This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
Article Cite This: ACS Omega 2018, 3, 8243−8252
http://pubs.acs.org/journal/acsodf
Copper-Catalyzed Benign and Efficient Oxidation of Tetrahydroisoquinolines and Dihydroisoquinolines Using Air as a Clean Oxidant Bo Zheng,†,‡ Tien Ha Trieu,‡ Feng-Lei Li,‡ Xing-Liang Zhu,‡ Yun-Gang He,‡ Qi-Qi Fan,‡ and Xiao-Xin Shi*,†,‡ Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, and ‡Department of Pharmaceutical Engineering, School of Pharmacy, East China University of Science and Technology, 130 Mei-Long Road, Shanghai 200237, P. R. China
Downloaded via 5.189.202.59 on July 30, 2018 at 05:34:45 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
†
S Supporting Information *
ABSTRACT: A green chemical method for mild oxidation of 1,2,3,4tetrahydroisoquinolines (THIQs) and 3,4-dihydroisoquinolines (DHIQs) has been developed using air (O2) as a clean oxidant. DHIQs and THIQs could be efficiently oxidized to isoquinolines in dimethyl sulfoxide at 25 °C under an open air atmosphere with CuBr2 (20 mol %) as the catalyst; different bases [NaOEt and/or 1,8diazabicyclo[5,4,0]undec-7-ene] were used for the reaction according to the patterns of substituents (R1, R2).
1. INTRODUCTION
Copper is a cost-effective transition metal with low toxicity, and air (O2) is an eco-friendly clean oxidant. Hence, increasing amounts of copper-catalyzed aerobic oxidation methods for various compounds have been recently developed.18 Herein, we report an efficient, practical, and very mild method for copper-catalyzed oxidation of THIQs and DHIQs using air (O2) as the clean oxidant.
Isoquinolines are a very important kind of compounds because of the following reasons. First, isoquinoline alkaloids are widely spread in nature and have been isolated from many natural resources.1 Second, isoquinoline alkaloids and their synthetic congeners have shown a broad spectrum of bioactivities.2 Third, isoquinolines have been used as versatile intermediates in comprehensive organic transformations.3 Fourth, chiral isoquinoline ligands and N-oxides have been successfully used in asymmetric catalysis.4 Fifth, isoquinolines or their metal complexes have also been used as various functional materials.5 In view of the abovementioned wide utilities of isoquinolines in drug discovery, organic chemistry, and material science, development of new methods for the synthesis of isoquinolines is of considerable interest and has already attracted much attention from many chemists in the recent years.6 Because 1,2,3,4-tetrahydroisoquinolines (THIQs) and 3,4dihydroisoquinolines (DHIQs) can be readily prepared via Pictet−Spengler reaction7 or Bischler−Napieralski cyclization,8 dehydrogenation or oxidation of THIQs and DHIQs might be good approaches for the synthesis of isoquinolines. However, dehydrogenation of THIQs/DHIQs usually needed precious metallic catalysts (Pd, Ru, Ir, etc.) and higher temperature;9 oxidation of THIQs/DHIQs often suffered from the use of poisonous and hazardous strong oxidants such as KMnO4,10 IBX,11 PCC,12 (KSO3)2NO,5f,13 NaIO4,14 V2O5,15 MnO2,16 and PhSSPh.17 To overcome these drawbacks, development of an efficient, mild, and eco-friendly method for the conversion of THIQs and DHIQs to isoquinolines is highly desirable and remains to be a challenging task for organic chemists. © 2018 American Chemical Society
2. RESULTS AND DISCUSSION At first, we attempted to find out the optimized reactions for the Cu-catalyzed oxidative conversion of THIQs to isoquinolines. With the oxidative conversion of 1-phenyl-6,7dimethoxy-THIQ 1a to 1-phenyl-6,7-dimethoxy-DHIQ 2a and 1-phenyl-6,7-dimethoxyisoquinoline 3a as the model reaction, we tried the reaction under various conditions, and the results are summarized in Table 1. As can be seen from Table 1, a copper catalyst was necessary for the reaction, otherwise no reaction occurred (Table 1, entry 1). When 20 mol % of CuBr2 was used as the catalyst and 1,8diazabicyclo[5,4,0]undec-7-ene (DBU) was used as the base, the reaction occurred in dimethyl sulfoxide (DMSO) to produce DHIQ 2a in high yield, but only trace amount of desired isoquinoline 3a was detected (entries 2 and 3). If a strong base such as NaOEt or NaOMe was further added, the reaction took place smoothly at 25 °C to afford the desired isoquinoline 3a in high yield (Table 1, entries 4 and 5). Other copper salts including CuCl2, Cu(OAc)2, CuCl, CuBr, CuSO4, Received: April 29, 2018 Accepted: June 6, 2018 Published: July 24, 2018 8243
DOI: 10.1021/acsomega.8b00855 ACS Omega 2018, 3, 8243−8252
ACS Omega
Article
Table 1. Optimization of Reaction Conditions for the Cu-Catalyzed Aerobic Oxidative Conversion of 1-Phenyl-6,7-dimethoxyTHIQ 1a to 1-Phenyl-6,7-dimethoxyisoquinoline 3aa
entry
catalystb
base-1/base-2 (equiv)
solvent
T (°C)
t1/t2 (h)
yields (%)c (2a/3a)
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
none CuBr2 CuBr2 CuBr2 CuBr2 CuCl2 Cu(OAc)2 CuBr CuCl CuSO4 Cu2(OH)2CO3 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2 CuBr2
DBUd(2.0)/NaOEt(2.0) DBU(2.0)/none DBU(2.0)/DBU(2.0) DBU(2.0)/NaOEt(2.0) DBU(2.0)/NaOMe(2.0) DBU(2.0)/NaOEt(2.0) DBU(2.0)/NaOEt(2.0) DBU(2.0)/NaOEt(2.0) DBU(2.0)/NaOEt(2.0) DBU(2.0)/NaOEt(2.0) DBU(2.0)/NaOEt(2.0) DBNg(2.0)/NaOEt(2.0) DMAPh(2.0)/NaOEt(2.0) Py(2.0)/NaOEt(2.0) Et3N(2.0)/NaOEt(2.0) none DBU(2.0)/K2CO3(2.0) DBU(2.0)/Na2CO3(2.0) DBU(2.0)/NaOEt(2.0) DBU(2.0)/NaOEt(2.0) DBU(2.0)/NaOEt(2.0) DBU(2.0)/NaOEt(2.0) DBU(2.0)/NaOEt(2.0) DBU(1.0)/NaOEt(1.0) DBU(1.0)/NaOEt(1.0) DBU(1.0)/NaOEt(1.0) DBU(0.5)/NaOEt(1.0) DBU(0.5)/NaOEt(0.5)
DMSOe DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMFi CH3CN EtOH THFj DMEk DMSO DMSO DMSO DMSO DMSO
25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 25 35 45 65 65 80
10/8 10/0 10/10 10/8 10/8 10/8 10/8 10/8 10/8 10/8 10/8 10/8 10/8 10/8 10/8 25/0 10/12 10/12 10/10 10/10 10/10 10/10 10/10 15/15 12/12 10/10 15/10 12/12
0/0 93/
