Ni-Catalyzed Enantioselective Intermolecular Hydroamination of

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Ni-Catalyzed Enantioselective Intermolecular Hydroamination of Branched 1,3-Dienes Using Primary Aliphatic Amines Gaël Tran, Wen Shao, and Clément Mazet J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 22 Aug 2019 Downloaded from pubs.acs.org on August 22, 2019

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Journal of the American Chemical Society

Ni-Catalyzed Enantioselective Intermolecular Hydroamination of Branched 1,3-Dienes Using Primary Aliphatic Amines Gaël Tran, Wen Shao, and Clément Mazet* Department of Organic Chemistry, University of Geneva, 30 quai Ernest Ansermet, 1211 Geneva, Switzerland. ABSTRACT: A Ni-catalyzed intermolecular enantioselective hydroamination of branched 1,3-dienes is reported. The method is broadly applicable, highly regio-, chemo- and enantioselective and provides direct access to valuable chiral allylic amines starting from linear or -branched aliphatic primary amines or secondary amines. Mechanistic studies have been conducted using 31P NMR spectroscopy for reaction progress monitoring, isotopic labeling experiments (2H) and kinetic analysis. The resting state of the catalyst is a Ni--allyl complex and the outer-sphere nucleophilic attack of H-bonded amine aggregates is proposed to be the rate-determining step. This hypothesis guided the identification of an improved set of reaction conditions for the enantioselective hydroamination of branched 1,3-dienes.

The transition-metal catalyzed stereocontrolled addition of an amine across a carbon-carbon double bond – the hydroamination of olefins – is a fundamental chemical process which attracts continuous attention from academia and industry (Figure 1, A).1 While it provides a direct and atom-economical access to highly valuable chiral nitrogencontaining molecules, it also poses several selectivity issues associated with regio-, diastereo- and enantiocontrol. In spite of the great advances made in developing enantioselective hydroamination reactions during the last decade, several important challenges remain to be addressed. Most notably, there is no report of enantioselective intermolecular hydroamination of alkenes using non-activated primary aliphatic amines for the synthesis of chiral secondary amines, in part due to potential overreaction and/or detrimental exchange processes.1,2 Not surprisingly, current hydroamination methods for the synthesis of chiral secondary amines typically rely on the use of modified amine transfer reagents.3 The hydroamination of polyunsaturated substrates such as allenes, enynes or conjugated dienes is a particularly appealing transformation because (i) it produces amines with functional handles adjacent to the newly generated C‒N bond and (ii) it is potentially amenable to enantioselective catalysis (Figure 1, B-C). In this context, a Pd-catalyzed asymmetric hydroamination of cyclic 1,3-dienes with primary aryl amines has been developed by Hartwig and coworkers, affording the corresponding allylamines with excellent levels of enantiocontrol.4 The Dong group reported a broadly applicable and highly enantioselective Rh-catalyzed Markovnikov 1,2-hydroamination of linear 1,3-dienes using indoline nucleophiles.5 Similar performances were achieved by Malcolmson and co-workers with these substrates using secondary aliphatic amines under Pd catalysis.6 Branched dienes constitute a substrate sub-class which is synthetically equally attractive and challenging because up to 11 isomers can be generated upon hydrofunc-

Figure 1. (A) Hydroamination of alkenes. (B) Selective hydroamination of dienes. (C) Selectivity challenge for the hydroamination of branched dienes. (D) Ni-catalyzed enantioselective intermolecular Markovnikov 3,4-hydroamination of branched dienes.

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-tionalization (Figure 1, C).7 A Rh-catalyzed 3,4-hydroamination of 2-substituted 1,3-dienes with anti-Markovnikov selectivity was recently disclosed by Dong and co-workers.8 The corresponding homoallylic amines were obtained with high regioselectivity using indoline derivatives and 2-alkyl as well as 2-aryl substituted dienes.

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hydroamination of 1a were the major side-products observed. Representative results of our optimization study are disclosed in Table 1. In the absence of TFE, no reaction occurred (Entry 2). The use of diphenylphosphinic acid led to increased catalytic activity, excellent regioselectivity but a slightly diminished enantioselectivity (Entry 3). No product was formed when TFA was employed instead of TFE, and hexafluoroisopropanol led to a similar outcome (Entries 4-5). Almost no hydroamination product was detected when equimolar amounts of diene and benzylamine were employed (Entry 6). Whereas other C2-symmetric bisphosphine ligands performed poorly (Entries 7-8), high to very high levels of enantioselectivity were achieved with C1-symmetric (P,N) ligands, albeit with moderate reactivity and/or regioselectivity (Entries 9-11). In contrast to CH2Cl2 in which no reaction occurred, excellent regio- and enantioselectivity were maintained in Et2O (Entries 12-13). Finally, a prolonged reaction time furnished 3aa as major regioisomer in 93% ee and 78% yield after purification (Entry 14)

To date, the development of an enantioselective 3,4-hydroamination of branched dienes with Markovnikov selectivity remains elusive.9 Its implementation would undoubtedly constitute a valuable addition to the current portfolio of methods to access chiral amines. Therefore, as a continuation of our interest in the selective functionalization of dienes,10 we decided to tackle this considerable challenge. We present herein the results of our investigations which led to the identification of a highly regio- and enantioselective nickel catalyst for the intermolecular 3,4hydroamination of branched dienes with primary aliphatic amines (Figure 1, D).

Table 1. Reaction optimizationa

Figure 2. Ni-catalyzed hydroamination of 1,3-dienes using TFA as protic additive. Our approach was inspired by a report from the Hartwig group who established that primary and secondary alkylamines are competent nucleophiles for the hydroamination of cyclic dienes using a catalytic combination of a bisphosphine-nickel(0) complex and trifluoroacetic acid (TFA) (Figure 2).11 While no reaction occurred in the absence of acid, the process was found to be reversible under the optimized conditions. Indeed, the authors highlighted the difficulty of developing an enantioselective variant of this transformation with the identification of exchange processes between allylic amines and free amines. The fine balance that exists between C‒N bond formation and C‒N bond cleavage was further evidenced by racemization experiments conducted on optically active cyclic allylic amines and by undesired post-reaction isomerizations observed for acyclic allylic amines. Cognizant of these serious impediments, we initiated our study using 2-aryl substituted diene 1a and benzylamine 2a as model substrates and mildly acidic additives. In line with observations made by Zhou and coworkers,12 we initially hypothesized that acids milder than TFA may still favor the formation of the putative nickel-hydride that should precede allyl formation while disfavoring reversible processes presumably occurring by oxidative addition of the protonated allylic amine product by a Ni(0) intermediate (Figure 2). After variation of several reaction parameters, we were able to achieve the desired 3,4-hydroamination and to generate allylic amine 3aa as the major regioisomer in 93% ee using trifluoroethanol (TFE) as additive, and a catalytic combination of Ni(cod)2, and BenzP*, both of which are commercially available (Table 1, Entry 1). During our optimization campaign, allylic amines 4aa and 5aa resulting from formal 1,4-

Entry

3aa:4aa:5aab

Variation from optimized

Conv.

conditions

(%)b

1

none

62

33:1:4

93

2

no TFE

nrd

-

-

3

Ph2P(O)OH instead of TFE

95

28:1:1

90

4

TFA instead of TFE

nr

-

-

5

(CF3)2CHOH instead of TFE

nr

-

-

6

1.0 equiv. BnNH2

90% in all cases except 3ae. The lack of reactivity of

aniline derivatives prompted us to evaluate 4-aminophenethylamine 2h under the optimized conditions. Gratifyingly, 3ah could be isolated not only with excellent regioand enantioselectivity but also with exquisite chemoselectivity. Although the use of -branched primary amines led to slightly diminished regioselectivity levels, excellent enantiocontrol could be maintained (3ai-3aj). Moreover, catalyst-controlled hydroamination reactions were achieved using both enantiomers of α-methylbenzylamine (S)-2k and (R)-2l, furnishing 3ak and 3al in 19:1 and 17:1 dr respectively. This is unusual given the proximity of the two stereocenters.15 Of note, the reduced reactivity of -branched amines may account for the lack of reactivity of the hydroamination products towards a second equivalent of diene. Finally, we found that secondary amines were competent nucleophiles (3am-3ao), delivering the chiral allylamine products with very high ee values but with reduced regioselectivity. Improved results were obtained using Ph2P(O)OH instead of TFE. Overall, the scope delineated by varying both the diene and the amine highlights the broad functional group tolerance of this hydroamination protocol.



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Figure 4. Access to an optically active -branched primary amine by a Ni-catalyzed hydroamination of 1,3-diene/Rhcatalyzed deallylation sequence.

Figure 6. Mechanistic experiments. (A) Assessment of the irreversible nature of the hydroamination of dienes. (B) Model catalytic hydroamination using TFE-d1 and BnND2. (C) Absence of post-reaction D-incorporation. (D) Synthesis of 10-dn using TFE-d1. (E) Synthesis of 10-dn using TFEd1 and BnND2. with ammonia surrogates.16 To further highlight the synthetic utility of our method, we established that allylamine 2p is a competent nucleophile in the hydroamination of 1a, delivering bis-allylamine 3ap in high yield and with excellent product selectivity and enantioselectivity (rr 8:1; 94% ee). Remarkably, the use of Wilkinson’s catalyst (1 mol%) 17 allowed the selective removal of the less substituted allyl fragment, furnishing -branched chiral primary amine 6a in high yield and without any measurable enantiomerization (Figure 4).

Figure 5. (A) In situ monitoring by 31P{1H} NMR by sequential addition of all components of the model reaction (Table 1, Entry 1). A-I: L1, [Ni(cod)2]. A-II: 1a, then 2a. A-III: TFE. Signal for L1 (‒26.7 ppm) not shown. (B) Observation of product-bound Ni complexes [(L1)Ni(3aa)]. (C) Independent synthesis of the product-bound Ni complexes [(L1)Ni(3aa)]. 7: grey ; 8: blue ; 9: red ; 10: green ; ligand oxide from commercial source: *. Direct access to primary amines in enantioselective catalytic allylation reactions remains a challenge. Examples relying on the direct use of ammonia are very rare and the most promising alternative strategies have been conducted

To obtain insights into the underlying mechanism of this Ni-catalyzed hydroamination reaction, we undertook a series of complementary mechanistic experiments. We initially aimed at identifying the resting state of the catalytic system by 31P NMR monitoring the sequential addition of each reaction component to a NMR tube. This approach enabled the detection of a number of reactive intermediates that are likely involved in catalysis (Figure 5). The identity of these species was established on the basis of independent syntheses (See the Supporting Information). First, mixing substoichiometric amounts of [Ni(cod)2] and ligand L1 (5 and 6 mol% respectively) in toluene-d8 at room temperature led to the rapid appearance of two singlets in a 3:1 ratio along with free ligand (Figure 5, A-I).18 The signal at 37.4 ppm corresponds to the homoleptic complex [(L1)2Ni] (7), while the signal at 49.2 ppm corresponds to the heteroleptic complex [(L1)Ni(cod)] (8).19 Addition of 1.0


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Journal of the American Chemical Society 0.45

0.45

0.4

0.35 0.3

0.3

0.3

0.2 0.15

0.1

0.1

0.05

0.05

5.E+04

1.E+05

2.E+05

2.E+05

3.E+05

[Ni]=0.041 M

0.4

0.2

0 0.E+00

0.1

1.E+03

2.E+03

3.E+03

4.E+03

0 0.E+00

0.45

0.4

0.4

0.4

0.35

0.35

[TFE]=0.29 M [TFE]=0.41 M

0.3

Series1

0.25

0.2

0.2

0.2

0.15

0.15

0.15

0.1

0.1

0.1

0.05

0.05

0.05

1.E+05

2.E+05

3.E+05

4.E+05

5.E+05

0 0.E+00

1.E+05

2.E+05

2.E+05

3.E+05

3.E+05

5.E+04

1.E+05

2.E+05

2.E+05

3.E+05

Series2

0.3

Series2

0.25

0 0.E+00

5.E+04

0.45

0.3

[TFE]=0.53 M

[Diene]i=0.61 M

0.2

0.45

0.35

[Diene]i=0.41 M

0.5

0.25

0.15

0 0.E+00

0.6 [Ni]=0.0205M

0.35

[Diene]i=0.25 M; [BnNH2]=1.50 M

0.25

0.7

0.4

[Diene]i=0.41 M; [BnNH2]=1.64 M

Series1

0.25

3.E+05

0 0.E+00

1.E+05

2.E+05

3.E+05

4.E+05

Figure 7. Visual kinetic analysis for the nickel-catalyzed hydroamination of 1a using benzylamine 2a and TFE. (A) ‘Same excess experiment’. (B) Order in catalyst. (C) Order in 1,3-diene 1a. (D) Order in TFE. (E) Order in benzylamine 2a using a suboptimal concentration against the standard conditions. (F) Order in benzylamine using an excess of 2a against the standard conditions. equivalent of diene 1a resulted in the gradual disappearance of 8 and the concomitant formation of a new species characterized by two broad signals resonating at 40.4 and 57.9 ppm, which we attribute to the diene-bound complex [(L1)Ni(1a)] (9) (Figure 5, A-II).20 No significant change occurred upon addition of 4.0 equivalents of benzylamine 2a to this solution. The addition of TFE (1.0 equiv.) led to full consumption of 9, rapidly generated a set of two sharp doublets at 59.0 and 62.0 ppm and initiated catalysis. The new resonances were ascribed to a -allyl complex [(L1)Ni(3-allyl)][OCH2CF3] (10) (Figure 5, A-III).21 All attempts to isolate or crystallize it were unsuccessful and complex 9 was regenerated upon removal of the solvent. Nevertheless, the tridimensional structure of 10 was established by in situ 2D NMR analyses and unambiguously revealed an anti geometry of the 3-bound allyl fragment, an orientation favorable to minimize steric interactions with the bulkier ligand substituents (See the Supporting Information). Whether the trifluoroethoxide ligand is covalently bound in complex 10 remains unclear. However, 19F,1H-HOESY experiments indicate that the nickel center and the fluorinated alkoxo ligand are intimately associated in solution (See the Supporting Information). The low polarizability of mesitylene and the strength of late transition metal alkoxides bonds are additional arguments in favor of the formation of a neutral nickel complex.22 Over time, several sets of doublets emerged from the base line between ~39-52 ppm. Based on the independent experiments disclosed on Figure 5 B and C, we attribute these resonances to two isomeric product-bound nickel complexes. Importantly, complex 10 remained the main species present

in solution until completion of the hydroamination reaction, suggesting that it is likely the resting state of the catalytic process. Furthermore, the geometry of 10 may help in understanding the origin of enantioselectivity in the hydroamination reaction as the absolute configuration of the products is consistent with an external nucleophilic attack at C3.23,24 When product 3aa was engaged under the optimized reaction conditions in the presence of 4 equivalents of n-butylamine 2b no traces of 3ab were detected after 72 h, indicating the hydroamination is irreversible in nature (Figure 6, A). Subsequently, a set of complementary isotopic labeling experiments was conducted (Figure 6 B-E). When engaging 1a in a catalytic reaction with 2a-d2 and TFE-d1, 3aadn was obtained in similar yield and selectivity than those of the model reaction (Figure 6, B). 1H NMR analysis revealed that D-incorporation in 3aa-dn occurred exclusively at C1 and C4, in similar extent, and that an average of 2.16 D atoms was incorporated per molecule. Neither deuterium incorporation, nor enantiomerization were detected when subjecting (R)-3aa to the standard reaction conditions using isotopically labeled benzylamine 2a-d2 and TFE-d1 (Figure 6, C). The addition of TFE-d1 to [(L1)Ni(cod)] (8) led to the formation of the -allyl complex (10-dn). Monitoring by 2H NMR showed very rapid D-incorporation at C4 within minutes whereas D-incorporation at C1 was barely detectable after 48 h (Figure 6, D). In contrast, significant D-incorporation at C1 was found to occur within minutes when a similar experiment using a 1:1 mixture of TFE-d1 and BnND2 was performed. Consistent with observations made during optimization of the reaction (Table 1, Entry 6), only traces of product-bound Ni complexes



[(L1)Ni(3aa)] were detected (Figure 6, E). Collectively, the results of these experiments indicate that (i) the hydroamination reaction is irreversible in nature, (ii) the formation of the -allyl complex 10 which occurs only in the presence of TFE is fast and reversible, (iii) that several -allyl complexes involving either C1/C2/C3 or C2/C3/C4 are in equilibrium when both TFE and the amine are present in solution, and (iv) that benzylamine is not only involved in the productive catalytic manifold but also in the competing regeneration of [(L1)Ni(1a)] (9). This could occur either by direct interaction of benzylamine 2a with 10 or by modulation of the pH of the medium. Due to the mildness of the reaction conditions, the absence of paramagnetic species and the excellent mass balance of the reaction with respect to all reagents, variable time normalization analyses (VTNA) were performed using 1H NMR spectroscopy.25 The hydroamination employing benzylamine 2a was used to monitor the disappearance of 1,3-diene 1a over the entire course of the reaction (Figure 7). Experiments performed at different initial concentrations of 1a but with the same excess in concentration in 2a generated a very good graphical overlay, indicating that there is neither catalyst deactivation nor product inhibition over the course of the hydroamination reaction (‘same excess’ experiment) (Figure 7, A). A series of ‘different excess’ experiments was next conducted for each of the reaction components.26 The reaction was found to be first order in catalyst and zeroth order in diene 1a (Figure 7, B-C). In the present system, as the concentration of TFE was varied from 0.29 to 0.53 M, an inverse and partial order of -0.7 was deduced (Figure 7, D). We note a slight deviation from the overlay at high conversion for the reaction run at 0.53 M. Determining the order in protic reagents is notoriously difficult due to their intrinsic propensity to form hydrogen bonds and this often results in the measure of partial orders, which may not be constant values over the course of the reaction. In addition, non-integer orders are typically indicative of a more complex mechanism and/or the presence of off-cycle equilibrium.27 For benzylamine, the situation is more intriguing. Whereas a nearly first order (0.8) dependence in 2a was found when concentrations of 1.29 M and 1.64 M were employed (~3.0 and 4.0 equiv. respectively), a second order dependence (2.2) in 2a was found for concentrations of 1.64 and 1.96 M (4.0 and ~5.0 equiv. respectively), indicating that the catalytic system is sensitive to variations in the benzylamine stoichiometry (Figure 7, D-E). Because the catalytic hydroamination reaction is conducted in a nonpolar aprotic solvent, the formation of amine aggregates – typically dimers – is likely to occur and to intervene in several elementary steps. Such systems often lead to order in amine greater than unity.28 Moreover, titration studies by 1H NMR indicated that TFE and BnNH interact strongly, 2 our data being consistent with either a 1:2 or a 2:1 binding model.29 Finally, subtle changes in the polarity of the media upon variation of amine concentration may also account for the different orders obtained when correlating the optimized system with either a lower or a higher stoichiometry in 2a with respect to the optimized conditions.

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Two mechanistic proposals consistent with the results of the reaction monitoring, the isotopic labeling experiments and that fits the kinetic data are disclosed in Figure 8 and Figure 9. In both cases, the catalytic reaction starts after displacement of 1,5-cyclooctadiene in [(L1)Ni(cod)], to generate the corresponding substrate-bound nickel complex [(L1)Ni(1a)] (I). Addition of TFE generates the -allyl complex 10 (noted II), which we believe constitutes the resting state of the catalytic reaction. This process is fast and reversible and regeneration of I may also proceed by reaction with benzylamine 2a, or an aggregate thereof. Our two mechanistic scenarios differ in the steps following the resting state.

Figure 8. Proposed catalytic cycle (A) for the Ni-catalyzed hydroamination of 1,3-dienes by primary amine nucleophiles in the presence of TFE.

Figure 9. Alternative catalytic cycle (B) for the Ni-catalyzed hydroamination of 1,3-dienes by primary amine nucleophiles in the presence of TFE.


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In our first proposal (Figure 8), in line with the inverse order in TFE, subsequent ligand exchange between the alkoxo ligand and the primary amine occurs (II→III). The equilibrium between the amido complex and the trifluoroethoxide complex should lie very much on the side of the latter.30 Nevertheless, this step is reminiscent of the ligand exchange process described by Hartwig in the Pd-catalyzed arylation of fluoroalkyls and by Buchwald in the Pd-catalyzed arylation of weakly binding amines.31 In the present system, we propose that formation of III likely involves rapid and reversible equilibrium between numerous  and allyl intermediates. Collectively, our experimental data are congruous with the outer-sphere nucleophilic addition of 2a (or an aggregate of 2a) to the amido--allyl complex III being the rate-determining step of the catalytic hydroamination reaction. Rapid proton exchange and amine decoordination would follow to generate the product-bound nickel complexes observed by NMR (IV→V). Product coordination is not inhibitory and displacement by chelation of a molecule of substrate to regenerate I should be favorable. In this mechanistic proposal, it is unclear yet why intermediate III would exhibit an enhanced reactivity towards nucleophilic attack compared to II. An alternative proposal is depicted in Figure 9. The initial steps leading to the nickel -allyl complex (II), which constitutes the resting state of the catalyst, are identical. At this point, the direct addition of benzylamine aggregates [BnNH2]n or of mixed adducts [CF3CH2OH•••NH2Bn]n to the alkoxo-nickel intermediate (II) could be invoked for the generation of (III). Even though less nucleophilic, the implication of the mixed adducts in the rate-determining step would provide a plausible explanation for the inverse order in TFE and would be consistent with the titration experiments which revealed a strong interaction between both protic reagents.32 Finally, participation in varying relative contributions of both types of H-bonded aggregates in the outer-sphere nucleophilic addition seems very likely to occur and would account for the partial orders measured for both reagents (TFE: -0.7; BnNH2: 0.8 and 2.2). Although both mechanistic scenarios are formally consistent with the data obtained, the second hypothesis may provide a better interpretation as it takes into account the subtle interactions between the two protic reagents. From the observation that the reaction is highly dependent on the concentration of the amine and that H-bonded aggregates are certainly involved, we postulated that inexpensive aprotic N-containing Lewis bases may be used as additive to form either mixed aggregates [BnNH2•••NR3]n or to dissociate the mixed adducts [CF3CH2OH•••NH2Bn]n. The objective would be to accelerate the reaction and to reduce the stoichiometry in the potentially more precious nucleophile. To test this hypothesis, the model reaction between 1,3-diene 1a and BnNH2 2a was revisited using only 2 equivalents of 2a along with 2 equivalents of various nitrogenous bases (Table 2). When the hydroamination reaction was performed with 2 equivalents of benzylamine, 3aa was generated in only 17% after 48 h with a similar regioselectivity but a reduced enantioselectivity compared to the model reaction (86% ee vs 93% ee) (Table 2, Entry 1).

While DBU had an inhibitory effect on the catalytic system, both iPr2NEt and pyridine led to improved conversion in 3aa (Entries 2-4). Gratifyingly, the 3-fold rate acceleration observed with triethylamine validated our initial hypothesis (Entry 5) and enabled the isolation of the hydroamination product in 72% yield, rr 8:1 and 93% ee by extending the reaction time to 72 h (Entry 6). Table 2. Effect of added nitrogenous base on rate and selectivitya

Entry

Base

Conv. 3aa (%)b

rrb

ee 3aa (%)c

1

none

17

7:1

86

2

DBU

6

nd

nd

3

iPr2NEt

31

6:1

88

4

pyridine

34

5.5:1

91

5

Et3N

52

8:1

93

6d,e

Et3N

75 (72)f

8:1

93

a

b

1H

0.1 mmol scale. Determined by NMR using an internal standard. c Determined by HPLC. d 0.25 mmol scale. e 72 h. f Isolated yield after purification in parenthesis. In conclusion, we have identified experimental conditions for the Ni-catalyzed enantioselective hydroamination of 2-substituted 1,3-dienes using primary and secondary amines. The reaction is achieved with high yield, high regioselectivity and excellent enantioselectivity and is compatible with a wide range of functional groups. It provides access to valuable secondary amines without resorting to elaborated amination reagents. An enantioenriched chiral primary allylamine was prepared by an operationally simple hydroamination/deallylation sequence. Reaction monitoring by NMR spectroscopy, supporting organometallic syntheses, isotopic labeling experiments and kinetic analysis shed light on some of the mechanistic intricacies of this reaction. We have determined that a Ni--allyl complex is the catalytic resting state, while an outer sphere nucleophilic addition is rate-determining. The hypothesis that H-bonded aggregates are involved in the amination reaction guided the re-optimization of the initial experimental protocol and led to the identification of an improved catalytic system. We believe that the mechanistic subtleties unveiled in this study will accelerate the development of related hydrofunctionalizations of alkenes.

ASSOCIATED CONTENT Supporting Information. Experimental procedures, characterization of all new compounds, spectroscopic, spectrometric and X-ray data for compound (R)-3aa.HCl (CCDC 1938704). This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION



Corresponding Author * Prof. Clément Mazet. University of Geneva, Organic Chemistry Department. Quai Ernest Ansermet 30, Geneva 1211 Switzerland. [email protected]

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT We thank the University of Geneva for financial support. Dr. C. Besnard (University of Geneva) is warmly acknowledged for solving the X-ray structure reported in this study, and Stéphane Rosset (University of Geneva) for measuring HRMS analyses. We do thank one of the reviewers for his/her insightful comments and constructive suggestions regarding the kinetic experiments reported in this study.

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Ed. 2012, 51, 3470. (c) Meza, A. T.; Wurm, T.; Smith, L.; Kim, S. W.; Zbieg, J. R.; Stivala, C. E.; Krische, M. J. Amphiphilic π-Allyliridium C,O-Benzoates Enable Regio- and Enantioselective Amination of Branched Allylic Acetates Bearing Linear Alkyl Groups. J. Am. Chem. Soc. 2018, 140, 41275. (d) Ghorai, S.; Chirke, S. S.; Xu, W.-B.; Chen, J.-F.; Li, C. Cobalt-Catalyzed Regio- and Enantioselective Allylic Amination. J. Am. Chem. Soc. 2019, 141, 11430. (10) (a) Fiorito, D.; Folliet, S.; Liu, Y.; Mazet, C. A General NickelCatalyzed Kumada Vinylation for the Preparation of 2‑Substituted 1,3-Dienes. ACS Catal. 2018, 8, 1392. (b) Liu, Y.; Fiorito, D.; Mazet, C. Copper-Catalyzed Enantioselective 1,2-Borylation of 1,3-Dienes. Chem. Sci. 2018, 9, 5284. (c) Fiorito, D.; Mazet, C. Ir-Catalyzed Selective Hydroboration of 2-Substituted 1,3-Dienes: A General Method to Access Homoallylic Boronates. ACS Catal. 2018, 8, 9382. (11) Pawlas, J.; Nakao, Y.; Kawatsura, M.; Hartwig, J. F. A General Nickel-Catalyzed Hydroamination of 1,3-Dienes by Alkylamines: Catalyst Selection, Scope and Mechanism. J. Am. Chem. Soc. 2002, 124, 3669. (12) (a) Xiao, L.-J.; Fu, X.-N.; Zhou, M.-J.; Xie, J.-H.; Wang, L.-X.; Xu, X.-F.; Zhou, Q.-L. Nickel-Catalyzed Hydroacylation of Styrenes with Simple Aldehydes: Reaction Development and Mechanistic Insights. J. Am. Chem. Soc. 2016, 138, 2957. (b) Xiao, L.-J.; Chen, L.; Feng, W.-M.; Li, M.-L.; Xie, J.-H.; Zhou, Q.-L. Nickel(0)catalyzed Hydroarylation of Styrenes and 1,3-Dienes with Organoboron Compounds. Angew. Chem., Int. Ed. 2018, 57, 461. (c) Cheng, L.; Li, M.-M.; Xiao, L.-J.; Xie, J.-H.; Zhou, Q.-L. Nickel(0)Catalyzed Hydroalkylation of 1,3-Dienes with Simple Ketones. J. Am. Chem. Soc. 2018, 140, 11627. (13) An experiment conducted using only 2.5 mol% of [Ni(cod)2] and 3 mol% of the chiral ligand gives similar performances than the model reaction provided the reaction time is extended to 96 h (77% yield, rr 6:1, 92% ee). (14) If the hydroamination leading to 3ia is interrupted after 24 h, similar product distribution and ee are measured, suggesting that the reaction is not reversible. Moreover, a supporting organometallic experiment involving the reaction between Ni(cod)2 (1.0 equiv), (R,R)BenzP* (1.0 equiv), diene 1i (1.0 equiv) and Ph2PO2H (5.0 equiv) in toluene-d8 led to a mixture of at least 4 different allyl Ni complexes. It is therefore likely that the poor selectivities observed for 2-alkyl substituted dienes originates from poor stereocontrol in the formation of the nickel -allyl complexes. (15) Walsh, P. J.; Kozlowski, M. C. Fundamentals of Asymmetric Catalysis; Univ. Science Books: Sausalito, CA, 2009. (16) (a) Weihofen, R.; Tverskoy, O.; Helmchen, G. Salt-Free Iridium-Catalyzed Asymmetric Allylic Aminations with N,N-Diacylamines and ortho Nosylamide as Ammonia Equivalents. Angew. Chem., Int. Ed. 2006, 45, 5546. (b) Pouy, M. J.; Leitner, A.; Weix, D. J.; Ueno, S.; Hartwig, J. F. Enantioselective Iridium-Catalyzed Allylic Amination of Ammonia and Convenient Ammonia Surrogates. Org. Lett. 2007, 9, 3949. (c) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Iridium-Catalyzed Synthesis of Primary Allylic Amines from Allylic Alcohols: Sulfamic Acid as Ammonia Equivalent. Angew. Chem., Int. Ed. 2007, 46, 3139. (d) Nagano, T.; Kobayashi, S. Palladium-Catalyzed Allylic Amination Using Aqueous Ammonia for the Synthesis of Primary Amines. J. Am. Chem. Soc. 2009, 131, 4200. (e) Pouy, M. J.; Stanley, L. M.; Hartwig, J. F. Enantioselective, Iridium-Catalyzed Monoallylation of Ammonia. J. Am. Chem. Soc. 2009, 131, 11312. (f) Xu, K.; Wang, Y.-H.; Khakyzadeh, V.; Breit, B. Asymmetric Synthesis of Allylic Amines via Hydroamination of Allenes with Benzophenone Imine. Chem. Sci. 2016, 7, 3313. (17) Doi, H. ; Sakai, T. ; Yamada, K.-I. ; Tomioka, K. N-Allyl-N-tertButyldimethylsilylamine for Chiral Ligand-Controlled Asymmetric Conjugate Addition to tert-Butyl Alkenoates. Chem. Commun. 2004, 1850.

(18) The use of toluene as solvent led to similar yield, ee and rr than mesitylene (see Table S2 in the Supporting Information). (19) Batch-dependent residual signals originating from monooxidized L1 were also present at (ppm) = 45.9 (d, J = 2.2 Hz) and 19.4 (d, J = 2.2 Hz). Due to the strong polarity of the P=O bond, the signal at 45.9 ppm can be significantly shifted by up to 5 ppm depending on the H-bonding properties of the reagents present in the reaction mixture. (20) Upon cooling to 168 K, these broad signals could be resolved to two better defined doublets at  (ppm) = 69.8 (d, J ~34Hz), 32.0 (d, J ~37 Hz) (See the Supporting Information). Due to the rapid precipitation of the sample at such a low temperature, further analysis could not be carried out under these conditions. (21) We have not been able to detect any potential [Ni‒H] intermediate during the formation of the Ni -allyl complex 10. Several mechanisms have been documented to account for the formation of related Ni -allyl complex. See: (a) Guihaumé, J.; Halbert, S.; Eisenstein, O.; Perutz, R. N. Hydrofluoroarylation of Alkynes with Ni Catalysts. C‒H Activation via Ligand-to-Ligand Hydrogen Transfer, an Alternative to Oxidative Addition. Organometallics 2012, 31, 1300. (b) Bair, J. S.; Schramm, Y.; Sergeev, A. G.; Clot, E.; Eisenstein, O.; Hartwig, J. F. Linear-Selective Hydroarylation of Unactivated Terminal and Internal Olefins with TrifluoromethylSubstituted Arenes. J. Am. Chem. Soc. 2014, 136, 13098. (c) Nett, A. J.; Montgomery, J.; Zimmerman, P. M. Entrances, Traps, and RateControlling Factors for Nickel-Catalyzed C–H Functionalization. ACS Catal. 2017, 7, 7352. (22) (a) Bryndza, H. E.; Fong, L. K.; Paciello, R. A.; Tam, W.; Bercaw, J. E. Relative Metal-hydrogen, -oxygen, -nitrogen, and carbon Bond Strengths for Organoruthenium and Organoplatinum Compounds; Equilibrium Studies of Cp*(PMe3)2RuX and (DPPE)MePtX Systems. J. Am. Chem. Soc. 1987, 109, 1444. (b) Poulton, J. T.; Sigalas, M. P.; Folting, K.; Streib, W. E.; Eisenstein, O.; Caulton, K. G. RuHX(CO)(PR3)2: Can CO Be a Probe for the Nature of the Ru-X bond? Inorg. Chem. 1994, 33, 1476. (c) Kita, Y.; Sakaguchi, H.; Hoshimoto, Y.; Nakauchi, D.; Nakahara, Y.; Carpentier, J.-F.; Ogoshi, S.; Mashima, K. Pentacoordinated Carboxylate -Allyl Nickel Complexes as Key Intermediates for the NiCatalyzed Direct Amination of Allylic Alcohols. Chem. Eur. J. 2015, 21, 14571. (23) In contrast to our observation, in a related Pd-catalyzed enantioselective hydroamination of vinylarenes and consistent with the Curtin-Hammett principle, the observed major 3-benzyl-Pd intermediate produces the minor enantiomer. See: Nettekoven, U.; Hartwig, J. F. A New Pathway for Hydroamination. Mechanism of Palladium-Catalyzed Addition of Anilines to Vinylarenes. J. Am. Chem. Soc. 2002, 124, 1166. (24) The kinetic selectivity observed for the branched product may be explained by the geometry of the -allyl complex 10. The Ni-C3 bond is probably longer than the Ni-C1 bond due to increased steric interactions with the ligand-backbone around C3, thus leading to preferential nucleophilic attack at the most congested terminus of the allyl fragment. (25) (a) Burés, J. Variable Time Normalization Analysis: General Graphical Elucidation of Reaction Orders from Concentration Profiles. Angew. Chem., Int. Ed. 2016, 55, 16084. (b) Nielsen, C. D.T.; Burés, J. Visual Kinetic Analysis. Chem. Sci. 2019, 10, 348. (26) Blackmond, D. A. Reaction Progress Kinetic Analysis: A Powerful Methodology for Mechanistic Studies of Complex Catalytic Reactions. Angew. Chem., Int. Ed. 2005, 44, 4302. (27) (a) Anslyn, E.; Dougherty, D. Modern physical organic chemistry; Univ. Science Books: Sausalito, CA, 2008. (b) Levine, I. A. Physical Chemistry, 6th ed.; McGraw-Hill Higher Education: Boston, MA, 2008. (28) (a) Nudelman, N. S.; Alvaro, C. E. S.; Yankelevitch, J. S. Aggregation Effects in the Reactions of 2,4-Dinitrochlorobenzene



with Aniline in Aprotic Solvents. J. Chem. Soc., Perkin Trans. 2, 1997, 2125. (b) Dhahri, N.; Boubaker, T.; Goumont, R. Mechanism and Linear Free Energy Relationships in Michael-Type Addition of 4-Substituted Anilines to Activated Olefin in Acetonitrile. Int. J. Chem. Kinet. 2013, 45, 763. (c) Alvaro, C. E. S.; Bergero, F. D.; Bolcic, F. M.; Ramos, S. B.; Nudelman, N. S. Aromatic Nucleophilic Substitution in Aprotic Solvents Using Hydrogen-Bonded Biological Amines. Kinetic Studies and Quantum Chemical Calculations. J. Phys. Org. Chem. 2016, 29, 65. (29) Titration was performed by sequential addition of TFE to a [1.64] solution of 2a in toluene-d8 and was monitored by 1H NMR spectroscopy. The shifts of the signal of the non-labile benzylic protons were used to quantify the interaction between TFE and benzylamine. Bindfit0.5 was used to fit the data. (See Supporting Information for details). (a) Thordarson, P. Determining Association Constants from Titration Experiments in Supramolecular Chemistry. Chem. Soc. Rev. 2011, 40, 1305. (b) Hibbert, D. B.; Thordarson, P. The Death of the Job Plot, Transparency, Open Science and Online Tools, Uncertainty Estimation Methods and

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Other Developments in Supramolecular Chemistry Data Analysis. Chem. Commun. 2016, 52, 12792. (30) Holland, P. L.; Andersen, R. A.; Bergman, R. G.; Huang, J.; Nolan, S. P. Monomeric Cyclopentadienylnickel Methoxo and Amido Complexes: Synthesis, Characterization, Reactivity, and Use for Exploring the Relationship between H−X and M−X Bond Energies. J. Am. Chem. Soc. 1997, 119, 12800. (31) (a) Brusoe, A. T.; Hartwig, J. F. Palladium-Catalyzed Arylation of Fluoroalkylamines. J. Am. Chem. Soc. 2015, 137, 8460. (b) Dennis, J. M.; White, N. A.; Liu, R. Y.; Buchwald, S. L. Pd-Catalyzed C– N Coupling Reactions Facilitated by Organic Bases: Mechanistic Investigation Leads to Enhanced Reactivity in the Arylation of Weakly Binding Amines. ACS Catal. 2019, 9, 3822. (32) Nudelman, N. S.; Marder, M.; Gurevich, A. Reaction of 2,6Dinitroanisole with Cyclohexylamine in Toluene-Octanol Binary Solvents. Further Support for the 'Dimer Nucleophile Mechanism' in Aromatic Nucleophilic Substitution J. Chem. Soc., Perkin Trans. 2, 1993, 229.


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Ni-Catalyzed Enantioselective Intermolecular Hydroamination of

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