Patent Application
20240279184
The present invention concerns heteroaromatic analogues of 3-benzylmenadione derivatives, as well as processes for their preparation.
Unsymmetrical methylene-linked biaryl systems are important building blocks in medicinal chemistry. When applied to the 3-benzylmenadione series, no general or versatile synthetic strategy has been developed. In 1991, a team from Takeda Pharmaceutical (formerly Takeda Chemical Industry) published the synthesis of numerous quinones bearing a 3-picolinyl group. One of these was the synthesis of 3-(3-picolinyl)menadione, one of the target molecules. This team inserted a bromomethyl or chloromethyl group in position 3 to achieve a direct coupling with a lithiated 3-pyridine (Ohkawa S, Terao S, Terashita Z-1, Shibouta Y, Nishikawa K. Dual inhibitors of thromboxane A2 synthase and 5-lipoxygenase with scavenging activity of active oxygen species (AOS). Synthesis of a novel series of (3-pyridylmethyl)benzoquinone derivatives. J. Med. Chem. 1991, 34, 267-276. doi: 10.1021/jm00105a042).
In the simple di(hetero)arylmethane series, benzyl halides were efficiently coupled with various aromatic and especially heteroaromatic boronic acids by a pallado-catalysed Suzuki coupling (Henry N, Enguehard-Gueiffier C, Thery I, Gueiffier A. One-Pot Dual Substitutions of Bromobenzyl Chloride, 2-Chloromethyl-6-halogenoimidazo[1,2-a]pyridine and —[1,2-b]pyridazine by Suzuki-Miyaura Cross-Coupling Reactions. Eur. J. Org. Chem. 2008, 4824-4827. doi: 10.1002/ejoc.200800544). But, no methylene-linked biaryl systems were built within the quinone series using the Suzuki coupling reaction.
The aim of the present invention is to provide new heteroaromatic analogues of 3-benzylmenadione derivatives that could be useful as ligands or components for active oxygen barriers in plastic polymers for food and drink preservation.
Another aim of the present invention is to provide new heteroaromatic analogues of 3-benzylmenadione derivatives that could be useful as therapeutic compounds.
Another aim of the present invention is also to provide a new efficient process for the preparation of heteroaromatic analogues of 3-benzylmenadione derivatives with a satisfying yield.
The present invention thus relates to a compound having the formula (1):
wherein:
According to the invention, R2 is an optionally substituted heteroaryl group as defined above being different from the following heteroaryl groups, optionally substituted:
According to an embodiment, R2 is an optionally substituted heteroaryl group as defined above being different from the following heteroaryl groups, optionally substituted:
The following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The expression “Ct-Cz” means a carbon-based chain which can have from t to z carbon atoms, for example C1-C3 means a carbon-based chain which can have from 1 to 3 carbon atoms.
The term “alkyl group” means: a linear or branched, saturated, hydrocarbon-based aliphatic group comprising, unless otherwise mentioned, from 1 to 6 carbon atoms. By way of examples, mention may be made of methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl or pentyl groups.
The term “aryl group” means: a cyclic aromatic group comprising between 6 and 10 carbon atoms. By way of examples of aryl groups, mention may be made of phenyl or naphthyl groups.
When an alkyl radical is substituted with an aryl group, the term “arylalkyl” or “aralkyl” radical is used. The “arylalkyl” or “aralkyl” radicals are aryl-alkyl-radicals, the aryl and alkyl groups being as defined above. Among the arylalkyl radicals, mention may in particular be made of the benzyl or phenethyl radicals.
The term “halogen” means: a fluorine, a chlorine, a bromine or an iodine.
The term “alkoxy group” means: an —O-alkyl radical where the alkyl group is as previously defined. By way of examples, mention may be made of —O—(C1-C4)alkyl groups, and in particular the —O-methyl group, the —O-ethyl group as —O—C3alkyl group, the —O-propyl group, the —O-isopropyl group, and as —O—C4alkyl group, the —O-butyl, —O-isobutyl or —O-tert-butyl group.
The term “haloalkyl group” means: an alkyl group as defined above, in which one or more of the hydrogen atoms is (are) replaced with a halogen atom. By way of example, mention may be made of fluoroalkyls, in particular CF3 or CHF2.
The term “haloalkoxy group” means: an —O-haloalkyl group, the haloalkyl group being as defined above. By way of example, mention may be made of fluoroalkyls, in particular OCF3 or OCHF2.
The abovementioned “alkyl” radicals can be substituted with one or more substituents. Among these substituents, mention may be made of the following groups: amino, hydroxyl, thiol, oxo, halogen, alkyl, alkoxy, alkylthio, alkylamino, aryloxy, arylalkoxy, cyano, trifluoromethyl, carboxy or carboxyalkyl.
The term “alkylthio” means: an —S-alkyl group, the alkyl group being as defined above.
The term “alkylamino” means: an —NH-alkyl group, the alkyl group being as defined above.
The term “aryloxy” means: an —O-aryl group, the aryl group being as defined above.
The term “arylalkoxy” means: an aryl-alkoxy-group, the aryl and alkoxy groups being as defined above.
The term “carboxyalkyl” means: an HOOC-alkyl-group, the alkyl group being as defined above. As examples of carboxyalkyl groups, mention may in particular be made of carboxymethyl or carboxyethyl.
The term “heteroalkyl group” means: an alkyl group as defined above, in which one or more of the carbon atoms is (are) replaced with a heteroatom, such as 0 or N.
The term “carboxyl” means: a COOH group.
The term “oxo” means: “═O”.
The term “heterocycloalkyl group” means: a 4- to 10-membered, saturated or partially unsaturated, monocyclic or bicyclic group comprising from one to three heteroatoms selected from O, S or N; the heterocycloalkyl group may be attached to the rest of the molecule via a carbon atom or via a heteroatom. As an example, one may cite oxetanyl.
According to an embodiment, in formula (1), R2 is a heteroaryl group comprising a 5- to 10-membered aromatic monocyclic or bicyclic group containing from 1 to 4 heteroatoms selected from O, S or N.
As examples of heteroaryl groups, mention may be made of imidazolyl, thiazolyl, oxazolyl, furanyl, thiophenyl, pyrazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl, benzothiazolyl, isobenzothiazolyl, benzotriazolyl, quinolinyl and isoquinolinyl groups.
By way of a heteroaryl comprising 5 to 6 atoms, including 1 to 4 nitrogen atoms, mention may in particular be made of the following representative groups: pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl and 1,2,3-triazinyl.
Mention may also be made, by way of heteroaryl, of thiophenyl, oxazolyl, furazanyl, 1,2,4-thiadiazolyl, naphthyridinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, cinnolinyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothiophenyl, thienopyridyl, thienopyrimidinyl, pyrrolopyridyl, imidazopyridyl, benzoazaindole, 1,2,4-triazinyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, purinyl, quinazolinyl, quinolinyl, isoquinolyl, 1,3,4-thiadiazolyl, thiazolyl, isothiazolyl, carbazolyl, and also the corresponding groups resulting from their fusion or from fusion with the phenyl nucleus.
According to an embodiment, the compounds of the invention are compounds having the formula (1) as defined above wherein R1 is H or F.
According to an embodiment, the compounds of the invention are compounds having the formula (1) as defined above wherein R2 is selected from the group consisting of: pyridinyl other than
pyrimidinyl other than
quinolinyl, thiophenyl, and furanyl groups, said groups being optionally substituted with at least one substituent selected from the group consisting of: halogen, amino, halo(C1-C6)alkyl, (C1-C6)alkoxy, —C≡C—, and CN.
According to an embodiment, the compounds of the invention are compounds having the formula (1) as defined above wherein R2 is selected from the group consisting of: pyridinyl, pyrimidinyl, quinolinyl, thiophenyl, and furanyl groups, said groups being optionally substituted with at least one substituent selected from the group consisting of: halogen, amino, halo(C1-C6)alkyl, (C1-C6)alkoxy, —C≡C—, and CN, wherein said pyridinyl has the following formula
and wherein said pyrimidinyl has the following formula:
According to an embodiment, the compounds of the invention are compounds having the formula (1) as defined above wherein R1 is H or F, and R2 is selected from the group consisting of: pyridinyl other than
pyrimidinyl other than
quinolinyl, thiophenyl, and furanyl groups, said groups being optionally substituted with at least one substituent selected from the group consisting of: halogen, amino, halo(C1-C6)alkyl, (C1-C6)alkoxy, —C≡C—, and CN.
As preferred compounds according to the invention, the followings may be mentioned:
The compounds of formula (1) according to the invention are for example used as drug-candidates or compounds with therapeutic properties, or as ligands or components for active oxygen barriers in plastic polymers for food and drink preservation.
The present invention also relates to a process for the preparation of a compound having the formula (1):
wherein:
said process comprising the preparation of a compound having the following formula (IV):
wherein:
by the chloromethylation or bromomethylation of a compound having the following formula (V):
wherein R1 is selected from the group consisting of: H, F, (C1-C6)alkoxy, and halo(C1-C6)alkyl.
Depending on the nature of the R2 group, the compounds of formula (I) may be further submitted to a post-functionalization step, especially for modifying the nature of the possible substituent present on the heteroaryl group.
According to an embodiment, the chloromethylation or bromomethylation step as defined above is carried out with a mixture of hydrochloric acid or hydrobromic acid with paraformaldehyde (or aqueous formaldehyde) in the presence of a solvent selected from the group consisting of: water, acetic acid, and dioxane.
Preferably, the chloromethylation or bromomethylation step is carried out in a mixture of hydrochloric acid or hydrobromic acid and paraformaldehyde.
According to an embodiment, the chloromethylation or bromomethylation step is carried out for a duration comprised from one hour to 24 hours, preferably for 3 hours.
According to an embodiment, the chloromethylation or bromomethylation step is carried out at a temperature comprised from 20° C. to 100° C., preferably at 80° C.
Preferably, the chloromethylation or bromomethylation step mentioned above is a chloromethylation step. Therefore, preferably, the obtained compounds from the compounds of formula (V) as defined above are compounds having the following formula (IV-1):
R1 being as defined above in formula (IV).
Preferably, the chloromethylation step is carried out in a mixture of hydrochloric acid and paraformaldehyde.
According to an embodiment, the chloromethylation step is carried out for a duration comprised from one hour to 24 hours, preferably for 3 hours when R1 is H, or 18 hours R1 is F.
According to an embodiment, the chloromethylation step is carried out at a temperature comprised from 20° C. to 100° C., preferably at 80° C. when R1 is H, or 60° C. when R1 is F.
According to an embodiment, the process of the invention further comprises the pallado-catalyzed Suzuki coupling of the compound of formula (IV) as defined above with a boronic acid compound having the formula (III) or (III′):
wherein R2 is as defined above in formula (I), in order to obtain a compound having the following formula (II):
R1 and R2 being as defined above in formula (1).
According to an embodiment, the pallado-catalyzed coupling is carried out with a palladium catalyst selected from the group consisting of: Pd(PPh3)4, PdCl2, PdCl2(dppf), Pd(OAc)2 and PPh3, and with a base selected from the group consisting of: Na2CO3, K2CO3, KOtBu, Cs2CO3, NaOH, and NEt3, or with K3PO4 in toluene.
Preferably, the pallado-catalyzed coupling is carried out with a palladium catalyst being Pd(PPh3)4, and with a base being Na2CO3.
Preferably, the amount of palladium catalyst is comprised from 2 to 5% in moles in comparison with the number of moles of compound of formula (IV) or (IV-1).
Preferably, the amount of base is comprised from 2 to 5 equivalents, and is preferably 2.1 equivalents.
According to an embodiment, the pallado-catalyzed coupling is carried out in the presence of a solvent selected from the group consisting of: dimethoxyethane (DME)/water, tetrahydrofuran (THF)/water, dioxane/water, dimethylformamide (DMF)/water, toluene/water, preferably in a mixture DME/water.
According to an embodiment, the pallado-catalyzed coupling is carried out for a duration comprised from 30 minutes to 6 hours, preferably for 1 hour.
According to an embodiment, the pallado-catalyzed coupling is carried out at a temperature comprised from 70° C. to 150° C., preferably at 100° C.
According to an embodiment, the process of the invention further comprises an oxidative demethylation step of the compound of formula (II) as defined above in the presence of an oxidant, in order to obtain the compound of formula (1) as defined above.
Preferably, the oxidant is selected from the group consisting of: ceric ammonium nitrate (CAN), silver oxide (AgO/Ag2O), OsO4/NalO4, oxone, BBr3 with O2 or open air, and boron trichloride/Tetra-n-butylammonium iodide (BCl3/TBAI) with O2 or open air.
According to an embodiment, the oxidative demethylation step is carried out in the presence of a solvent selected from the group consisting of: a mixture of acetonitrile and water, dichloromethane for BBr3 or BCl3/TBAI, preferably in a mixture of acetonitrile and water.
According to an embodiment, the oxidative demethylation step is carried out for a duration comprised from 10 minutes to 6 hours, preferably for 1 hour.
According to an embodiment, the oxidative demethylation step is carried out at a temperature comprised from 4° C. to 50° C., preferably at room temperature (22-25° C.).
According to an embodiment of the process according to the invention, the compound of formula (V) is prepared by reacting a compound having the following formula (VI):
The compound of formula (V) as defined above is thus obtained from the compound of formula (VI) by the implementation of a reduction step, followed by a methylation step.
According to an embodiment, the reducing agent is selected from the group consisting of: SnCl2 and HCl, and sodium dithionite.
According to an embodiment, the reduction step is carried out in the presence of a solvent selected from the group consisting of: MeOH, EtOH, or MeOH/water, EtOH/water for sodium dithionite, preferably in ethanol or methanol.
According to an embodiment, the reduction step is carried out for a duration comprised from one hour to 4 hours, preferably for 2 hours.
According to an embodiment, the reduction step is carried out at a temperature comprised from 15° C. to 50° C., preferably at room temperature (22-25° C.).
According to an embodiment, the methylation step is carried out with a methylation agent, said methylation agent being selected from the group consisting of: Me2SO4, and ICH3.
According to an embodiment, the methylation step is carried out in the presence of a solvent being acetone.
According to an embodiment, the methylation step is carried out in the presence of a base selected from the group consisting of NaOH, and KOH.
According to an embodiment, the methylation step is carried out for a duration comprised from one hour to 16 hours, preferably for 4 hours.
According to an embodiment, the methylation step is carried out at a temperature comprised from 40° C. to 60° C., preferably at 60° C.
According to an embodiment, R2 is selected from the group consisting of: pyridinyl, pyrimidinyl, quinolinyl, thiophenyl, and furanyl groups, said groups being optionally substituted with at least one substituent selected from the group consisting of: halogen, halo(C1-C6)alkyl, (C1-C6)alkoxy, and CN.
According to an embodiment, R1 is H or F.
The present invention also relates to a compound having the following formula (II):
wherein:
As compounds of formula (II), the followings may be mentioned:
The present invention also relates to a compound having the following formula
As compounds of formula (IV), the followings may be mentioned:
The present invention also relates to a compound having the following formula
As compounds of formula (V), the followings may be mentioned:
Heteroarylboronic acids and reactants were purchased from commercial sources, such as Fluorochem, Sigma-Aldrich and Alfa Aesar. 1,4-dimethoxy-2-methylnaphthalene and 6-fluoro-1,4-dimethoxy-2-methylnaphthalene were synthetized according to a previously published method (T. Mller, L. Johann, B. Jannack, M. Bruckner, D. A. Lanfranchi, H. Bauer, C. Sanchez, V. Yardleyll, C. Deregnaucourt, J. Schrevel, M. Lanzer, R. H. Schirmer, E. Davioud-Charvet, J. Am. Chem. Soc. 2011, 133, 30, 11557-11571). The 6-fluoro-1,4-dimethoxy-2-methylnaphthalene was synthesized from the 6-fluoro-menadione, prepared according to Cesar Rodo E., Feng L., Jida, M., Ehrhardt K., Bielitza M., Boilevin J., Lanzer M., Williams D. L., Lanfranchi, D. A., Davioud-Charvet, E. A platform of regioselective methodologies to access to polysubstituted 2-methyl-1,4-naphthoquinones derivatives: scope and limitations. Eur. J. Org. Chem. 2016, 11, 1982-1993. doi: 10.1002/ejoc.201600144.
The compounds of formula (1) according to the invention are prepared according to the following general scheme:
The compounds of formula (II) wherein R1═H are prepared according to the following reaction scheme:
1,4-dimethoxy-2-methylnaphthalene (1 equiv., 4 g, 19.8 mmol), paraformaldehyde (5 equiv., 3.13 g, 2.89 mL, 98.9 mmol) and 37% C, aqueous HCl (50 mL) were heated at 80° C. during 2 h. The OMe mixture was cooled down, diluted with water and extracted three times with EtOAc. The reunited organic layers were washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The crude oil was purified by silica gel chromatography using 8:2 Cyclohexane:Toluene as eluant system to afford 4.086 g (81% yield) of 2-(chloromethyl)-1,4-dimethoxy-3-methylnaphthalene as a colorless oil which crystallized on standing. 1H NMR (400 MHz, CDCl3) δ 8.17-8.00 (m, 2H), 7.64-7.41 (m, 2H), 4.92 (s, 2H), 4.04 (s, 3H), 3.89 (s, 3H), 2.54 (s, 3H).
In a sealable tube, 2-(chloromethyl)-1,4-dimethoxy-3-methylnaphthalene (1 equiv), the corresponding heteroarylboronic acid (1.2 equiv) and sodium carbonate (2.1 equiv) were dissolved in a 2:1 mixture of dimethoxyethane:water (0.15M). The mixture was bubbled 30 min with argon, and then tetrakis(triphenylphosphine)palladium (2-5 mol %) was added at once. The tube was sealed and the mixture was heated 1 h at 100° C. under stirring. The mixture was then, allowed to cool down to room temperature, diluted with water and extracted three times with ethyl acetate. Reunited organic layers were washed with brine, dried over magnesium sulfate and the solvent was removed under reduced pressure to afford a crude, which was purified on silica gel chromatography using the adequate eluant system to afford the corresponding coupling product.
5 mol % Pd(PPh3), Eluant Cyclohexane:Ethyl acetate (7:3), yellowish solid, 97% yield. 1H NMR (500 MHz, CDCl3) δ 8.92 (d, J=2.3 Hz, 1H), 8.17-8.10 (m, 2H), 8.07 (dd, J=8.4, 1.0 Hz, 1H), 7.69-7.59 (m, 3H), 7.58-7.50 (m, 2H), 7.46 (ddd, J=8.1, 6.7, 1.2 Hz, 1H), 4.44 (s, 2H), 3.87 (s, 6H), 2.29 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 151.95, 150.90, 150.77, 146.96, 133.87, 133.49, 129.24, 128.85, 128.36, 128.30, 127.90, 127.58, 127.38, 126.73, 126.19, 125.81, 122.69, 122.46, 62.58, 61.61, 30.50, 12.89. HRMS (ESI) calcd. for C23H22NO2: 344.1645. Found: 344.1659 (MH+).
5 mol % Pd(PPh3), Eluant Cyclohexane:Ethyl acetate (1:1), yellowish solid, 71% yield. 1H NMR (500 MHz, CDCl3) δ 8.50N (dd, J=2.3, 1.0 Hz, 1H), 8.41 (dd, J=4.8, 1.6 Hz, 1H), 8.12-8.04 (m, 2H), 7.63-7.42 (m, 2H), 7.39-7.32 (m, 1H), 7.13 (ddd, J=7.8, 4.8, 0.9 Hz, 1H), 4.25 (s, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 2.26 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 150.75, 150.70, 149.92, 147.50, 136.08, 135.67, 128.28, 128.00, 127.30, 126.64, 126.12, 125.77, 123.55, 122.60, 122.43, 62.45, 61.58, 30.28, 12.83. HRMS (ESI) calcd. for C19H20NO2: 294.1489. Found: 294.1490 (MH+).
5 mol % Pd(PPh3), Eluant Cyclohexane:Ethyl acetate (1:1), N beige solid, 87% yield. 1H NMR (500 MHz, CDCl3) δ 9.04 (s, IN 1H), 8.54 (s, 2H), 8.13-7.98 (m, 2H), 7.61-7.41 (m, 2H), 4.22 (s, 2H), 3.88 (s, 3H), 3.86 (s, 3H), 2.29 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 156.91, 156.77, 150.91, 150.80, 133.90, 128.49, 127.29, 126.68, 126.40, 125.99, 122.62, 122.52, 62.46, 61.66, 28.10, 12.92. HRMS (ESI) calcd. for C18H19N2O2: 295.1441. Found: 295.1450 (MH+).
5 mol % Pd(PPh3), Eluant Cyclohexane:Ethyl acetate (9:1), translucid oil, 97% yield. 1H NMR (500 MHz, CDCl3) δ 8.64 (d, J=1.4 Hz, 1H), 8.16-8.04 (m, 2H), 7.61-7.46 (m, 4H), 4.31 (s, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 150.81, 150.77, 150.08, 145.99 (q, J=34.6 Hz), 139.66, 136.79, 128.42, 127.24, 127.05, 126.29, 126.17, 125.88, 122.55, 121.78 (q, J=273.7 Hz), 120.31 (q, J=2.7 Hz), 62.33, 61.50, 30.13, 12.77. 19F NMR (471 MHz, CDCl3) δ−67.68. HRMS (ESI) calcd. for C20H19F3NO2: 362.1362. Found: 362.1368 (MH+).
2 mol % Pd(PPh3), Eluant Cyclohexane:Ethyl acetate (9:1), white solid, 89% yield. 1H NMR (400 MHz, CDCl3) δ 7.94-7.70 (m, 3H), 7.40-7.19 (m, 3H), 6.54 (ddd, J=8.4, 3.1, 0.6 Hz, 1H), 3.98 (s, 1H), 3.63 (s, 3H), 3.61 (s, 3H), 2.03 (s, 3H). 19F NMR (377 MHz, CDCl3) δ−72.09 (d, J=8.0 Hz). 13C NMR (101 MHz, CDCl3) δ 162.42 (d, J=237.2 Hz), 150.78, 150.65, 146.98 (d, J=14.4 Hz), 141.02 (d, J=7.6 Hz), 133.65 (d, J=4.5 Hz), 128.33, 127.92, 127.29, 126.39, 126.21, 125.84, 122.59, 122.46, 109.33 (d, J=37.4 Hz), 62.43, 61.58, 29.38 (d, J=1.5 Hz), 12.78. HRMS (ESI) calcd. for C19H19FNO2: 312.1394. Found: 312.1403 (MH+).
5 mol % Pd(PPh3), Eluant Cyclohexane:Ethyl acetate (9:1), white solid, 87% yield. 1H NMR (400 MHz, CDCl3) δ 8.19 (dd, J=2.6, 0.8 Hz, 1H), 8.07-7.91 (m, 2H), 7.51-7.38 (m, 2H), 7.26 (dd, J=8.2, 2.5 Hz, 1H), 7.08 (dd, J=8.2, 0.7 Hz, 1H), 4.13 (s, 2H), 3.78 (s, 3H), 3.77 (s, 3H), 2.18 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 150.80, 150.72, 149.55, 149.22, 138.71, 135.12, 128.38, 127.56, 127.28, 126.34, 126.27, 125.88, 124.18, 122.60, 122.48, 62.46, 61.60, 29.57, 12.82. HRMS (ESI) calcd. for C19H19ClNO2: 328.1099. Found: 328.1102 (MH+).
2 mol % Pd(PPh3), Eluant Cyclohexane:Ethyl acetate (8:2), white solid, 97% yield. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 2H), 8.13-8.00 (m, 2H), 7.61-7.43 (m, 2H), 4.18 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 2.29 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.40, 150.96, 150.73, 132.58, 128.54, 127.23, 126.50, 126.22, 126.05, 125.67, 122.59, 122.52, 62.42, 61.63, 27.32, 12.90. HRMS (ESI) calcd. for C18H18ClN2O2: 329.1051. Found: 329.1054 (MH+).
2 mol % Pd(PPh3), Eluant Cyclohexane:Ethyl acetate (8:2), white solid, 71% yield. 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 2H), 8.23-7.97 (m, 2H), 7.68-7.33 (m, 2H), 4.28 (s, 2H), 3.90 (s, 3H), 3.86 (s, 3H), 2.30 (s, 3H). 19F NMR (377 MHz, CDCl3) δ−70.15. HRMS (ESI) calcd. for C17H12F3N2O2: 333.0845. Found: 333.0868 (MH+).
2 mol % Pd(PPh3)4, Eluant Cyclohexane:Ethyl acetate (95:5), translucid oil, 69% yield. 1H NMR (400 MHz, CDCl3) δ 8.14-8.04 (m, 2H), 8.02-7.94 (m, 1H), 7.58-7.44 (m, 2H), 7.32 (dd, J=8.5, 2.6 Hz, 1H), 6.61 (dd, J=8.6, 0.7 Hz, 1H), 4.16 (s, 2H), 3.89 (s, 3H), 3.85 (s, 3H), 3.85 (s, 3H), 2.28 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.80, 150.63, 150.59, 146.04, 138.87, 128.68, 128.57, 128.16, 127.33, 126.73, 125.98, 125.67, 122.57, 122.39, 110.72, 62.43, 61.55, 53.41, 29.37, 12.75. HRMS (ESI) calcd. for C20H22NO3: 324.1594. Found: 324.1617 (MH+).
2 mol % Pd(PPh3)4, Eluant Cyclohexane:Ethyl acetate (60:40), translucid oil, 71% yield. 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 2H), 8.18-7.95 (m, 2H), 7.60-7.44 (m, 2H), 4.13 (s, 2H), 3.95 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 2.30 (s, 3H). HRMS (ESI) calcd. for C19H20N2NaO3: 347.1366. Found: 347.1357 (MNa+).
2 mol % Pd(PPh3)4, Eluant Cyclohexane:Ethyl acetate (99:1 up to 98:2), translucid oil, 99% yield. 1H NMR (400 MHz, CDCl3) δ 8.19-8.03 (m, 2H), 7.62-7.46 (m, 2H), 7.34 (dd, J=1.8, 0.9 Hz, 1H), 6.27 (dd, J=3.2, 1.9 Hz, 1H), 5.85 (dq, J=3.2, 1.1 Hz, 1H), 4.27 (s, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 2.41 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 154.30, 150.68, 150.37, 141.15, 128.18, 127.29, 127.06, 126.87, 125.98, 125.54, 122.62, 122.31, 110.37, 105.90, 62.63, 61.46, 26.34, 12.45. HRMS (ESI) calcd. for C18H19O3: 283.1329. Found: 283.1334 (MH+).
To a solution of sodium cyanide (2 equiv., 44.7 mg, 0.912 mmol) and DABCO (0.2 equiv., 10.8 mg, 0.0912 mmol), in a mixture of DMSO (1.5 mL) and water (0.2 mL), 2-chloro-5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)pyrimidine (1 eq., 150 mg, 0.456 mmol) in DMSO (1.5 mL) was added dropwise and the reaction mixture was stirred at 50° C. 20 h. After TLC analysis showed complete conversion, the mixture was allowed to cool down to room temperature and was extracted twice with diethyl ether. The reunited organic layers were washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography was performed using 75:25 Cyclohexane:Ethyl Acetate as eluant system to afford 122 mg (84% yield) of 5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)pyrimidine-2-carbonitrile as white solid. 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 2H), 8.16-7.97 (m, 2H), 7.63-7.43 (m, 2H), 4.27 (s, 2H), 3.90 (s, 3H), 3.86 (s, 3H), 2.29 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 157.79, 151.07, 150.80, 143.08, 137.17, 128.69, 127.21, 126.68, 126.19, 125.51, 125.46, 122.60, 122.58, 115.87, 62.40, 61.68, 28.33, 12.98. HRMS (ESI) calcd. for C17H12N3O2: 290.0924. Found: 290.0918 (MH+).
To a solution of 2-chloro-5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)pyrimidine (1 equiv., 150 mg, 0.456 mmol) in propionitrile (1.5 mL) was added trimethylbromosilane (2 equiv., 139 mg, 0.12 mL, 0.912 mmol). A white precipitate appeared. The mixture was heated at reflux 5 h and allowed to cool down to room temperature. The mixture was treated with an aqueous saturated sodium bicarbonate solution. The aqueous layer was extracted three times with ethyl acetate, the reunited organic layers were washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography was performed using 95:5 Toluene:Ethyl Acetate as eluant system to afford 160 mg (94% yield) of 2-bromo-5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)pyrimidine as a translucid solid. m.p: 99-100° C. 1H NMR (500 MHz, CDCl3) δ 8.37 (s, 2H), 8.11-7.98 (m, 2H), 7.65-7.47 (m, 2H), 4.16 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 2.29 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 159.33, 150.97, 150.80, 150.74, 133.07, 128.55, 127.23, 126.52, 126.13, 126.07, 125.67, 122.61, 122.54, 62.44, 61.66, 27.39, 12.92. HRMS (ESI) calcd. for C16H12BrN2O2: 343.0077. Found: 343.0099 (MH+).
2 mol % Pd(PPh3), Eluant Cyclohexane:Ethyl acetate (8/2), white solid, 80% yield. 1H NMR (400 MHz, CDCl3) δ 8.04-8.00 (m, 2H), 7.99 (s, 2H), 7.57-7.51 (m, 2H), 6.45 (s, 2H), 3.97 (s, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.7, 157.8 (2C), 150.34, 150.30, 129.1, 127.8, 127.1, 126.7, 126.5, 126.3, 122.7, 122.5, 121.5, 62.6, 61.6, 26.8, 12.9. HRMS (ESI+) calcd. for C18H20N3O2: 310.1550. Found: 310.1539 (MH+). M. p.=198-200° C.
2 mol % Pd(PPh3), Eluant cyclohexane/ethyl acetate (8/2) then pentane/diethyl ether (gradient from 9/1 to 0/1), colourless oil, 55% yield. 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.09 (dd, J=9.2, 5.6 Hz, 1H), 7.66 (dd, J=10.3, 2.5 Hz, 1H), 7.53 (d, J=1.4 Hz, 2H), 7.28 (ddd, J=9.2, 8.3, 2.6 Hz, 1H), 4.30 (s, 2H), 3.84 (s, 6H), 2.24 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.4, 159.9, 151.0 (d, 5JC-F=1.3 Hz), 150.3 (d, 4JC-F=5.4 Hz), 150.1, 146.2 (q, 2JC-F=34.7 Hz), 140.0-138.9 (m), 136.8, 128.6, 128.3 (d, 3JC-F=8.6 Hz), 125.5 (d, 3JC-F=7.2 Hz), 125.4 (d, 3JC-F=9.0 Hz), 121.8 (q, 1JC-F=273.7 Hz), 120.4 (q, 4JC-F=2.7 Hz), 116.6 (d, 2JC-F=25.4 Hz), 106.4 (d, 2JC-F=22.4 Hz), 62.3, 61.7, 30.3, 12.7. 19F NMR (377 MHz, CDCl3): δ−67.71, −114.25 (ddd, J=10.1, 8.4, 5.6 Hz). HRMS (ESI+) calcd. for C20H18F4NO2: 380.126818. Found: 380.125589 (MH+).
2 mol % Pd(PPh3), Eluant cyclohexane/ethyl acetate (7/3) then pentane/diethyl ether (7/3), colourless oil, 83% yield. 1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.10 (dd, J=9.2, 5.6 Hz, 1H), 7.84 (d, J=8.2 Hz, 2H), 7.70 (dd, J=10.4, 2.5 Hz, 1H), 7.34-7.25 (m, 2H), 4.43 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 2.27 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.0 (d, 1JC-F=245.2 Hz), 150.8 (d, 5JC-F=1.1 Hz), 150.2 (d, 4JC-F=5.3 Hz), 139.0, 130.3, 128.4, 128.3, 126.4 (2C), 126.2 (d, 4JC-F=2.4 Hz), 125.23, 125.17 (d, 3JC-F=8.9 Hz), 122.7, 121.7 (2C), 116.1 (d, 2JC-F=25.4 Hz), 106.3 (d, 2JC-F=22.3 Hz), 62.3, 61.6, 32.8, 12.7. 19F NMR (377 MHz, CDCl3): δ-114.78 (ddd, J=10.2, 8.5, 5.7 Hz). HRMS (ESI+) calcd. for C21H19FNO2S: 368.111504. Found: 368.110660 (MH+).
2 mol % Pd(PPh3), Eluant cyclohexane/ethyl acetate (7/3) then pentane/diethyl ether (7/3), white solid, 81% yield. 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.22-8.04 (m, 2H), 7.89 (s, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.60-7.48 (m, 2H), 7.31 (d, J=8.2 Hz, 1H), 4.46 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 2.31 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 154.3, 153.8, 150.7, 150.5, 139.2, 131.3, 128.8, 128.1, 127.3, 126.9, 126.3, 125.9, 125.5, 122.7, 122.5, 122.3, 121.6, 62.4, 61.5, 32.7, 12.8. HRMS (ESI+) calcd. for C21H20NO2S: 350.120926. Found: 350.120240 (MH+). M.p.=139-141° C.
2 mol % Pd(PPh3), Eluant cyclohexane/ethyl acetate (8/2), colourless oil, 91% yield. 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.14-8.10 (m, 2H), 8.03 (d, J=8.4 Hz, 1H), 7.59 (s, 1H), 7.55-7.51 (m, 2H), 7.41-7.37 (m, 1H), 4.43 (s, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 2.28 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 153.5, 151.8, 150.8, 150.7, 138.6, 134.3, 128.9, 128.3, 127.4, 127.2, 127.0, 126.1, 125.7, 123.4, 122.7, 122.4, 120.8, 62.5, 61.6, 32.8, 12.9. HRMS (ESI+) calcd. for C21H20NO2S: 350.120926. Found: 350.121033 (MH+).
2 mol % Pd(PPh3), Eluant cyclohexane/ethyl acetate (8/2), colourless oil, 62% yield. 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.11 (dd, J=9.2, 5.6 Hz, 1H), 8.04 (br d, J=4.4 Hz, 1H), 7.71 (dd, J=10.4, 2.5 Hz, 1 H), 7.61 (s, 1H), 7.38 (br d, J=2.8 Hz, 1H), 7.28 (td, J=8.8, 2.5 Hz, 1H), 4.41 (s, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.0 (d, 1JC-F=245.4 Hz), 153.8, 152.2, 150.8 (d, 4JC-F=1.2 Hz), 150.2 (d, 3JC-F=5.3 Hz), 138.2, 134.7, 130.4, 128.3 (d, 3JC-F=8.6 Hz), 127.1, 126.2 (d, 4JC-F=2.5 Hz), 125.3, 125.2, 123.4, 120.7, 116.2 (d, 2JC-F=25.4 Hz), 106.4 (d, 2JC-F=22.3 Hz), 62.3, 61.7, 32.9, 12.7. 19F NMR (CDC3, 377 MHz): δ-114.66 (ddd, J=10.2, 8.4, 5.7 Hz). HRMS (ESI+) calcd. for C21H9NO2S: 368.111504. Found: 368.111827 (MH+).
7 mol % Pd(PPh3), Eluant ethyl acetate, orange solid, 72% yield. 1H NMR (400 MHz, CDCl3) δ 8.08 (tdd, J=5.3, 4.0, 3.2 Hz, 2H), 7.91 (s, 1H), 7.74-7.61 (m, 2H), 7.15 (dd, J=8.5, 2.3 Hz, 1H), 6.38 (d, J=8.4 Hz, 1H), 4.36 (s, 2H), 4.10 (s, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 2.28 (s, 3H). 13C {1H} NMR (101 MHz, CDCl3) δ 171.2, 156.7, 150.4, 147.1, 137.9, 128.6, 128.5, 125.8, 125.5, 122.4, 122.2, 108.8, 62.3, 61.4, 29.3, 12.6.
To a solution of oxetan-3-ol (110 μL, 1.73 mmol, 5.0 equiv.) in anhydrous DMSO (800 μL), NaH (42 mg, 1.73 mmol, 5.0 equiv.) was added portion-wise under argon atmosphere. The mixture was stirred until homogenous and was added dropwise to a solution of 5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)-2-fluoropyridine (108 mg, 0.35 mmol, 1.0 equiv.) in anhydrous DMSO (500 μL), in a sealed tube, and stirred for 18 h at room temperature under argon atmosphere. The reaction mixture was quenched with a 1 M aqueous solution of hydrochloric acid and diluted with dichloromethane. The layers were separated and the aqueous layer was extracted twice with dichloromethane. The organic phase was washed with water, brine, dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (Cyclohexane/ethyl acetate, 8/2, v/v, UV) to afford 64 as a colourless oil (64 mg, 50%). 1H NMR (CDC3, 400 MHz): δ 8.12-8.04 (m, 2H), 7.88 (d, J=1.8 Hz, 1H), 7.53-7.46 (m, 2H), 7.37 (dd, J=8.5, 2.4 Hz, 1H), 6.66 (d, J=8.5 Hz, 1H), 5.55 (p, J=5.8 Hz, 1H), 4.95 (t, J=7.0 Hz, 2H), 4.71 (dd, J=7.6, 5.6 Hz, 2H), 4.15 (s, 2H), 3.86 (d, J=1.4 Hz, 6H), 2.28 (s, 3H). 13C {1H}NMR (CDCl3, 126 MHz): δ 160.9, 150.6, 150.5, 146.1, 139.2, 129.3, 128.4, 128.2, 127.3, 126.6, 126.0, 125.7, 122.5, 122.4, 110.7, 78.4 (2C), 69.0, 62.4, 61.5, 29.4, 12.7. HRMS (ESI+) calcd. for C22H24NO4: 366.169985. Found: 366.169403 (MH+).
In a flame-dried tube was added 2-chloro-5-((1,4-dimethoxy-3-methylnaphthalen-2-yl)methyl)pyrimidine (100 mg, 0.304 mmol, 1 equiv.), oxetan-3-ol (39 μL, 0.608 mmol, 2 equiv.), anhydrous THF (1.5 mL) and potassium tert-butoxide (68.3 mg, 0.608 mmol, 2 equiv.). The tube was sealed and the mixture stirred at room temperature during 3 hours. The mixture was diluted with water addition and extracted three times with ethyl acetate. The crude residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 1/1, v/v, UV) to afford 65 (82 mg, 74%) as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ 8.29 (s, 2H), 8.11-8.03 (m, 2H), 7.55-7.47 (m, 2H), 5.53 (q, J=6.2 Hz, 1H), 4.96-4.89 (m, 2H), 4.76 (dd, J=8.0, 5.5 Hz, 2H), 4.12 (s, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 2.30 (s, 3H). 13C {1H} NMR (CDCl3, 101 MHz): δ 162.9, 159.2 (2C), 150.9, 150.6, 128.4, 127.7, 127.3, 127.2, 126.3, 125.98, 125.95, 122.6, 122.5, 78.0 (2C), 70.1, 62.4, 61.6, 27.1, 12.9. HRMS (ESI+) calcd. for C21H23N2O4: 367.165324. Found: 367.165015 (MH+).
In a flame-dried tube was added 36 (92 mg, 0.27 mmol, 1 equiv.), oxetan-3-ol (34 μL, 0.53 mmol, 2 equiv.), anhydrous THF (1.3 mL) and potassium tert-butoxide (60 mg, 0.53 mmol, 2 equiv.). The tube was sealed and the mixture stirred at room temperature overnight. The mixture was diluted with water addition and extracted three times with ethyl acetate. The crude residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 1/1, v/v, UV) to afford MR00331 (85 mg, 83%) as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ 8.28 (s, 2H), 8.07 (dd, J=9.2, 5.5 Hz, 1H), 7.64 (dd, J=10.3, 2.5 Hz, 1H), 7.27 (ddd, J=9.2, 8.3, 2.6 Hz, 1H), 5.53 (p, J=6.0 Hz, 1H), 4.92 (t, J=7.1 Hz, 2H), 4.76 (dd, J=7.8, 5.6 Hz, 2H), 4.10 (s, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 2.27 (s, 3H). 13C {1H} NMR (CDCl3, 101 MHz): δ 162.9, 161.1 (d, 1JC-F=245.9 Hz), 159.1 (2C), 151.0 (d, 5JC-F=1.3 Hz), 150.1 (d, 4JC-F=5.4 Hz), 128.7, 128.3 (d, 3JC-F=8.7 Hz), 127.4, 125.44 (d, 5JC-F=1.1 Hz), 125.36 (d, 3JC-F=8.9 Hz), 125.2 (d, 4JC-F=2.5 Hz), 116.6 (d, 2JC-F=25.4 Hz), 106.4 (d, 2JC-F=22.4 Hz), 77.9 (2C), 70.1, 62.3, 61.8, 27.2, 12.7. 19F NMR (CDCl3, 377 MHz): δ-114.23 (ddd, J=10.1, 8.4, 5.6 Hz). HRMS (ESI+) calcd. for C21H22FN2O4: 385.155812. Found: 385.156295 (MH+).
In a flame-dried tube was added 34 (83 mg, 0.25 mmol, 1 equiv.), oxetan-3-ol (32 μL, 0.50 mmol, 2 equiv.), anhydrous THF (1.3 mL) and potassium tert-butoxide (56 mg, 0.50 mmol, 2 equiv.). The tube was sealed and the mixture stirred at 55° C. overnight. The mixture was diluted with water addition and extracted three times with ethyl acetate. The crude residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 8/2, v/v, UV) to afford MR00340 (74 mg, 77%) as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ 8.07 (dd, J=9.2, 5.6 Hz, 1H), 7.86 (d, J=1.9 Hz, 1H), 7.66 (dd, J=10.4, 2.5 Hz, 1H), 7.36 (dd, J=8.5, 2.4 Hz, 1H), 7.29-7.22 (m, 1H), 6.67 (d, J=8.5 Hz, 1H), 5.55 (p, J=5.8 Hz, 1H), 4.95 (t, J=7.0 Hz, 2H), 4.74-4.67 (m, 2H), 4.13 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 2.26 (s, 3H). 13C {1H} NMR (CDCl3, 101 MHz): δ 161.0 (d, 1JC-F=245.4 Hz), 160.9, 150.8 (d, 5JC-F=1.2 Hz), 150.0 (d, 4JC-F=5.4 Hz), 146.0, 139.2, 130.0, 129.0, 128.30, 128.27 (d, 3JC-F=8.6 Hz), 125.8 (d, 4JC-F=2.5 Hz), 125.21 (d, 3JC-F=8.8 Hz), 125.20, 116.2 (d, 2JC-F=25.4 Hz), 110.8, 106.3 (d, 2JC-F=22.3 Hz), 78.4 (2C), 69.0, 62.2, 61.6, 29.4, 12.6. 19F NMR (CDCl3, 377 MHz): δ-114.64 (ddd, J=10.2, 8.4, 5.7 Hz). HRMS (ESI+) calcd. for C22H23FNO4: 384.160563. Found: 384.161191 (MH+).
In a flame dried sealable tube, under argon, to a solution of 33 (100 mg, 0.27 mmol, 1 equiv.) in triethylamine (8.5 mL) was added dichlorobis(triphenylphosphine)palladium(II) (11.9 mg, 0.017 mmol, 0.05 equiv.) followed by iodocopper (6.5 mg, 0.034 mmol, 0.1 equiv.). The mixture reaction was degassed with argon before the addition of ethynyl(trimethyl)silane (0.14 mL, 1.018 mmol, 3 equiv.). The tube was sealed and stirred at 70° C. for 24 hours. At room temperature, the mixture reaction was quenched with a solution of brine and water (1/1, v/v). The resulting aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography on silica gel (cyclohexane/toluene, 8/2, v/v, UV) to afford 68′ (104 mg, 99% yield) as a brown oil. 1H NMR (CDCl3, 400 MHz): δ 8.49 (s, 2H), 8.13-8.03 (m, 2H), 7.58-7.47 (m, 2H), 4.21 (s, 2H), 3.85 (s, 3H), 3.85 (s, 3H), 2.26 (s, 3H), 0.27 (s, 9H). 13C {1H} NMR (CDCl3, 101 MHz): δ 157.0 (2C), 150.9, 150.8, 150.4, 132.8, 128.5, 127.2, 126.4, 126.3, 125.9, 125.8, 122.6, 122.5, 102.4, 93.8, 62.4, 61.6, 28.0, 12.9, 1.1 (3C). HRMS (ESI+) calcd. for C23H27SiN2O2: 391.183631. Found: 391.181585 (MH+).
To a solution of 68′ (324 mg, 0.83 mmol, 1 equiv.) in THF (4.2 mL) was added dropwise a solution of tetra-n-butylammonium fluoride (602 mg, 1.91 mmol, 2.3 equiv.) in THF (4.2 mL). The reaction mixture was stirred at room temperature for 1.5 h. The mixture was quenched with a saturated aqueous solution of NH4Cl. The aqueous layers were extracted three times with diethyl ether. The organic extracts were dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 95/5, v/v, UV) to afford BDU0090 (163 mg, 62% yield) as a brown oil. 1H NMR (CDCl3, 400 MHz): δ 8.50 (s, 2H), 8.18-7.96 (m, 2H), 7.61-7.44 (m, 2H), 4.21 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.07 (s, 1H), 2.27 (s, 3H). 13C {1H} NMR (CDCl3, 101 MHz): δ 157.1, 150.9, 150.8, 150.0, 133.3, 128.5, 127.2, 126.4, 126.2, 126.0, 125.8, 122.6, 122.5, 81.9, 75.4, 62.4, 61.6, 28.1, 12.9. HRMS (ESI+) calcd. for C20H19N2O2: 319.144104. Found: 319.143171 (MH+).
The compounds of formula (1) wherein R1═H or F are prepared according to the following reaction scheme:
Suzuki coupling derivative (1 equiv) was dissolved in stirring acetonitrile. Then, at room temperature, CAN (2.1 equiv) dissolved in water was added drop by drop (ratio ACN/H2O 3:1, 0.05M). The mixture was stirred at room temperature during 1 h. Then after TLC analysis showed complete conversion, the aqueous layer was extracted three times with dichloromethane. Combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification by silica gel chromatography was performed using the adequate eluent.
Eluant Cyclohexane:Ethyl acetate (1:1), yellow solid, 74% yield. 1H NMR (400 MHz, CDCl3) δ 8.54-8.51 (m, 1H), 8.43 (dd, J=4.8, 1.6 Hz, 1H), 8.16-7.97 (m, 2H), 7.70 (dd, J=5.8, 3.3 Hz, 2H), 7.54 (ddd, J=7.9, 2.4, 1.6 Hz, 1H), 7.18 (ddd, J=7.8, 4.8, 0.9 Hz, 1H), 4.01 (s, 2H), 2.25 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 185.16, 184.56, 150.05, 148.02, 144.83, 144.37, 136.22, 133.93, 133.78, 133.76, 132.16, 131.98, 126.61, 126.51, 123.69, 30.00, 13.44. HRMS (ESI) calcd. for C17H14NO2: 264.1019. Found: 264.1018 (MH+).
Eluant Cyclohexane:Ethyl acetate (1:1), yellow solid, 86% yield. 1H NMR (400 MHz, CDCl3) δ 8.87 (d, J=2.2 Hz, 1H), 8.14-8.06 (m, 2H), 8.05 (dd, J=8.5, 1.0 Hz, 1 H), 7.92 (dd, J=2.3, 1.0 Hz, 1H), 7.75-7.68 (m, 3H), 7.64 (ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.49 (ddd, J=8.1, 6.8, 1.2 Hz, 1H), 4.20 (s, 2H), 2.31 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 185.20, 184.58, 151.69, 147.08, 144.91, 144.38, 134.76, 133.80, 133.78, 132.19, 132.02, 131.12, 129.29, 129.20, 128.14, 127.57, 126.94, 126.65, 126.54, 30.19, 13.58. HRMS (ESI) calcd. for C21H16NO2: 314.1176. Found: 314.1177 (MH+).
Eluant Cyclohexane:Ethyl acetate (1:1), yellow solid, 88% yield. 1H NMR (500 MHz, CDCl3) δ 9.04 (s, 1H), 8.64 (s, 2H), 8.10-7.98 (m, 2H), 7.76-7.61 (m, 2H), 3.98 (s, 2H), 2.27 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 184.80, 184.28, 157.22, 157.01, 145.07, 143.18, 133.96, 133.89, 132.05, 132.01, 131.79, 126.62, 27.82, 13.53. HRMS (ESI) calcd. for C16H13N2O2: 265.0972. Found: 265.0982 (MH+).
Eluant Cyclohexane:Ethyl acetate (8:2), yellow solid, 87% yield. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=2.2 Hz, 1H), 8.20-7.97 (m, 2H), 7.89-7.68 (m, 3H), 7.58 (dd, J=8.1, 0.8 Hz, 1H), 4.09 (s, 2H), 2.28 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 184.92, 184.43, 150.31, 146.62 (q, J=34.8 Hz), 145.23, 143.50, 137.47, 137.40, 133.99, 133.92, 132.11, 131.86, 126.66, 126.64, 121.62 (q, J=279.6 Hz), 120.54 (q, J=2.7 Hz), 30.00, 13.56. 19F NMR (471 MHz, CDCl3) δ−67.81. HRMS (ESI) calcd. for C18H13F3NO2: 332.0893. Found: 332.0915 (MH+).
Eluant Cyclohexane:Ethyl acetate (8:2), yellow solid, 97% yield. 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J=2.6 Hz, 1H), 8.08 (ddd, J=7.4, 5.8, 3.3 Hz, 2H), 7.72 (dd, J=5.8, 3.3 Hz, 2H), 7.67 (td, J=8.1, 2.6 Hz, 1H), 6.84 (dd, J=8.4, 3.0 Hz, 1H), 4.00 (s, 2H), 2.27 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 185.12, 184.59, 162.61 (d, J=238.4 Hz), 147.46 (d, J=14.7 Hz), 144.83, 144.17, 141.52 (d, J=7.8 Hz), 133.91, 133.86, 132.15, 131.95, 131.52 (d, J=4.7 Hz), 126.64, 126.60, 109.63 (d, J=37.5 Hz), 29.15, 13.45. 19F NMR (377 MHz, CDCl3) δ−70.88 (d, J=7.7 Hz). HRMS (ESI) calcd. for C17H13FNO2: 282.0925. Found: 282.0920 (MH+).
Eluant Cyclohexane:Ethyl acetate (8:2), yellow solid, 99% yield. 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J=2.5 Hz, 1H), 8.11-7.96 (m, 2H), 7.75-7.63 (m, 2H), 7.51 (dd, J=8.2, 2.6 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 3.97 (s, 2H), 2.25 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 184.98, 184.45, 149.79, 149.75, 144.92, 143.86, 139.11, 133.88, 133.82, 132.87, 132.08, 131.86, 126.59, 126.55, 124.33, 29.30, 13.45. HRMS (ESI) calcd. for C17H13ClNO2: 298.0629. Found: 298.0648 (MH+).
Eluant Cyclohexane:Ethyl acetate (7:3), yellow solid, 93% yield. 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 2H), 8.20-7.92 (m, 2H), 7.85-7.57 (m, 2H), 3.96 (s, 2H), 2.29 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 184.58, 184.14, 159.74, 159.58, 145.09, 142.64, 133.97, 133.89, 131.93, 131.63, 130.56, 126.58, 126.55, 27.06, 13.49. HRMS (ESI) calcd. for C16H12ClN2O2: 299.0582. Found: 299.0596 (MH+).
Eluant Cyclohexane:Ethyl acetate (8:2), yellow solid, 3 95% yield. 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 2H), 8.25-8.01 (m, 2H), 7.84-7.65 (m, 2H), 4.08 (s, 2H), 2.32 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 184.63, 184.23, 158.01, 155.31 (q, J=37.1 Hz), 145.49, 142.43, 134.44, 134.19, 134.08, 132.06, 131.72, 126.77, 126.73, 119.66 (q, J=275.1 Hz), 27.91, 13.68. 19F NMR (377 MHz, CDCl3) δ−70.23. HRMS (ESI) calcd. for C17H12F3N2O2: 333.0845. Found: 333.0868 (MH+).
Eluant Cyclohexane:Ethyl acetate (90:10), yellow solid, 87% yield. m.p: 120-121° C. 1H NMR (400 MHz, CDCl3) δ 8.11-7.95 (m, 3H), 7.67 (dd, J=5.8, 3.3 Hz, 2H), 7.50 (dd, J=8.6, 2.5 Hz, 21), 6.67 (d, J=8.6 Hz, 1H), 3.91 (s, 2H), 3.88 (s, 3H), 2.24 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 185.19, 184.61, 162.78, 145.90, 144.66, 144.43, 139.91, 133.70, 133.67, 132.11, 131.97, 126.66, 126.52, 126.43, 111.02, 53.79, 29.03, 13.31. HRMS (ESI) calcd. for C18H15NO3: 294.112470. Found: 294.112517 (MH+).
Eluant Cyclohexane:Ethyl acetate (70:30), yellow solid, 74% yield. m.p: 161-162° C. 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 2H), 8.10-7.96 (m, 2H), 7.67 (dd, J=5.8, 3.3 Hz, 2H), 3.92 (s, 3H), 3.87 (s, 2H), 2.25 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 184.91, 184.33, 164.61, 159.22, 144.51, 143.77, 133.81, 133.76, 132.01, 131.82, 126.51, 126.48, 124.86, 54.91, 26.75, 13.37. HRMS (ESI) calcd. for C17H15N2O3: 295.107719. Found: 295.108670 (MH+).
Eluant Cyclohexane:Ethyl acetate (98:2), orange solid, 74% yield. m.p: 83-84° C. 1H NMR (400 MHz, CDCl3) δ 8.21-7.95 (m, 1H), 7.86-7.58 (m, 1H), 7.27 (dd, J=1.9, 0.9 Hz, OH), 6.26 (dd, J=3.2, 1.9 Hz, OH), 6.07 (dd, J=3.2, 0.9 Hz, OH), 4.03 (s, 1H), 2.28 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 185.34, 184.06, 151.27, 145.02, 142.41, 141.62, 133.62, 133.58, 132.21, 132.05, 126.56, 126.41, 110.55, 106.79, 25.57, 13.11.
m.p.=96-97° C. 1H NMR (CDCl3, 400 MHz): δ 8.11-8.03 (m, 2H), 7.71-7.65 (m, 2H), 7.11 (dd, J=4.5, 1.8 Hz, 1H), 6.89 (d, J=4.5 Hz, 2H), 4.18 (s, 2H), 2.29 (s, 3H). 13C NMR (CDCl3, 101 MHz): 5 185.3, 184.2, 144.4, 144.1, 139.9, 133.61, 133.59,132.1,132.0, 126.9, 126.5, 126.4, 125.8, 124.2, 27.0, 13.1. HRMS calculated for C16H12NaO2S [M+Na]+: 291.045021. Found 291.045521.
Eluant Cyclohexane:Ethyl acetate (7:3), yellow solid, 87% yield. 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 2H), 8.10-7.99 (m, 2H), 7.81-7.61 (m, 2H), 4.06 (s, 2H), 2.31 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 184.50, 184.17, 158.11, 145.67, 143.40, 142.05, 135.19, 134.23, 134.09, 132.00, 131.62, 126.77, 126.69, 115.68, 28.20, 13.72. HRMS (ESI) calcd. for C17H12N3O2: 290.0924. Found: 290.0918 (MH+).
Eluant Cyclohexane:Ethyl acetate (75:25), yellow solid, 96% yield. m.p: 165-166° C. 1H NMR (400 MHz, CDCl3) 5 8.48 (s, 2H), 8.11-8.00 (m, 2H), 7.80-7.60 (m, 2H), 3.94 (s, 2H), 2.28 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 184.67, 184.23, 159.56, 151.26, 145.20, 142.67, 134.09, 134.00, 132.03, 131.73, 131.14, 126.69, 126.66, 27.24, 13.61. HRMS (ESI) calcd. for C16H12BrN2O2: 343.0077. Found: 343.0099 (MH+).
46 was isolated by purification by flash chromatography on silica gel (dichloromethane/methanol, 9/1, v/v, UV) with 60% yield as an orange solid. 1H NMR (CDCl3, 500 MHz): δ 8.12 (s, 2H), 8.01-7.96 (m, 2H), 7.84-7.80 (m, 2H), 6.46 (s, 2H), 3.73 (s, 2H), 2.18 (s, 3H). 13C {1H} NMR (CDCl3, 126 MHz): δ 184.6, 184.2, 162.4, 144.8, 143.8, 133.9, 133.8, 131.7, 131.5, 125.9, 125.8, 119.5, 26.1, 13.0. HRMS (ESI+) calcd. for C16H14N3O2: 290.1081. Found: 280.1081 (MH+). M.p.=degradation after 200° C.
47 was isolated by purification by flash chromatography on silica gel (cyclohexane/ethyl acetate, 7/3 then pentane/diethyl ether, 8/2, v/v, UV) with 61% yield as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.65 (s, 1H), 8.13 (dd, J=8.5, 5.2 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.70 (dd, J=8.5, 2.5 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.37 (td, J=8.3, 2.4 Hz, 1H), 4.09 (s, 2H), 2.29 (s, 3H). 13C {1H} NMR (CDCl3, 101 MHz): δ 183.6, 183.4, 166.2 (d, 1JC-F=257.5 Hz), 150.5, 146.7 (q, 2JC-F=34.9 Hz), 145.5, 143.6 (d, 5JC-F=1.6 Hz), 137.5, 137.2, 134.4 (d, 3JC-F=7.9 Hz), 130.0 (d, 3JC-F=8.9 Hz), 128.7 (d, 4JC-F=3.2 Hz), 121.6 (q, 1JC-F=273.7 Hz), 121.2 (d, 2JC-F=22.5 Hz), 120.6 (d, 4JC-F=2.2 Hz), 113.4 (d, 2JC-F=23.5 Hz), 30.2, 13.7. 19F NMR (CDCl3, 377 MHz): δ-67.80, −101.84 (td, J=8.2, 5.3 Hz). HRMS (ESI+) calcd. for C18H12F4NO2: 350.079868. Found: 350.079641 (MH+). M.p.=122-124° C.
48 was isolated by purification by flash chromatography on silica gel (cyclohexane/ethyl acetate, 7/3, v/v, UV) and by recrystallization in ethanol with 91% yield as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 9.04 (s, 1H), 8.13 (dd, J=8.5, 5.2 Hz, 1H), 7.95 (s, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.72 (dd, J=8.5, 2.5 Hz, 1H), 7.46-7.30 (m, 2H), 4.20 (s, 2H), 2.29 (s, 3H). 13C {1H} NMR (CDCl3, 101 MHz): δ 184.0, 183.6, 166.1 (d, 1JC-F=256.9 Hz), 155.3, 154.2, 145.2 (d, 5JC-F=1.8 Hz), 145.2, 136.5, 134.7 (d, 3JC-F=7.9 Hz), 132.4, 129.8 (d, 3JC-F=8.8 Hz), 128.8 (d, 4JC-F=3.2 Hz), 126.8, 123.1, 122.2, 120.9 (d, 2JC-F=22.6 Hz), 113.3 (d, 2JC-F=23.5 Hz), 32.4, 13.6. 19F NMR (CDCl3, 377 MHz): δ-102.4 (td, J=8.3, 5.3 Hz). HRMS (ESI+) calcd. for C19H13FNO2S: 338.064554. Found: 338.063505 (MH+). M.p.=109-111° C.
49 was isolated by purification by flash chromatography on silica gel (cyclohexane/ethyl acetate, 8/2, v/v, UV). 1H NMR (CDCl3, 400 MHz): δ 8.97 (s, 1H), 8.06 (dt, J=5.7, 3.1 Hz, 2H), 7.95 (s, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.83-7.57 (m, 1H), 7.36 (d, J=8.1 Hz, 2H), 4.18 (s, 2H), 2.27 (s, 3H). 13C {1H} NMR (CDCl3, 101 MHz): δ 185.3, 184.6, 154.8, 153.9, 145.0, 144.8, 136.6, 133.6 (2C), 132.1 (2C), 132.0, 126.7, 126.5, 126.4, 123.1, 122.0, 32.3, 13.4. HRMS (ESI+) calcd. for C19H13NNaO2S: 342.055920. Found: 342.055527 (MNa+). M.p.=148-149° C.
50 was isolated by solubilisation in ethanol with 85% yield as a yellow solid. 1H NMR (CD3OD, 400 MHz): δ 8.47 (s, 1H), 8.36 (dd, J=9.1, 1.8 Hz, 1H), 8.12-8.04 (m, 2H), 7.82-7.75 (m, 2H), 7.42 (d, J=9.0 Hz, 1H), 5.48 (ddt, J=9.6, 6.9, 2.6 Hz, 1H), 4.97 (dd, J=12.3, 9.8 Hz, 1H), 4.82 (dd, d apparent because of HDO peak, J=7.0 Hz, 1H), 4.13 (s, 2H), 4.03 (dd, J=13.1, 2.4 Hz, 1H), 3.80 (dd, J=13.1, 2.9 Hz, 1H), 2.31 (s, 3H). 13C {1H} NMR (CD3OD, 101 MHz): δ 185.9, 185.6, 161.1, 150.6, 147.3, 143.4, 137.8, 135.0, 134.9, 133.4, 133.1, 132.4, 127.3, 127.2, 111.0, 86.2, 62.4, 53.2, 29.7, 13.4. H RMS (ESI+) calcd. for C20H18NO4: 336.123034 Found: 336.123633 (MH+). M.p.=125-127° C.
51 was isolated by purification by flash chromatography on silica gel (cyclohexane/ethyl acetate, 8/2, v/v, UV) with 78% yield as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.95 (s, 1H), 8.15-8.06 (m, 2H), 8.04 (d, J=8.3 Hz, 1H), 7.81 (s, 1H), 7.71 (dd, J=5.7, 3.3 Hz, 2H), 7.42 (d, J=7.8 Hz, 1H), 4.19 (s, 2H), 2.29 (s, 3H). 13C {1H} NMR (CDCl3, 101 MHz): δ 185.3, 184.7, 154.3, 152.4, 144.9, 144.7, 135.9, 134.8, 133.65, 133.64, 132.1, 132.0, 127.3, 126.6, 126.4, 123.6, 121.5, 32.4, 13.5. HRMS (ESI+) calcd. for C19H14NO2S: 320.074032 Found: 320.074032 (MH+). M.p.=146-147° C.
52 was isolated by purification by flash chromatography on silica gel (cyclohexane/ethyl acetate, 8/2, v/v, UV) as a yellow solid with 42% yield. 1H NMR (CDCl3, 500 MHz): δ 8.96 (s, 1H), 8.13 (dd, J=8.6, 5.2 Hz, 1H), 8.04 (d, J=7.5 Hz, 1H), 7.80 (s, 1H), 7.73 (dd, J=8.6, 2.6 Hz, 1H), 7.44-7.34 (m, 2H), 4.17 (s, 2H), 2.29 (s, 3H). 13C {1H} NMR (CDCl3, 126 MHz): δ 184.0, 183.7, 166.1 (d, 1JC-F=257.0 Hz), 154.4, 152.2, 145.18, 145.17, 145.1, 135.8, 134.6 (d, 3JC-F=7.8 Hz), 129.8 (d, 3JC-F=8.8 Hz), 128.8 (d, 4JC-F=3.1 Hz), 127.3, 123.8, 121.6, 120.9 (d, 2JC-F=22.5 Hz), 113.4 (d, 2JC-F=23.5 Hz), 32.6, 13.6. 19F NMR (CDCl3, 377 MHz): δ-102.28 (td, J=8.2, 5.3 Hz). HRMS (ESI+) calcd. for C19H13FNO2S: 338.064554 Found: 338.064817 (MH+). M.p.=170-172° C.
53 was isolated after precipitation in dichloromethane with 39% yield as a yellow solid. 1 H NMR (DMSO-d6, 400 MHz): δ 9.24 (d, J=2.5 Hz, 1H), 9.04 (d, J=2.4 Hz, 1H), 8.07-7.95 (m, 2H), 7.90-7.82 (m, 2H), 5.45 (ddt, J=9.7, 6.9, 3.2 Hz, 1H), 4.88 (dd, J=12.7, 9.8 Hz, 1H), 4.65 (dd, J=12.7, 7.1 Hz, 1H), 4.09 (s, 2H), 3.88 (dd, J=13.0, 2.5 Hz, 1H), 3.74 (dd, J=13.0, 3.7 Hz, 1H), 2.21 (s, 3H). 13C {1H} NMR (DMSO-d6, 101 MHz): δ 184.4, 183.7, 169.3, 159.7, 148.0, 146.0, 141.1, 134.1, 134.0, 131.8, 131.5, 127.0, 126.0, 83.6, 60.7, 50.8, 25.9, 13.2. HRMS (ESI+) calcd. for C19H17N2O4: 337.118684 Found: 337.118684 (MH+). M.p.=degradation after 165° C.
54 was isolated after precipitation in dichloromethane with 98% yield as a yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ9.23 (d, J=2.5 Hz, 1H), 9.02 (d, J=2.3 Hz, 1H), 8.14 (dd, J=9.3, 5.4 Hz, 1H), 7.72 (ddd, J=8.8, 6.2, 2.7 Hz, 2H), 5.45 (ddt, J=9.9, 6.8, 3.2 Hz, 1H), 4.86 (dd, J=12.6, 9.8 Hz, 1H), 4.64 (dd, J=12.7, 7.1 Hz, 1H), 4.09 (s, 2H), 3.88 (dd, J=13.0, 2.5 Hz, 1H), 3.73 (dd, J=13.0, 3.7 Hz, 1H), 2.21 (s, 3H). 13C {1H}NMR (DMSO-d6, 101 MHz): δ 183.2, 182.7 (d, 4JC-F=1.2 Hz), 169.4, 165.3 (d, 1JC-F=254.0 Hz), 159.7, 148.0, 146.3, 141.3 (d, 5JC-F=1.8 Hz), 134.3 (d, 3JC-F=7.9 Hz), 129.7 (d, 3JC-F=9.2 Hz), 128.8 (d, 4JC-F=3.0 Hz), 126.8, 121.2 (d, 2JC-F=22.6 Hz), 112.4 (d, 2JC-F=23.4 Hz), 83.7, 60.7, 50.8, 26.0, 13.2. 19F NMR (CD3OD, 377 MHz): δ-105.18 (td, J=8.6, 5.3 Hz). HRMS (ESI+) calcd. for C19H16FN2O4: 355.108862 Found: 355.107660 (MH+). M.p.=degradation after 165° C.
0 55 was isolated by purification by flash chromatography on silica gel (ethyl acetate) with 68% yield as an orange solid. 1H NMR (400 MHz, CDCl3) δ 8.08 (dt, J=5.9, 3.0 Hz, 2H), 7.95 (s, 1H), 7.76-7.60 (m, 2H), 7.35 (dd, J=8.5, 2.3 Hz, 1H), 6.44 (d, J=8.5 Hz, 1H), 4.59 (s, 2H), 3.86 (s, 2H), 2.26 (s, 3H). 13C {1H} NMR (101 MHz, CDCl3) δ 185.3, 184.7, 156.8, 146.6, 144.9, 144.2, 138.9, 133.6, 132.1, 131.9, 126.4, 126.3, 109.1, 28.9, 13.2.
56 was isolated by purification by flash chromatography on silica gel (cyclohexane/ethyl acetate, 8/2, v/v, UV) as an orange solid with 70% yield. 1H NMR (CDCl3, 500 MHz): δ 8.63 (s, 2H), 8.13-7.99 (m, 2H), 7.81-7.61 (m, 2H), 3.99 (s, 2H), 3.09 (s, 1H), 2.28 (s, 3H). 13C {1H} NMR (CDCl3, 126 MHz): δ 184.8, 184.3, 157.4 (2C), 150.5, 145.3, 142.8, 134.1, 134.0, 132.1, 131.8, 131.4, 126.7 (2C), 81.7, 75.9, 27.9, 13.6. HRMS (ESI+) calcd. For C18H13N2O2: 289.097154 Found: 289.096682 (MH+). M.p.=160-162° C.
The compounds of formula (II) wherein R1═F are prepared according to the following reaction scheme:
According to the previously published method (T. Mller, L. Johann, B. Jannack, M. Bruckner, D. A. Lanfranchi, H. Bauer, C. Sanchez, V. Yardleyll, C. Deregnaucourt, J. Schrevel, M. Lanzer, R. H. Schirmer, E. Davioud-Charvet, J. Am. Chem. Soc. 2011, 133, 30, 11557-11571), this compound was purified by flash chromatography on silica gel (Toluene, UV) with 63% yield (beige solid). m.p.=52-53° C. 1H NMR (CDCl3, 400 MHz): δ 8.07 (dd, J=9.2, 5.6 Hz, 1H), 7.88 (dd, J=10.6, 2.7 Hz, 1H), 7.32 (ddd, J=9.2, 8.3, 2.7 Hz, 1H), 6.64 (s, 1H), 3.95 (s, 3H), 3.89 (s, 3H), 2.48 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 160.4 (d, 1JC-F=243.9 Hz), 150.9 (d, 4JC-F=5.1 Hz), 147.1 (d, 5JC-F=1.4 Hz), 126.1 (d, 3JC-F=8.8 Hz), 125.8 (d, 5JC-F=0.8 Hz), 124.8 (d, 4JC-F=2.5 Hz), 124.2 (d, 3JC-F=8.7 Hz), 116.3 (d, 2JC-F=25.2 Hz), 108.0, 106.3 (d, 2JC-F=22.5 Hz), 61.2, 55.5, 16.1. 19F NMR (CDCl3, 377 MHz): δ-116.24 (ddd, J=10.3, 8.4, 5.5 Hz). HRMS calculated for C13H14FO2 [M+H]+: 221.097234. Found 221.097121.
A solution of 6-fluoro-1,4-dimethoxy-2-methylnaphthalene (250 mg, 1.14 mmol, 1 eq) and paraformaldehyde (538 mg, 17.03 mmol, 15 eq) in 37% aqueous hydrochloric acid (9 mL) was stirred at 60° C. overnight. The reaction mixture was cooled down, diluted with water, and extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (Toluene/cyclohexane, 9/1, v/v, UV) to afford the expected product (200 mg, 66%, white solid). m.p.=100-102° C. 1H NMR (CDCl3, 400 MHz): δ 8.07 (dd, J=9.2, 5.5 Hz, 1H), 7.68 (dd, J=10.2, 2.5 Hz, 1H), 7.29 (ddd, J=9.2, 8.2, 2.6 Hz, 1H), 4.89 (s, 2H), 4.02 (s, 3H), 3.87 (s, 3H), 2.52 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 161.1 (d, 1JC-F=246.0 Hz), 150.9 (d, 4JC-F=5.4 Hz), 150.7 (d, 5JC-F=1.3 Hz), 128.2 (d, 3JC-F=8.7 Hz), 128.0, 126.3 (d, 5JC-F=0.6 Hz), 125.6 (d, 4JC-F=2.5 Hz), 125.3 (d, 3JC-F=8.8 Hz), 117.1 (d, 2JC-F=25.3 Hz), 106.7 (d, 2JC-F=22.4 Hz), 63.1, 61.6, 38.9. 19F NMR (CDCl3, 377 MHz): δ-114.27 (m). HRMS calculated for C14H15CIFO2 [M+H]+: 269.073912. Found 269.073883.
In a flame dried sealable tube, under argon, 2-(chloromethyl)-6-R-1,4-dimethoxy-2-methylnaphthalene (1 eq), boronic acid (1.2 eq), sodium carbonate (2.1 eq) were introduced successively in a mixture of dimethoxyethane and water (ratio 2/1, v/v). The solvent was degassed and tetrakis(triphenylphosphine)palladium (0.02 eq) was added in the solution. The tube was sealed and stirred at 100° C. for 1 h. The reaction mixture was diluted with water and extracted 3 times with dichloromethane. The organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel to afford the expected product.
This compound was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, 9/1, v/v, UV) with 71% yield (colourless oil). 1H NMR (CDCl3, 400 MHz): δ 8.10 (dd, J=9.3, 5.7 Hz, 1H), 8.07 (s, 1H), 7.69 (dd, J=10.3, 2.5 Hz, 1H), 7.52 (td, J=8.2, 2.3 Hz, 1H), 7.28 (td, J=9.2, 2.6 Hz, 1H), 6.80 (dd, J=8.4, 2.9 Hz, 1H), 4.22 (s, 2H), 3.86 (d, J=1.7 Hz, 6H), 2.27 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 162.4 (d, 1JC-F=237.3 Hz), 161.0 (d, 1JC-F=246.4 Hz), 150.9 (d, 5JC-F=2.0 Hz), 150.1 (d, 4JC-F=5.4 Hz), 146.9 (d, 3JC-F=14.5 Hz), 141.0 (d, 3JC-F=7.7 Hz), 133.3 (d, 4JC-F=4.6 Hz), 129.4, 128.3 (d, 3JC-F=8.7 Hz), 125.6 (d, 4JC-F=2.5 Hz), 125.3, 125.2 (d, 3JC-F=9.1 Hz), 116.3 (d, 2JC-F=25.4 Hz), 109.3 (d, 2JC-F=37.5 Hz), 106.3 (d, 2JC-F=22.4 Hz), 62.2, 61.6, 29.4, 12.6. 19F NMR (CDCl3, 377 MHz): δ-114.42 (ddd, J=10.1, 8.4, 5.7 Hz). HRMS calculated for C1H18F2NO2 [M+H]+: 330.130012. Found 330.131085.
This compound was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, 4/1, v/v, UV) with 70% yield (white solid). m.p.=132-134° C. 1H NMR (CDCl3, 400 MHz): δ68.60 (d, J=1.36 Hz, 1H), 8.08 (dd, J=9.2, 5.6 Hz, 1H), 7.65 (dd, J=10.3, 2.5 Hz, 1H), 7.59-7.45 (m, 2H), 7.32-7.23 (m, 1H), 4.29 (s, 2H), 3.91-3.79 (m, 6H), 2.23 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 161.1 (d, 1JC-F=246.1 Hz), 151.3, 151.0 (d, 5JC-F=1.3 Hz), 150.2 (d, 4JC-F=5.4 Hz), 140.3, 136.5, 131.6, 128.4, 128.22 (d, 3JC-F=8.7 Hz), 128.15, 125.5 (d, 5JC-F=1.1 Hz), 125.4 (d, 3JC-F=8.9 Hz), 125.2 (d, 4JC-F=2.5 Hz), 117.4, 116.6 (d, 2JC-F=25.4 Hz), 106.3 (d, 2JC-F=22.4 Hz), 62.2, 61.7, 30.6, 12.7. 19F NMR (CDCl3, 377 MHz): δ-114.04 (ddd, J=10.1, 8.4, 5.6 Hz). HRMS calculated for C20H18FN2O2[M+H]+: 337.134682. Found 337.135223.
This compound was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, 4/1, v/v, UV) with 70% yield (white solid). m.p.=139-141° C. 1H NMR (CDCl3, 400 MHz): δ8.41 (s, 2H), 8.06 (dd, J=9.2, 5.6 Hz, 1H), 7.63 (dd, J=10.2, 2.5 Hz, 1H), 7.26 (td, J=8.8, 2.6 Hz, 1H), 4.15 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 2.25 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 161.1 (d, 1JC-F=246.2 Hz), 159.4, 159.3 (2C), 151.1 (d, 4JC-F=1.3 Hz), 150.1 (d, 4JC-F=5.4 Hz), 132.3, 128.2 (d, 3JC-F=8.7 Hz), 127.8, 125.5 (d, 5JC-F=0.5 Hz), 125.4 (d, 3JC-F=8.9 Hz), 124.9 (d, 5JC-F=2.5 Hz), 116.6 (d, 2JC-F=25.4 Hz), 106.3 (d, 2JC-F=22.4 Hz), 62.2, 61.7, 27.3, 12.7. 19F NMR (CDCl3, 377 MHz): δ-113.94 (ddd, J=10.1, 8.4, 5.6 Hz). HRMS calculated for C18H17CIFN2O2[M+H]+: 347.095710. Found 347.097652.
This compound were isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, gradient from I/O to 99/1, v/v, UV) with 83% yield (colourless oil). 1H NMR (CDCl3, 400 MHz): δ 8.09 (dd, J=9.2, 5.6 Hz, 1H), 7.68 (dd, J=10.4, 2.6 Hz, 1H), 7.32 (br d, J=1.1 Hz, 1H), 7.26 (ddd, J=9.1, 8.3, 2.6 Hz, 1H), 6.26 (dd, J=3.1, 1.9 Hz, 1H), 5.87-5.82 (m, 1H), 4.23 (s, 2H), 3.87 (d, J=3.4 Hz, 6H), 2.36 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 161.0 (d, 1JC-F=245.2 Hz), 154.0, 150.5 (d, 5JC-F=1.4 Hz), 150.2 (d, 4JC-F=5.4 Hz), 141.3, 128.4, 128.3 (d, 3JC-F=8.7 Hz), 126.3 (d, 4JC-F=2.4 Hz), 125.3, 125.2 (d, 3JC-F=8.9 Hz), 116.2 (d, 2JC-F=25.4 Hz), 110.4, 106.4 (d, 2JC-F=22.3 Hz), 106.0, 62.5, 61.6, 26.5, 12.4. 19F NMR (CDCl3, 377 MHz): δ-114.95 (ddd, J=10.4, 8.4, 5.7 Hz). HRMS calculated for C18H18FO3 [M+H]+: 301.123449. Found 301.123811.
This compound was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, 4/1, v/v, UV) with 73% yield (colourless oil). 1H NMR (CDCl3, 400 MHz): δ 8.69 (s, 2H), 8.08 (dd, J=9.2, 5.6 Hz, 1H), 7.64 (dd, J=10.2, 2.5 Hz, 1H), 7.28 (ddd, J=9.1, 8.4, 2.6 Hz, 1H), 4.27 (s, 2H), 3.85 (d, J=12.1 Hz, 6H), 2.28 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 161.2 (d, 1JC-F=246.3 Hz), 157.6 (2C), 154.9 (q, 2JC-F=36.9 Hz), 151.2 (d, 5JC-F=1.3 Hz), 150.2 (d, 4JC-F=5.3 Hz), 136.1, 128.6 (d, 3JC-F=8.7 Hz), 127.4, 125.7, 125.5 (d, 3JC-F=8.9 Hz), 124.9 (d, 4JC-F=2.5 Hz), 119.8 (d, 1JC-F=275.7 Hz), 116.8 (d, 2JC-F=25.4 Hz), 106.4 (d, 2JC-F=22.5 Hz), 62.2, 61.8, 28.1, 12.8. 19F NMR (CDC3, 377 MHz): δ-70.12, −113.87 (ddd, J=10.1, 8.4, 5.6 Hz).
A solution of 36 (100 mg, 0.29 mmol, 1 eq) in DMSO (1.0 mL) was added a solution of sodium cyanide (28.26 mg, 0.58 mmol, 2 eq) and DABCO (6.81 mg, 0.058 mmol, 0.2 eq) in DMSO (1 mL) and water (0.4 mL). The reaction mixture was stirred at 50° C. for 72 h. The reaction mixture was diluted with water and extracted twice with diethyl ether. Reunited organic layers were washed with brine and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, 4/1, v/v) to afford 40 as a white solid (19 mg, 20%). m.p.=167-169° C. 1H NMR (CDCl3, 400 MHz): δ 8.63 (s, 2H), 8.09 (dd, J=9.2, 5.6 Hz, 1H), 7.64 (dd, J=10.2, 2.5 Hz, 1H), 7.30 (ddd, J=9.1, 8.4, 2.6 Hz, 1H), 4.25 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 2.27 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 161.3 (d, 1JC-F=246.7 Hz), 157.8 (2C), 151.3 (d, 5JC-F=1.3 Hz), 150.3 (d, 4JC-F=5.5 Hz), 143.2, 136.9, 128.3 (d, 3JC-F=8.7 Hz), 127.1, 125.8, 125.5 (d, 3JC-F=8.9 Hz), 124.7 (d, 4JC-F=2.5 Hz), 117.0 (d, 2JC-F=25.4 Hz), 115.8, 106.4 (d, 2JC-F=22.5 Hz), 62.3, 61.9, 28.4, 12.9. 19F NMR (CDCl3, 377 MHz): δ-113.65 (ddd, J=9.9, 8.4, 5.6 Hz). HRMS calculated for C19H17FN3O2[M+H]+: 338.129931. Found 338.131588.
The compounds of formula (1) wherein R1═F are prepared according to the following reaction scheme:
To a solution of 3-R-6-R′-1,4-dimethoxy-2-methylnaphetalene (1 eq) in acetonitrile was added dropwise a solution of ceric ammonium nitrate (2.2 eq) in water. The solution was stirred at room temperature for 15 min. The reaction mixture was diluted with water and extracted twice with dichloromethane. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure.
The crude residue was purified by flash chromatography on silica gel to afford the desired product.
0 4 was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, gradient from 4/1 to 7/3, v/v, UV) with 71% yield (yellow solid). m.p.=141-143° C. 1H NMR (CDCl3, 400 MHz): δ8.12 (dd, J=8.6, 5.1 Hz, 2H), 7.70 (dd, J=8.5, 2.6 Hz, 1H), 7.66 (dd, J=8.1, 2.4 Hz, 1H), 7.36 (td, J=8.4, 2.6 Hz, 1H), 6.83 (dd, J=8.4, 3.0 Hz, 1H), 3.98 (s, 2H), 2.27 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 183.8, 183.5 (d, 4JC-F=1.4 Hz), 166.2 (d, 1JC-F=257.3 Hz), 162.6 (d, 1JC-F=238.5 Hz), 147.4 (d, 3JC-F=14.6 Hz), 145.1, 144.3 (d, 5JC-F=1.0 Hz), 141.5 (d, 3JC-F=7.8 Hz), 134.5 (d, 3JC-F=7.9 Hz), 131.3 (d, 4JC-F=4.6 Hz), 129.9 (d, 3JC-F=8.9 Hz), 128.7 (d, 4JC-F=3.3 Hz), 121.1 (d, 2JC-F=22.6 Hz), 113.3 (d, 2JC-F=23.5 Hz), 109.7 (d, 2JC-F=37.5 Hz), 29.2, 13.5. 19F NMR (CDCl3, 377 MHz): δ-70.7 (m), −102.03 (td, J=8.3, 5.3 Hz). HRMS calculated for C17H12F2NO2 [M+H]+: 300.083061. Found 300.083945.
0 15 was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, gradient from 4/1 to 7/3, v/v, UV) with 85% yield (yellow solid). m.p.=153-154° C. 1H NMR (CDCl3, 400 MHz): δ 8.62 (d, J=1.6 Hz, 1H), 8.11 (dd, J=8.6, 5.2 Hz, 1H), 7.68 (td, J=8.4, 7.6, 2.3 Hz, 2H), 7.60 (d, J=8.0 Hz, 1H), 7.37 (td, J=8.3, 2.6 Hz, 1H), 4.07 (s, 2H), 2.27 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 183.4, 183.3 (d, 4JC-F=1.5 Hz), 166.1 (d, 1JC-F=257.6 Hz), 151.5, 145.7, 143.2 (d, 4JC-F=1.9 Hz), 138.1, 137.1, 134.3 (d, 3JC-F=8.0 Hz), 132.1, 130.0 (d, 3JC-F=8.9 Hz), 128.7 (d, 4JC-F=3.3 Hz), 128.5, 121.2 (d, 2JC-F=22.5 Hz), 117.2, 113.3 (d, 2JC-F=23.5 Hz), 30.3, 13.6. 19F NMR (CDCl3, 377 MHz): δ-101.69 (td, J=8.2, 5.3 Hz). HRMS calculated for C18H12FN2O2 [M+H]+: 307.087732. Found 307.088742.
18 was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, gradient from 4/1 to 7/3, v/v, UV) with 14% yield (sticky yellow dark solid). 1H NMR (CDCl3, 400 MHz): δ 8.12 (dd, J=8.6, 5.3 Hz, 1 H), 7.73 (dd, J=8.6, 2.6 Hz, 1H), 7.35 (td, J=8.3, 2.7 Hz, 1H), 7.27 (dd, J=1.8, 0.7 Hz, 1H), 6.27 (dd, J=3.2, 1.9 Hz, 1H), 6.08 (dd, J=3.2, 0.8 Hz, 1H), 4.03 (s, 2H), 2.29 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 184.1, 183.0 (d, 4JC-F=1.4 Hz), 166.1 (d, 1JC-F=256.8 Hz), 151.0, 145.4, 142.6 (d, 5JC-F=2.0 Hz), 141.7, 134.7 (d, 3JC-F=7.9 Hz), 129.8 (d, 3JC-F=8.9 Hz), 128.9 (d, 4JC-F=3.3 Hz), 120.8 (d, 2JC-F=22.6 Hz), 113.3 (d, 2JC-F=23.5 Hz), 110.6, 106.9, 25.7, 13.2. 19F NMR (CDCl3, 377 MHz): δ-102.49 (td, J=8.3, 5.3 Hz). HRMS calculated for C16H12FO3 [M+H]+: 271.076499. Found 271.078115.
16 was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, 4/1, v/v, UV) with 72% yield (yellow solid). m.p.=167-168° C. 1H NMR (CDCl3, 400 MHz): δ 8.53 (s, 2H), 8.13 (dd, J=8.6, 5.2 Hz, 1H), 7.69 (dd, J=8.5, 2.6 Hz, 1H), 7.38 (td, J=8.3, 2.6 Hz, 1H), 3.96 (s, 2H), 2.30 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 183.4, 183.2 (d, 4JC-F=1.5 Hz), 166.2 (d, 1JC-F=258.6 Hz), 160.0, 159.7 (2C), 145.5, 142.9 (d, 5JC-F=1.9 Hz), 134.3 (d, 3JC-F=7.9 Hz), 130.4, 130.0 (d, 3JC-F=8.9 Hz), 128.6 (d, 4JC-F=3.3 Hz), 121.3 (d, 2JC-F=22.5 Hz), 113.4 (d, 2JC-F=23.6 Hz), 27.2, 13.7. 19F NMR (CDCl3, 377 MHz): δ -101.54 (td, J=8.2, 5.2 Hz). HRMS calculated for C16H11CIFN2O2[M+H]+: 317.048760. Found 317.049497.
20 was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, 4/1, v/v, UV) with 75% (yellow solid). m.p.=187-188° C. 1H NMR (CDCl3, 400 MHz): δ 8.76 (s, 2H), 8.15 (dd, J=8.6, 5.2 Hz, 1H), 7.71 (dd, J=8.4, 2.6 Hz, 1H), 7.41 (td, J=8.3, 2.6 Hz, 1H), 4.06 (s, 2H), 2.33 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 183.20, 183.18, 166.3 (d, 1JC-F=258.1 Hz), 158.1 (2C), 146.0, 143.6, 142.2, 134.9, 134.2 (d, 3JC-F=7.9 Hz), 130.2 (d, 3JC-F=8.9 Hz), 128.7 (d, 4JC-F=3.3 Hz), 121.5 (d, 2JC-F=22.6 Hz), 115.7, 113.5 (d, 2JC-F=23.6 Hz), 28.3, 13.8. 19F NMR (CDCl3, 377 MHz): δ -101.19 (td, J=8.2, 5.3 Hz). HRMS calculated for C17H11FN3O2[M+H]+: 308.082981. Found 308.084056.
17 was isolated by purification by flash chromatography on silica gel (Cyclohexane/Ethyl acetate, 7/3, v/v, UV) with 96% yield (yellow solid). m.p.=195-197° C. 1H NMR (CDCl3, 400 MHz): δ 8.81 (s, 2H), 8.14 (dd, J=8.6, 5.2 Hz, 1H), 7.70 (dd, J=8.4, 2.6 Hz, 1H), 7.39 (td, J=8.3, 2.7 Hz, 1H), 4.07 (s, 2H), 2.33 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 183.3, 183.2 (d, 4JC-F=1.4 Hz), 166.3 (d, 1JC-F=257.9 Hz), 158.0, 155.4 (q, 2JC-F=37.1 Hz), 145.8, 142.6 (d, 5JC-F=1.8 Hz), 134.3 (d, 3JC-F=8.2 Hz), 134.2, 130.1 (d, 3JC-F=8.9 Hz), 128.7 (d, 4JC-F=3.3 Hz), 121.4 (d, 2JC-F=22.5 Hz), 119.6 (d, 1JC-F=275.3 Hz), 113.5 (d, 2JC-F=23.6 Hz), 28.0, 13.7. 19F NMR (CDCl3, 377 MHz): δ-70.24, −101.44 (td, J=8.2, 5.3 Hz). HRMS calculated for C17H11F4N2O2 [M+H]+: 351.075117. Found 351.075663.
M.p.=60-62° C. 1H NMR (CDCl3, 400 MHz): δ8.10 (dd, J=8.6, 5.3 Hz, 1H), 7.73 (dd, J=8.6, 2.6 Hz, 1H), 7.34 (td, J=8.3, 2.7 Hz, 1H), 7.11 (dd, J=4.9, 1.4 Hz, 1H), 6.92-6.85 (m, 2H), 4.17 (s, 2H), 2.29 (s, 3H). 13C NMR (CDCl3, 101 MHz): δ 184.1, 183.2 (d, 4JC-F=1.4 Hz), 166.1 (d, 1JC-F=256.9 Hz), 144.6 (d, 5JC-F=1.9 Hz), 144.4, 139.7, 134.6 (d, 3JC-F=7.9 Hz), 129.7 (d, 3JC-F=8.8 Hz), 128.8 (d, 4JC-F=3.2 Hz), 127.0, 125.9, 124.3, 120.8 (d, 2JC-F=22.6 Hz), 113.3 (d, 2JC-F=23.2 Hz), 27.1, 13.2. 19F NMR (CDCl3, 377 MHz): δ-102.36 (td, J=8.3, 5.3 Hz). HRMS calculated for C16H12FO2S [M+H]+: 287.053655. Found 287.054700.
It was shown that the order of the steps is essential for the process of the invention for the preparation of the intermediate compounds of formula (IV).
The following reaction was carried out:
By carring out a chloromethylation step from menadione, the compound of formula (IV) could not be obtained.
Moreover, the yield for this chloromethylation step was lower in comparison with the yield for this step in the preparation of compounds of formula (IV) from compounds of formula (V).
Regioisomeric compounds were synthetized using the process of WO 2020/252414 based on organozinc intermediates. MR00397 and MR00407 were obtained with very low yields (Scheme 2, Table):
The synthesis of pyridinyl/pyrimidinyl derivatives of formula (I) according to the invention was investigated using the same method. Unfortunately, both molecules were obtained in inseparable mixtures. The mixtures were allowed to react with CAN. MR00418 was isolated with a second fluorinated compound and MR00419 with 4 other fluorinated compounds. The structures of the (non separated) side-products were not elucidated.
The method according to the invention is thus the most efficient synthetic pathway to synthetize MR00418 and MR00419. With this method, MR00418 was obtained with total 84% yield in 2 steps from MD705. MR00419 was synthetized in 2 steps from MD705 with total 67% yield in 2 steps
The first primary screening, performed with the Plasmodium falciparum NF54 strain and the rat L6 myoblast cell line, showed that both MR00418 and MR00419 displayed more potent and specific antimalarial activities than the regioisomers MR00397 and MR00407, respectively:
| Number | Date | Country | Kind |
|---|---|---|---|
| 21305755.7 | Jun 2021 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/065255 | 6/3/2022 | WO |
