C-H Functionalization via Iron-Catalyzed Carbene-Transfer Reactions

Abstract

The direct C-H functionalization reaction is one of the most efficient strategies by which to introduce new functional groups into small organic molecules. Over time, iron complexes have emerged as versatile catalysts for carbine-transfer reactions with diazoalkanes under mild and sustainable reaction conditions. In this review, we discuss the advances that have been made using iron catalysts to perform C-H functionalization reactions with diazoalkanes. We give an overview of early examples employing stoichiometric iron carbene complexes and continue with recent advances in the C-H functionalization of C(sp²)-H and C(sp³)-H bonds, concluding with the latest developments in enzymatic C-H functionalization reactions using iron-heme-containing enzymes.

Keywords: C-H functionalization; carbene; diazoalkane; iron.

Scheme 1

Strategies for the functionalization of C-H bonds. (a) directing-group-assisted C-H activation, (b) innate reactivity of organic molecules, (c) direct C-H functionalization of C-H bonds.

Scheme 2

Photochemical C-H functionalization of diethyl ether with diazomethane.

Scheme 3

(a) Seminal iron-catalyzed cyclopropanation by Hossain et al. [22]. (b) Privileged iron catalysts in carbene-transfer reactions.

Scheme 4

Mechanism of the formation of iron carbene complexes.

Scheme 5

Intramolecular C-H insertion reactions for the synthesis of cyclopentane derivatives (13,14) by Helquist and coworkers [29,30].

Scheme 6

Possible products in the iron-catalyzed functionalization of toluene 15 by carbene insertion.

Scheme 7

(Left): functionalization of arenes 21 with ethyl diazoacetate 2; (Right): iron-pytacn complex.

Scheme 8

Proposed reaction pathway for the C-H functionalization reaction of arenes (21) using ethyl diazoacetate 2.

Scheme 9

Chemoselectivity between C(sp²)-H bond and C(sp³)-H bond insertion reaction investigated by Woo and coworkers [34].

Scheme 10

Iron-catalyzed arylation of donor-acceptor diazo compound 29 with N,N-dialkyl anilines 28 by the Zhou group [36].

Scheme 11

Iron-catalyzed reaction of ethyl diazoacetate 2 with indole 31 and pyrrole 32.

Scheme 12

Enantioselective iron-catalyzed C-H functionalization of TBS-indole (34) with α-aryl-α-diazoesters (29), described by Zhou et al. [38].

Scheme 13

Reaction of diazoacetonitrile 38 with indole heterocycles using Fe(TPP)Cl, reported by Koenigs, Weissenborn, and coworkers [39].

Scheme 14

Hypothesized mechanism for the C-H functionalization of indole with iron carbene complexes and experimental evidence. (a) mechanistic proposal by Zhou et al., [38], (b) experimental evidence from the reaction with methyl phenyldiazoacetate [38], (c) evidence from the reaction with diazoacetonitrile [39].

Scheme 15

Reaction of α-aryl-α-diazoesters with cyclohexane (47), THF (49), and mesitylene (52).

Scheme 16

Studies on the selectivity of iron-catalyzed C(sp³)-H insertion reactions.

Scheme 17

Intramolecular cyclisation via C-H functionalization for the synthesis of sulfonate esters.

Scheme 18

Intramolecular alkylation reaction for the synthesis of five membered rings.

Scheme 19

Enzyme-catalyzed C3-alkylation reaction of indoles.

Scheme 20

Mechanistic investigations and proposed catalytic cycle by the Fasan group.

Scheme 21

Indole C3-alkylation with engineered P411-HF enzymes; regioselective alkylation of 1-methylpyrrole 53.

Scheme 22

C-H functionalization using engineered P411-CHF and P411-PFA enzymes.