Planar boron heterocycles with nucleic acid-like hydrogen-bonding motifs

Article abstract of DOI:10.1021/ja963784i

To promote the development of boron-containing purine analogues that exist in planar, non-zwitterionic dominant structural form. in aqueous solution, rigorous solution and solid state structural analyses of 1-hydroxy-1H-2,3,1-benzoxazaborine (1), 1,2-dihydro-1-hydroxy-2,3,1-benzodiazabo (2), and related 2,3,1-benzodiheteraborines were undertaken. With the aid of isotope-enriched compounds, a multisolvent ¹H, ¹³C, ¹¹B, and ¹⁵N NMR spectroscopic analysis of 1 and 2 was conducted, providing structurally-diagnostic chemical shift data for all non-oxygen atoms that constitute their heterocyclic peripheries. In addition, single-crystal X-ray diffraction analyses of 1 and 2 were performed. In stark contrast to their 2,4,1 isomeric counterparts, the 2,3,1-benzoxaza- and benzodiazaborines exist in planar structural form in protic solution and in the solid state and display proton dissociative and associative tendencies reflective of the predominant Bronsted, yet still Lewis acidic-capable character of the B-OH group together with the basic one at the C4-N3 imine group. In the solid state, 1 and 2 display intermolecular hydrogen-bonding patterns not too dissimilar from the motifs of certain natural nucleic acid bases. Diazaborine 2 was shown by VT-NMR to undergo a triple hydrogen-bonding solution association with a 2',3',5'-tri-O-protected cytidine in a demonstration of one biomimetic potential held by a 1-hydroxy-2,3,1-diheteraborine periphery. In general, 1, 2, and related 1-hydroxy-2,3,1-benzodiheteraborine heterocycles were found to be characterized by an environment-dependent O1 → N3 Bronsted prototropy and B-OH group Bronsted/Lewis acid ambidency so sensitive and subtle that certain past difficulties encountered in attempts to delineate their physicochemical properties now become readily appreciated.

Full text of DOI:10.1021/ja963784i

J. Am. Chem. Soc. 1997, 119, 7817-7826
7817
Planar Boron Heterocycles with Nucleic Acid-Like
Hydrogen-Bonding Motifs†
Michael P. Groziak,*,‡,§ Liya Chen,§ Lin Yi,§ and Paul D. Robinson|
Contribution from the Department of Chemistry and Biochemistry and the Department of
Geology, Southern Illinois UniVersity, Carbondale, Illinois 62901-4409
ReceiVed October 31, 1996. ReVised Manuscript ReceiVed May 23, 1997X
Abstract: To promote the development of boron-containing purine analogues that exist in planar, non-zwitterionic
dominant structural form in aqueous solution, rigorous solution and solid state structural analyses of 1-hydroxy-
1H-2,3,1-benzoxazaborine (1), 1,2-dihydro-1-hydroxy-2,3,1-benzodiazaborine (2), and related 2,3,1-benzodihetera-
1
borines were undertaken. With the aid of isotope-enriched compounds, a multisolvent H, 13C, 11B, and 15N NMR
spectroscopic analysis of 1 and 2 was conducted, providing structurally-diagnostic chemical shift data for all non-
oxygen atoms that constitute their heterocyclic peripheries. In addition, single-crystal X-ray diffraction analyses of
1 and 2 were performed. In stark contrast to their 2,4,1 isomeric counterparts, the 2,3,1-benzoxaza- and
benzodiazaborines exist in planar structural form in protic solution and in the solid state and display proton dissociative
and associative tendencies reflective of the predominant Brønsted, yet still Lewis acidic-capable character of the
B-OH group together with the basic one at the C4-N3 imine group. In the solid state, 1 and 2 display intermolecular
hydrogen-bonding patterns not too dissimilar from the motifs of certain natural nucleic acid bases. Diazaborine 2
was shown by VT-NMR to undergo a triple hydrogen-bonding solution association with a 2′,3′,5′-tri-O-protected
cytidine in a demonstration of one biomimetic potential held by a 1-hydroxy-2,3,1-diheteraborine periphery. In
general, 1, 2, and related 1-hydroxy-2,3,1-benzodiheteraborine heterocycles were found to be characterized by an
environment-dependent O1fN3 Brønsted prototropy and B-OH group Brønsted/Lewis acid ambidency so sensitive
and subtle that certain past difficulties encountered in attempts to delineate their physicochemical properties now
become readily appreciated.
Introduction and Background
of the 2,4,1-benzodiheteraborine subclasses of boron hetero-
cycles, and it was suggested that the 1,4-hydrate-related
structural features of the resultant zwitterions were particularly
attractive as they are encouraging to the design of “transition-
state” analogue inhibitors of adenosine deaminase, a purine
nucleoside-utilizing enzyme. When viewed from the context
of access to more broadly useful planar, uncharged boron
mimics of the naturally occurring purine aglycons existent in
aqueous solution, however, these same structural features are
seen to be disadvantaging.
A renewal of interest in the development of boron-containing
analogues of biologically derived and/or active molecules is now
emerging at a time when the synthetic methodologies for
preparation and the analytical techniques for characterization
of these often unique substances are more sophisticated than
when, for instance, boroaromatic heterocycles were avidly
studied in the 1950s and 1960s. Many have recognized an
untapped potential value held by boron-containing compounds
to biomedical and other types of investigations.1 Some of the
efforts in this laboratory directed toward the preparation of
boron-based purine analogues bearing a boron atom at the
6-position are focused on 6-hydroxy-1,3,6-oxaza- and 4-hy-
droxy-1,3,4-diazaborines because they bear the closest peripheral
resemblance to the pyrimidine ring portion of many naturally
occurring purines. In an initial study of models of these types
of purine mimics,2 a susceptibility to facile 1,4-hydration in
aqueous solution was demonstrated to be an endemic property
A relocation of the imine nitrogen atom at the position
transannular to the boron center in these compounds should
provide classes of boron heterocycles resistant at the least to
1,4-hydration. Accordingly, attention also is being given to the
imine “inverted” isomeric 6-hydroxy-1,2,6-oxaza- and 3-hy-
droxy-1,2,3-diazaborines in a parallel research effort. To ensure
the most rapid access to materials with which to examine
hydration susceptibilities and to obtain compounds for proper
direct comparisons to ones of the previous study, benzo-fused
members (1-hydroxy-1H-2,3,1-benzoxazaborine (1) and 1,2-
dihydro-1-hydroxy-2,3,1-benzodiazaborines (2-4)) were se-
lected as the subjects for the initial study of these diheteraborines
related herein.
† Presented in part: (a) Groziak, M. P.; Yi, L.; Merrill, J. M.; Robinson,
P. D. Abstracts of Papers, 209th National Meeting of the American
Chemical Society, ORGN Division, Anaheim, CA, 1995; Abstr. 181. (b)
Groziak, M. P.; Chen, L.; Yi, L.; Robinson, P. D. 25th National Medicinal
Chemistry Symposium, 1996, Ann Arbor, MI, 1996; Abstr. 115.
‡ New address: SRI International, Pharmaceutical Discovery Division,
333 Ravenswood Avenue, Menlo Park, CA 94025-3493.
§ Department of Chemistry and Biochemistry.
| X-ray Crystallographer, Department of Geology.
X Abstract published in AdVance ACS Abstracts, August 1, 1997.
(1) Reviews: (a) Morin, C. Tetrahedron 1994, 50, 12521-12569. (b)
Goudgaon, N. M.; El-Kattan, G. F.; Schinazi, R. F. Nucleosides Nucleotides
1994, 13, 849-880. (c) Spielvogel, B. F.; Sood, A.; Shaw, B. R.; Hall, I.
H. In Current Topics in the Chemistry of Boron; Kabalka, G. W., Ed.; The
Royal Society of Chemistry: Cambridge, U.K., 1994; pp 193-198. (d)
Hawthorne, M. F. Angew. Chem., Int. Ed. Engl. 1993, 32, 950-984. (e)
Terashima, M.; Ishikura, M. AdV. Heterocycl. Chem. 1989, 46, 143-167.
(2) Groziak, M. P., Ganguly, A. D.; Robinson, P. D. J. Am. Chem. Soc.
1994, 116, 7597-7605.
S0002-7863(96)03784-5 CCC: $14.00 © 1997 American Chemical Society

7818 J. Am. Chem. Soc., Vol. 119, No. 33, 1997
Groziak et al.
for the expected development of imidazo-fused versions of 1
and 2 into nonhydrating boron mimics of the 2-aza-3-deaza-
purines,12 then, it was apparent that a detailed reinvestigation
of these and related heterocycles was in order. With the aid of
1
isotope-enriched compounds, a multisolvent H, 13C, 11B, and
15N NMR spectroscopic survey of 1 and 2 was conducted to
provide structurally diagnostic chemical shift data for all non-
oxygen atoms that constitute their heterocyclic peripheries. In
addition, single-crystal X-ray diffraction analyses of 1 and 2
were performed to define atom connectivity-related topographies
and intermolecular hydrogen-bond associations in the solid state.
Finally, the interactions of these heterocycles with certain
reagents, solvents, and nucleosides bearing potential hydrogen-
bonding complementarities were examined to assess properties
of particular importance to those solution-based characteristics
to be expected of the imidazo-fused versions under development.
Historical Context and Specific Aims
While we were the first to access 4,3 the benzo-fused
heterocycles 1-3 and certain derivatives were studied over 30
years ago by Dewar4 and Snyder.5 Thiophene-based versions
of 1-3 have been examined quite extensively by Gronowitz,6
and furan-7 and even selenophene-based8 versions of 1 and 2
have received some attention. Some of the more recent of these
investigations likely were prompted in part by the discovery
that certain N-aryl/alkylsulfonylated derivatives9 of 2 possess
good biocidal properties.10 Even under all of this previous
scrutiny, though, certain endemic properties of carbocycle- and
heterocycle-fused 6-hydroxy-1,2,6-oxazaborines and 3-hydroxy-
1,2,3-diazaborines closely related to the structural forms they
adopt in various solution environments or in the solid state have
for some reason remained elusive.11 To finally gain a knowl-
edge of these structural forms and thereby provide a firm basis
Results and Discussion
Synthesis of Unlabeled Materials. Heterocycles 1-3 were
prepared in unlabeled form from 2-formylbenzeneboronic acid
via slightly modified literature procedures. Torssell had pre-
pared the formylboronic acid precursor in low to moderate yield
from 2-MeC6H4B(OH)2 via hydrolysis of the R,R-dibromo
derivative.13 Snyder5f and Dewar4c had also used a variant of
this approach, but Gronowitz had prepared it from the dioxolane
of 2-BrC6H4CHO along a halogen-metal exchange route.14
Although this latter method provided a more rapid access and
an improved yield (57%), it was found to sometimes generate
di- and triarylboronic acid byproducts that were difficult to
remove. As Washburn et al.15 had found the Grignard-based
synthesis of C6H5B(OH)2 to proceed without such complications,
we decided to utilize an organomagnesium reagent in the
Gronowitz approach. 2-Bromobenzaldehyde was converted to
the dioxolane, which via the Grignard derivative (in THF, not
Et2O) gave the formylboronic acid in a 68% yield. Published
procedures4c,5f were used to condense this aldehyde with NH2-
OH to afford 1 (99%) and with NH2NH2 and MeNHNH2 to
afford 2 (83%) and 3 (79%), respectively. Condensation with
Me2NNH2 did not yield 4 directly but, instead, gave a tridehydro
trimeric form (boroxin 53) from which 4 could be generated by
mild hydrolysis (H2O, 24 h, 25 °C). More forcing conditions
(H2O, 24 h, 100 °C) effected a deboronation in 5, presumably
via the intermediacy of 4.
(3) Robinson, P. D.; Groziak, M. P.; Yi, L. Acta Crystallogr. 1996, C52,
2826-2830. For a report describing related 1,1-dimethylhydrazones derived
from 2-formylthiophene-3-boronic acid and 3-formylthiophene-2-boronic
acid, see ref 6j.
(4) (a) Davis, F. A.; Dewar, M. J. S.; Jones, R. C. J. Am. Chem. Soc.
1968, 90, 706-708. (b) Dewar, M. J. S.; Jones, R. Ibid. 1967, 89, 2408-
2410. (c) Dewar, M. J. S.; Dougherty, R. C. Ibid. 1964, 86, 433-436. (d)
Dewar, M. J. S.; Dougherty, R. C. Ibid. 1962, 84, 2648-2649.
(5) (a) Catlin, J. C; Snyder, H. R. J. Org. Chem. 1969, 34, 1660-1663.
(b) Dunn, H. E.; Catlin, J. C.; Snyder, H. R. Ibid. 1968, 33, 4483-4486.
(c) Haynes, R. R.; Snyder, H. R. Ibid. 1964, 29, 3229-3233. (d) Tschampel,
P.; Snyder, H. R. Ibid. 1964, 29, 2168-2172. (e) Lennarz, W. J.; Snyder,
H. R. J. Am. Chem. Soc. 1960, 82, 2172-2175. (f) Snyder, H. R.; Reedy,
A. J.; Lennarz, W. J. Ibid. 1958, 80, 835-838.
(6) (a) Gronowitz, S.; Maltesson, A. Acta Chem. Scand. 1977, B31, 765-
767. (b) Gronowitz, S.; Roos, C.; Sandberg, E.; Clementi, S. J. Heterocycl.
Chem. 1977, 14, 893-897. (c) Gronowitz, S.; Glennow, C. Chem. Scr. 1977,
11, 76-82. (d) Gronowitz, S.; Maltesson, A. Acta Chem. Scand. 1975, B29,
461-467. (e) Gronowitz, S.; Maltesson, A. Ibid. 1975, B29, 457-460. (f)
Gronowitz, S.; Roos, C. Ibid. 1975, B29, 990-998. (g) Gronowitz, S.;
Toresson, C. Chem. Scr. 1972, 2, 143. (h) Gronowitz, S.; Dahlgren, T.;
Namtvedt, J.; Roos, C.; Rose´n, G; Sjo¨berg, B.; Forsgren, U. Acta Pharm.
Suecica 1971, 8, 623-638. (i) Gronowitz, S.; Maltesson, A. Acta Chem.
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(k) Namtvedt, J.; Gronowitz, S. Ibid. 1968, 22, 1373-1374. (l) Gronowitz,
S.; Namtvedt, J. Ibid. 1967, 21, 2151-2166. (m) Gronowitz, S.; Bugge, A.
Ibid. 1965, 19, 1271-1285.
(7) (a) Florentin, D.; Fournie´-Zaluski, M.-C.; Roques, B. P. J. Chem.
Res. (S) 1977, 158-159. (b) Florentin, D.; Roques, B. P.; Metzger, J.-M.;
Colin, J.-P. Bull. Soc. Chim. Fr. 1974, 11, 2620-2622. (c) Roques, B.;
Florentin, D. J. Organomet. Chem. 1972, 46, C38-C40. (d) Roques, B.;
Florentin, D.; Juhasz, J.-P. C. R. Acad. Sci. Paris, Se´r. C 1970, 270, 1898-
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(8) Semard, D.; Paulmier, C.; Morel, J.; Pastour, P. Int. J. Sulfur Chem.,
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(11) Reviews: (a) Gronowitz, S. In Lectures in Heterocyclic Chemistry;
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pp 235-263. (c) Dewar, M. J. S. In AdVances in Chemistry, Vol. 42; Gould,
R. F., Ed.; American Chemical Society: Washington, DC, 1964; pp 235-
263. (d) Letsinger, R. L. In AdVances in Chemistry, Vol. 42; Gould, R. F.,
Ed.; American Chemical Society: Washington, DC, 1974; pp 1-16. (e)
Maitlis, P. M. Chem. ReV. 1962, 62, 223-245. (f) Fritsch, A. J. Chem.
Heterocycl. Compd. 1977, 30, 381-440. (g) Ander, I. In ComprehensiVe
Heterocyclic Chemistry; Katritzky, A. R., Ed.; Pergamon: Oxford, U.K.,
1985; Vol. 1, pp 629-663. (h) Friedrichsen, W. In ComprehensiVe
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1985; Vol. 4, pp 1000-1001. (i) Friedrichsen, W. In ComprehensiVe
Heterocyclic Chemistry; Katritzky, A. R., Ed.; Pergamon: Oxford, U.K.,
1985; Vol. 4, pp 1029-1032. Also, see the discussion in the following: (j)
Mikhailov, B. M.; Kuimova, M. E. J. Organomet. Chem. 1976, 116, 123-
133.
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S.; Aschauer, H.; Kollenz, G.; Ho¨genauer, G.; Turnowsky, F. J. Biol. Chem.
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Antimicrob. Chemother. 1987, 20, 37-45. (e) Grassberger, M. A.; Turn-
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(12) (a) Naguib, F. N. M.; Iltzsch, M. H.; el Kouni, M. M.; Panzica, R.
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(13) Torssell, K. ArkiV Kemi 1956, 10, 507-511.
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(15) Washburn, R. M.; Levens, E.; Albright, C. F.; Billig, F. A. Organic
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Vol. IV, pp 68-72.

Planar Boron Heterocycles
J. Am. Chem. Soc., Vol. 119, No. 33, 1997 7819
state and in CD3CN solution but reverted to 1 upon exposure
to water. That this hydrolysis occurs via an addition-
In an alternative approach to 2, the dianion-based protocol
of Sharp and Skinner16 was applied to the N-tosylhydrazone of
2-bromobenzaldehyde to afford 6, one of the known competent
biocides,10e in an excellent (93%) yield. Precursor 6 was readily
converted to 2 (65%) upon exposure to NH2NH2 in a transfor-
mation likely to be SN(ANRORC)17 in nature. The nitrone 718
and oxime 85b,19 desired as NMR reference compounds each
were prepared according to their respective literature procedures.
elimination route rather than via a demethylative SN2 displace-
ment was verified by establishing that 18O isotope acquisition
by 1 occurs upon hydrolysis in H218O. Even under forcing
conditions (anhydrous CH3OH, 65 °C, 24-30 h), heterocycles
2, 3, and 6 resisted the formation of B-methoxy derivatives. By
UV, neither 2 nor 3 is substantially affected by dissolution in
CH3CN, CH3OH, or H2O. An attempt to convert 9 to a B-amino
derivative by exposing it to anhydrous NH3 gave an extremely
hygroscopic material suspected to be the desired material, but
this was found to hydrolyze to 1 simply upon exposure to the
atmosphere. Upon rigorous desiccation, 1 could be converted
to an isolable, hygroscopic B-O-B anhydro dimer. Diazabo-
rines 2 and 3 resisted such dehydration even though anhydro
dimer ions were observed in their ACE mass spectra. The
triphenylboroxin 5 was found to undergo methanolysis simply
upon dissolution in absolute CH3OH, affording a 2:1 mixture
of mono- and dimethoxylated boronic acid derivatives, by 11B
NMR. Upon heating to effect dissolution in water, the O-methyl
oxime 8 was found to undergo facile demethylation to 1, by 1H
and 11B NMR. Potentiometric measurement of the pH of
aqueous solutions of 1-3 and 6 revealed a pKa of ca. 4.8 for 1
and ca. 8 for each the three diazaborines.
Synthesis of Labeled Materials. Commercial [formyl-13C]-
PhCHO was selected as a likely convenient precursor to the
doubly isotope-enriched [4-13C,2-15N]1 and the triply isotope-
1
enriched [4-13C,2,3-15N2]2 needed for H, 13C, and especially
15N NMR spectroscopic analyses. Because no previous syn-
thesis of 2-formylbenzeneboronic acid4c,5f,13,14,19 had employed
PhCHO as starting material, though, a new synthesis had to be
developed. Guided by works of Comins and Brown20 on low-
temperature ortho-lithiation of the R-amino alkoxide derived
from lithiated N,N,N′-trimethylethylenediamine and PhCHO,
Snieckus et al.21 on the synthesis of arylboronic acids via the
directed lithiation of benzamides, and Washburn et al.15 on the
beneficial effect of low temperature and extended reaction time
in the PhMgBr/B(OMe)3-based preparation of C6H5B(OH)2, a
highly expedient one-step synthesis of the requisite labeled
formylboronic acid was developed. The B(OMe)3-mediated
boronation of the BuLi-generated dianion derived from the
PhCHO/MeN(Li)CH2CH2NMe2 adduct was found to be highly
temperature and time dependent, requiring a 24 h equilibration
at -78 °C to effect a 50% conversion. The doubly isotope-
enriched [4-13C,2-15N]1 was prepared in a 90% yield by
condensation of the resultant labeled formylboronic acid and
[15N]NH2OH‚HCl in warm pH 4-5 aqueous solution. The
triply isotope-enriched [4-13C,2,3-15N2]2 was prepared in an 86%
yield by a similar condensation employing [15N2]-NH2NH2‚
H2SO4 in aqueous EtOH containing NaOH.
18O Isotope Acquisition. Equilibration of 1 or 2 with excess
H218O in CH3CN solution at 69-75 °C for 12 h resulted in
little or no 18O isotope acquisition by the former heterocycle,
but complete isotope acquisition by the latter one, as determined
by low-resolution ACE-mass spectral analysis. Even when
subjected to these conditions for 36 h, 1 was found to acquire
a single 18O atom only to a 50% extent. A careful scrutiny of
the low-intensity (1%) [2M - H2O]+ peak pattern in the 274-
280 m/e mass-spectral region of this material revealed the same
single 18O-atom content in the minor, possibly spectrometer-
generated anhydro dimer species, thereby eliminating the
possibility that the isotopic enrichment in 1 had origins in the
hydrolysis of a 100% single-labeled anhydro dimer by propitious
unenriched water during post-H218O-equilibration handling.
Diazaborine 2 was found to so readily exchange its O1 atom
with that of H218O that the process occurred with reasonable
facility (t1/2 of ca. 4 h) even at 23 °C. A similar propensity
toward 18O isotope acquisition was noted for 3, suggesting that
the diazaborines, perhaps due to a weaker inherent Brønsted
acidity (Vide infra), display a more pronounced Lewis acidic
character than does the oxazaborine 1. The sluggish 18O isotope
acquisition by 1 could be overcome by equilibration in 2 N
Li18OH/H218O (23 °C, 1 h) followed by neutralization with
HOAc, whereby a >50% acquisition was achieved. The
diazaborines’ reactivity was also enhanced in this manner in
the order 3 . 2 ∼ 6.
Interconversions and Acidities. Although 6 had readily
afforded 2 upon exposure to NH2NH2, it did not afford 1 when
treated with NH2OH. Oxazaborine 1, which like 6 gave 2 (54%)
upon treatment with NH2NH2, was found to give a low melting
hygroscopic B-methoxy derivative (9) simply upon recrystal-
lization from CH3OH. Heterocycle 9 was stable in the solid
(16) Sharp, J. T.; Skinner, C. E. D. Tetrahedron Lett. 1986, 27, 869-
872.
(17) van der Plas, H. C. Khim. Geterotsikl. Soedin. 1994, 1649-1668.
(18) Kliegel, W.; Nanninga, D. J. Organomet. Chem. 1983, 247, 247-
252.
(19) Scouten, W. H.; Liu, X.-C.; Khangin, N.; Mullica, D. F.; Sappenfield,
E. L. J. Chem. Crystallogr. 1994, 24, 621-626. Experimental details of
preparation and characterization contained therein are strikingly similar to
those found in refs 5b,d.
(20) Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49, 1078-1083.
(21) (a) Sharp, M. J.; Cheng, W.; Snieckus, V. Tetrahedron Lett. 1987,
5093-5096. (b) Sharp, M. J.; Snieckus, V. Ibid. 1985, 5997-5600. (c)
Iwao, M.; Mahalanabis, K. K.; Watanabe, M.; de Silva, S. O.; Snieckus,
V. Tetrahedron 1985, 39, 1955-1962.

7820 J. Am. Chem. Soc., Vol. 119, No. 33, 1997
Groziak et al.
Table 1. 1H, 13C, 11B, and 15N NMR Data for Boron-Containing Compounds, (δ in ppm, coupling constants in Hz)
1
compd
solvent OHa NH
CHO/H4 CHO/C4 JCHO/C4-H
B1b
N2b
1JN2-H
N3b
1JN3-C4
CD3CN 6.66
(CD3)2SO 8.25
CD3OD
D2O
aq NaOH
10.05
10.13
6.00
197.0
194.2
105.1
197.1
176.9
175.9
168.5
177.5
29.9 (90)
-
30.9 (187)
30.3 (211)
7.1 (105)
9.93
CD3CN
6.78
8.45
8.65
8.49
8.45
151.2
150.0
151.2
150.3
177.6
178.5
178.4
180.8
28.8 (99)
-
24.6 (125)
18.7 (125)d
2.2 (71)
-12.1 (4)
-11.6 (1)
-33.6 (40)
-35.4 (70)
3.5
4.4
-
(CD3)2SO 9.42
CD3ODc
D2O
aq NaOH
-
CD3CN
6.00 8.95e 7.98
140.5
138.5
141.7
139.7
178.1
177.3
178.2
175.8
28.2 (87)
-
27.7 (138)
27.5 (100)
26.9 (319)
-216.3 (29) 90.8 -54.9 (8)
5.3
8.6
-
(CD3)2SO 8.20 9.96f 8.00
-212.0 (1)
-222.6 (76)
-219.1 (33)
90.9 -52.0 (4)
-68.8 (38)
CD3OD
D2O
aq NaOH
8.02
8.07
-71.2 (8)
8.8
CD3CN
(CD3)2SO 8.54
CD3OD
D2O
aq NaOH
6.22
7.98
8.00
7.92
8.02
138.8
137.4
139.4
28.0 (83)
-
27.4 (152)
26.8 (111)
26.2 (326)
H2O
8.25
3.9 (123)
CD3CN
(CD3)2SO
CD3OD
8.53, 8.10g
8.47, 8.28g
8.14, 7.41g
162.0
160.9
140.4
28.9 (102), 4.8 (103)g
-
26.6 (121), 5.8 (38)h
aq NaOH
1.4 (166)
D2O
aq NaOH
8.49
8.49
150.7
151.2
4.3 (126)
4.0 (130), 2.0 (75)
CD3CN
CD3OD
32.6 (103)
2
a Acquisition of H upon addition of D2O, t1/2 of <1 min at 23 °C. b Line widths in Hz shown in parentheses. c Verified as 1 and not 9 by a
comparison of the 11B NMR chemical shift values. d Highly variable and temperature dependent. Other values at room temperature, 14.9 (140 Hz),
2
13.0 (134 Hz), and 6.8 ppm (115 Hz). Values at 70 °C, 19.7 (277 Hz) and 15.2 ppm (130 Hz). e Acquisition of H upon addition of D2O, t1/2 40
min at 23 °C; 2JN3-NH and 4JH4-NH, 6.6 and 8.6 Hz, respectively. f Acquisition of 2H upon addition of D2O, t1/2 of 4 h at 23 °C; 2JN3-NH and 4JH4-NH
,
7.5 and 7.5 Hz, respectively. g Integration ratio 1:2. h Integration ratio 2:1.
NMR Solution Structures. Data from extensive multisol-
vent 1H, 13C, 11B, and 15N NMR spectroscopic analyses of 1-4
and related compounds are shown in Table 1.22 The upfield
chemical shifts for the CHO group proton and carbon resonances
of 2-formylbenzeneboronic acid when in CD3OD solution are
clear indications that this solvent readily adds to the aldehyde
to produce a methoxylated borophthalide species.5d In every
other combination of compound and neutral solvent, however,
no other such addition to a CdO or CdN moiety was revealed.
Thus, importantly, heterocycles 1-3 maintain the integrity of
their C4-N3 imine unit in every solvent examined, a conclusion
corroborated by the observation of a large (175-180 Hz) 1JC4-H
coupling constant in every case. The B-OH group proton
chemical shift in 1-3 and even for 2-formylbenzeneboronic acid
itself experiences a large (1.6-2.7 ppm) downfield displacement
upon transfer from CD3CN to (CD3)2SO, no doubt caused by
the greater hydrogen-bond accepting ability of the latter solvent.
This effect is more pronounced in 1 than in 2, indicating that
the oxazaborine is the more Brønsted acidic. In a finding
somewhat related to that noted previously for a furo[3,2-d][1,2,3]-
diazaborine,7a the N2-H group proton chemical shift in 2 shows
a similar (1.0 ppm) displacement as it too acts a hydrogen-
bond donor to solvent (CD3)2SO. That the N2-H group of 2
can donate a hydrogen bond is further documented by the results
of the X-ray crystal structure determination (Vide infra) of this
heterocycle. However, a comparison of the t1/2 values for
deuterium exchange from D2O into this group in the two polar
aprotic solvents reveals this process to be significantly faster
in CD3CN, suggesting that the H2 atom in 2 exchanges not as
a direct result of Brønsted acid behavior on the part of the N2-H
unit, but rather as an indirect consequence of a 1,2-addition of
D2O to the 2,3,1-diazaborine ring Via a 1,2-zwitterion like 4.
The retarded rate of such a hydration of 2 when in (CD3)2SO
(22) The expected utility of 15N and 11B solution NMR spectroscopic
analyses to the solution structure elucidation of boron heterocycles similar
to 1 and 2 was recognized in at least one prior investigation. See ref 7b.

Planar Boron Heterocycles
J. Am. Chem. Soc., Vol. 119, No. 33, 1997 7821
containing D2O is likely a result of the rendering of the B1
atom less electron-deficient by the partial ionization of the
Brønsted acidic B-OH group. This interpretation gains support
from the results of experiments that revealed 2 to be susceptible
to 18O isotope acquisition from H218O even at room temperature
under neutral conditions. An elimination-addition pathway for
H2 deuterium exchange in 2 is indirectly rendered doubtful by
the finding that 3 acquires an 18O isotope from H218O under
neutral conditions with at least equal facility to that of 2.
Besides this, the non-zwitterionic BdN moiety of the putative
intermediate along such a pathway has no known precedent.23
Except for the fact that they were consistently smaller for
species in CH3CN solution, the 11B line widths were found to
be of little diagnostic utility. On the other hand, the 11B
chemical shifts were quite diagnostic of the amount of charge
at, and to a limited degree, the hybridization state of the boron
center in the heterocycle solution species. No signals ever were
obtained from (CD3)2SO solutions of these compounds,24 but
the chemical shift values of 1-3 in all other neutral solvents
save for 1 in H2O were found to be in the 25-30 ppm range
characteristic of the trigonal-planar substituted sp2-hybridized
neutral boron centers of CBO2 or CB(O)N molecular fragments.
The intermediate 11B chemical shift value of 18.7 ppm for 1 in
H2O shows an increase in electron density near this center, but
not nearly to the extent indicated by the δ value of 1 or 6 in
aqueous NaOH or of 4 or 7 in H2O. The upfield 11B chemical
shift of 1 in H2O is best explained by the presence of species
A, the product of a proton dissociation from the B-OH group
acting in Brønsted acid fashion, rather than by that of B, the
Figure 1. ORTEP diagram and atomic numbering scheme for one of
the 1,2-dihydro-2,3,1-benzodiazaborines formed by intramolecular
chelation in bis(8-B-4)-1,3,5-tris[2-[(dimethylhydrazono)methyl]phenyl]-
boroxin (5).3
there is little or no oxyanion charge delocalized onto the boron
center. By electrostatic repulsion, the presence of the adjacent
p-electron-rich, sp2-hybridized nitrogen center in the diazaborine
conjugate bases may preclude such charge accumulation by the
boron atom. Thus, we conclude that the 11B NMR chemical
shift value of 2 and 3 is insensitive to their Brønsted-type
ionization in alkali, in contrast to the great sensitivity of this
shift for 1 even in neutral aqueous solution. Interestingly, this
6-hydroxy-1,2,6-oxazaborine exhibits a 11B NMR chemical shift
value diagnostic of species B in alkaline solution, and the
3-hydroxy-1,2,3-diazaborine 6 also adopts such a Lewis acid
conjugate base form in this medium.27
Upon transfer from an aprotic to a protic solvent, the 15N
chemical shift in oxazaborine 1 undergoes a moderate (22.5
ppm) upfield displacement reflective of a protophilic association
with solvent. This same solvent effect is noted for diazaborine
2 but to a lesser extent (∆δ 16.5 ppm) that is suggestive of a
slightly lower basicity. Despite its juxtaposition with the 11B
quadrupolar nucleus, the 15N NMR signal from the N2 atom of
[4-13C,2,3-15N2]2 was observed and was found to be in a
chemical shift range (δ 217 ( 5 ppm) typical of an amide-type
nitrogen in all four neutral solvents. That this nitrogen in 2 is
truly amide-like in character is further supported by the 91 Hz
1JN2-H coupling constant magnitude for this heterocycle found
in the two aprotic solutions.
X-ray Crystal Structures. An X-ray crystallographic analy-
sis of 5, the tridehydro form of 4 which exists in the solid state
and in aprotic solution, was conducted and the details have been
reported elsewhere.3 In a solid state structure likely to be found
similar to those of earlier-reported imine derivatives of 2-formyl-
benzeneboronic acid,5b crystalline 5 is the first triaryl-substituted
boroxin28 found to display two B3O3-ring chelations. These
occur on opposite faces of the boroxin ring and assemble 1,1,2,2-
tetrasubstituted 1,2-dihydro-2,3,1-benzodiazaborine moieties of
relevance to the discussion of the heterocycles of the present
work. An ORTEP representation of one of these is shown in
Figure 1. In an alleviation of eclipsing interactions, each of
the chelation-derived diazaborine heterocyclic fragments in
crystalline 5 displays a severe twist at the B-N site of ring
saturation that places the four substituents at these two heteroa-
toms into near-perfect axial and equatorial positionings (select
hydration product of the B-OH group acting in Lewis acid
fashion. In A,25 a species properly viewed as a B-O for CdN
isoelectronic replacement analogue of the conjugate base of
phthalazin-1(2H)-one,26 the delocalization of charge from the
oxyanion onto the boron center in a π-bond-forming fashion
accounts for both the observed upfield shifted 11B signal for 1
in water and for the sluggishness of 18O isotope acquisition from
H218O by 1 in CH3CN. Moreover, a Brønsted-type ionization
of 1 to produce A in water is consistent with the observation
that the 300 nm “boroaromatic” diagnostic absorption in the
UV spectrum of 1 observed in CH3CN, (CH3)2SO, and CH3-
OH is absent for 1 in aqueous solution.
According to the NMR data, the integrity of the diheteraborine
ring and, surprisingly, the electronic environment of the boron
center as measured by 11B NMR chemical shifts in 2 or 3 remain
largely unaffected under high-pH conditions despite the fact that
their aqueous pKa value of ca. 8 together with their ready
dissolution in alkali are clearly suggestive of ionization in this
environment. The best explanation for this seemingly contra-
dictory set of findings is that both 2 and 3 do indeed form
Brønsted conjugate bases in a strongly alkaline medium, but
(23) See for example the MNDO study described in the following:
Sporzynski, A.; Szatylowicz, H. J. Organomet. Chem. 1994, 470, 31-33.
(24) Facile aggregate formation in this medium provides one explanation
for this phenomenon.
(25) A BdO containing resonance structural representation of 7-H2O
similar to that depicted for A can be found in ref 17.
(26) An insight into the reason why diazaborines like 2 and 3 do not
readily dissociate in Brønsted fashion as does 1 to form A can be gained
by the realization that the resultant anions are species properly viewed as
B-N for CdC isoelectronic replacement analogues of the conjugate bases
of isoquinolin-4(3H)-ones (i.e., enolate anions).
(27) Note Added in Proof: By X-ray crystallographic analysis of the
enzyme-inhibitor complexes, it has recently been shown that 6-like thieno-
fused and benzo-fused 1,2,3-diazaborine antibacterial agents condense with
NAD+ to form species B-like bisubstrate analogue inhibitors of Escherichia
coli enoyl reductase: Baldock, C.; Rafferty, J. B.; Sedelnikova, S. E.; Baker,
P. J.; Stuitje, A. R.; Slabas, A. R.; Hawkes, T. R.; Rice, D. W. Science
1996, 274, 2107-2110.
(28) (a) Brock, C. P.; Minton, R. P.; Niedenzu, K. Acta Crystallogr.
1987, C43, 1775-1779. (b) Yalpani, M.; Boese, R. Chem. Ber. 1983, 116,
3347-3358. (c) Ko¨ster, R.; Angermund, K.; Sporzynski, A.; Serwatowski,
J. Chem. Ber. 1986, 119, 1931-1952.

7822 J. Am. Chem. Soc., Vol. 119, No. 33, 1997
Groziak et al.
Table 3. Selected Bond Lengths (Å) for C7H6BNO2 (1) and
C7H7BN2O (2)
1
2
H(1)-O(1)
O(1)-B(1)
B(1)-C(8a)
B(1)-O/N(2)
O/N(2)-N(3)
N(3)-C(4)
C(4)-C(4a)
C(4a)-C(5)
C(4a)-C(8a)
C(5)-C(6)
C(6)-C(7)
C(7)-C(8)
C(8)-C(8a)
0.86(4)
0.87(2)
1.350(6)
1.533(6)
1.388(6)
1.419(6)
1.283(5)
1.452(6)
1.406(6)
1.394(7)
1.372(7)
1.393(8)
1.380(6)
1.395(6)
1.371(3)
1.530(3)
1.432(3)
1.373(2)
1.291(3)
1.445(3)
1.401(3)
1.406(3)
1.370(3)
1.389(3)
1.375(3)
1.405(3)
Figure 2. ORTEP diagram and atomic numbering scheme for
1-hydroxy-1H-2,3,1-benzoxazaborine, C7H6BNO2 (1).
Table 4. Selected Bond Angles (deg) for C7H6BNO2 (1) and
C7H7BN2O (2)
1
2
O(1)-B(1)-C(8a)
O(1)-B(1)-O/N(2)
B(1)-O(1)-H(1)
O/N(2)-B(1)-C(8a)
O/N(2)-N(3)-C(4)
N(3)-C(4)-C(4a)
N(3)-C(4)-H(4)
N(3)-O/N(2)-B(1)
C(4)-C(4a)-C(5)
C(4)-C(4a)-C(8a)
C(4a)-C(4)-H(4)
C(4a)-C(5)-C(6)
C(4a)-C(8a)-B(1)
C(4a)-C(8a)-C(8)
C(5)-C(4a)-C(8a)
C(5)-C(6)-C(7)
C(6)-C(7)-C(8)
C(7)-C(8)-C(8a)
C(8)-C(8a)-B(1)
122.5(4)
118.0(4)
118(3)
119.4(5)
117.3(4)
127.8(4)
116
121.9(3)
121.1(4)
117.7(4)
116.13
118.9(5)
115.9(4)
118.2(4)
121.2(4)
120.8(4)
119.9(4)
121.0(5)
125.9(5)
128.08(18)
116.68(18)
114.9(15)
115.24(17)
116.74(15)
126.80(19)
117
125.62(15)
120.68(18)
118.62(19)
117
120.07(19)
116.70(17)
117.44(19)
120.69(18)
120.2(2)
120.20(19)
121.35(19)
125.86(18)
Figure 3. ORTEP diagram and atomic numbering scheme for 1,2-
dihydro-1-hydroxy-2,3,1-benzodiazaborine, C7H7BN2O (2).
Table 2. Selected Crystal Data and Structure Refinement for
C7H6BNO2 (1) and C7H7BN2O (2)
1
2
formula
C7H6BNO2
146.94
orthorhombic
Fdd2
C7H7BN2O
145.96
monoclinic
P21/c
Table 5. Selected Torsion Angles (deg) for C7H6BNO2 (1) and
C7H7BN2O (2)
fw, g mol-1
crystal system
space group
1
2
color
a, Å
b, Å
c, Å
colorless
colorless
7.791(2)
7.2907(10)
12.3990(16)
96.33(2)
700.0(2)
1.3850(4)
4
O(1)-B(1)-C(8a)-C(4a)
O(1)-B(1)-C(8a)-C(8)
O(1)-B(1)-O/N(2)-N(3)
B(1)-O/N(2)-N(3)-C(4)
O/N(2)-B(1)-C(8a)-C(4a)
O/N(2)-B(1)-C(8a)-C(8)
O/N(2)-N(3)-C(4)-C(4a)
N(3)-C(4)-C(4a)-C(5)
N(3)-C(4)-C(4a)-C(8a)
C(4)-C(4a)-C(5)-C(6)
C(4)-C(4a)-C(8a)-B(1)
C(4)-C(4a)-C(8a)-C(8)
C(4a)-C(5)-C(6)-C(7)
C(5)-C(4a)-C(8a)-B(1)
C(5)-C(4a)-C(8a)-C(8)
C(5)-C(6)-C(7)-C(8)
C(6)-C(7)-C(8)-C(8a)
C(7)-C(8)-C(8a)-B(1)
C(7)-C(8)-C(8a)-C(4a)
C(8a)-B(1)-O/N(2)-N(3)
C(8a)-C(4a)-C(5)-C(6)
H(1)-O(1)-B(1)-C(8a)
H(1)-O(1)-B(1)-O/N(2)
-176.3(4)
2.1(8)
177.4(4)
-0.3(6)
3.1(7)
-174.3(2)
6.4(3)
174.46(17)
1.7(3)
11.2028(15)
30.390(8)
8.1221(17)
â, deg
5.6(3)
V, Å3
2765.2(10)
1.4119(5)
16
0.040
0.031
-178.5(5)
-173.66(19)
F(calcd), g‚cm-3
1.7(7)
2.2(3)
Z
R
Rw
180.0(15)
-0.5(7)
179.7(5)
-1.9(6)
179.5(4)
0.6(8)
177.7(4)
-0.9(7)
-0.6(8)
-0.1(10)
-177.5(5)
0.9(8)
177.4(2)
-1.5(4)
-176.1(2)
-2.6(3)
176.7(2)
-0.6(3)
178.5(2)
-2.1(3)
-2.1(4)
2.7(3)
178.7(2)
-0.6(3)
-5.5(3)
2.7(3)
0.041
0.029
2.29
goodness-of-fit
2.40
O-B-N-C dihedral angle values of -170.2(4)° and
-174.4(4)°). The 1,2-zwitterionic molecular fragment shown
in Figure 1 is a reasonable model for the aqueous solution
structure of 4. If for the minor 1,2-hydrate aqueous solution
form of 2 or 3 as well, it provides an insight into the structure
of the Lewis conjugate bases derived from these through which
18O isotope acquisition from H218O occurs.
Crystal structure determinations of 1 and 2 were also obtained,
and selected data from these analyses are shown in Figures 2
and 3 and are collected in Tables 2-5. Structures for
comparison with and contrast to 1 include 4-ethyl-1-hydroxy-
3-(4-hydroxyphenyl)-1H-2,1-benzoxaborine (10)29 and 2-formyl-
benzeneboronic acid and its O-methyl oxime 8, both of which
-2.1(7)
0.2(7)
170(4)
-9(4)
6.1(17)
-173.8(17)
have been found to exist in planar, seven-membered ring
intramolecularly hydrogen-bonded form.19 For comparison with
that of 2, the crystal structure determination30 of 6,7-dihydro-
7-hydroxy-6-methylthieno[2,3-d][1,2,3]diazaborine (11, a thio-
phene analogue of 3), is of particular interest. Finally, for both
(29) Arcus, V. L.; Main, L.; Nicholson, B. K. J. Organomet. Chem. 1993,
460, 139-147.

Planar Boron Heterocycles
J. Am. Chem. Soc., Vol. 119, No. 33, 1997 7823
Figure 5. View of intermolecular hydrogen bonding motif of 2.
Figure 4. View of intermolecular hydrogen bonding motif of 1.
Table 6. Hydrogen Bonding Parameters (Å or deg) for C7H6BNO2
(1) and C7H7BN2O (2)
1 and 2, the 6-hydroxypyridazin-3(2H)-one (12)31 ambident
lactam/lactim of maleic hydrazide is seen to provide valuable
comparison data.
D‚‚‚A
D-H
H‚‚‚A
D-H‚‚‚A
O(1)-H(1)‚‚‚N(3) in 1 2.781(4) 0.86(4) 1.95(4)
O(1)-H(1)‚‚‚N(3) in 2 2.810(2) 0.87(2) 1.97(2)
165(5)
161(2)
174
N(2)-H(2)‚‚‚O(1) in 2 3.021(2) 0.95
2.07
1 is shorter than that in 2, and in the latter, this group also
accepts a hydrogen bond from the N2-H unit of a neighbor.
FTIR spectral analyses revealed patterns consistent with the
different hydroxyl-centered solid state hydrogen-bonding motifs
found in 1 and 2. The OH stretch in the 3200-2800 cm-1
region for 1 (as well as for 3) is broad, not unlike that of a
carboxylic acid dimer even though 1 forms infinite hydrogen-
bonded chains and not dimers in the solid state. By contrast,
the FTIR spectrum of 2 shows narrow absorbances at 3330 and
3294 cm-1 assigned to the OH and NH stretches, respectively.
Although the position of the hydrogen atom of the B-OH group
in diazaborine 11 had not been located precisely,30 it is apparent
from the molecular orientations in the projection of the crystal’s
unit cell onto a plane perpendicular to the a axis provided in
the report that its O1-H1 bond vector orientation is the same
as that found for 2 herein. An evaluation of the 2-alkylated
2,3,1-diazaborine 3 by NOESY NMR revealed a through-space
spin-interactive proximity of the B-OH and H8 protons, thereby
providing evidence for such an orientation in solution as well.
Interestingly, though, the D‚‚‚A distance of 2.789(4) Å reported
for 11 is closer to that in 1 rather than in 2.
Solution Hydrogen-Bonding Properties. The coexistence
of a Brønsted acidic B1-OH group and a basic site at N3 in 1
and 2 as evidenced by the solution NMR data and the solid
state X-ray data discussed above suggested that the heterocyclic
peripheries of 1 and 2 would be capable of entering into multiple
hydrogen-bond associations with those of the aglycons of certain
select natural nucleoside partners. Specifically, the hydrogen-
bond complementarity between 1 and guanosine and between
2 and cytidine both appeared reasonable. Experiments with
admixtures of the former pair of partners failed to reveal
evidence of an associative interaction, but those with an
admixture of the latter pair did. VT-NMR spectroscopic
analysis32 (Figure 6 and Figure 7) of a 1:1 admixture (0.4 M in
each component) of 2 and 2′,3′,5′-tri-O-(methoxymethyl)cytidine
in CD3CN solution was conducted, and the effect of temperature
on the chemical shift values for the active hydrogen atoms was
Crystalline 1 and 2 are seen to be planar boron heterocycles
displaying a distinct deformation of angles at the site of
hydroxyl-group ring attachment such that the O1 atom is
distanced from the benzene ring. This feature is more pro-
nounced in 2 than in 1 (as it is more so in 1130 than in 1029)
and cannot be directly related to intermolecular hydrogen-
bonding interactions (Vide infra) as the directionality of the OH
group hydrogen bond donation in 1 and 2 differ. A cursory
comparison of the three bond angles at the boron reveals that
those at 1 and 10 are similar to each other and closely match
their counterparts in the lactim fragment of 12, while those at
2 and 11 are similar to each other and more closely match their
counterparts in the lactam fragment of the pyridazinone.
The C4-N3 double-bond length in each heterocycle is typical
for endocyclic heterocycle imine moieties, but a striking
difference between crystalline 1 and 2 is seen in the position of
the 2-heteroatom relative to its neighbors within the 2,3,1-
benzodiheteraborine ring. The short (1.388(6) Å) B1-O2 and
long (1.419(6) Å) O2-N3 distances in crystalline 1 reveals it
to be more naphthalene-like than 2, wherein the bond length
alternation is reversed. In 2, the B1-N2 distance is long (1.432-
(3) Å) and the N2-N3 short (1.373(2) Å). Since the electron-
deficient boron center is likely better stabilized by the adjacent
nitrogen in 2 than by the endocyclic oxygen in 1 (2,1-azaborines
are generally regarded as being more “boroaromatic” than 2,1-
oxaborines), it might simply require closer proximity to the
2-heteroatom in the latter. Despite this proximity, though, 1
remains the more Brønsted acidic and also the more chemically
reactive under ring transformative conditions.
Both 1 and 2 undergo intermolecular hydrogen-bond associa-
tion in the solid state, as shown in Figures 4 and 5, respectively.
Numerical data for these interactions are shown in Table 6. The
B-OH group intermolecular hydrogen bond to N3 in crystalline
(30) Aurivillius, B.; Lo¨fving, I. Acta Chem. Scand. 1974, B28, 989-
992.
(32) Whitesides, G. M.; Simanek, E. E.; Mathias, J. P.; Seto, C. T.; Chin,
(31) Cradwick, P. D. J. Chem. Soc., Perkin Trans. 2 1976, 1386-1389.
D. N.; Mammen, M.; Gordon, D. M. Acc. Chem. Res. 1995, 28, 37-44.

7824 J. Am. Chem. Soc., Vol. 119, No. 33, 1997
Groziak et al.
1
Figure 6. Effect of temperature (60, 50, 40, 23, 0, -20, and -40 °C, from the top) upon the H NMR spectrum of a 1:1 (0.4 M) admixture of 2
and 2′,3′,5′-tri-O-(methoxymethyl)cytidine in CD3CN solution.
and other neutral solution environments, and thus their peripher-
ies are certainly attractive for the development of planar,
uncharged boron-containing analogues of nitrogen heterocycle
substances. While the B-OH moiety in both 1 and 2 is
characterized by a predominant Brønsted acidity, it retains some
degree of Lewis acidity and thereby creates an ambidency that
is more pronounced in 2 than in 1. The increased electron
deficiency at the boron center of 1 due to its juxtaposition to a
ring oxygen, rather than nitrogen atom enhances the Brønsted
acidity of the appended hydroxyl group to the extent that
significant proton dissociation from this group occurs in neutral
aqueous solution. As a consequence of the resulting oxyanion
development, the boron center in 1 in this medium becomes
less electron-deficient due to charge delocalization and conse-
quently is rendered less reactive as a Lewis acid toward covalent
hydration when compared to that in 2. In short, the members
Figure 7. Effect of temperature upon the 1H NMR chemical shifts of
of the benzo-fused 2,3,1-dihetera subclasses of borine hetero-
the exchangeable protons in a 1:1 (0.4 M) admixture of 2 and 2′,3′,5′-
cycles display a subtle environment-dependent prototropy so
tri-O-(methoxymethyl)cytidine in CD3CN solution. Shift values for the
sensitive that certain past difficulties11j encountered in attempts
B-OH (δ 8.98) and N2-H (δ 6.00) moieties of uncomplexed 2 and
for the 4-NH2 one of uncomplexed 2′,3′,5′-tri-O-(methoxymethyl)-
to delineate their physicochemical properties now become
readily appreciated.
cytidine at room temperature have been marked with an asterisk.
ascertained. By this, evidence of a temperature-dependent
multiple hydrogen-bond association was found. The most likely
structure of a heterodimeric aggregate of 2 and the cytidine
derivative is one in which these partners are held in relative
orientation by three hydrogen bonds constituting both an eight-
and a seven-membered ring, as shown below. No other binary
interactive orientation was deemed to be consistent with the
VT-NMR study results.
In a finding predictive of the physicochemical properties
likely to extend to future 6-hydroxy-1,2,6-oxaza- and 3-hydroxy-
1,2,3-diazaborine-containing compounds, the Brønsted acidic
B-OH group in 1 and 2 is seen to have an excellent and flexible
capability of entering into hydrogen-bonding interactions as a
donor, and in 2, additionally as an acceptor. Both 1 and 2
exhibit solid state intermolecular hydrogen-bonding motifs
containing some of the features present in C‚G DNA base-pair
interactions. The finding that 2 undergoes a hydrogen-bond
association with a tri-O-protected cytidine in CD3CN solution
provides further support for the expectation that boron-contain-
ing peripheries like those in the boron heterocycles 1 and 2
will serve well as “platforms” for the development of close
mimics of biologically derived and/or active nitrogen heterocycle-
based compounds such as the 2-aza-3-deazapurines.
Experimental Section
Conclusions and Implications for Boron Analogue
Development
Compounds 1-3 maintain an sp2-hybridized, trigonal planar-
substituted, neutral boron center in the solid state and in aqueous
General Procedures, Methods, and Materials. Melting points
were determined on a Thomas-Hoover UniMelt capillary apparatus and
are uncorrected. Radial preparative-layer chromatography was per-
formed on a Chromatotron instrument (Harrison Research, Inc., Palo

Planar Boron Heterocycles
J. Am. Chem. Soc., Vol. 119, No. 33, 1997 7825
Alto, CA) using Merck silica gel-60 PF254 as the adsorbent. Flash
column chromatography was performed using 230-400 mesh ASTM
Merck silica gel-60. TLC analyses were performed using Analtech
250 µm silica gel GF Uniplates, and visualizations were done with
short-wave (254 nm) UV light. Lyophilizations were conducted on a
Labconco Lypho-Lock 4.5 L bench-top freeze-dryer. 1H and 13C NMR
spectra were recorded on a Varian VXR-300 (300 and 75 MHz) or
VXR-500 (500 and 125 MHz) instrument. These spectra were recorded
with tetramethylsilane or 2,2-dimethyl-2-silapentane-5-sulfonic acid,
was allowed to warm slowly to room temperature and was kept under
argon overnight. The solution was then treated with excess 2 M HCl
and the layers were separated. The aqueous layer was extracted with
ether (3 × 10 mL), and the ether extracts combined with the original
THF layer. This organic solution was extracted with 2 M NaOH (3 ×
15 mL), and the NaOH extracts were combined before adjustment of
the pH to ca. 3 (2 M HCl). Finally, this acidified aqueous solution
was extracted with ether (3 × 15 mL), and the combined organic
extracts were dried (MgSO4) and were rotary evaporated to give 6.3 g
(68%) of 2-formylbenzeneboronic acid as a white solid, mp 124-126
°C (lit.13 115-123 °C (H2O); lit.5d 118-120 °C (H2O); lit.4c 120-123
°C (H2O); lit.5d dehydrates to anhydride at 110-120 °C, resolidifies at
125-130 °C, (boroxin) melts at 163-165 °C (dec) (H2O)).
1
sodium salt (DSS) (δ ) 0.0 for H), and CDCl3 (δ ) 77.0 for 13C),
(CD3)2SO (δ ) 39.5 for 13C), CD3OD (δ ) 49.0 for 13C), CD3CN (δ
) 1.3 for 13C), or 1,4-dioxane (δ ) 66.5 for 13C) in D2O as internal
reference. Signals from carbons directly attached to a boron atom were
not observed due to strong quadrupolar line-broadening although those
from 15N isotope-enriched nitrogens in a similar setting were observed.
11B NMR spectra were recorded at 96.2 MHz without field frequency
lock on the VXR-300 instrument using nondeuterated solvents and neat
external BF3‚(OEt)2 (δ ) 0.0) as reference. Resonances appearing
downfield of the reference signal were assigned positive values. UV
spectra were recorded on a Shimadzu UV-160U spectrophotometer.
Methanol-d4 (99%) was purchased from Isotec, Inc. [formyl-13C]Ph-
CHO, [15N2]NH2NH2‚H2SO4, and [15N]NH2OH‚HCl were purchased
from Cambridge Isotope Laboratories. Butyllithium in hexanes was
purchased from the Aldrich Chemical Co. and was titrated by the
modified Watson-Eastham procedure.33 Methanol was dried by distil-
lation from Mg(OMe)2 under argon. THF and diethyl ether were dried
by distillation from sodium benzophenone ketyl under argon. N,N,N′-
Trimethylethylenediamine and trimethylborate were dried over and
distilled from CaH2 and Na, respectively, under argon. Estimation of
pKa values were made by potentiometric measurement of pH. Mass
spectral and combustion elemental microanalyses were obtained from
the University of Illinois.
[formyl-13C]-2-Formylbenzeneboronic Acid. A solution of N,N,N′-
trimethylethylenediamine (0.82 mL, 6.40 mmol) in 16 mL of dry THF
at -20 °C was treated dropwise with 4.46 mL of a 1.388 M solution
of n-BuLi in hexanes (6.2 mmol) under argon while stirring. After 30
min, [formyl-13C]benzaldehyde (0.613 mL, 6.0 mmol) was added
dropwise. The reaction mixture was stirred at -20 °C for 30 min, and
then another 12.97 mL of the n-BuLi solution (18.0 mmol) was added
dropwise via syringe. After the reaction was stirred for 24 h at -24
°C (freezer), and then trimethylborate (5.45 mL, 48 mmol) freshly
distilled from Na was added dropwise at -78 °C via syringe over 15
min. The resulting boronation reaction mixture was kept for 24 h at
-78 °C. (After 3 h, it had gelatinized and required brief warming to
ca. -55 °C.) The mixture was then stirred for 40 min from -70 °C
to room temperature, for 40 min at -20 °C, and for 30 min at 0 °C.
The reaction mixture was cooled to -70 °C and was quenched by the
addition of 1.5 N HCl. The layers of the biphasic mixture were
separated, and the top, organic layer was extracted with water. The
aqueous extracts were combined with the former bottom, acidified
aqueous layer, and this was then extracted with CH2Cl2. The organic
extracts were rotary evaporated to give a residue that was treated with
water and distilled until all of the hydrophobic, oily material had either
distilled off or had adhered to the walls of the flask. The aqueous
solution was removed by decanting and its volume was reduced to ca.
1 mL in a beaker on a hot plate. The yellow precipitate that formed
upon cooling was collected by suction filtration and was washed with
a small amount of cold water followed by CH2Cl2 to give 190 mg (32%)
of NMR-pure [formyl-13C]formylbenzeneboronic acid: mp 120-123
°C. This sample was used directly for the synthesis of [4-13C,2,3-15N2]-
2, while the residue (87 mg, 15%) obtained from the aqueous filtrate
was used directly for the synthesis of [4-13C,3-15N]1.
1-Hydroxy-1H-2,3,1-benzoxazaborine (1). Dewar’s modification4c
of Snyder’s procedure5f was used to prepare 1 in a 99% yield: mp
262-265 °C (H2O) (lit.5f 150-155 °C (H2O); lit.4c 264-265 °C with
slow heating, phase change at 164 °C (H2O); lit.5b 148-150 °C with
slow heating, decomposition (bubbling) at 158 °C, then resolidification
at 164 °C (H2O)). Low-resolution ACE-mass spectra: EI, m/e 276.1
([2M - H2O]+, 86%), 147.1 (M+, 84%); CI, m/e 277.1 ([2M - H2O]-
H+, 71%), 148.1 (MH+, 100%). pKa 4.8.
[4-13C,2-15N]1. A solution of 87 mg (0.6 mmol) of [formyl-13C]-
formylbenzeneboronic acid in 4 mL of H2O was treated with 133 mg
(1.89 mmol) of [15N]NH2OH‚HCl and was adjusted to pH 4 by the
addition of 1 N NaOH, producing a copious yellow precipitate. The
reaction mixture was stirred with heating (steam bath) for 1 h, and
upon cooling to room temperature, the precipitate was collected by
suction filtration and washed with cold water and then CH2Cl2 to afford
130 mg (90%) of [4-13C,2-15N]1 as a white solid.
Crystallographic Data Collections and Structure Determinations.
Data Collection. X-ray quality crystals of 1 were obtained via slow
evaporation of an EtOAc solution. Those of 2 were obtained in a
similar fashion from CH3CN. Each suitable crystal was mounted on a
glass fiber with epoxy, and data were collected by a Rigaku AFC-5S
diffractometer with graphite monchromated Mo KR radiation. The
incident beam collimator was 1.0 mm, the crystal to detector distance
was 285 mm, and the detector aperture was 6.0 × 6.0 mm. Cell
constants and an orientation matrix for data collection, obtained from
a least-squares refinement using the setting angles of 25 carefully
centered reflections, corresponded to the cells with dimensions listed
in Table 2, where details of the data collection are summarized. The
weak reflections (I < 10σ(I)) were rescanned (maximum of four
rescans), and the counts were accumulated to assure good counting
statistics. Stationary background counts were recorded on each side
of the reflection. The ratio of peak counting time to background
counting time was 2:1.
Data Reduction. The intensities of three representative reflections
were measured after every 100 reflections. No decay correction was
applied. The data were corrected for Lorentz and polarization effects.
Structure Determination and Refinement. The structures of 1
and 2 were solved by direct methods and expanded using Fourier
techniques. Measured nonequivalent reflections with I > 1.5σ(I) were
used for the structure determinations. The non-hydrogen atoms were
refined with anisotropic displacement factors. Those hydrogen atoms
not refined with isotropic displacement factors were included in fixed
positions. All calculations were performed using a TEXSAN crystal-
lographic software package of the Molecular Structure Corp.
1-Methoxy-1H-2,3,1-benzoxazaborine (9). A solution of 1 (0.5
g, 3.4 mmol) in 1.5 mL of methanol was heated at reflux for a short
time and then was allowed to cool to room temperature. The crystals
that deposited were collected by suction filtration to afford 0.45 g (81%)
of 1-methoxy-1H-2,3,1-benzoxazaborine: mp 90.5-92 °C. 1H NMR
(CDCl3): δ 8.40 (s, 1H, CH), 8.05 (d, J ) 7.5 Hz, 1H, PhH), 7.76-
7.65 (m, 2H, PhH), 7.55 (d, 1H, PhH). Low-resolution ACE-mass
spectra: EI, m/e 161.7 (M+, 3%), 146.3 (M+ - CH3, 100%); CI, m/e
162.7 (MH+, 32%), 147.1 (MH+ - CH3, 64%), 122.3 (100%). High-
resolution EI-mass spectrum: m/e 161.064 923 (C8H8B1NO2 requires
161.064 809).
2-Formylbenzeneboronic Acid. A flask containing magnesium
turnings (1.53 g, 63 mmol) was flame-dried under argon and then was
charged with 150 mL of THF and 0.1 mL of 1.6 M MeMgBr in THF.
2-(2-Bromophenyl)-1,3-dioxolane14 (14.2 g, 62 mmol) was then added
at room temperature dropwise with stirring. After 30 min, the reaction
mixture was heated at reflux for 4 h. The resulting Grignard reagent
solution was cooled to 0 °C and was transferred under positive argon
pressure to a precooled -78 °C stirred solution of freshly distilled
B(OMe)3 (7.27 g, 70 mmol) in THF (150 mL). After 4 h, the mixture
1,2-Dihydro-1-hydroxy-2,3,1-benzodiazaborine (2). The condi-
tions in the literature procedure of Dewar4c were modified slightly (95%
(33) Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9, 165-
168.

7826 J. Am. Chem. Soc., Vol. 119, No. 33, 1997
Groziak et al.
EtOH, reflux, 2 h) to give 2 in an 83% yield: mp 236-238 °C (H2O)
(lit.4c,d mp 243-243.5 °C (H2O), referred to as the anhydride). Low-
resolution ACE-mass spectra: EI, m/e 274.1 ([2M - H2O]+, 6%), 146.1
(M+, 100%); CI, m/e 275.2 ([2M - H2O]H+, 2%), 147.1 (MH+, 100%).
pKa 7.7.
From 1. A mixture of 1 (100 mg, 0.68 mmol) and NH2NH2 (47
µL of 97%, 1.5 mmol) in 10 mL of distilled H2O was heated at reflux
for 8 h, by which time 1 had been consumed (TLC analysis). The
clear solution was allowed to cool to room temperature slowly, and
the needle-like crystals of 2 (39 mg) that deposited were collected by
filtration: mp 235-237 °C. The filtrate was concentrated and the
residue obtained was purified by column chromatography using MeOH
as eluent to afford an additional 15 mg of 2 as a white solid, for a
combined yield of 54%. The 1H NMR spectrum was identical to that
of 2 obtained as described above.
and MeNHOH‚HCl (167 mg, 2.0 mmol) in 10 mL of 50% aqueous
EtOH was adjusted to pH 7 by the addition of 1 N NaOH, and the
reaction mixture was kept at room temperature for 12 h. The solvent
was then removed by rotary evaporation at 50 °C to give an oil which
was dissolved in 5 mL of MeOH and suction filtered to remove
insolubles. Rotary evaporation gave a residue which was dissolved in
5 mL of water and rotary evaporated again to give a white solid. This
solid was washed several times with (CH3)2CO and dried in air to give
320 mg (99%) of 7: mp 245-246 °C (lit.18 239 °C). The solid was
dried in vacuo (Abderhalden, P2O5, 56 °C). pKa 5.1. 1H NMR (D2O):
δ 8.51 (s, 1H, H4), 7.76-7.45 (m, 4H, PhH), 3.91 (s, 3H, 3-Me); 13C
NMR (D2O): δ 150.7 (C4), 138.5, 133.0, 132.8, 131.0, 130.0, 51.9
(3-Me). An aqueous solution of 50 mg of the dry solid in 2 mL of
H2O was lyophilized to furnish a white powdery solid: mp 241-243
°C. 1H NMR ((CD3)2SO): δ 8.79 (s, 1H, H4), 8.04-7.35 (m, 4H,
PhH). 1H NMR (CDCl3): δ 8.19 (s, 1H, H4), 7.97-7.33 (m, 4H, PhH).
2′,3′,5′-Tri-O-(methoxymethyl)cytidine. This compound was pre-
pared from cytidine in a 68% yield according to a method35 developed
for the preparation of the corresponding tri-O-protected uridine: mp
140-140.5 °C. 1H NMR ((CD3)2SO): δ 7.73 (d, J ) 7.45 Hz, 1H,
H6), 7.22 (m, exchanges with D2O, 2H, NH2), 5.88 (d, J ) 4.05 Hz,
1H, H1′), 5.74 (d, J ) 7.45 Hz, 1H, H5), 4.7-4.6 (m, 6H, three CH2-
OCH3), 4.2-4.1 (m, 3H, H2′, H3′, and H4′), 3.70 (m, 2H, 5′-CH2),
3.3 (s, 6H, two CH2OCH3), 3.28-3.21 (2s, 3H, CH2OCH3). ACE-
mass spectrum: CI, m/e 376.2 (MH+). Anal. Calcd for C15H25N3O8:
C, 48.00; H, 6.71; N, 11.19. Found: C, 47.71; H, 6.80; N, 11.63.
Isotope Acquisition by 1 and 2 from H218O. A solution of 5 mg
of 1 or 2 in 0.5 mL of dry CH3CN was treated with 0.1 mL of H218O,
and the clear solution was kept at 69-75 °C under argon for 12 h. The
solution was allowed to cool to room temperature, and the volatiles
were removed by slow evaporation under a gentle argon flow. The
yellow crystalline solids obtained were analyzed by low-resolution
ACE-MS. The spectra of material derived from 1 revealed little 18O
isotope incorporation, but that from 2 showed essentially complete
incorporation: EI, m/e 148.1 ([18O]2 M+, 100%); CI, m/e 149.1 ([18O]-
2 MH+, 100%). When another 5 mg sample of 1 was subjected to the
above conditions for 36 h, low-resolution ACE-MS analysis of the
derived material revealed ca. 50% isotope incorporation: EI, m/e 149
([18O]1 M+, 84%), 147.1 (1 M+, 81%); CI, m/e 150 ([18O]1 MH+,
100%), 148.1 (1 MH+, 89%). A careful analysis of the low intensity
(1%) [2M - H2O]+ peaks present in the 274-280 amu region revealed
a similar degree of isotope incorporation in the anhydro dimer species,
thereby eliminating the possibility that the single isotopic enrichment
in 1 was due to the hydrolysis of a singly isotope-enriched anhydro
dimer by propitious unenriched water during handling.
From 6. A solution of 6 (100 mg, 0.33 mmol) in 5 mL of 95%
ethanol was treated with NH2NH2 (22 µL of 97%, 0.7 mmol). The
reaction mixture was heated at reflux for 12 h, by which time 6 had
been consumed (TLC analysis). The reaction mixture was rotary
evaporated to near dryness, and the residue was purified by radial
chromatography using 1:3:16 MeOH/hexanes/CH2Cl2 as eluent to afford
1
31 mg (65%) of 2 as a light yellow solid: mp 228-232 °C. The H
NMR spectrum was identical to that of 2 obtained as described above.
[4-13C,2,3-15N2]2. An ice-cooled, stirred solution of 100 mg (2.52
mmol) of NaOH in 0.5 mL of H2O was treated sequentially with 167
mg (1.26 mmol) of [15N]NH2NH2‚H2SO4, 3 mL of EtOH, and 95 mg
(0.629 mmol) of [formyl-13C]formylbenzeneboronic acid. The reaction
mixture was heated at reflux for 3 h and was then diluted by the addition
of 4 mL of H2O. The volume of solution was then reduced to ca. 1
mL, and upon cooling to room temperature a white solid was produced.
This solid was collected by suction filtration and was washed
successively with cold water and CH2Cl2 afforded 80 mg (86%) of
[4-13C,2,3-15N2]2.
1,2-Dihydro-1-hydroxy-2-methyl-2,3,1-benzodiazaborine (3). Dew-
ar’s procedure4c was used to prepare 3 in a 79% yield: mp 159-161
°C (aqueous EtOH) (lit.4c 154-156 °C with resolidification and
remelting at 168 °C (aqueous EtOH)). pKa 8.1. Compound 3 in (CD3)2-
SO solution was analyzed by COSY and NOE NMR, permitting the
following spectral assignments to be made: 8.51 (s, 1H, OH), 8.27 (d,
1H, H8), 8.00 (s, 1H, H4), 7.74-7.68 (m, 2H, H5 and H6), 7.59 (t,
1H, H7), 3.52 (s, 3H, NMe). COSY interactions included H4/H5, H6/
H7, and H7/H8; NOE ones included OH/H8 and H4/H5.
Bis-(8-B-4)-1,3,5-tris[2-[(dimethylhydrazono)methyl]phenyl]-
boroxin (5) and (8-B-4)-[2-[(Dimethylhydrazono)methyl]phenyl]-
dihydroxyboron (4). A solution of 2-formylbenzeneboronic acid (500
mg, 3.3 mmol) and 1,1-dimethylhydrazine (0.42 mL, 5.4 mmol) in 2.0
mL of 95% EtOH was treated with concentrated HCl (0.1 mL). The
reaction mixture was stirred at room temperature for 5 h, and the white
crystalline product that deposited was collected and was washed
successively with water, 95% EtOH, Me2CO, and then Et2O to give
500 mg (88%) of 5: mp 227-229 °C (Me2CO). Low-resolution ACE-
mass spectrum: EI, m/e 522.4 (40%, M+), CI, m/e 522.4 (100%, M+).
A stirred suspension of 5 in D2O kept at 25 °C for 24 h produced
(8-B-4)-[2-[(dimethylhydrazono)methyl]phenyl]dihydroxyboron (4) by
1H NMR. A sample of 5 in H2O heated at reflux for 24 h produced
B(OH)3 (11B NMR) and PhCHdNNMe2 (1H NMR and TLC).
1,2-Dihydro-1-hydroxy-2-(4-methylbenzenesulfonyl)-2,3,1-benzo-
diazaborine (6). A dry (Abderhalden, P2O5, 110 °C, 3 d) sample of
the p-toluenesulfonylhydrazone of 2-bromobenzaldehyde was subjected
to conditions of Sharp and Skinner16 to afford 6 in a 93% yield: mp
159-161 °C (lit.34 156-158 °C).
Acknowledgment. This work was supported by grant
GM44819 from the National Institutes of Health. Mr. John M.
Merrill, an Undergraduate NIGMS Summer Scholar in 1993,
prepared some of the boron heterocycles for this study. Ms.
Colleen Lawler, another Undergraduate researcher, prepared and
characterized the 2′,3′,5′-tri-O-(methoxymethyl)cytidine. This
article is dedicated to Dr. Nelson J. Leonard, California Institute
of Technology, Pasadena, CA, on the occasion of his 80th
birthday.
Supporting Information Available: Selected FTIR data for
1-3 and 5, multisolvent UV data for 1-5, full crystal data and
data collection parameters, and positional and thermal param-
eters for 1 and 2 (3 pages). See any current masthead page for
ordering and Internet access instructions.
1,2-Dihydro-1,1-dihydroxy-3-methyl-1H-2,3,1-benzoxazaborine
(7). A mixture of 2-formylbenzeneboronic acid (200 mg, 2.0 mmol)
JA963784I
(34) Mu¨ller, B. W. HelV. Chem. Acta 1978, 61, 325-327.
(35) Groziak, M. P.; Koohang, A. J. Org. Chem. 1992, 57, 940-944.