Secondary Grignard reactions

The alkaloids cotamine (259), hydrastinine (261), and berberinal (260), each possessing a grouping formed by interaction of an aldehyde with a secondary amino group in their molecule, are unusual. The Grignard reaction of free base 166 does not occur as readily as that of the corresponding salt 167. Both reactions lead to the alkylated product 168. For example, only 50% of hydrastinine reacts and 50% is regenerated, whereas hydrastinine hydrochloride reacts almost quantitatively (261). The salt undoubtedly contains a C=N double bond. In the case of the free base, the presence of a C=N double bond was not proven, and the reaction probably occurs by direct cleavage of the C—OH bond. 

Tertiary alky] Grignard reagents are extremely unreactive toward ethylene oxide, giving rise exclusively to ethylene haJohydrins under conditions normally suitable for reactions with primary or secondary Grignard reagents.898 s b jn other words, in terras of the... 

Bicyclobulanolides A-substituted-1-butenolides. 1 Primary and secondary Grignard reagents react with the bicyclic anhydride 1 to form bicyclobulanolides (2) in 80-100% yield. Distillation of 2 effects a retro Diels-Alder reaction to give 4-disubstituted 2-butenolides (3). 

Furthermore, bromothioethenes were reported as fairly useful electrophiles for the coupling reaction with secondary Grignard reagents (Table 5.1, entries 18 and 19) [13]. These transformations occur highly stereo- and chemoselectively at the vinyl bromide moiety whereas the thiophene functionality remains conserved under the described reaction conditions. 

Because the target molecule is an eight-carbon secondary alcohol and the problem restricts our choices of starting materials to alcohols of hve carbons or fewer, we are led to consider building up the carbon chain by a Grignard reaction. 

The Grignard reaction is the only simple method available that is capable of producing primary, secondary, and tertiary alcohols. To produce a primary alcohol, the Grignard reagent is reacted with formaldehyde. 

The Grignard Reaction is the addition of an organomagnesium. halide (Grignard reagent) to a ketone or aldehyde, to form a tertiary or secondary alcohol, respectively. The reaction with formaldehyde leads to a primary alcohol. 

Fig. Synthesis of primary, secondary, and tertiary alcohols by the Grignard reaction.

We found that Friedel-Crafts alkylation of CTM or CTR was possible, as well as acylation [364). In this manner, a number of CTM homologs were obtained (365-367). Dehydration of the CTM alcohols gave us the alkenyl derivatives. Reduction of the acylated derivatives and use of Grignard reactions were a source of secondary and tertiary alcohols whose dehydration gave us the alkenyl derivatives [Nesmeyanov, Anisimov, Kolobova, Zlotina (368, 369)]. 

As in the Grignard reaction we may use any aliphatic aldehyde, ketone, ester or acid chloride, or an aryl compound of the same type and also, we may use either alkyl magnesium halides or aryl magnesium halides the synthesis makes possible the preparation of practically any desired secondary or tertiary alcohol either aliphatic or aromatic. Also if formaldehyde, in the form of its polymer, tri-oxy methylene, is used in the second reaction we will obtain primary alcohols. In the third reaction formic acid esters yield secondary instead of tertiary alcohols. These syntheses of alcohols by the Grignard reaction give us an idea of its importance in synthetic work. 

Primary and secondary Grignard reagents all gave addition reaction products in yields between 10 and 20%, but the rates of reaction increased by a factor of 10 for each hydrogen in the -position. Table 5 presents some of the results obtained. A six-center transition state seems indicated in which the -hydrogen atom is very close to an azo-nitrogen. Comparison of the results obtained with benzophenone as the substrate did not lead to satisfactory answers for the exact mechanisms involved. 

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