Unnatural α-Amino Acid Synthesized through α-Alkylation of Glycine Derivatives by Diacyl Peroxides

Article abstract of DOI:10.1021/acs.orglett.0c01574

We have developed a protocol for catalyst- and additive-free α-alkylation reactions of glycine derivatives with diacyl peroxides, which proceed by a pathway involving addition of alkyl radicals to imine intermediates. The diacyl peroxide substrate acts as both alkylation agent and oxidizing agent, which means it is atom-economical. It was applied to various glycine derivatives, dipeptides, and a 3,4-dihydroquinoxalin-2(1H)-one derivative and could be carried out on a gram scale, indicating its utility for late-stage functionalization.

Full text of DOI:10.1021/acs.orglett.0c01574

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Letter
Unnatural α‑Amino Acid Synthesized through α‑Alkylation of
Glycine Derivatives by Diacyl Peroxides
Hao Tian, Wentao Xu, Yuxiu Liu, and Qingmin Wang*
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ABSTRACT: We have developed a protocol for catalyst- and
additive-free α-alkylation reactions of glycine derivatives with
diacyl peroxides, which proceed by a pathway involving addition of
alkyl radicals to imine intermediates. The diacyl peroxide substrate
acts as both alkylation agent and oxidizing agent, which means it is
atom-economical. It was applied to various glycine derivatives,
dipeptides, and a 3,4-dihydroquinoxalin-2(1H)-one derivative and
could be carried out on a gram scale, indicating its utility for late-
stage functionalization.
Scheme 1. Modification of α-Amino Acids
nnatural α-amino acids have been used for various
U
purposes, including asymmetric synthesis and the
modification of bioactive peptides to enhance their bio-
chemical and pharmacokinetic properties.1 Therefore, increas-
ing attention has been paid to the development of methods for
site-specific chemical modification of peptides and natural
amino acids. Transition-metal catalysis is one such method, but
most of the uses reported to date involve side-chain
modification and require Pd catalysts and halide-derived
coupling partners and are thus expensive and environmentally
unfriendly.2 In recent years, several investigators have reported
strategies that utilize photoredox catalysis and inexpensive
metal catalysts for structural modification of amino acids.3
One potentially straightforward method for synthesizing
unnatural α-amino acids is α-C(sp3)−H alkylation of α-amino
acids. However, only a few examples have been reported,4
including those by Segundo and Correa, Xu and Wang et al.
(Scheme 1a),4e,f,g and all of these examples require catalysts
and additives. Therefore, an economical, metal-free method for
modification of α-amino acids remains to be developed.
We speculated that diacyl peroxides might be useful for this
purpose. Diacyl peroxides are inexpensive and environmentally
friendly and have been used as alkylation reagents for a variety
of substrates.5 In fact, we previously showed that diacyl
peroxides can be used in direct C(sp3)−H alkylation
reactions.5o Inspired by this previous work, we have now
explored the modification of α-amino acids with diacyl
peroxides.
desired product 3aa (entries 4−7). Varying the amount of 2a
or the concentration of 1a did not substantially increase the
yield of 3aa (compare entry 6 with entries 8−11). Notably, a
65% yield was obtained when the reaction was carried out
under air instead of under argon (entry 12), which suggests
that the reaction involved the addition of an alkyl radical to an
imine.
With the optimized conditions in hand (Table 1, entry 1),
we examined the substrate scope of the reaction with respect to
the α-amino acid derivative by testing various N-aryl α-amino
Received: May 7, 2020
We began by carrying out reactions of ethyl 2-(phenyl-
amino) acetate (1a) as a model substrate and dilauroyl
peroxide (2a) as the alkylation reagent (Table 1). Screening of
several organic solvents indicated that both MeCN and
dioxane were suitable (entries 2, 3, and 5). A reaction
temperature of 60 °C was found to favor the formation of
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© XXXX American Chemical Society
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A

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a
Table 1. Optimization of Reaction Conditions
Scheme 3. Substrate Scope with Respect to the Diacyl
a
Peroxide
b
entry
temp (°C)
equiv
solvent
yield (%)
1
2
3
4
60
40
40
rt
1.5
1
1
MeCN
acetone
dioxane
MeCN
74
32
37
d
1
N.R.
5
6
7
8
9
10
11
40
60
80
60
60
60
60
60
1
1
1
2
1.5
1.5
1.5
1.5
MeCN
MeCN
MeCN
MeCN
0.4 M 1a in MeCN
0.1 M 1a in MeCN
0.05 M 1a in MeCN
MeCN
36
63
57
52
76
53
50
65
c
12
a
Reaction conditions, unless otherwise noted: 1a (0.2 mmol) and 2a
(0.3 mmol) in MeCN (1 mL) were stirred in an 8 mL vial at 60 °C
b
c
under Ar for 24 h. Isolated yields are given. Under air condition.
N.R.= no reaction.
d
a
Reaction conditions, unless otherwise noted: 1a (0.2 mmol) and 2
(0.3 mmol) in MeCN (1 mL) were stirred in an 8 mL vial at rt under
Ar for 24 h.
acid esters and amides in reactions with 2a (Scheme 2). To our
delight, N-phenyl α-amino acid esters with either an electron-
Scheme 2. Substrate Scope with Respect to the α-Amino
Acid Derivative
or tert-butyl group; an ester group; and even a thiophene group
were also viable substrates, giving the desired products (3ae−
3aj) in good yields. However, peroxides bearing a secondary or
tertiary alkyl group were unsuitable. We attributed this result
to the fact that the corresponding secondary and tertiary
acyloxy radicals could readily undergo decarboxylation rather
than oxidizing amino acid 1a.
a
Control experiments provided information about the
possible mechanism of the reaction. First, when 2.5 equiv of
TEMPO was added to the mixture as a radical trap,6 the
desired reaction was completely suppressed, and alkylated
TEMPO product 3ak was detected (Scheme 4a). When a
Scheme 4. Control Experiments
a
Reaction conditions, unless otherwise noted: 1a (0.2 mmol) and 2
(0.3 mmol) in MeCN (1 mL) were stirred in an 8 mL vial at rt under
Ar for 24 h.
withdrawing or an electron-donating substituent in the para
position of the benzene ring (3ba−3ha) proved to be viable
substrates. Furthermore, substrates with a substituent at other
sites on the benzene ring, with multiple substituents, and with
other aromatic rings (3ia−3ma) were also suitable. In addition
to ethyl and methyl esters, amides were also acceptable
substrates (3aa, 3na−3sa), suggesting that the reaction could
be used to modify short peptides.
We also investigated the scope with respect to the diacyl
peroxide (Scheme 3). Reactions of 1a with peroxides 2 bearing
unsubstituted linear alkyl chains gave good to moderate yields
of the corresponding products (3aa−3ad). In addition,
peroxides with an alkyl chain bearing a cyclopentyl, cyclohexyl,
diacyl peroxide bearing an alkenyl moiety (2l) was used as a
substrate, cyclization product 3al was obtained in a 35%
isolated yield (Scheme 4b).7 These two observations imply
that the reaction proceeded via a radical mechanism. Finally, in
the reaction of 2a with imine 1t (Scheme 4c),4e α-alkylation
product 3aa was obtained in 59% yield. This result suggests
that 1t was an intermediate and that the reaction proceeded via
a free-radical addition.
B
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On the basis of the above-described results, a mechanistic
pathway is proposed in Scheme 5 for the reaction of 1a and 2a.
a catalyst- and additive-free protocol for α-alkylation of glycine
derivatives. Various glycine esters, amides, dipeptides, and a
3,4-dihydroquinoxalin-2(1H)-one derivative were suitable
substrates. Control experiments indicated that the mechanism
involves a free-radical addition reaction between an alkyl
radical and an imine intermediate. This protocol has the
advantages of being metal- and additive-free and atom-
economical.
Scheme 5. Proposed Mechanism
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01574.
• General Information; Preparation of Substrates; Inves-
tigation of the Key Reaction Parameters; Investigation of
the Mechanism; Experimental Procedures and Product
Characterization; References; NMR Spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
Upon heating of the reaction mixture, homolysis of the diacyl
peroxide produces an acyloxy radical, which undergoes
decarboxylation to produce alkyl radical A and CO2. Imine
intermediate B is formed by oxidation of 1a by the acyloxy
radical. Then a free-radical addition reaction between A and B
generates radical intermediate C. Finally, hydrogen abstraction
by C generates product 3aa. Note that high-resolution mass
spectrometry revealed traces of a byproduct generated by the
addition of a second alkyl radical.
■
Qingmin Wang − State Key Laboratory of Elemento-Organic
Chemistry, Research Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China; Collaborative Innovation Center of
Chemical Science and Engineering (Tianjin), Tianjin 300071,
People’s Republic of China; orcid.org/0000-0002-6062-
3766; Email: wangqm@nankai.edu.cn
We also explored the synthetic utility of our protocol. First,
we carried out a gram-scale (5.0 mmol) reaction between 1a
and 2a, which afforded target product 3aa in 71% yield
(Scheme 6a). In addition, reactions of dipeptides 1u and 1v
Authors
Hao Tian − State Key Laboratory of Elemento-Organic
Chemistry, Research Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China
Scheme 6. Demonstration of Synthetic Utility
Wentao Xu − State Key Laboratory of Elemento-Organic
Chemistry, Research Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China
Yuxiu Liu − State Key Laboratory of Elemento-Organic
Chemistry, Research Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01574
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21732002, 21672117) for generous financial support
for our programs.
gave acceptable yields of desired alkylation products 3ua and
3va, respectively (Scheme 6b). In addition, the protocol could
be utilized to modify a 3,4-dihydroquinoxalin-2(1H)-one
(Scheme 6c). It is worth noting that after the free-radical
addition reaction, further oxidation and aromatization afforded
a quinoxalin-2(1H)-one compound. However, there still a
limitation that this protocol can be only used on glycine
derivatives and N-substituted peptides (see SI for more
details).
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