Facile catalyst-free synthesis of perfluoroalkylated cis-spiropyrimidine-5,1′-quinolizines and pyrano[2,3-d]pyrimidines
Introduction
Multi-component reactions (MCRs) are efficient and powerful procedures for the rapid synthesis of highly selective products, wherein, multiple and diverse new bonds have been created in highly efficient and atom-economical manner in one pot, thus saving time and energy and evading multistep purification of various intermediates. In recent years, MCRs have been an attractive synthetic strategy in drug discovery research [1].
Barbituric acid derivatives are significant pharmacophores and found in a wide range of bioactive natural products and drug molecules [2]. They display various activities such as sedative, anesthetic, anxiolytic, anticonvulsant, analeptic, anticancer, anti-AIDS and immunomodulating activities etc [3,4].
Among these compounds, spirobarbiturates have attracted much attention due to their various useful pharmacological and physiological activities [5]; many synthetic methods for spirobarbiturates have been developed [6]. One of the best methods to synthesize spirobarbiturates is using 5-arylidinebarbituric acids which can be easily obtained by Knoevenagel condensation between barbituric acid and corresponding carbonyl derivatives (aldehydes and ketones).
In addition, as an important kind of fused-barbiturates, pyrano[2,3‐d]pyrimidinedione derivatives also have caused wide interest from chemists because of their useful characteristics [7]. Various efficacious methodologies for the construction of this skeleton have been reported to date [[8], [9], [10]]. Of those methodologies, the most common method is the one-pot multi-component synthesis of barbituric acid derivatives, various aldehydes and malononitrile in the presence of various catalysts [10].
In spite of merits involved in the use of the previously reported methods for the synthesis of spirobarbiturates and pyrano[2,3-d]pyrimidinediones, some of them have their disadvantages such as the use of the substoichiometric catalysts, harsh reaction conditions, long reaction time, tedious work-up procedures, expensive and moisture-sensitive reagents, and the low yield of product etc. Hence, finding newer and more efficient methods for the synthesis of these types of compounds is still important.
Due to the unique physical, chemical and biological properties of the fluorine atom, the selective introduction of one or more fluorine atoms or perfluoroalkyl group into specific positions in a bioactive molecule has led to the development of novel medicinal agents and new strategies in drug discovery and development [11].
On considering no reports for the synthesis of biologically potential perfluoroalkylated cis-spiropyrimidine-5,1′-quinolizines and pyrano[2,3-d]pyrimidines, and as a part of our ongoing research program related to perfluoroalkylated heterocycles, [12] herein, we report a simple, rapid, and new MCRs procedure for the synthesis of these compounds under mild conditions without any catalysts.
Section snippets
Results and discussion
Inspired by our recent study on the catalyst-free one-pot three-component synthesis of first diastereoselective synthesis of perfluoroalkylated cis-spiropyrido[2,1-a]isoquinoline-1,5′-pyrimidines starting from 5-arylidenebarbituric acids 1, methyl perfluoroalk-2-ynoates 2, and isoquinolines [13], the replacement of isoquinolines with pyridines has further been examined in the present paper.
According to our previously established reaction conditions (Table 1, entry 1), the three-component
Conclusions
We have developed a simple, practical, catalyst-free protocol for access to perfluoroalkylated cis-spiro[pyrimidine-5,1′-quinolizine]-3′-carboxylates and pyrano[2,3-d]pyrimidines from 5-arylidene-1,3-dimethyl-barbituric acids, methyl perfluoroalk-2-ynoates and pyridines. This cascade strategy proceeded with high chemo- and regioselectivities, leading to sole cis-isomer of spirobarbiturates 4 at -10 °C and pyrano[2,3-d]pyrimidines 5 as major products in most cases at 65 °C. The mechanism was
General information
Reagents and solvents were purchased from commercially sources and used without further purification. 5-arylidene-1,3-dimethyl-barbituric acids 1 and methyl perfluoroalk-2-ynoates 2 were prepared according to the known literatures. [18,19] Melting points were recorded on a WRS-1 instrument and are uncorrected. 1H, 19F and 13C NMR spectra were recorded on a Bruker DRX- 500 MHz spectrometer. All chemical shifts are reported in parts per million downfield (positive) of the standard: C6F6 for 19F,
Acknowledgements
The authors are grateful to the National Natural Science Foundation of China (Grant No. 21672138) for their financial support.
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