Geminal group-directed olefinic C-H functionalization via four- to eight-membered exo-metallocycles

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, functionalization of a C(alkenyl)-H bond geminal to the directing group via exo-metallocycle pathway 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-palladacycles 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.

A lkenes are commonly present structural motifs and are versatile building blocks in organic synthesis 1 . Direct functionalization of unactivated alkenyl C-H bonds represents the most straightforward way to valuable alkenes from simpler ones [2][3][4][5][6][7][8] . A fundamental transformation for direct olefinic C-H functionalization is the Heck reaction, which proceeds by olefin insertion followed by β-hydride elimination [2][3][4] . In recent years, radical C-H alkenylations have also been developed with a variety of carbon/heteroatom-centered radicals, proceeding through radical addition to alkenes and following single-electrontransfer (SET) oxidation/elimination 5 . However, the site-and stereo-selectivity of these methods are largely governed by intrinsic steric and electronically biased properties of the alkene substrates due to the addition-elimination mechanisms. Actually, controlling the site-and stereo-selectivity of C(alkenyl)-H cleavage still remains a formidable challenge due to very subtle differences in terms of bond strength and electronic properties.
Pioneered by Murai´s work on Ru-catalyzed carbonyl-directed ortho-C-H activation, broadly defined directing groups (DGs) have served as highly effective tools for controlling C-H bond activations via cyclometallations [6][7][8] . Most of the directed aromatic-and aliphatic C-H activations proceeded through a normal fiveor six-membered cyclometallated intermediate, however, there are very limited reports on protocols by distinct cyclometallations. The Yu group previously disclosed a Pd(II)-catalyzed aromatic C-H functionalizations directed by distal weakly coordinating functional groups via six-or seven-membered cyclopalladation 9 . The same group also reported a nitrile-based template directed meta-selective C-H alkenylation, proceeding by a macrocyclic pre-transition state 10,11 . Functionaliztion of para C-H bonds was addressed as well using the similar templatebased strategy by the Maiti group 12 . Chelation-assisted strategy was also widely used in aliphatic C-H activations 13 . The Gaunt group reported a palladium-catalyzed C-H bond activation through a four-membered cyclopalladation pathway, leading to the selective synthesis of nitrogen heterocycles 14 . Sanford and coworkers described a nitrogen-directed transannular C(alkyl)-H activation of alicyclic amine cores 15 . Very recently, the Yu group disclosed an aliphatic γ-C-H arylation protocol to be proceeded by conventionally disfavored six-membered cyclopalladation, using a strained directing group derived from pyruvic acid 16 . Considering the number of novel reactions that have arisen from metallacycle intermediates, identification of distinct cyclometallation pathways would lead to novel C-H bond transformations.
Hydroxyl, carbamate and amide are valuable and widely occurring functionalities which have been used in C-H functionalizaiton [6][7][8] , and we envisioned that these weak and monodentate directing group could also enable the distal geminal C (alkenyl)-H activation by mono-cyclic exo-cyclometallation. Comparing to thermodynamically more stable and bicyclic palladacycles by N,N-bidentate chelation, mono-dentate-chelation protocol may functionalize widespread geminal carbon centers that are one or more bonds further away from functional groups, by the formation of small-to medium-sized mono-cyclic metallocycle intermediate, which are transient but less strained. While the formation of four-membered metallocycle is highly challenging, seven-and eight-membered cyclometallation are also much less favored in general as the aliphatic carbon between the alkenyl motif and the coordinating group rotates freely and increases the entropic barrier significantly 9,14 . In line with our ongoing interest in olefinic C-H activation 19,34 , herein, we focus on gem-olefinic C-H activation via four-to eight-membered exo-cyclometallation, and the utility is characterized by the C-H functionalization of a wide range of functionalized alkenes, including synthetically valuable homoallyl-, bishomoallyl-and allyl alcohols/carbamates/ amides that constitute integral structural motifs in natural products and drug design (Fig. 1d, e).

Results
Development of gem-group-directed alkenyl C-H alkenylation.
Substrate scope. With the optimized reaction conditions in hand, we firstly examined the scope and limitation of alkenes 2 by employing alcohol 1a as the substrate (Table 2). It was found that a wide variety of acrylates 2 could provide the alkenylated products in 39-81% yields (3aa-3ai). Remarkably, vinyl ketones were also suitable coupling partners (3aj and 3ak). Moreover, both vinyl phosphonate and styrene were reacted smoothly, affording products 3al and 3am in 75% and 54% yields, respectively. Even acrylamides reacted well, though amides are usually prone to coordination (3an and 3ao). Thereafter, we turned our attention to expand the scope of the reaction to other representative homoallylic alcohols 1. Alcohols bearing longer alkyl chain also reacted well (3ba and 3ca). Introducing of alkyl group at the allylic position showed moderate yield (3da). The versatile catalytic system was not limited to primary alcohols. Indeed, we were pleased to identify easily oxidized secondary alcohols as viable substrates in this protocol likewise 47 . Incorporation of alkyl, aryl and even alkenyl groups at the carbon adjacent to hydroxyl group showed good results (3ea-3sa). In particular, aryl ring bearing substituents such as F and Cl can be well tolerated in this protocol (3na and 3oa), which is synthetically useful for further elaborations of the products. Unfortunately, alkenyl alcohol bearing sensitive para-Br led to decreased yield due to undesired side reactions (3qa). Interestingly, easily decomposed tertiary alcohol also reacted, but leading to cyclization products 3A (33%) and 3A′ (17%) due to restricted conformational freedom and bond angle compression. Herein, the Z-configuration of product 3A′ implied the involvement of the anti-alkoxypalladation process in the cyclization 41,42 . Moreover, 4-phenyl-3-buten-1-ol converted well (3ua). Cyclic alcohol such as 2-cyclohexene-1-methanol also reacted, albeit with reduced efficiency (3ta).
The carbamate was usually employed as both a DG and an alcohol surrogate in C-H activation. Herein, allylic alcohol masked as its carbamate could be well C-H functionalized with the help of Ac-Gly-OH ligand instead (Table 3). Various acrylates could be served as coupling partners (5aa-5ah). Different dialkyl carbamates were examined to optimize the C-H activation, and installation of bulky isopropyl group led to alkenylated product in 62% yield (5da-5fa). Carbamate derived from secondary alcohol also converted without any decrease in efficiency (5ga). 3-Hydroxyl cyclohexene is a widely occurring skeleton in bioactive molecules and is highly attractive substrate for C-H functionalization (Fig. 1e). To our delight, carbamate masked 3-hydroxyl cyclohexene provided 62-70% yields (5ha and 5ia). Notably, cyclohexene bearing quaternary carbon, which can be found in medical molecules such as galantamine, led to 95% yield (5ja). Finally, this protocol also highlighted tolerance of sensitive benzyl and even cinnamyl moieties, producing products 5ka and 5la in 98% and 63% yields respectively.

ARTICLE
Next, we focused on substrate scope of alkyl amide directed geminal C(alkenyl)-H fucntionalization by 5-to 8-membered palladacycles ( Table 4). The C-H alkenylation proceeded smoothly with various olefinic coupling partners such as acrylates, vinyl ketone and even styrene, providing 43-74% yields (7aa-7ah). Differently N-substituted secondary amides also reacted well with acrylates (7ba-7ea). Although primary amide led to trace product, tertiary amides led to good yields (7ha and 7ia). Incorporation of alkyl and benzyl groups at the carbon adjacent to amide group showed good results (7ja, 7ka and 7la). Differently N-substituted alkenyl amides 6m-6q also led to moderate yields proceeded by 5-membered exo-palladacycles. Notably, although alkenyl 6r exhibited decreased reactivity due to the difficulty in the formation of 7-membered exo-palladacycle, incorporation of methyl group greatly facilitate the C-H alkenylation (7sa, 60% yield). Interestingly, amide 6t bearing longer alkyl chain still showed limited reactivity toward acrylate (7ta).

Competition experiments and mechanistic considerations.
Next, competition experiments were performed for acrylate 2a and alcohols 1 or amides 6 under optimal conditions to rank the relative reactivities, thus demonstrating the preferential formation of the related alkenyl metallocycle intermediates (see Fig. 2 and Supplementary Tables 4-5).
On the basis of the data compiled from intermolecular competition experiments, the relative reactivities of alcohols 1a, 1v, 8 and 1z´ were ranked to be 1a > 8 > 1v > 1z´ (Fig. 2a, trend under Cond. A). These results exhibited that alkenyl C-H activation by 5-membered exo-palladacycle (1a) occurred preferentially over 4-membered exo-palladacycle (1v), and the C-H activation by 6-membered exo-palladacycle (1z') was the most disfavored because the added freely rotating sp 3 carbon center significantly increases the entropic barrier for assembling the desired transition state, being consistent with our observation in substrate scoping (Table 2). Notably, vicinal C sp2 -H functionalization by 5-membered endo-palladacycle (8) was also efficient under Cond. A. However, formation of 5-exo-metallocycle was found to be more competitive than the formation of 5-endometallocycle (1a > 8). An alcohol 9 bearing two alkenyl moieties was synthesized and reacted under Cond. A, and the C-H alkenylation only occurred on Z-alkenyl moiety to provide product 9a (Fig. 2b). Both of the inter-and intra-molecular competition experiments showed the preferential formation of 5-exo-palladacycle over 5-endo-palladacycle, being inconsistent with previous reports 38,41 . Similarly, while 4-methyl-4pentenamide exhibited limited reactivity (14% yield) and poor selectivity under conditions C, 7ra was obtained in 37% yield, suggesting the preferential formation of exo-palladacycle. Also, competition studies were performed for acrylate 2a with amide 6h, 6q, 6r or 6t under conditions C, and the relative reactivities of amides were ranked to be 6 h > 6q > 6r > 6t. These results were generally consistent with prior substrate scoping (Table 4) and the kinetically and thermodynamically favored exo-cyclopalladation dominating the geminal C sp2 -H activation (Fig. 2a, trend under Cond. C). Notably, both substrates 1z' and 6h converted by the formation of 6-membered exo-palladacycles, but alkenyl amide 6h reacted efficiently because the carbonyl group reduced conformational degrees of freedom. Moreover, while amide 6r did react via 7-exo-cyclopalladation, homoallyl carbamate did not convert even at elevated temperatures (Table 1, entry 9), exhibiting the great influence of coordinating effect. All of these primary results exhibited that the exoand endo-cyclometallations were governed by coordination strength and conformation effects on the C-H activation step 9,16 , and the detailed mechanistic studies will be discussed in a later report. Deuterium incorporation experiments supported the irreversibility of the C-H activation steps, and no Z/E isomerization excluded other possible mechanistic pathway such as π-allylpalladium(II) formation or nucleometalation/β-X elimination 39,50 . These results combined with kinetic isotope effect (KIE) experiments exhibited that the irreversible C-H bond cleavage step originated the site selectivity, thus possible mechanisms based on exopalladacycles are proposed (see Supplementary Figs. 1-4) 51 .
Preparative scale synthesis and coordinating group removal. To establish scalability, the conversion of 1a was run at a gram scale to give 3aa in 71% yield (Fig. 3a). Olefinic C-H alkenylation of 4j at a preparative scale was also successful. The removal of the carbamate in 5ja was readily accomplished by reduction at room temperature to give diol 11 in 73% yield (Fig. 3b)  Late-stage C-H functionalization. To further demonstrate the utility of our methods, we attempted late-stage C-H functionalization of natural and medicinal compounds (Fig. 4). Gratifyingly, these protocols were characterized by high chemoselectivity, highlighting the successful conversion of sensitive geraniol and (+)-dehydroabietylamine as well as the cholesteryl derivatives (3ap, 3aq, 3ar and 5jp). Ricinoleate derivatives were smoothly reacted, delivering the targets in good to excellent yields (10aa-10bl, 59-82% yields) (Fig. 4a). Methyl-1-testosterone is an anabolic 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).
Given that many therapeutic agents contain alkenyl alcohol moieties, we expect our methodology to provide valuable opportunities for streamlining analog generation and thereby accelerating structure-activity relationship studies in drug discovery. Finally, if an inseparable mixture of Zand E-alkenyl amides 6h was subjected to Cond. C, Z-alkene reacted smoothly to provide diene 7ha in 75% yield, with the unreacted E-isomer successfully recovered (Fig. 4c).

Discussion
In summary, we have presented a chelation-assisted geminal C (alkenyl)-H functionalization of alkenyl alcohols, carbamates and amides by palladium catalysis. Such olefinic C-H functionalization proceeds via unconventional four-to eight-membered exopalladacycles and allows the alkenylation of (Z)-configurated and cyclic homoallyl-, bishomoallyl-, and allyl alcohols/carbamates/ amides, which are particularly important features of numerous natural products and pharmaceutical agents. The protocols tolerate a wide variety of distances between the olefinic C-H bonds and the coordinating groups, enable the gram-scale preparation and modification of ricinoleate and even steroid derivatives, demonstrating the practicality and versatility. Furthermore, the carbamate and amide auxiliary are smoothly removed under mild reduction or hydrolysis conditions. This work greatly expands the utility of current C(alkenyl)-H activation reactions that are based on fiveand six-membered endo-/exo-cyclometallation, and we anticipate that this method will find broad applicability in multifarious synthetic endeavors.
General procedure for C-H alkenylation of carbamates. An oven-dried vial was charged with Pd(OAc) 2 (10 mol%, 0.02 mmol), Ac-Gly-OH (20 mol%, 0.04 mmol), Ag 2 CO 3 (3.0 equiv, 0.60 mmol) and CF 3 CH 2 OH (1.0 mL). Then, carbamate 4 (1.0 equiv, 0.20 mmol) and alkene 2 (2.0 equiv, 0.40 mmol) were added into the solution in sequence. The vial was sealed under argon and heated to 80°C with stirring for 16-24 h. After cooling down, the mixture was filtered and concentrated to give the crude product which was directly applied to a flash column chromatography for separation (EtOAc/petroleum ether mixtures).