Reports: ND149836-ND1: New Cycloaddition Reactions of Anionically Activated Dipoles

Daesung Lee, PhD , University of Illinois (Chicago)

We haveexplored new cycloaddition chemistry ofthe anion of trimethylsilyldiazoalkane with a,b-unsaturated cyclic ketones as well asketones with tethered alkenes andalkynes. The scope of this new cycloaddition reaction was examined underthree main objectives: (1) Exploration ofthe general reaction profiles of metallated diazoalkanes with a,b-unsaturated carbonyl compounds inintermolecular fashion, (2) Intramolecular cycloadditions by in situ generationof the required 1,3-dipole from metallated trimethylsilyl diazoalkane andappropriately substituted ketones, and (3) Tandem cycloadditions based onsequential 1,4-, 1,2-addition and 1,3-silyl migration processes. Theseobjectives are successfully realized as planned yet reactions of more diversesubstrates with different structural characteristics and the reactionmechanisms are to be studied further. While exploring these reactions, a quiteunusual transformation involving lithiated trimethylsilyldiazomethane (Li-TSD)and a-silylketones to generate cyclopropenes wasobserved, which was further studied in detail.

We have observed that the excellent reactivityof the anionically activated trimethylsilyl-diazomethane toward cyclic a,b-unsaturated carbonyl compounds under mildconditions. Importantly, high reactivity and selectivity of cycloaddition over1,2-addition was realized with lithiated trimethylsilyldiazomethane a varietyof cyclic ketones including even tetrasubstituted alkenes. Representativeexamples are shown below. Metallated trimethylsilyldiazomethan with othermetals including Mg, Ti, Na, and K were found to be inferior to thecorresponding lithiated reagent.

The preferred cycloaddition/1,4-addition over 1,2 addtion ofLi-TSD was found to be specific for cyclic a,b-unsaturated carbonyl compounds. Under the same reaction conditions,acyclic a,b-unsaturated ketones provided only the1,3-enyne, which is the consequence of 1,2-addition followed by alkylidenecarbene formation and its 1,2-alkyl shift.

With this favorable cycloaddition of a,b-unsaturated carbonyl compounds, cycloadditionsreaction of carbonyl compounds containing tethered unactivated alkenes andalkynes. The initial reaction between the carbonyl group and Li-TSD followed by1,3-silyl migration to generate the required anionically activated dipoleultimately ensued the cycloaddtion effectively. A few salient features observedin this reaction include: (1) formation structurally complex pyrazoline andpyrazole cycloadducts due to the intramolecular nature of the tandem inter- andintramolecular reaction process, (2) formation of only D1-pyrazolines, (3) mild reactionconditions for cycloaddition even with unactivated alkenes.

On the basis of the tandem1,2-addtion/cycloaddition with an unactivated alkene, triple tandem reactionsincluding cycloaddition-1,2-addition/1,3-Brook rearrangement-cycloaddtionstarting from a,b-unsaturated carbonyl compounds containinga  tethered alkene were developed.This complex tandem processe provided highly functionalized bispyrazolinederivatives with excellent stereoselectivity control starting from readilyavailable terpene derived ketones such as carvone and jasmone.

Furthermore, during reaction thereactivity of initially formed bis-Li-TSD adducts could be controlled toundergo carbon-carbon cleavage to generate novel pyrazoles.  The key aspect of this unusualGrob-type fragmentation is based on the stability of the bis-adduct in thereaction conditions at low temperature, the behavior of which could be steeredby low temperature protonation or by thermal elimination of thelithiumsilanolate to induce a subsequent carbene formation and itsGrob-fragmentation.

Similarly, related tandem reaction sequence wasdeveloped using other type of substrate, for example, carvone and itsderivatives. The initially formed bis-Li-TSD adduct could be protonated andring-expanded to provide a structurally new pyrazoline. Also, the sameintermediate upon warming induced Grob-fragmentation to deliveralkyne-containing pyrazoles. Yet, another type of reaction product with a novelbicyclo[3.2.0] skeleton was observed with b-alkylatedcarvone. Probably, the alkylidene carbene intermediate can directly undergoC–N bond formation, if the Grob-fragmentation does not lead to athermodynamically stable end product such as pyrazole.

Whilestudying the reactivity of Li-TSD toward various ketones, we have observed anunprecedented reaction where the reaction a-silylketonesbetween and Li-TSD providedsilylated cyclopropenes efficiently. Thescope of the reaction focusing on the selectivity of C–Si insertion overC–H insertion or C=C bond insertion by the putative alkylidene carbenewas studied in detail.

Tobroaden the scope and utility of this efficient cyclopropeneation method, a newcatalytic protocol for the formation of a-silylketoneswas developed. In addition, the reactivity of silylated cyclopropeneswas investigated, which led to a new efficient carbophilic Lewis-acid-catalyzedconversion of cyclopropenes to the corresponding allenes. A streamline sequenceallows a convenient and efficient synthesis of a-silylketonesand its conversion to the corresponding cyclopropene, which ultimately can berearranged to silylated allenes.  

The supported of the ACS Petroleum ResearchFund allowed the PI to broaden his research scope and theme into a new areacompletely unrelated to what he has been engaged in. This expansion of researchscope was not possible without the support. This new research developedand executed under the financial support not only allow the PI to explore newchemistry reshaping the research direction, but alsogives a profound impact on the career of the graduate students engaged in theresearch. Especially, these students did more exploratory research in anunknown territory rather than just expanding and embellishing thewell-established research of the PI such that they should have a greatopportunity to become a more intellectually developed and independentresearcher.

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