Palladium-Catalyzed meta-C–H Functionalization of Masked Aromatic

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Palladium Catalyzed meta-C–H Functionalization of Masked Aromatic Aldehydes Marcus E. Farmer, Peng Wang, Hang SHi, and Jin-Quan Yu ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b01599 • Publication Date (Web): 05 Jul 2018 Downloaded from http://pubs.acs.org on July 5, 2018

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ACS Catalysis

Palladium Catalyzed meta-C–H Functionalization of Masked Aromatic Aldehydes Marcus E. Farmer†, Peng Wang†, Hang Shi†, Jin-Quan Yu*,† †

Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037.

ABSTRACT: Palladium catalyzed meta-C–H functionalization enabled by transient mediators has the potential to extend the utility of directed ortho-C–H functionalization to remote positions. However, there have been no reports of palladium catalyzed meta-C–H functionalization of aromatic aldehyde derivatives, which are highly versatile intermediates in organic synthesis. Herein we report the development of a directing group that, in the presence of a norbornene derived mediator and an appropriate pyridone ligand, allows palladium catalyzed meta-C–H functionalization of masked aromatic aldehydes. Mechanistic insight regarding the impact of the directing group length on this catalysis is also discussed.

KEYWORDS: Aryl-Aldehyde, Benzaldehyde, Meta-C–H Activation, C-H Activation, Palladium, Pyridone Ligand The aldehyde functional group is among the most versatile functional groups in organic synthesis and can be leveraged to provide access to a wide range of synthetic targets (Figure 1). This versatility causes aromatic aldehydes to serve as popular building blocks in the synthesis of drugs and drug candidates, agrochemicals, and materials. To further expand the versatility of this common building block, it would be ideal to have synthetic methods that selectively functionalize the C–H bonds on the arene portion of either a masked or unmasked aromatic aldehyde. Many groups have recognized this and have developed transition metal catalyzed methodology that functionalizes the ortho-C–H bonds of aromatic aldehydes directly1, or by using either pre-installed2 or transient3 directing groups wherein an aryl-aldimine serves as the active directing group. However, methods that functionalize the meta- or para-C–H bonds on aryl-aldehyde derivatives remain scarce. To the best of our knowledge, the sole example of transition metal catalyzed meta-C–H functionalization of aromatic aldehyde derivatives is the elegant iridium catalyzed C–H borylation recently developed by the Chattopadhyay group.4 It is important to note that while aromatic aldehydes electronically direct electrophilic aromatic substitution (EAS) reactions to the meta-position, this effect is overridden by the directing effects of electron rich substituents and therefore EAS is not a general approach to functionalizing the metaposition of these compounds. We recognized the lack of a general protocol to functionalize the meta-C–H bond of aromatic aldehydes as an opportunity for invention and set out to develop a palladium catalyzed meta-C–H functionalization of masked aromatic aldehydes. Herein, we report the development of a new directing group for aromatic aldehydes that serves to temporarily mask the aldehyde functional group and enables palladium catalyzed

meta-C–H arylation or amination in the presence of an appropriate transient mediator and pyridone ligand.

Figure 1. Versatility of aromatic aldehydes Though several sterically guided transition metal catalysts have been developed,5 the majority of general metaC–H functionalizations, thus far, rely on a directing group to guide the catalyst.6-9 Exemplary of this, one approach towards meta-C–H functionalization is inspired by the Catellani reaction,10 wherein norbornene serves to relay palladium to an adjacent carbon and back. This relay process, when preceded by an ortho-cyclopalladation, allows for a net meta-C–H functionalization of aromatics.9 Since

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the first successful disclosures of this strategy9a,b our group and others have developed methodology that leverages norbornene derived transient mediators to achieve meta-C–H alkylation,9a,c arylation,9a-d,g-h alkynylation,9e amination,9e,g and chlorination9f reactions of a variety of substrates. The apparent generality of this approach prompted us to investigate this catalysis in the context of developing a meta-C–H functionalization of masked aromatic aldehydes.

dehyde with minimal formation of side products, indicating to us that a simple unmasking protocol should be possible.15 With this in mind, we set out to evaluate the reactivity of these new directing groups. Table 1. Scope of electrophilic coupling partnersa

Our initial investigations aimed at utilizing imine based directing groups to initiate our desired catalysis. Sun and coworkers have developed a palladium catalyzed ortho-C– H olefination of aryl-aldoximes11 and the Takemoto group has developed a palladium catalyzed annulation of aryl ketoximes with norbornene,12 albeit in poor yields after long reaction times. Despite the precedent laid forth by these works, we were unable to observe significant metaC–H functionalization with any of the imines we employed in our studies. This led us to hypothesize that the planar 5-membered palladacycles resulting from cyclometalation of aromatic imines with palladium catalysts were too stable to engage in kinetically competent migratory insertion with the transient mediator under conditions that were amenable to the subsequent steps of our desired catalysis. The recalcitrance of such palladacycles to undergo olefin insertion reactions is reflected in the work of Widdowson wherein either strongly acidic or forcing conditions were required to successfully convert imine-derived palladacycles to the desired olefinated products.13 These failed attempts with imine derived directing groups led us to design a new directing group for aromatic aldehydes. Our experience in developing meta-C–H functionalization reactions with nobornene derived transient mediators has demonstrated to us that pyridine based directing groups that form 7-membered palladacycles synergize well with Catellani inspired meta-C–H functionalization.9d-g Such directing groups, in the presence of a palladium pyridonate catalyst and norbornene derived transient mediator, have enabled meta-C–H functionalization of aniline,9d-f phenol,9d-f, benzylamine9g derived substrates. This led us to reason that if we could develop an analogous directing group for aryl-aldehydes, we should be able to observe similar generality.

Scheme 1. Synthesis of masked aromatic aldehydes.

a Reaction Conditions: 1a (0.1 mmol), 2a-r (0.25 mmol), PdOAc2 (10 mol%), Ligand (20 mol%), Ag2CO3 (0.25 mmol), PX-NBE (0.15 mmol), CHCl3 (0.5 mL), 100 oC, 16 h. bSee SI for reaction conditions.

We considered that addition of a 2(lithiomethyl)pyridine to an aldehyde14 and subsequent trapping of the resulting alcohol with TBSCl would provide a masked aldehyde possessing the requisite functionality to direct palladium to the ortho-position, providing a 7-membered palladacycle (see Scheme 1). The retro-ene reaction of analogous substrates has been previously studied and found to proceed irreversibly to the aromatic al-

After a brief optimization (see supporting information) — including an evaluation of a variety of directing group derivatives, solvents, and silver based halide scavengers9d — we set out to explore the scope of this reaction. As can be seen in table 1, substitution at the 4-position of the aryl iodide coupling partner is well tolerated (3b(a-g)). We were delighted to find that 4-iodobenzaldehyde was a good coupling partner for this transformation as the re-

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ACS Catalysis sulting product 3bb contains both a masked and an unmasked aldehyde that can be sequentially functionalized. Other notable functional groups that were well tolerated at this position include the free N-H of 2g and the potentially reactive bromine of 2e. An evaluation of substituents at the 3-position of the aryl iodide indicates that while electron rich substituents are tolerated, electron poor substitution is favored. 2-Iodomethylbenzoate also served as an efficient coupling partner, though noncoordinating ortho-substituents such as a methyl group are not tolerated on the aryl-iodide coupling partner under the current conditions. Both 3,4- and 3,5disubstituted aryl iodides could be utilized in this reaction and the resulting products were formed in moderate to good yields (3b(m-o)). We were delighted to find that several heterocyclic coupling partners could be coupled, as long as they were substituted at the 2-position (3bp & 3bq). Finally, under slightly modified reaction conditions9g (see SI for details), O-benzoyl hydroxylmorpholine (4a) could be used as a coupling partner to effect a metaC–H amination reaction, providing 5ba in modest yield. Table 2. Scope of Masked Aryl-Aldehyde Substrates a,b

Benzaldehyde derived substrate 1a provided a mixture of mono and di meta-arylated products. Electron rich metasubstituted substrates 1b-d provided the desired products in high yields. A gram-scale reaction proceeded well to provide 3bs in 89% yield, indicating this reaction can be used as a preparative method for preliminary medicinal chemistry investigations. Gratifyingly, substrates bearing halogens (1e-g) and electron withdrawing groups (1h) at the meta-position were suitable substrates for this reaction. Notably, for substrates 1e, 1f and 1h PdCl2(MeCN)2 was used as a more effective precatalyst. Orthosubstitution was also tolerated, though we noticed a steric effect wherein substituents larger than a methyl group prohibited catalysis. This is likely due to a steric clash between the ortho-substituent and the sterically bulky OTBS group of the directing group preceding cyclopalladation, thereby inhibiting the process. Para-substitution was also tolerated under these reaction conditions as demonstrated by substrates 1m-n. The mono-selectivity observed with substrate 1n is in line with previous work9 on this catalysis and we currently attribute it to a sterically induced rotation of the methoxy group after the first arylation that prohibits the second arylation event. Gratifyingly, methoxypyridine derived substrate 1o that contained a potentially coordinating pyridyl nitrogen successfully participated in this catalysis to provide 3os in moderate yield.

Scheme 2. Unmasking protocol At this stage we deemed it was important to evaluate the feasibility of an unmasking protocol to reveal the desired aryl-aldehyde. We considered that a retro-aldol like reaction would take place upon heating our substrate in the presence of a slight excess of TBAF. To our delight, heating substrate 3bs in dilute DMF with 1.1 equivalents of TBAF cleanly provided aryl-aldehyde 5bs (Scheme 2).

aReaction Conditions: 1a-p (0.1 mmol), 2s (0.25 mmol), Pd(OAc) (10 2 mol%), L2 (20 mol%), Ag2CO3 (0.25 mmol), PX-NBE (0.15 mmol), CHCl3 (0.5 mL), 100 oC, 16 h. bAr = 2-NO2C6H4 cGram Scale. d10 mol% Pd(MeCN)2Cl2 was used instead of Pd(OAc)2, 0.3 mmol of 2s was used.

Having established a relatively broad scope of aryl iodide coupling partners that can be used in this transformation we set our sights on evaluating the breadth of the masked aryl-aldehydes that can be employed (Table 2).

Scheme 3. Effect of Palladacycle Ring Size

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Our success in developing a palladium catalyzed metaC–H functionalization of masked aromatic aldehydes prompted us to investigate how the length of the directing group we developed for this transformation influences the catalysis. In order to de-convolute as many steric and electronic effects as possible, we studied the reactivity of substrates 7a-c. As can be seen from scheme 3, 7a did not participate in our meta-C–H arylation when using 2k as the coupling partner. This is in line with our studies concerning imine based directing groups that form similar 5membered palladacycles. As shown in scheme 3a, substrates 7b and 6c could successfully couple with 2k to provide the desired products in moderate to good yields. It is worth noting that changing the silver source to AgOAc was necessary to provide efficient coupling with substrate 7b; however, a re-evaluation of silver sources did not influence the reactivity of 7a. To further examine what could be causing the difference in reactivity between these various palladacycles, we attempted ortho-C–H olefination reactions of substrates 7a-c under similar conditions to those employed for our meta-C–H functionalization protocol. This was done in an attempt to evaluate the effect of palladacycle ring size on 1,2-migratory insertion, a key event in our desired catalysis. As can be seen from Scheme 3b, substrate 7a did not provide the desired ortho-olefinated products in significant yields, while substrates 7b and 7c reacted smoothly with ethyl acrylate to provide the desired products in moderate to good yields. This lends support to our hypothesis that the necessity for a larger palladacycle ring size is, at least in part, inherently linked to the migratory insertion step of this catalysis.

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after proceeding through intermediates III & IV. We propose that the directing group we developed for this transformation enables this catalysis by allowing this step to be kinetically facile under our reaction conditions. This newly formed palladacycle undergoes an oxidative addition reaction with an aryl iodide to provide a Pd(IV) intermediate (VI) that reductively eliminates to provide a new CC bond and releases the palladium from the palladacycle to provide intermediate VII. β-carbon elimination provides palladacycle VIII which undergoes a protodepalladation reaction to release the desired product, regenerating the palladium catalyst I. 3. Conclusion In summary, we have developed a new directing group that allows palladium catalyzed meta-C–H functionalization of masked aromatic aldehydes. We have demonstrated that this directing group can serve as a masking group for aromatic aldehydes that is easy to install and remove. Preliminary mechanistic studies indicate that this directing group allows for the critical migratory insertion step of this catalysis to proceed smoothly. Future efforts are concerned with garnering a better understanding of the role of the pyridone ligand in this catalysis, as well as development of a silver free meta-C–H functionalization utilizing norbornene as a transient mediator.

AUTHOR INFORMATION Corresponding Author * Email: [email protected]

Supporting Information. Experimental procedures, optimization tables, and characterization data

ACKNOWLEDGMENT We gratefully acknowledge The Scripps Research Institute and the NIH (NIGMS, 5R01 GM102265) for financial support. REFERENCES (1)

Figure 2. Proposed Mechanism A proposed mechanism is depicted in Figure 2. We propose that this reaction proceeds via a Pd(II)/(IV) catalytic cycle. The catalysis is initiated by coordination of the directing group to the palladium catalyst, followed by cyclopalladation to provide palladacycle II. This intermediate engages with the transient mediator to relay the palladium to the adjacent site, providing palladacycle V

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(9) For select examples of palladium catalyzed meta-C–H functionalization employing a transient mediator approach, see: (a) Wang, X.-C.; Gong, W.; Fang, L.-Z.; Zhu, R.-Y.; Li, S.; Engle, K. M.; Yu, J.-Q. Ligand-enabled meta-C-H activation using a transient mediator. Nature 2015, 519, 334-338. (b) Dong, Z.; Wang, J.; Dong, G. Simple Amine-Directed MetaSelective C–H Arylation via Pd/Norbornene Catalysis. J. Am. Chem. Soc. 2015, 137, 5887-5890. (c) Shen, P.-X.; Wang, X.C.; Wang, P.; Zhu, R.-Y.; Yu, J.-Q. Ligand-Enabled Meta-CH Alkylation and Arylation Using A Modified Norbornene. J. Am. Chem. Soc. 2015, 137, 11574-11577. (d) Wang, P.; Farmer, M. E.; Huo, X.; Jain, P.; Shen, P.-X.; Ishoey, M.; Bradner, J. E.; Wisniewski, S. R.; Eastgate, M. E.; Yu, J.-Q. Ligand-Promoted Meta-C-H Arylation of Anilines, Phenols, and Heterocycles. J. Am. Chem. Soc. 2016, 138, 9269-9276. (e) Wang, P.; Li, G.-C.; Jain, P.; Farmer, M. E.; He, J.; Shen, P.-X.; Yu, J.-Q. Ligand-Promoted Meta-C-H Amination and Alkynylation. J. Am. Chem. Soc. 2016, 138, 14092-14099. (f) Shi, H.; Wang, P.; Suzuki, S.; Farmer, M. E.; Yu, J.-Q. Ligand Promoted meta-C-H Chlorination of Anilines and Phenols. J. Am. Chem. Soc. 2016, 138, 14876-14879. (g) Wang, P.; Farmer, M. E.; Yu, J.-Q. Ligand-Promoted Meta-C-H Functionalization of Benzylamines. Angew. Chem. Int. Ed. 2017, 56, 5125-5129. (h) Li, Q.; Ferreira, E. M. Meta-Selective C-H Arylation of Aromatic Alcohols with a Readily Attachable and Cleavable Molecular Scaffold. Chem. Eur. J. 2017, 23, 11519-11523. (10) (a) Catellani, M.; Frignani, F.; Rangoni, A. A Complex Catalytic Cycle Leading to a Regioselective Synthesis of o,o′‐ Disubstituted Vinylarenes. Angew. Chem., Int. Ed. 1997, 36, 119-122. For reviews on norbornene mediated transformations, see: (b) Ye, J.; Lautens, M. Palladium-catalysed norbornene-mediated C–H functionalization of arenes. Nat. Chem. 2015, 7, 863-870. (c) Della Ca, N.; Fontana, M.; Motti, E.; Catellani, M. Pd/Norbornene: A Winning Combination for Selective Aromatic Functionalization via C–H Bond Activation. Acc. Chem. Res. 2016, 49, 1389-1400. (11) Xu, Z.; Xiang, B.; Sun, P. ortho‐Olefination of Arylaldehyde O‐Methyloximes through Palladium‐Catalyzed C–H Activation. Eur. J. Org. Chem. 2012, 16, 3069-3073. (12) Nanjo, T.; Tsukano, C.; Takemoto, Y. Palladium-Catalyzed Double C–H Functionalization of Arenes at the Positions ortho and meta to Their Directing Group: Concise Synthesis of Benzocyclobutenes. Chem. Pharm. Bull. 2016, 64, 13841392. (13) Girling, I. R.; Widdowson, D. A. Cyclopalladiated aromatic imines in organic synthesis: the preparation of cinnamonitriles, cinnamates, unsymmetrical stilbenes, isoquinolones, and isoquinolines. J. Chem. Soc. Perkin. Trans. 1, 1988, 13171323. (14) Rendler, S.; Plefka, O.; Karatas, B.; Auer, G.; Frölich, R.; Mück-Lichtenfeld, C.; Grimme, S.; Oestreich, M. Stereoselective alcohol silylation by dehydrogenative Si-O coupling: scope, limitations, and mechanism of the cu-h-catalyzed non-enzymatic kinetic resolution with silicon-stereogenic silanes. Chem. Eur. J. 2008, 14, 11512-11528. (15) Houminer, Y.; Williams, D. L. The solution thermolysis of 2, 3-, and 4-(2-hydroxy-2-arylethyl)pyridines. J. Org. Chem. 1983, 48, 2622-2625.

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