Development of Barbier-Grignard-type alkylation reaction using unactivated alkyl halides in water.
Shen, Zhi Liang.
Date of Issue2007
School of Physical and Mathematical Sciences
The Barbier-Grignard-type alkylation reaction is one of the most important carbon-carbon bond formation reactions in organic synthesis. Classical methods developed for the Barbier-Grignard-type alkylation reaction are mainly limited to the use of moisture sensitive organometallic reagents such as Grignard reagent (RMgX). Therefore, the development of Barbier-Grignard-type alkylation reaction with the suppression of side reactions arose from the use of Grignard reagent in water are highly desirable. This thesis provides our premilinary studies towards the development of Barbier-Grignard-type alkylation reaction that can work in water. In chapter 2, Barbier-Grignard-type alkylation reaction of aldehydes using unactivated alkyl halides in water has been investigated. Using indium-copper or indium-silver as radical initiator, Barbier-Grignard-type alkylation reaction of aldehydes with unactivated alkyl halides proceeded efficiently in water to give the desired products in moderate to good yields. Among the several metals tested, indium proved to be the best metal for this transformation than zinc, aluminum, tin etc. Without CuI or AgI, the reactions proceeded sluggishly to give the desired products in poor yields. In addition, low yield was obtained without the addition of I2. Furthermore, the reaction proceeded more efficiently in water than in conventional organic solvents. This method is practical and it works well with a wide variety of aldehydes (including aliphatic aldehydes). A radical-type mechanism has been proposed based on the product obtained using 4-pentenal as substrate. On the basis of above observations, an efficient and practical method for the Barbier-Grignard-type alkylation reaction of simple imines using a one-pot condensation of various aldehydes, amines (including aliphatic and chiral version), and secondary alkyl iodides has been developed in water in the presence of indium-copper. The reaction proceeded more efficiently in water than in organic solvents. Without the use of CuI, it mainly afforded imine self-reductive coupling product other than alkylated product. Good diastereoselectivities (up to 99:1 dr) were obtained when L-valine methyl ester was used as substrate. In addition, indium-silver and zinc-silver couples were also demonstrated to be efficient systems for the successful achievements of above transformations, comparable results have been obtained. In chapter 4, an efficient method was developed for the conjugate addition of alkyl groups to a,b-unsaturated carbonyl compounds using indium-copper in water at room temperature. Both CuI and InCl3 are important for the efficient progress of the reaction. In addition, the reaction proceeded more efficiently in water than in organic solvents. This method is practical and it works well with a wide variety of a,b-unsaturated carbonyl compounds. In addition, its application to the conjugate addition of alkyl groups to a,b-unsaturated esters incorporated with chiral auxiliary also has been studied. Furthermore, preliminary results concerning the alkyl addition to C=C double bond of styrene was disclosed. In chapter 5, two efficient methods have been developed for the synthesis of enantiomerically enriched O-acetyl cyanohydrins via one-pot lipase-catalyzed kinetic resolution of the in situ generated racemic cyanohydrins or O-acetyl cyanohydrins in ionic liquid [omim]PF6. Ionic liquid [omim]PF6 served as both reaction media and promoter for the two one-pot reactions. In addition, it was found that the reactions proceeded more efficiently in [PF6]- type ionic liquid than in [BF4]- or Cl- type ionic liquid. This reaction is quite general and it works with a wide variety of aldehydes (including aromatic, aliphatic and conjugate aldehydes) in the absence of any metal complexes. In all cases, the desired O-acetyl cyanohydrins were obtained in good to excellent yields with moderate to high enantioselectivities.