Superelectrophiles in ring-forming reactions

Superelectrophiles are inherently reactive species and there have been many recent applications of these intermediates in cyclization reactions. Diverse electrophilic centers have been utilized in these synthetic reactions including carboxonium, carbenium, carbonium, iminium


Introduction
In a 1964 paper, Staskun described the influence of excess H 2 SO 4 or AlCl 3 on the cyclizations of β-ketoamides (the Knorr reaction). 1He suggested the enhanced yields for the Knorr reaction -in the presence of excess acid -is likely due to the multiple protonations of the dicarbonyl compound.This represented the first mention of highly ionized electrophiles in acid-promoted reactions and it was a predecessor of the superelectrophilic reactivity theory.The concept of superelectrophilic reactivity was formally developed in the 1970s by Olah and coworkers. 2In their seminal paper, an explanation was brought forth to explain the exceptionally high electrophilic reactivities of nitronium and acetylium salts (1 and 4) in superacid media (Scheme 1).It was suggested that the cationic species are partially or completely protonated -leading to greater positive charge and higher electrophilic reactivities.Ions, such as 2, 3, and 5, became known as superelectrophiles.Multidentate coordination to strong Lewis acids may similarly produce superelectrophilic ions.Since this report, numerous other superelectrophilic systems have been described in the literature. 3They have been studied in both the condensed and gas phase.Many outstanding theoretical studies have likewise been reported in the literature, as the computational work explores the novel reactivities and structures of these highly charged organic ions.

Scheme 1
Most superelectrophilic synthetic transformations use highly acidic or even superacidic reaction conditions. 4Because monocationic electrophiles are very weak bases, strong acids are usually required for further protonation of these species.Perhaps the most commonly used superacid is trifluoromethane sulfonic acid, CF 3 SO 3 H (triflic acid).Triflic acid has several advantages, including a very high acid strength (H o -14.1).It is also not HF-based, it is non-oxidizing, and it is commercially available in large quantities.Moreover, a procedure has been reported for the quantitative recycling of triflic acid. 5Occasionally, stronger superacids have been used in these synthetic methods, such as HF-SbF 5 , CF 3 SO 3 H-SbF 5 , and FSO 3 H-SbF 5 .Among the Lewis acids, the most common reagents are the aluminum halides.Several recent superelectrophilic reactions use excess AlCl 3 or AlBr 3 to accomplish the chemistry.
As highly reactive electrophilic species, the superelectrophiles are capable of reacting with weak nucleophiles.This includes deactivated arene nucleophiles, such as acyl-, halogen-, and nitro-substituted arenes.Numerous superelectrophilic cyclizations have also been reported involving reactions with tethered aryl groups.Several reports have even described superelectrophilic reactions with alkanes.In these cases, the superelectrophile may insert directly into a C-H or C-C σ-bond.The chemistry of superelectrophiles was reviewed in 2008 by Olah and Klumpp in a monograph on this topic. 3In the following paper, superelectrophilic cyclization chemistry will be reviewed -with emphasis on studies published after 2007.

Carboxonium Ion Superelectrophiles
Carboxonium ions are well known for the high electrophilic reactivities. 6The work of Mayr and colleagues have shown ions 6 and 7 to possess electrophilicity parameters of 2.97 and 1.12 (Scheme 2). 7This level of reactivity is of similar magnitude to some benzhydryl and allylic carbocations.It has been well established that adjacent electron

Scheme 2
withdrawing groups and cationic charge centers can greatly enhance the reactivities of carboxonium ion groups.Not surprisingly, the high reactivities of superelectrophilic carboxonium ions has proven useful in synthetic chemistry.
Among the recent cyclization strategies using carboxonium ions, Ohwada and coworkers examined the superacid-promoted cyclizations of a series β-ketoesters and related systems. 8For example, compound 8 reacts in excess triflic acid (10 equivalents) to provide the indene 9 in 88% yield as a mixture of ester and acid products (72:28 ratio).NMR studies indicate that the β-ketoesters are diprotonated at the carbonyl groups (10) at an acid strength of H o -11.In kinetic studies, it was observed that the cyclization rate increased linearly with acid strengths above H o -11.This was taken as evidence for further protosolvation and the involvement of a tricationic superelectrophile (i.e., 11 or 12).Theoretical calculations show a dramatic lowering of the LUMO with formation of the trication -an electronic effect that likely triggers cyclization.

Scheme 3
There have been other reports of dicarbonyl compounds forming of superelectrophiles -often from diprotonation.A recent study demonstrated the conversion of α-acyl N-aryl cinnamamides to indeno[2,1c]quinolin-6(7H)-ones promoted by polyphosphoric acid (Scheme 4). 9For example, the amide (11) leads to the heterocyclic product (13) in good yield.Although the exact sequence of bond forming steps is not completely known, the chemistry is initiated by the diprotonated species 12.In a related reaction, a novel synthesis of quinolin-2(1H)-ones has been reported in which penta-2,4-dienamides were used as precursors. 10he H 2 SO 4 -mediated reaction of substrate 14 provides the heterocycle 15 in good yield.The authors suggest a mechanism involving formation of the dicationic superelectrophile 16 and cyclization.An unusual styrene elimination step from 17 then leads to the final product (15).

Scheme 4 Scheme 5
It has been known for several years that protonated N-heterocycles may contribute to superelectrophilic systems. 11This strategy was utilized to prepare indenes by cyclodehydrations. 12For example, pyridyl ketone (18) undergoes cyclization in the presence of CF 3 SO 3 H to provide the pyridylsubstituted indene (19) in 76% yield (Scheme 6).The chemistry is assumed to go through the dicationic carboxonium ion (20) which leads to the indene.Similar conversions were accomplished with pyrimidine, imidazole, oxazole, thiazole, quinoline, and benzothiazole systems (70-98% yields).A key aspect of the chemistry involves the lowering of the LUMO at the carboxonium ion by the influence of the neighboring cationic group.This is seen by comparing 1,3-diphenylpropan-1-one with pyridyl ketone (18).The two isoelectronic species 20 and 21 exhibit dramatically different electronic structures, as the dicationic species 20 has a calculated LUMO at -11.96 eV and the analogous monocation (21) has a LUMO at -9.74 eV.While 1,3diphenylpropan-1-one does undergo cyclodehydration to form 1-phenylindene, the chemistry requires forcing conditions. 13

Scheme 6
In a related cyclodehydration, a series of imidazo[1,2-a]pyridines were prepared from heterocyclic ketones. 14Compound 22 provides the condensed arene 24 in 85% from cyclization in triflic acid (Scheme 7).The superelectrophilic carboxonium ion 23 is a key reactive intermediate, as its formation triggers formation of the new C-C bond.Further dehydration steps give product 24.

Scheme 8
The fluorene ring system has been generated by cyclization reactions involving heterocyclic ketones. 16or example, the pyrazine derivative 30 undergoes reaction in superacid with benzene to give the 9,9diarylfluorene product 34 in 91% yield (Scheme 9).The cyclization step is thought to involve the tricationic carboxonium (31) as the intermediate leading to the new carbocycle.Dehydration through the oxonium ion 32 leads to the highly electrophilic fluorenyl ion 33.This tricationic species has been directly observed by low temperature NMR using stable ion conditions. 17Reaction with benzene gives 34 as the final product.The condensation chemistry was also adapted to a polymer synthesis wherein the fluorene ring system is part of the polymer backbone.

Scheme 9
Aryl-substituted oxindoles are known for their biological activities and several synthetic approaches have utilized superelectrophiles.One such method involves cyclizations of α-ketoamides (Scheme 10). 18For example, substrate 35 condenses in the presence of superacid and an arene nucleophile.A mechanism is proposed involving protonation of both carbonyl groups -forming superelectrophile 37a or 37b -followed by cyclization.A second dicationic intermediate (38) reacts with the arene to provide the final condensation product 39.

Carbocation superelectrophiles: carbenium ions -sp 3 centers
A series of unusual ring-fused heterocycles were prepared by ionization of triaryl alcohols. 19For example, substrate 40 gives compound 41 in excellent yield.These reactions are thought to involve an equilibrium between tri-and dicationic species (i.e., 42 and 43).Theoretical calculations revealed that direct cyclization of the trication is unlikely, but rather that deprotonation occurs to give the dication and subsequent C-N bond formation leads to the new ring.While it may seem counterintuitive -forming an unprotonated benzimidazole ring in superacid -it is suggested that the high charge density of ion 42 leads to increased N-H acidity.

Scheme 11
In addition, more highly-ionized structures give the expected cyclization products. 20Thus, substrate 44 gives the pyrido[1,2-a]indole 47 in 85% yield from a reaction in superacid (Scheme 12).This transformation involves an equilibrium between the tetracationic species (45, observable by NMR) and the tricationic species 47.As above, the highly-charged tetracationic structure facilitates N-deprotonation -despite being in the presence of a superacid -and the trication 46 is formed.This leads to the cyclization.Theoretical calculations were also done, showing an energy barrier of 13.6 kcal•mol -1 for the cyclization step.Likewise, substrate 48 leads to the functionalized pyrido[1,2-a]indole 49 in 90%.It is assumed that the cyclization occurs via a tetracationic superelectrophilic intermediate.

Scheme 12
Diazafluorenones are the starting point for an interesting group of superelectrophiles leading to spirocyclic products. 21Compound 50 reacts in superacid with, for example, 1-naphthol to give the spirocyclic product 51 in 45% yield (Scheme 13).The conversion likely involves tricationic species, such as superelectrophile 52.
A route to functionalized aza-polycyclic aromatic compounds has been described and the chemistry utilizes superelectrophilic carbocations. 22The ring closing and opening cascade involves ionization of substrates such as alcohol 53 to give dication 54.This species undergoes cyclization to initially provide structure 55.Ring opening -by protonated at the ipso position of the aryl group -leads to the final product 56.Aromatization of the new ring likely drives the equilibrium towards product 56.

Scheme 13 Scheme 14
Carbocation cyclization involving olefinic bonds is well-known in synthetic chemistry and biochemistry.Some examples are also known among superelectrophilic cyclizations.For example, a recent study examined the chemistry N-dienes and their reactions in superacid. 23Among the report transformations, diene 57 provides the piperidine derivative 61 in 55% from HF-SbF 5 (Scheme 15).The chemistry is thought to involve formation of several superelectrophiles.First, the 1,3-dication (58) is formed and this lead to an initial cyclization intermediate, dication 59.Charge separation is a powerful driving force in the chemistry of superelectrophiles, and as such, the 1,3-dication 59 isomerizes to the 1,4-dication 60.Fluoride attack at the carbocation site then leads to the final product (61).

Scheme 15 3.2 Carbocation superelectrophiles: vinyl cations
The study of vinyl cations began in the 1960s and it soon became apparent that -like aliphatic carbocationsthe vinyl cations were reactive electrophilic species. 24The first vinyl cations having dicationic character were generated from aminoalkynes in acid-catalyzed reactions leading heterocycles. 25,26Although the original reports did not identify the intermediates as dications, protonation of the aminoalkynes in strong acid almost certainly gave the superelectrophilic vinyl cations.More recently, superectrophilic vinyl cations have been used in several ring-forming synthetic reactions.Some of this chemistry is described in a recent review of protonation of acetylenic compounds. 27asilyev and coworkes have examined a variety of superelectrophilic vinyl cations, using experimental and theoretical methods.For example, a synthetic route leading to 3,4-dihydroquinolin-2(1H)-ones was reported. 28The chemistry utilizes aryl-substituted propiolamides in triflic acid-promoted reactions.Amide 62 gives the heterocycle 63 in good yield and a mechanism is proposed involving two superelectrophilic intermediates -a carboxonium-vinyl dication (64) and the carboxonium-carbenium dication (65).
A method for preparing functionalized indenes has been developed using enynones as the starting material. 30Treatment of compound 66 gives the indene product 67 is nearly quantitative yield (Scheme 17).A key step involves formation of the superelectrophile 68, which reacts with benzene.The resulting intermediate then undergoes cyclization to the indene 67 via the carboxonium ion (69) or a more highly protonated species.

Carbocation superelectrophiles: carbonium ions
According to the nomenclature proposed by Olah, trivalent carbocations (i.e., CH 3 +) are described as carbenium ions and higher coordinate carbocations (i.e., CH 5 +) are described as carbonium ions. 31Both types of cationic centers are known in superelectrophilic systems. 3Carbonium ions are generally characterized by 3 center-2 electron bonding.While numerous di-and tricationic carbonium ions have been studied computationally, fewer superelectrophilic carbonium ions have been generated in the condensed phase.
The first example of a superelectrophilic carbonium ion cyclization was reported recently by Thibaudeau and coworkers. 32This remarkable cyclization involves anti-Markovnikov additions to N-allylic derivatives.One such conversion produced the tetrahydroquinoline product 71 from the nitroaniline derivative 70 (Scheme 18).On the basis of theoretical calculations, a mechanism has been proposed wherein a tricationic species is formed that includes a symmetrical hydrido-bridged, carbonium structure (from protonation of the olefin).Cyclization at the protonated olefin then provides the tetrahydroquinoline product.The chemistry is particularly striking when considering the deactivating effects of the nitro group on arenes and aryl groups.

Nitrogen-Based Superelectrophiles
A variety of nitrogen-based superelectrophiles are known.As described in the introduction, the protionitronium ion (3, NO 2 H 2+ ) was one of the first ions to be recognized for its superelectrophilic reactivity.Several studies have also shown protonated nitro groups to be useful components of superelectrophilic systems.Other nitrogen-based groups have been demonstrated to be useful in superelectrophilic chemistry, including nitrilium ions, iminium ions, and ammonium ions.This includes cyclization chemistry.
In one such study, the superacid-catalyzed cyclizations of arylcyanopropionates was examined. 33eaction of nitrile 73 provides the dihydronathalene derivative 75 in good yield.A mechanism is proposed involving the distonic superelectrophile 74 as the key reactive intermediate leading to cyclization.NMR studies of a model cyanopropionate in superacid provide further evidence for the nitrilium-carboxonium dication intermediates.

Scheme 19
A superelectrophilic aza-Nazarov reaction has been reported. 34Starting from the hydrazone 76, treatment with excess (7 equivalents) of triflic acid and acetic anhydride leads to the pyrrole 77 (Scheme 20).A mechanism is proposed involving the superelectrophile 79, where the carbonyl oxygen and hydrazone nitrogen are protonated.Computational studies showed that an aza-Nazarov cyclization involving the superelectrophile 79 has a barrier of just 6.0 kcal•mol -1 , while a similar cyclization with the monocationic intermediate has a transition state located 13.1 kcal•mol -1 above ion 78.

Scheme 20
Another aza-Nazarov cyclization has been reported which utilizes amido-acetal substrates. 35For example, compound 80 reacts in superacid to gives the ring-fused isoindolinone (81).The conversion involves formation of the N-acyliminium ion (82).Though direct cyclization of the monocationic species 82 cannot be ruled out, computational studies indicate that carbonyl protonation (partial or complete) lowers the energy of cyclization.It is suggested that formation of the dication 83 enhances the delocalization of π-electronsfacilitating the 4 π -electron electrocyclization.

Scheme 21
A superelectrophilic system has been reported which provides 3,4-dihydroisoquinolin-1(2H)-ones and related products from aryl-substituted ureas. 36Despite the exceptional stability of the urea functional group, the 2-nitrophenyl substituent activates the urea in superacidic media.Thus, reaction of compound 84 in triflic acid provides the hetrocycle 85 in good yield.The chemistry is thought to involve protonation of the nitro and urea groups, giving the dicationic species 86 and 87 (in excess triflic acid, the pyridyl group is also protonated).DFT calculations suggest that the preferred reaction path leads to an equilibrium between 86 and 87 (structure 87 is calculated to be 11 kcal•mol -1 less stable; R = Ph) and cleavage of 87 to a protonated isocyanate.Cyclization then occurs by a Friedel-Crafts type reaction between the neighboring phenyl group and the protonated isocyanate.

Scheme 22
In a similar respect, intramolecular Freidel-Crafts acylation has been accomplished using an amide. 37hus, substrate 88 is reacted with superacid to give the indanone product (89).Amides have typically not been useful as reagents in Freidel-Crafts reactions, however compound 88 is doubly protonated in superacid.This leads to cleavage to the acylium cation via transition state 90.DFT calculations were done on a model system, indicating that N-protonation at the amide leads to an intermediate with a low barrier to acylium ion cleavage (+2.3 kcal•mol -1 ).

Fluorinated Superelectrophiles
Because of the useful properties of fluorine-substituted organic compounds, there has been an ever intensifying need for new synthetic methods leading to these products.Fluorine substitution by itself is known to enhance the reactivities of electrophiles.Nevertheless, fluorine atoms and the -CF 3 groups have also been present on several types of superelectrophiles.For example, Vasilyev and coworkers utilized trifluoromethyl-substituted enones and demonstrated them to be useful building blocks leading to functionalized indanes. 38Thus, compound 91 reacts in FSO 3 H and benzene at low temperature to give the hydroarylation product 92 in 68% yield.Treatment of this intermediate with triflic acid and benzene provides the indane 93 in 76% yield.The initial transformation is thought to involve superelectrophile 95.Some of the obtained products exhibited biological activities as cannabinoid receptor ligands.

Scheme 24
Trifluoromethyl-substituted acrylic acids provides thiochrom-4-ones (from thiophenols) in good yields from triflic acid. 39This chemistry was likewise useful in preparing trifluoromethyl-substituted indanones and dihydrocoumarins (Scheme 25). 40Trifluoromethyl-substituted superelectrophiles, such as 96, are proposed in these transformations.In a related transformation, crotonic and methacrylic acids were shown to give thiochrom-4-ones from thiophenols in a superacid promoted transformation. 41The proposed mechanism also invokes a superelectrophile arising from double protonation of the α,β-unsaturated carboxylic acids.

Scheme 25
A set of fluorinated quinolin-2-ones have been prepared from cinnamamides utilizing excess AlCl 3 (Scheme 26). 42For example, compound 98 is prepared in about 50 % yield from the precursor cinnamamide (97).The chemistry is thought to involve superelectrophile 99, wherein X is a coordinating proton (formed by adventitious water) or Lewis acid.The reactivity of this electrophile is apparent by its attack on a tetrafluorophenyl group -a very weak nucleophile.A final step involving elimination of benzene provides the quinolin-2-one 98. Scheme 26

Conclusions
Superelectrophiles are known to exhibit novel reactivities -often reacting with relatively inert reagents and functional groups.Moreover, a diverse set of functional groups can lead to superelectrophilic structures.Consquently, superelectrophilic chemistry is useful in the synthesis of various carbocyclic and heterocyclic structures.In the 50 years since Staskun suggested dicationic intermediates in the Knorr cyclization, there has been great progress in the use of superelectrophiles in cyclization reactions.Almost certainly, the next 50 years will see many more exciting advances in this chemistry.