Method for the preparation of compounds containing the 2,5-dihydrobenzoxepin structure by photochemical rearrangement

Abstract

The present invention belongs to the field of synthesis of chemical compounds having a dihydrobenzoxepin structure. In particular, the present invention relates to a method for preparing chemical compounds containing a 2,5-dihydro-1-benzoxepin structure from chemical compounds having a chromene structure by photochemical rearrangement.

Description

[Technical field]

[0001] The present invention belongs to the field of synthesis of chemical compounds having dihydrobenzoxepin structure.In particular, the present invention relates to a method for preparing chemical compounds containing 2,5-dihydro-1-benzoxepin structure from chemical compounds having chromene structure by photochemical rearrangement.The method is particularly applicable to preparing dihydrobenzoxepin derivatives having biological activity, especially herbicidal activity, from the corresponding chromene. [Background technology]

[0002] Benzoxepin or benzoxepin is a bicyclic heterocyclic compound consisting of a fused benzene ring and an oxepin. There are three isomers which can be represented by the following formula: [C1] JPEG2025508697000001.jpg54170

[0003] Chemical compounds with the dihydrobenzoxepine structure, also known as dihydrobenzoxepine derivatives, are compounds in which one double bond of the oxepine ring is hydrogenated.

[0004] Benzoxepin derivatives often exhibit biological activity and therefore constitute a compound series of interest in various fields, particularly in the pharmaceutical field (for example in the case of the antidepressant doxepin) or in the phytomedicinal field (in the case of laduranin A and H, which have herbicidal activity). In particular, bibenzyl derivatives having a 2,5-dihydro-1-benzoxepin ring include structures of the following formula: [Case 2] JPEG2025508697000002.jpg43170

[0005] Natural dihydrobenzoxepins can be isolated from moss plants known as liverworts. They are allelopathic compounds known for their herbicidal activity. Among such compounds, mention may be made in particular of the benzoxepin derivatives described in patent application FR3 094 869, in particular radulanine A of the following formula: [C3] JPEG2025508697000003.jpg58170

[0006] Several synthetic routes to compounds containing the 2,5-dihydrobenzoxepin structure have already been presented in the literature.

[0007] The first synthetic route uses a ruthenium complex-catalyzed ring-closing olefin metathesis reaction (M. Yoshida et al., Tetrahedron, 2009, 65, 5702-5708) to condense the double bond of the 2,5-dihydrooxepin ring according to the following scheme: [C4] JPEG2025508697000004.jpg47170

[0008] The second synthetic route uses the Mitsunobu reaction (S. Yamaguchi et al., Tetrahedron Letters, 2000, 41, 4787-4790) to form a cycloether bond according to the following scheme: [5] JPEG2025508697000005.jpg38170

[0009] The third synthetic route uses a retro-Claisen-type rearrangement reaction starting from a vinylcyclopropane precursor (W. Zhang et al., Chem. Eur. J., 2019, 25, 8643-8648) followed by aromatization according to the following scheme: [6] JPEG2025508697000006.jpg45170

[0010] These synthetic routes take a long time to carry out, since they generally require a large number of steps to carry out reactions that are difficult to carry out due to the sensitivity of the reagents involved or the use of expensive metals such as ruthenium used as catalysts, and therefore none of these reactions can be used to efficiently, quickly and economically synthesize laduranin, or more generally, compounds containing the 2,5-dihydro-1-benzoxepin structure. Summary of the Invention [Problem to be solved by the invention]

[0011] Therefore, there is a need for a process that provides economical access to chemical compounds having the 2,5-dihydrobenzoxepin structure, i.e. in few steps and without the use of expensive metals. [Means for solving the problem]

[0012] Therefore, the object of the present invention is to overcome the above-mentioned drawbacks of the prior art and to provide a method for synthesizing chemical compounds having a 2,5-dihydrobenzoxepin structure.

[0013] Thus, the object of the present invention is to provide a compound of formula (I): [7] JPEG2025508697000007.jpg47170[In the formula, - R 1 represents a hydrogen atom or a C1-C6 alkyl radical, - R 2 , R 3 and R 4 are each independently a hydrogen atom, a halogen atom, a C1-C5 alkyl or cycloalkyl radical, or -OH, -COOH, -COOR 6 , -OR 6 and SO2R 6 R represents a group selected from 6is a C1-C5 alkyl or cycloalkyl radical, said C1-C5 alkyl or cycloalkyl radical being optionally substituted with one or more substituents selected from halogen atoms and hydroxy groups; - R 5 is a hydrogen atom, a halogen atom, a C1-C5 alkyl or cycloalkyl radical, or -OH, -COOH, -COOR 6 , -OR 6 and -SO2R 6 R represents a group selected from 6 is a C1-C5 alkyl or cycloalkyl radical, which may be substituted with one or more substituents selected from halogen atoms and hydroxy groups; or R 5 represents the group -LA, where * L represents a linking arm selected from linear and branched alkylene chains having at least one carbon atom, said linear or branched alkylene chains being optionally interrupted and / or terminated with one or more heteroatoms selected from oxygen, sulfur or substituted nitrogen atoms; * A represents an aromatic group selected from phenyl, naphthyl, furyl, thiophenyl, pyrrolyl, pyridinyl, indolyl, isoindolyl, benzofuryl, benzothiophenyl, quinolyl and isoquinolyl, imidazolyl, oxazolyl, thiazolyl, pyrimidyl, pyridazyl, pyrazyl, pyrazolyl and triazolyl, said aromatic group A being a halogen atom, a C1-C5 alkyl or cycloalkyl radical, a -OH group, a -COOH group, a -COOR group, 7 Group, -OR 7 Group, and -SO2R 7 and R 7 is a C1-C5 alkyl or cycloalkyl radical, the C1-C5 alkyl or cycloalkyl radical being optionally substituted with one or more substituents selected from halogen atoms and hydroxy groups or one of the organic and inorganic salts thereof, wherein - Group R 2 , R3 , R 4 and R 5 at least one of which represents an -OH group] 1. A method for synthesizing a compound of the formula The method comprises the steps of: [8] JPEG2025508697000008.jpg38170[where, R 1 , R 2 , R 3 , R 4 and R 5 have the same meaning as given above for the compounds of formula (I). irradiating a solution of the compound of formula (I) in a solvent with ultraviolet light.

[0014] Thus, the method according to the invention involves carrying out a ring extension reaction of a compound containing a 2-methylchromene structure, preferably a 2-alkyl-2-methylchromene, most preferably a 2,2-dimethylchromene, said reaction being carried out under photochemical conditions. The chromene precursor can be synthesized in several steps from a phenol and an α,β-unsaturated aldehyde using acid catalysis.

[0015] In the above formulas (I) and (II), R 1 The alkyl radical shown for may be linear or branched. It is preferably selected from the group comprising the methyl, ethyl and t-butyl radicals, the methyl radical being particularly preferred.

[0016] Examples of inorganic salts of the compounds of formula (I) include the alkali metal and alkaline earth metal salts of the compounds of formula (I).

[0017] Examples of organic salts of the compounds of formula (I) include ammonium salts of the compounds of formula (I).

[0018] In the present invention, a C1-C5 alkyl or cycloalkyl radical may be straight-chain or branched, preferably straight-chain.

[0019] For the purposes of the present invention, halogen is selected from F, Cl, Br and I, preferably F and Cl. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] R 2 、R 3 、R 4 and R 5 Definition of base R 2 , R 3 , R 4 or R 5 An alkyl or cycloalkyl radical as is preferably an alkyl radical, particularly preferably a straight-chain alkyl radical, very particularly preferably a straight-chain C1-C3 alkyl radical.

[0021] base R 6 The alkyl or cycloalkyl radical as is preferably an alkyl radical, in particular a straight-chain alkyl radical, more in particular a straight-chain C1-C3 alkyl radical.

[0022] base R 2 , R 3 , R 4 or R 5 Said alkyl or cycloalkyl radical as may be optionally substituted with one or more substituents selected from halogen atoms and hydroxy groups.

[0023] According to a particularly preferred embodiment of the present invention, the group R 2 , R 3 , R 4 and R 5 At least one of the following represents an -OH group: In this case, said at least one hydroxy group is preferably in the 6-position.

[0024] In this embodiment, the other two groups R 2 , R 3 , or R 2 and R 4 or R 3 and R4 Two of them represent hydrogen atoms, and R 5 represents the group -LA.

[0025] Definition of L L preferably represents a linear or branched alkylene chain having 1 to 6 carbon atoms, particularly preferably a linear alkylene chain having 2 to 3 carbon atoms, and further particularly preferably a linear alkylene chain having 2 carbon atoms.

[0026] The straight or branched alkylene chain as the linking arm L may be interrupted and / or terminated with one or more heteroatoms selected from oxygen, sulfur and substituted nitrogen atoms, preferably one or more oxygen atoms.

[0027] The nitrogen may be substituted with a C1-C5, preferably a C1-C3 alkyl group, said alkyl radical being preferably a straight chain alkyl radical.

[0028] Definition of A Alkyl or cycloalkyl radicals as substituents of the group A are preferably alkyl radicals, particularly preferably straight-chain alkyl radicals, even more particularly more preferably straight-chain C1-C3 alkyl radicals.

[0029] base R 7 The alkyl or cycloalkyl radical as is preferably an alkyl radical, in particular a straight-chain alkyl radical, more in particular a straight-chain C1-C3 alkyl radical.

[0030] Group A or Group R 7 Said alkyl or cycloalkyl radical as a substituent of may be substituted with one or more substituents selected from halogen atoms and hydroxy groups.

[0031] Preferably, A represents an aromatic group selected from the phenyl, naphthyl and pyridinyl groups, particularly preferably a phenyl group.

[0032] The process of the present invention can be carried out in a stationary mode or in continuous flow.

[0033] According to a first embodiment, the process is carried out in stationary mode, which makes it possible to obtain a conversion of the compound of formula (II) of 90-100%, with a yield of the compound of formula (I) of the order of 10-50%.

[0034] According to this first embodiment, the method according to the invention is carried out in an immersion well, which comprises a UV-transparent tube, for example made of Pyrex, immersion-cooled in ice water and containing a UV lamp.

[0035] According to a second embodiment, the method is carried out in a continuous flow. This second embodiment allows for improved reaction rate, reproducibility and yield of the compound containing the structure of formula (I). In this case, the conversion rate of the starting compound of formula (II) can be in the range of 90-100%, and the yield of the compound containing the structure of formula (I) is about 30-50%. This second embodiment is preferred.

[0036] According to this second embodiment, the method is carried out in a continuous flow reactor consisting of a UV-transparent tube made of a thermoplastic material, for example perfluoroalkoxyalkane (PFA). The tube is wrapped around a UV lamp fitted with a Pyrex-type filter. A degassed solution of the compound of formula (II) is injected into the reactor in a continuous flow, with a flow rate that may in particular range from 0.5 to 2 mL / min.

[0037] The solvent of the solution may be selected from aromatic hydrocarbons such as benzene and toluene, acetonitrile and ethyl acetate, among which acetonitrile and ethyl acetate are preferred, with acetonitrile being particularly preferred.

[0038] The duration of the irradiation step is generally about 5 minutes to 5 hours.

[0039] According to a first embodiment of the invention, the method is carried out in a stationary mode, the duration of said irradiation step being between 1 and 5 hours, preferably between 1 and 2 hours.

[0040] According to a second embodiment of the invention, the method is carried out in a continuous flow and the duration of said irradiation step is between 5 and 20 minutes, preferably between 8 and 12 minutes.

[0041] According to the present invention, ultraviolet radiation means invisible radiation emitted in the wavelength range of 100 to 400 nanometers (nm).

[0042] According to a preferred embodiment of the present invention, the irradiation step is carried out at a wavelength of about 200-400 nm, even more preferably around 250-350 nm.

[0043] Ultraviolet light can be conventionally generated by an ultraviolet (UV) radiation lamp. According to the present invention, a medium pressure mercury ultraviolet lamp having a power of about 100 to 400 W, preferably about 150 W, is preferably used.

[0044] According to the present invention, "medium pressure" means 1.10 5 ~1.10 6 It means pressure in Pascals.

[0045] According to a particularly preferred embodiment of the present invention, the method comprises the steps of: [9] JPEG2025508697000009.jpg40170[where, R 1 , R 2 , R 3 , R 4 , A and L have the same meanings as given above for compounds of formula (I). In this case, the compound of formula (II) subjected to the irradiation step has the following formula (IIa): [C10] JPEG2025508697000010.jpg35170[wherein, R 1 , R 2 , R3 , R 4 , A and L have the same meanings as given above for compounds of formula (I).

[0046] Preferably, in the compounds of formula (Ia), the group R 2 , R 3 and R 4 at least one of them represents an -OH group. In this case, said at least one hydroxy group is preferably in position 6. Also particularly preferably, the group -LA is in position 8, L represents an ethylene chain and A is a phenyl ring.

[0047] According to a particularly preferred embodiment of the present invention, the method is carried out for the preparation of laduranin A of formula (Ia-1) below: [C11] JPEG2025508697000011.jpg54170

[0048] Therefore, laduranin A is R 1 represents a methyl radical, and the group R 2 , R 3 and R 4 One of the groups represents the OH group at the 6th position, and the other two groups R 2 and R 3 , R 3 and R 4 represents a hydrogen atom, and R 5 is a group -LA, which is in the 8-position and corresponds to a compound of formula (Ia) in which A is a phenyl ring.

[0049] Several synthetic methods can be used to obtain the chromenes of formula (II), such as those described in particular by R. Pratap et al, Chem. Rev, 2014, 114, 10476-10526.

[0050] In particular, the method comprises: 1 and R 5 is as defined in formula (I), and the group R 2 , R 3 and R 4One of the groups represents the OH group at the 6th position, and the other two groups R 2 and R 3 , R 3 and R 4 represents a hydrogen atom (compound of formula (I')), the corresponding chromene of formula (II) (chromene of formula (II')) can be prepared by reacting R with R in a closed reactor (e.g. sealed tube) under reflux and inert atmosphere in the presence of an acid catalyst such as ethylenediammonium diacetate (EDDA) according to the method described by Lee et al. (Tetrahedron Lett. 2005, 46, 7539-7543), or a Lewis acid such as Yb(OTf)3, ZnCl2, or a Brönsted acid such as ammonium acetate (NH4OAc), trifluoroacetic acid (TFA), or acetic acid (AcOH); 5 has the same meaning as in formula (I) and diphenols of formula (III) and R 1 are obtained by condensing an α,β-unsaturated aldehyde of formula (IV), which has the same meaning as in formula (I). [C12] JPEG2025508697000012.jpg46170

[0051] If the precursors of formulae (III) and (IV) are not commercially available, they can be synthesized according to conventional methods. For example, unsaturated aldehydes can be obtained by Horner-Wadsworth-Emmons type olefination reaction on carbonyl derivatives with triethyl phosphonoacetate followed by reduction of the ester function to the aldehyde. Phenol derivatives can be obtained by various methods of electrophilic aromatic substitution well known to those skilled in the art, or by cross-coupling of activated derivatives, or even by functionalization of groups already present in the aromatic system.

[0052] The reaction solvent may be selected from toluene, xylene, benzene, dichloromethane and acetic acid.

[0053] Further features, options and advantages of the method according to the invention will become apparent on reading the following exemplary embodiments, which are given by way of illustration of the invention and which do not limit it. EXAMPLES

[0054] Toluene, acetonitrile and benzene were distilled over calcium hydride before use and degassed by bubbling nitrogen gas as necessary.

[0055] Analytical thin-layer chromatography (TLC) was performed on aluminized silica gel plates (silica gel 60, F254, Merck) and monitored by exposure to ultraviolet light and / or basic potassium permanganate solution or p-anisaldehyde staining solution followed by heating.

[0056] Flash column chromatography was performed on silica 60 (40-63 pm).

[0057] Nuclear magnetic resonance spectrum ( 1 H NMR and 13 C NMR) was performed on a Bruker Avance 400 spectrometer (400 MHz, 1 HNMR, 100MHz 13 C NMR was recorded at 25 °C using CDCl as the reference solvent for residual CHCl (δH = 7.26 ppm, δC = 77.1 ppm). Chemical shifts are given in ppm and coupling constants (J) are given in Hertz. 1 H NMR spectral data are reported as follows: chemical shift ppm (br s = broad singlet, s = singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, td = triple doublet, ddd = double double doublet, m = multiplet, coupling constant, integral).

[0058] Infrared spectra were recorded on a PerkinElmer FTIR spectrometer using the attenuated total reflectance (ATR) technique. max ) is the wave number (cm -1) to report.

[0059] High resolution mass spectra (HRMS) were obtained using a JEOL JMS-GCmate II spectrometer and are reported in m / z.

[0060] Batch photochemistry experiments in static mode were carried out in 500 mL immersion wells or 10 mL Pyrex sealed tubes illuminated with a 150 W medium pressure Hg Heraeus lamp.

[0061] Flux photochemistry experiments were carried out on a Vapourtec E-series system equipped with a UV-150 photoreactor fitted with a medium pressure Hg lamp (75–150 W) used in combination with a Pyrex filter.

[0062] Example 1: Synthesis of laduranin A (compound of formula Ia-1) according to the method according to the invention Laduranin A was prepared according to the method of the present invention, which performs the photochemical rearrangement in a continuous flow according to the steps shown in the following scheme. [C13] JPEG2025508697000013.jpg125170

[0063] 1.1 Step 1: Preparation of (E)-3,5-dimethoxystilbene (compound 3) The first step is the Horner-Wadsworth-Emmons reaction. In an inert atmosphere, potassium tert-butylate (t-BuOK) (10.8 g, 96.3 mmol) and anhydrous tetrahydrofuran (THF) (120 mL) were added to a flame-dried 500 mL flask equipped with a magnetic stir bar. The mixture was cooled in an ice bath, and then diethyl benzylphosphonate (compound 1) (20.6 mL, 90.3 mmol) was added dropwise over 30 min, followed by the addition of 3,5-dimethoxybenzaldehyde (compound 2) (10.0 g, 60.2 mmol) in small portions. The mixture was allowed to warm to room temperature and stirred for 2 h. The THF was removed in vacuo, and then a mixture of water and methanol (HO:MeOH) (2:1, ca. 60 mL) was added until the product precipitated. Filtration and drying in vacuum gave (E)-3,5-dimethoxystilbene (compound 3) as a white solid (13.5 g, 56.0 mmol, 93% yield). 1 H NMR (400MHz, CDCl3): δ=7.53-7.49(m,2H),7.39-7.33(m,2H),7.29-7.23(m,1H),7.09(d,J= 16.3Hz, 1H), 7.04 (d, J = 16.3Hz, 1H), 6.69-6.66 (m, 2H), 6.40 (t, J = 2.3Hz, 1H), 3.83 (s, 6H).

[0064] 1.2 Second step: Preparation of 1,3-dimethoxy-5-phenethylbenzene (compound 4) The second step is the catalytic hydrogenation of the double bond to embody ammonium formate. Thus, the use of hydrogen gas is avoided. (E)-3,5-dimethoxystilbene (14.0 g, 58.2 mmol) prepared in the previous step and 10% Pd / C (1.40 g, 10 wt%) were added to a flame-dried 500 mL flask, followed by ethyl acetate (243 mL, 0.245 M). Ammonium formate (18.4 g, 291 mmol) was then added and the mixture was stirred overnight at room temperature. The reaction mixture was then filtered through a Celite pad and evaporated in vacuum. The remaining ammonium formate was precipitated by adding dichloromethane, and the mixture was filtered again and evaporated in vacuum to give the expected 1,3-dimethoxy-5-phenethylbenzene (compound 4) as a pale yellow oil (12.7 g, 52.4 mmol, 90% yield). 1 H NMR (400MHz, CDCl3): δ=7.32-7.25(m,2H),7.23-7.17(m,3H),6.36-6.30(m,3H),3.76(s,6H),2.95-2.82(m,4H).

[0065] 1.3. Step 3: Preparation of dihydropinosylvin (compound 5) The third step is the demethylation of phenol in an acidic aqueous medium. To a 250 mL flask equipped with a magnetic stir bar, 1,3-dimethoxy-5-phenethylbenzene (2.03 g, 8.38 mmol) prepared in the previous step was added, followed by hydrobromic acid (HBr) (24.6 mL, 48 wt % in water) and glacial acetic acid (24.6 mL, HBr:AcOH 1:1 v / v, final concentration 0.15 M). The reaction mixture was then heated under reflux for 4 h and cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with diethyl ether (Et2O) (3 x 50 mL). The organic phase was treated with activated charcoal, filtered and reduced in vacuo to give dihydropinosylvin as a white solid (1.68 g, 7.86 mmol, 94%). 1 H NMR (400MHz, CDCl3): δ = 7.33-7.25 (m, 2H), 7.24-7.15 (m, 3H), 6.31-6.18 (m, 3H), 4.71 (br s, 2H), 2.93-2.75 (m, 4H).

[0066] 1.4 Fourth step: Preparation of 2,2-dimethyl-7-phenethyl-2H-chromen-5-ol (compound 6) In an inert atmosphere, a flame-dried sealed tube equipped with a magnetic stir bar was charged with the dihydropinosylvin obtained in the previous step (4.00 g, 18.7 mmol-1 equiv.), followed by anhydrous toluene (0.1 M) and 3-methyl-2-butenal (prenal) (1.5 equiv.). Ethylenediammonium diacetic acid (EDDA, ​​5 mol%) was then added. The vessel was sealed and heated to 115° C. for 1 h. This procedure (addition of EDDA and heating) was repeated three times (total of 15 mol% EDDA added), then cooled to room temperature, after which a small amount of silica was added and the solvent removed under vacuum. The crude mixture was purified by flash silica column chromatography (dry loading) eluting with hexane / ethyl acetate to give the expected 2,2-dimethyl-7-phenethyl-2H-chromen-5-ol (compound 6) as a viscous brown liquid (4.28 g, 15.3 mmol, 82% yield). 1 H NMR (400MHz, CDCl3): δ=7.31-7.24(m,2H),7.22-7.15(m,3H),6.58(d,J=10 .0,1H),6.32-6.29(m,1H),6.14-6.10(m,1H),5.55(d,J=10.0,1H),4.59(br s, 1H), 2.92-2.83 (m, 2H), 2.80-2.73 (m, 2H), 1.42 (s, 6H).

[0067] 1.5. Fifth step: Preparation of laduranin A (compound (Ia-1)) by photochemical rearrangement in continuous flow A solution of compound 6 (200 mg, 0.713 mmol) obtained in the previous step was prepared in anhydrous acetonitrile (713 mL, 0.001 M) degassed with nitrogen in a flame-dried 1 L flask under nitrogen atmosphere. The continuous flow system was first rinsed with anhydrous degassed acetonitrile, and then the solution of compound 6 was transferred to a photochemical reactor equipped with a Pyrex filter at 100% lamp power (150 W) and a flow rate of 1.2 mL.min. -1(Residence time in the reactor: 8.44 min), pressure: 300 KPa, and reactor temperature: 30° C. The collected solution was evaporated in vacuum, and the crude mixture was purified by flash column chromatography eluting with 2-10% EtOAc:hexane to give laduranin A (compound of formula (Ia-1)) as a brown oil (52.2 mg, 0.186 mmol, 26%).

[0068] The NMR analysis of laduranin A is shown below: 1 H NMR (400MHz, CDCI3): δ=7.32-7.24 and 7.22-7.14(m,5H),6.53(d,J=1.5Hz,1H),6.37(d,J=1.5Hz,1H),5.64-5.57(m,1H),4.84(br s, 1H), 4.44-4.37 (m, 2H), 3.44-3.34 (m, 2H), 2.91-2.83 and 2.83-2.75 (m, 4H), 1.57-1.50 (m, 3H).

[0069] Example 2: Synthesis of laduranin A (compound of formula Ia-1) by the method of the present invention in static mode Laduranin A was prepared following the same steps as shown in the synthetic scheme given in Example 1 above, except that the fifth photochemical rearrangement step was carried out in stationary mode.

[0070] Under an inert atmosphere, compound 5 (2.70 mg, 0.00963 mmol), prepared in step 4 of Example 1 above, and dry, degassed benzene (9.00 mL, 0.001 M) were added to a sealed 10 mL flame-dried Pyrex tube equipped with a magnetic stir bar. The tube was attached directly to the cooling jacket of a 150 W medium pressure mercury lamp. The reaction mixture was irradiated with stirring for 1 h. The solvent was evaporated in vacuo and the crude reaction mixture was eluted. 1 H NMR analysis revealed complete conversion of compound 5 to laduranin A. 1H NMR (400MHz, CDCI3): δ=7.32-7.24 and 7.22-7.14(m,5H),6.53(d,J=1.5Hz,1H),6.37(d,J=1.5Hz,1H),5.64-5.57(m,1H),4.84(br s, 1H), 4.44-4.37 (m, 2H), 3.44-3.34 (m, 2H), 2.91-2.83 and 2.83-2.75 (m, 4H), 1.57-1.50 (m, 3H).

[0071] Example 3: Synthesis of 3,8-dimethyl-2,5-dihydrobenzoxepin-6-ol (compound of formula I-1) by the method of the present invention in static mode 3,8-Dimethyl-2,5-dihydrobenzoxepin-6-ol was prepared according to the method of the present invention, which performs the photochemical rearrangement step in a continuous flow according to the steps shown in the following scheme. [C14] JPEG2025508697000014.jpg109170

[0072] 3.1 First step: Preparation of 2,2,7-trimethyl-2H-chromen-5-ol (compound 7) In an inert atmosphere, a flame-dried sealed tube equipped with a magnetic stir bar was charged with orcinol (1 eq.), followed by anhydrous toluene (0.1 M) and prenal (1.5 eq.). Ethylenediammonium diacetate (EDDA, ​​5 mol%) was then added. The vessel was sealed and heated to 115° C. for 1 h. This procedure (addition of EDDA and heating) was repeated three times (total of 15 mol% EDDA added) and then cooled to room temperature, after which a small amount of silica was added and the solvent removed under vacuum. The crude mixture was purified by flash silica column chromatography (dry loading) eluting with hexane / EtOAc to give the expected 2,2,7-trimethyl-2H-chromen-5-ol (compound 7). 1 H NMR (400MHz, CDCl3): δ=6.57(d,J=10.0,1H),6.26-6.24(m,1H),6.14-6.11(m,1H),5.53(d,J=10.0Hz,1H),4.60(br s, 1H), 2.22-2.20 (m, 3H), 1.41 (s, 6H).

[0073] 3.2. Step 2: Preparation of 3,8-dimethyl-2,5-dihydrobenzoxepin-6-ol (compound of formula I-1) Compound 7 (75 mg, 0.394 mmol) obtained in the previous step and anhydrous benzene (250 mL, 0.00158 M) degassed by bubbling nitrogen were introduced into a 500 mL immersion well equipped with a 150 W mercury lamp, a water-cooled jacket and a magnetic stir bar under an inert atmosphere. The reaction mixture was stirred and irradiated for 30 min before cooling. This procedure was repeated 10 times until the mixture was irradiated for a total of 5 h. The reaction mixture was then evaporated in a flask under vacuum and the crude mixture was purified by flash column chromatography eluting with 1:1 hexane:CHCl to give the expected compound of formula (Ia-1) as a yellow oil (35.3 mg, 0.185 mmol, 47%). Rf=0.19(1:1 hexane / CH2Cl2) 1 H NMR (400MHz, CDCl3): δ=6.50-6.52(m,1H),6.39-6.36(m,1H),5.65-5.57(m,1H),4.80(br s,1H),4.44-4.37(m,2H),3.43-3.36(m,2H),2.25-2.23(m,3H),1.56-1.51(m,3H). 13 C NMR (101MHz, CDCl3): δ=159.7,152.0,137.4,134.0,120.7,120.1,114.5,112.2,74.3,21.6,21.0,20.1. IR(ATR):3350,2931,1715,1619,1583,1450,1378,1311,1207,1068,986,836,753. HRMS(EI+):C 12 H 15 O 2+ Theoretical value: 191.1067; Measured value: 191.1064.

Claims

1. Formula (I): [C15] [In the formula, - R １ is a hydrogen atom or C １ -C ６ represents an alkyl radical, - R ２ , R ３ and R ４ are each independently a hydrogen atom, a halogen atom, or C １ -C ５ Alkyl or cycloalkyl radicals, or -OH, -COOH, -COOR ６ , -OR ６ and -SO ２ R ６ represents a group selected from ６ is C １ -C ５ is an alkyl or cycloalkyl radical, １ -C ５ The alkyl or cycloalkyl radicals may be substituted with one or more substituents selected from halogen atoms and hydroxy groups; - R ５ represents a hydrogen atom, a halogen atom, or C １ -C ５ Alkyl or cycloalkyl radicals, or -OH, -COOH, -COOR ６ , -OR ６ and -SO ２ R ６ represents a group selected from ６ is C １ -C ５ is an alkyl or cycloalkyl radical, １ -C ５ The alkyl or cycloalkyl radical may be substituted with one or more substituents selected from halogen atoms and hydroxy groups, or alternatively, R ５ represents the -LA group, where: ＊ L represents a linking arm selected from linear and branched alkylene chains having at least one carbon atom, said linear or branched alkylene chains being optionally interrupted and / or terminated with one or more heteroatoms selected from oxygen, sulfur or substituted nitrogen atoms; and ＊ A represents an aromatic group selected from phenyl, naphthyl, furyl, thiophenyl, pyrrolyl, pyridinyl, indolyl, isoindolyl, benzofuryl, benzothiophenyl, quinolyl and isoquinolyl, imidazolyl, oxazolyl, thiazolyl, pyrimidyl, pyridazyl, pyrazyl, pyrazolyl and triazolyl, and the aromatic group A is selected from halogen atoms, C １ -C ５ Alkyl or cycloalkyl radical, —OH group, —COOH group, —COOR ７ group, -OR ７ group, and —SO ２ R ７ and R ７ is C １ -C ５ is an alkyl or cycloalkyl radical, １ -C ５ The alkyl or cycloalkyl radical may be substituted with one or more substituents selected from halogen atoms and hydroxy groups or one of the organic and inorganic salts thereof, wherein: - group R ２ , R ３ , R ４ and R ５ At least one of the groups represents an —OH group.

1. A method for synthesizing a compound of formula (I), comprising: The method comprises reacting a compound of formula (II): [C16] [In the formula, R １ , R ２ , R ３ , and R ５ has the same meaning as given above for compounds of formula (I). irradiating a solution of the compound of formula (I) in a solvent with ultraviolet light.

2. 2. The method of claim 1, wherein the solvent of the solution is selected from aromatic hydrocarbons, acetonitrile and ethyl acetate.

3. 2. The method of claim 1, wherein the method is carried out in static mode and the duration of the irradiation step is between 1 and 5 hours.

4. 10. The method of claim 1, wherein the method is carried out in continuous flow.

5. 5. The method of claim 4, wherein the duration of the irradiation step is between 5 and 20 minutes.

6. 2. The method of claim 1, wherein the irradiation step is carried out at a wavelength of 250 to 350 nm.

7. 2. The method of claim 1, wherein the at least one hydroxy group is at the 6-position.

8. The other two groups R ２ , R ３ , or R ２ and R ４ or R ３ and R ４ represents a hydrogen atom, R ５ 2. The method of claim 1, wherein represents the group -LA.

9. 2. The method of claim 1, wherein L represents a linear alkylene chain having 2 to 3 carbon atoms.

10. 2. The method of claim 1, wherein A represents an aromatic group selected from phenyl, thiophenyl and pyridinyl groups.

11. Formula (Ia) below: [C17] [In the formula, R １ , R ２ , R ３ , R ４ , A and L have the same meanings as given for the compounds of formula (I). is carried out for the preparation of a compound of The compound of formula (II) subjected to the irradiation step has the following formula (IIa): [C18] [In the formula, R １ , R ２ , R ３ , R ４ , A and L have the same meanings as given for the compounds of formula (I).

2. The method of claim 1, wherein the method corresponds to:

12. 12. The method of claim 11, wherein the group -LA is in the 8-position, L represents an ethylene chain and A is a phenyl ring.

13. The following formula (Ia-1): [C19] 13. The method according to claim 11 or 12, characterized in that it is carried out for the preparation of laduranin A of the formula:

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