Transition-metal-free benzannulation for diverse and polyfunctionalized biaryl formation

Article abstract of DOI:10.1021/acs.orglett.5b00996

A novel and efficient synthesis of highly functionalized and diverse biaryls via mild base-promoted transition-metal-free benzannulation was achieved in good yield from readily available β-ketoesters, β-ketoamides, or 1,3-diketones with cinnamaldehydes or aryl aldehydes. This transformation comprises a sequence of the formation of three new bonds through multicomponent reactions as a one-pot procedure. This novel biaryl formation proceeds through domino Michael addition/intramolecular and intermolecular aldol/[1,5]-hydrogen shift/tautomerization. This protocol provides a great advantage in introducing various functional groups on the aromatic ring of biaryls.

Full text of DOI:10.1021/acs.orglett.5b00996

Letter
pubs.acs.org/OrgLett
Transition-Metal-Free Benzannulation for Diverse and
Polyfunctionalized Biaryl Formation
Tej Narayan Poudel and Yong Rok Lee*
School of Chemical Engineering, Yeungnam University, Gyeongsan 712-749, Republic of Korea
S
* Supporting Information
ABSTRACT: A novel and efficient synthesis of highly functionalized and diverse biaryls via mild base-promoted transition-
metal-free benzannulation was achieved in good yield from readily available β-ketoesters, β-ketoamides, or 1,3-diketones with
cinnamaldehydes or aryl aldehydes. This transformation comprises a sequence of the formation of three new bonds through
multicomponent reactions as a one-pot procedure. This novel biaryl formation proceeds through domino Michael addition/
intramolecular and intermolecular aldol/[1,5]-hydrogen shift/tautomerization. This protocol provides a great advantage in
introducing various functional groups on the aromatic ring of biaryls.
iaryl units are one of the most important structural motifs
found in biologically active natural products, pharmaceut-
bonds have been developed.6 These approaches include the
arylation of arenes by aryl halides in the presence of strong alkali
metal bases and ligand, which proceed via a radical-type
mechanism. These reactions provide biaryl molecules by cross-
coupling between the two aromatic rings of the aryl metals and
aryl halides, arenes and aryl halides, or arenes and arenes.7
Recently, direct biaryl formation through the hydroarylation of
arynes (path a, Scheme 2)8 or hexadehydro Diels−Alder reaction
B
icals, and agrochemicals.1 They are used widely as important
scaffolds and building blocks for the construction of optical and
functional materials.2 Several methods for aryl−aryl bond
formation have been reported. Among these, transition-metal-
catalyzed traditional cross-coupling (Suzuki, Stille, Hiyama, etc.)
has become a useful tool for constructing an Ar−Ar bond by the
reaction of aryl halides and aryl metals (path a, Scheme 1).3
Scheme 2. Diaryl Formation by Benzannulation without Using
Cross-Coupling Reactions
Scheme 1. Transition-Metal-Catalyzed Biaryl Formation
Using Cross-Coupling Reactions
Recently, transition-metal-catalyzed C−H arylation (path b,
Scheme 1)4 and the oxidative cross-coupling of arenes (path c,
Scheme 1)5 have emerged as an important cross-coupling
strategy to form Ar−Ar bonds. This direct arylation reduces the
number of synthetic steps and has the advantages of lower cost
and environmental benignity. Although a number of methods for
the direct formation of an Ar−Ar bond by transition-metal-
catalyzed reactions have been well developed, the loading of
catalyst tends to have a high economic cost in industrial
processes.
(path b, Scheme 2)9 has been reported without cross-coupling
reactions between two aromatic compounds. These reactions
provide various complex molecules bearing biaryl skeletons by
benzannulation through aryne intermediates.
Currently, benzannulation is one of the most important
reactions for the formation of substituted benzenes.10 Over the
past decade, several synthetic methods for benzannulation have
been reported by Diels−Alder reaction,11 Bergman cyclization,12
Therefore, the development of a facile transition-metal-free
process is essential and quite significant. Recently, several
transition-metal-free methods for the formation of aryl−aryl
Received: February 10, 2015
Published: April 15, 2015
© 2015 American Chemical Society
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Letter
Danheiser annulation,13 ring-closing metathesis,14 Dotz [3 + 2 +
cinnamaldehyde (2a), the yield of 3 was increased to 35%. To
increase the yield, other bases were next examined. With NaOMe
(1.0 equiv) and K2CO3 (1.0 equiv) in refluxing toluene, product 3
was formed in 63 and 71% yield, respectively. Importantly, the
yield of 3 was increased to 83% when the reaction was carried out
in the presence of Cs2CO3 (1.0 equiv) in refluxing toluene for 4 h.
Cs2CO3 was found to be superior to other bases in this cascade
process. Recently, Cs2CO3 has been widely used as an excellent
base in various organic transformations because of its mild base
strength.22 With the use of higher (2.0 equiv) or lower (0.2 equiv)
catalytic amounts of Cs2CO3 in refluxing toluene, the yield of 3
did not increase. For other solvents, the reaction in refluxing
benzene or 1,2-dichloroethane (DCE) provided compound 3 in
61 and 10% yield, respectively. However, product 3 was not
formed in polar solvents, such as dimethyl sulfoxide (DMSO) or
water. The structure of 3 was determined by analyzing the
spectral data. The 1H NMR spectrum of 3 showed a characteristic
singlet peak for the −OH group at δ 10.88 ppm, benzylic
methylene protons at δ 3.60 ppm (J = 6.0 Hz) as a doublet, two
vinylic protons at δ 6.46−6.37 ppm as multiplets, and at δ 6.50
ppm as a doublet (J = 15.9 Hz). The coupling constant value of
15.9 Hz suggests the E-configuration of the double bond. The
regio- and stereochemistry of 3 was deduced from the X-ray
crystallographic analysis of structurally related compound 14 (see
the Supporting Information).
̈
1] reaction,15 Wulff [5 + 1] ortho benzannulation,16 and
rhodium(II)-catalyzed benzannulation.17 Moreover, synthesis
of phenol derivatives by benzannulation from 1,3-dicarbonyls
and Michael acceptors have been also reported.18 Herein, we
report a novel, facile and efficient one-pot biaryl formation
through a three-component reaction starting from commercially
available β-ketoesters, β-ketoamides, or 1,3-diketones with α,β-
unsaturated aldehydes (eq 1) or α,β-unsaturated aldehydes and
aryl aldehydes (eq 2, Scheme 3) in the presence of mild base.
Scheme 3. Diverse and Polysubstituted Biaryl Formation by
Benzannlation through Three-Component Reactions
Multicomponent reactions of 1,3-dicarbonyls have received
great attention in the past few years in the sythesis of diverse and
complex organic molecules.19 A number of Michael additions of
1,3-dicarbonyl compounds to α,β-unsaturated aldehydes have
been explored by many groups to afford various useful organic
molecules.20,21 Among these, representative approaches include
N-heterocyclic carbene-catalyzed Michael addition for dihydro-
pyranones,20 organocatalytic domino reactions for epoxycyclo-
hexanones, and multicatalytic cascade reactions to furnish
cyclopentanes.21
To examine the generality and scope of this methodology,
additional reactions of β-ketoesters, β-ketoamides, or 1,3-
diketones with several cinnamaldehydes were next carried out
under optimized conditions. The results are summarized in Table
2. The reactions between methyl acetoacetate (1a) and
Table 2. Additional Reactions for the Synthesis of Various
a
Polysubstituted Diaryl Compounds
To afford the Michael addition products, the reactions of
methyl acetoacetate (1a) with cinnamaldehyde (2a) were first
attempted under several bases and solvents. The results are listed
in Table 1. Reaction of methyl acetoacetate (1a, 0.5 mmol) and
Table 1. Reaction of Methyl Acetoacetate (1a) with
Cinnamaldehyde (2a) under Several Conditions
a
Reaction conditions: 1,3-diketones (1, 0.5 mmol), cinnamaldehydes
(2, 1.0 mmol), Cs2CO3 (0.5 mmol), and toluene (5.0 mL).
cinnamaldehyde (2a, 0.5 mmol) in the presence of triethylamine
(1.0 equiv) in refluxing toluene for 12 h did not give any products;
instead, the starting materials were recovered (entry 1, Table 1).
Upon treatment of 1a (0.5 mmol) with 2a (0.5 mmol) in the
presence of DBU (1.0 equiv) in refluxing toluene for 12 h,
unexpected aromatic compound 3 was produced in 15% yield
through a pseudo-three-component reaction between methyl
acetoacetate and two cinnamaldehydes (entry 2). With 2 equiv of
cinnamaldehydes 2b,c bearing electron-donating (−OMe) or
electron-withdrawing group (−F) on the 4-position of the
benzene ring in the presence of Cs2CO3 in refluxing toluene
provided products 4 and 5 in good yields (entries 1 and 2, Table
2). Similarly, reactions of ethyl acetoacetate (1b) with
cinnamaldehydes 2a−c were also successful and afforded the
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products 6−8 in good yields (entries 3−5, Table 2). With allyl 3-
oxobutanoate (1c) or benzyl 3-oxobutanoate (1d), the expected
products 9−11 were produced in a range of 74−80% yield
(entries 6−8). The substrate scope was also extended successfully
with various β-ketoamides. The treatment of 2a or 2c with 3-oxo-
N-phenylbutanamide (1e) provided compounds 12 and 13 in
good yields (entries 9−10). With β-ketoamides bearing an
electron-donating (−OMe, −Me) or electron-withdrawing
group (−Cl) at the 2- or 4-position on benzene, the desired
products were obtained with good yields. For example, with N-
(4-methoxyphenyl)-3-oxobutanamide (1f), 3-oxo-N-p-tolylbu-
tanamide (1g), and 3-oxo-N-o-tolylbutanamide (1h) having
electron-donating groups on the benzene ring, products 14−21
were produced in the range of 73−81% yield (entries 11−18).
When N-(4-chlorophenyl)-3-oxobutanamide (1i) and N-(2-
chlorophenyl)-3-oxobutanamide (1j) bearing electron-with-
drawing groups were used, products 22−28 were isolated in
good yields (entries 19−25). On the other hand, reaction of 2,4-
pentanedione (1k) with cinnamaldehyde (2a) provided desired
compound 29 with decreased yield (48%) (entry 26) compared
to that of ketoesters or ketoamides.
Scheme 6. Control Experiments of Michael Donor and
Michael Acceptor Ability
ketoamide 1e (0.5 mmol) with cinnamaldehyde (2a, 1.0 mmol)
in the presence of 0.5 mmol of Cs2CO3 in refluxing toluene for 6 h
provided products 3 and 12 in 30 and 45% yield, respectively (eq
1, Scheme 6). This result did not show a significant difference in
the Michael donor ability between β-ketoester and β-ketoamide,
but N-phenyl-substituted β-ketoamide was found to be a slightly
better Michael donor than β-ketoester. A further control
experiment was attempted to explore the reactivity of different
cinnamaldehydes. The reactions of 1a (0.5 mmol) with three
different cinnamaldehydes 2a−c (1.0 mmol, each) bearing no
substituent, electron-donating, and electron-withdrawing groups
in refluxing toluene for 6 h provided compound 5 in 60% yield
(eq 2, Scheme 6). This result suggests that the electron-
withdrawing group on the cinnamaldehyde moiety acts as an
excellent Michael acceptor compared to cinnamaldehyde bearing
no substituent or electron-donating groups.
Scheme 4 presents a proposed mechanism for the formation of
3 through Cs2CO3-mediated multicomponent cascade reaction.
Scheme 4. Proposed Mechanism for the Formation of 3
Having seen the general applicability of the multicomponent
reactions between β-ketoesters or β-ketoamides and cinnamal-
dehydes, other cross-cascade reactions were next attempted for
the synthesis of the benzyl-substituted biaryls (Scheme 7). The
Scheme 7. Additional Synthesis for Biaryls 36−39 by Three-
Component Reactions of 1,3-Dicarbonyl Compounds and
Arylaldehydes with 4-Methoxycinnamaldehyde
In basic medium, the Michael addition of the enolate 30 to 2a
forms intermediate 31, which then undergoes intramolecular
aldol reaction to give another intermediate 32. The aldol-type
reaction of 32 with 2a in the basic medium produces 33, which
further undergoes 1,5-H shift followed by tautomerization to
form the final product 3.
To prove this mechanism, control experiments were carried
out. Isolation of the intermediate 31 under several bases such as
K2CO3, NaHCO3, and Na2CO3 at room temperature was not
successful. Therefore, we performed an additional experiment
using cinnamaldehyde-3-d (2e) under optimized reaction
conditions (Scheme 5). Importantly, reaction of 1f with 2e in
reaction of β-ketoester 1a with cinnamaldehyde (2a) and
benzaldehyde (35a) did not observe any desired biaryl product
with 2a and 35a being incorporated; instead, product 3 was
isolated in 36% yield. With 4-fluorocinnamaldehyde (2c) and
benzaldehyde (35a), compound 5 was produced in 37% yield.
However, the reaction of 1a with 4-methoxycinnamaldehyde
(2b) and 2-chlorobenzaldehyde (35b) in refluxing toluene for 6.5
h provided product 36 in 66% yield. The combinations of β-
ketoester 1b or β-ketoamides 1g and 1i with 2b and 35b or 35c
provided the corresponding products 37−39 in 68, 65, and 63%
yield, respectively.
To further demonstrate the versatility of this multicomponent
reaction, we examined the reactions with 3-(furan-2-yl)-
acrylaldehyde (2f) or 3-(anthracen-9-yl)acrylaldehyde (2g) for
the synthesis of various biaryls bearing furanyl or anthracenyl ring
(Scheme 8). The reactions of 1a−c or 1i with 2f in refluxing
toluene for 4−5 h afforded the corresponding products 40−43 in
Scheme 5. Control Experiment for Formation of 34
refluxing toluene for 5 h provided the desired product 34 bearing
a deuterium on each of the benzylic carbons in 71% yield. This
result shows that the reaction pathway proceeds through the
formation of intermediate 33 followed by [1,5]-H shift.
The additional control experiments of Michael donor ability of
two different 1,3-dicarbonyl compounds 1a and 1e were explored
(Scheme 6). The reaction of β-ketoester 1a (0.5 mmol) and β-
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Scheme 8. Additional Reactions for the Synthesis of Diverse
Biaryls 40−45 Bearing Furanyl or Anthracenyl Rings
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Nano Material Technology
Development Program of the Korean National Research
Foundation (NRF) funded by the Korean Ministry of Education,
Science, and Technology (Grant No. 2012-049675). This work
was also supported by the Korean National Research Foundation
(NRF) grant funded by the Korean government (MSIP) (NRF-
2014R1A2A1A11052391).
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