Ionic liquids as novel media for electrophilic/onium ion chemistry and metal-mediated reactions: a progress summary

The account presented here summarizes progress from the author’s laboratory during the past 15 years on the application of room temperature ionic liquids (RTILs) as solvents and catalysts in electrophilic/onium ion chemistry as well as in metal-mediated bond forming reactions.


Introduction
Application of ionic liquids (ILs) in synthetic chemistry and catalysis has been growing steadily over the past two decades and the trajectory continues to remain positive.The progress in this evolving and dynamic area has been summarized over the years in a number of reviews, commentaries, and highlights.  Hav worked for many years in carbocation and onium ion chemistry, starting in 1999 we began tinkering with room temperature ionic liquids (RTILs) bearing low nucleophilicity counter ions (OTf, PF 6 , BF 4 , and NTf 2 ).We were intrigued by the idea that the cationic core in [BMIM][X] and [EMIM][X] imidazolium ILs (Figure 1) may be sufficiently Lewis-acidic for the IL to act not only as solvent but also as catalyst, and that the Lewis acidity of the cationic core could be increased by introducing electron withdrawing group(s), or by employing less nucleophilic counter ions.We envisaged that through these structural changes ILs could be tailor-made for a variety of acid-catalyzed reactions.Ease of product isolation/work-up, recycling and reuse of the ILs provided additional impetus.We later learned that various onium salts could be made to dissolve in imidazolium ILs such as [BMIM][PF 6 ] and [BMIM][BF 4 ] with the help of sonication, and this motivated us to focus on developing or improving on synthetic methods that utilize onium salts as reagent, and by doing so increase the synthetic value of onium salts for method development.An important objective was to develop newer, environmentally more acceptable, synthetic methods for fundamentally important/textbook transformations, especially those that are practiced on large scale in industry such as nitration and halogenation.Combinations of [BMIM][X] ILs as solvent and metallic triflates M(OTf) 3 , or Brønsted acidic ILs [BMIM(SO 3 H)][OTf] or [PMIM(SO 3 H)][OTf] as catalyst (Figure 1) proved rewarding in a variety of acid-catalyzed carbocationic transformations, as well as in heterocyclic synthesis, and in organofluorine chemistry.Imidazolium ILs also proved quite useful as solvent in Pd-catalyzed C-C coupling reactions.The present account summarizes these studies.

Nitration
One of the earliest studies we made was to determine the scope of aromatic nitration in imidazolium ILs. 26 The most promising systems identified in a survey study with simple arenes were isoamyl nitrate/TfOH, isoamyl nitrate/BF 3 .Et 2 O, and NH 4 NO 3 /TFAA, as well as AgNO 3 /Tf 2 O (Scheme 1).In most cases the yields and isomer distributions (ortho/para ratios) for nitration in ILs were comparable to those employing conventional methods, suggesting similarity in the mechanism.

Scheme 1. Nitration of arenes in imidazolium ILs.
In a later study we employed ethylammonium nitrate (EAN) as a cheap and easily accessible IL.EAN in combination with TFAA or Tf 2 O acts as an in-situ source of trifluoroacetyl nitrate (CF 3 COONO 2 ) and triflyl nitrate (TfONO 2 ) respectively (Scheme 2). 27hese systems proved quite effective for nitration of a wide variety of aromatic and heteroaromatic compounds, with EAN/Tf 2 O being superior for nitration of deactivated compounds.
In another study we examined the utility and scope of arene nitration with bismuth nitrate (BN) in IL solvent. 28

Aromatic Benzylation
Aromatic benzylation is a widely practiced fundamental transformation for the preparation of diarylmethanes which are important synthetic intermediates.Benzylation of arenes with PhCH 2 Cl and PhCH 2 OH were conveniently performed in [BMIM][OTf] or [BMIM][PF 6 ] by using TfOH, Sc(OTf) 3 , or Yb(OTf) 3 .xH 2 O as catalysts (Scheme 4).29a TfOH was superior for benzylation with BzOH, producing little or no dibenzyl ether (DBE).Substrate selectivity (K T /K b ) and regioselectivity (isomer distribution) for benzylation in the IL solvents employing TfOH or Yb(OTf) 3 were in similar range to those reported in molecular solvents employing Nafion-H.29b The advantages offered by this method are high yields and chemoselectivity (absence of DBE), easy isolation, and recycling/reuse of the IL.

Adamantylation of Aromatics
The system [BMIM][OTf]-TfOH proved highly efficient for adamantylation of arenes with 1-AdaX (X = OH, Cl, Br) (Scheme 5). 30The reactions exhibited high para selectivity, produced little or no adamantane byproduct, and the conversions were quantitative or near quantitative.The synthetic scope of the reaction was investigated and competitive reactions were carried out to shed light on the mechanistic issues, in particular the origin of high meta in TfOH-catalyzed adamantylation of toluene in DCE as solvent.Notable differences in substrate selectivity (K t /K b values were in the range 16-17 in the ionic liquid solvent and close to unity in DCE), and chemo-, and regioselectivity were observed in [BMIM][OTf] versus DCE. 30 The data implied a comparatively later (more benzenium ion like) TS in the IL solvent, involving a more selective electrophile.Scheme 5. Adamantylation of arenes in IL solvent.

Transacylation and Deacylation
Sterically hindered acetophenones undergo acyl group transfer to reactive aromatic nucleophile receptors (anisole, toluene) in imidazolium ILs as solvent with TfOH as promoter (Scheme 6).These superacid promoted reactions likely involve a deacetylation/reacetylation process.Chemoselectivity (transacylation versus deacylation) depends on the reaction temperature.High conversions could be achieved by tweaking the reaction conditions namely the arene/TfOH ratio, choice of arene receptor, and the reaction time. 31Scheme 6. Transacylation and deacylation

Fluorodediazoniation
The finding that arenediazonium salts could be made to dissolve in imidazolium ILs provided the motivation to develop a new method for the classical Balz-Schiemann reaction. 32The classical procedure suffered from drawbacks with regard to reproducibility and variable yields depending on the choice of the arene.The arenediazonium tetrafluoroborates were allowed to dediazoniate in [BMIM][BF 4 ] or [BMIM][PF 6 ] to cleanly furnish the corresponding fluoroaromatic compounds essentially in quantitative yields.The reaction could also be carried out in one-pot starting from the anilines by in-situ diazotization with nitrosonium salts (Scheme 7).

Aromatic Fluorination with Selectfluor (F-TEDA-BF 4 )
As an onium dication salt Selectfluor dissolves in excess imidazolium ILs and this "immobilization" process is aided by sonication, providing a convenient medium for arene fluorination (Scheme 8).By using this approach the scope of arene fluorination was investigated, and the corresponding fluoro derivatives were obtained under mild conditions in reasonable yields as determine by NMR and GC. 33The study was subsequently extended to fluorination of bicyclic and polycyclic arenes.The substrate selectivity measured in competitive reaction (K mesitylene : K durene = 10) is in line with a conventional polar mechanism. 33

Arene
Ar-F Scheme 8. Arene fluorination with Selectfluor in imidazolium-ILs.). 34Further fluorination to the gem-difluoro derivatives was effected by addition of another equivalent of Selectfluor.Direct gemdifluorination could be achieved starting from the corresponding carbonyl compounds by using two equivalents of Selectfluor.This synthetic method was also applicable to -monofluorination of α-nitroketones. 34Scheme 9. -Fluorination of carbonyl compounds.) provided a convenient method for the synthesis of the corresponding halo-and azido-arenes in good yields with minimal formation of ArF and ArH (Scheme 10). 35The reactions could also be performed starting from the corresponding amines by in-situ diazotization with nitrosonium salts.NMR monitoring of the progress of these reactions provided evidence that TMSX reacts with with the latter as major product, along with minimal amount of the Schiemann product ArF. 36his study demonstrated that despite the highly non-nucleophilic character of NTf 2 anion it acts as an ambident nucleophile toward Ar + .The process is likely to involve rapid metathesis to form [ArN 2 ][NTf 2 ] followed by dediazoniation.It is noteworthy that synthesis of ArO-SO(CF 3 )=NTf compounds by other means is highly challenging, and the present method underscores the power of the IL method to get easy access to this compound through in-situ metathesis and dediazoniation. . 37The mono-versus di-chlorination was tuned by changing the arene to TCICA ratio (Table 1).This transformation benefits from high atom economy by producing three moles of ArCl from each mole of TCICA.

Aromatic Halogenation
Scheme 12. Aromatic chlorination with TCICA catalyzed by Brønsted acidic IL.Whereas activated and moderately activated alkyl-and halo-benzenes were successfully mono-and di-chlorinated by using this method, nitrobenzene did not react.A triprotonated/protosolvated TCICA was proposed as key intermediate for these reactions (Scheme 13).DFT calculations suggested that sequential [N-Cl] + bond cleavage followed by Nprotonation is energetically favorable and exhibit negative enthalpy for a trication.By contrast Cl + transfer from the dication and monocation were increasingly more endothermic showing positive G and H values.

Halofunctionalization with I 2 /H 2 O 2 and with N-halosuccinimides (NXS)
In joint projects with collaborators in Slovenia a convenient high yielding method for iodofunctionalization of activated aromatics was developed by using elemental iodine with H 2 O 2 (30% aq.) as oxidant and with [BMIM][PF 6 ] or [BMIM][BF 4 ] as solvent. 38Activated arenes were ring iodinated whereas arylalkyl ketones were regioselectively iodinated alpha to carbonyl. 38In another study it was shown that [BMIM(SO 3 H)][OTf] acts as solvent and catalysts in halogenation of activated organic compounds with NXS (Scheme 14). 39In both cases the ILs could be reused several times with no noticeable decrease in efficiency.Scheme 14. Brønsted acidic IL-mediated halofunctionalization.

Metal and H 2 O 2 free aerobic oxidative aromatic halogenation
In another joint effort, an efficient and green method was introduced for aerobic oxidative halogenation of arenes under mild conditions and in high yields by employing multi-functional ILs [RNH 3 + ][NO 3 -]/HX and [BMIM(SO 3 H)][(NO 3 ) x (X) y ] (X = Br, Cl) as solvent and promoter (Scheme 15). 40

The Schmidt reaction of aldehydes
A new high yielding method for the conversion of structurally diverse aromatic and heteroaromatic aldehydes to nitriles was developed via the Schmidt reaction by using TMSN 3 , IL-1 as solvent, and IL-2 as catalysts, with recycling and reuse of IL-1 (Scheme 17). 42 Scheme 17. Schmidt reaction of aldehydes.

Rearrangement of 1,2-diaryl epoxides
The aryl versus H migration pathways in the rearrangement of trans-stilbene oxide as well as a series of singly substituted 1,2-diphenyl-oxiranes were studied in various BMIM-ILs and in DCM as solvents.Metallic triflates, in particular Bi(OTf) 3 , and Brønsted acid IL [BMIM(SO 3 H)][OTf] proved highly efficient as catalyst for this transformation.Reactions were also performed without promoter by using microwave (Scheme 18). 43In the majority of cases selective formation of aryl migration products (aldehydes) were observed.Ketone formation (H migration) was observed with the p-CN and p-NO 2 derivatives, and under MW in [BMIM][PF 6 ] solvent.The study identified new methods and reagents for catalytic and regioselective conversion of 1,2-diarylepoxide to carbonyl compounds.

Building heterocyclic systems
The RC(OR) 2 + cations generated in-situ by ionization of orthocarboxylic acid esters in Brønsted acid ILs [EtNH 3 ][NO 3 ] "EAN" or [PMIM(SO 3 H)][OTf] were used as building blocks for facile synthesis of tetrazoles, benzazoles, and other ring systems (Scheme 19). 44This method provided easy access to a library of 1H-1,2,3,4-tetrazoles and benzazoles, as well as a series of quinazolinones form readily available building blocks.Scheme 19.Building heterocyclic systems with RC(OR) 2 .

Development of Facile Propargylation Methods in ILs
The discovery that propargylic alcohols are efficiently ionized in imidazolium-ILs by addition of catalytic amounts of metallic triflates, TfOH, or Brønsted acid IL to form "tamed" propargylic cations, enabled the development of a number of IL-based methods for the synthesis of a wide variety of propargylated small molecule building blocks.

Propargylated Arenes, Heteroarenes, and Ethers
Arenes and heteroarenes were efficiently propargylated, and a host of symmetrical and unsymmetrical propargylated ethers were prepared by coupling two propargyl alcohols or by coupling a propargyl alcohol with a primary or secondary alcohol (Scheme 21). 46

Propargylation of indoles and carbazole
Convenient methods were developed for the synthesis of propargylated indoles and carbazole by employing bismuth nitrate as catalyst and [BMIM][PF 6 ] as solvent.Dipropargylation of carbazole was achieved when TfOH was used as catalysts in place of bismuth nitrate.The IL solvent could be recovered and reused (Scheme 23). 48,49heme 23.Propargylation of indoles and mono-and di-propargylation of carbazoles.

Coupling of allyl-and alkynylsilanes with propargylic, allylic and benzylic alcohols
The 1,5-Enynes were prepared in respectable yields by coupling propargylic alcohols with allyl-TMS, employing Bi(OTf) 3 in IL solvent.Similarly, allylic and benzylic alcohols were coupled to allyl-and alkynylsilanes. 49A host of propargylic, propargylic/allylic, bis-allylic, allylic, and benzylic alcohols were reduced with Et 3 SiH by using Bi(OTf)   In another study, polyfluoroarenes were coupled with simple arenes in the IL solvent by using catalytic amounts of Pd(OAc) 2 (Scheme 27). 53heme 27.Cross coupling of polyfluoroarenes.By using a piperidine-tethered imidazolium-IL as dual solvent and base, Sonogashira crosscoupling between ArI and a variety of alkynes were effected without copper, external base, or additive.The method was applied to the synthesis of SF 5 -substituted alkynes (Scheme 28).A facile Pd(OAc) 2 catalyzed method for the conversion of Schiff bases to 2-aryl-and 2heteroarylbenzoxazoles and benzthiazoles was also developed (Scheme 29). 55

Summary
The present account gives a glimpse into the various projects carried out in my laboratory on the development of synthetic methods that utilize ionic liquids as solvent.Combination of an IL acting as solvent, and a Brønsted-acidic IL or a metallic triflate acting as catalyst, offers interesting possibilities for developing synthetic methods involving carbocations and onium ions.
The finding that onium salts can be dissolved in imidazolium-ILs has opened up new and improved prospects in fluorination and in diazonium ion chemistry including metal-mediated coupling reactions.The recycling and reuse of the IL solvent provides an added advantage.

Scheme 3 .
Scheme 3. Nitration of arenes with BN/IL and comparison with BN/DCE.
These are prepared in situ by addition of HBr or HCl to ethyl-or propylammonium nitrate (EAN or PAN), and to [BMIM(SO 3 H)][NO 3 ].The reactions could be repeated over several cycles.

[Scheme 25 .
Scheme 25.Mild conversion of propargylic alcohols to cyclic and acyclic enones via the Rupe rearrangement in ILs, and a one-pot Rupe-aldol-Nazarov sequence leading to 3-phenylhexahydroindenone.

Table of Contents
Halofunctionalization with I 2 /H 2 O 2 and with N-Halosuccinimides (NXS) 8.3 Metal and H 2 O 2 Free Aerobic Oxidative Aromatic Halogenation 9. Catalysis by Metallic Triflates and Brønsted Acidic IL