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Free Radicals in Heterocycle Functionalization

  • Jomy Joseph
  • Andrey P. Antonchick
Chapter
Part of the Topics in Heterocyclic Chemistry book series (TOPICS, volume 54)

Abstract

Functionalization of heterocycles through free radical intermediates has been widely employed in a diverse array of synthetic transformations. This chapter focuses on the recent developments in the light-assisted as well as traditional free radical generation methodology and the subsequent utilization in functionalization of various heterocycles.

Keywords

Alkylation Arylation Cross-dehydrogenative coupling Free radicals Heterocycles Minisci reaction Photocatalysis 

1 Introduction

Functionalized heterocycles are present in many biologically active molecules. Therefore, any effort that scientific community makes to expand the methodology for the synthesis of such molecules is justified. Various strategies are routinely employed for heterocyclic synthesis and functionalization. As the topic is broad, this discussion is solely concentrated on heterocyclic functionalization through radical intermediates. Radical heterocyclic functionalization by means of light (photocatalysis), metals, peroxides, persulfates, and hypervalent iodine compounds have dramatically advanced in the recent years.

Photocatalysis opens diverse pathways to realize previously challenging transformations [1, 2]. This is possible through the capacity of long living excited states of suitable photoactive organic molecules or metal complexes to interact with different chemical entities through electron transfer. The general scheme is shown below (Fig. 1).
Fig. 1

Redox pathways of photocatalysis (PC = photocatalyst): Radical formation through direct (A) and indirect (B) interactions with photocatalyst

There are two modes in which a potent free radical could be generated by means of photocatalysis. In one mode, the excited state of the photocatalyst promotes an oxidative/reductive quenching with one of the intended coupling partners to its radical ions (cation or anion) through single-electron transfer (SET), which eventually leads to the corresponding radical formation (Fig. 1A). When the interaction of a photocatalyst with either of the intended coupling partners, e.g., due to mismatching of the optimum electrochemical potential, does not lead to a productive radical formation, the free radical generation is still possible through the intermediacy of a suitable mediator (second type) that can interact with the photocatalyst and catalyze the electron transfer (Fig. 1B).

Traditional ways of functionalization mostly use the innate reactivity of heterocycles. Such innate reactivity of heterocycles, in general, can be propelled by suitable nucleophilic (Minisci type reactions) [3, 4, 5] or electrophilic radicals that are formed through the abovementioned strategies (ionic processes are also possible but are not discussed here). Therefore, this chapter is entirely focused on the recent but important developments of heterocyclic functionalization through radical intermediates for the formation of new carbon–carbon and carbon–heteroatom bonds. A new branch which combines polar intermediates and free radicals also found remarkable success in the recent years [6].

2 Functionalization of Saturated Heterocycles

2.1 Functionalization of Saturated Heterocycles Through C-H Bond Transformation

The development of photocatalysis contributed to the progress of saturated heterocycle functionalization. By making use of an accelerated serendipity driven approach, MacMillan and coworkers reported a coupling reaction between trisubstituted amines and cyanoarenes under photoredox catalysis using Ir(ppy)33+ as photocatalyst [7]. The benzylamine products were formed under mild conditions (Scheme 1). Various cyclic amines like pyrrolidine, piperidine, morpholine, N-(Boc)piperazine, and azepane rings provided excellent yields of benzyl amines. As aryl counterparts, benzonitriles substituted with esters, amides, phosphonate esters, and electron-deficient tetrazoles were found to be suitable substrates. Synthetic utility of the process was also showcased by the direct derivatization of a pharmaceutical agent.
Scheme 1

Photocatalytic functionalization of saturated heterocycles

Subsequently, Nishibayashi’s, Reiser’s, and Yoon’s research groups independently showed that α-amino alkyl radicals generated through photoredox catalysis could be trapped by electron deficient alkenes through conjugative addition (Scheme 2) [8, 9, 10].
Scheme 2

Photocatalytic alkylation of amines

All these aforementioned reactions were proposed to proceed through either oxidative or reductive quenching of the photocatalyst with one of the coupling partners and resulted in the formation of the key α-amino radical C as depicted below. These α-amino radicals were further engaged in radical-radical coupling with the second coupling partner and formed the corresponding products (Fig. 2).
Fig. 2

Photocatalytic α-amino radical formation

In a further report, α-oxyradical was generated using photocatalyst (Ir(ppy)2(dtbbpy)PF6) through the thiyl radical (generated from D), coupled with Schiff bases and formed the corresponding β-amino ethers (Scheme 3) [11].
Scheme 3

Photocatalytic functionalization via α-oxyradicals

Molander’s group reported the cooperative association of polar intermediates and free radicals for saturated heterocycle functionalization. The authors developed a Ni/Ir cooperatively catalyzed process for the arylation of various oxygen, nitrogen and sulfur containing heterocycles with electron deficient aryl bromides (Scheme 4) [12]. The process started with an oxidative addition of aryl halide onto a nickel complex to the corresponding Ar-Ni(II)-Br complex. A light energy driven dissociation mechanism mediated by Ir photocatalyst dissociated Ar-Ni(II)-Br complexes to the corresponding bromine radical. This bromine radical could be utilized for α-hydrogen atom abstraction of aliphatic heterocycles and formed the corresponding α-heteroatom free radical. This radical recombined with Ni(I) complex and was further engaged in reductive elimination to the intended product.
Scheme 4

Cross-coupling reaction between saturated heterocycles and aryl bromides

In a similar mechanistic approach, Doyle’s group showed that the α-oxy alkyl radicals of aliphatic ethers (linear and cyclic) could be generated by means of chlorine radical, which is formed through photocatalysis. The resulting α-oxyalkyl radicals could intercept polar nickel intermediates and thus be used to functionalize oxygen containing heterocycles (Scheme 5) [13]. Homolytic fragmentation of the Ni(III)-Cl complex through photon absorption was responsible for the Cl radical formation. This chlorine radical abstracted the hydrogen in α-position to oxygen and formed an α-oxy radical which recombined to the Ni(II) complex.
Scheme 5

Cross-coupling reaction between saturated heterocycles and aryl chlorides

A direct acylation of nitrogen containing heterocycles was further reported using photoredox [Ir(ppy)2(dtbbpy)PF6] and nickel catalysis [Ni(cod)2] [14]. In this process, an α-amino radical was formed through a photoredox cycle intercepted by a Ni(II)-acyl complex, which generated the corresponding Ni(III) complex. A subsequent reductive elimination formed the desired product. Various anhydrides or thioesters were found to be acylating reagents of choice (Scheme 6).
Scheme 6

Direct acylation of nitrogen heterocycles

Though the Ir-Ni photocatalysis finds more applications, corresponding radical-based palladium-catalyzed cross-coupling processes are rare. One such example was provided by Xuan et al. where the authors succeeded in the development of an α-allylation of amines with various allylic compounds, combining visible light iridium photocatalysis and palladium catalysis (Scheme 7). The proposed mechanism involved the generation of α-amino and allyl radicals through iridium single electron transfer (SET) cycles. The method was also successfully applied for the synthesis of an intermediate of an 8-oxoptotoberberine derivative [15].
Scheme 7

Allylation of saturated heterocycles with cooperative Ir-Pd catalysis

MacMillan et al. achieved a free radical interception of polar intermediates through a novel triple catalytic system. In this mode, three catalytic cycles, i.e., an organocatalytic cycle, a Ni-based catalytic cycle and a photocatalytic cycle were synergistically operated. Proposed mechanistic cycles are depicted below (Fig. 3). Electron deficient aryl(hetero) halides (Cl or Br) were coupled with nitrogen heterocycles through this pathway (Scheme 8) [16].
Fig. 3

Mechanism of arylation of saturated heterocycles through a triple catalytic system

Scheme 8

Arylation of saturated heterocycles through a triple catalytic system

2.2 Functionalization of Saturated Heterocycles Through C-Z (Z = COOH, BF3K, Halides) Bond Transformation

MacMillan’s group developed a method where α-heteroatom substituted carboxylic acids were used to generate α-amino/α-oxy radicals under Ir(II)-Ir(III) or Ir(III)-Ir(IV) photoredox conditions. Oxidative single electron transfer from the suitable Ir catalyst towards the carboxylic acid was responsible for the radical generation (Scheme 9).
Scheme 9

α-Amino and α-oxy radical formation from corresponding carboxylic acids

The readily formed radicals were thereby used for arylation [17], alkylation [18] or alkenylation. On the other hand, when vinyl sulfones were used as coupling partner, the corresponding allylic amines were readily formed (Scheme 10) [19].
Scheme 10

Alkenylation of heterocycles

A photocatalytic method of direct interception of radical intermediates towards polar metal complexes was reported by MacMillan and coworkers. This process was developed for the cross-coupling reaction between N-substituted α-amino acids and aryl halides (I or Br) with catalytic amounts of NiCl2.glyme and Ir(III) photocatalyst [Ir{dF(CF3)ppy}(dtbbpy)PF6]. The benzylamine product was formed in excellent yield under mild conditions [20]. Tetrahydrofuran-2-carboxylic acid was arylated using the same protocol (Scheme 11).
Scheme 11

Arylation of saturated heterocycles through Ir-Ni cooperative catalysis

Based on the mechanistic proposal, Ni(II) intermediate, which was formed by the oxidative addition of Ni(0) to aryl halide, was intercepted by α-amino radical A (formed by SET from excited state *Ir(III) catalyst to amino acid, followed by CO2 and proton expulsion) formed a new nickel(III) complex B. A reductive elimination of Ni(III) to Ni(I) caused the formation of a new C-aryl bond. Ni(I) was reduced to Ni(0) by a SET process with Ir(II) reductant (Fig. 4).
Fig. 4

Mechanism of heterocyclic functionalization through photo-Ni cooperative catalysis

In a following report, this new type of cooperative Ir/Ni catalysis was utilized for the cross-coupling between α-oxocarboxylic acids and alkenyl halides to afford the corresponding alkenylated oxygen heterocycles [21]. 2-Trifluoroboratochromanones were found to be a potent source of α-oxy radicals under photoredox conditions. Such chromanones were arylated with aryl bromides using a 4CzIPN/NiCl2.dme dual catalytic system to give the corresponding flavanones [22]. 4CzIPN was the active photoredox catalyst in this process (Scheme 12).
Scheme 12

Trifluoroborates in free radical coupling

Photoassisted alkyl radical formation was also proposed to proceed through the intermediacy of bromine radicals. By this mode, MacMillan et al. showed that saturated heterocyclic bromides could be cross-coupled with aryl bromides (Scheme 13) [23].
Scheme 13

Cross-coupling process between aliphatic bromoheterocycles and arylbromides

3 Functionalization of Maleimides

Maleimides are also an important class of heterocycles and were engaged in a variety of free radical reactions. Manna and Antonchick developed a novel copper-catalyzed stereoselective cyclopropanation of maleimides with acetophenone derivatives. In this process, α-carbonyl alkyl radical could be generated from acetophenones under Cu(I)/Cu(II)-peroxide-mediated conditions (Scheme 14) [24].
Scheme 14

Cyclopropanation of maleimides with acetophenones

The proposed mechanism involved, initially, Cu(II)-catalyzed hydrogen abstraction of methyl ketones to α-carbonyl alkyl free radical A. This radical added to maleimide’s olefinic bond and formed the free radical B which underwent SET with Cu(II) to intermediate C [Cu(III)] which upon enolate-directed elimination of t BuOH led to the cyclic intermediate D. The intermediate further rearranged to a four-membered transition state followed by reductive elimination of Cu(III) to Cu(I) which formed the corresponding cyclopropane E (Fig. 5).
Fig. 5

Mechanism of copper-catalyzed cyclopropanation of maleimides

A free radical-mediated cyclization between maleimide and alkyl anilines was reported with Eosin Y as a photocatalyst [25]. Energized Eosin Y promoted SET with amines to the corresponding α-amino radicals, which were efficiently trapped by maleimides through a radical cascade. As a result, six-membered tetrahydroisoquinoline rings were formed. Amines containing both electron deficient and electron rich substituents were equally reactive under the developed conditions (Scheme 15).
Scheme 15

Organic photocatalytic tetrahydroisoquinoline synthesis

The triplet excited state of Eosin Y (Eosin Y*) oxidized amines to the α-amino radicals A through an initial SET, followed by proton abstraction. This radical A was captured by maleimide, further moved through a radical cascade to the corresponding cyclized intermediate C. Intermediate C underwent hydrogen atom transfer and the corresponding tetrahydroisoquinoline was formed. Catalytic cycle was completed by a reaction of reductant Eosin Y radical anion with molecular oxygen (Fig. 6).
Fig. 6

Mechanism of Eosin Y photocatalytic tetrahydroisoquinoline synthesis

Recently, two new photocatalytic systems, one based on chlorophyll/O2 [26] and another one based on N-hydroxyphthalimide (NHPI) [27] were developed for the same transformation. Antonchick’s group developed a metal-free method of cyclization between maleimides and tertiary alkyl anilines. The α-aminoalkyl radicals as reaction intermediates were formed under a TBAI (tetrabutylammonium iodide)/TBHP (tert-butylhydroperoxide) system without formation of the corresponding iminium ions. A broad range of tricyclic tetrahydroquinoline products were smoothly formed under the developed reaction conditions with good yields (Scheme 16) [28]. A plausible mechanism was proposed. Initially, tert-butoxyl and tert-butylperoxyl radicals were formed by a reaction between tert-butylperoxide and an iodide ion. A SET from N,N-dimethylaniline to tert-butoxyl or tert-butylperoxyl radicals followed by deprotonation formed the α-aminoalkyl radical. This nucleophilic radical added onto the maleimide followed by cyclization, oxidation, and deprotonation, forming the desired product. Yadav and coworkers also developed a method of cyclization of N-methylanilines with maleimides using K2S2O8 as a cheap radical initiator [29].
Scheme 16

Metal-free cyclization of maleimides with alkyl anilines

4 Functionalization of Unsaturated Heterocycles

Unsaturated heteroaromatic functionalization largely deals with the cases when radicals are added to heteroaromatic bases (Minisci type reactions). The topic was extensively covered by Duncton where a comprehensive picture related to common heterocyclic structures and free radical precursors and various biological applications was provided [30]. Another promising area in free radical-mediated unsaturated heterocyclic functionalization is based on recently explored cross-coupling strategies as already discussed in saturated heterocyclic cases. In the following section, reports related to both processes are presented.

4.1 Organoboranes as Alkyl/Aryl Radical Sources

Organoboranes are useful radical precursors for C–C bond forming reactions. Molander et al. reported that potassium alkyl- and alkoxymethyltrifluoroborates could be nucleophilic radical precursors for the alkylation of N-heteroarenes. Mn(OAc)3 was found to be effective for the generation of alkyl radicals from organoboranes. This protocol represented an efficient way for the introduction of unique alkyl substituents (e.g., cyclobutyl and alkoxymethyl groups) into diverse N-heteroarenes (including quinolones, isoquinolines, benzopyrimidines, benzimidazoles, and benzothiazoles) (Scheme 17) [31, 32].
Scheme 17

Alkylation and alkoxymethylation of heterocycles

Chen’s group employed alkylboronic acids as radical precursors for C-H alkylation of N-heteroarenes via a photoredox strategy. A broad range of primary and secondary alkyl groups were efficiently incorporated into various N-heteroarenes using [Ru(bpy)3]Cl2 as photocatalyst and acetoxybenziodoxole (BI-OAc) as oxidant under mild conditions (Scheme 18) [33]. This reaction exhibited excellent substrate scope and functional group tolerance, and offered a broadly applicable method for late-stage functionalization of drug molecules. In the alkylation, the active species Bl-2 initiated with the SET from photo-excited Ru(II)* to Bl-OAc was crucial for the formation of alkyl radical from alkylboronic acid.
Scheme 18

Boronic acids as alkyl radical source

An important advancement in the Minisci type reaction was reported from Baran’s laboratory, where was successfully generated nucleophilic aryl radicals from aryl boronic acids under standard Minisci conditions. The reaction conditions were mild and operationally simple. A mixture of regioisomers was observed in most cases in which the reaction was mainly selective at the C2 and C4 positions (Scheme 19) [34].
Scheme 19

Arylation of nitrogen heterocycles

A mechanistic explanation showed that in the presence of Ag(I) salt, persulfate anion disproportionated into sulfate dianion and sulfate radical anion (A). The reaction between these radical anions and boronic acid generated aryl radical (B), which further reacted with protonated heterocycles and furnished a radical cation. This radical cation then reoxidized by Ag(II), providing the product and regenerating the Ag(I) catalyst (Fig. 7).
Fig. 7

Mechanism of aryl radical generation from arylboronic acids

Maity and coworkers extended the use of aryl boronic acid as a source of aryl radical for their C3 arylation of 2-pyridones under iron catalysis. Mechanistically, the process was similar to Baran’s work. Electron rich arenes were more compatible with this procedure though the yields in almost all cases were moderate to low (Scheme 20) [35].
Scheme 20

Arylation of 2-pyridones with boronic acids

The ferric (II) sulfide/K2S2O8 combination was also reported to generate sulfate radical anion (SO4) which was capable of producing aryl radicals from arylboronic acids. A variety of heterocycles like pyridines, pyrimidines, pyrazine, quinolone, quinoxaline, and pyridazine were prone to arylation under these conditions [36]. On the other hand, pyrrole, imidazole, indole, benzoxazole, quinine, and caffeine were unreactive. Except for the cases in which formation of regioisomers was not possible, a mixture of various regioisomers was observed. A metal-free arylation of electron deficient heterocycles with K2S2O8 at elevated temperatures was also reported [37].

4.2 Functionalization with Fluorine-Containing Radicals

The fluorinated alkyl groups play a privileged role in the medicinal chemistry because its incorporation into small molecules often enhances biological activities like cellular membrane permeability, promotion of electrostatic interactions with targets, and increase of robustness towards oxidative drug metabolism. Therefore, the introduction of such groups gained tremendous attention. Both photocatalytic and traditional ways of fluoroalkyl radical formation and its subsequent consumption with suitable heterocycles were developed.

A facile trifluoromethylation of various arenes and heteroarenes was reported by MacMillan et al. The reaction relied on the capacity of excited *Ru(phen)32+ photocatalyst to generate CF3 radical from CF3SO2Cl. A set of pyrazine, pyrimidine, pyridine, and pyrone heterocycles were perfluoromethylated in a highly regioselective manner (Scheme 21). The method was also effectively utilized to functionalize biologically active molecules [38].
Scheme 21

Photocatalytic perfluoromethylation of heterocycles

Stephenson and coworkers extended the trifluoromethylation protocols by using trifluoroacetic anhydride as CF3 radical source in presence of pyridine N-oxide under photoredox catalysis. The reaction was susceptible with a range of vinyl, aryl, and heteroaryl substrates (Scheme 22). The CF3 radical generation from trifluoroacetic anhydride was assumed to proceed through a decarboxylation pathway. The difficulties of such decarboxylation processes were overcome by appending a sacrificial redox auxiliary, pyridine N-oxide. This combination was supposed to shift the requisite electrochemical potential in favor of CF3 radical formation by the use of a photocatalyst. Ru(bpy)3Cl2 was found to be the optimum catalyst for this purpose [39, 40].
Scheme 22

N-oxide-mediated perfluorination of heterocycles with trifluoroacetic anhydride

A photocatalytic Smiles rearrangement was reported by Stephenson and coworkers to introduce the difluoroethanol group into aryl or heteroaryl cores. In this process aryl/heteroaryl sulfonates tailed with a difluorobromo group underwent rearrangement in the presence of photocatalyst Ru(bpy)3·6H2O to yield the corresponding difluorosubstituted scaffolds. In summary, the sulfonyl group was replaced through ipso attack. Amine salt was used to function as an electron source. The method was also applied in the synthesis of a key intermediate of the antidepression and/or anti-obesity drug ORL-1 (opioid receptor-like 1) (Scheme 23) [41].
Scheme 23

Difluoroethanolation of aromatic heterocycles through photocatalytic Smiles rearrangement

A novel method for visible-light photoredox-catalyzed difluoromethylation of electron-rich N-, O-, and S-containing heteroarenes under mild reaction conditions was developed by Wang’s group. Mechanistic investigation indicated that the net C−H difluoromethylation proceeded through an electrophilic radical-type pathway (Scheme 24) [42].
Scheme 24

Difluoromethylation of heteroarenes with difluoroiodomethylbenzene sulfonate

A metal-free radical trifluoromethylation of indoles, pyrroles, and thiophenes was reported by Scaiano and coworkers (Scheme 25). In this metal-free method, methylene blue was used as an organic photocatalyst under mild conditions [43].
Scheme 25

Trifluoromethylation of indoles, pyrroles, and thiophenes

The conventional ways of fluorinated heteroaromatics syntheses also flourished these days through the effort of primarily Baran and coworkers. An operationally simple trifluoromethylation of heteroaromatic systems that is scalable and proceeds at ambient temperature was developed. Among various trifluoromethyl sources tested, Langlois reagent (sodium trifluoromethanesulfinate, CF3SO2Na, benchtop stable), which generated an electrophilic trifluoromethyl radical with TBHP, was found to be broadly effective on a variety of electron-deficient and -rich heteroaromatic systems. Along with its user-friendly conditions, the key advantages of the protocol included direct usability on unprotected molecules, functional group compatibility (keto, cyano, halo, amino, ester, and amide groups are compatible), and predictable positional selectivity (Scheme 26) [44].
Scheme 26

Trifluoromethylation of heterocycles with Langlois reagent

A mechanistic explanation of the process was given as following. CF3SO2• was generated from tert-butoxy radical, presumably generated from metals trace or another initiator and CF3SO2. This transient intermediate released SO2 and CF3 radical, through α-scission. The formed CF3 radical was trapped with heteroarenes thereby the corresponding heteroaryl radical formation occurred. This was followed by a reoxidation to the corresponding products (Fig. 8). Undesired by-products also observed through the consumption of CF3• radical by other two competing pathways. In one pathway, abstraction of hydrogen atom produced CF3H. In the second pathway, CF3• radical was consumed by isobutene, which was supposed to be formed through a reaction between tert-butylhydroperoxide and molecular oxygen.
Fig. 8

Mechanism of peroxide-mediated trifluoromethyl radical formation

Following this initial development, the same group came up with a new set of zinc sulfinate salts for the effective installation of fluorinated alkyl groups and alkyl groups, including zinc trifluoromethanesulfinate (TFMS), zinc difluoromethanesulfinate (DFMS), zinc trifluoroethanesulfinate (TFES), zinc monofluoromethanesulfinate (MFMS), zinc isopropylsulfinate (IPS), zinc triethyleneglycolsulfinate (TEGS), and zinc bis(phenylsulfonylmethanesulfinate) (PSMS) (Scheme 27). Through these easily accessible zinc salts which were capable of releasing alkyl free radicals by the reaction with peroxides, a variety of heterocycles including xanthines, pyridines, quinoxalines, pyrimidines, pyridazines, and pyrroles were functionalized into their fluoro-alkylated and alkylated counterparts [45, 46, 47].
Scheme 27

Different zinc fluoroalkylsulfinate salts for the fluoroalkylation of heterocycles

Recently, Li and coworkers developed a simple trifluoromethylation protocol of various heterocycles using sodium triflinate (NaSO2CF3) as trifluoromethyl source. In this process, photo-excited acetone or diacetyl acted as radical initiators to generate CF3 radical from sodium triflinate [48].

Beller and coworkers developed a Pd(OAc)2/BuPAd2-catalyzed trifluoromethylation of heteroarenes and arenes using CF3Br as CF3 radical source. This new method was suitable for trifluoromethylation of different heterocycles like indoles, pyrroles, thiophene, and bioactive molecules including melatonin, caffeine, pentoxifylline, and theophylline (Scheme 28). Regioselectivity was observed at the 2-position to the nitrogen atom. Based on experimental observations, a CF3 radical formation by the reaction between PdL2 and CF3Br was proposed which reacted with arenes and formed the corresponding products [49].
Scheme 28

Palladium-catalyzed trifluoromethylation of heterocycles

A unique way for CF3 radical generation and its trapping with heterocycles was reported by Fensterbank et al. In this method, a well-defined Cu(II) complex A [Cu2+(LSQ)2; SQ = iminosemiquinone] converted electrophilic CF3+ species (Togni’s reagent) into CF3 radical by reduction. This redox communication was mediated by a redox-active ligand through a SET process (ligand-centered oxidation), the redox state of copper being unchanged and the electronic transfer occurring only on the ligand (Fig. 9). Pyrrole, indoles, and furans were trifluoromethylated under this new, mild protocol (Scheme 29) [50].
Fig. 9

Mechanism of copper-catalyzed trifluoromethylation of heterocycles

Scheme 29

Copper-catalyzed trifluoromethylation of heterocycles

Togni and coworkers developed a perfluoroalkylation strategy of ketene silyl acetals by using perfluoroalkyl substituted hypervalent iodine reagents (Scheme 30).
Scheme 30

Trifluoromethylation of ketene silyl acetals

TMSNTf2 was employed as a catalyst, which was responsible for the activation of hypervalent iodine reagent for the generation of the CF3 radical (Fig. 10). The generated radical was trapped by the heterocyclic compounds [51, 52].
Fig. 10

Mechanism of perfluoroalkylation with hypervalent iodine

Later, the authors developed a similar system in which lactam-derived ketene silyl amides were converted to perfluoromethylated lactams. Various fluoro-containing radicals were efficiently produced and utilized under the developed conditions [53].

The C5 position of 8-aminoquinoline was difluoroalkylated with various difluorobromides under nickel(II)-catalyzed conditions (Scheme 31) [54].
Scheme 31

Difluoroalkylation of nitrogen heterocycles

The effective difluoroalkyl radical generation was postulated by a reaction between Ni(II) complex and difluorobromides through a single electron transfer-guided dissociation (Fig. 11).
Fig. 11

Mechanism of nickel-catalyzed difluoroalkylation

4.3 Hydrocarbons and Cyanides as Alkyl Radical Sources

A photoactive Ir-thiol cooperative redox catalysis is efficient to produce allyl radicals from olefins equipped with allylic hydrogens. The corresponding radicals could be trapped by electron deficient sites of various heterocycles. Pyridines and indole were allylated through this pathway. Triisopropylsilanethiol was found to be the optimum thiol catalyst (Scheme 32) [55].
Scheme 32

Allylation of aromatic heteroarenes

Similarly to thiols, peroxides can generate free radicals from aliphatic hydrocarbons through the following general mechanism (Scheme 33). These free radicals could be trapped with various heterocycles. A radical cross-coupling of substituted indoles with cycloalkanes was reported by Yi’s group using di-tert-butyl peroxide (DTBP) as the oxidant. In this process, various substituted indoles were alkylated (pentane, hexane, heptane, octane, dodecane) with moderate to good regioselectivity. C4, C2 and C7-cycloalkylated products were obtained with differently substituted indoles, in which predominant alkylation occurred at the C4 position. When C4 position was blocked, C2-cycloalkylation occurred preferentially (Scheme 34) [56].
Scheme 33

General mechanism of free radical formation from peroxides

Scheme 34

DTBP-mediated alkylation of indoles

A similar DTBP-mediated metal-free indole cycloalkylation strategy was also reported by Kwong et al. under oxidative conditions. In their case, C3 or C2-alkylated indole derivatives were obtained [57]. An iron(III)-catalyzed C-3 alkylation of flavones has been reported by Patel et al. using a tert-butyl peroxybenzoate (TBPB)-K2S2O8 oxidant combination (Scheme 35). Different flavones containing both electron-withdrawing as well as electron-donating substituents were functionalized at C3 with various cycloalkanes. Yields were good to moderate in most cases. Mechanistic investigations showed the formation (by the reaction of cycloalkanes with peroxide) and the addition of cycloalkyl radical to flavones and regeneration of the double bond to the desired compounds [58].
Scheme 35

Iron-catalyzed alkylation of chromones

A variety of chromones were alkylated with a range of alkanes (cyclic and acyclic) via alkyl free radicals. The process was mediated by the oxidant DTBP (di-tert-butylperoxide). Chromones with different electronic environments afforded their anticipated 2-alkylchromanones in moderate to good yields (50–83%). (Scheme 36) [59].
Scheme 36

Metal-free conjugate addition of alkanes with chromones

Alkylation of C3-substituted coumarins with control over C3 or C4 positions was achieved. C3-alkylation was promoted with the Fe(III)/DTBP (di-tert-butylperoxide) system. On the other hand, C4 alkylation was achieved by metal-free conditions in which DTBP was used as oxidant in presence of acetic acid. In the case of C4 alkylation, C3 peroxidation also occurred (Scheme 37) [60].
Scheme 37

Peroxide-mediated alkylation of coumarins

Metal-free radical C-H alkylation of purine nucleosides with cycloalkanes was reported with DTBP (di-tert-butylperoxide) at elevated temperatures. By proper control of reaction time and DTBP loading, C6-monocycloalkylated or C6, C8-dicycloalkylated purine nucleosides could be selectively obtained (Scheme 38). C5-cyclohexylation of uracil and related nucleosides could also be achieved with high regioselectivity by this protocol [61].
Scheme 38

Peroxide-mediated alkylation of purines

Guo and coworkers also reported a C8 selective cycloalkylation of purines with oxidant DTBP (di-tert-butylperoxide) under metal-free conditions. However, under CuI/DTBP catalytic conditions, N-alkylation of N6 via C–N bond formation occurred (Scheme 39) [62]. A cycloalkyl radical was believed to be responsible for C8 alkylation while the cycloalkyl carbocation was involved in C–N bond formation. This cycloalkyl carbocation was generated from cycloalkyl radical via CuI-mediated oxidation. Various purines, benzothiazole, purine nucleosides, and benzoxazole reacted smoothly, giving good yield of products.
Scheme 39

DTBP-mediated alkylation of purines

An efficient oxidative cross-coupling of heteroarenes with simple unfunctionalized alkanes was reported by Antonchick et al. The corresponding alkyl radical was formed through the combined activity of PIFA [PhI(OCOCF3)2]/NaN3. Various nitrogen containing heterocycles and (thio)chromones were alkylated through this novel method (Scheme 40) [63, 64].
Scheme 40

Alkylation of nitrogen heterocycles and chromones

Nitriles also could be a source of alkyl free radicals under metal-catalyzed conditions. In a CuCl/DCP (dicumyl peroxide)-mediated process, various furans, thiophenes, indoles, and pyrroles were C2-cyanoalkylated with alkyl cyanides (Scheme 41) [65]. Mechanistically, the reaction between Cu(I) and DCP (dicumyl peroxide) produced Cu(II), acetophenone, t-BuO anion, and a methyl radical. Subsequently, hydrogen atom transfer from nitrile to the methyl radical generated CH4 and α-cyanomethylenyl radical, which added to the heterocycle leading to the final product.
Scheme 41

Copper-catalyzed cyanoalkylation of heterocycles

4.4 Carbonyls, Ethers, and Amines as Alkyl Radical Sources

A photocatalytic β-arylation of carbonyls with cyano-substituted aryls or heteroaryls was developed by MacMillan and coworkers (Scheme 42) [66].
Scheme 42

β-Arylation of carbonyls

Aliphatic aldehydes could provide an alkyl radical for alkylation of electron-deficient heterocycles. By treatment with tert-butyl peroxybenzoate (TBP), aliphatic aldehydes underwent a decarbonylation process to generate an alkyl radical in the absence of metal catalyst. This alkyl radical was trapped with various electron-deficient heteroarenes to produce alkylated N-heteroarenes at 130°C for 12 h (Scheme 43) [67].
Scheme 43

Aliphatic aldehydes as alkyl radical sources

Molecular oxygen-trifluoroacetic acid combination was found to be effective for the generation of alkyl radicals from aliphatic aldehydes through decarbonylation. The proposed reaction mechanism showed that the auto-oxidation of aldehyde with molecular oxygen produced acyl radical, which then delivered the corresponding alkyl radical for alkylation of N-heteroarenes under heating conditions (Scheme 44) [68].
Scheme 44

Alkylation of heterocycles with aldehydes as alkyl sources

The α-oxy radical, generated from benzyl ethers through thiol-mediated photoredox catalysis was shown to couple with electron deficient aryl cyanides to form the corresponding benzylated arenes (Scheme 45) [69].
Scheme 45

Benzylated heteroarene synthesis

Sodium persulfate was also shown to be susceptible to SET with excited photocatalyst *Ir(III) and formed the corresponding radical anion. This sulfate radical anion abstracted α-protons from ethers and formed the corresponding α-oxy-radical. Various heterocycles like pyridines, isoquinolines, and pyrimidines were etherified using this procedure (Scheme 46) [70].
Scheme 46

Etherification of heterocycles

Cyclic or acyclic ethers could be used to generate α-alkoxy radicals by means of persulfate under metal free conditions. This radical was also coupled with a variety of electron-deficient heteroarenes such as isoquinolone, quinoline, pyridine, pyrazines, and pyrimidines and generated the corresponding α-oxyalkyl containing heteroarenes in moderate to excellent yields. Along with monosubstituted products, disubstitution also occurred in some cases [71]. A combination of Cu(OTf)2/K2S2O8 system was successful in alkylating benzo and non-benzo fused azoles with cyclic ethers (Scheme 47) [72].
Scheme 47

Cyclic ethers as alkyl radical sources

Wang and coworkers showed that TBHP (tert-butylhydroperoxide) as oxidant is sufficient for the direct C2-alkylation of azoles with alcohols or ethers. Azoles such as benzothiazoles, benzoxazoles, and benzimidazoles were suitable for this alkylation. Primary and secondary alcohols were compatible in this process (Scheme 48) [73].
Scheme 48

Direct C-2 alkylation of azoles with alcohols or ethers

Watson and coworkers showed that pyridinium salts could be used as source of alkyl radicals through C–N bond homolytic cleavage [74]. They proposed, this was realized through a SET from a Ni(II) source onto pyridinium salts to the corresponding radical cation, which propelled homolytic fragmentation of the C–N bond (Fig. 12). Pyridines and indoles could be alkylated through this way (Scheme 49). In a report by MacMillan and coworkers, chloroheteroarenes were shown to be possible coupling partners for the α-arylation of a variety of cyclic and acyclic amines [75].
Fig. 12

Nickel-catalyzed alkyl radical generation from pyridinium salts

Scheme 49

Cross-coupling of boronic acid with alkyl free radicals

4.5 Alcohols and Alkyl Halides as Alkyl Radical Sources

Very recently, methanol as well as diverse alcohols could be treated as source of alkyl radicals under photocatalytic conditions as well. A variety of N-heteroarenes such as isoquinolines, quinolines, phthalazines, phenanthridines, and pyridines underwent easy methylation at the electron deficient position of the heterocycles (Scheme 50) [76].
Scheme 50

Methylation of aromatic heterocycles

An elaborated mechanistic picture is provided below for the alkylation of heterocycles using alcohols (Fig. 13).
Fig. 13

Mechanism of photocatalytic methylation of heteroaromatics

Mechanistic description started with single electron transfer from *Ir(ppy)2(dtbbpy)+ (A) to heterocyclic substrate. This led to the formation of Ir(ppy)2(dtbbpy)2+ (B). B was engaged in single electron transfer with thiol to form the thiyl radical C. The key step involved the α-hydrogen abstraction from alcohol by the thiyl radical to form α-oxy radical D. This nucleophilic α-oxy radical was trapped by a heterocycle through a Minisci type pathway and formed aminyl radical cation E. A subsequent deprotonation from E led to the formation of α-amino radical F. F suffered a spin-center shift (SCS) that eliminated a water molecule and formed the benzylic radical G. A second single electron transfer between A and G along with protonation led to the desired alkylation product.

Lectka et al. found that, in the presence of manganese (IV) dioxide and TFA, a ring-opening of cyclopropanols occurred for direct alkylation of heteroarenes to afford a variety of ketone-containing alkylated heteroarenes in moderate to good yields with broad functional group tolerance. The proposed reaction mechanism showed that two different oxidation states of manganese (III and IV) might play a role in the cyclopropanol C–C bond cleavage and rearomatization steps (Scheme 51) [77].
Scheme 51

Manganese dioxide-mediated alkylation of heterocycles with cyclopropanol as alkyl free radical source

Tertiary cycloalkanols could also be a source of free radicals under persulfate-mediated, silver-catalyzed conditions. The resulting free radicals could be trapped by quinoline or benzothiazole to afford the corresponding 2-substituted derivatives (Scheme 52) [78].
Scheme 52

Tertiary cycloalkanols as a source of alkyl radicals

Hydroxyalkyl groups can also be attached to heteroarenes through a radical oxidative C-H alkylation process. Neubert et al. developed a hydroxyalkylation of 3,6 dichloropyridazines with diverse alkyl alcohols in the presence of TBHP (tert-butylhydroperoxide) and TiCl3 (Scheme 53). The key free radical formation step was also shown [79].
Scheme 53

Titanium-catalyzed hydroxyalkylation of heterocycles

A free radical-mediated palladium-catalyzed Minisci reaction of N-heterocycles with simple alcohols was reported by Li and coworkers [80]. An interesting, highly selective cross-coupling reaction between aryl halides with alkyl halides under Ni(II) catalysis was developed by Weix and coworkers. In this process, aryl (or heteroaryl) halides were effectively coupled with alkyl iodides or bromides in the presence of catalytic amounts of Ni(II) complex, bipyridyl ligand and stoichiometric Zn or Mn powder. The corresponding C(sp2)-C(sp3) bond was formed selectively (Scheme 54) [81, 82, 83].
Scheme 54

Nickel-catalyzed cross-coupling between alkyl bromide and aryl(heteroaryl) bromide

The mechanistic studies revealed that the cross selectivity arose through a catalytic cycle where both polar and free radical intermediates effectively combined to form the new C–C bond. The transformation of Ni(I)I–Ni(II)I2, assisted with alkyl iodide (halogen abstraction mechanism), generated the key alkyl radical (Fig. 14). The observed selectivity was justified by two factors: (a) The relative rate of oxidative addition of LnNi(0) towards halides was in the order Ar-X > alkyl-X, and (b) The relative rate of halogen abstraction of LnNi(I) towards halides was in the order alk-X > Ar-X. Later, they found that 2-chloropyridines were more viable substrates for the cross-coupling with alkyl halides in the presence of bathophenanthroline ligand [84].
Fig. 14

Mechanism of nickel-catalyzed cross-coupling between alkyl halide and aryl(heteroaryl) halide

4.6 Acids and Acid Derivatives as Alkyl Radical Sources

DiRocco and coauthors applied alkylation strategies through visible-light photoredox catalysis on pharmaceutically important leads and drug candidates. In this promising study, organic acylperoxides were used as source of alkyl radicals under photocatalyzed conditions. Diverse mono- or dialkylated drugs were prepared under mild reaction conditions [85] (Scheme 55).
Scheme 55

Organic acylperoxides as alkyl radical sources

Aliphatic acids could be efficient alkyl radical precursors in Minisci reactions. Guo et al. reported a C6 selective alkylation of purine nucleosides at room temperature (Scheme 56). The process was catalyzed by AgNO3 in the presence of ammonium persulfate as oxidant. Various purine nucleosides (such as ribosyl, deoxyribosyl, and arabinosyl purine nucleosides) and aliphatic acids (including primary, secondary, and tertiary aliphatic carboxylic acids) were compatible with the developed conditions [86].
Scheme 56

Alkylation of purine nucleosides with alkyl carboxylic acids as alkyl source

Employing similar conditions, Estrada et al. showed that electron-deficient pyrimidines could also be alkylated with carboxylic acids (Scheme 57) [87].
Scheme 57

Alkylation of pyrimidines with alkyl carboxylic acids as alkyl source

A room temperature, silver-catalyzed decarboxylative alkylation of heterocycles was also reported to functionalize benzothiazoles, thiazoles, and benzoxazoles at the C-2 position. Potassium persulfate was used as the superstoichiometric oxidant in this protocol (Scheme 58) [88]. The decarboxylative free radical formation and its utilization are depicted below (Fig. 15).
Scheme 58

Silver-catalyzed C-2 alkylation of azoles using alkyl carboxylic acids

Fig. 15

Mechanism silver-catalyzed C-2 alkylation of azoles using alkyl carboxylic acids

In a silver(I)-catalyzed process, a variety of protonated N-heteroarenes were alkylated with natural and unnatural amino acids. Various pyridines, pyrimidines, pyrazines, and pyridazines were predominantly monoalkylated with different amino acid sources. An excess of ammonium persulfate was used as the oxidant. According to mechanism below, the amino acids underwent an oxidative decarboxylation to form aminoalkyl radicals. Subsequent oxidation and hydrolysis produced the corresponding alkyl aldehydes. A decarbonylation of aldehyde afforded alkyl radicals for the next alkylation (Scheme 59) [89].
Scheme 59

Silver-catalyzed alkylation of heterocycles with amino acids as alkyl source

4.7 Arylation and Acylation Through Aryl and Acyl Radicals

The common sources of aryl radicals, which are used to functionalize heteroaromatics, either originate from aryl diazonium salts, diaryliodonium salts, aryl sulfonyl chlorides, or aryl halides (iodide, bromides, chloride). In the following section, the use of various photocatalytic processes towards heterocyclic functionalization, is discussed.

An interesting arylation of furans, pyrroles(N-Boc) and thiophenes with aryl diazonium salts was developed by König and coworkers [90]. The transformation was catalyzed by Eosin Y photocatalyst under mild conditions. In general, aryl diazonium salts substituted with electron withdrawing groups gave higher yields compared to their electron donating counterparts (Scheme 60).
Scheme 60

Eosin Y-catalyzed arylation of furans, pyrroles, and thiophenes

The reaction proceeded through the involvement of an aryl radical, formed through single electron transfer from excited state Eosin Y to aryl diazonium salts. This electron transfer endorsed self-fragmentation of aryl diazonium salt in such a way, that an aryl radical and N2 were formed. A subsequent radical trap with heterocycle, a reductive quenching of the photocatalyst with the heterocycle-aryl free radical adducts and a final deprotonation were responsible for the arylated heterocycle formation (Fig. 16).
Fig. 16

Eosin Y-catalyzed aryl radical formation

Heterogeneous TiO2-visible light combination was also used to generate aryl radicals from aryl diazonium salts. Such aryl radicals were used to functionalize various furans, thiophenes, and pyridines [91]. In two independent reports, various N-heteroarenes were arylated with aryldiazonium salts in the presence of ruthenium photocatalyst, [Ru(bpy)3]Cl2·6H2O. Pyridines, xanthenes, thiazoles, pyrazines, and pyridazines were compatible with these new arylation conditions. The mechanism of the process was similar to the previously discussed case of eosin with the only difference being that excited state of ruthenium promotes the diazonium salt dissociation [92, 93].

Suitably tuned porphyrins can act as photocatalysts and can generate aryl radicals from aryldiazonium tetrafluoroborate salts. Gryco and coworkers developed an arylation of various heterocycles by means of photocatalyst tetraphenylporphyrin (H2TPP). Various heterocycles such as furans, benzofurans, thiophenes, indoles, and coumarins were susceptible to this free radical process and formed the corresponding arylation products (Scheme 61). On the other hand, arylation of pyrroles was found to be challenging under the given conditions [94].
Scheme 61

Arylation of heterocycles with porphyrin as a photocatalyst

In another report, in situ generated aryl diazonium salts from aryl amines and t-BuONO were employed as aryl radical sources under photocatalytic conditions. Various heterocyclic diazonium salts containing pyridines, thiazole, and quinoline moieties were coupled with furans, thiophenes, and N-substituted pyrroles by using this method [95].

Xiao and Chatani’s research groups independently reported that diaryliodonium salts could be an alternative source for aryl radicals under photocatalytic conditions (Fig. 19) which could be used for the functionalization of numerous heterocycles [96, 97]. In another interesting report, Natarajan and coworkers revealed that aryl sulfonyl chloride could be a potent source for aryl radicals (Fig. 17). In this case, various substituted pyrroles, furans, and thiophenes were arylated as well [98].
Fig. 17

Aryl radical formation from diaryliodonium salts or aryl sulfonyl chlorides

Wang and coworkers showed that triazenes could be used as sources of aryl free radicals under Ag(I)/S2O82−-mediated conditions. The aryl radicals thus generated were used to functionalize various heterocycles like pyridine, quinoline, isoquinoline, pyrimidine, pyridazine, pyrazine, phthalazine, quinoxaline, and their substituted derivatives (Scheme 62) [99]. Regioisomeric products were generally observed in the cases of substrates where a clear regioselectivity preference was not attainable.
Scheme 62

Aryl triazenes as aryl radical for heterocyclic functionalization

Aryl radical generation from aryl halides, especially bromides and chlorides, is a challenging process due to the high energy barrier associated with the corresponding homolytic cleavage. König and coworkers devised a solution to this problem through a double photo-excitation strategy of the organic dye PDI [N,N-bis(2,6-diisopropyl)perylene-3,4,9,10-bis(dicarboximide)], thereby acquiring sufficient energy to perform a charge transfer to the aryl halide (Fig. 18). Triethylamine was used as sacrificial oxidant. This novel pathway resulted in the formation of an aryl radical which was trapped with various substituted pyrroles. Various aryl iodides, bromides and chlorides were smoothly converted into the corresponding aryl radical through this process (Scheme 63) [100].
Fig. 18

Electron transfer to PDI to generate the corresponding radical anion

Scheme 63

Organo-photocatalyzed cross-coupling of heterocycles with aryl halides

In a further report, they developed a sequential activation of polyhalogenated aryl halides with different light sources [101]. Heteroaryl radicals could be generated from heteroaryl bromides under photocatalytic conditions. Weaver’s group achieved a reductive alkylation of 2-bromoazoles with an Ir photocatalyst where the key heteroaryl radical was formed through an oxidative quenching of heteroaryl bromide with excited iridium photocatalyst (Scheme 64) [102].
Scheme 64

Cross-coupling of heterocyclic bromides with olefins

When compared to alkylation or arylation, photocatalytic acylations through acyl radicals are rare. MacMillan’s group employed photoredox catalytic conditions to generate the acyl radical from α-oxocarboxylic acids to realize decarboxylative acylation with different aryl and alkyl iodides/bromides [103]. Here, the target ketone could be seen as a result of the cross-coupling between newly generated acyl radical and organic halides by cooperative photoredox and nickel-catalytic cycles (Scheme 65).
Scheme 65

Ni-Photocatalytic cross-coupling of heterocyclic halides with α-oxocarboxylic acids

A similar transformation was also achieved by Fu et al. using palladium instead of nickel catalyst under otherwise identical conditions. In this case, the desired decarboxylated coupling product could also be achieved from monoamide oxalates, which gave different amides (Scheme 66) [104].
Scheme 66

Pd-Photocatalytic cross-coupling between heterocyclic halides and α-oxocarboxylic acids

Indoles (free and N-substituted) could be easily acylated with α-oxocarboxylic acids to 3-acyl indoles using organo-photoredox catalysis. Rose Bengal was found to be the most efficient organo-photocatalyst when 3W green LEDs were used as light source in ethanol medium under air (Scheme 67). Mechanistically, an acyl radical formation was postulated by a reaction between singlet oxygen (1O2) and α-oxocarboxylic acids through decarboxylation of the latter. On the other hand, singlet oxygen was formed by the reaction between exited state Rose Bengal (*RB) with molecular oxygen. A variety of indoles containing both electron donating and withdrawing groups were acylated using this protocol [105].
Scheme 67

Rose Bengal-catalyzed cross-coupling of indoles with α-oxocarboxylic acids

C2 as well as C3 acylation of indoles was achieved through dual photoredox/transition metal catalysis. Van der Eycken et al. showed that N-pyrimidylindoles could be acylated at the C2 position with various aromatic and aliphatic aldehydes at room temperature. Pd(OAc)2 and fac-Ir(ppy)3 were employed as the corresponding metal and photocatalyst in a batch process or micro flow process (Scheme 68) [106]. Free and N-alkyl indoles were acylated at the C3 position with α-oxo acids under visible light induced Ir/Ni co-catalytic conditions (Scheme 68) [107].
Scheme 68

Ni/Pd-Ir synergistic catalysis for the cross-coupling of indoles with aldehydes and α-oxocarboxylic acids

In a similar way, acylation of phenanthridines was also achieved by thermolytic and photolytic methods. The thermolytic method was mediated by substoichiometric amounts of TBAB (tetrabutylammonium bromide, 30 mol%) and K2S2O8 as oxidant, whereas in the photocatalytic method, K2S2O8/TBAB was replaced by (NH4)2S2O8 and fac-Ir(ppy)3 was used under visible light irradiation. This intermolecular acylation reaction provided an easy access to 6-acylated phenanthridine derivatives (Scheme 69) [108].
Scheme 69

Acylation of phenanthridines using persulfate or Ir photocatalysis

Antonchick et al. developed an efficient acylation of nitrogen heterocycles with aldehydes under PIFA/TMSN3-mediated conditions. Along with the functionalization of various heterocycles like isoquinoline, quinoxaline, pyridine, benzothiazole, and caffeine, the method was also employed for the synthesis of a collection of natural products (Scheme 70) [109].
Scheme 70

Hypervalent iodine-mediated acylation of N-heterocycles

The key nucleophilic acyl radical was generated from aldehyde by the acyl hydrogen abstraction with N3 radical. The latter on the other hand was formed through a homolytic cleavage of PhI(N3)2, which was formed by the double exchange of trifluoracetyl groups in A by azide ions. Nucleophilic acyl radical B targeted the electrophilic position of the protonated heterocycle. Rearomatization of C provided the desired product (Fig. 19).
Fig. 19

Hypervalent iodine-mediated acylation of N-heterocycles

Following this study, new reports were published for the same transformation using different stoichiometric systems like TBAB/K2S2O8 [110], NCS/TBHP [111], or TBHP/TFA [112]. In all these systems, the acyl radical was proposed to be the key intermediate.

Patel and coworkers employed a substituted methyl arene/TBHP combination as acyl radical source. AlCl3 was used as the catalyst. The developed process is suitable for functionalizing a variety of isoquinolines, quinolines, and quinoxalines [113]. Instead of AlCl3, MnO2 could also be used as an efficient catalyst in the case of isoquinoline functionalization (Scheme 71) [114].
Scheme 71

Use of toluene as an acyl radical source

A decarboxylative acylation of pyridine N-oxides was reported with various α-oxocarboxylic acids as free radical source. The process was catalyzed by silver nitrate under K2S2O8-mediated conditions. Silver salt of carboxylic acids underwent decarboxylation in the presence of sulfate radical anion, thereby forming an acyl radical which further promoted acylation (Scheme 72) [115].
Scheme 72

Decarboxylative acylation of N-oxides

3- or 4-Aryl pyridines suitably substituted with α-acyl carboxylic acid underwent sulfate radical anion (SO4)-mediated decarboxylation and formed acyl radicals. This acyl radical was trapped by the pyridine fragment resulting in the formation of azafluorinones (Scheme 73) [116]. A mixture of regioisomers was formed depending on the substrate structure.
Scheme 73

Intramolecular acylation of heterocycles

4.8 Heterocyclic Functionalization Through Metal Hydride–Hydrogen Atom Transfer Process

Olefins can be the radical source for unsaturated heterocyclic functionalization through Minisci type reactions or cross-coupling. In this process, the radical generation is achieved through metal hydride–hydrogen atom transfer (MH-HAT).

An iron-catalyzed C–C bond formation, which could also functionalize heterocycles, was devised by Baran’s Group. In this operationally simple system, through the intermediacy of either Fe(acac)3 or Fe(dibm)3 and PhSiH3, two different olefinic bonds were coupled under air or moisture compatible conditions (Scheme 74). The free radical donor component could also be accommodated with various heterocycles, which is a notable advantage of the protocol. Common acceptors include carbonyl or sulfonyl attached olefins (Scheme 74, Eq. 1) [117]. Under slightly modified conditions, various heterocycles were employed as suitable acceptors and simple olefins as donors (Scheme 74, Eq. 2) [118].
Scheme 74

Alkylation of heterocycles through cobalt-mediated hydrogen atom transfer

The mechanism involves a metal-hydride HAT process (MH-HAT) to the olefin to form the carbon centered radical. This radical was trapped with olefin acceptor to form the free radical intermediate. The radical was reduced with iron catalyst followed by proton abstraction to reach the end product (Fig. 20).
Fig. 20

Mechanism of alkylation of heterocycles through iron-mediated hydrogen atom transfer mechanism

Shenvi et al. devised a method for the facile synthesis of 8-aryl/heteroaryl menthol starting from isopulegol through a radical arylation process. The process was based on the ability of Mn-H, which is formed from Mn(dpm)3 and PhSiH3, to proceed with a hydrogen atom transfer (HAT) to terminal alkene, thereby forming a carbon-centered radical which was prone to ipso attack with heteroaryl sulfonyl group to form a heteroaryl radical. This radical further underwent Smiles rearrangement and reduction to form the target compound (Scheme 75) [119].
Scheme 75

Alkylation of heterocycles through manganese-mediated hydrogen atom transfer mechanism

Herzon and coworkers showed that carbon centered free radicals derived from unfunctionalized alkenes through cobalt-mediated HAT could be coupled with various N-methoxy heterocyclic salts. These salts include N-methoxypyridinium, N-methoxypyridiazinium, N-methoxyquinolinium, and N-methoxyisoquinolinium derivatives. The resulting alkylated heterocycles were formed in good yields. Et3SiH and Co(acac)2 were used as corresponding hydride source and catalyst. Site selectivity in case of pyridinium derivatives (C2/C4) was influenced by the nature of the radical intermediates. Selective C2 alkylation was observed with secondary radicals. With tertiary radicals, predominant C4 alkylation was observed (Scheme 76) [120, 121].
Scheme 76

N-Methoxy heterocyclic salts as acceptors for MH-HAT

Shenvi and coworkers reported a branch selective (Markovnikov) olefin hydroarylation that combined MH-HAT with a nickel catalytic cycle. Terminal alkenes reacted with various aryl(hetero aryl) iodides in the presence of a dual catalytic system based on Ni(II) and Co(II) (Scheme 77) [122].
Scheme 77

Alkylation of heterocycles through a coupled Co-mediated MH-HAT/Ni-catalyzed cross-coupling

4.9 Carbon–Heteroatom Bond Formations

Along with carbon–carbon bond forming reactions, radical-mediated carbon–heteroatom bond formation was also well studied. A unique amidation of heterocycles was developed by Baran et al. by employing the new amide source N-succinimidyl perester (NSP) as a source of nitrogen centered radical. The reaction was operated in presence of catalytic amounts of Cp2Fe. A variety of heterocycles, i.e., pyridines, pyrroles, pyrimidines, thiophenes, thiazoles, pyrazines, and purines, were functionalized through this new method. The regioselectivity pattern observed is similar to aromatic electrophilic substitution in which electron-richer positions are preferred (Scheme 78) [123].
Scheme 78

Iron-catalyzed amination of heterocycles

A transition metal-free photocatalytic amidation of heterocycles was achieved by a reaction between aryloxy amide and various heterocycles through free radical intermediates. Organic dye eosin Y was used as a photoredox catalyst (Scheme 79). Different heterocycles like indoles, azaindoles, pyrroles, furan, and thiazoles were amidated using aryloxy amide. Amidyl-free radical as the amide source was generated through a SET process between the eosin Y excited state (*EY) as a reductant and aryloxy amide, thereby forming a radical anion B and concomitant release of aryloxide anion [124].
Scheme 79

Organo-photocatalytic amidation of N, O, S-heterocycles

A method for the introduction of trifluoromethylthio groups into coumarin-3-carboxylic acids was developed by Hoover and coworkers. Silver salt of trifluoromethylthiolate was used as the source of the trifluorothiolate group. This methodology utilized existing carboxylic acid functionalities for the direct conversion into CF3S groups and resulted in a broad scope of 3-trifluoromethylthiolated coumarins, including analogues of natural products, in moderate to excellent yields. The authors proposed a persulfate-mediated formation of CF3S radical from AgSCF3 and its subsequent reaction with coumarin-3-carboxylic acids (Scheme 80) [125].
Scheme 80

Trifluoromethylthiolation of coumarin-3-carboxylic acids

Li’s group introduced photo-induced halogen exchange for the iodination of aryl/heteroaryl bromides (aromatic Finkelstein reaction) with sodium iodide by means of UV-light irradiation. Molecular iodine was used as catalyst in this process. Heterocycles like indole, pyrimidine, quinolone and isoquinolines were smoothly iodinated under mild conditions (Scheme 81). Mechanistic explanation was provided based on an iodide and UV light-mediated heterolytic or homolytic C–Br bond cleavage of aryl bromide [126, 127]. The resulting aryl radical combines with iodine radical forms the final product.
Scheme 81

Photoinduced iodination of heteroaryl bromides

A regioselective iodination of heterocycles was realized by means of a K2S2O8/NaI/Ce(NO3)3·6H2O system. Quinolines, quinolones, pyridines, and pyridines proceeded with C3 or C5 iodination depending on the substituent attached to the heterocyclic ring (Scheme 82). The reaction was proposed to proceed through the intermediary of an iodine radical along with a sulfate radical anion, which was formed by a reaction of K2S2O8 with NaI at higher temperature. Ce(III) was used for a single electron transfer with sulfate radical anion to yield the corresponding sulfate dianion [128].
Scheme 82

Persulfate-mediated iodination of nitrogen heterocycles

Nitrogen heterocycles were also regioselectively iodinated using molecular iodine and TBHP through free radical intermediates. Iodination was effective at the C-3 position [129].

Mn(OAc)3-mediated radical phosphonylation/phosphinylation of heterocycles through intermediary of phosphonyl radical [(RO)2PO•] or phosphinoyl radicals [R2PO•], is a well-studied process [130, 131]. Benzothiazoles and thiazoles were also phosphinylated with diphenylphosphine oxide under ball-milling conditions [132].

Recently, a novel, base-assisted, pyridine-catalyzed, metal-free cross-coupling reaction between aryl(hetero) or alkenyl halides (I or Br) and bis(pinacolato)diboron [B2pin2] was developed by Jiao and coworkers (Scheme 83). Various heterocycles like pyridines, furans and thiophenes were borylated through this new pathway albeit with moderate yield under mild conditions. Potassium methoxide and 4-phenylpyridine were found to be the optimum base and catalyst in this process [133].
Scheme 83

Borylation of heterocycles

Mechanistic explanation of the protocol was given on the basis of free radical involvement. The key features involved methoxide ion addition to B2pin2 to an -ate complex A, which further led to the complex B by the reaction with pyridine. Complex B underwent a homolytic cleavage, thereby yielding pyridine stabilized boryl radical C and methoxyboronate radical anion D. The required aryl radical E was formed through a SET process with aryl halide and complex D. Aryl radical E was then trapped with complex C and formed the corresponding C–B bond (Fig. 21).
Fig. 21

Mechanism of borylation of heterocycles

5 Conclusions

The purpose of this review is to report recent developments in the field of heterocyclic functionalization through radical intermediates. A variety of alkyl, aryl, acyl, and heteroatom-centered radical sources and their subsequent incorporation on various heterocycles are reviewed. In a broad sense, Minisci-type reactions and polar-free radical cooperative catalysis were more explored in heterocyclic functionalization in the recent years. The radical sources have been extended to carboxylic acids, alcohols, alkyl and aryl halides, aldehydes, organoboranes, and other sources. In addition, photoredox strategy presents promising alternatives for C-H functionalization of various heterocycles with high efficiency and mild conditions. The current trend shows significant expansion of the field, where investigations are taking place for quick installation of various functional groups onto heterocyclic drugs. It is expected that these attempts will lead to an exponential progress in the drug development area.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Department of Chemical BiologyMax-Planck Institute for Molecular PhysiologyDortmundGermany
  2. 2.Department of Chemistry and Chemical BiologyTechnische Universität DortmundDortmundGermany

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