Br?nsted Acid Catalyzed Cyclization of Aminodiazoesters with Aldehydes to 3a'Carboxylatea'Na'Heterocycles

Article abstract of DOI:10.1021/acs.orglett.0c02125

A Br?nsted acid catalyzed cyclization of aminodiazoesters with aldehydes is described. This reaction features broad substrate generality and functional group compatibility, affording a wide range of 5a'7-membered 3-carboxylate-N-heterocycles containing different functional groups. The title products are able to be further elaborated through simple functional group transformations to produce synthetically useful N-heterocycles.

Full text of DOI:10.1021/acs.orglett.0c02125

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Letter
Brønsted Acid Catalyzed Cyclization of Aminodiazoesters with
Aldehydes to 3‑Carboxylate‑N‑Heterocycles
Yang Jiao, Anrong Chen, Bangkui Yu, and Hanmin Huang*
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ABSTRACT: A Brønsted acid catalyzed cyclization of aminodiazoesters with aldehydes
is described. This reaction features broad substrate generality and functional group
compatibility, affording a wide range of 5−7-membered 3-carboxylate-N-heterocycles
containing different functional groups. The title products are able to be further
elaborated through simple functional group transformations to produce synthetically
useful N-heterocycles.
N-Heterocycles are privileged scaffolds in synthetic and
medicinal chemistry,1 which not only frequently exist in a
wide range of bioactive molecules but also are valuable
synthetic building blocks that can be transformed into a series
of valuable structures. Especially, the 3-carboxylate-N-hetero-
cycles are well-known scaffolds for constructing a number of
bioactive molecules.2 For example, the 3-nucleoside derivatives
prepared from 3-carboxylate-pyrrole display potent inhibition
of the human disease-relevant kinases.2 (R)-Tiagabine
featuring piperidine-3-carboxylic acid serves as an efficient
GABA uptake inhibitor,3,4 and the antiplasmodial exhibits the
antimalarial activity (Figure 1).5 In spite of the substantial
in which the diazo functionality is reserved.9 In contrast, with
N-alkyl imines as electrophiles, the N2 is able to be extruded to
form aziridines via sequential nucleophilic addition and
substitution (Scheme 1a).10 In this context, the intramolecular
Scheme 1. New Method for the Synthesis of 3-Carboxylate-
N-Heterocycles
Figure 1. Selected examples of biologically active compounds bearing
3-carboxylate-N-heterocycles.
interest in these 3-carboxylate-N-heterocycles and their
applications in drug design, only a few catalytic synthetic
methods have been developed, with the majority of them being
of limited scope.6 As a result, the development of more general
and straightforward synthetic methods toward these com-
pounds is desirable.
α-Diazocarbonyl compounds are quite valuable building
blocks in synthetic organic chemistry due to their versatile
reactivity and remarkable synthetic utility.7 As the carbon atom
of the diazo group possesses a partial negative charge, it can be
used as a nucleophile for a diverse type of nucleophilic addition
reactions.8 The Lewis acid catalyzed or base mediated
nucleophilic addition of α-diazocarbonyl compounds to
activated imines (bearing a strong electron-withdrawing
group at the nitrogen atom) has been extensively explored
for the construction of β-amino-α-diazocarbonyl compounds,
nucleophilic addition reaction of imine diazocarbonyl com-
pounds would be expected to provide an alternative approach
to 3-carboxylate-N-heterocycles once a driving force for
releasing N2 from the reaction is identified. However, as far
as we know, only one special example for the synthesis of 3-
carboxylate indoles with iminophenyl-diazoacetates as reac-
Received: June 27, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02125
© XXXX American Chemical Society
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Letter
tants by using this strategy has been reported, in which the
aromatization might be the driving force to release the N2 to
furnish the cyclization reaction.11 In connection with our
interest in exploring new reactions with diazo compounds as
starting materials,12 herein, we wish to report a nucleophilic
cyclization reaction of aminodiazoesters with aldehydes,
leading to the furnishing of a series of 5−7-membered 3-
carboxylate-N-heterocycles (Scheme 1b). The in situ formed
iminium ion was adopted as an electrophile to furnish the
cyclization and the inherent positive charge imparted a driving
force to extrude the N2. The products were able to be further
transformed via conventional functional group transformations
and successfully applied to the formal synthesis of the
precursors of nucleoside derivatives and Tiagabine.
MePhCOOH, 2-ClPhCOOH, 2-NO2PhCOOH, and nicotinic
acid, were also able to promote this reaction, but only
moderate yields were achieved (Table 1, entries 13−16).
Finally, when molecular sieves with different pore sizes were
introduced into the reaction system to eliminate the
disturbance of water that was produced from the reaction,
no better results were observed (Table 1, entries 17−19).
With the optimized reaction conditions in hand, we next
tested the generality of this synthetic method under the
catalysis of PhCOOH (Scheme 2). First, the substrate scope of
a
Scheme 2. Substrate Scope of Aldehyde
We commenced our studies by attempting the proposed
reaction using ethyl 4-(benzylamino)-2-diazobutanoate (1a)
and benzaldehyde (2a) as substrates with a series of Lewis
acids as catalysts in CH2Cl2 at 80 °C. After an extensive
screening of common Lewis acids such as Fe(OTf)2, B(C6F5)3,
AlCl3, and Sc(OTf)3 (Table 1, entries 1−4), the target adduct
a
Table 1. Optimization of Reaction Conditions
b
entry
cat.
solvent
additive
yield (%)
1
2
3
4
5
6
7
8
Fe(OTf)2
B(C6F5)3
AlCl3
Sc(OTf)3
−
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
MeOH
EtOH
i-PrOH
CH3CN
HFIP
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
16
55
47
61
51
15
81
85
58
57
70
51
50
67
53
67
48
54
69
−
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
2-MePhCOOH
2-ClPhCOOH
2-NO2PhCOOH
Nicotinic acid
PhCOOH
PhCOOH
PhCOOH
9
10
11
12
13
14
15
16
17
18
19
3 Å MS
4 Å MS
5 Å MS
a
Reaction conditions: 1a (0.5 mmol), 2 (0.6 mmol), PhCOOH (10
b
mol %), MeOH (2.5 mL), 12 h, 80 °C; isolated yield. 1a (0.66
mmol), 2z (0.30 mmol), PhCOOH (20 mol %).
a
Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), cat. (10 mol
b
%), solvent (1.0 mL), additive (20 mg), 12 h. 80 °C. Isolated yield.
aldehyde was examined with the aminodiazoesters 1a as the
model substrate. To our delight, a wide range of aldehydes
reacted smoothly with aminodiazoester 1a to afford the
corresponding adducts 3 in moderate to good yields. Of the
aromatic aldehydes, both electron-rich and electron-deficient
groups on the phenyl ring of the benzaldehydes were tolerated
to deliver the corresponding products with moderate to good
yields (58−76% yields). The aldehydes with an electron-rich
group (−Me, −t-Bu, and −OMe) at the ortho-, para-, or meta-
position proceeded smoothly to give the corresponding
products in good yields (Scheme 2, 3ab−3af). Besides, the
substrates bearing electron-deficient groups (−CN, −CF3, −F,
−Cl, and −Br) at the ortho-, para-, or meta-position were
applicable in the present catalytic system (3ag−3am) to afford
3aa was obtained in 61% yield with Sc(OTf)3 as the catalyst
(Table 1, entries 4). To further improve the desired product
yield of the reaction, we utilized a Brønsted acid as the catalyst.
To our great delight, the target product 3aa was obtained in
81% yield when PhCOOH served as the catalyst (Table 1,
entry 7). In contrast, the reaction activity decreased in the
absence of the catalyst (Table 1, entries 5 and 6). Encouraged
by these results, we next carried out further experiments by
screening other reaction parameters to improve the efficiency
of the reaction. Screening of solvents disclosed that MeOH was
the most efficient solvent for the title reaction (Table 1, entries
7−12). On the other hand, Brønsted acids, such as 2-
B
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pubs.acs.org/OrgLett
Letter
the corresponding products in good yields. Meanwhile,
disubstituted benzaldehydes (1n−1p) also smoothly pro-
ceeded to produce the desired products in good yields
(1an−1ap). In addition, 2-naphthaldehyde 1t was also
compatible with this new reaction to deliver 3at in 73%
yield. As expected, aromatic heterocycle aldehydes were also
able to give the desired products with good yields (3aq−3as).
Moreover, aliphatic aldehydes could react smoothly with
aminodiazoester 1a to give the corresponding products in
moderate to good yields (3au−3aw). For example, the
paraformaldehyde reacted with aminodiazoester 1a smoothly
to give the corresponding product (3au) in 80% yield.
Meanwhile, the chiral (−)-perillaldehyde (2x) could also be
transformed into the desired adduct (3ax) in 60% yield. When
phthalimide derived aliphatic aldehyde (2y) as the substrate,
the corresponding product 3ay was able to be produced in
60% yield. Interestingly, the double 4,5-dihydro-1H-pyrrole-3-
carboxylate product (3az) was obtained in 44% yield when
terephthalaldehyde (2z) was utilized as the coupling partner.
Next, we examined the scope and the limitation of
aminodiazoesters. As shown in Scheme 3, the substrates
Moreover, the reactions with different aldehydes and amino-
diazoester 1g proceeded well to the give the six-membered ring
products (3gs, 3ha, and 3ia) in moderate yields. In these
reactions, the ethyl benzylprolinate resulted from the
competitive intramolecular thermal N−H insertion reaction
and aminodiazoester 1g was observed as a byproduct.13 By
further change of the structural motif of the substrate, a
benzene-fused seven-membered ring product (3ja) was
produced in 70% yields. However, the analogous product
(3ka) was not observed under the catalysis of PhCOOH. To
our delight, when Sc(OTf)3 was utilized to catalyze the
reaction, 3ka, the desired product, was obtained in 42% yield.
To substantiate the effectiveness of this catalytic protocol,
the transformations of the resulting 3-carboxylate-N-hetero-
cycles were explored (Scheme 4). The Brønsted acid enabled
Scheme 4. Synthetic Transformations
a
Scheme 3. Substrate Scope of Aminodiazoester
cyclization process proved to be scalable in the presence of 8
mol % of PhCOOH, maintaining the transformation yield
(3au, 80% yield) at the same time. The scalability of this
transformation indicates its potential application value in
preparing fine chemicals. Then the product (3au) could be
oxidized by O2 in DMSO to afford the corresponding ethyl 1-
benzyl-1H-pyrrole-3-carboxylate 4 in 58% yield.6k Meanwhile,
hydrolysis of the ester gave carboxylic acid 5 in 83% yield.14 It
can be used as a synthetic intermediate for nucleoside
derivatives.2 On the other hand, the 3gs could be facilely
transferred to ethyl 3-piperidinecarboxylate 6 in 70% yield
through Pd/C-catalyzed hydrogenation and hydrogenolysis.
The ethyl piperidine-3-carboxylate 6 could be facilely trans-
formed to Tiagabine according to the reported procedures.4
In accordance with the above experimental results, a
plausible mechanism is proposed (Figure 2) for the reaction.
In the first stage, the intermediate A would form under the
activation of Brønsted acid PhCO2H, which is then
nucleophilically attacked by the aminodiazoester 1a, producing
intermediate B. Then, the unstable intermediate B is prone to
dehydration to produce iminium cation C. Subsequently, the
carbon atom of the diazo group attacks the imine ion and
cyclizes to give intermediate D. Finally, the product 3aa is
obtained through the process of deprotonation and denitroge-
nation under the assistance of the basic anion.
a
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), PhCOOH (10
b
mol %), MeOH (2.5 mL), 12 h, 80 °C; isolated yield. Sc(OTf)3 (10
mol %), CH3CN (2.5 mL).
aminodiazoesters with different ester groups (1b−1d) could
afford the corresponding products with a five-membered ring
in good yields (3ba−3da). The p-methoxybenzyl and p-
bromobenzyl protected aminodiazoesters proceeded smoothly
to give the desired product (3ea and 3fa) in good yields.
However, no desired reaction took place when the Ts-
protected aminodiazoesters was subjected to the standard
reaction conditions. To our delight, the catalyzed reaction was
also suitable for the cyclization of ethyl 5-(benzylamino)-2-
diazopentanoate (1g) with benzaldehyde, giving the corre-
sponding ethyl 1-benzyl-2-phenyl-1,4,5,6-tetrahydropyridine-3-
carboxylate (3ga) with a six-membered ring in 57% yield.
In summary, a Brønsted acid catalyzed cyclization reaction
of aminodiazoesters with aldehydes has been developed in this
work. This transition-metal-free protocol provides a direct and
efficient way for the synthesis of 3-carboxylate-N-heterocycles.
The reaction operates under mild reaction conditions and
exhibits broad substrate generality as well as functional group
compatibility. The products can also be readily transformed
C
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02125.
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Experimental details and full spectroscopic data for all
new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
Hanmin Huang − Hefei National Laboratory for Physical
Sciences at the Microscale and Department of Chemistry,
University of Science and Technology of China, Hefei 230026,
P. R. China; Center for Excellence in Molecular Synthesis of
CAS, Hefei 230026, P. R. China; orcid.org/0000-0002-
0108-6542; Email: hanmin@ustc.edu.cn
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2003, 9, 4068−4076.
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Authors
Yang Jiao − Hefei National Laboratory for Physical Sciences at
the Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei 230026, P. R. China
Anrong Chen − Hefei National Laboratory for Physical Sciences
at the Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei 230026, P. R. China
Bangkui Yu − Hefei National Laboratory for Physical Sciences at
the Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei 230026, P. R. China
(10) For selected examples, see: (a) Mohan, J. M.; Uphade, B. S.;
Choudhary, V. R.; Ravindranathan, T.; Sudalai, A. Chem. Commun.
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Chin. J. Chem. 2020, 38, 389−393.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02125
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21925111, 21790333, 21672199, and 21702197) for financial
support.
(13) Hansen, S. R.; Spangler, J. E.; Hansen, J. H.; Davies, H. M. L.
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Lett. 2019, 21, 9114−9118.
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