A rare γ-pyranopyrazole skeleton: Design, one-pot synthesis and computational study

Article abstract of DOI:10.1039/c6ob01099g

Drawing upon a consecutive amide coupling and intramolecular cyclisation pathway, a one-pot, straightforward synthetic route has been developed for a range of pyrazole fused γ-pyrone derivatives. The reaction mechanism proposed for the chemoselective form

Full text of DOI:10.1039/c6ob01099g

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2016, DOI: 10.1039/C6OB01099G.
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A rare γ-pyranopyrazole skeleton: design, one-pot synthesis and
computational study
Received 00th January 20xx,
Accepted 00th January 20xx
Muhammed Üçüncüa, Ceren Cantürka, Erman Karakuꢀa, Hüseyin Zeybeka, Uğur
Bozkayab, Emine Soydaꢀc, Ertan ꢁahinc and Mustafa Emrullahoğlu*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
Drawing upon a consecutive amide coupling and intramolecular of which however still employ harsh reaction conditions (i.e.,
cyclisation pathway, a one-pot, straightforward synthetic route refluxing in acetic or sulphuric acid). Deng et al. have recently
has been developed for a range of pyrazole fused γ-pyrone introduced an elegant approach to the same γ-pyranopyrazole
derivatives. The reaction mechanism proposed for the skeleton that relies on a tandem cyclisation process employing
chemoselective formation of γ-pyranopyrazole is furthermore fully certain diazo compounds as starting materials.9 Nevertheless,
supported by experimental and computational studies.
other concise methods of constructing new γ-pyrone
structures with potential biological activities continue to be in
demand.
Heterocyclic compounds bearing a pyrone scaffold (e.g., 4-
pyrone or γ-pyrone) exhibit an array of biological and
pharmacological activities.1 Since the biological activity of the
pyrone ring is closely linked to the core structure’s substitution
pattern, incorporating other ring motifs into the pyrone
skeleton could greatly contribute to the parent molecule’s
biological activity.2 In terms of biological diversity, constructing
ring-fused pyrone derivatives has attracted significant
attention; however, despite widespread interest in and efforts
toward constructing new pyrone derivatives, ring-fused pyrone
derivatives remain extremely rare,3 given the lack of practical
and effective synthetic protocols and guidelines for their
construction.
Fig. 1 Structure of γ-pyrone and γ-pyranopyrazole
In response, we herein report a straightforward, one-pot
synthetic protocol for constructing γ-pyranopyrazoles with a
rare structural skeleton. This rare γ-pyranopyrazole skeleton
differs from the common skeleton insofar as the nitrogen of
pyrazole ring is located on the bridge of the fused ring system
(Fig. 1). To the best of our knowledge, only one report has
described the preparation of this skeleton, namely as a low-
yield by-product that remains to be thoroughly investigated.10
As part of our continued interest in synthesizing fluorescent
labelling molecules, we have outlined a synthetic approach for
Representing an unusual example of a fused pyrone ring, the
pyranopyrazole ring system can participate in diverse
biological activities including analgesic, anti-inflammatory,
antimicrobial, fungicidal, and cytotoxic activity.4 Certain
derivatives of pyranopyrazoles have been evaluated for their
affinity to bind with bovine brain adenosine receptors.5 At the
same time, the γ-pyranopyrazole ring system is photoactive
and apt to undergo photochemical reactions such as
photodimerization and photocleavage.6
The general method for preparing the known pyrano[3,2-
c]pyrazole skeleton relies on a two-step synthetic process,
which Gelin et al. have described (Fig. 1).7 Over the years,
improved versions of the method have been published,8 most
preparing 1,5-diazabicyclo [3.3.0]octadienediones (D) (9,10-
dioxabimanes) (Scheme 1). We proposed a two-step synthetic
pathway, first involving a classical amide coupling between
pyrazolone (
was anticipated to cyclize in an intramolecular
hydroamination process to yield the expected Bimane
A) and 2-propiolic acid (B) (Scheme 1). Compound
C
structure
Bimane (
(
D
). Surprisingly, however, instead of creating
), compound cyclized unexpectedly from the
: a γ-pyrone
D
C
oxygen atom over the alkyne to yield compound
E
derivative fused with a pyrazole ring. We thus experimentally
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investigated the mechanism for the chemoselective formation initially determined by mass spectrometry analysis as the
of γ-pyranopyrazole ( ) over Bimane ( ), the results of which expected compound with a Bimane structure ( ), since the
E
B
D
were unambiguously supported by theoretical calculations.
mass data of the compound agreed closely with the expected
mass data of Bimane [MS (EI, m/z): 282.2 (M+)]. However, after
1
a close inspection of its H-NMR spectrum, we discovered that
the phenyl ring protons of the unknown structure resonated at
distinctly different frequencies, which contradicted 1H-NMR
data of the reference Bimane derivative shown in the
literature.10 In fact, the phenyl ring protons of a symmetric
Bimane structure were expected to resonate at almost same
frequencies, a surprising observation that casts doubt on an
alternative molecular structure (Fig. 3).
Fig. 3 Comparative 1H-NMR spectra of a) Bimane (
compound 6aa
D
) and b)
E
(
)
Scheme 1 Retrosynthetic approach for the preparation of γ-
pyranopyrazole
We commenced our investigation by optimizing the reaction
conditions for C–N coupling, which uses pyrazolone (1a) and
phenylpropiolic acid (2a) as the model substrates (Fig. 2).
Fig. 2 Optimized reaction conditions for the amide formation
step
The reaction of 1a with 2a in the presence of classical cou-
pling reagents such as dicyclohexylcarbodiimide (DCC) and
N,N-dimethylaminopyridine (DMAP) was performed in various
solvent systems and followed carefully by thin-layer
chromatography (TLC) and nuclear magnetic resonance (NMR)
spectroscopy. The efficacy of C–N bond formation greatly
depended on the nature of the solvent system. The reaction of
1a with 2a proceeded smoothly in general, though most
quickly (1h, >95% conversion) in tetrahydrofuran (THF),
whereas the conversion time of 1a in alternative solvent
systems (e.g., DCM and CH3CN) was quite longer (7–16 h).
When 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI,
1.2 equiv.) was used as the coupling reagent, no dramatic
differences in either conversion or reaction time were
observed. For practical reasons, DCC was chosen as the
coupling agent in the optimization study, in which the reaction
condition for the first coupling step used a 1:1 ratio of both
substrates (1a and 2a), with a combination of DCC (1.2 equiv.)
and DMAP (0.3 equiv.) in THF at room temperature.
O
O
N
N
Ph
Ph
6aa
Fig. 4 X-ray diffraction analysis of compound 6aa with thermal
ellipsoids drawn at the 40 % probability level
To further inspect the structure of the unknown product, we
performed X-ray diffraction analysis on the single crystal of 6aa
recrystallized over
Fortunately, the fluorescent molecule, first assigned as a
Bimane structure ( ), was in fact a γ-pyranopyrazole derivative
6aa) bearing the chemical structure displayed in Fig. 4.
a cold hexane–DCM solvent system.
In these conditions, the model reaction yielded the amide 3aa
along with a trace amount of a fluorescent molecule 6aa, as
observable on the TLC plate. The chemical identity of 6aa was
D
(
2 | J. Name., 2012, 00, 1-3
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Having unambiguously clarified the chemical identity of the efficiently than with any other base. Surprisingly, none of the
fluorescent compound as a pyrazole-fused γ-pyrone derivative tested alkynophilic metal species had enough power to
and having optimized the conditions of the first reaction, we catalyse intramolecular cyclisation. Namely, in the presence of
next focused our attention on intramolecular cyclisation.
alkynophilic metal species such as AuCl3, CuI, AgSbF6 and
To that end, the amide 3aa prepared in situ was treated Pd(OAc)2, no cyclisation occurred, likely due to the
respectively with a series of bases, including C2CO3, K2CO3, deactivation of the metal species by either the DMAP or DCC
DBU, and Et3N (1 equiv. of each), added to the reaction vessel reagents present in the one-pot environment (Table 2, Entries
soon after the starting materials were entirely consumed, as 6–9). In fact, employing a base11 instead of a metal species for
revealed on the TLC plate (ca. 0.5-1.0 hours). Only in the
a
chemical process is advantageous for mitigating
presence of Cs2CO3 (1 equiv.) within the one-pot protocol, the environmental problems such as metal pollution and metal
cyclisation step proceeded smoothly and produced 6aa in a toxicity.
good yield (82%); (Table 1, Entry 3). In consistent with other Given these results, we eventually established the most
reports,11a-c Cs2CO3 showed superior activity compared to suitable coupling partners for the one-pot synthetic protocol
other bases due to its mild base strength. Increasing the were DCC and DMAP, the solvent was THF, and the reagent
equivalency of Cs2CO3 showed no observable contribution to driving cyclisation to completion was Cs2CO3 (Table 1, Entry 2).
improving the yields (Table 1, Entry 6), whereas lowering the The reaction time for the one-pot reaction at room
amount of the base to catalytic levels (0.1 equiv.) negatively temperature varied from 3 to 6 h, depending on the structure
affected both reaction yield and time (Table 1, Entry 5). of the substrates used (Table 2).
Importantly, in the presence of acidic reagents such as
CF3COOH (Table 1, Entry 11) no cyclisation was monitored,
while at elevated temperatures the cyclisation could be Table 2 Substrate scope for the one-pot process
triggered to some extent (Table 1, Entry 12).
Table 1 Effect of certain bases and metal ion additives on the
cyclisation of 3aa
Entry
1
1
(R1)
2
(R2)
2a (Ph)
6
Timec(h) Yieldb (%)
6aa
6ab
6ac
6ad
6ae
6af
3
3
3
3
3
3
3
4
4
5
5
6
6
4
4
4
4
1a(Ph)
82
25
57
50
80
85
74
73
75
73
47
50
45
85
90
76
81
1a
2b (H)
2
1a
2c (Me)
3
Entry Reagentsa
Timec (h)
3
Yieldb 6aa(%)
34
1a
2d (n-Pent)
2e (4-MeC6H4)
2f (4-MeOC6H4)
2g (4-ClC6H4)
2h (2-MeC6H4)
2i (3-MeC6H4)
4
1
Et3N
1a
5
K2CO3
2
4
60
1a
1a
Cs2CO3
6
3
3
82
DBU
6ag
6ah
6ai
4
3
38
7
Cs2CO3 (0.1 equiv.)
Cs2CO3 (2 equiv.)
AuCl3 (0.1 equiv.)
AgSbF6 (0.1 equiv.)
CuI (0.1 equiv.)
Pd(OAc)2 (0.1 equiv.)
CF3COOH (3 equiv.)
noned
5
8
40
1a
8
6
3
85
1a
9
7
24
24
24
24
8
<1(trace)
trace
trace
trace
trace
25
1a
2j (3,5-(CF3)2C6H3) 6aj
10
11
12
13
14
15
16
17
8
1b(Me)
1b
2a (Ph)
6ba
6be
9
2e (4-MeC6H4)
10
11
12
13
1b
2j (3,5-(CF3)2C6H3) 6bj
1c(p-Tolyl)
2a
6ca
6da
6ea
6
1d(p-Cl-Ph) 2a
1e(m-Tolyl) 2a
DMAPe
4
35
a 1 equivalent of the reagents, otherwise indicated; b isolated
c
d
1a
2k(4-MeOCOC6H4) 6ak
yields; reaction time at room temperature; without any
additional reagent at 80oC; e 3 equiv. of DMAP
a
b
1 equivalents of the reagents, otherwise indicated; isolated
yields; c reaction time at room temperature
Transition metal–catalysed alkyne activation reactions have
been common in synthetic chemistry and attracted great
attention during the last decade. With that in mind, we aimed
to substitute the base with a Lewis acidic metal species in the
hope of catalysing the intramolecular cyclisation step more
With optimized conditions at hand, we next explored the
scope and limitations of the sequential amide formation and
cyclisation process by testing the reactions of various propiolic
acid derivatives (2a
–
k) with a range of pyrazolone derivatives
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1a ) (Table 2). The substrate scope is shown in Table 2. A
Journal Name
(
-e
variety of aryl propiolic acid derivatives bearing electron-
donating or -withdrawing groups as substituents on the 2-, 3-,
and 4-positions of aryl ring underwent reactions smoothly and
yielded the desired compound in moderate to good yields.
Electronic properties of the substituents displayed a slight
effect on both the yield and reaction time; namely, yields for
substrates bearing electron-donating groups on the aryl ring
were slightly higher. Although the cyclisation of aliphatic
propiolic acid derivatives (2b
cyclisation and the reaction yields were distinctly lower than
that of aryl propiolic acid derivatives (2a 2e ).
–d) proceeded as well, the rate of
,
–k
Based on experimental and computational results, we
proposed a reasonable mechanism for the formation of γ-
pyranopyrazole as outlined in Scheme 2. Mechanistically, the
reaction proceeds by way of a two-step consecutive process,
the first step of which is a classical C–N coupling. Compound 3,
formed in the first step, subsequently undergoes a base-
Fig. 5 Potential energy profile related to the formation of the
mediated intramolecular 6-endo-dig ring closure from the
products, intermediates and transition states. Energies of
oxygen atom over the alkyne to yield γ-pyranopyrazole (
(Scheme 2).
6)
structures
3, 6, and 7 are computed relative to 3x+H, since
they have different stoichiometry.
The TS (transition state) of 3x
/
4x and 3y
/
4y are considered to
and 6,
be the rate-determining steps for structure
7
respectively. Calculations confirmed that the activation energy
barrier for forming intermediate 4x was considerably higher
than 4y (Table S2, Entries 10, 14 and see in the ESI†); namely,
the difference between the reaction barriers of 4x and 4y was
calculated to be 7.1 kcal/mol (Fig. 5). Furthermore, the TS
theory rate constants at room temperature were calculated to
be 5.0 × 10-4 s-1 and 47 s-1 for 4x and 4y, respectively (Table S2,
see in the ESI†). Accordingly, compound
6 is the kinetically
Scheme
2 Proposed reaction mechanism supported by
favourable product, which also reveals that compound
unobservable.
7 was
theoretical calculations.
Selective formation of the γ-pyranopyrazole ring over the
Bimane ring was computationally investigated to explain the
product selectivity (Scheme 2). Geometrical parameters were
optimized with the density-functional theory (B3LYP/6-
311G++(d,p)).12-14 Reaction energies and activation energy
barriers are shown in Tables S2 (see in the ESI†), and the
potential energy profile of the cyclisation step appears in Fig.
5.
O
H
O
N
N-
H
3cb
Fig. 6 Electron density potential map of structure 3cb
The electrostatic potential map (EPM) of 3cb (R1 and R2= H)
was calculated to investigate the resonance hybrid structures
that significantly contributed to the structure of compound 3.
We surmised that the resonance structure with the negatively
charged oxygen atom was the dominant hybrid of 3cb. To
verify that assumption, we considered the structure of 3cb
(Fig. S1, see in the ESI†), which shows that the C–O bond
length (1.231 Å) in the pyrazolidine fragment is noticeably
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4
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bond character, which accounts for the intermolecular
cyclisation over the oxygen atom. Also, EPM of 3cb (Fig. 6)
demonstrates that the negative charge is located on the
oxygen atom of the pyrazolidine ring. In short, a favourable
geometry associated with the formation of γ-pyrone (
allowed compound to undergo a 5-exo-dig hydroamination
ring closure necessary to yielding a Bimane ring ( ).
6) never
3
7
Most of the γ-pyrone derivatives synthesized herein displayed
strong fluorescence emission under ultraviolet light. For that
reason, we further determined the photophysical properties of
all new γ-pyrone derivatives by measuring their absorption
and emission wavelengths, fluorescence quantum yields, and
absorption coefficients. Table S1 summarizes all these
properties for all new γ-pyrone derivatives. Among them,
5
6
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,
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7
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Conclusions
In sum, we developed a one-pot, two-step synthetic method
for constructing a range of highly emissive γ-pyranopyrazole
derivatives. Remarkably, this one-pot system is based on a
transition metal–free synthetic protocol involving the use of an
inorganic base (e.g. Cs2CO3) to promote an intramolecular 6-
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Acknowledgements
We thank İzmir Institute of Technology (IZTECH) and TUBİTAK
(113Z157) for financial support. U.B. acknowledges the
support from Turkish Academy of Sciences, Outstanding Young
Scientist Award (TÜBA-GEBİP 2015).
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