Reducing agents LiAlH

Lithium aluminium hydride, LiAlH, is a very active reducing agent, and is used particularly for the ready reduction of carboxylic acids (or their esters) to primary alcohols R-COOH -> R CH,OH. 

The other way of reducing nitriles to aldehydes involves using a metal hydride reducing agent to add 1 mol of hydrogen and hydrolysis, in situ, of the resulting imine (which is undoubtedly coordinated to the metal). This has been carried out with LiAlH4, LiAlH(OEt)3, LiAlH(NR2)3, and DIBAL-H. The metal hydride method is useful for aliphatic and aromatic nitriles. 

Chemoselectivity between aldehydes and ketones is demonstrated by this method in the competitive reduction of a mixture of pentanal and cyclohexanone. The ratios of primary and secondary alcohols are 75 25 when catechol is used at 0° and 79 21 when 2,2/-dihydroxybiphenyl is used at room temperature. These regents are not as chemoselective as other reducing agents such as LiAlH(OBu-i)3 (87 13) and LiAlH(OCEt3)3 (94 6) at 0°.93... 

The reduction of carboxylic acids or esters requires very powerful reducing agents such as lithium aluminum hydride (LiAlH,) or sodium (Na) metal. Aldehydes and ketones are easier to reduce, so they can use sodium borohy-dride (NaBH,j). Examples of these reductions are shown in Figure 3-13. 

Sterically bulky reducing agents, e.g. lithium tri-t-butoxyaluminium hydride, can selectively reduce acid chlorides to aldehydes at low temperatures (—78 °C). Lithium tri-t-butoxyaluminium hydride, LiAlH(0-t-Bu)3, has three electronegative oxygen atoms bonded to aluminium, which makes this reagent less nucleophilic than LiAlH4. 

The Ferrier (II) reaction is quite efficient to form six membered carbocycles, but is unsuitable to prepare cyclopentitols. Five membered enollactone 14 was converted to the cyclopentanone derivative 16 as a single epimer upon treatment by LiAlH(OtBu)3 (Scheme 4) [41]. Spectroscopic studies established some mechanistic details. Accordingly, the hydride of the reducing agent rapidly added to the carbonyl and formed with the metal a stable alu-minate complex. The carbocydization occurred by protonation followed by fragmentation and aldol type cyclization process. 

Switching from alkali metal to LiAlH as reducing agent for Btp—E—X the first alkyne analogue could be finally isolated and structurally characterized, not for E = Ge and Sn, however, but for E = Pb. While in the Sn case the novel Sn(II) hydride BtpSnH (58) was isolated instead (see Section II), the putative Pb(II) hydride is not stable and dehydrogenates, finally yielding BtpPb=PbBtp (99)95. 

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. 

With milder reducing agents such as DIBAL-H and LiAlH[OC(CH3)3]3, the process stops after reaction with one equivalent of Hr and the aldehyde is formed as product. With a stronger reducing agent like LiAlH4, two equivalents of H are added and a 1° alcohol is formed. 

Examples of Li MH use are found in reviews " " and in"" Table 1. Although LiAlH is a more powerful reducing agent than NaBH, the latter is used frequently in EtOH, while LiAlH requires ether. Comparison of Table 1 with the corresponding table in 1.10.7.1 shows that transition-metal hydrides can be prepared by the use of either reagent. 

Amides have been converted into imidoyl chlorides and then reduced to aldimines with LiAlH(OBu ).3, as in Scheme 15. Although not claimed as a synthesis of aldehydes, the aldimines can be hydrolyzed to aldehydes quite readily. Interestingly, the authors say that an excess of the reducing agent can be used because further reduction to the amine requires 24 h, whereas the first stage to the aldimine requires only 30 min at -78 C. 

Both LiAlH(0Me)3 and NaAlH2(OCH2CH20Me)2 are convenient reducing agents for low temperature, copper-mediated 1,4-reduction, as shown for the latter by Scheme 41.Partial reduction of cy-clopentenedione has been achieved with several of these reagents. 

Lithium aluminum hydride, LiAlH, is another reducing agent often used for reduction of ketones and aldehydes. A grayish powder soluble in ether and tetrahydrofuran, LiAlH4 is much more reactive than NaBH4 but also more dangerous. It reacts violently with water and decomposes explosively when heated above 120°C. 

The aldehyde intermediate can be isolated if 1 equivalent of diisobutyl aluminum hydride (DIBAH) is used as the reducing agent instead of LiAlH The reaction has to be carried out at -78 C to avoid further reduction i. the alcohol. 

Treatment of the long-chain imidazolium salts 263 with potassium, sodium, and tetra-n-butylammonium borohydrides affords the acyclic diamines 264 and 265. The isomer ratio was not reported. Sodium cyanobo-rohydride failed to reduce the same salt under a variety of conditions. The imidazoline 266 reacts with LAH in THF above — 10°C to give the 1,2-di-aminoethane 267. Sodium borohydride is a less effective reducing agent in this reaction, achieving the same conversion over a longer period of time. Other less reactive hydrides [LiBH4, NaBHjCN, LiAlH(0-t-Bu)j] do not react. 

Carboxylic acids and esters frequently must be protected against the attack of organometallic reagents, e.g. metal alkyls and hydrides, and reducing agents like LiAlH. For this purpose they usually are converted to orthoesters, oxazolines or oxazoles. 

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. 

---