Rapid abnormal [3+2]-cycloaddition of isatinN,N′-cyclic azomethine imine 1,3-dipoles with chalcones

Article abstract of DOI:10.1039/d0nj00887g

The rapid synthesis of novel dicyclic spiropyrrolidine was reported, using [3+2]-cycloaddition of isatinN,N′-cyclic azomethine imine 1,3-dipoles, generated from the condensation of substituted isatins and pyrazolidones, with chalcones in 2-5 min. The dicy

Full text of DOI:10.1039/d0nj00887g

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DOI: 10.1039/D0NJ00887G
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Rapid abnormal [3+2]‐cycloaddition of isatin N,N’‐cyclic
azomethine imine 1,3‐dipoles with chalcones
Guizhou Yue,*a† Zhengjie Dou,a† Zexi Zhou,a Li Zhang,a Juhua Feng,a Huabao Chen,b Zhongqiong Yin,c
Received 00th January 20xx,
Accepted 00th January 20xx
Xu Song,c Xiaoxia Liang,c Xianxiang Wang,a Hanbing Raoa and Cuifen Lu*d
DOI: 10.1039/x0xx00000x
The rapid synthesis of novel dicyclic spiropyrrolidine was reported, using [3+2]‐cycloaddition of isatin N, N’‐cyclic azomethine
imine 1,3‐dipoles, generated from the condensation of substituted isatins and pyrazolidones, with chalcones in 2‐5 min. The
dicyclic spiropyrrolidine oxoindole were smoothly acquired in moderate to excellent yileds (35‐95%) with high
diastereoselectivities (>20:1 dr).
www.rsc.org/
Introduction
Heterocycles are privileged structural units that are frequently
encountered in biologically active natural products as well as in
pharmaceuticals and agrochemicals.1 In particular, dinitrogen‐
fused heterocycles are the core moieties in many biologically
active compounds. The N, N‐bicyclic pyrazolidinone skeletons
are not only structurally interesting but also have been
investigated as antibiotics,2 antitumor agents,3 pesticides and
herbicides,4 calcitonin agonists5 and potent drugs to relieve
Alzheimer’s disease (Fig. 1).6 On the other hand, various
derivatives of spiroprrolidine oxindole possess diverse
activities,7 for example antitumor,8 antibacterial,9 antifungal,10
antiviral,11 and local anaesthetic12 activities (Fig. 1). Therefore,
to explore the practical and efficient methods for the synthesis
of dinitrogen‐fused heterocycles have attracted much attention
between organic and pharmaceutical chemists around the
world. Undoubtedly, the 1,3‐diploar cycloaddition of
azomethine imines (divided into four groups: acyclic imines, C,
N‐cyclic imines, N, N’‐cyclic imines and C, N, N′‐cyclic imines)
was one of the most popular methods among various
protocols.13 The N, N′‐cyclic azomethine imines, prepared easily
by the condensation of pyrazolidine‐3‐one with carbonyl
compounds, have been widely applied in all kinds of
cycloaddition reactions, such as [3+1], [3+2], [3+3], [3+2+1],
[4+3] and [3+2+3] types, and other reactions.14
Fig. 1. Representatives of bioactive pyrazolone and spirospyrrolidine
oxindole derivatives ( ).
I‐V
Very recently, Wang and co‐workers15 reported the elegant
synthesis of tricyclic spiropyrrolidine oxindoles via an
unexpected abnormal [3+2]‐cycloaddition of isatin N, N′‐cyclic
azomethine imines with maleimide catalyzed by 1,4‐
diazabicyclo‐[2.2.2]octane (DABCO), which generated 22
corresponding products in moderate to excellent yields (53‐
96%) and low to high diastereoselectivities (2.4:1‐32.3:2 dr).
However, this method had a large limitation that N‐
unsubstituted isatin N, N′‐cyclic azomethine imines only
obtained trace amount of product. To date, the reactions of
isatin N, N′‐cyclic azomethine imines were rarely studied and
demonstrated by only a few of examples (dipolarophiles: β‐
nitrostyrenes, MBH carbonates, o‐chloromethylaryl amides and
Knoevenagel adducts).16 So, to explore the new 1,3‐diploar
cycloaddition of isatin N, N′‐cyclic azomethine imines become
be urgent. As far as we know, the 1,3‐diploar cycloaddition of
isatin N, N′‐cyclic azomethine imines with chalcones has not
been reported so far. Chalcones can be easily prepared by the
condensation of arylaldehydes and arylmethyl ketones under
basic conditions,17 so that they are used largely in organic
synthesis as synthons. Furthermore, chalcone derivatives by
themselves also exhibited broad bioactivities,18 such as anti‐
infective, anticancer, anti‐inflammatory and antileishmanial.
Based on our previous studies of 1,3‐diploar cycloaddition and
a. College of Science, Sichuan Agricultural University, Ya’an, Sichuan, 625014, China.
E‐mail: yueguizhou@sicau.edu.cn
b. Address here. College of Agricultural Sciences, Sichuan Agricultural University,
Chengdu, Sichuan, 611130, China.
c. College of Veterinary Medicine, Sichuan Agricultural University, Chengdu,
Sichuan, 611130, China.
d. Hubei Collaborative Innovation Center for Advanced Organochemical Materials &
Ministry‐of‐Education Key Laboratory for the Synthesis and Application of Organic
Functional Molecules, Hubei University, Wuhan 430062, China. E‐mail:
lucf@hubu.edu.cn
† These two authors contributed equally to this work and are joint first authors.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Michael addition with chalcones,19 We have described herein 4). Except for TLC analysis, the reaction progress was also
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rapid protocols for the synthesis of novel bicyclic oxoindole monitored directly by colour changesDoOfI: 1t0h.e103s9o/Dlu0tNioJn008(8se7Ge
derivatives via the abnormal [3+2] cycloaddition of isatin N, N′‐ supporting information). Next, to further improve the yield,
cyclic azomethine imines from the condensation of isatin and various bases were screened. Common tertiary amines TEA and
pyrazolidones with chlacones in 2‐5 min.
DABCO also gave the cycloadducts in lower yields (entries 5 and
6). We made our attention to inorganic bases. Cs2CO3, Na2CO3
and KHCO3 provided the adducts in 21‐50% yields (entries 7‐11),
and then stronger bases, such as NaOH, EtONa, t‐BuOK, also
showed worse results than K2CO3 (entries 12‐14). Therefore,
K2CO3 was a best one. Furthermore, we examined the
equivalents of base and 4‐nitrochalcone, and the reaction
concentration (entries 15‐17). Both reduction of base and
enhance of reaction concentration drop the yields off
dramatically, while in excess of 2a (2 equiv.) the yield improved
Results and discussion
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In the beginning of our study, isatin N, N’‐cyclic azomethine
imine 1a and 4‐nitrochalcone 2a were chosen as model
substrates to search for efficient systems (Table 1). Initially, we
carried out the reaction in the presence of DABCO in CHCl3 at rt
to refluxing reported by Wang.15 Unfortunately, the reaction
did not give the predicted product 3a (entry 1). After many trials,
we found that the reaction proceeded rapidly and obtained 3a
in 31% yield in the present of 2.0 equiv. K2CO3 in DMF (entry 2).
The above result prompted us to further optimize the reaction.
First, various solvents were tested. Solvents, including EtOH,
toluene, THF, DCM and dioxane, did not work at all, while DMA
led to 44% yield (entry 3). More polar DMSO showed the better
result that the reaction finished in only 3 minutes and obtained
3a in 67% yields with high diastereoselectivity (> 20:1 dr) (entry
Table 1. The condition optimization of model reaction.a
Table 2. Synthesis of dicyclic spiropyrrolidine oxindoles
N’‐cyclic azomethine imine
and 4‐nitrochalcones 2 a
3
from isatin N,
1
.
Yield
(%)b,c
88
Entry
Compound
R
R1
Ar1
C6H5
4‐MeC6H4
2‐
MeOC6H4
4‐
1
2
3a
3b
H
H
H
H
H
H
65
3
3c
61
H
H
4
3d
78
MeOC6H4
2‐FC6H4
3‐FC6H4
4‐FC6H4
2‐ClC6H4
3‐ClC6H4
4‐ClC6H4
2‐BrC6H4
4‐BrC6H4
2‐furanyl
2‐thienyl
2‐Py
5
6
7
8
3e
3f
3g
3h
3i
3j
3k
3l
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
91
86
Entry
1
Reaction Condition
Yield (%)b
NRd
drc
95 (90)d
64
DABCO, CHCl3, overnight, rt to
reflux
e
‐
9
73
89
85
93
82
81
53
e
2
K2CO3, DMF, 15 min
K2CO3, DMA, 5 min
31
44
67
41
60
21
43
32
49
50
49
45
23
46
55
‐
10
11
12
13
14
15
e
3
‐
4
K2CO3, DMSO, 3 min
TEA, DMSO, 4 min
>20:1
e
3m
3n
3o
5
‐
6
DABCO, DMSO, 3 min
Cs2CO3, DMSO, 8 min
Na2CO3, DMSO, 20 min
Li2CO3, DMSO, 30 min
KHCO3, DMSO, 15 min
NaHCO3, DMSO, 35 min
NaOH, DMSO, 2 min
EtONa, DMSOf, 2 min
t‐BuOK, DMSOf, 2 min
1.0 equiv. K2CO3, DMSO, 3 min
K2CO3, 1.5 mL DMSO, 5 min
K2CO3, 2.0 equiv. 2a, DMSO, 3
min
>20:1
e
7
‐
3,4‐
8
16
3p
(OMe)2C6H 81
3
e
9
‐
17
18
19
20
21
22
23
24
25
26
27
28
29
3q
3r
3s
3t
3u
3v
3w
3x
3y
H
H
H
H
H
H
H
Bn
Et
allyl
propinyl
n‐C7H15
H
H
H
H
H
H
H
2,4‐Cl2C6H3 72
e
10
11
12
13
14
15
16
‐
4‐FC6H4
4‐FC6H4
4‐FC6H4
4‐FC6H4
4‐FC6H4
4‐FC6H4
4‐FC6H4
4‐FC6H4
4‐FC6H4
4‐FC6H4
4‐FC6H4
4‐FC6H4
66
73
76
84
61
78
67
93
83
80
73
50
e
‐
e
‐
‐
e
e
‐
‐
5‐Me
5‐OMe
5‐F
5‐Cl
6‐Br
5‐I
e
e
‐
3z
17
85
>20:1
3aa
3ab
3ac
aUnless otherwise indicated, the reaction was performed at the 0.5 mmol
scale in a solvent (3.0 mL) with base (2.0 equiv.), and the molar ratio of 1a 2a
was 1:1. bisolated yield. The selectivity was determined by H NMR. dNo
7‐CF3
:
aReaction conditions: 1a (1.0 mmol),
2 (2.0 mmol), K2CO3 (2.0 mmol), and
c
1
DMSO (6.0 mL), rt, 2‐5 min. bIsolated yield via column chromatography. cThe
selectivity (>20:1 dr) was determined by 1H NMR. dThe yield of gram scale for
1a (9.8 mmol), reaction time: 10 min.
e
f
reaction. The selectivity was not determined. The solvent was pre‐dried
with CaH2. DABCO: 1,4‐diazabicyclo[2.2.2]octane; DMSO: dimethyl sulfoxide;
DMF: N,N‐dimethylformamide; DMA: N,N‐dimethylacetamide.
2 | J. Name., 2012, 00, 1‐3
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to 85% (entry 17). Unfortunately, the yield hardly increased oxidized to 6a (72% yield) in the present of DDQ,VaienwdArrtieclde uOcnleinde
with 3 equiv. or even more of 2a. Finally, considering all of the to 6b (69% yield) under the condition of DNOaIB: H104..1039/D0NJ00887G
active parameters, the optimal reaction condition for the 1,3‐
dipolar cycloaddition was established as isatin N, N′‐cyclic
azomethine imine 1a (1 equiv.), chalcone 2a (2.0 equiv.) and
base K2CO3 (2.0 equiv.) in DMSO at 20oC within only 3 minutes.
9
After the optimal reaction conditions were established, a wide
range of different substituted aryl 4‐nitrochalcones were
explored for this reaction. As summarized in Table 2, the
reaction of 1a with 2a under 1 mmol scale under the most
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optimal conditions to give higher yields of cycloaddition (88%). Scheme 1. Synthesis of dicyclic spiropyrrolidine oxindoles
5 from isatin
When Ar1 was electron‐donating groups methyl‐ or N, N’‐cyclic azomethine imine
methoxylphenyl, the yields significantly reduced (entries 2‐4).
On the whole, the yields were consistent with 2a (85‐95%,
entries 5‐7 and 10‐12), while Ar1 were halogenphenyl groups,
except for 2‐ and 3‐ClC6H4. Among them, 4‐fluorophenyl group
obtained the highest yield (3g, 95%) (entry 7). Electron‐rich
heteroaryl, and disubstituted chalcones also have a good
performance in the standard reaction conditions (entries 13, 14,
16 and 17), but 2‐pyridinyl one gave 53% yield. Next, we chose
1 and 4‐subsititued chalcones 4.
4‐nitro‐4‐fluorochalcone and substituted N, N’‐cyclic Scheme 2. deriverziation of 3g
.
azomethine imine at N‐atom or aromatic ring of isatin segement To achieve an asymmetric version of the present reaction, two chiral
as substrates to carry out this reaction. When R1 was Bn, Et, allyl, catalysts (20 mol%), L‐proline and quinine, were screened in the
nC7H15 and R was H, unfortunately, all yields of the reactions model reaction of 3a. All reactions were finished completely at 60oC,
dramatically dropped off (entries 18‐22). Aromatic ring bearing while they hardly proceeded at rt. Unfortunately, the catalysts were
various substitution (R= halogen, Me and OMe) of
1 also led to not suitable for this reaction (48 and 81% yields; 13 and 11% ee).
lower yields, except 5‐F group (entries 23‐29), and 7‐CF3‐ On the basis of the literature reports,15,21 the experimental
substituted azomethine imine generated the cycloadducts in results and X‐ray analysis, plausible reaction pathways are
lowest yield (entry 29). It was worth noting that all the above proposed as illustrated in Scheme 3. The reaction may be
reactions had high diastereoselctivites (> 20:1 dr). Furthermore, initiated by the resonance form
the structure and stereochemistry of products were under a base, the delocalized intermediate II was formed.
confirmed unambiguously by the single crystal X‐ray diffraction Intermediate II transformed to the more stable resonance form
of 3t (Fig. 2).20 We also carried out the reaction of 1a and 4‐ III, which reacted with chalcone
or to give the final product
via 1,3‐dipolar cycloaddition. Path A leads to the
formation of the exo‐cycloadducts P1 or ), whereas path B
I of 1a. After tautomerism
3
2
4
nitro‐4’‐fluorochane on the gram scale, to offer 3g without a
3 or 5
significant loss in yield (90%).
(
3
5
affords the endo‐products P2. The observed major product P1
might be explained by the two carbonyls of the products are
trans to each other to minimize electrostatic repulsion, along
with avoiding steric effect of pyrazolidone and Ar2 groups.
O
O
HO
HO
N
N
HN
HN
N
B:
N
N
N
O
O
O
O
N
H
N
N
H
N
H
H
I
II
III
HO
Ar2
O
O
Ar2
Ar1
HN
Ar2
Fig. 2. X‐ray crystal structure of 3t.
HN
N
Ar1
Ar1
exo
N
O
In order to further expand the practicality of the method, we
selected other substituents instead of nitro group in 4’‐position
of chalcones (Scheme 1). Whereas, the yields dropped
dramatically to 35 and 43% respectively, when R was H or
methyl. Conversely, the reactions all worked well and provided
71‐84% yields, when R were electron‐withdrawing groups
(halogen and CN), except for COOMe group. To demonstrated
the synthetic value of this 1,3‐diploar cycloaddition, we tried to
transform 3g into other compounds (Scheme 2). 3g was
N
N
path A
O
H
O
O
O
O
N
H
N
N
H
H
P1 (3 or 5)
HO
Ar2
O
O
Ar2
Ar1
Ar2
O
HN
HN
N
Ar1
endo
N
O
N
N
path B
Ar1
H
O
O
O
N
N
H
N
H
P2
O
H
Scheme 3. The plausible reaction mechanism.
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