DIBAL Nitrile reduction

Step 2a Controlled reduction of the nitrile with DIBAL-H (1.1 eq). 

The reduction of nitriles with DIBAL can be stopped at this stage of the iminoalane C. The hydrolysis of this iminoalane gives the aldehyde. The iminoalane C also can be reacted—more slowly—with another equivalent of DIBAL to the aminoalane D. The latter yields the amine upon addition of water. 

You can now clearly see the similarity with our target molecule , grandisol, but there are several more steps to carryout yet. The nitrile needs to be got rid of completely—we showed you a few ways of getting rid of fimctional groups in the last chapter, and the one used here was the Wolif-Kishner reduction of an aldehyde. The aldehyde comes from reduction of the nitrile with DIBAL. 

The chemistry of diene iron tricarbonyl complexes described above has been in a number of total syntheses. An iterative stereospecific 1,3-migration of the iron tricarbonyl moiety was used to prepare compounds with multiple chiral centers. An example of one iteration can be seen in Scheme 168. Ester hydrolysis of (105) and protection of the resulting alcohol gives (106). Reduction of the nitrile with DIBAL-H followed by olefination furnished (107). Treatment of (107) with a base resulted in the migration of iron toward the nitrile to give (108). The uncomplexed double bond can... 

The aldehyde 145 has been made by reduction of the nitrile with DIBAL, and was used as a precursor for the hydantoin analogue 146 of showdomycin, obtained as a mixture of diastereoisomers.l A full account has been given of the use of a siinilar aldehyde to produce an... 

Fischer Esterification—Acid-Catalyzed Conversion of Carboxylic Acids to Esters 848 Conversion of Carboxylic Acids to Amides with DCC 850 Acid-Catalyzed Hydrolysis of an Ester to a Carboxyhc Acid 851 Base-Promoted Hydrolysis of an Ester to a Carboxyhc Acid 852 Amide Hydrolysis in Base 856 Hydrolysis of a Nitrile in Base 864 Reduction of a Nitrile with LiAlH4 865 Reduction of a Nitrile with DIBAL-H 866... 

The key intermediate 25 was prepared efficiently from aldehyde 23, obtained by reduction of nitrile 22 with Dibal-H. Treatment of 23 with the lithium salt of frans-diethyl cinnamylphosphonate furnishes compound 24 in 75 % yield and with a 20 1 ratio of E Z olefin stereoisomers. The stage is now set for the final and crucial operations to complete the molecular skeletons of endiandric acids A and B. 

To investigate the feasibility of employing 3-oxidopyridinium betaines as stabilized 1,3-dipoles in an intramolecular dipolar cycloaddition to construct the hetisine alkaloid core (Scheme 1.8, 77 78), a series of model cycloaddition substrates were prepared. In the first (Scheme 1.9a), an ene-nitrile substrate (i.e., 83) was selected as an activated dipolarophile functionality. Nitrile 66 was subjected to reduction with DIBAL-H, affording aldehyde 79 in 79 % yield. This was followed by reductive amination of aldehyde x with furfurylamine (80) to afford the furan amine 81 in 80 % yield. The ene-nitrile was then readily accessed via palladium-catalyzed cyanation of the enol triflate with KCN, 18-crown-6, and Pd(PPh3)4 in refluxing benzene to provide ene-nitrile 82 in 75 % yield. Finally, bromine-mediated aza-Achmatowicz reaction [44] of 82 then delivered oxidopyridinium betaine 83 in 65 % yield. 

The reaction tolerates ketone, chloride, internal C=C bonds, esters, nitriles, and ether functional groups. Given that the DIBAL-H reduction of acid derivatives often suffers from over-reduction to alcohols, these catalytic procedures are of synthetic value for laboratory-scale syntheses. However, it is likely that the requirement for excess (tBuCO)20 will prevent this reaction from ever being used in commercial production. 

The mechanism for both of these reactions is very similar to the mechanism for the reduction of acyl chlorides by LATB—H. The first step is an acid-base reaction between an unshared electron pair on oxygen or nitrogen with the aluminum atom of the DIBAL—H. The second step is the transfer of a hydride ion from the DIBAL—H to the carbon atom of the carbonyl or nitrile group. The last step is the hydrolysis of the aluminum complex to form the aldehyde. 

Chiral addition of allyl metals to imines is one of the useful approaches toward the synthesis of homoallylic amines. These amines can be readily converted to a variety of biologically important molecules such as a-, / -, and y-amino acids. Itsuno and co-workers utilized the allylborane 174 derived from diisopropyl tartrate and cr-pinene for the enantioselective allylboration of imines. The corresponding iV-aluminoimines 173 are readily available from the nitriles via partial reduction using diisobutylaluminium hydride (DIBAL-H) <1999JOM103>. Recently, iV-benzyl-imines 176 have also been utilized for the asymmetric allylboration with allylpinacol boronate 177 in the presence of chiral phosphines as the chiral auxiliaries to obtain homoallylic A -benzylamines 178 in high yield and selectivity (Scheme 29) <2006JA7687>. 

The aldehyde was made by alkylation of the nitrile 45 and reduction (actually using ITAIH4, though we might prefer DIBAL), an HWE olefination and conversion of the ester 46 into the ketone 42. Finally, the rearrangement11 required 400 °C. 

Products of the Reduction of Nitriles with LiAlH4 and DIBAL... 

Fig. 17.64. Mechanism of the LiAlH4 reduction (top) and the DIBAL reduction (bottom) of nitriles.

The two reducing agents considered so far in this section—LiAlH4 and DIBAL—also are the reagents of choice for the reduction of nitriles (Figure 17.64). The mechanistic details of these reactions can be gathered from the figure, and the result can be summarized as follows. 

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. 

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