$\bf{Cu-Catalyzed [3+2] Cycloaddition and Hydrocyanation Reactions of $\alpha$-Diazoesters}$
$\bf{Part 1. Cu-Catalyzed Reaction of $\alpha$-Aryl Diazoesters with Terminal Alkynes: A Formal [3+2] Cycloaddition Route Leading to Indene Derivatives}$
An efficient method for the preparation of 1-carboxylated 3-aryl indenes has been developed via Cu-catalyzed reaction of $\alpha$-aryl diazoesters with terminal alkynes. It turned out that cationic copper species accelerated the formation of desired indene with the help of silver and sodium salts. Among copper catalysts which had been tested, copper chloride bearing v\bf{N}$-heterocyclic carbene ligands gave the most satisfactory yields. The reaction was not affected by electronic properties of $\alpha$-aryl diazoesters albeit those of alkynes significantly controlled the reaction efficiency.
According to the proposed mechanistic pathway, the reaction is believed proceed via tandem processes: alkyne insertion into copper-carbenoid, intramolecular electrophilic attack on the aromatic ring, and then isomerization.
The regioselectivity of indene product could be controlled by the addition of stoichiometric amount of base. 3$\bf{H}$-indenes were isomerized to 1$\bf{H}$-indenes during the reaction by potassium acetate.
$\bf{Part 2. Acetone Cyanohydrin as a Source of HCN in the Cu-Catalyzed Hydrocyanation of $\alpha$-Aryl Diazoacetates}$
We have developed a mild and efficient protocol of hydrocyanation of $\alpha$-aryl diazoester with acetone cyanohydrin via Cu catalysis. Acetone cyanohydrin could be served as a safe and mild alternative for hydrogen cyanide. The reaction turned out to be sensitive to types of copper catalyst. Only $Cu(CH_3CN)_4PF_6$ and its derivatives could be applied the developed protocol. We also found that catalytic amount of additional TMSCN could accelerate the reaction efficiency.
The developed protocol has a wide range of substrate scope. It was revealed that the steric bulkiness of substituents on $\alpha$-aryl diazoesters is more important factor for the reaction efficiency than electronic properties of them.
Although enantioselective hydrocyanation of $\alpha$-aryl diazoesters with various chiral ligands was not successful, diastereoselective hydrocyanation using (-)-menthyl and (-)-phenylmenthyl group as chiral auxiliaries produced moderate diastereomeric ratio. Especially, optically pure (-)-menthyl $\alpha$-cyanophenylacetate could be obtained after recrystallization of the crude reaction mixture. Selective reduction of the obtained $\alpha$-aryl cyanoester with $Mg(BH)_4$ gave the corresponding aryl $\beta$-cyanoalcohol in good yield.
It is believed that a reaction of TMSCN with hexafluorophosphate counterion generates a free cyanide ion that can be involved in the catalytic cycle.
$\bf{Part 3. Cu-Mediated Direct Cyanation using Acetone Cyanohydrin as a Cyanide Source}$
We have been investigating copper-mediated direct cyanation using acetone cyanohydrin as a mild cyanating reagent. To avoid the deactivation of copper (II) acetate by cyanide ions in reaction media, acetic acid was used as an additive. The addition of acetic acid increased the yield of the desired cyanated product without slow addition of acetone cyanohydrin. The strategy that setting acetone cyanohydrin as a limiting reagent was quite effective as a part of reducing cyanide ion in reaction media.
Although stoichiometric amount of copper (II) acetate is needed for effective direct cyanation at this stage, it is anticipated that the combination of proper oxidant, ligands, or other conditions could increase the yield of the desired product.
초산구리와 아세톤 시아노히드린을 이용하여 2-페닐피리딘의 탄소-수소 결합을 활성화 시켜 새로운 탄소-탄소 결합을 형성하는 반응을 개발하였다. 기존의 시안화 반응은 탄소-수소 결합을 미리 할로겐그룹등의 다른 작용기를 도입한 후 진행이 되거나 매우 독성이 강한 트리메틸실릴 시아나이드 등의 시안화 물질을 이용하여 진행했던 반면에, 새로 개발된 반응은 탄소-수소 결합의 사전 활성화 단계를 줄이고, 독성이 없는 시안화 물질을 이용하여 탄소-수소 결합을 활성화하여 새로운 탄소-탄소 결합을 형성하는 데 의의를 둘 수 있다.
또한, 아세트산의 첨가로 인해 반응 용액에서의 시안화 이온의 농도를 줄이기 위해 사용된 주사 펌프를 사용하지 않을 수 있게 되어 그 효용 범위를 넓히게 되었고, 시안화 물질인 아세톤 시아노히드린을 한계시약으로 사용함으로 해서 그 반응 효율이 올라가게 됨을 밝혀내었다.
