Carbonyl cross-metathesis via deoxygenative gem-di-metal catalysis.

Carbonyls and alkenes are versatile functional groups, whose reactivities are cornerstones of organic synthesis. The selective combination of two carbonyls to form an alkene-a carbonyl cross-metathesis-would be a valuable tool for their exchange. Yet, this important synthetic challenge remains unsolved. Although alkene/alkene and alkene/carbonyl cross-metathesis reactions are known, there is a lack of analogous methods for deoxygenative cross-coupling of two carbonyl compounds. Here we report a pair of strategies for the cross-metathesis of unbiased carbonyls, allowing an aldehyde to be chemo- and stereoselectively combined with another aldehyde or ketone. These mild, catalytic methods are promoted by earth-abundant metal salts and enable rapid access to an unprecedentedly broad range of either Z- or E-alkenes by two distinct mechanisms-entailing transiently generated (1) carbenes and ylides (via Fe catalysis) or (2) doubly nucleophilic gem-di-metallics (via Cr catalysis).

Carbene reactivity from alkyl and aryl aldehydes.

Carbenes are highly enabling reactive intermediates that facilitate a diverse range of otherwise inaccessible chemistry, including small-ring formation and insertion into strong σ bonds. To access such valuable reactivity, reagents with high entropic or enthalpic driving forces are often used, including explosive (diazo) or unstable (gem-dihalo) compounds. Here, we report that common aldehydes are readily converted (via stable α-acyloxy halide intermediates) to electronically diverse (donor or neutral) carbenes to facilitate >10 reaction classes. This strategy enables safe reactivity of nonstabilized carbenes from alkyl, aryl, and formyl aldehydes via zinc carbenoids. Earth-abundant metal salts [iron(II) chloride (FeCl2), cobalt(II) chloride (CoCl2), copper(I) chloride (CuCl)] are effective catalysts for these chemoselective carbene additions to σ and π bonds.

γ C-H Functionalization of Amines via Triple H-Atom Transfer of a Vinyl Sulfonyl Radical Chaperone.

A selective, remote desaturation has been developed to rapidly access homoallyl amines from their aliphatic precursors. The strategy employs a triple H-atom transfer (HAT) cascade, entailing (i) cobalt-catalyzed metal-HAT (MHAT), (ii) carbon-to-carbon 1,6-HAT, and (iii) Co-H regeneration via MHAT. A new class of sulfonyl radical chaperone (to rapidly access and direct remote, radical reactivity) enables remote desaturation of diverse amines, amino acids, and peptides with excellent site-, chemo-, and regioselectivity. The key, enabling C-to-C HAT step in this cascade was computationally designed to satisfy both thermodynamic (bond strength) and kinetic (polarity) requirements, and it has been probed via regioselectivity, isomerization, and competition experiments. We have also interrupted this radical transfer dehydrogenation to achieve γ-selective C-Cl, C-CN, and C-N bond formations.

Radical Aza-Heck Cyclization of Imidates via Energy Transfer, Electron Transfer, and Cobalt Catalysis.

A radical aza-Heck cyclization has been developed to afford functionally rich products with four contiguous C-heteroatom bonds. This multi-catalytic strategy provides rapid syntheses of dense, medicinally relevant motifs by enabling the conversion of alcohol-derived imidates to heteroatom-rich fragments containing vinyl oxazolines/oxazoles, allyl amines, ß-amino alcohols/halides, and combinations thereof. Mechanistic insights of this process show how three distinct photocatalytic cycles cooperate to enable: (1) imidate radical generation by energy transfer, (2) dehydrogenation by Co catalysis, and (3) catalyst turnover by electron transfer.

Aza-Heterocycles via Copper-Catalyzed, Remote C-H Desaturation of Amines.

The majority of medicines contain a nitrogen atom within a five- or six- membered ring. To rapidly access both such aza-heterocycles, we sought to develop a remote C-H desaturation of amines. Inspired by the Hofmann-Löffler-Freytag synthesis of five-membered pyrrolidines, we tackled the century-old challenge of synthesizing six-membered piperidines by H-atom transfer. We present herein a double, vicinal C-H oxidation by dual catalysis, entailing Ir photocatalytic initiation of 1,5-HAT by an N-centered radical and Cu-catalyzed interception of the C-centered radical to facilitate desaturation. By this mechanism, two C-H bonds (δ and ε to N) are regioselectively removed from unbiased, remote positions of an alkyl chain. Over 50 examples illustrate efficiency, selectivity, functional group tolerance, and medicinal utility of this synthesis of both internal and terminal δ vinylic amines and aza-heterocycles. Mechanistic experiments probe the alkylcopper intermediate, as well as kinetics and regioselectivity of the HAT and elimination steps.

Regioselective Radical Amino-Functionalizations of Allyl Alcohols via Dual Catalytic Cross-Coupling.

The regioselective amination and cross-coupling of a range of nucleophiles with allyl alcohols has been enabled by a dual catalytic strategy. This approach entails the combined action of an Ir photocatalyst that enables mild access to N-radicals via an energy transfer mechanism, as well as a Cu complex that intercepts the ensuing alkyl radical upon cyclization. Merger of this Cu-catalyzed cross-coupling enables a broad range of nucleophiles (e.g. CN, SCN, N3, vinyl, allyl) to engage in radical amino-functionalizations of olefins. Notably, stereo, regio, and kinetic probes provide insights into the nature of this Cu-based radical interception.

Thermal and Barrier Characterizations of Cellulose Esters with Variable Side-Chain Lengths and Their Effect on PHBV and PLA Bioplastic Film Properties.

Cellulose esters (CEs) are promising biodegradable substitutes for traditional petroleum-based plastic materials. Research on structure-property relationships of CEs is necessary to evaluate their suitability for industrial applications such as food packaging. Cellulose esters with different side-chain lengths were synthesized and studied. Their thermal and moisture barrier properties were characterized. Cellulose triheptanoate (CTH) was proved to have an optimal moisture barrier (WVTR = 0.31 g·mil/day/in.2) and was used to blend with poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) and polylactic acid (PLA) bioplastics. CTH addition improved the PLA thermal stability, enhanced the ductility, and increased the moisture barrier by 32%, while it decreased the PHBV thermal stability, weakened the ductility, and reduced the moisture barrier by 90%. We demonstrated that by proper choice of the combination of CE and bioplastic, bioplastic blends with unique and useful synergistic properties can be obtained. These blends can potentially be used for commercial applications, such as biodegradable flexible packaging.

Cross-Selective Aza-Pinacol Coupling via Atom Transfer Catalysis.

A cross-selective aza-pinacol coupling of aldehydes and imines has been developed to afford valuable ß-amino alcohols. This strategy enables chemoselective conversion of aliphatic aldehydes to ketyl radicals, in the presence of more easily reduced imines and other functional groups. Upon carbonyl-specific activation by AcI, a photoinitiated Mn catalyst selectively reduces the resulting α-oxy iodide by an atom transfer mechanism. The ensuing ketyl radical selectively couples to imines, precluding homodimerization by a classical reductive approach. In this first example of reductive, ketyl coupling by atom transfer catalysis, Zn serves as a terminal reductant to facilitate Mn catalyst turnover. This new strategy also enables ketyl radical couplings to alkenes, alkynes, aldehydes, propellanes, and chiral imines.

Enantioselective radical C-H amination for the synthesis of ß-amino alcohols.

Asymmetric, radical C-H functionalizations are rare but powerful tools for solving modern synthetic challenges. Specifically, the enantio- and regioselective C-H amination of alcohols to access medicinally valuable chiral ß-amino alcohols remains elusive. To solve this challenge, a radical relay chaperone strategy was designed, wherein an alcohol was transiently converted to an imidate radical that underwent intramolecular H-atom transfer (HAT). This regioselective HAT was also rendered enantioselective by harnessing energy transfer catalysis to mediate selective radical generation and interception by a chiral copper catalyst. The successful development of this multi-catalytic, asymmetric, radical C-H amination enabled broad access to chiral ß-amino alcohols from a variety of alcohols containing alkyl, allyl, benzyl and propargyl C-H bonds. Mechanistic experiments revealed that triplet energy sensitization of a Cu-bound radical precursor facilitates catalyst-mediated HAT stereoselectivity, enabling the synthesis of several important classes of chiral ß-amines by enantioselective, radical C-H amination.

Vicinal, Double C-H Functionalization of Alcohols via an Imidate Radical-Polar Crossover Cascade.

A double functionalization of vicinal sp3 C-H bonds has been developed, wherein a ß amine and γ iodide are incorporated onto an aliphatic alcohol in a single operation. This approach is enabled by an imidate radical chaperone, which selectively affords a transient ß alkene that is amino-iodinated in situ. Overall, the radical-polar-crossover cascade entails the following key steps: (i) ß C-H iodination via 1,5-hydrogen atom transfer (HAT), (ii) desaturation via I2 complexation, and (iii) vicinal amino-iodination of an in situ generated allyl imidate. The synthetic utility of this double C-H functionalization is illustrated by conversion of aliphatic alcohols to a diverse collection of α,ß,γ substituted products bearing heteroatoms on three adjacent carbons. The radical-polar crossover mechanism is supported by various experimental probes, including isotopic labeling, intermediate validation, and kinetic studies.

Radical cascade synthesis of azoles via tandem hydrogen atom transfer.

A radical cascade strategy for the modular synthesis of five-membered heteroarenes (e.g. oxazoles, imidazoles) from feedstock reagents (e.g. alcohols, amines, nitriles) has been developed. This double C-H oxidation is enabled by in situ generated imidate and acyloxy radicals, which afford regio- and chemo-selective ß C-H bis-functionalization. The broad synthetic utility of this tandem hydrogen atom transfer (HAT) approach to access azoles is included, along with experiments and computations that provide insight into the selectivity and mechanism of both HAT events.

Development of an Imine Chaperone for Selective C-H Functionalization of Alcohols via Radical Relay.

The design of a radical relay chaperone to promote selective C-H functionalizations is described. A saccharin-based imine was found to be uniquely suited to effect C-H amination of alcohols via an in situ generated hemiaminal. This radical chaperone facilitates the mild generation of an N-centered radical while also directing its regioselective H atom transfer (HAT) to the ß carbon of an alcohol. Upon ß C-H halogenation, aminocyclization, and reductive cleavage, an NH2 is formally added vicinal to an alcohol. The development, synthetic utility, and chemo-, regio-, and stereoselectivity of this imine chaperone-mediated C-H amination is presented herein.

Heteroarene Phosphinylalkylation via a Catalytic, Polarity-Reversing Radical Cascade.

A polarity-reversing radical cascade strategy for alkene di-functionalization by vicinal C-C and C-P bond-formation has been developed. This approach to concurrently adding phosphorous and a heteroarene across an olefin is enabled by photocatalytic generation of electrophilic P-centered radicals. Upon chemoselective addition to an olefin, the resulting nucleophilic C-centered radical selectively combines with electrophilic heteroarenes, such as pyridines. This multi-component coupling scheme for phosphinylalkylation complements classic two-component methods for hydrophosphinylation of alkenes and C-H phosphinylation of arenes. Included competition and photo-quenching experiments provide insight into the selectivity and mechanism of this polarity-reversal pathway.

Multi-component heteroarene couplings via polarity-reversed radical cascades.

A multi-component radical addition strategy enables difunctionalization of alkenes with heteroarenes and a variety of radical precursors, including N3, P(O)R2, and CF3. This unified approach for coupling diverse classes of electrophilic radicals and heteroarenes to vinyl ethers allows for direct, vicinal C-C as well as C-N, C-P, and C-Rf bond formation.

Site-Selective C-H Functionalization of (Hetero)Arenes via Transient, Non-Symmetric Iodanes.

A strategy for C-H functionalization of arenes and heteroarenes has been developed to allow site-selective incorporation of various anions, including Cl, Br, OMs, OTs, and OTf. This approach is enabled by in situ generation of reactive, non-symmetric iodanes by combining anions and bench-stable PhI(OAc)2. The utility of this mechanism is demonstrated via para-selective chlorination of medicinally relevant arenes, as well as site-selective C-H chlorination of heteroarenes. Spectroscopic, computational, and competition experiments describe the unique nature, reactivity, and selectivity of these transient, unsymmetrical iodanes.

Catalytic ß C-H amination via an imidate radical relay.

The first catalytic strategy to harness imidate radicals for C-H functionalization has been developed. This iodine-catalyzed approach enables ß C-H amination of alcohols by an imidate-mediated radical relay. In contrast to our first-generation, (super)stoichiometric protocol, this catalytic method enables faster and more efficient reactivity. Furthermore, lower oxidant concentration affords broader functional group tolerance, including alkenes, alkynes, alcohols, carbonyls, and heteroarenes. Mechanistic experiments interrogating the electronic nature of the key 1,5 H-atom transfer event are included, as well as probes for chemo-, regio-, and stereo-selectivity.

δ C-H (hetero)arylation via Cu-catalyzed radical relay.

A Cu-catalyzed strategy has been developed that harnesses a radical relay mechanism to intercept a distal C-centered radical for C-C bond formation. This approach enables selective δ C-H (hetero)arylation of sulfonamides via intramolecular hydrogen atom transfer (HAT) by an N-centered radical. The radical relay is both initiated and terminated by a Cu catalyst, which enables incorporation of arenes and heteroarenes by cross-coupling with boronic acids. The broad scope and utility of this catalytic method for δ C-H arylation is shown, along with mechanistic probes for selectivity of the HAT mechanism. A catalytic, asymmetric variant is also presented, as well as a method for accessing 1,1-diaryl-pyrrolidines via iterative δ C-H functionalizations.

Chiral piperidines from acyclic amines via enantioselective, radical-mediated δ C-H cyanation.

Piperidines are the most prevalent heterocycle found in medicines. Yet, while they are often chiral, there remain no robust methods for their asymmetric syntheses. To solve this challenge, we have interrupted the century-old Hofmann-Löffler-Freytag (HLF) reaction to afford this privileged heterocycle. The catalytic, regio- and enantio- selective δ C-H cyanation of acyclic amines described herein, incorporates a carbonyl equivalent selectively at the δ position. This δ C-H cyanation is enabled by a chiral Cu catalyst, which both initiates and terminates intramolecular hydrogen atom transfer (HAT) by an N-centered radical relay mechanism. The broad scope and utility of this highly enantioselective method for δ C-C formation is presented, as well as conversion of the resulting enantioenriched δ amino nitriles to a family of chiral piperidines. Experiments probing the chemo-, regio-, and enantio- selectivity of this HAT mechanism are also included to enable extension to other stereoselective δ C-H functionalizations.