Base-catalyzed bicyclization of dialkyl glutaconates with cinnamoylacetamides: A synthetic strategy for isoquinolinedione derivatives

Article abstract of DOI:10.1039/c3cc46931j

We report here that polysubstituted dihydroisoquinolones and isoquinolones can be constructed by the one-pot reaction of the readily available acyclic α,β-unsaturated carbonyl precursors and dialkyl glutaconates under mild basic conditions (1-45 min for the former vs. 1-6 h for the latter) via the domino process involving [3+3] annulation/intramolecular aza-cyclization. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3cc46931j

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Base-catalyzed bicyclization of dialkyl glutaconates
with cinnamoylacetamides: a synthetic strategy for
isoquinolinedione derivatives†
Cite this: Chem. Commun., 2014,
50, 6458
Received 11th September 2013,
Accepted 17th April 2014
Lei Li, Yu-Long Zhao,* He Wang, Yi-Jin Li, Xianxiu Xu and Qun Liu*
DOI: 10.1039/c3cc46931j
www.rsc.org/chemcomm
We report here that polysubstituted dihydroisoquinolones and easily available acyclic starting materials in a single step under very
isoquinolones can be constructed by the one-pot reaction of the mild conditions remains a formidable challenge.
readily available acyclic a,b-unsaturated carbonyl precursors and
Domino reactions are attractive in industry and research
dialkyl glutaconates under mild basic conditions (1–45 min for the laboratories because of their potential to save solvents, reagents, time
former vs. 1–6 h for the latter) via the domino process involving and energy.13 In our recent research to develop new domino
[3+3] annulation/intramolecular aza-cyclization.
reactions based on various easily available vinyl ketone precursors,14
polysubstituted benzenes were prepared through a base-catalyzed
The isoquinolone skeleton is a basic structural feature found in many [3+3] aerobic oxidative benzannulation of a,b-unsaturated carbonyl
natural and biologically active products, including the alternarlactam, compounds 1 with dimethyl glutaconate 2a (Scheme 1, path A).15 On
pancratistatin, aromathecin alkaloids and (Z)-6-bromo-4-((4-(pyrrolidin- the basis of the above results, we envisioned that compounds
1-ylmethyl)phenylamino)methylene)isoquinoline-1,3-dione (Fig. 1).1 containing the isoquinoline core, such as dihydroisoquinoline-1,3-
These compounds possess diverse pharmacological and biological diones 4 and isoquinoline-1,3-diones 6, could be constructed
properties as well as structural complexity1,2 and have attracted through a domino reaction involving an initial intermolecular
considerable attention from organic and medicinal chemists. For [3+3] annulation of a,b-unsaturated carbonyl compounds 1
the construction of the isoquinolone framework, the condensation/ with dimethyl glutaconate 2a, followed by an intramolecular
cyclization routes,3 transition-metal-catalyzed coupling annulations,4 aza-cyclization/aromatization process under basic conditions if
aza-Wackertype reactions,5 Pomeranz–Fritsch reactions,6 denitro- suitable acetamide groups were inserted at the a0-position of
genative7 and decarbonylative8 cycloadditions, transition-metal- a,b-unsaturated carbonyl compounds 1 (path B). Compared
catalyzed oxidative annulation of benzamides with alkynes9 or with the approaches mentioned above,3–12 the new method
olefins,10 etc.,11 have been reported, in which an aromatic substrate has the advantages of employing readily available starting
is generally required. On the other hand, although several procedures materials and cheap reagents, as well as providing good regio-
using the acyclic precursors have been developed,12 they suffer from selectivities without the requirement of metal catalysts. Herein,
the limited substrate scope, the lack of readily available precursors, the preliminary results are described.
tedious synthetic procedures or harsh reaction conditions. Thus, the
In the present study, initially, the model reaction of N-aryl-
direct and convenient synthesis of isoquinolone derivatives from cinnamoylacetamide 1a with dimethyl glutaconate 2a was examined
carefully to optimize the reaction conditions (Table 1). Indeed, the
desired 5,6-dihydroisoquinoline-1,3-dione 4a could be obtained in
high yields when 1a (0.5 mmol) was treated with 2a (1.0 mmol) in
MeOH (4.0 mL) in the presence of NaOH (0.10 mmol), t-BuOK
(0.10 mmol) or DBU (0.10 mmol; DBU = 1,8-diazabicyclo[5.4.0]undec-
7-ene) at room temperature for 18 min (entries 3, 6 and 7).16 Further
Fig. 1 Selected examples of biologically active and natural products
containing the isoquinolone skeleton.
Department of Chemistry, Northeast Normal University, Changchun, 130024,
P. R. China. E-mail: zhaoyl351@nenu.edu.cn, liuqun@nenu.edu.cn
† Electronic supplementary information (ESI) available: Experimental procedures
Scheme 1 Cyclization strategy of a,b-unsaturated carbonyl compounds
and characterization data for all new compounds. CCDC 957105 (4c). For ESI and
with dimethyl glutaconate.
crystallographic data in CIF or other electronic format see DOI: 10.1039/c3cc46931j
6458 | Chem. Commun., 2014, 50, 6458--6460
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Table 1 Optimization of reaction conditions
5,6-dihydroisoquinoline-1,3-diones 4a–e in high yields at room
temperature for 18–30 min. Similarly, the reaction of substrate
1f bearing a phenylvinyl R1 group can give the desired 4f in 70%
yield (entry 6). On the other hand, various aromatic and benzyl
R2 groups at the nitrogen of 1 are also well-tolerated in the reaction
and the corresponding polysubstituted 5,6-dihydroisoquinoline-1,3-
diones 4a–o were prepared in high yields (entries 1–15). In addition,
in the case of diethyl glutaconate 2b, the bicyclization reaction also
worked well, yielding the desired product 4p in 80% yield (entry 16).
To test the generality of this new approach for the construction of
the dihydroisoquinolone core, the reactions of dimethyl glutaconate
2a with selected 1-cinnamoylcyclopropanecarboxamides 5a–g were
examined under identical conditions as above. Fortunately, poly-
substituted 5,6-dihydroisoquinoline-1,3-diones 4q–w can also be
prepared in good to high yields, respectively (Table 3, entries 1–7).
On the basis of the above experimental results together with
the consideration of the structural feature of dihydroisoquinolones 4,
we reasoned that the isoquinolones 6 can be prepared from
cinnamoylacetamides 1 or 5 and dimethyl glutaconate 2a following
a sequential intermolecular [3+3] annulation, intramolecular aza-
cyclization and aromatization procedure in a single step under
suitable reaction conditions, respectively. Detailed examination of
the reaction conditions indicated that the isoquinoline-1,3-dione 6a
could be obtained in 90% yield from 1a (0.5 mmol) and 2a
(1.0 mmol) in MeOH (4.0 mL) in the presence of NaOH (0.25 mmol)
at 60 1C for 4 h in open air (Scheme 2). Similarly, the corresponding
polysubstituted isoquinoline-1,3-diones 6b–g were synthesized in
high yields from reactions of 2a with 1b, 1c, 1f, 1l, 1p and 1q,
respectively (Scheme 2). Notably, the isoquinoline-1,3-diones 6h and
6i could be prepared in 75% and 65% yields at room temperature for
6 h under otherwise identical conditions as above (Scheme 2). In
addition, in the case of the reactions of 1-cinnamoylcyclopro-
panecarboxamides 5d–f with 2a, the cyclization–aromatization reac-
tion could also proceed at room temperature for 1 h to give the
corresponding isoquinoline-1,3-diones 6j–l in high yields under
otherwise identical conditions as above (Scheme 2). The above
reaction not only provides a facile and efficient access to isoquino-
lones in a single step from easily available acyclic starting materials
under mild conditions, but also offers further enhancement of the
efficiency of the bicyclization strategy.
Entry
Base (equiv.)
2a (equiv.)
Solvent
t/h
4aa (%)
1
2
3
4
5
6
7
8
NaOH (0.1)
NaOH (0.2)
NaOH (0.2)
NaOH (0.2)
NaOH (0.5)
DBU (0.2)
t-BuOK (0.2)
K2CO3 (0.2)
DABCO (0.2)
NaOH (0.2)
NaOH (0.2)
NaOH (0.2)
2.0
1.0
2.0
2.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
CH3CN
THF
24
1
0.3
0.3
0.3
0.3
0.3
0.5
35
74
86
81
84
86
83
76
51
61
30
0
9
24
10
11
12
3
5
5
DMF
a
Isolated yield.
increasing the amounts of NaOH and 2a did not improve the yield of
4a (entries 4 and 5). Other bases, such as K2CO3 and 1,4-diazabi-
cyclo[2.2.2]octane (DABCO), were less effective (entries 8 and 9).
Among the solvents tested, methanol seemed to be the best choice.
Other solvents, such as CH3CN and THF, gave lower product yields
(entries 10 and 11). No desired 4a could be detected when the
reaction was carried out in DMF (entry 12).
Next, the scope of the reaction was investigated under the
optimal conditions, described in Table 1, entry 3, and the results
are summarized in Table 2. It was found that the tandem reaction
showed broad tolerance for various R1 and R2 groups of substrates 1.
All selected substrates, 1a–e bearing phenyl (entry 2), electron-
deficient (entry 3), electron-rich aryl (entry 1) and heteroaryl
(entries 4 and 5) R1 groups, reacted smoothly with dimethyl
glutaconate 2a to give the corresponding polysubstituted
Table 2 Synthesis of 5,6-dihydroisoquinoline-1,3-diones 4a–pa
Entry
1
R1
R2
R3
t/min Yieldb (%)
Table 3 Synthesis of 5,6-dihydroisoquinoline-1,3-diones 4q–wa
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1b
4-MeC6H4
C6H5
4-ClC6H4
2-Furyl
2-Thienyl
PhCHQCH 4-MeC6H4
4-ClC6H4
C6H5
4-ClC6H4
4-MeC6H4
C6H5
4-ClC6H4
4-MeC6H4
C6H5
4-ClC6H4
C6H5
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
Me 18
Me 20
Me 20
Me 30
Me 30
Me 18
Me 30
Me 25
Me 25
Me 30
Me 25
Me 20
Me 20
Me 20
Me 20
4a (85)
4b (74)
4c (82)
4d (75)
4e (74)
4f (70)
4g (84)
4h (84)
4i (80)
4j (73)
4k (82)
4l (81)
4m (74)
4n (76)
4o (76)
4p (80)
Entry
5
R1
5a 4-ClC6H4
R2
4-MeOC6H4 20
t/min Product Yieldb (%)
4-ClC6H4
4-ClC6H4
C6H5
C6H5
C6H5
CH2C6H5
CH2C6H5
CH2C6H5
2,4-MeC6H3
4-MeC6H4
9
1
2
4q
4r
75
55
58
81
83
77
84
10
11
12
13
14
15
16
5b 4-MeC6H4 4-MeOC6H4 40
5c C6H5
5d C6H5
5e 4-MeC6H4 Bn
5f
3
4-MeOC6H4 20
4s
4t
4c
5c
6c
7c
Bn
1
1
1
1
4u
4v
4w
4-ClC6H4
Bn
Bn
5g 2-Thienyl
Et
45
a
Reaction conditions: 5 (0.5 mmol), 2a (1.0 mmol), NaOH (0.10 mmol),
a
b
Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), NaOH (0.10 mmol), MeOH (4.0 mL), room temperature for 1–40 min. Isolated yield.
b
c
MeOH (4.0 mL), room temperature for 18–45 min. Isolated yield.
A trace amount of isoquinolone 6 was observed by TLC.
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NaOH, the reaction starts from the intermolecular Michael addition
of 2 to 1 or 5 to give intermediate A. Subsequently, the intermediate B,
generated via CQC double bond isomerization of intermediate A
under basic conditions, undergoes an intramolecular aldol cyclization,
followed by dehydration to afford the six-membered intermediate D.
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carbon under basic conditions and leads to an intramolecular aza-
cyclization to produce the 5,6-dihydroisoquinoline-1,3-dione 4,
which undergoes an oxidative aromatization with molecular oxy-
gen (from air) to give the isoquinoline-1,3-dione 6 (Scheme 3).
In conclusion, we have developed a new domino strategy for the
rapid and efficient synthesis of polysubstituted dihydroisoquinolone
and isoquinolone derivatives. The reaction involves a sequential
intermolecular [3+3] annulation/intramolecular aza-cyclization
procedure and allows the construction of 5,6-dihydroisoquinoline-
1,3-diones and isoquinoline-1,3-diones in a single step from the
easily available acyclic substrates in good to high yields under mild
metal-free conditions. This strategy shows the highly efficient use of
the reactive sites of substrates and further expands the synthetic
potential of dialkyl glutaconates in organic synthesis. Further
studies are in progress.
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Financial support of this research by the National Natural
Sciences Foundation of China (21172032) is greatly acknowledged.
6460 | Chem. Commun., 2014, 50, 6458--6460
This journal is ©The Royal Society of Chemistry 2014