Lithium tris aluminum hydride aldehydes

H. C. Brown and co-workers found that lithium aluminum hydride in ether solution reacts with 4 moles of methanol, ethanol, or isopropanol but with only 3 moles of t-butanol. Dropwise addition of 1 mole of /-butanol at room temperature to a stirred solution of 0.31 mole of LiAlH, in ether produces a white precipitate of lithium tri-/-butoxyaluminum hydride in essentially quantitative yield. The new reagent proved to be a milder reducing agent than LiAlH4, since it reduces aldehydes, ketones, and acid chlorides in diethyl ether or diglyme at 0° but fails to react with esters and nitriles. 

One of the more difficult partial reductions to accomplish is the conversion of a carboxylic acid derivative to an aldehyde without over-reduction to the alcohol. Aldehydes are inherently more reactive than acids or esters so the challenge is to stop the reduction at the aldehyde stage. Several approaches have been used to achieve this objective. One is to replace some of the hydrogens in a group III hydride with more bulky groups, thus modifying reactivity by steric factors. Lithium tri- -butoxyaluminum hydride is an example of this approach." Sodium tri- butoxyaluminum hydride can also be used to reduce acyl chlorides to aldehydes without over-reduction to the alcohol." The excellent solubility of sodium bis(2-methoxyethoxy)aluminum hydride makes it a useful reagent for selective... 

Several reagents reduce aldehydes preferentially to ketones in mixtures of both. Very high selectivity was found in reductions using dehydrated aluminum oxide soaked with isopropyl alcohol and especially diisopropylcarbinol [755], or silica gel and tributylstamane [756]. The best selectivity was achieved with lithium trialkoxyalumimm hydrides at —78°. In the system hexanal/ cyclohexanone the ratio of primary to secondary alcohol was 87 13 at 0° and 91.5 8.5 at —78° with lithium tris(/er/-butoxy)aluminum hydride [752], and 93.6 6.4 at 0° and 99.6 0.4 at —78° with lithium tris(3-ethyl-3-pentyl-oxy)aluminum hydride [752],... 

Better reagents than lithium aluminum hydride alone are its alkoxy derivatives, especially di- and triethoxyaluminohydrides prepared in situ from lithium aluminum hydride and ethanol in ethereal solutions. The best of all, lithium triethoxyaluminohydride, gave higher yields than its trimethoxy and tris(/er/-butoxy) analogs. When an equimolar quantity of this reagent was added to an ethereal solution of a tertiary amide derived from dimethylamine, diethylamine, W-methylaniline, piperidine, pyrrolidine, aziridine or pyrrole, and the mixture was allowed to react at 0° for 1-1.5 hours aldehydes were isolated in 46-92% yields [95,1107], The reaction proved unsuccessful for the preparation of crotonaldehyde and cinnamaldehyde from the corresponding dimethyl amides [95]. 

Acylthiazolidine-2-thiones (593), easily prepared from carboxylic acids and thiazolidine-2-thione, can be reduced to the corresponding aldehydes with diisobutyl-aluminum hydride in toluene at -78 to -40 °C in 70-90% yield or with lithium tri-f-butoxyaluminum hydride in THF at -20 to 0 °C in 80-90% yield (Scheme 130) (79BCJ555). The formation of the aluminum-containing six-membered chelate (594) in this reaction process is probable and is supported by the fact that no decrease in yield is observed on changing the mole ratio of DIBAL from 1.2 to 2.1 equivalents. 

As to the preparation of MAM, the exact same sequence was used, except for the employment of n-amyl bromide. The benzaldehyde crystallized from methanol with amp of79-80 °C, and formed amalononitrile derivative which was bright yellow and melted at 103-104 °C. The nitrostyrene, when pure, melted at 57-58.5 °C but proved very difficult to separate from the aldehyde. The final product, 4-(n)-amyloxy-2,5-dimethoxyamphetamine hydrochloride (MAM) was obtained by lithium aluminum hydride reduction in ether and melted at 125-127 °C. It was assayed at up to 16 milligrams, at which level there was noted a heaviness in the chest and head at the 2-hour point, but no cardiovascular disturbance and no mydriasis. This was called an inactive level, and no higher one has yet been tried. 

Reduction by mild reducing agents converts acyl chlorides, esters, and nitrites into aldehydes. The reducing agents of choice are usually lithium tri-tert-butoxy aluminum hydride (LATB—H) and diisobuty-laluminum hydride (DIBAL—H). Following are the structures for these compounds ... 

Reduction to Aldehydes Reduction of carboxylic acids to aldehydes is difficult because aldehydes are more reactive than carboxylic acids toward most reducing agents. Almost any reagent that reduces acids to aldehydes also reduces aldehydes to primary alcohols. In Section 18-10, we saw that lithium tri-ferf-butoxyaluminum hydride, LiAlH(0-f-Bu)3 is a weaker reducing agent than lithium aluminum hydride. It reduces acid chlorides to aldehydes because acid chlorides are strongly activated toward nucleophilic addition of a hydride ion. Under these conditions, the aldehyde reduces more slowly and can be isolated. Therefore, reduction of an acid to an aldehyde is a two-step process Convert the acid to the acid chloride, then reduce using lithium tri-ferf-butoxyaluminum hydride. 

Hydroxyketones are versatile intermediates in the synthesis of pharmaceutical intermediates and heterocyclic molecules. a-Aryl hydroxyketones have been prepared by reaction of aryl aldehydes with 1,4-dioxane followed by reduction with lithium aluminum hydride (LAH) and by the selective LAH reduction of a-silyloxy a,P-unsaturated esters." WissneC has shown that treatment of acid chlorides with tris(trimethylsilyloxy)ethylene affords alkyl and aryl hydroxymethyl ketones. 1-Hydroxy-3-phenyl-2-propanone (3) has been generated by the osmium-catalyzed oxidation of phenylpropene and by the palladium-catalyzed rearrangement of phenyl epoxy alcohoP both in 62% yield. 

The best way to prepare peptide aldehydes from the corresponding N -protected amino acids is by using a handle based on the Weinreb amide.f This commercial handle allows classical solid-phase elongation of peptides using protected Boc or Fmoc amino adds and, at the end of the synthesis, the peptide aldehyde is formed by reduction and concomitant cleavage from the resin with lithium aluminum hydride. Although the 4-hydro-xybenzoic acid handle also allows the preparation of peptide aldehydes by reduction of the resin-bound phenyl ester with lithium tri-tert-butoxyaluminum hydride, a noixture of the aldehyde and the alcohol is always formed. 

A comparison of four tri-f-alkoxyaluminum hydrides revealed that lithium tris[(3-ethyl-3-pen-tyl)oxy]aluminum hydride, prepared from LAH and 3-ethyl-3-pentanol, was the most selective for reduction of aldehydes over ketones of all types. Even the less reactive benzaldehyde was reduced in THE at -78 C faster than cyclohexanone (97.7 2.3). A good correlation between the steric demands of the reducing agent and the observed chemoselectivity was observed. 

Modified lithium aluminum hydride has been used successfully for the reduction of esters at temperatures of about 0 °C. Thus, lithium tri-f-butoxyaluminum hydride readily reduces phenyl esters of carboxylic acids to aldehydes in 33-77% yields other esters are reported to be unreactive, as are many other functional groups (acyl chlorides react with the same reagent at -70 °C, however). Phenylbenzoate and phenyl cyclopropanecarboxylate do not give the aldehyde. Iminium salt esters (11 equation 4) can be reduced with lithium tri-f-butoxyaluminum hydride (see Section 1.11.3). ... 

Ozonides are rarely isolated [75, 76, 77, 78, 79], These substances tend to decompose, sometimes violently, on heating and must, therefore, be handled with utmost safety precautions (safety goggles or face shield, protective shield, and work in the hood). In most instances, ozonides are worked up in the same solutions in which they have been prepared. Depending on the desired final products, ozonide cleavage is done by reductive or oxidative methods. Reductions of ozonides to aldehydes are performed by catalytic hydrogenation over palladium on carbon or other supports [80, 81, 82, S3], platinum oxide [84], or Raney nickel [S5] and often by reduction with zinc in acetic acid [72, 81, 86, 87], Other reducing agents are tri-phenylphosphine [SS], trimethyl phosphite [89], dimethyl sulfide (DMS) [90, 91, 92], and sodium iodide [93], Lithium aluminum hydride [94, 95] and sodium borohydride [95, 96] convert ozonides into alcohols. 

Treatment of 860 with tri- -butyltin hydride and AIBN under high dilution conditions leads to cyclized product 861 as a 3 1 mixture of EjZ isomers (60-71%). Conversion of the TMS-olefin to an aldehyde (863), phenylselenation, reduction of the aldehyde, and acetylation furnishes 864. Oxidation and subsequent elimination of the selenoxide followed by reduction of all carbonyl groups with lithium aluminum hydride gives the natural product 850. 

SYNTHESIS The starting material 3,5-dimethoxy-4-bromobenzoic acid (made from the commercially available resorcinol by the action of methyl sulfate) was a white crystalline solid from aqueous EtOH with a mp of 248-250 °C. Reaction with thionyl chloride produced 3,5-dimethoxy-4-bromobenzoyl chloride which was used as the crude solid product, mp 124-128 °C. This was reduced with tri-0-(t)-butoxy lithium aluminum hydride to produce 3,5-dimethoxy-4-bromobenzaldehyde which was recrystallized from aqueous MeOH and had a mp of 112-114 °C. Anal. (C9H9Br03) C,H. This aldehyde, with nitroethane and anhydrous ammonium acetate in acetic acid, was converted to the nitrostyrene 1-(3,5-dimethoxy-4-bromophenyl)-2-nitropropene, with a mp of 121-121.5 °C. Anal. 

Reduction of the intermediate generated from a carboxylic acid and DMFCl provides aldehydes with Lithium Tri-tert-butoxy-aluminum Hydride, and alcohols with Sodium Borohydride both in high yield and chemoselectivity. 

Cha et al[12] have reported that acyloxy-9-BBN derivatives are also readily reduced by lithium aluminum hydride in the presence of pyridine, and the reduction stops at the aldehyde stage. Further, Cha and coworkers have found that lithium tris(diethylamino) aluminum hydride (LTDEA), readily prepared [13] from the reaction of LiAlH and 3 equiv of diethylamine in THE (Eq. 7.2), reduces the acyloxy group to the corresponding aldehyde in fair yield. However, in the presence of 2 equiv of pyridine the reduction stops at the aldehyde stage, and hydrolysis affords excellent yields of aldehydes (Eq. 7.3, Table 7.5) [13]. 

The reaction between an acid chloride and LAH cannot be used to produce an aldehyde. Using one equivalent of LAH simply leads to a mess of products. Producing the aldehyde requires the use of a more selective hydride-reducing agent that will react with acid chlorides more rapidly than aldehydes. There are many such reagents, including lithium tri(r-butoxy) aluminum hydride. 

When treated with excess LAH, acid chlorides are reduced to give alcohols because two equivalents of hydride attack. Selective hydride-reducing agents, such as lithium tri(t-butoxy) aluminum hydride, can be used to prepare the aldehyde. 

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