Intramolecular [3+2]-cycloaddition of salicylaldehydes-based cyclic azomethine imines to access novel tetrahydrochromeno[4,3-c]pyrazolo[1,2-a]pyrazol-9-ones

Article abstract of DOI:10.1016/j.tet.2021.131992

An efficient intramolecular [3 + 2]-cycloaddition of in situ-formed salicylaldehyde-based N,N′-cyclic azomethine imines was successfully developed to access novel tetracyclic skeleton bearing three contiguous stereogenic centres. This established protocol features high functional-group tolerance, excellent chemical yields, good diastereoselectivities, and variable reaction conditions.

Full text of DOI:10.1016/j.tet.2021.131992

Tetrahedron 83 (2021) 131992
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Intramolecular [3þ2]-cycloaddition of salicylaldehydes-based cyclic
azomethine imines to access novel tetrahydrochromeno[4,3-c]
pyrazolo[1,2-a]pyrazol-9-ones
,
Mei-Chun Wu a b, Peng-Ju Xia a, Yuan-Zhuo Hu a, Zhi-Peng Ye a, Kai Chen a,
,
, *
Hao-Yue Xiang a **, Hua Yang a
a College of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, PR China
b College of Chemistry & Materials Engineering, Huaihua University, Huaihua, 418008, PR China
a r t i c l e i n f o
a b s t r a c t
An efficient intramolecular [3 þ 2]-cycloaddition of in situ-formed salicylaldehyde-based N,N0-cyclic
azomethine imines was successfully developed to access novel tetracyclic skeleton bearing three
contiguous stereogenic centres. This established protocol features high functional-group tolerance,
excellent chemical yields, good diastereoselectivities, and variable reaction conditions.
© 2021 Elsevier Ltd. All rights reserved.
Article history:
Received 7 December 2020
Received in revised form
25 January 2021
Accepted 29 January 2021
Available online 6 February 2021
Keywords:
Intramolecular
[3þ2]-cycloaddition
Tetracyclic skeleton
1. Introduction
pyrazolidin-3-ones have emerged as a stable, easily accessed and
versatile building blocks for the construction of dinitrogen-fused
Nitrogen-containing skeletons are widely encountered in mar-
keted drugs and pharmaceuticals [1]. As such, rapid assembly of
these privileged frameworks is of outmost importance for drug
discovery. Up to now, enormous efforts have been made to
construct nitrogen-containing heterocycles with structural
complexity and diversity [2].Despite these impressive advances,
new efficient methods to access diversified multicyclic nitrogen-
containing skeletonsis still extremely attractive and urgent,
allowing for broad exploitation of their medicinal potentials. Un-
doubtedly, cycloaddition reactions offer the most straightforward
pathways for rapid construction of heterocycles. [3]. Among these
methods, 1,3-dipolar [3 þ 2]-cycloadditions is particularly powerful
transformations to furnish a set of structurally significant five-
membered nitrogen-containing heterocycles [4], including pyrro-
line [4a-4b], pyrrole [4c], oxazole [4d],etc. Since reported by Dorn
and Otto in 1968 [5], N,N0-cyclic azomethine imines derived from
heterocycles with various dipolarophiles (Scheme 1) [6]. For
example, in 2003, an elegant asymmetric Cu-catalyzed [3 þ 2]-
cycloaddition of N,N0-cyclic azomethine imines with alkynes were
established by Fu’s group [7]. After that, a range of diverse dipo-
larophiles especially activated alkenes have been identified to be
suitable counterparts in 1,3-dipolar cycloaddition reactions of N,N0-
cyclic azomethine imines under transition metal- or organo-
catalysis [8]. In addition to [3 þ 2]-cycloadddition transformation,
[3 þ 3] [9] or [3 þ 4] [10] cycloadditions of N,N0-cyclic azomethine
imines have also been realized as well in recent years, affording six-
or seven-membered dinitrogen-fused heterocycles. In 2019, Chen
and co-authors documented a formal [5 þ 3] cycloaddition reaction
of N,N0-cyclic azomethine imines with unmodified Mor-
itaꢀBaylisꢀHillman alcohols via double activation catalysis [11].
More recently, isatin N,N0-cyclic azomethine imine 1,3-dipolar cy-
clic azomethine imines were devised and employed in the con-
struction of diversified spirooxindole cores by Wang’s group [12].
Notably, almost all these reported transformations were restricted
to the intermolecular type.
* Corresponding author.
** Corresponding author.
E-mail addresses: xianghaoyue@csu.edu.cn (H.-Y. Xiang), hyangchem@csu.edu.
cn (H. Yang).
It was well accepted that intramolecular cycloaddition possesses
unparalleled advantages in assembling challenging multicyclic ring
systems. Despite intramolecular variant of [3 þ 2] cycloaddition of
https://doi.org/10.1016/j.tet.2021.131992
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

M.-C. Wu, P.-J. Xia, Y.-Z. Hu et al.
Tetrahedron 83 (2021) 131992
hex-5-enal for the assembly of diaza-triquinane framework [14].
Very recently, Kim, Hong and co-authors reported a tandem CeH
allylation and [3 þ 2] dipolar cycloaddition of this type of cyclic
azomethine imines, leading to a series of indenopyrazolopyr-
azolones [15] (Scheme 1). To achieve the intramolecular annulation
reaction, a well-designed linker is crucial to facilitate the occur-
rence of this process. Following this rationale, we designed new
precursors to merge the N,N0-cyclic azomethine imine moiety with
olefin unit by using salicylaldehyde as the linker, in which the
dipolar and dipolarophile moiety can be intentionally preinstalled
on the salicylaldehyde scaffold. Practically, the designed precursors
could be formed in situ during the reaction process. As part of our
continued interest in construction of complex heterocycles [16], we
herein disclose our success in diastereoselective assembly of un-
precedented fused tetracyclic skeleton bearing three contiguous
stereogenic centres from pyrazolidin-3-one and 2-(cinnamyloxy)
benzaldehydes. As a result, a range of tetrahydrochromeno [4,3-c]
pyrazolo [1,2-a]pyrazol-9-ones were easily prepared, which might
demonstrate the synergistic effects of both chromane and pyrazo-
line scaffolds as a new class of heterocycles for medicinal studies.
2. Results and discussion
2.1. Optimization of the reaction conditions
At the outset of our study, optimization of the reaction condi-
tions was carried out with pyrazolidin-3-one (1a) and 2-(cinna-
myloxy)benzaldehyde (2a) as the substrates (Table 1). Pleasingly,
the corresponding product 4a was isolated as a single diastereo-
isomer in both protonic and aprotic solvents at 80 ꢁC, while heating
in oil bath (Table 1, conditions A). And CH3CN was the optimal
choice. However, no desired product 4a was formed when using
water as solvent. Lowering the reaction temperature resulted in the
decrease in yield. To our delight, the reaction time could be
shortened to 30 min by performing this intramolecular cycloaddi-
tion reaction under MW irradiation, albeit with a slightly lowered
yield (Table 1, conditions B). Ultimately, inspired by our previous
Scheme 1. Profiles for [3 þ 2] cycloaddition reaction of N,N0-cyclic azomethine imines.
other azomethine imines, such as those directly derived from linear
hydrazines [13] were well achieved, the intramolecular fashion of
cycloaddition for N,N0-cyclic azomethine imines with dipolar-
ophiles has been rarely realized ever since. Back to 2011, Li and
Meng’s group designed a intramolecular 1,3-dipolar cycloaddition
of N,N0-cyclic azomethine imines that formed from sugar-derived
Table 1
Investigation of reaction conditionsa.
a
Reagents and conditionsA and B:1a (0.6 mmol, 3 equiv.) and 2a (0.2 mmol, 1 equiv.) in solvent (2 mL), isolated yield, >20:1 dr determined by crude 1HNMR; Conditions C:
3a (0.2 mmol, 1 equiv.) in solvent (2 mL), 2 mol% fac-Ir (ppy)3, rt, isolated yield, >20:1 dr determined by crude 1HNMR.
2

M.-C. Wu, P.-J. Xia, Y.-Z. Hu et al.
Tetrahedron 83 (2021) 131992
studies on the photochemical behavior of N,N0-cyclicazomethine
imines under visible light [17], we were also curious that this
transformation might be driven by photocatalytic conditions. Un-
fortunately, adding fac-Ir (ppy)3 to the above reaction systems
under irradiation of a blue light-emitting diode (LED) only rendered
a fairly complex reaction, and the corresponding product were
unable to be isolated. Interestingly, while the pre-prepared pre-
cursor 3a was employed in the protocol, the desired product 4a
could be obtained albeit in lower yield (Table 1, conditions C).
Considering the solubility of substrate 3a, we slightly modified the
solvent system to DMSO, leading to an increased chemical yield
within a shorter reaction time. Compared to the thermally induced
transformation, the photocatalytic reaction conditions offered a
milder alternative pathway. When TEMPO was added into the
photo-induced reaction, no desired product was detected. These
results indicate that a radical pathway may be involved.
Table 2
Exploration of substrate scope.
2.2. Scope and limitations of substrates
With these conditions in hand, we next shifted our attention to
the scope of this new intramolecular [3 þ 2]- cycloaddition, as well
as the compatibility of the reaction conditions. A range of 2-(cin-
namyloxy)benzaldehydes derived from commercially available
salicylaldehydes were prepared and subjected to the corresponding
photo- or thermal-reaction conditions (Table 2). Both electron-
donating and electron-withdrawing substituents were well toler-
ated and the presence of electron-withdrawing groups usually gave
slightly higher yields than electron-donating groups (4a-4c vs 4d-
4l). It is worth mentioning that the photocatalytic conditions
generally gave inferior chemical yields. As for the thermal pro-
cesses, these two different heating ways exhibited similar reaction
efficacy. Specifically, substrates bearing NO2 or dihalogenated
groups could afford the desired products 4j-4l successfully. The
subsequent transformation of NO2 or halogen groups would facil-
itate the expansion of the synthetic potentials for these function-
alized heterocycles. However, the substituents on the olefin of side
chain for compounds 2 were merely limited to aromatic ringat the
current stage. Phenyl-substituted pyrazolidin-3-one was unsuit-
able for this transformation. The structure of product 4l was
unambiguously confirmed by X-ray crystallographic analysis.
3. Conclusion
In summary, a new intramolecular [3 þ 2]-cycloaddition by
employing azomethineylides formed from 2-(cinnamyloxy)benz-
aldehyde and pyrazolidin-3-one was designed and successfully
developed. This transformation occurred smoothly under photo-
catalytic and thermal reaction conditions, with wide scope and
excellent diastereoselectivity. As such,
a series of tetrahy-
integration. 13C NMR data were collected at 100 MHz with complete
proton decoupling. Chemical shifts were reported in ppm from the
tetramethylsilane with the solvent resonance as internal standard.
Infrared spectra (IR) were measured by FT-IR apparatus. High res-
olution mass spectroscopy (HRMS) was recorded on TOF MS
ES þ mass spectrometer and acetonitrile was used to dissolve the
sample. Column chromatography was carried out on silica gel
(200e300 mesh). The starting materials 2 and 3 were prepared
according to the previously described method [18,19].
drochromeno [4,3-c]pyrazolo [1,2-a]pyrazol-9-ones were facilely
assembled, which would surely enrich the library of heterocycles
and provide more options for drug screening in the future. Further
biological studies of these privileged scaffolds are ongoing in our
laboratory.
4. Experimental section
Unless otherwise noted, all the reagents were purchased from
commercial suppliers and used without further purification. 1H
NMR spectra were recorded at 400 MHz. The chemical shifts were
recorded in ppm relative to tetramethylsilane and with the solvent
resonance as the internal standard. Data were reported as follows:
chemical shift, multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet,
q ¼ quartet, p ¼ quint, m ¼ multiplet), coupling constants (Hz),
4.1. General procedures for synthesis of 2a-2l
To a solution of salicylaldehyde derivatives in DMF (2 mL) was
added cinnamyl bromide (6 mmol, 1.2 equiv) and K2CO3 (6 mmol,
1.2 equiv). Subsequently, the reaction mixture was stirred at rt for
3

M.-C. Wu, P.-J. Xia, Y.-Z. Hu et al.
Tetrahedron 83 (2021) 131992
2 h. Then, the resulting mixture was concentrated under reduced
pressure and purified by flash column chromatography on silica gel
(PE/EA ¼ 95/5e80/20) to afford the corresponding products.
2.9 Hz,1H), 6.90e6.87 (m, 2H), 4.52 (s,1H), 4.32 (dd, J ¼ 10.8, 4.9 Hz,
1H), 4.18 (t, J ¼ 10.9 Hz, 1H), 3.86 (d, J ¼ 5.6 Hz, 1H), 3.71 (td, J ¼ 8.2,
2.1 Hz, 1H), 3.27 (dt, J ¼ 12.3, 8.7 Hz, 1H), 2.87e2.67 (m, 3H); 13C
NMR (100 MHz, Chloroform-d)
d
164.7, 156.9 (d, 1JC-F ¼ 240.3 Hz),
4
3
4.2. General procedures for synthesis of 4a-4l
151.3 (d, JC-F ¼ 2.1 Hz), 138.1, 129.0, 128.2, 126.2, 118.8 (d, JC-
¼ 7.9 Hz), 118.8 (d, 3JC-F ¼ 7.1 Hz), 117.0 (d, 2JC-F ¼ 23.2 Hz), 115.9 (d,
F
4.2.1. Conventional heating process
2JC-F
¼
22.8 Hz), 65.5, 59.8, 57.6, 50.5, 49.8, 36.5; HRMS
2-(Cinnamyloxy)benzaldehydes 2a-2l (0.2 mmol, 1.0 equiv) was
added to a solution of pyrazolidin-3-one 1a (0.60 mmol, 3equiv.) in
CH3CN (2 mL). Then, the reaction mixture was stirred in the oil bath
at 80 ꢁC for 12 h. The crude product was purified by flash chro-
matography on silica gel (PE/EtOAc ¼ 3/2).
(ESI):C19H17FN2O2Naþ [MþNa]þCalcd 347.1166, Found 347.1181.
2-Chloro-7-phenyl-6a,10, 11, 12a-tetrahydro-6H,7H,9H-chro-
meno [4,3-c]pyrazolo [1,2-a]pyrazol-9-one 4e: yellow solid 57.8 mg
(oil bath), 47.6 mg (mw), 40.8 mg (hv); m. p. 165e167 ꢁC; IR (neat)
n
2914, 1702, 1384, 1252, 678 cmꢀ1; 1H NMR (400 MHz, Chloroform-
d)
d
7.39e7.31 (m, 5H), 7.20 (dd, J ¼ 8.8, 2.4 Hz, 1H), 7.16 (d,
4.2.2. Microwave process
J ¼ 2.4 Hz, 1H), 6.87 (d, J ¼ 8.7 Hz, 1H), 4.51 (s, 1H), 4.34 (dd, J ¼ 10.8,
5.2 Hz, 1H), 4.20 (t, J ¼ 11.0 Hz, 1H), 3.84 (d, J ¼ 5.6 Hz, 1H), 3.72 (td,
J ¼ 8.4, 1.9 Hz, 1H), 3.27 (dt, J ¼ 12.5, 8.6 Hz, 1H), 2.86e2.68 (m, 3H);
2-(Cinnamyloxy)benzaldehyde 2 (0.2 mmol, 1.0 equiv) was
added to a solution of pyrazolidin-3-one 1a (0.60 mmol, 3equiv) in
CH3CN (2 mL). The resulting mixture in a sealed vial was irradiated
in the 250 w microwave at 80 ꢁC for 0.5 h. The crude product was
purified by flash chromatography on silica gel (PE/EtOAc ¼ 3:2).
13C NMR (100 MHz, Chloroform-d)
d 164.6,153.8,138.0,130.0,129.7,
129.0, 128.2, 126.8, 125.8, 119.3, 119.0, 65.4, 59.6, 57.5, 50.6, 49.7,
36.6; HRMS (ESI):C19H17ClN2O2Naþ [MþNa]þCalcd 363.0871,
Found 363.0885.
4.2.3. Photo-induced process
2-Bromo-7-phenyl-6a,10, 11, 12a-tetrahydro-6H,7H,9H-chro-
meno [4,3-c]pyrazolo [1,2-a]pyrazol-9-one 4f: yellow solid 57.6 mg
2-(Cinnamyloxy)benzylidene-5-oxopyrazolidin-2-ium-1-ides 3
(0.2 mmol, 1.0 equiv), Ir (ppy)3 (2.0 mmol%) were well mixed in
DMSO (2 mL). Then the reaction mixture was stirred at room
temperature for 3 h under irradiation of 30 W blue LEDs (distance
app. 5 cm). The resulting mixture was purified by flash chroma-
tography on silica gel (PE/EtOAc ¼ 3:2).
(oil bath), 63.0 mg (mw), 43.0 mg (hv); m.p. 170e172 ꢁC; IR (neat)
n
2918, 1721, 1393, 1256, 1102, 703 cmꢀ1
roform-d)
;
1H NMR (400 MHz, Chlo-
d
7.40e7.30 (m, 7H), 6.82 (d, J ¼ 8.7 Hz, 1H), 4.50 (s, 1H),
4.35 (dd, J ¼ 10.8, 5.0 Hz, 1H), 4.20 (t, J ¼ 11.0 Hz, 1H), 3.84 (d,
J ¼ 5.4 Hz, 1H), 3.73 (td, J ¼ 8.4, 1.8 Hz, 1H), 3.27 (dt, J ¼ 12.5, 8.5 Hz,
1H), 2.86e2.77 (m, 2H), 2.77e7.69 (m, 1H); 13C NMR (100 MHz,
Tetrahydrochromeno [4,3-c]pyrazolo [1,2-a]pyrazol-9-one 4a:
yellow solid 49.6 mg (oil bath), 50.8 mg (mw), 46.5 mg (hv); m. p.
Chloroform-d)
d 164.5, 154.3, 137.9, 132.9, 132.7, 129.1, 128.3, 126.2,
122e124 ꢁC; IR (neat)
n
2908, 1680, 1386, 1222, 1018, 737 cmꢀ1; 1H
119.8, 119.4, 113.0, 65.4, 59.5, 57.5, 50.7, 49.6, 36.7; HRMS
(ESI):C19H17BrN2O2Kþ [MþK]þCalcd 423.0105, Found 423.0126.
1-Chloro-7-phenyl-6a,10, 11, 12a-tetrahydro-6H,7H,9H-chro-
meno [4,3-c]pyrazolo [1,2-a]pyrazol-9-one 4g: yellow solid 63.2 mg
NMR (400 MHz, Chloroform-d)
d 7.40e7.18 (m, 7H), 6.97e6.92 (m,
2H), 4.54 (s, 1H), 4.34 (dd, J ¼ 10.8, 4.9 Hz, 1H), 4.27 (t, J ¼ 10.9 Hz,
1H), 3.92 (d, J ¼ 4.6 Hz, 1H), 3.70 (td, J ¼ 8.2, 2.3 Hz, 1H), 3.34e3.27
(m, 1H), 2.91e2.83 (m, 1H), 2.79e2.65 (m, 2H); 13C NMR (100 MHz,
(oil bath), 63.9 mg (mw), 49.0 mg (hv); m. p. 144e146 ꢁC; IR (neat)
n
Chloroform-d)
d
163.9, 154.2, 137.3, 129.2, 129.0, 128.0, 127.1, 125.2,
2919, 1704, 1408, 1257, 1047, 763 cmꢀ1
roform-d)
;
1H NMR (400 MHz, Chlo-
120.1, 116.6, 64.3, 58.9, 56.7, 49.4, 48.9, 35.5; HRMS
(ESI):C19H18N2O2Naþ [MþNa]þCalcd 329.1260, Found 329.1264.
3-Methyl-7-phenyl-6a,10, 11, 12a-tetrahydro-6H,7H,9H-chro-
meno [4,3-c]pyrazolo [1,2-a]pyrazol-9-one 4b: yellow solid 31.4 mg
d
7.41e7.37 (m, 4H), 7.33e7.29 (m, 1H), 7.17 (t, J ¼ 8.1 Hz,
1H), 7.01 (dd, J ¼ 8.9, 1.3 Hz, 1H), 6.85 (d, J ¼ 8.3, 1.3 Hz, 1H), 4.70 (s,
1H), 4.42 (d, J ¼ 5.2 Hz, 1H), 4.37 (dd, J ¼ 11.0, 5.0 Hz, 1H), 4.23 (t,
J ¼ 11.1 Hz, 1H), 3.56 (t, J ¼ 7.9 Hz, 2H), 2.92e2.59 (m, 3H); 13C NMR
(oil bath), 32.5 mg (mw), 51.2 mg (hv); m. p. 141e143 ꢁC; IR (neat)
n
(100 MHz, Chloroform-d) d 164.3, 155.4, 136.9, 134.7, 129.2, 128.0,
2919, 1688, 1405, 1042, 790, 680 cmꢀ1
roform-d)
;
1H NMR (400 MHz, Chlo-
127.1, 125.0, 121.1, 115.2, 115.1, 64.1, 56.5, 54.6, 50.9, 47.6, 35.5; HRMS
(ESI):C19H17ClN2O2Hþ [MþH]þCalcd 341.1051, Found 341.1007.
3-Fluoro-7-phenyl-6a,10, 11, 12a-tetrahydro-6H,7H,9H-chro-
meno [4,3-c]pyrazolo [1,2-a]pyrazol-9-one 4h: yellow solid
46.0 mg (oil bath), 39.5 mg (mw), 39.5 mg (hv); m.p. 137e139 ꢁC; IR
d
7.41e7.25 (m, 5H), 7.08 (d, J ¼ 7.7 Hz,1H), 6.78e6.75 (m,
2H), 4.54 (s, 1H), 4.30 (dd, J ¼ 10.8, 4.9 Hz, 1H), 4.21 (t, J ¼ 10.8 Hz,
1H), 3.90 (d, J ¼ 5.3 Hz, 1H), 3.69 (dd, J ¼ 9.7, 7.2, 2.8 Hz, 1H), 3.28
(dt, J ¼ 11.9, 9.1 Hz, 1H), 2.85 (dtd, J ¼ 10.8, 5.4, 2.2 Hz, 1H),
2.72e2.63 (m, 2H), 2.30 (s, 3H); 13C NMR (100 MHz, Chloroform-d)
(neat)
Chloroform-d) d
n
2909, 1680, 1380, 1226, 1020, 738 cmꢀ1; 1H NMR (400 MHz,
7.40e7.39 (m, 4H), 7.35e7.30 (m, 1H), 7.14 (dd,
d
164.1, 154.1, 139.3, 139.4, 128.9, 127.9, 127.0, 125.2, 121.2, 116.9,
113.7, 64.4, 58.7, 56.7, 49.2, 49.1, 35.4, 20.2; HRMS
(ESI):C20H20N2O2Naþ [MþNa]þCalcd 343.1417, Found 343.1432.
6- Methoxy-7-phenyl-6a,10, 11, 12a-tetrahydro-6H,7H,9H-chro-
meno [4,3-c]pyrazolo [1,2-a]pyrazol-9-one 4c: yellow solid 47.0 mg
J ¼ 8.4, 6.3 Hz,1H), 6.71e6.64 (m, 2H), 4.52 (s,1H), 4.36 (dd, J ¼ 10.8,
6.0 Hz, 1H), 4.22 (t, J ¼ 11.0 Hz, 1H), 3.87 (d, J ¼ 5.5 Hz, 1H), 3.68 (td,
J ¼ 8.1, 2.0 Hz, 1H), 3.26 (dt, J ¼ 12.4, 8.6 Hz, 1H), 2.85e2.68 (m, 3H);
1
13C NMR (100 MHz, Chloroform-d)
d
163.6, 162.4 (d, JC-
3
3
(oil bath), 42.3 mg (mw), 38.3 mg (hv); m. p. 177e179 ꢁC; IR (neat)
n
¼ 247.6 Hz), 155.3 (d, JC-F ¼ 12.2 Hz), 137.0, 130.3 (d, JC-
F
2924, 1680, 1400, 1257, 1020, 696 cmꢀ1
;
1H NMR (400 MHz, Chlo-
¼ 10.2 Hz), 127.9, 127.2, 125.2, 112.6, 107.7 (d, 2JC-F ¼ 22.2 Hz), 103.8
F
2
roform-d) 7.39e7.25 (m, 5H), 6.87e6.81 (m, 2H), 6.71e6.70 (m,
d
(d, JC-F ¼ 24.4 Hz), 64.4, 58.5, 56.6, 49.5, 48.6, 35.5; HRMS
(ESI):C19H17FN2O2Naþ [MþNa]þCalcd 347.1166, Found 347.1177.
3-Bromo-7-phenyl-6a,10, 11, 12a-tetrahydro-6H,7H,9H-chro-
meno [4,3-c]pyrazolo [1,2-a]pyrazol-9-one 4i: yellow solid 73.4 mg
1H), 4.52 (s, 1H), 4.20 (dd, J ¼ 10.7, 4.8 Hz, 1H), 4.08 (t, J ¼ 10.8 Hz,
1H), 3.80 (d, J ¼ 5.6 Hz, 1H), 3.76 (s, 3H), 3.73e3.69 (m, 1H), 3.27 (dt,
J ¼ 8.8, 8.8 Hz, 1H), 2.87e2.65 (m, 3H); 13C NMR (100 MHz, Chlo-
roform-d)
d
163.9, 152.8, 148.2, 137.3, 128.0, 127.1, 125.2, 117.3, 117.2,
(oil bath), 53.8 mg (mw), 56.1 mg (hv); m. p. 150e152 ꢁC; IR (neat)
n
114.7, 113.9, 64.5, 59.1, 56.6, 54.8, 49.5, 49.1, 35.4; HRMS
(ESI):C20H20N2O3Naþ [MþNa]þCalcd 359.1366, Found 359.1374.
2-Fluoro-7-phenyl-6a,10, 11, 12a-tetrahydro-6H,7H,9H-chro-
meno [4,3-c]pyrazolo [1,2-a]pyrazol-9-one 4d: yellow solid 55.1 mg
2923, 1690, 1251, 1013, 695 cmꢀ1; 1H NMR (400 MHz, Chloroform-
d) 7.40e7.39 (m, 4H), 7.34e7.30 (m, 1H), 7.11e7.03 (m, 3H), 4.50 (s,
d
1H), 4.34 (dd, J ¼ 10.8, 5.0 Hz, 1H), 4.20 (t, J ¼ 11.1 Hz, 1H), 3.83 (d,
J ¼ 5.3 Hz, 1H), 3.67 (td, J ¼ 8.4, 1.9 Hz, 1H), 3.25 (td, J ¼ 12.6, 8.5 Hz,
1H), 2.85e2.76 (m, 2H), 2.74e2.67 (m, 1H); 13C NMR (100 MHz,
(oil bath), 59.0 mg (mw), 46.7 mg (hv); m. p. 154e156 ꢁC; IR (neat)
n
2917, 1700, 1245, 1029, 712 cmꢀ1; 1H NMR (400 MHz, Chloroform-
d)
7.39e7.38 (m, 4H), 7.35e7.29 (m, 1H), 6.97 (dd, J ¼ 9.2, 7.9,
Chloroform-d)
d 164.6, 155.8, 138.0, 131.3, 129.0, 128.3, 126.2, 124.4,
d
123.2, 120.8, 116.8, 65.4, 59.4, 57.5, 50.6, 49.6, 36.7; HRMS
4

M.-C. Wu, P.-J. Xia, Y.-Z. Hu et al.
Tetrahedron 83 (2021) 131992
(ESI):C19H17BrN2O2Naþ [MþNa]þCalcd 407.0366, Found 407.0377.
2-Nitro-7-phenyl-6a,10, 11, 12a-tetrahydro-6H,7H,9H-chromeno
[4,3-c]pyrazolo [1,2-a]pyrazol-9-one 4j: yellow solid 60.4 mg (oil
N. Sciammetta, D. Adpressa, R. Sarpong, C.S. Yeung, Org. Lett. 22 (2020)
6578e6583;
(b) M. Sau, K. Verma, T. Das, J. Heterocycl. Chem. (2020) 1e13;
(c) T. Yang, W.-J. Xia, J.-Q. Shang, Y. Li, X.-X. Wang, M. Sun, Y.-M. Li, Org. Lett.
21 (2019) 444e447;
bath), 64.6 mg (mw), 46.3 mg (hv); m. p. 173e175 ꢁC; IR (neat)
n
2924, 1678, 1237, 1027, 750 cmꢀ1; 1H NMR (400 MHz, Chloroform-
d)
(d) W. Liang, K. Nakajima, K. Sakata, Y. Nishibayashi, Angew. Chem. Int. Ed. 58
(2019) 1168e1173.
d
8.17e8.14 (m, 2H), 7.39 (s, 5H), 7.03 (d, J ¼ 8.7 Hz, 1H),
[3] (a) C. Curti, G. Rassu, M. Lombardo, V. Zambrano, L. Pinna, L. Battistini,
A. Sartori, G. Pelosi, F. Zanardi, Angew. Chem. Int. Ed. 59 (2020) 2e12;
(b) F. Krauskopf, K.i-N. Truong, K. Rissanen, C. Bolm, Eur. J. Org Chem. (2020)
2761e2765.
4.52e4.49 (m, 2H), 4.33 (t, J ¼ 11.3 Hz, 1H), 3.93 (d, J ¼ 5.2 Hz, 1H),
3.75 (t, J ¼ 8.1 Hz, 1H), 3.35 (dt, J ¼ 12.9, 8.3 Hz, 1H), 2.93e2.84 (m,
2H), 2.77 (dd, J ¼ 16.1, 7.8 Hz, 1H); 13C NMR (100 MHz, Chloroform-
[4] (a) S. Padilla, J. Adrio, J.C. Carretero, J. Org. Chem. 77 (2012) 4161e4166;
ꢀ
ꢀ
ꢀ
d)
d 164.0, 160.3, 141.4, 137.5, 129.1, 128.4, 126.5, 126.2, 125.8, 118.3,
(b) F. Pozgan, H.A. Mamari, U. Groselj, J. Svete, B.Stefane. Molecules. 23 (2017)
2e30;
118.1, 65.8, 59.3, 57.4, 50.8, 49.1, 36.8; HRMS (ESI):C19H17N3O4Naþ
[MþNa]þ Calcd 374.1111, Found 374.1155.
(c) W. Gan, P.J. Moon, C. Clavette, N.D. Neves, T. Markiewicz, A.B. Toderian,
A.M. Beauchemin, Org. Lett. 15 (2013) 1890e1893;
(d) J.-U. Park, H.-I. Ahn, H.-J. Cho, Z. Xuan, J.H. Kim, Adv. Synth. Catal. 362
(2020) 1836e1840.
2,4-Dibromo-7-phenyl-6a,10, 11, 12a-tetrahydro-6H,7H,9H-
chromeno [4,3-c]pyrazolo [1,2-a]pyrazol-9-one 4k: white solid
92.6 mg (oil bath), 92.7 mg (mw), 78.0 mg (hv); m. p.194e196 ꢁC; IR
[5] (a) H. Dorn, A. Otto, Chem. Ber. 101 (1968) 3287;
(b) H. Dorn, A. Otto, Angew. Chem., Int. Ed. Engl. 7 (1968) 214.
[6] (a) K. Tomomitsu, F. Shuhei, U. Yutaka, I. Katsuhiko, Chem. Lett. 37 (2008)
342e343;
(neat)
Chloroform-d)
n
2914, 1680, 1393, 1252, 1013, 681 cmꢀ1; 1H NMR (400 MHz,
d
7.64 (d, J ¼ 2.0 Hz, 1H), 7.40e7.33 (m, 5H),
(b) T. Imaizumi, Y. Yamashita, S. Kobayashi, J. Am. Chem. Soc. 134 (2012)
20049e20052;
(c) W. Chen, X.-H. Yuan, R. Li, W. Du, Y. Wu, L.-S. Ding, Y.-C. Chen, Adv. Synth.
Catal. 14 (2006) 1818e1822;
(d) M. Yoshida, N. Sassa, T. Kato, S. Fujinami, T. Soeta, K. Inomata, Y. Ukaji,
Chem. Eur J. 20 (2014) 2058e2064.
7.26e7.25 (m, 1H), 4.50e4.46 (m, 2H), 4.26 (t, J ¼ 11.2 Hz, 1H), 3.82
(d, J ¼ 5.4 Hz, 1H), 3.69 (td, J ¼ 8.3, 1.8 Hz, 1H), 3.24 (dt, J ¼ 12.7,
8.3 Hz, 1H), 2.89e2.71 (m, 3H); 13C NMR (100 MHz, Chloroform-d)
d
163.0, 150.1, 136.6, 134.7, 130.9, 128.0, 127.3, 125.1, 119.7, 111.8,
111.4,
65.0,
58.4,
56.3,
49.8,
48.4,
35.7;
HRMS
[7] R. Shintani, G.C. Fu, J. Am. Chem. Soc. 125 (2003) 10778.
[8] (a) A. Chan, K.A. Scheidt, J. Am. Chem. Soc. 129 (2007) 5334e5335;
(b) R. Na, C. Jing, Q. Xu, H. Jiang, X. Wu, J. Shi, J. Zhong, M. Wang, D. Benitez,
E. Tkatchouk, W.A. Goddard, H. Guo, O. Kwon, J. Am. Chem. Soc. 133 (2011)
13337e13348;
(ESI):C19H16Br2N2O2Naþ [MþNa]þCalcd 484.9471, Found 484.9499.
2,4-Dichloro-7-phenyl-6a,10, 11, 12a-tetrahydro-6H,7H,9H-
chromeno [4,3-c]pyrazolo [1,2-a]pyrazol-9-one 4l: white solid
70.3 mg), 73.3 mg (mw), 68.8 mg (hv); m.p. 180e182 ꢁC; IR (neat)
n
(c) Q. Jin, J. Zhang, C. Jiang, D. Zhang, M. Gao, S. Hu, J. Org. Chem. 83 (2018)
8410e8416;
(d) L. Wei, Z.-F. Wang, L. Yao, G. Qiu, H. Tao, H. Li, C.-J. Wang, Adv. Synth. Catal.
358 (2016) 3955e3959;
2918, 1702, 1413, 1255, 1126, 697 cmꢀ1
;
1H NMR (400 MHz, Chlo-
roform-d) 7.42e7.31 (m, 6H), 7.08 (s, 1H), 4.51e4.48 (m, 2H), 4.27
d
(t, J ¼ 11.0 Hz, 1H), 3.84 (d, J ¼ 5.5 Hz, 1H), 3.71 (d, J ¼ 8.8 Hz, 1H),
(e) L. Liang, Y. Huang, Org. Lett. 18 (2016) 2604e2607.
[9] (a) T.P. Reddy, A.V. Krishna, D.B. Ramachary, Org. Lett. 20 (2018) 6979e6983;
(b) A. Chan, K.A. Scheidt, J. Am. Chem. Soc. 129 (2007) 5334;
(c) E.M. Phillips, T.E. Reynolds, K.A. Scheidt, J. Am. Chem. Soc. 130 (2008) 2416;
(d) T. Das, M. Sau, B. Daripa, D. Karmakar, S. Chakraborty, Chem. Select 5
(2020) 7605e7626;
(e) Y. Zhu, Y. Huang, Synthesis 52 (2020) 1181e1202.
[10] (a) M. Wang, Z. Huang, J. Xu, Y.R. Chi, J. Am. Chem. Soc. 136 (2014) 1214;
(b) J. Wu, C. Mou, Y.R. Chi, Chin. J. Chem. 36 (2018) 333;
(c) H. Wang, X. Chen, Y. Li, J. Wang, S. Wu, W. Xue, S. Yang, Y.R. Chi, Org. Lett.
20 (2018) 333;
3.22e3.29 (m, 1H), 2.90e2.71 (m, 3H); 13C NMR (100 MHz, Chlo-
roform-d)
d 163.0, 148.7, 136.6, 129.2, 128.0, 127.3, 127.2, 125.2,
124.5, 122.3, 119.3, 64.9, 58.4, 56.4, 49.8, 48.4, 35.7; HRMS
(ESI):C19H16Cl2N2O2Naþ [MþNa]þCalcd 397.0481, Found 397.0493.
Declaration of competing interest
The authors declare no competing financial interest.
Acknowledgements
(d) B. Liu, W. Wang, R. Huang, J. Yan, J. Wu, W. Xue, S. Yang, Z. Jin, Y.R. Chi, Org.
Lett. 20 (2018) 260;
(e) D.-C. Bai, T. Xu, C.-R. Ma, X. Zheng, B.-X. Liu, F. Xie, X.-W. Li, ACS Catal. 8
(2018) 4194e4200;
(f) M. Sau, K. Verma, T. Das, J. Heterocycl. Chem. (2020) 1e13.
[11] Q.-Q. Yang, X. Yin, X.-L. He, W. Du, Y.-C. Chen, ACS Catal. 9 (2019) 1258e1263.
[12] (a) W. Chen, X.-H. Yuan, R. Li, W. Du, Y. Wu, L.-S. Ding, Y.-C. Chen, Adv. Synth.
Catal. 348 (2006) 1818;
(b) W. Chen, W. Du, Y.Z. Duan, Y. Wu, S.Y. Yang, Y.-C. Chen, Angew. Chem. Int.
Ed. 46 (2007) 7667.
[13] (a) R. Grigg, W. Dowling, W.W. Jordan, V. Sridwaran, Tetrahedron 43 (1987)
5873;
(b) Y. Shimizu, M. Miki Hayashi, K. Teramura, J. Org. Chem. 52 (1987) 2277;
(c) W. Oppolzer, Tetrahedron Lett. 35 (1970) 309.
[14] Y. Li, Y. Meng, X. Meng, Z. Li, Tetrahedron 67 (2011) 4002e4008.
[15] H. Lee, D. Kang, S.H. Han, R. Chun, A.K. Pandey, N.K. Mishra, S. Hong, I.S. Kim,
Angew. Chem. Int. Ed. 58 (2019) 9470e9474.
We gratefully acknowledge the financial support from National
Natural Science Foundation of China (21776318 and 81703365).
Natural Science Foundation of Hunan Province (2018JJ3868 and
2020JJ4682), and Central South University. Compound character-
ization was supported by the Open Sharing Fund for the Large-scale
Instruments and Equipments of Central South University.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.131992.
[16] (a) J.-A. Xiao, Q. Liu, J.-W. Ren, J. Liu, R.G. Carter, X.-Q. Chen, H. Yang, Eur. J. Org
Chem. (2014) 5700e5704;
(b) Z.-X. Deng, Z.-Z. Xie, Y. Zheng, J.-A. Xiao, R.-J. Wang, H.-Y. Xiang, H. Yang,
Org. Biomol. Chem. 17 (2019) 2187e2191;
(c) Y.-L. Qian, P.-J. Xia, J. Li, Q.-L. Zhao, J.-A. Xiao, H.-Y. Xiang, H. Yang, Org.
Biomol. Chem. 15 (2017) 8705e8708.
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5