Tetrahedron Letters 44 (2003) 4957–4960
Polymer-supported triacetoxyborohydride: a novel reagent of choice for reductive amination
>Sukanta Bhattacharyya,* Sunil Rana, Owen W. Gooding and Jeff Labadie
Argonaut Technologies, 1101 Chess Drive, Foster City, CA 94404, USA
Received 19 April 2003; accepted 12 May 2003
Abstract—A novel polymer-supported triacetoxyborohydride reagent for reductive amination of aldehydes and ketones is reported. The bound reagent was found to be shelf-stable and provided broad scope and reactivity in reductive amination reactions under mild reaction conditions. Streamlined protocols for its application in reductive amination reactions using both primary and secondary amines are described. 2003 Elsevier Science Ltd. All rights reserved.
The use of polymer-supported reagents and scavengers1 is a powerful tool for integrated organic synthesis and purication. By using bound reagents and scavengers the reaction by-products and excess starting materials can be selectively removed from the crude reaction mixture by simple ltration of resin. Immobilized reagents on polymer supports are particularly useful in high throughput parallel synthesis due to their wellknown attributes for dispensing and removal from reaction mixtures. Moreover, polymer-supported reagents can provide unique advantages relative to their soluble counterparts including selectivity, isolable reactive intermediates and the ability to simultaneously use incompatible reagents, or perform multiple transformations in a single ask. In addition, they are adaptable to automated parallel synthesis and continuous ow reactors.2 Amines and their carboxamide derivatives comprise the most abundant structural moieties present in the comprehensive medicinal chemistry database.3 The reductive amination of carbonyl compounds provides an expedient access to structurally diverse amines and has wide applications in synthetic organic chemistry.4,5 The sequence proceeds through the formation of an imine or iminium intermediate upon reaction of a carbonyl compound with ammonia, primary amine or secondary amine followed by in situ reduction to an amine of higher order. A variety of borohydride-based reducing systems5 have been developed for this transformation. Among these, sodium triacetoxyborohydride has
emerged as one of the most commonly employed reagents.6 This reagent has gained preference relative to other reducing agents due to mild reaction conditions that are compatible with a variety of functional groups, and a broad scope of reactivity. However, sodium triacetoxyborohydride is moisture-sensitive and has poor solubility in most of the commonly used organic solvents. The reagent is therefore dispensed as a solid or slurry, thereby limiting its use in automated platforms. Following a reaction, product isolation requires an aqueous quench followed by liquid–liquid extraction and column chromatography further limiting the throughput in parallel synthesis. In the context of our program on the development of polymer-supported reagents and scavengers for expedited organic synthesis, we envisioned a polymer-bound triacetoxyborohydride. Polymer-bound borohydride and cyanoborohydride reagents are known in the literature,7 however, triacetoxyborohydride reagent on polymer support is unknown. Nonetheless, the scope and reactivity of bound borohydride and cyanoborohydride reagents in reductive amination reactions are limited in comparison to sodium triacetoxyborohydride. For example, bound cyanoborohydride requires moderately strong acidic reaction conditions7,8 that are incompatible with acid-labile functional groups. The use of polymer-bound borohydride in reductive amination reactions is restricted as it lacks chemoselectivity. The reagent readily reduces carbonyl compounds along with imines and, therefore, is only suitable for reactions with preformed imines.9 We describe here the rst synthesis of an immobilized triacetoxyborohydride reagent10 and demonstrate that it is a powerful reducing system for reductive amination reactions. The bound reagent
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0040-4039/03/$ - see front matter 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0040-4039(03)01167-5
S. Bhattacharyya et al. / Tetrahedron Letters 44 (2003) 4957–4960
offers broad scope and reactivity under mild reaction conditions, combined with the well-known attributes of a polymer-supported reagent for handling and purication. Polymer-bound borohydride and cyanoborohydride resins have been prepared7 by straightforward anion exchange reactions on quaternary ammonium chloride resins using aqueous solutions of the corresponding borohydrides. However, attempts to immobilize triacetoxyborohydride by anion exchange reaction on resin bound tetraalkylammonium chloride failed, as sodium triacetoxyborohydride is sparingly soluble in, or incompatible with, solvents used for ion exchange. In an alternative approach, the polymer-bound triacetoxyborohydride reagent was conveniently synthesized in one-step from MP-Borohydride11 (Scheme 1). Treatment of MP-Borohydride (capacity, 3 mmol/g) with 3 equiv. of glacial acetic acid in anhydrous THF afforded the supported triacetoxyborohydride in nearly quantitative yield, as revealed by the mass increase of the isolated resin. The active hydride content of the resulting resin was determined by measuring the volume of hydrogen gas evolved upon treatment of a resin sample with aqueous hydrochloric acid. The capacity was found to be 2.0 mmol/g or 99% of the theoretical value, indicating quantitative formation of the triacetoxyborohydride. The isolated resin typically contained about 10% (w/w) THF as calculated from the 1H NMR spectrum of a CDCl3 extract. In the process of synthesis and isolation of the triacetoxyborohydride resin, we discovered that the residual THF was critical to retain the activity of the resin. When all THF was removed by vacuum drying at the end of the synthesis, as normally done in resin isolation, the dried resins showed little or no activity within a few days. This is an unusual nding since a similar effect with sodium or tetraalkylammonium triacetoxyborohydride is unknown. The THF imbibed reducing polymer remained stable towards storage without any loss of activity and behaved like free-owing dry beads in their handling rather than like a wet solid. This novel reducing system, further referred to as MP-Triacetoxyborohydride, proved to be a highly effective reagent for reductive amination reactions. The scope and reactivity of MP-Triacetoxyborohydride have been evaluated for the synthesis of secondary and tertiary amines (Table 1). Typical conditions for reductive amination required 2.5 equiv. of MP-Triacetoxyborohydride relative to the limiting reagent. The reactions proceeded overnight at room temperature in tetrahydrofuran (THF) and unlike the case of sodium
triacetoxyborohydride, no acetic acid was required (Scheme 2). THF was found to be preferred to dichloroethane (DCE) due to the incompatibility of reactive amines with chlorinated solvents. Polar aprotic solvents, e.g. N,N-dimethylformamide (DMF) or Nmethylpyrrolidinone (NMP), were effective solvents for substrates with low solubility in THF. For synthesis of secondary amines, the starting primary amine was used in 20% excess in order to control selectivity toward monoalkylation. After the reaction was complete a bound aldehyde, PS-Benzaldehyde,12 was added to the reaction mixture to selectively scavenge the excess primary amine. Products were then isolated in pure form by simple ltration and evaporation of solvent. The results are summarized in Table 1. The product amines were characterized by GC and NMR analysis.13 Acid sensitive functional groups were tolerated, as exemplied by successful reductive amination of 1,4-cyclohexanedione mono-ethylene ketal (entries 2, 3 and 8, Table 1). Acetophenone underwent reductive amination consistent with sodium triacetoxyborohydride (entry 4, Table 1). Reductive amination using secondary amines was carried out with carbonyl compounds as the limiting reagent.14 Upon completion of the reaction a bound isocyanate, PS-Isocyanate,12 was added to the reaction mixture to selectively scavenge excess secondary amine. Cyclic and acyclic secondary amines were effective substrates (entries 8–10, Table 1). These reactions may also be carried out with the secondary amine as the limiting reagent to drive the reaction to completion. In these cases, the product amines were puried from non-basic impurities by ‘catch and release’ using a polymer-bound sulfonic acid, MP-TsOH.12 Reductive amination using hydrochloride salts of amino esters was carried out using DMF in the presence of 3.5 equiv. of MP-Triacetoxyborohydride with amine as the limiting reagent (entries 5–7, Table 1).15 The additional equivalent of resin was used to neutralize the HCl present in the form of amine hydrochloride. Notably, overalkylation was not observed even in the presence of excess carbonyl compound. DMF and NMP were equally effective. Since carbonyl compounds were used in excess, the products were puried by ‘catch and release’ using MP-TsOH.12 This method effected convenient DMF separation from the product by elution with MeOH prior to product release with ammonia/methanol.
Scheme 1. Synthesis of MP-Triacetoxyborohydride.
Scheme 2. Reductive amination using primary and secondary amines. Reagents: (a) MP-BH(OAc)3, 2.5 equiv., THF; (b) PS-Benzaldehyde (R2=H) or PS-NCO (R2=alkyl) or MPTsOH.
S. Bhattacharyya et al. / Tetrahedron Letters 44 (2003) 4957–4960
Table 1. Examples of reductive amination reactions using MP-Triacetoxyborohydride
In summary, we have described the rst synthesis of polymer-bound triacetoxyborohydride. The novel reagent system was isolated with a high capacity of 2 mmol/g and found to be shelf-stable in the presence of residual THF. MP-Triacetoxyborohydride displayed
wide scope in reductive amination chemistry along with the benets of integrated synthesis and purication associated with immobilized reagents. Further studies expanding the scope of this reagent are underway and will be reported shortly.
S. Bhattacharyya et al. / Tetrahedron Letters 44 (2003) 4957–4960
1. For a few important reviews, see: (a) Kaldor, S. W.; Siegel, M. G. Curr. Opin. Chem. Biol. 1997, 1, 101; (b) Flynn, D. L.; Devraj, R. V.; Naing, W.; Parlow, J. J. Med. Chem. Res. 1998, 8, 219; (c) Shuttleworth, S. J.; Allin, S. M.; Wilson, R. D.; Nasturica, D. Synthesis 2000, 1035; (d) Bhattacharyya, S. Comb. Chem. High Throughput Screening 2000, 3, 65; (e) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1 2000, 3815; (f) Kirschning, A.; Monenschein, H.; Wittenberg, R. Angew Chem., Int. Ed. 2001, 40, 650. 2. Taylor, R. T. In Polymer Reagents and Catalysts; Ford, W. T.; Ed.; ACS Symposium Series 308; American Chemical Society: Washington, DC, 1986; pp. 132–154. 3. (a) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. J. Comb. Chem. 1999, 1, 55; (b) Henkel, T.; Brunne, R. M.; Mueller, H.; Reichel, F. Angew. Chem., Int. Ed. Engl. 1999, 38, 643. 4. Reductive amination reactions have been extensively reviewed, see for example: (a) Emerson, W. S. Org. React.; Wiley, 1948; Vol. 4, p. 174; (b) Lane, C. F. Synthesis 1975, 135; (c) Hutchins, R. O.; Hutchins, M. K. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 8, pp. 25–78; (d) Tarasevich, V. A.; Kozlov, N. G. Russ. Chem. Rev. 1999, 68, 55. 5. Baxter, E. W.; Reitz, A. B. Org. React.; Wiley, 2002; Vol. 59, p. 1 and references cited therein. 6. (a) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. S. J. Org. Chem. 1996, 61, 3849; (b) Abdel-Magid, A. F. In Reductions in Organic Synthesis; Abdel-Magid, A. F., Ed.; ACS Symposium Series; American Chemical Society: Washington, DC, 1996; pp. 201–216; (c) Gribble, G. W. Chem. Soc. Rev. 1998, 27, 395; (d) Gribble, G. W. In Handbook of Reagents for Organic Synthesis: Oxidizing and Reducing Agents; Burke, S. D.; Danheiser, R. L., Eds.; Wiley: NY, 1999; pp. 429–432. 7. (a) Gibson, H. W.; Bailey, F. C. J. Chem. Soc., Chem. Commun. 1977, 815; (b) Hutchins, R. O.; Natale, N. R.; Taffer, I. M. J. Chem. Soc., Chem. Commun. 1978, 1088. 8. (a) Ley, S. V.; Bolli, M. H.; Hinzen, B.; Gervois, A. G.; Hall, B. J. J. Chem. Soc., Perkin Trans. 1 1998, 2239; (b) Habermann, J.; Ley, S. V.; Scott, J. S. J. Chem. Soc., Perkin Trans. 1 1998, 3127. 9. (a) Yoon, N. M.; Park, K. B.; Gyoung, Y. S. Tetrahedron Lett. 1983, 24, 5367; (b) Sande, A. R.; Jagdale, M. H.; Mane, R. B.; Salunkhe, M. M. Tetrahedron Lett. 1984, 25, 3501. 10. A preliminary account of this work was presented in part: Labadie, J.; Rana, S.; Lindberg, T.; Gooding, O. W.; Bhattacharyya, S. Abstracts of Papers, 222nd National 11.
Meeting of the American Chemical Society, Chicago, IL; American Chemical Society: Washington, DC, 2001; ORGN 517. MP-Borohydride, a macroporous triethylammonium methylpolystyrene borohydride, is commercially available from Argonaut Technologies. The polymer-bound reagents PS-Benzaldehyde, PS-Isocyanate and MP-TsOH were obtained from Argonaut Technologies. Reductive amination using primary amine (entry 2, Table 1): A THF solution of N-(3-aminopropyl)morpholine (1.2 mL, 0.6 mmol, 0.5 M) was added to a THF solution of 1,4-cyclohexanedione mono-ethylene ketal (1 mL, 0.5 mmol, 0.5 M). MP-Triacetoxyborohydride (2 mmol/g, 0.625 g, 1.25 mmol) was then added and the mixture was agitated for 16 h at room temperature. After which PS-Benzaldehyde12 (0.42 g, 0.5 mmol) and THF (3 mL) were added and the mixture was further agitated for a period of 6 h. The solution was ltered and the resin was washed with THF. The combined solution was concentrated to afford the product secondary amine as the acetate salt in 77% yield and 100% purity, as characterized by gas chromatography and 1H NMR (300 MHz, CDCl3). Reductive amination using secondary amines (entry 8, Table 1): A THF solution of N-methylpiperazine (1.2 mL, 0.6 mmol, 0.5 M) was added to a THF solution of 1,4-cyclohexanedione mono-ethylene ketal (1 mL, 0.5 mmol, 0.5 M). MP-Triacetoxyborohydride (2 mmol/g, 0.625 g, 1.25 mmol) was then added and the mixture was agitated for 16 h at room temperature. After which PS-Isocyanate12 (0.4 g, 0.5 mmol) and THF (2 mL) were added and the mixture was further agitated for a period of 6 h. The solution was ltered and the resin was washed with THF. The combined solution was concentrated to afford the tertiary amine product in 85% yield and 100% purity, as identied by 1H NMR (300 MHz, CDCl3) and GC analysis. Reductive amination of amine hydrochloride (entry 7, Table 1): A DMF solution of HCl-Tyr(OBn)-OMe (2 mL, 0.5 mmol, 0.25 M) was added to a DMF solution of cyclohexylcarboxaldehyde (1.2 mL, 0.6 mmol, 0.5 M). MP-Triacetoxyborohydride (2 mmol/g, 0.875 g, 1.75 mmol) was then added and the mixture was agitated for 16 h at room temperature. The resin was ltered and washed with DMF. The combined ltrate was agitated with MP-TsOH12 (1 g, 1.5 mmol) for 45 min. The MPTsOH resin was ltered and washed with MeOH (4×8 mL) to remove non-basic impurities. The amine product was released from MP-TsOH by washing with 2 M NH3/MeOH, and MeOH (2×8 mL). The combined solution was concentrated to afford the secondary amine product in 74% yield and 98% purity. The secondary amine was characterized by GC and 1H NMR (300 MHz, CDCl3).