Aldehydes from ester reduction

In the amide reduction scheme on p. 618, the step framed in green gives an iminium ion. Stopping the reaction here would therefore provide a way of making aldehydes from amides. Because these tetrahedral intermediates are rather more stable than those from ester reduction, this can often be achieved simply by carrying out the amide reduction, and quenching, at 0°C (-70 °C is usually needed to stop esters overreducing to alcohols). 

Hydrogenation in alcoholic acid converts ketones into ethers Good yields of aldehydes from esters as well as hydroxyaldehydes from lactones can be obtained by reduction with NaAlH4 at low temp. The preparation of aldehydes under mild conditions by cleavage of p-dimethylaminophenlycarbinols with diazotized sul-... 

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]... 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

The strategy for the construction of 13 from aldehyde 16 with two units of phosphonate 15 is summarized in Scheme 12. As expected, aldehyde 16 condenses smoothly with the anion derived from 15 to give, as the major product, the corresponding E,E,E-tri-ene ester. Reduction of the latter substance to the corresponding primary alcohol with Dibal-H, followed by oxidation with MnC>2, then furnishes aldehyde 60 in 86 % overall yield. Reiteration of this tactic and a simple deprotection step completes the synthesis of the desired intermediate 13 in good overall yield and with excellent stereoselectivity. 

The dynamic resolution of an aldehyde is shown in Figure 8.40. The racemization of starting aldehyde and enantioselective reduction of carbonyl group by baker s yeast resulted in the formation of chiral carbon centers. The enantiomeric excess value of the product was improved from 19 to 90% by changing the ester moiety from the isopropyl group to the neopentyl group [30a]. 

ALDEHYDES BY OXIDATION OF TERMINAL OLEFINS WITH CHROMYL CHLORIDE 2,4,4-TRIMETHYL-PENTANAL, 51, 4 ALDEHYDES FROM ACID CHLORIDES BY MODIFIED ROSENMUND REDUCTION 3,4,5—TRIMETHOXYBENZ-ALDEHYDE, 51, 8 ALDEHYDES FROM ACID CHLORIDES BY REDUCTION OF ESTER MESYLATES WITH SODIUM BOROHY-DRIDE CYCLOBUTANECARBOXAL-DEHYDE, 51, 11... 

Kinetic studies established that tetra-n-butylammonium borohydride in dichloromethane was a very effective reducing agent and that, by using stoichiometric amounts of the ammonium salt under homogeneous conditions, the relative case of reduction of various classes of carbonyl compounds was the same as that recorded for the sodium salt in a hydroxylic solvent, i.e. acid chlorides aldehydes > ketones esters. However, the reactivities, ranging from rapid reduction of acid chlorides at -780 C to incomplete reduction of esters at four days at 250 C, indicated the greater selectivity of the ammonium salts, compared with sodium borohydride [9], particularly as, under these conditions, conjugated C=C double bonds are not reduced. 

AT-Boc group, was followed by reductive debenzylation of 30 and Yamaguchi lactonization of the resultant hydroxy acid to provide macrodiolide 31 in 25% yield accompanied by a dimer. Finally, removal of the N-Boc group and reductive N-methylation yielded pamamycin-607 (lb). In total, ca. 40 steps were required to access the target from ester 4, aldehyde 22, and allyl stannanes 10 and ent-lO. 

In contrast to phenolic hydroxyl, benzylic hydroxyl is replaced by hydrogen very easily. In catalytic hydrogenation of aromatic aldehydes, ketones, acids and esters it is sometimes difficult to prevent the easy hydrogenolysis of the benzylic alcohols which result from the reduction of the above functions. A catalyst suitable for preventing hydrogenolysis of benzylic hydroxyl is platinized charcoal [28], Other catalysts, especially palladium on charcoal [619], palladium hydride [619], nickel [43], Raney nickel [619] and copper chromite [620], promote hydrogenolysis. In the case of chiral alcohols such as 2-phenyl-2-butanol hydrogenolysis took place with inversion over platinum and palladium, and with retention over Raney nickel (optical purities 59-66%) [619]. 

One-step reduction of aldehyde and ester functions in intermediate 263a (R = Me, = H) results in a di-alcohol, which, when treated with P2O5, undergoes cyclization into oxazepine 264 (Scheme 56 (2005BMCL2515)). Similarly, this reaction sequence can start from monoester 263b (R = H, r2 = OH (2001JCS(P1)1039)). 

Tetracaine Tetracaine, the 2-diethylaminoethyl ester of 4-butylaminobenzoic acid (2.1.6), is also structurally analogous to procaine, in which the amino group of the benzene ring is replaced by a butylamine radical. The methods for its synthesis are the same as the above-mentioned methods for procaine or chloroprocaine, with the exception of using 4-butylaminobenzoic acid in place of 4-aminobenzoic acid. There is also a proposed method of synthesis that comes directly from procaine (2.1.1). It consists on its direct reaction with butyric aldehyde and simultaneous reduction by hydrogen using a palladium on carbon catalyst [6]. 

ALDEHYDES FROM ACID CHLORIDES BY REDUCTION OF ESTER-MESYLATES WITH SODIUM BOROHYDRIDE CYCLOBUTANECARBOXALDEHYDE... 

Primary and tertiary alcohols are obtained conveniently from esters by the reduction of LiAlH4 and two molar equivalents of organometallic reagents (R MgX or R Li), respectively (see Sections 5.7.22 and 5.5.5). A less powerful reducing agent, diisobutylaluminium hydride (DIBAH), reduce an ester to an aldehyde (see Section 5.7.22). 

Notes A reducing agent. Alcohols are generated from aldehydes, ketones, esters and acid chlorides. Nitriles can be converted to aldehydes. Tosylates will be replaced by -H halides are inert. Amides are reduced to amines. Reduction of lactones can provide a useful synthetic strategy ... 

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). 

N-Methylated y-amino-p-hydroxy acids are accessible by the usual synthetic sequences, i.e. aldol condensation or y-amino-P-oxo ester reduction, starting from the corresponding N-methylated a-amino acids, but are obtained with low diastereoselectivity. 61-63 Alternatively, Brown allylboration of the ALBoc-ALMe amino aldehyde 16 (R1 = Bzl, X=Boc, Y = Me) gives the allyhc N-methylated intermediate 27 in 64% yield and 90% de (Scheme 12). 64 Oxidative cleavage of the alkenol is performed using the two-step ozonolysis and sodium chlorite oxidation sequence. 

Attempts to synthesize C-terminal peptide aldehydes using other reductive techniques are less successful. 24"29 The reduction of a-amino acid esters with sodium amalgam and lithium aluminum hydride reduction of tosylated a-aminoacyldimethylpyrazoles resulted in poor yields. 26,29 The Rosemond reduction of TV-phthaloyl amino acid chlorides is inconvenient because the aldehyde is sensitive to hydrazine hydrate that is used to remove the phthaloyl group. 27 28 jV -Z-Protected a-aminoacylimidazoles, which are reduced to the corresponding aldehydes using lithium aluminum hydride, are extremely moisture sensitive and readily decomposed. 25 The catalytic reduction of mixed carbonic/carboxylic acid anhydrides, prepared from acylated a-amino acids, leads to poor reproducibility and low yields. 24 The major problems associated with these techniques are overreduction, racemization, and poor yields. 

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