Aldehydes sulfonate esters

The key intermediate in these transformations was the hydrazide 83 obtained from the ester 82 by simple treatment with hydrazine hydrate. This intermediate was then transformed by aldehydes, sulfonic chlorides, and isothiocyanates to obtain various aryl hydrazones 84, sulfonylhydrazines 85, and thiocarbazides 86. 

Another important reaction in synthetic chemistry leading to C-C bond formation is the Michael addition. The reaction typically involves a conjugate or nucleophilic 1,4-addition of carbanions to a,/l-unsaturated aldehydes, ketones, esters, nitriles, or sulfones 157) (Scheme 21). A base is used to form the carbanion by abstracting a proton from an activated methylene precursor (donor), which attacks the alkene (acceptor). Strong bases are usually used in this reaction, leading to the formation of byproducts arising from side reactions such as condensations, dimerizations, or rearrangements. 

The cyclopropanation of alkenes using zinc carbenoids displays excellent chemoselec-tivities. A large number of functional groups are compatible with these reagents, such as alkynes, silanes, stannanes, germanes, alcohols, ethers, sulfonate esters, aldehydes. 

A large number of reactions have been presented in this chapter. However, all of these reactions involve an enolate ion (or a related species) acting as a nucleophile (see Table 20.2). This nucleophile reacts with one of the electrophiles discussed in Chapters 8, 18, and 19 (see Table 20.3). The nucleophile can bond to the electrophilic carbon of an alkyl halide (or sulfonate ester) in an SN2 reaction, to the electrophilic carbonyl carbon of an aldehyde or ketone in an addition reaction (an aldol condensation), to the electrophilic carbonyl carbon of an ester in an addition reaction (an ester condensation) or to the electrophilic /3-carbon of an a,/3-unsaturated compound in a conjugate addition (Michael reaction). These possibilities are summarized in the following equations ... 

Nitro is just one of a number of groups that are also deactivating towards electrophiles and metadirecting because of electron withdrawal by conjugation. These include carbonyl groups (aldehydes, ketones, esters, etc.), cyanides, and sulfonates and their ]H NMR shifts confirm that they remove electrons from the ortho and para positions. 

The DTBMS ester was prepared (THF, DTBMSOTf, Et N, rt) to protect an ester so that a lactone could be reduced to an aldehyde. The ester is cleaved with aq. HF/THF or BtUtNE in wet THF. A THP derivative can be deprotected (pyridinium p-toluene-sulfonate, warm ethanol) in the presence of a DTBMS ester. ... 

Many types of reactive molecules are well known to medicinal chemists acyl halides, aldehydes, aliphatic esters, aliphatic ketones, alkyl halides, anhydrides, alpha-halocarbonyl compounds, aziridines, 1,2-dicarbonyl compounds, epoxides, halopyrimidines, heteroatom-heteroatom single bonds, imines, Michael acceptors and (l-heterosubstituted carbonyl compounds, perhalo ketones, phosphonate esters, thioesters, sulfonate esters, and sulfonyl halides, to name a few [14]. This is not to say that these functionalities are not useful - some even appear in approved drugs -but all of these can react covalently with proteins, and thus should be regarded with suspicion. However, molecules can react covalently with proteins even if they do not contain functionalities that raise alarm. Jonathan Baell has referred to these as pan assay interference compounds, or PAINS, and has published a list of moieties to watch out for, as well as strategies to detect them [15, 16]. 

A few years later the Swem laboratory then developed an activator which they claimed to be the most successful in activating dimethyl sulfoxide toward oxidation, namely, oxalyl chloride. Since oxalyl chloride reacted violently and exothermically with dimethyl sulfoxide, successful activation required the use of low temperatures to form the initial intermediate.6 Swem et al. reported the oxidation of long chain primary alcohols to aldehydes which was previously unsuccessful by first converting to the sulfonate ester (either mesylate or tosylate) and then employing the dimethyl sulfoxide-acetic anhydride procedure. They found that long-chain saturated, unsaturated, acetylenic and steroidal alcohols could all be oxidised with dimethyl sulfoxide-oxalyl chloride in high yields under mild conditions. 

In a reaction originating with Michael69 and Claisen,70 compounds containing active hydrogen add to, / -unsaturated aldehydes, ketones, esters, nitriles, sulfones, or nitro compounds, the C-C bond being formed to the vinyl carbon atom that is / to the carbonyl (or analogous) group ... 

The conjugate base of an alkyne is an alkyne anion (older literature refers to them as acetylides), and it is generated by reaction with a strong base and is a carbanion. It funetions as a nucleophile (a source of nucleophilic carbon) in Sn2 reactions with halides and sulfonate esters. Acetylides react with ketones, with aldehydes via nucleophilic acyl addition and with acid derivatives via nucleophilic acyl substitution. Acetylides are, therefore, important carbanion synthons for the creation of new carbon-carbon bonds. Some of the chemistry presented in this section will deal with the synthesis of alkynes and properly belongs in Chapter 2. It is presented here, however, to give some continuity to the discussion of acetylides. 

In this process, 3° alcohols react faster than 2° alcohols. Heterolytic bond cleavage of a halide or sulfonate ester (C-X, X = Br, Cl, I, OMs, OTs, etc.) in aqueous solvents (usually with heating) generates tertiary cations easily, secondary alcohols with difficulty, and primary cations with extreme difficulty. Reaction of aldehydes and ketones with an acid catalyst gives the oxygen-stabilized cation (see 1 and 4). Reaction of amines with nitrous acid (HNO2) initially gives a diazonium salt (5, also see sec. 13.9.B) but alkyl diazonium salts readily decompose to cations. ... 

DONORS. Acetoacetates Aldehydes Carboxylic esters Cyanoacetates Ketones Malonates Nitriles Nitro compounds and Sulfones. 

The sodium acetylide solution thus prepared may be used for a variety of organic syntheses by the addition of alkyl halides, sulfates, sulfonates, ketones, aldehydes, and esters. Where a fine suspension of the dry acetylide is desired in an inert solvent such as ether or a hydrocarbon, the solvent is added to the ammonia solution and the mixture is stirred whde the ammonia is evaporated. Extra solvent must be used to replace that entrained by the ammonia, the last traces of which are removed by a period of refluxing. Such a suspension gives better yields of, for example, propiolic acid (by the reaction with carbon dioxide) than sodium acetylide prepared in any other way. 

Muniz and co-workers prepared a series of substituted indoles (e.g., 76) using a modified Koser reagent that was made from iodosobenzene and 2,4,5-tris-isopropylbenzene sulfonic acid (77, TIPBSA). The hypervalent iodine reagent was used either stoichiometrically or in catalytic amounts with mCPBA as the terminal oxidant. A variety of N-protecting groups were tolerated and substituents on the aryl ring of 75 include halogens, carbonyls (aldehydes, ketones, esters), alkynes, and nitriles (HAG(I)7349). 

In summary, the reactivity of various functional groups toward Li 9-BBNH is classified into four broad categories [18] (1) rapid- or fast-reduction aldehyde, ketone, ester, lactone, acylchloride, acid anhydride, epoxide, disulfide, -alkyli-odide, and tosylate (2) slow-reduction tertiary amide, alkylbromide, and aromatic nitrile (3) sluggish-reduction carboxylic acid, aliphatic nitrile, primary amide, nitro and azoxy compounds, and secondary alkylbromide and tosylate (4) inert olefin, oxime, alkylchloride, sulfoxide, azo-compound, sulfide, sulfone, and sulfonic acid. 

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