Dibal diisobutylaluminum aldehydes

The conversion of carboxylic acid derivatives (halides, esters and lactones, tertiary amides and lactams, nitriles) into aldehydes can be achieved with bulky aluminum hydrides (e.g. DIBAL = diisobutylaluminum hydride, lithium trialkoxyalanates). Simple addition of three equivalents of an alcohol to LiAlH, in THF solution produces those deactivated and selective reagents, e.g. lithium triisopropoxyalanate, LiAlH(OPr )j (J. Malek, 1972). 

A significant modification of the Bradsher method was introduced recently by Castle to effect homoannulation of structurally appropriate methyl derivatives of condensed thiophenes in four steps (Scheme 28a, where NBS = N-bromosuccinimide DIBAL = diisobutylaluminum hydride).658 106a l26a The main feature is the conversion of a methyl substituent to the—CH=CH— unit of a peri-condensed ring structure. Yields reported for the steps in the transformation 358c -> 76 are 76, 72%, and 32% (last two steps). The intermediate aldehyde 358d undergoes cyclization at C-l. In the same manner, overall yields of 6% for 34a, 9% for 77, and 27% for 79 were obtained. 

The other stereoselective synthesis/281 shown in Scheme 8, foresees conversion of Boc-L-Asp-OtBu 20 into the related (3-aldehyde 22 via the Weinreb amide 21 and its reduction with diisobutylaluminum hydride (DIBAL-H). Wittig condensation of 22 with the ylide derived from (3-carboxypropyl)triphenylphosphonium bromide using lithium hexamethyldisilaza-nide at —78 to 0°C, produces the unsaturated compound 23 which is catalytically hydrogenated to the protected L-a-aminosuberic acid derivative 24. Conversion of the co-carboxy group into the 9-fluorenylmethyl ester, followed by TFA treatment and reprotection of the M -amino group affords Boc-L-Asu(OFm)-OH (25). 

Several synthetic methods for the reduction of a-amino esters have also been reported. The reduction of methyl or ethyl esters by diisobutylaluminum hydride (DIBAL-H) at low temperature (—78 °C) has been described as useful for the preparation of a-amino aldehydes. 1118 20 Again, this method suffers from overreduction. Reductive methods involving mild reductive agents have been described. The reduction of phenyl esters 6 21 (readily prepared from the corresponding amino acid 5) with lithium tri-ferf-butoxyaluminum hydride is efficient for the preparation of various Boc-a-amino aldehydes including Na-Boc-7V J-nitroargininal and A7a-Boc-W"-Z-argininal (Scheme 5). 

The Homer-Emmons addition of dialkyl carboalkoxymethylenephosphonates to aldehydes [22] has been widely used to generate a,p-unsaturated esters which, in turn, can be reduced to allylic alcohols. Under the original conditions of the Homer-Emmons reaction, the stereochemistry of the oc,(3-unsaturated ester is predominantly trans and therefore the trans allylic alcohol is obtained upon reduction. Still and Gennari have introduced an important modification of the Homer-Emmons reaction, which shifts the stereochemistry of the a,[i-unsaturated ester to predominantly cis [23], Diisobutylaluminum hydride (DIBAL) has frequently been used for reduction of the alkoxycarbonyl to the primary alcohol functionality. The aldehyde needed for reaction with the Homer-Emmons reagent may be derived via Swern oxidation [24] of a primary alcohol. The net result is that one frequently sees the reaction sequence shown in Eq. 6A. 1 used for the net preparation of 3E and 3Z allylic alcohols. 

Step 2a Utilization of 1 eq of diisobutylaluminum hydride (DIBAL-H) ensures reduction of the ester group stops to the corresponding aldehyde. 

Aluminum hydrides can reduce nitriles to the corresponding aldehydes. Diisobutylaluminum hydride, abbreviated (i-Bu AlH or DIBAL-H, is commonly used for the reduction of nitriles. The initial reaction forms an aluminum complex that hydrolyzes in the aqueous workup. 

Diisobutylaluminum hydride (DIBAL-H) reduces esters directly to aldehydes at dry ice temperature, about -78 °C. Unlike LiAlH4 (which reduces esters to primary alcohols), cold DIBAL-H usually does not reduce the aldehyde further. The initial reaction forms an aluminum complex that is stable toward further reduction, but hydrolyzes to the aldehyde in the aqueous workup. 

Acid chlorides are more reactive than other acid derivatives, and they are reduced to aldehydes by mild reducing agents such as lithium tri-ferf-butoxyaluminum hydride. Diisobutylaluminum hydride (DIBAL-H) reduces esters to aldehydes at low temperatures, and it also reduces nitriles to aldehydes. These reductions were covered in Sections 18-9,18-10, and 20-13. 

The Introduction of the side chain containing carbon atoms 16 to 11 was accomplished as shown In Scheme 2. Selective tosylatlon of 9A followed by displacement with cyanide ion and protection of the 19 alcohol with tert-butyldimethylsilyl (TBS) chloride gave 11. Subsequent reduction with diisobutylaluminum hydride (DIBAL) and hydrolysis gave the aldehyde 12. Wittig reaction of 12 with (carbethoxyethyl i dene) tri phenl ypfiosphorane provided the o,b... 

Efficient conjugate reduction of several a,)9-unsaturated carbonyl substrates was similarly realized by the combined use of ATPH and diisobutylaluminum hydride-n-butyllithium ate complex (DIBAL-n-BuLi) as a reducing agent (Scheme 6.94) [117]. Diisobutylaluminum hydride-tert-butyllifhium (DIBAL-t-BuLi) was more effective for the 1,4-reduction of a,/f-unsaturated aldehydes. 

Thiomethyl-PS 6b, prepared from Merrifield s resin la by reaction with thioacetate followed by reduction, can be acylated to give thioesters [263]. The resin-bound thioesters have been converted to silyl enol ethers, which were shown to form aldol products that could be released from the resin by three methods [264], Thus, reduction with lithium borohydride or diisobutylaluminum hydride (DIBAL) gave diols and aldehydes, respectively alternatively, base hydrolysis afforded carboxylic acids. Resin 6b thereby extends the range of functional groups available compared with cleavage of related molecules from an ester anchor. 

Domino reduction/aldol cydization was applied for the synthesis of ( )-fredericamydn A 44, a potent antitumor and antibiotic agent, by Kelly et al. [18] in 1988 (Scheme 9.10). DIBAL-H (diisobutylaluminum hydride) reduction of lactone 45 afforded an intermediate 46 having both enolate and aldehyde. Subsequent cychzation via aldol reaction gave a diastereomeric mixture of spiro hydroxy ketone 47, which was further converted into ( )-fredericamycin A 44 by sequential organic transformations. A similar strategy was employed by Mehta et al. [19] for the synthesis of bicyclo[3.3.1]nonan-9-one core of hyperforin, an antidepressant. 

Another useful reagent is the dimeric diisobutylaluminum hydride (DIBAL-H), (t-Bu2AlH)2, which can reduce esters and nitriles in a controlled manner. Thus, unlike for LAH, only one hydride is transferred to the organic substrate, so for esters the reduction stops at the aldehyde stage. 

By varying the groups on aluminum, different reactivities can be achieved. One such useful reagent is diisobutylaluminum hydride (DIBAL-H). This selective reagent only partially reduces acid chlorides, esters, and nitriles to give aldehyde products (addition of hydride to a C=N triple bond gives a C=N double bond that is hydrolyzed to a C O double bond upon workup). 

Oxidation of a 2° alcohol produces a ketone, while partial oxidation of a 1° alcohol (PCC or Swem) gives aldehyde products. Ozonolysis of an alkene, followed by a reductive workup, gives ketone and/or aldehyde products, depending on the alkene starting material. Esters, acid chlorides, and nitriles can be partially reduced with diisobutylaluminum hydride (DIBAL-H) to produce aldehydes as well. 

In 1980, Baldwin developed a modification of the de Mayo reaction using dioxinone heterocycles as covalently locked enol tautomers of P-keto esters. Thus intermolecular cycloaddition of 2,2,6-trimethyl-1,3-dioxolenone 133 occurs in good yield using stoichiometric quantities of a variety of alkenes. For example, irradiation of 133 with tetramethylethylene yields the cyclobutane adduct 135 in 90% yield. This adduct is converted to cyclohexenone 138 in two steps. Controlled reduction of 135 with diisobutylaluminum hydride (DIBAL) gives keto aldehyde 137 (after spontaneous loss of acetone from hemiacetal 136 and retro-dXdo cyclobutanol fragmentation), which on exposure to acidic conditions affords cyclohexenone 138 in 76% yield. 

As with acid chlorides, other metal hydrides that permit isolation of the intermediate aldehydes have heen developed. For example, diisobutylaluminum hydride (DIBAL-H) reduces ketones to alcohols, but can be used to prepare the intermediate aldehydes from esters (Fig. 18.38). ... 

Diisobutylaluminum hydride (DIBAL-H) will not reduce the aldehyde if the reaction is carefully run... 

PROBLEM 19.88 Diisobutylaluminum hydride (DIBAL-H), like lithium aluminum hydride (LiAJH4) and sodium boro-hydride (NaBH4), can reduce aldehydes and ketones to alcohols. 

The synthesis of trans-3-acyl- 3-lactam methyl esters 107 has been reported by Almqvist and coworkers [81, 82] by the Staudinger reaction of ketenes, generated from the Meldrum s acids 105, with methyl (i )-thiazoline-4-carboxylate 106 in benzene in the presence of hydrogen chloride (Scheme 3.36). An exceptionally low yield of 38% was obtained in the reaction of acetylketene. These esters could then be selectively reduced to the corresponding aldehydes 108 in moderate yields using diisobutylaluminum hydride (DIBAL-H). The Meldrum acids are well-known precursors of ketenes [83, 84]. They undergo a pericyclic reaction under thermal influence to generate ketenes with the release of carbon monoxide and acetone. 

A second method of aldehyde synthesis is one that we ll mention here just briefly and then return to in Section 21.6. Certain carboxylic acid derivatives can be partially reduced to yield aldehydes. The partial reduction of an ester by diisobutylaluminum hydride (DIBAH, or DIBAL-H), for instance, is an important laboratory-scale method of aldehyde synthesis, and mechanistically related... 

Nitriles and esters, especially lactones, may be reduced to aldehydes or hemiacetals using diisobutylaluminum hydride (DIBAL) (Eqs. 6.22 and 6.23) [37,38] or various alkoxyaluminum hydrides [39]. 

The reduction of an ester either by lithium aluminum hydride or by catalytic hydrogenation at high temperatures under a high pressure of hydrogen yields a primary alcohol. Any aldehyde intermediate that forms is much more easily reduced than the ester. Diisobutylaluminum hydride, [(CH3)2CHCH2)]2A1H, is less reactive than lithium aluminum hydride. At—78 °C in toluene, the reagent, known as DIBAL, reduces esters to aldehydes. 

Esters are reduced to aldehydes using the mild reducing agent diisobutylaluminum hydride (DIBAL). To avoid subsequent reduction of the aldehyde, exactly one equivalent of the reagent is used, and the reaction is carried out at —78 °C. 

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