Decarboxylative Csp3 -N Bond Formation by Electrochemical Oxidation of Amino Acids

Article abstract of DOI:10.1021/acs.orglett.9b03696

Decarboxylative C_sp³-N coupling reactions have been developed through electrochemical oxidation of amino acids. The reaction proceeds via anodic oxidative decarboxylation of carboxylic acids to form stabilized carbocations, which are

Full text of DOI:10.1021/acs.orglett.9b03696

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
3
Decarboxylative C −N Bond Formation by Electrochemical
sp
Oxidation of Amino Acids
Xiaoqing Shao, Yue Zheng, Lifang Tian, I, †n maculada Martín-Torres,‡,§
†
,∥
†,∥
†,∥
,
‡,§
Antonio M. Echavarren,*
and Yahui Wang*
†Institute of Advanced Synthesis (IAS), School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing 211816,
China
‡
Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute of Science and Technology, Av. Països Catalans 16, 43007
Tarragona, Spain
§
Departament de Química Analítica i Química Organica, Universitat Rovira i Virgili, C/Marcel·li Domingo s/n, 43007 Tarragona,
̀
Spain
*
S Supporting Information
3
ABSTRACT: Decarboxylative C −N coupling reactions have been developed through electrochemical oxidation of amino
sp
acids. The reaction proceeds via anodic oxidative decarboxylation of carboxylic acids to form stabilized carbocations, which are
trapped by azoles or amides to construct C−N bonds. This method avoids the preactivation of carboxylic acids and the use of
expensive transition-metals and external chemical oxidants.
3
arbon-nitrogen bond formation is one of the most
important transformations in organic chemistry owing to
the prevalence of nitrogen-containing motifs in natural
products, pharmaceuticals, agrochemicals, and functional
Although several precedents of decarboxylative C −N
sp
C
couplings have been reported, they are limited to special
substrates or intramolecular reactions. Very recently, the
decarboxylative C−N cross-coupling was reported by Fu,
Hu, and Macmillan via photoredox and copper catalysis
Scheme 1A). In these processes, alkyl carboxylic acids were
first converted into the corresponding redox active esters, N-
hydroxyphthalimide (NHPI) esters or iodomesitylene dicar-
boxylates (IMDC), thus enabling CO2 extrusion in the
presence of a photocatalyst to generate the required alkyl
radicals for copper-catalyzed C−N cross-coupling. Despite the
ground-breaking nature of these transformations, the preacti-
vation of carboxylic acids is still necessary for the
decarboxylation event.
13
14
1
15
16
2
materials. Transition-metal-catalyzed C −N coupling proce-
sp
dures with prefunctionalized reagents, such as C−halide and
C−metal have been developed as a powerful tool to construct
(
2
C−N bonds, under basic or oxidative conditions. Among
3
4
them, Buchwald−Hartwig coupling, Ullmann-type reactions,
5
and Chan−Lam oxidative amination are notable methods for
2
3
sp
C −N cross-couplings. However, broad-scope C −N cross-
sp
couplings are very scarce, and classical methods, such as
6
nucleophilic substitution with alkyl halides, reductive
amination with carbonyls, Curtius rearrangement, and
Mitsunobu reaction with alcohols, are still commonly used
7
8
9
The direct use of carboxylic acids as reactants would be ideal
for a broad-scope C−N cross-coupling. Carboxylic acids can be
decarboxylated by anodic oxidation to radicals, which
3
sp
for C −N bond formation. Therefore, new methods and
3
sp
strategies for efficient C −N bond formation with easily
17
available starting materials under mild conditions are greatly
demanded. For example, the recent development of cross
normally undergo addition to double bonds or can combine
18
10
to form symmetrical dimers in the Kolbe electrolysis. Radical
intermediates formed under Kolbe conditions can be further
oxidized to generate the corresponding carbocations, in a
process referred to as non-Kolbe electrolysis or Hofer−Moest
3
sp
dehydrogenative couplings of N−H and C −H bonds and
transition-metal-catalyzed alkylation of nitrogen nucleophiles
with aliphatic halides have attracted much attentions.
Due to the characteristics of carboxylic acids, including great
availability, high stability, low-cost, and nontoxic nature, this
class of compounds is one ideal reactant for organic synthesis.
Decarboxylative reactions have been demonstrated to be
11
19
reaction (Scheme 1B). Recently, the group of Baran applied
Received: October 18, 2019
12
applicable to the formation of C−C and C−X bonds.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03696
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Decarboxylative C−N Cross-Couplings
should display good stabilities under electrolysis. Since azoles
25
are important moieties in organic chemistry and normally
26
serve as good nucleophiles, we decided to start our study
with azoles to construct C−N bonds by electrochemical
decarboxylation.
The optimization of the reaction conditions for the
decarboxylative C−N bond coupling was performed using
Boc-L-proline (1a) as the carboxylic acid and benzimidazole
(
2a) as the nucleophile (Table 1). The best results were
a
Table 1. Optimization of Reaction Conditions
b
entry
deviation from standard conditions
yield (%)
1
2
3
4
5
6
7
8
none
reaction time: 2 h
99
85
82
65
20
-
n
Bu NBF as supporting electrolyte
4
4
LiClO as supporting electrolyte
4
n
Bu NClO as supporting electrolyte
4
4
n
Bu NI as supporting electrolyte
4
graphite as cathode
no electricity
24
-
a
n
Reaction conditions: 1a (0.5 mmol), 2a (0.3 mmol), Bu NPF
4
6
b
(0.025 M), 8 mL of MeCN, 23 °C, under air. Yield determined by
these electrogenerated carbocations to synthesize hindered
dialkyl ethers from carboxylic acids, demonstrating the power
1
H NMR analysis of the crude reaction mixture using (E)-1,2-
diphenylethene as an internal standard.
20
of electrochemical decarboxylation for C−O bond formation.
In contrast, although intramolecular C−N bond coupling by
21
electrochemical decarboxylation is known, intermolecular
obtained by conducting the electrolysis for 3 h under a
constant current of 7 mA in an undivided cell equipped with a
graphite anode and a nickel cathode at room temperature in
acetonitrile. Under these conditions, the C−N coupled
product 3a was obtained in almost quantitative yield (Table
1, entry 1). Shortening the reaction time and replacing
supporting electrolyte or electrode led to lower yields (Table 1,
entries 2−7). A control experiment showed that electricity is
crucial for the success of the desired reaction (Table 1, entry
8).
With the optimized conditions established to obtain product
3a, the scope of the reaction was then explored by first varying
the carboxylic acids (Scheme 2). Commercially available cyclic
N-protected α-amino acids, such as proline, azetidinecarboxylic
acid, and six-membered α-amino acids reacted well with
benzimidazole (2a) to give the desired C−N coupled products
(3a−3e) in good yields. Similarly, acyclic amino acid
derivatives, including alanine (3f, 3m), valine (3g), leucine
(3h), phenylalanine (3i, 3n), lysine (3j), methionine (3k), and
glycine (3l), were all found to be suitable substrates for
decarboxylation, leading to products with a free N−H bond
during electrolysis. Moreover, dipeptide derivative (Gly-Pro)
also underwent decarboxylative C−N bond formation with
benzimidazole to provide 3s in 50% yield. In addition,
tetrahydrofuroic acid, 4-methoxyphenylacetic acid, and 2,2-
diphenylacetic acid were successfully applied in this reaction,
affording 3o, 3p, and 3q, respectively, although with lower
yields. Furthermore, γ-lactam moiety was also tolerated in the
formation of product 3r.
1
8
reactions are restricted to solvolysis with MeCN or N-
22
formylation of amines via decarboxylation of glyoxylic acid.
We envisioned that the C−N coupling could take place if the
appropriate nitrogen nucleophiles would trap the carbocations
generated by anodic oxidative decarboxylation (Scheme 1B).
This anticipated C−N bond formation by electrochemical
method would exhibit several advantages: 1) no need to
preactivate carboxylic acids; 2) transition-metal- and expensive
photocatalyst-free; 3) no external oxidant. However, the
carbocations generated at the anode are usually very reactive
18
species, referred to as “hot carbocations”, and easily undergo
reactions with mild nucleophilic solvents (e.g., MeCN, MeOH,
etc.), rearrangement, or elimination to form alkenes.
Accordingly, in order to facilitate the formation of C−N
bonds, the carbocation intermediates should be sufficiently
long-lived to undergo disengagement from the electrode
surface, therefore allowing the effective molecular collision
with nitrogen nucleophile. For example, neighboring heter-
oatoms, such as N and O, are expected to stabilize the
2
3
carbocations generated by electrochemical oxidation of
abundant biomass resources, such as α-amino acids and α-
2
4
hydroxy acids. Therefore, this efficient electrochemical
decarboxylative C−N cross-coupling could enable the direct
conversion of inexpensive α-amino acids into complex and
medicinally relevant pharmacophores under mild and green
conditions. We report herein the successful transition-metal-
3
free decarboxylative C −N cross-coupling via electrochemical
sp
oxidation of amino acids with a broad-range of N-nucleophiles.
In order to efficiently trap the relatively stable iminium
cations generated by anodic oxidation of amino acids, N-based
nucleophiles should be reactive enough and, at the same time,
We next tested a variety of N-based nucleophiles (Scheme
2). Pyrazole, 1,2,3- and 1,2,4-triazole, benzotriazole, and
tetrazole derivatives were found to be efficient nucleophiles
B
DOI: 10.1021/acs.orglett.9b03696
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Scope of Decarboxylative C−N Bond Formation by Electrochemical Oxidation
a
n
Reaction conditions: 1 (0.5 mmol), 2 (0.3 mmol), Bu NPF (0.01 M), 8 mL of MeCN, 23 °C, under air, constant current (7 mA), 3.5 h. Isolated
4
6
b
c
yields after column chromatography. The reaction was performed in MeCN/DMSO = 8 mL/0.2 mL. 2,6-Lutidine (0.26 mmol) was added, and
the reaction was performed for 4 h. Et NPF (0.01 M), BF ·OEt (0.02 mmol), 8 mL of MeCN, 23 °C.
d
4
6
3
2
to trap the iminium cation generated by decarboxylation of
Boc-L-proline (1a) to give products 3t−3aa in good yields with
excellent regioselectivities, which were determined by NMR
analysis. Further studies revealed that, under slightly modified
conditions, primary amides as well as β- and γ-lactams and
oxazolidin-2-one can also be used as the N-based nucleophiles
to form the desired C−N coupled products 3ab−3ai in
moderate to good yields.
Scheme 3. Gram-Scale Synthesis and Intramolecular
Reaction
Importantly, the reaction is scalable (Scheme 3). For
example, the desired product 3a can be produced in excellent
yield (96%, 1.37 g) under high concentration conditions (5
mmol, 8 mL MeCN). 5-Amino-2-pyrrolidinones would be
expected to have pharmacological activities and previously
require multistep synthesis. By electrolysis, the intra-
molecular reaction of Boc-L-glutamine (1aj) was also
successful to give the cyclized product 3aj in 60% yield
In order to understand the oxidation/reduction potentials
for the substrates, cyclic voltammetry (CV) experiments were
carried out with Boc-L-proline (1a) and benzimidazole (2a) in
acetonitrile (Figure 1). For benzimidazole (2a), no obvious
2
7
28
(Scheme 3).
oxidation peak was observed. Boc-L-proline (1a) showed an
C
DOI: 10.1021/acs.orglett.9b03696
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
in order to compare our results with those obtained under
photoredox catalysis, two redox active esters of Boc-L-proline,
4
a and 4b, were synthesized and subjected to the reported
15,16
photoredox conditions
with benzimidazole (2a) as the N-
nucleophile (Scheme 4b). However, no desired product 3a was
28
detected. These results show that our decarboxylative C−N
coupling reaction via electrochemical oxidation is a comple-
mentary method to photoredox catalysis, especially in the case
of α-amino acids as the substrates.
3
In summary, we have achieved the decarboxylative C −N
sp
coupling by electrochemical oxidation with readily available α-
amino acids as substrates and a wide variety of azoles and
carboxamides as the N-nucleophiles. In this protocol,
carboxylic acids are directly used without any preactivation
under transition-metal- and external-oxidant-free conditions.
We expect that this efficient C−N bond formation reaction
that proceeds under green conditions will find wide
applications in organic synthesis.
Figure 1. CV of Boc-L-proline (1a) and benzimidazole (2a). Cyclic
n
voltammograms recorded in 0.01 M Bu NPF -MeCN solution: scan
4
6
−1
rate, 50 mV s ; starting potential, 0 V; glass carbon (3 mm diameter,
Working Electrode); platinum plate (Counter Electrode); Ag/AgNO3
(
0.01 M AgNO in MeCN, Reference Electrode). Concentrations:
3
benzimidazole (0.06 mmol, 8 mL MeCN) and Boc-L-proline (0.1
mmol, 8 mL MeCN).
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03696.
oxidative potential around 2.36 V in its CV. These results and
2
0,23
the literature
indicate that carboxylic acids most likely
undergo oxidation to their respective cations at the anode in
our electrochemical reactions. To further confirm that the
reactive intermediates are generated at the anode, we
performed control experiments using H-type divided cell
separated by an AMI-7001 membrane, expecting that the final
Data and spectral copies of H, 13C NMR, and HRMS
for starting materials and target compounds (PDF)
1
AUTHOR INFORMATION
Corresponding Authors
28
■
product would be obtained in the anodic chamber. The
reactions were conducted under the standard conditions, and
both the divided anodic chamber and cathodic chamber
contained the same solution, including substrates, solvent, and
supporting electrolyte. Indeed, in the case of Boc-L-proline
*E-mail: aechavarren@iciq.es.
*E-mail: ias_yhwang@njtech.edu.cn.
ORCID
(
1a) and benzimidazole (2a), the desired product 3a was
Antonio M. Echavarren: 0000-0001-6808-3007
Yahui Wang: 0000-0003-4109-8318
Author Contributions
exclusively produced in the anodic chamber. Compound 3a
was obtained in 12% yield in this experiment due to the lower
efficiency of the electrolysis in the divided cell.
∥
In addition, although electrochemical oxidation on cyclic
These authors contributed equally.
23
amine derivatives can also generate iminium cations, this
process does not compete under our reaction conditions as
shown, for example, in the successful formation of tetrahy-
droisoquinoline derivative 3e, which bears a potentially
oxidizable benzylic amine (Scheme 2). Moreover, when Boc-
ethylamine (1f-H) was used instead of Boc-alanine (1f),
product 3f was not detected at all (Scheme 4a). Furthermore,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge National Natural Science Foundation of
China (21702105), Natural Science Foundation of Jiangsu
Province, China (BK20170981), Nanjing Tech University, the
Agencia Estatal de Investigacio
CTQ2016-75960-P), and CERCA Program/Generalitat de
Catalunya for financial support.
́
n (AEI)/FEDER, UE
Scheme 4. Control Experiments: (a) Decarboxylation vs
Dehydrogenation and (b) Comparison Experiments with
Photoredox Catalysis
(
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1
(
F
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