1,6 Additions, Grignard

An alternative strategy is to put a 3-(-2-dioxolanyl)ethanoyl substituent in place first and then add the C7-substituent by a Grignard addition. This approach was applied to the synthesis of 8.2C but in this case it was found necessary to remove the tosyl protecting group prior to cyclization[l]. 

Titanium tetrakis(diethylamide) selectively adds to aldehydes in the presence of ketones and to the least hindered ketone in compounds containing more than one ketone. The protection is in situ, which thus avoids the usual protection-deprotec-tion sequence. Selective aldol and Grignard additions are readily performed employing this protection methodology. ... 

Application of the cuprous chloride-catalyzed conjugate Grignard addition to A -5a-3-ketones (13) gives la-methyl compounds (14) in yields up to... 

Grignard addition occurs towards the j5-face of the molecule with A -5)5-3-ketones (18) to form the axial lj5-methyl compounds (19). The reaction is not influenced by the presence of an 11a- or 1 l)5-hydroxyl group, an 11-ketone or a 9(1 l)-double bond. ... 

Grignard additions to conjugated ketones preparation of la-methyl-17,20 20,21-bismethylenedioxypregna-4,6-diene-... 

The number of examples of reaction with alkyllithium reagents is very limited (14,48). The similarity of the reaetion to Grignard addition suggests that similar products will be obtained. This suggestion is supported by the examples shown in Table 6. 

Formally analogous to the foregoing Grignard additions are the intramolecular condensations of amides with aromatic systems, found in the Bischler-Napieralski reaction 101), which is of particular interest in isoquinoline and indole alkaloid syntheses (102). Condensations of amidines with reactive methylene compounds also led to enamines (103-106). 

Grignard and alkyl lithium reagents were found to add to the carbonyl group of a tricyclic vinylogous amide. However, the same compound underwent the usual vinylogous reduction with lithium aluminum hydride (712). Grignard additions to di- and trichloroenamines gave a-chloro- and dichloroketones (713). 

Another example is tamoxifen (89). Its synthesis begins with Grignard addition of reagent to aryl ketone giving carbinol Dehydration leads to the readily separable and... 

The reduction of carbonyl compounds by reaction with hydride reagents (H -) and the Grignard addition by reaction with organomagnesium halides (R - +MgBr) are examples of nucleophilic carbonyl addition reactions. What analogous product do you think might result from reaction of cyanide ion with a ketone ... 

At the stage of the ketone 20, or the analogous methyl carboxylate, further substituents can be introduced diastereoselectively by Grignard additions or by enolate methodology4 6. 

The Grignard addition to unsymmelrica] cyclic imides proceeds with high rcgioselectivity with preferential addition to the less hindered carbonyl group50 54. 

Acids (11) and (12) were both made by Grignard addition to COg rather than by cyanide displaceinent (p T 80). Why ... 

Cyanide displacement is impossible on halide (14) and gives much elimination on secondary halide (13), The Grignard addition avoids these problems and gives high yields. ... 

Grignard addition to COg must be the answer with this crowded acid and this leads us back to alcohol (20), Disconnection of any group now gives a simple ketone and an available alkyl halide. As we shall see in Chapter 11, it is best to divide the molecule into two nearly equal parts, so we shall use disconnection (a). 

Note that (35) must be the stereoisomer with Ph and Cl trans for the anti-peri-planar arrangement required for the stereospecific rearrangement, and so the GrIgnard addition must be highly stereoseleetive. This all makes sense by con formatlonal analysis. 

Optically active ketone (6) was needed for a study of asymmetric induction It could be made from acid (7) by a Friedel Crafts route or from nitrile (8) by Grignard addition, but neither of these compounds could be made by alkylation as the branchpoint is on the 3 carbon ( in each). The 1,3 C-C disconnection, e.g. (6b) is not good as it destroys the chiral centre. 

Problems of acyl anion equivalents met above in the synthesis of similar TMs disappear if (25) is made from the alkene (26), A Wittig is the obvious method to make (26) and reaction between (27) and PhgCO will probably give (26), An alternative is the dehydration of (28), made by Grignard addition to ester (20), Osmium tetroxide was used for the hydroxylation. 

Several Grignard reactions are used on an industrial scale in drug synthesis.95 The syntheses of both tamoxifen and droloxifene, which are estrogen antagonists used in treatment of breast cancer and osteoporosis, respectively, involve Grignard addition... 

Grignard additions are sensitive to steric effects and with hindered ketones a competing process leading to reduction of the carbonyl group can occur. A cyclic TS is involved. 

The enantioselective synthesis in Scheme 13.22 is based on stereoselective reduction of an a, (3-unsaturated aldehyde generated from (—)-(.V)-limonene (Step A). The reduction was done by Baker s yeast and was completely enantioselective. The diastereoselectivity was not complete, generating an 80 20 mixture, but the diastere-omeric alcohols were purified at this stage. After oxidation to the aldehyde, the remainder of the side chain was introduced by a Grignard addition. The ester function... 

The ketone 15 was eventually prepared by Grignard addition to Weinreb amide 21, as shown in Scheme 5.5. The Weinreb amide 21 was prepared from p-iodobenzoic acid (20). The phenol of readily available 3-hydroxybenzaldehyde (22) was first protected with a benzyl group, then the aldehyde was converted to chloride 24 via alcohol 23 under standard conditions. Preparation of the Grignard reagent 25 from chloride 24 was initially problematic. A large proportion of the homo-coupling side product 26 was observed in THF. The use of a 3 1 mixture of toluene THF as the reaction solvent suppressed this side reaction [7]. The iodoketone 15 was isolated as a crystalline solid and this sequence was scaled up to pilot plant scale to make around 50 kg of 15. 

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