Palladium-catalyzed asymmetric allylic alkylation of 2-acylimidazoles as ester enolate equivalents

Article abstract of DOI:10.1021/ja103771w

A broad range of highly enantioenriched 2-acylimidazoles are synthesized by palladium-catalyzed decarboxylative asymmetric allylic alkylation (DAAA) of 2-imidazolo-substituted enol carbonates. The enantioenriched 2-acylimidazole products can easily be converted to the corresponding carboxylic acid, ester, amide, and ketone derivatives with complete retention of the enantiopurity. The synthetic utility of this new method is demonstrated in the short, efficient synthesis of cetiedil.

Full text of DOI:10.1021/ja103771w

Published on Web 06/15/2010
Palladium-Catalyzed Asymmetric Allylic Alkylation of 2-Acylimidazoles as
Ester Enolate Equivalents
Barry M. Trost,* Konrad Lehr, David J. Michaelis, Jiayi Xu, and Andreas K. Buckl
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received May 3, 2010; E-mail: bmtrost@stanford.edu
Table 1. Selected Optimization Studies
The stereocontrolled alkylation of carbonyl compounds is a staple
reaction in organic synthesis for the construction of highly enantioen-
riched materials. In particular, the alkylation of ester enolate equivalents
has found widespread use due to the versatility of the resulting ester
or amide products.1 Success in the field of ester enolate alkylations
has relied on the use of chiral auxiliaries to direct the stereochemical
outcome of the alkylation.2 Catalytic asymmetric ester enolate alky-
lations, although more desirable, are rare.3,4 Andrus and co-workers
have reported the alkylation of a single 2-acylimidazole derivative (1-
(1-methyl-1H-imidazol-2-yl)-2-(naphthalen-2-ylmethoxy)ethanone)5 with
allylic and benzylic bromides that gives products with 75-99% ee
under phase transfer catalysis using chiral cinchonidinium catalysts.
They later disclosed a similar, albeit less stereoselective, alkylation of
specifically phenethyl 2-naphthylacetate.6 While promising, these
examples have only been demonstrated for a 2-naphthyl substituent
and require superstoichiometric amounts of base and alkylating agents.
In this report we describe the first catalytic asymmetric allylic alkylation
(AAA) of a broad range of 2-acylimidazole-derived enol carbonates,
the products of which are easily converted to a variety of ketone and
carboxylic acid derivatives.
Yield
(%)b
ee
(%)c
entrya
solvent
Nu
R
Ln
3
1
2
3
4
5
6
7
8
9
10
Dioxane
CH2Cl2
Toluene
THF
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
1a
1a
1a
1a
1b
1c
1d
1b
1b
1b
Me
Me
Me
Me
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
3a
3a
3a
3a
3b
3c
3d
3b
3b
3b
89
10
83
65
96
95
99
99
93
99
87
n.d.
76
80
92
89
87
76
76
58
Ph
2-Tol
1-naph
Ph
Ph
Ph
a Reactions performed using 0.2 mmol of substrate, 2.5 mol % 2, and
6 mol % Ln in 1 mL of solvent at ambient temperature for 16 h.
b Isolated yields. c Determined by chiral HPLC analysis. n.d. ) not
determined.
The transformation of 2-acylimidazoles to carboxylic acid deriva-
tives was first reported by Ohta and co-workers.7 They found that while
2-acylimidazoles did not undergo acyl transfer reactions, alkylation
of the imidazole nitrogen generated an activated leaving group that
allowed substitution to occur (eq 1). Based on this finding, we
envisioned expanding the scope of our AAA reaction of enol carbonates
to include 2-acylimidazoles as the first efficient and general example of
catalytic asymmetric alkylations of ester enolate equivalents.
carbonates8 (4a-d) participate in the reaction to generate 2-a-
cylimidazole products 5a-d in high yield and high ee (entries 2-
5). Aryl and alkyl substitution on the enol carbonate are also
tolerated (entries 6-9). The mild reaction conditions also permit
the presence of alkynes (entry 6) and heteroaromatic substituents
(entry 9). A variety of O-protected R-hydroxyketones can also be
generated in good yield and ee using L2. To demonstrate the
scalability of this process, reaction of enol carbonate 1b was
performed on a 2 mmol scale using just 1 mol % 2 and 2.5 mol %
L1 to generate product 3b in 97% yield and 94% ee (entry 13).9
Our attention next turned to conversion of the 2-acylimidazole
products to the corresponding carboxylic acid or ketone derivatives.
While acyl transfer reactions of 2-acylimidazoles are well prece-
dented,10 we were unsure whether the transformations could be
performed without racemizing the R-keto stereocenter. We were
delighted to find that hydrolysis of the imidazole under standard
Our initial studies focused on the decarboxylative allylic alky-
lation reaction of allyl enol carbonates
1 catalyzed by
Pd2(dba)3 · CHCl3 (2) and L1 (Table 1, entries 1-4). While the
reaction proceeded in a number of solvents, conducting it in dioxane
generated alkylated product 3a with the highest yield and ee (entry
1). Varying the N-substituent on the imidazole portion of the enol
carbonate from methyl (1a) to phenyl (1b) led to higher yields and
a higher ee of the product 3b (entry 5). Further varying R to
2-methylphenyl (1c) or 1-naphthyl (1d) gave similar yields but led
to a small decrease in the ee of the products 3c-d (entries 6-7).
In addition, varying the ligand from L1 to L2-L4 gave product
3b in good yields, but with lower enantioselectivity.
The reaction scope under our optimized conditions (Table 1, entry
5) is summarized in Table 2. A variety of acyclic and cyclic allylic
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10.1021/ja103771w  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 8915–8917 8915

C O M M U N I C A T I O N S
Table 2. Reactions of Different Imidazole Enol Carbonates
with methyl triflate and then amino alcohol 13 produces cetiedil in
89% yield and 90% ee.
Scheme 1. Synthesis of Cetiedil
a Unless otherwise noted, reactions were performed using 0.2 mmol
substrate, 2.5 mol % 2, and 6 mol % L1 in 1 mL of solvent at ambient
temperature for 16 h. b Isolated yields. c Determined by 1H analysis of
the crude reaction mixture. d Determined by chiral HPLC analysis.
e Reaction run for 48 h. f L4 was employed. g L2 was employed.
h Reaction time was 30 min. i Performed on a 2 mmol scale with 1 mol
% 2 and 2.5 mol % L1 for 18 h. j 10:1 mixture trans/cis diene.
conditions (treatment with MeOTf in MeCN followed by addition of
H2O and DBU) gave carboxylic acid 6 in 85% yield with complete
retention of stereochemistry (eq 2). In a similar fashion, 2-acylimidazole
3b was converted to the benzyl ester derivative in 96% yield (eq 3).
During our derivatization studies we found that direct conversion of
the 2-acylimidazoles to amides or thioesters gave racemic products;
converting the 2-acylimidazole first to the acid and then to the amide
prevents racemization (eq 4). Conversion of imidazole ketone 5c to
the corresponding alkyl ketone by treatment of the methylated imidazole
with n-hexylmagnesium bromide also proceeded smoothly to give ketone
9 in good yield (eq 5). Synthesizing R-chiral aliphatic ketones using this
methodology circumvents the otherwise difficult alkylation of unsym-
metrical ketones where regioselective enolization is challenging.
In summary, we report the synthesis of highly enantioenriched
2-acylimidazoles by palladium-catalyzed decarboxylative asymmetric
allylic alkylation of 2-imidazolo-substituted enol carbonates. The
absolute configuration of the products of alkylation were established
by comparison of carboxylic acid 615 and our synthetic cetiedil13 to
known materials. In contrast to previously reported methods, the
catalytic asymmetric alkylation methodology presented herein is quite
general in scope for both the allylic electrophile and enolate nucleo-
phile. The enantioenriched 2-acylimidazole products can easily be
converted to the corresponding carboxylic acid, ester, amide, and ketone
derivatives with complete retention of the enantiopurity.
The synthetic utility of this new methodology is demonstrated
by the concise synthesis of cetiedil (Scheme 1). Cetiedil is currently
used clinically in racemic form for the treatment of vascular
disease.11 While enantiomerically pure cetiedil is generally obtained
by fractional crystallization,12 one asymmetric synthesis has been
reported.13 Ours begins with acylation of 1-phenylimidazole with
Weinreb amide 10 to give 2-acylimidazole 11. Formation of enol
carbonate 4i by O-acylation of the sodium enolate, followed by
decarboxylative allylic alkylation of 4i generates 2-acylimidazole
5i in 98% yield and 97% ee. Hydrogenation of the double bond in
5i gives ketone 12 in 90% yield and 90% ee.14 Treatment of 12
Acknowledgment. We thank the National Science Foundation
and the National Institutes of Health, General Medical Sciences
Grant GM33049, for their generous support of our programs. K.L.
thanks the Deutscher Akademischer Austausch Dienst (DAAD) for
a fellowship. D.J.M. thanks the NIH for a postdoctoral fellowship
(F32 GM093467-01).
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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(6) Andrus, M. B.; Harper, K. C.; Christiansen, M. A.; Binkley, M. A.
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