Ring-opening metathesis and ring-closing metathesis of bicyclo[4.2.0]octene-ynes: application to the synthesis of tricyclic compounds

Ring-opening metathesis and ring-closing metathesis (ROM-RCM) of bicyclo[4.2.0]octene-ynes and their application to the synthesis of tricyclic derivatives have been demonstrated using a second-generation ruthenium carbene complex. When bicycloalkene having a propargylamino group as an alkyne tether was reacted with a second-generation ruthenium carbene complex under an ethylene atmosphere, ROM-RCM proceeded to give tricyclic heterocycles in good yield. On the other hand, when the effect of the substituent on the alkyne was examined, cross metathesis (CM) of the alkyne part with ethylene proceeded to provide a conjugated diene derivative.


Introduction
Olefin metathesis contains a cleavage of carbon-carbon double bonds concomitantly with the formation of other ones by a metal carbene complex. 1 Currently, it has become a powerful synthetic method for the formation of carbon-carbon double bonds in the field of synthetic organic chemistry.Enyne metathesis, 2 which takes place between a double bond and triple bond, is of particular interest.The diene derivative is obtained by enyne metathesis, although a twocarbon unit is thrown away as an ethylene by olefin metathesis.When enyne metathesis is carried out as an intramolecular reaction, the olefin part of enyne is cleaved and its alkylidene part is transferred to an alkyne.As a result, a cyclized diene derivative is obtained (Scheme 1).

Scheme 1. Enyne metathesis.
After the first report of enyne metathesis by Katz and co-workers, 3 the progressive results, which contain the total synthesis of stemoamide 2g and the effect of ethylene, 2f were reported. 2ecently, we developed ROM-RCM of cycloalkene-ynes. 4,5When a metathesis reaction of cycloalkene-yne, whose tether having an alkyne part is connected to the C-1 position of cycloalkene, was carried out in the presence of 1 under an ethylene atmosphere, ROM-RCM proceeded smoothly to provide bicyclic compound 3 in good yield (Scheme 2).

Scheme 2. Ring-Opening Metathesis and Ring-Closing Metathesis of Cycloalkene-ynes.
The reaction mechanism of ROM-RCM is shown in Scheme 3.

Scheme 3. Plausible reaction mechanism for ROM-RCM of cycloalkene-ynes.
The reaction of the alkyne part of enyne I with a ruthenium methylidene complex gives ruthenacyclobutene II, which was converted into vinyl carbene complex III.If this carbene complex III reacts with a cycloalkene part, ruthenacyclobutane IV would be formed and it should be converted into V.If carbene complex V reacts with a vinyl group intramolecularly, ring-closing metathesis would proceed to provide bicyclic compound VII, together with a ruthenium methylidene complex.Interestingly, the initial n-membered ring is converted into an (n + 2)-membered ring size in this reaction.The other ring size depends on the chain lengths between the double bond and the triple bond.We recently developed ROM-RCM of cyclobutenylmethylamine 4 having an alkyne moiety in a tether catalyzed by second-generation Grubbs catalyst 1, and isoquinoline derivatives 5 could be obtained in good yields in a one-step reaction (Scheme 4).4d Scheme 4. ROM-RCM of cyclobutene-ynes.
Herein we report the synthesis of tricyclic compounds 7 by ROM-RCM of bicyclo[4.2.0]octene-ynes 6 for the further application of our previous development (Scheme 5).
Scheme 5. Plan for synthesis of tricyclic heterocycles.

Results and Discussion
Enynes 6 were prepared according to the synthetic route shown in Scheme 6. Alcohol 9 was synthesized by the literature procedure. 6[2+2] cocyclization of silyl enol ether 8 and ethyl propiolate, promoted by ZrCl4 and followed by treatment with DIBAL-H, gave primary alcohol 9 in 66% yield.Enynes 6a~c were obtained by a Mitsunobu reaction 7 of 9 with tosylamide 10 or 11 in good to high yield.Enyne 6d, having a phenyl group on the terminal alkyne, was synthesized by Sonogashira cross coupling 8 of 6b and Iodobenzene.Scheme 6. Preparation of substrate 6.
ROM-RCM of 6a was examined and the results are shown in Table 1.When a reaction of 6a was carried out in the presence of 20 mol% of ruthenium carbene complex 1 in CH2Cl2 under an ethylene atmosphere and reflux for 48 h, compound 12 was obtained in 24% yield (entry 1).Although tricyclic compound 7a was not obtained, changing a solvent from CH2Cl2 to toluene was effective for the synthesis of 12 and conjugated diene derivative 12 was obtained in 90% yield (entry 2 a All reactions were carried out in the presence of 20 mol% 1 under ethylene atmosphere. Probably, ruthenium carbene complex 1 would react with the alkyne part of 6a to provide carbene complex ii, although a recent study strongly supported the predominance of the initial cyclometallation on an alkene over an alkyne. 9Ruthenium carbene complex ii reacts with ethylene intermolecularly, not the alkene part of cycloalkene.Then triene derivative 12 would be obtained through ruthenacyclobutane intermediate iii (Scheme 7, path a).

Scheme 7. Possible reaction pathway.
Enyne 6b, which has a retrenched alkyne side chain compared to 6a, was examined (Scheme 8).When a dichloromethane solution of 6b was stirred in the presence of 10 mol% of 1 under reflux for 1 h, desilylated tricyclic compound 13 was isolated in 60% yield after the usual workup by column chromatography on silica gel.The crude product was explored by 1 H NMR measurement in order to get to the root of the desilylation.As a result, we could confirm that non-aromatized product 7b was obtained in 69% yield.Presumably, ROM-RCM of 6b proceeded to provide 7b, which was aromatized to 13 during column chromatography on silica gel.
Subsequently, the effect of the substituent on the terminal alkyne was examined (Table 2).When a CH2Cl2 solution of 6c having a methyl group on the alkyne was stirred in the presence of 10 mol% of 1 under reflux for 1 h, triene derivative 14c was obtained in 72% yield (entry 1).Although we found that the reaction of phenyl-substituted ene-ynamide 6d did not proceed to recover 6d in 79% yield (entry 2), triene derivative 14d could be obtained in 98% yield after stirring of 6d at for 0.5 in toluene (entry 3).

Conclusions
We have studied the ROM-RCM of bicyclo[4.2.0]octene-ynes 6.When enyne 6a was used as the substrate, intermolecular CM with ethylene proceeded to give triene derivative 12.The improved yield of 12 was confirmed not so much in the case of CH2Cl2 but as toluene.ROM-RCM of cycloalkene-yne 6b proceeded smoothly to provide tricyclic compound 7b, which aromatized easily to 6,6,5-fused ring compound 13 by desilylation under purification on column chromatography.The intermolecular CM of 6c,d with ethylene proceeded to give triene derivative 14 in high yield although remarkable advancement was not observed when the substituent on the alkyne was examined.

Experimental Section
General.The metathesis reactions were carried out under an atmosphere of ethylene (

General procedure A for metathesis reaction
To a solution of cycloalkene-ynes in CH2Cl2 (0.02 M) was added ruthenium carbene complex 1, and the mixture was refluxed under ethylene atmosphere.Ethylvinyl ether was added to the mixture at 0 °C, and the volatiles were removed under reduce pressure.The residue was purified by column chromatography on silica gel to provide the product.

General procedure B for metathesis reaction
To a solution of cycloalkene-ynes in toluene (0.02 M) was added ruthenium carbene complex 1, and the mixture was stirred at 80 °C under ethylene atmosphere.Ethylvinyl ether was added to the mixture at 0 °C, and the volatiles were removed under reduce pressure.The residue was purified by column chromatography on silica gel to provide the product.

[6-(t-Butyldimethylsilyloxy)-bicyclo[4.2.0]oct-7-en-7-yl]-methanol (9).
To a suspension of ZrCl4 (1.34 g, 5.73 mmol) in CH2Cl2 (20 mL) was added a solution of 8 (1.22 g, 5.73 mmol) in CH2Cl2 (9 mL) after the addition of Ethyl propiolate (0.87 mL, 8.60 mmol) at -78 °C, and the reaction mixture was stirred for 20 min.The reaction mixture was warmed to room temperature after addition of Diethyl ether (30 mL) and H2O (10 mL) at -78 °C, and water phase was separated.The organic phase was washed with saturated NaCl solution, and dried with MgSO4.The volatiles were removed under reduce pressure to obtain crude product, which was used directly next reaction.To a solution of the crude product in THF (4.8 mL) was added DIBAL-H (2.9 mL, 2.9 mmol, 1 M THF solution) at -78 °C, and the mixture was stirred for 1 h at the same temperature.Ethyl acetate (6 mL) and saturated potassium sodium tartrate solution (30 mL) was added to the mixture, which was warmed to room temperature and stirred over 12 h.The mixture was extracted with ethyl acetate.The organic phase was washed with saturated NaCl solution, and dried with MgSO4.The volatiles were removed under reduce pressure, and the residue was purified by column chromatography on silica gel (Hexane / EtOAc, 3:1) to provide 9 (169.

Table 2 .
Substituent effect on the alkynes 1 atm) unless otherwise mentioned.All other manipulations were carried out under an atmosphere of argon unless otherwise mentioned.Ruthenium complexes were purchased from Aldrich Chemical Company.All other solvents and reagents were purified when necessary using standard procedure.Column chromatography was performed on silica gel 60 N (spherical, neutral, 40-60 µm, Kanto Chemical Co.).IR spectra were recorded on PERKIN ELMER FT-IR 1725X. 1 H and13C NMR spectra were recorded on JEOL JNM-EX270 ( 1 H: 270 MHz, 13 C: 67.8 MHz) spectrometer.Chemical shift values were reported in ppm () downfield from tetramethylsilane as an internal standard, or residual solvent peak [ 1H NMR, CHCl3 (7.24):13C NMR, CHCl3 (77.0)].Coupling constants (J) are reported in Hertz(Hz).EI mass spectra were measured on JEOL JMN-DX 303/JMA-DA 5000.