Synthesis of 1,2-bis(aminomethyl)-1,2-dicarba-closo-dedocaborane hydrochloride and its easy degradation research

Article abstract of DOI:10.1016/j.inoche.2011.03.035

bis-C(cage)-substituted 1,2-bis(aminomethyl)-1,2-dicarba-closo-dedocaborane hydrochloride was obtained from the reaction of 1,2-bis(phthalimidomethyl)-1,2- dicarba-closo-dodecaborane with sodium borohydride, followed by acid hydrolysis with glacial acetic acid. When the compound dissolved in DMSO, the easy degradation from the closo-stucture compound to corresponding nido-carborane derivative at room temperature occured.

Full text of DOI:10.1016/j.inoche.2011.03.035

Inorganic Chemistry Communications 14 (2011) 934–936
Contents lists available at ScienceDirect
Inorganic Chemistry Communications
journal homepage: www.elsevier.com/locate/inoche
Synthesis of 1,2-bis(aminomethyl)-1,2-dicarba-closo-dedocaborane hydrochloride
and its easy degradation research
⁎
Juan Zhao, Shan Chen, Pengcheng Huang, Gong Chen
Materials Science and Engineering School, Beihang University, Beijing 100191, People's Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
bis-C(cage)-substituted 1,2-bis(aminomethyl)-1,2-dicarba-closo-dedocaborane hydrochloride was obtained
from the reaction of 1,2-bis(phthalimidomethyl)-1,2-dicarba-closo-dodecaborane with sodium borohydride,
followed by acid hydrolysis with glacial acetic acid. When the compound dissolved in DMSO, the easy
degradation from the closo-stucture compound to corresponding nido-carborane derivative at room
temperature occured.
Received 25 January 2011
Accepted 14 March 2011
Available online 22 March 2011
Keywords:
© 2011 Elsevier B.V. All rights reserved.
Bis-aminomethyl
Dicarbadodecaborane
Degradation
BNCT
As high-boron content molecules, carborane and its derivatives
applied to boron neutron capture therapy (BNCT) remain an active
area of research, and a lot of carborane containing bioactive molecules
have been prepared to treat certain tumors[1]. The amine derivatives
of carborane are useful synthons for the synthesis of bioactive amino
acids and DNAs, especially the short-chain-amino substituted o-
carboranes. As the important building block, they can be used in the
design of bioactive substances with high molecular weight. Due to the
sensitivity of carborane to amine[2], there were rare reports about the
synthesis of short-chain-amino substituted o-carboranes, especially
bis-substituted o-carboranes[3]. In order to obtain the stable amino
substituted o-carborane compounds, the amine chlorhydric acid salts
were usually formed and stored[4].
Carborane and its derivatives are stable in acid and high
temperature environment, but they can be degraded to nonbiotoxic
nido-carborane compouds in basic alcohol and amine solution[5]. It
was also found that the carborane derivatives with electron
withdrawing group can be cleaved to nido-structure in neutral
aqueous solution such as DMSO and methanol [6].
bis(acetonitrile)decaborane with 1,4-diphthalimido-2-butyne in
52.7% yield. The treatment of 1,2-bis(phthalimidomethyl)-1,2-
dicarba-closo-dodecaborane with sodium borohydride, 1,2-Bis (((2-
(hydroxymethyl)benzoyl)amino) methyl)-1,2-dicarba-closo-dodeca-
borane 2 was easily produced at room temperature. When THF is
added to the reaction mixture, the reaction could occur homoge-
neously and completely with the THF/isopropanol/water solution at
the ratio of 10:5:1(volume).
Theoretically, compound 3 will be acid hydrolyzed easily to form
the amine salt 1,2-bis(aminomethyl)-1,2-dicarba-closo-dodecabor-
ane hydrochloride 3 in glacial acetic acid/hydrochloric acid system.
We had made many attempts to get the target product under this
condition, but the 1H NMR result of the residue after removal of the
volatiles from the reaction mixture revealed no broad characteristic
peak of carborane cage between 0–3 ppm. Obviously, the carboranyl
group was broken and eliminated as the reaction proceeded.
Considering 1,2-bis(aminomethyl)-1,2-dicarba-closo-dedocaborane,
the intermediates produced by the hydrolysis, are very unstable for
their easy degradation to the corresponding nido-structure product,
they might be deboronated before salifying with hydrochloric acid. In
other words, the reaction was a competing process between the
degradation of the diamine substance and the generation of the
hydrochloride salt. When the concentration of the intermediate
product was great, the amount of the amine group was also large,
which made the degradation easier to occur. In order to control the
concentration of the intermediate product and restrain the formation
of the nido structure side product, two methods had been used: one
was raising the flow of the hydrochloric gas and the other was adding
material 2 little by little. In the end, the white crystalline precipitate 3
was successfully separated from the reaction solution in 54.4% yield
(Scheme 1).
Herein, we described the synthesis of 1,2-bis(aminomethyl)-1,2-
dicarba-closo-dedoca-borane hydrochloride, and first reported its
unusually easy deboronation of closo- to nido- carborane in DMSO at
room temperature. This observation may be important for its
application in BNCT.
Instead of the substitution of dilithium salt of the [closo-1,2-
C2B10H10
dicarba-closo-dodecaborane 1 was prepared from the reaction of 6,9-
]
2-[7], the starting material 1,2-bis(phthalimidomethyl)-1,2-
⁎
Corresponding author. Tel./fax: +86 010 82338299.
E-mail address: chengongbuaa@126.com (G. Chen).
1387-7003/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.inoche.2011.03.035

J. Zhao et al. / Inorganic Chemistry Communications 14 (2011) 934–936
935
Scheme 1. Synthesis of 1,2-bis(aminomethyl)-1,2-dicarba-closo-dedocaborane hydrochloride.
Compound 3 had been characterised by multinuclear(1H, 13C, 11B)
NMR spectrometry, elemental analyses, IR spectrum and electrospray
ionisation mass spectrometry (ESI-MS). The IR spectrum, elemental
analyses and ESI-MS were consistent with the expected di-substituted
closo-carborane derivative. The substance was demonstrated from
the result of high resolution ESI-MS(see Fig. 1).
The correlation between experimental and theoretical spectra was
excellent in all cases. The ion peak located at m/z 205.24715 is the signal of
[M+H]+. M refers to the fragmentation after the loss of the hydrochloric
acid ligand from the molecule. The high resolution accurate mass
measurement was conducted to confirm the formula of the expected
product.
mixture of the closo- and nido-structure 1,2-bis(aminomethyl)-1,2-
dicarba-o-dedocaborane hydrochloride are shown in Table 1.
As can be seen in Table 1, all of the 1H NMR chemical shifts of the nido-
carborane amine salt apparently moved to high field compared with the
corresponding data of the closo-component. The reason was perhaps that
the negatively charged ions of nido-carborane compound was generated
after the left of the B vertex adjacent to the two carbon atoms, then the
negative charge was delocalized around the whole molecule and
increased the electronic density of all of the hydrogen protons, so the
chemical shift was reduced at the same time. The deboronation of 1,2-bis
(aminomethyl)-1,2-dicarba-o-dedocaborane hydrochloride generates
asymmetry, which is reflected in the 1H NMR spectrum for each proton
of the diastereotopic N-CH2 unit: δ2.90 and 3.18. According to the HSQC
spectrum, the two protons assigned to the same carbon atom were
chemically unequivalent. Likewise, the solid 11B NMR has no signal peak
with the chemical shift less than −30 ppm, but the 11B NMR spectrum in
DMSO indicated the presence of a closo-carborane contaminated with the
nido-carborane,which was identified by characteristic signals of nido-
structure at δB −33.75, −36.60.
It was interesting that part of the closo-carborane products were
transformed to nido-structure 4 in a moment when the compound 3
was dissolved in deuterated DMSO. The NMR data (1H, 13C, 11B) of the
When 1,2-Bis(aminomethyl)-1,2-dicarba-closo-dodecaborane hy-
drochloride dissolved in deuterated DMSO at room temperature for
24 h, it was clearly confirmed that the closo- compound was changed
into the nido- structure derivative 4 completely by the 1H NMR
spectrum, and the signal peaks were in full accord with the proposed
structure of compound 4. Compared with the signals of the compound
3 dissolved in deuterated DMSO for a moment, the most obvious sign
Table 1
1H, 13C and 11B NMR chemical shifts for the mixture of closo- and nido- structure when
compound 3 was dissolved in deuterated DMSO.
δ (ppm)
Carborane-H
CH2
closo-structure
1.1−3.1
4.04
nido-structure
−0.5–2.5
2.90,3.18
NH3Cl
8.99
8.07
Carborane-C
CH2
Carborane-B
76.8
40.9
−5.11,−11.07
55.5
42.2
Fig. 1. Experimental (top) and theoretical (bottom) isotopic distribution pattern for the
−11.07,−17.34,−33.75,−36.60
[M+H]+ ion (M·2HCl represents the molecule of compound 3).

936
J. Zhao et al. / Inorganic Chemistry Communications 14 (2011) 934–936
delivery agent for boron neutron capture therapy of brain tumors, J. Med. Chem.
49 (2006) 5513–5523;
f. V.J. Reddy, M.M. Roforth, C. Tan, M.V.R. Reddy, Synthesis of functionalized
carboranes as potential anticancer and BNCT agents, Inorg. Chem. 46 (2007)
381–383;
was that the signal of the closo-carborane cage (δH 1.1–3.1 (br)) was
disappeared and replaced by two characteristic broad peaks of nido-
structure(δH −2.4 to −2.9 and −0.5 to 2.5). In addition, the peak
corresponding to the amine hydrochloric acid of the closo- structure
(δH 8.99) disappeared, which allowed the identification of the
degradation of closo-carborane derivative 3.
g. C.D.I. Meo, L. Panza, D. Capitani, L. Mannina, A. Banzato, M. Rondina, D. Renier, A.
Rosato, V. Crescenzi, Hyaluronan as carrier of carboranes for tumor targeting in
boron neutron capture therapy, Biomacromolecules 8 (2007) 552–559.
[2] a. D. Grafstein, J. Bobinski, J. Dvorak, H. Smith, N. Schwartz, M.S. Cohen, M.M. Fein,
III. Reactions of the carboranes, Inorg. Chem. 2 (1963) 1120–1125;
b. L.I. Zakharkin, V.S. Kirillova, Cleavage of o-carboranes to (3)-l,2-dicarbaunde-
carborates by amines, Russ. Chem. Bull. 24 (1975) 2484–2486.
Appendix A. Supplementary material
[3] A. Varadarajan, M.F. Hawthorne, Novel carboranyl amino acids and peptides:
reagents for antibody modification and subsequent neutron-capture studies,
Bioconjug. Chem. 2 (1991) 242–253.
Supplementary data to this article can be found online at
doi:10.1016/j.inoche.2011.03.035.
[4] a. J.G. Wilson, A.K.M. Anisuzzaman, F. Alam, A.H. Soloway, Development of
carborane synthons: synthesis and chemistry of (aminoalkyl)carboranes, Inorg.
Chem. 31 (1992) 1955–1958;
References
b. A.S. Batsanov, A.E. Goeta, J.A.K. Howard, A.K. Hughes, J.M. Malget, The synthesis
of closo- and nido-(aminoalkyl)dicarbaboranes: a re-examination of contra-
dictory literature reports, crystal structure of [7-{H3N(CH2)3}-7,8-C2B9H11]·-
NH2NH2, J. Chem. Soc. Dalton Trans. (2001) 1820–1826.
[1] a. J.F. Valliant, K.J. Guenther, A.S. King, P. Morel, P. Schaffer, O.O. Sogbein, K.A.
Stephenson, The medicinal chemistry of carboranes, Coord. Chem. Rev. 232
(2002) 173–230;
b. L. Ma, J. Hamdi, F. Wong, M.F. Hawthorne, Closomers of high boron content:
synthesis, characterization, and potential application as unimolecular nano-
particle delivery vehicles for boron neutron capture therapy, Inorg. Chem. 45
(2006) 278–285;
c. S. Ronchi, D. Prosperi, C. Thimon, C. Morin, L. Panza, Synthesis of mono- and
bisglucuronylated carboranes, Tetrahedron Asymmetr. 16 (2005) 39–44;
d. Z. Yinghuai, A.T. Peng, K. Carpenter, J.A. Maguire, N.S. Hosmane, M. Takagaki,
Substituted carborane-appended water-soluble single-wall carbon nanotubes:
new approach to boron neutron capture therapy drug delivery, J. Am. Chem. Soc.
127 (2005) 9875–9880;
[5] R.A. Wiesboeck, M.F. Hawthorne, Dicarbaundecaborane(13) and derivatives, J. Am.
Chem. Soc. 86 (1964) 1642–1643.
[6] a. J.J. Schaeck, S.B. Kahl, Rapid cage degradation of 1-formyl- and 1-alkyloxycar-
bonyl-substituted 1,2-dicarba-closo-dodecaboranes by water or methanol in
polar organic solvents, Inorg. Chem. 38 (1999) 204–206;
b. L.O. Kononov, A.V. Orlova, A.I. Zinin, B.G. Kimel, I.B. Sivaev, V.I. Bregadze,
Conjugates of polyhedral boron compounds with carbohydrates. 2. Unexpected
easy closo- to nido-transformation of a carborane–carbohydrate conjugate in
neutral aqueous solution, J. Organomet. Chem. 690 (2005) 2769–2774.
[7] Y. Zhu, H. Zhang, J.A. Maguire, N.S. Hosmane, Synthesis and crystal structure of 1,2-
e. Y. Byun, B.T.S. Thirumamagal, W. Yang, S. Eriksson, R.F. Barth, W. Tjarks,
Preparation and biological evaluation of10B-enriched 3-[5-{2-(2,3-Dihydroxy-
prop-1-yl)-o-carboran-1-yl} pentan-1-yl]thymidine (N5-2OH), a new boron
bis(phthalimidomethyl)-1,2-dicarba-closo-dodecaborane(12):
a precursor to
polyamines, Inorg. Chem. Commun. 4 (2001) 447–449.