Article pubs.acs.org/joc
Praseodymium(III)-Catalyzed Regioselective Synthesis of C3‑NSubstituted Coumarins with Coumarins and Azides Jiu-ling Li,† Da-chao Hu,† Xin-ping Liang,† Ying-Chun Wang,‡ Heng-Shan Wang,*,† and Ying-ming Pan*,† †
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, People’s Republic of China ‡ College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, People’s Republic of China S Supporting Information *
ABSTRACT: A series of C3-N-substituted coumarins were synthesized in good yields directly from coumarins and azides in the presence of Pr(OTf)3 without any additives or ligands needed. The selected compounds 3a, 3c−e, 3g, 3i, 3q, 3u, and 3v exhibited good anticancer activities against MGC-803, A549, and NCI-H460 cell lines with IC50 in the range 8.75−38.54 μmol L−1.
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INTRODUCTION Coumarins are privileged scaffolds found in many biologically active synthetic molecules and natural products, which have exhibited manifest biological activities including anti-inflammatory, antimicrobial, anti-HIV, and anticancer activities.1 Therefore, a remarkably large number of studies have been reported in recent years, aiming to synthesize and screen coumarin compounds for drug discovery.2 It has been revealed that the C3-N-substituted coumarins are active pharmaceutical ingredients and important intermediates to construct highly conjugated structures.1f,2,3 However, there are only a few methods to synthesize C3-N-substituted coumarins.3,4 Nucleophilic substitution, such as amino-substituted coumarins coupling with benzyl bromide,3a and nucleophilic substitution of benzylamine with halogenated coumarins,4b−d and other traditional methods (Scheme 1) are the most widely used methods.4a For these synthesis methods, the reaction substrates are difficult to obtain and the scope of substrates is narrow.
Therefore, it is necessary to explore novel and efficient methods for the synthesis of C3-N-substituted coumarins. Selecting an appropriate amination reagent to form the desired C3-aminated coumarins has been a challenge. In recent years, organic azides have been widely used for the intermolecular amination of sp3 and sp2 C−H bonds.5 On the basis of our previous work6 and the work of Aubé’s group,7 it is expected that azides can be used to aminate coumarins to produce the C3-N-substituted coumarins. In the present work, we reported a facile method for the synthesis of C3-N-substituted coumarins via Pr(III)-catalyzed azide−alkene 1,3-dipolar cycloaddition/ring cleavage/1,2-H migration/denitrogenation, followed by 1,3-H migration. No additives or ligands except for the praseodymium(III) catalyst were required to achieve C3-N-substituted coumarins in good yields. To the best of our knowledge, such a method for the construction of C3-N-substituted coumarins with simple and easily accessible coumarins and azides has not been reported. Our work provided an attractive alternative method for the synthesis of C3-N-substituted coumarin derivatives.
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Scheme 1. Synthesis Methods of C3-N-Substituted Coumarins
RESULTS AND DISCUSSION We initiated our study with the model reaction of coumarin 1a with benzyl azide 2a to optimize the reaction conditions (Table 1). No reaction was observed in the absence of a catalyst or with Pd(OAc)2 as the catalyst (Table 1, entries 1 and 2). Other metal catalysts including Cu(OTf)2, Zn(OTf)2, AgOTf, AuBr3, RhCl3, In(OTf)3, Ce(OTf)3, and Sc(OTf)3 were tested, and no desired products were achieved (Table 1, entries 3−10). Yields greater than 50% of the desired product 3a were obtained using Sm(OTf)3, Yb(OTf)3, and Pr(OTf)3 as the catalysts (Table 1, entries 11−13), and the Pr(OTf)3-catalyzed reaction gave the Received: June 7, 2017 Published: August 10, 2017
© 2017 American Chemical Society
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DOI: 10.1021/acs.joc.7b01410 J. Org. Chem. 2017, 82, 9006−9011
Article
The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa
entry
catalyst (mol %)
solvent
temp (°C)
yieldb (%, 3a)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
none Pd(OAc)2 (5) Cu(OTf)2 (5) Zn(OTf)2 (5) AgOTf (5) AuBr3 (5) RhCl3 (5) In(OTf)3 (5) Ce(OTf)3 (5) Sc(OTf)3 (5) Sm(OTf)3 (5) Yb(OTf)3 (5) Pr(OTf)3 (5) TMSOTf (5) Pr(OTf)3 (5) Pr(OTf)3 (5) Pr(OTf)3 (5) Pr(OTf)3 (5) Pr(OTf)3 (5) Pr(OTf)3 (50)
toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene DMF PhCl DMSO toluene toluene toluene
120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 120 140 100 120
nd nd
