Cyclic Diaryl  3 -Bromanes: a Rapid Access to Molecular Complexity via Cycloaddition Reactions Matteo Lanzi, Racha Abed Ali Abdine, ‡ Maxime De Abreu, ‡ and Joanna Wencel-Delord* (France) Supporting Information Placeholder ABSTRACT: Biaryls have widespread applications in organic synthesis. However, sequentially polysubstituted biaryls are underdeveloped due to their challenging preparation. Herein, we report the synthesis of unsymmetric 3 3 -substituted biaryls via pericyclic reactions of cyclic diaryl  3 -bromanes. The functional groups tolerance and atom economy allow access to molecular complexity in a single reaction step. Continuous flow protocol has been designed for the scale-up of the reaction, while post-functionalizations have been developed taking advantage of the residual bromide.

The direct access to molecular complexity under sustainable, simple, and mild reaction conditions is a critical challenge of modern organic chemistry. Biaryl compounds are ubiquitous motifs in many fields of chemistry, including medicinal chemistry, agrochemistry, material science, and ligand design. A straightforward synthesis of highly decorated biaryls thus remains an important challenge. 1 In particular, dissymmetrical 3 3 -substituted biaryls are poorly explored motifs due to the arduous synthesis via standard cross-coupling reactions which require densely decorated precursors. Albeit scarcely investigated, a general and straightforward alternative approach based on a modular functionalization via pericyclic reactions of a finely designed biaryl benzyne precursor represents an attractive solution to this synthetic issue (Scheme 1a). 2 However, multiple drawbacks hamper the state-of-the-art of the aryne-based approach (Scheme 1b): 1) lengthy synthetic routes for the preparation of aryne precursors; 2) the limited atom economy resulting from the aryne generation with the removal of leaving groups (-OTf and -TMS; -X and -OR; Aux-I) which translate into significant waste formation and 3) the limited functional group tolerance as the base-and fluorine-sensitive moieties are generally incompatible. [3][4][5] Accordingly, the implementation of the pericyclic reactions to rapidly access dissymmetrical 3 3 -substituted biaryls diversity requests design of original biaryl aryne precursors, activated under mild reaction conditions and in presence of a weak base.

Despite being known since the 19th century and albeit their unique reactivity, hypervalent bromane (III) reagents have received much less attention compared to the corresponding iodine compounds. 6 The lack of general and simple synthetic routes deliver-Scheme 1: a) Common aryne precursors; b) Aryne strategy to ortho-, ortho-, meta-substituted biaryls, c) Cyclic diaryl  3 -bromanes as aryne precursors in pericyclic approach towards ortho-, ortho-, meta-substituted biaryls (this work).

ing these unique scaffolds has drastically hampered the development of bromane (III) chemistry, [START_REF] Ochiai | Highly Regioselective Amination of Unactivated Alkanes by Hypervalent Sulfonylimino- 3 -Bromane[END_REF] and thus the rare advances in this field have been reported only recently. 8 Our group has latterly established a simple, safe, and scalable protocol for the preparation of cyclic diaryl  3bromanes in good to excellent yields. [START_REF]W -D J y Diaryl λ 3 -m O y Angew[END_REF] The superior electron-withdrawing effect and the nucleofugality of hypervalent bromane (III) compared to the iodine (III) counterpart (approximately 10 6 times higher), confer them a complementary reactivity. 10 Encouraged by the disclosed reactivity of cyclic diaryl  3 -bromanes towards the construction of carbon-oxygen and carbon-nitrogen bonds, we speculate that they could represent a new family of biaryl coupling partners for pericyclic reactions (Scheme 1c). Moreover, cyclic hypervalent  3 -bromane products carry a residual functional bromine atom which opens additional perspectives for further post-functionalizations, while warranting excellent atom economy of the overall process. Thus unique reactivity provides a new strategy for the synthesis of valuable and unprecedented highly decoymm 3 3 -substituted biaryls, helicenes [START_REF] Shen | Synthesis and Applications[END_REF] and four consequently substituted aromatic units. 4e,12 Our investigation begun by studying the reaction between the well-known cyclic diaryl  3 -iodanes and furan 2a (Table 1, entry 2), but no product formation was observed neither by GC-MS nor 1 HNMR (see Supporting Information). Remarkably, while using cyclic diaryl  3bromane 1a-OTf and 2a, in a presence of cesium carbonate and DCM, the desired product 3aa was afforded in 92% yield after 16 hours at room temperature (entry 1), unambiguously illustrating the unique reactivity of these reagents.

No reactivity was observed in the absence of Cs2CO3 (entry 3). Further investigation showed that the nature of the base holds a key role. Despite being a stronger base, tBuONa provided 3aa in lower yield, while K2CO3 performed poorly (entry 4). Finally, the role of a chlorinated polar solvent, namely CH2Cl2, was confirmed (entry 5). Surprising, albeit in low yield, the reaction occurred in water media. [START_REF] Yoshimura | Pseudocyclic Arylbenziodoxaboroles: Efficient Benzyne Precursors Triggered by Water at Room Temperature[END_REF] With the optimal reaction conditions in hand, the scope of this cycloaddition was explored, focusing on various cyclic diaryl  3 -bromanes 1a-l and aromatic cyclic Diels-Alder partners 2b-2d (Scheme 2). The symmetric bromane 1b, presenting inductive electrondonating methyl groups provided the desired product 3ba in good yield (69%). Regioselective functionalizations took place in presence of asymmetric substrates, such as 1c, 1d, and 1e, where the enhanced reactivity of one aryl moieties translated into the formation of a unique products in good yields. The introduction of the methyl group in orthoposition directs the desired transformation onto one aromatic ring, thus promoting the formation of 3fa in moderate yield (51%). Bifunctional dissymmetric  3 -bromanes bearing methyl ester and chlorine afforded 3ga and 3ha in 59% and 98% yields respectively. Finally, monosubstituted cyclic diaryl  3 -bromanes were tested. A weak electron-donating methyl group, 1i, unsurprisingly leads to a 1:1 mixture of products 3ia and 3ia', while the enhanced electron-withdrawing character of methyl ester 1j, chloro 1k and trifluoromethyl 1l enabled the preferential formation of one regioisomer with good selectivity. Moreover, substituted furans, 2b and 2c and N-protected pyrrole 2d were well tolerated under our reaction conditions, affording the desired products in good yields. Moreover, the dissymmetric bromane 1h reacted smoothly with 2d offering the highly functionalized bromo, chloro cycloadduct 3hd in 84% yield. Targeting a rapid generation of a broad range of diverse molecules, we have challenged the  3bromanes with other arynophiles. Various azides have been successfully coupled with 1a-OTf, furnishing highly decorated bromo benzotriazole derivatives. Simple benzyl azides 2e and substituted 2f -2i supplied the desired regioisomeric 3 and 3' in moderate to good yields, which were straightforwardly separated via column providing the pure products. The single-crystal X-ray analysis of 3af' confirmed the triazole structure and the regioselectivity. Remarkably, thanks to the fluorine-free conditions, the silyl-protected phenols 3ai and 3ai' could be obtained in excellent yields, highlighting the complementarity of this protocol. The cholesterol-de derived 2j and the cyclohexyl azide 2k react smoothly under the standard reaction conditions. Diazomethane 2l (TMSCHN2) also proved to be an excellent arynophile, yielding 3al and 3cl in 92% and 50% yields respectively, albeit as a mixture of two cycloadducts. In accordance with the aryne distorted and steric models, a moderate regiocontrol has been observed in the 1,3dipolar cycloaddition where the nucleophilic nitrogen reacts with the more distorted alkyne terminus position furnishing the less steric demanding product as major isomer. 14 While Diels-Alder reactions involving aryne have been largely investigated, [START_REF] Bhojgude | Employing Arynes in Diels-Alder Reactions and Transition-Metal-Free Multicomponent Coupling and Arylation Reactions[END_REF] the [2+2] reactions have received much less attention despite the interest of the resulting peculiar structures. 16 Rewardingly, the reaction of 1a-OTf with 2,3-dihydrofuran 2m and 2,3-dihydropyran 2n conducted to the selective formation of 3am and 3an in excellent yields, furnishing a single regioisomer with a ratio up to 14.3:1. Moreover, strained cycloalkenes, namely norbornene 2o and norbornadiene 2p, provided the desired cyclobutene products 3ao and 3ap with good yields. Interestingly, an elusive [2+2+2] mechanism has been observed within 1a-OTf and 2p yielding the uncommon a Reaction conditions:  3 -X-Y (0.1 mmol), furan (1.2 equiv), r.t. 16h; b 1 HNMR yields using CH2Br2 as internal standard; c Isolated yield; d 5 equiv furan. 3ap' in 17% yield. The acrylate 2q showed sufficient reactivity under our reaction conditions. Asymmetric  3bromanes 1h, 1c and 1g provided the highly decorated biaryls 3hm, 3cn and 3go in excellent yields. Finally, structurally condensed polycyclic aromatic compounds, valuable motifs in material science, were targeted. We investigated the reaction of 1a-OTf with the -bromostyrenes 2r. After a minor reoptimization of the reaction conditions, a cascade [4+2] cycloaddition/base-mediated aromatization occurred smoothly, at room temperature, in dioxane yielding the endo-product 3ar as a single regioisomer. Electronrich bromo styryls showed higher reactivity, delivering 3as and 3ay respectively in 85% and 58% yields. The single-crystal X-ray analysis of 3as confirmed the formation of the endo-product. Electron withdrawing groups, such as trifluoromethyl, impact the reaction outcome, delivering 3at in a decreased yield.

On the other hand, halogenated aromatic rings 2u, 2v, 2w and 2x, offered synthetically useful bifunctional products in moderate to high yields. The electron-rich, protected bromo caffeic acid derivative 2z turned out to be suitable for the synthesis of highly decorated phenyl phenanthrene 3az, providing a functional dibromo compound. Sterically demanding substrate 2A furnished the conformationally stable atropoisomers 3aA. Finally, when dissymmetric  3 -bromane 1f was tested, a selective functionalization occurred, yielding 3fs. Remarkably, the excellent regioselectivity reached in all of these cases, providing the sterically hindered endo-regioisomers as unique product, outcompetes the literature precedents. 17

Encouraged by the high versatility observed using cyclic diaryl  3 -bromanes, we endeavored on developing a flow protocol for this reaction (Scheme 3). Despite clear advantageous of flow chemistry approach as scalability, safety and reduction of the reaction time, implementation of this process into the aryne chemistry remains rare and the chemically difficult. 18 The difficulty in our case lays in the use of insoluble Cs2CO3, however, attempts to replace it with organic bases failed. (see Supporting Information). Accordingly, the flow-reaction was performed in a biphasic system, which involved a water solution of Cs2CO3 and a solution of 1a-OTf and 2a in CH3CN. The optimal flowreaction conditions enabled the synthesis of 516 mg of 3aa (66% yield) within 22 min of residence time at 60 °C. Interesting, the substrate 1a-OTf is stable under these reaction conditions and the unreacted portion was recovered via precipitation with Et2O from the reaction steam. The conspicuous reduction of the reaction time and the use of green solvents make this approach a suitable alternative to the batch protocol, especially for further reaction scale-up.

Beyond the mild reaction conditions for the aryne generation and the high functional group tolerance demonstrated, the cycloadduct products feature a bromine atom which can serve as an additional handle for the incorporation of molecular complexity (Scheme 4). Initially, the robustness of our procedures was confirmed by performing the reactions on 1 or 2 mmol scales, furnishing 3aa, 3ar, 3as and 3au in multi milligram scale. The functionalization of the 3aa through lithium-mediated bromine exchange provided the corresponding carboxylic acid 4, aldehyde 5, and the new phosphine 6 in 64%, 93% and 76% yields respectively. Moreover, a standard deoxygenation protocol generated 7 in 74% yield. Also, bromo-biphenyl phenanthrenes 3ar, 3as and 3au are synthetically interesting scaffolds and the residual bromine enables access to highly adorned structures. Pdcatalyzed cross-couplings, such as Sonogashira and Suzuki reactions granted the introduction of alkyne 8 and aryl 9 moieties with useful yields. Furthermore, a Buchwald-Hartwig Pd-catalyzed couplings delivered 10 and the sterically challenging 11 diaryl amines, in good yields. A lithium exchange protocol using 3ar, 3as and 3au, led to the versatile aldehydes 12, 13 and 14. A subsequent Wittig reaction involving the aldehyde 13 provided the stereoisomers E-15 and Z-15 in good yield (70% + 17% respectively), which were easily separated by flash chromatography. To further illustrate the utility of the bromine moiety, the synthesis of screw-shaped helicene was envisioned. A standard Corey-Fuchs alkyne synthesis using the aldehyde 14 furnished 17. Then, a Pt-catalyzed cyclization afforded the desired [5]-helicene 18 in 12% overall yield.

In conclusion, we demonstrated herein the peculiar versatility, chemoselectivity and atom economy of cyclic diaryl  3 -bromanes as biaryl aryne precursors in cycloaddition reactions for the synthesis of highly decoratymm 3 3 -substituted biaryl motifs. The mild aryne generation conditions, namely carbonate base and room temperature, allowed a wide arynophiles compatibility, together with great functional group tolerance. Robustness of these aryne precursors guaranteed an efficient biphasic flow protocol for the pericyclic reaction further improving the sustainability. High molecular complexity via multiple C-C and C-N bonds formation was attained in a single reaction step, while subsequent functionalizations further expand access to a plethora of complex functional compounds.

ASSOCIATED CONTENT Supporting Information

Experimental procedures, synthesis of reagents, copies of NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

Notes

The authors declare no conflict of interest.

ACKNOWLEDGMENT

We thank the CNRS (Centre National de la Recherche Scientifique), h " è h h " F J W D M.D.A. are very grateful to European Commission for the ERC-G " " °9 9 W D Lydia Karmazin, Dr. Corinne Bailly and Dr. Nathalie Gruber for X-ray diffraction analysis (Service de Radiocristallographie, CNRS-Université de Strasbourg, Strasbourg, France). Authors are also very grateful to Dr. Morgan Donnard, Dr. Armen Panossian and Dr. Frédéric R. Leroux for helpful discussions on flow-chemistry.

  Scheme 2: Synthesis of 3aa via flow-chemistry approach

Table 1 . Optimization of the Diels-Alder Reaction with cyclic diaryl hypervalent bromanes a

 1

	entry	deviation from standard conditions	yield (%) b
	1	none	92% c
	2	 3 -I-OTf/-OMs instead of 1a-OTf	-d
	3	no Cs2CO3	-d
	4	tBuONa / K2CO3 instead to Cs2CO3	59%	/
			23%
	5	CH3CN / H2O instead to CH2Cl2	69%	/
			13%

Scheme 4: Synthesis of functional biaryl compounds from 3aa, 3ar, 3as and 3au

	OMe							TMS
	9, 94%	Pd(Ph 3 ) 4 (10 mol%) K 2 CO 3 (10 eq) 4-MeOOC 6 H 4 B(OH) 2 (3 eq) To luene/H 2 O/EtOH, 90 °C R = H	Pd(PPh 3 ) 4 (5 mol%) CuI (10 mol%) PPh 3 (10 mol%) Et 3 N/Piperidine 80 °C, R = H	8, 32%	O	OH	O	nBuLi (3 eq) then CO 2 Et 2 O	nBuLi (1.6 eq) DMF (10 eq) THF	O	5, 93%	O
	R 11 , R = 2,4,6-trimethyl, 52% NH 10, R = 4-Cl, 71%	Pd(PPh 3 ) 4 (10 mol%) tBuOK (3 eq) ArNH 2 (1.5 -3 eq) Toluene, 95 or 110 °C DMF (10 eq) nBuLi (1.6 eq) R = H	Br -78 °C to r.t THF R 3ar, 50% (166 mg) 3au, 67% (247 mg) 3as, 64% (232 mg)	Standard Conditions (1 mmol scale)	1a-OTf	2 mmol scale 81% (486 mg) 4, 64% Standard Conditions	Br	3aa	O	nBuLi (3 eq) Ph 2 PCl (3.1 eq) Et 2 O, -78 °C CH 3 CN NaI (3eq) TMSCl (3 eq)	PPh 2 6, 76% Br	O
	COOMe		Ph 3 P	O	CBr 4 (2.5 eq)		Br	Br				H	7, 74%
			MeOOC		PPh 3 (5 eq)				nBuLi (2.5 eq)		PtCl 2 (7 mol%)
			DCM, r.t.		DCM, 0 °C					THF			To luene
			R = Cl							-78 °C to r.t.		80 °C
	Cl E-15, 70% + Z-15, 17%			R 12, R = H, 92% 13, R = Cl, 43%			MeO 16, 81%			MeO 17, 58%	MeO 18, 66%
				14, R = OMe, 59%

AUTHOR INFORMATION

Corresponding Author * Author Contributions ‡These authors contributed equally.


Nicolas Jacob

Yassir Zaid

João C A Oliveira

Lutz Ackermann

Joanna Wencel-Delord

Cobalt-Catalyzed Enantioselective C-H Arylation of Indoles

Keywords: C-H activation, axial chirality, arylation, cobalt, heterobiaryls, catalysis, atropoisomerism, indole, DFT calculations, mechanism

Atropoisomeric (hetero)biaryls are scaffolds with increasing importance in the pharmaceutical and agrochemical industries. Although it is the most obvious disconnection to construct such compounds, the direct enantioselective C-H arylation through the concomitant induction of the chiral information remains extremely challenging and uncommon. Herein, the unprecedented earth-abundant 3d-metal-catalyzed atroposelective direct arylation is reported, furnishing rare atropoisomeric C2-arylated indoles. Kinetic studies and DFT computation revealed an uncommon mechanism for this asymmetric transformation, with the oxidative addition being the rate-and enantio-determining step. Excellent stereoselectivities were reached (up to 96% ee), while using an unusual N-heterocyclic carbene-ligand bearing essential remote substituent. Attractive dispersion interactions along with positive C-H---π interactions exerted by the ligand were identified as key factors to guarantee the excellent enantioselection.

INTRODUCTION

Medicinal chemistry and drug design are in a constant quest for new three-dimensional motifs, providing appealing biological activities and specific interactions with the targeted biological sites. 1 For decades, the introduction of stereogenic carbons was used to implement threedimensionality within the drug candidates, thus giving the promise of advanced and more selective interactions with enzymatic sites. 2 During the recent years, significant attention has shifted to the implementation of atropoisomers within the drug design (Figure 1A). 3 Indeed, the presence of biaryl units featuring restricted rotation around an Ar-Ar axis and thus, exhibiting stable three-dimensional structure, frequently accounts for significantly improved biological activities and fewer side effects. In addition, applications of atropoisomerism to crop protection and material sciences, in combination with asymmetric catalysis further highlight the fascinating features of this chiral motif.

With the rapidly increasing importance of atropoisomerism in both fundamental research and industrial settings, the design of new atropoisomeric scaffolds together with efficient, rapid and sustainable strategies are in urgent need. While various approaches have recently burgeoned to complement the classical protocols for asymmetric atroposelective synthesis, 4 including Suzuki-Miyaura couplings and oxidative arylations, C-H activationbased strategies 5 are particularly attractive in terms of sustainability, access to simple starting materials, and generality. In this context, atroposelective ortho-C-H functionalization of pre-existing biaryl substrates have established themselves as an attractive route to diversified chiral biaryls and heterobiaryls (Figure 1B). 6,7 Examples of C-H couplings with highly reactive diazo-compounds have also been reported. 8 In sharp contrast, synthetic routes based on direct atroposelective Ar-H/Ar-X coupling remain hardly explored. [START_REF] Wencel-Delord | Challenging Atroposelective C-H Arylation[END_REF] The challenging character of this transformation arises from the antagonism between, on the one hand, the essential steric hindrance of both coupling partners required to warrant the atropostability of the newly generated Ar-Ar products, and, on the other hand, exceedingly mild reaction conditions necessary to enable high stereoinduction and avoid in-situ racemization. While a pioneering contribution has

Figure 1. Towards new sustainable assembly of atropoisomeric C2-arylated indoles been reported by the groups of Yamaguchi and Itami, 10 the application of the catalytic system remained rather limited.

Wencel-Delord and Colobert reported atropodiastereoselective arylation delivering terphenyl compounds with two fully controlled chiral axes, [START_REF] Dherbassy | Two Stereoinduction Events in One C-H Activation Step: A Route towards Terphenyl Ligands with Two Atropisomeric Axes[END_REF] while the first truly efficient enantioselective system was very recently reported by Baudoin and Cramer. [START_REF] Nguyen | Intermolecular Palladium(0)-Catalyzed Atropo-Enantioselective C-H Arylation of Heteroarenes[END_REF] Further, the portfolio of atroposelective C-H couplings has been complemented with iridium-catalyzed arylation of naphthylimines. [START_REF] Woźniak | Atropo-Enantioselective Oxidation-Enabled Iridium(III)-Catalyzed C-H Arylations with Aryl Boronic Esters[END_REF] However, all these catalytic systems are severely limited by the use of precious palladium or iridium catalysts, while sustainable approaches benefiting from the exploitation of inexpensive and less toxic earthabundant 3d-metals remain unprecedented. 14 The use of 3d-transition metals in the C-H activation arena has strongly induced the recent development of this field as not only being more sustainable, less expensive, and environmentally benign catalysts, but also new mechanistic scenarios are frequently viable. [START_REF] Gandeepan | 3d Transition Metals for C-H Activation[END_REF] In particular, unprecedented reactivity may be reached with cobaltbased catalysts. 16 Hence, while high-valent cobalt(III) species tend to often perform rather similarily to rhodium(III) complexes, the mechanistic scenario based on low-valent cobalt intermediates is largely underexplored. 17 Due to the increased reactivity of the low-valent cobalt species towards the key C-H metalation step, 18 cobalt(I)-catalyzed transformations generally occur at lower, close to room temperatures, thus offering unique perspectives for atroposelective functionalizations. However, despite recent advances in implementing 3d-metal catalysis within stereo-controlled direct functionalizations, 14 only a single example of the enantioselective low-valent cobaltcatalyzed C-H activation has been reported, delivering Cstereogenic indole derivatives with moderate to good ees (up to 93.5:6.5 er). [START_REF] Lee | Cobalt-Catalyzed Enantioselective Directed C-H Alkylation of Indole with Styrenes[END_REF][START_REF] Whyte | For a rare example of cobalt(I)-catalyzed asymmetric hydroarylation[END_REF] Besides, a handle of enantioselective cobalt(III)-catalyzed reactions further illustrates the importance and challenging character of this field. 21 Based on this analysis, we hypothesized that directed, cobalt(I)-catalyzed atroposelective C2-arylation of indoles should be feasible under mild reaction conditions, thereby delivering biaryls bearing a five-membered cycle. 4b The development of such an unprecedented cobalt-catalyzed direct indole arylation also delineates a great prospect from a medicinal chemistry viewpoint. Indeed, indoles are amongst the key motifs in medicinal chemistry, frequently found in antiviral agents, kinase inhibitors or anticancer agents, among others (Figure 1C). 22 However, although strategies are available to construct atroposelectively C3arylindoles, 23 the enantioselective synthesis of their C2functionalized congeners remains underdeveloped. Rare and very recently disclosed approaches consist in centralto-axial chirality transfer [START_REF] Hu | Conversion of Two Stereocenters to One or Two Chiral Axes: Atroposelective Synthesis of 2,3-Diarylbenzoindoles[END_REF] or stereoselective formation of the aromatic ring, 25 thus requiring finely designed substrates and catalysts. The development of significantly more user-friendly strategies benefiting from nonfunctionalized indole substrates, together with inexpensive and abundant catalysts, is thus urgently needed to provide innovative structures for biological studies.

RESULTS AND DISUSSIONS

Reaction development At the outset (Figure 1D), we hypothesized that indole 1a might be a suitable substrate for atroposelective cobalt-catalyzed direct C2-arylation. Indeed, the presence of the methyl group on the N-atom should limit its coordinating properties and bring about the steric hindrance necessary for the room-temperature atropostability of the newly generated Ar-Ar linkage. The imine substituent at the C3 position should enable chelation assistance, facilitating regioselective C2-metallation. 26 1-chloronaphthalene 2a was selected as the substrate to ensure atropostability of the newly generated product, while catalytically active cobalt(I) was in-situ generated via reduction of CoBr2. Orienting experiments showed chiral N-heterocyclic carbene precursors (NHC) 27 as uniquely effective chiral inductors (Figure 2). Despite initial disappointing enantio-inductions observed with standard NHCs, such as L1, L2 and L3, a remarkable improvement was achieved in the presence of L4, previously optimized for asymmetric iron-catalyzed C-H activation. [START_REF] Loup | Asymmetric Iron-Catalyzed C-H Alkylation Enabled by Remote Ligand Meta-Substitution[END_REF] Figure 2. Ligand optimization. Reaction conditions: indole (1 equiv.), 1-chloronaphthalene (2 equiv.), CoBr2 (10 mol%), ligand (10 mol%), t-BuCH2MgBr (2 equiv.) and THF (0.28 M), 0 °C to r.t., 16 h. Ratio between 3 and 4 was determined by 1 H NMR analysis of the crude reaction mixture. The yields refer to isolated product and the ee values were determined by HPLC with a chiral column.

A combination of this meta-adamantyl substituted ligand and CoBr2 furnished the desired product 3 in an exceptional 93:7 er and 70% isolated yield, with only a trace amount of the undesired side product 4 being generated. Based on this outstanding starting point, the structure of the ligand L4 was further probed. While replacing the ortho-substituent by more hindered iso-propyl or less sterically encumbered methoxy motifs (L5 and L6, respectively), a significant drop in chiral induction was observed. In contrast, an excellent enantioselectivity of 95.5:4.5 er was reached while introducing an additional methylsubstituent in the para-position of the aromatic ring (L7). Modification of the chiral backbone did not improve further the chiral induction; a comparable enantioselectivity was observed with NHC L8 bearing 1-naphthyl substituent, but mesityl-substituted L9 was clearly less selective. Finally, the optimal chiral induction of 92% ee and 99% isolated yield were obtained while further increasing the electrondonating properties of the ligand by introducing a methoxy-group in the para-position (L10). Of note is that other reaction parameters, such as the cobalt precursor or the nature of a coordinating solvent poorly impacted the reaction outcome, while the selection of the reducing base was crucial for the efficiency of the catalytic system (see SI).

Scope With the optimized reaction conditions in hand, the generality of this atroposelective direct arylation was challenged (Figure 3). First, differently N-substituted indoles (1a-v) were reacted with 1-chloronaphthalene 2a under otherwise identical reaction conditions. Dioxolane and benzyl-protected indoles underwent the desired transformation, affording products 6 and 7 with high enantioselectivities. In contrast, the presence of a MOM group seemed inadequate. PMB-substituted indole performed equally well and furnished indole 9 with 96:4 er, while slightly lower chiral induction (93.5:6.5 er) was observed for the product 8 bearing a phenyl-substituent.

Subsequently, the reaction was performed in the presence of different 1-chloronaphthalenes (10-18), bearing various functionalities. Electron-donating groups at the 4position of the 1-chloronaphthalene only slightly impacted the atroposelectivity of the reaction (products 10, 11 and 12). The optimal enantiomeric ratio was obtained when using the fluorinated substrate, delivering 15 with 98:2 er and 54% yield. Interestingly, an extension of the polyaromatic system to 1-chlorophenanthrene provided 16 in high yield and 90:10 er but a significant drop of chiral induction occurred when using 1-chloropyrene 2i. Moreover, due to the too high steric hindrance, the C-H coupling was not effective when 2-substituted 1chloronaphthalene 2j was used, even upon heating at 60 °C (product 18). Finally, o-chlorotoluene 2k is also a potent substrate, but product 19 was isolated in 61% yield and a lower enantioselectivity (77:23 er).

Remarkably, the catalytic system showed high compatibility with an array of functionalized indoles (1f-v). Both electron-rich and electron-poor substituents could thus be installed at different positions of the carbocycle, while only modestly impacting atroposelective outcome of the transformation. Importantly, thioether-and thiophenesubstituted products 26 and 27 could be isolated in 88% and 82% yields, and 95.5:4.5 and 93.5:6.5 er, respectively. Notably, the compatibility with different fluorinated groups, including F, CF3, OCF3 and SF5 (products 22, 29-32, 34) should represent key advantage from a medicinal chemistry viewpoint. Worth highlighting is also the efficiency of this C-H arylation with the azaindole substrate, affording the chiral product 35 with excellent yield and er. To characterize the newly synthesized compounds, the rotational barriers were experimentally determined. Product 3 features a rotational barrier of 28.5 kcal mol -1 at 100 °C, as was experimentally determined (estimated by DFT calculations: 29.8 kcal mol -1 , Table S9) thus no racemization occurs at room temperature on a month's scale. A higher rotational barrier of 30.0 kcal mol -1 was observed for indole 6, indicating increased steric hindrance induced by the dioxolane motif. In clear contrast, the presence of phenyl-group on the N-atom translates into significantly atropostability decrease of 8 to only 26.0 kcal mol -1 (at 80 °C); generation of this compound in atropoisomerically pure form would not be possible under higher reaction temperatures, since at 110 °C, the racemization occurs within only 5 min.

To further explore the synthetic potential of our strategy, a large-scale reaction was performed, furnishing the expected product 3 in unchanged optical purity (Figure 4A). Interestingly, hydrolysis of the imine directing group is not necessary and atropoisomerically pure imine-indole 37 could be isolated in an optical purity of 95:5 er and excellent yield. Importantly, simple recrystallization further increased the optical purity of the compound 3 to afford efficiently 99:1 er with 62% yield. Finally, to explore the synthetic potential of our new chiral building blocks, different post-modifications have been performed using compound 3 as a substrate. First, different transformations of the formyl moiety have been carried out. Reduction of aldehyde 3 occurred efficiently, furnishing the corresponding alcohol 38. Reductive amination using methylamine performed well, affording product 39. Notably, a Wittig reaction led to product 40. Aldehyde 3 reacted also with different Grignard reagents, thereby delivering the corresponding alcohols 41 and 42 with low to moderate diastereoselectivities and excellent yields. Both diastereoisomers could be separated by simple column chromatography. It is worth noting that all these transformations occurred without erosion of the optical purity of the chiral C-C axis. Finally, we took advantage of the presence of the formyl group as a weakly coordinating group to enhance C4-direct functionalization via C4 rhodium(III)catalyzed direct alkylation, 29 Product 43 could thus be synthesized in a good yield and without racemization of the atropisomeric axis. Subsequent intramolecular crotonization led to 3,4-fused tricyclic indole 44. The product 44 features a decreased steric hindrance around the Ar-Ar bond, translating into the lost of the chiral information (racemization within less than 24 hours). Ultimately, a double-Wittig reaction efficiently furnished diene 45 in 96% ee. (Figure 4B).

Diversification of the generated atropoisomeric compounds.

Mechanistic Studies Considering the relatively limited mechanistic understanding of the low-valent cobaltcatalyzed C-H arylation, we endeavored on detailed mechanistic and kinetic investigations combining experimental investigations with DFT calculations.

First, detailed kinetic studies have been performed (Figure 5). The kinetic isotope effect (KIE) study (competi-tive experiment and initial rate determination) indicated a KIE value close to 1, thus clearly suggesting that the C-H activation step is not the rate-determining step (Figure 5A). This finding corroborates previous investigations on the cobalt(I)-catalyzed C-H activation. [START_REF] Oliveira | Insights into the Mechanism of Low-Valent Cobalt-Catalyzed C-H Activation[END_REF] Then, qualitative in operando infrared spectroscopy unrevealed an extremely fast character of the direct arylation during the first halfhour of the reaction (Figure 5B). Indeed, the C-H activation reaction furnished product 3 in 65% isolated yield after only 30 min at 0 °C. However, an increased reaction time is necessary to reach full conversion of the starting material. Analysis of the initial reaction rate (Figure 5C) revealed a zeroth order in the concentration of indole. In contrast, the reaction rate was depending on the concentration of 1-chloronaphthalene 2a according to a first order dependence, with saturation kinetics.

Next, DFT calculations for the oxidative addition and reductive elimination elementary steps were carried out at the PW6B95-D4/def2-TZVP+SMD(THF)//TPSS-D3(BJ)/def2-SVP level of theory (Figure 6 and Figures S5-S9, for detailed information see SI). 30 Given the d 8electronic configuration of the cobalt(I) intermediates I-1, both high-spin (triplet) and low-spin (singlet) complexes were taken into consideration for both the (R)-and the (S)enantiomers for the C-H activation and oxidative addition steps through transition states TS(1-2) and TS(2-3) respectively (Figures S5 andS6). [START_REF]A mechanism through an Co(0) intermediate can not unambiguously be ruled out[END_REF] This gives rise to cobalt(III) complexes I-4, which undergo reductive elimination through TS(4-5) (Figures S5 andS6). For the cobalt(III) complexes the possible singlet, triplet, quintet spin states were assessed. The extensive analysis of the possible spin states highlighted the triplet surface as the energetically favored pathway for both enantiomers with no spin-crossover reactivity. A comparison between the most energetically favored triplet surfaces of (R)-and (S)enantiomers is disclosed on Figure 6.

C-H activation was found to be facile with an activation energy of only 5 kcal mol -1 suggesting that the C-H activation step is not rate-determining. This is in good agreement with the experimental findings, highlighting the robustness and suitability of the computational method approach.

Calculations indicated that oxidative addition proceeds through a barrier of 9.3 kcal mol -1 for the experimentally observed (S)-enantiomer which is stabilized by 0.7 kcal mol -1 over the (R)-enantiomer. This stabilization is found to result from attractive dispersion interactions of the substrate and the meta-aryl substituent of the remote NHC ligand, which is more pronounced in the (S)-enantiomer transition state structure (Figure 7a). These are mostly localized in the region defined by the plane of the NHC substituted moiety and the substrate that is parallelly orientated (Figure 7b). Additionally, the presence of positive CH---π interactions between the adamantyl group from the NHC side-chain and the para-methoxyphenyl moiety of the substrate contributes to the stabilization of the transition state structure TS(3-4) S over the TS(3-4) R (Figure 7a-b), highlighting the intrinsic ability of the meta-adamantyl-substituted ligand L4 to serve as a remote dispersion energy donor. [START_REF] Bursch | Understanding and Quantifying London Dispersion Effects in Organometallic Complexes[END_REF] To support such observation, calculations were also performed in the absence of dispersion corrections at the PW6B95/def2-TZVP+SMD(THF)//TPSS/def2-TZVP level of theory. A direct comparison between the TPSS and TPSS-D3(BJ) data was carried out in terms of NBO and NCIPLOT analysis. The NCIPLOT analysis in the absence of dispersion corrections revealed a decrease in the weak attractive surface for both (R)-and (S)-enantiomers (Figure S10). The direct comparison between calculations in the absence and in the presence of dispersion corrections revealed in the second-order perturbation theory of the Fock matrix within the NBO analysis (Table S13-S16) for TS(3-4) of (S)-enantiomer a stabilization of 1.1 kcal mol -1 when dispersion effects were considered. In contrast, for the (R)-enantiomer, only a stabilization of 0.5 kcal mol -1 was observed. These results support that dispersion interactions play an important role in the stabilization of TS(3-4) S .

During the reductive elimination (TS(4-5)) the (S)enantiomer is 3.2 kcal mol -1 more stable than the (R)enantiomer. Our results demonstrate the oxidative addition to be the rate-determining step and responsible for the enantioinduction. The energy gap of 0.7 kcal mol -1 in TS(3-4) between the two enantiomers results in an ee of 72% in favor of the (S)-enantiomer, as was observed experimentally. The minor difference to the experimentally found ee of 86%, i.e. 1.1 kcal mol -1 , can be rationalized by secondary solvent effects.

Based on detailed DFT analysis and in accordance with experimental mechanistic investigations, a plausible catalytic cycle as is proposed in

CONCLUSIONS

In conclusion, we have reported the first atropoenantioselective cobalt-catalyzed C-H arylation to deliver rare atropoenriched C2-arylated indoles. The high reactivity of the cobalt(I) species enables an efficient C-H arylation at room temperature, thus guaranteeing atropostability of the newly generated compounds. Carbene ligands presenting remote meta-dispersion donor motifs were found to be essential for the stereoselectivity, as rationalized by detailed DFT calculations, elucidating for the first time a stereoselection rationale for the atroposelective 3d-metal catalyzed C-H arylation.

Figure 3 .

 3 Figure 3. Scope of the atropoenantioselective indoles arylation. For general reaction conditions, see Figure 2. a 60 h reaction time.

Figure 5 .Figure 6 .

 56 Figure 5. Kinetic studies

Figure 7 .

 7 Figure 7. a) Visualisation of the non-covalent interactions calculated with the help of the NCIPLOT program for the transition states involved in the oxidative addition step for both (R)-and (S)enantiomers. In the plotted surfaces, red corresponds to strong repulsive interactions, while green and blue correspond to weak and strong interactions, respectively. Superscripts R and S correspond to the (R)and (S)-enantiomers respectively. b) Identification of relevant interactions in the transition state structures, for the oxidative addition elementary step in the triplet surface, for the (R)-and (S)enantiomers obtained at the TPSS-D3(BJ)/def2-SVP level of theory with the chiral ligand L4. Non-relevant hydrogens were omitted for clarity. Superscripts R and S correspond to the (R)-and (S)enantiomers respectively.

Figure 8 .

 8 First, the catalytically active cobalt(I) species is generated via reduction by the base and the coordination with the imine delivers intermediate A. The C-H metalation step is fast, affording the metallacycle B. Subsequent stereo-and rate-determining oxidative addition takes place delivering cobalt(III)intermediate C, while the expected enantiopure product is released via reductive elimination, along with ligand exchange.

Figure 8 .

 8 Figure 8. Proposed catalytic cycle

ACKNOWLEDGMENT

J.W.-D. thanks the CNRS (Centre National de la Recherche Scientifique), the « Ministère de l'Éducation Nationale et de la Recherche » (France) for financial support. J.W.-D., L.A. and N. J. acknowledge ANR (Agence Nationale de la Recherche) and DFG collaborative project ANR PRCI (grant number ANR-17-CE07-0049-01). L.A. thanks the DFG (SPP 1807, AC 118/9-1). Y.Z. is very grateful to ANR for the postdoctoral fellowship (project ANR-ERC-T « Alchimie »). We are also very grateful to Dr. Lydia Karmazin, Dr. Corinne Bailly and Nathalie Gruber for single crystal X-ray diffraction analysis.

AUTHOR INFORMATION Corresponding Authors

Lutz.Ackermann@chemie.uni-goettingen.de wenceldelord@unistra.fr

Author Contributions

The manuscript was written through contributions of all authors.