Palladium-catalyzed dehydrative Heck olefination of secondary aryl alcohols in ionic liquids: Towards a waste-free strategy for tandem synthesis of stilbenoids

Article abstract of DOI:10.1002/anie.201107261

All in one: A tandem strategy has been developed wherein secondary aryl alcohols are directly coupled with aryl halides to provide stilbenoids through a dehydrative Heck sequence in the ionic liquid [hmim]Br, and with water as a by-product under microwave irradiation (see scheme). Classical methods do not permit this sequence to proceed in one pot, and some methods require multiple steps. hmim=1-n-hexyl-3-methylimidazolium. Copyright

Full text of DOI:10.1002/anie.201107261

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Angewandte
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DOI: 10.1002/anie.201107261
Cross-Coupling
Palladium-Catalyzed Dehydrative Heck Olefination of Secondary Aryl
Alcohols in Ionic Liquids: Towards a Waste-Free Strategy for Tandem
Synthesis of Stilbenoids**
Rakesh Kumar, Amit Shard, Richa Bharti, Yogesh Thopate, and Arun Kumar Sinha*
The development of new environmentally benign, tandem,
cross-coupling strategies constitute one of the most cherished
goals of contemporary organic synthesis because of several
inherently unique benefits in terms of efficacy, economy, and
environmental impact.[1,2] The above objective becomes addi-
tionally fruitful if expensive and unstable coupling partners
can be replaced with readily available and inexpensive
precursors.[1d]
sometimes commercially unavailable or synthesized by the
bromination of aryl alcohols with PBr3 (Scheme 1), thus not
ideal substrates from an atom-economical point of view.
The palladium-catalyzed cross-coupling of styrenes with
aryl halides, known as the Heck reaction[3] is a powerful
method for the synthesis of bioactive stilbenoids, including
the anticancer agent resveratrol, DMU-212, et cetera. How-
ever, substituted styrenes are not frequently available and
involve multistep synthesis in addition to the problem of
storage because of their propensity towards polymeriza-
tion.[1c] Thus, realization of a tandem Heck reaction by in situ
formation of styrene and subsequent coupling with an aryl
halide would be practically useful.
Currently, alcohols that are readily accessible have
received great attention as precursors in various tandem
oxidative[1a,4]/dehydrative[1d] cross-coupling strategies. How-
ever, direct use of secondary aryl alcohols as an in situ source
of styrene (by dehydration) in Heck coupling has remained
unexplored. The main reason is the cross-contamination of
reagents/catalysts resulting from different media require-
ments in the Heck (basic) and dehydration (acidic) steps.
Thus designing the above two steps to occur in one pot is
a major problem. Moreover, secondary aryl alcohols under
Heck-type conditions are generally converted into the
respective carbonyls[5] through isomerization[5a] or oxida-
tion[5b] processes.
Scheme 1. Prevalent approaches (a) and present work (b) for the
conversion of secondary aryl alcohols into stilbenoids.
Our ongoing interest on the use of ionic liquids[7] (ILs) as
well as the development of various tandem cross-coupling
strategies[8] encouraged us to explore a hitherto unknown
approach towards waste-free dehydrative Heck olefination
through the concurrent coupling of in situ formed styrenes
with aryl halides in ILs where water is the only by-product
(Scheme 1).
After an initial survey of reaction conditions, 4-iodoani-
sole (0.2 g, 0.85 mmol, 1 equiv) was reacted with 1-(naphtha-
len-2-yl)ethanol (1a, 1.5 equiv) in [hmim]Br using Pd(OAc)2
(4 mol%), PPh3 (5 mol%), and Et3N (1.5 equiv) as a base
under microwave (MW) irradiation (120W, 1508C) for
40 minutes (Table 1, entry 1). Thereafter, the crude reaction
mixture was analyzed preferably by HPTLC (over HPLC/
GC),[9] and 1b was obtained in only 8% yield (Figure 1 and
Table 1, entry 1). To further increase the yield of 1b, various
other organic and inorganic bases were rapidly screened
through HPTLC analysis (Figure 1 and Table 1, entries 2–9),
and HCOONa surprisingly provided 1b in 69% yield (56%
upon isolation; entry 9). Furthermore, the synergism of two
bases,[10] that is HCOONa (1.5 equiv) and piperidine
(1 equiv), not only increased the reaction performance
(entry 16), but also reduced the reaction time to 15 minutes
from 40 minutes.
In contrast, secondary aryl-substituted alkyl bromides
(instead of secondary aryl alcohols) have been utilized for the
synthesis of stilbenoids through a dehydrohalogenation/Heck
methodology.[6] However, such substituted bromides are
[*] R. Kumar, A. Shard, R. Bharti, Y. Thopate, A. K. Sinha
Natural Plant Products Division
CSIR-Institute of Himalayan Bioresource Technology
(Council of Scientific and Industrial Research)
Palampur-176061 (H.P.) (India)
Subsequently, a detailed optimization study was con-
ducted to evaluate the effect of other ILs, palladium catalysts,
and additives (Table 2). However, commonly used ILs such as
[bmim]BF4 and [bmim]PF6 for the Heck reaction[11] provided
1b in very low yield (entries 2 and 3) because of their
inefficiency for the dehydration of 1a in comparison to
[hmim]Br. Interestingly, no reaction was observed with DMF
(entry 5), thus emphasizing the crucial role of the IL. Use of
E-mail: aksinha08@rediffmail.com
[**] This work was supported by the Council of Scientific and Industrial
Research (project MLP 0025). Thanks to Arti Katiyar and Nandini
Sharma for help regarding HPTLC experiments. We gratefully
acknowledge the Director, IHBT, Palampur, for his kind cooperation
and encouragement. I.H.B.T. Communication No. 2263.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107261.
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Table 1: Screening of different bases for the palladium-catalyzed tandem
dehydrative Heck coupling in [hmim]Br.[a]
Entry
Base
Equiv.
t [min]
Yield [%][b]
1
2
3
4
5
6
7
8
Et3N
Bu3N
piperidine
DBU
Cs2CO3
K2CO3
NaOAc
NH4OAc
HCOONa
HCOONH4
HCOOK
HCOONa
HCOONa
HCOONa + K2CO3
HCOONa + piperidine
HCOONa + piperidine
HCOONa + piperidine
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1
40
40
40
40
40
40
40
40
40
40
40
40
40
15
15
15
15
8
30
32
5
6
7
n.d.
13
9
69 (56)[c]
(41)[c]
(52)[c]
(50)[c]
(52)[c]
(59)[c]
(64)[c]
(69)[c]
(66)[c]
10
11
12
13
14
15
16
17
2.5
1.5+1.5
1.5+1.5
1.5+1.0
1.5+0.5
[a] CEM monomode microwave; General conditions: 4-iodoanisole
(0.85 mmol), 1a (1.28 mmol), Pd(OAc)2 (4 mol%), PPh3 (5 mol%),
base, [hmim]Br (1.5 g), 120 W, 1508C. [b] Yields determined by HPTLC
using a reference standard. [c] Yield of isolated product 1b (in
parentheses). hmim=1-n-hexyl-3-methylimidazolium, n.d.=not deter-
mined.
[PdCl2(PPh3)2] as a catalyst along with LiCl[8b,12] as an additive
proved optimum (entry 10). The product 1b was obtained
with exclusively E selectivity (based upon NMR spectrosco-
py; see the Supporting Information). Earlier, this E isomer
(1b), a naphthalene analogue of the anticancer agent
combretastatin,[13] was isolated in 20% yield after a multistep
Wittig protocol and tedious separation of the E/Z isomers.[13]
In contrast, conventional heating (oil bath, 1508C) of 1a using
[hmim]Br provided 1b in low yield (20% after 14 h) along
with polymeric side products (entry 13), thus emphasizing the
crucial role of the MW conditions, wherein creation of
microscopic hot spots[14] (having temperature well above
1508C) are probably responsible for significant rate enhance-
ment.
Figure 1. a) HPTLC CCD image at 254 nm: standard samples (A–E) of
1b at different concentrations; samples (1–9 correspond to Table 1,
entries 1–9) indicating formation of 1b. b) Three-dimensional HPTLC
densitogram of samples 1–9 (all tracks at 254 nm). Yields expressed in
terms of percent peak area, wherein yield varies from 0 to 69%
(Table 1, entries 1–9, and see the Supporting Information). Rf=reten-
tion factor.
Mechanistically, it is presumed that the incipient styrene
(formed in situ by IL/MW assisted dehydration[7] contempo-
rary to bromination/dehydrobromination[15] sequence) simul-
taneously undergoes palladium-catalyzed cross-coupling[8b]
with an aryl halide leading to formation of stilbenes in one
pot (Scheme 2).
The utility of the optimized protocol was additionally
ascertained through tandem synthesis of a diverse array of
stilbenes possessing electron-donating as well as electron-
withdrawing groups either on the secondary aryl alcohol or on
the aryl halide moiety (Table 3). Notably, polyaromatic
alcohols (entries 1–5 and 7–9) provided good yields whereas
electron-deficient (entry 10) or methoxylated benzyl alcohols
(entries 11 and 12) provided moderate yields as a result of the
polymerization tendency of the intermediate styrene[16] and
formation of the dehalogenated aryl halide as a side product.
Also, coupling of aryl alcohol with p-electron-deficient
heteroaryl halides[17] (entry 6) afforded 6b in 47% yield. In
addition, the developed methodology successfully provided
the hydroxylated stilbenoids (entries 2, 7, and 9), including
a naphthyl analogue of the anticancer agent combretastatin
(2b),[13] in very good yields without any protection/depro-
tection manipulations. However, a primary alcohol (entry 13)
was found to be reluctant to undergo dehydration and
subsequent Heck coupling.
Under similar reaction conditions, the acetylated deriva-
tive of alcohols underwent
a novel one-pot tandem
deacetoxylative Heck coupling to afford the corresponding
stilbenes in good yields (Scheme 3).
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Table 2: Screening of palladium catalysts, ILs, and additives for the
Table 3: Substrate scope of tandem dehydrative Heck coupling.[a]
tandem dehydrative Heck coupling under microwave irradiation.[a]
Entry Aryl alcohol
Ar
t [min] Yield [%][b]
(Aryl iodide)
Entry Ionic liquid Pd catalyst
Ligand Additive t [min] Yield[b]
1
2
3
4
5
6
7
8
[hmim]Br
Pd(OAc)2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
–
–
–
–
–
–
–
–
–
15
25
25
25
50
15
15
15
15
15
15
69
22
21
19
n.d.[d]
71
68
72
74
78
67
62
20
[bmim]BF4 Pd(OAc)2
[bmim]PF6 Pd(OAc)2
[bmim]OH Pd(OAc)2
1
2
3
4
5
4-MeOC6H4
4-HOC6H4
4-ClC6H4
4-NO2C6H4
4-CF3C6H4
15
30
15
15
15
78 (1b)
77 (2b)
84 (3b)
89 (4b)
83 (5b)
DMF[c]
Pd(OAc)2
PdCl2
[Pd(PPh3)4]
[hmim]Br
[hmim]Br
[hmim]Br
[hmim]Br
[hmim]Br
[hmim]Br
[hmim]Br
Pd(CF3COO)2 PPh3
9
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
[PdCl2(PPh3)2]
–
–
–
–
–
–
6
3-C5H4N
25
47 (6b)
10
11
12
13
LiCl
Ag2O
Ag2CO3 15
LiCl 840
[hmim]Br[e] [PdCl2(PPh3)2]
7
8
4-HOC6H4
4-COCH3C6H4 15
30
75 (7b)
76 (8b)
[a] CEM monomode microwave; General conditions: 4-iodoanisole
(0.85 mmol), 1a (1.28 mmol), Pd catalyst (4 mol%), ligand (5 mol%),
additive (8 mol%), HCOONa (1.28 mmol), piperidine (0.85 mmol),
ionic liquid (1.5 g), 120 W, 1508C. [b] Yield of isolated product. [c] Ionic
liquid was replaced with 4 mL of DMF. [d] Not detected on the basis of
NMR spectroscopy. [e] Conventional heating (oil bath 1508C) instead of
microwave. DMF=N,N’-dimethylformamide, bmim=1-butyl-3-methyl-
imidazolium.
9
4-HOC6H4
30
74 (9b)
10
4-COCH3C6H4 15
4-COCH3C6H4 15
59 (10b)
11
12
63 (11b)
68 (12b)
4-CNC6H4
15
13
4-MeOC6H4
30
n.d.[c] (13b)
Scheme 2. Proposed mechanism for tandem dehydrative Heck
coupling in an IL under microwave irradiation.
[a] CEM monomode microwave; General conditions: aryl halide
(0.85 mmol), aryl alcohol (1.28 mmol), [PdCl2(PPh3)2] (4 mol%), LiCl
(8 mol%), HCOONa (1.28 mmol), piperidine (0.85 mmol), [hmim]Br
(1.5 g), 120 W, 1508C. [b] Yield of isolated product. [c] Not detected.
Scheme 3. Deacetoxylative Heck sequence.
Scheme 4. Tandem dehydration/Heck/Knoevenagel–Doebner conden-
sation sequence.
Subsequently, another novel tandem strategy involving
hitherto unknown sequential dehydration/Heck/Knoevena-
gel–Doebner condensation into the stilbene cinnamoyl hybrid
14b, a naphthalene[13] analogue of a PTPIB inhibitor,[18] was
successfully accomplished in one pot with 52% yield
(Scheme 4) instead of the reported tedious seven-step proto-
col.[18]
phere. The developed method is an efficient, atom-economic,
and ecofriendly alternative to the exisiting multistep
approaches as it eliminates the isolation of the polymerization
prone styrenes, as well as protection/deprotection manipu-
lations in the case of hydroxy-substituted stilbenoids.
In conclusion, a new one-pot approach towards a waste-
free strategy for the preparation of stilbenoids involving
a dehydrative Heck sequence assisted by the ionic liquid
[hmim]Br has been developed. The method utilizes readily
accessible and inexpensive secondary aryl alcohols as an in
situ source of styrenes and do not require an inert atmos-
Experimental Section
Representative procedure for the synthesis of 2-[(E)-2-(4-methox-
yphenyl)ethenyl]naphthalene (1b): A mixture of 1-(naphthalen-2-
yl)ethanol 1a (0.22 g, 1.28 mmol), 4-iodoanisole (0.2 g, 0.85 mmol),
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[PdCl2(PPh3)2] (4 mol%), HCOONa (1.28 mmol), piperidine
(0.85 mmol), and LiCl (8 mol%) in [hmim]Br (1.5 g) was irradiated
under focused MW (120W, 1508C) for 15 min. Thereafter water
(20 mL) was added to the reaction mixture and the organic phase was
extracted with EtOAc (2 ꢀ 25 mL). The EtOAc fraction was washed
with water (2 ꢀ 10 mL), brine (1 ꢀ 10 mL), dried over Na2SO4, and
evaporated under vacuum. The obtained residue was subsequently
purified by column chromatography on silica gel (60–120 mesh size)
using 2% ethyl acetate in hexanes to give a white solid, which was
then recrystallized in methanol to provide pure 1b in 78% yield.
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analyzed through the commonly used C18 reverse-phase HPLC
analysis because of its precipitation in the mobile phase (e.g. in
a mixture of MeOH or ACN and H2O etc.). Similarly, GC/MS
analysis of the same was unsuccessful, probably because of low
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Received: October 13, 2011
Published online: February 1, 2012
Keywords: alcohols · arenes · Heck reaction · ionic liquids ·
.
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