Tandem [4 + 1 + 1] annulation and metal-free aerobic oxidative aromatization: Straightforward synthesis of highly substituted phenols from one aldehyde and two ketones

Article abstract of DOI:10.1039/c0cc02313b

Polysubstituted phenols are efficiently assembled from one aldehyde and two different methyl ketones in a one-pot operation via a newly base-induced regiospecific [4 + 1 + 1] annulation and sequential metal-free oxidative aromatization using molecular oxygen (from air) as the sole oxidant at room temperature.

Full text of DOI:10.1039/c0cc02313b

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Tandem [4 + 1 + 1] annulation and metal-free aerobic oxidative
aromatization: straightforward synthesis of highly substituted phenols
from one aldehyde and two ketonesw
Mang Wang,* Zhenqian Fu, Hui Feng, Ying Dong, Jun Liu and Qun Liu*
Received 1st July 2010, Accepted 29th September 2010
DOI: 10.1039/c0cc02313b
Polysubstituted phenols are efficiently assembled from one
aldehyde and two different methyl ketones in a one-pot operation
via a newly base-induced regiospecific [4 + 1 + 1] annulation
and sequential metal-free oxidative aromatization using molecular
oxygen (from air) as the sole oxidant at room temperature.
Phenols are important building blocks for constructing
pharmaceuticals, polymers, natural products, and oxygenated
heterocycles.1 Consequently, the establishment of new efficient
synthetic methods for highly substituted phenols, with
selective control of substitution patterns, from readily available
and simple acyclic substrates continues to be actively pursued.1ꢀ4
In this area, although several attractive methods, such as Dotz
¨
benzannulation, a formal [3 + 2 + 1] cycloaddition of Fischer
carbene complexes with alkynes,2aꢀc have proven to be
powerful and efficient methods for the facile construction of
various phenol derivatives,1ꢀ4 these methods are restricted to
alkynes and the regioselectivity depends on the structure of the
alkyne substrates. To the best of our knowledge, there is no
report in the construction of highly substituted phenols via
multicomponent reactions (MCRs)5 involving three or more
different starting materials.
Scheme 1 Strategy for the synthesis of highly substituted phenols.
Initially, the reaction of 2-(bis(ethylthio)methylene)-1-phenyl-
butane-1,3-dione 1a, benzaldehyde 2a, and acetophenone 3a
was employed as a model reaction to screen reaction condi-
tions for the three-component reaction. Among the various
basic systems tested, including t-BuOK/THF, t-BuOK/DMF,
t-BuOK/MeCN, NaOH/DMF, and NaOMe/DMF, t-BuOK/
DMF proved the most efficient. The reaction of 1a (1.0 mmol),
2a (1.1 mmol) and 3a (1.1 mmol) in dry DMF (10 mL) in the
presence of t-BuOK (2.0 equiv.) at room temperature for 35 h
gave 2-cyclohexenone 4a in 62% yield (Table 1, entry 1). It was
found that the addition order of reagents has a significant
influence on the yield of 4a (entries 1ꢀ4). In the case of
addition order D, i.e., treatment of 2a (1.1 mmol) and 3a
(1.1 mmol) with t-BuOK (1.0 equiv.) under solvent-free con-
ditions at room temperature for 1.0 h and then adding 1a
(1.0 mmol) and additional t-BuOK (1.0 equiv.) in 10 mL of dry
DMF and reacting for another 19 h, cyclohexenone 4a was
obtained in 82% yield (entry 4).
Previously, we developed a [5C + 1C] annulation of five-
carbon 1,5-dielectrophiles (Scheme 1, for example, compounds 10)
with nitroalkanes for the synthesis of polysubstituted
phenols.6a,b In a recent report, we also successfully synthesized
2-cyclohexenones 4 based on this [5C + 1C] annulation
using methyl aryl ketones 3 as the one-carbon nucleophiles
(Scheme 1, Path A).6c This result prompts us to pursue a more
convenient [4C + 1C + 1C] annulation procedure suitable
for the synthesis of phenols by combining the significant
advantages of MCRs like cheap and easily available starting
materials and product diversity.5 In the present work, we
choose a kind of four-carbon 1,4-dipolar synthons 1 as the
four carbon component in a multicomponent reaction which
allows the straightforward synthesis of highly substituted
phenols from three different starting materials including a
1,4-dipolar synthon 1, an aldehyde 2 and a methyl ketone 3
under mild conditions (Scheme 1, Path B). Notably, we also
emphasize a novel metal-free oxidative aromatization of
2-cyclohexenones leading to phenols using molecular oxygen
from air as the sole oxidant under basic conditions.7,8
The above results (entries 1, 3 and 4) support the design strategy
outlined in Scheme 1 for developing the [4 + 1 + 1] annula-
tion (Path B), a more convenient route to 2-cyclohexenones.6c
Fortunately, it was found that phenol 5a could be obtained
simply by increasing the amount of t-BuOK. As can be seen
from the comparison (entries 5ꢀ11), the best results were
obtained by using 4.0 equivalent of t-BuOK and by following
the addition order D. Under the optimized conditions, i.e., the
mixture of 2a (1.1 mmol) and 3a (1.0 mmol) was treated with
t-BuOK (0.5 mmol) at room temperature under solvent-free
condition for 0.5 h and then adding 1a (1.0 mmol in 10 mL of
Department of Chemistry, Northeast Normal University, Changchun
130024, China. E-mail: wangm452@nenu.edu.cn, liuqun@nenu.edu.cn;
Fax: +86 431 85099759; Tel: +86 431 85099759
w Electronic supplementary information (ESI) available: Detailed
experimental procedures, analytical and spectral data for all the
compounds 5a–p. See DOI: 10.1039/c0cc02313b
c
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Table 1 Screening of reaction conditionsa
The regiospecific preparation of highly substituted phenols
is one of the challenging problems in organic synthesis.1–4,6 To
the best of our knowledge, the synthesis of phenol 5a provides
the first example of multicomponent synthesis of highly sub-
stituted phenols which combines an aldehyde and two different
methyl ketones. It is worth noting that the oxidative aromati-
zation step after the [4 + 1 + 1] annulation is very important
for the successful implementation of the [4 + 1 + 1] oxidative
aromatization strategy since similar conditions are used in
both cases. It is true that the utilization of molecular oxygen as
a terminal oxidant in oxidative transformations is a highly
attractive strategy in current organic synthesis, while there
remain challenges.7ꢀ9 The oxidative aromatization reaction of
2-cyclohexenones is an important transformation for the
synthesis of phenol derivatives. In general, the reaction requires
the use of oxidants (such as MnO2, N-tert-butylbenzene-
sulfinimidoyl chloride, or molecular iodine, etc.), or is
achieved by aerobic oxidative aromatization via catalytic
dehydrogenation in the presence of metal catalyst, for example,
catalytic amounts of VOSO4 and 50 mol% HBr aq. (48%) or
CuBr2/LiBr mixture.8,9 By comparison, the aerobic oxidative
aromatization of 2-cyclohexenone 4a as described above
preceded smoothly under basic condition without the assis-
tance of metal catalyst. So, it provides a very important means
by which 2-cyclohexenones can be easily aromatized to the
corresponding phenols under more simple and lower cost
reaction conditions.7ꢀ9
Yieldc (%)
Entry Addition orderb t-BuOK (eq.) T/1C t/h
4a
5a
1
2
3
4
5
6
7
8
A
B
2.0
2.0
2.0
2.0
3.0
4.0
4.0
4.0
4.0
5.0
4.0
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
60
35
35
20
20
12
62
20
65
82
34
0
0
0
0
C
D
D
D
A
B
C
D
D
0
38
67
12
0
14
66
63
3.0
3.0 41
3.0 32
3.0 15
9
10
11
2.5
2.0
0
0
a
1a (1.0 mmol), 2a (1.1 mmol), 3a (1.1 mmol), dry DMF (10 mL).
Addition order A: a mixture of 1a, 2a and 3a in dry DMF was
b
treated with t-BuOK; addition order B: a mixture of 1a and 2a in dry
DMF was treated with t-BuOK and then reacted with 3a; addition
order C: a mixture of 2a and 3a in dry DMF was treated with t-BuOK
and then reacted with 1a; addition order D: a mixture of 2a and 3a
was treated with t-BuOK under solvent-free conditions and then
c
reacted with 1a and additional t-BuOK in dry DMF. Isolated yield
based on 1a.
Considering the significant combination of the MCR and
oxidative aromatization, the scope of this process was inves-
tigated under the optimized conditions (Table 1, entry 6) and
dry DMF) and t-BuOK (3.5 mmol) and reacting for another
2.5 h, the 2,3,4,5-tetrasubstituted phenol 5a was obtained in
67% isolated yield (entry 6).
Based on the experimental results summarized in Table 1,
the formation of phenol 5a should be reasonably expressed as
a [4 + 1 + 1] annulation/oxidative aromatization or [4 + 1 + 1]
oxidative aromatization process as indicated in Scheme 2. This
MCR arises from the base-mediated aldol condensation of, for
example, preferably acetophenone 3a with benzaldehyde 2a,
leading to chalcone intermediate A. Under basic conditions,
subsequent intermolecular Michael addition of acetyl ketene
dithioacetal 1a to intermediate A leads to intermediate B and
then furnishes 2-cyclohexenone 4a through intramolecular
Michael addition followed by elimination of ethanethiol
(SNV).6 Finally, 5a is produced by oxidative aromatization
of 4a using molecular oxygen as the sole oxidant (exposed to
the open air).
Table 2 Synthesis of phenols 5az
Yieldb
(%)
Entry R1
R2
R3
t/h
5
1
PhCO
Ph
Ph
Ph
Ph
Ph
3.0 5a 67
3.0 5b 77
3.0 5c 58
3.0 5d 55
5.0 5e 62
3.0 5f 54
3.0 5g 73
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
PhCO
CO2Et
CN
4-ClC6H4
4-NO2C6H4
4-MeC6H4
3,4-CH2O2C6H3 Ph
4-MeOC6H4
2-furyl
Cy
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
Ph
Ph
c
3.0
—
—
4-ClC6H4 3.0 5h 69
4-MeC6H4 3.0 5i 65
2-furyl
Me
Ph
Ph
Ph
Ph
Ph
Ph
3.0 5j 54
3.0
c
—
—
3.0 5k 70
3.0 5l 55
3.0 5m 51
3.0 5n 68
3.0 5o 55
4.0 5p 40
MeCO
4-MeOC6H4 4-ClC6H4
H
H
Ph
4-ClC6H4
a
General reaction conditions:
(1.1 mmol), t-BuOK (4.0 equiv.), DMF (10 mL), rt. Isolated yield
1
(1.0 mmol), 2 (1.1 mmol), 3
b
c
based on 1. Complex mixture was obtained.
Scheme 2 Proposed mechanism for the formation of phenols 5.
9062 Chem. Commun., 2010, 46, 9061–9063
c
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the results are summarized in Table 2.10 Clearly, the results
suggest a wide scope of substituents at the a-position of acetyl
ketene dithioacetals 1, including benzoyl (entries 1–12), ethox-
ycarbonyl (entry 13), cyano (entry 14), acetyl (entry 15), aryl
(entry 16), and hydrogen (entries 17 and 18). Accordingly, a
wide range of aldehydes 2 bearing phenyl (entries 1 and 17),
electron-deficient (entries 2, 3, 9ꢀ16, 18), electron-rich
(entries 4–6) aromatic and hetero aromatic groups (entry 7)
are suitable aldehyde components for this tandem procedure.
By comparison, the reaction with cyclohexanecarbaldehyde
led to an inseparable mixture (entry 8). In the case of
methyl ketones, all aryl methyl ketones 3 tested afforded
the desired highly substituted phenols 5 in good yields except
that the reaction with acetone gave a complex mixture
(entry 12).
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In conclusion, a facile multicomponent synthesis of highly
substituted phenols has been developed starting from readily
available acyclic precursors under mild conditions. In the first
stage, the [4 + 1 + 1] annulation of an aldehyde and two
different methyl ketones, involving an aldol condensation/
intermolecular Michael addition/intramolecular Michael
addition/elimination of ethanethiol sequence, is highly chemo-
and regioselective since the two ketones show different reactivities.
In the second stage, the 2-cyclohexenones (the [4 + 1 + 1]
annulation products) are efficiently converted to the corres-
ponding phenols through a metal-free dehydrogenation oxida-
tion using molecular oxygen from air as the oxidant. This
work provides (1) a new entry to highly substituted 2-cyclo-
hexenones; (2) a new entry to highly substituted phenols;
and more importantly, (3) a new and low cost approach
for efficient transformation of 2-cyclohexenones to the corres-
ponding phenol derivatives using molecular oxygen from air as
the only oxidant. Further studies are in progress.
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7 For a review of oxidative aromatization reactions of a,b-unsatu-
rated cyclic compounds, see: M. J. Mphahlele, Molecules, 2009, 14,
5308–5322.
We gratefully acknowledge NNSFC-20872015/20972029
and the Fundamental Research Funds for the Central Univer-
sities (NENU-STC08007/07007) for funding support of this
research.
8 For aromatization of 2-cyclohexenones using N-tert-butylbenzene-
sulfinimidoyl chloride and other reagents, see: N. Z. Burns,
I. N. Krylova, R. N. Hannoush and P. S. Baran, J. Am. Chem.
Soc., 2009, 131, 9172–9173 and references therein.
Notes and references
9 For
a review of homogeneous bio-inspired copper-catalyzed
oxidation reactions, see: (a) P. Gamez, P. G. Aubel,
W. L. Driessen and J. Reedijk, Chem. Soc. Rev., 2001, 30,
376–385; (b) S. S. Stahl, Angew. Chem., Int. Ed., 2004, 43,
3400–3420; (c) S. S. Stahl, Science, 2005, 309, 1824–1826.
10 Attempt to synthesize pentasubstituted phenols was unsuccessful.
The reaction of 4,4-bis(ethylthio)-1,3-diphenylbut-3-en-2-one,
benzaldehyde and acetophenone or the reaction of 4-(bis(ethylthio)
methylene)heptane-3,5-dione, benzaldehyde and acetophenone
gave a complex mixture of products in which no trace of the
desired phenols could be isolated.
z General procedure for the multicomponent synthesis of poly substi-
tuted phenols 5 (taking 5a as an example): to a well-stirred mixture
of benzaldehyde 2a (0.11 mL, 1.1 mmol) with acetophenone 3a
(0.128 mL, 1.1 mmol) was added t-BuOK (56 mg, 0.5 mmol) at room
temperature. After the reaction mixture was stirred at room tempera-
ture for 0.5 h, a mixture of 2-(bis(ethylthio)methylene)-1-phenyl-
butane-1,3-dione 1a (294 mg, 1.0 mmol) and t-BuOK (392 mg, 3.5 mmol)
in dry DMF (10 mL) was added and the resulting reaction mixture was
stirred at room temperature for additional 2.5 h. After completion of
the reaction as indicated by TLC, the reaction was quenched by
saturated sodium chloride aqueous (20 mL), neutralized with dilute
HCl aqueous, and extracted with dichloromethane (3 ꢁ 20 mL). The
combined organic phase was washed with water (3 ꢁ 20 mL), dried
over anhydrous MgSO4 and concentrated in vacuo. The crude product
was purified by flash chromatography (silica gel, eluent, petroleum
ether–diethyl ether: 3/1, v/v) to give (3-(ethylthio)-5-hydroxybiphenyl-
2,4-diyl) bis(phenylmethanone) 5a (293 mg, 67%) as a yellow oil.
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 9061–9063 9063