Efficient multicomponent strategy to pentacyclic pyrazole-fused naphtho[1,8-fg]-isoquinolines through cleavage of two carbon - Carbon bonds

Article abstract of DOI:10.1021/ol302452j

Multicomponent reactions of acenaphthylene-1,2-dione with diaroylmethanes and electron-rich pyrazol-5-amines have been discovered. A series of new and polyfunctionalized pentacyclic pyrazole-fused naphtho[1,8-fg]isoquinolines were regioselectively synthesized. The reactions were easy to perform simply by mixing three common reactants in AcOH. During these reaction processes, the insertion of active methylene of diaroylmethane into the sp²-sp ² C-C bond of the cyclohexa-2,5-dienone ring was readily achieved and two C-C bonds were cleaved under transition-metal-free conditions.

Full text of DOI:10.1021/ol302452j

ORGANIC
LETTERS
2012
Vol. 14, No. 18
4894–4897
Efficient Multicomponent Strategy to
Pentacyclic Pyrazole-Fused Naphtho[1,8-fg]-
isoquinolines through Cleavage of Two
CarbonÀCarbon Bonds
Wen-Juan Hao, Xiao-Ping Xu, Hui-Wen Bai, Shun-Yi Wang,* and Shun-Jun Ji*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China
shunyi@suda.edu.cn; shunjun@suda.edu.cn
Received August 10, 2012
ABSTRACT
Multicomponent reactions of acenaphthylene-1,2-dione with diaroylmethanes and electron-rich pyrazol-5-amines have been discovered. A series
of new and polyfunctionalized pentacyclic pyrazole-fused naphtho[1,8-fg]isoquinolines were regioselectively synthesized. The reactions were
easy to perform simply by mixing three common reactants in AcOH. During these reaction processes, the insertion of active methylene
of diaroylmethane into the sp2Àsp2 CÀC bond of the cyclohexa-2,5-dienone ring was readily achieved and two CÀC bonds were cleaved under
transition-metal-free conditions.
Efficient and rapid construction of structurally complex
and functionally diverse multicyclic skeletons is a chal-
lenging theme in organic, medicinal, and combinatorial
chemistry.1 In light of this, multicomponent reactions
(MCRs) for use in total syntheses of natural products or
natural-like structures were one of the key tools that
enabled the multiring-junction frameworks to be predicted
by controlling the reaction process.2,3 These reactions can
avoid time-consuming and costly processes for purifica-
tion of various precursors and isolation of intermediates.4
They also form an ideal platform for rapid generation of
both complexity and diversity in a collection of com-
pounds with predefined functionality, e.g., ligands for
catalysis or bioactive compounds. Therefore, the design
of efficient MCRs involving CÀC bond cleavage is a chal-
lenge in organic chemistry. However, to the best of our
knowledge, the utilization of a multicomponent strategy
combined with double CÀC bond cleavages for the
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r
10.1021/ol302452j
Published on Web 09/12/2012
2012 American Chemical Society

construction of a pentacyclic pyrazole-fused naphthoiso-
quinoline skeleton has not been achieved so far.
such as EtOH and MeOH. AcOH and HCOOH at 70 °C
gave similar outcomes (Table 1, entries 9 and 10), while a
23% yield of 4a was obtained in TFA (Table 1, entry 12).
Subsequently, the reaction temperatures were elevated
in both AcOH and HCOOH to observe the variation of
yields of 4a. Gratifyingly, it was found that the reac-
tion worked efficiently in AcOH under reflux conditions,
which afforded the corresponding product 4a in 74% yield
(Table 1, entry 7), while the lower yield (50%) of product
4a was isolated in HCOOH under reflux conditions
(Table1, entry 11). It was determined that acetic acid can
serve not only as a suitable medium but also asan adequate
Brønsted acid promoter for this multicompoent reaction.
Recently, our group and others have developed various
multicomponent reactions that can provide easy access to
important polyfunctionalized ring structures of chemical and
pharmaceutical interest.5À7 During our continuous efforts on
the development of useful multicomponent reactions,5 herein,
we report the challenging ring expansion and annulation
of acenaphthylene-1,2-dione with diaroylmethanes and
electron-rich pyrazol-5-amines yielding multifunctionalized
pentacyclic pyrazole-fused naphthoisoquinolines (Scheme 1).
A great aspect of the present multicomponent insertion
reactions is shown by the fact that the formation of two new
six-membered rings (cyclohexaenone and pyridine rings)
and four σ-bonds was readily achieved via a metal-free ring
expansion reaction in an intermolecular manner and in a one-
pot operation; the cyclopentenedione ring was converted into
the corresponding cyclohexadienone unit by the insertion of
the active methylene of diaroylmethane into the sp2Àsp2
CÀC bond of the cyclopentenedione ring under transition-
metal-free conditions.
Table 1. Optimization of Reaction Conditions for the Multi-
component Reactions
yield (%)a
Scheme 1. Synthesis of Pentacyclic Pyrazole-Fused Naphtho-
[1,8-fg]isoquinolines
entry
solvent
temp (°C)
1
DMF
150
trace
trace
trace
19
2
DCE
reflux
reflux
reflux
reflux
reflux
reflux
80
3
CH3CN
toluene
EtOH
MeOH
AcOH
AcOH
AcOH
HCOOH
HCOOH
TFA
4
5
trace
trace
74
6
7
8
45
9
70
38
10
11
12
70
35
An initial reaction using acenaphthylene-1,2-dione
(1a), dibenzoylmethane (2a), and 3-methyl-1-phenyl-1H-
pyrazol-5-amine (3a) as a simple model substrate was
investigated to establish the feasibility of the strategy and
to optimize the reaction conditions (Table 1). Different
solvents such as AcOH, HCOOH, trifluoroacetic acid
(TFA), EtOH, MeOH, toluene, DMF, 1,2-dichloroethane
(DCE), and CH3CN were explored. The results are listed
in Table 1. As shown in Table 1, the reaction scarcely pro-
ceeded in nonprotonic solvents, such as DMF, DCE, and
CH3CN. A poor yield (19%) of product 4a was observed
using toluene as solvent. Also, the reaction failed to gen-
erate the desired product 4a in the weak protic solvents
reflux
70
50
23
a Isolated yield.
We next explored the scope of this cascade reaction
of acenaphthylene-1,2-dione 1, diaroylmethanes 2, and
electron-rich pyrazol-5-amines 3 under the optimized con-
ditions (AcOH, reflux). The results are summarized in
Table 2. It was found that the nitrogen-tethered substitu-
ents on the pyrazole ring 3 did not hamper the reaction
process. Several different N-substituents 3dÀ3e bearing
electron-withdrawing or -donating groups were tried and
found to be suitable for this cascade reaction. N-Methyl
substituted pyrazol-5-amine 3f and 3g underwent the cycli-
zation to afford corresponding pentacyclic pyrazole-fused
naphthoisoquinolines 4f and 4g in 77% and 75% yields,
respectively. Moreover, reactions of methyl, phenyl, and
cyclopropyl substituents at the 3-position of pyrazol-
5-amines with acenaphthylene-1,2-dione 1 and diaroyl-
methanes 2 all worked well to afford the desired products
in moderate yields. p-OMePh and p-ClPh diaroylmethanes
were also examined in the meantime. As expected, the re-
actions proceeded smoothly to give the corresponding
products in moderate to good yields. Indeed, the protocol
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Org. Lett., Vol. 14, No. 18, 2012
4895

Table 2. Scope Investigation for the Reaction of 1 with 2 and 3
Scheme 2. Proposed mechanism for the products 4
provides an unusual route for the generation of complex
pentacyclic pyrazole-fused naphtho[1,8-fg]isoquinolines,
which are difficult to synthesize by other methods. More-
over, it also provides a new example of metal-free insertion
in an economical and atom-efficient manner, which was
generally catalyzed by transition metals.8À10
closure cascade reactions that consist of initial enamine
A formation from 2 and 3, intermolecular nucleophilic addi-
tion (A to B), tautomerization and H transfer (B to D),
subsequent intramolecular addition (D to E), ring opening of
acenaphthylene-1,2-diols through CÀC bond cleavage (E to
G), a second intramolecular cyclization (G to H), and a third
nucleophilic addition (H to I) and subsequent elimination to
final product 4 via a second CÀC bond cleavage.
A plausible mechanism for this three-component reac-
tion is postulated in Scheme 2. The reaction involves ring
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In all cases, the complexity of the resulting products
from this new reaction illustrates the remarkable regio-
selectivity of the sequence starting from very common
starting materials. In most cases, the products can pre-
cipitate out after cold water was poured into the reaction
mixture. The structural elucidation and the attribution of
regioselectivity were unequivocally determined by NMR
spectroscopic analysis and X-ray diffraction of a single
crystal of pyrazolo[3,4-c]isoquinolines 4a (Figure 1). Dur-
ing these processes, up to two new rings and four σ-bonds
were formed accompanied by cleavage of two CÀC bonds
of acenaphthylene-1,2-dione and diaroylmethanes. The
insertion of the active methylene of diaroylmethane into
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4896
Org. Lett., Vol. 14, No. 18, 2012

acenaphthylene-1,2-dione that led to new structures of
the pentacyclic pyrazole-fused naphthoisoquinoline skele-
ton with high regioselectivity. The present work provides
an attractive strategy for the synthesis of structurally
diverse naphthoisoquinoline derivatives. Other features
of this tactic include mild conditions, convenient one-pot
operations, and excellent regioselectivity. Due to the easy
availability of the starting materials and potential utilities
of products, this method could be useful in organic synthe-
sis and medicinal chemistry.
Acknowledgment. We gratefully acknowledge the
Natural Science Foundation of China (No. 21042007,
21172162), the Young National Natural Science Founda-
tion of China (No. 21202111), the Young Natural Science
Foundation of Jiangsu Province (BK2012174), PAPD,
and Soochow University for financial support.
Figure 1. X-ray structural of 4a.
the sp2Àsp2 CÀC bond of the cyclopentenedione ring was
simultaneously achieved under transition-metal-free condi-
tions (Table 2). This observation is very interesting and
useful in organic chemistry.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
In conclusion, we have successfully established the
first insertion-based three-component reactions of
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 18, 2012
4897