Lithium Tri-t-butoxyaluminum Hydride1

LiAlH(OR)3
(R = t-Bu)

[17476-04-9]  · C12H28AlLiO3  · Lithium Tri-t-butoxyaluminum Hydride  · (MW 254.32) (R = Et3C)

[79172-99-9]  · C21H46AlLiO3  · Lithium Tris(3-ethyl-3-pentoxy)aluminum Hydride  · (MW 380.59) (R = Et)

[17250-30-5]  · C6H16AlLiO3  · Lithium Triethoxyaluminum Hydride  · (MW 170.14) (R = Me)

[12076-93-6]  · C3H10AlLiO3  · Lithium Trimethoxyaluminum Hydride  · (MW 128.05)

(reducing agent for many functional groups; cleaves cyclic ethers)

Physical Data: R = t-Bu: mp 300-319 °C (dec); sublimes at 280 °C/2 mmHg. All the other reagents are unstable and are prepared in situ.

Solubility: R = t-Bu: (at 25 °C) diglyme (41 g/100 mL), THF (36 g/100 mL), DME (4 g/100 mL), ether (2 g/100 mL).

Form Supplied in: R = t-Bu: solid; 0.5 M or 1.0 M solutions in diglyme or THF. The other reagents are prepared in situ just prior to use.

Preparative Methods: for R = Me,2 Et,3 or 3-ethyl-3-pentyl,4 in situ preparation can be carried out as follows: addition of 3 mol of the desired alcohol to 1 mol of standardized Lithium Aluminum Hydride solution in ether, THF, or diglyme results in the formation of the corresponding trialkoxyaluminohydride reagent. The t-Bu5 derivative can also be prepared in situ by this method.

Analysis of Reagent Purity: standardization of LiAlH(O-t-Bu)3 solutions is best carried out by reduction of cyclohexanone and with GC and/or spectroscopic analysis to measure the extent of reaction. Iodometric titrations are not suitable in this case.6

Handling, Storage, and Precautions: the dry solid and solutions are corrosive and/or highly flammable and must be stored in the absence of moisture. While the t-BuO compound appears to have long term stability in terms of storage, the MeO compound degrades in its reactivity within one week. Therefore it is advised to use freshly prepared reagent solutions.2a

Functional Group Reductions.

The high reactivity for reduction exhibited by LiAlH4 can be attenuated by modifying this reagent. Altered reagents can be prepared by the addition of an alcohol such that a 3:1 complex of alcohol:LiAlH4 is formed. The reactivity of these new trialkoxyaluminohydride reagents can be modulated by the selection of the appropriate alcohol. In terms of relative reactivity one can rank7 hydride reagents as follows: LiAlH4 > LiAlH(OMe)3 > LiAlH(O-t-Bu)3 > NaBH4. Table 1 provides a comparison of the aluminum based reagents with various functional groups. For a detailed discussion of the reduction properties of LiAlH4, see Lithium Aluminum Hydride.

This observation of diminished reactivity of the trialkoxyaluminohydrides is opposite to that observed with NaBH4 and its alkoxy analogs (see Sodium Borohydride and Sodium Trimethoxyborohydride). The stoichiometry for the reaction can be determined from the theoretical number of hydrides required for the reduction based on the observation that the trialkoxyaluminohydrides can be considered to be the source of one hydride. For example, the reduction of an aldehyde or ketone theoretically requires one hydride and so one equivalent of the reagent is needed for this reduction.

The differential reducing abilities of these reagents allows selective reduction of one functional group in the presence of another. While simple saturated aldehydes can be reduced by both LiAlH(OMe)3 and LiAlH(O-t-Bu)3 as rapidly as by LiAlH4 at 0 °C, cyano aldehydes can be reduced at low temperature to the corresponding alcohol derivatives (eq 1).8 Aldehyde lactones can also be reduced chemoselectively (eq 2).9

The reduction of aldehyde esters can lead to the formation of lactones with or without subsequent acidic workup (eqs 3 and 4).10,11 Aldehydes can also be reduced preferentially in the presence of ketones (eq 5).4

With unsaturated aldehydes such as cinnamaldehyde, LiAlH(O-t-Bu)3 gives the corresponding allylic alcohol, whereas LiAlH(OMe)3 affords the saturated alcohol. This difference in reactivity can be exploited (eq 6).12 The course of the reduction can be changed if a copper species is also used (eq 7).13

Similarly, ketones can be reduced with LiAlH(O-t-Bu)3 in the presence of esters,14a lactones,14b amides,5 halogens,15 epoxides,5 O-alkyl oximes,5 azides,16 and cyano groups.5 A ketone can be reduced in the presence of an aldehyde, provided the aldehyde is first masked as an aldimine, for example. The reduction of an acid halide to the corresponding alcohol can be carried out with LiAlH(O-t-Bu)3 at 0 °C, while the corresponding aldehyde can be obtained if the reduction is performed at -80 °C in diglyme.17 Aldehydes can also be obtained by the reduction of nitriles3a or tertiary amides3b if LiAlH(OEt)3 is used as the reductant.

In addition to the differences in relative functional group reactivities that LiAlH(OR)3 has over LiAlH4, these reagents also exhibit improved stereoselectivities in these reductions.18 For example, the reduction of norbornanone to give the endo-alcohol proceeds with greater control (eq 8).2b Further examples of this stereoselectivity are illustrated in eqs 9-11.19-21 The use of LiAlH4-Lithium Iodide in the reaction depicted in eq 11 results in complete inversion of stereochemistry (syn:anti = 5:95). Therefore the choice of reagents allows preparation of either diastereomer.

Enantioselective reductions are also possible if the alcohol used to form the trialkoxyaluminohydride is optically active. For example, treating LiAlH4 with MeOH and BINAL-H22 in a mole ratio of 1:1:1 in dry THF generates an optically active hydride23 reagent which can reduce ynones with good enantioselectivity, as shown in eq 12. The (R)-antipode of BINAL-H results in the isolation of the (R)-propargylic alcohol. See Lithium Aluminum Hydride-2,2-Dihydroxy-1,1-binaphthyl for additional examples of this type.

While unsubstituted lactams are reduced to the corresponding amines, the intermediates in these reductions can be diverted into other reactions when the substrate is suitably functionalized. One example is shown in eq 13.24 The trialkoxyaluminohydrides are capable of reducing most nitrogen based functional groups; however, imides do not react. This attribute has been used in a diastereoselective synthesis of D-threo-sphingamine (eq 14).25 Oximes react with these reagents only to generate hydrogen. No reduction is observed. N-Methylamines are formed by the reduction of isocyanates with LiAlH(OMe)3,2a,26 while LiAlH(O-t-Bu)3 gives formamides (eq 15).5b,27 Unsaturated isocyanates are also reduced to the corresponding vinylic formamide (eq 16).28 Thiocyanates are inert to LiAlH(O-t-Bu)3.29

The trialkoxyaluminohydrides generate 1 equiv of hydrogen upon exposure to thiols and are inert to dialkyl and/or aryl sulfides, while disulfides are reduced to thiols (eq 17).30 Alkyl 1-alkynyl sulfides are reduced to the corresponding alkyl cis-1-alkenyl sulfides when the reaction is carried out in the presence of Copper(I) Bromide (eq 18).31 The trans-isomer is obtained with LiAlH4. Two equivalents of hydride are required to reduce sulfoxides by LiAlH(OMe)3,2a,26 while LiAlH(O-t-Bu)332 is unreactive to sulfoxides. Sulfones do not react with these reagents.2a,5b,26 While alkyl mesylates and tosylates are inert to the trialkoxyaluminohydrides, LiAlH(OMe)3 can reduce acetylenic mesylates to the corresponding allene in an anti fashion to maintain chirality (eq 19).33

A related reagent is NaAlH2(OCH2CH2OMe)2, which is abbreviated to SMEAH or Red-Al, and has in some cases comparable reactivity and chemistry and in other cases complementary activity (see Sodium Bis(2-methoxyethoxy)aluminum Hydride).

Reductive Cleavage of Ethers.

Dialkyl ethers, alkyl aryl ethers, diaryl ethers, and cyclic ethers react very slowly with these reductants, if at all. However, the addition of Triethylborane, in varying amounts, produces a complex which is capable of ring opening some cyclic ethers (eqs 20 and 21).34 Epoxides also react very slowly with LiAlH(O-t-Bu)3,26 which allows for differentiating functional groups during their reduction. Formation of a complex with BEt3 now can be used to open the epoxide (eq 22).29,35 A mixture of LiAlH(OMe)3 and Copper(I) Iodide can also be used to open epoxides (eq 23).36

Reduction of Halogenated Compounds.

The reduction of 1-iodoalkanes with LiAlH(OMe)3 is comparable to reduction by LiAlH4, while the reactivity with bromo and chloro compounds is very low. There is no reaction of LiAlH(O-t-Bu)3 with chloro compounds. As a result, one can reduce aldehydes in the presence of chloro groups. The mixture of CuI and LiAlH(OMe)3 provides a species which is capable of reducing primary chlorides, and primary and secondary bromides.5b,37

Related Reagents.

Copper(I) Bromide-Lithium Trimethoxyaluminum Hydride; Copper(I) Iodide-Lithium Trimethoxyaluminum Hydride.


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Paul Galatsis

University of Guelph, Ontario, Canada



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