Aldehydes from Acid Equivalents

Reductive Methods.—Aldehydes from Acid Equivalents. In a two-step process which formally constitutes a reduction, carboxylic acids are first reduced to the corresponding alkyl borate ester by the borane-dimethyl sulphide complex, which in turn is oxidized in high overall yield to the aldehyde [equation (1)].  

Aliphatic, alicyclic, and aromatic acid chlorides are reduced in variable yields to the corresponding aldehydes by the readily prepared copper(i) tetrahydroborate (10)-,  

Di-isobutylaluminium hydride (DIBAL) reduces acid imidazolides to aldehydes in high yields this method has been successfully applied to the synthesis of a-amino-aldehydes from a-amino-acids/ Similarly the acid thiazolidine derivatives (11), which are also readily obtained from carboxylic acids, are reduced by either DIBAL or lithium tri-t-butoxyaluminium hydride to the corresponding aldehyde.  

Aldehydes are also obtained in variable yields from the lithium-methylamine reduction of carboxamides/ Cinnamaldehyde or 3-phenylpropanal can be prepared by the Raney nickel-catalysed hydrogenation of cinnamonitrile, though the generality of the method is not reported/  

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Bisamides (or biscarbamates), which are easily obtainable from the reaction of an aldehyde with two equivalents of a primary amide (carbamate), are converted into the corresponding A-acyliminium ions on heating, often in the presence of strong (Lewis) acids or acylating compounds1 3. 

Precursor y-halogeno alcohols are frequently prepared by the classic sequence of addition of hydrogen halide to a,/3-unsaturated aldehydes, ketones, acids or esters, followed by Grignard reaction or hydride reduction. Recently a novel and general synthesis of 3-methoxyoxetanes from 3-phenylseleno-2-propenal was reported. This method comprises a sequence of Grignard addition to the aldehyde function, treatment with two equivalents of MCPBA, and then reaction with methanolic sodium hydroxide (equation 78) (80JOC4063). 

The Stacker reaction has been employed on an industrial scale for the synthesis of racemic a-amino acids, and asymmetric variants are known. However, most of the reported catalytic asymmetric Stacker-type reactions are indirect and utilize preformed imines, usually prepared from aromatic aldehydes [24]. A review highlights the most important developments in this area [25]. Kobayashi and coworkers [26] discovered an efficient and highly enantioselective direct catalytic asymmetric Stacker reaction of aldehydes, amines, and hydrogen cyanide using a chiral zirconium catalyst prepared from 2 equivalents of Zr(Ot-Bu)4, 2 equivalents of (R)-6,6 -dibromo-1, l -bi-2-naphthol, (R)-6-Br-BINOL], 1 equivalent of (R)-3,3 -dibromo-l,l -bi-2-naphthol, [(R)-3-Br-BINOL, and 3 equivalents of N-methylimida-zole (Scheme 9.17). This protocol is effective for aromatic aldehydes as well as branched and unbranched aliphatic aldehydes. 

Alkaloids of Delphinium dictyocarpum DC.—Dictysine [C21H33N03 m.pt 184—186°C] has been assigned structure (37) on the basis of chemical and spectroscopic studies.25" An unpublished X-ray analysis256 demonstrates that (37) is incorrect and that the structure should be as shown in (37a). Derivatives of dictysine (38)—(42) are shown here as the corrected structures. This alkaloid was isolated from the epigeal parts of Delphinium dictyocarpum DC.26 On acetylation of dictysine with acetyl chloride, the triacetate (38) and the two diacetates, (39) and (40), were obtained. The reaction of dictysine with one molar equivalent of periodic acid for three hours gave the a-hydroxy-ketone (41), while treatment with excess periodic acid for three days yielded the aldehyde carboxylic acid (42). These structures were supported by mass-spectral, i.r., and XH and 13C n.m.r. analyses. This is the first example of a C20 diterpenoid alkaloid which contains hydroxyl groups at C-16 and C-17. 

If the hydride ion comes from 55, the final step is a rapid proton transfer. In the other case, the acid salt is formed directly, and the alkoxide ion acquires a proton from the solvent. Evidence for this mechanism is (I) The reaction can be first order in base and second order in substrate (thus going through 55) or, at higher base concentrations, second order in each (going through 56) and (2) when the reaction was run in D2O, the recovered alcohol contained no a deuterium, indicating that the hydrogen comes from another equivalent of aldehyde and not from the medium. 

Strategy Acid-catalyzed reaction of a ketone or aldehyde with 2 equivalents monoalcohol or 1 equivalent of a diol yields an acetal, in which the carh oxygen atom is replaced by two -OR gi oups from the alcoliol. 

When aldehydes are prepared by ozonolysis, exactly the correct amount of ozone must be added, because excess ozone converts aldehydes to acids and peracids. In addition, alcohols, ethers, double bonds, or other functional groups present in the molecule may be attacked. This brings up the problem of determining when to stop the ozonolysis reaction. The theoretical amount of ozone may be added, but several cases are recorded in which more than one molar equivalent of ozone is required to cleave one double bond. One may stop when ozone appears in the effluent gas from the reactor. However, preliminary experiments have shown that at this low temperature ozone begins to overflow very soon after the reaction has started. A more useful method has been to stop the ozonolysis when the reaction mixture no longer shows unsaturation. This may be detected qualitatively by the use of bromine in carbon tetrachloride, tetranitromethane, etc. An infrared method makes it possible to follow quantitatively the rate of disappearance of trans double bonds and to locate the end point more exactly. The method was applied to the ozonolysis of stigmastadienone with good results. 

Other derivatives that can be prepared are the Schiff bases and semicarbazones. Condensation of the aldehyde with an equivalent of primary aromatic amine yields the Schiff base, for example aniline at lOtP for 10-30minutes. Semicarbazones are prepared by dissolving semicarbazide hydrochloride ca Ig) and sodium acetate (ca 1.5g) in water (8-lOmL) and adding the aldehyde or ketone (0.5-lg) with stirring. The semicarbazone crystalhses out and is recrystallised from ethanol or aqueous ethanol. These are hydrolysed by steam distillation in the presence of oxalic acid or better by exchange with pyruvic acid (Hershberg7 Org Chem 13 542 1948) [see entry under Ketones]. 

B.vii. Acid Dianions. All of the named reactions discussed in Section 9.4 constitute relatively minor variations of the fundamental condensation reaction of aldehydes, ketones, or acid derivatives with another aldehyde, ketone, or acid derivative. The ability to produce kinetic enolates from acid derivatives has made possible another useful modification of the enolate reaction. Carboxylic acids have an acidic proton that is removed by 1 equivalent of base to first give a carboxylate (see 226). Addition of a second equivalent of a powerful base such as a dialkylamide leads to the dianion (227). Subsequent reaction with an electrophilic species, in this case 1-bromobutane, occurred first at the more nucleophilic a-carbon to give hexanoic acid. 2 The carboxylate is usually generated with n-butyllithium and the enolate with LDA, although 2 equivalents of LDA can be used. As discussed in Chapter 8, treatment of a carboxylic acid with an excess of an organo-... 

One of the most useful applications of the alkoxy reagents is in the preparation of aldehydes from carboxylic acids by partial reduction of the acid chlorides or dialkylamides. Acid chlorides are readily reduced with lithium aluminium hydride or with sodium borohydride to the corresponding alcohols, but with one equivalent of lithium tri-t-butoxyaluminium hydride, high yields of the aldehyde can be obtained, even in the presence of other functional groups (7.74). 

In Chapter 20 we established that enolates can be formed from acid chlorides, but that they decompose to ketenes. Enolates can be formed from amides with difficulty, but with primary or secondary amides one of the NH protons is likely to be removed instead. For the remainder of this section we shall look at how to make specific enol equivalents of acids, esters, aldehydes, and ketones. 

The Hantzsch pyridine synthesis is the condensation of two equivalents of a P-dicarbonyl compound such as ethylacetoacetate, one equivalent of an aldehyde, and one equivalent of a nitrogen donor such as ammonia (or ammonium acetate) in refluxing alcohol or acetic acid. The immediate resulted from this three-component coupling, 1,4-dihydropyridine 138, is then oxidized, driven by aromatization, to substituted pyridine 139. Saponification and decarboxylation of the 3,5-ester substituents then leads to symmetric 2,4,6-tri-substituted pyridine 140. 

Electrophilic attack on olefin ligands coordinated to electron-rich, strongly backbonding metals is illustrated by the reactions of (P group 4 olefin and alkyne complexes, as well as some electron-rich olefin complexes. Zirconocene- and and hafnocene-olefin complexes generated by reaction of zirconocene dichloride with two equivalents of alkyl lithium and isolated upon addition of a phosphine ligand react with carbonyl compounds and weak protic acids to form insertion products and alkyl complexes. Several examples of the reactions of these complexes with electrophiles are shown in Equations 12.65-12.66. Zirconocene-alkyne complexes prepared by thermolysis of vinyl alkyl complexes and titanium-alkyne complexes generated by the reduction of Ti(OPr ) also react with electrophiles, such as aldehydes and acid, to form products from insertion into the M-C bond and protonation of the M-C bond respectively. 

This transformation is illustrated by the reaction of a ketal such as 1,1-dimethoxycyclopentane (55) with an acid catalyst and a large excess of water to give cyclopentanone (9), along with two equivalents of methanol. An acetal reacts in an identical manner to give the corresponding aldehyde and two equivalents of the alcohol. Removal of methanol from this reaction by distillation drives the reaction to the right with formation of 9. 

Chiral oxazaborolidines are also efficient catalysts for the enantioselective reduction of aldehydes labeled with isotopic hydrogen at the carbonyl function. Treatment wifli cate-cholborane in the presence of (/ )- or (S)-B-n-butyloxazaborolidine (3 d) affords Cl-deuteriated or tritiated primary alcohols with enantiomeric excesses generally exceeding 90%. Use of catecholborane is essential, since for BH3 THF the achiral uncatalyzed process is competitive with the chiral catalyst-mediated pathway, thereby reducing the enantiomeric purity of products. Enantiomerically enriched [ 1 - H]- and [ 1- H] alcohols have been extensively used in the study of enzymatic mechanisms and biosynthetic pathways , and as precursors for chiral [ H, H, H]acetic acid and [ H, H]fluoroacetic acid . Equivalent results are obtained when BusSnH is employed in the presence of BITIP (58, prepared in situ from (R)- or (5)-l,l -bi-2-naphthol and Ti(0-/-Pr)4 2 1) ° (Figure 11.23). 

Silyl enol ethers are other ketone or aldehyde enolate equivalents and react with allyl carbonate to give allyl ketones or aldehydes 13,300. The transme-tallation of the 7r-allylpalladium methoxide, formed from allyl alkyl carbonate, with the silyl enol ether 464 forms the palladium enolate 465, which undergoes reductive elimination to afford the allyl ketone or aldehyde 466. For this reaction, neither fluoride anion nor a Lewis acid is necessary for the activation of silyl enol ethers. The reaction also proceed.s with metallic Pd supported on silica by a special method[301j. The ketene silyl acetal 467 derived from esters or lactones also reacts with allyl carbonates, affording allylated esters or lactones by using dppe as a ligand[302]... 

Reaction of (T)-(-)-2-acetoxysuccinyl chloride (78), prepared from (5)-mahc acid, using the magnesiobromide salt of monomethyl malonate afforded the dioxosuberate (79) which was cyclized with magnesium carbonate to a 4 1 mixture of cyclopentenone (80) and the 5-acetoxy isomer. Catalytic hydrogenation of (80) gave (81) having the thermodynamically favored aH-trans stereochemistry. Ketone reduction and hydrolysis produced the bicycHc lactone acid (82) which was converted to the Corey aldehyde equivalent (83). A number of other approaches have been described (108). 

According to a kinetic study which included (56), (56a) and some oxaziridines derived from aliphatic aldehydes, hydrolysis follows exactly first order kinetics in 4M HCIO4. Proton catalysis was observed, and there is a linear correlation with Hammett s Ho function. Since only protonated molecules are hydrolyzed, basicities of oxaziridines ranging from pii A = +0.13 to -1.81 were found from the acidity rate profile. Hydrolysis rates were 1.49X 10 min for (56) and 43.4x 10 min for (56a) (7UCS(B)778). O-Protonation is assumed to occur, followed by polar C—O bond cleavage. The question of the place of protonation is independent of the predominant IV-protonation observed spectroscopically under equilibrium conditions all protonated species are thermodynamically equivalent. 

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