Esters and Other Carboxylic Acid Derivatives to Aldehydes

Esters and Other Carboxylic Acid Derivatives to Aldehydes 4.4.1 Diisobutylaluminium Hydride 

Diisobutylaluminium hydride (DIBAL-H) is a bulky hydride reducing agent that is very useful for the stereoselective reduction of prochiral ketones and reductions at 

To a solution of the /V-inethyl-O-meihyl amide (1.65 g, 3.06 mmol) in THF (30 mL) at -78 °C was added DIBAL-H (2.90 mL of a 1.5 M solution in toluene, 4.35 mmol). After the reaction was stirred for 45 min, a saturated solution of potassium sodium tartrate (100 mL) was added and the mixture extracted with ether. The combined organic layers were dried, filtered, and concentrated. Purification by flash chromatography afforded 1.37 g (93%) of the aldehyde as a colorless oil. 

To a solution of the /-lactone (0.880 g, 5.47 mmol) in dry CH2C12 (30 mL) maintained at -78 °C was added DIBAL-H (1.5 M in toluene, 4.0 mL, 6 mmol), and the mixture was stirred for 30 min at -78 °C. Solid ammonium chloride (0.4 g) and methanol (1 drop) were added, and the mixture was filtered through a short column of silica gel which was subsequently rinsed with 5% methanol in EtOAc. The filtrate was concentrated under reduced pressure, and the residue was chromatographed (20 g of silica gel, EtOAc hexane, 1 1) to afford 0.621 g (76%) of the lactol as a colorless oil. 

Fukuyama reduction is a mild method for the conversion of thioesters to aldehydes in the presence of other susceptible functional groups, including amides, esters, lactones, and acetonides. Review Fukuyama, T. Tokuyama, H. Aldrichimica Acta 2004, 37, 87-96. 

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The carbonyl group is one of the most prevalent of the functional groups and is involved in many synthetically important reactions. Reactions involving carbonyl groups are also particularly important in biological processes. Most of the reactions of aldehydes, ketones, esters, carboxamides, and the other carboxylic acid derivatives directly involve the carbonyl group. We discussed properties of enols and enolates derived from carbonyl compounds in Chapter 6. In the present chapter, the primary topic is the mechanisms of addition, condensation and substitution reactions at carbonyl centers. We deal with the use of carbonyl compounds to form carbon-carbon bonds in synthesis in Chapters 1 and 2 of Part B. 

Until about 1950, reduction of carboxylic acids and their derivatives to aldehydes was not straightforward, and even one of the best methods, the Rosenmund hydrogenation of acid chlorides, required very careful control of both the reaction conditions and preparation of catalyst. The advent of aluminum and boron hydrides and their ready commercial availability transformeKl the situation to such an extent that the formation of aldehydes from carboxylic acids, acid chlorides, esters, amides, nitriles and similar groups in the presence of other reducible functional groups has become a relatively easy operation on both small and large scale. 

By judicious choice of chiral auxiliary-reagent pairs, it has been possible to extend this chemistry to the enantioselective synthesis of p-hydroxy-a-methyl-carboxylic acid derivatives having either anti or syn stereochemistry (Schemes 24 and 25). For example, the boron azaenolate obtained upon reaction of (65) with diisopinocamphenylboryl triflate reacts with a series of aldehydes to provide adducts that are readily converted to the anti methyl esters (66) in good overall yields (Scheme 24). The anti.syn ratios for these reactions are typically >9 1, and the percentage enantiomeric excesses for the anti adducts are in the range of 77-85%. On the other hand, the boron azaenolate derived from oxazoline (61c) and 9-borabicyclononane triflate reacts with aldehydes to give adducts that can be converted into the methyl esters of the jyn-carboxylic acids (67 Scheme 25). The symanti ratios in these reactions are typically... 

It is possible to reduce a few other carbonyl compounds using catalytic hydrogenation, but not all. Partial reduction is also possible. Carboxylic acid derivatives are an obvious choice, but carboxylic acids themselves, as well as esters, are difficult to reduce by catalytic hydrogenation. Likewise, amides are very difficult to reduce, but acid chlorides are an exception. Acid chlorides are converted to alcohols via catalytic hydrogenation with an excess of hydrogen gas. However, it is also possible to reduce an acid chloride to an aldehyde with the proper catalyst and control of the number of molar equivalents of hydrogen gas. 

In conjugate reduction of enones with other transition metals such as chromium, the rates of reduction were shown to be dependent on the conformation of the substrate, with faster reactions being observed with the cisoid forms as compared with the transoid onesJ However, with the Pd/Si/Zn system, the rigid transoid enone of cyclohexenone and the flexible enone of acetylcyclohexene are both reduced in comparable rates. This indicates that palladium interacts exclusively with the olefinic part of the enone without significant participation of the carbonyl. Interestingly, this method is highly selective for unsaturated ketones and aldehydes, as the reduction of corresponding o,jS-unsaturated carboxylic acid derivatives, such as esters, amides, and nitriles, is very slow under the conditions used. Thus, ben-zylideneacetone is selectively and cleanly reduced in the presence of methyl cinnamate, dnnamonitrile, or dnnamamide.t" ... 

Hydrolysis of the pyrethroids may occur prior to hydroxylation. For dichloro groups (i.e., cyfluthrin, cypermethrin and permethrin) on the isobutenyl group, hydrolysis of the trans-isomers is the major route, and is followed by hydroxylation of one of the gem-dimethyls, the aromatic rings, and hydrolysis of the hydroxylated esters. The cis-isomers are not as readily hydrolyzed as the tran -isomers and are metabolized mainly by hydroxylation. Metabolism of the dibromo derivative of cypermethrin, deltamethrin, is similar to other pyrethroids (i.e., cyfluthrin, cypermethrin, and permethrin) that possess the dichloro group. Type 11 pyrethroid compounds containing cyano groups (i.e., cyfluthrin, cypermethrin, deltamethrin, fenvalerate, fenpropathrin, and fluvalinate) yield cyanohydrins (benzeneacetonitrile, a-hydroxy-3-phenoxy-) upon hydrolysis, which decompose to an aldehyde, SCN ion, and 2-iminothia-zolidine-4-carboxylic acid (TTCA). Chrysanthemic acid or derivatives were not used in the synthesis of fenvalerate and fluvalinate. The acids (i.e., benzeneacetic acid, 4-chloro-a-(l-methylethyl) and DL-valine, Af-[2-chloro-4-(trifluoromethyl) phenyl]-) were liberated from their esters and further oxidized/conjugated prior to elimination. Fenpropathrin is the oifly pyrethroid that contains 2,2,3,3-tetramethyl cyclopropane-carboxylic acid. The gem-dimethyl is hydroxylated prior to or after hydrolysis of the ester and is oxidized further to a carboxylic acid prior to elimination. 

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-... 

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