N-acyliminium Ion Research Articles

Constructing Saturated Guanidinum Heterocycles by Cycloaddition of N-Amidinyliminium Ions with Indoles.

We report that structurally complex guanidinium heterocycles can be prepared in one step by regio- and stereoselective [4 + 2]-cycloadditions of N-amidinyliminium ions with indoles or benzothiophene. In contrast to reactions of these heterodienes with alkenes, density functional theory (DFT) calculations show that these cycloadditions take place in a concerted asynchronous fashion. The [4 + 2]-cycloaddition of N-amidinyliminium ions (1,3-diaza-1,3-dienes) with indoles and benzothiophene are distinctive, as related [4 + 2]-cycloadditions of N-acyliminium ions (1-oxa-3-aza-1,3-dienes) are apparently unknown.

Application of Design of Experiments (DoE) Approach for the Optimization of Phase-transfer Catalyzed Biginelli Dihydropyrimidinone (DHPM) Synthesis

The conventional Biginelli synthesis is more cumbersome and produces lower yields. Several improved methods are reported in the literature to replace the Biginelli catalyst. The design of biocompatible organic transformation is a major concern and a versatile greener procedure to construct Biginelli analogs is in great demand. Factorial design guided, energy-efficient, and versatile synthesis of 3,4-dihydropyrimidin-2-(1H)-ones (DHPM) was developed. One-factor-at-a time (OFAT) and factorial design (2<sup>3</sup>) studies were utilized for screening the independent variables. The optimum levels of potential variables (benzyl-n-triethylammonium chloride (BTEAC) and glacial acetic acid) were determined through studies. The factorial design (3<sup>2</sup>) analysis inferred the use of BTEAC (10.25 mol%) and glacial acetic acid (7.6 ml) as optimal for the 60 min condensation. Thirteen new 3,4- dihydropyrimidine-2-(1H)-one (DHPM) analogs were synthesized using optimized reaction conditions. The quaternary ammonium ion of BTEAC stabilizes the polarization of carbonyl group in aryl aldehydes and enolizable ketone (alkyl acetoacetate) to facilitate the cyclocondensation, in order to produce DHPMs through N-acyliminium ion and Michael adducts formation. The biocompatible strategy, simple product isolation (non-chromatographic method), and good to excellent yields are attractive features of this new protocol. Hence, the newly developed methodology is superior to the literature methods.

New approaches towards the synthesis of 1,2,3,4-tetrahydro isoquinoline-3-phosphonic acid (TicP)

Two new strategies for the efficient synthesis of racemic 1,2,3,4-tetrahydroisoquinoline-3-phosphonic acid (TicP) (±)-2 have been developed. The first strategy involves the electron-transfer reduction of the easily obtained α,β-dehydro phosphonophenylalanine followed by a Pictet-Spengler cyclization. The second strategy involves a radical decarboxylation-phosphorylation reaction on 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic). In both strategies, the highly electrophilic N-acyliminium ion is formed as a key intermediate, and the target compound is obtained in good yield using mild reaction conditions and readily available starting materials, complementing existing methodologies and contributing to the easy accessibility of (±)-2 for further research.

Synthesis of dihydro-[1,3]oxazino[4,3-a] isoindole and tetrahydroisoquinoline through Cu(OTf)2-catalyzed reactions of N-acyliminium ions with ynamides

An efficient approach to access functionalized dihydro-[1,3]oxazino[4,3-a] isoindole and tetrahydroisoquinoline skeletons has been developed through the addition-cyclization process of ynamides 8 with N-acyliminium ions generated from N,O-acetals 6,7. The reactions were conducted under the catalysis of Cu(OTf)2, and a number of functionalized dihydro-[1,3]oxazino[4,3-a] isoindoles 9a-9y and tetrahydroisoquinolines 10a-10g, 11a-11p were generated in 48–98% yields. When chiral ynamides 8n-8u were used, optically pure products 11a-11p could be obtained with good to excellent yields and diastereoselectivities.

An Intramolecular Schmidt Reaction of δ-Azido N-Acylbenzotriazoles.

A Lewis acid promoted intramolecular Schmidt reaction of N-acylbenzotriazoles with alkyl azides was designed and realized. The benzotriazole was not only employed as an efficient activator for initiating the Schmidt rearrangement but also used as a powerful terminator for the subsequent nucleophilic trapping of the isocyanate ion and/or N-acyliminium ion from the rearrangement. Thirteen δ-azido N-acylbenzotriazoles were investigated, and the conversion afforded the desired benzotriazole-1-carboxamides and lactams with good to excellent yields.

Synthesis of spirocyclic heterocycles from α,β-unsaturated N-acyliminium ions.

The reactions of α,β-unsaturated N-acyliminium ions, generated in situ from 4(S)-O-substitutedhydroxy-5-hydroxy-5-vinyl-N-alkylpyrrolidin-2-ones, with allylsilanes and indoles leading to the formation of spirocyclic heterocycles, are reported. Six single crystal X-ray structures and extensive 2D NMR experiments confirmed the structures and stereochemistries of these products. In addition, computational studies provided mechanistic insights and an understanding of the stereochemical outcomes of these reactions.

De Novo Approach to Izidines via A Gold-Catalyzed Hydroamination–N-acyliminium Ion Cyclization of Acyclic Ynamides

De Novo Approach to Izidines via A Gold-Catalyzed Hydroamination–N-acyliminium Ion Cyclization of Acyclic Ynamides

Synthesis of pyrimido[2,1-a]isoindolone and isoindolo[2,1-a]quinazolinone via intramolecular aza-Prins type reaction.

A novel aza-Prins type cyclization reaction involving N-acyliminium ions and amides is reported for the synthesis of tetrahydropyrimido[2,1-a]isoindole-2,6-dione and 6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione derivatives in excellent yields. The strategy features inexpensive reagents, mild reaction conditions, and metal-free synthesis of N-heterocyclic frameworks. Further, post-synthetic modification results in the unprecedented formation of its triazole, tetracyclic diazacyclopenta[def]phenanthrene-1,4(9a1H)-dione and carbonyl derivatives.

Synthesis of aminal-type Lilium candidum alkaloids and lilaline; determination of their relative configuration by the concerted use of NMR spectroscopy and DFT conformational analysis

Abstract We hereby report the synthesis of six racemic alkaloids isolated from Lilium candidum L. Their common structural feature is a five-membered lactam ring which is, in the case of the flavonoid alkaloid lilaline, attached to the molecule’s aromatic core, while in the case of the other five compounds, it is connected to the nitrogen atom of a pyrrolinone ring by an aminal function. The syntheses of these natural products were achieved via Mannich-type alkylations through cyclic N-acyliminium ions as intermediates. Besides the synthesis, the so far unexplored stereochemistry of these natural products was determined by a combination of NMR-based proton–proton distance measurements and theoretical conformational analyses carried out at the DFT level.

Synthesis and X-ray diffraction structure of a novel steroid-pyrrolidinoisoquinoline alkaloid hybrid

A novel steroid – pyrrolidinoisoquinoline alkaloid hybrid has been successfully synthesized by Diels-Alder reaction N-acyliminium ion cyclization sequence.

Tertiary Enamide-Promoted Diastereoselective Domino: N-Acyliminium Ion Trapping and Nazarov Cyclization.

N-Acyliminium ions generated from enamidyl vinyl ketones provided cyclopentenoid-fused diazepines diastereoselectively using BF3·Et2O in one pot through a domino N-acyliminium ion trapping/Nazarov reaction, simultaneously generating three new stereogenic centers. The particular structural design of the cross-conjugated dienone dictates the torquoselectivity observed in this polarized Nazarov reaction. Various N-bridgehead polycyclic scaffolds of putative pharmacological interest were obtained. Cyclic voltammetry was used to support the preferred reaction sequence within this domino reaction.

Cis-Dihydroxylated α-Trifluoromethylated N,O-Acetal from l-Tartaric Acid: Synthesis of Tetrasubstituted Stereocenter via Diastereoselective Pictet-Spengler Cyclization of N-Acyliminium Ions.

The synthesis of cyclic, chiral α-trifluoromethylated N,O-acetals having a protected cis-diol moiety has been readily achieved in two steps from a known bis-Weinreb amide derived from l-tartaric acid. The reaction of O-acetyl analogues of these N,O-acetals with triflic acid in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) at 0 °C generated in situ the corresponding electrophilic α-trifluoromethyl N-acyliminium ions that undergo Pictet-Spengler-type cyclizations. After only 10 min of reaction, the original enantiopure aza-tricyclic scaffolds bearing a trifluoromethyl substituent at the bridgehead position were obtained with diastereoselectivities ranging from 75:25 to 97:3.

N-Acyliminium Ion Chemistry: Improving the Access to Unsaturated γ-Lactams and Their N-α-Methoxylated Derivatives: Application to an Expeditive Synthesis of (±)-Crispine A

An improved synthesis of unsaturated γ-lactams by condensation of various primary amines with 2,5-dimethoxy-2,5-dihydrofuran is described. A modified mechanism for this reaction is suggested. Synthesis of their N-α-methoxylated derivatives, as N-acyliminium ion precursors, is also reported. Finally, a short synthesis of (±)-crispine A is presented as an illustrative application.

Experimental and Computational Studies Unraveling the Peculiarity of Enolizable Oxoesters in the Organocatalyzed Mannich-Type Addition to Cyclic N-Acyl Iminium Ions.

γ− and δ-Oxoesters are easily available starting materials that have been sparingly used in some organocatalyzed reactions proceeding with a high enantioselectivity. In our experimentation we found that the use of these compounds as the enolizable (nucleophilic) component in organocatalyzed Mannich-type reactions using in situ-generated cyclic N-acyl iminium ions gave low diastereoselectivity and low to moderate values of enantioselectivity. This significant drop of facial selectivity with respect to simple aliphatic aldehydes has been rationalized by means of density functional theory (DFT) calculations.

Synthesis of Functionalized Isoindolinones via Calcium Catalyzed Generation and Trapping of N-Acyliminium Ions.

Herein we report our full investigation into the calcium catalyzed generation and trapping of N-acyliminium ions from readily available 3-hydroxyisoindolinones. We have successfully employed a range of traditional nucleophiles including carbon, nitrogen, and sulfur containing reactive partners. The reaction is tolerant to a wide range of functionalities and provides high value scaffolds in good to excellent yields.

Synthetic Studies Towards Spirocyclic Imine Marine Toxins Using N-Acyl Iminium Ions as Dienophiles in Diels–Alder Reactions

Cyclic imine marine toxins have attracted considerable attention from the synthetic community in the past two decades due to their unique chemical structures and clinically relevant biological activities. This review presents recent efforts of our group in the development of various strategies to efficiently construct the common spirocyclic imine fragments of the cyclic imine toxins. In particular, the use of α,β-unsaturated N-acyl iminium ion dienophiles in Diels–Alder reactions are highlighted, whereby direct access to spirocyclic imine motifs was obtained and important mechanistic details were discovered. Alternative approaches to spirocyclic imine systems involving hydroamination of amino alkynes are also summarized. One such approach led to serendipitous access to N-vinyl amide products, while our most recently ­reported approach involving an intermolecular Diels–Alder/cross-­coupling sequence using novel 2-bromo-1,3-butadienes to access 5,6-spirocyclic imines is also discussed. Additionally, the development of a novel method to construct another challenging motif present in the portimines is also introduced.1 Introduction2 Strategies towards the Spirocyclic Imine Fragment of Cyclic Imine Toxins2.1 Diels–Alder Cycloadditions of α,β-Unsaturated N-Acyl Iminium Dienophiles2.2 Early Studies Using in situ-Generated Iminium Ion Dienophiles2.3 Use of More Stable Iminium Ion Dienophiles for Diels–Alder Reactions2.4 Other Notable Strategies towards Spirocyclic Imines2.5 Recent Efforts towards the 5,6-Spirocyclic Imine Marine Toxin Portimine A2.6 Construction of Another Challenging Motif of Portimine A3 Conclusion and Future Perspectives

Anodic Oxidation for the Stereoselective Synthesis of Heterocycles.

Stereodefined aliphatic heterocycles are one of the fundamental structural motifs observed in natural products and biologically active compounds. Various strategies for the synthesis of these building blocks based on transition metal catalysis, organocatalysis, and noncatalytic conditions have been developed. Although electrosynthesis has also been utilized for the functionalization of aliphatic heterocycles, stereoselective transformations under electrochemical conditions are still a challenging field in electroorganic chemistry. This Account consists of four main topics related to our recent efforts on the diastereo- and/or enantioselective synthesis of aliphatic heterocycles, especially N-heterocycles, using anodic oxidations as key steps. The first topic is the development of stereoselective synthetic methods for multisubstituted piperidines and pyrrolidines from anodically prepared α-methoxy cyclic amines. Our strategies were based primarily on N-acyliminium ion chemistry, and the key electrochemical transformations were diastereoselective anodic methoxylation, diastereoselective arylation, and anodic deallylative methoxylation. Furthermore, we found a unique property of the N-cyano protecting group that enabled the electrochemical α-methoxylation of α-substituted cyclic amines. The second topic of investigation is memory of chirality in electrochemical decarboxylative methoxylation. We observed that the electrochemical decarboxylative methoxylation of oxazolidine and thiazolidine derivatives with the appropriate N-protecting group occurred in a stereospecific manner even though the reaction proceeded through an sp2 planar carbon center. Our findings demonstrated the first example of memory of chirality in N-acyliminium ion chemistry. The third topic is the synthesis of chiral azabicyclo-N-oxyls and their application to chiral organocatalysis in the electrochemical oxidative kinetic resolution of secondary alcohols. The final topic is stereoselective transformations utilizing anodically generated halogen cations. We investigated the oxidative kinetic resolution of amino alcohol derivatives using anodically generated bromo cations. We also developed an intramolecular C-C bond formation of keto amides, a diastereoselective bromoiminolactonization of α-allyl malonamides, and an oxidative ring expansion reaction of allyl alcohols. It is noteworthy that most of the electrochemical reactions were performed in undivided cells under constant-current conditions, which avoided a complicated reaction setup and was beneficial for a large-scale reaction. In addition, we developed some enantioselective electrochemical transformations that are still challenges in electroorganic chemistry. We hope that our research will contribute to the further development of diastereo- and/or enantioselective transformations and the construction of valuable heterocyclic compounds using an electrochemical approach.

Palladium-Catalyzed Hydrocarbonylative Cyclization Enabled by Formal Insertion of Aromatic C═N Bonds into Pd-Acyl Bonds.

An efficient new formal insertion strategy via combination of reductive elimination and oxidative addition sequence was reported, in which the transient N-acyliminium ions formed via hydrocarbonylation function as key intermediates. This strategy has enabled a novel palladium-catalyzed hydrocarbonylative cyclization of azaarene-tethered alkenes or dienes via sequential insertion of a C═C bond, CO, and a C═N bond into palladium-hydride bonds. This method provides a new and highly efficient synthetic approach to quinolizinones and its derivatives with extended π-conjugated systems, possessing tunable emission wavelengths and good photoluminescence capabilities.

Synthesis of 5-Substituted 2-Pyrrolidinones by Coupling of Organozinc Reagents with Cyclic N-Acyliminium Ions

A coupling reaction between cyclic N-acyliminium ions with organozinc reagents is described. The cyclic N-acyliminium ions, generated in situ from N-substituted-5-hydroxy-2-pyrrolidinones by treatment with boron trifluoride–diethyl ether complex or titanium tetrachloride, are trapped by the organozinc reagent, which is formed from an alkyl bromide in the presence of zinc in the same reaction medium. The N-substituted-5-allyl-2-pyrrolidinones generated using this method serve as versatile intermediates for the synthesis of azabicyclic systems with indolizidine and pyrroloazepinolizidine cores.

Intramolecular Mannich and Michael Annulation Reactions of Lactam Derivatives Bearing Enals To Afford Bicyclic N-Heterocycles.

Acid-catalyzed intramolecular vinylogous Mannich reactions and intramolecular Michael reactions affording pyrrolizinone-fused N-heterocycles from hydroxylactam derivatives bearing enals have been developed. Depending on the substituent on the hydroxylactam, the enal moiety acted either as a nucleophile (i.e., as an enol/enolate) or as an electrophile to react with the N-acyliminium ion or enamide generated from the hydroxylactam moiety, respectively. The reactions were demonstrated in the construction of fused N-heterocycles with 5- to 8-membered rings.