C(sp³)–H hydroxylation of fluorenes, oxindoles and benzofuranones with a Mg(NO₃)₂-HP(O)Ph₂ oxidation system

Abstract

A novel oxidation system in which magnesium nitrate [Mg(NO₃)₂] is used as an oxidant in the presence of diphe-nylphosphine oxide [HP(O)Ph₂] permits the C(sp³)–H hydroxylation of fluorenes, oxindoles, and benzofuranones. This method features high efficiency, good functional group tolerance, and operational simplicity. The synthetic utility is highlighted by further transformations to valuable organic materials.

The selective oxygenation of C(sp³)–H bonds from simple starting materials is an important type of transformation in organic chemistry, which leads to the direct synthesis of valuable oxygen-containing compounds.¹ Over the past few years, extensive progress has been achieved in the exploration of new approaches to C(sp³)−H hydroxylation. Typically, chemists utilize strong oxidants such as dioxiranes,² perfluorinated oxaziridines,³ and metal-oxo complexes⁴ (Scheme 1a). Dioxiranes and oxaziridines often need to be pregenerated, though a few catalytic methods for dioxirane and oxaziridine-mediated hydroxylation have been reported.^5,4f Recently, a practical electrochemical oxidation of inactivated C−H bonds was developed by Baran group, which used readily available materials and illustrated a scalable oxidation, enabling the employment of this hydrocarbon oxidation strategy in a large scale industrial process (Scheme 1b).⁶

Scheme 1.

Representative strategies for C(sp³)−H bond hydroxylation

The fluorene moiety is widespread in natural products and exhibits biological activities. As a result, these structures have been extensively applied in the field of chemistry, material science,⁷ and medicinal chemistry.⁸ Due to the high significance of these compounds, new synthetic methods for the functionalization of fluorenes have drawn much attention. With this backdrop, the construction of hydroxyl fragments based on fluorenes has become very important.⁹ In 2014 and 2015, Shao et al.¹⁰ and Walsh et al.¹¹ have independently reported the synthesis of 9-aryl-9-hydroxyfluorenes via tandem arylation/oxidation in one-pot. In 2016, Zhang group¹² demonstrated a Barbier-Grignard type arylation of ketones affording the 9-hydroxyfluorenes in good yields. Other methods rely on the use of strong base¹³ or high energy light¹⁴ in combination with O₂ to hydroxylate 9-arylfluorenes. Even so, mild and simple methods relying on commercial reagents are desirable. Herein, the discovery of a novel oxidation system comprised of magnesium nitrate hexahydrate [Mg(NO₃)₂^.6H₂O] as oxidant and di-phenylphosphine oxide [HP(O)Ph₂] accomplishing the hydroxylation of fluorene and oxindole derivatives is described (Scheme 1c).

On the basis of our ongoing efforts to develop synthetic methods to generate new organophosphorus compounds,¹⁵ we initially designed a cross dehydrogenative coupling reaction between 9-phenylfluorene (1a) and HP(O)Ph₂ (2a). We hypothesized that a P-centered radical process mediated by di-tert-butylperoxide (DTBP) and Mg(NO₃)₂ could occur (Scheme 2).¹⁶ Unexpectedly, 9-hydroxyfluorene 3a was generated under these conditions in 87% yield without any of the targeted cross coupling product 3a’ (Scheme 2). At this point, our attention turned to this interesting finding. To ascertain the most effective, minimal reaction conditions, different parameters such as oxidant, additive, temperature, and solvent were carefully evaluated; see Supporting Information (SI) for details. To our surprise, the best yield (92%) was ultimately obtained without the peroxide oxidant. Further, control experiments indicated that both 2a and Mg(NO₃)₂ were essential to this transformation (Table S1).

Scheme 2.

Model reaction employed for condition optimization

With the optimized reaction conditions in hand, an exploration of the substrate scope was undertaken (Scheme 3). Electron-donating and electron-withdrawing groups attached to the aryl ring provided good to excellent yields. Remarkably, the current method also afforded the hydroxylation product of a 9-alkylfluorene smoothly (3n). Moreover, reaction with hindered 9-naphthalenylfluorenes (3o, 3p) also proceeded well. Un-fortunately, poor reactivity was observed for 9H-fluorene and substrates with heterocyclic aromatic groups.

Scheme 3.

Hydroxylation of substituted fluorenes^a

^aReaction conditions: 1 (0.25 mmol), 2a (0.5 mmol), Mg(NO₃)₂^.6H₂O (0.25 mmol) in 1,4-dioxane (2 mL) in air at 100 °C for 12 h; isolated yield. ^bConducted on a 1 mmol scale.

To check the generality of this novel oxidation system, we turned our attention to other classes of compounds: oxindoles and benzofuranones. 3-Hydroxy oxindoles and benzofuranones are found in a number of natural products and pharmaceutical targets (Figure 1).¹⁷

Figure 1.

Bioactive hydroxy oxindole and benzofuranone structures

Using the same conditions developed for the fluorenes, a series of C-3 hydroxylated oxindoles and benzofuranones were obtained in moderate to good yields (Scheme 4). Electron neutral or electron rich aryl oxindoles performed best (5a-5d, 81–95% yield). An oxindole with electron-withdrawing substituent on the phenyl ring (5e) was less effective (48% yield). Meanwhile, oxindoles bearing alkyl groups, such as Me and Bn (5f, 5g) generated the corresponding products in moderate yields (58%, 44%). An N-benzyl substituted oxindole also exhibited good reactivity (5h). This hydroxylation is also effective with benzo-furanones as substrates, affording the corresponding products in 38–68% yields (5i-5n). In 2018, Wei group developed hydroxylation of oxindoles with peroxides in water.¹⁸ Meanwhile, Nayak et al. reported hydroxylation of benzofuranones employing PCC/H₅IO₆ oxidation system.¹⁹ However, the scope of their protocol was limited. Further, when we employed the TBHP/SDS or the PCC/H₅IO₆ oxidation systems in the hydroxylation of fluorene 1a, over 90% starting material was recovered for the former system and decomposition of 1a occurred for the latter, which highlights the unique effectiveness of the current Mg(NO₃)₂-HP(O)Ph₂ system.

Scheme 4.

Hydroxylation of substituted oxindoles and benzofuranones^a

^aReaction conditions: 4 (0.25 mmol), 2a (0.5 mmol), Mg(NO₃)₂^.6H₂O (0.25 mmol) in 1,4-dioxane (2 mL) in air at 100 °C for 12 h; isolated yield.

Next, in an attempt to further explore the potential utilitiy of the Mg(NO₃)₂-HP(O)Ph₂ oxidation system, additional substrates were screened (Scheme 5). Subjection of substrates 6-9 to the reaction conditions did not afford any of the desired products. However, triphenylmethane gave the corresponding product 10, albeit in low yield (31%).¹¹ Overall, the reactivity appears governed by either the pKa or the strength of the C–H being cleaved. The C–H pKa values and bond dissociation energies of 6 (pKa up to ~40), 7 (pKa = 26.3), 8 (pKa = 32.3) and 9 (pKa = 27.9) are all higher than those of the sub-strates 1 (pKa ~17.3) and 4 (oxindole: pKa~18.5, benzo-furanone: pKa~13.5).²⁰ Triphenylmethane is an exception to the pKa trend producing low yields of product even though it has a higher pKa (30.6). Further experiments, using a preformed silyl ketene acetal of benzofuranone 4i failed to give the targeted product under the current reaction conditions pointing away from enolization and pKa being the predominant factor. C-H bond strengths are more consistent with all the results except that for 9; we theorize that the hydroxylation product of 9 is not stable under the reaction conditions accounting for the consumption of 9 and the lack of hydroxylation product.

Scheme 5.

Further substrate evaluation

The Mg(NO₃)₂-HP(O)Ph₂ oxidation system can also be used to access chemical materials (Scheme 6). Fluorene 12 can be synthesized in 30% yield from commercially available 11 in 4 steps.²¹ Upon hydroxylation using the present Mg(NO₃)₂-HP(O)Ph₂ oxidation system, product 13 was obtained in 47% yield. Compound 13 could be easily transformed to fully conjugated 6,12-diphenyl indeno[1,2-b]fluorene (IF) 14, which can serve as an active layer in an organic field-effect transistor (OFET).²² Moreover, hydroxylated fluorene 3a can be converted to compound 16 in 28% yield by Friedel-Crafts-type substitution, which is a promising compound for organic semiconductors.²³

Scheme 6.

Product transformation and application

In contrast to other reported methods for hydroxylation, a nonconventional oxidant, nitrate, is used in this system. Nitrates represent an important class of oxidants, typically under acidic conditions by action of the nitrogen dioxide cation. However, examples of controlled oxidation of alkanes are rare.²⁴ There are even fewer reports of oxidation with nitrates via the nitrogen dioxide radical,²⁵ the most likely candidate here given the well-known propensity for diphenyl phosphine oxide to form radical intermediates.²⁶ Control experiments indicated more than one mechanism may be involved in this interesting reaction (see ESI) and further studies are underway to understand the precise mechanism of this intriguing transformation Even so, this preliminary report highlights the potential utility of nitrate salts in controlled oxidation under neutral or basic conditions that provides a stimulus for further studies in this area.

Conclusions

In conclusion, we have described the development of a novel oxidation system Mg(NO₃)₂-HP(O)Ph₂ to provide a very practical method for the synthesis of hydroxylated fluorene, oxindole and benzofuranone derivatives in good to excellent yields. The broad substrate scope, use of readily available commercial reagents, mild conditions, and high efficiency make it an attractive method of choice for practical use. The utility of this method is further highlighted by facile modification of the products to access organic materials.