Synthesis of (Het)aryl 2-(2-hydroxyaryl)cyclopropyl Ketones

A simple general method for the synthesis of 1-acyl-2-(ortho-hydroxyaryl)cyclopropanes, which belong to the donor–acceptor cyclopropane family, has been developed. This method, based on the Corey–Chaykovsky cyclopropanation of 2-hydroxychalcones, allows for the preparation of a large diversity of hydroxy-substituted cyclopropanes, which can serve as promising building blocks for the synthesis of various bioactive compounds.

Despite the promising reactivity and bioactivity of 2-hydroxyaryl-substituted cyclopropanes, their investigation is restricted by the absence of simple and efficient methods for their synthesis. In particular, the preparation of the corresponding cyclopropane-1,1-diesters requires protection of the phenolic oxygen [41,50], while the Corey-Chaykovsky cyclopropanation of easily available 2-hydroxychalcones produced a variety of products [56][57][58][59][60]. This presumably resulted from the highly activating effect of ortho-hydroxy group [50,60] on three-membered ring opening as well as the possible involvement of the nucleophilic phenoxy moiety into diverse transformations of 2-hydroxyaryl-derived D-A cyclopropanes. We report here the efficient procedure for the preparation of 1-acyl-2-(2-hydroxyaryl)cyclopropanes as potent bioactive compounds and promising building blocks for the synthesis of various acyclic, alicyclic and heterocyclic compounds.

Results and Discussion
We investigated the reaction of trimethylsulfoxonium iodide with 2-hydroxychalcone 1a as a model substrate. Varying base, solvent, temperature, ratio of the reacting compounds and order of their additiion, we found that cyclopropane 2a can be obtained in 70% yield, when the solution of trimethylsulfoxonium iodide in DMSO/THF mixture was treated with 3 equivalents of sodium hydride followed by addition of enone 1a to the formed reaction mixture at −10 • C and stirring for 3 h (Scheme 2).
Molecules 2020, 25, x 2 of 15 being selective antagonists of orexin 2 receptors [54] and showing antimicrobial and nematicidal activity [55]. Despite the promising reactivity and bioactivity of 2-hydroxyaryl-substituted cyclopropanes, their investigation is restricted by the absence of simple and efficient methods for their synthesis. In particular, the preparation of the corresponding cyclopropane-1,1-diesters requires protection of the phenolic oxygen [41,50], while the Corey-Chaykovsky cyclopropanation of easily available 2hydroxychalcones produced a variety of products [56,57,58,59,60]. This presumably resulted from the highly activating effect of ortho-hydroxy group [50,60] on three-membered ring opening as well as the possible involvement of the nucleophilic phenoxy moiety into diverse transformations of 2hydroxyaryl-derived D-A cyclopropanes. We report here the efficient procedure for the preparation of 1-acyl-2-(2-hydroxyaryl)cyclopropanes as potent bioactive compounds and promising building blocks for the synthesis of various acyclic, alicyclic and heterocyclic compounds.

Results and Discussion
We investigated the reaction of trimethylsulfoxonium iodide with 2-hydroxychalcone 1a as a model substrate. Varying base, solvent, temperature, ratio of the reacting compounds and order of their additiion, we found that cyclopropane 2a can be obtained in 70% yield, when the solution of trimethylsulfoxonium iodide in DMSO/THF mixture was treated with 3 equivalents of sodium hydride followed by addition of enone 1a to the formed reaction mixture at −10 °C and stirring for 3 h (Scheme 2). The control of temperature and quenching procedure were found to be important for the good yield of the target product. Thus, the yield dropped significantly, if sodium hydride was added to the ice-cooled solution of starting compounds followed by removal of cooling bath. Moreover, compound 2a was formed in trace amounts only, when all steps of process occurred at room The control of temperature and quenching procedure were found to be important for the good yield of the target product. Thus, the yield dropped significantly, if sodium hydride was added to the ice-cooled solution of starting compounds followed by removal of cooling bath. Moreover, compound 2a was formed in trace amounts only, when all steps of process occurred at room temperature, the reaction being performed in DMF. Nevertheless, when addition of 1a to the preformed ylide and stirring the reaction mixture were performed at 0 • C, product 2a was obtained with acceptable yield.
Quenching of the highly basic reaction mixture with ammonium chloride afforded 2a in a good yield, while only trace amounts of cyclopropane 2a was obtained when acetic acid was used for quenching.
With the optimized reaction conditions in hand, we synthesized a series of 2-hydroxychalcone derivatives (see Experimental part) and studied the scope of Corey-Chaykovsky cyclopropanation of these substrates. We found that diverse substituents in the phenolic moiety (alkoxy, halogens, nitro group) were tolerant to the reaction conditions, and the corresponding cyclopropanes 2 were obtained in reasonable to high yields (Scheme 3). Electron-releasing substituents in the aroyl fragment have also no significant effect on the reaction yield. Oppositely, enones 1 with electron-depleted aroyl group, such as nicotinoyl or 4 -nitrobenzoyl, failed to produce the desired cyclopropane 2 due to side processes realization. temperature, the reaction being performed in DMF. Nevertheless, when addition of 1a to the preformed ylide and stirring the reaction mixture were performed at 0 °C , product 2a was obtained with acceptable yield. Quenching of the highly basic reaction mixture with ammonium chloride afforded 2a in a good yield, while only trace amounts of cyclopropane 2a was obtained when acetic acid was used for quenching.
With the optimized reaction conditions in hand, we synthesized a series of 2-hydroxychalcone derivatives (see Experimental part) and studied the scope of Corey-Chaykovsky cyclopropanation of these substrates. We found that diverse substituents in the phenolic moiety (alkoxy, halogens, nitro group) were tolerant to the reaction conditions, and the corresponding cyclopropanes 2 were obtained in reasonable to high yields (Scheme 3). Electron-releasing substituents in the aroyl fragment have also no significant effect on the reaction yield. Oppositely, enones 1 with electrondepleted aroyl group, such as nicotinoyl or 4′-nitrobenzoyl, failed to produce the desired cyclopropane 2 due to side processes realization. Earlier it was pointed out that Corey-Chaykovsky cyclopropanation of the related enones proceeds typically with the retention of stereochemistry [61,62]. Indeed, all products were obtained as single diasteromers; trans-arrangement of donor and acceptor substituents in cyclopropane 2e was unambiguously proved by single-crystal X-ray analysis ( Figure 1). Crystal data for compound 2e Similar values of coupling constants for protons of three-membered rings support the conclusion that all synthesized cyclopropanes 2 have the same relative configuration of two stereocenters. It is noteworthy that C(1)-C(2) bond length in 2e (1.536 Å ) is significantly larger than the bond length in the unsubstituted cyclopropane (1.510 Å , [63]). This bond elongation results from the significant polarization of the C(1)-C(2) bond due to the cooperative effect of donor and acceptor substituents at the vicinal atoms of three-membered ring. On the other hand, this bond is significantly shorter than the corresponding bond in dimethyl 2-(5-bromo-2-hydroxyphenyl)cyclopropane-1,1-dicarboxylate (1.558 Å , [50]). This allows to suppose the lower reactivity of 2e bearing 4-methoxybenzoyl group as an acceptor in comparison with the aforementioned diester. Earlier it was pointed out that Corey-Chaykovsky cyclopropanation of the related enones proceeds typically with the retention of stereochemistry [61,62]. Indeed, all products were obtained as single diasteromers; trans-arrangement of donor and acceptor substituents in cyclopropane 2e was unambiguously proved by single-crystal X-ray analysis ( Figure 1). Crystal data for compound 2e (C 17  Similar values of coupling constants for protons of three-membered rings support the conclusion that all synthesized cyclopropanes 2 have the same relative configuration of two stereocenters. It is noteworthy that C (1) -C (2) bond length in 2e (1.536 Å) is significantly larger than the bond length in the unsubstituted cyclopropane (1.510 Å, [63]). This bond elongation results from the significant polarization of the C (1) -C (2) bond due to the cooperative effect of donor and acceptor substituents at the vicinal atoms of three-membered ring. On the other hand, this bond is significantly shorter than the corresponding bond in dimethyl 2-(5-bromo-2-hydroxyphenyl)cyclopropane-1,1-dicarboxylate (1.558 Å, [50]). This allows to suppose the lower reactivity of 2e bearing 4-methoxybenzoyl group as an acceptor in comparison with the aforementioned diester.

General Information
The structures of synthesized compounds were elucidated with the aid of 1D ( 1 H, 13 C) and 2D (HSQC, NOESY) NMR spectroscopy. NMR spectra were acquired on Avance 500 and Avance 400 (Bruker, Billerica, MA, USA) spectrometers at room temperature; the chemical shifts δ were measured in ppm with respect to solvent ( 1 H: CDCl3, δ = 7.26 ppm, DMSO-d6, δ = 2.50 ppm; 13 C: CDCl3, δ = 77.16; DMSO-d6, δ = 39.52 ppm). Splitting patterns are designated as s, singlet; d, doublet; m, multiplet; dd, double doublet; br., broad. Coupling constants (J) are in Hertz. 19 F NMR spectra were recorded at 471 MHz with fluorobenzene as an external reference (δ = −113.1 in DMSO-d6). Infrared spectra were recorded on an FTIR spectrometer ALPHA II (Bruker, Billerica, MA, USA) in KBr for solid substances and in nujol for oils. High resolution and accurate mass measurements were carried out using a micrOTOF-Q TM ESI-TOF (Electrospray Ionization/Time of Flight, Bruker, Billerica, MA, USA) using ESI modes. X-Ray diffraction data were collected at 100 K on a Quest D8 diffractometer (Bruker, Billerica, MA, USA) equipped with a Photon-III area-detector (graphite monochromator, shutterless φ-and ω-scan technique) using Mo Kα-radiation. Elemental analyses were performed with an EA-1108 CHNS elemental analyser instrument (Fisons, Ipswich, UK). Melting points (mp) are uncorrected and were measured on a 9100 capillary melting point apparatus (Electrothermal, Stone, UK). Analytical thin layer chromatography (TLC) was done on silica gel plates (silica gel 60, F254, supported on aluminium); visualization was done using a UV lamp (365 and 254 nm). Column chromatography was performed on silica gel 60 (230-400 mesh, Merck, Darmstadt, Germany). All reactions were performed using freshly distilled and dry solvents. Compound 1a and other commercial reagents employed in the synthesis were analytical grade, obtained from Aldrich (St. Louis, MI, USA) or Alfa Aesar (Ward Hill, MO, USA). The NMR spectra for new compounds are available in the supplementary material.

General Procedure for the Synthesis of 2-Hydroxychalcones 1
To a solution of aryl methyl ketone (4-10 mmol, 1 equiv) and (substituted) salicylaldehyde (4-10 mmol, 1 equiv), in EtOH (5-12 mL) was added 40% aq. NaOH (0.6-1.5 mL, 2.5 equiv) and the mixture was stirred at room temperature (or elevated temperature, if precipitation of intermediates occurred after addition of NaOH) for 12-48 h until the disappearance of starting material (monitored by thin layer chromatography). The reaction was poured into cold water (100-250 mL) and the mixture was neutralized with 2 M HCl to neutral or slightly acidic pH. The resulting precipitate was filtered, washed with water and air dried to afford the desired product. Crude product can be purified by recrystallization from appropriate solvent.

General Information
The structures of synthesized compounds were elucidated with the aid of 1D ( 1 H, 13 C) and 2D (HSQC, NOESY) NMR spectroscopy. NMR spectra were acquired on Avance 500 and Avance 400 (Bruker, Billerica, MA, USA) spectrometers at room temperature; the chemical shifts δ were measured in ppm with respect to solvent ( 1 H: CDCl 3 , δ = 7.26 ppm, DMSO-d 6 , δ = 2.50 ppm; 13 C: CDCl 3 , δ = 77.16; DMSO-d 6 , δ = 39.52 ppm). Splitting patterns are designated as s, singlet; d, doublet; m, multiplet; dd, double doublet; br., broad. Coupling constants (J) are in Hertz. 19 F NMR spectra were recorded at 471 MHz with fluorobenzene as an external reference (δ = −113.1 in DMSO-d 6 ). Infrared spectra were recorded on an FTIR spectrometer ALPHA II (Bruker, Billerica, MA, USA) in KBr for solid substances and in nujol for oils. High resolution and accurate mass measurements were carried out using a micrOTOF-Q TM ESI-TOF (Electrospray Ionization/Time of Flight, Bruker, Billerica, MA, USA) using ESI modes. X-Ray diffraction data were collected at 100 K on a Quest D8 diffractometer (Bruker, Billerica, MA, USA) equipped with a Photon-III area-detector (graphite monochromator, shutterless ϕand ω-scan technique) using Mo K α -radiation. Elemental analyses were performed with an EA-1108 CHNS elemental analyser instrument (Fisons, Ipswich, UK). Melting points (mp) are uncorrected and were measured on a 9100 capillary melting point apparatus (Electrothermal, Stone, UK). Analytical thin layer chromatography (TLC) was done on silica gel plates (silica gel 60, F 254 , supported on aluminium); visualization was done using a UV lamp (365 and 254 nm). Column chromatography was performed on silica gel 60 (230-400 mesh, Merck, Darmstadt, Germany). All reactions were performed using freshly distilled and dry solvents. Compound 1a and other commercial reagents employed in the synthesis were analytical grade, obtained from Aldrich (St. Louis, MI, USA) or Alfa Aesar (Ward Hill, MO, USA). The NMR spectra for new compounds are available in the Supplementary Materials.

General Procedure for the Synthesis of 2-Hydroxychalcones 1
To a solution of aryl methyl ketone (4-10 mmol, 1 equiv) and (substituted) salicylaldehyde (4-10 mmol, 1 equiv), in EtOH (5-12 mL) was added 40% aq. NaOH (0.6-1.5 mL, 2.5 equiv) and the mixture was stirred at room temperature (or elevated temperature, if precipitation of intermediates occurred after addition of NaOH) for 12-48 h until the disappearance of starting material (monitored by thin layer chromatography). The reaction was poured into cold water (100-250 mL) and the mixture was neutralized with 2 M HCl to neutral or slightly acidic pH. The resulting precipitate was filtered, washed with water and air dried to afford the desired product. Crude product can be purified by recrystallization from appropriate solvent.

Conclusions
To conclude, we developed a simple general approach to (het)aryl 2-(2-hydroxyaryl)cyclopropyl ketones 2 based on the Corey-Chaykovsky cyclopropanation of 2-hydroxychalcones, determined the scope and limitations of this reaction. The obtained D-A cyclopropanes are promising building blocks for the synthesis of diverse heterocyclic compounds and bioactive substances.