Palladium-Catalyzed, Enantioselective Formal Cycloaddition between Benzyltriflamides and Allenes: Straightforward Access to Enantioenriched Isoquinolines

Palladium-Catalyzed, Enantioselective Formal Cycloaddition between Benzyltriflamides and Allenes: Straightforward Access to Enantioenriched Isoquinolines Xandro Vidal, JoseL. Mascarenas,*and Moise s Gulías* Centro Singular de Investigacion en Química Bioloxica e Materiais Moleculares (CIQUS) and Departamento de Química Orga nica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain * SSupporting Information ABSTRACT: Benzyl and allyltriflamides can engage in Pd-catalyzed oxidative (4+2) annulations with allenes, to produce highly valuable tetrahydroisoquinoline or dihydropyridine skeletons. The reaction is especially efficient when carried out in the presence of designed N-protected amino acids as metal ligands. More importantly, using this type of chiral ligands, it is possible to perform desymmetrizing, annulative C−H activations of prochiral diarylmethylphenyl amides, and thus obtain the corresponding isoquinolines with high enantiomeric ratios. The metal-catalyzed functionalization of nonactivated C− H bonds has emerged as an extremely powerful synthetic tool. 1 Moreover, if the C−H activation is appropriately harnessed to encompass a concomitant annulation reaction, the methodology allows a direct assembly of cyclic skeletons from simple, nonfunctionalized acyclic starting materials. 2 In this context, we have reported several Rh and Pd-catalyzed annulations of alkenylphenols and alkenylanilides with different unsaturated partners. These strategies allow to build a variety of heterocyclic products in a straightforward manner. 3 The use of allenes as annulation partners is particularly attractive owing to their inherent reactivity, and because they favor reductive elimination versus β-hydride elimination steps in key metallacyclic intermediates. 4 Owing to this special reactivity, we wondered if allenes could engage in annulative C−H functionalizations of benzyl- or allylamines, as this would allow to build highly valuable tetrahydroisoquinoline and tetrahydropyridine skeletons from simple precursors. Achieving these transformations is far from obvious, not only because of the difficulties associated with the C−H activation and allene insertion steps but also because of competing benzylic or allylic oxidation reactions. Indeed, the only precedent in this type of annulations involves the use of α,α-disubstituted benzylamines (which cant be oxidized) and monosubstituted allenes, and provides mixtures of isomeric adducts. 5,6 Herein, we report the discovery of conditions that allow to carry out efficient Pd-catalyzed annulations between benzylamides and allenes. The reaction works for α-unsubstituted and monosubstituted benzyltriflamides, and different types of allene partners, and takes place with excellent regio- and stereoselectivities. The annulation can be extended to allyl and even homoallylamines, thereby allowing to build dihydropyridine and azepine skeletons. More importantly, we demonstrate that the tetrahydroisoquinoline products can be assembled in an efficient and highly enantioselective manner via desymmetrization of prochiral starting materials (Scheme 1A). While several desymmetrizing C−H activation/functionalization processes have been described, especially under Pdcatalysis, 7−9 to the best of our knowledge, palladium-catalyzed enantioselective formal cycloadditions relying on C−H activations are unknown. 10 Moreover, the number of reports on any desymmetrizing metal-mediated annulations involving C−H activations is marginal. 11 Finally, it is important to note that tetrahydroisoquinoline skeletons are privileged scaffolds present in a vast amount of bioactive natural products and drugs (Scheme 1B), and therefore the development of enantioselective approaches to these cyclic skeletons is of major significance. 12 Considering our previous work on the annulation of alkenylanilides and allenes under palladium catalysis, 3e we Received: November 25, 2018 Published: January 13, 2019 Scheme 1. Asymmetric C−H Activation/Annulation Approach to Isoquinoline Skeletons Communication pubs.acs.org/JACS Cite This: J. Am. Chem. Soc. 2019, 141, 1862−1866 © 2019 American Chemical Society 1862 DOI: 10.1021/jacs.8b12636 J. Am. Chem. Soc. 2019, 141, 1862−1866 This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License, which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes. Downloaded via UNIV DE SANTIAGO DE COMPOSTELA on May 2, 2019 at 12:22:08 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. began our research by exploring the reaction between benzyltriflamide 1a and vinylidenecyclohexane (2a) in the presence of 1.5 equiv of Cs2CO3, and using Pd (OAc)2as catalyst, and Cu(OAc)2as reoxidant. With tert-amyl alcohol as solvent, the desired (4+2) cycloadduct was isolated in a modest 15% yield. The use of other solvents, at the same temperature (80 °C), allowed for little improvements (up to 23−25% yield, Table 1, entries 1−5). Although the presence of the triflyl substituent in the amine slows down the benzylic oxidation, the formation of undesired benzylaldehyde was still significant (observed after the work-up). While the addition of DMSO in toluene allowed a slight increase in the yield to 34%, we found that adding protected amino acids (entries 6−10), and especially 2,6-F,F-Bz-Leu-OH (L, 40 mol %), boosts the yield up to 85% (entry 11). This could be further improved by adding 15 equiv of DMSO to the reaction mixture (95% yield, entry 12), with the reaction being complete after only 40 min. The role of the DMSO is unclear, but it may help to stabilize Pd(0) intermediates and favor a more effective reoxidation to Pd(II). Finally, the amount of Cu(OAc)2can be decreased to 50 mol % without significantly affecting the yield (entry 13). Using the optimized conditions, we found that the reaction can be extended to different types of allenes (see Table 2). Thus, other 1,1-dibsubstituted allenes like 5-vinylidenenonane (2b) or (4-methylpenta-1,2-dien-3-yl)benzene (2c) led to the corresponding isoquinolines 3ab and 3ac in 85 and 86% yield. 1,3-Disubstituted allenes 2d and 2e provided the corresponding adducts 3ad and 3ae, as only one stereo- and regioisomer (80 and 74% yield, respectively). Monosubstituted allenes like propa-1,2-dien-1-ylcyclohexane also work, to give 3af as 1.1:1 mixture of E:Zisomers. More impressively, trisubstituted allenes led to only one cycloadduct in a very efficient manner (3ag and 3ah, 80 and 90% yield, respectively). It is important to note that diphenylacetylene or styrene failed to react with 1a under the standard reaction conditions, which supports the special reactivity of allenes in this type of palladium catalyzed annulations. The reaction is not limited to unsubstituted benzyltriflamides, and thereby α-alkyl benzyltriflamides can participate in the annulations, providing for efficient kinetic resolutions. Therefore, treatment of 2 equiv of (1-phenylpropyl)triflamide (1b) with allene 2a, using standard conditions, produced a 91% yield of cycloadduct 3ba (45% yield based on the triflamide 1b,Table 2) with a very good 93:7 enantiomeric ratio (er). We also isolated a 40% yield of enantioenriched starting amide (er = 86:14). Next, we wondered if the annulation could be extended to more challenging triflamides bearing alkenyl instead of benzyl pendants. Palladium-catalyzed activations of olefinic C(sp2)− H bonds has been much less developed than that of their aromatic counterparts, in part because of competing alkene addition reactions. Gratifyingly, using the above conditions, allene 2a reacted efficiently with allylamines 1c and 1d to produce the expected tetrahydropyridines 3ca and 3da in 71 and 88% yield (Table 3). 13 This reaction is general for other allenes as exemplified with trisubstituted derivative 2g that led to the formation of 3cg in an excellent 90% yield. Interestingly, in a rare example of a formal (5+2) annulation, the transformation can be extended to homoallylic amines, as demonstrated with the assembly azepine 3ea (83%). This preliminary result proposes a trivial and practical entry to seven-membered azaheterocycles, and warrants further future research to explore the scope of the process. While the above examples demonstrate that using N-triflyl protected amines and allenes it is possible to achieve very appealing annulative C−H activations, the efficiency of the kinetic resolution to give optically active isoquinoline 3ba, called for exploring asymmetric variants based on desymmetrization strategies. Gratifyingly, treatment of the diphenylmethylamide 1f with allene 2a, under standard conditions at 90 °C, gave the expected cycloadduct 3fa with an excellent 85% yield and a very good 94:6 enantiomeric ratio. Similar results were obtained with other disubstituted allenes such 2b and 2c, Table 1. Optimization of the Reaction Conditions a Entry Solvent TLigand b Yield c 1t-AmyOH 80 °C−15% 2 Dioxane 80 °C−23% 3 DCE 80 °C−24% 4CH 3CN 80 °C−9% 5 Toluene 90 °C−25% 6 d Toluene 90 °C−34% 7 Toluene 90 °C Boc-Leu-NHOMe 37% 8 Toluene 90 °C Boc-Phe-NHOMe 31% 9 Toluene 90 °C Boc-Ala-OH 58% 10 Toluene 90 °C Boc-Val-OH 69% 11 Toluene 90 °C 2,6-F,F-Bz-Leu-OH 85% 12 d Toluene 90 °C 2,6-F,F-Bz-Leu-OH 95% e 13 d Toluene 90 °C 2,6-F,F-Bz-Leu-OH 86% e , f a Conditions: 0.333 mmol 1a, 0.167 mmol of allene 2a, 2 mL of solvent, under air, 16 h. b 40% of ligand. c Yields based on 2a, calculated by using an internal standard. d 15 equiv of DMSO added. e Isolated yield based on 2a. f 0.5 equiv of Cu(OAc)2·H2O Table 2. Pd(II)-Catalyzed Annulation of N- Benzyltriflimides with Allenes a a Isolated yield based on allenes, after 16 h. b E:Zand regioisomeric ratios are >20:1, unless otherwise noted. c Inseparable isomers. Regioisomeric ratio determined by crude 1H NMR. Journal of the American Chemical Society Communication DOI: 10.1021/jacs.8b12636 J. Am. Chem. Soc. 2019, 141, 1862−1866 1863 which gave the products 3fb and 3fc with yields between 66 and 95%, and 95:5 er ratios. Remarkably, using a monosubstituted allene (propa-1,2-dien-1-ylcyclohexane, 2f), we obtained an excellent yield (81%) and er (93:7) of the adduct 3ffand, contrary to the reaction with the unsubstituted benzyltriflamide (Table 2), we only observed the Zisomer. Other prochiral substrates featuring different substituents at the aryl moiety also participated in the annulation. Therefore, products like 3ga or 3gf, in which the phenyl groups have ortho methyl substituents, were produced in excellent yields and with enantiomeric ratios of 97:3 and 98:2. A crystal structure of 3ga allowed to stablish the absolute configuration of the chiral center (Table 4). For the case of para substituted aromatic rings, the reaction was also very efficient, and products 3ha, 3hb,3ia and 3ib, were isolated in yields of 86−95% yields, and enantiomeric ratios of up to 95:5. Finally, cycloadducts with methoxy substituents in para or meta positions of the aromatic rings were also efficiently formed (3ja and 3ka), although the enantiomeric ratio slightly dropped to 90:10 for the latter. A hypothetical catalytic cycle depicted in Scheme 2 allows to infer key elements that are critical for the success of the above annulations. The triflyl group should favor deprotonation at the nitrogen, and the formation of intermediates like I,in which eliminations of benzylic hydrogens might be not especially easy. 14 The amino acid ligand likely plays a key role in facilitating the C−H activation to give palladacycle IIb, which after coordination of the allene would form intermediate III. This intermediate evolves by migratory insertion to give a π-allylic palladacycle (IV), which undergoes a N−Csp 2 reductiveelimination,favoredbythepresenceofthe coordinating exoalkene group. Pd(0) is reoxidized to the active Pd(II) catalyst through a combination of Cu(OAc)2and air. In the case of the desymmetrization process, the palladacycle intermediate of type II is chiral, and the preferred formation of one of the enantiomer over the other must be attributed to steric clashing effects in the C−H activation step (Ito II), as proposed for simple functionalization reactions. 14 In conclusion, we have developed a straightforward access to highly valuable tetrahydroisoquinoline and tetrahydropyridine skeletons through a palladium-catalyzed formal (4+2) cycloaddition of benzyl and allylamines to allenes. The reaction relies on a Pd-catalyzed Csp2−H activation, and presents excellent levels of chemo- and regioselectivity; being also highly appealing in terms of atom economy. More important, the annulation can be performed in an enantioselective fashion using prochiral diarylmethylamines, leading to enantiomeric Table 3. Pd(II)-Catalyzed Annulation between N-Allyl (and Homoallyltriflamides) and Allenes a a Isolated yields based on allenes 2after 16 h. b 105 °C. c An equimolar amount of 1e and 2a was used. Table 4. Enantioselective Pd(II)-Desymmetrization of Diarylmethyltriflamide a , b a Conditions: 0.333 mmol of amides 1, 0.167 mmol of allenes 2, under air, 16 h. Isolated yields based on 2. b Structure of the major product shown. c 70 °C, 3 days. d 0.167 mmol of triflamide 1g, 0.333 mmol of allenes 2a and 2d. Yield based on 1g. e Hydrogens omitted for clarity. Note: Ar represents the same aromatic ring than that undergoing the transformation, as corresponds for a symmetric substrate. Scheme 2. Mechanistic Proposal Journal of the American Chemical Society Communication DOI: 10.1021/jacs.8b12636 J. Am. Chem. Soc. 2019, 141, 1862−1866 1864 ratios up to 98:2. This type of palladium-catalyzed annulative C−H activation/desymmetrization processes, which had not been previously reported, represents an important new addition to the armory of catalytic asymmetric methods. ■ASSOCIATED CONTENT * SSupporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b12636. Experimental procedures and spectroscopic data for new compounds (PDF) CIF file for compound 3ba (CIF) CIF file for compound 3ga (CIF) ■AUTHOR INFORMATION Corresponding Authors *[email protected] *[email protected] ORCID JoseL. Mascarenas: 0000-0002-7789-700X Moise s Gulías: 0000-0001-8093-2454 Notes The authors declare no competing financial interest. ■ACKNOWLEDGMENTS This work has received financial support from Spanish grants (SAF2016-76689-R, CTQ2016-77047-P and FPU fellowship to X.V.), the Conselleri  a de Cultura, Educacion e Ordenacion Universitaria (ED431C 2017/19, 2015-CP082 and Centro Singular de Investigacion de Galicia accreditation 2016-2019, ED431G/09), the European Regional Development Fund (ERDF), and the European Research Council (Advanced Grant No. 340055). The orfeo-cinqa network CTQ2016- 81797-REDC is also kindly acknowledged. ■REFERENCES (1) For selected recent reviews of metal-catalyzed C−H functionalizations, see: (a) Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord. Mild metal-catalyzed C−H activation: examples and concepts. Chem. Soc. Rev. 2016,45, 2900−2936. (b) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Weak coordination as a powerful means for developing broadly useful C−H functionalization reactions. Acc. Chem. Res. 2012,45, 788−802. (c) Yeung, C. S.; Dong, V. M. Catalytic dehydrogenative cross-coupling: forming carbon−carbon bonds by oxidizing two carbon−hydrogen bonds. Chem. Rev. 2011, 111, 1215−1292. (d) Chen, D. Y.-K.; Youn, S. W. C-H activation: a complementary tool in the total synthesis of complex natural products. Chem. - Eur. J. 2012,18, 9452−9474. (e) Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. Transition metalcatalyzed C-H bond functionalization by the use of diverse directing groups. Org. Chem. Front. 2015,2, 1107−1295. (2) For a recent review on the field, see: Gulías, M.; Mascarenas, J. L. Metal-catalyzed annulations through activation and cleavage of C-H bonds. Angew. Chem., Int. Ed. 2016,55, 11000−11019. (3) For selected examples, see: (a) Seoane, A.; Casanova, N.; Quinones, N.; Mascarenas, J. L.; Gulías, M. Rhodium(III)-catalyzed dearomatizing (3 + 2) annulation of 2-alkenylphenols and alkynes. J. Am. Chem. Soc. 2014,136, 7607−7610. (b) Seoane, A.; Casanova, N.; Quinones, N.; Mascarenas, J. L.; Gulías, M. Straightforward assembly of benzoxepines by means of a rhodium(III)-catalyzed C−H functionalization of o-vinylphenols. J. Am. Chem. Soc. 2014,136, 834−837. (c) Casanova, N.; Seoane, A.; Mascarenas, J. L.; Gulías, M. Rhodium-catalyzed (5 + 1) annulations between 2-alkenylphenols and allenes: a practical entry to 2,2-disubstituted 2H-chromenes. Angew. Chem., Int. Ed. 2015,54, 2374−2377. (d) Palladium(II)-catalyzed annulation between ortho-alkenylphenols and allenes. Key role of the metal geometry in determining the reaction outcome. Casanova, N.; Del Rio, K. P.; García-Fandino, R.; Mascarenas, J. L.; Gulías, M. ACS Catal. 2016,6, 3349−3353. (e) Cendon, B.; Casanova, N.; Comanescu, C.; García-Fandino,R.;Seoane,A.;Gulías,M.; Mascarenas, J. L. Palladium-catalyzed formal (5 + 2) annulation between ortho-alkenylanilides and allenes. Org. Lett. 2017,19, 1674− 1677. (f) Font, M.; Cendon, B.; Seoane, A.; Mascarenas, J. L.; Gulías, M. Rhodium(III)-catalyzed annulation of 2-alkenylanilides with alkynes via C-H activation: a direct access to 2-substituted indolines. Angew. Chem., Int. Ed. 2018,57, 8255−8259. (4) For a discussion on the role of the geometry of the metal center and the π-allyl system in favoring the reductive elimination, see ref 3d. (5) Rodríguez, A.; Albert, J.; Ariza, X.; Garcia, J.; Granell, J.; Farra s, J.; La Mela, A.; Nicolas, E. J. Catalytic C−H activation of phenylethylamines or benzylamines and their annulation with allenes. J. Org. Chem. 2014,79, 9578−9585. (6) For selected examples of metal-catalyzed C−H functionalization with allenes, see: (a) Zeng, R.; Wu, S.; Fu, C.; Ma, S. Roomtemperature synthesis of trisubstituted allenylsilanes via regioselective C−H functionalization. J. Am. Chem. Soc. 2013,135, 18284−18287. (b) Gandeepan, P.; Rajamalli, P.; Cheng, C.-H. Rhodium(III)- catalyzed [4 + 1] annulation of aromatic and vinylic carboxylic acids with allenes: an efficient method towards vinyl-substituted phthalides and 2-furanones. Chem. - Eur. J. 2015,21, 9198−9203. (c) Nakanowatari, S.; Ackermann, L. Ruthenium(II)-catalyzed C-H functionalizations with allenes: versatile allenylations and allylations. Chem. - Eur. J. 2015,21, 16246−16251. (d) Thrimurtulu, N.; Dey, A.; Maiti, D.; Volla, C. M. R. Cobalt-catalyzed sp2-C−H activation: intermolecular heterocyclization with allenes at room temperature. Angew. Chem., Int. Ed. 2016,55, 12361−12365. (e) Zeng, R.; Fu, C.; Ma, S. Highly selective mild stepwise allylation of N-methoxybenzamides with allenes. J. Am. Chem. Soc. 2012,134, 9597−9600. (f) Wang, H.; Glorius, F. Mild rhodium(III)-catalyzed C−H activation and intermolecular annulation with allenes. Angew. Chem., Int. Ed. 2012, 51, 7318−7322. (g) Wu, L.; Meng, Y.; Ferguson, J.; Wang, L.; Zeng, F. Palladium-catalyzed oxidative annulation of ortho-alkenylanilines and allenes: an access to benzo[b]azepines. J. Org. Chem. 2017,82, 4121−4128. (h) For a review, see: Santhoshkumar, R.; Cheng, C.-H. Fickle reactivity of allenes in transition-metal-catalyzed C−H Functionalizations. Asian J. Org. Chem. 2018,7, 1151. (7) For reviews in enantioselective C−H functionalization, see: (a) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q. Transition metal-catalyzed C−H activation reactions: diastereoselectivity and enantioselectivity. Chem. Soc. Rev. 2009,38, 3242−3272. (b) Newton, C. G.; Wang, S.-G.; Oliveira, C. C.; Cramer, N. Catalytic enantioselective transformations involving C−H bond cleavage by transition-metal complexes. Chem. Rev. 2017,117, 8908−8976. (c) Saint-Denis, T. G.; Zhu, R.-Y.; Chen, G.; Wu, Q.-F.; Yu, J.-Q. Enantioselective C(sp3)−H bond activation by chiral transition metal catalysts. Science 2018,359, eaao4798. (8) For recent examples of enantioselective Pd(II)-catalyzed C−H activations, see: (a) Gao, D.-W.; Shi, Y.-C.; Gu, Q.; Zhao, Z.-L.; You, S.-L. Enantioselective synthesis of planar chiral ferrocenes via palladium-catalyzed direct coupling with arylboronic acids. J. Am. Chem. Soc. 2013,135,86−89. (b) Cheng, X.-F.; Li, Y.; Su, Y.-M.; Yin, F.; Wang, J.-Y.; Sheng, J.; Vora, H. U.; Wang, X.-S.; Yu, J.-Q. Pd(II)- catalyzed enantioselective C−H activation/C−O bond formation: synthesis of chiral benzofuranones. J. Am. Chem. Soc. 2013,135, 1236−1239. (c) Xiao, K.-J.; Chu, L.; Yu, J.-Q. Enantioselective C−H olefination of α-hydroxy and α-amino phenylacetic acids by kinetic resolution. Angew. Chem., Int. Ed. 2016,55, 2856−2860. (d) Chen, G.; Gong, W.; Zhuang, Z.; Andra, M. S.; Chen, Y.-Q.; Hong, X.; Yang, Y.-F.; Liu, T.; Houk, K. N.; Yu, J.-Q. Ligand-accelerated enantioselective methylene C(sp3)−H bond activation. Science 2016,353, 1023−1027. (e) Shen, P.-X.; Hu, L.; Shao, Q.; Hong, K.; Yu, J.-Q. Pd(II)-catalyzed enantioselective C(sp3)−H arylation of free carboxylic acids. J. Am. Chem. Soc. 2018,140 (21), 6545−6549. Journal of the American Chemical Society Communication DOI: 10.1021/jacs.8b12636 J. Am. Chem. Soc. 2019, 141, 1862−1866 1865 (f)Shi,H.;Herron,A.N.;Shao,Y.;Shao,Q.;Yu,J.-Q. Enantioselective remote meta-C−H arylation and alkylation via a chiral transient mediator. Nature 2018,558, 581−585. For recent examples of enantioselective reactions through C−H activation with other metals, see: (g) Zheng, J.; Cui, W.-J.; Zheng, C.; You, S.-L. Synthesis and application of chiral spiro Cp ligands in rhodiumcatalyzed asymmetric oxidative coupling of biaryl compounds with alkenes. J. Am. Chem. Soc. 2016,138, 5242−5245. (h) Shen, B.; Wan, B.; Li, X. Enantiodivergent desymmetrization in the rhodium(III)- catalyzed annulation of sulfoximines with diazo compounds. Angew. Chem., Int. Ed. 2018,57, 15534−15538. (i) Sun, Y.; Cramer, N. Enantioselective synthesis of chiral-at-sulfur 1,2-benzothiazines by CpxRhIII-catalyzed C−H functionalization of sulfoximines. Angew. Chem., Int. Ed. 2018,57, 15539−15543. (j) Shan, G.; Flegel, J.; Li, H.; Merten, C.; Ziegler, S.; Antonchick, A. P.; Waldmann, H. C−H Bond activation for the synthesis of heterocyclic atropisomers yields hedgehog pathway inhibitors. Angew. Chem., Int. Ed. 2018,57, 14250−14254. (9) For enantioselective reactions with benzylamines, see: (a) Chu, L.; Wang, X.-C.; Moore, C. E.; Rheingold, A. L.; Yu, J.-Q. Pdcatalyzed enantioselective C−H iodination: asymmetric synthesis of chiral diarylmethylamines. J. Am. Chem. Soc. 2013,135, 16344− 16347. (b) Chu, L.; Xiao, K.-J.; Yu, J.-Q. Room-temperature enantioselective C-H iodination via kinetic resolution. Science 2014, 346, 451−455. (c) Laforteza, B. N.; Chan, K. S. L.; Yu, J.-Q. Enantioselective ortho-C-H cross-coupling of diarylmethylamines with organoborons. Angew. Chem., Int. Ed. 2015,54, 11143−11146. (d) Xiao, K.-J.; Chu, L.; Chen, G.; Yu, J.-Q. Kinetic resolution of benzylamines via palladium(II)-catalyzed C−H cross-coupling. J. Am. Chem. Soc. 2016,138, 7796−7800. (10) For some related examples of enantioselective annulations involving allenes and organic halides, see: Shu, W.; Yu, Q.; Ma, S. Development of a new spiro-BOX ligand and its application in highly enantioselective palladium-catalyzed cyclization of 2-iodoanilines with allenes. Adv. Synth. Catal. 2009,351, 2807−2810. (e) Shu, W.; Ma, S. Synthesis of a new spiro-BOX ligand and its application in enantioselective allylic cyclization based on carbopalladation of allenyl hydrazines. Chem. Commun. 2009,0, 6198−6200. (11) For formal annulations based on the enantioselective desymmetrizing functionalizations with rhodium catalysts, see: (a) Tran, D. N.; Cramer, N. Enantioselective Rhodium(I)-catalyzed [3 + 2] annulations of aromatic ketimines induced by directed C-H activations. Angew. Chem., Int. Ed. 2011,50, 11098−11102. (b) Tran, D. N.; Cramer, N. Rhodium-catalyzed dynamic kinetic asymmetric transformations of racemic allenes by the [3 + 2] annulation of aryl ketimines. Angew. Chem., Int. Ed. 2013,52, 10630−10634. (c) Lin, L.; Fukagawa, S.; Sekine, D.; Tomita, E.; Yoshino, T.; Matsunaga, S. Chiral carboxylic acid enabled achiral rhodium(III)-catalyzed enantioselective C-H functionalization. Angew. Chem., Int. Ed. 2018, 57, 12048−12052. (12) For a review in enantioselective synthesis of tetrahydrosisoquinolines, see: Chrzanowska, M.; Grajewska, A.; Rozwadowska, M. D. Asymmetric synthesis of isoquinoline alkaloids: 2004−2015. Chem. Rev. 2016,116, 12369−12465. (13) Using allyltriflamide, we observed mixtures of products, and partial decomposition of the starting material. (14) For mechanistic studies in the C−H activation with chiral mono-N-protected amino acid ligands, see: (a) Musaev, D. G.; Kaledin, A.; Shi, B.-F.; Yu, J.-Q. Key mechanistic features of enantioselective C−H bond activation reactions catalyzed by [(chiral mono-N-protected amino acid)−Pd(II)] complexes. J. Am. Chem. Soc. 2012,134, 1690−1698. (b) Hill, D. E.; Bay, K. L.; Yang, Y.-F.; Plata, R. E.; Takise, R.; Houk, K. N.; Yu, J.-Q.; Blackmond, D. G. Dynamic ligand exchange as a mechanistic probe in Pd-catalyzed enantioselective C−H functionalization reactions using monoprotected amino acid ligands. J. Am. Chem. Soc. 2017,139, 18500−18503. (c) Plata, R. E.; Hill, D. E.; Haines, B. E.; Musaev, D. G.; Chu, L.; Hickey, D. P.; Sigman, M. S.; Yu, J.-Q.; Blackmond, D. G. A Role for Pd(IV) in catalytic enantioselective C−H functionalization with monoprotected amino acid ligands under mild conditions. J. Am. Chem. Soc. 2017, 139, 9238−9245. (d) Park, Y.; Niemeyer, Z. L.; Yu, J.-Q.; Sigman, M. S. Quantifying structural effects of amino acid ligands in Pd(II)- catalyzed enantioselective C−H functionalization reactions. Organometallics 2018,37, 203−210. Journal of the American Chemical Society Communication DOI: 10.1021/jacs.8b12636 J. Am. Chem. Soc. 2019, 141, 1862−1866 1866