ARTICLE https://doi.org/10.1038/s41467-019-13098-1 OPEN Geminal group-directed olefinic C-H functionalization via four- to eight-membered exo-metallocycles Keke Meng1, Tingyan Li1, Chunbing Yu1, Cong Shen1, Jian Zhang1* & Guofu Zhong1* Great efforts have been made in the activation of a C(alkenyl)-H bond vicinal to the directing group to proceed via five- or six-membered endo-metallocycles. In stark contrast, functio- 1234567890():,; nalization of a C(alkenyl)-H bond geminal to the directing group via exo-metallocycle path- way continued to be elusive. Here we report the selective transformation of an olefinic C-H bond that is geminal to the directing group bearing valuable hydroxyl, carbamate or amide into a C-C bond, which proceeds through four- to eight-membered exo-palladacycles. Compared to the reported mechanisms proceeding only through six-membered exo-palla- dacycles via N,N-bidentate chelation, our weak and O-monodentate chelation-assisted C (alkenyl)-H activations tolerate longer or shorter distances between the olefinic C-H bonds and the coordinating groups, allowing for the functionalizations of many olefinic C-H bonds in alkenyl alcohols, carbamates and amides. The synthetic applicability has been demonstrated by the preparative scale and late-stage C-H functionalization of steroid and ricinoleate derivatives. 1 College of Materials, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 311121, China. *email: [email protected]; [email protected] NATURE COMMUNICATIONS | (2019) 10:5109 | https://doi.org/10.1038/s41467-019-13098-1 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-13098-1 lkenes are commonly present structural motifs and are coordinating functional groups via six- or seven-membered Aversatile building blocks in organic synthesis1. Direct cyclopalladation9. The same group also reported a nitrile-based functionalization of unactivated alkenyl C-H bonds template directed meta-selective C–H alkenylation, proceeding by represents the most straightforward way to valuable alkenes from a macrocyclic pre-transition state10,11. Functionaliztion of para simpler ones2–8. A fundamental transformation for direct olefinic C–H bonds was addressed as well using the similar template- C-H functionalization is the Heck reaction, which proceeds by based strategy by the Maiti group12. Chelation-assisted strategy olefin insertion followed by β-hydride elimination2–4. In recent was also widely used in aliphatic C–H activations13. The Gaunt years, radical C-H alkenylations have also been developed with a group reported a palladium-catalyzed C–H bond activation variety of carbon/heteroatom-centered radicals, proceeding through a four-membered cyclopalladation pathway, leading to through radical addition to alkenes and following single-electron- the selective synthesis of nitrogen heterocycles14. Sanford and co- transfer (SET) oxidation/elimination5. However, the site- and workers described a nitrogen-directed transannular C(alkyl)-H stereo-selectivity of these methods are largely governed by activation of alicyclic amine cores15. Very recently, the Yu group intrinsic steric and electronically biased properties of the alkene disclosed an aliphatic γ-C–H arylation protocol to be proceeded substrates due to the addition-elimination mechanisms. Actually, by conventionally disfavored six-membered cyclopalladation, controlling the site- and stereo-selectivity of C(alkenyl)-H using a strained directing group derived from pyruvic acid16. cleavage still remains a formidable challenge due to very subtle Considering the number of novel reactions that have arisen differences in terms of bond strength and electronic properties. from metallacycle intermediates, identification of distinct Pioneered by Murai´s work on Ru-catalyzed carbonyl-directed cyclometallation pathways would lead to novel C–H bond ortho-C–H activation, broadly defined directing groups (DGs) transformations. have served as highly effective tools for controlling C–H bond Remarkable efforts have been made in the vicinal group- activations via cyclometallations6–8. Most of the directed aro- directed olefinic C-H bond functionalization such as alkenyla- matic- and aliphatic C-H activations proceeded through a normal tion17–19, alkynylation20–22, alkylation23,24, and others25–34. five- or six-membered cyclometallated intermediate, however, However, their applicability can be severely curtailed by vicinal there are very limited reports on protocols by distinct cyclome- selectivity displayed through the only 5- or 6-membered endo- tallations. The Yu group previously disclosed a Pd(II)-catalyzed metallocycles, and by the biased electronic and steric properties of aromatic C-H functionalizations directed by distal weakly the alkene substrates (Fig. 1a). Moreover, the cyclometallation a Vicinal group-directedb Geminal group-directed Directing group R1 A Directing 1 n R A [M] group n A n X X A n X [M] R2 M M X M = Pd, Ru, Rh 3 2 3 H R R H R Underdeveloped Well-defined Endo-metallocycle X = N, O R1 R2 R1 R2 A = C, N, O 5- and 6-membered Exo-metallocycle n = 0, 1 c Limited reports on geminal C-H activation O O N O II N HN HN via Pd N N L X H N N ′ H Bicyclic I R R′ R Iodination Alkenylation + Only 6-membered metallocycles H H R Carreira et al. R R H Engle et al. + Strong N,N-bidentate chelation (2019) X = O or CH2 (2018) + Carboxylic acid enabled d This work 3 4 NR3R4 NR R + 4, 5, 6, 7 and 8-membered exo-metallocycles R3 OH O + Weak O-monodentate chelation assisted n O II O O Pd L H m + Alkyl hydroxyl/carbamate/amide directed 2 H R H 2 via R2 R L + Monoprotected amino acid (MPAA) enabled R + 1° and 2° alkenyl alcohol/carbamate/amide R1 H Mono-cyclic R1 H R1 H n = 0, 1, 2 m = 0, 1, 2, 3 4, 5, 6, 7, 8-membered 97 examples, up to 98% yield Alkenyl alcohol Alkenyl carbamate Alkenyl amide exo-metallocycles e Related natural products and drugs OH Me OR COOiPr N HO O H O O O H OH MeO Ph OH N Me O HO HO HO H OH Me OH Galantamine Griffonilide Latanoprost Ricinoleate Morphine (open angle glaucoma) (deodorants) (pain medication) (cognitive decline) Fig. 1 Chelation-assisted olefinic C-H functionalization. a, b Type of group-directed olefinic C–H activation. c Reports on geminal olefinic C–H activation by bicyclic palladacycles. d Geminal olefinic C–H functionalization of alkenyl alcohols, carbamates and amides (this work). e Structurally related bioactive and natural molecules 2 NATURE COMMUNICATIONS | (2019) 10:5109 | https://doi.org/10.1038/s41467-019-13098-1 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-13098-1 ARTICLE Table 1 Development of gem-group-directed olefinic C–H alkenylation R1 n = 0, 1, 2, 3, 4 n [Pd] FG R1 OBu conditions A, B or C 2 n + R FG R1 OBu 2 O n R H O Via FG 1 or 4 or 6 2a R2 [Pd] 3 or 5 or 7 Exo-metallocycle Functional group (FG) Conditions A Conditions B Conditions C FG1 = OH 2 1 (0.2 mmol), 2a (2.0 equiv), 4 (0.2 mmol), 2a (2.0 equiv), 6 (0.2 mmol), 2a (2.0 equiv), FG = OCONMe2 Pd(OAc) (10 mol%) Pd(OAc)2 (10 mol%) FG3 = CONHMe Pd(OAc)2 (10 mol%) 2 4 Ac-Gly-OH (20 mol%) Ac-Phe-OH (50 mol%) FG = CONMe2 Ac-Phe-OH (50 mol%) Ag CO (1.5 equiv) FG5 = OAc Ag2CO3 (1.5 equiv) Ag2CO3 (3.0 equiv) 2 3 6 o LiOH (30 mol%) FG = OMe Cs2CO3 (30 mol%) CF3CH2OH, 80 C, 16 h 7 CF CH OH (5.0 equiv) FG = HNCONMe2 CF3CH2OH (10.0 equiv) 3 2 8 o o FG = O-N=C(Me)2 1,4-dioxane, 70 C, 16 h MeCN, 70 C, 16 h FG9 = CONHOMe FG10 = CONHTs entry FG R1 R2 n conditions yield (%)a metallocycleb 1FG1 Pr H 0 A 30 (3va) 4 2FG1 Et H 1 A 69 (3aa) 5 3FG1 pentyl H 2 A 15 (3za) 6 4FG1 Et H 3 A <5 7 5FG1 Me Me 1 A <5 5 6FG1 HEt1A 5 5 7FG1 H H 1 A <5 5 8FG2 Pr H 0 B 56 (5aa) 6 9FG2 Et H 1 B <5 7 10 FG2 Me Me 0 B 0 6 11 FG2 HH0B 0 6 12 FG2 HPr0B 0 6 13 FG3 pentyl H 1 C 74 (7aa) 6 14 FG4 pentyl H 1 C 60 (7ha) 6 15 FG4 pentyl H 0 C 40 (7qa) 5 16 FG4 Et H 2 C 37 (7ra) 7 17 FG4 Et H 3 C 18 (7ta) 8 18 FG4 Me Me 1 C 0 6 19 FG4 HH1C 0 6 20 FG4 HMe1C 0 6 21 FG5 Et H 0,1 A,B,C 0 – 22 FG6 Et H 0,1 A,B,C <5 – 23 FG7 Pr H 0,1 A,B,C 0 – 24 FG8 Pr H 0,1 A,B,C 0 – 25 FG9 pentyl H 0,1 A,B,C 0 – 26 FG10 pentyl H 0,1 A,B,C 0 – aThe yields are isolated yields bThe sizes of exo-metallocycles concept has been remarkably expanded to positional selective C- intermediate, using picolinamide as the bidentate-chelation H bond activation in arenes and alkanes6–16, but its utilization in directing group (Fig. 1c)40. However, the major limitation is site-selective C(alkenyl)-H bond functionalization still remains that the exquisite selectivity is strictly restricted to the cleavage of elusive17–35. the C(alkenyl)–H bond that will result in six-membered exo- Formation of exo-metallocycle is rare in catalytic reactions36–39 cyclopalladation. Moreover, the installation and removal of and is often less competitive when forming an endo-metallocycle strongly coordinating directing group may impede the wide- is possible, presumably due to added conformational degrees of spread application of these transformations.