Recent advances in C(sp3)–H bond functionalization via metal–carbene insertions

Recent advances in C(sp3)–H bond functionalization via metal–carbene insertions Bo Wang, Di Qiu, Yan Zhang and Jianbo Wang* Review Address: Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China Email: Jianbo Wang* - Open Access Beilstein J. Org. Chem. 2016, 12, 796–804. doi:10.3762/bjoc.12.78 Received: 01 February 2016 Accepted: 06 April 2016 Published: 25 April 2016 This article is part of the Thematic Series "C–H Functionalization/activation in organic synthesis". * Corresponding author Guest Editor: R. Sarpong Keywords: alkane; diazo compounds; C–H bond functionalization; C–H bond insertion; metal–carbene; site-selectivity © 2016 Wang et al; licensee Beilstein-Institut. License and terms: see end of document. Abstract The recent development of intermolecular C–H insertion in the application of C(sp3)–H bond functionalizations, especially for light alkanes, is reviewed. The challenging problem of regioselectivity in C–H bond insertions has been tackled by the use of sterically bulky metal catalysts, such as metal porphyrins and silver(I) complexes. In some cases, high regioselectivity and enantioselectivity have been achieved in the C–H bond insertion of small alkanes. This review highlights the most recent accomplishments in this field. Introduction Direct functionalization of inactivated C–H bonds, especially C(sp3)–H bonds, have attracted significant attentions in recent years. The C(sp3)–H bond activation strategies based on radical reactions and transition metal catalysis have been explored, alongside the development of various directing groups for controlling the site-selectivity of the reaction. Regardless of the great efforts devoted to the field, the intermolecular C(sp3)–H bond activation of simple alkanes still remains a formidable challenge, obviously attributed to the inertness and ubiquitous nature of simple aliphatic C(sp3)–H bonds. In this context, catalytic metal–carbene C(sp3)–H bond insertion represents an alternative and unique approach for this purpose. Metal–carbene insertion into a C(sp3)–H bond, well-recognized as one of the typical reactions of carbene species, have been studied extensively over the decades [1-8]. Mechanistically, the C(sp 3 )–H bond insertion reaction is considered to follow a concerted reaction pathway with a three-center two electron transition state (Scheme 1). Since late transition metals, typically Rh(II) complexes, are most commonly employed as the catalysts, the carbenic carbon of the metal–carbene species is positively charged in general, as shown by the resonance structure. Consequently, when the electron-deficient carbenic carbon approaches the C(sp3)–H bonds, the C–H bonds with high electron density will react preferentially [9]. However, the site- 796 Beilstein J. Org. Chem. 2016, 12, 796–804. Scheme 1: Pathway for transition-metal-catalyzed carbene insertion into C(sp3)–H bonds. selectivity of C(sp3)–H bond insertion is also affected by steric factors. High regioselectivity of C(sp3)–H bond insertions has been observed in intramolecular reactions in most cases, in which the C(sp3)–H bond positioned 5 atoms away from the carbene center will normally react preferentially (1,5 C–H insertion). However, 1,3-, 1,4, and 1,6 C–H insertions are also possible, depending on the substrates and the catalysts. Although the site-selectivity of intramolecular metal–carbene C(sp 3 )–H bond insertion is affected by the combination of factors such as steric and electronic factors as well as catalysts, high site-selectivity is generally achievable, which makes this type of reaction a valuable tool for the construction of carbocycles from readily available starting materials [1-6]. While most of the site-selective metal–carbene C(sp3)–H bond insertions are based on intramolecular reaction systems, or with relatively active C–H bonds, such as allylic, benzylic or the C–H bonds adjacent to the oxygen or nitrogen, the corresponding site-selective metal–carbene insertion into simple aliphatic C(sp3)–H bonds has also been challenged in intermolecular reaction systems and one has witnessed some exciting advances along this line. Thus, it would be an appropriate time to summarize the field in connection with direct C–H bond functionalization. Since catalytic metal–carbene C(sp3)–H bond insertions have been discussed in a series of excellent reviews [1-8], this short article will highlight the most recent developments in the field, with the emphasis on simple aliphatic C(sp3)–H bond insertions. Review been successfully incorporated into the steps in natural product synthesis. Herein some selected recent examples are highlighted. The C–H bond insertions at the α-positions of oxygen or nitrogen Attributed to the stabilizing effect of oxygen and nitrogen toward the positive charge development at the neighboring positions, the metal–carbene C–H bond insertions at these positions are favored. Davies and co-workers have recently reported a highly site-selective and enantioselective C–H bond insertion of methyl ethers [21]. The use of 2,2,2-trichloroethyl aryldiazoacetates, in combination with sterically crowded chiral Rh(II) catalysts Rh2(R-BPCP)4, enhances the site-selectivity and the enantioselectivity of the reaction. Interestingly, the C–H bonds of a methyl group show high reactivity over the secondary C–H bonds, even the secondary benzylic C–H bonds (Scheme 2). Notably, for the site-selectivity of carbene insertion into primary, secondary and tertiary C–H bonds, the electronic and steric factors operate in the opposite directions. It is thus possible to tune or even revise the selectivity by judicious combination of reagents and catalysts. Rh(II)-catalyzed site-selective and enantioselective intramolecular carbene insertion into the C–H bond at the α-position of a tertiary amine have been previously established by Davies and co-workers [22-24]. Recently, this methodology has been used in the late-stage C–H functionalization of complex alkaloids and drug molecules (Scheme 3) [25]. Metal carbene C(sp3)–H bond insertions into relatively active C–H bonds C–H bond insertions at the allylic and benzylic positions Compared to ordinary aliphatic C(sp3)–H bonds, the C(sp3)–H bonds located at allylic and benzylic sites and those at the α-position of oxygen or nitrogen, show high activity because of the stabilization of the partial positive charge developed in the transition state of the metal–carbene C–H bond insertion process. Such type of intramolecular metal–carbene C–H insertions shows high selectivities in many cases [10-20], and they have Metal–carbene C–H insertion is also favored for allylic and benzylic sites. In 2014, Davies and co-workers reported an enantioselective C–H insertion catalyzed by chiral dirhodium catalysts. The reaction took place selectively at the (...truncated)