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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 CC vs CN 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 CH [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. A 59% yield of 2 with 85% ee along respectively. In comparison, catalytic reactions 42 with 15% yield of C-H arylation product 3 were 43 featuring C-H amidation of alkyl carboxamide obtained using 4 equiv of I-2, 20 mol% of 3,3’-di-aryl substrates could provide a more straightforward 44 (3,5-di-CF3-C6H3) substituted BINOL-derived 45 disconnection strategy. Racemic versions of this type phosphate ligand L46a and 30 mol% of 46 of transformation have been achieved via promoting dibenzylideneacetone (dba) additive at 100 oC without 47 C-N RE from high valent metal intermediates under any solvent 48 oxidative conditions.19, 20 To make this transformation 49 Table 2. Pd-catalyzed quinoline-directed enantioselective intramolecular C(sp3)-H amidation of 1 using chiral BINOL 50 ligand. 51 52 ArI (4 equiv) (AQ) N Ligand (20 mol%) N o 53 Cs2CO3 (1.5 equiv), Ar, 100 C, 48 h N + HN Ar HN 54 H H standard conditions B: N Ph O 55 O PdCl2(PhCN)2 (10 mol%) * * O I-6 & L-9, 1,3-di-CF3Ph/t-AmOH (3/2) 56 1 2 3-(1-12) 57 Entry Change from the standard conditions [B] Yield of 2 {ee%}/3 a,b recovered 1 ee of 2 58 59 60 ACS Paragon Plus Environment ACS Catalysis Page 4 of 9

(equiv) (%) (%) 1 1 Conditions [B]: I-6 & L-9 90 (84c) / 6 ~1 89 2 2 [B’]: Cs2CO3  Ag2CO3 13 / 2 76 55 3 3 [B’]: PdCl2(PhCN)2  Pd(OAc)2 59 / 13 23 74 4 4 [B’]: PdCl2(PhCN)2  PdCl2(CH3CN)2 88 / 5 ~1 82 5 5 [B’]: 1,3-di-CF3Ph/tAmOH  m-xylene 65 / 20 10 46 6 6 [B’]: I-6 (4  2 equiv) 72 / 14 12 81 7 7 [B’]: AQ (Q-1) Q-2 92 (88c) / 5d 0 87 8 8 [B’]: AQ (Q-1) Q-9 92 (89c) / 6d 0 94 9 Selected results under conditions [B']: one of the three factors (ligand, ArI, or Q) in conditions B is modified as specified

10 Ligand: Ar': 3',5'-di-CF3-C6H3- Cl Ph F 11 Ar'

12 OH OH OH OH OH OH OH OH 13 OH OH

14 Cl Ph F Ar' 15 L-5 L-6 L-7 L-8 L-9 16 2/3 (%): 31/11 2/3 (%): 75/15 2/3 (%): 82/14 2/3 (%): 74/16 2/3 (%): 90/6 ee% of 2: 53 ee% of 2: 73 ee% of 2: 62 ee% of 2: 69 ee% of 2: 89 17 ArI:

18 F F C CF 19 F F 3 3 MeO Cl CF3 Cl

20 F F F F MeO MeO MeO MeO OMe I 21 I I I I I I I I I I I I-1 I-2 I-3 I-4 I-5 I-6 I-7 I-8 I-9 I-10 I-11 I-12 22 2/3 (%): 55/0 2/3 (%): 80/12 2/3 (%): 95/0 2/3 (%): 12/87 2/3 (%): 42/53 2/3 (%): 90/6 2/3 (%): 91/4 2/3 (%): 90/3 2/3 (%): 36/57 2/3 (%): 26/0 2/3 (%): 0/0 2/3 (%): 8/88 23 ee% of 2: 80 ee% of 2: 83 ee% of 2: 84 ee% of 2: 87 ee% of 2: 84 ee% of 2: 89 ee% of 2: 87 ee% of 2: 77 ee% of 2: 83 ee% of 2: 49 ee% of 2: 81 24 Q analogs: Ar'': 25 CF3 MeO N N Cl 26 N OMe N NO2 N I N Ar'' OMe

27 H2N H N H N H2N H N CF 2 2 2 H2N 3 OMe OMe 28 Q-1 (AQ) Q-2 (MQ) Q-3 Q-4 Q-5 Q-6 Q-7 Q-8 Q-9 (PQ) Q-10 29 2/3 (%): 90/6 2/3 (%): 92/5 2/3 (%): 0/0 2/3 (%): 84/9 2/3 (%): 81/10 2/3 (%): 95/4 2/3 (%): 88/7 2/3 (%): 93/6 2/3 (%): 92/6 2/3 (%): 95/4 ee%f o 2: 89 ee% of 2: 87 ee% of 2: 85 ee% of 2: 79 ee% of 2: 82 ee% of 2: 82 ee% of 2: 72 ee% of 2: 94 30 ee% of 2: 87 31 (a) Yields are based on 1H-NMR analysis of reaction mixture on a 0.1 mmol scale. (b) ee was determined by HPLC using a chiral 32 column. (c) Isolated yield . (d) Product bearing the corresponding modified Q group. See Supporting Information for additional 33 screening conditions and ArI oxidants. 34 (entry 1, standard conditions A). The structure of the best results. Reaction of 1 with 4 equiv of I-6, 10 35 quinoline auxiliary also had an impact on reactivity mol% of PdCl (PhCN) catalyst, 20 mol% of L-9 in the 36 2 2 21 o 37 and ee. Q-2 (MQ) , a C5-methoxy analog of AQ, gave mixed solvent of 1,3-di-CF3-Ph and tAmOH at 100 C 38 lactam product in significantly improved yield and ee gave 2 in 90% yield with 89% ee along with 6% of 39 (entry 9). Beside electron-deficient ArIs, we found arylation byproduct (entry 1, standard conditions B). 40 electron-rich ArIs bearing various ortho substituents The use of MQ gave comparable results to AQ under 41 can also promote the formation of 2 to varied extent. conditions B’ (entry 1 vs 7). Q-9 (PQ) with an ortho- 42 For example, I-10 bearing an ortho-methyl group methoxyphenyl group on the C5 of AQ gave lactam 43 exclusively gave cyclization product but low reactivity. product with the highest ee of 94% (entry 8). It is also 44 I-8 bearing two ortho-MeO groups gave 2 in 58% yield worth noting that 1) Use of Cs CO is critical for 45 2 3 23 46 and with moderate ee. obtaining high ee. 2) Addition of Ag additives e.g. 47 As outlined in Table 2, we were pleased to find that Ag2CO3 gave significantly decreased ee (entry 2). 3) 48 use of chiral BINOL ligands also gave moderate to Use of Pd(OAc)2 catalyst gave lower ee (entry 3). 4) 4 49 good enantioselectivity with both electron rich and equiv of ArI is needed to achieve high yield (entry 6). 50 poor ArI oxidants.6b, 11, 12 I-5 bearing an ortho-MeO Substrate scope. The reaction scope using AQ, MQ 51 group gave more 2 than I-4 bearing a meta-MeO and I- and PQ auxiliary groups under the optimized reaction 52 53 12 (PhI). As seen in I-6 and I-7, installation of electron- conditions B were summarized in Scheme 2. The 3- 54 withdrawing group on C5 position of I-5 further arylpropanamide starting materials can be readily 55 improved the chemo-selectivity. Due to the low cost, I- prepared via Pd-catalyzed mono-selective β C−H 56 6 was chosen for further reaction optimization.22 The arylation of the corresponding auxiliary-coupled 57 combination of di-F-BINOL ligand L-9 and L-6 gave propanamide precursors with aryl iodides (see SI for 58 59 60 ACS Paragon Plus Environment Page 5 of 9 ACS Catalysis

details).5c, 19a The performance of auxiliaries slightly amination gave compound 2c. Interestingly, the PQ 1 fluctuates depending on the β-aryl groups. In general, group can also be removed by the treatment of CAN to 2 27 3 substituents on the meta and para positions of aryl give 17 in moderate yield and with 94% ee. The ee 4 groups were well tolerated (see 4, 8). Ortho-substituted value of 17 was increased to 99% after one 5 or electron-deficient aryl groups gave significantly recrystallization in hexanes and ethyl acetate. Amide 6 lower yield and ee (14, 11, 15). As exemplified by 13, activation of 17 by Boc and cleavage with LiOH gave 7 intramolecular amination of the unactivated C(sp3)-H phenyl substituted β-amino acid 20 in good yield and 8 bond gave very low yield and moderate ee under the 99% ee.28 Hartwig-Buchwald coupling of 17 with aryl 9 standard conditions.24 iodide gave 21 in 90% yield. 10 R'' A) I-6 (4 equiv) 1) PhI (1.5 equiv), Pd(OAc)2 (10 mol%), 11 (MQ) CuF (1.5 equiv), DMA, 100 oC, 76% N R'' L-9 (20 mol%) 2 12 PdCl2(PhCN)2 (10 mol%) N OMe mono-selective  C-H arylation H N (Q') Cs2CO3 (1.5 equiv) (mono:di = 10:1) N 13 HN N H H Ph O Ar O H HN 2) Cyclization, 88%, 87% ee 1,3-di-CF Ph/t-AmOH (3/2) * 14 Ar O 3 * o 3) Removal of MQ: CAN (3 equiv) Ar, 100 C, 48 h AQ (R" = H) O o CH3CN/H2O = 4:1, 0 C, 3 h 17 15 standard conditions B MQ (R" = OMe) 16 75%, 87% ee 16 PQ (R" = 2'-OMe-Ph) CAN (5 equiv), CH CN/H O = 4:1 R = H 3 2 17 40 oC, 12 h, Q' 2, 84% (89% ee) [AQ] Q' 1) Cu(OAc) (15 mol%) 30%, 94% ee 18 N 2b, 88% (87% ee) [MQ] N 2 R O 2c, 89% (94% ee) [PQ] O NaI (2.0 equiv) (~ 35% of 2c recovered) 19 * * PhI(OAc) (2.0 equiv) R = CH3 2 20 4a, 93% (89% ee) [AQ] 8a, 84% (73% ee) [AQ] PivOH (30 mol%) 8b, 92% (94% ee) [MQ] 1) mono- 4b, 91% (74% ee) [MQ] 1,4-dioxane, 50 oC 21 8c, 81% (91% ee) [PQ] N selective OMe 4c, 94% (92% ee) [PQ] air, 6 h, 93% PQ C-H arylation HN 78% 22 R = OCH iodination 3 Q' HN 5a, 86% (86% ee) [AQ] O 2) Cyclization (PQ) 23 N 2) Pd(PPh3)2Cl2 (5 mol%) N 5b, 94% (64% ee) [MQ] O 19 89%, 94% ee O 18 ArB(OH)2 (1.5 equiv) N 24 X-ray of 2c 5c, 78% (73% ee) [PQ] * Na2CO3 (2.0 equiv) Ph O * 25 R = Br dioxane/H2O = 1:1 2c 6a, 61% (63% ee) [AQ] 9a, 83% (94% ee) [AQ] 90 oC, Ar, 12 h, 90% 26 6b, 75% (83% ee) [MQ] 9b, 92% (77% ee) [MQ] 27 6c, 56% (83% ee) [PQ] 9c, 91% (88% ee) [PQ] B) R = F 1) Boc2O (2.5 equiv), DMAP NHBoc 28 7a, 57% (88% ee) [AQ] (1.1 equiv), THF, rt, 2 h CO2H 7b, 62% (83% ee) [MQ] Ph * 29 H 2) LiOH.H O (3 equiv) 7c, 41% (88% ee) [PQ] 2 20 30 Q' N THF:H2O = 2:1, rt, 2 h a OCH Q' MeO2C Q' Ph O 75% over 2 steps, 99% ee 3 N * 31 N N O O O * 17 32 * * 99% ee 4-MeO-PhI (2 equiv) (after recrystallization) 33 10a, 64% (90% ee) [AQ] 11a, 60% (75% ee) [AQ] 12a, 85% (93% ee) [AQ] CuI (5 mol%), DMEDA (10 mol%) N 10b, 89% (83% ee) [MQ] 11b, 53% (83% ee) [MQ] 12b, 95% (91% ee) [MQ] K PO (2 equiv), dioxane, 110 oC Ph O 34 10c, 87% (85% ee) [PQ] 11c, 27% (66% ee) [PQ] 12c, 93% (93% ee) [PQ] 3 4 * 24 h, Ar, 90%, 99% ee 21 35 Q' OCH3 Q' Q' 36 N N N Scheme 3. Synthetic transformations. Isolated yield on a O O O2N O 37 * * * 0.2 mmol scale. a) ee of 20 was measured by HPLC analysis 13a, 0% [AQ] 14a, 57% (47% ee) [AQ] 15a, 0% [AQ] 38 13b, 3% (67% ee) [MQ] 14b, 45% (29% ee) [MQ] 15b, 0% [MQ] of its benzyl ester (See SI). 39 13c, 4% (69% ee) [PQ] 14c, 47% (48% ee) [PQ] 15c, 0% [PQ] 40 Scheme 2. Substrate scope of -C(sp3)-H amidation. Mechanistic study. This Pd-catalyzed 41 Isolated yield of lactam products/1H-NMR yield of aminoquinoline-directed intramolecular C-H 42 arylation products on a 0.1 mmol scale under standard amidation reaction is believed to follow the main 43 conditions B. sequence of C-H palladation, oxidative addition (OA), 44 and reductive elimination (RE) (Scheme 4A). As in the 45 As shown in Scheme 3A, Pd-catalyzed mono- previously reported PdII-catalyzed C(sp3)-H 46 selective β C-H arylation of MQ-coupled propenamide 47 functionalization reactions,5,6 C-H palladation under 16 with PhI and subsequent β C-H amination gave 48 the asymmetric control of either BINOL-based compound 2b. Removal of the MQ group of 2b by the 49 phosphate or di-F-BINOL ligand is likely the enantio- treatment of cerium ammonium nitrate (CAN) in 50 determining step of this reaction, forming an acetonitrile and water gave the NH-free β-lactam 51 enantioenriched PdII-palladacycle (22). Following the product 17 in 75% yield and with 87% ee.21,25 As 52 OA with ArI, PdIV intermediate 23 can undergo either 53 exemplified by 19, the Ar’’ group on the C5 position of C-C or C-N RE to give the arylated or cyclized 54 AQ can be readily installed by Cu-mediated products 24 and 25 respectively. Protodepalladation 55 regioselective iodination26and Pd-catalyzed Suzuki 56 and dissociation of I- ligand regenerates the active PdII coupling with the corresponding aryl boronic acid. Pd- 57 catalyst. To understand the roles of the ArI oxidant on catalyzed PQ-directed β C-H arylation and β C-H 58 the chemoselectivity, density functional theory (DFT) 59 60 ACS Paragon Plus Environment ACS Catalysis Page 6 of 9

calculations were performed to study the C-C and C-N both 23 and 26 were considered computationally. As 1 RE transition states (TS) in reactions of model substrate shown in Scheme 4B, the calculated chemoselectivity 2 29-32 3 1 with various ArIs. Since previous computational of C-C vs C-N RE of 26 agreed well with the 4 studies of the Pd-catalyzed directed C-H arylation experimental product ratios. In comparison, the 5 with ArI suggested the I--bound PdIV intermediate may calculated chemoselectivity of RE of the I--bound 23, 6 undergo anionic ligand exchange prior to the RE,31c we particularly with I-4, notably deviated from the - 7 expect that 23 may react with HCO3 generated in situ observed ratios. Similar to the C6F5-I 8 to form a new PdIV intermediate 26. Therefore, RE from 9 A) Proposed reaction pathways O Ph 10 N O O Ar O CC Ar 11 Ar PdII AQ N HN II N - N HO2CO Pd , Cs CO , chiral L Ph Ar-I Ph N HCO3 Ph 27 12 2 3 PdII PdIV PdIV RE Ph O N N O 13 enantioselective OA N ligand O O CH palladation exchange 1 I Ph N 14 22 23 HO 26 CN 15 RE Ar PdII N CN CC HO2CO 16 28 O 17 O Ph 18 Ph N N Ar II 19 Ar PdII N Pd I N 20 I 25 24 21 B) DFT calculations of RE barriers from 26 and 23 22 from 26 from 23 ‡ ‡ ∆∆G‡ ∆G‡ (kcal/mol) ∆∆G 23 TS ∆G (kcal/mol) (CC)- CC CN (CC)- CC CC CN RE RE (CN) RE OMe Cl 24 RE ArI RE RE (CN) RE F3C CF3 25 I-2 13.1 10.2 2.9 14.5 8.7 5.8 MeO MeO CN 26 I I-2 I I-4 I I-5 I I-6 RE I-4 10.5 12.0 -1.5 13.8 10.9 2.9 27 26 80/12 12/87 42/53 90/6 or 23 14.3 10.7 3.6 28 I-5 9.8 10.0 -0.2 experimental ratio of (CN) / (CC) RE products using different ArI 29 I-6 10.2 9.2 1.0 15.0 10.1 4.9 30 31 C) CC and CN RE transition states in the reaction with I-6 32 O 33 Cl O N 34 N Ph N unfavorable N Cl Pd stabilizing 35 Pd OMe-Pd steric MeO OMe repulsions coordination 36 Ph OCO2H OCO2H 37 CC RE TS CN RE TS ‡ 38 (∆G‡ = 10.2 kcal/mol) (∆G = 9.2 kcal/mol) 39 40 Scheme 4. Mechanistic studies. 41 42 (I-1) oxidant used in Wu’s racemic system, reagent I-2 lactam with the use of ortho-methyl substituted I-10 is 43 bearing two strongly electron-withdrawing CF3 due to similar steric effects that suppress the C-C RE. 44 groups promotes the lactam formation by However, reaction with I-10 suffers from low 45 disfavouring C-C RE of PdIV through electronic effects. reactivity, which is probably caused by the difficulty of 46 The enhanced selectivity for lactam products with the initial OA to palladacycle.33 47 electron-rich ArIs bearing ortho-methoxyl groups (I-5 Conclusion 48 and I-6) is likely due to the steric repulsions between 49 the ortho-OMe group of ArI and the β-Ph that In summary, we have developed the first PdII- 50 3 51 destabilize the C-C RE transition state (Scheme 4C). A catalyzed enantioselective intramolecular C(sp )–H 52 weak o-OMe–Pd coordination in the C-N RE transition amidation reaction with up to 94% ee. It offered a 53 state may further promote the C-N bond formation. streamlined method for the asymmetric synthesis of - 54 Addition of an electron-withdrawing Cl group at C5’ aryl -lactams from propanoic acid and aryl iodides 55 of I-5 fine-tuned the electronic property of I-6 and the precursors. The identification of 2-methoxy-5- 56 selectivity for C-N RE. The above computational chlorophenyl iodide oxidant is critical to achieve high 57 analysis suggests that the good chemoselectivity for chemoselectivity. Mechanistic studies suggest that 58 59 60 ACS Paragon Plus Environment Page 7 of 9 ACS Catalysis

both steric and electronic effects of the unconventional Chen, G. Syntheses and Transformations of α-Amino Acids 1 3 aryl iodide oxidant are responsible for controlling the via Palladium-Catalyzed Auxiliary-Directed sp C-H 2 Functionalization. Acc. Chem. Res. 2016, 49, 635-645. competing C-N vs C-C reductive elimination 3 3. a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. Highly IV 4 pathways of Pd intermediate. The quinoline auxiliary Regioselective Arylation of sp3 C-H Bonds Catalyzed by 5 group of the lactam products can be removed under Palladium Acetate. J. Am. Chem. Soc. 2005, 127, 13154-13155. 6 mild conditions. Other Pd-catalyzed bidentate b) Shabashov, D.; Daugulis, O. Auxiliary-Assisted 7 auxiliary-directed enantioselective C(sp3)–H Palladium-Catalyzed Arylation and Alkylation of sp2 and 3 8 functionalization reactions are under current sp Carbon-Hydrogen Bonds. J. Am. Chem. Soc. 2010, 132, 3965-3972. 9 investigation. 10 4. For selected examples of Pd-catalyzed bidentate DG- 3 11 AUTHOR INFORMATION mediated C(sp )−H functionalization: a) Nadres, E. T.; 12 Daugulis, O. Heterocycle Synthesis via Direct C−H/N−H 13 Corresponding Author Coupling. J. Am. Chem. Soc. 2012, 134, 7-10. b) Zhang, L.-S.; 14 Peng Liu: [email protected], Chen, G.; Wang, X.; Guo, Q.-Y.; Zhang, X.-S.; Pan, F.; Chen, K.; Shi, Z.-J. Direct Borylation of Primary C-H Bonds in 15 Gang He: [email protected], Functionalized Molecules by Palladium Catalysis. Angew. 16 Gong Chen: [email protected]. Chem. Int. Ed. 2014, 53, 3899-3903. c) Xu, J.-W.; Zhang, Z.-Z.; 17 The authors declare no competing financial interest. Rao, W.-H.; Shi, B.-F. Site-Selective Alkenylation of δ-C(sp3)- 18 ASSOCIATED CONTENT H Bonds with Alkynes via a Six-Membered Palladacycle. J. 19 Am. Chem. Soc. 2016, 138, 10750-10753. d) Kim, Y.; Kim, S.-T.; 20 Detailed synthetic procedures, compound characterization, Kang, D.; Sohn, T.-I.; Jang, E.; Baik, M.-H.; Hong, S. 21 NMR spectra, X-ray crystallographic data, and computational Stereoselective Construction of Sterically Hindered 22 details are provided. This material is available free of charge Oxaspirocycles via Chiral Bidentate Directing Group- 23 via the Internet at http://pubs.acs.org. Mediated C(sp3)-O Bond Formation. Chem. Sci. 2018, 9, 1473- 24 1480. 25 ACKNOWLEDGMENT 5. a) Yan, S.-B.; Zhang, S.; Duan, W.-L. Palladium-Catalyzed 26 G.C. thanks NSFC-21672105, NSFC-21421062, NSFC- Asymmetric Arylation of C(sp3)-H Bonds of Aliphatic 27 91753124 and NSFC-21725204, the Ph.D. Candidate Amides: Controlling Enantioselectivity Using Chiral 28 Research Innovation Fund of the College of Chemistry Nankai Phosphoric Amides/Acids. Org. Lett. 2015, 17, 2458-2461. b) 29 University and Laviana for financial support of the Wang, H.; Tong, H.-R.; He, G.; Chen, G. An Enantioselective 30 experimental part of this work. P.L. thanks NSF CHE-1654122 Bidentate Auxiliary Directed Palladium-Catalyzed Benzylic 31 for financial support. DFT calculations were performed at the C-H Arylation of Amines Using a BINOL Phosphate Ligand. 32 Center for Research Computing at the University of Angew. Chem. Int. Ed. 2016, 55, 15387-15391. c) Tong, H.-R.; 33 Pittsburgh and the Extreme Science and Engineering Zheng, S.; Li, X.; Deng, Z.; Wang, H.; He, G.; Peng, Q.; Chen, G. Pd(0)-Catalyzed Bidentate Auxiliary Directed 34 Discovery Environment (XSEDE) supported by NSF. 35 Enantioselective Benzylic C–H Arylation of 3- 36 REFERENCES Arylpropanamides Using the BINOL Phosphoramidite Ligand. ACS Catal. 2018, 8, 11502-11512. 37 1. 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