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Palladium/L-Proline-Catalyzed Enantioselective #Arylative Desymmetrization of Cyclohexanones Ren-Rong Liu, Bao-Le Li, Jun Lu, Chong Shen, Jian-Rong Gao, and Yi-Xia Jia J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b01214 • Publication Date (Web): 14 Apr 2016 Downloaded from http://pubs.acs.org on April 14, 2016
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Journal of the American Chemical Society
Palladium/L‐Proline‐Catalyzed Enantioselective ‐Arylative Desymmetrization of Cyclohexanones Ren‐Rong Liu,† Bao‐Le Li,† Jun Lu, Chong Shen, Jian‐Rong Gao, and Yi‐Xia Jia* College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China Supporting Information Placeholder ABSTRACT: A highly enantioselective palladium/L‐proline‐ catalyzed ‐arylative desymmetrization of cyclohexanones was developed. The new strategy for ‐arylation reaction led to a series of optically active morphan derivatives bearing ‐ carbonyl tertiary stereocenters in good yields and excellent enantioselectivities (up to 99% ee).
Transition‐metal‐catalyzed enantioselective ‐arylation of carbonyls represents one of the most important approaches 1 to optically active ‐aryl carbonyl compounds. Since seminal 2 studies from the groups of Buchwald, Hartwig, and Muria, a range of carbonyl compounds have been investigated in the enantioselective cross‐coupling with aryl halides, including 3 4 5 6 ketones, aldehydes, esteres, and amides. However, the aforementioned approaches are very limited to the construc‐ tion of quaternary carbon stereocenters as the benzylic ‐H atom of tertiary carbon stereocenter is more acidic and prone to racemization under basic conditions. In addition, the de‐ mand of commercially unavailable chiral ligands still remains an issue for these transformations. It’s noteworthy that a few other catalytic enantioselective arylation protocols to gener‐ ate ‐carbonyl benzylic tertiary stereocenters have been de‐ veloped, which include 1) cross‐coupling of ‐halo carbonyls 7 with arylmetal reagents, 2) electrophilic coupling of diaryli‐ odonium salts with silyl ketenimides, silyl enolates, or alde‐ 8 hydes, 3) cross‐coupling of aryl triflates with silyl ketene 9 acetals or tin enolates. In comparison, the direct coupling of readily available aryl halides with ‐C‐H bonds of carbonyl moieties to form the tertiary carbon stereocenters is highly attractive from the viewpoint of atom economy and step efficiency. In recent years, cooperative catalysis by merging transi‐ tion‐metal and organic catalysis has enabled a series of new 10 enantioselective transformations. Among this, the com‐ bined use of palladium/enamine catalysis has been widely 11 investigated for asymmetric allylic alkylation reactions. Consequently, we envisaged an enantioselective ‐arylation of ketones might be realized by this strategy through the formation of enamine intermediates and subsequent Heck
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arylation (eq a, Scheme 1). Herein, we communicate a pal‐ ladium/L‐proline‐catalyzed intramolecular ‐arylative desymmetrization of cyclohexanones, which delivers a series of chiral compounds containing hexahydro‐2,6‐methano‐1‐ benzazocine structural motifs in excellent enantioselectivi‐ 13,14 ties (eq b, Scheme 1). It is worth to note that racemic vari‐ 15 ant of this reaction has been established by the Solé’s group. The resulting unique bridged ring system is analogous to the 16 important morphan scaffold (2‐azabicyclo[3.3.1]nonane) and frequently occurring in many natural products, such as 17 sespenine, aspernomine, and strychnochromine (Figure 1). More importantly, ‐carbonyl tertiary stereogenic center is generated in this bridged ring system and its racemization is prevented due to the rigid structural property.
Scheme 1. Palladium/enamine catalysis for ‐ arylation of ketone a) Proposed -arylation of ketone via palladium/enamine catalysis * N
Pd(0) Ar-X
* N PdX Ar
* N base
* N Ar or
O Ar H2O
Ar
Pd(0) b) -Arylative desymmetrization of cyclohexanone O H Pd(0)/L X O chiral amine Ar Ar N N H R R
Figure 1. Selected natural products containing hexahy‐ dro‐2,6‐methano‐1‐benzazocine framework At the outset, 4‐(benzyl(2‐bromophenyl)amino)cyclohex‐ anone 1a was prepared and its intramolecular arylation reac‐ tion was studied (Table 1). The first test began with the reac‐ tion of 1a under the catalysis of 5 mol% of Pd(OAc)2/12 mol% of achiral PPh3 ligand combined with 10 mol% of L‐proline in
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THF with Cs2CO3 (1.5 equiv) as a base. As expected, the de‐ sired arylation product 2a was isolated in 60% yield and with o 23% ee value at 85 C (oil bath) for 48 h (entry 1). When t stronger base NaO Bu was used, the ee was even poor in spite of an increased yield (entry 2). In contrast, the enantioselec‐ tivity was enhanced to 60% when a weaker base K3PO4 was used, while no reaction occurred in the presence of K2CO3 (entries 3‐4). Subsequent experiments revealed that the addi‐ tion of 1.5 equiv acid was beneficial for the enantioselectivi‐ ties. A range of carboxylic acid additives resulted in the products over 70% ee but showed different reactivity (entries 5‐11). Acetic acid led to an excellent yield with moderate en‐ antioselectivity (entry 10). As a comparison, higher enanti‐ oselectivity but relatively lower yield were observed for TFA (entry 9). TsOH was proved to be an inferior additive (entry 11). Followed investigation revealed a significant solvent ef‐ fect. Poor yield was observed when the reaction was per‐ formed in DMSO and poor ee value was detected in toluene (entries 12‐13). To our delight, however, excellent yield and enantioselectivity were achieved in MeOH and in this case TFA additive led to comparable results as acetic acid (entries 14‐15). Moreover, the reaction was also dramatically affected by the nature of the catalyst and other palladium precursors (Pd(dba)2 and Pd(PPh3)4) delivered inferior results (entries o 16‐17). Finally, lowering the temperature to 70 C resulted in a significant lower yield (entry 18). Therefore, the optimal reaction conditions were determined as the followings: Pd(OAc)2 (5 mol%), PPh3 (12 mol%), L‐proline (10 mol%), 1.5 equiv K3PO4, and 1.5 equiv CH3CO2H in MeOH (2.0 mL) at 85 o C for 48 h.
Table 1. Optimization of the reaction conditionsa
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e
K3PO4
MeOH
CH3CO2H
50
76
f
K3PO4
MeOH
CH3CO2H
31
nd
17 18 a
Reaction conditions: 1a (0.2 mmol), Pd(OAc)2 (5 mol%), PPh3 (12 mol%), L‐proline (10 mol%), base (0.3 mmol), and o the solvent (2.0 mL) in a sealed Schlenk tube at 85 C (oil b bath) for 48 h; nr = no reaction, nd = not detected. Isolated c d yield. Determined by chiral HPLC. With 5 mol% Pd(dba)2 e instead of Pd(OAc)2. With 5 mol% Pd(PPh3)4 instead of f o Pd(OAc)2 and PPh3. At 70 C (oil bath) for 60 h. Under the optimal conditions, we examined the scope of this reaction and the results were shown in Scheme 2. The effect of halogen was first examined. In comparison with the bromo‐substrate, the yield and ee were both slightly de‐ creased for the reaction of iodo‐substrate. However, almost no reaction took place for the chloro‐substrate under the standard condition. In this case, modification of PPh3 to PCy3 led to product 2a in 50% yield and 60% ee. Next, the influ‐ ence of the substituted groups at C4‐C6 position on the ben‐ zene ring of aniline was examined. Electron‐withdrawing and electron‐donating substituents were generally well‐tolerated, affording the desired products 2b‐2m bearing alkyl, halide, alkoxyl, and ester functionalities in good yields and excellent enantioselectivities. Remarkably, a free carboxylic acid was compatible in the reaction and product 2h was obtained in 96% ee. Moreover, N‐protecting groups have a remarkable effect on the reaction outcome. The reactions of substrates bearing methyl or substituted benzyl protecting groups pro‐ ceeded smoothly to afford products 2n‐2r in good yields and excellent enantioselectivities. However, the reaction was influenced unfavorably by N‐benzoyl and N‐ethoxycarbonyl groups, which afforded products 2s and 2t in remarkably lower yields and enantioselectivities.
Scheme 2. Substituent effect of substrate 1a yield (%)b 60
ee (%)c 23
‐‐
71
