Grignard reaction with acetaldehyde

Now let s draw the forward scheme. Hydrolysis of acetonitrile gives acetic acid which is subsequently reduced to ethanol upon treatment with excess LAH, followed by water work-up. Upon treatment with PBrj, ethanol is converted to ethyl bromide which is then converted to ethyl magnesium bromide (a Grignard reagent). A Grignard reaction with acetaldehyde (produced by PCC oxidation of ethanol, as shown), followed by water work-up, produces the desired alcohol, 2-butanol. 

Miscellaneous Reactions. Sodium bisulfite adds to acetaldehyde to form a white crystalline addition compound, insoluble in ethyl alcohol and ether. This bisulfite addition compound is frequendy used to isolate and purify acetaldehyde, which may be regenerated with dilute acid. Hydrocyanic acid adds to acetaldehyde in the presence of an alkaU catalyst to form cyanohydrin the cyanohydrin may also be prepared from sodium cyanide and the bisulfite addition compound. Acrylonittile [107-13-1] (qv) can be made from acetaldehyde and hydrocyanic acid by heating the cyanohydrin that is formed to 600—700°C (77). Alanine [302-72-7] can be prepared by the reaction of an ammonium salt and an alkaU metal cyanide with acetaldehyde this is a general method for the preparation of a-amino acids called the Strecker amino acids synthesis. Grignard reagents add readily to acetaldehyde, the final product being a secondary alcohol. Thioacetaldehyde [2765-04-0] is formed by reaction of acetaldehyde with hydrogen sulfide thioacetaldehyde polymerizes readily to the trimer. 

Metalloid azoles frequently show expected properties, especially if not too many heteroatoms are present. Thus Grignard reagents prepared from halogen-azoles (see Section 4.02.3.9.3) show normal reactions, as in Scheme 60. 2-Lithioimidazoles react normally, e.g. with acetaldehyde (Scheme 61) (70AHC(12)103) 5-lithioisothiazoles (see Scheme 62) (72AHC(14)1) and 2-lithiothiazoles undergo many of the expected reactions. 

Glycine ethyl ester hydrochloride, 14, 46 16, 86 17, 92 Grignard reaction in -butyl ether, 11, 84 with acetaldehyde, 12, 48 with butyl p-toluenesulfonate, 10, 4 with carbon dioxide, 11, 80 with dimethyl sulfate, 11, 66 with ethyl carbonate, 11, 98... 

Eliel s oxathiane auxiliary was used for stereoselective transformations and has been reviewed in part <2003H(60)1477>. As expected, reaction of the lithiated auxiliary with acetaldehyde gave the addition product with low stereoselectivity at the side-chain stereocenter <1997M201>. Better stereocontrol was observed, when methyl Grignard reagent was added to 2-acyl-l,3-oxathiane <2000JCCS63>. Reaction of 2-vinyl-l,3-oxathiane with 1,1-diphenylethene, mediated by TiCU, afforded dihydrothiopyrans in 82% yield, albeit with low enantioselectivity (Scheme 84) <2003T1859>. 

On the other hand, the adducts with a carbon-carbon linkage, e.g. 6-cyanodihydrobenzophenanthridines (Scheme 1, Nu = CN) are rather re-sistent to acids. A number of reactions with carbon nucleophiles (cyanide, Grignard reagent, nitromethane, acetone, butanone, acetaldehyde) are known and weU documented in the literature [8], Only a little is known about QBA reactions with oxygen, nitrogen, and sulfur nucleophiles [8]. 

An acceptable method is to oxidize methyl benzyl carbinol (l-phenyl-2-propanol) to phenylacetone (methyl benzyl ketone) with chrome oxide (CrO3) in pyridine solvent. The problem with this is that methyl benzyl carbinol is not commercially available, and so must be made from benzyl chloride grignard reagent and acetaldehyde. This grignard works well, although there can be a problem getting unreacted benzyl chloride out of the product. Their boiling points are very close, so distillation does not separate them completely. But the real question is Why make the synthesis of phenylacetone a two-step process when it can be done with one reaction ... 

Bakuzis has explored the use of an interesting (B-acrylate anion equivalent in his synthesis of 9 (Scheme 4.5) ° The Grignard reagent from 3-bromopropyl phenyl sulfide was condensed with acetaldehyde and the resulting alkoxide was acylated to procure 24 (70%). Oxidation of the sulfide to aldehyde 25 proceeded in 74% yield. Reaction of 25 with ethyl 3-nitropropionate followed by elimination of HNO2 from the intermediate afforded 26. The latter step, equivalent to the addition of the p-carbanion of ethyl acrylate, occurred in 38% yield. Oxidation of alcohol 26, protection of the resulting ketone, and saponification gave 17. This intermediate was then dimerized as previously described to a mixture of 9 and its meso diastereomer. 

The key step in a basealdol reaction is nucleophilic addition of the enolate anion from one carbonyl-containing molecule to the carbonyl group of another carbonyl-containing molecule to form a tetrahedral carbonyl addition intermediate. This mechanism is illustrated by the aldol reaction between two molecules of acetaldehyde. Notice that OH is a true catalyst An OH is used in Step 1, but another OH is generated in Step 3. Notice also the parallel between Step 2 of the aldol reaction and the reaction of Grignard reagents with aldehydes and ketones (Section 12.5) and the first step of their reaction with esters (Section 14.7). Each type of reaction involves the addition of a carbon nucleophile to the carbonyl carbon of another molecule. 

The substrate also plays a key role in the reactivity of the [CH3MgL2] ions. This is dramatically illustrated for the reaction of aldehydes containing enolizable protons, which reacted via enolization (Eq. (6.21)) rather than via the Grignard reaction (Eq. (6.22)). This is consistent with DFT calculations on the competition between enolization and the Grignard reaction for [CH3MgCl2] ions reacting with acetaldehyde, which suggest that while the latter has a smaller barrier, it is entropically disfavored. 

The acetylenic group can be a handle for further functionalization. Typical examples are conversion into a propyne, as in the reaction of a sodium salt with methyl iodide 223), or into the 3-butene-1-yne substituent found in 1. The latter reaction, illustrated in Scheme 22, forms product 1 by thermal dehydration of the alcohol obtained when the Grignard reagent reacts with acetaldehyde 199). In an alternative... 

Now let s draw the forward scheme. Ethyl bromide is converted into ethyl magnesium bromide, which is then treated with acetaldehyde (to give a Grignard reaction), followed by water work-up, to give 2-butanol. Oxidation of 2-butanol with chromic acid gives 2-butanone, which can then be converted into a cyanohydrin upon treatment with KCN and HCl. And finally, hydrolysis of the cyano group gives the desired product ... 

Similar to reactions of iodopyrimidines previously mentioned in Section 6.2.2.2 (60 —> 61), the Grignard reagent 171, efficiently prepared from halopyridazine 170, was quenched with electrophiles such as acetaldehyde, ethyl cyanoformate, DMF or phenylsulfide to give 172 in acceptable yields <00T265>. 

Reaction of an aldehyde with a Grignard or organolithium reagent generates a secondary alcohol. For example, acetaldehyde reacts with methyl magnesium bromide to give 2-propanol. 

An example of a sugar-derived chiral -haloketone is offered by 24. When ulosyl bromide 24 is coupled to acetaldehyde in a Grignard-type process, a mixture of isomeric adducts is formed, where the 50% is represented by 25, possessing the (R) configuration at the hydroxy ethyl substituent (equation 21). The same protocol is applied in an efficient nucleophilic C-glycosidation reaction of 24 with galactose-derived aldehyde 26 to give 27 (equation 22)20. 

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