Atom Transfer Radical Cyclization Research Articles

A lutidine-promoted photoredox catalytic atom-transfer radical cyclization reaction for the synthesis of 4-bromo-3,3-dialkyl-octahydro-indol-2-ones.

Reported herein is a visible-light-catalyzed photoredox atom-transfer radical cyclization (ATRC) halo-alkylation of 1,6-dienes with α-halo-ketones as the ATRC reagent. This process exhibits high atom economy, high step economy, and high redox economy, which can directly construct a 4-bromo-3,3-dialkyl-octahydro-indol-2-one core under mild conditions in one pot, and lutidine is found to be the key promoter for this ATRC process.

Aroylchlorination of 1,6-Dienes via a Photoredox Catalytic Atom-Transfer Radical Cyclization Process.

A method using aroyl chlorides as atom-transfer radical cyclization agents in a novel visible-light photocatalytic aroylchlorination reaction is developed. The overall transformation involves the formation of two new C-C bonds and one new C-Cl bond in a one-pot process. The advantages of this reaction include high atom/step/redox economy, mild conditions, operational simplicity, and broad substrate scopes.

Total Synthesis of Viridin and Viridiol.

The asymmetric total synthesis of (-)-viridin and (-)-viridiol, antifungal metabolites, was achieved in 17 and 18 steps from a commercially available starting material. An intramolecular [3+2] cycloaddition was applied to an easily available l-ribose derivative in order to construct the highly substituted D ring containing the key chiral cis-triol fragment. Co-catalyzed metal-hydride H atom transfer (MHAT) radical cyclization was utilized to form the C-ring and the all-carbon quaternary center at C-10. This convergent strategy provides a scalable approach to prepare viridin and viridiol for biological studies.

Visible-Light-Promoted Manganese-Catalyzed Atom Transfer Radical Cyclization of Unactivated Alkyl Iodides

An expedient visible-light-promoted atom transfer radical cyclization (ATRC) reaction of unactivated alkyl iodides facilitated by earth-abundant and inexpensive manganese catalysis is described. The practical protocol shows a broad substrate scope and good functional-group tolerance, allowing for the preparation of synthetically valuable alkenyl iodides and diquinanes under simple and mild reaction conditions. Notably, the method provides a net redox-neutral strategy for ATRC reactions that avoids classic hydrogen atom transfer mechanism.

Visible-Light-Induced Atom Transfer Radical Addition and Cyclization of Perfluoroalkyl Halides with 1,n-Enynes

A mild and efficient visible-light-induced atom transfer radical addition and cyclization of 1,n-enynes (n = 6, 7) with perfluoroalkyl halides, leading to halo-perfluorinated N-heterocycles, has be...

Transition-Metal (Pd, Ni, Mn)-Catalyzed C-C Bond Constructions Involving Unactivated Alkyl Halides and Fundamental Synthetic Building Blocks.

The catalytic construction of C-C bonds between organohalide or pseudohalide electrophiles and fundamental building blocks such as alkenes, arenes, or CO are widely utilized metal-catalyzed processes. The use of simple, widely available unactivated alkyl halides in these catalytic transformations has significantly lagged behind the use of aryl or vinyl electrophiles. This difference is primarily due to the relative difficulty of activating alkyl halides with transition metals under mild conditions. This Account details our group's work toward developing a general catalytic manifold for the construction of C-C bonds using unactivated alkyl halides and a range of simple chemical feedstocks. Critical to the strategy was the implementation of new modes of hybrid organometallic-radical reactivity in catalysis. Generation of carbon-centered radicals from alkyl halides using transition metals offers a solution to challenges associated with the application of alkyl electrophiles in classical two-electron reaction modes. A major focus of this work was the development of general palladium-catalyzed carbocyclizations and intermolecular cross-couplings of unactivated alkyl halides (alkyl-Mizoroki-Heck-type reactions). Initial studies centered on the use of alkyl iodides in these processes, but subsequent studies determined that the use of an electron-rich ferrocenyl bisphosphine (dtbpf) enables the palladium-catalyzed carbocyclizations of unactivated alkyl bromides. Mechanistic studies of these reactions revealed interesting details regarding a difference in mechanism between reactions of alkyl iodides and alkyl bromides in carbocyclizations. These studies were consistent with alkyl bromides reacting via an autotandem catalytic process involving atom-transfer radical cyclization (ATRC) followed by catalytic dehydrohalogenation. Reactions of alkyl iodides, on the other hand, involved metal-initiated radical chain pathways. Recent studies have expanded the scope of alkyl-Mizoroki-Heck-type reactions to the use of a first-row transition metal. Inexpensive nickel precatalysts, in combination with the bisphosphine ligand Xantphos, efficiently activate alkyl bromides for both intra- and intermolecular C-C bond-forming reactions. The reaction scope is similar to the palladium-catalyzed system, but in addition, alkene regioisomeric ratios are dramatically improved over those in reactions with palladium, solving one of the drawbacks of our previous work. Initial mechanistic studies were consistent with a hybrid organometallic-radical mechanism for the nickel-catalyzed reactions. The novel reactivity of the palladium catalysts in the alkyl-Mizoroki-Heck-type reactions have also paved the way for the development of other C-C bond-forming processes of unactivated alkyl halides, including aromatic C-H alkylations as well as low-pressure alkoxycarbonylations. Related hybrid organometallic-radical reactivity of manganese has led to an alkene dicarbofunctionalization using alkyl iodides.

Visible‐Light‐Mediated Chlorosulfonylative Cyclizations of 1,6‐Enynes

AbstractDescribed herein is a visible‐light‐mediated atom‐transfer radical cyclization (ATRC) using 1,6‐enynes as substrates. The sulfonyl chlorides not only served as sulfonyl radical sources but also provided a chlorine atom to enable the formation of highly functionalized cyclic products. This visible‐light‐mediated photocatalytic method is a mild and practical strategy for synthesizing chloroalkyl‐substituted cyclic alkenyl sulfones.magnified image

Copper-Catalyzed Annulation Cascades of Alkyne-Tethered α-Bromocarbonyls with Alkynes: An Access to Heteropolycycles.

We here describe a new Cu-catalyzed annulation cascade of alkyne-tethered α-bromocarbonyls with common alkynes for the synthesis of various heteropolycycle frameworks, including 1 H-benzo[ de]quinolin-2(3 H)-ones, 4 H-dibenzo[ de,g]quinolin-5(6 H)-one, and benzo[ de]chromen-2(3 H)-one, which were constructed with high selectivity. This was achieved by two-component annulation cascades, rather than atom-transfer radical cyclization (ATRC), with alkyne-tethered α-bromocarbonyls for one-step accessing heteropolycycles via C-Br bond split, intramolecular cyclization, intermolecular [4 + 2] annulation, and aryl C(sp2)-H functionalization cascades.

Total Syntheses of Daphenylline, Daphnipaxianine A, and Himalenine D.

We report the total syntheses of daphenylline (1), daphnipaxianine A (5), and himalenine D (6), three Daphniphyllum alkaloids from the calyciphylline A subfamily. A pentacyclic triketone was prepared by using atom-transfer radical cyclization and the Lu [3+2] cycloaddition as key steps. Inspired by the proposed biosynthetic relationship between 1 and another calyciphylline A type alkaloid, we developed a ring-expansion/aromatization/aldol cascade to construct the tetrasubstituted benzene moiety of 1. The versatile triketone intermediate was also elaborated into 5 and 6 through a C=C bond migration/aldol cyclization approach.

Synthesis and molecular crystal of 3-Chloro-2-(1-chloro-1-methyl-ethyl)-2,3-dihydro-1H-naphtho[2,1-b]oxepin-4-one

CuCl/TMEDA-promoted halogen atom transfer radical cyclization (HATRC) of dichloroacetic acid 1-(3-methyl-but-2-enyl)-naphthalen-2-yl ester in refluxing DCE gave chlorine containing 7-member lactone 3-Chloro-2-(1-chloro-1-methyl-ethyl)-2,3-dihydro-1H-naphtho[2,1-b]oxepin-4-one via 7-exo trig radical cyclization reaction. The structure of the Lactone was confirmed by X-ray diffraction data.

DPPF-Catalyzed Atom-Transfer Radical Cyclization via Allylic Radical.

A general iron-catalyzed strategy for the atom-transfer radical cyclization (ATRC) of allylic halide is reported. Critical to this strategy is the use of DPPF [1,1'-bis(diphenylphosphino)ferrocene] as catalyst, which allows for efficient generation of the allylic radical species via a single-electron transfer (SET) process. The feasibility of achieving ATRC reactions of propargyl chlorides is also demonstrated, which affords products with an exocyclic allene moiety.

Palladium-Catalyzed Carbocyclizations of Unactivated Alkyl Bromides with Alkenes Involving Auto-tandem Catalysis.

The development of a general catalytic system for the palladium-catalyzed carbocyclization of unactivated alkyl bromides with alkenes is described. This approach uses a commercially available bisphosphine ligand and avoids the use of carbon monoxide atmosphere present in prior studies involving alkyl iodides. Detailed mechanistic studies of the transformation are performed, which are consistent with auto-tandem catalysis involving atom-transfer radical cyclization followed by catalytic dehydrohalogenation. These studies also suggest that reactions involving alkyl iodides may proceed through a metal-initiated, rather than metal-catalyzed, radical chain process.

Enantioselective Construction of the ABCDE Pentacyclic Core of the Strychnos Alkaloids.

An efficient enantioselective 12-step synthesis of the ABCDE pentacyclic core of the Strychnos alkaloids is described. A key feature of this approach is an organocatalyzed enantioselective desymmetrization to generate the morphan core in high ee and dr. After palladium-catalyzed installation of the indole moiety, a subsequent 5-exo-trig dearomatizing atom transfer radical cyclization was developed to construct the C-ring. Following a series of functional group interconversions, the pentacyclic amine core was obtained with all the relevant architecture including five stereocenters pertaining to the Strychnos alkaloids.

Substrate‐Controlled Diastereoselective Synthesis of Sugar‐Based Chlorinated Perhydrofuro[2,3‐b]pyrans via Copper(I)‐Catalyzed Radical Cyclization

AbstractThe work describes the first copper(I) chloride/2,2′‐bipyridine‐catalyzed atom transfer radical cyclization (ATRC) of unsaturated carbohydrate‐derived chloroacetals to generate chlorinated perhydrofuro[2,3‐b]pyrans via an effective diastereoselective route. Various glycals (glucal, galactal and lactal) underwent the Ferrier rearrangement with 2,2,2‐trichloroethanols to give acetal precursors stereoselectively, R‐selective with galactal in contrast to S‐selective with glucal. The radical cyclization of the Ferrier products occurred smoothly to afford cis‐fused bicyclic products with the transfer of the chlorine atom at the non‐anomeric carbon in the cyclized radical intermediate predominantly from the equatorial direction. The carbohydrate templates controlled the stereochemistry of both Ferrier rearrangement and ATRC steps. The stereostructures of the products were also supported by single crystal X‐ray diffraction crystallography. The products possess biologically important structural segments such as a glycosidic linkage, a fused bicyclic acetal unit and a chlorosugar unit which are potential sources for biological studies and further synthetic elaborations.magnified image

Radical Cyclization of Trichloroacetamides: Synthesis of Lactams

Trichloroacetamides can act as radical precursors to synthesize nitrogen-containing heterocycles in a variety of processes, mainly involving atom transfer radical cyclizations (ATRC), mediated by Cu(I) or Ru(II) catalysts, and the hydride reductive method, employing either Bu₃SnH or (Me₃Si)₃SiH, or recently NaBH₃CN. Additionally, amine-mediated single-electron transfer cyclizations, as well as radical processes promoted by Ni, Fe, Mn, Ti, and Ag, have been developed. 1 Introduction 2 Atom Transfer Radical Cyclizations (ATRC) 2.1 Copper-Mediated Reactions 2.2 Ruthenium(II)-Mediated Reactions 2.3 ATRC Promoted by Other Metals 3 Photocyclization Reactions 4 Reductive Cyclization via Single-Electron Transfer Processes 4.1 Ni/AcOH-Promoted Cyclizations 4.2 Titanocene(III)-Catalyzed Reactions 4.3 Silver Acetate Mediated Reactions 4.4 Amine-Mediated Single-Electron Transfer 5 Cyclization Involving M–H Hydrogen Atom Donors (M = Sn, Si, B) 5.1 Bu₃SnH-Mediated Reactions 5.2 (Me₃Si)₃SiH (TTMSS)-Mediated Reactions 5.3 Borohydride-Mediated Radical Cyclizations 6 Concluding Remarks

Visible-Light-Promoted Atom Transfer Radical Cyclization of Unactivated Alkyl Iodides

A visible-light-mediated atom transfer radical cyclization of unactivated alkyl iodides is described. This protocol operates under mild conditions and exhibits high chemoselectivity profile while avoiding parasitic hydrogen atom transfer pathways. Preliminary mechanistic studies challenge the perception that a canonical photoredox catalytic cycle is being operative.

ChemInform Abstract: Copper(I)‐Promoted Synthesis of Highly Substituted and Functionalized Tetrahydrothiophenes.

AbstractHalogen atom transfer radical cyclization of 2,2,2‐trihaloethylallyl sulfides leads to highly functionalized tetrahydrothiophenes.

An efficient method for the synthesis of some chlorinated and heteroatom rich triazole-linked β-lactam glycoconjugates

The synthetic utility of chlorinated bicyclic C-fused tetrahydrofuro[3,2-c] azetidin-2-ones synthesized in our laboratory by Cu(I)-catalyzed halogen atom transfer radical cyclization (ATRC) has been illustrated through the synthesis of some novel β-lactam glycoconjugates. The chlorine atom of the chloromethyl side chain of the bicyclic C-fused tetrahydrofuro[3,2-c] azetidin-2-ones was subjected to nucleophilic substitution with azide group followed by Cu(I)-catalyzed azide-alkyne click reaction (CuAAC) with propargyl glycosides to generate the desirous β-lactam glycoconjugates. A sequential optimization of the reaction procedure for CuAAC was carried out to obtain an efficient catalyst system to achieve β-lactam glycoconjugates in good yields. The β-lactam glycoconjugates are the compounds of interesting architecture and structurally suitable for bioactivity evaluation. Therefore, these β-lactam glycoconjugates were screened for in vitro antibacterial activity. Additionally, a representative β-lactam glycoconjugate was also tested for biocompatibility and cytotoxic activity against L929 cancer cell lines.

ChemInform Abstract: Copper Catalyzed Atom Transfer Radical Cyclization Reactions

AbstractReview: [64 refs.

Copper Catalyzed Atom Transfer Radical Cyclization Reactions

AbstractAtom transfer radical cyclization (ATRC) is a powerful technique to prepare functionalized 4–10 membered ring systems using transition metal catalysts. In this review recent advances in the use of copper complexes are described. In particular the effect of different ligands on reactivity, selectivity and product outcome are illustrated with application to heterocycle and natural product synthesis. New approaches that increase catalyst efficiency with supplemental reducing agents are reviewed and examples using green solvents, benign reducing agents (e.g. ascorbic acid) and with catalyst loadings as low as 0.05 mol‐% are highlighted. Radical addition to aromatic rings and rearrangement reactions under ATRC conditions as well as application to radical‐polar crossover reactions are also described.