Praseodymium(III)-Catalyzed Regioselective Synthesis of C3-N

Subscriber access provided by University of Rochester | River Campus & Miner Libraries

Article

Praseodymium(III)-Catalyzed Regioselective Synthesis of C3-N-substituted Coumarins with Coumarins and Azides Jiu-ling Li, Da-chao Hu, Xin-ping Liang, Ying-Chun Wang, Heng-Shan Wang, and Ying-ming Pan J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01410 • Publication Date (Web): 10 Aug 2017 Downloaded from http://pubs.acs.org on August 10, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

The Journal of Organic Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Praseodymium(III)-Catalyzed Regioselective Synthesis of C3-N-substituted Coumarins with Coumarins and Azides Jiu-ling Li,a Da-chao Hu,a Xin-ping Liang,a Ying-chun Wang,b Heng-shan Wanga,* and Ying-ming Pana,*

a

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. b

College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000, People’s Republic of China

*E-mail: [email protected]; [email protected]

Pr(OTf)3 (5 mol%)

R1

+ Z Z = O, NMe

O

R2

N3

toluene, 120 oC

H N

R2

1

R

Z

O

23 examples up to 78% yield

R2 = aryl, alkyl No ligand No additive

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-3e, 3g, 3i, 3q, 3u and 3v exhibited good anticancer activities against MGC-803, A549 and NCI-H460 cell lines with IC50 in the range of 8.75–38.54 µmol·L−1.

1

ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

INTRODUCTION Coumarins are privileged scaffolds found in many biologically active synthetic molecules and natural products, which have exhibited manifest biological activities including anti-inflammatory, anti-microbial, anti-HIV and anti-cancer activities1. 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 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-4d 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.

Scheme 1. Synthesis methods of C3-N-substituted coumarins 2


Page 2 of 20

Page 3 of 20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Selecting an appropriate amination reagent to form desired C3-aminated coumarins has been a challenge. In recently years, organic azides have been widely used for the intermolecular amination of sp3 and sp2 C–H bonds.5 Based on our previous work

6

and the work of Aubé’s group7, 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 any additives or ligands except for praseodymium(III) catalyst were required to achieve C3-N-substituted coumarins in good yields. To the best our knowledge, such method for the construction of C3-N-substituted coumarins with simple and easily acessible coumarins and azides has not been reported. Our work provided an attractive alternative method for the synthesis of C3-N-substituted coumarins derivatives.

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 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). Over 50% yields of the desired product 3a were obtained using Sm(OTf)3, 3



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Yb(OTf)3 and Pr(OTf)3 as the catalyst respectively (Table 1, entries 11-13) and the Pr(OTf)3 catalyzed reaction gave the highest yield. TMSOTf also was tested, and the TLC analysis indicated no desired product formed (Table 1, entry 14). Various solvents were tested as the reaction solvent and the results indicated that DMF, chlorobenzene and DMSO visibly inhibited the reaction (Table 1, entries 15-20). Especially, DMF completely inhibited the reaction. High reaction temperature was not able to distinctly improve the yield (Table 1, entry 13 vs. entry 18) and the yield was decreased 28% at the reaction temperature lower than 100 oC (Table 1, entry 19). Compared with 5 mol % Pr(OTf)3, 0.5 equiv of Pr(OTf)3 slightly increased the yield of 3a (Table 1, entry 20 vs. entry 13). Therefore, the reaction conditions were optimized as: catalyst, 5 mol % Pr(OTf)3; solvent, toluene; and reaction temperature, 120°C (Table 1, entry 13). The scope of organic azides 2 was then expanded under the optimum reaction condition. As summarized in Table 2, the substituents at the phenyl ring of benzyl azides slightly influenced the reactivities of the substrates, yet the desired products were produced in good yields (3a-3j). The structure of a representative product 3a8 was unambiguously confirmed by X-ray crystallographic analysis (Fig. 1). Especially, the steric hindrance did not seem to adversely affect the eaction efficiency (3g). In addition, the substitutions at the meta (3f and 3j) and ortho (3i) positions were not detrimental to the reaction yield. The fused ring (3k) and diphenyl (3l) azides were

4


Page 4 of 20

Page 5 of 20

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 1. Optimization of Reaction Conditions a

a

Entry

Catalyst (mol%)

Solvent

Temp. (oC)

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

n. d. n. d.

Praseodymium(III)-Catalyzed Regioselective Synthesis of C3-N

Recommend Documents