Transition metal-free domino sequential synthesis of (E)-stilbenes, biaryl methanes and biaryl ethers using Et2AlCl as a Lewis acid

Article abstract of DOI:10.1039/c3ra42955e

A transition metal-free domino process has been developed, for the first time, to synthesize (E)-stilbenes, biaryl methanes and biaryl ethers from substituted α,β-unsaturated ketones, benzyl acetones and phenacyl ethers, respectively, in moderate to good yields at room temperature using diethyl aluminium chloride (Et₂AlCl) as a Lewis acid. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra42955e

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Transition metal-free domino sequential synthesis of
(E)-stilbenes, biaryl methanes and biaryl ethers using
Et2AlCl as a Lewis acid3
Cite this: RSC Advances, 2013, 3, 18755
Received 13th June 2013,
Accepted 5th August 2013
Satinath Sarkar,a Manoranjan Janab and Narender Tadigoppula*a
DOI: 10.1039/c3ra42955e
www.rsc.org/advances
A transition metal-free domino process has been developed, for
the first time, to synthesize (E)-stilbenes, biaryl methanes and
biaryl ethers from substituted a,b-unsaturated ketones, benzyl
acetones and phenacyl ethers, respectively, in moderate to good
yields at room temperature using diethyl aluminium chloride
(Et2AlCl) as a Lewis acid.
between aryl metals and benzylic halides,19 or aryl halides and
benzylic metals (prepared from benzylic halides), have been also
used for the synthesis of biaryl methanes.20
Biaryl ethers are common structural features in numerous
natural products and in biologically active compounds.21
Vancomycin and other glycopeptide antibiotics, as well as anti-
HIV agents like chloropeptin contain this core.22 Ulmann
reactions between phenol and aryl iodide under stoichiometric
ratios of copper at elevated temperatures are the most useful tool
for the synthesis of biaryl ethers.23 Copper-catalyzed coupling at
room temperature between aryl boronic acids and phenol in the
presence of ligands,24 and Pd-catalyzed coupling at high
temperatures between phenols and aryl iodides in the presence
of expensive ligands, are the other protocols for the synthesis of
biaryl ethers.25
The discovery of an efficient, transition metal-free process for
the synthesis of these classes of compounds is always in high
demand. As a part of our ongoing programme on domino
reactions26,27 for the synthesis of carbocyclic molecules, we
intended to synthesize (E)-stilbenes, biaryl methanes, and biaryl
ethers using Lewis acid. Therefore, we initiated our work with the
synthesis of (E)-7-methyl-1-phenylocta-1,6-dien-3-one (2a) from
commercially available (E)-4-phenylbut-3-en-2-one (1a) through a
Stilbenes are a well known class of naturally occurring phyto-
chemicals demonstrating a wide range of biological activities.1 For
example cis and trans isomers of combretastain A4 (Fig. 1) have
antitumor activity.2 Resveratrol (Fig. 1) has shown cancer
chemopreventive, antiplatelet aggregation, antioxidative, antibac-
terial, anti-inflammatory, and antidyslipidemic activities.3
Pterostilbene acts as an effective PPARa agonist and hypolipidemic
agent and possesses lipid- and glucose-lowering effects.4 Synthetic
stilbenes are used as optical brighteners,5 phosphors6 and
scintillators.7 The classical reactions for the synthesis of stilbenes
such as Meerwein arylation,8 the Heck reaction9 or Mizoroki–Heck
reaction,10 Suzuki–Heck reaction11 and condensation reactions12
e.g. Knoevenagel-type, Wittig and Wittig–Horner reaction are well
reported in the literature. Transition metal-free C–C bond forming
reactions in the synthesis of (E)-stilbenes are also of crucial
importance.13
Biaryl methanes frequently appear as subunits in macrocycles
and calixarenes.14 Macrobicyclic receptors are an important class
of host molecules for the selective binding of amino acids.15
Calixarenes are developed for the recognition of ion-neutral
organic molecules16 and are also used as chiral recognition
devices for solid phase extraction as a stationary phase and
modifiers.17 Biaryl methanes have been synthesized by the
Friedel–Crafts alkylation of aromatic compounds and benzylic
halides or the SN2-type reaction of aryl metals and benzylic
halides.18 Alternatively, metal catalyzed cross-coupling reactions
aMedicinal and Process Chemistry Division, CSIR-Central Drug Research Institute,
Chattar Manzil Palace, Lucknow-226-001, India. E-mail: t_narendra@cdri.res.in;
tnarender@rediffmail.com; Fax: +91-522-2623405; Tel: +91-522-22612411
bDepartment of Chemistry, University of Kalyani, Kalyani, Nadia-741235, W. B.,
India
Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra42955e
Fig. 1 Stilbene, biaryl ether and biaryl methane scaffold in bioactive compounds.
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Table 1 Optimization of the reaction conditionsa for the synthesis of stilbene,
3a
Entry Lewis acid (eq.)
Solvent Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
AlCl3 (0.5)
AlCl3 (0.5)
AlCl3 (1.5)
AlCl3 (1.5)
AlCl3 (1.5)
BF3–OEt2 (1.5)
TiCl4 (1.5)
ZnCl2 (1.5)
SnCl4 (1.5)
SnCl2 (1.5)
Et2AlCl 1 M in hexane (0.5) Dioxane
Et2AlCl 1 M in hexane (0.5) Dioxane 12
Et2AlCl 1 M in hexane (0.5) THF 12
Et2AlCl 1 M in hexane (0.5) CH3CN 12
Et2AlCl 1 M in hexane (1.5) Dioxane
Dioxane
Dioxane 12
Dioxane 12
4
Trace
Trace
35
25
Trace
—
—
—
25
—
20
22
Trace
Trace
61
THF
12
CH3CN 12
Dioxane 15
Dioxane 15
Dioxane 20
Dioxane 10
Dioxane 12
Scheme 1 Synthesis of (E)-stilbenes, biaryl methanes and biaryl ethers using
Et2AlCl as a Lewis Acid.
9
10
11
12
13
14
15
4
the best of our knowledge such a transition metal-free domino
protocol has not been reported in the literature.
With the above optimized reaction conditions, we have
performed the domino reaction with various substituted a,b-un-
saturated ketones 1b–j and obtained respective stilbenes 3b–j with
moderate to good yields (Scheme 2). Specifically, a,b-unsaturated
ketones with m- or p-substituted electron-donating groups are all
successfully involved in this reaction (3a–3j). a,b-Unsaturated
ketones with highly electron-donating p-substituted methoxy and
chloro groups gave moderate yields (3b and 3c). (E)-4-(4-
Bromophenyl)but-3-en-2-one also gave moderate yields.
Satisfactorily, a,b-unsaturated ketones with electron-donating m
and p-substituted alkyl groups reacted with good yields (3d–3e and
3g–3j).
4
a
All the reactions were conducted with 0.46 mmol or 1 equivalent of
2a, Lewis acids were used at an equivalent ratio with respect to 2a,
unless otherwise noted. Isolated yield of 3a with respect to 2a.
b
prenylation reaction (see ESI ) using NaH and by choosing 2a as a
model substrate for the optimization of the reaction conditions for
the synthesis of stilbene, 3a (Table 1).
3
It was observed that using AlCl3 at different equivalents
resulted in a small amount of 3a at room temperature irrespective
of the solvent used (dioxane, THF and CH3CN) and reaction time
(entries 1–5, Table 1). No reaction occurred with Lewis acids such
as BF3–OEt2, TiCl4, ZnCl2 and SnCl2 in dioxane at room
temperature (entries 6–8 and 10). Employment of 1.5 eq. of
SnCl4 resulted in a poor yield (entry 9). The reaction with 0.5 eq.
diethyl aluminium chloride (1 M in hexane) in dioxane at room
temperature gave 3a in a 20% yield (entry 11) and no improvement
in yield was observed with other solvents and reaction conditions
(entries 12–14). However, 1.5 eq. diethyl aluminium chloride (1 M
in hexane) in dioxane provided the desired stilbene 3a (3-methyl-
stilbene) in 61% yield after 4 h (entry 15, Table 1) at room
temperature.
The optimization of the reaction conditions revealed that
diethyl aluminium chloride is efficient for carrying out the
domino reaction for the synthesis of (E)-stilbenes. We wish to
further explore diethyl aluminium chloride for the synthesis of
various (E)-stilbenes, biaryl methanes and biaryl ethers. Diethyl
aluminium chloride is an excellent Lewis acid used in ene-
reactions,28 various organic transformations29 and named reac-
tions such as Ziegler–Natta polymerization,30 Diels–Alder reac-
tions,31 and Friedel–Crafts reactions.32 Herein we report a
transition metal-free domino sequential synthesis of (E)-stilbenes,
biaryl methanes, and biaryl ethers from substituted a,b-unsatu-
rated ketones, benzyl acetones and phenacyl ethers respectively
using diethyl aluminium chloride as a Lewis acid (Scheme 1). To
Scheme 2 Synthesis of stilbenes 3a–3j through domino reactions of substituted
a,b-unsaturated ketones 1b–j, and their isolated yields and reaction times.
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Scheme 3 Synthesis of biaryl methanes 6a–6d formed through domino reactions
of substituted benzyl acetones 4a–4d, and their isolated yields and reaction times.
We then focused on the synthesis of the biaryl methane class of
compounds using the same above optimized reaction conditions.
Commercially available substituted benzyl acetones 4a–d were
prenylated using NaH to generate the intermediates 5a–d
(Scheme 3). These prenylated compounds 5a–d were reacted with
diethyl aluminium chloride (1 M in hexane) in dry dioxane
providing the anticipated biaryl methanes (6a–d) in good yields
(Scheme 3). Better yields and shorter reaction times were observed
for the formation of biaryl methanes in comparison to stilbenes
(Scheme 2). The presence of conjugation in alkenylated ketones
(2a–2j) might be the reason for the lower yields and longer
reaction times in the formation of stilbenes.
The applicability of this reaction was further explored for the
synthesis of biaryl ethers. To synthesize biaryl ethers, substituted
phenacyl ethers 7a–7c were prenylated to afford the intermediates
8a–8c respectively, and further domino reactions were performed
under the above optimized conditions, to obtain the respective
biaryl ethers (9a–9c) in moderate yields (Scheme 4).
The reaction mechanism for the formation of (E)-stilbenes,
biaryl methanes and biaryl ethers is depicted in Fig. 2. The
reaction might be initiated through the diethyl aluminium
chloride-mediated intramolecular carbonyl-ene reaction to provide
an ene-adduct-Et2AlCl complex33 (cyclobutanol intermediate I)
which might be reacted to afford ethane and ene-adduct-
aluminum alkoxide II. Next, ring expansion of II gives a six
membered carbocyclic ring as in III and the cleavage of the
carbon–oxygen bond34 of III produced IV or V. The simultaneous
dehydrogenation35 of IV or V (aerial oxidative aromatization)
Fig. 2 Plausible reaction mechanism for the synthesis of (E)-stilbenes, biaryl
methanes, and biaryl ethers using Et2AlCl.
convincingly furnishes the desired (E)-stilbene, biaryl methane
and biaryl ether (Fig. 2). Further studies, however, are required to
confirm the exact reaction mechanism. The reaction mechanism
for formation of 3a, 6a and 9a is presented in Fig. 2 as
representative examples from each class of compounds.
In conclusion, we have developed a novel domino protocol for
the synthesis of (E)-stilbenes, biaryl methanes and biaryl ethers for
the first time from prenylated a,b-unsaturated ketones, benzyl
acetones and phenacyl ethers respectively with diethyl aluminium
chloride in moderate to good yields at room temperature. This
efficient process specifically synthesized three different classes of
systems (3a–3j, 6a–6d and 9a–9c) with 3-methyl substitution and
avoids the use of transition metals or metal-catalyzed cross-
coupling reactions (Meerwein arylation, Mizoroki–Heck reactions,
Ullmann reactions).
The authors are thankful to Dr T. K. Chakraborty, Director,
CSIR-CDRI, for his constant encouragement on the program of
natural products’ synthesis, and CSIR and DST (New Delhi) for
financial support. S.S. is grateful to the University of Kalyani for
admission in Ph.D. programme. This is CDRI Communication
number 8527.
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