Cross-dehydrogenative coupling of coumarins with Csp3–H bonds using an iron–organic framework as a productive heterogeneous catalyst

The iron–organic framework VNU-20 was utilized as an active heterogeneous catalyst for the cross-dehydrogenative coupling of coumarins with Csp3–H bonds in alkylbenzenes, cyclohexanes, ethers, and formamides. The combination of DTBP as the oxidant and DABCO as the additive led to high yields of coumarin derivatives. The VNU-20 was more active towards this reaction than numerous other homogeneous and heterogeneous catalysts. Heterogeneous catalysis was confirmed for the cross-dehydrogenative coupling transformation utilizing the VNU-20 catalyst, and the contribution of active iron species in the liquid phase was insignificant. The iron-based framework was reutilized many times for the functionalization of coumarins without a remarkable decline in catalytic efficiency. To the best of our knowledge, these reactions of coumarins have not previously been conducted using heterogeneous catalysts.


Introduction
Coumarins represent an important family of precious structural units, largely distributed in a wide range of natural products and pharmaceutical candidates. [1][2][3][4] The functionalization of naturally occurring skeletons has gained signicant attention, as interesting and unexpected biological properties would be generated. [5][6][7] Among several synthetic strategies, reactions via direct C-H bond activation have exhibited signicant advantages, avoiding the preparation of prefunctionalized reactants and the purication of intermediate products. [8][9][10] However, the transformation of coumarin skeletons via direct C-H bond activation has been very limited in the literature. Niu et al. previously performed the direct couplings of coumarins with cyclic ethers using a FeCl 3 catalyst. 11 Wang et al. synthesized a variety of C-3 functionalized coumarins via the Cu(OAc) 2catalyzed reaction with cyclic ethers and cycloalkanes. 12 Cao et al. developed a novel approach for the direct Csp 2 -H radical triuoromethylation of coumarins in the presence of Mn(OAc) 3 . 13 Zhou et al. reported the cross-dehydrogenative coupling of coumarins with benzylic Csp 3 -H bonds utilizing Cu(OAc) 2 catalyst. 14 Cheng et al. prepared several biologically active coumarin derivatives via Pd(OAc) 2 -catalyzed intramolecular cross-dehydrogenative coupling reaction. 15 For more environmentally benign synthetic strategies, transformations of coumarins utilizing heterogeneous catalysts should be explored to achieve simple workup, recyclability, and reusability.
Metal-organic frameworks (MOFs), a signicant class of multidimensional crystalline polymeric materials, have been extensively explored during the last decade owing to their encouraging applications in numerous areas. [16][17][18][19] Depending on the nature of metal cations, the structure of organic linkers, as well as synthetic conditions, a broad range of MOFs with various connectivity and symmetry have been generated. [20][21][22][23] Due to the exibility in designing the active sites on the framework, MOFs have been considered as promising candidates in catalysis eld. [20][21][22][23][24] Both organic and inorganic constituents in MOFs could create catalytically active sites, thus leading to advantages over traditional catalytic materials. [20][21][22][23] Along with MOFs constructed using a single kind of linker, several structures containing a mixture of two or more bridging organic ligands have been explored. [24][25][26] If two linkers are present in the frameworks, attractive properties might be achieved. 27 A variety of organic transformations utilizing iron-based MOFs as heterogeneous catalysts were previously reported in the literature. [28][29][30][31][32][33][34] We recently reported the functionalization of coumarins with N,N-dimethylanilines in the presence of a mixed-linker iron-based MOF VNU-20 as heterogeneous catalyst. 35 In this work, we would like to expand the catalytic application of this MOF to the cross-dehydrogenative coupling of coumarins with alkylbenzenes, cycloalkanes, ethers, and formamides. To the best of our knowledge, this

Catalytic studies
In a representative experiment, 6-methylcoumarin (0.040 g, 0.25 mmol), mesitylene (1 mL), 1,4-diazabicyclo[2.2.2]octane (DABCO; 0.028 g, 0.25 mmol), and diphenyl ether (0.04 mL) as internal standard were introduced to a pressurized vial containing the VNU-20 catalyst. Di-tert-butylperoxide (DTBP; 0.094 mL, 0.75 mmol) as oxidant was then added dropwise to the vial. The mixture was magnetically stirred at 120 C for 6 h. The reaction mixture was diluted with ethyl acetate (30 mL). The ethyl acetate solution was washed with HCl solution (5% in water, 3 Â 5 mL), and subsequently with saturated NaHCO 3 solution (3 Â 5 mL). The organic layer was dried utilizing anhydrous Na 2 SO 4 . Reaction yields were recorded from GC analysis results concerning the diphenyl ether internal standard. The expected product was isolated using column chromatography. The product structure was conrmed by GC-MS, 1 H NMR, and 13 C NMR. For the catalyst recycling studies, the VNU-20 was isolated by centrifugation, washed carefully with DMF and methanol, activated at room temperature under vacuum on a Shlenkline, and reutilized for new catalytic experiments.

Catalyst synthesis and characterization
The VNU-20 was synthesized following solvothermal protocol in 75% yield by conducting the reaction between 1,3,5-benzenetricarboxylic acid, 2,6-napthalenedicarboxylic acid, and iron(II) chloride. The iron-based framework was consequently characterized by utilizing numerous analysis methods (Fig. S1-S7 †). Highly sharp peaks existed in the X-ray powder diffraction result, conrming that the VNU-20 was truly crystalline (Fig. S1 †). Scanning electron microscopy analysis also supported the crystal form of the iron-based framework (Fig. S2 †). Transmission electron microscopy micrograph exhibited a porous structure for the VNU-20 (Fig. S3 †). Nevertheless, it was noticeable that the pore structure of the framework was complicated. Nitrogen physisorption measurements demonstrated a pore diameter of less than 10Å, verifying that the material contained microporous pores (Fig. S4 †). Additionally, Langmuir surface areas of 760 m 2 g À1 were obtained for the Fe-MOF, as calculated from isotherm nitrogen physisorption data (Fig. S5 †). TGA result revealed that the iron-based framework was stable up to over 300 C (Fig. S6 †). FT-IR spectra of the VNU-20 was also compared to those of 1,3,5-benzenetricarboxylic acid, and 2,6-napthalenedicarboxylic acid (Fig. S7 †). These two carboxylic acids have the characterization peak centered at 1710 cm À1 and 1674 cm À1 . Peaks of the coordinated carboxylate group of BTC 3À and NDC 2À in the VNU-20 were shied to lower wavelength as higher energy would be needed for the stretching vibration of these functional groups.

Catalytic studies
The iron-organic framework VNU-20 was initially explored as a heterogeneous catalyst for the cross-dehydrogenative coupling of 6-methylcoumarin with mesitylene to produce 3-(3,5-dimethylbenzyl)-6-methyl-2H-chromen-2-one as the major product (Scheme 1). First, the inuence of temperature on the transformation was studied (Fig. 1). The reaction was conducted at 3 mol% catalyst in mesitylene for 6 h, in the presence of 3 equivalents of DTBP and 1 equivalent of DABCO, at room temperature, 100 C, 120 C, and 140 C, respectively. It was noticed that the cross-dehydrogenative coupling reaction did not occur at ambient temperature, and no evidence of the desired product was detected aer 6 h. Boosting the temperature to 100 C did not accelerate the reaction considerably, affording the major product in only 13% yield. Low yield of the cross-coupled product was still observed for the reaction conducted at 110 C. It was noticed that the reaction proceeded readily at 120 C, producing 3-(3,5-dimethylbenzyl)-6-methyl-2H-chromen-2-one in 89% yield. However, extending the temperature to 140 C did not favor the transformation, with 73% yield being recorded aer 6 h. This could be explained based on the partial decomposition of coumarin at high temperature. Similar to other cross-dehydrogenative coupling reactions, an oxidant should be present in the reaction mixture. We consequently determined to explore the impact of different oxidants on the coupling of 6-methylcoumarin with mesitylene to produce 3-(3,5-dimethylbenzyl)-6-methyl-2H-chromen-2-one using the VNU-20 catalyst. The reaction was conducted in mesitylene at 120 C in the presence of 3 mol% catalyst for 6 h, using 1 equivalent of DABCO, with 3 equivalents of an oxidant, including DTBP, tert-butyl hydroperoxide in water (aqueous TBHP), tert-butyl hydroperoxide in decane (TBHP in decane) di-tert-butyl azodicarboxylate (DBAD), (2,2,6,6tetramethylpiperidin-1-yl)oxy (TEMPO), hydrogen peroxide (H 2 O 2 ), and potassium persulfate (K 2 S 2 O 8 ), respectively. Experimental results indicated that DBAD, H 2 O 2 , and K 2 S 2 O 8 should not be utilized for this reaction, with no trace amounts of product being recorded. Moving to aqueous TBHP, the transformation proceeded to 75% yield aer 6 h, while the yield was improved to 84% for the case of TBHP in decane. Compared to these oxidant, DTBP was the oxidant of choice, generating 3-(3,5-dimethylbenzyl)-6-methyl-2H-chromen-2one in 89% yield aer 6 h (Fig. 2a). Moreover, the quantity of oxidant also exhibited a considerable inuence on the cross-dehydrogenative coupling reaction (Fig. 2b). Best yield was achieved for the reaction utilizing 3 equivalents of DTBP, while increasing the amount of the oxidant resulted in lower yield. It should be noted that no trace evidence of the desired product was detected in the absence of the oxidant.
One more issue that should be investigated for the coupling of 6-methylcoumarin with mesitylene to produce 3-(3,5-dimethylbenzyl)-6-methyl-2H-chromen-2-one is the required catalyst amount. Zhou et al. previously employed 5 mol% Cu(OAc) 2 catalyst for the cross-dehydrogenative coupling of coumarins with benzylic Csp 3 -H bonds, 14 and Niu et al. utilized 10 mol% FeCl 3 catalyst for the direct couplings of coumarins with cyclic ethers. 11 Wang et al. performed the cross-dehydrogenative coupling of coumarins with ethers and cycloalkanes in the presence of 10 mol% Cu(OAc) 2 catalyst. 12 The reaction was then performed at 120 C in mesitylene for 6 h, in the presence of 3 equivalents of DTBP and 1 equivalent of DABCO, at 1 mol%, 3 mol%, 5 mol%, and 7 mol% VNU-20 catalyst, respectively. It was noticed that less than 12% yield of 3-(3,5-dimethylbenzyl)-6methyl-2H-chromen-2-one was detected aer 6 h in the absence of the VNU-20, thus indicating that iron species should be required for the transformation. The yield of the major product was remarkably improved in the presence of the iron-organic framework catalyst. Utilizing 1 mol% catalyst, 81% yield was obtained aer 6 h. Extending the catalyst amount to 3 mol%, the reaction afforded 89% yield of the desired product aer 6 h.  Higher initial rates were observed for the reaction utilizing 5 mol% and 7 mol% catalyst. However, aer 6 h, 89% yield of 3-(3,5-dimethylbenzyl)-6-methyl-2H-chromen-2-one was recorded for both cases (Fig. 3). We therefore employed 3 mol% catalyst for this reaction in further studies.
Experimental results indicated that only 18% yield of 3-(3,5dimethylbenzyl)-6-methyl-2H-chromen-2-one was detected for the reaction in the absence of DABCO as additive. This observation conrmed the importance of the additive in the crossdehydrogenative coupling reaction using the VNU-20 catalyst. Previously, Niu et al. performed the direct couplings of coumarins with cyclic ethers using FeCl 3 catalyst in the presence of 1 equivalent of DABCO or DBU. 11 We accordingly explored the transformation with various additives, including DABCO, triphenylphosphine, trimethylamine, hexaethylenetetramine, potassium tert-butoxide, and sodium carbonate, respectively (Fig. 4a). The reaction was then conducted at 120 C in mesitylene for 6 h, in the presence of 3 equivalents of DTBP, with 3 mol% catalyst, using 1 equivalent of the additive. It was noticed that triphenylphosphine, trimethylamine, potassium tert-butoxide, and sodium carbonate were not appropriate for the cross-dehydrogenative coupling reaction, affording the expected product in 4%, 35%, 1%, and 26% yields, respectively, aer 6 h. Hexaethylenetetramine exhibited better performance, with 51% yield being recorded aer 6 h. DABCO emerged as the most suitable additive, producing 3-(3,5-dimethylbenzyl)-6-methyl-2H-chromen-2-one in 89% yield aer 6 h. Furthermore, it was noticed that the amount of DABCO displayed a considerable impact on the crossdehydrogenative coupling reaction. Best result was obtained for the reaction using 1 equivalent of DABCO. Increasing or decreasing the amount of DABCO resulted in lower yield of the desired product (Fig. 4b).
Since the cross-dehydrogenative coupling of 6-methylcoumarin with mesitylene to produce 3-(3,5-dimethylbenzyl)-6-methyl-2H-chromen-2-one was performed in solution, it is crucial to explore the leaching phenomenon. Indeed, the formation of product might be achieved via homogeneous catalysis because a portion of catalyst was dissolved into the liquid phase. Control experiments were accordingly carried out to conrm if active iron species were migrated from the VNU-20 to mesitylene phase or not. The reaction was performed at 120 C in mesitylene for 6 h, in the presence of 3 equivalents of DTBP and 1 equivalent of DABCO, at 3 mol% catalyst. Aer the rst 2 h with 39% yield of 3-(3,5-dimethylbenzyl)-6-methyl-2Hchromen-2-one being noted, the iron-based framework was  This journal is © The Royal Society of Chemistry 2018 isolated. The mesitylene phase was thereaer transferred to a new and clean reactor, and the mixture was heated at 120 C for additional 4 h. The formation of product during these 4 h, if any, was monitored by GC analysis. Under these conditions, 47% yield of the expected product was recorded aer 6 h. It should be noted that the transformation afforded 89% yield in the presence of the VNU-20 aer 6 h, and that 12% yield was detected aer 6 h in the absence of the catalyst (Fig. 5). These data suggested that the cross-dehydrogenative coupling of 6methylcoumarin with mesitylene proceeded via heterogeneous catalysis, and the contribution of active iron species in liquid phase was insignicant.
To obtain more information about the pathway of the crossdehydrogenative coupling of 6-methylcoumarin with mesitylene to produce 3-(3,5-dimethylbenzyl)-6-methyl-2H-chromen-2-one, additional control experiments were also executed. First, the reaction was performed at 120 C in mesitylene for 6 h, in the presence of 3 equivalents of DTBP and 1 equivalent of DABCO, at 3 mol% catalyst. Aer 1 h reaction period, ascorbic acid as antioxidant was introduced to the reactor, and the mixture was heated at 120 C for additional 5 h. The presence of ascorbic acid in the reaction mixture displayed a remarkable inuence on the formation of 3-(3,5-dimethylbenzyl)-6-methyl-2Hchromen-2-one. Certainly, this experiment led to 39% yield of the desired product aer 6 h reaction time. Similarly, (2,2,6,6tetramethylpiperidin-1-yl)oxyl (TEMPO) as antioxidant was employed, and only 29% yield was detected aer 6 h (Fig. 6a). It should be noted that the reaction afforded 89% yield in the presence of the VNU-20 aer 6 h. These data implied that ascorbic acid or TEMPO trapped the radicals generated in the cycle of the catalytic conversion, therefore ceasing the crossdehydrogenative coupling reaction. In an other test, pyridine as a catalyst poison, was used to deactivate the catalyst aer the rst 1 h reaction period, and the mixture was heated at 120 C for additional 5 h. It was noted that the presence of pyridine considerably refrained the transformation (Fig. 6b). The low yield of 3-(3,5-dimethylbenzyl)-6-methyl-2H-chromen-2-one could be explained based on the strong interaction between Lewis acid sites on the VNU-20 and the pyridine as a Lewis base. Indeed, Dhakshinamoorthy et al. previously pointed out that the interaction of pyridine as a base with the Lewis acid sites in metal-organic frameworks resulted in the deactivation of the MOF-based catalysts. 36 Therefore, the free coordination iron sites in the VNU-20 framework should be responsible for the catalytic coupling reaction, and the deactivation of these sites would terminate the transformation. From these observations and previous reports, 7,8,10 a plausible mechanism was suggested (Scheme 2). Initially, hydrogen extraction from mesitylene by  DTBP created a stable benzylic radial. Next, the interaction between 6-methylcoumarin and this radical produced another benzylic radical. Releasing of a proton, the coupling product was formed, and the Fe(II) species was regenerated.
To emphasize the remarkable aspect of this iron-organic framework, the catalytic activity of the VNU-20 in the crossdehydrogenative coupling of 6-methylcoumarin with mesitylene to produce 3-(3,5-dimethylbenzyl)-6-methyl-2H-chromen-2one was compared to a series of homogeneous catalysts and heterogeneous catalysts. The reaction was performed at 120 C in mesitylene for 6 h, in the presence of 3 equivalents of DTBP and 1 equivalent of DABCO, at 3 mol% catalyst. The transformation progressed slowly in the presence of FeCl 2 catalyst, generating the desired product in only 16% yield aer 6 h. FeCl 3 displayed similar activity, with 19% yield being noted aer 6 h under similar conditions. FeSO 4 and Fe 2 (SO 4 ) 3 were also not appropriate as catalysts for this reaction, forming 3-(3,5-dimethylbenzyl)-6-methyl-2H-chromen-2-one in 29% and 22% yields, respectively, aer 6 h. Fe(NO 3 ) 3 was more active than other iron salts, and using this catalyst resulted in 42% yield aer 6 h. Interestingly, the VNU-20 offered remarkably higher catalytic activity towards the cross-dehydrogenative coupling than these homogeneous catalysts, with 89% yield being recorded aer 6 h (Fig. 7a).
Next, several MOF-based catalysts were explored for this reaction, including VNU-20, Fe 3 O(BDC) 3  to higher initial rates. However, 81% and 82% yields were obtained for the reaction aer 6 h. The transformation using the VNU-20 catalyst proceeded with lower initial rate in the rst 4 h reaction time. Nevertheless, the yield of 3-(3,5-dimethylbenzyl)-6-methyl-2H-chromen-2-one was upgraded to 89% aer 6 h (Fig. 7b). Previously, Zhou et al. performed the crossdehydrogenative coupling of coumarins with benzylic Csp 3 -H bonds at 100 C for 24 h utilizing 5 mol% Cu(OAc) 2 catalyst. 14 Wang et al. conducted the coupling reaction of coumarins with cyclic ethers and cycloalkanes at 100 C for 24 h in the presence of 10 mol% Cu(OAc) 2 catalyst. 12 Niu et al. carried out similar transformation at 120 C for 36 h using 10 mol% FeCl 3 catalyst. 11 Although interesting results were achieved, it was difficult to recycle and reuse these homogeneous catalysts. The fact that coumarin derivatives were produced by utilizing a recyclable catalyst was therefore of signicant advantages.
As pointed out previously, compared to numerous homogeneous and heterogeneous catalysts, the VNU-20 was more active towards the cross-dehydrogenative coupling of 6-methylcoumarin with mesitylene to produce 3-(3,5-dimethylbenzyl)-6methyl-2H-chromen-2-one. To spotlight the remarkable aspect of using this iron-based MOF in this transformation, the promptness of reusability was accordingly explored with 6 sequential catalytic runs. The reaction was performed at 120 C in mesitylene for 6 h, in the presence of 3 equivalents of DTBP and 1 equivalent of DABCO, at 3 mol% catalyst. Aer each experiment, the VNU-20 was isolated by centrifugation, washed carefully with DMF and methanol, and activated at room temperature under vacuum on a Shlenkline. The recovered VNU-20 was subsequently reutilized for new catalytic experiments using similar reaction conditions. GC analysis results indicated that it was possible to reutilize the VNU-20 many times for the formation of 3-(3,5-dimethylbenzyl)-6-methyl-2Hchromen-2-one without a remarkable decline in catalytic efficiency. Certainly, the cross-dehydrogenative coupling reaction afforded 85% yield in the 6th catalytic run (Fig. 8). Additionally, some characterization experiments were conducted to explore if the structure of the VNU-20 was maintained. FT-IR results of the recovered framework (Fig. S32 †) was similar to those of the fresh catalyst. The crystallinity of the VNU-20 was not destroyed during the catalytic experiments, although slight difference was noted in XRD analysis results (Fig. S33 †).

Conclusions
Iron-organic framework VNU-20 emerged as an active heterogeneous catalyst for the cross-dehydrogenative coupling of coumarins with different benzylic Csp 3 -H bonds. The reaction required an oxidant, and a basic additive. The combination of DTBP as the oxidant and DABCO as the additive led to high yields of coumarin derivatives. The VNU-20 was more active towards this transformation than a series of homogeneous and heterogeneous catalysts, thus emphasizing the signicant aspect of utilizing this iron-organic framework for the reaction. Heterogeneous catalysis was conrmed for the crossdehydrogenative coupling transformation utilizing the VNU-20 catalyst, and the contribution of active iron species in liquid phase was insignicant. It was possible to reutilize the VNU-20 many times for the formation of 3-(3,5-dimethylbenzyl)-6methyl-2H-chromen-2-one without a remarkable decline in catalytic efficiency. Moreover, the protocol was also expanded to the cross-dehydrogenative coupling of coumarins with cycloalkanes, ethers, and formamides. The fact that coumarins could be functionalized via cross-dehydrogenative coupling with Csp 3 -H bonds in the presence of a recyclable heterogeneous catalyst would be protable to the chemical and pharmaceutical industry.

Conflicts of interest
There are no conicts to declare.