Main-Group-Catalyzed Reductive Alkylation of Multiply Substituted

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Main-Group-Catalyzed Reductive Alkylation of Multiply Substituted Amines with Aldehydes Using H

2

Yoichi Hoshimoto, Takuya Kinoshita, Sunit Hazra, Masato Ohashi, and Sensuke Ogoshi J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b03626 • Publication Date (Web): 23 May 2018 Downloaded from http://pubs.acs.org on May 23, 2018

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Journal of the American Chemical Society

Main-Group-Catalyzed Reductive Alkylation of Multiply Substituted Amines with Aldehydes Using H2 Yoichi Hoshimoto,*1,2 Takuya Kinoshita,1 Sunit Hazra,1 Masato Ohashi,1 Sensuke Ogoshi*1 1

Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan Frontier Research Base for Global Young Researchers, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan 2

KEYWORDS: Main-group catalysis; Reductive alkylation of amines; Hydrogenation; Frustrated Lewis pairs; Bioactive amines

ABSTRACT: Given the growing demand for green and sustainable chemical processes, the catalytic reductive alkylation of amines with main-group 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(2,6-Cl2C6H3)(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 or intramolecular dehydration reactions, respectively. The reaction showed a zeroth-order and a first-order dependence on the concentration of an imine intermediate and B(2,6-Cl2C6H3)(p-HC6F4)2, respectively. In addition, the reaction progress was significantly affected by the concentration of H2. These results suggest a possible mechanisms in which the heterolysis of H2 is facilitated by the FLP comprising THF and B(2,6-Cl2C6H3)(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 atomefficient functionalization methods that employ readily available catalysts

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Table 1. Optimization of the Reaction Conditions.a

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

and reagents of low toxicity.3 The main-group-catalyzed reductive alkylation of amines (or reductive aminaFigure 1. Selected bioactive amine molecules containing multiple COOH/OH/NH2 tion of carbonyl species)2f-l with mogroups. lecular hydrogen as the reductant would therefore represent an ideal method, given that H2O is generated as the sole byproduct.4 So a far, such a process remains highly challenging,5 as on one General conditions: all reactions were carried out in an auhand, the catalyst should be sufficiently reactive to activate H2, toclave reactor (30 mL). 1a (0.40 mmol), 2a (0.40 mmol), yet, on the other hand, it should simultaneously be tolerant to BAr3, and 4 Å MS (100 mg) were mixed in THF (8 mL), folthe in-situ-generated H2O as well as innocent toward carbonyl lowed by pressurization with H2 and heating at 100 °C for 2 h. Yield of the product was determined by NMR analysis. bYield substrates. Moreover, previously reported catalytic reductive after 15 h. n.d.: not detected. alkylation systems have rarely been applied to amines bearing multiple carboxyl, hydroxyl, and/or additional amino A.12 Ingleson et al. have investigated the deactivation of trigroups.2g,f,j Indeed, bioactive molecules often contain benzylarylboranes in the borane-catalyzed reductive alkylation of amine or the corresponding heteroaromatic moieties together amines using hydrosilanes, and suggested that the use of less with carboxyl, hydroxyl, and/or amino groups (Figure 1).1b,6 Lewis-acidic boranes could allow for broader substrate The development of a practical and environmentally benign scopes.10b In these reactions, an excess of hydrosilanes could reductive alkylation system that enables direct access to these 7 irreversibly eliminate H2O from the reaction mixture, whereas multiply functionalized amines is thus of high interest. Herein, the absorption of H2O on MS is generally an equilibrium and we report the reductive alkylation of primary amines with H2, would be insufficient at 100 °C. Thus, other reported triarylwhich proceeds via a tandem reaction that consists of an orboranes, including B(C6Cl5)(C6F5)2 developed by Ashley et ganoborane-catalyzed formation of an imine, and a subsequent al.,9k B(p-HC6F4)3 developed by Stephan et al.,9l and B(2,6hydrogenation of this imine catalyzed by a frustrated Lewis Cl2C6H3)(p-HC6F4)2 developed by Soós et al.,9e were examined pair (FLP).5,8-10 A variety of multiply substituted amines were (entries 2‒6) in order to identify the optimal borane with suffiefficiently functionalized using the present catalyst system, in cient stability toward deactivation to form [LB‒H][HO‒BAr3] which H2O was generated as the sole byproduct (Scheme 1). (e.g., LB = 2a, 3aa and/or A). The use of B(2,6-Cl2C6H3)(pRESULTS AND DISSCUSION. To achieve our goal, we HC6F4)2 in THF afforded 3aa in >99% yield (entry 5), whereas focused on the use of FLP-based catalysts, since the chemistry all other triarylboranes examined in this study failed to yield of the FLP-catalyzed hydrogenation of imines and carbonyls 3aa in more than 10% yield.12 The FLP generated from our 9,11 has been extensively developed. For the optimization of the original B(2-CF3C6H4)(p-HC6F4)2 also catalytically furnished reaction conditions, we initially employed benzaldehyde (1a), 3aa; however, the yield remained low (21%) (entry 6). Thereaniline (2a), H2 (80 atm), and 4 Å molecular sieves (MS) in after, we explored the solvent effects using Et2O, 1,4-dioxane, THF in the presence of 5 mol% B(C6F5)3 (entry 1, Table 1a). and toluene, which resulted in the formation of 3aa in 62%, However, the targeted N-phenylbenzylamine (3aa) was ob16%, and 45%, respectively.12 Thus, THF was used in the tained in only 2% yield after heating to 100 °C for 2 h. Altfollowing experiments as the optimal solvent. Reducing the hough the formation of N-benzylideneaniline (A) was conhydrogen pressure to 20 atm also afforded 3aa quantitatively firmed in 91% yield, the subsequent hydrogenation of A did within 2 h (entry 7, Table 1b). In contrast, 10 atm of H2 was not proceed under these reaction conditions. In this case, insufficient to complete the reaction in the same period (66%). B(C6F5)3 was converted to [LB‒H][HO‒B(C6F5)3] by reaction Under these conditions, completion of the reaction was not with H2O and Lewis bases (LBs), where the LB is 2a and/or observed even after 15 h, which yielded 3aa in 91% (entry 8).


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In the presence of 2 mol% B(2,6-Cl2C6H3)(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(2,6-Cl2C6H3)(p-HC6F4)2 and 20 atm of H2 as the standard conditions for the exploration of the substrate scope. 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 a increment of the concentration of in-situ-generated H2O. In fact, the presence of C6H2F4 in the reaction mixture was confirmed by 19F 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 was clearly decreased.



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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). para-Substituted benzaldehydes containing 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 FLP-catalyzed hydrogenation of 1h, followed by deoxygenation.13 The use of 2-pyridinecarboxaldehyde (1j) and furfural (1k) afforded 3ja and 3ka in >99% and 94%, respectively. 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) Scheme 2. Scheme FLP-Catalyzed 3. (a) FLP-Catalyzed Reductive Alkylation Reductive of Amines Alkylation (2y) Affording with Aldehydes Isoindolinones (1x) with from H2.a 1o, and 3-Aminophthalic Anhydrides from 2u. (b) Synthesis of 4au.

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.


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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 4aminosalicylic acid (2i) as well as 4-amino-3-hydroxybenzoic acid (2j) under 80 atm of H2 to furnish 3ai and 3aj in 47% (with 10 mol% borane) and 70% (with 15 mol% borane) yield, respectively. The functionalization of 3,4′-diamino-4nitrodiphenyl 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 3ar in only 34%. 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 equivalents 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 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%), 3mu (>99%) were 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

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



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(2,6Cl2C6H3)(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


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Journal of the American Chemical Society 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 FLPcatalyzed hydrogenations in non-coordinating solvents such as toluene and CH2Cl2.8a,9b,9c In order to clarify the reaction mechanism, detailed mechanistic studies were carried out (Figure 3). Firstly, the reaction between 1a and 2a was monitored under the conditions shown in Figure 3a in order to confirm the catalysis by B(2,6Cl2C6H3)(p-HC6F4)2 during the formation of imine A. In the presence of both 4 Å MS and B(2,6-Cl2C6H3)(p-HC6F4)2 (5 mol%), A was obtained in 83% yield within 5 min, whereas almost no reaction was observed in the absence of B(2,6Cl2C6H3)(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)(p-HC6F4)2, and 4 Å MS. Thus, the B(2,6-Cl2C6H3)(p-HC6F4)2-catalyzed formation of the imines should be operative under these conditions. Secondly, the reductive alkylation of 1a and 2a was monitored under the optimized conditions, and the resultanting 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 least-squares fitting of this profile to zeroth-order rate equations. The linear increase in the yield of 3aa suggests that the auto-induced 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.16b To clarify this issue, the reaction of 1a and 2a was monitored by NMR in the presence of 20 mol% B(2,6Cl2C6H3)(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 timeconcentration profile, which afforded kIm = 3.82(5) [10‒4 mol m‒3 s‒1] (R2 > 0.99). Based on these results, it seems feasible to conclude that the kinetic order in [A] is zero. Thirdly, the kP values were estimated by varying the concentration of B(2,6-Cl2C6H3)(p-HC6F4)2, demonstrating a firstorder kinetic in [B(2,6-Cl2C6H3)(p-HC6F4)2] (Figures 3d and 3e). The significant dependence of the reaction progress on the Figure 3. Results of mechanistic studies. B(2,6-Cl2C6H3)(p-HC6F4)2 isamount shown as . (a) also Effect of additives on the the yield formation of A. of BAr H2 3was observed when of 3aa was Yield was determined by NMR analysis. (b) The time-concentration profiles forby thevarying reactionthe of pressure 1a and 2aofunder optimized reaction evaluated H2 from 5 to 40 atm unconditions. Yield was determined by NMR analysis of the crude reaction mixtures with hexamethylbenzene der the conditions shown in Figure 3f.as the internal standard. For the detailed experimental procedures, see SI. (c) The time-concentration profiles for the reaction of 1a and 2a with 20 mol% BAr3 All these results demonstrate that (i) B(2,6-Cl C6H3]. )(pand 5 atm H2 in THF-d8. Yield was by NMR analysis using hexamethylbenzene as the internal standard. (d) Kinetic order in 2[BAr 3 HC F ) is involved in both catalytic cycles of the present tan6 4 2 (e) The log[BAr ] vs. log(k ) profiles. (f) Effect of the H pressure (from 5 to 40 atm) on the yield of 3aa in the reaction between 1a 3

p

2

and 2a. Yield was determined by NMR analysis of the crude reaction mixture using hexamethylbenzene as the internal standard.



dem processes; (ii) the rate-limiting heterolytic cleavage of H2 would be mediated by the FLP comprising THF and B(2,6Cl2C6H3)(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)(pHC6F4)2 in THF. 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)(pHC6F4)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(2,6-Cl2C6H3)(p-HC6F4)2 and MS; (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. 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 dry box techniques. Molecular sieves (4 Å) were activated by heating in vacuo (~0.2 mmHg, heat gun, 5 min). All commercially available reagents including super-dehydrated 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(2,6-Cl2C6H3)(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, which 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, which 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), 3aminophthalic acid 2u (72.5 mg, 0.40 mmol), B(2,6-

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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 cooled to room temperature, degassed, extracted with acetone, and passed through a glass filter. Subsequently, the filtrate was concentrated in vacuo, which provide 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(2,6Cl2C6H3)(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 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%).

ASSOCIATED CONTENT Supporting Information. The following files are available free of charge. Full details pertaining to the experimental methods and identification of compounds (PDF)

AUTHOR INFORMATION Corresponding Author *[email protected] *[email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by Grants-in Aid for Scientific Research (B) (JSPS KAKENHI Grant Numbers 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 Number 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 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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Main-Group-Catalyzed Reductive Alkylation of Multiply Substituted

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