Additions of Organometallic Reagents

Alkyl and aryllithium compounds have been found to undergo 1,4-addition with the salts of a, (3-unsaturated acids.328 This result reflects the much reduced reactivity of the carboxylate carbonyl group as an electrophile. 

Similar reactions have also been observed with tertiary amides and the adducts can be alkylated by tandem SN2 reactions. 

Lithiated A-allylcarbamates add to nitroalkenes. In the presence of (-)-sparteine, this reaction is both diastereoselective (anti) and enantioselective.331 

Reactions of Carbon Nucleophiles with Carbonyl Compounds 

The enantioselectivity is due to the retention of the chiral sparteine in the lithiated reagent. The adducts have been used to synthesize a number of pyrrolidine and piperidine derivatives. 

On the basis of a detailed analysis of the resultant akylated and arylated pyridazines 54 and 55 produced by this reaction, Letsinger and Lasco found that the ratio of addition at position 3 to that at position 4 was sensitive to the metal in the organometallic reagent105 Grignard species attacked preferentially at position 4, while organolithiums produced the 3-substituted pyridazines. Both workers106,107 also indicated that the solvent has a marked effect upon orientation, noting that ether promoted formation of 54, while tetrahydrofuran increased the yield of 55. 

In addition, an interesting example of nucleophilic 1,2- and 1,4-addition of thienyllithium to pyridazine, with the formation of corresponding 1,6- (56) and 1,4-dihydropyridazine (57), has been published [Eq. (10)].107 

The product l,4-dihydro-4-(2-thienyl)pyridazine (57) undergoes thermal rearrangement to l,4-dihydro-3-(2-thienyl)pyridazine (58), which is induced by stronger stabilization conjugation between the two rings. 

The addition of organometallics to substituted pyridazines was studied extensively.108-121 Symmetrically 3,6-disubstituted pyridazines yield homogeneous 4-substituted products, but if the substituents differ, the formation of distinct 4- and 5-substituted products is expected. 

On the other hand, pyridazines 59b, c, and d were found to react with tert-butyl Grignard to give primarily the 1,4-dihydro compounds 61b, c, and 

This route has been widely exploited because of the availability of a-amino azomethine compoimds from natural (S)-a-amino acids, through the corresponding a-amino aldehydes, which are configurationally stable provided that the amino function is suitably protected. Moreover, some a-amino acids are available with the R configuration and a number of enzymatic and chemical transformations have been described for the preparation of optically active unnatural a-amino acids. Overall, the route suffers from the additional steps required for protection/deprotection of the amino function and, in the case of hydrazones and nitrones, cleavage of the N - N or N - O bond. 

The chiral a-pyrrolidino imine that is formed in situ in the reaction of a-sulfonyl amide 141 with allylic zinc reagents undergoes addition with mod- 

by selective oxidative removal of the chiral auxiliary and subsequent hy-drogenolysis of the N-benzyl substituents. 

N-substituted and N,N-disubstituted chiral a-amino nitrones are also available from the corresponding a-amino aldehydes. In a first study, it was shown that the addition of phenylmagnesium bromide to N-Boc derivatives exclusively gave the syn N-Boc a-aminohydroxylamines with good yields, but 

On the other hand, following the same sequences from the differently protected serine-derived nitrone 168, through the formation of hydroxylamines 169, C2 epimers of carboxylic acid and aldehydes are obtained, i.e., (2S,3R)-170 and (2S,3R)-171. Moreover, the syn adducts 164 were exclusively obtained in the addition of Grignard reagents to the nitrone 163, whereas the same reactions on nitrone 168 occurred with a partial loss of diastereoselectivity [80]. Q, j6-Diamino acids (2R,3S)- and (2R,3R)-167 can also be prepared from the a-amino hydroxylamines 164 and 169 by reduction, deprotection and oxidation steps. The diastereoselective addition of acetylide anion to N,N-dibenzyl L-serine phenyhmine has been also described [81]. 

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Scheme 2.40 1,4-Addition of organometallic reagents to bis-heterosubstituted enynes.

Addition of Organometallic Reagents to Enones in Aqueous Media Rhodium-catalyzed 1,4-addition of organometallic reagents to a,p-unsaturated compounds was first developed by Miyaura in 1997. Thus, Rh(acac)(CO)2/dppb was found to catalyze the 1,4-addition of aryl- and alkenylboronic acids to several ot,(3-unsaturated ketones in water-containing solvents at 50°C. The reaction conditions were successfully modified for the development of an asymmetric variant of this process by Hayashi and Miyaura in 1998. The important points of modification are (1) the use of Rh(acac)(C2H4)2/(5)-binap as a catalyst and... 

Orignard and Reformatsky reagents also react in this way to give one enantiomer in 10-20% optical yield. Use of the chiral solvent also permits enantioselective 1,4-additions of organometallic reagents to a,/3-unsaturated carbonyl compounds,... 

Hayashi, T. Rhodium-catalyzed Asymmetric 1,4-addition of Organometallic Reagents. Russ. Chem. Bull. 2003,52,2595-2605. 

Selective 1,4-additions of organometallic compounds to o ,/Tun saturated ketones can also be achieved starting from organocopper and organozinc reagents. We will treat this in Section 10.6. 

These products can be used as synthetic equivalents of a,/3-unsaturated aldehydes in Michael reactions. Thus C6HsSCH=CHCH2Cl can be used as the equivalent of acrolein, CH2 =CHCHO, which normally undergoes 1,2- rather than 1,4-addition with organometallic reagents. An interesting example is the preparation of an intermediate (1) to the pyridine annelation reagent of Danishefsky and Cain. ... 

Arylalkylamines 6 by Addition of Organometallic Reagents to 1,3-Oxazolidines 4 and Oxidative Cleavage and Hydrolysis General Procedure22 ... 

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