Palladium-catalyzed methylene C(sp³)–H arylation of the adamantyl scaffold

Abstract

The adamantyl group is prevalent as a key pharmacophore element in drugs. We describe herein a palladium-catalyzed C–H functionalization logic for the methylene C(sp³)–H arylation of the adamantyl scaffold with the assistance of an amide group. The resulting arylated adamantyl amide was smoothly converted to an amine, providing facile access to the memantine analog.

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Honggen Wang

Honggen Wang was born in China in 1984, and obtained his BSc degree from Sun Yat-sen University in pharmaceutical sciences and computer science in 2006. He then moved to Guangzhou Institutes of Biomedicine and Health (GIBH), CAS, and received his PhD under the supervision of Prof. Qiang Zhu. He spent two years as a postdoctoral researcher with Prof. Frank Glorius at Westfälische Wilhelms-Universität Münster, Germany. In 2013, he started his independent research at Sun Yat-sen University. Honggen Wang was selected in the 11th batch of the “1000 Talents Program for Young Scholars” (2015).

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Introduction

Since the discovery of amantadine (1-adamantanamine) as a potent anti-influenza agent as early as 1964,¹ the polycyclic adamantane motif has been recognized as the key structural element in numerous drugs, as in the anti-Alzheimer's disease agent memantine,² anti-virus agents rimantadine³ and tromantadine,⁴ anti-diabetic drugs vildagliptin⁵ and saxagliptin,⁶ and the anti-acne agent adapalene⁷ (Fig. 1).⁸ It is well accepted that the incorporation of the adamantyl group increases the lipophilicity and metabolic stability of drugs, thereby improving their pharmacokinetic properties. In addition, as a bulky motif, the adamantyl group frequently occurs in ligands and catalysts in organic synthesis.⁹ Synthetically, the parent adamantane has become easily available since its seminal synthesis by Schleyer.¹⁰ Thereafter, the synthetic modifications of this cage hydrocarbon have yielded a number of adamantane derivatives. However, while the modifications at the adamantyl methine positions are fruitful due to the intrinsic weaker tertiary C–H bonds therein,¹¹ the direct functionalization at the methylene positions poses a greater challenge and thus has been far less successful.¹²

Fig. 1 Adamantane-containing therapeutics and strategies for adamantane C–H functionalization.

The transition metal-catalyzed direct functionalization of inert C–H bonds has matured as a powerful tool for the facile assembly of a variety of C–C and C–heteroatom bonds in recent years.¹³ In this regard, palladium-catalyzed C(sp³)–H activation reactions are particularly useful and well suited for the functionalization of aliphatic hydrocarbons.¹⁴ For instance, it has been demonstrated that the catalytic C–H functionalization of aliphatic amines¹⁵ or carboxylic acid¹⁶ derivatives is feasible under the catalysis of palladium. Considering the lack of transformable functional groups at the methylene positions of adamantane and our preceding experience in the direct C–H functionalization of 3-pinanamine,¹⁷ we envisioned that a palladium-catalyzed C(sp³)–H activation strategy might be suitable for a late-stage modification¹⁸ of adamantane. 1-Adamantanamine and 1-adamantanecarboxylic acid are easily available and useful adamantane-containing compounds. We reasoned that the amino or the carboxylic acid functional group could serve as a directing group which would therefore facilitate the C–H activation event. Herein we report our realization of a Pd(0)-catalyzed direct arylation of the methylene C–H bond of adamantane directed by an amide group. It should be noted that the Pd(0)-catalyzed arylation reactions, especially intermolecular examples, have rarely been developed.^19,20 By simple functional group manipulation, the resulting benzamides can be converted to the memantine analog (Fig. 1).

Results and discussion

At the outset of our studies, we investigated the C–H activation of 1-adamantanamine by installing a picoloyl functionality as the directing group. We anticipated that this synthetic logic would directly give the amantadine or memantine analogs after removal of the auxiliary. To our disappointment, no desired product 2 was observed after extensive screening of the reaction conditions. We suspected that this might be attributed to the difficulty of forming a disfavored four-membered-ring cyclometalated intermediate after the C–H activation event. Realizing this, we then turned our attention to the C–H activation of 1-adamantanecarboxylic acid derivative 3, bearing an 8-aminoquinoline bidentate directing group. To our delight, the reaction of 3 with 4-iodoanisole in the presence of Pd(OAc)₂ as a catalyst and AgOAc as a base indeed gave the desired arylation product 4 in 3% yield. Unfortunately, attempts to further improve the yield failed in our hands.

Encouraged by this promising result, we then investigated the reaction effected by a monodentate N-arylamide (CONHAr_F) auxiliary devised by Yu.^19d Some representative results are summarized in Table 1. The arylation of 6a gave 7a in 14% isolated yield under the reaction conditions of Pd(OAc)₂ (10 mol%), PCy₃·HBF₄ (10 mol%) and CsF (3.0 equiv.) in toluene at 110 °C for 20 h (Table 1, entry 1). Further optimization including the screening of different palladium sources, solvents, ligands, and bases was conducted, and it turned out that these parameters have trivial effects on the yield (entries 2–10). However, by increasing the loading of the ligand PPh₃ to 50 mol% and the amount of 4-iodoanisole to 5.0 equivalents, the yield was doubled (35%, entry 11). It was found that the transformation is sensitive to the reaction concentration. When the reaction was performed at 0.5 M rather than 0.2 M, the yield was significantly improved to 53% (entry 12). As one might have predicted, a diarylation reaction (around 16% diarylation product) was also observed, which makes the separation difficult. Therefore, 6b bearing two methyl groups at the methine position was chosen as the model substrate to evaluate the substrate scope of this reaction. The methyl groups were anticipated to cause sufficient steric hindrance to the adjacent methylene position, thereby making mono-arylation exclusive. Indeed, when 6b was subjected to the standard reaction conditions, the mono-arylation product 7b was obtained in 54% yield, with no di-arylation product found (entry 13). The use of PivOH as an additive eliminated the reactivity (entry 14).

Table 1 Optimization of the reaction conditions^a

Entry	R	Ligand	Solvent	Additive	Yield
a Conditions: entries 1–9: 3.0 equiv. of p-iodoanisole, 10 mol% ligand, 3.0 equiv. of base, 0.2 M; entries 11–14: 5.0 equiv. of p-iodoanisole, 50 mol% ligand. b The yield was determined by ^1H NMR analysis of the crude product using dimethyl terephthalate as the internal standard. c 0.5 M, isolated yield. d 16% diarylation product was found.
1	H	PCy3·HBF4	Toluene	CsF	14%^b
2	H	PCy3·HBF4	o-Xylene	CsF	21%^b
3	H	PCy3·HBF4	DCE	CsF	14%^b
4	H	PCy3·HBF4	CH3CN	CsF	9%^b
5	H	PPh3	o-Xylene	CsF	21%^b
6	H	PPh3	o-Xylene	Cs2CO3	19%^b
7	H	PPh3	o-Xylene	K2CO3	9%^b
8	H	P^tBu3·HBF4	o-Xylene	CsF	8%^b
9	H	IPr·HCl	o-Xylene	CsF	17%^b
10	H	—	o-Xylene	CsF	16%^b
11	H	PPh3	o-Xylene	CsF	35%^b
12	H	PPh3	n-Hexane	CsF	53%^c^,^d
13	CH 3	PPh 3	n-Hexane	CsF	54%
14	CH3	PPh3	n-Hexane	PivOH	0^c

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With the optimized conditions in hand (entry 13, Table 1), we next explore the scope of this reaction. As shown in Table 2, this arylation protocol permits the direct C–H arylation of adamantyl amides 6 with a wide range of aryl iodides. Functional groups regardless of their electronic nature, such as alkoxy (7a, 7b, 7p), chloro (7c, 7d, 7o), bromo (7l), fluoro (7i, 7j, 7q), aryl (7e, 7h), alkyl (7f, 7g, 7q), ester (7m, 7n) and trifluoromethyl (7k) groups, were well tolerated, affording the corresponding monoarylation products in moderate to good yields. The structure of 7d was unambiguously determined by X-ray crystallographic analysis (Fig. 2).²¹

Fig. 2 Absolute configuration of 7d.

Table 2 Substrate scope of methylene C–H functionalization

Reaction conditions: 0.1 mmol of substrate, 5.0 equiv. of Ar–X, 10 mol% Pd(TFA)₂, 3.0 equiv. of CsF, 0.2 mL hexane, 120 °C, 24 h. All yields are based on the isolated products unless otherwise specified. ^at-AmylOH was used as a solvent.

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Not only aryl iodides but also aryl bromides were applicable to this transformation, albeit in lower yields. Disappointingly, the use of nitrogen or sulfur containing heterocyclic halides eliminated the reactivity completely, probably due to the deleterious coordination of the nitrogen or sulfur atoms to the palladium catalyst.

To evaluate the reaction efficacy on the preparative scale, a gram scale reaction was performed. The reaction of 6b with 1-chloro-3-iodobenzene gave 1.34 g of the arylation product 7d in 50% yield, demonstrating that the reaction is practical (Scheme 1a).

Scheme 1 Gram-scale preparation, removal of the directing group and product derivatization.

The directing group N-arylamide (CONHAr_F) moiety could be conveniently removed upon the treatment with TFA/conc. HCl (2 : 1) at 110 °C, giving the corresponding carboxylic acid 8 in 75% yield (Scheme 1b). Thereafter, by a Curtius rearrangement, the carboxylic acid could be converted to an amino group, thus providing a memantine analog 12 in 76% overall yield (Scheme 1c).²² The synthesis of the arylated analogs of memantine using this protocol and their biological evaluation are underway in our laboratories and will be reported in due course.

Conclusions

In summary, we have realized a palladium-catalyzed direct arylation of methylene C(sp³)–H of the 1-adamantane carboxylic acid derivative. A variety of aromatic iodides and bromides containing different functional groups were well tolerated in this process, giving the arylated products in moderate to good yields. A gram scale reaction was conducted to showcase the efficacy of this reaction. The utility of this method was further demonstrated by the successful synthesis of a memantine analog. Given the importance of the adamantane scaffold in biologically active compounds and in organic synthesis, we anticipate that the methodology developed herein will find applications.

Acknowledgements

We are grateful for the support of this work by the “1000-Youth Talents Plan”, a start-up grant from Sun Yat-sen University and the National Natural Science Foundation of China (81402794 and 21472250).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1047296. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5qo00218d

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