INTRODUCTION

Palladium-catalyzed directed C(sp 3 )-H functionalization has emerged as a powerful strategy to construct various aliphatic frameworks. 1 Among the directing groups, amide-linked bidentate auxiliaries have shown unique advantage of high reactivity and versatility in forming new bonds. [2][3][4] However, the complexation mode of these bidentate auxiliaries also caused inherent obstacles for enantiocontrol due to the lack of suitable coordination sites on metal center. Despite the challenge, recent endeavors showed such enantio-induction is possible (Scheme 1A). [5][6][7][8] Notably, Duan reported that Pd II -catalyzed aminoquinoline (AQ)-directed benzylic -C-H arylation of 3arylpropanamides with aryl iodides can proceed in moderate to good enantioselectivity using BINOLbased chiral phosphoric acid or amide ligands. 5a Shi reported Pd II -catalyzed pyridinylisopropylamine (PIP)-directed enantioselective -C(sp 3 )-H alkynylation of 3-alkyllpropanamides with alkynyl bromide can proceed in good to excellent ee using a fluoro-substituted 3,3'-di-F-BINOL ligand. 6b To further expand the synthetic utility of bidentate auxiliary-mediated C(sp 3 )-H functionalization chemistry, new enantioselective reaction modes needs to be developed.

Recently, Wu demonstrated the reaction pathway of Pd II -catalyzed AQ-directed -C-H functionalization of 3-alkyl and 3-aryl propanamide can be modulated to give -lactam products in high yield and chemoselectivity when excess amount of pentafluorophenyl iodide was used as oxidant (Scheme 1B). 9 It was believed that the strong electronwithdrawing property of C 6 F 5 group is responsible for suppressing the C-C reductive elimination (RE) of Pd IV intermediate, promoting the intramolecular C-N RE. 10 Herein, we report a streamlined method for asymmetric synthesis of -aryl -lactams via Pd II -catalyzed quinoline-directed enantioselective intramolecular C(sp 3 )-H amidation of 3-arylpropylamines using 3,3'-di-F-BINOL chiral ligand 6b,11,12 and 2-methoxy-5-chlorophenyl iodide as oxidant.

RESULTS AND DISCUSSION

-Lactams are important scaffolds in drug design and frequently used as reactive intermediates in organic synthesis. 13,14 C-H functionalization strategy via metal-catalyzed intramolecular C-H carbene insertion has long been employed for synthesis of lactams. 15 In recent years, Pd-catalyzed intramolecular C(sp 3 )-H functionalization reactions including C-H alkylation, 16 carbonylative amination 17 , carbamoylation 18 process via Pd 0/II or Pd II/0 catalytic cycles have offered new ways to construct -lactams. Among these reactions, enantioselective transformations based on C-H alkylation 16 and carbamoylation 18 have also been demonstrated using chiral phosphonite and phosphoramidites ligand respectively. In comparison, catalytic reactions featuring C-H amidation of alkyl carboxamide substrates could provide a more straightforward disconnection strategy. Racemic versions of this type of transformation have been achieved via promoting C-N RE from high valent metal intermediates under oxidative conditions. 19,20 To make this transformation enantioselective, a proper combination of chiral ligand and oxidant need to be exploited.

During our recent re-investigation of Pd II -catalyzed AQ-directed enantioselective C(sp 3 )-H arylation of 3phenylpropanamide 1 with aryl iodides, we noticed that -lactam 2 was formed as a side product in varied yield and enantioselectivity using chiral phosphate ligands (Table 1). 5c While pentafluoro phenyl iodide I-1 oxidant gave the best reactivity and chemoselectivity (lactam vs C-H arylation) in Wu's racemic system (Pd(OAc) 2 as catalyst and AgOAc as I - scavenger at 150 o C), 9a it gave poor reactivity under the conditions of PdCl 2 (CH 3 CN) 2 catalyst, Cs 2 CO 3 base and chiral phosphate ligand at lower temperature (100 o C), which are critical to achieve high enantioselectivity in this AQ-directed system. 5 In comparison, 3,5-di-CF 3 -phenyl iodide (I-2) stood out among the electron-deficient ArI oxidants tested, offering the best balance of chemo-and enantioselectivity. A 59% yield of 2 with 85% ee along with 15% yield of C-H arylation product 3 were obtained using 4 equiv of I-2, 20 mol% of 3,3'-di-aryl (3,5-di-CF 3 -C 6 H 3 ) substituted BINOL-derived phosphate ligand L4 6a and 30 mol% of dibenzylideneacetone (dba) additive at 100 o C without any solvent (entry 1, standard conditions A). The structure of quinoline auxiliary also had an impact on reactivity and ee. Q-2 (MQ) 21 , a C5-methoxy analog of AQ, gave lactam product in significantly improved yield and ee (entry 9). Beside electron-deficient ArIs, we found electron-rich ArIs bearing various ortho substituents can also promote the formation of 2 to varied extent. For example, I-10 bearing an ortho-methyl group exclusively gave cyclization product but low reactivity. I-8 bearing two ortho-MeO groups gave 2 in 58% yield and with moderate ee.

As outlined in Table 2, we were pleased to find that use of chiral BINOL ligands also gave moderate to good enantioselectivity with both electron rich and poor ArI oxidants. 6b, 11, 12 I-5 bearing an ortho-MeO group gave more 2 than I-4 bearing a meta-MeO and I-12 (PhI). As seen in I-6 and I-7, installation of electronwithdrawing group on C5 position of I-5 further improved the chemo-selectivity. Due to the low cost, I-6 was chosen for further reaction optimization. 22 The combination of di-F-BINOL ligand L-9 and L-6 gave the best results. Reaction of 1 with 4 equiv of I-6, 10 mol% of PdCl 2 (PhCN) 2 catalyst, 20 mol% of L-9 in the mixed solvent of 1,3-di-CF 3 -Ph and tAmOH at 100 o C gave 2 in 90% yield with 89% ee along with 6% of arylation byproduct (entry 1, standard conditions B). The use of MQ gave comparable results to AQ under conditions B' (entry 1 vs 7). Q-9 (PQ) with an orthomethoxyphenyl group on the C5 of AQ gave lactam product with the highest ee of 94% (entry 8). It is also worth noting that 1) Use of Cs 2 CO 3 is critical for obtaining high ee. 23 2) Addition of Ag additives e.g. Ag 2 CO 3 gave significantly decreased ee (entry 2). 3) Use of Pd(OAc) 2 catalyst gave lower ee (entry 3). 4) 4 equiv of ArI is needed to achieve high yield (entry 6). details). 5c, 19a The performance of auxiliaries slightly fluctuates depending on the β-aryl groups. In general, substituents on the meta and para positions of aryl groups were well tolerated (see 4, 8). Ortho-substituted or electron-deficient aryl groups gave significantly lower yield and ee (14, 11, 15). As exemplified by 13, intramolecular amination of the unactivated C(sp 3 )-H bond gave very low yield and moderate ee under the standard conditions. 24 As shown in Scheme 3A, Pd-catalyzed monoselective β C-H arylation of MQ-coupled propenamide 16 with PhI and subsequent β C-H amination gave compound 2b. Removal of the MQ group of 2b by the treatment of cerium ammonium nitrate (CAN) in acetonitrile and water gave the NH-free β-lactam product 17 in 75% yield and with 87% ee. 21,25 As exemplified by 19, the Ar'' group on the C5 position of AQ can be readily installed by Cu-mediated regioselective iodination 26 and Pd-catalyzed Suzuki coupling with the corresponding aryl boronic acid. Pdcatalyzed PQ-directed β C-H arylation and β C-H amination gave compound 2c. Interestingly, the PQ group can also be removed by the treatment of CAN to give 17 in moderate yield 27 and with 94% ee. The ee value of 17 was increased to 99% after one recrystallization in hexanes and ethyl acetate. Amide activation of 17 by Boc and cleavage with LiOH gave phenyl substituted β-amino acid 20 in good yield and 99% ee. 28 Hartwig-Buchwald coupling of 17 with aryl iodide gave 21 in 90% yield.

Mechanistic study.

This Pd-catalyzed aminoquinoline-directed intramolecular C-H amidation reaction is believed to follow the main sequence of C-H palladation, oxidative addition (OA), and reductive elimination (RE) (Scheme 4A). As in the previously reported Pd II -catalyzed C(sp 3 )-H functionalization reactions, 5,6 C-H palladation under the asymmetric control of either BINOL-based phosphate or di-F-BINOL ligand is likely the enantiodetermining step of this reaction, forming an enantioenriched Pd II -palladacycle (22) Addition of an electron-withdrawing Cl group at C5' of I-5 fine-tuned the electronic property of I-6 and the selectivity for C-N RE. The above computational analysis suggests that the good chemoselectivity for lactam with the use of ortho-methyl substituted I-10 is due to similar steric effects that suppress the C-C RE. However, reaction with I-10 suffers from low reactivity, which is probably caused by the difficulty of the initial OA to palladacycle. 33

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Conclusion

In summary, we have developed the first Pd IIcatalyzed enantioselective intramolecular C(sp 3 )-H amidation reaction with up to 94% ee. It offered a streamlined method for the asymmetric synthesis of aryl -lactams from propanoic acid and aryl iodides precursors. The identification of 2-methoxy-5chlorophenyl iodide oxidant is critical to achieve high chemoselectivity. Mechanistic studies suggest that both steric and electronic effects of the unconventional aryl iodide oxidant are responsible for controlling the competing C-N vs C-C reductive elimination pathways of Pd IV intermediate. The quinoline auxiliary group of the lactam products can be removed under mild conditions. Other Pd-catalyzed bidentate auxiliary-directed enantioselective C(sp 3 )-H functionalization reactions are under current investigation.