Synthesis and biological evaluation of novel benzoxaboroles as potential antimicrobial and anticancer agents

Article abstract of DOI:10.1002/jhet.1777

Several novel benzoxaborole derivatives were synthesized starting from 2-formylphenylboronic acid utilizing Baylis-Hillman reaction, Barbier allylation, Passerini reaction, and aldol reaction protocols as the key step. All the synthesized benzoxaboroles have been evaluated for their antibacterial, antifungal, and anticancer activities.

Full text of DOI:10.1002/jhet.1777

814
Synthesis and Biological Evaluation of Novel Benzoxaboroles as Potential
Antimicrobial and Anticancer Agents
Vol 50
J. Sravan Kumar,a M. A. Alam,a Shirisha Gurrapu,a Grady Nelson,a Michael Williams,a Michael A. Corsello,b
b
Joseph L. Johnson,a Subash C. Jonnalagadda, and Venkatram R. Mereddya
*
aDepartment of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, Minnesota 55812, USA
bDepartment of Chemistry and Biochemistry, Rowan University, Glassboro, New Jersey, 08028, USA
*
E-mail: jonnalagadda@rowan.edu
Received February 13, 2012
DOI 10.1002/jhet.1777
Published online 24 June 2013 in Wiley Online Library (wileyonlinelibrary.com).
Several novel benzoxaborole derivatives were synthesized starting from 2-formylphenylboronic acid
utilizing Baylis–Hillman reaction, Barbier allylation, Passerini reaction, and aldol reaction protocols as the
key step. All the synthesized benzoxaboroles have been evaluated for their antibacterial, antifungal, and
anticancer activities.
J. Heterocyclic Chem., 50, 814 (2013).
INTRODUCTION
of methyl acrylate with boronobenzaldehyde 6a in the
presence of catalytic amount of DABCO proved to be
sluggish, and many unreacted starting material remained
even after stirring for 3 days. However, increasing the
amount of DABCO to stoichiometric quantities led to the
completion of the reaction in 24h to afford the product
benzoxaborole 7a in 58% yield (entry 1, Table 1). Similarly,
the other borono aldehydes 6b–c also reacted with methyl
acrylate furnishing the corresponding benzoxaboroles 7b–c
in 54% and 56% yields, respectively, in the presence of
stoichiometric DABCO (entries 2–3, Table 1). However,
the reaction with both of these aldehydes proved to be quite
slow presumably because of the electron donating alkoxy
substituents present on the benzene ring thereby resulting
in the diminished reactivity. In these cases, the reaction
required longer time (5–7 days) for completion.
The reaction of boronoaldehydes 6a–c with phenyl
acrylate proved facile, and the products benzoxaboroles
7d–f were isolated in good yields (entries 4–6, Table 1).
Similarly, the BH reaction of boronobenzaldehydes 6a–c
with other activated alkenes such as methyl vinyl ketone
and acrylonitrile provided benzoxaboroles 7g–i (entries
7–9, Table 1) and 7j–l (entries 10–12, Table 1), respec-
tively, in moderate to good overall yields (Table 1).6a
We further extended the utility of this methodology to the
reaction of a,b-unsaturated cyclic ketones with boronoalde-
hyde. Thus, the reaction of cyclohex-2-enone with borono-
benzaldehyde 6a in the presence of PBu3 provided clean
product 7m in 56% yield (Scheme 1).
B-Hydroxy-1,2-oxaborolanes (benzoxaboroles) are
extremely valuable cyclic boronic acid synthons in organic
synthesis for Suzuki cross-coupling reactions.[1,2] These
cyclic compounds are chemically very stable, and some
of these compounds were found to possess excellent
material[3] and biological properties as antifungal, antibac-
terial, antimalarial, and anti-inflammatory agents (Fig. 1).
[4,5] We have been working on the development of novel
synthetic methodologies for the synthesis of functionalized
benzoxaboroles as potential therapeutic agents.[6] Previ-
ously, we have synthesized several benzoxaboroles using
Baylis–Hillman (BH),6a Barbier allylation,6a and Passerini
reaction6b protocols. In continuation of our interest on
the development of structurally diverse benzoboroxoles,
we synthesized several novel derivatives starting from
2-formylphenylboronic acid utilizing aldol reaction as the
key step. In this account, we report our studies on the synthe-
sis of diversely functionalized benzoxaboroles and studies
on their biological properties as potential antimicrobial and
anticancer agents.
RESULTS AND DISCUSSION
We first initiated the project with the synthesis of
a-acrylate substituted benzoxaboroles via BH reaction.
[7] This reaction is a highly atom-efficient and environmen-
tally benign carbon–carbon bond-forming reaction, and it
forms highly functionalized allylic alcohols upon condensa-
tion of acrylates with aldehydes.[7] For this reaction, we
chose methyl acrylate, phenyl acrylate, methyl vinyl ketone,
and acrylonitrile as the activated olefins and three borono-
benzaldehydes 6a–c as the boron counterparts. The reaction
After obtaining the benzoboroxoles 7a–m, we investi-
gated the synthesis of homologs of these boroles. For this
purpose, we chose Barbier allylation of boronoaldehydes
6a–c with allylic bromides 9a–b derived from BH reaction.
© 2013 HeteroCorporation

July 2013
Synthesis and Biological Evaluation of Novel Benzoxaboroles as
Potential Antimicrobial and Anticancer Agents
815
OH
OH
OH
HO
OH
NC
B
OH
B
B
B
B
O
O
O
O
O
O
O
F
4
Cl
2
3
1
5
AN2728
AN2718
AN2690
Activity against
Plasmodium
falciparum
anti-inflammatory
activity against Psoriasis
Activity against
Tenia Pedis
Activity against
Onychomycosis
Figure 1. Clinically important benzoxaboroles.
Table 1
Baylis–Hillman reaction of boronobenzaldehyde for the synthesis of functionalized benzoxaboroles.
Entry
1
Aldehyde
(CH2═CH)EWG
Product
Yield
58
6a
7a
2
3
54
56
6b
7e
6c
6a
7i
4
5
45
43
7b
6b
7f
(Continues)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

816
J. Sravan Kumar, M. A. Alam, S. Gurrapu, G. Nelson, M. Williams, M. A. Corsello,
J. L. Johnson, S. C. Jonnalagadda, and V. R. Mereddy
Vol 50
Table 1 (Continued)
Entry
6
Aldehyde
(CH2═CH)EWG
Product
Yield
41
6c
6a
7j
7
8
49
44
7c
6b
7g
9
41
6c
6a
7k
7d
10
11
69
62
6b
6a
7h
12
54
7l
Journal of Heterocyclic Chemistry
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Synthesis and Biological Evaluation of Novel Benzoxaboroles as
Potential Antimicrobial and Anticancer Agents
817
Scheme 1. Preparation of a-cyclohexenonyl benzoxaborole.
We then utilized the boronoaldehyde for Passerini
reaction[8] to synthesize a-amido benzoxaboroles 15a–i.
The reaction of aldehyde 6a with benzyl isonitrile 14a,
O
OH
B
HO
t
B
O
O
cyclohexyl isonitrile 14b, and butyl isonitrile 14c and the
OH
product boroles 15a–c were obtained in good yields upon
silica gel column chromatography (Scheme 3).6b Similarly
the aldehydes 6b–c were also reacted with the three
isonitriles 14a–c to provide the corresponding benzoxabor-
oles 15d–i in good yields (Scheme 3).
O
PBu3
56%
6a
H
7m
We also explored the aldol reaction of methyl ketones with
boronoaldehyde 6a to synthesize b-ketobenzoxaboroles. The
initial reaction of acetophenone 16a with bases such as NaH,
sodium hydroxide, and boronoaldehyde 6a did not result in
clean product formation in synthetically useful yields. How-
ever, the enolate generation with LDA at À78ꢀC followed by
the addition of boronoaldehyde 6a provided yield of the
corresponding aldol product in 60% yield based on recovered
starting material (brsm) (Scheme 4). Similar conditions were
employed in the reaction of various substituted acetophenones
The requisite bromides were prepared in two steps using lit-
erature procedure starting from BH reaction of formaldehyde
8a and acetaldehyde 8b with methyl acrylate followed by
bromination.[7] Reaction of allyl bromides 9a–b with
boronoaldehydes 6a–c in the presence of zinc and saturated
NH4Cl under standard Barbier conditions provided the
homologated benzoboroxoles 10a–f in good yields
(Scheme 2).6a The products benzoboroxoles 10a–f obtained
from acetaldehyde-derived BH bromide 12b were obtained
in predominantly syn stereochemistry as was confirmed by
single crystal X-ray analysis of 10d (Fig. 2).
such as p-nitroacetophenone,
p-bromoacetophenone, and
3,4,5-trimethoxyacetophenone to provide the corresponding
Scheme 2. Preparation of functionalized benzoxaboroles.
OH
O
HO
O
R1
B
(a)
B
O
O
OH
O
6a-c
O
R3
O
O
DABCO
(b) HBr, H2SO4
R2
R3
H
H
Br
R3
O
R3 = H, 8a
R3 = Me, 8b
R2
R3 = H, 9a
R3 = Me, 9b
Zn, NH4Cl
THF, 25oC
10a-f
R1
R1 = R2 = R3 = H, 10a, 75%
R1 = OMe, R2 = H, R3 = H, 10b, 72%
R1 = OEt, R2 = F, R3 = H, 10c, 79%
R1 = R2 = H, R3 = CH3, 10d, 76%
R1 = OMe, R2 = H, R3 = CH3, 10e, 74%
R1 = OEt, R2 = F, R3 = CH3, 10f, 68%
Figure 2. X-ray crystal structure of 10d. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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J. Sravan Kumar, M. A. Alam, S. Gurrapu, G. Nelson, M. Williams, M. A. Corsello,
J. L. Johnson, S. C. Jonnalagadda, and V. R. Mereddy
Vol 50
HO
HO
HO
Scheme 3. Synthesis of a-amido benzoxaboroles.
B
O
O
O
O
B
O
O
B
O
O
HO OH
HO
B
O
O
B
O
O
H
N
14a-c
C
RN
H
R
17e, 40%
DMF, 25oC
O
O
O
R = Bn, Chx, tBu
R2
R2
17f, 61%
17g, 62%
15a-i
R1 6a-c
R1
Figure 3. b-Ketobenzoxaboroles via aldol reaction.
HO
HO
HO
B
O
B
O
B
O
H
N
H
N
H
N
antimicrobial activity was determined based on the zone
of inhibition around the agar disk, whereas the anticancer
cell lines were carried out using sulforhodamine-B assay.
Unfortunately, none of the compounds showed any activity
even at 50 mM concentration; accordingly, the IC50 values
were not calculated.
15a
15d
O
O
76%
O
15c
65%
15b
81%
HO
HO
HO
B
O
B
O
B
O
H
H
H
N
N
N
O
O
O
15f
61%
55%
15e
66%
O
O
O
CONCLUSIONS
HO
HO
HO
B
O
F
B
O
B
O
H
H
N
H
N
N
In conclusion, we have synthesized several novel classes
of functionalized benzoxaboroles starting from o-borono-
benzaldehydes utilizing BH reaction, Barbier allylation,
Passerini, and aldol reaction protocols. All the synthesized
compounds were evaluated for antimicrobial and antican-
cer properties. Although biological results are not in the
anticipated lines, these methodologies offer robust protocols
for the synthesis of the title compounds, and the versatility
of these protocols allows for further facile modifications to
understand the structure activity relationship to identify a
lead therapeutic molecule.
15g
O
O
O
F
F
54%
49%
58%
15i
15h
O
O
O
products 17b–d. In all of these cases, regardless of the amount
of base used, ~30–50% of starting material was recovered as
well. The reaction of acetone dimethyl malonate and diethyl
malonate with boronoaldehyde 6a was also very facile, and
the corresponding benzoboroxoles 17e–g were obtained in
40–62% yields (Fig. 3).
After synthesizing various classes of diversely functiona-
lized benzoxaboroles, we evaluated their potential applicabil-
ity as antibacterial, antifungal, antitubercular, and anticancer
agents. For antibacterial studies, we chose one gram positive
(Streptococcus thermophilus) and one gram negative (Pseu-
domonas aeruginosa) bacteria. For the antifungal studies,
Candida albicans was chosen as a representative example,
whereas the tuberculosis studies were carried out with
Mycobacterium smegmatis (m smeg). The anticancer studies
were carried out with MCF-7 (breast cancer) cell lines. The
EXPERIMENTAL
Representative procedure for the preparation of
benzoboroxoles via Baylis–Hillman reaction: 7a. To a stirred
suspension of 2-boronobenzaldehyde 6a (0.3g, 2.0 mmol) and
methyl acrylate (0.7 mL, 8.0 mmol) was added DABCO (224 mg,
2.0 mmol) and stirred for 2 days at room temperature. Upon
completion (TLC), the reaction mixture was quenched with dilute
HCl and worked up with ethyl acetate (3Â 10 mL). The combined
organic layers were dried (MgSO4), concentrated in vacuo, and
purified via silica gel column chromatography (hexane : ethyl
Scheme 4. Synthesis of b-ketobenzoxaboroles.
HO OH
B
O
HO
O
H
B
O
O
R1
R2
6a
R1
R2
16a-d
R2
17a-d
R2
HO
HO
HO
HO
B
O
O
B
O
O
B
O
O
B
O
O
O
O
17d, 47%
17c, 45%
17a, 60%
17b, 50%
Br
NO2
O
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2013
Synthesis and Biological Evaluation of Novel Benzoxaboroles as
Potential Antimicrobial and Anticancer Agents
819
acetate, 3:1) to obtain 0.25 g (58%) of benzoboroxole 7a as a
white powder. mp: 91–93ꢀC, (Found: C, 60.62%; H, 5.25%;
C12H13BO4 requires: C, 60.60%; H, 5.09%); 1H NMR
(400MHz, CDCl3): d 9.45 (s, 1H), 7.70–7.72 (m, 1H), 7.40–7.44
(m, 1H), 7.25–7.35 (m, 2H), 6.16 (s, 1H), 5.93 (s, 1H), 5.79–5.80
(m, 1H), 3.67 (s, 3H); 13C NMR (100 MHz, CDCl3): d 166.2,
155.5, 140.6, 131.5, 131.2, 128.1, 126.6, 122.3, 79.3, 52.5;
ESI-MS: 217 [(MÀ H)+, 100%].
Acknowledgments. We thank the Department of Chemistry and
Biochemistry, University of Minnesota Duluth and Rowan
University for the funding. Partial support for this work was
also provided by research grants from the University of
Minnesota Academic Health Center Faculty Development Grant
(VRM), Whiteside Institute for Clinical Research (VRM), and
Rowan University Non-Salary Financial Support Grants
(NSFSG) (SCJ). We thank Dr Victor G. Young, Jr. (University
of Minnesota X-ray Crystallographic Laboratory) for providing
the crystal structure.
Representative procedure for the preparation of
benzoboroxoles via Barbier allylation 10a.
To a stirred
suspension of 2-boronobenzaldehyde 6a (0.3 g, 2.0 mmol) and
zinc (0.19 g, 3.0 mmol) in 4.0 mL THF was added methyl
a-bromomethylacrylate 9a (0.72 g, 4.0 mmol) and saturated
NH4Cl (1mL) and stirred overnight at room temperature. Upon
completion (TLC), the reaction mixture was filtered over celite
and worked up with water and ethyl acetate (3Â 10 mL). The
combined organic layers were dried (MgSO4), concentrated in
vacuo, and purified via silica gel column chromatography (hexane
: ethyl acetate, 3:1) to obtain 0.35g (75%) of benzoboroxole 10a
as a viscous liquid. (Found: C, 62.01%; H, 5.52%; C12H13BO4
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requires: C, 62.11%; H, 5.65%); H NMR (400 MHz, CDCl3): d
9.24 (s, 1H), 7.67 (d, J= 7.2 Hz, 1H), 7.41–7.45 (m, 1H), 7.29–7.36
(m, 2H), 6.12 (d, J= 1.2 Hz, 1H), 5.69 (d, J= 1.2 Hz, 1H), 5.26 (dd,
J= 4.0, 8.4 Hz, 1H), 3.64 (s, 3H), 2.89 (dd, J= 8.4, 14.4 Hz, 1H),
2.39 (dd, J= 8.4, 14.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d
167.6, 156.8, 136.9, 131.2, 131.1, 128.2, 127.9, 122.2, 79.1, 52.5,
39.2; ESI-MS: 231 (M À H)+, 189 (100%).
Representative procedure for the preparation of
benzoboroxoles via Passerini reaction 15c.
To a stirred
solution of boronoaldehyde 6a (0.3 g, 2.0 mmol) in 2 mL DMF
was added tert-butyl isonitrile 14c (0.23 mL, 2.0 mmol) and
stirred overnight at room temperature. Upon completion (TLC),
the reaction mixture was worked up with water and ethyl
acetate (3 Â 25 mL). The combined organic layers were dried
(MgSO4), concentrated in vacuo, and purified via silica gel
column chromatography (hexane : ethyl acetate, 3:1) to
obtain 0.30 g (65%) of benzoxaborole 15c. (Found: C, 61.53;
H, 8.10; N, 6.02 %; C12H16BNO3 requires: C, 61.84; H,
6.92; N, 6.01%); 1H NMR (500 MHz, DMSO-d6): 9.33
(bs, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H),
7.36 (t, J = 7.4 Hz, 1H), 7.26 (t, J = 7.4 Hz, 1H), 6.52 (s, 1H),
5.27 (s, 1H), 1.21 (s, 9H); 13C NMR (125 MHz, CDCl3):
169.4, 152.3, 131.3, 130.8, 128.1, 122.9, 80.2, 51.1, 28.9;
ESI-MS: 232 [(M À H)+, 100%].
Representative procedure for the preparation of
benzoboroxoles via aldol reaction 17a. To a stirred solution
of acetophenone 16a (10 mmol) in 20 mL THF was added LDA
(12 mmol) at À78ꢀC and stirred for 1 h. A solution of 2-
boronobenzaldehyde 6a (9 mmol) in 5 mL THF was added to
the reaction at À78ꢀC and stirred overnight at room
temperature. Upon completion (TLC), the reaction was
quenched with NH4Cl and worked up with ethyl acetate. The
combined organic layers were dried (MgSO4), concentrated in
vacuo, and purified by silica gel column chromatography to
obtain the pure benzoxaborole 17a in 60% yield. 1H NMR
(500 MHz, DMSO-d6): d 9.21 (s, 1H), 8.03 (d, J = 8.0 Hz, 2H),
7.74 (d, J = 7.5 Hz, 1H), 7.65–7.68 (m, 1H), 7.48–7.57 (m, 4H),
7.37–7.40 (m, 1H), 5.71 (dd, J = 4.0, 8.8 Hz, 1H), 3.58 (dd,
J = 3.5 Hz, 17.5 Hz, 1H), 3.34 (dd, J = 8.5 Hz, 17.0 Hz, 1H); 13C
NMR (125 MHz, CDCl3): 198.6, 157.5, 137.7, 134.3, 131.6,
131.4, 129.7, 129.2, 128.2, 122.5, 77.7, 46.3; ESI-MS: 251
[(M À H)+, 100%].
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DOI 10.1002/jhet

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J. Sravan Kumar, M. A. Alam, S. Gurrapu, G. Nelson, M. Williams, M. A. Corsello,
J. L. Johnson, S. C. Jonnalagadda, and V. R. Mereddy
Vol 50
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet