A New Synthesis of Enantiopure Amine Fragment: An Important Intermediate to the Anti-HIV Drug Lenacapavir.

Herein, we describe a new seven-step approach to prepare ()-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine (()-) from the inexpensive 2-(3,5-difluorophenyl)acetic acid. The key steps in the sequence include (1) the Weinreb amide-based ketone synthesis to provide an entry point to the core structure; (2) simple functional group transformations to afford the racemic amine -; and (3) dynamic kinetic resolution (DKR) to access the chiral amine ()-. This seven-step process delivered the enantiopure amine ()- in an overall isolated yield of approximately 15%.

Superelectrophilic Nonclassical Carbocations.

The chemistry of dicationic and tricationic 2-norbornyl cations has been studied. A series of -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.

Practical Synthesis of 7-Bromo-4-chloro-1-indazol-3-amine: An Important Intermediate to Lenacapavir.

7-Bromo-4-chloro-1-indazol-3-amine is a heterocyclic fragment used in the synthesis of Lenacapavir, a potent capsid inhibitor for the treatment of HIV-1 infections. In this manuscript, we describe a new approach to synthesizing 7-bromo-4-chloro-1-indazol-3-amine from inexpensive 2,6-dichlorobenzonitrile. This synthetic method utilizes a two-step sequence including regioselective bromination and heterocycle formation with hydrazine to give the desired product in an overall isolated yield of 38-45%.

Friedel-Crafts Reactions with -Heterocyclic Alcohols.

-Heterocyclic alcohols are shown to be excellent substrates for superacid-promoted Friedel-Crafts reactions. The -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 (CFSOH). 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.

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.

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

The conjugate addition reactions of -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 NH and 1° or 2° amines to provide menthol glycinates.

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 -position. This is thought to occur by the formation of a temporary carbamic acid anhydride group, which cleaves upon -functionalization.

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 CFSOH, 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-]indole rings.

Functionalized fluorenes 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 -heterocyclic ketones in a superacidic solution.

Electrophilic Carboxamidation of Ferrocenes with Isocyanates.

Ferrocenes undergo one-step carboxamidation by reaction with isocyanates in CFSOH 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.

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.

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.

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 FSOH-SbF-SOClF solution.

Intramolecular Conjugate Additions with Heterocyclic Olefins.

The intramolecular reactions of olefinic N-heterocycles have been studied. In triflic acid-promoted reactions, conjugate addition is observed with pyrazine-, 2-pyrimidine-, and 2-quinoxaline-based olefins and a phenyl group nucleophile. Markovnikov addition is observed with pyridine and 5-quinoxaline-based olefins.

Cyclodehydrations leading to indene products having N-heterocyclic substituents.

In this Note, we describe superacid-promoted cyclodehydrations leading to functionalized indenes. The product indenes are synthesized having N-heterocyclic substituents, including pyridyl, imidazolyl, pyrimdyl, and other groups. A mechanism is proposed involving dicationic, superelectrophilic intermediates.

Preparation of sulfonamides from -silylamines.

Sulfonamides have been prepared in high yields by the reactions of -silylamines with sulfonyl chlorides and fluorides. In a competition experiment, the sulfonyl chlorides were found to be far more reactive than sulfonyl fluorides. The chemistry may be used to prepare aliphatic, aromatic, tertiary, secondary, and primary sulfonamides.