Cyclization Sequence Research Articles

The [3+2] Annulation of CF3-Ketimines by Re Catalysis: Access to CF3-Containing Amino Heterocycles and Polyamides.

SummaryTransition metal catalyzed [3 + 2] annulation of imines with double bonds via directed C-H activation offers a direct access to amino cyclic motifs. However, owing to weak coordination and steric hindrance, trifluoromethylated ketimines have been an unaddressed challenge for TM-catalyzed annulations. Here, a rhenium-catalyzed [3 + 2] annulation of trifluoromethylated ketimines with isocyanates via C(sp2)-H activation has been disclosed. This approach provides an efficient platform for rapid access to a privileged library of CF3-containing iminoisoindolinones and polyamides by utilizing challenging CF3-ketimines as the annulation component. The capability of gram scale synthesis, the post-functionalization of the cyclization adduct, the derivation of complex natural molecules and the facile synthesis of polyamides highlight a diversity of synthetic potential of the current methodology.

Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 3: Development of a One-Pot Formylation–Cyclization Sequence to the Diaminopyrimidine Core

The development of a safe, robust, and efficient manufacturing route for the synthesis of diaminopyrimidine 1, a key intermediate to gefapixant citrate (MK-7264), is described. A full mechanistic u...

Short Synthesis of Alkaloid (-)-205B.

The alkaloid (-)-205B has in the past served as a testing ground for novel approaches in nitrogen heterocycle synthesis. We herein report a highly straightforward synthesis of (-)-205B in just six synthetic steps, making it the shortest route currently known. The central steps of our approach are a vinylogous Mukaiyama-Mannich reaction to establish the first two stereogenic centers with excellent diastereo- and enantiocontrol followed by zinc-mediated Barbier allylation to set the third chiral center with high substrate control. Upon cyclization of the Barbier product to lactam and enolate methylation, the third ring is annulated by a one-pot sequence of lactam reduction and aza-Prins cyclization to directly set the final stereogenic center with complete cis-stereoselectivity. As the iminium ion undergoing the aza-Prins cyclization rapidly isomerized to a planar enamine intermediate, the alkaloid was eventually obtained as a 1:1 mixture of C6 diastereomers, which were readily separated by chromatography. Yet, the target natural product was obtained isomerically pure in an overall yield of 12%, which compares favorably with all previous syntheses.

Intermolecular Dearomatization of Naphthalene Derivatives by Photoredox‐Catalyzed 1,2‐Hydroalkylation

AbstractAn intermolecular hydroalkylative dearomatization of naphthalenes with commercially available α‐amino acids is achieved via visible‐light photoredox catalysis. With an organic photocatalyst, a series of multi‐substituted 1,2‐dihydronaphthalenes are obtained in good‐to‐excellent yields. Intriguingly, by tuning the substituents at the C2 position of naphthalenes, formal dearomative [3+2] cycloadditions occur exclusively via a hydroalkylative dearomatization–cyclization sequence. This overall redox‐neutral method features mild reaction conditions, good tolerance of functionalities, and operational simplicity. Diverse downstream elaborations of the products are demonstrated. Preliminary mechanistic studies suggest the involvement of a radical–radical coupling pathway.

Metal‐Free Oxidative [5+1] Cyclization of 1,5‐Enynes for the Synthesis of Pyrazine 1‐Oxide

AbstractA chemo‐selective nitrosylation of 1,5‐enynes via a sequence of NO radical incorporation and intramolecular radical cyclization was reported. The formation of two C−N bonds and one C−O bond make this [5+1] cycloaddition reaction an efficient approach to synthesize pyrazine 1‐oxides in moderate to good yields. Metal‐free, short reaction time and mild conditions render this strategy more practical, eco‐friendly and convenient. Synthetic utility of this protocol is highlighted by scaffolds diversification.magnified image

Triflic acid mediated sequential cyclization of ortho-alkynylarylesters with ammonium acetate

A triflic acid (TfOH) mediated sequential cyclization of ortho-alkynylarylesters and ammonium acetate (NH4OAc) was reported. The reaction took place via a Brønsted acid-mediated intramolecular cyclization of ortho-alkynylarylesters followed by an ammonium acetate participated substitution reaction, forming isoquinolin-1-ones as the major products. Different from most of the known synthetic methods of isoquinolin-1-ones, no metal catalyst was required in the reported reaction. The regioisomers – isoindolin-1-ones were obtained together with isoquinolin-1-ones in a few cases. The intermediate compounds – isochromen-1-ones and isobenzofuran-1-ones were also isolated. The interconversion experiments showed that the regioisomers formed during the Brønsted acid induced intramolecular cyclization of ortho-alkynylarylesters. A natural product – ruprechstyril was prepared in a moderate yield employing the new method.

One-pot and regioselective synthesis of functionalized γ-lactams via a metal-free sequential Ugi 4CR/Intramolecular 5-exo-dig cyclization reaction

A new one-pot and regioselective synthesis of functionalized γ-lactams by a metal-free Ugi 4CR/intramolecular 5-exo-dig cyclization sequence under mild conditions has been developed. The reaction of propenoic acids, aldehydes, amines, and isocyanides produced γ-lactams regioselectively in 72–89% yields via sequential Ugi 4CR/intramolecular 5-exo-dig cyclization reaction in the presence of Cs2CO3.

Catalyst‐Free Preparation of Perfluoroalkyl‐Phosphoryl Substituted Furans from 1‐Perfluoroalkyl 1,3‐Diketones in Two Steps

AbstractA two‐step catalyst‐free procedure for the construction of 3‐perfluoroalkyl‐2‐(phosphoryl)methyl furans from commercially available 1‐perfluoroalkyl 1,3‐diketones is reported. Propargylic alcohols, prepared by direct alkynylation of the diketones, react with PCl3 via [2,3]‐sigmatropic rearrangement – enolate cyclization sequence, leading to multifunctional furans. The reaction mechanism is supported by DFT study. In addition, the bioactivity modifying effect of phosphoryl group on 3‐perfluoroalkyl furans is depicted.magnified image

Ultrasonic promoted synthesis of 1,6-naphthyridine derivatives catalyzed by solid acid in water

An efficient and highly eco-friendly approach to poly-substituted 1,6-naphthyridine derivatives with good to excellent yield has been reported using simple and readily available 4-aminopyridinone, aromatic aldehyde or isatin, and 1,3-cyclohexanedione as substrates. The method features low-cost and readily accessible starting materials, green ultrasonic irradiation in water, recycle heterogeneous solid acid catalyst, broad substrate scope as well as simple one-pot operation make this strategy highly attractive. Mechanistic studies indicate that this transformation involves Knoevenagel condensation, Michael addition, and cyclization sequence.

Efficient C-H Amination Catalysis Using Nickel-Dipyrrin Complexes.

A dipyrrin-supported nickel catalyst (AdFL)Ni(py) (AdFL: 1,9-di(1-adamantyl)-5-perfluorophenyldipyrrin; py: pyridine) displays productive intramolecular C-H bond amination to afford N-heterocyclic products using aliphatic azide substrates. The catalytic amination conditions are mild, requiring 0.1-2 mol% catalyst loading and operational at room temperature. The scope of C-H bond substrates was explored and benzylic, tertiary, secondary, and primary C-H bonds are successfully aminated. The amination chemoselectivity was examined using substrates featuring multiple activatable C-H bonds. Uniformly, the catalyst showcases high chemoselectivity favoring C-H bonds with lower bond dissociation energy as well as a wide range of functional group tolerance (e.g., ethers, halides, thioetheres, esters, etc.). Sequential cyclization of substrates with ester groups could be achieved, providing facile preparation of an indolizidine framework commonly found in a variety of alkaloids. The amination cyclization reaction mechanism was examined employing nuclear magnetic resonance (NMR) spectroscopy to determine the reaction kinetic profile. A large, primary intermolecular kinetic isotope effect (KIE = 31.9 ± 1.0) suggests H-atom abstraction (HAA) is the rate-determining step, indicative of H-atom tunneling being operative. The reaction rate has first order dependence in the catalyst and zeroth order in substrate, consistent with the resting state of the catalyst as the corresponding nickel iminyl radical. The presence of the nickel iminyl was determined by multinuclear NMR spectroscopy observed during catalysis. The activation parameters (ΔH‡ = 13.4 ± 0.5 kcal/mol; ΔS‡= -24.3 ± 1.7 cal/mol·K) were measured using Eyring analysis, implying a highly ordered transition state during the HAA step. The proposed mechanism of rapid iminyl formation, rate-determining HAA, and subsequent radical recombination was corroborated by intramolecular isotope labeling experiments and theoretical calculations.

Facile Synthesis of Xanthenesdiones and Acridinediones through TEMPO/CuCl2 Catalyzed Aerobic Oxidation of Benzyl Alcohols and Cyclization with Cyclohexane-1,3-Dicarbonyl Compounds

A series of xanthenediones, 3 were synthesized from benzyl alcohols, 1 via TEMPO/CuCl2 catalyzed aerobic oxidation, and sequential cyclization with cyclohexane-1,3-dicarbonyl compounds has been achieved. Similarly, the acridine-diones, 5 were obtained using a similar strategy from various benzyl alcohols. The strategy offers a simple experimental procedure, ease of access, within short reaction period, without the use of any hazardous solvents, and expensive chemicals.

A simple method for the rapid synthesis of 2-amino-7,7-dimethyl-5-oxo-1,4-diaryl-hexahydroquinoline-3-carboxamide derivatives

Simple synthesis of oxoquinoline carboxamide derivatives via one-pot, multi-component reaction of enaminones derived from the addition of dimedone to various anilines with aromatic aldehydes and cyanoacetamide is described. Optimal reaction conditions for the synthesis of products were obtained, when EtOH/H2O (1:1) was used as the solvent at 80 °C, in the presence of piperidine as the catalyst. The reactions are completed within 5–25 min, in good to high yields (74–85%). This protocol involves Michael reaction, imine-enamine tautomerization, and cyclization sequences. The structures of products were deduced from their IR, mass, 1H NMR, and 13C NMR spectra. This method includes some important aspects including simple operation under mild conditions, easy accessibility of reactants, workup procedure, high atom economy, and the use of ethanol/water as a green media.

An Efficient Strategy for the Synthesis of 1,6-Naphthyridine-2,5-dione Derivatives under Ultrasound Irradiation

A flexible and efficient three-component reaction has been established for the synthesis of bioactive 1,6-naphthyridine-2,5-diones by using low-cost and readily accessible aminopyridinones, aromatic aldehydes, and Meldrum’s acid as starting materials. The main advantage of this synthetic method is that the yields of the resulting 1,6-naphthyridine-2,5-dione derivatives under ultrasound irradiation in water with acetic acid as catalyst are higher than those from the classical-heating method. The probable reaction mechanism indicates that the process involves a Knoevenagel condensation, Michael addition, and cyclization sequence.

Synthesis and cytotoxic effects on HeLa cervical cancer cells of (E)-2-aroyl-4-(4-fluorobenzylidene)-5-oxopyrrolidine

Seven ( E)-2-aroyl-4-(4-fluorobenzylidene)-5-oxopyrrolidines were synthesized via a tandem Ugi 4CC/SN cyclization sequence starting from a Baylis-Hillman-derived acid, primary amines, arylglyoxals, and isocyanides in one pot. In addition, the cytotoxicity of these compounds on the cervical cancer cell line HeLa was studied by MTT assay. The results showed that most of the compounds could inhibit the proliferation of HeLa cells significantly.

Sequential One-Pot Vilsmeier-Haack and Organocatalyzed Mannich Cyclizations to Functionalized Benzoindolizidines and Benzoquinolizidines.

The development of new one-pot sequential cyclizations involving a Vilsmeier-Haack reaction followed by an organocatalyzed Mannich reaction is reported. This synthetic strategy gives access to functionalized indolizidines and quinolizidines in one operation from readily synthesized precursors. Yields and diastereoselectivities are good to excellent when formamides are used to trigger the key step, bearing either an electron-rich aryl or a pyrrole as the nucleophilic partner in the first cyclization.

Direct Propargylation of ortho-Quinone Methides with Alkynyl Zinc Reagents: An Application to the One-Pot Synthesis of 2,3-Disubstituted Benzofurans

A transition-metal-free propargylation of ortho-quinone methides (o-QMs) with alkynyl zinc reagents was achieved. A conjugate alkynylation of an o-QM and subsequent cyclization sequence in the presence of KOt-Bu for the synthesis of 2,3-disubstituted benzofurans in one pot was developed. This efficient strategy exhibits good functional-group compatibility and gives moderate to good yields. The present reaction might serve as an attractive method for the synthesis of polysubstituted benzofurans.

Frontispiece: Enantioselective Total Synthesis and Absolute Configuration Assignment of (+)‐Tronocarpine Enabled by an Asymmetric Michael/Aldol Reaction

Natural Product Synthesis In their Communication on page 3834, F.-S. Han et al. report the asymmetric total synthesis and absolute configuration determination of (+)-tronocarpine. The [6.5.7.6.6] pentacyclic core was constructed by using a sequential cyclization strategy.

Enantioselective Total Synthesis and Absolute Configuration Assignment of (+)‐Tronocarpine Enabled by an Asymmetric Michael/Aldol Reaction

AbstractWe present the first asymmetric total synthesis and absolute configuration determination of (+)‐tronocarpine. The [6.5.7.6.6] pentacyclic core was constructed at an early stage by using a sequential cyclization strategy through a newly developed catalytic asymmetric Michael/aldol cascade to build the aza[3.3.1]‐bridged cycle and a tandem reduction/hemiamidation procedure to assemble the seven‐membered lactam. The side‐chain functionalities were incorporated at a late stage by several appropriately orchestrated manipulations under mild conditions. The synthesis of enantiomerically pure (+)‐tronocarpine was achieved through a 20‐step longest linear sequence from tryptamine.

Enantioselective Total Synthesis and Absolute Configuration Assignment of (+)-Tronocarpine Enabled by an Asymmetric Michael/Aldol Reaction.

We present the first asymmetric total synthesis and absolute configuration determination of (+)-tronocarpine. The [6.5.7.6.6] pentacyclic core was constructed at an early stage by using a sequential cyclization strategy through a newly developed catalytic asymmetric Michael/aldol cascade to build the aza[3.3.1]-bridged cycle and a tandem reduction/hemiamidation procedure to assemble the seven-membered lactam. The side-chain functionalities were incorporated at a late stage by several appropriately orchestrated manipulations under mild conditions. The synthesis of enantiomerically pure (+)-tronocarpine was achieved through a 20-step longest linear sequence from tryptamine.

Syntheses of cis- and trans-Jamtine and Their N-Oxides via a Benzyl Configuration-Inversion Approach

A novel synthesis of the tetrahydroisoquinoline alkaloid jamtine and its epimer is reported. The synthetic strategy hinges on a one-pot conjugate reduction/Robinson cyclization sequence and an efficient benzyl configuration inversion by an oxidation/reduction approach. The N-oxide derivatives of the jamtine isomers were also synthesized and identified by X-ray crystallographic analysis. Additionally, a density functional theory calculation for the four possible N-oxide structures was exploited to gain further insight into the structure of the natural product in comparison to those of the synthetic N-oxides, because the NMR data of the synthetic derivatives did not match those reported for natural jamtine N-oxide.