Process for preparing compounds containing a 2,5-dihydrobenzoxepine structure by photochemical rearrangement

Abstract

The present invention relates to the field of synthesis of chemical compounds possessing a dihydrobenzoxepin structure. In particular, the invention relates to a process for preparing chemical compounds having a 2,5-dihydro-1-benzoxepin structure by photochemical rearrangement of chemical compounds possessing a chromene structure. Figure to be published: none

Description

Title of the invention: Process for the preparation of compounds comprising a 2,5-dihydrobenzoxepin structure by photochemical rearrangement

[0001] The present invention applies to the field of the synthesis of chemical compounds having a dihydrobenzoxepin structure. In particular, the invention relates to a process for the preparation of chemical compounds having a 2,5-dihydro-1-benzoxepin structure by photochemical rearrangement from chemical compounds having a chromene structure. This process is particularly applicable to the preparation of dihydrobenzoxepin derivatives having biological activity and in particular herbicidal activity, from the corresponding chromene derivatives.

[0002] Benzoxepin or benzooxepin is a bicyclic heterocyclic compound consisting of a benzene ring fused with that of oxepin. There are three isomers which can be represented by the following formulas:

[0003] [Chem.l] 1-benzoxepine 2-benzoxepine 3-benzoxepine

[0004] Chemical compounds having a dihydrobenzoxepin structure, also called dihydrobenzoxepin derivatives, are compounds in which a double bond of the oxepin ring is hydrogenated. Benzoxepin derivatives often exhibit biological activity and therefore constitute a family of compounds of interest for various applications, particularly in the pharmaceutical field — this is the case, for example, of doxepin, which is an antidepressant — or in the phytopharmaceutical field — this is the case of radulanins A and H, which have herbicidal activity. In particular, bibenzyl derivatives with a 2,5-dihydro-l-benzoxepin nucleus have a structure of the following formula:

[0005] [Chem.2] 2 5-dhydro-1 -benzoxepin

[0006] Natural dihydrobenzoxepines can be isolated from plant mosses called liverworts. These are allelopathic compounds known for their herbicidal activity. Among such compounds, we can particularly mention the benzoxepine derivatives described in patent application FR 3 094 869 and which include in particular radulanine A of the following formula: [Chem 3]

[0007] Several synthetic routes for obtaining compounds comprising a 2,5-dihydrobenzoxepin structure have already been proposed in the literature.

[0008] A first synthetic route uses a cyclizing olefin metathesis reaction catalyzed by a ruthenium complex allowing the fusion of the double bond of the 2,5-dihydrooxepine ring (M. Yoshida et al., Tetrahedron, 2009, 65, 5702-5708), according to the following scheme: [Chem 4]

[0009] A second synthetic route uses a Mitsunobu reaction to form the cycloether bond (S. Yamaguchi et al., Tetrahedron Letters, 2000, 41, 4787-4790) according to the following scheme: [Chem 5]:

[0010] A third synthetic route uses a retro-Claisen type rearrangement reaction from a vinylcyclopropane precursor (W. Zhang et al., Chem. Eur. J., 2019, 25, 8643-8648), followed by aromatization, according to the following scheme: [Chem 6]:

[0011] These synthetic routes are long to implement because obtaining the precursors of radulanine generally requires numerous steps involving reactions that are difficult to carry out, either due to the sensitivity of the reagents involved, or due to the use of expensive metals such as ruthenium used as a catalyst. None of these reactions therefore allows the synthesis of radulanine, and more generally of compounds comprising a 2,5-dihydro-l-benzoxepin structure, in an efficient, short and economical manner.

[0012] There is therefore a need for a process which makes it possible to access economically, i.e. in a few steps and without using expensive metals, chemical compounds having a 2,5-dihydrobenzoxepin structure.

[0013] Thus, the aim of the present invention is to overcome the drawbacks of the aforementioned prior art and to provide a process for the synthesis of chemical compounds having a 2,5-dihydrobenzoxepin structure.

[0014] The present invention thus relates to a process for the synthesis of a compound comprising a 3-methyl-2,5-dihydro-l-benzoxepin structure of the following formula (I): [Chem 7] in which R1 represents a hydrogen atom or a Cr alkyl radical C6, characterized in that said method comprises a step of irradiation with ultraviolet radiation of a solution in a solvent of a compound comprising a 2,2-dimethylchromene structure of the following formula (II): [Chem 8] in which R1 has the same meaning as in formula (I).

[0015] The process according to the present invention thus implements a ring extension reaction of a compound comprising a 2,2-dimethylchromene structure. conducted under photochemical conditions. Chromene precursors can be synthesized in few steps from phenols and α,[3-unsaturated aldehydes using acid catalysis.

[0016] In formulas (I) and (II) above, the alkyl radical indicated for R1 may be linear or branched. It is preferably chosen from the group comprising a methyl radical, an ethyl radical and a t-butyl radical, the methyl radical being particularly preferred.

[0017] The method of the invention can be carried out in static mode or in continuous flow.

[0018] According to a first embodiment, the process is carried out in static mode. This first embodiment makes it possible to obtain conversion rates of the compound of formula (II) of 90 to 100%, with yields of compound of formula (I) of the order of 10 to 50%.

[0019] According to this first embodiment, the method according to the invention is carried out in an immersion well equipped with a tube transparent to UV radiation, for example made of Pyrex, immersed and cooled with iced water and containing a UV lamp.

[0020] According to a second embodiment, the process is carried out in continuous flow. This second embodiment makes it possible to improve the reaction speed, the reproducibility and the yields of compounds comprising a structure of formula (I). In this case, the conversion rate of the starting compound of formula (II) can vary from 90 to 100% and the yield of compound comprising a structure of formula (I) is of the order of approximately 30 to 50%. This second embodiment is preferred.

[0021] According to this second embodiment, the method is carried out in a continuous flow reactor consisting of a tube transparent to UV radiation, for example made of a thermoplastic material such as a perfluoroalkoxy alkane (PFA). This tube is wound around a UV lamp equipped with a pyrex-type filter. A degassed solution of the compound of formula (II) is injected into this reactor, in a continuous flow at a flow rate which can in particular vary from 0.5 to 2 mL / min.

[0022] The solvent of the solution may be chosen from aromatic hydrocarbons such as, for example, benzene and toluene, acetonitrile and ethyl acetate. Among such solvents, acetonitrile and ethyl acetate are preferred, acetonitrile being particularly preferred.

[0023] The duration of the irradiation step is generally from 5 minutes to 5 hours approximately.

[0024] According to the first embodiment of the invention, the method is carried out in static mode and the duration of the irradiation step is 1 to 5 hours, preferably 1 to 2 hours.

[0025] According to the second embodiment of the invention, the method is carried out in continuous flow and the duration of the irradiation step is 5 to 20 minutes, preferably 8 to 12 minutes.

[0026] According to the invention, ultraviolet radiation is understood to mean any invisible radiation which emits in the wavelength range of 100 to 400 nanometers (nm).

[0027] According to a preferred embodiment of the invention, the irradiation step is carried out at a length of approximately 200 to 400 nm, and even more preferably of approximately 250 to 350 nm.

[0028] The UV radiation can, conventionally, be generated by a lamp emitting in the ultraviolet (UV) range. According to the invention, a medium-pressure mercury UV lamp having a power of approximately 100 to 400 W, preferably of the order of approximately 150 W, is preferably used.

[0029] According to the invention, and by definition, “medium pressure” means a pressure of the order of 1.105 to 1.106 Pascal.

[0030] According to a particular and preferred embodiment of the invention, the process is carried out for the preparation of a compound of the following formula (Ia): [Chem 9] in which: - R1 has the same meaning as in formula (I) above,

[0031] - R2, R3 and R4, independently of each other, represent an atom hydrogen, a halogen atom, a C1-C5 alkyl or cycloalkyl radical, or a group selected from -OH, -COOH, -COOR6, -OR6 and -SO2R6, with R6 being a C1-C5 alkyl or cycloalkyl radical, said C1-C5 alkyl or cycloalkyl radical possibly being substituted by one or more substituents selected from a halogen atom and a hydroxyl group;

[0032] - R5 represents a hydrogen atom, a halogen atom, an alkyl radical or C1-C5 cycloalkyl, or a group selected from -OH, -COOH, -COOR6, -OR6 and -SO2R6, with R6 being a C1-C5 alkyl or cycloalkyl radical, said C1-C5 alkyl or cycloalkyl radical possibly being substituted by one or more substituents selected from a halogen atom and a hydroxyl group, or R5 represents a -LA group in which: * L represents a linker arm chosen from linear and branched alkylene chains having at least one carbon atom, said linear or branched alkylene chains being able to be interrupted and / or terminated by one or more heteroatoms chosen from an oxygen, sulfur, and substituted nitrogen atom, and * A represents an aromatic group selected from phenyl, naphthyl, furyl, thiophenyl, pyrrolyl, pyridinyl, indolyl, isoindolyl, benzofuryl, benzothiophenyl, quinolyl, isoquinolyl, imidazolyl, oxazolyl, thiazolyl, pyrimidyl, pyridazyl, pyrazyl, pyrrazolyl, and triazolyl, said aromatic group A may be substituted by one or more substituents selected from a halogen atom, a C1-C5 alkyl or cycloalkyl radical, an -OH group, a -COOH group, a -COOR7 group, an -OR7 group, and a -SO2R7 group, with R7 being a C1-C5 alkyl or cycloalkyl radical, said C1-C5 alkyl or cycloalkyl radical may be substituted by one or more substituents selected from a halogen atom and a hydroxyl group or to one of its organic and inorganic salts. In this case, said compound of formula (II) subjected to said irradiation step corresponds to the following formula (IIa): in which R1, R2, R3, R4, and R5 have the same meaning as indicated below for compounds of formula (Ia).

[0033] As examples of inorganic salts of the compound of formula (Ia), mention may be made of the alkali and alkaline earth salts of the compound of formula (Ia).

[0034] As examples of organic salts of the compound of formula (Ia), mention may be made of the ammonium salts of the compound of formula (Ia).

[0035] In the present invention the C 1 to C 5 alkyl or cycloalkyl radical may be linear or branched, and is preferably linear.

[0036] For the purposes of the present invention, a halogen is chosen from F, Cl, Br and I, and preferably from F and Cl. Definition of R2, R3, R4 and R5

[0037] The alkyl or cycloalkyl radical as group R2, R3, R4 or R5 is preferably an alkyl radical, particularly preferably a linear alkyl radical, and more particularly preferably a linear C1 to C3 alkyl radical.

[0038] The alkyl or cycloalkyl radical as group R6 is preferably an alkyl radical, particularly preferably a linear alkyl radical, and more particularly preferably a linear C1 to C3 alkyl radical.

[0039] Said alkyl or cycloalkyl radical as group R2, R3, R4 or R5 may be substituted by one or more substituents chosen from a halogen atom and a hydroxyl group.

[0040] According to a particularly preferred embodiment of the invention, at least one of the groups R2, R3, R4 and R5 represents an -OH group. In this case, said at least one hydroxyl group is preferably in position 6.

[0041] In this embodiment, two of the other groups R2, R3, or R2 and R4 or R3 and R4 represent a hydrogen atom and R5 represents a -LA group.

[0042] Definition of L L preferably represents a linear or branched alkylene chain having from 1 to 6 carbon atoms, particularly preferably a linear alkylene chain having from 2 to 3 carbon atoms, and more particularly preferably a linear alkylene chain having 2 carbon atoms.

[0043] The linear or branched alkylene chain as linker arm L may be interrupted and / or terminated by one or more heteroatoms chosen from an oxygen, sulfur, and substituted nitrogen atom, and preferably by one or more oxygen atoms.

[0044] The nitrogen may be substituted by a C1-C5, preferably C1-C3, alkyl group, said alkyl radical preferably being a linear alkyl radical.

[0045] Definition of A The alkyl or cycloalkyl radical as a substituent of group A is preferably an alkyl radical, particularly preferably a linear alkyl radical, and more particularly preferably a linear C1-C3 alkyl radical.

[0046] The alkyl or cycloalkyl radical as group R7 is preferably an alkyl radical, particularly preferably a linear alkyl radical, and more particularly preferably a linear C1-C3 alkyl radical.

[0047] Said alkyl or cycloalkyl radical as a substituent of group A or group R7 may be substituted by one or more substituents chosen from a halogen atom and a hydroxyl group.

[0048] A preferably represents an aromatic group chosen from phenyl, naphthyl, and pyridinyl groups, and particularly preferably is a phenyl group.

[0049] According to a particularly preferred embodiment of the invention, the process is carried out for the preparation of a compound of the following formula (Ib): [Chem 11] in which R1, R2, R3, R4, A and L have the same meaning as indicated above for the compounds of formula (Ia). In this case, said compound of formula (II) subjected to said irradiation step corresponds to the following formula (IIb): [Chem 12]

[0050] in which R1, R2, R3, R4, A and L have the same meaning as indicated below for the compounds of formula (Ia).

[0051] Preferably, in the compounds of formula (Ib), at least one of the groups R2, R3 and R4 represents an -OH group. In this case, said at least one hydroxyl 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.

[0052] According to a particularly preferred embodiment of the invention, the process is carried out for the preparation of radulanin A of formula (Ib-1) following: [Chem 13] Radulanine A thus corresponds to a compound of formula (Ib) in which R1 represents a methyl radical, one of the groups R2, R3 and R4 represents an OH group in position 6, the other two groups R2 and R3, respectively R3 and R4, represent a hydrogen atom and R5 is a group -LA is in position 8, and A is a phenyl ring.

[0053] Several synthetic methods can be used to access the chromenes of formula (II). Such methods are in particular described by R. Pratap et al., Chem. Rev., 2014,114, 10476-10526.

[0054] In particular, when the process is carried out for the preparation of a compound of formula (Ia) in which R1 and R5 are as defined in formula (Ia), one of the groups R2, R3 and R4 represents an OH group in position 6, the other two groups R2 and R3, respectively R3 and R4 represent a hydrogen atom (compounds of formula (Ia'), then they are preferably obtained by condensation of a diphenol of formula (III) in which R5 has the same meaning as in formula (Ia) and an α,[3-unsaturated aldehyde of formula (IV) in which R1 has the same meaning as in formula (Ia), according to the following reaction scheme:

[0055] [Chem. 14] (HQ ¢^) (la')

[0056] in the presence of an acid catalyst such as ethylene diammonium 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 Bronsted acid such as ammonium acetate (NH4OAc), trifluoroacetic acid (TFA), or acetic acid (AcOH); a solvent, in a closed reactor (e.g. sealed tube), at reflux, and under an inert atmosphere.

[0057] When the precursors of formula (III) and (IV) are not commercially available, they can be synthesized according to conventional methods. For example, unsaturated aldehydes can be obtained by a Horner-Wadsworth-Emmons type olefination reaction on a carbonyl derivative with triethyl phosphonoacetate, followed by a reduction of the ester function to aldehyde. Phenolic 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 by functionalization of a group already present on the aromatic system.

[0058] The reaction solvent may be chosen from toluene, xylene, benzene, dichloromethane, and acetic acid.

[0059] Other characteristics, variants and advantages of the method according to the invention will become more apparent on reading the following exemplary embodiments, given by way of illustration and not limitation of the invention. EXAMPLES

[0060] Toluene, acetonitrile, and benzene were distilled over calcium hydride before use and, if necessary, degassed by bubbling nitrogen gas through.

[0061] Analytical thin layer chromatographies (TLC) were performed on silica gel on aluminum plates (silica gel 60, F254, Merck) and visualized by exposure to ultraviolet light and / or exposure to basic potassium permanganate solution or p-anisaldehyde staining solution followed by heating.

[0062] Flash column chromatographies were carried out on silica 60 (40-63 qm).

[0063] Nuclear magnetic resonance spectra (H NMR and C NMR) were recorded at 25 °C with a Bruker Avance 400 spectrometer (400 MHz, H to 400 MHz, C NMR to 100 MHz) using CDCl as solvent referenced to residual CHCl (H = 7.26 ppm, C = 77.1 ppm). Chemical shifts are given in ppm and coupling constants (J) in Hertz. Data for H NMR spectra are reported as follows: chemical shift ppm (br s = broad singlet, s = singlet, d = doublet, t = triplet, q = quadruplet, dd = doublet of doublets, td = triplet of doublets, ddd = doublet of doublets of doublets, m = multiplet, coupling constants, integration).

[0064] Infrared spectra were recorded on a PerkinElmer FTIR spectrometer using the Attenuated Total Reflectance (ATR) technique. Absorption maxima (vmax) are reported in wavenumbers (cm1).

[0065] High resolution mass spectra (HRMS) were obtained on a JEOL JMS-GCmate II spectrometer and reported as m / z.

[0066] Static batch photochemical experiments were performed in a 500 mL immersion well or 10 mL sealed Pyrex tubes irradiated using a 150 W medium pressure Heraeus Hg lamp.

[0067] The flow photochemical experiments were carried out on a Vapourtec E-series system equipped with a UV-150 photoreactor provided with a medium pressure Hg lamp (75-150 W) used in combination with a Pyrex filter.

[0068] EXAMPLE 1: Synthesis of radulanin A (compound of formula I b-1) according to the process according to the present invention

[0069] Radulanin A was prepared according to a process in accordance with the present invention implementing a continuous flow photochemical rearrangement step according to the steps illustrated in the following scheme: [Chem 15]

[0070]

[0071] 1.1 First step: _ Preparation of (E)-3,5-dimethoxystilbene _ _(compound 3) The first step is a Homer-Wadsworth-Emmons reaction. To a flame-dried 500 mL flask equipped with a magnetic stir bar, under an inert atmosphere, was added potassium tert-butoxide (t-BuOK) (10.8 g, 96.3 mmol) and anhydrous tetrahydrofuran (THF) (120 mL). The mixture was cooled in an ice bath, then diethyl benzylphosphonate (compound 1) (20.6 mL, 90.3 mmol) was added dropwise over 30 minutes, followed by the portionwise addition of 3,5-dimethoxybenzaldehyde (compound 2) (10.0 g, 60.2 mmol). The mixture was allowed to warm to room temperature and then stirred for 2 h. The THF was removed in vacuo, and then a mixture of water and methanol (H2O:MeOH) (2:1, approximately 60 mL) was added until the product precipitated.Filtration and drying under vacuum gave (E)-3,5-dimethoxystilbene (compound 3) as a white solid (13.5 g, 56.0 mmol, 93% yield). 'H NMR (400 MHz, CDC13): ô = 7.53 - 7.49 (m, 2H), 7.39 - 7.33 (m, 2H), 7.29 - 7.23 (m, 1H), 7.09 (d, J = 16.3 Hz, 1H), 7.04 (d, J = 16.3 Hz, 1H), 6.69 - 6.66 (m, 2H), 6.40 (t, J = 2.3 Hz, 1H), 3.83 (s, 6H). L2. Second step: Preparation of L3-dimethoxy-5-phenethylbenzene (compound 4) The second step is a catalytic hydrogenation reaction of the double bond using ammonium formate. This avoids the use of of hydrogen gas. To a flame-dried 500 mL flask, (E)-3,5-dimethoxystilbene as prepared in the previous step (14.0 g, 58.2 mmol) and 10% Pd / C (1.40 g, 10% by weight) were added, followed by ethyl acetate (243 mL, 0.245 M). Ammonium formate (18.4 g, 291 mmol) was then added and the mixture was allowed to stir overnight at room temperature. The reaction mixture was then filtered through a pad of Celite and evaporated in vacuo. The remaining ammonium formate was precipitated by the addition of dichloromethane and the mixture was filtered again and then evaporated in vacuo to give the expected 1,3-dimethoxy-5-phenethylbenzene (compound 4) as a light yellow oil (12.7 g, 52.4 mmol, 90% yield). 'H NMR (400 MHz, CDC13): ô = 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).

[0072] L3. Third step: Preparation of dihydropinosylvin (compound 5) The third step is a demethylation of phenols in acidic aqueous medium. To a 250 mL flask equipped with a magnetic stir bar, 1,3-dimethoxy-5-phenethylbenzene as prepared in the previous step (2.03 g, 8.38 mmol) was added, followed by hydrobromic acid (HBr) (24.6 mL, 48% by weight in water) and glacial acetic acid (24.6 mL, HBr:AcOH 1:1 v / v, final concentration of 0.15 M). The reaction mixture was then heated at reflux for 4 h and allowed to cool 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 carbon, filtered and reduced in vacuo to give dihydropinosylvin as a white solid (1.68 g, 7.86 mmol, 94%). 'H NMR (400 MHz, CDC13): ô = 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).

[0073] 1.4 Fourth step: Preparation of 2,2-dimethyl-7-phenethyl-2H-chromen-5-ol (compound 6) To a sealed, flame-dried tube equipped with a magnetic stir bar under an inert atmosphere, dihydropinosylvin obtained in the previous step (4.00 g, 18.7 mmol - 1 equiv.) was added, followed by anhydrous toluene (0.1 M) and 3-methyl-2-butenal (prenal) (1.5 equiv.). Ethylenediammonium diacetate (EDDA, ​​5 mol%) was then added. The container was sealed and heated to 115°C for 1 h. This procedure (EDDA addition and heating) was repeated 3 times (totaling an addition of 15 mol% EDDA), then after returning to room temperature a small amount of silica was added and the solvent was removed under vacuum. The crude mixture was purified by flash silica column chromatography (dry loading), eluting with hexane / ethyl acetate to give 2,2-dimethyl-7-phenethyl-2H-chromen-5- ol (compound 6) expected as a viscous brown liquid (4.28 g, 15.3 mmol, 82% yield). 'H NMR (400 MHz, CDC13): ô = 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).

[0074] 1.5. Fifth step: Preparation of radulanin A (compound (I b -1)) by continuous flow photochemical rearrangement In a 1 L flame-dried flask under nitrogen atmosphere, a solution of compound 6 (200 mg, 0.713 mmol) as obtained in the previous step in nitrogen-degassed anhydrous acetonitrile (713 mL, 0.001 M) was prepared. The continuous flow system was first rinsed with degassed anhydrous acetonitrile, and then the solution of compound 6 was injected into the photochemical reactor equipped with a Pyrex filter at 100% lamp power (150 W), at a flow rate of 1.2 mL.min-1 (8.44 min residence time in the reactor), a pressure of 300 KPa and a reactor temperature of 30 °C. The collected solution was evaporated in vacuo and the crude mixture purified by flash column chromatography, eluting at 2-10% EtOAc:hexane to give radulanin A (compound of formula (Ib-1)) as a brown oil (52.2 mg, 0.186 mmol, 26%).

[0075] The NMR analysis of radulanin A is given below: 'H NMR (400 MHz, CDC13): ô = 7.32 - 7.24 and 7.22 - 7.14 (m, 5H), 6.53 (d, J = 1.5 Hz, 1H), 6.37 (d, J = 1.5 Hz, 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).

[0076] EXAMPLE 2: Synthesis of radulanine A (compound of formula I b -1) according to the process in accordance with the invention in static mode

[0077] Radulanin A was prepared according to the same steps as those illustrated in the synthesis scheme presented above in Example 1, but implementing a fifth step of photochemical rearrangement in static mode. To a sealed 10 mL flame-dried Pyrex tube equipped with a magnetic stir bar under an inert atmosphere, compound 5 (2.70 mg, 0.00963 mmol) as prepared above in step 4 of Example 1 and degassed dry benzene (9.00 mL, 0.001 M) were added. The tube was directly attached to the cooling sheath of a 150 W medium-pressure mercury lamp. The reaction mixture was irradiated for 1 hour with stirring. The solvent was evaporated in vacuo and the crude reaction mixture was subjected to *H NMR analysis, to reveal complete conversion of compound 5 to radulanin A.

[0078] 'H NMR (400 MHz, CDC13): ô = 7.32 - 7.24 and 7.22 - 7.14 (m, 5H), 6.53 (d, J = 1.5 Hz, 1H), 6.37 (d, J = 1.5 Hz, 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).

[0079] EXAMPLE 3: Synthesis of 3,8-dimethyl-2,5-dihy d robenzoxepin-6-ol (compound of formula I a-1 ) according to the process according to the invention in static mode

[0080] 3,8-Dimethyl-2,5-dihydrobenzoxepin-6-ol was prepared according to a process in accordance with the present invention implementing a continuous flow photochemical rearrangement step according to the steps illustrated in the following scheme: [Chem 16]

[0081] 3.1 First step: Preparation of 2,2,7-trimethyl-2H-chromen-5-ol (compound?) To a sealed, flame-dried tube equipped with a magnetic stir bar under an inert atmosphere was added orcinol (1 equiv.) followed by anhydrous toluene (0.1 M) and prenal (1.5 equiv.). Ethylenediammonium diacetate (EDDA, ​​5 mol%) was then added. The container was sealed and heated to 115 °C for 1 h. This procedure (addition of EDDA and heating) was repeated 3 times (totaling an addition of 15 mol% EDDA), then after returning to room temperature 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).

[0082] 'H NMR (400 MHz, CDC13): ô = 6.57 (d, J = 10.0, 1H), 6.26 - 6.24 (m, 1H), 6.14 -6.11 (m, 1H), 5.53 (d, J = 10.0 Hz, 1H), 4.60 (br s, 1H), 2.22 - 2.20 (m, 3H), 1.41 (s, 6H).

[0083] 3.2, Second step: Preparation of 3,8-dimethyl-2,5-dihydrobenzoxepin-6-ol (compound of formula I a-1 )

[0084] In a 500 mL immersion well equipped with a 150 W mercury lamp, a water cooling jacket and a magnetic stir bar, under an inert atmosphere, compound 7 obtained above in the previous step (75 mg, 0.394 mmol) and anhydrous benzene and degassed by bubbling nitrogen (250 mL, 0.00158 M) were introduced. The reaction mixture was stirred and irradiated for 30 minutes and then cooled. This procedure was repeated 10 times until the mixture had been irradiated for a total of 5 hours. The reaction mixture was then evaporated in a flask under vacuum, and the crude mixture was purified by flash column chromatography, eluting with hexane:CH2Cl2 1:1, to provide the expected compound of formula (Ia-1) as a yellow oil (35.3 mg, 0.185 mmol, 47%).

[0085] Rf = 0.19 (hexane / CH2Cl2 1:1)

[0086] RMN ‘H (400 MHz, CDC13) : ô = 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).

[0087] RMN 13C (101 MHz, CDC13) : ô = 159.7, 152.0, 137.4, 134.0, 120.7, 120.1, 114.5, 112.2, 74.3,21.6,21.0, 20.1.

[0088] IR (ATR) : 3350, 2931, 1715, 1619, 1583, 1450, 1378, 1311, 1207, 1068, 986, 836, 753.

[0089] HRMS (EI+) : Calculé pour Ci2H15O2+ : 191.1067; obtenu : 191.1064.

Claims

1. Claims Process for the synthesis of a compound of the following formula (Ia): [Chem 17] "2 -, R s ,1 / r1 ^ai R in which: - R1 represents a hydrogen atom or a C1-C6 alkyl radical, - R2, R3 and R4 represent, independently of each other, a hydrogen atom, a halogen atom, a C1-C5 alkyl or cycloalkyl radical, or a group chosen from -OH, -COOH, -COOR6, -OR6 and -SO2R6, with R6 being a C1-C5 alkyl or cycloalkyl radical, said C1-C5 alkyl or cycloalkyl radical possibly being substituted by one or more substituents chosen from a halogen atom and a hydroxyl group; - R5 represents a hydrogen atom, a halogen atom, a C1-C5 alkyl or cycloalkyl radical, or a group chosen from -OH, -COOH, -COOR6, -OR6 and -SO2R6, with R6 being a C1-C5 alkyl or cycloalkyl radical, said C1-C5 alkyl or cycloalkyl radical possibly being substituted by one or more substituents chosen from a halogen atom and a hydroxyl group, or R5 represents a -LA group in which: * L represents a linker arm chosen from linear and branched alkylene chains having at least one carbon atom, said linear or branched alkylene chains being able to be interrupted and / or terminated by one or more heteroatoms chosen from an oxygen, sulfur, and substituted nitrogen atom, and * A represents an aromatic group selected from phenyl, naphthyl, furyl, thiophenyl, pyrrolyl, pyridinyl, indolyl, isoindolyl, benzofuryl, benzothiophenyl, quinolyl, isoquinolyl, imidazolyl, oxazolyl, thiazolyl, pyrimidyl, pyridazyl, pyrazyl, pyrrazolyl, and triazolyl groups, said aromatic group A possibly being substituted by one or more substituents selected from a halogen atom, an alkyl or cycloalkyl radical in C1 to C5, an -OH group, a -COOH group, a -COOR7 group, an -OR7 group, and an -SO2R7 group, with R7 being a C1 to C5 alkyl or cycloalkyl radical, said C1 to C5 alkyl or cycloalkyl radical possibly being substituted by one or more substituents chosen from a halogen atom and a hydroxyl group or one of its organic and inorganic salts, and in which - at least of the groups R2, R3, R4 and R5 represent an -OH group, characterized in that said method comprises a step of irradiation with ultraviolet radiation of a solution in a solvent of a compound of the following formula (IIa): [Chem 18]

2.

3.

4.

5.

6.

7.

8. in which R1, R2, R3, R4, and R5 have the same meaning as indicated below for compounds of formula (Ia). Process according to claim 1, characterized in that the solvent of the solution is chosen from aromatic hydrocarbons, acetonitrile and ethyl acetate. Method according to claim 1 or 2, characterized in that it is carried out in static mode and that the duration of the irradiation step is 1 to 5 hours. Method according to claim 1 or 2, characterized in that it is carried out in continuous flow. Method according to claim 4, characterized in that the duration of the irradiation step is 5 to 20 minutes. Method according to any one of the preceding claims, characterized in that the irradiation step is carried out at a wavelength of 250 to 350 nm. Method according to any one of the preceding claims, characterized in that said at least one hydroxyl group is in position 6. A method according to any one of the preceding claims, characterized in that two of the other groups R2, R3, or R2 and R4 or R3 and R4 represent a hydrogen atom and R5 represents a -LA group.

9. Process according to any one of the preceding claims, characterized in that L represents a linear alkylene chain having from 2 to 3 carbon atoms.

10. 0 Process according to any one of the preceding claims, characterized in that A represents an aromatic group chosen from phenyl, thiophenyl, and pyridinyl groups.

11. 1 Process according to any one of the preceding claims, characterized in that said process is carried out for the preparation of a compound of the following formula (Ib): [Chem 19] .. R2 A / 4 ZE f / Z in which R1, R2, R3 R4, A and L have the same meaning as that indicated for the compounds of formula (Ia), and in that said compound of formula (II) subjected to said irradiation step corresponds to the following formula (IIb): [Chem 20] R2 XZ" ''û" 'CH. A----------L in which R1, R2, R3, R4, A and L have the same meaning as that indicated for the compounds of formula (Ia).

12. 2 Method according to claim 11, characterized in that the LA group is in position 8, L represents an ethylene chain and A is a phenyl ring.

13. 3 Process according to claim 11 or 12, characterized in that it is carried out for the preparation of radulanin A of formula (Ib-1) following: [Chem 21] (One-1).