An Efficient Synthesis of Spiropyrroloquinolines by the Domino Reaction of α-Dicarbonyl Compounds and Anilinosuccinimides

Article abstract of DOI:10.1002/ejoc.201701356

A domino annulation reaction of various α-dicarbonyl compounds with anilinosuccinimides takes place with Br?nsted-acid catalysis under microwave irradiation to give functionalized spiropyrroloquinolines. The reaction involves activation of the ortho hydrogen of the different aniline derivatives.

Full text of DOI:10.1002/ejoc.201701356

A Journal of
Accepted Article
Title: An Efficient Synthesis of Spiropyrroloquinolines by Domino
Reaction of α-Dicarbonyl Compounds and Anilinosuccinimides
Authors: Chao-Guo Yan, Man Xiao, Qiu Sun, and Jing Sun
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10.1002/ejoc.201701356
European Journal of Organic Chemistry
FULL PAPER
An Efficient Synthesis of Spiropyrroloquinolines by Domino
Reaction of α-Dicarbonyl Compounds and Anilinosuccinimides
Man Xiaoa, Qiu Suna, Jing Suna, and Chao-Guo Yana*
anticonvulsant activity, sirtuin activation, and inhibition.9,10
Because of the intense utility of these two cores, several
groups have paid their full attention on the development of
the synthetic methodology for the synthesis of
spiro[dihydropyridineoxindoles].11,12 In recent years, domino
Abstract: Under the catalysis of Brønsted acid, the domino
annulation reaction of different α-dicarbonyl compounds with
or tandem processes have become an efficient method for
anilinosuccinimides
under
microwave
irradiation
afforded
the synthesis of various spirooxindoles due to its simple
process, easy operation, efficiency and high atomic
economy.13 The cascade reaction of isatins with β-
enaminones is one of convenient way for synthesis of these
useful spiro[dihydropyridineoxindoles]. However, we found
very few examples on the synthesis of this spiro core
involving the activation of ortho-H in different aniline
derivatives.14,15,16 To synthesis this useful products efficiently
and under green chemical conditions, with our continuous
functionalized spiropyrroloquinolines involving the activation of ortho-
H in different aniline derivatives.
Introduction
Recently, the development of spiro compounds has emerged
as a field of strong attention owing to their attractive
conformational features, potential medicinal applications,
catalysis, and optical materials.1 Spirooxindolines which
comprise many natural products, pharmaceuticals and
biologically active molecules2, containing biological activities,
which include cholinesterase inhibition,3 anticancer,4
antibacterial,5 and anti-inflammatory activities.5 Among them,
some alkaloids like horsifiline, alstonisine,6 and
effort,
we
have
successfully
synthesized
spiro[dihydropyridineoxindole] derivatives using substituted
anilinosuccinimides with various α-dicarbonyl compounds by
domino reaction where the ortho-attack of the aniline system
occurs to form the spiro center under microwave irradiation.
spirotryprostatins
A and B, isolated from the fermentation
Results and Discussion
broth of Aspergillus fumigatus, were found to completely
inhibit the G2/M progression of cellular division in
mammalian tsFT210 cells (Figure 1).7
Initially, we set the reaction of 4-methoxy-anilinosuccinimide
(1a) and 1-benzyl-5-chloro-indoline-2,3-dione (2a) as the
O
model reaction for optimizing reaction conditions. Various
solvents, the ratio of solvent, temperature and reaction time
were examined (Table 1). In the first attempt, 1,4-Dioxane
and Ac2O was used for this reaction under microwave
irradiation at 120 oC, the reaction scarcely proceeded to give
desired product 3a (Table 1, entry 1). To our pleased, when
Ac2O was changed to AcOH, spiropyrroloquinolines 3a was
isolated in 62% yield, which is different from the [3+2] type
cyclization frequently reported (entry 2), eventually, the
structural of single crystal 3a was unequivocally determined
by X-ray diffraction (Figure 1). Encouraged by this result,
other reaction conditions were detailly optimized.
Experiments were carried out in different acidic sysytem
solvents of p-TsOH/Diox, AcOH/Tol, AcOH/CAN and
AcOH/EtOH, which were found to be inefficient for this
transformation (entries 3-6). Raise the temperature to 150 oC,
desired product 3a could been isolated in 86% yield (entry 7).
Prolonging reaction time to 30 minutes led to the same yield
(entry 8). Meanwhile, different ratio of co-solvents resulted
in lower yield of 43% and 28% (entries 9-10). The reaction
cannot proceed in a single solvent of 1,4-Dioxane or AcOH
(entries 11-12), and also cannot proceed without microwave
irradiation (entry 13). On the basis of these results, we found
Me
N
N
H
H
O
H
O
H
Me
N
O
O
O
H
N
NH
N
H
O
H
O
N
O
O
N
Me
H
N
N
MeO
MeO
H
H
Spirotryprostatin B
Spirotryprostatin A
horsfiline
alstonisine
Figure. 1 Examples of natural products and synthetic therapeutic agents
containing spiroxindole core
On the other hand, 1,4-dihydropyridines are of particular
interest, owing to their biological and pharmacological
actions. First of all, they represent one of the most important
groups of calcium-channel modulating agents and they are
used in the treatment of cardiovascular diseases.8 In addition,
it is also the common core structure of various biologically
active compounds having selective adenosine-A3 receptor
antagonism,
along
with
radioprotective
activity,
a. [a] College of Chemistry and Chemical Engineering, Yangzhou University,
Yangzhou, 225002, China. E‐mail: cgyan@yzu.edu.cn
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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10.1002/ejoc.201701356
European Journal of Organic Chemistry
FULL PAPER
that the optimized reaction conditions for the domino reaction
was in the co-solvents of Diox/AcOH with the ratio of 1:1
under microwave irradiation for approximately 20 minutes at
150 oC.
indoline-2,3-diones under established conditions, and
afforded the expected spiropyrroloquinolines 3b–3q in
moderate to good yields of 65–85% (Table 2, entries 1-15).
The substituent on the other position seems to influence the
results, due to the steric effect, reactions of o-methyl-
anilinosuccinimide gave 3c in only 65% yield (entry 2).
However, anilinosuccinimide bearing electron-withdrawing
substituents, showed poor activity even after prolonged
reaction time of 1 h (entries 17-18). Apparently, the reaction
is currently limited to electron-rich anilinosuccinimide. On the
other hand, both electron-rich (entries 3, 9, 11, and 15) and
electron-deficient (entries 1-2, 4-8, 10, 12, 14-15) indoline-
2,3-dione led to the desired spiropyrroloquinolines in more
than 65% yields. The substituents on N atom also does not
seem to influence the results (entries 1-15). The structures
of the compounds 3a-3o were fully characterized by IR,
Table 1. Reaction Optimization for the Synthesis of 3aa
H
N
O
O
O
H
H3CO
Cl
N
Cl
Conditions
N
CH3
N
CH3
O
H3CO
N
Bn
O
O
N
O
Bn
3a
1a
2a
Entry
Acid/Solvent
Ac2O/Diox
AcOH/Diox
p-TsOH/Diox
AcOH/Tol
AcOH/CAN
AcOH/EtOH
AcOH/Diox
AcOH/Diox
AcOH/Diox
AcOH/Diox
Diox
Ratiob
T (oC)
t (min)
20
Yield (%)c
Trace
62
1
2
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
2:1
1:2
-
120
120
120
120
120
120
150
150
150
150
150
150
150
20
3
20
Trace
Trace
Trace
Trace
86
1
HRMS, H and 13C NMR spectroscopy. The single-crystal
4
20
structures of the spiro compounds 3e, 3g and 3o (Figure S1-
5
20
S3) were successfully determined by X-ray diffraction.
6
20
Table 2. Substrate scope 3b-ra
7
20
H
N
8
30
86
O
O
O
H
R1
R2
R2
N
9
20
43
Diox/AcOH
MWI
N
CH3
O
N
CH3
N
R3
R1
10
11
12
13d
20
28
O
O
N
O
R3
20
trace
trace
trace
1
2
3b-r
AcOH
-
20
AcOH/Diox
1:1
20
Entry
1
Compd
R1
R2
Cl
R3
Bn
Bn
Yield (%)b
78
aReaction conditions: 1a anilinosuccinimide (0.5 mmol), 2a 1-
3b
3c
3d
3e
3f
H
benzylindoline-2,3-dione (0.5 mmol), solvent (2 mL) under microwave
2
o-CH3
F
65
irradiation
dWithout microwave irradiation.
.
bThe ratio of the amount of solvent and acid; cIsolated yield.
3
m-CH3
m-CH3
CH3
Cl
C4H9
Bn
76
4
78
5
p-CH3
Cl
H
80
6
3g
3h
3i
p-CH3
Cl
Bn
82
7
p-CH3
F
Bn
85
8
p-CH3
Cl
C4H9
C4H9
C4H9
H
82
9
3j
m-OCH3
m-OCH3
p-OCH3
p-OCH3
p-OCH3
p-OCH3
p-C(CH3)3
p-F
CH3
Cl
77
10
11
12
13
14
15
16c
17c
3k
3l
75
CH3
Cl
76
3m
3n
3o
3p
3q
3r
H
72
H
Bn
78
F
Bn
86
CH3
CH3
CH3
C4H9
Bn
82
Trace
Trace
Figure. 1 Molecular structure of compound 3a
p-Br
Bn
aReaction conditions:
V(Diox/AcOH) = 1:1) under microwave irradiation at 150 oC , 20 mins;
bIsolated yield; c1h reaction time.
1
(0.5 mmol), 2 (0.5 mmol), solvent (2 mL,
With the optimized reaction conditions (Table 1, entry 7) in
hand, we examined the substrate scope. The results are
summarized in Table 2. Derivatives of anilinosuccinimide
bearing different electron-donating substituents at ortho-,
meta-, or para-positions reacted smoothly with various
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10.1002/ejoc.201701356
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For developing the scope of this reaction, other α-dicarbonyl
compounds were also used in the reaction. As to ninhydrin,
the results were summarized in Table 3. For
anilinosuccinimide bearing a single electron-donating group,
the expected spiro compounds were obtained in yields of
68−87% (Table 3, entries 2-7). The reaction showed its limit
with the bulkier o-methyl-anilinosuccinimide, which resulted
in the corresponding spiro compounds (5b) in 65% yield. It is
worth mentioning that anilinosuccinimide bearing electron-
withdrawing group at the meta or para position resulted in the
spiro products in 70-76% yields. However, these results
could not be observed in other α-dicarbonyl compounds. The
When acenaphthequinone was employed in the reaction,
we found that the reaction proceeded sluggishly in the above
mentioned system of AcOH/Diox. When acetic acid was
used both as acid catalyst and solvent, the expected spiro
compounds were prepared in satisfactory yields. The results
are summaried in Table 4. For anilinosuccinimide bearing a
single electron-donating group at the meta or para position,
good yields of 74−82% were obtained (Table 4, entries 2-6).
Only trace yield was obtained for the bulkier substrate with
substituent at the ortho position and anilinosuccinimide
bearing with electron-withdrawing groups. Meanwhile, the
structures of the compounds 7a-7f were also fully
structures of the compounds 5a
-
5k were fully characterized
characterized by IR, HRMS, 1H and 13C NMR spectroscopy.
The single-crystal structures of the spiro compound 7d
(Figure S5) was successfully determined by X-ray diffraction.
by IR, HRMS, H and 13C NMR spectroscopy. The single-
crystal structures of the two spiro compounds 5b (Figure. 3)
and 5c (Figure. S4) were successfully determined by X-ray
diffraction.
1
Table 4 Substrate scope 7a-fa
O
H
Table 3 Substrate scope 5a-ka
N
O
H
N
R
N
O
CH3
O
MWI/AcOH
O
H
R
N CH3
+
O
N
O
O
O
O
H
N
N
CH3
R
MWI / 150 oC
O
1
R
6
O
+
N
CH3
O
AcOH
1,4-dioxane
O
O
7a g
-
O
Entry
Compd
7a
R
H
Yield (%)b
68
4
1
1
2
5a k
-
Yield (%)b
7b
m-CH3
74
Entry
1
Compd
5a
R
H
3
7c
p-CH3
m-OCH3
p-OCH3
p-C(CH3)3
p-F
80
82
68
77
84
78
87
82
73
76
70
72
4
7d
76
2
5b
5c
o-CH3
m-CH3
p-CH3
m-OCH3
p-OCH3
p-C(CH3)3
m-Cl
5
7e
82
3
6
7f
78
4
5d
5e
7c
8c
7g
trace
trace
5
7h
p-Cl
6
5f
7
5g
5h
5i
aReaction conditions:
1 (0.5 mmol), 2 (0.5 mmol), AcOH as solvent (2 mL)
under microwave irradiation at 150 oC, 20 mins; bIsolated yield; c1h reaction
time.
8
9
p-Cl
To demonstrate the utility of the reactions, we also carried
10
11
5j
m-Br
out the reaction of indoline-2,3-diones ( ) with 5,5-dimethyl-
2
5k
p-Br
3-(phenylamino)cyclohex-2-en-1-one (8) with different
aReaction conditions:
1 (0.5 mmol), 4 (0.5 mmol), solvent (2 mL,
substituents under microwave irradiation. The results are
listed in Table 5. The reaction proceeded smoothly for both
electron-rich (Table 5, entry 5) and electron-deficient (entries
1-4) indoline-2,3-diones in more than 67% yields. Similarly,
the reaction also limited to electron-rich 5,5-dimethyl-3-
(phenylamino)cyclohex-2-en-1-one. The indoline-2,3-dione
without substituent at N atom shows lower reactivity than
those substituted isatins at N atom (entry 6). This finding is
totally different from those of reactions reported by Shi et al.,
in which only pyrrolo[2,3,4-kl]acridin-1-one derivatives
products were formed in refluxing condition catalyzed by L-
proline.12b The single crystal structure of the compound 9a
(Figure 4) and 9c (Figure S6) were also determined by X-ray
V(Diox/AcOH) = 1:1) under microwave irradiation at 150 oC , 20 mins;
bIsolated yield.
Figure. 3 Molecular structure of compound 5b
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10.1002/ejoc.201701356
European Journal of Organic Chemistry
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O
H
N
diffraction method. These results reveal that the reaction
have a wide variety of substrates.
R1
R3
O
O
H
N
N
OH
R3
HOAc
R1
Table 5 Substrate scope 9a-fa
+
O
N
O
O
N
R2
N
R2
H
N
O
O
H
N
R1
R3
R1
1
2
O
A
MWI
O
O
H
N
AcOH,
1,4-dioxane
O
O
H
N
R2
O
R3
N
R1
N
H+/ MWI
- H2O
F-C
R2
R1
R3
N
N
R3
2
8
9a f
-
O
O
O
O
N
N
R2
Entry
Compd
9a
R1
Cl
R2
Bn
R3
Yield (%)b
R2
1
2
3
4
5
6
p-OCH3
p-OCH3
p-OCH3
p-CH3
76
78
71
74
67
51
B
3
9b
F
Bn
9c
Cl
C4H9
Bn
Scheme 1 Plausible reaction mechanism for domino reaction
9d
Cl
9e
CH3
CH3
C4H9
H
p-CH3
Conclusions
9f
p-OCH3
aReaction conditions:
2 (0.5 mmol), 8 (0.5 mmol), solvent (2 mL,
In summary, we have successfully established a facile and green
domino annulation reaction for the synthesis of functionalized
spiro[dihydropyridine-oxindoles]. The synthesized spiro system
here involves the activation of ortho-H atom of various aniline
derivatives. All different α-dicarbonyl compounds studied with
good chemoselectivity under microwave irradiation. This domino
reaction established a very practical application for the domino C–
C coupling reaction in organic synthesis. Further studies on
V(Diox/AcOH) = 1:1) under microwave irradiation at 150 oC , 20 mins;
bIsolated yield.
domino
coupling
reactions
for
the
synthesis
of
spiro[dihydropyridine-oxindoles] and the effective of biological
activity about these useful products are in progress in future
studies.
Experimental Section
Figure. 4 Molecular structure of compound 9a
1. General procedure for the synthesis of 3: 1-methyl-3-(phenylamino)-
1H-pyrrole-2,5-dione (1 mmol), indoline-2,3-dione or 1H-indene-1,2,3-
trione (1 mmol), acetic anhydride (1 mL) and dioxane (1 mL) were
introduced in a 10 mL initiator reaction vial. Subsequently, the reaction vial
was capped and then pre-stirring for 20 second. The mixture was irradiated
(Time: 20 min, Temperature: 150 oC; Absorption Level: High; Fixed Hold
Time) until TLC (petroleum ether: ethyl acetate 4:1) revealed that
conversion of the starting material 1was completed. The reaction mixture
was then cooled to room temperature and then diluted with cold water (25
mL). The solid product was collected by Büchner filtration and was washed
with 95% EtOH to give almost pure 3 and 5. The solid was further purified
by flash column chromatography (silica gel, mixtures of ethyl acetate / n-
hexane, 4:1, v/v) for its NMR and HRMS analysis.
The mechanism hypothesis for these reactions was
proposed and shown in Scheme 1. Firstly, the nucleophilic
addition of anilinosuccinimide to the carbonyl group of isatin
afforded the intermediate A. In the presence of acetic acid
and microwave irradiation, a carbocation
B was generated in
the system. Then, the further intramolecular Friedel–Crafts
alkylation gave the final spiro compound. Apparently, the
reaction could not compatible with the electron-withdrawing
groups on the β-enaminone and no spiro compound was
obtained. This finding is totally different from that of reaction
between β-enaminone with dicarbonyl compounds under
other conditions.
1-benzyl-5-chloro-7'-methoxy-2'-methylspiro[indoline-3,9'-
pyrrolo[3,4-b]quinoline]-1',2,3'(2'H,4'H)-trione (3a). Yellow solid, 82%,
m.p. >300 oC; 1H NMR (400 MHz, DMSO-d6) δ: 10.97 (s, 1H, NH), 7.44 (d,
J = 7.6 Hz, 2H, ArH), 7.36 (t, J = 7.2 Hz, 2H, ArH), 7.30 (t, J = 7.6 Hz, 2H,
ArH), 7.27-7.22 (m, 2H, ArH), 6.94-6.92 (m, 1H, ArH), 6.70 (d, J = 8.2 Hz,
1H, ArH), 5.92 (s, 1H, ArH), 5.07-4.96 (m, 2H, CH2), 3.51 (s, 3H, OCH3),
2.83 (s, 3H, CH3); 13C NMR(100 MHz, DMSO-d6) δ:177.4, 169.1, 165.3,
156.6, 142.5, 140.7, 138.4, 136.3, 130.0, 129.0, 127.9, 127.7, 127.6, 125.3,
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10.1002/ejoc.201701356
European Journal of Organic Chemistry
FULL PAPER
123.7, 120.2, 115.2, 112.7, 111.3, 96.3, 55.6, 50.3, 43.6, 23.4; IR (KBr) υ:
3204, 2962, 1766, 1699, 1609, 1542, 1438, 1328, 1317,1229, 1174, 1083,
1036, 995, 877, 748, 701 cm-1; MS (m/z): HRMS (ESI) Calcd For
C27H20ClN3O4 ([M+Na]+): 508.1040. Found: 508.1026.
We are grateful to the National Natural Science Foundation of
China (No. 21572196) and the Priority Academic Program
Development of Jiangsu Higher Education Institutions for financial
support (No. BK2013016). The Analytical Center of Yangzhou
University is acknowledged for the analyticalassistance.
General procedure for the synthesis of 7: 1-methyl-3-(phenylamino)-
1H-pyrrole-2,5-dione (1 mmol), acenaphthequinone (1 mmol) and acetic
acid (2 mL) were introduced in a 10 mL initiator reaction vial. Subsequently,
the reaction vial was capped and then pre-stirring for 20 second. The
mixture was irradiated (Time: 20 min, Temperature: 150 oC; Absorption
Level: High; Fixed Hold Time) until TLC (petroleum ether: ethyl acetate
4:1) revealed that conversion of the starting material 1 was completed. The
reaction mixture was then cooled to room temperature and then diluted
with cold water (25 mL). The solid product was collected by Büchner
filtration and was washed with 95% EtOH to give almost pure 7. The solid
was further purified by flash column chromatography (silica gel, mixtures
of ethyl acetate / n-hexane, 4:1, v/v) for its NMR and HRMS analysis.
Keywords: domino annulation reaction• spiro[dihydropyridine-
oxindoles]• cyclization• microwave irradiation• chemoselectivity
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2'-methyl-2H-spiro[acenaphthylene-1,9'-pyrrolo[3,4-b]quinoline]-
1',2,3'(2'H,4'H)-trione(7a). Yellow solid, 68%, m.p. >300 oC; 1H NMR (400
MHz, DMSO-d6) δ: 10.91 (s, 1H, NH), 8.36 (d, J = 8.0 Hz, 1H, ArH), 8.07
(d, J = 7.2 Hz, 1H, ArH), 7.99 (d, J = 8.0 Hz, 1H, ArH), 7.91 (t, J = 8.0 Hz,
1H, ArH), 7.65 (t, J = 7.6 Hz, 1H, ArH), 7.36 (d, J = 6.8 Hz, 1H, ArH), 7.16
(t, J = 7.6 Hz, 1H, ArH), 6.74 (t, J = 7.6 Hz, 1H, ArH), 6.09 (d, J = 7.6 Hz,
1H, ArH), 2.72 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6) δ: 203.7, 165.4,
145.0, 142.3, 141.6, 136.5, 132.7, 132.5, 131.6, 130.2, 129.9, 129.4, 129.0,
128.9, 128.8, 128.4, 125.2, 124.8, 124.4, 123.7, 122.1, 121.6, 118.7, 100.6,
54.9, 23.3; IR(KBr) υ: 3248, 2917, 1764, 1707, 1663, 1527, 1468, 1359,
1207, 1032, 969, 804, 758 cm-1; MS (m/z): HRMS (ESI) Calcd For
C23H14N2O3 ([M+H]+): 367.1083. Found: 367.1098.
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2. General procedure for the synthesis of 9: 5,5-dimethyl-3-
(phenylamino)cyclohex-2-en-1-one (1 mmol), indoline-2,3-dione (1 mmol)
acetic anhydride (1 mL) and dioxane (1 mL) were introduced in a 10 mL
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1'-benzyl-5'-chloro-7-methoxy-3,3-dimethyl-3,4-dihydro-2H-
spiro[acridine-9,3'-indoline]-1,2'(10H)-dione(9a). White solid, 76%, m.p.
>300 oC; 1H NMR (400 MHz, DMSO-d6) δ: 9.76 (s, 1H, NH), 7.54 (d, J =
7.2 Hz, 2H, ArH), 7.35 (t, J = 7.6 Hz, 2H, ArH), 7.28 (t, J = 7.2 Hz, 1H, ArH),
7.17-7.14 (m, 1H, ArH), 6.98-6.96 (m, 1H, ArH), 6.85 (d, J = 7.2 Hz, 1H,
ArH), 6.83-6.82 (m, 1H, ArH), 6.81-6.79 (m, 1H, ArH), 5.92-5.91 (m, 1H,
ArH), 5.01-4.91 (m, 2H, CH2), 3.43 (s, 3H, OCH3), 2.52-2.51 (m, 2H, 2CH),
2.14-2.00 (m, 2H, 2CH), 1.06 (s, 3H, CH3), 1.03 (s, 3H, CH3); 13C NMR
(100 MHz, DMSO-d6) δ: 192.3, 179.2, 153.4, 141.4, 141.1, 137.1, 133.1,
132.7, 129.3, 128.9, 128.1, 127.8, 127.4, 126.7, 126.5, 123.0, 122.9, 116.6,
110.4, 103.8, 51.1, 50.4, 43.6, 41.0, 32.6, 28.6, 27.6, 20.7; IR(KBr)υ: 3066,
3111, 1695, 1595, 1496, 1345, 1169, 1032, 948, 881, 746 cm-1; MS (m/z):
HRMS (ESI) Calcd For C30H27ClN2O3 ([M+H]+): 498.1788. Found:
498.1801.
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Acknowledgements
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10.1002/ejoc.201701356
European Journal of Organic Chemistry
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10.1002/ejoc.201701356
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Entry for the Table of Contents
Man Xiao, Qiu Sun, Jing Sun, Chao-Guo
Yan*
Page No. – Page No.
Title
15 examples, 65-86%
6 examples, 68-82%
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