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Asymmetric Synthesis of Β-Lactam Via Palladium-Catalyzed

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Asymmetric Synthesis of Β-Lactam Via Palladium-Catalyzed Page 1 of 9 ACS Catalysis 1 2 3 4 5 6 7 Asymmetric Synthesis of -Lactam via Palladium-Catalyzed 8 3 9 Enantioselective Intramolecular C(sp )–H Amidation 10 1 2 1 1 2 1 11 Hua-Rong Tong, Wenrui Zheng, Xiaoyan Lv, Gang He, * Peng Liu, * and Gong Chen * 12 1State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, 13 14 Tianjin 300071, China 15 2Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA 16 17 18 ABSTRACT: β-Lactams are important scaffolds in drug design and frequently used as reactive intermediates in 19 organic synthesis. Catalytic reactions featuring intramolecular C–H amidation of alkyl carboxamide substrates 20 could provide a straightforward disconnection strategy for β-lactams synthesis. Herein, we report a streamlined 21 method for asymmetric synthesis of β-aryl β-lactams from propanoic acid and aryl iodides via Pd-catalyzed 22 sequential C(sp3)-H functionalization. The lactam-forming reaction provides an example of PdII-catalyzed 23 enantioselective intramolecular C(sp3)–H amidation reaction, and proceeds in up to 94% ee. The use of a 2- 24 IV 25 methoxy-5-chlorophenyl iodide oxidant is critical to control the competing reductive elimination pathways of Pd 26 intermediate to achieve the desired chemoselectivity. Mechanistic studies suggest that both steric and electronic 27 effects of the unconventional aryl iodide oxidant are responsible for controlling the competing C-N vs C-C 28 reductive elimination pathways of PdIV intermediate. Key words: Pd, C−H amidation, enantioselective, -lactams, 29 bidentate auxiliary 30 31 32 33 INTRODUCTION mediated C(sp3)–H functionalization chemistry, new enantioselective reaction modes needs to be developed. 34 Palladium-catalyzed directed C(sp3)–H 35 functionalization has emerged as a powerful strategy Recently, Wu demonstrated the reaction pathway of 36 1 PdII-catalyzed AQ-directed -C–H functionalization of 37 to construct various aliphatic frameworks. Among the 3-alkyl and 3-aryl propanamide can be modulated to 38 directing groups, amide-linked bidentate auxiliaries 39 have shown unique advantage of high reactivity and give -lactam products in high yield and 40 versatility in forming new bonds.2-4 However, the chemoselectivity when excess amount of 41 complexation mode of these bidentate auxiliaries also pentafluorophenyl iodide was used as oxidant 42 caused inherent obstacles for enantiocontrol due to the (Scheme 1B).9 It was believed that the strong electron- 43 lack of suitable coordination sites on metal center. withdrawing property of C6F5 group is responsible for 44 IV Despite the challenge, recent endeavors showed such suppressing the C-C reductive elimination (RE) of Pd 45 5-8 intermediate, promoting the intramolecular C-N RE.10 46 enantio-induction is possible (Scheme 1A). Notably, II Herein, we report a streamlined method for 47 Duan reported that Pd -catalyzed aminoquinoline 48 (AQ)-directed benzylic -C–H arylation of 3- asymmetric synthesis of -aryl 49 arylpropanamides with aryl iodides can proceed in 50 moderate to good enantioselectivity using BINOL- 51 based chiral phosphoric acid or amide ligands.5a Shi 52 reported PdII-catalyzed pyridinylisopropylamine 53 (PIP)-directed enantioselective -C(sp3)-H 54 55 alkynylation of 3-alkyllpropanamides with alkynyl 56 bromide can proceed in good to excellent ee using a 57 fluoro-substituted 3,3’-di-F-BINOL ligand.6b To further 58 expand the synthetic utility of bidentate auxiliary- 59 60 ACS Paragon Plus Environment ACS Catalysis Page 2 of 9 A) Enantioselective C(sp3)-H functionalization using bidentate DG Scheme 1. Pd-catalyzed enantioselective C(sp3)–H 1 functionalization directed by N,N-bidentate auxiliary O 2 O Duan P groups. N OH 3 (AQ) O (NH ) AQ 4 2 Ar' HN H H HN + Ar'-I 5 Ar * O Ar O PdCl2(CH3CN)2 (cat) o up to 82% ee 6 Cs2CO3, p-xylene, 140 C 7 F 8 OH Shi R' 9 (PIP) N OH 3,3'-di-F- R' BINOL PIP 10 HN H H HN + F 11 R * O R O PdI2 (cat) 12 X up to 96% ee 13 B) Synthesis of -lactam via intramolecular C-H amidation 14 O N 15 R RE of PdIV: IV Pd CC vs CN 16 N 17 Ar 18 F F F 19 Wu 20 F I [Ox] 21 F R' (Q) N R' Pd(OAc)2 (cat), AgOAc 22 MW, 150 oC N HN racemic 23 H H N Ar O 24 Ar O OMe * 25 CH [Ox] Ar-I Cl I 26 arylation - Q Q 3,3'-di-F-BINOL (ligand) HN this 27 PdCl2(PhCN)2 (cat) H work N O sol, Cs CO , 100 oC 28 2 3 Ar O propanamide up to 94% ee * 29 excellent chemoselectivity 30 Table 1. Pd-catalyzed quinoline-directed enantioselective intramolecular C(sp3)-H amidation of 1 using chiral phosphate 31 ligand. 32 33 ArI (4 equiv) Ligand (20 mol%) (AQ) N N o 34 Cs2CO3 (1.5 equiv), Ar, 100 C, 48 h N + 35 HN Ar HN H H standard conditions A: N PdCl (CH CN) (10 mol%) Ph O 36 O 2 3 2 * * O I-2 & L-4, + dba (30 mol%), neat 37 1 2 3 38 Entry Change from the standard conditions [A] Yield of 2 /3 (%)a,b recovered 1 ee of 2 39 (equiv) (%) (%) 40 1 Conditions [A]: I-2 & L-4 59 (54c) / 15 25 85 41 2 [A’]: Cs2CO3 Ag2CO3 54 / 17 20 0 42 3 [A’]: Cs2CO3 K2CO3 44 / 8 47 4 43 4 [A’]: PdCl2(CH3CN)2 Pd(OAc)2 46 / 18 28 69 44 5 [A’]: Neat m-xylene 54 / 18 22 72 45 6 [A’]: Neat 1,3-di-CF3Ph 77 / 16 5 82 46 7 [A’]: No dba 59 / 18 21 73 47 8 [A’]: I-2 (4 2 equiv) 31 / 8 54 60 48 9 [A’]: AQ (Q-1) Q-2 87d / 11d 0d 86 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment Page 3 of 9 ACS Catalysis Selected results under modified conditions [A']: one of the three factors (ligand, ArI or Q) in standard conditions A is modified as specified 1 Ligand: Ar': 3',5'-di-CF3-C6H3- Q analogs: 2 F Ar' 3 O O O O O O O O 4 P P P P N N OMe O OH O NH2 O OH O OH H N 5 2 H2N F Ar' Q-1 (AQ) Q-2 (MQ) 6 L-1 L-2 L-3 L-4 7 2/3 (%): 38/7 2/3 (%): 20 / 6 2/3 (%): 52/11 2/3 (%): 59/15 2/3 (%): 59/15 2/3 (%): 87/11d ee% of 2: 11 ee% of 2: 56 ee% of 2: 52 ee% of 2: 85 ee% of 2: 85 8 ee% of 2: 86 9 ArI: F 10 F C CF F F 3 3 MeO Cl CF3 Cl 11 F F F F MeO MeO MeO MeO OMe 12 I I I I I I I I I I I I 13 I-1 I-2 I-3 I-4 I-5 I-6 I-7 I-8 I-9 I-10 I-11 I-12 2/3 (%): 35/3 2/3 (%): 59/15 2/3 (%): 32/0 2/3 (%): 13/64 2/3 (%): 19/33 2/3 (%): 43/11 2/3 (%): 55/6 2/3 (%): 58/0 2/3 (%): 26/34 2/3 (%): 15/0 2/3 (%): 0/0 2/3 (%): 9/40 14 ee% of 2: 8 ee% of 2: 85 ee% of 2: 46 ee% of 2: 60 ee% of 2: 58 ee% of 2: 54 ee% of 2: 60 ee% of 2: 55 ee% of 2: 63 ee% of 2: 57 ee% of 2: 79 15 1 16 (a) Yields are based on H-NMR analysis of reaction mixture on a 0.1 mmol scale. (b) ee was determined by HPLC using a chiral 17 column. (c) Isolated yield. (d) Product bearing the corresponding modified Q group. See SI for additional screening conditions 18 and ArI oxidants. 19 -lactams via PdII-catalyzed quinoline-directed enantioselective, a proper combination of chiral ligand 20 enantioselective intramolecular C(sp3)-H amidation of and oxidant need to be exploited. 21 3-arylpropylamines using 3,3’-di-F-BINOL chiral During our recent re-investigation of PdII-catalyzed 22 ligand6b,11,12 and 2-methoxy-5-chlorophenyl iodide as oxidant. 23 AQ-directed enantioselective C(sp3)-H arylation of 3- 24 RESULTS AND DISCUSSION phenylpropanamide 1 with aryl iodides, we noticed 25 that -lactam 2 was formed as a side product in varied 26 -Lactams are important scaffolds in drug design yield and enantioselectivity using chiral phosphate 27 and frequently used as reactive intermediates in ligands (Table 1).5c While pentafluoro phenyl iodide I- 28 13,14 organic synthesis. C-H functionalization strategy 1 oxidant gave the best reactivity and chemo- 29 via metal-catalyzed intramolecular C-H carbene selectivity (lactam vs C-H arylation) in Wu’s racemic 30 insertion has long been employed for synthesis of - - system (Pd(OAc)2 as catalyst and AgOAc as I 31 lactams.15 In recent years, Pd-catalyzed intramolecular 32 scavenger at 150 oC),9a it gave poor reactivity under the C(sp3)-H functionalization reactions including C-H 33 conditions of PdCl2(CH3CN)2 catalyst, Cs2CO3 base 16 17 34 alkylation, carbonylative amination , and chiral phosphate ligand at lower temperature (100 18 0/II II/0 35 carbamoylation process via Pd or Pd catalytic oC), which are critical to achieve high 36 cycles have offered new ways to construct -lactams. enantioselectivity in this AQ-directed system.5 In 37 Among these reactions, enantioselective comparison, 3,5-di-CF3-phenyl iodide (I-2) stood out 38 16 transformations based on C-H alkylation and among the electron-deficient ArI oxidants tested, 39 18 carbamoylation have also been demonstrated using offering the best balance of chemo- and 40 chiral phosphonite and phosphoramidites ligand 41 enantioselectivity.
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