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 strategy for both
cross-electrophile coupling and 1,2-dicarbofunctionalization
of olefins has been developed. Carbon-centered radicals are generated
from alkyl bromides by merging benzophenone hydrogen atom transfer
(HAT) photocatalysis and silyl radical-induced halogen atom transfer
(XAT) and are subsequently intercepted by a nickel catalyst to forge
the targeted C(sp
3
)–C(sp
2
) and C(sp
3
)–C(sp
3
) bonds. The mild protocol is fast
and scalable using flow technology, displays broad functional group
tolerance, and is amenable to a wide variety of medicinally relevant
moieties. Mechanistic investigations reveal that the ketone catalyst,
upon photoexcitation, is responsible for the direct activation of
the silicon-based XAT reagent (HAT-mediated XAT) that furnishes the
targeted alkyl radical and is ultimately involved in the turnover
of the nickel catalytic cycle.
A general strategy for the synthesis of arylthio cyclopropyl carbaldehydes and ketones via acid catalysed arylthiol addition/ring contraction reaction sequence has been exploited. The procedure led to a wide panel of cyclopropyl carbonyl compounds in high yields and broad substrate scope.
A continuous flow Norrish–Yang photocyclization of 1,2-diketones has been developed and applied to the synthesis of functionalized 2-hydroxycyclobutanones, under blue light irradiation.
A general
strategy for the synthesis of indolyl cyclopropanecarbaldehydes
and ketones via a Brønsted acid-catalyzed indole nucleophilic
addition/ring-contraction reaction sequence has been exploited. The
procedure leads to a wide panel of cyclopropyl carbonyl compounds
in generally high yields with a broad substrate scope.
An original tandem reaction consisting of a Wittig reaction−ring contraction process between α-hydroxycyclobutanone and phosphonium ylides has been developed. Highly functionalized cyclopropanecarbaldehydes are obtained in good to high yield.
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