Cyclic aldimines as superior electrophiles for Cu-catalyzed decarboxylative mannich reaction of β-ketoacids with a broad scope and high enantioselectivity

Article abstract of DOI:10.1021/ol500929d

A novel Cu-catalyzed enantioselective decarboxylative Mannich reaction of cyclic aldimines with β-ketoacids is described. The cyclic structure of these aldimines, in which the C=N bond is constrained in the Z geometry, appears to be important, allowing Mannich condensation to proceed in high yields with excellent enantioselectivities. A chiral chroman-4-amine was synthesized from the decarboxylative Mannich product in several steps without loss of enantioselectivity.

Full text of DOI:10.1021/ol500929d

Letter
pubs.acs.org/OrgLett
Cyclic Aldimines as Superior Electrophiles for Cu-Catalyzed
Decarboxylative Mannich Reaction of β‑Ketoacids with a Broad
Scope and High Enantioselectivity
Heng-Xia Zhang, Jing Nie, Hua Cai, and Jun-An Ma*
Department of Chemistry, Key Laboratory of Systems Bioengineering (the Ministry of Education), Tianjin University, and
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, P. R. of China
S
* Supporting Information
ABSTRACT: A novel Cu-catalyzed enantioselective decar-
boxylative Mannich reaction of cyclic aldimines with β-
ketoacids is described. The cyclic structure of these aldimines,
in which the CN bond is constrained in the Z geometry,
appears to be important, allowing Mannich condensation to
proceed in high yields with excellent enantioselectivities. A
chiral chroman-4-amine was synthesized from the decarboxylative Mannich product in several steps without loss of
enantioselectivity.
hiral β-amino ketones are valuable synthetic intermediates,
which can be easily transformed into other versatile
compounds of pharmaceutical significance.9 Furthermore, the
relevance has stimulated the recent development of catalytic
asymmetric DMRs leading to the formation of chiral nonracemic
β-amino ketones.10 However, the use of aldimines in asymmetric
DMRs of β-ketoacids suffers from a limited substrate scope and/
or unsatisfactory stereoselectivity. For example, Lu and co-
workers described an organocatalytic asymmetric DMR of β-
ketoacids with acyclic aldimines to afford β-amino ketones with a
maximum ee value of 83% (Scheme 1a).10f Herein, we report a
novel approach that utilizes cyclic aldimines as superior
electrophiles and copper-bisoxazoline (Box) complexes as chiral
catalysts to deliver high yields of β-amino ketones in excellent
enantioselectivity (Scheme 1b).11,12 The cyclic structure of these
aldimines, in which the CN bond is constrained in the Z
C
building blocks, such as amines, β-amino alcohols, and β-
amino acid derivatives.1 Furthermore, structural motifs derived
from chiral β-amino ketones can be found in a number of natural
products and biologically active compounds, such as Tropine I,2
Lycopodine II,3 Septicine III,4 the Human Bradykinin B1
receptor antagonist IV,5 and potassium channel blocker V.6
Scheme 1. Catalytic Enantioselective DMRs of β-Ketoacids
with Aldimines
Over the past decades, common methods for the construction
of chiral β-amino ketones have focused on the Mukaiyama−
Mannich reactions of silyl enol ethers7 and the organocatalytic
Mannich reactions of inactivated ketones8 with various imines.
Accordingly, the former requires the corresponding silyl enol
ethers to be prepared beforehand, whereas the latter is limited to
the use of only acetone and cyclic alkyl ketones. Noteworthily,
the decarboxylative Mannich reaction (DMR) of β-ketoacids
with imines provides an alternative means of accessing β-amino
ketones, and many DMRs have been successfully applied as the
key step for the efficient synthesis of natural products and
Received: March 28, 2014
Published: April 24, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
geometry, appears to be very important for the success of the
reactions.
of copper(I) complexes could induce high enantioselectivity
(entries 8−10), whereas the use of copper(II) complexes caused
a significant drop in stereoselectivity (entries 11 and 12). In
addition, the solvent was found to have an important effect on the
reactivity and enantioselectivity (entries 13−17). Among the
solvents tested, THF was found to be the solvent of choice for
this decarboxylative Mannich reaction with respect to both
catalytic activity and asymmetric induction. The effect of catalyst
loading was next examined, and excellent results were still
obtained when the catalyst loading was lowered to 1 mol %
(entry 18).
In the initial study, the reaction between benzoxathiazine-2,2-
dioxide 1a and benzoylacetic acid 2a was performed in
tetrahydrofuran (THF) at room temperature with a 5 mol %
loading of a Lewis acid catalyst prepared in situ from a copper salt
and a chiral bisoxazoline ligand. Excellent enantioselectivity but a
very low yield of the decarboxylative Mannich product 3a was
obtained in the presence of the CuI/(R,R)-Ph-Box (L1) complex
(Table 1, entry 1). The major byproduct was acetophenone,
Table 1. Optimization of Reaction Conditions for Cu-
Catalyzed DMR of Cyclic Aldimine 1a with β-Ketoacid 2a
Remarkably, even at a loading of 0.1 mol %, the CuI/(R,R)-Ph-
Box (L1) complex could also deliver comparable results (95%
yield and 90% ee) when the reaction was run on a gram scale for
an extended reaction time by sequential addition of benzoylacetic
acid 2a (Scheme 2). In contrast, a one-portion addition of 1.5
equiv of β-ketoacid resulted in the formation of the mass of
acetophenone byproduct.
a
temp (°C)/
time (h)
yield
b
ee
(%)
c
entry catalyst (mol %)
solvent
(%)
Scheme 2. Scaled-up DMR of Aldimine 1a with β-Ketoacid 2a
1
CuI/L1 (5)
CuI/L1 (5)
CuI/L1 (5)
CuI/L2 (5)
CuI/L3 (5)
CuI/L4 (5)
CuI/L5 (5)
CuBr/L1 (5)
CuCl/L1 (5)
CuTPC/L1 (5)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
25/12
23
98
98
99
90
97
93
97
98
95
90
94
95
97
92
78
77
3
2
0/12
3
−20/12
−20/16
−20/60
−20/16
−20/72
−20/12
−20/36
−20/72
−20/36
4
5
6
7
With the optimized conditions in hand, we turned our focus to
the substrate scope and generality of this decarboxylative
Mannich reaction (Scheme 3). First, a series of cyclic aldimines
1 were examined for their reactions with benzoylacetic acid 2a.
The introduction of electron-donating and -withdrawing groups
on the phenyl ring had little influence on enantioselectivity. The
corresponding products 3a−3l were obtained in high yields with
excellent enantioselectivity. Subsequently, the β-ketoacid sub-
strate scope was investigated. In the presence of 5 mol % CuI/
(R,R)-Ph-Box complex, the reaction of ortho-, meta-, and para-
substituted phenyl β-ketoacids with benzoxathiazine-2,2-dioxide
1a all proceeded smoothly, thus generating the Mannich adducts
3m−3w in consistently high yield (94−99%) and enantiose-
lectivity (92−99% ee). The product 3v was isolated as a
crystalline compound, and the structure was characterized by X-
ray crystallographic analysis. The absolute configuration for the
stereogenic carbon center formed in the reaction is of R
stereochemistry (see the Supporting Information).13 Fused-ring
aryl or heteroaryl-substituted β-ketoacids could also be used as
the nucleophilic partners, thus providing β-amino ketones 3x−3z
in high yields with excellent ee values. Additionally, it is found
that linear, branched, and cyclic alkyl substituted β-ketoacids
could also be used as the substrates, and excellent results were
obtained for the condensation products 3a′−3g′. Notably, in all
cases the reaction can be conducted under mild reaction
conditions without the need for inert gas protection.
8
94
96
94
30
9
10
11
Cu(OTf)2/L1
(5)
12
Cu(OAc)2/L1
THF
−20/36
95
76
(5)
13
14
15
16
17
18
CuI/L1 (5)
CuI/L1 (5)
CuI/L1 (5)
CuI/L1 (5)
CuI/L1 (5)
CuI/L1 (1)
Et2O
25/36
25/36
25/120
25/120
25/60
25/24
96
98
85
90
98
98
96
94
30
80
63
93
CH3CN
CH2Cl2
toluene
MeOH
THF
a
General reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), and
catalyst (1−5 mol %) in solvent for the stated time. Isolated yield.
Determined by HPLC analysis on a chiral stationary phase.
b
c
which results from decarboxylative protonation of 2a. Mindful of
this detrimental background reaction which could lead to the
observed low yield, the reaction was performed at a lower
temperature, and as expected, the yield was improved from 23%
to 98% (entries 2 and 3). A subsequent investigation of ligands
(Figure 1) confirmed that L1 provided higher ee’s than other
substituted bidentate ligands L2−L4 (entries 4−6). The use of
tridentate ligand L5 led to the formation of an almost racemic
product (entry 7). A series of other copper salts were then
evaluated in THF using L1 as the chiral ligand. Interestingly, all
The stereochemical outcome can be explained using a
transition-state model as shown in Figure 2. The [Cu((R,R)-
Ph-box)]I catalyst undergoes coordination with the enol of β-
ketoacid to form a square-planar complex, and the chelation of
the sulfonyl oxygen of the imine to copper creates a more
compact reaction sphere. The sterically favored intermediate B
allows the nucleophilic approach of β-ketoacid from the Re face
of cyclic aldimine which generates the R enantiomer.
The chroman-4-amines are important intermediates in the
Figure 1. Ligand structures tested in the model reaction.
construction of several biological active compounds.5,6 A short
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Letter
Scheme 3. Scope for Copper-Catalyzed Enantioselective DMR of Cyclic Aldimines 1 with β-Ketoacids 2
carbamate 5, which was then converted into chroman-4-amine 6
by means of a Mitsunobu cyclization. In all of the processes, no
loss of enantiomeric purity was observed.
For a comparison with cyclic aldimines, we examined the
decarboxylative Mannich reaction of acyclic benzaldimines 7a−c
with β-ketoacid 1a under the standard reaction conditions
(Scheme 5). The corresponding Mannich products 8a−c were
Figure 2. Stereochemical model.
Scheme 5. Catalytic Enantioselective DMRs of β-Ketoacids
with Acyclic Benzaldimines
synthesis of chiral nonracemic chroman-4-amine 6 was
conducted from the decarboxylative Mannich product (Scheme
4). In the presence of m-chlorobenzoperoxoic acid (m-CBPA)
and Na2HPO4, the Baeyer−Villiger oxidation of 3q afforded the
corresponding ester 4 in 82% yield. Reduction of 4 with LiAlH4
at reflux14 and subsequent protection with Boc2O provided
Scheme 4. Further Synthetic Transformation of the Decarboxylative Mannich Product 3q into the Chroman-4-amine 6
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Letter
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could have a negative impact upon stereoselectivity.
In summary, a new catalytic asymmetric decarboxylative
Mannich reaction of β-ketoacids with cyclic aldimines in the
presence of chiral CuI−bisoxazoline complexes has been
presented. The cyclic structure of these aldimines, in which the
CN bond is constrained in the Z geometry, appears to be
important, allowing Mannich condensation to proceed in high
yields (90−99%) with excellent enantioselectivities (92−99%
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optically active chroman-4-amines. Further development and
application of this reaction, as well as study of the mechanism, is
underway in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
Experimental details, spectral data of all the new compounds, and
the CIF information on 3v. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
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(13) CCDC 990136 (3v) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
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data_request/cif.
*E-mail: majun_an68@tju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Nos. 21172170 and 21225208) and the
National Basic Research Program of China (973 Program,
2014CB745100).
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