Synthesis of Carboranyl Amino Acids, Hydantoins, and Barbiturates

Article abstract of DOI:10.1021/ic9511229

The syntheses of three novel boronated hydantoins, 5-(o-carboran-1-ylmethyl)hydantoin, 14, the tetraphenylphosphonium salt of 7-(hydantoin-5-ylmethyl)dodecahydro-7,8-dicarba-nido-undecaborate, 15, 5-(o-carboran-1-ylmethyl)-2-thiohydantoin, 16, and two new barbiturates, 5,5-bis(but-2-ynyl)barbiturate, 18, and 5,5-bis[(2-methyl-o-carboran-1-yl)methyl]barbiturate, 20, are described. Hydantoins 14-16 were synthesized from o-carboranylalanine (Car, 13). The detailed syntheses of Car and two other carborane-containing amino acids, O-(o-carboran-1-ylmethyl)tyrosine (CBT, 5a) and p-(o-carboran-1-yl)phenylalanine (CBPA, 5b), presented earlier as a communication,¹⁶ are also described. Hydantoin 14 and barbiturates 18 and 20 were tested for their potential anticonvulsant activity. Initial qualitative screening showed moderate activities for hydantoin 14 and barbiturate 18. Barbiturate 20 had no activity. Compound 14 appeared to be nontoxic at doses of 300 mg/kg (mice, ip) and 50 mg/kg (rats, oral). However, 18 was very toxic under similar conditions.

Full text of DOI:10.1021/ic9511229

Inorg. Chem. 1996, 35, 4541-4547
4541
Synthesis of Carboranyl Amino Acids, Hydantoins, and Barbiturates
Iwona M. Wyzlic, Werner Tjarks, Albert H. Soloway,* Douglas J. Perkins,
Minerva Burgos, and Kevin P. O’Reilly
College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, Ohio 43210
ReceiVed August 24, 1995X
The syntheses of three novel boronated hydantoins, 5-(o-carboran-1-ylmethyl)hydantoin, 14, the tetraphenylphos-
phonium salt of 7-(hydantoin-5-ylmethyl)dodecahydro-7,8-dicarba-nido-undecaborate, 15, 5-(o-carboran-1-
ylmethyl)-2-thiohydantoin, 16, and two new barbiturates, 5,5-bis(but-2-ynyl)barbiturate, 18, and 5,5-bis[(2-methyl-
o-carboran-1-yl)methyl]barbiturate, 20, are described. Hydantoins 14-16 were synthesized from o-carboranylalanine
(Car, 13). The detailed syntheses of Car and two other carborane-containing amino acids, O-(o-carboran-1-
ylmethyl)tyrosine (CBT, 5a) and p-(o-carboran-1-yl)phenylalanine (CBPA, 5b), presented earlier as a com-
munication,16 are also described. Hydantoin 14 and barbiturates 18 and 20 were tested for their potential
anticonvulsant activity. Initial qualitative screening showed moderate activities for hydantoin 14 and barbiturate
18. Barbiturate 20 had no activity. Compound 14 appeared to be nontoxic at doses of 300 mg/kg (mice, ip) and
50 mg/kg (rats, oral). However, 18 was very toxic under similar conditions.
Introduction
and des-Arg9-bradykinin ([Car5]-des-Arg9-bradykinin) showed
a decreased activity but significantly prolonged duration of
o-, m-, and p-carboranes are slightly distorted icosahedral
structures that consist of ten boron atoms and two carbon atoms;
the latter are in either the 1,2- (o), 1,7- (m), or 1,12- (p)
positions.1 They are highly lipophilic (i.e., the hydrophobic
parameter, π, for o-carborane is +4.202) with an extraordinary
chemical and thermal stability. It is possible to carry out a
variety of chemical reactions on the C-substituents of carboranes
without degrading the cage. Many carborane-containing com-
pounds have been synthesized but little is known about their
toxicity or metabolic fate. However, LD50 values of 1400 mg/
kg (oral, rats) and 1000 mg/kg (subcutaneous, mice) for
m-carborane indicate a generally low toxicity for the boron
cluster itself.3 Despite the large number of carborane-containing
compounds that have been synthesized, their medical use, with
only few exceptions,4 has been largely limited to their potential
as boron neutron capture therapy (BNCT) agents.5 Leukart et
al.6 recognized that the volume of the o-carborane cage was
only slightly larger than the volume occupied by a phenyl ring,
rotating about its C1-C4 axis. Therefore, they synthesized L-o-
carboranylalanine (L-Car)6 to replace phenylalanine in biologi-
cally-active peptides. L-Car was used to replace aromatic
residues in tripeptide inhibitors of R-chymotrypsin7 and in
[Leu5]-enkephalin.8 Studies showed that Car may bind to the
hydrophobic Phe recognition site of R-chymotrypsin to give a
strongly inhibitory tripeptide and to the opiate receptors in rat
brain extracts in which [Car4,Leu5]-enkephalin showed an
affinity 3 times higher than the natural peptide [Leu5]-enkepha-
lin.7,8 Carboranyl analogues of angiotensin II ([Sar1,Car8]AT
action compared with their phenylalanine-containing counter-
parts.9,10 The authors assumed that the prolonged duration of
action was related to the enhanced lipophilicity of the peptides
containing the hydrophobic carborane cage. These results led
to more useful syntheses of o-carboranylalanine as the D- and
L-forms,11-14 L-form,15 and the racemic mixture.16 The detailed
synthesis of Car 13 and two other carborane-containing amino
acids, O-(o-carboran-1-ylmethyl)tyrosine (CBT, 5a) and p-(o-
carboran-1-yl)phenylalanine17 (CBPA, 5b), presented earlier as
a communication,16 are described in this paper.
Aryl-containing hydantoins and barbiturates have been widely
used as anticonvulsant drugs. However, toxicological studies
revealed important side effects, e.g. teratogenicity and hyper-
sensitivity, stemming from the formation of highly reactive
metabolic intermediates, such as arene oxides.18,19 Replacement
(9) Escher, E.; Guillemette, G.; Leucart, O.; Regoli, D. Eur. J. Pharmacol.
1980, 66, 267.
(10) Couture, R.; Drouin, J.-N.; Leucart, O.; Regoli, D. Can. J. Physiol.
Pharmacol. 1979, 57, 1437.
(11) Petersson, P.; Malmquist, J.; Markides, K. E.; Sjoberg, S. J. Chro-
matogr., A 1994, 670, 239.
(12) Andersson, A.; Andersson, J.; Burgman, J-O.; Capala, J.; Carlsson,
J.; Conde, H.; Crawford, J.; Graffmann, S.; Grusell, E.; Holmberg,
A.; Johansson, E.; Larsson, B. S.; Larsson, B.; Liljefors, T.; Lindstrom,
P.; Malmquist, J.; Pellettieri, L.; Pettersson, O.; Ponten, J.; Roberti,
A.; Russel, K.; Reist, H.; Salford, L.; Sjo¨berg, S.; Stenerlow, B.;
Stro¨mberg, P.; Westermark, B. In Progress in Neutron Capture
Therapy for Cancer; Allen, B. J., et al., Eds.; Plenum Press: New
York, 1992; p 41.
(13) Kahl, S. B.; Radel, P. A. In Current Topics in the Chemistry of Boron;
Kabalka, G. W., Ed.; Royal Society of Chemistry: Cambridge, U.K.,
1994; p 155.
(14) Radel, P. A.; Kahl, S. B. In AdVances in Neutron Capture Therapy;
Soloway, A. H., Barth, R. F., Carpenter, D. E., Eds.; Plenum Press:
New York, 1993; p 277.
X Abstract published in AdVance ACS Abstracts, June 15, 1996.
(1) Grimes, R. N. Carboranes; Academic Press, Inc.: New York, 1970.
(2) Fauchere, J. L.; Do, K. Q.; Jow, P. Y. C.; Hansch, C. Experientia
1980, 36, 1203.
(3) Denisenko, P. P.; Lebedeva, D. P.; et al. Gig. Tr. Prof. Zabol. 1978,
22, 42; Chem. Abstr. 1978, 88, 99962.
(4) Kliegel, W. Bor in Medizin und Pharmazie; Springer-Verlag: Berlin,
Heidelberg, New York, 1980.
(5) Barth, R. F.; Soloway, A. H.; Fairchild, R. G.; Brugger, R. M. Cancer
1992, 40, 2995.
(6) Leukart, O.; Caviezel, M.; Eberle, A.; Escher, E.; Tun-Kyi, A.;
Schwyzer, R. HelV. Chim. Acta 1976, 59, 2184.
(7) Fischli, W.; Leukart, O.; Schwyzer, R. HelV. Chim. Acta 1977, 60,
959.
(8) Eberle, A.; Leukart, O.; Schiller, P.; Fauchere, J.-L.; Schwyzer, R.
FEBS Lett. 1977, 82, 325.
(15) Karnbrock, W.; Musiol, H.-J.; Moroder, L. Tetrahedron 1995, 51,
1187.
(16) Wyzlic, I. M.; Soloway, A. H. Tetrahedron Lett. 1992, 33, 7489.
(17) (a) Wyzlic, I. M.; Soloway, A. H.; Barth, R. F.; Rotaru, J. In AdVances
in Neutron Capture Therapy; Soloway, A. H., Barth, R. F., Carpenter,
D. E., Eds.; Plenum Press: New York, 1993; p 281. (b) Prashar, J.
K.; Moore, D. E.; Wilson, J. G.; Allen, B. J. In AdVances in Neutron
Capture Therapy; Soloway, A. H., Barth, R. F., Carpenter, D. E., Eds.;
Plenum Press: New York, 1993; p 265. (c) Prashar, J. K.; Moore,
D. E. J. Chem. Soc., Perkin Trans. 1 1993, 1051.
(18) Levy, R. H., Dreifuss, F. E., Mattson, R. H., Meldrum, B. S., Penry,
J. K., Eds.; Antiepileptic Drugs, 3rd ed.; Raven Press, Ltd.: New York,
1989.
S0020-1669(95)01122-0 CCC: $12.00 © 1996 American Chemical Society

4542 Inorganic Chemistry, Vol. 35, No. 16, 1996
Wyzlic et al.
to an ice-cooled solution of 5.4 g (50.0 mmol) of p-cresol in 45 mL of
dry DMF. The mixture was stirred for 50 min at 0 °C until hydrogen
evolution had ceased. Then, 5.4 mL (60.0 mmol) of proparagyl bromide
was slowly added to the ice-cooled solution, and the solution was stirred
for an additional 5 h and allowed to warm to room temperature. The
reaction mixture was concentrated and filtered to remove the NaBr.
The filtrate was evaporated to dryness. The resulting yellow oil was
purified by column chromatography (hexanes/ethyl acetate, 4:1, v/v).
6: yield 5.3 g (73%) of light yellow oil; Rf 0.73 (hexanes/ethyl acetate,
of the aromatic function with a carborane moiety having
comparable 3-dimensional space and increased metabolic stabil-
ity and lipophilicity might yield compounds with improved
therapeutic efficacy. Also, related CNS depressants were shown
not only to enter the brain rapidly but to achieve concentration
differentials between primary brain tumors and normal brain
of 4:1.20,21 Therefore, carboranyl hydantoins and barbiturates
might be considered as potential agents for BNCT.
Zakharkin et al.22 investigated the sedative effect of a number
of C-substituted closo- and nido-carboranes and found high
activity for compounds possessing a side chain amino function
with no other specific structural characteristics. These results
and the availability of o-carboranylalanine16 prompted the
synthesis of novel boronated hydantoins and barbiturates.
In 1970, the first carboranyl hydantoins and barbiturates were
described. Brattsev et al.23 synthesized boron-containing bar-
biturate and thiobarbiturate compounds by the condensation of
barbituric or thiobarbituric acids with carboranyl aldehydes.
Zakharkin et al.24 synthesized 5-(o-carboranylmethyl)barbiturate,
from o-carboranylmethyl malonic ester and urea, as well as the
first boronated hydantoin, 5-(methyl-o-carboranylmethyl)hy-
dantoin. The latter was formed by the action of potassium
cyanide and ammonium carbonate on the bisulfite derivative
of methylcarboranylacetaldehyde. Recently, Kazantsev et al.25
described the synthesis of carboranylthiohydantoins by the
reaction of benzylidene-2-thiohydantoins with 1-isopropyl-2-
lithio-o-carboranes. To our knowledge, none of these com-
pounds were evaluated with respect to their anticonvulsant
activity or for their potential as BNCT agents.
1
4:1, v/v); MS (FAB+, 3-NBA) m/z 149 (M + 3H); H-NMR (CDCl3)
δ 2.33 (s, 3H, -CH3-), 2.53 (t, 1H, -CtCH, J1,3-propynyl ) 2.4), 4.69
(d, 2H, -CH2CtCH), 6.92, 7.14 (2d, 4H, aromat, J ) 8.5); 13C-NMR
(CDCl3) δ 20.41 (q, CH3), 55.86 (t, CH2), 75.24 (d, CH), 78.80 (d of
t, -CH2CCH), 114.79, 129.86 (2d, aromat), 130.81, 155.44 (2s, aromat).
Anal. Calcd for C10H10O: C, 82.16; H, 6.89. Found: C, 82.23; H,
6.91.
p-[(o-Carboran-1-ylmethyl)oxy]toluene (7). A solution of 1.8 g
(12.2 mmol) of p-[(3-prop-1-ynyl)oxy]toluene (6) and 2.5 g (12.2 mmol)
of decarborane-acetonitrile in 50 mL of dry toluene was heated for 5
h at 90 °C. The progress of the reaction was checked by TLC (hexanes/
ethyl acetate, 4:1, v/v). Following evaporation of the toluene, the
remaining residue was purified on a silica gel column (hexanes/ethyl
acetate, 10:1, v/v). 7: yield 2.4 g (75%) of white crystals; Rf 0.52
(hexanes/ethyl acetate, 10:1, v/v); mp 109-110 °C; MS (FAB+, 3-NBA)
m/z 264 (M); 1H-NMR (CDCl3) δ 1.6-2.8 (br, m, 10H, BH), 2.29 (s,
3H, -CH3), 4.06 (br s, 1H, carborane H), 4.36 (s, 2H, -CH2-), 6.73,
7.09 (2d, 4H, aromat, J ) 8.5); 13C-NMR (CDCl3) δ 20.49 (q, CH3),
57.74 (d, CH), 69.74 (t, CH2), 71.72 (s, carborane-C-), 114.66, 130.24
(2d, aromat), 132.12, 155.08 (2s, aromat). Anal. Calcd for
C10H20B10O: C, 45.43; H, 7.63. Found: C, 45.74; H, 7.77.
p-[(o-Carboran-1-ylmethyl)oxy]benzyl Bromide (1a). A solution
of 370 µL (7.2 mmol) of Br2 in 5 mL of carbon tetrachloride was added
dropwise to a solution of 1.9 g (7.0 mmol) of p-[(o-carboran-1-
ylmethyl)oxy]toluene (7) in 30 mL of carbon tetrachloride. The reaction
mixture was stirred and heated for 4 h at 50 °C. The progress of the
reaction was monitored by TLC (hexanes/ethyl acetate, 6:1, v/v).
Following evaporation of the solvent, the remaining residue was purified
by column chromatography (hexanes/ethyl acetate, 6:1, v/v). 1a: yield
1.9 g (79%) of white crystals; Rf 0.52 (hexanes/ethyl acetate, 6:1, v/v);
mp 78-79 °C; MS (FAB+, 3-NBA) m/z 343 (M); 1H-NMR (CDCl3) δ
1.6-2.8 (br, m, 10H, BH), 4.05 (br s, 1H, carborane H), 4.40 (s, 2H,
-CH2O-), 4.46 (s, 2H, -CH2Br), 6.81, 7.36 (2d, 4H, J ) 8.7, aromat);
13C-NMR (CDCl3) δ 32.95 (t, -CH2Br), 57.76 (d, CH), 69.27 (t,
-CH2O), 71.29 (s, carborane-C-), 115.00, 130.71 (2d, aromat),
132.20, 156.98 (2s, aromat). Anal. Calcd for C10H19B10OBr: C, 34.99;
H, 5.58. Found: C, 35.25; H, 5.47.
Phase-Transfer Alkylation of [(Diphenylmethylene)amino]ac-
etonitrile with p-[(o-Carboran-1-ylmethyl)oxy]benzyl Bromide (1a).
To a solution of 1.2 g (3.5 mmol) of p-[(o-carboran-1-ylmethyl)oxy]-
benzyl bromide (1a) and 0.8 g (3.5 mmol) of [(diphenylmethylene)-
amino]acetonitrile (2) in 25 mL of acetonitrile were added 2.9 g (21.0
mmol) of anhydrous potassium carbonate and 0.34 g (1.1 mmol) of
tetra-n-butylammonium bromide, and the solution was refluxed under
argon for 5 h. The progress of the reaction was monitored by TLC
(hexanes/ethyl acetate, 6:1, v/v). The reaction mixture was cooled to
room temperature and filtered to remove the solid, which was washed
with dichloromethane. The filtrate and washings were combined and
concentrated. The remaining residue was purified by a column
chromatography (hexanes/ethyl acetate, 6:1, v/v) and recrystallized from
hexanes/ethyl acetate (6:1). 3a: yield 1.2 g (71%) of white crystals;
Rf 0.33 (hexanes/ethyl acetate, 6:1, v/v); mp 94-96 °C; MS (FAB+,
3-NBA) m/z 483 (M + H)+; 1H-NMR (CDCl3) δ 1.5-2.9 (br m, 10H,
BH), 3.12, 3.19 (d of ABq, 2H, -CH2CH-, JAB ) 13.6, JBX ) 7.6,
JAX ) 6.2), 4.04 (br s, 1H, carborane H), 4.35 (dd, 1H, -CHCH2-,
JAX ) 6.3, JBX ) 7.6), 4.37 (s, 2H, -CH2O-), 6.7-7.8 (m, 14H,
aromat); 13C-NMR (CDCl3) δ 40.27 (t, -CH2CH-), 54.88 (d,
-CHCH2-), 57.76 (d, HC- of carborane), 69.32 (t, -CH2O-), 71.46
(s, -CH2C- of carborane), 119.10 (s, -CN), 114.81-156.37 (aromat),
173.33 (s, -NdCPh2). Anal. Calcd for C25H30B10N2O: C, 62.22; H,
6.27; B, 22.40; N, 5.80. Found: C, 62.06; H, 6.45; B, 22.25; N, 5.62.
3-[-p-((o-Carboran-1-ylmethyl)oxy]phenyl]-2-aminopropioni-
trile (4a). A 0.4 g (0.8 mmol) quantity of compound 3a dissolved in
Experimental Section
FT-NMR spectra (proton and carbon) were obtained at The Ohio
State University Chemical Instrument Center using a Bruker AM500
(carbon and proton) and in the College of Pharmacy at OSU using a
Bruker AC250 (proton spectra). Chemical shifts (δ) are reported in
ppm downfield from an internal tetramethylsilane standard. Coupling
constants (J) are reported in hertz. IR spectra were recorded on a RFX
40 FT-IR spectrometer (Laser Precision Corp.). The spectra were in
accordance with the proposed structures. Melting points were deter-
mined on a Fisher-Johns melting point apparatus and are reported
uncorrected. Mass spectra were obtained at The Ohio State University
Chemical Instrument Center on Finnigan MAT-900 mass spectrometer.
HPLC was performed by use of Rainin HPLC System with Dynamax
Model UV-1 detector. Column Dynamax-60A 8 µm C8, 25 cm × 4.6
mm, with a guard module Dynamax-60A 8 µm C8, 1.5 cm × 4.6 mm,
was applied. Elemental analyses were performed by Galbraith Labo-
ratories, Inc., Knoxville, TN; Atlantic Microlab, Inc., Norcross, GA;
and Analytische Laboratorien, Gummersbach, Germany. Silica gel 60-
F254 glass plates (Merck) were used for TLC. Compound visualization
was achieved with UV light (254 nm), iodine, and spraying with 0.06%
PdCl2/% HCl (boron) and subsequent heating at 120 °C for 10-15
min. Silica gel 60 (70-230 mesh ASTM, Merck) was used for column
chromatography. Reagent grade solvents were used for reactions and
chromatography. Toluene and THF were distilled from sodium.
p-[(3-Prop-1-ynyl)oxy]toluene (6). A 2.4 g (60.0 mmol) quantity
of sodium hydride (60% dispersion in mineral oil) was slowly added
(19) Sanner, M. A.; Higgins, T. J. In Annual Reports in Medicinal
Chemistry, Vol. 26; Bristol, J. A., Ed.; Academic Press, Inc.: San
Diego, CA, 1991; Chapter 19.
(20) Grieg, N. H. Cancer Treat. ReV. 1987, 14, 1.
(21) Rosenblum, T.; Stein, A. Biochem. Pharmacol. 1963, 12, 1453.
(22) Zakharkin, L. I.; Zhigareva, G. G.; Kirillova, V. S.; Tolmacheva, N.
S.; Raevskii, K. S. Khim.-Farm. Zh. 1976, 10, 63; Pharm. Chem. J.
(Engl. Transl.) 1976, 10, 50.
(23) Brattsev, V. A.; Al’perovich, N. E.; Stanko, V. I. Zh. Obshch. Khim.
1970, 40, 1328.
(24) Zakharkin, L. I.; Grebennikov, A. V.; L’vov, A. I. IzV. Akad. Nauk
SSSR, Ser. Khim. 1970, 106.
(25) Kazantsev, A. V.; Kazantsev, Yu. A. IzV. Akad. Nauk Resp. Kaz., Ser.
Khim. 1992, No. 2, 66.

Carboranyl Amino Acids, Hydantoins, and Barbiturates
Inorganic Chemistry, Vol. 35, No. 16, 1996 4543
5 mL of benzene was reacted with 15 mL of 6 N HCl. After 18 h of
stirring at room temperature, the aqueous layer was adjusted to pH
8-9, and the organic layer was removed, dried (MgSO4), and
evaporated to dryness. The remaining residue was purified by column
chromatography (chloroform/methanol, 6:1, v/v). 4a: yield 235 mg
(90%) of a yellow, hygroscopic glasslike compound; Rf 0.9 (chloroform/
methanol, 6:1, v/v); MS m/z (FAB+, 3-NBA) 319 (M + H)+; 1H-NMR
(CDCl3) δ 1.5-2.9 (br m, 10H, BH), 1.78 (br s, 2H, -NH2) 3.00, 2.94
(d of ABq, 2H, -CH2CH-, JAB ) 13.8, JBX ) 7.1, JAX ) 5.9), 3.89 (t,
1H, -CHCH2-, J ) 6.822, 6.128), 4.07 (br s, 1H, carborane H), 4.40
(s, 2H, -CH2O-), 6.83, 7.24 (2d, 4H, aromat, J ) 8.6); 13C-NMR
(CDCl3) δ 40.23 (t, -CH2CH-), 44.71 (d, -CHCH2-), 57.85 (d, HC-
of carborane), 69.28 (t, -CH2O-), 71.45 (s, -C- of carborane), 115.08
(d, aromat), 121.34 (s, -CN), 129.03 (s, aromat), 131.00 (d, aromat),
156.61 (s, aromat). Since compound 4a was hygroscopic, it was used
directly in the formation of the amino acid 5a.
O-(o-Carboran-1-ylmethyl)tyrosine (5a). A 0.16 g (3.1 mmol)
quantity of 3-[-p-((o-carboran-1-ylmethyl)oxy)phenyl]-2-aminopropi-
onitrile (4a) was reacted with 10 mL of 75% H2SO4 at 95 °C for 24 h.
The mixture was cooled (ice-water bath) and filtered. The resulting
yellow solid was washed with water and dried. The product was
purified by reversed-phase flash chromatography (C8, 40 µm, 60 Å,
MeOH/H2O, 9:1, v/v). 5a: yield 115 mg (70%) of white solid; Rf 0.6
(n-BuOH/CH3COOH/H2O, 4:1:1, v/v/v); HPLC retention time 13.64
(Dynamax-60A 8 µm C8, flow rate 0.75 mL/min, solvent system 25%
H2O/75% MeOH, injection pressure 0.91 kpsi); ninhydrin positive; mp
196-197 °C; MS (FAB+, 3-NBA) m/z 338 (M + H)+; 1H-NMR
(MeOH-d4) δ 1.1-3.3 (br m, 10H, BH), 2.97-3.23 (d of ABq, 2H,
-CH2CH-, JAB ) 14.6, JBX ) 8.4, JAX ) 4.5), 3.73 (dd, 1H,
-CHCH2-, JAX ) 4.5, JBX ) 8.4), 4.51 (s, 2H, -CH2O-), carborane
H overlapped by MeOH, 6.92, 7.24 (2d, 4H, aromat, J ) 8.6). Anal.
Calcd for C12H23B10NO3: C, 42.71; H, 6.87; N, 4.15; B, 32.04.
Found: C, 42.45; H, 6.77; N, 4.00; B, 31.91.
10:1, v/v). The mixture was cooled to room temperature and filtered.
The solid was washed with dichloromethane, and the filtrates were
combined and concentrated. The residue was purified by column
chromatography (hexanes/ethyl acetate, 10:1, v/v) and crystallized from
ethyl acetate/hexanes, 1:5. 3b: yield 202 mg (59%) of white crystals;
Rf 0.24 (hexanes/ethyl acetate, 10:1, v/v); mp 162-163 °C; MS (FAB+,
3-NBA) m/z 453 (M + H)+; 1H-NMR (CDCl3) δ 1.7-3.3 (br m, 10H,
BH), 3.15, 3.22 (d of ABq, 2H, -CH2CH-, JAB ) 13.5, JBX ) 7.6,
JAX ) 6.0), 3.92 (br s, 1H, carborane H), 4.37, 4.38 (dd, 1H,
-CHCH2-, J ) 7.5), 6.8-7.8 (m, 14H, aromat); 13C-NMR (CDCl3)
δ 40.40 (t, -CH2CH-), 54.39 (d, -CHCH2-), 60.07 (d, HC- of
carborane), 75.94 (s, -C- of carborane), 118.82 (s, -CN), 127.07-
138.044 (aromat), 173.57 (s, -NdCPh2). Anal. Calcd for
C24H28N2B10: C, 63.69; H, 6.24; N, 6.19; B, 23.89. Found: C, 63.47;
H, 6.18; N, 6.02; B, 23.68.
p-(o-Carboran-1yl)phenylalanine (5b). A 0.28 g (0.62 mmol)
quantity of 3b dissolved in 10 mL of benzene was hydrolyzed with 15
mL of 6 N HCl. After the mixture was stirred for 17 h at room
temperature, the organic layer was removed and the aqueous layer was
extracted with ether. The combined organic solutions were dried and
evaporated to dryness. The residue was purified by column chroma-
tography (chloroform/methanol, 10:1, v/v), yielding 80 mg of the
corresponding aminonitrile. This was immediately reacted with 15 mL
of 70% H2SO4 at 95 °C for 24 h. The mixture was cooled (ice-water
bath) and filtered, and the resulting yellow solid was washed with water,
dried under vacuum, and purified by reversed-phase flash chromatog-
raphy (C8, 40 µm, 60 Å, MeOH/H2O, 8.5:1.5, v/v). 5b: yield 150 mg
(79% total yield of hydrolysis) of white solid; Rf 0.56 (n-BuOH/CH3-
COOH/H2O, 4:1:1, v/v/v); HPLC retention time 6.7 (Dynamax-60A 8
µm C8, flow rate 0.63 mL/min, solvent system 15% H2O/85% MeOH,
injection pressure 0.75 kpsi); ninhydrin positive; mp 200-201 °C; MS
1
(FAB+, 3-NBA) m/z 308 (M + H)+; H-NMR (MeOH-d4) δ 1.2-3.3
(br m, 10H, BH), 3.04, 3.27 (d of ABq, 2H, -CH2-, JAB ) 14.5, JBX
) 8.3, JAX ) 4.7), 3.78 (dd, 1H, -CHCH2-), 5.11 (br s, 1H, carborane
H), 7.32, 7.53 (2d, 4H, aromat, J ) 8.4). Anal. Calcd for C11H21-
NO2B10: C, 42.98; H, 6.89; N, 4.56; B, 35.17. Found: C, 42.68; H,
6.67; N, 4.41; B, 35.20.
p-(o-Carboran-1-yl)toluene (8). A solution of 4.7 g (40.5 mmol)
of 4-ethynyltoluene and 9.1 g (45.2 mmol) of a decaborane-acetonitrile
complex in 200 mL of dry toluene was heated for 5 h at 90 °C. The
progress of the reaction was monitored by TLC (hexanes/ethyl acetate,
10:1, v/v). Following evaporation of the toluene, the residue was
purified on a silica gel column (hexanes/ethyl acetate, 10:1, v/v). 8:
yield 6.6 g (70%) of white crystals; Rf 0.53 (hexanes/ethyl acetate, 10:
1, v/v); subl 133-134 °C/760 mm Hg; MS (FAB+, 3-NBA) m/z 235
(M + H)+; 1H-NMR (CDCl3) δ 1.2-3.6 (br m, 10H, BH), 2.34 (s, 3H,
-CH3), 3.92 (br s, 1H, carborane H), 7.13, 7.36 (2d, 2H, aromat, J )
8.3). Anal. Calcd for C9H18B10: C, 46.13; H, 7.74; B, 46.13. Found:
C, 45.95; H, 7.63; B, 46.03.
2-[(Diphenylmethylene)amino]pent-4-ynenitrile (10). To a solu-
tion of 6.7 g (30.5 mmol) of [(diphenylmethylene)amino]acetonitrile
(2) in 300 mL of acetonitrile were added 50.4 g (365.0 mmol) of
anhydrous potassium carbonate and 5.9 g (18.2 mmol) of tetra-n-
butylammonium bromide. Propargyl bromide (6 mL, 67.3 mmol) was
added dropwise to the refluxing solution under argon for 3 h. The
reaction mixture was carefully monitored by TLC (hexanes/ethyl
acetate, 6:1, v/v). The reaction mixture was cooled to room temperature
and filtered to remove the solid, which was washed with dichlo-
romethane. The filtrate and washings were combined and concentrated,
and the residue was purified by column chromatography (hexanes/ethyl
acetate, 10:1, v/v). 10: yield 5.0 g (63.5%) of light yellow crystals;
Rf 0.50 (hexanes/ethyl acetate, 6:1, v/v); mp 93-93.5 °C; MS (FAB+,
3-NBA) m/z 259 (M + H)+; 1H-NMR (CDCl3) δ 2.095 (t, 1H, HCtC-,
J1,3-propynyl ) 2.6), 2.78, 2.90 (d of ABq, 2H, -CH2-, JAB ) 16.6, JBX
) 6.7, JAX ) 7.4, J1,3-propynyl ) 2.6), 4.40 (t, 1H, -HCCH2-, J ) 7.05),
7.25-7.81 (m, 10H, aromat); 13C-NMR (CDCl3) δ 25.43 (t, -CH2-),
52.25 (d, -CHCH2-), 72.05 (d, HCtC-), 78.24 (s, -CtCH), 118.30
(s, -CH), 127.56, 128.26, 129.09, 129.21, 129.56, 130.06, 131.42,
132.40 (8d, aromat), 134.95, 138.27 (2s, aromat), 174.36 (s, -NdCPh2).
Anal. Calcd for C18H14N2: C, 83.69; H, 5.46; N, 10.84. Found: C,
83.44; H, 5.51; N, 10.73.
3-(o-Carboran-1-yl)-2-[(diphenylmethylene)amino]pro-
pionitrile (11). A solution of 4.4 g (17.0 mmol) of 2-[(diphenyl-
methylene)amino]pent-4-ynenitrile (10) and 3.8 g (18.7 mmol) of the
decaborane-acetonitrile complex in 70 mL of dry toluene was heated
for 4 h at 90 °C. The progress of the reaction was followed by TLC
(hexanes/ethyl acetate, 6:1, v/v). After evaporation of the toluene, the
residue was purified on a silica gel column (hexanes/ethyl acetate, 10:
1, v/v). 11: yield 2.4 g (36%) of yellow glasslike compound; Rf 0.21
(hexanes/ethyl acetate, 10:1, v/v); MS (FAB+, 3-NBA) m/z 377 (M +
H)+; 1H-NMR (CDCl3) δ 1.5-2.8 (br m, 10H, BH), 2.905, 2.95 (d of
ABq, 2H, -CH2-, JAB ) 15.3, JBX ) 6.9, JAX ) 6.0), 3.81 (br s, 1H,
HC- of carborane), 4.34 (t, 1H, -CH-), 7.21-7.62 (m, 10H, aromat);
13C-NMR (CDCl3) δ 42.220 (t, -CH2-), 51.576 (d, -HCHC2-),
p-(o-Carboran-1-yl)benzyl Bromide (1b). To an ice-cooled solu-
tion of 0.26 g (1.1 mmol) of p-(o-carboran-1-yl)toluene (8) in 10 mL
of carbon tetrachloride irradiated with a 600-W photolamp was added
dropwise with stirring a solution of 60 µL (1.2 mmol) of bromine in 3
mL of carbon tetrachloride. The reaction was complete in 15 min.
Following evaporation of the solvent, the residue was isolated on a
silica gel column (hexanes/ethyl, acetate 10:1, v/v) and contained 1b
(major) and p-(o-carboran-1-yl)benzaldehyde (9). 1b: yield 257 mg
(77%) of white crystals; Rf 0.36 (hexanes/ethyl acetate, 10:1, v/v), mp
110-112 °C; MS (FAB+, 3-NBA) m/z 312 (M - H)+; 1H-NMR
(CDCl3) δ 1.2-3.6 (br m, 10H, BH), 3.94 (br s, 1H, carborane H),
4.44 (s, 2H, -CH2-), 7.36, 7.46 (2d, 4H, aromat, J ) 8.5). Anal.
Calcd for C9H17B10Br: C, 34.51; H, 5.47; B, 34.51. Found: C, 34.34;
H, 5.28; B, 34.58. 9: yield 21 mg (5%) of white crystals; Rf 0.13
(hexanes/ethyl acetate, 10:1, v;v); mp 126 °C; MS (FAB+, 3-NBA)
1
m/z 248 (M); H-NMR (CDCl3) δ 1.0-3.3 (br m, 10H, BH), 4.03 (br
s, 1H, carborane H), 7.66, 7.86 (2d, 4H, aromat, J ) 8.5), 10.04 (s,
1H, -CHO). Anal. Calcd for C9H16B10O: C, 43.53; H, 6.49; B, 43.53.
Found: C, 43.50; H, 6.29; B, 43.26.
Phase-Transfer Alkylation of [(Diphenylmethylene)amino]-
acetonitrile with p-(o-Carboran-1-yl)benzyl Bromide (1b). To a
solution of 0.24 g (0.76 mmol) of p-(o-carboran-1-yl)benzyl bromide
(1b) and 0.17 g (0.76 mmol) of [(diphenylmethylene)amino]acetonitrile
(2) in 10 mL of acetonitrile were added 0.63 g (2.86 mmol) of
anhydrous potassium carbonate and 0.07 g (0.23 mmol) of tetrabuty-
lammonium bromide. The reaction mixture was refluxed under argon
for 4 h, and progress was followed by TLC (hexanes/ethyl acetate,

4544 Inorganic Chemistry, Vol. 35, No. 16, 1996
Wyzlic et al.
60.193 (d, HC- of carborane), 70.710 (s, -C- of carborane), 117.808
(s, -CN), 126.515-137.682 (8d, 2s, aromat), 175.563 (s, -NdCPh2).
Anal. Calcd for C18H24N2B10‚4/3H2O: C, 53.98; H, 6.71; B, 26.99.
Found: C, 54.06; H, 6.84; B, 26.60.
136.4 (5d, aromat, Ph4P+), 198.5, 195.0 (2s, CdO). Anal. Calcd for
C30H36N2O2PB6: C, 61.61; H, 6.20; N, 4.79. Found: C, 61.43; H,
6.24; N, 4.73.
5-(o-Carboran-1-ylmethyl)-2-thiohydantoin (16). A solution of
0.10 g (0.43 mmol) of o-carboranylalanine (13) and 39.50 g (0.52 mmol)
of ammonium thiocyanate was refluxed for 30 min in 5 mL of acetic
anhydride/acetic acid (9:1, v/v). The solvents were evaporated, and
the residue was stirred for 15 h at room temperature in 25 mL of
acetone/10% aqueous HCl (3:2, v/v). Subsequently, the acetone was
evaporated and the aqueous phase was extracted three times with 10
mL of ethyl acetate. The combined organic layers were dried over
anhydrous magnesium sulfate, filtered, and evaporated to dryness. The
residue was purified by column chromatography (hexane/ethyl acetate,
5:3, v/v). 16: yield 93 mg (79%) of white powder; mp 245 °C (subl
under dec); Rf 0.43 (hexane/ethyl acetate, 5:3, v/v); MS (FAB-) m/z
3-(o-Carboran-1-yl)-2-aminopropionitrile (12). A 2.0 g (5.3
mmol) quantity of 3-(o-carboran-1-yl)-2-[(diphenylmethylene)amino]-
propionitrile (11) was dissolved in 80 mL of benzene, and the solution
was stirred with 100 mL of 6 N HCl for 17 h at room temperature.
The organic layer was removed, and the aqueous layer was extracted
with ether (2 × 100 mL). The combined organic layers were dried
(MgSO4), and the solvents were evaporated. The residue was purified
by column chromatography (chloroform/methanol, 10:1, v/v). 12: yield
1.0 g (92%) of white solid; Rf 0.5 (chloroform/methanol, 10:1, v/v);
1
mp 112-113 °C; MS (FAB+, 3-NBA) m/z 213 (M + H)+; H-NMR
(CDCl3) δ 1.5-2.8 (br m, 10H, BH), 2.62, 2.75 (d of ABq, 2H, -CH2-,
JAB ) 15.4, JAX ) 5.04, JBX ) 8.98), 3.85 (dd, 1H, JBX ) 8.9895, JAX
) 5.07), 4.24 (br s, 1H, carborane H); 13C-NMR (CDCl3) δ 41.835 (t,
-CH2-), 42.380 (d, -CHCH2-), 59.898 (d, HC- of carborane),
70.697 (s, -C- of carborane), 120.102 (s, -CN). Anal. Calcd for
C5H16N2B10: C, 28.29; H, 7.60; N, 131.9; B, 50.92. Found: C, 28.45;
H, 7.50; N, 13.14; B, 50.86.
1
271 (M - H+)-; H-NMR (acetone-d6) δ 1.5-3.1 (br m, 10H, BH),
2.91, 3.025 (d of ABq, 2H, -CH2-, JA,B ) 16.0, JA,H-5 ) 7.75, JB,H-5
) 4.1), 4.57-4.59 (apparent q[dd], 1H, H-5, JA,H-5 ) 7.8, JB,H-5 ) 4.1),
4.82 (br s, 1H, carborane H), 8.905 (br s, 1H, H-1), 10.69 (br s, 1H,
H-3); 13C-NMR (CDCl3) δ 40.050 (t, -CH2-), 61.224 (d, CH), 63.513
(d, HC- of carborane), 73.745 (s, -C- of carborane), 174.505 (s,
CdO), 184.450 (s, CdS). Anal. Calcd for C6H16N2OSB10: C, 26.46;
H, 5.92; N, 10.29. Found: C, 26.80; H, 5.78; N, 10.29.
o-Carboranylalanine (13). A 0.42 g (2.0 mmol) quantity of 3-(o-
carboran-1-yl)-2-aminopropionitrile (12) was reacted with 25 mL of
75% H2SO4 at 95 °C for 24 h. The mixture was cooled (ice-water
bath), and the white solid was filtered off. The product was dissolved
in water and neutralized with aqueous ammonia to pH 4.3-4.4. After
cooling overnight, the crystalline amino acid was filtered off and dried
under vacuum (0.5 mm). 13: yield 416 mg (90%); Rf 0.64 (n-BuOH/
CH3COOH/H2O, 4:1:1, v/v/v) [Rf lit.7 0.63]; MS (FAB+, 3-NBA) m/z
Bis(but-2-ynyl)malonic Acid Diethyl Ester (17). To a cooled
solution of 6 mL (39.5 mmol) of diethyl malonate in 44 mL of absolute
ethanol was added with stirring a solution of 6.3 g (93.0 mmol) of
sodium ethoxide in 200 mL of absolute ethanol. To this mixture was
added a solution of 16.8 g (75.0 mmol) of 4-tosylbut-2-yne (Rf ) 0.67,
hexane/ethyl acetate, 5:3, v/v) in 100 mL of absolute ethanol. The
addition occurred under cooled and anhydrous conditions. After 20
min of stirring at 0 °C, the reaction mixture was allowed to gradually
warm to room temperature and then refluxed for 3 h. Ethanol was
evaporated, and the residue was suspended in 150 mL of water. The
suspension (pH 14) was extracted with diethyl ether, and the organic
layer was dried over anhydrous magnesium sulfate, filtered, and
evaporated to dryness. The residue was purified by column chroma-
tography (hexane/ethyl acetate, 5:3, v/v). 17: yield 9.3 g (89%) of a
clear oil that crystallizes when stored in a refrigerator; bp 150 °C (3.2
mm); Rf 0.83 (hexane/ethyl acetate, 5:3, v/v); MS (FAB+) m/z 265 (M
1
232.3 (M + H)+; H-NMR (MeOH-d4) δ 1.1-3.4 (br m, 10H, BH),
2.72, 3.13 (d of ABq, 2H, -CH2-, JAB ) 16.0, JBX ) 4.8, JAB ) 6.3),
3.94 (t, 1H, -CH-, J ) 5.2), 4.81 (br s, 1H, carborane H); 13C-NMR
(MeOH-d4) δ 39.97 (CH2), 55.02 (CH), 63.62 (HC- of carborane),
74.30 (-C- of carborane), 171.78 (C÷xdbdO). Anal. Calcd for
C5H17NO2B10: C, 25.96; H, 7.41; N, 6.06; B, 46.74. Found: C, 25.78;
H, 7.30; N, 5.99; B, 46.50.
5-(o-Carboran-1-ylmethyl)hydantoin (14) and Tetraphenylphos-
phonium 7-(Hydantoin-5-ylmethyl)-D,L-dodecahydro-7,8-dicarba-
nido-undecaborate (15). A solution of 1.0 g (4.32 mmol) of
o-carboranylalanine (13) and 0.34 g (5.23 mmol) of sodium cyanate in
10 mL of water was refluxed with stirring until the components were
completely dissolved (10-15 min). Then 3 mL of concentrated HCl
was added, and the reaction mixture was stirred under flux for an
additional 20-30 min, cooled to room temperature, and filtered. Crude
5-(o-carboran-1-ylmethyl)hydantoin (14) was washed three times with
20 mL of water, dried under vacuum (0.2 mm) over anhydrous calcium
sulfate, and purified by column chromatography (hexane/ethyl acetate;
1:1, v/v). 14: yield 685 mg (62%) of white powder; mp 226 °C; Rf
0.07 (hexane/ethyl acetate, 5:3, v/v); MS (FAB+): m/z 257 (M + H)+;
1H-NMR (acetone-d6) δ 1.5-3.1 (br m, 10H, BH), 2.75, 2.98 (d of
ABq, 2H, -CH2-, JA,B ) 15.8, JA,H-5 ) 8.9, JB,H-5 ) 3.2), 4.37-4.395
(m, 1H, CH), 4.815 (br s, 1H, carborane H), 7.14 (br s, 1H, H-1), 9.76
(br s, 1H, H-3); 13C NMR (acetone-d6) δ 41.386 (t, -CH2-), 58.614
(d, CH), 63.550 (d, HC- of carborane), 74.185 (s, -C- of carborane),
157.475, 173.988 (2s, CdO). Anal. Calcd for C6H16N2O2B10: C,
28.12; H, 6.29; N, 10.93. Found: C, 28.26; H, 6.38; N, 10.71.
A solution of 1.2 g (3.2 mmol) of tetraphenylphosphonium chloride
in 10 mL of water was added to the combined filtrates. The resulting
precipitate, consisting mainly of tetraphenylphosphonium 7-(hydantoin-
5-ylmethyl)-D,L-dodecahydro-7,8-dicarba-nido-undecaborate (15), was
filtered off, washed three times with 20 mL of water, dried under
vacuum (0.2 mm) over anhydrous calcium sulfate, and purified by
column chromatography (dichloromethane/methanol, 5:1, v/v). 15:
yield 580 mg (23%) of white powder; mp 238 °C; Rf 0.00 (hexane/
ethyl acetate, 5:3, v/v); MS (FAB-) m/z 246 [(M)- for the anion]; 1H-
NMR (acetone-d6) δ -2.7 (br d, 1H, nido-carborane “extra” proton),
-0.50 to 3.00 (br m, 9H, BH), 1.6-2.3 (m, 3H, -CH2-, carborane
H), 4.02 (apparent q[dd], ∼0.5H, H-5, JB,H-5 ) 3.3, JA,H-5 ) 9.2), 4.17
(apparent q[dd], ∼0.5H, H-5, JB,H-5 ) 2.6, JA,H-5 ) 9.9), 6.33 (br d,
1H, H-1), 7.85-7.90 (m, 20H, aromat), 9.39 (br s, 1H, H-3); 13C NMR
(acetone-d6) δ 30.106, 30.260 (2d, CH), 42.8, 43.2 (2t, -CH2-), 60.7,
61.7 (2s, -C- of carborane), 118.7, 119.4 (2s, aromat, Ph4P+), 131.3-
1
+ H)+; H-NMR (CDCl3) δ 1.23 (t, 6H, CH2CH3, J ) 7.1), 1.72 (t,
6H, CtCCH3, J ) 2.5), 2.87 (q, 4H, CH2CtC), 4.19 (q, 4H, CH2-
CH3). Anal. Calcd for C15H20O4: C, 68.16; H, 7.63. Found: C, 68.33;
H, 7.73.
5,5-Bis(but-2-ynyl)barbiturate (18). A solution of 7.5 g (28.4
mmol) of bis(but-2-ynyl)malonic acid diethyl ester (17), 1.9 g (28.4
mmol) of sodium ethoxide, and 1.7 g (28.4 mmol) of urea was refluxed
in 200 mL of absolute ethanol for 12 h under anhydrous conditions.
The reaction mixture was allowed to cool to room temperature, acidified
with concentrated HCl to pH 2-3, and evaporated to dryness. The
residue was suspended in 100 mL of water and extracted twice with
100 mL of ethyl acetate. The organic layer was dried over anhydrous
magnesium sulfate, filtered, and evaporated to dryness. The residue
was purified by column chromatography (hexane/ethyl acetate, 5:3, v/v).
18: yield 4.4 g (67%) of white crystals; mp 182 °C; Rf 0.35 (hexane/
ethyl acetate, 5:3, v/v); MS (FAB+) m/z 233 (M + H)+; 1H-NMR
(DMSO-d6) δ 1.72 (s, 6H, CH3), 2.69, 2.70 (2s, 4H, CH2), 12.7-13.3
(br s, 2H, NH). Anal. Calcd for C12H12N2O3: C, 62.06; H, 5.21; N,
12.06. Found: C, 61.81; H, 5.31; N, 11.99.
5,5-Bis[(2-methyl-o-carboran-1-yl)methyl]barbiturate (20).
A
solution of 1.3 g (5.7 mmol) of 5,5-bis(but-2-ynyl)barbiturate (18) in
20 mL of 1,1,1,3,3,3-hexamethyldisilazane, 25 mL of THF, and 0.3
mL of chlorotrimethylsilane was refluxed under anhydrous conditions.
Ammonia evolved and ammonium chloride precipitated in the reflux
condenser. After 4 h, no further precipitation of ammonium chloride
could be observed, and the mixture was cooled to room temperature.
The solvents were thoroughly evaporated at 50 °C, and the waxlike
residue was redissolved in 75 mL of anhydrous toluene. A 2.9 g (14.3
mmol) quantity of the decarborane-acetonitrile complex was added,
and the reaction mixture was stirred for 12 h at 100 °C. Toluene was
evaporated, and the residue was suspended in a mixture of 30 mL of
MeOH, 60 mL of acetone, and 30 mL of 10% aqueous HCl. The
suspension was refluxed for 3 h, the organic solvents were evaporated,

Carboranyl Amino Acids, Hydantoins, and Barbiturates
Inorganic Chemistry, Vol. 35, No. 16, 1996 4545
Scheme 1
Scheme 2
and the remaining aqueous phase was extracted three times with 50
mL of ethyl acetate. The combined organic phases were dried over
anhydrous magnesium sulfate, filtered, and evaporated to dryness. The
residue was purified by column chromatography (hexane/ethyl acetate,
5:3, v/v). 20: yield 720 mg (27%) of white powder; mp >300 °C; Rf
0.46 (hexane/ethyl acetate, 5:3, v/v); MS (FAB+, 3-NBA, DMSO) m/z
1
469 (M + H)+; H-NMR (DMSO-d6) δ 1.30-3.00 (br m, 20H, BH),
2.10 (s, 6H, CH3), 3.05 (s, 4H, CH2), 12.30 (br s, 2H, NH); 13C-NMR
(DMSO-d6) δ 22.80 (q, CH3), 43.11 (t, CH2), 52.26 (s, C-5), 74.41 (s,
CH3C- of carborane), 78.98 (s, CH2C- of carborane), 149.52 (s, C-4,
C-6), 169.37 (s, C-2). Anal. Calcd for C12H32N2O3B20: C, 30.76; H,
6.88; N, 5.98. Found: C, 31.03; H, 7.03; N, 5.71.
Scheme 3
Results and Discussion
The reaction sequences for the syntheses of the amino acids
O-(o-carboran-1-ylmethyl)tyrosine (CBT, 5a) and p-(o-carboran-
1-yl)phenylalanine (CBPA, 5b) and of o-carboranylalanine (Car,
13) are shown Schemes 1 and 3. Phase-transfer alkylation26,27
of commercially available [(diphenylmethylene)amino]aceto-
nitrile (2) with carborane-containing bromides 1a and 1b,
followed by a two-step hydrolysis (6 N HCl, room temperature;
70% H2SO4, 95 °C) gave amino acids 5a and 5b in 77% and
71% yields, respectively. Strongly acidic conditions did not
alter the carborane cage. The chemical structure of amino acids
1
5a and 5b was confirmed by elemental analysis, MS, and H
and 13C NMR spectroscopy.
The synthesis of the carborane-containing bromides 1a and
1b is shown in Scheme 2. The O-alkylation of p-cresol with
propargyl bromide gave p-[(3-prop-1-ynyl)oxy]toluene, 6. Bo-
ronation of compound 6 with the bis(acetonitrile)-decaborane
complex yielded the carboranyl derivative 7, which was
subsequently brominated with bromine in carbon tetrachloride.
The major product of the bromination was p-[(o-carboran-1-
ylmethyl)oxy]benzyl bromide (1a; 79%). A small amount of
the dibromide (less than 5%) could be isolated. A similar
approach has been applied in synthesizing the bromide 1b.
Boronation of commercially available 4-ethynyltoluene with the
decaborane-acetonitrile complex gave p-(o-carboran-1-yl)-
toluene, 8. However bromination of 8 under comparable
conditions used in forming 1a yielded, probably due to the
presence of the carborane-phenyl conjugated system, the
carborane-containing aldehyde 9. Dropwise addition of a
(26) O’Donnell, M. J.; Eckrich, T. M. Tetrahedron Lett. 1978, No. 47, 4625.
(27) O’Donnell, M. J.; Polt, R. L. J. Org. Chem. 1982, 47, 2663.

4546 Inorganic Chemistry, Vol. 35, No. 16, 1996
Wyzlic et al.
Scheme 4
Scheme 5
bromine solution to an irradiated, ice-cooled solution of 8 gave
mainly the expected product, p-(o-carboran-1-yl)benzyl bromide,
1b (77% yield), and only a small amount (5%) of 9. The
chemical structures of bromides 1a and 1b, as well as aldehyde
5-(o-Carboran-1-ylmethyl)hydantoin (14) was formed in 62%
yield by the reaction of Car (13) with sodium cyanate. In the
residual aqueous filtrate, the nido analgoue, 15, was isolated in
approximately 23% yield. Partial degradation of Car under the
reaction conditions with subsequent cyclization of nido-Car with
sodium cyanate may be the basis for the formation of 15.
Sjoberg et al.40 showed that o-carboranylalanine degrades
spontaneously by an intramolecular process to a mixture of nido
diastereomers in water and methanol solutions. Our studies
confirm this self-degradation.41 Proton and carbon-13 NMR
spectra of 15 indicate the formation of a diastereoisomeric
mixture of nido-hydantoin, 15, in a 1:1 ratio. The proton NMR
spectrum shows two apparent quartets [dd] at 4.02 and 4.17
ppm for 5-H, stemming from its coupling with protons on the
methylene group attached at the 5-position of the hydantoin ring.
The carbon-13 NMR spectrum also displays two sets of carbons
for both diastereomeric nido forms. The basic degradation of
1-phenyl-o-carborane with formation of nido enantiomers was
previously reported by Hawthorne et al.42
Car was also used to synthesize the corresponding thiohy-
dantoin, 16, by an analogous procedure43-47 (Scheme 5) using
ammonium thiocyanate in an acetic anhydride/acetic acid
mixture. The corresponding N-acetyl derivative of 16 was also
formed. The Rf values for the both thiohydantoin 16 and its
3-acetyl derivative are very close, requiring careful monitoring
of the reaction by TLC. The 5-(o-carboran-1-ylmethyl)-2-
thiohydantoin, 16, was isolated in 79% yield.
1
9, were confirmed by elemental analysis, MS, and H and 13C
NMR spectroscopy. This demonstrated that the photochemical
bromination does not alter the carborane nucleus.
The synthesis of o-carboranylalanine (Car, 13) is described
in Scheme 3. The phase-transfer alkylation of compound 2 with
propargyl bromide afforded derivative 10. The reaction was
monitored by TLC (hexanes/ethyl acetate, 6:1, v/v) to avoid
the formation of the dialkylated product. Boronation of
compound 10 with the decaborane-acetonitrile complex, fol-
lowed by a two-step hydrolysis, gave o-carboranylalanine in
70% total yield.
The initial approach for synthesizing the carborane-containing
hydantoins involved carboranyl ketones,28-33 such as methyl-
o-carboranyl methyl ketone, bis(methyl-o-carboranyl) ketone,
bis(methyl-o-carboranyl) R-diketone, and bis(o-carboran-1-
ylmethyl) ketone.34 Unfortunately, the reactions of these ketones
with potassium cyanide in the presence of ammonium carbonate
(Bucherer-Berg reaction)35-38 did not provide the desired
cyclized products. The fact that the carboranyl ketones did not
react and could be recovered almost quantitatively indicates that
the physicochemical and electronic properties of the carborane
cage may be responsible for this lack of reactivity and not its
steric mass. Our second approach was to prepare hydantoins
via amino acids.35,39 The synthetic procedure utilized o-
carboranylalanine (Car, 13) and is presented in Scheme 4.
The reaction sequence for the synthesis of carboranylbarbi-
turate 20 is shown in Scheme 6. The alkylation48 of diethyl
malonate with 4-tosylbut-2-yne49 afforded bis(but-2-ynyl)-
malonic acid diethyl ester, 17. The reaction of 17 with urea50
in the presence of sodium ethoxide in ethanol under anhydrous
(28) Zakharkin, L. I. IzV. Akad. Nauk SSSR, Ser. Khim. 1964, 539; Dokl.
Akad. Nauk SSSR 1965, 162, 817.
(29) Zakharkin, L. I.; L’vov, A. I. IzV. Akad. Nauk SSSR, Ser. Khim. 1966,
151; Bull. Acad. Sci. USSR, DiV. Chem. Sci. (Engl. Transl.) 1966,
130.
(30) Zakharkin, L. I.; Chapovski, A.; Brattsev, V. A.; Stanko, V. I. S. Zh.
Obshch. Khim. 1965, 36, 878.
(31) Zakharkin, L. I.; L’vov, A. I.; Soshka, S. A.; Shepilov, I. P. Zh. Obshch.
Khim. 1968, 38, 255.
(32) Grafstein, D.; Bobinski, J.; Dvorak, J.; Smith, H.; Schwartz, N.; Cohen,
M. S.; Fein, M. M. Inorg. Chem. 1963, 2, 1120.
(40) Lindstrom, P.; Gogoli, A.; Rousell, P.; Sjoberg, S. BUSA IVsWorkshop
on Boron Chemistry, Syracuse, NY, July 1994.
(41) Wyzlic, I. M. Unpublished results.
(42) Hawthorne, M. F.; Young, D. C.; Garett, P. M.; Owen, D. A.;
Schwerin, S. G.; Tebbe, F. N.; Wegner, P. A. J. Am. Chem. Soc. 1968,
90, 826.
(33) Heying, T. L.; Ager, J. W.; Clark, S. L.; Alexander, R. P.; Papetti, S.;
Reid, J. A.; Trotz, S. I. Inorg. Chem. 1963, 2, 1097.
(34) Wyzlic, I. M.; Soloway, A. H. In Current Topics in the Chemistry of
Boron; Kabalka, G. W., Ed.; Royal Society of Chemistry: Cambridge,
U.K., 1994; p 177.
(43) Johnson, T. B.; Nicolet, B. H. J. Am. Chem. Soc. 1912, 33, 1973.
(44) Johnson, T. B.; Nicolet, B. H. J. Am. Chem. Soc. 1913, 49, 197.
(45) Johnson, T. B.; Scott, W. M. J. Am. Chem. Soc. 1913, 35, 1136.
(46) Johnson, T. B. J. Am. Chem. Soc. 1913, 49, 68.
(47) Johnson, T. B.; Hemingway, E. H. J. Am. Chem. Soc. 1916, 38, 1550.
(48) Organic Synthesis, 2nd ed.; Gilman, H., Blatt, A. H., Eds.; John Wiley
& Sons, Inc.: New York, 1948; Collect. Vol. I, pp 250-251.
(49) Marszak-Fleury, A. Bull. Soc. Chim. Fr. 1958, 490.
(50) Organic Synthesis, 2nd ed.; Blatt, A. H., Ed.; John Wiley & Sons,
Inc.: New York, 1948; Collect. Vol. II, p 60.
(35) Ware, E. Chem. ReV. 1950, 46, 403.
(36) Henze, H. R.; Speer, R. J. J. Am. Chem. Soc. 1942, 64, 522.
(37) Pinner, A. Ber. Dtsch. Chem. Ges. 1988, 21, 2320.
(38) Henze, H. R.; Isbell, A. F. J. Am. Chem. Soc. 1954, 76, 4152.
(39) Dakin, H. D. Am. Chem. J. 1910, 44, 48.

Carboranyl Amino Acids, Hydantoins, and Barbiturates
Inorganic Chemistry, Vol. 35, No. 16, 1996 4547
Scheme 6
conditions gave 5,5-bis(but-2-ynyl)barbiturate, 18 (67% yield).
Excess of sodium ethoxide in the cyclization reaction should
be avoided, since base, especially under refluxing conditions,
causes ring opening between C-1 and C-6 and between C-3 and
C-4 with the loss of urea.51 The cyclized product, the acetylenic
barbiturate 18, was of interest per se, since compounds
possessing the acetylenic function show hypnotic properties.52
It is well-known that acetylenes containing a free hydroxyl
or amino group destroy decaborane and fail to give any
carborane products.1 To prevent such degradation, the imide
functions of 18 were protected with trimethylsilyl groups (19)
and the resulting compound was boronated by the usual
procedure. The low yield (27%) of 20 can be explained by
steric hindrance due to two carborane cages in close proximity
at the 5-position. This conclusion is supported by the observa-
tion that the monoboronated product was the main product when
the reaction was terminated after 4-5 h even in the presence
of a 2.5 molar excess of the bis(acetonitrile)-decaborane
complex. However, it is also conceivable that the trimethylsilyl
protective groups are not optimal ones in this reaction. The
chemical structures of barbiturates 18 and 20 were confirmed
compound’s potential anticonvulsant activity: one evaluated the
compound’s ability to prevent seizure spread following maximal
electroshock (MES); and the second measured its ability to raise
the seisure threshold following the subcutaneous administration
of pentylenetetrazole (sc Met). The hydantoin, 14, showed
activity in mice only at the maximal dose of 300 mg/kg and in
rats after oral administration. There was no apparent toxicity
at these levels. Barbiturate 18 showed activity in mice at
dosages of 100 mg/kg and higher and in rats as well. However,
this compound was toxic at these levels. Compound 20, on
the other hand, showed no anticonvulsant activity.
Conclusion
The compounds described here represent novel boron-
containing amino acids,1 hydantoins, and barbiturates. Amino
acids 5a, 5b, and 13 were synthesized in good yields from
readily available materials. o-Carboranylalanine (13) was used
in the synthesis of three novel carboranyl hydantoins: closo-
hydantoin (14), nido-hydantoin (15), and closo-thiohydantoin
(16). Also two new barbiturates 18 (acetylenic) and 20
(carboranyl) were readily synthesized. Hydantoin 14 exhibited
moderate activity in mice and rats without toxic effects. This
warrants the synthesis and anticonvulsant screening of new
carboranylhydantoins that more closely resemble the therapeuti-
cally used hydantoins Dilantin and Nirvanol. The biological
evaluation of these compounds as potential boron carriers for
BNCT is in progress and will be presented separately.
1
by elemental analysis, MS, and H NMR.
Attempts to synthesize 5,5-bis(o-carboran-1-ylmethyl)barbi-
turate, using the procedure described in Scheme 6, were
unsuccessful. The alkylation of diethyl malonate with propargyl
bromide afforded bis(prop-1-ynyl)malonic acid diethyl ester, but
cyclization of this ester with urea did not occur.
Pharmacology Studies
Acknowledgment. This research was supported by the U.S.
Public Health Service (Grant R01 CA-53896) and the Depart-
ment of Energy (Contracts DE-FG02-90ER60972 and DE-
AC02-76CH00016). We wish to acknowledge Drs. H. J.
Kupferberg and J. P. Stables of the Preclinical Pharmacology
Section of the National Institute of Neurological Disorders and
Strokes for anticonvulsant screening of compounds 14, 18, and
20. We also wish to thank the Callery Chemical Co. for
providing decaborane, Dr. C. E. Cottrell of the Campus
Chemical Instrumentation Center of The Ohio State University
for recording the 1H NMR and 13C NMR spectra on the Bruker
AM500, and Dr. D. H. Chang of the Campus Chemical
Instrumentation Center of The Ohio State University for
recording the high-resolution mass spectra on the Finnigan
MAT-900.
Initial evaluations of the anticonvulsant activities of the
hydantoin 14 and barbiturates 18 and 20 were performed by
the Antiepileptic Drug Development (ADD) Program, Epilepsy
Branch, Neurological Disorders Program, National Institutes of
Neurological Disorders and Stroke. The test procedures have
been previously described.53 The animals used in these studies
were male Carworth Farms no. 1 (CF1) mice and male Sprague-
Dawley rats. The compounds were suspended in 0.5% aqueous
methylcellulose and were administered in mice intraperitoneally
at three dosage levels (30, 100, and 300 mg/kg) and orally in
rats (50 mg/kg). Two animal models were used to determine a
(51) Chao, M. K. C.; Albert, K. S.; Fusori, S. A. Anal. Profiles Drug Subst.
1978, 7, 359.
(52) Lauger, P.; Prost, M.; Charlier, R. HelV. Chim. Acta 1959, 42, 2379.
(53) Kupferberg, H. J. Epilepsia 1989, 30 (Suppl.), S51.
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