Key words one-pot synthesis - catalyst-free - 6,6a-dihydroisoindolo[2,1-
a ]quinazoline-5,11-dione - 5-phenylisoindolo[2,1-
a ]quinazolin-11(6a
H )-one - 2-formyl benzoic acid
Quinazolines, quinazolinones and isoindolinone, represent common structural units
in many natural alkaloids including rutaecarpine (1 ). They also show a range of biological activities.[
1
]
. In addition many unnatural quinazolinones show significant biological activities acting
as anticancer,[
2
] antibacterial,[
3
] anti-inflammatory,[
4
] antihypertensive,[
5
] antidiabetic,[
6
] anticonvulsant,[
7
] and antianxietic agents.[
8
] Figure [1 ] shows the chemical structures of some potent biologically important quinazolinone,
isoindolin-1-one-based compounds and the general structure of our synthesized prototype.
The kinesin spindle protein inhibitor 2
[
9
] displays antimitotic activity and is in phase II clinical trials, while methaqualone
(3 ) is a clinically used sedative.[
10
] Furthermore, diproqualone 4 is used primarily for the treatment of inflammatory pain associated with osteoarthritis,[
11
] while compound 5 possesses potent nicotinic acid receptor agonist activity for the treatment of dyslipidemia.[
12
] The isoindolinone (phthalimidine) motif occurs as a core structure not only in several
natural products such as lennoxamine (6 )[
13
] but also in a number of pharmacologically relevant synthetic molecules, such as
pagoclone (7 ).[
14
]
Hybrid molecules that combine two heterocyclic structural units of different nature
generally lend themselves well to rational drug design and often possess improved
biological activities.[
15
] A number of biologically potent hybrids have been described in the literature such
as steroid antibiotics,[
16
] steroid nucleosides,[
17
] triterpenoid peptides,[
18
] and DNA-cleaving-agent amino acids.[
19
] Multicomponent reactions (MCRs), have proven to be one of the most powerful methods
to access complex structures in a single synthetic operation from simple building
blocks[
20
] and are very useful in the construction of diverse chemical libraries of ‘drug-like’
molecules.[21 ]
[22 ] Recently, Pal et al. synthesized 6,6a-dihydroisoindolo[2,1-a ]quinazoline-5,11-dione derivatives 8 by employing a three-component reaction of isatoic anhydride, an amine and 2-formylbenzoic
acid, using montmorillonite K10 as the catalyst.[
23a
] Additionally, Bunce et al. reported the synthesis of substituted quinazolinones
using a dissolving metal reduction–condensative cyclization strategy.[
23b
] However, such syntheses are still suboptimal because of use of catalysts, forcing
reaction conditions and long reaction times.
Scheme 1 Reaction of isatoic anhydride (1 ), p -toluidine (2i ) and 2-formylbenzoic acid (3 )
Figure 1 Biologically active quinazolinone, isoindolinone-based compounds 1 –7 and our prototype 8
As a part of our ongoing studies devoted towards the development of a practical synthesis
of biologically interesting heterocyclic molecules,[
24
] we have explored the possibility of an operatively simple, catalyst-free synthesis
of 6,6a-dihydroisoindolo[2,1-a ]quinazoline-5,11-dione derivatives. In the initial phase of this study we investigated
the cyclization reaction of 2-formylbenzoic acid (3 ) with isatoic anhydride (1 ) and p -toluidine (2i ) in the absence of catalyst in ethanol under heating (Scheme [1 ]) for two hours which yielded the required compound 4i in 45% yield (Table [1 ], entry 1). Further optimization results are presented in Table [1 ]. Replacement of ethanol with acetic acid caused a sharp increase in the yield of
this reaction (85%; Table [1 ], entry 6). The solvent was found to have a dramatic impact on the efficiency of
the reaction (Table [1 ], entries 9–13). On the other hand, the use of CF3 COOH completely closed down the reaction (Table [1 ], entry 8). The cyclization ability of various binary solvent systems such as ethanol–acetic
acid (Table [1 ], entry 9), acetonitrile–acetic acid (Table [1 ], entry 10) and DMF–acetic acid (Table [1 ], entry 11) was also tried without success.
Table 1 Effect of Reaction Conditions on the Cyclization of Isatoic Anhydride (1 ), p -Toluidine (2i ) and 2-Formylbenzoic Acid (3 )
Entry
Solvent
Temp (°C)
Time (h)
Yield (%)a
1
EtOH
90
2.0
45
2
i -PrOH
90
2.0
35
3
DMF
110
2.0
30
4
DMSO
110
2.0
30
5
MeCN
90
2.0
40
6
AcOH
110
2.0
85
7
1,4-dioxane
110
2.0
40
8
CF3 COOH
110
2.0
–
9
AcOH–EtOH (7:3)
100
2.0
70
10
AcOH–MeCN (7:3)
100
2.0
73
11
AcOH–DMF (7:3)
110
2.0
70
12
AcOH
110
1.0
85
13
AcOH
110
0.75
85
14
AcONa
90
2.0
10
a Yields after recrystallization from chloroform–hexane (2:8).
We also carried out the reaction in the absence of acetic acid to confirm the cyclization
ability of acetic acid. Thus, among the solvents screened, only the acetic acid promoted
effective cyclization in high yield and short reaction time (Table [1 ], entry 13). Further increases in the reaction time did not increase the yield of
the reaction (Table [1 ], entries 6 and 12).
The scope of this one-pot three-component synthesis of 6,6a-dihydroisoindolo[2,1-a ]quinazoline-5,11-dione derivatives was next investigated. To explore the applicability
of our reaction, we employed a variety of substituted aliphatic and aromatic amine
derivatives in the reaction. Though the reaction worked well in all cases, the yields
were better for the more nucleophilic aliphatic amines than aromatic amines (Table
[2 ]).
All the synthesized[
25
] compounds were confirmed by 1 H NMR, 13 C NMR, IR spectroscopy and mass spectrometry and their comparison with published data
in the case of known compounds (4a –e ,h ,m ,n ).[
23
]
A plausible mechanism for the formation of 6,6a-dihydroisoindolo[2,1-a ]quinazoline-5,11-diones is depicted in Scheme [2 ].[
23a
] In order to elucidate the possible role of acetic acid the reaction was performed
at two different pK
a values. The reaction with sodium acetate (a weak base) in ethanol (Table [1 ], entry 14) resulted in low yield of the product. The best results were obtained
in acetic acid (pK
a 4.76; Table [1 ], entries 6, 12 and 13), while the reaction when performed in trifluoroacetic acid
(pK
a 0.23; Table [1 ], entry 8) did not give any products, possibly because trifluoroacetic acid used
in large excess as solvent, is too strong an acid. These initial results indicate
the important role of acetic acid as a solvent with optimum pK a and, in some way, as an activator of the cyclization process.
Scheme 2 Plausible mechanism for the formation of 6,6a-dihydroisoindolo[2,1-a ]quinazoline-5,11-diones derivatives
Table 2 General Synthesis of 6,6a-Dihydroisoindolo[2,1-a ]quinazoline-5,11-diones Derivatives from Suitable Precursors
Entry
Amine 2
Product 4
Time (min)
Yield (%)a
1
NH4 OAc2a
4a
45
92
2
MeNH2
2b
4b
50
92
3
2c
4c
45
91
4
2d
4d
48
90
5
2e
4e
50
92
6
2f
4f
50
90
7
2g
4g
55
89
8
2h
4h
48
80
9
2i
4i
45
85
10
2j
4j
50
80
11
2k
4k
60
80
12
2l
4l
60
82
13
2m
4m
50
85
14
2n
4n
55
85
15
2o
4o
60
83
16
2p
4p
60
85
17
2q
4q
60
82
a Yields after recrystallization from chloroform–hexane (2:9).
The structural diversity of this reaction was further increased by using 2-aminobenzophenone
(5b ) instead of isatoic anhydride under similar reaction conditions, leading to the formation
of new 5-phenylisoindolo[2,1-a ]quinazolin-11(6aH )-one derivatives (Table [3 ], compounds 6a –e ).
According to Table [3 ], in all the cases the reactions were accomplished in relatively short reaction time
and the products were obtained in good to excellent yields (more than 70%). To determine
the scope of this protocol, various aliphatic and aromatic amine derivatives were
employed. However the reaction worked well with 2-aminobenzophenone derivatives only.
All compounds were characterized through 1 H NMR, 13 C NMR, HRMS and IR spectroscopic studies[
26
] (please refer to the Supporting Information).
Table 3 Three-Component Synthesis of 5-Phenylisoindolo[2,1-a ]quinazolin-11(6aH )-one Derivatives 6a –e in One Pot
Entry
R1
R2
R3
Time (min)
Product (yield, %)a
1
H
H
H
60
6a (75)
2
Cl
H
H
45
6b (80)
3
Cl
F
H
60
6c (75)
4
Cl
F
F
60
6d (80)
5
H
H
Br
60
6e (70)
a Yields are of the isolated product after purification by column chromatography.
The proposed mechanism for the formation of the 5-phenylisoindolo[2,1-a ]quinazolin-11(6aH )-ones is shown in Scheme [3 ].[23a ]
[27 ]
[28 ] The reaction is expected to proceed via aldimine benzophenone intermediate A generated in situ from the reaction of 5b with 2-formylbenzoic acid in acetic acid. The reaction of intermediate A with ammonium acetate results in the second intermediate imine B which subsequently participates in an intramolecular cyclization (C ) followed by nucleophilic attack of the ring nitrogen on the carbonyl of the carboxylic
acid leading to the formation of 6b .
Scheme 3 Plausible mechanism for the formation of 6b
In summary, we have developed an alternative, catalyst-free synthesis of 6,6a-dihydroisoindolo[2,1-a ]quinazoline-5,11-diones and 5-phenylisoindolo[2,1-a ]quinazolin-11(6aH )-ones with excellent yields and short reaction times. Attractive features of this
methodology are its versatility, the readily available starting materials needed,
and the efficiency in creating a complex core in a single operation.
