Titanium(III)‐Catalyzed Reductive Decyanation of Geminal Dinitriles by a Non‐Free‐Radical Mechanism

Abstract A titanium‐catalyzed mono‐decyanation of geminal dinitriles is reported. The reaction proceeds under mild conditions, tolerates numerous functional groups, and can be applied to quaternary malononitriles. A corresponding desulfonylation is demonstrated as well. Mechanistic experiments support a catalyst‐controlled cleavage without the formation of free radicals, which is in sharp contrast to traditional stoichiometric radical decyanations. The involvement of two TiIII species in the C−C cleavage is proposed, and the beneficial role of added ZnCl2 and 2,4,6‐collidine hydrochloride is investigated.

The controlled cleavage of carbon-carbon bonds is ah ighly topical research area and ac hallenge to modern transitionmetal catalysis. [1][2][3] One particular type is the cleavage of CÀCN bonds,w hich can be used either as an entry point for subsequent bond-constructing events, [4] or for ar eductive, selective decyanation. [5,6] In this context, the reductive decyanation of geminal dinitriles provides direct access to functionalized alkylnitriles from easy-to-prepare malononitrile precursors,m aking it ap owerful alternative to conventional nitrile a-functionalizations. [7] However,o nly al imited number of stoichiometric examples have been reported for this transformation to date.T hese comprise traditional freeradical defunctionalizations with tin hydride,tris(trimethylsilyl)silane,a nd NHC-borane reagents as hydrogen radical donors, [8] or strongly reducing conditions with stoichiometric amounts of SmI 2 /HMPAa nd other so-called "super-electron donors" (Scheme 1). [9,10] With the goal to close this methodological gap,w eh erein report ab roadly applicable catalytic reductive decyanation that proceeds in the presence of at itanium(III) single-electron-transfer catalyst. [11,12] The reaction is not to be confused with free-radical nitrile translocation reactions. [13] Thec atalytic decyanation was first investigated using 2-benzylmalononitrile (1a)a ss ubstrate,h aving both nitriles in ah omobenzylic position (Scheme 2). An initial optimiza-tion study showed that nitrile 2a could be obtained in agood yield of 80 %a fter 48 hf rom ar eaction with titanocene dichloride (10 mol %), zinc as reducing agent, and 2,4,6collidine hydrochloride (Coll·HCl) and chlorotrimethylsilane (TMSCl) as additives in THF at 35 8 8C. Without either additive,t he yield of 2a was inferior.T he reaction was highly chemoselective (spot-to-spot) and worked also for 2phenylmalononitrile (1b), albeit with as ignificantly lower yield (30 %) of benzyl cyanide (2b). Interestingly,itwas found that adding 2b to the decyanation of 1a also greatly diminished the reaction outcome to 23 %y ield. Based on previous reports on titanium(III)-nitrile complexes and our experience in titanium(III) catalysis involving nitriles, [14,15] product inhibition of the catalyst was concluded. Further experimentation revealed that this inhibition could be prevented and the catalyst activity even be improved by adding zinc chloride to the decyanations,giving 82 %yield for 2a and 74 %y ield for 2b after only 24 h. This scenario was supported by preliminary DFT calculations,which confirmed the product inhibition and the liberation of the inhibited catalyst upon addition of ZnCl 2 . [16] Only traces of the Scheme 1. Free-radical decyanations and the envisioned titanium(III) catalysis.
Scheme 2. Initial optimization studies. decyanation product were observed without the titanium catalyst.
Several malononitriles were then decyanated accordingly on 0.5 mmol scale with as imple filtration as as ufficient workup procedure (Scheme 3). Ther eaction showed an unusually broad substrate scope for aC ÀCN cleavage method. Fore xample,d ecyanationa tahomobenzylic position proceeded smoothly in the presence of bromo (2c), ester (2d), acetoxy (2e), nitrile (2f), thioether (2g), ether and free alcohol functions (2h). Thearylated malononitriles 1i and 1j, containing trifluoromethyl and methoxy groups,a lso underwent the decyanationt ot he corresponding benzyl nitriles 2i and 2j in 44 %a nd 70 %y ield, respectively.L ikewise,a n ortho-tolylmalononitrile was mono-decyanated in 71 %y ield (2k). Symmetric and unsymmetric quaternary malononitriles could be employed as well, which led to nitriles 2l-2n (54-88 %). Here,t he increased steric hindrance led to as lower reaction, which was compensated by ap rolonged reaction time of 48 h. Other structurally diverse substrates containing cyclohexyl and indole groups smoothly underwent the decyanation to the corresponding nitriles 2o and 2p.M alononitriles containing as tyryl moiety or a b-vinyl group were decyanated to give 2q and 2r in 72 %a nd 42 %( 48 h) yield, respectively.T he catalytic reductive decyanation reaction of 1a was also demonstrated on a9mmol (1.4 g) scale,resulting in as lightly lower yield (70 %).
We also tested whether the reaction could be extended towards the removal of ad ifferent functional group,a nd it was found that a-cyanosulfone 3 indeed underwent clean desulfonylation to 2ain 56 %yield (Scheme 4). As thiophenol was observed as ab yproduct, the amounts of zinc and hydrochloride were increased to compensate for the additional sulfone reduction and thiolate protonation. Unreacted 3 accounted for the mass balance,and no background reaction took place.T he further elaboration of this catalytic desulfonylation will be reported separately.
Aseries of experiments were then carried out to elucidate the decyanation mechanism. Geminal dinitriles with at ethered pent-4-en-1-yl group were previously reported to readily undergo 5-exo-trig cyclization after ah omolytic C À CN cleavage under free-radical conditions. [8b,c] Thet itanium(III) catalysis,however,led to exclusive decyanationofcompound 4 to nitrile 5 without the generation of the cyclization product 6 (Scheme 5a). Further proof of an on-free-radical mechanism was unambiguously obtained by the decyanation of radical clock substrate 7,which only led to the desired nitrile 8 without the formation of any ring-opened products.T he decyanation of 1a was then carried out with 94 %-deuterated Coll·DCl to confirm that the newly introduced hydrogen atom was transferred by proton transfer from the collidinium salt. Ad euterium incorporation of 68 %w as achieved, while ar eaction with Coll·HCl run in [D 8 ]THF as the solvent resulted in no deuterium transfer. Next, the order in catalyst was determined from two experiments run with 5.0 and 12.5 mol %ofCp 2 TiCl 2 on a4mmol scale that were followed by NMR analysis of taken samples (Figure 1). Visual kinetic analysis then revealed the order in catalyst by time normalization: [17] Ap lot of the yield versus t [cat] 2.0 led to an excellent overlay of the two curves,w hich confirmed the second order in the catalyst.
Af irst mechanistic proposal was derived (Scheme 6), in which the geminal dinitrile coordinates two equivalents of in situ generated [Cp 2 TiCl] (A), giving complex B.T hen, single electron transfer (SET) from both titanium(III) centers triggers the C À Cc leavage,g iving one equivalent of ketenimine-titanium(IV) complex C and N-coordinated titanium-(IV) cyanide complex D or, alternatively,i ts C-coordinated isomer.T he participation of two titanium(III) species in the CÀCN scission is in agreement with the observed second order in catalyst and the non-free-radical behavior. Protonation of C by Coll·HCl then releases the nitrile product and Cp 2 TiCl 2 (E). Ther eaction of D with TMSCl simultaneously liberates the second equivalent of E and formally one equivalent of TMSCN.The formation of cyanide [presumably TMSCN or Zn(CN) 2 ]was confirmed by ion chromatographic analysis of the aqueous layer obtained from the workup. Finally,z inc regenerates the titanium(III) catalyst.
In conclusion, at itanium(III)-catalyzedd ecyanation of geminal dinitriles has been developed that represents the first example of such adecyanation reaction proceeding by singleelectron-transfer catalysis.T he reaction occurs under mild conditions,f eatures ab road substrate scope,a nd shows excellent chemoselectivity.I th as been demonstrated that the cleavage does not proceed through af ree-radical mechanism but via au nique catalyst-controlled C À CN scission involving two titanium species,w hich renders it complementary to previous decyanation protocols.F urther applications towards other CÀCa nd CÀheteroatom bond cleavage reactions are currently being studied and will be reported in due course.