A novel four-component bicyclization strategy has been established, allowing a flexible and practical approach to 37 examples of multicyclic pyrazolo[3,4-b]pyridines from low-cost and readily accessible arylglyoxals, pyrazol-5-amines, aromatic amines, 4-hydroxy-6-methyl-2H-pyran-2-one, and cyclohexane-1,3-diones. The polysubstituted cyclopenta[d]pyrazolo[3,4-b]pyridines were stereoselectively synthesized through a microwave-assisted special [3+2+1]/[3+2] bicyclization with good control of the spatial configuration of exocyclic double bonds. The novel [3+2+1]/[2+2+1] bicyclization resulted in 17 examples of unreported pyrazolo[3,4-b]pyrrolo[4,3,2-de]quinolones. Reasonable mechanisms for forming two new types of multicyclic pyrazolo[3,4-b]pyridines are also proposed.
A novel four-component bicyclization strategy has been established, allowing a flexible and practical approach to 37 examples of multicyclic pyrazolo[3,4-b]pyridines from low-cost and readily accessible arylglyoxals, pyrazol-5-amines, aromatic amines, 4-hydroxy-6-methyl-2H-pyran-2-one, and cyclohexane-1,3-diones. The polysubstitutedcyclopenta[d]pyrazolo[3,4-b]pyridines were stereoselectively synthesized through a microwave-assisted special [3+2+1]/[3+2] bicyclization with good control of the spatial configuration of exocyclic double bonds. The novel [3+2+1]/[2+2+1] bicyclization resulted in 17 examples of unreported pyrazolo[3,4-b]pyrrolo[4,3,2-de]quinolones. Reasonable mechanisms for forming two new types of multicyclic pyrazolo[3,4-b]pyridines are also proposed.
The development of
highly efficient atom- and step-economic synthesis
of multiheterocyclic scaffolds, particularly pyridine ring-containing
ones, is of chemical and biomedical importance and has been actively
pursued in organic and medicinal research for several decades.[1,2] The structurally diverse and intriguing cyclopenta[c]pyridine family has been found to exist in monoterpene alkaloids
that are represented by oxerine,[3] actinidine,[4] and aucubinine A and B[5] (Figure 1) that showed significant biological
activities with respect to abortive and animal stimulating effects.[3,4] In addition, a variety of synthetic functionalized pyrazolo[3,4-b]pyridine system represents a core skeleton of pharmaceutical
heterocycles with many other biological activities.[6,7] A
survey of the literature shows that many approaches to cyclopenta[c]pyridines[8] and pyrazolo[3,4-b]pyridines[9] have been developed,
and there are a few reports of the combination of both above bioactive
motifs into one compound.[10] Hence, an exploration
of a direct access to cyclopenta[d]pyrazolo[3,4-b]pyridines would be highly valuable for the discovery of
new bioactive compounds.
Figure 1
Some bioactive cyclopenta[c]pyridine alkaloids.
Some bioactive cyclopenta[c]pyridine alkaloids.Multicomponent reactions (MCRs) have emerged as effective
methods
for the assembly of complex cyclic structures by the combination of
two or more distinct reactions into a one-pot transformation.[11,12] Among them, a branching multicomponent bicyclization not only enhances
annulation efficiency but also features bond forming efficiency and
high levels of structural complexity and minimizes the generation
of waste.[13] In recent years, enormous efforts
have been made by conducting multicomponent bicyclizations toward
the formation of various heterocycles.[14,15] Recently,
we have also established a new multicomponent reaction of arylglyoxals
with electron-rich pyrazol-5-amines and aromatic amines, providing
highly substituted pyrazolo[3,4-b]pyridines (Scheme 1).[16] When 4-hydroxy-6-methyl-2H-pyran-2-one was trapped in this reaction system, tricyclic
cyclopenta[d]pyrazolo[3,4-b]pyridines
were unexpectedly obtained through a four-component bicyclization
(Scheme 1). Further investigations revealed
that replacing 4-hydroxy-6-methyl-2H-pyran-2-one
with cyclohexane-1,3-diones delivered the unprecedented pyrazolo[3,4-b]pyrrolo[4,3,2-de]quinolones. In this
paper, we report our interesting observations. This work represents
special examples for the regioselective construction of tri- and tetracyclic
heterocycles containing a pyrazolo[3,4-b]pyridine
unit with the concomitant formation of two new rings and five σ-bonds.
In addition, the spatial configuration of exocyclic double bonds has
been controlled well in the former reaction, because of the intramolecular
hydrogen bond.
Scheme 1
Synthesis of Skeletally Diverse Pyrazolo[3,4-b]pyridine
Derivatives
Results and Discussion
To develop a new four-component bicyclization, we began our investigation
with condition optimization by reacting 2,2-dihydroxy-1-phenylethanone 1a with 3-methyl-1-phenyl-1H-pyrazol-5-amine 2a, aniline 3a, and 4-hydroxy-6-methyl-2H-pyran-2-one 4 in DMF solvent under microwave
(MW) heating. In our previous report, the multicomponent reaction
of arylglyoxals with pyrazol-5-amines and aromatic amines promoted
by p-TsOH gave highly substituted pyrazolo[3,4-b]pyridines.[16] To continue our
efforts on this project, we assume that when 4-hydroxy-6-methyl-2H-pyran-2-one was placed into the system described above,
the reaction would proceed in another direction to form cyclopenta[d]pyrazolo[3,4-b]pyridines using appropriate
promoters, based on the fact that ring opening of 4-hydroxy-6-methyl-2H-pyran-2-one with a proper nucleophile has been well established.[17] With this notion in mind, four reactants with
an equivalent molar ratio were treated with common promoters that
have been widely used in heterocyclic synthesis [e.g., K2CO3, p-TsOH, and CF3COOH (entries
1–3, respectively, in Table 1)]. Unfortunately,
the desired product 5a was not observed at all in the
presence of the promoters mentioned above using DMF as a reaction
solvent. Further screening of promoters revealed that the use of HOAc
led to tricyclic product 5a, albeit with a low yield
of 15% (entry 4). A higher yield of 57% was achieved when the reaction
was conducted in HOAc at an enhanced temperature of 80 °C. The
reaction works more efficiently in HOAc at 110 °C, affording
a 74% yield of 5a (entry 7). Further increasing the temperature
above 110 °C did not show improvement and even gave diminished
chemical yields.
Table 1
Optimization for the Synthesis of 5a under MW Heating
entry
solvent
promoter (equiv)
temp (°C)
time (min)
yielda (%)
1
DMF
K2CO3 (1.0)
80
25
trace
2
DMF
p-TsOH (1.0)
80
25
trace
3
DMF
CF3CO2H (1.0)
80
25
trace
4
DMF
HOAc (1.0)
80
25
15
5
DMF
HOAc (4.0)
80
25
39
6
HOAc
–
80
25
57
7
HOAc
–
110
25
74
Isolated yield.
Isolated yield.
Four-Component Bicyclization for Cyclopenta[d]pyrazolo[3,4-b]pyridines
Reaction conditions: 1 (1.0 mmol), 2 (1.0
mmol), 3 (1.0 mmol), 4 (1.0 mmol), acetic
acid (1.5 mL), 110 °C, MW. Isolated
yields based on substrate 2.
Domino
Synthesis of Cyclopenta[d]pyrazolo[3,4-b]pyridines
Reaction conditions: 1 (1.0 mmol), 2 (2.0 mmol), 4 (1.0 mmol),
acetic acid (1.5 mL), 110 °C, MW. Isolated yields based on substrate 2.Once the feasibility of the proposed
pathway had been validated,
we examined its scope generality by using various readily available
arylglyoxals, pyrazol-5-amines, and aromatic amines through a new
four-component bicyclization reaction. The experimental results are
presented in Scheme 2 and showed that a broad
spectrum of substituted arylglyoxals bearing both electron-donating
and electron-withdrawing groups were successfully transformed into
the corresponding tricyclic products 5a–n in good
to excellent yields. Notably, halogen-containing arylglyoxals could
be utilized and tolerated well under the optimal reaction conditions,
furnishing the desired products in good yields, which offer possibilities
for further functionalizations by modern coupling. The variation of
nitrogen-tethered substituents on the pyrazole ring, including methyl
or phenyl groups, worked well. After successful utilization of different
substituents of arylglyoxals and pyrazol-5-amines, we next extended
our study to a variety of arylamines with different functional groups
such as chloro, methyl, and nitro on the phenyl ring. These functional
groups are compatible in the system presented here, providing the
desired products in 55–84% yields. Even for a challenging case
in which a strong electron-withdrawing effect exists on the ortho
position on the aromatic ring (5e), a good yield of 55%
was obtained. Alternatively, instead of arylamines, this bicyclization
reaction of 1 with 2 and 4 in
a 1:2:1 molar ratio could also proceed, leading to the corresponding
tricyclic cyclopenta-fused pyrazolo[3,4-b]pyridines5o–t in 61–82% yields. Interestingly, this protocol
provides an unusual pathway for the construction of multifunctionalized
tricyclic cyclopenta-fused pyrazolo[3,4-b]pyridines
that are challenging to obtain through other methods (Schemes 2 and 3).
Scheme 2
Four-Component Bicyclization for Cyclopenta[d]pyrazolo[3,4-b]pyridines
Reaction conditions: 1 (1.0 mmol), 2 (1.0
mmol), 3 (1.0 mmol), 4 (1.0 mmol), acetic
acid (1.5 mL), 110 °C, MW. Isolated
yields based on substrate 2.
Scheme 3
Domino
Synthesis of Cyclopenta[d]pyrazolo[3,4-b]pyridines
Reaction conditions: 1 (1.0 mmol), 2 (2.0 mmol), 4 (1.0 mmol),
acetic acid (1.5 mL), 110 °C, MW. Isolated yields based on substrate 2.
After successfully
synthesizing cyclopenta-fused pyrazolo[3,4-b]pyridines 5, we attempted to further probe
the reaction scope using dimedone (5,5-dimethylcyclohexane-1,3-dione)
(6a) to replace 4-hydroxy-6-methyl-2H-pyran-2-one 4 (Scheme 4). The
reaction of 1–3 and 6 proceeded in
another direction to form the unprecedented pyrazolo[3,4-b]pyrrolo[4,3,2-de]quinolones. Encouraged by the
interesting results, we screened different Brønsted acid promoters
to optimize the reaction conditions for this protocol. The reaction
of 2,2-dihydroxy-1-(p-tolyl)ethanone (1e), 2a, 3a, and 6a in HOAc
at 110 °C gave product 7a in 25% yield. After optimization,
we were pleased to find the use of 1.0 equiv of p-TsOH in DMF at 120 °C pushed this reaction forward, affording
a 56% chemical yield of product 7a. An additional 1.0
equiv of CF3SO3H and CF3CO2H in DMF showed poor catalytic activity and almost did not promote
this reaction. Using 1.0 equiv of p-TsOH as a promoter
and DMF as a solvent, a set of diverse substituted arylglyoxals, with
groups such as methyl, methoxy, chloro, and bromo groups, were well
incorporated into these current bicyclization reactions. Arylamines
containing either electron-withdrawing or -donating substituents did
not hamper the reaction process, allowing a bicyclization strategy
to structurally complex pyrazolo[3,4-b]pyrrolo[4,3,2-de]quinolones in moderate yields. Similarly, cyclohexane-1,3-dione
can also take part in this domino bicyclization (7p and 7q). Moreover, it allows one-pot access to important tetracyclic
products and gives a new bicyclization tool in an atom-efficient fashion,
providing a valuable strategy for drug discovery.
Scheme 4
Expanding the Scope
of the Bicyclization Reaction
Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.0
mmol), 6 (1.0 mmol), p-TsOH (1.0 mmol),
DMF (1.5
mL), 120 °C, MW. Isolated yields based on substrate 2.
Expanding the Scope
of the Bicyclization Reaction
Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.0
mmol), 6 (1.0 mmol), p-TsOH (1.0 mmol),
DMF (1.5
mL), 120 °C, MW. Isolated yields based on substrate 2.In all cases, the complexity of the products
illustrates the remarkable
chemo- and stereoselectivity of the reaction sequence starting from
simple and common reactants. The structural elucidation and attribution
of relative stereochemistry were unambiguously determined by X-ray
diffraction analysis of single crystals of 5a, 5o, and 7d (see the Supporting
Information) and other analysis. As shown in Schemes 2–4, the present four-component
reaction can occur at fast speeds and can reach completion within
40 min. Water is nearly a sole byproduct, which makes workup convenient.
As mentioned previously, these heterocyclic motifs are widely prevalent
in bioactive molecules and pharmaceutical targets.To understand the mechanistic
hypothesis, a preformed 6-methyl-1-phenylpyridine-2,4(1H,3H)-dione 8,[18] derived from 4-hydroxy-6-methyl-2H-pyran-2-one
and aniline, was reacted with 1c and 2a under
the standard conditions. The corresponding tricyclic
product 5f was obtained in 75% yield (Scheme 5, eq 1). Treatment with preformed pyrazolo[3,4-b]quinolones 9(19) and aniline 3a generated a trace amount of pyrazolo[3,4-b]pyrrolo[4,3,2-de]quinolones 7d (Scheme 5, eq 2). When the reaction of 5,5-dimethyl-3-(phenylamino)cyclohex-2-enone 10 with 1c and 2a was conducted,
a 53% yield of 7d was isolated (Scheme 5, eq 3). These observations suggested that 4-hydroxy-6-methyl-2H-pyran-2-one and cyclohexane-1,3-diones may be, prior to
reacting with arylamines, producing intermediates 8 and 10, which were further converted into the corresponding products 5 and 7, respectively.
Scheme 5
Control Experiments
On the basis of
the experimental results, we proposed mechanisms
to explain the structural formation of multifunctionalized pyrazolo[3,4-b]pyridines 5 and 7 (Schemes 6 and 7). In the former, 4-hydroxy-6-methyl-2H-pyran-2-one 4 initially reacted with aryl
amines 3 to give intermediate 8, which undergoes
Knoevengel condensation with arylglyoxals 1 to give adducts A, followed by Michael addition and tautomerization to form
intermediate B. Next, intramolecular cyclization occurs
to afford fused pyrazolo[3,4-b]pyridines C. Subsequent ring opening of the pyridine skeleton and cycloisomerization
yield final tricyclic cyclopenta-fused pyrazolo[3,4-b]pyridines 5. Similar to the former, the latter is subjected
to a sequential enamine formation/Knoevengel condensation/Michael
addition/double cyclization sequence, resulting in tetracyclic pyrazolo[3,4-b]pyrrolo[4,3,2-de]quinolones 7 (Scheme 7).
Scheme 6
Proposed Mechanism
for the Synthesis of 5
Scheme 7
Proposed Mechanism for the Synthesis of 7
In conclusion, we have successfully
established a new, flexible,
and practical four-component bicyclization reaction for the construction
of multicyclic pyrazolo[3,4-b]pyridines with good
to excellent yields using low-cost and readily accessible arylglyoxals,
pyrazol-5-amines, aromatic amines, and 4-hydroxy-6-methyl-2H-pyran-2-one (and cyclohexane-1,3-diones). Two straightforward
and operationally simple methods involve complex cascades of sequences
consisting of a Knoevengel condensation, Michael addition, and double
cyclization and allow selective access to skeletally diverse multicyclic
pyrazolo[3,4-b]pyridines by varying reaction substrates.
The characteristics of reliable scalability, flexibility of structural
modification, and wide substrate scope make this bicyclization strategy
a powerful tool for the creation of multiheterocyclic scaffolds of
general chemical and biomedical interest. We believe this methodology
may be of value to others seeking original synthetic fragments with
unique activities for medicinal and pharmaceutical studies.
Experimental Section
General
Microwave
irradiation was conducted with Initiator
2.5 Microwave Synthesizers from Biotage (Uppsala, Sweden). The reaction
temperatures were measured with an infrared detector during MW heating.
General Procedure for the Synthesis of 5
Example of
the Synthesis of 5a
3-Methyl-1-phenyl-1H-pyrazol-5-amine (2a, 1.0 mmol, 173 mg) was
introduced into a 10 mL Initiator reaction vial, and 2,2-dihydroxy-1-phenylethanone
(1a, 1.0 mmol, 152 mg), aniline (3a, 93
mg), and 4-hydroxy-6-methyl-2H-pyran-2-one (4, 1.0 mmol, 126 mg) as well as acetic acid (1.5 mL) were
then successively added. Subsequently, the reaction vial was capped,
and then the contents were prestirred for 20 s. The mixture was irradiated
(time, 28 min; temperature, 110 °C; absorption level, high; fixed
hold time) until TLC [4/1 (v/v) petroleum ether/acetone] revealed
that conversion of the starting material 2a was complete.
The system was diluted with cold water (20 mL). The solid product
was collected by Büchner filtration and purified by flash column
chromatography (silica gel, petroleum ether/ethyl acetate mixtures)
to afford the pure product 5a.
3-Methyl-1-phenyl-1H-pyrazol-5-amine (2a, 2.0 mmol, 346 mg) was
introduced into a 10 mL Initiator reaction vial, and 2,2-dihydroxy-1-phenylethanone
(1a, 1.0 mmol, 152 mg) and 4-hydroxy-6-methyl-2H-pyran-2-one (4, 1.0 mmol, 126 mg) as well
as acetic acid (1.5 mL) were then successively added. Subsequently,
the reaction vial was capped, and then the contents were prestirred
for 20 s. The mixture was irradiated (time, 25 min; temperature, 110
°C; absorption level, high; fixed hold time) until TLC [4/1 (v/v)
petroleum ether/acetone] revealed that conversion of starting material 2a was complete. The system was diluted with cold water (20
mL). The solid product was collected by Büchner filtration
and purified by flash column chromatography (silica gel, petroleum
ether/ethyl acetate mixtures) to afford pure product 5o.
5,5-Dimethylcyclohexane-1,3-dione
(6a, 1.0 mmol, 140 mg) and aniline (3a,
1.0 mmol, 93 mg) were introduced into a 10 mL Initiator reaction vial,
and 2,2-dihydroxy-1-(p-tolyl)ethanone (1e, 1.0 mmol, 166 mg), 3-methyl-1-phenyl-1H-pyrazol-5-amine
(2a, 1.0 mmol, 173 mg), and p-TsOH (1.0
mmol, 172 mg) as well as N,N-dimethylformamide
(DMF, 1.5 mL) were then successively added. Subsequently, the reaction
vial was capped, and then the contents were prestirred for 20 s. The
mixture was irradiated (time, 28 min; temperature, 120 °C; absorption
level, high; fixed hold time) until TLC [4/1 (v/v) petroleum ether/acetone]
revealed that conversion of starting material 2a was
complete. The system was neutralized with diluted chlorhydric acid
and then diluted with cold water (40 mL). The solid product was collected
by Büchner filtration and purified by flash column chromatography
(silica gel, petroleum ether/ethyl acetate mixtures) to afford pure
product 7a.
Authors: Sylvine Deprèle; Boris A Kashemirov; James M Hogan; Frank H Ebetino; Bobby L Barnett; Artem Evdokimov; Charles E McKenna Journal: Bioorg Med Chem Lett Date: 2008-04-08 Impact factor: 2.823
Authors: Andrea Cappelli; Chiara Nannicini; Andrea Gallelli; Germano Giuliani; Salvatore Valenti; Gal la Pericot Mohr; Maurizio Anzini; Laura Mennuni; Flora Ferrari; Gianfranco Caselli; Antonio Giordani; Walter Peris; Francesco Makovec; Gianluca Giorgi; Salvatore Vomero Journal: J Med Chem Date: 2008-03-05 Impact factor: 7.446
Figure 1
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7