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https://doi.org/10.1038/s41467-019-13098-1 OPEN 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 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 -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 , 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, and Chemical Engineering, Hangzhou Normal University, Hangzhou 311121, China. *email: [email protected]; [email protected]

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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 /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

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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 (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. freedom and increased energy (Fig. 1b)41. Dong and co-workers Hydroxyl, carbamate and amide are valuable and widely demonstrated an exo-directing-group-enabled functionalization occurring functionalities which have been used in C–H functio- of sp3 C–H bonds via five-membered exo-palladacycles to provide nalizaiton6–8, and we envisioned that these weak and mono- 1,2-diols38. Recently, Engle’s group reported a carboxylic acid- dentate directing group could also enable the distal geminal C enabled C(alkenyl)-H functionalization via a characterized six- (alkenyl)-H activation by mono-cyclic exo-cyclometallation. membered palladacycle, using strong N,N-bidentate auxiliary Comparing to thermodynamically more stable and bicyclic pal- which was removable under nickel-catalyzed methanolysis con- ladacycles by N,N-bidentate chelation, mono-dentate-chelation ditions39. Carreira and co-workers also demonstrated an alkenyl protocol may functionalize widespread geminal carbon centers C–H iodination via six-membered alkenyl palladacycle that are one or more bonds further away from functional groups,

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Table 2 Olefinic C–H alkenylation of homoallylic alcoholsa

Pd(OAc)2 (10 mol%) 2 R n = 0, 1, 2 Ac-Phe-OH (50 mol%) 2 R1 OH 1 R Ag CO (1.5 equiv) R OH n 2 3 Cs CO (30 mol%) n H 2 3 (E) CF CH OH (10.0 equiv) R5 R3 3 2 3 + R5 R 1,4-dioxane, 70 oC, 16 h 4 R 4 Cond. A R 12 3a

Homoallyl alcohols R = Bu, 3aa, 69% R = Hex, 3ab, 75% (98/2) OH OH OH OH Cl O O O OH 3ac OEt O R = Me, , 73% (98/2) P Me R = Et, 3ad, 81% (97/3) O n OEt R = t-Bu, 3ae, 67% Me OR Me O Me Me Me R = Bn, 3af, 39% 3ai n = 0, 3aj, 55% R = CH CF , 3ag, 44% , 73% 3al, 75% 3am, 54% (88/12) 2 3 n = 3, 3ak, 54% (96/4) R = OMe 3ah, 78%

OH R OH O OH OH O OH Me OH O O n O O R OBu OBu Me N Me OBu OBu OBu Me Me Me Me n Me n Me Me

R = OMe, 3an, 65% n = 2, 3ba, 73% 3da, 48% R = Et, n = 0, 3ea, 52% n = 0, 3ga, 52% 3ia, 46% R = Me, 3ao, 71% n = 3, 3ca, 69% R = Me, n = 1, 3fa, 59% n = 1, 3ha, 52%

Br Me R OH R = H, 3ka, 56% OH Me OH Me OH O OH O O O O R = Me, 3la, 48% Me OBu R = OMe, 3ma, 55% OBu OBu OBu OBu R = Cl, 3na, 48% Me Me Me Me Me R = F, 3oa, 53% 3ja, 51% R = Ph, 3pa, 60% 3qa, 31% 3ra, 47% 3sa, 42%

Allyl alcohols O OH Bishomoallyl alcohol O O Me OH O OH O OBu OH Me OBu R OBu OBu O Me Me 3ta, 33% Me 3A, 33% OBu b R = H, 3va, 30% (44%) 3xa, 37%b Me HO R = Me, 3wa, 20% O O 3za, 15% (22%)c O OH O Me OBu OBu Me OBu (Z) Me Me 3ua, 52% (94/6) 3A′, 17% 3ya, 43%b

by the formation of small- to medium-sized mono-cyclic metal- we started investigation by employing previously reported Ru-, locycle intermediate, which are transient but less strained. While Rh- or Pd-catalyzed systems for hydroxyl-chelation-assisted C–H the formation of four-membered metallocycle is highly challen- alkenylation reactions42–44. Unfortunately, (E)-3-hexen-1-ol with ging, seven- and eight-membered cyclometallation are also much acrylate led to trace alkenylated/ product and/or poor less favored in general as the aliphatic carbon between the alkenyl regioselectivity under a variety of catalytic conditions. In this motif and the coordinating group rotates freely and increases the context, we envisioned that (Z)-alkenyl alcohol could be suitable entropic barrier significantly9,14. In line with our ongoing interest due to the following two inherent effects. First, incorporation of in olefinic C–H activation19,34, herein, we focus on gem-olefinic R1 group would make target olefinic C–H bond more reactive C-H activation via four- to eight-membered exo-cyclometallation, (Fig. 1b) due to increased nucleophilicity toward transition metal and the utility is characterized by the C–H functionalization of a and block or obviate competitive vicinal C-H activation sites. wide range of functionalized alkenes, including synthetically Second, absence of R2 group would avoid steric repulsion and valuable homoallyl-, bishomoallyl- and allyl alcohols/carbamates/ facilitate subsequent insertion step. Although various of ligands amides that constitute integral structural motifs in natural pro- were inefficient, mono-N-protected amino acid (MPAA) com- ducts and drug design (Fig. 1d, e). bined with palladium was found to promote the alkenylation reaction45,46, with Ac-Phe-OH emerging as the best one (see Results Supplementary Table 1). Fine-tuning the chain length between Development of gem-group-directed alkenyl C-H alkenylation. the hydroxyl and olefinic carbon greatly influenced such C-H As the alcohol can be naturally incorporated into the product functionalization. While the reactions of (Z)-3-hexen-1-ol (1a) without installation and removal steps in C–H functionalization, (5-exo) reacted smoothly with acrylate to provide diene 3 in 69%

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Table 3 Olefinic C–H alkenylation of alkenyl carbamatesa

NR3R4 NR3R4 Pd(OAc)2 (10 mol%) O O Ac-Gly-OH (20 mol%) O O Ag2CO3 (3.0 equiv) 5 H 5 R 1 + R 1 R o R CF 3CH2OH, 80 C, 16 h R2 Cond. B R2 4 2 5

R1 R2 R = Bu, 5aa, 56% N NMe2 NMe2 Me, 5ab , 45% NMe2 NMe2 Et, 5ac, 46% O O O O O O O O O O O O Hex, 5ad , 49% O O O OBu O OBu OR i-Bu, 5ae, 55% O OBu Me Ph, 5af, 46% Me Me Me Me OMe 5ag, 50% 5ah , 47% 5ba, 48% 5ca, 51% 5da, R1 = R2 = Et, 54% 5ea , R1 = Et, R2 = Me, 53%

i N Pr2 i i N Pr2 N Pr2 i NR2 N Pr2 NMe2 O O O O O O O O O O O O O O O O O O OBu OBu OBu OBu OBu Me OBu Me Me Me Me Me Me Me Me 5fa, 62% 5ga, 48% R = Me, 5ha, 62% 5ja, 95% 5la, 63% i-Pr, 5ia, 70% 5ka, 98% a The yields are isolated yields based on carbamate 4. yield, cis-2-hexen-1-ol (4-exo) and cis-4-decen-1-ol (6-exo) led to (FG8) and amides with acidic N-H bonds (FG9 and FG10), desired products in only 30% and 15% yields respectively were also tested, but none of them could furnish desired C-H (Table 1, entries 1–3). However, cis-5-octen-1-ol (7-exo) failed to functionalization (Table 1, entries 21–26). react (Table 1, entry 4). Reactions of differently substituted alkenyl alcohols were performed to investigate the steric and electronic influences on geminal C-H activation. Unfortunately, Substrate scope. With the optimized reaction conditions in hand, (E)-3-hexen-1-ol and 4-methyl-3-penten-1-ol led to trace product we firstly examined the scope and limitation of alkenes 2 by due to the difficulty in formation of exo-palladacycle and/or employing alcohol 1a as the substrate (Table 2). It was found that alkenylation by steric repulsion (Table 1, entries 5 and 6). a wide variety of acrylates 2 could provide the alkenylated pro- Meanwhile, terminal alkenyl alcohol showed very limited reac- ducts in 39–81% yields (3aa-3ai). Remarkably, vinyl were tivity presumably due to the decreased nucleophilicity of C-H also suitable coupling partners (3aj and 3ak). Moreover, both bond toward transition metal (Table 1, entry 7). Carbamate vinyl phosphonate and styrene were reacted smoothly, affording derived from (Z)-allylic alcohol also led to satisfactory results products 3al and 3am in 75% and 54% yields, respectively. Even with the help of Ac-Ile-OH ligand instead via 6-membered exo- acrylamides reacted well, though amides are usually prone to palladacycle (Table 1, entry 8). However, homoallyl carbamate coordination (3an and 3ao). Thereafter, we turned our attention did not react (7-exo) (Table 1, entry 9). Similarly, other differently to expand the scope of the reaction to other representative substituted alkenyl carbamate exhibited no reactivity toward homoallylic alcohols 1. Alcohols bearing longer alkyl chain also acrylate due to disfavored steric and/or electronic influences reacted well (3ba and 3ca). Introducing of alkyl group at the (Table 1, entries 10–12). Although acrylamides were commonly allylic position showed moderate yield (3da). The versatile cata- used in alkenyl C-H fucntionalization, there is still no report on lytic system was not limited to primary alcohols. Indeed, we were 17–35 Csp2-H transformation of nonconjugated alkenyl amides . pleased to identify easily oxidized alcohols as viable Herein, amide was successfully demonstrated to be effective in substrates in this protocol likewise47. Incorporation of alkyl, aryl geminal C-H functionalization. Both secondary and and even alkenyl groups at the carbon adjacent to hydroxyl group amides provided corresponding geminal products in good yields, showed good results (3ea-3sa). In particular, aryl ring bearing which proceeded by 6-membered palladacycles (Table 1, entries such as F and Cl can be well tolerated in this protocol 13 and 14). Notably, this protocol also allowed palladium catalyst (3na and 3oa), which is synthetically useful for further elabora- to functionalize alkenes bearing longer or shorter chain lengths tions of the products. Unfortunately, alkenyl alcohol bearing between the amide and olefinic carbon, which proceeded by 5- sensitive para-Br led to decreased yield due to undesired side and even 7-membered palladacycles, albeit with moderate yields reactions (3qa). Interestingly, easily decomposed tertiary alcohol (Table 1, entries 15 and 16). Interestingly, a weak coordinating of also reacted, but leading to cyclization products 3A (33%) and amide to form 8-membered palladacycle was also observed, albeit 3A′ (17%) due to restricted conformational freedom and bond with most of the amide substrate recovered (Table 1, entry 17). angle compression. Herein, the Z-configuration of product 3A′ Moreover, steric and electronic influences on geminal C-H acti- implied the involvement of the anti-alkoxypalladation process in vation were consistent with the reactions of alcohols and carba- the cyclization41,42. Moreover, 4-phenyl-3-buten-1-ol converted mates (Table 1, entries 18–20). All of these results showed a well (3ua). Cyclic alcohol such as 2-cyclohexene-1-methanol also precise recognition of distance and geometry in these alkenyl C-H reacted, albeit with reduced efficiency (3ta). functionalizations. Other alcohol-derived functional groups Notably, simple allyl alcohols, widely used as allylation (FGs), such as ester (FG5), ether (FG6), urea (FG7), oxime reagent48,49, are seldom C-H functionalized due to competitive

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Table 4 Olefinic C–H alkenylation of alkenyl amidesa

n = 0, 1, 2, 3 Pd(OAc)2 (10 mol%) Ac-Phe-OH (50 mol%) O R3 O R3 Ag2CO3 (1.5 equiv) N N LiOH (30 mol%) R1 R4 1 4 n R n R CF3CH 2OH (5.0 equiv) + R5 o R2 R2 H MeCN, 70 C, 16 h a 5 62Cond. C 7 R

Me 6-membered exo-palladacycle Me O Me Me O Me Me O Me O Me R = Bu, 7aa, 74% NH NH NH NH R = Me, 7ab, 70% R = Et, 7ac, 64%

R = t-Bu, 7ad, 72% Me R = Ph, 7ae, 61% OBu OR R = OCH2CH2 OMe, 7af, 49% 7ag, 48% O 7ah, 43% 7ba, 67% O O Cl Me O Me Me O Me O Ph O Me NH Me O NH NH NH NH Me Me

OBu OBu O OBu R = Bu, 7da, 41% 7ea, 43% 7ca, 64% O OR O 7fd O 7ga, 63% O R = t-Bu, 7dd, 63% , 46% O

Me O Me Me O Me Me O Me Me O Me O Me N N N NH N Me Me Me Ph Me Me

OBu OBu OBu OBu OBu 7ha, 60% 7ia, 58% 7ja, 62% O 7ka, 45% 7la, 40% O O O O

5-membered exo-palladacycle

Me Me Me Me Me Me Me HN NH N HN N Me Ph O Me O O O O

OBu OMe OBu OBu OBu 7na, 45% O 7pa, 51% 7qa, 40% 7ma, 51% O 7oa, 43% O O O

7-membered exo-palladacycle 8-membered exo-palladacycle

O Me O O Me N Me Me N Me N Me Me Me Me Me

OBu OBu 7ra, 37% 7sa, 60% O O OBu 7ta, 18% O a The yields are isolated yields based on amide 6.

C–H cleavage sites and easy decomposition under catalytic could be served as coupling partners (5aa-5ah). Different dialkyl conditions. Meanwhile, four-membered metallocycle is very carbamates were examined to optimize the C–H activation, and rare in catalytic reactions14, whose utilization in olefinic C–H installation of bulky isopropyl group led to alkenylated product activation has not been reported17–35. To our satisfaction, in 62% yield (5da-5fa). Carbamate derived from secondary (Z)-allyl alcohols could be alkenylated in moderate yields, using alcohol also converted without any decrease in efficiency (5ga). N-acetyl-L-isoleucine (Ac-Ile-OH) as the ligand (3va-3ya). 3-Hydroxyl cyclohexene is a widely occurring skeleton in Moreover, cis-4-decen-1-ol was proved to be reactive, albeit with bioactive molecules and is highly attractive substrate for C–H reduced efficiency (3za). The synthetic flexibility afforded by functionalization (Fig. 1e). To our delight, carbamate masked allyl- and bishomoallyl alcohols greatly expands the range of core 3-hydroxyl cyclohexene provided 62–70% yields (5ha and 5ia). structures that can subsequently be accessed. Notably, cyclohexene bearing quaternary carbon, which can be The carbamate was usually employed as both a DG and an found in medical molecules such as galantamine, led to 95% yield alcohol surrogate in C–H activation. Herein, allylic alcohol (5ja). Finally, this protocol also highlighted tolerance of sensitive masked as its carbamate could be well C–H functionalized with benzyl and even cinnamyl moieties, producing products 5ka and the help of Ac-Gly-OH ligand instead (Table 3). Various acrylates 5la in 98% and 63% yields respectively.

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a Intermolecular competition

Trend under Cond. A Me OH OH OH Me (4-exo) (6-exo) OH H H > > H H > H H Me H (5-exo) (5-endo) Me H 1a 8 1v 1z′

Trend under Cond. C Me Me O O Me NMe2 NMe2 Me

NMe2 O > > > NMe (7-exo) H 2 H (6-exo) H (5-exo) H (8-exo) O 6h 6q 6r 6t

b Intramolecular competition (selective C-H functionalization)

Me Me H Me H Me Me H 2a (2.0 equiv) H Cond. A Me H OH OH COOBu OH 3 h H H H H H (5-exo > 5-endo) COOBu Not observed 9 9a, 30%

Fig. 2 Competition experiments. a Intermolecular competition experiments using alkenyl alcohols or alkenyl amides to rank the reaction trend under Cond. A or Cond C. b Intramolecular competition experiment using compound 9

Next, we focused on substrate scope of alkyl amide directed product 9a (Fig. 2b). Both of the inter- and intra-molecular geminal C(alkenyl)-H fucntionalization by 5- to 8-membered competition experiments showed the preferential formation of palladacycles (Table 4). The C-H alkenylation proceeded 5-exo-palladacycle over 5-endo-palladacycle, being inconsistent smoothly with various olefinic coupling partners such as with previous reports38,41. Similarly, while 4-methyl-4- acrylates, vinyl and even styrene, providing 43–74% yields pentenamide exhibited limited reactivity (14% yield) and poor (7aa-7ah). Differently N-substituted secondary amides also selectivity under conditions C, 7ra was obtained in 37% yield, reacted well with acrylates (7ba-7ea). Although primary amide suggesting the preferential formation of exo-palladacycle. Also, led to trace product, tertiary amides led to good yields (7ha and competition studies were performed for acrylate 2a with amide 7ia). Incorporation of alkyl and benzyl groups at the carbon 6h, 6q, 6r or 6t under conditions C, and the relative reactivities of adjacent to amide group showed good results (7ja, 7ka and 7la). amides were ranked to be 6h> 6q > 6r > 6t. These results were Differently N-substituted alkenyl amides 6m-6q also led to generally consistent with prior substrate scoping (Table 4) and moderate yields proceeded by 5-membered exo-palladacycles. the kinetically and thermodynamically favored exo-cyclopallada- Notably, although alkenyl 6r exhibited decreased reactivity due tion dominating the geminal Csp2-H activation (Fig. 2a, trend to the difficulty in the formation of 7-membered exo-palladacycle, under Cond. C). Notably, both substrates 1z’ and 6h converted by incorporation of methyl group greatly facilitate the C-H the formation of 6-membered exo-palladacycles, but alkenyl alkenylation (7sa, 60% yield). Interestingly, amide 6t bearing amide 6h reacted efficiently because the reduced longer alkyl chain still showed limited reactivity toward acrylate conformational degrees of freedom. Moreover, while amide 6r (7ta). did react via 7-exo-cyclopalladation, homoallyl carbamate did not convert even at elevated temperatures (Table 1, entry 9), Competition experiments and mechanistic considerations. exhibiting the great influence of coordinating effect. All of these Next, competition experiments were performed for acrylate 2a primary results exhibited that the exo- and endo-cyclometalla- and alcohols 1 or amides 6 under optimal conditions to rank the tions were governed by coordination strength and conformation relative reactivities, thus demonstrating the preferential formation effects on the C-H activation step9,16, and the detailed of the related alkenyl metallocycle intermediates (see Fig. 2 and mechanistic studies will be discussed in a later report. Deuterium Supplementary Tables 4-5). incorporation experiments supported the irreversibility of the On the basis of the data compiled from intermolecular C-H activation steps, and no Z/E isomerization excluded competition experiments, the relative reactivities of alcohols 1a, other possible mechanistic pathway such as π-allylpalladium(II) 1v, 8 and 1z´ were ranked to be 1a > 8 > 1v > 1z´ (Fig. 2a, trend formation or nucleometalation/β-X elimination39,50. These under Cond. A). These results exhibited that alkenyl C-H results combined with kinetic isotope effect (KIE) experiments activation by 5-membered exo-palladacycle (1a) occurred pre- exhibited that the irreversible C-H bond cleavage step originated ferentially over 4-membered exo-palladacycle (1v), and the C-H the site selectivity, thus possible mechanisms based on exo- activation by 6-membered exo-palladacycle (1z’) was the most palladacycles are proposed (see Supplementary Figs. 1–4)51. disfavored because the added freely rotating sp3 carbon center significantly increases the entropic barrier for assembling the desired transition state, being consistent with our observation in Preparative scale synthesis and coordinating group removal. substrate scoping (Table 2). Notably, vicinal Csp2-H functiona- To establish scalability, the conversion of 1a was run at a gram lization by 5-membered endo-palladacycle (8) was also efficient scale to give 3aa in 71% yield (Fig. 3a). Olefinic C-H alkenylation under Cond. A. However, formation of 5-exo-metallocycle was of 4j at a preparative scale was also successful. The removal of the found to be more competitive than the formation of 5-endo- carbamate in 5ja was readily accomplished by reduction at room metallocycle (1a > 8). An alcohol 9 bearing two alkenyl moieties temperature to give diol 11 in 73% yield (Fig. 3b). Moreover, was synthesized and reacted under Cond. A, and the C-H geminal C-H olefination of alkenyl amides reacted smoothly at alkenylation only occurred on Z-alkenyl moiety to provide gram-scale, providing 7aa and 7ha in good yields. Notably, amide

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ab Gram-scale preparation of 3aa Gram-scale preparation of 5ja and carbamate removal

O Me 2a NiPr OH OH Me 2 2a O Cond. B Me Me O Me NiPr Me Cond. A 2 Gram scale H O H Gram scale 5ja, 92% COOBu 1a, 1.0 g 3aa, 71% COOBu 4j, 1.0 g c Gram-scale preparation of 7aa/7ha and amide removal Carbamate DIBAL-H Me O removal Me O Me Me O Me (R = Me) OH 2a N N Cond. C R 1. NaOH (aq) Me R + OH Gram scale 2. H3O Me H OH COOBu Amide removal 12, 67% O 6, 1.0 g R = H, 7aa, 67% 11, 73% OH R = Me, 7ha, 60%

Fig. 3 Gram-scale synthesis and directing group removal. a Gram-scale synthesis of compound 3aa. b Gram-scale synthesis of compound 5ja and carbamate removal. c Gram-scale synthesis of compound 7aa/7ha and amide removal

a Olefinic C-H modifications including natural products and drug derivatives

(+)-dehydroabietylamine derivative Geraniol derivative i N Pr2 HO O HO HO Me O Me Me O O O O Me Sitosteroxyl O Me Sitosteroxyl Me N H Me H Me Me Me Me Me 3ap, 45% 3aq, 62% 3ar, 54% 5jp, 74% Cond. A Cond. A Cond. A Cond. B

Me Me Ricinoleate derivatives Sitosteroxyl = OH OH Me Me O Me Me R Me R O H Me H HO MeO

H H R = OBu, 10aa, 82% R = COOBu, 10ba, 67% O R = Sitosteroxyl 10ap, 59% R = PO(OEt)2, 10bl, 61% Fromβ -sitosterol Cond. A Cond. A

b Olefinic C-H modifications of methyl 1-testosterone derivative

H H O H OCONiPr O NiPr 2 NaBH 2 H H 4 H H H H Cond. B O H H R H Me Me 2 H Me NaH, H HO HO HO Me i Me Me ClCONHPr2 Me Me Me Methyl 1-testosterone, 13 13a, 53% (2 steps) R = COOBu, 13aa, 76% an designed to R = PO(OEt)2, 13al, 68% treat testosterone deficiency R = SO2Ph, 13aq, 55%

c Selective olefinic C-H alkenylation of inseparable Z/E alkenes

O O Me O Me O NMe2 NMe2 NMe2 NMe2 2a Cond. C + +

6h-(Z ) 6h-(E ), 70% recovered 6h-(E ) 7ha, 75% COOBu Me Me 1:1 mixture (inseparable) Separable!

Fig. 4 Late-stage C–H functionalization of natural and pharmaceutical compounds. a Olefinic C–H modifications including natural products and drug derivatives. b Olefinic C–H alkenylation of methyl 1-testosterone derivative. c Selective conversion of inseparable Z/E alkenyl amides

8 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 removal was realized by simple hydrolysis, yielding dienoic acid alkene 2 (2.0 equiv, 0.4 mmol) were added into the solution in sequence. The vial 12 in good yield (Fig. 3c). was sealed under argon and heated to 70 °C with stirring for 16 h. After cooling down, the mixture was concentrated to give the crude product which was directly applied to a flash column chromatography for separation (EtOAc/Petroleum ether Late-stage C-H functionalization. To further demonstrate the mixtures). utility of our methods, we attempted late-stage C–H functionali- zation of natural and medicinal compounds (Fig. 4). Gratifyingly, Data availability these protocols were characterized by high chemoselectivity, The authors declare that all data supporting the findings of this study are available within highlighting the successful conversion of sensitive geraniol and the article and its Supplementary Information files. All data are also available from the (+)-dehydroabietylamine as well as the cholesteryl derivatives corresponding authors upon reasonable request. (3ap, 3aq, 3ar and 5jp). Ricinoleate derivatives were smoothly reacted, delivering the targets in good to excellent yields (10aa- Received: 1 September 2018; Accepted: 21 October 2019; 10bl,59–82% yields) (Fig. 4a). Methyl-1-testosterone is an ana- bolic steroid derivative to treat male testosterone deficiency. Herein, using steroid-derived carbamate 13a as a representative drug molecule for diversification, three different alkenylation analogs were readily accessed (13aa-13aq,55–76% yields, Fig. 4b). 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J.Z. catalyzed oxidative coupling of N-allyl arenesulfonamides with alkynes. acknowledges a Xihu Scholar award from Hangzhou City, China. Angew. Chem., Int. Ed. 51, 12348–12352 (2012). 32. Morimoto, M., Miura, T. & Murakami, M. Rhodium-catalyzed Author contributions dehydrogenative borylation of aliphatic terminal alkenes with pinacolborane. J.Z. and G.Z. supervised and J.Z. conceived the project. K.M., T.L., C.Y., and C.S. per- Angew. Chem., Int. Ed. 54, 12659–12663 (2015). formed all of the experiments, and K.M., T.L., and C.Y. contributed equally. J.Z. prepared 33. Kuppusamy, R., Muralirajan, K. & Cheng, C.-H. Cobalt(III)-catalyzed [5 + 1] this manuscript with the assistance of G.Z., K.M., and T.L. All of the authors participated annulation for 2H-chromenes synthesis via vinylic C-H activation and in data analysis and discussions. intramolecular . ACS Catal. 6, 3909–3913 (2016). 34. Yu, C., Zhang, J. & Zhong, G. One step synthesis of γ-alkylidenebutenolides from simple vinyl carboxylic acids and alkenes. Chem. Commun. 53, Competing interests 9902–9905 (2017). The authors declare no competing interests. 35. Wang, K., Hu, F., Zhang, Y. & Wang, J. Directing group-assisted transition- metal-catalyzed vinylic C-H bond functionalization. Sci. Chin. Chem. 58, Additional information 1252–1265 (2015). Supplementary information 36. Kong, W.-J. et al. Pd-catalyzed α-selective C-H functionalization of olefins: en is available for this paper at https://doi.org/10.1038/s41467- route to 4-imino-β-lactams. J. Am. Chem. Soc. 138, 2146–2149 (2016). 019-13098-1. 37. Tsai, H.-C., Huang, Y.-H. & Chou, C.-M. Rapid access to ortho-alkylated Correspondence vinylarenes from aromatic acids by dearomatization and tandem and requests for materials should be addressed to J.Z. or G.Z. decarboxylative C-H olefination/ rearomatization. Org. Lett. 20, 1328–1332 Peer review information (2018). Nature Communications thanks the anonymous reviewer(s) for 38. Ren, Z., Mo, F. & Dong, G. Catalytic functionalization of unactivated sp3 C-H their contribution to the peer review of this work. bonds via exo-directing groups: synthesis of chemically differentiated 1,2- Reprints and permission information diols. J. Am. Chem. Soc. 134, 16991–16994 (2012). is available at http://www.nature.com/reprints 39. Liu, M. et al. C(alkenyl)-H activation via six-membered palladacycles: catalytic – Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in 1,3-diene synthesis. J. Am. Chem. Soc. 140, 5805 5813 (2018). fi 40. Schreib, B. S. & Carreira, E. M. Palladium-catalyzed regioselective C−H published maps and institutional af liations. iodination of unactivated alkenes. J. Am. Chem. Soc. 141, 8758–8763 (2019). 41. Mawo, R. Y., Mustakim, S., Young, V. G., Hoffmann, M. R. & Smoliakova, I. P. 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Ruthenium(II)-catalyzed synthesis of material in this article are included in the article’s Creative Commons license, unless isochromenes by C-H activation with weakly coordinating aliphatic hydroxyl indicated otherwise in a credit line to the material. If material is not included in the groups. Chem. Eur. J. 20, 5409–5413 (2014). article’s Creative Commons license and your intended use is not permitted by statutory 44. Morimoto, K., Hirano, K., Satoh, T. & Miura, M. Synthesis of isochromene regulation or exceeds the permitted use, you will need to obtain permission directly from and related derivatives by rhodium-catalyzed oxidative coupling of benzyl and the copyright holder. To view a copy of this license, visit http://creativecommons.org/ – allyl alcohols with alkynes. J. Org. Chem. 76, 9548 9551 (2011). licenses/by/4.0/. 45. Wang, D.-H., Engle, K. M., Shi, B.-F. & Yu, J.-Q. Ligand-enabled reactivity and selectivity in a synthetically versatile aryl C-H olefination. Science 327, 315–319 (2010). © The Author(s) 2019

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