One-Pot Synthesis of B -Aryl Carboranes with Sensitive Functional Groups Using Sequential Cobalt- and Palladium-Catalyzed Reactions

: The simple and efficient method was developed for the one-pot synthesis of B -substituted aryl derivatives of ortho -carborane with functional groups sensitive to organolithium and organomagnesium reagents using 9-iodo- ortho -carborane and generated in situ organozinc compounds. The method proposed was used to prepare a series of 9-aryl- ortho -carboranes, including those containing nitrile and ester groups, 9-RC 6 H 4 -1,2-C 2 B 10 H 11 (R = p -Me, p -NMe 2 , p -OCH 2 OMe, o -OMe, p -OMe, o -CN, p -CN, o -COOEt, m -COOEt, and p -COOEt). It was demonstrated that the same approach can be used for synthesis of diaryl derivatives of ortho -carborane 9,12-(RC 6 H 4 ) 2 -1,2-C 2 B 10 H 10 (R = H, p -Me). The solid-state structures of 9-RC 6 H 4 -1,2-C 2 B 10 H 11 (R = p -NMe 2 , p -OCH 2 OMe, o -OMe, o -CN, p -CN, m -COOEt, and p -COOEt) and 9,12-( p -MeC 6 H 4 ) 2 -1,2-C 2 B 10 H 10 were determined by single crystal X-ray diffraction.


Introduction
Aryl derivatives of icosahedral carboranes C 2 B 10 H 12 ( Figure 1) are of interest for a wide variety of applications, starting with medical chemistry [1][2][3][4] and ending with the development of new materials [5][6][7][8][9][10][11][12]. This necessitates the development of new convenient methods for their synthesis. Since the properties of the CH and BH groups in carboranes differ significantly, different methods are used to synthesize their Cand B-aryl derivatives. There are several methods for synthesis of C-arylcarboranes, where an aryl group is directly bonded to the cage carbon [13]. A general method involves the use of decaborane nido-B10H14 and reacting it with Lewis bases, such as dialkyl sulfides, acetonitrile or alkylamines. This leads to the formation of compounds with a general formula of 6,9-arachno-B10H12L2. On reacting this species with

Results and Discussion
The possibility of synthesis of B-aryl derivatives of ortho-carborane using organozinc reagents has been demonstrated earlier [40,41]. However, the preparation of these organozinc compounds was achieved by a transmetallation reaction of preformed organolithium or magnesium counterparts with zinc halide. Later, various methods were elaborated for preparation of zinc organometallics bearing highly sensitive functional groups [45,46]. However, most of these methods are based on the use of bimetallic zinc-lithium or zinc-magnesium reagents and, despite their indisputable synthetic utility, the use of such activated zinc reagents requires specific conditions together with careful handling. Therefore, such methods for the synthesis of organozinc compounds that do not require the use of organolithium and organomagnesium reagents are of particular interest. We chose the method based on Co-catalyzed preparation of arylzinc organics starting from readily available aryl bromides and zinc dust [47][48][49]. Thus, the obtained organozinc species can be easily coupled with various aryl iodides in the presence of a catalytic amount of (Ph 3 P) 2 PdCl 2 [49]. In addition to the formation of the C-C bond, this approach can be used to form the C-B bond in the reaction of aryl bromides with haloboronic esters, leading to the formation of the corresponding arylboronates [50]. The reaction was found to be tolerate to many functional groups including nitriles and esters. Earlier this approach was used for synthesis of 1,4-bis(ortho-carboran-8 -yl)benzene staring from 8-iodo-ortho-carborane [51].
Arylzinc bromides containing various substituents including sensitive functional groups (-CN, -COOEt) were prepared by the reaction of the corresponding aryl bromides with allyl zinc chloride/bromide generated from allyl chloride and zinc metal in the presence of 25 mol % of CoBr 2 and catalytic amount of trifluoroacetic acid in acetonitrile at ambient temperature (Scheme 1).
The possibility of synthesis of B-aryl derivatives of ortho-carborane using organozinc reagents has been demonstrated earlier [40,41]. However, the preparation of these organozinc compounds was achieved by a transmetallation reaction of preformed organolithium or magnesium counterparts with zinc halide. Later, various methods were elaborated for preparation of zinc organometallics bearing highly sensitive functional groups [45,46]. However, most of these methods are based on the use of bimetallic zinc-lithium or zinc-magnesium reagents and, despite their indisputable synthetic utility, the use of such activated zinc reagents requires specific conditions together with careful handling. Therefore, such methods for the synthesis of organozinc compounds that do not require the use of organolithium and organomagnesium reagents are of particular interest. We chose the method based on Co-catalyzed preparation of arylzinc organics starting from readily available aryl bromides and zinc dust [47][48][49]. Thus, the obtained organozinc species can be easily coupled with various aryl iodides in the presence of a catalytic amount of (Ph3P)2PdCl2 [49]. In addition to the formation of the C-C bond, this approach can be used to form the C-B bond in the reaction of aryl bromides with haloboronic esters, leading to the formation of the corresponding arylboronates [50]. The reaction was found to be tolerate to many functional groups including nitriles and esters. Earlier this approach was used for synthesis of 1,4-bis(ortho-carboran-8′-yl)benzene staring from 8-iodo-ortho-carborane [51].
Arylzinc bromides containing various substituents including sensitive functional groups (-CN, -COOEt) were prepared by the reaction of the corresponding aryl bromides with allyl zinc chloride/bromide generated from allyl chloride and zinc metal in the presence of 25 mol % of CoBr2 and catalytic amount of trifluoroacetic acid in acetonitrile at ambient temperature (Scheme 1). The reactions of the prepared arylzinc bromides with 9-iodo-ortho-carborane in the presence of 2 mol.% of [(Ph3P)2PdCl2] in acetonitrile at room temperature lead to its nearly quantitative conversion to the corresponding 9-aryl-ortho-carboranes with isolated yields varying from 60 to 91% (Schemes 2 and 3). The reactions of the prepared arylzinc bromides with 9-iodo-ortho-carborane in the presence of 2 mol.% of [(Ph 3 P) 2 PdCl 2 ] in acetonitrile at room temperature lead to its nearly quantitative conversion to the corresponding 9-aryl-ortho-carboranes with isolated yields varying from 60 to 91% (Schemes 2 and 3). The synthesized 9-aryl-ortho-carboranes were characterized by the methods of 1 H, 13 C and 11 B NMR and IR spectroscopy. The 1 H and 13 C NMR spectra of all compounds contain signals of the corresponding aryl substituents as well as the signals of two non-equivalent carborane CH groups in the Catalysts 2020, 10, 1348 4 of 13 range of 3.3-3.7 ppm and 48-53 ppm, respectively. The 11 B NMR spectra of the 9-aryl-ortho-carboranes contain singlet of the C-substituted boron atom at~6-8 ppm and five doublets with a total integral ratio of 1:1:2:2:2:2 (except for the spectra of 9-cyanophenyl and 9-ethoxycarbonylphenyl derivatives with a ratio of 1:1:2:4:2 ratio). The solid-state structures of all new 9-aryl-ortho-carboranes (except for 6, which is liquid) were determined by single crystal X-ray diffraction (Figures 2 and 3). The synthesized 9-aryl-ortho-carboranes were characterized by the methods of 1 H, 13 C and 11 B NMR and IR spectroscopy. The 1 H and 13 C NMR spectra of all compounds contain signals of the corresponding aryl substituents as well as the signals of two non-equivalent carborane CH groups in the range of 3.3-3.7 ppm and 48-53 ppm, respectively. The 11 B NMR spectra of the 9-aryl-orthocarboranes contain singlet of the C-substituted boron atom at ~ 6-8 ppm and five doublets with a total integral ratio of 1:1:2:2:2:2 (except for the spectra of 9-cyanophenyl and 9-ethoxycarbonylphenyl derivatives with a ratio of 1:1:2:4:2 ratio). The solid-state structures of all new 9-aryl-ortho-carboranes (except for 6, which is liquid) were determined by single crystal X-ray diffraction (Figures 2 and 3).     The same approach can be used for synthesis of disubstituted aryl derivatives: the reactions of phenyland p-tolylzinc bromides with 9,12-diiodo-ortho-carborane in the presence of 4 mol. % of [(Ph 3 P) 2 PdCl 2 ] in acetonitrile at room temperature lead to the corresponding 9,12-diaryl-ortho-carboranes (Scheme 4).
Catalysts 2020, 10, x FOR PEER REVIEW 6 of 14 The solid-state structures of 9,12-di(p-tolyl)-ortho-carborane 14 was determined by single crystal X-ray diffraction ( Figure 4). The solid-state structures of 9,12-di(p-tolyl)-ortho-carborane 14 was determined by single crystal X-ray diffraction ( Figure 4). The solid-state structures of 9,12-di(p-tolyl)-ortho-carborane 14 was determined by single crystal X-ray diffraction ( Figure 4).  (14) showing atomic numbering. Thermal ellipsoids are drawn at 50% probability level. The molecule occupies special position. Numbering of symmetrically dependent part are marked with letter "A".  (14) showing atomic numbering. Thermal ellipsoids are drawn at 50% probability level. The molecule occupies special position. Numbering of symmetrically dependent part are marked with letter "A".

General Methods
9-Iodo-ortho-carborane (1) [52], 9,12-diiodo-ortho-carborane (12) [28] and bis(triphenylphosphine) palladium dichloride [53] were prepared according to the literature procedures. Anhydrous cobalt dibromide was prepared from cobalt bromide hexahydrate by heating at 160 • C under vacuum for 3 h and stored under argon atmosphere. Acetonitrile was dried using standard procedures [54]. All other chemical reagents were purchased from Sigma Aldrich, Acros Organics and ABCR and used without purification. All reactions were carried out at argon atmosphere. The reaction progress was monitored by thin layer chromatography (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 MHz ( 1 H), 128 MHz ( 11 B) and 100 MHz ( 13 C) were recorded with Varian Inova 400 spectrometer. The residual signal of the NMR solvent relative to tetramethylsilane was taken as the internal reference for 1 H and 13 C NMR spectra. 11 B NMR spectra were referenced using BF 3 •Et 2 O as external standard. Infrared spectra were recorded on an IR Prestige-21 (SHIMADZU) instrument.

General Synthetic Procedure and Characterization of Monosubstituted B-Aryl Derivatives of Ortho-Carborane
Allyl chloride (82 µL, 77 mg, 1.00 mmol) and trifluoroacetic acid (25 µL, catalytic amount) were added to a blue mixture of zinc powder (490 mg, 7.50 mmol) and anhydrous cobalt dibromide (55 mg, 0.25 mmol) in 2.5 mL of fresh distilled acetonitrile. The resulting dark orange mixture was stirred at room temperature for 15 min. Then corresponding aryl bromide (2.50 mmol) was added, and reaction was stirred at room temperature for another 1 h. Then 9-iodo-ortho-carborane (270 mg, 1.00 mmol) with bis(triphenylphosphine)palladium dichloride (14 mg, 0.02 mmol, catalytic amount) were added. The reaction was stirred at room temperature overnight. After removal of volatiles under reduced pressure, the residue was washed with water (25 mL), dichloromethane (3 × 25 mL) and acetone (until no trace of carborane appeared on TLC). The organic phases were combined, dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica to give the corresponding B-aryl derivative of ortho-carborane.

General Synthetic Procedure and Characterization of Disubstituted B-Aryl Derivatives of Ortho-Carborane
Allyl chloride (82 µL, 77 mg, 1.00 mmol) and trifluoroacetic acid (25 µL, catalytic amount) were added to a blue mixture of zinc powder (490 mg, 7.50 mmol) and anhydrous cobalt dibromide (55 mg, 0.25 mmol) in 2.5 mL of freshly distilled acetonitrile. The resulting dark orange mixture was stirred at room temperature for 15 min. Then corresponding aryl bromide (2.50 mmol) was added, and reaction was stirred at room temperature for another 1 h. Then 9,12-diiodo-ortho-carborane (198 mg, 0.50 mmol) with bis(triphenylphosphine)palladium dichloride (14 mg, 0.02 mmol, catalytic amount) were added. The reaction mixture was stirred at room temperature overnight and filtered, the solid was washed with hot acetonitrile (until no trace of carborane appeared on TLC). The organic phases were combined and concentrated under reduced pressure. The crude product was washed by 5% HCl and water to remove inorganic solids and by Et 2 O and acetone to remove starting materials to give the corresponding diaryl derivatives of ortho-carborane.

Conclusions
In conclusion, the simple and efficient method was developed for the one-pot synthesis of B-substituted aryl derivatives of ortho-carborane with functional groups sensitive to organolithium and organomagnesium reagents using 9-iodo-ortho-carborane and generated in situ organozinc compounds. The method proposed provides near quantitative conversion of the starting 9-iodo-ortho-carborane to the corresponding aryl derivativs. A series of 9-aryl-ortho-carboranes, including those containing nitrile and ester groups, 9-RC 6 H 4 -1,2-C 2 B 10 H 11 (R = p-Me, p-NMe 2 , p-OCH 2 OMe, o-OMe, p-OMe, o-CN, p-CN, o-COOEt, m-COOEt, p-COOEt) was synthesized. The same approach was used for synthesis of the diaryl derivatives of ortho-carborane 9,12-(RC 6 H 4 ) 2 -1,2-C 2 B 10 H 10 (R = H, p-Me). The study of the applicability of this approach for the synthesis of aryl derivatives using other iodo derivatives of carboranes and metallacarboranes is in progress.