Pd(ii)-Catalyzed alkyne annulation through allylic isomerization: synthesis of spiro-cyclopentadiene pyrazolones

Article abstract of DOI:10.1039/d1cc02155a

The Pd(ii)-catalyzed activation of Csp²-H bond and double alkyne annulation which proceedsviaallylic isomerization is reported for the first time. This reaction of antipyrines with alkynes provides an efficient synthetic route for the biologically important spiro-cyclopentadiene pyrazolones. In the presence of Lawesson's reagent, this Pd(ii)-catalyzed annulation reaction affords another spiro-cyclopentadiene pyrazolone which displays very good fluorescence properties.

Full text of DOI:10.1039/d1cc02155a

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Pd(II)-Catalyzed alkyne annulation through allylic
isomerization: synthesis of spiro-cyclopentadiene
pyrazolones†
Cite this: Chem. Commun., 2021,
57, 6027
Received 23rd April 2021,
Accepted 11th May 2021
a
Sumi Changmai,a Sabera Sultana,a Bipul Sarmab and Sanjib Gogoi
*
DOI: 10.1039/d1cc02155a
rsc.li/chemcomm
The Pd(II)-catalyzed activation of Csp2–H bond and double alkyne 4-spiro-5-pyrazolones and their derivatives have attracted con-
annulation which proceeds via allylic isomerization is reported for the siderable attention recently, due to their interesting biological
first time. This reaction of antipyrines with alkynes provides an efficient activities. These compounds exhibit miticidal activity, inhibit
synthetic route for the biologically important spiro-cyclopentadiene type-4 phosphodiesterases and they are also used as PPARa
pyrazolones. In the presence of Lawesson’s reagent, this Pd(II)-catalyzed antagonists (Fig. 1).7 Therefore, a new efficient method to
annulation reaction affords another spiro-cyclopentadiene pyrazolone access this core structure is highly desirable. Furthermore, we
which displays very good fluorescence properties.
developed an unprecedented Pd(II)-catalyzed Lawesson’s
reagent mediated cascade annulation reaction of antipyrines
In the past few decades, transition-metal-catalyzed hetero atom with alkynes for the synthesis of spiro-pyrazolones which
directed C–H bond activation and oxidative alkyne annulation proceeds via 1,2-methyl shift (Scheme 1, eqn (4)).
reactions have emerged as a powerful tool for the construction
Initially, antipyrine 1a and alkyne 2a were chosen to opti-
of a wide range of heterocycles.1 Jiao and co-workers developed mize the reaction conditions for the synthesis of the spiro
a Pd-catalyzed reaction to activate two C(sp2)–H bonds and compound 3aa. As shown in Table S1 (ESI†), among the metal
alkyne annulation for the synthesis of aromatic carbocycles.2 complexes studied for this annulation reaction, Pd(OAc)2
Nakao and co-workers developed a Ni-catalyzed alkyne annula- catalyst along with the additive Cu(OAc)2, provided the highest
tion reaction of formamides via functionalization of one yield of 3aa (48%) in 1,4-dioxane (entry 3). Then, studies on
t
C(sp3)–H bond and one C(sp2)–H bond (Scheme 1, eqn (1)).3 solvents revealed toluene and AmOH as the most suitable
Lam and co-workers performed the alkyne annulation via solvents that provided 74% and 79% yields of 3aa, respectively
C(sp2)–H bond activation, sequential keto enol tautomerization (entries 9 and 11). These optimized reaction conditions were
and C(sp3)–H bond activation for the synthesis of spirocycles then tested to study the substrate scope of various substituted
(Scheme 1, eqn (2)).4 Yao et al. reported a Rh-catalyzed alkyne pyrazolones 1a–k with alkyne 2a which is shown in Table 1.
annulation via enol directed formal C(sp3)–H bond activation of
a-arylidene pyrazolones for the synthesis of spiro-pyrazolones
(Scheme 1, eqn (3)).5 In continuation of our work on metal-
catalyzed reactions,6 herein, we report an unprecedented
alkyne annulation reaction which involves the activation of
one olefinic C(sp2)–H bond, and the annulation proceeds via
the allyl bond isomerization (Scheme 1, eqn (4)). This
Pd-catalyzed annulation reaction of antipyrines and alkynes
provides an efficient route to access 4-spiro-5-pyrazolones. The
a Applied Organic Chemistry, Chemical Sciences & Technology Division,
CSIR-North East Institute of Science and Technology, Jorhat-785006,
AcSIR-Ghaziabad-201002, India. E-mail: skgogoi1@gmail.com
b Department of Chemical Sciences, Tezpur University, Tezpur-784028, India
† Electronic supplementary information (ESI) available: Experimental proce-
dures, spectroscopic data and copies of 1H NMR, 13C NMR and HRMS spectrum
of the synthesized compounds. CCDC 1944638 and 2079413. For ESI and crystal-
Scheme 1 Examples of various alkyne annulation reactions.
Chem. Commun., 2021, 57, 6027–6030 | 6027
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substituted pyrazolone 1c was also found to be a good substrate
to provide 3ca in 71% yield. Then, the annulation reaction of
pyrazolones containing substituents at 5-position of the pyra-
zolone ring was studied. Thus, the studied typical pyrazolones
substituted at 5-position with n-propyl and iso-propyl groups
1h–j were also found to be suitable substrates to perform this
annulation reaction to afford 3ha–ja in 62–67% yields. The
spiro compound 3ha was a mixture of both the geometrical
isomers (E : Z = 3 : 1) which was determined by the NOE spec-
trum. Finally, pyrazolone substituted with a benzyl group at
1-position 1k was tested for the annulation reaction with 2a to
afford 3ka in 77% yields. The structures of all the compounds were
determined with the help of NMR spectroscopy and finally con-
firmed by single X-ray crystallography studies of compound 3aa.8
Then the scope of the alkynes 2b–i was studied with anti-
pyrine (1a) as shown in Table 2. The symmetrically substituted
alkynes, substituted with electron-releasing and electron-
withdrawing substituents such as methyl, methoxy and fluoro
at 4-position of the phenyl ring 2b–d afforded the spiro com-
pounds 3ab–ad with yields in the range of 66–76%. Similarly,
symmetrical disubstituted alkyne substituted with an electron-
withdrawing fluoro substituent at the 3-position of the phenyl
ring 2e was also found to be a suitable substrate for this
reaction to provide 3ae in 73% yield. The reaction of the aryl
and alkyl group substituted alkyne 2f with 1a was highly
regioselective to provide only one isomer of the spiro com-
pound 3af. However, alkyne 2g substituted with a phenyl group
and an ethyl group afforded a 3 : 1 mixture of spiro compound
3ag. The regioselectivity of these unsymmetrical alkynes is
similar to the previously reported metal-catalyzed alkyne annu-
lation reactions, where the sterically hindered phenyl ring
containing centre of the alkyne binds with the metal during
the insertion of alkyne in the C–M bond, leading to the
preferential formation of one isomer.9 Finally, the dialkyl
substituted alkynes 2h–i were tested for this annulation reac-
tion, and they also turned out to be suitable substrates for this
annulation reaction to provide spiro compounds 3ah–ai, though
Fig. 1 Representative bioactive spiro-pyrazolones.
The pyrazolones possessing electron-donating and electron-
withdrawing substituents such as methyl, isopropyl, fluoro
and chloro on the 2-phenyl ring 1b, 1d–g were tested with 2a.
These reactions provided the spiro compounds 3ba, 3da–ga
with yields in the range of 56–70%, irrespective of the position
of the substituent on the phenyl ring. Similarly, dimethyl
Table 1 Scope of antipyrines 1a–k with 2aa
Table 2 Scope of alkynes 2b–i with 1aa
a
a
Reaction conditions:
1
(0.5 mmol), 2a (1.0 mmol), Pd(OAc)2
Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol), Pd(OAc)2
t
t
(5.0 mol%) and Cu(OAc)2ÁH2O (1.0 equiv.) in AmOH (5.0 mL) at 90 1C (5.0 mol%) and Cu(OAc)2ÁH2O (1.0 equiv.) in AmOH (5.0 mL) at 90 1C
b
b
for 8 h under air. For clarity one molecule is shown (for details for 8 h under air. Major isomer is shown, ratio of regioisomers (r.r.)
see ESI).
was determined by 1H NMR.
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with comparatively less yields (52–55%). The terminal alkynes,
trimethyl(phenylethynyl)silane, methyl 3-phenylpropiolate and 1-
methyl-2,5-diphenyl-1,2-dihydro-3H-pyrazol-3-one were not found
to be suitable substrates for this reaction.
To see the synthetic utility of the spiro product, we per-
formed some of the transformation reactions of 3aa. As shown
in Scheme 2, the hydrogenation reaction of 3aa in the presence
of Pd/C as the catalyst provided a mixture of hydrogenated
products 4a and 4b, which could be separated using silica gel
column chromatography. Hydroboration of 3aa with borane
complex and subsequent reduction of the resultant boron
complex in the presence of Pd/C in methanol provided the
same exocyclic double bond reduced product 4a. Interestingly,
the bromination reaction of 3aa provided a geminal dibromo
spiro compound 4c. This dibromo compound 4c was formed
from 3aa via bromination–dehydrobromination and subsequent
repeated bromination–dehydrobromination of the resulted mono-
bromo olefin. This dibromo compound would be a suitable
Scheme 3 LR-mediated synthesis of spiro-pyrazolones. a Reaction con-
ditions: 1 (0.5 mmol), 2 (1.0 mmol), Pd(OAc)2 (5.0 mol%) and Cu(OAc)2ÁH2O
(1.0 equiv.) in toluene (5.0 mL), 90 1C for 8 h under air, then Lawesson’s
synthon for further functionalization. Next, we attempted to reagent (0.5 mmol), 90 1C for 6 h. b Yield from two-step reaction per-
formed in toluene starting with 3 at 90 1C for 6 h.
transform the pyrazolone 3aa to its corresponding thiopyrazolone
by treatment with Lawesson’s reagent in toluene. Interestingly,
instead of providing the thiopyrazolone, this reaction provided
A plausible mechanism for the formation of 3aa is proposed
the spiro-cyclopentadiene pyrazolone 4aa in 84% yield (Scheme 3).
in Scheme 4. Initially, direct activation of the olefinic C(sp2–H)
Further studies revealed that 4aa could also be synthesized in one
bond of antipyrine forms the Pd(II) complex A. Then, metal–
pot from 1a and 2a, using the optimized reaction conditions and
alkyne coordination followed by insertion of the alkyne into the
toluene as the solvent, followed by the addition of Lawesson’s
Pd–C bond results in the Pd(II) complex B. Subsequent allylic
reagent into the reaction mixture (Scheme 3). Owing to the
isomerization affords p-allylpalladium species C.12 Insertion of
importance of these spiro-pyrazolones,7 we studied these novel
one more molecule of an alkyne into the Pd–C bond of C
one-pot and two-steps reactions to synthesize some of the repre-
affords a six membered Pd-complex D. Finally, reductive elim-
sentative spiro-pyrazolones which is shown in Scheme 3. The
ination and subsequent oxidation of the metal in the presence
one pot synthesis provided inferior yields of spiro compounds
of air and Cu(OAc)2 provides 3aa and the active catalyst. Again,
(42–59%) as compared to the two-steps reaction (64–84%). The
[3+2] cycloaddition of 3aa with LR generates E, which on
structure of these compounds was determined using NMR
subsequent 1,2-methyl shift followed by elimination of phos-
spectroscopy and confirmed using X-ray crystallography studies
phorous sulphide G13 finally led to the formation of 4aa.
of compound 4aa.10 Moreover, treatment of 1a alone under
In conclusion, we have developed a new Pd-catalyzed alkyne
standard conditions in D2O for 4 h provided deuterated 1a, where
annulation reaction, where annulation proceeds via the activa-
the fourth C–H bond of 1a is exchanged with D atom (35%).
tion of one olefinic C(sp2–H) bond followed by the rearrange-
Recently, the polyarylated compounds have attracted consider-
ment of one allylic C(sp3–H) bond. This annulation reaction of
able attention owing to their notable photochemical properties,
antipyrines and disubstituted alkynes provides an efficient
which make them useful compounds for organic semiconductors.
method for the synthesis of 4-spiro-5-pyrazolones which are
Therefore, a preliminary study of the optical properties of all the
the key structural motif of several bioactive compounds.
synthesized compounds was carried out.11 The absorption bands
of all the synthesized spiro-pyrazolones appeared in the region
320–360 nm. Among all the compounds studied, only compounds
shown in Scheme 3 exhibited intense fluorescence in the range
from 438 to 457 nm with quantum efficiency (F) of 48% (4aa),
75% (4ab), 64% (4ad), 52% (4ca), 61% (4da), 30% (4fa) and 47%
(4ga) (Fig. 2).
Fig. 2 Fluorescence (2.0 Â 10À5 M, excitation at 340 nm) spectra of spiro-
Scheme 2 Transformation of 4-spiro-5-pyrazolone.
pyrazolones 4 in toluene using quinine sulfate (QS) as the standard.
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Moreover, we have developed another unprecedented Lawes-
son’s reagent mediated and Pd-catalyzed annulation reaction for
the synthesis of spiro-cyclopentadiene pyrazolones which exhib-
ited fluorescence properties.
Authors thank SERB-New Delhi for financially supporting them
via the CRG/2019/001898 project. We are grateful to the Director,
CSIR-NEIST for his keen interest. We thank Dr Babulal Das, IIT
Guwahati for his help in solving the structure of a compound. S.
Changmai thanks DST for the INSPIRE-JRF fellowship.
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Conflicts of interest
There are no conflicts to declare.
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