A Comprehensive Review of Radical-Mediated Intramolecular Cyano-Group Migration

Abstract

The radical-mediated intramolecular translocation of cyano groups has been recognized as a useful tool for the site-selective functionalization of organic molecules. The process is believed to proceed through the addition of an in situ-generated carbon-centered radical to the nitrile triple bond, followed by the β-scission of the resulting cyclic iminyl radical intermediate to relocate the cyano group and produce a more stable carbon radical for further elaboration. Beginning in the early 1960s and continuing for the next forty years, the research in this particular area has seen a surge of growth during the past two decades with advancements in radical chemistry and photocatalysis. The present article attempts to conduct a comprehensive review of existing studies on this topic by covering the literature from 1961 to 2025. The procedures developed for the purpose are grouped and discussed in four sections according to the strategies used to generate the initial carbon radicals, which include (i) hydrogen-atom transfer (HAT), (ii) radical addition to the π system, (iii) halogen-atom transfer (XAT), and (iv) the homolytic fission of a C-C single bond. In each section, a specific emphasis will be placed on reaction conditions, substrate scopes, and mechanisms.

Keywords: cyano group; intramolecular migration; nitrile; photocatalysis; radicals; site-selective functionalization; translocation.

Scheme 16

Synthesis fluorinated ketonitriles via photoredox-promoted 1,4-cyano-migration (Zhu, 2017) [68].

Scheme 17

Synthesis of 1,8-diketones via photoredox-promoted coupling and 1,4-cyano migration (Zhu, 2019) [70].

Scheme 18

Cyanotrifluoromethylthiolation of alkynes via radical-mediated CN migration (Zhu, 2018) [71].

Scheme 1

General schemes for radical-mediated cyano-group migration.

Figure 1

DFT energy calculation for radical cyclization onto nitrile group (Lafzi, 2023) [37].

Scheme 2

1,4-cyano migrations of steroidal cyanohydrins via HAT (a) with 20-hydroxy-20-cyano-steroid (b) with 11β-nitrite steroidal cyanohydrin (Kalvoda, 1961 and 1970) [29,38].

Scheme 3

Conversion of α-peracetoxynitriles into δ-ketonitriles via HAT-mediated 1,4-CN migration (Watt, 1976) [39].

Scheme 4

Conversion of cyanohydrins into δ-ketonitriles under photoredox catalytic conditions (Zhu, 2019) [43].

Figure 2

Concept of using radical sampling strategy to achieve 1,4-cyano translocation.

Scheme 5

Selected examples for 1,4-CN migration of nitriles via radical sampling strategy (Xu, 2023) [46].

Scheme 6

Trichloromethyl radical-triggered 1,3-cyano-migration (Johnson, 1982) [48].

Scheme 7

2-Cyano-isopropyl radical-triggered 1,3-CN migration (Montevecehi, 1997) [49].

Scheme 8

Radical-mediated carbocyanation of olefins (Inoue, 2012) [50].

Scheme 9

Annulation involving radical-addition-triggered 1,4-CN migration (Curran, 1992) [51].

Scheme 10

Amidyl radical-induced cyclization involving 1,4-CN migration (Zard, 1994) [52].

Scheme 11

Formation of 5-substituted 1,3-dimethyluracil via the photoaddition of alkene to 6-cyanouracil (Saito, 1980) [53].

Scheme 12

1,3-Migration of cyano group via photolysis of geranonitrile (Wolff, 1978) [54].

Scheme 13

Strategies for radical-mediated alkene difunctionalization (a) via radical coupling, oxidation-nucleophilic addition or organometallation (b) via cyano-group migration.

Scheme 14

Radical-mediated azidocyanation of alkenes via 1,4(5)-CN migration (Zhu, 2016) [65].

Scheme 15

Radical-mediated cyanotrifluoromethylthiolation of alkenes via 1,4(5)-CN migration (Zhu, 2017) [67].

Scheme 19

Diverse difunctionalization of alkenes via radical-mediated 1,4(5)-CN migration (Liu, 2016) [72].

Scheme 20

Copper-catalyzed 1,2-aminocyanation of alkenes via 1,4-CN migration (Wang, 2020) [80].

Scheme 21

Benzoylcyanation of alkene via Photoredox-promoted 1,4-CN migration (Ngai, 2019) [82].

Scheme 22

Construction of cyclohexene via radical-mediated cyanofunctionlization of alkene and HWE olefination (Feng, 2021) [83].

Scheme 23

Electrochemical alkene azidocyanation via 1,4-nitrile migration (Morrill, 2022) [84].

Scheme 24

Trifunctionalization of hexenenitriles via azido radical-mediated cyano-migration (Zhu, 2022) [85].

Scheme 25

Photochemical alkene trifluoromethylimination involving 1,4-CN migration (Yang, 2023) [86].

Scheme 26

NHC-catalyzed radical-relay trifluoromethylation-acylation of hexenenitriles via cyano-migration (Du, 2023) [87].

Scheme 27

Dual NHC/photoredox catalytic trifluoromethylation-acylation of hexenenitriles via cyano-migration (Du, 2024) [89].

Scheme 28

Copper-catalyzed 1,5-trifluoromethylthio- or selenocyanation of 5-hexenenitriles via cyano-migration (Guo, 2025) [90].

Scheme 29

Construction of oxindoles via tandem sulfonylation-initiated cyano-migration/cyclization cascade (2025, Wang) [91].

Scheme 30

Photoredox functionalization of hexenenitriles with Togni II reagent and external nucleophiles (Chen, 2022) [92].

Scheme 31

Photoredox functionalization of hexenenitriles with BrCF₂CO₂Et in MeCN (Guo, 2023) [93].

Scheme 32

Photoredox diamidation of hexenenitriles using O-acyl hydroxylamine in MeCN (Akondi, 2025) [94].

Scheme 33

Construction of substituted cyclopentanes via radical-triggered transannular cyano-migration (Zhu, 2025) [95].

Scheme 34

Alkylcyanation of unactivated Alkenes with protic C(sp³)-H feedstocks via cyano-group migration (Deng, 2025) [97].

Scheme 35

Cyano-migration-mediated radical–polar crossover cyclopropanation and formation of sultine product (Zhu, 2024) [99].

Scheme 36

Formation of olefinic β-cyanosulfones via radical-mediated functionalization of diphenyl hexenenitriles (Zhu, 2023) [100].

Scheme 37

Photolytic reactions of alkenyl malononitriles with trifluoromethyl thianthrenium salt (Huang, 2023) [101].

Scheme 38

Photo/cobalt-catalyzed functionalization of alkenes via FGM and co-promoted HAT (Wang, 2024) [102].

Scheme 39

Branch-selective cyanation of alkenes through photo-induced traceless functional group translocation (Shu, 2025) [105].

Scheme 40

Di-π-ethane rearrangement of cyano groups via energy-transfer catalysis (Huang, 2024) [106].

Scheme 41

Diastereoselective synthesis of 5/6fFused bicyclic ring systems via radical cyano-group migration (Wang, 2025) [108].

Scheme 42

Synthesis of cyclic imines via radical-triggered 1,3-cyano migration of N-allyl enamines (Pan, 2024) [109].

Scheme 43

Homopolymerization of linear α-olefins enabled by radical-mediated 1,4-cyano-group migration (2024, Li) [112].

Scheme 44

XAT-mediated CN migration of o-bromophenyl and bromovinyl cyanoacetates (Beckwith, 1987, 1988) [114,115].

Scheme 45

Reactions reported for α-(bromophenylamino)nitrile 146 under the same conditions (a) Cossy’s report. (b) Sulsky’s report (Cossy, 1995; Sulsky, 1999) [116,117].

Figure 3

Configuration inversion during the cyclization of 150 into 151 (Sulsky, 1999) [117].

Scheme 46

Nitrile transfer or cyclization reactions influenced by α-substituents (Bowman, 2000) [118].

Scheme 47

XAT-mediated cyano-migration of 1,3-dioxane-4-nitriles (Ryclmovsky, 1997) [119].

Scheme 48

Preparation of β-rhamnopyranoside from thioglycoside via nitrile transfer/fragmentation (Crich, 2006) [120].

Scheme 49

Total synthesis of a natural tetrasaccharide via one-pot quadruple radical fragmentation (Crich, 2006) [121].

Scheme 50

Synthesis of lennoxamine through cyano-migration (Orito, 2009) [122].

Scheme 51

Functionalization of cyclic ketones via LMCT-mediated C-C bond cleavage and cyano-migration (Zou, 2020) [123].

Scheme 52

Preparation of δ-sulfonyl nitriles via decarboxylation-triggered 1,4-cyano-migration (Chen, 2024) [124].

Scheme 53

1,3-Cyano migration triggered by reductive ring opening (Zhu, 2017) [125].