Triacetoxyborohydride reduction

Various methods have been applied for the reduction of alicyclic p-enamino esters, but these reactions in general gave diastereomeric mixtures [64-69]. For example, the sodium triacetoxyborohydride reduction of enamino ester 30 (R = Ph, CH2Ph) resulted in about 10% tram isomer 32 besides the main cis product 31 [69]. 

Sodium or tetramethylammonium triacetoxyborohydride has become the reagent of choice for diastereoselective reduction of P-hydroxyketones to antidiols. Trialkylborohydrides, eg, alkaH metal tri-j -butylborohydrides, show outstanding stereoselectivity in ketone reductions (39). 

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]. 

Syn stereoselectivity in reduction of acylic chiral ketoxime ethers of type 91 (equation 63) can be obtained using bulky tetramethylammonium triacetoxyborohydride that produces FeUdn-type products with high selectivity . Reaction of a-tolylsulfinylketoximes 92 (equation 64) with L-Selectride also results in syn products 93. 

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... 

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. 

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... 

Evans DA, Chapman KT et al (2002) Directed reduction of P-hydroxy ketones employing tetramethylammonium triacetoxyborohydride. J Am Chem Soc 110 3560-3578... 

It is important to recognise that it is only through alkoxy/acetoxy interchange around the parent triacetoxyborohydride that a sufficiently reactive hydride donor can be generated that can perform the ketone reduction at an acceptable rate. Ordinarily, Me4NBH(OAc)3 will reduce ketones exceedingly slowly. 

The stereoselective reduction of the ketone function of 9 leads to a direct entry to selectively protected aldopentoses ( inversion strategy ) (Borysenko et al. 1989), which greatly expand the potential of this new protocol (Scheme 5). Following Evans protocol the tetramethylammo-nium triacetoxyborohydride-mediated reduction provides the yyn-diol 15 constituting a protected D-ribose (95%, >96% de). The anti-selective reduction to 17 was obtained after silyl protection of the free hydroxyl group of 9 to the OTBS-ether 16 using L-selectride. The aldopentose 18 was then accessible via chemoselective acetal cleavage followed by in situ cyclization (47% over two steps, >96% de). 

An alkylation by reductive amination using aldehyde 253 in the presence of sodium triacetoxyborohydride in 1,2-dichloroethane afforded the adamantyl compound 253, which after further deprotection produced an A, A -disu Instituted guanidine derivative 254 interesting for potential biological activity (Scheme 105 <2000JME2362>). 

Breitenbucher and Hui (104) have recently reported the SP synthesis of a medium-large discrete library L3 of 8448 benzopyrans using the reductive amination cocktail formed from titanium isopropoxide and sodium triacetoxyborohydride, known in solution but whose applications to SP were rare and limited to single experiments (105, 106). The benzopyran scaffold is present in a number of biologically active compounds (107-110), and this library was tested in several biological assays (111). 

The synthetic importance of reaction (a) ° comes from the fact that it reduces to one step the pathway for conversion of an acid chloride into a nitrile (instead of the classical and rather inconvenient two-step route via an acid amide). Reaction is an example of a new transformation for aliphatic amines. Previously, there were no methods available for the direct transformation of an amino into a nitro group and the stepwise procedures were too cumbersome to be of practical use. Transformation of a nitro group into a carbonyl is a well-known reaction. Its modification, shown in reaction represents a welcome opportunity to obtain a protected carbonyl group as the immediate result of such a transformation. The viability of the sequential reactions (b) plus (c) enables the employment of a > CHNH2 moiety as a synthetic equivalent to a protected carbonyl group. A one-pot sequence of imine formation and its reduction with sodium triacetoxyborohydride represents a convenient... 

Tetra-n-butylammonium triacetoxyborohydride in refluxing benzene reduced aldehydes but not acyclic ketones, the selectivity was demonstrated in competition experiments and keto aldehyde reductions. The more reactive cyclohexanones were reduced only slowly under the same conditions. The limitation of this convenient method is that proximal hydroxy groups activated the reagent enabling the... 

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