Development of practical methodologies for the synthesis of functionalized benzoboroxoles

Article abstract of DOI:10.1016/j.tetlet.2010.06.077

2-Formylphenylboronic acids upon reaction with activated olefins such as acrylates, methyl vinyl ketone, and acrylonitrile provide functionalized benzoboroxoles. The corresponding homologated benzoboroxoles were synthesized via the reaction of 2-formylphenylboronic acids with α- bromomethylacrylates.

Full text of DOI:10.1016/j.tetlet.2010.06.077

Tetrahedron Letters 51 (2010) 4482–4485
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Development of practical methodologies for the synthesis of functionalized
benzoboroxoles
J. Sravan Kumar a, Christopher M. Bashian b, Michael A. Corsello b, Subash C. Jonnalagadda b,
,
*
Venkatram R. Mereddy a,
*
a Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, United States
b Department of Chemistry and Biochemistry, Rowan University, Glassboro, NJ 08028, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Formylphenylboronic acids upon reaction with activated olefins such as acrylates, methyl vinyl ketone,
and acrylonitrile provide functionalized benzoboroxoles. The corresponding homologated benzoborox-
oles were synthesized via the reaction of 2-formylphenylboronic acids with a-bromomethylacrylates.
Received 24 May 2010
Revised 7 June 2010
Accepted 14 June 2010
Available online 19 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Baylis–Hillman reaction
Benzoboroxoles
Barbier allylation
1. Introduction
Despite the surging applications of benzoboroxoles in various
fields, the study of their synthesis and properties has been limited
and the synthetic methods for rapid diversification of this novel
structure are highly desired. The impressive application profile of
these molecules and our interest8 in the synthesis of novel boronat-
ed molecules for medicinal chemistry prompted us to undertake
the current project for the synthesis of functionalized benzoborox-
oles. In this Letter, we describe the development of two convenient
and versatile protocols for the synthesis of densely functionalized
benzoboroxoles based on Baylis–Hillman chemistry of 2-form-
ylphenylboronic acids.
Boronic acids and boronates are highly useful classes of inter-
mediates for cross-coupling and several other reactions in organic
synthesis.1 In medicinal chemistry, several boronic acid-based
molecules have been investigated as inhibitors of multiple en-
zymes.2 However, in general, boron-based molecules have been
largely underutilized in modern medicinal chemistry research.
The approval of drug bortezomib for the treatment of multiple
myeloma has increased the enthusiasm for boronated molecules
as a novel class of pharmaceutical compounds.3
Benzoboroxoles are cyclic hemiesters of phenylboronic acids.4
As compared to the corresponding acyclic boronic acids, benzobo-
roxoles exhibit high stability because of the presence of a stable
five-membered ring. Although simple benzoboroxole 1 has been
known for over 50 years, only recently great attention has been
paid toward the new applications of this structural unit in medi-
cine (e.g., 2–4)5 (Fig. 1).
2. Results and discussion
Baylis–Hillman reaction is an important synthetic transforma-
tion that provides highly substituted allylic alcohols and amines
in one step.9 The reaction is highly atom efficient and the product
alcohols undergo a facile isomerization with a variety of nucleo-
philes to afford valuable synthons. We envisaged that the BH
Several benzoboroxoles have also been used as steroid conju-
gates for molecular imprinting, dyes, biosensors of a-hydroxy-car-
boxylic acids, biocides for plastic biodegradation, etc.6 Some of the
benzoboroxoles have also been found to selectively complex with
naturally occurring oligosaccharides to effect direct glycosidation
of the sugars and are used for the selective recognition of cell sur-
face glycoconjugates.7
OH
OH
OH
OH
NC
B
B
B
B
O
O
O
O
O
F
4
Cl
2
3
1
AN2728
AN2718
AN2690
anti-inflammatory
Activity against
Activity against
Onychomycosis
activity against Psoriasis
Tenia Pedis
* Corresponding authors. Tel.: +1 218 726 6766.
E-mail addresses: jonnalagadda@rowan.edu (S.C. Jonnalagadda), vmereddy@d.
umn.edu (V.R. Mereddy).
Figure 1. Functionalized benzoboroxoles.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.077

J. S. Kumar et al. / Tetrahedron Letters 51 (2010) 4482–4485
4483
reaction of boronoaldehydes with electron-deficient olefins in the
presence of tertiary amines like 1,4-diazabicyclo[2.2.2] octane
(DABCO) should provide a wide variety of functionalized benzobo-
roxoles very easily. We also envisioned that allylic bromides de-
rived from BH alcohols could provide further functionalized
homologated benzoboroxoles upon Barbier type allylation. For
the present study, we chose formylboronic acids 5a–c as the elec-
trophiles and several activated olefins such as methyl acrylate 6a,
phenyl acrylate 6b, acrylonitrile 6c, methyl vinyl ketone 6d, and
acrolein 8 as olefin partners. The initial reaction of aldehyde 5a
with 2 equiv of methyl acrylate in the presence of 10% DABCO
was sluggish, and only a partial reaction took place to afford 20%
of the benzoboroxole 7a after 12 h. Prolonged continuation of the
reaction for an additional 48 h did not improve the yield as well.
However, complete consumption of the aldehyde was observed
upon using stoichiometric amounts of DABCO, and benzoboroxole
7a was obtained in 58% yield after silica gel column chroma-
tography.10
The BH reaction of methyl acrylate with simple benzaldehyde
typically takes more than a week. Even the reaction with 4-boron-
obenzaldehyde proved to be very sluggish and a synthetically use-
ful yield of the product alcohol was not obtained even after stirring
the reaction mixture for two weeks. The increased rate of reactivity
with 2-boronobenzaldehyde 5a could be attributed to the activa-
tion of the carbonyl oxygen via coordination with a proximal Lewis
acidic boronic acid group. The reaction with boronoaldehydes
5b–c was relatively slow presumably due to the electron-donating
capability of the alkoxy group on the aromatic ring. The reaction
took 5–7 days for the completion and the product benzoboroxoles
7b–c were obtained in 54% and 56% yield, respectively. Similarly,
the BH reaction of aldehydes 5a–c with phenyl acrylate 6b pro-
vided the corresponding benzoboroxoles 7d–f in 41–45% yield
(Scheme 1).
The BH reaction with acrylonitrile 6c was facile with all the
boronoaldehydes 5a–c and the product benzoboroxoles 7g–i were
obtained in moderate to good yields. The reaction of aldehydes
5a–c with methyl vinyl ketone 6d provided the benzoboroxoles
7j–l in 41–49% yield (Scheme 1).
Acrolein 8 is a sensitive monomer and undergoes rapid polymer-
ization in the presence of amines, and generally is not considered to
be a good BH substrate for unreactive aldehydes. Boronoaldehyde
5a was found to be sufficiently reactive to afford the corresponding
product 9 in 20% yield along with 60% of recovered starting mate-
rial. Extended reaction time or excess quantities of acrolein did
not help improve the yield of the product. The reaction was done
in THF as the solvent at 0 °C to minimize the polymerization of
acrolein (Scheme 2).
After obtaining the benzoboroxoles 7a–l, we carried out the
allylation of bromides 12a–b with boronoaldehydes 5a–c under
Barbier conditions. The requisite bromides 12a–b were prepared
in two steps starting from BH reaction of formaldehyde 10a and
acetaldehyde 10b with methyl acrylate 6a to afford the allylic alco-
hols 11a–b followed by the treatment with HBr and H2SO4. Allyla-
tion of bromides 12a–b with aldehydes 5a–c in the presence of
zinc and saturated ammonium chloride provided the homologated
benzoboroxoles 13a–f in good yields (Scheme 3).11 In the case of
BH bromide 12b derived from acetaldehyde, as expected, the prod-
uct benzoboroxoles 13d–f were obtained in predominantly syn ste-
reochemistry. The relative configuration was confirmed by single
crystal X-ray analysis of 13d (Fig. 2).
O
OH
B
HO
OH
8
H
B
O
O
O
H
DABCO
THF, 0ºC
1h
H
5a
20%
9
OH
Scheme 2. Reaction of b-boronoaldehydes with acrolein.
OH
B
EWG
B
6a
EWG = COOMe,
OH
O
EWG = COOPh, 6b
EWG = CN, 6c
O
EWG
R1
O
6d
EWG = COMe,
DABCO
OH
O
R2
H
R1
O
HBr
H2SO4
R2
O
5a
R1 = R2 = H,
41-69%
6a
R3
O
R
1 = OMe, R2 = H, 5b
R1 = OEt, R2 = F,
7a-l
R3
H
5c
DABCO
R3 = H, 10a
R3 = Me, 10b
R3 = H, 11a
R3 = Me, 11b
OH
B
OH
B
OH
B
OH
O
O
O
O
O
O
OH
B
O
B
R1
O
O
O
O
O
OH
O
O
R3
58%
54%
R3
O
F
56%
R2
O
7b
7c
7a
5a-c
H
Br
R1
OH
B
O
R2
OH
B
OH
B
R3 = H, 12a
Zn, NH4Cl
THF, 25ºC
12b
13a-f
R3 = Me,
O
O
O
O
O
O
Ph
Ph
Ph
OH
O
OH
OH
B
O
N
O
45%
OH
B
B
7d
O
O
7f
7e
41%
43%
OH
F
O
O
O
OH
B
B
B
13c
13a
13b
O
O
O
O
O
O
O
O
O
F
72%
N
N
75%
69%
O
O
O
O
54%
O
O
7i
OH
B
OH
B
62%
69%
7h
OH
7g
F
B
OH
B
OH
B
OH
B
O
O
O
O
O
O
O
O
O
13e
74%
13f
13d
O
O
O
O
F
68%
76%
44%
49%
O
O
41%
7j
O
7k
F
7l
O
Scheme 1. Baylis–Hillman reaction of b-boronoaldehydes.
Scheme 3. Synthesis of homologated benzoboroxoles.

4484
J. S. Kumar et al. / Tetrahedron Letters 51 (2010) 4482–4485
Figure 2. X-ray crystal structure of 13d.
Owing to the importance of several benzoboroxoles exhibiting
References and notes
significant antimicrobial activity, all the synthesized molecules
have been tested for their efficacy as antibacterial and antifungal
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tococcus thermophilus (Gram positive) for antibacterial studies and
Candida albicans, and Aspergillus niger as representative examples
for antifungal evaluation. The microbial colonies were grown in
Mueller Hinton broth at 37 1 °C overnight. The microbial sus-
pension was swabbed on to a Mueller Hinton agar plate. Twenty
microliters of the test dilution were added to sterile empty paper
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Eur. J. 1999, 5, 2584; (e) Nicolaou, K. C.; Natarajan, S.; Li, H.; Jain, N. F.; Hughes,
R.; Solomon, M. E.; Ramanjulu, J. M.; Boody, C. N. C.; Takayanagi, M. Angew.
Chem., Int. Ed. 1998, 37, 2708.
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3. Conclusions
In conclusion, we have developed two convenient protocols
based on Baylis–Hillman chemistry for the practical synthesis of
functionalized benzoboroxoles. These methodologies provide rapid
diversification of the benzoboroxole scaffold and are highly ame-
nable to scale-up. Some of these molecules were evaluated for their
antibacterial and antifungal activities. The importance of benzobo-
roxoles in various fields, the paucity of synthetic procedures, and
the versatility of BH chemistry make the current procedures highly
significant.
7. (a) Oshima, K.; Aoyama, Y. J. Am. Chem. Soc. 1999, 121, 2315; (b) Dowlut, M.;
Hall, D. G. J. Am. Chem. Soc. 2006, 128, 4226; (c) Pal, A.; Berube, M.; Hall, D. G.
Angew. Chem., Int. Ed. 2010, 49, 1492–1495.
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779–782; (b) Gunasekera, D. S.; Gerold, D. A.; Aalderks, N. A.; Jonnalagadda, S.
C.; Kiprof, P.; Zhdankin, V. V.; Reddy, M. V. R. Tetrahedron 2007, 63, 9401–9405.
9. For reviews on Baylis–Hillman reaction, please refer: (a) Singh, V.; Batra, S.
Tetrahedron 2008, 64, 4511; (b) Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc.
Rev. 2007, 26, 1581; (c) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811; (d) Ciganek, E. In Organic Reactions; Paquette, L. A., Ed.; John
Wiley & Sons: New York, 1997; Vol. 51, p 201; (e) Basavaiah, D.; Rao, P. D.;
Hyma, R. S. Tetrahedron 1996, 52, 8001; (f) Drewes, S. E.; Roos, G. H. P.
Tetrahedron 1988, 44, 4653.
10. Representative procedure for the preparation of benzoboroxoles 7a–l: To a stirred
suspension of 2-boronobenzaldehyde 5a (0.3 g, 2.0 mmol) and methyl acrylate
6a (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 was
quenched with dilute HCl and worked up with ethyl acetate (3 Â 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
Acknowledgments
We thank the Departments of Chemistry and Biochemistry,
University of Minnesota Duluth and Rowan University for the facil-
ities and funding. Partial support for this work was also provided
by research grants from the National Institutes of Health
(CA129993) (V.R.M.), Whiteside Institute for Clinical Research
(V.R.M.), and Rowan University Non-Salary Financial Support
Grants (NSFSG) (S.C.J.). We thank Dr. Victor G. Young, Jr. (Univer-
sity of Minnesota X-ray Crystallographic Laboratory) for providing
the crystal structure.

J. S. Kumar et al. / Tetrahedron Letters 51 (2010) 4482–4485
4485
obtain 0.25 g (58%) of benzoboroxole 7a as a white powder. Mp: 91–93 °C
(Found: C, 60.62; H, 5.25; C12H13BO4 requires: C, 60.60; H, 5.09); 1H NMR
(400 MHz, 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 [(MÀH)+, 100%].
over Celite, and worked up with water and ethyl acetate (3 Â 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 0.35 g (75%) of benzoboroxole 13a as a viscous liquid (Found: C, 62.01;
H, 5.52; C12H13BO4 requires: C, 62.11; H, 5.65); 1H 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 (MÀH)+, 189 (100%).
11. Representative procedure for the preparation of benzoboroxoles 13a–f: To
a
stirred suspension of 2-boronobenzaldehyde 5a (0.3 g, 2.0 mmol) and zinc
(0.19 g, 3.0 mmol) in 4.0 mL THF was added methyl -bromomethylacrylate
a
12a (0.72 g, 4.0 mmol), and saturated NH4Cl (1 mL) and stirred overnight at
room temperature. Upon completion (TLC), the reaction mixture was filtered