Reaction of hydantoin with boronic acids

Article abstract of DOI:10.1002/hlca.201000022

We have examined the reaction of hydantoin (=imidazolidine-2,4-dione) with (formylphenyl)boronic acids, where the addition of a boronic acid group is hoped to increase bioactivities. Addition of (2-formylphenyl)boronic acid to hydantoin gave an unexpected azaborine compound, which presumably arises by initial formation of the (phenylmethylidene)hydantoin, with subsequent loss of H₂O to give the cyclized product. Reactions of (3-formylphenyl)- and (4-formylphenyl)boronic acids with hydantoin gave the corresponding [(Z)-phenylmethylidene]hydantoins in good-to-excellent yields. Attempts to use (3-formylthiophen-2-yl)boronic acid gave a product where the boronic acid group has been cleaved.

Full text of DOI:10.1002/hlca.201000022

Helvetica Chimica Acta – Vol. 93 (2010)
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Reaction of Hydantoin with Boronic Acids
by Erin A. Gwynnea), Jenna C. Holta), Jerrod R. Dwana), Francis E. Appoha),
Christopher M. Vogelsa), Andreas Deckenb), and Stephen A. Westcott*a)
a) Department of Chemistry and Biochemistry, Mount Allison University, Sackville, NB E4L 1G8,
Canada (phone: þ 1-506-364-2372; fax: þ 1-506-364-2313; e-mail: swestcott@mta.ca)
b) Department of Chemistry, University of New Brunswick, Fredericton, NB E3B 5A3, Canada
We have examined the reaction of hydantoin (¼ imidazolidine-2,4-dione) with (formylphenyl)bor-
onic acids, where the addition of a boronic acid group is hoped to increase bioactivities. Addition of (2-
formylphenyl)boronic acid to hydantoin gave an unexpected azaborine compound, which presumably
arises by initial formation of the (phenylmethylidene)hydantoin, with subsequent loss of H2O to give the
cyclized product. Reactions of (3-formylphenyl)- and (4-formylphenyl)boronic acids with hydantoin
gave the corresponding [(Z)-phenylmethylidene]hydantoins in good-to-excellent yields. Attempts to use
(3-formylthiophen-2-yl)boronic acid gave a product where the boronic acid group has been cleaved.
Introduction. – There has been recent considerable interest in compounds
containing boronic acids, HB(OH)2, or boronate esters, HB(OR)2, as synthons in
the Suzuki – Miyaura cross-coupling reaction [1] and as molecular sensors [2]. These
remarkable compounds are also being examined for their potential biological activities
[3]. For instance, a-aminoboronic acid derivatives are well-known for their ability to
act as serine protease inhibitors. Indeed, bortezomib (aka PS-341 and Velcade; Fig. 1) is
a boronic acid dipeptide that potently, selectively, and reversibly inhibits 26S
proteasome and was developed specifically for the therapy of human tumors [4].
Studies at the National Cancer Institute have shown that bortezomib inhibited
proliferation at a mean IC50 value of 7 nm in 60 cell lines. B-Containing amino acid
derivatives have also been investigated for their use in boron neutron capture therapy
for the treatment of cancer [5]. Unfortunately, the preparation of amino acids
containing boron is somewhat limited due to the sensitive nature and incompatibility of
the Lewis-acidic boronic acid group with many synthetic methods. In an elegant study,
Kabalka and co-workers reported the hydroboration of hydantoin derivatives as a
precursor to amino acids (Scheme 1) [6].
Hydantoins (¼ imidazolidine-2,4-diones), a class of cyclic imides, are an interesting
family of compounds with potent pharmacological properties, including antitumor,
Fig. 1. Bortezomib
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 93 (2010)
Scheme 1
fungicidal, herbicidal, anti-inflammatory, anti-HIV, and antihypertensive activities
[7][8]. A number of (phenylmethylidene)hydantoins, prepared by the base-catalyzed
condensation of hydantoins with substituted benzaldehydes, possess good anticonvul-
sant activity and are being examined as a potential treatment for epilepsy [8] as well as
prostate cancer [9]. As part of our ongoing investigation into preparing novel
antifungal boron compounds [10], and considering the bioactivities found in
hydantoins, we decided to examine the reactions of hydantoin with B-containing
(formylphenyl)boronic acids, where the addition of a boronic acid group is expected to
increase bioactivities.
Results and Discussion. – Reactions were conducted in H2O using a catalytic
amount of Et3N [11], and all new compounds have been prepared in good-to-excellent
yields and characterized by a number of physical methods including multinuclear NMR
spectroscopy. Interestingly, we have found that addition of (2-formylphenyl)boronic
acid to hydantoin gave the unexpected fused azaborine 1. Compound 1 presumably
arises by initial formation of the (phenylmethylidene)hydantoin, with subsequent loss
of H2O to give the cyclized product (Scheme 2). Related diazaborines are remarkable
compounds that display potent activity against a number of Gram-negative bacteria as
well as malaria [12]. A broad peak at around 30 ppm in the 11B-NMR spectra for 1
suggests that the B-atom lies in a three-coordinate environment in solution [13]. These
results were confirmed by a single-crystal X-ray diffraction study (Fig. 2 and Table 1).
The bond distances of B(4)ꢀN(3A) 1.435(4) ꢂ, B(4)ꢀO(3) 1.366(4) ꢂ, and
B(4)ꢀC(4A) 1.546(4) ꢂ are typical for those observed in related structures where
the B-atom is three-coordinate [14] (Table 2).
Scheme 2

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Fig. 2. ORTEP Plot of 1 with H-atoms omitted for clarity (50% probability ellipsoids)
Table 1. Crystallographic Data-Collection Parameters
Complex
1
2
Formula
Molecular weight
Crystal system
Space group
a [ꢂ]
b [ꢂ]
c [ꢂ]
a [8]
b [8]
C10H7BN2O3
213.99
C10H9BN2O4 · Me2SO
310.13
monoclinic
P2(1)/c
7.218(6)
19.423(15)
6.787(5)
90
106.098(11)
90
914.1(12)
4
triclinic
ꢀ
P1
8.7386(12)
8.9309(12)
9.3512(13)
83.920(2)
79.177(2)
83.418(2)
709.43(17)
2
g [8]
V [ꢂ3]
Z
1calc. [mg mꢀ3
]
1.555
1.452
Crystal size [mm3]
Temp. [K]
0.40 ꢁ 0.10 ꢁ 0.025
0.40 ꢁ 0.20 ꢁ 0.13
173(1)
173(1)
Radiation
MoKa (l ¼ 0.71073)
0.115
MoKa (l ¼ 0.71073)
0.250
m [mmꢀ1
]
Total reflections
3512
4831
Total unique reflections
No. of variables
3512
147
3072
250
q Range [8]
2.10 to 27.50
0.315/ ꢀ 0.305
1.026
0.0633
0.1844
2.23 to 27.49
0.403/ ꢀ 0.227
1.068
0.0326
0.0928
Largest difference peak/hole [e ꢂꢀ3
S (GoF) on F2
]
R1a) (I > 2s(I))
wR2b) (all data)
b
a) R1 ¼ S jj Fo jꢀj Fc jj /S j Fo j . ) wR2 ¼ (S[w(Fo2 ꢀ Fc2 )2]/S[wF4o])1/2, where w ¼ 1/[s2(F2o ) þ (0.0912 · P)2]
(1) and 1/[s2(Fo2 ) þ (0.0459 · P)2 þ (0.2821 · P)] (2), where P ¼ (max (Fo2, 0) þ 2 · F2c )/3.
Reactions of (3-formylphenyl)- and (4-formylphenyl)boronic acids with hydantoin
gave the corresponding (phenylmethylidene)hydantoins 2 – 5 in good-to-excellent

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Helvetica Chimica Acta – Vol. 93 (2010)
Table 2. Intramolecular Bond Distances and Bond Angles in Molecule 1
Bond distance [ꢂ]
Bond angle [8]
C(1)ꢀO(1)
1.218(3)
1.372(3)
1.484(4)
1.384(3)
1.213(3)
1.404(3)
1.400(3)
1.435(4)
1.366(4)
1.546(4)
1.465(4)
1.349(3)
O(1)ꢀC(1)ꢀN(2)
126.8(2)
128.4(2)
104.7(2)
112.7(2)
128.6(2)
124.9(2)
106.5(2)
109.5(2)
122.2(2)
128.3(2)
121.9(3)
122.8(2)
115.3(3)
118.2(2)
122.8(3)
119.1(2)
C(1)ꢀN(2)
O(1)ꢀC(1)ꢀC(9A)
N(2)ꢀC(1)ꢀC(9A)
C(1)ꢀN(2)ꢀC(3)
C(1)ꢀC(9A)
N(2)ꢀC(3)
C(3)ꢀO(2)
O(2)ꢀC(3)ꢀN(2)
C(3)ꢀN(3A)
N(3A)ꢀC(9A)
N(3A)ꢀB(4)
B(4)ꢀO(3)
O(2)ꢀC(3)ꢀN(3A)
N(2)ꢀC(3)ꢀN(3A)
C(9A)ꢀN(3A)ꢀC(3)
C(9A)ꢀN(3A)ꢀB(4)
C(3)ꢀN(3A)ꢀB(4)
O(3)ꢀB(4)ꢀN(3A)
O(3)ꢀB(4)ꢀC(4A)
N(3A)ꢀB(4)ꢀC(4A)
C(5)ꢀC(4A)ꢀC(8A)
C(5)ꢀC(4A)ꢀB(4)
C(8A)ꢀC(4A)ꢀB(4)
B(4)ꢀC(4A)
C(8A)ꢀC(9)
C(9)ꢀC(9A)
yields (Scheme 2). Although geometric isomers ((E)- and (Z)-isomers) are possible
due to restricted rotation about the exocyclic C¼C bond, the 1H-NMR spectra for 2 – 5
showed the diagnostic alkene peak at d 6.39 – 6.66 ppm, suggesting that these
complexes are in the (Z)-form [15]. The H-atoms in the (Z)-form are deshielded
with respect to their (E)-isomers (observed at d 6.20 – 6.30 ppm) owing to the
anisotropic effect exerted by the nearby C¼O group. Of interest is the observation that
the IR spectra for 2 – 5 shows the stretching of the C¼C bond appearing between
1666 – 1637 cmꢀ1, compared to those expected for the (E)-isomers, which appear at
somewhat lower frequencies (1640 – 1630 cmꢀ1). To confirm the formation of (Z)-
derivatives of hydantoin in these reactions, we carried out an X-ray study on 2
(Table 1), and the molecular diagram of the expected (Z)-isomer is shown in Fig. 3.
Fig. 3. ORTEP Plot of 2 with H-atoms and the molecule of DMSO omitted for clarity (50% probability
ellipsoids)

Helvetica Chimica Acta – Vol. 93 (2010)
1097
Bond distances and angles are consistent with those in related systems [16] (Table 3).
The molecules form chains via H-bonding between adjacent boronic acid groups [17],
and the OH and NH bonds of the hydantoin groups. These chains are further linked by
H-bonding with the DMSO solvent molecules.
Table 3. Intramolecular Bond Distances and Bond Angles in Molecule 2
Bond distance [ꢂ]
Bond angle [8]
B(1)ꢀO(3)
B(1)ꢀO(4)
B(1)ꢀC(8)
N(1)ꢀC(2)
N(1)ꢀC(3)
N(2)ꢀC(3)
N(2)ꢀC(4)
O(1)ꢀC(2)
O(2)ꢀC(3)
C(4)ꢀC(5)
C(5)ꢀC(6)
1.356(2)
1.366(2)
1.577(2)
1.3620(19)
1.3933(19)
1.3745(19)
1.3951(18)
1.2249(18)
1.2120(18)
1.341(2)
O(3)ꢀB(1)ꢀO(4)
O(3)ꢀB(1)ꢀC(8)
O(4)ꢀB(1)ꢀC(8)
C(2)ꢀN(1)ꢀC(3)
C(3)ꢀN(2)ꢀC(4)
O(1)ꢀC(2)ꢀN(1)
O(1)ꢀC(2)ꢀC(4)
N(1)ꢀC(2)ꢀC(4)
O(2)ꢀC(3)ꢀN(2)
O(2)ꢀC(3)ꢀN(1)
N(2)ꢀC(3)ꢀN(1)
C(5)ꢀC(4)ꢀN(2)
C(5)ꢀC(4)ꢀC(2)
N(2)ꢀC(4)ꢀC(2)
C(4)ꢀC(5)ꢀC(6)
119.29(14)
118.22(13)
122.45(13)
111.65(12)
111.12(12)
127.05(14)
127.20(13)
105.75(12)
127.28(14)
126.24(14)
106.49(12)
134.22(14)
120.83(13)
104.94(12)
132.15(13)
1.459(2)
Attempts to use (3-formylthiophen-2-yl)boronic acid did not lead to the expected
B-containing hydantoin, but to compound 6, where the boronic acid group has been
cleaved during the course of the reaction (Scheme 3). Although it is unclear at this time
what causes this unusual reactivity, thiophene analogues of diazaborinines are known
to decompose rapidly in air [14]. Reactions of other (formylthiophenyl)boronic acid
also lead to deboronated products.
Scheme 3
In conclusion, we have presented a convenient route to B(OH)-containing
hydantoin derivatives which are valuable precursors to phenylalanines, amino acids
that are well-known as interesting compounds in cancer research. Further work from
our group will examine the biological activity of these unusual compounds, and the
results will be published in due course.
Thanks are gratefully extended to the Canada Research Chairs Program, Canadian Foundation for
Innovation-Atlantic Innovation Fund, Merck Frosst Canada & Co., and Mount Allison University for
financial support. We also thank Roger Smith and Dan Durant for expert technical assistance and
anonymous reviewers for very helpful comments.

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Experimental Part
General. Reagents and solvents used were obtained from Aldrich Chemicals. M.p.: Mel-Temp
apparatus; uncorrected. IR Spectra: Mattson Genesis II FT-IR spectrometer; reported in cmꢀ1. NMR
Spectra: JEOL JNM-GSX270 FT spectrometer; 1H-NMR chemical shifts are reported in ppm and
referenced to residual solvent H-atoms in deuterated solvent at 270 MHz; 11B-NMR chemical shifts are
reported in ppm and are referenced to BF3 · OEt2 as an external standard at 87 MHz; 13C-NMR chemical
shifts are reported in ppm and referenced to solvent C-atom resonances as internal standards at 68 MHz;
and 19F-NMR chemical shifts are reported in ppm and are referenced to CF3CO2H as an external
standard at 254 MHz; ov. ¼ overlapping. Microanalyses for C, H, and N: Vario EL III.
General Procedure. Hydantoin (¼ imidazolidine-2,4-dione) was dissolved in hot H2O, and the pH
was adjusted to 7 by the addition of NaHCO3. An EtOH soln. of the appropriate boronic acid (1:1 molar
ratio) and a catalytic amount of Et3N (1 mol-%) were added, and the soln. was heated at reflux for 72 h.
Upon cooling to r.t., a white precipitate formed and was collected by suction filtration to afford the
desired product.
5-Hydroxyimidazo[1,5-b][2,1]benzazaborine-1,3(2H,5H)-dione (1). Yield: 93%. M.p. 344 – 3478
(dec.). IR (nujol): 3744, 3459, 3201, 2928, 2854, 2724, 2359, 2335, 1828, 1771, 1708, 1645, 1542, 1449, 1340,
1
1226, 1180, 1088, 1052, 1027, 993, 959, 893, 830, 774, 703, 663, 564. H-NMR ((D6)DMSO): 11.70 (br. s,
NH); 9.05 (br. s, BOH); 8.20 (d, J ¼ 7.4, 1 arom. H); 7.78 (d, J ¼ 7.4, 1 arom. H); 7.66 (ov. dd, J ¼ 7.4, 1
arom. H); 7.51 (ov. dd, J ¼ 7.4, 1 arom. H); 7.13 (s, C¼CH). 11B-NMR (THF): 29. 13C{1H}-NMR
((D6)DMSO): 164.8; 156.7; 140.4; 133.8; 132.6; 130.6; 130.2; 130 (br., CꢀB); 128.7; 110.2. Anal. calc. for
C10H7BN2O3 (214.00): C 56.12, H 3.30, N 13.09; found: C 56.43, H 3.42, N 12.91.
3-[(Z)-(2,5-Dioxoimidazolidin-4-ylidene)methyl]phenylboronic Acid (2). Yield: 85%. M.p. 302 –
3058 (dec.). IR (nujol): 3334, 3246, 3180, 3062, 2929, 2913, 2858, 2359, 2335, 1764, 1724, 1660, 1597,
1
1423, 1396, 1352, 1265, 1205, 1066, 1024, 871, 790, 685, 651. H-NMR ((D6)DMSO): 11.30 (br. s, NH);
10.39 (br. s, NH); 8.19 (s, B(OH)2); 7.86 (s, 1 arom. H); 7.70 (d, J ¼ 7.7, 1 arom. H); 7.61 (d, J ¼ 7.7, 1 arom.
H); 7.36 (t-like, J ¼ 7.7, 1 arom. H); 6.39 (s, C¼CH). 11B-NMR (THF): 26. 13C{1H}-NMR ((D6)DMSO):
166.2, 156.4, 135.5 (br., CꢀB), 134.9, 134.5, 132.7, 132.2, 128.8, 128.3, 109.2. Anal. calc. for C10H9BN2O4
(232.02): C 51.76, H 3.92, N 12.08; found: C 51.43, H 4.15, N 12.22.
4-Methoxy-3-[(Z)-(2,5-dioxoimidazolidin-4-ylidene)methyl]phenylboronic Acid (3). Yield: 85%.
M.p. 264 – 2668 (dec.). IR (nujol): 3405, 3231, 3135, 3069, 2925, 2753, 2357, 2334, 1752, 1713, 1666, 1560,
1503, 1400, 1338, 1251, 1191, 1144, 1098, 1023, 875, 740, 711, 652, 597. 1H-NMR ((D6)DMSO): 10.23 (br. s,
NH); 8.07 (br. s, B(OH)2); 7.79 (s, 1 arom. H); 7.72 (d, J ¼ 8.2, 1 arom. H); 7.03 (d, J ¼ 8.2, 1 arom. H);
6.66 (s, C¼CH); 3.85 (s, MeO). 11B-NMR (THF): 27. 13C{1H}-NMR ((D6)DMSO): 166.2; 159.5; 156.3;
137.3; 134.7; 128.2; 126 (br., CꢀB); 121.6; 111.2; 103.4; 56.3. Anal. calc. for C11H11BN2O5 (262.05): C
50.41, H 4.24, N 10.69; found: C 50.65, H 4.03, N 11.02.
4-[(Z)-(2,5-Dioxoimidazolidin-4-ylidene)methyl]phenylboronic Acid (4). Yield: 85%. M.p. 282 –
2858 (dec.). IR (nujol): 3459, 3155, 2943, 2906, 2860, 2724, 2360, 2341, 1711, 1637, 1462, 1377, 1194,
1103, 1022, 877, 844, 764. 1H-NMR ((D6)DMSO): 11.29 (br. s, NH); 10.58 (br. s, NH); 8.15 (s, B(OH)2);
7.80 (d, J ¼ 7.4, 2 arom. H); 7.56 (d, J ¼ 7.4, 2 arom. H); 6.39 (s, C¼CH). 11B-NMR (THF): 28. 13C{1H}-
NMR ((D6)DMSO): 166.2; 156.3; 135.2 (br., CꢀB); 135.1; 135.0; 129.0; 128.9; 109.0. Anal. calc. for
C10H9BN2O4 (232.02): C 51.76, H 3.92, N 12.08; found: C 52.03, H 4.23, N 11.89.
3-Fluoro-4-[(Z)-(2,5-dioxoimidazolidin-4-ylidene)methyl]phenylboronic Acid (5). Yield: 92%. M.p.
300 – 3028 (dec.). IR (nujol): 3732, 3563, 3461, 3275, 3173, 3056, 2978, 2930, 2854, 2728, 2360, 2342, 1765,
1714, 1657, 1633, 1556, 1508, 1429, 1370, 1305, 1249, 1154, 1105, 1054, 1019, 898, 819, 766, 676, 595.
1H-NMR ((D6)DMSO): 11.38 (br. s, NH); 10.64 (br. s, NH); 8.32 (s, B(OH)2); 7.71 – 7.54 (ov. m, 3 arom.
H); 6.42 (s, C¼CH). 11B-NMR (THF): 28. 13C{1H}-NMR ((D6)DMSO): 165.8; 160.1 (d, J(C,F) ¼ 246,
CꢀF); 156.1; 137.9 (br., CꢀB); 130.8 (d, J(C,F) ¼ 3, Ar); 130.5; 129.3; 122.8 (d, J(C,F) ¼ 12, Ar); 120.7
(d, J(C,F) ¼ 19, Ar); 99.4 (d, J(C,F) ¼ 6, Ar). 19F-NMR ((D6)DMSO): ꢀ 118.0. Anal. calc. for
C10H8BFN2O4 (250.01): C 48.04, H 3.23, N 11.21; found: C 48.42, H 3.47, N 11.37.
5-[(Z)-(Thiophen-3-yl)methylidene]imidazolidine-2,4-dione (6). Yield: 64%. M.p. 260 – 2638 (dec.).
IR (nujol): 3732, 3524, 3455, 3280, 3108, 3014, 2750, 2358, 2050, 1737, 1711, 1658, 1519, 1395, 1351, 1246,
1220, 1172, 1101, 1025, 947, 894, 866, 830, 780, 695, 656, 633, 598. 1H-NMR ((D6)DMSO): 7.94 (s, 1 arom.

Helvetica Chimica Acta – Vol. 93 (2010)
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H); 7.58 (d, J ¼ 5.2, 1 arom. H); 7.47 (d, J ¼ 5.2, 1 arom. H); 6.46 (s, C¼CH). 13C{1H}-NMR
((D6)DMSO): 166.4, 156.2, 134.9, 129.1, 127.5, 127.4, 127.3, 103.9. Anal. calc. for C8H6N2O2S (194.23): C
49.47, H 3.12, N 14.43; found: C 50.13, H 3.36, N 14.22.
X-Ray Crystallography. Crystals of 1 and 2 were grown from sat. aq. and DMSO solns., resp., at r.t.
Single crystals were coated with Paratone-N oil, mounted using a Cryo-loop (crystals of 1) or a polyimide
MicroMount (crystals of 2), and frozen in the cold stream of the goniometer. A hemisphere of data were
collected on a Bruker AXS P4/SMART 1000 diffractometer using w and q scans with a scan width of 0.38
and 40-s exposure times. The detector distance was 5 cm. The data were reduced [18] and corrected for
absorption. The structures were solved by direct methods and refined by full-matrix least squares on F2.
All non-H-atoms were refined anisotropically. The H-atoms were included in calculated positions and
refined using a riding model. Crystallographic information has also been deposited with the Cambridge
Crystallographic Data Centre (CCDC-747582 and -747610). Copies of the data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB21EZ, UK; fax: þ 441223336033; or deposit@ccdc.cam.ac.uk).
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Received September 23, 2009