One-pot tandem catalysis: A concise route to fused bicyclic scaffolds from acyclic β-ketoesters and alkynyl aldehydes

Article abstract of DOI:10.1002/chem.201001729

Quick-step synthesis: A rapid and highly efficient route to fused polycyclic scaffolds from simple, readily available β-ketoesters and alkynyl aldehydes was developed (see scheme) as a one-pot reaction by combining three fundamental reactions, that is, the Knoevenagel condensation, Nazarov cyclization, and Conia-ene reactions. Piperidinium acetate was found to be a tandem catalyst in these one-pot reactions.

Full text of DOI:10.1002/chem.201001729

COMMUNICATION
DOI: 10.1002/chem.201001729
One-Pot Tandem Catalysis: A Concise Route to Fused Bicyclic Scaffolds from
Acyclic b-Ketoesters and Alkynyl Aldehydes
Lu Liu,[a] Lai Wei,[a] Yong Lu,[a] and Junliang Zhang*[a, b]
The fused bicyclic skeleton is an important subunit in
many natural products, pharmaceuticals, and organic build-
ing blocks in organic synthesis (some examples are depicted
here).[1] Thus, it is not surprising that various new synthetic
into this reaction and its synthetic applications in total syn-
thesis have been well demonstrated by Trauner[6h–j] and Ei-
senberg and Frontier[6a–g]. In addition, domino reactions and
ꢀone-potꢁ tandem catalyses[7] have shown their unrivalled
power in organic synthesis due to their ability to merge sev-
eral reactions into one operation. Herein, we report an effi-
cient InACHTUNRGTNE(UNG OTf)3-catalyzed (OTf=trifluoromethanesulfonate),
highly regio- and diastereoselective tandem reaction, featur-
ing Nazarov-cyclization/Conia-ene-type reactions, that syn-
thesizes fused bicyclic scaffolds from alkynyl dienones
(Scheme 1). Furthermore, a concise one-pot strategy was
successfully accomplished by combining these tandem reac-
tions with a Knoevenagel condensation, which provides
rapid and efficient access to fused bicyclic compounds from
readily available b-ketoesters (1) and alkynyl aldehydes (2;
Scheme 1). In this one-pot reaction, piperidinium acetate
methods have been developed for their construction.[2]
Within this context, the Conia-ene reaction[3,4] of an alkyne
with an enolizable carbonyl group is a fundamental method
for carbon–carbon bond formation and is widely used in car-
bocyclization reactions. For example, Nakamura[4a–c] and
Toste[4g–i] have explored metal-catalyzed intramolecular
Conia-ene-type reactions, providing a rapid route to a di-
verse range of carbocycles and heterocycles. The Nazarov
cyclization[5,6] is another very versatile method for the syn-
thesis of five-membered carbocycles due to the stereospecif-
ic nature of the cyclization. Recently, mechanistic insights
[a] Dr. L. Liu, L. Wei, Dr. Y. Lu, Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green Chemistry and
Chemical Processes
Department of Chemistry
East China Normal University
3663 North Zhongshan Road, Shanghai 200062 (P.R. China)
Fax : (+86)21-6223-5039
E-mail: jlzhang@chem.ecnu.edu.cn
[b] Prof. Dr. J. Zhang
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001729.
Scheme 1. Our proposed strategies for the construction of fused polycyc-
lic scaffold 5.
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Table 1. Study into the scope of the tandem reactions through variation
of the vinyl nucleophile.
was found to be a novel tandem catalyst that plays impor-
tant roles in not only the Knoevenagel condensation but
also the subsequent tandem reactions.
Entry Substrate
Conditions[a]
Product
Yield [%][b]
In our efforts to develop tandem reactions,[8] we became
interested in the synthesis of the fused polycyclic scaffold 5.
After retrosynthetic analysis of scaffold 5 (Scheme 1), three
possible strategies were proposed for its synthesis from
readily available b-ketoesters (1) and alkynyl aldehydes (2).
Strategy I is stepwise through the successive construction of
rings B and C; Strategy II involves a tandem reaction con-
sisting of a Nazarov cyclization and a Conia-ene-type reac-
tion from precursor 3, which can be easily prepared by a
Knoevenagel condensation of a b-ketoester and an alkynyl
aldehyde; the final, ꢀone-potꢁ strategy (Strategy III) is the
most concise and effective and merges the three different
reactions. Evidently, the tandem bicyclization is the key to
both strategies II and III. Therefore, we began our study by
examining the tandem reactions of 3a under various condi-
tions.
1
2
3a
3a
A, 808C, 3 h
B, 808C, 7 h
5a
5a
66
70
3
3b
B, 608C, 24 h
5b
89
After numerous attempts, InACHTNUGTRENUNG(OTf)3 (10 mol%) was found
to be an effective catalyst for both the Nazarov cyclization
and the subsequent 5-exo-dig Conia-ene reaction, affording
5a in 66% yield, at 808C, in toluene (Table 1, entry 1, condi-
tions A). If 1,8-diazabicycloundec-7-ene (DBU; 5 mol%;
conditions B) was added the yield could be improved slight-
ly to 70%, despite the longer time required by the reaction,
indicating that the DBU may help the intramolecular
Conia-ene reaction by improving the nucleophilicity of the
generated enol (Table 1, entry 2; for more details, please see
SI-Table 1 in the Supporting Information). Substrates 3b–e,
containing a range of vinyl nucleophiles, were examined
under the optimal reaction conditions (Table 1). All of the
reactions were highly selective, forming the desired products
5b–d as single diastereoisomers with a cis configuration of
the two newly formed five-membered rings and an E config-
uration[4f] of the exo double bond. The endo product was
not detected in the NMR spectrum of the crude product. It
was found that the benzo[d]-1,3-dioxol-5-yl moiety in 3a
could be replaced by both aromatic rings and substituted al-
kenes (Table 1, entries 3–5). To our delight, substrate 3e,
with a phenyl group as the vinyl nucleophile, gave the corre-
sponding product 5e in 81% yield (Table 1, entry 6).
Next, we examined the effects of the alkyne moiety and
the linking chain on the reaction (Table 2). Most of the
tandem reactions proceeded smoothly to give the corre-
sponding polycyclic compounds 5 with cis configuration and
exo selectivity. The stereochemistry of the exo double bond
was E except in 5 f, g, and l. Reactions of 3i, containing a
trimethylsilyl (TMS) group, and 3j gave the same product
5j, indicating that the TMS group was not compatible with
the reaction conditions (Table 2, entries 4 and 5). The intro-
duction of two electron-donating MeO groups into the
linked phenyl ring (3k) led to a higher yield, which may
result from the easier Nazarov cyclization (comparison of
3a and k).[6b,f] Delightfully, the linked phenyl ring can be re-
placed by an alkane or an alkene to give the corresponding
products in moderate yields (Table 2, entries 7–10). In some
4
5
6
3c
3d
3e
B, 708C, 24 h
B, 608C, 12 h
B, 1108C, 11 h
5c
5d
5e
71
65
81
[a] Conditions A: substrate (0.1m) in toluene (3 mL) and In
(10 mol%); conditions B: substrate (0.1m) in toluene (3 mL), In
(10 mol%), and DBU (5 mol%). [b] Yield of isolated product.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
cases (Table 2, entries 8 and 10), the exo double bond under-
goes isomerization under the reaction conditions.[9,10] Fur-
thermore, substrates with longer linking chains were also ex-
amined. For example, substrate 3p, with a three-atom chain,
produces compound 5p, containing a six-membered carbo-
cyclic ring, in 75% isolated yield (Table 2, entry 11). A
seven-membered heterocyclic ring can also be formed
(Table 2, entry 12). In contrast, a simple Nazarov cyclization
product 4r (65% yield) along with decarboxylation product
4r’ (15% yield) were obtained in the attempts to construct
an eight-membered heterocyclic ring (Table 2, entry 13).[11]
After realizing strategy II, we were eager to examine the
ꢀone-potꢁ synthetic strategy III, which uses b-ketoesters 1
and alkynyl aldehydes 2 as the starting materials. To our de-
light, this ꢀone-potꢁ strategy was successfully accomplished
by the employment of piperidinium acetate (10 mol%) as
the catalyst with 4 ꢃ molecular sieves (MS) as an additive
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One-Pot Tandem Catalysis
COMMUNICATION
Table 2. Study into the scope of the tandem reaction through variation of the terminal substituent and linking chain.
Entry Substrate
Conditions[a]
Product
Yield [%][b] Entry Substrate
Conditions[a]
Product
Yield [%][b]
1
2
3
4
5
3 f R=nBu
3g R=cHex
3h R=cPr
3i R=TMS
3j R=H
A, 1008C, 2 h
B, 808C, 3 h
B, 808C, 12 h
A, 1008C, 1 h
B, 808C, 1 h
5 f R=nBu
70 (22)[c]
10
3o
A, 1008C, 2 h
5o’
61
5g R=cHex 53 (27)[c]
5h R=cPr
5j R=H
5j R=H
80
81
86
6
3k
B, 808C, 1 h
5k
95
11
12
3p (3:2)[e]
A, 1108C, 3 h
5p E=CO2Me 75
7
8
3l R=Ph
3m R=nBu
B, 808C/24 h
A, 708C, 3 h
5l R=Ph
5m R=nBu
25 (24)[c]
42[d]
3q
A, 1108C, 1 h
5q E=CO2Me 61
9
3n
A, 808C, 6 h
5n
70
13
3r
A, 808C, 6 h
4r
65[f]
[a] Conditions A: substrate (0.1m) in toluene (3 mL), In
(OTf)3 (10 mol%); conditions B: substrate (0.1m) in toluene, In
U
(5 mol%); cHex=1-cyclohexenyl; cPr=cyclopropyl. [b] Isolated yield. [c] Isolated yield of Z isomer. [d] see ref. [9]. [e] Ratio of E,Z isomer. [f] see
ref. [11].
in toluene and the final products were isolated in 59–85%
yields by adding a catalytic amount of In(OTf)3, with or
piperidinium slows down the transformation of 3q, but is
beneficial to the formation of 5q. We then used 4q as the
substrate to study the Conia-ene reaction, see [Eq. 2]. After
6.5 h, 4q was consumed completely and gave 5q in 95%
AHCTUNGTRENNUNG
without DBU, after the first condensation step had occurred
(Scheme 2). Unexpectedly, the yields of this ꢀone-potꢁ strat-
egy were higher than those of strategy II and the by-product
of the whole process is H2O, indicating that this process is
highly efficient and environmentally benign.[12]
yield under conditions C [In
nium acetate (10 mol%)], whereas 5q was only formed in
5% yield under conditions A [In(OTf)3 (10 mol%)]. This
ACHTUNGRTEN(NUNG OTf)3 (10 mol%) and piperidi-
AHCTUNGTRENNUNG
Control experiments (Scheme 3) showed that piperidini-
um acetate is a novel tandem catalyst,[7d–e] which may pro-
mote not only the condensation step but also the Nazarov
cyclization/intramolecular Conia-ene-type reactions that
follow. The reaction of 3a under conditions A and piperidi-
nium acetate (10 mol%) gave product 5a in 74% yield,
while 83% yield was obtained under conditions B with pi-
peridinium acetate (10 mol%). Both of these yields are
higher than if the piperidinium acetate was absent (66–70%,
Table 1, entries 1 and 2).
indicates that the piperidinium acetate accelerates the
Conia-ene reaction, but may slightly hinder the Nazarov
cyclization.
In summary, we have developed an InACTHNUTRGENUN(G OTf)3-catalyzed,
highly diastereoselective tandem Nazarov cyclization/intra-
molecular Conia-ene-type reaction of alkynyl dienone 3 to
synthesize fused polycyclic scaffolds with a quaternary
carbon stereocenter. It should be noted that the reactions
displayed exo selectivity and the fused cyclic systems were
formed in cis configurations. Furthermore, a one-pot strat-
egy from b-ketoesters 1 and alkynyl aldehydes 2 has been
accomplished and is the best strategy,[12] providing efficient
and rapid access to polycyclic scaffolds from readily avail-
To gain insight into the role of piperidinium acetate in
this tandem reaction, a series of parallel experiments were
carried out using substrate 3q. From [Eq. 1], the addition of
Chem. Eur. J. 2010, 16, 11813 – 11817
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J. Zhang et al.
bining Nazarov cyclization or Conia-ene reactions with
other reactions are ongoing in our laboratory.
Acknowledgements
We are grateful to the NSFC (20702015), the Science and Technology
Commission of Shanghai Municipality, and the Ministry of Education of
PRC for financial support. This work was also sponsored by the 973 pro-
gram (2009CB825300).
Scheme 2. The ꢀone-potꢁ synthetic strategy from b-ketoesters 1 and alkyn-
yl aldehydes 2, the numbers in parenthesis indicate the isolated yield of
the Z isomer.
Keywords: bicyclic compounds · domino reactions · ene
reaction · Nazarov cyclization · one-pot reactions · tandem
catalysis
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One-Pot Tandem Catalysis
COMMUNICATION
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[13] CCDC-760111 (5k) contains the supplementary crystallographic
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[9] The reaction of 3m gave the normal product 5m in 42% yield,
along with a 28% yield of 5m’.
[10] If the reaction of 3o was quenched after 1 h, a 10% yield of 5o
could be obtained, along with a 45% yield of isomer 5o’ and 10%
of 3o was recovered.
Received: June 17, 2010
Published online: August 31, 2010
Chem. Eur. J. 2010, 16, 11813 – 11817
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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