Synthesis of Nitrogen-Containing Heterocycles via Imidoyl or Iminyl Radical Intermediates

Abstract

Synthesis of nitrogen-containing heterocycles with isocyanides, isothiocyanates, nitriles, imines, oxime derivatives, and other related compounds has been deeply investigated in organic synthesis. This chapter mainly focuses on summarizing radical cyclization reactions of these C-N unsaturated precursors to afford N-heterocycles in the past decade as well as some earlier feature examples. In most cases, imidoyl or iminyl radicals are involved in cyclizing onto unsaturated systems or heteroatoms to generate N-heterocycles, such as phenanthridines, (iso)quinolines, pyridines, indoles, and pyrroles. A few examples via other types of radical intermediates starting from isothiocyanates, isocyanates, and analogous structures are also included.

1 Introduction

Structures containing carbon-nitrogen unsaturated bonds, including double and triple bonds, are widely distributed, showing diverse reactivity in organic synthesis.

Substrates containing C-N unsaturated bonds are also extensively applied in radical reactions. In this chapter, radical cyclization reactions involving isocyanides, isothiocyanates, nitriles, imines, oxime derivatives, and other related compounds to afford N-heterocycles are summarized. In most of the processes, imidoyl and iminyl radical intermediates are formed, generated from the corresponding C- and N-centered radicals. The review is organized around functional groups that generate these two types of radicals.

Imidoyl radical was first described over 50 years ago, and a comprehensive review covering its history, generation, structure, and reactivity was presented by Nanni in 2007 [1]. General structure of imidoyl radical can be described as a carbon radical with a single electron occupying the σ-orbital of the imidoyl group [2]. The most common way to give an imidoyl radical is α-addition of carbon-, tin-, sulfur-, phosphine-, oxygen-, and tellurium-centered radicals onto isocyanide. Radical addition to isothiocyanates also generates the corresponding sulfur-containing imidoyl radical, although limited examples were available in the literature. Homolysis of imines and their derivatives is also an efficient way to give related imidoyl radicals. The unique structure of imidoyl radical leads to three special reactivities, such as α-scission to go back to isocyanide [3] or β-scission to generate nitrile and another radical [4], which is used in cyanation or deamination [5]; oxidation of imidoyl radicals to nitriliums followed by nucleophilic attack to provide amide derivatives is also reported (Scheme 1) [6, 7].

Scheme 1

Generation and conversion of imidoyl radicals

Most importantly, like other radicals, imidoyl radicals can be trapped by alkenes, alkynes, or arenes, to generate a variety of N-heterocycles when processes take place intramolecularly. This process is probably the most useful transformation of imidoyl radicals, and thus it has been deeply investigated during the past decade. The products are normally 5-membered or 6-membered heterocycles including pyridines, pyrroles, pyrazine, and imidazoles (Scheme 2).

Scheme 2

Scaffolds of cyclization products of imidoyl radicals

The study of iminyl radicals through EPR spectroscopy traces back to 50 years ago, [8] figuring that the single electron occupies a 2p orbital that lies orthogonal to the π-orbitals of the C-N double bond [9, 10]. The practical generation pathways of iminyl radicals include addition of carbon or nitrogen radicals to nitriles; thermal or photo-homolysis of N-X bonds in oxime derivatives, in which X may refer to O, S, N, Cl, and H; and decomposition of organic azides to release nitrogen and iminyl radicals (Scheme 3). However, organic azides are not covered in this chapter for their special structure and reactivity [11, 12]. Like imidoyl radicals, the major fate of iminyl radicals is trapping by intramolecular functional groups to give nitrogen heterocycles including pyridines/pyrazines, dihydropyrroles, isothiazoles, etc. (Scheme 4). Other pathways to iminyl radical include β-scission into nitriles and alkyl radicals [13] and hydrogen abstraction to form imines and subsequent hydrolysis into ketones. Recently, Walton and Castle reported several reviews on synthesis utilizing iminyl radicals [14,15,16].

Scheme 3

Generation and transformation of iminyl radicals

Scheme 4

Basic scaffolds of annulation products of iminyl radicals

Cyclization of imidoyl/iminyl radicals can result into the following two types of products: one in which both C and N atoms in the C=N bond are present into the ring (route a, b, c, Scheme 4) and the other in which only the carbon in C=N participates to the ring construction, the N atom in the heterocycle coming from other functionalities (route d, Scheme 4). In the following parts, radical cyclization has been organized around the nature of the substrate functional groups.

2 Cyclization via Imidoyl Radicals

2.1 Starting from Isocyanides

Isocyanide which is isoelectronic to carbon monoxide is well-known for its versatility in bond formation. The resonance structures of isocyanide can be described as in Eq. (1). The two resonance forms are responsible for its amphiphilic reactivity [17,18,19,20], its reactivity in radical-mediated [21], and in transition metal-catalyzed insertion [22,23,24].

(1)

The terminal divalent carbon of isocyanide can form an imidoyl radical by accepting a radical species, forming simultaneously a σ-bond and a radical on the geminal carbon. Subsequent intramolecular addition of the resulting imidoyl radical onto unsaturated bonds or heteroatoms forms nitrogen heterocycles after radical termination. Thus, the whole cyclization process consists in the formation of two chemical bonds from the isocyanide carbon.

Cyclization of imidoyl radical to synthesize nitrogen heterocycles has been reported for decades. A seminal application of this strategy was developed by Curran for the synthesis of camptothecin and its derivatives [25,26,27]. Another early example was demonstrated in indole alkaloids synthesis, also known as Fukuyama indole synthesis [28,29,30,31]. These reactions could be performed under mild conditions with high bond forming efficiency, thus providing efficient alternatives for N-heterocycle construction. However, toxic tin reagents were inevitably used in these processes (Scheme 5).

Scheme 5

Fukuyama’s indole synthesis and Curran’s approach to camptothecin

In recent years, significant development has been made in this area owing to the application of new free radical generation protocol and diversified functionalized isocyanides. Reviews on the synthesis of nitrogen heterocycles via imidoyl radical intermediates generated from isocyanides were reported by Studer, Xu, and Zhu group [32,33,34].

The phenanthridine core is widely distributed in natural and synthetic compounds exhibiting various biological activities [35, 36]. In 1995, Nanni reported the synthesis of 6-cyanopropyl-substituted phenanthridines with 2-isocyanobiphenyl with the aid of AIBN via an imidoyl radical intermediate [37]. Beyond cyanopropyl radical generated from AIBN, phenyl and tristrimethylsilylsilyl radicals may also be incorporated at C6 in phenanthridines. In 2000, Smith described another high-yield approach to 6-alkyl phenanthridines, starting from 2′-iodo-2-isocyanobiphenyls in the presence of n-Bu₃SnH/AIBN (Scheme 6) [38]. Interestingly, in the presence of excess vinyl t-butyl ether, addition of phenanthridine C6 radical to vinyl t-butyl ether affords C6-alkylated products.

Scheme 6

Phenanthridine synthesis with 2′-iodo-2-isocyanobiphenyls

In 2012, Chatani reported a novel imidoyl radical cyclization reaction starting from 2-isocyanobiphenyls and boronic acids promoted by Mn(acac)₃ to afford the C6-aryl- or alkyl-substituted phenanthridines in good yields (Scheme 7) [39]. Mechanistic studies revealed that over two equivalents of manganese were necessary, since Mn(acac)₃ acted as a single-electron oxidant for both radical generation from boronic acids and oxidation of the cyclohexadienyl radical into the corresponding cation. Moreover, the reaction was shut off by addition of TEMPO, suggesting that radical intermediates were involved in the reaction. The mechanism they proposed was well accepted, and similar mechanisms were reported in most of the following studies using other radical species.

Scheme 7

Synthesis of 6-aryl/alkylphenanthridines from organoborons and Mn(acac)₃

Zhu reported an alternative method for the synthesis of 6-arylphenanthridines using aryl radicals generated in situ from inexpensive and readily available anilines and t-BuONO [40]. Both radical clock and radical inhibition experiments revealed that aryl radical intermediates were involved. It is known that imidoyl radicals are prone to oxidation into nitriliums. Therefore, a competitive reaction pathway was proposed, including an intramolecular homolytic aromatic substitution (HAS) or a SET oxidation to nitrilium followed by an electrophilic aromatic substitution. When water was added into the reaction medium, the related amide product derived from addition of water to the nitrilium intermediate was isolated in low yield (vide infra). The Hammett curve with unsymmetrical 2,6-diaryl phenylisocyanides suggested that both pathways involving S_EAr of nitrilium cation and HAS of imidoyl radical were likely involved in the annulation step (f vs. a, Scheme 8). The importance of phenanthridine scaffold has prompted the incorporation of various radicals including CF₃, aryl, alkyl, C_xH_yF_z, acyl, phosphine, and silyl radicals to synthesize various C6-substituted phenanthridines [32,33,34].

Scheme 8

Synthesis of 6-arylphenanthridines from anilines and t-BuONO

Beyond phenanthridines, other heterocycles can also be synthesized with this method by modifying isocyanide structure. For example, Studer reported radical trifluoromethylation/cyclization of 2-vinyl-substituted arylisocyanide 11 with hypervalent iodine-CF₃ reagent (Togni’s reagent) and TBAI as an initiator to afford 2-trifluoromethylated indoles 12 via 5-exo-trig cyclization (Scheme 9) [41, 42]. When R¹ is a hydrogen, the 3-alkenyl product was trifluoromethylated further with excess Togni’s reagent to provide 13.

Scheme 9

Synthesis of 2-trifluoromethylated indoles with 2-vinyl arylisocyanides

When 2-alkynyl arylisocyanide was used as radical acceptor, 2-substituted quinolines were synthesized. Ogawa described the synthesis of 2,4-bis-chalcogenated quinolines via visible-light-induced chalcogenation of isocyanides in modest to good yield (Scheme 10) [43]. Besides the mechanism involving an imidoyl radical-mediated cyclization, an alternative approach through addition of a phenyltellurium radical to alkyne, followed by capture of the resulting vinyl radical with isocyanide, was proposed. The 2-quinolinyl radical was then quenched by dichalcogenides to give the final product 15.

Scheme 10

Reaction of O-ethynylarylisocyanides with dichalcogenides

When vinyl isocyanide was used as substrate, isoquinoline or pyridine derivatives could be obtained. In 2014, Yu reported visible-light-promoted cyclization of vinyl isocyanides with diaryliodonium salts to afford isoquinolines 17 (Scheme 11) [44]. Later on, they used 1,3-dienyl isocyanides to synthesize 2-(fluoro)alkylated pyridine derivatives 19 in the presence of Umemoto’s reagent under visible-light conditions (Scheme 12) [45].

Scheme 11

Synthesis of isoquinolines using isocyanide and diaryliodonium salt

Scheme 12

Reaction of vinyl isocyanides and Umemoto’s reagent to synthesize polysubstituted pyridines

Recently, Studer and Yu independently explored reactions of ortho-diisocyanoarenes as radical acceptors with (perfluoro)alkyl iodides to provide (perfluoro)alkyl-substituted iodoquinoxalines 21 [46, 47]. The former used traditional AIBN or Bu₃SnH/hv to initiate the reaction; the latter applied amines as halo-bond acceptor to promote the generation of fluoro-bearing radicals under visible-light irradiation. Following double addition of perfluoroalkyl radicals to isocyanide, an atom transfer radical addition (ATRA) took place to furnish 2-iodo-3-(perfluoro)alkyl quinoxalines in modest to excellent yields (Scheme 13).

Scheme 13

Synthesis of iodinated (perfluoro)alkyl quinoxalines using ortho-diisocyanoarenes

The unsaturated functionality to trap the imidoyl radical intermediate may also be introduced in situ. Pioneering work in this context was reported by Curran and coworkers during their studies on the synthesis of camptothecin and analogous alkaloids [25,26,27]. Later development on this protocol was developed by Studer [48, 49]. In their approach, thermal homolysis of vinyl-substituted alkoxyamines generated alkyl radicals, which added intermolecularly to isocyanides. Sequential 5-exo-trig cyclization of imidoyl radical, HAS process of the alkyl radical intermediate, and rearomatization led to quinolines 23 or dihydroquinolines 24, depending on the nature of R¹ substituent (Scheme 14).

Scheme 14

Quinoline synthesis with arylisocyanide and alkoxyamines

Studer and coworkers developed a multicomponent reaction in which they observed a double addition of (perfluoro)alkyl radical to arylisocyanide, yielding 2-substituted indole-3-imines 25 in low to modest yields (Scheme 15) [50].

Scheme 15

Synthesis of indole-3-imines via a three-component reaction involving isocyanides

In most cases, intramolecular imidoyl radical cyclization forms a C-C σ-bond. However, heteroatoms, like sulfur (see Sects. 2.2 and 2.3) and nitrogen, can also trap imidoyl radicals. Very recently, Zhu’s group reported the first intramolecular nitrogen trap for imidoyl radicals to synthesize 2-substituted benzoimidazoles starting from 1-azido-2-isocyanoarenes 26 (Scheme 16) [51, 52]. Phosphinoyl, aryl, and alkyl radicals were added to the isocyanide carbon, which was followed by a denitrogenative imidoyl radical cyclization affording the desired products. Tandem reactions to achieve synthesis of complex heterocycle-linked benzoimidazole derivatives were also realized.

Scheme 16

Synthesis of benzoimidazoles from 1-azido-2-isocynoarenes

Preparation of aliphatic heterocycles from isocyanide is less common in literature. Bachi reported the synthesis of pyrrolines from amino acid-derived isocyanides with suitable alkenyl or alkynyl substitution [53]. Sulfur-centered radical initiated the cyclization, delivering 2-thiopyrrolines or pyroglutamates when using 2-mercaptoethanol (Scheme 17).

Scheme 17

Cyclization of amino acid-derived isocyanides to access 2-thiopyrrolines

Very recently, Yadav reported radical cyclization reaction of N-methylanilines with isocyanides to synthesize 3-iminodihydroindoles 34 with the help of N-hydroxyphthalimide (NHPI) under visible-light conditions [54]. N-methylanilines reacted with N-hydroxyphthalimide radical by SET to form a radical cation. Then, N-methyl radical was formed after proton transfer, followed by addition to isocyanide, imidoyl radical cyclization, and aromatization to give the final 3-iminodihydroindoles (Scheme 18).

Scheme 18

Cyclization of N-methylanilines with isocyanides to genesis of 3-iminodihydroindoles

2.2 Starting from Isothiocyanates

Isothiocyanates are heterocumulenes which are widely used in cycloaddition and nucleophilic addition reactions [55]. They can react with radicals as well. However, both sulfur and carbon atoms in isothiocyanates are ready to accept radicals, leading to the corresponding thioimidoyl and sulfur radicals, respectively (see part 4, Miscellaneous). This section focuses on reactions involving thioimidoyl radical intermediates. Thioimidoyl radical can also be obtained by reaction of an isocyanide with a thiyl radical (RS) [53, 56]. Cascade cyclizations of thioimidoyl radical provide an efficient way to construct complex heterocycles, although competing β-scission to produce thiocyanates may also take place [1].

In 2003, Nanni and Zanardi reported a cascade radical addition/cyclization of 2-alkynylisothiocyanates 35 with aryl diazonium salts as radical precursors (Scheme 19) [56]. A mixture of tetracyclic nitrogen heterocycles, arising from nonselective 6-endo- and 5-exo-cyclization of the vinyl radical intermediate, was obtained. Reaction of alkynyl aryl diazonium with arylisothiocyanates 37 gave similar results [57]. Cyclohexyl radical generated from cyclohexane/dibenzoyl peroxide was also used in the reaction with 35a, delivering a unique spiro skeleton 39 via a 1,5-H migration. The formation of the thioimidoyl radical was confirmed by reacting isocyanide with an alkylthiol under standard radical conditions (Scheme 19) [58].

Scheme 19

Cascade radical cyclization of alkynyl-substituted aryl isothiocyanates

Bachi used alk-3-enyl- and alk-4-enylisothiocyanates 40 with tri-n-butyltin hydride and AIBN to produce tinthioimidoyl radicals, which were trapped intramolecularly by alkenes to give γ- and δ-thiolactams 41 (Scheme 20) [59]. Thomas and coworkers exploited an intramolecular addition of thioimidoyl radicals onto sulfur with cleavage of the C-S bond to provide thiazolines using methyl 6β-isothiocyanatopenicillanate 42 in the presence of n-Bu₃SnH and AIBN. Subsequent cleavage of the tin-sulfur bond was realized by treatment with TBAF (Scheme 21) [60].

Scheme 20

Synthesis of thiolactams with isothiocyanates

Scheme 21

Tinthioimidoyl radical-induced sulfur-carbon cleavage

2.3 Starting from Imine Derivatives

Imidoyl radicals generated by homolysis of imines or their derivatives could also be applied to heterocycle synthesis, which was reviewed by Nanni in 2007 [1]. Interestingly, no larger than 6-membered ring construction was realized from isocyanide-derived imidoyl radicals. However, a work by Nanni demonstrated that imidoyl radical generated by hydrogen abstraction in N-arylidene-2-phenoxyanilines 45 allowed the formation of 7-membered oxazepine 46, albeit in very low yield (Scheme 22) [61, 62]. Benzophenones were isolated as by-products, resulting from intermediate I and consequent hydrolysis. Leardini reported a novel synthesis of benzothiazoles by reaction of 2-phenylthioarylimines 48 with diisopropyl peroxydicarbonate (DPDC), which resulted in the capture of imidoyl radicals by sulfur with phenyl radical as a leaving group (Scheme 23) [63]. In another example reported by Nanni, arylimine reacted with phenylacetylene to afford polysubstituted quinoline 51 in modest yield. However, along with the desired quinoline product, a regioisomer was also isolated, resulting from a 5-membered ipso-cyclization of a vinyl radical intermediate (Scheme 24) [3]. Besides carbon unsaturated system, diethyl azodicarboxylate (DEAD) could act as an intermolecular imidoyl radical trap to give 1,2,4-triazine derivatives 53 (Scheme 25) [64].

Scheme 22

Synthesis of 7-membered ring starting from imines

Scheme 23

Synthesis of benzothiazoles from imines via a radical pathway

Scheme 24

Intermolecular trapping of imidoyl radical with alkynes to approach polysubstituted quinoline

Scheme 25

Intermolecular capture of imidoyl radical with DEAD to provide 1,2,4-triazines

However, little progress has been made on this topic in the past 10 years. In 2013, Zhou reported a photoinduced intermolecular alkyne addition and cyclization of trifluoroacetimidoyl chlorides to form 2-trifluoromethylquinolines such as 55 at ambient temperature (Scheme 26) [65]. The reaction was initiated by photoactivation of [Ru(bpy)₃]²⁺ to [Ru(bpy)₃]²⁺*, followed by SET from (n-Bu)₃N to [Ru(bpy)₃]²⁺*. The resulting [Ru(bpy)₃]⁺ was oxidized by the imidoyl chloride affording the imidoyl radical. The latter then underwent sequential intermolecular addition to alkynes, followed by an intramolecular homolytic aromatic substitution (HAS) to provide a cyclohexadienyl radical intermediate. Then, another SET led to the cyclohexadienyl cation intermediate. Finally, elimination of a proton and aromatization provided the quinoline products. Later, Zhou and Fu independently reported light-induced intramolecular versions to synthesize trifluoromethyl-substituted 3-acylindoles 57 and phenanthridines 59 (Scheme 27) [66, 67].

Scheme 26

Visible-light-promoted imidoyl radical addition and cyclization to provide quinolines

Scheme 27

Synthesis of 2-trifluoromethyl indoles and 6-trifluoromethyl phenanthridines with imidoyl chloride

3 Cyclization via Iminyl Radicals

3.1 Starting from Nitriles

Nitriles can also act as free radical acceptors, generating iminyl radicals after addition of a radical species on the carbon center. Two modes of cyclization have been documented to construct heterocycles via iminyl radical intermediates. One is the intramolecular addition of heteroatom-centered radicals onto the nitrile followed by H-abstraction; the other is a cyclization of the iminyl radical onto an unsaturated system. In some cases, side reaction such as β-scission may occur depending on the nature of the substituents [68].

To illustrate the first type of cyclization, Spagnolo and Leardini reported a reaction of azidoalkyl malononitrile in the presence of n-Bu₃SnH and AIBN. Stannylaminyl radical was initially formed from tin radical and azide, followed by 5- or 6-exo-cyclization onto one of the cyano groups to give aminoiminyl radicals. H-abstraction gave the cyclic amidines 61 [69]. The iminyl radicals could also be trapped by an internal alkene functionality, delivering bicyclic amidines 62 (Scheme 28).

Scheme 28

Reductive cyclization of azide onto substituted nitriles mediated by tin hydride

For the second type of cyclization, Curran reported that vinyl radical could undergo tandem radical cyclization to give quinolines in good yields. The reaction was initiated by a tin radical, which was formed from hexamethylditin through photo-irradiation (Scheme 29) [70].

Scheme 29

Synthesis of quinolines from alkenylnitriles bearing a vinyl bromide moiety

By elegant design, cascade iminyl and imidoyl radical formation have been utilized in the construction of complex heterocyclic systems. Nanni pioneered the area in 1998 with the reaction of cyano-substituted alkyl iodide 65 and arylisocyanide in the presence of hexamethylditin and sunlamp irradiation, which afforded cyclopentaquinoxalines 66 (Scheme 30) [71]. In this study, cyano-substituted thiols and disulfides were also examined as substrates to give thienoquinoxalines 68 and 70 in modest yields under thermal or photochemical conditions.

Scheme 30

Cascade radical process of arylisocyanides and functionalized nitriles

In 2014, Yu reported visible-light-promoted cascade reaction of arylisocyanides and bromo-substituted alkylnitriles to prepare quinoxalines 72 under mild conditions in 43–88% yields (Scheme 31) [72]. Homolysis of the C-Br bond generated alkyl radicals with the help of a photocatalyst and light, which then added onto the isocyanide.

Scheme 31

Visible-light-mediated cascade reactions of arylisocyanides and bromo-substituted alkylnitriles

Nanni and coworkers reported another example of imidoyl and iminyl radical cyclization cascades starting from 2-cyanoaryl diazonium salts 73 and arylisothiocyanates 37. The reaction proceeded through an intermolecular thioimidoyl radical formation, then a 5-exo-dig cyclization on the cyano group, followed by an ortho- or ipso-aryl cyclization of the resulting iminyl radical intermediate. After rearrangement (in case of the ipso-aryl cyclization), SET oxidation, and deprotonation-aromatization, a tetracyclic fused scaffold 74 was formed in one step (Scheme 32) [73].

Scheme 32

Radical cascades starting from arylisothiocyanates and 2-cyanoaryl diazonium salts

3.2 Starting from Cyano-Amides

Cyano-amides in this review refer to structures in which the cyano group is located one or more carbons away from nitrogen or the cyano group is directly attached to the nitrogen amide. Guanidines and quinazolinone-type alkaloids were approached efficiently with the latter strategy, which was pioneered by Lacôte, Malacria, Fensterbank, and coworkers [74, 75].

Bowman reported an alternative approach to Curran’s synthesis of camptothecin. 2-Cyanopyridinone derivatives 75 were exposed to hexamethylditin and t-butylbenzene under UV irradiation at 150°C to give tetracyclic alkaloids 76 in low to good yields (Scheme 33) [76, 77].

Scheme 33

Synthesis of tetracyclic and pentacyclic alkaloids via iminyl radicals

A Ti(III)-assisted reductive cyclization of β-lactams containing epoxide and nitrile functionalities as in 77 and 79 was reported by Grande and coworkers [78]. The reaction was regio- and diastereoselective via 5-exo or 6-exo processes, affording carbapenem and benzocarbacephem scaffolds. Reductive ring opening of the epoxide with Cp₂TiCl generated alkyl radicals, which cyclized onto the cyano group. Reduction of the iminyl radical intermediate and hydrolysis gave the corresponding cyclic ketones 78 and 80 (Scheme 34). Later, these authors extended the protocol to 1,5- and 1,6-epoxynitriles [79].

Scheme 34

Reductive cyclization of epoxynitriles with Ti(III) species

Cascade radical addition to alkenes and cyclization onto nitriles were applied to the construction of quinoline-2,4(1H,3H)-diones [80,81,82,83,84]. With this protocol, aldehydes [80], phenylglyoxylic acids [80], sodium trifluoromethanesulfonate [81], sulfinic acid salts [81], diphenylphosphine oxide [82], sulfonylhydrazides [83], and alcohols [84] acted as radical precursors under oxidative conditions (Scheme 35).

Scheme 35

Radical cascades of O-cyanoarylacrylamides

In this context, Sun developed a novel and efficient visible-light-induced cascade reaction for the preparation of ester-functionalized pyrido[4,3,2-gh]phenanthridine derivatives 86 under metal-free conditions (Scheme 36) [85]. The reaction was initiated by an intermolecular radical addition to N-arylacrylamide derivatives using alkylcarbazates as the ester source, followed by the cyclization of the resulting iminyl radical onto the cyano group. The desired products were obtained in moderate to good yields with broad substrate scope.

Scheme 36

Visible-light-induced cascade reaction of N-(2-cyano-[1,1-biphenyl]-3-yl)-N-arylacrylamides

Fensterbank et al. designed a series of N-acylcyanamide for the synthesis of natural and biologically active quinazolinone derivatives [86, 87]. They tested alkyl phenylselenates as alkyl radical precursors to prepare quinazolinones 88 under slow addition of Bu₃SnH and AIBN in refluxing benzene [88]. Iodoaryl-substituted N-acylcyanamides 89 were designed to approach alkaloids of the luotonin A family in modest yield [89, 90]. Interestingly, during their study using vinyl iodide 91 in cascade annulation reactions, the same authors found an unprecedented substituent migration from the ortho-position of aryl groups to the alkenyl moiety [91]. The migration could be finely controlled with a selection of solvent. Finally, azide-substituted N-acylcyanamide was also used in cascade reactions to generate guanidines 94 in modest to good yields (Scheme 37) [92].

Scheme 37

Radical cyclization of N-acylcyanamide to access quinazolinones

Hu reported a SmI₂-promoted cascade cyclization with imine-substituted cyanamides or cyanamines 95 to provide polycyclic nitrogen heterocycles 96 (Scheme 38) [93]. Aryl radical generated by single-electron reduction of SmI₂ initiated the radical addition, which was followed by the cyclization through the resulting aminoiminyl radical intermediate.

Scheme 38

Radical cascades of imine-substituted cyanamide to generate heterocycles

Recently, Cui reported a phosphorylation/cyclization cascade of N-acylcyanamide 97 bearing an alkenyl moiety to access dihydroisoquinolinones 98 or quinazolinones 99 [94]. Reaction of diphenylphosphine oxide with AgNO₃ provided the phosphoryl radical. Subsequent radical addition of the latter to the alkene fragments generated alkyl radicals, which were trapped by the aryl group or the cyano group, depending on the proximity between alkyl radical and the cyano group (Scheme 39).

Scheme 39

Phosphorylation/cyclization cascade of N-cyanamide alkenes to provide heterocycles

3.3 Starting from Oxime and Derivatives

Oxime and its derivatives, like hydrazones and sulfenimines, contain relative weak N-X (X refers to O, S, N, halo, etc.) bonds which can be cleaved homolytically into iminyl radicals and X-centered radicals under thermal conditions, transition metal catalysis, UV irradiation, or photoredox catalysis. Many oxime derivatives are easily available, nontoxic, and bench stable, making them versatile precursors of iminyl radicals for heterocycle synthesis [95]. Recently, Walton and Castle independently reviewed this chemistry [14,15,16].

Yu and Zhang reported visible-light-promoted cyclization of acyl oximes to access 6-membered azaheterocycles [96]. They carefully screened acyl substituents in acyl oximes to find that p-trifluoromethylbenzoate oxime substrate is highly active with fac-Ir(ppy)₃ (ppy = 2-phenylpyridine) as photocatalyst at room temperature. The active photocatalyst reduced acyl oxime into iminyl radicals, which were then engaged into cyclization processes. With this methodology, phenanthridines 10, pyridines 101, and quinolines 102 were prepared in good to excellent yields. Moreover, this protocol was used as a key step in a five-step total synthesis of biologically active alkaloids noravicine and nornitidine (Scheme 40).

Scheme 40

Visible-light-promoted iminyl radical formation from acyl oximes for the elaboration of pyridines, quinolines, and phenanthridines

Chiba and coworkers designed an oxidative skeletal rearrangement of 5-aryl-4,5-di- hydro-1,2,4-oxadiazoles 103 into quinazolinones 104 in DMSO at 120°C [97]. The proposed mechanism involved thermolysis of dihydro-1,2,4-oxadiazoles to generate iminyl radicals I, which gave heterocyclic products after HAS and SET process. To demonstrate the utility of this protocol, they synthesized an indoloquinazoline alkaloid and a key precursor of ispinesib, a potent, specific, and reversible inhibitor of kinesin spindle protein (Scheme 41).

Scheme 41

Synthesis of quinazolinones via oxidative radical rearrangement

Walton discovered that 2-(aminoaryl)alkanone O-phenyl oximes 108 and carbonyl compounds could provide dihydroquinazolines 109 under microwave conditions in ionic liquid emimPF₆ [98, 99]. Possible mechanism involved the imine formation and thermolysis of the N-O bond of the oxime into an iminyl radical. Toluene acted as a hydrogen donor to trap the aminyl radical. In the presence of ZnCl₂, aromatic quinazolines 110 were formed instead of dihydroquinazolines (Scheme 42).

Scheme 42

Synthesis of dihydroquinazolines or quinazolines with O-phenyl imines

In 2015, Yu and coworkers developed two efficient photochemical protocols for the generation of iminyl radicals from easily available 2-(N-arylcarbamoyl)-2-chloroiminoacetates 111 via N-Cl cleavage (Scheme 43) [100]. Ru(phen)₃Cl₂ acted as a photoredox catalyst under visible-light irradiation to induce N-Cl bond cleavage by a single-electron transfer pathway. Interestingly, when the reaction was performed in DMF in the presence of Na₂CO₃, only visible light was required to initiate the reaction without a photocatalyst. The methodology provided a practical approach to quinoxalin-2(1H)-ones 112 via iminyl radical intermediates.

Scheme 43

Photoinduced iminyl radical cyclization via N-Cl bond cleavage

Besides carbon unsaturated systems, benzylthio- and selenoethers were also suitable traps for iminyl radicals [101]. Schiesser and coworker realized cyclization of benzylseleno-substituted thiohydroxamic esters 113 to produce l,2-benzoselenazoles 114 in modest yield [102]. Upon irradiation, oxime 113 decomposed, through release of a 2-pyridinethiyl radical, followed by decarboxylation and elimination of formaldehyde, into an iminyl radical, which reacted at selenium (homolytic substitution) affording benzoselenazoles. A benzyl radical was also formed which dimerized (Scheme 44).

Scheme 44

Synthesis of benzoselenazoles with O-carboxymethyl oxime derivatives

For aliphatic heterocycle synthesis, Bower reported copper-catalyzed radical cyclization of alkenyl oxime esters 115, which provides alkene-substituted dihydropyrroles 116 in high yields [103]. No corresponding alkyl-substituted by-product 117 was found. Later, they investigated the Pd-catalyzed cyclization of alkene-substituted oxime esters 118 [104]. Interestingly, the reaction mechanism was ligand-dependent. Electron-deficient phosphine ligands like P[3,5-(CF₃)₂C₆H₃]₃ led to aza-Heck products, while electron rich ligands such as 1,1′-bis(di-tert-butylphosphino)ferrocene (dt-bpf) resulted in 119 through iminyl radical intermediates (Scheme 45).

Scheme 45

Copper- or palladium-catalyzed cyclization via iminyl radicals

Leonori developed iminyl radical-mediated cyclizations of unactivated olefins under visible-light irradiation (Scheme 46) [105]. When organic dye eosin Y was used as a photocatalyst in the presence of 1,4-cyclohexadiene (CHD) as a hydrogen donor and K₂CO₃, dihydropyrroles 121 were obtained in good yields (route a, Scheme 46). Interestingly, when the reaction was irradiated in the absence of a photocatalyst, a complementary iminohydroxylation process occurred to deliver alcohol 122 (route b, Scheme 46). The oxygen atom in the alcohol products 122 was believed to originate from one of the nitro groups of the leaving phenoxy moiety.

Scheme 46

Visible-light-mediated hydroimination and iminohydroxylation cyclizations of iminyl radicals

Later, to extend the scope of the valuable imine motif, Leonori reported decarboxylation of oxyacid 123 with methyl acridinium perchlorate 124 under visible-light conditions, generating an iminyl radical, which cyclized in a 5-exo-mode (Scheme 47) [106]. The resulting radical then reacted intermolecularly with various radical acceptors, including N-chlorosuccinimide (NCS), N-iodosuccinimide (NIS), N-fluorobenzenesulfonimide (NFSI), but also TsN₃, DEAD, or ethynylbenziodoxolones and vinylbenziodoxolones, as carbon sources.

Scheme 47

Imino-functionalizations of alkenes under photoredox conditions

Independently, Studer developed a related decarboxylation of α-imino-oxy propionic acids 126 to form iminyl radicals using photoredox catalyst 127 (Scheme 48) [107]. Through this initiation process, they achieved the carboimination of alkenes. The sequence of iminyl radical generation, 5-exo-trig cyclization, intermolecular conjugate addition to a Michael acceptor, completed with a SET reduction process, was shown to provide various pyrrole derivatives 128.

Scheme 48

Genesis of iminyl radicals by oxidation of α-imino-oxy acids

When iminyl radical undergoes cascade cyclization and functionalization instead of hydrogen abstraction, densely substituted pyrroline derivatives 130 are expected. Loh applied silyl enol ethers as coupling partners to trap the alkyl radical intermediate generated from iminyl radical cyclization, which eventually gave alkyl ketone-substituted pyrrolines (Scheme 49) [108].

Scheme 49

Visible-light-induced cascade cyclization and functionalization of iminyl radicals

Wu reported a novel N-radical-initiated cyclization, followed by sulfonylation and alkene addition under visible-light irradiation and catalyst-free conditions (Scheme 50) [109]. A range of sulfonyl compounds 132 could be easily produced through the cascade radical process involving sulfur dioxide insertion using 1,4-diazabicyclo[2.2.2]octane disulfate (DABCO·(SO₂)₂ or DABSO) as surrogate of gaseous sulfur dioxide.

Scheme 50

Photoinduced N-radical-mediated cyclization through insertion of sulfur dioxide

3.4 Starting from N-H Ketimines or Amidines

Single-electron oxidation of N-H ketimines or amidines could also generate iminyl radical in an environmentally benign manner. Chiba and coworkers reported a series of transformations involving iminyl radicals generated from imines under copper-catalyzed aerobic conditions [110]. They used biaryl-2-carbonitriles 133 and Grignard reagents to generate imines in situ. Cu-iminyl radical was formed after aerobic oxidation, and subsequent cyclization delivered phenanthridine derivatives 134 (Scheme 51) [111]. Based on a similar protocol, azaspirocyclohexadienone 136 synthesis was also achieved efficiently from the corresponding arylnitriles (Scheme 52) [112].

Scheme 51

Cu-iminyl radical cyclization to phenanthridine via Cu/O₂ oxidation of imines

Scheme 52

Cu/O₂ oxidation of imines to provide azaspirocyclohexadienones

Very recently, Nagib reported an unprecedented β-C−H amination of imidates 137 using a NaI/PhI(OAc)₂ system to generate β-amino alcohols (Scheme 53) [113]. The process includes the oxidation of a trichloroacetimidate or a benzimidate into an imidate radical, which is followed by a 1,5-hydrogen atom transfer (HAT), generating regioselectively a carbon radical. The latter is then trapped by an iodine radical, nucleophilic substitution eventually forming oxazoline 138. A simple hydrolysis finally leads to the related β-amino analogs.

Scheme 53

β-C−H amination of imidates under oxidative conditions

Yu used stable α-imino-N-arylamides 141 as precursors of iminyl radical [114]. In this reaction, TBHP/TBAI promoted iminyl radical formation through single-electron oxidation of the imino moiety. Subsequent intramolecular 5-exo-mode cyclization onto the aryl group gave azaspirocyclohexadienyl radical intermediates, which were trapped by oxygen to form azaspirocyclohexadienones 142. In the absence of oxygen, quinoxalin-2-ones were detected as by-products (Scheme 54).

Scheme 54

Oxidation of imine with TBHP/TBAI to approach azaspirocyclohexadienones

Electron-rich amidines are relatively stable and easy to handle. Oxidation of N-H bond of amidines generates amidinyl radicals, which can be used in nitrogen heterocycle synthesis as well. Very recently, Xu reported the anodic cleavage of N-H bonds of amidines 143 to provide aminoiminyl radicals, which were captured by (hetero)arenes to afford tetracyclic benzimidazoles 144 (Scheme 55) [115].

Scheme 55

Anodic cleavage of N-H bonds of amidines to access tetracyclic benzimidazoles

4 Miscellaneous

Both sulfur and carbon atoms in isothiocyanates can accept radical attack, generating the corresponding imidoyl radical and sulfur radical, respectively. Some related structures like isocyanates, ketenimines, and carbodiimides exhibit similar reactivity (Scheme 56). In this section, only scattered examples are given using these heterocumulenes in radical cyclization (Scheme 57).

Scheme 56

Structure of isothiocyanates, isocyanates, ketenimines, and carbodiimides

Scheme 57

Reaction mode of isothiocyanates, isocyanates, ketenimines, and carbodiimides

Yadav reported a copper-catalyzed synthesis of 2-alkylbenzoxa(thia)azoles from arylisocyanates/isothiocyanates and simple alkanes [116]. The protocol utilized di-tert-butyl peroxide (DTBP) as a radical initiator to generate the alkyl radical, which adds onto the NCX moiety at the central carbon. Sequential C-C and C-X (X=O, S) bond formation was followed by aromatization to afford expected 146 (Scheme 58).

Scheme 58

Construction of 2-alkylbenzo-1,3-azoles from iso(thio)cyanates and alkanes

Zhu et al. described the reaction between aryl isothiocyanates and formamides under metal-free conditions, which led to the synthesis of 2-aminobenzothiazoles 147 (Scheme 59) [117]. Mechanistic studies suggest that the reaction is initiated by decarbonylative aminyl radical formation in the presence of n-Bu₄NI and TBHP, followed by aminyl radical addition to isothiocyanates and cyclization via sulfur-centered radical intermediates.

Scheme 59

Synthesis of 2-aminobenzothiazoles from isothiocyanates and formamides

Lei also developed a mild method for the synthesis of 2-aminobenzothiazoles 148 from isothiocyanates and commercially available amines via an intramolecular dehydrogenative C-S bond formation. Catalyst- and external oxidant-free electrolytic conditions were demonstrated to be efficient in this cross-coupling reaction (Scheme 60) [118].

Scheme 60

Synthesis of 2-aminobenzothiazoles from isothiocyanates and amines under undivided electrolytic conditions

Walton reported that radical cyclization of 2-(2-isocyanatophenyl)ethyl bromide 149 led to 2,3-dihydroindole-1-carbaldehyde 150 and 3,4-dihydro-1H-quinolin-2-one 151, respectively, in 16% and 44% yield [119]. In this case, the 6-endo-mode for the cyclization of the alkyl radical was preferable over the 5-exo-cyclization onto the isocyanate. DFT calculations of reaction enthalpies and rate constants were performed to rationalize the selectivity (Scheme 61).

Scheme 61

Isocyanates as radical acceptors in cyclization

Another isocyanate that participated in radical cyclization reaction was reported by Wood and coworkers during their studies on the synthesis of welwitindolinone A [120,121,122]. The key step involved a SmI₂-mediated reductive cyclization of a precursor bearing an isocyanate, to build up the spiro-oxindole core structure 154 in good yield. The reaction was highly regio- and diastereoselective (Scheme 62).

Scheme 62

SmI₂-promoted reductive cyclization of isocyanate

Ketenimines and carbodiimides were also reported to be potent radical acceptors in radical annulation reactions [123]. Vidal reported an intramolecular addition of benzylic radical to ketenimines, leading to 2-alkylindoles 156, 157, and 159 in low to modest yields [124, 125]. The fate of the triarylmethyl-type radical intermediate was determined by the nature of the radical initiator. A lauroyloxy fragment was thus incorporated into the product when lauroyl peroxide was used, while H-abstraction product was obtained when di-tert-butyl peroxide in chlorobenzene was applied. Later, they reported a similar reaction of ketenimines with a pending phenyl selenide in the presence of a silane and AIBN to afford indole derivatives with the 1-cyano-1-methylethyl group from AIBN being trapped (Scheme 63) [126].

Scheme 63

Construction of 2-substituted indole core with ketenimines

Takemoto reported a SmI₂-mediated reductive cyclization of carbodiimides bearing an α,β-unsaturated carbonyl moiety to give spiro-2-iminoindolines 161 [127]. The proposed mechanism included a one-electron reduction of the unsaturated carbon group into a radical anion, a subsequent addition to the carbodiimide moiety, further reduction by SmI₂ to an amidinate, and finally hydrolysis by t-BuOH to afford the iminoindoline (Scheme 64). They also used the strategy to construct the core structure of perophoramidine [128].

Scheme 64

Reductive cyclization of carbodiimides to approach spiro-2-iminoindolines

5 Conclusion

This chapter described various radical cyclizations of isocyanides, isothiocyanates, nitriles, and other C-N unsaturated bond systems. A variety of 5- and 6-membered nitrogen-containing heterocycles were prepared via imidoyl or iminyl radical intermediates. In general, multiple chemical bonds are formed in these processes, and the reaction conditions are mild, representing an environmentally benign approach for heterocycle synthesis. With the rapid growth especially in the area of photoinduced radical processes, more practical heterocycle synthesis is expected in not too distant a future, which should meet with the strong requirements for application in medicinal chemistry and material science.