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Selective Removal of Aminoquinoline Auxiliary by IBX Oxidation Zhiguo Zhang, Xiang Li, Mengmeng Song, Yameng Wan, Dan Zheng, Guisheng Zhang, and Gong Chen J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01362 • Publication Date (Web): 06 Jun 2019 Downloaded from http://pubs.acs.org on June 10, 2019
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The Journal of Organic Chemistry
Selective Removal of Aminoquinoline Auxiliary by IBX Oxidation Zhiguo Zhang,*a Xiang Li,a Mengmeng Song,a Yameng Wan,a Dan Zheng,a Guisheng Zhang,*a and Gong Chen*b a
Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, Collaborative Innovation Center of Henan Province for Green
Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China. b
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China.
O PhthN R
N H R'
IBX HFIP/H 2O, 60 oC N
or 2-IBA, oxone HFIP/H 2O, 70 oC
TBN AcOH
O PhthN R
NH 2 R'
75 oC, 3 h
O PhthN R
OH R'
C− N cleavage
Abstract: 8-Aminoquinoline (AQ) is a widely used bidentate auxiliary in metal-catalyzed directed C-H functionalization reactions. Herein, we report an efficient and chemoselective method to convert various N-quinoly carboxamides to primary amides with the treatment of stoichiometric amount of 2iodoxybenzoic acid (IBX) oxidant or the combination of catalytic amount of 2-iodobenzoic acid (2-IBA) and Oxone co-oxidant in mixed solvents of H2O and HFIP. Its unique compatibility with the Phthprotected a-amino acid (aAA) substrates enhances the overall synthetic utility of AQ-directed palladiumcatalyzed C-H functionalization strategy for synthesis of complex aAAs. Key words: IBX; C(sp2)-N bond cleavage; metal-free; amino acids
Introduction 8-Aminoquinoline (AQ) has been widely used as a bidentate auxiliary in various metalcatalyzed C-H functionalization reactions.1 A number of protocols, including hydrolysis or alcoholysis of amide under acidic or basic conditions,2 Boc activation/LiOH cleavage,3
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Scheme 1. Removal of amide-linked AQ group.
ozonolysis/cleavage of imide;4 oxidative cleavage of 5-methoxy-8-aminoquinoline (MQ)5 and Ni-catalyzed alcoholysis,6 have been reported for the removal of the AQ group, forming free carboxylic acid or primary amide (Scheme 1). Despite these advances, important practical issues such as chemoselectivity, functional group tolerance and racemization of chiral Ca remain to be improved. Methods suitable for complex substrates such as peptides bearing different amide groups are still greatly desired to achieve broader application of AQ-directed C-H functionalization chemistry. Herein, we report an efficient and chemoselective method to convert various N-quinoly carboxamides to primary amides with the treatment of stoichiometric 2iodoxybenzoic acid (IBX) oxidant or the combination of catalytic 2-iodobenzoic acid (2-IBA) and Oxone co-oxidant in mixed solvent of H2O and HFIP.7 Its unique compatibility with the Phthprotected a-amino acid (aAA) substrates greatly enhances the overall synthetic utility of AQdirected palladium-catalyzed C-H functionalization strategy for synthesis of complex aAAs.
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The Journal of Organic Chemistry
Results and Discussion Recently, we demonstrated that reactions of N-aryl carboxamides featuring relatively electronrich arenes with IBX in hexafluoro-2-propanol (HFIP) and water at room temperature undergo C(aryl)-N cleavage to give primary amides in good yield and selectivity.8 Notably, mechanism of the C(aryl)-N cleavage reaction was not well understood.9 Encouraged by that discovery, we wondered whether a similar operation can be used to remove the AQ auxiliary attached to N-Phthprotected aAA substrates. Previous work from others and our lab have shown that palladiumcatalyzed AQ-directed side chain C-H functionalization offered a powerful strategy to construct various complex aAA from simple aAA precursors.2b,10 However, facile removal of the AQ group of the complex aAA products remains challenging especially for the sterically encumbered b-disubstituted compounds. As shown in Table 1, we were pleased to find that reaction of Ala substrate 1 with 2 equiv of IBX in mixed solvents of HFIP and H2O (1:1) at 60 °C for 1.5 h gave primary amide product 2 in excellent isolated yield (89%) and with excellent maintenance of chirality at Ca (> 99% ee) (entry 1). Quinoline7,8-dione 3 and 2-IBA 5 were identified as the by-products. Lower loading of IBX gave a lower conversion of starting material (entries 2 and 3). Dess-Martin periodinane (DMP, I(V)) gave a slightly lower yield than IBX (entry 4). Use of hydroxy benziodoxolone (BI-OH, I(III)) oxidant only gave a trace amount of 2 (entry 5).11 Phenyliodonium diacetate (PIDA, I(III)) or iodosobenzene (PhIO, I(III)) gave 2 in low yield (entries 6 and 7). Interestingly, quinoline-5,8-dione 4 was isolated as the only quinolone byproduct when the organoiodine (III) reagents were used. Use of ceric ammonium nitrate (CAN) gave a complex mixture (entry 8).5 The mixed solvents of HFIP and H2O in 1:1 ratio is critical to obtain a high yield of 2 (entries 1 vs 9 and 10). No reaction took place in the absence of H2O (entry 11). Other organic solvents including 2,2,2-trifluoroethanol (TFE), DMSO, THF, and DMF gave much inferior results
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Table 1. Reaction Optimization of Phth-Ala-AQ 1.a
Entry
Change from the standard conditions reagents
Time (h)
2%
1
Standard conditions A
2
3%
1%
1.5
89 (75 b)
27 c
0
IBX (2 equiv) ® (1.0 equiv)
9
37
10
50
3
IBX (2 equiv) ® (1.5 equiv)
9
61
19
32
4
IBX ® DMP
11
73
0
10
5
IBX ® BIOH
9
