Carbon Grignard reactions

For some purposes in the Grignard reaction) solid carbon dioxide, narketed as Dry Ice or Drikold, may be employed. 

Unfortunately this route gives only a 40% yield IJ. Amer. Cham. Soc 1951, 73, 3237) in the Grignard reaction, largely because benzyl Grignard reagents easily give radicals which polymerise. In any case, it s poor tactics to chop off carbon atoms one at a time, and a better disconnection would be ... 

Total syntheses have been reported by E.J. Corey (1978B, 1979). We outline only the stereoselective synthesis of a protected fragment (A) which contains carbon atoms 1—9. This fragment was combined with fragment (B) by a Grignard reaction and cyclized by one of the methods typical for macrolide formation (see p. 146). 

TT-Allylpalladium chloride (36) reacts with the nucleophiles, generating Pd(0). whereas tr-allylnickel chloride (37) and allylmagnesium bromide (38) reacts with electrophiles (carbonyl), generating Ni(II) and Mg(II). Therefore, it is understandable that the Grignard reaction cannot be carried out with a catalytic amount of Mg, whereas the catalytic reaction is possible with the regeneration of an active Pd(0) catalyst, Pd is a noble metal and Pd(0) is more stable than Pd(II). The carbon-metal bonds of some transition metals such as Ni and Co react with nucleophiles and their reactions can be carried out catalytic ally, but not always. In this respect, Pd is very unique. 

In Grignard reactions, Mg(0) metal reacts with organic halides of. sp carbons (alkyl halides) more easily than halides of sp carbons (aryl and alkenyl halides). On the other hand. Pd(0) complexes react more easily with halides of carbons. In other words, alkenyl and aryl halides undergo facile oxidative additions to Pd(0) to form complexes 1 which have a Pd—C tr-bond as an initial step. Then mainly two transformations of these intermediate complexes are possible insertion and transmetallation. Unsaturated compounds such as alkenes. conjugated dienes, alkynes, and CO insert into the Pd—C bond. The final step of the reactions is reductive elimination or elimination of /J-hydro-gen. At the same time, the Pd(0) catalytic species is regenerated to start a new catalytic cycle. The transmetallation takes place with organometallic compounds of Li, Mg, Zn, B, Al, Sn, Si, Hg, etc., and the reaction terminates by reductive elimination. 

RM can be a traditional Grignard reagent or an organolithium, 2inc, aluminum, or mercury compound. The Grignard route is employed commercially for production of tertiary phosphines, even though these reactions are subject to side reactions. Yields are often low, eg, 40—50% for (C4H )2P prepared via a Grignard reaction (18). A phosphoms—carbon bond can form from the metathetical reaction of a phosphoms haUde and a pseudohaUde salt. 

Properties of zinc salts of inorganic and organic salts are Hsted in Table 1 with other commercially important zinc chemicals. In the dithiocarbamates, 2-mercaptobenzothiazole, and formaldehyde sulfoxylate, zinc is covalendy bound to sulfur. In compounds such as the oxide, borate, and sihcate, the covalent bonds with oxygen are very stable. Zinc—carbon bonds occur in diorganozinc compounds, eg, diethjizinc [557-20-0]. Such compounds were much used in organic synthesis prior to the development of the more convenient Grignard route (see Grignard reactions). 

Cesium forms simple alkyl and aryl compounds that are similar to those of the other alkah metals (6). They are colorless, sohd, amorphous, nonvolatile, and insoluble, except by decomposition, in most solvents except diethylzinc. As a result of exceptional reactivity, cesium aryls should be effective in alkylations wherever other alkaline alkyls or Grignard reagents have failed (see Grignard reactions). Cesium reacts with hydrocarbons in which the activity of a C—H link is increased by attachment to the carbon atom of doubly linked or aromatic radicals. A brown, sohd addition product is formed when cesium reacts with ethylene, and a very reactive dark red powder, triphenylmethylcesium [76-83-5] (C H )2CCs, is formed by the reaction of cesium amalgam and a solution of triphenylmethyl chloride in anhydrous ether. 

Addition of hydrogen cyanide to an aldose to form a cyanohydrin is the first step in the Kiliani-Fischer method for increasing the carbon chain of aldoses by one unit. Cyanohydrins react with Grignard reagents (see Grignard reaction) to give a-hydroxy ketones. 

The classical Reformatsky reaction consists of the treatment of an a-halo ester 1 with zinc metal and subsequent reaction with an aldehyde or ketone 3. Nowadays the name is used generally for reactions that involve insertion of a metal into a carbon-halogen bond and subsequent reaction with an electrophile. Formally the Reformatsky reaction is similar to the Grignard reaction. 

As with the reduction of carbonyl compounds discussed in the previous section, we ll defer a detailed treatment of the mechanism of Grignard reactions until Chapter 19. For the moment, it s sufficient to note that Grignard reagents act as nucleophilic carbon anions, or carbanions ( R ), and that the addition of a Grignard reagent to a carbonyl compound is analogous to the addition of hydride ion. The intermediate is an alkoxide ion, which is protonated by addition of F O"1 in a second step. 

What product would you expect to obtain from Grignard reaction of an excess of phenylmagnesium bromide with dimethyl carbonate, CH30C02CH3 ... 

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... 

Finally, the necessity arose for the synthesis of pentulose 21, labeled with, 3C on the central carbons, C-2 and C-3, for an independent biosynthetic study, which is reported in Section III.5.27 The doubly labeled ester 34 (Scheme 14) is readily available by a Wittig- Homer condensation of benzyloxyacetaldehyde with commercially available triethylphosphono-(l,2-l3C2)acetate. Chirality was introduced by the reduction of ester 34 to the allylic alcohol, which produced the chiral epoxide 35 by the Sharpless epoxidation procedure. This was converted into the tetrose 36, and thence, into the protected pentulose 37 by the usual sequence of Grignard reaction and oxidation. 

For reviews of the addition of organometallic compounds to carbonyl groups, see Eicher, T. in Patai, Ref. 2, p. 621 Kharasch, M.S. Reinmuth, O. Grignard Reactions of Nonmetallic Substances, Prentice-Hall Englewood Cliffs, NJ, 1954, p. 138. For a review of reagents that extend carbon chains by three carbons, with some functionality at the new terminus, see Stowell, J.C. Chem. Rev., 1984, 84, 409. 

In 1991, Whitesides etal. reported the first application of aqueous medium Barbier-Grignard reaction to carbohydrate synthesis through the use of tin in an aqueous/organic solvent mixture (Eq. 8.48).106 These adducts were converted to higher carbon aldoses by ozonolysis of the deprotected polyols followed by suitable derivatization. The reaction showed a higher diastereoselectivity when there was a hydroxyl group present at C-2. However, no reaction was observed under the reaction conditions when there was an /V-acctyl group present at the C-2 position. 

One of these products (49) was used as a key intermediate for the synthesis of the Amaryllidaceae alkaloids a- and /-lycorane (Scheme 12)53. A copper-catalyzed Grignard reaction with 49 afforded 50 via a selective y-anti displacement of the chloride. Hydrogenation followed by Bischler-Napieralski cyclization gave 51. Interestingly, reversal of the latter two steps gave the isomer 52 where an epimerization at the benzylic carbon had occurred in the cyclization step (>99% selectivity). Subsequent reduction of the amide in each case afforded the target molecules a- and y-lycorane, respectively. The purity of the final product was very high with respect to the opposite stereoisomer. Thus <0.2% of /-lycorane was present in a-lycorane and vice versa. 

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