Grignard reagents ketone synthesis

Nakamura E, Kubota K, Sakata G, Addition of zincated hydrazone to vinyl grignard reagent, Ketone synthesis by one-pot assembly of four components, J. Am. Chem. Soc., 119 5457-5458, 1997. 

An ability to form carbon-carbon bonds is fundamental to organic synthesis The addition of Grignard reagents to aldehydes and ketones is one of the most frequently used reactions m synthetic organic chemistry Not only does it permit the extension of carbon chains but because the product is an alcohol a wide variety of subsequent func tional group transformations is possible... 

Tertiary alcohols can be prepared by a variation of the Grignard synthesis that uses esters as the source of the carbonyl group Methyl and ethyl esters are readily available and are the types most often used Two moles of a Grignard reagent are required per mole of ester the first mole reacts with the ester converting it to a ketone... 

Alcohol synthesis via the reaction of Grignard reagents with carbonyl com pounds (Section 14 6) This is one of the most useful reactions in synthetic organ ic chemistry Grignard reagents react with formaldehyde to yield primary alco hols with aldehydes to give secondary alcohols and with ketones to form terti ary alcohols... 

Synthesis of alcohols using organolithi um reagents (Section 14 7) Organolithi um reagents react with aldehydes and ketones in a manner similar to that of Grignard reagents to produce alcohols... 

Craig s synthesis of nicotine (V to VII, p. 42) proceeds via nomicotine. Nicotinic acid nitrile reacts with the Grignard reagent derived from ethyl y-bromopropyl ether to give 3-pyridyl-y-ethoxypropyl ketone (V). This yields an oily oxime (VI) reducible to a-(3-pyridyl)-a-amino-8-ethoxy-w-butane (VII), which with 48 per cent, hydrobromic acid at 130-3° gives womicotine, and this on methylation yields dZ-nicotine. 

All that has been said in this section applies with equal force to the use of organo-lithium reagents in the synthesis of alcohols. Grignard reagents are one source of nucleophilic carbon organolithium reagents are another. Both have substantial carbanionic char acter in their- car bon-metal bonds and undergo the same kind of reaction with aldehydes and ketones. 

Synthesis of acetylenic alcohols (Section 14.8) Sodium acetylide and acetylenic Grignard reagents react with aldehydes and ketones to give alcohols of the type... 

For an improved procedure with amides, see Olah, G.S. Prakash, G.K.S. Arvanaghi, M. Synthesis, 1984, 228. See Martin, R. Romea, R Tey, C. Urpi, R Vilarrasa, J. Synlett, 1997, 1414 for reaction with an amide derived from morpholine and Grignard reagents, whch gives the ketone in good yield. See Kashima, C. Kita, I. Takahashi, K. Hosomi, A. J. Heterocyclic Chem., 1995, 32, 25 for a related reaction. 

Reaction of a-sulphinyl carboxylic esters 421 with carbonyl compounds has usually been performed using a Grignard reagent as a base. No condensation products are obtained using f-butyllithium or sodium hydride - (equation 251). The condensation products formed are convenient starting materials for the synthesis of a, ) -unsaturated esters and j -ketones . ... 

Trialkylsilyl groups have a modest stabilizing effect on adjacent carbanions (see Part A, Section 3.4.2). Reaction of the carbanions with carbonyl compounds gives (3-hydroxyalkylsilanes. (3-Hydroxyalkylsilanes are converted to alkenes by either acid or base.270 These eliminations provide the basis for a synthesis of alkenes. The reaction is sometimes called the Peterson reaction.211 For example, the Grignard reagent derived from chloromethyltrimethylsilane adds to an aldehyde or ketone and the intermediate can be converted to a terminal alkene by acid or base.272... 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

One reaction that is quite efficient for lithium reagents but poor for Grignard reagents is the synthesis of ketones from carboxylic acids.112 The success of the... 

Moreover, the authors were able successfully to apply this process to the synthesis of the antibiotic (+)-CP-263,114 (2-912) (Scheme 2.203) [454]. Transformation of the bromide 2-908 into the vinyl Grignard reagent 2-909, followed by addition to the ketone 2-910, led to the bridged carbocyclic compound 2-911 which was then transformed into the target compound within a few steps. 

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