Lewis Acid/Hexafluoroisopropanol: A Promoter System for Selective ortho-C-Alkylation of Anilines with Deactivated Styrene Derivatives and Unactivated Alkenes Shengdong Wang, Guillaume Force, Régis Guillot, Jean-François Carpentier, Yann Sarazin, Christophe Bour, Vincent Gandon, David Lebœuf

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Shengdong Wang, Guillaume Force, Régis Guillot, Jean-François Carpentier, Yann Sarazin, et al.. Lewis Acid/Hexafluoroisopropanol: A Promoter System for Selective ortho-C-Alkylation of Anilines with Deactivated Styrene Derivatives and Unactivated Alkenes. ACS Catalysis, American Chemical Society, 2020, 10 (18), pp.10794-10802. ￿10.1021/acscatal.0c02959￿. ￿hal-02961178￿

HAL Id: hal-02961178 https://hal-univ-rennes1.archives-ouvertes.fr/hal-02961178 Submitted on 8 Oct 2020

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1 2 3 4 5 6 7 Lewis Acid/Hexafluoroisopropanol: A Promoter System for Selective 8 ortho-C-Alkylation of Anilines with Deactivated Styrene Derivatives 9 10 and Unactivated Alkenes 11 a a a b b 12 Shengdong Wang, Guillaume Force, Régis Guillot, Jean-François Carpentier, Yann Sarazin, 13 Christophe Bour,a Vincent Gandon*,a,c and David Lebœuf*,d 14 15 a Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO), CNRS UMR 8182, Université Paris-Saclay, Bâtiment 16 420, 91405 Orsay, France. 17 b Univ. Rennes, CNRS UMR 6226, Institut des Sciences Chimiques de Rennes (ISCR), 35000 Rennes, France. 18 c.Laboratoire de Chimie Moléculaire (LCM), CNRS UMR 9168, Ecole Polytechnique, Institut Polytechnique de Paris, route de Saclay, 91128 Palaiseau cedex, France. 19 d 20 Institut de Science et d’Ingénierie Supramoléculaires (ISIS), CNRS UMR 7006, Université de Strasbourg, 8 allée Gaspard 21 Monge, 67000 Strasbourg, France. 22 KEYWORDS alkenes, anilines, hexafluoroisopropanol, Lewis acid, ortho-C-alkylation 23 ABSTRACT: Aniline derivatives are frequently encountered in molecules of industrial relevance such as dyes or antioxidants, 24 which make the development of synthetic methods for the functionalization of these privileged structures highly sought-after. 25 A general protocol for the hydroarylation of electronically diverse alkenes with anilines would be ideal to provide densely 26 functionalized compounds. Yet, this transformation has been underexplored compared to more traditional hydroarylation of 27 unactivated alkenes because of the significant challenges associated with the control of the selectivity and its substrate 28 tolerance. Herein, we describe a selective, versatile and user-friendly ortho-C-alkylation of anilines with alkenes that hinges 29 on the beneficial combination of a Lewis acid (Ca(II)) and hexafluoroisopropanol as a solvent. This protocol allows for the 30 extension of this transformation to highly deactivated styrenes and demonstrates a remarkable improved reactivity regarding 31 aliphatic alkenes, styrene derivatives and dienes. In addition, DFT computations were performed which, combined with 32 experimental observations, suggest a nearly concerted mechanism that impart the ortho-selectivity. 33 34 35 Diarylamines, and generally simple anilines, are prevalent compounds prepared through non-covalent interactions (- 36 building blocks in organic synthesis. They offer a wide anion, lone pair- or - interactions).9 In the realm of 37 variety of applications, including pharmaceuticals, hydroarylation of unactivated alkenes, a traditional agrochemicals, and functional organic materials.1 Besides, 38 approach involves the use of a Lewis or Brønsted acid, they can be rapidly converted into acridinium derivatives,2 which typically triggers the formation of a stabilized 39 which have emerged as powerful catalysts for photoredox carbocation species and a subsequent trapping by 40 transformations.3 Within this context, the identification of (hetero)arene nucleophiles.4 Yet, this strategy often leads to 41 synthetic methods to increase the molecular complexity both ortho- and para-products, limiting its applicability. The 42 and diversity of these compounds has been thoroughly problem becomes even more pronounced in the case of 43 investigated over the last decades. Among them, the anilines, which can also undergo hydroamination reactions 44 hydroarylation of unactivated alkenes with anilines (Schemes 1a-1c).10 To account for the formation of the 45 represents arguably an ideal process: an atom- and step- ortho-alkylated product, Beller and coworkers alluded to a 46 economic transformation featuring feedstock alkenes and concerted mechanism that would differ from that of a 47 anilines to form key CC bonds in an efficient manner.4 typical proton-catalyzed hydroarylation (Scheme 1c).6a 48 Despite many studies outlined in Scheme 1,5-7 the intrinsic However, in the case of Lewis and Brønsted acid-based 49 limitations associated with this transformation have still to strategies, the transformation led to uneven selectivities 50 be addressed, including its unpredictable selectivity (ortho- between ortho-C alkylation and hydroamination depending 6a,6c-6l,6n 51 C alkylation/para-C alkylation/hydroamination), its on the promoter system used (from 1:0 to 0:1), incompatibility with highly deactivated styrenes and N- suggesting competing reaction pathways. To date, the 52 (alkyl or aryl) diarylamines and its limited reactivity iridium-catalyzed enantioselective ortho-alkylation of 53 regardingAccepted aliphatic alkenes. In particular, the dearth of Manuscriptacetanilides described by the group of Bower can be 54 reports regarding highly deactivated styrenes8 that considered as a reference in terms of selectivity (Scheme 55 incorporate strong electron-withdrawing groups is 1f);6o,6t yet, no highly deactivated styrene was investigated, 56 detrimental to discovering new applications, as such a specific directing-group was required, and tertiary 57 substrates may impart original properties to the anilines were incompatible with the reaction conditions. In 58 59 60 ACS Paragon Plus Environment ACS Catalysis Page 2 of 10

Scheme 1. Hydroarylation and hydroamination of olefins with aniline derivatives. 1 2 I: Lewis and Brønsted Acid Strategies II: Transition-Metal Strategies a) Stephan (ref. 6n): [(C6F5)3PF][B(C6F5)4] d) Hartwig (ref. 11c) 3 H Ph H Ph N N [Pd] CN 4 NH2

5 Ph + [Pd] HN 6 Ph CN R [P] H C NH2 7 H17C8 17 8 e) Bertrand (ref. 6m) 8 b) Bergman (ref. 6f): PhNH3B(C6F5)4·Et2O R1 R2 N N 9 N [Au] R-NH2 R1 [Au] 10 N mixture R1 + R + N Ph Ph H of isomers 11 observed R R 12 (o/N) Ph + Bower c) Beller (ref. 6a): HBF4 f) (ref. 6o and ref. 6t) if R2 = H 13 NHAc 1 14 R R1 Ac N H N H N Ph + [Ir] [Ir] H 15 H H * R DG Ph 16 R Ph NHAc critical for the reaction only example of 17 moderate electrophilicity of anilinium (no reaction with NMeAc) enantioselective version 18 III: Radical Strategies IV: This Work Envisioned catalytic cycle with the promoter system: [Ca], HFIP 19 g) Patureau (ref. 6u) 20 R1 S R2 H S N O 2 21 [Ca] S H N 1 Ph [Ag] O CF3 CF3 R 22 + NH N N H H n Ph CF3 CF3 2 23 N2 Ph 3 R (HFIP)n R 3 24 plausible mechanism R [Ca(OCH(CF3)2)]

25 h) Zhang (ref. 12) X 3 1 Ph H * Ph R R 26 N Ph 1 N Ph N R H n+1 Ph 2 2 27 Ph N Cu N N R 3 R Ph + [Cu] n R Cu Ln Ln H 28 Blue LED 40 W Ph CF3 Ph R3 H high ortho-selectivity Ph O 29 O CF3 highly deactivated styrenes [Ca] 30 CF3 CF3 aliphatic alkenes Current limitations of strategies I-III: n dienes 31 - precise control of the selectivity - no reactions for highly deactivated styrenes key: harnessing electrophilicity of N-alkyldiarylamines 32 - no reactions for tertiary diarylamines - scarce examples for aliphatic alkenes and dienes anilinium to favor ortho-C-alkylation 33 Manuscript 34 35 contrast, transition-metal-catalyzed reactions are more dienes and styrene derivatives, which typically generate 36 prone to produce hydroamination adducts11 or give rise to oligomers in HFIP,16 could be tolerated. Herein, we disclose 37 para-selectivity in the absence of directing groups our findings regarding this transformation with a special 38 (Schemes 1d-1e).6m,6q Visible-light photoredox protocols emphasis on highly deactivated styrenes and their synthetic 39 are curbed with similar limitations (Schemes 1g-1h).12 applications. This approach provides an amenable and 40 broadly applicable method to break the stalemate on the Our recent studies demonstrated that the use of HFIP as a selective ortho-C-alkylation of anilines. The mechanistic 41 solvent13 paired with a Lewis or Brønsted acid enables the considerations are further supported by DFT computations. 42 activation of highly unreactive olefins.8f,14 Conceptually, the Moreover, this study shows how the nature of the 43 role of the catalyst in these examples is not to directly substrates can dictate the ortho/para selectivity.17 44 activate the nucleophile or the electrophile, but, instead, to 45 augment the acidity of a H-bond network of HFIP At the outset, we examined the feasibility of this concept by 46 molecules.8f,14a In search of a reliable and selective ortho-C- investigating the inherent reactivity of highly deactivated 4- 47 alkylation of anilines with olefins and inspired by the work cyanostyrene 1a with diphenylamine 2a6u (4 equiv.) in the 48 of Beller, we reasoned that, under highly acidic conditions, presence of the promoter system that we previously 49 anilines would provide an anilinium cation, which could described for hydrofunctionalizations: Ca(NTf2)2/nBu4NPF6 18 50 react through a 6-membered transition state to generate the (20 mol%) in HFIP (0.2M) (Table 1). With respect to this 51 targeted ortho-alkylated product exclusively. This is where system, the role of the ammonium salt of weakly the use of HFIP would be paramount for the success of the coordinating hexafluorophosphate is to promote an anion 52 transformation as it may sufficiently harness the acidity of metathesis to form the heteroleptic salt Ca(NTf )(PF ), 53 2 6 the Accepted anilinium to even react with highly deactivated which is more prone to activate the H-bond network of HFIP 54 15 19 substrate, in contrast with the use of common solvents. than the sole Ca(NTf2)2. Although the reaction required a 55 Importantly, the strategy could be applied irrespective of prolonged heating at 120 °C for 4 d to proceed to full 56 the nature of the aniline (primary, secondary or tertiary). conversion, the targeted compound 3aa was obtained as a 57 Additionally, since the aniline would act as a buffer, even sole product in an excellent yield of 92% (entry 1). The 58 59 60 ACS Paragon Plus Environment Page 3 of 10 ACS Catalysis

structure of 3aa was further confirmed by X-ray analysis 1 (Figure 1). Reactions with reduced number of equivalents 2 of diphenylamine 2a still yielded 3aa, albeit in lower yields 3 (entries 2-4).20 On the other hand, we found that the 4 reaction was significantly affected by the catalyst loading as 5 the yield decreased to 55% in the presence of 10 mol% of 6 catalyst (entry 5). Importantly, no reaction was observed by 7 conducting the transformation in common solvents (entries 8 6-8), while 1a remained intact. Besides, reactions in solvent mixtures to decrease the amount of HFIP employed gave 9 Figure 1. ORTEP drawing of compound 3aa. Thermal inferior results (entries 9-11). While reactions in the ellipsoids are shown at 50% probability level. 10 presence of Ca(NTf ) occurred with the highest yields, 11 2 2 With the identified reaction conditions, we sought to Ca(NTf2)2 is not pivotal in the process; reactions in the 12 presence of a wide series of Lewis and Brønsted acids also explore the generality of the protocol with a large range of 13 furnished product 3aa in high yields (55-87%) (entries 12- alkene and aniline derivatives (Scheme 2). Initially, we 14 17), indicating that HFIP is the true cornerstone of the focused our efforts on the reactivity of different styrene 15 reaction. Given the results obtained, Ca(NTf ) has the derivatives bearing distinct electronic properties and 2 2 substitution patterns. The reaction proved to be compatible 16 major advantage to be easy to handle when compared to with a large variety of strong electron-withdrawing groups 17 HNTf2, which is highly hygroscopic and becomes rapidly deliquescent. Of note, the sole presence of HFIP is not to yield the corresponding products in good to excellent 18 yields (3aa-3ga and 3ka-3na, 56-95%). Substituents at 19 sufficient to mediate the reaction (entry 18). The robustness of this reaction was also evaluated on a scale-up ortho-, meta- and para-positions were well tolerated. 20 However, in the case of even more deactivated substrates 21 experiment (5 mmol) and 3aa could be synthesized on a 1.33 g scale (89%). such as 1m and 1n, the reaction required 6 d for the styrene 22 to be fully consumed. The reaction could also be expanded 23 Table 1. Reaction optimization for the formation of to styrenes bearing moderate electron-withdrawing groups 24 diarylethane 3aa.[a] (1h and 1i) and even unsubstituted styrene 1j, which is 25 typically prone to undergo oligomerization in HFIP,16 26 Catalyst (20 mol%) confirming the role of buffer of the amine in the reaction to nBu NPF (20 mol%) N 4 6 H preclude the side-process. These transformations could be 27 + NH solvent (0.2 M) NC conducted under milder reaction conditions (20 °C), which 28 120 °C, 96 h 1a NC represents a notable improvement when compared to 29 2a (X equiv) 3aa previous reports that required higher temperatures (up to 30 160 °C).6 Furthermore, aliphatic alkenes (1p-1r) were entry catalyst solvent X yield [%][d] 31 competent substrates for the reactions, forming the 32 products in 80-95% yields. Even a substrate incorporating 1 Ca(NTf2)2 HFIP 4 92 33 Manuscriptan additional functional group (1r) that may engage in an 2 Ca(NTf ) HFIP 3 89 34 2 2 intramolecular process reacted in a target fashion. It should 35 3 Ca(NTf2)2 HFIP 2 78 be emphasized that, in all reactions studied, no products

36 4 Ca(NTf2)2 HFIP 1 75 arising from the isomerization of the double bond were [b] observed. The reaction was also not limited to mono- 37 5 Ca(NTf2)2 HFIP 4 55 38 substituted styrenes: both - and -methylstyrenes 1s and 6 Ca(NTf2)2 1,2-DCE 4 NR 39 1t afforded the products in 89% and 63% yields, 7 Ca(NTf ) toluene 4 NR 40 2 2 respectively. Reactions of cyclic alkenes such as norbornene 41 8 Ca(NTf2)2 MeNO2 4 NR 1u and 1,3-cyclohexadiene 1v gave also excellent results (88% and 87% yields). Finally, we examined the reactivity 42 9 Ca(NTf2)2 1,2-DCE/HFIP (3:1) 4 43 of hindered styrenes such as (E)-stilbene 1w, which led to 43 10 Ca(NTf ) toluene/HFIP (3:1) 4 60 2 2 compound 3wa in a moderate yield (35%).21 44 11 Ca(NTf2)2 MeNO2/HFIP (3:1) 4 23 45 Next, we evaluated a broad range of diarylamines in a model 12[c] HNTf HFIP 4 87 46 2 reaction with 4-cyanostyrene 1a. Initially, we investigated [c] 47 13 HOTf HFIP 4 87 symmetrical diarylamines (3ab-3ah). In addition to diphenylamine 2a, this catalytic process was applied to 48 14 Sc(OTf)3 HFIP 4 80 prepare a number of frameworks of interest such as 49 15 Cu(OTf)2 HFIP 4 55 phenothiazine (3ab, 63%), phenoxazine (3ac, 72%), 50 16 Bi(OTf)3 HFIP 4 83 dihydroacridine (3ad, 85%) or iminodibenzyl (3ae, 90%). 51 17 Al(OTf)3 HFIP 4 85 One exception was carbazole 2f, which furnished both 52 18 - HFIP 4 NR ortho- and para-products in a combined yield of 84% (o/p 53 Accepted 67:33). An important feature of this protocol is also the use 54 [a] Reactions performed in a sealed tube. [b] Reaction in the presence of of dissymmetrical diarylamines. We noticed that, by relying Ca(NTf ) (10 mol%) and nBu NPF (10 mol%). [c] Reaction in the absence of 55 2 2 4 6 on the electronic properties of the aryl rings with electron- nBu4NPF6. [d] Yields of isolated 3aa. NR = no reaction. 56 donating or electron- withdrawing groups, it was possible 57 to execute the reaction with a good control of the selectivity, 58 59 60 ACS Paragon Plus Environment ACS Catalysis Page 4 of 10

Scheme 2. Scope and limitations of the C-alkylation of anilines with olefins.[a] 1 2 N Ar Ca(NTf2)2 (20 mol%) Ar 3 Ar N nBu4NPF6 (20 mol%) + N or 4 HFIP (0.2 M) H H 5

6 Mono- and Di-substituted Alkenes 7 N F N 8 H H N CF N N F3C N H 3 H F H H F C N 9 3 H F F 10 R CF3 F 11 3aa, R = CN (92%, 120 °C, 96 h) 3ka (95%, 120 °C, 48 h) 3la (92%, 120 °C, 48 h) 3ma (83%, 120 °C, 144 h) 3na (56%, 120 °C, 144 h) 3oa (87%, 20 °C, 24 h) 3pa (84%, 120 °C, 48 h) 3ba, R = CO2Me (93%, 120 °C, 24 h) 12 3ca, R = CF3 (93%, 120 °C, 48 h) 3da, R = SF5 (84%, 120 °C, 72 h) N TsHN 3ea, R = CO H (91%, 120 °C, 96 h) H 13 2 N N N N H H 3fa, R = NO2 (62%, 120 °C, 96 h) N N H H H H 14 3ga, R = OTs (86%, 120 °C, 2 h) CH3 CH 3ha, R = Br (88%, 20 °C, 72 h) 3 F3C F3C 15 3ia, R = F (63%, 20 °C, 3 h)[b] 3qa (95%, 120 °C, 24 h) 3ra (80%, 120 °C, 168 h) 3ta (63%, 120 °C, 96 h) 3ua 3va (87%, 20 °C, 1 h) 3wa (35%, 120 °C, 96 h) 3ja, R = H (86%, 20 °C, 18 h) 3sa (89%, 20 °C, 96 h) (88%, exo/endo>95:5, 16 120 °C, 24 h) 17 Diarylamines 18 S O MeO OMe N N N N N N N H 19 H H H H H H 20 NC NC NC NC NC NC NC 21 3ab (63%, 120 °C, 18 h) 3ac (72%, 80 °C, 1 h) 3ad (85%, 120 °C, 96 h) 3ae (90%, 120 °C, 24 h) 3af (84%, o/p 67:33, 3ag (81%, 120 °C, 96 h) 3ah (94%, 120 °C, 96 h) 22 120 °C, 18 h) 23 Br CN MeO

24 a N a N a N a N a N N H b H b H b H b H b 25 CH3 26 NC NC NC NC NC NC 3ai (47%, a/b>95:5, 120 °C, 48 h) 3aj (52%, a/b 82:18, 120 °C, 48 h) 3ak (73%, a/b 77:23, 120 °C, 96 h) 3an 27 3al (86%, a/b 67:33, 120 °C, 96 h) 3am (81%, a/b 91:9, 120 °C, 24 h) (57%, 120 °C, 96 h) 28 Anilines Electron-rich alkenes R 29 CH3 CH3 N N CH3 H3C CH3 3co, R = H (93%, 120 °C, 96 h) H HN HN N HN NH2 CH3 30 3cp, R = OMe (83%, 120 °C, 72 h)[c] 3cq, R = Cl (91%, 120 °C, 72 h) 31 F3C F3C F C 32 3 3cr (57%, 120 °C, 96 h) 3cs (<5%, 120 °C, 96 h) CH3 CH3 CH3 33 X Manuscript CH3 N [d] 34 NH2 N NH2 3'ya 3'yr 3'ys (83%, 80 °C, 3 h) 3'za (89%, 20 °C, 2 h) H H (95%, 20 °C, 2 h) (94%, 80 °C, 2 h) 35 CH3 CH3 CH3 HN F3C F3C F3C 36 HN NH2 HN 3so (83%, 120 °C, 96 h) 3sr (83%, 120 °C, 96 h) 3st (92%, 120 °C, 96 h) 3jo, R = H (94%, 120 °C, 48 h) 37 3jp, R = OMe (93%, 120 °C, 24 h) 38

39 CH3 N NH2 NH2 H NH2 R MeO 40 3'zaa, R = Me (74%, 20 °C, 1 h) 3'zbo 3'zda 3'zea (87%, 20 °C, 3 h) (82%, 20 °C, 1 h) (68%, 20 °C, 2 h) 41 NC 3'zba, R = OMe (93%, 20 °C, 1 h) 3'zca, R = NH2 (79%, 20 °C, 1 h) 42 3jr (90%, 120 °C, 40 h) 3au (83%, 120 °C, 72 h) 3ju (85%, 120 °C, 1 h) 3xo (58%, 120 °C, 96 h) Triarylamines 43 MeO

44 N N N N N 45 MeO

N + 46 a b 47 Ph HO C 48 NC O2N 2 NC NC 49 3'av (95%, 120 °C, 24 h) 3'fv (72%, p/o 92:8, 120 °C, 96 h) 3'ev (93%, p/o 88:12, 120 °C, 3 h) 3'ov (71%, 20 °C, 24 h) 3aw (51%, a/b 90:10, 120 °C, 96 h) 3'aw (38%, 120 °C, 96 h) 50 [a] Reactions performed in a sealed tube. [b] o/p 88:12. [c] o/N 93:7. [d] ortho-product obtained in 7% yield. 51 ranging from 67:33 to > 95:5. Gratifyingly, engaging the compounds in well-documented Lewis and Brønsted acid 52 tertiary diarylamine 2n in the reaction gave 3an in 57% catalysis.6a,6c-6l,6n Here, they reacted with highly deactivated 53 yield.Accepted styrenes to generate exclusively ortho-products in high 54 yields (up to 93%). Similarly, the reaction between styrene We also studied the title process with primary anilines, N- 55 and aniline derivatives afforded the targeted products (up alkyl anilines and 1-naphthylamine, which were previously 56 to 94%). One limitation of our method was the reactivity of found to form hydroamination products along the targeted 57 a highly basic aniline such as N,N-dimethylaniline 2s, which 58 59 60 ACS Paragon Plus Environment Page 5 of 10 ACS Catalysis

proved to be unreactive under standard reaction which delivered compound 3p as a major product, resulting 1 conditions. The results are in agreement with the from an isomerization/hydroarylation sequence in a typical 2 hypothesized mechanism, where the reduced proton-catalyzed process. On the other hand, when the 3 electrophilicity of the corresponding anilinium compared to same reaction was conducted in the presence of 2a, the 4 those previously studied along with the low nucleophilicity reaction provided 3pa as a sole product, while neither 3p 5 of styrene 1c is prohibitive for the reaction to occur. nor 3’p was detected. Besides, when the protonation of the alkene occurred in the case of electron-rich alkenes, we 6 We noted that the electron density of the alkene is another 7 noted that only the formation of the para-products was key factor in this transformation. Indeed, when - observed. 8 methylstyrene 1y was employed instead of electron- 9 deficient styrene 1s, we observed a complete switch of the Scheme 4. Reactivity of aliphatic alkenes

10 selectivity from ortho to para, independently of the aniline OMe OMe used. These results hint at a different mechanism with MeO 11 MeO OMe 12 electron-rich alkenes, which would first involve the Ca(NTf2)2 (20 mol%) MeO nBu4NPF6 (20 mol%) 13 protonation of the alkene with the formation of highly + + stable carbocation under the reaction conditions and a HFIP (0.2 M), 80 °C, 3 h 1p 4 equiv 14 3'p (44%) subsequent electrophilic aromatic substitution. Similarly, 3p 15 H (53%) other electron-rich alkenes such as 1,1-diphenylethylene N 16 1z, 4-methylstyrene 1za, 4-methoxystyrene 1zb, 4- 17 aminostyrene 1zc, (E)-1-phenyl-1,3-butadiene 1zd and 2a (4 equiv) 18 acenaphthylene 1ze delivered the para-products in high Ca(NTf2)2 (20 mol%) nBu4NPF6 (20 mol%) N 19 yields (68-93% yield). On the other hand, introducing an H + 3p (-) + 3'p (-) 20 HFIP (0.2 M), 80 °C, 24 h electron-withdrawing group on oxygen (1g) allows to 3pa (41%) 21 restore the ortho-selectivity (3ga, 86%). The use of 22 triphenylamine 2v led also to the generation of para- Secondly, although the hydroaminated adduct was not 23 adducts (3’av, 3’ev, 3’fv and 3’ov) (71-95% yields). Our detected in the previous examples, we cannot rule out the 24 assumption is that the reactivity of 2v might be directly possibility that a Hofmann-Martius rearrangement,24 which + consists in the rearrangement of N-alkylated aniline into the 25 linked to the pKa of its conjugated acid Ph3NH (pKa = 3.9) + ortho-C-alkylated aniline, occurred during the reaction. 26 in comparison to the ones of Ph2NH2 (pKa = 0.8) and + 22 + Indeed, in the case of norbornene 1u, we could observe the 27 PhNH3 (pKa = ). Indeed, Ph3NH should protonate the + + formation of the hydroamination product 3’uo along with alkene more easily than Ph2NH2 or PhNH3 and, in that case, 28 3uo (Scheme 5). Upon prolonged heating at 160 °C, 3’uo 29 an electrophilic aromatic substitution would occur. This trend could be partly counterbalanced through electronic could be mostly converted into 3uq (81%). We also 30 11a effects by introducing an electron-donating group (4- prepared in parallel the secondary amine 3’’co and 31 MeOPh)Ph NH+, pKa ~ 2.4)23 to form the ortho-C-alkylated subjected it to the reaction conditions. After 96 h, 3’’co 32 2 product 3aw in 51% yield. However, we cannot exclude that remained fully intact, indicating that this reaction pathway 33 Manuscriptis unlikely to take place in the case of highly deactivated the ortho-alkylation may also take place and that the 34 increased stability of the carbocation intermediate may styrenes. 35 facilitate the retro-alkylation to eventually generate the Scheme 5. Possibility of a Hofmann-Martius 36 more stable para-alkylated product. Indeed, when rearrangement. 37 compound 3zbo6h was subjected to the reaction conditions, 38 we observed its conversion into para-product 3’zbo, albeit Hofmann-Martius rearrangement 39 in a moderate yield (57%) (Scheme 3).

Ca(NTf2)2 (20 mol%) 40 NH2 HN NH2 Scheme 3. Possibility of a rearrangement from ortho- to nBu4NPF6 (20 mol%) 41 para-product. + + (1) 42 HFIP (0.2 M) NH 1u 2o (4 equiv) 100% conversion 43 2 3uo 3''uo 120 °C, 24 h0 ratio 17:83 44 Ca(NTf2)2 (20 mol%) 120 °C, 120 h ratio 61:39 NH 2 nBu4NPF6 (20 mol%) 140 °C, 120 h ratio 68:32 45 160 °C, 144 h ratio 90:10 (3uo, 81%, exo/endo >95:5) 46 HFIP (0.2 M), 20 °C, 3 h MeO MeO 47 Ca(NTf2)2 (20 mol%) 3zbo 3'zbo (57%) nBu NPF (20 mol%) 48 HN 4 6 NH2 X 49 The overall excellent ortho-selectivities observed led us to HFIP (0.2 M), 120 °C, 96 h 50 examine in more detail the mechanism governing this CF3 CF3 51 transformation, notably its potentially concerted nature. As 3''co 3co (-) 52 mentioned above, no isomerization product was obtained in To shed more light on the reaction mechanism, we studied 53 the Accepted case of aliphatic alkenes, which seems in agreement the reaction of aniline with styrene by DFT computations, 54 with a plausible concerted mechanism for the formation of performed at the M06-2X/6-311+G(d,p) level of theory. The the targeted products. To confirm this hypothesis, we 55 values discussed below are Gibbs free energies at 393.15 K conducted the hydroarylation of allylbenzene 1p with 1,2- (G393 kcal/mol), which include a solvent correction. A 56 dimethoxybenzene under standard conditions (Scheme 4), 57 detailed discussion is presented in the Supporting 58 59 60 ACS Paragon Plus Environment ACS Catalysis Page 6 of 10

Information and only the main conclusions are summarized The N-alkylation was also calculated, and it was found to 1 here. As mentioned above, the Ca(NTf2)2/nBu4NPF6 is likely require 1.6 kcal/mol more free energy of activation than 19 + 2 to generate Ca(NTf2)(PF6). Thus, the Ca(NTf2) ion has going to the ortho-C-alkylation transition state (see the 3 been used in the computations. In agreement with our Supporting Information). We can thus conclude that the N- 4 previous computational studies on calcium-catalyzed alkylation/Hofmann-Martius pathway, which could also 5 reactions in alcoholic media, a direct activation of the explain the formation of the ortho-C-alkylation product, + 8f,14a,19c 6 substrates by Ca(NTf2) proved to be inefficient. should be a minor process with aniline and styrene 7 Simple H-bonded (HFIP)n clusters (n = 1, 2, 3) also led to compared to the ortho-C-alkylation proposed in Scheme 5. prohibitively high energy barriers. We then studied various It should also be noted that the para-alkylation transition 8 + combinations of Ca(NTf2) and HFIP molecules (up to state was found much higher in energy than [TSAB] (39.9 9 + three). The lowest energy was obtained with one Ca(NTf2) kcal/mol). Thus, at least with primary anilines, and in line 10 and two HFIPs (Scheme 6). Once HFIP is ligated to the with the experimental results, the para-alkylation seems 11 calcium center, its acidity is strengthened, and it unlikely compared to the ortho-alkylation pathway. Overall, 12 25,26 + spontaneously protonates aniline to give adduct A. N-to- this set of computations shows that the Ca(NTf2) /HFIP 13 C proton transfer requires 24.6 kcal/mol of free energy of mixture provides an acidic medium able to protonate 14 activation. The resulting carbocation (not shown) collapses aniline and facilitate a proton transfer to styrene which, 15 to the Wheland-type intermediate B, located at 7.0 although not thermodynamically favored, is triggered by 16 kcal/mol. The formation of B can thus be considered as the virtually concomitant formation of the C-C bond and a 17 nearly concerted. The deprotonation could be modeled facile deprotonation of the Wheland intermediate. This 18 directly from B, but a lower energy path was obtained from process can only take place in the ortho position, hence the 19 the more stable isomer C, lying at -1.4 kcal/mol on the free regioselectivity observed with primary amines. energy surface. In C, it is HFIP that is bound to the 20 From a synthetic perspective, those compounds were ammonium instead of the calcium alcoholate. This new 21 engaged in several derivatizations to build useful arrangement of the fragments benefits from a -arene 22 frameworks that could be tedious to prepare otherwise calcium interaction,27 which lowers the deprotonation 23 (Scheme 7). Because the reaction of carbazole led to a barrier ([TS ], 11.5 kcal/mol) and provides the final - CD mixture of products, we tested an approach to circumvent 24 arene calcium complex D, more stable than A by 19.5 this issue. A simple Pd-catalyzed oxidative CC bond 25 kcal/mol. 26 formation of 3aa gave access to carbazole 3af in 73% 28 27 Scheme 6. Simplified free energy profile (G393, kcal/mol) yield. Another envisaged application was to engineer a of the [Ca(NTf )(HFIP)]+-triggered ortho-C-alkylation of 28 2 Scheme 7. Derivatizations of the ortho-C-alkylated aniline with styrene. 29 compounds. 30 31 Pd(OAc) (5 mol%) 32 2 N N K CO (10 mol%) H 33 ManuscriptH 2 3 PivOH, 120 °C, 48 h 34 NC NC 35 3aa 3af (73%) [TSAB] 36 24.6 37 N N 38 H DEAD (2.2 equiv)

39 CHCl3, 20 °C, 12 h [TSCD] 11.5 F3C F3C 40 3st 4 (94%) 41 7.0 F F 42 H H N F F CF 43 H H F 3 N N 0.0 O F DEAD (2.2 equiv) CH CF3 -1.4 H 44 3 O H Ca CF3 CF3 H CHCl3, 50 °C, 2 h H F F O O H 45 CF N CF3 O S S 3 H O NC NC CF3 CF3 F H 3ad 5 (96%) 46 O O N O H F CH3 CF3 F F O S B 47 N H O F F F Ca MeO OMe O S (Tf2N)Ca CF3 48 O O O H C -19.7 F N CAN (3 equiv) O 49 H F F H H N 50 H A MeCN/H2O (3:1), 0 °C, 1 h NC 51 NC 3ag 6 (86%) 52 53 Accepted D CuCl (6 equiv) 54 N N H KBH4 (7 equiv) H 55 MeOH, 20 °C, 0.5 h 56 O2N 3fa H2N 7 (93%) 57 58 59 60 ACS Paragon Plus Environment Page 7 of 10 ACS Catalysis

dehydrogenation of tetrahydroquinoline 3su and Transformation of Esters in Heterocyclic Fluorophores. Angew. 1 dihydroacridine 3ad in the presence of diethyl Chem. Int. Ed. 2018, 57, 2436-2440. 2 azodicarboxylate (DEAD).29 In this way, formal ortho-C- (3) (a) Romero, N. A.; Nicewicz, D. A. Organic Photoredox 3 alkylated products of quinoline (4) and acridine (5) were Catalysis. Chem. Rev. 2016, 116, 10075-10166. (b) Magrey, K. A.; Nicewicz, D. A. A General Approach to Catalytic Alkene Anti- 4 delivered in 94% and 96% yields, respectively. Of note, Markovnikov Hydrofunctionalization Reactions via Acridinium 5 quinoline and acridine are unreactive under our standard Photoredox Catalysis. Acc. Chem. Res. 2016, 49, 1997-2006. 6 conditions. In the same vein, because the benzylation of (4) For reviews on hydroarylation of unactivated alkenes, see: 30 7 quinone is challenging, we used our strategy as a relay to (a) Rueping, M.; Nachtsheim, B. J. A Review of New Developments 8 access such type of products (6 in 86% yield) through the in the Friedel-Crafts Alkylation. Beilstein J. Org. Chem. 2010, 6, No. oxidation of 3ag in the presence of cerium ammonium 6. (b) Andreatta, J. R.; McKeown, B. A.; Gunnoe, T. B. Transition 9 nitrate (CAN). Moreover, the primary aniline 7 could be Metal Catalyzed Hydroarylation of Olefins Using Unactivated 10 obtained by reduction of 3fa in 93% yield,31 while it could Substrates: Recent Developments and Challenges. J. Organomet. Chem. 2011, 696, 305-315. (c) Dong, Z.; Ren, Z.; Thompson, S. J.; Xu, 11 not be accessed starting from 4-aminostyrene 1zc. 12 Y.; Dong, G. Transition-Metal-Catalyzed CH Alkylation Using 13 In conclusion, we have devised a general and efficient Alkenes. Chem. Rev. 2017, 117, 9333-9403. 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R.; Trauthwein, H. Catalytic Alkylation 21 styrenes, aliphatic alkenes and dienes. It further buttresses of Aromatic Amines with Styrene in the Presence of Cationic 22 the utility of hexafluoroisopropanol in organic synthesis to Rhodium Complexes and Acid. Synlett 1999, 243-245. (b) 23 develop hitherto unsolved transformations. Additionally, Uchimaru, Y. NH Activation vs. CH Activation: Ruthenium- Catalysed Regioselective Hydroamination of Alkynes and we emphasized that the nature of the aniline and the alkene 24 Hydroarylation of an Alkene with N-Methylaniline. Chem. Commun. 25 had a major impact on the ortho/para selectivity of the 1999, 1133-1134. (c) Ackermann, L.; Kaspar, L. T.; Gschrei, C. J. reaction. 26 TiCl4-Catalyzed Intermolecular Hydroamination Reactions of 27 Norbornene. Org. Lett. 2004, 6, 2515-2518. (d) Kaspar, L. T.; ASSOCIATED CONTENT 28 Fingerhut, B.; Ackermann, L. Titanium-Catalyzed Intermolecular Hydroamination of Vinylarenes. Angew. Chem. Int. Ed. 2005, 44, 29 Supporting Information. Experimental procedures, characterization data and NMR 5972-5974. (e) Cherian, A. E.; Domski, G. J.; Rose, J. M.; Lobkovsky, 30 spectra of all new compounds. This material is available free of E. B.; Coates, G. W. Acid-Catalyzed ortho-Alkylation of Anilines with 31 charge via the Internet at http://pubs.acs.org/ Styrenes: An Improved Route to Chiral Anilines with Bulky 32 Substitutents. Org. Lett. 2005, 7, 5135-5137. (f) Anderson, L. L.; 33 AUTHOR INFORMATION ManuscriptArnold, J.; Bergman, R. G. Proton-Catalyzed Hydroamination and Hydroarylation Reactions of Anilines and Alkenes: A Dramatic 34 Corresponding Authors Effect of Counteranions on Reaction Efficiency. J. Am. Chem. Soc. 35 2005, 127, 14542-14543. (g) Lapis, A. A. M.; DaSilveira Neto, B. A.; * [email protected] 36 Scholten, J. D.; Nachtigall, F. M.; Eberlin, M. N.; Dupont, J. 37 * [email protected] Intermolecular Hydroamination and Hydroarylation Reactions of Alkenes in Ionic Liquids. Tetrahedron Lett. 2006, 47, 6775-6779. 38 Notes (h) Marcseková, K.; Doye, S. HI-Catalyzed Hydroamination and 39 The authors declare no competing financial interest. Hydroarylation of Alkenes. Synthesis 2007, 145-154. (i) Wei, H.; 40 Qian, G.; Xia, Y.; Li, K.; Li, W. BiCl3-Catalyzed Hydroamination of 41 ACKNOWLEDGMENT Norbornene with Aromatic Amines. Eur. J. Org. Chem. 2007, 4471- 42 4474. (j) Prades, A.; Corberán, R.; Poyatos, M.; Peris, E. A simple We gratefully thank the ANR (ANR-17-CE07-0003 funding Catalyst for the Efficient Benzylation of Arenes by Using Alcohols, 43 for SW and ANR-16-CE07-0022 funding for GF), the CNRS, Ethers, Styrenes, Aldehydes, or Ketones. Chem. Eur. J. 2009, 15, 44 Ecole Polytechnique and Université Paris-Saclay for the 4610-4613. (k) Babu, N. S.; Reddy, K. M.; Prasad, P. S.; 45 support of this work. We used the OCCIGEN high Suryanarayana, I.; Lingaiah, N. Intermolecular Hydroamination of 46 performance cluster of the CINES. 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Dehydrative Friedel-Crafts Reactions. Chem. Sci. 2018, 9, 8528- Reilly, J.; Hickinbottom, W. J. Intramolecular Rearrangement of the 1 8533. (j) Bernhardt, A.; Kelm, H.; Patureau, F. W. The Strong -CF3 Alkylarylamines: Formation of 4-Amino-n-butylbenzene. J. Chem. 2 Shielding Effect in Hexafluoroisopropanol and 100 Other Organic Soc., Trans. 1920, 117, 103-137. 17 3 Solvents Revisited with O NMR Spectroscopy. ChemCatChem. (25) In our attempts to determine the reactive species, we 2018, 10, 1547-1551. (k) D’Amato, E. M.; Borgel, J.; Ritter, T. performed NMR studies, which suggests the formation of 4 Aromatic C-H Amination in Hexafluoroisopropanol. Chem. Sci. Ca(NTf2)(OCH(CF3)2) when mixing Ca(NTf2)(PF6), HFIP and aniline 5 2019, 10, 2424-2428. (l) Zhou, Z.; Cheng, Q.-Q.; Kürti, L. Aza- (see Supporting Information for details). 6 Rubottom Oxidation: Synthetic Access to Primary - (26) For the stabilization of calcium salts via Ca···F interactions, 7 Aminoketones. J. Am. Chem. Soc. 2019, 141, 2242-2246. (m) Y. Zhu, see: (a) Sarazin, Y.; Liu, B.; Roisnel, T.; Maron, L.; Carpentier, J.-F. 8 I. Colomer, A. L. Thompson, T. J. Donohoe. HFIP Solvent Enables Discrete, Solvent-Free Alkaline-Earth Metal Cations: Alcohols to Act as Alkylating Agents in Stereoselective Metal···Fluorine Interactions and ROP Catalytic Activity. J. Am. 9 Heterocyclization. J. Am. Chem. Soc. 2019, 141, 6489-6493. (n) Chem. Soc. 2011, 133, 9069-9087. (b) Rosca, S.-C.; Roisnel, T.; 10 Chatupheeraphat, A.; Rueping, M.; Magre, M. Chemo- and Dorcet, V.; Carpentier, J.-F.; Sarazin, Y. Potassium and Well-Defined 11 Regioselective Magnesium-Catalyzed ortho-Alkenylation of Neutral and Cationic Calcium Fluoroalkoxide Complexes: 12 Anilines. Org. Lett. 2019, 21, 9153-9157. (o) Nielsen, C. D.-T.; Structural Features and Reactivity. Organometallics 2014, 33, 5630-5644. (c) Sarazin, Y.; Carpentier, J.-F. Calcium, Strontium and 13 White, A. J. P.; Sale, D.; Bures, J.; Spivey, A. C. Hydroarylation of Alkenes by Protonation/Friedel-Crafts Trapping: HFIP-Mediated Barium Homogeneous Catalysts for Fine Chemical Synthesis. Chem. 14 Access to Per-aryl Quaternary Stereocenters. J. Org. Chem. 2019, Rec. 2016, 16, 2482-2505. (d) Sarazin, Y.; Carpentier, J.-F. In 15 84, 14965-14973 (p) Wang, S.; Guillot, R.; Carpentier, J.-F.; Sarazin, Noncovalent Interactions in Catalysis; Mahmudov, K. T.; 16 Y.; Bour, C.; Gandon, V.; Lebœuf, D. Synthesis of Bridged Kopylovich, M. N.; Guedes da Silva, M. F. C.; Pombeiro, A. J. L., Eds.; 17 Tetrahydrobenzo[b]azepines and Derivatives through an Aza- RSC, 2019, pp94-121. (27) (a) Buchanan, W. D.; Allis, D. G.; Ruhlandt-Senge, K. 18 Piancatelli cyclization/Michael Addition Sequence. Angew. Chem. Int. Ed. 2020, 59, 1134-1138. Synthesis and Stabilization-Advances in Organoalkaline Earth 19 (16) Kuznetsov, D. M.; Tumanov, V. V.; Smit, W. A. Cationic Metal Chemistry. Chem. Commun. 2010, 46, 4449-4465. (b) 20 Polymerization of Styrenes under Essentially Neutral Conditions. J. Causero, A.; Ballmann, G.; Pahl, J.; Zijlstra, H.; Färber, C.; Harder, S. 21 Polym. Res. 2013, 20, 128-133. Stabilization of Calcium Hydride Complexes by Fine Tuning of 22 (17) During the preparation of this manuscript, Colomer Amidinate Ligands. Organometallics 2016, 35, 3350-3360. (c) Pahl, J.; Brand, S.; Elsen H.; Harder, S. Highly Lewis Acidic Cationic 23 reported the hydroarylation of electron-rich alkenes with anilines. The overall transformation and key to reactivity (HFIP) are the Alkaline Earth Metal Complexes. Chem. Commun. 2018, 54, 8685- 24 same, but our catalyst furnishes complementary regioselectivity. 8688. (d) Garcia, L.; Anker, M. D.; Mahon,M. F.; Maron, L.; Hill, M. S. 25 Colomer, I. ACS Catal. 2020, 10, 6023-6029. Besides, we tested his Coordination of Arenes and Phosphines by Charge Separated 26 catalytic system (NaOAc in HFIP) in our model reaction between Alkaline Earth Cations. Dalton Trans. 2018, 47, 12684-12693. (e) 27 1a and 2a and we did not observe any reactivity. Wilson, A. S. S.; Hill, M. S.; Mahon. M. F. Calcium Hydride Insertion Reactions with Unsaturated C−C Bonds. Organometallics 2019, 38, 28 (18) For reviews on Ca(II) catalysis, see: (a) Begouin, J.-M.; Niggemann, M. Calcium-Based Lewis Acid Catalysts. Chem. Eur. J. 351-360. (f) Garcia, L.; Mahon, M. F.; Hill, M. S. Multimetallic 29 2013, 19, 8030-8041. (b) Lebœuf, D.; Gandon, V. Carbon-Carbon Alkaline-Earth Hydride Cations. Organometallics 2019, 38, 3778- 30 and Carbon-Heteroatom Bond-Forming Transformations 3785. (g) Schorpp, M.; Krossing, I. Soft Interactions with Hard 31 Catalyzed by Calcium(II) Triflimide. Synthesis 2017, 49, 1500- Lewis Acids: Generation of Mono- and Dicationic Alkaline-Earth 32 1508. (c) Rauser, M.; Schröder, S.; Niggemann, M. In Early Main Metal Arene-Complexes by Direct Oxidation. Chem. Sci. 2020, 11, 2068-2076. 33 Group Metal Catalysis: Concepts and Reactions; Harder, S., Ed.; Manuscript Wiley-VCH, 2020, pp279-310. (28) Liégault, B.; Lee, M.; Huestis, M. P. Stuart, D. R.; Fagnou, K. 34 (19) (a) Haubenreisser, S.; Niggemann, M. Calcium-Catalyzed Intermolecular Pd(II)-Catalyzed Oxidative Biaryl Synthesis Under 35 Direct Amination of -Activated Alcohols. Adv. Synth. Catal. 2011, Air: Reaction Development and Scope. J. Org. Chem. 2008, 73, 5022- 36 353, 469-474. (b) Davies, J.; Leonori, D. The First Calcium-Catalysed 5028. 37 Nazarov Cyclisation. Chem. Commun. 2014, 50, 15171-15174; (c) (29) Bang, S. B.; Kim, J. Efficient Dehydrogenation of 1,2,3,4- Tetrahydroquinolines Mediated by Dialkyl Azodicarboxylates. 38 Lebœuf, D.; Marin, L.; Michelet, B.; Perez-Luna, A.; Guillot, R.; Schulz, E.; Gandon, V. Harnessing the Lewis Acidity of HFIP Synth. Commun. 2018, 48, 1291-1298. 39 Through its Cooperation with a Calcium(II) Salt: Application to the (30) Xu, X.-L.; Li, Z. Catalytic Electrophilic Alkylation of p- 40 Aza-Piancatelli Reaction. Chem. Eur. J. 2016, 22, 16165-16171. Quinones through a Redox Chain Reaction. Angew. Chem. Int. Ed. 41 (20) Although diphenylamine 2a was used in excess (4 2017, 56, 8196-8200. 42 equivalents), it could be easily recovered by flash column (31) He, Y.; Zhao, H.; Pan, X.; Wang, S. Reduction with Metal Borohydride-Transition Metal Salt System. I. Reduction of 43 chromatography during the purification of the crude material. (21) The reaction was also attempted with activated alkenes Aromatic Nitro Compounds with Potassium Borohydride- 44 such as ethyl acrylate but led only to the aza-Michael addition Copper(I) Chloride. Synth. Commun. 1989, 19, 3047-3050. 45 product. 46 Ca(NTf2)2 (20 mol%) 47 N nBu4NPF6 (20 mol%) 48 EtO2C + NH HFIP (0.2 M), 120 °C, 24 h 49 CO2Et 50 2a (4 equiv) 8 (78%) 51 (22) For those pKa values, see: Kaljurand, I.; Lilleorg, R.; 52 Murumaa, A.; Mishima, M.; Burk, P.; Koppel, I.; Koppel, I. A.; Leito, I. 53 The AcceptedBasicity of Substituted N,N-Dimethylanilines in Solution and in 54 the Gas Phase. J. Phys. Org. Chem. 2013, 26, 171-181. (23) Calculated using Advanced Chemistry Development 55 (ACD/Labs) Software V11.02 (© 1994-2020 ACD/Labs). 56 (24) (a) Hofmann, A. W.; Martius, C. A. Methylirung der 57 Phenylgruppe im Anilin. Ber. Dtsch. Chem. Ges. 1871, 4, 742. (b) 58 59 60 ACS Paragon Plus Environment ACS Catalysis Page 10 of 10

1 SYNOPSIS TOC 2 3 Ar Ca(NTf2)2 Ar N 4 nBu4NPF6 5 + N H HFIP 6 7 51 examples (35-95%) 8 - Excellent ortho-C selectivity 9 - Use of previously unreactive substrates 10 - High yields and gram-scale - Functional group tolerance 11 - Mechanism supported by DFT computations 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 Manuscript 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 Accepted 54 55 56 57 58 59 60 ACS Paragon Plus Environment