Sodium triacetoxyborohydride

Sodium triacetoxyborohydride is an alternative to NaBH3CN for reductive amination. This reagent can be used with a wide variety of aldehydes or ketones with primary and secondary amines, including aniline derivatives.93 This reagent has been used successfully to alkylate amino acid esters.94... 

Another route to the formation of piperidine heterocycles is cyclization via reductive animation utilizing various hydride sources. The scheme below depicts a bis reductive animation, using sodium triacetoxyborohydride as the hydride source, to generate exo-178 and endo-179 azabicyclo[3.2.1]octane amino acids in moderate yields <06JOC8467>. 

Sodium cyanoborohydride [123], sodium triacetoxyborohydride [124] or NaBH4 coupled with sulfuric acid [125] are common agents used for the reductive amination of carbonyl compounds. These reagents either generate waste or involve the use of corrosive acids. The environmentally friendlier procedures developed by Varma and coworkers have been extended to a solvent-free reductive amination protocol for carbonyl compounds using moist montmorillonite K 10 day supported sodium borohydride that is facilitated by microwave irradiation (Scheme 6.39) [126]. 

For the preparation of N- 2-(methoxyphenyl)cthyl ]-4-mcthylbcn-zenesulfonamide (1) from Ameba resins A and Ba-Bd, 100 mg (0.089 mmol) Ameba resin A was added to a glass peptide reaction vessel, suspended in 3.0 mL 1,2-dichloroethane (DCE note 2), and treated with 26 pL (0.18 mmol, 2.0 Eq.) 2-(4-methoxy-phenyl)ethylamine (note 2) and 38 mg (0.178 mmol, 2.0 Eq.) sodium triacetoxyborohydride (note 2). The suspension was shaken for 1 h treated with 5 mL MeOH filtered on a glass frit and washed with DCM (2x5 mL), DMF (2x5 mL), MeOH (2 x 5 mL), and DCM (2x5 mL). The resin was dried under vacuum (0.5 torr) at room temperature overnight. The resin was suspended in 1.5 mL DCM, treated with 155 pL (0.89 mmol, 10.0 Eq.) N,N-diisopropylethylamine (note 2) and 85 mg (0.445 mmol, 5.0 Eq.) p-toluenesulfonyl chloride (note 2), and shaken for 3.5 h. The reaction mixture was filtered on a glass frit, washed with DCM (2 x 5 mL), DMF (2x5 mL), MeOH (2x5 mL), and DCM (2 x 5 mL), and dried under vacuum (0.5 torr) at room temperature for 2h. The resin was treated with 2.5 mL of a solution of 5% trifluoroacetic acid (note 2) in DCM, shaken for 15 min, filtered on a glass frit, and washed with DCM (3x5 mL). The combined filtrate and washings were concentrated and dried under vacuum (0.5 torr) at room temperature overnight to afford 18.0 mg (66%) N- [2-(methoxyphenyl)ethyl] -4-methylbenzenesulfonamide (1). 

A reductive amination/cyclization step was performed on the aldehyde 392 upon reaction with a variety of amines in the presence of sodium triacetoxyborohydride in THF/AcOH at room temperature to give the tetrahydropyr-ido[2,3 pyrituidine 393 (Equation 34) <2005BML1829>. 

For ammonia and primary amines there are two possible pathways, but when secondary amines are involved, only the hydrogenolysis pathway is possible. Other reducing agents167 can be used instead of hydrogen and a catalyst, among them zinc and HCI, sodium cyano-borohydride NaBHjCN,168 sodium triacetoxyborohydride,169 sodium borohydride,170 iron pentacarbonyl and alcoholic KOH,171 BH -pyridine,172 and formic acid. When the last is used, the process is called the Wallach reaction. In the particular case where primary or secondary amines are reductively methylated with formaldehyde and formic acid, the method is called the Eschweiler-Clarke procedure. It is possible to use ammonium (or amine) salts of formic acid,173 or formamides, as a substitute for the Wallach conditions. This method is called the Leuckart reaction, and in this case the products obtained are often the N-formyl derivatives of the amines instead of the free amines. Primary and secondary amines can be N-ethylated (e.g., ArNHR —< ArNREt) by treatment with NaBH4 in acetic acid.175... 

See also Sodium triacetoxyborohydride (this volume), for a specific use of these reagents in synthesis. 

Sodium triacetoxyborohydride, 283 Titanium(III) chloride, 302 Tributyltin hydride, 316 Zinc borohydride, 167 of alkenes to alkanes (R)-(-F)- and (S)-(-)-2,2 -Bis(di-phenylphosphine)-l,1 -binaphthyl, 36 [1,4-Bis(diphenylphosphine)-butanej(cycloheptatriene)-rhodium(I) tetrafluoroborate, 89 [ 1,4-Bis(diphenylphosphine)butane]-(norbornadiene)rhodium(I) tetrafluoroborate, 37... 

Sodium triacetoxyborohydride, 283 Other reducing agents Dichlorotris(triphenylphosphine)-ruthenium(II), 107 Dicyclopentadienyldihydrido-zirconium, 108 Samarium(II) iodide, 270 Sodium-Alcohol, 277 Tributyl tin hydride, 316 Reagents which can be used to reduce cyclic ketones to axial (less stable) alcohols... 

Sodium triacetoxyborohydride, 283 Tetrabutylammonium iodide-Boron trifluoride etherate, 287 Tributylborane, 325 Tributyl borate, 326 Triethylborane, 33, 292 Trimethyl borate, 218 Zinc borohydride, 167 Chromium Compounds Arene(tricarbonyl)chromium complexes, 19... 

Bal resin (0.4 g, 0.45 mmol/g, 0.18 mmol, Perseptive Biosystems) was weighed into a fritted polypropylene tube and swelled with 4 ml of DCM. To the suspension was added oxazolidinone HC1 salt 2 (96 mg, 0.27 mmol), sodium triacetoxyborohydride (190 mg, 0.90 mmol), and acetic acid (80 pi,... 

Solid-Phase Synthesis Terminated by Tetramic Acid Cyclative Cleavage (Scheme 2). The Fmoc-L-Val resin (loading 0.7 mmol/g) is first deprotected with 20% piperidine in DMF for 20 min, and the resin washed and dried. The resin ( 0.3 g, 0.67 mmol/g) is shaken with p-anisaldehyde (0.25 ml, 10 molar equiv.) and sodium triacetoxyborohydride (0.65 g, 15 molar equiv.) in 10 ml CH2C12 for 8 h, followed by washing and drying to give resin 4. 

The example previously described in Fig. 12 involves a reductive alkylation, a widely used derivatization reaction in combinatorial chemistry. The use of sodium triacetoxyborohydride has been thoroughly validated for the solid-phase reaction format. With this reagent the pH is maintained... 

Reductive Animation for Synthesis of PAL-Resin-Bound Amines (59) (Fig. 10)15. To a suspension of 4-formyl-3,5-dimethoxyphennoxymethyl functionalized polystyrene resin (PAL)25 (10.0 g, 11.3 mmol) in DMF (350 ml) a primary amine (56.5 mmol) is added followed by addition of sodium triacetoxyborohydride (7.18 g, 33.9 mmol) and acetic acid (6.52 ml, 113 mmol). The suspension is shaken gently at RT overnight. Resin 59 is washed with methanol (4 x 300 ml) and CH2C12 (4 x 300 ml) and dried under vacuum. Subsequent derivatization products can be cleaved from the resin by a 2 h treatment with CH2Cl2/TFA/Me2S/H20 45 45 5 5. 

Oxo-2,3-dihydro-5H-pyrido[l,2,3-de][l,4]benzoxazine-3-carbalde-hydes were reacted with tert-bu tyl piperidin-4-ylcarbamate, then the reaction mixture was treated with sodium triacetoxyborohydride to give 3-[4-(ferf-butoxycarbonylamino)piperidin-l-yl)methyl derivatives (08WOP2008/120003). 8-Fluoro-3-oxo-2,3,6,7-tetrahydro-5H-pyrido [l,2,3-cfe][l,4]benzoxazin-7-carbaldehyde was similarly reacted with cyclic amines, then with (polystyrylmethyl)trimethylammonium cya-noborohydride in acidified MeOH (08WOP2008/116815). 

A dynamic kinetic resolution has been employed to achieve a catalytic asymmetric reductive amination of aldehydes.332 Reductive amination of ketones and aldehydes by sodium triacetoxyborohydride has been reviewed, highlighting its advantage over other reagents.333... 

The selected example by Sim and Ganesan [19] reported the design of a 3078-member discrete thiohydantoin library, prepared without purification of intermediates, with a three-step synthesis, which is shown in Figure 7.2. Nine amino acid esters were reacted with eighteen aromatic aldehydes to produce imines, which were reduced by sodium triacetoxyborohydride. The resulting amines were treated with nineteen isothiocyanates in the presence of triethylamine (TEA), producing intermediate isoureas, which eventually cyclized to the final thiohydantoins. 

Sodium triacetoxyborohydride, NaBH(OAc)3, is a mild reducing agent that reduces aldehydes much more quickly than ketones. It can be used to reduce aldehydes in the presence of ketones, such as in the following reaction ... 

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