COMMUNICATION
pubs.acs.org/JACS
Aza-Oxy-Carbanion Relay via Non-Brook Rearrangement:
Efficient Synthesis of Furo[3,2-c]pyridinones
Fushun Liang,* Shaoxia Lin, and Ying Wei
Department of Chemistry, Northeast Normal University, Changchun 130024, China
S Supporting Information
b
aza-Michael addition and aldol condensation (entry 4). To our
delight, when the reaction was conducted using NaH in DMSO
at 80 °C, the expected 7-benzylidene-5,6-diphenyl-2,3,6,7-tetra-
hydrofuro[3,2-c]pyridin-4(5H)-one 3a was obtained in 85%
yield (entry 5). The reaction between 1a and 2a did not occur
when Et3N or DBU was employed as the base (entries 6 and 7).
Under the optimized conditions (Table 1, entry 5), a range of
reactions was carried out with various substrates 1 and aldehydes
2 (Table 2). All of the reactions proceeded smoothly to afford the
corresponding substituted 2,3,6,7-tetrahydrofuro[3,2-c]pyridin-
4(5H)-ones 3a-j in good to excellent yields (entries 1-10).
The aryl substituents Ar1 and/or Ar2 on substrates 1 may be
either electron-rich or electron-deficient (entries 1-5). The
scope of aldehydes 2 was also broad, including an electron-rich
aryl aldehyde (entry 6), an electron-deficient aryl aldehyde (entry
7), heteroaryl aldehydes (entries 8 and 9), and an alkenyl aldehyde
(entry 10). However, the reaction with an aliphatic aldehyde such
as 3-phenylpropionaldehyde led to a complex mixture (entry 11).
The structures of 3g and 3j and their stereochemistries were
confirmed by single-crystal X-ray diffraction (Figure S1 in the
Supporting Information).7 All of the above results indicate the
efficiency of the anion relay cascade reactions reported here.
Next, under conditions identical to those above, we exam-
ined the scope of the anion relay reactions by replacing the
aldehyde with other electrophiles (Scheme 2).8 The reaction
of substrate 1b with 1.1 equiv of R,β-unsaturated enones bear-
ing different Ar3 groups (phenyl, 4-chlorophenyl, and 2-furyl)
as the Michael acceptor gave high yields of the corresponding
expected products 6a-c with three contiguous stereogenic
centers.
ABSTRACT: An aza-oxy-carbanion relay via tandem
Michael addition/ring opening of cyclopropane and
recyclization/carbanion migration/electrophile trapping has
been developed by the utilization of 1-cinnamoylcyclopro-
panecarboxamides to react with various electrophiles. This
represents the first example of anion relay chemistry via non-
Brook rearrangement. This novel protocol has been applied
in the facile and efficient synthesis of biologically active
bicyclic furo[3,2-c]pyridinone compounds.
ince first exploited in 1979 by Matsuda,1a anion relay chemi-
S
stry (ARC) has attracted considerable attention as an effective
tactic for diversity-oriented synthesis of architecturally complex
natural and unnatural products.1 However, almost all of the
anion relays reported to date have been established by virtue of
the Brook rearrangement.1 Development of ARC via non-Brook
rearrangement by exploring new chemical building blocks is of
great significance and still remains a challenge.
In our research on the synthetic potential of β-ketoamides2
bearing both electrophilic and nucleophilic centers toward various
carbo- and heterocycles,3 we envisioned that under appropriate
conditions, a tandem aza-oxy-carbanion relay may be realized
by the utilization of 1-cinnamoylcyclopropanecarboxamides 1
as starting materials (Scheme 1). With this idea in mind, the
reactions of a series of electrophiles with substrates 1 were
investigated. Consequently, bicyclic furo[3,2-c]pyridinones were
efficiently attained. Furo[3,2-c]pyridinone alkaloids are wide-
spread among the Rutaceae family of plants and display impor-
tant biological activities.4 Although a few synthetic approaches
for the construction of this kind of heterocycle have been
reported, most of them may suffer from tedious steps, low yields,
and poor regioselectivity.5 Our present work has provided not
only an efficient route to the structurally interesting and bio-
logically significant N,O-bicyclic furo[3,2-c]pyridinone skeleton
from readily available starting materials in a single step but also a
new protocol for an anion relay cascade that involves a tandem aza-
Michael addition/ring opening of cyclopropane and recyclization/
carbanion migration/electrophile trapping.6
In order to elucidate the possible mechanism, the reaction of
substrate 1b in the absence of additional electrophile was carried
out, and 5-phenyl-6-p-tolyl-2,3,6,7-tetrahydrofuro[3,2-c]pyridin-
4(5H)-one (7) was isolated in 82% yield (eq 1):
Obviously, the control experiment gave support to the proposed
aza-oxy-carbanion relay cascade starting from 1 (Scheme 1).
In particular, with NaH as the base, amide anion is produced.
Upon initiation by intramolecular aza-Michael addition, enolate
intermediate II is formed.9 Next, an oxyanion-triggered 1,3-
sigmatropic carbon rearrangement takes place,10 giving bicyclic
Initially, the model reaction of 1-cinnamoyl-N-phenylcyclo-
propanecarboxamide (1a) with phenylaldehyde (2a) was exam-
ined under basic conditions (Table 1). The reaction in NaOH/
EtOH at reflux gave compound 4 in 77% yield (entry 1).3f The
same result was observed in the cases using NaH as the base,
whether in THF at reflux or DMF at 80 °C (entries 2 and 3).
When the reaction was performed using t-BuOK in t-BuOH at 80 °C,
compound 5 with an intact cyclopropane ring was produced via
Received: December 3, 2010
Published: January 10, 2011
r
2011 American Chemical Society
1781
dx.doi.org/10.1021/ja110870f J. Am. Chem. Soc. 2011, 133, 1781–1783
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Liang, Fushun
