Recent developments in intermolecular radical arylations of arenes and heteroarenes

Accepted Manuscript Recent developments in intermolecular radical arylations of arenes and heteroarenes Josefa Hofmann, Markus R. Heinrich PII: DOI: Reference:

S0040-4039(16)31033-4 http://dx.doi.org/10.1016/j.tetlet.2016.08.034 TETL 48005

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Tetrahedron Letters

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9 July 2016 10 August 2016

Please cite this article as: Hofmann, J., Heinrich, M.R., Recent developments in intermolecular radical arylations of arenes and heteroarenes, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.08.034

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Recent developments in intermolecular radical arylations of arenes and heteroarenes Josefa Hofmann, Markus R. Heinrich

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Tetrahedron Letters

Recent developments in intermolecular radical arylations of arenes and heteroarenes Josefa Hofmann and Markus R. Heinrich a

Department of Chemistry and Pharmacy, Pharmaceutical Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany

A RT I C L E I N F O

A BS T RA C T

Article history: Received Received in revised form Accepted Available online

This short review gives an overview over recent developments in the field of intermolecular radical arylations of arenes and heteroarenes. Transformations of this type are formally comparable to C-H activation reactions and more simple starting materials can thus be used than in most organometallic cross-coupling procedures. 2009 Elsevier Ltd. All rights reserved .

Keywords: Radical reactions Biaryls Diazonium salts Arylhydrazines Arylation

———  Corresponding author. Tel.: +49-9131-85-24115; fax: +49-9131-85-22585; e-mail: [email protected]

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Tetrahedron 1. Introduction

Intermolecular radical aryl-aryl coupling reactions1 can represent valuable alternatives to transition-metal catalyzed transformations2 since they usually require much less elaborate starting materials. Being formally comparable to aromatic C-H activation reactions,3 the radical access to biaryl compounds dates back to the Gomberg-Bachmann reaction, which was first published in 1924.4 Since then, several new sources A for aryl radicals B have been studied in addition to the classical aryldiazonium salts, and a broad variety of conditions and radical acceptors C have been explored (Scheme 1).1 Most functionalizations of substituted benzenes however remain challenging due the relatively slow aryl radical addition to such substrates5 as well as due to an often insufficient regioselectivity in the crucial step leading to adduct D.6 Radical arylations of heteroarenes, in contrast, can frequently be achieved with good regioselectivity, but rearomatization of the radical intermediate D to the desired biaryl E is not always guaranteed.1e Depending on the reductive potential of the adduct D and the nature of the aryl radical source A, rearomatization to biaryl E may occur along with the generation of a new aryl radical B from A, so that the overall reaction proceeds as a radical chain and only small amounts of an initiator are required.7 In the case that the reductive potential of D is not sufficient for the formation of a new radical B, the cycle may be closed through a photoredox catalyst.8 As demonstrated by newly developed base-promoted arylations, the reductive potential of D may as well be enhanced through deprotonation, which transforms D into a strongly reducing radical anion intermediate.9

Arylation reactions with aryldiazonium salts 11 need to be conducted with stoichiometric amounts of a reductant if the reductive potential created in the rearomatization step (Scheme 1, D → E) is not sufficient to initiate the generation of a new aryl radical B from source A. A reductant, which has been found particularly useful for arylations of phenols under strongly acidic conditions is titanium(III)-chloride. By using water as single or main solvent, undesired hydrogen atom transfer from the phenolic hydroxy group to the aryl radical can be effectively suppressed.12 Arylations of phenols are of synthetic value since the corresponding biphenyls are formed with good regioselectivity for the ortho position, especially when the para position is blocked by a substituent.13 This strategy could be applied in different fields of medicinal chemistry including the straight-forward preparation neurotensin14 and US28 receptor ligands.15 An example for a titanium(III)-mediated arylation, in which an usual substitution pattern on the diazonium ion was used, is shown in Scheme 2.16 Diazonium ions bearing a hydroxy group in ortho- or para-position17 had so far mainly be applied as precursors or quinone diazides and later on carbenes.18 The fact that the reaction converting 1 and pyridine 2 to biaryl 3 has to be conducted with an excess of titanium(III)-chloride can be rationalized by the electron-poor nature of the heterocyclic system 2. Aryl radical addition to 2 leads to an as well electronpoor radical adduct of type D (Scheme 1) which is unable to propagate a possible chain through reduction of 1.

Scheme 2. Arylation of ethyl pyridine-4-carboxylate (2) with ortho- and para-hydroxyphenyldiazonium ions.

Scheme 1. General pathway for radical arylation reactions of arenes and heteroarenes.

In this short review, an overview over recent developments in the field of intermolecular radical aryl-aryl coupling reactions is given. The single sections are structured according to the aryl sources which have been used. As it is the main focus to demonstrate the synthetic scope of application, mechanistic details will only briefly be discussed with each reaction. For more information on related intramolecular transformations,1 as well as on radical-organometallic hybrid reactions,10 the reader is referred to a number of recent review articles and book chapters. An excellent review on transition metal-mediated direct C-H arylation of heteroarenes involving aryl radicals has been given by Bonin and Felpin.1e 2. Recent developments 2.1 Arylations with aryldiazonium salts and related derivatives

The synthesis of biaryls via a radical chain reaction including diazonium ions can be achieved in two ways. In one case, strongly electron-deficient diazonium ions are applied, which are sufficiently effective oxidants to allow chain propagation through oxidation of the cyclohexadienyl adduct D (Scheme 1). 19 Illustrative examples are arylations of benzene with 2,4-dinitrophenyldiazonium ions described by Kochi.20 Due to the underlying chain mechanism, such reactions only require catalytic amounts of iodide as initiator. Alternatively, strongly donor-substituted aryl radical acceptors can enable chain reactions. In combination with phenylene-1,4-diamine (5), the diazonium ions 4 do not have to be particularly activated by acceptor substitution to give biphenyls 6 (Scheme 3),21 as the corresponding adduct D is now far more more easily oxidized (Scheme 1).

Scheme 3. Arylation of phenylene-1,4-diamine (5) with aryldiazonium ions.

The principle of using donor-subsituted aryl radical acceptors to allow chain reactions with aryldiazonium salts also holds true for electron-rich heterocycles. First examples on the arylation of furans, which could be conducted with catalytic amounts of titanium(III)-chloride as initiator, have been described by Wetzel.12 An extension to other 5-membered heterocycles, now including furans, thiophene and pyrrols 8, was achieved by

3 König (Scheme 4).22 A broad range of biaryls 10 was accessible from a variety of diazonium salts 7.

Scheme 4. Eosin-photocatalyzed arylations of furans, thiophene and pyrrols.

In these reactions, eosin (9) acts as photocatalyst to initiate and possibly also to support the propagation of the radical chain, thus increasing the substrate scope. Further photocatalyzed radical arylation reactions with diazonium salts and furans, in which titanium dioxide is used as photocatalyst, have been devised by Rueping.23 Photocatalyzed arylations of pyridines 12, as they have been developed by Xiao,24 strongly depend on the participation of the ruthenium catalyst in the chain propagation step. Adduct D (Scheme 1) resulting from the aryl radical addition to pyridine 12 would otherwise be unable to generate a new aryl radical from diazonium salt 11 along with its own rearomatization to biaryl 13.

are known as intermediates of the classical GombergBachmann reaction,6a,26 do not represent sufficiently protected diazonium salts for reactions with anilines. Diazonium derivatives, which are also strongly protected against ionic side reactions, are diazosulfides. Such reagents have been successfully applied in photoinduced arylations of phenolates under strongly basic conditions without significant occurrence of azo coupling products.27 Several synthetic methods leading to biaryls have recently appeared, in which the required diazonium ions were formed in situ from their corresponding anilines. An example is depicted in Scheme 7.28 After diazotization of 17 with tert-butyl nitrite, generation of aryl radicals is achieved through catalytic amounts of ascorbic acid. Furan (18) is one of the prefered radical acceptors for this transformation, as the arylation process can then more easily proceed as radical chain. The assumption of an underlying chain mechanism is further supported by the fact that acceptor-substituted anilines 17 give better yields, as their corresponding diazonium ions are better suited for the oxidation of adduct radical (c.f. D, Scheme 1) to the biaryls 19. In addition, this valuable transformation could be extended to benzene and a variety of other heterocycles.

Scheme 7. Arylation of furans with in situ-generated diazonium ions.

Scheme 5. Ruthenium-photocatalyzed arylation of pyridines.

Arylations of electron-rich aromatic systems, such as anilines, can usually not be conducted with free diazonium ions, since azo coupling would then occur as predominant side-reaction. Notable exceptions are the reactions of phenylene-1,4-diamine (5) (Scheme 3), in which the diazonium ions are quickly enough reduced to avoid this side-process. In combination with common anilines, the diazonium ions have to be present in the reaction mixture in a protected form that is however still capable of generating aryl radicals. Recent studies under strongly basic conditions have shown that suitable protection against ionic reactions can be achieved via the formation of aryldiazotates 14 (Scheme 6).25 At elevated temperatures, the diazotates are converted to aryl radicals, which then provide 2-aminophenyls 16 from anilines 15 in highly regioselective aromatic substitutions.

Earlier examples for radical reactions with in situ generated diazonium ions have been published by Doyle29 in relation with Meerwein arylations. Starting from various anilines, the general principle could recently be applied to copper-catalyzed arylations of N-Boc-pyrrole (21) (Scheme 8). 30 Similar to the reactions promoted by ascorbic acid (Scheme 7), these transformations depend on the presence of electron-withdrawing or at least electron-neutral substituents on the aniline 20 to give biaryls 22 in good to high yields.

Scheme 8. Arylation of N-Boc-pyrrol (21) with in situ-generated diazonium ions.

An extension of the in situ diazotization strategy to the arylation of quinones with anilines has also been reported.31 Besides diazonium salts, the generation of aryl radicals is possible from a number of derivatives which can be classified as protected or masked diazonium ions. Such compounds offer the additional option to modify the aromatic core before entering the radical reactions, which is generally troublesome with free diazonium ions. Well-known examples for protected diazonium ions are triazenes.32 A recently published synthetic pathway exploiting the protective character of the triazene formation is shown in Scheme 9.33

Scheme 6. Arylation of anilines with aryldiazotates as protected diazonium ions.

Diazoanhydrides (Ar-N=N-O-N=N-Ar), as they are formed from aryldiazonium ions under weakly basic conditions, and as they

4

Tetrahedron

Scheme 9. Triazenes as protected diazonium ions.

Diazotization of 2-fluoroaniline (23) and conversion to the triazene was followed by alkylation of the aromatic core with methyl 2,3,3-trifluoroacrylate (24). Liberation of the diazonium ion from 25 under acidic conditions was combined with a thermally induced radical reaction leading to biphenyl 26.11 Benzotriazoles can be considered as cyclic triazenes, and upon irradiation, such compounds may be used as precursors for aryl radicals as well (Scheme 10).34 Exposure of benzotriazole (27) to UV light at first triggered the formation of the diradical 28, which was converted to 29 under loss of nitrogen. Addition of 29 to benzene (30) and rearomatization of 31 under hydrogen atom transfer provided 2-aminobiphenyl (32) in quantitative yield.

Scheme 11. Preparation of a 18-fluorine-labeled norepinephrine transporter ligand 37.

2.2 Arylations with arylhydrazines A particular difficulty in radical arylations with diazonium ions is their high reactivity towards a broad range of nucleophiles. To circumvent this problem, and as an alternative to the use of protected diazonium derivatives, aryl radicals may be generated through the oxidation of phenylhydrazines.40,41 This strategy was recently found to be especially well suited for the arylation of anilines.42 To exploit the highly directing effect of the amino group and to achieve regioselectivity in the arylation, basic conditions are required (c.f. Scheme 6). In the presence of sodium hydroxide and at slightly elevated temperatures, the desired arylation of 39 with arylhydrazines 38 can be performed in a metal-free transformation with oxygen from air as the only oxidant to give 2-aminobiphenyls 40 (Scheme 12).43

Scheme 10. Radical arylation using benzotriazole as aryl radical source.

In a strict sense, phenylazocarboxylic esters (PhN=NCOOR) do not belong to the group of protected diazonium ions, as acidic or thermally induced decarboxylative removal of the ester group leads to a phenyldiazene.35 Phenyldiazenes are however useful precursors for aryl radicals,36,37 and similar to the reactions of triazenes, the azocarboxylic ester units allows modifications on the aromatic core prior to generation of aryl radicals.35,38 Due to the strongly electron-withdrawing character of the azo ester moiety, such transformations are preferably nucleophilic aromatic substitutions. A particularly useful application is the introduction of [18F]fluoride, which can be achieved from trimethylammonium salt 33 in short reaction times and high yields.39 Due to the significant difference in polarity between reactant 33 and product 34, the radiofluorinated compound 34 can be readily separated from the large excess of its unlabeled precursor 33. With regard to a subsequent radical reaction, it was found to be beneficial to convert the ester 34 first to the carboxylate 35. Under acidic conditions, radical arylation of 36 finally gave the norepinephrine transporter ligand 37, which was prepared for a further use in studies by positron emission tomography (PET).

Scheme 12. Regioselective arylation of anilines with arylhydrazines and oxygen from air.

Closely related metal-free44 and cobalt-porphyrin-catalyzed 45 arylations of anilines with arylhydrazines were afterwards published by Zou. Silver(I)- and manganese(III)-mediated arylations of furan, thiophenes and pyridines with arylhydrazines have been reported by Thomson46 and Demir,47 respectively. 2.3 Arylations with chloro, bromo and iodoarenes Turning away from nitrogen as a leaving group during radical generation, a broad access to aryl radicals is generally provided by aryl chlorides, bromides and iodides. The required transfer of the halogen atom is commonly achieved with stannyl or silyl radicals,48 whereby only the latter are suitable for reactions with aryl chlorides.49 Most examples reported for tin hydride-mediated aryl-aryl coupling reactions are intramolecular Pschorr-type cyclizations,1d including a number of ipso substitutions.50 Tris(trimethylsilyl)silane,49 which can be seen as a modern replacement for the otherwise widely used tributylstannane,51 has recently been applied as reductant in radical cyclizations (Scheme 13).52 Importantly, reactions such as the conversion of aryl iodide 41 into the tricyclic system 42 showed the beneficial effect of oxygen on the rearomatization step (D->E, Scheme 1).

5

Scheme 13. Tris(trimethylsilyl)silane-mediated cyclization under air.

Alternatively, base-mediated arylations can be achieved under irradiation (Scheme 16).67 In this case, the formation of the biphenyls 51 from aryl iodides, bromides or chlorides 49 and benzene (50) does not require elevated temperatures. Furthermore, no dependence on the substitution pattern of the aryl halide can be observed, which makes this method broadly applicable.

A beautiful application of a tris(trimethylsilyl)silane-mediated radical arylation in the synthesis of the natural product cavicularin has been reported by Harrowven. 53 Improved conditions, under which aryl radicals can be generated from aryl bromides or aryl iodides involve strong bases such as alcoholates and a transition metal catalyst. In this way, the arylation of pyridines was achieved by Hua54 and Yamakawa55 under gold catalysis or nickel catalysis, respectively. The use of a cobalt complex allowed the arylation of furans and thiophenes with aryl iodides, as reported by Chan.56 As an even more attractive alternative for biaryl synthesis from aryl halides, base-promoted homolytic aromatic substitutions (BHAS) have recently evolved and gained great interest. Pioneering work in this field has been reported by Itami,57 who developed a base-mediated access to biaryls 45 from heterocycles such pyrazine (44) and aryl iodides and bromides 43 (Scheme 14).

Scheme 14. Base-mediated arylation of pyrazine (44) with aryl bromides and iodides.

Further examples for this reaction type, in which additives such as phenanthrolines or ethylenediamines were added to the alkoxide, have later been devised by Shi,58 Hayashi59 and Lei.60 More recently, intramolecular versions of the base-mediated arylation were applied to the synthesis of phenanthridines 61 and polycyclic alkaloids.62 Moreover, the range of additives or ligands, which were found useful for this type of transformation, was extended to N-heterocyclic carbenes63 and a macrocyclic pyridone pentamer.64 The use of amido-functionalized imidazolium salts further allowed the preparation of biphenyls from aryl chlorides.65 From a mechanistic point of view, the role of the strong alkoxide base is to deprotonate the cyclohexadienyl radical intermediate D (Scheme 1). In this way, a highly reducing radical anion is generated, which can close the mechanistic cycle through reductive cleavage of the aryl-halogen bond of the starting material.9 In an improved version of the base-mediated radical aryl-aryl coupling, phenylhydrazine was used as initiator (Scheme 15).66 Through this modification, the desired biphenyls 48 were obtained from a variety of aryl halides 46 and benzenes 47 in the absence of a ligand and under milder conditions.

Scheme 15. Base-mediated radical aryl-aryl coupling using phenylhydrazine as initiator.

Scheme 16. Photoinduced, base-mediated radical aryl-aryl coupling.

An iridium-catalyzed version of the photoinduced and basemediated coupling of aryl halides with benzenes was developed by Li.68 Earlier work by Moorthy17 had shown that Pschorr-type, intramolecular radical aryl-aryl coupling reactions with aryl bromides can also be conducted under irradiation, but do not require the presence of a base. 2.4 Arylations with arylboronic acids Aryl boronic acids, which are well-known starting materials for Suzuki-type cross-coupling reactions, can also serve as sources for aryl radicals under oxidative conditions and are thus useful reactants for radical biaryl syntheses. Early examples in this field were published by Demir69 and Saraf70 who achieved aryl radical generation from boronic acids through stoichiometric amounts of the strong oxidants manganese(III) acetate or potassium permanganate. An improved catalytic version was recently developed by Hayashi.71 In the presence of di-tert-butyl peroxide and catalytic amounts of an iron-phenanthroline catalyst, a variety of biphenyls 54 could be obtained from aryl boronic acids 52 and benzenes 53.

Scheme 17. Iron-catalyzed radical aryl-aryl coupling with phenylboronic acids.

Radical arylations of various heteroarenes with aryl boronic acids were achieved with stoichiometric amounts of the oxidant potassium persulfate in the presence of silver72 or iron catalysts.73,74 2.5 Arylations with diphenyliodonium salts Similar to arylboronic acids, diphenyliodonium salts are established reactants for a broad range of transition metalcatalyzed arylation reactions,75 but only comparably few reactions are yet known in which they act as sources for aryl radicals. As an example, the photocatalyzed functionalization of N-methylpyrrole (56) is depicted in Scheme 18.76 In the reaction course, the photoactivated ruthenium catalyst first takes the role of a reductant to generate aryl radicals from iodonium salts 55. After aryl radical addition to the pyrrole 56, the original oxidation state of the catalyst is regained in the rearomatization step leading to biaryl 57. Under the conditions reported,

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Tetrahedron

diphenyliodonium salts can also be used for the arylation of various other heterocycles as well as for the functionalization of benzenes.

3.

4. Scheme 18. Photoredox-catalyzed arylation of N-methylpyrrole (56) with diphenyliodonium salts.

A comparable transformation can be performed in the presence of the strong base sodium hydroxide at elevated temperatures (Scheme 19).77 With pyrrole (59) as radical acceptor and diphenyliodonium salts 58 as aryl radical sources, the biaryls 60 were obtained in good to high yields. Similar to the reaction shown in Scheme 18, the strongly basic conditions are also applicable to the arylation of other heterocycles and substituted benzenes.

5. 6.

7. 8.

9. 10. 11. 12.

13. 14. Scheme 19. Base-initiated arylation of pyrrole (59) with diphenyliodonium salts.

In summary, this short review shows that intermolecular radical arylation reactions of arenes and heteroarenes have become very popular in recent years with many new developments and improvements, especially regarding substrate scope, regioselectivity and reaction conditions. Many transformations, which formerly required stoichiometric amounts of oxidants or reductants can now be conducted catalytically or even as metalfree processes. Based on the broad advances in this field, it will be interesting to follow how this valuable group of carbon-carbon forming reaction will expand further in the future.

15. 16. 17.

18.

Acknowledgments The authors would like to thank the Deutsche Forschungsgemeinschaft (DFG) for financial support in the related projects HE5413/3-3 and GRK1910/B3. The support of J. H. by the Graduate School of Molecular Science (GSMS) is gratefully acknowledged.

19. 20. 21. 22.

References and notes 1.

2.

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8

Tetrahedron

Highlights: This short review summarizes recent developments in the field of intermolecular radical arylation of arenes and heteroarenes. The article covers different radical sources (aryldiazonium, arylhydrazines, aryl halides, arylboronic acids and diaryliodonium salts) and radical acceptors (arenes and heteroarenes). Moreover, underlying mechanisms and improvements of the reaction conditions are discussed.