Letter reSeArCH
Notably, when the reaction was run in the presence of a second, The initial N–H oxidative addition gave rise to a mixture of Ir(iii)
bulkier 1,3-diene—such as 2,3-dimethyl-1,3-butadiene—the result- hydride isomers (157 and 159), in which the exocyclic C–C bond of the
ing C-allylation intermediate led to a formal one-carbon homologa- dihydropyrazole was considerably weakened (bond dissociation energy
tion product upon ozonolysis (Fig. 3b). Various ketones with different of 39.0 kcal mol−1 and 36.5 kcal mol−1 for 157 and 159, respectively).
skeletons, including those with multiple substitutions at α and/or β From 159, the homolytic C–C cleavage (160-TS; Gibbs energy of acti-
positions, readily reacted and gave decent yields of the homologation vation ΔG‡ = 29.5 kcal mol−1 with respect to 159) yielded a transient
products over two steps. Various functional groups—such as aryl Ir(ii) species (161) and an alkyl radical, which then rapidly recom-
iodides (74) and bromides (73), aryl boronic esters (71) and silanes bined to form 162. The computed NICS(1)zz aromaticity index values
(70), epoxides (88), esters (69, 83), lactones (68), nitros (77), amides revealed a substantial increase in the aromaticity of the five-membered
(75, 76), sulfonamides (43, 52) and sulfones (46)—were tolerated. The ring that stabilizes 160-TS. As a comparison, without the driving force
strained cyclobutane motif remained untouched (80). This formal- of aromatization, the corresponding C–C cleavage of pyrazolidine 165′
homologation approach also enabled the preparation of 1,7-ketoesters requires a much higher barrier (Extended Data Fig. 3b). From 162,
(83) and enantioselective synthesis of ketones with γ-stereocentres an alkane and the pyrazole product 3 are formed via C–H reductive
(86) from readily available precursors. Ketones derived from natural elimination and subsequent ligand exchange. With understanding of the
products, such as the one from α-ionone (87), could also be used as reaction mechanism, future work will focus on enhancing the reaction
substrates. Compared with the classical carbenoid-mediated homolo- efficiency and discovering new transformations or applications based
gation28, this method features high reactivity and excellent site- and on this C–C activation mode.
Conversely, when cyclic ketones were used as substrates, a redox- Online content
neutral deconstructive pyrazole synthesis method was realized16,17
Any methods, additional references, Nature Research reporting summaries, source
(Fig. 4, Extended Data Fig. 1). As a highly important class of pharma-
cophores, pyrazoles are commonly found in bioactive compounds and
approved drugs29—for example celecoxib, rimonabant, fomepizole and
Received: 27August 2018;Accepted: 22 January 2019;
sildenafil. Although many methods have been developed for pyrazole
Published online 30 January 2019.
synthesis29, it could still be attractive to devise a straightforward and
oxidant-free approach to prepare complex functionalized pyrazoles
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0.7 g of product 91 was isolated in 90% yield (Fig. 4b). Compared
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mono-ketone functional group to be used as a handle. Thus, it provides
a simple and distinct strategy for the introduction of pyrazole moieties
into complex natural products or biologically interesting scaffolds
(Extended Data Fig. 2). In addition, simply by switching the 1,3-diene
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be difficult to access via conventional approaches. Given the wide avail-
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