Structures of N,N'-bis(1,2-dicarba-closo-dodecaboran-1-yl)-phenylureas: Building blocks for carborane-containing macromolecules

Article abstract of DOI:10.1016/S0040-4039(00)01212-0

We report the preparation and structural analysis of carborane-containing diphenylureas (1a-c and 2a-c). The secondary ureas (1) exist in trans-conformation. In spite of the bulkiness of the carborane cage, the N-methylated ureas (2) exist in cis-conforma

Full text of DOI:10.1016/S0040-4039(00)01212-0

Tetrahedron Letters 41 (2000) 7065±7070
0
Structures of N,N -bis(1,2-dicarba-closo-dodecaboran-1-yl)-
phenylureas: building blocks for carborane-containing
macromolecules
a
a
a
b
Chalermkiat Songkram, Aya Tanatani, Ryu Yamasaki, Kentaro Yamaguchi,
a,
a
Hiroyuki Kagechika and Yasuyuki Endo *
aGraduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
bChemical Analysis Center, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 250-8522, Japan
Received 5 June 2000; revised 13 July 2000; accepted 14 July 2000
Abstract
We report the preparation and structural analysis of carborane-containing diphenylureas (1a±c and 2a±c).
The secondary ureas (1) exist in trans-conformation. In spite of the bulkiness of the carborane cage, the
N-methylated ureas (2) exist in cis-conformation, both in solution and in the solid-state. The results should
make it possible to utilize the construction of more complex molecules. # 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: carboranes; ureas; conformation; molecular design.
Icosahedral carboranes (dicarba-closo-dodecaboranes) are a class of carbon-containing boron-
cluster compounds having remarkable thermal and chemical stability and exceptional hydrophobic
character, compared with other boron-containing compounds. Their unusual properties make
them uniquely suitable for several specialized applications in the ®eld of materials sciences and
biomedical sciences. The high boron contents and chemical and thermal stability of the carboranes
1
have been utilized in the preparation of thermostable polymers and carrier molecules for boron
2
neutron capture therapy. The delocalization of 26 skeletal electrons in the cage has been utilized
3
4
in the preparation of materials for liquid crystals and non-linear optics. We have recently
reported applications of carboranes for biologically active molecules based on the spherical
5
geometry and hydrophobic surface of the cage. Carboranes have also attracted interest as both
6
guest and host molecules in the ®eld of supramolecular chemistry. Recent studies in this area
7
include the e€ects of p-bonding interactions between cage CH and aromatics, and the synthesis
and inclusion complexes of macrocyclic arrays of carboranes.8
*
Corresponding author. Tel: +81-3-5841-4734; fax: +81-3-5841-4768; e-mail: yendo@mol.f.u-tokyo.ac.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01212-0

7
066
On the other hand, we have described the conformational alteration caused by N-methylation
9
10
11
of aromatic amides, guanidine and ureas. The N-methyl group in these compounds exists in
12
cis-orientation to the carbonyl group, both in the crystal and in solution. Combination of the
cis-preference of N-methylamides and regulation of the C-substituent on the carborane cage
should be useful for construction of cyclic, layered or helical molecules with both hydrophobic
and hydrogen-bonding characters. These considerations led us to design and synthesize
compounds having carborane and urea moieties (1a±c and 2a±c), as shown in Fig. 1, to see
whether they might be suitable building blocks for construction of more complex molecules. In
icosahedral cage structures throughout this paper, ®lled circles (*) represent carbon atoms and
other vertexes represent BH units.
Figure 1. Structures of the designed ureas (1a±c and 2a±c)
0
The syntheses of the designed ureas are outlined in Scheme 1. The N,N -diphenylureas and the
0
0
N,N -dimethyl-N,N -diphenylureas (1 and 2) were synthesized in several steps starting from
m- and p-nitrophenylcarborane13 (3a and 3b). The nitrophenylcarboranes were reduced to the
corresponding aniline derivatives (4a and 4b) in 81±82% yields. The anilines were allowed to react
with triphosgene in the presence of triethylamine to give the secondary ureas (1a and 1b) in
8
2±83% yields. Alternatively, formylation of the anilines (4a and 4b) with formic acetic anhydride
followed by reduction gave the N-methylanilines (5a and 5b) in 80±89% yields. The N-methylanilines
were then allowed to react with triphosgene under re¯ux to a€ord the desired N-methylated ureas
(2a and 2b) in 68±72% yields. The synthesis of the designed secondary and N-methyl ureas with
two carboranyl groups on an aromatic nucleus was started from 2,6-diiodo-4-nitroaniline.
Deamination of the nitroaniline was performed by diazotization followed by reduction to give
3
,5-diiodo-4-nitrobenzene.14 The nitrobenzene was allowed to react with ethynyltrimethylsilane
to a€ord bis(trimethylsilylethynyl)nitrobenzene (6) in a quantitative yield. After removal of the
trimethylsilyl groups (84%) of 6, construction of the o-carborane cage with nido-decaborane(14)
a€orded 3,5-dicarboranyl-4-nitrobenzene (7) in 12% yield. Compound 7 was reduced to the
corresponding aniline derivative (8, 86%), which was converted to the secondary urea 1c in 31%
yield. The N-methylaniline (9) was also converted to the N-methylated urea 2c in 39% yield. All
of the compounds synthesized were con®rmed to have appropriate elemental analysis and NMR
spectroscopic data.15

7
067
0
0
0
Scheme 1. Synthesis of N,N -diphenylureas (1) and N,N -dimethyl-N,N -diphenylureas (2)
16
The crystal structures of ®ve ureas are shown in Fig. 2. Two secondary ureas, 1a and 1b, have
0
(trans, trans) conformation in the crystals, like unsubstituted N,N -diphenylurea. As observed in
the crystal structures of several ureas, both compounds form intermolecular hydrogen bonds
17
Ê
distance between carbonyl oxygen and nitrogen atoms, 2.86±3.27 A) that line the molecules in
(
chains. The dihedral angles between the two hydrogen-bonding amide planes are 90.7 for 1a, and
ꢀ
ꢀ ꢀ
4
4.2 and 56.7 for 1b (two molecules in the asymmetric unit). Thus, each molecule of 1a exists
perpendicular to the neighboring molecules. Interestingly, in the chain structure of 1a, both car-
borane moieties in one molecule are located on the amide plane of the neighboring molecule.
Consequently, the hydrogen-bonding urea chains are surrounded by hydrophobic groups,
phenyls and carboranes.
N-Methylated ureas, 2a±c, have di€erent crystal structures from the secondary ureas, 1a and
0 0
11
1
b, and exist in (cis, cis) conformations, as observed in N,N -dimethyl-N,N -diphenylurea. Thus,
the bulky carborane substituents did not a€ect the cis conformational preference of N-methylated
aromatic ureas. Selected structural parameters are listed in Table 1. The structures of the
secondary urea skeletons depend on the substituents (or crystal packings). The diarylurea moiety
0
of 1a is more planar, compared to unsubstituted N,N -diphenylurea, with twisting between the
aromatic rings and the urea plane. Similarly, one of the two molecules of 1b in the asymmetric
unit exists in a rather planar conformation, while the other has a twisting conformation at the
phenyl±nitrogen bond. This may be caused by intermolecular T-shaped phenyl±phenyl interaction:
the dihedral angle between the phenyl rings and the distance between the ring centers are
ꢀ
Ê
18
8
conformations of 2a±c are similar to each other, including unsubstituted N,N -dimethyl-N,N -
9.0 and 5.19 A, respectively. On the other hand, the diarylurea structures of (cis, cis)
0
0
ꢀ
diphenylurea. The two aromatic rings are twisted with respect to the urea plane at around 60±70 ,

Figure 2. Crystal structures of carborane-containing ureas. Two molecules exist in an asymmetric unit of 1b. Unre®ned solvent molecules in the crystals of
b and 2c are omitted
2

7
069
Table 1
Selected torsion and dihedral angles of diarylurea skeletons
ꢀ
and are located face-to-face with 25±40 dihedral angles, independent of the existence of bulky
carboranyl substituents.
1
The structures of the ureas in solution were also examined by H NMR. In all cases, the
N-methylated compounds (2a±c) exhibited the signals of the aromatic protons at higher ®eld than
the corresponding secondary ureas (1a±c). For example, the protons ortho to the urea bonds of 2
are observed at about 0.6 ppm higher than those of 1, which is similar to the di€erence between
0
0
0
N,N -diphenylurea and N,N -dimethyl-N,N -diphenylurea (0.56 ppm). The detailed conformational
features could not be evaluated because of their fast equilibration; there was no signi®cant change of
1
H NMR spectra even at 183 K. However, comparison of the chemical shifts indicated that all three
N-methylated ureas (2) exist predominantly in (cis, cis) conformations, like those in the crystals.
In conclusion, N-methylation of aromatic ureas having carborane moieties caused conformational
alteration from trans to cis, regardless of the bulkiness of the substituents. We have shown that
the cis conformational preference of N-methylated ureas is useful to construct aromatic molecules
with unique structures and chemical or biological properties.19 The results described here should
make it possible to utilize aromatic molecules with carborane cages.
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2
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. Endo, Y.; Iijima, T.; Ohta, K.; Kagechika, H.; Kawachi, E.; Shudo, K. Chem. Pharm. Bull. 1999, 47, 585±587.

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Iijima, T.; Endo, Y.; Tsuji, M.; Kawachi, E.; Kagechika, H.; Shudo, K. Chem. Pharm. Bull. 1999, 47, 398±404.
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1
504. Endo, Y.; Iijima, T.; Yamakoshi, Y., Kubo, A.; Itai, A. Biomed. Chem. Lett. 1999, 9, 3313±3318. Endo, Y.;
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Chem. Eur. J. 1999, 5, 1828±1833.
6
7
8
. Clegg, E.; Gill, W. R.; MacBride, J. A. H.; Wade, K. Angew. Chem., Int. Ed. Engl. 1993, 32, 1328. Zheng, Z. P.;
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. Itai, A.; Toriumi, Y.; Saito, S.; Kagechika, H.; Shudo, K. J. Am. Chem. Soc. 1992, 114, 10649±10650. Azumaya,
I.; Yamaguchi, K.; Okamoto, I.; Kagechika, H.; Shudo, K. J. Am. Chem. Soc. 1995, 117, 9083±9084.
9
1
0. Tanatani, A.; Kagechika, H.; Azumaya, I.; Fukutomi, R; Ito, Y.; Yamaguchi, K; Shudo, K. Tetrahedron Lett.
997, 38, 4425±4428.
1. Yamaguchi, K.; Matsumura, G.; Kagechika, H.; Azumaya, I.; Ito, Y.; Itai, A.; Shudo, K. J. Am. Chem. Soc. 1991,
13, 5474±5475.
1
1
1
1
1
1
1
2. Saito, S.; Toriumi, Y.; Tomioka, N.; Itai, A. J. Org. Chem. 1995, 60, 4715±4720.
3. Hawthorne, M. F.; Berry, T. E.; Wegner, P. A. J. Am. Chem. Soc. 1965, 87, 4746±4750.
4. Ozasa, S.; Fujioka, Y.; Kikutake, J.; Ibuki, E. Chem. Pharm. Bull. 1983, 31, 1572±1581.
ꢀ
1
5. Compound 1a: mp 270±271 C (n-hexane±ethyl acetate). H NMR (400 MHz, DMSO-d
.73 (s, 2H), 7.19 (dd, J=7.7, 1.8 Hz, 2H), 7.31 (t, J=7.9, Hz, 2H), 7.51 (dd, J=7.7, 1.8 Hz, 2H), 7.75 (t, J=1.8
Hz, 2H), 8.96 (s, 2H). Anal. calcd for C H B N O: C, 41.11; H, 6.49; N, 5.64. Found: C, 40.94; H, 6.36; N, 5.43.
6
) ꢀ 1.3±3.2 (br m, 20H),
5
1
7
32 20
2
ꢀ
1
3
Compound 1b: mp >298 C (n-hexane±dichloromethane). H NMR (400 MHz, CDCl ) ꢀ 1.4±3.1 (br m, 20H),
3
.88 (br, s, 1H), 6.48 (s, 1H), 7.33 (d, J=8.8 Hz, 2H), 7.43 (d, J=8.9 Hz, 2H). Anal. calcd for C17
H
32
B
20
N
2
O: C,
1.11; H, 6.49; N, 5.64. Found: C, 40.88; H, 6.32; N, 5.52. Compound 2a: mp 287±288 C (n-hexane±
ꢀ
4
dichloromethane). H NMR (400 MHz, DMSO-d
1
6
) ꢀ 1.4±3.0 (br m, 20H), 3.11 (s, 6H), 5.67 (br s, 2H), 6.92 (m,
2
6
H), 6.96 (s, 2H), 7.10 (m, 4H). Anal. calcd for C19 O: C, 43.49; H, 6.92; N, 5.34. Found: C, 43.25; H,
ꢀ
36 20 2
H B N
1
.74; N, 5.04. Compound 2b: mp 268±269 C (n-hexane±dichloromethane). H NMR (400 MHz, CDCl ) ꢀ 1.6±3.2
3
(
br m, 20H), 3.36 (s, 6H), 3.81 (br s, 2H), 6.74 (d, J=8.8 Hz, 4H), 7.16 (d, J=8.8 Hz, 4H). Anal. calcd for
ꢀ
C B
hexane±dichloromethane). H NMR (400 MHz, CDCl
19
H
36
20
N
2
O: C, 43.49; H, 6.92; N, 5.34. Found: C, 43.22; H, 6.80; N, 5.41. Compound 1c: mp 294±295 C (n-
1
3
) ꢀ 1.5±3.4 (br m, 40H), 3.96 (br s, 4H), 6.97 (br s, 2H),
7
.31 (t, J=1.7 Hz, 2H), 7.60 (d, J=1.7 Hz, 4H). Anal. calcd for C H B N O: C, 32.29; H, 6.71; N, 3.59. Found:
2
21
52 40
ꢀ
1
C, 32.27; H, 6.61; N, 3.59. Compound 2c: mp >298 C (n-hexane±dichloromethane). H NMR (400 MHz, CDCl
1.6±3.2 (br m, 40H), 3.17 (s, 6H), 3.81 (br s, 4H), 6.99 (d, J=1.7 Hz, 4H), 7.22 (d, J=1.7 Hz, 2H). Anal. calcd
for C H B N O: C, 34.14; H, 6.98; N, 3.46. Found: C, 34.15; H, 6.93; N, 3.59.
3
)
ꢀ
2
3
56 40
2
Ê
1
6. Crystal data of the ureas. Compound 1a: orthorhombic; space group, Pcca; Z=4; a=22.393(2) A; b=13.9983(8)
3
Ê
Ê
Ê
3
1
A; c=10.0129(8) A; V=3138.7(3) A ; Dcalc=1.051 g/cm ; R=0.100. Compound 1b: monoclinic; space group, P2 /
Ê
Ê
Ê
ꢀ
Ê
3
3
c; Z=8; a=15.194(7) A; b=22.088(7) A; c=17.80(1) A; b=101.48(4) ; V=5927(4) A ; D =1.113 g/cm ;
calc
Ê
R=0.096. Compound 2a: triclinic; space group, P-1; Z=2; a=11.10(1) A; b=13.34(2) A; c=10.98(2) A;
Ê
Ê
ꢀ ꢀ ꢀ
Ê
3
3
ꢁ
=112.15(6) ; ꢂ=96.18(9) ; ꢃ=85.16(7) ; V=1495(3) A ; Dcalc=1.165 g/cm ; R=0.092. Compound 2b:
triclinic; space group, P-1; Z=2; a=11.0843(4) A; b=12.8759(5) A; c=13.1756(4) A; ꢁ=83.069(2) ;
Ê
Ê
Ê
ꢀ
ꢀ
ꢀ
Ê
3
3
ꢂ=85.0080(10) ; ꢃ=64.9700(10) ; V=1690.03(10) A ; D =1.129 g/cm ; R=0.085. Compound 2c: monoclinic;
calc
Ê Ê Ê Ê
ꢀ
space group, P2
3;
calc=1.160 g/cm ; R=0.090. There are unre®ned solvent molecules in the unit cells of 2b and 2c. The
1
/c; Z=4; a=12.139(1) A; b=22.920(2) A; c=22.474(2) A; ꢂ=100.756(2) ; V=6143.4(8) A
3
D
preliminary crystallographical analysis indicated (trans, trans) conformation of 1c, but the presence of several
unre®ned solvents, which made it impossible to re®ne the data. No signi®cant changes in the bond lengths and
0
bond angles of the urea bonds were observed by introduction of carborane moieties on N,N -diphenylurea or
0
0
N,N -dimethyl-N,N -diphenylurea skeletons.
7. Dannecker, W.; Kopf, J.; Rust, E. Cryst. Struct. Commun. 1979, 8, 429±432.
8. Jorgensen, W. L.; Severance, D. L. J. Am. Chem. Soc. 1990, 112, 4768±4774. Hobza, P.; Selzle, H. L.; Schlag, E. W.
J. Am. Chem. Soc. 1994, 116, 3500±3506. Azumaya, I.; Kagechika, H.; Yamaguchi, K.; Shudo, K. Tetrahedron
1
1
1995, 51, 5277±5290.
9. Fukutomi, R.; Tanatani, A.; Kakuta, H.; Tomioka, N.; Itai, A.; Hashimoto, Y.; Shudo, K.; Kagechika, H.
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1