New Strategy for the Synthesis of Heterocycles via Copper-Catalyzed Oxidative Decarboxylative Amination of Glyoxylic Acid

Article abstract of DOI:10.1002/ejoc.201901538

A copper-catalyzed oxidative decarboxylative amination of glyoxylic acid with substrates having two nitrogen-nucleophilic sites was first demonstrated. Using this novel approach, 1,3,5-triazines, quinazolinones and quinazolines were obtained in up to 93 % yields. Notably, glyoxylic acid was employed as the C1 synthon for heterocycles. This strategy enriches the application of glyoxylic acid for the synthesis of valuable heterocycles.

Full text of DOI:10.1002/ejoc.201901538

A Journal of
Accepted Article
Title: New Strategy for the Synthesis of Heterocycles via Copper-
Catalyzed Oxidative Decarboxylative Animation of Glyoxylic Acid
Authors: Bin Niu, Shaoqing Li, Chang Cui, Yizhe Yan, Lin Tang, and
Jianyong Wang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901538
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10.1002/ejoc.201901538
European Journal of Organic Chemistry
COMMUNICATION
New Strategy for the Synthesis of Heterocycles via Copper-
Catalyzed Oxidative Decarboxylative Animation of Glyoxylic Acid
Bin Niu,[a] Shaoqing Li,[a] Chang Cui,[a] Yizhe Yan,*[a] Lin Tang[c] and Jianyong Wang*[b]
Abstract: A copper-catalyzed oxidative decarboxylative amination of
glyoxylic acid with substrates having two nitrogen-nucleophilic sites
was first demonstrated. Using this novel approach, 1,3,5-triazines,
quinazolinones and quinazolines were obtained in up to 93% yields.
Notably, glyoxylic acid was employed as the C1 synthon for
heterocycles. This strategy enriches the application of glyoxylic acid
for the synthesis of valuable heterocycles.
In the past decades, catalytic decarboxylative coupling of
carboxylic acids with various coupling partners has emerged as
an important strategy for direct construction of C–X bond due to
their low cost, great structural diversity, step economical
advantages.[1] Recently, glyoxylic acid or glyoxylic acid acetal
has been employed as a novel formylation reagent through
decarboxylative cross-couplings. In 2017, Wang[2] and Xu[3]
successfully reported chemoselective and regioselective
hydroformylation of alkenes with glyoxylic acid acetal for alkyl
aldehydes. After that, Wang and Fu also reported the direct
decarboxylative formylation of aryl boronic acids[4] or aryl
halides[5,6] with glyoxylic acid (glyoxylic acid acetal) to afford aryl
aldehydes. In 2018, Tao reported
a palladium-catalyzed
hydroformylation of terminal arylacetylenes with glyoxylic acid,
giving a broad range of α, β-unsaturated aldehydes.[7] Recently,
Wu reported a nickel and iron-catalyzed dehydrogenative–
decarboxylative 3-formylation of indoles with glyoxylic acid.[8]
Nevertheless, all these methods were always used to construct
C-CHO motif. Very recently, Huang reported the electrochemical
decarboxylation formylation of amines with glyoxylic acid, which
resulted in one C-N formation.[9] Based on our studies about the
synthesis of heterocycles using novel carbon synthons,[10]
glyoxylic acid is likely to be employed as a novel carbon synthon
to construct heterocycles via oxidative decarboxylative coupling.
1,3,5-triazines are a valuable class of nitrogen-containing
heterocycles due to its good biological activity.[11] Although many
methods have been achieved, low atom economy and
generated toxic byproducts limited their further applications.[10,12]
Herein, we report a copper-catalyzed oxidative decarboxylative
amination of glyoxylic acid with substrates having two nitrogen-
Scheme 1. New strategies with glyoxylic acid as the C1 synthon
nucleophilic sites. A series of nitrogen-containing heterocycles
such as 1,3,5-triazines, quinazolinones and quinazolines were
obtained in moderate to good yields. Glyoxylic acid was
employed as the C1 synthon for the synthesis of heterocycles
with the release of CO2. Notably, one C-N bond and one C=N
bond were formed in pot via an oxidative decarboxylation. This
method provides a new strategy to synthesize valuable nitrogen-
containing heterocycles.
Initially, benzamidine hydrochloride (1a) and glyoxylic acid
(2a) were chosen as model substrates to start our study. The
reaction of 1a and 2a with 20 mol % of Cu(OTf)2 and 2 equiv of
tert-butyl hydroperoxide (TBHP, 70% in aqueous) in the
presence of Cs2CO3 (1 equiv) gave trace amount of 2,4-
diphenyl-1,3,5-triazine (3a) (Table 1, entry 1). When TBHP was
replaced with di-tert-butyl peroxide (DTBP) or K2S2O8, only
DTBP gave 3a with a 60% yield (Table 1, entries 2 and 3). The
absence of glyoxylic acid resulted in the failure of the reaction,
which proved that the extra carbon atom of 1,3,5-triazine
originated from glyoxylic acid (Table 1, entry 4). After the
optimization of various copper catalysts, no higher yields were
obtained (Table 1, entries 5-12). 3a was obtained in lower yield
when the reaction was performed in CH3CN or dioxane (Table 1,
entries 13 and 14). When organic bases were examined, no
better result was obtained (Table 1, entry 15). When 20 mol% of
1,10-phenanthroline or N,N,N',N'-tetramethylethylenediamine
(TMEDA) was employed as the ligand, TMEDA gave the highest
93% yield (Table 1, entries 16 and 17). Therefore, the optimal
conditions were established as described in entry 17.
[a]
Dr. B. Niu, S. Li, C. Cui, Prof. Dr. Y. Yan
School of Food and Biological Engineering, Henan Collaborative
Innovation Center of Food Production and Safety, Henan Key
Laboratory of Cold Chain Food Quality and Safety Control
Zhengzhou University of Light Industry
Zhengzhou, 450000, P. R. China
E-mail: yanyizhe@mail.ustc.edu.cn
https://www.researchgate.net/profile/Yizhe_Yan
Prof. Dr. J. Wang
School of Light Industry and Engineering
Qilu University of Technology (Shandong Academy of Sciences)
Jinan, 250353, P. R. China
[b]
[c]
Prof. Dr. L. Tang
School of Light Industry and Engineering
Qilu University of Technology (Shandong Academy of Sciences)
Jinan, 250353, P. R. China
Supporting information for this article is given via a link at the end
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10.1002/ejoc.201901538
European Journal of Organic Chemistry
COMMUNICATION
Table 1. Optimization of reaction conditions.[a]
Entry
[Cu]
[O]
Solvent
Yield (%)[b]
1
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuCl2
TBHP
DTBP
K2S2O8
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CH3CN
dioxane
DCE
DCE
DCE
trace
60
2
3
trace
trace
50
4[c]
5
6
CuBr2
50
7
Cu(OAc)2
Cu(TFA)2
CuCl
trace
53
8
9
52
10
11
12
13
14
15
16[f]
17[g]
CuBr
50
CuI
52
Cu2O
trace
55
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
55
49[d], trace[e]
72
93
Scheme 2. Synthesis of symmetrical 2,4-disubstituted 1,3,5-triazines. [a]
Reaction conditions: 1 (0.4 mmol), 2 (0.4 mmol), Cu(OTf)2 (0.08 mol), TMEDA
(0.08 mol), DTBP (0.8 mmol), Cs2CO3 (0.4 mmol), DCE (1 mL), 120 °C, 24 h;
isolated yield. [b] 1,10-Phen.
[a] Reaction conditions: 1a (0.4 mmol), 2a (0.4 mmol), Cu catalyst (0.08 mol),
ligand (0.08 mol), oxidant (0.8 mmol), base (0.4 mmol), solvent (1 mL),
120 °C, 24 h. [b] Isolated yield. [c] In the absence of glyoxylic acid. [d] DBU. [e]
NEt3. [f] 1,10-Phen. [g] TMEDA.
Under the optimal reaction conditions, the scope of amidines
1 was investigated (Scheme 2). First, both electron-deficient and
electron-donating
aryl
amidines
(1a-1k)
could
give
corresponding symmetrical 2,4-diaryl-1,3,5-triazines (3a-3k) in
45-93% yields. The ortho-substitued aryl amidines (1j or 1k)
gave lower yields in comparison to the para-subsititued ones (1b
or 1f) due to the steric hindrance. Moreover, cyclopropane-
carboximidamide (1l) also could give the corresponding product
3l in 25% yield. In addition, when 2a was replaced with 2-
oxopropanoic acid (2b) or 2-oxopropanoic acid (2c), the desired
2-methyl-4,6-diphenyl-1,3,5-triazine (3m) or 2,4,6-triphenyl-
1,3,5-triazine (3n) was obtained in 28% or 40%, respectively,
which indicated that the extra carbon atom of 1,3,5-triazines
might be from the formyl gourp rather than the carboxyl group of
glyoxylic acid.
Subsequently, the synthesis of unsymmetrical 2,4-
disubstituted 1,3,5-triazines was also investigated (Scheme 3).
After the optimization, the reaction of 4 equiv of benzamidine (1a)
with 1 equiv of 4-methoxybenzamidine (1g) generated an
unsymmetrical product 3ag in 36% yield with only symmetrical
product 3a being obtained in 33% yield. When 1a was replaced
with 1c or 1f, the unsymmetrical 3cg or 3fg was also obtained in
25% or 35% yields, respectively. In addition, the reaction of 1a,
1m and glyoxylic acid also afforded the unsymmetrical product
3am in 30% yield.
Scheme 3. Synthesis of unsymmetrical 2,4-disubstituted 1,3,5-triazines..
Reaction conditions: 1 (0.8 mmol), 1’ (0.2 mmol), 2a (0.4 mmol), Cu(OTf)2
(0.04 mol), TMEDA (0.04 mol), DTBP (0.4 mmol), Cs2CO3 (0.4 mmol), DCE (1
mL), 120 °C, 24 h; isolated yield.
Quinazolinone as an important structural motif has been
widely applied in pharmaceutical chemistry due to good
bioactivites.[13] Many great efforts have been made for the
synthesis of quinazolinones in recent years.[14] Therefore, the
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10.1002/ejoc.201901538
European Journal of Organic Chemistry
COMMUNICATION
Scheme 5. Control experiments and gram-scale synthesis
Scheme 4. Synthesis of quinazolinones using glyoxylic acid as the C1 synthon.
Reaction conditions: 4 (0.2 mmol), 2a (0.4 mmol), Cu(OTf)2 (0.04 mmol),
TMEDA (0.04 mmol), DTBP (0.4 mmol), DCE (1 mL), 120 °C, 24 h; isolated
yield.
reaction of 2-aminobenzamides with glyoxylic acid was
conducted to produce quinazolinones under standard conditions
(Scheme 4). Expectedly, both N-aryl (4a-4e) and N-alkyl 2-
aminobenzamide (4f and 4g) afforded the corresponding
products 5a-5g in satisfactory yields. Moreover, 2-amino-4-
chloro-N-phenylbenzamide (4h) and 2-amino-5-chloro-N-
phenylbenzamide (4i) could give the desired 5h and 5i in 64%
and 65% yields, respectively. Quinazoline is also an important
class of heterocycle with goodbiological activities, which has
been employed as the intermediate of many commercial drugs,
such as Lapatinib, Prazosin, Iressa, Erlotinib and Linagliptin.[15]
To our delight, 2-aminobenzophenone (6) could give the desired
4-phenylquinazoline (7) with a 71% yield in the presence of
NH4OAc under standard conditions (Eq 1).
Scheme 6. A plausible mechanism
experiment was performed with an 80% yield of 3a obtained
(Scheme 5d).
On the basis of the results above and previous reports[1, 16]
,
two plausible reaction pathways are proposed (Scheme 6, Path
A and B). Initially, the condensation of the substrates (1, 4 or 6)
with glyoxylic acid gives an intermediate A, which can be further
transformed to a CuII complex B through a ligand exchange of
Cu(OTf)2 (Path A). Then B can give a new CuII complex C with
the escape of CO2. Subsequently, the oxidation of C gives a CuIII
complex D by removing one water molecule. Then D is
transformed into the heterocyclic product (3, 5 or 7) and CuOTf
through reductive elimination. Finally, Cu(OTf)2 is regenerated
via the oxidation of CuOTf to realize the copper catalytic cycle.
Furthermore, a minor pathway may occur according to the
control experiment. The substrates and in-situ generated HCHO
can afford the heterocycles via a tandem condensation and
oxidation process (Path B).
To gain an insight into the reaction mechanism, several
control experiments were performed (Scheme 5). First, the
reaction was not completely inhibited in the presence of two
equiv of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as the
radical inhibitor (Scheme 5a). This result indicated that this
reaction might not undergo a radical decarboxylation process.
Moreover, Nash reagent (acetylacetone 8 and ammonia) was
used to detect the possible intermediate formaldehyde
generated via direct decarboxylation of glyoxylic acid (Scheme
5b). Under standard conditions, no Nash product 9 was
observed but its oxidative product 9’ was obtained in 16% yield.
In addition, when formaldehyde was used instead of glyoxylic
acid under standard conditions, 3a was obtained in 54% yield
(Scheme 5c). These results indicated that formaldehyde might
be a minor intermediate to form heterocycles. Finally, to
examine the practicability of this protocol, a 10 mmol scale
In summary, we have developed
a copper-catalyzed
oxidative decarboxylative amination of glyoxylic acid with
substrates having two nitrogen-nucleophilic sites, giving 1,3,5-
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10.1002/ejoc.201901538
European Journal of Organic Chemistry
COMMUNICATION
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yields. Notably, glyoxylic acid was employed as a C1 synthon to
access heterocycles with the release of CO2. Compared to
previous methods, this novel protocol is distinguished by (1)
cheap copper catalysis, (2) operational simplicity, (3) broad
substrate scope, (4) the generaton of low toxic wastes such as
CO2 and H2O. Further research about glyoxylic acid as the C1
synthon for valuable heterocycles is underway in our laboratory.
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Acknowledgments
We are grateful to the National Natural Science Foundation of
China (21502177), the Program for Science and Technology
Innovation Talents in Universities of Henan Province
(20HASTIT037), the Science and Technology Basic Research
Program of Henan Province (182102110248, 182102310903,
192102110104, 192102110213), the Basic Research Plan of
Higher Education School Key Scientific Research Project of
Henan Province (19zx012), and the Higher Education School
Young Backbone Teacher Training Program of Henan Province
(2018GGJS093).
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Keywords: glyoxylic acid • copper • decarboxylation • C-N
coupling• heterocycle
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European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Decarboxylative Amination*
Bin Niu, Shaoqing Li, Chang Cui, Yizhe
Yan,* Lin Tang, Jianyong Wang*
Page No. – Page No.
New Strategy for the Synthesis of
Heterocycles via Copper-Catalyzed
Oxidative Decarboxylative Amination
of Glyoxylic Acid
A copper-catalyzed oxidative decarboxylative amination of glyoxylic acid with
substrates having two nitrogen-nucleophilic sites was first demonstrated, affording
1,3,5-triazines, quinazolinones and quinazolines in up to 93% yields.
This article is protected by copyright. All rights reserved.