Tandem heck/decarboxylation/heck strategy: Protecting-group-free synthesis of symmetric and unsymmetric hydroxylated stilbenoids

Article abstract of DOI:10.1002/anie.201206346

Ride the (micro)wave: The title strategy has been developed for the synthesis of various symmetric or unsymmetric hydroxylated stilbenoids utilizing 4-halophenols and acrylic acid as coupling partners (see scheme; DMA=N,N-dimethylacetamide, MW=microwave). Protecting groups are not necessary and a single palladium catalyst is used. Copyright

Full text of DOI:10.1002/anie.201206346

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Angewandte
Communications
DOI: 10.1002/anie.201206346
Cross-Coupling
Tandem Heck/Decarboxylation/Heck Strategy: Protecting-Group-Free
Synthesis of Symmetric and Unsymmetric Hydroxylated Stilbenoids**
Amit Shard, Naina Sharma, Richa Bharti, Sumit Dadhwal, Rajesh Kumar, and Arun K. Sinha*
The use of inexpensive[1] raw materials and performing
reactions either in a tandem[2] or sequential[3] manner has
emerged as an elegant approach in organic synthesis in terms
of efficiency, economy, and waste minimization. In this
context, the unrivalled diversity of the transition-metal-
catalyzed reactions has made them important mediators for
the elaboration of tandem processes.[2c]
Notably, palladium-catalyzed Heck coupling[4] between an
olefin[4a] and aryl halide (or its surrogates)[4b,c] has garnered
significant attention for generating numerous biologically
active stilbenoids like resveratrol,[4d] pterostilbene,[4e] etc.
However, one of the coupling partners, that is, styrene, is
inevitably prone to polymerization, difficult to synthesize, and
Scheme 1. Synthesis of symmetric and unsymmetric hydroxylated stil-
benoids and distyrylbenzene by a tandem HDH strategy. The ratios
given within parentheses represent the 4-iodophenol/acrylic acid/aryl
halide ratio for the reactions.
tricky to purify. To counteract this problem, generation of
styrene[5] in situ (by Knoevenagel decarboxylation,[5a–c] Huns-
diecker,[5d] Wittig–Horner,[5e] dehydrohalogenation Heck[5f]
reaction) and subsequent tandem coupling with an arylhalide
to yield stilbenoids have come to the forefront. In contrast,
the synthetic efficiency for hydroxy[6] functionalized stilbe-
noids is hampered by the involvement of additional protec-
tion/deprotection strategies.[6b]
nol (1.83 g, 8.32 mmol) and one equivalent of acrylic acid
(0.3 g, 4.16 mmol) was carried out using Pd(OAc)2 (4 mol%),
PPh3 (5 mol%), and piperidine/sodium formate (1.5 equiv
each) under microwave (MW) irradiation (120W, 1508C) for
40 minutes in [hmim]Br (1 g), thus providing 1[5c] in 17% yield
(Table 1, entry 1). The [hmim]Br was replaced with N,N-
dimethylacetamide[9] (DMA) and other bases were screened
(Table 1, entries 3–11). Piperidine as a base improved the
yield of 1 up to 45% (Table 1, entry 8).
Further, a detailed optimization study was conducted to
evaluate the effect of various solvents, palladium catalysts,
and additives (Table 2). Interestingly, use of [Pd(PPh3)4] and
LiCl as an additive in DMA provided 1 in 52% yield under
microwave irradiation (180W, 1608C) after 40 minutes
(Table 2, entry 10). In contrast, carrying out the same reaction
in an oil bath (1608C) provided 1 in 41% yield (Table 2,
entry 13) with a longer reaction time of 360 minutes. Halo-
phenols[10] are a useful class of synthons[10a] and serve as
important synthetic handles for the elaboration of numerous
organic transformations like the Heck lactonization of 2-
halophenols into coumarins[10b] and benzofurans.[10c] How-
ever, there is no report on the utilization of their positional
variants, such as 4-halophenols, along with acrylic acid for the
synthesis of hydroxylated stilbenoids without using a protec-
tion/deprotection strategy.[6]
Herein, we describe the palladium-catalyzed tandem
Heck/decarboxylation/Heck (HDH) cross-coupling of 4-halo-
phenols with acrylic acid to yield unprecedented symmetric or
unsymmetric hydroxylated stilbenoids (C6-C2-C6 unit) or
distyrylbenzene (C6-C2-C6-C2-C6 unit) in a protecting-group-
free manner. The method allows tuning of the concentration
of the coupling partners, and CO2 is the only by-product with
respect to the acrylic acid (Scheme 1); conventional coupling
of 4-halophenols and acrylic acid are known to provide 4-
hydroxy cinnamic acid (C6-C3 unit).[7]
Inspired by our recent tandem dehydrative Heck meth-
od,[8a] which utilizes in situ generated styrene to construct
stilbenoids in ionic liquids (IL),[8] we further envisaged
carrying out tandem HDH reactions for the generation of
symmetric hydroxylated stilbenoids in neutral ionic liquids.[8a]
To accomplish this, coupling of two equivalents of 4-iodophe-
[*] A. Shard, N. Sharma, R. Bharti, S. Dadhwal, R. Kumar, A. K. Sinha
Natural Plant Products Division, C.S.I.R.-Institute of Himalayan
Bioresource Technology, Council of Scientific and Industrial
Research, Palampur-176061 (H.P.) (India)
E-mail: aksinha08@rediffmail.com
[**] This work was supported by the Council of Scientific and Industrial
Research (project MLP 0008 and MLP 0052/ORIGIN). A.S. and R.K.
thank the C.S.I.R. for an SRF award. The authors gratefully
acknowledge the Director the IHBT, Palampur, for his kind
cooperation and encouragement. I.H.B.T. Communication No.
2384.
Conventionally, the hydroxy stilbene 1 can be accessed
through a protection/deprotection strategy[11] involving Heck
coupling between 4-iodoanisole (protected halophenol) and
acrylic acid with a subsequent Hunsdiecker reaction[5d,11a]
/
Suzuki coupling,[11b] and a final demethylation[11c] with boron
trihalide. Hence, the utility of our optimized HDH protocol
was ascertained through synthesis of a diverse array of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206346.
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Table 1: Screening of different bases for synthesis of symmetric
Table 3: Tandem HDH strategy for a three-step, one-pot synthesis of
symmetric hydroxylated stilbenoids.[a]
hydroxylated stilbenoids[a] using a tandem HDH strategy.
Entry ArOH
1
Product
Yield [%][b]
52
1
1
Entry Base
Equiv.
t [min] Yield [%][b]
1
2
piperidine+HCOONa in IL[c] 1.5+1.5 40
17
25
40
13
11
6
2
3
41
35
piperidine+K2CO3 in IL[c]
1.5+1.5 40
1.5+1.5 40
1.5+1.5 40
3
3
3
3
3
3
3
[d]
3
piperidine+K2CO3
[d]
4
HCOONa+K2CO3
[d]
5
6
7
8
9
10
11
K2CO3
40
40
40
40
40
40
40
2
HCOONa[d]
KOH[d]
25
45
22
18
18
piperidine[d]
Et3N[d]
Bu3N[d]
4
5
3
4
85
76
DBU[d]
[a] Reaction conditions: 4-iodophenol (8.32 mmol), acrylic acid
(4.16 mmol), Pd(OAc)2 (4 mol%), PPh3 (5 mol%), base, solvent 8 mL,
180 W, 1608C using a CEM monomode microwave. [b] Yield of product
isoalted after purification using silica gel column chromatography.
[c] [hmim]Br (1-hexyl 3-methyl imidazolium bromide) was used. [d] IL
was replaced by DMA in the reactions shown in entries 3–11. DBU=1,8-
diazabicyclo[5.4.0]undec-7-ene.
6
7
8
5
6
7
30
40
Table 2: Screening different solvents and palladium catalysts for the
HDH sequence for synthesis of stilbenoids.[a]
n.d.
Entry
Solvent
Pd catalyst
Ligand
Additive
Yield[b]
9
8
9
n.d.
n.d.
1
2
3
4
5
6
7
8
DMA
NMP
DMF
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(CF3COO)2
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
–
–
–
–
–
–
–
–
–
–
–
–
–
45
21
32
24
22
25
20
26
48
52
50
46
41[c]
10
PEG 200
water
toluene
DMA
DMA
DMA
DMA
DMA
DMA
DMA
[a] Reaction conditions: acrylic acid (4.16 mmol), halophenol
(8.32 mmol), [Pd(PPh3)4] (4 mol%), LiCl (8 mol%), piperidine
(12.44 mmol), DMA (8 mL), 180W, 1608C using a CEM monomode
microwave. [b] Yield of isolated product. n.d.=not detected.
9
–
10
11
12
13
LiCl
Ag2CO3
Cs2CO3
LiCl
halophenols having electron-withdrawing substituents
(Table 3, entries 4 and 5) provided stilbenes in higher yields
(up to 85%) relative to the halophenols having electron-
donating substituents (entries 3, 6, and 7), which provided
stilbenes in moderate yield (up to 40%).This drastic differ-
ence in yields may be due to the electron-withdrawing groups
facilitating decarboxylation of the intermediate 4-hydroxy
cinnamic acid to generate 4-hydroxystyrene (Table 3,
entries 4 and 5). Such a discernible difference in yields was
also observed by Zhang[13] et al., who reported that cinnamic
esters obtained from acrylates and aryl halides were formed in
higher yields particularly in the presence of electron-with-
drawing substituents. As expected, a 2-halophenol variant of
4-halophenol did not provide 7 because of its poor reactivity
towards the Heck coupling/decarboxylation or tendency to
form coumarin (Table 3, entry 8).[10b] In a control experiment,
reaction of a 3-halophenol or 4-haloanisole (Table 3, entries 9
[a] Reaction conditions: 4-iodophenol (8.32 mmol), acrylic acid
(4.16 mmol), Pd catalyst (4 mol%), ligand (5 mol%), additive
(8 mol%), piperidine (3 equiv), 180W, 1608C using a CEM monomode
microwave. [b] Yield of isolated product. [c] Conventional heating for 6 h
at 1608C. DMF=N,N’-dimethylformamide, NMP=N-methylpyrroli-
done, PEG=polyethyleneglycol.
symmetric hydroxylated stilbenoids using acrylic acid and
halophenols bearing different substitutents (Table 3,
entries 1–7). As expected, coupling of 4-iodophenol and
acrylic acid provided 1 (Table 3, entry 1) in good yield relative
to the coupling between 4-bromophenol and acrylic acid
(entry 2) because 4-iodophenol participates more readily in
the Heck reaction[12] (I > Br). It was also observed that 4-
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Table 4: One-pot sequential HDH strategy for the synthesis of unsym-
metric hydroxylated stilbenoids.
and 10) with acrylic acid did not lead to the respective
stilbenes because they did not undergo the quinomethide[14]
mechanism, thus emphatically demonstrating the crucial role
played by hydroxy substitution at the para position of
aromatic ring. Moreover the prerequisite of ethylene gas[15]
or the protection/deprotection[16] protocol was altogether
avoided for the stilbenoids 1–6.
Mechanistically, it is presumed that 4-halophenol reacts
with acrylic acid to form 4-hydroxy cinnamic acid (first Heck
coupling; Scheme 2) which undergoes decarboxylation
according to the quinomethide[5a] mechanism to form 4-
hydroxystyrene in situ. The second Heck coupling proceeds
with another 4-halophenol to form the symmetric hydroxy-
lated stilbenoid. When 4-haloanisole is used for the second
Heck coupling an unsymmetric stilbene results from the
HDH protocol.
Now, our goal was to extend the tandem protocol to the
synthesis of unsymmetric hydroxylated stilbenoids (see
Table 4) which enjoy the status of being privileged motifs in
terms of their diverse biological[17] and unambiguous phys-
icochemical[18] profiles. To achieve this, 4-iodophenol, acrylic
acid, and 4-iodoanisole were used in 1:1:1 ratio and irradiated
Yields are those of the isolated product.
(1408C, 8 h) failed to afford the second Heck
coupling product 10 under completely aqueous
conditions. It was then decided to use a co-
solvent for making the second Heck coupling
more facile. Surprisingly, addition of 12 mL
DMA[21] (four times the volume of water) and
4-iodoanisole to the same pot with refluxing at
1408C for 8 hours afforded the desired unsym-
metric stilbene 10 in 65% yield (71% on HPLC
basis) with E selectivity by the tandem-sequen-
tial HDH strategy (see the Supporting Informa-
Scheme 2. Plausible mechanism for the synthesis of hydroxylated stilbenoids in one
tion).
These optimized reaction conditions were
applied to different halophenols, arylhalides,
pot.
using a microwave at 1608C for 40 minutes in DMA (8 mL),
and the desired 4-hydroxy-4’-methoxy stilbene (10) was
furnished in 5% yield along with the undesired 4-methoxy
cinnamic acid (25% yield), but without formation of the
desired intermediate 4-hydroxy cinnamic acid as evidenced
by HPLC analysis (see the Supporting information). Addi-
tionally, a number of combinations of reaction conditions
were applied and conventional heating was preferred pre-
sumably because the fast dissipation of energy by MW
irradiation[19] could be leading the HDH reaction to favor of
the formation of the symmetric stilbene 1 (Table 3) along with
cinnamic acid, rather than desired unsymmetric stilbene (10).
Therefore, the HDH reaction run in sequential one-pot
manner to improve the yield of 10 (see the Supporting
Information).
and acrylic acid and successfully provided the unsymmetric
stilbenoids 10–21 in moderate to good yields (35–75%).
Moreover the methodology provides a concise synthesis of
the indole-containing[22] stilbene 4-[(E)-2-(1H-indol-6-yl)e-
thenyl]phenol (19) and the anticancer natural Pterostilbene[4c]
(21) in 54% overall yield (scalable up to 1 gm), whereas
a previous multistep protocol[23] provides 21 in 24% overall
yield.
Interestingly, the distyrylbenzene (DSB)[24] (E,E)-1,4-
bis(4-hydroxystryl)benzene (22; Scheme 3), possessing wide
applications in diagnosis and therapeutics of Alzheimerꢀs
Finally, the first Heck coupling between 4-iodophenol
(1.0 equiv) and acrylic acid (1.0 equiv) with KOH[20] (3 equiv)
in water (3 mL) under conventional heating (858C, 3 h)
provided the intermediate 4-hydroxy cinnamic acid in 95%
yield (based upon HPLC analysis). But subsequent addition
of 4-iodoanisole to the same pot with heating by refluxing
Scheme 3. Tandem sequential synthesis of (E,E)-1,4- bis(4-hydroxy)-
styrylbenzene.
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disease,[24b] was also successfully synthesized by the one-pot
sequential coupling of halophenol (1.0 equiv) and acrylic acid
(1.0 equiv) in the first step to deliver 4-hydroxy cinnamic acid
in aqueous medium, and subsequent refluxing with diiodo-
benzene (0.5 equiv) in the presence of DMA in the second
step to afford the hydroxylated DSB in 43% yield by a Heck/
decarboxylation/double Heck (HDHH) sequence. This over-
all yield is in contrast to the reported 16% overall yield.[24c]
In summary, we have for the first time devised a practical
tandem/sequential HDH approach for the synthesis of
diversely substituted symmetric and unsymmetric hydroxy-
lated stilbenoids and distyrylbenzene. Here, acrylic acid acts
as an ethylene surrogate and offers a unique platform for the
self-coupling of two molecules of halophenols for the
formation of a symmetric stilbene, while cross-coupling of
acrylic acid with a halophenol and arylhalide (three coupling
partners) provides an unsymmetric stilbene. This diversity
oriented construction of hydroxylated stilbenoids offers
several advantages such as utilizing readily accessible pre-
cursors and it is a protecting-group-free and waste free (-CO2
as by-product) synthesis. The synthesized stilbenoids are
amenable to downstream modification as their medicinal and
electronic properties can be easily tuned using differently
substituted halophenols and aryl halides.
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Received: August 7, 2012
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