Communication pubs.acs.org/OPRD
Continuous Reductions and Reductive Aminations Using Solid NaBH4 Kerry Gilmore,† Stella Vukelić,‡ D. Tyler McQuade,†,§ Beate Koksch,‡ and Peter H. Seeberger*,†,‡ †
Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustraβe 3, 14195 Berlin, Germany § Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306 United States ‡
S Supporting Information *
using THF as solvent. Leaching and precipitation of unidentified solids caused fluctuations in both pressure and conversion. While the introduction of SiO2 plugs terminating the column eliminated the formation of visible solid material in the exit stream, benzaldehyde reductions still resulted in incomplete conversion. Significant accelerations of polymer-supported borohydride reductions using substoichiometric amounts of LiCl in both ethanol16 and methanol17 have been reported. Thus, we worked on the assumption that the addition of solid LiCl to the NaBH4 column and use of an alcoholic cosolvent would be effective. Conversion was measured as a function of cosolvent (MeOH) with 0.7 equiv of LiCl17a added to the column mixture. The reduction to benzyl alcohol is dependent on methanol concentration, and a maximum conversion is achieved using 9−9.5 equiv MeOH with respect to benzaldehyde (Figure 1).18 Methanol likely acts to break down ROBH3Li(Na) intermediates.19
ABSTRACT: Most successful reactions carried out under continuous flow conditions mix homogeneous solutions yielding homogeneous products. Using solids is avoided to prevent pump and reactor clogging; even though solid reagents may often be the best choice for a given transformation. Here we demonstrate that by pumping aldehydes, ketones, or in situ formed imines through a specially formulated NaBH4 column results in efficient reductions. The column design and performance characteristics, along with substrate scope, are discussed. ontinuous flow reactors, both on micro- and mesoscales, offer significant advantages relative to batch reactors including increased solution−solid phase interactions as well as the facility of sequential reactions.1 Supported catalysts exhibit higher reaction rates since each mole of reactant contacts an increased number of catalytic sites when compared to batch conditions.2 However, the use of solid reagents in flow remains challenging, and solids are often avoided as particles clog both pumps and reactors.3 Clogging can be partially avoided by using sonication to continually resuspend and disperse particles.4 Alternatively, solids can also be leached into solution from packed-beds5 to generate homogeneous catalysts, as has been demonstrated for the organocatalyst proline6,7 or for the formation of Cu(I)−NHC complexes.8 Carbonyl reductions are a ubiquitous transformation in organic synthesis.9 However, in continuous flow, only soluble reductants such as DIBAL10 and Superhydride11 or supported borohydride species are being used to date.12−14 While these approaches are effective, soluble and resin-supported hydride sources are significantly more expensive than sodium borohydride (NaBH4). We hypothesized that reactive solids such as NaBH4 could be effectively used in flow if the reagent was packed in an appropriately designed column. Herein, we demonstrate that a specific composition of NaBH4, lithium chloride (LiCl), and Celite yield a packed-bed that not only reduces aldehydes and ketones but also facilitates reductive aminations.
C
Figure 1. Effect of methanol (equivalents with respect to starting material) on the reduction of benzaldehyde (BnAl) to benzyl alcohol (BnOH). The column was prepared using (1:1:0.76 w/w) Celite− NaBH4−LiCl (see Experimental Section). The concentration of benzaldehyde was 0.66 M (THF) with 0−12 equiv of MeOH added, run at 0.5 mL/min (Tres = 5.6 min).20
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RESULTS AND DISCUSSION Efficient noncontinuous reductions of micromolar amounts of aldehydes or ketone were observed as early as 1975 when passed over a pipet packed with Celite and NaBH4.15 In our hands, a column packed with a 1:1 (w/w) mixture of Celite and NaBH4 gave inconsistent reductions of benzaldehyde in flow © XXXX American Chemical Society
Received: September 30, 2014
A
dx.doi.org/10.1021/op500310s | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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Next, we examined product formation as a function of flow rate, with full conversion observed over 0.5−7 mL/min, the latter corresponding to a productivity of 2.93 mmol/min (19 g/ h).21 Reactions at higher flow rates were limited due to high back pressure (>25 bar). The stoichiometry of the reaction was determined as a function of benzaldehyde throughput (Figure 2). The yield of benzyl alcohol drops rapidly once one
Cinnamaldehyde also exhibited high yields and was chemoselective towards the carbonyl (entry 3). Hexanal provided good yields with quantitative conversion (entry 4).23 Ketones were also reduced in good yields (entry 5−7). While this substrate scope is not exhaustive, it suggests that that the approach is general for aldehydes and ketones. Although NaBH4 has been used for the selective reduction of aldehydes and ketones for 60 years, this is the first example of solid NaBH4 being used in a flow reactor. Flow chemistry allows for multiple synthetic transformations to be performed in series, an advantage for reductive aminations. Traditionally, reductive aminations have been performed using NaCNBH3,24 a toxic reagent that produces stoichiometric amounts of cyanide byproduct.25 While NaBH4 has been used to produce amines,25a,26 to the best of our knowledge no reductive aminations where amine, carbonyl, and NaBH4 are simply mixed to yield amines have been reported. Initial tests using the optimized conditions (Table 1) with benzaldehyde and propylamine resulted in mixtures of the reductive amination product as well as benzyl alcohol. However, a slight excess (1.5 equiv) of amine resulted in the clean and selective reductive amination product in good yields (Table 2). More significantly, we were able to selectively Table 2. In-flow reductive aminationa
Figure 2. Stoichiometric reduction of benzaldehyde is observed under optimized conditions. Two equivalents benzaldehyde were passed through the column with aliquots removed to determine conversion to benzyl alcohol (BnOH) by 1H NMR. Column prepared using (1/1/ 0.76 w/w) Celite/NaBH4/LiCl (see Experimental Section). The concentration of benzaldehyde was 0.66 M (THF) with 9.5 equiv of MeOH added, run at 0.5 mL/min (Tres = 5.6 min).20
entry 1 2 3 4 5 6 7
equivalent of benzaldehyde is passed through the column, indicating that only one of the four boron−hydrogen bonds is capable of performing the reduction. This observation further supports our model that methanol rapidly decomposes the ROBH3Li(Na) intermediate. Using the optimized conditions, a variety of aldehydes and ketones were examined. All substrates were successfully reduced in good-to-excellent yields (Table 1).22 As expected, aryl-aldehydes were reduced quantitatively (entries 1 and 2).
1 2 3 4 5 6 7
R1 C6H5 4-CNC6H4 (E)-C6H5CHCH CH3(CH2)4 Ph CH(Ph)2 −CH2(CH2)3CH2−
R2
yield
H H H H Ph CH3
97% 99% 94% 74% 83% 74% 89%
R2
C6H5
H −(CH2)5− −(CH2)5−
C6H5
H −(CH2)5− 4-CNC6H4 H C6H5 C6H5
R3
yield
nPr CH2C6H5 CH2CCH Meb Meb Meb Meb
80% 86% 65% 64% 37% 45% 0%c
a
Column prepared using (1:1:0.76 w/w) Celite/NaBH4/LiCl (see Experimental Section). The concentration of aldehyde/ketone was 1.2 M (THF) with 9.5 equiv of MeOH distributed between SM and amine (1.5 equiv) to make equal volume solutions. Both reagents were run at 0.2 mL/min (Tres = 7 min).20 bMeNH2 (2.0 M THF; 2.2 equiv). c Quantitative formation of benzhydrol was observed.
Table 1. In-flow reduction of aldehydes and ketones to the respective alcoholsa
entry
R1
produce monomethylated secondary amines using 2.2 equiv of methylamine from both aldehydes and ketones. The reaction fails, however, for the use of conjugated carbonyls, for example benzophenone, where quantitative reduction to benzhydrol was observed (Table 2, entry 7).
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CONCLUSION Continuous chemistry is no longer limited to the use of expensive soluble hydride sources or supported reagents whose syntheses are time-consuming. We have developed a facile, gram-scale method for the reduction of aldehydes and ketones in flow using a NaBH4/Celite/LiCl column. By taking advantage of these additives and cosolvents, the reductions were accelerated and column stabilized. The column leaches the active borohydride and is stoichiometric with respect to the reductant. Reductive aminations could also be performed on in situ generated imines, yielding both benzylated and monoalkylated, including methylated, amines selectively. Further
a
The column was prepared using (1:1:0.76 w/w) Celite/NaBH4/LiCl (see Experimental Section). The concentration of aldehyde/ketone was 0.66 M (THF) with 9.5 equiv of MeOH added, run at 0.5 mL/ min (Tres = 5.6 min).20 B
dx.doi.org/10.1021/op500310s | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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flow rate of 0.5 mL/min. The entirety of the output was collected (including one column volume of pure solvent following the reaction to ensure full elution of product), washed with distilled water (20 mL), and washed three times with dichloromethane (15 mL × 3). The combined organic phase was dried over Na2SO4, filtered, and dried using rotary evaporation. General Procedure for Reductive Aminations. Benzaldehyde (0.4 mL, 3.9 mmol) and propan-1-amine (0.48 mL, 5.9 mmol) were dissolved in 3.3 mL of THF (1.2 M), each in separate vials. A sample of 1.5 mL of methanol (37.2 mmol) was divided between the two vials to create equal volumes. After flushing the column with THF, the two reagents were combined, using the Vapourtec software, each at a flow rate of 0.2 mL/min. The entirety of the output was collected (including one column volume of pure solvent following the reaction to ensure full elution of product), washed with distilled water (20 mL), and washed three times with dichloromethane (15 mL × 3). The combined organic phase was dried over Na2SO4, filtered, and dried using rotary evaporation. Safety Concerns. The integrity of the OmniFit end-caps were compromised at high pressure (>20 bar), which led to rapid release of pressure and column packing material. As a result, slow flow rates were utilized in the majority of the study. Upon completion of the reaction, the residual column material was emptied into a beaker, and residual active material was quenched with methanol. Following quenching, the solid material was filtered and can be disposed of as solid waste. Data. Phenylmethanol. Phenylmethanol was prepared according to general procedure for aldehyde/ketone reduction with benzaldehyde (1.66 g) dissolved in a mixture of MeOH (5.71 mL) and THF (23.76 mL). After drying, benzyl alcohol (1.65 g) was obtained as a clear, colorless oil (97%). 1H NMR: 7.38−7.29 (m, 5H), 4.67 (s, 2H), 2.1 (s, 1H). Matches literature data: Dieskau, A. P.; Begouin, J.-M.; Plietker, B. Eur. J. Org. Chem. 2011, 27, 5291−5296.
work in this area, including increasing the scale and throughput of the column, is currently underway.
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EXPERIMENTAL SECTION General. All chemicals were reagent grade and used as obtained from commercial suppliers. Critically, the NaBH4 was purchased from Merck (fine granular for synthesis). NaBH4 purchased from Sigma-Aldrich, either the Pulvar or granular 10−40 mesh, did not yield satisfactory results. THF and methanol were distilled using a dry solvent system by JC Meyer Solvent Systems. HPLC grade hexane and ethyl acetate were used for purification as obtained. Compounds were purified using a BioTag Flash Chromatography system. 1H NMR spectra were recorded on a Varian 400-MR spectrometer (at 400 MHz) at ambient temperature. The proton signal of residual nondeuterated solvent (δ 7.26 ppm for CHCl3) was used as an internal reference for 1H spectra. Data are reported as follows: chemical shift in parts per million (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, m = multiplet, and br = broad), coupling constant reported in Hertz (Hz), and integration. Analytical thin layer chromatography (TLC) was performed on Kieselgel 60 F254 glass plates precoated with a 0.25 mm thickness of silica gel. The TLC plates were visualized with UV light and by staining with an aqueous solution of potassium permanganate (KMnO4). Column chromatography was performed using Kieselgel 60 (230−400 mesh) silica gel with a typical 50− 100:1 weight ratio of silica gel to crude product. Column Construction. Portions of 650 mg of Celite, 650 mg of NaBH4, and 520 mg of LiCl were ground together in a mortar and pestle. After inserting the end-cap (with either 10− 40 μm filter) into a 6.6 mm Omni-Fit column, 150 mg of silica gel was added, followed by the ground Celite/NaBH4/LiCl mixture, packed by tapping on the benchtop. A sample of 150 mg of silica gel was then added to the top of the mixture and the column sealed with an end-cap. The column was further packed by flowing THF through the column at 2.5 mL/min for 5 min or until no air bubbles were observed. The column volume, averaging 2.8 mL, was determined via the difference between the dry and wet weights divided by the density of the solvent (THF). Flow Set-up. A Vapourtec R2+/R4 flow system (commercially available, http://www.vapourtec.co.uk) was used to perform the transformations. For aldehyde/ketone reductions, a 50 cm fluorinated ethylene−propylene copolymer (FEP) tube (IDEX Health and Science, natural color, 1.57 mm outer diameter, 0.76 mm inner diameter tube) was connected to the instrument as well as to the top of the column. Solvent flowed down the column to avoid the formation of gas pockets developing in the middle of the column during the reaction. A 50 cm FEP tube connected the outflow of the column to an 8 bar back-pressure regulator (BPR). A subsequent 50 cm FEP tube connected the BPR back to the collection flask. For reductive aminations, the two reagent streams were connected to a T-mixer via 6 cm FEP tubing from the instrument and a 50 cm FEP tube connected the T-mixer to the column, which was treated in the same way as the aldehyde/ketone reductions described above. General Procedure for Aldehyde/Ketone Reductions. Benzaldehyde (1.6 mL, 15.7 mmol) was dissolved in 23.8 mL of THF (0.66 M) and 5.7 mL of methanol (141 mmol) was added. After flushing the column with THF, the solution was pushed through the column using the Vapourtec software at a
4-(Hydroxymethyl)benzonitrile. 4-(Hydroxymethyl)benzonitrile was prepared according to general procedure for aldehyde/ketone reduction with p-cyanobenzaldehyde (1.23 g) dissolved in a mixture of MeOH (1.9 mL) and THF (14.2 mL). After drying, pure p-cyanobenzyl alcohol (1.24 g) was obtained as a white solid (99%). 1H NMR: 7.65 (d, J = 8 Hz, 2H), 7.49 (d, J = 8 Hz, 2H), 4.79 (s, 2H), 1.9 (s, 1H). Matches literature data: Dieskau, A. P.; Begouin, J.-M.; Plietker, B. Eur. J. Org. Chem. 2011, 27, 5291−5296.
(E)-3-Phenylprop-2-en-1-ol. (E)-3-Phenylprop-2-en-1-ol was prepared according to general procedure for aldehyde/ ketone reduction with cinnamaldehyde (1.507 g) dissolved in a mixture of MeOH (2.31 mL) and THF (15.07 mL). After drying, pure 3-phenyl-2-propenol (1.529 g) was obtained as a colorless oil (94%). 1H NMR: 7.39 (m, 2H), 7.31 (m, 2H), 7.24 (m, 1H), 6.61 (dt, J = 16, 4 Hz, 1H), 6.35 (dt, J = 16, 4 Hz), 4.31 (td, J = 4,
