Synthetic Strategies for 5- and 6-Membered Ring Azaheterocycles Facilitated by Iminyl Radicals

The totality of chemical space is so immense that only a small fraction can ever be explored. Computational searching has indicated that bioactivity is associated with a comparatively small number of ring-containing structures. Pyrrole, indole, pyridine, quinoline, quinazoline and related 6-membered ring-containing aza-arenes figure prominently. This review focuses on the search for fast, efficient and environmentally friendly preparative methods for these rings with specific emphasis on iminyl radical-mediated procedures. Oxime derivatives, particularly oxime esters and oxime ethers, are attractive precursors for these radicals. Their use is described in conventional thermolytic, microwave-assisted and UV-vis based preparative procedures. Photoredox-catalyzed protocols involving designer oxime ethers are also covered. Choice can be made amongst these synthetic strategies for a wide variety of 5- and 6-membered ring heterocycles including phenanthridine and related aza-arenes. Applications to selected natural products and bioactive molecules, including trispheridine, vasconine, luotonin A and rutaecarpine, are included.


Introduction
Several recent articles have drawn attention to the virtually boundless extent of chemical space; the domain that contains the totality of all possible compounds [1,2]. The total number of molecules that could be made from only 30 atoms is in the range 10 20 to 10 24 [3], "drug-like" chemical space comprises over 10 60 molecules [4,5] and, of course, even these huge numbers are insignificant in comparison with the protein or nucleic acid spaces. The number of polypeptide chains of modest (250 unit) length, drawn from the 20 natural amino acids, exceeds the 'trans-astronomical' number of 10 325 [6]. The CAS registry currently contains about 10 8 chemical substances. Its present rate of growth is about 5ˆ10 6 substances per year, so that at this rate more than 10 54 years would be needed just to explore "drug-like" chemical space! It is abundantly evident that only a minute fraction of chemical space can ever be preparatively accessed. To address this problem, computational algorithms are being devised capable of virtual screening and/or for locating, within the total space, "islands" or "trees" of substances with potentially desirable properties such as bioactivity [1,2,7]. Ertl and co-workers developed self-organising neural networks which showed that a comparatively small number of ring structural units is associated with bioactivity. They listed 30 heterocyclic moieties as of crucial importance and 22 of these contained one or more N-atoms [7]. Pyrrole, indole and related structures figured prominently, as did pyridine, quinoline, quinazoline and analogous 6-membered ring-containing aza-arenes. The immense size of chemical space presents exciting opportunities of discovering hitherto unknown and extraordinary substances with properties beneficial to human society. Its size also represents a huge challenge for preparative chemists such that it is imperative to open up every possible avenue that might facilitate the task. The exploration and exploitation of identified "islands" depends critically, of course, on the availability of practical preparative methods.
Dioxime oxalates 8 are another type of oxime ester that proved convenient for clean generation of iminyl radicals. Symmetrical types were made by treatment of an oxime 6 with oxalyl chloride to yield oxime oxalyl chlorides 7 as intermediates (Scheme 3). Although these could be isolated, they hydrolysed and degraded quickly, so immediate treatment with another equivalent of either the same This review also focuses on the iminyl radical based synthetic methodology developed for the sets of aza-arenes identified above as of importance in the bioactivity islands of chemical space.

Syntheses of Dihydropyrroles and Pyrroles
Organotin promoted radical methodology is justly famed because it works seamlessly in so many situations and has proved so dependable. Many ingenious syntheses of azaheterocycles have employed organotin hydrides or ditins for the generation of iminyl or aminyl radicals. Zard, for example, described tin hydride-mediated syntheses of dihydropyrroles, indolizidines and other aza-heterocycles from sulfenimines (PhS-N=C<), thionocarbazones and other derivatives [34,35]. Nanni and co-workers generated iminyl radicals by ring closures of C-centred radicals onto organic nitriles and hence prepared many heterocyclic systems. They also employed tin-free thermolytic and other processes [36][37][38]. Much of this earlier research has been reviewed by Bowman and Aldabbagh [39][40][41] and/or by Fallis and Brinza [42]. Recently, Zhang and Studer have published an outstanding review of aza-arene syntheses flowing from radical additions to organic isonitriles [43]. This methodology exploits the formation and ring closures of amidoyl radicals (Ar-N=C ‚ -R).

Pyrrole and Dihydropyrrole Preparations from Carbonyl Oximes
Numerous alkaloids contain pyrrole, dihydropyrrole or related rings and many biological roles are associated with these structures [44][45][46]. Oxime esters 1 can easily be prepared from oximes reacting with either carboxylic acids or acyl halides [47,48]. On photolysis they release an iminyl radical together with an acyloxyl radical and the latter rapidly extrudes CO 2 with production of a C-centred radical [48,49] (Scheme 2). Rodrigues, Sampedro and co-workers used acyl oximes such as 2 as efficient sources of iminyl radicals [50][51][52]. With this precursor type, the radical co-produced with the iminyl during UV photolyses was acyloxyl [CH 3 CO 2 ‚ ] that simply furnished volatile CH 4 and CO 2 as by-products. They reported that the iminyls could be conscripted into syntheses of many types of heterocycles including dihydropyrroles. UV photolysis of 2 through Pyrex released iminyl radical 3 with an alkenyl side chain. These selectively cyclised in the 5-exo mode with production of pyrolidinylmethyl radical 4 that subsequently abstracted an H-atom from co-reactant cyclohexa-1,4-diene (CHD) to yield 3,4-dihydropyrrole derivative 5 (Scheme 2). Dioxime oxalates 8 are another type of oxime ester that proved convenient for clean generation of iminyl radicals. Symmetrical types were made by treatment of an oxime 6 with oxalyl chloride to yield oxime oxalyl chlorides 7 as intermediates (Scheme 3). Although these could be isolated, they hydrolysed and degraded quickly, so immediate treatment with another equivalent of either the same oxime 6, or a different oxime, yielded the symmetrical dioxime oxalates 8 or unsymmetrical types such as 11a-d respectively [53,54]. Dioxime oxalates 8 were "clean" and atom-efficient because, apart from CO 2 , they delivered only iminyl radicals 9 on UV photolysis. Photo-dissociations were aided by inclusion of 4-methoxyacetophenone (MAP) as photosensitizer and by the presence of an aryl substituent adjacent to the C=N bond. oxime 6, or a different oxime, yielded the symmetrical dioxime oxalates 8 or unsymmetrical types such as 11a-d respectively [53,54]. Dioxime oxalates 8 were "clean" and atom-efficient because, apart from CO2, they delivered only iminyl radicals 9 on UV photolysis. Photo-dissociations were aided by inclusion of 4-methoxyacetophenone (MAP) as photosensitizer and by the presence of an aryl substituent adjacent to the C=N bond. 3,4-Dihydropyrrole derivatives 10 were obtained in moderate yields with toluene acting as both solvent and H-atom donor (Scheme 3). Unsymmetrical dioxime oxalates such as 11 incorporated an aryl-oxime unit, to promote photo-dissociation, as well as an alkenic acceptor unit. These precursors enabled non-aromatic dihydropyrroles such as 12a,b to be accessed. Attempts to convert the latter to pyrolizidines 13 and indolizidines 14 were unsuccessful.

Pyrrole and Dihydropyrrole Preparations from Oxime Ethers
Thermal preparative methods are often superior because of their simplicity and non-hazardous nature. O-Phenyl oxime ethers 15 can easily be made by treatment of carbonyl compounds with the commercially available O-phenylhydroxylamine hydrochloride. Conventional thermolyses of appropriate derivatives were shown to provide dialkyl-or diaryl-iminyl radicals [55]. Subsequently it was established that microwave heating (μwave) was a particularly efficient means of releasing iminyl radicals and mediating dihydropyrrole preparations [56,57].
The optimum procedure utilized toluene as both solvent and H-donor together with an equivalent of the ionic liquid (IL) 1-ethyl-3-methyl-1H-imidazol-3-ium hexafluorophosphate (emimPF6) to promote microwave absorbance. This method enabled ketones with but-3-enyl type side chains to be converted to dihydropyrroles 16 in good yields in two steps (Scheme 4). The phenoxyl radicals released from 15 also abstracted H-atoms from the solvent to afford phenol as an easily separable by-product. When oxime ether 17 with an alkyne side chain was microwave irradiated under similar conditions, pyrrole 19 was isolated in good yield. Evidently the first-formed methylene-dihydropyrrole 18 rearranged under the reaction conditions.
Castle and co-workers prepared a set of alkyne-substituted oxime ethers 20 and carried out Scheme 3. Preparation of dioxime oxalates and their use in dihydropyrrole syntheses [54].
3,4-Dihydropyrrole derivatives 10 were obtained in moderate yields with toluene acting as both solvent and H-atom donor (Scheme 3). Unsymmetrical dioxime oxalates such as 11 incorporated an aryl-oxime unit, to promote photo-dissociation, as well as an alkenic acceptor unit. These precursors enabled non-aromatic dihydropyrroles such as 12a,b to be accessed. Attempts to convert the latter to pyrolizidines 13 and indolizidines 14 were unsuccessful.

Pyrrole and Dihydropyrrole Preparations from Oxime Ethers
Thermal preparative methods are often superior because of their simplicity and non-hazardous nature. O-Phenyl oxime ethers 15 can easily be made by treatment of carbonyl compounds with the commercially available O-phenylhydroxylamine hydrochloride. Conventional thermolyses of appropriate derivatives were shown to provide dialkyl-or diaryl-iminyl radicals [55]. Subsequently it was established that microwave heating (µwave) was a particularly efficient means of releasing iminyl radicals and mediating dihydropyrrole preparations [56,57].
The optimum procedure utilized toluene as both solvent and H-donor together with an equivalent of the ionic liquid (IL) 1-ethyl-3-methyl-1H-imidazol-3-ium hexafluorophosphate (emimPF 6 ) to promote microwave absorbance. This method enabled ketones with but-3-enyl type side chains to be converted to dihydropyrroles 16 in good yields in two steps (Scheme 4). The phenoxyl radicals released from 15 also abstracted H-atoms from the solvent to afford phenol as an easily separable by-product. When oxime ether 17 with an alkyne side chain was microwave irradiated under similar conditions, pyrrole 19 was isolated in good yield. Evidently the first-formed methylene-dihydropyrrole 18 rearranged under the reaction conditions.

Photoredox Catalyzed Preparations of Pyrroles and Dihydropyrroles from Oxime Derivatives
Photoredox catalytic methodology [25,27,59] has also been developed for production of dihydropyrroles from O-aryl oxime ethers substituted with electron withdrawing groups (EWG) in their O-aryl units. Narasaka and co-workers prepared oxime ethers 23 containing 4-CN (or 2,4-di-NO2 or 4-CF3) aryl substituents. On inclusion of a catalytic amount of 1,5-dimethoxynaphthalene (DMN) and irradiation with UV light in 1,4-cyclohexadiene, dihydropyrroles 25 were isolated in good yields (Scheme 5) [60]. The incident light raised the photocatalyst to an excited triplet state (PC*) that then transferred an electron to the oxime ethers with production of the radical anions 24 (Scheme 5). Loss of the stable phenolate type anions then occurred with release of the corresponding iminyl radicals that subsequently underwent 5-exo cyclisation and H-atom transfer with CHD to afford dihydropyrroles 25. Scheme 4. Preparation of oxime ethers and microwave-promoted syntheses of dihydropyrroles and pyrroles [56][57][58].
Castle and co-workers prepared a set of alkyne-substituted oxime ethers 20 and carried out microwave irradiations of mixtures with tetramethylpiperidine-N-oxide (TEMPO) in benzotrifluoride solvent [58]. The ring closed radicals were trapped by the TEMPO with production of intermediates 21 (Scheme 4). These also rearranged, with loss of a piperidinyl radical, so providing 2-acylpyrroles 22 in good to excellent yields.

Photoredox Catalyzed Preparations of Pyrroles and Dihydropyrroles from Oxime Derivatives
Photoredox catalytic methodology [25,27,59] has also been developed for production of dihydropyrroles from O-aryl oxime ethers substituted with electron withdrawing groups (EWG) in their O-aryl units. Narasaka and co-workers prepared oxime ethers 23 containing 4-CN (or 2,4-di-NO 2 or 4-CF 3 ) aryl substituents. On inclusion of a catalytic amount of 1,5-dimethoxynaphthalene (DMN) and irradiation with UV light in 1,4-cyclohexadiene, dihydropyrroles 25 were isolated in good yields (Scheme 5) [60]. The incident light raised the photocatalyst to an excited triplet state (PC*) that then transferred an electron to the oxime ethers with production of the radical anions 24 (Scheme 5). Loss of the stable phenolate type anions then occurred with release of the corresponding iminyl radicals that subsequently underwent 5-exo cyclisation and H-atom transfer with CHD to afford dihydropyrroles 25.
Furthermore, Leonori and co-workers reported recently that the dye Eosin Y (as PC) catalysed dihydropyrrole formation, simply with light of visible wavelength, when oxime ethers with O-2,4-dinitroaryl substitution 27 were employed as reactants [28]. Remarkably, Et 3 N could replace Eosin Y: visible light irradiation of 27 (EWG = 2,4-di-NO 2 ) with Et 3 N in CH 3 CN furnished imino-alcohols 31 in yields up to 85%. The complex of Et 3 N with the electron-poor ring of 27, on excitation with visible light, generated a radical anion that dissociated to give 2,4-dinitrophenoxide together with pyrrolidinylmethyl radical 28. The oxygen atom was believed to arise from an dihydropyrroles from O-aryl oxime ethers substituted with electron withdrawing groups (EWG) in their O-aryl units. Narasaka and co-workers prepared oxime ethers 23 containing 4-CN (or 2,4-di-NO2 or 4-CF3) aryl substituents. On inclusion of a catalytic amount of 1,5-dimethoxynaphthalene (DMN) and irradiation with UV light in 1,4-cyclohexadiene, dihydropyrroles 25 were isolated in good yields (Scheme 5) [60]. The incident light raised the photocatalyst to an excited triplet state (PC*) that then transferred an electron to the oxime ethers with production of the radical anions 24 (Scheme 5). Loss of the stable phenolate type anions then occurred with release of the corresponding iminyl radicals that subsequently underwent 5-exo cyclisation and H-atom transfer with CHD to afford dihydropyrroles 25. Scheme 5. Photoredox catalytic routes from oxime ethers to dihydropyrroles [28,60]. Scheme 5. Photoredox catalytic routes from oxime ethers to dihydropyrroles [28,60].
Weinreb and co-workers described an alternative strategy in which oximes 31 could be used directly when treated with 2,6-dimethylbenzenesulfinyl chloride in the presence of Hunig's base (N,N-diisopropylethylamine, DIEA) and a radical trapping agent in dichloromethane (DCM) [61]. The best radical traps (Z) were found to be TEMPO and diphenyl diselenide; but CHD could also be used when in great excess (Scheme 6). Probably sulfinate esters 32 were first formed that dissociated to a caged iminyl/sulfonyl radical pair 33. The reformed N-sulfonylimines 34 then released iminyl radicals that cyclised and were trapped to afford functionalised dihydropyrroles 35 in moderate to good yields (Scheme 6). Furthermore, Leonori and co-workers reported recently that the dye Eosin Y (as PC) catalysed dihydropyrrole formation, simply with light of visible wavelength, when oxime ethers with O-2,4dinitroaryl substitution 27 were employed as reactants [28]. Remarkably, Et3N could replace Eosin Y: visible light irradiation of 27 (EWG = 2,4-di-NO2) with Et3N in CH3CN furnished imino-alcohols 31 in yields up to 85%. The complex of Et3N with the electron-poor ring of 27, on excitation with visible light, generated a radical anion that dissociated to give 2,4-dinitrophenoxide together with pyrrolidinylmethyl radical 28. The oxygen atom was believed to arise from an intermediate such as 29 that fragmented to nitrosophenoxide and a pyrrolidine-containing alkoxyl radical. The latter picked up an H-atom to deliver imino-alcohols 30 as the products (Scheme 5).
Weinreb and co-workers described an alternative strategy in which oximes 31 could be used directly when treated with 2,6-dimethylbenzenesulfinyl chloride in the presence of Hunig's base (N,N-diisopropylethylamine, DIEA) and a radical trapping agent in dichloromethane (DCM) [61]. The best radical traps (Z) were found to be TEMPO and diphenyl diselenide; but CHD could also be used when in great excess (Scheme 6). Probably sulfinate esters 32 were first formed that dissociated to a caged iminyl/sulfonyl radical pair 33. The reformed N-sulfonylimines 34 then released iminyl radicals that cyclised and were trapped to afford functionalised dihydropyrroles 35 in moderate to good yields (Scheme 6).

Preparations of Pyridine, Quinoline, Phenanthridine and Related Aza-Arenes
Compounds containing the quinoline unit are hugely important to the well-being of society because they play essential roles across the areas of medicine, pharmacology, nutrition, dyes, and even electronics [62]. Bioactive natural products containing quinoline cores are widely distributed in many plants, marine plants, corals, sponges [63][64][65][66][67] and even in chestnut honey [68]. Much the same can be said for compounds containing phenanthridine units. They are noted for their ability to bind to DNA [69] and have antimicrobial, anti-inflammatory, and anti-tumor activities [70][71][72][73][74]. Because of this importance to the field of drug development, synthetic methods for molecules containing these structural units, particularly short, mild and atom-efficient ones, have attracted great attention.

Preparations of Aza-Arenes from Carbonyl Oximes
Iminyl radicals 36 containing suitably sited aromatic acceptor units usually ring close in 6-endo mode with formation of a 6-membered N-containing ring 38 (Scheme 7). This rule holds good for cyclisations onto a wide range of aromatic acceptors including benzene, naphthalene, furan, thiophene,

Preparations of Pyridine, Quinoline, Phenanthridine and Related Aza-Arenes
Compounds containing the quinoline unit are hugely important to the well-being of society because they play essential roles across the areas of medicine, pharmacology, nutrition, dyes, and even electronics [62]. Bioactive natural products containing quinoline cores are widely distributed in many plants, marine plants, corals, sponges [63][64][65][66][67] and even in chestnut honey [68]. Much the same can be said for compounds containing phenanthridine units. They are noted for their ability to bind to DNA [69] and have antimicrobial, anti-inflammatory, and anti-tumor activities [70][71][72][73][74]. Because of this importance to the field of drug development, synthetic methods for molecules containing these structural units, particularly short, mild and atom-efficient ones, have attracted great attention.

Preparations of Aza-Arenes from Carbonyl Oximes
Iminyl radicals 36 containing suitably sited aromatic acceptor units usually ring close in 6-endo mode with formation of a 6-membered N-containing ring 38 (Scheme 7). This rule holds good for cyclisations onto a wide range of aromatic acceptors including benzene, naphthalene, furan, thiophene, indole, pyridine and analogous moieties. As would be expected for less-favoured 6-endo processes, the rate constants for these iminyl ring closures are significantly smaller than for 5-exo cyclisations [75]. Never-the-less practicable preparative protocols have been established for many mono-and poly-cyclic heterocycles. restoration of aromaticity to the acceptor ring has usually been observed as in quinoline derivative 41. This can result when some radical in the system abstracts the highly labile tertiary H-atom of the cyclohexadienyl ring in radical 38. However, this is a disproportionation that requires two radicals to meet and so is not favored because reactive radical concentrations are always very low. The alternative is that an acceptor molecule A is either added, or is adventitiously present, and single electron transfer (SET) occurs with production of the corresponding cyclohexadienyl cations 40. These rapidly deprotonate to yield cyclised products 41 with restored aromaticity. This oxidative process is facilitated by non-H-atom donor solvents such as PhCF3 or t-BuOH. Scheme 7. Iminyl radical 6-endo ring closures onto aromatic acceptors.
Huang, Deng and co-workers recently described a novel method of making 2-arylpyridines by treatment of O-acyl oxime esters and acroleins with iodine and triethylamine in toluene at 120 °C [76]. The method had wide scope and yields ranged from moderate to excellent. It is usually necessary to work with precursors having the second imine substituent R 1 either Me or Ar. If R 1 is H (or a branched alkyl group) formation of a nitrile 37 is either the main process, or 37 is an important by-product (Scheme 7). Nitrile formation may entail an electrocyclic process of the oxime ester; in which case the proportion may be diminished by suitable solvent choice. With several types of oxime esters cyclisations onto aromatic rings initially create cyclohexadienyl type radicals 38. If a suitable H-donor is present as solvent, or otherwise, H-atom transfer to radicals 38 yields cyclohexadienes 39 as a mixture of isomers. In practice this route has rarely been developed. Instead restoration of aromaticity to the acceptor ring has usually been observed as in quinoline derivative 41. This can result when some radical in the system abstracts the highly labile tertiary H-atom of the cyclohexadienyl ring in radical 38. However, this is a disproportionation that requires two radicals to meet and so is not favored because reactive radical concentrations are always very low. The alternative is that an acceptor molecule A is either added, or is adventitiously present, and single electron transfer (SET) occurs with production of the corresponding cyclohexadienyl cations 40. These rapidly deprotonate to yield cyclised products 41 with restored aromaticity. This oxidative process is facilitated by non-H-atom donor solvents such as PhCF 3 or t-BuOH.
Huang, Deng and co-workers recently described a novel method of making 2-arylpyridines by treatment of O-acyl oxime esters and acroleins with iodine and triethylamine in toluene at 120 °C [76]. The method had wide scope and yields ranged from moderate to excellent. Scheme 8. Preparations of tri-and tetra-cyclic heterocycles from acyl oximes [50,52].
Huang, Deng and co-workers recently described a novel method of making 2-arylpyridines by treatment of O-acyl oxime esters and acroleins with iodine and triethylamine in toluene at 120˝C [76]. The method had wide scope and yields ranged from moderate to excellent.
Symmetrical dioxime oxalates containing aromatic acceptors 48 were prepared in essentially quantitative yields, via the oxime oxalyl chlorides, from the corresponding oximes. On UV photolyses at ambient temperature in MeCN solution these returned phenanthridines 49 in clean and atom-efficient processes [54]. Best yields were obtained on inclusion of MAP (ArMeC=O) and it seems this acted as both a photosensitizer and as an electron acceptor to facilitate the final re-aromatization (see Scheme 9). Symmetrical dioxime oxalates containing aromatic acceptors 48 were prepared in essentially quantitative yields, via the oxime oxalyl chlorides, from the corresponding oximes. On UV photolyses at ambient temperature in MeCN solution these returned phenanthridines 49 in clean and atom-efficient processes [54]. Best yields were obtained on inclusion of MAP (ArMeC=O) and it seems this acted as both a photosensitizer and as an electron acceptor to facilitate the final re-aromatization (see Scheme 9). Scheme 9. Preparation of phenanthridines from dioxime oxalates [54].
Oxime carbamates 56 offer another alternative for aza-arene syntheses but have not yet been much exploited. The Et 2 N aminyl group is sufficiently small that by-products derived from it volatilize away. UV irradiation of 56 in PhCF 3 at room temperature and with MAP additive provided 3-methoxy-6-methylphenanthridine 57 in 60% yield (Scheme 11) [78]. A slightly higher yield (61%) was obtained in the absence of MAP. This was a worthwhile finding because residues of the photosensitizer can be troublesome to remove. carbonyldiimidazole (CDI) (see Scheme 10). For the preparation of aza-arenes commercial ethyl chloroformate (50, R 2 = Et) was found to be very convenient because the main by-product (EtOH) is volatile and easily separated. UV photolyses of appropriately functionalised oxime carbonates, with MAP as additive, enabled phenanthridines 53, methylfuro-and methylthieno-[2,3-c]quinolines 54 to be prepared as well as the 5-methylbenzofuro-and 5-methylbenzo [4,5]thieno-[3,2-c]isoquinolines 55 in generally good yields [75,77]. Scheme 10. Preparations of aza-arenes from oxime carbonates [75,77].
Oxime carbamates 56 offer another alternative for aza-arene syntheses but have not yet been much exploited. The Et2N aminyl group is sufficiently small that by-products derived from it volatilize away. UV irradiation of 56 in PhCF3 at room temperature and with MAP additive provided 3-methoxy-6methylphenanthridine 57 in 60% yield (Scheme 11) [78]. A slightly higher yield (61%) was obtained in the absence of MAP. This was a worthwhile finding because residues of the photosensitizer can be troublesome to remove. Scheme 10. Preparations of aza-arenes from oxime carbonates [75,77].

Preparations of Aza-Arenes from Oxime Ethers
As mentioned above (Section 2.2) O-aryl oxime ethers, including those with appropriately placed aryl acceptor units, can easily be made from carbonyl compounds. The 3-phenylpropanone O-phenyl oxime ethers 58 were subjected to microwave irradiation at 160 °C in t-BuPh together with emimPF6 ionic liquid. Quinoline 59a and tetrahydroacridine 59b were thereby produced in moderate yields [56,57] (Scheme 12).

Preparations of Aza-Arenes from Oxime Ethers
As mentioned above (Section 2.2) O-aryl oxime ethers, including those with appropriately placed aryl acceptor units, can easily be made from carbonyl compounds. The 3-phenylpropanone O-phenyl oxime ethers 58 were subjected to microwave irradiation at 160˝C in t-BuPh together with emimPF 6 ionic liquid. Quinoline 59a and tetrahydroacridine 59b were thereby produced in moderate yields [56,57]

Photoredox Catalyzed Preparations of Aza-Arenes from Oxime Derivatives
The advantages of photoredox catalyzed processes include that visible light, rather than more damaging UV radiation, is usually sufficient and that only catalytic quantities of the PC are required. Several such methods have been reported recently for aza-arene preparations with oxime derivatives as starting materials For example, Zhang, Yu and co-workers generated iminyl radicals from a wide range of aroyl oximes with fac-[Ir(ppy) 3 ] (ppy = 2-phenylpyridine) as PC [79]. The most reliable and efficient aroyl group was shown to be 4-trifluoromethylbenzoyl; although other electron deficient benzoates succeeded to variable extents. Visible light irradiations of biphenyl aroyl oximes 66 with catalytic quantities of fac-[Ir(ppy) 3 ] in DMF produced phenanthridine derivatives 67 in very impressive yields (Scheme 13). The PC catalysed the formation of a radical anion from the substrate that then released an iminyl radical together with the 4-trifluorobenzoate anion. The non-H-atom donor solvent DMF favoured production of the fully aromatic products shown. Using similar methodology, the precursors 68 yielded quinolines 69 with a good range of functionality. Furthermore, aroyl oxime esters 70, with butadienyl substituents, led to iminyl radicals that ring closed selectively in 6-endo mode with eventual production of pyridine derivatives 71, generally in very good yields. Yu and An developed a convenient one-pot tactic that enabled aza-arenes to be prepared in one step from readily available carbonyl compounds [80]. A somewhat related method was reported by de Lijser and co-workers who employed 2′-arylbenzaldehyde oxime ethers 76 together with 9,10-dicyanoanthracene (DCA) [29]. Photolyses at 420 nm in CD3CN solutions enabled a set of substituted phenanthridines 80 to be obtained. This process was believed to proceed via radical cation 77 that ring closed by nucleophilic attack of the aromatic unit onto the N-atom of the oxime ether 78 (Scheme 14). Subsequent loss of methoxyl radicals led to cyclohexadienyl cations 79 that underwent deprotonation to afford the product phenanthridines. Yields were variable with strongly electron-releasing substituents Y being deleterious. The main by-Scheme 13. Photoredox methods for preparations of aza-arenes from oxime derivatives [79,80].
Yu and An developed a convenient one-pot tactic that enabled aza-arenes to be prepared in one step from readily available carbonyl compounds [80]. A somewhat related method was reported by de Lijser and co-workers who employed 2 1 -arylbenzaldehyde oxime ethers 76 together with 9,10-dicyanoanthracene (DCA) [29]. Photolyses at 420 nm in CD 3 CN solutions enabled a set of substituted phenanthridines 80 to be obtained. This process was believed to proceed via radical cation 77 that ring closed by nucleophilic attack of the aromatic unit onto the N-atom of the oxime ether 78 (Scheme 14). Subsequent loss of methoxyl radicals led to cyclohexadienyl cations 79 that underwent deprotonation to afford the product phenanthridines. Yields were variable with strongly electron-releasing substituents Y being deleterious. The main by-product was the volatile and innocuous MeOH and no nitrile formation was observed.
Yu and An developed a convenient one-pot tactic that enabled aza-arenes to be prepared in one step from readily available carbonyl compounds [80]. They used O-(4-cyanobenzoyl)hydroxylamine [ArC(O)ONH2] in conjunction with biphenyl aldehydes 72. To promote aroyl oxime formation 4-chlorobenzenesulfonic acid (CBSA) was employed as additive. On irradiation with visible light from white LED strips, phenanthridines 74 were obtained directly without isolation of the intermediate oxime esters 73. A similar one-pot procedure, but employing blue LED strip illumination, was established for preparations of quinoline derivatives 75 from cinnamaldehyde type precursors.
A somewhat related method was reported by de Lijser and co-workers who employed 2′-arylbenzaldehyde oxime ethers 76 together with 9,10-dicyanoanthracene (DCA) [29]. Photolyses at 420 nm in CD3CN solutions enabled a set of substituted phenanthridines 80 to be obtained. This process was believed to proceed via radical cation 77 that ring closed by nucleophilic attack of the aromatic unit onto the N-atom of the oxime ether 78 (Scheme 14). Subsequent loss of methoxyl radicals led to cyclohexadienyl cations 79 that underwent deprotonation to afford the product phenanthridines. Yields were variable with strongly electron-releasing substituents Y being deleterious. The main byproduct was the volatile and innocuous MeOH and no nitrile formation was observed.

Preparations of Quinazoline Derivatives
Aminoarylalkanone O-phenyl oximes 81 can be efficiently prepared from the corresponding ketones (Scheme 15). On mixing these starting materials with an aldehyde and microwave irradiating at 160˝C, in toluene as H-donor solvent, with emimPF 6 as ionic liquid, imine intermediates 82 were formed. Dissociation to phenoxyl and iminyl radicals 83 took place in one pot, without the need to isolate the imine intermediates 82. Ring closure was exclusively in the 6-endo mode with production of aminyl radicals 84 that were reduced to 1,2-dihydroquinazolines 85 by H-atom donation from the solvent [98,99] (Scheme 15).
This proved to be a rapid, mild, reproducible and efficient process with aliphatic, aromatic and heterocyclic aldehydes; the only by-product being phenol. Analogous methodology with 81 and ketones was not successful, except with a few ketones such as cyclohexanone. The dihydroquinazolines 85 slowly oxidized to the corresponding quinazolines in air or oxygen. Alternatively, they could be converted to the latter in high yields by µwave irradiation with DDQ (2,3-dichloro-5, 6-dicyanobenzoquinone) at 100˝C in dichloromethane solvent. ketones (Scheme 15). On mixing these starting materials with an aldehyde and microwave irradiating at 160 °C, in toluene as H-donor solvent, with emimPF6 as ionic liquid, imine intermediates 82 were formed. Dissociation to phenoxyl and iminyl radicals 83 took place in one pot, without the need to isolate the imine intermediates 82. Ring closure was exclusively in the 6-endo mode with production of aminyl radicals 84 that were reduced to 1,2-dihydroquinazolines 85 by H-atom donation from the solvent [98,99] (Scheme 15). This proved to be a rapid, mild, reproducible and efficient process with aliphatic, aromatic and heterocyclic aldehydes; the only by-product being phenol. Analogous methodology with 81 and ketones was not successful, except with a few ketones such as cyclohexanone. The dihydroquinazolines 85 slowly oxidized to the corresponding quinazolines in air or oxygen. Alternatively, they could be converted to the latter in high yields by μwave irradiation with DDQ (2,3-dichloro-5,6dicyanobenzoquinone) at 100 °C in dichloromethane solvent.
Inclusion of ZnCl2, a known promoter of imine formation [100], in practice led directly to the corresponding fully aromatic quinazolines 87. Good to excellent yields were obtained with aliphatic aldehydes, aromatic aldehydes having either electron-withdrawing or electron releasing substituents and with heterocyclic aldehydes. The method was also tolerant of substituents in the aminoaryl rings. It's likely that, in addition to encouraging imine formation, the ZnCl2 forms a complex with the iminyl N-atom in radical cation 86. The acidity of the H-atom adjacent to the cation would thereby be increased, thus facilitating proton-coupled electron transfer (PCET) and thence to the quinazolines 87 (Scheme 15).
Inclusion of ZnCl 2 , a known promoter of imine formation [100], in practice led directly to the corresponding fully aromatic quinazolines 87. Good to excellent yields were obtained with aliphatic aldehydes, aromatic aldehydes having either electron-withdrawing or electron releasing substituents and with heterocyclic aldehydes. The method was also tolerant of substituents in the aminoaryl rings. It's likely that, in addition to encouraging imine formation, the ZnCl 2 forms a complex with the iminyl N-atom in radical cation 86. The acidity of the H-atom adjacent to the cation would thereby be increased, thus facilitating proton-coupled electron transfer (PCET) and thence to the quinazolines 87 (Scheme 15).
Conventional organic preparations of quinazolinones usually start with derivatives of anthranilic acid [89,101]. Several good Pd-and Cu-catalyzed methods for compounds containing this structure have also been published [102][103][104]. Malacria, and co-workers devised an ingenious radical cascade for making quinazolinones starting from N-acyl-N-(2-iodobenzyl)cyanamides 88 [105][106][107]. Iminyl radicals 89 were obtained by 5-exo-cyclisation onto the nitrile group of the first-formed aryl radicals. Subsequent ring closure took place efficiently onto a variety of aromatic and heteroaromatic rings yielding quinazolin-2-ones 90 (Scheme 16). The method was subsequently extended to the analogous 2-azidoalkyl-N-acylcyanamides 91 and these yielded guanidines 92 [108]. The disadvantages of this methodology were the need to use toxic cyanogen bromide in the syntheses of the precursors and the stoichiometric amounts of organotin hydride needed for the ring closures. Aware that 5-aryl-4,5-dihydro-1,2,4-oxadiazoles 93 are readily available, either from 1,3-dipolar cycloadditions of nitrile oxides to aldimines, or from reactions of amidoximes with carbonyls [109,110], Chiba and co-workers adopted these as their iminyl radical precursors [111]. They discovered that on treatment in DMSO solution simply with dry air at 120 °C, oxidative rearrangements of 93 were set in motion and resulted in formation of quinazolinones 96 (Scheme 17). Iminyl radicals 94 were generated either via a SET and proton loss process, or by abstraction of the tertiary benzylic H-atom followed by β-scission (Scheme 17). The dominant ring closure was in the 6-endo mode yielding cyclohexadienyl radicals 95 that were oxidised to the quinazolinone products 96 usually in very good yields. The process was tolerant of electron withdrawing and electron releasing substituents, as well Scheme 16. Cascade preparations of quinazolinones and guanidines [105][106][107][108].
Aware that 5-aryl-4,5-dihydro-1,2,4-oxadiazoles 93 are readily available, either from 1,3-dipolar cycloadditions of nitrile oxides to aldimines, or from reactions of amidoximes with carbonyls [109,110], Chiba and co-workers adopted these as their iminyl radical precursors [111]. They discovered that on treatment in DMSO solution simply with dry air at 120˝C, oxidative rearrangements of 93 were set in motion and resulted in formation of quinazolinones 96 (Scheme 17). Iminyl radicals 94 were generated either via a SET and proton loss process, or by abstraction of the tertiary benzylic H-atom followed by β-scission (Scheme 17). The dominant ring closure was in the 6-endo mode yielding cyclohexadienyl radicals 95 that were oxidised to the quinazolinone products 96 usually in very good yields. The process was tolerant of electron withdrawing and electron releasing substituents, as well as 5-heteroaryl substituents. Substrates with orthoor meta-substituents R 3 gave rise to mixtures of isomeric quinazolinones (see structure 99).
Aware that 5-aryl-4,5-dihydro-1,2,4-oxadiazoles 93 are readily available, either from 1,3-dipolar cycloadditions of nitrile oxides to aldimines, or from reactions of amidoximes with carbonyls [109,110], Chiba and co-workers adopted these as their iminyl radical precursors [111]. They discovered that on treatment in DMSO solution simply with dry air at 120 °C, oxidative rearrangements of 93 were set in motion and resulted in formation of quinazolinones 96 (Scheme 17). Iminyl radicals 94 were generated either via a SET and proton loss process, or by abstraction of the tertiary benzylic H-atom followed by β-scission (Scheme 17). The dominant ring closure was in the 6-endo mode yielding cyclohexadienyl radicals 95 that were oxidised to the quinazolinone products 96 usually in very good yields. The process was tolerant of electron withdrawing and electron releasing substituents, as well as 5-heteroaryl substituents. Substrates with ortho-or meta-substituents R 3 gave rise to mixtures of isomeric quinazolinones (see structure 99). Scheme 17. Preparations of quinazolinones from 4,5-dihydro-1,2,4-oxadiazoles [111].

Preparations of Quinoxaline Derivatives
The quinoxaline and quinoxalin-2-one structural units are also associated with many natural products and biologically active substances [112][113][114][115]. These rings have been assembled in several ways based on initial addition of C-, or S-centered radicals to aromatic isonitriles 101. Nanni and co-workers generated cyano-substituted alkyl radicals by treatment of 4-iodobutanenitrile 102 with hexamethylditin in t-butylbenzene at 150˝C [116]. Additions to the isonitriles generated imidoyl radicals 103 that ring closed onto the pendant cyano group in 5-exo mode to afford cyclic iminyl radicals 104. The cascade continued with a further cyclisation on to the aromatic nucleus followed by oxidative re-aromatization to produce cyclopentaquinoxalines 105 in moderate yields (Scheme 18). Significantly, the 2-cyanophenyl disulfide 106 was employed in an analogous process that was free of organotin compounds. UV photolysis of 106, together with an isonitrile, in benzene solution at r.t. gave rise to benzo [4,5]thieno [2,3-b]quinoxalines 108 in fair yields via α-thioimidoyl radicals and polycyclic-iminyl radicals 107 (Scheme 18).
More recently, photoredox catalyzed versions of the isonitrile insertion process requiring only visible light, have been deployed for quinoxaline preparations. Sun et al. demonstrated that diethyl 2-bromo-2-(2-isocyanoethyl)malonate 109 was a suitable precursor for 3-cyano-alkyl radicals when irradiated by blue LED light in the presence of fac-Ir(ppy) 3 as PC. Cyclopenta-iminyl radicals were obtained as intermediates and afforded cyclopentaquinoxalines 110 in moderate to excellent yields [117] (Scheme 18). Jamison and co-workers generated alkyl radicals from readily accessible phenyliodine(III) dicarboxylates [118] with visible light and fac-Ir(ppy) 3 in DMF [119]. Their substrates were aromatic isonitriles with ortho-pyrrole or analogous heteroarene substituents 111. The alkyl radicals coupled with the isonitriles giving imidoyl radical intermediates 112 that ring closed to pyrrolo[1,2-a]quinoxalines (and related structures) 113 without the intermediacy of iminyl radicals (Scheme 18). The process was tolerant of many substituent types enabling a good range of polycyclic heteroarenes to be prepared. Efficiency was enhanced by their development of a continuous flow system that integrated isonitrile formation with the photo-redox cascade. visible light, have been deployed for quinoxaline preparations. Sun et al. demonstrated that diethyl 2-bromo-2-(2-isocyanoethyl)malonate 109 was a suitable precursor for 3-cyano-alkyl radicals when irradiated by blue LED light in the presence of fac-Ir(ppy)3 as PC. Cyclopenta-iminyl radicals were obtained as intermediates and afforded cyclopentaquinoxalines 110 in moderate to excellent yields [117] (Scheme 18). Jamison and co-workers generated alkyl radicals from readily accessible phenyliodine(III) dicarboxylates [118] with visible light and fac-Ir(ppy)3 in DMF [119]. Their substrates were aromatic isonitriles with ortho-pyrrole or analogous heteroarene substituents 111. The alkyl radicals coupled with the isonitriles giving imidoyl radical intermediates 112 that ring closed to pyrrolo[1,2-a]quinoxalines (and related structures) 113 without the intermediacy of iminyl radicals (Scheme 18). The process was tolerant of many substituent types enabling a good range of polycyclic heteroarenes to be prepared. Efficiency was enhanced by their development of a continuous flow system that integrated isonitrile formation with the photo-redox cascade. [116,117,119].

Iminyl Radical Mediated Preparations of Natural Products and Bioactive Compounds
A significant number of iminyl radical based preparative methods have been developed for one or more stages in total or partial syntheses of natural products and bioactive compounds. Trispheridine 114 occurs naturally in flowering plants of the family Amaryllidaceae [120,121]. Trispheridine itself, as well as related compounds, are known to possess anti-tumor activity [122], high anti-retroviral activity [123] and neuro-protective activity [124]. At least six iminyl radical-mediated preparations of trispheridine have been devised and these are summarized in Scheme 19.

Iminyl Radical Mediated Preparations of Natural Products and Bioactive Compounds
A significant number of iminyl radical based preparative methods have been developed for one or more stages in total or partial syntheses of natural products and bioactive compounds. Trispheridine 114 occurs naturally in flowering plants of the family Amaryllidaceae [120,121]. Trispheridine itself, as well as related compounds, are known to possess anti-tumor activity [122], high anti-retroviral activity [123] and neuro-protective activity [124]. At least six iminyl radical-mediated preparations of trispheridine have been devised and these are summarized in Scheme 19.
Three of these rely on UVA irradiations; all of easily prepared precursors including dioxime oxalate 115 [54], O-acyl oxime ester 116 [52] and O-phenyl oxime carbonate 117 [77]. All three precursors were made in high yields, essentially in three steps, from commercially available 6-bromopiperonal. The highest reported yield (59%) was that from dioxime oxalate 115 but it is probable that yields from all three processes could be increased by optimization studies. The µwave promoted process from O-phenyl oxime ester 118 was short, clean and comparatively efficient (70%) [57]. Compound 118 was made in high yield in two steps from 6-bromopiperonal and the reaction conditions were clean and straightforward. The two photoredox catalyzed methods starting from aldehyde 119 [80] and trifluoromethylbenzoyl oxime ester 120 [79] had the highest reported yields and reaction conditions were benign (Scheme 19). The fac-Ir(ppy) 3 catalyzed preparation, starting from aldehyde 119, took only two steps from 6-bromopiperonal. It should be noted, however, that the co-reactant O-(4-cyanobenzoyl)hydroxylamine is not commercial; although it can be made in two high-yielding steps from 4-cyanobenzoyl chloride. and straightforward. The two photoredox catalyzed methods starting from aldehyde 119 [80] and trifluoromethylbenzoyl oxime ester 120 [79] had the highest reported yields and reaction conditions were benign (Scheme 19). The fac-Ir(ppy)3 catalyzed preparation, starting from aldehyde 119, took only two steps from 6-bromopiperonal. It should be noted, however, that the co-reactant O-(4-cyanobenzoyl)hydroxylamine is not commercial; although it can be made in two high-yielding steps from 4-cyanobenzoyl chloride. Vasconine 123, along with assoanine, oxoassoanine, pratosine and ismine, constitute another group of alkaloids, isolated from Narcissus plants of the Amaryllidaceae family, that contain phenanthridine rings [125,126]. The acyl oxime 121 was targeted as a key compound and prepared in six steps from commercial 2-(3-bromophenyl)ethanol [52]. UV irradiation of this through Pyrex in MeCN solution afforded phenanthridinylethanol derivative 122 in 53% yield (Scheme 20). Compound 122 can be converted to vasconine 123 by treatment with PBr3 and can also act as precursor for assoanine, oxoassoanine, and pratosine [125].
Natural products that contain the indolizino[1,2-b]quinolin-9(11H)-one structure 130a include camptothecine, mappicine and the nothapodytines [129]. Camptothecine has been obtained from the bark of Camptotheca acuminata (Camptotheca, Happy tree, Tupelo family) [130] and mappicine from Mappia foetida miers (Olacaceae family) [131]. The high bioactivity of these compounds stimulated the production of many synthetic and semi-synthetic analogues [132,133]. Several pharmaceuticals containing this core have been licensed for use including irinotecan (Camptosar ® , Campto ® ) which is used for the treatment of colon cancer and Topotecan (trade name Hycamtin ® ) which is approved for treatment of several cancers including ovarian and lung types [134]. A number of total syntheses, incorporating important radical-mediated steps, have been reported. Of particular note are those of Curran and co-workers, most of which have key steps involving amidoyl radicals obtained from additions to aromatic isonitriles [135][136][137][138][139][140][141].
Natural products that contain the indolizino[1,2-b]quinolin-9(11H)-one structure 130a include camptothecine, mappicine and the nothapodytines [129]. Camptothecine has been obtained from the bark of Camptotheca acuminata (Camptotheca, Happy tree, Tupelo family) [130] and mappicine from Mappia foetida miers (Olacaceae family) [131]. The high bioactivity of these compounds stimulated the production of many synthetic and semi-synthetic analogues [132,133]. Several pharmaceuticals containing this core have been licensed for use including irinotecan (Camptosar ® , Campto ® ) which is used for the treatment of colon cancer and Topotecan (trade name Hycamtin ® ) which is approved for treatment of several cancers including ovarian and lung types [134]. A number of total syntheses, incorporating important radical-mediated steps, have been reported. Of particular note are those of Curran and co-workers, most of which have key steps involving amidoyl radicals obtained from additions to aromatic isonitriles [135][136][137][138][139][140][141].
Luotonins A, B, E (132a-c) and congeners are structurally related to the mappicines and combine the 2,3-dihydro-1H-pyrrolo[3,4-b]quinoline ring system with the quinazolinone unit. They have been isolated from plant species of the genus Peganum found in China and are well-recognized as remedies in traditional Chinese medicine [144]. They are given for disorders including rheumatism, inflammation, influenza, hepatitis and leukemia and are known antagonists for human DNA topoisomerase I [145,146]. Structure/activity relationships have been investigated for heterocycles of this class [147]. Various non-radical syntheses have been devised [148][149][150][151]. Bowman and co-workers adapted their radical cascade protocol for a comparatively short synthesis of luotonin A 123a [143]. The vinyl iodide radical precursor 131 was made by alkylation of 4-oxo-3,4-dihydroquinazoline-2-carbonitrile with a substituted cinnamyl bromide. On UV irradiation of a solution of 131 and hexamethylditin in t-BuPh, luotonin A 132a was isolated in a very modest yield of 21% (Scheme 22). A slightly improved yield Scheme 21. Radical-mediated preparations of indolizino[1,2-b]quinolin-9(11H)-ones [142,143].
Luotonins A, B, E (132a-c) and congeners are structurally related to the mappicines and combine the 2,3-dihydro-1H-pyrrolo[3,4-b]quinoline ring system with the quinazolinone unit. They have been isolated from plant species of the genus Peganum found in China and are well-recognized as remedies in traditional Chinese medicine [144]. They are given for disorders including rheumatism, inflammation, influenza, hepatitis and leukemia and are known antagonists for human DNA topoisomerase I [145,146]. Structure/activity relationships have been investigated for heterocycles of this class [147]. Various non-radical syntheses have been devised [148][149][150][151]. Bowman and co-workers adapted their radical cascade protocol for a comparatively short synthesis of luotonin A 123a [143]. The vinyl iodide radical precursor 131 was made by alkylation of 4-oxo-3, 4-dihydroquinazoline-2-carbonitrile with a substituted cinnamyl bromide. On UV irradiation of a solution of 131 and hexamethylditin in t-BuPh, luotonin A 132a was isolated in a very modest yield of 21% (Scheme 22). A slightly improved yield (30%) was obtained when the reaction was carried out in a sealed tube, at 120˝C, with added di-t-butyl peroxide.
Courillon, Malacria and co-workers devised an alternative strategy in which the starting material was the N-acyl-N-(2-iodobenzyl)cyanamide 133 [105] (Scheme 22). For the luotonin synthesis, 3-(azidomethyl)-2-iodoquinoline was prepared in four steps from quinoline chlorcarbaldehyde and then reduced to the corresponding amine and benzoylated to give 133. UV irradiation of the latter, with hexamethylditin, in refluxing toluene for 6 h, gave a 43% yield of luotonin A 132a.
Courillon, Malacria and co-workers devised an alternative strategy in which the starting material was the N-acyl-N-(2-iodobenzyl)cyanamide 133 [105] (Scheme 22). For the luotonin synthesis, 3-(azidomethyl)-2-iodoquinoline was prepared in four steps from quinoline chlorcarbaldehyde and then reduced to the corresponding amine and benzoylated to give 133. UV irradiation of the latter, with hexamethylditin, in refluxing toluene for 6 h, gave a 43% yield of luotonin A 132a. The same research team also discovered an organotin-free protocol employing the same N-acyl-N-(2-iodobenzyl)cyanamide 133 [107]. When this was UV photolyzed with pyridine (5 equiv.) in refluxing benzene, in air, luotonin A (132a) was obtained in an improved yield of 54%.
Ispinesib 140 is a synthetic quinazolinone that is under study as a potential anti-cancer agent [154,155]. A similar strategy was employed in a short iminyl radical-mediated synthesis [111]. Alkylated phthalimide 137 was prepared from L-valine and thence to dihydro-1,2,4-oxadiazole 138 as a mixture of diastereoisomers in three steps. On heating one stereoisomer in aerated DMSO the quinazoline derivative 139, which is a key precursor for ispinesib, was obtained in moderate yield The same research team also discovered an organotin-free protocol employing the same N-acyl-N-(2-iodobenzyl)cyanamide 133 [107]. When this was UV photolyzed with pyridine (5 equiv.) in refluxing benzene, in air, luotonin A (132a) was obtained in an improved yield of 54%.
(30%) was obtained when the reaction was carried out in a sealed tube, at 120 °C, with added di-t-butyl peroxide.
The same research team also discovered an organotin-free protocol employing the same N-acyl-N-(2-iodobenzyl)cyanamide 133 [107]. When this was UV photolyzed with pyridine (5 equiv.) in refluxing benzene, in air, luotonin A (132a) was obtained in an improved yield of 54%.
Ispinesib 140 is a synthetic quinazolinone that is under study as a potential anti-cancer agent [154,155]. A similar strategy was employed in a short iminyl radical-mediated synthesis [111]. Alkylated phthalimide 137 was prepared from L-valine and thence to dihydro-1,2,4-oxadiazole 138 as a mixture of diastereoisomers in three steps. On heating one stereoisomer in aerated DMSO the quinazoline derivative 139, which is a key precursor for ispinesib, was obtained in moderate yield Scheme 23. Syntheses of rutaecarpine and ispinesib derivatives via dihydro-1,2,4-oxadiazoles [111].
Ispinesib 140 is a synthetic quinazolinone that is under study as a potential anti-cancer agent [154,155]. A similar strategy was employed in a short iminyl radical-mediated synthesis [111]. Alkylated phthalimide 137 was prepared from L-valine and thence to dihydro-1,2,4-oxadiazole 138 as a mixture of diastereoisomers in three steps. On heating one stereoisomer in aerated DMSO the quinazoline derivative 139, which is a key precursor for ispinesib, was obtained in moderate yield though with some racemization [156]. These dihydro-1,2,4-oxadiazole rearrangements provide a benign, metal-free and atom-economical protocol with great promise as a general synthetic tool for the incorporation of quinazolinone units.

Conclusions
Five-and six-membered ring aza-arenes are hugely important in nutrition, medicine and pharmacology because of their many useful therapeutic properties. Short, mild and atom-efficient synthetic methods for compounds containing these units are clearly provided by iminyl radical mediated systems. Although iminyl radicals can be accessed by a variety of ways, carbonyl oximes and oxime ethers are particularly effective non-toxic precursors with long shelf lives. These starting materials lend themselves to 'clean' preparative protocols, free of harsh acid/base or redox reagents, and employing photolysis, µwave irradiation or photoredox catalysis. Iminyl radicals generated by these means and suitably substituted with acceptor units facilitate syntheses of a large variety of such compounds. Suitable acceptor groups include aromatics, heteroarenes, alkenes and alkynes. Reproducible and efficient syntheses of good scope and impressive generality have thereby been devised for diverse families of heterocycles. Significantly, iminyl radical based steps have been chosen for natural products and bioactive molecules containing phenanthridine, indole and quinazoline core units. It seems certain that further variations of these methods will be devised and find additional roles and applications. It can be reliably concluded that iminyl-radical based synthetic methods form a most valuable toolkit to expedite the exploration of 'drug-like' chemical space.