Ruthenium Carbenes as Catalysts in stereoselective ene-yne Metathesis/Diels-Alder and ene-yne Metathesis/Diels-Alder/Cross coupling multicomponent reactions

An ene-yne cross metathesis of silyl substituted alkynes and alkenes followed by a Diels-Alder reaction of the metathesis product 2-silyl-1,3-dienes has been developed. The dienes thus prepared in situ were shown to participate in highly diastereoselective Diels-Alder reactions. In one case the silicon substituted Diels-Alder cycloadduct was subsequently used without isolation and purification in a Hiyama cross coupling reaction. The cross coupling reactions enable these silicon dienes to be used as synthons for a variety of other dienes. Introduction Reports of 2-boron and 2-silicon substituted 1,3-dienes are relatively rare in organic chemistry. In 2008, we published a review which covered boron and silicon substituted diene preparation and reaction chemistry up through 2007. A review on the preparation and reaction chemistry of silyl substituted 1,3-dienes has been published in 2011 as well as a review of silatranes as one class of trialkyoxysilyl species where 1,3-dienes have M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT 2 been reported. Krische and co-workers have also reported a ruthenium catalyzed hydrohydroxyalkylation of silyl substituted 1,3 butadienes in 2011 as well. We reported our initial studies in 2007 and 2009 on the preparation and reaction chemistry of 2-trialkoxysilyl-1,3-butadienes. In 2010 we reported a ruthenium catalyzed ene-yne metathesis route to silyl substituted 1,3 dienes which we subsequently used in thermal Diels-Alder reactions. In the work that follows we report that the ene-yne metathesis and Diels-Alder reactions can be performed as a one pot multicomponent process which is also more stereoselective than our originally reported sequential two pot reactions. 2. Results and discussion Silyl Substituted 1,3-Diene In situ Preparation and Trapping via Diels-Alder Reactions. Two examples of ruthenium carbene complex catalyzed tandem or domino reactions were reported in 2010 which gave us cause to attempt the reaction chemistry which we now report here. Fuwa and coworkers reported the Hoveyda-Grubbs 2 generation catalyst catalyzed cross metathesis of a hydroxyl tethered olefin 1 and methyl vinyl ketone 2. The cross metathesis product 3 then underwent a stereoselective intramolecular conjugate addition to produce tetrahydropyran 4. Also in 2010, Nandurdikar and coworkers reported a tandem ene-yne metathesis/ intramolecular Diels-Alder reaction of 5 to produce 6 which utilized the Grubbs 2 generation ruthenium carbene as the catalyst. M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT 3 Gratifyingly, when we combined the benzyldimethyl silyl alkyne 7, styrene 8, and Nphenylmaleimide (NPM) 9 with Hoveyda-Grubbs 2 generation catalyst (10%) in THF at 25 C we isolated the anticipated cycloadduct 10 in 66% yield. This reaction when originally run at 0.8M in THF required 67 hours to go to completion and we subsequently found that if run at 2.0M in THF we could isolate the desired product 10 in 62% yield after 24 h. We also noted that if the reaction was performed at 90C then the desired product 10 could be isolated in 57% yield after only 2 hours. Changing solvents from THF to toluene, benzene, or dichloromethane had virtually no impact on the yield whereas reducing the amount of ruthenium carbene complex present to 5% rather than 10% reduced the isolated yield of product 10 to 23%. M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT 4 We noted that having a ruthenium complex present was not necessary to effect the Diels-Alder reaction since diene 11 reacted completely with NPM at 90 C in THF overnight, however, the multicomponent one pot reaction produced the syn (endo) product 10 as the only detectable stereoisomer whereas the thermal reaction of the silicon diene 11 with NPM produced 10 as only a 7.7:1 mixture of diastereomers. Grubbs and coworkers have noted that ruthenium hydrides are present in solution in these metathesis reactions and that those ruthenium hydrides can be decomposed by the addition of 1,4 benzoquinone. When we performed this multicomponent reaction in the presence of 10 mol% Hoveyda-Grubbs 2 generation ruthenium carbene complex and 20 mol% 1,4 benzoquinone we still isolated the Diels-Alder cycloadduct 10 in 59% yield as the only detectable diastereomer so we conclude that a ruthenium complex other than the hydride may be responsible for the improved stereochemical outcome noted here. Overall for this tandem reaction we propose a ruthenium carbene complex catalyzed ene-yne metathesis followed by a Diels-Alder reaction. The syn:anti diastereomeric ratio of the isolated cycloadduct (10) of the reaction with N-phenylmaleimide is much higher when the reaction sequence is performed in the presence of ruthenium. M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT 5 Scope and Limitations of the Tandem Ene-Yne Metathesis/Diels-Alder Reaction With an optimized protocol, we then conducted a scope and limitations study with various aryl and alkyl olefins as well as dienophiles of varied double bond substitution (Table 1). As seen with the original ene-yne metathesis reaction we reported in 2010, the para-substituted styrene derivatives 4-vinyl anisole and 4-chlorostyrene performed well in this reaction (entries a,b). Alkyl olefin 4,4-dimethyl-1-pentene also produced product in moderate yield (entry d). In varying the dienophile used, mono-, di-, and trisubstituted dienophiles resulted in the corresponding cycloadducts in moderate to good yields (entries e–g). In reference to the regioselectivity of entries e and g, a significant preference for the para regioisomer was seen in both reactions. With cycloadduct 13e this regiochemistry was determined by HMBC NMR spectroscopy (see supplementary material). Limitations to this reaction were seen in two cases. When attempting to use 2trifluoromethylstyrene no product was recovered (entry c). Monitoring this reaction by GC/MS revealed that neither silyl acetylene 7 nor olefin (R = o-CF3Ph) were consumed; indicating that ene-yne metathesis did not occur. In entry h, the use of 3,4dimethylmaleic anhydride as the dienophile also resulted in no cycloadduct formation. In this case GC/MS analysis revealed the formation of the intermediate silyl diene 11 as expected so we suspect that the steric bulk of the tetrasubstituted dienophile 12h inhibited the Diels–Alder reaction. M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT 6 Table I. Scope and Limitations of Multicomponent Reaction Cross-coupling Incorporation into the Multicomponent Reaction To further elaborate on the transformations available in this process we attempted to effect cross-coupling in the same pot. Once the tandem ene-yne metathesis/DielsAlder process was complete (monitored by GC/MS), palladium(0), iodobenzene, copper(I) iodide, and TBAF were added to the reaction. Unfortunately this resulted in decomposition of the silicon-substituted cycloadduct 10; presumably due to the basic reaction conditions. We believe that this outcome was the result of catalyst “poisoning” by whatever ruthenium species is remaining in solution. An attempt was made to prevent this poisoning by reduction of the ruthenium species present at the end of the tandem reaction with sodium borohydride but this proved ineffective. Another attempt at removal of ruthenium was conducted using aqueous hydrogen peroxide. It is reported that, under these conditions, ruthenium species are oxidized to ruthenium oxides which Entry R Dienophile Cycloadduct % Yield a p -MeOPh NPM 13a 69 b p -ClPh NPM 13b 53 c o -CF 3 Ph NPM No 13c observed d (CH 3 ) 3 CCH 2 NPM 13d 51 e Ph ethyl acrylate 13e 46 (13:1 para : meta ) f Ph diethyl maleate 13f 62 (5:1 cis:trans) g Ph citraconic anhydride 13g 52 (8:1 para : meta ) h Ph 3,4-dimethylmaleic anhydride No 13h observed