Synthesis and structure of diethyl (1-benzyloxycarbonylamino-1-carboranyl- 3,3,3-trifluoropropyl)phosphonate

Article abstract of DOI:10.1007/s11172-013-0279-7

A reaction of C-carboranylmethylmagnesium bromide with diethyl (N-benzyloxycarbonyl- 2,2,2-trifluoroethaneimidoyl)phosphonate gave P- And N-protected aminophosphonic acid, an organophosphorus analog of alanine. The phosphonate was characterized by ¹H, ¹⁹F, and ³¹P NMR spectroscopy. X-ray diffraction analysis of diethyl (1-benzyloxycarbonylamino-1- carboranyl-3,3,3-trifluoropropyl)phosphonate showed that the molecules form dimers in crys- Tals due to the intermolecular hydrogen bond.

Full text of DOI:10.1007/s11172-013-0279-7

Russian Chemical Bulletin, International Edition, Vol. 62, No. 8, pp. 1934—1937, August, 2013
1934
Synthesis and structure of diethyl (1ꢀbenzyloxycarbonylaminoꢀ1ꢀcarboranylꢀ
3,3,3ꢀtrifluoropropyl)phosphonate*
S. V. Timofeev, E. A. Prikaznova, Z. A. Starikova,† S. N. Osipov, and V. I. Bregadze
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Eꢀmail: timofeev@ineos.ac.ru
A reaction of Cꢀcarboranylmethylmagnesium bromide with diethyl (Nꢀbenzyloxycarbonylꢀ
2,2,2ꢀtrifluoroethaneimidoyl)phosphonate gave Pꢀ and Nꢀprotected aminophosphonic acid,
1
an organophosphorus analog of alanine. The phosphonate was characterized by H, 19F, and
31P NMR spectroscopy. Xꢀray diffraction analysis of diethyl (1ꢀbenzyloxycarbonylaminoꢀ1ꢀ
carboranylꢀ3,3,3ꢀtrifluoropropyl)phosphonate showed that the molecules form dimers in crysꢀ
tals due to the intermolecular hydrogen bond.
Key words: aminophosphonate, carborane, Xꢀray diffraction analysis.
Aminophosphonic acids are analogs of natural amino
acids and have been attracting attention of researchers as
potential agents for cancer therapy.
Experimental
Anhydrous solvents were prepared according to the standard
procedures. Synthesis was carried out under dry argon. Diethyl
(Nꢀbenzyloxycarbonylꢀ2,2,2ꢀtrifluoroethaneimidoyl)phosphonꢀ
ate (1) was synthesized according to the described procedure.6
1H and 31P NMR spectra were recorded on a Bruker Avanceꢀ400
spectrometer (400.13 and 161.98 MHz, respectively), 19F NMR
spectra were recorded on a Bruker Avanceꢀ300 spectrometer
(282.40 MHz). Elemental analysis was performed in Laboratory
of Microanalysis of A. N. Nesmeyanov Institute of Organoꢀ
element Compounds of the Russian Academy of Sciences.
Synthesis of diethyl (1ꢀbenzyloxycarbonylaminoꢀ1ꢀcarboranꢀ
ylꢀ3,3,3ꢀtrifluoropropyl)phosphonate (2). A solution of Cꢀcarboꢀ
ranylmethylmagnesium bromide (3) in diethyl ether (25 mL)
(prepared from bromomethylcarborane7 (1.19 g, 5.0 mmol) and
magnesium (0.14 g, 6.0 mmol)) was added dropwise over 40 min
to a solution of diethyl (Nꢀbenzyloxycarbonylꢀ2,2,2ꢀtrifluoroꢀ
ethaneimidoyl)phosphonate (1) (2.20 g, 6.0 mmol) in diethyl
ether (10 mL) cooled to –78 C. The temperature of the reaction
mixture was slowly raised to the ambient, and the mixture was
allowed to stand for 2 days. Then, a solution of ammonium
chloride (1 g, 18.9 mmol) in water (10 mL) was added, the orꢀ
ganic layer was separated, the aqueous phase was extracted with
diethyl ether (2×20 mL), dried with anhydrous sodium sulfate,
the solvent was evaporated, the residue was purified on a column
with silica gel, using dichloromethane : hexane (1 : 1) as an eluꢀ
ent. The product was recrystallized from hot hexane and dried to
obtain a white crystalline compound. The yield was 1.65 g (63%).
One of the possibilities of using the carboraneꢀconꢀ
taining aminocarboxylic and aminophosphonic acids can
be the boron neutron capture therapy (BNCT) of canꢀ
cer.1,2 This suggestion is based on the fact that pꢀdiꢀ
hydroxyboronphenylalanine (BPA), which is one of the
agents for BNCT used in clinical practice, is also an amino
acid. It should be taken into account that the normal and
cancer cells fundamentally differ in the increased speed of
growth and division of the tumor cells. This means that
cancer cells consume considerably larger amount of comꢀ
pounds necessary for the cell replication. Therefore, comꢀ
pounds which serve as cell building blocks (in particular,
amino acids and peptides) or their analogs should be preꢀ
dominantly consumed by cancer cells, that makes it posꢀ
sible to selectively deliver 10B to tumors.
It is also known that the introduction of fluorine or
fluoroalkyl substituents in the amino acid molecules in
a number of cases leads to an increase in their biological
activity.3 In chemistry of peptides and amino acids,
ꢀfluoroꢀsubstituted ꢀamino acids are of special interest,
since they are irreversible enzyme inhibitors.4,5 They posꢀ
sess a wide range of bioactivity, including antiviral and
antitumor activity.3
1
Thus, the synthesis of phosphorus analog of alanine
containing both a ꢀtrifluoromethyl and a ꢀcarboranyl
group in the molecule is of much interest.
M.p. 143—146 C. H NMR (CDCl ), : 7.45 (s, 4 H, Ph); 5.55
3
(d, 1 H, NH, J = 11.5 Hz); 5.20 (dd, 2 H, CH2 (benz.), J = 21.7 Hz,
J = 12.0 Hz); 4.41 (s, 1 H CHcarb); 4.29 (dd, 4 H, CH3CH2O,
J = 15.8 Hz, J = 7.7 Hz); 3.48 (m, 2 H, CH2); 1.43 (q, 6 H,
CH3CH2O, J = 6.8 Hz). 19F NMR (CDCl3), : 68.20 (s, 3 F,
CF3). 31P NMR (CDCl3, : 14.98 (s, 1 P, P(O)(OEt)2). Found (%):
C, 38.80; H, 5.93; N, 2.75; B, 20.55. C17H31B10F3NO5P. Calcuꢀ
lated (%): C, 38.86; H, 5.95; N, 2.67; B, 20.57.
* Dedicated to the memory of Mikhail Yuvenal´evich Antipin,
outstanding crystallographic chemist, who made a great contriꢀ
bution to the development of Xꢀray diffraction studies.
†
Decesased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1934—1937, August, 2013.
1066ꢀ5285/13/6208ꢀ1934 © 2013 Springer Science+Business Media, Inc.

Synthesis of carboranyl fluorophosphonate
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 8, August, 2013
1935
Table 1. Crystallographic data and parameters of refinement of
the structure
the corresponding H atom is bonded; n = 1.5 (for Me group) and
n = 1.2 (for all the other groups).
The principal parameters characterizing obtaining the exꢀ
perimental data, solution and refinement of the structure are
given in Table 1. The atomic coordinates, bond distances and
bond angles, temperature parameters were deposited with the
Cambridge Structural Database (CCDC 940277) and can be obꢀ
tained free of charge at www.ccdc.cam.uk/conts/retrieving.html
(or CCDC, 12 Union Road, Cambridge CB2 1EZ; fax: +44 1223
335 033; deposit@ccdc.cam.ac.uk).
Parameter
Value
Formula
Molecular weight
Space group
Т/K
a/Å
b/Å
C17H31B10F3NO5P
525.50
P21/c
100(2)
14.5497(19)
10.6960(14)
17.867(2)
113.437(3)
2551.2(6)
4
c/Å
Results and Discussion
/deg
3
V/Å
Earlier,8,9 we have shown that the reaction of organoꢀ
metallic ꢀcarborane derivative with highly electrophilic
methyl trifluoropyruvate imines led to the corresponding
ꢀamino acid derivatives.
The replacement of the carboxylic acid moiety with
the phosphonate group in the starting imine makes it posꢀ
sible to obtain a phosphorus analog of alanine containing
ꢀtrifluoromethyl and ꢀcarboranyl groups in the moleꢀ
cule (Scheme 1).
Z
dcalc./g cm–3
1.368
0.161
5546
/mm–1
Number of independent
reflections (Rint
R1 (on F for reflections with I > 2(I))
wR2 (on F for all the reflections)
Number of refined parameters
GOOF
)
(0.1147)
0.0498 (3218)
0.1140
336
1.001
1088
F(000)
The reaction was carried out under mild conditions
with cooling in diethyl ether. The use of a standard proceꢀ
dure described earlier8 gave the final product in only 21%
isolated yield. Therefore, to avoid the side reactions we
changed the sequence of addition: the Grignard reagent
(obtained from bromomethylcarborane) was added to the
ethereal solution of diethyl (Nꢀbenzyloxycarbonylꢀ2,2,2ꢀ
trifluoroethaneimidoyl)phosphonate (1). This allowed us
to triple the yield to 63%. The isolation was carried out in
air, the product was purified by column chromatography
on silica gel with subsequent recrystallization from hot
hexane.
Diethyl [2ꢀbenzyloxycarbonylaminoꢀ1ꢀcarboranylꢀ
3,3,3ꢀtrifluoropropyl]phosphonate (2) was characterized
by 1H, 19F, and 31P NMR spectroscopy, elemental analyꢀ
sis, as well as by Xꢀray crystallography. This white crystalꢀ
line compound is stable in air at room temperature, soluꢀ
ble in most common organic solvents and insoluble in
water. Its 1H NMR spectrum exhibits seven groups of
signals in the region from  7.4 to 1.4. In the 19F NMR
2
Note. Weight scheme w–1 =  (Fo2) + (0.0355P)2 + 1.1262P,
where P = 1.3(Fo2 + 2Pc2).
Xꢀray diffraction studies. Single crystal of compound 2 suitꢀ
able for Xꢀray diffraction analysis was obtained by crystallization
from hexane. An experimental set of 25888 reflections was obꢀ
tained on a Bruker APEX II diffractometer at 100 K (MoꢀК
irradiation, 2max = 54.00) from the colorless needleꢀlike single
crystal 0.45×0.25×0.20 mm. After averaging the equivalent reꢀ
flections 5546 independent reflections (Rint = 0.1147) were obꢀ
tained, which were used for the solution and refinement of the
structure. The structure was solved by direct method, all the
nonhydrogen atoms were localized in the differential syntheses
of electron density and refined on F2 in anisotropic approxiꢀ
hkl
mation. Positions of hydrogen atoms H(s) were calculated geoꢀ
metrically, the hydrogen atoms of the amino group H(N) and
the carborane core H(B) were found in the differential syntheꢀ
ses. All the hydrogen atoms were included in the refinement of
the structure using the riding model with U(H) = nU(X), where
U(X) is the atomic equivalent temperature factor, with which
Scheme 1

1936
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 8, August, 2013
Timofeev et al.
C(13)
C(8)
C(12)
C(11)
C(7)
O(5)
C(17)
C(16)
C(9)
C(10)
O(4)
C(6)
O(1)
O(3) H(1N)
N(1)
C(2)
P(1)
B(6)
C(3)
B(3)
C(1)
B(7)
C(4)
C(14)
B(11)
B(12)
O(2)
F(2)
C(5)
F(1)
C(15)
B(4)
F(3)
B(10)
B(9)
B(5)
B(8)
Fig. 1. The structure of molecule 2 in crystal, thermal ellipsoids are given with probability р = 50%.
spectrum, a singlet at  68.20 is observed, in the 31P NMR
spectrum, a singlet at  14.98. Crystallization from hexane
also gave a single crystal suitable for the Xꢀray diffraction
studies.
The structure of molecule 2 is shown in Fig. 1. The
bond geometric parameters are close to the standard values.
The bond distances: Р(1)—O(1) 1.464(2) Å, Р(1)—O(2)
1.561(2) Å, Р(1)—O(3) 1.564(2) Å, C(6)—N(1) 1.357(3) Å,
C(6)—O(4) 1.208(3) Å, C(6)—O(5) 1.351(3) Å, the
C(1)—C(2) bond distance in carborane (1.654(4) Å) is
slightly shorter than that for 1,2ꢀdialkylꢀsubstituted
1,2ꢀdicarbaꢀclosoꢀdodecaboranes.
Molecules in crystal form centrosymmetric dimers
(Fig. 2) due to the intermolecular hydrogen bond
P(1A)
O(1A)
N(1A)
H(1NA)
O(5)
H(1N)
N(1)
O(1)
P(1)
C(6)
O(4)
O(2)
O(3)
Fig. 2. The structure of centrosymmetric dimer.

Synthesis of carboranyl fluorophosphonate
Russ.Chem.Bull., Int.Ed., Vol. 62, No. 8, August, 2013
1937
...
...
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H(1N) O(1A) (and, respectively, H(1N)A O1). The disꢀ
...
...
tance N(1) O(1) is 2.882(3) Å, H(1N) O(1A) is 2.02 Å,
the angle H(1N)—N(1)—O(1A) is 171. Besides, in each
molecule atoms H(1N) form short intramolecular conꢀ
...
tacts with the fluorine atom F(1): H(1N) F(1) 2.49 Å,
the distances between atoms H(B(5)) and H(B(6)) of
carborane and atom F(1) are also slightly shorter: 2.60
and 2.53 Å, respectively.
In conclusion, we showed that an approach to the synꢀ
thesis of carboraneꢀcontaining ꢀtrifluoromethylꢀꢀamino
acids developed earlier can be also used for the synthesis of
phosphorus analogs. We used this approach to synthesize
and characterize Nꢀ and Pꢀprotected aminophosphonate,
the molecule of which contains both the carboranyl and
the trifluoromethyl fragments.
8. I. P. Beletskaya, V. I. Bregadze, S. N. Osipov, P. V. Petroꢀ
vskii, Z. A. Starikova, S. V. Timofeev, Synlett, 2004, 1247.
9. S. V. Timofeev, V. I. Bregadze, S. N. Osipov, I. D. Titanyuk,
P. V. Petrovskii, Z. A. Starikova, I. V. Glukhov, I. P. Beꢀ
letskaya, Russ. Chem. Bull. (Int. Ed.), 2007, 56, 791 [Izv.
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This work was financially supported by the Russian
Foundation for Basic Research (Project No. 13ꢀ03ꢀ00581).
References
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Received June 6, 2013,
in revised form July 18, 2013