Borohydrides selective aldehyde reduction

In pharmaceutical appHcations, the selectivity of sodium borohydride is ideally suited for conversion of high value iatermediates, such as steroids (qv), ia multistep syntheses. It is used ia the manufacture of a broad spectmm of products such as analgesics, antiarthritics, antibiotics (qv), prostaglandins (qv), and central nervous system suppressants. Typical examples of commercial aldehyde reductions are found ia the manufacture of vitamin A (29) (see Vitamins) and dihydrostreptomycia (30). An acyl azide is reduced ia the synthesis of the antibiotic chloramphenicol (31) and a carbon—carbon double bond is reduced ia an iatermediate ia the manufacture of the analgesic Talwia (32). 

Much emphasis has been placed on the selectivity of quaternary ammonium borohydrides in their reduction of aldehydes and ketones [18-20]. Predictably, steric factors are important, as are mesomeric electronic effects in the case of 4-substituted benzaldehydes. However, comparison of the relative merits of the use of tetraethyl-ammonium, or tetra-n-butylammonium borohydride in dichloromethane, and of sodium borohydride in isopropanol, has shown that, in the competitive reduction of benzaldehyde and acetophenone, each system preferentially reduces the aldehyde and that the ratio of benzyl alcohol to 1-phenylethanol is invariably ca. 4 1 [18-20], Thus, the only advantage in the use of the ammonium salts would appear to facilitate the use of non-hydroxylic solvents. In all reductions, the use of the more lipophilic tetra-n-butylammonium salt is to be preferred and the only advantage in using the tetraethylammonium salt is its ready removal from the reaction mixture by dissolution in water. 

An excellent, broad review of the last 60 years of hydride reductions has been published,235 and the use of selectrides, Li and K tri-.v-butylborohydridcs or trisiamylborohydrides, has also been reviewed.236 A review of sodium borohydride-carboxylic acid as a reagent with novel selectivity in reductions has been written in particular, this reagent is useful for the A -alkylation of primary and secondary amines, through a sequence that is believed to involve sequential carboxylic acid to aldehyde reduction followed by reductive animation.237... 

The product of the initial reduction is most often more reactive than the starting material therefore a second addition is very common (AdN then Ep, then AdN, covered in Section 9.2). An Ad f then Ep product can be obtained with acyl halides and one equivalent of a less reactive metal hydride at low temperature. Borohydrides selectively react with aldehydes and ketones in the presence of less reactive esters and amides. 

Diazene 19 was synthesized in the manner portrayed below. Thus, treatment of anhydride 20 with sodium borohydride selectively reduces one carbonyl to a methylene unit. Reduction of the resulting lactone with DIBAL followed by a Wittig reaction and oxidation with PCC afforded aldehyde 22. When treated with cyclopentadiene in the presence of diethylamine in methanol, 22 undergoes a smooth and efficient conversion to fulvene 23. Diels-Alder cycloaddition to the azodicarboxylate 24 proceeded rapidly, a characteristic of reactions with this electron deficient chlorinated dienophile [8]. Selective reduction of the endocyclic n bond using diimide generated in situ, followed by the electrochemical reductive cleavage of the biscarbamate led to diazene 19 [6]. 

Ethanolic solutions of sodium borohydride reduce aldehydes and ketones in the presence of epoxides, esters, lactones, acids, nitriles, and nitro groups. 1 419 xhe reaction is very selective for reactive functional groups such as acid chlorides, aldehydes or ketones, and the yields are commonly > 80%. The reduction of simple aldehydes or ketones that are part of more complex structures is perhaps the most prevalent use of sodium borohydride. The reduction of the ketone moiety in 91 to give the secondary alcohol in 92 (88% yield)l 0is a typical application involving sensitive functionality. Sodium borohydride often gives the 1,2-... 

Examples of hydride reduction of aldehydes and ketones are shown in Figure 14.51. Notice in the first reaction that sodium borohydride selectively reduces the aldehyde in the presence of an ester nitro and nitrile groups are also tolerated. In the second reaction, the borohydride reduction of a ketone, the diastereoselectivity, reflects the steric hindrance to the approach of the methyl groups on the bridging carbon atom block the approach from the top face of the molecule. By contrast, little diastereoselectivity is observed in the reduction of 2-hydroxyclobutanone. The final example illustrates the reduction of an a,p-unsaturated ketone. 

Potassium and sodium borohydride show greater selectivity in action than lithium aluminium hydride thus ketones or aldehydes may be reduced to alcohols whilst the cyano, nitro, amido and carbalkoxy groups remain unaffected. Furthermore, the reagent may be used in aqueous or aqueous-alcoholic solution. One simple application of its use will be described, viz., the reduction of m-nitrobenzaldehyde to m-nitrobenzyl alcohol ... 

Common catalyst compositions contain oxides or ionic forms of platinum, nickel, copper, cobalt, or palladium which are often present as mixtures of more than one metal. Metal hydrides, such as lithium aluminum hydride [16853-85-3] or sodium borohydride [16940-66-2] can also be used to reduce aldehydes. Depending on additional functionahties that may be present in the aldehyde molecule, specialized reducing reagents such as trimethoxyalurninum hydride or alkylboranes (less reactive and more selective) may be used. Other less industrially significant reduction procedures such as the Clemmensen reduction or the modified Wolff-Kishner reduction exist as well. 

Devaky and Rajasree have reported the production of a polymer-bound ethylenediamine-borane reagent (63) (Fig. 41) for use as a reducing agent for the reduction of aldehydes.87 The polymeric reagent was derived from a Merrifield resin and a 1,6-hexanediol diacrylate-cross-linked polystyrene resin (HDODA-PS). The borane reagent was incorporated in the polymer support by complexation with sodium borohydride. When this reducing agent was used in the competitive reduction of a 1 1 molar mixture of benzaldehyde and acetophenone, benzaldehyde was found to be selectively reduced to benzyl alcohol. 

One of the most attractive features of borohydride reductions is that under micro-wave-enhanced conditions they can be performed in the solid state, and rapidly. We were attracted by the work of Loupy [57], and in particular Varma [58, 59] who has shown that irradiation of a number of aldehydes and ketones in a microwave oven in the presence of alumina doped NaBH4 for short periods of time led to rapid reduction (0.5-2 min) in good yields (62-93%). In our study [60] seven aldehydes and four ketones were reduced (Tab. 13.3). Again reduction was complete within 1 min, the products were of high purity (>95%), of high isotopic incorporation (95%, same as the NaBD4) and the reactions completely selective. 

Although there is evidence that quaternary ammonium salts are cleaved by sodium borohydride at high temperature [7], initial studies suggested that the quaternary ammonium borohydrides might have some synthetic value in their selectivity, e.g. aldehydes are reduced by an excess of the quaternary ammonium salts under homogeneous conditions in benzene at 25 °C, whereas ketones are recovered unchanged and are only partially reduced at 65 °C [2], The reduction of esters also requires the elevated temperature, whereas nitriles are not reduced even after prolonged reaction at 65 °C. Evidence that the two-phase (benzene water) reduction of octan-2-one by sodium borohydride was some 20-30 times faster in the presence of Aliquat, than in the absence of the catalyst [8], established the potential use of the mote lipophilic catalysts. 

Kinetic studies established that tetra-n-butylammonium borohydride in dichloromethane was a very effective reducing agent and that, by using stoichiometric amounts of the ammonium salt under homogeneous conditions, the relative case of reduction of various classes of carbonyl compounds was the same as that recorded for the sodium salt in a hydroxylic solvent, i.e. acid chlorides aldehydes > ketones esters. However, the reactivities, ranging from rapid reduction of acid chlorides at -780 C to incomplete reduction of esters at four days at 250 C, indicated the greater selectivity of the ammonium salts, compared with sodium borohydride [9], particularly as, under these conditions, conjugated C=C double bonds are not reduced. 

Palladium catalysts are more often modified for special selectivities than platinum catalysts. Palladium prepared by reduction of palladium chloride with sodium borohydride Procedure 4, p. 205) is suitable for the reduction of unsaturated aldehydes to saturated aldehydes [i7]. Palladimn on barium sulfate deactivated with sulfur compounds, most frequently the so-called quinoline-5 obtained by boiling quinoline with sulfur [34], is suitable for the Rosenmund reduction [i5] (p. 144). Palladium on calcium carbonate deactivated by lead acetate Lindlar s catalyst) is used for partial hydrogenation of acetylenes to cw-alkenes [36] (p. 44). 

Reduction of cuprous chloride with sodium borohydride gives copper hydride which is a highly selective agent for the preparation of aldehydes from acyl chlorides [775]. 

A method for the conversion of unsaturated aliphatic aldehydes to saturated aldehydes is a gentle catalytic hydrogenation. Palladium is more selective than nickel. Hydrogenation over sodium borohydride-reduced palladium in methanol at room temperature and 2 atm reduced crotonaldehyde to butyralde-hyde but did not hydrogenate butyraldehyde [57]. Nickel prepared by reduction with sodium borohydride was less selective it effected reduction of crotonaldehyde to butyraldehyde but also reduction of butyraldehyde to butyl alcohol, though at a slower rate [57]. Hydrogenation of 2,2,dimethyl-... 

Complex hydrides can be used for the selective reduction of the carbonyl group although some of them, especially lithium aluminum hydride, may reduce the a, -conjugated double bond as well. Crotonaldehyde was converted to crotyl alcohol by reduction with lithium aluminum hydride [55], magnesium aluminum hydride [577], lithium borohydride [750], sodium boro-hydride [751], sodium trimethoxyborohydride [99], diphenylstarmane [114] and 9-borabicyclo[3,3,l]nonane [764]. A dependable way to convert a, -un-saturated aldehydes to unsaturated alcohols is the Meerwein-Ponndorf reduction [765]. 

Apart from reactions with sodium borohydride, which is frequently used in water or water-alcohol mixtures to selectively reduce ketones or aldehydes, water is rarely used in reductions because of chemical incompatibility with most reducing agents. Nevertheless, water was shown to influence these types of reactions. 

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