Bioinspired Deamination of α-Amino Acid Derivatives Catalyzed by a Palladium/Nickel Complex

Article abstract of DOI:10.1002/adsc.201800823

An efficient bioinspired deamination method of both natural and unnatural amino acid derivatives has been developed. This method provides easy access to a wide variety of useful α, β-unsaturated carbonyl compounds. The reaction is realized with two transition metal catalysts (palladium and Nickel) in-easy handling procedure. A possible reaction pathway is also proposed and the control experiments support the involvement of the palladium-catalyzed inert sp³ C?H activation as one of the key steps. (Figure presented.).

Full text of DOI:10.1002/adsc.201800823

Title: Bioinspired Deamination of alpha-Amino Acid Derivatives by a
Palladium/Nickel Complex
Authors: Gongtao Deng, Jie Chen, Wangbin Sun, Kehan Bian, Yaojia
Jiang, and Teck-Peng Loh
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800823
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10.1002/adsc.201800823
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Bioinspired Deamination of -Amino Acid Derivatives Catalyzed
by a Palladium/Nickel Complex
Gongtao Deng,a Jie Chen,a Wangbin Sun,a Kehan Bian,a Yaojia Jiang, a,* and Teck-
Peng Loha,b*
a
Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic
Innovation Center for Advanced Materials (SICAM), Nanjing Tech University, Nanjing 211816 (China)
E-mail: iamyjjiang@njtech.edu.cn
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang
b
Technological University, Singapore 637371 (Singapore)
E-mail: teckpeng@ntu.edu.sg
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: An efficient bioinspired deamination method of
both natural and unnatural amino acid derivatives has been
developed. This method provides easy access to a wide
variety of useful α, β-unsaturated carbonyl compounds. The
reaction is realized with two transition metal catalysts
(palladium and Nickel) in-easy handling procedure. A
possible reaction pathway is also proposed and the control
experiments support the involvement of the palladium-
catalyzed inert sp3 C-H activation as one of the key steps.
Keywords: bioinspired reactions; C-H activation;
deamination; synthetic methods
Figure 1. Deamination Methods.
Ammonia-lyases[1] and
aminomutases[2] are
extremely useful enzymes that catalyze the
deamination[3] and/or isomerization of amino acids[4] in
nature. Accordingly, much work has been directed to
the understanding of these diverse enzymes[5] as well
as to develop new synthetic methods that mimick these
useful processes.[6] Inspired by these bioprocesses, our
group have developed efficient methods for the amino
group migration reaction using copper or iodine
catalysts in the presence of an oxidant.[7] Inspired by
the power of ammonia-lyases deamination reaction,[8]
we decided to develop new method for the
deamination of amino acids or derivatives. In our
continuing interest in palladium catalyzed inert sp3 C-
H activation chemistry,[9] we envisaged that by
utilizing 8-aminoquinoline[10] as bidentate directing
group on the amino acids may effect β-sp3 C-H
activation generating the C-metal intermediate that
may then cleave the C-N bond (Figure 1).
Initialy, phenylalanine derivative 1a was chosen as
the model substrate to optimize the reaction conditions
(Table 1). The desired product 2a could be
successfully obtained in 12% yield in the presence of
o
Pd(OAc)2 and FeCl2 at 120 C (Table 1, entry 1).
Screenning other known lewis acidic metals found that
nickel catalyst was much more effective compared to
iron and cobalt catalysts (Table 1, entries 2-3). The
acid (PhCOOH) was proved to be particulary effective
additive and increased to 86% yield (Table 1, entries
4-5). Different nickel salts were then evaluated and the
Ni(OAc)2 showed improved reaction reactivity with
90% yield (Table 1, entries 6-8). Futher study found
that florine solvent hexafluoroisopropanol (HFIP)
could increase the yield up to 95% (Table 1, entries 9-
12). Different leaving groups including cyclic and
acyclic amino substitutions were also investigated. The
results revealed that cyclic amide leaveing groups
afforded the alkenyl product 2a in lower yields (74%
and 71%), while dibenzyl substitution failed to give
the desired product under the reaction condition
1
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10.1002/adsc.201800823
Advanced Synthesis & Catalysis
(Table 1, entries 13-15). Finally, control experiments such as methyl, t-butyl and phenyl substituted
were performed in the absence of either Pd(OAc)2 or phenylalanine derivatives gave the desired products in
Ni(OAc)2 to give 0% and 8% yields, respectively. It moderate to good yields (2f-2h). The strong electron-
indicates that both the Pd(OAc)2 and Ni(OAc)2 metal donating functional groups such as methoxyl group
catalysts are essential to this unqiue bioinspired was performed excellently in 95% yield (2i and 2j).
deaminated transformations (Table 1, entries 16-17).
Electron-withdrawing groups (NO2, CN, CF3 and
carbonyl groups) exerted good reaction efficiency and
afforded the unsaturated compounds in good to
excellent yields (2k-2r). It is worthy to note that the
useful formyl group (2r) could be survived in this
catalytic system albeit in decreased yield (64%). Heter-
Table 1. Optimization of Reaction Conditions[a]
Solve Yield
nt
DCE
Entry Metal
Additive
LG
(%)b
12
1
2
3
4
5
FeCl2
—
—
—
K2CO3
PhCO2H
PhCO2H
LG1
LG1
CoCl2
NiCl2
NiCl2
NiCl2
NiBr2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
TCE
27
63
4
86
46
66
90
54
LG1
LG1
LG1
LG1
LG1
LG1
LG1
LG1
LG1
LG1
LG2
LG3
LG4
LG1
LG1
6
7
8
9
Ni(acac)2 PhCO2H
Ni(OAc)2 PhCO2H
Ni(OAc)2 PhCO2H
Ni(OAc)2 PhCO2H
Ni(OAc)2 PhCO2H
Ni(OAc)2 PhCO2H
Ni(OAc)2 PhCO2H
Ni(OAc)2 PhCO2H
Ni(OAc)2 PhCO2H
Ni(OAc)2 PhCO2H
10
11
12
13
14
15
16c
17
ACN ND
THF 49
HFIP 95(92)
HFIP 74
HFIP 71
HFIP
HFIP
HFIP
0
0
8
—
PhCO2H
[a]
Unless otherwise noted, the reactions were carried out in
the presence of phenylalanine derivative 1a (0.20 mmol),
Pd(OAc)2 (10 mol %), lewis acid (40 mol %), additive (20
mol %) in solvent (2 mL) in sealed tube, and the reaction
mixtures were stirred for 48 h.
[b]
1
The yield was determined by H NMR using 1,1,2,2-
tetrachloroethane as the internal standard.
[c] No Pd(OAc)2 participate.
DCE = dichloroethane, TCE = tetrachloroethane, THF =
tetrahydrofuran, HFIP = hexafluoroisopropanol.
With the optimized reaction conditions in hand, we
then examined the substrate scope of this new type of
bioinspired deamination reactions (Scheme 1). In
general, various functional substitutions were tolerated
in the reaction conditions. Different halogen
substituents (F, Cl, Br and I) at para-position of phenyl
group all reacted smoothly to give the corresponding
products in good to excellent yields (2b-2e). Notably,
the chloro, bromo and iodo functional groups are
useful synthons in transtion-metals catalyzed coupling
reactions.[11] Electronic effect was then examined, and
it shows slightly influnce on the reactivity. For
instance, the weak electron-donating functional groups,
[a]
Unless otherwise specified, the reactions were carried out
in sealed tube in the presence of amide derivative 1a (0.20
mmol), Pd(OAc)2 (10 mol%), Ni(OAc)2.4H2O (40 mol%),
PhCOOH (20 mol%)) in HFIP (2 mL) in sealed tube, and
the reaction mixtures were stirred until the starting material
was consumed completely.
[b] Isolated yield.
Scheme 1. Substrate Scope.
2
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10.1002/adsc.201800823
Advanced Synthesis & Catalysis
-ocycles were then investigated, both thienyl and with phthalimide to afford intermediate D. The product
indolyl functionalities were tolerated in the reaction 2 is finally obtained via β-C-N bond cleavage with the
conditions and gave promising yields (2s and 2t). elimination of phthalimide-metals complex E. Finally,
When different alkyl substitutions were conducted in both of the Pd(II) and Ni(II) catalysts were regenerated
the reaction conditions, the desired products could be through acidolysis of complex E with phthalimide as
succesfully obtained albeit in obvious decreased yields byproduct which could be isolated in the reaction.
(2u-2w). The alkenyl and alkynyl substitutions were
unfortunately failed to give the desired products with
recovering the starting materials (2x and 2y). Overall,
the reactivity of this bioinpired deamination catalytic
system has a close relationship with the different
functionalities.
To better understanding the reaction mechanism,
isotope labelling and control experiments were
explored (Scheme 2). When the reaction was
performed in the presence of radical trapping reagents
such as 2,2,6,6-tetramethyl-1-piperidinoxyl (TEMPO),
5,5-dimethyl-1-pyrroline N-oxide (DEMPO) and
butylated hydroxytoluene (BHT) (Scheme 2, a), the
unsaturated amide compound 2a was successfully
obtained in slightly decreased yield (68%, 65% and
71%). This rules out the possible radical pathway
through single electron transfer (SET) process. When
the reaction was carried out in the absence of either
Ni(OAc)2 or Pd(OAc)2, the catalytic system was
Scheme 3. Proposed Mechanism.
deactivated dramaticily (Table 1, entries 16-17). It
indicates that both transition metals take part in the
Then we turned our attention to explore the
catalytic cycles. Furthermore, deuterium labeling result
synthetic applications of this new bio-inspired
methodology (Scheme 4). To our delight, the reaction
was observed at β-(C-H) bond of the amide with 79%
yield (Scheme 2, b). It supported that the palladium
could be extended to gram scale and afforded 1.06 g
catalyst may be involved in the inert sp3 C-H bond
cinnamamide 2a. The directing group 8-aminoquinolin
could be easily removed in base condition to give
activation step. When dibenzylamino phthalimide
derivative 1a’ was conducted in the reaction condition,
cinnamic acid 3a in 91% yield.[12] Cinnamamide 2a is
it was failed to give the desired product (Table 1, entry
recently widely used as important substrate in the
15). We believed that the carbonyl group of the
transition-metals catalysed sp2 C-H activation with 8-
phenalimide might take important role to coordinate
aminoquinoline as directing group. For instance, it could
with nickel catalyst.
be underwent [4+2] cycloaddition with either alkene[13] or
Scheme 2. Mechanism Study.
Based on the obtained results, a possible reaction
pathway is proposed as shown in Scheme 3. Initially,
the Pd(II) coordinates with the 8-aminoquinoline
auxiliary to give the intermediate A, which
consequently activates the inert β-sp3(C-H) bond of the
amide to generate the cyclometalic complex-B. The
Ni(II) catalyst may function as lewis acid and takes
part in the process to coordinate with 1, 4-carbonyl
oxygens to give bimetalic complex C. The
Scheme 4. Applications of , β-Unsaturated Amides.
cyclopalladium complex then undergoes ring opening
with the assitance of acid (HX) and re-coordinates
3
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10.1002/adsc.201800823
Advanced Synthesis & Catalysis
alkyne[14] in the presence of cobalt catalyst to generate [3] a) N. D. Ratnayake, U. Wanninayake, J. H. Geiger, K. D.
aza-heterocycles in 51% and 42% yields, respectively.
Furthermore, a cobalt-catalyzed [3+2] cycloaddition of
cinnamamide 2a with bicyclic alkene has been realized
to afford polycycle 3d in 40% yield.[15]
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Experimental Section
Synthesis of N-(quinolin-8-yl)cinnamamide 2a: A Schlenk
tube was charged with 2-(1,3-dioxoisoindolin-2-yl)-3-
phenyl-N-(quinolin-8-yl)propanamide 1a (0.2 mmol, 84.3
mg), Pd(OAc)2 (10 mol %, 4.5 mg), Ni(OAc)2·4H2O (40
mol%, 19.9 mg) and PhCOOH (20 mol%, 4.9 mg) in
hexafluoroisopropanol (0.1 M, 2 mL). The tube was then
sealed under air atmosphere, and the reaction was heated to
120 °C with stirring until the starting material was
consumed completely. After cooling down, the mixture was
diluted with ethyl acetate, washed with water and brine. The
organic layer was dried over anhydrous Na2SO4, filtered and
concentrated to give the crude product, which was purified
through a flash column chromatography (eluent: 5% to 15%
ethyl acetate in petroleum solution) to afford N-(quinolin-8-
yl)cinnamamide 2a (50.5 mg, 0.184 mmol, 92% yield).
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Acknowledgements
The authors gratefully acknowledge funding from the National
Natural Science Foundation of China (21502089), Jiangsu
Province Funds Surface Project (BK 20161541) and the Starting
Funding of Research (39837107) from Nanjing Tech University.
We also thank the financial support by SICAM Fellowship by
Jiangsu National Synergetic Innovation Center for Advanced
Materials.
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4
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Advanced Synthesis & Catalysis
5
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10.1002/adsc.201800823
Advanced Synthesis & Catalysis
COMMUNICATION
Bioinspired Deamination of Amino Acid
Derivatives Catalyzed by a Palladium/Nickel
Complex
Adv. Synth. Catal. 2018, 359, Page – Page
G. Deng, J. Chen, W. Sun, K. Bian, Y. Jiang*, T.-
P. Loh*
6
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