DOI: 10.1002/chem.201400097

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Reactions of Nucleophiles with Nitroarenes: Multifacial and Versatile Electrophiles Mieczysław Ma˛kosza*[a] Dedicated to Professor Oleg Chupakhin, Professor Leon Ghosez, Professor Armand Lattes, and Professor Binne Zwanenburg on the occasion of their 80th birthday

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Concept ducts (one para and two ortho). In analyzing the addition of nucleophiles to the ring, one should consider two major cases: the addition at positions occupied by a nucleofugal group, X, such as a halogen atom, to form sX adducts and the addition at positions occupied by a hydrogen atom to form sH adducts. Notably, the nitro group itself can also behave as a nucleofugal group and, when it is located at a position that is ortho or para to an electron-withdrawing substituent, the addition can proceed at the position occupied by the nitro group. Rearomatization of the sX adducts (X = halogen or NO2) proceeds rapidly through spontaneous departure of X or NO2 to form the products of conventional nucleophilic aromatic substitution, SNAr (Scheme 2). This conventional nucleophilic aromatic substitution was the subject of thorough mechanistic studies and is widely used in organic synthesis, particularly in the context of industrial processes.[1, 2] The pathway of this reaction—nucleophilic addition to form sX adducts, a process connected with the loss of aromaticity, followed by rearomatization through fast departure of X —is supported by many observations, one particularly convincing observation being that substitution of a fluorine atom is usually much faster than substitution of a chlorine atom, indicating that the addition the slowest, and thus, the rate-limiting step.[3]

Abstract: In this overview, it is shown that there are many initial reactions between nitroarenes and nucleophiles: addition to the electron-deficient ring at positions occupied by halogen and hydrogen atoms, addition to the nitro group, single-electron transfer (SET), and other types of initial reactions. The resulting intermediates react further in a variety of ways to form products of nucleophilic substitution of a halogen atom (SNAr), a hydrogen atom (SNArH), and others. Many variants of these processes are briefly discussed, particularly in relation of rates of the initial reactions and further transformations.

1. Introduction Nitroarenes are very interesting electrophiles because they are able to react with nucleophiles in many ways. The nitro group causes the aromatic ring to be electron deficient, mostly at the conjugated ortho- and para positions. Moreover, the nitro group is also an electron-deficient fragment in itself. Nitroarenes are also active single-electron-accepting agents. Owing to these properties, the initial reactions of nucleophiles with nitroarenes can proceed in a variety of ways, for example, through direct addition to the ring to form nitrocyclohexadienyl adducts, through abstraction of a proton from the ring to form nitroaryl carbanions, through attack on the nitro group, and through single-electron transfer (SET; Scheme 1).

Scheme 2. Nucleophilic substitution of halogen atoms and the nitro group in nitroarenes.

Scheme 1. Initial reactions of nucleophiles with nitroarenes.

These initial steps can be followed by a few further reactions, thus resulting in a plethora of reactions depending on the nature of the nucleophile and the nitroarene and the reaction conditions. Usually, the initial reaction between the nucleophile and the nitroarene involves addition to the activated positions ortho- or para to the nitro group, behavior that is somewhat similar to the addition of nucleophiles to electrondeficient alkenes (Michael acceptors). However, unlike the latter process, addition to the electron-deficient ring of a nitroarene is connected with destruction of the aromatic system (dearomatization), thus causing the adducts to exhibit a strong tendency to rearomatize. Moreover, the addition can occur at positions occupied by a hydrogen atom or other substituents, resulting in the formation of two or even three isomeric ad-

Because the SNAr reaction is well known and presented in textbooks[4] and monographs,[1, 2] it will not be discussed here in depth. However , it should be stressed at the very beginning that descriptions of this reaction in textbooks[4] and older monographs[1] are incomplete, if not incorrect. It was unambiguously shown that the addition of nucleophiles to halonitroarenes proceeds faster at positions occupied by hydrogen atoms than at similarly activated positions occupied by halogen atoms, even fluorine atoms.[5, 6] However, the corresponding sH adducts, contrary to sX adducts, do not have the possibility to rearomatize through spontaneous departure of the hydride anion, thus generally the rearomatization proceeds through departure of the nucleophile. This means that fast addition at positions occupied by hydrogen atoms is reversible. Because sH adducts usually dissociate, slower but irreversible formation of the sX adducts leads to the substitution of the halogen atom, SNAr, whereas formation of sH adducts and pre-equilibration is overlooked. The situation is presented in Scheme 3.

[a] Prof. Dr. M. Ma˛kosza Institute of Organic Chemistry, Polish Academy of Sciences ul. Kasprzaka 44/52, PO Box 58, 01-224 Warszawa 42 (Poland) Fax: (+ 48) 22-632-66-81 E-mail: [email protected]

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Concept

Scheme 4. Reactions of p-chloronitrobenzene with OH anions: fast primary ONSH and slow secondary SNAr processes.

Scheme 3. Relation of rates of the formation of sX and sH adducts.

2. Nucleophilic substitution of hydrogen atoms, SNArH1 From the relation of rates of the addition (Scheme 3), it is evident that nucleophilic substitution of hydrogen atoms can dominate over SNAr substitution of halogen atoms, provided that the rate of further conversion of sH adducts (k2H) is faster than the rate of formation of the sX adducts. The obvious way for such conversion of sH adducts appears to be the removal of the hydride anion by external oxidants.

Scheme 5. ONSH in 2,4-dinitrochlorobenzene with ammonia

ONSH with nucleophiles that are sensitive to oxidation such as carbanions (case b) proceeds when the addition equilibrium is shifted towards the sH adducts. This occurs when the carbanions are sufficiently nucleophilic and the reaction is carried out at low temperature, when, owing to the entropy factor, dissociation of the sH adducts is disfavored. Sterically demanding tertiary carbanions add at the para position[9] whereas secondary (methylenic) carbanions add at the both para and ortho positions.[10] When the para position is occupied, even by a fluorine atom, the addition occurs at a position ortho to the nitro group.[10] The sH adducts of carbanions can be oxidized either by KMnO4 in liquid ammonia or by DDQ in THF/DMF to form products of ONSH. It appears that oxidation by using these oxidants proceeds through direct abstraction of the hydride anions, a step that is rate limiting, as supported by the high value of the kinetic isotope effects.[11] On the other hand, oxidation of the sH adducts with dimethyl dioxirane (DMD) occurs at the negatively charged nitro group to give substituted phenols as the ultimate products (Scheme 6).[12] Oxidation with O2 is limited to the sH adducts of secondary and primary carbanions. Because this reaction proceeds efficiently only in the presence of an excess of base, we suppose that sH adducts are deprotonated and thus, it is actually the dianions that are oxidized with O2.[13] Direct synthesis of substi-

2.1. Oxidative nucleophilic substitution of hydrogen atoms, ONSH Nucleophiles are, in general, sensitive to oxidation; therefore, the overall process, oxidative nucleophilic substitution of hydrogen (ONSH), can proceed when an oxidant oxidizes the sH adducts and not the nucleophiles. This can occur in the following cases: a) when the nucleophiles are resistant towards oxidation; b) when the equilibrium of the addition is shifted towards the sH adducts; c) when the addition is an irreversible process. The most interesting example for case a is oxidative hydroxylation of p-chloronitrobenzene, as presented in Scheme 4.[7] The hydrolysis of p-chloronitrobenzene, a transformation that occurs through SNAr substitution of the chlorine atom with hydroxyl anions at elevated temperature, is presented in every textbook and is a slow secondary process, whereas ONSH with these anions is a much faster primary reaction. Ammonia is a nucleophile that is resistant towards oxidation by potassium permanganate; therefore, the reaction of 2,4-dinitrochlorobenzene with KMnO4 in liquid ammonia results in oxidative substitution of a hydrogen atom,[8a] whereas conventional substitution of the chlorine atom is much slower. Notably, oxidative amination of electron-deficient arenes, particularly azines, by using a solution of KMnO4 in liquid ammonia, is a valuable general process that is often referred to as the oxidative Tchitchibabin reaction.[8] The results presented in Schemes 4 and 5 confirm the relation of rates shown in Scheme 3. 0

Variants of nucleophilic substitution of hydrogen atoms in electron-deficient arenes have commonly accepted acronyms: ONSH, VNS, cine- etc. It is thereScheme 6. ONSH in nitroarenes with 2-phenylpropionitrile carbanion

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Concept 2.2. Conversion of the sH adducts into substituted nitrosoarenes Another way to convert nucleophile–nitroarene sH adducts into products of nucleophilic substitution of a hydrogen atom, one that is somewhat related to ONSH, involves the conversion of the adducts into substituted nitrosoarenes. This reaction, which proceeds according to intramolecular redox stoichiometry, is promoted by protonation, silylation, or Lewis acid association of the negatively charged oxygen atoms of the nitro group, followed by elimination of water, silanol, or oxygenated Lewis acid, respectively. This reaction is a really versatile and useful process that takes place between nitroarenes and carbon-, nitrogen-, and even phosphorus-based nucleophiles. Because nitrosoarenes are active electrophiles, they usually cannot be isolated and often react further. For instance, the carbanion of phenylacetonitrile reacts with p- and o-chloronitrobenzenes in this way in protic media, whereas in dipolar aprotic solvents, conventional SNAr substitution of the chlorine atom takes place,[17] as shown in Scheme 10.

Scheme 7. Synthesis of nitroindoles through direct ONSH in meta-nitroaniline with enolates of ketones.

tuted nitroindoles in the reaction of m-nitroanilines with enolates of methyl and methylenic ketones apparently proceeds in this way (Scheme 7).[14] The anion of diphenylphosphine also adds to nitroarenes preferentially at positions occupied by hydrogen atoms to form sH adducts. Thus potassium diphenylphosphide added in liquid ammonia to p-fluoronitrobenzene and subsequent oxidation of the produced sH adduct by KMnO4 gives diphenyl-2nitro-5-fluorophenyl phosphine oxide (Scheme 8).[15]

Scheme 8. ONSH in nitroarenes with diphenylphosphine anion.

Addition of the primary alkyl Grignard reagents and alkyllithiums to nitroarenes to form sH adducts proceeds irreversibly (case c); therefore, the substitution of halogen atoms in halonitroarenes (SNAr reaction) with these nucleophiles is not observed. The sH adducts of Grignard reagents can be oxidized with a variety of oxidants,[16a] the most effective being KMnO4 used as a solution in liquid ammonia (Scheme 9).[16b] This reaction is an attractive way for effecting the nucleophilic alkylation of nitroarenes. The presented examples indicate that oxidation of sH adducts with external oxidants is a versatile tool for the introduction of substituents, such as those based on oxygen, nitrogen, carbon, and phosphorous, into nitroaromatic rings through the replacement of a hydrogen atom (ONSH reaction).

Scheme 10. Reactions of phenylacetonitrile carbanion with p-chloronitrobenzene in protic and aprotic media.

Another type of reaction that belongs to this category is that of anilines with nitroarenes, particularly p-halonitrobenzenes. Whereas heating anilines with p-fluoro- or p-chloronitrobenzene results in substitution of the halogen atom (SNAr reaction) to form diarylamines, these reactants in the presence of a strong base (for example, tBuOK), at low temperature, form the sH adducts that are converted into substituted 2-nitrosodiarylamines.[18] This is a general and efficient way for preparing 2-nitrosodiarylamines (Scheme 11), which are versatile starting materials for the synthesis of a variety of heterocycles.[19]

Scheme 11. Formation of nitrosodiarylamines in the reaction of anilines with nitroarenes. Scheme 9. Nucleophilic alkylation of p-chloronitrobenzene through ONSH with a Grignard reagent.

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Concept elimination, the sH adducts should be produced in the reaction mixtures in a reasonable concentration. Thus the reaction does not proceed between carbanions of low nucleophilicity and moderately electrophilic nitroarenes because of the unfavorable equilibrium of the initial addition. For instance, the carbanion of dimethyl chloromalonate does not react with nitrobenzene, but reacts efficiently with the much more active nitrothiazoles (Scheme 14).[23]

2.3 Vicarious nucleophilic substitution of halogen atoms, VNS When nucleophiles contain nucleofugal groups L at the nucleophilic centers, for example, a-halocarbanions, the produced sH adducts undergo base-induced b-elimination of HL to produce nitrobenzylic carbanions, which upon protonation give products of vicarious nucleophilic substitution of a hydrogen atom (VNS).[20] For instance, the base-induced reaction of chloromethyl phenyl sulfone with p-chloronitrobenzene gave 2-nitro-5-chlorobenzyl phenyl sulfones, the product of a nucleophilic replacement of a hydrogen atom (Scheme 12).[21]

Scheme 14. VNS in 2-chloro-5-nitrothiazole with the carbanion of dimethyl chloro-malonate.

The addition of carbanions is a fast process thus unstable trichloromethyl carbanion that dissociate rapidly to form dichlorocarbene enters VNS with nitroarenes (Scheme 15).[24]

Scheme 12. VNS in p-chloronitrobenzene with the carbanion of chloromethyl phenyl sulfone.

To show strong preference for nucleophilic substitution of a hydrogen atom over conventional substitution of a halogen atom, it should be mentioned that a-halocarbanions react with 2,4-dinitrofluorobenzene, the Sanger reagent, exclusively according to the VNS pathway; substitution of a fluorine atom by using these carbanions is not observed when the reaction is carried out at low temperature in the presence of an excess of base (Scheme 13).[22]

Scheme 15. Dichloromethylation of nitroarenes through VNS with trichloromethyl carbanion.

The VNS reaction is not limited to carbanions. Nitrogen anions containing a variety of nucleofugal groups, derivatives of hydrazine[25] and hydroxylamine,[26] react with nitroarenes according to a similar mechanistic scheme. The VNS amination of nitroarenes is an efficient method for the synthesis of orthoand para-nitroanilines (Scheme 16).

Scheme 13. VNS in the Sanger reagent with a-halocarbanions.

Scheme 16. Amination of nitroarenes through VNS with various aminating agents.

The reaction has wide scope with respect to nitroarenes, which can contain almost an unlimited variety of substituents. For a nitroarene to enter the VNS reaction, it is sufficient that one position, either ortho- or para- to the nitro group, is occupied by a hydrogen atom. The reaction also has wide scope with respect to the carbanions, provided that they contain, at the carbanion center, nucleofugal groups L that are able to be eliminated from the sH adducts as HL. Besides halogen atoms (Cl, Br), other substituents such as MeO, PhO, MeS, PhS, R2NCS2, and CF3SO2 can act as leaving groups L. Because the second step of the reaction is the bimolecular base-induced bChem. Eur. J. 2014, 20, 1 – 11

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The anions of tert-butyl and cumyl hydroperoxides are nucleophiles with the nucleofugal group at the nucleophilic center thus they react with nitroarenes via the formation of the sH adducts followed by base-induced b-elimination of alcohols to produce nitrophenols. This reaction, that is, the VNS hydroxylation, is a versatile tool for the synthesis of nitrophenols through direct nucleophilic substitution of a hydrogen atom by the hydroxy group (Scheme 17).[27] 5

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Concept

Scheme 17. Hydroxylation of 2,4-dinitrochlorobenzene through VNS with tert-butylhydroperoxide.

It should be stressed that the VNS reaction of ortho- and para-halonitrobenzenes with a-halocarbanions, as well as the corresponding amination and hydroxylation reactions, proceed faster than the classical substitution of halogen atoms. One can therefore formulate the following paradoxal statement: halogen atoms in nitroaromatic rings protect the positions they occupy against nucleophilic attack.

Scheme 19. Reactions of nitroarenes with the carbanion of ethyl isocyanoacetate.

2.4 Cine- and tele substitution of hydrogen atoms Besides the three major ways that result in the conversion of nucleophile–nitroarene sH adducts, as presented above, there are also some less general pathways, for example, cine and tele substitution.[28] Cine substitution is a process in which further conversion of the sH adducts proceeds through the departure of a nucleofugal group located on the nitroarene in the vicinity of the addition site. This process can be exemplified by the reaction of the carbanion of a-chloropropyl phenyl sulfone with 2,4-dichloronitrobenzene. The carbanion adds to this highly electrophilic arene at the position occupied by a hydrogen atom. Protonation of the initially formed sH adduct by a strong acid followed by elimination of nitrous acid gives the product of the cine substitution, whereas in the presence of an excess of base, VNS takes place, (Scheme 18).[29]

Scheme 20. Tele substitution involving 3-trichloromethylnitrobenzene with n-butylmagnesium chloride.

On the basis of many variants and examples of nucleophilic substitution of hydrogen atoms (SNArH) presented in this section, one can conclude that this is a general process of wide scope with respect to nucleophiles and nitroarenes. Thus, it is a process of exceptional value for organic synthesis, particularly when many variants of the reaction are taken into account.[32, 33] It is also evident that nucleophilic substitution of a hydrogen atom is the fast primary reaction between nucleophiles and nitroarenes, whereas conventional nucleophilic substitution of a halogen atom, the SNAr reaction, is just a slower secondary process.[5, 6] Unfortunately, in spite of numerous publications that present this situation in an unambiguous way,[5, 6, 20] the presentation of the reactions of nucleophiles with nitroarenes in modern textScheme 18. Cine substitution versus VNS in the reaction of a-chloropropyl phenyl sulfone with 2,4-dichloronitrobooks[4] and even in reviews[34] benzene. and original papers is limited to SNAr of halogens. Besides the great value of nucleophilic substitution of hydroSomewhat similar to the cine substitution reactions are reacgen atoms in nitroarenes for organic synthesis, these reactions tions between nitroarenes and carbanions of ethyl isocyanoaare also interesting tools for mechanistic studies. For instance, cetate and isocyanoacetonitrile. The initially formed sH adducts the effects of substituents on the electrophilic activities of niof such carbanions undergo further conversion to form isointroarenes, determined on the basis of rates of SNAr reactions,[1] doles or pyrimidine N-oxides (Scheme 19).[30] H On the other hand, when s adducts are converted by the are not reliable, because this reaction is a secondary process. departure of a nucleofugal group from a position remote in reSuch true effects were determined when VNS with a-halocarbspect to the addition site, the reaction is considered a tele subanions were used as a reliable toolbox.[35] stitution. This process can be exemplified by the reaction of Grignard reagents with 3-trichloromethylnitrobenzene (Scheme 20).[31] &

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Concept 3. Reactions proceeding through the addition of nucleophiles to the nitro group

Direct addition of nucleophiles to the nitrogen atom of the nitro group occurs in the reaction of nitroarenes with allylic Grignard reagents and gives N-aryl-N-allyl-hydroxylamines.[39] A similar reaction proceeds between nitroarenes and aryl Grignard reagents to give diarylamines as the ultimate products.[40] The reaction course of these processes is, however, more complicated because they proceed through initial singleelectron transfer SET.[41] Reactions that proceed through addition of nucleophiles to the oxygen atom of the nitro group are interesting and important. The reaction of vinyl Grignard reagents with nitroarenes that contain a substituent in the ortho position forms substituted indoles, a reaction that is known as the Bartoli indole synthesis (Scheme 23).[42] This multistep process proceeds also through initial SET and will be discussed later.

The nitro group exerts a strong electron-withdrawing effect on an aromatic ring, but it is also an electron-deficient entity in itself. The nitrogen atom connected with two oxygen atoms is positively charged and could behave as an electrophilic site. However, direct addition of nucleophiles to the nitrogen atom of the nitro group of nitroaromatics is not a common process because the two oxygen atoms hinder the approach of nucleophilic agents. These difficulties can be overcome when the nucleophilic center is located in a side chain of the nitroaromatic rings ortho to the nitro group. In such a situation, the eventual intramolecular addition of the nucleophile to the ring is possible only at a position meta to the nitro group; therefore it is disfavored, whereas addition to the nitrogen atom of the nitro group is favored for both electronic and steric reasons. These intramolecular reactions usually proceed in a manner that is similar to the aldol–Knoevenagel-type reactions, that is, addition followed by elimination of water and further reactions to produce heterocyclic systems of indoles and quinolines, for example. Early examples of such reactions were reviewed;[36] a more recent example is shown in Scheme 21.[37]

Scheme 23. Bartoli indole synthesis through the reaction of vinyl Grignard reagents with nitroarenes.

Also, the reactions of nitroarenes with trialkyl- or triarylphosphites belong to this category.[43] Thus, heating trialkylphosphites with nitroarenes results in a stepwise deoxygenation of the nitro group to give nitrosoarenes and, subsequently, arylnitrenes. The nitrenes can then undergo a variety of further transformations (Scheme 24).

Scheme 21. Synthesis of substituted quinoline N-oxides through a domino reaction of o-nitrobenzyl sulfones with dimethyl fumarate or maleate.

In spite of the difficulties mentioned above, there are few examples of the intermolecular addition of carbanions to the nitro groups of nitroarenes. The most interesting examples are the reactions of enolates of acetophenone with some nitroarenes that give arylaminochalcones.[38a] A similar reaction of cyclohexanone results in the formation of relatively unstable ohydroxydiarylamines, which were isolated in the form of the corresponding methyl ethers (Scheme 22).[38b]

Scheme 24. Deoxygenation of nitroarenes with trialkylphosphites leads to arylnitrenes.

It should be stressed that hydrogen atoms in nitroaromatic rings, particularly in positions that are ortho and para to the nitro group, exhibit enhanced acidity. Nucleophiles that are strong bases can therefore abstract protons from these positions to form the respective nitroarenic carbanions. Such a reaction course is documented by many observations, a particularly clear cut observation being an isotope-exchange reaction occurring through the action of strongly basic nucleophiles on nitroarenes. For instance, treatment of 4-chloro-2,6-dideuterionitrobenzene with tBuOK and tBuOH results in isotope exchange that proceeds much faster than the SNAr reaction involving a chlorine atom (Scheme 25).[44]

Scheme 22. Intermolecular addition of cyclohexanone enolate to the nitro group. Chem. Eur. J. 2014, 20, 1 – 11

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Concept sequently oxidized with a variety of external oxidants to give products of ONSH, oxidative nucleophilic alkylation of nitroarenes (Scheme 9).[16] Protonation of such sH adducts, or their treatment with Lewis acids, results in the formation of alkylated nitrosoarenes according to the intramolecular redox stoichiometry.[16a] The reactions of nitroarenes with allyl-, aryl-, and vinylmagnesium halides are more complex. The allyl- and aryl radicals generated in the initial SET add to the nitrogen atom of the nitroaromatic anion radical to give N-aryl-N-allyl hydroxylamines and diarylamines as the ultimate products.[41]

Scheme 25. Deprotonation of the nitroarene ring by a strongly basic nucleophile.

4. Electron-transfer processes Mobile p-electron systems of aromatic rings are able to accept an electron to form aromatic anion radicals. This SET process is the initial step in the Birch reduction of arenes[45] and in the nucleophilic substitution of halogen atoms in haloarenes that proceed according to the SNR1 mechanism.[46] Owing to the conjugation of the aromatic system with the strongly electron-withdrawing nitro group, nitroarenes are active electron acceptors. In fact, one of the most common and important processes, the reduction of a nitro group with metals to give anilines, proceeds through initial single-electron transfer. Under proper conditions, the anion radical of nitrobenzene shows a long lifetime that is sufficient to produce a clear-cut ESR spectrum.[47] Owing to the facile SET from carbanions and other nucleophiles to nitroarenes, this process is often considered as the initial step of nucleophilic aromatic substitution (SNAr). According to this hypothesis, the s adducts are formed not through direct nucleophilic addition but through initial SET, followed by coupling of the anion radical with the radical produced from the nucleophile.[48] The main evidence that supports this hypothesis is the formation of the anion radicals of nitroarenes when these compounds are exposed to nucleophiles, particularly carbanions, as detected by ESR spectroscopy. However, the ESR signal cannot be used as reliable evidence for the SET mechanism because of the very high sensitivity of this method. This hypothesis was sometimes abused, for example, in paper by Zhang and Yang,[49] the errors being highlighted by us in a subsequent publication.[50] To differentiate between the formation of s adducts through direct addition and a two-step SET pathway, much more reliable are tests in which so-called radical clocks are used, species that, upon conversion into radicals, undergo fast rearrangements. Using this approach, it was shown that addition of Grignard reagents to nitroarenes proceeds through the SET mechanism.[41] On the other hand, the formation of the carbanion–nitroarene sH adducts through a step in the VNS reaction does not involve SET, as was shown in experiments with a very fast radical clock.[51] It was shown by the research group of Bartoli that singleelectron transfer (SET) is the initial process in reactions of nitroarenes with Grignard reagents (Scheme 26). The subsequent fate of the initially formed anion radicals and radicals depends on the structure of the Grignard reagent and, as a consequence, the structure of the radicals formed through SET.[41] Primary alkyl radicals produced through SET between primary alkylmagnesium halides and nitroarenes add to the ring of nitroarene anion radicals at positions ortho and para to the nitro group, thus producing sH adducts. These adducts can be sub&

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Scheme 26. a) Initial step of the reaction of the Grignard reagents with nitroarenes. b) Subsequent formation of N-aryl-N-allyl hydroxylamines.

The reactions of nitroarenes with vinylmagnesium halides are even more complicated. The vinyl radicals produced in the initial SET process (Scheme 26 a) add initially to the oxygen atom of the anion radical, the adduct subsequently dissociating to form nitrosoarene and enolate of the aldehyde or the ketone derived from the Grignard reagent. Next, a second molecule of the vinyl Grignard reagent adds to the oxygen atom of the nitrosoarene and the adduct undergoes a [3,3]sigmatropic rearrangement followed by immediate cyclization to form an indole ring (Scheme 27).

Scheme 27. Mechanistic pathway of the Bartoli indole synthesis.

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Concept It should be stressed that the presented reaction course of the vinylmagnesium halides with nitroarenes to produce indoles proceeds only when there is a substituent at a position ortho to the nitro group; therefore, the method is limited to the synthesis of 7-substituted indoles. The variety of reaction between nitroarenes and nucleophiles discussed above give products that preserve aromaticity. Highly electron-deficient nitroarenes are able to react with azomethine ylides to form stable products of 1,3-cycloaddition (Scheme 28).[52]

The initial reaction of nitroarenes and nucleophiles involves fast addition at positions occupied by a hydrogen atom to form sH adducts. There are a few ways that effect fast conversion of sH adducts into products of nucleophilic substitution of a hydrogen atom (SNArH). The formation of sH adducts is a reversible process; thus, depending on the nature of the reactants and the reaction conditions, fast conversion of the sH adducts does not proceed; they dissociate and slower addition to positions occupied by nucleofugal groups X, for example, halogen atoms, results in the formation of sX adducts. Fast spontaneous departure of X from these adducts gives products of conventional nucleophilic substitution of a halogen atom (SNAr reaction). There is also a possibility that the initial process is a single electron transfer, SET to form nitroaromatic anion-radicals and radicals. These paramagnetic species can enter a variety of reactions - they can combine via addition of radicals to the ring giving sH or sX adducts that enter further transformations into products of substitution of hydrogen or SNAr reaction. The radicals can add to the nitrogen or oxygen of the nitro group of Scheme 28. 1,3-Dipolar cycloaddition of azomethine ylide to nitronaphtathe anion radicals as it is the case of the allyl, aryl and vinyl lene radicals. Further transformations of these adducts lead to N,Nallylarylhydroxylamines, diarylamines and indoles. When the produced radicals are stabilized they can combine, so dimerization of nucleophiles and reduction of nitroarenes is ob5. Conclusion served.[53] On the basis of the numerous variants of reactions between niThere are at least five initial processes involving the reaction troarenes and nucleophiles that were presented and exempliof nitroarenes with nucleophiles: addition in positions occufied in this paper, one can conclude that the majority of reacpied by a hydrogen atom to form sH adducts, addition in positions between nucleophiles and nitroarenes proceed through tions occupied by nucleofugal groups X to form sX adducts, addition to the ring: fast addition at positions occupied by addition to the nitrogen atom of the nitro group, addition to a hydrogen atom, thus forming sH adducts, and slower addioxygen atom, and single-electron transfer. All of these initial processes are followed by further steps to form final products. tion at positions occupied by nucleofugal groups X, thus formOf these five initial processes, the most interesting and proing sX adducts. These additions usually proceed as one-step ductive is the formation of sH adducts because it is the fastest processes; it is also possible that the addition proceeds through a two-step process initiated by SET. Thus, one can proprocess and there are several ways for converting these adpose a general picture of a variety of the reactions between ducts into a variety of products of nucleophilic substitution of nucleophiles and nitroarenes (Scheme 29). a hydrogen atom. Depending on the nature of the nucleophile and the reaction conditions, the system equilibrates, slower addition at positions occupied by a halogen atom occurs, followed by the rapid departure of the halogen anions, thus resulting in SNAr. Therefore, nucleophilic substitution of a hydrogen atom is a fast primary process, whereas the reaction involving conventional nucleophilic substitution of a halogen atom is a secondary ipso process. A convincing example that supports this reasoning is the reaction between carbanions of 2-phenoxy and 2-methoxyphenylacetonitrile and o-chloronitrobenzene. At low temperature, 65 8C, fast addition at the para position gives sH adducts that, upon action of oxidants, form products of ONSH; in the presence of an excess of base, VNS takes place, whereas the addition of a protic solvent results in intramolecular redox process to give nitrosoarenes that undergo further reaction with the carbanion. When the temperaScheme 29. General pathway of the initial reactions between nucleophiles and nitroarture of the mixture is increased in the absence of oxienes. Chem. Eur. J. 2014, 20, 1 – 11

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Concept [12] a) W. Adam, M. Ma˛kosza, K. Stalin´ski, C. G. Zhao, J. Org. Chem. 1998, 63, 4390 – 4391; b) W. Adam, M. Ma˛kosza, C.-G. Zhao, M. Surowiec, J. Org. Chem. 2000, 65, 1099 – 1101. [13] M. Ma˛kosza, M. Sypniewski, Tetrahedron 1994, 50, 4913 – 4920. [14] N. Moskalev, M. Barbasiewicz, M. Ma˛kosza, Tetrahedron 2004, 60, 347 – 358. [15] M. Ma˛kosza, M. Paszewski, D. Sulikowski, Synlett 2008, 2938 – 2940. [16] a) G. Bartoli, Acc. Chem. Res. 1984, 17, 109 – 115; b) M. Ma˛kosza, M. Surowiec, J. Organomet. Chem. 2001, 624, 167 – 171. [17] R. B. Davis, L. C. Pizzini, J. Org. Chem. 1960, 25, 1884 – 1886. [18] Z. Wrbel, A. Kwast, Synthesis 2010, 3865 – 3872. [19] a) Z. Wrbel, K. Stachowska, K. Grudzien´, A. Kwast, Synlett 2011, 1439 – 1443; b) A. Kwast, K. Stachowska, A. Trawczyn´ski, Z. Wrbel, Tetrahedron Lett. 2011, 52, 6484 – 6488. [20] M. Ma˛kosza, J. Winiarski, Acc. Chem. Res. 1987, 20, 282 – 289. [21] M. Ma˛kosza, J. Golin´ski, J. Baran, J. Org. Chem. 1984, 49, 1488 – 1494. [22] M. Ma˛kosza, J. Stalewski, Liebigs Ann. Chem. 1991, 605 – 606. [23] M. Ma˛kosza, A. Rydz, Z. Wrbel, Pol. J. Chem. 1995, 69, 918 – 921. [24] M. Ma˛kosza, Z. Owczarczyk, J. Org. Chem. 1989, 54, 5094 – 5100. [25] a) A. R. Katritzky, K. S. Laurenzo, J. Org. Chem. 1986, 51, 5039 – 5040; b) P. F. Pagoria, A. R. R. Mitchell, D. Schmidt, J. Org. Chem. 1996, 61, 2934 – 2935. [26] a) M. Ma˛kosza, M. Białecki, J. Org. Chem. 1998, 63, 4878 – 4888; b) S. Seko, K. Miyake, Chem. Commun. 1998, 1519 – 1520. [27] M. Ma˛kosza, K. Sienkiewicz, J. Org. Chem. 1998, 63, 4199 – 4208. [28] J. Suwin´ski, K. S´wierczek, Tetrahedron 2001, 57, 1639 – 1642. [29] S. Błaz˙ej, A. Kwast, M. Ma˛kosza, Tetrahedron Lett. 2004, 45, 5413 – 5421. [30] a) T. Murashima, K. Fujita, K. Ono, T. Ogawa, H. Uno, N. Ono, J. Chem. Soc. Perkin Trans. 1 1996, 1403 – 1407; b) T. W. Lash, M. L. Thompson, T. M. Werner, J. O. Spence, Synlett 2000, 213 – 216. [31] M. Ma˛kosza, G. Varvounis, M. Surowiec, T. Giannopoulo, Eur. J. Org. Chem. 2003, 3791 – 3797. [32] a) O. N. Chupakhin, V. N. Charushin, H. C. van der Plas Nucleophilic Aromatic Substitution of Hydrogen, Academic Press, San Diego, CA, 1994; b) V. N. Charushin, O. N. Chupakhin, Mendeleev Commun. Mendeleev Comm. 2007, 17, 249 – 254. [33] M. Ma˛kosza, K. Wojciechowski, Chem. Rev. 2004, 104, 2631 – 2666. [34] M. Schlosser, R. Ruzziconi, Synthesis 2010, 2111 – 2123. [35] S. Błaz˙ej, M. Ma˛kosza, Chem. Eur. J. 2008, 14, 11113 – 11122. [36] P. N. Preston, G. Tennant, Chem. Rev. 1972, 72, 627 – 677. [37] M. Ma˛kosza, A. Tyrała, Acta Chem. Scand. 1992, 46, 689 – 691. [38] a) N. Moskalev, M. Tartynova, Russ. Chem. Bull. 1998, 47, 1603 – 1604; b) M. Ma˛kosza, N. Moskalev, Chem. Commun. 2001, 1248 – 1249. [39] L. Barboni, G. Bartoli, E. Marcantoni, M. Petrini, J. Chem. Soc. Perkin Trans. 1 1990, 2133 – 2138. [40] I. Sapountzis, P. Knochel, Synlett 2004, 955 – 958. [41] R. Dalpozzo, G. Bartoli, Curr. Org. Chem. 2005, 9, 163 – 178. [42] G. Bartoli, G. Palmieri, M. Bosco, R. Dalpozzo, Tetrahedron Lett. 1989, 30, 2129 – 2132. [43] Organophosphorous Reagents in Organic Synthesis (Ed.: J. I. Cadogan), Academic Press, 1979, Chapter 6. [44] T. Lemek, M. Ma˛kosza, J. Golin´ski, Tetrahedron 2001, 57, 4753 – 4757. [45] A. J. Birch, Pure Appl. Chem. 1996, 68, 553 – 556. [46] J. F. Bunnett, Acc. Chem. Res. 1978, 11, 413 – 420. [47] G. A. Russell, E. G. Janzen, E. T. Strom, J. Am. Chem. Soc. 1964, 86, 1807 – 1814. [48] I. I. Bilkis, S. M. Shein, Tetrahedron 1975, 31, 969 – 971. [49] X. Zhang, D. Yang, J. Org. Chem. 1993, 58, 224 – 227. [50] M. Ma˛kosza, R. Podraza, A. Kwast, J. Org. Chem. 1994, 59, 6796 – 6799. [51] M. Ma˛kosza, A. Kwast, Eur. J. Org. Chem. 2004, 2125 – 2530. [52] S. Lee, S. Diab, P. Queral, M. Sebban, I. Chataigner, S. R. Piettre, Chem. Eur. J. 2013, 19, 7181 – 7192. [53] M. Ma˛kosza, M. Jagusztyn-Grochowska, M. Ludwikow, M. Jawdosiuk, Tetrahedron 1974, 30, 3723 – 3735. [54] M. Ma˛kosza, D. Sulikowski, Eur. J. Org. Chem. 2011, 6887 – 6892.

Scheme 30. Five reactions of the carbanion of a-alkoxyphenyl-acetonitrile with 2-chloronitrobenzene.

dants and base, the system equilibrates and a slower addition at the position occupied by a chlorine atom results in SNAr (Scheme 30).[54] The author hopes that this short presentation and discussion of reactions between nitroarenes and nucleophiles will result in the necessary corrections to chapters of textbooks covering aromatic nucleophilic substitution. I also hope that the presentation of the many variants and examples of reactions between nitroarenes and nucleophiles, particularly reactions involving nucleophilic substitution of a hydrogen atom (SNArH) will stimulate interest in this fascinating field of organic chemistry and promote the discovery of new reactions.

Acknowledgement The author is deeply indebted to Prof. Krzysztof Wojciechowski for valuable discussion. Keywords: carbanions · nitroarenes · oxidation · singleelectron transfer · vicarious nucleophilic substitution [1] J. Miller, Aromatic Nucleophilic Substitution, Elsevier, Amsterdam, 1968. [2] F. Terrier, Modern Nucleophilic Aromatic Substitution, Wiley-VCH, Weinheim, 2013. [3] J. F. Bunnett, R. E. Zahler, Chem. Rev. 1951, 49, 273 – 412. [4] a) J. Clayden, N. Greeves, S. Warren, P. Wothers, Organic Chemistry, Oxford University Press, New York, 2001; b) E. V. Anslyn, D. A. Dougherty, Modern Physical Organic Chemistry, University Science Books, Sausalito, 2006; c) M. G. Moloney, Structure and Reactivity in Organic Chemistry, Blackwell, Oxford, 2008. [5] M. Ma˛kosza, Synthesis 2011, 2341 – 2356. [6] M. Ma˛kosza, Chem. Soc. Rev. 2010, 39, 2855 – 2868. [7] E. V. Malykhin, G. A. Kolesnichenko, V. D. Shteingarts, Zh. Org. Khim. 1985, 21, 1150 – 1159. [8] a) B. Szpakiewicz, M. Grzegozek, Russ. J. Org. Chem. 2004, 40, 829 – 833; b) H. C. van der Plas, M. Woz´niak, Croat. Chem. Acta 1986, 58, 33 – 49; c) M. Woz´niak, A. Baran´ski, B. Szpakiewicz, Liebigs Ann. Chem. 1991, 875 – 878. [9] M. Ma˛kosza, K. Stalin´ski, Chem. Eur. J. 1997, 3, 2025 – 2031. [10] M. Ma˛kosza, D. Sulikowski, J. Org. Chem. 2009, 74, 3827. [11] M. Ma˛kosza, K. Stalin´ski, Tetrahedron Lett. 1998, 39, 3575 – 3576.

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Chem. Eur. J. 2014, 20, 1 – 11

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Received: January 9, 2014 Published online on && &&, 0000

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Concept

CONCEPT & Nitroarenes M. Ma˛kosza* && – && Reactions of Nucleophiles with Nitroarenes: Multifacial and Versatile Electrophiles The electrophile with many faces: Nucleophiles can react with nitroarenes in many ways: they can add to the ring in positions occupied by hydrogen or halogen atoms to form sH and sX adducts; they can add to the nitrogen or oxygen atoms of the nitro group; they can

react through single-electron transfer (see figure). These initial processes are followed by a plethora of further transformations, thus making the reaction of nitroarenes with nucleophiles a rich and versatile toolbox in organic synthesis.

Nucleophiles and Nitroarenes In his Concept article on page && ff., M. Ma˛kosza gives an overview of the rich chemical reactivity involving nitroarenes and nucleophiles. Nucleophiles can initially combine with nitroarenes through ipso attack at sp2 carbon positions bearing hydrogen or halogen atoms, through direct attack at the nitro group, or through single-electron transfer. The resulting adducts can then undergo a variety of further transformations to give a variety of useful products.

Chem. Eur. J. 2014, 20, 1 – 11

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These are not the final page numbers! ÞÞ

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