Radical Reactions in Organic Synthesis: Exploring in-, on-, and with-Water Methods

Abstract

Radical reactions in water or aqueous media are important for organic synthesis, realizing high-yielding processes under non-toxic and environmentally friendly conditions. This overview includes (i) a general introduction to organic chemistry in water and aqueous media, (ii) synthetic approaches in, on, and with water as well as in heterogeneous phases, (iii) reactions of carbon-centered radicals with water (or deuterium oxide) activated through coordination with various Lewis acids, (iv) photocatalysis in water and aqueous media, and (v) synthetic applications bioinspired by naturally occurring processes. A wide range of chemical processes and synthetic strategies under different experimental conditions have been reviewed that lead to important functional group translocation and transformation reactions, leading to the preparation of complex molecules. These results reveal how water as a solvent/medium/reagent in radical chemistry has matured over the last two decades, with further discoveries anticipated in the near future.

Keywords: bioinspired reactions; on-water reactions; organic synthesis; photocatalysis; radical reactions; water and aqueous media; water coordination with Lewis acids.

Figure 22

Proposed mechanism in a tricyclic system [114].

Figure 44

(a) Transformation of ribonucleotides to 2′-deoxy-ribonucleotides by ribonucleotide reductases class Ia, active in eukaryotes and microorganisms (taken from Ref. [190]). (b) Some details of the complex radical mechanism at the active site of enzyme; in particular, the reaction 19 → 20 is the reduction of ketone by disulfide radical anion (taken from Ref. [195]).

Figure 45

(a) Hydrogen sulfide (H₂S/HS⁻) affords the sulfhydryl radical (HS^•/S^•−) by a variety of methods and adds reversibly to the parent compound to form the dimeric radical anion. (b) Dual catalytic/radical chain mechanism for the deoxygenation of cis-1,2-cyclopentanediol (22) to cyclopentanol 24) via cyclopentanone (23) in aqueous solutions (taken from Ref. [190]). (c) Dual radical chain mechanism for the deoxygenation of 2-hydroxycyclohexanone (29).

Figure 1

Mechanistic details of the formation of 2-deoxyribonolactone from 2′-deoxynucleosides: the C1′ radical is oxidized by addition to molecular oxygen, heterolytic cleavage with release of O₂^•−, followed by hydrolysis.

Figure 2

Oxidation of guanine moiety and the reaction with water, ultimately yielding 8-oxo-dG.

Figure 3

Radical chain mechanisms of (a) functional group reduction (X = atom or group) by a reducing agent MH; (b) halogen atom transfer in the new C–C bond formation.

Figure 4

Radical-based reactions using H₃PO₂ or Et₂P(O)H as reducing reagents in aqueous environments.

Figure 5

(a) Silyl-radical-mediated C–H alkylation of heterocycles with non-activated alkyl bromides. (b) Silyl-radical-mediated protocol for the fluorination of secondary alkyl bromides.

Figure 6

(a) Two examples of halogen atom transfer in intramolecular and intermolecular C–C bond formation, respectively. (b) Synthesis of ketones from alkenylsilanes under radical conditions with air as the oxidant.

Figure 7

A light-driven, copper-mediated, site-selective trifluoromethylation for C(sp³)–CF₃ formation in aqueous solution: (a) starting from alkyl bromides and Et₃SiH; (b) starting from O-alkyl thiocarbonates and (TMS)₃SiH; (c) starting from benzylic C–H and i-Pr₃SiH; bpp = 2,2′-bipyridine.

Figure 8

Copper-catalyzed trifluoromethylation using CF₃SO₂Na: (a) the mechanism of CF₃^• generation from CF₃SO₂Na and tert-butyl hydroperoxide (TBHP), and the addition products of two heterocycles where the yields refer to a 1 g scale; (b) trifluoromethylation of aryl and heteroaryl boronic acids; (c) decarboxylative trifluoromethylation of cinnamic acids; (d) synthesis of a variety of CF₃-containing oxindoles from N-arylacrylamides ‘‘on water’’ at room temperature.

Figure 9

(a) Aldehyde oxidation “on water”. (b) Tandem aldehyde oxidation/Passerini reaction “on water” including the reaction mechanism.

Figure 10

Photochemical hydroacylation of unactivated olefins “on water”.

Figure 11

The use of (TMS)₃SiH as a reducing agent in an aqueous environment: (a) two different experimental approaches depending on whether the substrate is water-insoluble or water-soluble, where an amphiphilic thiol is needed; (b) mechanism of the reduction of a functional group (X = atom or group) by the (TMS)₃SiH/HOCH₂CH₂SH coupling, where the hydrogen atom donor to R^• is the thiol.

Figure 12

Radical reduction of a variety of compounds by the (TMS)₃SiH/HOCH₂CH₂SH coupling.

Figure 13

Carbon–carbon bond formation mediated by (TMS)₃SiH: (a) perfluoroalkylation of olefins; (b) synthesis of a nitrogen-containing heterocycle.

Figure 14

(a) An example of the synthesis of N,C-difunctionalized bicyclo[1.1.1]pentanes. (b) Comparison of three protocols using (TMS)₃SiH, the water-soluble 1-ethylpiperidine hypophosphite (EPHP), or H₃PO₂/NaHCO₃, respectively. (c) Radical addition to the C=N bond in hydrazone derivatives.

Figure 15

Thioxanthate radical deoxygenation by J. L. Wood and coworkers, and proposed water “activation” [91].

Figure 16

Mechanistic proposal for the MeO–H bond weakening [99].

Figure 17

(a) Valence bond representation of common-features TSs accessed from three different classes of reactions. Though these are radical reactions, the TS features a Lewis acid/base interaction between O and B. (b) Three chains interlock with the reduction deiodination chain and with each other [50].

Figure 18

Revised mechanism for the deoxygenation of xanthate employing D₂O as the deuterium atom source [92].

Figure 19

(a) Remote site-selective radical C(sp³)–H monodeuteration of amides and selected examples. (b) Proposed mechanism [93].

Figure 20

Synthesis of deuterated (E)-alkenes [107].

Figure 21

(a) Calculated BDE for the O-H bond of water complexed with Cp₂Ti(III)Cl [88]; (b) active reductant forms according to ESR and theoretical calculations [112]; (c) proposed mechanism and intermediates [88].

Figure 23

Revised mechanism for the Titanocene(III)/Mn-promoted reduction of ketones in aqueous media [114].

Figure 24

Proposed reduction of a ketone by Sm(II)I₂–water proceeding through a highly ordered transition state.

Figure 25

(a) Reaction scheme and substrate scope for the SmI₂–water-mediated reduction of enamines. (b) Proposed PCET and HAT mechanisms for the reduction of enamines by SmI₂-H₂O [89].

Figure 26

Spontaneous hydrogen evolution from a molybdenum Mo–aqua complex.

Figure 27

Reaction of a germanium corrole complex with water [94].

Figure 28

Reaction of H₂O with a Bi(II) complex generates H₂ and a Bi(III) hydroxy complex [96].

Figure 29

(a) Hydroxytrifluoroethylation of styrenes by photoredox catalysis in aqueous media and representative examples; (b) proposed reaction mechanism.

Figure 30

(a) Arylation of styrene by photoredox catalysis in MeCN:H₂O as reaction media and representative examples; (b) proposed reaction mechanism.

Figure 31

(a) Synthesis of aromatic ketones by deoxygenative carbon–carbon coupling of aryl-carboxylic acids with olefins in an aqueous phase and representative examples; (b) proposed reaction mechanism.

Figure 32

(a) Intermolecular atom transfer radical addition (ATRA) to olefins by photoredox catalysis in aqueous media and representative examples, (^a) without LiBr; (b) proposed reaction mechanism.

Figure 33

Representative examples for the photocatalyzed iodoperfluorohexylation of olefins and alkynes in water; (^a) in MeOH:H₂O (1:2).

Figure 34

Photoredox-catalyzed and silane-mediated hydrofluoromethylation of unactivated alkenes in water, and representative examples.

Figure 35

(a) Photocatalytic single C(sp³)–F bond activation of perfluoroalkyl iminosulfides with alkenes in water and selected examples; (b) proposed reaction mechanism.

Figure 36

(a) Photocatalyzed arylation of pyridine hydrochloride derivatives in water and representative examples; (b) proposed reaction mechanism.

Figure 37

(a) Photocatalyzed synthesis of phenanthridine-6-carboxylates from N-biarylglycine esters in water and representative examples; (b) proposed reaction mechanism.

Figure 38

(a) Photocatalyzed C-H fluoroalkylation of arenes in water promoted by vitamin B12 and Rose Bengal, and representative examples; (^a) water:acetonitrile (1:1); (b) proposed reaction mechanism.

Figure 39

(a) Late-stage photocatalytic fluoroalkylation of aromatic crown ethers in aqueous media and representative examples; (b) proposed reaction mechanism.

Figure 40

(a) Diastereoselective synthesis of trifluoromethylated cyclobutane derivatives by [2+2]-photocycloaddition followed by water-assisted hydrodebromination. (b) Photoredox cross-electrophile coupling of alkyl bromides with DNA-tagged aryl iodides in aqueous solution.

Figure 41

Photoredox catalysis for radical deuteration: (a) an example of H/D exchange of an unactivated C(sp³)–H bond; (b) two examples of site- and enantioselective incorporation of deuterium into organic compounds.

Figure 42

(a) Optimized conditions for the photocatalytic phosphine-mediated water activation for radical hydrogenation and selected examples; (b) proposed mechanistic scheme.

Figure 43

(a) Structures of 5′,8-cyclo-2′-deoxyadenosine (cdA) and 5′,8-cyclo-2′-deoxyguanosine (cdG) in their 5′R and 5′S diastereomeric forms. (b) Bioinspired radical transformations for the synthesis of 5′,8-cyclopurines (cPu). (c) Radical cascade reaction that mimics the DNA damage for the synthesis of 5′,8-cyclopurines (cPu).

Figure 46

(a) The radical chain reaction for the reduction of ketones to the corresponding alcohols; (b) the mechanism for the reduction of 2-cyclopenten-1-one (19) involves dual radical chain reactions A and B (taken from Ref. [195]).