Studies On The Highly Selective Carbometallation Reactions Of Some Unsaturated Carbon-Carbon Bonds With Organometallic Reagents

Carbometallations are the insertion reactions of unsaturated carbon-carbon bonds into the carbon-metal bonds, which have been widely used in organic synthesis. Due to accessibility and high reactivity, many chemists focus their research interests on developing new methodologies base on organometallic reagents, especially highly selective carbometallation of unsaturated carbon-carbon bonds.In this dissertation, I have focused on the design and development of some new methodologies with a combination of organometallic reagents and propargylic alcohols or functionalized allenes to realize highly selective carbometallation of unsaturated carbon-carbon bonds.Part I: Selectivity-controllable Cu(I)-catalyzed or mediated carbometallation reactions of secondary or tertiary propargylic alcohols with Grignard reagentsIn principle, the carbometallation reactions of the propargylic alcohols with oragnometallic reagents can afford branched and linear products. Duboudin et al. reported that the Cu(I)-catalyzed carbomagnesiation of primary propargylic alcohol with Grignard reagents in ether leads to the highly selective formation of 2-substituted prop-2-enols via the hydroxyl-group controlled anti-carbomagnesiation. However, it was also noted that the reaction of secondary or tertiary propargylic alcohols afforded a mixture of two regioisomeric products. Therefore, we tried to solve these problems.1) We solved the problem of anti-carbometallation reaction of secondary terminal propargylic alcohols with Grignard reagents by using THF as the solvent to afford the branched anti-carbometallation products. The five-membered metallacyclic intermediate formed due to chelation between the metal atom and the hydroxyl group can be trapped with different electricphiles, such as saturated NH₄Cl, iodine, or PhI (under the catalysis of Pd(PPh₃)₄). When the R group of Grignard reagents were alkyl groups, the reactions afforded branched products with moderate to high regioselectivity (77/23～>99/1). By using this method optically active allylic alcohols can be prepared from the optically active propargylic alcohols without obvious loss of the enantiopurity.2) We prepared the Grignard reagents in toluene and controllably realized the copper-mediated syn-carbometallation reaction of secondary or tertiary terminal propargylic alcohols with Grignard reagents in toluene to afford the linear syn-carbometallation products with high opposite regio- and stereoselectivity. Upon treatment with I₂ after the carbometallation, iodides may be obtained, which may undergo Sonogashira coupling reaction and highly stereoselective Novozym-435-catalyzed kinetic resolution to afford the optically active products. R¹ group from Grignard reagents is introduced into the terminal position of alcohols while the iodine is added to the other terminal of the triple bond in a syn-manner. The regioselectivity was 93/7～>99/1.3) We explored the synthetic applications of allylic alcohols prepared by above methods. The organic iodide can undergo Sonogashira coupling reaction to afford alk-3-en-5yn-2,7-diols, which may be transformed into polysubstituted furan derivative by the PdCl₂-catalyzed cyclization in the presence of allyl bromide.Part II: Highly regio- and stereoselective CuCl-mediated carbometallation of 2,3-allenols with Grignard reagentsAlthough we have successfully achieved the goal of selectivity-controllable carbometallation reaction of secondary or tertiary terminal propargylic alcohols with Grignard reagents, the problem for non-terminal propargylic alcohols remains. Due to the higher reactivity of allenes, we were interested in developing the carbometallation reaction of 2,3-allenols, which may afford fully substituted allylic alcohols to solve this issue. Highly regio- and stereoselective CuCl-mediated carbometallation reaction of 2,3-allenols with Grignard reagents followed by iodination was developed to synthesize fully substituted Z-allylic alcohols, in which the R⁴ group from Grignard reagents is introduced into the terminal position of 2,3-allenols and the iodine is connected to the middle carbon atom of the allene moiety in 2,3-allenols. In the reaction, the five-membered metallacyclic intermediate may again be formed due to chelation between the metal atom and the hydroxyl group. Optically active allylic alcohols may be prepared from the optically active 2,3-allenols without obvious loss of the enantiopurity.Part III: Iron-catalyzed highly regio- and stereoselective conjugate addition of 2,3-allenoates with Grignard reagentsAfter being successful in the carbometallation reaction of 2,3-allenols, we showed a growing interest in carbometallation reaction of functionalized allene with an electron-withdrawing group. Thus, an efficient highly regio- and stereoselecitive iron-catalyzed conjugate addition of 2,3-allenoates with 1°- and 2°-alkyl, phenyl or vinyl Grignard reagents has been developed. R⁴ group from the Grignard reagents is introduced to theβ-position of the ester group trans to the R¹ group at the 4-position in the remainingβ,γ-carbon-carbon double bond (Scheme 5). A plausible mechanism has been proposed. The in-situ formed magnesium 1,3-dienolate can be treated with acyl chloride to afford theα-acylβ,γ-unsaturated Z-alkenoate. It is worth to know that theα-acylβ,γ-unsaturated E-alkenoate may be prepared by the reaction with allylic acetate. Further more, the magnesium dienolate reacted with allylic acetate under the catalysis of Pd(PPh₃)₄ to provide theα-allylicβ,γ-unsaturated Z-alkenoate. However,α-allylicβ,γ-unsaturated E-alkenoates was produced by the reaction of the intermediate with allylic bromide catalyzed by Cu(I).Part IV: The addition-cyclization reaction of 2,3-allenoates with organic zinc reagentsWhen different organometallic reagents were tried to react with 2,3-allenoates, we observed a highly regio- and stereoselective addition-cyclization of two molecules of 2,3-allenoates with organic zinc reagents. Theα,β-unsaturated cyclohex-2-enones were produced with high diastereoselectivity referring to the chiral centers at 4- and 6-positions and Z-configuration of the remaining carbon-carbon double bond at 5-position on the ring. When optically active 2,3-allenoates were applied, optically activeα,β-unsaturated cyclohexenones can be prepared without obvious racemization. A plausible mechanism has been discussed.