Synthesis of sterically-hindered 1,7-dicarba-closo-dodecarborane thiourea analogs

Article abstract of DOI:10.1016/j.jorganchem.2013.03.003

We herein report the first successful synthesis of 1-thioisocyanato-1,7- dicarba-closo-dodecarborane, which afforded novel lipophilic thiourea analogs by reacting with weak and bulky nucleophilic amines including 1-adamantylamine, and m-carboranylamine, a

Full text of DOI:10.1016/j.jorganchem.2013.03.003

Journal of Organometallic Chemistry 733 (2013) 49e52
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Journal of Organometallic Chemistry
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Synthesis of sterically-hindered 1,7-dicarba-closo-dodecarborane thiourea
analogs
,b,
Seunghyun Choi a, Youngjoo Byun a
*
a College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong 339-700, South Korea
b Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical School, Baltimore, MD 21287, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We herein report the first successful synthesis of 1-thioisocyanato-1,7-dicarba-closo-dodecarborane,
which afforded novel lipophilic thiourea analogs by reacting with weak and bulky nucleophilic amines
including 1-adamantylamine, and m-carboranylamine, aniline, and 2-aminopyridine. Newly synthesized
thiourea analogs were fully characterized by NMR, ESI-MS, and FTIR.
Received 28 November 2012
Received in revised form
19 February 2013
Accepted 5 March 2013
Ó 2013 Elsevier B.V. All rights reserved.
Keywords:
Carborane
Isothiocyanate
Thiourea
Conjugation
1. Introduction
amino acids of peptides. Isothiocyanate-containing fluorescent
dyes such as fluorescein isothiocyanate (FITC) and rhodamine B
Carboranes (C2B10H12), polyhedral borane clusters, have been
evaluated as effective boron-delivery moieties for boron-neutron
capture therapy (BNCT) for more than 50 years due to the fact
that they can efficiently achieve the necessary boron concentra-
tions for BNCT due to the high number of boron atoms per molecule
[1e6]. Recently, they have been exploited as surrogates of lipophilic
pharmacophores to replace hydrophobic benzene or cyclohexane
rings in the field of medicinal chemistry because they can increase
the lipophilicity of the parent drugs, improve their metabolic sta-
bility, and enhance their binding affinities for target proteins via
hydrophobic interactions [7e14]. Furthermore, the unique features
of carboranes such as high thermal stability, neutron shielding and
electron transmission have also been applied in the field of polymer
and material chemistry [15e18].
isothiocyanate (RBITC) have been extensively utilized as labeling
agents of peptides and proteins in the research field of flow
cytometry and molecular imaging [22,23].
Carboranyl isothiocyanates are attractive boron-containing
molecules because they can be easily conjugated with
pharmacologically-active compounds and, thus, can be potentially
utilized as lipophilic pharmacophores in medicinal chemistry and
as boron carriers for BNCT. To the best of our knowledge, however,
the successful synthesis of carboranyl isothiocyanates has never
been reported up to date. We herein report the first simple and
facile synthesis of m-carboranyl isothiocyanate and investigate its
chemical reactivity with less nucleophilic amines such as aromatic/
heteroaromatic amines and sterically hindered amines.
Isothiocyanate (N]C]S) is an important functional group in
drug research and development. It has been investigated as the
reactive electrophilic group toward nucleophiles of proteins in
bioconjugate chemistry, leading to produce stable thioureas
and sulfur-containing heterocyclic analogs [19e21]. Phenyl-
isothiocyanate (PITC, Fig. 1) was used as reactant with N-terminal
amino group of peptides in Edman degradation for sequencing
2. Experimental
2.1. General
m-Carborane was purchased from Katchem s.r.o. (Prague, Czech
Republic). The other chemicals and solvents were purchased from
Aldrich and Acros. 1H NMR, 11B NMR and 13C NMR spectra were
recorded on a BRUKER Biospin AVANCE 600 MHz and 300 MHz
spectrometer. Chemical shifts are reported as
d values downfield
from internal TMS in appropriate organic solutions. Mass spectra
were recorded on a Agilent 6530 Accurate Q-TOF LC/MS spec-
trometer. IR spectra were recorded on Thermo NICOLET 6700 FT-IR
* Corresponding author. College of Pharmacy, Korea University, 2511 Sejong-ro,
Sejong 339-700, South Korea. Tel./fax: þ82 44 860 1619.
E-mail address: yjbyun1@korea.ac.kr (Y. Byun).
0022-328X/$ e see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jorganchem.2013.03.003

50
S. Choi, Y. Byun / Journal of Organometallic Chemistry 733 (2013) 49e52
Fig. 1. Isothiocyanate-containing molecules.
spectrometer. Column chromatography was performed using
Merck Silica Gel F254
1H NMR (600 MHz, CDCl3):
H), 1.28e3.78 (m, 10H, BcareH). 13C NMR (150 MHz, CDCl3):
d
2.89 (s, 1H, CcareH), 2.30 (s, 2H, Ne
87.61
.
d
(CcareN), 53.18 (CcareH). 11B NMR (192 MHz, CDCl3):
2.1.1. 1,7-Dicarba-closo-dodecarborane-1-carboxylic acid (1a)
To a solution of m-carborane (2.0 g, 13.9 m mol) in diethylether
(150 mL) was added n-BuLi (9.6 mL, 15.4 m mol, 1.6 M in hexane)
slowly over 20 min. The reaction mixture was stirred for another
20 min at ꢀ78 ꢁC. Dry ice (5.0 g) was crushed into small pieces and
added immediately to the reaction mixture, which was stirred for
1 h at room temperature. The excessive solvent was removed under
reduced pressure. Water (60 mL) was added to the residue and
unreacted m-carborane was extracted with hexanes (30 mL ꢂ 2).
The aqueous layer was acidified with 3 N HCl and extracted with
hexanes (30 mL ꢂ 4). The combined organic layer was dried over
MgSO4, filtered and concentrated under reduced pressure to afford
1a in 95% yield as a white solid.
d
ꢀ3.27, ꢀ10.12, ꢀ11.96, ꢀ11.91. HRMS (ESIꢀ): [M ꢀ H]ꢀ calcd for
,
C9H17B10N2S (m/z): 160.2127, found: 160.2127.
2.1.4. 1-Thioisocyanato-1,7-dicarba-closo-dodecarborane (2)
To
a solution of 1-amino-1,7-dicarba-closo-dodecarborane
(230 mg, 1.44 m mol) in THF was added triethylamine (0.35 mL,
3.456 m mol) and thiophosgene (0.13 mL,1.130 m mol) at ꢀ20 ꢁC. The
reaction mixture was stirred at ꢀ20 ꢁC for additional 3 h. After
monitoring the progress of the reaction by TLC, the excessive solvent
was removed under reduced pressure. The residue was extracted
with n-hexanes (30 mL) and washed with 1 N HCl solution
(15 mL ꢂ 2). The combined organic layer was dried over MgSO4,
filtered and concentrated under reduced pressure. The crude prod-
uct was subjected to the silica-gel chromatography (hexane/ethyl
acetate ¼ 500:3) to afford 2 in 88% yield as a white solid.
1H NMR (600 MHz, CDCl3):
1H, CcareH),1.27e3.28 (m,10H, BcareH). 13C NMR (150 MHz, CDCl3):
167.21 (COOH), 71.04 (CcareC), 54.84 (CcareH).
d 10.48 (s, 1H, CcareCOOH), 3.03 (s,
d
1H NMR (600 MHz, CDCl3):
10H, BcareH). 13C NMR (150 MHz, CDCl3):
d
2.94 (s, 1H, CcareH), 1.73e3.43 (m,
142.36 (N]C]S), 79.07
d
2.1.2. tert-Butyl-N-(1,7-dicarba-closo-dodecaborane-1-yl)
carbamate (1b)
(CcareN), 52.93 (CcareH). 11B NMR (192 MHz, CDCl3):
d
ꢀ3.59, ꢀ10.52, ꢀ11.80, ꢀ14.81, ꢀ15.28. HRMS (ESIꢀ): [M ꢀ H]ꢀ,
To a solution of 1a (0.950 g, 5.01 m mol) in tert-butanol (150 mL)
was added triethylamine (2 mL, 14.34 m mol) and a catalytic
amount of 4-DMAP (60 mg, 0.3 m mol) at room temperature, fol-
lowed by the slow addition of diphenylphosphoryl azide (1.376 g,
5.00 m mol) over 5 min. The reaction mixture was stirred under
reflux for 18 h at 120 ꢁC. The excessive solvent was removed under
reduced pressure. The residue was dissolved in ethyl acetate
(100 mL) and washed with 1 N HCl solution, followed by brine. The
organic layer was dried over MgSO4, filtered and concentrated
under reduced pressure. The crude product was subjected to the
silica-gel chromatography (hexane/ethyl acetate ¼ 10:1, Rf ¼ 0.42)
to afford 1b in 72% yield as a white solid.
calcd for C3H10B10NS (m/z): 200.1537, found: 200.1542. FT-IR
(cmꢀ1): 2611 (BcareH), 2002 (N]C]S) cmꢀ1
.
2.1.5. 1-(1,7-Dicarba-closo-dodecaboran-1-yl)-3-phenyl thiourea (3)
To a solution of 2 (80 mg, 0.40 m mol) in acetonitrile was added
aniline (0.38 mL, 0.408 m mol) at ꢀ20 ꢁC. The reaction mixture was
stirred at ꢀ20 ꢁC for 2 hrs. After monitoring the progress of the
reaction by TLC, the excessive solvent was removed under reduced
pressure. The residue was extracted with ethylacetate (10 mL) and
washed with 1N HCl solution (10 mL ꢂ 2). The combined organic
layer was dried over MgSO4, filtered and concentrated under
reduced pressure. The crude product was subjected to the silica-gel
chromatography (hexane/ethylacetate ¼ 5:1 Rf ¼ 0.26) to afford 3
in 44% yield as a white solid.
1H NMR (600 MHz, CDCl3):
H), 1.43 (s, 9H), 1.28e3.78 (m, 10H, BcareH). 13C NMR (150 MHz,
d 5.19 (s, 1H, NeH), 2.90 (s, 1H, Ccare
CDCl3):
d
151.89 (C]O), 81.71(CeO), 81.07 (CcareN), 52.86 (CcareH),
1H NMR (300 MHz, CDCl3):
ArH), 6.45 (s,1H, NH), 3.01 (s,1H, CcareH),1.78e4.08 (m,10H, BcareH).
13C NMR (75 MHz, CDCl3):
179.22 (C]S),136.30 (AreC),129.87 (Are
C), 127.69 (AreC), 124.99 (AreC), 84.85 (CcareN), 53.08 (CcareH). 11
d 7.83 (s, 1H, NH), 7.29e7.48 (m, 5H,
28.13 (CH3). HRMS (ESIꢀ): [M ꢀ H]ꢀ, calcd for C7H20B10NO2 (m/z):
258.2445, found: 258.2445.
d
B
2.1.3. 1-Amino-1,7-dicarba-closo-dodecarborane (1c)
NMR (192 MHz, CDCl3):
d
ꢀ4.42, ꢀ10.90, ꢀ12.14, ꢀ14.81, ꢀ15.34.
To a solution of compound 1b in dichloromethane (15 mL) was
added trifluoroacetic acid (4 mL). The reaction mixture was stirred for
4 h at room temperature. After monitoring the reaction progress, the
excessive solvent was removed under reduced pressure. The crude
productwasdissolved in ethyl acetate (30 mL)and washed with water
(30 mL) and with brine (30 mL). The organic layer was dried over
MgSO4, filtered and concentrated under reduced pressure. The crude
productwas subjected tothe silica-gel chromatography (hexane/ethyl
acetate ¼ 9:1, Rf ¼ 0.23) to afford 1c in 63% yield as a white solid.
HRMS (ESIꢀ): [M ꢀ H]ꢀ, calcd for C9H17B10N2S (m/z):293.2116, found:
293.2122.
2.1.6. 1-(1,7-Dicarba-closo-dodecaboran-1-yl)-3-(2-pyridyl)
thiourea (4)
Compound
described for compound
4
was prepared according to the procedure
using 1-thioisocynato-1,7-dicarba-
3
closo-dodecarborane (90 mg, 0.447 m mol) and 2-aminopyridine
(42 mg, 0.446 m mol) at ꢀ20 ꢁC for 2 h. Purification by silica-gel

S. Choi, Y. Byun / Journal of Organometallic Chemistry 733 (2013) 49e52
51
chromatography (hexane/ethyl acetate ¼ 4:1, Rf ¼ 0.21) to afford 4
synthetic procedures [24e26]. During the 2nd step for the prepa-
ration of 1c, Curtius rearrangement was carried out using diphe-
nylphosphoryl azide (DPPA) and a catalytic amount of 4-
in 43% yield as a white solid.
1H NMR (600 MHz, CDCl3):
d
13.26 (s, 1H, NH), 8.15 (d, 1H,
J ¼ 5.2 Hz, 1.8 Hz), 8.12 (s, 1H, NH), 7.66 (dt, 1H, ArH, J ¼ 7.2 Hz,
1.8 Hz), 7.01 (dd, 1H, ArH, J ¼ 7.2 Hz, 5.1 Hz), 6.66 (d, 1H, ArH,
J ¼ 8.1 Hz), 2.95 (s, 1H, CcareH), 1.78e4.10 (m, 10H, BcareH). 13C NMR
(dimethylamino)pyridine (DMAP) in tert-butanol (t-BuOH) at
120 ꢁC for 18 h. The overall yield from m-carborane to 1c in 3 steps
was 33%. In order to convert 1 into the m-carboranyl isothiocyanate
2, we first tried the mild reagents such as carbon disulfide/di-tert-
butyl dicarbonate (CS2/Boc2O) and carbon disulfide/dicyclohex-
ylcarbodiimide (CS2-DCC), but the desired product was not ob-
tained due to the low eletrophilicity of carbon disulfide and the
moderate nucleophilicity of the carboranylamine group of 1c
[27,28]. Therefore, we employed thiophosgene, a highly reactive
electrophile for the transformation of amines into the corre-
sponding isothiocyanates, and could obtain the desired m-carbor-
anyl isothiocyanate 2 by reacting it with 1c.
Among several different conditions, reaction of 1c with thio-
phosgene in anhydrous THF at ꢀ20 ꢁC for 3 h afforded 2 with the
highest yield of 88% (see Table 1). Compound 2 was purified by
silica gel chromatography using a mixture of hexane and ethyl
acetate (500/3). TLC analysis studies showed that the Rf value of m-
carboranyl isothiocyanate 2 (Rf: 0.73 in hexane only) is higher than
those of phenylisothiocyanate (Rf: 0.51 in hexane only) and cyclo-
hexylisothiocyanate (Rf: 0.32 in hexane only). The chemical struc-
ture of 2 was confirmed by 1H NMR, 13C NMR, 11B NMR, FT-IR and
ESI-HRMS (see all spectra in the Supporting information). The
isothiocyanate carbon (N]C]S) of 2 has a chemical shift value of
142.26 ppm at the 13C NMR spectrum. We also observed the diag-
nostic N]C]S stretching peak at 2002 cmꢀ1 at the IR spectrum of
2. Furthermore, ESI-HRMS in negative mode clearly showed an
isotope pattern of carborane with a highest [M ꢀ H]ꢀ peak of 2 at
200.1538. This is the first report on the successful synthesis of
carboranyl isothiocyanate. It is noted that the isothiocyanate group
of 2 is directly linked to the carbon atom of m-carborane.
To prepare novel lipophilic m-carboranyl thioureas, we selected
aromatic or bulky amines as nucleophiles. The tested amines were
aromatic aniline, heteroaromatic 2-aminopyridine, sterically hin-
dered 1-adamantylamine, and m-carboranylamine (Scheme 2). Our
initial attempt to react 2 with an excess of aniline at room tem-
perature produced the desired thiourea 3 in a very low yield (<3%).
The corresponding nido form of 3 (molecular formula:C9H18B9N2S1,
the mass spectrum in the Supporting information) turned out to be
a major product due to the fact that the excess aniline degraded the
closo carborane into the nido one at room temperature. To mini-
mize the production of by-products, 2 was treated with 1 equiva-
lent of aniline in anhydrous acetonitrile (CH3CN) at low
temperature. We obtained 1-(1,7-dicarba-closo-dodecaboran-1-
yl)-3-phenyl thiourea 3 in 44% yield at ꢀ20 ꢁC with a trace
amount of the nido compound (Scheme 2). By employing the same
synthetic procedure to prepare 3, compounds 4 and 5 were ob-
tained by reacting 2 with 2-aminopyridine and 1-adamantylamine
at ꢀ20 ꢁC in 43% and 48% yields, respectively. Interestingly,
compound 5, 1-(1,7-dicarba-closo-dodecaboran-1-yl)-3-(tricyclo
[3.3.1.1]decan-1-yl) thiourea, was precipitated during the reaction
(75 MHz, CDCl3):
d 178.66 (C]S), 152.42 (AreC), 145.39 (AreC),
118.52 (AreC), 118.90 (AreC), 82.95 (CcareN), 52.68 (CcareH). 11B
NMR (192 MHz, CDCl3):
d
ꢀ3.19, ꢀ10.38, ꢀ12.49, ꢀ15.11, ꢀ15.42.
HRMS (ESIꢀ): [M ꢀ H]ꢀ, calcd for C8H16B10N3S (m/z):294.2068,
found: 294.2054.
2.1.7. 1-(1,7-dicarba-closo-dodecaboran-1-yl)-3-(tricyclo[3.3.1.1]
decan-1-yl) thiourea (5)
Compound
described for compound
5
was prepared according to the procedure
using 1-thioisocynato-1,7-dicarba-
3
closo-dodecarborane (80 mg, 0.40 m mol) and 1-adamantylamine
(52.5 mg, 0.40 m mol) at ꢀ20 ꢁC for 2 h. Purification by silica-gel
chromatography (hexane/ethyl acetate ¼ 7:1, Rf ¼ 0.32) to afford
5 in 48% yield as a white solid.
1H NMR (300 MHz, CDCl3):
d 6.41 (s, 1H, NH), 6.15 (s, 1H, NH),
2.98 (s, 1H, CcareH), 2.23 (d, 6H, J ¼ 2.4 Hz), 2.14 (d, 3H, J ¼ 2.4 Hz),
1.71 (d, 6H, J ¼ 2.4 Hz), 1.28e3.42 (m, 10H, BcareH). 13C NMR
(150 MHz, CDCl3):
d 177.66 (C]S), 82.66 (CcareN), 55.95 (CeN),
52.81 (CcareH), 40.90 (CH2), 36.10 (CH2), 29.41(CH). 11B NMR
(192 MHz, CDCl3):
d
ꢀ5.22, ꢀ11.33, ꢀ11.80, ꢀ14.73, ꢀ15.15. HRMS
(ESIꢀ): [M ꢀ H]ꢀ calcd for C13H27B10N2S (m/z):351.2898, found:
,
351.2904.
2.1.8. 1,3-Di(1,7-dicarba-closo-dodecaboran-1-yl) thiourea (6)
Compound
described for compound
6
was prepared according to the procedure
using 1-thioisocynato-1,7-dicarba-
3
closo-dodecarborane (80 mg, 0.40 m mol) and 1-amino-1,7-
dicarba-closo-dodecarborane (63 mg, 0.395 m mol) at room tem-
perature for 6 h. Purification by silica-gel chromatography (hexane/
ethyl acetate ¼ 8:1, Rf ¼ 0.34) to afford 6 in 21% yield as a white
solid.
1H NMR (300 MHz, CDCl3):
H), 1.28e3.42 (m, 10H, BcareH). 13C NMR (75 MHz, CDCl3):
d
6.61 (s, 2H, NH), 2.99 (s, 2H, Ccare
177.96
d
(C]S), 81.91 (CcareN), 53.05 (CcareH). 11B NMR (192 MHz, CDCl3):
d
ꢀ4.50, ꢀ10.45, ꢀ11.10, ꢀ11.95, ꢀ14.77, ꢀ15.44. HRMS (ESIꢀ):
[M ꢀ H]ꢀ, calcd for C5H23B20N2S (m/z): 359.3588, found: 359.3619.
FT-IR (cmꢀ1): 2604 (BcareH), 1548, 1370, 1266.
3. Results and discussion
The synthesis of 1-thioisocyanato-1,7-dicarba-closo-dodeca-
rborane (m-carboranyl isothiocyanate) was achieved from com-
mercial m-carborane in 4 steps as shown in Scheme 1. Compound
1c (1-amino-1,7-dicarba-closo-dodecarborane), the key precursor
for the synthesis of 2, was synthesized by modifying the published
Table 1
Reaction conditions for the conversion of 1c into 2.
Entry
Reagents
Temperature
RT
Yield
1
2
3
4
5
6
CSCl2
CSCl2
CSCl2
22%
62%
88%
53%
Trace
Trace
0
ꢁC
ꢀ20 ꢁC
ꢀ78 ꢁC
RT
CSCl2
CS2/Boc2Oa
CS2/DCCb
RT
a
CS2 (10 eq), triethylamine (1 eq), EtOH, 0 ꢁC, 30 min / Boc2O (1 eq), DMAP
(0.1 eq), rt, 2 h.
b
Scheme 1. Synthesis of m-carboranyl isothiocyanate 2.
CS2 (10 eq), DCC (1 eq), THF, ꢀ10 ꢁC, 10 min / rt, 2 h.

52
S. Choi, Y. Byun / Journal of Organometallic Chemistry 733 (2013) 49e52
m-carboranyl isothiocyanate with the bulky and weak nucleo-
philic amines afforded four novel sterically-hindered m-carbor-
anyl thiourea analogs in moderate yield. The newly synthesized
compounds were fully characterized by means of 1H NMR, 13C
NMR, 11B NMR, and ESI-HRMS. The unique chemical and phys-
iochemical properties of the m-carboranyl isothiocyanate have a
potential to be utilized as boron-delivery moiety for BNCT and
lipophilic pharmacophore in medicinal chemistry.
Acknowledgments
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea Government (MEST) (No.
2012R1A1A1010000 and No. 20110018933).
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.jorganchem.2013.03.003.
Scheme 2. Synthesis of m-carboranyl thiourea analogs 3e6.
References
Table 2
Featured spectroscopic properties of the m-carboranyl isothiocyanate 2 and m-
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Yield
[M ꢀ H]ꢀ
2
3
4
5
6
2.94 (CcareH)
142.36 (N]C]S) 79.07 200.1542 88%
(CcareN) 52.93 (CcareH)
7.83 (NH) 6.45
(NH)3.01 (CcareH)
13.26 (NH) 8.12
(NH) 2.95 (CcareH) (CcareN) 52.68 (Ccar),
6.41 (NH) 6.15 177.66 (C]S) 82.66
(NH) 2.98 (CcareH) (CcareN) 52.81 (CcareH)
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6.61 (NH) 2.99
177.96 (C]S) 81.91
(CcareH)
(CcareN) 53.05 (CcareH)
and purified by simple filtration. However, m-carboranylamine
when treated with 2 at ꢀ20 ꢁC afforded the corresponding thiourea
6 in a yield lower than 5%. The starting materials 2 and m-carbor-
anylamine remained unreacted, suggesting that the weaker
nucleophilicity of the m-carboranylamine than the other amines
may lower the conjugation yield. After a longer reaction time of 6 h
at room temperature, 21% conversion of 2 into 1,3-di(1,7-dicarba-
closo-dodecaboran-1-yl) thiourea 6 occurred.
The chemical structures of the synthesized compounds 3e6
were fully analyzed and confirmed by 1H NMR, 13C NMR, 11B
NMR, and ESI-HRMS. The diagnostic signal for the carbon of thio-
urea (NHC(]S)NH) appeared at around 179 ppm from the 13C NMR
spectra. We also observed the broad singlet peaks for two NHs from
the 1H NMR spectra and carborane isotope patterns with a highest
[M ꢀ H]- peak from ESI-HRMS spectra of 3e6 (see all the spectra in
Supporting information). Featured spectroscopic properties of 3e6
and the m-carboranyl isothiocyanate 2 are summarized in Table 2.
4. Conclusions
We have successfully achieved the first synthesis of the
m-carboranyl isothiocyanate in high yield. Reaction of the
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