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Ni-catalyzed Carboxylation of Unactivated Alkyl Chlorides with CO2 Marino Börjesson, Toni Moragas, and Ruben Martin J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b04088 • Publication Date (Web): 07 Jun 2016 Downloaded from http://pubs.acs.org on June 7, 2016
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Journal of the American Chemical Society
Ni-catalyzed Carboxylation of Unactivated Alkyl Chlorides with CO2 Marino Börjesson,† Toni Moragas† and Ruben Martin†§* †Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països Catalans 16, 43007 Tarragona, Spain § Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluïs Companys, 23, 08010, Barcelona, Spain Supporting Information Placeholder ABSTRACT: A catalytic carboxylation of unactivated primary, secondary & tertiary alkyl chlorides with CO2 at atmospheric pressure is described. This protocol represents the first intermolecular cross-electrophile coupling of unactivated alkyl chlorides, thus leading to new knowledge in the cross-coupling arena.
Catalytic cross-electrophile coupling processes of organic (pseudo)halides have gained considerable momentum,1 representing straightforward alternatives to classical nucleophilic/electrophilic regimes based on welldefined, and in many instances, air-sensitive organometallic reagents (Scheme 1, path b vs path a).2 While notorious difficult transformations have been developed, the formidable high activation energy required for effecting C(sp3)–Cl cleavage and the inherent proclivity of alkyl metal species towards parasitic β-hydride elimination or homodimerization pathways3 has contributed to the prevailing perception that unactivated alkyl chlorides cannot be utilized in intermolecular cross-electrophile events.4,5 If successful, however, such a largely void terrain would not only lead to new knowledge in retrosynthetic analysis, but also would set the stage for iterative techniques with polyhalogenated backbones,6 a highly rewarding scenario that would dramatically improve our ever-expanding synthetic portfolio.
In recent years, carbon dioxide (CO2) has gained considerable momentum as C1 synthon in catalytic endeavors, holding promise to create new paradigms in synthetic sequences.7 Among these, the ability to prepare carboxylic acids from CO2 is particularly appealing due to the ubiquity of these recurrent motifs in a myriad of biologically-relevant molecules.8 Prompted by the work of Osakada,9 we10 and others11 have described catalytic carboxylation techniques of organic (pseudo)halides. Despite the advances realized, (a) the carboxylation of unactivated secondary or tertiary organic (pseudo)halides still constitutes a daunting, yet unsolved, challenge and (b) unactivated alkyl chlorides cannot be employed as coupling partners, neither in carboxylation events nor in intermolecular cross-electrophile coupling reactions.4 Herein, we describe the realization of all these challenges by designing a catalytic carboxylation that allows for the coupling of unactivated primary, secondary and even tertiary alkyl chlorides (Scheme 1, bottom). This protocol operates with an exquisite chemoselectivity profile at atmospheric pressure of CO2 while obviating the need for stoichiometric organometallic reagents. Table 1. Optimization of the Reaction Conditions.a
Scheme 1. Unactivated Alkyl Chlorides in Cross-Coupling. "Unconventional" crosselectrophile regimes
"Classical" nucleophileelectrophile regimes δ- M nucleophile H M=MgX,ZnX,..
catalyst path a
well-defined R-M ample precedents
δ+ electrophile
δ+ X H X = Cl
