Protic Ionic Liquid as Reagent, Catalyst, and Solvent: 1‐Methylimidazolium Thiocyanate

Abstract We propose a new concept of the triple role of protic ionic liquids with nucleophilic anions: a) a regenerable solvent, b) a Brønsted acid inducing diverse transformations via general acid catalysis, and c) a source of a nucleophile. The efficiency of this strategy was demonstrated using thiocyanate‐based protic ionic liquids for the ring‐opening of donor‐acceptor cyclopropanes. A wide variety of activated cyclopropanes were found to react with 1‐methylimidazolium thiocyanate under mild metal‐free conditions via unusual nitrogen attack of the ambident thiocyanate ion on the electrophilic center of the three‐membered ring affording pyrrolidine‐2‐thiones bearing donor and acceptor substituents at the C(5) and C(3) atoms, respectively, in a single time‐efficient step. The ability of 1‐methylimidazolium thiocyanate to serve as a triplex reagent was exemplarily illustrated by (4+2)‐annulation with 1‐acyl‐2‐(2‐hydroxyphenyl)cyclopropane, epoxide ring‐opening and other organic transformations.


Introduction
Modern demands of synthetic chemistry require the selection of reaction conditions providing both high yields of the target products due to high chemo-, regio-, and stereoselectivity of the processes employed and conformity with the fundamental principles of green chemistry. [1] Among them, the essential ones are concepts such as atom and step economy, [2] design and application of less hazardous reagents and catalysts,aswell as minimization of waste production. [3,4] One of the most attractive solutions to all these problems is the use of protic ionic liquids (PILs), i.e., low-melting salts of Brønsted acid and base. [5] On the one hand, PILs can pursue at hreefold role serving cooperatively as:a )a n excellent reaction medium, dissolving both hydrophobic and hydrophilic molecules,b )p rocess initiator via acid-base catalysis,a nd c) reagent, if the PIL contains highly nucleophilic species,red-ox agent, etc. On the other hand, PILs can be easily recycleda nd employed repeatedly,s atisfying environmental demands. [5] So much more astonishing, to the best of our knowledge,isthe absence of reports on the use of this triple role of PILs in organic synthesis (Scheme 1a).
To test this new strategy,w es elected transformations of donor-acceptor (D-A) cyclopropanes [6] due to our longstanding interest in this rapidly growing area of synthetic chemistry,w hich gave birth to ap lethora of reactions,f rom quite simple to very unusual ones, [7] and continues to inspire and guide the elaboration of interesting original processes. Thus,w ea nd others have developed ring-openings of D-A cyclopropanes with diverse nitrogen-containing nucleophiles followed by an ew ring formation as ap owerful tool for the synthesis of N-heterocycles, [8] including pharmacologically important ones (Scheme 1b). Nevertheless,the reaction of D-Ac yclopropanes with various sources of thiocyanate ion has not been reported yet.
We believe that this reaction can be performed using at hiocyanate-based PIL as Brønsted acids are known to induce reactions of D-A cyclopropanes. [8b,e, 9] PILs provide ah igh concentration of both nucleophile and proton, facilitating atransformation. Moreover,the protonation of an intermediate enolate ion in the acidic media allows the avoidance of:a )t he process reversibility,p roved in the related ring-opening with azide ion, [10] and b) CH-acid elimination, detected in the reaction of D-A cyclopropanes with sodium cyanide. [11] Herein, we describe the synthesis of relevant PILs and their utilization for the chemoselective ring-opening of D-A cyclopropanes 1 via nitrogen attack on the three-membered ring affording pyrrolidine-2-thiones 2 bearing two acceptor groups at the C(3) and donor substituent at the C(5) atom in as ingle time-efficient step (Scheme 1c). Such behavior of ambident thiocyanate ion differs crucially from the typical reactivity of this nucleophile with saturated carbon atoms when S-attack proceeds predominantly or exclusively. [12] It should be noted that our previous two-step transformation of cyclopropanes 1 to pyrrolidine-2-thiones 2 required prolonged heating and tremendous combined reaction times, provided much lower yields and involved toxic reagents. [13]

Results and Discussion
We started this work by searching for optimal reaction conditions.T obeastable reaction medium, PIL should have afull proton transfer from an acid to abase; [5] full ionicity is also desired for the highest nucleophilicity of the thiocyanate ion in the PIL. This is best achieved when the difference of the pK a values (DpK a )o ft he two PIL-forming components is larger than 8. [14] Fort hiocyanate-derived PILs,i sothiocyanic acid (HNCS) should be considered as an acidic component; its pK a was determined to be À1.28, [15] therefore,BH + should have ap K a > 6.7. Nevertheless,t he PIL should be acidic enough to induce ar ing-opening of D-A cyclopropanes,i .e., pK a (BH + )value should be as low as possible.Alkyl-, dialkyl-, and trialkylammonium thiocyanates, which were typically studied as PILs in electrochemistry,chromatography,etc., [5,16] have pK a (BH + )values between 9.5 and 11; [17] these PILs are expected to have low activity in initiating reactions of D-A cyclopropanes.T oc heck these assumptions,w ed ecided to investigate PILs with three different basic components:1methylimidazole (Mim, pK a (BH + )7.1 [18] )asabase of choice; triethylamine as non-nucleophilic species with basicity,typical for alkylamines (pK a (BH + )1 0.7); [19] and N,N,N',N'-tetramethylguanidine (Tmg) as an amine with increased basicity (pK a (BH + )1 3.6). [19] To obtain salts formed by (iso)thiocyanic acid with amines,t wo main approaches are usually applied:a nion metathesis by ar eaction of the corresponding ammonium halides with metal thiocyanate [16b,20] and cation metathesis by the displacement of ammonia in NH 4 SCN with more basic amines. [21] Fort he preparation of 1-methylimidazolium thiocyanate (HMimNCS, 3a), we applied the first method, using the modified procedure for the reaction of commercial HMimCl with sodium thiocyanate. [22] On the contrary to the original report, wherein the product was poorly purified and almost uncharacterized, we obtained HMimNCS on am olar scale as an analytically pure bench-stable compound and proved its structure by single-crystal X-ray analysis (Scheme 2a). [23,24] Tw oo ther thiocyanate-based PILs Et 3 N·HNCS (3b) [21b] and HTmgNCS (3c)w ere synthesized by the reaction of ammonium thiocyanate with the corresponding amines; triethylammonium thiocyanate was characterized by singlecrystal X-ray analysis (Scheme 2b). We found that the completeness of the cation metathesis can be controlled by an "ammonium test": if the dissolution of the obtained PIL (ca. 150 mg) in CDCl 3 (ca. 550 mL) during the preparation of an NMR sample was not accompanied by the appearance of av isible suspension of NH 4 SCN,t he PIL contained no residual ammonium ion. Scheme 1. General strategy of using PIL as solvent, reagent, and catalyst and its application for the ring-opening of D-A cyclopropanes with thiocyanate ion.
Thea bove optimizations were performed at 1Mconcentration of 1a in HMimNCS (ca. 8equiv), which ensured the homogeneity of reaction mixtures.T he attempt to decrease PIL quantity resulted in ad iminished yield of 2a (Table 1, entry 6). This outcome can be explained by the fact that the excess of 3a not only facilitates the reaction but also allows suppression of side-processes as D-A cyclopropanes possess numerous modes of reactivity,i ncluding rearrangements and dimerizations.T hus,t he optimal excess of HMimNCS corresponded to 1Msolution of D-A cyclopropane 1a in PIL.
As for other less acidic PILs,at708 8C, the conversion of 1a was moderate in triethylammonium thiocyanate (3b)a nd very low,ifatall, in HTmgNCS (3c)( We also tested reaction conditions,s imilar to those employed for the ring-opening of D-A cyclopropanes with sodium azide. [10] However,h eating of 1a with sodium thiocyanate and Et 3 N·HCl as ap roton source in N,Ndimethylformamide (DMF) produced crude 2a in moderate yield and conversion even after 4h at 100 8 8C ( Table 1, entry 10). Atremendous increase in the reaction time allowed us to achieve almost complete conversion of the starting material (Table 1, entry 11). However,t he yield of 2a was even lower than that after 4h.T he attempt to improve the above results by switching from Et 3 N·HCl to HMimCl was unsuccessful (Table 1, entry 12). Thus,t he conventional reaction conditions were rendered unsuitable for the title transformation. Finally,the reaction of 1a with acombination of NaSCN and PILs containing no nucleophilic anion (Table 1, entries 13, 14) produced ac omplex mixture of non-identified products.
With the optimized conditions in hand (method A), we investigated the scope of this formal (3+ +2)-cycloaddition of D-A cyclopropanes to the C = Nb ond of unstable isothiocyanic acid. We found that abroad range of cyclopropane-1,1dicarboxylates bearing electron-releasing groups at the C(2) atom of the three-membered ring efficiently participate in the disclosed reaction (Scheme 3).
Good yields of 2 were obtained in reactions of D-A cyclopropanes containing mono-, di-and trialkoxyphenyl groups (1a-h,k). Thelower yields of pyrrolidine-2-thiones 2i,j can be explained by the partial hydrolysis of the acetal moiety during the reaction followed by side processes involving the formed phenolic group. [25] D-A cyclopropanes 1l and 1m afforded the target products 2l and 2m,r espectively,i nl ow yields (16 %a nd 13 %). These substrates are too reactive and undergo as ignificant decomposition under the reaction conditions. However,i naless acidic PIL Et 3 N·HNCS,y ields of pyrrolidines 2l and 2m [23] were much better (59 %a nd 56 %), especially when substrates were slowly added to preheated PIL (method B), that allowed minimization of side product formation. Oppositely,c yclopropane 1n,b earing the 4dimethylamino-2-nitrophenyl group,p roduced pyrrolidine 2n in good yield.
When the electron-releasing effect of methoxy group is attenuated by the involvement of an additional aromatic ring between donor group and three-membered ring (1o), the yield of 2o dropped to 40 %. Oppositely,the efficiency of the transformation of 6-methoxy-2-naphthyl-substituted cyclopropane 1p did not principally differ from that of substrates 1c-1h and 1k.Areasonably good yield of the target product was also obtained in the reaction of phthalimido derivative 1q,b ut the corresponding aminal 2r bearing as uccinimidyl group was formed in moderate yield (45 %). These results are well consistent with am uch higher reactivity of 1q vs. 1r in the Lewis acid-catalyzed (3 + 2)-cycloaddition with aldehydes. [26] Heteroaryl-substituted cyclopropanes 1s-1u containing 2-furyl, 2-and 3-thienyl groups as donor as well as (1benzylindol-4-yl)-derived cyclopropane 1w were found to participate in the discussed transformation providing the target heterocycles in reasonable to excellent yields.O nt he contrary,( 1-methylpyrrol-2-yl)-substituted D-A cyclopropane 1v was found to be too reactive,producing asignificant quantity of admixtures.S imilarly to the behavior of 1l and 1m,t he replacement of HMimNCS by the less acidic triethylammonium thiocyanate allowed for increasing yield
Unfortunately,d imethyl cyclopropane-1,1-dicarboxylates bearing aryl groups,which stabilize the cationic center only in am oderate manner, such as para-methyl-or para-fluorophenyl, produced ac omplex mixture of products under heating in both HMimNCS and Et 3 N·HNCS. [24] As imilar difference in the reactivity of diversely substituted D-A cyclopropanes was earlier pointed out in some other transformations. [11,26,27] This problem was usually solved by aproper selection of Lewis or Brønsted acid for the process initiation. This work is currently in progress.
Theeffect of electron-withdrawing groups on the reaction efficiency is more ambiguous.T he substitution of methoxycarbonyl functionalities by ethoxycarbonyl ones influenced insignificantly the reaction efficiency providing 2ad in 73 % yield. Cyanoester 1ae produced two diastereomeric products in as imilar total yield. Thes tructure of the major diastereomer was unambiguously proved by single-crystal X-ray analysis. [23] On the other hand, Meldrumsa cid-derived D-A cyclopropanes 1af,ag were transformed into pyrrolidines 2af,ag despite the presence of the phenyl and even paracyano-phenyl group as the aryl substituent decelerating cyclopropane reactivity significantly.
Therefore,reactive D-A cyclopropanes 1 can be efficiently transformed into 2 by heating in 1-methylimidazolium thiocyanate,w hich serves as as ynthetic equivalent of isothiocyanic acid, at 70 8 8C. If substrates were extremely active (1l, 1m, 1v,e tc.), the target products were obtained with low yields as various side reactions proceeded. We showed that tuning of PIL allows for solving this problem. In the less acidic triethylammonium thiocyanate,p roducts 1l and 1m were obtained in reasonable yields.Avariety of acceptor substituents in cyclopropanes 1 are tolerated by the reaction conditions.M oreover,w es howed that D-A cyclopropanes 1 bearing donor groups with lower cation-stabilizing ability could be introduced into this formal (3+ +2)-cycloaddition if more efficient electron acceptors were present in the molecule.Namely,Meldrumsacid-derived cyclopropanes 1af,ag underwent at ransformation into pyrrolidines 2af,ag, which can be easily converted into the corresponding methyl diesters. [28] Thed eveloped procedure can be scaled up without the loss of efficiency and sustainability. [24,29] Thus,when 10 mmol (3 g) of 1a were introduced into the reaction, product 2a was isolated in 89 %y ield. Moreover,P ILs 3a and 3b can be efficiently recovered. In particular, the outcome of 2a did not change after 4cycles of regeneration, the yield of regenerated 3a being close to quantitative. [24,29] Pyrrolidine-2-thiones 2 are products of the formal (3+ +2)cycloaddition of HNCS with D-A cyclopropanes 1.However, (3+ +2)-cycloadditions of D-A cyclopropanes with diverse alkyl and aryl isothiocyanates afforded 2-iminotetrahydrothiophenes,b ut not pyrrolidine-2-thiones. [27g, 30] Both these literature data and our results demonstrate that products 2 are formed by astepwise mechanism, including protonation of an acceptor group in the D-A cyclopropane followed by an S N 2like attack on the protonated substrate 1·H + with thiocyanate ion leading to intermediate A.T he intramolecular attack of the emerging enol functionality on the isothiocyanate moiety and proton shift accomplished the pyrrolidine-2-thione formation (Scheme 4, path a).
Based on multiple reports that S-attack of thiocyanate is kinetically preferred in both S N 2a nd S N 1r eactions, [12,31] the alternative mechanism including an initial formation of thiocyanate B followed by its isomerization to A could also be supposed (Scheme 4, path b). Thec yclization of intermediate A to the target pyrrolidine-2-thione 2 [13] is akey step for both possible mechanisms.O ur failure to identify thiocyanates B in reaction mixtures supports path a,but cannot be considered as an argument against the alternative route.
Additionally,w es howed that the obtained pyrrolidine-2thiones 2 could be easily modified to prepare other important products.Inparticular, we found that the oxidation of 2a with meta-chloroperbenzoic acid (mCPBA) led to the corresponding pyrrolidone 5,which can be considered as the product of the formal (3+ +2)-cycloaddition of D-A cyclopropane 1a with HNCO (Scheme 5). Moreover,w ed emonstrated that the alkylation of 2a with dimethyl sulfate afforded thioimidate 6 (Scheme 5). This compound corresponds to the product of the formal (3+ +2)-cycloaddition of D-A cyclopropanes 1 with alkyl thiocyanates,aprocess that has not been studied yet.
To achieve further proof of concept for the triple role of PILs,w ee mployed 1-methylimidazolium thiocyanate to perform the annulation of isothiocyanic acid with 2-hydroxyphenyl-derived cyclopropane 1ah, [32] serving as the equivalent of the corresponding ortho-quinone methide. [33] Indeed, under heating in HMimNCS at 70 8 8C, cyclopropane 1ah was smoothly transformed into [1,3]benzoxazine-2-thione 7 in reasonable yield. We believe that this reaction proceeds by as imilar stepwise mechanism, including the nucleophilic opening of at hree-membered ring with thiocyanate ion followed by an attack of the ortho-hydroxy group on the formed isothiocyanate moiety (Scheme 6). This process, together with the reported transformations of 2-hydroxyphenyl-containing D-A cyclopropanes, [33,34] could be responsible for the diminished yields of pyrrolidine-2-thiones 2i and 2j in the reactions of the corresponding cyclopropane-1,1diesters 1i,j (Scheme 3).
Taking into account the somewhat sophisticated character of the D-A cyclopropanes 1 as substrates,weopted to transfer the triple role PILs concept onto organic transformations proceeding with conventional starting materials (Scheme 7). First, the treatment of cyclohexene oxide (8)with astoichiometric amount of HMimNCS at r.t. resulted in the S-selective nucleophilic ring-opening producing 2-hydroxycyclohexyl thiocyanate 9 [35] (Scheme 7a). Heating of HMimNCS with 1-(3-aminopropyl)imidazole (10)at808 8Cled to the displacement of 1-methylimidazole in HMimNCS with the more basic amine providing new protic ionic liquid 11 via ac ation metathesis reaction (Scheme 7b). This compound may find broad use as ar oom temperature PIL;f urther,i tm ight possess interesting biological properties accounting for the nature of the cationic part. [36] Under harsher conditions,Lproline 12 underwent formal (3+ +2)-cycloaddition with isothiocyanic acid affording bicyclic2 -thiohydantoin 13 (Scheme 7c). Yields of products 9 and 13 were unoptimized as our goal was only to demonstrate aprincipal possibility for these transformations to proceed in triple-role protic ionic liquids. Nevertheless,itisnoteworthy that the described synthesis of 13 was carried out under much milder conditions compared to the single reported one-step preparation of this compound. Namely,t he reaction of l-proline with thiourea required heating of an inhomogeneous mixture at 170-210 8 8Cu nder careful control of the reaction, as local over-heating led to significant decrease of the yield. [37] This indicates the high potential for further applications of PIL in various transformations.

Conclusion
In summary,w eh ave demonstrated that protic ionic liquids containing nucleophilic anions are able to serve in concert as aresplendent trio,namely,asrecoverable reaction medium, as Brønsted acid, initiating the process as acatalyst, and as as ource of the nucleophile.T he efficiency of this strategy was exemplarily shown for the ring-opening of donoracceptor cyclopropanes with the thiocyanate ion. 1-Methylimidazolium thiocyanate was selected as an appropriate PIL possessing an almost perfect balance of acid-base properties of components forming this reagent that can be regarded as ab ench-stable surrogate of isothiocyanic acid. Unusual chemoselectivity of the ambident thiocyanate ion was found for this process:a ttack of the nitrogen rather than the sulfur on the activated three-membered ring produced isothiocyanate,w hich underwent immediate cyclization affording 3,5disubstituted pyrrolidine-2-thiones,p roducts of the formal (3+ +2)-cycloaddition of D-A cyclopropanes with isothiocyanic acid. Ab road scope of D-A cyclopropanes was successfully employed. Scaling up and PIL recovery were demonstrated. Other applications of thiocyanate-containing PILs as triplex reagents in diverse reactions were also investigated. Further development of the triple-role PILs is in progress now; the results will be reported in due course.