1 Introduction
The cyclopropane ring is a versatile building block in organic synthesis [1]. Cyclopropanes possess unique physical, chemical, and electronic properties as a result of
ring strain (27.5 kcal/mol) [2, 3]. Found in numerous natural products, the smallest
carbocycle has been both a challenge and an inspiration for synthetic organic
chemists [4, 5]. Cyclopropanes are also commonly encountered in current drug
targets, where they act as conformational restrictors, thereby orienting a molecule
into its bioactive conformation and potentially increasing its potency or providing
an improvement in metabolic stability of certain compounds [6]. Recently, the
cyclopropane ring was ranked 10th in a top 100 list of the most frequently used
rings in the synthesis of small molecule drugs, thus highlighting its continual
relevance in medicinally active compounds [7].
Significant efforts have been dedicated to the syntheses of cyclopropanes in both
racemic or enantioenriched forms [8–10]. Cyclopropanes may also act as precursors
en route toward accessing more chemical complexity, via involvement in various
reactions such as cycloadditions, ring openings, or cross-couplings. In particular,
there is ample literature precedence for the functionalization of cyclopropanes via
cross-coupling reactions [11]. The cyclopropane can act as either the “nucleophile”
(organometallic reagent) or “electrophile” (cyclopropyl halide). Both roles can
require numerous synthetic steps to achieve the pre-functionalized partners,
resulting in unnecessary waste. One solution to the problem of
pre-functionalization would be to use only one pre-functionalized coupling partner
and employ the cyclopropyl C–H bond as a functional group. The inherent ring
strain of the three-membered ring and orbital rehybridization results in enhanced
acidity of cyclopropane C–H bonds, thereby facilitating such transformations. A
commonly encountered problem in the activation of alkanes with transition metals
is their propensity for β-hydride elimination [12]. In cyclopropanes, β-hydride
elimination would result in the formation of a cyclopropene species, which is
unfavorable thermodynamically [11]. While C–H bond functionalization at sp
2
and sp
3 centers has been vastly explored in the last decades [13–16], full reports
concerning cyclopropanes have only lately appeared in the literature. The current
chapter presents a comprehensive review of the direct transformations of the
cyclopropane C–H bond via transition-metal catalysis.
2 Early Contributions from the Yu and Sanford Groups
The functionalization of cyclopropanes such as 1 via amide-directed metalation
followed by quenching with an electrophile (e.g., iodine) is well known in the
literature (Scheme 1a) [17, 18]. However, it was not until 2005 that the first
example of a transition-metal-catalyzed direct functionalization process of a cyclopropane C–H bond was disclosed [19]. The use of a chelating oxazoline-based
auxiliary (derived from (S)-tert-leucinol) enabled iodination of primary C(sp
3 )–H
92
D. Sustac Roman and A.B. Charette
The cyclopropane ring is a versatile building block in organic synthesis [1]. Cyclopropanes possess unique physical, chemical, and electronic properties as a result of
ring strain (27.5 kcal/mol) [2, 3]. Found in numerous natural products, the smallest
carbocycle has been both a challenge and an inspiration for synthetic organic
chemists [4, 5]. Cyclopropanes are also commonly encountered in current drug
targets, where they act as conformational restrictors, thereby orienting a molecule
into its bioactive conformation and potentially increasing its potency or providing
an improvement in metabolic stability of certain compounds [6]. Recently, the
cyclopropane ring was ranked 10th in a top 100 list of the most frequently used
rings in the synthesis of small molecule drugs, thus highlighting its continual
relevance in medicinally active compounds [7].
Significant efforts have been dedicated to the syntheses of cyclopropanes in both
racemic or enantioenriched forms [8–10]. Cyclopropanes may also act as precursors
en route toward accessing more chemical complexity, via involvement in various
reactions such as cycloadditions, ring openings, or cross-couplings. In particular,
there is ample literature precedence for the functionalization of cyclopropanes via
cross-coupling reactions [11]. The cyclopropane can act as either the “nucleophile”
(organometallic reagent) or “electrophile” (cyclopropyl halide). Both roles can
require numerous synthetic steps to achieve the pre-functionalized partners,
resulting in unnecessary waste. One solution to the problem of
pre-functionalization would be to use only one pre-functionalized coupling partner
and employ the cyclopropyl C–H bond as a functional group. The inherent ring
strain of the three-membered ring and orbital rehybridization results in enhanced
acidity of cyclopropane C–H bonds, thereby facilitating such transformations. A
commonly encountered problem in the activation of alkanes with transition metals
is their propensity for β-hydride elimination [12]. In cyclopropanes, β-hydride
elimination would result in the formation of a cyclopropene species, which is
unfavorable thermodynamically [11]. While C–H bond functionalization at sp
2
and sp
3 centers has been vastly explored in the last decades [13–16], full reports
concerning cyclopropanes have only lately appeared in the literature. The current
chapter presents a comprehensive review of the direct transformations of the
cyclopropane C–H bond via transition-metal catalysis.
2 Early Contributions from the Yu and Sanford Groups
The functionalization of cyclopropanes such as 1 via amide-directed metalation
followed by quenching with an electrophile (e.g., iodine) is well known in the
literature (Scheme 1a) [17, 18]. However, it was not until 2005 that the first
example of a transition-metal-catalyzed direct functionalization process of a cyclopropane C–H bond was disclosed [19]. The use of a chelating oxazoline-based
auxiliary (derived from (S)-tert-leucinol) enabled iodination of primary C(sp
3 )–H
92
D. Sustac Roman and A.B. Charette