Chiral primary amine/palladium dual catalysis for asymmetric allylic alkylation of β-ketocarbonyl compounds with allylic alcohols

Article abstract of DOI:10.1002/anie.201505946

An efficient dual catalytic system composed of a chiral primary amine and a palladium complex was developed to promote the direct asymmetric allylic alkylation (AAA) of β-ketocarbonyl compounds. In particular, the synergistic dual catalytic system enabled

Full text of DOI:10.1002/anie.201505946

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201505946
German Edition: DOI: 10.1002/ange.201505946
Dual Catalysis
Chiral Primary Amine/Palladium Dual Catalysis for Asymmetric
Allylic Alkylation of b-Ketocarbonyl Compounds with Allylic Alcohols
Han Zhou, Long Zhang, Changming Xu, and Sanzhong Luo*
Abstract: An efficient dual catalytic system composed of
a chiral primary amine and a palladium complex was
developed to promote the direct asymmetric allylic alkylation
(AAA) of b-ketocarbonyl compounds. In particular, the
synergistic dual catalytic system enabled the AAA reaction of
challenging acyclic aliphatic ketones, such as b-ketocarbonyl
compounds and 1,3-diketones.
T
ransition-metal-catalyzed asymmetric allylic alkylation
(AAA) reactions serve as a versatile and powerful tool for
[1]
À
enantioselective C C bond formation. One of the most
recent developments along this line are enamine-based AAA
reactions. As versatile nucleophilic synthons and catalytic
intermediates, enamines, either preformed or generated in
situ, have long been investigated for allylic alkylation
reactions.[2] The merging of aminocatalysis, an iconic form
of organocatalysis, with transition-metal catalysis has enabled
asymmetric allylic alkylation reactions of simple aldehydes
and ketones (Scheme 1I), for which the typical enolate-based
approaches were generally less effective owing to the require-
ment of a stoichiometric base as well as associated issues with
racemization and side pathways.[3–5] Córdova first introduced
the dual amine/palladium-catalyzed allylic alkylation with
aldehydes and cyclic ketones in 2006.[4e] Later on, the
synergistic amine–transition-metal-catalyzed asymmetric
allylic alkylation was extended to a-branched aldehydes
through elegant contributions from the research groups of
List and Carreira.[4a,d] Despite these advances, acyclic ketones
remained elusive substrates for this reaction.
The direct use of free allylic alcohols in AAA reactions
has attracted much attention owing to the high reaction
economy. However, free allylic alcohols are normally sluggish
substrates requiring higher reaction temperatures or addi-
tional activators for the generation of the active p-allyl
intermediates; hence, most such reactions have been limited
to achiral transformations.[6] Transition-metal-catalyzed AAA
reactions with allylic alcohols under mild conditions are still
rare.[2c,6a,7] On the other hand, b-ketocarbonyl compounds are
versatile synthetic intermediates for the synthesis of natural
and bioactive products, and the development of stereoselec-
Scheme 1. Strategies and scope of enamine AAA reactions. LG=leav-
ing group, Tf =trifluoromethanesulfonyl.
tive transformations of b-ketocarbonyl compounds is of long-
standing interest in organic chemistry. Although the creation
of quaternary carbon stereocenters with cyclic b-ketocarbonyl
compounds by AAA reactions has been well documented by
Trost and co-workers and others,[1e, 5e,8] asymmetric allylic
alkylation with acyclic b-ketocarbonyl compounds remains an
unaddressed issue in this field.[1e,8a,c,9] In particular, the
successful combination of simple allylic alcohols and acyclic
b-ketocarbonyl compounds has not been reported previously.
Herein, we describe an unprecedented asymmetric allylic
alkylation of acyclic b-ketocarbonyl compounds with free
allylic alcohols under mild conditions (Scheme 1II). The
reaction was enabled by a synergistic combination of our
developed chiral primary amine and palladium catalyst[10] and
features the enantioselective construction of quaternary
stereocenters with challenging acyclic aliphatic ketones,
such as b-ketocarbonyl compounds and 1,3-diketones.
Our initial investigation was performed with tert-butyl 2-
methyl-3-oxobutanoate (1a, 0.15 mmol), cinnamyl alcohol
(2a, 0.1 mmol), [{Pd(allyl)Cl}2] (5 mol%), PPh3 (20 mol%),
and the primary amine 4a (20 mol%) in CH3CN (0.5 mL) for
36 h at 408C. We obtained the desired product in excellent
yield and with a moderate ee value (Table 1, entry 1). The two
most commonly used palladium-catalyst precursors were
tested next, but none of the desired product was formed
(Table 1, entries 2 and 3). We then investigated other
primary–tertiary-diamine catalysts (Table 1, entries 4–12)
and found that tert-leucine-derived primary-tertiary diamines
gave the best results (Table 1, entries 4–9); other primary-
amine catalysts gave inferior results or were even inert for the
reaction (Table 1, entries 10–12). We synthesized a series of
primary–tertiary diamines with the tert-leucine skeleton with
variations in the tertiary-amine moiety. It was found that the
steric encumbrance of the tertiary-amine moiety significantly
[*] H. Zhou, Dr. L. Zhang, C. Xu, Prof. Dr. S. 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)
E-mail: luosz@iccas.ac.cn
Homepage: http://luosz.iccas.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505946.
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Table 1: Screening and optimization.
a variety of b-ketocarbonyl compounds. The identified
catalysts 4b and 4 f were both examined in a few selected
cases. Different ester moieties of various sizes were generally
tolerated to give the desired adducts in good yields with
excellent enantioselectivity (Scheme 2, products 3aa–fa). The
catalyst 4b showed higher reactivity with substrates 1a and
1b. On the other hand, better enantioselectivity was generally
obtained with catalyst 4 f (products 3aa and 3ba). Bulky a-
substituents were found to lead to reduced reactivity and
enantioselectivity (Scheme 2, products 3ga and 3ha), and the
less bulky catalyst 4b was preferable for the substrate with
a bulky propyl substituent (3ha). Cyclic b-ketoesters were
also tolerated and transformed into the desired products 3ja
and 3ka with high enantioselectivity and reactivity. A
piperidone-derived substrate was also used in the reaction
to give the desired product 3la with 97 and 92% ee under the
two sets of optimal conditions. Even the b-diketone substrate
1m, once regarded as an challenging substrate for the
transition-metal-catalyzed AAA reaction owing to the steric
and electronic similarities of the two keto moieties, was
compatible with our primary–tertiary diamine/palladium
catalytic system and was converted into the desired product
3ma in 60% yield with 91% ee. When the bulkiness of one
keto moiety was increased, the enantioselectivity was not
affected, and the desired products 3na and 3oa were obtained
in good yield with high enantioselectivity. Notably, a a-
Entry
[Pd] source
Amine
Yield [%][a]
ee [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
[{Pd(allyl)Cl}2]
Pd(PPh3)4
Pd2(dba)3
4a
4a
4a
4b
4c
4d
4e
4 f
4 f
5
90
54
n.r.
trace
94
88
92
n.d.
93
62
88
70
[{Pd(allyl)Cl}2]
[{Pd(allyl)Cl}2]
[{Pd(allyl)Cl}2]
[{Pd(allyl)Cl}2]
[{Pd(allyl)Cl}2]
[Pd(allyl)Cl]2
[{Pd(allyl)Cl}2]
[{Pd(allyl)Cl}2]
[{Pd(allyl)Cl}2]
[{Pd(allyl)Cl}2]
–
94
25[b]
92[c]
n.r.
83
>99
98
6
7
–
14
n.r.
trace
n.r.
n.r.
n.d.
4b
[{Pd(allyl)Cl}2]
4b[d]
[a] Reaction conditions: 1a (0.15 mmol), 2a (0.10 mmol), chiral amine
(20 mol%), Pd precursor (5 mol%), PPh3 (20 mol%), CH3CN (0.5 mL),
408C, 36 h. [b] Reaction time: 40 h. [c] The reaction was carried out with
3 equivalents of ketoester 1a, and the reaction time was extended to
72 h. [d] The reaction was carried out without the conjugate acid HOTf.
dba=dibenzylideneacetone, n.r. =no reaction, n.d.=not determined.
influenced the enantioselectivity of the reaction to form the
desired product. With bulkier substituents, improved enan-
tioselectivity was observed (Table 1, entries 4–8); optimal
results were obtained with the isopropyl-substituted catalyst
4b and pentan-3-yl-substituted catalyst 4 f (Table 1, entries 4
and 8). In the presence of 4b, the reaction gave 3aa in 94%
yield with 93% ee (Table 1, entry 4), whereas the more
sterically hindered catalyst 4 f gave the product with
> 99% ee, albeit at the expense of catalytic activity (25%
yield; Table 1, entry 8). In this case, when the reaction time
was prolonged and the ratio of 1a to 2a was increased to 3:1,
the product was formed in 92% yield with 98% ee (Table 1,
entry 9). Control experiments revealed that the reaction did
not proceed with either a palladium catalyst or a primary-
amine catalyst alone (Table 1, entries 13 and 14). The
conjugated acid TfOH was also essential for this reaction
(Table 1, entry 15). Mechanistically, it is known that TfOH
could expedite the formation of the enamine intermediate,[10]
and it may also facilitate the formation of the p-allyl
intermediate in this context.[11]
Scheme 2. Scope of the reaction with respect to the b-ketocarbonyl
substrate (1a–p). Method A: The reaction was performed with
1 (0.30 mmol), 2a (0.10 mmol), 4 f (20 mol%), [{PdCl(allyl)}2]
(5 mol%), and PPh3 (20 mol%) in CH3CN (0.5 mL) at 408C for 72 h.
Method B: The reaction was performed with 1 (0.15 mmol), 2a
(0.10 mmol), 4b (20 mol%), [{PdCl(allyl)}2] (5 mol%), and PPh3
(20 mol%) in CH3CN (0.5 mL) at 408C for 36 h. [a] Reaction time:
96 h. Bn=benzyl, Boc=tert-butoxycarbonyl.
Having optimized the reaction conditions, we first exam-
ined the functional-group tolerance of the reaction with
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nonsubstituted b-ketoamide was also tested, and the desired
monoalkylation product 3pa was obtained in high yield with
65% ee (Scheme 2). Asymmetric allylic alkylation reactions
with such compounds have not succeeded previously.[6a,f]
We then set out to explore the scope of the AAA reaction
with regard to the allylic-alcohol component. A range of
cinnamyl alcohols bearing either electron-donating or elec-
tron-withdrawing groups at the ortho, meta, or para position
of the arene moiety participated in the allylic alkylation of
tert-butyl 2-methyl-3-oxobutanoate (1a) to furnish the
desired products in good to high yield with excellent
enantioselectivity (Table 2, entries 1–9, products
3ab–aj). A 2-naphthyl-substituted allylic alcohol
was also applicable and was converted into the
expected product in 87% yield with 98% ee
(Table 2, entry 10). Cinnamylic alcohols incorpo-
rating heteroarenes were also proved to be good
substrates and were converted into the correspond-
ing products in moderate yield with excellent
enantioselectivity (Table 2, entries 11 and 12). The
aliphatic allylic alcohols prop-2-en-1-ol was also
51% yield with 86% ee in 12 h. Secondary allylic alcohols,
such as 2-cyclohexen-1-ol and 4-phenyl-2-butenol, showed
very low reactivity, probably as a result of the inertness of
these allylic alcohols toward the formation of a p-allyl
intermediate, and they could be recovered quantitatively
after treatment under the present conditions.[12]
To evaluate the practicality of the present method, we
performed a large-scale synthesis with both acyclic and cyclic
b-ketoesters 1a and 1j in the presence of only 10 mol% of 4b
or 4 f and 2.5 mol% of [{PdCl(allyl)}2]. Comparable results
were obtained with a prolonged reaction time (Scheme 3).
tested, and the desired product was obtained in
Scheme 3. Gram-scale experiments with 1a and 1j.
On the basis of a previous report,[8d] the absolute
Table 2: Scope of the reaction with respect to the allylic alcohol (2a–n).
configuration of the newly formed quaternary stereocenter
was assigned to be S.[10,13] Accordingly, Si-facial attack of the
p-allylpalladium complex on the enamine intermediate can
be proposed to account for the observed stereoinduction
(Figure 1). In this mode, steric effects play a key role in
channeling the attack of the p-allylpalladium species, for
which a notable H-bonding site is lacking. The observed effect
of bulky substituents on the tertiary amino moiety is clearly in
support of this steric model (Table 1). Besides serving as
a steric directing group, the protonated tertiary amine also
participates in intramolecular H-bonding, as previously
verified,[14] and results in a restricted conformation, which is
also beneficial for stereoselectivity.
In summary, we have developed a highly enantioselective
allylic alkylation of b-ketocarbonyl compounds with simple
allylic alcohols by merging primary–tertiary-diamine and
palladium catalysis. The reaction features the versatile
enantioselective construction of a quaternary stereocenter
in an acyclic compound under rather mild conditions. The
synergistic combination of chiral primary–tertiary-diamine
and transition-metal catalysis enables unprecedented asym-
metric allylation reactions of acyclic aliphatic ketones,
Entry
1
R
Product
Method
Yield [%]
ee [%]
4-CH3C6H4
3ab
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
B
B
74
64
96
96
61
99
71
92
92
96
91
89
91
75
87
91
72
34
87
95
42
92
59
51
97
93
96
93
97
92
98
93
98
90
97
93
97
94
98
93
98
92
98
93
97
90
91
86
2
3
4-CH3OC6H4
4-tBuC6H4
3-CH3OC6H4
2-CH3OC6H4
4-FC6H4
3ac
3ad
3ae
3af
3ag
3ah
3ai
4
5
6
7
4-ClC6H4
8
3-FC6H4
9
2-FC6H4
3aj
10
11
2-naphthyl
2-furyl
3ak
3al
12
2-thiophenyl
H
3am
3an
13[b]
[a] Method A: 1a (0.30 mmol), 2 (0.10 mmol), 4 f (20 mol%), [{PdCl-
(allyl)}2] (5 mol%), PPh3 (20 mol%), CH3CN (0.5 mL), 408C, 72 h.
Method B: 1a (0.15 mmol), 2 (0.10 mmol), 4b (20 mol%), [{PdCl-
(allyl)}2] (5 mol%), PPh3 (20 mol%), CH3CN (0.5 mL), 408C, 36 h.
[b] Reaction time: 12 h. The ee value of the desired product was
determined after one-step transformation into 3aa through olefin cross-
metathesis (see the Supporting Information).
Figure 1. Proposed transition state for the S-selective AAA reactions.
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Yasuda, Heterocycles 2012, 86, 745 (up to 66% yield and
60% ee).
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Experimental Section
General procedure: tert-Butyl 2-methyl-3-oxobutanoate (1a, 0.15 or
0.30 mmol), cinnamyl alcohol (2a, 0.1 mmol), [{Pd(allyl)Cl}2]
(5 mol%), PPh3 (20 mol%), and a primary amine (4b or 4 f,
20 mol%) were placed in a flame-dried Schlenk tube equipped with
a magnetic stir bar, and the mixture was diluted with anhydrous
CH3CN (0.5 mL) and then degassed 3 times by a standard freeze–
thaw method. The mixture was stirred at 408C for 36 or 72 h. The
solvent was then removed, and the residue was purified by silica-gel
chromatography (5% EtOAc in petroleum ether) to give 3aa as
a colorless oil. The ee value was determined by HPLC (OJ-H
column).
Acknowledgements
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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Keywords: allylic alcohols · asymmetric allylic alkylation ·
chiral primary amines · palladium · b-ketocarbonyl compounds
How to cite: Angew. Chem. Int. Ed. 2015, 54, 12645–12648
Angew. Chem. 2015, 127, 12836–12839
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Received: June 29, 2015
Published online: September 4, 2015
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