Boron-Containing Heterocycles: Syntheses, Structures, and Properties of Benzoborauracils and a Benzoborauracil Nucleoside

Article abstract of DOI:10.1021/jo991176q

Benzo-fused boron-containing heterocycles (benzoborauracils), 1-hydroxy-1H-2,4,1-benzodiazaborin-3-one (3a), 1-hydroxy-2-methyl-1H-2,4,1-benzodiazaborin-3-one (3b), and 1-hydroxy-2-phenyl-1H-2,4,1-benzodiazaborin-3-one (3c) were synthesized, and their structures were established on the basis of ¹H, ¹³C, and ¹¹B NMR spectroscopies, mass spectrometry, and microelemental analyses. The structures of compounds 3b and 3c were unambiguously confirmed by X-ray crystallographic analyses. ¹¹B NMR spectral analyses of the methanolic solutions of benzoborauracils 3a-c confirmed the formation of the corresponding bis-methanol adducts 13a-c. The structure of the N-Ph bis-methanol adduct 13c was confirmed by X-ray crystallography. The stabilities of these bis-methanol adducts depend on the substituent at the N2 position of 3a-c. The bis-methanol adducts are readily reconverted to the corresponding benzoborauracils upon removal of methanol. The first stable benzoborauracil nucleoside, 4-[5-O-(tert-butyldimethylsilyl)-2,3-O-disopropylidene-α-D-ribofuranosyl]- 1-hydroxy-2-methyl-1H-2,4,1-benzodiazaborin-3-one (25) was prepared in two steps by treatment of 2-aminophenylboronic acid with 5-O-(tert-butyldimethylsilyl)-2,3-O-diisopropylidene-D-ribofuranose followed by its reaction with methylisocyanate.

Full text of DOI:10.1021/jo991176q

9566
J . Org. Chem. 1999, 64, 9566-9574
Bor on -Con ta in in g Heter ocycles: Syn th eses, Str u ctu r es, a n d
P r op er ties of Ben zobor a u r a cils a n d a Ben zobor a u r a cil Nu cleosid e
J in-Cong Zhuo,*,† Albert H. Soloway,† J ohn C. Beeson,‡ Weihua J i,† Beverly A. Barnum,†
Feng-Guang Rong,† Werner Tjarks,† Glenn T. J ordan IV,§ J ianping Liu,§ and
Sheldon G. Shore§
College of Pharmacy and the Department of Chemistry, The Ohio State University, Columbus, Ohio 43210
Received J uly 23, 1999
Benzo-fused boron-containing heterocycles (benzoborauracils), 1-hydroxy-1H-2,4,1-benzodiazaborin-
3-one (3a ), 1-hydroxy-2-methyl-1H-2,4,1-benzodiazaborin-3-one (3b), and 1-hydroxy-2-phenyl-1H-
2,4,1-benzodiazaborin-3-one (3c) were synthesized, and their structures were established on the
1
basis of H, 13C, and 11B NMR spectroscopies, mass spectrometry, and microelemental analyses.
The structures of compounds 3b and 3c were unambiguously confirmed by X-ray crystallographic
analyses. 11B NMR spectral analyses of the methanolic solutions of benzoborauracils 3a -c confirmed
the formation of the corresponding bis-methanol adducts 13a -c. The structure of the N-Ph bis-
methanol adduct 13c was confirmed by X-ray crystallography. The stabilities of these bis-methanol
adducts depend on the substituent at the N2 position of 3a -c. The bis-methanol adducts are readily
reconverted to the corresponding benzoborauracils upon removal of methanol. The first stable
benzoborauracil nucleoside, 4-[5-O-(tert-butyldimethylsilyl)-2,3-O-disopropylidene-R-D-ribofurano-
syl]-1-hydroxy-2-methyl-1H-2,4,1-benzodiazaborin-3-one (25) was prepared in two steps by treatment
of 2-aminophenylboronic acid with 5-O-(tert-butyldimethylsilyl)-2,3-O-diisopropylidene-D-ribofuran-
ose followed by its reaction with methylisocyanate.
In tr od u ction
similar to their naturally occurring counterparts and
become selectively incorporated into either proliferating
or metabolically active tumor cells, then they may have
potential as BNCT agents.
The chemistry of boron neutron capture therapy (BNCT)
has been summarized in a recent review.1 This potential
use of boron compounds for the treatment of cancer is
based upon the unique nuclear properties of the nonra-
dioactive 10B nucleus and its propensity to absorb thermal
neutrons. The resulting activated 11B nucleus, following
this capture reaction, undergoes prompt fission. The size
and energy of the particles emitted are very large by
nuclear standards and provide the basis for attempting
to destroy malignant cells selectively without adversely
affecting surrounding or nearby normal cells. In essence,
this is a binary chemoradiotherapeutic procedure that
is totally dependent upon the specific targeting of tumor
cells by boron compounds.
Boron-containing nucleosides7 are potentially attrac-
tive compounds because they may be (1) taken up
selectively into tumors due to the high mitotic rate of
tumor cells vs normal cells, (2) intracellularly converted
to the corresponding nucleotides through phosphorylation
by appropriate enzymes such as TK1 or dCK, and (3)
potentially incorporated into tumor DNA, thereby en-
hancing the cytotoxity of the neutron capture reaction.
Early work focused on the development and synthesis of
boron-containing purine and pyrimidine bases in which
the boron atom was placed within the purine or pyrimi-
The boron-containing delivery agent should be non-
toxic, selectively target tumor cells, and ideally localize
within the nucleus. Various boron-containing analogues
of biologically active compounds, such as amino acids,2
peptides,3 porphyrins,4 polyamines,5 as well as DNA
binders,6 have been synthesized and considered as po-
tential agents for BNCT. If they function in a manner
(3) (a) Leush, A.; J ungblut, L.; Moroder, L. Synthesis 1994, 305. (b)
Kane, R. R.; Pak, R. H.; Hawthorne, M. F. J . Org. Chem. 1993, 58, 8.
991-992. (c) Kane, R. R.; Hawthorne, M. F. Bioconjugate Chem. 1991,
2, 242-253. (d) Schwyzer, R.; Do, K. Q.; Eberle, A. N.; Fauche`re, J . L.
Helv. Chim. Acta 1981, 24, 1409.
(4) (a) Miura, M.; Micca, P. L.; Fisher, C. D.; Gordon, C. R.;
Heinrichs, J . C.; Slatkin, D. N. Br. J . Radiol. 1998, 71, 773-781. (b)
Phadke, A. S.; Morgan, A. R. Tetrahedron Lett. 1993, 34, 1725-1728.
(c) Miura, M.; Gabel, D.; Oenbrink, G.; Fairchild R. G. Tetrahedron
lett. 1990, 31, 2247-2250. (d) Kahl S. B.; Koo M.-S. J . Chem. Soc.,
Chem. Commun. 1990, 1769-1771.
(5) (a) Cai, J .; Soloway, A. H.; Barth, R. F.; Adams, D. M.; Hariharan,
J . R.; Wyzlic, I. M.; Radcliffe, K. J . Med. Chem. 1997, 40, 3887-3896.
(b) Cai, J .; Soloway, A. H. Tetrahedron Lett. 1996, 9283-9286.
(6) (a) Yamamoto, Y.; Cai, J .; Nakamura, H.; Sadayori, N.; Asao,
N.; Nemoto, H. J . Org. Chem. 1995, 60, 3352-3357. (b) Kelly, D. P.;
Bateman, S. A.; Hook, R. J .; Martin, R. F.; Reum, M. E.; Rose, M.;
Whittaker, A. R. D. Aust. J . Chem. 1994, 47, 1751-1769. (c) Kelly, D.
P.; Bateman, S. A.; Martin, R. F.; Reum, M. E.; Rose, M.; Whittaker,
A. R. D. Aust. J . Chem. 1994, 47, 247-262.
(7) (a) Soloway, A. H.; Zhuo, J .-C.; Rong, F.-G.; Lunato, A. J .; Ives,
D. H.; Barth, R. F.; Anisuzzaman, A. K. M.; Barth, C. D.; Barnum, B.
A. J . Organomet. Chem. 1999, 581, 150-155. (b) Lesnikowski, Z. J .;
Schinazi, R. F. Pol. J . Chem. 1995, 69, 827-840. (c) Goudgaon, N. M.;
El-Kattan, G. F.; Schinazi, R. F. Nucleosides Nucleotides 1994, 13,
849-880.
† College of Pharmacy.
‡ Deceased.
§ Department of Chemistry.
(1) Soloway, A. H.; Tjarks, W.; Barnum, B. A.; Rong, F.-G.; Barth,
R. F.; Codogni, I. M.; Wilson, J . G. Chem. Rev. 1998, 98, 1515.
(2) (a) Nakamura, H.; Fujiwara, M.; Yamamoto, Y. J . Org. Chem.
1998, 63, 7529-7530. (b) Malan, C. Morin C. J . Org. Chem. 1998, 63,
8019-8020. (c) Takagaki, M.; Ono, J .; Oda, Y.; Kikuchi, H.; Nemoto,
H.; Iwamoto, S.; Cai, J .; Yamamoto, Y. Cancer Res. 1996, 56, 2017-
2020. (d) Wyzlic, I. M.; Tjarks, W.; Soloway, A. H.; Perkins, D. J .;
Burgos, M.; O’Reilly, K. P. Inorg. Chem. 1996, 35, 4541-4547. (e)
Nemoto, H.; Cai, J .; Asao, N.; Iwamoto, S.; Yamamoto, Y. J . Med.
Chem. 1995, 38, 1673-1678. (f) Radel, P. A.; Kahl S. B. J . Org. Chem.
1996, 61, 4582-4588. (g) Karnbrock, W.; Musiol, H. J ; Moroder, L.
Tetrahedron 1995, 51, 1187-1196.
10.1021/jo991176q CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/02/1999

Boron-Containing Heterocycles
J . Org. Chem., Vol. 64, No. 26, 1999 9567
F igu r e 1.
F igu r e 2.
dine nucleus and flanked by two nitrogen atoms.8
A
Resu lts a n d Discu ssion
number of these compounds proved to be too toxic or
hydrolytically unstable and therefore were of little use
as potential BNCT agents.7 Recently, several boron-
containing nucleosides have been synthesized with a
borane, cyanoborane, dihydroxyboryl, or carborane group
attached directly to a nucleic acid base.9 One of our major
efforts in developing boron-containing nucleosides has
focused on the incorporation of stable boron clusters into
various nucleosides. We have synthesized several types
of boronated nucleosides with a carborane group tethered
to the pyrimidine moiety at the N3- or C5-position.10
Though a higher percentage of boron in a nucleoside
would appear desirable, of greater importance is that
these boron analogues simulate more closely the natu-
rally occurring nucleosides in their biochemical at-
tributes. To achieve this objective, we11 and others12,13
have attempted to replace the carbonyl function at the
4-position in the pyrimidine nucleus with the B-OH
group such as 4-borauracil (1a ) and 4-borathymine (1b)
shown in Figure 1. They may be viewed as boron isosteres
of naturally occurring pyrimidines, i.e., uracil (2a ) and
thymine (2b), respectively. A brief description of the
synthesis of benzoborauracils 3a -c, the boron analogue
of 2,4-(1H,3H)-quinazolinediones 4a ,b (Figure 2), has
been reported by us previously.11 Subsequently, the
synthesis of 3b and other analogues have also been
published elsewhere by Hughes and Smith in 1997.12 The
present paper describes the details of the synthesis,
structures, and properties of these benzoborauracils and
a ribonucleoside derivative of 3b.
Ben zobor a u r a cil. Several benzo-fused boron hetero-
cycles 5-8 (Figure 3) are known.14-16 We first success-
fully synthesized compound 5b by reduction of (2-
nitrophenyl)boronic acid (9) in 50% aqueous acetic acid
under platinum oxide catalysis.15 Recently, this com-
pound was directly prepared by acetylation of (2-ami-
nophenyl)boronic acid (10).14 Compound 5a was obtained
in same way and was converted to the benzo-fused
boronated pyrimidine 8a by treatment with liquid NH3
followed by its recrystallization from MeOH, elimination
of one molecule of methanol, hydrolysis, and lyophiliza-
tion.14 The stability of benzo-fused boronated pyrimidines
7 and 8 led to attempts to synthesize 4-borouracil. To
investigate the stability of such heterocyclic rings, ben-
zoborauracils 3a -c were first synthesized. Reaction of
(2-aminophenyl)boronic acid (10) with methyl isocyanate
in acetonitrile gave a colorless crystalline solid that was
the expected benzoborauracil, 1-hydroxy-2-methyl-1H-
2,4,1-benzodiazaborin-3-one (3b) (Scheme 1). Similarly,
addition of phenyl isocyanate to 10 afforded the N-Ph-
substituted compound 3c. The N-unsubsituted benzobo-
rauracil 3a was synthesized by the reaction of 10 with
H-NdCdO, generated in situ by the reaction of potas-
sium cyanate with dilute aqueous acetic acid.
The structures of these benzoborauracils 3a -c were
established by NMR spectroscopy, mass spectrometry,
and microelemental analyses. Compounds 3b and 3c
were unambiguously confirmed by X-ray crystallographic
analyses (see the Supporting Information), which show
that the fused benzene ring and heterocyclic ring systems
in 3b and 3c are essentially coplanar. The dihedral angle
between the benzene ring and heterocyclic ring is 2.0-
(3)° and 3.7(6)° for 3b and 3c, respectively. As expected,
owing to steric bulk of the phenyl group at N-2 in
compound 3c, the phenyl ring is twisted out of the plane
of the heterocyclic ring by 71.4(0.1)°.
(8) Chissick, S. S.; Dewar, M. J . S.; Maitlis, P. M. J . Am. Chem.
Soc. 1959, 81, 6329-6330.
(9) (a) Graciet, J .-C. G.; Shi, J .; Schinazi, R. Nucleosides Nucleotides
1998, 17, 711-727. (b) Hasan, A.; Tomasz, J .; Shaw, B. R. Bioconjugate
Chem. 1997, 8, 813-818. (c) Yamamoto, Y.; Imamura, K.-I. Bioorg.
Med. Chem. Lett. 1996, 6, 1855-1858. (d) Kattan, G. F.-El; Goudgaon,
N. M.; Ilksoy, N.; Huang, J .-T.; Watanabe, K. A.; Sommadossi, J .-P.;
Schinazi, R. J . Med. Chem. 1994, 37, 2583-2588. (e) Yamamoto, Y.;
Seko, T.; Nemoto, H. J . Org. Chem. 1989, 54, 4734-4736. (f) Schinazi,
R. F.; Prusoff, W. H. J . Org. Chem. 1985, 50, 841. (g) Schinazi, R. F.;
Goudgaon, N. M.; Fulcrand, G.; ElKattan, Y.; Lesnikowski, Z.; Ullas,
G.; Moravek, J .; Liotta, D. C. Int. J . Rad. Oncol. Biol. Phys. 1994, 28,
1113-1120.
The X-ray data show that the structures of heterocyclic
system in benzoborauracils is very similar to uracils and
benzouracils, as shown by their relative bond lengths
(Table 1). The bond lengths of the urea moiety (d1, d2,
(10) (a) Rong, F.-G.; Soloway, A. H.; Ikeda, S.; Ives, D. H. Nucleosides
& Nucleotides 1997, 16, 379-401 1997. (b) Lunato, A. J .; Anisuzzaman,
A. K. M.; Rong, F.-G.; Ives, D. H.; Ikeda, S.; Soloway, A. H. In Cancer
Neutron Capture Therapy; Mishima, Y., Ed.; Plenum Press: New York,
1996; pp 151-155. (c) Rong, F. G.; Soloway, A. H.; Ikeda, S.; Ives, D.
Nucleosides & Nucleotides 1995, 14, 1873-1887. (d) Rong, F. G.;
Soloway, A. H.; Ikeda, S.; Ives, D. H. Nucleosides Nucleotides 1994,
13, 2021-2034. (e) Lunato, A. J .; Wang, J .; Woollard, J . E.; Anisuz-
zaman, A. K. M.; J i; W.; Rong, F.-G.; Ikeda, S.; Soloway, A. H.;
Eriksson, S.; Ives, D. H.; Blue, T. B.; Tjarks, W. J . Med. Chem. 1999,
42, 3378-3389.
(14) Groziak, M. P.; Ganguly, A. D.; Robinson, P. D. J . Am. Chem.
Soc. 1994, 116, 7597-7605.
(15) Soloway, A. H. J . Am. Chem. Soc. 1960, 82, 2442-2444.
(16) (a) Cai, X. S.; Keana, J . F. W. Bioconjugate Chem. 1991, 2, 317-
322. (b) Vorontsova, L. G.; Chizhov, O. S.; Boldyreva, O. G.; Dorokhov,
V. A.; Mikhailov, B. M. Izv. Akad. Nauk SSSR, Ser. Khim. 1985, 329-
332. (c) Boldyreva, O. G.; Dorokhov, V. A.; Mikhailov, B. M. Izv. Akad.
Nauk SSSR, Ser. Khim. 1985, 428-430. (d) Zolotarev, B. M.; Dorokhov,
V. A.; Lavrinovich, O. S.; Mikhailov, B. M. Izv. Akad. Nauk SSSR,
Ser. Khim. 1979, 80-84. (e) Dorokhov, V. A.; Boldyreva, O. G.;
Zolotarev, B. M.; Mikhailov, B. M. Izv. Akad. Nauk SSSR, Ser. Khim.
1979, 174-180. (f) Dorokhov, V. A.; Zolotarev, B. M.; Boldyreva, O.
G.; Mikhailov, B. M. Izv. Akad. Nauk SSSR, Ser. Khim. 1979, 411-
418. (g) Mikhailov, B. M.; Kuimova, M. E. J . Organomet. Chem. 1976,
116, 123-133.
(11) Barnum, B. A.; Beeson, J . C.; Rong, F.-G.; Soloway, A. H.;
Tjarks, W.; J ordan IV, G. T.; Shore, S. G. In Advances in Boron
Chemistry; Siebert, W., Ed.; The Royal Society of Chemistry: Cam-
bridge, U.K., 1997; pp 240-243.
(12) Hughes, M. P.; Smith, B. D. J . Org. Chem. 1997, 62, 4492-
4499.
(13) Matteson, D. S. Unpublished results, personal communication.

9568 J . Org. Chem., Vol. 64, No. 26, 1999
Zhuo et al.
F igu r e 3.
Sch em e 1
Ta ble 1. Selected Bon d Len gth s (Å) for Ben zobor a u r a cils, Ur a cils, a n d Ben zou r a cils
compd
d1
d2
d3
d4
d5
d6
d7
3b
3c
2a
4b
11
12
1.389
1.401
1.358
1.400
1.387
1.401
1.359
1.350
1.371
1.353
1.380
1.371
1.358
1.373
1.376
1.417
1.403
1.342
1.451
1.464
1.371
1.408
1.371
1.517
1.543
1.531
1.430
1.455
1.470
1.576
1.385
1.393
1.340
1.399
1.405
1.241
1.251
1.215
1.225
1.214
1.241
d3 and d7) in the boracyclic system are comparable to
the related bonds in uracil 2a ,17 benzouracils 4b,18 and
1119 (Table 1) and are essentially identical to those
observed for the tetracoordinated anion 12.12 The C-B
bond lengths, d5 (3b: 1.543(4) Å; 3c: 1.531(3) Å) are
slightly shorter than those observed for phenylboronic
acid (1.565(3) Å)20 and tetracoordinated anion 12 (1.576-
(6) Å).12 The B-N bond lengths, d4 (3b: 1.451(3) Å; 3c:
1.464(2) Å) are considerably shorter than the B-N single
bond (1.57-1.63 Å)21 as well as those found in tetraco-
ordinated boron compounds (1.517-1.657 Å).22 They are
very close to those observed for borazine (1.44(2) Å),23
(dimethylamino)dimethylborane (1.42(3) Å),24 tri(1,3,2-
benzodioxaborol-2-yl)amine (1.438(11) Å),25 and (diphen-
ylmethyleneamino)dimesitylborane (1.38(2) Å).26 This
suggests a partial double bond character of the B-N bond
in the benzoborauracils, contributing to the pz orbital
N f B interaction that requires the sp2 hybridization of
the B and N atoms in the heterocycle. The sum of the
bond angles around the B and the N atoms in both
compounds 3b and 3c are exactly 360 °, meeting the
requirement of the N f B interaction.
11B NMR is a particularly useful tool for studying the
hybridization of the boron atom.27 The sp2 hybridization
of the B atom can be shown by the 11B shift value. The
shift value of ca. 30 ppm (referenced to Et2O‚BF3)
indicates a trigonal-planar substituted, sp2-hybridized
boron atom, and that of ca. 5 ppm arises from a
tetrahedral-substituted, sp3-hybridized boron atom. The
11B NMR spectra of benzoborauracils 3a -c were recorded
in acetone-d6, DMSO-d6, and MeOH-d4.
In acetone-d6 and DMSO-d6, a signal at ca. 30 ppm,
observed for each compound, is in agreement with the
existence of an sp2-hybridized boron atom in the hetero-
cyclic system. In MeOH-d4, a new signal at ca. 5 ppm
was observed. Accordingly, the NMR shift observed for
the benzoborauracils 3a -c is consistent with their
transformations from a trigonal planar sp2-hybridized
boron atom to a tetrahedral sp3-hybridized boron atom;
demonstrating the formation of a tetrahedral substituted
boron center. This formation in compounds 3a -c in
DMSO-d6/MeOH can be shown in Figure 4 by the 11B
NMR spectra.
(17) Stewart, B. F. Acta Crystallogr. 1967, 23, 1102-1105.
(18) Peeters, O. M.; Blaton, N. M.; De Ranter, C. J . Cryst. Struct.
Commun. 1982, 11, 375-379.
(19) Ardebili, M. H. P.; White, J . G. Acta Crystallogr. 1978, B34,
2890-2891.
(20) Rettig, S. J .; Trotter, J . Can J . Chem. 1977, 55, 3071-3075.
(21) Wells, A. F. Structural Inorganic Chemistry; Oxford University
Press: London, 1962.
(22) (a) Rettig, S. J .; Trotter, J . Can. J . Chem. 1977, 55, 958-965.
(b) Rettig, S. J .; Trotter, J . Can. J . Chem. 1976, 54, 3130-3141. (c)
Rettig, S. J .; Trotter, J . Can. J . Chem. 1975, 53, 1393. (d) Rettig, S. J .;
Trotter, J . Can. J . Chem. 1973, 51, 1288.
(23) (a) Harshbarger, W.; Lee, G.; Porter, R. F.; Bauer, S. H.
Inorganic Chem. 1969, 8, 1683-1689. (b) Bauer, S. H. J . Am. Chem.
Soc. 1938, 60, 524.
(24) Bullen, G. J .; Clark, N. H. J . Chem. Soc. A 1970, 992-996.
(25) Bullen, G. J .; Maillinson, P. R. J . Chem. Soc. A 1970, 2213-
2221.
(27) (a) No¨th, H.; Wrackmeyer, R. Nuclear magnetic Resonance
Spectroscopy of Boron Compounds. In NMR-Basic Principles and
Progress; Diehl, P., Fluck, E., Kosfeld, R., Eds.; Springer-Verlag:
Berlin, 1978. (b) Wrackmeyer, B. Ann. Rep. NMR Spectrosc. 1988, 20,
61-203. (c) Herˇma´nek, S. Chem. Rev. 1992, 92, 325-362.
(26) Bullen, G. J . J . Chem. Soc., Dalton Trans. 1973, 858-863.

Boron-Containing Heterocycles
J . Org. Chem., Vol. 64, No. 26, 1999 9569
F igu r e 4. 11B NMR spectra of compounds 3a -c and 25: (1) 3a (a) DMSO-d6; (b) DMSO-d6/MeOH ) 1:1; (c) DMSO-d6/MeOH )
1:2; (d) DMSO-d6/MeOH ) 1:5; (e) MeOH-d4; (2) 3b (a) DMSO-d6; (b) DMSO-d6/MeOH ) 2:1; (c) DMSO-d6/MeOH ) 1:1; (d) DMSO-
d6/MeOH ) 1:2; (e) MeOH-d4; (3) 3c (a) DMSO-d6; (b) DMSO-d6/MeOH ) 5:1; (c) DMSO-d6/MeOH ) 2:1; (d) DMSO-d6/MeOH )
1:1; (e) MeOH-d4; (4) 25, (a) DMSO-d6; (b) DMSO-d6/MeOH ) 1:1; (c) DMSO-d6/MeOH ) 1:2; (b) DMSO-d6/MeOH ) 1:5; (b)
MeOH-d4.
Ta ble 2. Equ ilibr iu m of 3a -c a n d 13a -c a n d 25 a n d 26 in DMSO-d 6/MeOH or MeOH-d 4 As Obser ved by 1H NMR
DMSO-d6/
DMSO-d6/
DMSO-d6/
DMSO-d6/
MeOH
3a
13a
MeOH
3b
13b
MeOH
3c
13c
MeOH
25
26
1:0
1:1
1:2
1:5
0:1a
100
94
85
80
70
0
6
15
20
30
1:0
2:1
1:1
1:2
0:1a
100
92
70
47
15
0
8
30
53
85
1:0
5:1
2:1
1:1
0:1a
100
75
35
15
∼5
0
25
65
85
∼95
1:0
1:1
1:2
1:5
0:1a
100
88
73
42
22
0
12
27
48
78
a
In MeOH-d4.
The equilibrium between a trigonal planar sp2-hybrid-
ized boron atom and a tetrahedral sp3-hybridized boron
atom is dependent upon the solvent systems used and
the substituent at N atom. In DMSO-d6/MeOH, an
increased amount of methanol led to the enhancement
in the signal at ca. 5 ppm and a diminution of the signal
at ca. 30 ppm (Table 2). In DMSO-d6/MeOH (1:1) solution,
phenyl-substituted benzoborauracil 3c is transformed to
its tetrahedral product, which was isolated in 85% yield
as a colorless crystalline solid. X-ray crystallographic
study of this product revealed it to be a bis-methanol
adduct 13c (see the Supporting Information) of 3c. In
MeOH-d4 solution, the methyl-substituted benzobora-
uracil 3b contains 85% of the bis-methanol adduct 13b,
whereas the unsubstituted analogue 3a only forms 30%
of the adduct 13a . The equilibrium, as observed by NMR,
between 3a -c and 13a -c are summarized in Table 2.
From these findings one can infer that the degree of ring
strain is a determining factor in the percentage of sp2-
and sp3-hybridized boron atoms in the compound.
observed in the 1H NMR spectra of compound 13c in
DMSO-d6/MeOH (see the Supporting Information). A
possible mechanism for this reversible transformation is
shown in Scheme 2. Groziak et al. observed a similar
transformation for 2,4,1-oxaza- and diazaborines that
undergo reversible 1,4-additions across the B1 and N4
atoms with water or methanol.14
The ready elimination of methanol from the adduct 13c
may be attributed to its weak B-O bond (between the
boron atom and the oxygen atom in the urea moiety). The
X-ray data of 13c show that this B-O bond length (1.588-
(4) Å) is considerably longer than the B-OMe bonds
(1.436(4) and 1.448(4) Å) and those observed in tri(1,3,2-
benzodioxaborol-2-yl)amine (1.381(5) Å),25 2-phenyl-1,3,2-
benzodioxaborol (1.394(3) Å),28 phenylboronic acids (1.371-
(7) Å).20 This can be attributed to the O f B interaction
in these molecules. The O f B bond observed for
(salicyaldehydato)diphenylboron is 1.574(4) Å,29 slightly
shorter than that in 13c.
The reversible transformation of a sp2-hybridized and
a sp3-hybridized boron species was also observed for the
analogues 3a and 3b. In MeOH-d4 solution, the formation
of the corresponding adducts 13a and 13b are temper-
ature dependent, with lower temperatures leading to
The adduct 13c is stable in MeOH solution or in the
solid state. In DMSO-d6 solution, 13c is converted to 3c
by hydrolysis and to 14c by elimination of 1 equiv of
MeOH. In DMSO-d6/MeOH, both compounds 3c and 13c
were observed. Increasing the amount of methanol in the
mixture shifted the equilibrium to compound 13c. This
indicates the reversible transformation of sp2-hybridized
and sp3-hybridized boron atoms, which were directly
(28) Zettler, Von F.; Hausen, H. D.; Hess, H. Acta Crystallogr. 1974,
B30, 1876.
(29) Rettig, S. J .; Trotter, J . Can. J . Chem. 1976, 54, 1168-1175.

9570 J . Org. Chem., Vol. 64, No. 26, 1999
Zhuo et al.
Sch em e 2
acid (10) with appropriate alkylisocyanates. An important
question was whether a nucleoside of a benzoborauracil
could be synthesized and by implication whether the
boron analogue of uridine would be a stable molecule.
It is known that 2,4-(1H,3H)-quinazolinediones (4a ),
the carbon analogues of these benzoborauracils 3a -c, can
form both ribofuranosyl and deoxyribofuranosyl nucleo-
sides.33 However, attempts to prepare the benzobora-
uracil nucleoside were unsuccessful by the procedures for
preparing normal nucleosides under various reaction
conditions.34 Condensation of the TMS protected N-
methyl benzoborauracil 17 and 1-O-Ac-2,3,5-tri-O-ben-
zoyl-ribofuranose (18a ) in MeCN with catalytic amounts
of trimethylsilyl triflate or SnCl4 resulted in a multi-
product mixture, but it did not afford the desired nucleo-
side 19 (Scheme 3). Nucleoside formation also did not
occur in the reactions of tri-O-benzoyl-D-ribofuranosyl
chloride (18b)35 with the TMS-protected N-methyl ben-
zoborauracil 17 in MeCN with catalytic amounts of
trimethylsilyl triflate, CuI, ZnCl2, or SnCl4.
F igu r e 5.
increased percentages of the 13a and 13b. Furthermore,
upon removal of methanol, 3a and 3b were recovered.
This may be due to the longer B-O bond lengths in the
adducts 13a and 13b as was observed for 13c. Hughes
and Smith12 also reported a comparable reversible in-
tramolecular rearrangement with the difluoroboronate
15.
It should be mentioned that the structural data for
compound 13c are very close to those observed for
analogue 15, a proven zwitterion.12 However, the B-O
bond length (1.588(4) Å) is considerably longer than that
in compound 15 (1.520(2) Å). Another zwitterion boron
heterocycle observed by Groziak et al. is a bis-methanol
adduct of 1,2-dihydro-1-hydroxy-2,4,1-benzodiazaborine
(16) (Figure 5).14 We observed that the C-N bond lengths
in 13c (1.339(3) Å and 1.331(3) Å) are between those in
N,N,N′,N′-tetramethylformamidinium perchlorate (1.30-
(1) Å)30 and N,N,N′,N′-tetramethylurea (1.3706(13) Å).31
In addition, the C-O bond length (1.272(3) Å) in 13c is
considerably longer and shorter than that in N,N,N′,N′-
tetramethylurea (1.226(2) Å) and the C-O single bond
(1.43 Å),32 respectively, but it is between the CdO bond
in the O f B interaction (salicyaldehydato)diphenylboron
(1.263(4) Å)29 and in the zwitterion boronate heterocycle
15 (1.285(2) Å). We conclude the possible existence of
O f B interaction with the boron atom possessing a
limited partial negative charge with the partial positive
charge delocalized over the urea moiety in the heterocy-
clic system.
It is known that ribose reacts with aniline to give the
corresponding N-phenyl sugar.36 Similarly, condensation
of D-ribose and D-deoxyribose 20a ,b with 10 gave the
corresponding adducts 21a ,b, respectively (Scheme 4).
Unfortunately, reaction of 21a ,b with methylisocyanate
in MeCN or DMSO did not give the expected nucleosides
22a ,b, respectively. This may be due to the free hydroxyl
groups on the carbohydrate moiety. Thus, the hydroxyl
groups in D-ribose 20b were protected first by condensa-
tion with acetone under acidic conditions followed by
treatment with TBDMSCl producing compound 23.37
Reaction of the latter compound with 10 followed by
condensation with methylisocyanate afford the desired
nucleoside 25. The 1H NMR spectrum indicates that
crude product 25 consists of anomeric isomers in ap-
proximately 2:1 ratio. After chromatography, only the
major product was obtained in 82% yield, indicating that
the minor product undergoes subsequent anomerization
N-Meth yl Ben zobor a u r a cil Nu cleosid e. The syn-
thesis of benzoborauracils 3a -c can be conveniently
achieved by the condensation of (2-aminophenyl)boronic
(33) Stout, M. G.; Robins, R. J . Org. Chem. 1968, 33, 1219-1225.
(34) Townsend, L. B. Chemistry of Nucleosides and Nucleotides;
Plenum Press: New York, NY, 1988.
(30) Prick, P. A. J .; Beurskens, P. T. Cryst. Struct. Commun. 1979,
8, 293-298.
(35) Kissman, H. M.; Pidacks, D.; Baker, B. R. J . Am. Chem. Soc.
1955, 77, 18-24.
(31) Frampton, C. S.; Parkes, K. E. B. Acta Crystallogr. 1996, C52,
3246-3248.
(36) Chavis, C.; De Gourcy, C.; Dumont, F.; Imbach, J .-L. Carbohydr.
Res. 1983, 113, 1-20.
(32) Allen, F. A.; Kennard, O.; Waston, D. G.; Brammer, L.; Orpen,
A. G.; Tayler, R. J . Chem. Soc., Perkin Trans. 2 1987, S1.
(37) Kaskar, B.; Heise, G. L.; Michalak, R. S.; Vishnuvajjala, B. R.
Synthesis 1990, 1031-1032.

Boron-Containing Heterocycles
J . Org. Chem., Vol. 64, No. 26, 1999 9571
Sch em e 3
Sch em e 4
during chromatography on silica gel. The major product
also undergoes anomerization in CDCl3 solution with the
minor product (∼5%) being observed after a few days.
To determine whether the structure of 25 is the R- or
amounts of methanol (Table 2). About 78% of compound
25 was transformed to the corresponding bis-methanol
adduct 26 in MeOH-d4 solution, a slightly lower percent-
age than that observed for 3b. Compound 25 could be
recovered after evaporation of methanol, demonstrating
that the transformation between the sp3-hybridized boron
center and the sp2-hybridized boron center is reversible
(Scheme 5).
1
â-anomer, 2D H-1H NOESY experiments were carried
out in CDCl3 solution. The assignments of the chemical
shifts of the protons at the sugar moiety were achieved
1
on the basis of 2D H-1H COSY experiments. The 2D
1H-1H NOESY spectrum indicates that the C(1′)-H
proton at δ ) 6.79 (d, J ) 4.7 Hz) shows an enhanced
NOE with C(2′)-H (δ ) 5.09 ppm, dd, J ) 6.6, 4.7 Hz),
C(3′)-H (4.99 (dd, J ) 6.6, 0.6 Hz), and C(5′)-H (δ ) 3.83
ppm, dd, J ) 15.0, 3.3 Hz and δ ) 3.79 ppm, dd, J )
15.0, 2.9 Hz). In addition, an enhanced NOE was also
observed between C(8)-H (δ ) 7.92 ppm, dd, J ) 8.8, 1.0
Hz) and C(4′)-H (δ ) 4.41 ppm, dd, J ) 2.6, 2.3 Hz). MM+
calculations indicate a distance between the C(8)-H and
C(4′)-H protons of 3.04 Å in the R-anomeric configuration
and 4.16 Å in the â-anomeric configuration.38 Thus, the
NOESY results are in good agreement with the R-ano-
meric configuration for compound 25, the predominant
structure in CDCl3.
Con clu sion s
This work shows that the benzoborauracils and a
derived ribose nucleoside can be conveniently synthesized
and are chemically stable. Bis-methanol adducts 13a -c
and 26, rearrangement products of 3a -c and 25, respec-
tively, could only be observed in the presence of methanol.
Upon solvent evaporation, the benzoborauracils and the
nucleoside were recovered. However, 13c, a colorless
crystalline solid, was isolated in 85% yield from the
methanolic solution of 3c. In the case of compounds 3b,c,
the comparable adduct 13b,c could not be obtained. This
suggests the heterocyclic ring structure [-CdCB(OH)-
NC(O)N-] is generally stable. It remains to be deter-
mined whether the boron analogues of the naturally
occurring bases, such as 4-borauracil and 4-borathymine,
can be prepared and if these structures are actually as
resistant toward hydrolytic/physiological conditions, de-
composition and rearrangement as are their correspond-
ing benzo analogues. Standard glycosylation procedures
on a benzoborauracil base failed to produce the required
The 11B signal of the nucleoside 25 was observed at
29.5 ppm in DMSO-d6 solution. The addition of methanol
generated a new signal at ca. 7 ppm [see (4) in Figure
4], indicating a tetrahedral substitued sp3-hybridized
boron center. As observed for benzoborauracils 3a -c, the
signal at ca. 7 ppm was enhanced with increasing
(38) HyperChem Release 5.1, Hypercube, Inc., 1997.

9572 J . Org. Chem., Vol. 64, No. 26, 1999
Zhuo et al.
Sch em e 5
dd, J ) 8.2, 0.6, C(8)-H), 6.98 (1H, td, J ) 7.3, 0.6, C(6)-H),
2.98 (3H, s, CH3); 13C (DMSO-d6) δ 155.1 (CdO), 145.4 (CN),
132.3, 132.2, 120.4, 114.0, 113.8 (br, CB), 27.3 (CH3); 11B NMR
(DMSO-d6) δ 30.3; 11B NMR(MeOH-d4) 28.7; 11B NMR (acetone-
d6) 30.7; IR (KBr) 3354vs, 1641vs, 1563vs; HRMS calcd for
C8H9BN2O2 176.0757, found 176.0767. Anal. Calcd for C8H9-
BN2O2: C, 54.60; H, 5.15; N, 15.92; B, 6.14. Found: C, 54.50;
H, 5.13; N, 15.78; B, 6.26.
benzoborauracil nucleoside. The alternative route, as
shown in Scheme 4, resulted in the formation of the
nucleoside in an R-anomeric configuration according to
NOE-NMR data. The synthesis of 4-borauridine/4-
borathymidine with the biologically relevant â-configu-
ration remains to be accomplished.
1-H yd r oxy-2-p h en yl-1H -2,4,1-b en zod ia za b or in -3-on e
(3c). Phenyl isocyanate (20 µL, 0.184 mmol) was added via a
syringe to a stirred solution of 10 (39.3 mg, 0.287 mmol) in
acetonitrile (3 mL). After being stirred for 18 h at room
temperature, the mixture was filtered and dried in vacuo. The
product was recrystallized from ethyl acetate to give 48.7 mg
(73%) of 3c as colorless needles: mp 197.5-198.5 °C; 1H NMR
(DMSO-d6) δ 10.40 (br s, 1H, N(1)-H), 9.04 (s, 1H, BOH), 7.99
(1H, d, J ) 7.4, C(5)-H), 7.46 (1H, ddd, J ) 8.0, 7.4, 1.0, C(7)-
H), 7.38 (m, 2H, Ph-H), 7.28 (m, 1H, Ph-H), 7.15 (m, 2H, Ph-
H), 7.08 (1H, d, J ) 8.0, C(8)-H), 7.03 (1H, t, J ) 7.4, C(6)-H);
13C (DMSO-d6) δ 153.9, 145.4, 139.0, 132.4, 132.3, 128.6 (2C),
128.0 (2C), 125.9, 120.4, 114.0 (The resonance assigned to C-B
was unobservable due to strong quadurupolar line-broaden-
ing); 11B NMR (DMSO-d6) δ 30.5; 11B NMR (MeOH-d4) δ 30.5;
11B NMR (acetone-d6) δ 30.0; IR (KBr) 3292s, 1634vs, 1564vs;
HRMS calcd for C13H11BN2O2 238.0914, found 238.0921. Anal.
Calcd for C13H11BN2O2: C, 65.59; H, 4.66; N, 11.77; B, 4.54.
Found: C, 64.86; H, 4.61; N, 11.51; B, 4.73.
Bis-m eth a n ol Ad d u ct of 1-Hyd r oxy-2-m eth yl-1H-2,4,1-
ben zod ia za bor in -3-on e (13a ). A sample of 3a (20 mg) was
dissolved in methanol-d4. 1H NMR spectrum analysis showed
that the solution contained 13a (30%) and 3a (70%): 1H NMR
(MeOH-d4) δ 7.37 (1H, dd, J ) 7.3, 1.3, Ar), 7.17 (1H, dd, J )
8.0, 7.3, 1.3, Ar), 7.03 (1H, m, Ar), 6.78 (1H, d, J ) 8.0, Ar);
13C NMR (MeOH-d4) δ 160.0 (CdO), 140.3 (C-N), 132.8 (CH),
128.7 (CH), 124.8 (CH), 115.0 (CH); 11B NMR (MeOH-d4) δ
5.1.
Bis-m eth a n ol Ad d u ct of 1-Hyd r oxy-2-m eth yl-1H-2,4,1-
ben zod ia za bor in -3-on e (13b). A sample of 3b (15 mg) was
dissolved in methanol-d4. 1H NMR spectrum analysis showed
that the solution contained 13b (85%) and 3b (15%): 1H NMR
(MeOH-d4) δ 7.37 (1H, dd, J ) 7.2, 1.0, Ar), 7.17 (1H, dd, J )
8.0, 7.2, 1.0, Ar), 7.04 (2H, m, Ar); 13C NMR (MeOH-d4) δ 159.0
(CdO), 140.6 (C-N), 132.8 (CH), 128.8 (CH), 124.6 (CH), 114.9
(CH), 27.2 (Me); 11B NMR (MeOH-d4) δ 4.5.
Bis-m eth a n ol Ad d u ct of 1-Hyd r oxy-2-p h en yl-1H-2,4,1-
ben zod ia za bor in -3-on e (13c). Methanol (15 mL) was added
to a solution of compound 3c (120 mg, 0.5 mmol) in dimethyl
sulfoxide (DMSO, 3 mL) at room temperature. The precipitate
formed was filtered, washed with methanol, and dried to give
120 mg (85%) of 13c as a colorless crystalline solid: mp 168-
169 °C; 1H NMR (MeOH-d4) δ 9.86 (1H, br, NH), 9.37 (1H, br,
NH), 7.41 (2H, m, Ph), 7.35 (3H, m, Ph), 7.17 (2H, m, Ph),
7.05 (1H, td, J ) 7.3, 0.8, Ar), 6.85 (1H, d, J ) 8.0, Ar), 3.35
(6H, s, 2 OMe); 1H NMR (DMSO-d6/MeOH ) 1:1) δ 10.04 (1H,
br, NH), 9.54 (1H, br, NH), 7.37 (2H, m, Ph), 7.32 (2H, m, Ph),
7.26 (1H, dd, J ) 7.2, 1.0, Ar), 7.14 (1H, dd, J ) 8.0, 7.2, 1.0,
Ar), 7.11 (1H, m, Ph), 7.00 (1H, t, J ) 7.2, Ar), 6.83 (1H, d,
J ) 8.0, Ar), 3.24 (6H, s, 2 OMe); 13C NMR (MeOH-d4) δ 157.1
(CdO), 140.1 (C), 137.5 (C), 132.6 (CH), 130.3 (2 CH), 129.0
(CH), 126.5 (CH), 125.2 (CH), 123.1 (2 CH), 115.7 (CH), 50.0
(MeO).13C NMR (DMSO-d6/MeOH ) 1:1) δ 156.3 (CdO), 139.7
(C), 137.4 (C), 132.3 (CH), 129.8 (2 CH), 128.2 (CH), 125.4
Exp er im en ta l Section
Gen er a l P r oced u r es a n d Ma ter ia ls. Melting points were
determined with a Fisher-J ohns melting point apparatus and
are uncorrected. Coupling constants (J ) are reported in hertz.
11B chemical shifts were referenced to external BF3‚OEt2 (δ )
0.0 ppm) with a negative sign indicating an upfield shift. Flash
column chromatography was carried out on Merck silica gel
60 (0.040-0.063 mm, 230-400 Mesh). The reagents were
purchased from various chemical companies and used directly
without further purification unless otherwise specified. An-
hydrous ethyl ether and tetrahydrofuran (THF) were distilled
from sodium/diphenyl ketone. Benzene and acetonitrile were
distilled from CaH2. Chloroform (CHCl3) and carbon tetra-
chloride (CCl4) were distilled from P2O5. 2-Nitrophenylboronic
acid and 2-aminophenylboronic acid were prepared according
to literature procedures.12 Phenylboronic acid, potassium
isocyanate, methyl isocyanate, phenyl isocyanate, and HMDS
were purchased from the Aldrich Chemical Co. Palladium
(10%) on charcoal was purchased from either Aldrich Chemical
Co or Strem Chemical Co. Acetic anyhdride, acetic acid, fuming
nitric acid, methanol, and absolute ethanol were used as
received from Fisher Scientific. Acetonitrile and tetrahydro-
furan and were purchased from Fisher and purified before use.
1-Hyd r oxy-1H-2,4,1-ben zod ia za bor in -3-on e (3a ). Potas-
sium isocyanate (182 mg, 2.24 mmol) was added to a stirred
solution of 10 (288 mg, 2.104 mmol) in glacial acetic acid (5
mL) and water (30 mL). After the mixture was stirred for 2
min at room temperature, a white precipitate began to form,
and the reaction was continued for 14 h after which time it
was cooled at 0 °C for 1 h. The mixture was filtered, washed
with water, and dried in vacuo to give 248 mg (73%) of 3a as
pale fine yellow needles: mp >300 °C; 1H NMR (DMSO-d6) δ
10.00 (br s, 1H, N(1)-H), 8.65 (s, 1H, BOH), 7.90 (br, 1H, N(3)-
H), 7.83 (dd, J ) 7.3, 1.4, 1H, C(5)-H), 7.39 (ddd, J ) 8.2, 7.3,
1.4, 1H, C(7)-H), 7.00 (d, J ) 8.2, 1H, C(8)-H), 6.96 (t, J )
7.3, 1H, C(6)-H); 13C NMR (DMSO-d6) δ 154.6 (CdO), 146.6
(C(8a)), 132.3, 132.1, 120.5, 114.6 (br, C(4a)), 114.3; 11B NMR
(DMSO-d6) δ 31.1; 11B NMR (MeOH-d4) δ 29.3; 11B NMR
(acetone-d6) δ 30.9; IR (KBr) 3233vs (br), 1684vs; HRMS calcd
for C7H7BN2O2 162.0601, found 162.0604. Anal. Calcd for C7H7-
BN2O2‚H2O: C, 46.72; H, 5.04; N, 15.57; B, 6.01. Found: C,
46.46; H, 4.67; N, 15.11; B, 6.44.
1-H yd r oxy-2-m et h yl-1H -2,4,1-b en zod ia za b or in -3-on e
(3b). Methyl isocyanate (0.2 mL, 3.30 mmol) was added via a
syringe to a stirred solution of 10 (261 mg, 1.904 mmol)
dissolved with gentle heating in acetonitrile (15 mL). After the
mixture was stirred for 2 min at room temperature, a white
solid began to form, and the reaction was continued for 4 h.
The mixture was filtered, washed with hot acetonitrile, and
dried in vacuo to give 291.5 mg (87%) of 3b as a colorless
crystalline solid: mp >300 °C; 1H NMR (DMSO-d6) δ 10.27
(br s, 1H, N(1)-H), 9.18 (s, 1H, BOH), 7.93 (1H, dd, J ) 7.3,
1.0, C(5)-H), 7.40 (1H, ddd, J ) 8.2, 7.3, 1.0, C(7)-H), 7.01 (1H,

Boron-Containing Heterocycles
J . Org. Chem., Vol. 64, No. 26, 1999 9573
(CH), 124.4 (CH), 122.0 (2 CH), 115.4 (CH), 49.8 (MeO); 11B
NMR (MeOH-d4) δ 6.1; 11B NMR (DMSO-d6/MeOH ) 1:1) δ
7.3; IR (KBr) 3369-2650br, 1633s, 1587s, 1556s; HRMS calcd
for C15H18BN2O3 (M + H) 285.1410, found 285.1395, and for
C14H13BN2O2 (M - MeOH) 252.1070, found 252.1079.
1-Met h oxy-2-p h en yl-1H -2,4,1-b en zod ia za b or in -3-on e
(14c). 1H NMR spectrum of compound 13c (10 mg) in DMSO-
d6 (0.5 mL) indicated that the solution contains a mixture of
14c (75%), 13c (7%), and 3c (18%): 1H NMR (DMSO-d6) δ
10.51 (br s, 1H, NH), 7.99 (1H, d, J ) 7.4, C(5)-H), 7.50 (1H,
ddd, J ) 8.0, 7.4, 1.0, C(7)-H), 7.38 (m, 2H, Ph-H), 7.29 (m,
1H, Ph-H), 7.16 (m, 2H), 7.13 (1H, d, J ) 8.0, C(8)-H), 7.06
(1H, t, J ) 7.4, C(6)-H), 3.74 (s, 3H, MeO); 13C (DMSO-d6) δ
153.9, 145.6, 139.5, 132.6 (2 C), 129.0 (2C), 128.4 (2C), 126.5,
120.9, 114.7, 113.8 (C-B), 54.6 (OMe); 11B NMR (DMSO-d6) δ
29.3.
[2-[N-(Deoxy-D-r ibofu r a n osyl)a m in o]p h en yl]bor on ic
Acid (21a ). 10 (70 mg, 0.51 mmol) was added to a solution of
2-deoxy-D-ribose (75 mg, 0.5 mmol) in EtOH (5 mL). The
mixture was stirred at room temperature for 24 h. The solvent
was evaporated under reduced presure. The residue was
treated with ether, filtered, and dried in vacuo to afford 260
mg of 21a (97%): 1H NMR(DMSO-d6) δ 7.46 (dd, J ) 7.4, 1.7,
1H, Ar-H), 7.24 (ddd, J ) 8.3, 7.4, 1.7, 1H, Ar-H), 6.74 (d, J )
8.3, 1H, Ar-H), 6.59 (td, J ) 7.4, 0.4, 1H,Ar-H), 6.47 (d, J )
8.0, 1H, NH), 5.36 (m, 1H, C(1′)-H), 4.94 (ddd, J ) 7.7, 3.0,
2.8, 1H, C(4′)-H), 4.59 (dt, J ) 7.7, 3.0, 2.8, 1H, C(3′)-H), 3.69
(dd, J ) 13.0, 3.0, 1H, C(5′)-H), 3.49 (dd, J ) 13.0, 2.8, 1H,
C(5′)-H), 2.44 (ddd, J ) 16.0, 7.1, 2.8, C(2′)-H), 2.12 (dd, J )
16.0, 3.0, C(2′)-H); 13C NMR(DMSO-d6) δ 151.5 (C(2)), 136.4,
133.1, 116.7 and 111.0 (4 CH), 109.8 (C, C-B), 76.0 (C(2′)),
73.9, 72.4, 62.7, 29.9 (C(3′); IR (KBr) 3424s, 3410s, 1602vs,
1575vs; HRMS calcd for C11H16BNO5 253.1121, found 253.1097.
[2-[N-(D-r ib ofu r a n osyl)a m in o]p h en yl]b or on ic Acid
(21b). This compound was prepared from 20b using the
method for 21a (97%): 1H NMR(DMSO-d6) δ 7.51 (dd, J )
7.4, 1.5, 1H, Ar-H), 7.23 (ddd, J ) 8.2, 7.4, 1.5, 1H, Ar-H), 7.02
(d, J ) 10.3, 1H, NH), 6.83 (d, J ) 8.2, 1H, Ar-H), 6.64 (t, J )
7.4, 1H, Ar-H), 5.7 (d, J ) 2.5, 1H, B-OH), 5.22 (d, J ) 10.3,
1H, C(1′)-H), 4.25 (br s, 1H), 4.10 (br s, 1H), 4.00 (br s, 1H),
3.65 (s, 2H, C(5′)-H2);13C NMR (DMSO-d6) δ 150.4 (C(2)), 135.5,
131.5, 117.0, 111.9, 79.7, 72.9, 69.1, 66.3, 64.6; IR (KBr)
3393vs, 1602vs, 1576vs; HRMS calcd for C11H16BNO6 269.1071,
found 269.1103.
Bis-m eth a n ol Ad d u ct of 4-[5-O-(ter t-Bu tyld im eth ylsi-
lyl)-2,3-O-isop r op ylid en e-r-D-r ibofu r a n osyl]-1-h yd r oxy-
2-m eth yl-1H-2,4,1-ben zod ia za bor in -3-on e (26). A sample
of 25 (15 mg) was dissolved in methanol-d4. 1H NMR spectrum
analysis showed that the solution contained 26 (78%) and 25
(22%): 1H NMR (MeOH-d4) δ 7.42 (1H, dd, J ) 7.2, 1.6, Ar),
7.24 (1H, ddd, J ) 8.0, 7.2, 1.6, Ar), 7.14 (1H, td, J ) 7.2, 0.8,
Ar), 7.03 (1H, d br, J ) 8.0, Ar), 6.16 (1H, d, J ) 3.8, C(1′)-H),
4.94 (1H, dd, J ) 6.3, 3.8, C(2′)-H), 4.92 (1H, d, J ) 6.3, C(3′)-
H), 4.41 (1H, dd, J ) 2.6, 2.3, C(4′)-H), 3.91 (1H, dd, J ) 11.0,
2.6, C(5′)-H), 3.86 (1H, dd, J ) 11.0, 2.3, C(5′)-H), 2.95 (s, 3H,
N-Me), 1.44 and 1.35 (2 s, 2 × 3H, CMe2), 0.91 (s, 9H, CMe3),
0.13 and 0.11 (2 s, 2 × 3H, SiMe2); 13C NMR (MeOH-d4) δ 160.6
(CdO), 143.9 (Ar, CN), 133.1 (CH, Ar), 128.9 (CH, Ar), 125.7
(CH, Ar), 122.6 (CH, Ar), 118.5 (br, CB), 114.2 (C, OCO), 93.5
(C(1′)), 83.8, 83.1, 81.5, 66.8 (C(5′), 49.8 (2 MeO), 28.1 (NMe),
25.4 (SiCMe3), 25.8 (Me), 23.7 (Me), 19.0 (SiCMe3), -5.5 and
-5.6 (SiMe2); 11B NMR (MeOH-d4) δ 7.3.
Attem p t To Syn th esize th e Nu cleosid e 19 by Con d en -
sa tion of 17 w ith 18a ,b. The Hilbert-J ohnson silyl reaction
was employed to synthesize the boron-containing nucleosides.
Compound 3b was dissolved in dry THF. Hexamethyldisila-
zane (HMDS) (2 equiv) and catalytic amounts of TMSCl (0.01
equiv) were added, and the solution was refluxed. The byprod-
uct, NH4Cl, sublimed and was periodically removed from the
condensor tip when necessary. The cessation of NH4Cl subli-
mation indicated the completion of reaction. Removal of THF
and excess HMDS by evaporation left clear oily residues that
were TMS-protected benzoborauracil 17 and were used im-
mediately for the condensation. The oils were dissolved in
MeCN or CHCl3 and freshly prepared 2,3,5-tri-O-benzoylri-
bofuranosyl chloride (1.25 equiv), and appropriate catalysts
(CuI, or ZnCl2 or SnCl4 or TMSSO3CF3, 0.01 equiv) were added.
The reactions were stirred for up to 2 d. TLC (4:1 hexanes-
ethyl acetate) showed a multiproduct mixture. After flash
chromatography, no expected nucleoside 19 was obtained and
the starting materials 3b and 18b were not recovered. About
30% of 2,3,5-tri-O-benzoylribofuranose, a hydrolysis product
of 18b, was obtained in the reaction. Similarly, the reactions
of the TMS-protected benzoborauracil 17 with R-D-2-deoxy-
3,5-di-O-p-toluoylribofuranosyl chloride and ZnCl2 (0.01 equiv)
in CCl4 or CHCl3 or with 1-O-Ac-2,3,5-tri-O-benzoylribofur-
anose and SnCl4 or TMSSO3CF3 in MeCN did not produce the
expected nucleoside.
4-[5-O-(ter t-Bu tyld im eth ylsilyl)-2,3-O-isop r op ylid en e-
r-D-r ibofu r a n osyl]-1-h yd r oxy-2-m eth yl-1H-2,4,1-ben zod i-
a za bor in -3-on e (25). 10 (135 mg, 1 mmol) was added to a
solution of 5-O-(tert-butyldimethylsilyl)-2,3-O-isopropylidene-
D-ribofuranose (23, 305 mg, 1 mmol) in EtOH (10 mL). The
mixture was stirred at room temperature for 3 d. The solvent
was evaporated under reduced pressure. The residue was
dissolved in benzene (10 mL), and methyl isocyanate (0.07 mL,
1 mmol) was added to the solution. The resulting mixture was
allowed to stand at room temperature for 1 d. After evapora-
tion of the solvent, the residue was flash chromatographed
(EtOAc/hexane ) 1:4) to afford 380 mg of 25 (82%) as a
colorless crystalline solid: mp 126.3-127.3 °C; 1H NMR-
(CDCl3) δ 7.92 (dd, J ) 8.8, 1.0, 1H, C(8)-H), 7.58 (dd, J )
7.5, 1.7, 1H, C(5)-H), 7.45 (ddd, J ) 8.8, 7.0, 1.7, 1H, C(7)-
H), 7.08 (ddd, J ) 7.5, 7.0, 1.0, 1H, C(6)-H), 6.79 (d, J ) 4.7,
1H, C(1′)-H), 5.09 (dd, J ) 6.6, 4.7, 1H, C(2′)-H), 4.99 (dd, J )
6.6, 0.6, 1H, C(3′)-H), 4.49 (ddd, J ) 3.3, 2.9, 0.6, 1H, C(4′)-
H), 3.83 (dd, J ) 15.0, 3.3, 1H, C(5′)-H), 3.79 (dd, J ) 15.0,
2.9, 1H, C(5′)-H), 3.17 (s, 3H, N-Me), 1.46 and 1.35 (2 s, 2 ×
3H, CMe2), 0.95 (s, 9H, CMe3), 0.11 and 0.10 (2 s, 2 × 3H,
SiMe2); 13C NMR(CDCl3) δ 155.9 (C(2)), 145.1 (C(4a)), 131.5
(CH, Ar), 129.7 (CH, Ar), 121.5 (CH, Ar), 119.7 (CH, Ar), 113.2
(C, -OCO-), 90.6 (C(1′)), 82.2, 82.0, 80.7, 65.2 (C(5′), 28.6
(NMe), 25.9 (SiCMe3), 25.2 (Me), 23.4 (Me), 18.2 (SiCMe3), -5.4
and -5.7 (SiMe2); 11B NMR(CDCl3) δ 29.7; 11B NMR(DMSO-
d6) δ 29.5; 11B NMR (MeOH-d4) δ 29.3; IR (KBr) cm-1 3354 br,
1618vs, 1594vs; HRMS calcd for C22H35BN2O6Si 462.2357,
found 462.2350. Anal. Calcd for C22H35BN2O6Si: C, 57.14; H,
7.63; N, 6.06; B, 2.34. Found: C, 57.23; H, 7.77; N, 5.89; B,
2.02.
Str u ctu r e Deter m in a tion for 3b,c a n d 13c. Single
crystals of 3b were grown by recrystallization from acetone,
3c from ethyl acetate and 13c from methanol solution. Crystals
of suitable size were mounted in glass capillaries and sealed
under nitrogen. The crystallographic data were collected on
an Enraf-Nonius CAD4 diffractometer with graphite-mono-
chromated Mo KR radiation (λ ) 0.710 73 Å). Unit cell
parameters were obtained by a least-squares refinement of the
angular setting from 25 reflections, well distributed in recipro-
cal space and lying in a 2θ range of 24-30°. All reflection data
were corrected for Lorentz and polarization effects.
The structures of compounds 3b and 3c were solved by the
direct methods Multan 11/82 and difference Fourier synthesis
with analytical atomic scattering factors used throughout the
structure refinement with both the real and imaging compo-
nents of the anomalous dispersion included for all non-
hydrogen atoms using MOLEN39 on a Dec Vax Station 3100
computer. The molecular structure of 13c was solved by
SHELXTL40 on a PC. Full-matrix least-squares refinements
were employed. After all of the non-hydrogen atoms were
located and refined, hydrogen atoms were located from the
difference map. All hydrogen atoms were refined isotropically,
and all non-hydrogen atoms were refined anisotropically.
Ack n ow led gm en t . This work was supported
by U.S. Department of Energy Grants (DE-FG02-
90ER60972 and DE-AC02-76CH000616) and NCI R01
(39) MOLEN Crystal Structure Analysis, Enraf-Nonius, 1990.
(40) SHELXTL (Version 5.1), Bruker Analytic X-ray Systems, 1997

9574 J . Org. Chem., Vol. 64, No. 26, 1999
Zhuo et al.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR (400 MHz)
spectra of compounds 3a -c, 13c, and 25 in DMSO-d6/MeOH,
CA-53896 and the Ohio State University Comprehen-
sive Cancer Center Grant (P30 CA-16058). The X-ray
work was supported by NSF Grant CHE91-04035 and
a Proctor and Gamble Graduate Fellowship to G.T.J .
This investigation was supported by the National
Cancer Institute, National Research Service Award
(NRSA) CA-09338, Division of Cancer Prevention and
Control, to B.A.B. We wish to acknowledge the support
of the Ohio State University Campus Chemical Instru-
ment Center.
1
2D H-1H COSY, NOESY, and ROESY spectra of compound
25, table of the reaction of 17 and 18a ,b under various
conditions, ORTEP drawings, atomic coordinates, bond lengths
and angles, thermal parameters, and least-squares planes for
3b,c and 13c. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O991176Q