Synthesis and antifungal and antibacterial bioactivity of cyclic diamines containing boronate esters

Article abstract of DOI:10.1039/b304500e

Novel N₂B heterocycles (1-5) are formed from the reaction of ethylenediamine derivatives with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzaldehyde (2-HC(O)C₆H₄Bpin; pin = 1,2-O ₂C₂Me₄). X-ray diffraction studies have been carried out on four examples and show that reactions are selective in giving the isomer where the least substituted amine coordinates to the Lewis-acidic boron atom. Reaction of 2-HC(O)C₆H₄Bpin with diethylenetriamine gave a heterocycle (6) with a pendant primary amine group, which reacts further with 2-pyridinecarboxaldehyde to give a potential ligand (7) for transition metals. All new compounds show considerable antifungal activity against Aspergillus niger and Aspergillus flavus and moderate antibacterial activity against Bacillus cereus.

Full text of DOI:10.1039/b304500e

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Synthesis and antifungal and antibacterial bioactivity of cyclic
diamines containing boronate esters
Alison M. Irving,a Christopher M. Vogels,a Liliya G. Nikolcheva,a Janet P. Edwards,a
Xiao-Feng He,a Michael G. Hamilton,a Mark O. Baerlocher,b Felix J. Baerlocher,b
Andreas Deckenc and Stephen A. Westcott*a
a
Department of Chemistry, Mount Allison University, Sackville NB E4L 1G8, Canada
Department of Biology, Mount Allison University, Sackville NB E4L 1G7, Canada
Department of Chemistry, University of New Brunswick, Fredericton NB E3B 5A3, Canada
b
c
Received (in New Haven, CT, USA) 23rd April 2003, Accepted 9th June 2003
First published as an Advance Article on the web 21st August 2003
Novel N2B heterocycles (1–5) are formed from the reaction of ethylenediamine derivatives with
2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2-HC(O)C6H4Bpin; pin ¼ 1,2-O2C2Me4).
X-ray diffraction studies have been carried out on four examples and show that reactions are selective in
giving the isomer where the least substituted amine coordinates to the Lewis-acidic boron atom. Reaction of
2-HC(O)C6H4Bpin with diethylenetriamine gave a heterocycle (6) with a pendant primary amine group, which
reacts further with 2-pyridinecarboxaldehyde to give a potential ligand (7) for transition metals. All new
compounds show considerable antifungal activity against Aspergillus niger and Aspergillus flavus and moderate
antibacterial activity against Bacillus cereus.
niger and Aspergillus flavus. As part of our ongoing investiga-
Introduction
tion into generating biologically active boron compounds, and
considering the wealth of bioactivities found in aminoboronic
acid derivatives, we decided to examine the reactivity of the
pinacol derivative of 2-HC(O)C6H4B(OH)2 with diamines.
Initial results are presented herein.
Compounds containing boronic acids (RB(OH)2) or boronate
esters (RB(OR’)2) have received considerable attention in
catalysed carbon–carbon bond formation reactions,1–5 solid-
phase synthesis,6 macrocyclic chemistry,7 organometallic and
organic synthesis,8–12 and as glucose sensors for diabetes ther-
apy.13–16 Interest in these compounds also arises from their
potent biological activities.17–32 For instance, a-aminoboronic
acids (R2NCR0R00B(OH)2 , Fig. 1a) are effective and reversible
inhibitors of serine proteases, a diverse group of proteolytic
enzymes whose numerous physiological functions include
digestion, growth, differentiation, and apoptosis. Proteases
are also vital in the generation of most disease processes
and, as a result, much effort has focused on the synthesis of
a-aminoboronic acids for possible applications as enzyme inhi-
bitors. Analogous amino acids containing boronic acids have
also been investigated for their use in boron neutron capture
therapy (BNCT) for the treatment of cancer.33–42 BNCT is
a bimodal form of therapy which depends on selectively
depositing boron-10 atoms into the cancerous tumour prior
to irradiation by slow (thermal) neutrons. 4-Dihydroxyboryl-
phenylalanine (BPA, 4-H2NCH(CO2H)CH2C6H4B(OH)2 ,
Fig. 1b) is a simple second generation BNCT compound which
has shown promise in the treatment of brain tumours.42
Recent work has shown that certain boron compounds also
show considerable antifungal43 and antibacterial44 activity.
Indeed, 2-formylphenylboronic acid (2-HC(O)C6H4B(OH)2 ,
Fig. 1c) is a strongly fungicidal agent against both Aspergillus
Results and discussion
Synthesis of cyclic diamines
The synthesis of simple aldimines containing boronate esters
from the addition of primary amines to benzaldehydes is well
established.43,45 In an attempt to generate similar diimines we
decided to examine the reactivity of diamines with organic
soluble 2-HC(O)C6H4Bpin (pin ¼ 1,2-O2C2Me4). Interest-
ingly, we found that addition of ethylenediamine (H2NCH2-
CH2NH2) to 2-HC(O)C6H4Bpin did not give the expected
diimine product, but rather the novel heterocyclic diamine 1.
1
The H NMR spectra for 1 show a broad singlet at d 5.20
ppm for the CH peak bound to both amines and two separate
resonances for the CH2 groups of the ethylene backbone. A
peak at 10.8 ppm in the 11B NMR spectra signifies that the
boron atom lies in a tetrahedral environment,46 arising from
coordination of the amine nitrogen atom. This result is some-
what unusual as the reduced Lewis-acidic nature of the Bpin
group usually precludes adduct formation.43 An X-ray diffrac-
tion study on 1 was conducted to confirm the formation of this
novel heterocycle (Fig. 2). Crystallographic data are given in
Table 1 and selected bond distances and angles shown in Table
˚
2. The B-O bond distances of 1.446(3) and 1.469(3) A are typi-
cal for those observed in chelate complexes with diphenylbori-
47
˚
nic acid (ca. 1.5 A), where the boron atom is four coordinate.
˚
Likewise, the B-N(20) distance of 1.684(3) A is similar to those
reported for Schiff base complexes derived from arylboronic
acids.48 The nitrogen carbon bonds C(16)–N(20) and C(19)–
˚
N(20) are 1.535(3) and 1.500(3) A, respectively, and are consis-
tent with single bond lengths.
Fig. 1 Biologically active boron compounds: (a) a-aminoboronic
acids, (b) BPA, and (c) 2-HC(O)C6H4B(OH)2 .
DOI: 10.1039/b304500e
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An X-ray study on 3 (Fig. 4) shows that the nitrogen (N(20))
on the unsubstituted methylene group is coordinated to boron
˚
at a distance of 1.7023(16) A. It is possible that steric crowding
between the methyl groups on the backbone and the bulky
pinacol groups precludes the formation of the other isomer,
where the nitrogen on the disubstituted methylene carbon
would be bound to the boron. Crystals of 3 are comprised
of a racemic mixture of chiral molecules. Hydrogen bonding
0
˚
(O(2)ꢀ ꢀ ꢀH(20) ¼ 2.089 A) leads to the formation of dimers
which in turn form octamers through additional hydrogen
0
˚
bonding (O(5)ꢀ ꢀ ꢀH(14) ¼ 2.527 A). Hydrogen bonding has
been used extensively to control molecules or ions in the solid
state for applications in crystal engineering and supramole-
cular synthesis.50–57
Similar reactivities were observed with N-phenylethylenedia-
mine (H2NCH2CH2NHPh), which gave 4 in high yields. Two
distinct Bpin methyl resonances are observed, however, in both
the 1H and 13C NMR spectra for 4. The molecular structure of 4
(Fig. 5) confirms that in the solid state coordination of the least
substituted amine to the boron atom is once again occurring.
Bond distances are similar to 1 and 3, except that the C(16)–
Fig. 2 View of one of the two molecules of 1 with ellipsoids drawn at
30% probability level.
Compound 1 is presumably generated in this reaction via
initial aldimine formation at one of the amine groups followed
by an intramolecular hydroamination of the activated double
bond with the other amine.49 To test this hypothesis, we pre-
pared the aldimine derived from addition of propylamine to
2-HC(O)C6H4Bpin. Although 11B NMR data suggested that
the imine nitrogen was coordinated to the boron atom, atte-
mpts to carry out an intermolecular hydroamination on this
imine with various primary amines proved unsuccessful. This
result is not unexpected as the intramolecular variant of this
reaction affords a thermodynamically stable five-membered
ring (Scheme 1).
Several other diamines, including 1,3-diaminopropane
(H2NCH2CH2CH2NH2), 1,4-diaminobutane (H2NCH2CH2-
CH2CH2NH2), and 1,2-diamino-2-methylpropane (H2NCH2-
C(Me)2NH2) were allowed to react with 2-HC(O)C6H4Bpin
to examine the scope of this reaction. Although reaction
of 1,3-diaminopropane gave the analogous heterocycle 2 as
the only new aminoboron product (Fig. 3), several products
were observed with the larger 1,4-diaminobutane, including
some of the diimine. Reactions with the substituted
H2NCH2C(Me)2NH2 gave selective formation of one isomer
(3) as indicated by NMR spectroscopy. Only one resonance
was observed in the 1H NMR spectra at 4.47 ppm for the
CH bound to the two nitrogen atoms. A single peak was
also observed for the methylene backbone resonances at
2.88 ppm.
˚
N(20) distance of 1.4831(15) A is somewhat shorter in 4 (cf.
1.535(3) for 1 and 1.5297(17) for 3).
To examine the effect of introducing an aromatic group into
the backbone, we attempted to prepare analogous diamines
by reactions with 1,2-phenylenediamine (1,2-(H2N)2C6H4).
Unfortunately, all attempts to affect this reaction proved
unsuccessful and gave only the diimine product. Interestingly,
reaction of 2-aminobenzylamine (2-H2NC6H4CH2NH2) gave
the novel heterocycle (5) in high yields (84%). Inequivalent
protons arising from the benzyl methylene group are observed
1
in the H NMR spectra at d 4.11 and 3.52 ppm with coupling
constants of J ¼ 16 Hz. The11B NMR spectra show one peak
at 12.9 ppm attributed once again to a four-coordinate boron
atom.
We then decided to examine the reactivity of 2-
HC(O)C6H4Bpin with diethylenetriamine (HN(CH2CH2-
NH2)2) to see if we could generate a novel heterocycle with a
pendant primary amine group. The availability of a primary
amine would allow us to further functionalize these com-
pounds and design ligands for transition metals. Reaction of
diethylenetriamine with 2-HC(O)C6H4Bpin did indeed give
1
the novel heterocycle 6. The H NMR spectra show the CH
bound to the two nitrogen atoms at d 4.82 ppm and the pen-
dant amine hydrogens as a broad peak at 1.41 ppm. Addition
of 2-pyridinecarboxaldehyde to 6 gave a novel iminopyridine
Table 1 Summary of data collection and refinement for crystals 1,3,4, and 7
1ꢀ0.5THF
34H54B2N4O5
3
4ꢀacetone
7ꢀ0.25Et2O
Formula
M
T/K
C
C17H27BN2O2
302.22
173(1)
C24H33BN2O3
408.40
173(1)
C96H134B4N16O9
1699.70
173(1)
620.54
173(1)
Triclinic
Cryst. syst.
Space group
Tetragonal
¯
P42(1)c
Triclinic
¯
P1
Monoclinic
P2(1)/n
¯
P1
˚
a/A
10.0250(16)
10.9140(17)
17.365(3)
106.609(2)
105.779(2)
93.244(2)
1733.4(5)
2
12.5263(6)
12.5263(6)
21.7284(16)
9.5447(12)
10.5484(13)
10.9073(13)
95.987(2)
92.320(2)
91.666(2)
1090.7(2)
2
19.5646(9)
16.3302(8)
31.1144(16)
˚
b/A
˚
c/A
a/deg
b/deg
g/deg
107.5480(10)
3
˚
V/A
3409.4(3)
8
9478.3(8)
4
0.077
Z
m/mmꢁ1
0.078
1.189
0.076
1.178
0.71073
0.0463
0.1266
P
0.079
1.207
d/g cmꢁ3
1.194
˚
l/A
R1
0.71073
0.0557
0.1399
0.71073
0.0391
0.1126
0.71073
0.0568
0.1817
a
b
wR2
P
P
P
a
b
R1
¼
||Fo| ꢁ |Fc||/ |Fo|. All data, wR2 (F2) ¼ ( [w(F2o ꢁ F2c )2]/ [Fo4]1/2
.
1420
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Table 2 Selected bond lengths (C) and angles (ꢃ) for 1,3,4, and 7
1a
3
4
7b
B(1)–O(5)
B(1)–O(2)
1.446(3)
1.469(3)
1.607(3)
1.684(3)
1.448(3)
1.535(3)
1.500(3)
1.4341(16)
1.4731(15)
1.6082(19)
1.7023(16)
1.4582(16)
1.5297(17)
1.4968(16)
1.4176(16)
1.4490(16)
1.5960(18)
1.6808(16)
1.4515(16)
1.4831(15)
1.4767(16)
1.439(3)
1.467(3)
1.606(3)
B(1)–C(10)
B(1)–N(20)
1.696(3)
1.453(2)
C(16)–N(17)
C(16)–N(20)
1.538(2)
1.501(3)
1.461(4)
C(19)–N(20)
C(24)–N(23)
O(5)–B(1)–O(2)
O(5)–B(1)–C(10)
O(2)–B(1)–C(10)
O(5)–B(1)–N(20)
O(2)–B(1)–N(20)
C(10)–B(1)–N(20)
C(19)–N(20)–C(16)
C(19)–N(20)–B(1)
C(16)–N(20)–B(1)
C(18)–N(17)–C(16)
105.31(18)
115.56(17)
118.37(17)
113.39(17)
105.58(16)
98.22(17)
106.48(10)
117.14(10)
116.56(10)
111.85(10)
106.23(9)
97.92(9)
106.80(10)
116.06(10)
118.56(10)
112.40(10)
105.64(9)
96.60(9)
106.49(16)
116.36(17)
117.44(19)
112.77(17)
105.55(16)
97.62(15)
104.79(15)
115.92(17)
108.73(15)
102.61(16)
104.62(17)
119.91(16)
108.88(16)
104.60(19)
105.44(9)
115.81(9)
108.76(9)
106.35(10)
103.88(9)
114.21(9)
107.95(9)
110.54(10)
a
b
Average for two independent molecules per asymmetric unit. Average for four independent molecules per asymmetric unit.
system 7. The molecular structure of 7, shown in Fig. 6, con-
firms the presence of the imine functionality. The average aldi-
Experimental
˚
Chemistry: materials and methods
mine C–N distance is 1.461(4) A and is consistent with a
carbon–nitrogen double bond found in similar structures.43
Future work with this system will examine its potential to
act as a didentate ligand for biologically-active metals, the
results of which will be reported in due course.
Reagents and solvents were purchased from Aldrich Chemicals
and used as received. The melting points were determined
using a Mel-Temp apparatus and they are uncorrected. The
infrared spectra were obtained using a Mattson Genesis II
FT-IR spectrometer in Nujol and are reported in cmꢁ1
.
NMR spectra were recorded on a JEOL JNM-GSX270 FT
NMR (1H 270 MHz; 13C 68 MHz; and 11B 87 MHz) spectro-
meter. Chemical shifts (d) are reported in ppm [relative to
internal TMS (1H and 13C) or external BF3ꢀOEt2 (11B)] and
coupling constants (J) in Hz. Multiplicities are reported as
singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint),
multiplet (m), broad (br), and overlapping (ov). Elemental
analyses were performed by Desert Analytics (Tucson, AZ)
and Canadian Microanalytical Services (Delta, BC). 2-(4,4,-
Biological results
Recent studies have shown that related heterocyclic boron
compounds show appreciable antifungal activity.58–61 We
therefore decided to examine these new heterocyclic derivatives
for their antifungal and antibacterial activities. Selected results
for these compounds are shown in Table 3. Benzaldehyde
(Entry 8) was tested as a control and, as expected, showed
no antimicrobial activity against two fungi (Aspergillus niger
or Aspergillus flavus) and two bacteria (Escherichia coli and
Bacillus cereus). Remarkably, all compounds strongly inhib-
ited both A. niger and A. flavus and were moderately effective
against B. cereus. Interesting, however, is the observation that
the unprotected boronic acid 1b (Entry 2), prepared by the
addition of ethylenediamine to 2-HC(O)C6H4B(OH)2 , showed
a reduced fungitoxicity compared to its pinacol derivative 1
(Entry 1). Although the pinacol group in these compounds
seems to enhance toxicities, further work is needed to elucidate
the role boron plays in these systems.
In summary, we have prepared a number of novel hetero-
cyclic aminoboron compounds from the addition of 2-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde to
ethylenediamine derivatives. The least substituted amine coor-
dinates to the boron atom to form a heterocyclic ring system.
These compounds display significant antifungal and moderate
antibacterial activity.
5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde
prepared as described previously.43
was
Syntheses
Synthesis of 2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl]imidazolidine. The addition of 2-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.04 g, 4.48
mmol) in 3 mL of diethyl ether to a 2 mL diethyl ether solution
of ethylenediamine (0.27 g, 4.48 mmol) resulted in the
precipitation of 1. After 4 h, the solid was collected by suction
filtration and washed with cold methylene chloride (1 mL) and
diethyl ether (2 ꢂ 5 mL) to afford a white powder. Yield 0.94 g,
77%. Mp ¼ 192 ꢃC. IR (Nujol): 3251, 3120, 2970, 2883, 1454,
1
1379, 1261, 1157, 1043, 910, 733 cmꢁ1. H NMR (CDCl3): d
Scheme 1
Fig. 3 Novel heterocycles 2–7.
New J. Chem., 2003, 27, 1419–1424
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Fig. 6 View of one of the four molecules of 7 with ellipsoids drawn at
30% probability level.
Fig. 4 The molecular structure of 3 with ellipsoids drawn at 30%
probability level.
(5 ꢂ 10 mL) to afford an off-white powder. Yield 0.99 g,
69%. Mp ¼ 156–158 ꢃC. IR (Nujol): 3050, 2964, 2893, 1462,
7.45 (d, 1H, Ar, J ¼ 7 Hz), 7.24 (ov td, 1H, Ar, J ¼ 7, 1 Hz),
7.13 (ov td, 1H, Ar, J ¼ 7, 1 Hz), 6.93 (d, 1H, Ar, J ¼ 7 Hz),
5.20 (s, 1H, CHN), 3.73 (br s, 1H, NH), 3.26–3.15 (2nd order
m, 2H, NCH2), 3.09–2.99 (2nd order m, 2H, NCH2), 1.67 (br
s, 1H, NH), 1.27 (s, 12H, BO2C2(CH3)4). 11B NMR (CDCl3):
d 10.8. 13C NMR (CDCl3): d 145 (br, C–B), 142.0, 130.6, 128.9,
128.1, 122.9, 82.1, 80.0, 46.8, 25.9. Anal. found: C, 58.92; H,
7.59; N, 8.92. Calcd. for C15H23N2O2Bꢀ0.5 CH2Cl2 (316.73):
C, 58.77; H, 7.65; N, 8.85%.
1377, 1344, 1176, 1147, 1097, 1014, 975, 883, 748, 725 cmꢁ1
.
1H NMR (CDCl3): d 7.51 (m, 1H, Ar), 7.25–7.22 (ov m, 3H,
Ar), 5.33 (s, 1H, CHN), 3.00–2.82 (ov m, 4H, NCH2-
CH2CH2N), 2.75 (br s, 1H, NH), 1.59 (app quint, 2H, NCH2-
CH2CH2N, J ¼ 5 Hz), 1.20 (s, 12H, BO2C2(CH3)4). 11B NMR
(CDCl3): d 9.4. 13C NMR (CDCl3): d 146.1 (br, C–B), 142.3,
130.3, 128.0, 127.4, 122.3, 79.6, 73.7, 41.3, 25.8, 24.7. Anal.
found: C, 66.54; H, 8.31; N, 9.60. Calcd. for C16H25N2O2B
(288.24): C, 66.67; H, 8.76; N, 9.72%.
Synthesis of 2-(2-phenylboronic acid)imidazolidine. The addi-
tion of 2-HC(O)C6H4B(OH)2 (0.25 g, 1.67 mmol) in 5 mL of
dichloromethane to a 2 mL dichloromethane solution of ethy-
lenediamine (0.10 g, 1.67 mmol) resulted in the precipitation of
1b. The reaction was allowed to proceed for 3 days, at which
point the solid was collected by suction filtration and washed
with dichloromethane (5 ꢂ 5 mL) and diethyl ether (2 ꢂ 5
mL) to afford a white powder. Yield 0.18 g, 56%. Mp ¼
176 ꢃC. IR (Nujol): 3288, 3186, 2943, 2912, 2860, 1460, 1376,
1360, 1336, 1304, 1253, 1200, 1120, 1034, 958, 841, 766, 615
Synthesis of 4,4-dimethyl-2-[2-(4,4,5,5-tetramethyl-1,3,2-di-
oxaborolan-2-yl)phenyl]imidazolidine. The addition of 2-(4,4,
5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (0.45 g,
1.94 mmol) in 3 mL of dichloromethane to a 2 mL dichloro-
methane solution of 1,2-diamino-2-methylpropane (0.17 g,
1.94 mmol) resulted in the precipitation of 3. After 1 day,
the solvent was removed under vacuum and the resultant solid
dissolved in diethyl ether (5 mL) and stored at 5 ꢃC for 5 days.
The precipitate was then collected by suction filtration to give
a white solid. Yield 0.54 g, 92%. Mp ¼ 160–162 ꢃC. IR
(Nujol): 3288, 3118, 2941, 2872, 1464, 1377, 1362, 1261,
1228, 1192, 1153, 1109, 1086, 1043, 982, 941, 860, 781, 762,
cmꢁ1 1H NMR (D2O): d 7.41–7.38 (m, 1H, Ar), 7.33–7.25
.
(ov m, 3H, Ar), 5.61 (s, 1H, CHN), 3.06–2.92 (ov m, 4H,
NCH2CH2N). 11B NMR (D2O): d 7.0. 13C NMR (D2O): d
146.4 (br, C–B), 141.8, 129.4, 128.9, 128.4, 123.4, 81.1, 46.0
(br s, NCH2CH2N).
725, 619, 584, 525 cmꢁ1 1H NMR (CDCl3): d 7.44 (d, 1H,
.
Ar, J ¼ 7 Hz), 7.24 (t, 1H, Ar, J ¼ 7 Hz), 7.10 (t, 1H, Ar,
J ¼ 7 Hz), 6.65 (d, 1H, Ar, J ¼ 7 Hz), 4.47 (t, 1H, CHN,
J ¼ 7 Hz), 2.88 (t, 2H, NCH2 , J ¼ 7 Hz), 2.01 (br s, 1H,
NH), 1.26 (s, 12H, BO2C2(CH3)4), 1.19 (s, 3H, NCCH3),
1.18 (s, 3H, NCCH3). 11B NMR (CDCl3): d 11.5. 13C NMR
(CDCl3): d 143.5 (br, C–B), 142.5, 130.5, 128.9, 127.9, 123.4,
81.0, 80.0, 62.4, 56.9, 26.2, 25.9, 25.8. Anal. found: C, 67.62;
H, 8.91; N, 9.35. Calcd. for C17H27N2O2B (302.27): C, 67.55;
H, 9.02; N, 9.27%.
Synthesis of 2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl]hexahydropyrimidine. The addition of 2-(4,4,5,5-tet-
ramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.15 g, 4.96
mmol) in 3 mL of diethyl ether to a 2 mL diethyl ether solution
of 1,3-diaminopropane (0.37 g, 4.96 mmol) resulted in the pre-
cipitation of 2. After 2 days, the solvent was removed under
vacuum and the resultant solid triturated with diethyl ether
Synthesis of 1-phenyl-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)-phenyl]imidazolidine. A 2 mL dichloromethane
solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ben-
zaldehyde (0.50 g, 2.16 mmol) was added dropwise to a 3 mL
dichloromethane solution of N-phenylethylenediamine (0.29 g,
2.16 mmol). After 1 day, the solvent was removed under
vacuum to afford a yellow solid, which was triturated with hex-
ane (2 ꢂ 5 mL) and diethyl ether (2 ꢂ 5 mL). The resulting solid
was dissolved in a minimum (3 mL) amount of ethanol and
stored at 5 ꢃC until a precipitate formed. The precipitate was
filtered by suction filtration to afford a white solid. Yield
0.63 g, 83%. Mp ¼ 163–164 ꢃC. IR (Nujol): 3140, 2954,
2929, 2858, 1599, 1502, 1460, 1381, 1325, 1234, 1186, 1151,
1101, 1047, 995, 945, 858, 781, 742, 688, 584, 509 cmꢁ1
.
1H NMR (CDCl3): d 7.45 (d, 1H, Ar, J ¼ 7 Hz), 7.34 (t,
1H, Ar, J ¼ 7 Hz), 7.21 (t, 1H, Ar, J ¼ 7 Hz), 7.11 (t, 2H,
Ar, J ¼ 7 Hz), 6.98 (d, 1H, Ar, J ¼ 7 Hz), 6.77 (t, 1H, Ar,
J ¼ 7 Hz), 6.44 (br s, 1H, NH), 6.26 (d, 2H, Ar, J ¼ 7 Hz),
Fig. 5 The molecular structure of 4 with ellipsoids drawn at 30%
probability level.
1422
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Table 3 Antifungal and antibacterial testing
A. niger
A. flavus
E. coli
B. cereus
Dose/
mg diskꢁ1
Clear
zone/mm
Dose/
mg diskꢁ1
Clear
zone/mm
Dose/
mg diskꢁ1
Clear
zone/mm
Dose/
mg diskꢁ1
Clear
zone/mm
Entry
Compound
1
2
3
4
5
6
7
8
1
1b
25
100
25
26
0
25
100
25
22
3
100
100
100
100
100
100
100
100
0
0
0
0
0
0
0
0
50
50
50
50
50
50
50
50
31
31
30
29
30
29
29
0
2
25
24
17
14
23
0
23
23
23
18
24
0
3
25
25
25
25
4
5
100
25
100
25
6
PhC(O)H
100
100
5.94 (s, 1H, CHN), 3.44–3.37 (ov m, 2H, NCH2), 3.33–3.25 (ov
m, 2H, NCH2), 1.25 (s, 6H, BO2C2(CH3)4), 1.14 (s, 6H,
BO2C2(CH3)4). 11B NMR (CDCl3): d 11.5. 13C NMR (CDCl3):
d 146.5, 143.8, 142.9 (br, C–B), 131.3, 129.3, 128.5, 128.3,
123.0, 118.3, 113.0, 79.7, 79.2, 47.1, 44.5, 25.6, 24.9. Anal.
found: C, 70.39; H, 8.24; N, 7.28. Calcd. for C21H27N2O2Bꢀ
0.5 CH3CH2OH (373.35): C, 70.77; H, 8.12; N, 7.51%.
was heated for 8 hours in the presence of molecular sieves.
The solvent was removed under vacuum, redissolved in 10
mL of diethyl ether and stored at 5 ꢃC for 24 hours at which
point a precipitate formed and was collected by suction filtra-
tion to afford a white solid. Yield 0.14 g, 44%. Mp ¼ 120–
121 ꢃC. IR (Nujol): 3122, 2937, 2870, 1649, 1464, 1375, 1228,
1157, 1035, 982, 943, 851, 752, 721, 631 cmꢁ1 1H NMR
.
(CDCl3): d 8.65 (d, 1H, Ar, J ¼ 7 Hz), 8.40 (s, 1H,
C(H) ¼ N), 8.02 (d, 1H, Ar, J ¼ 7 Hz), 7.76 (t, 1H, Ar,
J ¼ 7 Hz), 7.47 (d, 1H, Ar, J ¼ 7 Hz), 7.32 (t, 1H, Ar,
J ¼ 7 Hz), 7.22–7.09 (ov m, 3H, Ar), 5.64 (br s, 1H, NH),
5.48 (s, 1H, CHN), 3.82 (m, 1H, NCH2), 3.70 (m, 1H,
NCH2), 3.50–3.42 (ov m, 2H, NCH2), 3.19–2.95 (ov m, 3H,
NCH2), 2.80 (m, 1H, NCH2), 1.28 (s, 6H, BO2C2(CH3)4),
1.27 (s, 6H, BO2C2(CH3)4). 11B NMR (CDCl3): d 10.6. 13C
NMR (CDCl3): d 163.9, 154.1, 149.5, 143.1, 140 (br, C–B),
136.9, 130.4, 128.5, 128.1, 125.1, 122.8, 121.6, 87.3, 80.0,
61.4, 55.7, 51.0, 43.6, 25.8, 25.3.
Synthesis of 2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl]-1,2,3,4-tetrahydroquinazoline. A 2 mL diethyl ether
solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ben-
zaldehyde (0.25 g, 1.08 mmol) was added dropwise to a 3 mL
diethyl ether solution of 2-aminobenzylamine (0.13 g, 1.08
mmol). After 2 h, the reaction was filtered to afford a white
solid. Yield 0.30 g, 84%. Mp ¼ 172–176 ꢃC. IR (Nujol):
3458, 3207, 2937, 2868, 1612, 1460, 1375, 1265, 1198, 1153,
1097, 1034, 1018, 999, 872, 845, 744, 642 cmꢁ1 1H NMR
.
(CDCl3): d 7.34 (d, 1H, Ar, J ¼ 7 Hz), 7.22–7.15 (ov m, 2H,
Ar), 7.06 (d, 1H, Ar, J ¼ 7 Hz), 6.98 (d, 1H, Ar, J ¼ 7 Hz,),
6.91–6.80 (ov m, 3H, Ar), 5.51 (d, 1H, C(H)N or NH, J ¼ 6
Hz), 5.13 (d, 1H, C(H)N or NH, J ¼ 6 Hz,), 4.11 (d, 1H,
CH2N, J ¼ 16 Hz), 3.52 (d, 1H, CH2N, J ¼ 16 Hz), 2.08 (br
s, 1H, NH), 1.28 (s, 6H, BO2C2(CH3)4), 1.23 (s, 6H,
BO2C2(CH3)4). 11B NMR (CDCl3): d 12.9. 13C NMR (CDCl3):
d 143.4 (br, C–B), 141.9, 131.1 (two peaks), 128.3, 128.0, 127.7,
127.6, 123.4, 121.2, 120.5, 118.9, 80.5, 71.9, 44.9, 26.3, 25.7.
Anal. found: C, 71.42; H, 7.63; N, 8.38. Calcd. for
C20H25N2O2B (336.28): C, 71.43; H, 7.51; N, 8.33%.
X-Ray data
Crystals of 1 (THF), 3 (THF), 4 (acetone), and 7 (Et2O) were
grown from saturated solutions at 5 ꢃC. Single crystals were
coated with Paratone-N oil, mounted using a glass fibre and
frozen in the cold stream of the goniometer. A hemisphere of
data were collected on a Bruker AXS P4/SMART 1000 dif-
fractometer using o and f scans with a scan width of 0.3ꢃ
and 10 s (3) or 30 s (1, 4, 7) exposure times. The detector dis-
tance was 4 cm (3), 5 cm (7), or 6 cm (1, 4). The data were
reduced62 and corrected for absorption.63 The structure was
solved by direct methods and refined by full-matrix least
squares on F2.64 All non-hydrogen atoms were refined aniso-
tropically. Hydrogen atoms were located in Fourier difference
maps and refined isotropically, with the exception of the
solvent molecule in 7, where hydrogen atoms were included
in calculated positions and refined using a riding molecule.
CCDC reference numbers 212668–212671. See http://
www.rsc.org/suppdata/nj/b3/b304500e/ for crystallographic
files in .cif or other electronic format.
Synthesis of 2-{2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)phenyl]imidazolidin-1-yl}ethylamine. The addition of 2-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(0.75g,
3.23 mmol) in 5 mL of diethyl ether to a 5 mL diethyl ether
solution of diethylenetriamine (0.33 g, 3.23 mmol) resulted in
the precipitation of 6. After 1 day, the precipitate was col-
lected by suction filtration to afford an off-white solid. Yield
0.70 g, 68%. Mp 142–145 ꢃC. IR (Nujol): 3165, 3111, 2970,
2881, 1462, 1377, 1303, 1155, 1032, 978, 845, 723 cmꢁ1
.
1H NMR (CDCl3): d 7.45 (d, 1H, Ar, J ¼ 7 Hz), 7.27–
7.17 (m, 2H, Ar), 6.87 (d, 1H, Ar, J ¼ 7 Hz), 6.45 (br s,
1H, NH), 4.82 (s, 1H, CHN), 3.51 (m, 1H, NCH2), 2.93
(ov m, 1H, NCH2), 2.77–2.50 (ov m, 4H, NCH2), 2.44–
2.35 (m, 2H, NCH2), 1.41 (br s, 2H, NH2), 1.28 (s, 12H,
Biological testing
New compounds were tested for antifungal activity against
pure cultures of Aspergillus niger and Aspergillus flavus, and
for antibacterial activity against pure cultures of Escherichia
coli and Bacillus cereus, all of which were provided by Ward’s
Natural Science Ltd. (St. Catharines, Ontario, Canada). Cul-
tures were maintained on malt agar. Six plugs (10 mm dia-
meter) were cut from a 5–8 day-old colony and homogenized
in distilled, sterilized water (4 mL). From this suspension, 0.5
mL was transferred aseptically to a Petri plate with 15 mL malt
extract agar (1% malt extract, 1.5% agar) and spread evenly
over the entire surface. Each plate was provided with four
evenly spaced paper disks (7 mm Whatman Number 1 filter
BO2C2(CH3)4). 11B NMR (CDCl3):
d
10.3. 13C NMR
(CDCl3): d 145.0 (br, C–B), 143.9, 130.0, 128.3, 128.1,
123.1, 86.3, 79.9, 57.9, 51.7, 42.8, 41.2, 26.3, 25.4. Anal.
found: C, 64.18; H, 8.96; N, 13.08. Calcd. for C17H28N3O2B
(317.29): C, 64.35; H, 8.91; N, 13.25%.
Synthesis of pyridin-2-ylmethylene-(2-{2-[2-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)-phenyl]imidazolidin-1-yl}ethyl-
amine. Compound 6 (0.25 g, 0.79 mmol) in 5 mL of dichloro-
methane was added to a 5 mL dichloromethane solution of
2-pyridinecarbaldehyde (0.08 g, 0.79 mmol) and the reaction
New J. Chem., 2003, 27, 1419–1424
1423

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and bacterial homogenates were incubated at room tempera-
ture for 48 h. Three replicate plates were used for each test.
Antifungal and antibacterial activity was taken by the dia-
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33 L. Weissfloch, M. Wagner, T. Probst, R. Senekowitsch-
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Acknowledgements
Thanks are extended to the Research Corporation (Cottrell
College Science Award), the Canada Research Chairs pro-
gram/Canadian Foundation for Innovation/Atlantic Inno-
vation Fund, and Mount Allison University for financial
support. We also thank Dan E.C.S. Durant for expert techni-
cal assistance and anonymous reviewers for helpful comments.
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