A Dynamic Kinetic Asymmetric Heck Reaction for the Simultaneous

Page 1 of 11 Journal of the American Chemical Society

1 2 3 4 5 6 7 A Dynamic Kinetic Asymmetric Heck Reaction for the Simultaneous 8 Generation of Central and Axial Chirality 9 10 José Alberto Carmona,§ Valentín Hornillos,*, §,∫ Pedro Ramírez-López,§ Abel Ros,§,∫ Javier Iglesias-Sigüenza,∫ En- 11 § ,∫ ,§ 12 rique Gómez-Bengoa, Rosario Fernández,* José M. Lassaletta* 13 § Instituto de Investigaciones Químicas (CSIC-US) and Centro de Innovación en Química Avanzada (ORFEO-CINQA), Avda. Amé- 14 rico Vespucio, 49, 41092 Sevilla, Spain. 15 ∫ 16 Departamento de Química Orgánica, Universidad de Sevilla and Centro de Innovación en Química Avanzada (ORFEO-CINQA), 17 C/ Prof. García González, 1, 41012 Sevilla, Spain. 18 § Departamento de Química Orgánica I, Universidad del País Vasco, UPV/EHU, Apdo. 1072, 20080 San Sebastián, Spain 19 20 21 ABSTRACT: A highly diastereo- and enantioselective, scalable Pd-catalyzed dynamic kinetic asymmetric Heck reaction of heterobiaryl sul- 22 fonates with electron-rich olefins is described. The coupling of 2,3-dihydrofuran or N-boc protected 2,3-dihydropyrrole with a variety of quinoline, quinazoline, phthalazine and picoline derivatives takes place with simultaneous installation of central and axial chirality, reaching excellent 23 diastereo- and enantiomeric excesses when in situ formed [Pd0/DM-BINAP] was used as the catalyst, with loadings reduced down to 2 mol% 24 in large scale reactions. The coupling of acyclic, electron-rich alkenes can also be performed using a [Pd0/Josiphos ligand] to obtain axially 25 chiral heterobiaryl a-substituted alkenes in high yields and enantioselectivities. Products from Boc-protected 2,3-dihydropyrrole can be easily 26 transformed into N,N ligands or appealing axially chiral, bifunctional proline-type organocatalysts. Computational studies suggest that a b- 27 hydride elimination is the stereocontrolling step, in agreement with the observed stereochemical outcome of the reaction. 28 29 30 31 Scheme 1. Asymmetric intermolecular Heck reactions. 32 INTRODUCTION 33 The Heck reaction is a fundamental palladium-catalyzed Previous work: generation of carbon stereogenic centers 34 C–C bond-forming transformation with numerous applica- A) Cyclic alkenes [Pd], L* 2 2 1 R R 35 tions in the synthesis of natural products and valuable syn- R X + 2 or R Z 1 Z 1 36 1 Z High ee’s R R thetic intermediates. Since the first intermolecular asymmet- X = OTf, Br, Cl R2 = H, alkyl 37 ric version reported in 1991 by the group of Hayashi,2 these R1 = Ar, alkenyl, Bn Z = O, NR, CH 38 couplings have become a benchmark to validate the design of 2 39 novel chiral ligands and catalysts rather than finding suitable B) Acyclic alkenes 2 [Pd], L* 2 40 3 R R1 R applications in stereoselective organic synthesis. Only very Ar X + OH 1 O 41 recently, the synthetic utility of the asymmetric Heck reaction R n High ee’s Ar n X = N +BF −, B(OH) 42 has been expanded thanks to the outstanding performance of 2 4 2 43 chiral mixed phosphine/phosphine oxide ligands in several This work: 44 C) Dynamic kinetic asymmetric Heck Reaction representative transformations.4 Additionally, methods to en- 45 5 W W − W Y X able the use of benzylic electrophiles and previously elusive 2 R2 Y Y 46 R + R2 aryl halides6 have also appeared. Moreover, conditions for the N N L Z N 47 Pd [Pd], L* highly enantioselective construction of quaternary stereocen- X L' 48 ?? Z ters from trisubstituted dihydrofurans have also been re- 49 3 7 R 1 R3 R3 50 ported (Scheme 1A). The redox relay Heck-Matsuda reac- R R1 R1 8 tions of acyclic alkenyl alcohols have also significantly ex- (±)-1: X = OTf, ONf IOA Z = O, NBoc 51 W, Y = CH, N panded the synthetic value of the reaction, a strategy that has Stereogenic axis & center 52 generated at once 53 been also extended to oxidative Heck reactions using boronic acids as reactants (Scheme 1B).9,10 Mention is also due to the 54 12 55 dynamic kinetic resolution of atropoisomeric o-iodoacryl- The direct asymmetric cross-coupling approach to axially 56 anilides.11 chiral biaryls has failed so far for the synthesis of heterobiaryls 57 such as QUINAP and related derivatives. Among a handful of 58 59 60 ACS Paragon Plus Environment Journal of the American Chemical Society Page 2 of 11

alternative approaches,13 our group has recently described Pd- promising 82% ee for the major product 3b (Table 1, entry 1). 1 catalyzed dynamic kinetic asymmetric C–C, C–P and C–N An excess of dihydrofuran was used (8 equiv.), due to the vol- 2 cross-coupling reactions of racemic heterobiaryl sulfonates atility of this compound. A screening of ligands and condi- 3 1.14 On the other hand, more complex ligands/catalysts com- tions was then performed to optimize this reaction [Table 1 4 bining central and axial chirality have found a number of re- and Table S1 (supporting information)]. At lower tempera- 5 15 6 cent applications in asymmetric catalysis, but their synthesis ture (60 °C, entry 2) the conversion dropped substantially but 7 usually require tedious multi-step procedures. In fact, exam- the enantioselectivity raised up to 88% ee. No improvements 8 ples of catalytic procedures for the simultaneous generation of were observed using related P,P ligands such as L2 (entry 3) 16 9 axial and central chirality are rare, and none of them were di- or L3 (entry 4), while Josiphos derivative L4 was unproduc- 10 rected to the synthesis of catalysts/ligands with practical ap- tive (entry 5). Not surprisingly, hemilabile ligand L5 afforded 11 plications. In this context, the dynamic kinetic asymmetric the non-isomerized Heck product 3'b exclusively with high 12 Heck reaction from 1 appears as an appealing strategy for the diastereoselectivity, although in low ee (entry 6). Remarka- 13 synthesis of bifunctional heterobiaryls with central and axial bly, though, ligands L6 or L7 were ineffective (entries 7 and 14 stereogenic elements (Scheme 1C). This transformation, 8); a faster alkene insertion may be favored with less σ-donat- 15 however, is particularly challenging for two main reasons: ing P,N and P,O ligands, since they form more electrophilic 16 First, in contrast with the common cationic Heck reaction cationic aryl palladium(II) centers. However, a stronger bind- 17 pathway,17 the oxidative addition intermediate IOA has no va- ing of the pyridine/isoquinoline nitrogen is also expected in 18 cant coordination sites; the relatively good isoquinoline/pyr- this case, preventing further coordination of the olefin. 19 idine N ligand must be displaced by a neutral olefin on the PdII 20 center. Second, the reaction with internal olefins can afford up Table 1. Screening of Reaction Conditions and Ligands. 21 to 8 different Heck stereoisomers considering the formation Pd(dba)2 (10 mol%) 22 N L (11 mol%) N N of two stereogenic elements and the possible double bond mi- + 2 + 23 ONf gration. Therefore, the chiral ligand will be required to per- DIPEA (5 eq.), toluene, 18h O O 24 form an exquisite control of both the generation of the stere- 25 rac-1b 3b 3 b ogenic axis and the migratory insertion event in order to af- 26 ford a satisfactory result. 27 P(tBu) PPh PPh PPh2 2 2 2 MeO Ph2P Fe 28 PPh PPh2 RESULTS AND DISCUSSION 2 MeO PPh2 Me 29 In a preliminary experiment, it was observed that the reac- L4: SL-J002 30 L1: (R)-BINAP L2: (R)-H8-BINAP L3: (R)-MeO-BIPHEP 31 tion of 2-(pyridin-2-yl)phenyl nonaflate 1a and 2,3-dihydro-

32 furan 2 fails to give any reaction product under common Heck PAr2 PPh P(O)Ph O PAr conditions [Pd(dba)2/(R)-BINAP (cat.), DIPEA, toluene, 80 2 2 2 33 OMe PPh2 Ph2P N 34 °C], thus confirming our initial concerns (Scheme 2). It was tBu OA L8: (R)-Tol-BINAP (Ar = p-Tolyl) 35 assumed that the formation of a very stable I (R = R’ = H) L5: (R)-MOP L6: (R)-BINAP(O) L7 (S)-tBu-phox L9: (R)-DM-BINAP (Ar = 3,5-Xylyl) 36 intermediate prevents coordination of the olefin and further b b c 37 migratory insertion. Despite this discouraging result, we en- Entry L T (°C) conv (%) 3b:3'b dr ee 38 visaged that in more strained (less stable) IOA palladacycles (R 1 L1 80 50 10:1 >20:1 82 39 = R’ ≠ H; e.g. from 1-(isoquinolin-1-yl)naphthalene-2-yl no- 2 L1 60 28 6:1 >20:1 88 40 naflate 1b), dissociation of the N–Pd bond would be facili- 3 L2 60 27 11:1 >20:1 82 41 tated by release of steric strain. 42 4 L3 60 11 n.d. n.d. n.d. Scheme 2. Preliminary experiments. 43 5 L4 60 <5 n.d. >20:1 n.d. 44 6d L5 80 40 <1:20 >20:1 13e 45 N Pd(dba)2 (10 mol%), (R)-BINAP (11 mol%) 46 + NO REACTION 7 L6 60 <5 n.d. n.d. n.d. ONf DIPEA (5 eq.), Toluene, 80 °C, 48h 47 O 2 8 L7 60 <5 n.d. n.d. n.d. 48 1a 49 + + 9 L8 60 16 8:1 >20:1 96 R = R 50 10 L9 60 22 6:1 >20:1 99 N P N Difficult N−Pd bond dissociation R R P 51 Pd Pd R P R R = R 11 L9 80 >99 >20:1 >20:1 97 52 P steric f repulsion 53 OA N−Pd bond dissociation facilitated 12 L9 80 97 >20:1 >20:1 97 I 54 aConditions: 0.1 mmol of rac-1b, 0.8 mmol of dihydrofuran in 0.5 mL of 55 toluene. bDetermined by 1H NMR spectroscopy of the crude reaction mix- 56 In fact, the reaction of 1b and 2 under the above conditions ture. cDetermined by chiral HPLC analysis. dReaction in dioxane. eee of 3'b. f 57 afforded the desired product as a 10:1 3b:3'b mixture with a [Pd] (5 mol%)/L9 (6 mol %). 58 59 60 ACS Paragon Plus Environment Page 3 of 11 Journal of the American Chemical Society

Finally, a major improvement was observed after modification Figure 1. X-ray structures of (Sa,S)-3b and (Sa,S)-5'b. Ther- 1 of the diarylphosphino group:use of Tol-BINAP L8 and DM- mal ellipsoids drawn for 50% probability. H atoms are omitted 2 BINAP L9 afforded the desired product 3b with near perfect for clarity. 3 dr and ee, although the conversion remained low (entries 9 4 and 10). To our delight, full conversion, high diastereoselec- 5 tivity (dr >20:1) and regioselectivity (>20:1) were achieved 6 N1 N1 7 by using L9 at 80 °C without significantly affecting the enantioselectivity (97% ee, entry 11). Moreover, the catalyst load- N2 8 O2 ing could be reduced to 5 mol% to obtain a similar result (en- 9 O1 10 try 12). O1 11 The Pd/DM-BINAP catalyst was successfully applied to (S ,S)-3b 12 the dynamic kinetic asymmetric Heck reaction of 2,3-dihy- a (Sa,S)-5b 13 drofuran 2 with other heterobiaryl sulfonates, including 14 quinazoline- (1c), phthalazine- (1d) and picoline (1e) deriv- enantioselectivity. The same absolute configuration for (S,S)- 15 atives. Different substituents at the naphthalene unit in iso- 3b and the minor isomer (S,S)-5'b were determined by X-ray 16 quinoline derivatives 1f-h were also tolerated (Table 2). Im- diffraction analysis (Figure 1); while those of other products 17 portantly, the method could also be extended to the reaction 3 and 5 were assigned by analogy. These data indicate that in 18 with N-Boc-2,3-dihydropyrrole 4 for the synthesis of deriva- our case there is no kinetic resolution from hydrido-alkene Pd 19 complex intermediates.18 Remarkably, a similar trend has 20 tives 5, although in this case DMSO proved to be the solvent of choice. Remarkably, all products 3 and 5 were obtained been previously reported for asymmetric Heck reactions us- 21 ing 3,3’-disubstituted DM-BINAP ligands.19 Not surprisingly, with excellent dr’s (>20:1), along with very high ee’s (up to 22 the reaction performed with simple cycloalkenes such as cy- >99%). Good selectivity (s) ratios, ranging from 6:1 to >20:1, 23 clopentene or cyclohexene failed to give any products, even were observed for dihydrofuran derivatives (3/3'), while di- 24 under forcing conditions. This lack of reactivity reflects again 25 hydropyrrole products were obtained in slightly lower 5/5' se- the difficult displacement of the heterocycle N atom by the 26 lectivities (s = 3:1 to 6:1). As a remarkable exception, and for olefin, which requires not only some steric strain in the pal- 27 unknown reasons, the pyrenyl 5'h isomer was formed exclu- ladacycle but also a relatively high electron richness in the 28 sively, although again with an excellent diastereo- and 29 C=C bond. Likewise, attempts to perform reactions with 5- 30 methyl-2,3-dihydrofuran failed to give any reaction products. Table 2. Scope of Heck reactions with cyclic alkenes.a 31 In this case, the lack of reactivity is attributed to the high level 32 of steric crowding expected at the oxidative addition interme- 2 R X R2 X R2 X Y 2: Z = O (8 equiv) Y Y 4: Z = NBoc (5 equiv) diate (see proposed mechanism below), thus preventing an 33 N Z 1 N N R R1 R1 34 X Pd(dba)2 (5 mol%), L9 (6 mol%) effective coordination/carbometallation of hindered alkenes. Z Z DIPEA (3-5 eq.), 80 °C, 18-96 h + 35 5 Importantly, a large scale synthesis of 3b and 5b (1.8 mmol and R R5 R5 4 3 36 R R R4 R3 R4 R3 1.5 mmol, respectively) could be performed with a lower catalyst rac-1b-d, 1f-h: X= ONf (Sa,S)-3b-h: Z = O (Sa,S)-3b-h: Z = O 37 rac-1e: X = OTf (Sa,S)-5b-h: Z = NBoc (Sa,S)-5b-h: Z = NBoc loading (2 mol% [Pd]; 2.4 mol% L9) to obtain the products with 38 similar results (3b: 81% yield, s >20:1, dr >20:1, 97% ee; 5b: N 39 N N N N N 60% yield (pure major isomer), s 6:1, dr >20:1, 99% ee). 40 H3C O O O O We investigated also the reaction with acyclic electron rich al- 41 kenes. Unfortunately, the reaction of 1b with butyl vinyl ether 42 3c: 92%; s 14:1; 94% ee 3d: 52%; s 10:1; 90% ee 3e: 99%; s >20:1; >99% ee 3b: 90%; s >20:1; 97% ee 6 under the optimized conditions afforded the product 11b 43 N with a lower enantioselectivity (83% ee, Table S3 in the Sup- 44 N N N porting Information). However, further screening revealed 45 O O O N that the Josiphos-type ligand L4 performs better in this case, 46 Boc OCH3 CH3 reaching a satisfactory 92% ee (Table 3). This ligand was then 47 3f: 53%; s 6:1; 99% ee 3g: 84%; s >20:1; 99% ee 3h: 66%; s 4.9:1; 98% ee 5b: 76%; s 6:1: 99% ee 48 used in the reactions of vinyl ethers 6-9 with heterobiaryls N N N 1b,c,e to afford the corresponding Heck products 11-15 in 49 N N N H3C 50 N high yields and enantioselectivities. On the other hand, L9 N N N Boc 51 Boc Boc Boc was required again in the reaction of 1b with vinyl acetamide

b 52 5c: 76%; s 4:1; 96% ee 5d: 80%; s 5:1; 98% ee 5e: 70%; s 3:1; 99% ee 5h: 60%; s <1:20; >99% ee 10 to yield product 15b in 90% yield and 82% ee. 53 a 54 Reactions performedat 0.1 mmol scale in 0.5 mL of solvent (toluene for 2; DMSO for 5). Isolated yields of pure major isomer after chromatog- 55 raphy; dr´s (>20:1 for products 3 and 5) and selectivities were determined 56 by 1H NMR in the crude reaction mixtures. Ee's determined by HPLC on 57 chiral stationary phases. bYield of an inseparable mixture of 5d/5’d. 58 59 60 ACS Paragon Plus Environment Journal of the American Chemical Society Page 4 of 11

Table 3. Reaction Scope using Acyclic Olefins.a Scheme 4. Control experiments. 1

R2 X 2 2 Y R X 6-9: Z = OR (3 equiv) Y N Z Pd(dba)2 (5 mol%), L9 (6 mol%) 1 10: Z = N(Me)Ac (3 equiv) N 3 R R1 + DIPEA (5 eq.) X Pd(dba)2 (5 mol%), L4 (6 mol%) ONf 4 Z O O DIPEA (3 eq.), toluene, 80 °C, 18-48 h Toluene, 80 °C 5 5 R R5 2 full conversion 4 3 R R R4 R3 17 18: s >20:1, 9% ee 6 rac-1b,c: X= ONf (Sa)-11-15b,c,e 7 rac-1e: X = OTf 8 N O N N N 9 N Cl OTf OTf

10 OnBu OEt OCy O 11 rac-19 rac-20 11b: 90%; 92% ee 12b: 70%; 94% ee 13b: 90%; 91% ee 14b: 75%; 94% ee 12 unreactive substrates N N

13 N N N Cl N H3C O Pd(dba)2 (5 mol%), L9 (6 mol%) 14 N OnBu OCy O N Me NaOtBu (5 eq.) N 15 Me + Br O Toluene, 80 °C, 72 h 11c: 80%; 84% ee 13c: 70%; 87% ee 14e: 90%; 80% ee 15b:b 90%; 82% ee O 16 2 17 a Reactions performed at 0.1 mmol scale in 0.5 mL of solvent. Ee's deter- rac-1b (Br) 3b: s > 1:20, 93% ee 18 mined by HPLC on chiral stationary phases. bLigand L9 was used. 19 20 during the stereocontrolling step of the reaction. Moreover, Preliminary experiments have also demonstrated that this 21 no coupling product was formed from the more sterically de- DYKAT process can be extended to the hydroarylation of bi- 22 manding nonaflate rac-19, showing that the coordinating iso- cylic olefins (Scheme 3). Thus, reaction of rac-1b with nor- 23 quinolyl/pyridyl N atom is required for a facile chelate-as- bornadiene in the presence of formic acid as the hydride 24 sisted oxidative addition step. Similarly, no reaction was ob- source and L4 as the ligand afforded product 16 as a single di- 25 served with N-oxide rac-20, indicating that the formation of a astereomer in 98% ee, although in moderate yield. Nonethe- 26 five membered cationic palladacycle is also essential to reactiv- less, no double hydroarylation was observed in this transfor- 27 ity. Finally, a much slower reaction was observed when 1-(2- mation. The structure of ent-16∙HCl20 was determined by X- 28 bromonaphthalen-1-yl)isoquinoline 1b(Br), in combination 29 ray diffraction analysis, and its absolute (Ra,S,R,R) configura- with NaOtBu as the base, was used as the starting material 30 tion is consistent with a uniform stereochemical outcome ° 31 with the Heck products 3 or 5. (23% conversion after 72h at 80 C). Interestingly, though, 32 the non-isomerized product 3’b was exclusively formed in 33 Scheme 3. Hydroarylation of norbornadiene and X-ray struc- 93% ee. 34 ture of ent-16∙HCl. Thermal ellipsoids drawn for 50% proba- We next turned to DFT studies in order to gain insight into 35 bility. H atoms, except NH, are omitted for clarity. the reaction mechanism and the origin of the high levels of en- 36 antio- and diastereoselectivity observed. We assumed that the 37 fundamental steps of the catalytic cycle would be the oxidative N Pd(dba)2 (5 mol%), L4 (6 mol%) N 38 HCO H (3 equiv) 0 2 Sa R addition of the racemic substrates 1 to the Pd catalyst leading ONf + S 39 DIPEA (5 eq.), DMSO 80 °C, 60 h + ® 8 equiv S to cationic intermediate I , followed by transligation ( II), 40 II rac-1b insertion of the alkene into the Pd –C bond (®III), and re- 41 16: 31%, dr > 20:1; 98% ee 42 installation of the double bond in the final products 3 by b- 43 hydride elimination (®IV), leading to the final products after 44 N1 decoordination or, eventually, double bond migration after + Cl 45 N b Cl H reinsertion (hydropalladation) and a second -hydride elimi- R R Ra a S 21 46 S nation. The reaction between 1b and 2 with the catalyst R 47 R based on the optimal ligand L9 was chosen for the computa- 48 R ent-16·HCl tional studies. Eight different isomeric products could be a pri- 49 ori formed by combination of the different configurations of 50 ent-16·HCl the stereogenic axis and center, and the final position of the 51 double bond (Figure 2). We started from diastereomeric 52 complexes (Sa)-A (G = 0) and (Ra)-A (ΔG = +1.0 kcal/mol) 53 In a control experiment, biphenyl nonaflate 17 was made to react with 2 under the optimized conditions to afford the ex- formed by coordination of both enantiomers of substrate 1b 54 0 to the [Pd (L9)] catalyst (Figure 3). Transition states (Ra)- 55 pected Heck product 18 with high selectivity but a negligible 56 9% ee (Scheme 4). This result highlights the synergistic effect TS0 and (Sa)-TS0 for the oxidative addition step were located ǂ 57 between the chiral ligand and the heterobiaryl moiety for both atropoisomers at ΔG = 18.4 and 32.4 kcal/mol, 58 59 60 ACS Paragon Plus Environment Page 5 of 11 Journal of the American Chemical Society

Figure 2. Proposed mechanism. Shaded structures are drawn for pathways leading to non-detected products. 1

2 (Sa,S)-3/5 (major) S R R S R S R 3 a Sa Ar R Ra R Z R Z R Z N N R R N Pd P a 4 R S R Z R S R R H N R S Sa R R not detected a P Ra a not detected 5 R Z R Z R Z R Z N N Ar N N 6. β-Hydride elimination (Sa,S)-VI 3/5 (traces) 6. β-Hydride elimination + 6 +decoordination 6. β-Hydride elimination + decoordination decoordination not detected 3’/5’ (minor) not detected not detected 7 Ar Ar P Ar Ar Ar R 0 R R R Pd + + 8 + + P P P P R P R Pd R Pd R Z Pd Z Z Z Pd N Ar N N 9 N P P 5’. Decoordination P P 5’. Decoordination [Pd(L9)] Ar Ar Ar 10 Ar START HERE (R ,S)-V (S ,S)-V (Sa,S)-V (Ra,R)-V a a 5. Reinsertion 5. Reinsertion 11 1 1. Oxidative addition 5. Reinsertion 12 5. Reinsertion Ar Ar Ar Ar Ar Ar P P P P + P R R 13 R + P + P R + P R + + P Pd R Pd Pd P Pd Ar Ar Pd R Pd R R R P R P Ar Ar 14 H H R N N N Z H N Z N Z N Z H Ar Ar 15 (S ,R)-IV (R ,S)-IV a (Sa,S)-IV + + (Ra,R)-IV a 16 (Sa)-I (Ra)-I 17 4. β-Hydride elimination 4. β-Hydride elimination 2. Transligation Ar Ar Ar Ar Ar Ar 18 P P R R P P R + R + + P R + P R + R + Pd P Pd P R Z Pd P Pd P 19 R and/or R Pd Pd R and/or R Ar Ar N P 2/4 N P Ar Ar N Z N Z Z Z N Z N Z 20 Ar Ar 3. Insertion 3. Insertion 21 (Sa,R)-III (R ,R)-III (R ,S)-III (Sa,S)-III (Sa)-II (Ra)-II a a 22 23 + 24 Figure 3. Formation of cationic intermediates I and com- for the different diastereomeric transition states. In fact, the ǂ 25 puted energies. low barrier computed for this epimerization (TSepi: ΔG =

26 Ar − 21.0 kcal/mol) demonstrates the feasibility of the rotation Ar Ar TfO P 22 27 OTf P + P around the chiral axis at this point. As expected, the coor- Pd Pd TfO Pd 28 N P P P N N dination of the dihydrofuran substrate 2 to form intermedi- Ar 29 Ar Ar ates II in the next step requires decoordination of the iso- + (Sa)-A (S )-I 30 (Sa)-I a quinoline N atom, and rotation of the biaryl group above or 31 below the coordination plane. Surprisingly, the calculations Epimerization TSepi 32 − Ar TfO indicate that the ligand exchange is concerted: in the located 33 Ar Ar P transition states TS1, the dihydrofuran molecule is moving 34 TfO P Pd + P Pd TfO P Pd into the coordination sphere of palladium as the same time 35 N P N N P Ar as the isoquinoline is rotating away from the metal center 36 Ar Ar (R )-A (R )-I + (Figure 4). In (Sa)-TS1, for example, the Pd-N and Pd-al- 37 a a (Ra)-I kene distances are 3.2 Å and 3.7 Å respectively. During this 38 (Sa)-TS0 process, the ligands are moving in a very sterically crowded 39 +32.4 ǂ (Ra)-TS0 environment, inducing a significant activation barrier of ΔG 40 +18.4 41 = 23.2 kcal/mol for (Ra)-TS1). In the following alkene in- (Sa)-A (Ra)-A 42 0.0 +1.0 sertion into the C(Aryl)-Pd bond, eight different transition states (TS2) were located for the four forming diastere- 43 (S )-I (R )-I a TSepi a 44 −17.5 −18.9 −17.4 omers and two possible orientations for the isoquinoline

45 (S )-I+ ring (above or below the coordination plane) in each case. a (R )-I+ −37.7 a 46 −39.9 Noteworthy, some of them present relatively low free activa- 47 tion energies, with a minimum of ΔGǂ = 21.3 kcal/mol for 48 (Ra,R)-TS2, which is actually lower than that of the previous respectively, leading to intermediates (Sa)-I and (Ra)-I of 49 ǂ - - step [(Ra)-TS1]. The highest activation energy (ΔG = 50 similar energies (ΔG = 17.5 and 17.4 kcal/mol). As ex- 27.7) corresponds to (Sa,S)-TS2, in sharp contrast with the 51 pected, displacement of the triflate by the isoquinoline N- + + experimental results (obtention of Sa,S as the major stereoi- atom to form cationic intermediates (Sa)-I and (Ra)-I pro- 52 somer, with high levels of selectivity). These inconsistencies 53 vides an additional stabilization of 20.2 and 22.5 kcal/mol, suggest that TS2 might not be the rate determining nor the 54 respectively (Figure 3). To make possible an efficient dy- stereocontrolling step, which should therefore be located at 55 namic kinetic resolution, these diastereomeric Pd(II) inter- a later stage in the catalytic cycle. In this regard, the reaction 56 mediates have to interconvert in a fast equilibrium and the 57 subsequent steps must present different activation barriers evolves through TS3 to reinstall the alkene functionality 58 59 60 ACS Paragon Plus Environment Journal of the American Chemical Society Page 6 of 11

Figure 4. Computed energies for key intermediates and transition states performed at the M06/def2tzvpp//B3LYP/6-31G(d,p) 1 (Pd,SDD) (IEFPCM,toluene) level. Selected 3D structures are illustrated using CYLview.23 2 3 R,R preferred TS2 Major reorganization S,S preferred 4 Sa,S: –12.2 −1) required R ,S: –13.7 TS3 TS1 a R ,S: –14.5 Sa: –16.3 a 5 Sa,R: –15.8 Ra: –16.7 6 Ra,R: –18.6 7 Sa,R: –19.7 Ra,R: –21.7 III’ 8 G (kcal mol II R ,S: –25.6 S ,S: −25.3 9 Sa,S: −26.1 reversible a a S ,R: –27.5 III a 10 R ,R: –29.5 R ,S: –29.8 a a R ,R: –31.0 IV TS4 a S ,S: –31.5 11 Sa,S: –31.7 a Sa,R: –32.8 Sa,S: −33.0 S ,S: –34.4 TS5 12 a S ,S: –35.2 + a VI I Sa,S: –36.4 13 S : −37.7 V a S ,S: –39.4 R ,R: –39.8 a 14 Ra: −39.9 a 15 16 Pd–N = 3.21 Å 17 18 19 126.7° 20 124.6° 21 Pd–C = 2.93 Å 22 23 Pd–C = 2.40 Å 24 (Sa,S)-II (S )-I+ (S )-TS1 25 a a Pd–C = 3.66 Å

26 π-staking 27 28 29 Pd–C = 2.20 Å Pd–C = 2.09 Å 30 31 32 33 Pd–C = 2.11 Å C–C = 2.08 Å Pd–C = 2.41 Å 34 (S ,S)-III (S ,S)-TS2 a Pd–H = 1.92 Å 35 a (Sa,S)-III’ Pd–C = 2.14 Å 36 37 Pd–C = 2.27 Å Pd–C = 2.40 Å 38 Pd–H = 1.57 Å 39 40 41

42 C–H = 1.27 Å C–H = 1.88 Å 43 Pd–H = 1.58 Å Pd–C = 2.35 Å 44 Pd–C = 2.26 Å (Sa,S)-IV 45 (Sa,S)-TS4 (Sa,S)-TS3 46 Pd–C = 2.17 Å 47 Pd–H = 1.89 Å 48 49 Pd–C = 2.31 Å 50 51 C–H = 1.62 Å 52 Pd–H = 1.62 Å 53

54 Pd–C = 2.09 Å 55 Pd–C = 2.38 Å Pd–C = 2.64 Å

56 (Sa,S)-VI (Sa,S)-V (Sa,S)-TS5 57 58 59 60 ACS Paragon Plus Environment Page 7 of 11 Journal of the American Chemical Society

after a b-hydride elimination. We were pleased to find that Figure 5. Comparison of intermediates III and III’ in the 1 this step also presents a notable activation barrier, especially (Ra,R) and (Sa,S) series. Ligand omitted for the sake of clarity. 2 due to the high stability of the insertion intermediate III. In- 3 4 terestingly enough, the isomer preference reverses at this 5 point, and (Sa,S)-TS3 becomes the most favored diastere- ǂ C4 6 omer (ΔG = 14.6 kcal/mol), in fair agreement with the exper- 7 imental results. Moreover, the (Ra,S)-TS3 or (Sa,R)- TS3, C3 8 leading to experimentally undetected products are the highest C ǂ 3 9 in energy (ΔG = 25.4 and 20.2 kcal/mol, respectively), while Pd C4 P 10 ǂ syn (Ra,R)-TS3 has an activation barrier of ΔG = 18.2 kcal/mol, Psyn Pd 11 accounting for the high levels of enantioselectivity observed. Ptrans 12 For these reasons, TS3 becomes a solid candidate to be the Ptrans (R ,R)-III 13 stereo-determining step of the reaction. This proposal re- a (Ra,R)-III’ 14 quires that TS2 is a reversible step, and indeed, the barrier for 15 the reversion from (Ra,R)-III to (Ra,R)-TS2 shows an afford- 16 able energy of 21.4 kcal/mol. 17 C4 18 On the other hand, the inspection of the structure of the C3 19 elimination transition states (TS3) indicates that they cannot C3 20 be directly accessed from the previous III-type intermediates. Pd C4 P 21 A large reorientation and rotation of the biaryl moiety must syn Pd Psyn 22 take place to prepare the substrate for the b-hydride elimina- Ptrans 23 tion. Indeed, a second intermediate structure III’ was located, (Sa,S)-III P (Sa,S)-III’ trans 24 presenting an agostic interaction of palladium with the adja- 25 cent C–H bond, immediately preceding the b-elimination. Summarizing, the combination of the reversibility of TS2, 26 The participation of intermediates III and III’ in the mecha- at least for some of the isomers, together with the large energy 27 nism could be also confirmed through forward and backward difference between the isomeric TS3 transition states and a 28 IRC calculations starting from TS2 and TS3 respectively. Un- difficult reorganization from III to III’ can explain the prefer- 29 fortunately, any attempts to find suitable transition state(s) ential formation of the Sa,S isomer. This unprecedented 30 for the conversion of intermediates III into III’ were unsuc- 31 mechanistic profile appears to be governed by the hetero- 32 cessful, but a comparative analysis of their structures reveals biaryl moiety: in reactions with simple aryl triflates, the inser- 33 that a major reorganization in a sterically very crowded envi- tion step appears to be the stereodetermining one. Conse- 18 19 34 ronment is required. Remarkably, this reorganization appears quently, the use or (Ra)-BINAP or (Ra)-DM-BINAP as the 35 to be particularly complex for the (R,R) isomer. For instance, ligands in this case results in the formation of major products 36 change in the Psyn-Pd-C3(furane)-C4(furane) dihedral angle serves with the R configuration in low to moderate enantiomeric ex- 24 37 as an illustrative index: it moves from 66.6° in (Ra,R)-III to cesses. 38 150.5° in (Ra,R)-III’, while the same rotation in the (Sa,S) se- In the reaction of 1b(Br), it is assumed that the precipita- 39 ries is significantly shorter (from −93.0° to -144°) (Figure 5). tion of NaBr in toluene causes a ligand exchange 40 Furthermore, a potential energy surface scan was performed (Br→OtBu).14d Therefore, the main difference with the origi- 41 for the variation of the dihedral angle in (Sa,S)-III from 93° to nal reaction from 1b is the basicity and coordination ability of 42 144° without any noticeable limitation, while the angle in the counteranion (OtBu versus OTf). According to the pro- 43 (Ra,R)-III presents a rotation restricted to the interval be- posed mechanism, the poor reactivity observed for 1b(Br) is 44 tween 67° and 110° due to the steric collision between the then explained by the lower concentration of the reactive in- 45 quinoline and the aryl phosphine moieties at that point. To termediate II, in equilibrium with the unproductive neutral 46 t 47 complete the rotation, the phospines must move largely aside species II(O Bu) (Scheme 5). Similarly, the exclusive for- 48 with the accompanying energetic cost. mation of 3’b can tentatively be attributed to a fast deproto- t 49 From this point forward, intermediates IV evolve to either nation of the intermediate (Sa,S)-IV(O Bu) with respect of 50 the minor products 3’ by decoordination or, after reinsertion the reinsertion of the hydride. 51 [→V via TS4] and a second b-hydride elimination [→VI via 52 TS5], the major (or unique) products 3. The calculated acti- 53 vation energies for these last steps are very low (ΔGǂ = 0.2 and 54 4.2 kcal/mol for (Sa,S)-TS4 and (Sa,S)-TS5, respectively) 55 and, therefore, they don’t have any influence on the stereo- 56 chemical outcome of the reaction. 57 58 59 60 ACS Paragon Plus Environment Journal of the American Chemical Society Page 8 of 11

Scheme 5. Singularities in the reaction of 1b(Br) with 2. In order to illustrate the synthetic utility of the methodol- 1 ogy, compound 5b was subjected to N-Boc deprotection with 2 Ar Ar Ar + P + P TFA and the resulting cyclic imine 21 was employed as ligand N P N 3 Pd Pd Pd II t for the synthesis of the chiral Pd (allyl) complex 22 (Scheme 4 BuO P N P Z P Ar Ar Ar 6). Additionally, reduction of the imine group of 21 with 5 II (OtBu) I II 6 NaBH4 afforded bifunctional pyrrolidine derivative 23 pos- 7 Ar sessing appealing structural characteristics for its use in asym- R P 3 metric organocatalysis. Importantly, no epimerization was 8 R Pd0 tBuOH P 9 N O observed in any of these transformations. Ar Ar P 10 fast + P R Pd Scheme 6. Representative transformations from 5b. 11 Ar R H 12 N O + − slow − 13 tBuO R tBuO (S ,S)-IV (OtBu) R 3 Pd a Ar 1) [PdCl(allyl)] N 14 2 SbF N O + N 6 15 Pd P 2) AgSbF6 94% 16 P Ar 17 22: dr >20:1; 99% ee 18 N N Several attempts to obtain and characterize the cationic ox- TFA/CH2Cl2 19 + N 0 ºC to rt N idative addition intermediate I with the optimal ligand (Ra)- 90% 20 Boc DM-BINAP L9 were unsuccessful. We hypothesized that the 5b, dr >20:1; 99% ee 21, dr >20:1; 99% ee 21 very high steric crowding in this intermediate could be re- 22 N sponsible for its instability. (Ra)-BINAP L1 is a very similar NaBH4, MeOH N 23 H ligand that provided also good reactivity and selectivity, but 87% 24 the corresponding intermediate has a lower steric demand 23, dr >20:1; 99% ee 25 around the Pd center. In fact, equimolar amounts of 26 0 27 [Pd(Cp)(allyl)] as the Pd precursor, rac-1b(OTf) and L1 CONCLUSION cleanly reacted to afford the expected intermediate IL1(OTf) 28 In summary, we have developed a highly regio-, diastereo 29 as a relatively stable, crystalline compound whose structure was unequivocally confirmed by X-ray diffraction analysis and enantioselective dynamic kinetic asymmetric Heck reac- 30 tion of racemic heterobiaryl sulfonates with electron-rich ole- 31 (Figure 6). Interestingly, the stereogenic axis in the solid state fins. This transformation represents the first example of the 32 shows the same (Ra) configuration as the most stable calcu- + use of an asymmetric Heck reaction to resolve both a stereo- 33 lated intermediate (Ra)-I . Nevertheless, the stoichiometric 34 reaction of this isolated intermediate with dihydrofuran 2 in genic axis and a stereocenter simultaneously, showing a broad scope of axially chiral heterobiaryl compounds with electron- 35 toluene at 80 °C afforded the product (Sa,S)-3a in 82% yield rich cyclic and acyclic olefins using L9 and L4, respectively. 36 and 77% ee. 37 Facile stereoretentive transformations led to appealing axially chiral heterobiaryl complexes and bifunctional organocata- 38 Figure 6. Synthesis of IL1(OTf) and ORTEP drawing of the + lysts whose applications are currently under investigation in 39 cation IL1 . 40 our laboratories. + − 41 TfO Ph Ph ASSOCIATED CONTENT 42 N Toluene N P L1 + Pd + OTf Pd 43 80 °C P The Supporting Information is available free of charge on the 44 Ph Ph ACS Publications website. 45 rac-1a(OTf) Experimental procedures, optimization studies, characterization 46 data, NMR spectra for new compounds, and HPLC traces 47 (PDF). 48 Crystallographic data for (Sa,S)-3b (CIF)

49 N P Crystallographic data for (Sa,S)-5’b (CIF) 50 (R) Crystallographic data for ent-16∙HCl (CIF) 51 Pd Crystallographic data for IL1(OTf) (CIF) 52 P Detailed computational study. Calculated structures and ener- 53 gies (PDF) 54 Three-dimensional structural data of (Sa)-A (PDB) 55 + IL1 Three-dimensional structural data of (Ra)-A (PDB) 56 Three-dimensional structural data of (Sa)-TS0 (PDB) 57 Three-dimensional structural data of (Ra)-TS0 (PDB) 58 59 60 ACS Paragon Plus Environment Page 9 of 11 Journal of the American Chemical Society

Three-dimensional structural data of (Sa)-I (PDB) (5) Yang, Z.; Zhou, J. J. Am. Chem. Soc. 2012, 134, 11833. 1 (6) Wu, C.; Zhou, J. J. Am. Chem. Soc. 2014, 136, 650. Three-dimensional structural data of (Ra)-I (PDB) 2 + (7) (a) Borrajo-Calleja, G. M.; Bizet, V.; Burgi,̈ T.; Mazet, C. Chem. Sci. Three-dimensional structural data of (Sa)-I (PDB) 3 + 2015, 6, 4807. (b) Zhang, Q.-S.; Wan, S.-L.; Chen, D.; Ding, C.-H.; Hou, X.- Three-dimensional structural data of (Ra)-I (PDB) 4 L. Chem. Commun., 2015, 51, 12235 . Three-dimensional structural data of TSepi (PDB) (8) (a) Werner, E. W.; Mei, T.-S.; Burckle, A. J.; Sigman, M. S. Science 5 Three-dimensional structural data of (Sa)-TS1 (PDB) 2012, 338, 1455. (b) Oliveira, C. C.; Angnes, R. A.; Correia, C. R. D. J. Org. 6 Three-dimensional structural data of (Sa,S)-II (PDB) Chem. 2013, 78, 4373. (c) Oliveira, C. C.; Pfaltz, A.; Correia, C. R. D. Angew. 7 Chem. Int. Ed. 2015, 54, 14036. Three-dimensional structural data of (Sa,S)-TS2 (PDB) 8 (9) Zhang, C.; Santiago, C. B.; Kou, L.; Sigman M. S. J. Am. Chem. Soc. Three-dimensional structural data of (Sa,S)-III(PDB) 9 2015, 137, 7290. Three-dimensional structural data of (Sa,S)-III’(PDB) 10 (10) (a) Mei, T.-S.; Werner, E. W.; Burckle, A. J.; Sigman, M. S. J. Am. Three-dimensional structural data of (Ra,R)-III(PDB) Chem. Soc. 2013, 135, 6830. (b) Mei, T.-S.; Patel, H. H.; Sigman, M. S. Na- 11 Three-dimensional structural data of (Ra,R)-III’(PDB) ture 2014, 508, 340. (c) Zhang, C.; Santiago, C. B.; Crawford, J. M.; Sigman, 12 Three-dimensional structural data of (Sa,S)-TS3 (PDB) M. S. J. Am. Chem. Soc. 2015, 137, 15668 (d) Chen, Z. M.; Hilton, M. J.; 13 Sigman, M. S. J. Am. Chem. Soc. 2016, 138, 11461. Three-dimensional structural data of (Sa,S)-IV (PDB) 14 (11) Lapierre, A. J. B.; Geib, S. J.; Curran, D. P. J. Am. Chem. Soc. 2007, Three-dimensional structural data of (Sa,S)-TS4 (PDB) 15 129, 494. (b) Guthrie, D. B.; Geib, S. J.; Curran, D. P. J. Am. Chem. Soc. Three-dimensional structural data of (Sa,S)-V (PDB) 16 2011, 133, 115. Three-dimensional structural data of (Sa,S)-TS5 (PDB) 17 (12) Selected reviews: (a) Cherney, A. H.; Kadunce, N. T.; Reisman, S. Three-dimensional structural data of (Sa,S)-VI (PDB) 18 E. Chem. Rev. 2015, 115, 9587. (b) Zhang, D.; Wang , Q. Coord. Chem. Rev. 2015, 286, 1. (c) Pauline, L.; Manoury, E.; Poli, R.; Deydier, E.; Labande, A. 19 AUTHOR INFORMATION Coord. Chem. Rev. 2016, 308, 131 20 (13) Selected reviews: (a) Ma, G.; Sibi, M. P. Chem. Eur. J. 2015, 21, Corresponding Author 21 11644. (b) Wencel-Delord, J.; Panossian, A.; Leroux, F. R.; Colobert, F. 22 *[email protected]. Chem. Soc. Rev. 2015, 44, 3418. (c) Tanaka, K. Chem. Asian J. 2009, 4, 508. 23 *[email protected]. Selected examples: (d) Gao, D.-W.; Gu, Q.; You, S.-L. ACS Catal. 2014, 4, 2741. (e) Staniland, S.; Adams, R. W.; McDouall, J. J. W.; Maffucci, I.; Con- 24 *[email protected]. tini, A.; Grainger, D. M.; Turner, N. J.; Clayden, J. Angew. Chem. Int. Ed. 25 2016, 55, 10755. (f) Zheng, J.; You, S.-L. Angew. Chem. Int. Ed. 2014, 53, 26 Notes 13244. 27 The authors declare no competing financial interests (14) (a) Ros, A.; Estepa, B.; Ramírez-López, P.; Alvarez,́ E.; Fernández, 28 R.; Lassaletta, J. M. J. Am. Chem. Soc. 2013, 135, 15730. (b) Ramírez-López, ACKNOWLEDGMENT 29 P.; Ros, A.; Estepa, B.; Fernández, R.; Fiser, B.; Gómez-Bengoa, E.; Las- saletta, J. M. ACS Catal. 2016, 6, 3955. (c) See also: Bhat, V.; Wang, S.; 30 Dedicated to Professor Miguel Yus on the occasion of his 70th Stoltz, B. M.; Virgil, S. C. J. Am. Chem. Soc. 2013, 135, 16829. (d) Ramírez- 31 birthday. We thank the Spanish Ministerio de Ciencia e Inno- López, P.; Ros, A.; Romero-Arenas, A.; Iglesias-Siguenza,̈ J.; Fernández, R.; 32 vación (Grants CTQ2016-76908-C2-1-P, CTQ2016-76908- Lassaletta, J. M. J. Am. Chem. Soc. 2016, 138, 12053. (e) Hornillos, V.; Ros, 33 C2-2-P, CTQ2016-78083-P and contract RYC-2013-12585 for A.; Ramírez-Lopez, P.; Iglesias- Siguenza,̈ J.; Fernández, R.; Lassaletta, J. M. 34 A.R.), European funding (ERDF), Junta de Andalucía (Grant Chem. Commun. 2016, 52, 14121. 35 2012/FQM 10787 and fellowship for J. A. C.). VH thanks the (15) Selected examples: (a) Denmark, S. E.; Fan, Y. Tetrahedron: Asym- 36 metry 2006, 17, 687. (b) Nareddy, P.; Mantilli, L.; Guenée, L.; Mazet, C. An- Junta de Andalucía and the European Union’s Seventh Frame- gew. Chem. Int. Ed. 2012, 51, 3826. (c) Shibatomi, K.; Soga, Y.; Narayama, 37 work Program, Marie Skłodowska-Curie actions for a Talent A.; Fujisawa, I.; Iwasa, S. J. Am. Chem. Soc. 2012, 134, 9836. (d) Wang, S.; 38 Hub fellowship (COFUND - Grant Agreement nº 291780) and Li, J.; Miao, T.; Wu, W.; Li, Q.; Zhuang, Y.; Zhou, Z.; Qiu, L. Org. Lett. 2012, 39 the University of Seville for a research grant (no 1800511201). 14, 1966. (e) Bai, X.-F.; Song, T.; Xu, Z.; Xia, C.-G.; Huang, W. S.; Xu, L.-W. 40 E.G.-B. thanks IZO-SGI SGIker of UPV-EHU for human and Angew. Chem. Int. Ed. 2015, 54, 5255. (f) Zhang, J.-W.; Xu, J.-H.; Cheng, D.- 41 technical support. We also thank Prof. Celia Maya for assistance J.; Shi, C.; Liu, X.-Y.; Tan, B. Nat. Commun. 2016, 7, 10677. (g) Race, N. J.; 42 Faulkner, A.; Fumagalli, G.; Yamauchi, T.; Scott, J. S.; Rydén-Landergren, with the X-ray crystallographic studies. M.; Sparkes H. A.; Bower; J. F. Chem. Sci. 2017, 8, 1981. 43 (16) (a) Rios, R.; Jimeno, C.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 44 REFERENCES 2002, 124, 10272. (b) Shibata, T.; Otomo, M.; Tahara, Y.; Endo, K. Org. Bi- 45 (1) Reviews: (a) Heck, R. F. Acc. Chem. Res. 1979, 12, 146. (b) The Mi- omol. Chem. 2008, 6, 4296. (c) Iorio, N. D.; Righi, P.; Mazzanti, A.; Manci- 46 zoroki-Heck Reaction; Oestreich, M., Ed.; Wiley: New York, 2009. (c) Bräse, nelli, M.; Ciogli, A.; Bencivenni, G. J. Am. Chem. Soc. 2014, 136, 10250. (d) 47 S.; de Meijere, A. In Metal-Catalyzed Cross-Coupling Reactions; de Meijere, Liu, H.-C.; Tao, H.-Y.; Cong, H.; Wang, C.-J. J. Org. Chem. 2016, 81, 3752. (e) Yang, Y.; Liu, H.; Peng, C.; Wu, J.; Zhang, J.; Qiao, Y.; Wang, X.-N.; 48 A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2014; pp 533-633. Chang, J. Org. Lett. 2016, 18, 5022. (f) Borie, C.; Vanthuyne, N.; Bertrand, 49 (2) Ozawa, F.; Kubo, A.; Hayashi, T. J. Am. Chem. Soc. 1991, 113, 1417. (3) Reviews: (a) Loiseleur, O.; Hayashi, M.; Keenan, M.; Schmees, N.; M. P.; Siri, D.; Nechab, M. ACS Catal. 2016, 6, 1559. (g) Min, C.; Lin, Y.; 50 Pfaltz, A. J. Organomet. Chem. 1999, 576, 16. (b) Tietze, L. F.; Ila, H.; Bell, Seidel, D. Angew. Chem. Int. Ed. 2017, 56, 15353. (h) Liu, Y.; Tse, Y.-L. S.; 51 H. P. Chem. Rev. 2004, 104, 3453. (c) McCartney, D.; Guiry, P. J. Chem. Soc. Kwong, F. Y.; Yeung, Y.-Y. ACS Catal. 2017, 7, 4435. 52 Rev. 2011, 40, 5122. (d) Shibasaki, M.; Vogl, E. M.; Ohshima, T. Adv. Synth. (17) Knowles, J. P.; Whiting, A. Org. Biomol. Chem. 2007, 5, 31. 53 Catal. 2004, 346, 1533. (18) Ozawa, F.; Kubo, A.; Matsumoto, Y.; Hayashi, T.; Nishioka, E.; Yan- (4) (a) Wöste, T. H.; Oestreich, M. Chem. Eur. J. 2011, 17, 11914. (b) agi, K.; Moriguichi, K. Organometallics 1993, 12, 4188. 54 (19) Rankic, D. A.; Lucciola, D.; Keay, B. A. Tetrahedron Lett. 2010, 51, 55 Hu, J.; Hirao, H.; Li, Y.; Zhou, J. Angew. Chem. Int. Ed. 2013, 52, 8676. (c) Hu, J.; Lu, Y.; Li, Y.; Zhou, J. Chem. Commun. 2013, 49, 9425. (d) Liu, S.; 5724. 56 Zhou, J. Chem. Commun. 2013, 49, 11758. (e) Oestreich, M. Angew. Chem. (20) Obtained by reaction of 1b with norbornadiene using (S)-DM- 57 Int. Ed. 2014, 53, 2282. BINAP as the ligand followed by treatment with HCl. 58 59 60 ACS Paragon Plus Environment Journal of the American Chemical Society Page 10 of 11

(21) For a theoretical study of the asymmetric Heck reaction using P,N- 1 ligands see: Henriksen, S. T.; Norrby, P.-O.; Kaukoranta, P.; Andersson, P. 2 G. J. Am. Chem. Soc. 2008, 130, 10414. 0 3 (22) For a similar result using a related [Pd (QUINAP] system see ref 4 14b. (23) Legault, C. Y. CYLview, 1.0b; Université de Sherbrooke: Sher- 5 brooke, Canada, 2009 (http://www.cylview.org). 6 (24) Remarkably, an erosion of the enantioselectivity of the major prod- 7 uct is observed when the original system reported by Hayashi [Ref. 18, 8 PhOTf / (R)-BINAP; 82% ee (R)] is modified with a bulkier ligand [ref 17: 9 PhOTf / (R)-DM-BINAP, 21% ee (R)] or combination of bulkier ligand and substrate [this work, biphenyl triflate / (R)-DM-BINAP, 9% ee (S)]. 10 This observation puts in context the excellent results observed with hetero- 11 biaryl substrates. 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment Page 11 of 11 Journal of the American Chemical Society

1 SYNOPSIS TOC (Word Style “SN_Synopsis_TOC”). 2 R2 X R2 X R2 X 3 Y Y Y N N N R1 R1 R1 4 Z Z OSO2R 5 Z [Pd] [Pd] Z Z = OR, N(Me)Ac Z = O, NBoc R5 R5 R5 6 high yields high yields R4 R3 R4 R3 R4 R3 7 up to 94% ee racemic >20:1 dr’s X, Y = CH, N 8 up to 99% ee 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment