Abstract
The paper consolidates the data published on the synthetic pathways to condensed N-heterocycles via direct functionalization of C–H fragments in nitroarenes in the ortho-position relative to the nitro group.
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1 Introduction
Nitrogen heterocycles represent one of the most important classes of organic compounds. Found in nature or synthesized, they have gained wide appreciation as pharmaceuticals or dyes. Despite the extensive achievements done in this field, the development of novel synthetic methods for the preparation both of the known compounds as well as of their analogues, which may possess better properties or a considerably higher biological activity, seems to be a promising research task. There is also a growing fundamental interest in the synthesis of new heterocyclic systems. This is evidenced by a number of reviews and monographs on the synthesis, chemical, and biological properties of nitrogen heterocycles that have been published over the last decade [1–4].
In this review, we consider aromatic nitro compounds (nitroarenes) with the vacant ortho-position relative to the nitro group, as a basis for the synthesis of condensed nitrogen heterocycles (benzo-annelated N-heterocycles) (Scheme 1).
Nitroarenes is a class of aromatic compounds, which are known to possess a dual reactivity. Indeed, an aromatic nitro group activates the carbon atoms located in the ortho- and para-positions of the benzene ring towards a nucleophilic attack. When a good leaving group is present in one of these positions, the nucleophilic ipso-substitution takes place. Aromatic nucleophilic substitution (SN Ar) is well established to be a two-step process, which involves a nucleophilic addition at the carbon atom bearing a leaving group (σipso-adduct formation) and departure of a nucleofuge. Further formation of a heterocyclic ring is possible either via cyclization with participation of the nitro group or through displacement of the latter (it should be noted that the nitro group itself is a good leaving group as well) (Scheme 2).
On the other hand, if hydrogen atoms occupy the ortho-positions relative to the nitro group, a nucleophile addition might also result in the formation of anionic σН-complexes. However, their further transformations are hampered because the hydride ion (a formal leaving group) is a thermodynamically unstable particle not prone to solvation. Moreover, the energy of the C–H bond is rather high. Therefore, the intermediate σН-complexes can be converted into aromatic compounds (SN H product) either by means of oxidation (oxidative nucleophilic substitution of hydrogen, ONS) or through elimination of HX, provided a leaving group X is present in the nucleophilic reagent (vicarious nucleophilic substitution of hydrogen, VNS) (Scheme 3).
Another important feature is that the nitro group is an electron-withdrawing substituent, increasing electrophilicity of an aromatic system. Due to this fact, nitroarenes sometimes exhibit the reactivity, which is similar to that of conjugated nitroalkenes, and are able to undergo pericyclic reactions (Scheme 4).
In the following sections of this chapter, we will consider some other possibilities for the formation of heterocyclic compounds by using functionalization of C–H fragments in nitroarenes.
2 Synthesis of Condensed N-heterocycles via Nucleophilic Substitution of Hydrogen (SN H) in Nitroarenes
The SN H methodology is currently recognized as one of the most efficient synthetic tools for functionalization of aromatic and heteroaromatic compounds. In particular, the SN H reactions allow one to annelate a heterocyclic ring to π-deficient arenes and hetarenes [5–7]. An obvious advantage of this strategy is that there is no need to introduce a leaving group into the molecule of the starting material (as in the case of nucleophilic ipso-substitution), because a nucleophilic attack takes place at the unsubstituted carbon atom of a (hetero)aromatic system. For this reason, it is the aromatic substrate that must be activated. Carbocyclic aromatic compounds are usually activated by electron-withdrawing substituents, and, indeed, nitroarenes appear to belong to the family of the most activated aromatic systems. It should be noted that, in most cases, the SN H reactions are somewhat similar to SN ipso-substitutions; however, the formation of σН-complexes proceeds much faster than a similar reaction, leading to the σipso-complexes. As a result, interaction of π-deficient aromatic substrates with nucleophiles proceeds under rather mild conditions (at low temperature) in the presence of an excess of base, thus leading to substitution of hydrogen, whereas products of the displacement of good leaving groups can be obtained under more drastic conditions. Numerous examples of such transformations are summarized in the review articles [8–10].
In this section, we will focus on two main approaches to the synthesis of condensed N-heterocycles based on nitroarenes using the SN H methodology: vicarious nucleophilic substitution of hydrogen (VNS) and oxidative nucleophilic substitution of hydrogen (ONS).
2.1 Vicarious Nucleophilic Substitution of Hydrogen
The concept of vicarious nucleophilic substitution of hydrogen in electron-deficient arenes was originally developed at the beginning of 1980s by M. Makosza and co-workers, and since then has been thoroughly elucidated [11, 12]. The reaction is initiated by fast and reversible addition of carbanion, bearing a leaving group X (e.g., halogen), to nitroarene, followed by the base-induced β-elimination of H-X from the resultant σH-adduct (Scheme 5). At least two equivalents of the base are necessary to cause the reaction, one for deprotonation of CH acid, thus generating the corresponding carbanion, and the second one to induce the β-elimination of H-X. The last step is C-protonation of the nitronate intermediate leading to the substituted nitrobenzene (Scheme 5) [13–16]. It has been reported that the choice of solvent, the nature and concentration of the base, as well as the steric demands for the carbanion have considerable influence on the ratio of isomeric products [17]. When a high excess of the base is present, the H-X elimination does occur much faster than dissociation of the σH-adduct, and, as a result, the reaction becomes irreversible. A low reaction temperature and a high concentration of the base guarantee the reaction to proceed under kinetic control with irreversible formation of the σH-adduct (Scheme 5). Since the β-elimination of HX from the σH-adducts is much faster than the reverse reaction (k2[B] >> k−1) [18, 19], the ratio of products reflects the ratio of rate constants k1 for the addition step.
The VNS process, as an attractive and convenient method for incorporation of alkyl-, amino-, or hydroxy groups in nitroarenes, was first reviewed in 1987 [12]. An interested reader may be referred to several reviews generalizing the data on the synthesis of fused nitrogen heterocycles (indoles, quinolines, purines, etc.) on the basis of VNS reactions [9, 20, 21].
The formation of heterocycles by the VNS methodology has been shown to occur either by direct intramolecular VNS processes or through transformations of the ortho-nitrobenzyl derivatives resulting from intermolecular VNS reactions.
Scheme 6 exemplifies the first path. Intramolecular cyclization of sulfonamides 1 is caused by action of a base, thus resulting in the formation of nitroaromatics fused with five- or six-membered heterocycles [22–24]. It should be emphasized that in some cases the formation of isomeric products can be observed due to a nucleophilic attack at the para-position relative to the nitro group. Also it is worth noting that the cyclic sulfamides 2 and 3 can be used as precursors to obtain some other N-heterocyclic compounds, such as isoindoles 4 [25] or 1,2,3,4-tetrahydroquinolines 5 [24] (Scheme 6).
Another example of intramolecular VNS cyclization of sulfamides leading to peri-annelated heterocycles is shown in Scheme 7 [23].
Treatment of guanidine 8 with a base in DMSO gives rise to 2-butylamino-4-nitrobenzimidazole 9 in 57% yield [26] (Scheme 8). In this case, the intramolecular VNS reaction proceeds exclusively at the ortho-position relative to the nitro group, while the methoxy group acts as a leaving group.
2-Nitronaphthalene and 6-nitroquinoline have been found to react easily with 2-chloronitriles and the corresponding esters in the presence of NaH [27] (Scheme 9). Depending on solvent, it is possible to obtain either VNS products 10 or cyclic nitronates 11.
The authors have found that nitronates 11 are derived from intramolecular nucleophilic displacement of the chloro atom with oxygen of the nitro group (Scheme 9). Moreover, the intramolecular VNS reactions of nitroarenes proved to be a successful procedure for the synthesis of various indole derivatives. For instance, cyclization of 3-nitrochloroacetanilide 12 caused by action of t-BuOK affords N-substituted oxindole 13, which is hardly accessible by other methods [28] (Scheme 10).
A number of publications deal with the use of nitroaryl isocyanides as direct precursors of nitroindoles. The starting isocyanides have been obtained by using the VNS reactions. Thus, in the reaction of 3-isocyanonitrobenzene 14 with (phenylthio)acetonitrile 15, the initial displacement of hydrogen is followed by the base-induced intramolecular cyclization, affording 3-cyano-6-nitroindole 16 in 60% yield [29] (Scheme 11).
A similar reaction of compound 17 with phenyl(chloromethyl)sulfone 18, as a vicarious nucleophile, affords 3-sulfonylindole 19 [29] (Scheme 12).
An easily occurring ortho-alkylation of nitroarenes under VNS conditions has allowed a convenient approach to indole derivatives hardly accessible by other methods.
This approach is nicely illustrated by cyanomethylation of substituted nitrobenzenes 20 [30, 31], followed by hydrogenation of ortho-nitroacetonitriles 21 [32, 33] (Scheme 13).
Another approach deals with reduction of the nitro group in VNS products, such as sulfones 22, their transformation into imines, isocyanides or imidates 23 which are prone to base-promoted cyclization into functionalized indoles 24 [34, 35] (Scheme 14).
Both approaches described above have been used for the synthesis of indoles bearing the pentafluorosulfanyl group [36, 37]. The reaction of meta- and para-nitro(pentafluorosulfanyl)benzene 25 with phenoxyacetonitrile (Scheme 15) under VNS conditions followed by hydrogenation gave rise to SF5-substituted indoles 26. At the same time, the reaction of nitro compounds 25 with chloromethyl phenyl sulfone and the subsequent reduction of the nitro group in substitution products led to amines 27 - precursors of 2-substituted indoles 28 (Scheme 15).
An aromatic nitro group sometimes participates in the formation of indoles, in particular of N-hydroxy derivatives. For example, the reaction of ortho-nitroaryl substituted acetonitriles 29 with acetaldehyde followed by treatment with K2CO3 afforded N-hydroxyindoles 30, as the major products [38] (Scheme 16).
Use of other reagents for the cyclization step (i.e., Me3SiCl/Et3N) allowed quinoline N-oxide derivatives 31 to be obtained in high yields [38] (Scheme 17).
Polyfunctional N-hydroxyindole derivatives 32 have been synthesized by using the sequence of reactions, involving the VNS of hydrogen, alkylation, and base-catalyzed cyclization [39] (Scheme 18).
Use of Me3SiCl/Et3N system for the cyclization step in a similar reaction (Scheme 19) has also resulted in the formation of N-hydroxy indole 33 in high yield [40].
There are several synthetic pathways to benzo[c]isoxazoles (anthranils) based on application of the VNS methodology in nitroarenes. Dehydration of ortho-nitrobenzyl derivatives 34 by action of Me3SiCl/Et3N affords 3-substituted anthranils 35 [41] (Scheme 20).
Besides, benzo[c]isoxazole derivatives were obtained when the VNS products derived from bicyclic nitroarenes were treated with potassium phenolate [42] or thiophenolate [43]. In case of 5-nitroquinoline 36 (Scheme 21) a mixture of two condensed isoxazoles 37 and 38 was obtained.
The VNS methodology has been reported to be effective for the synthesis of benzo-annelated six-membered N-heterocycles. Indeed, the reaction of ortho-nitrobenzyl sulfones 39 with diethyl maleate (or fumarate) takes place in the presence of K2CO3 under phase-transfer conditions to give quinoline N-oxides 40 [44] (Scheme 22).
Compounds (41) derived from condensation of ortho-nitrobenzyl cyanides with aliphatic aldehydes can be transformed by action of base into 4-cyanoquinoline-1-oxides 42 [45] (Scheme 23).
A number of tricyclic heterosystems have been synthesized from nitroindoles and nitroindazoles [46, 47]. In these transformations the vicarious amination of bicyclic compounds 43 at the ortho-position relative to the nitro group proved to be the key step. 1,1,1-Trimethylhydrazonium iodide (TMHI) was used as the VNS-aminating agent (Scheme 24). Reduction of amines 44 followed by heterocyclization resulted in the formation of various types of heterocycles 45–48.
Nitroamines 44 as well as their analogues 49 were used for the synthesis of tricyclic furoxan derivatives 50 [46–48] (Scheme 25).
Benzo-annelated nitrogen heterocycles (indoles, quinolines, isoquinolines, etc.) are often found to be a part of biologically active compounds of both natural and synthetic origin. In a considerable body of data on the syntheses of these compounds, which have so far been documented in the literature, the crucial step is vicarious nucleophilic substitution of hydrogen in nitroarenes. Good examples are presented by the synthesis of nordehydrobufotenine [49], eupolauramine [50, 51], damirone [52], and aklavinone [53].
In conclusion, it is worth noting that the VNS methodology is now commonly recognized as a convenient and versatile synthetic tool to obtain a great deal of nitrogen-containing heterocycles from nitroarenes. The data presented in this section are not intended to be exhaustive ones. Availability of nitroarenes and a variety of substituents, which can be introduced into the core structures of nitroarenes by using the VNS reactions, provide an easy access to a wide range of nitrogen-containing heterocycles.
2.2 Oxidative Nucleophilic Substitution of Hydrogen
Another important type of the SN H processes is oxidative nucleophilic substitution of hydrogen (ONS). It suggests that aromatization of the intermediate σН-adduct (Scheme 26) proceeds by action of an oxidative agent: either an external one (e.g., KMnO4, CAN), or air oxygen, or one of components being present in the reaction mixture, for example, the starting nitro compound [5].
The ONS reactions usually occur at the ortho- and/or para-positions of nitroarenes relative to the nitro group depending on the structure of reagents.
It is a common knowledge that ONS reactions allow one to introduce substituted alkyl fragments or heteroatom functional groups in nitroarenes. There are plenty of examples illustrating intramolecular ONS processes leading to the formation of heterocyclic compounds. However, in this section, we will focus only on the reactions, which give rise to the formation of nitrogen-containing heterocycles.
One of the simplest methods for indole synthesis was accomplished when meta-nitroanilines 51 were treated with carbonyl compounds in the presence of base (Scheme 27). The authors have suggested that the intermediate σН-complexes undergo oxidation by atmospheric oxygen followed by cyclization into indoles 52 [54].
It is worth noting that in addition to 4-nitroindoles 52, the major products, the formation of 6-nitroindoles in trace quantities has been observed.
The steric factor has a significant influence on the direction of ONS in meta-nitroanilines 53 by action of substituted acetonitriles [55] (Scheme 28). In case of acetonitrile (R = H), the ONS process takes place at the ortho-position relative to the nitro and amino groups, whereas in other cases, the group X is replaced. An air oxygen is likely to act as oxidant, similarly to the abovementioned reactions.
The intramolecular ONS in meta-nitroanilides 56 affords oxoindole derivatives 57 [56, 57] (Scheme 29). In addition, 6-nitroindole 58 was obtained in the reaction with acetamide.
Being heated in aqueous or ethanolic Na2CO3, amides 59 are converted into isoindoles 60 in moderate yields. At the same time, use of an external oxidant increases yields of the products [58] (Scheme 30).
Another example, illustrating use of intramolecular ONS reactions for the synthesis of N-heterocycles, is shown in Scheme 31. In this case, the annelation of a six-membered heterocycle proceeds by action of t-BuOK as base and CAN as an oxidant. The cyclization product 62 seems to be intermediate for the synthesis of makaluvamine С, the naturally occurring antitumor agent [59, 60].
A sequence of ONS and nucleophilic ipso-substitution has been described to occur in di- and trinitrobenzene series by action of DBU [61] (Scheme 32).
The initially formed σ-complex 65 is most likely to be oxidized by the starting nitro compounds into the intermediate 66, which in turn undergoes intramolecular substitution of the nitro group to give polycyclic compounds 67 in low yields (Scheme 32).
Similarly, 1,3,5-trinitrobenzene 64 reacts with O,N- and S,N-bifunctional nucleophiles (aminophenols and aminothiophenols) [62]. As a result, 1,3-dinitrophenoxazines and 1,3-dinitrophenothiazines 68 were isolated, respectively (Scheme 33).
We have established that the starting nitro compound, not air oxygen, is likely to be an oxidizing agent, since these reactions proceed pretty well under inert atmosphere.
Cyclocondensation takes place on reacting 6-nitroquinoline with substituted hydrazones 69 (Scheme 34) in the presence of NaH in DMF, thus giving rise to 3-aryl-1(3)H-pyrazolo[3,4-f]quinolines 70 and/or 3-aryl[1.2.4]triazino[6,5-f]quinolines 71 [63, 64]. Yields are varied from low to moderate, while the direction of the reaction depends mainly on the structure of hydrazones: electron-donating groups in the benzene ring of hydrazones favor the triazine ring formation.
Isomeric triazinoquinolines 72 were synthesized by cyclocondensation of 6-nitroquinoline with amidines [65] (Scheme 35).
The same authors reported that the reaction of nitronaphthalenes 73 with guanidines in the presence of t-BuOLi gave amino-1,2,4-triazines 74 fused with naphthalene [65] (Scheme 36).
The reaction of 4-substituted 3-fluoronitrobenzenes 75 with guanidine results in the formation of a mixture of isomeric benzotriazines with a predominance of compound 76 [66] (Scheme 37). The first step of this process is likely to be ONS of hydrogen with guanidine residue by action of air oxygen followed by the intramolecular condensation on the nitro group to give the corresponding N-oxides 77, which can further be reduced into aminobenzotriazines 76 and 78.
The fused benzimidazoles can also be obtained based on the intramolecular ONS reactions of cyclic guanidines 79 [67] (Scheme 38).
The direction of the ONS substitution reactions depends on the nature of an oxidant. Thus, use of MnO2 gave compound 80 as a single product. When no external oxidant was added, a mixture of ortho- and para-substitution products 81 and 82 was obtained.
Amination of benzo[d]isoxazoles 83 proceeds regioselectively under the ONS conditions, thus leading to ortho-nitroamines 84 [47] (Scheme 39). The reaction was carried out in a saturated methanolic solution of NH3, with the silver complex Ag(Py)2MnO4 being used as an oxidant. Treatment with PhI(OAc)2 allowed to convert amines 84 into furoxan derivatives. According to the 1Н NMR data the reaction product in DMSO solution existed as two isomers 85 and 86 in the ratio of 5:1.
The intramolecular addition of carbanions 87 generated from N-alkylsulfonamide does occur predominantly at the ortho-position relative to the nitro group [24, 68, 69] (Scheme 40). The oxidation of σH-adducts into the target compounds 88 and 89 proceeds most likely by action of air oxygen.
Sometimes the nucleophilic addition at carbon atom of the nitroaromatic ring may cause aromatization to go through transformation of the σH-adduct into a nitroso compound (i.e., via intramolecular redox process). In other words, oxidation of σH-adduct proceeds due to reduction of the nitro group. The resulting nitroso compounds undergo further transformations, including heterocyclizations. For example [70, 71], the reaction of para-chloronitrobenzenes 90 with phenyl acetonitrile in the presence of KOH affords benzo[c]isoxazoles 91. The authors suggest the formation of 91 through intermediacy of the corresponding nitroso compound 92 (Scheme 41).
Oxidation of anionic σH-adducts of 1,3,5-trinitrobenzene (93) [72] by action of CuBr/CCl4 provides an access to 3-substituted 4,6-dinitrobenzo[c]isoxazoles 94 (Scheme 42). This approach gives one more example of the formation of N-heterocycles based on the ONS process in nitroarenes.
In summary, we have discussed the very representative examples of how nitroarenes can be used as precursors for the synthesis of nitrogen heterocycles on the basis of SN H reactions. A number of publications dedicated to elucidation of such processes are growing permanently [6, 9, 10, 73]. It undeniably indicates a considerable interest in the SN H methodology, which is now widely used in heterocyclic chemistry.
3 Barton–Zard Reaction
It is a common point of view that the Barton–Zard reaction is a favorable one for the pyrrole synthesis. It is based on interaction of conjugated nitroalkenes with isocyanoacetates in the presence of a base [6, 74–76] and, basically, involves three steps (Scheme 43): the Michael-type addition of isocyanide carbanion to the C=C double bond of nitroalkene, cyclization of the resulting anion to give pyrroline derivative, and elimination of the nitrite anion followed by aromatization.
Nitroarenes [77–79] and nitrohetarenes [80] have been used, instead of nitroalkenes, in similar cyclizations providing an access to fused pyrrole derivatives, isoindoles, and other polyheterocyclic systems.
The reactions of nitrobenzene and 1- and 2-nitro-substituted naphthalenes with ethyl isocyanoacetate in the presence of DBU were found to proceed very slowly [81, 82], and yields of the target isoindoles proved to be extremely low, with conversion of the starting nitro compounds not exceeding 10% (Scheme 44).
However, nitroaromatic compounds with a profound nitroalkenic character, as well as their dinitro derivatives, proved to undergo the Barton–Zard reaction much easier to give moderate-to-good yields of the target products. Indeed, 1,3-, 1,5-, and 2,7-dinitronaphthalenes gave the corresponding isoindoles in the presence of DBU in 25–45% yields [82, 83] (Scheme 45). When the phosphazene base 95 was used instead of DBU, it became possible to increase yields of isoindoles up to 31–78%. Besides, the formation of bis-annelation product 98 was observed in case of 1,3-dinitronaphthalene.
Polycyclic nitroaromatic compounds 99 and 100 have been found to react with alkyl isocyanoacetates into the corresponding pyrroles 101 [82] and 102 [81, 84] (Scheme 46).
Analogously, nitrophenanthrene and phenanthroline derivatives 103 and 104 (Scheme 47) were transformed into dibenzo- and dipyridinoisoindoles, respectively [77, 81, 84, 85].
Other derivatives of the family of benzo-annelated heterocycles bearing the nitro group in the benzene ring react in a similar manner. For instance, the reaction of 6-nitroquinoline with ethyl isocyanoacetate results in the formation of isoindole 107 in 47% yield, while 5-nitroisoquinoline gave compound 108 in 26% yield [82] (Scheme 48). It should be emphasized that, in this particular case, phosphazene 95 was effective as a base, because use of DBU did not give any fused pyrroles.
However, the Barton–Zard reaction seems to be rather sensitive to the structure of starting nitroarenes, and depending on position of the nitro group, the reaction results in the formation of various heterocycles. 4-Nitrobenzothia- and selenadiazoles have been shown to react with ethyl isocyanoacetate/DBU to give the expected isoindoles in moderate yields [78, 81, 86], while isomeric 5-nitro derivatives afford pyrimidines fused with benzoazoles under the same reaction conditions [78] (Scheme 49).
It has been found that the target isoindoles can be obtained in the presence of phosphazene 95 [87] (Scheme 50), while fused pyrimidines 112 were isolated only as traces.
Varying base allows to obtain a wide range of functionalized isoindoles fused with the thiadiazole ring or bearing substituents in the pyrrole ring [88].
C.M. Cillo et al. reported on the synthesis of porphyrins condensed with 2,1,3-benzoxa- and selenadiazoles [89]. Also pyrrolobenzodiazoles 114 were prepared by the Barton–Zard reaction from 4-nitrobenzofurazans or benzoselenadiazoles and isocyanoacetic esters in the presence of DBU (Scheme 51).
The authors have shown that low yields of condensation products described in the earlier publications are mainly due to a low solubility of the starting nitro compounds in THF. It was found that yields could be considerably higher if the reactions were carried out in dilute solutions [83, 86, 89].
From the data considered above it is clear that the Barton–Zard condensation of nitroarenes is a convenient method for the synthesis of polycyclic compounds of the isoindole family. Formally the reaction involves the SN H process and further cyclization into the pyrrole ring accompanied by elimination of HNO2.
4 Mannich Cyclization of Anionic Adducts of Nitroarenes
This section deals with the reactions in which the formation of N-heterocycles proceeds through the Mannich-type cyclocondensations of anionic σ-adducts of nitroarenes. The reactions of σ-adducts with formaldehyde and primary amines result in 1,3-annelation of the piperidine ring to the core structure of nitroarenes. Depending on nitroarene structure, there are two main routes for these reactions to take: (a) the σ-adduct is formed via the addition of С-nucleophile to a nitroarene bearing the hydroxy group and (b) cyclocondensation of hydride adducts of nitroarenes, where the hydride ion acts as a nucleophile. At least two meta-positioned nitro groups in aromatic ring are necessary for these reactions to proceed. Scheme 52 demonstrates both of these options.
Scheme 53 illustrates the path (а). In one of the pioneer publications on such type of transformations, Severin et al. [90] described the interaction of disodium salt 115 (adduct of 2,4-dinitrophenol and acetone) with methylamine and formaldehyde in the presence of acetic acid. As a result, bicyclic derivative 116a of 3-azabicyclo[3.3.1]nonane was isolated in 62% yield (Scheme 53). Analogous product 116b was obtained in 48% yield, when cyclohexanone was used as C-nucleophile [90].
Another research group has applied this approach to the synthesis of polyfunctional 3-azabicyclo[3.3.1]nonanes from 2,4-dinitrophenol [91]. It has been reported that various alkyl amines and amino acids can be successfully used in these transformations.
Reduction of adducts 115 with sodium borohydride proceeds selectively on non-conjugated carbonyl group [90]. Treatment of alcohols 117 with methylamine and formaldehyde results in the formation of polycyclic compounds 118 (Scheme 54).
A number of condensed 3-azabicyclo[3.3.1]nonanes 119 were synthesized from 2,4-dinitronaphthol [92, 93] and 5,7-dinitro-8-hydroxyquinoline [94] (Scheme 55).
Another pathway to 3-azabicyclo[3.3.1]nonanes from nitroarenes involves the formation of hydride adducts by action of NaBH4. These adducts undergo the double Mannich reaction with formaldehyde and primary amines (Scheme 52, path b). This reaction was found to take place with meta-dinitrobenzenes bearing a variety of functional groups. 1,3-Dinitrobenzene and its numerous derivatives were allowed to react with NaBH4 followed by treatment with a mixture of methylamine, aqueous formaldehyde, and acetic acid [95–97] to give 3-azabicyclo[3.3.1]nonanes 120 (Scheme 56).
A number of 7-polyfluoroalkoxy 1,5-dinitro-3-azabicyclo[3.3.1]non-6-enes 121 were synthesized by means of reduction of polyfluoroalkyl ethers of 3,5-dinitrophenol with sodium borohydride followed by the Mannich reaction with formaldehyde and alkyl amines [98] (Scheme 57).
3,5-Dinitrobenzoic acid has been shown to undergo the Mannich cyclization similarly to give the corresponding azabicyclo[3.3.1]non-6-enes 122 in moderate yields [99] (Scheme 58).
meta-Dinitronaphthalene and its quinoline analogue have been shown to react smoothly with NaBH4, followed by cyclization into 3-azabicyclo[3.3.1]nonanes 123 fused with the benzene or pyridine ring, respectively [100] (Scheme 59).
In a similar cyclization of 8-hydroxy-5,7-dinitroquinoline the corresponding ketones 124, in which the 3-azabicyclo[3.3.1]nonane skeleton is fused with the pyridine ring, have been isolated [101] (Scheme 60).
The data on the synthesis of azabicyclo[3.3.1]nonanes fused with azoles have recently been published [102–104]. The first step of the reaction is the formation of hydride adducts 125 by action of NaBH4 (Scheme 61). These adducts undergo the Mannich condensation with formaldehyde and alkyl amines to give 3-R-1,5-dinitroazabicyclo[3.3.1]nonanes 126, fused with azole fragments across the С(7)–С(8) bond.
In conclusion it is worth noting that 1,3-dinitrobenzenes, bearing functional groups, as well as their structural analogues with the fused benzene ring or N-heterocyclic fragments can be regarded as appropriate substrates for preparation of a variety of 3-azabicyclo[3.3.1]nonanes via the Mannich condensation of intermediate σH-adducts, derived from the addition of carbanions, or the hydride ion at unsubstituted C-2 of 1,3-dinitroarenes.
5 Pericyclic Reactions of Nitroarenes
Pericyclic cycloaddition reactions have attracted a considerable interest of chemists due to some distinct advantages. First of all, a new ring is formed from two reacting molecules without elimination of any group or atom. Secondly, the reactions are accompanied by overall decrease in bond multiplicity. The most significant pericyclic cycloaddition reactions are [4+2]-cycloaddition (Diels–Alder reaction) and [3+2]-cycloaddition (1,3-dipolar cycloaddition) [105–107].
The [4+2]-cycloaddition reactions lead to the formation of six-membered rings through interaction of conjugated 1,3-dienes (4π system) with alkenes and acetylenes (dienophiles, 2π system) [108] (Scheme 62).
1,3-Dienes and dienophiles are usually to undergo [4+2] cycloaddition reactions in those cases when these compounds contain activating groups.
Carbocyclic compounds are formed if all atoms a-f are carbons. However, a variety of heterodienes, such as C=C–C=N, C=C–C=O, and N=C–C=N, as well as heterodienophiles, such as –C=N, –C=O, –C=S, –N=N–, –S=O, and –N=O, can also undergo [4+2]-cycloaddition reactions to give six-membered heterocycles. [4+2] Cycloaddition appears to be one of the most widely applied reactions in organic chemistry [106, 108–110]. It is used for the synthesis of various polycyclic compounds, including enantioselective [4+2] cycloadditions, which proved to be an effective synthetic tool to obtain natural compounds and their analogues [111, 112].
[3+2]-Cycloaddition (1,3-dipolar cycloaddition) involves the addition of 1,3-dipolar molecules to multiple bonds of various dipolarophiles leading to five-membered heterocycles [113, 114] (Scheme 63).
5.1 [4+2]-Cycloaddition Reactions
The publication of Terrier et al. [115] appears to be the first major contribution to understanding of such transformations. These researchers have observed that mixing of equimolar amounts of 4,6-dinitrobenzofuroxan (DNBF, 127) and indene in DMSO, CH2Cl2, or methanol results in the formation of the product with unusual spectral characteristics, which are significantly different from those of the previously isolated σ-complexes of DNBF. Comparing these data with the results published earlier, the authors concluded that the compound obtained proved to be dihydro-1,2-oxazine N-oxide 128 (Scheme 64). A plausible mechanism for the formation of 128 was suggested to be either a two-step process through the σ-complex or a concerted reaction proceeding through a cyclic transition state, i.e., [4+2]-cycloaddition with an inverse electron demand (IED).
The same group of authors has reported on the formation of similar DNBF cycloadducts with other dienophiles, in particular, with ethyl vinyl ether [116]. When the reaction is carried out in the presence of 2.5 equivalents of dienophile, it results in the formation of diastereomeric dihydro-1,2-oxazine N-oxides 129a and 129b, in the ratio 4:1(Scheme 65).
When ethyl vinyl ether was used as solvent, a mixture of several diastereomeric bis-adducts 130 was obtained [116]. Stereochemical features for the major products have been studied, and the reaction mechanism proved to be in agreement with an inverse electron demand cyclization.
The dual reactivity of DNBF in [4+2]-cycloaddition reactions is illustrated nicely by the reaction of benzofuroxan with cyclopentadiene [117]. The addition of an excess of the diene to a solution of 127 in chloroform at 0°C leads only to one diastereomer 131, which has been isolated as a racemic mixture (Scheme 66).
Use of 1H NMR spectroscopy revealed that, at a low reaction temperature (−30°C), the adducts 132a,b are initially formed, which then react subsequently upon a gradual increase of temperature into polycyclic compound 131 (Scheme 66). It is clear that at the initial step there are two competing reactions, which are in accord with NED and IED. This is the IED reaction, which leads to annelation of the oxazine ring.
Also, a number of other highly electrophilic nitroarenes (superelectrophiles, see below) were used as heterodienes in the Diels–Alder reaction. When a structural analogue of DNBF, 4,6-dinitro-2-picrylbenzotriazole-1-oxide (133), was treated with an excess of cyclopentadiene, the [4+2]-cycloadduct 134a with the fused oxazine ring was obtained in 92% yield (Scheme 67) [118].
4,6-Dinitrobenzofurazan (135) and 4,6-dinitrobenzothiadiazole (136) behave similarly [119] (Scheme 67) and are capable of reacting with cyclopentadiene into bis-adducts 134b,c in 68% and 32% yields, respectively. It is worth noting that 4,6-dinitrobenzoselenadiazole (X = Se, n = 0) did not give any stable adduct. It was later shown that this Diels–Alder reaction takes place only in the series of those nitroarenes, which were referred by F. Terrier as superelectrophiles. A characteristic feature of the latter is the ability to form anionic σH-adducts with water (or MeOH) without any base added [120] (Scheme 68). The equilibrium of this process is determined by pKa H 2 O, and superelectrophiles have pKa H 2 O ≤7.5–8.
Another example of nitroarenes capable of undergoing [4+2]-cycloaddition with IED is 4,6-dinitrobenzo[c]isoxazole (137) [121], which can be considered as a structural analogue of 4,6-dinitrobenzofurazan (Scheme 69). Although the CH fragment replaces only one of the nitrogen atoms in the structure of benzofurazan 135, anthranil 137 possesses the reactivity sufficient for annelation of two oxazine fragments to the benzene ring in the reaction of 137 with an excess of ethyl vinyl ether.
Kurbatov et al. [122] studied properties of 4-nitrobenzodifuroxan 139 (NBDF) and found that, in spite of the formal aromatic structure, the C=C–NO2 fragment has pronounced nitroalkene character. NBDF was found to undergo cycloaddition with dienes (in accord with NED), and, as a heterodiene, it is capable of reacting with ethyl vinyl ether (in accord with IED) to give polycondensed heterocycles 140 and 141, respectively (Scheme 70).
However, it has been established on the basis of both experimental and calculated data [123] that the reaction of 139 with cyclopentadiene proceeds through the formation of IED intermediate 142 (Scheme 71), which then rearranges into the thermodynamically more stable NED product 140.
Superelectrophilic properties of nitroarenes are retained when one of the furoxan rings in NBDF is replaced with electron-deficient isoxazole [124] or pyridine fragments [125]. As in case of NBDF, the reactions of these fused nitroarenes with ethyl vinyl ether were found to lead to the corresponding benzoxazine N-oxides 143 and 144 condensed with heterocyclic rings (Scheme 72).
It has to be concluded that superelectrophilic nitroarenes possess a dual reactivity in the Diels–Alder reactions, thus giving rise to the formation of either carbocyclic (NED) or heterocyclic (oxazine, IED) rings. The ability of highly electrophilic nitroarenes, as heterodienes, to undergo the Diels–Alder reaction with nucleophilic dienophiles provides a general method for annelation of one or two oxazine rings to an aromatic system. This possibility can be explained by a low aromatic character of the benzene ring activated by the nitro group and annelated heterocyclic fragments in this family of fused heteroaromatics.
5.2 [3+2]-Cycloaddition Reactions
Nitroalkenes are known to react readily with various 1,3-dipoles to give a broad range of five-membered heterocycles [126]. Nitroarenes also contain the C=C–NO2 fragment and, therefore, one might expect these compounds to be able to add some dipoles, at least the nucleophilic ones.
However, the data on 1,3-dipolar cycloaddition reactions of nitroarenes, acting as dipolarophiles, are scarcely available in the literature. There have been only a few examples describing the addition of aliphatic diazo compounds to the benzene ring of nitrobenzoazoles. For example, the reaction of 3-substituted 6-nitrobenzo-[c]isoxazoles 145 with excess of diazomethane (Scheme 73) affords 7-methyl-6-nitro compound 146 [127].
Although the intermediate [3+2] cycloadducts 147 have neither been registered nor isolated, Chandra Boruah et al. [127] claim that these intermediates can be detected chromatographically at a low temperature.
In the reactions of 4- and 5-nitrobenzofuroxans 148 and 149 with alkyl diazoacetates, the initially formed cycloadducts undergo aromatization with the loss of nitrous acid (Scheme 74) to give pyrazolobenzofuroxans 150 and 151 in good yields [128].
During the last decade we have been carrying out a systematic study of the reactions of nitroarenes with N-alkyl azomethine ylides. A fundamentally new approach has been advanced for the synthesis of polycyclic heterosystems bearing important pharmacophoric fragments, such as pyrrolidines, pyrrolines, and pyrroles.
The first example of the cycloaddition of azomethine ylides on an aromatic C=C double bond activated by the nitro group is the reaction of highly electron-deficient nitroaromatics, such as 4,6-dinitrobenzazoles or 6,8-dinitroquinoline 152, with unstabilized N-methyl azomethine ylide (153) [129, 130] (Scheme 75).
In all cases, cycloadditions were observed across both C=C–NO2 fragments to give polycyclic systems 154 containing two pyrrolidine rings. The reactions proved to proceed in a stereoselective manner: the first and the second cycloadditions took place from different sides of the benzene ring plane. Such a behavior of dinitrobenzazoles is a characteristic feature of [4+2]-cycloaddition reactions (see, e.g., Scheme 69) and may be attributed to a diminished aromaticity and, as a consequence, increased reactivity of these aromatic systems due to the presence of two nitro groups and fused heterocycles.
It has been found [131] that mononitrobenzazoles 155 (4- and 5-nitrobenzofurazans, -thiadiazoles, -selenadiazoles, and -[c]isoxazoles) are able to form cycloadducts 156 with N-methyl azomethine ylide 153 (Scheme 76). This dipole adds only at the C=C bond activated by the nitro group, thus giving tetrahydroisoindoles condensed with azoles.
Sulfonyl derivatives 157 containing one nitro group behave analogously (Scheme 77). However, the intermediate cycloadducts 158 undergo aromatization under the reaction conditions, with the loss of nitrous acid.
It is worth noting that steric factors have a considerable effect on feasibility of 1,3-dipolar cycloaddition in the series of nitrobenzazoles. It has been shown, for instance, that 5-methyl-4-nitrobenzofurazan 160, in contrast to 4-nitrobenzofurazan 155a, lacking a substituent at position 5, did not form a cycloaddition product (Scheme 78) [132].
At the same time, isomeric 7-methyl-4-nitrobenzofurazan 161 proved to react with N-methyl azomethine ylide 153 in a similar to benzofurazan 155a manner to give tetrahydroisoindole 162 in a high yield (Scheme 78).
We have also studied the [3+2]-cycloaddition of N-methyl azomethine ylide 153 to 4-X-7-nitrobenzofurazans 163 (Scheme 79) [132]. It has been established that the nature of substituent X has a significant effect on feasibility of the reaction. In case X=SR and OR, the reaction proceeds normally to give cycloadducts 164 in high yields, but when dialkylamino or arylamino group is present at the para-position relative to the nitro group, no cycloadduct formation is observed. This failure is likely due to a large contribution of the betaine 165 to the structure of 7-amino compounds (Scheme 79).
8-X-5,7-Dinitroquinolines 166 are also able to react with dipole 153 (Scheme 80). However, in this particular case, the reaction is governed by the nature of substituent X in position 8 [133]. 8-SR-Derivatives undergo the addition of this dipole exclusively across the С(5)–С(6) bond to give pyrrolines 167. On the other hand, in case of 8-OR-derivatives, the displacement of OR- with NMe2-group was found to be the main process.
Lee et al. reported on the reaction of mono- and dinitro-substituted benzenes, naphthalenes, and some other benzo-annelated heterocycles with unstabilized N-benzyl azomethine ylide, which was generated in situ from hemiaminal 169 by action of catalytic amounts of trifluoroacetic acid (Scheme 81) [134].
As a result, cycloadducts containing one or two pyrrolidine rings condensed with the benzene ring were obtained depending on the molar ratio of reagents and the structure of dipolarophile. The reactions were shown to require the presence of the nitro group and another electron-withdrawing substituent in the benzene ring (mononitrobenzene does not react with azomethine ylide under these reaction conditions). However, the presence of one nitro group was sufficient in the series of naphthalenes [134].
In continuation of our systematic studies, we have investigated the reactions of substituted di- and trinitrobenzenes with a series of N-alkyl azomethine ylides [135]. It has been found that 1,3-di- and 1,3,5-trinitrobenzenes react with N-methyl azomethine ylide (153) to give isoindoles 172 in moderate yields (Scheme 82).
It is of interest to note that, in contrast to nitrobenzazoles, after the formation of [3+2]-cycloadducts of polynitrobenzenes with this dipole, a rapid loss of HNO2 and subsequent oxidation have been observed (Scheme 83) [135].
Although these reactions were carried out in the presence of air oxygen, nitroaromatic substrates were likely to be oxidizing agents, since yields proved to be the same in inert atmosphere. Furthermore, it should be noted that, in case of monocyclic di- and trinitrobenzenes, the dipole adds only across the C=C bond activated by the nitro group, specifically, at positions 2 and 3 relative to substituent R1 (Scheme 83).
Use of cyclic amino acids instead of sarcosine to generate the corresponding dipole as well as the subsequent [3+2]-cycloaddition allowed to obtain condensed isoindoles [135]. Thus, tricyclic derivatives 173 were obtained in the case of proline (Scheme 84).
When thiazolidine-4-carboxylic acid was used under these conditions, the corresponding isoindolines 176 could not be fully oxidized to isoindoles 177 (Scheme 85).
One more example of 1,3-dipolar cycloaddition with nitroarenes is the reaction of nitrobenzazoles with mesoionic 1,3-oxazolium-5-olates (münchnones) [136]. Münchnones are known to react as 1,3-dipoles with conjugated nitroalkenes [137] and some nitroheterocyclic compounds [138]. The münchnone molecule contains a cyclic azomethine ylide fragment. Thus, the reaction of this compound with nitroalkenes leads to bicyclic intermediates, which then undergo elimination of HNO2 and CO2 to give pyrroles (Scheme 86).
The reactions of asymmetrical münchnone 178a with nitro derivatives of benzofurazan, benzothiadiazole, and benzoselenadiazole gave a mixture of isomeric isoindoles 179 and 180, condensed with the corresponding azoles [136] (Scheme 87).
Each isomer can be isolated, using flash chromatography. In case of 2,4-dimethyl münchnone 178b the reactions with 4- or 5-nitrobenzofurazans gave the same isoindole 181 (Scheme 88).
In summary, we have succeeded in developing a novel one-step method for the synthesis of isoindoles by annelation of the pyrrole ring to the benzene ring of nitroarenes.
6 Other Transformations
Aside from chemical transformations described above, there are some other approaches to the synthesis of nitrogen heterocycles using CH-functionalization of nitroarenes; among them an acid-promoted cyclization of O-nitrophenyl ketoximes 182 appears to be of particular interest [139] (Scheme 89).
The starting О-aryl oximes can be obtained through nucleophilic substitution of the nitro group in polynitrobenzenes. Heating these oximes under reflux in the presence of acids gives 4,6-dinitrobenzofurans 183 (Scheme 89). Reduction of one of two nitro groups in compounds 182 affords the corresponding nitroamines 184. The cyclization of the latter in acidic media gives a mixture of 4-nitro-6-aminobenzofurans 185 and 4-hydroxynitroindoles 186 [140] (Scheme 90).
The authors suggested a plausible reaction scheme (Scheme 91) explaining the formation of both types of heterocycles.
Another approach to N-heterocycles on the basis of nitroarenes is represented by cyclization of nitroaryl-substituted hydrazones of carbonyl compounds into indoles (Fisher indole synthesis) [141] (Scheme 92).
This cyclization is known to proceed smoothly, if electron-releasing substituents are present in the benzene ring of the intermediate hydrazones. Nevertheless, meta-nitrophenyl hydrazones of aldehydes and ketones undergo this reaction as well, although under more drastic conditions and in smaller yields.
For example, heating 3-nitrophenyl hydrazone of propioaldehyde 187 in a mixture of toluene – 85% orthophosphoric acid gave rise to a hardly separable mixture of two regioisomers 188 and 189 (Scheme 93) in 70% overall yield [142].
When substituents in the para-position to the nitro group are present, the corresponding hydrazones afford the only possible isomer of indoles [143, 144] (Scheme 94).
3-Nitrophenyl hydrazones of ketones reacted similarly. On heating arylhydrazones of pyruvic ester 192 with polyphosphoric acid (PPA), mixtures of ethyl 4- and 6-nitroindole-2-carboxylates were formed [145, 146] (Scheme 95).
Hydrogenated derivatives of β-carboline [147], carbazole [148–150], and some other polycyclic systems [151–153] with the nitro group in the benzene ring (Scheme 96) were synthesized from hydrazones of cyclic ketones 195.
The reactions have usually been carried out in the presence of sulfuric acid, PPA, or hydrogen chloride to give various products, depending on the structure of the starting hydrazones: if para-position to the nitro group is occupied, the only regioisomer has been obtained; otherwise mixtures of compounds are formed. This methodology has also been applied successfully to the synthesis of highly substituted indoles [154–157].
7 Conclusion
The survey of the literature data has shown that nitroarenes with unsubstituted ortho-position relative to the nitro group can be functionalized directly by using various types of C–H functionalizations to give nitrogen heterocycles or their precursors. The results presented in this chapter may provide a good basis for the directed synthesis of diversely functionalized nitrogen bi- and poly heterocyclic systems. The general features and plausible pathways for these chemical transformations have been described.
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Shevelev, S., Starosotnikov, A. (2013). Direct Functionalization of C–H Fragments in Nitroarenes as a Synthetic Pathway to Condensed N-Heterocycles. In: Charushin, V., Chupakhin, O. (eds) Metal Free C-H Functionalization of Aromatics. Topics in Heterocyclic Chemistry, vol 37. Springer, Cham. https://doi.org/10.1007/7081_2013_112
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DOI: https://doi.org/10.1007/7081_2013_112
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