Pd-tetraethyl tetra-t -butylcalixarene-tetra(oxyacetate) complex catalyzed acylodeboronation of arylboronic acids with benzoyl chloride or acetic anhydride

The palladium-tetraethyl tetra-t -butylcalixarene-tetra(oxyacetate) complex, in the form of [NaL] + [PdCl 3 ] – , exhibited high catalytic efficiency for the acylodeboronation reaction of arylboronic acids with benzoyl chloride or acetic anhydride, producing the corresponding ketones in good to excellent yields under mild reaction conditions. Various arylboronic acids, benzoyl chlorides and acetic anhydrides were tolerated in this method. Moreover, a typical method for synthesis of acetyl aryl ketones was obtained.


Introduction
Due to the wide occurrence of aryl ketone moiety in a large number of biologically active compounds 1 , natural products, 2 cosmetics, 3 pharmaceutical, fragrance, dye, agrochemicals and functional material industries as well as in organic synthesis, 4 considerable efforts have been made for its synthesis.6][7] Such method can avoid the restrictions of the regioselectivity limitation of para position (traditional Friedel-Crafts acylation 8 ), using of toxic carbon monoxide and the formation of biaryl side products (carbonylative Suzuki-Miyaura cross-coupling 9 ), the requirement of directing group (carbonylative C-H activation 10 ), harsh reaction conditions (oxidation of benzyl alcohols 11 and addition of organometallic reagents to carboxylic derivatives or nitriles 12 ) and incompatibility with electron-deficient groups etc. 7,[13][14][15] However, there are still some limitations for the synthesis of aliphatic acyl phenone using aliphatic acyl chloride or acetic anhydride as acyl reagent, especially for the synthesis of various acetophenone from acetic chloride or anhydride.5c,5f,6g,7a The coupling between phenylboronic acid and acetic anhydride were scatteredly reported 5c,5f,6d and only Gooben 5f obtained satisfactory results.Thus, it is challenging to develop catalytic carbonylation of aliphatic acyl chloride or acetic anhydride with high efficiency.
Nowadays, calixarenes are emerging as a versatile family of ancillary ligands in a variety of catalytic processes. 16For example, calixarenes bearing phosphines or NHCs functional groups have been reported to exhibit notably high catalytic activities in transition metal catalyzed C-C bond formation reactions. 17In addition, calix [4]aryl acetates showed remarkably high sodium ion affinity and selectivity owing to the "size fitting effect".18a-18c Recently, our group reported the synthesis of a kind of tetraethyl tetra-t-butylcalixarene-tetra(oxyacetate) and its catalytic activity in Suzuki cross-coupling reaction.18d In this paper, we wish to report the palladiumtetraethyl tetra-t-butylcalixarene-tetra(oxyacetate) complex catalyzed acylodeboronation reaction of arylboronic acids with benzoyl chloride or acetic anhydride respectively for the easy preparation of aryl ketones.To the best of our knowledge, this is the first report on the coupling of carboxylic anhydride or acyl chloride catalyzed by 0.5% catalyst loading of palladium complex based on tetraethyl tetra-t-butylcalixarene-tetra(oxyacetate).

Synthesis of the catalyst and its characterization
Tetraethyl tetra-t-butylcalixarene-tetra(oxyacetate) (L) was synthesized according to the general procedure. 19Palladium complex was obtained according to the literature and characterized by Xray 18d analysis.

Catalytic survey Studies on acylodeboronation reaction of arylboronic acid with benzoyl chloride
The coupling reaction of phenyl boronic acid and benzoyl chloride was chosen as a model reaction (Table 1) to test the reactivity of Cat. 1.To compare the catalytic activities, Pd(OAc)2 and PdCl2 were used under the same reaction conditions, and relatively lower yields were obtained respectively (entries 2-5).Yamamoto's and Goossen's studies have showed that the phosphine ligands played key roles in the successful execution of the reactions. 20Gratifyingly, the carbonylation coupling proceeded smoothly and gave benzophenone in 68% isolated yield when Cat. 1 was used as a catalyst in the presence of PPh3 and K3PO4 in toluene at 90 o C under air (Table 1, entry 7).These results indicated that the combination of tetraethyl tetra-tbutylcalixarene-tetra(oxyacetate) and PPh3 promoted the procedure of acylodeboronation.
With the standard conditions in hand, we then examined the scope and limitation of Cat. 1 in the acylodeboronation reaction.Various arylboronic acids and benzoyl chloride were applied to this system (Table 2, entries 1-14).The results listed in Table 2 showed that this catalytic system tolerated various functional groups, such as CH3, CH3O, Br, Cl, F, CHO, and CH3CO.Both electron-rich and electron-deficient arylboronic acids could provide the desired products in moderate to excellent yields (Table 2, entries 1-10).1-Naphthyl and 2-thienyl boronic acids also reacted smoothly with benzoyl chloride, yielding the corresponding aryl ketones in 89% and 95% yields, respectively (Table 2, entries 11-12).Some ketones, such as 3b, 3f, 3i and 3j, usually difficult to obtain from traditional Friedel-Crafts methods by using benzoyl chloride as substrate, 8 were produced successfully with moderate to good yields in this protocol (Table 2, entries 2, 6, 9, 10).

Studies on the acylodeboronation reaction of arylboronic acid with acetic anhydride
When Na2CO3 was used as base (Table 1, entry 9), trace amount of benzophenone was observed.Benzoic acid anhydride was obtained as main product (determined by GC analysis).Treating the obtained benzoic acid anhydride with phenylboronic acid (new added), the desired benzophenone was isolated in 96% yield.These results revealed that the formation of ketone may proceed via the intermediate of benzoic acid anhydride, and Cat. 1 was also an efficient catalyst for the carbonylation reaction of arylboronic acid with acid anhydride (Scheme 2).Acetophenone derivatives are useful intermediates in industry as well as in organic synthesis.Carbonylation reaction of acetyl chloride or anhydride with boronic acid could also be used for its synthesis.Bandgar 6g has reported the reaction of arylboronic acid with benzoyl chloride by using PdCl2 as catalyst and Na2CO3 as base.But the catalyst loading is high (3.3%) and the coupling between acetyl chloride with boronic acid remains unsuccessful 6g,7a or only in moderate yields.5c Also the coupling between acetic anhydride with arylboronic acid has been reported by Gooben 5f by using Pd(OAc)2 as catalyst, expensive P(p-MeOPh)3 as ligand, and excess of arylboronic acid.Scheme 2. Study on the effect of Na2CO3 as base for acylodeboronation reaction of phenylboronic acid with benzoic acid chloride.

Tabel 3. Study on acylodeboronation reaction of phenyl boronic acid with acetic anhydride
Under the optimal conditions, the scope of arylboronic acids and anhydrides for this acylodeboronation transformation was investigated.As shown in Table 4, the carbonylation yields were influenced by electron effect.Arylboronic acids with electron-rich groups such as CH3 or CH3O, as well as 1-naphthyl motif could be coupled with acetic anhydride in moderate to good yields (Table 4, entries 1-5).When arylboronic acids bearing electron-deficient groups were applied, moderate yields were still obtained (Table 4, entries 6-8).Other kinds of anhydrides were also applied, yielding the corresponding ketones in lower yields (Table 4, entries 9-10).

Mechanistic study
In order to provide evidence that the enhanced yields using Cat. 1 were not due to the use of a Na2PdCl4 instead of Pd(OAc)2 or PdCl2, the carbonylation reaction of benzoyl chloride with phenylboronic acid was conducted by using the mixture of Na2PdCl4 pre-catalyst and triphenylphosphine.It is clear that the high catalytic efficiency were attributed to the "size fitting effect" between tetraethyl tetra-t-butylcalixarene-tetra(oxyacetate) L and palladium anion (Table 5, entries 1-4).Furthermore, a investigation on the catalytic activity of Na2PdCl4 with different phosphine ligands such as PPh3, dppe or dppf was undertaken to clarify the role of tetraethyl ptert-butyl-calix [4]aryl tetraacetate (L) in the formation of the catalytically active species (Table 5, entries 5-7).Na2PdCl4 with the mixture of L and different phosphine as ligands showed slightly lower activity under the same reaction conditions.Except the ligand dppe, the mixture of Na2PdCl4, L and PPh3 or dppf resulted in the homo-coupling of phenylboronic acid.Na2PdCl4+L+dppf 15 c a benzoyl chloride (1.0 mmol), phenyl boronic acid (0.5 mmol), K2CO3 (1.0 mmol), complex 1 (0.5 mol%), tetraethyl tetra-t-butylcalixarene-tetra(oxyacetate) L (0.005 mmol), NaCl (0.005 mmol), PdCl2 (0.005 mmol), Pd(OAc)2 (0.005 mmol), phosphine ligand (0.01 mmol) and toluene (2.0 mL), 70 o C, 24 h.b GC yields by using 3a as internal standard substances.c the side product (~70% GC yield) was determined by using biphenyl as internal standard substances.

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Based on the ligature and results obtained above, a possible reaction mechanism was proposed as outlined in Scheme 3. Firstly, Pre-activation of Cat.1 generated the active palladium catalyst PdL'2 in the anion of Pd2Cl6 -.We hypothesized that the active palladium catalyst covered on the anion as shown in Scheme 4. The benzoyl chloride 2a was transported one by one through the cage of tetraethyl tetra-t-butylcalixarene-tetra(oxyacetate) L to access the active palladium catalyst from two side (Scheme 4).Fast oxidative addition gave the intermediate.After the completion of transmetallation of phenylboronic acid 1a, the catalytic cycle was finished followed by the reductive elimination finally.It is reliable that the catalytic cycle was finished in the anion part of Pd2Cl6 -since the biphenyl was observed as main product when the ligand L was mixed with 1a and 2a (Table 5, entry 5).We resumed that the efficiency of Pd-tetraethyl tetra-t-butylcalixarene-tetra (oxyacetate) complex in the carbonylation reaction could be attributed to its surface properties, and its capacity to bind strongly to benzoyl chloride into its hydrophobic pocket, which enhanced the ability to interact with the reagents and palladium (Scheme 4).18d

Conclusions
In summary, Pd-tetraethyl tetra-t-butylcalixarene-tetra(oxyacetate) complex, in the form of [NaL] + [PdCl3] -, catalyzed cross-coupling reactions of various arylboronic acids with benzoyl chloride or acetic anhydride were successfully achieved with low catalyst loading of 0.5 mol%.This protocol has the advantages of straightforward, easy handling and cheap substrates as coupling partner.Most important, the advantage of high functional group tolerance made this method possible to obtain several acetophenones difficult to access by traditional Friedel-Crafts reaction.Moreover, this study provides a particular method to synthesize methyl aryl ketones by acetylation using acylodeboronation reactions.

Experimental Section
General.Melting points were measured on a XT-5 microscopic apparatus.GC analyses were performed on Agilent 4890D gas chromatograph. 1 H NMR and 13 C NMR spectra were recorded on a Bruker DPX 400 instrument using CDCl3 or DMSO-d6 as the solvent and TMS as the internal standard.Palladium complex based on a tetraethyl tetra-t-butylcalixarene-tetra(oxyacetate) was synthesized according to the literature.3d All solvents were tried by the standard methods.The chemicals were reagent grade and used without further treatment.

Table 1 .
Study on acylodeboronation reaction of phenyl boronic acid with benzoyl chloride

Table 5 .
Studies on the role of tetraethyl tetra-t-butylcalixarenetetra(oxyacetate) L