Dimethyloxonium and Methoxy Derivatives of nido-Carborane and Metal Complexes Thereof

9-Dimethyloxonium, 10-dimethyloxonium, 9-methoxy and 10-methoxy derivatives of nido-carborane (9-Me2O-7,8-C2B9H11, 10-Me2O-7,8-C2B9H11, [9-MeO-7,8-C2B9H11], and [10-MeO-7,8-C2B9H11], respectively) were prepared by the reaction of the parent nido-carborane [7,8-C2B9H12] with mercury(II) chloride in a mixture of benzene and dimethoxymethane. Reactions of the 9 and 10-dimethyloxonium derivatives with triethylamine, pyridine, and 3-methyl-6-nitro-1H-indazole result in their N-methylation with the formation of the corresponding salts with 9 and 10-methoxy-nido-carborane anions. The reaction of the symmetrical methoxy derivative [10-MeO-7,8-C2B9H11] with anhydrous FeCl2 in tetrahydrofuran in the presence of t-BuOK results in the corresponding paramagnetic iron bis(dicarbollide) complex [8,8-(MeO)2-3,3-Fe(1,2-C2B9H10)2], whereas the similar reactions of the asymmetrical methoxy derivative [9-MeO-7,8-C2B9H11] with FeCl2 and CoCl2 presumably produce the 4,7′-isomers [4,7-(MeO)2-3,3-M(1,2-C2B9H10)2] (M = Fe, Co) rather than a mixture of rac-4,7′and meso-4,4′-isomers.


Introduction
Cyclic oxonium derivatives of polyhedral boron hydrides are well studied due to their use as convenient starting compounds for the preparation of various functional derivatives [1,2].In particular, this approach was used for synthesis of various derivatives of nido-carborane, including boron-containing biomolecules [3][4][5] and crown ethers [6,7].At the same time, in the literature there are only a few examples of acyclic oxonium derivatives of polyhedral boron hydrides [8][9][10][11][12][13][14], and to the best of our knowledge, there are no examples of dimethyloxonium derivatives.
The comparative analysis of 1 H NMR spectral data of a series of polyhedral boron hydride derivatives BL (L = SMe 2 , 1,4-dioxane) and the corresponding MX 5 L complexes (M = Nb, Ta; X = F, Cl) demonstrated their very close similarity that could be explained by comparable electronic effects of the metal and boron moieties in these compounds [22].It is known that NbCl 5 is effective reagent for removal of the methoxy methyl ether protecting group in organic synthesis [23].More detailed study of reactions of MX 5 (M = Nb, Ta; X = F, Cl) with acetals/ketals (1,1-dialkoxyalkanes) or trimethylformate revealed that the ethereal bonds can be broken by the MX 5 Lewis acids and the rate of the process is enhanced by the presence of the further vicinal ether function.The reaction pathway was found to include formation of the MX 5 (OMe 2 ) complexes, which were identified by NMR spectroscopy [24,25].It prompted us to study reaction of nido-carborane with dimethoxymethane MeOCH 2 OMe in the presence of HgCl 2 .
We found that the reaction of potassium 7,8-dicarba-nido-undecaborate K[7,8-C 2 B 9 H 12 ] with mercury(II) chloride in a mixture of dimethoxymethane and benzene results in the formation of mixture of symmetrically and asymmetrically substituted dimethyloxonium derivatives 1 and 2, as well as the corresponding methoxy derivatives K [3] and K [4] (Scheme 1), that was separated by column chromatography on silica.
The comparative analysis of 1 H NMR spectral data of a series of polyhedral boron hydride derivatives BL (L = SMe2, 1,4-dioxane) and the corresponding MX5L complexes (M = Nb, Ta; X = F, Cl) demonstrated their very close similarity that could be explained by comparable electronic effects of the metal and boron moieties in these compounds [22].It is known that NbCl5 is effective reagent for removal of the methoxy methyl ether protecting group in organic synthesis [23].More detailed study of reactions of MX5 (M = Nb, Ta; X = F, Cl) with acetals/ketals (1,1-dialkoxyalkanes) or trimethylformate revealed that the ethereal bonds can be broken by the MX5 Lewis acids and the rate of the process is enhanced by the presence of the further vicinal ether function.The reaction pathway was found to include formation of the MX5(OMe2) complexes, which were identified by NMR spectroscopy [24,25].It prompted us to study reaction of nido-carborane with dimethoxymethane MeOCH2OMe in the presence of HgCl2.
We found that the reaction of potassium 7,8-dicarba-nido-undecaborate K[7,8-C2B9H12] with mercury(II) chloride in a mixture of dimethoxymethane and benzene results in the formation of mixture of symmetrically and asymmetrically substituted dimethyloxonium derivatives 1 and 2, as well as the corresponding methoxy derivatives K [3] and K [4] (Scheme 1), that was separated by column chromatography on silica.[11,15,17].The 1 H NMR spectrum of 1 contains signal of the dimethyloxonium group at 4.17 ppm, signal of the carborane CH groups at 1.94 ppm, broad signal of the BH groups in the range 2.6-0.1 ppm and signal of the endo-BH hydrogen at −2.6 ppm.The 13 C NMR spectrum of 1 contains signals of the dimethyloxonium group and the carborane CH groups at 73.4 ppm and 43.1 ppm, respectively.Taking into account the strong electron-donating effect of the boron cage, the   ] where the methyl groups are not equivalent [27] due to interaction of a sulfur lone pair with the B9-B10 antibonding orbital of the nido-carborane cage [28], both methyl groups in 2 are equivalent indicating free rotation around the B-O bond and low inversion barrier at the oxygen atom.The 13 C NMR spectrum of 2 contains signals of the dimethyloxonium group at 72.0 ppm and the carborane CH groups at 41.5 and 34.4 ppm.
The dimethyloxonium derivatives of nido-carborane can be easily demethylated to the corresponding methoxy derivatives with triethylamine or pyridine within 30 min at ambient temperature (Scheme 2).These results demonstrated that the dimethyloxonium derivatives 1 and 2 are active methylating agents.signals of the dimethyloxonum group are very close to those of the trimethyloxonium cation Me3O + (4.68 and 78.8 ppm, respectively) [26].
The 11 B{ 1 H} NMR spectrum of 2 contains nine non-equivalent signals at 8.3, −12.9, −13.8, −19.1, −21.9, −22.8, −25.3, −34.0, and −39.9 ppm, which is consistent with asymmetry of B( 9)-substituted nido-carborane cage.The signal corresponding to the B( 9) is observed at 8.3 ppm, which is close to the corresponding signal in the diethyloxonium derivative [9-Et2O-7,8-C2B9H11] [11].The 1 H NMR spectrum of 2 contains signal of the dimethyloxonium group at 4.12 ppm, signals of the carborane CH groups at 1.94 and 2.02 ppm, broad signal of the BH groups in the range 2.6-0.1 ppm and signal of the bridging BHB hydrogen at −2.5 ppm.It is worth noting that, unlike the analogous dimethylsulfonium derivative  where the methyl groups are not equivalent [27] due to interaction of a sulfur lone pair with the B9-B10 antibonding orbital of the nido-carborane cage [28], both methyl groups in 2 are equivalent indicating free rotation around the B-O bond and low inversion barrier at the oxygen atom.The 13 C NMR spectrum of 2 contains signals of the dimethyloxonium group at 72.0 ppm and the carborane CH groups at 41.5 and 34.4 ppm.
high-field signal at −443.2 ppm due to the boron atoms, which are directly connected to the metal with a general relative integral ratio 2:4:4:2:6.M = Fe (Bu 4 N) [8] Co (Bu 4 N) [9] (45 %) The reason for the formation of solely the 4,7′-isomers of the dimethoxy derivatives of iron and cobalt bis(dicarbollides) is not very clear, but it probably caused by a lower stability of the corresponding 4,4′-isomers.high-field signal at −443.2 ppm due to the boron atoms, which are directly connected to the metal with a general relative integral ratio 2:4:4:2:6.The reason for the formation of solely the 4,7′-isomers of the dimethoxy derivatives of iron and cobalt bis(dicarbollides) is not very clear, but it probably caused by a lower stability of the corresponding 4,4′-isomers.The reason for the formation of solely the 4,7 -isomers of the dimethoxy derivatives of iron and cobalt bis(dicarbollides) is not very clear, but it probably caused by a lower stability of the corresponding 4,4 -isomers.

General Procedures and Instrumentation
The potassium salt of 7,8-dicarba-nido-caborane was prepared according to the literature procedure [55].Dimethoxymethane, tetrahydrofuran and iron(II) chloride were purchased from Sigma-Aldrich and used without further purification.Triethylamine, pyridine, 3-Methyl-6-nitro-1H-indazole, ethyl acetate and benzene were commercially analytical grade reagents and used without further treatment.Acetonitrile was dried by distillation over CaH 2 using the standard procedure [ High resolution mass spectra (HRMS) were measured on a Bruker micrOTOF II instrument (Bruker, Bremen, Germany) using electrospray ionization (ESI).The measurements were done in a negative ion mode (3200 V); mass range from m/z 50 to m/z 3000; external or internal calibration was done with ESI Tuning Mix, Agilent (Santa Clara, CA, USA).A syringe injection was used for solutions in acetonitrile (flow rate 3 mL/min).Nitrogen was applied as a dry gas; interface temperature was set at 180 • C. The electron ionization mass spectra were obtained with a Kratos MS 890 instrument (Kratos Analytical Ltd, Manchester, UK) operating in a mass range of m/z 50-800.The potassium salt of 7,8-dicarba-nido-undecaborate (1.00 g, 5.80 mmol) and mercury(II) chloride (1.60 g, 5.80 mmol) in a mixture of benzene (20 mL) and dimethoxymethane (20 mL) was heated under reflux for about 4 h.After cooling to room temperature, the solution was decanted, and the residue was washed with benzene.The washings were combined with the solution and evaporated under reduced pressure.The column chromatography on silica gel was used for the separation of the substances with ethyl acetate as an eluent to give white crystalline products 1-4.The first fraction (TLC R F = 0.88) contained 2, the second (TLC R F = 0.81) contained 1, the third (TLC R F = 0.62) was identified as 4, and the fourth (TLC R F = 0.17) contained 3.

Figure 1 .
Figure 1.Pazopanib hydrochloride and critical stage of its manufacture.
56].Anhydrous CoCl 2 was prepared by dehydration of CoCl 2 .6H 2 O using the standard procedure[57].The reaction progress was monitored by a TLC (Merck F254 silica gel on aluminum plates) and visualized using 0.5% PdCl 2 in 1% HCl in aq.MeOH (1:10).Acros Organics silica gel (0.060-0.200 mm) was used for column chromatography.The NMR spectra at 400.1 MHz ( 1 H), 128.4 MHz ( 11 B) and 100.0 MHz ( 13 C) were recorded with a Bruker Avance-400 spectrometer (Bruker, Zurich, Switzerland) (See Supplementary Materials).The residual signal of the NMR solvent relative to tetramethylsilane was taken as the internal reference standard for 1 H and 13 C NMR spectra.11BNMR spectra were referenced using BF 3 •Et 2 O as the external standard.Infrared spectra were recorded on an IR Prestige-21 (SHIMADZU) instrument (Shimadzu Corporation, Duisburg, Germany).