Synthesis of spiro[isoquinolinone-4,2′-oxiranes] and isoindolinones via a multicomponent reaction of 2-acetyl-oxirane-2-carboxamides, arylaldehydes and malononitrile

Article abstract of DOI:10.1039/c4cc02141j

Efficient synthesis of spiro[isoquinolinone-4,2′-oxiranes] was achieved based on a multicomponent one-pot reaction of readily available cis-2-acetyl-oxirane-2-carboxamides, arylaldehydes and malononitrile at room temperature. However, in the reaction with trans-2-acetyl-oxirane-2-carboxamide substrates, 3-iminoisoindolinones were obtained in moderate to high yields. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02141j

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Synthesis of spiro[isoquinolinone-4,20-oxiranes]
and isoindolinones via a multicomponent reaction
of 2-acetyl-oxirane-2-carboxamides, arylaldehydes
and malononitrile†
Cite this: Chem. Commun., 2014,
50, 6995
Received 22nd March 2014,
Accepted 9th May 2014
Bing Liu,a Enxiang Wei,a Shaoxia Lin,a Baozhong Zhaoa and Fushun Liang*ab
DOI: 10.1039/c4cc02141j
www.rsc.org/chemcomm
Efficient synthesis of spiro[isoquinolinone-4,20-oxiranes] was achieved
based on a multicomponent one-pot reaction of readily available cis-
2-acetyl-oxirane-2-carboxamides, arylaldehydes and malononitrile at
room temperature. However, in the reaction with trans-2-acetyl-
oxirane-2-carboxamide substrates, 3-iminoisoindolinones were
obtained in moderate to high yields.
Scheme 1 Substrate preparation.
The substrates, 2-acetyl-oxirane-2-carboxamides, were prepared
according to the literature reported procedure with slight modifi-
cation.7 Two regioisomers 1 and 10 were easily isolated through
column chromatography (Scheme 1).8 The structure of 2-acetyl-
N,3-diphenyloxirane-2-carboxamide (1a0) and the stereochemistry
were confirmed by the X-ray single-crystal diffraction (Fig. 1). The
different types of intramolecular hydrogen bonding in 1 and 10
were established, which are supported by a distinctly different
molecular polarity of 1 and 10, comparison of their 1H NMR
spectra and the X-ray single-crystal structure of 10.9
With substrates 1 and 10 in hand, a multicomponent reaction of
cis-2-acetyl-oxirane-2-carboxamide 1a, benzaldehyde and malononitrile
was conducted first (Table 1). Using K2CO3 (2.2 equiv.) as the base and
DCM as the solvent, no reaction was observed (entry 1). When NaOH
(2.2 equiv.) was used, product 3a was obtained in 11% yield (entry 2).
The structure of 3a was confirmed unambiguously by X-ray single
crystal diffraction (Fig. 2). DBU (2.2 equiv.) gave an increased yield
of 35% (entry 3). To our delight, in the reaction using piperidine
(2.2 equiv.) as the base in DCM at room temperature for only 1 h, the
yield of 3a reached up to 83% (entry 4). Other solvents tested like
MeCN, THF and DMF were not as effective as DCM (entries 5–7).
1.1 equiv. of piperidine led to a decreased yield of 45% (entry 8).
Under the optimal conditions established above (Table 1, entry 4),
a range of reactions was carried out with various substrates 1,
Multicomponent reactions (MCRs) have been refined in recent
years as powerful and useful tools in synthetic chemistry and
have attracted increasing attention due to the advantages of
greater efficiency, atom economy and structural complexity.1
On the other hand, the utility of cyclopropane derivatives in
organic chemistry has been recognized due to their ‘‘unsaturated’’
character.2 In this context, the development of multicomponent
reactions based on appropriately substituted cyclopropanes
appears to be of significance and some studies have been reported
by independent groups.3 We have reported three-component
reactions with highly functionalized 1-acetyl-1-carbamoyl cyclo-
propanes as the starting material.3g,h In the continued work, we
started to explore the reaction based on electron-withdrawing
groups-activated oxarines.4 In the Knoevenagel reaction-initiated
multicomponent reaction of 2-acetyl-oxirane-2-carboxamides,
arylaldehydes and malononitrile, biologically important fused
heterocycles 1H-spiro[isoquinoline-4,20-oxiran]-3(2H)-ones and
3-iminoisoindolinones were synthesized with high efficiency.
Isoquinolones constitute an important class of heterocyclic com-
pounds, which displays important biological activities including
vasorelaxation, cardiotonic effects and anticancer effects.5
Isoindolinones contain the core found in many compounds
in the heliannuol family of natural products.6
a Department of Chemistry, Northeast Normal University, Changchun 130024,
China. E-mail: liangfs112@nenu.edu.cn; Fax: +86-431-85099759
b Key Laboratory for UV-Emitting Materials and Technology of Ministry of Education,
Northeast Normal University, Changchun 130024, China
† Electronic supplementary information (ESI) available: Experimental details and
characterization for all new compounds and crystal structure data. CCDC 971864
(1a0), 965575 (3a) and 977863 (4a). For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c4cc02141j
Fig. 1 X-ray crystal structure of 1a0.
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Table 1 Optimization of the reaction conditions
Table 2 Reaction of cis-2-acetyl-oxirane-2-carboxamides (1), aldehydes
and malononitrile leading to 1H-spiro[isoquinoline-4,20-oxiran]-3(2H)-ones 3a
Entry
Base (2.2 equiv.)
Solvent
Time (h)
Yielda (%)
Entry
R1
R2
R3
3
Yieldb (%)
1
2
3
4
5
6
7
8
K2CO3
NaOH
DBU
Piperidine
Piperidine
Piperidine
Piperidine
Piperidineb
DCM
DCM
DCM
DCM
MeCN
THF
24
24
24
1
1
1
Nr
11
35
83
70
45
10
45
1
2
3
4
5
6
7
8
Ph
4-MeC6H4
4-ClC6H4
Bn
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
83
74
68
70
80
73
72
67
69
66
77
78
73
71
4-MeC6H4
DMF
DCM
1
1
4-BrC6H4
4-Pyridyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
4-MeOC6H4
2-MeOC6H4
4-ClC6H4
4-BrC6H4
3-NO2C6H4
2-Thienyl
a
b
Isolated yields. 1.1 equiv. of piperidine.
9
10
11
12
13
14
Ph
a
Reactions were carried out with 1 (1.0 mmol), 2 (1.1 equiv.), malono-
nitrile (2.2 equiv.), piperidine (2.2 equiv.) in CH2Cl2 (4.0 mL) at room
b
temperature for around 1 h. Isolated yield.
Table 3 Reaction of trans-2-acetyl-oxirane-2-carboxamides (10), aryl-
aldehydes and malononitrile leading to isoindolinones 4a
Entry
R1
R2
Ar
4
Yieldb (%)
Fig. 2 X-ray crystal structures of 3a and 4a.
1
2
3
4
5
6
7
8
9
10
Ph
4-MeC6H4
4-ClC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-BrC6H4
4-Pyridyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4a
4a
4d
4e
4f
85
79
61
80
71
48
66
75
77
70
aldehydes and malononitrile (Table 2). The reactions proceeded
smoothly to afford the corresponding highly substituted 1H-spiro-
[isoquinoline-4,20-oxiran]-3(2H)-ones 3 in moderate to high yields.10
The R1 substituents on the N atom of substrates 1 may be either
aryls such as phenyl, 4-chlorophenyl and 4-methylphenyl
(entries 1–3) or alkyls such as benzyl (entry 4). The R2 substituents
on the cyclopropyl ring of substrates 1 included phenyl, 4-methyl-
phenyl, 4-bromophenyl and 4-pyridyl (entries 1, 5–7). The scope of
aldehydes 2 was also examined.11 Both electron-rich and electron-
poor arylaldehydes (entries 8–13) and an heteroarylaldehyde
(entry 14) gave good results.
Ph
4-MeC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
2-Thienyl
Ph
Ph
4g
4h
Ph
a
Reactions were carried out with 1 (1.0 mmol), 2 (1.1 equiv.), malono-
nitrile (2.2 equiv.), DBU (1.1 equiv.) in CH2Cl2 (4.0 mL) at room
temperature for 48 h. Isolated yield.
b
water (Scheme 2). Intermediate 5 could be further converted
into 4a in 83% yield in 48 h at room temperature.
In the following work, trans-2-acetyl-oxirane-2-carboxamides
(10) were subjected to the multi-component reaction with aryl-
aldehydes and malononitrile (Table 3). However, in this case,
1H-spiro[isoquinoline-4,20-oxiran]-3(2H)-ones 3 were not obtained.
Instead, isoindolinones 4 were isolated after the reaction proceeded
at room temperature for 48 h.12 The structure of 4a was confirmed
by X-ray single crystal diffraction (Fig. 2). The yields were higher
when DBU was used as the base to replace piperidine, affording
4a–h in 48–85% yields (entries 1–9).13
Based on all the above results, along with the previous work by
Ge and Li14a and Yan,14b,c a possible mechanism for the formation
of 1H-spiro[isoquinoline-4,20-oxiran]-3-ones 3 has been proposed in
Scheme 3. The process involves tandem Knoevenagel condensation,
In an isolated reaction of 1a0 with phenylaldehyde and
malononitrile, intermediate 5 could be separated in 86% yield
when the reaction proceeded for 0.5 h and quenched by Scheme 2 Control experiment.
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Scheme 3 Plausible mechanism for the formation of 1H-spiro[iso-
quinoline-4,20-oxiran]-3-ones 3.
intermolecular Michael addition, intramolecular carbo-cyclization
(to form the six-membered carbon ring), aromatization via elimi-
nation of the cyanide anion and intramolecular aza-cyclization
(to form the six-membered nitrogen ring). The mechanism for
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In conclusion, room-temperature multicomponent reactions based
on 2-acetyl-oxirane-2-carboxamides, arylaldehydes and malononitrile
have been developed. Depending on the different intramolecular
hydrogen bonding modes in 2-acetyl-oxirane-2-carboxamide sub-
strates, reactions with cis-2-acetyl-oxirane-2-carboxamides afford 1H-
spiro[isoquinoline-4,20-oxiran]-3(2H)-ones in a short time (around 1 h).
Upon reaction with trans-2-acetyl-oxirane-2-carboxamides, 3-iminoiso-
indolinones were obtained in 48 h. Further work on the application of
highly functionalized oxarines in organic synthesis is ongoing.
Financial support from NSFC (21172034 and 21372039) is
gratefully acknowledged.
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It was noteworthy that arylaldehyde side product, R2CHO, could be
observed in the reaction system.
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Chem. Commun., 2014, 50, 6995--6997 | 6997