ES2387225A1 - Procedure for the synthesis of 3-arilbenzofuran derivatives. (Machine-translation by Google Translate, not legally binding) - Google Patents

Abstract

Procedure for the synthesis of 3-arylbenzofurans derivatives. The present invention relates to a process that concerns the catalytic transformation, through an intramolecular cyclization reaction of 2-hydroxyaryl ketones of general formula (II) in 3-arylbenzofurans compounds of general formula (I), by means of a compound of copper and a quinoline derivative using a solvent of amidic nature and in the presence of oxygen. (Machine-translation by Google Translate, not legally binding)

Description

 Procedure for the synthesis of 3-arylbenzofuran derivatives.

FIELD OF THE INVENTION

The present invention falls within the field of chemical synthesis related to the chemical and / or pharmaceutical sector. In particular, the present invention relates to a process that concerns the transformation, through an intramolecular cyclization reaction of hydroxyaryl ketones into 3-arylbenzofurans, by means of a copper compound and a quinoline derivative using an amide solvent and in the presence of oxygen.

BACKGROUND OF THE INVENTION

3-arylbenzofurans are interesting structures due to their presence in the skeleton of various kinds of natural heterocycles, drugs and active biological molecules [Kim, I; Lee, S. H .; Lee, S. Tetrahedron Lett. 2008, 49, 6579; Okamoto Y .; Ojika M .; Suzuki S .; Murakami M .; Sakagami Y. Bioorg. Med. Chem. 2001, 9, 179; Okamoto Y .; Ojika M .; Sakagami, Y. Tetrahedron Lett. 1999, 40, 507; Greve, H .; Meis, S .; Kassack, M. U .; Kehraus, S .; Krick, A .; Wright, A. D .; König, G. M. J. Med. Chem. 2007, 50, 5600; Ishikawa, T .; Miyahara, T .; Asakura, M .; Higuchi, S .; Miyauchi, Y .; Saito S. Org. Lett. 2005, 7, 1211; Nicolaou, K. C .; Snyder, S. A .; Bigot, A .; Pfefferkorn, J. A. Angew. Chem. Int. Ed. 2000, 39, 1093; Cheng, X. M .; Liu, X. W. J. Comb. Chem. 2007, 9, 906; Santini, C .; Berger, G. D .; Han, W .; Mosley, R .; MacNaul, K .; Berger, J .; Doebber, T .; Wu, M .; Moller, D. E .; Tolman, R. L .; Sahoo, S. P. Bioorg. Med. Chem. Lett. 2003, 13, 1277; Menke, J. G .; MacNaul, K. L .; Hayes, N. S .; Baffic, J .; Chao, Y. S .; Elbrecht, A .; Kelly, L. J .; Lam, M. H .; Schmidt, A .; Sahoo, S .; Wang, J .; Wright, S. D .; Xin, P .; Zhou, G .; Moller, D. E .; Sparrow, C.

P. Endocrinology 2002, 143, 2548], some of them having an outstanding application in the field of agriculture [Patel, J. M .; Soman, S. S. J. Heterocycl. Chem. 2007, 44, 945]. The antifungal and bacterial activity of some of these molecules [Cherkupally, S. R .; Gurrala, P. R .; Adki, N .; Avula, S. Org. Commun. 1: 4 2008, 84], or its ability to regulate diverse biological functions [Srivastava, V .; Negi, A. S .; Kumar, J. K .; Faridi, U .; Sisodia,

B. S .; Darokar, M. P .; Luqman, S .; Khanuja, P. S. Bioorg. Med. Chem. Lett. 2006, 16, 911]. The therapeutic properties shown by several 3-arylbenzofurans can be exemplified by their use in the treatment of Alzheimer's [Saitoh, M .; Kunitomo, J .; Kimura, E .; Iwashita, H .; One and.; Onishi, T .; Uchiyama, N .; Kawamoto, T .; Tanaka, T .; Mol, C. D .; Dougan, D. R .; Textor, G. P .; Snell, G. P .; Takizawa, M .; Itoh, F .; Kori, M. J. Med. Chem. 2009, 52, 6270].

Originally the preparation of 3-arylbenzofurans was carried out through intramolecular cyclization under acidic conditions of o-hydroxybenzyl ketones [Kalyanasundaram, M .; Rajagopalan, K .; Swaminathan, S. Tetrahedron Lett. 1980, 21, 4391], and the dehydration cyclization of D- (phenoxy) alkyl ketones [Wright, J. B. J. Org. Chem. 1960, 25, 1867; Horaguchi, T .; Iwanami, H .; Tanaka, T .; Hasegawa, E .; Shimizu, T. J. Chem. Soc., Chem. Commun. 1991, 44]. Although less frequent, examples have also been described in which the synthesis of 3-arylbenzofurans is carried out by means of cycloofragmentation of oxiranes [Nicolau, K. C .; Snyder, S. A .; Bigot, A .; Pfefferkorn, J. A. Angew. Chem. Int. Ed. 2000, 39, 1093].

At present, the catalytic methods have solved some limitations associated with the use of these protocols. In this context, methods for the synthesis of 3-arylbenzofurans using palladium catalysts have been described, generally based on arylacetylenes cyclisations [Ishikawa, T .; Miyahara, T .; Asakura, M .; Higuchi, S .; Miyauchi, Y .; Saito S. Org. Lett. 2005, 7 (7), 1211-1214; Katritzky, A. R .; Ji, Y .; Fang, Y .; Prakash, I. J. Org. Chem. 2001, 66, 5613-5615; Willis, M. C .; Taylor, D. Gillmore, A. T. Org. Lett. 2004, 6 (25), 47554757; Honey, M. A .; Blake, A. J .; Campbell, I. B .; Judkins, B. D .; Moody, C. J. Tetrahedron 2009, 65, 8995-9001; Roshchin, A. I .; Kel’chevski, S. M .; Bumagin, N. A. J. Organomet. Chem. 1998, 560, 163-167; Aslam, S. N .; Stevenson, P. C .; Phythian, S. J .; Veitch, N. C .; Hall, D. R. Tetrahedron 2006, 62, 4214-4226; Davarani, S. S. H .; Najafi, N. M .; Ramyar, S .; Masoumi, L .; Shamsipur, M. Chem. Pharm. Bull. 2006, 54 (7), 959-962]. These methods, however, entail a high cost associated with the use of palladium catalysts, and a problematic separation of the products.

In general, it can be stated that in the vast majority of the production methods described above, several reaction steps are necessary, which increases the necessary amount of reagents, solvents, etc., and decreases the overall yield of the method in question. In addition, the use of catalysts and / or toxic reagents has associated environmental disadvantages and the need to use additional resources for waste management and / or recycling. Therefore, there is still a need in the prior art for the need or convenience of providing an alternative method of synthesis of 3-arylbenzofuran derivatives that overcomes at least part of the aforementioned disadvantages.

In this sense, inventors of the present invention have surprisingly discovered that the suitable combination of a copper salt, a quinolinic ligand, a carbonate type base and an aprotic polar solvent of an amide nature allows the catalytic transformation of 2-hydroxyaryl ketones into 3-arylbenzofurans. using molecular oxygen, as a non-toxic, low cost and environmentally benign oxidizing medium.

DESCRIPTION OF THE INVENTION

The present invention therefore provides a catalytic process, hereinafter process of the invention for the preparation of compounds of general formula (I):

(I)

 is selected from an aryl group and an optionally substituted heteroaryl group and where the substituents Ra, Rb, Rc, and Rd equal or different from each other, are selected from hydrogen, alkyl, alkoxy and halogen;

which comprises treating a 2-hydroxyaryl ketone derivative of the general formula (II)

OH OR

where the substituent

Rc

(II)

where the substituents and Ra, Rb, Rc, and Rd have the same meaning defined in the compound of general formula (I);

25 with molecular oxygen at atmospheric pressure, in the presence of a copper compound, a quinoline derivative and a base and using a solvent of formula (III)

  (III)

30 where the substituents R ’, R’ ’and R’ ’are alkyl, equal or different from each other,

optionally, in the form of one of the stereoisomers, preferably enantiomers or diastereoisomers, a racemate or in the form of a mixture of at least two of the stereoisomers, preferably enantiomers and / or 35 diastereoisomers in any proportion in the mixture or a corresponding salt of the same or a corresponding solvate thereof.

In the context of the present invention the term "alkyl" refers to a linear hydrocarbon chain radical.

or branched carbon and hydrogen atoms that do not contain saturation, which have 1 to 6 atoms of

40 carbon and which is attached to the rest of the molecule by a single bond, for example, methyl, ethyl, i-propyl, butyl, etc.

The term "aryl" refers to single and multiple ring radicals that include multiple ring radicals containing separate and / or fused aryl groups. Typical aryl groups contain 1 to 3 separate or fused rings and 6 to 18 carbon atoms in the ring such as a phenyl, naphthyl, indenyl, phenanthryl or anthracil radical. The aryl radical may optionally be substituted by one or more substituents as defined.

previously in one or more positions available.

The term "heteroaryl" refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and 1 to 4 heteroatoms selected from the group consisting of N, O and S, preferably a 4 to 8 ring members with one or more heteroatoms, more preferably, a 5 or 6 member ring with one or more heteroatoms. It can be aromatic or non-aromatic, be partially or completely saturated. In the context of the invention it may be a monocyclic, bicyclic, tricyclic ring system which may include fused ring systems. Examples of such heteroaryls include but are not limited to azepines, benzimidazole, benzothiazole, furan, isothiazole imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran, coumarin, morpholine, pyrrole, pyrazol oxazole isoxazole, triazole, imidazole ., The heteroaryl radical may optionally be substituted by one or more substituents as defined above at one or more available positions.

The term "alkoxy" refers in this description to a radical of the formula -OR 'where R' is an alkyl radical as defined above for example methoxy, epoxy, propoxy, etc.

The term "halogen" refers to chlorine, bromine, fluorine or iodine.

In the context of the invention the term "2-hydroxyaryl ketone derivative" is equivalent to the term "2-hydroxybenzophenone derivative" since the process of the invention refers to the cyclization experienced by aromatic or heteroaromatic ketones, a reaction that is schematized as follows:

base

(II) (I)

The treatment with molecular oxygen (dioxygen) at atmospheric pressure of the process of the present invention refers to placing the compound of formula (I) in the presence of an oxygen atmosphere. The process of the invention takes place in the presence of a copper compound. In a particular embodiment of the process of the invention, the copper compound is selected from the group consisting of Cu (I) salts, Cu (II) salts and mixtures thereof. In a preferred embodiment, the compound is a copper salt, more preferably a salt selected from the group consisting of Cu (I) acetate, Cu (II) acetate, copper (I) iodide, Cu (II) chloride and their mixtures In an even more preferred embodiment, the copper salt is Cu (I) acetate.

In the context of the present invention the quinoline derivative refers to a compound of general formula (IV)

R4 R5 R3

R2

(IV)

wherein the substituents R1, R2, R3, R4 and R5, the same or different from each other, are independently selected from hydrogen, amino (-NH2), hydroxy, halogen, alkyl, alkoxy and carboxy (-COOH). In a preferred embodiment R2, R3, R4 and R5 are the same or different from each other, and are independently selected from hydrogen, hydroxy and carboxy; and R1 is selected from hydrogen and hydroxy. In a more preferred embodiment, the compound of general formula (IV) is 8-hydroxyquinoline.

In the process of the present invention the quinoline derivative acts as a ligand, coordinating the copper species present in the reaction medium. Without wishing to be linked to a specific theory, the inventors believe that it may be possible for said quinoline derivative to participate in the formation of reaction intermediates.

The process of the invention is carried out in the presence of a metal carbonate that acts as a base. In a particular embodiment said carbonate is an alkali metal carbonate, preferably potassium carbonate.

In a preferred embodiment the solvent of formula (III) is dimethylacetamide or dimethylformamide. Preferably the solvent used is anhydrous.

The reaction can be carried out using different combinations of copper compound and solvent. In a particular embodiment, the combination of CuOAc (copper acetate (I)) and dimethylformamide (DMF) is used. In another particular embodiment, the combination of copper (II) acetate dihydrate and dimethylacetamide (DMA) is used. In a preferred embodiment, the combination of CuOAc and dimethylacetamide is used. The copper (II) acetate used in the present invention can be anhydrous or hydrated by presenting the formula Cu (OAc) 2 · nH2O where n is between 1 and 6.

In principle, the amount of the copper compound is not a critical parameter for the process of the invention to take place. A catalytic amount, equal to or greater than 10 mol% with respect to the moles of the compound of general starting formula (II) is sufficient for the reaction to take place. In a particular embodiment 50% molar is used with respect to the moles of the compound of the general starting formula (II).

The nature and amount of the quinoline derivative and the nature and amount of the base are important for a proper conversion of the reaction.

In a preferred embodiment, the combination of potassium carbonate and 8-hydroxyquinoline is used.

With respect to the amounts used, an amount of base equal to or greater than 0.8 equivalents with respect to the amount of the compound of general starting formula (II) is sufficient to observe a total conversion thereof although the preferred amount is 1 equivalent .

With respect to the amount of compound of general formula (IV) amounts between 0.2 and 1 equivalents with respect to the amount of the compound of general formula (II) starting give rise to the reaction, but the maximum conversion has been observed when 0.4 equivalents are used.

When copper salts are used, the degree of hydration thereof as well as the percentage of water in the amide solvent of formula (III) used must be controlled. In this sense, it has been observed that very good reaction results are generally obtained using anhydrous solvents and / or copper salts (which can be purchased commercially). However, no purging, drying, degassing or supplementary procedures are necessary to ensure the anhydricity of the process. Therefore in a preferred embodiment the amide solvent is anhydrous. In another preferred embodiment the copper salt is anhydrous.

The volume of the amide solvent influences the conversion of the compound of starting formula (II). In a particular embodiment dimethylacetamide is used, and preferably between 9 ml and 11 ml of dimethylacetamide for each millimol of said starting compound.

The temperature at which the reaction is carried out affects the compound conversion of starting formula (II) and depends in each case for example on the starting compound itself. In general, the reaction can be carried out within a wide range of temperatures, which the expert can easily determine in each case. Typically the reaction is carried out at a temperature between 120 ° C and 160 ° C. In a preferred embodiment said temperature is 140 ° C.

Reaction times vary depending on the compound of starting formula (II), and in principle they vary within a wide range. In a particular embodiment the reaction time is at least 24 hours. However, in each particular case the expert can determine this parameter in a conventional way.

In a particular embodiment of the process of the invention, the compound of general formula (I) obtained

it has a substituent, where it represents an aryl or heteroaryl, optionally substituted with a substituent selected from alkyl, aryl, alkoxy and halogen.

In a preferred embodiment of the process of the invention, the compound of general formula (I) obtained

it has a substituent where this is a phenyl group optionally substituted with a substituent selected from methoxy, phenyl, chlorine and bromine.

In another preferred embodiment of the process of the invention, the compound of general formula (I) obtained

presents a substituent

 where this is a 4-pyrazolyl group, optionally substituted with a substituent

In another particular embodiment of the process of the invention, the compound of general formula (I) obtained has in the benzofuran benzene ring one or two substituents in any positions, equal or different from each other, selected from alkyl, alkoxy and halogen; preferably said one or more substituents are selected from methoxy, tert-butyl, chlorine, bromine and fluorine.

In a particular embodiment of the process of the invention, the 3-arylbenzofuran derivative compound of general formula (I) obtained is one of the following compounds:

[1] 3-phenylbenzofuran 10 [2] 5-chloro-3-phenylbenzofuran

[3] 5-Bromo-3-phenylbenzofuran

[4] 5-tert-butyl-3-phenylbenzofuran

[5] 1-phenyl-1H-pyrazol-4-yl-benzofuran

 [6] 3- (4'-chlorophenyl) -5-fluorobenzofuran 15 [7] 3- (4'-chlorophenyl) benzofuran

[8] 3- (4'-methoxyphenyl) benzofuran

[9] 3- (4'-bromophenyl) -5-tert-butylbenzofuran

[10] 5,7-Chloro-3-phenylbenzofuran

 [11] 7-methoxy-3-phenylbenzofuran

The process of the present invention allows to obtain 3-arylbenzofuran compounds of general formula (I) in an alternative way to the prior art methods using a copper catalyst, oxygen as oxidizing medium and a solvent of an amide nature, of a Economic mode, operationally simple and high efficiency.

25 Copper catalysts are an advantageous and attractive alternative to other catalysts such as those of Pd used in state-of-the-art procedures, in view of their industrial application, due to their low price and low toxicity. Following this line, molecular oxygen is a desirable oxidant for any oxidation reaction, according to criteria of economy of atoms, low cost, low toxicity of the generated waste and

30 sustainability It is a very convenient reagent, with easy access and handling at atmospheric pressures

Similarly, as regards the compounds of formula (II) involved, these are easily accessible, and low cost. In this sense they can be obtained commercially or can be synthesized in a simple way by conventional procedures known to an expert.

Accordingly, the process of the invention is an economic process and also advantageous in terms of occupational safety, since it is carried out at atmospheric pressure. Finally, it should be noted that, in addition to the aforementioned operational and environmental benefits, the process of the invention is highly effective as well as chemoselective and compatible with numerous functional groups present in the substrates of

Heading, such as alkyl, alkoxide or halogen groups, for example.

In any case, it is evident that the process of the invention comprises, if necessary, additional protection and deprotection steps of one or more functional groups that are sensitive to the conditions of the process reaction. Protective groups as well as protective reactions and

Deprotection is well known to a person skilled in the art and is widely described in literature for example [Greene, T. W .; Wuts, P. G. M. "Protecting groups in organic synthesis", 4th ed., Wiley-VCH; Hoboken (USA), 2007]

Below are examples of the process of the invention set forth for a better understanding of the invention and in no case should it be considered as a limitation on the scope thereof.

EXAMPLES

Example 1: Preparation of 3-phenylbenzofuran

1.1 Preparation of 3-phenylbenzofuran using CuOAc and 8-hydroxyquinoline

In a round bottom flask, 2-hydroxybenzophenone (50 mg, 0.222 mmol), copper (I) acetate (15 mg, 0.123 mmol), 8-hydroxyquinoline (15 mg, 0.103 mmol) and K2CO3 (35 mg, 0.222) were mixed mmol) in anhydrous DMA (2.5 ml) at room temperature under oxygen atmosphere. The mixture was heated at 140 ° C for 24 hours, maintaining vigorous stirring at all times. It was allowed to temper, and H2O (5 ml) was added. This aqueous phase was then extracted with ethyl acetate (AcOEt) (4 x 6 ml). The combined organic phases were washed with a saturated solution of NaCl in water (1 x 15 ml), dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue thus obtained was purified by flash chromatography (AcOEt / Hexane 1: 9) to provide 3-phenylbenzofuran as a yellow oil (39 mg, 80%). 1H NMR (5, ppm) 7.85 (d, 1H, J = 7.6 Hz), 7.80 (s, 1H), 7.66 (d, 2H, J = 6.6 Hz), 7 , 55 (d, 1H, J = 7.1 Hz), 7.48 (t, 2H, 7.7 Hz), 7.38 (t, 1H, J = 6.9 Hz), 7.357.30 (m , 2H); NMR-13C (5, ppm) 155.8, 141.2, 132.0, 128.9, 127.5, 127.4, 124.5, 122.9, 122.3, 120.3, 111, 7; IR (film) 2922, 1740, 1662, 1602, 1480, 1446; MS (m / z) (%) 194 (M +, 100), 166 (54), 139 (9); EMAR Calculated for C14H11O 194.0732; found, 194.0736.

1.2 Preparation of 3-phenylbenzofuran using Cu (OAc) 2 · 2H2O and 8-hydroxyquinoline

In a round bottom flask, 2-hydroxybenzophenone (50 mg, 0.222 mmol), copper (II) acetate dihydrate (25 mg, 0.123 mmol), 8-hydroxyquinoline (15 mg, 0.103 mmol) and potassium carbonate (K2CO3) were mixed (35 mg, 0.222 mmol) in anhydrous DMA (2.5 ml) at room temperature under oxygen atmosphere. The mixture was heated at 140 ° C for 24 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in Example 1.1, 3-phenylbenzofuran was obtained as a yellow oil (37 mg, 75%).

1.3 Preparation of 3-phenylbenzofuran using copper iodide (CuI) and 8-hydroxyquinoline

In a round bottom flask, 2-hydroxybenzophenone (50 mg, 0.252 mmol), copper iodide (10 mg, 0.05 mmol), 8-hydroxyquinoline (15 mg, 0.103 mmol) and K2CO3 (35 mg) were mixed 0.222 mmol) in anhydrous DMA (2.5 ml) at room temperature under oxygen atmosphere. The mixture was heated at 140 ° C for 24 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in Example 1.1, 3-phenylbenzofuran was obtained as a yellow oil (26 mg, 53%).

1.4 Preparation of 3-phenylbenzofuran using anhydrous Cu (OAc) 2 and 8-hydroxyquinoline

In a round bottom flask, 2-hydroxybenzophenone (50 mg, 0.222 mmol), anhydrous copper (II) acetate (25 mg, 0.123 mmol), 8-hydroxyquinoline (15 mg, 0.103 mmol) and K2CO3 (35 mg, 0.222 mmol) in anhydrous DMA (2.5 ml) at room temperature under oxygen atmosphere. The mixture was heated at 140 ° C for 24 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in Example 1.1, 3-phenylbenzofuran was obtained as a yellow oil (23 mg, 48%).

1.5 Preparation of 3-phenylbenzofuran using CuOAc (20 mol%) and 8-hydroxyquinoline

In a round bottom flask, 2-hydroxybenzophenone (50 mg, 0.222 mmol), copper (I) acetate (6 mg, 0.050 mmol), 8-hydroxyquinoline (15 mg, 0.103 mmol) and K2CO3 (35 mg, 0.222) were mixed mmol) in anhydrous DMA (2.5 ml) at room temperature under oxygen atmosphere. The mixture was heated at 140 ° C for 24 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in Example 1.1, 3-phenylbenzofuran was obtained as a yellow oil (18 mg, 37%).

1.6 Preparation of 3-phenylbenzofuran using CuOAc and 8-hydroxyquinoline (120 ° C)

In a round bottom flask, 2-hydroxybenzophenone (50 mg, 0.222 mmol), copper (I) acetate (15 mg, 0.123 mmol), 8-hydroxyquinoline (15 mg, 0.103 mmol) and K2CO3 (35 mg, 0.222) were mixed mmol) in anhydrous DMA (2.5 ml) at room temperature under oxygen atmosphere. The mixture was heated at 120 ° C for 24 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in Example 1.1, 3-phenylbenzofuran was obtained as a yellow oil (15 mg, 30%).

1.7 Preparation of 3-phenylbenzofuran using CuOAc and 8-hydroxyquinoline (30 mol%)

In a round bottom flask, 2-hydroxybenzophenone (50 mg, 0.222 mmol), copper (I) acetate (15 mg, 0.123 mmol), 8-hydroxyquinoline (11 mg, 0.076 mmol) and K2CO3 (35 mg, 0.222) were mixed mmol) in anhydrous DMA (2.5 ml) at room temperature under oxygen atmosphere. The mixture was heated at 140 ° C for 24 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in Example 1.1, 3-phenylbenzofuran was obtained as a yellow oil (23 mg, 48%).

1.8 Preparation of 3-phenylbenzofuran using CuOAc and 8-hydroxyquinoline (50 mol% carbonate)

In a round bottom flask, 2-hydroxybenzophenone (50 mg, 0.222 mmol), copper (I) acetate (15 mg, 0.133 mmol), 8-hydroxyquinoline (15 mg, 0.103 mmol) and K2CO3 (17 mg, 0.126 were mixed mmol) in anhydrous DMA (2.5 ml) at room temperature under oxygen atmosphere. The mixture was heated at 140 ° C for 24 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in Example 1.1, 3-phenylbenzofuran was obtained as a yellow oil (20 mg, 40%).

1.9 Preparation of 3-phenylbenzofuran using CuOAc and 8-hydroxyquinoline (concentrated DMA).

In a round bottom flask, 2-hydroxybenzophenone (50 mg, 0.222 mmol), copper (I) acetate (15 mg, 0.123 mmol), 8-hydroxyquinoline (15 mg, 0.103 mmol) and K2CO3 (35 mg, 0.222) were mixed mmol) in anhydrous DMA (1.5 ml)

10 at room temperature under oxygen atmosphere. The mixture was heated at 140 ° C for 24 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in Example 1.1, 3-phenylbenzofuran was obtained as a yellow oil (26 mg, 53%).

15 1.10 Preparation of 3-phenylbenzofuran using CuOAc and 8-hydroxyquinoline. Catalyst recycling

In a round bottom flask, 2-hydroxybenzophenone (50 mg, 0.222 mmol), copper (I) acetate (15 mg, 0.123 mmol), 8-hydroxyquinoline (15 mg, 0.103 mmol) and K2CO3 (35 mg, 0.222) were mixed mmol) in anhydrous DMA (2.5 ml) at room temperature under oxygen atmosphere. The mixture was heated at 140 ° C for 24 hours, keeping in

20 every moment a vigorous agitation. After the preparation and purification steps described in Example 1.1, 3-phenylbenzofuran was obtained as a yellow oil (39 mg, 80%). Catalyst recycling: After extraction with ethyl acetate, the aqueous phase recovered from the previous reaction was deposited in a round bottom flask and concentrated in vacuo (membrane pump). 2-Hydroxybenzophenone (50 mg, 0.222 mmol), K2CO3 (35 mg, 0.222 mmol) in anhydrous DMA (2.5 ml) was added at temperature

25 atmosphere under oxygen atmosphere. The mixture was heated at 140 ° C for 24 hours, maintaining vigorous stirring at all times. This recycling operation, using identical amounts of all reagents, was repeated twice with the results shown in Table 1.

Table 1 30

 Initial reaction

1st recycling 2nd recycling

Performance (%)

80% 64% 54%

Example 2 Preparation of 5-chloro-3-phenylbenzofuran

In a round bottom flask, 5-chloro-2-hydroxybenzophenone (50 mg, 0.215 mmol), copper (I) acetate (13 mg, 0.107 mmol), 8-hydroxyquinoline (12 mg, 0.086 mmol) and K2CO3 were mixed (30 mg, 0.215 mmol) in anhydrous DMA (2.1 ml) at room temperature under oxygen atmosphere. The mixture was heated at 140 ° C for 24 hours, maintaining vigorous stirring at all times. After the elaboration and purification stages described

In Example 1.1, 5-chloro-3-phenylbenzofuran was obtained as a yellow oil (40 mg, 77%). 1H NMR (5, ppm) 7.80 (s, 1H), 7.79 (s, 1H), 7.60 (d, 2H, J = 7.4 Hz), 7.50-7.46 ( m, 3H), 7.39 (t, 1H, J = 7.4 Hz), 7.30 (dd, 1H, J = 8.7, 2.0 Hz); NMR-13C (5, ppm) 154.2, 142.5, 131.3, 129.1, 128.7, 127.9, 127.8, 127.5, 124.8, 122.1, 120, 1, 112.7; IR (film) 2952, 1734, 1684, 1653, 1558, 1540, 1488; MS (m / z) (%) 230 (M + 1, 42), 229 (M +, 91), 228 (100); EMAR Calculated for C14H10ClO 229.0420; found, 229.0430.

Example 3 Preparation of 5-Bromo-3-Phenylbenzofuran

In a round bottom flask, 5-bromo-3-hydroxybenzophenone (50 mg, 0.188 mmol), copper (I) acetate (11 mg, 0.107 mmol), 8-hydroxyquinoline (10 mg, 0.072 mmol) and K2CO3 ( 25 mg, 0.188 mmol) in anhydrous DMA (1.8 ml) at room temperature under oxygen atmosphere. The mixture was heated at 140 ° C for 24 hours, maintaining vigorous stirring at all times. After the elaboration and purification stages described

5 in Example 1.1, 5-bromo-3-phenylbenzofuran was obtained as a yellow oil (36 mg, 75%). 1H NMR (5, ppm) 7.95 (s, 1H), 7.78 (s, 1H), 7.60 (d, 2H, J = 7.5 Hz), 7.49 (t, 2H, J = 7.6 Hz), 7.44-7.38 (m, 3H); NMR-13C (5, ppm) 154.5, 142.4, 131.3, 129.1, 128.7, 128.5, 127.8, 127.5, 123.1, 122.0, 116, 2, 113.2; IR (film) 3061, 2923, 1810, 1749, 1645, 1625, 1596, 1489, 1456; MS (m / z) (%) 275 (M + 2, 52), 274 (M + 1, 100), 273 (M +, 51), 272 (89), 194 (71); EMAR Calculated for C14H10BrO 272.9915; found, 272.9916.

Example 4 Preparation of 5-tert-butyl-3-phenylbenzofuran

In a round bottom flask, 5-tert-butyl-2-hydroxybenzophenone (50 mg, 0.197 mmol), copper (I) acetate (12 mg, 0.099 mmol), 8-hydroxyquinoline (11 mg, 0.079 mmol) were mixed and K2CO3 (27 mg, 0.197 mmol) in anhydrous DMA (1.9 ml) at room temperature under oxygen atmosphere. The mixture was heated at 140 ° C for 24 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in Example 1.1, 5-tert-butyl-3-phenylbenzofuran was obtained as a yellow oil (49 mg, 90%). NMR-1H (5,

20 ppm) 7.81 (s, 1H), 7.75 (s, 1H), 7.65 (d, 2H, J = 8.3 Hz), 7.53-7.38 (m, 5H), 1.40 (s, 9H); NMR-13C (5, ppm) 154.0, 146.1, 141.5, 132.3, 129.0, 127.6, 127.3, 126.1, 122.4, 116.3, 111, 0, 34.8, 31.9, 29.7; IR (film) 2924, 1772, 1684, 1652, 1558, 1540, 1457; MS (m / z) (%) 251 (M +, 82), 250 (100), 235 (75); EMAR Calculated for C18H19O 251.1436; found, 251.1427.

Example 5 Preparation of 1-phenyl-1H-pyrazol-4-yl-benzofuran

In a round bottom flask, 2-hydroxyphenyl 1-phenyl-1H-pyrazol-4-yl ketone (50 mg, 0.189 mmol) was mixed,

30 copper (I) acetate (12 mg, 0.095 mmol), 8-hydroxyquinoline (11 mg, 0.076 mmol) and K2CO3 (26 mg, 0.189 mmol) in anhydrous DMA (1.9 ml) at room temperature under oxygen atmosphere . The mixture was heated at 140 ° C for 24 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in Example 1.1, 1-phenyl-1H-pyrazol-4-yl-benzofuran was obtained as a yellow oil (29 mg, 62%). 1H-NMR (5, ppm) 8.23 (s, 1H), 8.02 (s, 1H), 7.83 (s, 1H), 7.77 (d, 2H, J = 7.8 Hz) , 7.57-7.46 (m, 4H), 7.38-7.33 (m, 3H); NMR-13C

35 (5, ppm) 155.5, 140.7, 139.5, 129.5, 126.7, 126.5, 124.7, 123.9, 123.0, 120.0, 119.2, 113.0, 111.8; IR (film) 2921, 1718, 1656, 1635, 1596, 1540, 1487, 1461; MS (m / z) (%) 261 (M +, 100), 260 (75); EMAR Calculated for C17H13N2O 261,1035; found, 261,1028.

Example 6 Preparation of 3- (4'-chlorophenyl) -5-fluorobenzofuran

In a round bottom flask 4-chlorophenyl-5-fluoro-2-hydroxybenzophenone (50 mg, 0.199 mmol) was mixed,

Copper (I) acetate (12 mg, 0.099 mmol), 8-hydroxyquinoline (11 mg, 0.080 mmol) and K2CO3 (27 mg, 0.199 mmol) in anhydrous DMA (2.0 ml) at room temperature under oxygen atmosphere. The mixture was heated at 140 ° C for 24 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in Example 1.1, 3- (4'-chlorophenyl) -5-fluorobenzofuran was obtained as a yellow oil (41 mg, 80%). NMR-1H

5 (5, ppm) 7.81 (s, 1H), 7.53 (d, 2H, J = 8.4 Hz), 7.49-7.44 (m, 3H), 7.42 (dd, 1H, J = 8.7, 2.5 Hz), 7.08 (dt, 1H, J = 9.0, 2.6 Hz); NMR-13C (5, ppm) 152.2, 143.1, 133.6, 130.0, 129.3, 128.5, 112.8, 112.6, 112.5, 112.4, 106, 0, 105.7; IR (film) 2927, 1749, 1683, 1652, 1588, 1488, 1465; MS (m / z) (%) 248 (M + 1, 41), 247 (M +, 69), 246 (100); EMAR Calculated for C14H9ClFO 247.0326; found, 247.0329.

10 Example 7 Preparation of 3- (4'-chlorophenyl) benzofuran

4-Chlorophenyl-2-hydroxybenzophenone (50 mg, 0.189 mmol), acetate was mixed in a round bottom flask

15 copper (I) (12 mg, 0.095 mmol), 8-hydroxyquinoline (11 mg, 0.076 mmol) and K2CO3 (26 mg, 0.189 mmol) in anhydrous DMA (1.9 ml) at room temperature under oxygen atmosphere. The mixture was heated at 140 ° C for 24 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in Example 1.1, 3- (4'-chlorophenyl) benzofuran was obtained as a yellow oil (30 mg, 69%). 1H NMR (5, ppm) 7.81-7.77 (m, 2H), 7.60-7.54 (m, 3H), 7.47-7.44 (m, 2H), 7.40 -7.32 (m, 2H); NMR-13C (5, ppm) 151.3, 143.0, 132.9,

20 130.6, 129.0, 128.7, 128.1, 127.6, 124.8, 119.6, 118.9; IR (film) 2930, 1792, 1684, 1655, 1576, 1550, 1489, 1448; MS (m / z) (%) 231 (M + 2, 23), 230 (M + 1, 41), 229 (M +, 69), 228 (100); EMAR Calculated for C14H10ClO 229.0426; found, 229.0411.

Example 8 Preparation of 3- (4'-methoxyphenyl) benzofuran

In a round bottom flask, 4-methoxyphenyl-2-hydroxybenzophenone (50 mg, 0.219 mmol), copper (I) acetate (13 mg, 0.109 mmol), 8-hydroxyquinoline (13 mg, 0.088 mmol) and K2CO3 ( 30 mg, 0.219 mmol) in anhydrous 30 DMA (2.2 ml) at room temperature under oxygen atmosphere. The mixture was heated at 140 ° C for 24 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in Example 1.1, 3- (4'-methoxyphenyl) benzofuran was obtained as a yellow oil (38 mg, 71%). 1H NMR (5, ppm) 7.83-7.80 (m, 1H), 7.74 (s, 1H), 7.59-7.54 (m, 3H), 7.36-7.30 (m, 2H), 7.04-7.01 (m, 2H), 3.87 (s, 3H); NMR-13C (5, ppm) 160.6, 156.4, 142.4, 129.7, 126.3, 124.7, 123.5, 122.3, 121.3, 114.8, 111, 5, 55.8; IR (film) 2921, 2835, 35 1798, 1740, 1696, 1666, 1596, 1504, 1453; MS (m / z) (%) 226 (M + 1, 12), 225 (M +, 74), 224 (100); EMAR Calculated

for C15H13O2 225.0916; found, 225.0923.

Example 9 Preparation of 3- (4'-bromophenyl) -5-tert-butylbenzofuran

In a round bottom flask, 4-bromophenyl-5-tert-butyl-2-hydroxybenzophenone (50 mg, 0.174) was mixed

10

mmol), copper (I) acetate (11 mg, 0.087 mmol), 8-hydroxyquinoline (10 mg, 0.070 mmol) and K2CO3 (24 mg, 0.174 mmol) in anhydrous DMA (1.7ml) at room temperature under atmosphere of oxygen. The mixture was heated at 140 ° C for 24 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in Example 1.1, 3- (4'-bromophenyl) -5-tert-butylbenzofuran was obtained as a yellow oil (43 mg, 74%). 1H NMR (5, ppm) 7.75 (s, 1H), 7.73 (d, 1H, J = 8.6 Hz), 7.63-7.60 (m, 2H), 7.52- 7.41 (m, 4H), 1.39 (s, 9H); NMR-13C (5, ppm) 154.0, 146.4, 141.6, 132.1, 129.1, 124.4, 122.8, 121.5, 121.3, 121.1, 116, 0, 111.2, 34.9, 31.9, 29.7; IR (film) 2962, 1806, 1631, 1486, 1393, 1363; MS (m / z) (%) 330 (M + 1, 100), 329 (M +, 39), 331 (35), 313 (56), 250 (64); EMAR Calculated for C18H18BrO 329.0541; found, 329.0529.

Cl

In a round bottom flask, 3,5-chloro-2-hydroxybenzophenone (50 mg, 0.187 mmol), copper (I) acetate (11 mg, 0.093 mmol), 8-hydroxyquinoline (11 mg, 0.075 mmol) were mixed and K2CO3 (26 mg, 0.187 mmol) in anhydrous DMA (1.9 ml) at room temperature under oxygen atmosphere. The mixture was heated at 140 ° C for 24 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in Example 1.1, 5,7-chloro-3-phenylbenzofuran was obtained as a yellow oil (47 mg, 93%). 1H NMR (5, ppm) 7.85 (s, 1H), 7.69 (d, 2H, J = 19 Hz), 7.61-7.53 (m, 2H), 7.50 (t, 2H, J = 7.7 Hz), 7.43 (d, 1H, J = 7.6 Hz), 7.38 (d, 1H, J = 1.8 Hz); NMR-13C (5, ppm) 151.3, 143.0, 132.9, 130.6, 129.2, 129.0, 128.7, 128.1, 127.6, 124.8, 119, 6, 118.9; IR (film) 2926, 1615, 1596, 1570, 1455; MS (m / z) (%) 265 (M + 2, 52), 264 (M + 1, 71), 263 (M +, 83), 262 (100); EMAR Calculated for C14H9Cl2O 263.0030; found, 263.0034.

OMe

In a round bottom flask, 2-hydroxy-3-methoxybenzophenone (100 mg, 0.438 mmol), copper (I) acetate (27 mg, 0.219 mmol), 8-hydroxyquinoline (25 mg, 0.175 mmol) and K2CO3 ( 60 mg, 0.438 mmol) in anhydrous DMA (4.3 ml) at room temperature under oxygen atmosphere. The mixture was heated at 140 ° C for 24 hours, maintaining vigorous stirring at all times. After the preparation and purification steps described in Example 1.1, 7-methoxy-3-phenylbenzofuran was obtained as a yellow oil (52 mg, 53%). 1H NMR (5, ppm) 7.80 (s, 1H), 7.65 (d, 2H, J = 8.0 Hz), 7.50-7.35 (m, 5H), 6.87 ( d, 1H, J = 7.4 Hz), 4.05 (s, 3H); NMR-13C (5, ppm) 145.7, 145.2, 141.4, 132.0, 128.9, 128.2, 127.5, 127.4, 123.7, 122.6, 112, 7, 106.6, 56.1; IR (film) 2926, 2830, 1790, 1750, 1696, 1666, 1596, 1589, 1499; MS (m / z) (%) 225 (M +, 83), 224 (100); EMAR Calculated for C15H13O2 225.0909; found, 225.0916.

Claims (16)

1. Procedure for the preparation of compounds of general formula (I): Rc    (I) where the substituent  is selected from an aryl group and an optionally substituted heteroaryl group and where the substituents Ra, Rb, Rc, and Rd equal or different from each other, are selected from hydrogen, alkyl, alkoxy and halogen; which comprises treating a 2-hydroxyaryl ketone derivative of the general formula (II) Rc  15 (II) and Ra, Rb, Rc, and Rd have the same defined meaning for the compound of general formula (I); where the substituents 20 with molecular oxygen at atmospheric pressure, in the presence of a copper compound, a quinoline derivative and a base using a solvent of general formula (III) R '' '   (III) Where the substituents R ', R' 'and R' '' are alkyl, the same or different from each other, optionally, in the form of one of the stereoisomers, preferably enantiomers or diastereoisomers, a racemate or in the form of a mixture of at least two of the stereoisomers, preferably enantiomers and / or diastereoisomers in any proportion in the mixture or a corresponding salt thereof or a corresponding solvate thereof. 2. The method according to claim 1, wherein the copper compound is selected from the group consisting of Cu (I) salts, Cu (II) salts and mixtures thereof. 3. The method according to the preceding claim wherein said copper salt is selected from the group consisting of Cu (I) acetate, Cu (II) acetate, copper (I) iodide, Cu (II) chloride and their mixtures 4. Process according to any one of the preceding claims, wherein the quinoline derivative is a compound of formula (IV) R4 R5 (IV) wherein the substituents R1, R2, R3, R4 and R5, the same or different from each other, are independently selected from hydrogen, amino, hydroxy, halogen, alkyl, alkoxy and carboxy.

5.

 Process according to claim 4, wherein the quinoline derivative is 8-hydroxyquinoline.

6.

 Process according to any one of the preceding claims in which the base is an alkali metal carbonate.

7.

 Process according to any one of the claims in which the solvent of formula (III) is dimethyl formamide or dimethylacetamide, preferably anhydrous.

8.

 Process according to any one of the claims in which one of the following combinations of copper salt and solvent is used:

(i)

 copper (I) acetate and dimethylformamide;

(ii)

 copper (II) acetate dihydrate and dimethylacetamide; or

(iii) copper acetate (I) and dimethylacetamide.

9.

 Process according to any one of the claims in which an amount of the copper compound equal to or greater than 10 mol% is used with respect to the moles of the compound of the general formula (II).

10.

 Process according to any one of the claims in which potassium carbonate is used as the base and as compound of formula (IV) 8-hydroxyquinoline.

eleven.

 Process according to any one of the claims in which the amount of base is equal to or greater than 0.8 equivalents with respect to the amount of the compound of the general starting formula (II).

12.

 Process according to any one of the claims in which the amount of compound of general formula (IV) is comprised between 0.2 and 1 equivalents with respect to the compound amount of general formula

(II) starting.

13.

 Process according to any one of the preceding claims, wherein between 9 ml and 11 ml of dimethylacetamide is used for each millimol of the starting compound of general formula (II).

14.

 Process according to any one of the preceding claims in which the temperature at which the reaction is carried out is comprised between 120 ° C and 160 ° C, preferably is 140 ° C.

fifteen.

 Process according to any one of the preceding claims in which the compound of general formula (I) obtained is one of the following compounds:

[1] 3-phenylbenzofuran [2] 5-Chloro-3-phenylbenzofuran [3] 5-Bromo-3-phenylbenzofuran [4] 5-tert-butyl-3-phenylbenzofuran [5] 1-phenyl-1H-pyrazol-4-yl-benzofuran  [6] 3- (4'-chlorophenyl) -5-fluorobenzofuran [7] 3- (4'-chlorophenyl) benzofuran [8] 3- (4'-methoxyphenyl) benzofuran [9] 3- (4'-bromophenyl) -5-tert-butylbenzofuran [10] 5,7-Chloro-3-phenylbenzofuran  [11] 7-methoxy-3-phenylbenzofuran SPANISH OFFICE OF THE PATENTS AND BRAND Application no .: 201130229 SPAIN Date of submission of the application: 02.22.2011 Priority Date: REPORT ON THE STATE OF THE TECHNIQUE 51 Int. Cl.: C07D307 / 79 (2006.01) C07D405 / 04 (2006.01)  RELEVANT DOCUMENTS

Category

56 Documents cited Claims Affected

TO

US 7473786 B1 (UNIVERSITY OF MASSACHUSETTS) 06.01.2009, columns 2.3. 1-15

Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application

This report has been prepared • for all claims • for claims no:

Date of realization of the report 13.12.2011

Examiner M. P. Fernández Fernández Page 1/4

REPORT OF THE STATE OF THE TECHNIQUE Application number: 201130229 Minimum documentation sought (classification system followed by classification symbols) C07D Electronic databases consulted during the search (name of the database and, if possible, terms of search used) INVENTIONS, EPODOC, WPI, CAS, REGISTRY State of the Art Report Page 2/4  WRITTEN OPINION Application number: 201130229 Date of Completion of Written Opinion: 13.12.2011 Statement

Novelty (Art. 6.1 LP 11/1986)

Claims Claims 1-15 IF NOT

Inventive activity (Art. 8.1 LP11 / 1986)

Claims Claims 1-15 IF NOT

The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986). Opinion Base.- This opinion has been made on the basis of the patent application as published. State of the Art Report Page 3/4  WRITTEN OPINION Application number: 201130229 1. Documents considered.- The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.

Document

Publication or Identification Number publication date

D01

US 7473786 B1 (UNIVERSITY OF MASSACHUSETTS) 06.01.2009

2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement The application relates to a catalytic process for the synthesis of 3-arylbenzofuran derivatives of general formula (I) (claim 1) comprising treating a 2-hydroxyaryl ketones derivative of formula (II) (claim 1) with molecular oxygen in the presence of salts of Cu (I) and / or Cu (II) (claim 2), of a quinoline derivative of formula (IV) (claim 4), specifically 8-hydroxyquinoline and also in the presence of a base such as a carbonate of alkali metal (claim 6). The solvent used is an amide of formula (III) (see claim 1) as dimethylformamide or dimethylacetamide. The reaction that occurs is an intramolecular cyclization of the 2-hydroxyaryl ketones of formula (II). Document D1 discloses (see columns 2 and 3) the use of a Cu (I) catalyst for the synthesis of 2-aryl benzo [b] furans by coupling arylacetylenes and phenols (see Figures Ia and Ib of D1). Although in both cases it is a question of using Cu catalysts in order to avoid palladium catalysts, in D1 it is sought to obtain the 2-archaeologists and in the application the 3-aryl ones, the starting products in D1 being totally different from those proposed. in the application Consequently, novelty and inventive activity are appreciated in the invention of the application since the synthesis procedure and the choice of the starting products will depend on the position of the substituents in the final product. Accordingly, claims 1-15 of the application meet the requirements of novelty and inventive activity set forth in Articles 6.1 and 8.1 of Patent Law 11/1986. State of the Art Report Page 4/4