Atom-economical group-transfer reactions with hypervalent iodine compounds Andreas Boelke, Peter Finkbeiner and Boris J. Nachtsheim* Review Open Access Address: Beilstein J. Org. Chem. 2018, 14, 1263–1280. Institute for Organic and Analytical Chemistry, University of Bremen, doi:10.3762/bjoc.14.108 28359 Bremen, Germany Received: 22 February 2018 Email: Accepted: 02 May 2018 Boris J. Nachtsheim* - [email protected] Published: 30 May 2018 * Corresponding author This article is part of the Thematic Series "Hypervalent iodine chemistry in organic synthesis". Keywords: atom economy; benziodoxolones; homogeneous catalysis; Guest Editor: T. Wirth hypervalent iodine; iodonium salts © 2018 Boelke et al.; licensee Beilstein-Institut. License and terms: see end of document. Abstract Hypervalent iodine compounds, in particular aryl-λ3-iodanes, have been used extensively as electrophilic group-transfer reagents. Even though these compounds are superior substrates in terms of reactivity and stability, their utilization is accompanied by stoi- chiometric amounts of an aryl iodide as waste. This highly nonpolar side product can be tedious to separate from the desired target molecules and significantly reduces the overall atom efficiency of these transformations. In this short review, we want to give a brief summary of recently developed methods, in which this arising former waste is used as an additional reagent in cascade trans- formations to generate multiple substituted products in one step and with high atom efficiency. Introduction Atom economy (AE) is an important parameter which helps to nomical transformations using hypervalent iodine reagents evaluate the overall efficiency of a chemical reaction or a chem- (iodanes) as electrophilic group-transfer reagents. Iodanes, in ical process [1,2]. It is defined as the quotient between the mo- particular iodonium salts, are well-balanced reagents in terms of lecular mass of the desired reaction product(s) and the molecu- stability, reactivity and synthetic and/or commercial availabili- lar mass of all reactants (Equation 1): ty and therefore it is not surprising to see these compounds as key reagents in a great number of recently developed transfor- In an ideal reaction with 100% atom economy, every atom of mations [3-15]. However, in terms of atom economy, they have the reactants is becoming part of the desired product. In this an intrinsic problem: their high reactivity is based on the emer- short review, we want to discuss recent advances in atom-eco- gence of aryl iodides as supernucleofuges. λ3-Iodanes are the (1) 1263 Beilstein J. Org. Chem. 2018, 14, 1263–1280. generally preferred hypervalent iodine compounds for electro- depicted in Scheme 1. Here, only the molecular mass of the cor- philic group transfer reactions, during which the central iodine responding iodane substrates is taken into account for AE esti- atom is transformed from a high energy hypervalent state into a mation. normal valent state by a two-electron reduction. The high stability of the newly formed aryl iodide is the thermodynamic The transfer of only one functional group, for instance in driving force for all λ3-iodane-mediated oxidative transforma- iodane-mediated electrophilic monoarylations, produces not tions. Even though this process guarantees the high reactivity of only the aryl iodide, but also stoichiometric amounts of salt these reagents, it has one major obstacle: after the oxidation side-products, limiting the AE of these transformations to process, stoichiometric amounts of the aryl iodide are produced roughly 10–20% (Scheme 1, reaction (a)). In the second case, as waste. Aryl iodides, as nonpolar organic waste, are often- both organic residues (one carbon or heteroatom ligand plus the times hard to separate from the desired reaction products since arene of the former aryl-λ3-iodane or aryliodonium salt) are they cannot be simply washed out with aqueous solutions. transferred to the substrate (Scheme 1, reaction (b)). The loss of Instead, they must be separated by column chromatography. In iodine and the counterion still limits the overall AE to 30–40%. terms of AE, the high atomic mass of iodine (126.9 u) leads to a A dramatic increase in AE arises, if the iodine atom is incorpo- dramatic negative impact of iodanes on this “green” reaction rated in the desired reaction product as well (Scheme 1, reac- parameter. To overcome this obstacle, promising approaches tion (c)). This does not only lead to an overall AE of up to 70% are the use of iodoarenes as precatalysts in combination with but also produces synthetically versatile intermediates for external co-oxidants and the utilization of specific hypervalent subsequent transformations, in particular metal-catalyzed cross- iodine compounds (polymer-supported as well as non-poly- coupling reactions. If benziodoxolones or benziodoxoles are meric species), whose reduced forms are easy to recycle used as group-transfer reagents, nearly 100% AE is possible [3,4,16,17]. On the other hand, the additional incorporation of since the counterion (the carboxylate or alcoholate) is cova- the former iodoarene waste into the reaction product via a lently attached to the aryl iodide and hence does not get lost cascade reaction does not only improve the overall AE of a during the reaction cascade (Scheme 1, reaction (d)). This is chemical reaction but also directly leads to highly functionali- very effective, if this ortho-functionality is a desired part of the zed target molecules. A rough estimate about the impact final reaction product or if it can be readily transformed into of the incorporation efficiency of the iodane on the AE is synthetically useful functional groups. Scheme 1: Overview of different types of iodane-based group-transfer reactions and their atom economy based on the molecular mass of the corresponding λ3-iodane. 1264 Beilstein J. Org. Chem. 2018, 14, 1263–1280. In this short review, we will give a brief summary of very common structural motif for λ3-iodanes, recent theoretical in- recent efforts toward the atom-economical use of aryl-λ3- vestigations revealed a potential role of the cationic, normal iodanes, in particular aryliodonium salts in group-transfer reac- valent tetrahedral form, in atom transfer processes (Scheme 2a) tions. In our definition, this includes transformations in which at [23]. Throughout this review, iodonium salts will be shown least two of the three ligands attached to the iodane are part of consequently in the latter structure due to clarity and due to lit- the target molecule or in which the iodane acts as an oxidant erature habits. and a group-transfer reagent in a consecutive reaction sequence. The chapters are divided by the structure of the transferred Typically, only one of the two aryl ligands is transferred to the functional groups, starting from simple diarylations and oxida- substrate, yielding a monoarylated reaction product and aryl tive arylations with moderate AE to highly atom efficient trans- iodide as stoichiometric waste. Examples for their atom-eco- formations using alkynyl and azide-substituted benz- nomical utilization, in which at least both aryl ligands are trans- iodoxolones. The given AE values are simplified and were ferred, are still rare. A general approach would involve at first a calculated on the basis of the key substrates, whereas the re- metal-catalysed or metal-free arylation step of a suitable sub- quired equivalents of all starting materials (iodane and usually strate A with the diaryliodonium salt 1 to give monoarylated its reaction partner) are taken into account. Other additives, intermediate B. Subsequently, a metal-catalysed cross-coupling such as additional bases, acids or catalysts were neglected. initiated by an oxidative addition of the metal catalyst into the C–I bond of the emerging iodoarene 2 affords the diarylated Review product C (Scheme 2b). 1. Diaryliodonium salts 1.1. Acyclic diaryliodonium salts A first report utilizing this strategy was published by Bumagin Acyclic diaryliodonium salts 1 find widespread application in and co-workers as early as 1995 [24]. Here, symmetrical numerous metal-free and transition metal-mediated electro- diaryliodonium salts 1 were used in a palladium-catalysed philic arylation protocols [18-22]. While in solid state they cross-coupling reaction with sodium tetraphenylborate clearly have a T-shaped pseudotrigonal bipyramid structure, the (Scheme 3). This reaction not only provides excellent yields of Scheme 2: (a) Structure of diaryliodonium salts 1. (b) Diarylation of a suitable substrate A with one equivalent of diaryliodonium salt 1. 1265 Beilstein J. Org. Chem. 2018, 14, 1263–1280. Scheme 3: Synthesis of biphenyls 3 and 3’ with symmetrical diaryliodonium salts 1. the respective biphenyls 3 but also exhibits a high AE (57% for 45% of the molecular weight of the starting iodonium salt 1 is Ar = Ph). However, its general synthetic utility is limited since present in the product 3’. it requires highly reactive boron compounds as nucleophiles. Diaryl thioethers 5 can be synthesized using either cyclic Symmetrical biphenyls 3’ can be generated from the corre- iodonium salts (will be discussed briefly in section 1.2) or sponding symmetrically substituted diaryliodonium salts 1 their acyclic counterparts 1 (Scheme 4) [26,27]. Jiang and and bis(pinacolato)diboron as demonstrated by Muñiz and co-workers developed a Cu(II)-catalysed methodology for the co-workers [25]. In the first step, a mild carbon–boron bond for- conversion of acyclic diaryliodonium salts 1 and potassium mation gives one equivalent of arylboronic ester 4 and an thioacetate to the corresponding thioethers 5 (pathway (a)) and iodoarene 2 through a metal-free boron arylation. Subsequent later applied the optimized reaction conditions towards cyclic cross coupling under Suzuki conditions affords symmetrical iodonium salts. In an independent work, Li and co-workers suc- biphenyls 3’ in good yields. Due to the temporary introduction cessfully utilized a catalytic system based on FeCl3 with and cleavage of the boron moiety the formal atom economy for comparable results (pathway (b)).