Radical Carboazidation Research Articles

Iron-Catalyzed Three-Component Asymmetric Carboazidation of Alkenes with Alkanes and Trimethylsilyl Azide

AbstractThe fusion of transition-metal catalysis with radical chemistry provides a versatile platform for the asymmetric radical carboazidation of alkenes to enable the rapid assembly of highly functionalized chiral azide compounds. Here, we present an iron-catalyzed asymmetric three-component radical carboazidation that processes electron-deficient alkenes by direct activation of aliphatic C–H bonds. This strategy provides access to a range of valuable chiral azides from readily available chemical feedstocks bearing a tetrasubstituted carbon stereocenter, and their synthetic potential is further showcased through straightforward transformations to provide other valuable enantioenriched building blocks.

Asymmetric Three-Component Radical Alkene Carboazidation by Direct Activation of Aliphatic C-H Bonds.

Azide compounds are widely present in natural products and drug molecules, and their easy-to-transform characteristics make them widely used in the field of organic synthesis. The merging of transition-metal catalysis with radical chemistry offers a versatile platform for radical carboazidation of alkenes, allowing the rapid assembly of highly functionalized organic azides. However, the direct use of readily available hydrocarbon feedstocks as sp3-hybridized carbon radical precursors to participate in catalytic enantioselective carboazidation of alkenes remains a significant challenge that has yet to be addressed. Herein, we describe an iron-catalyzed asymmetric three-component radical carboazidation of electron-deficient alkenes by direct activation of aliphatic C-H bonds. This approach involves intermolecular hydrogen atom transfer between a hydrocarbon and an alkoxy/aryl carboxyl radical, leading to the formation of a carbon-centered radical. The resulting radical then reacts with electron-deficient alkenes to generate a new radical species that undergoes chiral iron-complex-mediated C-N3 bond coupling. An array of valuable chiral azides bearing a quaternary stereocenter were directly accessed from widely available chemical feedstocks, and their synthetic potential is further demonstrated through more facile transformations to give other valuable enantioenriched building blocks.

Iron-Catalyzed Enantioselective Radical Carboazidation and Diazidation of α,β-Unsaturated Carbonyl Compounds.

Azidation of alkenes is an efficient protocol to synthesize organic azides which are important structural motifs in organic synthesis. Enantioselective radical azidation, as a useful strategy to install a C-N3 bond, remains challenging due to the inherently instability and unique structure of radicals. Here, we disclose an efficient enantioselective radical carboazidation and diazidation of α,β-unsaturated ketones and amides catalyzed by chiral N,N'-dioxide/Fe(OTf)2 complexes. An array of substituted alkenes was transformed to the corresponding α-azido carbonyl derivatives in good to excellent enantioselectivities, benefiting the preparation of chiral α-amino ketones, vicinal amino alcohols, and vicinal diamines. Control experiments and mechanistic studies proved the radical pathway in the reaction process. The DFT calculations showed that the azido transferred to the radical intermediate via an intramolecular five-membered transition state with the internal nitrogen of the Fe-N3 species.

Iron-catalysed asymmetric carboazidation of styrenes

Carboazidation of olefins is an efficient process to convert hydrocarbons directly into nitrogen-containing molecules. Such chemicals find broad applications in medicine and material sciences. Despite the fast development of carboazidation reactions, asymmetric radical carboazidations are still elusive. Here, we report a radical asymmetric carboazidation of olefins via an iron-catalysed group transfer mechanism. The method affords valuable chiral halogenated organoazides from inexpensive industrial chemical feedstocks. This radical azidation reaction is supported by mechanistic studies and should inspire further development of enantioselective radical reactions. The carboazidation of olefins represents an effective strategy to introduce both carbon and nitrogen substituents into hydrocarbons, but asymmetric versions of this reaction remain elusive. Now, an iron-catalysed asymmetric radical carboazidation is introduced that yields chiral halogenated organoazides in high enantiomeric ratios.

Formal Synthesis of (−)‐Cephalotaxine

AbstractA formal synthesis of (−)‐cephalotaxine (1) by means of a highly stereoselective radical carboazidation process is reported. The synthesis begins with the protected (S)‐cyclopent‐2‐en‐1‐ol derivative 10 and uses the concept of self‐reproduction of a stereogenic center (Schemes 5 and 6). For this purpose, the double bond adjacent to the initial chiral center in 10 is converted into an acetonide after stereoselective dihydroxylation. The initial alcohol function is used to build an exocyclic methylene group suitable for the carboazidation process 8→7 (Scheme 7). Finally the protected diol moiety is converted back to an alkene (14→15→6) and used for the formation of ring B via a Heck reaction (6→(−)‐16; Scheme 8).

ChemInform Abstract: Radical Azidation Reactions and Their Application in the Synthesis of Alkaloids

AbstractReview: 49 refs.

Radical azidation reactions and their application in the synthesis of alkaloids

Recent advances in radical azidation using sulfonyl azides are presented. For instance, radical carboazidation using α-iodoketones, desulfitative carboazidation, and anti-Markovnikov hydroazidation of alkenes are described. These novel methods tolerate a large number of functional groups and allow the synthesis of organic azides that would be difficult to synthesize otherwise. The transformation of the azides using reductive processes as well as a Schmidt reaction under nonacidic conditions were used to synthesize alkaloids including indolizidine 167B, monomorine I, cylindricine C, and lepadiformine C.

ChemInform Abstract: Concise Synthesis of Pyrrolidine and Indolizidine Alkaloids by a Highly Convergent Three‐Component Reaction.

AbstractA radical carboazidation of alkenes with α‐iodoketones followed by intramolecular reductive amination reaction is successfully applied to the synthesis of a variety of pyrrolidine and indolizidine alkaloids, e.g. monomorine I (XVII).

Concise Synthesis of Pyrrolidine and Indolizidine Alkaloids by a Highly Convergent Three‐Component Reaction

The synthesis of pyrrolidine and indolizidine derivatives through radical carboazidation of alkenes with α-iodoketones, followed by reductive amination, is described. When properly substituted, further lactamization afforded pyrrolizidinones in good yield. This carboazidation/reductive amination sequence was efficiently applied to the total synthesis of three different simple alkaloids, including (±)-monomorine I.

Diastereoselectivity Control of the Radical Carboazidation of Substituted Methylenecyclohexanes

A systematic study of the diastereoselectivity of the radical carboazidation of methylenecyclohexane derivatives is presented. Several substitution patterns leading to a high level of stereocontrol have been identified. Axial attack is the preferred reaction pathway for cyclohexyl radicals, and excellent stereoselectivities can be obtained by introducing an axial substitutent at position 2. In this case, a second equatorial substituent at position 2 may be tolerated without a large detrimental effect on the diastereoselectivity. Finally, a high level of equatorial attack is observed with a very bulky substituent at position 2.

Total Synthesis of the Marine Alkaloid (±)-Lepadiformine via a Radical Carboazidation

[reaction: see text] The total synthesis of lepadiformine has been achieved in 10 steps and 15% overall yield from cyclohexanone. The amino-substituted quaternary carbon center is created through a radical carboazidation reaction. The tricyclic core of lepadiformine is built via an efficient hydrogenation process, involving reduction of the azide and intramolecular reductive amination of a ketone, followed by lactamization of the intermediate gamma-aminoester. The hydroxymethyl side chain is introduced according to a modified Takahata procedure after conversion of the lactam into a thiolactam.

A Convenient Tin‐Free Procedure for Radical Carboazidation and Azidation.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Radical Carboazidation: Expedient Assembly of the Core Structure of Various Alkaloid Families.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Tin-Free Radical Carboazidation

The radical carboazidation of alkenes could be achieved in water using triethylborane as initiator. This efficient process is complete in one hour at room temperature in an open system. These new tin-free azidation and carboazidation conditions are environmentally friendly and enable reactions to be run with an excess of either the alkene or the radical precursor. Furthermore, 3-pyridinesulfonyl azide could be used in order to avoid tedious purifications, especially when the reaction product has a similar chromatographic behavior to benzenesulfonyl azide, our original azidation reagent.

A convenient tin-free procedure for radical carboazidation and azidation.

The radical carboazidation of alkenes has been achieved in water with triethylborane as initiator. This efficient process is complete in 1 h at room temperature in an open system. These new tin-free carboazidation conditions are environmentally friendly and allow running reactions with an excess of either the alkene or the radical precursor. They are also suitable for simple radical azidation of alkyl iodides as well as for more complex cascade reactions involving annulation processes.

Radical carboazidation: expedient assembly of the core structure of various alkaloid families.

A procedure for one-pot intermolecular radical addition of 2-iodoesters to terminal alkenes followed by azidation of the radical adduct has been developed. This sequential reaction represents an alkene carboazidation process. Its efficacy is demonstrated by the two-step preparation of various lactams such as pyrrolidinones, pyrrolizidinones, and indolizidinones. An easy access to spirolactams bearing an amino-substituted quaternary carbon center is also described. These compounds are important building blocks for the synthesis of numerous alkaloids such as, for instance, FR901483.

Radical Carboazidation of Alkenes: An Efficient Tool for the Preparation of Pyrrolidinone Derivatives.

Radical Carboazidation of Alkenes: An Efficient Tool for the Preparation of Pyrrolidinone Derivatives.

Radical carboazidation of alkenes: an efficient tool for the preparation of pyrrolidinone derivatives.

Radical carboazidation of alkenes: an efficient tool for the preparation of pyrrolidinone derivatives.