Bronsted acid accelerated Pd-catalyzed direct asymmetric allylic alkylation of azlactones with simple allylic alcohols: A practical access to quaternary allylic amino acid derivatives

Article abstract of DOI:10.1021/ol502535z

A Bronsted acid accelerated Pd-catalyzed asymmetric allylic alkylation of azlactones with simple allylic alcohols under mild reaction conditions has been realized, which provides a direct and readily scalable approach for the synthesis of all-carbon quaternary allylic amino acid derivatives in excellent yields and good enantioselectivities. (Chemical Equation Presented).

Full text of DOI:10.1021/ol502535z

Letter
pubs.acs.org/OrgLett
Brønsted Acid Accelerated Pd-Catalyzed Direct Asymmetric Allylic
Alkylation of Azlactones with Simple Allylic Alcohols: A Practical
Access to Quaternary Allylic Amino Acid Derivatives
Hui Zhou,†,§ Huameng Yang,† Muwen Liu,†,§ Chungu Xia,*,† and Gaoxi Jiang*,†,‡
†State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, P. R. China
‡Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, P. R. China
§Graduate University of Chinese Academy of Sciences, Beijing 100049, P. R. China
S
* Supporting Information
ABSTRACT: A Brønsted acid accelerated Pd-catalyzed asym-
metric allylic alkylation of azlactones with simple allylic alcohols
under mild reaction conditions has been realized, which provides
a direct and readily scalable approach for the synthesis of all-
carbon quaternary allylic amino acid derivatives in excellent
yields and good enantioselectivities.
evelopment of straightforward and atom/step-economic
approaches for enantioselective C−C bond formation
Zhang4d independently. They successfully extended such
transformations to other available nucleophiles such as
aldehydes, pyrazol-5-ones, and ketones. Despite these im-
portant advances, the direct use of simple allylic alcohols for an
efficient AAA reaction under mild reaction conditions remains a
great challenge. Further exploration of the useful methodology
for other biologically important compounds is of great interest
and significance.
D
from readily available starting materials is a fundamental goals
in the area of chemical synthesis.1 Among these strategies, Pd-
catalyzed asymmetric allylic alkylation (AAA) represents a
powerful synthetic tool and has been widely utilized in organic
synthesis.2 Conventionally, AAA reactions involve activated
allylic alcohol derivatives, for instance, carbonates, amines,
acetates, and halides, as a π-allyl fragment source, which require
an equivalent strong base and inevitably result in stoichiometric
waste (Scheme 1, eq 1).3 From the viewpoint of environmental
A quaternary amino acid is not only a prominent structural
motif found in numerous natural products with vital biological
activities but also a very important class of valuable synthetic
blocks in organic chemistry.5 Among the numerous methods
for its synthesis, the transition-metal-catalyzed AAA reaction of
azlactones provides a facile access to quaternary allylic amino
acids, and the introduced double bond makes its further
functionalization particularly versatile. Remarkable progress has
come from the Trost group6 and Hartwig group.7 They
developed Pd-, Mo-, and Ir-catalysts for the AAA reaction of
azlactones, independently (Scheme 2, eq 1). Nevertheless,
these methods need stoichiometric amounts of bases or special
additives and simultaneously generate stoichiometric waste.
Therefore, the direct use of allylic alcohol to undergo the useful
transformation is highly desired. Herein, we report a Brønsted
acid accelerated Pd-catalyzed direct and readily scalable method
for the AAA reaction of azlactones with allylic alcohols
(Scheme 2, eq 2), which provides a more concise and practical
entry to linear quaternary allylic amino acid derivatives.
Initially, we treated azlactone 1a with cinnamic alcohol 2a in
the presence of 3.0 mol % of Pd2(dba)3, 7.0 mol % of Trost
ligand P-1, and 5 Å molecular sieves (5 Å MS) in toluene at 60
°C for 12 h. The reaction furnished the desired product 3aa in
Scheme 1. Profile of AAA Reaction
issues and atom/step economy, undoubtedly, the direct use of
allylic alcohol itself instead of its derivatives is much more
practical due to only water being formed as a byproduct
(Scheme 1, eq 2). However, presumably because of the poor
reactivity of allylic alcohol, examples of such reactions are very
sparse.4 A breakthrough was made by the Trost group in
2006.4a They succeeded in the direct AAA reaction of indoles
with allylic alcohols by using stoichiometric amounts of borane
as the critical promoter. Quite recently, significant achieve-
ments based on chiral phosphoric acid assisted Pd-catalysis and
a multicatalyst strategy were reported by List,4b Gong,4c and
Received: August 28, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol502535z | Org. Lett. XXXX, XXX, XXX−XXX

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Letter
(entries 3 and 4). Lowering the reaction temperature from 60
to 40 °C increased the enantioselectivity to 90% but decreased
the yield to 45% (entry 5). Changing the ligand to P-2−P-6
resulted in an adverse effect in the reaction (entries 6−10). The
replacement of Pd2(dba)3 with (allyl)2Pd2Cl2 resulted in a 90%
yield and 76% ee (entry 11). 3aa was isolated in 86% yield and
83% ee in the absence of 5 Å MS (entry 12). Control
experiments including solvent and dessiccant examinations did
not improve the reaction (for details, see Supporting
Information).
Scheme 2. Asymmetric Allylation of Azlactones
Under the optimized reaction conditions, the substrate scope
with respect to both azlactones and allylic alcohols was
investigated to evaluate the generality of the reaction. First,
we were pleased to find that a range of azlactones is quite
applicable to the straightforward allylic alkylation reaction. As
summarized in Table 2, using 2a as the allylic reagent,
a
Table 2. Substrate Scope of Azlactones
30% yield and 82% ee (Table 1, entry 1). Gratifyingly, adding
5.0 mol % of PhCO2H accelerated the reaction, affording 3aa in
95% yield and 84% ee (entry 2), in which PhCO2H might
activate cinnamic alcohol 2a by hydrogen bonding to expel the
hydroxyl group, followed by insertion of a Pd(0) catalyst for the
generation of the key π-allyl-Pd intermediate.4b,c,8 Use of
CF3CO2H and (PhO)2PO2H led to similar enantioselectivities
entry
Ar
R
3
yield (%) ee (%)
1
2
Ph
Ph
Me
Bn
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
82
85
87
93
85
91
98
98
95
92
80
77
81
81
88
88
78
90
84
93
86
82
b
3
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
2-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
(C3H5)CH2
b
4
C3H5
b
a
5
C6H11
Table 1. Optimization of Reaction Conditions
b
6
4-CF3C6H4CH2
7
Me
8
Me
9
i-Pr
3ja
10
11
(CH3)2CHCH2
Bn
3ka
3la
a
Reaction conditions: 1 (0.1 mmol), 2a (0.12 mmol), Pd2(dba)3 (3.0
mol %), P-1 (7.0 mol %), acid (5.0 mol %), 5 Å MS (50 mg), toluene
(2.0 mL), 60 °C, 12 h; all yields are isolated; ee were determined by
b
HPLC analysis. Pd2(dba)3 (10.0 mol %), P-1 (22.0 mol %).
azlactones 1b−l gave the desired products 3ba−la in high
yields with good enantioselectivities. Phenyl-substituted
azlactones 1b and 1c afforded the products 3ba and 3ca in
82−85% yield and 77−81% ee, respectively (entries 1 and 2).
The substrates containing a methyl group at the para position
that seem less reactive underwent the reaction with good
outcomes, although an increased catalyst loading to 10 mol %
was required (entries 3−6). Azlactones bearing a chlorophenyl
group, 1h−l, under the standard reaction conditions afforded
3ha−la in 80−98% yields and 82−93% ee (entries 7−11).
Next, a range of functionalized allylic alcohols was employed
under the standard reaction conditions. Accordingly, the
treatment of 1h or 1j with substituted allylic alcohols 2/2′
facilely furnishes the allylated products 3hb−hd, 3jb, and 3jd in
excellent yields and good enantioselectivities (Table 3). It is
noteworthy that both electron-withdrawing and -donating
groups at allylic alcohols are well tolerated (entries 1−3).
Importantly, in contrast to linear allylic alcohols 2a and 2b,
branched allylic alcohols 2e′ and 2f′ are also suitable for the
practical allylation process, and the reactions afforded
exclusively linear allylated products 3ha and 3hb in similar
yields and enantioselectivities (entries 4 and 5), which reveal
that the reaction might require a cationic π-allylpalladium(II)
entry
ligand
acid
yield (%)
ee (%)
1
2
3
4
P-1
P-1
P-1
P-1
P-1
P-2
P-3
P-4
P-5
P-6
P-1
P-1
−
30
95
97
68
45
97
77
36
66
82
84
81
85
90
59
11
16
15
−
PhCO2H
CF3CO2H
(PhO)2PO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
b
5
6
7
8
9
c
10
N.R.
d
11
e
90
86
77
12
83
a
Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), Pd2(dba)3 (3.0
mol %), ligand (7.0 mol %), acid (5.0 mol %), 5 Å MS (50 mg),
toluene (2.0 mL), 60 °C, 12 h; all yields are isolated; ee were
determined by HPLC analysis. At 40 °C. N.R. means no reaction.
b
c
d
e
(Allyl)2Pd2Cl2 was used instead of Pd2(dba)3. Without 5 Å MS.
B
dx.doi.org/10.1021/ol502535z | Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Table 3. Substrate Scope of Allylic Alcohols
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: cgxia@lzb.ac.cn.
*E-mail: gxjiang2012@sinano.ac.cn.
Notes
The authors declare no competing financial interest.
entry
substates
R
3
yield (%)
ee (%)
1
2
3
4
5
6
7
1h/2b
1h/2c
1h/2d
1h/2e′
1h/2f′
1j/2b
1j/2d
4-MeOC6H4
4-ClC6H4
3hb
3hc
3hd
3ha
3hb
3jb
95
98
89
93
93
93
88
88
86
76
90
87
90
94
ACKNOWLEDGMENTS
■
4-CF3C6H4
C6H5
Financial support from Hundred Talent Program of Chinese
Academy of Sciences (CAS) and the National Natural Science
Foundation of China (21202175) is gratefully acknowledged.
4-MeOC6H4
4-MeOC6H4
4-CF3C6H4
3jd
REFERENCES
■
a
Reaction conditions: 1h or 1j (0.1 mmol), 2 or 2′ (0.12 mmol),
Pd2(dba)3 (3.0 mol %), P-1 (7.0 mol %), acid (5.0 mol %), 5 Å MS
(50 mg), toluene (2.0 mL), 60 °C, 12 h; all yields are isolated; ee were
determined by HPLC analysis.
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derivative 4 in 81% yield and >99.5% ee after a single
recrystallization (Scheme 3).
Scheme 3. “One-Pot” Gram-Scale Reaction
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In summary, we have demonstrated a direct and concise
allylic alkylation of azlactones with simple allylic alcohols
catalyzed by the combination of a palladium complex with a
commercially available Trost ligand and PhCO2H under mild
conditions, which provides a straightforward and practical
access to allylic amino acid derivatives. Importantly, the
protocol can be easily extended to gram scale. An all-carbon
quaternary allylic amino acid derivative was smoothly obtained
in 81% yield and >99.5% ee after a single recrystallization which
would exhibit great potential and be of significance in the
synthesis of biologically active molecules. Further applications
of the useful method to the total synthesis of some interesting
natural products are under investigation in our laboratory and
will be reported in due course.
ASSOCIATED CONTENT
■
S
* Supporting Information
Complete experimental details and characterization data for the
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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