Asymmetric enamine catalysis with β-ketoesters by chiral primary amine: Divergent stereocontrol modes

Article abstract of DOI:10.1021/jo502152w

α-Branched ketones remain a challenging type of substrates in aminocatalysis due to their congested structures as well as the associated difficulties in controlling chemo- and stereoselectivity. In this work, we have explored asymmetric aminocatalysis with α-substituted β-ketoesters. A simple chiral primary amine catalyst was identified to enable unprecedentedly effective catalysis of β-ketoesters in α-hydrazination and Robinson annulation reaction with good yields and high enantioselectivities. Stoichiometric experiments with preformed enamine ester intermediates revealed their enamine-catalytic nature as well as the critical roles of acidic additives in facilitating catalytic turnovers and in tuning the chemo- and stereoselectivity. With the identical catalytic system, the two reactions demonstrated opposite chiral inductions in terms of the absolute configurations of the newly formed stereogenic centers. Investigations into this intriguing issue by DFT have revealed divergent stereocontrol modes. For α-hydrazination, H-bonding-directed facial attack determines the stereoselectivity, whereas a steric model is applied to the Robinson annulation where dual activations of both β-ketoester and vinyl ketone/aldehyde are involved.

Full text of DOI:10.1021/jo502152w

Article
pubs.acs.org/joc
Asymmetric Enamine Catalysis with β‑Ketoesters by Chiral Primary
Amine: Divergent Stereocontrol Modes
Changming Xu, Long Zhang, and Sanzhong Luo*
Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
S
* Supporting Information
ABSTRACT: α-Branched ketones remain a challenging type of
substrates in aminocatalysis due to their congested structures as well
as the associated difficulties in controlling chemo- and stereo-
selectivity. In this work, we have explored asymmetric amino-
catalysis with α-substituted β-ketoesters. A simple chiral primary
amine catalyst was identified to enable unprecedentedly effective
catalysis of β-ketoesters in α-hydrazination and Robinson annulation
reaction with good yields and high enantioselectivities. Stoichio-
metric experiments with preformed enamine ester intermediates
revealed their enamine-catalytic nature as well as the critical roles of
acidic additives in facilitating catalytic turnovers and in tuning the
chemo- and stereoselectivity. With the identical catalytic system, the
two reactions demonstrated opposite chiral inductions in terms of the absolute configurations of the newly formed stereogenic
centers. Investigations into this intriguing issue by DFT have revealed divergent stereocontrol modes. For α-hydrazination, H-
bonding-directed facial attack determines the stereoselectivity, whereas a steric model is applied to the Robinson annulation
where dual activations of both β-ketoester and vinyl ketone/aldehyde are involved.
Scheme 1. Overview of Enamine Catalysis
INTRODUCTION
■
With enamine catalysis stepping into its second decade ever
since its renaissance, scopes of studies have now included either
un-, mono-, or disubstituted enamine intermediates in a
number of C−C or C−X bond-forming reactions. Though
extensively explored, the reaction with α-branched ketones via
trisubstituted enamines, an appealing process to access chiral
ketones bearing α-quaternary stereogenic carbons, has yet to be
realized (Scheme 1).1 Presumably, the challenges can be
understood by considering the sterically hindered nature of α-
branched ketones and the issues in controlling the geometry of
the forming enamines as well as in steering selectively the
subsequent bond formations.
Recently, we have explored the aminocatalysis with acyclic β-
ketocarbonyls, wherein asymmetric catalysis via a trisubstituted
enamine was pursued.2 Though well explored as latent enol-
type nucleophiles in many catalytic asymmetric transforma-
tions, acyclic β-ketocarbonyls as versatile ketone synthons have
not been used in iminium/enamine catalysis so far. The idea of
aminocatalytic turnover with β-ketocarbonyls also seems
counterintuitive because it is also known that amines tend to
form stabilized enamines with β-ketoesters as a result of
intramolecular H-bonding. In fact, enaminone carbonyls
derived from chiral primary amines have been reported as
readily preformed nucleophiles in asymmetric synthesis.3
Synthetic enaminones have been successfully used as the
haptens to induce the evolution of antibody aldolases (Scheme
1).4 As a continuation to our efforts in primary aminocatalysis,5
we have explored chiral primary amines in the catalysis with
acyclic β-ketoesters.2 In this paper, we present a full account on
our efforts in exploring the aminocatalysis with β-ketoesters in
the α-amination as well as Robinson-type annulation reactions.
Our detailed mechanistic studies have revealed divergent
stereocontrol modes for the same primary amine catalyst.
Received: September 19, 2014
© XXXX American Chemical Society
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RESULTS AND DISCUSSION
Table 1. Screening and Optimization for α-Hydrazination of
β-Ketoesters
■
a
α-Amination. Recently, we reported a chiral primary amine
catalyzed α-amination of β-ketocarbonyls wherein an enamine
catalytic cycle was successfully telescoped with Cu(I)-mediated
aerobic oxidation of N-hydroxycarbamate.2a The reactions
occurred smoothly under aerobic conditions to give the
amination adducts with excellent enantioselectivities, thus
providing a facile route for the synthesis of α-quaternary
amino acids (Scheme 2). In this process, it was found that the
b
c
entry
catalyst
solvent
time (h)
yield (%)
ee (%)
1
2
3a
3b
3c
3d
3e
3a
3a
3a
3a
3a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
THF
30
40
72
80
72
96
40
48
48
30
91
68
50
55
74
93
37
52
73
14
95
95
87
91
92
91
94
94
95
81
3
Scheme 2
4
5
6
7
8
Et2O
9
toluene
MeOH
10
a
The reactions were performed at room temperature in 0.2 mL solvent
with 1a (0.10 mmol), 2a (0.12 mmol), 3-TfOH (10 mol %) and m-
b
c
nitrobenzoic acid (10 mol %). Isolated yields. Determined by chiral
HPLC.
yields (Table 1, entries 2−5). Further optimization revealed
that dichloromethane is the solvent of choice (Table 1, entries
6−10). To the best of our knowledge, the current primary
aminocatalyst furnishes so far the best outcome in organo-
catalytic α-hydrazination of acyclic β-ketoesters.
challenging issue on catalytic turnover with an enaminone
intermediate could be addressed by judiciously tuning multi-
acidic additives, consistent with the known acidic effects in
aminocatalysis as well as our previous studies in primary amine
catalysis.6 In addition, the catalytically active enamine
intermediate was determined to be mainly in the Z-
configuration in both solid and solution phase. The H-bonding
network involving the protonated tertiary amine moiety as well
as the enamine N−H in this Z-enamine would stereoselectively
guide the approach of electrophile, e.g., nitrosocarbonyl,
accounting for the high chemo- and stereoselectivity observed
experimentally (Scheme 2).2b
Parallel to the work on oxidative amination, we have also
investigated the direct α-hydrazination of β-ketoesters with
readily available electrophilic azodicarboxylates. The same
reaction has been extensively explored with Lewis acid
catalysis,7 H-bond catalysis,8 and phase-transfer catalysis.9
Unfortunately, most of the organocatalytic reactions are limited
to cyclic β-ketoesters, and the attempts with acyclic β-
ketoesters normally gave poor enantioselectivities.8,9 Recently,
the Deng group has reported an enantioselective α-hydrazina-
tion of acyclic β-ketoesters but with thioester derivatives.10
Our previously developed primary amines were quickly
found to be viable catalysts for the reaction of acyclic β-
ketoester 1a and dibenzyl azodicarboxylate 2a. The catalyst 3a
derived from tert-leucine, an optimal catalyst in the oxidative
amination reaction, was identified to be the optimal catalyst for
asymmetric α-hydrazination of acyclic β-ketoester 1a. The
desired adduct was isolated with 91% yield and 95% ee in
dichloromethane (Table 1, entry 1). The use of other catalysts
(e.g., 3b−e) also led to high enantioselectivities but moderate
The scope of the α-hydrazination was next explored. As
shown in Table 2, acetoacetates 1 with ethyl, methyl, as well as
butyl ester can be equally applied in the reactions to afford the
desired adducts in high yields and excellent enantioselectivities
(Table 2, entries 1−3). Substrates bearing sterically bulky tert-
butyl ester, benzyl ester, unsaturated allyl ester, and α-allyl or
propargyl substituents were also smoothly converted to the
expected products at 40 °C in moderate yields and high
enantioselectivities (Table 2, entries 4−8). Furthermore, the
cyclic β-ketoester 1j can also be employed as a nucleophile to
furnish the desired product with 73% yield and 96% ee (Table
2, entry 10). This reaction is also compatible with diethyl
azodicarboxylates 2b as nitrogen source to give the desired
amination adducts in high yields and excellent enantioselectiv-
ities (Table 2, entries 11 and 12). For bulky β-ketoesters, higher
temperature was necessary to speed up the reaction but slightly
sacrificed the enantioselectivity. The absolute configuration of
the α-hydrazination adducts 4a and 4j was determined to be R
by comparison with the literature.7b
Robinson Annulation. Recently, we reported chiral
primary amine 3a−TfOH catalyzed Robinson annulation
between 1,3-cyclohexanediones and methyl vinyl ketone
(MVK), furnishing a practical protocol for asymmetric
synthesis of Wieland−Miescher ketones (1−100 g) (Scheme
3).11 In this study, we further extended the reaction to acyclic
1,3-diketones, particularly β-ketoesters. This seemingly minor
substrate extension turned out to be nontrivial as the reaction
involves the creation of an all-carbon quaternary stereogenic
center from acyclic substrate, a scenario distinctive from its
counterpart with 1,3-cyclohexanediones wherein a cyclic
quaternary stereocenter is generated from a desymmetric
B
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a,b
ketoesters has not been achieved in organocatalysis in spite of
the prevalence of aminocatalysis.3a,12−14
Table 2. Asymmetric α-Hydrazination of β-Ketoesters
In order to further extend the scope of aminocatalysis with β-
ketoesters, we have explored the Robinson annulation with
MVK. Initially, the reaction of β-ketoester 1a and MVK
catalyzed by primary amine 3a−TfOH was found to give 7 with
moderate yield and low enantioselectivity (Table 3, entry 1).
Interestingly, the addition of a second weak acid, m-nitro-
benzoic acid, led to the isolation of 6a with high
enantioselectivity (Table 3, entry 2). Further increasing the
loading of m-nitrobenzoic acid favored the formation of 6a,
with a concurrent reduction in 7 (Table 3, entry 3 vs 2). The
dramatically different chiral induction observed with 6a and 7 is
a clear indication of two competing reaction pathways in this
reaction system. Conditions were then searched in order to
suppress the unselective 7-forming process. It was soon
discovered that portionwise addition of MVK to maintain an
excess β-ketoester 1a in the reaction mixture was in favor of the
formation of 6a (Table 3, entry 4). The screening of different
solvents was then followed, and the reaction was found to
afford only product 6a with 54% yield and 94% ee in CH3CN;
no 7 could be isolated in this case (Table 3, entry 9). In other
solvents, adduct 7 was generally isolated in varied amounts
(Table 3, entries 5−12); occasionally, uncyclized product 8, a
likely precursor for 7, was isolated. Both 7 and 8 were
determined to be of low enantioselectivities (Table 3, entries 5
and 10). Finally, the yield of 6a could be significantly improved
by syringe pump addition of MVK (Table 3, entries 13 and 14).
Under the optimal conditions, we then examined the
substrate scope of this Michael−aldol domino reaction. Both
MVK and acrolein 5b could be employed as Michael acceptors
to furnish the target products with moderate yields and high to
excellent enantioselectivities (Table 4, entries 1−5). However,
when the R2 substituent of acetoacetates was changed to larger
a
The reactions were performed at room temperature in 0.2 mL of
CH2Cl2 with 1 (0.10 mmol), 2 (0.12 mmol), 3a−TfOH (10 mol %),
and m-nitrobenzoic acid (10 mol %). Isolated yields. Reaction
conducted with 0.15 mmol of 2a.
b
c
Scheme 3
n
group Pr, the yield declined dramatically, but the enantiose-
lectivity was maintained (Table 4, entry 6). Other substrates
t
bearing a bulky group (e.g., Bn and Bu) in either the R2 or R3
position gave poor outcomes (<20% yield).
The absolute configuration of the cyclized product 6a was
determined to be S- from the X-ray structure of p-
bromobenzoylhydrazone derivative 9 (Figure 1), which was
opposite to the absolute configuration of α-hydrazination and
α-hydroxyamination products of β-ketoesters. This unexpected
stereoinduction is strongly suggestive of a distinctive catalytic
mode in the reaction.
aldol condensation. In addition, as both ketoesters and vinyl
ketones are amenable to aminocatalysis, there would be two
competing reaction pathways (I and II) leading to two
annulation adducts (e.g., 6a and 7, Scheme 4), respectively,
hence adding further challenges to the Robinson annulation of
β-ketoester and MVK. In fact, such a reaction with acyclic β-
MECHANISTIC STUDIES
■
With the established catalysis with β-ketoesters, we then carried
out detailed experimental and theoretical studies for better
understanding of the mechanism. Specifically, the synthesis of
enamine ester intermediates, their stoichiometric reactions, as
well as the origins of stereocontrols were investigated with our
identified optimal catalyst.
Scheme 4
1. Stoichiometric Chemistry of Enamine Ester Inter-
mediates. Synthesis and Characterization of Enamine Ester
Intermediates. It was found that a catalytic amount of m-
nitrobenzoic acid could effectively promote the stoichiometric
reactions of acetoacetates 1 and chiral primary amine 3a to give
the expected enamine esters (Table 5, entry 1 vs 2). After quick
filtration on a basic alumina column, the enamine esters 10
could be obtained as analytically pure compounds. As shown in
Table 5, there seems to be virtually no obstacle to forming
enamine with β-ketoesters bearing bulky ester groups (entries
C
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Table 3. Optimization for Robinson Annulation
b
c
yield /ee (%)
a
entry
method
solvent
x
6a
7
8
1
A
A
A
B
B
B
B
B
B
B
B
B
C
C
neat
0
trace
51/23
29/4
2
neat
10
20
20
20
20
20
20
20
20
20
20
20
20
10/80
18/89
54/95
14/84
16/81
21/90
46/82
54/94
7/94
3
neat
15/24
28/20
5/63
4
neat
5
DCM
THF
17/61
trace
trace
trace
6
21/37
16/30
21/30
trace
7
Et2O
8
toluene
MeCN
MeOH
DMF
DMSO
MeCN
MeCN
9
10
11
12
13
49/4
5/5
10/81
13/83
26/94
73/95
46/−11
41/−23
trace
trace
trace
14/43
d
14
trace
a
Method A: reactions were performed for 60 h with 1a (0.2 mmol), MVK (0.24 mmol), catalyst 3a−TfOH (20 mol %), and m-nitrobenzoic acid
(0−20 mol %). Method B: MVK (0.2 mmol) was added in portions (one-fifth every 6 h) into the mixture of 1a (0.4 mmol), catalyst 3a-TfOH (20
mol %), and m-nitrobenzoic acid (20 mol %) in solvent (0.3 mL). Method C: MVK (0.2 mmol) was dissolved in MeCN (0.3 mL) and slowly added
into the mixture of 1a (0.4 mmol), catalyst 3a−TfOH (20 mol %), m-nitrobenzoic acid (20 mol %), and MeCN (0.2 mL) using a syringe pump for
b
c
d
20 h. Isolated yields. Determined by chiral HPLC. The reaction was performed for 60 h.
a
a
Table 4. Michael−Aldol Domino Reactions
Table 5. Synthesis of Trisubstituted Enamine Intermediates
b
entry
1
R1
R2
R3
yield (%)
b
c
entry
R2
R3
R5
yield (%)
ee (%)
Me
Me
Me
Me
Me
Me
Me
(CH2)4
Et
Me
Me
Me
Me
Me
Bn
Et
87 (10a)
28 (10a)
85 (10b)
76 (10c)
43 (10d)
67 (10e)
65 (10f)
78 (10g)
20 (10h)
47 (10h)
c
d
d
2
Et
1
2
3
4
5
6
Me
Me
Et
Et
Me
H
73 (68) (6a)
95 (95)
93
3
4
5
6
7
8
9
Me
Bn
tBu
Me
Me
Et
Me
Me
Et
71 (6b)
63 (6c)
56 (6d)
65 (6e)
31 (6f)
H
89
Et
H
95
Me
nPr
Et
H
95
allyl
Et
H
93
a
All reactions were performed at room temperature in 0.5 mL of
Me
Me
Me
Me
MeCN with 1 (0.4 mmol), MVK or acrolein (0.2 mmol dissolved in
d
10
Et
0.3 mL MeCN, slow addition using syringe pump), 3a−TfOH (20 mol
b
a
%), and m-nitrobenzoic acid (20 mol %) for 60 h. Isolated yields.
All reactions were performed at room temperature in 0.5 mL of
CH2Cl2 with 1 (0.2 mmol), 3a (0.21 mmol), and m-nitrobenzoic acid
c
d
Determined by chiral HPLC. 1.0 mmol scale reaction.
b
c
(20 mol %) for 6 h. Isolated yields. In the absence of m-nitrobenzoic
acid. Reaction was conducted for 48 h.
d
3−5). Furthermore, when R2 was changed to a larger group,
such as Bn or allyl, the reaction occurred smoothly with slightly
reduced isolated yields (entries 6 and 7). It was noted that
cyclic β-ketoester, though completely in its enol form as
1
observed by HNMR, also underwent enamine formation with
catalyst 3a to give the desired enamine ester 10g in 78% yield
(entry 8). However, ethyl ketone (R1 = Et) reacted very slowly,
and the expected enamine ester 10h was obtained in only 47%
yield after 48 h (entries 9 and 10). The observed reactivity
trend is consistent with the respective catalytic behaviors.
Figure 1. X-ray crystal structure for compound 9. H atoms are omitted
for clearance; thermal ellipsoids set at 30%.
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Stability of Enamine Intermediates. The stability of
enamine ester is considered an unfavorable feature for enamine
turnover with ketoesters. During the purification of enamine
esters 10, we noticed that the enamines 10 were rather unstable
and underwent facile hydrolysis in the presence of silica gel.
Indeed, when the synthesized enamine 10a was treated with
TfOH/m-NO2PhCOOH, complete hydrolysis was observed by
NMR.2a These observations indicated the catalytic turnover
with enamine esters should not be an issue under our catalytic
conditions.
Figure 2. Opposite chiral inductions in hydrazination and Robinson
annulation reaction.
Stoichiometric Reactions. The reactivity of enamine 10a
was then examined in this Michael−aldol domino process with
MVK. There was no reaction between enamine 10a and MVK
in the absence of acidic additives (Scheme 5, A, entry 1). The
frequency) or a transition state (one imaginary frequency) by
calculation of harmonic vibrational frequencies. The SMD
continuum solvation model17 with acetonitrile as the solvent
were used in single-point energy calculations, and these
calculations were performed at the M06-2x/6-311+G(d,p)
level with gas-phase optimized structures.
Origins of Stereoselectivity for α-Hydranization Reaction.
The absolute configuration of the hydranization adduct, e.g., 4a,
was determined to be the same as with the α-amination adduct
derived from nitrosocarbonyls (Figure 2). Previously, we have
found the major R-product was formed via Re-facial attack to Z-
s-trans enamine, the most stable enamine intermediate with β-
ketoesters, while the Si-facial addition to E-s-trans enamine led
to minor S-product.2b This model has also been tested in the
current hydranization reaction with dimethyl azodicarboxylate
as the model substrate. The computed free energy difference
between these two transition states is 5.9 kcal/mol favoring the
formation of R-product, in agreement with the experimental
observation (Figure 3).
Scheme 5. Control Reactions of Enamine Intermediates 10a
with MVK (A) or 2a (B)
Origins of Stereoselectivity for Robinson Annulation. (1)
Reaction Pathway. As both β-ketoesters and MVK are
amenable to aminocatalysis, the possible reaction pathways
were first analyzed. Accordingly, the reaction may be initialized
via enamine activation of β-ketoesters (Scheme 6, pathway I) to
addition of either strong acid TfOH or weak acid m-
nitrobenzoic acid was found to facilitate the reaction, and
both 6a and 7 were isolated in these cases. Notably, in the
presence of TfOH high enantioselectivity (94% ee) was
achieved for 6a but not for 7, although the latter was obtained
as the major adduct (A, entries 2 and 3). Consistent with the
catalytic behavior, the joint use of TfOH and m-nitrobenzoic
acid can suppress the formation of 7, leading to sole production
of 6a in high enantioselectivity (A, entry 4). A similar acidic
additive effect has also been observed in the stoichiometric
reaction of enamine ester 10a with dibenzyl azodicarboxylate
2a (Scheme 5, B).
2. Origin of Stereoselectiviy. A close inspection revealed
that the chiral inductions in the two examined reactions are
opposite in the sense of the absolute configurations (4a vs 6a),
though the same catalytic system was applied in both cases
(Figure 2). This intriguing stereocontrol issue was then further
investigated by DFT calculations with the Gaussian 09 program
package.15 The recently developed M06-2X functional16
together with the 6-31G(d) basis set were used for the
geometry optimizations and vibrational calculations. Each
geometry was confirmed as a minimum (no imaginary
Figure 3. Amination transition states.
E
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Scheme 6. Proposed Catalytic Cycle for the Michael−Aldol Cascade Reactions
give 6a or competitively via iminium ion activation of MVK to
give 7 (Scheme 6, pathway II). Compounds 6a and 7 may also
be formed from two bifurcating pathways with a common
intermediate. However, this possibility can be ruled out as 6a
and 7 are generally obtained in dramatically different
enantioselectivities indicating two competitive pathways. The
fact that slow addition of MVK can suppress the formation of 7
is in line with the proposed mechanistic scenario (Scheme 6). It
is noted that when MVK was added in one portion, only 7 was
formed with low ee (Table 3, entry 1), indicating that the
formation of iminium ion 13 is much faster than the formation
of enamine 10a and the iminum cycle is a less enantioselective
pathway. However, the slow addition of MVK by syringe pump
to the reaction system ensured the prior formation of enamine
10a; thus, the enamine catalytic cycle could dominate in the
reaction.
together with the low enantioselectvity of 7 and 8 indicates that
the formation of side product 8 is coupled with the nonselective
iminium cycle (pathway II) and that product 6a could only
come from the enamine catalytic sequence wherein the initial
Michael addition is the critical stereogenic C−C forming step
(pathway I).
(2) Initial Explorations on Stereocontrol. The stereo-
control in the enamine cycle for cyclohexenone (S)-6 was then
explored by DFT calculations. Following the successes in α-
oxidative amination and α-hydrazination reactions, the H-
bonding mode (Figure 4, I) involving the protonated
The enamine catalytic nature as well as the critical roles of
acidic additives has also been verified by the stoichiometric
experiments. A sole production of 6a in the presence of both
TfOH and m-nitrobenzoic acid (Scheme 5, A) clearly indicates
that the use of combined acids significantly facilitate the
enamine coupling in preference to enamine hydrolysis as well
as the subsequent iminium activation of MVK. The formation
of 7 with either TfOH or m-nitrobenzoic acid only was
probably caused by the partial hydrolysis of the enamine as well
as the participation of iminium catalytic cycle under the
conditions. In addition, a linear Michael adduct 8, derived from
either intermediate 11/12 or 14/15, has also been isolated.
Under the catalytic conditions, the cyclization of 8 proceeded
smoothly to furnish 7 as a sole adduct without any
enantioselectivity enrichment (Scheme 7). This observation
Figure 4. Possible S-selective modes for (S)-6a formation.
ammonium moiety was first considered. Accordingly, we have
successfully located all the possible transition states correspond-
ing to Re-facial attack and Si-facial attack onto enamine
intermediates. In this regard, only enamine intermediates with
the lowest free energy were considered in the calculations (for a
full list of all the possible enamine intermediates, see the
Supporting Information). Unexpectedly, the Re-facial attack TS
was found to be significantly favored over those Si-facial attack
by >2.0 kcal/mol, leading to R-selective product, which is
against the experimental observation. Other possible Si-facial
modes were hence explored, and these include bidentate H-
bonding with acid (mode II) and enelike processes III and IV
(Figure 4). Unfortunately, all these S-selective TSs are
disfavored by >3.7 kcal/mol over the R-selective TS (see the
Supporting Information for details), indicating they are not able
to account for the observed S-selectivity (Figure 5).
Scheme 7. Intramolecular Aldol Reactions of Compound 8
(3) Dual Aminocatalytic Mode. At this point, we
reinvestigated the presumed one-catalyst participation mode.
The nonlinear effect (NLE) study of the model reaction was
performed. As shown in Figure 6, a positive NLE was observed,
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Figure 7. Dual aminocatalytic mode for stereocontrol.
Scheme 8
Figure 5. Transition states with H-bonding activated electrophiles
(mode I, energies in kcal/mol).
To verify the dual catalysis, we investigated the stereogenic
C−C bond formation using enamine 10a−TfOH and 13 as the
coupling components. The two most favored orientations of
iminium ion were considered, and we have obtained all four
TSs corresponding to the respective Re- or Si-facial additions. It
is noted that all these dual-activation TSs are of much lower
activation energy that those of sole enamine catalysis (Figure 8
vs Figure 5), indicating the dual catalysis is a favored reaction
pathway. More delightfully, Si-facial attack TS is now favored
over Re-TS by 3.2 kcal/mol, corresponding to 99% ee favoring
the S-product, which is in accordance with the experimental
results.
On the basis of the above results, the initial proposed
catalytic cycle was revised as follows (Scheme 9). The target
product 6a was formed by the coupling of enamine 10a−TfOH
and imine 13 via an enamine−imininium dual catalytic process,
and the tautomerization of imine intermediate 11 to enamine
intermediate 12 led to the formation of 6a.
CONCLUSIONS
■
In conclusion, chiral primary amine catalyzed α-hydrazination
and Robinson-type annulation of β-ketoesters have been
developed. This unprecedented enamine catalysis of β-
ketoesters is enabled by a simple chiral primary amine derived
from tert-leucine in concert with a strong acid, TfOH, and a
weak acid, m-nitrobenzoic acid. The joint use of two acidic
additives is critical to facilitate the catalytic turnover and to tune
the chemo- and stereoselectivity. Our experimental and
theoretical studies have revealed distinctively divergent stereo-
control modes for the same catalytic system, wherein the α-
hydrazination reaction follows the typical H-bonding model
and the Robinson annulation tends to be sterics-guided as a
result of its dual-activation nature. This mechanistic scenario
sets the basis for future exploration on aminocatalysis with β-
ketocarbonyls.
Figure 6. Nonlinear effects of Robinson annulation.
which indicated that more than one molecule of catalyst 3a−
TfOH was likely to be involved in the transition state. Provided
with the tendency of MVK undergoing iminium activation, we
invoked a dual aminocatalytic mode wherein two in situ
generated active species, i.e., enamine ester (e.g., 10a) and
iminium ion (e.g., 13), derived from two catalyst molecules,
respectively, are coupled to forge the critical C−C bond. In this
scenario, the critical enamine addition may become sterics-
guided instead of H-bonding-directed as proven in the α-
amination reaction, and the Si-facial attack may thus be
rendered a favored pathway (Figure 7). Similar dual catalysis
has recently been reported in a related Robinson-type reaction
wherein a chiral secondary amine in concert with a
stoichiometric amount achiral primary amine was reported to
fulfill the desired catalysis with good enantioselectivity (Scheme
8).18
EXPERIMENTAL SECTION
■
General Information. Commercial reagents were used as received
1
unless otherwise indicated. H and 13C NMR spectra were measured
G
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Figure 8. Biactivation transition states (energies in kcal/mol).
1
(major). H NMR (300 MHz, CDCl3) δ: 7.32−7.26 (m, 10H), 6.70
(s, 1H), 5.22−5.15 (m, 4H), 3.74 (s, 3H), 2.34 (s, 3H), 1.64 (s, 3H).
IR (thin film, cm−1): 3302, 1747, 1731, 1715, 1455. HRMS (ESI):
calcd for C22H24O7N2Na+ 451.1476, found 451.1473.
Scheme 9. Catalytic Cycle of Robinson Annulation
4c: colorless oil, 32.9 mg, 70% yield. [α]25 = −14.0 (c = 1.0,
D
CH2Cl2). HPLC (OD-H, hexane/2-propanol = 4:1, flow rate = 1.0
mL/min, λ = 210 nm): 96% ee, 21.65 min (major), 25.50 min
1
(minor). H NMR (300 MHz, CDCl3) δ: 7.32−7.26 (m, 10H), 6.65
(s, 1H), 5.22−5.14 (m, 4H), 4.16 (s, 2H), 2.34 (s, 3H), 1.72−1.59 (m,
5H), 1.36−1.31 (m, 2H), 0.91 (t, J = 9 Hz, 3H). IR (thin film, cm−1):
3300, 1738, 1731, 1715, 1455. HRMS (ESI): calcd for
C25H30O7N2Na+ 493.1945, found 493.1943.
4d: colorless oil, 29.1 mg, 64% yield. [α]25 = −9.6 (c = 1.0,
D
CH2Cl2). HPLC (AD-H, hexane/2-propanol = 4:1, flow rate = 1.0
mL/min, λ = 210 nm): 74% ee, 20.51 min (minor), 25.61 min
1
(major). H NMR (300 MHz, CDCl3) δ: 7.32−7.26 (m, 10H), 6.65
(s, 1H), 5.86−5.80 (m, 1H), 5.35−5.14 (m, 6H), 4.65 (s, 2H), 2.34 (s,
3H), 1.67 (s, 3H). IR (thin film, cm−1): 3306, 1738, 1731, 1715, 1498,
1455. HRMS (ESI): calcd for C24H26O7N2Na+ 477.1632, found
477.1629.
4e: colorless oil, 29.2 mg, 58% yield. [α]25 = −12.0 (c = 0.5,
D
CH2Cl2). HPLC (OD-H, hexane/2-propanol = 4:1, flow rate = 1.0
mL/min, λ = 210 nm): 74% ee, 18.65 min (major), 22.42 min
1
(minor). H NMR (300 MHz, CDCl3) δ: 7.33−7.26 (m, 15H), 6.61
on an NMR instrument (300 and 600 MHz for 1H NMR, 75 MHz for
13C NMR). Tetramethylsilane (TMS) served as the internal standard
for 1H NMR, and CDCl3 served as the internal standard for 13C NMR.
The enantiomeric excesses were determined by HPLC analysis on AD-
H, OD-H, AS-H, OJ-H, and IA columns. Optical rotation was
(s, 1H), 5.27−5.08 (m, 6H), 2.31 (s, 3H), 1.65 (s, 3H). IR (thin film,
cm−1): 3305, 1731, 1498, 1455. HRMS (ESI): calcd for
C28H28O7N2Na+ 527.1789, found 527.1784.
4g: colorless oil, 25.4 mg, 56% yield. [α]25 = −1.2 (c = 0.5,
D
CH2Cl2). HPLC (OD-H, hexane/2-propanol = 4:1, flow rate = 1.0
mL/min, λ = 210 nm): 87% ee, 12.10 min (minor), 15.52 min
measured on a commercial polarimeter and reported as follows: [α]25
D
1
(major). H NMR (300 MHz, CDCl3) δ: 7.33−7.26 (m, 10H), 6.63
(c = g/100 mL, solvent). HRMS was measured in ESI mode, and the
mass analyzer of the HRMS was orbitrap.
Materials. β-Keto esters 1a−f were prepared by alkylation of the
corresponding α-unsubstituted β-keto esters with alkyl iodide.19 β-
Keto ester 1g was prepared by allylation of the corresponding
acetoacetate with allyl bromide.19 β-Keto esters 1h20 and 1j21 were
prepared according to literature precedent.
(s, 1H), 5.83 (s, 1H), 5.15−5.0 (m, 6H), 3.72 (s, 3H), 2.83 (s, 2H),
2.34 (s, 3H), 1.64 (s, 3H). IR (thin film, cm−1): 3305, 1738, 1731,
1498, 1455. HRMS (ESI): calcd for C24H26O7N2Na+ 477.1632, found
477.1627.
4h: colorless oil, 26.2 mg, 58% yield. [α]25D = 2.4 (c = 0.5, CH2Cl2).
HPLC analysis: (OD-H, hexane/2-propanol = 4:1, flow rate = 1.0 mL/
min, λ = 210 nm): 55% ee, 16.04 min (minor), 21.94 min (major). 1H
NMR (300 MHz, CDCl3) δ: 7.33−7.26 (m, 10H), 6.82 (s, 1H), 5.17
(s, 4H), 3.78−3.68 (m, 3H), 3.10 (s, 2H), 2.43 (s, 3H), 2.03 (s, 1H).
IR (thin film, cm−1): 3290, 2920, 1747, 1731, 1498, 1455. HRMS
(ESI): calcd for C24H24O7N2Na+ 475.1476, found 475.1470.
General Procedure for the α-Amination of β-Keto Esters. To
β-keto ester 1 (0.10 mmol), 3a−TfOH (10 mol %), and m-
nitrobenzoic acid (10 mol %) in a standard glass vial with stir bar
was added azodicarboxylate 2 (0.12 mmol) followed by CH2Cl2 (0.20
mL). The reaction was stirred at room temperature or 40 °C until
completion as indicated by TLC. The mixture was directly loaded onto
a silica gel column and eluted with ethyl acetate/petroether to give the
target products. The products 4a, 4f, 4j−k,7b and 4i8b are known
compounds.
4l: colorless oil, 30.3 mg, 88% yield. [α]25 = −13.6 (c = 1.0,
D
CH2Cl2). HPLC (AS-H, hexane/2-propanol = 4:1, flow rate = 1.0 mL/
min, λ = 210 nm): 97% ee, 10.86 min (minor), 13.47 min (major). 1H
NMR (300 MHz, CDCl3) δ: 6.23 (s, 1H), 4.29−4.13 (m, 6H), 2.91−
2.70 (m, 1H), 2.46−2.05 (m, 4H), 1.90−1.53 (m, 3H), 1.31−1.21 (m,
9H). IR (thin film, cm−1): 3295, 1732, 1507, 1218. HRMS (ESI):
calcd for C15H24O7N2Na+ 367.1476, found 367.1475.
4b: colorless oil, 37.7 mg, 88% yield. [α]25 = −12.4 (c = 1.0,
D
CH2Cl2). HPLC (OD-H, hexane/2-propanol = 4:1, flow rate = 1.0
mL/min, λ = 210 nm): 91% ee, 15.90 min (minor), 17.62 min
H
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General Procedure for Robinson annulation. To β-keto ester 1
(0.40 mmol), 3a−TfOH (20 mol %), m-nitrobenzoic acid (20 mol %),
and MeCN (0.2 mL) in a standard glass vial with stir bar was added 5
(0.2 mmol in 0.3 mL MeCN) slowly using a syringe pump for 60 h at
room temperature. Another 3 h later, the mixture was directly loaded
onto silica gel column and eluted with ethyl acetate/petroether to give
the target products. The products 6a, 7,13 and 814e are known
compounds.
mmol). The reaction was stirred at room temperature. After 6 h, the
mixture was loaded onto basic alumina and eluted quickly with ethyl
acetate/petroether (1:10) to give enamine 10. Enamine intermediates
10a and 10c are known compounds.2a
10b: colorless oil, 48.3 mg, 85% yield. 1H NMR (300 MHz,
CD3CN) δ: 9.61 (d, J = 9.2 Hz, 1H), 3.59 (s, 3H), 3.31 (td, J = 10.3,
2.2 Hz, 1H), 2.68−2.47 (m, 3H), 2.44−2.21 (m, 3H), 2.00 (s, 3H),
1.78 (s, 3H), 0.98−0.89 (m, 15H). 13C NMR (75 MHz, CD3CN) δ:
172.0, 162.8, 84.7, 62.0, 56.9, 50.5, 48.5, 35.2, 26.9, 16.3, 13.0, 12.5. IR
(thin film, cm−1): 2967, 1641, 1601, 1457, 1620. HRMS (ESI): calcd
6b: colorless oil, 23.9 mg, 71% yield. [α]25 = 17.6 (c = 0.5,
D
MeOH). HPLC (AD-H × 2, hexane/2-propanol = 99:1, flow rate =
0.5 mL/min, λ = 210 nm): 93% ee, 49.19 min (major), 52.70 min
+
for C16H33O2N2 285.2537, found 285.2534.
1
(minor). H NMR (300 MHz, CDCl3) δ: 6.97−6.85 (m, 1H), 6.04
10d: colorless oil, 28.0 mg, 43% yield. 1H NMR (300 MHz, CDCl3)
δ: 9.33 (d, J = 10.6 Hz, 1H), 3.16 (t, J = 10.0 Hz, 1H), 2.61 (dd, J =
13.6, 2.0 Hz, 1H), 2.54−2.27 (m, 5H), 1.93 (s, 3H), 1.75 (s, 3H), 1.46
(s, 9H), 0.98−0.90 (m, 15H). 13C NMR (75 MHz, CDCl3) δ: 171.3,
159.9, 86.8, 61.6, 56.2, 48.1, 35.0, 28.8, 28.1, 27.0, 16.2, 13.7, 12.4. IR
(thin film, cm−1): 2968, 1638, 1602, 1455, 1272. HRMS (ESI): calcd
(dt, J = 10.2, 2.0 Hz, 1H), 3.69 (s, 3H), 2.56−2.27 (m, 3H), 1.93−1.87
(m, 1H), 1.39 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 197.0, 173.2,
149.6, 129.0, 53.5, 52.6, 33.4, 23.8, 20.5. IR (thin film, cm−1): 1733,
1682, 1622, 1456, 1258. HRMS (ESI): calcd for C9H12O3Na+
191.0679, found 191.0678.
6c: colorless oil, 22.9 mg, 63% yield. [α]25 = 18.0 (c = 0.5,
D
+
for C19H39O2N2 327.3006, found 327.3004.
MeOH). HPLC (AD-H × 2, hexane/2-propanol = 99:1, flow rate =
10e: colorless oil, 48.2 mg, 67% yield. 1H NMR (300 MHz, CDCl3)
δ: 9.83 (d, J = 10.6 Hz, 1H), 7.30−7.06 (m, 5H), 3.69 (d, J = 7.2 Hz,
2H), 3.61 (s, 3H), 3.27−3.14 (m, 1H), 2.64 (dd, J = 13.6, 2.0 Hz, 1H),
2.58−2.27 (m, 5H), 1.92 (s, 3H), 0.97−0.92 (m, 15H). 13C NMR (75
MHz, CDCl3) δ: 171.8, 163.1, 143.5, 128.1, 127.8, 125.3, 88.4, 62.1,
56.3, 50.4, 48.1, 34.7, 32.9, 26.9, 16.0, 12.4. IR (thin film, cm−1): 2966,
0.5 mL/min, λ = 210 nm): 89% ee, 44.56 min (major), 50.15 min
1
(minor). H NMR (300 MHz, CDCl3) δ: 6.91−6.86 (m, 1H), 6.07−
5.96 (m, 1H), 3.69 (s, 3H), 2.59−2.40 (m, 2H), 2.40−2.26 (m, 1H),
2.04−1.88 (m, 2H), 1.85−1.73 (m, 1H), 0.91 (t, J = 7.5 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ: 196.5, 172.2, 149.4, 129.4, 57.4, 52.4, 29.6,
26.9, 23.8, 9.2. IR (thin film, cm−1): 1732, 1683, 1622, 1435, 1241.
HRMS (ESI): calcd for C10H14O3Na+ 205.0835, found 205.0835.
+
1640, 1600, 1492, 1450, 1261. HRMS (ESI): calcd for C22H37O2N2
6d: colorless oil, 22.0 mg, 56% yield. [α]25 = 24.0 (c = 0.5,
361.2850, found 361.2848.
D
10f: colorless oil, 40.3 mg, 65% yield. 1H NMR (300 MHz, CDCl3)
δ: 9.69 (d, J = 10.5 Hz, 1H), 5.90−5.78 (m, 1H), 4.96−4.87 (m, 2H),
3.63 (s, 3H), 3.20 (td, J = 10.4, 2.1 Hz, 1H), 3.04−2.96 (m, 2H), 2.62
(dt, J = 13.8, 2.9 Hz, 1H), 2.55−2.26 (m, 5H), 1.94 (s, 3H), 0.98−0.90
(m, 15H). 13C NMR (75 MHz, CDCl3) δ: 171.4, 162.6, 139.1, 112.7,
87.2, 62.0, 56.2, 50.4, 48.1, 34.8, 31.4, 26.9, 15.6, 12.4. IR (thin film,
cm−1): 2968, 1640, 1601, 1452, 1265. HRMS (ESI): calcd for
MeOH). HPLC (AD-H × 2, hexane/2-propanol = 99:1, flow rate =
0.5 mL/min, λ = 210 nm): 95% ee, 39.28 min (major), 43.55 min
(minor). 1H NMR (300 MHz, CDCl3) δ: 6.94−6.80 (m, 1H), 6.00 (d,
J = 9.0 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.57−2.39 (m, 2H), 2.36−
2.24 (m, 1H), 2.01−1.89 (m, 2H), 1.84−1.72 (m, 1H), 1.21 (t, J = 7.1
Hz, 3H), 0.91 (t, J = 7.5 Hz, 3H).13C NMR (75 MHz, CDCl3) δ:
196.5, 171.7, 149.2, 129.4, 61.2, 57.3, 29.6, 26.8, 23.8, 14.2, 9.1. IR
(thin film, cm−1): 1729, 1685, 1622, 1238. HRMS (ESI): calcd for
C11H16O3Na+ 219.0992, found 219.0990.
+
C18H35O2N2 311.2693, found 311.2692.
10g: colorless oil, 50.5 mg, 78% yield. 1H NMR (300 MHz, CDCl3)
δ: 9.20 (d, J = 10.6 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.23−3.11 (m,
1H), 2.65−2.34 (m, 6H), 2.31−2.11 (m, 4H), 1.67−1.46 (m, 4H),
1.25 (t, J = 7.1 Hz, 3H), 0.98−0.89 (m, 15H). 13C NMR (75 MHz,
CDCl3) δ: 171.1, 161.1, 87.7, 60.3, 58.5, 56.5, 48.2, 34.8, 27.1, 26.9,
24.2, 23.2, 22.7, 14.9, 12.5. IR (thin film, cm−1): 2966, 1643, 1600,
6e: colorless oil, 23.7 mg, 65% yield. [α]25 = 20.0 (c = 0.5,
D
MeOH). HPLC (AD-H × 2, hexane/2-propanol = 99:1, flow rate =
0.5 mL/min, λ = 210 nm): 95% ee, 47.71 min (major), 51.27 min
1
(minor). H NMR (300 MHz, CDCl3) δ: 6.95−6.85 (m, 1H), 6.04
(dt, J = 10.2, 1.9 Hz, 1H), 4.16 (q, J = 7.0 Hz, 2H), 2.55−2.41 (m,
2H), 2.40−2.27 (m, 1H), 1.94−1.83 (m, 1H), 1.38 (s, 3H), 1.22 (t, J =
7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ: 197.1, 172.8, 149.4,
129.1, 61.4, 53.5, 33.5, 23.8, 20.5, 14.2. IR (thin film, cm−1): 1730,
1684, 1623, 1456, 1254. HRMS (ESI): calcd for C10H14O3Na+
205.0835, found 205.0835.
+
1455, 1235. HRMS (ESI): calcd for C19H37O2N2 325.2850, found
325.2848.
10h: colorless oil, 11.9 mg, 20% yield. 1H NMR (300 MHz, CDCl3)
δ: 9.50 (d, J = 10.2 Hz, 1H), 3.64 (s, 3H), 3.19−3.07 (m, 1H), 2.62
(dd, J = 13.7, 2.2 Hz, 1H), 2.58−2.18 (m, 7H), 1.79 (s, 3H), 1.10 (t, J
= 7.7 Hz, 3H), 0.92 (dd, J = 12.7, 5.6 Hz, 15H). 13C NMR (75 MHz,
CDCl3) δ: 171.9, 166.7, 83.7, 62.0, 56.8, 50.3, 48.2, 34.7, 27.0, 21.9,
12.2, 12.2, 12.0. IR (thin film, cm−1): 2968, 1640, 1601, 1441, 1620.
6f: colorless oil, 13.0 mg, 31% yield. [α]25D = 26.0 (c = 0.5, MeOH).
HPLC (AD-H × 2, hexane/2-propanol = 99:1, flow rate = 0.5 mL/
min, λ = 210 nm): 93% ee, 43.23 min (major), 51.17 min (minor). 1H
NMR (300 MHz, CDCl3) δ: 6.92−6.80 (m, 1H), 6.05−5.95 (m, 1H),
4.15 (q, J = 7.1 Hz, 2H), 2.58−2.40 (m, 2H), 2.37−2.26 (m, 1H),
1.99−1.82 (m, 2H), 1.75−1.66 (m, 1H), 1.36−1.25 (m, 2H), 1.21 (t, J
= 7.1 Hz, 3H), 0.92 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3)
δ: 196.5, 171.7, 149.2, 129.3, 61.24, 57.2, 36.0, 30.1, 23.9, 18.0, 14.6,
14.2. IR (thin film, cm−1): 1729, 1685, 1623, 1448, 1226. HRMS
(ESI): calcd for C12H18O3Na+ 233.1148, found 233.1147.
+
HRMS (ESI): calcd for C17H35O2N2 299.2693, found 299.2690.
Control Reactions of Enamine 10a or 10a−TfOH with 5a. To
a solution of enamine 10a (0.30 mmol) in dried CH2Cl2 (10 mL) was
added TfOH (0.30 mmol, 1.0 equiv) dropwise with vigorous stirring.
After being stirred for 10 min, the solvent was removed under reduced
pressure to give 10a−TfOH as a white solid. To 10a (0.10 mmol) or
10a−TfOH (0.10 mmol), m-nitrobenzoic acid (1.0 equiv or none),
and MeCN (0.2 mL) in a standard glass vial with stir bar was added 5a
(0.10 mmol) in one portion. The reaction was stirred at room
temperature. After 60 h, the mixture was directly loaded onto a silica
gel column and eluted with ethyl acetate/petroether (1:10) to give the
target products.
Control Reactions of Enamine 10a or 10a−TfOH with 2a. To
10a (0.10 mmol) or 10a−TfOH (0.10 mmol), m-nitrobenzoic acid
(1.0 equiv or none), and CH2Cl2 (0.2 mL) in a standard glass vial with
stir bar was added 2a (0.10 mmol) in one portion. The reaction was
stirred at room temperature. After 30 h, the mixture was directly
loaded onto silica gel column and eluted with ethyl acetate/petroether
(1:3) to give the target products.
Synthesis of Compound 9. To a solution of compound 6a (0.3
mmol) in EtOH (10 mL) was added p-bromobenzoylhydrazone (0.3
mmol). After being refluxed for 12 h, the mixture was concentrated in
vacuo. The residue was loaded on column chromatography and eluted
with ethyl acetate/petroether to give the target product 9 (97.6 mg,
83% yield) as a white solid: [α]25 = 153.6 (c = 0.5, CHCl3). Mp:
D
140−142 °C. 1H NMR (300 MHz, CDCl3) δ: 9.15 (s, 1H), 7.82−7.55
(m, 4H), 6.28 (s, 1H), 4.11 (s, 2H), 2.36−2.20 (m, 3H), 1.93 (s, 3H),
1.71 (s, 1H), 1.33−1.19 (m, 6H). IR (thin film, cm−1): 3340, 2927,
1726, 1653, 1589, 1529, 1480, 1254. HRMS (ESI): calcd for
C18H21O3N2BrNa+ 415.0628, found 415.0623.
Synthesis of Compounds 10a−h. To a round-bottom flask
containing β-ketoester 1 (0.20 mmol), chiral primary amine 3a (0.21
mmol), and CH2Cl2 (0.5 mL), was added m-nitrobenzoic acid (0.04
I
dx.doi.org/10.1021/jo502152w | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 11342.
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ASSOCIATED CONTENT
* Supporting Information
CIF file of compound 9, NMR spectra, and HPLC traces for
the products. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
̀
Gade, L. H. Chem.Eur. J. 2009, 15, 5450. (n) Pericas, A.; Shafir, A.;
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AUTHOR INFORMATION
Corresponding Author
*E-mail: luosz@iccas.ac.cn.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Science Foundation of China (21390400,
21025208 and 21202171) and the National Basic Research
Program of China (2011CB808600) for financial support. S. L.
is supported by the National Program of Top-notch Young
Professionals and the CAS Youth Innovation Promotion
Association.
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