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(1)Venpure® NaBH4 for Reductive Aminations Enhancing Borohydride’s Reductive Selectivity. Introduction: Sodium borohydride is a water soluble reducing agent exhibiting unique properties in organic synthesis. It is established as the benchmark reducing agent for aldehydes, ketones, acid chlorides and anhydrides. Over the past 40 years, significant progress has been made to fine-tune borohydride’s chemoselectivity to make it either more selective, or a stronger reductant. Hence, NaBH4 can be tuned to reduce acid, ester, halide, amide, lacton and lactam functions. Some of these reductions occur by virtue of the in-situ generation of boranes from NaBH4. Especially in the last 20 years, sodium borohydride has become established as the reductant of choice in the large-scale synthesis of active ingredient in applications beyond aldehyde/ketone reductions. Also its use as a reductant with good diastereo-selectivity has become more and more established, e.g. in the ketone reduction of the Statins (Atorvastatin, Fluvastatin). This data sheet focuses on enhancing borohydride’s reductive selectivity so that it may accomplish reductive aminations in one pot.. The following systems are discussed: 1. 2. 3.. Neat borohydride ester reductions Sodium triacetoxyborohydride Sodium borohydride with carboxylic acid. For reasons of confidentiality, public information only is discussed. Reaction schemes are often amenable to optimization for a higher-efficiency use of NaBH4. For information regarding reductions other than reductive aminations, please do not hesitate to contact Rohm and Haas.. Typical Properties Mol. weight: 37.85 Form: White crystalline solid Melting point: Decomposes above 400oC without melting A comprehensive overview of the physical and chemical properties of sodium borohydride can be found in Rohm and Haas Company’s Sodium Borohydride Digest.. Benefits of NaBH4 for Reductive Chemistry: Of the commercially available metal hydrides used for synthetic organic reductions, NaBH4 enjoys the largest industrial use, with an estimated (equivalent) market share greater than 50%. Some of the benefits of using borohydride chemistry: • • • • • •. the least expensive metal hydride commercially available (on a hydride equivalent basis) safe with regards to storage and use & handling industrial implementation requires no or limited equipment investment ease of work-up (water soluble boron salts) ubiquitous solvents such as water and methanol are typically employed unique and versatile as a hydride reducing agent for both chemo- and diastereo-selectivity. Product Stewardship Rohm and Haas offers metal hydride products as part of a comprehensive Product & Services package, including: • the highest product quality • the broadest range of product grades • formulations stable under various transport conditions • the availability of a choice of package sizes • safety audits and training • technical advice with regards to both the safe handling and the cost-efficient synthetic use. Availability With its 50+ years of manufacturing experience, Rohm and Haas Company is unique as a borohydride supplier by offering the most complete range of products: − − − − − −. VenPure SF Powder VenPure AF granules, VenPure SF granules VenPure AF caplets VenPure solution, VenPure 20/20 solution VenPure Potassium Borohydride Organic NaBH4 solutions available upon request. All products are available in an ample choice of packages, such as metal pails and drums, mini-bulk containers, and tank trucks or railway cars for bulk quantities..

(2) If any of these compounds are present, it is likely that the imine formation will be slow and neat sodium borohydride will not give good yields. One possibility to drive the reaction to the right, is to increase the temperature of the reaction to azeotrope the water away.. 1. Reductive Amination In the past year a comprehensive review of the advancements in the use of sodium borohydride for the reductive amination/alkylation reaction has been published. In this technical datasheet we intend to highlight some of these advancements1. Reductive amination is a technique to alkylate amines. It consists of two subsequent reactions :. It should also be noted that if the starting amine were chiral the final product would also contain a chiral amine.. 1.. 2.3 Solvent Effects :. condensation of an amine with an aldehyde/ketone to an imine, with abstraction of water R'. R' + R. It has been demonstrated that methanol favors imine formation more than tetrahydrofuran or 1,2 dichloroethane... OH. O R' NH2. 1. R. N. H. O. R. N. - H2O. HO. H. 2.. H3CO. reduction of the imine to the corresponding amine. R'. [H+]. N. H. H3CO. Br. NH2. This reaction has been demonstrated on a 100 kg scale without any problems. 2. 2.4 Acidic Additives. R-X. NH. +. H-X. N. +. R R'. + R. R' R. 1. The addition of an acid enhances the reactivity of the imine intermediate. Reaction conditions involving acid buffers and sulfuric acid in THF mixtures have been used to demonstrate this technique3.. R'. +. NH. H. As compared to SN2 substitutions, which are often employed for amine alkylations, reductive aminations have the advantage that they do not favor over-alkylation. In that respect, they have proven to be synthetically useful in the conversion of primary to secondary amines. NH2. 2) 0.76 NaBH4, Water, NaOH 30 oC HO Yield 94.2. R. N. NaBH4. R. H. R'. Br +. R'. R' N+. R. H 1) EtOH, reflux 4h. R N+. R. 2. Reductive Amination with NaBH4 2.1 NaBH4 Alone Sodium borohydride can reduce imines in the same manner as it reduces carbonyls (aldehydes and ketones). To eliminate the possibility of any carbonyl starting material being reduced in a one pot synthesis, it is necessary that the carbonylamine condensation reaction has come to completion prior to any sodium borohydride being added. As a result, neat sodium borohydride should be used for alkylation of those amines that show a favorable formation of the imine, or when this equilibrium can be forced to completion. Please find hereunder some of the parameters that determine how imine formation occurs: Substrates that are known to form imines sluggishly are : - weakly electrophylic carbonyl groups - poor nucleophilic amines - sterically hindered reactive centers. O R. H. NH. NH2 1) H2SO4 THF. +. 2) NaBH4, 5oC, 2h Yield 87 %. NO2. NO2. It should be noted that acid catalyzes the decomposition of sodium borohydride into : NaBH4 + 4 H2O Æ 4 H2 + NaB(OH)4 To counter this side-reaction, Rohm and Haas has a special NaBH4 product form that allows for slow release, viz VenPure AF caplets.. 1. 2.5 Zinc Salts. Zinc salts such as zinc chloride and zinc trifluoroaceate in an inert solvent such as THF or isopropyl acetate can result in the formation of the final product in high yields. It is believed that this chemistry goes via the in-situ formation of zinc borohydride. Indeed, when off-the-shelf Zn(BH4)2 is used, then comparably (high) yields are obtained4..

(3) PhH O. PhH. N. R. + R'H2N. R. R’ Metal Hydride. Ph. Me. R. PhH. Me. HN. R'. R. Me. R' R,R. Catalytic Hydrogenation, when used for reductive aminations, may have the potential to reduce the NO2 or -CN groups. Also, when weak bases such as aniline are employed, the formation of imine intermediate is not favored, which will result in the hydrogenation of the starting carbonyl.1. T Time Yield Decomp. °C (h) (%) (%) 0.25 82 74 Me Zn(BH4)2/THF 0 NaBH4/THF RT 20 77 76 NaBH4/MeOH 0 2 60 49. O. NH2. 54%. 87%. 21%. 80%. NH2. i. Titanium(IV) salts such as TiCl4 and Ti( OPr)4 can be used to promote abstraction of H2O, thereby improving the formation of the imine intermediate 5 .. O R1. STAB. O. 2.6 Titanium (IV) Salts. R2. Catalytic Hydrogenation. Ti(OiPr)4. NaBH4. MeNH, MeOH RT, 6h. RT, 2h. HN R2. R1. R1 = alkyl or hydrogen R2 = alkane, aryl. This system is compatible with the following functional groups, chloro, methoxy, cyano, nitro and urethane. Yields are typically 85 %.. Cyanoborohydride is a reagent that often appears in the academic literature for reductive aminations. Whereas cyanoborohydride has its value for reductive aminations, there are some issues with regards to its large-scale implementation6 : - when a alcoholic solvent is used, cyanoborohydride may generate ketal and acetal by-products - residual cyanide is an environmental risk. 1. 2.7 Dehydration Agents. Another way to encourage the formation of the imine intermediate is by removing the water formed during the reaction. This can be accomplished by the addition of dehydrating agents such as molecular sieves. Other drying agents that have been used include anhydrous sodium, calcium and magnesium sulfates. Another method is to azeotrope the water with benzene or toluene.. O. H N. SCBH. STAB. 34. 86. O. Pyridine-Borane has been reported to be a possible reagent for reductive aminations. Yields are consistently lower than when using STAB6. 3. STAB : NaBH(OAc) 3 Sodium triacetoxy borohydrides (STAB) is more selective a reducing agent than NaBH4 : at pH = 5-6, it reduces imines and aldehydes whereas it does not reduce ketones. The seminal work of Abdel-Magid has expanded the understanding of this reductive technology.6. STAB is ideal for reductive amination reaction using aliphatic and aromatic aldehydes as well as aliphatic, cyclic and bicyclic ketones. One of the true strengths of STAB is its ability to accomplish reductive aminations with weakly basic amines, for example, aromatic amines containing withdrawing groups such as -NO2 and -CN. For such substrates, STAB is unique in its selectivity as compared to catalytic hydrogenation and sodium cyanoborohydride.. O. O. H. +. OEt N. H. Pyridine STAB Borane _____________________ 12%. 96%. Solubility of STAB : STAB is soluble is carboxylic acids, slightly soluble in ethers, cyclic ethers and chlorinated hydrocarbon..

(4) Stability of STAB : STAB will react with protic solvent such as water, and alcohols. Reactivity of STAB : The addition of a small amount of acid has been shown to increase the yield of STAB mediated reductive amination reaction.7 OEt OEt. O. OEt + N Bn. OEt. 1) HOAc, Na2SO4 2) NaBH(OAc)3, 15 oC Yield 80 %. HN. CO2Me. NaBH(OAc)3, pH =7 H2 N. CO2Me. If a carboxylic acid is used as the solvent for a NaBH4 reaction, then a very effective reductive amination system results. Seminal work by and review by Gribble describes this technology9-11. It has been demonstrated that, upon addition of acetic acid to NaBH4, STAB is generated in situ. This technique allows for a One Pot / One Step approach. It has been reported that in situ generated STAB is more efficient a reducing system than ex situ produced STAB.12. H2N. H2N. Yield low. O. O. N Bn. H2N O HO. Sodium triacetoxy-borohydride (STAB) is formed from the reaction of sodium borohydride with three moles of a acetic acid (AcOH) in an inert solvent such as toluene. Other acids, such as ethyl and propionic acids, may also be used to obtain comparable reducing agents Feel free to contact Rohm and Haas’s Technical Support Team for further details In addition to imine reductions, STAB-based technologies have been developed to convert Lactones to Lactams using near-stoichiometric quantities of starting materials and STAB. Acceptable yields have been reported for alkylamines8. O Cl O + 1.1 RNH2 Cl OH. O 1.5 NaBH(OAc)3 24h, RT, Solvent. NH2. NH2. Cl N R Cl. R= Alkyl, Yield 70-90% Aryl, Yield 40-75 %. •-Lactams is an important synthon for the synthesis of many drugs such as Neurontin, ®-Baclofen, CI1008, Rolipram, Rolicyprine and gaminebutyric acid.. 1) NaBH4 H2NHOO. O HO H3CHN. CH3. 4.1. Sodium Borohydride and Acetic Acid Sodium triacetoxy borohydride (STAB) is formed from the reaction of sodium borohydride with three moles of acetic acid in an inert solvent such as toluene. The most common acid used is acetic acid. A slight excess of acetic acid will increase the yields of reductive amination.. O. 2) CHCl3 + Acetic Acid. OH. HO H3CHN. CH3 OH. 40 oC. eq Reducing Agent. Yield (%). 7 NaBH(OAc)3 ex-situ Commercial 7 NaBH(OAc)3 ex-situ Home Made 8 NaBH4/3 AcOH in-situ 8 KBH4/3 AcOH. 78 87 96 72. 4.2 Sodium Borohydride, Carboxylic Acid, and Amines So far, we have only discussed how aldehydes and ketones can be used to alkylate amines. Alternatively, carboxylic acids can be used thereto. As compared to the above described Reductive Amination, the conversion using carboxylic acid includes one additional ketone reduction step. The reaction conditions are similar to the ‘normal’ reductive amination, but somewhat higher reaction temperatures may be required. OH. O. O. 4. Sodium Borohydride and Carboxylic Acid. NHEt. O. NH2. O. R'. R' NH2. + R. OH. N. R. [NaBH4]. R' N. R. H. H R' - H2O. N. Just as different aldehydes/ketones can be used for different amine alkylations, different acids can be used for the introduction of different alkyl groups: formic acid leads to a methyl group, priopionic acid to a propyl13 group, and butyric acid to a t-butyl14 group.. R.

(5) SO2CH3. SO2CH3 THF, -5 oC. H. A final example to illustrate the synthetic capability of in-situ STAB generation from NaBH4 and acetic acid (AcOH) 16 :. H N. NH 7..3 propionic acid. 4.27 MeNH2 + EtOH. 2.9 NaBH4 63oC 16h. toluene. N. Yield = 71.6%. O. 3 AcOH 1.3 NaBH4. CH3. 13h, 2 oC. N. NHCH3 CH3. Double alkylation using acetic acid and temperature.. Depending on the reaction conditions sodium borohydride with carboxylic acids can be used to either mono- or di- alkylated amines in high yields with the use of a auxiliary carbonyl compound.15 HOAc, NaBH4, 25 oC. NH2. Yield 88 %. N H. 1) HOAc, NaBH4, 55 oC Yield 74 %. N. The example hereunder shows how an amine is first alkylated by using acetone, and then subsequently by using acetic acid. It is a One Pot / Two Step reaction, whereby the second step consists of merely increasing the temperature15. HOAc, NaBH4, 25 oC. NH2 O. Yield 84 %. +. N H. o. 1) HOAc, NaBH4, 25 C 2) 55 oC Yield 82%. N. Yield = 100 % !!. References 1) Baxter, E.W.; Reitz, A.B. Organic Reactions 2002 59, 1 2) Kuenburg, B.; Czollner L.; Frohlich J.; Jordis, U. Org. Proc. Res. Dev. 1999, 3, 425 3) Verado G.; Giumanini A.G.; Stazzolini P Synth. Commun. 1994, 24, 609 4) Cimarelli, C.; Palmieri, G. Tetrahedron Assym. 2000, 11, 2555 5) Bhattacharyya S. Synth. Commun. 2003, 33, 14116) AbdelMagid, A.F.; Carson, K.G.; Harris, B.D.; Maryanoff, C.A.; Shah, R.D. J. Org. Chem. 1996, 61, 3849 7) Coe, J.W.; Vetelino, M.G. Bradlee, M.J. Tet. Lett. 1996, 37, 6045 8) Zhang, J.; Blazecka, P.G.; Davidson, J.G. Org. Lett. 2003 5, 553 9) Gribble, G.W. Chem. Soc. Rev. 1998, 27, 395 10) Gribble, G.W.; Nutaitis, C.F. Org. Prep. Prod. Int. 1985, 17, 317 11) Gribble, G.W. ACS Symposium Series # 641. 1996, 167 12) Nam, G.; Kim, S.H.; Kim, J.H.; Shin, J.H.; Jang, E.S. Org. Proc. Res. Dev. 2002 6, 78 13) Lipton, F.L.; Mauragis, F.A.; . Maloney, F.T.; Veley, M.F.; VanderBor, D.W.; Newby, J.J.; Appell, R.B.; Daugs, E.D. Org. Proc. Res. Dev. 2003, 7, 385 14) Gribble, G.W.; Jasinski, J.M.; Pellicone, J.T.; Panetta, J.A. Synthesis 1978, 766 15) Gribble, G.W.; Lord, P.D.; Skotnicki, J.; Dietz, S.E.; Eaton, J.T.; Johnson, J.L. J. Am. Chem. Soc. 1974, 96, 7812 16) Rippen D.H.B. et al. Org. Proc. Res. Dev. 2003, 7, 115. Please feel free to contact us via hydride@rohm haas.com Updated information can be found at http://www.hydridesolutions.com/ Find your local Rohm and Haas Representative: http://www.hydridesolutions.com/contact.html. VENPURE is a trademark of Rohm and Haas Company, Philadelphia, U.S.A. To the best of our knowledge the information contained herein is correct. All products may present unknown health hazards and should be used with caution. Although certain hazards are described herein, we cannot guarantee that these are the only hazards which exist. Final determination of suitability of the product is the sole responsibility of the user. Users of the product should satisfy themselves that the conditions and methods of use assure that the product is used safely. NO REPRESENTATIONS OR WARRANTIES, EITHER EXPRESS OR IMPLIED, OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE OR ANY OTHER NATURE ARE MADE HEREUNDER WITH RESPECT TO THE INFORMATION CONTAINED HEREIN OR THE PRODUCT TO WHICH THE INFORMATION REFERS. Nothing herein is intended as a recommendation to use our products so as to infringe any patent. We assume no liability for customer’s violation of patent or other rights. The customer should make his own patent investigation relative to his proposed use. ©2003 Rohm and Haas Company. September 2003.

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