A Type of Stable Amides Behaves as Acyl Transfer Reagents upon Visible-Light Irradiation through Self-Aromatization.

Organic molecules with light-modifiable reactivity are important in many fields because they can serve as the "switch" for light to trigger chemical processes. Herein, we disclose a new type of stable non-twisted amides, the reactivity of which can be turned on by light as acyl transfer reagents. Upon photo-activation, these amides react with various nucleophiles including amines, phenols, hydroxide, thiols, boronic acids, and alkynes either under metal-free or metal-catalysis conditions. This reactivity hinges on the design and synthesis of a photo-activatable reagent (7-nitro-5,6-dihydrophenanthridine), which undergoes self-aromatization enabled by an internal oxidant under light. This masked acyl donor group is anticipated to be useful in scenarios where light is preferred to trigger a chemical process.

Amide Skeletal Elongation via Amino Acid Insertion.

Amide derivatization is useful to access valuable organic compounds considering the ready availability of molecules containing amide functionality. Current methods to derivatize amide mainly focus on the synthesis of carbonyl-containing compounds and amines. Incorporating both parts of the initial amide into the new derivatives is rare. Herein, we describe a simple and practical amide derivatization through amino acid insertion to prepare more complex amides. This insertion is applicable to a wide range of amino acids and more importantly, the chiral information is completely conserved during the insertion. Comparison of this insertion strategy with conventional amide synthesis demonstrates the synthetic advantages of this new protocol.

Reactivity Umpolung of Tertiary Amide Enabled by Catalytic Reductive Stannylation.

Reactivity umpolung is an important concept in organic chemistry. Established reactivity umpolung mainly focuses on the aldehyde and umpolung of amide carbonyl group is not known. In this report, we describe a process to obtain the umpolung reactivity of tertiary amide. This process hinges on the efficient reductive stannylation catalyzed by Ir/silane and facile Sn-Li exchange. By leveraging this umpolung reactivity, drug Fluoxetine was derivatized to 12 different analogues via reacting with various electrophiles and four biologically active molecules were prepared concisely. This unlocked umpolung reactivity of tertiary amide is expected to find applications to synthesize complex amines from amides.

Simple and Practical Conversion of Benzoic Acids to Phenols at Room Temperature.

Phenols are important organic molecules because they have found widespread applications in many fields. Herein, an efficient and practical approach to prepare phenols from benzoic acids via simple organic reagents at room temperature is reported. This approach is compatible with various functional groups and heterocycles and can be easily scaled up. To demonstrate its synthetic utility, bioactive molecules and unsymmetrical hexaarylbenzenes have been prepared by leveraging this transformation as strategic steps. Mechanistic investigations suggest that the key migration step involves a free carbocation instead of a radical intermediate. Considering the abundance of benzoic acids and the utility of phenols, it is anticipated that this method will find broad applications in organic synthesis.

Catalytic dehydrogenative synthesis of α,ß-unsaturated secondary amides without external oxidants.

Direct dehydrogenative synthesis of α,ß-unsaturated secondary amides still represents an elusive transformation. Herein we describe a palladium-catalyzed redox-neutral desaturation to prepare α,ß-conjugated secondary amides. Without external oxidants, this approach relies on the N-O bond cleavage as the driving force to achieve formal dehydrogenation. Complementary to known protocols, this transformation is enabled by the unique reactivity of hydroxamate, thereby representing a novel strategy to accomplish carbonyl desaturation. Desired conjugated secondary amides can be efficiently synthesized in the presence of more reactive esters and even ketones, thus providing a solution to the long-standing issue of α,ß-unsaturated secondary amides via C-C desaturation.

Unified ionic and radical C-4 alkylation and arylation of pyridines.

C-H Functionalization of pyridines is an efficient strategy to access pyridine derivatives occurring in pharmaceuticals, agrochemicals, and materials. Nucleophilic additions to pyridiniums via both ionic and radical species have proven particularly useful. However, these reactions suffer from poor regioselectivity. By identifying an enzyme-mimic pocket-type urea activation reagent, we report a general platform for pyridine C-4 functionalization. Both ionic and radical nucleophiles can be incorporated to achieve the alkylation and arylation. Notably, the highly regioselective C-4 radical arylation is disclosed for the first time. The broad scope of nucleophiles and pyridines renders this platform applicable to the late-stage functionalization of drug-like molecules and the preparation of complex biologically important molecules.

Dual role of nitroarenes as electrophiles and arylamine surrogates in Buchwald-Hartwig-type coupling for C-N bond construction.

One of the most widely utilized methods for the construction of C(sp2)-N bonds is the transition-metal-catalyzed cross-coupling of aryl halides/boronic acids with amines, known as Ullmann condensation, Buchwald-Hartwig amination, and Chan-Lam coupling. However, aryl halides/boronic acids often require multi-step preparation while generating a large amount of corrosive and toxic waste, making the reaction less attractive. Herein, we present an unprecedented method for the C(sp2)-N formation via Buchwald-Hartwig-type reactions using synthetically upstream nitroarenes as the sole starting materials, thus eliminating the need for arylhalides and pre-formed arylamines. A diverse range of symmetrical di- and triarylamines were obtained in a single step from nitroarenes, and more importantly, various unsymmetrical di- and triarylamines were also highly selectively synthesized in a one-pot/two-step process. Furthermore, the success of the scale-up experiments, the late-stage functionalization of a drug intermediate, and the rapid preparation of hole-transporting material TCTA showcased the utility and practicality of this protocol in synthetic chemistry. Mechanistic studies indicate that this transformation may proceed via an arylamine intermediate generated in situ from the reduction of nitroarenes, which is followed by a denitrative Buchwald-Hartwig-type reaction with another nitroarene to form a C-N bond.

Decarboxylative Enamide Synthesis from Carboxylic Acid and Alkenyl Isocyanate.

Herein, we reported a protocol to access the enamide via employing carboxylic acid and alkenyl isocyanate as the precursors promoted by DMAP without involving any metal catalysts and dehydration reagents. This protocol is simple and practical and tolerates numerous functional groups. Considering the simplicity, the ready availability of both starting materials, and the significance of the enamides, we expect that this reaction will find broad application.

Selective Hydrolysis of Primary and Secondary Amides Enabled by Visible Light.

Amide hydrolysis is a fundamentally important transformation in organic chemistry. Developing hydrolysis procedures under mild conditions with a broad substrate scope is desirable. Herein, by leveraging a photoresponsive auxiliary o-nitroanilide, we established a mild two-step protocol for the hydrolysis of primary and secondary amides. This protocol is driven by visible light irradiation at room temperature under neutral conditions, which tolerates numerous acid- and base-sensitive functional groups. Various drugs, natural product-, and amino acid-derived amides can be selectively hydrolyzed.

Deaminative Addition of Alkylpyridinium Salt to Aldehyde.

Here we show that a primary amine can engage in the nucleophilic addition to an aldehyde to synthesize an alcohol following preactivation of the amine. The enabling reagent for this radical-polar crossover process is CrCl2. This reaction is selective for aldehydes and compatible with numerous functional groups, which are not tolerated under classical Grignard-type conditions. Complementary to the well-established imine synthesis, this deaminative alcohol synthesis can broadly expand the chemical space constructed by aldehydes and amines.