Synthetic Process Development of (R)-(+)-1,2-Epoxy-5-hexene: An Important Chiral Building Block.

Herein, we describe two practical approaches to synthesize (R)-(+)-1,2-epoxy-5-hexene from inexpensive and readily available raw materials and reagents. The first approach is a two-step sequence, involving an epoxidation with meta-chloroperoxybenzoic acid (mCPBA) and a chiral resolution with (salen)Co(II), producing (R)-(+)-1,2-epoxy-5-hexene in 24-30% overall yield. The second approach utilizes readily available (R)-epichlorohydrin as the starting material and features an epoxide ring-opening reaction with allylMgCl and the NaOH-mediated ring closure reaction. Development of this two-step process affords R-(+)-1,2-epoxy-5-hexene in overall isolated yields of 55-60% with an exceptional purity profile. Both approaches have been successfully demonstrated on 100-200 g scales.

Superelectrophilic Nonclassical Carbocations.

The chemistry of dicationic and tricationic 2-norbornyl cations has been studied. A series of N-heterocyclic functionalized norborneol substrates were prepared and ionization of these compounds in superacid provided superelectrophilic species. These highly charged 2-norbornyl cations were found to react with arene nucleophiles in high yields and stereoselectivity. Density functional theory computational studies suggest that increasing positive charge on the structures tends to enhance the degree of nonclassical (or 3-center-2-electron) bonding through separation of the cationic charges.

Friedel-Crafts Reactions with N-Heterocyclic Alcohols.

N-Heterocyclic alcohols are shown to be excellent substrates for superacid-promoted Friedel-Crafts reactions. The N-heterocyclic alcohols ionize to produce reactive, dicationic intermediates which provide good to excellent yields of arylation products.

Synthesis of warfarin analogs: conjugate addition reactions of alkenyl-substituted N-heterocycles with 4-hydroxycoumarin and related substrates.

We have developed a procedure for the Michael addition of 4-hydroxycoumarins to vinyl-substituted N-heterocycles. The chemistry is also suitable for thiocoumarins and quinolinones. A mechanism is proposed involving nucleophilic attack at the vinyl-group of the protonated N-heterocycle.

Superacid Promoted Synthesis of 9,9'-Spirobifluorenes and Related Aza- and Diazaspirocycles.

A variety of 9,9'-spirobifluorenes and related azaspirocycles and diazaspirocycles have been prepared in high yields by intramolecular Friedel-Crafts reaction using the Brønsted superacid, triflic acid (CF3SO3H). Compared to weaker Brønsted acids, the superacid consistently provides better yields along with reduced reaction times and it eliminates the need for heating. The superacid is particularly effective when dicationic electrophilic intermediates are generated in the conversions, for example with the diazaspirocycle syntheses.

Double Addition Reactions Involving Vinyl-Substituted N-Heterocycles and Active Methylene Compounds.

A series of conjugate addition reactions have been performed with vinyl-substituted N-heterocycles in acid-catalyzed conversions. Using active methylene compounds, double conjugate addition reactions have been accomplished to provide dipyridyl and related heterocyclic products. These conversions have utilized 1,3-dicarbonyl compounds, cyano esters, a cyano sulfone, and malonyl nitrile as nucleophiles. The Michael accepting groups include vinyl-substituted pyridines, quinoline, and pyrazine. Double conjugate addition reactions have also been accomplished with 2,6-divinylpyridine and related systems.

Superacid-promoted synthesis of quinoline derivatives.

A series of vinylogous imines have been prepared from anilines and cinnamaldehydes. These substrates react in superacidic media to provide quinolines and related compounds. A mechanism for the conversion is proposed which involves the cyclization of dicationic superelectrophilic intermediates. Aromatization of the quinoline ring is thought to occur by superacid-promoted elimination of benzene.

Michael Addition with an Olefinic Pyridine: Organometallic Nucleophiles and Carbon Electrophiles.

The conjugate addition reactions of trans-1,2-di(2-pyridyl)ethylene have been studied. This substrate reacts with organolithium nucleophiles, and the resulting anionic intermediates may be trapped by proton or various carbonyl-based electrophiles. It is suggested that the dipyridyl structure stabilizes the intermediate carbanion, allowing the Michael adduct to be captured by an added electrophile.

Superelectrophiles: Recent Advances.

Superelectrophiles are reactive species that often carry multiple positive charges. They have been useful in numerous synthetic methods and they often exhibit highly unusual reactivities. Recent advances in superelectrophile chemistry are discussed in this review.

Synthesis of Menthol Glycinates and Their Potential as Cooling Agents.

A convenient method of synthesis has been developed for a new class of potential cooling agents, menthol glycinates. These compounds are prepared in two synthetic steps, starting from bromoacetyl bromide and (-)-menthol. The resulting brominated menthol ester readily undergoes substitution reactions with NH3 and 1° or 2° amines to provide menthol glycinates. For most of the prepared compounds, the two-step synthetic procedure requires no aqueous phase extractions.

Superelectrophiles in Synthesis: Preparation of Aromatic Imides.

Aromatic carboxylic acids are found to undergo reactions with isocyanates, wherein triflic acid promotes the formation of aromatic imide products in fair to good yields. It is proposed that the carboxylic acid group directs the isocyanate electrophile to the ortho-position. This is thought to occur by the formation of a temporary carbamic acid anhydride group, which cleaves upon ortho-functionalization. A series of imide products are synthesized, and the synthesis of a potential selective inhibitor of tyrosyl DNA phosphodiesterase II is performed.

Superelectrophilic carbocations: preparation and reactions of a substrate with six ionizable groups.

A substrate has been prepared having two triarylmethanol centers and four pyridine-type substituent groups. Upon ionization in the Brønsted superacid CF3SO3H, the substrate undergoes two types of reactions. In the presence of only the superacid, the highly ionized intermediate(s) provide a double cyclization product having two pyrido[1,2-a]indole rings. With added benzene, an arylation product is obtained. A mechanism is proposed involving tetra-, penta-, or hexacationic species.

Functionalized fluorenes via dicationic electrophiles.

Dicationic fluorenyl cations are shown to react with nitriles to provide amide-functionalized fluorenes. A similar reaction with alcohols gives ether derivatives. The chemistry is initiated by the reactions of N-heterocyclic ketones in a superacidic solution. This leads to cyclizations involving 2-biphenyl groups and formation of the reactive fluorenyl cations.

Diels-Alder Reactions with Ethylene and Superelectrophiles.

Diels-Alder reactions have been accomplished with ethylene as the dienophile through the use of inverse-electron demand Diels-Alder chemistry. As a key aspect of the chemistry, the dienes are part of tri- or dicationic superelectrophilic systems. Theoretical calculations reveal that the highly charged superelectrophiles possess exceptionally low lying LUMOs, and this facilitates the cycloaddition chemistry with ethylene. The chemistry has been used to prepare a series of tetrahydroquinoline products. This represents the first application of superelectrophilic activation in a cycloaddition reaction, and a new method of utilizing ethylene as a C2 building block.

Electrophilic Carboxamidation of Ferrocenes with Isocyanates.

Ferrocenes undergo one-step carboxamidation by reaction with isocyanates in CF3SO3H solution. The chemistry is most efficient in excess superacid, and it has been accomplished with aryl and aliphatic isocyanates. In conversions with ferrocene carboxylic acids, isocyanates provide imides in good yields. A mechanism for this conversion is suggested involving carbamic acid anhydride formation and subsequent intramolecular reaction at the substituted cyclopentadienyl ring.

Michael Additions Involving Amino Acid Esters with Alkenyl N-Heterocycles.

Michael addition has been achieved with a variety of amino acid esters and 2- or 4-vinylpyridine. Similar reactions were accomplished with an alkenyl-substituted pyrimidine, pyrazine, thiazole, quinoxaline, benzoxazole, and quinolone. In reactions at a prochiral center, modest diastereoselectivities were observed with the formation of the new stereogenic carbon. NMR experiments indicate that the addition reaction is reversible under acidic conditions.

Synthesis of Heterocycle-Containing 9,9-Diarylfluorenes Using Superelectrophiles.

A superacid-promoted method for the synthesis of 9,9-diarylfluorenes is described. The chemistry involves cyclizations and arylations with biphenyl-substituted heterocyclic ketones and a mechanism is proposed involving superelectrophilic intermediates. The key reactive intermediates-dicationic and trication fluorenyl cations have been observed by low-temperature NMR and the mechanism has been further studied using DFT calculations.

Use of Charge-Charge Repulsion to Enhance π-Electron Delocalization into Anti-Aromatic and Aromatic Systems.

A series of 9-fluorenyl cations has been studied and it is shown that increasing charge on a heterocyclic substituent group enhances the anti-aromatic character of the carbocation system. Similarly, a series of dibenzosuberenyl cations has been studied and increasing charge on a substituent group is shown to enhance aromatic character in the carbocation system. These studies include the direct observations of dicationic and tricationic species using stable-ion conditions and low temperature NMR. The structures of these ions were further characterized using DFT calculations, confirming that highly charged organic ions may exhibit unusual distributions of π-electrons and delocalization of electrons in 4n or 4n+2 π-systems.

Tetra- and Pentacationic Electrophiles and Their Chemistry.

A tetracationic electrophile has been generated in superacid and shown to undergo an arylation reaction with benzene. A cyclization product is also obtained in the absence of benzene, presumably from a tricationic intermediate. Using low-temperature NMR, the tetracationic species is directly observed from a FSO3H-SbF5-SO2ClF solution. Similar chemistry is described with a system involving penta- and tetracationic intermediates. These highly ionized structures and their chemistry were also examined by DFT calculation.