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Home > Cyclic Hypervalent Iodine Reagents: Enabling Tools for Bond Disconnection via Reactivity Umpolung
Cyclic Hypervalent Iodine Reagents: Enabling Tools for Bond Disconnection via Reactivity Umpolung
Durga Prasad Hari,† Paola Caramenti,† and Jerome Waser
1.INTRODUCTION AND CONTEXT
Organic compounds have a deep impact on our everyday life as drugs, agrochemicals, or materials. Over the last century, organic synthesis has matured as a craft and a science. Guidelines have been conceptualized to harness the fundamental properties of atoms, such as their electronegativity, to select adequate disconnections for bond formation.1 For example, functional groups containing electronegative atoms, such as nitrogen, halogens, oxygens, or sp2 and sp3 hybridized carbons, are best introduced as nucleophiles onto the carbon skeleton of organic compounds (Figure 1a). This approach is highly successful, but does not allow chemists to make all disconnections, as nucleophilic positions cannot be functionalized. To extend the versatility of organic synthesis, Seebach has introduced the concept of Umpolung (reversal of reactivity):2 If the innate reactivity of synthons can be inverted, new disconnections become possible, leading to greater diversity and synthetic efficiency.
In this context, hypervalent iodine reagents have taken a privileged position based on the work of pioneers such as Beringer, Koser, Valvoglis, Moriarty, Zhdankin, Kita, Ochiai, and many others (Figure 1b).3 Both iodanes and iodonium salts allow the Umpolung of many nucleophiles into electrophilic synthons. Even if the concept of hypervalency is still a subject of controversy,4 it has been successfully used to rationalize the exceptional properties of hypervalent iodine reagents. However, their high reactivity can also lead to instability in the presence of strong bases, transition metals or when heating. In this context, benziodoxol(on)es (BX, Figure 1c), a class of cyclic hypervalent iodine reagents, have shown increased stability due to the inclusion of the iodine atom into a heterocycle.5,6 In particular, the groups of Ochiai and Zhdankin successively reported stable ethynyl (EBX),7,8 azido (ABX),9 and cyano (CBX)10 benziodoxol(on)es. A further advantage of BX reagents is the modulation of their reactivity through the trans-effect in the hypervalent bond.11 Derivatives bearing carboxy, isopropyl, and hexafluoroisopropyl substituents have been most broadly used. For many years, structural studies on benziodoxolones have dominated the field, with few attempts in developing new synthetic applications. The situation changed in 2006, when Togni and co-workers reported the use of benziodoxol(on)es for trifluoromethylation.12 The so-called Togni reagents are now broadly used for the introduction of pharmaceutically relevant trifluoromethyl groups on organic compounds.13 Since 2008, our group has explored the potential of other BX reagents for group transfer reactions. We demonstrated that this class of reagents constitutes a unique toolbox for synthetic chemistry, which are superior to simple iodonium salts in many direct, transition metal- and photoredox- catalyzed transformations. After having focused on electrophilic alkynylation,14 we moved to azidation and cyanation. In 2017, we introduced a new class of benziodoxolone reagents for the Umpolung of electron-rich heterocycles, in particular indoles and pyrroles. Many other groups have since then used BX compounds in group-transfer reactions.15,16 Herein, we will present an overview of our 10 year journey in the fascinating reactivity of these reagents
2.ELECTROPHILIC ALKYNYLATION
2.1.Alkynylation of Acidic C−H Bonds
We first encountered EBX reagents in 2010, when using alkynyliodonium salts for the alkynylation of enolates using reported methods.17,18 We were facing serious issues of reproducibility and were not able to induce enantioselectivity under phase-transfer conditions. Building on the higher stability of EBX reagents,7,8 we successfully used TMS-EBX (1a) and TBAF with stabilized enolates to give terminal alkynes 2a−f in excellent yields (Scheme 1).19 Asymmetric induction was now possible using Maruoka’s phase transfer catalyst (4) (Scheme 2).
Two mechanisms can be envisaged (Scheme 3): Addition− elimination on the iodine atom (a) or conjugate addition to the alkyne, followed by reductive elimination and 1,2 shift (b). The use of 13C-labeled reagent 1b led to product 9,19 which is in agreement with the 1,2 shift pathway.
In 2014, as the phase-transfer approach was limited in both scope and enantioselectivity, we reported an alternative strategy to access quaternary stereocenters: Racemic alkynylation, followed by an enantioselective Tsuji−Trost allylation.
2.2.Alkynylation of Heteroatoms
In 2013, we wondered if EBX reagents could also contribute to a more efficient synthesis of thioalkynes. These compounds are usually synthesized by addition of acetylides to oxidized thiol precursors.22 Whereas only disulfides were obtained when the alkynylation was attempted with alkynyliodonium salts, a quantitative yield was realized using TIPS-EBX (1c) (Scheme 5).23,24 The reaction proceeded in 5 min at room temperature in an open flask with a wide range of EBX reagents and thiol or selenol substrates (products 10a−m).
A mechanism for the thiol-alkynylation reaction was proposed based on computational studies (Scheme 6).24 First, thiolate I could attack on the iodine atom of EBX to give II, which then undergoes reductive elimination to give the product. However, intermediate II was not observed in the computational studies.
As an alternative, conjugate addition of thiolate I to give vinyl benziodoxolone III, which undergoes α-addition followed by 1,2 shift, leads to the product. This pathway was observed with a transition state energy of 23 kcal/mol. Nevertheless, a concerted pathway via asynchronous transition state IV with significant Hirshfeld charge separation was identified with a lower energy of 10.8 kcal/mol. In 2015, we further identified a four-atom transition state V leading to β-addition, which is favorable for alkyl groups on EBX, whereas α-addition is favored for electron withdrawing groups.25
The very fast and selective reaction of EBX reagents with thiols under mild conditions motivated us to investigate applications in chemical biology. In 2015, Adibekian and our group reported a method for proteomic profiling of enzymes with hyperactive cysteines in living cells by using the azide- substituted EBX JW-RF-010 (1e) (Scheme 7).26 The utility of the method was further demonstrated by identifying one target of curcumin in HeLa cells.
As a last effort in the area of heteroatom functionalization, we further demonstrated the use of EBX reagents for the alkynylation of other sulfur and phosphorus nucleophiles. Sulfones 11a−e were obtained from Grignard reagents or aryl iodides using DABSO (diazabicycloctane bis(sulfur dioxide)) as sulfur source (Scheme 8)27 and alkynyl phosphorus derivatives 12a−e were synthesized from H-phosphi(na)tes and secondary phosphine oxides (Scheme 9).28
2.3.C−H Alkynylation of Hetero(arenes)
Our research on EBX reagents with simple nucleophiles had been highly successful, and we wondered if they could be also applied in the more complex settings of transition metal catalysis. Since 2007, using alkynyliodonium salts, C−H functionalization had been a major project in our group, but without success, as the sensitive reagents constantly decom- posed in the presence of the metal catalyst. In 2009, we had our first success with the direct alkynylation of indoles using TIPS- EBX (1c) and AuCl as catalyst (Scheme 10a).29 C3 alkynylate indoles 13a−c were obtained in good yields. The formation of C2-alkynylated indoles was observed when the C3 position was blocked (Scheme 10b, products 13d,e).30,31 The direct C−H alkynylation reaction was further extended to pyrroles (Scheme 10c, products 14a−c),32 thiophenes (Scheme 10d, products 15a−c),33 furans (Scheme 10e, products 16a−c),34 benzofurans (Scheme 10f, products 17a−c),35 and anilines and trimethoxy arenes (Scheme 11, products 18a−d).36
Initially, we hypothesized two mechanisms involving either an oxidative mechanism or a π-activation for the C−H alkynylation (Scheme 12).32 Oxidative addition of EBX on Au(I) would give Au(III) intermediate I. Electrophilic auration leads then to II and reductive elimination gives 13f. The π-activation involves coordination of Au(I) to the triple bond to give III, followed by nucleophilic attack leading to IV. Finally, α-elimination followed by 1,2-shift gives 13f. No silicon-shift was observed when C13 labeled reagent 1b was used. This result supports the oxidative mechanism. However, Ariafard found by computations that both the oxidative and π-activation mechanisms were too high in energy and proposed a iodine to gold shift on the alkyne to give intermediate V.37 Indole addition to V, followed by β- elimination and rearomatization would lead to 13f. Common to the three mechanisms is an electrophilic aromatic substitution step, which explains the high regioselectivity observed. In 2013, we also reported a palladium-catalyzed selective C2 alkynyla- tion.38 Other research groups later demonstrated that EBX reagents can be used for C−H alkynylation using a broad range of transition metal catalysts.
2.4.Alkynylation Involving Domino Reactions
In our work on heterocycles, we had demonstrated that EBX reagents could be used for a single sp2−sp bond formation. We then investigated their use in domino reactions leading to the alkynylation of sp3 centers. We reported the first example of such a transformation with the palladium-catalyzed intramolecular oxy- and amino-alkynylation of olefins using phenols, carboxylic acids, and imides as nucleophiles.
Initially, we proposed a mechanism involving a Pd(IV) intermediate II (Scheme 14).39 Oxy/aminopalladation of the olefin gives intermediate I, which undergoes oxidative addition with TIPS-EBX (1c) to give II, followed by reductive elimination. Ariafard proposed a different mechanism involving formation of palladium allenylidene intermediate III (in equilibrium with the iodine bound alkynyl palladium complex IV) based on computational studies.41 1,2-Shift followed by β- elimination of 2-iodobenzoic acid leads to the product.
We then wondered then if domino processes could be also used for the synthesis of alkynylated heterocycles not accessible via C−H functionalization. As a proof of concept, we realized a one-pot synthesis of C3-alkynylated indoles 23a−c upon reaction of anilines with TIPS-EBX (1c) using a gold catalyst.
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