Synthesis and antimicrobial properties of cyclic fluorodiamines containing boronate esters

Article abstract of DOI:10.1002/hc.21405

Eight new aminoboron compounds derived from primary diamines and the pinacol-protected product of 3-fluoro-2-formylphenylboronic acid have been prepared and characterized fully. Reactions proceed to give the corresponding cyclic products arising via initial aldimine formation followed by a secondary hydroamination step. One compound contains a pendant amine group which was used to make a novel boron-containing Schiff base ligand along with the corresponding zinc(II) metal complex. All compounds were tested for their initial antimicrobial activities against a number of fungi and bacteria.

Full text of DOI:10.1002/hc.21405

Received: 6 July 2017
DOI: 10.1002/hc.21405
Revised: 20 September 2017
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R E S E A R C H A R T I C L E
Synthesis and antimicrobial properties of cyclic fluorodiamines
containing boronate esters
Diya Zhu1
Carmanah D. Hunter1
Stephen J. Geier1
Samuel R. Baird1
Bradley R. Davis2
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Allyson Bos2
Christopher M. Vogels1
Andreas Decken3
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Christopher A. Gray2,3
Stephen A. Westcott1
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1Department of Chemistry and
Biochemistry, Mount Allison University,
Sackville, NB, Canada
Abstract
Eight new aminoboron compounds derived from primary diamines and the pinacol-
protected product of 3-fluoro-2-formylphenylboronic acid have been prepared and
characterized fully. Reactions proceed to give the corresponding cyclic products
arising via initial aldimine formation followed by a secondary hydroamination step.
One compound contains a pendant amine group which was used to make a novel
boron-containing Schiff base ligand along with the corresponding zinc(II) metal
complex. All compounds were tested for their initial antimicrobial activities against
a number of fungi and bacteria.
2Department of Biology, University of New
Brunswick, Saint John, NB, Canada
3Department of Chemistry, University of
New Brunswick, Fredericton, NB, Canada
Correspondence
Stephen A. Westcott, Department of
Chemistry and Biochemistry, Mount
Allison University, Sackville, NB, Canada.
Email: swestcott@mta.ca
and
Christopher A. Gray, Department of
Biology, University of New Brunswick,
Saint John, NB, Canada.
Email: cgray@unb.ca
Funding information
Natural Sciences and Engineering Research
Council of Canada
the plasma cells) and mantle cell lymphoma (a cancer of the
lymph nodes). After, not as this remarkable step forward in
1
INTRODUCTION
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boron pharmaceutical chemistry, Tavaborole or Kerydin,®
(Figure 1B) a simple fluorine-containing boron compound,
has been marketed as a topical antifungal medication for the
treatment of onychomycosis, a fungal infection of the nail
and nail bed.[8]
Interest in small-molecule boron pharmaceutical chemistry
has grown tremendously in recent years as researchers con-
tinue to discover new and remarkable applications for these
interesting molecules. A number of excellent reviews have
recently been published describing the history and current
directions of bioactive boron chemistry.[1-7] α-Aminoboronic
acids have been well recognized as being a unique class of
potent enzyme inhibitors for several decades. Only recently,
however, has the boropeptide Velcade® (Figure 1A) been
approved by the FDA as the first ever boron-containing
pharmaceutical molecule. Indeed, Velcade, or bortezomib,
is used for the treatment of multiple myeloma (a cancer of
The bioactivity associated with small-molecule boron
compounds is believed to arise from the electrophilic nature
of the three-coordinate boron atom, which contains an essen-
tially empty formally p-derived orbital. The boron atom can
readily form dative Lewis acid-base bonds with nucleophiles
(ie, the hydroxyl group in serine) and transform from a neu-
tral trigonal three-coordinate species into a four-coordinate
tetrahedral adduct. Unlike covalent bonds generated when
using organic “suicide inhibitors,” this dative bonding in-
teraction can be reversible but also provide great stability,
Contract grant sponsor: Natural Sciences and Engineering Research Council
of Canada.
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Heteroatom Chemistry. 2017;e21405.
https://doi.org/10.1002/hc.21405
wileyonlinelibrary.com/journal/hc
© 2017 Wiley Periodicals, Inc.
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ZHU et al.
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atom upon complexation,[14] and elemental analysis data are
consistent with the proposed structure. Compound 2 presum-
ably arises via initial aldimine formation followed by an in-
tramolecular hydroamination of the activated aldimine C=N
double bond using the pendant amine group.[9] The Lewis
acid-mediated and metal-catalyzed intramolecular hydroami-
nation of imines to give 5- and 6-membered heterocycles is
an area of considerable recent interest.[15-19]
(B)
(A)
Similar reactivity was observed for reactions of 1 with
1,3-diaminopropane which afforded 3 in moderate isolated
yields. However, attempts to add 1,4-diaminobutane to 1 lead
to the formation of the corresponding polycyclic compound,
which contains a seven-membered diamine ring, along with a
number of unidentified products, and isolation was therefore
not attempted. Reactions of 1,2-diamino-2-methylpropane
were of singular interest as they gave selective formation of
compound 4 in high yields as deduced by multinuclear NMR
spectroscopy. Two possible regioisomeric mixtures could be
envisioned from this reaction if there was little differentia-
tion of the primary amine group that initially attacks the al-
dehyde electrophilic carbon atom and forms the intermediate
aldimine. However, only one set of resonances was observed
FIGURE 1 Small-molecule boron compounds (A) Velcade and
(B) Tavaborole
differentiating small-molecule boron compounds from tra-
ditional pharmaceuticals. We have previously disclosed that
addition of certain diamines to 2-formylphenylboronic acid,
and the corresponding pinacol boronate ester, afforded a fam-
ily of novel cyclic boron compounds that showed significant
antimicrobial activities.[9] Inspired by the recent success of
Tavaborole, where the fluorine substituent was essential for
the compound’s efficacy, we have expanded on our initial
findings and report herein on a series of cyclic diamines de-
rived from pinacol-protected 3-fluoro-2-formylphenylboronic
acid.
1
in the H and 13C NMR data, suggesting one major race-
mic (chiral at the ipso carbon and the coordinated nitrogen
atom) regioisomer mixture where the two methyl groups in
the backbone play a significant role in the regiochemistry of
the reaction. To confirm the structure of 4, we carried out an
X-ray diffraction study and the molecular structure of which
is shown in Figure 2A and crystallographic data provided in
Table 1. As expected, the amine group bonded to the boron
atom is the sterically least congested one where the dimethyl
groups avoid the steric bulk of the large pinacolato fragment.
Bond distances and angles are similar to those reported pre-
viously for related systems.[9]
To examine the possibility of using N-substituted diamines,
we then investigated the reaction of N-phenylethylenediamine
with 1 and found the reaction proceeded selectively at room
temperature to give one regioisomeric mixture, 5, where the
least sterically hindered amine group is bound to the boron
atom. Once again, spectroscopic data are consistent with this
formula, and an X-ray diffraction study confirmed the forma-
tion of this racemic isomer (Figure 2B). Bond distances and
angles are also consistent with those found in compound 4.
Addition of a diethyl ether solution of 2-aminobenzylamine to
1 gave the corresponding cyclic product 6, where the least ste-
rically hindered amine group is presumably bound to the boron
atom. To confirm the regioselectivity in this reaction, we car-
ried out a single crystal X-ray diffraction study on this com-
pound, the molecular structure of which is shown in Figure 3.
We then turned our attention to reactions of 1 with dieth-
ylenetriamine to give the cyclic product 7, which contains a
pendant primary amine linkage that allows for the potential
functionalization into a wide array of possible groups. To
2
RESULTS AND DISCUSSION
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The incorporation of fluorine into small molecules is a well-
known strategy for increasing the bioactivity and efficacy
of small-molecule pharmaceuticals.[10-12] As such, we have
extended our initial work in this area by examining the chem-
istry and bioactivities of diamines derived from commer-
cially available 3-fluoro-2-formylphenylboronic acid (FBA).
Protection of the boronic acid group via dehydration with
pinacol afforded the corresponding boronate ester 1 in high
yields (>90%). Unlike the boronic acid precursor, which is
prone to further dehydration to afford the insoluble anhydride
trimeric boroxine,[13] compound 1 is remarkably soluble in
common organic solvents such as THF and diethyl ether. The
reaction of 1 with one equivalent of ethylenediamine in di-
ethyl ether at room temperature resulted in the heterocyclic
diamine 2, which was isolated in 97% yield as a white pre-
cipitate (Scheme 1). Interestingly, the 11B NMR data for 2
show a sharp singlet at 10.3 ppm, which is consistent with the
boron atom being four coordinate in solution.[9] By compari-
son, the three-coordinate boron atom in the starting aldehyde
1 appears as a broad peak at 30 ppm. Two disparate sets of
resonances are also observed in the 1H NMR data for 2 at 2.98
and 2.76 ppm for the ethylene hydrogens in the backbone of
the five-membered diamine ring. A singlet at 5.28 ppm is ob-
served for the methine hydrogen on the carbon bound to the
arene ring and the two amine groups. As expected, no signifi-
cant change is observed in the 19F NMR data for the fluorine

ZHU et al.
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SCHEME 1 Synthetic pathways to diamines 2-7
demonstrate this point, the reaction of 7 with salicylaldehyde
in CH2Cl2 at reflux afforded the novel Schiff base derivative
8, albeit in somewhat low isolated yields (20%). To investigate
the potential use of this compound as a ligand for transition
metals, we decided to examine its reactivity with diethylzinc
as Zn(II) Schiff base complexes are well known to display po-
tent antimicrobial activities.[20-25] We were delighted to find
that addition of 8 at low temperatures to solutions of ZnEt2 af-
forded the corresponding Schiff base complex 9 in moderate
yields (Scheme 2). The observation that a peak is unchanged
in the 11B NMR spectra at 10.4 ppm confirms that the boron
group remains intact during this reaction. Spectroscopic data
and elemental analysis are consistent with the proposed struc-
ture but, unfortunately, all attempts to grow single crystals of
9 suitable for X-ray diffraction studies proved unsuccessful.
With elementally pure samples in hand, we decided to inves-
tigate compounds 1-9 and the non-fluorine-containing deriva-
tiveof2asacontrol(10)fortheirpotentialantibacterial(Table 2)
and antifungal (Table 3) activity. In our initial screening assays,
none of the compounds significantly inhibited the growth of
Enterococcus faecium or Pseudomonas aeruginosa (ie, in-
duced more than 20% inhibition when tested at 100 μmol L−1).
However, all of the compounds did exhibit antibacterial
activity against Staphylococcus aureus and methicillin-resistant
Staphylococcus aureus (MRSA). Compounds 1, 5, and 9 also
exhibited weak activity against Escherichia coli.
All compounds showed antifungal activity against
Saccharomyces cerevisiae and, with the exception of the non-
fluorine-containing control compound (10), weaker activity
against Candida albicans. The observation of selective an-
tibacterial activity in both gram-positive (ie, E. faecium and
S. aureus) and gram-negative (ie, P. aeruginosa and E. coli)
in conjunction with the broad antifungal activity exhibited by
the analogues suggests a mode of action that transcends gen-
eral cellular toxicity and differential membrane permeability.
Further work is required to elucidate the mechanism of action
exhibited by the boronate esters and allow the synthesis of
more potent and specific biocides based on these templates.
3
CONCLUSIONS
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We have prepared and characterized fully eight new amino-
boron compounds derived from the pinacol-protected prod-
uct of 3-fluoro-2-formylphenylboronic acid. Reactions of
primary diamines proceed to give the corresponding cyclic

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FIGURE 2 The molecular structures of (A) rac-4 and (B) rac-5 with probability ellipsoids drawn at the 50% confidence level and hydrogen
atoms and molecules of solvent for rac-5 omitted for clarity. Selected bond distances (Å) and angles (°) for rac-4: B(1)-O(1) 1.427(3), B(1)-O(2)
1.469(3), B(1)-C(13) 1.626(3), B(1)-N(1) 1.710(3); O(1)-B(1)-O(2) 107.23(15), O(1)-B(1)-C(13) 116.57(18), O(2)-B(1)-C(13) 116.16(17),
O(1)-B(1)-N(1) 112.22(17), O(2)-B(1)-N(1) 106.14(15). Selected bond distances (Å) and angles (°) for one molecule of rac-5 in the asymmetric
unit: B(1)-O(1) 1.437(3), B(1)-O(2) 1.460(3), B(1)-C(7) 1.603(4), B(1)-N(1) 1.707(3); O(1)-B(1)-O(2) 106.6(2), O(1)-B(1)-C(7) 116.8(2), O(2)-
B(1)-C(7) 117.24(17), O(1)-B(1)-N(1) 112.97(16), O(2)-B(1)-N(1) 105.03(19)
products arising via initial aldimine formation followed by a
secondary hydroamination step. While all compounds were
tested for their initial antimicrobial activities, it appears that
the Zn(II) Schiff base complex 9 shows broader and overall
more potent activity than the other test compounds. Further
studies are currently underway to understand this structure-
activity relationship in an effort to design more potent amino-
boron antifungal and antibacterial agents, the results of which
will be reported in due course.
Bacto™ Brain Heart Infusion broth for E. faecium, Difco™
Sabouraud Dextrose broth for C. albicans, and Difco™ Yeast
Mold broth for S. cerevisiae in nontissue culture treated 96-well
microtiter plates. Optical densities (OD) were measured using a
Molecular Devices Emax microplate reader with a 600-nm filter.
4.1
Synthesis
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4.1.1
Synthesis of 2-fluoro-6-(4,4,5,5-
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tetramethyl-1,3,2-dioxaborolan-2-yl)
benzaldehyde (1)
4
EXPERIMENTAL
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3-Fluoro-2-formylphenylboronic acid (0.84 g, 5.00 mmol)
and pinacol (0.59 g, 5.00 mmol) were combined in CH2Cl2
(20 mL) in the presence of activated molecular sieves (4 Å,
10 g). The reaction was allowed to proceed at RT for 1 day at
which point the sieves were removed by suction filtration and
1 was isolated as a pale-yellow oil upon removal of solvent
under vacuum. Yield: 1.14 g (91%). IR: 2977 (br), 1694 (m),
1569 (m), 1480 (m), 1344 (s), 1130 (s), 945 (m), 791 (m).
1H NMR (400 MHz, CDCl3) δ: 10.39 (s, 1H, CH=O), 7.55
(m, 1H, Ar), 7.33 (d, J = 7.3 Hz, 1H, Ar), 7.15 (m, 1H, Ar),
Reagents and solvents used were obtained from Sigma-
Aldrich. 2-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl)imidazolidine (10), the non-fluorine-containing
derivative of 2, was prepared as previously reported.[9]
NMR spectra were recorded on a JEOL JNM-GSX400 FT
NMR (1H: 400 MHz; 11B: 128 MHz; 13C: 100 MHz; 19F:
188 MHz) spectrometer. Chemical shifts (δ) are reported in
ppm [relative to residual solvent peaks (1H and 13C) or exter-
nal BF3·OEt2 (11B) and CF3CO2H (19F)]. Multiplicities are
reported as singlet (s), doublet (d), triplet (t), multiplet (m),
broad (br), and overlapping (ov) with coupling constants (J)
reported in Hertz. Melting points were measured uncorrected
with a Stuart SMP30 apparatus. FT-IR spectra were obtained
with a Thermo Fisher Scientific Nicolet iS5 FT-IR spectrom-
eter in ATR mode and are reported as weak (w), medium (m),
or strong (s) in cm−1. Elemental analyses for carbon, hydro-
gen, and nitrogen were carried out at Laboratoire d’Analyse
Élémentaire de l’Université de Montréal (Montréal, QC).
Air-sensitive reactions were performed under an atmosphere
of nitrogen in an MBraun LabMaster glovebox.
1.41 (s, 12H, pin). 11B NMR (128 MHz, CDCl3) δ: 30 (br).
13C{1H} NMR (100 MHz, CDCl3) δ: 188.9 (d, JCF = 5.6 Hz),
164.2 (d, JCF = 259.7 Hz), 135.7 (d, JCF = 8.6 Hz), 135 (br,
Antibiotic susceptibility assays were performed using
BBL™ Mueller Hinton II cation-adjusted broth for S. aureus,
methicillin-resistant S. aureus, E. coli, and P. aeruginosa,

ZHU et al.
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TABLE 1 Crystallographic data
collection parameters for 4, 5, and 6
Complex
4
5
6
Formula
C17H26BFN2O2
C21H26BFN2O2·½CH
2Cl2
C20H24BFN2O2·2CHCl3
Molecular weight
Crystal system
Space group
a/Å
b/Å
c/Å
α/°
β/°
320.21
Tetragonal
P-421c
12.578(10)
12.578(10)
21.846(17)
90
90
90
3456(5)
8
410.71
592.96
Triclinic
P-1
Monoclinic
P2(1)/c
22.557(9)
10.564(4)
19.196(8)
90
111.360(6)
90
4260(3)
8
10.6408(19)
10.9101(19)
12.125(2)
82.127(2)
75.954(2)
89.447(3)
1352.2(4)
2
γ/°
V/Å3
Z
ρ
calc./mg/m
1.231
0.60 × 0.40 × 0.40
208(1)
1.281
0.90 × 0.40 × 0.20
208(1)
1.456
0.70 × 0.50 × 0.40
173(1)
Crystal size/mm3
Temp/K
Radiation
Mo-Kα
Mo-Kα
Mo-Kα (λ = 0.71073 Å)
(λ = 0.71073 Å)
(λ = 0.71073 Å)
µ/mm−1
Total reflections
Total unique
reflections
0.087
19 792
3872
0.207
28 061
9486
0.666
9304
5845
No. of variables
θ Range/°
223
1.87 to 27.48
522
411
0.97 to 27.50
0.415 and −0.434
1.88 to 27.50
1.106 and −0.862
Largest difference 0.282 and −0.257
peak/hole/e Å−3
S (GoF) on F2
R1a (I > 2σ(I))
wR2b (all data)
0.997
0.0538
0.1310
1.038
0.0558
0.1771
1.040
0.0544
0.1498
aR1 = Σ||Fo| − |Fc||/Σ|Fo|.
bwR2 = (Σ[w(Fo2 − Fc2)2]/Σ[wFo4])1/2, where w = 1/[σ2(Fo2) + (0.0721·P)2] (4), 1/[σ2(Fo2) + (0.0789·P)2 + (0.
6333·P)] (5), and 1/[σ2(Fo2) + (0.0779·P)2 + (1.2633·P)] (6), where P = (max (Fo2, 0) + 2·Fc2)/3.
CB), 128.9 (d, JCF = 3.8 Hz), 127.6 (d, JCF = 7.7 Hz), 117.4
(d, JCF = 20.1 Hz), 84.5, 24.9. 19F{1H} NMR (188 MHz,
CDCl3) δ: −121.0. Anal. Calc. for C13H16BFO3 (250.07 g/
mol) (%): C 62.44, H 6.45. Found: C 62.73, H 6.66.
1456 (w), 1353 (m), 1265 (s), 1099 (s), 966 (m), 869 (s),
1
776 (s). H NMR (400 MHz, CDCl3) δ: 7.27-7.12 (ov m,
2H, Ar), 6.78 (ddd, JHF = 9.2 Hz, JHH = 7.8, 0.9 Hz, 1H,
Ar), 5.28 (s, 1H, CHN2), 2.98 (m, 2H, NCH2), 2.76 (m, 2H,
NCH2), 1.23 (s, 12H, pin). 11B NMR (128 MHz, CDCl3) δ:
10.3 (sharp). 13C{1H} NMR (100 MHz, DMSO-d6) δ: 159.0
4.1.2
Synthesis of 2-(2-fluoro-6-(4,4,5,5-
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tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)
imidazolidine (2)
A Et2O (5 mL) solution of 1 (0.62 g, 2.48 mmol) was added
dropwise to a Et2O (5 mL) solution of ethylenediamine
(0.15 g, 2.50 mmol). The reaction was allowed to proceed at
RT for 4 hours at which point a white precipitate was col-
lected by suction filtration and washed with Et2O (3 × 5 mL)
to afford 2 as a white solid. Yield: 0.70 g (97%); mp 212-
213°C (decomposition). IR: 3255 (w), 3096 (br), 2913 (br),

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(m, 1H, NCHH), 1.55 (m, 1H, NCHH), 1.11 (s, 12H, pin).
11B NMR (128 MHz, CDCl3) δ: 9.4 (sharp). 13C{1H} NMR
(100 MHz, CDCl3) δ: 158.8 (d, JCF = 249.7 Hz), 151 (br,
CB), 130.3 (d, JCF = 5.8 Hz), 128.5 (d, JCF = 9.6 Hz), 125.6
(d, JCF = 1.4 Hz), 114.1 (d, JCF = 20.1 Hz), 79.7, 71.8, 42.8,
26.1, 23.0. 19F{1H} NMR (188 MHz, CDCl3) δ: −124.3.
Anal. Calc. for C16H24BFN2O2·0.5 H2O (315.19 g/mol) (%):
C 60.97, H 8.01, N 8.89. Found: C 60.84, H 7.86, N 8.98.
FIGURE 3 The molecular structure of rac-6 with ellipsoids
drawn at the 50% probability level and hydrogen atoms and solvent
molecules omitted for clarity. Selected bond distances (Å) and angles
(°): B(1)-O(2) 1.435(3), B(1)-O(1) 1.438(3), B(1)-C(7) 1.620(3),
B(1)-N(2) 1.706(3); O(2)-B(1)-O(1) 108.19(16), O(2)-B(1)-C(7)
116.03(17), O(1)-B(1)-C(7) 117.14(17), O(2)-B(1)-N(2) 111.80(16),
O(1)-B(1)-N(2) 108.13(15)
4.1.4
Synthesis of 2-(2-fluoro-6-(4,4,5,5-
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tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-
4,4-dimethylimidazolidine (4)
A
Et2O (5 mL) solution of 1 (0.98 g, 3.92 mmol)
(d, JCF = 248.3 Hz), 150 (br, CB), 130.2 (d, JCF = 6.1 Hz),
130.1 (d, JCF = 10.7 Hz), 126.4 (d, JCF = 3.5 Hz), 114.1 (d,
JCF = 19.4 Hz), 79.7 (br s), 78.5, 47.4 (br s), 45.8 (br s),
26.1 (br s), 26.0 (br s). 19F{1H} NMR (188 MHz, CDCl3) δ:
−120.4. Anal. Calc. for C15H22BFN2O2 (292.16 g/mol) (%):
C 61.67, H 7.59, N 9.59. Found: C 61.04, H 7.88, N 9.05.
was added dropwise to a Et2O (5 mL) solution of
1,2-diamino-2-methylpropane (0.35 g, 3.97 mmol). The re-
action was allowed to proceed for 24 hours at which point
a white solid was collected by suction filtration and washed
with Et2O (3 × 2 mL) to afford 4. Yield: 1.23 g (97%); mp
197-198°C. IR: 3291 (w), 3108 (m), 2986 (m), 1466 (m),
1345 (m), 1243 (s), 1157 (s), 1110 (s), 989 (m), 967 (m), 801
1
(s), 721 (s), 618 (w), 591 (w). H NMR (400 MHz, CDCl3)
4.1.3
Synthesis of 2-(2-fluoro-6-(4,4,5,5-
|
δ: 7.29-7.23 (ov m, 2H, Ar), 6.80 (app t, J = 7.4 Hz, 1H, Ar),
6.52 (br s, 1H, NH), 4.84 (br s, 1H, CHN), 2.90 (2nd order m,
2H, NCH2), 1.26 (s, 12H, pin), 1.25 (s, 3H, CH3), 1.24 (s, 3H,
CH3). 11B NMR (128 MHz, CDCl3) δ: 10.3 (sharp). 13C{1H}
NMR (100 MHz, CDCl3) δ: 158.2 (d, JCF = 251.1 Hz), 148
(br, CB), 131.3 (d, JCF = 5.8 Hz), 128.3 (d, JCF = 13.4 Hz),
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)
hexahydropyrimidine (3)
A Et2O (5 mL) solution of 1 (0.94 g, 3.76 mmol) was added
dropwise to a Et2O (5 mL) solution of 1,3-diaminopropane
(0.28 g, 3.78 mmol). The reaction was allowed to proceed at
RT for 48 hours at which point a white precipitate was col-
lected by suction filtration and washed with Et2O (3 × 5 mL)
to afford 3 as a white solid. Yield: 0.74 g (64%); mp 180-
182°C. IR: 3255 (w), 3097 (br), 2907 (br), 1571 (w), 1464
(w), 1373 (w), 1239 (s), 1077 (s), 871 (s), 742 (m), 630 (w).
1H NMR (400 MHz, CDCl3) δ: 7.26-7.18 (ov m, 2H, Ar),
6.84 (app t, J = 7.8 Hz, 1H, Ar), 5.20 (br s, 1H, CHN2),
3.52 (br s, 1H, NH), 3.07-2.95 (ov m, 4H, 2× CH2), 1.90
SCHEME 2 Synthesis of a Zn(II)
Schiff base complex containing pendant
aminoboron groups

ZHU et al.
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126.0 (d, JCF = 5.8 Hz), 114.9 (d, JCF = 5.8 Hz), 80.3, 77.6,
62.8, 56.3, 26.1, 26.0, 25.8. 19F{1H} NMR (188 MHz, CDCl3)
δ: −119.1. Anal. Calc. for C17H26N2BFO2 (320.21 g/mol)
(%): C 63.77, H 8.18, N 8.75. Found: C 63.62, H 8.30, N 8.93.
Et2O (3 × 1 mL) to afford 6 as a white solid. Yield: 0.84 g
(63%); mp 187-189°C. IR: 3204 (w), 2985 (w), 1369 (w),
1465 (m), 1343 (w), 1270 (m), 1150 (m), 1055 (m), 996 (m),
1
876 (m), 719 (s). H NMR (400 MHz, CDCl3) δ: 7.18-7.10
(ov m, 3H, Ar), 7.05 (d, J = 7.3 Hz, 1H, Ar), 6.88-6.83 (ov
m, 2H, Ar), 6.78 (d, J = 8.2 Hz, 1H, Ar), 5.43 (d, J = 6.0 Hz,
1H, NH), 5.11 (br s, 1H, CHN), 4.35 (br m, 1H, NH), 4.23
(dd, J = 15.4, 8.5 Hz, 1H, NCHH), 3.77 (dd, J = 15.4, 5.8 Hz,
1H, NCHH), 1.19 (s, 6H, pin), 1.14 (s, 6H, pin). 11B NMR
(128 MHz, CDCl3) δ: 11.6 (sharp). 13C{1H} NMR (100 MHz,
CDCl3) δ: 158.9 (d, JCF = 248.2 Hz), 148 (br, CB), 142.4,
130.5 (d, JCF = 5.6 Hz), 128.4, 127.6 (d, JCF = 9.6 Hz), 127.3,
126.4, 120.0, 116.6, 116.4, 114.8 (d, JCF = 21.1 Hz), 80.5,
69.1, 44.2, 26.0, 25.7. 19F{1H} NMR (188 MHz, CDCl3) δ:
−122.6. Anal. Calc. for C20H24N2BFO2 (354.23 g/mol) (%): C
67.81, H 6.83, N 7.91. Found: C 67.71, H 6.94, N 7.98.
4.1.5
Synthesis of 2-(2-fluoro-6-(4,4,5,5-
|
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-
phenylimidazolidine (5)
A CH2Cl2 (5 mL) solution of 1 (0.96 g, 3.84 mmol)
was added dropwise to a CH2Cl2 (5 mL) solution of N-
phenylethylenediamine (0.52 g, 3.82 mmol). After 5 hours,
the solvent was removed under vacuum to afford an off-white
solid which was washed with hexane (3 × 1 mL) to afford 5
as white solid. Yield: 1.39 g (99%); mp 187-189°C. IR: 3070
(w), 2970 (w), 1600 (w), 1491 (m), 1372 (m), 1236 (m), 1153
(s), 1096 (m), 993 (w), 868 (w), 842 (m), 748 (s), 596 (w).
1H NMR (400 MHz, CDCl3) δ: 7.39 (m, 1H, Ar), 7.28 (d,
JHH = 7.3 Hz, 1H, Ar), 7.21 (app t, JHH = 7.3 Hz, 2H, Ar),
6.95 (dd, JHH = 8.2 Hz, 1H, Ar), 6.87 (app t, JHH = 7.3 Hz, 1H,
Ar), 6.64 (d, JHH = 8.2 Hz, 2H, Ar), 6.24 (br s, 1H, NH), 5.90
(d, J = 4.1 Hz, 1H, CHN), 3.71 (m, 1H, NCHH), 3.61 (m, 1H,
NCHH), 3.14-3.01 (ov m, 2H, NCH2), 1.19 (s, 6H, pin), 1.04 (s,
6H, pin). 11B NMR (128 MHz, CDCl3) δ: 10.4 (sharp). 13C{1H}
NMR (100 MHz, CDCl3) δ: 159.2 (d, JCF = 250.8 Hz), 148 (br,
CB), 147.4, 130.9 (d, JCF = 6.7 Hz), 129.4 (d, JCF = 13.4 Hz),
129.3, 128.9 (d, JCF = 10.5 Hz), 126.4 (d, JCF = 3.8 Hz),
120.2, 115.5 (d, JCF = 9.6 Hz), 115.3 (d, JCF = 8.6 Hz), 80.1,
77.2, 46.4, 43.9, 25.7, 25.3. 19F{1H} NMR (188 MHz, CDCl3)
δ: −118.9. Anal. Calc. for C21H26N2BFO2 (368.25 g/mol) (%):
C 68.49, H 7.12, N 7.61. Found: C 68.51, H 7.29, N 7.71.
4.1.7
Synthesis of 2-(2-(2-fluoro-6-(4,4,5,5-
|
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)
imidazolidin-1-yl)ethanamine (7)
A Et2O (5 mL) solution of 1 (0.68 g, 2.72 mmol) was added
dropwise to a Et2O (5 mL) solution of diethylenetriamine
(0.28 g, 2.71 mmol). The reaction was allowed to proceed
for 24 hours, at which point the solvent was removed under
vacuum to afford a white solid. Recrystallization from
CH2Cl2 (10 mL) and hexane (5 mL) afforded 7 as a white
precipitate. Yield: 0.51 g (56%); mp 168-169°C. IR: 3346
(w), 3116 (w), 2966 (w), 1573 (w), 1456 (w), 1358 (m), 1244
(m), 1152 (s), 991 (w), 878 (m), 784 (s), 709 (m), 634 (w).
1H NMR (400 MHz, CDCl3) δ: 7.28-7.23 (ov m, 2H, Ar),
6.85 (m, 1H, Ar), 6.50 (br s, 1H, NH), 4.92 (d, J = 4.8 Hz,
1H, CHN), 2.69-2.48 (ov m, 8H, 4× NCH2), 1.52 (br s, 2H,
NH2), 1.28 (s, 12H, pin). 11B NMR (128 MHz, CDCl3) δ:
10.0 (sharp). 13C{1H} NMR (100 MHz, CDCl3) δ: 159.0
4.1.6
Synthesis of 2-(2-fluoro-6-(4,4,5,5-
|
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-
1,2,3,4-tetrahydroquinazoline (6)
A Et2O (5 mL) solution of 1 (0.94 g, 3.76 mmol) was added
dropwise to a Et2O (5 mL) solution of 2-aminobenzylamine
(0.46 g, 3.76 mmol). The reaction was allowed to proceed at
RT for 30 hours, at which point the solvent was removed under
vacuum to afford an off-white solid which was washed with

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ZHU et al.
|
TABLE 2 Antibacterial activities (IC50s and MICs in μmol L−1) of compounds 1-10
S. aureus
MRSA
E. coli
Compound
IC50 [95% CI]a
MICb
IC50c [95% CI]a
MICb
IC50 [95% CI]a
MICb
1
2
3
4
5
6
7
8
9
83.0 [65.6, 91.0]
70.6 [57.9, 86.2]
94.1 [75.5, 117.1]
108.8 [88.0, 134.6]
91.5 [72.7, 115.1]
104.2 [90.3, 120.3]
98.9 [81.7, 119.7]
87.4 [70.8, 108.0]
43.8 [33.3, 57.5]
95.5 [80.6, 113.1]
1000
1000
1000
1000
500
128.5 [121.0, 136.5]
94.3 [87.4, 101.8]
119.6 [113.5, 126.0]
223.1 [209.5, 237.6]
103.8 [98.3, 109.6]
96.5 [90.4, 103.0]
229.6 [213.3, 247.1]
376.4 [350.5, 404.2]
158.2 [150.2, 166.7]
66.02 [61.4, 70.9]
500
1000
1000
1000
1000
184.9 [170.8, 200.2]
Inactived
500
Inactived
Inactived
Inactived
500
Inactived
Inactived
219.5 [208.9, 230.6]
Inactived
1000
1000
Inactived
Inactived
Inactived
500
>1000
>1000
1000
>1000
>1000
1000
Inactived
Inactived
173.4 [160.7, 187.0]
Inactived
10
>1000
1000
Inactived
a95% confidence interval (n = 3).
bMIC is defined as the lowest testing concentration which inhibited growth by a mean value of >90%.
cIC50 values estimated by Trimmed Spearman-Karber method.
dLess than 20% inhibition in initial screening (100 μmol L−1) was considered inactive.
TABLE 3 Antifungal activities (IC50s and MICs in μmol L−1) of compounds 1-10
S. cerevisiae
C. albicans
Compound
IC50 [95% CI]a
MICb
IC50 [95% CI]a
MICb
1
2
3
4
5
6
7
8
9
10
71.0 [64.8, 77.8]
36.6 [33.7, 39.8]
86.1 [81.7, 90.7]
17.1 [13.3, 21.8]
95.5 [89.6, 101.9]
88.3 [82.8, 94.1]
108.9 [65.1, 182.1]
94.1 [89.1, 99.3]
56.5 [53.2, 60.0]
187.5 [173.2, 202.9]
125
62.5
125
250
250
250
250
250
125
500
103.7 [99.6, 107.9]
107.4 [101.3, 113.9]
108.3 [101.9, 115.1]
122.0 [111.3, 133.7]
118.4 [111.4, 125.7]
111.5 [105.4, 118.0]
140.6 [132.2, 149.5]
129.1 [124.4, 133.9]
66.6 [59.2, 74.8]
250
250
250
500
250
250
500
250
125
Inactivec
Inactivec
a95% confidence interval (n = 3).
bMIC is defined as the lowest testing concentration which inhibited growth by a mean value of >90%.
cLess than 20% inhibition in initial screening (100 μmol L−1) was considered inactive.
(d, JCF = 249.8 Hz), 149 (br, CB), 130.8 (d, JCF = 5.7 Hz),
129.4 (d, JCF = 9.5 Hz), 125.5 (d, JCF = 3.8 Hz), 115.1 (d,
JCF = 20.0 Hz), 83.7 (d, JCF = 2.9 Hz), 80.2, 58.3, 51.9,
42.8, 41.0, 26.2, 25.5. 19F{1H} NMR (188 MHz, CDCl3) δ:
−119.7. Anal. Calc. for C17H27N3BFO2 (335.22 g/mol) (%):
C 60.91, H 8.12, N 12.53. Found: C 61.03, H 8.22, N 12.66.
of salicylaldehyde (0.37 g, 3.03 mmol), and the reaction
was heated at reflux for 8 hours. The solvent was removed
under vacuum, and the resulting yellow solid was recrys-
tallized from CH2Cl2 (5 mL) and hexane (10 mL) to afford
8 as a yellow solid. Yield: 0.27 g (20%); mp 90-91°C. IR:
3122 (w), 2972 (w), 1635 (m, νC=N), 1460 (w), 1279 (w),
1
1243 (m), 989 (m), 966 (m), 841 (m), 786 (s), 757 (w). H
NMR (400 MHz, CDCl3) δ: 13.35 (br s, 1H, OH), 8.29 (s,
1H, HC=N), 7.31-7.22 (ov m, 4H, Ar), 6.94 (d, J = 8.2 Hz,
1H, Ar), 6.92-6.85 (ov m, 2H, Ar), 6.62 (br s, 1H, NH), 4.91
(d, JHH = 5.0 Hz, 1H, CHN), 3.62 (br m, 2H, NCH2), 3.40
(m, 2H, NCH2), 2.98-2.74 (ov m, 2H, NCH2), 2.65 (m, 2H,
NCH2), 1.30 (s, 12H, pin). 11B NMR (128 MHz, CDCl3) δ:
10.0 (sharp). 13C{1H} NMR (100 MHz, CDCl3) δ: 166.4,
4.1.8
Synthesis of 2-(((2-(2-(2-fluoro-6-
|
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)
phenyl)imidazolidin-1-yl)ethyl)imino)methyl)
phenol (8)
To a stirred CH2Cl2 (5 mL) solution of compound 7
(1.01 g, 3.01 mmol) was added a CH2Cl2 (5 mL) solution

ZHU et al.
9 of 11
|
161.2, 158.9 (d, JCF = 252.1 Hz), 149 (br, CB), 132.3, 131.5,
130.9 (d, JCF = 5.8 Hz), 129.2 (d, JCF = 9.6 Hz), 125.7 (d,
JCF = 2.9 Hz), 118.9, 118.7, 117.1, 115.1 (d, JCF = 19.2 Hz),
83.4, 80.3, 59.0, 55.6, 52.8, 43.1, 26.2, 25.6. 19F{1H} NMR
(188 MHz, CDCl3) δ: −125.8. Anal. Calc. for C24H31N3BFO3
(439.33 g/mol) (%): C 65.61, H 7.11, N 9.56. Found: C 65.73,
H 7.43, N 9.76.
26.3 (br), 25.7 (br). 19F NMR (188 MHz, DMSO-d6) δ:
−113.8. Anal. Calc. for C48H60N6B2F2O6Zn (942.03 g/
mol) (%): C 61.20, H 6.42, N 8.92. Found: C 61.37, H
6.44, N 8.72.
4.2
Stability testing of boron compounds
|
In an NMR tube, compounds 1-10 were dissolved in DMSO
and analyzed by 11B NMR spectroscopy. The solutions were
stored at 37°C for 2 days at which point the compounds were
reanalyzed by 11B NMR spectroscopy. No significant degra-
dation of the compounds was observed over this time period.
4.3
X-ray crystallography
|
4.1.9
Synthesis of bis-(2-((E)-((2-(2-
|
Crystals of 4 and 5 were grown from saturated solutions of
CH2Cl2 and Et2O (1:1 volume) stored at 5°C. Crystals of 6
were grown from a saturated solution of CHCl3 stored at RT.
Single crystals were coated with Paratone-N oil, mounted
using a polyimide MicroMount, and frozen in the cold ni-
trogen stream of the goniometer. A hemisphere of data was
collected on a Bruker AXS P4/SMART 1000 diffractometer
using ω and ϕ scans with a scan width of 0.3° and 10-second
exposure times. The detector distance was 5 cm. The data
were reduced (SAINT)[26] and corrected for absorption
(SADABS).[27] The structure was solved by direct methods
and refined by full-matrix least squares on F2 (SHELXTL).[28]
All nonhydrogen atoms were refined using anisotropic dis-
placement parameters. Hydrogen atoms were included in cal-
culated positions and refined using a riding model with the
exception of N-H hydrogen atoms for 4 that were found in
Fourier difference maps and refined using isotropic displace-
ment parameters. Crystallographic data have been deposited
with the Cambridge Crystallographic Data Centre as supple-
mentary publication numbers 1557696-1557698.
(2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)phenyl)imidazolidin-1-yl)
ethyl)imino)methyl)phenoxy)zinc(II) (9)
Complex 9 was synthesized under an atmosphere of dini-
trogen. At −78°C, a THF (3 mL) solution of compound 8
(0.53 g, 1.21 mmol) was added dropwise to a stirred THF
(3 mL) solution of diethylzinc (0.6 mL of a 1 mol L−1 so-
lution in hexanes, 0.6 mmol). The reaction was allowed
to warm to RT over a period of 12 hours at which point
solvent was removed under vacuum. The resulting yellow
solid was dissolved in CH2Cl2 (5 mL), and hexane (5 mL)
was added and the solution stored at −30°C. An off-white
precipitate was collected by suction filtration and washed
with cold hexane (2 × 1 mL) to afford 9. Yield: 0.35 g
(62%); mp 157-158°C. IR: 2970 (w), 1617 (s, νC=N), 1536
(m), 1447 (s), 1322 (m), 1245 (m), 1149 (m), 1093 (m),
1
967 (m), 892 (m), 755 (m), 597 (m). H NMR (400 MHz,
DMSO-d6) δ: 8.43 (s, 2H, HC=N), 7.22-7.12 (ov m, 6H,
Ar), 7.01 (d, J = 7.3 Hz, 2H, Ar), 6.80-6.73 (ov m, 2H,
Ar), 6.61 (m, 2H, Ar), 6.51 (t, J = 7.3 Hz, 2H, Ar), 5.42
(m, 2H, CHN), 3.67 (br m, 4H, NCH2), 3.14 (br m, 2H,
NCH2), 2.94 (br m, 2H, NCH2), 2.74 (br m, 2H, NCH2),
2.66-2.63 (br ov m, 4H, NCH2), 2.43 (m, 2H, CH2), 1.09
(br s, 24H, pin). 11B NMR (128 MHz, (CD3)2CO) δ: 10.4
(sharp). 13C{1H} NMR (100 MHz, DMSO-d6) δ: 173.2,
170.5, 158.8 (d, JCF = 249.8 Hz), 152 (br, CB), 136.6,
134.8, 130.3 (d, JCF = 5.8 Hz), 129.3 (d, JCF = 8.6 Hz),
126.0, 122.8, 118.8, 114.3, 114.1 (d, JCF = 20.1 Hz), 82.9,
82.7, 79.6, 59.5, 59.4, 54.6, 54.4, 52.3, 52.1, 42.5, 42.2,
4.4
Antibiotic susceptibility
|
screening assay
Antibacterial activity against Staphylococcus aureus (ATCC
29213), methicillin-resistant Staphylococcus aureus (MRSA,
ATCC 33591), Enterococcus faecium (ATCC 35667),
Escherichia coli (ATCC 25922), and Pseudomonas aerugi-
nosa (ATCC 10145) and antifungal activity against Candida
albicans (ATCC 14053) and Saccharomyces cerevisiae
(ATCC 9763) were evaluated using a microbroth dilution
antibiotic susceptibility assay modified from McCulloch
et al.[29] Stock solutions (50 mmol/L) of compounds 1-10
were prepared in sterile-filtered DMSO, stored at 4°C, and
used within 1 week. Immediately prior to use, the stock solu-
tions (30 μL) were diluted with the appropriate nutrient broth
(720 μL). The resulting test solutions (100 μL) were then

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ZHU et al.
|
transferred to nonperipheral wells of a 96-well microtiter
plate in triplicate. Sterile water (100 μL) was added to perim-
eter wells to reduce evaporation from the plate. Wells were
then inoculated with suspensions of the appropriate micro-
bial strain (100 μL) of cell density 5 × 105 colony-forming
units (CFU)/mL. Positive controls consisted of an appropri-
ate antibiotic tested in triplicate (0.625 μg/mL erythromycin
for S. aureus; 5 μg/mL vancomycin for methicillin-resistant
S. aureus; 0.625 μg/mL tetracycline for E. faecium; 1.25 μg/
mL gentamicin for E. coli; 10 μg/mL gentamicin for P. aer-
uginosa; 2.5 μg/mL nystatin for C. albicans; and 2.5 μg/mL
amphotericin B for S. cerevisiae) as 4% DMSO solutions in
the appropriate broth inoculated with suspensions of the ap-
propriate organism (100 μL). In addition to test and positive
control wells, each plate contained three untreated controls
[4% DMSO in the appropriate nutrient broth (100 μL) inocu-
lated with suspensions of the appropriate pathogen (100 μL)]
and three uninoculated blanks (200 μL of 2% DMSO in the
appropriate nutrient broth). The optical densities of the wells
were measured before and after a 24-hour incubation period
(37°C), and the change in optical density (ΔOD) was calcu-
lated by subtracting the initial optical density from the final
optical density of corresponding wells. ΔOD values were
corrected for background absorbance of the media by sub-
tracting the mean ΔOD readings of the blanks from the mean
ΔOD readings of the control and test compound wells. The
percentage inhibition of bacterial or fungal growth was then
defined as [1 − (mean test or positive control ΔOD/mean
negative control ΔOD)] × 100.
ACKNOWLEDGMENTS
The authors thank Dan Frostilicus Durant for his expert
chemical assistance, Mount Allison University (ISRG-DZ),
the University of New Brunswick (CAG) and NSERC (SAW
& CAG) for funding, and an anonymous reviewer for their
very helpful comments.
ORCID
Stephen A. Westcott
http://orcid.org/0000-0002-5324-2295
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