N-heterocyclic carbene-catalyzed enantioselective mannich reactions with α-aryloxyacetaldehydes

Article abstract of DOI:10.1021/ja9094044

(Chemical Equation Presented) N-Heterocyclic carbenes (NHCs) catalyze a new Mannich-type reaction to form β-amino acid derivatives in high yield and enantioselectivity. The reaction is initiated by the addition of an NHC to an C-aryloxyaldehyde followed by elimination of a phenoxide anion which generates an enol/enolate. A Mannich addition to a tosylimine proceeds with excellent control over enantioselectivity. In a new carbene catalysis concept, catalyst regeneration is promoted by return, or rebound, and acylation of the phenoxide group which served as the activating component in the first step of the catalytic cycle. The activated ester products formed in situ are manipulated to form a variety of useful compounds including β-amino acids, β-amino amides, and peptides.

Full text of DOI:10.1021/ja9094044

Published on Web 11/30/2009
N-Heterocyclic Carbene-Catalyzed Enantioselective Mannich Reactions with
r-Aryloxyacetaldehydes
Yasufumi Kawanaka, Eric M. Phillips, and Karl A. Scheidt*
Department of Chemistry, Center for Molecular InnoVation and Drug DiscoVery, Chemistry of Life Processes
Institute, SilVerman Hall, Northwestern UniVersity, EVanston, Illinois 60208
Received September 1, 2009; E-mail: scheidt@northwestern.edu
Scheme 1. Proposed Catalytic Pathway
The catalytic generation of enolates is a crucial enterprise due
to the broad utility of these nucleophiles in synthesis.1 Direct access
to enolates employing transition metals as catalysts has been
reported by many groups over the past decade.2 A complementary
strategy using secondary amines as catalysts has undergone a
resurgence of activity and become a powerful, general method for
enantioselective enolate additions.3 Most recently, N-heterocyclic
carbenes (NHCs) have emerged as a different class of small
molecules which catalyze and control new enolate reactions.4 In
addition to investigating carbene-catalyzed reactions to access
Umpolung reactivity patterns (e.g., acyl anions), we have been
developing access to new enolate reactions by the protonation of
homoenolate intermediates and oxidation of NHC-aldehyde ad-
ducts.5 An intriguing possibility for these carbene-catalyzed approaches
is to have an activating group on the aldehyde induce enolate formation
and then rebound, regenerating the catalyst and creating a useful
activated ester in the process.5e,6 Herein, we report a new enantiose-
lective Mannich reaction using this strategy (eq 1).
Table 1. Optimization of Conditionsa
entry
azolium salt
base
solvent
yield (%)b
ee (%)c
1
2
3
4
A
A
B
C
C
C
C
Et3N
Et3N
Et3N
Et3N
NaHe
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF/CH2Cl2
THF/CH2Cl2
6
-
30
37
31
24
59
72
-
68
88
85
95
94
5d
6d,f
7i
g
g
h
h
NaOC6H4NO2
NaOC6H4NO2
We explored additions to activated imines (Mannich reaction)
to investigate this new reaction and capture the enolate generated
in this process. The products would be ꢀ-amino carbonyl com-
pounds which are important in chemistry, biology, and medicine.7
Our idea for this reaction focused on accessing a particular Breslow
intermediate (I) from the initial tetrahedral intermediate (Scheme
1).8 With a properly tuned leaving group (OAr), this would induce
an elimination, generating aryloxy anion III and enol II. In the
presence of the imine, the Mannich reaction occurs and generates
acyl azolium IV. If properly balanced in terms of leaving group
ability vs nucleophlicity, the aryloxy anion could undergo acylation
which would (a) result in the formation of the ꢀ-amino ester (V)
and (b) allow the NHC to reenter the catalytic cycle. Several
challenges needed to be addressed for this pathway to be operative.
First, the leaving group must be competent in an elimination step
to generate the enol. Once ejected, this anion must be nucleophilic
enough to regenerate the catalyst after the desired C-C bond
forming process. Lastly, carbene addition to the secondary elec-
trophile (in this case, the imine) must be reversible.
a Reactions run with 10 mol % of azolium salt and base and 0.07 M
in solvent unless otherwise noted. b Isolated yields. c Determined by
HPLC. d 2 equiv of 1. e 1 equiv of NaH. f 4 Å MS used as additive. g 1
equiv of base. h 1:4 THF/CH2Cl2 (0.1 M). i 3 equiv of 1 and 4 Å MS
used as an additive.
encouraged us to investigate the stereoselectivity of this process
(Table 1). Due to isolation issues with the corresponding aryl ester,
benzyl amine was added to the reaction after consumption of 2a,
leading to higher yields of the amide (3). Employing aminoindanol-
derived precatalyst B facilitated product formation in a similar yield
but led to an enantioenrichment of 68% (entry 3).
The phenyalanine-derived azolium salt C5b significantly im-
proved the enantioselectivity but led to no improvement of the yield.
At this point, a survey of bases was conducted. Interestingly, sodium
4-nitrophenoxide increased the yield to 59% (entry 6). Finally, 3
equiv of 1 with sodium 4-nitrophenoxide provided a good yield
(72%) of 3 with high selectivity (94% ee, entry 7).9 This anion is
(a) surprisingly basic enough to generate the active carbene catalyst
from the azolium precursor and (b) nucleophilic enough to re-enter
We began by surveying R-substituted acetaldehydes with azolium
salts and bases. The stable, easy to prepare 4-nitrophenoxyacetal-
dehyde emerged as a competent substrate for facile formation of
the enolate in the presence of carbenes. Azolium salt A with Et3N
and CH2Cl2 led to formation of amide 3 in poor yield (37%) but
9
18028 J. AM. CHEM. SOC. 2009, 131, 18028–18029
10.1021/ja9094044  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Substrate Scopea
forms a new ꢀ-amino acid, C-C bond, and amide linkage in a
single operation (51% yield).
In summary, we have developed a highly selective and versatile
Mannich reaction using a new concept in carbene catalysis.
Beginning from an R-aryloxyacetaldehyde, the addition of a carbene
initiates the elimination of an aryloxy anion with concomitant enol/
enolate formation. In the presence of activated imines, a Mannich
reaction occurs to afford ꢀ-amino acyl azolium intermediates. The
aryloxy anion can “rebound” by re-entering the catalytic cycle,
regenerating the catalyst, and delivering a useful activated inter-
mediate. These ꢀ-amino esters can be intercepted in situ to yield
valuable nitrogen-containing compounds. Current investigations are
focused on enhancing and exploring this rebound strategy in carbene
catalysis which will be reported in due course.
entry
R
product
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
Ph
3
4
5
6
7
8
9
10
11
12
72
70
66
61
75
69
64
71
56
64
94
95
92
90
91
91
88
90
95
92
4-Me-C6H4
2-naphth
1-naphth
3-Br-C6H4
4-Cl-C6H4
2-Cl-C6H4
3,4-Cl-C6H3
4-F-C6H4
10
3-MeO-C6H4
Acknowledgment. Support for this work was generously
provided by NIGMS (RO1 GM73072), Amgen, GSK, AstraZeneca,
and the Alfred P. Sloan Foundation. E.M.P is a recipient of a
2008-2009 ACS Division of Organic Chemistry fellowship. Y.K.
thanks Ono Pharmaceuticals for support.
a 3 equiv of
1 in 0.1 M
THF/CH2Cl2 (1:4). b Isolated yields.
c Determined by HPLC with a chiral stationary phase.
Table 3. Synthetic Transformations
Supporting Information Available: Experimental procedures and
spectral data for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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a Isolated yields. b Determined by HPLC with a chiral stationary phase.
c See Supporting Information for absolute configuration determination.
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azolium intermediate (IV).10
4-Nitrophenoxyacetaldehyde with several aromatic imines affords
products with good yields and excellent enantioselectivity (Table 2).
Electron-withdrawing groups are accommodated in different positions
with a minimum 88% ee for the products (entries 6-9). Naphthyl
derivatives are also tolerated with good yields and excellent enanti-
oselectivity (entries 3 and 4). Halogen substitution is allowed with
varying positions and types of substitution. Imines derived from
aliphatic aldehydes are not successful coupling partners.
To demonstrate the value of this rebound catalysis strategy, we
intercepted the initial amino ester formed in situ (V in Scheme 1)
with a variety of nucleophiles (Table 3). Once the starting material
is consumed, several reagents can be added directly to the reaction
to furnish useful compounds. Basic conditions (MeOH/aq. NaOH)
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the addition of sodium methoxide promoted facile transesterification
to the corresponding methyl ester in 61% yield. The reduction of
the phenyl ester was achieved with LiBH4 to yield 1,3-amino
alcohols without loss of the stereochemical integrity (70% yield,
98% ee). Since peptides containing ꢀ-amino acids are useful, the
initial 4-nitrophenyl ester provided the impetus for us to investigate
the synthesis of these compounds using this new reaction.12 The
peptide coupling with benzyl protected alanine is successful and
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