The design of a readily attachable and cleavable molecular scaffold for ortho-selective C–H alkenylation of arene alcohols† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c5sc03948g

A novel molecular scaffold with distinct features (easily attachable, removable, recoverable) induces Pd-catalyzed oxidative olefinations when attached to arene alcohols.


Introduction
The ability to forge an array of bond types via metal-catalyzed selective C-H functionalization is well appreciated. 1 A substantial percentage of these transformations rely on the directing capability of the substrate. That is, the appropriate positioning of a Lewis basic functional group will present a metal catalyst center to a specic site, enabling the precise activation of the commonly unreactive C-H bond. 2 Several commonly encountered functional groups can impart this directing capability. Alcohols can conceivably be one such group, but there are noted restrictions. 3 Almost all cases of directed catalytic C-H functionalization employ tertiary alcohols; 4 there are, to our knowledge, very few outliers using primary and secondary alcohols, with functionalizations in comparatively diminished yields. 4a-c Implicit hypotheses suggest that this general substrate class is prone to oxidation, fragmentation, and other decomposition pathways.
An alternative strategy is the utilization of alcohol surrogates, species that can be directly attached to and later removed from the alcohol functional group, which will permit metalcatalyzed functionalizations when connected. 5 In addition to a few cases where this approach has been employed in sp 3 C-H functionalization, 6 this strategy has been applied toward arene sp 2 C-H reactions. Interestingly, the large majority of examples have been based on phenolic precursors (Fig. 1a), including both Pd-catalyzed 7-11 and non-Pd-catalyzed examples. 12, 13 In contrast, few catalytic sp 2 C-H functionalizations have been based on aliphatic alcohol surrogates. Hartwig's iridium-catalyzed dehydrogenative functionalization with a silane is a landmark example (Fig. 1b). 14 Tan 15 and Yu 16 have both developed attachable and cleavable groups for alcohols that induce metaselective alkenylations. Recently, oximes have been demonstrated by both Zhao 17 and Dong 18 to be competent functional groups for Pd-catalyzed ortho-selective functionalizations of benzylic and homobenzylic alcohol precursors (Fig. 1c). In these latter oxime cases, they exploit the "exo-directing mode" of the functional group for cyclometalation to afford alkenylated, arylated, and acetoxylated products. Although the oxime has proven viable in this capacity, its synthetic manipulation does have its requisite demands (e.g., generally 3 steps for the transformation of alcohol / oxime, 19 lack of recoverability, reductive oxime removal), and thus surrogates of different design may offer unique advantages. Herein, we disclose the development of a novel molecular scaffold based on a heterocycle-incorporated acetal, delineating the structural features required to impart this desired type of reactivity. Additionally, we illustrate how the scaffold is readily attached and cleaved, highlighting the lability of this specic system and its translation to an overall streamlined process.

Results and discussion
We anticipated at the onset that certain common functional groups may serve as straightforward solutions for our goal. It was expected that known protecting groups may exploit the potential Lewis basicity of the alcohol oxygen, or more likely, attach a functional group that endows its own directing capacity to induce the metalation. Our analysis of select groups in oxidative olenations, using ligand-accelerated conditions inspired by the developments of Yu and coworkers 20 (ethyl acrylate, 10 mol% Pd(OAc) 2 , 20 mol% Ac-Gly-OH, 3 equiv. AgOAc, HFIP, 90 C), is depicted in Table 1. As can be seen, standard protecting groups were uniformly ineffectual. Ethers, acetals, esters, and carbamates all gave little to no reactivity. The di-tert-butyl-silanol group, which had been applied for phenol-based functionalization, 7 also did not afford appreciable reactivity (entry 8). Pyridyl-incorporated esters and ethers also failed to induce directed olenation (entries 9, 10).
For our goal to ultimately be realized, it was clear that we needed to devise a more unique solution. The design of an original scaffold to address this challenge required particular components: namely (1) a robust directing group, (2) a functional group to allow straightforward attachment and removal, and (3) structural features that would ideally induce proximal direction. Hybridizing these requirements led us to compound 6 (Scheme 1). Pyridines as intramolecular directing groups are well-established, the acetal linkage would enable simple connectivity, and the fused ring system may substantially lower the entropic barriers for the desired cyclometalation. To that end, we synthesized the PyA (Pyridyl-Acetal) scaffold, available in two steps from commercial dimethyl pyridine-2,3dicarboxylate. 21 To our delight, we found that scaffold attachment to benzyl alcohol was straightforward using 5Å molecular sieves, and subsequent Pd-catalyzed functionalization proceeded with marked improvement over the other cases (Table 1, entry 11 and Scheme 2). We were able to observe notably high levels of alkenylation, isolating monoolen 8aa mono and diolen 8aa di in 51% and 31% yield, respectively. 22 A range of scaffold-attached benzylic alcohol substrates were evaluated in the oxidative olenation using either ethyl acrylate or N,N-dimethylacrylamide (Table 2). In cases where only monoolenation can occur (i.e., ortho-substituted arenes), moderate to very good yields of alkene products were observed. In several of these cases, alcoholysis was also performed immediately following olenation (HCl, EtOH, 23 C), 23 and the resulting alcohols were formed in synthetically useful levels for the two-step sequence. 24 Heterocycles are compatible with this reaction (e.g., compound 8gb). For cases where mono-and Si(t-Bu) 2 OH 7 diolenation were possible, approximately 3 : 1 mixtures were generally produced, with monoolenation products being formed with ranging regioselectivities. 25 Aryl bromides were incompatible with this process, likely due to competitive oxidative addition pathways. A secondary alcohol-based substrate was reactive and remarkably selective for monoalkenylation (8lb); a tertiary alcohol-based substrate, in contrast, was unproductive under these conditions. Alkene partners were also evaluated ( Table 3). In addition to ethyl acrylate and N,N-dimethylacrylamide, other acrylates and acrylamides were effective reactants (8bc-g). Electron-decient styrenes were competent participants (8bh, 8bi), while more electron-neutral ones afforded the products in diminished yields (8bj, 8bk). Oxazolidinones and phosphine oxides were compatible (8bl, 8bm), but acrylonitrile was only marginally reactive (8bn). 26 It merits mention that the PyA scaffold can be employed as a protecting group akin to conventional acetal species. Scheme 3 is illustrative; desilylation, oxidation, etherication, and Cucatalyzed amidation 27 were all effective in the presence of this moiety. A key attribute of this scaffold is its ability to be leveraged in protecting group strategies. Alkenylations of the respective products proceeded smoothly to generate diversely functionalized olenic compounds. Of note, under these alkenylation conditions, the PyA scaffold outcompetes the ketone, ether, and acetamide for reactivity, despite these latter functional groups' directing capacity for Pd-catalyzed functionalization. 28 Toward increasing the breadth of utility, we sought to expand the transformations to more remote cases (i.e., beyond benzylic alcohols). Examples of these types of remote bondforming events have been more rare, presumably due to the challenges of forming larger cyclometalated species. The substrates derived from both homobenzylic and bishomobenzylic alcohols can be effectively olenated using this approach (Scheme 4). 29 In comparison, when the parent alcohols (12, 16) were subjected to the alkenylation conditions, little a 17% yield of the nonolenated alcohol was also recovered. b 36% yield of the nonolenated alcohol was also recovered. c 24% yield of the nonolenated alcohol was also recovered. d A complex mixture was observed. e The PyA group was attached on this hindered alcohol in only 29% yield.  to no reactivity was observed. Preliminary attempts to functionalize the further-extended acetal (20) were also unsuccessful.
We encountered a limitation of this system when we attempted attaching particularly electron decient alcohol substrates. For example, the use of alcohol 1q, bearing an electron-withdrawing ester moiety, was ineffective in attachment using acetal 6 (Scheme 5). 30 Gratifyingly, however, the application of hemiacetal 5 under dehydrative conditions (10 mol% TsOH$H 2 O, 3 equiv. MgSO 4 ) circumvented this problem, and attachment and alkenylation were both possible. 31 The ease of this hemiacetal approach, where residual hemiacetal 5 was readily removed in the reaction workup, also established a path for the execution of a telescoping sequence. 32 As illustrated in Scheme 5, benzylic alcohol 1b could be converted to the olenic product without any intermediary purications, representing a net alcohol-based directed ortho-functionalization. 33 The scaffold can also be recovered in the alcoholysis, further highlighting the utility of this scaffold.
The nature of the directing group merits further discussion. As mentioned above, we anticipated that this particular scaffold possessed specic features that rendered it uniquely effective for this function. Structural variants were revealing (Scheme 6). No reactivity was observed in the cases of acetal 22 or pyridine 23. 34 When pyridyl ether 24 was subjected to the alkenylation conditions, minimal reactivity was observed. 35 When compound 26 was tested, however, high reactivity was restored. From this set of experiments, a few conclusions can be drawn. First, the bidentate capability of the nitrogen and oxygen atoms is likely important at some stage of the overall reaction. 36 Second, the fused ring system decreases the conformational degrees of freedom, presumably encouraging a proximal relationship between the metal center and the C-H bond. Lastly, the acetal functional group is not important for catalytic functionalization and only facilitates attachment and cleavage. Based on this data, we believe cyclometalated species 28, with scaffold bidentate coordination, is a probable intermediate in the overall alkenylation. 37

Conclusions
New strategies in catalytic C-H functionalizations that improve utility hold potential for achieving broad synthetic applicability. Our efforts herein outline a convenient and straightforward functionalization of alcohol-based substrates based on a simple molecular scaffolding approach. The scaffold is easily synthesized 38 and is attachable and removable with high-yielding recovery. It has the capacity to serve as an alcohol protecting group, it can be incorporated into a telescoping process, and it can induce olenations from notably remote positions on a molecule. We anticipate that these scaffold attributes will provide distinct advantages in catalytic functionalization Scheme 4 Remote functionalization using PyA scaffold.
Scheme 5 Alternative scaffold attachment method, telescoping, and recovery.
Scheme 6 Reaction analysis of PyA scaffold variants. chemistry. 39 Further developments and applications in catalysis are underway and will be reported in due course.