Ruthenium catalyzed dimerization–ring expansion reaction of acetylenylcyclobutanols

A novel type of ring expansion reaction of acetylenylcyclobutanols which involves a dimerization process has been developed. The reaction simply proceeds in the presence of ruthenium catalyst to afford the ring-expanded dimer in moderate yield


Introduction
Transition-metal-promoted ring expansion reactions of cyclobutanol derivatives are well investigated reactions that are triggered by release in the strain of the four-membered ring systems. 1,2Most of these ring expansions are triggered by palladium catalysts, 1 whose methodologies have been successfully applied to the syntheses of natural products. 3On the other hand, few examples of ring expansion reactions catalyzed by other transition metals have been reported.Recently, we have developed a novel type of ring expansion reaction of allenylcyclobutanols triggered by ruthenium catalysis. 2,4The reaction enables the one-pot synthesis of α-substituted cyclopentanones from allenylcyclobutanols and α,β-unsaturated carbonyl compounds.During the course of our studies to explore the application of ruthenium catalyzed reactions, we found a novel type of ring expansion reaction of acetylenylcyclobutanols involving a dimerization process 5 (Scheme 1).The results of investigations of this process are presented below.

Results and Discussion
The substrates for ruthenium catalyzed ring expansions are synthesized as follows (Scheme 2).Alkynylcyclobutanols 3a-3d, which have various substituents at terminal position of alkynes are produced by the addition of corresponding alkynes 2a-2d to spiro [3.5]nonan-1-one 1 6  a The yields in parentheses are based on unrecovered starting material.
Our initial attempts at ruthenium-catalyzed ring expansion began with 3a-3e in the presence of 10 mol.% CpRu(MeCN) 3 PF 6 7 in DMF at 60°C (Table 1).Although no reactions proceed from the substituted alkynes 3a-3d (entries 1-4), the ring expanded product 5 accompanied by a dimerization process is obtained from the reaction of 3e, in 41% yield (entry 5).The stereochemistry of 5 is determined unambiguously by NOESY correlation of 6a and 6b, which are produced from the reaction of 5 with MeLi (Scheme 3).From the optimization studies in entries 6-13, it is clear that the best result is obtained when the reaction is carried out in 0.5M DMF solution at 60°C (52% yield, Entry 12).We next examined the reactions in the presence of various additives (Table 2).Attempts at the reactions using bases such as i Pr 2 NEt, Et 3 N and K 2 CO 3 failed completely (entries 1-3).On the other hand, the reactions in the presence of various acids afford 5 in moderate yield (entries 4-9) although the yields are not comparable to those in the absence of any additives.a All the reactions were carried out in the presence of 10 mol.% CpRu(MeCN) 3 PF 6 in DMF at 60°C.b One weight equivalent of Amberlyst 15 was added.
The ring expansion reaction also proceeds even for the silylated substrate 4, which produces the same product 5 in 31% yield (Scheme 4).
Scheme 5 shows the proposed mechanism for this dimerization-ring expansion reaction.It is expected that the key reaction intermediate is a ruthenacycle 8, 5 which is formed by coordination (7) of ruthenium catalyst with two molecules of acetylenylcyclobutanol.There would be an equilibrium between the complex 8 and a zwitterionic intermediate 9, which causes ring rearrangement followed by ring opening of the ruthenacycle (10) to form an alkenyl ruthenium hydride 11.Finally, reductive elimination of ruthenium from 11 produces a ring-expanded dimer 5 together with regenerated ruthenium catalyst.
[Ru] _ To support the reaction mechanism described above, a reaction was examined in the presence of D 2 O (Scheme 6).When the substrate 3e is subjected to the reaction in a mixture of DMF and D 2 O (10:1), deuterated product 5-d is obtained in 21% yield (45% deuterated).The result is compatible with that the reactions proceed via the formation of the ruthenacycle 8.

Conclusions
In conclusion, we have developed a novel type of ring expansion reaction of acetylenylcyclobutanols using ruthenium catalysis.The reaction enables the construction of the ring-expanded dimer in a stereoselective manner.Efforts to extend the scope of this reaction are currently in progress.

Experimental Section
General Procedures.All non-aqueous reactions were carried out under a positive atmosphere of argon or nitrogen in dried glassware, unless otherwise indicated.Materials were obtained from commercial suppliers and used without further purification except when otherwise noted.Solvents were dried and distilled according to standard protocols.The phrase "residue upon workup" refers to the residue obtained when the organic layer was separated and dried over anhydrous MgSO 4 and the solvent was evaporated under reduced pressure.Column chromatography was performed on silica gel 60N (Kanto Chemical Co., 100-210 µm), and flash column chromatography was performed on silica gel 60 (Kanto Chemical Co., 40-50 µm) using the solvent indicated.Reaction and chromatography fractions were analyzed by employing precoated silica gel 60 F 254 plates (Merck).All melting points were determined on Yanaco micro-melting point apparatus and are uncorrected.IR spectra were measured on a SHIMADZU FTIR-8300 spectrometer.NMR spectra were recorded on Varian Gemini 2000, JEOL AL400 or JEOL JNM-GX 500 spectrometers with tetramethylsilane or chloroform as internal standard.

Scheme 6 .
Scheme 6. Reaction in the presence of D 2 O.

Table 1 .
in 75% to quantitative yields.Desilylation of 3a in the presence of K 2 CO 3 in MeOH gives the unsubstituted substrate 3e in 94% yield, and further silylation of the tertiary alcohol moiety by TESOTf affords 4 in 93% yield.Initial attempts at the ruthenium catalyzed dimerization-ring expansion reaction

Table 2 .
Reactions of 3e in the presence of various additives a