Metal-free and solvent-free synthesis of m-terphenyls through tandem cyclocondensation of aryl methyl ketones with triethyl orthoformate

Reported here is a novel cyclocondensation of aryl methyl ketones and triethyl orthoformate for the simple synthesis of m-terphenyls. In the presence of a catalytic amount of TfOH, alkyl- and chloro-substituted acetophenones produced a series of terphenyls through a tandem reaction which merged six steps into a one-pot procedure. Moreover, the corresponding ester products were obtained when using other substituted acetophenones as the starting materials under the same reaction conditions.


Introduction
Owing to the amazing photophysical and optical properties, mterphenyls have been extensively applied in materials science, for example in conducting polymers, OLEDs, laser dyes, textile dye carriers, heat storage and transfer agents. 1 In addition, terphenyl scaffolds have also been found in several naturally occurring compounds with interesting biological properties, like dictyoterphenyl A, trifucol, dunnialol, etc. 2 The simplest m-terphenyl, 1,3-diphenylbenzene, can be synthesized by the addition of the Grignard agent to 1,3-cyclohexanedione (Scheme 1, route a). 3 To date, various methods have been reported to construct m-terphenyl frameworks. 4 Among these methods, the transition metal-catalyzed coupling reactions have been the most widely used approaches, especially Suzuki-Miyaura cross-coupling reactions (Scheme 1, route b). 5 Another traditional and superior strategy is benzannulation which can directly assemble acyclic precursors into benzene derivatives. 6 Various efficient benzannulation methods have been used to construct the terphenyl derivatives 7 (Scheme 1, route c). However, these methods are generally associated with various drawbacks, which include harsh reaction conditions, expensive metal catalysts, limited substrate scope, and poor chemo-or regioselectivity. Thus, there is still a great demand to develop simple, efficient and regioselective methods for the synthesis of m-terphenyls. Herein, we report a novel approach for the facile synthesis of m-terphenyls through cyclocondensation reaction of aryl methyl ketones and triethyl orthoformate. 8 Through an extensive literature research, we found that diverse compounds have been reported as the main product for the reaction of aryl ketones and triethyl orthoformate in the presence of acid under only slightly different conditions (Scheme 2). Open-chain carboxonium ions 4 were obtained when using an equivalent of HClO 4 or HBF 4 . 9 However, cyclic carboxonium ions (i.e. pyryliums 5) were produced under similar reaction conditions. 10 Based on their strong uorescence and high conductivity, carboxonium ions have been frequently employed as functional pigments, phototherapeutic agents and nonlinear optical glasses. Generally, when using trialkyl orthoformates for acetalization of carbonyl compounds in the presence of a catalytic amount of Lewis or Brønsted acid, both ketones and aldehydes could be transformed to their corresponding acetals 6 with excellent yields. 11 With the aid of microwave and a catalytic amount of boron triuoride, three equivalents of aryl ketones condensed with one equivalent of triethyl orthoformate to afford the product 7 in moderate yields. 12 Herein, we surprisingly found that an abnormal tandem cyclocondensation took place under strong acid and an elevated temperature conditions to furnish m-terphenyls 3 as its main product.
Scheme 1 Three types of synthetic strategy to m-terphenyls.

Results and discussion
In order to develop an efficient approach to m-terphenyls, acetophenone (1a) and triethyl orthoformate (2) were selected as model substrates (Table 1). When we chose three equivalents of triuoroacetic acid (CF 3 COOH) as catalyst, the reaction proceeded smoothly at 50 C to furnish a moderate yield of 1,3diphenylbenzene (3a) (Entry 3). A lower temperature would dramatically reduce the yield of 3a and benet the formation of carboxonium ions (4 or 5) (Entries 1 and 2), while the selfcondensation of 1a would be accelerate to generate the byproduct 1,3,5-triphenylbenzen (8a) at a higher temperature, 13 thus nally decreased the yield of the desired product (Entry 4). The choice of acids was of considerable importance in this cyclocondensation reaction. In fact, there was a low or no yield of 3a when inorganic acids or weak organic acids were employed (Entries 5-7), and an excess amount of the acid was necessary to guarantee the formation of the desired product (Entries 3 and 8-10). While using strong organic acids, the cyclocondensation reaction with only one equivalent of the acid could produce 3a in moderate yields (Entries 11-12). We believed that large amount of acid would result in the formation of carboxonium ions as byproducts. Therefore catalytic amount of a stronger organic acid was tested. We found that tri-uoromethanesulfonic acid (TfOH, 0.2 eq.) led to much cleaner reaction, and nally gave the best yields . Surprisingly, we found that the best molar ratio between acetophenone and orthoformate is 1 : 4 which is contradicted with what is dictated by the reaction equation. When reducing the amount of triethyl orthoformate, the yield of 3a was dramatically decreased (Entries [18][19]. Moreover, the reactions with different solvents were also examined (Entries [20][21][22][23], and yet both the reaction cleanness and the yields were not better than those obtained without any solvent. With an optimal set of catalysis conditions selected, we were then poised to test the tandem cyclocondensation process and evaluate the substrate scope. When the reaction was conducted at 50 C in the presence of a catalytic amount of TfOH, we were delighted to discover that different alkyl substituted acetophenones functioned efficiently in the reactions with triethyl orthoformate (Table 2, 1a-1j). Chloro-substituted acetophenones were also effective regardless of the para-or meta-position on the phenyl ring (Table 2, 1k and 1l). Additionally, simple 2acetonaphthone was also reacted smoothly to produce 1,3dinaphthylbenzene in a moderate yield (Table 2, entry 13). It was found that this tandem cyclocondensation reaction was very sensitive to electronic factors as well as steric ones. In fact, most acetophenones with electron donating or withdrawing groups failed to give the desired terphenyl products.
It was conceived that there should be a complicated reaction pathway for the formation of the desired m-terphenyls from aryl methylketones and orthoformate (Scheme 3). And we believed that the departure of a benzoyl ion V from the intermediate III should be the key step. 14 Therefore it is reasonable that an ester product should be produced in this type of reaction. 15 To our delight, both terphenyl 3n and ester 9n were obtained for the reaction of para-methoxyacetophenone 1n (Table 2, entry 14).
On the basis of our results and the related literatures, a tentative mechanism for the reaction between acetophenone (1a) and triethyl orthoformate under strong acidic conditions is proposed in Scheme 3. Triethyl orthoformate is substituted by

Entry Acid
Solvent

Conclusions
In summary, a cascade cyclocondensation reaction merged six steps into one-pot procedure has been disclosed. This reaction demonstrates a new protocol for the synthesis of m-terphenyls from simple starting materials without any metal catalysts and solvents.

General information
Nuclear magnetic resonance spectra ( 1 H and 13 C) were recorded on 600 MHz spectrometers with tetramethylsilane (TMS) as an internal standard. The splitting patterns are designated as singlet (s), doublet (d), triplet (t), quartet (q), dd (doublet of doublets); m (multiplets), and etc. All rst-order splitting patterns were assigned on the basis of the appearance of the multiplet. Splitting patterns that could not be easily interpreted are designated as multiplet (m) or broad (br). High resolution mass spectral analysis (HRMS) was performed on ESI-QTOP mass spectrometer. Purication was done by column chromatography and preparative TLC using silica gel. TLC analyses were performed on commercial glass plates bearing a 0.25 mm layer of silica gel GF 254 . Visualization was performed using a UV lamp or chemical stains like KMnO 4 and I 2 . Commercially available materials were used as received.
General procedure for the reaction between phenol and ahaloketone To a 25 mL two necked ask under nitrogen atmosphere at 50 C was added triethyl orthoformate (4.0 mmol) and acetophenones (1.0 mmol). Aer stirring for 0.5 hour, tri-uoromethanesulfonic acid (0.1 mmol) was added into the mixture. Aer completion of the reaction (monitored by TLC), it was quenched with a saturated sodium carbonate (10 mL), extracted with dichloromethane (3 Â 10 mL) and dried with anhydrous sodium sulphate. The organic mixture was concentrated under reduced pressure, and separated by silica-gel column chromatography using ethyl acetate-hexane as eluent in increasing polarity to yield the desired product.

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