A photochemical dehydrogenative strategy for aniline synthesis

Abstract

Chemical reactions that reliably join two molecular fragments together (crosscouplings) are essential to the discovery and following manufacture of high-value materials like pharmaceuticals and agrochemicals. 1,2 In this area, the introduction of amines onto functionalised aromatics at specific and pre-determined positions (ortho vs meta vs para) is currently a prerogative of transition metal-catalysed processes and requires halogen/boron-containing substrates. 3-6 The introduction of these groups around the aromatic unit is dictated by the intrinsic reactivity profile of the method (e.g. electrophilic halogenation, C-H borylation) so selective targeting of all possible positions is often not possible. Here we report a noncanonical cross-coupling approach for the programmable construction of anilines on demand, exploiting saturated cyclohexanones as aryl electrophile surrogates. The condensation between amines and carbonyls, a process extensively used by Nature and (bio)organic chemists, 7 is the enabling feature that ensures a predetermined and site-selective carbon-nitrogen bond formation, while a synergistic photoredox and cobalt catalytic system is simultaneously employed to progressively desaturate the cyclohexene ring en route to the aniline. As functionalised cyclohexanones are readily accessible with complete regiocontrol by well-established carbonyl chemistry, this approach offers a solution to bypass some of the frequent selectivity issues of aromatic chemistry. The utility of this novel C-N coupling protocol was demonstrated by the preparation of commercial medicines and the late-stage amination-aromatization of natural products, steroids and terpene feedstocks.Innovations in synthetic chemistry are integral to the discovery and production of highvalue materials and medicines, and as a result, the well-being of society. In particular, chemical transformations able to couple together complex and functionalized building blocks in a site-selective and programmable manner are fundamental to downstream access to increasingly complex molecules. Within the realm of cross-coupling reactions, processes leading to the construction of C-N bonds across aromatic systems have played a fundamental role in assembling anilines, key structural elements of drugs, agrochemicals and materials. [8][9][10] Currently, the most reliable way to selectively introduce amines into specific positions on functionalised aromatics (ortho vs meta vs para), is to use palladium-or coppercatalysed strategies. 11 For these processes to work, the aromatic coupling partner needs to be pre-equipped with a (pseudo)halide (Buchwald-Hartwig 4,12 and Ullmann 6 crosscouplings) or a boronic acid (Chan-Lam cross-coupling 5 ) in order to generate arylpalladium/copper species that, after amine coordination and reductive elimination,

A cross-dehydrogenative C(sp3)−H heteroarylation via photo-induced catalytic chlorine radical generation

“…The addition of the so-formed alkyl radical to another equivalent of heteroarene 1-H + followed by hydrogen atom removal would give the desired alkylated heteroarene 3-H + . Meanwhile, to efficiently quench the generated radical intermediate II, a readily accessible cobaloxime catalyst [Co(dmgH) 2 (py)]Cl was introduced to the system [51][52][53][54][55] not only to prevent the over-reduction of intermediate II but also to serve as a terminal oxidant for the rearomatisation of alkylated intermediate III though H 2 evolution.…”

Stereoretentive N‐Arylation of Amino Acid Esters with Cyclohexanones Utilizing a Continuous‐Flow System

“…Although transition metal‐catalyzed N ‐arylation of amines with aryl halides is practical for synthesizing aryl amines, [17–19] it cannot be easily applied to stereoretentive reactions of amino acid esters (Scheme 1a); this N ‐arylation is limited by racemization and other side reactions from stoichiometric or excess amounts of strong base reagents [13–16] . In contrast, the catalytic N ‐arylation of amines with cyclohexanones is a promising method that can be applied to the synthesis of amino acid esters (Scheme 1b) [20–24] . Unlike transition metal‐catalyzed C−N couplings using aryl halides, this reaction proceeds under neutral conditions in the absence of base reagents and will, therefore, be compatible with base‐sensitive amino acid compounds.…”

“…[13][14][15][16] In contrast, the catalytic N-arylation of amines with cyclohexanones is a promising method that can be applied to the synthesis of amino acid esters (Scheme 1b). [20][21][22][23][24] Unlike transition metal-catalyzed CÀ N couplings using aryl halides, this reaction proceeds under neutral conditions in the absence of base reagents and will, therefore, be compatible with basesensitive amino acid compounds. Furthermore, this reaction, which consists of consecutive condensation and dehydrogenative aromatization, has several advantages over conventional CÀ N couplings: (i) small amounts of co-products such as H 2 O are easily removable, (ii) cyclohexanones bearing various functional groups can be prepared using classical synthetic methodologies as halogen-free sources of aromatic rings, and (iii) the use of heterogeneous Pd catalysts can significantly reduce the costs associated with the catalysis and the purification process.…”

Synthesis of N-aryl amines enabled by photocatalytic dehydrogenation

“… 5,6 Very recently, Leonori and co-workers successfully overcame the above-mentioned hurdles via photocatalytic dehydrogenation of in situ generated enamines with photoredox/cobalt dual catalytic system. 7 …”