[5 + 1] Annulation: A synthetic strategy for highly substituted phenols and cyclohexenones

Article abstract of DOI:10.1021/ja043023c

A novel [5 + 1] annulation strategy is developed for the synthesis of highly substituted phenols and cyclohexenones from α-alkenoyl ketenedithioacetals and nitroalkanes. Copyright

Full text of DOI:10.1021/ja043023c

Published on Web 03/09/2005
[5 + 1] Annulation: A Synthetic Strategy for Highly Substituted Phenols and
Cyclohexenones
Xihe Bi, Dewen Dong,* Qun Liu,* Wei Pan, Lei Zhao, and Bing Li
Department of Chemistry, Northeast Normal UniVersity, Changchun, 130024, P. R. China
Received November 19, 2004; E-mail: dongdw663@nenu.edu.cn
Scheme 1. Reaction of R-Alkenoyl Ketene-(S,S)-Acetals 1 with
Nitroalkanes 2
The regiospecific preparation of polyfunctionalized aromatic
compounds represents a major challenge in organic synthesis.1
Classical approaches are established on the modification of given
arenes, which rely heavily on the conventional electrophilic or
nucleophilic substitutions, catalyzed coupling reactions, and meta-
lation-functionalization reactions. However, these synthetic routes
suffer from a long multistep reaction sequence, lower yields of target
products, and, in particular, serious regiochemical ambiguities due
to the activating/deactivating and orienting effects of the substit-
uents. Alternatively, important modern approaches are developed
by the regioselective construction of the aromatic skeleton from
acyclic precursors, in which the substitution pattern of the final
product is dictated by the structures and functionalities of the
precursors. The benzannulation reactions include [3 + 2 + 1] Do¨tz
reaction of Fisher carbene complexes,2 Danheiser alkyne-cyclobu-
tanone [4 + 2] cyclization,3 [4 + 2] cycloaddition of metalacy-
clopentadienes and alkynes,4 transition-metal-catalyzed [2 + 2 +
2] and [4 + 2] cycloaddition,5 [3 + 3] cyclocondensation of
bielectrophiles with binucleophiles,6 and 1,6-electrocyclic reaction.7
Some of these methodologies have been applied in the synthesis
of natural products and have met with considerable success since
the formation of a regioisomeric mixture can be avoided in most
cases.8 Nonetheless, regiochemistry still challenges the above
reactions. In the benzannulation of Fisher carbene complexes, for
example, terminal alkynes can be incorporated into the assembled
hydroquinone with high regioselectivity, while internal alkynes are
prone to much poorer regioselectivity.9 The inconvenience and
difficulty caused by unsymmetry and the complexity of acyclic
substrates limit the further application of these reactions. Conceptu-
ally, a [5C + 1C] strategy should be a regiospecific reaction, which
may overcome the above drawbacks. So far, to the best of our
knowledge, there is no such [5 + 1] benzannulation reaction
reported. This stems, at least to some extent, from the fact that the
unsaturated degree of aromatization is hard to attain.
Over the past decades, R-oxo ketene-(S,S)-acetals are emerging
as versatile intermediates in organic synthesis.10 As three-carbon
1,3-electrophilic synthons, R-oxo ketene-(S,S)-acetals have found
their application in the [3 + 3] strategy for the synthesis of
substituted and fused aromatic and heterocyclic structural frame-
works by reacting with Grignard reagent, Reformatsky reagent, and
3-trimethylsilylallyllithium.11 Recently, [4 + 2] Robinson aromatic
annulation of 4-bis(methylthio)-3-buten-2-one with active methylene
ketones to substituted phenols was also achieved.12
During the course of our studies on the chemistry of R-oxo
ketene-(S,S)-acetals,13 we investigated the aldol reactions of R-acyl
ketene-(S,S)-acetals with aromatic aldehydes. It is noted that
R-alkenoyl ketene-(S,S)-acetals 1 generated from the aldol reaction
show promising structural feature as novel organic intermediates
for their (1) double Michael acceptors serving as five-carbon 1,5-
bielectrophilic species, (2) dense and flexible substitution patterns,
and (3) good leaving alkylthio groups subjected to a SNV-type
Table 1. Reaction of 1a with 2a under Different Conditions
Yield (%)c
DBU
T
time
(h)
entrya
solvent
(equiv)
(
°
C)
3a
4a
1
2
3
4
5
6
THF
1.0
1.0
1.0
1.0
1.0
1.5
r.t.
r.t.
r.t.
r.t.
10
10
10
0.5
1.2
1.0
48
29
36
88
10
n.d.
32
40
48
trace
58
CH3CN
DMF
DMF
DMF
DMF
r.t. ∼ 70b
r.t. ∼ 70b
67
a Three equivalents of C2H5NO2 was used in all the reactions. b The
reaction mixture was heated to 70 °C after the consumption of 1a monitored
by TLC. c Isolated yields.
reaction.10 These prompted us to explore the feasibility of the
construction of a substituted phenolic ring relying upon utilization
of 1 as the five-carbon 1,5-bielectrophilic components in a [5 + 1]
annulation with various one-carbon nucleophilic components.
In this communication, nitroalkanes 2 are selected as the one-
carbon components since they are well-known carbon nucleophiles,
and the nitro group is a good leaving group in the â-elimination
reaction.14
The reaction of 2-[bis(ethylthio)methylene]-N-(4-chlorophenyl)-
3-oxo-5-p-tolylpent-4-enamide 1a with nitroethane 2a was inves-
tigated in the presence of various bases, such as K2CO3, Et3N, NaH,
and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). It was observed that
both substituted cyclohexenone 3a and substituted phenol 4a could
be obtained in the presence of the above bases (Scheme 1). Among
those examined, DBU proved to be the most efficient base for the
good yield to produce 4a. Obviously, 3a was a very stable
intermediate of the reaction and finally converted into 4a via an
aromatization process. The reaction media and the amount of DBU
were then examined; some of the results are listed in Table 1. All
of the reactions could proceed to afford 3a and/or 4a in the tested
solvents, such as THF, acetonitrile, and DMF. By comparison, DMF
was a more efficient solvent and was selected for the following
investigations. It is worth noting that the reaction could be controlled
to exclusively yield 3a or 4a by varying the amount of base and
the reaction temperature (entries 4 and 6).
Under the conditions described in Table 1, entry 6, a range of
reactions were carried out with systematically varied substrates 1
and nitroalkanes 2, and some results are listed in Table 2 (entries
1-14). It is observed that all of the reactions proceeded smoothly
under the essentially mild basic conditions to afford the corre-
sponding substituted phenols 4a-n in moderate to good yields. The
9
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J. AM. CHEM. SOC. 2005, 127, 4578-4579
10.1021/ja043023c CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reactions of R-Alkenoyl Ketene-(S,S)-Acetals 1 with Nitroalkanes 2
R
-Alkenoyl Ketene-(S,S)-Acetals
Nitroalkanes
R4
Cyclohexenones
entrya
phenols 4
yield (%)c
1
R1
R2
R3
2
3
yield (%)c
entryb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
67
72
80
76
82
75
64
72
79
56
77
65
78
52
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1a
1a
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
n-Bu
Et
4-ClC6H4NHCO
4-ClC6H4NHCO
4-ClC6H4NHCO
4-ClC6H4NHCO
4-ClC6H4NHCO
4-ClC6H4NHCO
4-ClC6H4NHCO
2-MeC6H4NHCO
PhCO
4-CH3C6H4
3,4-O2CH2C6H3
4-ClC6H4
4-FC6H4
2-thienyl
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
5m
5n
88
86
91
90
93
88
82
85
90
78
93
86
95
83
1′
2′
3′
4′
5′
6′
7′
8′
9′
10′
11′
12′
13′
14′
2-furyl
PhCHdCH
4-CH3C6H4
4-CH3C6H4
PhCHdCH
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
PhCO
4-ClC6H4NHCO
4-ClC6H4NHCO
4-ClC6H4NHCO
4-ClC6H4NHCO
Et
COOEt
a Reagents and conditions: DBU (1.5 equiv), r.t. to ∼70 °C, 1.0-1.5 h, DMF. b Reagents and conditions: DBU (1.0 equiv), r.t., 0.5-1.0 h, DMF.
c Isolated yields.
Scheme 2. Proposed Mechanism for the [5 + 1] Annulation
enones. The simplicity of execution, ready availability of substrates,
and broad range of potential products make this synthetic strategy
most attractive for academic research and practical applications.
Acknowledgment. Financial support of this research was
provided by the NNSFC (20272008) and the Key Grant Project of
Chinese Ministry of Education (10412).
results exhibit the scope and generality of the novel benzannulation
reaction with respect to a range of aliphatic and aromatic substrates.
Indeed, the protocol provides a straightforward pathway to construct
highly substituted phenols. Moreover, some other characteristics
of this reaction are noteworthy. It describes a new route to
asymmetric biaryls (e.g., in entries 1-4), which are generally
prepared via metal-catalyzed crossing-coupling reactions.15 The
reasonable result obtained for 4g and 4j illustrates the potential of
this reaction for the synthesis of configuration-locked hydroxylated
stilbenes, which are widely represented in nature and have become
of particular interest to scientists because of their wide range of
biological activity.16
In the next studies, a range of reactions with the same substrates
(1 and 2) as described above were performed with 1 equimolar
DBU at room temperature for a relatively short time (0.5-1 h).
The results are summarized in Table 2 (entries 1′-14′). To our
delight, the corresponding cyclohexenones 3 were obtained in high
yields in most cases (entries 1′-12′). Actually, substituted cyclo-
hexenones are also an important kind of organic molecule present
in numerous natural products along with bio- and pharmacological
activities. Therefore, we present a [5C + 1C] strategy for the
synthesis of such useful compounds.17 Interestingly, Michael
addition adducts 5m and 5n were obtained in cases 2b and 2c
(entries 13′ and 14′). This result provides the evidence for the
mechanism of the annulation reaction.
Supporting Information Available: Experimental details and
spectral data for 1a-l, 4a-n, 3a-l, 5m, and 5n. This material is
available free of charge via the Internet at http://pubs.acs.org.
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On the basis of all of the above results, a possible mechanism
for annulation of 1 and 2 is proposed as shown in Scheme 2. The
anion of nitroalkanes first adds to the double bond bearing an aryl
group, followed by an intramolecular addition-elimination (SNV)
reaction to afford a cyclohexenone of type 3, which sheds HNO2
and is then aromatized to furnish a target product of type 4.
In summary, a novel [5 + 1] annulation strategy is developed
for the synthesis of highly functionalized phenols and cyclohex-
JA043023C
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