A waste valorization strategy for the synthesis of phenols from (hetero)arylboronic acids using pomegranate peel ash extract

ABSTRACT Phenols are prominent in organic reactions and highly significant biologically active substances. We report a versatile and sustainable CuI-catalyzed protocol for their synthesis through an oxidative ipso-functionalization (hydroxy deborylation) strategy of (hetero)arylboronic acids [(H)ABAs] using the water extract of pomegranate peel ash (WEPA) in open-air. They are formed at room temperature (RT). This process shows high significance toward the environmental sustainability over the reported procedures of ipso-hydroxylation of (H)ABAs. The application of a waste-derived biorenewable basic reaction medium, air as an oxidant, wide substrate scope, high functional group tolerance, reusability of the catalyst, ambient conditions, less expensive and safer catalyst with low loading, aqueous medium, avoidance of volatile organic solvents, and external oxidant, and tremendous further scope are the noteworthy features of this protocol. GRAPHICAL ABSTRACT


Introduction
The development of technologies/methods to explore organic solid waste as vital feedstocks/reagents/catalysts for synthetically and commercially valuable chemical transformations is urgently required in synthetic chemistry. This seems to be the perfect ladder of sustainable development (1). It controls the environmental pollution caused by solid organic waste in accordance with the current rate of development and by the huge consumption of non-renewable resources and avenues toward a circular economy (1). The pomegranate peels are the household/industrial waste widely used as highly nutritious cattle feed (2,3). Furthermore, the pomegranate peels are used in water remediation (4)(5)(6), generation of feedstocks (7,8), a diverse range of organic transformations (1,(9)(10)(11), healthcare and biological applications (12)(13)(14)(15), stabilization of oils (16)(17)(18), obtaining the useful phenolics and polysaccharides (19,20), etc. This article discusses the application of pomegranate peel ash derivative for the CuI-catalyzed synthesis of phenols through ipso-hydroxylation of (hetero)arylboronic acids [(H)ABAs]. Moreover, the invention of sustainable protocols for efficient access to fine chemicals is a highly potential and urgently required assignment to replace the traditional organic procedures (1).
Phenols are the highly significant and valuable compounds, widely present in the structures of natural products and pharmaceuticals. They are occupied as versatile precursors to access polymers, herbicides, drugs, and antioxidants in a polyphenolic form (1,(20)(21)(22)(23). Up to now, several classes of phenols have been isolated from various natural resources that are structurally characterized, including lignans, flavonoids, and cardanols (20,(24)(25)(26). These natural substances and synthetic phenols are frequently applied in dietary regimes and display several biological activities, including antioxidant, antimicrobial, antitumor, antibiotic, antiviral, and cardiovascular protective effects (20,(24)(25)(26)(27). For these reasons, phenols are the principal substances for therapeutic design and drug innovation and other functional applications. The biological activities of natural and unnatural phenols can also be regulated by metabolism in cell via oxidative enzymatic systems, such as human liver microsomes/NAD(P)H oxidoreductase (28), prostaglandin synthase/arachidonic acid, horse-radish peroxidase/H 2 O 2 , dioxygenases, and myeloperoxidase/H 2 O 2 systems (29). Due to this significance, the synthesis of phenols is an ever progressing process in synthetic chemistry laboratories.
The classical methods of phenol preparation include Cu-promoted transformations of diazonium salts (50)(51) and transition-metal catalyzed C-X bond hydroxylations of aryl halides (52)(53)(54)(55). These have limitations, such as less availability of starting materials and the requirements of harsh reaction conditions, such as high-temperature and hazardous chemicals. The diazotization of the amino arenes to diazoarenes is often not compatible when the substrate has many other functional groups. Consequently, the synthesis of phenols from (H)ABAs via ipsohydroxylation receives vast attention for higher stability, easy availability of precursors, and a greater diversity of the functional groups (21,22). Fewer Cu-catalyzed oxidative ipso-hydroxylations of (H)ABAs have appeared in the literature, which include CuSO 4 -phen-KOH (56),   (66) and Cu 2 O-TiO 2 -K 2 CO 3 -white LED (67) systems. Many of these procedures require 1-3 equivalent non-renewable base, unconventional catalysts, ligands, or heating conditions or take a considerable reaction time. A detailed comparison of reported Cu-mediated methods of ipsohydroxylation of (H)ABAs has been provided in Table 3 in the results and discussion section (Section 3), and Scheme 1 is a glimpse of the reported advantageous methods for this purpose.
Although some efficient methods were reported in the literature for the ipso-hydroxylation of (H)ABAs, these require stoichiometric amounts of reagents or oxidants, problematic solvents, and photocatalytic activations (21,22,(68)(69)(70)(71)(72). As part of our continuous efforts in green and sustainable chemistry (1,3,(9)(10)(11)73,74), we disclose here a sustainable method for the Cu-catalyzed ipso-hydroxylation of (H)ABAs at RT shows tremendous benefits, such as the avoidance of stoichiometric amounts of oxidants/reagents with very low catalyst loading to access phenols from (H)ABAs using air as a sustainable oxidant. Scheme 1 shows the advantages of this protocol compared to some of the reported methods in this area (65,66). The present method uses biorenewable and waste-originated base and reaction media, and the reactions are quicker to give excellent yields of phenols (Scheme 1).

General information
The aryl/heteroarylboronic acids were purchased from Sigma-Aldrich, Alfa Aesar, and the AVRA synthesis was used with no further purification. The progress of reactions has been monitored by TLC (Thin layer chromatography) using precoated Merck silica gel plates (60F-254). Visualization of reactants and products was accomplished under UV light. The 1 H/ 13 C NMR spectra were recorded on a JEOL, JNM ECS NMR spectrometer operating at 400/100 MHz using CDCl 3 or DMSO-d 6 and tetramethylsilane (TMS) as a solvent and internal standards, Scheme 1. Cu-catalyzed significant procedures of ipso-hydroxylation of (H)ABAs. and chemical shifts (δ) are quoted in ppm while coupling constants (J ) in Hz.

Procedure for the synthesis of phenols using WEPA
A solution of aryl/heteroaryl boronic acid (1) (1.0 mmol) 3 mL of WEPA was added to 3 mol% of CuI, and the reaction allowed for stirring at RT for an appropriate time, as displayed in Table 2. The reaction mixture was added with 5 mL of water to quench the reaction after its completion as indicated by TLC, 3 × 5 mL of EtOAc was used to extract the crude product, and the combined EtOAc portion was evaporated used for the purification of phenol via column chromatography. The structures of phenols (2) were assigned using their 1 H NMR and 13 C NMR data. These data well matched with the reported data. The copies of 1 H NMR and 13   CuI (1) WEPA (3 mL) 4 53 4 CuI (1) WEPA (4 mL) 4 52 5 CuI (2) WEPA (3 mL) 2 69 6 CuI (3) WEPA CuI (3) Water (3 mL) 24 CuI (3) Neutral WEPA (∼3 mL) c 8 -11 CuI (

Characterization of WEPA
Our recent characterizations of WEPA, using EDAX, XPS, XRD, XRF, and FTIR analysis, revealed the followings: K 2 O and KCl in large quantities, along with SO 3 , Na 2 O, CaO, MgO, Al 2 O 3 , SiO 2 in minor quantities (3,(9)(10)(11)73,74). The XPS and XRF data of WEPA from our recent reports have been provided in the supporting information for convenience. These constituents of WEPA played a critical role in various organic transformations, including Ullmann coupling of aryl halides, Suzuki-Miyaura cross-coupling, self-coupling of (H)ABAs, aryl bromides, and aryl iodide synthesis (3,(9)(10)(11)73,74). In these cases, WEPA acted as an aqueous media and biorenewable base [pH was between 11.7 and 12.1 after several repetitions (3)] and (or) catalyst by the reduction/elimination of the requirement of non-renewable resourcesbased materials including bases/catalysts/volatile organics/oxidants/heating conditions, etc. Inspired by the steady, sustainable attributes in the chemical transformations using WEPA, we have investigated the applicability of WEPA to Cu-catalyzed phenol synthesis via ipso-hydroxylation of (H)ABAs.

Optimization studies of CuI-catalyzed ipsohydroxylation of ABAs in WEPA
For obtaining the optimized conditions for phenol synthesis, we have used the model reaction of phenylboronic acid (1a) (1 mmol) in 1 mL of WEPA and 1 mol% of CuI, and the phenol (2a) was formed with a 29% yield in 6 h at RT (Table 1, entry 1). The use of 2, 3 and 4 mL of WEPA at this stage was provided 2a in 40%, 53%, and 52% in 4 h ( Table 1, entries 2-4), which indicates the present phenol synthesis requires 3 mL of WEPA. Furthermore, the application of CuI in 2, 3, and 4 mol% provided the 2a with 69%, >99%, and >99% in 4, 0.4, and 0.4 h ( Table 1, entries 5-7), signifies that this conversion is effective using 3 mol% of CuI. The absence of WEPA (where 3 mL of water was used in the place of WEPA) or CuI showed no progress ( Table 1, entries 8 and 9), and hence this conversion requires the CuI and WEPA. The model reaction was not preceded using neutralized WEPA or acidified WEPA under the current reaction conditions ( Table 1, entries 10 and 11). Hence, the basicity of WEPA is crucial for this conversion. Furthermore, the pH of WEPA decreased from ∼12 to ∼8 after the completion of the reaction. The study of other copper salts such as CuCl 2 ·2H 2 O, CuBr, Cu(OAc) 2 and CuSO 4 , FeCl 3, and Ni(OAc) 2 showed no improvement in the current transformation (Table 1, entries 12-17). These analyses show that the present reaction requires 3 mol% of CuI and 3 mL of WEPA per 1 mmol of the substrate to obtain phenol with high yields at RT.

Plausible mechanism of CuI-catalyzed ipsohydroxylation of (H)ABAs
The mechanism of Cu-catalyzed ipso-hydroxylation of ABAs is not fully understood yet. However, we propose here a plausible mechanism of current ipso-hydroxylation of (H)ABAs in WEPA based on the observations shown in Table 1 along with some control experiments (Scheme 2), reusability studies (Section 3.5), and literature reports (56,63,65,(80)(81)(82).
The versatility of the Cu-catalyzed process is that it can undergo very quickly into one-or two-electron processes and shows easy access to its four oxidation states from 0 to +3 (82,83). The reaction of 1a in the presence of CuI (3 mol%), WEPA (3 mL) and 1 eq. of radical scavenger such as TEMPO was proceeded to give >99% of 2a in 0.4 h (Scheme 2), indicating no influence of TEMPO on the current reaction; hence, the reaction is not proceeding through a radical mechanism. The reaction of 1a did not proceed in the presence of an inert (N 2 ) atmosphere, but it shows similar results in open-air and in the presence of oxygen (Scheme 2), and these control experiments indicate that the current transformation requires oxygen to proceed, but the oxygen from the air is enough. Furthermore, the reusability studies (Section 3.5), a decrease in pH of WEPA after the reaction (Section 3.2) and no progress of the reaction in the presence of neutralized or acidified WEPA (Table 1, entries 10 and 11) indicates that the basic nature of WEPA is crucial for this transformation. Furthermore, the copper catalyst can be recycled and reused.
According to the above observations and the literature reports, initially, an ionic species, A, formed from the ABA and base of WEPA (i.e. MB) (82), may react with CuI to generate the intermediates i and B via the oxidative addition process (I) in the presence of molecular oxygen (O 2 , from the air) (Scheme 3). Further oxidative addition (II) of intermediates i and B in the presence of water may result the intermediate ii and C. Finally, intermediate ii may participate in reductive elimination (III) to produce phenol 2 and the catalyst, CuI. The other chemical substances of WEPA may also participate in this process by acting as promoters or phase transfer agents (3).

Reusability studies
After the completion of the reaction of 1a (Section 2.3), the product formed was extracted using Et 2 O, and 1 mmol of 1a was added to the resultant WEPA-CuI system for understanding the reusability of the WEPA-CuI mixture, but the reaction gave < 5% yield of 2a after 8 h. However, the evaporation of the resultant WEPA-CuI mixture to ∼0.3 mL followed by the addition of 3 mL of WEPA and 1 mmol of 1a was proceeded at RT to give a 96% yield of 2a in 0.4 h, and further repetition of this process showed 93%, 90% and 81% yields of 2a in 0.4 h during the third to fourth cycles.

Comparison of results
For identifying the effectiveness of the current protocol, a concise review of the existing Cu-catalyzed protocols of ipso-hydroxylation of phenylboronic acid (1a) has been provided in Table 3. This method avoids the nonrenewable resources-based bases, ligands, problematic solvents, promoters, heating conditions, significant reaction times, and tedious preparation of catalysts. The current method is significant to the scientific community, as we believe that the next generation of catalysis would use green and sustainable catalysts in organic synthesis. This process also becomes an attractive alternative to the protocols based on the application of stoichiometric amounts of green oxidants such as H 2 O 2 (21,84).

Conclusions
We have developed a Cu-catalyzed, room temperature protocol for synthesizing phenols from (H)ABAs using biorenewable and waste-originated WEPA as a primary reaction medium. This protocol shows broad substrate feasibility, vast functional group tolerability, and good catalyst reusability in the biorenewable base. A systematic comparison of the previously reported methods of the ipso-hydroxylations of (H)ABAs has displayed the advantages of this protocol as the use of biorenewable catalyst, ambient conditions, good yields of products, and ease of synthesis and purification of the end-products. Finally, this method could be one of the forefront sustainable procedures for the ipso-hydroxylation of (H)ABAs in the industry in the near future.