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1.
Nat Commun ; 13(1): 2764, 2022 05 19.
Article in English | MEDLINE | ID: mdl-35589714

ABSTRACT

2 + 2 Photocycloadditions are idealized, convergent construction approaches of 4-membered heterocyclic rings, including azetidines. However, methods of direct excitation are limited by the unfavorable photophysical properties of imines and electronically unbiased alkenes. Here, we report copper-catalyzed photocycloadditions of non-conjugated imines and alkenes to produce a variety of substituted azetidines. Design principles allow this base metal-catalyzed method to achieve 2 + 2 imine-olefin photocycloaddition via selective alkene activation through a coordination-MLCT pathway supported by combined experimental and computational mechanistic studies.


Subject(s)
Alkenes , Azetidines , Catalysis , Copper , Imines
2.
Org Biomol Chem ; 19(39): 8425-8441, 2021 10 14.
Article in English | MEDLINE | ID: mdl-34546272

ABSTRACT

The importance and prevalance of O-, N-, and S-atom containing saturated four-membered ring motifs in biologically active molecules and potential therapeutics continues to drive efforts in their efficient synthetic preparation. In this review, general and recent strategies for the synthesis of these heterocycles are presented. Due to the limited potential bond disconnections, retrosynthetic strategies are broadly limited to cyclizations and cycloadditions. Nonetheless, diverse approaches for accessing cyclization precursors have been developed, ranging from nucleophilic substitution to C-H functionalization. Innovative methods for substrate activation have been developed for cycloadditions under photochemical and thermal conditions. Advances in accessing oxetanes, azetidines, and thietanes remain active areas of research with continued breakthroughs anticipated to enable future applications.

3.
Science ; 371(6536): 1313, 2021 03 26.
Article in English | MEDLINE | ID: mdl-33766876
4.
Nature ; 584(7819): 46-47, 2020 08.
Article in English | MEDLINE | ID: mdl-32760040
5.
Chemistry ; 25(67): 15267-15271, 2019 Dec 02.
Article in English | MEDLINE | ID: mdl-31535414

ABSTRACT

Phenolic, lignin-derived substrates have emerged as desirable biorenewable chemical feedstocks for coupling reactions. A radical-mediated conversion of phenol derivatives to anilines is reported, using unfunctionalized hydroxamic acids as the N-centered radical source. The applicability of this triethyl phosphite mediated O-atom transfer approach, which tolerates a range of steric and electronic demands to naturally occurring phenols and lignin models, has been demonstrated in this work to access the corresponding aniline derivatives.

6.
Org Lett ; 21(19): 8031-8036, 2019 10 04.
Article in English | MEDLINE | ID: mdl-31552741

ABSTRACT

We report herein the development of a S atom transfer process using triethyl phosphite as the S atom acceptor that allows thiols to serve as precursors of C-centered radicals. A range of functionalized and electronically unbiased alkenes including those containing common heteroatom-based functional groups readily participate in this reductive coupling. This process is driven by the exchange of relatively weak S-H and C-S bonds of aliphatic thiols for C-H, C-C, and S-P bonds of the products formed.

7.
J Am Chem Soc ; 141(22): 8741-8745, 2019 06 05.
Article in English | MEDLINE | ID: mdl-31117662

ABSTRACT

Photocycloadditions are often typified by the oxetane-forming Paternò-Büchi reaction. However, the mechanistic constraints of carbonyl excitation and olefin interception have limited this attractive oxetane-forming pathway. Here we describe the use of a Cu(I) precatalyst that achieves selective olefin activation via coordination to the metal center. Significantly, this intermolecular 2 + 2 carbonyl-olefin photocycloaddition engages alkyl ketones, which are more challenging to accommodate via direct irradiation pathways. Mechanistic investigations support the in situ formation of a Cu-norbornene resting state that undergoes a MLCT leading to oxetane formation.

8.
J Am Chem Soc ; 140(39): 12318-12322, 2018 10 03.
Article in English | MEDLINE | ID: mdl-30192532

ABSTRACT

An intermolecular anti-Markovnikov hydroamination of alkenes has been developed using triethyl phosphite and N-hydroxyphthalimide. The process tolerates a wide range of alkenes, including vinyl ethers, silanes, and sulfides as well as electronically unbiased terminal and internal alkenes. The resultant N-alkylphthalimides can readily be transformed to the corresponding primary amines. Mechanistic probes indicate that the process is mediated via a phosphite promoted radical deoxygenation of N-hydroxyphthalimide to access phthalimidyl radicals.

9.
J Am Chem Soc ; 140(9): 3443-3453, 2018 03 07.
Article in English | MEDLINE | ID: mdl-29414238

ABSTRACT

The selective, intermolecular [1,4]-hydrovinylation of conjugated dienes with unactivated α-olefins catalyzed by α-diimine iron complexes is described. Value-added "skipped" diene products were obtained with exclusive [1,4]-selectivity, and the formation of branched, ( Z)-olefin products was observed with no evidence for alkene isomerization. Mechanistic studies conducted with the well-defined, single-component iron precatalyst (MesDI)Fe(COD) (MesDI = [2,4,6-Me3-C6H2-N═CMe]2); COD = 1,5-cyclooctadiene) provided insights into the origin of the high selectivity. An iron diene complex was identified as the catalyst resting state, and one such isoprene complex, (iPrDI)Fe(η4-C5H8), was isolated and characterized. A combination of single crystal X-ray diffraction, Mößbauer spectroscopy, magnetic measurements, and DFT calculations established that the complex is best described as a high-spin Fe(I) center ( SFe = 3/2) engaged in antiferromagnetic coupling to an α-diimine radical anion ( SDI = -1/2), giving rise to the observed S = 1 ground state. Deuterium-labeling experiments and kinetic analyses of the catalytic reaction provided support for a pathway involving oxidative cyclization of an alkene with the diene complex to generate an iron metallacycle. The observed selectivity can be understood in terms of competing steric interactions in the transition states for oxidative cyclization and subsequent ß-hydrogen elimination.


Subject(s)
Alkenes/chemistry , Imines/chemistry , Iron/chemistry , Vinyl Compounds/chemistry , Alkenes/chemical synthesis , Catalysis , Crystallography, X-Ray , Isomerism , Models, Molecular , Oxidation-Reduction , Vinyl Compounds/chemical synthesis
10.
Science ; 349(6251): 960-3, 2015 Aug 28.
Article in English | MEDLINE | ID: mdl-26315433

ABSTRACT

Cycloadditions, such as the [4+2] Diels-Alder reaction to form six-membered rings, are among the most powerful and widely used methods in synthetic chemistry. The analogous [2+2] alkene cycloaddition to synthesize cyclobutanes is kinetically accessible by photochemical methods, but the substrate scope and functional group tolerance are limited. Here, we report iron-catalyzed intermolecular [2+2] cycloaddition of unactivated alkenes and cross cycloaddition of alkenes and dienes as regio- and stereoselective routes to cyclobutanes. Through rational ligand design, development of this base metal-catalyzed method expands the chemical space accessible from abundant hydrocarbon feedstocks.


Subject(s)
Alkenes/chemistry , Cyclobutanes/chemistry , Cyclobutanes/chemical synthesis , Iron/chemistry , Catalysis , Cycloaddition Reaction , Dimerization , Kinetics , Ligands , Molecular Structure , Stereoisomerism
11.
J Am Chem Soc ; 137(24): 7903-14, 2015 Jun 24.
Article in English | MEDLINE | ID: mdl-26030841

ABSTRACT

Aryl-substituted bis(imino)pyridine cobalt dinitrogen compounds, ((R)PDI)CoN2, are effective precatalysts for the intramolecular [2π + 2π] cycloaddition of α,ω-dienes to yield the corresponding bicyclo[3.2.0]heptane derivatives. The reactions proceed under mild thermal conditions with unactivated alkenes, tolerating both amine and ether functional groups. The overall second order rate law for the reaction, first order with respect to both the cobalt precatalyst and the substrate, in combination with electron paramagnetic resonance (EPR) spectroscopic studies established the catalyst resting state as dependent on the identity of the precatalyst and diene substrate. Planar S = ½ κ(3)-bis(imino)pyridine cobalt alkene and tetrahedral κ(2)-bis(imino)pyridine cobalt diene complexes were observed by EPR spectroscopy and in the latter case structurally characterized. The hemilabile chelate facilitates conversion of a principally ligand-based singly occupied molecular orbital (SOMO) in the cobalt dinitrogen and alkene compounds to a metal-based SOMO in the diene intermediates, promoting C-C bond-forming oxidative cyclization. Structure-activity relationships on bis(imino)pyridine substitution were also established with 2,4,6-tricyclopentyl-substituted aryl groups, resulting in optimized catalytic [2π + 2π] cycloaddition. The cyclopentyl groups provide a sufficiently open metal coordination sphere that encourages substrate coordination while remaining large enough to promote a challenging, turnover-limiting C(sp(3))-C(sp(3)) reductive elimination.


Subject(s)
Alkenes/chemistry , Cobalt/chemistry , Catalysis , Cycloaddition Reaction , Electron Spin Resonance Spectroscopy , Electrons , Imines/chemistry , Models, Molecular , Nitrogen/chemistry , Pyridines/chemistry , Quantum Theory
12.
J Am Chem Soc ; 136(41): 14389-92, 2014 Oct 15.
Article in English | MEDLINE | ID: mdl-25232995

ABSTRACT

Transformations that selectively functionalize aliphatic C-H bonds hold significant promise to streamline complex molecule synthesis. Despite the potential for site-selective C-H functionalization, few intermolecular processes of preparative value exist. Herein, we report an approach to unactivated, aliphatic C-H bromination using readily available N-bromoamide reagents and visible light. These halogenations proceed in useful chemical yields, with substrate as the limiting reagent. The site selectivities of these radical-mediated C-H functionalizations are comparable (or superior) to the most selective intermolecular C-H functionalizations known. With the broad utility of alkyl bromides as synthetic intermediates, this convenient approach will find general use in chemical synthesis.

13.
J Am Chem Soc ; 133(34): 13320-2, 2011 Aug 31.
Article in English | MEDLINE | ID: mdl-21809867

ABSTRACT

The dioxygenation of alkenes using molecular oxygen and a simple hydroxamic acid derivative has been achieved. The reaction system consists of readily prepared methyl N-hydroxy-N-phenylcarbamate and molecular oxygen with a radical initiator, offering an alternative to common dioxygenation processes catalyzed by precious transition metals. This transformation capitalizes on the unique reactivity profile of hydroxamic acid derivatives in radical-mediated alkene addition processes.

14.
J Am Chem Soc ; 133(30): 11402-5, 2011 Aug 03.
Article in English | MEDLINE | ID: mdl-21732656

ABSTRACT

A radical-mediated approach to metal-free alkene oxyamination is described. This method capitalizes on the unique reactivity of the amidoxyl radical in alkene additions to furnish a general difunctionalization using simple diisopropyl azodicarboxylate (DIAD) as a radical trap. This protocol capitalizes on the intramolecular nature of the process, providing single regioisomers in all cases. Difunctionalizations of cyclic alkenes provide trans oxyamination products inaccessible using current methods with high levels of stereoselectivity, complementing cis-selective oxyamination processes.


Subject(s)
Alkenes/chemistry , Azo Compounds/chemical synthesis , Hydroxamic Acids/chemistry , Amination , Azo Compounds/chemistry , Cyclization , Molecular Structure , Stereoisomerism
15.
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