Synthesis of new ω-amino- and ω-azidoalkyl carboranes

Article abstract of DOI:10.1039/c3nj00677h

Novel carboranyl amines [7-NH₂(CH₂) _nS-7,8-C₂B₉H₁₁]^- were synthesized by alkylation of 1-mercapto-ortho-carborane with ω-bromoalkylphthalimides followed by removal of the protect

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A series of new carboranyl azides and amines were synthesized by alkylation of 1-
mercapto-ortho-carborane.
S(CH2)nN3
H
H
S(CH2)nN3
S(CH2)nNH2
n = 2,3

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LETTER
Synthesis of new ωꢀaminoꢀ and ωꢀazidoalkyl
carboranes†,‡
Cite this: DOI: 10.1039/c3nj00000x
Marina Yu. Stogniy,a Igor B. Sivaev,*,a Ivan A. Godovikov,a Zoya A. Starikova,a
Vladimir I. Bregadzea and Shicheng Qib
Received 00th XXXXX 2013,
Accepted 00th XXXXX 2013
DOI: 10.1039/c3nj00000x
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Novel carboranyl amines [7ꢀNH2(CH2)nSꢀ7,8ꢀC2B9H11]ꢀ were
synthesized by alkylation of 1ꢀmercaptoꢀorthoꢀcarborane with
the ωꢀbromoalkylphthalimides followed by removal of the
protecting group with hydrazine. closoꢀCarboranyl azides 1ꢀ
N3(CH2)nSꢀ1,2ꢀC2B10H11 were prepared by reaction of the
corresponding carboranyl alcohol/iodide with sodium azide
and converted to water soluble nidoꢀform [7ꢀN3(CH2)nSꢀ7,8ꢀ
C2B9H11]ꢀ with ammonium formate in refluxing methanol.
sometimes, by using specific reaction conditions for different types
of derivatives21ꢀ24. Some later, the introduction of mercapto group
followed by their alkylation was proposed as
a route to
monosubstituted carboranes25. Recently this approach was used for
synthesis of various functional derivatives of carboranes, including
carboxylic acids26, aminoacids27, and carbohydrates28. In this
contribution we describe synthesis of carborane based amines and
azides from 1ꢀmercaptoꢀorthoꢀcarborane.
The reaction of the triethylammonium salt of mercapto carborane
(Et3NH)[1ꢀSꢀ1,2ꢀC2B10H11] with commercially available ωꢀ
bromoalkylphthalimides in refluxing ethanol gives the corresponding
carboranyl alkylphthalimides 1ꢀ3. The 1H and 13C NMR spectra of 1ꢀ
3 contain characteristic signals of the phthalimide protecting group.
The reaction of 2 and 3 with hydrazine hydrate in refluxing ethanol
results in deprotection of amino group and partial degradation of the
closoꢀcarborane cage to the nidoꢀcarborane one giving the
corresponding amines 4a and 5a isolated as solvates with hydrazine
The development of new functional derivatives of carboranes for
potentional use in the boron neutron capture therapy (BNCT),1
radionuclide diagnostics2 and drug design3 remains an active area of
research. Simple functional groups like amine or azide can be used
for conjugation of carborane moiety with biomolecules that act as
tumorꢀtargeting vectors4. There are three main approaches to the
synthesis of ωꢀaminoalkyl carboranes 1ꢀNH2(CH2)nꢀ1,2ꢀC2B10H11.
The first one is based on the reaction of decaborane(14) with
protected ωꢀaminoalkylacetylenes followed by removal of protecting
groups.5ꢀ8 The similar approach includes alkylation of orthoꢀ
carborane with protected ωꢀhalogenalkylamines.9ꢀ11 The Nꢀ
phthalimide protecting group is the most typical for these two
synthetic schemes.5ꢀ10 Another approach includes preliminary
synthesis of ωꢀcarboranylalkyl halides or triflates 1ꢀX(CH2)nꢀ1,2ꢀ
C2B10H11 (X = Cl, Br, I, OTf) followed by their treatment with
various Nꢀnucleophiles.5,12 This synthetic scheme requires more
steps, however, it is more universal and can be used for synthesis of
ωꢀcarboranylalkyl azides as well.7,13,14 The same approach can be
used for introduction of the amino group into related carborane
systems.15ꢀ17
(Scheme 1).
O
SꢀEt3NH+
O
O
S(CH2)nN
C2H5OH
reflux
Br(CH2)nN
O
+
n=1
n=2
n=3
1
2
3
N2H4
C2H5OH
H
H
HNMe3
S(CH2)nNH2
S(CH2)nNH3
Me3N.HCl
H2O
The common problem in the carborane chemistry is synthesis of
their monosubstituted derivatives. It is caused by the tendency of
monolithio carborane to disproportionate to dilithio carborane and
the parent carborane that often results in mixtures of monoꢀ and
disubstituted derivatives.18,19 This problem can be solved by
introduction of tertꢀbutyldimethylsilyl protecting group20 or,
n=2
n=3 5a
4a
n=2
n=3
4
5
Scheme1
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Removal of the protecting group results in disappearance of corresponding orthoꢀ(hydroxymethyl)benzoyl derivative 6 in a low
1
characteristic signals in aromatic regions of the H and 13C NMR yield (Scheme 2).
spectra of 4a and 5a. The carborane decapitation produces a high
field shift and splitting of the CarbSCH2ꢀgroup in the 1H NMR
O
OH
spectra. The high field shift is caused by the reduction of electronꢀ
S(CH2)3N
S
(CH2)3NH
withdrawal effect of carborane on its transformation from the closoꢀ
to the nidoꢀform,29 whereas the signal splitting can be ascribed to
transformation of two primarily enantiotopic CarbSCH2ꢀ methylene
protons into magnetically nonequivalent diastereotopic ones on the
degradation of achiral 1ꢀRꢀclosoꢀC2B10H11 carborane to chiral 7ꢀRꢀ
nidoꢀC2B9H11 carborane.26 The carborane decapitation results in the
corresponding changes in the 11B NMR spectra as well.
NaBH4
O
O
i-PrOH, r.t.
3
6
Scheme 2
The structure of 5a was determined by single crystal Xꢀray
diffraction (Fig. 1). The amino group of nidoꢀcarborane in 5a is
protonated forming the inner ammonium salt. The ammonium
hydrogen atoms form hydrogen bonds with three solvate molecules
of hydrazine (Fig. S1). The hydrazine molecules are connected by
hydrogen bonds to form associates including a pair of the carborane
molecules (Figs. S2 and S3). A similar pattern of hydrogen bonds
between the protonated amino groups and solvate hydrazine
molecules was found earlier in the structure of closely related
However, acidic hydrolysis of
6
after standard workup7,30
unexpectedly resulted in nidoꢀcarborane 5a. The decreased stability
of the 1ꢀRSꢀ1,2ꢀC2B10H11 fragment can be explained by donation of
electron density from the sulfur atom to the carborane LUMO
orbital31 that favors the cage degradation.
The synthesis of the corresponding carboranyl azides was carried
out. To obtain 1ꢀ(2ꢀazidoethylthio)ꢀorthoꢀcarborane
triethylammonium salt of mercapto carborane (Et3NH)[1ꢀSꢀ1,2ꢀ
C2B10H11] was treated with 2ꢀ(2ꢀtetrahydropyranyloxy)ethyl bromide
in refluxing ethanol giving compound 7. The hydrolysis of the last
one with paraꢀtoluenesulfonic acid in methanol gave the
corresponding alcohol 8. The reaction of alcohol 8 with sodium
azide in a mixture of carbon tetrachloride and dimethylformamide in
the presence of PPh3 resulted in desired azide 9 (Scheme 3).
9
the
10
aminocarborane 7ꢀNH3CH2CH2CH2ꢀ7,8ꢀC2B9H11*N2H4.
O
SꢀEt3NH+
O(CH2)2Br
Br(CH2)3Cl
EtOH
reflux
EtOH
reflux
O
SCH2CH2O
SCH2CH2CH2Cl
7
10
acetone
MeOH
reflux
PTSA
NaI
reflux
SCH2CH2OH
SCH2CH2CH2I
Fig.1. Molecular structure and numbering scheme of 7ꢀ
NH3CH2CH2CH2Sꢀ7,8ꢀnidoꢀC2B9H11. Selected bond lengths [Å]:
С(7)ꢀС(8) 1.562(3), C(7)ꢀB(11) 1.628(3), C(8)ꢀB(9) 1.600(3), С(7)ꢀ
S(1) 1.781(2), N(1)ꢀC(3) 1.483(3), H(11A)ꢀB(11) 1.18(3), H(11A)ꢀ
B(10) 1.43(3).
11
8
S(CH2)nN3
NaN3
NaN3, PPh3
acetone
reflux
CCl4ꢀDMF
reflux
n=2
n=3 12
9
In aqueous solution there is equilibrium between the protonated
inner ammonium salts 4a and 5a and hydrazinium salts of
deprotonated amines 4 and 5. The deprotonated amines were isolated
by the treatment with trimethylamine hydrochloride in aqueous
solution. The driving force of this process is formation of the waterꢀ
insoluble trimethylammonium salts of nidoꢀcarboranes 4 and 5.
Our attempt to prevent degradation of the closoꢀcarborane cage by
carrying out the reaction of 3 with hydrazine hydrate in ethanol at
room temperature10 resulted in the formation of 3ꢀphthalmidopropyl
derivative of 7ꢀmercaptoꢀnidoꢀcarborane in 15 min. It means that the
transformation of 1ꢀRSꢀclosoꢀC2B10H11 to [7ꢀRSꢀnidoꢀC2B9H11]ꢀ
proceeds faster than the removal of phthalyl group. The reaction of 3
with sodium tetrahydroborate in isopropanol7 gave the
Scheme 3
1ꢀ(3ꢀAzidopropylthio)ꢀorthoꢀcarborane 12 was prepared using other
synthetic scheme. At first the reaction of the triethylammonium salt
of mercapto carborane (Et3NH)[1ꢀSꢀ1,2ꢀC2B10H11] with 1ꢀbromoꢀ3ꢀ
chloropropane in refluxing ethanol resulted in 1ꢀ(3ꢀchloroꢀ
propylthio)ꢀorthoꢀcarborane 10. The last one was converted to the
corresponding iodide 11 by the exchange reaction with sodium
iodide. Next, the compound 11 also was converted to azide 12 by the
reaction with NaN3 in refluxing acetone (Scheme 3).
2 | J. Name., 2012, 00, 1-3
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The closoꢀcarboranyl azides 9 and 12 were converted into water
soluble nidoꢀcarboranyl azides 13 and 14, respectively, by the
treatment with ammonium formate in refluxing methanol (Scheme
4). Similar degradation of the closoꢀcarborane cage upon refluxing
ammonium salt of 1,2ꢀdimercaptoꢀorthoꢀcarborane in ethanol was
described earlier.32
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H
S(CH2)nN3
NH4
S(CH2)nN3
NH4+HCOOꢀ
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MeOH
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9
n=2 13
n=3 14
Scheme 4
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A series of new carborane based amines [7ꢀH2N(CH2)nSꢀnidoꢀ7,8ꢀ
C2B9H11]ꢀ (n = 2, 3) azides 1ꢀN3(CH2)nSꢀclosoꢀ1,2ꢀC2B10H11 (n = 2,
3) and [7ꢀN3(CH2)nSꢀnidoꢀ7,8ꢀC2B9H11]ꢀ (n = 2, 3) were synthesized
by alkylation of 1ꢀmercaptoꢀorthoꢀcarborane followed by functional
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nidoꢀform.
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