Fe-Catalyzed Cross-Dehydrogenative Coupling Reactions
Leiyang Lv 0 1
Zhiping Li 0 1
0 Department of Chemistry, Renmin University of China , Beijing 100872 , China
1 & Zhiping Li
Cross-dehydrogenative coupling (CDC), which enables the formation of carbon-carbon (C-C) and C-heteroatom bonds from the direct coupling of two C-H bonds or C-H/X-H bonds, represents a new state of the art in the field of organic chemistry. Iron, a prominent metal, has already shown its versatile application in chemical synthesis. This review attempts to provide a comprehensive understanding of the evolution of cross-dehydrogenative coupling via iron catalysis, as well as its application in synthetic chemistry. This article is part of the Topical Collection ''Ni- and Fe-Based Cross-Coupling Reactions'', edited by Arkaitz Correa.
Cross-dehydrogenative coupling (CDC); Iron catalysis; C-C bond; C-X bond
1 Introduction
The development of selective, efficient, sustainable, and environmentally benign
synthetic methodologies for the formation of carbon–carbon (C–C) and C–
heteroatom bonds is an area of great interest to chemists, and one that is being
actively pursued. Carbon–hydrogen (C–H) bonds exist broadly in a variety of
organic molecules. Catalytic functionalization of C–H bonds has evolved as a
powerful tool for organic synthesis, which not only provides an atom-economic
alternative method, but also opens new routes to the target molecules. This trend is
evidenced by reports of the ever-increasing utilization of C–H bonds as substrates
for cross-coupling reactions [1–6]. Among reported methods,
crossdehydrogenative coupling (CDC), which enables C–C and C–heteroatom bond
formation from the direct coupling of two C–H bonds or C–H/X–H bonds, has
emerged as the most attractive—and also the most challenging [7–10]. It is worth
noting that in most cases, hydrogen gas (H2) is not produced in CDC transformation,
and an appropriate sacrificial oxidant is generally needed. The obvious benefit of
this strategy is that there is no need for preparation and isolation of activated
reagents, or for pre-functionalization of easily available chemicals, thus improving
atom and step economy. However, the conundrum that chemists must confront is
how to overcome the low reactivity of C–H bonds and achieve site-selective
functionalization of one C–H bond in the presence of all others. Li et al. have
pioneered work addressing this challenge, and have made significant contributions
in developing a series of synthetic methodologies in this field [11–16].
Iron, as one of the most abundant metals, is particularly attractive given its low
cost, non-toxicity, and environmentally benign character. Various iron complexes
have been incorporated into biological systems, with resulting low toxicity that is
critical in the pharmaceutical and food industries. In addition, versatile
ironcatalyzed organic transformations have been achieved over the past few decades.
Several instructive and significant reviews have been published on this fascinating
chemistry from various perspectives [
17–22
].
The current review focuses mainly on the evolution of iron-catalyzed CDC
through C–H bond oxidation. Advances in other metal-mediated and metal-free
CDC reactions have already been well documented and are beyond the scope of this
work. In general, iron-catalyzed CDC results mainly in the formation of C–C, C–N,
and C–O bonds. This review is structured around the hybridization of both of the C–
H coupling partners. We hope that this paper provides a comprehensive overview of
this topic, sheds light on new perspectives, and inspires chemists to work towards
further improving and expanding the application of CDC.
2 Coupling of C(sp3)–H with X(sp3)–H
Iron-catalyzed direct C–H oxidation for the construction of C–C and C–X bonds
(X=O, S, N, P, etc.), with its remarkable potential for step efficiency, atom
economy, and environmental sustainability, has emerged as one of the most
significant tools in synthetic organic chemistry. Oxidative C(sp)–H and C(sp2)–H
cross-coupling for the formation of C–C bonds has garnered much attention and has
seen great progress over the past decade. However, oxidative couplings involving
C(sp3)–H bonds remain challenging, given their low reactivity and lack of
suitable coordination site for the iron catalyst. The following section will focus on
advances in iron-catalyzed CDC reactions involving C(sp3)–H bonds. These
transformations are classified by the type of C–H bonds, including benzylic C–H
bonds and C–H bonds adjacent to heteroatoms (Fig. 1).
The general reaction pathway of iron-catalyzed CDC is depicted in Fig. 2. The
reaction with benzylic substrates proceeds as follows (Eq. 1): the initial hydrogen
abstraction of the substrate by the oxidant generates the carbon radical I. Then I is
further oxidized by the Fe catalyst through single-electron transfer (SET) to give the
radical cation II, which is trapped by a nucleophile to give the final product. The
process involving C(sp3)–H bonds adjacent (...truncated)