Synthesis, characterization, and binding property of isoelectronic analogues of nucleobases, B(6)-substituted 5-aza-6-borauracils and-thymines

Article abstract of DOI:10.1021/ol1012058

(Equation Presented). As isoelectronic BN-containing analogues of 6-substituted uracil and thymine, a series of B(6)-substituted 5-aza-6-borauracils (U_BNs) and-thymines (T_BNs) were synthesized and fully characterized. The crystallographic and spectroscopic analyses of the analogues revealed that the framework and hydrogen-bonding pattern of T_BNs were similar to those of the original nucleobase, thymine.

Full text of DOI:10.1021/ol1012058

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3386-3389
Synthesis, Characterization, and Binding
Property of Isoelectronic Analogues of
Nucleobases, B(6)-Substituted
5-Aza-6-borauracils and -thymines
Hiroshi Ito,*,†,§ Kyohei Yumura,† and Kazuhiko Saigo*,†,‡
Department of Chemistry and Biotechnology, Graduate School of Engineering, The
UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan, and School of
EnVironmental Science and Engineering, Kochi UniVersity of Technology, Miyanokuch,
Tosayamada-cho, Kami-shi, Kochi 782-8502, Japan
h-ito@sci.osaka-cu.ac.jp; saigo.kazuhiko@kochi-tech.ac.jp
Received May 26, 2010
ABSTRACT
As isoelectronic BN-containing analogues of 6-substituted uracil and thymine, a series of B(6)-substituted 5-aza-6-borauracils (UBNs) and
-thymines (TBNs) were synthesized and fully characterized. The crystallographic and spectroscopic analyses of the analogues revealed that the
framework and hydrogen-bonding pattern of TBNs were similar to those of the original nucleobase, thymine.
The substitution of a carbon-carbon double bond with an
isoelectronic boron-nitrogen bond (BN-substitution) is one
of the fascinating strategies for the invention of a new series
of heterocycles.1 Since Dewar and co-workers have reported
their pioneering research on BN-containing analogues of
aromatic and heteroaromatic systems,2 a numerous number
of BN-containing compounds have been developed.3 Re-
cently, the groups of Ashe,4 Piers,5 Paetzold,6 and Liu7 have
reported a new generation of BN-substituted heteroaromatics
with distinct photophysical and electrochemical properties
or biological activity. On the other hand, nucleobases having
a recognition site in their molecular frame are typical
heterocyclic compounds with carbon-carbon double bond(s)
and are extremely important components not only in
biochemistry but also in supramolecular chemistry.8 This
(4) (a) Ashe, A. J.; Fang, X. Org. Lett. 2000, 2, 2089. (b) Ashe, A. J.,
III; Fang, X.; Fang, X.; Kampf, J. W. Organometallics 2001, 20, 5413. (c)
Fang, X.; Yang, H.; Kampf, J. W.; Banaszak Holl, M. M.; Ashe, A. J., III
Organometallics 2006, 25, 513. (d) Pan, J.; Kampf, J. W.; Ashe, A. J., III
Organometallics 2009, 28, 506.
† The University of Tokyo.
‡ Kochi University of Technology.
(5) (a) Jaska, C. A.; Piers, W. E.; McDonald, R.; Parvez, M. J. Org.
Chem. 2007, 72, 5234. (b) Bosdet, M. J. D.; Jaska, C. A.; Piers, W. E.;
Sorensen, T. S.; Parvez, M. Org. Lett. 2007, 9, 1395. (c) Bosdet, M. J. D.;
Piers, W. E.; Sorensen, T. S.; Parvez, M. Angew. Chem., Int. Ed. 2007, 46,
4940.
§ Present Address: Department of Chemistry, Graduate School of Science,
Osaka City University, Sugimoto, Sumiyoshi-ku, Osaka-shi, Osaka 558-
8585, Japan.
(1) For a review see: Bosdet, M. J. D.; Piers, W. E. Can. J. Chem. 2009,
87, 8.
(6) Paetzold, P.; Stanescu, C.; Stubenrauch, J. R.; Bienmu¨eller, M.;
Englert, U. Z. Anorg. Allg. Chem. 2004, 630, 2632.
(2) (a) Dewar, M. J. S.; Kubba, V. P.; Pettit, R. J. Chem. Soc. 1958,
3073. (b) Dewar, M. J. S.; Kubba, V. P.; Pettit, R. J. Chem. Soc. 1958,
3076. (c) Chissick, S. S.; Dewar, M. J. S.; Maitlis, P. M. J. Am. Chem.
Soc. 1961, 83, 2708.
(7) (a) Marwitz, A. J. V.; Abbey, E. R.; Jenkins, J. T.; Zakharov, L. N.;
Liu, S.-Y. Org. Lett. 2007, 9, 4905. (b) Marwitz, A. J. V.; Matus, M. H.;
Zakharov, L. N.; Dixon, D. A.; Liu, S.-Y. Angew. Chem., Int. Ed. 2009,
48, 973. (c) Abbey, E. R.; Zakharov, L. N.; Liu, S.-Y. J. Am. Chem. Soc.
2008, 130, 7250.
(3) (a) White, D. G. J. Am. Chem. Soc. 1963, 85, 3634. (b) Schlze, J.;
Schmid, G. Angew. Chem., Int. Ed. Engl. 1980, 19, 54.
10.1021/ol1012058  2010 American Chemical Society
Published on Web 06/29/2010

means that BN-substituted nucleobases are very attractive
as the next generation of BN-substituted heterocyclic com-
pounds. Although the synthesis and π electron distribution
property of 5-aza-6-borauracil (UBN) and its derivatives, in
which the C(6)dC(5) bond of uracil is replaced with a
B(6)-N(5) bond, appear in a paper9 and a patent,10 these
reports are dubious because of irreproducible scant experi-
mental detail and characterization only with an elemental
analysis, as Bielawski et al. pointed out.11 Bielawski et al.
have also reported the synthesis of B(6)-phenyl-BN-uracil
(PhUBN), which was characterized by mass and IR spectra
and an elemental analysis; they reported neither NMR data
nor X-ray crystallographic data, presumably because of its
high moisture sensitivity, insolubility in nonpolar solvents,
and/or instability in polar solvents. In this paper, we report
the synthesis, full characterization, and binding property of
isoelectronic analogues of nucleobases, B(6)-substituted
5-aza-6-borauracils (UBNs) and -thymines (TBNs) (Figure 1).
Scheme 1. Synthesis of UBNs and TBNs
was strongly suggested by a mass spectrum, probably due
to its low stability/solubility. In contrast, MesUBN (1b) and
TBNs (1c-e) could be purified by silica-gel chromatography
and/or gel permeation chromatography (GPC). ThxTBN was
not so stable as similar BN-substituted compounds reported
by Dewar et al.2c It gradually decomposed under ambient
atmosphere to give 1-methylbiuret.12 On the other hand,
B-mesitylated MesUBN (1b), MesTBN (1d), and m1MesTBN
(1e) were highly air- and moisture-stable, and no decomposi-
tion was observed for up to two months; the high stabilities
made the full chracterization of the analogues possible (see
Supporting Information). In an aqueous methanol solution
under reflux, however, MesTBN was gradually hydrolyzed
to afford mesitylboric acid and 1-methylbiuret.13
The replacement of the C(6)dC(5) bond of uracil with a
B(6)-N(5) bond results in the same chemical environment
for the N(1) and N(5) amide protons in MesUBN; the amide
Figure 1. Design of BN-substituted uracils and thymines.
1
protons were observed to be equivalent in the H NMR of
MesUBN. Moreover, the chemical shift of the amide protons
was dependent on the concentration, implying that the proton
at the N(5)-position was also associated in the intermolecular
hydrogen-bonding interaction. Thus, MesUBN was distinc-
tively different from original uracil in molecular symmetry
and hydrogen-bonding ability.
To prevent the hydrolysis of UBNs and TBNs and to increase
their solubilities in common nonpolar solvents, we considered
that a proper substituent should be introduced on the boron
atom. Then, we selected thexyl and mesityl groups as typical
aliphatic and aromatic substituents, respectively, with the
expectation that their obvious bulkiness would obstruct the
nucleophilic attack of polar molecules to the boron atom in
the UBNs and TBNs and that their hydrophobicity would make
the UBNs and TBNs solubile in nonpolar solvents.
The B(6)-substituted UBNs and TBNs (1a-e) thus designed
were synthesized by the one-step cyclization reaction of
biurets (2a-c) with monosubstituted boranes (3a,b) in THF
(Scheme 1). Among the targeted five analogues, ThxUBN
could not be unfortunately isolated, although its formation
The crystalline-state structures of MesUBN and MesTBN
were determined by X-ray crystallography (Figure 2).14 In
both of the crystals, there are two different molecular forms
in each unit cell, depending on the hydrogen-bonding
patterns. In the crystal of MesUBN, one of the amide protons
interacts with the mesityl group of the neighbored molecule
by NH-π interaction,15 and the other constructs a hydrogen-
(12) ThxTBN was almost completely decomposed in a few days under
ambient atmosphere.
(13) 35% of MesTBN was decomposed, when it was heated in CD3OD
for 20 h at 60 °C (bath temperature). See Figure S5 (Supporting Information)
for details.
(14) CCDC 747972 (MesUBN) and CCDC747974 (MesTBN).
(15) (a) Kim, K. S.; Tarakeshwar, P.; Lee, J. Y. Chem. ReV. 2000, 100,
4145. (b) Tsuzuki, S.; Honda, K.; Uchimaru, T.; Mikami, M.; Tanabe, K.
J. Am. Chem. Soc. 2000, 122, 11450. (c) Mons, M.; Dimicoli, I.; Tardivel,
B.; Piuzzi, F.; Brenner, V.; Millie´, P. Phys. Chem. Chem. Phys. 2002, 4, 571.
(8) (a) Pranata, J.; Wierschke, S. G.; Jorgensen, W. L. J. Am. Chem.
Soc. 1991, 113, 2810. (b) Murray, T. J.; Zimmerman, S. C. J. Am. Chem.
Soc. 1992, 114, 4010. (c) Beijer, F. H.; Sijbesma, R. P.; Vekemans,
J. A. J. M.; Meijer, E. W.; Kooijman, H.; Spek, A. L. J. Org. Chem. 1996,
61, 6371.
(9) Maitra, A. Indian J. Chem. 1978, 16B, 85.
(10) Boone, J. L. U. S. Patent 3,060,234, 1962; C. A. 1963, 5704.
(11) Bielawski, J.; Niedenzu, K.; Weber, A.; Weber, W. Z. Naturforsch.
1981, 86b, 470.
Org. Lett., Vol. 12, No. 15, 2010
3387

Å) and MesTBN (1.422-1.442 Å) are obviously short,
compared to that in the borabenzene/pyridine complex17
(1.558 Å), and are close to those in BN-aromatic hydrocar-
bons (BN-naphthalene,4c 1.461 Å; BN-phenanthrene,5b 1.491
Å; BN-pyrene,5c 1.456 Å). These lengths suggest a significant
double-bond character of the B-N bonds in MesUBN and
MesTBN. Although the six-membered heterocyclic rings of
MesUBN and MesTBN are a little deformed by the substitution
of the CdC bond with a B-N bond, the almost flat shape
of the heterocyclic ring indicates that MesUBN and MesTBN
can be regarded as nucleobase analogues.
The absorption spectra of MesUBN and MesTBN were quite
different from those of original nucleobases (Figure 3). The
Figure 3. Absorption (A) and fluorescence (B) spectra of MesUBN
and TBNs (green, MesUBN; blue, MesTBN; red, ThxTBN). 2.0 mM
in CH2Cl2, λex ) 270 nm. Dashed red line is the ThxTBN spectrum
multiplied by 10.
Figure 2. Crystal structure of MesUBN and MesTBN (50% thermal
ellipsoids; hydrogen atoms are omitted for clarity). A, top view;
B, C, side view.
absorption of ThxTBN in CH2Cl2 is extremely weak, com-
pared with that of thymine, clearly indicating that the
π-electron distribution of TBNs is not so sufficient; the result
is distinctly different from that reported in the previous
paper.9 On the other hand, MesUBN and MesTBN in CH2Cl2
showed strong absorptions and emissions at 273 and 312
nm and at 270 and 302 nm, respectively, which would be
attributable to the interaction between the boron atom and
bonding network. On the other hand, a hydrogen-bonding
network in the crystal of MesTBN is similar to that of a
thymine derivative crystal.16 The lengths of the B(6)-N(5)
and C(4)dO bonds in MesUBN and MesTBN are similar to
those of the B(6)-N(1) and C(2)dO bonds, respectively.
The lengths of the B(6)-N(5) bonds in MesUBN (1.418-1.429
(17) Boese, R.; Finke, N.; Henkelmann, J.; Maier, G.; Paetzold, P.;
Reisenauer, H. P.; Schmid, G. Chem. Ber. 1985, 118, 1644.
(16) Reeke, G. N., Jr.; Marsh, R. E. Acta Crystallogr. 1966, 20, 703.
3388
Org. Lett., Vol. 12, No. 15, 2010

the aryl moiety.18 To the best of our knowledge, this is the
first example of a unique emission arising from an atom in
the framework of nucleobase analogues. Thus, MesUBN and
MesTBN would be applied as probes, which would play a
role analogously with uracil and thymine, respectively.
The structural characteristics prompted us to examine the
molecular-recognition ability of MesUBN, MesTBN, and
m1MesTBN. Because 2,6-diaminopyridine (DAP) is a typical
molecule to form supramolecular complexes with thymine
derivatives, in which hydrogen donating (D) and accepting
(A) groups complementarily alternate (ADA·DAD),19 we at
first tried the complexation of MesTBN with DAP. Fortu-
nately, the single crystal of a MesTBN/DAP complex (1:1)
was obtained by the slow evaporation of the solvents from
an equimolar mixture in chloroform/hexane. The X-ray
crystallographic analysis of the complex showed that there
exists complementary hydrogen bonds between MesTBN and
DAP, which are almost the same as those in the complex of
thymine with DAP (Figure 4).20
Figure 4. Crystal structure of MesTBN·DAP (50% thermal el-
lipsoids; chloroform is included; hydrogen atoms are omitted for
clarity) with hydrogen-bonding lengths (angstrom).
distribution, B(6)-mesitylated UBN and TBNs showed
unique absorption and emission, caused by B/aryl interac-
tion. The crystallographic studies on MesUBN, MesTBN
,
and the MesTBN·DAP complex revealed that the heterocyclic
rings of UBNs and TBNs were isoelectronic with uracil and
thymine, respectively, to show double bond character for the
B-N bond to some extent and that TBNs have a molecular-
recognition ability similar to thymine. These results strongly
imply that UBNs and TBNs are one of the fascinating classes
of uracil and thymine analogues. The introduction of these
new nucleobase analogues into nucleosides and further
applications are now under investigation.
In the next stage, we tried to measure the association
constant (Kassoc) of a TBN derivative with DAP; we used
m1MesTBN in the place of MesTBN because MesTBN has
possible binding sites not only at the N(3)-H/C(4)dO/
N(5)-H but also at the N(1)-H/C(2)dO/N(3)-H in a
solution. As a result, the Kassoc of m1MesTBN with DAP at
1
25 °C in CDCl3 was estimated to be 77 M-1 by H NMR,
which is close to that of original thymine.8c
In summary, we have successfully synthesized several
kinds of novel nucleobase analogues, UBNs and TBNs, by the
isoelectronic replacement of the CdC bond of uracil and
thymine with a B-N bond. Although no distinct ultraviolet
absorption was observed arising from the π-electron
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Young Scientists (B) (21750134) from the
Japan Society for the Promotion of Science.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Yamaguchi, S.; Akiyama, S.; Tamao, K. J. Am. Chem. Soc. 2000,
122, 6335.
(19) (a) Tsuzuki, S.; Kawanishi, Y.; Abe, S. Biosens. Bioelectron. 2005,
20, 1452. (b) South, C. R.; Burd, C.; Weck, M. Acc. Chem. Res. 2007, 40,
63.
(20) CCDC 747973.
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