Glyoxylic Acid: A Carboxyl Group-Assisted Metal-Free Decarboxylative Reaction Toward Propargylamines

Article abstract of DOI:10.1002/ejoc.202100383

Readily available propargylamines are not only fundamental building blocks in organic synthesis, but also possess many prominent biological activities. A highly efficient, concise and environmentally benign decarboxylative reaction of glyoxylic acid monohydrate with secondary amines and alkynes has been elaborated, and a variety of propargylamines are delivered in moderate to good yields under metal-free conditions. A mechanism involving a carboxyl group that assists the reactivity of alkynes, which makes the procedure of Michael addition proceeded smoothly, has been proposed.

Full text of DOI:10.1002/ejoc.202100383

Communications
doi.org/10.1002/ejoc.202100383
Glyoxylic Acid: A Carboxyl Group-Assisted Metal-Free
Decarboxylative Reaction Toward Propargylamines
Liliang Huang+,[a] Yujuan Xie+,[a] Panyuan Ge,[a] Junhai Huang,[b] and Huangdi Feng*[a]
Readily available propargylamines are not only fundamental
building blocks in organic synthesis, but also possess many
prominent biological activities. A highly efficient, concise and
environmentally benign decarboxylative reaction of glyoxylic
acid monohydrate with secondary amines and alkynes has been
elaborated, and a variety of propargylamines are delivered in
moderate to good yields under metal-free conditions. A
mechanism involving a carboxyl group that assists the reactivity
of alkynes, which makes the procedure of Michael addition
proceeded smoothly, has been proposed.
Propargylamine is a versatile synthon in organic chemistry that
has been extensively employed in the construction of
heterocycles[1,2] and natural products.[3] Meanwhile, propargyl-
amine frameworks which are of important structural subunits in
natural products and functional molecules have unique bio-
logical activities.[4] Recently, transition-metal-catalyzed decar-
Scheme 1. Functionalization of carboxylic acid.
boxylative coupling reactions have emerged as powerful
methods for the building of propargylamine derivatives due to
the advantages associated with the environmental-friendly
(releasing nontoxic CO2) and operational simplicity.[5] Further,
the metal-free decarboxylative coupling is also an attractive
alternative for forming propargylamines as it makes the process
concise and flexible,[6] avoiding metallic residues in the final
products. For example, Lee and co-workers reported an
intriguing protocol for the generation of propargylamines by
metal-free decarboxylative coupling of amines, formaldehyde,
and propiolic acids (Scheme 1a).[7] Later on, our group and
Kumar’s group independently developed the metal- or catalyst-
free decarboxylation of propiolic acids to access
propargylamines.[8] However, an obvious drawback of these
approaches is the requisite of expensive or non-commercial
propiolic acids, which typically results in poor step- and cost-
efficiency. Hence, it is evident that it is still necessary to develop
an alternative metal-free decarboxylative access to give prop-
argylamines using readily available starting materials.
Despite the remarkable achievements that have been made
in the decarboxylative coupling[9] and carboxyl group-directed
functionalization of carboxylic acids[10] (Scheme 1A), the avail-
able routes for enhancing the reactivity of the reaction through
a carboxyl group-assisted process are still underdeveloped.[11]
Among them, the well-known report is the multicomponent
Petasis reaction of a glyoxylic acid, an amine, and a boronic acid
where the carboxyl group can activate the boronic acid
followed by the migration of boronate substituent
(Scheme 1c).[12] Meanwhile, glyoxylic acid has been exploited for
the synthesis of 3-amino-1,4-enynes[13a] and polysubstituted
butenolides[13b] through transition-metal-catalyzed tandem
glyoxylic acid-amine-alkyne coupling process. These studies led
us to think about whether glyoxylic acid can enhance the
reactivity of alkynes with in situ formed iminium ion owing to
its distinctive chemical properties such as electron-withdrawing
effect and removability. However, some challenges remain: (1)
the activation of alkyne substrates under metal- and base-free
conditions, and (2) the control of the decarboxylation process
which may shut down the reactivity if it conducts in the
beginning.[14] Herein, we report a carboxyl group-assisted metal-
free decarboxylative transformation of glyoxylic acid, amines,
and alkynes into propargylamines where glyoxylic acid plays a
key role in the assembly of the reaction (Scheme 1d).
[a] Dr. L. Huang,+ Y. Xie,+ P. Ge, Prof. Dr. H. Feng
College of Chemistry and Chemical Engineering
Shanghai University of Engineering Science
Shanghai, 201620, China
E-mail: hdfeng@sues.edu.cn
https://www.x-mol.com/groups/FENG_Huangdi
[b] Prof. Dr. J. Huang
China State Institute of Pharmaceutical Industry
Shanghai Institute of Pharmaceutical Industry
Shanghai 201203, China
We commenced our investigation by conducting the model
reaction of N-methylbenzylamine 1a, glyoxylic acid monohy-
drate 2a, and ethynylbenzene 3a. Initially, we examined the
[+] L. Huang and Y. Xie contributed equally.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100383
°
reaction at 80 C for 12 hours in acetonitrile (MeCN) without any
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metal catalyst, and a 62% yield of desired product 4a was
observed (Table 1, entry 1). Subsequently, a series of solvents,
including toluene, tetrahydrofuran (THF), dioxane, 1,2-dichloro-
ethane (DCE), DMF, and ethanol, were evaluated (entries 2–7).
These results indicated that the yields were significantly
improved in DCE (entry 4) and slightly increased in toluene
(entry 2), respectively. Nevertheless, others delivered propargyl-
amine 4a in a poor yield. After that, further investigations were
performed using DCE as the solvent. When the amount of
substrate 3a was changed (entries 8 and 9), the corresponding
yield decreased to 61% and 71%, respectively. Concerning the
°
decarboxylative process, heating to 95 C resulted in an increase
of the yield from 78% to 86% (entry 10). A lower temperature
°
(60 C) did not facilitate this transformation (entry 11), which is
similar to the metal-free A3-coupling.[7,8c] These results indicated
that higher temperature was essential for the reaction. No
amelioration was observed when prolonging or shortening the
reaction time, providing 4a in 75% and 66% yield, respectively
(entries 12 and 13).
With the optimized conditions established, the substrate
scope of amines 1 and alkynes 3 was tested by decarboxylative
coupling of glyoxylic acid monohydrate (Scheme 2). First,
different amines 1 were examined. In general, the increase of
steric bulk on the amine substrate leads to higher reaction
yields maybe due to the intermediate 5 formed from the
sterically hindered amine is more stable (see Scheme 3
proposed mechanism). As expected, all N-alkyl substituted
benzylamines could be employed and afforded the correspond-
ing compounds 4a–4f in high yields except the product 4c. For
example, N-tert-butyl benzylamines with both electron-donat-
ing and -withdrawing groups on the phenyl moiety were well
tolerated and yielded the desired 4e and 4f in 93% and 78%
yields, respectively. Additionally, secondary aliphatic amines
reacted smoothly to provide the desired propargylamines 4g–
4j in 54–79% yields. However, when the cyclic and primary
Table 1. Optimization of the reaction conditions.[a]
Scheme 2. Scope of amines 1 and alkynes 3. Reaction conditions: 1
(0.25 mmol), 2a (0.30 mmol), 3 (0.30 mmol) were added to DCE (0.5 mL), and
°
Entry
Ratio of
1a:2a:3a
Solvent
Temp. [ C]
Yield[b] [%]
°
the solution was kept at 95 C for 12 h under atmospheric condition. Isolated
yield based on amine. n.d.=not determined.
1
2
3
4
5
6
7
8
1.0:1.2:1.2
1.0:1.2:1.2
1.0:1.2:1.2
1.0:1.2:1.2
1.0:1.2:1.2
1.0:1.2:1.2
1.0:1.2:1.2
1.0:1.2:0.8
1.0:1.2:1.4
1.0:1.2:1.2
1.0:1.2:1.2
1.0:1.2:1.2
1.0:1.2:1.2
MeCN
toluene
THF
80
80
80
80
80
80
80
80
80
95
60
95
95
62
68
25
78
13
27
54
61
71
86
8
DCE
amines were used, only the morpholine could produce a poor
yield of the target product 4k. Next, we investigated the scope
of alkynes 3. Phenylacetylenes with electron-donating substitu-
ents (methyl, t-butyl, methoxy) and electron-neutral substituent
(phenyl) formed the desired products 4o, 4p, 4r, and 4s in
good yields; when the 1-butyl-4-ethynylbenzene was used, the
reaction gave lower yield (4q, 39% yield). Similarly, the phenyl-
acetylenes with electron-withdrawing groups (chloro, fluoro,
trifluoromethyl) gave the desired products 4t–4w in 65–69%
yields. To our satisfaction, the aliphatic alkynes were also
tolerated well in the reaction and gave the target products 4x
dioxane
DMF
EtOH
DCE
DCE
DCE
DCE
DCE
DCE
9
10
11
12[c]
13[d]
75
66
[a] Reaction conditions: 1a (0.25 mmol), 2a (0.30 mmol), 3a (0.20 mmol–
0.35 mmol) were added to solvent (0.5 mL), and the solution was kept at
60–95 C for 12 h under atmospheric condition. [b] Isolated yield based on
°
1a. [c] 24 h instead of 12 h. [d] 4 h instead of 12 h.
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Afterwards, the reaction system was directly purified by running
silica gel flash column chromatography (5–10% ethyl acetate in
petroleum ether) to afford the desired products 4a–4y.
Acknowledgements
We gratefully acknowledge the National Natural Science Founda-
tion of China (Nos: 22078192, 81973453), and the Shanghai
University of Engineering Science’s Development Program (Nos:
20KY0420, 20KY0426) for financial support.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: A3-coupling · Decarboxylation · Metal-free reaction ·
Multicomponent reaction · Propargylamine
Scheme 3. Mechanistic studies.
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Based on experimental results and previous reports,[15]
a
rational pathway is considered (Scheme 3). Initially, the glyoxylic
acid monohydrate could undergo condensation with amine
forming iminium salt species 5. Subsequently, the carboxyl
group-assisted process presumably not only delivers unusual
deprotonation of the alkyne to activate the sp carbon, but also
produces the coupled product 7 in the subsequent Michael
addition through an unstable intermediate 6. Control experi-
ments, using the formaldehyde solution or paraformaldehyde
instead of glyoxylic acid monohydrate under standard con-
ditions (Scheme 3A), show that the metal-free addition of
alkyne to in situ formed iminium ion is uncommonly.[2b,7] Further
conversion of 7 results in the generation of the desired
propargylamine by metal-free decarboxylation.
In conclusion, we have described highly efficient metal-free
decarboxylative coupling of glyoxylic acid monohydrate with
amines and alkynes to produce propargylamines in moderate
to good yields. The results demonstrated that the carboxyl
group can enhance the activation of the alkynes to react with
iminium ion intermediate without any catalysts loading, thus
increasing the sustainability of the process. Development of
additional reactions that exploit the decarboxylation process for
the functionalization of the intermediate is in progress.
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Experimental Section
General procedure: Under atmosphere, a 10 mL reaction tube was
charged with the corresponding amine 1 (0.25 mmol, 1.0 equiv.),
glyoxylic acid monohydrate 2a (0.30 mmol, 1.2 equiv.), alkyne 3
(0.30 mmol, 1.2 equiv.) and DCE (0.5 mL), then sealed. Subse-
°
quently, the reaction mixture was stirred at 95 C for 12 h.
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Manuscript received: March 27, 2021
Revised manuscript received: April 10, 2021
Accepted manuscript online: April 13, 2021
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