Abstract
A series of new closo- and nido-carborane based functional derivatives 1-X(CH2)nS-1,2-C2B10H11 (X=COOH, N3, CH(NH2)COOH) and [7-X(CH2)nS-7,8-C2B9H11]− (X=COOH, N3, NH2, CH(NH2)COOH) was prepared by alkylation of 1-mercapto-ortho-carborane. Dialkylsulfonium derivatives of nido-carborane 9-R(Me)S-7,8-C2B9H11 and 10-R(Me)S-7,8-C2B9H11 with boron-sulfur bond were prepared by alkylation of the corresponding methyl-carboranyl thioether. New types of intramolecular B–H···X and B–H···π(C≡C) interactions were found in nido-carborane alkylmethyl sulfonium derivatives 9-XCH2S(Me)S-7,8-C2B9H11 and 10-RC≡CCH2S(Me)S-7,8-C2B9H11, respectively. Isomeric methylsulfide derivatives of transition metal bis(dicarbollide) complexes [X,Y-(MeS)2-3,3′-M(1,2-C2B9H10)2]− (M=Co, Fe) were prepared starting from the corresponding methylcarboranyl thioethers. The intramolecular CHcarb···S(Me)S hydrogen bonding between the dicarbollide ligands in cobalt bis(dicarbollide) complexes results in stabilization of definite rotational isomers – transoid in the case of the 8,8′-isomer and gauche in the case of the 4,4′- and 4,7′-isomers.
Introduction
Icosahedral carboranes and their derivatives are subjects of continuous research interest for over 50 years due to combination of their high cage stability and enormous possibilities of their modification by substitution of carbon and boron cluster atoms by various heteroatoms as well as by substitution of hydrogen atoms by various functional groups [1]. Currently, derivatives of carboranes and metallacarboranes have found many interesting applications in different fields starting from development of new materials and ending with drugs design [1], [2], [3], [4]. It requires development of novel approaches to synthesis of carborane and metallacarborane derivatives. In this contribution, we summarize our recent results on the synthesis of new sulfur-containing derivatives of carboranes and metallacarboranes.
Alkylsulfide derivatives of ortho- and nido-carboranes
The general approach to synthesis of carborane-containing compounds for medical applications is based on derivatization of carborane via one CH vertex. The CH groups of carboranes are weakly acidic and can be deprotonated by strong bases, such as alkyllithium or Grignard reagents, producing carborane anions that are sufficiently nucleophilic to react with a wide range of electrophiles including alkyl halides, aldehydes, carbon dioxide, etc. The substituent introduced may be a biologically active moiety that acts as the tumor-targeting vector, or a simple functional group (–COOH, –NH2, –NCO, –NCS, –N3) that could be used for conjugation with high molecular weight biomolecules using standard methods of bioorganic chemistry. However, the carborane anions are sufficiently basic to deprotonate α-carbonyl methylene groups, that precludes the direct synthesis of many functional derivatives via alkylation reactions. The problem can be solved using easily available 1-mercapto-ortho-carborane [5], [6] instead of the parent ortho-carborane. The much higher acidity of the mercapto derivative in comparison with the parent ortho-carborane (pKa 3.3 [5] against to 23.3 [7]) allows one to use alkylating reagents containing functional groups that are not compatible with organometallic compounds forming on the deprotonation of the carborane CH group (carboxylic acids, esters, nitriles, etc.). This approach was applied for the first time to prepare carboranyl thioglycolic acid by alkylation of the potassium salt of 1-mercapto-ortho-carborane with chloroacetic acid [8].
We used the same approach for preparation of a series of carborane-containing carboxylic acids 1-HOOC(CH2)nS-1,2-C2B10H11 (n=1–4) by the reactions of triethylammonium salt of 1-mercapto-ortho-carborane with various ethyl ω-bromoalkyl ethylcarboxylates and ω-bromoalkyl nitriles followed by the acid hydrolysis of the obtained esters and nitriles [9] (Scheme 1).
In the same manner, the reactions of the triethylammonium salt with ω-bromoalkylacetamido diethylmalonates followed by acid hydrolysis and decarboxylation gave a series of carborane-containing amino acids 1-HOOCCH(NH2)(CH2)nS-1,2-C2B10H11 (n=4–6) [10] (Scheme 1). The same approach was used for synthesis of carboranyl azides. The azidoethylthio derivative 1-N3(CH2)2S-1,2-C2B10H11 was prepared by the reaction of the triethylammonium salt with the THP-protected 2-bromoethanol followed by acidic removal of the protecting group and transformation of the obtained alcohol to the azide by the reaction with NaN3 in a mixture of CCl4 and DMF in the presence of PPh3. The azidopropylthio derivative 1-N3(CH2)3S-1,2-C2B10H11 was prepared using other synthetic scheme. At first the reaction of (Et3NH)[1-S-1,2-C2B10H11] with 1-bromo-3-chloropropane in refluxing ethanol resulted in 1-(3-chloro-propylthio)-ortho-carborane, which was converted to the corresponding iodide by the exchange reaction with sodium iodide and, in turn, to the desired azide by the reaction with NaN3 in refluxing acetone [11] (Scheme 1).
The nucleophile-induced removal of one boron atom from the parent ortho-carborane and its C-substituted derivatives producing the corresponding nido-carboranes is widely used to improve water solubility of carboranes for medicinal applications. A series of nido-carborane based carboxylic acids [7-HOOC(CH2)nS-nido-7,8-C2B9H11]− (n=1–4) [9] and amino acids [7-HOOCCH(NH2)(CH2)nS-7,8-C2B9H11]− (n=4–6) [10] were prepared by deboronation of the corresponding closo-derivatives with fluoride ion (Scheme 2). The nido-carborane based azides [7-N3(CH2)nS-7,8-C2B9H11]− (n=2, 3) were obtained by the deboronation of the corresponding closo-carborane derivatives with ammonium formate in ethanol [11] (Scheme 2).
The nido-carborane based amines [7-H3N(CH2)nS-7,8-C2B9H11] (n=2, 3) were obtained by the alkylation of the triethylammonium salt of 1-mercapto-ortho-carborane with ω-bromo-alkylphthalimides followed by the removal of the phthalimide protection with hydrazine hydrate (Scheme 3) [11]. The amines obtained were used to prepare conjugates with gold nanoclusters for imaging-guided targeted boron delivery to cancer tumor [12].
The same approach can be used for synthesis various boron-containing biomolecules, such as β-lactosylamine-nido-carborane glycoconjugates [13].
Alklylmethylsulfonium derivatives of nido-carborane
Another approach to synthesis of functional derivatives of nido-carborane includes an introduction of the dimethylsulfonium substituent followed by its demethylation and realkylation. We have developed new methods for regiospecific synthesis of symmetrically (10-Me2S-7,8-C2B9H11) and asymmetrically (9-Me2S-7,8-C2B9H11) substituted dimethylsulfonium derivatives of nido-carborane by the reactions of its protonated form 7,8-C2B9H13 with dimethylsulfide and dimethylsulfoxide, respectively. The treatment of the dimethylsulfonium derivatives with sodium amide in toluene results in its partial demethylation with formation of the corresponding methylsulfide derivatives [10-MeS-7,8-C2B9H11]− [14] and [9-MeS-7,8-C2B9H11]− [15].
The methylsulfide derivative [9-MeS-7,8-C2B9H11]− reacts with various alkylating agents to give alkylmethyl sulfonium derivatives 9-R(Me)S-7,8-C2B9H11 (R=Et, Pr, Bu, benzyl, allyl). The reaction of [9-MeS-7,8-C2B9H11]− with propargyl chloride gives the corresponding propargylmethyl sulfonium derivative 9-HC≡CCH2(Me)S-7,8-C2B9H11, whereas the reaction with propargyl bromide produces the allenylmethyl sulfonium derivative 9-H2C=C=CH(Me)S-7,8-C2B9H11, the latter one can be obtained as well by the treatment of the propargylmethyl derivative with triethylamine. The vinylmethyl sulfonium derivative 9-H2C=CH(Me)S-7,8-C2B9H11 was prepared by the treatment of [9-MeS-7,8-C2B9H11]− with 1,2-dibromoethane followed by elimination of hydrogen bromide with potassium carbonate [16] (Scheme 4). The same approach was used for synthesis of nido-carborane based carboxylic acids and amines using ω-bromoalkylcarboxylic acids and ω-bromoalkylphthalimides [17] (Scheme 4).
It should be noted that substitution at position 9 of the nido-carborane cage results in the formation of racemic mixture of enantiomers with the nido-carborane cage as the chiral center. If any additional chiral center arises on the substituent itself, as it takes place in the formation of the alkylmethyl sulfonium derivatives, it leads to a mixture of diastereomers (Fig. 1).
Since the sulfur atom is bound directly to the chiral nido-carborane cage, the latter one can affect the direction of alkylation attack resulting in some diastereomeric excess of one isomer. The diastereomeric excess can be determined by integration of appropriate signals in the 1H and 13C NMR spectra due to good differentiation of the α-hydrogen and α-carbon signals of the sulfonium group for different diastereomers. At the same time, signals of different diastereomers are not distinguishable in the 11B NMR spectra. However, the 11B{1H} NMR spectrum of the phthalimide derivative 9-C6H4(CO)2NCH2(Me)S-7,8-C2B9H11 demonstrates splitting signals corresponding to B(5) and B(10) atoms of the carborane cage in nearly the same integral ratio that was found for the diastereomer ratio based on the 1H NMR spectrum (Fig. 2) [17].
The same effect was found in other alkylmethyl sulfonium derivatives containing heteroatoms with lone electron pair at α-position of the alkyl group 9-XCH2(Me)S-7,8-C2B9H11 (X=Cl, Br, I, OMe) [15]. Taking into account that the splitting signals correspond atoms that are neighboring to the substituted B(9) atom, this splitting can be explained by the intramolecular B–H···X interactions between the corresponding BH groups and the heteroatom. It can be supposed that the diastereomer with heteroatom-containing group directed upward relatively to the open pentagonal face of the nido-carborane cage interacts with the B(10)H hydrogen, whereas the diastereomer with heteroatom containing group directed downwards relatively to the open pentagonal face forms the B–H···X bond with the B(5)H hydrogen (Fig. 3).
It should be noted that no signal splitting was observed in the 11B{1H} NMR spectra of the derivatives containing heteroatoms with lone electron pair at the β-position of the alkyl group (R=CH2CH2Br, CH2CH2OEt, CH2CH2N(CO)2C6H4) [15], [16] that could indicate an importance of proper cycle size for the intramolecular B–H···X interactions.
In a similar way, the symmetrically substituted methylsulfide [10-MeS-7,8-C2B9H11]− reacts with various alkylating agents to give the corresponding alkylmethyl sulfonium derivatives 10-R(Me)S-7,8-C2B9H11 (R=Et, Pr, Bu, benzyl, allyl, propargyl) (Scheme 5) [14].
In contrast to the 9-isomer, the introduction of substituent at the position 10 does not change the carborane cage symmetry. However, unexpectedly we found that the 11B{1H} NMR spectrum of the 10-propargylmethyl sulfonium derivative 10-HC≡CCH2(Me)S-7,8-C2B9H11 demonstrates complete splitting of all pairs of symmetrical boron atoms B(2/4), B(5/6) and B(9/11) in the carborane cage. Moreover, the 13C{1H} NMR spectrum also demonstrates signals of two non-equivalent Ccarb carbon atoms of the carborane cage at 45.8 and 47.1 ppm. It was suggested that such splitting can be caused by strong interactions between the substituent and the “extra” hydrogen atom, which prevents its free migration between the B(9)–H–B(10) and B(10)–H–B(11) positions in such a way effectively reducing the overall molecule symmetry. Since the substituent does not have functional groups other than the alkyne group it was supposed that the B–H···π(alkyne) interactions are responsible for this signal splitting in the 11B{1H} and 13C{1H} NMR spectra [14].
To prove existence of the B–H···π(alkyne) intramolecular interactions the related derivatives with internal alkyne group 10-RC≡CCH2(Me)S-7,8-C2B9H11 (R=Ph, SiMe3) were synthesized (Scheme 5). As it was expected, the 11B{1H} and 13C{1H} NMR spectra of these derivatives also demonstrate characteristic splitting of the corresponding signals with the maximum effect in the case of compound containing strong electron-donating trimethylsilyl group (ΔB(5/6)4.4 ppm, ΔB(9/11)1.6 ppm, ΔB(2/4)1.4 ppm, and ΔCcarb2.5 ppm) (Fig. 4). This correlates well with an increase of electron density on the alkyne group and thereby supports the conclusion that these interactions should be considered as classical hydrogen bonding [14].
The existence of the B–H···π(alkyne) intramolecular interactions in the solid state was confirmed by single crystal X-ray diffraction of the propargylmethyl sulfonium derivative 10-HC≡CCH2(Me)S-7,8-C2B9H11. The acetylenic fragment is turned in such a way that it is located over the B(9)–B(10) edge and forms shortened contact (2.658 Å) with the bridging hydrogen atom H(12) (the sum of van der Waals radii 2.87 Å) (Fig. 5) [14]. To the best of our knowledge this is the first example of the intramolecular B–H···π(C≡C) hydrogen bonding.
Methylsulfide derivatives of cobalt and iron bis(dicarbollide)
The removal of the “extra” proton from the methylsulfide derivatives of nido-carborane using NaOH followed by the reaction with cobalt chloride produces the corresponding methylsulfide derivatives of cobalt bis(dicarbollide). The symmetrically substituted methylsulfide [10-MeS-7,8-C2B9H11]− gives the single [8,8′-(MeS)2-3,3′-Co(1,2-C2B9H10)2]− isomer, whereas the asymmetrically substituted methylsulfide [9-MeS-7,8-C2B9H11]− produces a mixture of dd/ll-[4(7),4′(7′)-(MeS)2-3,3′-Co(1,2-C2B9H10)2]− and meso-[4,7′-(MeS)2-3,3′-Co(1,2-C2B9H10)2]− isomers which were separated by column chromatography on silica as the tetrabutylammonium salts (Scheme 6) [18].
The solid-state structures of the tetrabutylammonium salts of all the isomers were determined by single crystal X-ray diffraction. The transoid-conformation of the 8,8′-isomer and gauche-conformation of the 4,4′-isomers were found to be stabilized by four intramolecular CHcarb···S(Me)S hydrogen bonds, whereas the gauche-conformation of the 4,7′-isomer is stabilized by two intramolecular CHcarb···S(Me)S hydrogen bonds (Fig. 6) [18].
The similar paramagnetic methylsulfide derivatives of iron(III) bis(dicarbollide) were prepared by the reaction of the dimethylsulfonium derivatives of nido-carborane with ferrous chloride followed by the demethylation of the formed Me2S derivatives of iron(II) bis(dicarbollide) with BuSNa and oxidation of the iron(II) bis(dicarbollide) methylsulfide derivatives in air. When the asymmetrically substituted dimethylsulfonium derivative of nido-carborane 9-Me2S-7,8-C2B9H11 was used as the starting material, the chromatographic separation of dd/ll- and mesoisomers was performed at the stage of the dimethylsulfonium derivatives (Scheme 7).
Article note
A collection of invited papers based on presentations at the 16th International Meeting on Boron Chemistry (IMEBORON-16), Hong Kong, 9–13 July 2017.
Acknowledgment
This work was supported by the Russian Science Foundation (16-13-10331).
References
[1] R. N. Grimes. Carboranes, 3rd ed., Academic Press, Amsterdam (2016).10.1016/B978-0-12-801894-1.00004-4Search in Google Scholar
[2] I. B. Sivaev, V. I. Bregadze. Polyhedral Boron Hydrides in Use: Current Status and Perspectives. Nova Science Publishers, New York (2009).10.1002/ejic.200900003Search in Google Scholar
[3] N. S. Hosmane (Ed.). Boron Science: New Technologies and Applications, CRC Press, Boca Raton (2012).Search in Google Scholar
[4] N. S. Hosmane, R. Eagling (Eds.). Handbook of Boron Chemistry in Organometallics, Catalysis, Materials and Medicine, World Scientific Publishing, London (2018).10.1142/q0130-vol3Search in Google Scholar
[5] J. Plešek, S. Heřmanek. Collect. Czech. Chem. Comm.46, 687 (1981).10.1135/cccc19810687Search in Google Scholar
[6] C. Viñas, R. Benakki, F. Teixidor, J. Casabo. Inorg. Chem.34, 3844 (1995).10.1021/ic00118a041Search in Google Scholar
[7] O. A. Reutov, I. P. Beletskaya, K. P. Butin. CH-Acids, Pergamon Press, Oxford (1978).Search in Google Scholar
[8] J. Plešek, S. Heřmanek. Collect. Czech. Chem. Commun.44, 24 (1979).10.1135/cccc19790024Search in Google Scholar
[9] M. Yu. Stogniy, I. B. Sivaev, P. V. Petrovskii, V. I. Bregadze. Dalton Trans.39, 1817 (2010).Search in Google Scholar
[10] M. Yu. Stogniy, M. V. Zakharova, I. B. Sivaev, I. A. Godovikov, A. O. Chizhov, V. I. Bregadze. Polyhedron55, 117 (2013).10.1016/j.poly.2013.02.076Search in Google Scholar
[11] M. Yu. Stogniy, I. B. Sivaev, I. A. Godovikov, Z. A. Starikova, V. I. Bregadze, S. Qi. New J. Chem.37, 3865 (2013).10.1039/c3nj00677hSearch in Google Scholar
[12] J. Wang, L. Chen, J. Ye, Z. Li, H. Jiang, H. Yan, M. Yu. Stogniy, I. B. Sivaev, V. I. Bregadze, X. Wang. Biomacromolecules18, 1466 (2017).10.1021/acs.biomac.6b01845Search in Google Scholar PubMed
[13] L. M. Likhosherstov, O. S. Novikova, A. O. Chizhov, I. B. Sivaev, V. I. Bregadze. Russ. Chem. Bull.60, 2359 (2011).10.1007/s11172-011-0362-xSearch in Google Scholar
[14] S. A. Anufriev, I. B. Sivaev, K. Yu. Suponitsky, I. A. Godovikov, V. I. Bregadze. Eur. J. Inorg. Chem.2017, 4435 (2017).Search in Google Scholar
[15] S. A. Anufriev, I. B. Sivaev, K. Yu. Suponitsky, V. I. Bregadze. J. Organomet. Chem.849–850, 315 (2017).Search in Google Scholar
[16] M. V. Zakharova, I. B. Sivaev, S. A. Anufriev, S. V. Timofeev, K. Yu. Suponitsky, I. A. Godovikov, V. I. Bregadze. Dalton Trans.43, 5044 (2014).10.1039/C3DT52845FSearch in Google Scholar
[17] S. A. Anufriev, M. V. Zakharova, I. B. Sivaev, V. I. Bregadze. Russ. Chem. Bull.66, 1643 (2017).10.1007/s11172-017-1936-zSearch in Google Scholar
[18] S. A. Anufriev, S. A. Erokhina, K. Yu. Suponitsky, I. A. Godovikov, O. A. Filippov, F. Fabrizi de Biani, M. Corsini, A. O. Chizhov, I. B. Sivaev. Eur. J. Inorg. Chem.2017, 4444 (2017).10.1002/ejic.201700575Search in Google Scholar
©2018 IUPAC & De Gruyter. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. For more information, please visit: http://creativecommons.org/licenses/by-nc-nd/4.0/