BF3·OEt2-promoted concise synthesis of difluoroboron-derivatized curcumins from aldehydes and 2,4-pentanedione

Article abstract of DOI:10.1016/j.tetlet.2013.02.015

A concise and one-pot cascade method has been developed to achieve the synthesis of difluoroboron-derivatized curcumins (BF₂C). Treatment of 2,4-pentanedione with BF₃·OEt₂, followed by condensation with aldehydes in the pr

Full text of DOI:10.1016/j.tetlet.2013.02.015

Tetrahedron Letters 54 (2013) 2070–2073
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
BF3ÁOEt2-promoted concise synthesis of difluoroboron-derivatized curcumins
from aldehydes and 2,4-pentanedione
⇑
Kai Liu, Jiangmin Chen, Jeremy Chojnacki, Shijun Zhang
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298-0540, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise and one-pot cascade method has been developed to achieve the synthesis of difluoroboron-
derivatized curcumins (BF2C). Treatment of 2,4-pentanedione with BF3ÁOEt2, followed by condensation
with aldehydes in the presence of tributyl borate and butylamine at 65 °C in toluene furnished the cor-
responding symmetric (s-BF2C) and unsymmetric difluoroboron-derivatized curcumins (us-BF2C) in
good (60–99%) and moderate yields (23–42%) within 6–12 h, respectively.
Received 7 January 2013
Revised 1 February 2013
Accepted 4 February 2013
Available online 13 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
BF3ÁEt2O-promoted reaction
Concise synthesis
Difluoroboron complex
Curcumin analogue
Curcumin, a yellow spice and pigment isolated from the rhi-
zome of Curcuma longa, has been traditionally and widely used
as a food coloring additive.1 Recently, curcumin has attracted
extensive attention in biomedical research as multiple biological
activities of curcumin have been revealed including antioxidant,
anti-inflammatory, biometal chelating, anti-proliferative, and
anti-Ab activities, among others.2–5 Consequently, curcumin has
been tested in various disease models, such as arthritis, cancer,
and Alzheimer’s disease (AD) as both a preventive and treatment
agent.6–10 Since curcumin itself possesses a number of properties
that limit its potential as an effective medicinal agent, for example,
poor solubility and bioavailability, extensive efforts have been
made to develop more effective analogues with improved pharma-
cokinetic and pharmacological properties. Among the analogues
developed, a difluoroboron complex of curcumin was initially
developed with increased stability and inhibitory potency against
HIV protease.11 Furthermore, the difluoroboron-derivatized curcu-
min analogues such as CRANAD-2 and BF2C have been demon-
strated as novel near-infrared imaging (NIR) probes to detect Ab
plaques in AD and as chemical sensors for cyanide detection, In
addition, detailed photophysical and photochemical research dis-
closed that the optical properties can be optimized for different
purposes by phenyl ring modifications, thus indicating both thera-
peutic and diagnostic applications of such difluoroboron-deriva-
tized curcumin analogues.12,13
Despite the broad spectrum of biological activities and potential
applications for boron complexes of curcumin analogues, the syn-
thetic methodology to produce such analogues has remained quite
limited. The BF2C analogues are typically prepared by a two-step
process employing (A) 2,4-pentanedione and aldehydes or (B) cur-
cumin in the presence of BF3ÁOEt2 and Et3N (Scheme 1). But these
methods generally require long reaction times and give typical low
yields over the two-step. In addition, curcumin analogues with
substituents on phenolic oxygens are typically synthesized by
employing the Pabon reaction in another two-step process with
low yields.14 Therefore, a more concise and more efficient method
is needed to prepare such analogues.
As part of our ongoing studies developing novel curcumin ana-
logues as multifunctional ligands for AD treatment,15–17 we herein
report a new and concise method that allows one-pot selective
synthesis of symmetrical (s-BF2C) or unsymmetrical difluorobo-
ron–curcumin analogues (us-BF2C) via a BF3ÁOEt2 promoted sys-
tem. Furthermore, these BF2C analogues can be used as
intermediates to deliver a wide range of symmetric and unsym-
metric substituted curcumin analogues for biological screening.
First, we selected 2,4-pentanedione and vanillin as the model
system to optimize the reaction conditions. Preliminary studies re-
vealed that reaction of vanillin with 2,4-pentanedione in DMF in
the presence of excess of BF3ÁOEt2 (1.5 equiv) and catalytic amount
of n-BuNH2 afforded only a trace amount of 2a (Table 1, entry 1).
Efforts were then made to optimize the reaction conditions. As
shown in Table 1, the addition of tributyl borate as dehydrating
agent greatly improves the yield in this type of reaction. Of the sol-
vents screened, toluene afforded 2a in 94% yield at 65 °C (entry 8).
⇑
Corresponding author. Tel.: +1 804 6288266; fax: +1 804 8287625.
E-mail address: szhang2@vcu.edu (S. Zhang).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.015

K. Liu et al. / Tetrahedron Letters 54 (2013) 2070–2073
2071
Scheme 1. Traditional methods for preparation of BF2C.
Table 1
Optimization of the BF3ÁOEt2-promoted one-pot synthesis of difluoroboron-derivatized curcumin (BF2C)a
Entry
Solvent
Additive
Temp.
Timeb (h)
Yield of 2ac (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
DMF
DMF
DMF
EtOAc
EtOAc
Hexane
CHCl3
Toluene
Toluene
MeCN
Cyclohexane
THF
None
65
65
100
65
65
65
65
65
100
65
65
65
65
65
65
12
12
24
12
12
12
12
12
12
12
12
12
24
12
24
<5d
30d
32d
15d
80
74
81
94
95
(n-BuO)3B
(n-BuO)3B
None
(n-BuO)3B
(n-BuO)3B
(n-BuO)3B
(n-BuO)3B
(n-BuO)3B
(n-BuO)3B
(n-BuO)3B
(n-BuO)3B
(n-BuO)3B
(n-BuO)3B
(n-BuO)3B
70
68
54
DMAC
1,4-Dioxane
DMSO
35d
70
40d
a
Reaction conditions: 2,4-pentanedione (0.2 mmol) and BF3ÁOEt2 (0.3 mmol) were reacted in 2 mL of solvent under a nitrogen atmosphere in a Schlenk tube for 2 h. Then
vanillin (1a, 0.4 mmol), tributyl borate (0.4 mmol except entries 1 and 4), and butylamine (0.04 mmol) were added subsequently, and the reaction was continued for
indicated intervals.
b
The reaction was monitored by TLC.
Yield of precipitated product.
Isolated yields from flash chromatography.
c
d
No significant improvement in reaction yield was observed when
the reaction was carried out at 100 °C (entry 9). Notably, the diflu-
oroboron–curcumin analogue 2a was precipitated from toluene,
and the purity was determined to be >92% by HPLC, thus making
the isolation and purification process in this method quite practical
and accessible.
With the optimized reaction conditions established (Table 1,
entry 8), the scope of the BF3ÁOEt2-mediated reaction of 2,4-pen-
tanedione and aldehydes was then studied. As shown in Table 2,
all the adehydes tested yielded s-BF2C in good to excellent yields.
In general, substitutions on the phenyl ring of aryl aldehydes are
well tolerated under the experimental conditions, and both elec-
tron-donating and electron-withdrawing substituents improved
the yield slightly compared to unsubstituted compound (entry 2)
while with electron-donating substituents being better than elec-
tron-withdrawing substituents. Notably, the current method pro-
vided significantly improved reaction yield when compared to
the reported procedure as demonstrated by the synthesis of com-
pound 2f (Table 2, entry 6).12 Furthermore, when benzaldehyde
(entry 2) was replaced with a naphthalene-2-carbaldehyde (entry
11) or pyridine-3-carbaldehyde (entry 12), the yield was signifi-
cantly improved, while replacement with cinnamaldehyde (entry
13) afforded a significantly reduced reaction yield. These observa-
tions may indicate that the benzylidene moiety is essential for the
complex formation. This notion is further supported by the re-
duced yield of cyclopropanecarboxaldehyde (entry 14, 60% yield).
Since cyclopropanecarboxaldehyde also gave a reasonable yield
of 60%, this may suggest that non-aromatic aldehydes could be
good substrates for this reaction system. To further confirm this,
we tested propionaldehyde and 3-phenyl-propionaldehyde in this
reaction system. Surprisingly, no reaction was observed for both
non-aromatic aldehyde substrates. The reaction of cyclopropane-
carboxaldehyde may be due to the increased sp2 nature of the
cyclopropane in this specific aldehyde, thus indicating that aro-
matic aldehyde is best suited to this reaction system.
The transformation of aldehyde and 2,4-pentanedione to BF2C
under the BF3ÁOEt2-promoted reaction likely proceeds via a similar
mechanism to that of reported procedure12 as is outlined in
Scheme 2. The significant improvement of reaction yield in our
method may be due to the fact that the product can be precipitated

2072
K. Liu et al. / Tetrahedron Letters 54 (2013) 2070–2073
Table 2
Reaction of aldehydes 1 and 2,4-pentanedione for the synthesis of symmetric difluoroboron-derivatized curcumins 2 (s-BF2C)a
Entry
Ar1
Timeb (h)
Purityc (%)
Yield of 2d (%)
1
2
3
4
5
6
7
8
9
3-MeO-4-OH-C6H3–
C6H5–
12
12
6
8
12
8
12
12
12
12
96
94
95
93
97
96
97
97
95
99
94 (2a)
80 (2b)
99 (2c)
95 (2d)
87 (2e)
85 (2f)
79 (2g)
75 (2h)
84 (2i)
81 (2j)
4-HO-C6H4–
4-MeO-C6H4–
4-Me-C6H3–
4-Me2N-C6H4–
4-F-C6H4–
4-Cl-C6H4–
4-Br-C6H4–
3-NO2-C6H4–
10
11
12
13
12
12
12
98
99
99
94 (2k)
96 (2l)
60 (2m)
N
14
15
24
12
97e
96
60 (2n)
92 (2o)
3,4,5-(MeO)3C6H2–
a
Reaction conditions: 2,4-pentanedione (0.2 mmol) and BF3ÁOEt2 (0.3 mmol) were reacted in 2 mL of solvent under a nitrogen atmosphere in a Schlenk tube for 2 h. Then
aldehyde (1, 0.4 mmol), tributyl borate (0.4 mmol), and butylamine (0.04 mmol) were added subsequently, and the reaction was continued for several hours.
b
The reaction was monitored by TLC.
Determined by HPLC.
Isolated yields.
Purified by silica gel column chromatography.
c
d
e
the same conditions employed in Table 2, one pot reaction with
two different aldehydes afforded us-BF2C (Table 3) in acceptable
yields, albeit significantly lower than the mono-aldehyde versions.
The reactions afforded the us-BF2C either as a major product (entry
1, Table 3) or with comparable yield to the s-BF2C (entries 2–4 of
Table 3, two s-BF2C products), thus suggesting that further optimi-
zation is necessary to improve the yield of us-BF2C. Notably, the 4-
HO-benzaldehyde provided the best yield among the aldehydes
tested, consistent with results from Table 2. However, the yield
from pyridine-3-carbaldehyde was lower when compared to the
results from Table 2.
Finally, we employed 2a as a model compound to investigate
whether the difluoroboron-complex can be deprotected to deliver
curcumin efficiently. As shown in Scheme 3, the boron-complex
Scheme 2. Possible pathways toward symmetric s-BF2C.
can be deprotected in DMSO–MeOH at 100 °C to afford curcumin
in 90% yield, thus confirming that this method can be employed
to produce curcumin analogues with substituents on the phenolic
oxygens in both symmetric and unsymmetric formats efficiently.
In summary, we have developed a concise and efficient method
to allow the one-pot synthesis of difluoroboron-derivatized curcu-
mins (BF2C) employing a BF3ÁOEt2-promoted system. When mono
aldehyde is employed in the reaction, the s-BF2C can be obtained
in good to excellent yields. The improved yield could be due to
the precipitation of the product from the solvent of toluene, thus
driving the reaction to completion. When two different aldehydes
were introduced into this one-pot reaction system, the reaction
afforded the us-BF2C in moderate yield. Lastly, this method could
also be an efficient choice for preparation of curcumin analogues.
Based on the scope of this method and the commercial availability
of starting materials, this method should be of high interests for
both organic and pharmaceutical chemistry research.
from the reaction mixture, thus driving the continuing consump-
tion of the starting aldehyde and the difluoroboron-2,4-pentanedi-
one intermediate. Further studies are needed to understand the
mechanism of this method better.
Multicomponent reactions are becoming increasingly impor-
tant because they deliver complex and diverse chemical entities
from relatively simple starting materials in a one-pot reaction.18
With the optimal reaction conditions established for the synthesis
of s-BF2C, we investigated the feasibility of developing a multicom-
ponent version of this method to achieve synthesis of us-BF2C. If
successful, such a methodology will provide an efficient way to de-
liver unsymmetric curcumin analogues and this will consequently
facilitate the drug development process of such compounds. We
initially employed four aldehydes to react with vanillin to test
the feasibility and the results are summarized in Table 3. Under

K. Liu et al. / Tetrahedron Letters 54 (2013) 2070–2073
2073
Table 3
Reaction of vanillin (1a), aldehydes 3 and 2,4-pentanedione for the synthesis of asymmetric difluoroboron-derivatized curcumins 4a
Entry
Ar2
Timeb (h)
Yield of 4c (%)
1
2
3
4-HO-C6H4–
4-Br-C6H4–
4-NO2-C6H4–
6
12
24
42 (4a)
23 (4b)
25 (4c)
4
12
28 (4d)
N
a
Reaction conditions: 2,4-pentanedione (0.2 mmol) and BF3ÁOEt2 (0.3 mmol) were reacted in 2 mL of solvent under a nitrogen atmosphere in a Schlenk tube for 2 h. Then
vanillin (0.2 mmol), aldehyde (3, 0.2 mmol), tributyl borate (0.4 mmol), and butylamine (0.04 mmol) were added subsequently, and the reaction was continued for several
hours.
b
The reaction was monitored by TLC.
Isolated yields.
c
Scheme 3. Deprotection of BF2 group from difluoroboron-derivatized curcumin.
4. Motterlini, R.; Foresti, R.; Bassi, R.; Green, C. J. Free Radical Biol. Med. 2000, 28,
Acknowledgments
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