π-Coordinating Chiral Primary Amine/Palladium Synergistic Catalysis for Asymmetric Allylic Alkylation

Article abstract of DOI:10.1021/jacs.9b13026

We report an arene-containing chiral primary amine as a dual aminocatalyst and ligand: The π-coordinating aminocatalyst/palladium synergistic catalysis for asymmetric allylic alkylation of α-branched β-ketocarbonyls. The use of arene-containing chiral primary amine catalyst led to not only enhanced reaction rate but also reversed chiral induction compared with its sterically bulky derivative. Both enantiomers of the allylic adducts bearing acyclic all-carbon quaternary stereocenters could be obtained from the same configured chiral aminocatalysts with high efficiency and excellent regio-, stereo-, and enantioselectivity. Mechanistic studies revealed a distinctive Pd-arene π-coordination mode for effective catalysis. The π-coordinating chiral primary amine catalyst could be successfully applied in the asymmetric allylation reactions of vinylethylene carbonates, vinyl epoxides, or simple allylic alcohols.

Full text of DOI:10.1021/jacs.9b13026

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Article
#-Coordinating Chiral Primary Amine/Palladium
Synergistic Catalysis for Asymmetric Allylic Alkylation
Yaning Wang, Junli Chai, Chang You, Jie Zhang, Xueling Mi, Long Zhang, and Sanzhong Luo
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b13026 • Publication Date (Web): 17 Jan 2020
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-Coordinating Chiral Primary Amine/Palladium Synergistic Catalysis for
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Asymmetric Allylic Alkylation
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Yaning Wang, † Junli Chai, § Chang You, ‡ Jie Zhang, § Xueling Mi, § Long Zhang,* ‡ Sanzhong Luo*‡
†Key Laboratory for Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China; Department of Chemistry, University of Chinese Academy of Sciences,
Beijing, 100490, China;
‡Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing, China
§College of Chemistry, Beijing Normal University, Xinjiekouwai Street 19, Beijing 100875, China
E-mail: luosz@tsinghua.edu.cn
ABSTRACT: We report an arene-containing chiral primary amine as a dual aminocatalyst and ligand. The
π-coordinating aminocatalyst/palladium synergistic catalysis for asymmetric allylic alkylation of
-branched β-ketocarbonyls. The use of arene-containing chiral primary amine catalyst led to not only
enhanced reaction rate but also reversed chiral induction comparing with its sterically bulky derivative.
Both enantiomers of the allylic adducts bearing acyclic all-carbon quaternary stereocenters could be
obtained from the same configured chiral aminocatalyst with high efficiency and excellent regio-, stereo-
and enantioselectivity. Mechanistic studies revealed a distinctive Pd-arene π-coordination mode for
effective catalysis. The π-coordinating chiral primary amine catalyst could be successfully applied in the
asymmetric allylation reaction of vinylethylene carbonates, vinyl epoxides or simple allylic alcohols.
INTRODUCTION
By merging with transition metal, aminocatalysis has become a powerful and enabling strategy in
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facilitating unprecedented and challenging enantioselective transformations.1 The typical working mode
involves two catalysts working together by activating two different substrates, one an electrophile and the
other a nucleophile, respectively (Scheme 1, I).2 As Lewis bases, aminocatalysts tend to bind with
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transition metals. One primary concern has been the catalyst compatibility and in most successful
examples the two catalysts were usually selected without interfering to each other. Later on, favorable
interactions between two catalytic cycles were noted in amine/transition metal dual catalysis (Scheme 1, I).
For example, List described an ion-pair interaction in assembling enamine and allylpalladium intermediate.
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Similar ion pair was also proposed in a chiral amino acid mediated asymmetric allylation reaction by
Yoshida. 5 In Carreira’s cinchona-Ir catalysis, multi C-H/π interactions were revealed by DFT calculations
to play an important role in achieving the observed stereoselectivity. 6
Despite of these examples, the beneficial interaction between chiral aminocatalysts and transition metal
species has been largely neglected and its potential remains to be explored in synergistic amine/metal
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catalysis. In this regard, the development of chiral amine-ligand combined catalyst has been frequently
pursued by covalently installing a coordinating moiety onto typical aminocatalytic skeletons.
Unfortunately, the progress along this line has been rather limited. In 2012, Shibasaki et al. have developed
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a chiral pyrrolidine-phosphine catalyst with only moderate enantioselectivity (up to 60% ee). We also
explored chiral primary amine-phosphine type catalysts, but our attempts so far led to no successful
catalysis (Scheme 1, II). Herein, we explored an arene-coordination strategy in developing coordinating
chiral primary amine catalysts by replacing the aliphatic tertiary amine moiety with aromatic tertiary
amines. On the basis of known π-complexation property of arenes, 9 we found that the arene-containing
chiral primary aminocatalyst is feasible to π-coordinate with palladium intermediate (Scheme 1, II). The
resulted π-interaction not only leads to enhanced reaction rate, but also reversed stereo-induction
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comparing with its non-arene aliphatic derivatives.
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I: Typical aminocatalyst/metal dual catalysis
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C-H/ -interaction

ion pair interaction
*RO OR*
L
N
L
Y
L
P
O-
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M
O
H
O
Ir
L
N
N
H
R
Pd
OPdIILn
N
well known
H
Cl
Ph
R
E
NH
H
Ph
Me
List
Carreira, Sunoj
Yoshida
Non-interfering Dual Catalysis
II: Desinger Coordinating chiral aminocatalysts
Earlier examples: amino-phosphine catalyst
N
O
HN
N
N
PPh2
L
M
H
up to 60% ee
NH2
E
Ph2P
only cyclohexanone
1'
Our early attempts:
NO activity
This work:
-coordinating aminocatalyst
chiral secondary amine
chiral primary amine

Our design
:
OTf
H
N
-coordinating

arene
Enhanced catalytic activity
Reversed chiral induction
Air insensitivity
H
N
NH2
OTf
NH2
1b
(S)-selective
1d
(R)-selective
Scheme 1. Strategies on enamine/metal dual catalysis
We tested the arene-coordinating chiral amine catalyst in the palladium-catalyzed asymmetric allylic
alkylation (AAA) reaction (Tsuji−Trost allylation 11) of 1,3-diene monoepoxides and/or vinylethylene
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carbonates (VECs). 12-17 These reactions feature a zwitterionic Pd-allyl intermediate which can be captured
by either electrophiles or nucleophiles in a highly regio- and stereoselective manner. 12-17 In most cases, the
asymmetric allylic substitution reactions furnished branched allylic adducts. 12,17 Though linear addition to
12a-c,g,h
1,3-diene monoepoxides has been known since the 1980s by the works of Trost
and more recently
by Kleij, 16 a catalytic asymmetric version remains underdeveloped, however (Scheme 2, I). Following our
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initial successes in enamine-based AAA reactions, we explored the reactions of VECs or vinylepoxide by
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chiral primary amine catalysis. The joint force of our primary amine catalysts with palladium enabled a
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linear addition of prochiral carbon nucleophilie to VECs or vinylepoxide with high E-selectivity and
enantioselectivity (Scheme 2, II). An unexpected divergence of stereocontrol was observed when switching
the tertiary amine moiety from alkyl substituent to an arene-coordinating unit. The dual stereocontrol
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allows for facile access to both enantiomers from the same configurational chiral amines, an intriguing yet
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challenging subject in asymmetric catalysis.
We present herein a detailed account on both the
methodology and mechanistic studies in exploring this arene-coordinating chiral primary amine as dual
aminocatalyst and ligand.
I: Previous works: branched addition
O
Nu
O
[Pd*Ln]
O
HO
O
or
Nu = N, O, C
*
II: This work: an enamine strategy with linear addition
O
O
O
O
O
X

XH
R3
[Pd]
R2
+
R3
COR2
R1
or
Chiral primary
amine
R1
O
X = O, NR
Scheme 2. Asymmetric allylic substitution with VECs/vinylepoxide
RESULTS AND DISCUSSION
1. Asymmetric Allylic Alkylation of 1,3-Dicarbonyls with VECs
We started to first examine different primary-tertiary diamine catalysts 1 in the reaction of tert-butyl
2-methyl-3-oxo-butanoate 2a and VECs 3a in the presence of Pd(PPh3)4. A bulky tertiary aminocatalyst 1b
together with (S)-BINAP-Pd complex was quickly identified to give the optimal reactivity and
enantioselectivity (Table 1, entry 1). Match-mismatch effect was noted with (S)-aminocatalyst and
(S)-BINAP as the optimal combination, the use of (R)-BINAP led to inferior results in terms of both
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reactivity and enantioselectivity (Table 1, entry 7 vs entry 1). Control experiments indicated that chiral
aminocatalyst was the major source of stereocontrol, as the reaction with rac-BINAP or in the absence of
(S)-BINAP still gave good enantioselectivity (78% and 86% ee, Table 1, entries 5 and 6). In contrast, the
use of (S)-BINAP in the presence of racemic amine catalyst rac-1b gave only 25% ee (Table 1, entry 4).
In all these cases, only linear addition was observed and the obtained allylic adducts showed exclusively
E-geometry. When using vinylepoxide 3b instead of 3a, 83% yield and 93% ee were obtained (Table 1,
entry 8).
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By switching the aliphatic tertiary amine to aromatic amine, we observed an unexpected reversal of
chiral induction to R-selectivity with arene-containing aminocatalyst such as 1c (Table 1, entry 11),
indicating a divergence of the stereo-controlling mode. Further structural modification led to the
identification of 1d as the optimal stereo-reversing primary amine catalyst (Table 1, entry 10). The addition
of an achiral ligand such as tris(4-methoxyphenyl)phosphine ((PMP)3P) could significantly enhance the
reactivity as well as the stereoselectivity (Table 1, entries 12 and 13 vs entry 10). The use of 1d instead of
1b under S-selective condition still gave the configurationally switched adduct, albeit with lower reactivity
and decreased enantioselectivity (Table 1, entry 14). This result strongly indicated the leading role of 1d in
stereocontrol, in which the arene moiety would be the critical structural factor. It was clearly noted the
R-selective process was much faster than that of the S-process (entry 1 vs entry 10; 16 h vs 36 h for
complete conversion), highlighting the beneficial feature of arene-aminocatalyst in promoting the reaction.
Both R- and S-processes were quite robust to air, and the reaction could be conveniently conducted under
air with similar outcomes (Table 1, entries 9 and 16). When using vinyl epoxide 3b instead of 3a, the
reaction also worked well to give good yields and high enantioselectivities (Table 1, entries 8 and 15).
Table 1. Screening and Optimization a
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O
O
O
O
O
O
OH
Conditions
O
or
OtBu
t
+
CO2 Bu
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8
(R)-4a
2a
3a
3b
9
N
N
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NR2
1a
1b
: R = Et
NH2
1d
NH2
i
NH2
: R = Pr
1c
(S)-selective condition:
1b
(R)-selective condition:
1d
/TfOH (20 mol%),
/TfOH (20 mol%),
Pd(PPh3)4 (2.5 mol%)
(S)-BINAP (6.25 mol%),
CH3CN, 40 oC, Ar, 36 h
Pd2dba3 (2.5 mol%)
(PMP)3P (10 mol%),
CH3CN, r.t., Ar, 16 h
Entry
Variation from standard conditions
Yield (%) (E/Z)
ee (%)
(S)-selective process
1
none
1a instead of 1b
no amine
95
70
96
78
32
25
78
86
62
93
96
2
3
95 (10:1)
83
4
rac-1b
5
no (S)-BINAP
rac-BINAP
(R)-BINAP
3b instead of 3a
air
33 (10:1)
61
6
7
65
8
83
9
87
(R)-selective process
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12
13
14
15
16
none
1c instead of 1d
PPh3
96
88
79
91
15
95
83
-96
-81
-88
-88
-18
-93
-95
(p-Tol)3P
With Pd(PPh3)4/(S)-BINAP
3b instead of 3a
air
a The reaction was performed with 1a (0.15 mmol), 2a (0.10 mmol), chiral amine (20 mol %), Pd precursor
(2.5 mol %), and phosphine (10-20 mol %) in 0.3 mL of CH3CN under standard conditions, isolated yield,
E/Z ratio was determined by NMR, ee value was determined by HPLC.
With the optimized conditions in hand, we then investigated the scope of the reaction with VECs.
Different ester groups of various sizes were tolerated to give the expected allylic adducts for both
enantiomers in good yields and excellent enantioselectivities (Table 2, entry 1-6). The reaction worked well
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by varying α-substituents including long-chain alkyl group and allylic group (R1, Table 2, entries 7-10).
Unsymmetrical 1,3-diketones, normally considered challenging substrates in the typical enol process, could
also be incorporated to give allylic alkylation products in 96% yield, 94% ee for the R-process and 41%
yield, 94% ee for the S-process (Table 2, entry 11). Increasing the bulkiness of one keto moiety led to
slightly reduced reactivity with good enantioselectivity in both cases (Table 2, entry 12). The reaction with
cyclic β-ketoester such as cyclohexanone proceeded well to give the corresponding adducts with high
yieids and excellent enantioselectivities for both processes (Table 2, entry 14). For cyclopentanone, the
R-process proceeded well to give the desired adduct with high enantioselectivity, while the S-process
showed low enantioselectivity (Table 2, entry 13). In this case, the ketocarbonyl mainly exists as an enol
and background reaction via enol-process may happen as the S-selective processe is rather sluggish, hence
resulting in low enantioselectivity.
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Table 2. Substrates scope for VECs a
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O
O
O
R
O
R
O
R2
1d
/TfOH (20 mol%)
1b
/TfOH (20 mol%)
R3
XH
XH
X
R3
R3
+
Pd(PPh3)4 (2.5 mol%)
(S)-BINAP (6.25 mol%)
CH3CN, 40 oC
Pd2dba3 (2.5 mol%)
(PMP)3P (10 mol%)
CH3CN, r.t.
R1
R
3
R1 R2
R1 R2
4
4
(R)-
(S)-
2
9
a
. -ketocarbonyls scope
t
4a
4b
4c
4d
4e
: R = Bu, (S): 95%, 96% ee
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(R): 91%, 96% ee
O
1-5
6
7
O
O
: R = Ad, (S): 94%, 95% ee
(R): 98%, 90% ee
OH
OH
OH
t
CO2C(C2H5)3
CO2R
CO2 Bu
: R = Et, (S): 84%, 92% ee
(R): 99%, 87% ee
4f
4g
(S): 73%, 93% ee
(R): 94%, 85% ee
i
(S): 65%, 98% ee
(R): 70%, 96% ee
: R = Pr, (S): 92%, 92% ee
(R): 90%, 80% ee
: R = Me, (S): 50%, 81% ee
(R): 75%, 91% ee
8
O
9
O
11
O
O
10
OH
OH
OH
OH
t
t
CO2 Bu
5
t
COEt
4k
CO2 Bu
CO2 Bu
2
4h
4i
4j
(S): 41%, 95% eeb
(R): 96%, 94% ee
(S): 78%, 93% ee
(R): 84%, 86% ee
(S): 45%, 85% ee
(R): 83%, 82% ee
(S): 24%, 92% ee
(R): 90%, 89% ee
O
13
O
14
12
O
OH
OH
OH
t
t
COiPr
4l
(S): 52%, 80% eeb
CO2 Bu
CO2 Bu
4m
4n
(S): 83%, 27% eeb
(R): 75%, 95% ee
(S): 94%, 95% ee
(R): 98%, 91% ee
(R): 71%, 90% ee
b
. VECs scope
OH
O
15
16
O
17-20
O
NHR
OH
Ph
t
CO2 Bu
t
t
CO2 Bu
CO2 Bu
4p
4o
(S): 75%, 91%/96% ee, Z/E=4:1
(R): trace
(S): 70%, 95%/94% ee, E/Z=4:1
(R): trace
4q
: R = Ph, (S): 72%, 94% ee
(R): 73%, 96% ee
: R = p-CF3-Ph, (S): 91%, 94% ee
(R): 97%, 97% ee
: R = p-OMe-Ph, (S): 30%, 92% ee
(R): 47%, 94% ee
: R = p-Me-Ph, (S): 35%, 97% ee
(R): 62%, 96% ee
4r
O
21
22
O
H
H
4s
N
N
t
t
CO2 Bu
CO2 Bu
4t
CF3
CF3
4v
4u
(S): 43%, 90% eec
(R): 71%, 90% eec
(S): 72%, 89% eec
(R): 83%, 92% eec
a
The reaction was performed under standard condition, 36-96 h for (S)-process and 16-72 h for
(R)-process, E/Z > 19:1, isolated yield, ee value was determined by HPLC, E/Z ratio was determined by
NMR. b The reaction was performed with 2 (0.1 mmol). c under Ar.
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Substitution on VECs has also been examined. Methyl and phenyl group could be tolerated on the
internal position to give tri-substituted S-allylic adducts in good yields with high enantioselectivities (Table
2, entries 15-16). Unfortunately, the R-selective processes did not proceed at all with these substituted
VECs, likely a result of steric effect. The present catalytic systems could also be applied to the coupling
with vinylethylene carbamates (Table 2, entries 17-22). A range of N-aryl carbamates could be
incorporated to afford linear N-allylic anilines adducts with good yields and high enantioselectivities for
both R- and S-processes. In all examined cases, the reactions afforded exclusively linear adducts bearing
acyclic all-carbon quaternary centers and E-geometric olefins. Both R- and S-processes could be conducted
in larger scale with similar performance (Scheme 3), highlighting the applicability of the present
enantio-divergent catalysis.
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O
O
O
O
O
standard process
OH
O
+
OtBu
t
CO2 Bu
(S)-4a:
0.57 g, 79%, 95% ee
: 0.59 g, 81%, 95% ee
4a
(R)-4a
3a
2a
Scheme 3. Larger scale experiments
Then we investigated the scope of the reaction for vinyl epoxide. Different ester groups of various
sizes were tolerated well to give the expected allylic adducts for both enantiomers in good yields and
excellent enantioselectivities (Table 3, entries 1-4). For α-substituted ketoesters, the reaction worked well
for R-process in good yield with slightly lower ee than with VECs. For S-process, both the yield and ee
were reduced comparing with the VEC processes (R1, Table 3, entries 4-6). For cyclic ketoester, the
R-process went well to give the desired adduct with high yield and ee, while the S-process showed
relatively lower reactivity and enantioselectivity (Table 3, entry 7). A phenyl-substituted epoxide has also
been examined to give the expected tri-substituted S-allylic adduct 4o in 82% yield and 86% ee (Table 3,
entry 8), and unfortunately the R-selective processes did not proceed.
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Table 3. Substrates scope for vinyl epoxide a
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7
8
9
O
O
R
O
R
R2
1d
/TfOH (20 mol%)
1b
/TfOH (20 mol%)
R3
XH
O
XH
R3
R3
+
Pd(PPh3)4 (2.5 mol%)
(S)-BINAP (6.25 mol%)
CH3CN, 40 oC
Pd2dba3 (2.5 mol%)
(PMP)3P (10 mol%)
CH3CN, r.t.
R1
R1 R2
R1 R2
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4
4
(R)-
(S)-
2
3b
1-3
O
O
4
5
t
4a
4b
4c
: R = Bu, (S): 83%, 93% ee
OH
OH
O
(R): 95%, 93% ee
t
CO2C(C2H5)3
CO2 Bu
OH
: R = Ad, (S): 91%, 96% ee
(R): 90%, 91% ee
2
4f
4h
CO2R
: R = Et, (S): 91%, 87% ee
(R): 83%, 87% ee
(S): 26%, 78% ee
(R): 60%, 86% ee
(S): 75%, 97% ee
(R): 95%, 94% ee
OH
O
O
7
O
6
8
OH
OH
Ph
t
t
t
CO2 Bu
CO2 Bu
CO2 Bu
4o
4n
4j
(S): 82%, 86% /96% ee, Z/E = 4:1
(R): trace
(S): 47%, 79% ee
(R): 78%, 87% ee
(S): 52%, 87% ee
(R): 82%, 83% ee
a
The reaction was performed under standard condition, 36-96 h for (S)-process and 16-72 h for
(R)-process, E/Z > 19:1, isolated yield, ee was determined by HPLC, E/Z ratio was determined by NMR.
2. Mechanistic Studies
2.1 Control experiments
Electronic effect. To understand the divergence of stereocontrol when switching the tertiary amine
moiety from alkyl substituent to an arene unit, a series of control experiments were conducted. We first
investigated the effect of aromatic rings and found that only catalysts with aromatic rings could switch the
enantioselectivity. The swap of alkyl side chain to an arene group not only led to reversed chiral inductions
but also enhanced reaction rate by comparing 1a and 1c-e (Scheme 4A). The electronic effect of the arene
moiety was then explored. It was found that an electron-rich group (MeO-) in 1e led to much improved
enantioselectivity comparing with 1c (Scheme 4A). On the other hand, electron-withdrawing
bromo-substituted analogue 1f resulted in reductions of both the ee value and reactivity (Scheme 4A). In
this case, we believe electronic effect should be the major working factor at the remote sites, although steric
effect can’t be excluded.
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Ligand effect. The impact of the loading of achiral phosphine ligand was examined (Scheme 4B). 10
mol% of ligand loading is optimal in terms of both reactivity and stereoselectivity. Increasing to 15 mol%
loading led to a slight reduction of yield (80% vs 88%) with the same enantioselectivity. Further increase to
20 mol% led to a serious reduction in both yield and ee (30% yield and 33% ee), and a virtually racemic
reaction was observed at 30 mol% loading, though with recovered activity (74% yield). On the other hand,
increasing the ratio of 1d and achiral phosphine ligand by either decreasing the loading of phosphine ligand
(to 5 mol%) or increasing the loading of 1d resulted in serious reduction of the productivity. Unidentified
side products, likely arising from the decomposition of VEC were observed in these cases (Scheme 4C).
With 40 mol% of aminocatalyst 1d, only 57% yield of the desired product was isolated (Scheme 4C). This
observation stands in contrast to the S-process wherein increasing the loading of aminocatalyst resulted in a
faster reaction (Scheme 4C, 20 h, 83% yield, vs 20 h, 41% yield). Taken together, these results indicates a
competitive binding with palladium between aminocatalyst 1d and achiral phosphine and a delicate balance
is critical to achieve optimal activity and enantioselectivity.
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Excluding enol-process. In the R-process, the reaction proceeded well in the absence of chiral
aminocatalyst 1d, indicating a background enol-process (Scheme 4D). This stands in contrast to the high
enantioselectivity observed in the presence of aminocatalysts, suggesting that the background enol process
was not occurring. To verify this, controlled experiments with protonated amine such as NEt3/TfOH or
methylated-1d/TfOH were conducted and no activities were observed for both R- and S-process. These
results indicated that the enol processes are largely suppressed under the aminocatalytic conditions and the
reaction most likely proceeds via an enamine pathway in consistence with our previous studies. 20 We have
tried to conduct stoichiometric experiment with the preformed enamine intermediate I (Scheme 4, D),
unfortunately the instability of the expected enamine-I in the presence of acid precluded any meaningful
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observations. Nevertheless, we did observe the formation of enamine-I by in-situ ESI-MS analysis (see SI),
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verifying the enamine catalytic nature.
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A
)
R2
N
O
TfOH
O
O
O
NH2 R1
(20 mol%)
OH
O
OtBu
+
t
O
Pd2dba3 (2.5 mol%)
(PMP)3P (10 mol%)
MeCN, r.t., 24 h
CO2 Bu
9
Br
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Br
Br
N
N
N
N
OMe
1e
1f
1a
21%, 27% ee
1c
Br
88%, -81% ee
45%, -62% ee
83%, -90% ee
B
)
O
O
O
O
1d
/TfOH (20 mol%)
OH
O
O
OtBu
+
t
Pd2dba3 (2.5 mol%)
(PMP)3P (x mol%)
MeCN, r.t., 20 h
CO2 Bu
(PMP)3P (x mol%)
5
Ee (%)
Yield (%)
NR
--
10 (standard condition)
94
94
33
4
88
80
30
74
15
20
30
C
)
O
O
O
O
O
O
1d
/TfOH (x mol%)
OH
OtBu
+
t
Pd2dba3 (2.5 mol%)
(PMP)3P (x mol%)
MeCN, r.t., 20 h
CO2 Bu
amine (x mol%)
Ee (%)
Yield (%)
, 1d
R-process
, 10
91
95
93
93
52
96
70
57
, 1d
, 1d
, 1d
R-process
R-process
R-process
, 20
, 30
, 40
, 40
83
93
, 1b
S-process
D
)
O
O
O
O
amine (20 mol%)
O
O
OH
OtBu
+
t
Pd2dba3 (2.5 mol%)
(PMP)3P (10 mol%)
MeCN, r.t., 20 h
CO2 Bu
Variations from standard conditions
Ee (%)
Yield (%)
no amine (R)
87
rac
--
1d
Et3N/TfOH or methyled- /TfOH
NR
instead of amine (R/S)
N
H
N
O
RO
enamine (I)
Scheme 4: Control Experiments
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2.2 Complexation between aminocatalyst and palladium in solution and solid state
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9
Fluorescence spectroscopy. In order to further elucidate binding behavior of aminocatalyst and
palladium in solution, fluorescence spectroscopy was investigated. Figure 1 shows the absorption and
fluorescence emission spectra of arene catalyst 1d (Blue line a). Upon the addition of one equivalent of
TfOH, the emission of 1d was significantly enhanced (Figure 1, right, a vs b), a well-known feature of aryl
amines due to the interruption of photoinduced electron transfer (PET) upon protonation. 21 On the other
hand, the addition of palladium complex [Pd(C3H5)Cl]2 resulted in slightly quenching of the fluorescence
(Figure 1, right, a vs c), a feature distinctive from that of protonation and suggestive of arene-Pd interaction
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as a possible quenching mechanism.
800
1
c
b
600
400
200
0
a
b
0.65
0.3
a
c
-0.05
300
350
400
450
500
550
250
300
350
400
λ/nm
Figure 1. Absorption spectra (left) and emission spectra (right, λex = 285 nm, bandpass of 2.5 nm at the EX
slit and 10 nm at the EM slit), 1.0x10-4 M in MeCN. a: 1d; b: 1d/TfOH (1:1); c: 1d/[Pd(C3H5)Cl]2 (1:0.5).
We further conducted fluorescence titration to look into the interaction of palladium and aromatic rings.
To eliminate interference from nitrogen lone pair, a protonated salt composed of 1d and two equivalent of
TfOH was used for the titration. Figure 2 shows the fluorescence quenching of 1d/2TfOH by palladium
complex [Pd(C3H5)Cl]2 (Figure 2, a). Similar quenching behaviors were also observed with acenaphthene
(see SI) and a simplified catalyst analogue 6/TfOH (Figure 2, b).
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To determine the quenching effect is from specific complex formation (static quenching) instead of
transient collision (dynamic quenching), the Stern-Volmer analysis 1d/2TfOH quenched by Pd at different
temperature was first conducted (Figure 2, c). The interaction of 1d/2TfOH and Pd generated linear
Stern-Volmer plots and the slopes decreased with increasing temperature, suggesting the quench was
triggered by a static quenching mechanism. Secondly, we measured the fluorescence lifetime of 1d/2TfOH.
The fluorescence lifetime remained unchanged after adding quenching agent Pd (τ0 = 3.7 ns) (Figure 2, d).
2.3 × 1012
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Furthermore, the bimolecular quenching constant Kq (288 K: Kq =
L/mol/s; 298 K: Kq =
1.7 × 1012
1010
1.2 × 1012
2.0 ×
L/mol/s) was found to be substantially larger than
L/mol/s; 308 K: Kq =
, the diffusion-controlled bimolecular quenching constant, providing additional evidence on a static
quenching.
We next determined the binding constant by the plot between lg[(F0ꢀ−ꢀF)/F] and lg[Q] using double
9.3 × 102
22
logarithmic equation
4.0 × 103
(see SI) and the obtained binding constants were determined to be
L· mol-1,
L· mol-1 for 1d-2TfOH and 6-TfOH, respectively. The binding with 1d-2TfOH is
relatively weak, likely due to its dicatonic nature.23 These results add supports to the arene-palladium
interaction between 1d and palladium complex.
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b
( )
a
( )
4
5
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9
6000
4000
2000
0
6000
4000
2000
0
N
Pd
NH2
Pd
2TfOH
N
TfOH
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300
400
500
300
400
500
λ/nm
λ/nm
c
( )
d
( )
3
2.5
2
288 K
298 K
308 K
1.5
1
0
0.00005
0.0001
0.00015
[Q] (mol/L)
Figure 2. Fluorescence quenching of cat. 1d/2TfOH or analogues (10-4 M in CH3CN, λex = 285 nm,
bandpass of 2.5 nm at the EX slit and 10 nm at the EM slit) by [Pd(C3H5)Cl]2 (0-1.0x10-4 M). (a) the
fluorescence spectrophotometric titration of [Pd(C3H5)Cl]2 to 1d/2TfOH; (b) the fluorescence
spectrophotometric titration of [Pd(C3H5)Cl]2 to analogues 6; (c) Stern-Volmer plots for 1d/2TfOH-Pd at
8.566 × 103
6.245 × 103
=
various temperatures. 288 K: Ksv
L/mol/s, R2 = 0.9938; 308 K: Ksv =
=
L/mol/s, R2 = 0.9951; 298 K: Ksv
4.530 × 103
L/mol/s, R2 = 0.991; (d) transient photoluminescence
spectra of 1d/2TfOH (10-4 M in CH3CN, τ0 = 3.7 ns); upon adding 1.0 eq of [Pd(C3H5)Cl]2, the
fluorescence lifetime remains unchanged.
1
NMR. We also studied the 1d-2TfOH/palladium interaction in acetonitrile by NMR. H NMR analysis
showed that the resonances of arene C-H of 1d were shifted to lower field in the presence of TfOH
(Scheme 5, a vs b), while considerable shifts to a higher field appeared when adding palladium (Scheme 5,
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9g
c), an indication of peripheral π-coordination. It is possible the shift may be resulted from H-bonding
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with chloride anion of the palladium species (e.g. H-Cl bonding). To check this possibility, we have
examined NMR by adding ZnCl2 instead of the palladium complex under otherwise identical conditions
and no shift was observed (see SI), excluding H-bonding as the working factor.
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1d
c
b
/2TfOH + [Pd(C3H5)2Cl]2
Hb/Hb'
Hb/Hb'
Ha/Ha'
Ha/Ha'
Hc/Hc'
1d
/2TfOH
Hc/Hc'
Ha'
Hb'
Hb/Hb'
Hc/Hc'
N
Ha/Ha'
1d
a
NH2
Hc'
Hc
Ha
Hb
Scheme 5. 1H NMR Analysis in CD3CN
3.736
3.762
I
II
III
Figure 3. X-ray Crystal structure. Hydrogen atoms have been omitted for the sake of clarity. I:
[1d-Pd(C3H5)]+TfO-; II: [1d-TfOH]+[Pd(C3H5)Cl2]- and DFT optimized structure of III:
-
[1d-TfOH]+[Pd(C3H5)]+(BF4 )2.
X-ray Single Crystal Analysis. We also tried to crystallize the complex of 1d-TfOH and palladium.
From the solution of 1d-TfOH and [Pd(C3H5)Cl]2 in CH2Cl2/Et2O, we obtained two types of crystals, a N,
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N-Palladium complex I and a non-nitrogen-coordination complex II (Figure 3). In the structure of II, an
anionic [Pd(C3H5)Cl2]- species locates beneath the arene ring in a π-stacking manner and the lowest
distance of palladium center to arene is determined to be ca. 3.7 Å. Considering that the real active
palladium complex should be cationic in nature, we tried to switch chloride anion with non-coordinating
BF4 anion in II. The resulted complex III, upon DFT optimization, indeed showed a much shortened
distance between palladium and arene ring (ca. 3.2 Å, Figure 3, III), further supporting the existence of
arene π-binding of 1d with palladium.
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2.3 Proposed Catalytic Cycle
18
On the basis of our experimental observations as well as previous studies,
synergistic chiral
enamine/achiral palladium transition states were proposed to account for the observed stereoselectivities in
the key C-C bond formation step. The S-selective process with dialkylated aminocatalyst 1b would follow a
Si-facial attack mode as a result of steric effect (Scheme 6, TS1). The observed dependence of
enantioselectivity on steric hindrance of the tertiary amine moiety is clearly in line with this model. In the
R-selective process, a dual role of primary amine 1d as both aminocatalyst and π-coordination ligand was
invoked, and the Re-facial attack follows a π-coordination mode attributed to the arene and palladium
coordination (Scheme 6, TS2).
N
N
H
H
N
L
N
O
L
VS
O
Pd
Pd
RO
HO
HO
RO
TS1
L
TS2
Si
Re-facial attack favored
-facial attack favored
Steric Model
Pd-Arene Model
Scheme 6. Proposed transition states
Further verification of steric effect on (S)-process: Double Layer Sterimol Mode. We recently
developed a double-layered sterimol mode to account for the steric effect in the catalysis of chiral
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primary-tertiary diamines. 24 This mode was also applied in the current catalysis (Figure 4). The sterimol
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25
parameters were calculated following Sigman’s procedure
based on ground state structures,
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9
geometrically optimized using DFT calculations at B3LYP/6-31G(d) level in gas phase. 26 B1, B5 and L
were the sterimol parameters of the whole R group and the B1’, B5’ and L’ were the sterimol parameters of
the inner-sphere of R group. The calculated parameters and the experimental data were summarized in
Table 4. Multivariate linear least-squares regression analysis gave an equation：
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∆∆Ga = 2.37B1 + 2.29B'1 - 6.62
The above equation gave a good correlation between the predicted and measured enantioselectivity with
R2 = 0.93 (Figure 4), and the enantioselectivity was mainly affected by the out-sphere B1 and inner-sphere
B1’, which is in accordance with our previous results. 24
Table 4: The Sterimol parameters of N-substituents and the measured enantioselectivity
R, R
B1
B5
L
B1'
B5'
L'
ΔΔG(Kcal/mol)
Me, Me
Et, Et
1.7
2.2
3.02
4.37
4.4
1.17
1.7
1.17
2.21
2.21
3.68
5.16
1.17
1.17
2.26
3.12
3.13
5.19
7.29
2.26
2.27
0.41274
1.300981
2.421718
1.367241
1.367241
0.291453
0.469041
1.73
2.09
1.74
3.34
3.36
4.67
5.98
4.27
4.57
i-Pr, i-Pr
n-Bu, n-Bu
1.7
6.56
8.76
5.61
5.83
1.71
1.71
1.17
1.17
n-Hex, n-Hex 1.74
-(CH2)4-
-(CH2)5
1.83
1.95
i-Pr
2
1
0
n-Bu
n-Hex
R2 = 0.93
Et
N
H
H
H H
Innersphere
B1', B5', L
e.g.
R
N
R
(CH2)5
(CH2)4
H
H H
Outsphere
B1, B5, L
Me
Ga = 2.37B1 + 2.29B1' - 6.62
0
1
2
3
Mesured G (kcal/mol)
Figure 4. Correlation of predicted and observed enantioselectivity based on Double-Layered Sterimol
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Computational Studies of the R-process. In order to elucidate the arene effects, we calculated the reaction
profile of this R-selective process by DFT. As the enamine formation and the Pd-allyl formation was quite
known, we started with these two species: enamine intermediate I and the E-type Pd-allyl intermediate II.27
The assembly between these two intermediates causes a raise in free energy on both sides of the enamine
intermediates, likely a result of the steric repulsion between the phosphine ligands and tert-butyl or aryl
substituents. With the assembly int1 or int2, the reaction then proceed via C-C formation to give eventually
S- or R- selective product after a sequence of down-hill steps, respectively. We located an S-selective
transition state TS-S with a barrier of 22.8 kcal/mol (Scheme 7, TS-S). For the R-selective process, direct
attack of enamine I to Pd-allyl II may occur and the determined barrier was 33.8 kcal/mol (Scheme 7,
TS-3), largely disfavored over TS-S. In the disfavored TS-3, the palladium-phosphine coordination is
significantly weakened with lengthened Pd-P bonds (2.79 and 2.84 Å, respectively), meanwhile a close
contact between Pd and naphthalene C4 (2.82 Å, Figure 4, TS-3) is noted, a clear indication of strong
cation-π interaction.
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Assembly Int2 may also undergo ligand swap before C-C coupling and simultaneously form a
π-coordination complex Int3. We have mapped possible C-C forming pathways with Int3 and the most
favorable one was located with a barrier as low as 21.5 kcal/mol (Scheme 7, TS-R). In TS-R (Figure 5), the
distance between Pd and naphthalene ring was shortened to 2.62 Å; in addition, a Csp2-H-π interaction
between the enamine and phosphine ligand was also formed with a distance of 2.62 Å. These two π
interactions could be further verified by the large overlap of the Van der Waals surfaces between the
naphthalene ring and the electrophile species (Figure 5, TS-R vs TS-S and TS-3).28 Such π-interactions
could enormously stabilize the R-selective transition states, which should dictates the final enantiocontrol.
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The determined enantioselectivity based on TS-S/TS-R was 81% ee favoring the R-selectivity, in line with
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the experimental observation.
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G (kcal/mol)
M06-2X/6-311++G(d,p)(Pd,lanl2dz)//
M06-2X/6-31G(d)(Pd,lanl2dz)
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N
N
N
H
H
H
N
N
L
N
O
O
L
O
Pd
Pd
Pd
L
RO
RO
HO
RO
TS-S
HO
HO
L
L
TS-3
TS-R
L
R = Me
= (p-MeOC6H4)3P
33.8
TS-3
22.8
21.5
TS-R
TS-S
L
14.6
II
( )
L2PdAllyl
6.0
Int2
Int3
6.0
Int1
0.0
enamine
I
( )
R-Product
S-Product
C-C formation
N
Int assembly
Ligand swap
N
C-C formation
Int assembly
N
N
H
N
H
H
H
N
L
N
N
O
O
L
O
O
Pd
Pd
Pd
L
RO
HO
RO
HO
HO
RO
Int1
RO
L
L
enamine(I)
Int2
Int3
Scheme 7. DFT-Computed Free-Energy Profiles on the coupling of enamine with π-allyl.
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TS-S
TS3
TS-R
Figure 5. Van der Waals potential energy surface penetration diagram
3. Further application of the π-coordinating mode
Previously, we reported chiral primary amine and palladium co-catalyzed allylation reaction with free
allylic alcohols. We tested the π-coordinating primary amine catalyst 1d in the reaction with free allylic
alcohols. To our delight, reversed chiral induction was indeed observed in the reaction with cinnamyl
alcohol and a clear electronic effect in consistence with VEC reactions was also noted (Table 5, entries
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1-4), indicating the π-coordinating mode is applicable. Further investigation revealed the π-coordinating
primary amine catalyst 1d worked more favorably with smaller allylic alcohol such as allyl alcohol. In this
case, the reaction afforded the desired product with 87% ee and 80% yield, not only the chiral induction
was reversed, the reaction rate was also enhanced (Table 5, entry 5 vs 6). The reaction also worked well
with pent-2-ene-1,5-diol, a precursor of VEC, to give the desired adduct with 92% ee (Table 5, entry 7).
We then set out to explore the scope of the AAA reaction with regard to the allylic-alcohol
component. Different esters of various sizes and cyclic β-ketoesters were generally tolerated to give the
desired adducts in good yields and enantioselectivities (Table 5, entries 1-9) with the expected
stereo-inductions.
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Table 5. Asymmetric Allylic Alkylation with allylic alchol a
O
O
amine/TfOH (20 mol%)
O
[Pd(C3H5)2Cl]2 (5 mol%), ligand (20 mol%)
OtBu
R
OH
+
R
t
CH3CN, r.t., 48 h
CO2 Bu
6 4
5
2a
/
R = Ph
N
NR2
N
N
NH2
NH2
NH2
1e
NH2
i
1b
1g
: R = Pr
OMe
: R = CHEt2
1c
1d
Entry
Conditions
Yield (%)
ee (%)
R = Ph
1
1g, PPh3, 72 h
1d, (PMP)3P
1c, (PMP)3P
1e, (PMP)3P
92
90
83
92
98 (S)
47 (R)
22 (R)
31 (R)
2
3
4
R = H
5
6
1d, (PMP)3P
1g, PPh3,72 h
80
51
87 (R)
86 (S)
R = CH2OH
7
1d, (PMP)3P
65
92 (R)
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Substrates scope
:
O
4
O
1-3
5
6
7
8
9
t
O
6a
6b
6c
: R = Bu, 80%, 87% ee
t
CO2 Bu
6d
CO2Et
: R = Ad, 60%, 88% ee
: R = Et, 43%, 84% ee
6e
CO2R
67%, 91% ee
71%, 85% ee
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7
8-9
O
O
O
Ph
t
t
t
4a
4b
OH
: R = Bu, 65%, 92% ee
CO2 Bu
6g
CO2 Bu
6f
: R = Ad, 50%, 48% ee
CO2R
40%, 80% ee
90%, 47% ee
a The reaction was performed with 2 (0.15 mmol), 5 (0.10 mmol), chiral amine (20 mol %), [Pd(C3H5)Cl]2
precursor (5 mol %), and Phosphine ligand (20 mol %) in 0.3 mL of CH3CN for 36-60 h under standard
conditions, isolated yield, ee was determined by HPLC.
CONCLUSION
In summary, we have developed an arene-containing chiral primary amine as a dual aminocatalyst and
π-ligand. The π-coordinating aminocatalyst was successfully applied in the asymmetric allylic alkylation of
α-branched β-ketocarbonyls with a number of allylic precursors in synergy with palladium catalysis. The
resulted π-coordination not only led to much enhanced reaction rate but also reversed chiral induction
comparing with its non-arene dialkylated analogues bearing the same configurations. The current protocol
provides a facile access to both enantiomers of the allylic adducts bearing acyclic all-carbon quaternary
adducts from the same configured chiral aminocatalyst in high efficiency and excellent regio-, stereo- and
enantioselectivity. Detailed mechanistic studies by the joint force of experimental and computational
approaches verified the existence of π-coordination and elucidated its working mode in tuning both
reactivity and stereoselectivity. This study sheds new lights in pursuing a unified organocatalyst and ligand
in a chiral small molecular skeleton.
ASSOCIATED CONTENT
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Supporting Information
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Experimental details, characterization of new compounds and computational studies. The Supporting
Information is available free of charge on the ACS Publications website.
AUTHOR INFORMATION
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Corresponding Author
luosz@tsinghua.edu.cn
zhanglong@mail.tsinghu.edu.cn
Notes
Any additional relevant notes should be placed here.
ACKNOWLEDGMENT
We thank the Natural Science Foundation of China (21572232, 21672217, 21521002 and 21861132003)
and Tsinghua University for financial support. S.L. is supported by the National Program of Top-notch
Young Professionals.
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