Water compatible multicomponent cascade suzuki/heck-aldol, suzuki-aldol-suzuki, and aldol-suzuki-aldol reactions: An ecofriendly paradigm for multiple carbon-carbon bond formation in one pot

Article abstract of DOI:10.1002/chem.201303069

Aryls in hot water: A versatile strategy has been devised for the synthesis of biologically active biaryl(hetero)chalcones from readily available precursors (see scheme). The method is step, pot, and carbon economic, ligand-free, devoid of toxic reagents/solvents, and has a wide substrate scope. Copyright

Full text of DOI:10.1002/chem.201303069

COMMUNICATION
DOI: 10.1002/chem.201303069
Water Compatible Multicomponent Cascade Suzuki/Heck–Aldol, Suzuki–
Aldol–Suzuki, and Aldol–Suzuki–Aldol Reactions: An Ecofriendly Paradigm
À
for Multiple Carbon Carbon Bond Formation in One Pot
Rajesh Kumar,[a, b] Richa,[a] Nitin H. Andhare,[a] Amit Shard,[a] and Arun K. Sinha*[a, b, c]
Water is the most precious and abundant liquid on earth
and is the solvent of choice in nature for biochemical and
chemical reactions. In this context, the pioneering research
by Rideout and Breslow[1] in the early 1980s on Diels–Alder
reactions in water triggered more widespread interest be-
cause of sustainable environmental and economic concerns
over conventional reactions in organic solvents.
Among various organic transformations in water,[2]
Suzuki–Miyaura (S–M) cross-coupling[3] and Aldol conden-
sation (AC) reactions[4] occupy esteemed positions as both
reactions tend to enrich molecular diversity by formation of
Figure 1. Biologically potent biarylACTHUNTGRNEUNG(hetero)chalcone scaffolds.
À
C C and C=C bonds, respectively. However, cascade reac-
tions involving Suzuki–Miyaura cross-coupling and Aldol
condensation reactions in one pot in an aqueous environ-
ment for the generation of biarylchalcones (C6-C6-C=C-CO-
C6) is an important but still challenging transformation be-
cause of oxidative scission of the double bond in the pres-
ence of palladium catalysts,[5] the dehydroboration of boron-
ic acids with water at elevated temperatures,[6] and the for-
mation of b-arylated ketones as a side product.[7]
Biarylchalcones have gained significance in the field of
medicinal chemistry because of their anticancer activities[8]
(Figure 1). However, their synthesis[8,9] either proceeds
through one-pot two-step processes or in water–co-solvent
mixtures as the reaction media. Recently, the synergy be-
tween multicomponent and cascade reactions has emerged
as a tool for the generation of multifunctional molecules in
an operationally simple manner with the fewest possible
steps and high atom economy.[10] Therefore, it would be the
icing on the cake if a multicomponent cascade synthesis of
biarylchalcones was found that could be carried out solely in
an aqueous medium by overcoming the existing issues,[5–9]
including the incompatibility of the catalysts with different
substrates and their insolubility in water.
In continuation of our interest in the development of
tandem/sequential cross-coupling methods,[11] we herein
present a water-compatible, highly efficient multicomponent
cascade Suzuki–Miyaura–Aldol (S–M–A) reaction of readily
available precursors, to form biarylACTHNUTRGNEUNG(hetero)chalcones with-
out the requirement for a ligand or an organic solvent
(Scheme 1). This further enabled the construction of multi-
ple carbon–carbon bonds in one pot through Suzuki–
Miyaura–Aldol–Suzuki–Miyaura (S–M–A–S–M) and Aldol–
Suzuki–Miyaura–Aldol (A–S–M–A) reactions in pure water.
After an initial survey of reaction conditions, a mixture of
4-bromobenzaldehyde (1a, 0.05 g), phenylboronic acid (2a,
1.2 equiv), and acetophenone (3a, 1.1 equiv) was heated at
[a] R. Kumar, Richa, N. H. Andhare, A. Shard, Dr. A. K. Sinha
Natural Plant Products Division
CSIR-Institute of Himalayan Bioresource Technology
(Council of Scientific and Industrial Research)
Palampur-176061, H.P. (India)
908C for 6 h in water (4 mL) with PdACTHNGUTRENU(NG OAc)2 (4 mol%) as
the catalyst, Na2CO3 (2 equiv) as the base and tetrabutylam-
monium bromide (TBAB; 1.0 equiv) as the phase-transfer
catalyst (PTC). The crude reaction mixture was then ana-
lyzed by RP-HPLC (see the Supporting Information), which
confirmed the formation of the desired (2E)-1-phenyl-3-(4-
phenylphenyl)prop-2-en-1-one (5a) in 51% yield along with
the intermediate biphenyl-4-carboxaldehyde (4a) in 31%
yield (Table 1, entry 1). To further increase the yield of 5a,
different bases (Table 1, entries 2–8) were screened by using
TBAB as the PTC, and a maximum yield of 56% was ob-
tained in 6 h when K2CO3 was used as the base (Table 1,
entry 2).
E-mail: aksinha08@rediffmail.com
[b] R. Kumar, Dr. A. K. Sinha
Academy of Scientific and Innovative Research (AcSIR)
CSIR-Institute of Himalayan Bioresource Technology
Palampur-176061, H.P. (India)
[c] Dr. A. K. Sinha
Present Address: Medicinal and Process Chemistry Division
CSIR-Central Drug Research Institute
(Council of Scientific and Industrial Research)
Lucknow-226031, U.P. (India)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201303069.
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crease solvation; 2) increase
the rate of the coupling reac-
tion by activating the boronic
acid to form [ArB(OH)3]À-
AHCTUNGTRENNUNG
[R4N]+;[3i] and 3) efficiently
facilitate the condensation
reaction.
To further improve the yield
of 5a, different Pd catalysts
(Table 2, entries 1–3) were
screened, but unfortunately 5a
was obtained in inferior yields
with all catalysts except Pd-
AHCTUNRTGEG(NNNU OAc)2 (Table 1, entry 17). Fi-
nally, the maximum yield of 5a
(79%, isolated) was obtained
Scheme 1. Water compatible multicomponent cascade synthesis of biarylACTHNUGRTNEUNG(hetero)chalcones through a Suzuki–
Miyaura–Aldol strategy. The top reaction is reported in Reference [15d] and the middle reaction is reported in
Reference [15b]
with
1 mol%
PdACHTUNGTRENNUNG(OAc)2
(Table 2, entry 6). Further-
more, the use of different co-
solvents failed to have a positive influence on the yield of
5a (Table 2 entries 8 and 9).
Table 1. Screening of different bases and PTCs for the synthesis of biar-
ylchalcones through the Suzuki–Miyaura–Aldol strategy in water.[a]
Table 2. Screening of different palladium catalysts and solvents for the
synthesis of
a biarylchalcone through the Suzuki–Miyaura–Aldol
strategy.[a]
Entry
Base
PTC
Time [h]
Yield [%][b]
4a
5a
1
2
3
4
5
6
7
8
9
Na2CO3
K2CO3
NaHCO3
Cs2CO3
NH4OAc
KOH
NaOAc
Na2CO3 + NaOAc
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAI
TBACl
TBAF
CTAB
BTMAB
TBAB
TBAB
TBAB
TBAB
–
6
6
6
6
6
6
6
6
6
6
6
6
6
5
3
31
29
79
30
78
65
79
70
73
83
57
36
85
25
18
10
5
51 (45)[c]
56 (50)[c]
11
27
11
25
12
3
8
7
10
27
2
60
65
70
Entry
Pd catalyst
PdCl2
G
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
9
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O + EtOH
H2O + THF
59
62
45
75
77
79
70
68
39
A
R
Pd
Pd
Pd
Pd
Pd
Pd
N
10
11
12
13
14[d]
15[e]
16[e,f]
17[e,g]
18[g]
K2CO3
K2CO3
K2CO3
K2CO3
[a] General conditions: 1a (0.05 g), phenylboronic acid (1.2 equiv), aceto-
phenone (1.1 equiv), Pd catalyst, K2CO3 (4 equiv), TBAB (1.3 equiv),
H2O (4 mL), 908C. [b] Yield of the isolated product.
1.5
1.5
6
77 (70)[c]
3
K2CO3
39
With the optimized reaction conditions in hand, we set
out to explore the substrate scope of this method (Table 3).
For this, 4-bromobenzaldehyde (1a) and phenyl boronic
acid (2a) were coupled in water and subsequently con-
densed in the same pot with various electronically different
acetophenones (3a–e) and in the presence of a hydroxyl-
containing reagent (3 f), without relying on protection and
deprotection strategies, to form biarylchalcones (5a–f) in
varying yields (54–86%). Interestingly, acetyl derivatives of
pyridine and thiophene (3g and h) also successfully afforded
heterobiarylchalcones (5g and h) in 56 and 83% yields,
respectively.
[a] General conditions: 1a (0.05 g), phenylboronic acid (1.2 equiv), aceto-
phenone (1.1 equiv), Pd(OAc)2 (4 mol%), base (2.0 equiv), PTC
(1.0 equiv), H2O (4 mL), 908C; [b] yield on the basis of HPLC; [c] yield
of the isolated product is given in parentheses; [d] 1.2 equiv of TBAB
were used; [e] 1.3 equiv of TBAB were used; [f] 3 equiv of base were
used; [g] 4 equiv of base were used.
AHCTUNGTRENNUNG
Thereafter, different PTCs (Table 1, entries 9–13) were
screened in combination with K2CO3. The maximum yield
of 5a (77%; based on HPLC analysis, see the Supporting In-
formation) was obtained with 1.3 equivalents of TBAB and
4 equivalents of K2CO3 in a shorter reaction time of 1.5 h
(Table 1, entry 17). Product 5a was obtained in only 3%
yield in the absence of TBAB (Table 1, entry 18). This clear-
ly emphasizes the crucial threefold role of TBAB to 1) in-
On reversing the halogen coupling partner of the Suzuki–
Miyaura coupling, that is, replacing 4-bromobenzaldehyde
(1a; Table 3) with 4-bromoacetophenone (3aa), a reduced
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Multicomponent Cascade Carbon Carbon Bond Formation
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Table 3. Cascade Suzuki- Miyaura-Aldol reaction of 4-bromobenzalde-
hyde and aryl boronic acid with different acetophenones in water.[a]
(83%). This scaffold has attracted the attention of synthetic
and medicinal chemists because thiophene nuclei are found
in many natural products that show promising biological ac-
tivities,[12] including anticancer, antibacterial, and antifungal
activities.[13] Specifically, a thiophene nucleus flanked by
a phenyl ring on one side and a phenylpropenone on the
other imparted significant anti-breast-cancer activity.[13d]
There are a handful of reports for the synthesis of thio-
phene-centered biarylchalcones[14] through Suzuki-coupling–
Wittig-olefination reactions,[14a] direct arylation of thio-
phene-containing alkenes,[14b] and arylation of thiophene car-
boxaldehyde followed by Aldol condensation;[13d] however,
these methods are plagued by several limitations, such as
the requirement for one-pot two-step reactions, low selectiv-
ity for the product, and longer reaction times. Moreover,
heterobiarylcarboxaldehyde,[15] a key intermediate for the
synthesis of thiophene-centered biarylchalcones, is usually
formed in the presence of expensive ligand, such as dialkyl-
biphenylphosphinyl,[15a,b] with a metal catalyst in an organic
solvent. Keeping in mind the importance of the thiophene
scaffold, we were also intrigued to investigate whether our
catalytic system could efficiently result in the synthesis of
thiophene-centered biarylchalcone 7a by overcoming the ex-
isting gaps in reported protocols.[14,15]
Pleasingly, 5-bromo-2-thiophene carboxaldehyde (1aaa)
successfully coupled with arylboronic acid (2a) and subse-
quently condensed with 4-(methylthio)acetophenone (3b) in
a cascade manner, providing 7a in 84% yield. Thereafter,
different substituted boronic acids (2) were coupled with
1aaa and subsequently condensed with different acetophe-
nones, to afford thiophene-centered biarylchalcones
(Table 5, 7b–e) in good to excellent yields. To the best of
our knowledge, there are no reports available in which S–M
cross-coupling and AC reactions were carried out in a cas-
cade manner employing water as the sole reaction medium
for the synthesis of 7a–e. Furthermore, the significance of
the method was demonstrated through the successful cou-
pling and condensation of two thiophene moieties to form
bisthiophene-substituted enone derivatives (Table 5, 7 f–h)
in moderate to good yields.
5a, 79% (1.5 h)
5c, 76% (2 h)
5e, 83% (5 h)
5g, 56% (2 h)
5b, 86% (2 h)
5d, 64% (6 h)
5 f, 54% (6 h)
5h, 83% (2 h)
[a] Reaction conditions: 1a (0.05 g), aryl boronic acid (1.2 equiv), aceto-
phenone (1.1 equiv), Pd(OAc)2 (1 mol%), K2CO3 (4 equiv), TBAB
AHCTUNGTRENNUNG
(1.3 equiv), H2O (4 mL), 908C. [b] Yield of the isolated product.
yield of 5i and 5j (69 and 72%, respectively), containing C6-
C6-CO-C=C-C6 units, in comparison to 5a and 5b (79
and86%, respectively), containing C6-C6-C=C-CO-C6 units
was observed (Scheme 2).
In consideration of the effect of choosing 4-bromobenzal-
dehyde (1a) instead of 4-bromoacetophenone (3aa), the
generality of the optimized reaction conditions was tested
with different substituted boronic acids (2) as the coupling
partner with 4-bromobenzaldehyde (1a) and a selection of
acetophenones (3) for the construction of biaryl-
Under the optimized conditions,
a double Suzuki–
Miyaura–Aldol reaction is also possible, allowing the forma-
tion of interesting bisbiarylated chalcone 8a (Scheme 3) in
76% yield, with facile generation of multiple carbon–carbon
ACHTUNGTRENNUNG
À
bonds (i.e., one C=C and two C C bonds) in one pot
through a Suzuki–Miyaura–Aldol–Suzuki–Miyaura (S–M–
A–S–M) reaction.
(Tables 3 and 4), we observed that thiophene-containing
biarylchalcone 5h (Table 3) was obtained in excellent yield
It is known that bischalcones
possess wide-ranging medicinal
profiles including antimicrobi-
al, cytotoxic, and anti-inflam-
matory activities.[16] Thus, bis-
chalcone 9a (Scheme 4) was
also synthesized by using an
Aldol–Suzuki–Miyaura–Aldol
(A–S–M–A)
a one-pot process, whereas an
approach
in
Scheme 2. Cascade Suzuki–Miyaura–Aldol reaction between 4-bromoacetophenone, aryl boronic acid, and
benzaldehyde.
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A. K. Sinha et al.
Table 4. Cascade Suzuki–Miyaura–Aldol reaction of different aryl boronic acids with
4-bromobenzaldehyde and various acetophenones in water.[a]
analogue of 9a was previously synthesized by
a six-step route,[16c] demonstrating the generality
and robustness of our protocol.
Finally, the methodology was successfully ex-
tended to the synthesis of a hybrid molecule, stil-
benechalcone 10a (Scheme 5), in 53% yield by
using a cascade Mizoroki–Heck–Aldol (M–H–A)
strategy. It is worth mentioning that similar hybrid
molecules are known to possess potent biological
profiles against malaria.[11d]
Mechanistically, it is presumed that there are
two plausible pathways for the synthesis of biaryl
chalcone 5a, that is, an Aldol–Suzuki–Miyaura re-
action (path A) or a Suzuki–Miyaura–Aldol reac-
tion (path B; Scheme 6). In path A, 4-bromoben-
zaldehyde (1a) and acetophenone (3a) condense
first, leading to the formation of an aldol inter-
mediate (i.e., a bromochalcone), which is then
coupled with phenylboronic acid (2a) in the pres-
ence of the Pd catalyst to afford the desired prod-
uct 5a. In path B, in situ generated biaryl benzal-
dehyde 4a, formed through cross-coupling of 4-
bromobenzaldehyde (1a) with phenylboronic acid
(2a), subsequently condenses with acetophenone
(3a) to provide 5a. Therefore, to prove the exact
pathway, we performed HPLC analysis of the re-
action mixture at different time intervals, which
revealed the formation of product 5a via inter-
mediate 4a (see the Supporting Information), thus
revealing that the Suzuki–Miyaura–Aldol reaction
(path B) is the predominant path for the synthesis
of 5a.
6a, 77% (2 h)
6c, 55% (6 h)
6e, 70% (2.5 h)
6g, 58% (2 h)
6b, 66% (8 h)
6d, 48% (2.5 h)
6 f, 72% (2.5 h)
6h, 56% (2 h)
[a] Reaction conditions: 1a (0.05 g), aryl boronic acid (1.2 equiv), acetophenone
(1.1 equiv), Pd(OAc)2 (1 mol%), K2CO3 (4 equiv), TBAB (1.3 equiv), H2O (4 mL),
ACHTUNGTRENNUNG
908C. [b] Yield of the isolated product.
In summary, we have developed a highly effi-
cient, water compatible catalytic system for multi-
component cascade Suzuki–Miyaura–Aldol reac-
Table 5. Cascade synthesis of thiophene-centered biarylchalcones in water through
the Suzuki–Miyaura–Aldol reaction.[a]
tions
for
the
generation
of
biaryl-
AHCTUNGTREG(NNUN hetero)chalcones. In addition, we have uncovered
the threefold role of TBAB, which governs the ef-
ficiency of the cross-coupling and condensation re-
actions in one pot. Moreover, the method was ex-
panded for the cascade Suzuki–Miyaura–Aldol–
Suzuki–Miyaura, Aldol–Suzuki–Miyaura–Aldol,
and Mizoroki–Heck–Aldol reactions to form mul-
tiple carbon–carbon bonds in one pot, adding ben-
efits to its practical utility. Overall, the developed
method is carbon economic, ligand-free, environ-
mentally friendly, devoid of the use of toxic re-
agents/solvents, and has wide substrate scope. We
anticipate that this catalytic system will find appli-
cations in academia and industry.
7a, 84% (3 h)
7c, 71% (5 h)
7e, 68% (5 h)
7g, 74% (7 h)
7b, 74% (2.5 h)
7d, 64% (6 h)
7 f, 82% (3 h)
7h, 65% (5 h)
Experimental Section
Representative procedure: A mixture of 4-bromobenzalde-
hyde (1a, 0.05 g), boronic acid 2a (1.2 equiv), acetophenone
(3a, 1.1 equiv), PdACHTUNRGTNE(UNG OAc)2 (1 mol%), K2CO3 (4 equiv), tetra-
[a] Reaction conditions: 1a (0.05 g), aryl boronic acid (1.2 equiv), acetophenone
(1.1 equiv), Pd(OAc)2 (1 mol%), K2CO3 (4 equiv), TBAB (1.3 equiv), H2O (4 mL),
908C. [b] Yield of the isolated product.
ACHTUNGTRENNUNG
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Multicomponent Cascade Carbon Carbon Bond Formation
COMMUNICATION
sequently purified by column chroma-
tography on silica gel (60–120 mesh
size) using ethyl acetate (10%) in
hexane to give a yellow solid, which
was then recrystallized from metha-
nol to provide pure 5a in 79% yield.
Acknowledgements
Scheme 3. Cascade Suzuki–Miyaura–Aldol–Suzuki–Miyaura reaction in water.
RK, NHA, and AS are indebted to
CSIR and UGC, New Delhi, for the
award of research fellowships. This
work was supported by the Council
of Scientific and Industrial Research
(project CSC-0108 and ORIGIN).
The authors gratefully acknowledge
the Director, I.H.B.T., Palampur, for
his kind cooperation and encourage-
ment.
I.H.B.T.
Communication
No. 3539.
Scheme 4. Cascade Aldol–Suzuki–Miyaura–Aldol reaction in water.
Keywords: chalcones
·
condensation · cross-coupling ·
domino reactions
chemistry
·
water
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Received: August 2, 2013
Published online: && &&, 0000
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!

À
Multicomponent Cascade Carbon Carbon Bond Formation
COMMUNICATION
Aryls in hot water: A versatile strategy
has been devised for the synthesis of
biologically active biaryl-
Water Chemistry
R. Kumar, Richa, N. H. Andhare,
A. Shard, A. K. Sinha* ...... &&&& — &&&&
ACHTUNGTRENNUNG(hetero)chalcones from readily avail-
able precursors (see scheme). The
method is step, pot, and carbon eco-
nomic, ligand-free, devoid of toxic
reagents/solvents, and has wide sub-
strate scope.
Water Compatible Multicomponent
Cascade Suzuki/Heck–Aldol, Suzuki–
Aldol–Suzuki, and Aldol–Suzuki–
Aldol Reactions: An Ecofriendly Para-
À
digm for Multiple Carbon Carbon
Bond Formation in One Pot
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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&
ÞÞ
These are not the final page numbers!