A three-component, Zn(OTf)2-mediated entry into trisubstituted 2-aminoimidazoles

Article abstract of DOI:10.3762/bjoc.15.103

A three-component reaction involving in situ generation of propargylureas and subsequent Zn(OTf)₂-mediated cyclocondensation with a primary amine yielded trisubstituted 2-aminoimidazoles. These findings are in contrast to the previously reporte

Full text of DOI:10.3762/bjoc.15.103

A three-component, Zn(OTf)2-mediated entry into
trisubstituted 2-aminoimidazoles
Alexei Lukin1, Anna Bakholdina1, Anna Kryukova1, Alexander Sapegin2
and Mikhail Krasavin*2
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 1061–1064.
1Lomonosov Institute of Fine Chemical Technologies, MIREA –
Russian Technological University, Moscow 119571, Russian
Federation and 2Saint Petersburg State University, Saint Petersburg
199034, Russian Federation
doi:10.3762/bjoc.15.103
Received: 23 February 2019
Accepted: 29 April 2019
Published: 07 May 2019
Email:
Mikhail Krasavin* - m.krasavin@spbu.ru
This article is part of the thematic issue "Multicomponent reactions III".
Guest Editor: T. J. J. Müller
* Corresponding author
Keywords:
© 2019 Lukin et al.; licensee Beilstein-Institut.
License and terms: see end of document.
alkyne hydroamination; cyclocondensation; Lewis acid catalysis;
multicomponent reactions; propargylurea
Abstract
A three-component reaction involving in situ generation of propargylureas and subsequent Zn(OTf)2-mediated cyclocondensation
with a primary amine yielded trisubstituted 2-aminoimidazoles. These findings are in contrast to the previously reported base-
promoted unimolecular cyclization of propargylureas (leading to 2-imidazolones) and extend the range of Lewis acid-catalyzed
azole syntheses based on N-carbonyl propargylamines.
Introduction
The pioneering publications of Beller and co-workers verted to the respective 2-imidazolones via base-promoted
describing Zn(OTf)2-catalyzed, microwave-promoted conver- intramolecular amination of the propargyl group [5,6]. Howev-
sion of a mixture of a secondary propargylamide and an amine er, such transformations have not been studied under transition
into a trisubstituted imidazole 1 [1,2] inspired us to explore metal or Lewis acid catalysis. Moreover, the possibility to in-
several variants of this methodology. Last year, we described corporate of an external primary amine into the cyclization
the synthesis of differently substituted imidazoles 2 from process, which would lead to trisubstituted 2-aminoimidazoles 5
tertiary propargylamides and ammonium chloride under has not been explored (Figure 1). 2-Aminoimidazoles have a
conventional heating [3]. More recently, we applied the Beller remarkably broad utility in medicinal chemistry [7]. Moreover,
protocol to the synthesis of 2-substituted 5-methyloxazoles 3 ureas 4 can, in principle, be generated in situ from the respec-
from secondary propargylamides [4]. Being curious to explore tive isocyanates and propargylamine (or propagyl isocyanate
more variants of N-carbonyl propargylamines, we turned our and primary amines), thus could offer an opportunity to synthe-
attention to propargylureas 4. These have been previously con- size 2-aminoimidazoles 5 in a three-component format. Consid-
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Beilstein J. Org. Chem. 2019, 15, 1061–1064.
ering these premises, we started to explore the Zn(OTf)2-cata- amount of benzylamine in refluxing toluene in the presence of
lyzed reaction of 4 with primary amines. Herein, we present the various Lewis acids. To our delight, the desired product 5a was
preliminary results of these studies.
observed and isolated in all cases involving Zn(OTf)2 catalysis.
However, in contrast to previous reports on the preparation of
related compounds [1-4], the reaction required substantial
amounts (optimally, 50 mol %) of Zn(OTf)2 to achieve the best
yield (76%). Notably, neither Sc(OTf)2 nor Cu(OTf)2 em-
ployed as catalysts produced a trace of the desired product. To
rule out catalysis by adventitious TfOH, the reaction was per-
formed in the presence of an equimolar amount of triflic acid,
but no conversion could be detected (Table 1).
Considering that in situ preparation of ureas 4 could, in prin-
ciple, enable a three-component entry to imidazoles 5 (an attrac-
tive option from the standpoint of library array synthesis), we
compared the isolated yield of the above reaction (with the
ready-made urea 4a) with the yield obtained in the three-com-
ponent format. To our delight, the three-component format led
to only a slightly lower yield of 5a (62%). Viewing this as a
worthy toll for the convenience of multicomponent chemistry,
we proceeded investigating the scope of the newly established
synthesis of trisubstituted 2-aminoimidazoles 5 (Figure 2).
As it is evident from the data presented in Figure 2, the newly
developed approach to the synthesis of medicinally important
2-imidazolines allows for independent variation of two
periphery elements and provides generally good yields of the
target compounds. The reaction can be performed with both, ar-
omatic and aliphatic isocyanates. However, its scope is limited
to aliphatic amines as the reaction failed to work for anilines
(even electron-rich ones, such as p-anisidine). The tolerance of
Figure 1: Examples of imidazole (1 and 2) and oxazole (3) syntheses
from propargylamides previously reported and the reaction of propar-
gylureas 4 with primary amines studied in this work.
Results and Discussion
Urea 4a (prepared by reacting propargylamine with 4-(trifluo- acid-labile protecting groups such as Boc is particularly useful
romethoxy)benzyl isocyanate) was reacted with an equivalent as it offers an opportunity for further side-chain modifications.
Table 1: Catalyst screening results for the conversion of 4a to 5a.
Entry
Catalyst
Isolated yield (%)
1
2
3
4
5
6
7
Zn(OTf)2 (5 mol %)
Zn(OTf)2 (25 mol %)
Zn(OTf)2 (50 mol %)
Sc(OTf)2 (25 mol %)
Cu(OTf)2 (25 mol %)
TfOH (100 mol %)
none
8
28
76
0
0
0
0
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Beilstein J. Org. Chem. 2019, 15, 1061–1064.
Figure 2: Substrate scope for the three-component synthesis of 5.
From the mechanistic prospective, the reaction probably Conclusion
proceeds via Zn(OTf)2-catalyzed alkyne hydroamination fol- In summary, we have successfully employed propargylureas in
lowed by cyclodehydration as depicted in Figure 3, in full the synthesis of trisubstituted 2-aminoimidazoles. This is the
analogy with the previously proposed mechanism [2,3].
first example illustrating the utility of such ureas in the synthe-
Figure 3: Plausible mechanism for the formation of 5.
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Beilstein J. Org. Chem. 2019, 15, 1061–1064.
sis of imidazoles as previously reported syntheses only involved
base-promoted cyclization into 2-imidazolones. The reaction
can be conveniently conducted in a three-component format
which makes it a useful tool for library array synthesis. The in-
vestigation of other metal-catalyzed transformations of propar-
gylureas is underway in our laboratories and will be reported in
due course.
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/4.0). Please note
that the reuse, redistribution and reproduction in particular
requires that the authors and source are credited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
Supporting Information
Supporting Information File 1
(https://www.beilstein-journals.org/bjoc)
General experimental information, synthetic procedures,
analytical data and NMR spectra for the reported
compounds.
The definitive version of this article is the electronic one
which can be found at:
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-103-S1.pdf]
doi:10.3762/bjoc.15.103
Acknowledgements
This research was supported by the Russian Science Founda-
tion (grant no. 17-73-20185). We thank the the Center for
Chemical Analysis and Materials Research of the Saint Peters-
burg State University Research Park for measuring the analyti-
cal data.
ORCID® iDs
Mikhail Krasavin - https://orcid.org/0000-0002-0200-4772
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