Main-Group-Catalyzed Reductive Alkylation of Multiply Substituted

Article Cite This: J. Am. Chem. Soc. 2018, 140, 7292−7300

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Main-Group-Catalyzed Reductive Alkylation of Multiply Substituted Amines with Aldehydes Using H2 Yoichi Hoshimoto,*,†,‡ Takuya Kinoshita,† Sunit Hazra,† Masato Ohashi,† and Sensuke Ogoshi*,† †

Department of Applied Chemistry, Faculty of Engineering and ‡Frontier Research Base for Global Young Researchers, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan S Supporting Information *

ABSTRACT: Given the growing demand for green and sustainable chemical processes, the catalytic reductive alkylation of amines with maingroup catalysts of low toxicity and molecular hydrogen as the reductant would be an ideal method to functionalize amines. However, such a process remains challenging. Herein, a novel reductive alkylation system using H2 is presented, which proceeds via a tandem reaction that involves the B(2,6Cl2C6H3)(p-HC6F4)2-catalyzed formation of an imine and the subsequent hydrogenation of this imine catalyzed by a frustrated Lewis pair (FLP). This reductive alkylation reaction generates H2O as the sole byproduct and directly functionalizes amines that bear a remarkably wide range of substituents including carboxyl, hydroxyl, additional amino, primary amide, and primary sulfonamide groups. The synthesis of isoindolinones and aminophthalic anhydrides has also been achieved by a one-pot process that consists of a combination of the present reductive alkylation with an intramolecular amidation and intramolecular dehydration reactions, respectively. The reaction showed a zeroth-order and a first-order dependence on the concentration of an imine intermediate and B(2,6Cl2C6H3)(p-HC6F4)2, respectively. In addition, the reaction progress was significantly affected by the concentration of H2. These results suggest a possible mechanism in which the heterolysis of H2 is facilitated by the FLP comprising THF and B(2,6Cl2C6H3)(p-HC6F4)2.

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INTRODUCTION Amines are ubiquitous and essential in our daily lives as bioactive molecules such as natural products, pharmaceuticals, and agrochemicals.1,2 A variety of methods to functionalize amines have been established so far;2a−e however, the recent demand for green and sustainable chemical processes strongly requires the development of catalytic, waste-minimized, and atom-efficient functionalization methods that employ readily available catalysts and reagents of low toxicity.3 The maingroup-catalyzed reductive alkylation of amines (or reductive amination of carbonyl species)2f−l with molecular hydrogen as the reductant would therefore represent an ideal method given that H2O is generated as the sole byproduct.4 Thus far, such a process remains highly challenging5 as, on one hand, the catalyst should be sufficiently reactive to activate H2, yet, on the other hand, it should simultaneously be tolerant to the in-situgenerated H2O as well as innocent toward carbonyl substrates. Moreover, previously reported catalytic reductive alkylation systems have rarely been applied to amines bearing multiple carboxyl, hydroxyl, and/or additional amino groups.2g,f,j Indeed, bioactive molecules often contain benzylamine or the corresponding heteroaromatic moieties together with carboxyl, hydroxyl, and/or amino groups (Figure 1).1b,6 The development of a practical and environmentally benign reductive alkylation system that enables direct access to these multiply functionalized amines is thus of high interest.7 Herein, we report the reductive alkylation of primary amines with H2, © 2018 American Chemical Society

which proceeds via a tandem reaction that consists of an organoborane-catalyzed formation of an imine, and a subsequent hydrogenation of this imine catalyzed by a frustrated Lewis pair (FLP).5,8−10 A variety of multiply substituted amines were efficiently functionalized using the present catalyst system, in which H2O was generated as the sole byproduct (Scheme 1).

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RESULTS AND DISCUSSION To achieve our goal, we focused on the use of FLP-based catalysts, since the chemistry of the FLP-catalyzed hydrogenation of imines and carbonyls has been extensively developed.9,11 For the optimization of the reaction conditions, we initially employed benzaldehyde (1a), aniline (2a), H2 (80 atm), and 4 Å molecular sieves (MS) in THF in the presence of 5 mol % B(C6F5)3 (entry 1, Table 1a). However, the targeted N-phenylbenzylamine (3aa) was obtained in only 2% yield after heating to 100 °C for 2 h. Although the formation of Nbenzylideneaniline (A) was confirmed in 91% yield, the subsequent hydrogenation of A did not proceed under these reaction conditions. In this case, B(C6F5)3 was converted to [LB−H][HO−B(C6F5)3] by reaction with H2O and Lewis bases (LBs), where the LB is 2a and/or A.12 Ingleson et al. investigated the deactivation of triarylboranes in the boraneReceived: April 4, 2018 Published: May 23, 2018 7292

DOI: 10.1021/jacs.8b03626 J. Am. Chem. Soc. 2018, 140, 7292−7300

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Journal of the American Chemical Society

Figure 1. Selected bioactive amine molecules containing multiple COOH/OH/NH2 groups.

catalyzed reductive alkylation of amines using hydrosilanes and suggested that the use of less Lewis-acidic boranes could allow for broader substrate scopes.10b In these reactions, an excess of hydrosilanes could irreversibly eliminate H2O from the reaction mixture, whereas the absorption of H2O on MS is generally an equilibrium and would be insufficient at 100 °C. Thus, other reported triarylboranes, including B(C6Cl5)(C6F5)2 developed by Ashley et al.,9k B(p-HC6F4)3 developed by Stephan et al.,9l and B(2,6-Cl2C6H3)(p-HC6F4)2 developed by Soós et al.,9e were examined (entries 2−6) in order to identify the optimal borane with sufficient stability toward deactivation to form [LB−H][HO−BAr3] (e.g., LB = 2a, 3aa, and/or A). The use of B(2,6-Cl2C6H3)(p-HC6F4)2 in THF afforded 3aa in >99% yield (entry 5), whereas all other triarylboranes examined in this study failed to yield 3aa in more than 10% yield.12 The FLP generated from our original B(2-CF3C6H4)(p-HC6F4)2 also catalytically furnished 3aa; however, the yield remained low (21%) (entry 6). Thereafter, we explored the solvent effects using Et2O, 1,4-dioxane, and toluene, which resulted in the formation of 3aa in 62%, 16%, and 45%, respectively.12 Thus, THF was used in the following experiments as the optimal solvent. Reducing the hydrogen pressure to 20 atm also afforded 3aa quantitatively within 2 h (entry 7, Table 1b). In contrast, 10 atm of H2 was insufficient to complete the reaction in the same period (66%). Under these conditions, completion of the reaction was not observed even after 15 h, which yielded 3aa in 91% (entry 8). In the presence of 2 mol % B(2,6Cl2C6H3)(p-HC6F4)2 in THF, 3aa was formed in 28% (H2 20 atm) and >99% yield (H2 80 atm) (entries 9 and 10). The reaction conditions shown in entries 7 and 10 are also suitable for the FLP-catalyzed reductive alkylation of 2a with 1a, and we thus employed the reaction conditions using 5 mol % B(2,6Cl2C6H3)(p-HC6F4)2 and 20 atm of H2 as the standard conditions for exploration of the substrate scope. The concentration of substrates is an important factor to efficiently yield 3aa, and optimal results were obtained when [1a] and [2a] were 0.050 M. Indeed, the yield of 3aa decreased to 24% when the concentration of 1a and 2a was increased to 0.40 M, while the concentration of B(2,6-Cl2C6H3)(p-HC6F4)2 remained constant. This would be caused by an increment of the concentration of in-situ-generated H2O. In fact, the

Scheme 1. Main-Group-Catalyzed Reductive Alkylation of Multiply Substituted Amines with Aldehydes Using H2

Table 1. Optimization of the Reaction Conditionsa

a

General conditions: all reactions were carried out in an autoclave reactor (30 mL). 1a (0.40 mmol), 2a (0.40 mmol), BAr3, and 4 Å MS (100 mg) were mixed in THF (8 mL), followed by pressurization with H2 and heating at 100 °C for 2 h. Yield of the product was determined by NMR analysis. bYield after 15 h. n.d.: not detected.

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Journal of the American Chemical Society Scheme 2. FLP-Catalyzed Reductive Alkylation of Amines (2y) with Aldehydes (1x) with H2a

a

General conditions: all reactions were carried out in an autoclave reactor (30 mL). 1x (0.40 mmol), 2y (0.40 mmol), BAr3 (5 mol %), and 4 Å MS (100 mg) were mixed in THF (8 mL), followed by pressurization with H2 (20 atm) and heating at 100 °C for 6 h. Yield of the isolated product is given. b2 h. cAt 80 atm of H2. d10 mol % BAr3. e15 mol % BAr3. f15 h. g18 h. Molecular structure of 3aq: thermal ellipsoids set at 30% probability. 7294


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Scheme 3. (a) FLP-Catalyzed Reductive Alkylation Affording Isoindolinones from 1o and 3-Aminophthalic Anhydrides from 2u; (b) Synthesis of 4aua

a General conditions for a: all reactions were carried out in an autoclave reactor (30 mL). 1x (0.40 mmol), 2y (0.40 mmol), BAr3 (10 mol %), and 4 Å MS (100 mg) were mixed in THF (8 mL), followed by pressurization with H2 (80 atm) and heating at 100 °C for 15 h. Yield of the isolated product is given. b5 mol % BAr3/6 h. Molecular structures of (a) 3au and (b) 4au; thermal ellipsoids set at 30% probability.

Aliphatic aldehydes with α-branched structures such as 1l and 1m furnished the targeted secondary amines 3la and 3ma in excellent yield. In contrast, the use of octanal (1n) resulted in the formation of complicated mixtures including 3na, which was isolated in 29% yield. The scope of substituted aniline derivatives 2b−q was then surveyed to demonstrate the excellent functional group tolerance of the present reductive alkylation system. The tolerated functional groups on the para-substituted anilines include trifluoromethyl (2b), methoxy (2c), hydroxyl (2d), halogen (2e−g), carboxyl (2h), ester (2k), primary amide (2l), ketone (2m), and primary sulfonamide (2o) groups, all of which afforded the targeted products in 76−>99% isolated yield. Additional optimizations of the conditions were conducted for the reaction using 2c, 2d, 2h, and 2l, as the corresponding alkylated amines were formed under standard conditions in 92%, 68%, 99% yield. The present system was directly used for the reductive alkylation of 4-aminosalicylic acid (2i) as well as 4-amino-3hydroxybenzoic acid (2j) under 80 atm of H2 to furnish 3ai and 3aj in 47% (with 10 mol % borane) and 70% (with 15 mol %

presence of C6H2F4 in the reaction mixture was confirmed by 19 F NMR analysis, suggesting the deactivation of B(2,6Cl2C6H3)(p-HC6F4)2 by protodeboronation. Note that this deactivation process of B(2,6-Cl2C6H3)(p-HC6F4)2 was also observed under the standard conditions, while the rate of decomposition clearly decreased. The catalytic reductive alkylation of primary amines 2a−t was examined with aldehydes 1a−n under the optimized reaction conditions, which afforded the products that bear a remarkably wide range of functional groups (Scheme 2). Benzaldehyde derivativescontaining the para-substituents such as trifluoromethyl (1b), methoxy (1c), ester (1f), and nitro (1g) groups furnished secondary amines 3ba, 3ca, 3fa, and 3ga in >99% yield. Substrate 1d, in which the formyl group is sterically crowded, was also transformed into 3da in >99% yield. Treatment of terephthalaldehydic acid (1e) with 2a resulted in the formation of an amino acid derivative 3ea in 91% yield under 80 atm of H2. The Lewis-acidic (pinacolato) boron group was also tolerated under the optimized conditions, affording 3ia in 98% yield; however, the reaction with 1h, which bears a dimethylamino group, did not yield 3ha. In this case, N,N-dimethyl-p-toluidine was the major product, detected by NMR analysis of the crude mixture, suggesting the FLPcatalyzed hydrogenation of 1h, followed by deoxygenation.13 The use of 2-pyridinecarboxaldehyde (1j) and furfural (1k) afforded 3ja and 3ka in >99% and 94% yield, respectively. 7295


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Figure 2. Plausible reaction mechanisms, wherein B(2,6-Cl2C6H3)(p-HC6F4)2 is shown as B. Rate-limiting H2-activation step is mediated by an FLP comprising THF and B (path A) or Im and B (path B).

anti-inflammatory properties of indoprofen,15 was explored with phthalaldehydic acid (1o) (Scheme 3a). In the presence of B(2,6-Cl2C6H3)(p-HC6F4)2 (5 or 10 mol %) and H2 (80 atm) in THF, 3oa (96%), 3oi (94%), and 3oq (77%) were obtained via tandem catalytic reductive alkylation and intramolecular amidation processes. Again, the reaction with 2q proceeded predominantly at the 4′-NH2 group. Furthermore, a series of 3aminophthalic anhydride derivatives such as 3au (77%), 3bu (92%), 3eu (62%), and 3mu (>99%) was prepared directly from the synthetically important unnatural amino acid 2u. The molecular structure of 3au was unambiguously confirmed by a single-crystal X-ray diffraction analysis. When 1o was used, the formation of 3ou was confirmed as the sole product in 89% yield, indicating that the intramolecular amidation did not occur to furnish the corresponding isoindolinone. The anhydride moiety may serve as a useful synthetic precursor, and indeed, treatment of in-situ-formed 3au with aqueous NaOH followed by neutralization afforded unnatural amino acid 4au, which bears two carboxylic acid moieties, in 83% (Scheme 3b). Plausible reaction mechanisms are shown in Figure 2, wherein B(2,6-Cl2C6H3)(p-HC6F4)2 is shown as B. The present reaction proceeds via tandem processes comprising the Lewis acid-catalyzed formation of imines (Im) (left cycle) and their subsequent FLP-catalyzed hydrogenation (right cycle). Under the given reaction conditions, THF predominantly yields a classical Lewis adduct [THF−B] with B, which should be in equilibrium, even in the presence of Im and the alkylated amine, as experimentally confirmed (see Figures S23−25 in the Supporting Information). Coordination of aldehyde to B affords an aldehyde−B adduct (X), followed by nucleophilic addition of an amine to furnish Im. During the hydrogenation, the active FLP species would be generated from the combination of THF/B (path A) or Im/B (path B). It has already been reported that FLP species comprising THF and B(C6Cl5)x(C6F5)3‑x (x = 0−3) efficiently catalyze the hydrogenation of imines such as A shown in Table 1.9j In addition, it is commonly accepted that the H2 activation is mediated by ether solvents and triaryl boranes such as B(C6F5)3 and B(2,6-

borane) yield, respectively. The functionalization of 3,4′diamino-4-nitrodiphenyl ether (2q), bearing two amino groups, proceeded predominantly at the 4′-NH2 group, and 3aq was isolated in 95% yield. The molecular structure of 3aq was unambiguously determined by single-crystal X-ray diffraction analysis. Moreover, the straightforward synthesis of multiply functionalized amino acids such as 3eh (>99%) and 3eq (47%) was successfully achieved, manifesting the high utility of the present reductive alkylation. Although the formation of Nbenzylidene benzylamine occurred quantitatively from the reaction of 1a and 2r, hydrogenation of this imine proceeded to yield a 34% of 3ar. On the other hand, benzhydrylamine (2s) efficiently reacted with 1a, and 3as was obtained in >99% yield. In addition, valine ester 2t was employed to afford 3at (91%), although its direct use was hampered due to the insolubility of valine in THF. When the reaction between 1a and 2a was examined in the absence of 4 Å MS under the optimized reaction conditions shown in Scheme 2, a decrease in the reaction rate was confirmed, and 3aa was quantitatively obtained after 18 h (74% after 2 h). In the case of the reaction between 1a and 2s, 3as was obtained in 37% yield after 2 h (B(2,6-Cl2C6H3)(pHC6F4)2: 5 mol %; H2 80 atm) in the absence of 4 Å MS and in 48% yield in the presence of 4 Å MS. These results imply that the effect of in-situ-generated H2O (ca. 20 equiv with respect to the borane) is not negligible under the present catalytic conditions, and MS were added accordingly.12,14 As shown in Scheme 2, the present catalyst system was applied to the reductive alkylation of a wide range of substituted aromatic amines with H2, whereas the outstanding system recently reported by Soós et al. was mainly applied to aliphatic amines.5a In the Soós system, B(2-Cl-6-F-C6H3)(2,6Cl2C6H3)2, which is bulkier and far less electrophilic than B(2,6-Cl2C6H3)(p-HC6F4)2, was used in toluene, and therefore, compounds that show a substantial Lewis basicity might be required to generate an active FLP mediator. Thus, these two environmentally benign main-group-catalyzed systems are nicely complementary. The synthesis of N-substituted isoindolinones, which often exhibit important biological activity such as the analgesic and 7296


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Figure 3. Results of mechanistic studies. B(2,6-Cl2C6H3)(p-HC6F4)2 is shown as BAr3. (a) Effect of additives on the formation of A. Yield was determined by NMR analysis. (b) Time−concentration profiles for the reaction of 1a and 2a under optimized reaction conditions. Yield was determined by NMR analysis of the crude reaction mixtures with hexamethylbenzene as the internal standard. For the detailed experimental procedures, see the SI. (c) Time−concentration profiles for the reaction of 1a and 2a with 20 mol % BAr3 and 5 atm H2 in THF-d8. Yield was by NMR analysis using hexamethylbenzene as the internal standard. (d) Kinetic order in [BAr3]. (e) log[BAr3] vs log(kp) profiles. (f) Effect of the H2 pressure (from 5 to 40 atm) on the yield of 3aa in the reaction between 1a and 2a. Yield was determined by NMR analysis of the crude reaction mixture using hexamethylbenzene as the internal standard. 7297


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evaluated by varying the pressure of H2 from 5 to 40 atm under the conditions shown in Figure 3f. All these results demonstrate that (i) B(2,6-Cl2C6H3)(pHC6F4)2 is involved in both catalytic cycles of the present tandem processes and (ii) the rate-limiting heterolytic cleavage of H2 would be mediated by the FLP comprising THF and B(2,6-Cl2C6H3)(p-HC6F4)2, given that the reaction rate depends on the H2 pressure. Path A in Figure 2 is likely to occur for the reaction of 1a, 2a, and H2 in the presence of B(2,6-Cl2C6H3)(p-HC6F4)2 in THF.

Cl2C6H3)(p-HC6F4)2 in the FLP-catalyzed hydrogenation of carbonyl compounds.8,9 In the case of path A, the FLP comprising THF and B activates H2 to afford [THF−H][H−B], and the [THF−H]+ species continuously activates Im to form an iminium intermediate Y. A similar activation of aldehydes by [THF− H]+ has been theoretically studied by Pápai and Soós et al.9e Finally, a hydride transfer from [H−B]− to the iminium moiety in Y affords the reductively alkylated product with the concomitant regeneration of the FLP catalyst. On the other hand, in the case of path B, the FLP comprising Im and B activates H2 to afford [Im−H][H−B], which would subsequently be solvated by THF to form intermediate Y. This type of H2 activation has been proposed for FLP-catalyzed hydrogenations in noncoordinating solvents such as toluene and CH2Cl2.8a,9b,c In order to clarify the reaction mechanism, detailed mechanistic studies were carried out (Figure 3). First, the reaction between 1a and 2a was monitored under the conditions shown in Figure 3a in order to confirm the catalysis by B(2,6-Cl2C6H3)(p-HC6F4)2 during the formation of imine A. In the presence of both 4 Å MS and B(2,6-Cl2C6H3)(pHC6F4)2 (5 mol %), A was obtained in 83% yield within 5 min, whereas almost no reaction was observed in the absence of B(2,6-Cl2C6H3)(p-HC6F4)2, most likely due to the insufficient nucleophilicity of 2a toward 1a.16 It should be noted that the reaction was pressurized with H2 within 10 min after the preparation of the THF solution of 1, 2, B(2,6-Cl2C6H3)(pHC6F4)2, and 4 Å MS. Thus, the B(2,6-Cl2C6H3)(p-HC6F4)2catalyzed formation of the imines should be operative under these conditions. Second, the reductive alkylation of 1a and 2a was monitored under the optimized conditions, and the resultant time− concentration profile is shown in Figure 3b. For the disappearance of A (kIm) and the production of 3aa (kP), rate constants of kIm = 6.73(37) [10−3 mol m−3 s−1] and kP = 7.97(18) [10−3 mol m−3 s−1] were obtained from the leastsquares fitting of this profile to zeroth-order rate equations. The linear increase in the yield of 3aa suggests that the autoinduced catalysis of 3aa is not involved in this reaction.17,18 A slight amount of 1a (∼10%) was constantly observed throughout the progress of the reaction due to an equilibrium between the formation and the hydrolysis of A under these reaction conditions. These results should serve to rationalize both path A and path B in the proposed reaction mechanism (Figure 2). In the case of path A, the zeroth-order dependence on [A] indicates that A is not involved in the rate-limiting event.19 On the other hand, in the case of path B, a pseudo-first-order dependence on [A] should be expected since the concentration of A is much higher than that of B.16 To clarify this issue, the reaction of 1a and 2a was monitored by NMR in the presence of 20 mol % B(2,6-Cl2C6H3)(p-HC6F4)2 in THF-d8 (Figure 3c). In this experiment, the reaction was conducted without MS under 5 atm of H2.20 Again, a linear correlation was confirmed in the time−concentration profile, which afforded kIm = 3.82(5) [10−4 mol m−3 s−1] (R2 > 0.99). On the basis of these results, it seems feasible to conclude that the kinetic order in [A] is zero. Third, the kP values were estimated by varying the concentration of B(2,6-Cl2C6H3)(p-HC6F4)2, demonstrating a first-order kinetics in [B(2,6-Cl2C6H3)(p-HC6F4)2] (Figure 3d and 3e). The significant dependence of the reaction progress on the amount of H2 was also observed when the yield of 3aa was

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CONCLUSION In summary, a novel reductive alkylation system has been developed for the direct functionalization of amines that bear a remarkably wide range of functional groups, which include carboxyl, hydroxyl, and additional amino groups. Thus, a variety of amino acids (or their derivatives) were alkylated in good to excellent yield. The reaction proceeds via tandem processes comprising the B(2,6-Cl2C6H3)(p-HC6F4)2-catalyzed formation of imines and their subsequent hydrogenation catalyzed by a frustrated Lewis pair (FLP). The results of our mechanistic studies support the proposed mechanism: (i) the formation of the imine is significantly accelerated in the presence of B(2,6Cl2C6H3)(p-HC6F4)2 and MS and (ii) the rate-limiting heterolytic cleavage of H2 should be mediated by the FLP comprising THF and B(2,6-Cl2C6H3)(p-HC6F4)2. Moreover, H2 was used as the reductant, which generates H2O as the sole byproduct. In their entirely, the aforementioned results demonstrate that the present catalytic system represents an environmentally benign, atom-efficient, and practical route to functionalize multiply substituted amines.

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EXPERIMENTAL SECTION

General Considerations for the Experimental Conditions. Unless otherwise noted, all manipulations were conducted under an atmosphere of nitrogen using standard Schlenk line or drybox techniques. Molecular sieves (4 Å) were activated by heating in vacuo (∼0.2 mmHg, heat gun, 5 min). All commercially available reagents including superdehydrated solvents (toluene, Et2O, THF, and 1,4-dioxane) were employed as received. THF-d8 was stored over molecular sieves (4 Å) prior to use. General Procedures for Scheme 2. A 30 mL autoclave was charged with aldehyde 1 (0.40 mmol), amine 2 (0.40 mmol), B(2,6Cl2C6H3)(p-HC6F4)2 (9.1 mg, 0.020 mmol or 18.2 mg, 0.040 mmol or 27.3 mg, 0.060 mmol), 4 Å molecular sieves (100 mg), and THF (8 mL). Once sealed, the vessel was pressurized with H2 (20 or 80 atm), and the reaction mixture was stirred at 100 °C. The reaction mixture was then cooled to room temperature, degassed, extracted with acetone, and passed through a glass filter. Subsequently, the filtrate was concentrated in vacuo to provide the pure product after workup. General Synthesis of Isoindolinones from 1o. A 30 mL autoclave was charged with 2-formylbenzoic acid 1o (60.1 mg, 0.40 mmol), 2 (0.40 mmol), B(2,6-Cl2C6H3)(p-HC6F4)2 (9.1 mg, 0.020 mmol or 18.2 mg, 0.040 mmol), 4 Å molecular sieves (100 mg), and THF (8 mL). Once sealed, the vessel was pressurized with H2 (80 atm) and the reaction mixture was stirred at 100 °C for 6 or 15 h. The reaction mixture was then cooled to room temperature, degassed, extracted with acetone, and passed through a glass filter. Subsequently, the filtrate was concentrated in vacuo to provide the pure product after workup. General Synthesis of 3-Aminophthalic Anhydrides from 2u. A 30 mL autoclave was charged with 1 (0.40 mmol), 3-aminophthalic acid 2u (72.5 mg, 0.40 mmol), B(2,6-Cl2C6H3)(p-HC6F4)2 (18.2 mg, 0.040 mmol), 4 Å molecular sieves (100 mg), and THF (8 mL). Once sealed, the vessel was pressurized with H2 (80 atm) and the reaction mixture was stirred at 100 °C for 15 h. The reaction mixture was then 7298


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288−309. (g) Faísca Phillips, A. M.; Pombeiro, A. J. L. Org. Biomol. Chem. 2017, 15, 2307−2340. (h) Sharma, M.; Mangas-Sanchez, J.; Turner, N. J.; Grogan, G. Adv. Synth. Catal. 2017, 359, 2011−2025. (i) Schrittwieser, J. H.; Velikogne, S.; Kroutil, W. Adv. Synth. Catal. 2015, 357, 1655−1685. (j) Gomez, S.; Peters, J. A.; Maschmeyer, T. Adv. Synth. Catal. 2002, 344, 1037−1057. (k) Tararov, V. I.; Börner, A. Synlett 2005, 203−211. (l) Renaud, J.-L.; Gaillard, S. Synthesis 2016, 48, 3659−3683. (m) Chusov, D.; List, B. Angew. Chem., Int. Ed. 2014, 53, 5199−5201. (n) Fu, M.-C.; Shang, R.; Cheng, W.-M.; Fu, Y. Angew. Chem., Int. Ed. 2015, 54, 9042−9046. (o) Andrews, K. G.; Summers, D. M.; Donnelly, L. J.; Denton, R. M. Chem. Commun. 2016, 52, 1855−1858. (3) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.; Leazer, J. L., Jr.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411−420. (4) For the use of earth-abundant transition metals, such as Fe and Co, in the reductive alkylation of amines, see ref 2l. (5) (a) During the preparation of this manuscript, Soós et al. reported the B(2-Cl-6-F-C6H3)(2,6-Cl2C6H3)2-catalyzed, FLP-mediated reductive amination of carbonyls in toluene. This outstanding study mainly focuses on the development and properties of organoboranes, and the optimal catalyst system and applicable substrate scope (e.g., aliphatic and electron-rich aromatic amines) for the reductive amination thus complement our results. See: Dorkó, É.; Szabó, M.; Kótai, B.; Pápai, I.; Domján, A.; Soós, T. Angew. Chem., Int. Ed. 2017, 56, 9512−9516. (b) Tin(IV)-catalyzed reductive aminations of carbonyl compounds with H2 have very recently been reported, see: Sapsford, J. S.; Scott, D. J.; Allcock, N. J.; Fuchter, M. J.; Tighe, C. J.; Ashley, A. E. Adv. Synth. Catal. 2018, 360, 1066−1071. (6) (a) Rahman, L. K. A.; Chhabra, S. R. Med. Res. Rev. 1988, 8, 95− 156. (b) Grell, W.; Hurnaus, R.; Griss, G.; Sauter, R.; Rupprecht, E.; Mark, M.; Luger, P.; Nar, H.; Wittneben, H.; Müller, P. J. Med. Chem. 1998, 41, 5219−5246. (c) Devasthale, P. V.; Chen, S.; Jeon, Y.; Qu, F.; Shao, C.; Wang, W.; Zhang, H.; Cap, M.; Farrelly, D.; Golla, R.; Grover, G.; Harrity, T.; Ma, Z.; Moore, L.; Ren, J.; Seethala, R.; Cheng, L.; Sleph, P.; Sun, W.; Tieman, A.; Wetterau, J. R.; Doweyko, A.; Chandrasena, G.; Chang, S. Y.; Humphreys, W. G.; Sasseville, V. G.; Biller, S. A.; Ryono, D. E.; Selan, F.; Hariharan, N.; Cheng, P. T. W. J. Med. Chem. 2005, 48, 2248−2250. (d) Goossen, L. J.; Melzer, B. J. Org. Chem. 2007, 72, 7473−7476. (e) Blackburn-Munro, G.; DalbyBrown, W.; Mirza, N. R.; Mikkelsen, J. D.; Blackburn-Munro, R. E. CNS Drug Rev. 2005, 11, 1−20. (f) Levadala, M. K.; Banerjee, S. R.; Maresca, K. P.; Babich, J. W.; Zubieta, J. Synthesis 2004, 2004, 1759− 1766. (g) Imstepf, S.; Pierroz, V.; Raposinho, P.; Felber, M.; Fox, T.; Fernandes, C.; Gasser, G.; Santos, I. R.; Alberto, R. Dalton Trans. 2016, 45, 13025−13033. (7) The FLP-mediated tandem hydroamination/hydrogenation strategy also affords alkylated amines without using transition metals. For recent examples, see: (a) Mahdi, T.; Stephan, D. W. Angew. Chem., Int. Ed. 2013, 52, 12418. (b) Mahdi, T.; Stephan, D. W. Chem. - Eur. J. 2015, 21, 11134. (c) Tussing, S.; Ohland, M.; Wicker, G.; Flörke, U.; Paradies, J. Dalton Trans. 2017, 46, 1539. (8) (a) Stephan, D. W.; Erker, G. Angew. Chem., Int. Ed. 2015, 54, 6400−6441. (b) Stephan, D. W.; Erker, G. Angew. Chem., Int. Ed. 2010, 49, 46−76. (c) Stephan, D. W. Science 2016, 354, aaf7229. (d) Weicker, S. A.; Stephan, D. W. Bull. Chem. Soc. Jpn. 2015, 88, 1003−1016. (e) Welch, G. C.; Juan, R. R. S.; Masuda, J. D.; Stephan, D. W. Science 2006, 314, 1124−1126. (9) (a) Scott, D. J.; Fuchter, M. J.; Ashley, A. E. Chem. Soc. Rev. 2017, 46, 5689−5700. (b) Oestreich, M.; Hermeke, J.; Mohr, J. Chem. Soc. Rev. 2015, 44, 2202−2220. (c) Paradies, J. Synlett 2013, 24, 777−780. (d) Feng, X.; Du, H. Tetrahedron Lett. 2014, 55, 6959−6964. (e) Gyömöre, Á .; Bakos, M.; Földes, T.; Pápai, I.; Domján, A.; Soós, T. ACS Catal. 2015, 5, 5366−5372. (f) Bakos, M.; Gyömöre, Á .; Domján, A.; Soós, T. Angew. Chem., Int. Ed. 2017, 56, 5217−5221. (g) Scott, D. J.; Simmons, T. R.; Lawrence, E. J.; Wildgoose, G. G.; Fuchter, M. J.; Ashley, A. E. ACS Catal. 2015, 5, 5540−5544. (h) Scott, D. J.; Fuchter, M. J.; Ashley, A. E. J. Am. Chem. Soc. 2014, 136, 15813−15816. (i) Mahdi, T.; Stephan, D. W. J. Am. Chem. Soc. 2014, 136, 15809−

cooled to room temperature, degassed, extracted with acetone, and passed through a glass filter. Subsequently, the filtrate was concentrated in vacuo to provided the pure product after workup. Synthesis of 4au. A 30 mL autoclave was charged with 1a (42.5 mg, 0.40 mmol), 2u (72.5 mg, 0.40 mmol), B(2,6-Cl2C6H3)(pHC6F4)2 (18.2 mg, 0.040 mmol), 4 Å molecular sieves (100 mg), and THF (8 mL). Once sealed, the vessel was pressurized with H2 (80 atm) and the reaction mixture was stirred at 100 °C for 15 h. The reaction mixture was then cooled to room temperature, degassed, extracted with MeOH (8 mL), and passed through a glass filter. NaOH (2 M aq., 1 mL) was added to the filtrate, and the reaction mixture was stirred at 50 °C for 26 h. Then the reaction mixture was cooled to room temperature, and all volatiles were removed in vacuo, which afforded a white solid. After this solid was treated with HCl aq. (1 M) to establish pH = 5, the crude products were extracted with EtOAc, washed with brine, and dried in vacuo. The resulting yellow solid was washed with CHCl3, which afforded 4au as a pale yellow solid (89.8 mg, 0.33 mmol, 83%).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b03626. Full details pertaining to the experimental methods and identification of compounds (PDF) (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected] ORCID

Yoichi Hoshimoto: 0000-0003-0882-6109 Sensuke Ogoshi: 0000-0003-4188-8555 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by Grants-in Aid for Scientific Research (B) (JSPS KAKENHI Grant nos. 16KT0057 and 17H03057) and Grants-in Aid for Scientific Research on Innovative Areas “Stimuli-responsive Chemical Species (JSPS KAKENHI Grant Number JP15H00943)” and “Precisely Designed Catalysts with Customized Scaffolding (JSPS KAKENHI Grant no. JP15H05803)”. Y.H. acknowledges support from the Frontier Research Base for Global Young Researchers, Osaka University, on the program of MEXT. T.K. expresses his special thanks for a Grant-in-Aid for JSPS Fellows. The authors sincerely thank Prof. Dr. Norimitsu Tohnai (Graduate School of Engineering, Osaka University, Japan) for collecting the X-ray data.

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REFERENCES

(1) For relevant books, see: (a) Nicolou, K. C.; Montagnon, T. Molecules That Changed the World; Wiley-VCH: Weinheim, 2008. (b) Corey, E. J.; Czakó, B.; Kürti, L. Molecules and Medicine; WileyVCH: Weinheim, 2007. (2) (a) Lawrence, S. A. Amines: Synthesis, Properties and Applications; Cambridge University Press, 2004. (b) Legnani, L.; Bhawal, B. N.; Morandi, B. Synthesis 2017, 49, 776−789. (c) Salvatore, R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron 2001, 57, 7785−7811. (d) Li, B.; Sortais, J.-B.; Darcel, C. RSC Adv. 2016, 6, 57603−57625. (e) Nugent, T. C.; El-Shazly, M. Adv. Synth. Catal. 2010, 352, 753−819. (f) Gusak, K. N.; Ignatovich, Z. V.; Koroleva, E. V. Russ. Chem. Rev. 2015, 84, 7299


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Journal of the American Chemical Society 15812. (j) Scott, D. J.; Fuchter, M. J.; Ashley, A. E. Angew. Chem., Int. Ed. 2014, 53, 10218−10222. (k) Ashley, A. E.; Herrington, T. J.; Wildgoose, G. G.; Zaher, H.; Thompson, A. L.; Rees, N. H.; Krämer, T.; O’Hare, D. J. Am. Chem. Soc. 2011, 133, 14727−14740. (l) Ullrich, M.; Lough, A. J.; Stephan, D. W. J. Am. Chem. Soc. 2009, 131, 52−53. (m) Hounjet, L. J.; Bannwarth, C.; Garon, C. N.; Caputo, C. B.; Grimme, S.; Stephan, D. W. Angew. Chem., Int. Ed. 2013, 52, 7492. (10) For FLP-catalyzed reductive alkylations of amines with hydrosilanes, see: (a) Fasano, V.; Radcliffe, J. E.; Ingleson, M. J. ACS Catal. 2016, 6, 1793−1798. (b) Fasano, V.; Ingleson, M. J. Chem. - Eur. J. 2017, 23, 2217−2224. (c) Tiddens, M. R.; Klein Gebbink, R. J. M.; Otte, M. Org. Lett. 2016, 18, 3714−3717. (11) For recent contributions from our group, see: (a) Hoshimoto, Y.; Kinoshita, T.; Ohashi, M.; Ogoshi, S. Angew. Chem., Int. Ed. 2015, 54, 11666−11671. (b) Hazra, S.; Hoshimoto, Y.; Ogoshi, S. Chem. Eur. J. 2017, 23, 15238−15243. We examined the reaction of 1a, 2a, and H2 under the conditions shown in entry 1 (Table 1) with 5 mol % of complex [(N-phosphine oxide-substituted imidazolylidene)B(C6F5)3] as the FLP precursor; however, A was confirmed as the sole product. For details, see the SI (12) For details, see the SI. (13) (a) Lindqvist, M.; Sarnela, N.; Sumerin, V.; Chernichenko, K.; Leskelä, M.; Repo, T. Dalton Trans. 2012, 41, 4310−4312. (b) Mahdi, T.; Stephan, D. W. Angew. Chem., Int. Ed. 2015, 54, 8511−8514. (14) The reductive alkylation was examined under the optimized conditions shown in Scheme 2 using a reaction mixture of 1a and 2a, which was prepared in the presence of air and moisture (i.e., outside the glovebox), which resulted in a significant decrease of the yield of 3aa (

Main-Group-Catalyzed Reductive Alkylation of Multiply Substituted

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