Ferrocenium Cations as Catalysts for the Etherification of Cyclopropyl‐Substituted Propargylic Alcohols: Ene‐yne Formation and Mechanistic Insights

Abstract

Commercial ferrocenium hexafluorophosphate ([FeCp 2 ]PF 6 ) and ferrocenium boronic acid hexafluoroantimonate ([FcB(OH) 2 ]SbF 6 ) were found to be efficient catalysts for the etherification of terminal, tertiary, cyclopropyl-substituted propargylic alcohols through nucleophilic substitution with primary and secondary alcohols. The alcohol nucleophiles and the propargylic alcohols were employed in a nearly equimolar amount and no further additives were required. After 2 h reaction time at 40°C in CH 2 Cl 2 and 3 to 5 mol-% catalyst load, aromatic, cyclopropyl-substituted propargylic alcohols gave rearranged, conjugated ene-yne products as single isomers in 35 to 73 % isolated yields. Cyclopropyl-substituted propargylic alcohols [a] 7349 Accordingly, we decided to synthesize cyclopropyl-substituted propargylic alcohol substrates (4 in Scheme 1c) to investigate whether the reaction proceeds through a radical mechanism. Cyclopropyl-substituted radicals 6 (Scheme 1c) may ringopen to form alkenes, but carbocation 5 may also have this tendency (vide infra). As exemplified in Scheme 1c, ene-ynes 7 can form through rearrangement if a cyclopropyl-substituted propargylic alcohol 4 is employed. [35] The employment of cyclopropyl-substituted propargylic alcohols in reactions with alcohols to give conjugated, achiral enynes has been reported previously only four times, utilizing Yb(OTf ) 3 , [36a] triflic acid (TfOH), [36b] HAuCl 4[36c] and ruthenium complexes [36d] as catalysts. In these reports, the nucleophile was either the solvent [36b,36c] or employed in large excess. [36a,36d] Herein, we report ferrocenium-catalyzed substitution reactions with these substrates and isolated both ene-yne products and cyclopropylsubstituted products, depending on the substituent R in 4. Experimental evidence points toward an ionic mechanism through carbocation 5 (Scheme 1c). [37] Eur.Scheme 2. Formation of the cyclopropyl-substituted intermediate 21 and ring-opening.

Ferrocenophanium Stability and Catalysis

“…However, we were interested to determine how the stability changes in the presence of the catalysis substrates. As mentioned, we applied the ferrocenium cation as a catalyst for propargylic substitution reactions ( Scheme 1 , bottom), where, besides the catalyst, the tertiary propargylic alcohol 3 and alcohol nucleophiles such as n -butanol ( 4 ), MeOH or i -PrOH were present [ 46 , 47 ]. Related CV experiments have been performed by others with ferrocenophanes in the presence of an imidazole base [ 94 ].…”

“…The findings may have some mechanistic impacts. We assume for the propargylic substitution reaction in Scheme 1 (bottom) an ionic mechanism, where first a propargylic carbocation is generated, which then can be attacked by the alcohol nucleophile [ 46 ]. The ferrocenium or ferrocenophanium cations to be applied for chemistry like in Scheme 1 (bottom) may undergo a chemical change substantially in the presence of n -butanol prior to or during catalysis.…”

“…The reaction of the propargylic alcohol 3 with n -BuOH gave previously the propargylic ether product 5 [ 47 ]. The propargylic substitution reaction of the cyclopropyl-substituted propargylic alcohol 6 also resulted previously in the ring-opened eneyne product 7 when ferrocenium hexafluorophosphate (FcPF 6 ) was employed as a catalyst; the thiophenyl-substituted propargylic alcohol 8 gave the substitution product 9 with the cyclopropyl ring still intact [ 46 ].…”

“…While some product was observed by GC, we were able to isolate the products in only 1 to 44% yields. The reactions in Table 5 are routine in our laboratory, and when employing FcPF 6 , we obtain frequently yields of at least 30% and higher [ 46 , 47 ]. Of the alcohols employed in Table 5 , propargylic alcohol 3 showed the least activity in substitution reactions in our previous experiments [ 46 , 47 ].…”

“…We have employed a number of iron-based catalysts in the past in oxidation reactions [ 39 , 40 , 41 , 42 , 43 , 44 , 45 ], and during the course of our studies, we found that ferrocenium hexafluorophosphate (FcPF 6 ) catalyzes propargylic substitution reactions [ 46 , 47 ]. Ferrocenium cations have been increasingly applied as catalysts in a number of other reactions [ 48 ], such as Friedel-Crafts [ 49 , 50 ] and allylic alkylations [ 51 ], amine [ 52 ] or CH oxidations [ 53 ], cyanosilylation of carbonyl compounds [ 54 ], reductive etherification [ 55 ], aminolysis [ 56 ] or ring opening of epoxides [ 57 ], aromatic iodinations [ 58 ], the Strecker reaction [ 59 ], the Mannich reaction [ 60 ], photodecomposition [ 61 ], ring expansion [ 62 ], or polymerization reactions [ 63 , 64 , 65 , 66 ].…”