Dimethyl 2-{[2-(2-Methoxy-1-methoxycarbonyl-2-oxoethyl)-4,5,7-trimethoxy-3-(2,4,5-trimethoxyphenyl)-2,3-dihydro-1H-inden-1-yl]methyl}malonate

A simple synthetic approach to dimethyl 2-{[2-(2-methoxy-1-methoxycarbonyl-2-oxoethyl) -4,5,7-trimethoxy-3-(2,4,5-trimethoxyphenyl)-2,3-dihydro-1H-inden-1-yl]methyl}malonate has been developed, based on a B(C6F5)3-induced domino dimerization of 2-(2,4,5-trimethoxyphenyl) cyclopropane-1,1-diester.


Results and Discussion
Starting cyclopropane 2 was synthesized from commercial 2,4,5-trimethoxybenzaldehyde 3 via a two-step synthetic sequence which involves the Knövenagel condensation with dimethyl malonate to afford arylidenemalonate 4 followed by the Corey-Chaykovsky reaction (Scheme 1) [28]. The structure of 2,4,5-trimethoxyphenyl-substituted cyclopropane 2 was unambiguously confirmed by single crystal X-ray analysis ( Figure 2) [29]. In general, the structure of cyclopropane 2 closely matches the structure of related 2-arylcyclopropane-1,1-dicarboxylates described previously [30][31][32]. All of them have the same configuration of ester groups. The methoxycarbonyl group in the trans-position with respect to the donor aromatic substituent is located approximately along the bisector of the angle C(2)-C(1)-C(3) with the carbonyl oxygen atom directed towards the cyclopropane fragment, while the alkoxy group, respectively, in the opposite direction. The second ester group is usually arranged so that the carbonyl oxygen atom has an exo-location relative to the three-membered ring and the methoxy group is endo-located, the torsion angle between two ester groups being dependent on the nature of the cis-aromatic substituent. In line with our ongoing research related to D-A cyclopropane dimerizations [7,8,[11][12][13][14]20], herein, we report the synthesis of polyoxygenated indane 1, which is a structural analog of diazarone, via a B(C 6 F 5 ) 3 -induced (3 + 2)-cyclodimerization of 2-(2,4,5-trimethoxyphenyl)cyclopropane-1,1-diester 2 in one step in highly chemo-, regio-and stereoselective manner.

Results and Discussion
Starting cyclopropane 2 was synthesized from commercial 2,4,5-trimethoxybenzaldehyde 3 via a two-step synthetic sequence which involves the Knövenagel condensation with dimethyl malonate to afford arylidenemalonate 4 followed by the Corey-Chaykovsky reaction (Scheme 1) [28]. The structure of 2,4,5-trimethoxyphenyl-substituted cyclopropane 2 was unambiguously confirmed by single crystal X-ray analysis ( Figure 2) [29]. In general, the structure of cyclopropane 2 closely matches the structure of related 2-arylcyclopropane-1,1-dicarboxylates described previously [30][31][32]. All of them have the same configuration of ester groups. The methoxycarbonyl group in the trans-position with respect to the donor aromatic substituent is located approximately along the bisector of the angle C(2)-C(1)-C(3) with the carbonyl oxygen atom directed towards the cyclopropane fragment, while the alkoxy group, respectively, in the opposite direction. The second ester group is usually arranged so that the carbonyl oxygen atom has an exo-location relative to the three-membered ring and the methoxy group is endo-located, the torsion angle between two ester groups being dependent on the nature of the cis-aromatic substituent.
In general, the structure of cyclopropane 2 closely matches the structure of related 2-arylcyclopropane-1,1-dicarboxylates described previously [30][31][32]. All of them have the same configuration of ester groups. The methoxycarbonyl group in the trans-position with respect to the donor aromatic substituent is located approximately along the bisector of the angle C(2)-C(1)-C(3) with the carbonyl oxygen atom directed towards the cyclopropane fragment, while the alkoxy group, respectively, in the opposite direction. The second ester group is usually arranged so that the carbonyl oxygen atom has an exo-location relative to the three-membered ring and the methoxy group is endo-located, the torsion angle between two ester groups being dependent on the nature of the cis-aromatic substituent. In this paper, we studied the possibility of using B(C6F5)3 as a catalyst of cyclopropane 2 dimerization accounting for fact that this reagent is referred to as an ideal boron Lewis acid [34]. Our preliminary studies revealed that the use of conventional Lewis acids (BF3·Et2O, SnCl4) does not lead In this paper, we studied the possibility of using B(C 6 F 5 ) 3 as a catalyst of cyclopropane 2 dimerization accounting for fact that this reagent is referred to as an ideal boron Lewis acid [34]. Our preliminary studies revealed that the use of conventional Lewis acids (BF 3 ·Et 2 O, SnCl 4 ) does not lead to satisfactory results as complex mixtures of dimeric products and products of oligomerization were obtained. After a short screening of the reaction conditions, we have found that the best yields are obtained after heating 2 M solution of 2 in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) in the presence of B(C 6 F 5 ) 3 (10 mol %) under microwave irradiation at 58 • C for 7 h (Scheme 2).
In this paper, we studied the possibility of using B(C6F5)3 as a catalyst of cyclopropane 2 dimerization accounting for fact that this reagent is referred to as an ideal boron Lewis acid [34]. Our preliminary studies revealed that the use of conventional Lewis acids (BF3·Et2O, SnCl4) does not lead to satisfactory results as complex mixtures of dimeric products and products of oligomerization were obtained. After a short screening of the reaction conditions, we have found that the best yields are obtained after heating 2 M solution of 2 in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) in the presence of B(C6F5)3 (10 mol %) under microwave irradiation at 58 °C for 7 h (Scheme 2).

Scheme 2. Synthesis of dimer 1.
According to nuclear magnetic resonance spectroscopy (NMR) data, the dimerization of cyclopropane 2 produced 1 as a mixture of two isomers in 84:16 ratio. The relative configuration of the major isomer of dimer 1 was assigned on the basis of 2D nuclear Overhauser effect spectroscopy (NOESY) experiments (Scheme 3). For major isomer the trans,trans-arrangement of substituents in five-membered ring was established. The minor isomer of 1 was determined to be the C-1 epimer, and its spectral parameters completely correspond to the literature data for the related dimers [12,13]. .

Scheme 3.
Representative NOE responses for the major isomer of 1.

Scheme 2. Synthesis of dimer 1.
According to nuclear magnetic resonance spectroscopy (NMR) data, the dimerization of cyclopropane 2 produced 1 as a mixture of two isomers in 84:16 ratio. The relative configuration of the major isomer of dimer 1 was assigned on the basis of 2D nuclear Overhauser effect spectroscopy (NOESY) experiments (Scheme 3). For major isomer the trans,trans-arrangement of substituents in five-membered ring was established. The minor isomer of 1 was determined to be the C-1 epimer, and its spectral parameters completely correspond to the literature data for the related dimers [12,13].
In this paper, we studied the possibility of using B(C6F5)3 as a catalyst of cyclopropane 2 dimerization accounting for fact that this reagent is referred to as an ideal boron Lewis acid [34]. Our preliminary studies revealed that the use of conventional Lewis acids (BF3·Et2O, SnCl4) does not lead to satisfactory results as complex mixtures of dimeric products and products of oligomerization were obtained. After a short screening of the reaction conditions, we have found that the best yields are obtained after heating 2 M solution of 2 in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) in the presence of B(C6F5)3 (10 mol %) under microwave irradiation at 58 °C for 7 h (Scheme 2).

Scheme 2. Synthesis of dimer 1.
According to nuclear magnetic resonance spectroscopy (NMR) data, the dimerization of cyclopropane 2 produced 1 as a mixture of two isomers in 84:16 ratio. The relative configuration of the major isomer of dimer 1 was assigned on the basis of 2D nuclear Overhauser effect spectroscopy (NOESY) experiments (Scheme 3). For major isomer the trans,trans-arrangement of substituents in five-membered ring was established. The minor isomer of 1 was determined to be the C-1 epimer, and its spectral parameters completely correspond to the literature data for the related dimers [12,13]. .

Scheme 3.
Representative NOE responses for the major isomer of 1.

Scheme 3. Representative NOE responses for the major isomer of 1.
The predominant formation of trans,trans-isomer differs from the previously reported results on the exclusive formation of cis,trans-isomers of the related indanes in the cyclodimerization of the D-A cyclopropanes [12,13]. Taking into account the cis,trans-geometry of the naturally occurring analog, diazarone, we believe that this reversal of stereoselectivity can be explained by the nature of bulky Lewis acid used in this study. Unlike SnCl 4 and BF 3 , B(C 6 F 5 ) 3 coordinates to an acceptor group in cyclopropane 2 in such a way, that attack of isomeric alkene 5, formed by an initial isomerization of 2, on cyclopropane results in an intermediate 6 with anti-arrangement of substituents at carbon atoms that form a new bond (Scheme 4). Cyclization of 6 proceeds under thermodynamic control and affords the most stable trans,trans-1. diazarone, we believe that this reversal of stereoselectivity can be explained by the nature of bulky Lewis acid used in this study. Unlike SnCl4 and BF3, B(C6F5)3 coordinates to an acceptor group in cyclopropane 2 in such a way, that attack of isomeric alkene 5, formed by an initial isomerization of 2, on cyclopropane results in an intermediate 6 with anti-arrangement of substituents at carbon atoms that form a new bond (Scheme 4). Cyclization of 6 proceeds under thermodynamic control and affords the most stable trans,trans-1. In summary, the B(C6F5)3-induced cyclodimerization of 2-(2,4,5trimethoxyphenyl)cyclopropane-1,1-diester 2 provides a concise route to polyoxygenated indane 1, which is a structural analogue of diazarone and has a potential for pharmacological studies.

Materials and Methods
NMR spectra were acquired on Bruker AM-400 and Bruker Avance 600 spectrometers at room temperature; the chemical shifts δ were measured in ppm with respect to the solvent ( 1 Н: CDCl3, δ = 7.27 ppm; 13 C: CDCl3, δ = 77.0). The splitting patterns are designated as s, singlet; d, doublet; m, multiplet; dd, double doublet; br., broad. The coupling constants (J) were in Hertz. The 1 H-NMR, 13 C-NMR, 2D heteronuclear single quantum coherence (HSQC), heteronuclear multiple bond correlation (HMBC), nuclear Overhauser effect (NOESY) NMR spectra for the synthesized compound are available in the Supplementary Material. Infrared spectra were recorded on the Infralum FT-801 spectrometer. High resolution and accurate mass measurements were carried out using a micrOTOF-Q TM ESI-TOF (electro spray ionization/time of flight, Bruker, Billerica, MA, USA) and LTQ Orbitrap mass spectrometer (Thermo Fischer Scientific, Waltham, MA, USA). Elemental analyses were performed with an EA-1108 CHNS elemental analyzer instrument (Fisons, Ipswich, UK). X-ray analysis was performed on STOE STADIVARI PILATUS-100K diffractometer (Stoe & Sie, Darmstadt, Germany). The microwave reaction was performed in a Monowave 300-Anton Paar microwave reactor (Anton Paar Gmbh, Graz, Austria) in sealed reaction vessels. The temperature was monitored with the installed IR detector. The melting points (m.p.) were determined using a 9100 capillary melting point apparatus (Electrothermal, Stone, UK). Analytical thin layer chromatography (TLC) was carried out with silica gel plates (silica gel 60, F254, supported on aluminum); the revelation was done by UV lamp (365 nm). Column chromatography was performed on silica gel 60 (230-400 mesh, Scheme 4. The proposed mechanism of dimer 1 formation. In summary, the B(C 6 F 5 ) 3 -induced cyclodimerization of 2-(2,4,5-trimethoxyphenyl)cyclopropane -1,1-diester 2 provides a concise route to polyoxygenated indane 1, which is a structural analogue of diazarone and has a potential for pharmacological studies.

Materials and Methods
NMR spectra were acquired on Bruker AM-400 and Bruker Avance 600 spectrometers at room temperature; the chemical shifts δ were measured in ppm with respect to the solvent ( 1 H: CDCl 3 , δ = 7.27 ppm; 13 C: CDCl 3 , δ = 77.0). The splitting patterns are designated as s, singlet; d, doublet; m, multiplet; dd, double doublet; br., broad. The coupling constants (J) were in Hertz. The 1 H-NMR, 13 C-NMR, 2D heteronuclear single quantum coherence (HSQC), heteronuclear multiple bond correlation (HMBC), nuclear Overhauser effect (NOESY) NMR spectra for the synthesized compound are available in the Supplementary Material. Infrared spectra were recorded on the Infralum FT-801 spectrometer. High resolution and accurate mass measurements were carried out using a micrOTOF-Q TM ESI-TOF (electro spray ionization/time of flight, Bruker, Billerica, MA, USA) and LTQ Orbitrap mass spectrometer (Thermo Fischer Scientific, Waltham, MA, USA). Elemental analyses were performed with an EA-1108 CHNS elemental analyzer instrument (Fisons, Ipswich, UK). X-ray analysis was performed on STOE STADIVARI PILATUS-100K diffractometer (Stoe & Sie, Darmstadt, Germany). The microwave reaction was performed in a Monowave 300-Anton Paar microwave reactor (Anton Paar Gmbh, Graz, Austria) in sealed reaction vessels. The temperature was monitored with the installed IR detector. The melting points (m.p.) were determined using a 9100 capillary melting point apparatus (Electrothermal, Stone, UK). Analytical thin layer chromatography (TLC) was carried out with silica gel plates (silica gel 60, F 254 , supported on aluminum); the revelation was done by UV lamp (365 nm). Column chromatography was performed on silica gel 60 (230-400 mesh, Merck, Darmstadt, Germany). All reactions were carried out using freshly distilled and dry solvents. Commercial reagents employed in the synthesis were analytical grade, obtained from Aldrich (St. Louis, MI, USA) or Alfa Aesar (Ward Hill, MO, USA). CCDC 1972617 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44-1223-336033; E-mail: deposit@ccdc.cam.ac.uk).