Versatile and Sustainable Synthesis of Cyclic Imides from Dicarboxylic Acids and Amines by Nb2O5 as a Base‐Tolerant Heterogeneous Lewis Acid Catalyst

Catalytic condensation of dicarboxylics acid and amines without excess amount of activating reagents is the most atom‐efficient but unprecedented synthetic method of cyclic imides. Here we present the first general catalytic method, proceeding selectively and efficiently in the presence of a commercial Nb₂O₅ as a reusable and base‐tolerant heterogeneous Lewis acid catalyst. The method is effective for the direct synthesis of pharmaceutically or industrially important cyclic imides, such as phensuximide, N‐hydroxyphthalimide (NHPI), and unsubstituted cyclic imides from dicarboxylic acid or anhydrides with amines, hydroxylamine, or ammonia.     

Practical and efficient synthesis of N-halo compounds

A practical and efficient synthesis of N-halo compounds is described. Treatment of primary and secondary amines or amides with sodium hypohalite in the presence of tert-butanol and acetic acid afforded N-halo compounds in 90-100% yield.     

Recent developments in use of heteropolyacids, their salts and polyoxometalates in organic synthesis

Heteropolyacids, their salts and polyoxometalates have been used as catalysts in wide range of organic reactions such as multi components, oxidation, reductions, electrochemical and photochemical reactions. There have been tremendous and continued efforts to modify the catalytic performance of heteropoly acids such as supporting them on MCM, silica gel, etc. In this review, we have attempted to bring some of new applications of heteropolyacids in organic reactions and recent approaches on modifying them, into focus.     

Organoboranes for synthesis : Reaction of organoboranes with representative organic azides. A general stereospecific synthesis of secondary amines and N-substituted aziridines

Reaction of trialkylboranes with organic azides in refluxing xylene, followed by hydrolysis, leads to good yields of secondary amines. This reaction is highly dependent on the steric effects around both boron and the azide moiety. The reaction becomes much slower when the steric bulk of one of the reagents is increased and fails when both are hindered. The dialkylchloroboranes are more reactive than trialkylboranes and provide better yields of the desired secondary amines with a11 azides tested. The alkyldichloroboranes react with organic azides at temperatures between room temperature and 60°C and produce excellent yields of secondary amines. Furthermore, the stereochemistry of the original carbon-boron bond is retained. The mechanism of these reactions is discussed and the reaction applied to the synthesis of N-alkyl- and N-arylaziridines.     

Facile and efficient access to 2,6,9-tri-substituted purines through sequential N9, N2 Mitsunobu reactions

A facile, efficient and mild synthesis of 2,6,9-tri-substituted purines is presented, starting from commercially available 2-amino-6-chloropurine, which employs sequential N9 then N2 Mitsunobu reactions as key steps. Importantly, our synthetic approach to N2-functionalization of the purine nucleus obviates the harsh conditions required by the traditional nucleophilic aromatic substitution of a 2-halo group with primary amines. Benzylic, allylic, propargylic and aliphatic alcohols all coupled in very good to excellent yields in both Mitsunobu reactions. Significantly, excellent chemoselectivity and N9-regioselectivity were observed for the first coupling, and reactions were complete within 15 min at room temperature. Our novel methodology may be readily adapted to furnish N⁹-mono- or N²,N⁹-di-functionalized guanine analogues, and the utility of our protocol is further demonstrated by the efficient synthesis of the CDK inhibitor bohemine.     

Recent advances in chemoselective acylation of amines

N-chemoselective acylation of amines in the presence of competing nucleophiles, like alcohols and thiols, is by no means a simple achievement in organic synthesis and even more difficulties arise when distinctions between primary, secondary, and aromatic amines need to be made. The present digest will review some recent achievements in this field, ranging from transamidation reactions to carboxylic acid derivatives transacylations. In addition, more creative strategies, involving chemoenzymatic reactions and metal-catalyzed acylations and carbonylations, will be discussed in order to furnish a concise view of the state-of-the-art approaches to this synthetic challenge.     

Convenient Synthesis of Benziodazolone: New Reagents for Direct Esterification of Alcohols and Amidation of Amines

Hypervalent iodine heterocycles represent one of the important classes of hypervalent iodine reagents with many applications in organic synthesis. This paper reports a simple and convenient synthesis of benziodazolones by the reaction of readily available iodobenzamides with m-chloroperoxybenzoic acid in acetonitrile at room temperature. The structure of one of these new iodine heterocycles was confirmed by X-ray analysis. In combination with PPh₃ and pyridine, these benziodazolones can smoothly react with alcohols or amines to produce the corresponding esters or amides of 3-chlorobenzoic acid, respectively. It was found that the novel benziodazolone reagent reacts more efficiently than the analogous benziodoxolone reagent in this esterification.     

Heterocyclic group transfer reactions with I(iii) N-HVI reagents: access to N-alkyl(heteroaryl)onium salts via olefin aminolactonization

Pyridinium and related N-alkyl(heteroaryl)onium salts are versatile synthetic intermediates in organic chemistry, with applications ranging from ring functionalizations to provide diverse piperidine scaffolds to their recent emergence as radical precursors in deaminative cross couplings. Despite their ever-expanding applications, methods for their synthesis have seen little innovation, continuing to rely on a limited set of decades old transformations and a limited subset of coupling partners. Herein, we leverage (bis)cationic nitrogen-ligated I(iii) hypervalent iodine reagents, or N-HVIs, as “heterocyclic group transfer reagents” to provide access to a broad scope of N-alkyl(heteroaryl)onium salts via the aminolactonization of alkenoic acids, the first example of engaging an olefin to directly generate these salts. The reactions proceed in excellent yields, under mild conditions, and are capable of incorporating a broad scope of sterically and electronically diverse aromatic heterocycles. The N-HVI reagents can be generated in situ, the products isolated via simple trituration, and subsequent derivatizations demonstrate the power of this platform for diversity-oriented synthesis of 6-membered nitrogen heterocycles.

Complex N-alkyl (heteroaryl)onium salts are accessed via heterocyclic group transfer reactions of N-ligated I(iii) reagents with alkenoic acids. The reactions proceed in excellent yields, under mild conditions, and with broad substrate scope.     

Preparation of Heteroaromatic (Aryl)iodonium Imides as I−N Bond‐Containing Hypervalent Iodine

Hypervalent iodine(III) compounds containing iodine–nitrogen bonds are very attractive amination reagents in organic synthesis. Heteroaromatic (aryl)iodonium imides containing a iodine–nitrogen bond and a hypervalent iodine(III) atom were prepared from heteroarenes, bis(sulfon)imides and (diacetoxyiodo)arenes under mild conditions. These compounds were stable under air and in organic solvents, and could be easily purified by precipitation. X‐ray crystal structure analysis indicated that the structure of N‐pivaloyl indolyl(phenyl)iodonium bis(tosyl)imides and N‐pivaloyl indolyl(2‐butoxyphenyl)iodonium bis(tosyl)imides was a dimer with a T‐shaped geometry at the iodine atom linked to an indole group and a bis(tosyl)imide by a monomer unit. Moreover, the use of substituted iodoarenes facilitated the purification of some of the heteroaromatic (aryl)iodonium imides.     

Titanium-mediated syntheses of cyclopropylamines

The transformations of N,N-dialkylcarboxamides and nitriles with 1,2-dicarbanionic organometallics in situ generated from organomagnesium (Grignard) as well as organozinc reagents in the presence of stoichiometric or substoichiometric (semi-catalytic) quantities of a titanium alkoxide derivative of type XTi(OR)₃ with X=OR, Cl, Me and OR=OiPr, OEt are described. The key step in the transformation of a monocarbanionic into a 1,2-dicarbanionic organotitanium species is a disproportionation of a dialkyltitanium intermediate to form an alkane and a titanium alkene complex which has the reactivity of a titanacyclopropane derivative. The latter are able to undergo insertion of the carbonyl group of an N,N-dialkylcarboxamide or a cyano group to furnish, after ring contraction and hydrolysis, dialkylcyclopropylamines or cyclopropylamines, respectively. The titanium alkene complexes can also undergo ligand exchange with alkenes to afford new titanacyclopropanes, which subsequently react as 1,2-dicarbanionic equivalents. In many cases, these titanium-mediated formations of a wide range of synthetically and/or pharmacologically important cyclopropylamines proceed in good to very good yields (from 20% to 98% for dialkylcyclopropylamines from N,N-dialkylcarboxamides and from 27% to 73% for primary cyclopropylamines from nitriles) and with high chemo- and stereoselectivity. These circumstances in conjunction with the simplicity of the experimental handling and inexpensiveness of the reagents favor these reactions for an ever increasing range of applications in organic synthesis.     

Synthesis of enantiomerically pure 2-(N-aryl,N-alkyl-aminomethyl)aziridines: a new class of ligands for highly enantioselective asymmetric synthesis

A simple and effective synthesis of enantiomerically pure 2-(N-aryl-, N-alkyl-aminomethyl)aziridines from (2S)-N-tritylaziridine-2-carboxylic acid methyl ester has been developed. Treating of this key ester with several primary and secondary amines in the presence of AlMe₃ provided the corresponding chiral N-trityl-2-carboxamides, and their reduction performed with different reagents resulted in the formation of the expected 2-(aminomethyl)aziridines. The choice of reaction conditions allows to either keep or leave the trityl substituent in the product. Such 2-(aminoalkyl)aziridines have shown very high catalytic efficiency in the asymmetric arylation of aldehydes and in other testing asymmetric reactions. On the other hand, homochiral N-trityl-2-carboxamides are interesting building blocks for the synthesis of various biologically active compounds.     

Cesium carbonate as a mediated inorganic base in some organic transformations

Cesium carbonate is a type of alkali carbonate salt having a remarkable number of applications and has been demonstrated to be a mild inorganic base in organic synthesis. It has received much attention for its utility in C, N, O alkylation and arylation reactions. Cesium carbonate not only promotes successful carbonylation of alcohols and carbamination of amines, but also suppresses common side reactions traditionally encountered with other protocols. It is used also in six-membered annulation, intramolecular and intermolecular cyclizations, Suzuki coupling, aza-Henry, nucleophilic substitution, cross coupling and different cycloaddition reactions.     

A new class of fluorescent dyes based on 1,3-benzodioxole and [1,3]-dioxolo[4.5-f]benzodioxole

We report on synthesis and photophysical properties of a new class of fluorescent dyes. They are characterized by large Stokes-shifts, long fluorescence lifetimes in organic solvents and a pronounced dependency of the fluorescence lifetime on the solvent polarity. Also worthy of note is the high bleaching stability. To provide access to biochemical and medical applications a series of derivatives were prepared, which exhibit specific reactivity towards different biologically relevant functional groups (carboxylic acids, amines, maleimides, N-hydroxysuccinimide esters). Furthermore, two alkynes were prepared, which could be used in ‘Click’ chemistry.     

Approaches to primary tert-alkyl amines as building blocks

Primary tert-alkyl amines include analogues of amantadine, a fragment commonly linked to pharmacophoric groups to enhance biological activity. The preparation of primary tert-alkyl amines is considered to be a difficult problem. Four synthetic procedures, some of which have been previously reported for the synthesis of amines with primary (RCH₂NH₂) or secondary (RR'CHNH₂) alkyl and/or aryl groups, were tested for the synthesis of primary tert-alkyl amines (RR′R″CNH₂) in aliphatic series including adamantane adducts. These procedures included the formation and reduction of tert-alkyl azides, the Ritter reaction in standard and modified conditions, the addition of organometallic reagents to N-tert-butyl sulfinyl ketimines and one-pot reactions between nitriles and organometallic reagents in the presence of a Lewis acid, Τi(iPrO)₄ or CeCl_3. These synthetic routes are unexplored for primary tert-alkyl amines. Studies on the synthetic routes for primary tert-alkyl amines are currently lacking. The reaction conditions and substrate limitations were studied for each procedure, with the first procedure being the most general and applicable also for compounds bearing bulky adducts.     

Iterative addition of carbon nucleophiles to N,N-dialkyl carboxamides for synthesis of α-tertiary amines

A protocol for the synthesis of α-tertiary amines was developed by iterative addition of carbon nucleophiles to N,N-dialkyl carboxamides. Nucleophilic 1,2-addition of organolithium reagents to carboxamides forms anionic tetrahedral carbinolamine (hemiaminal) intermediates, which are subsequently treated with bromotrimethylsilane (Me₃SiBr) followed by organomagnesium (Grignard) reagents, organolithium reagents or tetrabutylammonium cyanide, affording α-tertiary amines. Employment of (trimethylsilyl)methylmagnesium bromide as the 2^nd nucleophile allowed for aza-Peterson olefination of the resulting α-tertiary (trimethylsilyl)methylamines with acidic work-up, resulting in the formation of 1,1-diarylethylenes.

We herein report a concise protocol for iterative addition of carbon nucleophiles to N,N-dialkyl carboxamides for the synthesis of α-tertiary amines.     

1,3-phosphorus zwitterions with cyano-group at anion center

This review focuses on synthesis and properties of 1,3-phosphorus-containing zwitterions that have at the anionic center cyano-group and either ester (type one) or carbamate (type two) moieties. Zwitterions belonging to type one possess dual nucleophile reactivity, i.e., depending on the properties of the electrophiles they may form either C- or N-derivatives. Zwitterions belonging to type two possess triple nucleophile reactivity. In their reactions with electrophiles, they may form even three types of derivatives, i.e., at the C-, O- or N-atoms. This nucleophile multiplicity is not just interesting from the theoretical standpoint but may also open the ways to the synthesis of new compounds that can be important from the practical standpoint, such as physiologically active compounds, catalysts, analytical reagents, etc.     

An Overview of Recent Advances in the Synthesis of Organic Unsymmetrical Disulfides

Organic unsymmetrical disulfides have been extensively applied in various academic and industrial fields including intermediates in organic synthesis, agriculture, and food science, natural materials, biochemistry, pharmaceutical and medicine chemistry, polymers, material engineering, etc. They play a crucial role in the fabrication of various biological active sulfur heterocycles. Due to broad and extensive applications, many methods have been developed for the synthesis of unsymmetrical S−S and efforts have been made to improve some issues such as cost, energy efficiency, green chemistry, avoid or minimizing waste generation. Several outstanding review articles have been previously published highlighting the advances of S−S bond formation, in general, using various reagents under different conditions in the absence or presence of oxidants/catalysts. In 2020, a review paper was published by our group focusing on recent developments since 2014 in the synthesis of organic symmetrical disulfides. However, investigations on new catalytic methods are being regularly reported and new types of unsymmetrical disulfides are synthesized. The present overview has attempted to systematically summarize recent advances in the process of unsymmetrical S−S bond formation with a major focus since 2010, highlighting mechanistic considerations, substrate scope, advantages, and limitations. The patents are not studied in this overview.     

Synthesis and application of <Emphasis Type="Italic">N</Emphasis>-hydroxy(tetrahydrofuran-2-yl)amines

Data on synthesis, reactivity and bioactivity of N-hydroxy(tetrahydrofuran-2-yl)amines were discussed in the present review. General approaches to chiral N-glycosylhydroxylamines based on reactions of hydroxylamine with cyclic five-membered hemiacetals or dihydrofurans as well as reactions of tetrahydrofuran-containing nitrones with nucleophiles were systematized. The application of N-hydroxy(tetrahydrofuran-2-yl)amines in the synthesis of chiral heterocycles, aminophosphonic acids, N-hydroxypropargylamines, as well as natural compounds (for example, sieboldin A), pharmaceuticals (Zileuton) and their analogs was demonstrated. It was found that depending on substituents, N-hydroxy(tetrahydrofuran-2-yl)-amines can act as lipoxygenase inhibitors, and show antioxidant, antitumor, antibacterial, and other types of activities.     

Development of a new linker for the solid-phase synthesis of N-hydroxylated and N-methylated secondary amines

Merrifield resin was modified by the introduction of an ortho-nitrophenylethanal group that served as a linker moiety to attach amines to the resin by reductive amination. Resin-bound tertiary amines were shown to be readily transferred into the respective liberated N-hydroxylated or N-methylated derivatives by either an oxidation/Cope elimination or a permethylation/Hofmann elimination protocol. With these two divergent liberation/derivatization options, the new resin offers new flexibility in the solid phase synthesis of N-modified secondary amines, for instance in spider toxin synthesis.     

N-Dealkylation of Amines

N-dealkylation, the removal of an N-alkyl group from an amine, is an important chemical transformation which provides routes for the synthesis of a wide range of pharmaceuticals, agrochemicals, bulk and fine chemicals. N-dealkylation of amines is also an important in vivo metabolic pathway in the metabolism of xenobiotics. Identification and synthesis of drug metabolites such as N-dealkylated metabolites are necessary throughout all phases of drug development studies. In this review, different approaches for the N-dealkylation of amines including chemical, catalytic, electrochemical, photochemical and enzymatic methods will be discussed.