Synthesis, Characterization, and Properties of a Benzofuran-based Cage-shaped Borate: Photo Activation of Lewis Acid Catalysts

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The precise control of Lewis acidity is very important for organic synthesis because activation of molecules mainly depends on the character of the Lewis acid. 1 The Lewis acidity is often controlled by the steric or electronic factors of the species.Recently, we developed cage-shaped borate esters that have a triphenolic ligand with a tripod-chelated structure such as 2, which shows significantly different characteristics than those of the planar structure of a common borate 1. 2 As shown in Scheme 1, a cage-shaped borate 3 can be tuned by the introduction of substituents, R, such as halogens 3 or aryl groups. 4The structure of the cage shape in 3 allows the precise control of the dihedral angles of C-O-B-O in the cage and LUMO levels by changing a tether atom, X, from carbon to silicon. 5 These factors lead to the formation of Lewis acids with the same type of template but a variety of characteristics.A complete replacement of the benzene rings with heteroaromatic rings or with a partial embedding of heteroatoms in the p-conjugated system has been an attractive approach to control either the physical or the chemical properties. 6hus, the ring-fusion of heteroaromatic moieties to the aromatic portions in the cage-shaped borates would cause electronic perturbations in the Lewis acid center without a steric effect, which would allow the precise control of the Lewis acidity.In the present study, heteroaromatic moieties in the form of benzofuran-frameworks were introduced into the cage structure, which conferred characteristics that differed from those of the previously synthesized borates 2 and 3. A benzofuran moiety has an intrinsic dipole 7 due to the ring oxygen with a polarity that affects the Lewis acidity of the complex.
We planned to prepare a benzofuran-based triphenolic ligand from a commercially available 5-methoxybenzofuran 5 (Scheme 2).As our previously reported synthetic route for the simple cage-shaped borate 2, 2a 5-methoxybenzofuran 5 was deprotonated by nBuLi and treated with ethyl chloroformate, giving an undesired regioisomeric carbinol 6 bound at the 2-position of the methoxybenzofuran.Then, as a regioselective bromination at the ortho-position of phenols has been reported, 8 5-hydroxybenzofuran 7 was prepared via the deprotection of a methoxy group of 5 by BBr 3 .The bromination of 7 8 by NBS/iPr 2 NH successfully afforded 4-bromo-5-hydroxybenzofuran 8.After the protection of OH in OMe, the addition of nBuLi for a halogenlithium exchange followed by treatment with ethyl chloroformate gave the desired triarylmethanol 10 selectively bound at the 4-position of methoxy-4-benzofuran.A reduction of 10 under acidic conditions in THF/MeCN 9 and the deprotection of the methoxy groups by BBr 3 afforded the tris(5-hydroxy-4-benzofuranyl)methane 12.A mixture of 12 with BH 3 ÁTHF in THF readily generated the cage-shaped borate 4ÁTHF (Scheme 2).
The NMR spectroscopy of 4ÁTHF showed typical signals for a cage-shaped borate; the upfield/downfield shift of the d( 1 H)/d( 13 C) of C-H at the tether position was compared with those of the ligand 12: (d( 1 H) 6.69 -6.32 ppm, d( 13 C) 38.9 -43.2 ppm). 3The coordinating THF showed broad signals at the lower chemical shifts compared with those of free THF.The recrystallization of 4ÁTHF from hexane/CH 2 Cl 2 gave a suitable crystal for X-ray analysis.The ORTEP drawings are shown in Fig. 1. 10 The bond length of B-O(THF) was 1.575(3) Å, which was shorter than that (1.595(8) Å) of the simple cage-shaped borate 2ÁTHF.The sum of the bond angles of O-B-O (O: ligand) was 343.961 for 4ÁTHF, while the sum of the bond angles (344.811) for 2ÁTHF was slightly larger.These structural features indicated that 4ÁTHF had a slightly higher Lewis acidity than 2ÁTHF.
Lewis acidity was also estimated via the NMR chemical shift d( 13 C) and infrared stretching frequency of 2,6-dimethyl-gpyrone 13 to borates 4, as shown in Table 1. 3 The Dd( 13 C) shift of C3 and the stretching frequency of the carbonyl (CQO) groups in 13 clearly show the degree of Lewis acidity.The borate 4 showed a large Dd ( 13 C) and Dn(CQO), which indicated a Lewis acidity that was slightly higher than that of 2.
The DFT calculations of 4 at the B3PW91/6-31+G(d,p) level showed it to be a ligand-free, three-coordinated structure, which would contribute to an active Lewis acid species during the reaction course (Fig. 2 and Table S1 in the ESI †).The dihedral angles C-O-B-O, which reflect the shape of the cage, were almost the same as those of the species 2. 2a However, an effective conjugation between the B atom and the benzofuran skeleton in 4 was estimated, which would lead to a decrease in the energy level of the unoccupied orbital of a Lewis acid (in this case, the next-LUMO level), while the orbital of 2 is located closer to its B atom.The energy level of the next-LUMO was À21.6 kcal mol À1 (À0.94 eV) for 4, which was lower than those of the benzene-based borates 2 (À18.3 kcal mol À1 ) and 3c (À16.8 kcal mol À1 ) (Table S1, ESI †). 3 Although a lower next-LUMO level of 4 was expected to contribute to a large reaction rate, the pyridine-complexation energy, DE, reflected a catalytic turnover of 4 (À18.8kcal mol À1 ) that was similar to that of 2 (À19.2kcal mol À1 ).Generally, when a next-LUMO energy level becomes lower, the stabilization energy shows larger (larger negative for DE), which means that the Lewis acidity and catalytic turnover have a trade-off relationship.It should be noted that the borate 4 showed an unexpected relationship that resulted in a high affinity for the substrate and a high catalytic turnover.Significant differences between 4 and 2 were found in the magnitude of the dipole moment and in the charge distribution (Fig. S1, ESI †).Both compounds had a dipole moment that was directed from the cage center to the tether position, but the magnitude of the dipole of 4 is 1.5 times larger Scheme 2 Synthesis of benzofuran-based triphenolic ligand 12 and cage-shaped borate 4.  than that of 2, presumably due to the effective fixation of the dipole vector of each furan ring that resulted from the formation of its rigid cage-structure.The Mulliken charge distribution also reflected the difference in dipole; the Mulliken charge of the B atom for 4 (+1.265a.u.) was more positive than that of 2 (+1.161 a.u.) (Fig. S2, ESI †).Precise tuning of the electronic features of 4 clearly characterized its catalytic activities.To estimate the Lewis acid catalytic ability, the Mukaiyama-type reaction 11 of a variety of aldehydes 14a-e with silylketene acetal 15 was examined in the presence of borate catalysts 4ÁTHF and 2ÁTHF. 12The borate 4ÁTHF gave a much higher yield of the product 16a-d compared with that given by 2ÁTHF for aromatic aldehydes 14a-d in a short time, although prolonging the reaction time led to high yields even in the catalytic reaction with 2ÁTHF (Table 2).Moreover, the borate 4ÁTHF showed high tolerance to a variety of functional groups.While 4 would have limited applicability to aliphatic aldehydes (entry 5), it should be noted that 4 catalyzed a wide range of aromatic aldehydes to give the desired products in moderate yields in a short time.As expected from the theoretical analyses, the borate 4 showed high affinity for the substrate and high catalytic turnover, which was accomplished via an effective p-conjugation between the Lewis acid center and the aromatic core with a large dipole moment in the cage structure.
To further explore the catalytic turnover, the ligandexchange rate was investigated.The mixture of the complex 4ÁDMAP in a pyridine-d 5 solution was observed via 1 H-NMR (Table S4, ESI †).The kinetic equation based on the first order of the borate in our previous report 3 unreasonably showed a large negative activation entropy, DS ‡ (À33.4 cal K À1 mol À1 ), 13 and, thus, the first-order hypothesis was found to be incorrect because a step for releasing the DMAP from the ligated complex led to an increase in entropy.Based on these results, ligand dissociation does not proceed via a simple dissociation of the ligand but includes the assistance of another boron complex to release the DMAP.Based on the bimolecular contribution of the borate-to-ligand dissociation, kinetic analysis gave the activation parameters DG ‡ 25.4 kcal mol À1 , DH ‡ 20.3 kcal mol À1 , and DS ‡ À17.2 cal K À1 mol À1 .This unusual mechanism came from the intermolecular interaction of 4 (see also the ESI †).
A bimolecular process requires the presence of an intermolecular interaction in the course of a ligand-exchange pathway.We performed UV measurements of 4ÁTHF under variable concentrations, since the electronic interactions between the chromophores cause spectral changes, which in most cases results in a hypochromic shift. 14The absorption spectra of 4ÁTHF were recorded in CH 2 Cl 2 in a concentration range from ca. 2.0 Â 10 À5 to 2.0 Â 10 À4 M.Under these conditions, the longest absorption bands of 4ÁTHF at 330-280 nm, which were mainly assigned to the HOMO -LUMO transition (pp*) via time-dependent DFT calculation (Fig. S3, ESI †), exhibited remarkable spectral changes that resulted in hypochromic effects with slight red shifts at 330-300 nm and hyperchromic effects with slight blue shifts at 300-280 nm (Fig. S4(A), ESI †).On the other hand, the spectra of 2ÁTHF in CH 2 Cl 2 exhibited no remarkable concentration dependence (Fig. S4(B), ESI †). 15 These results suggest that the benzofuran-based 4ÁTHF would benefit from self-intermolecular stabilization, presumably due to its dipole-dipole interaction. 16,17inally, we describe the effect of photo-irradiation on the control of Lewis acidity.A Mukaiyama-type aldol reaction of 14c with 15 upon exposure to black-light (centred at 365 nm) irradiation at room temperature under the slightly modified conditions was performed.Although no significant change in reactivity was observed in the presence of borate 2ÁTHF, borate 4ÁTHF afforded 16c in a 1.7-fold higher yield under the blacklight irradiated conditions (Table 3).While the mechanistic details of the effect of the photo-irradiation have not been clarified, the excitation energy of 4 was lower than that of 2 as a result of the expanded p-conjugation, as well as the molecular geometry changes and charge reorientations in the first excited state, and this may have played a key role in controlling the Lewis acidity.
We synthesized a cage-shaped borate 4 composed of a benzofuran framework, characterized its molecular geometry a Except for entry 5, the reaction time was 6 h.b The reaction time was 0.5 h.via X-ray crystallography, and estimated its electronic features via DFT calculations.The synthesized complex exhibited a high Lewis acidity with a high catalytic turnover, which was confirmed via Mukaiyama-aldol type reaction, ligand-exchange rate determination, and the concentration dependence of the electronic absorptions.For the benzofuran-based caged borate 4, an effective lowering of the next-LUMO level and an intermolecular stabilization of the ligand-free complex were achieved via photo-activation, which allowed us to successfully balance two conflicting aims for Lewis acid catalysts: acidity and catalytic turnover.Although there is still room for improvement in the versatilities of the reactions catalyzed by 4, the precise tuning of Lewis acid catalytic activity in association with the introduction of heteroaromatic moieties into the cage-shaped borate core holds the potential to construct photo-or electro-responsive Lewis acid catalysts.Theoretical studies as well as further experimental investigations of the obtained Lewis acid catalyst by our group are ongoing.This work was supported by the Ministry of Education, Culture, Sports, Science and Technology (Japan).This work was also supported by the Nagase Science and Technology Foundation.
A. K. wishes to thank the Research Capability Development Project (Professional development program for assistant professors) of Frontier Research Center of Graduate School of Engineering, Osaka University.We thank Dr Nobuko Kanehisa for the valuable advice regarding X-ray crystallography.Thanks are due to Mr H. Moriguchi, Faculty of Engineering, Osaka University, for assistance in obtaining the MS spectra.

Table 1
Complexation of boron compounds with carbonyl compound 13 Fig. 2 Optimum structures and MO diagrams of 4 and 2. This is © The Royal Society of Chemistry 2016

Table 3
Mukaiyama aldol reaction catalyzed by borates under photoirradiation a The yields in parentheses were performed under dark conditions.This journal is © The Royal Society of 2016 Chem.Commun., 2016, 52, 3348--3351 | 3351