CationâÏ Interactions in Organic Synthesis - Chemical Reviews (ACS

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Cite This: Chem. Rev. 2018, 118, 11353−11432

Cation−π Interactions in Organic Synthesis Shinji Yamada*

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Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan ABSTRACT: The cation−π interaction is an attractive noncovalent interaction between a cation and a π system. Due to the stronger interaction energy than those of the other π interactions, such as π−π and CH−π interactions, the cation−π interaction has recently been recognized as a new tool for controlling the regio- and stereoselectivities in various types of organic reactions. This review attempts to cover a variety of organic reactions controlled by cation−π interactions, which includes not only recent examples but also those reported before the term “cation−π interaction” was defined in 1990. This review will provide comprehensive knowledge on the role of cation−π interactions in organic synthesis.

CONTENTS 1. Introduction 2. Reactions Involving Cationic Intermediates or Transition States 2.1. Nucleophilic Addition 2.1.1. Addition to Pyridinium Ions 2.1.2. Addition to Quinolinium Ions 2.1.3. Addition to Iminium and Oxonium Ions 2.2. Conjugate Addition 2.2.1. Friedel−Crafts/Michael Reaction 2.2.2. Michael Reaction 2.3. Friedel−Crafts Reaction 2.3.1. Friedel−Crafts Alkylation 2.3.2. Friedel−Crafts Acylation 2.4. Nucleophilic Substitution 2.4.1. SN1 Reaction 2.4.2. SN2 Reaction 2.5. Cycloaddition 2.5.1. [4 + 2] Cycloaddition 2.5.2. [4 + 3] Cycloaddition 2.5.3. [1,3]-Dipolar Cycloaddition 2.6. Nucleophilic Catalysis 2.6.1. Asymmetric O-Acylation 2.6.2. Asymmetric C-Acylation 2.6.3. Deacylation and Hydrolysis 2.7. Halogenation 2.8. Rearrangement 2.8.1. Nucleophilic Rearrangement 2.8.2. Sigmatropic Rearrangement 2.9. Oxidation 3. Onium Ion-Assisted Reactions 3.1. Nucleophilic Reactions 3.1.1. Nucleophilic Addition 3.1.2. Cyclization of Alkynes 3.1.3. Nucleophilic Substitution 3.2. Photochemical Reactions 3.2.1. Photodimerization in Solution 3.2.2. Photodimerization in the Solid State 3.2.3. Intramolecular Photocyclization © 2018 American Chemical Society

3.3. Templated Synthesis 3.3.1. Template-Directed Synthesis 3.3.2. Dynamic Combinatorial Synthesis 3.4. Decarboxylation 4. Metal Cation-Assisted Reactions 4.1. Alkali Metal Cation-Assisted Reactions 4.1.1. Li+- and Na+-Assisted Reactions 4.1.2. K+- and Cs+-Assisted Reactions 4.2. Reactions in Zeolites 4.2.1. Oxidation and Reduction 4.2.2. Photochemical Reactions 5. Supramolecular Catalysis 5.1. Reactions in Supramolecular Receptors 5.2. Reactions in Self-Assembled Cages 5.2.1. Cationic Cages 5.2.2. Anionic Cages 5.2.3. Neutral Cages 6. Biocatalysis 6.1. Enzymatic Reactions 6.2. Reactions with Catalytic Antibodies 7. Conclusion Author Information Corresponding Author ORCID Notes Biography Acknowledgments Abbreviations References

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11397 11397 11399 11400 11400 11401 11401 11403 11406 11406 11407 11408 11408 11409 11409 11411 11413 11414 11414 11415 11417 11417 11417 11417 11417 11417 11417 11418 11418

1. INTRODUCTION In 1981, Kabarle expounded the existence of an attractive noncovalent interaction between alkali metal cations and aromatic compounds.1 Experiments for the formation of a benzene−K+ complex in the gas phase revealed the magnitude Received: June 18, 2018 Published: December 3, 2018 11353

DOI: 10.1021/acs.chemrev.8b00377 Chem. Rev. 2018, 118, 11353−11432

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of the interaction energy to be 19 kcal/mol.1 Furthermore, in 1985, Meot-Ner reported that the binding energies between quaternary ammonium ions and π systems are in the range of 10−22 kcal/mol.2,3 Since Dougherty proposed the term “cation−π interaction” to describe the attractive interactions between a cationic species and a π system in 1990,4−6 cation−π interactions have been recognized in a wide variety of biology and chemistry fields,5−7 such as structural biology,8−10 neurobiology,11,12 and host−guest13−16 and supramolecular chemistries, Figure 1.17,18

Table 1. Interaction Energies of Benzene Complexes (C6H6−X) with C6H6, C5H5N, C5H5NCH3+, C5H5NH+, and K+ a

X

Etotalb

Eesc

Eindd

Ecorre

Erepf

C6H6 C5H5N C5H5NMe+ C5H5NH+ K+ g

−2.48 −3.04 −9.36 −14.8 −17.2

0.9 0.39 −4.05 −8.12 −11.9

−0.25 −0.22 −3.52 −9.13 −12.8

−6.14 −6.48 −7.58 −5.63 −4.4

3.01 3.27 5.79 8.12 11.8

a

Energy in kcal/mol. bThe Etotal (total interaction energy) is ECCSD(T)(limit). cEes is the electrostatic energy. Ees was calculated as the interactions between distributed multipoles of monomers. dEind is the induction energy. Eind was calculated from the electric field produced by the distributed multipoles and atomic polarizabilities. e Ecorr (Etotal − EHF) is the electron correlation contribution to the total interaction energy. Ecorr is the difference between the calculated intermolecular interaction energies with and without electron correlation correction. Ecorr is mainly dispersion energy. fErep (EHF − Ees − Eind) is mainly exchange-repulsion energy. gReference 40.

Figure 1. Cation−π interactions between cations and π systems.

The origin of the attraction in a cation−π interaction has been shown to be electrostatic and inductive forces,5,6 which cause a relatively stronger attractive force than those of other aromatic interactions, such as π−π and CH−π interactions, the major force of which is dispersion.19 The strength of cation−π interactions was estimated by experimental studies using a variety of equilibrium systems, such as chemical double-mutant cycles,20−22 molecular balances23−25 and related compounds,26−28 tin−lithium exchange systems,29 and host− guest systems.13−16 These experiments revealed that the binding energies of quaternary ammonium ions to proteins involving aromatic amino acid residues is estimated to be 2.5− 2.8 kcal/mol,30,31 and the energy between benzene and pyridinium is 2−3 kcal/mol.22−25 For example, 1H NMR studies using seesaw balance 124,25 that adopts two distinct conformers 1-A and 1-B, which are stabilized by cation−π and π−π interactions, respectively, clarified that a pyridinium−π interaction is 1.5 kcal/mol larger than a π−π interaction in CDCl3 (Scheme 1).

component of Ecorr) is the major source of attraction in the benzene dimer. A similar tendency is observed in the benzene−pyridine complex. In contrast, the Ees and Eind for the benzene−pyridinium complexes are much larger than those of the benzene−pyridine complex. A large part of the Eind in these systems has its origin in the polarization of benzene by the electric field produced by pyridinium. These observations are similar to those of the benzene−K+ complex. Therefore, these results suggest that the attractive interaction of the benzene−pyridinium complexes should be categorized as cation−π interactions, while the interaction of the benzene− pyridine complex should be categorized as a π−π interaction. Table 2 shows the calculated interaction energies for the benzene complexes (C6H6−X) with CH4, NH3, NH4+, and Me4N+.34 Considerable differences in the total energies as well as the nature of the interactions were observed between the neutral and the cationic complexes. The major sources of attraction in the benzene−cation clusters are electrostatic and inductive interactions, which are similar to those of the benzene−pyridinium and benzene−alkali metal cation clusters. Therefore, quaternary ammonium−π interactions are generally categorized as cation−π interactions. It should be noted that cation−π interactions are often confused with π−π, CH−π, and charge-transfer interactions.41−44 For example, the interaction between a pyridinium and an aromatic ring is often defined as a π−π or CT interaction due to the similarity of the structural features between a cation−π interaction and those interactions. As the major forces involved in this type of interaction have been determined to be electrostatic and inductive forces, as described above,33 the pyridinium−π interactions should be categorized as cation−π interactions.33 It is also suggested that the attractive force in CT interactions is very weak in solution, despite dramatic spectral and color changes.41−44 A similar confusion is also noted for ammonium−π interactions.6 The N(CH2R)4+···π and NH4+···π interactions are structurally close to CH−π and NH−π interactions, respectively. However, the

Scheme 1. Molecular Seesaw Balance for the Evaluation of Cation−π Interactions

There have been a number of theoretical studies on the cation−π interaction energies for various systems,32−39 and these have helped elucidate the nature of cation−π interactions. Table 1 shows the calculated interaction energies for benzene complexes (C6H6−X) based on energy decomposition analysis.33 Comparison among the electrostatic (Ees), inductive (Eind), repulsive (Erep), and correlation (Ecorr) energies reveals that the dispersion energy (the major 11354


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Table 2. Interaction Energies of Benzene Complexes (C6H6−X) with CH4, NH3, NH4+, and N(CH3)4+ a

X

Etotalb

Eesc

CH4 NH3 NH4+ NMe4+

−1.45 −2.22 −19.30 −9.66

−0.25 −1.01 −11.04 −5.27

Eindd

Ecorre

Erepf

−13.58 −3.80

−2.30 −2.36 −4.26 −4.85

1.10 1.14 9.58 4.27

(4) As electrostatic and induction interactions are the major forces in a cation−π interaction, the attractive force works effectively even if the intermolecular distance is longer than the orbital interaction distance. There have been only a few reviews on the role of cation−π interactions in organic reactions47,48 and organocatalysis,49−51 suggesting the potential utility of cation−π interactions in small molecular systems in various synthetic processes. This review aims to introduce a variety of examples in which cation−π interactions play an important role in enhancing the reaction rate and controlling the regio-, chemo-, and stereoselectivities in solution and solid states as well as in supramolecular systems and biocatalysts. This review covers the reactions involving various cations, such as stable and unstable organic cations, and alkali metal ions as well as cationic species generated in the transition state. Regarding the π system, all unsaturated neutral compounds such as alkenes, alkynes, as well as aromatic and carbonyl compounds, and so on are covered. On the other hand, this review excludes the systems that do not fit the definition of a cation−π interaction even though it is useful for organic synthesis. Interactions with transition metals, in particular, are generally beyond the scope of this definition as they often involve orbital interactions.52−54 For example, the binding energy of the benzene−Cu+ complex is calculated to be −48.7 kcal/mol,55 which is significantly higher than that of benzene− Li+ (−36 kcal/mol). This is due to the major force being a 3d → π*C6H6 back-bonding interaction.55 As the term “cation−π interaction” was only defined in 1990, there are a number of “hidden” examples not only before 1990 but also after 1990 due to a lack of widespread recognition of the new term. This review sheds light on not only the recent literature but also such hidden examples in an attempt to provide a better understanding of the general role of cation−π interactions in a variety of organic reactions. Although it is often difficult to prove the existence of cation−π interactions in reaction systems, the author includes such systems if the presence of cation−π interactions is thought to be sufficiently likely.

a

Energy in kcal/mol. bThe Etotal (total interaction energy) is ECCSD(T)(limit). cEes is the electrostatic energy. Ees was calculated as the interactions between distributed multipoles of monomers. dEind is the induction energy. Eind was calculated from the electric field produced by the distributed multipoles and atomic polarizabilities. e Ecorr (Etotal − EHF) is the electron correlation contribution to the total interaction energy. Ecorr is the difference between the calculated intermolecular interaction energies with and without electron correlation correction. Ecorr is mainly dispersion energy. fErep (EHF − Ees − Eind) is mainly exchange-repulsion energy.

origin of the attraction for these interactions is electrostatic and induction interactions, whereas that for CH−π and NH−π interactions is dispersion (Table 2).34 The positive charge of the tetraalkylammonium ion is distributed to the C atoms next to the N atom, which is very different from that of the corresponding alkanes.45,46 Figure 2 illustrates the atomic

Figure 2. Atomic charges obtained by ab initio calculations at the MP2/6-311G** level. Atomic charges with hydrogens were summed into C atoms.

2. REACTIONS INVOLVING CATIONIC INTERMEDIATES OR TRANSITION STATES One variety of organic cations, such as carbon- and heteroatom-centered cations, and those with conjugated systems are known to generally undergo nucleophilic addition and substitution reactions, cycloaddition with enophiles or dienophiles, and rearrangement. In these reactions, cation−π interactions can control the conformation of the substrates or the transition state to give the desired products. In this section, various types of reactions involving reactive organic cations, in which cation−π interactions play an important role in enhancing the regio- and stereoselectivities as well as the rate of the reaction, are reviewed. These reactions involve both noncatalytic and catalytic processes. Figure 3 shows schematic representations of the noncatalytic processes. Figure 3a illustrates the general faceselective addition reaction of a cation intermediate in which a neighboring π component shields one side of the cationic plane through a cation−π interaction. This type of reaction is introduced in sections 2.1, 2.2, 2.5, and 2.6. Figure 3b and 3c shows two types of transition states for the reactions with the neutral and anionic nucleophiles, in which cationic charges

charges of the N-ethyl-N,N,N-trimethylammonium ion. This clearly shows that the methyl and methylene groups are positively charged, which is responsible for the structural similarity between the cation−π and the CH−π interactions. It is well known that cation−π interactions play key roles in the promotion of enzymatic reactions. On the other hand, in the field of synthetic organic chemistry, little attention had been paid to the role of cation−π interactions until recently. Since the beginning of this century, however, the importance of cation−π interactions in organic synthesis began to be recognized, and a number of papers have been published over the past decade in this emerging field. From the synthetic point of view, there are several feartures of the cation−π interactions as described below. (1) The interaction energy of cation−π interactions is generally larger than those of the other π interactions. (2) A variety of organic cations and alkali metal ions can be utilized as cationic components (Figure 1). (3) A variety of π systems, such as alkene, alkyne, aromatic, and carbonyl compounds, can be employed as π components (Figure 1). 11355


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catalyst provides a chiral environment around the N-acyl moiety, which can be used for asymmetric O- and C-acylation reactions as well as [2−3] sigmatropic rearrangement (sections 2.6 and 2.8). 2.1. Nucleophilic Addition

Pyridinium, quinolinium, iminium, and oxionium salts are readily prepared from the corresponding pyridine and quinoline derivatives and carbonyl and acetal compounds, respectively. These react with various nucleophiles to give adducts (Figure 5). When one side of the unsaturated plane of

Figure 3. Schematic representation of noncatalytic nucleophilic reactions.

develop at the nucleophile and the leaving group, respectively. These types of reactions are described in section 2.4. A schematic representation of electrophilic reactions is shown in Figure 3d. In the addition of electrophiles to alkenes and aromatic compounds, the produced cationic intermediates or transition states are stabilized by π components. This type of reaction is explained in sections 2.3 and 2.7. These stabilized intermediates and transition states with π components lead to the regio- and stereoselectivities in the products as well as the enhancement of the reaction rates. Figure 4 shows three types of catalytic reactions involving a cation or a cationic transition state. Cyclic and acyclic amines

Figure 5. Schematic representation of nucleophilic addition.

the cationic molecule is blocked by the π components through a cation−π interaction, the nucleophile attacks the cation from the unblocked side to produce the corresponding products in high stereoselectivity. This concept has been adapted to pyridinium and quinolinium salts (Figure 5a), iminium ions (Figure 5b), and oxonium ions (Figure 5c) for stereoselective synthesis. 2.1.1. Addition to Pyridinium Ions. Pyridinium ions serve as reactive intermediates and undergo nucleophilic attack by various nucleophiles. Nucleophilic addition to pyridinium ions produces 1,2-, 1,4-, and 1,6-dihydropyridines as well as their derivatives, which are key intermediates for the synthesis of a variety of natural products and bioactive compounds.56 Comins and co-workers developed a general method for the synthesis of chiral dihydropyridones using chiral chloroformates 2a bearing a (−)-8-phenylmenthyl (8-PhM) moiety as shown in Scheme 2.57,58 This method was applied to the Scheme 2. General Method for the Synthesis of Chiral Dihydropyridines Using Chiral Chloroformates

Figure 4. Three types of organocatalytic reactions.

such as imidazolidinone, imidazolidine, as well as other amino acid derivatives serve as catalysts for the various reactions of carbonyl compounds via the formation of iminium ions. MacMillan’s oxazolidinone catalyst is used in various asymmetric reactions, as shown in Figure 4a as a representative example. These catalytic reactions are introduced in sections 2.2, 2.3, and 2.5. Hydrogen-bond donors, Brønsted acids, and complexes of hydrogen-bond donors with Lewis acids activate a substrate to form a cation, which is stabilized with a neighboring aromatic moiety on the catalyst through a cation−π interaction. Figure 4b shows a schematic representation of a hydrogen-bond donor-promoted catalytic reaction. This type of reaction is used for a variety of organocatalytic reactions. Nitrogen-containing heterocyclic compounds such as pyridine-, imidazole-, and amidine-based derivatives are used as O- and C-acylation catalysts. Figure 4c shows a schematic representation of the kinetic resolution of a sec-alcohol with a pyridine catalyst. A cation−π interaction between a Nacylpyridinium intermediate and an aromatic moiety on the

synthesis of a number of alkaloids. For example, the addition of Cl(CH2)4MgBr to the acylpyridinium salt 3a, prepared in situ from 4-methoxy-3-(triisopropylsilyl) pyridine and chiral chloroformate 2a, produced 6-substituted dihydropyridone 4 in 77% yield with 86% de (Scheme 3a). The major diastereomer of 4 possesses an R configuration at C-6 of the dihydropyridone ring. This good stereoselectivity can be explained by TS-4 stabilized through cation−π interactions between the pyridinium ring and the aromatic ring of the chiral auxiliary as shown in Scheme 3a. This was used for the syntheses of quinolizidine alkaloids, (+)-myrtine, (−)-lasubine, and (+)-subcosine I.59 The X-ray crystal structure of the model 11356


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The reductive homocoupling of pyridinium salts 3b having a (+)-TCC moiety through the use of a titanium reducing agent produced C2-symmetric vicinal diamines 874 (Scheme 5a). The

Scheme 3. Stereoselective Addition of Grignard Reagents to Pyridinium Salts

Scheme 5. Reductive Homocoupling of a Pyridinium Salt

reduction of the pyridinium 3b affords a delocalized radical intermediate, which undergoes dimerization with auxiliarydirected facial selectivity to produce C2-symmetric dimer 7 (Scheme 5b). This was readily hydrolyzed to give dimer 8. The regioselective reaction at C6 may be due to the steric bulkiness of the methoxy and TIPS groups blocking the C2 and C4 positions. The authors developed a new chiral auxiliary (1S,2R,4S)-2(1-methyl-1-phenylethyl)-4-(2-propyl)-cyclohexanol, (−)-CPC 2c (Scheme 2), which is prepared from limonene oxide.75 This chiral auxiliary is often more effective than TCC derivatives due to having an isopropyl group at the cyclohexyl ring.76 The pyridinium salt 3c with CPC was used for the synthesis of indolizidine alkaloid (+)-209D77 and (−)-perhydrohistrionicotoxin.78 Chiral 1,4-dihydropyridines were synthesized by the faceselective addition of nucleophiles to a pyridinium salt with a chiral auxiliary. Yamada and co-workers used nicotinic amide 9 with an oxazolidine moiety as a chiral auxiliary that is readily prepared from an amino alcohol. The addition of a ketene silyl acetal to the pyridinium intermediates produced from 9a and 9b with methyl chloroformate in CH2Cl2 gave 1,4-dihydropyridines 10a and 10b, respectively (Scheme 6a).79 The stereoselectivity for the addition reaction of 9b having a benzyl group is much higher than that of 9a having a phenyl group, suggesting that the benzyl group is much more effective than the phenyl group in shielding one side of the pyridinium face. X-ray crystallographic analysis of the N-methylpyridinium salt 11 as a model of the N-acylpyridinium intermediate clarified that the phenyl and pyridinium rings are close together and arranged in face-to-face fashion with the distance between the two rings being about 3.4 Å.79 On the other hand, the phenyl ring of 9b is located far from the pyridine ring as shown in Scheme 6b. These differences in the geometries between 9b and 11 provide evidence for the significant contribution of the cation−π interaction in controlling the conformation of the pyridinium intermediate. CD spectral studies of 11 indicated a preference for the closed conformation in solution.80,81 A working model for this faceselective addition is shown in Scheme 6c. According to DFT

compound 9 shows the close proximity of the two rings shown in Scheme 3b, supporting the proposed transition state model TS-4, in which the pyridinium and benzene rings are close together.60 This strategy was employed for the synthesis of piperidine alkaloids.61,62 Comins and co-workers also exploited the new chiral auxiliary (−)-trans-2-(a-cumyl)cyclohexanol, (−)-TCC 2b,63 which is readily available from cyclohexenone oxide and organometallic reagent, and successive optical resolution. The addition of Grignard reagents to the pyridinium salt 3b possessing a TCC auxiliary was used for the syntheses of piperidine alkaloids,64 indolizidine alkaloids,65 flog alkaloid,66 and phlegmarine alkaloids.67 Copper reagents and lithium acetylides also serve as nucleophiles and could be successfully added to the pyridinium to give adducts, which were used for the syntheses of indolizidine alkaloids (−)-slaframine68 and allopumiliotoxin 267A,69 respectively. A variety of metal enolates were effectively added to the pyridinium salt 3a to produce the corresponding adducts in high diastereoselectivities, which were used for the syntheses of piperidine alkaloids,70 and macrocyclic polyamine alkaloids,71 and ladybird alkaloid.72 The zinc enolate was used for the synthesis of dihydropyridone 6 having a ketone moiety,73 which was derived to (+)-hyperaspine via TS-6, Scheme 4. Scheme 4. Synthesis of (+)-Hyperaspine via Addition of Zinc Enolate to a Pyridinium Salt

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Scheme 6. Face-Selective Addition of a Ketene Silyl Acetal to a Chiral Pyridinium Salt

Scheme 7. Nucleophilic Addition of a Ketene Silyl Acetal to a Nicotinamide with a Chiral Bicyclic Amine Group

Scheme 8. Addition of Allyltin and Allylindium Reagents to a Nicotinamide with a Chiral Oxazolidine Unit

calculations, the equilibrium between conformers 12-I and 12II favors 12-II. This supports the proposed mechanism in which a nucleophile attacks the conformer II from the less hindered side to give a chiral dihydropyridine. A similar face-selective addition was achieved for nicotinic amide 13 with a chiral bicyclic amine framework.82 The chiral auxiliary was prepared from a bicyclic ketone reported by Corey et al.83 The addition of ketene silyl acetals to nicotinic amides 13a and 13b afforded 1,4-dihydropyridine derivative 14a and 14b as major products, the diastereomer ratios of which were significantly dependent on the substituents of the chiral auxiliary. While the diastereoselectivity of 14a with a methyl substituent is 56% de, that of 14b having a benzyl substituent was 99% de. The fact that the chiral auxiliary with an aromatic substituent led to the highest stereoselectivity strongly suggests a major contribution by the cation−π interaction in the transition state of the addition reaction TS-14 as shown in Scheme 7. One side of the pyridinium face of intermediate 16 was effectively shielded by an aromatic substituent, enabling nucleophilic attacks from the unblocked side to produce 1,4-dihydropyridine in high diastereoselectivity. Allylindium and allyltributyltin reagents were effectively added to the pyridinium intermediate generated from 17 to afford 1,2-dihydropyridine 18, while the addition of prenylindium reagent produced 1,4-adduct 20 in good yields and diastereoselectivity (Scheme 8).84 The chiral auxiliaries oxazolidine-2-ones and thiazolidine-2thiones are also effective in providing face selectivity in the nucleophilic addition to the pyridinium and quinolinium salts.85−87 These chiral auxiliaries can be easily prepared from

amino alcohols and are readily removed after the addition reactions. The addition of ketene silyl acetal to the pyridinium salt produced from 22 afforded 1,4-adduct 24 in 91% yield with 74% de. The pyridinium salt of 23 is more effective than that of 22, and 1,4-dihydropyridine 25 was obtained in 98% yield with 94% de (Scheme 9a). In these reactions, intramolecular interactions between the pyridinium with the carbonyl group and the thiocarbonyl group are responsible for the face selectivities as shown in TS-24/25.88,89 The existence of attractive intramolecular (CO)···Py+ and (CS)···Py + interactions in the above reaction was determined using the model compound 28 by 1H and 13C NMR spectroscopies and X-ray crystallographic analyses.88,89 The superimposed X-ray crystal structures of 27 and 28 shown in Scheme 9b clarified the geometrical differences between them.89 The S atoms of the thiocarbonyl in 27 and 28 occupy positions significantly different from each other; while the S atom of 27 is on the side of the pyridine ring, that of 28 is located on the pyridinium plane. The C3···S distances for 27 and 28 are 3.211 and 3.051 Å, respectively, strongly suggesting the existence of attractive interactions between the CS group and the pyridinium ring. The origin of the interactions between the pyridinium with the carbonyl and the thiocarbonyl was investigated by computational analysis using a model system.89 The calculations predicted that the electrostatic and inductive interactions are the major forces of the attraction, suggesting that the (CO)···Py+ and the (CS)···Py+ interactions can be 11358


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ring by a cation−π interaction with the pyridinium ring. On the other hand, the pyridinium ion 26 prefers the cis conformer, which is stabilized by the interaction of the thiocarbonyl and the pyridinium ring as well as by the avoidance of steric and dipole repulsion between the carbonyl and the thiocarbonyl groups in the trans form (Scheme 10). This method for the synthesis of chiral 1,4-dihydropyridine was applied to the preparation of piperidine derivative 31, which is a key intermediate for the formal synthesis of (−)-paroxetine 32, an important class of serotonin reuptake inhibitor.90 Introduction of a 4-fluorophenyl group at the 4 position of 30 was performed by the face-selective addition of C6H4FCu through TS-30 to give adduct 30. After removal of the chiral auxiliary, hydrogenation of the double bonds and isomerization of the resulting cis-piperidine ester provided trans-3,4-disubstituted piperidine. Reduction of the ester moiety afforded 31 with a hydroxymethyl group, which is a precursor of (−)-paroxetine 32 (Scheme 11).

Scheme 9. Diastereoselective Addition to Pyridinium Salts through (CO)···π and (CS)···π Interactions

Scheme 11. Formal Synthesis of (−)-Paroxetine Using a Chiral Dihydropyridine

categorized as a cation−π interaction. The X-ray crystal structures of 28 and corresponding oxazolidinone derivative do not satisfy the geometrical requirements for n···π* or n···σ* interactions because the lone pair electrons of the S or O atom are not directed toward the π* or σ* orbital of the pyridinium ring. In addition, neither pyramidalization of the carbon atom nor C−C bond elongation was detected. It should be noted that the chiral auxiliaries of nicotinic amides 9b and 23 had an opposite effect on the product stereochemistry, despite having the same chirality. The stereogenic centers at C4 of 1,4-dihydropyridines 10b and 25, which were obtained from 9b with the (S)-4-oxazolidine moiety and 23 bearing the (S)-4-thiazolidine-2-thione moiety, respectively, are in an opposite absolute configuration to each other. This dramatic difference in the absolute configuration is attributable to the cis−trans conformational differences between the intermediate pyridinium ions 12b and 26 as shown in Scheme 10. The intermediate pyridinium ion 12b prefers the trans conformer due to stabilization of the aromatic

Face-selective allylation of β-carboline was achieved by use of the L-pyroglutamyl auxiliary having a 9-anthracenylmethyl group.91 The addition of allyltributyltin to β-carboline derivative 34 in the presence of trichloroethyl chloroformate afforded 1,2-adduct 35 in good selectivity. Removal of the chiral auxiliary gave 36 in 98% yield with 91% ee. MM3 optimization of the cation intermediate 37 showed that the βcarbolinium and anthracene moieties are close together, leading to good face selectivity for the addition of the tributylallyltin reagent through TS-35 (Scheme 12). 2.1.2. Addition to Quinolinium Ions. The nucleophilic addition to quinolinium rings gave similar results to those for the reactions of pyridinium derivatives. A variety of reagents, such as ketene silyl acetals87 and allyltin84 and allylindium84 reagents, served as nucleophiles. The addition of allyltributyltin to quinolinic amide having a chiral auxiliary 38 produced the corresponding 1,2-dihydroquinoline 39 in 78% de (Scheme 13a).84 The X-ray crystal structure of the N-Me quinolinium derivative 40 as a model of the N-acyl intermediate shows that the quinolinium and benzene rings are close together with

Scheme 10. Preference in the Cis−Trans Conformation of Intermediate Pyridinium Salts

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Scheme 12. Face-Selective Allylation of β-Carboline Using the L-Pyroglutamic Acid Derivative as a Chiral Auxiliary

Scheme 14. Addition of a Chiral Boronate Complex to Quinolinic Amide

Scheme 13. Addition of an Allyltin Reagent to a Quinolinamide with a Chiral Oxazolidine Unit

Scheme 15. Addition of Ammonium Ylide to Quinolinium Salt

state TS-48 can explain the regio- and diastereoselectivities; the H bond between the anilinium and bromide ion as well as a cation−π interaction between the quinolinium and the benzene rings could direct the nucleophile toward the C4 position, leading to the syn isomer as a major product. Asymmetric Reissert reactions of quinoline were achieved using a chiral oxazolidinone auxiliary. The addition of a cyanide ion to chiral N-acylquinolinium salt 51 led to 1,2adduct 52 with 55:45 dr (X = Cl−) and 83:17 dr (X = OTf−) through cation−π complex 53 (Scheme 16).94 Although the reason for the effect of the counteranion on the diaster-

a face-to-face orientation. The distance between the two rings is about 3.4 Å, suggesting the contribution of a cation−π interaction to this conformation (Scheme 13b). Aggarwal et al. reported the asymmetric addition of chiral boronate complexes to pyridinium, quinolinium, and iminium ions.92 The addition of chiral boronate complex 42 to quinolinic amide 41 in the presence of Troc-Cl afforded 1,4dihydroquinoline 43 in 87% yield with 99:1 dr and 100% es. A proposed transition state TS-43 shows that a cation−π interaction between the quinolinium and the aromatic ring of the boronate directs the approach of the nucleophile, leading to the differentiation between the quinolinium ion faces of 44 (Scheme 14). Hu and co-workers disclosed a new method for the regioand diastereoselective synthesis of tetra- and dihydroquinoline derivatives via the trapping of ammonium ylides 49 with Nbenzyl-3-ethoxycarbonylquinolinium salt 45.93 The Pd-catalyzed three-component reaction of 45, p-bromoaniline 47, and diazo compound 46 in the presence of [PdCl(η3-C3H5)]2 as a catalyst afforded 1,4-dihydroquinoline 48 in 96% yield with 93:7 dr (Scheme 15). In this reaction, palladium carbene intermediate produced from the diazo compound with the Pd catalyst first reacts with aniline to yield palladium-associated enolate 49, the addition of which to quinolinium salt gave adduct 48 in good diastereomer ratio. A plausible transition

Scheme 16. Asymmetric Reissert Reactions of Quinoline

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76% ee.98 In the proposed transition state TS-64, the phenylmenthyl moiety shields one side of the iminium plane through a cation−π interaction and the cyanide ion attacks from the opposite side to produce adduct 64 (Scheme 19). This transition state is similar to those predicted in the addition to pyridinium ions reported by Comins. The addition of β-CD improved the enantioselectivity to 91% ee.

eoselectivity remains unexplained, an electrostatic effect on the transition state TS-52 is speculated by the authors. Jørgensen and co-workers reported an annulation reaction of 2-(5-oxopentyl)isoquinolinium iodide 54 using 10 mol % of chiral pyrrolidine catalyst 55 (Scheme 17). The enantioseScheme 17. Catalytic Asymmetric Annulation of an Isoquinoline Derivative

Scheme 19. Addition of a Cyanide Ion to a N-Acyliminium Ion Generated by Anodic Oxidation

lective annulation afforded a chiral tricyclic compound 56 in high selectivity through 1,9-asymmetric induction.95 A proposed transition state TS-56, which was corroborated by calculations, suggests that the cation−π interaction of the isoquinolinium with the phenyl ring determines the face selectivity. The attractive interaction allows the Re face of the intermediate enamine 57 to approach the Si face of the isoquinolinium ring, delivering the corresponding tricyclic product in high ee.95 2.1.3. Addition to Iminium and Oxonium Ions. Comins reported the synthesis of tetrahydroisoquinoline alkaloids using Pictet−Spengler reactions (Scheme 18). The reaction of chiral

The intramolecular interaction between N-acyliminium and the N-sulfonyl group is used for the stereoselective synthesis of five- and six-membered bicyclic N,N-acetals (Scheme 20a).99 Scheme 20. Synthesis of Cyclic N,N-Acetals via the Addition of an N-Sulfonylamino Group to an N-Acyliminium ion

Scheme 18. Synthesis of Tetrahydroisoquinoline Alkaloids Using Pictet−Spengler Reactions

Treatment of substrate 66 with TMSOTf gave the corresponding cyclic trans aminal 67 in high yields with good diastereoselectivities. The remarkable feature here is that less stable trans isomers were obtained as a major product, which was predicted by DFT calculations. The optimized geometries of the intermediate iminium ion 68 calculated at the B3LYP/6-31G(d) level show close proximity between C1 and the SO group. While orbital interactions were not observed between them, the existence of a significant electrostatic interaction was observed by the electrostatic potential map. These suggest that an intramolecular cation−π interaction between the iminium and the sulfonyl groups plays a key role in the formation of the stereogenic center during cyclization (Scheme 20b).99 Jacobsen and co-workers reported thiourea-catalyzed asymmetric polyene cyclization starting from hydroxylactam as a cation precursor (Scheme 21). A survey of catalysts for the

carbamate 58 with vinyl ether provided a chiral tetrahydroisoquinoline 59 via an iminium intermediate 61; the reduction of the N-protective group with LiAlH4 produced (−)-laudanosin 60.96 The key to success in controlling the stereogenic center is the intramolecular interaction between the iminium and the benzene ring, which shields one side of the iminium plane, enabling the benzene ring to be attacked from the less hindered side as shown in TS-59. This method was used for the syntheses of tetrahydroisoquinoline and aporphine alkaloids.97 The addition of a cyanide ion to an N-acyliminium ion 63 generated by the anodic oxidation of 62 afforded adduct 64 in 11361


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with a variety of aromatic substituents on the catalyst framework for the cyclization of 73 revealed that a larger aromatic substituent is more effective than a smaller substituent. When the reaction was carried out at −60 °C in the presence of MgS2O3·6H2O with 20 mol % of catalyst 74c, the highest yield and enantioselectivity were obtained (65% yield, 92% ee). Although the mechanism for the stereoinduction is unclear, the proposed transition state TS-75 described in Scheme 22b can explain the enantioselectivity. Li et al. found that the intermediate oxazoline[3,2a]pyridinium 78, which is produced from acetal 77 by an acid, undergoes reaction with amines to afford N-substituted pyridones 79 and 2-substituted pyridines 81.102 The reaction of 78 with aliphatic amines afforded N-substituted pyridones 79, while phenylalkylamines favor attacking C2 of the pyridinium ring of the intermediate 78 to give 2-substituted pyridines 81 (Scheme 23). DFT calculations for the transition

Scheme 21. Thiourea-Catalyzed Asymmetric Polyene Cyclization

Scheme 23. Nucleophilic Reaction of Amines to Oxazoline[3,2-a]pyridinium

cyclization of hydroxylactam 69 revealed the most effective catalyst to be the 4-pyrenyl-substituted thiourea derivative 70.100 This is thought to be due to the stabilization of the transition state TS-71 of the cyclization process of cation intermediate 72 through a cation−π interaction. Kinetic studies on the enantioselectivities for the cyclization reactions with three catalysts show a correlation between the magnitude of the differential enthalpy and the enantioselectivity. The differential enthalpy increased as the size of the arene moiety increased, suggesting a significant contribution by the cation−π interactions similar to the biosynthetic cation cyclization noted in section 6. Zhao and co-workers found that BINOL-derived chiral Nphosphoramides 74 are effective catalysts for polyene cyclization reactions (Scheme 22a).101 A survey of catalysts Scheme 22. Chiral Brønsted Acid-Catalyzed Polyene Cyclization

state TS-80 at the B3LYP/6-31G(d) level revealed the regioselectivity.102 The aromatic ring of the amine interacts with the pyridinium ring of the intermediate to stabilize the transition state TS-80, facilitating the formation of 2substituted pyridine 81 via intermediate 80. A chiral oxazolinium ion 83 produced from acetal 82 by treatment with Lewis acid was reacted with silyl enol ethers to give α-substituted ketones 84a and 85a at a ratio of 95:5.103,104 Interestingly, the addition of the silyl enol ether containing an aromatic ring resulted in opposite stereoselectivity from that without an aromatic ring; the ratio of 84b:85b was 20:80 (Scheme 24a). The DFT calculations of the transition states TS-84b and TS-85b (calculated at the M06-2X/6-311+G(d,p) level) predicted that TS-85b would be more stable than TS84b (Scheme 24b), which shows that a cation−π interaction is mainly responsible for the stabilization of the transition state TS-85b.104 Neda et al. found that the glycosidation of glucose derivative 86 with a galactosyl donor 87 catalyzed by AgClO4 furnished β-galactosidation in a stereoselective manner to give 89 when using tetra-O-propylated conecalix[4]arene (TOPC) (Scheme 25).105 Although the reason for the observed stereoselectivity remains unclear, a complexation of the intermediate oxonium 11362


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Scheme 24. Synthesis of α-Substituted Ketones via the Addition of Ketene Silyl Acetal to an Oxazolinium Ion

Scheme 26. Mukaiyama Aldol-Type Reactions Catalyzed by a Chiral Squaramide in the Presence of TBOTf

an oxonium ion intermediate 96. This is stabilized by Trp77, and the adenine base attacks the oxonium ion from the opposite side of Trp77 to afford 97 (Scheme 27).107 Scheme 27. Proposed Mechanism for the Formation of cADPR by ADP-Ribosyl Cyclase

Scheme 25. Stereocontrolled β-Galactosidation in the Presence of TOPC

ion with TOPC in the cone cavity may be responsible for the selectivity. Banik, Levina, and Jacobsen reported that chiral squaramide catalysts 92 in the presence of TBSOTf promote the generation of oxocarbenium intermediate 94 from acetal substrates, which are used for the Mukaiyama aldol-type reaction (Scheme 26).106 The Lewis acid-promoted reaction of the trimethylsilyl enol ether 91 derived from acetophenone and 4-bromobenzaldehyde dibenzyl acetal 90 was conducted in the presence of TBSOTf (50 mol %) to give aldol product 93. As both reactivity and enantioselectivity were strongly responsive to the size of the aromatic ring on the pyrrolidine unit, the interaction of the aromatic moiety with the corresponding cationic intermediate 94 plays a decisive role in this reaction (Scheme 26). The role of the aromatic moiety seems to stabilize the intermediate oxonium ion and to control the face selectivity of the nucleophilic reaction through a cation−π interaction. It is known that cyclic ADP-ribose (cADPR) 97, which is produced from β-NAD 95 by ADP-ribosyl cyclase, elicits calcium release from intercellular calcium stores. In this enzymatic reaction it is proposed that Trp140 assists in the removal of the nicotine amide moiety through a cation−π interaction in the transition state, leading to the formation of

The cyclization of β-NAD+ 95 was performed not only by enzyme reaction but also by chemical reactions. β-NAD+ 95 was heated in DMSO in the presence of NaBr to give cADPR 97 in 28% yield (Scheme 28). As α-NAD+ 98 was also cyclized to give cADPR in 17% yield under similar reaction conditions, it is suggested that the reaction proceeds via an oxocarbenium ion 96 in a similar manner to the enzymatic reaction, as illustrated in Scheme 28. The adenine base may stabilize the transition state for the formation of the oxocarbenium ion through a cation−π interaction, and the adenine base subsequently attacks the oxocarbenium ion to produce cADPR 97 (Scheme 28).108 11363


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Scheme 28. Biomimetic Cyclization of β-NAD+ and α-NAD+

Scheme 29. Organocatalytic 1,4-Addition Reaction of NMethylpyrrole

2.2. Conjugate Addition

Scheme 30. Three Conformers of Iminium Intermediate

The reactions of chiral sec-amines with α,β-unsaturated aldehydes and ketones form α,β-unsaturated iminium ions, which receive nucleophilic 1,4-addition from the unhindered side, leading to the corresponding adducts stereoselectively. As the 1,4-adducts are readily hydrolyzed to recover the chiral amines, the reaction proceeds catalytically. If the nucleophile is an aromatic compound, a Friedel−Crafts/Michael reaction proceeds (Figure 6a). A variety of enolates undergo 1,4addition from the unblocked side to give β-substituted ketones (Figure 6b).

Gilmour et al.114−116 investigated the correlation between the quadrupole moment of the arene moiety (Qzz) and the enantioselectivity (es) in the catalytic Friedel−Crafts alkylation of N-methylpyrrole with (E)-cinnamaldehyde. They found that the catalysts possessing an electron-rich arene are more effective for es than those having electron-withdrawing arenes. These observations suggest that the electron-rich arene stabilizes conformer 101-B through a cation−π interaction, leading to a high ee (Scheme 31).

Figure 6. Schematic representations of Friedel−Crafts/Michael and Michael reactions.

Scheme 31. Correlation between the Quadrupole Moment of the Arene Moiety (Qzz) and the Enantioselectivity (ee) 2.2.1. Friedel−Crafts/Michael Reaction. MacMillan et al. developed chiral imidazolidinone catalysts that are particularly effective for various catalytic asymmetric reactions by the LUMO-lowering activation of α,β-unsaturated aldehyde and ketones.109,110 The imidazolidinone derivative 99 catalyzes asymmetric Friedel−Crafts alkylation reactions. The catalytic Friedel− Crafts alkylation of N-methylpyrrole with (E)-crotonaldehyde using the first-generation imidazolidinone catalyst 99 provided conjugate adduct 100 via iminium intermediate 101 in high enantioselectivity (Scheme 29).111 On the basis of the MM3 model of the iminium ion, a plausible transition state TS-100 was proposed, in which the addition occurs from the less hindered side of the cation−π-stabilized intermediate 101. The conformational analyses of the intermediate iminium ion 101 by experimental112 and theoretical113 studies show the existence of three conformers A−C, in which the major conformer is A and minor conformers are B and C, as shown in Scheme 30. As the benzyl moiety of the conformers A and B shields the Re face of the iminium ion and the Si face is exposed to cycloaddition, these conformers are responsible for the stereoselectivity of various types of imidazolidinone-based organocatalytic reactions. This mechanism can explain the stereoselectivity of the 1,4-addition reaction of the pyrrole ring described above.

MacMillan also designed the second-generation catalyst 105,117 which is more effective than the first-generation catalyst 99. This catalyst exhibits improved efficiency for iminium formation as the participating nitrogen lone pair receives little steric effect. In addition, the diastereotopic face of the iminium ion 107 is free from steric hindrance in the transition state, TS-106, leading to increased reactivity to carbon−carbon bond formation (Scheme 32a).118 The catalyst 105 was effective for the 1,4-addition of various electron-rich benzenes to α,β-unsaturated aldehydes.125 For example, this 11364


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Scheme 32. 1,4-Addition of an Electron-Rich Aromatic Compound to an Iminium Intermediate

catalyst promoted the addition of N,N-dimethyl-3-anisidine 104 to crotonaldehyde with 89% ee. This iminium activation strategy was applied to the synthesis of COX-2 inhibitor 109.117 The alkylation of the 5-methoxy-2methylindole 108 with crotonaldehyde, followed by oxidation of the formyl moiety, provided the COX-2 inhibitor 109 in 82% yield with 87% ee (Scheme 32b). Organocatalytic vinyl and Friedel−Crafts alkylations with trifluoroborate salts were also performed using this catalyst, which was applied to the total synthesis of (+)-frondosin B.119 Yamada and Mori suggested the contribution of cation−π interaction to the stabilization of the iminium intermediate through comparisons of the differences in the energies between two conformers A and B (ΔEA‑B) for iminium ions 107a and its noncharged C analogue 107b, 107c with a 4-methoxyphenyl group, and 107d with a 4-fluorophenyl group.120 The calculations show that conformer A is more stable than conformer B and the electron-donating group stabilized conformer A (Figure 7a). Furthermore, a comparison between 107a and the corresponding carbon analog 107b clearly showed the contribution of a positive charge on the stabilization of conformer A. Energy decomposition analyses on the model system of 107a-A-M1 indicated a significant contribution of the electrostatic and polarization terms to the attractive interactions between the benzene ring and the iminium cation. Comparison of these values with those of the chargeless C-analogue model 107b-A-M1 clarified the importance of the positive charge on the stabilization of the intermediate (Figure 7b). Seebach et al. elucidated the X-ray crystal structure of the related intermediate iminium salt 110, the benzyl moiety of which efficiently shields the (Z)-enoyl-iminium π system (Figure 8).121 This is in good agreement with the reported optimized geometries described above.

Figure 7. ΔEA‑B values for 107a−107d. Interaction energies were calculated at the MP2/6-311G(d,p) level.

Figure 8. X-ray crystal structure of iminium intermediate 110.

2.2.2. Michael Reaction. This catalyst was effective for the Mukaiyama−Michael reaction of silyloxy furan to give chiral γbutenolides.122 The enantioselective 1,4-addition of silyloxy furan 111 to crotonaldehyde catalyzed by imidazolidinone 105 afforded γ-butenolide 112 in 87% yield with 90% ee (Scheme 33). The transition state TS-112 can explain this stereoselectivity, which is similar to those of the other iminiumcatalyzed reactions. The conjugate addition of amines to α,βunsaturated aldehydes was also achieved using this catalyst.123 Imidazolidine catalyst 115, developed by Jørgensen, catalyzes the Michael addition of malonate nucleophiles to α,β-unsaturated ketones.124 For example, the addition of dibenzyl malonate 113 to conjugated ketone 114 afforded the Michael adduct 116 with an R configuration in 93% yield with 99% ee (Scheme 34a). The stereoselectivity can be explained by proposed transition state TS-116-i, in which the efficient shielding of the iminium intermediate 117 by the benzyl group allows the malonate to approach the open Si face of the β-carbon. 11365


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TS-116-ii, in which the indole moiety shields one side of the iminium intermediate 123 through a cation−π interaction, and the malonic ester activated by the sec-amino group attacks the iminium from the unhindered side to yield adduct 116 (Scheme 35).128 This catalyst is also used for the Friedel− Crafts alkylation of 4,7-dihydroindoles132 with enones, affording the corresponding adducts in high stereoselectivities.

Scheme 33. Organocatalytic Mukaiyama−Michael Reaction

Scheme 35. Michael Addition of Malonate to Enone Using a Non-Proline Diamine Catalyst

Scheme 34. Michael Addition of Malonate, Nitroalkane, and β-Ketoester to Enone Using a Imidazolidine Catalyst

Kudo et al. developed peptide-based helical primary aminocatalysts for use in the enantioselective Michael addition of nitromethane to α,β-unsaturated ketone 124 (Scheme 36).133 Among various resin-supported peptides, H-(Trp)2Scheme 36. Michael Addition of Nitromethane to Enone Using a Peptide-Based Helical Primary Aminocatalyst

An enantioselective conjugate addition of nitroalkane 118 to α,β-unsaturated ketone 114 was achieved to give adduct 119 using the same catalyst (Scheme 34b). On the basis of the absolute configuration of the product 119, the enantiodifferentiation seems to arise from the similar transition state described above.125 This organocatalytic conjugate addition was applied to an asymmetric domino Michael−aldol reaction of β-ketoester 120 and α,β-unsaturated ketone 114.126,127 The resultant Michael adducts successively underwent intramolecular aldol reaction to give cyclohexanone derivative 121 in high selectivity (Scheme 34c). Zhao and Wang developed nonproline primary−secondary diamine catalysts that were effective for the Michael additions of malonates,128,129 nitroalkanes,130 and indoline-3-one enolate.131 The Michael addition of benzyl malonante 113 to α,β-unsaturated ketone 114 catalyzed by chiral diamine 122 afforded adduct 116 in good enantioselectivity.128 This selectivity can be explained by the proposed transition state

(Leu-Leu-Aib)3-○ (125, Aib = 2-aminoisobutyric acid) effectively catalyzed the reaction to yield adduct 126 in 80% yield with 92% ee. The NOE experiments led to a possible transition model TS-126 for the enantioinduction as shown in Scheme 36, in which the tryptophan residue covers one side of the iminium ion 127 and a nucleophile activated by the amide residue attacks the substrate from the opposite side to give adduct 126. This is similar to the mechanism for the chiral diamine-catalyzed Michael addition of malonante as described above. The asymmetric organocatalytic hydride reduction of enals with Hantzsch ester gave chiral aldehydes in high ee.134 Exposure of 3-methyl-(E)-cinnamaldehyde 128 to ethyl Hantzsch ester 129 in the presence of 20 mol % of catalyst 105·TCA in CHCl3 at −30 °C afforded (S)-3-phenylbutanal 130 in 91% yield with 93% ee (Scheme 37). 11366


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Scheme 37. Enantioselective Organocatalytic Hydride Reduction

Scheme 38. Chiral Brønsted Acid-Catalyzed Polyene Cyclization

2.3. Friedel−Crafts Reaction

Chiral thiourea and aminoalcohol derivatives bearing an aromatic substituent are used as organocatalysts for Friedel− Crafts reactions. The carbocations produced from substrates are stabilized by the aromatic ring of the catalyst and undergo intra- and intermolecular Friedel−Crafts reactions to produce substituted aromatic compounds with a chiral center (Figure 9a and 9b). Intramolecular cation−π interactions enhance the

Scheme 39. Friedel−Crafts Reaction of N-Methylindole with Chiral α-Hydroxy Ester and α-Bromoester Figure 9. Schematic representation of Friedel−Crafts reactions with stabilized cations.

acid-promoted cation formation and control the conformation of the cation intermediates suitable for the stereoselective Friedel−Crafts reactions (Figure 9c). 2.3.1. Friedel−Crafts Alkylation. Thiourea catalyst 132 was effective in a Friedel−Crafts-type indole alkylation reaction through the enantioselective nucleophilic ring opening of the episulfonium ion 134 produced from racemic 131.135 Among a series of thiourea catalysts, those having a larger aromatic moiety were found to be the more efficient catalysts, indicating the contribution of cation−π interactions between the catalysts and the episulfonium ion as shown in Scheme 38. On the basis of the kinetic studies, the authors proposed transition state TS-133 for the ring-opening reaction of the intermediate episulfonium ion 134, in which the combination of attractive interactions in the phenanthryl-indole-episulfonium sequence is responsible for the stereoselectivity. The enantioselective addition of γ-pyrone derivative to indoles was also performed using thiourea catalyst 132 to give indole− pyrone adducts.136 A diastereoselective Friedel−Crafts reaction of N-methylindole 136 was achieved using 8-phenylmenthyl N-benzyl-2pyrryl-α-hydroxyacetate 135 to give 3-substituted N-methylindole 137 in 88% de (Scheme 39a).137 Treatment of the substrate with TMSOTf produced a planar conjugated cation 138 as a reactive intermediate. As one side of the cation 138 is blocked by the benzene ring of the 8-phenylmenthyl moiety, N-methylindole attacks the intermediate from the opposite side through the transition state TS-137. Although no experimental or computational evidence is provided to corroborate the role of a cation−π interaction, a similar transition state to the addition reaction to pyridinium salts

proposed by Comins is expected to exist in this case (see section 2.1, Scheme 3). Chiral α-bromoesters 139 were also used as cation precursors. The Friedel−Crafts reaction of N-methylindole 11367


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with chiral ester 139a produced a 1.4:1 mixture of diastereomers 140a.138 Similarly, the reaction with 139b afforded a 2.3:1 mixture of adducts 140b. The geometry optimization of the cation intermediates 141 and 142 at the B3LYP/6-31G(d) level showed that the aromatic rings of the chiral auxiliaries and the benzyl methylenes were close together, suggesting the contribution of cation−π interactions in both cations (Scheme 39b).138 MacMillan developed a new amino alcohol catalyst 144 that allows the enantioselective coupling of indoles with racemic αtosyloxy ketones. The reaction of α-tosyloxy cyclopentanone 143 and N-methylindole 136 using 20 mol % of catalyst 144 afforded α-heteroaryl ketone 145 in 91% yield with 92% ee (Scheme 40).139 In this reaction, the hydrogen bond between

Scheme 41. Intramolecular Friedel−Crafts Reaction of Aziridinium Ion

Scheme 40. Enantioselective Coupling of N-Methylindole with α-Tosyloxy Ketone via Oxyallyl Cation

2.3.2. Friedel−Crafts Acylation. Yamato et al. reported a significant cation-stabilizing effect of the aromatic ring in the acetylation of metaparacyclophane. The acetylation of 5-tertbutyl-8-methoxy[2.2]metaparacyclophane 151a with 1.2 equiv of acetyl chloride in the presence of AlCl3 afforded acetylated product 152a. On the other hand, no acetylation occurred for 151b having a cyano group (Scheme 42).141 The marked effect Scheme 42. Friedel−Crafts Acetylation of Cyclophanes

of the methoxy substituent at the 8 position on the reactivities of the para-benzene ring is considered to be due to the stabilization of the intermediate cation 153 by an electron-rich para-bridged benzene ring, though no experimental or computational evidence is provided to corroborate the proposed role of a cation−π interaction. A similar substituent effect was observed in the Friedel−Crafts alkylation of bromomethyl-substituted cyclophane.142

the substrate and the catalyst promotes the formation of intermediate cation 146, which is stabilized by the naphthyl moiety of the catalyst through a cation−π interaction. The subsequent addition of N-methylindole 136 to the intermediate cation 146 from the less sterically congested face provides α-heteroaryl ketone 145. DFT calculations at the B3LYP/6-31G(d) level supported the formation of the complex 146, where the oxyallyl cation top face was shielded with one of the naphthalene rings on the catalyst, suggesting that enantiodiscrimination is achieved via the proposed transition state TS-145. The synthesis of chiral 4-substituted tetrahydroisoquinoline 149 was achieved by ring expansion of the intermediary aziridinium ion 148, which was generated from β-bromoamine 147 by treatment with Lewis acid (Scheme 41).140 The stereochemistry of the product was significantly dependent on the N-substituent. When the N-substituent was a benzyl group, the initial stereochemistry was retained, meaning that the Friedel−Crafts reaction proceeds with inversion of the intermediate aziridinium. This would be due to the reaction proceeding through the stabilized transition state TS-149 by the intramolecular cation−π interaction as shown in Scheme 41, although no experimental or computational evidence is provided to corroborate the role of a cation−π interaction.

2.4. Nucleophilic Substitution

In SN1 reactions, enantioselection occurs when an aromatic ring on the chiral compounds stabilizes the produced carbocation and a nucleophile approaches from the opposite side from the aromatic ring. The formation of a carbocation is promoted by stabilization of the transition state through a cation−π interaction (Figure 10a). In SN2 reactions, when a neutral nucleophile attacks a substrate, the developing cationic charge in the nucleophile is stabilized by a π component

Figure 10. Schematic representation of nucleophilic substitution reactions. 11368


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(Figure 10b). In the case of the nucleophilic substitution of a cationic substrate with an anionic nucleophile, a cationic charge is partially lost from the substrate and the charge is transferred to the leaving group in the transition state, which is stabilized by a cation−π interaction, promoting the SN2 reaction (Figure 10c). 2.4.1. SN1 Reaction. Muneyuki and Tanida reported that the acetolysis of anti brosylate 154 gave corresponding acetate 155 in quantitative yield (Scheme 43a),143 whereas the

Scheme 44. Hydrolysis of 8-Bromomethyl [2.2]Metacyclophanes

Scheme 43. Acetolysis of Syn and Anti Brosylates and Hammet Plots for the Acetolysis of Syn Brosylates

cation−π interaction stabilized both the transition state TS165 for the formation of the carbocation and the intermediate carbocation 165.145 The acetolysis of [9]paracyclophane-4-tosylates 166a−168a produced the corresponding acetates, the reduction of which yielded the corresponding alcohols 166b−168b (Scheme 45a).146 A comparison among 166a−168a shows that the Scheme 45. Acetolysis of [9]Paracyclophanetosylates

acetolysis of syn brosylate 156 gave acetate 157 and rearranged products 158 and 159, which are produced from carbocation intermediate 160 (Scheme 43b). The acetolysis of syn brosylate 156 proceeded 20 times faster at 100 °C than does that of the anti isomer 154. The Hammet plots for the acetolysis of 156 with various substituents are shown in Scheme 43c. The negative ρ value indicates unequivocally that the strength of the attractive interaction increases with the introduction of an activating substituent into the aromatic ring. Taken together, these results suggest that the stabilization of the cationic transition state TS-160 by an electrostatic force is responsible for the higher reactivity of the syn isomer than that of the anti isomer. The hydrolysis of 8-bromomethyl[2.2]metacyclophanes 163 to the corresponding 8-hydroxymethyl derivatives 164 was carried out in 85% aqueous dioxane solution at rt (Scheme 44).144 The rate of hydrolysis was markedly dependent on the substituent attached to the other aromatic ring. Whereas the electron-withdrawing substituent diminished the hydrolysis rate, an electron-donating substituent enhanced it. On the basis of these observations, the authors speculated that a

rate of solvolysis for 166a and 168a is faster than that of 167a by a factor of 320 and 11, respectively. These results suggest the contribution of an aromatic ring to the stabilization of the transition structures TS-166a and TS-168a for carbocation formation. The significantly faster solvolysis rate of 166a than that of 168a can be explained by the difference in the magnitude of the cation−π interactions between them: the cation−π interaction in 166a is more effective than that in 168a due to the shorter distance between the cation and the benzene ring (Scheme 45b). Rueping et al. reported an asymmetric Brønsted acidcatalyzed intramolecular allylic substitution reaction.147 Treatment of phenol derivative 169 with 5 mol % of Ntriflylphosphoramide 170 in toluene at −78 °C produced chiral 2H-benzopyran derivative 171 in 92% ee (Scheme 46). The contribution of cation−π interactions between the allylic 11369


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and negative charges are developed in the transition state of the SN2 reaction. On the other hand, for the reaction of an anionic nucleophile and a cationic substrate, both positive and negative charges disappear during the reaction. In both cases, cation−π interactions stabilize the transition states. Dougherty and co-workers reported that a cyclophane host 179 acts as a biomimetic catalyst for Menshutkin reactions in aqueous media.149−151 Host 179 substantially accelerates the N-methylation reaction of quinoline with MeI. When the host possesses an electron-donating substituent at the aromatic ring, the rate of the reaction increases.152 This substituent effect is likely due to cation−π stabilization of the developed positive charge in the transition state TS-180 (Scheme 48).

Scheme 46. Asymmetric Brønsted Acid-Catalyzed Cyclization Reaction

Scheme 48. N-Methylation of Quinoline in a Cyclophane Host

cation 172 produced from 169 and the catalyst 170 in an ionic complex 173 is proposed for the enantioselection in the cyclization, Scheme 46. Jacobsen’s squaramide catalyst was particularly effective for the construction of quaternary stereocenters via enantioselective nucleophile addition into nonheteroatom-stabilized carbocations. The SN1 reaction of propargylic acetate 174 with allylsilane without catalyst afforded a 1:1 mixture of 176 and 177. On the other hand, in the presence of 10 mol % of catalyst 175a, the allylation reaction afforded 176 in high selectivity (40:1) with 91% ee (Scheme 47).148 In contrast, Scheme 47. Squaramide-Catalyzed SN1 Reaction of Propargylic Acetate Moore and Heemstra reported that phenylene ethynylene (PE) oligomers 181 form a helical structure and generate a hydrophobic cavity.153,154 They found that the rate of the Nmethylation of PE oligomers was dependent on the oligomer length. In the N-methylation of oligomer 181a−181c, the authors found that oligomer 181b having 13 monomer units reacted over 400 times faster than did oligomer 181a having 3 monomer units (Scheme 49a). The pyridine ring of 181b is sandwiched between the two phenyl rings, stabilizing the transition state TS-182 through pyridinium−π interactions. In contrast, 181a is not of sufficient length to receive such stabilization, resulting in the significant difference observed in the rate of reactions. The methylation reagent had a significant effect on the methylation rate of the oligomers. The methylation rate of 181c with 3-pentyl methyl sulfonate is 1600-fold larger than that of 181a. On the other hand, when using 1-adamantyl methyl sulfonate, the methylation rate is 8fold larger. These observations suggest that the oligomer forms a cavity which serves as reactive sieving.155,156 The pyridinium−π interaction enhances the basicity of the pyridine moiety; the pKa values of trimer 181a and tridecamer 181b are 14.0 and 14.3, respectively. This is due to differences in the stability of their protonated forms 183; the folding of 181b stabilizes the protonated species through cation−π interactions, enhancing the basicity of the pyridine ring of 181b (Scheme 49b).157 The cyclophane host 179 served not only as an Nmethylation catalyst but also as a demethylation catalyst of a sulfonium salt. Host 179 accelerates the demethylation of a

catalyst 175b with an NMe moiety is much less effective in both product selectivity and stereoselectivity, indicating the importance of the complex formation between TMSOTf and 175a in the catalytic ability. A linear correlation observed between the polarlizability values for the aryl substituent and the enantiomer ratio indicates that stabilizing aromatic interactions play an important role in enantiodifferentiation. The optimized structure for the ground state complex between catalyst 175a and a cation intermediate 178 at B3LYP/631G(d) level evidenced the existence of cation−π interactions. 2.4.2. SN2 Reaction. In SN2 reactions, when both a nucleophile and a substrate are neutral molecules, the positive 11370


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promoted by a chiral squaramide catalyst 187 with hydrochloric acid (Scheme 51a). The larger π system on the

Scheme 49. Effect of the Oligomer Length of Phenylene Ethynylene Oligomers on the Rate of N-Methylation and Their pKa Values

Scheme 51. Enantioselective Selenocyclization

pyrrolidine unit has a significant effect on the stereoselectivity, indicating the contribution of a cation−π interaction in the transition state.160 Scheme 51b shows a plausible mechanism, in which interactions between the equilibrated intermediate seleniranium ions 190-I and 190-II with a chiral squaramide 187 cause the difference in the rate of cyclization, leading to benzofuran (S,R)-189 as a major product.

sulfonium salt 184 with an iodide ion to afford sulfide 185 (Scheme 50). During this process, cation−π interactions are Scheme 50. Demethylation of a Sulfonium Ion Catalyzed by a Cyclophane Host

2.5. Cycloaddition

A π system with a positive charge can form a cation−π complex with a neutral unreactive π system, with the complex undergoing cycloaddition reactions on the unblocked side. The [4 + 2], [4 + 3], and [2 + 3] cycloaddition reactions of the cationic complex with dienophile, enophile, and polarophile proceed stereoselectively to give the corresponding adducts, respectively (Figure 11).

Figure 11. Schematic representation of the cycloaddition reactions.

2.5.1. [4 + 2] Cycloaddition. Corey et al. developed the (S)-tryptophan-derived oxazaborolidine catalyst 192 for Diels−Alder reactions.161,162 The [4 + 2] addition reaction of 2-bromoacroleine 191 and cyclopentadiene produced a chiral adduct 193. A transition state model TS-193 is provided on the basis of NOE as shown in Scheme 52, where the coordinated cationic enal moiety is brought close to the benzene ring of the indole moiety through an attractive interaction. This model, involving cation−π stabilization, can explain the face selectivity of the cycloaddition. MacMillan’s organocatalytic strategy to the activation of α,βunsaturated aldehyde was used for enantioselective Diels− Alder reactions. In the presence of 5 mol % catalyst 99, α,β-

responsible for the stabilization of the transition state TS185.158,159 This is closely related to the naturally occurring methylating agent SAM (S-adenosylmethionine) observed in methyltransferase. The crystal structure of cytosine DNA methyltransferase reveals that the S+−CH3 unit of SAM and the π face of a Trp41 residue are located close together with an ideal arrangement through cation−π interactions. The enantioselective selenocyclization reaction of o-allylsubstituted phenol 186 with selenylation reagent 188 is 11371


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transition structures was in close agreement with the enantioselectivity of the experimental results.164 This organocatalytic Diels−Alder reaction was applied to the total synthesis of the marine metabolite solanapyrone D (199), a phytotoxic polyketide isolated from the fungus Altenaria solani.165 As depicted in Scheme 53b, the cycloaddition of trienal 196 in the presence of 20 mol % of catalyst 105·TfOH afforded [4.3.0]bicyclic aldehyde 197 bearing four newly formed stereogenic centers. This was easily derived to solanopyrone D (199). When α,β-unsaturated ketones are activated by chiral amine catalyst 200 with a 2-(5-methylfuryl) moiety at the C5 position, they serve as dienophiles. The organocatalytic Diels− Alder reaction of ethyl vinyl ketone 202 and diene 201 yielded cis cyclic ketone 203 in very high stereoselectivity via an enantiofacial discrimination through a transition state similar to that described above (Scheme 54).166 Houk and Gordillo

Scheme 52. Diels−Alder Reaction Catalyzed by (S)Tryptophan-Derived Oxazaborolidine

Scheme 54. Organocatalytic Diels−Alder Reaction of α,βUnsaturated Ketone

unsaturated aldehyde and cyclopentadiene produced bicyclic aldehyde 194 and 195 in high ee.163 The first step of this reaction is the formation of the intermediary iminium ion 101 from the reaction of the catalyst with α,β-unsaturated aldehyde. The cyclopentadiene approaches the iminium dienophile from the less hindered side through TS-195 to give [4 + 2] adducts in high stereoselectivities (Scheme 53a). Scheme 53. Enantioselective Intra- and Intermolecular Organocatalytic Diels−Alder Reactions

revealed the differences in behavior between catalysts 99 and 200 in the cycloaddition reaction of diene with α,β-unsaturated ketones on the basis of DFT calculations.167 Jacobsen and co-workers described the organocatalytic Povarov reaction of protio-iminium ions and electron-rich olefins with sulfinamide urea catalyst 204. The [4 + 2] addition of benzylidene aniline 205 and 2,3-dihydrofuran catalyzed by 204 in the presence of o-nitrobenzenesulfonic acid afforded exoadduct 206 as a major product in 91% ee (Scheme 55a).168 The optimized geometry and the lowest energy transition Scheme 55. Organocatalytic [4 + 2] Cycloaddition of Benzylidene Aniline and 2,3-Dihydrofurane

The MM3 geometry of the intermediary iminium cation 101 predicts that the benzyl group on the catalyst framework shields the Re face of the iminium plane, leaving the Si face exposed to attack by the enophile.163 Kozlowski’s studies using functionality mapping supports the mechanism described above; a Boltzman distribution of the 11372


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structure TS-206 calculated at the B3LYP/6-31G(d) level suggests the contribution of aryl group π−π interactions between the catalyst and the iminium ion. In addition, a cation−π interaction between the iminium and the π system of the urea moiety is thought to be another important contributor (Scheme 55b).168 In the synthesis of N-acylthiophthalimide 211 by the Nacylation of thiophthalimide 208 with propionyl chloride in the presence of pyridine, Yamada et al. found the formation of an unexpected tricyclic compound 209 in 62% yield (Scheme 56).

Scheme 57. Asymmetric [4 + 3] Cycloaddition of an Allyl Cation and Furan

Scheme 56. One-Pot Synthesis of 1,2-Dihydropyridine with an N-Acylspirothiolactam Moiety

215 and furan afforded adduct 216 with high enantioselectivity. Scheme 58b shows the lowest energy transition structure The structure of 209 was confirmed by X-ray crystallographic analysis.169 One surprising feature is that the reaction provided a syn adduct with respect to the dihydropyridine and the benzene ring with an almost single stereoisomer, despite having three stereogenic centers. This suggests that the tricyclic compound is produced via the [4 + 2] cycloaddition reaction of an intermediate betaine 210 with N-acyldithiophthalimide 211 through an intermolecular cation−π interaction between the pyridinium cation and the aromatic moiety of Nacylthiophthalimide in the transition state TS-209. 2.5.2. [4 + 3] Cycloaddition. Hoffmann and co-workers demonstrated that the [4 + 3] cycloaddition of furan with an allyl cation, which is produced from the Lewis acid-promoted ionization of chiral silyl enol ether 212a, affords (1′S, 2S)bicyclic ketone 213a in 76% de as a major product (Scheme 57a).170,171 The observed stereoselectivity is thought to result from the preferential shielding of one side of the allyl cation by the phenyl ring on the chiral auxiliary through a cation−π interaction as shown in Scheme 57b. The larger steric repulsion in the proposed transition state TS-214a than that in TS-213a prevents the formation of diastereomer 214a. When the 1-phenylethyl moiety was replaced with a 1-(2naphthyl)ethyl group, the selectivity was remarkably improved to 100% de, reflecting the enhanced cation−π-controlled stabilization of the transition state as described above. Houk and Harmata proposed an open-chain transition state for the [4 + 3] cycloaddition reactions instead of the proposed transition state model described above.172 Computational analysis suggests that the contribution of a CH···π interaction in the transition state plays a key role in determining the stereoselectivity. The squaramide-promoted oxocarbenium formation described in Scheme 47 was applied for the [4 + 3] cycloaddition reaction of an oxyallyl cation and furan derivatives.106 The squaramide-catalyzed [4 + 3] cycloaddition reaction of acetal

Scheme 58. Catalytic Asymmetric [4 + 3] Cycloaddition of an Allyl Cation and Furan

TS-216 calculated at the B3LYP/6-31G(d) level of theory, which shows that the furan nucleophile is sandwiched between the aromatic substituent of the catalyst and the oxyallyl cation 217 generated from acetal 215. This indicates the existence of a stabilizing interaction between the furan and the catalyst, leading to high enantioselectivity. Harmata and co-workers found that the [4 + 3] cycloaddition reaction of furan 219 and silyloxypentadienal 218 catalyzed by MacMillan’s organocatalyst 105 afforded adduct 220 with an opposite facial selectivity173 to that observed in the Diels−Alder reactions of enals (Scheme 59).163 Computational analysis of the transition states TS-220-i and TS-220-ii for the [4 + 3] cycloaddition reaction can explain this opposite selectivity. The steric repulsion between the benzyl group and 11373


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Scheme 59. [4 + 3] Cycloaddition Reaction of Furan with Silyloxypentadienal

Figure 12. Schematic representation of nucleophilic catalysis.

N-acylpyridinium and the aromatic nucleophile assists enantiomer selection in the acyl-transfer reaction (Figure 12b). Deacylation of orthoesters with a neutral nucleophile is performed through cation−π stabilization between the developing positive charge and the π system in the transition state (Figure 12c). A variety of amidine-based catalysts have also been developed for O- and C-acylation reactions. 2.6.1. Asymmetric O-Acylation. A variety of asymmetric O-acylating catalysts have extensively been explored to date. These catalysts are used for kinetic resolution, desymmetrization, and dynamic kinetic resolution of various alcohols, as summarized in several reviews.176−180 In this section, the roles of cation−π interactions in these systems are described. Fu and co-workers developed the planar-chiral DMAPferrocene hybrid catalyst 225, which is effective for the asymmetric acylation of racemic alcohols.181,182 The nonenzymatic kinetic resolution of 1-phenylethanol 226 was performed using 2 mol % of catalyst 225 to give (S)-226 with 95% ee (s = 14) (Scheme 61a).181 The s value was dependent on the size of the alkyl group, with increases in the steric bulkiness of the substituent leading to increased s values. Desymmetrization of meso-diol 228 provided monoester 229 in 91% yield with 99.7% ee (Scheme 61b).181 The extended π system on the propargylic alcohols183 and aryl alkyl carbinols184 led to higher selectivity, suggesting the contribu-

the bulky TMS component of iminium 221 determines the conformation of the TMS moiety, leading to the furans approaching from the same side as the benzyl group of 221 to give adduct 220.174 2.5.3. [1,3]-Dipolar Cycloaddition. The organocatalytic 1,3-dipolar cycloaddition of nitrone 222 and crotonaldehyde using catalyst 99 afforded the endo-(4S)-isoxazolidine adduct 223 as a major product in high ee (Scheme 60).175 Analogous Scheme 60. Organocatalytic 1,3-Dipolar Cycloaddition of Nitrone and Crotonaldehyde

Scheme 61. Kinetic Resolution of Racemic sec-Alcohols with a Planar Chiral DMAP Catalyst

with the DA reaction described in Scheme 53a, the benzyl group on the iminium intermediate 101 effectively promotes cycloaddition from the Si face of the dipolarophile. A cation−π interaction between the aromatic ring of the nitrone 222 and the iminium ion 101 is likely to assist the Si face attack in the transition state TS-223. 2.6. Nucleophilic Catalysis

4-Dimethylaminopyridine (DMAP) and 4-pyrrolidinopyridine (PPY) are well-known nucleophilic catalysts for the acylation of alcohols. The chiral versions of these catalysts have been exploited extensively in asymmetric acylation reactions. As the N-acylpyridinium has a positive charge, nucleophiles attack the N-acyl group, leading to acyl-transfer reactions. When an aromatic moiety of the catalyst intramolecularly interacts with the N-acylpyridinium ring, the enantioselection of racemic alcohols occurs in the transition state of the acylation (Figure 12a). For a C-centered nucleophile, asymmetric C-acylation proceeds (Figure 12a). The cation−π interaction between the 11374


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Scheme 63. Kinetic Resolution of Racemic sec-Alcohols, Desymmetrization of meso-Diol, and Dynamic Kinetic Resolution of Hemiaminals Using a Chiral DMAP Catalyst

tion of a cation−π interaction in the transition state of the acylation. Diner et al. performed computational analysis of the asymmetric acetylation of 1-phenylethanol catalyzed by a planar chiral DMAP derivative 225. The lowest energy transition state TS-227 calculated at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d,p) level shows an interaction between the phenyl ring of the substrate and the pyridinium ring of the N-acyl intermediate 230 (Scheme 61c).185 Spivey developed an atropisomeric biaryl catalyst 231 for asymmetric acylation. Among various sec-alcohols employed, the s value of cis-cyclohexane-1,2-diol monobenzoate 232 was higher than those of the other substrates without an aryl moiety, indicating the contribution of an interaction between the pyridinium and the aromatic ring of the substrates in the transition state TS-233 (Scheme 62).186,187 Scheme 62. Kinetic Resolution of Racemic sec-Alcohols Using an Atropisomeric Catalyst

Yamada et al. developed the chiral DMAP catalyst 235 possessing a chiral thiazolidine-2-thione moiety at the 3 position of the pyridine nucleus. This asymmetric acyl-transfer catalyst is effective for various types of sec-alcohols. The kinetic resolution of racemic sec-alcohol 236,188,189 desymmetrization of diol 238,189 and dynamic kinetic resolution of hemiaminal 240190 by catalytic acylation with 235 were achieved in good stereoselectivities (Schemes 63a−c). The conformation of the N-acylpyridinium intermediate 242 is fixed through a cation−π interaction between the pyridinium and the N−CS moieties, providing a chiral environment around the pyridinium as shown in Scheme 63d. The superimposed X-ray crystal structure of model compound 243 and corresponding Nmethyl derivative 244 clearly shows that the thiocarbonyl of 244 is closer to the pyridinium than 243 (Scheme 63e). 1H NMR spectroscopic studies and DFT calculations for the Nacyl intermediate at the B3LYP/6-31G(d) level confirmed the structure to be similar in conformation to the X-ray crystal structure. In addition to intramolecular cation−π interactions, intermolecular cation−π interactions between the pyridinium intermediates and aromatic substrates in the transition state TS-237-i also appear to be important for the resolving racemic alcohols.

Sibi et al. reported that the 3-substituted DMAP derivative 245 is useful for the kinetic resolution of BINOL derivatives191 and dynamic kinetic resolution of biaryl atropisomers.192 Asymmetric acylation of O-allylbinol 246 was achieved using 10 mol % of catalyst 245 in good enantioselectivity. The transition model TS-247 described in Scheme 64, in which the naphthyl moiety is stacked with the pyridinium intermediate 248 through a cation−π interaction, can explain the enantioselectivity. Carbery and co-workers disclosed the first helicenoidal asymmetric organocatalyst 249, which was proven to be a particularly selective acylation catalyst for the kinetic resolution of secondary aryl alkyl alcohols.193,194 The highest s value was obtained for the asymmetric acylation of anthracenyl alcohol 250 by 0.5 mol % of catalyst 249 (s = 116) (Scheme 65a). Comparison of the proposed transition structures TS-251-i and TS-251-ii shows that an interaction between the aryl group of the substrate and the aminopyridine unit of the Nacyl intermediate 252 helps in the discrimination of the enantiomers (Scheme 65b). The fact that a higher selectivity was observed for the substrates having an electron-donating group indicated the contribution of a cation−π interaction. 11375


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Scheme 64. Kinetic Resolution of Monoallylated Bi-2naphthol Using a Chiral DMAP Catalyst

Scheme 66. Enantiomer Selective Acylation of Racemic secAlcohols Using a Chiral PPY Catalyst

Scheme 65. Kinetic Resolution of Aryl Alkyl Alcohols with a Helicenoidal Asymmetric DMAP Catalyst

and 257b without an aromatic ring showed good selectivities (s = 10.1 and 8.4, respectively), catalyst 257c without NH demonstrated much lower selectivity (s = 1.4) (Figure 13). From these observations, they speculated on the importance of the influence of the hydrogen bond between substrates and catalysts on the enantioselectivity.196

Figure 13. Kinetic resolution of racemic sec-alcohols using a chiral PPY catalyst with a proline moiety.

Gilmour et al. developed a PPY catalyst 258 containing a fluorine atom, in which a fluorine gauche effect controls torsional rotation in a class of fluorinated 4-(pyrrolidino)pyridine (PPY) analogues. Kinetic resolution of racemic 1phenetyl alcohol 259 by catalytic acetylation using catalyst 258 afforded ester 260 along with recovery of (S)-259 (Scheme 67a). The X-ray crystal structure of the HCl salt 261 suggests not only the existence of the gauche effect but also that of a cation−π interaction between the pyridinium and that of the phenyl rings (Scheme 67b).197 Zipse et al. studied the conformational properties of the Nacylpyridinium intermediates of a number of reported acylating catalysts using MP2 calculations. Among these catalysts, the Nacyl intermediates of catalysts 235, 253, and 257a were predicted to have a closed conformation through a cation−π interaction between the pyridinium and the aromatic rings, with these interactions playing a decisive role in their stereoselectivities.198 Connon et al. designed PPY-based catalysts with (S)-α,αdiphenylprolinol 262,199,200 inspired by the closed conformation of the N-acylpyridinium salt 12 bearing an oxazolidine chiral auxiliary (Scheme 6).89 Kinetic resolution of various racemic sec-alcohols was achieved using these catalysts. While the acylation of 263a with catalyst 262a gave a good s value, acylation of 263b with an electron-withdrawing group resulted in much lower selectivity, suggesting the importance of an electrostatic interaction between the catalyst and the substrate in the resolution process (Scheme 68a). The X-ray crystal structure of the N-benzyl derivative 265 supports the existence

Kawabata and co-workers developed an enantioselective acyl-transfer catalyst 253 possessing a 4-pyrrolidinopyridine (PPY) framework structure.195 The chiral PPY derivative catalyzed the kinetic resolution of racemic cis-2-hydroxycyclohexyl-4-(dimethylamino)benzoate 254 with a selectivity factor of 10. NOE experiments revealed the catalyst changed from an “open” to a “closed” conformation upon N-acylation. The closed conformation 256 generated by N-acylation gave rise to a chiral environment around the acyl moiety, enabling discrimination of the racemic alcohols (Scheme 66). The conformational change induced by N-acylation is postulated to be due to the interaction between the pyridinium and the naphthyl moiety. Campbell et al. prepared simpler PPY catalysts 257a−257c. The selectivity for the acylation of racemic alcohol 254 was based on the effect of the substituent at the amide moiety of the catalysts. While both catalyst 257a with an aromatic ring 11376


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Scheme 67. Kinetic Resolution of sec-Alcohol with a PPY Derivative

of an attractive interaction between the pyridinium and the benzene rings (Scheme 68b). This catalyst was used for the acylative kinetic resolution of Baylis−Hillman adducts. After the reaction of o-anisaldehyde 266 and methyl acrylate in the presence of DBU, the addition of isobutyric anhydride and catalyst 262b at −78 °C afforded 267 in 25% yield with 89% ee (Scheme 68c).201 Dynamic kinetic resolution of an intermediacy azole hemiaminal 270 was also achieved using catalyst 262b to give chiral ester 269 (Scheme 68d).202 A new chiral DMAP catalyst having a tert-leucinol unit at the 3 position was effective for similar DKR reactions.203 Hunter et al. developed PPY derivatives 271 containing peptide-based side chains at the 3 position of the pyridine ring. The catalyst having an indole residue was the most effective in the kinetic resolution of sec-alcohols.204 Kinetic resolution of 1naphthylethanol 272 in the presence of catalyst 271 gave (S)ester 273 with an s value of 10.7. 1H NMR and DFT geometry optimization for the N-acyl intermediate 274 suggested that the electron-rich indole ring is close to the N-acylpyridinium ring, leading to enantiomer-selective esterification, Scheme 69. Scheme 69. Kinetic Resolution of 1-Naphthylethanol Catalyzed by a PPY Derivative

Scheme 68. Kinetic Resolution of sec-Alcohols and Baylis− Hilmann Adducts, and the Dynamic Kinetic Resolution of Azole Hemiaminal

Birman and co-workers developed a series of amidine-based enantiomer-selective acyl-transfer catalysts 275−278 (ABCs) (Figure 14).205,206 Kinetic resolution of a variety of secondary

Figure 14. Amidine-based enantiomer-selective acyl-transfer catalysts.

benzylic alcohols using these catalysts successfully provided chiral alcohols in high selectivities207−210 (Scheme 70a). For example, asymmetric acylation of 1-phenylpropyl alcohol 279 with catalyst 275 afforded ester 280 together with the recovery of chiral alcohol 279 in high selectivity (s = 36).207,208 On the other hand, aromatic sec-alcohols having an electron-withdrawing substituent and nonaromatic alcohols led to lower enantioselectivities. The lowest energy transition state TS-280 obtained at the B3LYP/6-31G(d) level of theory shows that the aryl group of the substrate stacks on the pyridinium ring of 11377


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Scheme 70. Kinetic Resolution of Racemic sec-Alcohols with Amidine-Based Catalysts

performed using these catalysts.221,222 Furthermore, the kinetic resolution of various carboxylic acids,223−226 dynamic kinetic resolution of azlactones,227,228 and deacylation of N-acylthiazolidine-2-thions and N-acyloxazolidine-2-thions were also achieved.229 These reactions have all been summarized in review articles.205,206 Kinetic resolution of a Morita−Baylis−Hillman adduct 289 was achieved with an acyl-transfer catalyst An-PIQ 288 having an anthranyl group (Scheme 72)230 In this case, the interaction Scheme 72. Kinetic Resolution of Racemic sec-Alcohols with An-PIQ

between the N-acylated catalyst 291 and the conjugated carbonyl group was proposed in the transition state TS-290, which is similar to that in the face-selective addition to pyridinium salts described in Scheme 9.88,89 Shiina et al. succeeded in the asymmetric esterification of racemic 2-hydroxyalkanoates using free carboxylic acid and anhydride (Scheme 73).231,232 Catalytic acylation of 2-

the N-acylated catalyst 281 through a cation−π interaction, which can explain the observed enantioselectivity (Scheme 70b).210,211 Kinetic resolution of allylic alcohol 282 was achieved by use of the second-generation catalyst 276 with an extended π system (Scheme 70c).209 In this reaction, a cation−π interaction between the N-acyl intermediate 284 and the aromatic ring of the substrate is proposed to play an important role in the enantioselectivity as shown in TS-283, which is similar to TS-280.212 These catalysts were effective in the kinetic resolution of a variety of sec-alcohols, such as propargylic alcohols,213 2-substituted cycloalkanols,214,215 and 2,2-difluoro216 and 2,2,2-trifluoro-1-aryl ethanols.217 Desymmetrization of meso-diol 285 using a third-generation catalyst (S)-277 afforded chiral monoester 286 in high enantioselectivity. This was derived to (−)-lobeline 287, which has been used as an antiasthmatic, expectorant, respiratory stimulant, and smoking-cessation aid (Scheme 71).218 Kinetic resolution of β-lactams219 and oxazolidinones by N-acylation and desymmetrization of 1,3-diols220 were

Scheme 73. (R)-BTM-Catalyzed Asymmetric Esterification of Racemic 2-Hydroxyalkanoate with a Mixed Anhydride

Scheme 71. Desymmetrization of meso-Diols with AmidineBased Catalysts hydroxyalkanoate 292 with diphenylacetic acid using 5 mol % of catalyst 277 produced the corresponding ester 293 and recovery of the chiral alcohol 292 in 82% ee with high s value (s = 146). In the transition state TS-293-i, the interaction between the carbonyl group and the benzothiazolium moiety of intermediate 294 is thought to contribute to enantiomer differentiation. This interaction is similar to the intramolecular interaction observed for the N-acylnicotinium amide 2688,89 shown in Scheme 9. Recently, a similar transition structure was 11378


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elucidated by Cheong and Smith in the kinetic resolution of 3allyl-3-hydroxyoxindoles with BTM.233 Resolving the anti-inflammatory drugs ibuprofen, ketoprofen, fenoprofen, flurbiprofen, and naproxen was achieved through asymmetric esterification using X-BTM catalysts.234 In addition, a variety of HBTM derivatives (Figure 14) were used for the kinetic resolution of various sec-alcohols in high selectivities.235 Deng and Fossey developed a new class of planar chiral ferrocene catalyst 295 that combines both central and planar chiralities.236 This catalyst consists of Fu’s planar chiral DMAP and Birman’s amidine-based catalysts (ABCs) and was remarkably effective in the kinetic resolution of various secalcohols. The selectivity factor for 2,2-dimethyl-1-phenylpropanol 296 at −40 °C is 1892. A similar transition state model TS-297 to that for amidine-based catalysts (ABCs) was proposed for this reaction (Scheme 74). The kinetic resolution of heteroarylalkyl carbinols was successfully achieved using this catalyst.237

Scheme 75. Biomimetic Enantioselective Acyl-Transfer Reaction with a Peptide Catalyst

Scheme 76. Kinetic Resolution of sec-Alcohols with a Chiral Acyl Chloride

Scheme 74. Kinetic Resolution of Racemic sec-Alcohols Using a Catalyst with Both Planar and Central Chiralities

2.6.2. Asymmetric C-Acylation. Fu et al. reported a catalytic Steglich reaction of O-acylated benzofuranone 308 to C-acylated isomer 309 using a planar chiral acyl-transfer catalyst 307241 (Scheme 77a). The X-ray crystal structure of the salt of N-acylpyridinium 311 and benzofuranone enolate 310 showed the close proximity of the pyridinium ring of 311 and the benzene ring of the enolate 310 based on a cation−π interaction (Scheme 77b).241 This suggests that the enolate attacks the N-acyl moiety from a similar orientation to give chiral C-acylated benzofurane 309 with a new quaternary chiral center. Smith et al. found that an isothiourea catalyst 278 promoted the asymmetric Steglich reaction with O- to C-acyl group transfer of aryl oxazolyl carbonate 312.242 When the reaction was conducted at −50 °C, the C-acylated product 313 was obtained with the highest enantioselectivity and yield (Scheme 78a). The calculations on the rearrangement of oxazolyl carbonate 312 catalyzed by isothiourea 278 at the B3LYP/631G(d) level of theory revealed the lowest energy transition state TS-313 as shown in Scheme 78b, in which the phenyl group of the enolate 314 is over the cationic N-acylisothiourea 315. The molecular electrostatic potentials for 314 and 315 suggested an interaction between the cation intermediate of the catalyst and the enolate 314 in TS-313. The catalytic cycle

Miller et al. developed biomimetic enantioselective acyltransfer peptide catalysts 299a and 299b containing 3(imidazolyl)-(S)-alanine as the catalytic core and a (R)methylbenzylamide moiety at the C-terminus, respectively.238,239 This peptide catalyst 299a was effective in the kinetic resolution of racemic trans-2-(N-acetylamino)cyclohexan-1-ol 300 by acylation with acetic anhydride (s = 12.6). When the epimeric peptide 299b with (S)-methylbenzylamide at the C-terminus was used as a catalyst, a much lower selectivity was obtained (s = 3.5) (Scheme 75). This indicates that the benzene and imidazolium rings of the Nacylpeptide 302 are located close together through a cation−π interaction, thereby forming an effective conformation for enantiomer selectivity. N-Methylimidazole 303 promoted the kinetic resolution of sec-alcohol 236 by acylation with a chiral acyl chloride. The catalyst 303 and chiral acyl chloride 304 first produce a chiral intermediate acylimidazolium 305. This intermediate was reacted with 2-naphthylmethyl alcohol 236 via TS-306 to give the (S,S)-ester 306 and recovery of the (R)-substrate 236 with high ee (Scheme 76). The existence of the cation−π complex of 305 with 236 was confirmed by 2D NMR spectroscopy.240 11379


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Scheme 77. Enantioselective Synthesis of Oxindoles via Steglich Reaction

Scheme 79. Enantioselective Acylation of Ketene Silyl Acetal with 2-Naphthoyl Fluoride Using Both Thiourea and PPY as Catalysts

Scheme 78. Asymmetric Catalytic Steglich Reaction of Oxazolyl Carbonate

showed the highest activity (Scheme 80a). NOE experiments revealed the close proximity of the histidine proton and aromatic ring, indicating that the cation−π and CH−π interactions influence the folding and reactivity of the peptides. Although the exact structure of the transition state TS-324 of this reaction is not clear, these interactions are likely to stabilize the cationic transition state, leading to acceleration of the reaction rate. Waters et al. screened (His)-containing peptide catalysts for the deacylation of ester 322 to p-nitrophenol 323 and found that helical peptides 325 and 326 having an aromatic residue near the His display high activity (Scheme 80b).245 Although the exact roles of the pyridyl and naphthyl side chains are unclear, they are thought to stabilize the positive charge developed on the histidine in the transition state TS-323-i and TS-323-ii for deacylation stabilized by a cation−π interaction similar to the deacylation by 321a described above. Rajaram et al. found that the rate of hydrolysis for pmethoxybenzyl phenyl carbonate 328 with DABCO is 16-fold faster than that for isobutyl phenyl carbonate 327 (Scheme 81). This indicates that the transition state TS-329 is stabilized by a cation−π interaction between the ammonium and the phenyl moiety as shown in Scheme 81.246

for the acyl migration is thought to proceed via complex formation as described in Scheme 78b. The enantioselective acylation of ketene silyl acetal 316 with 2-naphthoyl fluoride 317 was achieved using both thiourea 318 and 4-pyrrolidinopyridine (PPY) 319 as catalysts (Scheme 79a). Scheme 79b shows the catalytic cycle for the enantioselective C-acylation. The acyl-transfer reaction proceeds through the ion pair formation of N-acyl-PPY and a fluoride-binding catalyst. Activation of ketene silyl acetal 316 by the fluoride-binding catalyst promotes C-acylation to afford chiral 320, in which the interaction between the Nacylpyridinium and the electron-rich carbazole moiety as well as the interaction between the N-acylpyridinium and the enolate are thought to stabilize the transition state TS-320.243 2.6.3. Deacylation and Hydrolysis. Waters et al. developed β-hairpin peptide catalysts for the deacylation of esters. The 8-mer peptides catalyzed the deacylation reaction of π-nitrophenylmethoxyacetate 322 to p-nitrophenol 323.244 Among the peptides 321a−321c, 321a with O-Me tyrosine

2.7. Halogenation

The halogenation of alkenes and aromatic compounds is generally achieved by an electrophilic addition and electrophilic aromatic substitution with a halonium ion, respectively. 11380


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Scheme 80. Peptides Catalyzed Deacylation Reactions

Figure 15. Schematic representation of halogenation reactions.

catalyst stabilizes the transition state for the addition of halonium ion and blocks one side of the π face, giving rise to stereocontrolled products (Figure 15c). Huc et al. found that the rate for the bromination of helical quinoline oligomers depends on the oligomer length. The bromination of tetramer 331b proceeded faster than that of dimer 331a and produced NO2-Q2XQ-OMe 332b in good selectivity. In the case of octamer NO2-Q8-OMe 331c, monobromination occurs on the position 5 of the third quinoline ring to give NO2-Q2XQ5-OMe 332c. This might be due to the stabilization of the cationic transition state TS-332 by the spatially closely located benzene ring in the helical geometry (Scheme 82).247 Scheme 82. Bromination of Helical Quinoline Oligomers

Scheme 81. Catalytic Hydrolysis of Benzyl Phenyl Carbonate with DABCO The fluorination of phenol with N-fluoropyridinium-2sulfonate 333 was achieved exclusively at the ortho position to give 334 (Scheme 83). This exclusive o-fluorination can be explained by hydrogen-bonding interactions between the Scheme 83. Fluorination of Phenol with NFluoropyridinium-2-sulfonate

If the substrate has a neighboring aromatic ring, the rate of the reaction might be accelerated by intramolecular cation−π stabilization (Figure 15a). The regioselective halogenation of aromatic compounds with N-halopyridinium ion was achieved through cation−π stabilization (Figure 15b). In the catalytic halogenation reactions of alkenes, the aromatic ring of the 11381


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thought to play an important role during stereodifferentiation by the catalyst.

sulfoxy anion and the phenol hydroxy group in transition state TS-334 involving a cation−π interaction between the electrondeficient pyridinium and the electron-rich phenol rings.248,249 α-Chlorolactone 337 was synthesized by the chlorination of ketene silyl acetal 336 with NCS using a chiral squaramide catalyst 92c (Scheme 84).250 The transition state TS-337 may

2.8. Rearrangement

Several types of rearrangement reactions are known to be controlled by cation−π interactions. When a substrate having an azide component undergoes cationic rearrangement triggered by N2 molecule elimination, a cation−π-stabilized conformer produces a marked effect on the directionality of the rearrangement and results in high stereoselectivity (Figure 16a). Ammonium ylides undergo [2−3] sigmatropic rearrange-

Scheme 84. Organocatalytic Chlorination of Ketene Silyl Acetal

Figure 16. Schematic representations of three types of rearrangement.

ment in a stereoselective manner through stabilization by a neighboring aromatic ring (Figure 16b). When the rearrangement of a neutral substrate involves a cation intermediate or a cationic transition state, the reaction often proceeds in a manner in which the cation or the transition state receives maximum stabilization through an intramolecular cation−π interaction. The organocatalytic rearrangement of neutral unsaturated molecules with a charge-separated transition state proceeds under the control of the stabilization of the transition state (Figure 16c). 2.8.1. Nucleophilic Rearrangement. In 1978, Prager et al. found that the migratory aptitude in the Schmidt reactions of 2-arylcyclohexanones 342 is significantly dependent on the substituent on the benzene ring.252 While the rearrangement of substrate 342a possessing a p-methyl group on the benzene ring gave lactam 343a as a major product, that of 342b having two nitro groups afforded lactam 344b as a sole product (Scheme 86a). The authors speculated that the results could

be stabilized by the hydrogen bonding of the amide NH with the succinimide and a cation−π interaction between the developing positive charge with the aromatic substituent on the pyrrolidine unit. Treatment of the product 337 with sodium azide, phenylthiolate, and cesium fluoride afforded corresponding substituted products with inverted stereochemistry in good yields. Jacobsen et al. developed a new method for the asymmetric difluorination of β-substituted styrene 339 involving the migration of the aryl moiety. The geminal difluorination was achieved with m-CPBA, an excess amount of pyr·9HF, and 20 mol % of iodide catalyst 338 to give a difluorinated rearranged product 341 (Scheme 85). This skeletal rearrangement is

Scheme 86. Rearrangement of Arylcyclohexanones

Scheme 85. 1,1-Difluorination of α,β-Unsaturated Ester

be explained by the formation of a π complex with an azide moiety. This complex (Z)-345 was stabilized with compensation for the steric repulsion by the interaction of Ar···N2+, leading to lactam 343a via TS-(Z)-343a. On the other hand, such stabilization was not expected for intermediate (E)-346, leading to 344b via TS-(E)-344b (Scheme 86b). Aube and Katz showed conclusive evidence for the contribution of N2+···π interactions in the determination of

thought to occur via a phenonium ion 340 produced from an iodonium intermediate. The substituent in the catalyst 338 is responsible for the enantioselectivities; catalysts 338b and 338c with a nonaromatic and an electron-withdrawing substituent, respectively, are much less effective than 338a. Although the exact mechanism for the achievement of good stereoselectivity is not clear,251 a cation−π interaction is 11382


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product diastereoselectivity in Schmidt reactions. The Lewis acid-promoted rearrangement of N,O-acetal 349 produced from 347 with 348 is significantly dependent on the conformation of the N, O-acetal ring.253,254 While the rearrangement of 349a produced 352a as the major product, the reaction of 349b with a phenyl group on the acetal ring yielded 352b and 353b in a ratio of 43:57 (Scheme 87a). This

Scheme 88. Substituent Effect on the Product Ratio in the Schmidt Reaction

Scheme 87. Schmidt Reaction via an Equilibrium Shift through a Cation−π Interaction

rearrangement proceeds via TS-358b to give 358b.257,258 Optimized transition state structures at the CPCM(water,UFF)-M06-2X/6-31g(d,p) level in the Schmidt reaction evidenced the contribution of a cation−π interaction between N2+ and an aromatic ring.259 2.8.2. Sigmatropic Rearrangement. Smith et al. reported the catalytic enantioselective [2,3]-rearrangement of allylic ammonium ylides catalyzed by isothiourea.260,261 The treatment of ammonium salt 359 with 20 mol % of benzotetramisole (BTM) 277 in the presence of iPr2NH, BnNH2, and HOBt at −20 °C afforded the [2,3]-rearranged αamino acid derivative 360 in 95:5 dr and 99% ee (Scheme 89a). In this reaction, BTM 277 serves as a nucleophilic catalyst to form intermediate 361, which undergoes [2,3] rearrangement via the formation of an ylide, and amidation with benzylamine to afford 360 (Scheme 89b). Computational studies of the transition state explained the high stereoselectivity. Scheme 89c shows the lowest energy transition structure TS-360, in which a cation−π interaction between the aromatic ring and the catalyst contributes to the stabilization.261 This method was applied to the synthesis of β-fluoro-β-arylα-aminopentamides 364.262 A survey of catalysts for the rearrangement of 362 revealed the most effective catalyst to be the tetramisole hydrochloride 363. Treatment of 362 with tetramisole hydrochloride 363 afforded the corresponding product 364 in 52% yield with 92:8 dr and 95:5 er. The observed stereocontrol is consistent with the [2,3] sigmatropic rearrangement proceeding through TS-364, where the attractive interaction between the phenyl substituent of the cinnamyl unit with the isothiouronium ion was proposed similar to that for TS-360. The authors developed a new tandem process for the synthesis of syn α-amino acid derivatives.263 Pd-catalyzed allylic ammonium salt generation from the allylic phosphate and glycine aryl ester and subsequent enantioselective [2,3]-sigmatropic rearrangement produced the corresponding allylic alcohol. Jacobsen and co-workers reported the enantioselective [3,3]sigmatropic rearrangement of substrate enol ether 366 to Ocrotyl 2-oxobutyrate 367 catalyzed by C2-symmetric guanidinium ion derivatives 365. Catalyst 365b, containing an electron-donating 4-dimethylamino substituent, provided the rearranged product 367 in higher enantioselectivity (78% ee) than did the unsubstituted 365a (73% ee), while catalyst 365c,

migratory aptitude of 349b can be explained by a preference for conformer B rather than conformer A due to stabilization by the intramolecular Ar···N2+ interaction.253,254 The migration from conformer B yields 351 via TS-351b, which is hydrolyzed to give 353b as a major product. A similar intramolecular Schmidt reaction was used for the synthesis of orthoamides.255 Radkiewicz-Poutsma et al.256 confirmed the importance of a cation−π interaction in determining the diastereoselectivities on the basis of calculations of model compounds 354. A comparison of the free energy difference between the axial and the equatorial conformers (ΔGax‑eq) demonstrated that a benzene substituent had a remarkable effect on the stabilization of the axial conformer. This strongly suggested that a cation−π interaction governs the conformer ratio, which subsequently determines the diastereoselectivity (Scheme 87b). This cation−π-controlled Schmidt reaction was applied to the synthesis of bicyclic lactams. The successive cyclization and rearrangement reaction of compound 355a afforded 357a and 358a, which are produced from conformers 356-A and 356-B, respectively, in a ratio of 57:17 as shown in Scheme 88. On the other hand, the rearrangement of 355b bearing a pmethoxybenzene group provided bridged bicyclic lactam 358b as a major product. These substituent-dependent differences in product selectivity suggest that the intermediate 356b prefers conformer B due to a cation−π interaction between the N2+ moiety and the aryl group, and the 11383


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Scheme 89. Catalytic Enantioselective [2,3]-Rearrangement of an Ammonium Salt with BTM

Scheme 90. Enantioselective [3,3]-Sigmatropic Rearrangement Catalyzed by C2-Symmetric Guanidinium Ion Derivatives

Scheme 91. Cope-Type Cyclization of Hydroxylamine with a Thiourea Catalyst

with an electron-withdrawing 4-fluoro substituent, exhibited the opposite effect (67% ee) (Scheme 90a). These substituent effects can be explained by the contribution of a cation−π interaction between the π system of the aromatic substituent of the catalyst and the cationic allyl fragment. The optimization for the complex of 366 and 365a at the B3LYP/6-31G(d) level predicted that the substrate has a pro-(S,S) conformation, and the methylene group is located in close proximity to the π face of the phenyl substituent on the catalyst. This complex provides 367 via TS-367a as shown in Scheme 90b.264 The Cope-type cyclization of hydroxylamine 369 to 370 was evaluated in the presence of thiourea catalyst 368 bearing diphenylpyrrole and 2-naphthylpyrrolidine components (Scheme 91a).265 This reaction first produces intermediate nitrone 371 by organocatalytic cyclization, and the subsequent proton transfer gives hydroxylamine 370. Computational studies predicted that a H bond of the N−OH group with the thioamide moiety and a cation−π interaction between the catalyst arene and the ammonium moiety stabilize the transitions state TS-371 as shown in Scheme 91b.

Figure 17. Schematic representation of an oxoammonium ion and Noxide stabilized by a cation−π interaction.

2.9. Oxidation

17b). During the formation of a N-oxide by oxidation, the neighboring aromatic ring stabilizes the transition state, enhancing the rate of N-oxidation. The oxidative kinetic resolution (OKR) of sec-alcohols was carried out using chiral azaadamantane oxoammonium ion 373, which was generated in situ from the alkoxylamine 372 (Scheme 92a).266 The catalytic cycle proposed by Iwabuchi et

The oxoammonium ions and amine N-oxides possess positive charges on the N atoms, and these species can interact with π systems through cation−π interactions (Figure 17a). The oxoammonium ions serve as oxidizing reagents for sec-alcohols to give ketones. The oxidation of pyridines and tert-amines produce pyridine N-oxides and amine N-oxides bearing separated positive and negative charges, respectively (Figure 11384


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Scheme 92. Oxidative Kinetic Resolution of sec-Alcohols with TCCA

chloride and successive deprotection of the Boc group afforded (+)-381 in good yield. Huc et al. investigated the effect of the folding of oligoamides on the promotion of an N-oxidation reaction at the peripheral reactive sites. The N-oxidation of pentamer 382a and heptamer 382b to corresponding N-oxides 383, which are composed from 2,6-diaminopyridine and 2,6pyridinedicarboxylic acid, is much faster than that of the monomer and dimer (Scheme 94a). The oligoamides fold into Scheme 94. N-Oxidation of the Pyridine Nuclei of Oligoamides

al. is shown in Scheme 92b. The cation−π-stabilized oxoammonium ion 374 is attacked by a sec-alcohol to yield adduct 375 and 376 (Scheme 92b). H abstraction by the Noxide via a more stable Cope-like planar five-membered cyclic transition state TS-375 produced ketones together with recovery of chiral alcohols. The utility of this organocatalytic oxidative kinetic resolution (OKR) was demonstrated by the synthesis of renin inhibitor (+)-381 (Scheme 93).267 The OKR of racemic 379 with the 374/TCCA system gave (+)-379 in 42% yield with >99% ee, the subsequent treatment of which with p-methoxybenzyl

stable single helices, enhancing the quaternization of the pyridine moiety. For example, the initial reaction rate of 382b is at least 400 times faster than the oxidation of the dimer derived from its two terminal units.268 Scheme 94b shows the crystal structure of the heptamer with its helical folding structure. Although the origin of this rate acceleration is not clear, cation−π stabilization in the transition state of the Noxidation and preassociation of MCPBA in the polar cavity of the oligomers may enhance the reactivity and site selectivity of the aromatic helices.268

Scheme 93. Synthesis of Renin Inhibitor via Oxidative Kinetic Resolution (OKR)

3. ONIUM ION-ASSISTED REACTIONS The previous section described a variety of examples of cation−π-controlled reactions involving cationic components that serve as reactive intermediates. On the other hand, there are a number of examples involving unreactive cations that assist various types of reactions. This section reviews organic reactions in which the substrates or reagents involve onium ions that are not reactive sites but assist the reactions and achieve regio- and stereoselectivity through cation−π interactions. These reactions are categorized to two types of onium ion-assisted reactions as follows (Figure 18): (a) reactions involving cation−π-stabilized intermediates produced from substrates and catalysts, where nucleophiles or electrophiles attack the intermediates from the less hindered side to give stereoselective products, and (b) onium ion-assisted reactions, 11385


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Scheme 95. Asymmetric Michael Addition Reactions of Cyclohexanone with a Pyrrolidine−Pyridine Catalyst

Figure 18. Two types of onium ion-assisted reactions.

where the complexes are produced from substrates and cationic templates and are attacked by nucleophiles or electrophiles from the less hindered side to give stereoselective products. 3.1. Nucleophilic Reactions

Scheme 96. Asymmetric Michael Addition and Aldol Reactions of Ketones with a Benzimidazolium−Pyrrolidine Catalyst

In addition reactions, when an onium ion shields one side of a π face, the reaction generally occurs on the unshielded side. When enamines with a cationic moiety form a complex with an aromatic compound through an intermolecular cation−π interaction, the electrophile approaches from the unshielded side to give a stereocontrolled adduct (Figure 19a). In the case

Figure 19. Schematic representation of a variety of nucleophilic reactions through cation−π interactions.

of aromatic imines, the nucleophile attacks the imine carbon from the less hindered side (Figure 19b). Pyridinium ylides and NHCs undergo cation-assisted face-selective reactions, leading to a variety of stereocontrolled products (Figure 19c). The intramolecular cyclization of alkynes produces cyclic cis olefins by activation of the triple bonds with a cation (Figure 19d). 3.1.1. Nucleophilic Addition. In the addition of nucleophiles to the sp2 carbons of substrates, the discrimination of the sp2 plane is a key to controlling the stereochemistry of the products. If the nucleophile or substrate has a cationic moiety on the molecule, it often affects the directionality of the nucleophile attacking the sp2 plane through an intra- or intermolecular cation−π interaction. Kotsuki et al. developed a bifunctional pyrrolidine−pyridine catalyst 385, which is effective for asymmetric Michael addition reactions of cyclohexanone to β-nitrostyrene 384.269 When 5 mol % of 2,4-dinitrobenzenesulfonic acid 386 was added, the stereoselectivity was remarkably increased to give adduct 387 in 99% ee. This indicates that the pyridinium ring effectively shields the Si face of the intermediate enamine 388 in the transition state TS-387 as shown in Scheme 95. Luo and Cheng used pyrrolidine-type chiral ionic liquids (CILs) as catalysts for asymmetric Michael addition reactions.270 A modified ionic liquid catalyst 390 having a benzimidazolium moiety is effective for the desymmetrization of 4-methylcyclohexanone 389 by Michael addition to βnitrostyrene 384.271 The enantioselectivity of the adduct 391 with three chiral centers was 97% ee (Scheme 96). A proposed transition state model TS-391 is similar to that in the Michael

addition using 385 described in Scheme 95, where the interaction between the benzimidazolium and the enamine moieties of the intermediate 392 determines the reactive face of the enamine. This catalyst can be used for aldol reactions involving cyclic and acyclic ketones (Scheme 96b).272 The aldol reaction of methyl ethyl ketone with p-nitrobenzaldehyde 393 gave aldol product 394 with complete regioselectivity in 96% yield and moderate diastereo- and enantioselectivities (76% de and 56% ee). Narumi et al. found an azolium salt-catalyzed the Friedel− Crafts-type conjugate addition of indole. In the presence of 10 mol % of imidazolium salt 396, indole attacked chalcone 395 to give adduct 397 in 97% yield under solvent-free conditions. The role of the imidazolium salt is thought to be the stabilization of the developing indole anion by a cation−π interaction between the imidazolium and the anion as shown in Scheme 97.273 High-level ab initio calculations for the complex revealed significant contributions by the electrostatic and induction interactions.273 11386


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Scheme 97. Azolium Salt-Catalyzed Friedel−Crafts-Type Conjugate Addition of Indole

Scheme 99. Stetter Cyclization of an Aromatic Aldehyde with a Thiazolium Catalyst

Paton and Smith reported chiral tetraalkylammoniumassisted catalytic intramolecular enantioselective cyclization reactions.274 Treatment of a malonate derivative 399 with a base in the presence of a chiral tetraalkylammonium ion 398 leads to 5-endo-trig cyclization to give substituted indene 400 in high enantio- and diastereoselectivities (Scheme 98). A

and thiazolium rings lie in a face-to-face fashion in the solid state, as shown in Scheme 99b, indicating that the catalyst conformation is controlled by a cation−π interaction. Similar geometry would be preserved during face-selective addition of N-heterocyclic carbene generated from 401 to the aldehyde carbon of 402 and successive intramolecular 1,4-addition reactions of the intermediary zwitterions. Gravel et al. developed the first general N-heterocyclic carbene (NHC)-catalyzed cross-benzoin reaction. The reaction of benzaldehyde and propionaldehyde using an achiral triazolium salt 405 as a catalyst produced a cross-benzoin product 406 in good selectivity (Scheme 100a).276 A chiral

Scheme 98. Chiral Tetraalkylammonium-Assisted Intramolecular Cyclization Reaction

Scheme 100. N-Heterocyclic Carbene-Catalyzed CrossBenzoin Reaction

proposed transition state TS-400 shows the interaction between the ammonium and the aromatic ring as well as the two carbonyl groups, leading to high stereoselectivities. A similar interaction between a tetraalkylammonium ion with a carbonyl group and a benzene ring has been reported in the tetrabutylammonium-assisted Norrish−Yang reaction (see section 3.2.3., Scheme 129). Vitamin B1 and its analogues, containing a thiazolium component, serve as catalysts for benzoin condensation and related reactions. Miller et al. developed peptide catalysts having thiazole components. The Stetter cyclization of aromatic aldehyde 402 with catalyst 401 gave a chroman-4one 403 in good enantioselectivity (Scheme 99a).275 The Xray crystal structure of one catalyst 404 revealed that the aryl

morpholinone-based valine-derived triazolium salt was also effective for the formation of the cross-benzoin product, though a high enantioselectivity was not achieved. DFT calculations for the transition state TS-406 of the C−C bond formation (M06-2X/6-31+G(d,p) level) suggest that a cation−π interaction plays a key role in lowering the transition state energy for the formation of cross-benzoin product 406 (Scheme 100b).277 11387


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Yamada et al. developed a new method for the synthesis of chiral cyclopropanes using a chiral pyridinium ylide 411 (Scheme 101a).278 The cyclopropanation of electron-deficient

Scheme 102. Catalytic Enantioselective Strecker Synthesis

Scheme 101. Synthesis of Chiral Cyclopropane Using a Pyridinium Ylide

Scheme 103. Diastereoselective Reduction of Ketone with Tetraalkylammonium Borohydride

alkene 408 with a chiral pyridinium salt 407 in the presence of Et3N afforded cyclopropane 409 with recovery of the chiral pyridine derivative 410. A chiral auxiliary with a phenyl group is effective for the discrimination of the reactive face of the alkene with respect to the ylide 411 in the transition state TS409. The X-ray crystal structure of a model pyridinium salt 412 shows that the pyridinium and benzene rings are close together as shown in Scheme 101b, clearly demonstrating the contribution of a cation−π interaction to conformation fixation during the reaction. Corey et al. developed a guanidine catalyst 413 for the enantioselective Strecker synthesis of chiral α-amino nitriles. Addition of HCN to N-benzhydril imine 414 catalyzed by 413 afforded adduct 415 in 96% yield with 86% ee.279 In the transition state TS-415 of the addition reaction, N-benzhydril imine 414, HCN, and the guanidine catalyst 413 form a molecular complex through H bonds and π−π and cation−π interactions and the cyanide ion attacks the Si face of the imine carbon from the unshielded side to give (R)-415 predominantly (Scheme 102). Li and Yang reported the diastereoselective reduction of ketone 416 using tetraalkylammonium borohydride in the course of the total synthesis of Maoecrystal V. The reduction of β-ketoester 416 with NaBH4 gave 418 as a major product. In contrast, treatment of 416 with Bu4NBH4 and Me4NBH4 in methanol/THF at rt afforded the desired alcohol 417 as a sole isomer in 65% and 81% yields, respectively (Scheme 103).280,281 The diastereoselectivity observed in this process was attributed to the directing and accelerating effects of the cation−π interaction between the tetrabutylammonium and

the phenyl ring of substrate 416, which assists in delivering the hydride to the Si face of the ketone via TS-417. Takenaka et al. showed that helicene molecule 420 having a pyridine N-oxide moiety is effective as a catalyst for the enantioselective propargylation of aldehydes with allenyltrichlorosilane 419 (Scheme 104). In the transition state TS-421, a cation−π interaction between the cationic helicene frameScheme 104. Enantioselective Propargylation of Benzaldehyde with Allenyltrichlorosilane Using a Helicene Catalyst

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work and the aromatic ring of the aldehyde is thought to determine the reactive face of the aldehyde.282,283 Hoveyda et al. reported the efficient stereoselective addition of the allyl boron reagent 423 to ketones using a valine-derived aminophenol 424 as a ligand.284 While the allylation of alkenyl ketone 422a gave adduct 425a in very high selectivity (98% ee), the reaction of alkynyl ketone 422b gave 425b in 62% ee (Scheme 105a). This lower enantioselectivity may be due to

Scheme 106. TBAF-Mediated Cyclization of Various Alkynes

Scheme 105. Addition of Allylboron Reagents to Ketones

chiral ammonium fluoride 433. Treatment of the substrate 434 with 10 mol % of chiral catalyst afforded dehydroazaproline 435 and recovery of the chiral substrate 434 with 93% ee (Scheme 107).292 Isoxazolines can also be prepared from the corresponding alkynes using TBAF.293

changes in the transition state associated with the replacement of the alkenyl ketone 422a with the alkynyl ketone 422b. In the reaction of 422a, the ion-dipole/H-bonding attraction between the catalyst and the CF3 group of the substrate controls the face selectivity in the transition state TS-425a, whereas in the case of 422b the competing intramolecular interaction between the alkynyl moiety and the ammonium ion may decrease the face selectivity in the transition state TS425b. 3.1.2. Cyclization of Alkynes. In 1992, Jacobi reported the TBAF-mediated cyclization of pyrrolohydrazides 426 having an alkyne unit to enamides 427. Heating substrate 426 with excess TBAF in THF afforded cyclic enamide 427 in 65−78% yields (Scheme 106a).285,286 Fustero and Hammond also found that TBAF is effective for the cyclization of difluoropropargyl amide 428 to γ-lactam 429 in THF at rt (Scheme 106b).287 In this case, the amide nitrogen attacks the activated internal alkyne through the interaction of TBA+ with the conjugated alkyne system via TS-429. Huguenot reported the similar TBAF-mediated cyclization of propargyl urea.288 Sakamoto and co-workers reported the TBAF-mediated cyclization reaction of N-(2-ethynylphenyl)sulfoneamide 430 to indole derivative 431,289,290 the photocyclization of which in the presence of iodine afforded furostifoline 432, a furo[3,2a]carbazole alkaloid (Scheme 106c).291 Although no experimental or computational evidence is provided to corroborate the proposed cyclization mechanisms, the interaction between TBA+ and the triple bond may be the reason for this unusual cyclization as Lepore proved such interaction by Raman spectroscopy as described later.294 Lepore et al. described the TBAX-catalyzed alkyne cyclization reaction of β-alkynyl hydrazines. This method was applied to the kinetic resolution of propargyl ester 434 with a

Scheme 107. Chiral Tetraalkylammonium-Mediated Cyclization Reaction of β-Alkynyl Hydrazine

Raman spectroscopic studies clarified the role of tetrabutylammonium on the rate enhancement of the cyclization process.294 When compound 434 was mixed with TBAB in THF, the wavenumber of the alkyne stretching band was shifted by −11 cm−1. This indicates that TBA+ makes the triple bond more electrophilic by a cation−π interaction between the alkyne and TBA+. Yasuhara and Sakamoto found that the cyclization of 2ethynylbenzyl alcohol 436 afforded an isobenzofuran derivative 437 in good yield (Scheme 108).295 They deduced that an interaction between the alkynyl triple bond and TBA + enhanced the cyclization of alkoxy component via TS-437. This method was applied to the cyclization of alkynylanilines and alkynylphenols for the syntheses of carbazole derivatives and benzo[b]furan natural products, such as vignafuran, coumestan, and coumestrol.296 11389


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Scheme 109. SN1-Type α-Alkylation of Ketone through Enamine Catalysis

Scheme 108. TBAF-Mediated Cyclization of 2Ethynylbenzyl Alcohol and Propargylic Amine with CO2

Scheme 110. Azidation of 2-Bromo-5-Nitorothiophene in an Ionic Liquid

Recently, Fujita et al. reported the TBAF-catalyzed carboxylative cyclization of propargylic amine 438 with CO2 (Scheme 108b).297 Stirring a t-BuOH solution of propargylic amine 438 for 12 h at 100 °C in the presence of 0.5 mol % of TBAF in an autoclave under a CO2 atmosphere of 1.0 MPa afforded the corresponding 2-oxazolidineone 440 in 85% yield. In this reaction, amine 438 first reacted with CO2 to form the corresponding carbamic acid intermediate 439 in situ. The propargylic moiety and the carboxylic group of the intermediate 439 seem to be activated by tetrabutylammonium and fluoride ions, respectively, to give 2-oxazolodinone 440 as shown in the proposed TS-440. 3.1.3. Nucleophilic Substitution. The bifunctional pyrrolidine-type catalyst 390 noted in section 3.1.1270,271 was also effective for the SN1-type α-alkylation of ketones and aldehydes. Biarylcarbinol 441 forms carbocation 444 by TFA, which reacts with the intermediate enamine 443 to give the αsubstituted cyclohexanone 442 via the hydrolysis of the iminium intermediate as described in Scheme 109.298,299 In this transition state TS-445 the authors speculated that the imidazolium moiety effectively shields the Si face of the enamine through an electrostatic interaction such as a cation−π interaction. D’Anna and Noto reported the nucleophilic aromatic substitution reaction of heterocyclic halides in ionic liquids.300,301 The reaction was much accelerated in an ionic liquid compared to that in an organic solvent. Azidation of 2bromo-5-nitorothiophene 446 was achieved under stirring for 2 h in an ionic liquid, 1-butyl-3-methylimidazolium tetrafluoroborate, to give the substituted product 447 in 62% yield. On the other hand, the reaction with NaN3 in acetonitrile for 168 h produced the same product in only 44% yield, indicating that the transition state TS-447 is stabilized by the interaction with the [bmim][BF4] (Scheme 110). QM/MM Monte Carlo simulations for the transition state of the above reaction suggested that the transition state was stabilized by the imidazolium ion through a cation−π intetraction.302

3.2. Photochemical Reactions

Controlling regio- and stereoselectivities during the photocyclodimerization of alkenes is one of the key issues in synthetic organic photochemistry. Preorientation of substrates before photochemical reactions using various organized media and supramolecular environments303−305 is particularly effective for the stereoselective formation of the products in both solution and solid states. This preorientation strategy using intermolecular cation−π interactions has been applied to [2 + 2] and [4 + 4] photodimerization (Figure 20a). A cationic template can interact with a substrate to control the substrate conformation prior to the photochemical reactions. [6π]-Electrocyclization reactions of cation−π complexes of acrylanilides, and successive [1,5] H shifts of the cyclic intermediate give lactams stereoselectively (Figure 20b). Similarly, a complex of

Figure 20. Schematic representation of a variety of photochemical reactions. 11390


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a substrate and a template is used for stereoselective cyclization via H abstraction of an excited carbonyl group (Figure 20c). 3.2.1. Photodimerization in Solution. The [2 + 2]306 and [4 + 4]307 photocyclization reactions are important fundamental reactions in organic photochemistry and are applied to the synthesis of a variety of natural products. In general, as a number of isomeric dimers are produced in these reactions, preorientation of the substrate in solution is a key issue. Williams et al. conducted pioneering studies on the [2 + 2] photodimerization of styrylpyridines.308 The authors found that while irradiation of 2-styrylpyridine in solution produced only a mixture of (Z)- and (E)-2-styrylpyridines, irradiation of the corresponding hydrochloride gave dimers as well as a mixture of (Z)- and (E)-substrates.309 In addition, it is reported that irradiation of 4-styrylpyridine in dilute hydrochloric acid afforded the synHT dimer.310−312 However, the reason why the product selectivity is dependent on whether the reaction is carried out under acidic or neutral conditions remains unexplained. Yamada et al. presumed that a cation−π interaction is largely responsible for the yields and regio- and stereoselectivities in the formation of photodimer, and systematically investigated the effects of the substituent and HCl concentration on the photodimerization reactions of 4-substituted (E)-4-styrylpyridines.313 The results are summarized in Scheme 111a. Irradiation of (E)-4-styrylpyridine 448a in methanol under neutral conditions afforded (Z)-448a as a major product as well as three dimers 449a, 450a, and 451a. On the other hand, when the irradiation was carried out in the presence of hydrochloric acid, the synHT dimer 449a yield dramatically increased and the (Z)-448a yield decreased. However, irradiation of 448b having a strong electron-withdrawing CF3 group in the presence of HCl resulted in lower selectivity. In contrast, the reaction of 448c having an OMe group afforded the synHT dimer 449c in considerably higher selectivity. These results suggest that the two molecules are preoriented in a head-to-tail manner through cation−π interactions before the photochemical reaction, leading to high regio- and stereoselectivities (Scheme 111b). A comparison of the X-ray crystal structures of 448a and its HCl salt 448a·HCl supported the existence of a pyridinium−π interaction in the acidic conditions. The packing diagrams of 448a show that the phenyl and pyridyl groups are located apart from each other without any stacking arrangement. In contrast, the packing diagram of 448a·HCl shows a photoreactive arrangement; the molecules are arranged in a head-to-tail fashion with the double bonds separated by a distance of 3.295 Å as shown in Scheme 111c. This contact reflects an attractive cation−π interaction between the pyridinium and the benzene rings. A similar preorientation strategy was applied to the photodimerization reactions of (E)-4-(2-(1-naphthyl)vinyl)pyridine and (E)-4-(2-(2-naphthyl)vinyl)pyridine. Their visible-light irradiation in the presence of HCl afforded corresponding syn-HT dimers. 3 1 4 The [2 + 2]photodimerization of the styrylpyridines having alkyl substituents on the phenyl group was achieved effectively in the presence of both HCl and cucurbit[8]uril.315−317 When (Z)-448a was employed as a substrate, the product distribution was markedly affected by the presence of an acid. In the absence of an acid, synHT dimer 449a and synHH dimer 450a were the major products. On the other hand, in the presence of a catalytic amount of acid, r-cct 453 and r-ctc 454

Scheme 111. [2 + 2] Photodimerization of (E)Styrylpyridines in the Presence of HCl

dimers were obtained in good yields (Scheme 112a).318 These dimers are produced from the [2 + 2] photocyclization of (Z)448a and (E)-448a generated from the photoisomerization of (Z)-448a. The cation−π interactions between the (Z)- and the (E)-styrylpyridines shown in Scheme 112b are responsible for the product stereochemistry. However, in the presence of more than 1 equiv of HCl, the synHT dimer 449a was the major product due to the faster isomerization of (Z)-448a than that of (E)-448a (Scheme 112a). In the case of azastilbene 455 possessing two pyridine rings, the amount of acid has a more significant effect on product distribution.319 Irradiation of azastilbene under neutral conditions in MeOH afforded a reduced compound as a major product as well as the syn and anti dimers 456 and 457. Addition of 0.8 equiv of HCl remarkably improved the yield of the syn dimer (Scheme 113a). On the other hand, an excess amount of HCl (more than 2 equiv) gave a saturated compound and a MeOH adduct in high yields. These observations show that a suitable amount of acid can shift the equilibrium of 455 to monoprotonated azastilbene 455·H+, the irradiation of which afforded the syn dimer through cation−π interactions between the pyridinium and pyridine rings (Scheme 113b). 11391


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Scheme 112. [2 + 2] Photodimerization of (Z)Styrylpyridines in the Presence of HCl

Scheme 114. [2 + 2] Photodimerization of Heterocyclic Olefins

is speculated that stabilization of the protonated head-to-tail excimer is more stable than that of the head-to-head form due to the dipolar attraction between the positively charged excited oxazole ring and the electron-rich benzene ring of the ground state molecule. 321 Yamada et al. proposed that the preorientation of substrates in acidic conditions through cation−π interactions is a key aspect of the formation of the head-to-tail excimer.323 The irradiation of 1-aryl-4-pyridylbutadiene 460a in the presence of 1 equiv of HCl produced syn and anti head-to-tail dimers 461a and 462a in 3% and 4% yield, respectively, whereas irradiation in the absence of HCl gave a complex mixture. In the case of diene 460b having a methoxy group, the yields of 461b and 462b were dramatically improved to 29% yield for each compound (Scheme 115).324 Scheme 115. [2 + 2] Photodimerization of 1-Aryl-4pyridylbutadienes

Scheme 113. [2 + 2] Photodimerization of Azastilbene in the Presence of HCl

The examples described above clearly show that the acid serves as a catalyst for the regio- and stereoselective [2 + 2] photodimerization of various alkenylpyridines using cation−π interactions between the pyridinium and the aromatic rings. Photodimerization of the oligo(p-phenylenevinylene) bolaamphiphile trimethylammonium derivative 463 afforded a syn head-to-tail dimer 464 as a major product. This can be produced from self-assembled OPV 463 with a head-to-tail organization in water, which is most likely favored by the interaction between the trimethylammonium group and the benzene ring (Scheme 116).325 The regio- and stereoselective [4 + 4] photodimerization of 1-azaanthracene 465 was achieved using the preorientation strategy (Scheme 117a). Irradiation of a methanol solution of 1-azaanthracene 465 gave a mixture of dimers 466−468. On the other hand, in an acidic methanol solution, the antiHT dimer 466 was obtained in good yield. Increasing the amount of HCl loading to 3 equiv led to a dramatic increase in the antiHT dimer 466 and a decrease in the antiHH and synHT

Similar to the photodimerization of the alkenylpyridines described above, [2 + 2] photodimerization reactions of olefins 458 containing a heterocyclic ring, such as oxazole 458a,320,321 benzoxazole 458b,322 and thiazole 458c−458e,323 afforded synHT dimers 459a−459e as major products under acidic conditions (Scheme 114). In the photodimerization of 458a, it 11392


Chemical Reviews

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improving the regioselectivity to afford a 1:1 mixture of the synHT and antiHT dimers.328,330 The contribution of cation−π interactions in these systems is not clear as the positive charges are close together in all transition states for the formation of the four dimers. An unexpected photodehydro-Diels−Alder reaction of 1phenyl-2-pyridylacetylene 471 occurred by irradiation in an acidic solution to give a new photodimer 473 with a 1,2,3triaryl-substituted naphthalene structure as the major product (Scheme 119). This result indicates that two protonated

Scheme 116. [2 + 2] Photodimerization of Bolaamphiphile Trimethylammonium Derivatives

Scheme 119. Photocycloaddition of Phenylpyridyl Acetylene

Scheme 117. [4 + 4] Photodimerization Reactions of 1Azaanthracene in Acidic Media

monomers 471·H+ reacted in a head-to-tail manner through pyridinium−π interactions. The reaction is thought to proceed in a stepwise manner to form a biradical intermediate, which cyclizes with the benzene ring to yield 1,2,3-triaryl-substituted naphthalene 473.331 3.2.2. Photodimerization in the Solid State. Reactivity and selectivity in solid-state reactions generally depend on the arrangement of the molecules in the crystal. A variety of intermolecular interactions are responsible for the arrangement of molecules in a crystal. Among these attractive interactions, however, the importance of cation−π interactions in crystal engineering has received little attention until recently. Yamada et al. reported the role of cation−π interactions between a pyridinium and an aromatic ring in the crystal engineering based on X-ray crystallographic analysis.332−334 In 1960, Williams reported that the irradiation of 2styrylpyridine 474 gave dimers 475 and 476 in only 2.6% yield, whereas that of 2-styrylpyridine hydrochloride 474·HCl or N-methyl iodide 474·MeI in a solid state gave synHT dimer 475·2RX and synHH dimer 476·2RX (R = H or Me, X = Cl or I) in good yield (Scheme 120).335 Similarly, the photodimerization of the quarternary salts of dipyridylethylene and dipyradylethylene afforded syn dimers, while the irradiation of neutral substrates gave a mixture of isomeric dimers in lower yields.336 Yamada et al. found that (E)-styrylpyridine hydrochloride 448a·HCl forms hydrate crystals with a head-to-tail columnar motif.337,313 The X-ray crystal structure of the hydrate crystals clearly showed that the columnar motif is stabilized by cation−π interactions as well as a hydrogen-bond network with water molecules through N−H···O hydrogen bonds (Scheme 121b). Irradiation of these crystals afforded the synHT dimer 449a in high regio- and stereoselectivities (Scheme 121a).337 On the other hand, when the crystals were heated at 100 °C

dimers (467 and 468). In these reactions, intermolecular cation−π interactions between the pyridinium cation and the benzene ring play a key role in preorientation as shown in Scheme 117b.326 [4 + 4] Photodimerization reactions of acridizinium salts and related compounds have been investigated by several groups, and those reports were reviewed by Ihmels.327 Irradiation of acridizinium 469 in acetonitrile gave dimer 470 and three isomeric dimers in lower selectivity (Scheme 118).328 The regioselectivity of the dimerization reaction is dependent on the substituent at the acridizinium salt. While lower selectivities were observed in the case of unsubstituted compounds,329 a 9-amino substituent was effective in Scheme 118. [4 + 4] Photodimerization Reactions of an Acridizinium Salt

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Scheme 120. [2 + 2] Photodimerization of 2-Styrylpyridine and Its Hydrochloride in the Solid State

Figure 21. Various alkenes that undergo stereoselective [2 + 2] photodimerization in the solid state.

Scheme 122. [2 + 2] Photodimerization of a Styrylquinolinium Salt Scheme 121. [2 + 2] Photodimerization of Styrylpyridine Hydrochloride Hydrate in the Solid State

Scheme 123. [2 + 2] Photodimerization of a Styrylpyrylium Salt

for 6 h, the dehydrate became photostable, indicating that the columnar motif was destroyed by dehydration. These observations also support the proposed head-to-tail preorientation of styrylpyridinium in solution described above (see section 3.2.1). A similar head-to-tail arrangement was observed for the crystals of (E)-4-(4-nitrostyryl)pyridinium salts 477, (E)-Nethyl-4-styrylpyidinium containing an 18-crown-6-ether fragment338 478, (E)-4-(2-(1-naphthyl)vinyl)pyridine hydrochlorides 479, N-ethylstyrylbenzothiazoles 480,339 (Figure 21) and styrylthiazoles 458c−458e. The photodimerization reactions of these alkenes yielded synHT dimers in high yields. Gromov reported an example of the solid-state photodimerization of styrylquinolinium salt 481 (Scheme 122a).340 The X-ray crystal structure of 481 clearly shows that the quinolinium and the benzene ring are close together, as shown in Scheme 122b, which is responsible for the formation of the synHT dimer 482 on irradiation. Novak et al. reported the photodimerization of the styrylpyrylium salt 483 in the crystalline state. When single crystals of styrylpyrylium trifrate 483 were exposed to visible light (>570 nm), [2 + 2] photodimerization proceeded to give the synHT dimer 484 (Scheme 123). This transformation proceeded under single-crystal to single-crystal (SCSC) processes.341

This transformation was applied to the synthesis of a twodimensional polymer. Schlü ter demonstrated the SCSC synthesis of a 2D polymer by the [2 + 2] photodimerization of 485 (Scheme 124a).342 The crystal structure of monomer 485 is shown in Scheme 124b, where the styrylpyrylium moieties are oriented in a head-to-tail fashion with the hexagonal arrangement of six monomers within a layer through intermolecular cation−π interactions. The monomers of the crystal were polymerized by [2 + 2] photocyclization to form the 2D polymer with a pore, the structure of which is shown in Scheme 124b. The solid-state [2 + 2] photodimerization of 4′-methoxy-4azachalcone 486 afforded the synHT dimer 487 and synHH dimer 488 in 20% and 67% yields, respectively (Scheme 125a). In contrast, irradiation of its hydrochloride 486·HCl gave only the synHT dimer 487 in quantitative yield (Scheme 125b). This significant difference in product selectivity is due to the difference in the orientation mode of the substrate crystals. Whereas the molecules of 486 are arranged in a head-to-head manner, the molecules of 486·HCl are arranged in a head-totail manner (Scheme 125c), strongly suggesting the contribution of cation−π interactions to the arrangement of the molecules in 486·HCl.343 11394


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Scheme 124. SCSC Synthesis of the 2D Polymer of a Styrylpyrylium Derivative by [2 + 2] Photodimerization, and the X-ray Crystal Structures before and after Irradiation

Scheme 126. Solid-State Cascade Reaction of 4′-Methoxy-4azachalcone

Figure 22. Photomicrographs of a single crystal of 486 (a) before and (b) after exposure to HCl gas for 10 min and (c) after irradiation of the resultant HCl salt for 24 h.

487, suggesting that the molecules in the HCl salt were arranged in a head-to-tail fashion. The driving force of the reorientation from head-to-head to head-to-tail on exposure to HCl gas is thought to be the cation−π stabilization of the produced HCl salt crystals. This is the first example of a solidstate cascade reaction. The effect of HCl on the regio- and stereoselectivities of the [4 + 4] photodimerization reaction of 1-azaanthracene 465 in solution was described in the previous section325 (see section 3.2.1). This HCl effect was more marked in the solid-state reactions. While irradiation of 465 in the solid state gave no dimer (Scheme 127a), irradiation of the corresponding HCl

Scheme 125. [2 + 2] Photodimerization of 4′-Methoxy-4azachalcone and Its Hydrochloride Salt

Scheme 127. [4 + 4] Photodimerization of 1-Azaanthracene and Its Hydrochloride

The [2 + 2] photodimerization reaction of 486 described above was applied to a solid-state cascade reaction. Exposure of crystals of 486 with a head-to-head arrangement to HCl gas yielded the corresponding HCl salt (486·HCl) with a head-totail stacked alignment. Irradiation of the obtained HCl salt afforded the synHT dimers in high regio- and stereoselectivities (Scheme 126).344 Figure 22 shows photomicrographs of a single crystal of 486 before and after exposure to HCl gas. After exposure for 10 min, unevenness and cracking were observed and the initial transparency was almost lost. Irradiation of the resultant HCl salt 486·HCl for 24 h resulted in some bending of the crystal. 1H NMR measurements of this crystal show the quantitative formation of the synHT dimer

salt afforded the antiHT dimer 466 in high yields (Scheme 127b). In these reactions, intermolecular pyridinium−π interactions play a key role in preorientation prior to the photodimerization reactions, which was confirmed by X-ray crystallographic analysis (Scheme 127c). Whereas the distance between the reactive sites of 465 is longer than the Schmidt requirement (

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