Synthesis and Reactivity of Cyclic Oxonium Derivatives of nido-Carborane: A Review

Nucleophilic ring-opening reactions of cyclic oxonium derivatives of anionic boron hydrides are a convenient method of their modification which opens practically unlimited prospects for their incorporation into various macroand biomolecules. This contribution provides an overview of the synthesis and reactivity of cyclic oxonium derivatives of nido-carborane as well as half-sandwich complexes based on it.

Currently the main approach to the synthesis of nido-carborane derivatives is based on the deboronation of the corresponding ortho-carborane derivatives. This approach is widely used for the synthesis of C-substituted derivatives of nido-carborane, as well as derivatives containing substituents at the lower belt of the nido-carborane cage [40]. There are several general methods for the synthesis of B-substituted derivatives with substituents in the upper belt of the nido-carborane cage; however, most of them are used to obtain asymmetrically substituted derivatives [9-X-7,8-C 2 B 9 H 11 ] − [41][42][43][44][45][46][47][48][49].
Several approaches to the synthesis of symmetrically substituted derivatives of nidocarborane [10-X-7,8-C 2 B 9 H 11 ] − with boron-sulfur [50,51] and boron-nitrogen [52][53][54][55] bonds have also been developed recently; however, the greatest interest is the functionalization of nido-carborane via its cyclic oxonium derivatives. Previously, this approach was successfully used for the synthesis of numerous derivatives of closo-decaborate and The proposed mechanism of this reaction includes the initial abstraction of hydrogen hydride from position 9 by iron(III) chloride as a Lewis acid with the formation of a quasiborinium cation. In the absence of strong nucleophiles, this intermediate can be isomerized to a more stable symmetric form with a quasi-electrophilic center at position 10, which is then attacked by an ether solvent molecule as a weak but most accessible nucleophile. As a result, a mixture of 9-and 10-substituted isomers is formed [60]. This mechanism is known as electrophile-induced nucleophilic substitution (EINS) and is considered as one of the main mechanisms of substitution of hydrogen atoms in polyhedral boron hydrides.
It is assumed that the selectivity of the reactions in these cases is determined by the fact that the endo-polyhedral hydrogen atom of nido-carborane cage is replaced at the first stage of the reaction by a mercury atom with the formation of η 1 -metallacarborane, in which mercury is bound to the B(10) atom of the dicarbollide ligand [64][65][66][67]. Heating of this complex results in elimination of mercury and generation of quasi-electrophilic center at position 10 followed by its attack by the nucleophile [60].
Another convenient method for the synthesis of 1,4-dioxane derivative of nido-carborane is to heat in 1,4-dioxane the protonated form of nido-carborane 7,8-C 2 B 9 H 13 , which is formed by treating a suspension of the triethylammonium salt of nido-carborane with concentrated sulfuric acid in toluene [68].

Properties of Oxonium Derivatives of nido-Carborane. Reactions with Nucleophiles
The use of ring opening reactions of cyclic oxonium derivatives of polyhedral boron hydrides under the action of nucleophiles for the preparation of their various derivatives is well known [56][57][58]. In the case of nido-carborane, this method has several advantages. First of all, the substituent is symmetrically located at position 10 of the boron cluster. This avoids the formation of racemic and diastereomeric mixtures of products and greatly facilitates the identification of compounds by NMR, which is one of the main methods for characterization of this type of compounds. Another advantage is that the yield of the target product is in most cases very high or nearly quantitative. In addition, the variety of oxonium derivatives makes it possible to obtain products with different lengths of the spacer between the nido-carborane cage and the substituent.
Thus, by the ring-opening reactions of tetrahydrofuran and 1,4-dioxane derivatives of nido-carborane with phenolates a series of nido-carborane-based carboxylic acids with different spacer lengths between nido-carborane cage and functional group was prepared. Phenolates were generated by the treatment of hydroxybenzoic acids with K 2 CO 3 in acetonitrile [60] (Scheme 3). The reaction of the 1,4-dioxane derivative of nido-carborane with methyl ether of p-hydroxybenzoate in the same conditions led to the corresponding K[10-(4-CH 3 OOCC 6 H 4 O)-CH 2 CH 2 OCH 2 CH 2 O-7,8-C 2 B 9 H 11 ] [76]. The obtaining of 10-substituted derivatives of nido-carborane in the case of oxonium derivatives and products of their ring-opening reactions leaves free the positions 9 and 11 of nido-carborane cage. This can be used for the following substitution, such as, for example, the halogenation, which was carried out for K[1 0-(4-HOOCC 6   The ring-opening reactions of 1,4-dioxane and tetrahydropyran derivatives of nidocarborane with 7-diethyl-4-hydroxycoumarin led to the water-soluble conjugates of the nido-carborane cluster with coumarin [77] (Scheme 6). The measurement of the distribution coefficients (log D 7,4 ) of the obtained compounds showed their appropriate lipophilicity for medicinal applications [77].  The nido-carborane thiol [10-HSCH 2 CH 2 OCH 2 CH 2 O-7,8-C 2 B 9 H 11 ] − can also be obtained directly by the reaction of 10-O(CH 2 CH 2 ) 2 O-7,8-C 2 B 9 H 11 with excess of aqueous sodium hydrosulfide in tetrahydrofuran. The by-product of this reaction is a thioether [(10-CH 2 CH 2 OCH 2 CH 2 O-7,8-C 2 B 9 H 11 ) 2 S] 2− [71].
The reactions of 1,4-dioxane [63,71] and tetrahydropyran [63] derivatives of nidocarborane with ammonia in tetrahydrofuran led to the corresponding ammonium derivatives of nido-carborane. The obtained compounds were used for the conjugation with 3-nitro-1,8-naphthalic anhydride in the presence of Et 3 N to give water-soluble boron containing 3-nitro-1,8-naphthalimides, which are potential interesting agents for boron neutron capture therapy [63] (Scheme 14). The molecular structure of 10-NH 3 CH 2 CH 2 OCH 2 CH 2 O-7,8-C 2 B 9 H 11 was determined by single crystal X-ray diffraction [71] (Figure 4). The charge-compensated nido-carborane-based conjugates with mitonafide were prepared in mild conditions by the ring-opening reactions of 1,4-dioxane and tetrahydropyran derivatives of nido-carborane with dimethylamino group of mitonafide [63] (Scheme 15). The molecular structure of 10-Me 2 SCH 2 CH 2 OCH 2 CH 2 O-7,8-C 2 B 9 H 11 was determined by single crystal X-ray diffraction [88] (Figure 5). The dimethyl-and diethyloxonium derivatives of nido-carborane are also easily reacted with nucleophiles with the loss of the methyl or ethyl group, respectively, and can be used as alkylating agents [72,73].

Half-Sandwich Complexes
At the moment, for nido-carborane-based half-sandwich complexes only derivatives with tetrahydrofuran are known. With rare exceptions, they were obtained randomly, due to the fact that reactions involving metallacarboranes are most often carried out in dry tetrahydrofuran.
The molecular structure of [3-(η 3 -C 3 H 5 )-3-(CO) 2 -3-Mo(8-Et 2 O-1,2-Me 2 -1,2-C 2 B 9 H 8 )] was determined by X-ray diffraction [92] (Figure 7).  In summary, the oxonium derivatives of nido-carborane offer a convenient and simple method for modifying the nido-carborane cluster, which allows both the introduction of necessary functional groups into the side substituent and the direct preparation of conjugates with the required molecules. The resulting products of their ring-opening reactions are symmetric derivatives free from enantiomeric and diasteriomeric mixtures.