Diarylation of N- and O-nucleophiles through a metal-free cascade reaction

Abstract

•Novel SNAr reactivity discovered with ortho-fluorinated diaryliodonium salts•Efficient diarylation of water, ammonia, primary amines, and anilines•Convenient and simple route to triarylamines with three different aryl groups•The products are easily derivatized through the retained iodide substituent Diaryl ethers, diarylamines, and triarylamines are key structural motives in natural products, pharmaceuticals, and material chemistry. Nevertheless, the production of highly functionalized derivatives of these substance classes often requires time-consuming and expensive multi-step syntheses, as methods for simultaneous introduction of two structurally different aryl groups are lacking. In this study, we present an atom-efficient and metal-free difunctionalization of N- and O-nucleophiles with two different aryl groups in one step. We anticipate this methodology to be a competitive and sustainable alternative to established arylation methods due to the broad scope, high functional group tolerance, and excellent yields. The simple reaction setup and avoidance of toxic, sensitive, or expensive reagents/catalysts grant utility outside of advanced organic chemistry laboratories. Importantly, the novel mechanism is expected to enable new opportunities in hypervalent chemistry. The arylation of heteroatom nucleophiles is a central strategy to reach diarylated compounds that are key building blocks in agrochemicals, materials, and pharmaceuticals. Nucleophilic aromatic substitution is a classical tool for such arylations, and recent developments in hypervalent iodine-mediated arylations allow a wider scope of products. Herein, we combine the benefits of these strategies to enable an efficient and transition-metal-free difunctionalization of N- and O-nucleophiles with two structurally different aryl groups and to provide di- and triarylamines and diaryl ethers in one single step (>100 examples). The core of this strategy is the unique reactivity discovered with specifically designed fluorinated diaryliodonium salts, which unveils novel reaction pathways in hypervalent iodine chemistry. The methodology is suitable for diarylation of aliphatic amines, anilines, ammonia, and even water. It tolerates a wide variety of functional and protecting groups, with the retained iodine substituent easily accessible for derivatization of the products. The arylation of heteroatom nucleophiles is a central strategy to reach diarylated compounds that are key building blocks in agrochemicals, materials, and pharmaceuticals. Nucleophilic aromatic substitution is a classical tool for such arylations, and recent developments in hypervalent iodine-mediated arylations allow a wider scope of products. Herein, we combine the benefits of these strategies to enable an efficient and transition-metal-free difunctionalization of N- and O-nucleophiles with two structurally different aryl groups and to provide di- and triarylamines and diaryl ethers in one single step (>100 examples). The core of this strategy is the unique reactivity discovered with specifically designed fluorinated diaryliodonium salts, which unveils novel reaction pathways in hypervalent iodine chemistry. The methodology is suitable for diarylation of aliphatic amines, anilines, ammonia, and even water. It tolerates a wide variety of functional and protecting groups, with the retained iodine substituent easily accessible for derivatization of the products. N- and O-arylated structural motifs are key building blocks in agrochemicals, materials, and pharmaceuticals.1Ruiz-Castillo P. Buchwald S.L. Applications of palladium-catalyzed C-N cross-coupling reactions.Chem. Rev. 2016; 116: 12564-12649https://doi.org/10.1021/acs.chemrev.6b00512Google Scholar, 2Chen T. Xiong H. Yang J.F. Zhu X.L. Qu R.Y. Yang G.F. Diaryl ether: a privileged scaffold for drug and agrochemical discovery.J. Agric. Food Chem. 2020; 68: 9839-9877https://doi.org/10.1021/acs.jafc.0c03369Google Scholar, 3Wang J. Liu K. Ma L. Zhan X. Triarylamine: versatile platform for organic, dye-sensitized, and perovskite solar cells.Chem. Rev. 2016; 116: 14675-14725https://doi.org/10.1021/acs.chemrev.6b00432Google Scholar The arylation of heteroatom nucleophiles with an electrophilic arylation reagent is a central strategy to reach diarylated compound classes, such as diaryl ethers and diarylamines. Despite considerable progress in method development, the synthesis of highly functionalized di- or tri-arylated products is frequently a challenging endeavor, and methods for simultaneous introduction of two structurally different aryl groups are lacking. Monoarylation of heteroatom nucleophiles can be achieved through the industrially important nucleophilic aromatic substitution (SNAr) methodology, although the scope is limited by the requirement for either highly reactive reagents with strong electron-withdrawing groups (EWG) or harsh reaction conditions with strong bases or elevated temperatures (Scheme 1A).4Brown D.G. Boström J. Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone?.J. Med. Chem. 2016; 59: 4443-4458https://doi.org/10.1021/acs.jmedchem.5b01409Google Scholar Transition metal-catalyzed arylations using established Buchwald-Hartwig,5Forero-Cortés P.A. Haydl A.M. 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Chem. 2017; 82: 11933-11938https://doi.org/10.1021/acs.joc.7b01778Google Scholar, 19Sandtorv A.H. Stuart D.R. Metal-free synthesis of aryl amines: beyond nucleophilic aromatic substitution.Angew. Chem. Int. Ed. 2016; 55: 15812-15815https://doi.org/10.1002/anie.201610086Google Scholar, 20Purkait N. Kervefors G. Linde E. Olofsson B. Regiospecific N-arylation of aliphatic amines under mild and metal-free reaction conditions.Angew. Chem. Int. Ed. 2018; 57: 11427-11431https://doi.org/10.1002/anie.201807001Google Scholar Although reactions with diaryliodonium salts often proceed under mild conditions without excess reagents, they suffer from the fundamental drawback of poor atom economy due to the stoichiometric formation of iodoarene byproduct (Scheme 1B). Although this disadvantage can be overcome in reactions with cyclic diaryliodonium salts or intramolecular aryl migrations in iodonium ylides or iodonium salts,21Malamidou-Xenikaki E. Spyroudis S. Zwitterionic iodonium compounds: useful tools in organic synthesis.Synlett. 2008; 2008: 2725-2740https://doi.org/10.1055/s-2008-1078261Google Scholar, 22Chen H. Han J. Wang L. Intramolecular aryl migration of diaryliodonium salts: access to ortho-iodo diaryl ethers.Angew. Chem. Int. Ed. 2018; 57: 12313-12317https://doi.org/10.1002/anie.201806405Google Scholar, 23Chen H. Wang L. Han J. Deacetylative aryl migration of diaryliodonium salts with C(sp2)–N bond formation toward ortho-iodo N-aryl sulfonamides.Org. Lett. 2020; 22: 3581-3585https://doi.org/10.1021/acs.orglett.0c01024Google Scholar limited structural diversity can be achieved in this fashion. Diarylation of heteroatom nucleophiles can be accomplished in several steps via the methods described earlier, often requiring different catalytic systems for each arylation. Alternatively, a metal-catalyzed Ar2IX arylation can be combined with a cross-coupling of the resulting iodoarene.24Wang M. Chen S. Jiang X. Atom-economical applications of diaryliodonium salts.Chem. Asian J. 2018; 13: 2195-2207https://doi.org/10.1002/asia.201800609Google Scholar,25Boelke A. Finkbeiner P. Nachtsheim B.J. Atom-economical group-transfer reactions with hypervalent iodine compounds.Beilstein J. Org. Chem. 2018; 14: 1263-1280https://doi.org/10.3762/bjoc.14.108Google Scholar This strategy is established with cyclic diaryliodonium salts, where the second arylation occurs intramolecularly.24Wang M. Chen S. Jiang X. Atom-economical applications of diaryliodonium salts.Chem. Asian J. 2018; 13: 2195-2207https://doi.org/10.1002/asia.201800609Google Scholar, 25Boelke A. Finkbeiner P. Nachtsheim B.J. Atom-economical group-transfer reactions with hypervalent iodine compounds.Beilstein J. Org. Chem. 2018; 14: 1263-1280https://doi.org/10.3762/bjoc.14.108Google Scholar, 26Zhu D. Liu Q. Luo B. Chen M. Pi R. Huang P. Wen S. 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We envisioned that a combination of the atom-efficient SNAr methodology with the broad scope and mild conditions of Ar2IX arylations would overcome the limitations of current diarylation methodologies and avoid the intrinsic formation of iodoarene waste. Hence, we designed a novel diaryliodonium reagent, carrying both a leaving group and a strong EWG, in addition to the highly electron-withdrawing iodonium moiety to evaluate the strategy (Scheme 1C). We speculated that the unusual structure of this reagent might enable an initial SNAr reaction instead of the usual ligand coupling (LC) pathway11Villo P. Olofsson B. Arylations promoted by hypervalent iodine reagents.in: Patai’s Chemistry of Functional Groups: The Chemistry of Hypervalent Halogen Compounds. Wiley, 2019: 461-522https://doi.org/10.1002/9780470682531.pat0950Google Scholar,35Ochiai M. Kitagawa Y. Toyonari M. On the mechanism of α-phenylation of β-keto esters with diaryl-λ3-iodanes: evidence for a non-radical pathway.Arkivoc. 2003; 2003: 43-48https://doi.org/10.3998/ark.5550190.0004.606Google Scholar to deliver a unique iodine(III) intermediate that could undergo a subsequent aryl transfer to yield a diarylated product. Such SNAr reactivity is unreported and would conceptually expand the chemistry of iodine(III) reagents beyond diarylations. In this article, we present the realization of this strategy, which enables a metal-free, high-yielding difunctionalization of N- and O-nucleophiles with two different aryl groups in a single reaction (Scheme 1D). Both aromatic rings from the diaryliodonium salt are transferred to the nucleophile, with concomitant loss of the fluorine atom under mild conditions. The reaction proceeds through a unique pathway where the iodine(III) moiety and the EWG together activate the aryl group sufficiently for an SNAr to outcompete the LC pathway. The methodology efficiently diarylates primary amines, ammonia, and water to give highly functionalized triarylamines, diarylamines, and diaryl ethers, respectively. The transformation of the iodonium group into an iodide is a key feature of the strategy,12Chen W.W. Cuenca A.B. Shafir A. The power of iodane-guided C−H coupling: a group-transfer strategy in which a halogen works for its money.Angew. Chem. Int. Ed. 2020; 59: 16294-16309https://doi.org/10.1002/anie.201908418Google Scholar,22Chen H. Han J. Wang L. Intramolecular aryl migration of diaryliodonium salts: access to ortho-iodo diaryl ethers.Angew. Chem. Int. Ed. 2018; 57: 12313-12317https://doi.org/10.1002/anie.201806405Google Scholar which enables SNAr reactivity at very mild conditions and still delivers products with only one EWG. Furthermore, the retained iodide increases the atom economy and enables downfield derivatization of the products to reach further molecular complexity. A proof of concept was performed with diaryliodonium salt 1a, carrying a fluoride leaving group and a para-nitro group to activate the aromatic ring for an SNAr pathway (Scheme 2A). To our delight, aliphatic amine 2a displayed the desired reactivity under our conditions for monoarylation of amines with diaryliodonium salts20Purkait N. Kervefors G. Linde E. Olofsson B. Regiospecific N-arylation of aliphatic amines under mild and metal-free reaction conditions.Angew. Chem. Int. Ed. 2018; 57: 11427-11431https://doi.org/10.1002/anie.201807001Google Scholar and gave diarylated product 3a in 68% yield. An extensive screening of the reaction conditions was then performed (Scheme 2B; Tables S1–S3), and the reaction proceeded well under basic conditions. Sodium carbonate was used for further optimization since aryne formation can be avoided with weak inorganic bases.36Stridfeldt E. Lindstedt E. Reitti M. Blid J. Norrby P.-O. Olofsson B. Competing pathways in O-arylations with diaryliodonium salts: mechanistic insights.Chem. Eur. J. 2017; 23: 13249-13258https://doi.org/10.1002/chem.201703057Google Scholar A solvent screening showed that decent yields could be obtained even in water, showing the resilience of the method. Further investigations revealed that reactions could be performed at significantly lower temperature in acetonitrile and an excellent yield of 3a was obtained with K2CO3 and 1.1 equiv of 2a at 50 °C. To demonstrate the versatility of the reaction, a wide variety of primary aliphatic amines were evaluated in reactions with diaryliodonium salt 1a (Scheme 3A). Unhindered amines provided diarylamines 3a–3c in good to excellent yields, and smooth scalability was demonstrated through a large-scale reaction (1 g) that delivered 3a in 96% yield. Although sterically demanding amines were less efficient nucleophiles (cf. 3c versus 3d), the method displayed high functional group tolerance in the nucleophilic coupling partner 2, including allylic, benzylic, and heterocyclic moieties (3e–3j). The formation of 3e in 81% yield is particularly fascinating since the monoterpenoid geranylamine is an important starting point for the synthesis of various natural products. The compatibility with more complex molecules was exemplified by diarylation of the ester-protected derivatives of glycine and the pharmaceutical Baclofen to yield 3k and 3l. To evaluate the scope of diaryliodonium salts 1, a library of novel reagents 1 was efficiently synthesized in one-pot reactions from the corresponding fluoroiodoarene and arene.37Bielawski M. Aili D. Olofsson B. Regiospecific one-pot synthesis of diaryliodonium tetrafluoroborates from arylboronic acids and aryl iodides.J. Org. Chem. 2008; 73: 4602-4607https://doi.org/10.1021/jo8004974Google Scholar, 38Bielawski M. Zhu M. Olofsson B. Efficient and general one-pot synthesis of diaryliodonium triflates: optimization, scope and limitations.Adv. Synth. Catal. 2007; 349: 2610-2618https://doi.org/10.1002/adsc.200700373Google Scholar, 39Dohi T. Ito M. Morimoto K. Minamitsuji Y. Takenaga N. Kita Y. Versatile direct dehydrative approach for diaryliodonium(III) salts in fluoroalcohol media.Chem. Commun. 2007; 40: 4152-4154https://doi.org/10.1039/B708802GGoogle Scholar There was wide tolerance for electronically variable aromatic rings B (Scheme 3B), ranging from the electron-withdrawing substituents CF3 and OCF3 (3m and 3n) to halides (3o and 3p) and electron-donating groups (EDG), including OPh and NHAc (3q–3t). Moreover, ester and thienyl groups were introduced in this position (3w and 3x). Arylations with sterically demanding mesityl (Mes) and triisopropylphenyl (TRIP) groups are highly challenging,40Petersen T.B. Khan R. Olofsson B. Metal-free synthesis of aryl esters from carboxylic acids and diaryliodonium salts.Org. Lett. 2011; 13: 3462-3465https://doi.org/10.1021/ol2012082Google Scholar,41Chartoire A. Boreux A. Martin A.R. Nolan S.P. Solvent-free aryl amination catalysed by [Pd(NHC)] complexes.RSC Adv. 2013; 3: 3840-3843https://doi.org/10.1039/C3RA40386FGoogle Scholar and Mes and TRIP are indeed used as non-transferrable groups in metal-catalyzed monoarylations with diaryliodonium salts.42Kalyani D. Deprez N.R. Desai L.V. Sanford M.S. Oxidative C-H activation/C-C bond forming reactions: synthetic scope and mechanistic insights.J. Am. Chem. Soc. 2005; 127: 7330-7331https://doi.org/10.1021/ja051402fGoogle Scholar,43Phipps R.J. Grimster N.P. Gaunt M.J. Cu(II)-catalyzed direct and site-selective arylation of indoles under mild conditions.J. Am. Chem. Soc. 2008; 130: 8172-8174https://doi.org/10.1021/ja801767sGoogle Scholar To our delight, iodonium salts with Mes or TRIP efficiently participated in the diarylation to provide 3u and 3v in good to excellent yields. Finally, structural variations of the aryl ring C were investigated (Scheme 3C; Table S4). The NO2 substituent could be exchanged for other strong EWG, such as SO2Me and SO2CF3 (3y and 3aa), as well as the weaker electron-withdrawing groups SF5, CN, CF3, and esters (3z, 3ab–3ad). Iodonium salts with multiple EWGs could also be employed (3ae and 3af). As illustrated in Scheme 3B+C, both aryl groups of reagent 1 could be varied simultaneously (3ag–3aj). However, exchanging the fluoride LG for a chloride resulted in no reaction (Scheme S1). We wanted to extend the methodology to the diarylation of aniline nucleophiles as an efficient route to triarylamines, which have industrial relevance in functional materials, such as solar cells.3Wang J. Liu K. Ma L. Zhan X. Triarylamine: versatile platform for organic, dye-sensitized, and perovskite solar cells.Chem. Rev. 2016; 116: 14675-14725https://doi.org/10.1021/acs.chemrev.6b00432Google Scholar,44Tan G. Das M. Maisuls I. Strassert C.A. Glorius F. Rhodium-catalyzed dealkenylative arylation of alkenes with arylboronic compounds.Angew. Chem. Int. Ed. 2021; 60: 15650-15655https://doi.org/10.1002/anie.202105355Google Scholar The synthesis of triarylamines can be challenging in particular when three structurally different aryl groups are to be introduced. Only traces of the desired triarylamines were obtained with anilines under the standard reaction conditions for aliphatic amines, which was expected as anilines are less nucleophilic,45Brotzel F. Chu Y.C. Mayr H. Nucleophilicities of primary and secondary amines in water.J. Org. Chem. 2007; 72: 3679-3688https://doi.org/10.1021/jo062586zGoogle Scholar and as the second arylation step results in a sterically hindered triarylamine product. To our satisfaction, an efficient synthesis of triarylamines 5 could be achieved upon carefully reoptimized reaction conditions (Table S5). The reaction proceeded well in pyridine at 40°C with two equivalents of aniline instead of external base and MgSO4 as an additive. Under these reaction conditions, aniline could be diarylated with salt 1a to give triarylamine 5a in 80% yield on a two-gram scale (Scheme 4A). The substrate scope of anilines 4 was investigated with diaryliodonium salt 1a (Scheme 4A). As substituents on anilines alter their reactivity,45Brotzel F. Chu Y.C. Mayr H. Nucleophilicities of primary and secondary amines in water.J. Org. Chem. 2007; 72: 3679-3688https://doi.org/10.1021/jo062586zGoogle Scholar the reaction yields strongly correlated with the electronic properties of 4. Alkylated anilines generally reacted smoothly to deliver triarylamines 5b–5e in high yields, whereas steric interference decreased the yield of o-methylated aniline (5f). Conjugated substituents were also tolerated (5g and 5h). Anilines with strong EDG, such as p-OMe, p-SMe, and p-NHAc, delivered high to excellent yields of triarylamines 5i–5o, also in the presence of halide substituents. The arylation of anilines bearing only EWG, e.g., m-OMe (5p), halides (5q–5t), and carboxylic acid (5u) was more demanding. To our delight, good yields with such substrates could be obtained by increasing the nucleophile loading (5p and 5r–5t) or introducing an electron-donating substituent (5j–5m and 5v). With this method, additional bromo- and iodo-substituents can be easily introduced into the products, which can be difficult with transition metal-catalyzed methods. Pleasingly, anilines with complex substituents were efficiently diarylated, and the high functional group tolerance was demonstrated by the synthesis of triarylamines containing imide (5w), heterocycles (5x–5z), large π-system (5aa), amino acid (5ab), peptide (5ac), and steroid (5ad) moieties. The scope of diaryliodonium salts 1 was evaluated next, and aryl group B was modified with a wide variety of functional groups (Scheme 4B). Both EWG (5ae–5ah) and EDG (5ai–5am) were well tolerated, and in this fashion, chloro-substituted triarylamine 5r was formed in good yield without a need for increased nucleophile amounts (vide supra). Importantly, the introduction of mesityl and triethylphenyl groups was feasible also with anilines, resulting in the highly sterically encumbered products 5ak and 5al. Triarylamines with such excessively crowded nitrogen centers are very uncommon in literature. The functional group tolerance of aryl group C proved to be less variable compared with the diarylation of aliphatic amines, and strong EWGs were required to compensate for the low nucleophilicity of the aniline (Scheme 4C). Although the nitro group could be exchanged with SO2CF3 (5an), the CF3, CN, and CO2Me groups gave no conversion. Further structural diversity was enabled through the insertion of additional EWG in other positions of aryl group C, thus delivering the products 5ao–5aq. Gratifyingly, the reaction remained completely regioselective with several fluorine substituents on ring C and delivered 5aq as the sole product with the other fluorine atoms untouched. Diarylamines and diaryl ethers are essential building blocks in agrochemicals, pharmaceuticals, and optical materials.1Ruiz-Castillo P. Buchwald S.L. Applications of palladium-catalyzed C-N cross-coupling reactions.Chem. Rev. 2016; 116: 12564-12649https://doi.org/10.1021/acs.chemrev.6b00512Google Scholar,2Chen T. Xiong H. Yang J.F. Zhu X.L. Qu R.Y. Yang G.F. Diaryl ether: a privileged scaffold for drug and agrochemical discovery.J. Agric. Food Chem. 2020; 68: 9839-9877https://doi.org/10.1021/acs.jafc.0c03369Google Scholar An extension of our methodology to nucleophiles such as ammonia and water would give access to these compound classes from simple substrates in a highly atom-efficient and straightforward manner. Simultaneous introduction of two different aryl groups to such nucleophiles is unprecedented.46Anderson K.W. Ikawa T. Tundel R.E. Buchwald S.L. The selective reaction of aryl halides with KOH: synthesis of phenols, aromatic ethers, and benzofurans.J. Am. Chem. Soc. 2006; 128: 10694-10695https://doi.org/10.1021/ja0639719Google Scholar The synthesis of diaryl ethers from water proved to be efficient after minor optimization of the reaction conditions (Scheme 5; Table S6). It was crucial to only use one equivalent of water to obtain high yields, and the results were further improved by changing the base to Cs2CO3 and the solvent to EtOAc. Under these conditions, diaryl ether 6a could be obtained in 97% yield. Analogous to our results with other nucleophiles, a variety of substituents were tolerated in diaryliodonium salts 1. Diaryl ethers were formed in good to excellent yields with EDGs (6b–6d), EWGs, (6e–6j), sterically demanding groups (6k and 6l), or a carbonyl group (6m) in the aryl ring B (Scheme 5B, left). As depicted in Scheme 5C (left), the EWG on the aryl ring C could be varied in a similar fashion to the reactions with aliphatic amines, giving products 6o–6s. Transfer of electron-rich aryl groups can be challenging due to their reduced reactivity in metal-free LC pathways.47Pinto de Magalhães H. Lüthi H.P. Togni A. Reductive eliminations from λ3-iodanes: understanding selectivity and the crucial role of the hypervalent bond.Org. Lett. 2012; 14: 3830-3833https://doi.org/10.1021/ol3014039Google Scholar This trend was observed with some of the electron-rich salts, which were low-yielding under the optimized conditions. Fortunately, this obstacle was overcome by raising the reaction temperature to 70°C (Table S7), which resulted in a good to excellent yields of diaryl ethers 6b and 6d. Increased temperature was also beneficial in the synthe