Complex hydrides alcohols

Another possibility for asymmetric reduction is the use of chiral complex hydrides derived from LiAlH. and chiral alcohols, e.g. N-methylephedrine (I. Jacquet, 1974), or 1,4-bis(dimethylamino)butanediol (D. Seebach, 1974). But stereoselectivities are mostly below 50%. At the present time attempts to form chiral alcohols from ketones are less successful than the asymmetric reduction of C = C double bonds via hydroboration or hydrogenation with Wilkinson type catalysts (G. Zweifel, 1963 H.B. Kagan, 1978 see p. 102f.). 

Reduction of l-methyl-2-alkyl-.d -pyrroline and l-methyl-2-alkyl-.d -piperideine perchlorates with complex hydrides prepared in situ by partial decomposition of lithium aluminum hydride with the optically active alcohols (—)-menthol and (—)-borneol affords partially optically active l-methyl-2-alkyl pyrrolidines (153, n = 1) and 1-methy 1-2-alkyl piperideines (153, n = 2), respectively (241,242). 

The presence of water is essential for the success of these reductions. In anhydrous THF, for example, treatment of iV-benzoylimidazole with NaBH4 leads to benzyl benzoate as the main product (73%), along with 19% benzyl alcohol.[33] Other reports, however, describe the conversion of carboxylic acid imidazolides to the corresponding alcohols by complex hydrides in organic solvents. Further alcohols have been synthesized via imidazolides ... 

Catalysts suitable specifically for reduction of carbon-oxygen bonds are based on oxides of copper, zinc and chromium Adkins catalysts). The so-called copper chromite (which is not necessarily a stoichiometric compound) is prepared by thermal decomposition of ammonium chromate and copper nitrate [50]. Its activity and stability is improved if barium nitrate is added before the thermal decomposition [57]. Similarly prepared zinc chromite is suitable for reductions of unsaturated acids and esters to unsaturated alcohols [52]. These catalysts are used specifically for reduction of carbonyl- and carboxyl-containing compounds to alcohols. Aldehydes and ketones are reduced at 150-200° and 100-150 atm, whereas esters and acids require temperatures up to 300° and pressures up to 350 atm. Because such conditions require special equipment and because all reductions achievable with copper chromite catalysts can be accomplished by hydrides and complex hydrides the use of Adkins catalyst in the laboratory is very limited. 

The reaction of complex hydrides with carbonyl compounds can be exemplified by the reduction of an aldehyde with lithium aluminum hydride. The reduction is assumed to involve a hydride transfer from a nucleophile -tetrahydroaluminate ion onto the carbonyl carbon as a place of the lowest electron density. The alkoxide ion thus generated complexes the remaining aluminum hydride and forms an alkoxytrihydroaluminate ion. This intermediate reacts with a second molecule of the aldehyde and forms a dialkoxy-dihydroaluminate ion which reacts with the third molecule of the aldehyde and forms a trialkoxyhydroaluminate ion. Finally the fourth molecule of the aldehyde converts the aluminate to the ultimate stage of tetraalkoxyaluminate ion that on contact with water liberates four molecules of an alcohol, aluminum hydroxide and lithium hydroxide. Four molecules of water are needed to hydrolyze the tetraalkoxyaluminate. The individual intermediates really exist and can also be prepared by a reaction of lithium aluminum hydride... 

Reagents of choice for reduction of epoxides to alcohols are hydrides and complex hydrides. A general rule of regioselectivity is that the nucleophilic complex hydrides such as lithium aluminum hydride approach the oxide from the less hindered side [511, 653], thus giving more substituted alcohols. In contrast, hydrides of electrophilic nature such as alanes (prepared in situ from lithium aluminum hydride and aluminum halides) [653, 654, 655] or boranes, especially in the presence of boron trifluoride, open the ring in the opposite direction and give predominantly less substituted alcohols [656, 657,658]. As far as stereoselectivity is concerned, lithium aluminum hydride yields trans products [511] whereas electrophilic hydrides predominantly cis products... 

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]. 

Transformation of ketones to alcohols has been accomplished by many hydrides and complex hydrides by lithium aluminum hydride [55], by magnesium aluminum hydride [89], by lithium tris tert-butoxy)aluminum hydride [575], by dichloroalane prepared from lithium aluminum hydride and aluminum chloride [816], by lithium borohydride [750], by lithium triethylboro-hydride [100], by sodium borohydride [751,817], by sodium trimethoxyborohy-dride [99], by tetrabutylammonium borohydride [771] and cyanoborohydride [757], by chiral diisopinocampheylborane (yields 72-78%, optical purity 13-37%) [575], by dibutyl- and diphenylstannane [114], tributylstanrume [756] and others Procedure 21, p. 209). 

The structure of the cyclic ketone is of utmost importance. Reduction of cyclic ketone by complex hydrides is started by a nucleophilic attack at the carbonyl function by a complex hydride anion. The approach of the nucleophile takes place from the less crowded side of the molecule (steric approach or steric strain control) leading usually to the less stable alcohol. In ketones with no steric hindrance (no substituents flanking the carbonyl group or bound in position 3 of the ring) usually the more stable (equatorial) hydroxyl is generated (product development or product stability control) [850, 851, 852, 555]. The contribution of the latter effect to the stereochemical outcome of... 

Reduction of unsaturated ketones to unsaturated alcohols is best carried out Nit v complex hydrides. a,/3-Unsaturated ketones may suifer reduction even at the conjugated double bond [764, 879]. Usually only the carbonyl group is reduced, especially if the inverse technique is applied. Such reductions are accomplished in high yields with lithium aluminum hydride [879, 880, 881, 882], with lithium trimethoxyaluminum hydride [764], with alane [879], with diisobutylalane [883], with lithium butylborohydride [884], with sodium boro-hydride [75/], with sodium cyanoborohydride [780, 885] with 9-borabicyclo [3.3.1]nonane (9-BBN) [764] and with isopropyl alcohol and aluminum isopro-... 

The reduction of free acids to alcohols became practical only after the advent of complex hydrides. Lithium aluminum hydride reduces carboxylic acids to alcohols in ether solution very rapidly in an exothermic reaction. Because of the presence of acidic hydrogen in the carboxylic acid an additional equivalent of lithium aluminum hydride is needed beyond the amount required for the reduction. The stoichiometric ratio is 4 mol of the acid to 3 mol of lithium aluminum hydride (Equation 12, p. 18). Trimethylacetic add was reduced to neopentyl alcohol in 92% yield, and stearic acid to 1-octadecanol in 91% yield. Dicarboxylic sebacic acid was reduced to 1,10-decanedioI even if less than the needed amount of lithiiun aluminum hydride was used [968]. 

Reduction of aromatic carboxylic acids to alcohols can be achieved by hydrides and complex hydrides, e.g. lithium aluminum hydride 968], sodium aluminum hydride [55] and sodium bis 2-methoxyethoxy)aluminum hydride [544, 969, 970], and with borane (diborane) [976] prepared from sodium borohydride and boron trifluoride etherate [971, 977] or aluminum chloride [755, 975] in diglyme. Sodium borohydride alone does not reduce free carboxylic acids. Anthranilic acid was reduced to the corresponding alcohol by electroreduction in sulfuric acid at 20-30° in 69-78% yield [979],... 

Disadvantages of the Rosenmund reduction are high temperature, sometimes necessary to complete the reaction, and long reaction times. In this respect, reduction with complex hydrides offers considerable improvement. Again special, not too efficient reagents must be used otherwise the reduction proceeds further and gives alcohols (p. 145). One of the most suitable complex... 

Catalytic hydrogenation is hardly ever used for this purpose since the reaction by-product - hydrogen chloride - poses some inconveniences in the experimental procedures. Most transformations of acyl chlorides to alcohols are effected by hydrides or complex hydrides. Addition of acyl chlorides to ethereal solutions of lithium aluminum hydride under gentle refluxing produced alcohols from aliphatic, aromatic and unsaturated acyl chlorides in 72-99% yields [5i]. The reaction is suitable even for the preparation of halogenated alcohols. Dichloroacetyl chloride was converted to dichloro-... 

Reductions of anhydrides of monocarboxylic acids to alcohols are very rare but can be accomplished by complex hydrides [55, 99]. More frequent are reductions of cyclic anhydrides of dicarboxylic acids, which give lactones. Such reductions were carried out by catalytic hydrogenation, by complex hydrides and by metals. 

Powerful complex hydrides like lithium aluminum hydride in refluxing ether [5i] or refluxing tetrahydrofuran [1017] reduce cyclic anhydrides to diols. Phthalic anhydride was thus transformed to phthalyl alcohol (o-hydroxy-methylbenzyl alcohol) in 87% yield [5i]. Similar yields of phthalyl alcohol were obtained from phthalic anhydride and sodium bis 2-methoxyethoxy) aluminum hydride [544, 969]. 

Both older methods for the reduction of esters to alcohols, catalytic hydrogenation and reduction with sodium, have given way to reductions with hydrides and complex hydrides which have revolutionized the laboratory preparation of alcohols from esters. 

Esters are also reduced by sodium aluminum hydride (yields 95-97%) [<9<9] and by lithium trimethoxyaluminum hydride (2 mol per mol of the ester) [94] but not by lithium tris tert-butoxy)aluminum hydride [96], Another complex hydride, sodium bis(2-methoxyethoxy)aluminum hydride, reduces esters in benzene or toluene solutions (1.1 -1.2 mol per ester group) at 80° in 15-90 minutes in 66-98% yields [969], Magnesium aluminum hydride (in the form of its tetrakistetrahydrofuranate) reduced methyl benzoate to benzyl alcohol in 58% yield on refluxing for 2 hours in tetrahydrofuran [59]. 

Iron and acetic or dilute hydrochloric acid can be safely used for the reduction of nitro group to an amino group in nitro esters. The problem arises when a nitro ester is to be reduced to a nitro alcohol. Nitro groups are not inert toward the best reagents for the reduction of esters to alcohols, complex hydrides. However the rate of reduction of a nitro group by lithium... 

Experimentally, this pathway has been well established from IR spectra of the [CpRuH(C0)(PCy3)]/(CF3)30H system in CH2CI2, where large variations in hydride/alcohol ratios did not affect slow transformation of the H H complexes to hydrogen-bonded ion pairs with k values between 1.4 X 10 and 1.6 X 10 s [25]. Activation parameters for this step (Table 10.3) have been determined in hexane [6]. It is probable that a similar mechanism operates for protonation of the hydrides [ReH2(NO)(CO)(PR3)2] with CF3COOH (Table 10.3) in CD2CI2, where the reaction corresponds to first-order kinetics on the acid at hydride/acid ratios > 1 [7]. 

Reduction of aldehydes and ketones. Earlier work on amine borane reagents was conducted mainly with tertiary amines and led to the conclusion that these borane complexes reduced carbonyl compounds very slowly, at least under neutral conditions, and that the yield of alcohols is low. Actually complexes of borane with primary amines, NHj or (CH3)3CNH2, reduce carbonyl compounds rapidly and with utilization of the three hydride equivalents. BH3 NH3 is less subject to steric effects than traditional complex hydrides. A particular advantage is that NH3 BH3 and (CH3)3CNH2 BH3 reduce aldehyde groups much more rapidly than keto groups, but cyclohexanone can be reduced selectively in the presence of aliphatic and aromatic acyclic ketones. 

The so-called crossed Cannizzaro reaction is synthetically more useful than the Cannizzaro reaction itself, as it can be applied for the preparation of alcohols in high yields, without loss of 50% of the product in the formation of the corresponding carboxylic acid. Typically, paraformaldehyde is used as a sacrificial reducing agent, together with the carbonyl compound which is to be transformed into the alcohol. The reaction thus serves as an alternative method to the use of complex hydrides for the reduction of aromatic aldehydes. 

The mechanism of the reaction of the alcohol (or water) with the acyl complex to produce ester (or acid) and regenerate the cobalt hydride complex is not known. Because the reaction of the analogous manganese complex with alcohols is known to proceed through a hemiacetal-like complex, this mechanism has been written for the carboxylation reaction (equation 42). 

The shortest Ge—H bond yet found in an organogermane occurs in the recently reported complex hydride [(CH3)3Si]2CH 2(OC2H5)GeH (118). The shortness of the Ge—H bond (1.46 A) must, at least in part, arise from the hybridization demands of the electronegative ethoxy group. Distortions in the tetrahedral environment about the germanium (Table I) arise from the steric requirements of the bis(trimethyl-silylmethyl) moieties, while the authors attribute to the same source the stability of this compound with respect to the reductive elimination of alcohol normally observed (127). 

Most efforts to explore the reactivity of ruthenium carbene complexes have employed the alkoxycarbene species so readily synthesized from the inter- or intramolecular reaction of vinylidene complexes with alcohols. These electrophilic alkoxycarbene complexes exhibit only limited reactivity at Ca, primarily with hydride reagents. For example, treatment of the 2-oxacyclopentylidene complex 97 with NaAlH2(OCH2CH2OMe)2 affords the neutral 2-tetrahydrofuranyl complex (98) [Eq. (89)] (55), as was anticipated from similar reductions of iron carbene complexes (87). 

Piperideines unsubstituted at the nitrogen atom may be prepared from the corresponding pyridine compounds by partial reduction with sodium and boiling alcohols (the Ladenburg reduction), by electrolytic reduction, or, preferably, by reduction with aluminum hydride. l-Alkyl-3-piperideines are prepared by reduction of quaternary pyridinium salts with formic acid (the Lukes reduction) or with complex hydrides. 

Reduction of a-methylthio ketones, a-Methylthio and a-phenylthio ketones (1) are reduced with high selectivity to sy/i-alcohols (2) by this complex hydride, except when... 

In this more interesting case, each monomer adds only to an end unit of the other kind (k = 0, km - 0). In the polymer, units MA and M then alternate. Coordination copolymerization of olefins and carbon monoxide, catalyzed by complex hydrides of Pd(II) or Rh(I) in the presence of an alcohol co-solvent to yield polyketo esters, provides an example [133,134] Olefin and carbon monoxide are added altematingly, and reaction with alcohol terminates the kinetic chain and restores the catalyst. For ethene as the olefin ... 

The reverse conversions of carbonyl compounds into alcohols are typically achieved with the utilization of complex hydrides such as LiAlH4, NaBH4, etc. Activity and selectivity of these reagents can be attenuated within wide limits by varying the nature of the hydride donor. Thus, one can finely tune the selectivity to a particular structural pattern (see discussion in the next section). 

Primary and secondary alcohols should first be converted into halides or sulfonates, followed with treatment by complex hydrides such as LiAlH4 in order to achieve hydrogenolysis ... 

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