Coupling of amino carboranes to carboxylic acid containing substrates

Article abstract of DOI:10.1021/ic981223h

The reactivity of the known amino carboranes 1-H₂NCH₂-1,2-C₂B₁₀H₁₁ and 7-H₃N-7-CB₁₀H₁₂ with carboxylic acid containing substrates was investigated. The reactions studied using the coupling reagent, 1,1′-carbonyldiimidazole, resulted in the preparation of a series of amides in moderate to high yield. The relative importance of this type of research resides in the fact that it allows the introduction of amino acids in close contact with the carborane cage. These compounds can constitute a new generation of substrates useful in boron neutron capture therapy. Our emphasis lies in the development of suitable synthetic schemes allowing the preparation of this type of compound. Experimental details and analytical data supporting the formulation of the prepared compounds are reported.

Full text of DOI:10.1021/ic981223h

Inorg. Chem. 1999, 38, 2025-2029
2025
Coupling of Amino Carboranes to Carboxylic Acid Containing Substrates
Ye Wu and William Quintana*
Department of Chemistry and Biochemistry, New Mexico State University, Box 30001, Department 3C,
Las Cruces, New Mexico 88003-8001
ReceiVed October 19, 1998
The reactivity of the known amino carboranes 1-H2NCH2-1,2-C2B10H11 and 7-H3N-7-CB10H12 with carboxylic
acid containing substrates was investigated. The reactions studied using the coupling reagent, 1,1′-carbonyldi-
imidazole, resulted in the preparation of a series of amides in moderate to high yield. The relative importance of
this type of research resides in the fact that it allows the introduction of amino acids in close contact with the
carborane cage. These compounds can constitute a new generation of substrates useful in boron neutron capture
therapy. Our emphasis lies in the development of suitable synthetic schemes allowing the preparation of this type
of compound. Experimental details and analytical data supporting the formulation of the prepared compounds are
reported.
Introduction
B10H14 + 2NaCN f Na2B10H13CN
(3)
(4)
Research dealing with the introduction of functionalized
molecules as substituents in close contact with carborane cages
has received considerable attention in recent years.1 Interest in
exploring the preparation of this type of compound is owed to
the potential use of the synthesized compounds in boron neutron
capture therapy (BNCT).2 The traditional synthetic method used
for the introduction of functionalized side chains into an
o-carborane cage relies in the reaction of decaborane (14) with
the suitable alkyne.3 This approach, albeit efficient, it is
somewhat limited, resulting from the incompability of certain
functional groups with the precursor decaborane (14) cage.4
Certain alkynes are known to be incompatible, resulting from
unwanted side reactions with the decaborane (14) precursor.
Those include alkynes which contain amines, alcohols, ketones,
and carboxylic acids as part of the side chain.4 Therefore,
alkynes bearing these functional groups cannot be used in the
preparation of functionalized o-carborane cages.
Na2B10H13CN + H+ f 7-H3N-7-CB10H12
Equations 1 and 2 were used in the preparation of the
aminomethyl o-carborane, and eqs 3 and 4 delineate the
preparation of the amino monocarbon carborane. Furthermore,
the preparation of these compounds is carried out in a single-
pot reaction, without need of isolating the intermediates.
These compounds where chosen because of their ease of
preparation and purification. In addition, the yield obtained from
(2) (a) Cai, J.; Soloway, A. H.; Barth, R. F.; Adams, D. M.; Hariharan, J.
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Nucleotides 1997, 16, 379-401. (c) Yang, W.; Barth, R. F.; Rotaru,
J. H.; Moeschberger, M. L.; Joel, D. D.; Nawrocky, M. M.; Goodman,
J. H.; Soloway, A. H. Int. J. Radiat. Oncol., Biol., Phys. 1997, 37,
663-672. (d) Barth, R. F.; Yang, W.; Rotaru, J. H.; Moeschberger,
M. L.; Joel, D. D.; Nawrocky, M. M.; Goodman, J. H.; Soloway, A.
H. Cancer Res. 1997, 57, 1129-1136. (e) Srivastava, R. R.; Singhaus,
R. R.; Kabalka, G. W. J. Org. Chem. 1997, 62, 4476-4478. (f) Miura,
M.; Gabel, D.; Oenbrink, G.; Fairchild, R. G. Tetrahedron Lett. 1990,
31, 2247-50. (g) Sjoeberg, S.; Hawthorne, M. F.; Wilmouth, S.;
Lindstroem, P. Eur. J. Chem. 1995, 1, 430-5. (i) Kim, Y. S.; Kane,
R. R.; Beno, C. L.; Romano, S.; Mendez, G.; Hawthorne, M. F.
Tetrahedron Lett. 1995, 36, 5147-50. (j) Chen, C.-J.; Kane, R. R.;
Primus, F. J.; Szalai, G.; Hawthorne, M. F.; Shively, J. E. Bioconjugate
Chem. 1994, 5, 557-64. (k) Drechsel, K.; Lee, C. S.; Leung, E. W.;
Kane, R. R.; Hawthorne, M. F. Tetrahedron Lett. 1994, 35, 6217-
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Soc. 1993, 115, 8853-4. (m) Hosmane, N. S.; Franken, A.; Zhang,
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Wilson, W. D.; Schinazi, R. F. J. Am. Chem. Soc. 1994, 116, 7494-
7501. (q) Fulcrand-El Kattan, G.; Goudgaon, N. M.; Ilksoy, N.; Huang,
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Chem. 1994, 37, 2583-2588. (r) Goudgaon, N. M.; Fulcrand El-
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Sjoberg, S. Tetrahedron 1997, 53, 17519-17526. (v) Tjarks, W.;
Gabel, D. J. Med. Chem. 1991, 34, 315-319. (w) Ketz, H.; Tjarks,
W.; Gabel, D. Tetrahedron Lett. 1990, 31, 4003-4006.
The approach used in this paper is the functionalization of
the known carboranes 1-H2NCH2-1,2-C2B10H11 and 7-H3N-7-
CB10H12, which are conveniently prepared by the methods of
Soloway and Knoth outlined below.5,6
B10H14 + HCtCCH2N(CO)2C6H4 f
1-C6H4(CO)2NCH2-1,2-C2B10H11 (1)
1-C6H4(CO)2NCH2-1,2-C2B10H11 + NaBH4 f
1-H2NCH2-1,2-C2B10H11 (2)
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14, 823-825. (b) Hawthorne, M. F. Angew. Chem., Int. Ed. Engl.
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J. Am. Chem. Soc. 1993, 115, 8853-8854. (d) Paxton, R. J.; Beatty,
R. G.; Varadarajan, A.; Hawthorne, M. F. Bioconjugate Chem. 1992,
3, 241-247. (e) Hawthorne, M. F.; Varadarajan, A.; Knobler, C. B.;
Chakrabarti, S.; Paxton, R. J.; Beatty, B. G.; Curtis, F. L. J. Am. Chem.
Soc. 1990, 112, 5365-5366. (f) Hawthorne, M. F. Pure Appl. Chem.
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Soloway, A. H. Cancer Res. 1997, 57, 4333-4339. (i) Kabalka, G.
W. Expert Opin. Ther. Pat. 1998, 8, 545-551. (j) Hawthorne, M. F.
Mol. Med. Today 1998, 4, 174-181.
10.1021/ic981223h CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/09/1999

2026 Inorganic Chemistry, Vol. 38, No. 9, 1999
Wu and Quintana
these reactions is reasonable, allowing the exploration of the
chemistry of these compounds in multigram quantities.
with simple amino acids, such as glycine, alanine, and phenyl-
alanine, in a simple and clear-cut manner. The methodology
employed is simple, straightforward, and efficient, as demon-
strated by the reaction yield of the products obtained. Addition-
ally, the reactivity of 7-H3N-7-CB10H12 with substrates con-
taining carbonyl groups was enhanced, when compared to the
previous report by Jenilek and co-workers, in which reactions
with this type of compound resulted in isolation of product only
under forcing conditions.9 The reactions described in this paper
were carried out at room temperature.
Recent developments in the preparation of compounds
suitable for use in BNCT suggest the feasibility of this
approach.7 The introduction of amino acid functionalities into
the o-carborane cage has been demonstrated by us, as well as
other groups, as a reasonable approach for the syntheses of
compounds which are potential candidates for use in BNCT.7
Coupling of carborane cages with biomolecules, such as simple
peptides, amino acids, barbiturates, monoclonal antibodies,
immunoproteins, phthalocyanines, and porphyrins, is currently
being investigated in the preparation of compounds suitable for
BNCT.7a,e,f,8 This article presents our synthetic methodology,
based on coupling of amino-containing carboranes with sub-
strates containing carboxylic acids. This is accomplished by
using the coupling reagent 1,1′-carbonyldiimidazole as a means
of preparing an amide linkage between the carborane cage and
the substrate. We have used this approach in the coupling of
aminomethyl o-carborane and the amino monocarbon carborane
This paper constitutes a continuation of our work in this area,
detailing the interest of development of synthetic pathways for
the preparation of boron-containing compounds bearing organic
recognition elements, crucial for success in BNCT.
Experimental Section
All experiments were carried out under purified dry nitrogen.
Solvents were dried and freshly distilled under reduced pressure prior
to use. NMR spectra: Gemini 200 (Varian); 1H NMR, standard (CH3)4-
Si; 13C NMR, standard (CH3)4Si. Unity 400 (Varian); 11B NMR,
standard, external BF3‚OEt2 in C6D6. IR spectra were recorded on a
(3) (a) Kutal, C. R.; Owen, D. A.; Todd, L. J. Inorg. Synth. 1968, 11,
19-23. (b) Heying, T. L.; Ager, J. W., Jr.; Clark, S. L.; Mangold, D.
L.; Goldstein, H. L.; Hillman, M.; Pollack, R. J.; Szymanski, J. W.
Inorg. Chem. 1963, 2, 1089-1092. (c) Fein, M. M.; Grafstein, D.;
Paustian, J. E.; Bobinski, J.; Liechstein, B. M.; Mayes, N.; Schwartz,
N. N.; Cohen, M. S. Inorg. Chem. 1963, 2, 1115-1119. (d) Zakharkin,
L. I.; Stanko, V. I.; Brattsev, V. A.; Chapovskii, Yu. A.; Klimova, A.
I.; Oxlobystin, O. Yu.; Ponomarenko, A. A. Dokl. Akad. Nauk SSSR
1964, 155, 1119-1122. (e) Dupont, J. A.; Hawthorne, M. F. J. Am.
Chem. Soc. 1973, 86, 1643. (f) Paxson, T. E.; Callahan, K. P.;
Hawthorne, M. F. Inorg. Chem. 1973, 12, 708-709. (g) Fein, M. M.;
Bobinski, J.; Mayes, N.; Schwartz, N.; Cohen, M. S. Inorg. Chem.
1963, 2, 1111-1115.
(4) The Chemistry of Boron and Its Compounds; Muetterties, E. L., Ed.;
John Wiley & Sons: New York, 1967.
(5) Wilson, G. J.; Anisuzzaman, A. K. M.; Alam, F.; Soloway, A. H.
Inorg. Chem. 1992, 31, 1955-1958.
(6) (a) Knoth, W. H.; Little, J. L.; Lawrence, J. R.; Scholer, F. R.; Todd,
L. J. Inorg. Synth. 1968, 11, 33-41. (b) Knoth, W. H. J. Am. Chem.
Soc. 1967, 89, 1274.
(7) (a) Wyzlic, I. M.; Tjarks, W.; Soloway, A. H.; Perkins, D. J.; Burgos,
M.; O’Reilly, K. P. Inorg. Chem. 1996, 35, 4541-4547. (b) Arterburn,
J. B.; Wu, Y.; Quintana, W. Polyhedron 1996, 15, 4355-4359. (c)
Wu, Y.; Carroll, P. J.; Kang, S. O.; Quintana, W. Inorg. Chem. 1997,
36, 4753-4761. (d) Wu, Y.; Carroll, P. J.; Quintana, W. Polyhedron
1998, 17, 3391-3407. (e) Kahl, S. B.; Kasar, R. A. J. Am. Chem.
Soc. 1996, 118, 1223-1224. (f) Varadarajan, A.; Hawthorne, M. F.
Bioconjugate Chem. 1991, 2, 242-253.
(8) (a) Wellman, F.; Gabel, D. Proc. First Int. Symp. Neutron Capture
Ther. (Brookhaven Nat. Lab.) 1983, BNL 51730, pp 276-80. (b)
Sweet, F.; Kao, M. S.; Williams, A.; Khachatrian, L.; Wessels, B.;
Kirsch, J. Proc. First Int. Symp. Neutron Capture Ther. (Brookhaven
Nat. Lab.) 1983, BNL 51730, pp 323-30. (c) Kahl, S. B. Proc. First
Int. Symp. Neutron Capture Ther. (Brookhaven Nat. Lab) 1983, BNL
51730, pp 294-303. (d) Hechter, O.; Schwartz, I. L. Proc. First Int.
Symp. Neutron Capture Ther. (Brookhaven Nat. Lab.) 1983, BNL
51730, pp 197-206. (e) Spielvogel, B. F.; Das, M. K.; McPhail, A.
T.; Onan, K. D.; Hall, I. H. J. Am. Chem. Soc. 1980, 102, 6343-
6344. (f) Spielvogel, B. F.; Wojnowich, L.; Das, M. K.; McPhail, A.
T. J. Am. Chem. Soc. 1976, 98, 5702-5703. (g) Feakes, D. A.; Shelly,
K.; Knobler, C. B.; Hawthorne, M. F. Proc. Natl. Acad. Sci. 1994,
91, 3029-3033. (h) Beatty, B. G.; Paxton, R. J.; Hawthorne, M. F.;
William, L. E.; Richard-Dickson, K. J.; Do, T.; Shively, J. E.; Beatty,
J. D J. Nucl. Med. 1993, 34, 1294-1302. (i) Shelly, K.; Feakes, D.
A.; Hawthorne, M. F.; Schmidt, P. G.; Krisch, T. A.; Beaver, W. F.
Proc. Natl. Acad. Sci. 1992, 89, 9039-9043. (j) Hawthorne, M. F.;
Varadarajan, A.; Paxton, R. J.; Beatty, B. G.; Curtis, C. L. Progress
in Neutron Capture Therapy for Cancer; Allen, B. J., Moore, D. E.,
Harrington, B. V., Eds.; Plenum Press: New York, 1992; p 277. (k)
Varadarajan, A.; Sharkey, R. M.; Goldenberg, D. M.; Hawthorne, M.
F. Bioconjugate Chem. 1991, 2, 102-110. (l) Schinazi, R. F.; Prussoff,
W. H. Tetrahedron Lett. 1978, 50, 4981-4984. (m) Schinazi, R. F.;
Prussoff, W. H. J. Org. Chem. 1985, 34, 841-847. (n) Matalka, K.
Z.; Barth, R. F.; Staubus, A. E.; Moeschberger, M.; Coderre, J. A.
AdVances in Neutron Capture Therapy; Soloway, A. H., Barth, R. F.,
Carpenter, D. E., Eds.; Plenum Press: New York, 1993; pp 249-52.
(o) Coderre, J. A.; Glass, J. D.; Fairchild, R. G.; Roy, U.; Cohen, S.;
Fand, I. Cancer Res. 1987, 47, 6377-6383.
Perkin-Elmer 1700 in the range 200-4000 cm-1
.
5
6
1-H2NCH2-1,2-C2B10H11 and 7-H3N-7-CB10H12 were prepared
according to the literature procedure. 1,1′-Carbonyldiimidazole, benzoic
acid, N-t-BOC alanine, N-t-BOC glycine, N-t-BOC phenylalanine, and
other reagents used in the syntheses of these compounds were obtained
commercially and used without further purification (Aldrich).
General Synthesis of 1-Amidomethyl-1,2-dicarba-closo-dode-
caborane (12) Derivatives. In a typical reaction, a solution of THF (3
mL) containing 0.5 mmol of the desired carboxylic acid was added to
0.5 mmol of 1,1′-carbonyldiimidazole and the resulting solution stirred
at room temperature for 30 min. A solution consisting of 0.5 mmol of
1-aminomethyl-1,2-dicarba-closo-dodecaborane (12) and 0.2 mL of
pyridine was added to this solution, and stirring was continued
overnight. The resulting white solid, pyridinium chloride, was filtered
off and the solvent and excess pyridine removed under reduced pressure,
leaving a residue that was dissolved in a minimum amount of methylene
chloride and separated by silica gel chromatography, using ethyl acetate
as the eluant. The characterization data for each compound synthesized
using this general procedure are summarized below.
1-C6H5CONHCH2-1,2-C2B10H11 (1). Yield: 0.106 g (76%), mp
202-4 °C. 1H NMR (acetone-d6): δ (ppm) 4.21 (2H, d, J ) 6.6 Hz),
4.69 (1H, bs), 7.49 (3H, m), 7.89 (2H, m), 8.62 (1 H, bs). 13C NMR
(acetone-d6): δ (ppm) 45.47 (CH2), 62.04 (carborane C), 77.33
(carborane C), 128.31, 129.47, 132.82, 134.56 (aromatic), 168.31 (Cd
O). 11B NMR (acetone-d6): δ (ppm, J) 2.59 (1B, 147 Hz), -0.61 (1B,
146 Hz), -4.79 (2B, 161 Hz), -6.41 (2B, coupling constant could not
be reliably calculated because of overlap), -7.81 (4B, coupling constant
could not be reliably calculated because of overlap). FT-IR (cm-1):
3432 (s, NH), 3308 (m, NH), 3048 (w, CH), 2576 (s, BH), 1644 (s,
CdO), 1552 (m), 1492 (w), 1428 (w), 1312 (w), 1020 (w), 800 (w),
724(w),692(w).MS: m/z279(M+,5.9%),105,(M+ -NHCH2C2B10H11,
100%), 77 (M+ - OdCNHCH2C2B10H11, 53.7%).
1-(N-tert-BOC-alanyl)amidomethyl-o-carborane (2). Yield: 0.140
g (81%), mp 165-8 °C. 1H NMR (acetone-d6): δ (ppm) 1.29 (3H, d,
J ) 7.2 Hz), 1.49 (9H, s), 4.05 (3H, m), 4.56 (1H, bs), 6.31 (1H, bs),
8.04 (1H, bs). 13C NMR (acetone-d6): δ (ppm) 18.03 (CHCH3), 28.84
(C(CH3)3), 44.76 (CH2), 51.53 (CHCH3), 61.64 (carborane C), 77.03
(carborane C), 79.96 (C(CH3)3), 156.84 (t-BOC CdO), 174.87 (amide
CdO). 11B NMR (acetone-d6): δ (ppm, J) 2.20 (1B, 146 Hz), 0.69
(1B, 145 Hz), -4.77 (2B, 158 Hz), -6.43 (2B, coupling constant could
not be reliably calculated because of overlap), -7.94 (4B, coupling
constant could not be reliably calculated because of overlap). FT-IR
(cm-1): 3380 (m, NH), 3300 (m, NH), 3064 (w, CH), 2984 (w, CH),
2592 (s, BH), 1696 (s, CdO), 1648 (m, CdO), 1524 (s, CdO), 1456
(9) Jelinek, T.; Plesek, J.; Hermanek, S.; Stibr, B. Collect. Czech. Chem.
Commun. 1985, 50, 1376-1382.

Coupling of Amino Carboranes
Inorganic Chemistry, Vol. 38, No. 9, 1999 2027
(w), 1420 (w), 1392 (w), 936 (w), 868 (w), 840 (w), 788 (w), 728 (w),
664 (w), 628 (w).
[Et3NH]+[7-(CH3)3COONHCH2CONH-7-CB10H12]- (7). Yield:
0.162 g (59%), mp 156-8 °C. 1H NMR (acetone-d6): δ (ppm) -3.27
(2H, bs), 1.42 (9H, s), 1.43 (9H, t, J ) 7.3 Hz), 3.44 (6H, q, J ) 7.3
Hz), 3.68 (2H, d, J ) 5.0 Hz), 7.47 (1H, s), 8.58 (1H, bs). 13C NMR
(acetone-d6): δ (ppm) 9.50 (CH2CH3), 28.63 (C(CH3)3), 48.06 (CH2-
CH3), 61.78 (carborane C), 79.68 (C(CH3)3), 156.82 (t-BOC CdO),
171.56 (amide CdO). 11B NMR (acetone-d6): δ (ppm) 1.52 (1B, 125
Hz), -5.24 (4B, 132 Hz), -18.50 (2B, 111 Hz), -21.94 (1B, 137 Hz),
-27.82 (140 Hz). FT-IR (cm-1): 3412 (s, NH), 2984 (m, CH), 2812
(w), 2736 (w), 2536 (s, BH), 1684 (s, CdO), 1520 (m, CdO), 1476
(w), 1448 (m), 1392 (w), 1368 (w), 1288 (w), 1252 (w), 1164 (m),
1040 (m), 992 (w), 944 (w), 852 (w), 784 (w), 708 (w), 648 (w).
[Et3NH]+[7-(CH3)3COONH(CH2C6H5)CHCONH-7-CB10H12]- (8).
Yield: 0.233 g (70%), mp 78-81 °C. 1H NMR (acetone-d6): δ (ppm)
-3.20 (2H, bs), 1.34 (9H, s), 1.42 (9H, t, J ) 7.3 Hz), 2.85-3.08 (2H,
m), 3.42 (6H, q, J ) 7.3 Hz), 4.28 (1H, m), 6.02 (1H, bs), 7.22 (5H,
m), 7.53 (1H, s). 13C NMR (acetone-d6): δ (ppm) 8.75 (CH2CH3), 27.74
(C(CH3)3), 38.52 (CH2), 47.31 (CH2CH3), 55.93 (CH), 61.40 (carborane
C), 78.75 (C(CH3)3), 126.49, 128.25, 129.61, 137.85 (aromatic), 155.20
(t-BOC CdO), 172.53 (amide CdO). 11B NMR (acetone-d6): δ (ppm)
1.53 (1B, J ) 122 Hz), -5.21 (4B, 119 Hz), -18.52 (2B, 111 Hz),
-21.94 (1B, 137 Hz), -27.80 (2B, J ) 138 Hz). FT-IR (cm-1): 3397
(m, NH), 2983 (m, CH), 2809 (w), 2734 (w), 2530 (s, BH), 1699 (s,
CdO), 1645 (s, CdO), 1498 (m), 1471 (w), 1456 (w), 1393 (w), 1366
(w), 1249 (w), 1162 (m), 1081 (w), 1039 (w), 961 (w), 892 (w), 835
(w), 778 (w), 754 (w), 703 (w), 646 (w), 502 (w).
Cleavage of t-BOC Group. The t-BOC protected carborane (0.4
mmol) was stirred at room temperature in a mixture of ethanol (3 mL)
and 12.0 M HCl (1.0 mL, 12 mmol) for 8 h. To the resulting solution,
20 mL of ethanol was added and then evaporated under reduced
pressure, while keeping the temperature below 30 °C. The product
obtained was a while solid, for which the analytical data are presented
below.
[Et3NH]+[7-H2NCH2CONH-7-CB10H12]- (9). Yield: 0.133 g (97%),
mp 72-4 °C. 1H NMR (CD3CN): δ (ppm) -3.27 (2H, bs), 1.28 (9H,
t, J ) 7.1 Hz), 3.12 (6H, q, J ) 7.1 Hz), 3.62 (2H, s), 7.55 (1H, s),
7.64 (2H, bs), 9.25 (1H, bs). 13C NMR (CD3CN): δ (ppm) 9.25
(CH2CH3), 41.59 (CH2), 47.43 (CH2CH3), 61.70 (carborane C), 166.97
(CdO). 11B NMR (CD3CN): δ (ppm) 1.74 (1B, coupling constant could
not be calculated because of overlap), -5.19 (4B, coupling constant
could not be calculated because of overlap), -18.35 (2B, coupling
constant could not be calculated because of overlap), -21.91 (1B, J )
129 Hz), -27.90 (2B, 135 Hz). FT-IR (cm-1): 3376 (m, NH), 2984
(m, CH), 2532 (s, BH), 1668 (s, CdO), 1472 (w), 1400 (w), 1268 (w),
1160 (w), 1120 (w), 1040 (w), 984 (w), 900 (w), 836 (w), 756 (w),
708 (w), 648 (w).
1-(N-tert-BOC-glycinyl)amidomethyl-o-carborane (3). Yield: 0.160
1
g (97%), mp 60-2 °C. H NMR (acetone-d6): δ (ppm) 1.43 (9H, s),
3.71 (2H, d, J ) 5.9 Hz), 4.03 (2H, d, J ) 6.7 Hz), 4.54 (1H, bs), 6.45
(1H, bs), 8.10 (1H, bs). 13C NMR (acetone-d6): δ (ppm) 27.87
(C(CH3)3), 43.88 (CH2), 60.74 (carborane C), 76.16 (carborane C),
79.07 (C(CH3)3), 156.46 (t-BOC CdO), 170.79 (amide CdO). 11B
NMR (acetone-d6): δ (ppm) 2.27 (1B, 146 Hz), -0.70 (1B, 144 Hz),
-4.82 (2B, 160 Hz), -6.45 (2B, coupling constant could not be reliably
calculated because of overlap), -7.95 (4B, coupling constant could
not be reliably calculated because of overlap). FT-IR (cm-1): 3317 (s,
NH), 3060 (w, CH), 2982 (w, CH), 2590 (s, BH), 1677 (s, CdO),
1523 (s, CdO), 1455 (w), 1426 (w), 1393 (w), 1284 (w), 1252 (w),
1164 (m), 1078 (w), 1047 (w), 1022 (w), 944 (w), 861 (w), 787 (w),
725 (w), 664 (w), 609 (w).
1-(N-tert-BOC-phenylalanyl)amidomethyl-o-carborane
(4).
Yield: 0.185 g (88%), mp 106-8 °C. 1H NMR (acetone-d6): δ (ppm)
1.35 (9H, s), 2.89-3.19 (2H, m), 3.86 (4.16 (2H, m)), 4.29 (1H, m),
4.46 (1H, bs), 6.31 (1H, d, J ) 7.1 Hz), 7.26 (5H, s), 8.10 (1H, bs).
13C NMR (acetone-d6): δ (ppm) 27.84 (C(CH3)3), 37.40 (CH2), 43.99
(CH2), 56.39 (CH), 60.59 (carborane C), 75.95 (carborane C), 79.09
(C(CH3)3), 126.71, 128.46, 129.45, 137.80 (aromatic), 155.87 (t-BOC
CdO), 172.72 (amide CdO). 11B NMR (acetone-d6): δ (ppm) 2.22
(1B, 145 Hz), -0.67 (1B, 144 Hz), -4.76 (2B, 159 Hz), -6.42 (2B,
coupling constant could not be reliably calculated because of overlap),
-7.91 (4B, coupling constant could not be reliably calculated because
of overlap). FT-IR (cm-1): 3316 (s, NH), 3064 (w, CH), 2980 (w,
CH), 2592 (s, BH), 1680 (s, CdO), 1520 (m, CdO), 1456 (w), 1392
(w), 1368 (w), 1300 (w), 1248 (w), 1164 (m), 1080 (w), 1044 (w),
1020 (w), 864 (w), 728 (w), 700 (w).
General Syntheses of [Et3NH]+[7-ROOCNH-7-CB10H12]-. A
solution of the desired carboxylic acid (0.67 mmol) was dissolved in
5 mL of THF. To this solution 0.67 mmol of 1,1′-carbonyldiimidazole
was added, and the resulting solution was stirred at room temperature
for 30 min. A solution containing 0.67 mmol of 7-H3N-7-CB10H12 and
0.3 mmol of triethylamine was added to the 1,1′-carbonyldiimidazole/
carboxylic acid solution and stirred at room temperature overnight. The
solvent was removed under reduced pressure, and the residue was
dissolved in 15 mL of ethyl acetate, washed with water (3 portions of
5 mL), and dried over magnesium sulfate. The ethyl acetate fraction
was removed under reduced pressure, and the resulting solid was
redissolved in dry ethyl acetate and chromatographed in a silica gel
column. The analytical data obtained from the pure compounds
separated in this fashion is presented below.
[Et3NH]+[7-C6H5CONH-7-CB10H12]- (5). Yield: 0.093 g (39%),
[Et3NH]+[7-H2N(CH2C6H5)CHCONH-7-CB10H12]- (10). Yield:
0.165 g (95%), mp 107-110 °C. 1H NMR (CD3CN): δ (ppm) -3.29
(2H, bs), 1.28 (9H, t, J ) 7.0 Hz), 3.10 (8H, m), 4.06 (1H, bs), 6.79
(2H, bs), 7.34 (5H, s), 9.25 (1H, bs). 13C NMR (CD3CN) δ (ppm) 9.11
(CH2CH3), 37.95 (CH2), 47.22 (CH2CH3), 53.30 (CH), 61.71 (carborane
C), 128.39, 129.71, 130.87, 135.09 (aromatic), 168.87 (CdO). 11B NMR
(CD3CN): δ (ppm) 1.80 (1B, coupling constant could not be calculated
because of overlap), -5.16 (4B, coupling constant could not be
calculated because of overlap), -18.33 (2B, coupling constant could
not be calculated because of overlap), -21.88 (1B, J ) 125 Hz), -27.89
(2B, J ) 131 Hz). FT-IR (cm-1): 3608 (sh, NH), 3376 (m, NH), 2984
(m, CH), 2684 (sh, BH), 2536 (s, BH), 1668 (s, CdO), 1588 (w), 1496
(w), 1472 (w), 1392 (m), 1260 (w), 1184 (w), 1160 (w), 1036 (w),
1012 (w), 988 (w), 960 (w), 836 (w), 808 (w), 756 (w), 648 (w), 624
(w), 576 (w), 552 (w), 488 (w).
1
colorless oil. H NMR (acetone-d6): δ (ppm) -3.02 (2H, bs), 1.39
(9H, t, J ) 7.3 Hz), 3.42 (6H, q, J ) 7.3 Hz), 7.46 (4H, m), 7.81 (1H,
m), 8.00 (1H, bs). 13C NMR (acetone-d6): δ (ppm) 9.62 (CH3), 48.21
(CH2), 63.27 (carborane C), 128.15, 129.41, 132.03, 136.61 (aromatic),
169.53 (CdO). 11B NMR (acetone-d6): δ (ppm) 1.61 (1B, 134 Hz),
-4.98 (4B, 140 Hz), -18.47 (2B, 117 Hz), -21.79 (1B, 138 Hz),
-27.69 (2B, 140 Hz). FT-IR (cm-1): 3404 (m, NH), 3148 (w), 3008
(s, CH), 2800 (w, CH), 2712 (w), 2536 (s, BH), 1696 (w), 1632 (s,
CdO), 1576 (w), 1520 (m), 1484 (w), 1396 (w), 1284 (m), 1280 (w),
1160 (w), 1128 (w), 1040 (m), 1008 (w), 972 (w), 928 (w), 888 (w),
880 (w), 836 (w), 800 (w), 736 (w), 730 (m), 648 (w), 552 (w).
[Et3NH]+[7-(CH3)3COOCNH(CH3)CHCONH-7-CB10H12]- (6).
Yield: 0.140 g (58%), mp 83-85 °C. 1H NMR (acetone-d6): δ (ppm)
-3.31 (2H, bs), 1.25 (1H, d, J ) 7.0 Hz), 1.41 (9H, s), 1.44 (9H, t, J
) 7.3 Hz), 3.44 (6H, q, J ) 7.3 Hz), 4.07 (1H, t, J ) 6.6 Hz), 6.18
(1H, bs), 7.53 (1H, bs). 13C NMR (acetone-d6): δ (ppm) 8.68 (CH2CH3),
18.00 (CHCH3), 27.76 (C(CH3)3), 47.13 (CH2CH3), 50.19 (CHCH3),
61.10 (carborane C), 78.74 (C(CH3)3), 155.15 (t-BOC, CdO), 174.16
(amide CdO). 11B NMR (acetone-d6): δ (ppm) 1.50 (102 Hz), -5.21
(4B, coupling constant could not be calculated because of overlap),
-18.56 (2B, J ) 94 Hz), -21.97 (1B, J ) 132 Hz), -27.86 (2B, J )
137 Hz). FT-IR (cm-1): 3388 (m, NH), 3312 (m, NH), 2984 (w, CH),
2804 (w, CH), 2732 (w), 2536 (s, BH), 1700 (s, CdO), 1644 (m, Cd
O), 1072 (w), 1036 (w), 980 (w), 896 (w), 836 (w), 788 (w), 740 (w).
Results and Discussion
The preparation of amido-containing carboranes was ac-
complished via the coupling reaction of 1-H2NCH2-1, 2-C2B10H11,
and 7-H3N-7-CB10H12 with carboxylic-containing substrates in
the presence of 1,1′-carbonyldiimidazole. The advantage of this
reaction lies in the fact that it allows the use of protected amino
acids as a substrate, as demonstrated by the reactions with N-t-
BOC protected alanine, glycine, and phenylalanine. In addition,

2028 Inorganic Chemistry, Vol. 38, No. 9, 1999
Wu and Quintana
Figure 1. Preparation of amido-containing carboranes.
Figure 2. Deprotection of N-t-BOC group.
deprotection of the carborane-bound amino acid is accomplished
in a simple manner, resulting in high yield of the free amino-
containing carborane amide.
to 0.42 mmol, a significant reduction. This is not to say that
completely enriched compounds obtained from 10B10H14 are not
needed, but this process can be time consuming and expensive.
Furthermore, the stability of the o-carborane cage and of
substituted 7-RNH-CB10H12- salts is another attractive feature
of this approach. No special precautions have to be taken in
storing these compounds once synthesized, since they are air
and moisture stable, unlike some other boron-containing com-
pounds that can degrade under analogous conditions.
Previous examples of the preparation of related compounds
relied on high-temperature reactions, which lead to either a low
yield of the desired compounds or decomposition of the reagents
prior to reaction.9 The methodology outlined in this paper results
in the formation of carborane-containing amino acids, linked
via an amide bond, leaving a free amino group once the N-t-
BOC protective group is removed, which in principle could be
coupled to other amino acids or small peptides in the same
manner.
The rationale of using boron-containing compounds having
at least 10 boron atoms is that no isotopic enhancement to the
active 10B compound is necessary to achieve relevant concentra-
tions of 10B within cells. It has been estimated that for BNCT
to be effective a mean concentration of uptake should be around
30 µg of 10B per gram of tumor.10 This translates to ap-
proximately 3.0 µmol of 10B present. In p-boronophenylalanine,
for example, to supply this amount of 10B, 3.05 mmol of
unenriched p-boronophenylalanine is needed. In contrast, to
supply the necessary amount of 10B with 1, this value decreases
The advantage of the synthetic protocol used for the syntheses
of the compounds delineated is the direct use of the amino
carboranes, instead of other derivatives such as isocyanate-
containing carboranes, which has been used in an analogous
fashion.7 This approach results in reducing the synthetic steps
needed for incorporation of the amino acid into the carborane
unit. The result is the isolation of the targeted compounds in
less time, using reagents which are stable without the need of
special precautions, just as it is true for isocyanato carboranes.7
The characterization of the compounds prepared in this study
1
was achieved by using H, 11B, 13C NMR techniques, IR, and
mass spectrometry for compound 1. For the carboranes derived
from 1-aminomethyl-o-carborane, the 11B NMR was analogous
for all the compounds studied. It consisted of five peaks having
relative intensities 1:1:2:2:4 between approximately -8.00 and
(10) Bond, V. P.; Laster, B. H.; Wielopolski, L. Radiation Res. 1995, 141,
287-293.

Coupling of Amino Carboranes
Inorganic Chemistry, Vol. 38, No. 9, 1999 2029
2.50 ppm. This spectrum is extremely similar to those reported
for monosubstituted carboranes containing urea linkage, based
on 1-OdCdN-(CH2)n-1,2-C2B10H11 (n ) 1, 3), which the
reported compounds are related.7
essentially complete after 8 h, resulting in the quantitative
recovery of the free amino group. The yield obtained for
compounds 9 and 10 was 97% and 95%, demonstrating the
synthetic utility of this procedure. Characterization of these
compounds was accomplished by 1H, 11B, and 13C NMR as well
as the FT-IR spectra for both compounds. The disappearance
of the carbonyl signal in the 13C NMR and on the IR spectra
indicated that transformation to the free amine was ac-
complished. Also disappearing from the 1H and 13C NMR was
the signals attributed to the tert-butyl group of the N-t-BOC
protective group. The 11B NMR indicated that the monocarbon
carborane cage survived the reaction intact, as the similarities
between the spectra of 9 and 10 to those of its precursors
molecules corroborate.
The reactivity exhibited by these amino carboranes with N-t-
BOC protected amino acids under coupling reaction conditions
using the readily available coupling reagent 1,1′-carbonyldi-
imidazole and subsequent deprotection of the N-t-BOC group
demonstrates the synthetic utility of this approach. Of particular
interest is the fact that the amino carborane 1-H2NCH2-1,2-
C2B10H11 was more reactive than 7-H3N-7-CB10H12, as dem-
onstrated by the reaction yield obtained from comparable
reactions. This is undoubtedly a result of the higher nucleophilic
character of the amino group on the o-carborane derivative. This
follows the trend observed earlier in 7-H3N-7-CB10H12 by
Jenilek and co-workers,9 which could couple this carborane,
under nucleophilic conditions, to other substrates only under
forcing conditions. Nonetheless, the coupling reagent 1,1′-
carbonyldiimidazole demonstrated that it can enhance the
reactivity of this compound and allow reactions to proceed at
room temperature with reaction yields ranging from low to
moderate (40-70%). The low nucleophilicity of this carborane
can be owed to the closeness of the amino group to the cage
and the fact that the carborane cage is negatively charged,
reducing the nucleophilicity of this compound when compared
to the o-carborane derivative.
1
The H and 13C NMR data were more informative, since it
showed the presence of all the types of hydrogen and carbon
atoms expected for the compounds having the proposed
formulation. Of particular interest is the presence of the N-t-
BOC carbonyl group, indicating that under the reaction condi-
tions this protective group was unreactive, allowing the prepa-
ration of the targeted compound in high yield. For compound
1, the mass spectral data showed the parent ion at m/z ) 279,
which corresponds to the proposed formulation of this com-
pound. Furthermore, sequential losses of NHCH2C2B10H11 and
OdCNHCH2C2B10H11 indicated that the proposed formulation
of 1 was correct. The IR spectrum was informative as much as
it clearly showed the presence of N-H, C-H, B-H, and Cd
O stretches associated with this molecule.
Because of the similarities of the 11B NMR spectra for
1
compounds 1-4, the characteristic H and 13C NMR signals
indicating the presence of the proper functional groups, and the
IR spectra of these compounds, which confirmed the presence
of N-H, C-H, B-H, and CdO groups, the identity of these
compounds was established. Figure 1 details the synthetic route
employed in the preparation of these compounds.
We also explored the chemistry of the known amino
carborane, 7-H3N-7-CB10H12, using the same synthetic strategy
for the o-carborane-containing compounds. One of the reasons
for this study is the fact that previous attempts of using this
compound directly as a reagent, involving reaction of the amino
group, was found to happen only under forcing conditions and
longer reaction times.9 For example, reaction of 7-H3N-7-
CB10H12 with chloroacetic acid, resulting in the formation of
7-HOOCCH2NH2-7-CB10H12, a boronated glycine derivative,
was accomplished in 29% yield in boiling ethanol after 48 h.9
An analogous compound, 7-C6H5CONH2-7-CB10H12, a benza-
mide carborane, was isolated in 55% yield by performing the
reaction in boiling ethyl acetate, also for 48 h.9 The yield
obtained for compounds 5-8, reported here, ranged from a low
of 38% to a high of 70%, and the reaction conditions were much
milder than those employed in the report of Jenilek and co-
workers.9
Having demonstrated that this approach results in the
preparation of amino acid substituted carboranes, the door is
opened to the extension of this methodology to peptides, taking
advantage of the reactions described here. We are continuing
the research in this area, and the results will be reported in the
future.
Acknowledgment. W.Q. thanks the National Science Foun-
dation for support of this project via a Career Award Grant.
The authors are thankful to Mr. Monte Mauldin for his help in
the NMR and mass spectrometry experiments. The authors also
show their appreciation for Dr. R. K. Bhada for partial support
of Y.W. for supplies and materials.
The deprotection of the N-t-BOC group was carried out by
the established synthetic protocol for protected amino groups
having this protecting group, Figure 2.11 The reaction was
(11) (a) Nudelman, A.; Bechor, Y.; Falb, E.; Fisher, B.; Wexler, B.;
Nudelman, A. Synth. Commun. 1998, 28, 471-4. (b) Peptides:
Synthesis, Structures and Applications; Gutte, B., Ed.; Academic
Press: San Diego, CA, 1995.
IC981223H