Synthesis of 3-Aryl-ortho-carboranes with Sensitive Functional Groups

A simple and efficient method was developed for the one-pot synthesis of 3-aryl derivatives of ortho-carborane with sensitive functional groups using 3-iodo-ortho-carborane and aryl zinc bromides that were generated in situ. A series of 3-aryl-ortho-carboranes, including those containing nitrile and ester groups, 3-RC6H4-1,2-C2B10H11 (R = p-Me, p-NMe2, p-OCH2OMe, p-OMe, o-CN, p-CN, o-COOEt, m-COOEt, p-COOEt) was synthesized using this approach. The solid-state structures of 3-RC6H4-1,2-C2B10H11 (R = p-OMe, o-CN, and p-CN) were determined by single crystal X-ray diffraction. The intramolecular hydrogen bonding involving the ortho-substituents of the aryl ring and the CH and BH groups of carborane was discussed.

The synthesis of the B-aryl derivatives of carboranes is mainly based on the Pdcatalyzed cross-coupling reactions of their iodo derivatives with aryl Grignard reagents (Kumada cross-coupling). In this way, various 9-aryl and 9,12-diaryl derivatives of orthocarborane, 9-aryl and 9,10-diaryl derivatives of meta-carborane, and 2-aryl derivatives of para-carborane were synthesized [34][35][36][37][38][39][40][41][42]. However, the available substituents on the aromatic ring in these reactions are strictly limited due to the high reactivity of the Grignard reagents. Mild B-arylation of carboranes via the Suzuki cross-coupling reactions of aryl boronic acids with 9-iodo-meta-and 2-iodo-para-carboranes were reported [43,44]. These cross-coupling reactions can be used for the direct introduction of functionalized aryl substituents that are not compatible with the Kumada reaction conditions. However, this approach turned out to be ineffective for ortho-carborane because in order to facilitate the transmetallation step in the Suzuki cross-coupling reactions, inorganic bases such as F − or OH − are usually used, which are strong nucleophiles that can lead to the deboronation of the ortho-carborane cage.
4,5-Diphenyl-and 3,6-diphenyl-ortho-carboranes were obtained from the Pd-and Rh-catalyzed B-H activation reactions that started from ortho-carborane derivatives containing removable carboxylic- [45] and imine-directing [46] functional groups, respectively. 3,6-Diphenyl-ortho-carborane was prepared as well by the Ir-catalyzed borylation of ortho-carborane via direct B-H activation followed by the Pd-catalyzed Suzuki crosscoupling of the resulting 3,6-(Bpin) 2 -ortho-carborane with phenyl bromide [47]. 3-Phenylortho-carborane and some its C-substituted analogues can be obtained via the insertion of a BPh fragment into the nido-carborane cage by the reaction with PhBCl 2 under basic conditions [48][49][50]. However, this approach cannot be applied to the synthesis of a wide range of 3-aryl derivatives due to the practical unavailability of many ArBCl 2 reagents, as well as because of their high reactivity, which excludes the use of aryls with sensitive functional groups. 3-Phenyl-and 3-(9-anthracenyl)-ortho-carboranes were prepared by the Pdcatalyzed cross-coupling of 3-iodo-ortho-carborane with the corresponding aryl Grignard reagents [51]. However, the range of available substituents on the aromatic ring in these reactions is also very limited due to the high reactivity of the Grignard reagents. Moreover, it was found that reactions 3-iodo-ortho-carborane with organometallic reagents, which are "hard" nucleophiles, in the presence of a catalytic amount of [Pd(PPh 3 ) 4 ] can lead to the loss of a halogen with the formation of 1,3-dehydro-ortho-carboryne [52], whereas the reaction with an equimolar amount of [Pd(PPh 3 ) 4 ] in the presence of K 2 CO 3 in DMF proceeds with the decapitation of the carborane cage resulting in nido-carborane [7,8-C 2 B 9 H 12 ] − as the final product [53]. The preparation of 3-phenyl-ortho-carborane by the reaction of the diazonium derivative of ortho-carborane [3-N 2 -1,2-C 2 B 10 H 11 ]BF 4 with the Grignard reagent was reported [54]; however, in our hands these reactions led exclusively to the 3-arylazo derivatives of ortho-carborane [55]. The attempt to use the Suzuki cross-coupling reaction of 3-iodo-ortho-carborane with aryl boronic acids only gave good results for aryls containing electron-donating substituents, while reactions with aryl boronic acids containing electron-withdrawing substituents (-CN, -NO 2 ) only led to the desired carboranes in low yields [56]. Recently, the direct arylation of ortho-carborane via Pd-catalyzed B-H activation has been reported, but this approach has been optimized for the synthesis of the 3,6-diaryl derivatives rather than the 3-aryl derivatives [57]. A series of 3-aryl derivatives of ortho-carborane were prepared by Pd-catalyzed B-H activation reactions with aryl iodides under functional group assistance; however, these reactions are currently only of academic interest rather than real synthetic methods [58,59]. Recently, we proposed a convenient and mild one-pot method for the synthesis of 9-aryl-and 9,12-diaryl-ortho-carboranes with sensitive functional groups, including esters and nitriles, using sequential Co-and Pd-catalyzed reactions [60].
In this contribution, we describe the application of this method for the synthesis of a series of 3-aryl-ortho-carboranes, including those containing sensitive functional groups.

Results and Discussion
The method proposed is based on the mild generation of aryl zinc reagents followed by their Pd-catalyzed cross-coupling with 3-iodo-ortho-carborane. The aryl zinc reagents were prepared via the Co-catalyzed reaction of aryl bromides containing various functional groups with zinc dust [61][62][63]. The organozinc compounds that are obtained in this way can be easily coupled with various aryl iodides in the presence of a catalytic amount of (Ph 3 P) 2 PdCl 2 [63]. Previously, we had successfully used this approach for the synthesis of 9-aryl-ortho-carboranes containing functional groups that were sensitive to organolithium and organomagnesium reagents [60].
Aryl zinc 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 that was generated from allyl chloride and zinc metal in the presence of 25 mol.% of CoBr 2 and a catalytic amount of trifluoroacetic acid in acetonitrile at ambient temperature (Scheme 1). of (Ph3P)2PdCl2 [63]. Previously, we had successfully used this approach for the synthesi of 9-aryl-ortho-carboranes containing functional groups that were sensitive to organolith ium and organomagnesium reagents [60].
Aryl zinc bromides containing various substituents, including sensitive functiona groups (-CN, -COOEt), were prepared by the reaction of the corresponding aryl bromide with allyl zinc chloride/bromide that was generated from allyl chloride and zinc metal in the presence of 25 mol.% of CoBr2 and a catalytic amount of trifluoroacetic acid in acetoni trile at ambient temperature (Scheme 1). The synthesized 3-aryl-ortho-carboranes were characterized by 1 H, 13 C and 11 B NMR spectroscopy. The 1 H and 13 C NMR spectra of all compounds contain signals of the corre sponding aryl substituents as well as the signals of the carborane cage. It should be noted that the signals of the aromatic hydrogens in the 1 H NMR spectra of 3-aryl-ortho-car boranes in CDCl3 are noticeably shifted to the downfield region in comparison with th signals of the corresponding 9-aryl-ortho-carboranes [60], with a difference in th weighted average chemical shift of aromatic hydrogens in the range of 0.11 to 0.34 ppm This is in agreement with the transition from the markedly electron-donating ortho-car boran-9-yl group to the slightly electron-accepting ortho-carboran-3-yl group [64]. In gen eral, the chemical shift of the carborane CH groups depends slightly on the presence o electron-donating (3.65-3.69 ppm) or electron-accepting (3.74-3.77 ppm) substituents in the aromatic ring. However, most notable is the strong downfield shift of the CH car borane signals in the case of ortho-substituted aryl groups (4.38 and 4.37 ppm for 3-(2′ EtOOCC6H4)-1,2-C2B10H11 (8) and 3-(2′-NCC6H4)-1,2-C2B10H11 (6), respectively). In the firs case, it can be explained by the formation of a hydrogen bond between the carborane CH group and the ester carbonyl group. It is known that the chemical shifts of the CH group of carboranes and metallacarboranes are very sensitive to the formation of intramolecula of (Ph3P)2PdCl2 [63]. Previously, we had successfully used this approach for the synthesis of 9-aryl-ortho-carboranes containing functional groups that were sensitive to organolithium and organomagnesium reagents [60]. Aryl zinc 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 that was generated from allyl chloride and zinc metal in the presence of 25 mol.% of CoBr2 and a catalytic amount of trifluoroacetic acid in acetonitrile at ambient temperature (Scheme 1). The synthesized 3-aryl-ortho-carboranes were characterized by 1 H, 13 C and 11 B NMR 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 the carborane cage. It should be noted that the signals of the aromatic hydrogens in the 1 H NMR spectra of 3-aryl-ortho-carboranes in CDCl3 are noticeably shifted to the downfield region in comparison with the signals of the corresponding 9-aryl-ortho-carboranes [60], with a difference in the weighted average chemical shift of aromatic hydrogens in the range of 0.11 to 0.34 ppm. This is in agreement with the transition from the markedly electron-donating ortho-carboran-9-yl group to the slightly electron-accepting ortho-carboran-3-yl group [64]. In general, the chemical shift of the carborane CH groups depends slightly on the presence of electron-donating (3.65-3.69 ppm) or electron-accepting (3.74-3.77 ppm) substituents in the aromatic ring. However, most notable is the strong downfield shift of the CH carborane signals in the case of ortho-substituted aryl groups (4.38 and 4.37 ppm for 3-(2′-EtOOCC6H4)-1,2-C2B10H11 (8) and 3-(2′-NCC6H4)-1,2-C2B10H11 (6), respectively). In the first case, it can be explained by the formation of a hydrogen bond between the carborane CH group and the ester carbonyl group. It is known that the chemical shifts of the CH groups of carboranes and metallacarboranes are very sensitive to the formation of intramolecular Scheme 2. Synthesis of 3-aryl-ortho-carboranes.

Zn, CoBr
The synthesized 3-aryl-ortho-carboranes were characterized by 1 H, 13 C and 11 B NMR 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 the carborane cage. It should be noted that the signals of the aromatic hydrogens in the 1 H NMR spectra of 3-aryl-orthocarboranes in CDCl 3 are noticeably shifted to the downfield region in comparison with the signals of the corresponding 9-aryl-ortho-carboranes [60], with a difference in the weighted average chemical shift of aromatic hydrogens in the range of 0.11 to 0.34 ppm. This is in agreement with the transition from the markedly electron-donating ortho-carboran-9-yl group to the slightly electron-accepting ortho-carboran-3-yl group [64]. In general, the chemical shift of the carborane CH groups depends slightly on the presence of electrondonating (3.65-3.69 ppm) or electron-accepting (3.74-3.77 ppm) substituents in the aromatic ring. However, most notable is the strong downfield shift of the CH carborane signals in the case of ortho-substituted aryl groups (4.38 and 4.37 ppm for 3-(2 -EtOOCC 6 H 4 )-1,2-C 2 B 10 H 11 (8) and 3-(2 -NCC 6 H 4 )-1,2-C 2 B 10 H 11 (6), respectively). In the first case, it can be explained by the formation of a hydrogen bond between the carborane CH group and the ester carbonyl group. It is known that the chemical shifts of the CH groups of carboranes and metallacarboranes are very sensitive to the formation of intramolecular hydrogen bonds [65,66]. On the other hand, the signals of the carbonyl group in the 13 C NMR spectra are also sensitive to the formation of hydrogen bonds [67,68]. Indeed, the signal of the carbonyl group in 3-(2 -EtOOCC 6 H 4 )-1,2-C 2 B 10 H 11 (8) (170.0 ppm) demonstrates a significant downfield shift compared to those found in 3-(3 -EtOOCC 6 H 4 )-1,2-C 2 B 10 H 11 (9) (166.5 ppm) and 3-(4 -EtOOCC 6 H 4 )-1,2-C 2 B 10 H 11 (10) (166.4 ppm), as well as in 9-(2 -EtOOCC 6 H 4 )-1,2-C 2 B 10 H 11 (161.5 ppm) [60], which is a clear confirmation of the formation of an intramolecular hydrogen bond. It is also worth noting that the mass spectrum of 8 in the negative mode, in contrast to the mass spectra of other 3-aryl-ortho-carboranes, exhibits a peak which, in addition to the loss of the carborane proton, corresponds to the abstraction of the ethanol molecule. This is caused by the attack of the carbonyl group by the nucleophile, which is formed upon the loss of the carborane CH proton, leading to intramolecular cyclization with the elimination of ethanol and the formation of carboranyl fluorenone 1,3-µ-C(O)C 6 H 4 -1,2-C 2 B 10 H 10 . In the case of 3-(2 -NCC 6 H 4 )-1,2-C 2 B 10 H 11 , the nature of the interactions involving the carborane CH group is less clear.
This prompted us to perform an X-ray diffraction study of the synthesized 3-aryl-orthocarboranes. The solid-state structures of carboranes 3, 5-7, 9 and 10 were determined by single crystal X-ray diffraction (Figure 1). The most characteristic feature of the structure of 3-aryl-ortho-carboranes is the deviation of the exo-polyhedral B-C bond from the B(3)-B(10) axis of the carborane cage towards the carborane C(1)-C(2) bond (See Table 1).
This can be related to the fact that the B(3)-C bonds are somewhat shorter than the B(3)-B bonds, as well as to the participation of the aryl substituents in intermolecular interactions. The orientation of the aryl ring with respect to the carborane cage in the obtained derivatives is different. For compounds 3, 5, 7, and 9, the projection line of the phenyl ring onto the C 2 B 3 plane passes through the B(7) or B(4) atom and the center of the opposite B-C bond, while for compounds 6 and 10, it passes through the C(2) atom and the center of the B(4)-B(8) bond. As shown in Figure 1, a C phen -H· · · H-B(C) contact is observed in all of the compounds. In some cases, it is slightly longer than the sum of the van-der-Waals radii (2.4 Å [69]), while it is somewhat shorter in the other cases. The shortest distance (2.18 Å) is observed for compound 6 with an ortho-cyanophenyl substituent. In structures 5 and 7, there are no short contacts between the aryl ring and the carborane cage, while in structure 6 the aryl ring is rotated in such a way that leads to the formation of a short (2.174 Å) C(2)H· · · HC(8) contact between the aryl and carborane hydrogens. It should be noted that the presence of such contacts was previously found in the structure of 1-phenylortho-carborane [70]. In addition, there is a slightly shortened contact of the B-H· · · π(N≡C-) type between the B(4)-H group of carborane and the cyano group of the aryl substituent. It should be mentioned that the existence of the intramolecular B-H· · · π(N≡C-) hydrogen bonds in the nido-carborane derivative 10-N≡CCH 2 (Me)S-7,8-C 2 B 9 H 11 was postulated earlier based on the NMR spectroscopy data [71].
In order to understand in more detail the observed differences in molecular conformation, we carried out a comparative quantum chemical study for compounds 7 and 6, which have paraand ortho-cyanophenyl substituents and significantly differ in their molecular conformation and intramolecular contacts. The calculation was done using the GAUSSIAN program [72] at the PBE0/def2tzvp level of theory that was shown to provide realistic geometrical and energetic properties for different types of compounds [73][74][75]. In order to search for preferential molecular conformation, the aryl substituent was rotated about the B  In order to understand in more detail the observed differences in molecular conformation, we carried out a comparative quantum chemical study for compounds 7 and 6, which have para-and ortho-cyanophenyl substituents and significantly differ in their  (9), and 3-(p-EtOOCC 6 H 4 )-1,2-C 2 B 10 H 11 (10) (both symmetrically independent molecules are presented) showing atomic numbering. Thermal ellipsoids are drawn at 50% probability level. For each structure, the shortest H· · · H and H· · · π contacts are shown by dashed lines. The H· · · H distances are equal to 2.43, 2.43, 2.18, 2.44, 2.47, 2.27, and 2.37 Å for compounds 3, 5, 6, 7, 9, 10A, and 10A , respectively. The distance of the H· · · π contact for 6 (from H atom δ to the center of the C≡N bond) is equal to 2.80(2) Å. Table 1. Some selected angles in 3-aryl-ortho-carboranes 3, 5-7, 9 and 10.

C(3)-B(3)-B(10) C(3)-B(3)-C(1) C(3)-B(3)-C(2) C(3)-B(3)-B(8) 3
173.72 (9) 121.84 (9) 122.88 (9) 128.70 (9)  5 171.88 (12) 120.71 (12) 120.91 (11) 130.56 (11)  6 171.08(10) 120.91 (9) 119.28 (9) 130.81 (9)  molecular conformation and intramolecular contacts. The calculation was done using the GAUSSIAN program [72] at the PBE0/def2tzvp level of theory that was shown to provide realistic geometrical and energetic properties for different types of compounds [73][74][75]. In order to search for preferential molecular conformation, the aryl substituent was rotated about the B(3)-C(3) bond with a step of 5°. The results are shown in Figure 2. As expected, for the para-cyanophenyl derivative (7), the barrier to rotation is small and the conformational curve is symmetrical with respect to the plane passing through the B(3) and B(8) atoms and the center of the C(1)-C(2) bond. The experimental structure corresponds to the global minimum. In the case of the ortho-cyanophenyl derivative (6), there are two equivalent local minima and a global minimum, which probably corresponds to structure 6 in solution, and which is ~5 kcal/mol lower in energy. Using the geometries of the local and global minima as starting points, we carried out an additional optimization without any restrictions. Both optimizations converged to true minima, global and local, respectively. The QTAIM theory [76] was utilized to analyze the intramolecular noncovalent interactions. A search for the bond critical points (using the AIMALL program [77]) revealed the presence of two intramolecular attractive interactions between the carborane cage and the aryl substituent for both local and global minima ( Figure 3). The energies of the observed noncovalent interactions were estimated using the empirical correlation between interaction energy and potential energy density at the bond critical point (E = 1/2V(r)) [78], which is frequently utilized for energetic analysis [73,79,80].
The stabilization of the global minimum was provided by the B-H…H-Cphen (−1.6 kcal/mol) and Ccarb-H···π (−3.8 kcal/mol) nonbonded interactions, while Ccarb-H···H-Cphen (−2.4 kcal/mol) and B-H···π (−1.3 kcal/mol) contacts were observed for the local minimum which, evidently, was weaker. At the same time, the experimentally observed solid-state structure of compound 6 corresponds to the local minima which should be caused by the crystal-packing influence. Indeed, in the crystal structure of 6, a relatively strong intermolecular hydrogen bond C(2)-H(2)···N(1) is formed ( Figure S1 in the Supplementary Materials). Such an interaction cannot exist for a molecular conformation corresponding to the global minima due to steric reasons. As expected, for the para-cyanophenyl derivative (7), the barrier to rotation is small and the conformational curve is symmetrical with respect to the plane passing through the B(3) and B(8) atoms and the center of the C(1)-C(2) bond. The experimental structure corresponds to the global minimum. In the case of the ortho-cyanophenyl derivative (6), there are two equivalent local minima and a global minimum, which probably corresponds to structure 6 in solution, and which is~5 kcal/mol lower in energy. Using the geometries of the local and global minima as starting points, we carried out an additional optimization without any restrictions. Both optimizations converged to true minima, global and local, respectively. The QTAIM theory [76] was utilized to analyze the intramolecular noncovalent interactions. A search for the bond critical points (using the AIMALL program [77]) revealed the presence of two intramolecular attractive interactions between the carborane cage and the aryl substituent for both local and global minima (Figure 3). The energies of the observed noncovalent interactions were estimated using the empirical correlation between interaction energy and potential energy density at the bond critical point (E = 1/2V(r)) [78], which is frequently utilized for energetic analysis [73,79,80]. Based on these results we can suggest that experimental molecular conformation of compound 10, for which intramolecular Cphen-H···H-Ccarb shortened contacts are observed, is also influenced by the crystal-packing effect ( Figure S2 in the Supplementary Materials).
In summary, the efficient method for the one-pot synthesis of 3-aryl-ortho-carboranes with sensitive functional groups using sequential Co-and Pd-catalyzed reaction was proposed. A series of functional aryl derivatives, including esters and nitriles, were synthesized and characterized by methods of the NMR spectroscopy and single crystal X-ray diffraction.

Experimental Part
General Synthetic Procedure and Characterization of 3-Aryl-ortho-Carboranes 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 an additional 1 h. Then, 3-iodo-ortho-carborane (1) (270 mg, 1.00 mmol) with bis(triphenylphosphine)palladium dichloride (14 mg, 0.02 mmol) were added. The reaction was stirred at room temperature overnight. After the 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 Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica to give the corresponding 3-aryl-ortho-carborane.
3-(4′-Methylphenyl)-ortho-carborane (2): 4-methylphenyl bromide (315 µL, 435 mg, 2.50 mmol) was used; diethyl ether was used as the eluent for column chromatography; a pale-yellow crystalline solid was obtained (195 mg, yield 83%). 1   The stabilization of the global minimum was provided by the B-H· · · H-C phen (−1.6 kcal/mol) and C carb -H· · · π (−3.8 kcal/mol) nonbonded interactions, while C carb -H· · · H-C phen (−2.4 kcal/mol) and B-H· · · π (−1.3 kcal/mol) contacts were observed for the local minimum which, evidently, was weaker. At the same time, the experimentally observed solid-state structure of compound 6 corresponds to the local minima which should be caused by the crystal-packing influence. Indeed, in the crystal structure of 6, a relatively strong intermolecular hydrogen bond C(2)-H(2)· · · N(1) is formed ( Figure S1 in the Supplementary Materials). Such an interaction cannot exist for a molecular conformation corresponding to the global minima due to steric reasons.
Based on these results we can suggest that experimental molecular conformation of compound 10, for which intramolecular C phen -H· · · H-C carb shortened contacts are observed, is also influenced by the crystal-packing effect ( Figure S2 in the Supplementary Materials).
In summary, the efficient method for the one-pot synthesis of 3-aryl-ortho-carboranes with sensitive functional groups using sequential Co-and Pd-catalyzed reaction was proposed. A series of functional aryl derivatives, including esters and nitriles, were synthesized and characterized by methods of the NMR spectroscopy and single crystal X-ray diffraction.

Experimental Part General Synthetic Procedure and Characterization of 3-Aryl-ortho-carboranes
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 an additional 1 h. Then, 3-iodo-ortho-carborane (1) (270 mg, 1.00 mmol) with bis(triphenylphosphine)palladium dichloride (14 mg, 0.02 mmol) were added. The reaction was stirred at room temperature overnight. After the 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 3-aryl-ortho-carborane.