Improving the Industrial Feasibility of Metal-Free Hydrogenation

Article pubs.acs.org/OPRD

Improving the Industrial Feasibility of Metal-Free Hydrogenation Catalysts Using Chemical Scavengers Jordan W. Thomson,† Jillian A. Hatnean,‡ Jeff J. Hastie,† Andrew Pasternak,† Douglas W. Stephan,‡ and Preston A. Chase*,† †

GreenCentre Canada, 945 Princess Street, Kingston, Ontario K7L 3N6, Canada Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada

‡

S Supporting Information *

ABSTRACT: A modified process using inexpensive poison scavengers has been developed that allows for more economical and practical scale-up of metal-free catalytic hydrogenation. The scavengers remove impurities such as water and aldehydes that can hinder catalysis allowing for the use of commercial-grade solvents, substrates and gases. In addition, the scavengers have the unique ability to regenerate poisoned catalysts, allowing for increased turnover numbers and longer catalyst lifetimes. Hydrogenations of unpurified imine substrates proceed with high yield using a variety of metal-free hydrogenation catalysts, demonstrating the general compatibility of this process.

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INTRODUCTION The hydrogenation of unsaturated organic substrates is a widely used and important reaction in the chemical industry.1 This transformation can be accomplished through the use of stoichiometric reductants such as LiAlH4 or NaBH4, transfer hydrogenation, organocatalysis as well as direct addition of hydrogen mediated by transition metal catalysts.2 The stoichiometric Al and B hydride-based reductants offer altered chemoselectivity compared to metal-based systems. However, they suffer from safety, environmental, and cost concerns onscale due to quenching excess reagent and disposing of large amounts of generated waste. Homogeneous transition metal catalysts offer the atom economy and clean reactivity of directly using hydrogen gas. However, they often consist of expensive and toxic metals. While removal of heterogeneous transition metal catalysts (e.g., Pd/C) is facile, removal of homogeneous transition metal catalysts can be difficult and costly and require removal to increasingly lower legislated levels.3 In 2006, the Stephan group demonstrated that the novel phosphonium hydridoborate 1a (Figure 1) could achieve

broadened the scope of substrates to include commercially relevant imines, for example precursors to sertraline and intermediates to herbicides and anticancer compounds, as well as silyl enol ethers and enamines using catalyst loadings as low as 0.1 mol %.8 In addition, syntheses of catalysts 1a and 1b have been demonstrated at a 100 g scale.9 These advances have been recently reviewed.10 Mechanistically, this process generates a borohydride intermediate, and thus exhibits reactivity similar to stoichiometric borohydride reagents, but without the safety issues of quenching excess reagent or the cost and environmental impact of disposing of large amounts of waste or removing toxic metals from products. These catalysts possess advantages over stoichiometric reductants and transition metal catalysts; however, they are sensitive to trace impurities present in solvents, gas streams, and substrates such as water and aldehydes which must be removed for optimal catalytic activity to be observed.8a Whereas drying solvents and purifying substrates in a research laboratory is common, improvements in the tolerance of impurities and untreated solvents must be implemented to make these catalysts suitable for scale-up and manufacturing. Achieving this goal removes the need for expensive drying of solvents and gases, increases the turnover number of catalysts (decreased materials cost), and gives more consistent yields under different conditions (i.e., due to different batches of solvent, gas, humidity, etc.). In this report, we present an inexpensive and general solution to this problem through the use of poison scavengers. Chemical scavengers have found use in a variety of industrial, homogeneous catalyzed processes, notably in the polymerization of ethylene using Ziegler−Natta chemistry.11 In this

Figure 1. Metal-free hydrogenation catalysts used in this study.

reversible metal-free activation of H2.4 This unique reactivity has since been observed in a number of sterically demanding combinations of Lewis acids and bases, now commonly termed ‘Frustrated Lewis Pairs (FLPs).5 Soon after the initial report of H2 activation, it was found that catalytic hydrogenation of imines and aziridines can be performed using these materials.6 Note that, in the case of catalyst 2, the Lewis basic partner is the imine substrate itself.7 Since then, a number of reports have © XXXX American Chemical Society

Special Issue: Engineering Contributions to Chemical Process Development Received: April 2, 2013

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dx.doi.org/10.1021/op4000847 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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triphenylsilane and triisopropylsilane did not show significant improvement above the standard scavenger-free hydrogenations. However, both chlorodimethylsilane and triethylsilane showed near quantitative conversions, an improvement of 30− 40% over the control experiments. The similar conversions of triethylsilane and chlorodimethylsilane imply that sterics are predominantly responsible for the improved reactivity compared to the phenyl and isopropyl substituted silanes as the chlorosilane Si−H should be less hydridic compared to triethylsilane. These types of steric effects are similar to those noted by Piers et al.12a These improvements are thought to arise from reaction of impurities, such as residual aldehyde or trace water by scavenger, preventing catalyst poisoning and effectively providing a higher concentration of active catalyst in solution. MAO, a scavenger commonly used in Ziegler−Natta chemistry, was also tested. In addition to MAO, we also used the alkylaluminiums triisobutylaluminium (TIBAL) and diisobutylaluminium hydride (DIBAL). In the initial screening results, it was found that all alkylaluminiums tested showed significant improvement over the control reactions with near quantitative conversions for TIBAL and DIBAL. MAO also showed improved reactivity, although conversions were less consistent than for TIBAL and DIBAL. The variable composition of commercial MAO in toluene could be responsible for this. We hypothesize that the improved conversions using alkylaluminiums also arise from the prevention of catalyst poisoning. It is known that alkylaluminiums can react directly with impurities such as water and aldehydes.11 Molecular sieves and an electron-rich borane, 9-borabicylco[3.3.1]nonane dimer (9-BBN), were also tested. Molecular sieves showed only moderate improvement above the control reaction. Triplicate runs would likely show an average conversion within the error of the control experiments. It should be noted that given the solid-state nature of sieves and size of the particles used, the effective molar percentage is significantly higher than 1%. It is expected that molecular sieves would show an improvement were the toluene not predried. Surprisingly, 9-BBN showed lower conversion than the control experiments. This demonstrates that simply being water reactive is not sufficient for a scavenger to be effective and other considerations, including interaction and compatibility with the catalysts, need to be satisfied. Of the scavengers tested, alkylaluminiums and sterically moderate Si−H containing silanes were found to be the most promising. Notably the form of the FLP catalysts containing a borohydride reacts directly with typical impurities, such as water, leading to catalytically inactive products. In essence, in the absence of added scavenger the FLP catalysts act as scavengers themselves; however, the catalyst is typically much more expensive than the general classes of identified scavengers. For instance, 1a, 1b, and 2 cost $527,000/mol, $164,000/mol, and $64,000/mol at research scale, respectively, compared to $115/mol for Me2SiHCl and $265/mol for TIBAL.14 Thus, the use of scavengers is clearly advantageous from a base materials cost perspective. In addition, the associated costs of reagent and solvent purification are also avoided (vide inf ra). The reaction of scavengers with poisoned catalysts was also probed to determine if the scavenger systems are simply preferentially reacting with the impurities or if the scavengers can regenerate deactivated catalyst. To this end, benzaldehyde

case, scavengers are typically alkylaluminiums such as trimethylaluminium or methyl aluminoxane (MAO), which are premixed with the substrate solution. These reagents react with impurities, such as water and alcohols that would otherwise poison the catalyst. As the active catalytic sites in the metal-free systems would be similar in composition to the precatalysts in olefin polymerization systems, these types of scavengers were deemed to be potentially applicable. Also, known work from the Piers group has shown that the Lewis acid B(C6F5)3 and derivatives will catalyze reaction of silanes with a variety of unsaturated substrates and can be used to mediate the reaction of alcohols and silanes.12 As such, a variety of silanes were also included in screening for scavenging agents.

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RESULTS AND DISCUSSION To apply this concept to metal-free hydrogenation catalysts, we initially screened a number of possible scavengers, as shown in Table 1. Scavengers were chosen on the basis of their potential Table 1. Initial scavenger screening reactions

catalyst (2.5 mol %) 1b 1b 1b 1b 1b 1b 1b 1b 1b 1b 2 2 2 2 2 2 2 2 2 a

scavenger (1 mol %) none triisopropylsilane triphenylsilane chlorodimethylsilane triethylsilane 9-borabicyclo[3.3.1]nonane dimer (9-BBN) diisobutylaluminium hydride (DIBAL) triisobutylaluminium (TIBAL) methylaluminoxane (MAO) molecular sieves none triisopropylsilane triphenylsilane chlorodimethylsilane triethylsilane 9-BBN DIBAL TIBAL MAO

conversiona (%) 64 (9) 67 64 98 95 (5) 65 96 97 (3) 86 (8) 75 72 (9) 79 80 91 (2) 99.7 (5) 61 100 98 (4) 94

Standard deviations calculated from triplicate runs using GC-FID.

ability to irreversibly react with water and/or carbonylcontaining impurities such as aldehydes. Initially, rigorously dry conditions were used, and N-benzylidene-tert-butylamine was employed as the model substrate. At a catalyst loading of 2.5 mol %, 60−70% imine reduction was achieved in 2 h at 100 atm H2 and 25 °C with catalysts 1b and 2, which provided a baseline for activity using these specific substrates, apparatus, and conditions. The remaining 30−40% consisted of unreacted imine with no other byproducts observed by 1H NMR spectroscopy. Conversions13 were then measured with the addition of 1 mol % scavenger to observe differences in reactivity. A range of Si−H containing silanes were tested with varying steric and electronic properties. Sterically bulky silanes such as B



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(2.5 mol %, 0.025 mmol)15 was added to a solution of Nbenzylidene-tert-butylamine in toluene followed by either catalyst 1b/2 (2.5 mol %, 0.025 mmol) inside a glovebox and then subjected to hydrogenation conditions of 100 atm H2 for 2 h at room temperature. An aliquot taken for GC analysis showed essentially no reaction with detected yields of product amine between 0 and 2%. The reactor was brought back into the glovebox, a scavenger (5 mol %, 0.05 mmol) was then added to the reaction mixture, and the hydrogenation was restarted (Table 2).

Scheme 1. Proposed mechanism of catalyst regeneration

Table 2. Catalyst poisoning and regeneration experiment resultsa

catalyst

scavenger

(2.5 mol %) 1b 2 1b 1b 1b a

TIBAL TIBAL Et3SiH Et3SiH/ 0.25% B(C6F5)3 MAO

conver. after add’n of benzaldehyde

conver. after add’n of scavenger

(2.5 mol %)

(5 mol %)

0 0 2 2

82 64 2 94

2

2

The corresponding reaction of 5 with one equivalent of MAO, which did not regenerate an active catalyst, showed a 11B NMR spectrum consistent with the formation of a 4-coordinate boron containing a B−CH3 bond as evidenced by a singlet at −14.5 ppm.17 This implies that alkyl-alkoxide exchange between Al and B is a chemically active pathway and, in this case, results in the formation of the phosphonium alkylborate 6, which is not an active hydrogenation catalyst (Scheme 1). The mechanism of the methyl group transfer has not been investigated, but it is known that MAO contains a number of Lewis acidic sites within its complex structure as well as some amounts of AlMe3.11 It is possible that a Lewis acidic site coordinates to the oxygen atom of 5 in a similar manner to TIBAL, ultimately leading to the formation of 6. The addition of one equivalent of triethylsilane to the phosphonium alkoxyborate 5 in CD2Cl2 resulted in no spectroscopic change at room temperature. However, upon addition of 0.1 equiv of B(C6F5)3 to the mixture, the immediate appearance of a doublet in the 11B NMR spectrum was observed, consistent with the regeneration of 1b; corresponding peaks in the 1H, 19F, and 31P NMR spectra confirm this assignment. In addition, the formation of benzyloxytriethylsilane was observed in the 1H NMR spectrum.18 Free B(C6F5)3 was also observed, suggesting the regeneration of poisoned catalyst occurs by catalytic Lewis acid activation of the silane (Scheme 2). Here, the added free Lewis acid B(C6F5)3 is needed to activate the Si−H bond, which generates a more reactive, silylium-like Si center to interact with the oxygen of the alkoxyborate. This chemistry is reminiscent of the direct silylation of alcohols with B(C6F5)3 as observed by Piers.12a Complexation of the oxygen with silicon activates it for separation from the boron center, and the hydride is transferred to the more Lewis acidic phosphonium borane (see Scheme 2).5a To our knowledge, alkyl/hydride exchange with these types of reagents and the resulting regeneration of poisoned FLP catalyst with chemical scavengers has not been previously demonstrated. Practically speaking, this strategy allows for increased turnover numbers, longer catalyst lifetimes, and less purification of reaction components. In addition, this allows for alternative synthetic methods to be used for the construction of new FLP catalysts or other complex borohydrides. In order to test the limits of the scavenger strategy and to provide insight on the potential practical application of these FLP catalysts, hydrogenations were performed using commercial reagents without further purification. Inside a nitrogen-filled glovebox, the imine was dissolved in ACS reagent grade toluene directly from a freshly opened bottle without drying (∼225 ppm H2O, 6.2 mol %), and additional catalyst poison

Conditions: 100 atm H2, 25 °C for 2 h.

The most promising scavengers identified from Table 1 were tested with poisoned catalyst. The addition of 5 mol % TIBAL to the catalytically inactive solution resulted in yields of 82% and 64% of the amine product for catalysts 1b and 2, respectively, a remarkable result given the strength of the boron−oxygen bond and stability of the poisoned catalysts. In the case of triethylsilane, no catalytic activity was initially noted; addition of a small amount of B(C6F5)3 (0.25 mol %, 0.0025 mmol) showed excellent conversion of 94% with 1b after deactivation with benzaldehyde. Interestingly, MAO failed to improve substrate conversion after addition to the poisoned catalyst, despite initial screening results. To probe the mode by which the scavenger acts to increase reactivity and regenerate the active catalyst, a number of smallscale experiments were undertaken. Stoichiometric mixtures of separately synthesized phosphonium alkoxyborate salt 5, which is the product of reaction with trace aldehyde and is known to be an inactive form of the FLP hydrogenation catalyst, and various scavengers were examined via multinuclear NMR spectroscopy. Compound 5 can be independently generated by addition of benzaldehyde to 1b.6 Subsequent addition of one equivalent of TIBAL to 5 in CD2Cl2 resulted in the immediate appearance of a doublet in the 11B NMR spectrum at −24.9 ppm. This, together with 1H, 19F and 31P NMR spectroscopic data, is consistent with the regeneration of the catalyst 1b. It is possible that the source of hydride is the β-hydrogens of TIBAL, which are known to be active for reduction of ketones and aldehydes.16 In this case, we hypothesize that the Lewis acidic TIBAL first coordinates to the oxygen of 5, forming an oxonium ion. This could then react further either intramolecularly or with another equivalent of TIBAL to form an aluminium alkoxide, isobutylene and 1b (Scheme 1). C



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Scheme 2. Proposed mechanism for regeneration of poisoned catalyst using triethylsilane and B(C6F5)3

demonstrate that scavengers are effective under conditions with significant amounts of impurities and allow for comparable if not superior performance compared to reactions performed under rigorously dry and pure conditions. While the results presented in Table 3 demonstrate the efficacy of the scavengers, they are limited to an electron-rich and sterically bulky imine, N-benzylidene-tert-butylamine, which is easily hydrogenated by the catalysts. In order for the scavengers to be used in manufacturing processes, tolerance of a range of substrates and catalysts is necessary. Thus, we expanded the number of substrates to include a range of steric and electronic properties, as well as increasing the number of catalysts in analogous reactions, as shown in Table 4.

benzaldehyde (2.5 mol %) was added. Catalyst (0.5 mol %) was added to the mixture, and the reactor was then pressurized to 100 atm H2 (no gas purifier) and heated to 80 °C for 18 h. As expected, this led to no detectable product formation. On the basis of the relative concentrations of the catalyst poisons, 10 mol % scavenger was found to be decidedly sufficient to consume all trace water and added benzaldehyde. The experiment was repeated, but the solvent, benzaldehyde, and substrate were premixed with 10 mol % scavenger before catalyst addition. Hydrogenation resulted in conversions comparable, if not superior, to those achieved under rigorously dry and pure conditions (Table 3).19 Table 3. Hydrogenation results under demanding conditionsa

catalyst

scavenger

conversion (%)

1b 2 2 2

TIBAL TIBAL Et3SiH Me2SiHCl

99 68 100 100

Table 4. Hydrogenation reactions with additional substrates and catalystsa

entry I II III IV V VI VII VIII IX X XI XII XIII XIV XV

Conditions: 80 °C, 100 atm H2, 18 h, 0.5 mol % catalyst, 2.5 mol % benzaldehyde, 10 mol % scavenger, 1 mmol N-benzylidene-tertbutylamine.

a

Chlorodimethylsilane and triethylsilane showed quantitative conversion with 2 at 0.5 mol % loading. Lower loadings were not tested, but given that no imine starting material was detected by GC-FID we anticipate loadings as low as 0.1 mol % are possible on the basis of previous results8a with ultrarigorous conditions. In this case, temperatures of 120 °C and pressures of 120 bar were needed, but less harsh conditions may be possible with the use of scavengers. A conversion of 68% was observed for catalyst 2 and TIBAL. Alkylaluminiums are known to undergo exchange reactions with B(C6F5)3 at room temperatures, leading to the formation of Al−C6F5 bonds.20 TIBAL shows very little exchange at room temperature, but it is possible that at 80 °C, the extent of exchange is increased and may lead to less catalytically active species. This could, in part, explain why lower conversions are observed with TIBAL compared to silanes for 2. On the other hand, TIBAL showed near quantitative conversion with 1b. This suggests that at higher temperatures, silanes are more appropriate scavengers for 2, while TIBAL is highly effective with 1b. In any case, the results presented in Table 3

catalyst (mol %) 1a 3 1b 2 1a 1b 1b 2 1b 1b 1b 4 4 4 4

(0.5%) (0.5%) (0.5%) (0.5%) (1%) (1%) (2.5%) (2.5%) (1%) (2.5%) (1%) (7.5%) (7.5%) (7.5%) (7.5%)

substrate

scavenger (10 mol %)

conversion (%)

PhCHNtBu PhCHNtBu PhCHNCHPh2 PhCHNCHPh2 PhCHNSO2Ph PhCHNSO2Ph PhCHNSO2Ph PhCHNSO2Ph 4-BrPhCHNPh 4-BrPhCHNPh 4-FPhCHNMes PhCHNCH2Ph PhCHNCH2Ph PhCHNCH2CH3 PhCHNCH2CH3

TIBAL TIBAL TIBAL Me2SiHCl Et3SiHb TIBAL TIBAL Me2SiHCl TIBAL TIBAL TIBAL TIBAL Me2SiHClb TIBAL Et3SiHb

61c 96c 100d 100d 49d 22d 100d 26 85d 100d 100d 100d 44d 100d 26d

a Conditions: 80 °C, 100 atm H2, 18 h, 10 mol % scavenger. b0.25 mol % B(C6F5)3 was used in addition to the scavenger and catalyst. c Measured by GC-FID. dMeasured by 1H NMR.

The electron-rich and sterically demanding imines, Nbenzylidene-tert-butylamine and N-benzylidenediphenyl ethanamine, showed excellent conversions at loadings of 0.5 mol % for catalysts 1b, 2 and 3 (entries II−IV). A lower conversion of 61% was observed for 1a with N-benzylidene-tertbutylamine and TIBAL as scavenger (entry I) compared to a quantitative conversion with 1b. The P−H proton in 1a is more acidic than in 1b, leading to faster proton transfer to the D



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substrate (the first step of hydrogenation of the imine6). However, the lower basicity also results in a slower reaction with hydrogen gas, which in this case likely lowers the rate of reaction leading to a lower conversion. In the case of electronpoor and sterically nondemanding imines such as Nbenzylidenephenylsulfonamide, 1a shows superior reactivity (entry V) compared to 1b and 2 (entries VI and VIII, respectively). The rate-determining step is proton transfer to the weakly basic imine nitrogen,6 which is significantly faster with the more acidic P−H of 1a. As a result of the slow proton transfer, even with 1a, higher catalyst loadings are needed, consistent with previous results.6 Nonetheless, reasonable conversions are observed using triethylsilane (49% conversion with 1 mol % 1a) and TIBAL (100% using 2.5 mol % 1b). The sterically bulky and electron poor imine N-(4-fluorobenzylidene)-2,4,6-trimethylaniline was also hydrogenated in quantitative conversion with 1 mol % 1b using TIBAL as a scavenger (entry XI). The four earliest incarnations of FLP hydrogenation catalysts, 1a/b, 2 and 3, allow for the hydrogenation of bulky and electron-rich substrates, as well as electron-poor substrates. Electron-rich/nonbulky imines are hydrogenated only stoichiometrically due to the strong adduct formed between the product amine and the borane catalyst, which prevents catalytic turnover.6 More recently, a linked aminoborane catalyst 48d has been shown to catalytically hydrogenate electron-rich/nonbulky imines in refluxing toluene with catalyst loadings of 8 mol %. We tested 4 with two electron-rich/nonbulky substrates with both TIBAL and silane scavengers. Catalyst 4 has significantly different electronic and steric properties from those of catalysts 1−3, with the presence of the much more reactive B−CH2 bond in 4 compared to B−C6F5 bonds present in 1−3. Quantitative conversion of both N-benzylideneethylamine and N-benzylidenebenzylamine were observed using TIBAL as a scavenger with a catalyst loading of 7.5 mol % (entries XIV and XII, respectively). Our results are consistent with conversions under ideal conditions in the original report,8d albeit with significantly lower temperatures (80 °C vs 110 °C) in the presence of a large quantity of water and aldehyde impurities. Lower conversions (25−44%) were observed when using silanes/B(C6F5)3 (entries XIII and XV). Remarkably, these results show the scavengers are compatible with a range of catalysts of varying steric and electronic character allowing for the efficient hydrogenation of a variety of substrates. Interestingly, we found catalyst 4 to show significantly lower catalytic activity with electron-rich/bulky imines such as Nbenzylidene, even under rigorously dry conditions. For instance, N-benzylidene-tert-butylamine shows virtually no conversion at room temperature with loadings of 2 mol % 4 over 2 h, and requires 6 mol % loading to give 67.6% conversion over 2 h at 100 atm H2 and 80 °C. This indicates that all of the currently identified FLP catalysts should have utility, and the type of substrate would dictate the choice of catalyst.

significant cost savings associated with this approach together with the ease of using commercial-grade solvents, substrates, and hydrogen gas without the need for the rigorous exclusion of water or impurities greatly enhances the potential for metalfree catalysts as a commercially viable option in hydrogenation catalysis.

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EXPERIMENTAL SECTION General Considerations. All synthetic manipulations were carried out under an atmosphere of dry, O2-free N2, employing a glovebox. Dry toluene was prepared by distillation from Na/ benzophenone and thoroughly degassed after purification (three freeze−pump−thaw cycles). CD2Cl2 was degassed by three freeze−pump−thaw cycles and dried over molecular sieves. Hydrogen gas was purchased from Air Liquide and was optionally passed through a drying unit (Harris model 8010) prior to use. AlphaGaz 2 purity was used for all experiments except those described in Table 3, in which AlphaGaz 1 purity gas was used. Hydrogenations were performed using a highpressure Parr Multiple Reactor System in stainless steel reactors equipped with glass reaction sleeves. 11B, 19F, and 31P NMR spectra were referenced to external standards: BF3·OEt2 (0 ppm), CFCl3 (0 ppm), and 85% H3PO4 (0 ppm), respectively. B(C6F5)3 was obtained from Boulder Scientific. Scavengers were purchased from Aldrich and used as received. The compounds (4-di-[2,4,6-trimethylphenyl]phosphonium-2,3,5,6tetrafluorophenyl)bis(pentafluorophenyl)borohydride (1a), (4di-tert-butylphosphonium-2,3,5,6-tetrafluorophenyl)bis(pentafluorophenyl)borohydride (1b), tri-tert-butylphosphonium tris(pentafluorophenyl)borohydride (3), and hydrido[bis(pentafluorophenyl)]{2-[(2,2,6,6-tetramethylpiperidinium-1-yl)methyl]phenyl}borate (4) were prepared by literature methods4,5b,e Compounds 1a and 1b are commercially available from Sigma Aldrich. The commercially available substrates N-benzylidenephenylsulfonamide (97%), N-benzylidene-N-(diphenylmethyl)amine (97%), N-benzylidenebenzylamine (99%), and N-benzylidene-ethylamine (97%) were purchased from Aldrich and used as received. The remaining imines were synthesized using standard methods via condensation of the corresponding aldehyde and amine in dichloromethane in the presence of a drying agent. Nbenzylidene-tert-butylamine was distilled once and contained 0.2% benzaldehyde as determined by 1H NMR spectroscopy. N-(4-bromobenzylidene)aniline was recrystallized (no benzaldehyde present by 1H NMR spectroscopy) and N-(4fluorobenzylidene)-2,4,6-trimethylaniline was used after drying in vacuo (3% 4-fluorobenzaldehyde present by 1H NMR). General Hydrogenation Procedure. Hydrogenation reactions were prepared inside a nitrogen-filled glovebox. In a typical experiment, the imine substrate (1 mmol) was added to a glass sleeve containing a 0.75-in Teflon-coated stirbar followed by toluene (5 mL). Dry, degassed toluene was used for experiments described in Tables 1 and 2, while degassed toluene out of the bottle was used for Tables 3 and 4. Scavenger (0.01−0.1 mmol) was then added to the solution and allowed to stand for approximately 10 min. Catalyst (0.005−0.075 mmol) was then added, and the reactors were sealed. The gas manifold on the Parr reactor system was thoroughly flushed with nitrogen gas for several minutes to purge the lines. If heated, the reactor was allowed to reach the desired temperature before being being pressurized to 100 atm H2 and sealed. The stirring rate was set to 1000 rpm. After the set time (2−18 h), the reactor was slowly depressurized in a

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CONCLUSIONS In summary, we have developed a simple and general solution to the problem of catalyst sensitivity in this new class of metalfree hydrogenation catalysts using inexpensive scavengers. The ability to employ low catalyst loadings in the presence of water and aldehyde impurities should greatly simplify the implementation of these catalysts into industrial-scale processes for hydrogenation and other potential FLP reactivity. The E



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(b) Welch, G. C.; Stephan, D. W. J. Am. Chem. Soc. 2007, 129, 1880− 1881. (c) Spies, P.; Erker, G.; Kehr, G.; Bergander, K.; Fröhlich, R.; Grimme, S.; Stephan, D. W. Chem. Commun. 2007, 47, 5072−5074. (d) Stephan, D. W.; Erker, G. Angew. Chem., Int. Ed. 2010, 49, 46−76. (e) Sumerin, S.; Schulz, F.; Atsumi, M.; Wang, C.; Nieger, M.; Leskela, M.; Repo, T.; Pyykko, P.; Rieger, B. J. Am. Chem. Soc. 2008, 130, 14117−14119. (6) Chase, P. A.; Welch, G. C.; Jurca, T.; Stephan, D. W. Angew. Chem., Int. Ed. 2007, 46, 8050−8053. (7) Chase, P. A.; Jurca, T.; Stephan, D. W. Chem. Commun. 2008, 1701−1703. (8) (a) Stephan, D. W.; Greenberg, S.; Graham, T. W.; Chase, P.; Hastie, J. J.; Geier, S. J.; Farrell, J. M.; Brown, C. C.; Heiden, Z. M.; Welch, G. C.; Ullrich, M. Inorg. Chem. 2011, 50, 12338−12348. (b) Rokob, T. A.; Hamza, A.; Stirling, A.; Soos, T.; Papai, I. Angew. Chem., Int. Ed. 2008, 47, 2435−2438. (c) Eros, G.; Mehdi, H.; Papai, I.; Rokob, T. A.; Kiraly, P.; Tarkanyi, G.; Soos, T. Angew. Chem., Int. Ed. 2010, 49, 6559−6563. (d) Sumerin, V.; Chernichenko, K.; Nieger, M.; Leskelä, M.; Rieger, B.; Repo, T. Adv. Synth. Catal. 2011, 353, 2093−2110. (e) Wang, H.; Fröhlich, R.; Kehr, G.; Erker, G. Chem. Commun. 2008, 45, 5966−5968. (9) Chase, P. A. Unpublished results. (10) Stephan, D. W. Org. Biomol. Chem. 2012, 10, 5740−5746. (11) Pedeutour, J. N.; Radhakrishnan, K.; Cramial, H.; Deffieux, A. Macromol. Rapid Commun. 2001, 22, 1095−1123. (12) (a) Blackwell, J. M.; Foster, K. L.; Beck, V. H.; Piers, W. E. J. Org. Chem. 1999, 64, 4887−4892. (b) Blackwell, J. M.; Sonmor, E. R.; Scoccitti, T.; Piers, W. E. Org. Lett. 2000, 2, 3921−3923. (c) Parks, D. J.; Blackwell, J. M.; Piers, W. E. J. Org. Chem. 2000, 65, 3090−3098. (d) Parks, D. J.; Piers, W. E. J. Am. Chem. Soc. 1996, 118, 9440−9441. (13) These conditions were modeled after those reported in ref 7, and conversions are comparable to those observed. (14) Aldrich research scale pricing as of March 14, 2013. http:// www.sigmaaldrich.com/. Catalogue numbers for 1a and 1b are 703095 and 703087, respectively. (15) Reaction of benzaldehyde with a variety of boron-based H2activated FLPs are known to give alkoxyborate complexes. These have been found to be inactive as catalysts. See refs 5c and 6. (16) (a) Diisobutylaluminium hydride (DIBAL-H) and Other Isobutyl Aluminium Alkyls (DIBAL-BOT, TIBAL) as Specialty Organic Synthesis Reagents, Azko-Nobel Technical Bulletin, OMS 06.388.03/April 2013. (b) Ashby, E. C.; Yu, S. H. J. Org. Chem. 1970, 35, 1034−1040. (17) Neu, R. C.; Otten, E.; Lough, A.; Stephan, D. W. Chem. Sci. 2011, 2, 170−176. (18) Park, S.; Brookhart, M. Organometallics 2010, 29, 6057−6064. (19) Near quantitative conversion to the product amine is achieved at 0.5 mol % catalyst loading, 120 atm H2, and 100 °C under dry conditions. See ref 8a. (20) Janiak, C.; Lassahn, P.-G. Macromol. Symp. 2006, 236, 54−62.

fumehood. An aliquot was taken and the solvent removed under reduced pressure. The resulting product was dissolved in CDCl3 and a crude NMR spectrum acquired. For Nbenzylidene-tert-butylamine samples, the reaction mixture was filtered through a 0.45 μm PTFE syringe filter, and 100 μL of filtered reaction solution was combined with 6.8 μL of decane (internal standard) and diluted to a total volume of 1 mL with toluene. This sample was analyzed using GC-FID. Catalyst Poisoning and Regeneration. Hydrogenation Representative Procedure. The hydrogenation procedure detailed above was followed, except that benzaldeyhde (2.5 μL, 0.025 mmol) was added to the imine solution prior to catalyst addition. After 2 h under 100 atm of H2, the reactor was brought back into the glovebox and a small aliquot removed for GC analysis. Scavenger (0.05 mmol) was then added to the solution and the reactor resealed and pressurized to 100 atm H2 for 2 h before standard workup and GC analysis. When triethylsilane was employed as scavenger, B(C6F5)3 (1.28 mg, 0.0025 mmol) was introduced after the addition of triethylsilane. NMR Experiments Representative Procedure. To a small vial was added 1b (25 mg, 0.039 mmol) in 0.8 mL of CD2Cl2 inside a nitrogen-filled glovebox. To this solution was added benzaldehyde (4.8 μL, 0.047 mmol). The solution was then added to a J. Young NMR tube, and the NMR spectra were acquired. When complete reduction of benzaldehyde was observed, triisobutylaluminium solution (25 wt % in toluene, 47 μL, 0.051 mmol) was then added, and the NMR spectra were acquired.

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ASSOCIATED CONTENT

S Supporting Information *

Characterization data for regeneration of poisoned catalysts and product amines. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank NSERC of Canada for funding this work through an Ideas to Innovationg Grant. REFERENCES

(1) Vries, J. G. d.; Elsevier, C. J. The Handbook of Homogeneous Hydrogenation; Wiley-VCH: Weinheim, Germany, 2007. (2) (a) Brown, H. C.; Ramachandran, P. V. Sixty Years of Hydride Reductions. In Reductions in Organic Synthesis; Abdel-Magid, A. F., Ed.; ACS Symposium Series; American Chemical Society: Washington, DC, 1996; Chapter 1, pp 1−30. (b) Crabtree, R. H. The Organometallic Chemistry of the Transition Metals, 2nd ed.; John Wiley & Sons: New York, 1994. (c) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138−5175. (3) (a) United States Pharmacopeia, 2010 standards. Pd, Pt, Ir, Rh cannot exceed 100 μg/day for a 50 kg person. Boron limit is 10,000 μg/day. The United States Pharmacopeia; United States Pharmacopeial Convention; Rockville, MD, 2010. (4) Welch, G. C.; San Juan, R. R.; Masuda, J. D.; Stephan, D. W. Science 2006, 314, 1124−1126. (5) (a) Welch, G. C.; Cabrera, L.; Chase, P. A.; Hollink, E.; Masuda, J. D.; Wei, P.; Stephan, D. W. Dalton Trans. 2007, 31, 3407−3414. F


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