Page  63 Special Issue Reviews and Accounts ARKIVOC 2009 (i) 63-80 Superelectrophiles in heterocyclic ring-forming reactions Douglas A. Klumpp Department of Chemistry and Biochemistry, Northern Illinois University DeKalb, IL 60115 E-mail: dklumpp@niu.edu Abstract Superelectrophiles are multiply charged cationic species which may exhibit remarkable reactivities towards weak nucleophiles. Since their discovery in the 1970s, many novel synthetic methodologies have been developed using superelectrophiles. In the following Account, superelectrophilic ring-forming reaction will be examined, specifically those reaction which produce heterocyclic systems. Keywords: Superelectrophiles, dications, superacids, heterocycles Table of Contents 1. Introduction 2. Ring-forming Reactions 2.1 Gitionic superelectrophiles 2.1.1 Gitionic superelectrophiles: geminal systems 2.1.2 Gitionic superelectrophiles: vicinal systems 2.1.3 Gitionic superelectrophiles: 1,3-dicationic systems 2.2 Distonic superelectrophiles 3. Summary 1. Introduction During the 1960s and 1970s, there were a number of reports describing electrophilic reactions in which the cationic electrophiles were notably more reactive in solutions of increasing acidities.1 These electrophiles were often capable of reacting with even the weakest nucleophiles, such as alkanes or deactivated arenes. This pattern of chemistry was first recognized by Olah with the proposed concept of superelectrophilic activation. As described in the early papers by the Olah group,1 superelectrophilic activation may occur when a cationic electrophile interacts with a ISSN 1551-7012 Page 63 ©ARKAT USA, Inc.

Page  64 Special Issue Reviews and Accounts ARKIVOC 2009 (i) 63-80 Brønsted or Lewis acid, generating a species with an increasing amount of positive charge.2 In the limiting cases, this may involve formation of a fully formed dicationic species. Because cationic electrophiles are typically very weak bases, the formation of superelectrophiles is most common in strong or superacidic solutions.3 Two important and typical superelectrophilic systems are the nitronium and acetyl cations. In aprotic solvents, nitronium tetrafluoroborate (NO2+BF4-) reacts readily with activated, electron rich arenes (i.e., good nucleophiles), but it does not react with strongly deactivated arenes, such as m-dinitrobenzene.4 In superacidic media however, m-dinitrobenzene reacts with nitronium tetrafluoroborate to give 1,3,5-trinitrobenzene in 70% yield. This increasing electrophilic reactivity can be explained by partial or complete protonation at the oxygen lone pair electrons to give superelectrophiles 2 or 3 (Scheme 1). In a similar respect, acetyl cation salts (i.e. CH3CO+SbF5-) are unreactive to iso-alkanes in SO2, SO2ClF, AsF3, or CH2Cl2.5 Reaction in superacidic HF-BF3 leads to efficient hydride abstraction from the iso-alkanes,6 and consequently, the superelectrophilic acetyl dication (5 or 6) is thought to be involved. In both the nitronium and acetyl ion superelectrophiles, the enhanced reactivities stem from the increasing dipositive charge on the electrophiles. This is the key element of superelectrophilic activation, as proposed by Olah and coworkers.2 Over the past several decades, the term “superelectrophile” has at times been used rather loosely, describing everything from metals in high oxidation states to compounds with multiple nitro groups. While these systems may exhibit novel reactivities and chemistry, they generally cannot be considered superelectrophiles according to Olah’s original concept. Increasing Reactivity •+ A H H ONO ONO ONO 123 44 56 Scheme 1. Nitronium and acetyl ion superelectrophiles. Superelectrophiles are organized into two categories, depending on the distance between the charge centers: gitionic (close) and distonic (distant) superelectrophiles. Gitionic superelectrophiles are defined as those in which the two positive charges are separated by no more than one carbon atom or heteroatom. The gitionic superelectrophiles are further broken Increasing Reactivity C O CH3 C O CH3 C O CH3 H A •+ C OH CH3 ISSN 1551-7012 Page 64 ©ARKAT USA, Inc.

Page  65 Special Issue Reviews and Accounts ARKIVOC 2009 (i) 63-80 down into geminal, vicinal, and 1,3-dicationic systems. Examples of the geminal systems are diprotonated H2S (H4S2+, 7) and the analogous heterocyclic system (8, Figure 1).7,8 With these systems, the two positive charges are centered at one atom. In polyatomic ions such as 7-8, it is understood that atomic charges are an approximation and that the charges are delocalized by resonance, induction, and other effects. The vicinal systems are characterized by cationic charge centers being located on adjacent atoms, such as in the bicyclic hydrazinium ion system (9).9 Finally, the 1,3-dicationic systems are considered those systems in which the positive charges are separated by a single atom. The piperidine derivative 10 is an example of a 1,3-dicationic system.10 The distonic superelectrophiles have cationic charge centers that are separated by two or more carbon (or hetero) atoms. There are many examples of heterocyclic distonic superelectrophiles, some of which (11-13) are shown in Figure 1.11 With increasing separation of charge centers, the dicationic species are no longer considered superelectrophiles. Several types of experimental studies have shown that such dicationic species (those with widely separated charge centers) exhibit electrophilic chemistry that is similar to monocationic electrophiles.2e For example, protonated acetophenone (14) is unreactive to benzene in the condensation chemistry (eq 1).12 However, 4-acetylpyridine (15) forms a reactive superelectrophile (16) that reacts readily with benzene and other arenes (eq 2).12 In the case of 16, the pyridinium ring enhances the electrophilic reactivity of the adjacent carboxonium ion, and consequently it is capable of reacting with the weak nucleophile benzene. When the pyridyl ring and ketone group are separated by several carbon atoms however, the carboxonium group does not show superelectrophilic reactivity despite forming a dicationic system (17, eq 3). Thus, superelectrophilic activation is directly related to the proximity of the charge centers. ISSN 1551-7012 Page 65 ©ARKAT USA, Inc.

Page  66 Special Issue Reviews and Accounts ARKIVOC 2009 (i) 63-80 Gitionic Distonic Superelectrophiles Superelectrophiles 2+ CH3 S S CH3 S S SS H3C H3C 8 11 Geminal N N N Ph OH 9 12 Vicinal CH3 S CH3N N H CH3 H H 10 13 1,3-Dicationic Figure 1. Types of superelectrophilic systems. O OH CF3SO3H (1) H3C H3C C6H6 14 Unreactive to C6H6 O OH Ph Ph CF3SO3H H3C H3C H3C (2) C6H6 N N N 96% H 15 16 Reactive to C6H6 CF3SO3H N O N (3) HO H C6H6 CH3 CH3 17 Unreactive to C6H6 Superelectrophilic chemistry has been studied extensively since Olah’s early publications in this area.2 Superelectrophiles are the basis for many useful synthetic transformations and they have been the subject of numerous mechanistic and theoretical studies. Moreover, a number of ISSN 1551-7012 Page 66 ©ARKAT USA, Inc.

Page  67 Special Issue Reviews and Accounts ARKIVOC 2009 (i) 63-80 gas-phase superelectrophiles have been generated in mass spectrometry studies, including both the nitronium and acetyl ion superelectrophiles (3 and 6).13 The chemistry of superelectrophiles has been reviewed several times, including most recently in a comprehensive monograph.2e In the following account, superelectrophilic heterocylic chemistry will be reviewed, with an emphasis on the synthetic aspects of this chemistry. This Account will specifically examine heterocylic ring-forming reactions involving superelectrophiles. Although a number of mechanistic studies have involved heterocyclic superelectrophiles, these reports will not be discussed. 2. Ring-forming Reactions 2.1.1 Gitionic superelectrophiles: geminal systems Although geminal-superelectrophiles are the least common type of superelectrophile, there have been a couple heterocycles prepared from this variety of superelectrophile. Ionization of the N- oxide (18) in CF3SO3H leads to the superelectrophile 19, which may be considered a type of nitrogen-centered geminal-superelectrophile on the basis of one of its resonance forms (eq 4).14 Cyclization then gives the natural product alkaloid (20). An oxygen-center geminalsuperelectrophile may be involved in the cyclization of 2,5-hexanediol in FSO3H-SbF5 at – 60°C.15 Upon warming the solution to –30°C, the diprotonated substrate gives the protonated tetrahydrofuran derivative (eq 5). It has been shown that water may be diprotonated in very strong superacid, forming H4O2+.16 Since a free hydroxy group is unlikely under these conditions, the geminal-superelectrophile 21 (or a partially protonated species) is proposed. H3CO N O CF3SO3H N H3CO H3CO N H3CO H3CO N H3CO H3CO 2+ -H2O 201918CH3 OH OH FSO3H-SbF5 -60°C H3C CH3 OH2 OH2 -30°C -H2O H3C O H3C OCH3 CH3H3C HH HH 2+ O -H+ (4) H3CO H3C CH3 (5) H 21 ISSN 1551-7012 Page 67 ©ARKAT USA, Inc.

Page  68 Special Issue Reviews and Accounts ARKIVOC 2009 (i) 63-80 2.1.2 Gitionic superelectrophiles: vicinal systems A number of vicinal-superelectrophiles have participated in ring-forming reactions. The Pictet- Spengler and Bischler-Napieralski reactions are useful synthetic methods to give the important isoquinoline ring system.17 With monocationic iminium ions, the cyclization is most effective with activated aryl nucleophiles. However in studies of the Pictet-Spengler reaction using superacidic conditions, Shudo and Ohwada found kinetic evidence for the involvement of vicinal-superelectrophiles.18 Moreover, they demonstrated that superelectrophilic activation enabled the cyclization to be done with less nucleophilic aryl groups (eq 6-7). In these reactions, an equilibrium is established between the iminium ion and the superelectrophile (i.e. 22) which cyclizes rapidly. N CF3SO3H (6) N NH NH 150°C H H Ph PhPh Ph 90% 22 (7) N CF3SO3H 69% 150°C NH Bis-sulfonium dications are well known species that may be considered vicinalsuperelectrophiles. The disulfonium-dication 25 can be prepared by reaction of the mono-Soxide with acid (eq 8).19 Dimethylsulfoxide has been shown to form the O,S-diprotonated species in superacid.20 By analogy, this suggests a mechanism in which protonation of monocation 23 leads to the vicinal-superelectrophile 24 and ring formation give the disulfonium-dication 25. However as noted by Nenajdenko and Alabugin, alternative mechanisms have been proposed for the conversion leading to 25.21 This species (25, X = CF3SO3-) has been shown to react with electron-rich arenes to provide arylated products (eq 9).22 H O O HO -H2O CF3CO2H H CF3CO2H S S S S (8) S S S S X 2 X 2 X 23 2425 -H S OH (9) SS S OH 2 CF3SO3 25 A diprotonated carbonyl group will also generate a vicinal-type of gitionic superelectrophile. Among the diprotonated carbonyl groups found in superelectrophilic chemistry, one example ISSN 1551-7012 Page 68 ©ARKAT USA, Inc.

Page  69 Special Issue Reviews and Accounts ARKIVOC 2009 (i) 63-80 involves heterocyclic ring formation. When ninhydrin is reacted with arenes in acidic media, product formation depends on acidity (eq 10).23 Condensation in H2SO4 gives high yields of the 2,2-diaryl-1,3-indandione (26), while reaction in superacidic CF3SO3H leads to formation of 3( diarylmethylene)-isobenzofuranones (27). If the 1,3-indandione is isolated and reacted with superacid, then the isobenzofuranone is obtained in quantitative yield. When the acid strengths are considered, it suggests a rearrangement mechanism involving the gitionic-superelectrophile 28 (eq 11). O O Br Br O O OH OH H2SO4, C6H5Br OO Br Br CF3SO3H, C6H5Br (10) 2697% 91% 27 Ph O OH2 OO Ph CF3SO3H Ph Ph (11) Ph Ph OO 28 2.1.3 Gitionic superelectrophiles: 1,3-dicationic systems Several 1,3-dicationic superelectrophiles have been shown to form new heterocyclic ring systems. Recently, a number of aza-Nazarov reactions have been described and one variety is thought to proceed by 1,3-dicationic superelectrophiles.24,25 For example, reaction of the Nacyliminium ion 29 with CF3SO3H gives the cyclized product 32 (eq 12). In CF3SO3H (Ho 14.1), the yield of the conversion is 50%, but in CF3CO2H (Ho -2.7) there is no cyclization product.25 This suggests the formation of either the superelectrophile 30 or the protosolvated species (31). Theoretical calculations have shown that formation of the superelectrophilic Nacyliminium ion leads to a decreased energy barrier (by more than 10 kcal/mol) for the cyclization. Over the years, the cyclizations of N-acyliminium ions have been an effective tool for alkaloid syntheses.26 O Cl OH O CF3SO3H N N N (12) 50% 30 32 29 •• H CF3SO3 O N 31 ISSN 1551-7012 Page 69 ©ARKAT USA, Inc.

Page  70 Special Issue Reviews and Accounts ARKIVOC 2009 (i) 63-80 The superacid promoted synthesis of isoquinolinones was described recently and based on the increasing yields and reaction rates, a superelectrophilic species (34) was proposed (eq 13).27 A modest degree of diastereoselectivity (90% d.r.) was obtained with cyclization of a chiral Nacyliminium ion 36 in superacid (eq 14).27 Ph Ph CH2 O CH3 CF3SO3H N N (13) • N HOTf Me95% OO Ph • 3334 35 Ph CF3 MeO CF3 O Ph CF3SO3H N OMe (14) N Ph Ph 27% yield XO 90% d.r. Ph 36 37 Several other types of heterocyclic systems have been prepared from cyclizations with adjacent benzyl groups. The pyrrolidinol 38 ionizes in CF3SO3H to give the 1,3-dication 39, and intramolecular reaction with the benzyl group occurs exclusively, despite the presence of a large amount of benzene (eq 15).28 Superelectrophiles similar to 39 were directly observed by low temperature NMR. Compounds 41-43 also react with the superacid to generate the vinyl- ammonium dications (44-46; Figure 2).29 In the case of 41, the silyl group is cleaved rapidly in superacid and the superelectrophile 44 is formed. Cyclization of 44 with the benzyl group leads to formation of an exocyclic methylene group, and further protonation give another 1,3dicationic superelectrophile (not shown). This reacts with benzene to give 47. Similar mechanisms are proposed for compounds 42-43 and their cyclizations to the heterocyclic products. CF3SO3H (15) N OH Ph N Ph 384067% N Ph 39H C6H6 ISSN 1551-7012 Page 70 ©ARKAT USA, Inc.

Page  71 Special Issue Reviews and Accounts ARKIVOC 2009 (i) 63-80 Substrate 1,3-Dication Product Yield 93%a TMS H H3C N N N H H H Ph 41 44 47 CH3 N N N 69%a H CH3 CH3 Ph CH3 42 4548 H N H N H3C 95%b N H 43 H 46 49 aConditions: Excess CF3SO3H with C6H6. bConditions: Excess CF3SO3H. Figure 2. Cyclizations of benzyl groups with 1,3-dicationic superelectrophiles. An interesting cyclization was reported from the reactions of some nitroolefins in superacid. When 1-nitrocyclohexene is reacted with CF3SO3H and benzene at 40°C, formation of an initial 1,3-dicationic superelectrophile (50) leads to subsequent reaction with benzene and cyclization (eq 16).30 In this case, the 4H-1,2-benzoxazine (51) is formed in good yield. Thermolysis of the product 4H-1,2-benzoxazines has been shown to provide good conversions to o-benzoquinone methides by retro-cycloaddition.31 N O O CF3SO3H C6H6 N OH OH N OH OH 50N H OH N O 51H+- 2 H+ - H2O (16) 87% 2.2 Distonic superelectrophiles A fairly significant number of heterocyclic synthetic methods have been developed based on the reactions of distonic superelectrophiles. For example, the Grewe cyclization is a well-known synthetic methodology used in the preparation of morphine analogs (i.e. 55) and it involves the ISSN 1551-7012 Page 71 ©ARKAT USA, Inc.

Page  72 Special Issue Reviews and Accounts ARKIVOC 2009 (i) 63-80 formation of a distonic superelectrophile (54, eq 17).32 Protonation of the olefinic group and nitrogen atom gives the 1,4-dication 54, which cyclizes to form the desired heterocyclic ring system (55). There are two important aspects in the success of this chemistry. Because of electrostatic repulsive effects, protonation at the double bond regioselectively forms the 1,4dication (as opposed to the 1,3-dication from protonation at the 4-carbon). This insures formation of the proper ring system. Moreover, strong acids are known to promote polymerizations of olefins, however the Grewe cyclizations are typically clean conversions. Based on the mechanism for cationic polymerization of olefins, an oligomerization of 52 would require attack of dication 54 on the monocation 53, an unlikely process due to electrostatic repulsive effects. Thus, the protonated nitrogen is a key element in the success of this reaction. NH OH N R OCH3 H3PO4 N R OCH3 H (17) 525455N R OCH3 H 53 The Knorr cyclization is another classical heterocyclic synthetic method involving distonic superelectrophiles.33 In 1964, Staskun reported that the Knorr cyclization is best conducted with excess Brønsted or Lewis acid, and remarkably, he proposed a mechanism involving dicationic intermediates.34 Recent experimental and theoretical evidence confirms the main idea in Staskun’s proposed mechanism (i.e., that dications are involved).35 The Knorr cyclization is accomplished by the reaction of •-ketoamides under conditions of high acidity to give quinolin2- one products (eq 18). As expected with a reaction involving a superelectrophilic intermediate, the conversions are best done in superacidic media (CF3SO3H), providing higher yields than with mineral acids (at lower temperature with shorter reaction times, too). The superelectrophile 57 is formed by protonation of the two carbonyl oxygen atoms which triggers cyclization. Superelectrophiles like 57 can be directly observed using low temperature 15N and 13C NMR and stable ion conditions.35 Experimental NMR data for the superelectrophile compared favorably with the NMR data from DFT calculations. CH3 OH OO OH CF3SO3H (18) N CH3 N CH3 HN O H H 56 57 90% In somewhat related conversions, •-ketoamides will cyclize in the presence of superacid and an arene nucleophile to give aryl-substituted oxyindoles (i.e. 60) and related products (eqs 1920). 36 The mechanism is thought to involve the O,O-diprotonated superelectrophile (59), which cyclizes to form the oxyindole ring system. Subsequent steps involve dehydration and reaction ISSN 1551-7012 Page 72 ©ARKAT USA, Inc.

Page  73 Special Issue Reviews and Accounts ARKIVOC 2009 (i) 63-80 with the arene nucleophile. The O,O-diprotonated superelectrophile (i.e., 59) was also characterized by spectroscopic experiments and theoretical calculations. H O N H CF3SO3H OH H N O (19) N Ph Ph 73% p-C6H4(OCH3)2 Ph O OH H3CO OCH3 58 59 60 O Ph Ph Ph O O O HN O CF3SO3H HN (20) C6H6 H3CO H3CO 52% Other cyclizations of carbocations with aryl groups have given heterocyclic systems. Olefinic and alkynyl systems readily generate the distonic superelectrophiles and may give heterocyclic systems (eqs 21-23).37-39 Although there is a general tendency to form dications with the greatest possible distance between the charges (vide infra), formation of the more highly-substituted carbocation generally outweighs the charge separation factors, as seen in the formation of superelectrophile 66. Formation of benzylic cations can facilitate the formation of the superelectrophilic intermediates, as seen in 71 and 75-76 (eqs 24-26).39,40 Ionization of alcohol or olefin substrates may lead to these reactive superelectrophiles. In the case of compounds 73 and 74, the superelectrophiles (75-76) are formed regioselectively due to the preference for maintaining the maximum distance between the two positive charges. ISSN 1551-7012 Page 73 ©ARKAT USA, Inc.

Page  74 Special Issue Reviews and Accounts ARKIVOC 2009 (i) 63-80 ISSN 1551-7012 Page 74 ©ARKAT USA, Inc. N N Ph Ph N N Ph Ph H N N Ph 87% Ph N CH3 Ph H3PO4 33% CH3 N H Ph H N CH3 Ph Ph N N Ph Ph 63 CF3SO3H N NH Ph Ph H3C 66 N N Ph 69 H3C 69% 62 65 68 61 64 67 (21) (22) (23) CF3SO3H 70 N N Ph Ph OH N N Ph 72 83% 71 HN N Ph Ph (24) CF3SO3H N Ph N 65% NH Ph NH Ph Ph 76 N Ph Ph 85% N 74 78 73 75 77 (25) (26) CF3SO3H CF3SO3H NH H NH Ph Ph 79 80 1,4-dication 1,5-dication Thus, dication 79 is not formed from protonation of the olefin. Theoretical calculations estimate the energy difference between 76 and 79 to be about 10 kcal/mol (MP2/6-311G (d) level).40 Under superacidic conditions, the phenyl group may be considered a type of leaving group and ipso protonation (80) of a phenyl group may lead to the formal elimination of benzene. This can occur in good yield, especially if an extended aromatic system is produced, as in products 77-78 (eqs 25-26). In the case of product 72 (eq 24), benzene elimination is

Page  75 Special Issue Reviews and Accounts ARKIVOC 2009 (i) 63-80 suppressed by use of mild reaction conditions. The preference for charge-separated dications may also be seen in the reaction of alcohol 81 (eq 27).41 Initial ionization of the alcohol (81) leads to formation of the 1,4-dication 82. Charge migration gives the 1,5-dication 83, which undergoes cyclization and benzene elimination to provide the final condensation product 84. Deuterium labeling experiments indicated that such charge migrations are the result of deprotonation-reprotonation steps rather than via 1,2-hydride shift.41 O O N N Ph N N Ph O 60% 81OHPh 84O (27) CF3SO3H O O N H N Ph 82Ph O N H N Ph 83Ph O 1,4-dication 1,5-dication Sommer has described several types of cyclizations involving amide-derived distonic superelectrophiles.42 For example, both the alkene and alkyne derivatives cyclize in strong and superacid media (eqs 28-29). OH O O H H H CF3SO3H N N N (28) Ph Ph Ph 25°C 85% Ph Ph Ph Nafion-H H (29) C6H6 OH 70% N N O N O 130°C H HH An interesting cyclization was reported by Koltunov et al. involving the reaction of 8hydroxyquinoline with benzene in excess AlCl3 or AlBr3.43 Initial reaction with acid leads to formation of 85 and the addition of benzene. Formation of another distonic superelectrophile 86 then leads to cyclization with the phenyl group and the heterocyclic alcohol 87 is produced (eq 30). It is notable that monocation 88 is unreactive to benzene. ISSN 1551-7012 Page 75 ©ARKAT USA, Inc.

Page  76 Special Issue Reviews and Accounts ARKIVOC 2009 (i) 63-80 ABr3 or AlCl3 C6H6 N (30) OH 88N HOH Ph N OH N HOH 85C6H6 OH 87 86 The reductive phenylation of nitroarenes in superacid has been shown to be an effective means for making biaryl bonds. An application of this chemistry yields the aporphine alkaloid ring system (eq 31).44 In this reaction, it is likely that the nitro group is at least monoprotonated in superacid, forming superelectrophile 90. This leads to positive charge formation in the aryl- ring and subsequent carbon-carbon bond formation. H3CO H3CO H3CO N N CH3 N H3CO CH3 CF3SO3H H3CO H3CO CH3 H (31) CF3CO2H Zn H3CO 68% NO2 H3CO H3CO N NH2 HO O 89 9091 In a conversion related to the Grewe cyclization, seven-member heterocyclic rings were prepared by reactions of cyclohexene derivative in mineral acids (eq 32).45 Although no mechanism is proposed for the conversion, it is likely that ring closure involves formation of the distonic superelectrophile 92. As noted by the authors of this study, this is one of the only examples of a Grewe-type cyclization leading to a seven-member heterocycle (93). H2SO4 N CH3 N (32) H3PO4 N CH3H 40% CH3 H3CO H3CO H3CO OH OH 92 93 OH Among the heterocycles prepared from superelectrophiles, the vast majority are nitrogen- containing heterocycles. Nevertheless, some oxygen-containing heterocycles have been formed from superelectrophiles. One unusual example came from the superacid protonation of lactic acid.46 In studies by Olah and Ku, reaction of lactic acid with FSO3H-SbF5-SO2 led to the formation of superelectrophile 94 which could be observed by low temperature NMR (eq 33). ISSN 1551-7012 Page 76 ©ARKAT USA, Inc.

Page  77 Special Issue Reviews and Accounts ARKIVOC 2009 (i) 63-80 Upon warming to –30°C, the lactic acid dimerizes to give the oxygen-containing heterocycle, diprotonated lactide (95). HO CH3 OH O FSO3H:SbF5 SO2 -80°C HO CH3 OH2 OH -30°C -2 H3O+ O O CH3 CH3 OH HO (33) 94 95 3. Summary Electrophile-nucleophile reactions constitute perhaps the most important type of chemical reaction in organic synthesis. By virtue of their high reactivities, superelectrophiles are often capable of reacting with very weak nucleophiles. This aspect allows superelectrophilic chemistry to further expand the scope of electrophile-nucleophile reactions. These properties have been exploited in the development of a variety of new methods for preparing heterocyclic products. Although this Account has been confined to discussing heterocyclic ring-forming reactions, there are also many superelectrophilic reactions that provide heterocycle functionalization, group transfer reactions, and side-chain modification.2e Thus, it is expected that superelectrophilic chemistry will continue to be a useful tool in the synthesis of heterocyclic products. Acknowledgements The support of the National Science Foundation is greatly appreciated (CHE-0749907), in particular for their support of research in the area of heterocyclic chemistry. References 1. Olah, G. A.; Germain, A.; Lin, H. C.; Forsyth, D. J. Am. Chem. Soc. 1975, 97, 2928. 2. (a) Olah, G. A.; Prakash, G. K. S.; Lammertsma, K. Res. Chem Intermed. 1989, 12, 141. (b) Olah, G. A. Angew. Chem. Int. Ed. 1993, 32, 767. (c) Olah, G. A.; Klumpp, D. A. Acct. Chem. Res. 2004, 37, 211. (d) Klumpp, D. A. Chem. Eur. J. 2008, 14, 2004. (e) Olah, G. A.; Klumpp, D. A. Superelectrophiles and Their Chemistry; Wiley & Sons: New York, 2008. (f) Klumpp, D. A. In Recent Developments in Carbocation and Onium Ion Chemistry, Laali, K., Ed.; ACS Symposium Series 395; American Chemical Society, Washington, DC, 2007; pp 144-159. 3. (a ) Olah, G. A.; Prakash, G. K. S.; Sommer, J. In Superacids; Wiley, New York, 1985. (b) Olah, G. A. Angew. Chem. Int. Ed. 1995, 34, 1393. ISSN 1551-7012 Page 77 ©ARKAT USA, Inc.

Page  78 Special Issue Reviews and Accounts ARKIVOC 2009 (i) 63-80 4. Olah, G. A.; Lin, H. C. Synthesis 1974, 444 5. (a) Ref. 1. (b) Y. Sato; M. Yato; T. Ohwada; S. Saito; K. Shudo J. Am. Chem. Soc. 1995, 117, 3037. (c) Olah, G. A.; Burrichter, A.; Rasul, G.; Prakash, G. K. S.; Hachoumy, M.; Sommer, J. J. Am. Chem. Soc. 1996, 118, 10423. 6. Brouwer, D. M.; Kiffen, A. A. Recl. Trav. Chim. Pays-Bas 1973, 92, 689. 7. Olah, G. A.; Prakash, G. K. S.; Marcelli, M.; Lammertsma, K. J. Phys. Chem. 1988, 92, 878. 8. Sato, S.; Ameta, H.; Horn, E.; Takahashi, O.; Furukawa, N. J. Am. Chem. Soc. 1997, 119, 12374. 9. Alder, R. W.; Sessions, R. B.; Mellor, J. M.; Rawlins, M. F. J. Chem. Soc., Chem. Commun. 1977, 747. 10. Klumpp, D. A.; Beauchamp, P. S.; Sanchez, Jr., G. S.; Aguirre, S.; de Leon, S. Tetrahedron Lett. 2001, 42, 5821. 11. (a) Miller, G. P.; Jeon, I.; Wilson, G.; Athans, A. J. Org. Lett. 1999, 1, 1771. (b) Zhang, Y.; Klumpp, D. A. Tetrahedron Lett. 2002, 43, 6841. (c) Zhang, Y.; McElrea, A.; Sanchez Jr., G. V.; Klumpp, D. A.; Do, D.; Gomez, A.; Aguirre, S. L.; Rendy, R. J. Org. Chem. 2003, 68, 5119. 12. Klumpp, D. A.; Garza, G; Sanchez, G. V.; Lau, S.; DeLeon, S. J. Org. Chem. 2000, 65, 8997. 13. (a) Weiske, T.; Koch, W.; Schwarz, H. J. Am. Chem. Soc. 1993, 115, 6312. (b) Koch, W.; Frenking, G.; Schwarz, H.; Maquin, F.; Stahl, D. Int. J. Mass Spec. Ion Proc. 1985, 63, 59. 14. Shudo, K.; Ohta, T.; Endo, Y.; Okamoto, T. Tetrahedron Lett. 1977, 105. 15. Olah, G. A.; Sommer, J. J. Am. Chem. Soc. 1968, 90, 927. 16. Olah, G. A.; Prakash, G. K. S.; Barzaghi, M.; Lammertsma, K.; Schleyer, P. v. R.; Pople, J. A. J. Am. Chem. Soc. 1986, 108, 1032. 17. (a) Royer, J.; Bonin, M.; Micouin, L. Chem. Rev. 2004, 104, 2311. (b) Nielsen, T. E.; Diness, F.; Meldal, M. Curr. Opin. Drug Discovery Dev. 2003, 6, 801. (c) Larghi, E. L.; Amongero, M.; Bracca, A. B. J.; Kauffman, T.S. ARKIVOC 2005, (vii), 98. (d) Cox, E. D.; Cook, J. Chem. Rev. 1995, 95, 1797. 18. Yokoyama, A.; Ohwada, T.; Shudo, K. J. Org. Chem. 1999, 64, 611. 19. (a) Nenajdenko, V. G.; Vertelezkij, P. V.; Koldobskij, A. B.; Alabugin, I. V.; Balenkova, E. S. J. Org. Chem. 1997, 62, 2483. (b) Ohkata, K.; Okada, K.; Akida, K. Heteroat. Chem. 1995, 6, 145. 20. Rasul, G.; Prakash, G. K. S.; Olah, G. A. J. Org. Chem. 2000, 65, 8776. 21. Nenajdenko, V. G.; Shevchenko, N. E.; Balenkova, E. S.; Alabugin, I. V. Chem. Rev. 2003, 103, 229. 22. Fujihara, H.; Akaishi, R.; Furukawa, N. Chem. Lett. 1988, 709. 23. Klumpp, D. A.; Fredrick, S.; Lau, S.; Prakash, G. K. S.; Jin, K. K.; Bau, R.; Olah, G. A. J. Org. Chem. 1999, 64, 5152. 24. (a) Dieker, J.; Froehlich, R.; Wuerthwein, E.-U. Eur J. Org. Chem. 2006, 23, 5339. (b) Ghavtadze, N.; Froehlich, R.; Wuerthwein, E.-U. Eur J. Org. Chem. 2008, 21, 3656. ISSN 1551-7012 Page 78 ©ARKAT USA, Inc.

Page  79 Special Issue Reviews and Accounts ARKIVOC 2009 (i) 63-80 25. Klumpp, D. A.; Zhang, Y.; O’Connor, M. J.; Esteves, P. M.; de Almeida, L. S. Org. Lett. 2007, 9, 3085. 26. Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104, 1431. 27. Zhang, Y.; Kindelin, P. J.; DeSchepper, D. J.; Zheng, C.; Klumpp, D. A., Synthesis 2006, 1775. 28. Klumpp, D. A.; Aguirre, S. L.; Sanchez, Jr., G. V.; de Leon, S. J. Org. Lett. 2001, 3, 2781. 29. (a) Rendy, R.; Zhang, Y.; Gomez, A.; McElrea, A.; Dang, H.; Klumpp, D. A. J. Org. Chem. 2004, 69, 8108. (b) Brooks, J. R.; Harcourt, D. N.; Waigh, R. D. J. Chem. Soc. Perkin Trans. I 1973, 2588. 30. Ohwada, T.; Okabe, K.; Ohta, T.; Shudo, K. Tetrahedron 1990, 46, 7539. 31. Yato, M.; Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1990, 112, 5341. 32. Palmer, D. C.; Strauss, M. J. Chem. Rev. 1977, 77, 1. 33. 33. Uff, B. C. in Comprehensive Heterocyclic Chemistry, Katritzky, A. R.; Rees, C. W.; Pergamon Press: Oxford, 1985; vol. 2, p. 425. 34. Staskun, B. J. Org. Chem. 1964, 29, 1153. 35. Solingapuran Sai, K. K.; Gilbert, T. M.; Klumpp, D. A. J. Org. Chem. 2007, 72, 9761. 36. Solingapuran Sai, K. K.; Esteves, P. M.; Tanoue da Penha, E.; Klumpp, D. A. J. Org. Chem. 2008, 73, 6506. 37. Klumpp, D. A.; Kindelin, P. J.; Li, A. Tetrahedron Lett. 2005, 46, 2931. 38. Takayama, H.; Suzuki, T.; Nomoto, T. Chem. Lett. 1978, 865. 39. Sheets, M. R.; Li, A.; Bower, E. A.; Weigel, A. R.; Abbott, M. P.; Gallo, R. M.; Mitton, A. A.; Klumpp, D. A. J. Org. Chem. 2009, 74, manuscript in press. 40. Li, A.; Gilbert, T. M.; Klumpp, D. A. J. Org. Chem. 2008, 73, 3654. 41. Li, A.; Kindelin, P. J.; Klumpp, D. A. Org. Lett. 2006, 8, 1233. 42. Koltunov; K. Y.; Walspurger, S.; Sommer, J. Chem. Comm. 2004, 1754. 43. Koltunov; K. Y.; Prakash, G. K. S.; Rasul, G.; Olah, G. A. J. Org. Chem. 2002, 67, 4330. 44. Ohta, T.; Machida, R.; Takeda, K.; Endo, Y.; Shudo, K.; Okamoto, T. J. Am. Chem. Soc. 1980, 102, 6386. 45. Lukacs, A.; Szabo, L.; Hazai, L.; Szantay, C.; Mak, M.; Gorka, A.; Szantay, C. Tetrahedron 2001, 57, 5843. 46. Olah, G. A.; Ku, A. T. J. Org. Chem. 1970, 35, 3913. ISSN 1551-7012 Page 79 ©ARKAT USA, Inc.

Page  80 Special Issue Reviews and Accounts ARKIVOC 2009 (i) 63-80 Author’s biography Douglas Klumpp obtained his undergraduate chemistry degree from the University of Oklahoma and his Ph.D in organic chemistry from Iowa State University. His graduate research was conducted with Walter S. Trahanovsky and it involved gas-phase thermolysis of heterocyclic substrates. His postdoctoral work was done at the University of Southern California with George A. Olah, where he worked on synthetic methodology development using superacid catalysis. Professor Klumpp’s first faculty appointment was at California State Polytechnic University, Pomona (1996-2003) as an assistant and then associate professor. His current position is at Northern Illinois University (2003-to date) where he has been recently promoted to full professor. ISSN 1551-7012 Page 80 ©ARKAT USA, Inc.