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Iron-Catalyzed Aerobic Dehydrogenative Kinetic Resolution of Cyclic Secondary Amines Ran Lu, Liya Cao, Honghao Guan, and Lei Liu J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b00615 • Publication Date (Web): 27 Mar 2019 Downloaded from http://pubs.acs.org on March 27, 2019
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Journal of the American Chemical Society
Iron-Catalyzed Aerobic Dehydrogenative Kinetic Resolution of Cyclic Secondary Amines Ran Lu,†,§ Liya Cao,†,§ Honghao Guan,‡,§ Lei Liu*,†,‡ †
School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China Supporting Information Placeholder ‡
ABSTRACT: A nonenzymatic iron-catalyzed dehydrogenative kinetic resolution of cyclic secondary amines using air as an oxidant has been reported. The economical and practical method is applicable to a series of cyclic benzylic amines, including 5,6dihydrophenanthridines and 1,2-dihydroquinolines, with diverse functional groups at the α position in high yields with excellent enantioselectivities. The direct dehydrogenative kinetic resolution of advanced intermediates of bioactive molecules that are difficult to access using existing catalytic asymmetric synthetic strategy was also demonstrated.
INTRODUCTION Catalytic nonenzymatic kinetic resolution (KR) of racemic starting materials represents a powerful and practical alternative to prepare valuable optically pure targets, especially in cases where other methods are not possible or provide insufficient enantiocontrol.1 Enantiomerically pure α-substituted cyclic amines are key constituents of bioactive natural products and synthetic pharmaceuticals. Present nonenzymatic KR of cyclic amines dominantly focused on enantioselective N-acylation strategy (Figure 1A).2-5 Dehydrogenation of secondary amines to imines is one of the most common transformations in chemistry.6 Transition-metal catalyzed dehydrogenative KR of secondary alcohols to furnish prochiral ketones has been well studied.7 In sharp contrast, pure chemically catalytic dehydrogenative KR of secondary amines remains scarce, principally due to two essential features of the NH moiety including the susceptibleness to oxidation and potential deactivation of chiral transition metal catalysts.8 To avoid such two issues, Akiyama developed a delicate chiral phosphoric acid catalyzed dehydrogenative KR of cyclic secondary amines based on transfer hydrogenation to imines (Figure 1B).9 However, no example of metal catalyzed dehydrogenative KR of secondary amines has been disclosed to date. On the other hand, the development of eco-friendly oxidative transformations using earthabundant metal catalyst is a broad goal in chemistry.10 In this context, molecular oxygen in air is the most ideal oxidant, and iron is the second most abundant metal in the earth’s crust.11,12 Seminal work from the Katsuki group demonstrated the possibility of iron(salan)-catalyzed asymmetric aerobic oxidation.13 Herein we communicate the first nonenzymatic iron-catalyzed dehydrogenative KR of cyclic amines using air as an oxidant (Figure 1C). RESULTS AND DISCUSSION
5,6-Dihydrophenanthridines with diverse α substituent patterns are present in a number of bioactive molecules possessing a wide range of pharmacological activities.14 However, surprising few catalytic enantioselective methods to access enantiopure compounds have been reported, and each method is typically suitable A) KR via N-acylation approach (Fu, Hou, Bode, Kozlowski) FG
n
R N H H
cat*, R'COX
n
FG N H
FG
+
R
n
R N COR'
B) Organocatalytic ODKR via transfer hydrogenation to imine (Akiyama) cat. chiral phosphoric acid
R N H H
N Ph
Ar
HN Ph
R Ar
R
+
N H
N H
H
C) Iron-catalyzed ODKR using air as oxidant (This work) Fe cat*, air additive N R H H
+ N H
R
N
R
challenges: NH moiety prone to oxidation and deactivation of chiral metal catalyst
Figure 1.Overview of KR of cyclic secondary amines for a specific substituent pattern of functionalities in the αposition as well as the heterocyclic skeleton.15 Therefore, dehydrogenative KR of 5,6-dihydrophenanthridine 1a under air at ambient temperature was selected as the model reaction for the search of chiral iron catalyst system (Table 1). No reaction was observed when Fe(salen) (R,R)-C1 was used as the catalyst (entry 1). Delightedly, Fe(salan) (R,R)-C2 showed oxidation catalysis reactivity, though no enantioselectivity was obtained (entry 2).16 Binuclear iron complex appeared to be a better catalyst than the parent monomer, and Fe(salan) (R,R)-C3 catalyzed dehydrogenative KR reaction proceeded providing recovered (R)-1a with 10% ee at the conversion of 30% (entry 3). An extensive investigation of additive effect revealed that catalytic amount of electron-rich phenol was beneficial for improving the reaction efficiency, and 4-methoxy-1-naphthol A5 was found to be optimal (entries 4-9). Further fine-tuning the binuclear iron complex identified (R,R)C9 bearing a diphenylethylenediamine unit to be the superior catalyst, furnishing recovered (R)-1a in 46% yield with 98% ee (entries 10-16). Using pure oxygen as the terminal oxidant provided a comparable result to that of the reaction with air (entry 17).
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Table 1. Reaction condition optimizationa
entry
catalyst
additive
conv. (%)b
ee (%)c
krel
1
C1
–
