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Published in final edited form as: J Am Chem Soc. 2025 Sep 9;147(37):33850–33858. doi: 10.1021/jacs.5c10482

Diversity-Oriented C–H Activation Reactions of Naphthalene Scaffold

Zhoulong Fan 1, Md Emdadul Hoque 1, Kevin Wu 1, Maximilian D Palkowitz 2, Upender Velaparthi 2, Kevin W Gillman 2, Jennifer X Qiao 2, Jin-Quan Yu 1,*
PMCID: PMC13086163  NIHMSID: NIHMS2162249  PMID: 40923558

Abstract

Diversity-Oriented Synthesis (DOS) has emerged as an efficient strategy for constructing diverse compound libraries, facilitating hit or lead identification in the drug discovery process. In parallel, developing diverse transformations at different sites is an appealing strategy to expand diversity of appendages on scaffolds. Owing to the availability of C–H bonds at multiple sites of pharmacophores, diversity-Oriented C–H activation reactions is an ideal approach to realize this goal. Given the pharmacophoric significance of the naphthalene scaffold in clinical drugs, diversity-oriented C–H functionalization reactions on this scaffold would be highly useful for drug discovery. The direct C–H activation at the challenging C6 and C7 positions has remained unexplored due to electronic similarity, remote distance from the directing group, and interference from geometrically identical positions (C7 vs. C3, C6 vs. C4). Herein, we report two types of templates designed to differentiate the C6 and C7 positions on the naphthalene scaffold. The success is attributed to the manipulation of the distance parameter in the template and the utilization of an oligopeptide ligand. Notably, the utility of this diversity-oriented C–H activation is showcased through the divergent modification of naphthalene-containing complex molecules.

Graphical Abstract

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INTRODUCTION

Synthetic strategies which expand chemical space are highly valuable for drug discovery campaigns. Diversity-Oriented Synthesis (DOS) aims to access broad chemical space by rapidly transforming simple building blocks into libraries of small molecules bearing diverse appendages, stereochemistry, and skeletons.1–5 It is equally important to develop diversity-oriented reactions (DOR) which can modify molecules at different sites with diverse transformations. C–H functionalization provides an ideal approach for developing diversity-oriented reaction given the ubiquity of C–H bonds on common scaffolds and the diversity of coupling partners available. Moreover, the recent development of distal and highly site-selective C–H activation reactions capable of functionalizing different sites on a scaffold offers the potential for regiochemical divergence in exploring chemical space. Despite the attractiveness of this strategy, there are few reliable C–H functionalization platforms for extended arenes without electronic bias or lacking Lewis basic heteroatoms. Naphthalene, one of the simplest fused aromatic systems, often requires lengthy synthetic sequences to systematically modify any of its positions with high regiochemical control. If selective C–H functionalizations could be achieved at seven different positions on a naphthalene scaffold in all conceivable combinations with ten coupling partners, it could potentially produce around 12 million analogues with diverse appendages, representing both a significant challenge and tremendous opportunity for de novo synthesis. (Fig. 1a).

Figure 1. Diversity-oriented C–H activation reaction for naphthalene scaffold.

Figure 1.

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a, Concept: Diversity-oriented reaction (DOR). b, Naphthyl-containing bioactive compounds. c, Diversity-oriented reactions on C–H bonds of Naphthalene scaffold. d, Challenges for C6 and C7-selective C–H activation. e, C6 and C7-selective functionalizations of naphthalene scaffold through template strategy (This work). DG, directing group; T, template.

Naphthalene scaffolds have been extensively used in drug development across a range of therapeutic areas.6 Over 20 medicines incorporate the naphthalene motif, including the antihypertension medication Propranolol,7 the non-steroidal anti-inflammatory drug (NSAID) Naproxen,8 and Adagrasib,9 recently approved by the FDA for treating K-Ras G12C positive non-small cell lung cancer (NSCLC) (Fig. 1b). Conventional methods for synthesizing naphthalenes involve the cyclization of substituted phenyl derivatives,10,11 aromatization of tetralones,12 and electrophilic aromatic substitutions of substituted naphthalenes.13,14 However, these approaches often require multiple steps and exhibit low regioselectivity, and as such are not suitable for the rapid diversification necessary for efficient SAR (structure-activity relationship) studies. Site-selective C–H functionalization represents a promising platform for achieving diversity and complexity in naphthalene. A successful proximal directing strategy has been developed to achieve C2-15–27 and C8-selective28–40 C–H diverse functionalizations. Furthermore, the C3 position has been functionalized by utilizing Cu catalysis,41 directing templates,42–45 and norbornene (NBE)-relay strategies.46–48 Single electron transfer (SET) C–H functionalizations have facilitated the introduction of diverse functional groups at the C449–52 or C553 positions of naphthylamine and naphthylphosphine. Nickel/aluminum cooperative catalysis afforded the C6 alkylation product with low 78% selectivity, accompanied by three undesired olefination byproducts.54 The only C7-arylation example was reported through a C8-palladation/aryl migration strategy.55 To the best of our knowledge, the direct C6 and C7-selective C–H activation remains challenging due to both electronic similarity and a considerable distance from the directing group (Fig. 1c).

Inspired by our recent work on the molecular editing of quinoline scaffolds,56 we hypothesized that a rational template strategy could selectively activate the C6–H and C7–H bonds on the naphthalene scaffold. The distinct distance and geometrical variations between the C6 and C7 positions offer the potential for differentiation between these two C–H bonds through meticulously designed templates. However, structural analysis revealed an additional concern: the C7 and C3 positions share the same geometry (meta vs. meta) but are one bond away, as are C6 and C4 (para vs. para). This observation suggests that the pre-assembled macrocyclophanes with different sizes may be capable of distinguishing between these geometrically identical C–H bonds (Fig. 1d).

Here we present two types of templates facilitating the C6 and C7-selective C–H activation of naphthylacetic acids and naphthols. In these studies, the distance parameter in template design plays a crucial role in distinguishing between geometrically identical C7 and C3, as well as C6 and C4. Notably, the utilization of an oligopeptide ligand has proven significant in achieving mono-selective C6-products by preventing overreactions on the competing C4 position. A user-friendly streamlined procedure has been established for this methodology, including template installation and removal. Furthermore, these site-selective C–H activation methods represent a form of diversity-oriented reactions, demonstrating extensive practicality in diversifying the naphthalene scaffold related to natural products or bioactive molecules to construct a drug-like compound library (Fig.1e).

RESULTS AND DISCUSSION

We initially attempted to design the directing templates for C6-selective olefination reactions, employing naphthylacetic acid as a model substrate (Fig. 2a). The utilization of the nitrile-substituted adamantane template T1, previously reported for para-selective C–H activation,57 resulted in the formation of C6-olefination product 2a with a 4% NMR yield and low selectivity (C6:others = 50:50). Considering the success of structural motifs such as T2 in C6-functionalization of quinoline,56 we incorporated it into naphthalene substrate 1a. Unfortunately, this led to olefination occurring at multiple sites, yielding a mixture of products. We next designed alcohol-type templates T3-T5 with different directing groups based on the biaryl backbone of T2. Although the yield of 2a slightly increased, there were no significant improvements in C6-selectivity. Further efforts to fine-tune the geometry led to the investigation of templates with 2-substituted pyridyls (T6-T9). To our delight, T8 incorporating a 2-methyl pyridyl moiety has proved to be successful, producing C6-olefination product 2a in 32% yield with an improved selectivity (C6:others = 83:17). Continuing our optimization, we explored T10-T15 containing 2,6-disubstituted pyridyls. The reaction conditions with T11 provided 2a in 65% yield with excellent C6-selectivity. T16, featuring a 4,6-disubstituted pyridyl directing group, did not exhibit C6-selectivity. Additionally, two backbone variants of T11 were investigated, resulting in lower yield and selectivity (T17 and T18). Notably, using Ac-Gly-OH as a ligand led to an overreaction at the geometrically identical C4 position, generating a difunctionalized by-product. We addressed this challenge by replacing Ac-Gly-OH with oligopeptides as ligands for the C–H activation reaction. Among various oligopeptides tested, pentaglycine significantly increased mono-C6-selectivity (mono:di = 94:6). In addition, a full study of oligopeptides as ligands to control selectivity in remote C–H activation reactions will be reported in due course.

Figure 2. Conditions optimization for C6 and C7-selective C–H activation reactions.

Figure 2.

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a, Conditions optimization for C6-olefination. b, Conditions optimization for C7-olefination. c, Site-selectivity controlled by distance. All Reactions were conducted on 0.1 mmol scale. Optimization yields and selectivities are determined by 1H NMR analysis. The di product represents both C4 and C6-olefinated product. aThis yield was based on the isolated template-substrate combination. bUsing Ac-Gly-OH instead of pentaglycine. cC6:C4:others = 67:11:22. dConditions: Pd(OAc)2 (10 mol%), Ac-Gly-OH (20 mol%), AgOAc (2 equiv), methyl acrylate (1.5 equiv), HFIP (0.05 M), 80 °C, 24 h.

The successful outcome of the C6-selective template strategy motivated us to investigate C7 selectivity as well (Fig. 2b). Beginning with 2-cyanophenols as templates,58 we observed a low level of C7 selectivity. Subsequently, we explored four nitrile-containing aliphatic templates T21-T24.57,59 Among them, T22 emerged as the optimal template, yielding the C7 product 3a in a 74% yield, accompanied by a high C7 selectivity (C7:others = 91:9). We hypothesized the site-selectivity is influenced by the distance of the templates (Fig. 2c). To demonstrate the impact of the distance parameter, we initially conducted reactions using both naphthylacetic acid and naphthylpropanoic acid as substrates under C7-selective standard conditions. Intriguingly, the site-selectivity exhibited a switch between C7 and C3, confirming the significant role of distance in determining site-selectivity. This phenomenon can be elucidated by the fact that the matched 12-membered macrocyclophane promotes pseudo-meta-selectivity.57 Although the 16-membered macrocyclophane proves advantageous for pseudo-para-selectivity, achieving C4-selectivity with naphthylpropanoic acid was not successful. Instead, multiple olefination products were observed, attributed to the insufficient rigidity of the template in promoting para-selectivity. The introduction of the rigid template T1 with naphthylpropanoic acid resulted in the generation of C6- and C4-selective products, further emphasizing the crucial role of template linker rigidity.57

With the established templates and conditions in hand, we examined the substrate scope of diversely functionalized naphthalene architectures. As depicted in Figure 3, an array of functional groups on the naphthalene scaffold exhibited excellent tolerance under both condition A and condition B. In most cases, these reactions led to the formation of C6- or C7-olefination products with moderate to good yields and high selectivities (2b-2m, 3b-3o). Interestingly, the reactions were also suitable for naphthalene-fused tricycles (2n, 2o, and 3p), including the phenanthrene ring. We then examined the scope of alkene partners. Our studies indicated that various acyclic or cyclic arylates (2p, 2q, and 3q-3t), vinylamides (2r, 2s, 3u, and 3v), vinylsulfone (2t and 3w), vinylphosphonate (3x), and pentafluorostyrene (2u) were suitable for site-selective C–H olefinations, yielding the corresponding C6 or C7 products with high selectivities. This site selective C–H olefination was also tested with 2-naphthoacetic acid under two conditions (A and B). In both cases, we observed unselective formation of mixed olefination products, which is not surprising considering the change of distance between the directing template and the target C–H bonds.

Figure 3. Reactions scope for C6 and C7-selective C–H activation reactions.

Figure 3.

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a, C6-olefination under condition A. b, C7-olefination under condition B. Reaction selectivities are determined by 1H NMR analysis. All yields are isolated yields.

To further enhance the diversity of C7-selective C–H activation, we subsequently evaluated C–H acetoxylation and arylation reactions on the naphthalene scaffold. This resulted in the generation of previously inaccessible products (4a-4d and 5) in synthetically useful yields, accompanied by high C7-selectivities, as depicted in Figure 4a–b. Unfortunately, C6 acetoxylation and arylation displayed poor reactivity and moderate selectivity under similar reaction conditions. Notably, C7-selective olefination reactions of naphthol substrates were successfully accomplished through the introduction of T22 with a carbonate linker (6a-6i) thus allowing for follow-up diversification of the resulting alcohol upon linker cleavage. These findings underscore the broad applicability of the template strategy in diversifying the naphthalene scaffold. Most importantly, we extended the application of both C6 and C7-selective reactions to biologically active complex molecules. The late-stage diverse products 7–12, often requiring lengthy syntheses with uncertainties, highlight the significance of site-selective C–H activation as a DOR with considerable advantages.

Figure 4. Other transformations for C7-selective C–H activation and diversity-oriented reactions for complex molecules.

Figure 4.

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a, C7-acetoxylation of naphthylacetic acid derivatives under condition C. b, C7-arylation of naphthylacetic acid derivative under condition D. c, C7-olefination of naphthol derivatives under condition E. d, Diversity-oriented reactions for complex molecules.

We then showcased the practical utility of our methods by transforming the carboxylic acid group of the C7-olefination product 13 into various synthetic functionalities. This included the conversion to amine (15),60 alcohol (16), nitrile (17),61 ketone (18),62 or aldehyde (19),63 providing diverse handles for subsequent elaborations. Moreover, our approach facilitates the straightforward synthesis of remote site-modified naphthalene derivatives, serving as versatile building blocks for accessing drug analogues in drug discovery. The C6-olefination naphthalene 20 underwent hydrogenation followed by hydrolysis, converting the free acid to an amine, amidation, and reduction, ultimately yielding an analogue of hyperparathyroidism drug Cinacalcet (23) (Fig. 5b).64 Additionally, starting from the C7-olefination naphthol derivative 6a, a sequence involving template removal, substitution, and ring-opening events was employed to produce a derivative of antihypertensive drug Propranolol (26) (Fig. 5c).7 Furthermore, by transforming the carboxylic acid of compound 5 into a Boc-amine, followed by reductive amination and methylation reactions, we accessed an analogue of antifungal agent Butenafine (28) (Fig. 5d).65

Figure 5. Synthetic applications.

Figure 5.

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a, Further transformations of C7-olefination product. b, Synthesis of cinacalcet analogue through C6-olefination. c, Synthesis of propranolol analogue through C7-olefination. d, Synthesis of butenafine analogue through C6-arylation.

CONCLUSIONS

In summary, we introduce the concept of Diversity-Oriented Reactions (DOR) as an efficient strategy for achieving molecular diversity and complexity in drug discovery campaigns. In our DOR approach, we employ a single reaction class (site-selective C–H activation) to access diverse regiochemical outcomes and functionalizations simply through a deliberate choice of templates or reagents. Considering the significance of the underappreciated naphthalene pharmacophore, we have devised two templates for facilitating remote C6 and C7-selective C–H activation on the naphthalene pharmacophore, thereby complementing existing methods and enabling the comprehensive editing of all C–H bonds in naphthalene. The distance parameter plays a crucial role in distinguishing between geometrically identical positions (C7 vs. C3, C6 vs. C4). Notably, we utilized an oligopeptide ligand to achieve mono-selective C6-products, thereby avoiding additional functionalization on geometrically identical C4-H bonds. Ultimately, the advantage of DOR in the construction of a diverse compound library was exemplified by site-selective C–H activation of complex naphthalene derivatives.

Supplementary Material

si

The Supporting Information is available free of charge at https://pubs.acs.org

Experimental procedures and characterization data for all reactions and products (PDF)

ACKNOWLEDGMENTS

We gratefully acknowledge The Scripps Research Institute, Bristol Myers Squibb, and NIH (National Institute of General Medical Sciences grant R01 GM102265) for their financial support. Dr. Jason Chen, Brittany Sanchez, Quynh Nguyen Wong, and Jason Lee are acknowledged for their assistance with HR-MS analysis.

Footnotes

The authors declare no competing financial interest.

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