Synthesis, structure, and antifungal activity of dihydropyridones containing boronate esters

Article abstract of DOI:10.1002/hc.20512

We have prepared a series of novel 2,3-dihydro-4-pyridones containing boronate esters using the aza Diels-Alder reaction with Danishejsky's diene and imines derived from formylphenylboronic acids. This reaction can be carried out in moderate to high yield

Full text of DOI:10.1002/hc.20512

Heteroatom Chemistry
Volume 20, Number 1, 2009
Synthesis, Structure, and Antifungal Activity of
Dihydropyridones Containing Boronate Esters
Francis E. Appoh,1 Susan L. Wheaton,1 Christopher M. Vogels,1
Felix J. Baerlocher,2 Andreas Decken,3 and Stephen A. Westcott1
1Department of Chemistry, Mount Allison University, Sackville, NB E4L 1G8, Canada
2Department of Biology, Mount Allison University, Sackville, NB E4L 1G7, Canada
3Department of Chemistry, University of New Brunswick, Fredericton, NB E3B 5A3, Canada
Received 12 March 2008; revised 6 July 2008
hibitors [3]. Bortezomib (PS-341, Velcade; Fig. 1b)
ABSTRACT: We have prepared a series of novel 2,3-
is a novel boronic acid dipeptide that potently, selec-
dihydro-4-pyridones containing boronate esters using
tively, and reversibly inhibits 26S proteasome and
the aza Diels–Alder reaction with Danishefsky’s diene
was developed specifically for the therapy of hu-
and imines derived from formylphenylboronic acids.
man tumors [4]. Preclinical studies have shown that
This reaction can be carried out in moderate to high
Bortezomib inhibited proliferation at a mean IC50 of
yields using Yb(OTf)3 as a Lewis acid catalyst. Two
7 nM in 60 cell lines included in the National Cancer
new boron compounds exhibited moderate antifungal
Institute’s panel. Amino acid derivatives containing
activity (at 100 μg disk−1) using Amphotericin B as a
boron have also been investigated for their use in
ꢀ
C
control. 2009 Wiley Periodicals, Inc. Heteroatom Chem
boron neutron capture therapy (BNCT) for the treat-
ment of cancer [5]. BNCT is a bimodal form of ther-
apy that depends on selectively depositing boron-10
20:56–63, 2009; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20512
atoms into the cancerous tumor before irradiation
by slow neutrons. 4-Dihydroxyborylphenylalanine
INTRODUCTION
(Fig. 1c) has shown promise in the treatment of
brain tumors. Also of importance is the recent ob-
servation that benzoxarole compounds (5-fluoro-
3H-benzo[c] [1,2]oxaborol-1-ol, Fig. 1d) display
considerable antifungal activity [6]. A remarkable
property of boron, and in particular boronic acids,
is their ability to selectively transport carbohydrates
and other molecules across lipophilic membranes
for potential applications in drug delivery [11]. A
considerable amount of research has therefore fo-
cused on the synthesis of these potentially valuable
compounds.
Compounds containing boronic acids [RB(OH)2] or
boronate esters [RB(OR’)2] are remarkably useful
precursors for the Suzuki–Miyaura cross-coupling
reactions [1] and as molecular recognition sensors
[2]. Interest in these compounds also arises from
their potent biological activities [3–10]. For instance,
boron amino acid derivatives (Fig. 1a) are strong in-
hibitors of human arginase II, whose primary func-
tion appears to be in L-arginase homeostasis. Re-
lated α-aminoboronic acid derivatives are also well
known for their ability to act as serine protease in-
As part of our ongoing investigation into making
novel boron compounds [12], and considering the
wealth of bioactivities found in aminoboronic acid
derivatives, we decided to examine the synthesis of
boron-containing 2,3-dihydro-4-pyridones using the
aza Diels–Alder reaction with Danishefsky’s diene.
Correspondence to: Stephen A. Westcott; e-mail: swestcott@
mta.ca.
Contract grant sponsor: Medical Research Fund of New
Brunswick, Canada.
c
ꢀ
2009 Wiley Periodicals, Inc.
56

Synthesis, Structure, and Antifungal Activity of Dihydropyridones Containing Boronate Esters 57
compounds having spectroscopic data consistent
with the aldimines 1a–h (Scheme 1). All imines
have been characterized by multinuclear NMR spec-
troscopy and show a signal for the N CH methine
proton between δ 8.43 and 9.18 ppm in the 1H NMR
spectra. A resonance at ca. 155 ppm in the 13C NMR
spectra corresponds to the sp2 carbon of the N CH
group. A broad peak at around 30 ppm in the 11B
NMR spectra suggests that the boron atom lies in a
three-coordinate environment in solution [16]. The
molecular structure of 1e has also been confirmed
by a single crystal X-ray diffraction study (Fig. 2).
˚
FIGURE 1 Bioactive boron compounds.
The imine C(10) N(9) bond distance of 1.277(3) A
is comparable to azomethine compounds derived
from salicylaldehyde and phenylboronic acid [17].
˚
The B O bond distances (avg. = 1.361(3) A) are also
Previous studies have shown that compounds con-
taining boronic acids can be extremely difficult to
characterize in terms of elemental composition, ow-
ing to the ease with which they partially dehydrate
to the corresponding trimeric and oligomeric anhy-
drides [13]. As such, we have decided to initially pre-
pare the corresponding boronate ester derivatives;
the results of which are presented herein.
typical for three-coordinate boron [16,18–20] and
significantly shorter than those observed in chelate
complexes with diphenylborinic acid [21] or phenyl-
˚
boronic acid derivatives (ca. 1.5 A) [22], where the
boron atom is four-coordinate.
Although a number of Lewis acids can be used to
facilitate the aza Diels–Alder reaction, we have found
that Yb(OTf)3 effectively catalyzes the addition of
these boron-containing imines to Danishefsky’s di-
ene in moderate to high yields (Scheme 1) [23–27].
Attempts to improve yields using other Lewis acids
or methodologies [27] proved unsuccessful. All new
2,3-dihydro-4-pyridones 2a–h have been character-
ized by a number of physical methods including
RESULTS AND DISCUSSION
Synthesis
The aza Diels–Alder reaction of Danishefsky’s di-
ene with imines is a powerful synthetic method
for preparing 2-substituted 2,3-dihydro-4-pyridones
that has received a considerable amount of atten-
tion. Dihydropyridone derivatives are highly versa-
tile synthetic intermediates for the preparation of
biologically important molecules [14]. As such, we
have decided to prepare a series of boron-containing
2,3-dihydro-4-pyridones using Danishefsky’s diene
and preformed imines containing boronate esters.
Imines incorporating boron groups have also re-
ceived significant attention. For instance, Whiting
and coworkers used imines containing boronate
esters to make enantio-enriched γ -phenyl-γ -amino
alcohols [15]. Incorporation of the boronate es-
ter functionality in these cases was accomplished
by deprotonation of acetophenone-derived imines
followed by alkylation with ICH2Bpin (pin = 1,2-
O2C2Me4) at low temperatures. Reduction of the
imine was achieved using BH3 reagents. In this
study, we found that pinacol protected derivatives
of formylphenylboronic acid [(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)benzaldehyde] add to ani-
sidine or 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)aniline (3-APBpin) in organic solvents to give
1
multinuclear NMR spectroscopy. The H NMR for
compounds 2a–h shows a diagnostic pair of doublets
for the alkene fragment of the pyridone ring in the
aromatic region and a sharp singlet at ca. δ 1.35 ppm
for the pinacol hydrogens. A broad peak at around
30 ppm is once again observed in the 11B NMR spec-
tra, where the boron atom remains three coordinate.
This result is somewhat surprising in light of boron’s
propensity to form coordinate bonds with Lewis ba-
sic atoms [28]. The corresponding 13C NMR data
are also consistent with the formation of these novel
pyridone, and the broad peak at ca. δ 140 ppm sig-
nifies the C B bond for the Ar-Bpin groups. Com-
pounds 2e and 2f have also been characterized by
single crystal X-ray diffraction studies (Figs. 3 and
4), and the average B O bond distances of 1.357(4)
˚
(2e) and 1.365(4) (2f) A are consistent with three-
coordinate boron compounds. Bond distances and
angles within the pyridone ring are well within the
range observed in related compounds [29]. No ap-
preciable intra- or intermolecular interactions be-
tween the Lewis acidic boron atom and the nitrogen
groups are observed in the solid state.
Heteroatom Chemistry DOI 10.1002/hc

58 Appoh et al.
SCHEME 1
aldimines derived from 3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)benzenamine. Benzylamine com-
pounds generated from this boron-containing ani-
line have shown moderate antifungal activities [30].
Antifungal Studies
Compounds 2f–h are of special interest as they con-
tain two boronate ester groups and are prepared
from the [4+2] addition of Danishefsky’s diene with
FIGURE 2 Perspective view of one of the independent molecules of 1e with atom labeling scheme. Thermal ellipsoids are
◦
˚
drawn at the 50% probability level, and hydrogen atoms are omitted for clarity. Selected bond lengths (A) and angles ( ):
N(9)–C(10) 1.277(3), C(14)–B(16) 1.559(3), C(14)–S(15) 1.727(2), B(16)–O(20) 1.358(3), B(16)–O(17) 1.364(3), C(11)–S(15)
1.731(2); C(10)–N(9)–C(6) 120.4(2), O(20)–B(16)–O(17) 114.6(2), O(20)–B(16)–C(14) 122.5(2), O(17)–B(16)–C(14) 122.9(2).
Heteroatom Chemistry DOI 10.1002/hc

Synthesis, Structure, and Antifungal Activity of Dihydropyridones Containing Boronate Esters 59
tives [32], we have studied the potential antifungal
activity of our new boron-containing compounds.
Initial studies were carried out using four fungi,
Aspergillus niger, A. flavus, Candida albicans, and
Saccharomyces cerevisiae, employing Amphotericin
B (AmB) as a control [12,33–35]. Although com-
pounds 2a and 2b both showed appreciable activity
(Table 1), the para derivative 2c was inactive (not
shown). Likewise, no activity was observed for 2f,
where the para methoxy substituent of the initial
aniline derivative has been replaced with a meta-
substituted boronate ester functionality. The non-
boron control, prepared by the methodology devel-
oped by Feng et al. [25–27], showed no apprecia-
ble antifungal activity in this study. It is unclear at
this time what role the boron groups have on the
observed activities, and further work is therefore
needed to fully understand the structure activity re-
lationships in these compounds in an effort to design
a more powerful antifungal agent.
CONCLUSION
FIGURE 3 Perspective view of 2e with atom labeling
In summary, we have prepared the first examples of
boron-containing 2,3-dihydro-4-pyridones from the
addition of imines, synthesized from commercially
available aldehydes containing boronic acids, and
Danishefsky’s diene. Products have been character-
ized by a number of physical methods, including X-
ray diffraction studies for 1e, 2e, and 2f. Although
most of these compounds showed no appreciable an-
tifungal activity, the 2- and 3-boronated derivatives
2a and 2b, respectively, showed good activity against
four fungi. We are in the process of preparing other
scheme. Thermal ellipsoids are drawn at the 50% probability
level, and hydrogen atoms are omitted for clarity. Selected
bond lengths (A) and angles ( ): O(1)–C(2) 1.234(3), C(3)–
C(4) 1.364(3), C(11)–B(13) 1.559(4), B(13)–O(14) 1.355(4),
B(13)–O(17) 1.358(4); O(1)–C(2)–C(3) 123.9(2), O(1)–C(2)–
C(7) 121.4(2), O(14)–B(13)–O(17) 114.6(3), O(14)–B(13)–
C(11) 121.6(3), O(17)–B(13)–C(11) 123.7 (3).
◦
˚
With this in mind, we have examined all new com-
pounds for their ability to act as antifungal agents.
Given the wealth of bioactivities exhibited by
2,3-dihydro-4-pyridones [31] and 4-pyridone deriva-
FIGURE 4 Perspective view of one of the independent molecules of 2f with atom labeling scheme. Thermal ellipsoids are
◦
˚
drawn at the 50% probability level, and hydrogen atoms are omitted for clarity. Selected bond lengths (A) and angles ( ):
O(1)–C(2) 1.233(4), C(3)–C(4) 1.349(4), C(13)–B(14) 1.575(5), B(14)–O(15) 1.360(4), B(14)–O(18) 1.370(4), B(29)–O(33)
1.360(4), B(29)–O(30) 1.369(4); O(1)–C(2)-C(3) 123.7(4), O(1)–C(2)–C(7) 120.5(3), O(15)–B(14)–O(18) 112.9(3), O(15)–
B(14)–C(13) 127.3(3), O(18)–B(14)–C(13) 119.7(3), O(33)–B(29)–O(30) 113.2(3), O(33)–B(29)–C(27) 124.7(3), O(30)–B(29)–
C(27)121.9(3).
Heteroatom Chemistry DOI 10.1002/hc

60 Appoh et al.
TABLE 1 Antifungal Testing at a Dosage of 100 μg Disk−1
a plug of silica gel. The CHCl3 eluent was fur-
ther purified by column chromatography, using
CHCl3/ethylacetate/hexanes (6:3:2) to afford the de-
sired product.
Clear Zone (mm)
Compound A. niger A. flavus C. albicans S. cerevisiae
2a
2b
2c
2d
2e
2f
2g
2h
AmB
7
10
0
0
0
0
0
0
11
0
7
0
0
0
0
0
0
11
7 halo
7 halo
7 halo
2,3-Dihydro-1-(4-methoxyphenyl)-2-(2-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridin-
4(1H)-one (2a). Yield: 68%; mp = 72–74◦C. 1H
NMR (CDCl3) δ: 7.86 (d, J = 6.7 Hz, 1H), 7.70 (d,
J = 6.4 Hz, 1H), 7.36–7.22 (ov m, 2H), 6.95 (d,
J = 8.3 Hz, 2H), 6.77 (d, J = 8.3 Hz, 2H), 6.08 (dd,
J = 7.8, 3.2 Hz, 1H), 5.27 (m, 2H), 3.72 (s, 3H),
3.30 (dd, J = 16.4, 7.8 Hz, 1H), 2.63 (dd, J = 16.4,
9
0
0
0
0
0
0
9
0
0
0
0
0
0
9
1
3.2 Hz, 1H), 1.35 (s, 12H); 13C{ H} NMR (CDCl3)
δ: 191.7, 156.6, 150.1, 145.4, 141 (br, C-B), 138.6,
137.7, 131.5, 127.0, 125.5, 120.5, 114.6, 101.2,
84.0, 60.4, 55.5, 44.6, 25.0;11B (CDCl3) δ: 30 (br).
FTIR (Nujol): 2955 (s), 2935 (s), 2919 (s), 2853
(s), 1612 (w), 1601 (w), 1537 (w), 1508 (m), 1462
(m), 1345 (w), 1236 (m), 1166 (w), 1030 (m), 762
(w), 638 (w). Anal. Calcd for C24H28BNO4 (405.29):
C 71.11, H 6.98, N 3.46; Found: C 71.22, H 6.96,
N 3.07. GCMS (CI+): required m/z = 405.2, found
[M + H]+ = 406.2, [M + Na]+ = 428.3.
2,3-dihydro-4-pyridones derived from formylphenyl-
boronic acids and aniline derivatives and will report
our findings in due course.
EXPERIMENTAL
General
Reagents and solvents used were purchased from
Aldrich Chemicals. The synthesis of imines [36] and
the transesterification of boronic acids with pinacol
[37] were performed by established methods. NMR
spectra were recorded on a JEOL JNM-GSX270 FT
spectrometer. 1H NMR chemical shifts are reported
in ppm and referenced to residual solvent protons
in deuterated solvent at 270 MHz. 11B NMR chem-
2,3-Dihydro-1-(4-methoxyphenyl)-2-(3-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridin-
4(1H)-one (2b). Yield: 78%; mp = 60–62◦C. 1H
NMR (CDCl3) δ: 7.84 (d, J = 6.4 Hz, 1H), 7.61 (d,
J = 7.3 Hz, 1H), 7.34–7.17 (ov m, 2H), 6.90 (d,
J = 7.5 Hz, 2H), 6.71 (d, J = 7.5 Hz, 2H), 6.04 (dd,
J = 7.3, 3.2 Hz, 1H), 5.19 (m, 2H), 3.73 (s, 3H),
3.25 (dd, J = 15.4, 7.3 Hz, 1H), 2.60 (dd, J = 15.4,
ical shifts are reported in ppm and are referenced
.
to BF3 OEt2 as an external standard at 87 MHz. 13C
1
3.2 Hz, 1H), 1.28 (s, 12H); 13C{ H} (CDCl3) δ:
NMR chemical shifts are referenced to solvent car-
bon resonances as internal standards at 68 MHz and
are reported in ppm. Multiplicities are reported as
singlet (s), doublet (d), broad (br), multiplet (m), and
overlapping (ov). The infrared spectra were obtained
using a Mattson Genesis II FTIR spectrometer and
are reported in cm−1. The melting points were de-
termined using a Mel-Temp apparatus and are un-
corrected. Microanalyses for C, H, and N were car-
ried out at Guelph Chemical Laboratories (Guelph,
ON, Canada). GCMS analyses were performed by
DalChem MS Lab (Halifax, NS, Canada).
190.8, 156.7, 153 (br, C-B), 150.0, 145.5, 138.6,
137.7, 131.5, 127.0, 125.5, 120.5, 114.6, 101.3, 84.0,
60.7, 55.6, 44.6, 25.0; 11B (CDCl3) δ: 31 (br). FTIR
(Nujol): 2933 (s), 2912 (s), 2858 (s), 1645 (w), 1590
(w), 1510 (w), 1462 (m), 1377 (m), 1348 (w), 1227
(w), 1142 (w), 1033 (w), 964 (w), 723 (w). Anal.
Calcd for C24H28BNO4 (405.29): C 71.11, H 6.98,
N 3.46; Found: C 71.09, H 7.06, N 3.14. GCMS
(CI+): required m/z = 405.2, found [M + H]+ = 406.4,
[M + Na]+ = 428.3.
2,3-Dihydro-1-(4-methoxyphenyl)-2-(4-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyridin-
4(1H)-one (2c). Yield: 75%; mp = 82–84◦C. 1H
NMR (CDCl3) δ: 7.72 (d, J = 7.3 Hz, 2H), 7.50 (d,
J = 7.9 Hz, 1H), 7.24 (d, J = 7.3 Hz, 2H), 6.90 (d,
J = 8.8 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 5.20 (d,
J = 7.9 Hz, 1H), 5.15 (m, 1H), 3.74 (s, 3H), 3.23
(dd, J = 15.7, 7.4 Hz, 1H), 2.75 (dd, J = 15.7, 4.1
General Synthesis
To a stirring solution of the appropriate boronate
ester in THF (20 mL), Danishefsky’s diene (2 equiva-
lents) and a catalytic amount of Yb(OTf)3 (20 mol%)
at RT were added. The reaction mixture was heated
at reflux for 8–24 h, at which point the solvent
was removed under vacuum. The resulting solid
was dissolved in CHCl3 (5 mL) and flashed through
1
Hz, 1H), 1.36 (s, 12H); 13C{ H} (CDCl3) δ: 189.9,
156.9, 149.9, 141.5, 138.2, 135.4, 129 (br, C-B),
Heteroatom Chemistry DOI 10.1002/hc

Synthesis, Structure, and Antifungal Activity of Dihydropyridones Containing Boronate Esters 61
125.8, 121.2, 114.7, 101.5, 83.9, 62.4, 55.5, 43.4,
131.5, 130.5, 129 (br, 2C, C-B), 128.9, 127.0, 125.3,
124.8, 121.2, 102.1, 84.2, 84.0, 59.8, 44.5, 24.9; 11B
(CDCl3) δ: 31 (br). FTIR (Nujol): 2966 (s), 2935 (s),
2873 (s), 2846 (s), 1684 (w), 1645 (w), 1581 (w),
1570 (w), 1462 (m), 1377 (m), 1317 (w), 1267 (w),
1213 (w), 1144 (w), 1115 (w), 962 (w), 760 (w), 723
(w), 660 (w). Anal. Calcd. for C29H37B2NO5 (501.23):
C 69.48, H 7.45, N, 2.79; Found: C 69.38, H 7.30,
N 2.43. GCMS (CI+): required m/z = 501.2, found
[M + H]+ = 502.4, [M + Na]+ = 524.4.
24.9; 11B (CDCl3) δ: 30 (br). FTIR (Nujol): 2978 (s),
2927 (s), 2918 (s), 2854 (s), 1613 (w), 1547 (w), 1508
(w), 1462 (m), 1376 (m), 1326 (w), 1251 (w), 1222
(w), 1141 (w), 1088 (w), 1029 (w), 638 (w). Anal.
Calcd for C24H28BNO4 (405.29): C 71.11, H 6.98, N
3.46; Found: C 70.89, H 6.93, N 3.08. GCMS (CI+):
required m/z = 405.2, found [M + Na]+ = 428.3.
2,3-Dihydro-1-(4-methoxyphenyl)-2-(5-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)furan-2-yl)pyri-
din-4(1H)-one (2d). Yield: 65%; mp = 145–147◦C.
1H NMR (CDCl3) δ: 7.30 (d, J = 7.6 Hz, 1H), 7.20 (d,
J = 7.6 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.94 (d,
J = 8.8 Hz, 2H), 6.86 (d, J = 3.2 Hz, 1H), 5.16–5.06
(ov m, 2H), 3.67 (s, 3H), 2.99–2.69 (ov m, 2H), 1.22
2,3-Dihydro-1,2-bis(3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)phenyl)pyridin-4(1H)-one
(2g).
Yield: 67%; mp = 82–84◦C. 1H NMR (CDCl3) δ: 7.76–
7.67 (ov m, 3H), 7.56–7.46 (ov m, 2H), 7.32–7.21 (ov
m, 3H), 6.95 (m, 1H), 5.30–5.24 (ov m, 2H), 3.25 (dd,
J = 15.4, 6.4 Hz, 1H), 2.78 (dd, J = 15.4, 3.3 Hz, 1H),
1
(s, 6H), 1.11 (s, 6H); 13C{ H} (CDCl3) δ: 190.3, 157.2,
1
1.36 (s, 24H); 13C{ H} (CDCl3) δ: 190.4, 148.9, 144.2,
155.8, 148.8, 138.1, 130 (br, C-B), 124.3, 121.9,
114.7, 108.9, 101.5, 84.3, 57.2, 55.5, 40.2, 24.8; 11B
(CDCl3) δ: 26 (br). FTIR (Nujol): 2952 (s), 2918
(s), 2856 (s), 1699 (w), 1577 (w), 1510 (w), 1462
(m), 1377 (m), 1350 (w), 1105 (w), 951 (w), 762
(w), 723 (w). Anal. Calcd for C22H26BNO5 (395.26):
C 66.84, H 6.64, N 3.54, Found: C 66.27, H 6.81,
N 3.23. GCMS (CI+): required m/z = 395.3, found
[M + Na]+ = 418.3.
137.2, 134.3, 132.7, 131 (br, 2C, C-B), 130.9, 129.0,
128.8, 128.2, 125.1, 121.4, 102.8, 84.2, 84.0, 61.7,
43.6, 25.0, 24.9; 11B (CDCl3) δ: 30 (br). FTIR (Nujol):
2943 (s), 2902 (s), 2860 (s), 1649 (w), 1581 (w), 1570
(w), 1462 (m), 1377 (m), 1265 (w), 1213 (w), 1144
(w), 962 (w), 708 (w). Anal. Calcd for C29H37B2NO5
(501.23): C 69.48, H 7.45, N 2.79; Found: C 69.75,
H 7.21, N 2.48. GCMS (CI+): required m/z = 501.3,
found [M + H]+ = 502.5, [M + Na]+ = 524.4.
2,3-Dihydro-1-(4-methoxyphenyl)-2-(5-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)-
pyridin-4(1H)-one (2e). Yield: 85%; mp = 173–
2,3-Dihydro-1-(3-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)phenyl)-2-(4-(4,4,5,5-tetramethyl-1,3,-
2-dioxaborolan-2-yl)phenyl)pyridin-4(1H)-one (2h).
Yield: 82%; mp = 86–88◦C. 1H NMR (CDCl3) δ: 7.75–
7.69 (ov m, 3H), 7.55–7.50 (ov m, 2H), 7.26–7.18
(ov m, 3H), 6.95 (dd, J = 6.4, 3.3 Hz, 1H), 5.30–5.24
(ov m, 2H), 3.23 (dd, J = 15.4, 6.4 Hz, 1H), 2.78
1
175◦C. H NMR (CDCl3) δ: 7.40 (d, J = 7.3 Hz, 1H),
7.36 (d, J = 8.5 Hz, 2H), 7.03 (m, 1H), 6.82 (d,
J = 8.5 Hz, 2H), 5.41 (dd, J = 7.5, 2.6 Hz, 1H), 5.21
(ov m, 2H), 3.78 (s, 3H), 3.28 (dd, J = 15.3, 7.5 Hz,
1H), 2.80 (dd, J = 15.3, 2.6 Hz, 1H), 1.31 (s, 12H);
1
13C{ H} (CDCl3) δ: 189.8, 157.2, 149.0, 148.7, 137.8,
1
(dd, J = 15.4, 3.3 Hz, 1H), 1.32 (s, 24H); 13C{ H}
137.0, 129 (br, C-B), 127.2, 126.2, 114.5, 101.8,
84.2, 58.9, 55.5, 43.4, 24.8; 11B (CDCl3) δ: 28 (br).
FTIR (Nujol): 2962 (s), 2945 (s), 2900 (s), 2870 (s),
1639 (w), 1576 (w), 1509 (w), 1462 (m), 1377 (m),
1346 (w), 1284 (w), 1242 (w), 1207 (w), 1142 (w),
1091 (w), 1025 (w), 955 (w), 829 (w), 665 (w). Anal.
Calcd for C22H26BNO4S (411.32): C 64.23, H 6.38, N
3.41; Found: C 64.55, H 6.21, N 3.08. GCMS (CI+):
required m/z = 411.3, found [M + Na]+ = 434.3.
(CDCl3) δ: 190.3, 149.0, 144.2, 141.2, 135.5, 130.9,
130 (br, 2C, C-B), 129.1, 125.7, 125.2, 121.6, 102.7,
84.2, 83.9, 61.8, 43.4, 25.9, 24.9; 11B (CDCl3) δ: 30
(br). FTIR (Nujol): 2943 (s), 2904 (s), 2858 (s), 1649
(w), 1581 (w), 1570 (w), 1462 (m), 1363 (w), 1327
(m), 1265 (w), 1219 (w), 1142 (w), 1088 (w), 1030
(w), 962 (w), 858 (w), 756 (w), 705 (w). Anal. Calcd
for C29H37B2NO5 · 2EtCO2CH3 (677.53): C 65.59, H
7.90, N 2.07; Found: C 65.19, H 7.34, N 2.28. GCMS
(CI+): required for C29H37B2NO5 m/z = 501.3, found
[M+ Na]+ = 524.4.
2,3-Dihydro-2-(2-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)phenyl)-1-(3-(4,4,5,5-tetramethyl-1,3,-
2-dioxaborolan-2-yl)phenyl)pyridin-4(1H)-one (2f).
Yield: 65%; mp = 76–78◦C. 1H NMR (CDCl3) δ: 7.91–
7.82 (ov m, 2H), 7.58–7.47 (ov m, 2H), 7.35–7.22 (ov
m, 3H), 6.98 (m, 1H), 6.17 (dd, J = 7.5, 2.5 Hz, 1H),
5.29–5.26 (ov m, 2H), 3.27 (dd, J = 15.6, 7.5 Hz,
1H), 2.64 (dd, J = 15.6, 2.5 Hz, 1H), 1.32 (s, 24H);
Biological Testing
Compounds were tested for antifungal activity
against pure cultures of A. niger, A. flavus, C. albi-
cans, and S. cerevisiae supplied by Ward’s Natural
Science Ltd. (St. Catharines, Ontario, Canada). All
cultures were maintained on Sabouraud dextrose
1
13C{ H} (CDCl3) δ: 191.1, 149.4, 145.4, 144.3, 137.7,
Heteroatom Chemistry DOI 10.1002/hc

62 Appoh et al.
◦
3
˚
˚
agar. Four agar plugs (10-mm diameter) of A. niger
or A. flavus were cut from a 5–8 day-old colony and
homogenized in distilled, sterilized water (2 mL).
From this suspension, 0.5 mL was transferred asep-
tically to a Petri plate with Sabouraud dextrose agar
(25 mL) and spread evenly over the entire surface.
A 0.5-mL aliquot of a 1-month old liquid culture
medium of C. albicans or S. cerevisiae was trans-
ferred and spread aseptically and allowed to dry.
Each plate was provided with four evenly spaced
paper disks (6-mm Fisherbrand P8 filter paper), con-
taining the compound (0, 25, 50, and 100 μg, respec-
tively). Each compound was applied to the disks as
a solution (15 mg compound per 3 mL of acetone)
where control disks were treated with neat acetone
(20 μL). Amphotericin B in acetone acted as a stan-
dard (100 μg). Test plates with fungal homogenates
were incubated at 20◦C for 48 h. Four replicate plates
were used for each test. Antifungal activity was taken
by the diameter of the clear zone surrounding the
disk; a halo indicates partial inhibition of growth.
A, β = 115.904(3) ,V = 2816.8(9) A , Z = 4, Dcalcd
=
1.182
g
cm−3, F(000) = 1072, μ = 0.078 mm−1,
R1 = 0.0518 (I > 2σ(I)), wR2 = 0.1203 (all data),
GoF = 1.007. Crystallographic information has also
been deposited with the Cambridge Crystallographic
Data Centre (CCDC 675383-675385).
ACKNOWLEDGEMENTS
The authors thank Mount Allison University,
the Canada Research Chairs Program, the Cana-
dian Foundation for Innovation/Atlantic Innovation
Fund, Merck Frosst Canada and Co., and the Medical
Research Fund of New Brunswick for financial sup-
port. The authors also thank Dan Durant (MtA) and
Roger Smith (MtA) for expert technical assistance
and anonymous reviewers for helpful comments.
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X-Ray Diffraction Studies
Crystals of 1e, 2e, and 2f were grown from saturated
THF solutions at 20◦C. Single crystals were coated
with Paratone-N oil, mounted using a polyimide Mi-
croMount and frozen in the cold nitrogen stream of
the goniometer. A hemisphere of data was collected
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˚
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˚
˚
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3
˚
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˚
◦
˚
3
clinic, P2(1)/c, a = 16.475(4) A, b= 11.295(3) A,
˚
˚
c= 12.109(3) A, β = 107.021(3) , V = 2154.6(8) A ,
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mm−1, R1 = 0.0487 (I > 2σ(I)), wR2 = 0.1489 (all
data), GoF = 1.038. Crystallographic data for 2f:
C29H37B2NO5, Mw = 501.22, monoclinic, P2(1),
˚
˚
a = 10.0450(19) A, b= 28.599(6) A, c = 10.900(2)
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