SYNLETT0936-52141437-2096 © Georg Thieme Verlag Stuttgart · New York 2015, 26, 2751–2762 2751 account Syn lett H. Sun, Y. Huang Account Recent Progress in the Development of Multitasking Directing Groups for Carbon–Hydrogen Activation Reactions Huan Sun Yong Huang* Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University, Shenzhen Graduate School, Shenzhen 518055, P. R. of China [email protected] Received: 17.05.2015 hydrogen bond (Scheme 1). This property enables the DG to Accepted after revision: 15.07.2015 govern the site selectivity of carbon–hydrogen functional- Published online: 07.09.2015 DOI: 10.1055/s-0035-1560169; Art ID: st-2015-a0376-a ization reactions. Many DGs, ranging from strongly chelating to weakly Abstract Selective carbon–hydrogen activation reactions can be ac- binding, have been developed for a wide range of carbon– complished in a predictive manner using directing auxiliaries. However, hydrogen coupling and annulation reactions.3 However, it the majority of directing groups discovered to date are difficult to re- move or to transform into a desirable functionality. Recently, remov- must be pointed out that this approach is a double-edged able, cleavable, and redox-neutral directing groups have been devel- sword because although it provides precise site selectivity, oped that significantly broaden both the substrate scope and synthetic it suffers from the fact that the DG remains as a functional diversity of carbon–hydrogen functionalization reactions. In this short entity in the product of the reaction. For example, DGs for account, we summarize recent progress we have made in the develop- 2 ment of multitasking (removable, cleavable, redox-neutral, manipula- sp -carbon–hydrogen functionalization reactions are typi- ble) directing groups for carbon–hydrogen activation reactions. cally linked to aromatic substrates via stable carbon–car- 1 Introduction bon, carbon–oxygen, or carbon–nitrogen bonds, which are 2 Triazene difficult to cleave. 3 Nitrous Amide Consequently, strategies have been devised to address 4 Pyrazolidinone 5 N-Oxyacetamide this problem, including incorporation of the DG into a het- 4 6 Conclusion erocyclic ring and use of a traceless DG that can be re- moved or is capable of a wide range of desirable ensuing Downloaded by: Chinese University of Hong Kong. Copyrighted material. Key words carbon–hydrogen activation, directing groups, multitask- chemical manipulations (Scheme 1).5 Recently, a number of ing functional groups, transition metals, substituted heterocycles traceless, cleavable, and redox-neutral DGs have been de- veloped that significantly broaden the applications of car- 1 Introduction bon–hydrogen activation reactions and the resulting prod- ucts. Over the past decades, the development of new carbon– In this account, we summarize the results of recent in- hydrogen activation strategies has re-emerged as a goal for vestigations we have carried out aimed at uncovering new next-generation synthetic organic chemists.1 The ability to multitasking DGs for carbon–hydrogen functionalization carry out direct functionalization reactions of ‘inert (non- reactions. activated)’ carbon–hydrogen bonds is one of the most straightforward approaches to increasing molecular com- plexity in organic molecules. The field of carbon–hydrogen 2 Triazene activation has enjoyed tremendous advances, thanks in part to the design of various directing groups (DGs) that enable In 2012, we reported that the triazene moiety serves as selective carbon–hydrogen bond cleavage and functional- a new traceless DG for rhodium(III)-catalyzed carbon– ization.2 A DG generally contains an electron lone pair that hydrogen functionalization reactions.6 In the study, we coordinates to a transition metal in a catalyst in order to found that the central nitrogen atom of the triazene group orient it properly for insertion into a neighboring carbon– © Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2751–2762 2752 Syn lett H. Sun, Y. Huang Account 2 CO2R [RhCp*Cl2]2 (5%) N N Cu(OAc)2 N (2 equiv) N N R1 2 N + CO2R R1 AgOAc (30%) MeOH CO2Bn CO2Bn CO2Bn N N Br N N N N Scheme 1 Strategies for transformations of directing groups CO2Bn CO2Bn 72% 82% (2.4:1) coordinates with rhodium(III) and guides its insertion into Ac N N ortho-aryl–hydrogen bonds to form five-membered metal- N lacycles. Subsequent insertion of an electron-deficient ole- fin into the labile rhodium–carbon bond leads to regioselec- CO2Bn tive carbon–hydrogen olefination (oxidative Heck reaction) 98% (Scheme 2). The catalytic cycle in this process is closed us- Scheme 2 Rhodium(III)-catalyzed carbon–hydrogen olefination reac- tions using triazene as a new directing group ing stoichiometric copper(II) acetate [Cu(OAc)2] to regener- ate the rhodium(III) catalyst. Similarly, a dialkyltriazene group was shown by the Bräse group to direct ortho-selective, silver(I)-promoted Electron-rich arenes undergo functionalization at room arene trifluoromethylation reactions (Scheme 3).7 It should temperature, while reactions of electron-deficient sub- be noted that excellent ortho-selectivity attends these pro- strates require gentle heating. Notably, although substances cesses even though, as the authors suggested, a radical containing the strong electron-withdrawing nitro group are mechanism might be operating. often poor substrates for the carbon–hydrogen activation The triazene-directed carbon–hydrogen olefination re- reactions, they are well tolerated under the conditions em- actions were observed to display a broad substrate scope. ployed in the triazene-guided process. When a 2-bromo- Biographical Sketches Huan Sun, originally from Any- University in 2011. She is now a Graduate School. Her research ang, Henan Province, P. R. of Ph.D. candidate in the research interests are focused on novel China, received her B.S. degree group of Professor Yong Huang transition-metal-catalyzed pro- Downloaded by: Chinese University of Hong Kong. Copyrighted material. in chemistry from Zhengzhou at Peking University, Shenzhen cesses. Yong Huang received his B.S. gy) from 2002 to 2004. He sub- 2014 Organic Letters Outstand- degree in chemistry from Pe- sequently worked as a senior ing Author of the Year Award, king University in 1997. He re- medicinal chemist at Merck Re- the Bayer Investigator Award, ceived his M.S. and Ph.D. search Laboratories in Rahway, the Roche Chinese Young Inves- degrees from the University of NJ, until 2009. In 2009, he start- tigator Award, and the Asian Chicago in 1998 and 2001, re- ed his independent academic Core Program Lectureship spectively. He worked as a post- career as a professor at Peking Award (2013 and 2014). doctoral fellow at Caltech (the University, Shenzhen Graduate California Institute of Technolo- School. He is the receipt of the © Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2751–2762 2753 Syn lett H. Sun, Y. Huang Account DG can be removed using boron trifluoride–diethyl ether complex under ambient conditions to yield the correspond- N N ing arene–hydrogen product in near quantitative yield N N N N FG (Scheme 4). Upon treatment with methyl iodide, the tria- AgCF3 up to 74% CF zene group is replaced by an iodine, which is capable of CF3 3 participating in a large number of cross-coupling reactions. R R = I, Br, Cl, F, CN, R R OMe, COOEt In the presence of an acid, the aryltriazene can be convert- FG = NH2, N3, CN, halogen, Ar, alkene, alkyne ed into an aryl cation or radical, which reacts with nucleop- Scheme 3 Triazene-directed trifluoromethylation reactions hiles or ‘SOMOphiles’ (SOMO = singly occupied molecular orbital), respectively. In addition, transition metals readily insert into the aryltriazene carbon–nitrogen bond as part of substituted substrate is used, double olefination occurs, direct cross-coupling reactions. Because of its chemical suggesting that the triazene moiety also directs carbon– flexibility toward structure diversification, the triazene bromine bond insertion. In contrast, the carbon–bromine moiety is unique among DGs. bond in a 3-bromo-substituted arene is not activated for Like other DGs, triazenes can be converted into N-het- olefination in this system. Interestingly, the triazene moiety erocycles. In 2011, Zhu and Yamane described a method for is stronger than other DGs in directing carbon–hydrogen the synthesis of cinnolines through reactions between 2- insertion. iodo-1-triazenylarenes and internal alkynes (Scheme 5, The use of the triazene moiety as a DG for carbon– part a).9 In our attempt to carry out a carbon–hydrogen ver- hydrogen activation reactions is highly advantageous be- sion of the Yamane cinnoline synthesis, we were surprised cause it can undergo a wide variety of reactions following to find that the triazine was converted instead into an NH the carbon–hydrogen functionalization step. For example, indole via an unprecedented nitrogen–nitrogen double compared with common DGs, the aryl–nitrogen bond of ar- bond cleavage process (Scheme 5, part b).10 yltriazenes is polarized and significantly weak owing to the Although carbon–hydrogen activation/annulation strat- electron negativity of the two other nitrogens. In fact, aryl- egies for indole synthesis using rhodium(III) have been ex- triazenes are documented to undergo a number of reac- plored previously, the formation of unprotected NH indoles tions that mimic aryl cation, radical, and organometallic in reactions of acetylenes with triazenes has unique advan- processes.8 tages.11,12 To demonstrate this feature, we applied this We and Bräse both described the chemical versatility of methodology to the preparation of a number of drug scaf- triazene products generated by carbon–hydrogen function- folds and substances that play a role in organic light-emit- alization reactions (Schemes 3 and 4). We found that the ting diode devices (Scheme 6). H Ph I CO Bn 2 CO2Me CO2Bn Pd(OAc) MeOH, 60 °C BF3⋅OEt2 Downloaded by: Chinese University of Hong Kong. Copyrighted material. styrene MeI, 115 °C r.t.