Pd-catalyzed orthogonal Knoevenagel/Perkin condensation-decarboxylation- heck/Suzuki sequences: Tandem transformations of benzaldehydes into hydroxy-functionalized antidiabetic stilbene-cinnamoyl hybrids and asymmetric distyrylbenzenes

Article abstract of DOI:10.1002/chem.201101174

Tandem reactions that involve chemoselective Knoevenagel/Perkin condensation-decarboxylation-Heck/Suzuki coupling or Heck-aldol sequences have been achieved. This enabled the first concise and efficient synthesis of several important hydroxy-functionalized compound classes, such as stilbene-cinnamoyl hybrids (potent protein tyrosine phosphatase1B inhibitors), cinnamoyl-cinnamic acid hybrids, asymmetric distyrylbenzenes, and biarylstyrenes. Previously reported synthesis require multiple steps and protection/deprotection manipulations.

Full text of DOI:10.1002/chem.201101174

DOI: 10.1002/chem.201101174
Pd-Catalyzed Orthogonal Knoevenagel/Perkin Condensation–
Decarboxylation–Heck/Suzuki Sequences: Tandem Transformations of
Benzaldehydes into Hydroxy-Functionalized Antidiabetic Stilbene–
Cinnamoyl Hybrids and Asymmetric Distyrylbenzenes
Naina Sharma,[a] Abhishek Sharma,[a, b] Amit Shard,[a] Rakesh Kumar,[a] Saima,[a] and
Arun K. Sinha*[a]
Abstract: Tandem reactions that involve chemoselective Knoevenagel/Perkin con-
densation–decarboxylation–Heck/Suzuki coupling or Heck–aldol sequences have
À
been achieved. This enabled the first concise and efficient synthesis of several im-
portant hydroxy-functionalized compound classes, such as stilbene–cinnamoyl hy-
brids (potent protein tyrosine phosphatase1B inhibitors), cinnamoyl–cinnamic acid
hybrids, asymmetric distyrylbenzenes, and biarylstyrenes. Previously reported syn-
thesis require multiple steps and protection/deprotection manipulations.
Keywords: C C coupling · conden-
sation · olefination · palladium · stil-
benoids
Introduction
drug candidates.[7] However, the only available synthetic
route to such hybrid stilbenoids provides an 11.5% overall
yield after a tedious seven-step protocol,[7] thereby hamper-
ing their broader utility. Similarly, the asymmetrically func-
tionalized hydroxy-distyrylbenzenes[8] (DSBs) are vital scaf-
folds in supramolecular[8a] and medicinal chemistry do-
mains.[8b] Relative to their symmetric counterparts,[9a,b] the
synthesis of DSBs that possess asymmetric[9c] hydroxy func-
tionalization poses a considerably greater challenge and
often involves multiple steps[8a] or functionalized precur-
sors.[8b] Moreover, to the best of our knowledge, a general
strategy for direct conversion of readily available and unpro-
tected hydroxybenzaldehydes into nonsymmetric DSBs has
not yet been reported (Scheme 1).
One of the central goals of contemporary organic synthesis
is the realization of new strategies for sequential formation
of multiple C=C bonds in one pot.[1] In this context, a prom-
inent and useful challenge involves harnessing conceptually
distinct reactions into novel tandem approaches.[2]
Condensation and transition-metal-catalyzed coupling re-
actions[3] constitute two of the most fundamental C=C bond-
forming strategies. However, it would be a significant ad-
vantage if these two classical approaches could be com-
bined[4] orthogonally.[3c,5] This would enable direct access to
highly functionalized and biologically potent molecules from
readily available precursors. The hydroxy-functionalized stil-
benoids are venerable compounds that possess a range of
biological activities.[6] In particular, hydroxystilbene–cinna-
moyl hybrids have recently been found to be potent protein
tyrosine phosphatase 1B (PTP1B) inhibitors, thus have af-
forded a new class of type-II antidiabetic and antiobesity
Results and Discussion
Pursuant to our interest in quinomethide-mediated reactivi-
ty of 4- and 2-hydroxybenzaldehydes,[10] under modified
Knoevenagel–Doebner (KD)[10a,b] or Perkin conditions,[10c]
we hypothesized that an unprecedented chemoselective[3c]
double KD reaction of 4-hydroxybenzaldehydes and 4-halo-
benzaldehydes would lead to the respective styrenes (C6–C2
unit)[10a] and halocinnamic acids (X-C6-C3 unit) which can,
in turn, undergo in situ Heck coupling. Thus, a mixture of 4-
iodobenzaldehyde (1a’, 1.3 mmol) and 4-hydroxy-3-methox-
ybenzaldehyde (1a, 1.8 equiv) was heated at reflux with ma-
[a] N. Sharma, Dr. A. Sharma, A. Shard, R. Kumar, Saima,
Dr. A. K. Sinha
Natural Plant Products Division
Council of Scientific and Industrial Research
Institute of Himalayan Bioresource Technology (I.H.B.T.)
Palampur (H.P.) 176061 (India)
Fax : (+91)1894-230433
E-mail: aksinha08@rediffmail.com
[b] Dr. A. Sharma
lonic acid (8.5 equiv), piperidine (9.5 equiv), PdACHTUNGTRENNUNG(OAc)2
(3 mol%), PPh3 (4 mol%), and LiCl (8 mol%) in DMF for
Present address: Department of Chemistry
Katholieke Universiteit Leuven
Celestijnenlaan 200F
50 min under microwave (MW) irradiation to obtain 1b in
1
34% yield (Table 1, entry 1). Detailed HRMS and H and
3001 Leuven (Belgium)
13C NMR spectroscopic analysis revealed 1b to be a novel
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101174.
hydroxystilbene–cinnamic acid hybrid (C6-C2-C6-C3 unit).
10350
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Chem. Eur. J. 2011, 17, 10350 – 10356

FULL PAPER
yields (76 and 74%, respectively) with a longer reaction
time in the case of former (Table 1, entry 14). On the other
hand, no formation of 1b was observed when K2CO3 was
used as the sole base (Table 1, entry 15).
With the optimized reaction conditions in hand (Table 1,
entry 14), we ventured to gauge the substrate scope, wherein
benzaldehydes 1a–4a were rapidly olefinated into hydroxys-
tilbene–cinnamic acid hybrids 1b–6b (Table 2, entries 1–6).
As expected,[10b] the absence of 4- or 2-hydroxy substitution
on the benzaldehyde, as in 5a and 6a (Table 2, entries 7 and
8), affected the reaction due to strong electronic effects. In-
terestingly, p-iodobenzaldehyde provided better reaction
performance than m- and o-substituted bromobenzalde-
hydes (Table 2, entries 1–3, 5 versus 4, 6).
Significantly, the above approach to stilbene–cinnamic
acid hybrids was also applicable for the first concise and ef-
ficient synthesis of 9c, a potent PTP1B inhibitor, from 7a
and 1a’;[7] 75% yield was achieved over two steps, compared
to 11.5% yield from a previously reported seven-step ap-
proach (Scheme 2). Further, 6b (Table 2, entry 6), an ana-
logue of anticancer agent salvianolic acid F, was also ac-
cessed in one step, compared to an earlier seven-step ap-
proach.[12]
After the successful synthesis of stilbene–cinnamic acid
hybrids, we were inspired to develop an analogous one-pot
approach to fuse cinnamic acids with a chalcone moiety be-
cause such hybrids (C6-C3-C6-C3 unit) possess plant
Scheme 1. a) Prevalent approaches for conversion of benzaldehydes into
hydroxystilbene–cinnamate hybrids, asymmetric hydroxy DSBs, and biar-
ylstyrenes. b) Present work.
Encouraged by this result, extensive optimization studies
(Table 1) were conducted, initially varying the reagent ratios
and catalyst. Thus, an increased amount of 1a (2.5 equiv)
and use of [PdACHTUNGTRENNUNG(PPh3)4] as catalyst improved the yield of 1b
(49%, Table 1, entry 11). To further increase the reaction
performance, LiCl was replaced by additives Ag2CO3 and
Cs2CO3, however, both led to lower yields (Table 1, en-
tries 12 and 13). Interestingly, the synergistic use of an addi-
tional base (K2CO3,[11] 1 equiv) led to a substantial enhance-
ment in the yield of 1b (81%, Table 1, entry 14). A similar
reaction under conventional heating or with p-bromobenzal-
dehyde as the coupling partner afforded marginally lower
Table 1. Optimization of the conditions for chemoselective tandem double KD-Decarboxylation-Heck sequence.[a]
Entry
1a [equiv]
CH
(COOH)2 [equiv]
Piperidine [equiv]
Pd Catalyst
Ligand
Additive
Yield[b] [%]
1
2
3
4
5
6
7
8
1.8
1.8
1.8
2.0
2.2
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
8.5
11
14
12
13
14
14
14
14
14
14
14
14
14
14
9.5
12
15
13
14
15
15
15
15
15
15
15
15
Pd
Pd
Pd
Pd
Pd
Pd
N
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
–
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
Ag2CO3
Cs2CO3
LiCl
LiCl
34
38
37
36
38
41
42
45
42
40
49
37
PdCl2
[Pd(CF3COO)2]
[Pd2C6H10Cl2]
[PdCl2A(PPh3)2]
(PPh3)4]
(PPh3)4]
G
9
10
11
12
13
14
15
G
E
[Pd
[Pd
E
–
–
–
–
N
Pd
[Pd
[Pd(PPh3)4]
40
15+1[c]
16[e]
N
81 (76,74)[d]
G
–
nd[f]
[a] General conditions: 1a’ (0.3 g, 1.3 mmol), catalyst (3 mol%), additive (8 mol%), ligand (4 mol%), DMF (15 mL), MW (CEMꢁ monomode, 180 W,
1508C, 50 min). [b] Yield of pure isolated product. [c] Piperidine (15 equiv), K2CO3 (1 equiv). [d] Respective yields under reflux conditions (10 h) that is,
without MW irradiation or with 4-BrC6H4CHO instead of 4-IC6H4CHO. [e] K2CO3 (16 equiv) used as the sole base. [f] Not detected.
Chem. Eur. J. 2011, 17, 10350 – 10356
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10351

A. K. Sinha et al.
activity.[13]
Thus, an unprecedented one-
pot Heck–aldol sequence was
envisaged, wherein Pd-cata-
lyzed reaction of 4-iodoaceto-
phenone with acrylic acid
would provide 4-acetylcinnam-
ic acid, which could undergo in
situ condensation with benzal-
dehydes 6a and 8a–10a in the
presence of an aqueous solu-
tion of NaOH to give a facile
access to novel cinnamoyl–cin-
namic acid hybrids 10b–13b
(Table 3, entries 10–13).
Table 2. Direct transformation of benzaldehydes into stilbene–cinnamic acid hybrids by a one-pot chemoselec-
tive double Knoevenagel condensation–decarboxylation/Heck sequence.[a]
growth-regulation
Entry
1
Ar1CHO
XAr2CHO
Product
Yield[b] [%]
81 (55)[c]
1a
1b
2
3
2a
3a
2b
3b
67
83
Having successfully realized
the above one-pot tandem[14]
reactions (Tables 2 and 3), it
was interesting to explore a
similar orthogonal condensa-
tion–coupling approach to
asymmetrically substituted hy-
droxy DSBs (C6-C2-C6-C2-C6
unit). Initially, we postulated
4
1a
4b
43
5
6
7
4a
3a
5a
5b
6b
7b
30
that
4-hydroxystilbene–cin-
46
namic acid hybrid 1b (Table 2,
entry 1) could undergo quino-
methide-mediated in situ de-
carboxylation[10b,c] into the re-
spective 4-vinylstilbene (C6-
C2-C6-C2 unit) which could
then participate in a tandem
Heck coupling with a suitable
aryl halide. Unfortunately, the
above approach was unsuccess-
ful because MW irradiation
(50–90 min) of stilbene–cin-
nd[d]
8
6a
8b
nd[d]
[a] General conditions; XAr2CHO (1.30 mmol), Ar1CHO (3.23 mmol), CH
(19.50 mmol), Pd(PPh3)4 (3 mol%), LiCl (8 mol%), K2CO3 (1.30 mmol), DMF (15 mL), MW (180 W, 1508C,
50 min). [b] Yield of pure isolated product (single run). The structures of all novel compounds were confirmed
by HRMS, 1H and 13C NMR spectroscopic analysis (see the Supporting Information for details). [c] Yield for
the three-step reaction (see the Supporting Information). [d] Not detected.
2ACHTUNGERTN(NUNG COOH)2 (18.20 mmol), piperidine
ACHTUNGTRENNUNG
namic
acid
hybrid
1b
[15]
(0.67 mmol) with Ag2CO3
(1.0 mmol),
(3 mol%),
Pd
ACHTUNGTRENNUNG(OAc)2
iodophenol
(0.67 mmol), PPh3 (4 mol%),
and LiCl (8 mol%) in DMF
gave only traces of the desired
asymmetric
(Scheme 3).
Subsequently,
DSB
14b
another
tandem strategy that involved
a hitherto unknown sequential
Perkin[10c]/Knoevenagel[10b]
double
condensation–decar-
boxylation–Heck transforma-
tion with two different benzal-
dehydes was envisioned. As
proof of concept, 1a was treat-
ed with 4-bromophenylacetic
acid and methylimidazole/pi-
Scheme 2. Concise and efficient synthesis of antidiabetic agent 9c.
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Tandem Transformations of Benzaldehydes
FULL PAPER
Table 3. Direct synthesis of cinnamoyl–cinnamic acid hybrids by a one-pot Heck–aldol sequence.[a]
Entry
Ar1CHO
Product
Yield[b]
[%]
10
11
12
8a
6a
9a
10b
11b
12b
68
70
72
13
10a
13b
55
[a] General conditions; 4-I-PhCOCH3 (1.21 mmol), acrylic acid (1.83 mmol), K2CO3 (3.65 mmol), PdACHTNUTRGNE(NUG OAc)2 (3 mol%), H2O (10 mL), MW (160 W,
1208C, 25 min), then Ar1CHO (1.46 mmol), NaOH (4.80 mmol), MeOH (10 mL), 5 h, RT. [b] Yield of pure isolated product (single run). The structures
of all novel compounds were confirmed by HRMS, 1H and 13C NMR spectroscopic analysis (see the Supporting Information for details).
The
optimized
protocol
(Table 4, entry 8) was subse-
quently used to evaluate the
scope of the tandem reaction.
Importantly, the approach de-
veloped was found to be versa-
tile and afforded the first
direct synthesis of diverse
asymmetric hydroxy-function-
alized DSBs 15b–17b from
benzaldehyde 3a (Table 5, en-
tries 15–17) without any pro-
Scheme 3. Decarboxylation–coupling approach for the synthesis of asymmetric DSB 14b.
peridine in PEG-200[10c] for 20 min under MW irradiation,
tection/deprotection manipulations.[8] Similarly, replacement
of the second hydroxybenzaldehyde Ar2CHO (a source of in
situ hydroxystyrene)[10b] with styrene (Table 5, entries 18–20)
followed by addition of 2a, malonic acid, piperidine, Pd-
ACHTUNGTRENNUNG(OAc)2, LiCl, and PPh3. Further MW irradiation for 45 min
afforded the desired asymmetric DSB 14b in 9% yield
(Table 4, entry 1). To further augment the yield of this
tandem reaction, we focused on making the second step
(Knoevenagel condensation–decarboxylation–Heck reac-
tion) compatible with an in situ Perkin condensation–decar-
boxylation sequence (Table 4). Thus, addition of co-solvent
DMF (8 mL) and use of a synergistic base combination of
piperidine and K2CO3 after initial Perkin condensation sig-
nificantly enhanced the reaction performance (Table 4,
entry 5), whereas use of DMF as the sole solvent for the
entire Perkin and Knoevenagel condensation–decarboxyla-
tion–Heck reaction sequence (Table 4, entry 3) led to con-
siderably lower yield. Interestingly, a further increase in
allowed a facile synthesis of mono-hydroxy-substituted
asymmetric DSBs 18b–20b, which are important scaffolds
for preparation of supramolecular materials.[8a] In contrast,
previous synthesis of 20b (Table 5, entry 20) required either
multiple steps[8a] or use of functionalized starting materi-
als.[8b]
The above tandem reaction plausibly proceeds through
synergistic combination of a three-pronged mechanistic
pathway (Scheme 4) that involves initial transformation of
the hydroxybenzaldehyde into the respective bromostilbene
by a modified Perkin condensation–decarboxylation reac-
tion.[10c] Subsequently, the bromostilbene is incorporated in
a Heck coupling, in which it is joined by a hydroxystyrene
derived from a concurrently occurring Knoevenagel conden-
sation–decarboxylation[10b] reaction.
yield was observed upon replacement of Pd
ACHTUNGRTENUN(NG OAc)2 with Pd-
ACHTUNGTRENNUNG
[15]
Ag2CO3 in place of K2CO3 did not improve the yield of
Finally, it was intriguing to further expand the repertoire
of such sequential reactions with a mechanistically different
Pd-catalyzed coupling. In this context, a tandem combina-
14b (Table 4, entry 9).
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10353

A. K. Sinha et al.
Table 4. Optimization data for one-pot tandem Perkin/Knoevenagel
double condensation–decarboxylation/Heck reaction.[a]
(PdACHTUNGRTENU(NG PPh3)4, [Pd2C6H10Cl2]) and solvents
(PEG, dioxane, glycerol). In contrast, a re-
verse approach appeared promising. Suzuki
coupling of 12a (0.72 mmol) with 4-me-
thoxyphenylboronic acid (1.13 mmol), Pd-
A
(0.072 mmol),
and
K2CO3
(0.95 mmol) in DMF provided the respec-
tive biaryl benzaldehyde which underwent further in situ
KD condensation with malonic acid in the presence of pi-
peridine to afford the desired hydroxy-biarylstyrene 22b,
albeit in only 10% yield. Gratifyingly, the yield of 22b was
significantly improved (40%, Scheme 5) upon replacement
of DMF with glycerol. The use of PEG as the reaction sol-
vent did not prove beneficial (15% yield). Subsequently, the
above protocol was applied to the direct synthesis of hy-
droxy-biarylstyrene 23b (Scheme 5).
Entry Solvent Base
Pd Catalyst
Ligand Yield[b]
[%]
1
2
PEG
200
PEG
200
piperidine
Pd
Pd
Pd
N
PPh3
9
piperidine+K2CO3
PPh3
15
3
4
5
6
7
8
9
DMF[c] piperidine+K2CO3
PPh3
PPh3
PPh3
–
14
48
49
48
47
52
49
DMF
DMF
DMF
DMF
DMF
DMF
piperidine+K2CO3
piperidine+K2CO3
piperidine+K2CO3
piperidine+K2CO3
piperidine+K2CO3
piperidine+Ag2CO3
PdCl2
Pd(OAc)2
[PdCl2A(PPh3)2]
AHCTUNGTRENNUNG
A
CHTUNGTRENNUNG
[Pd2C6H10Cl2] PPh3
[Pd
N
–
–
[d]
[Pd(PPh3)4]
A
[a] General conditions: 1a (1.97 mmol), BrPhCH2COOH (3.5 mmol), pi-
peridine (3.15 mmol), methylimidazole (2.9 mmol), PEG-200 (4 mL),
MW (180 W, 1508C, 20 min), then 4-hydroxybenzaldehyde (4.91 mmol),
Conclusion
We have developed new tandem condensation–coupling
strategies and their potential for direct synthesis of several
hydroxy-functionalized biologically and industrially impor-
tant compound classes is demonstrated. Importantly, an un-
precedented chemoselective double Knoevenagel condensa-
tion–decarboxylation/Heck cascade allowed the first concise
synthesis of stilbene–cinnamic ester 9c, a potent antidiabetic
drug candidate, along with various other stilbene–cinnamoyl
hybrids, from readily available benzaldehydes in substantial-
ly improved yields. The related cinnamoyl–cinnamic acid hy-
brids were also accessed in one pot by an analogous Heck–
aldol sequence. Significantly, a novel approach for the direct
olefination of benzaldehydes into diverse asymmetric hy-
droxy-distyrylbenzenes was achieved through the first
tandem Perkin/Knoevenagel double condensation–decar-
boxylation–Heck reaction. The scope of these sequential
condensation–coupling strategies was further extended to
direct conversion of benzaldehydes into industrially impor-
tant hydroxy-biarylstyrenes by a tandem Suzuki/Knoevena-
gel condensation–decarboxyla-
CH2ACHTUNGTRENNUNG(COOH)2 (19.6 mmol), piperidine (19.6 mmol), K2CO3 (1 equiv), Pd
catalyst (3 mol%), ligand (4 mol%), LiCl (8 mol%), DMF (8 mL), MW
(180 W, 1508C, 45 min). [b] Yield of pure isolated product (single run).
[c] DMF used for the entire reaction. [d] Ag2CO3 (1 equiv).
tion of KD condensation and Suzuki reaction appeared at-
tractive because it could also afford a, hitherto unknown,
direct conversion of benzaldehydes into industrially impor-
tant[16] hydroxy-biarylstyrenes (C6-C6-C2 unit). Thus, 4-hy-
droxy-5-iodo-3-methoxybenzaldehyde (12a, 0.72 mmol) was
heated at reflux with malonic acid (2.87 mmol) and piperi-
dine (2.87 mmol) in DMF to afford the respective 4-hy-
droxy-5-iodo-3-methoxystyrene. This styrene was subjected
to in situ Suzuki coupling with a substituted phenylboronic
acid (1.13 mmol), PdACHTUNGTRNENUG(OAc)2 (0.072 mmol), and K2CO3
(0.95 mmol) under MW irradiation (Scheme 5). However,
the above strategy proved unsuccessful; the intermediate
styrene did not undergo Suzuki coupling, even upon replace-
ment of PdACHTUNGTRENNUNG(OAc)2 and DMF with various other catalysts
tion reaction. The bioactivity
evaluation of the above syn-
thesized stilbenoids is current-
ly under investigation.
Experimental Section
For general experimental details, ad-
ditional representative procedures,
characterization data and NMR spec-
tra, see the Supporting Information.
Representative procedure for tandem
transformation of benzaldehydes into
hydroxystilbene–cinnamic acid hy-
brids by chemoselective double
Scheme 4. Plausible mechanism for one-pot tandem Perkin/Knoevenagel double condensation–decarboxyla-
tion–Heck reaction.
Knoevenagel condensation–decarbox-
ylation–Heck cascade reaction
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Tandem Transformations of Benzaldehydes
FULL PAPER
Table 5. Direct transformation of benzaldehydes into asymmetric hydroxy-distyrylbenzenes by one-pot
tandem Perkin/Knoevenagel condensation–decarboxylation/Heck reaction[a]
[D6]acetone): d=167.0, 147.7, 147.1,
144.2, 140.1, 133.2, 130.3, 129.3, 128.6,
126.5, 124.9, 120.7, 117.5, 115.1, 109.3,
55.3 ppm; HRMS (ESI): m/z calcd for
C18H16O4: 297.1121 [M+H]+; found:
297.1118.
Synthesis of 9c: Acetyl chloride
(1 mL) was added to a stirred solu-
tion of 9b (0.1 g, 0.34 mmol) in anhy-
drous MeOH (10 mL). The reaction
mixture was stirred at RT for 4 h or
until the reaction was complete. Sub-
sequently, the MeOH was evaporated
under vacuum, then ethyl acetate (2ꢂ
15 mL) was added. The solution was
washed with water (2ꢂ10 mL), dried
over Na2SO4, and the obtained organ-
ic layer (single spot on TLC) was
passed through silica gel column with
ethyl acetate followed by evaporation
Entry
14
Ar1CHO
Ar2CHO
Product
Yield[b] [%]
52 (9[c], 37[d]
)
1a
14b
15
16
3a
3a
15b
16b
47
54
under vacuum to obtain 9c as
a
yellow solid (0.099g, 95%; 75% over
two steps from the respective 4-iodo-
benzaldehyde).
M.p.
208–2108C;
1H NMR (300 MHz, [D6]DMSO): d=
9.32 (s, 1H), 9.11 (s, 1H), 7.72 (d, J=
7.9 Hz, 3H), 7.65 (t, J=10.5 Hz, 3H),
7.24 (d, J=15.6 Hz, 1H), 7.18 (d, J=
15.6 Hz, 1H), 6.96 (d, J=8.7 Hz, 1H),
6.82 (d, J=9.1 Hz, 1H), 6.67 (d, J=
16.7 Hz, 1H), 3.75 ppm (s, 3H);
13C NMR (75.4 MHz, [D6]DMSO):
d=167.7, 146.9, 146.3, 145.1, 140.7,
133.3, 131.3, 129.6, 129.3, 127.3, 125.0,
119.9, 117.7, 116.6, 114.4, 52.3 ppm;
HRMS (ESI): m/z calcd for C18H16O4:
17
3a
1a
3a
17b
18b
19b
51
33
31
18[e]
19[e]
297.1121ACTHNUTRGNEUNG
[M+H]+; found: 297.1103.
20[e]
2a
20b
21b
34
1H and 13C NMR spectroscopic data
were consistent with those previously
reported.[7] The structure was further
confirmed by 2D NMR spectroscopy
(HMBC, HMQC, and COSY; see the
Supporting Information).
21[e]
11a
nd[f]
Representative procedure for Pd-cat-
alyzed one-pot tandem transforma-
tion of benzaldehydes into asymmet-
rically functionalized hydroxy-distyr-
ylbenzenes by sequential Perkin/
Knoevenagel double condensation–
[a] General conditions: Ar1CHO (1.97 mmol), 4-BrPhCH2COOH (3.5 mmol), piperidine (3.15 mmol), methyli-
midazole (2.9 mmol), PEG-200 (4 mL), MW (180 W, 1508C, 20 min), then Ar2CHO (4.91 mmol), CH2-
ACHTUNGTRENNUNG(COOH)2 (19.6 mmol), piperidine (19.6 mmol), PdCAHUTNTGRENN(UGN PPh3)4 (3 mol%), LiCl (8 mol%), K2CO3 (1.95 mmol),
DMF (8 mL), MW (180 W, 1508C, 45 min. [b] Yield of pure isolated product (single run). The structures of all
1
novel compounds were confirmed by HRMS, H, and 13C NMR spectroscopic analysis (see the Supporting In-
formation for details). [c] Yield when PEG-200 was used as the solvent for the entire reaction. [d] Yield of the
decarboxylation–Heck
(Table 5, 14b): Aldehyde 1a (0.3 g,
1.97 mmol) was added to stirred
mixture of 4-bromophenylacetic acid
reaction
two-step reaction (see the Supporting Information). [e] Styrene was used in place of Ar2CHO. [f] Not detect-
ed.
a
(Table 2, 1b): Aldehyde 1a (0.49 g, 3.23 mmol), 4-iodobenzaldehyde
(0.76 g, 3.5 mmol), methylimidazole (0.23 mL, 2.9 mmol), and piperidine
(0.31 mL, 3.15 mmol) in PEG-200 (4 mL). The reaction mixture was
heated under MW irradiation (180 W) at 1508C for 20 min. A mixture of
malonic acid (2.04 g, 19.6 mmol), piperidine (1.67 mL, 19.6 mmol), 4-hy-
[11]
(0.3 g, 1.30 mmol), [Pd
G
(0.18 g,
1.30 mmol), and LiCl[17] (0.0044 g, 0.104 mmol) were added to a stirred
mixture of malonic acid (1.88 g, 18.20 mmol) and piperidine (1.93 mL,
19.50 mmol) in DMF (15 mL). The reaction mixture was heated under
MW irradiation (180 W, 1508C) for 50 min. The above mixture was
cooled to RT and filtered through Celite. The filtrate was poured into
water (150 mL), acidified with dilute aqueous HCl solution (pH 5–6), and
extracted with ethyl acetate (2ꢂ40 mL). The combined organic layers
were washed with water (2ꢂ15 mL), brine (1ꢂ10 mL), dried over
Na2SO4, and evaporated under vacuum. The obtained residue was puri-
fied by column chromatography on silica gel (60–120 mesh size) with
hexane/ethyl acetate (93:7) to give 1b as a yellow solid (0.31g, 81%).[18]
M.p. 232–2358C; 1H NMR (300 MHz, [D6]acetone): d=7.59–7.50 (m,
6H), 7.22–7.17 (m, 1H), 7.10–6.97 (m, 2H), 6.76 (d, J=7.9 Hz, 1H), 6.46
(d, J=15.9 Hz, 1H), 3.81 ppm (s, 3H); 13C NMR (75.4 MHz,
droxybenzaldehyde (0.6 g, 4.91 mmol), [PdACHTNUTRGEN(UNG PPh3)4] (0.068 g, 0.059 mmol),
K2CO3 (0.27 g, 1.95 mmol), and LiCl (0.007 g, 0.16 mmol) in DMF (8mL)
was added and the reaction mixture was heated under MW irradiation
(180 W) at 1508C for 45 min. The reaction mixture was cooled to RT and
filtered through Celite. The filtrate was poured into water (150 mL),
acidified with dilute aqueous HCl solution (pH 5–6), and extracted with
ethyl acetate (2ꢂ40 mL). The combined organic layers were washed with
water (2ꢂ15 mL), brine (1ꢂ10 mL), dried over Na2SO4, and evaporated
under vacuum. The obtained residue was purified by column chromatog-
raphy on silica gel (60–120 mesh size) with hexane/ethyl acetate (94:6) to
give 14b as a yellow-green solid (0.35 g, 52%).[19] M.p. 255–2578C;
1H NMR (300 MHz, 1:1 [D6]DMSO/CDCl3): d=9.35 (s, 1H), 8.87 (s,
Chem. Eur. J. 2011, 17, 10350 – 10356
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10355

A. K. Sinha et al.
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Scheme 5. Direct synthesis of hydroxy-biarylstyrenes.
1H), 7.49 (s, 4H), 7.40 (d, J=8.2 Hz, 2H), 7.10 (d, J=17.6 Hz, 3H),
7.00–6.96 (m, 3H), 6.93 (d, J=7.3 Hz, 1H), 6.87 (t, J=8.2 Hz, 2H),
3.94 ppm (s, 3H); 13C NMR (75.4 MHz, 1:1 [D6]DMSO/CDCl3): d=
156.8, 147.1, 146.8, 135.6, 134.8, 128.2, 127.6, 127.5, 127.0, 125.6, 124.5,
124.2, 119.5, 115.0, 114.9, 108.6, 55.1 ppm; HRMS (ESI): m/z calcd for
C23H20O3: 345.1485 [M+H]+; found: 345.1436.
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Acknowledgements
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N.S., A.S. and R.K. are indebted to C.S.I.R., New Delhi, for the award of
research fellowships. The authors gratefully acknowledge the Director,
I.H.B.T. Palampur, for his encouragement as well as providing infrastruc-
ture for conducting the above work. I.H.B.T. Communication No. 2162.
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[17] The use of LiCl as an additive was found to improve the tandem re-
action because it significantly reduced the formation of a regioiso-
meric a-arylated product. Similar findings have been observed in
earlier reports; see J. P. Ebran, A. L. Hansen, T. M. Gogsig, T.
Skrydstrup, J. Am. Chem. Soc. 2007, 129, 6931–6942.
[18] For comparative purposes: a) the reaction under conventional reflux
conditions provided 1b (76% yield after 10 h); b) the reaction was
also performed in a three-step, three-pot approach: a) synthesis of
4-iodocinnamic acid from condensation of 4-iodobenzaldehyde and
malonic acid (78%), b) formation of 4-ethenyl-2-methoxyphenol by
Knoevenagel–Doebner condensation/decarboxylation of vanillin and
malonic acid (71%), c) Heck coupling to obtain 1b (55% overall
yield).
[19] For comparative purposes, the reaction was also performed in a
three-step, three-pot approach: synthesis of bromostilbene by
Perkin reaction (69%) followed by Heck coupling (54%) with sty-
rene (synthesized separately from the respective benzaldehyde) to
provide 14b (37% overall yield).
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Received: April 16, 2011
Published online: August 2, 2011
10356
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Chem. Eur. J. 2011, 17, 10350 – 10356