carbons [Eq. (4)] and
9
10[d]
11
12
THF
[a] Reactions run using 0.2 mmol enol carbonate 1d, 0.005 mmol
[Pd2(dba)3]·CHCl3, and 0.014 mmol ligand at 0.2m for 10–30 min.
[b] Yield of isolated products. [c] Determined by HPLC analysis on a
chiral stationary phase. [d] Run for 12 h.
(entries 5–8), we found that the product could be obtained
with 75% ee using the stilbene diamine-derived bisphosphine
ligand 6a in THF as solvent. We next varied the structure of
the phosphine ligand, believing that increasing the steric bulk
around the phosphines could increase the selectivity of the
reaction. We were pleased to find that this was indeed the
case; o-tolyl-substituted bisphosphine 6b gave the product in
higher enantioselectivity (entry 9). This new approach to
ligand modification further demonstrates the modularity of
our class of enantiopure bisphosphine ligands and the ability
to selectively tune both the steric and electronic properties of
the ligand to improve selectivity. Other substitution on the
phosphine, however, did not lead to an increase in selectivity
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(entries 10, 11). In addition, varying the structure of the
diamine backbone to the 1,2-dicyclohexylethane diamine (8)
led to decreased yield and enantioselectivity (entry 12).
With optimal conditions in hand, we next explored the
substrate scope of the asymmetric alkylation reaction
(Table 3). In general, the substituted allyl carbonates proved
when prochiral electrophiles are employed (entry 4, > 95:5
d.r.).[17] The AAA reaction also proceeds efficiently with a
variety of substituents at R1. Mono- and disubstitution at the
b position of the enol is tolerated (entries 6, 12). However,
b,b-disubstituted enols (entries 12, 13) and longer alkyl chains
(entry 15) gave a small decrease in the enantioselectivity of
product formation. A variety of functional groups are also
tolerated in the reaction, including primary alkyl chlorides
(entry 14), esters (entry 15), and silyl ethers (entries 16, 17).
This process is also readily conducted on large scale: when
Table 3, entry 2 was conducted on 4.0 mmol scale, 2e was
obtained in 66% yield and 97% ee.
Table 3: Substrate scope for the asymmetric alkylation reaction.
A major goal of this research was to develop an efficient
asymmetric alkylation of ester enolate equivalents that could
be derivatized to any number of carboxylic acid derivatives
under mild conditions. We were delighted, therefore, to find
that the alkylated products can be functionalized under very
mild conditions without significant loss of enantiopurity
(Scheme 1).[2] The benzoxazolinone moiety was cleaved
Entry[a]
R1
R2
Yield
[%][b]
ee
[%][c]
1
2
Me
Me
2d
2e
99
89
85
97
3[d]
4[e]
Me
Me
2 f
82
58
82
99
2g
5[d,f]
6[g]
Me
Et
2h
2i
96
68
90
88
7[h]
Et
2j
93
97
8[h]
nPr
nPr
2k
2l
76
83
94
97
92
95
9[f]
10[h]
2m
11
CH2Ph
2n
73
94
12
13[f]
cyclohexyl
cyclohexyl
2o
2p
77
80
80
83
14[h]
15[g]
16[h]
2q
2r
66
71
94
95
79
95
Scheme 1. Functionalization of chiral acylbenzoxazolidinone 2e.
Bn=benzyl, LAH=lithiumaluminum hydride.
2s
efficiently to generate the corresponding acid (9), ester (10),
and thioester (11) by simply treating the imide with the
respective lithium anion of the nucleophile. In addition,
reduction to the alcohol (12) proceeded in good yield.
Importantly, little or no racemization of the a stereocenter
of the products was observed for these transformations. The
absolute stereochemistry of the alkylation was confirmed by
comparison of acid 9 to previously reported materials.[18]
Having established that the benzoxazolinone auxiliary
was an excellent leaving group for substitution reactions, we
next wondered what additional nucleophiles could react with
the enantioenriched imide products. We found that simple
treatment of product 2s with a primary amine led to
formation of amide product 13 in just 4 h in high yield
(97%) and with complete retention of enantiopurity [Eq. (6);
TBDPS = tert-butyldiphenylsilyl]. This transformation dem-
onstrates the mild reaction conditions under which substitu-
tion of the benzoxazolinone can occur, even when compared
with Evansꢀ chiral oxazolidinone auxiliary, which generally
17[d]
2t
72
81
[a] See Table 1 for experimental details. Reactions run on 0.1–0.2 mmol
scale for 4–24 h. [b] Yield of isolated products. [c] Determined by HPLC
analysis on a chiral stationary phase. [d] Using ligand 6a. [e] Diastereo-
meric ratio of 2g is >95:5, see Ref. [14] for relative stereochemistry
assignment. [f] Linear/branched ratio of 2h, 2l, 2p is >10:1. [g] Run at
508C. [h] Run with 5 mol% [Pd2(dba)3]·CHCl3 and 14 mol% 6b.
to be excellent substrates. Specifically, substitution at the
internal position of the olefin (entries 2, 3), the allylic position
(entry 4) or the terminus of the olefin (entry 5) is tolerated
and in most cases serves to increase the enantioselectivity of
the reaction over the simple allyl electrophile. Where
regioselectivity in the alkylation is possible, excellent regio-
meric ratios are observed in favor of the linear product
(entries 5, 9, 13, > 10:1 linear/branched selectivity). In
addition, the reaction proceeds with high diastereoselectivity
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alcohol, and amide derivatives without need for prior
activation or oxidation of the substrate, providing easy
access to a variety of highly useful enantioenriched building
blocks for organic synthesis.
Experimental Section
General procedure for synthesis of enol carbonates: Into a 25 mL
round bottom flask was placed 3-propionylbenzo[d]oxazol-2(3H)-one
(0.466 g, 2.43 mmol) and allylchloroformate (0.308 g, 2.56 mmol,
1.05 equiv) in 7 mL THF and the flask was cooled to À788C in a
dry ice/acetone bath. To this solution was slowly added a À788C
solution of sodium bis(trimethylsilyl)amide (0.492 g, 2.68 mmol,
1.1 equiv) in 7 mL THF via cannula. The reaction was stirred for 1 h
then quenched with pH 7 phosphate buffer. The mixture was poured
into a separatory funnel and the aqueous layer extracted with 3 ꢁ
30 mL Et2O. The combined organics were dried over Na2SO4 and
filtered through a short plug of silica gel. The solvent was then
removed and the product purified on a column of silica gel, eluting
with 5:1 hexanes/Et2O to give 0.434 g (65% yield) of the desired
product 1d as a colorless oil.
requires stoichiometric trialkylaluminum additives to effect
the analogous transformation.[19] In addition, this direct
conversion into amide products is a marked improvement
over our previous system[10] where the 2-acylimidazole
products had to be converted into the carboxylic acid
before subsequent amide bond formation, or racemization
would occur.
The absolute sense of stereochemistry in this decarbox-
ylative alkylation reaction can be rationalized using the wall
and flap cartoon model,[20] which was developed in our
laboratory to predict the selective formation of one enantio-
mer when the diphenylphosphinobenzoic acid-based chiral
ligand scaffolds are employed. Using the R,R enantiomer of
our stilbene diamine-derived ligand, our working model
correctly indicates that selective formation of the S enan-
tiomer of the allylation product should occur based on
unfavourable steric interactions in the transition state for
formation of the corresponding R enantiomer (Scheme 2).
The selective formation of the S enantiomer in this reaction is
also in accordance with the structure-based rationale pre-
sented by Lloyd-Jones and co-workers.[21]
General procedure for asymmetric alkylation reaction: Into an
oven-dried 2 Dram vial was placed [Pd2(dba)3]·CHCl3 (5.3 mg,
0.005 mmol, 0.025 equiv) and Trost stilbene ligand (R,R)-6b
(9.5 mg, 0.012 mmol, 0.06 equiv), and the vial was flushed with
argon from a balloon for 5 min. Freshly distilled and degassed THF
(1 mL) was then added and the solution was sonicated at room
temperature for ca. 20 min until the reaction turned from heteroge-
neous deep red to homogeneous deep red-orange in color. The
catalyst solution was then transferred via syringe to a degassed 2
Dram vial containing 1d (0.055 g, 0.2 mmol) in 1 mL degassed THF.
The reaction was stirred 10 min, at which time TLC showed complete
consumption of starting material. The solvent was then removed and
the product was purified on silica gel with 8:1 then 6:1 hexanes/Et2O
as eluent to give 0.044 g (96% yield) of the desired product with 85%
ee.
Received: August 16, 2011
Revised: September 2, 2011
Published online: November 16, 2011
Keywords: allylic alkylation · asymmetric catalysis ·
.
benzoxazolinones · ester enolates · palladium
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In summary, we report a general asymmetric allylic
alkylation of ester enolate equivalents at the carboxylic acid
oxidation state. Specifically, a variety of N-acylbenzoxazoli-
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yields and are excellent substrates for the palladium-cata-
lyzed asymmetric alkylation reaction. For the first time,
variation of the steric properties of the phosphine moiety on
this class of bis(phosphine) ligands was shown to provide
increased enantioselectivity in an allylic alkylation reaction.
An important improvement over previous methods is that the
activated ester derivatives are easily accessed from readily
available carboxylic acids by simple amide bond formation. In
addition, the enantioenriched imide products are readily
transformed to the corresponding acid, ester, thioester,
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