Key words
spiro compounds - quinazolinones - isatoic anhydride - amines - cycloalkanones - multicomponent
reactions
The exploration of synthetic efficiency while minimizing needless synthetic steps
is key to the synthesis of complex organic skeletons.[1] One-step synthetic strategies are increasingly used to access drug-like molecules.[2] Specifically, heterocyclic frameworks bearing spiro centers possess structural rigidity
resulting from conformational restriction, and they have consequently received attention
due to their enhanced activities against a number of pharmacological targets.[3]
Table 1 Optimization of Reaction Conditions for Synthesis of Spiro Product 4a
a
|
Entry
|
Catalyst (mol %)
|
Solvent
|
Time (min)
|
Yieldb (%)
|
|
1
|
–
|
EtOH
|
180
|
trace
|
|
2
|
PTSA (20)
|
EtOH
|
120
|
51
|
|
3
|
NH2SO3H (20)
|
EtOH
|
120
|
57
|
|
4
|
AcOH (20)
|
EtOH
|
75
|
91
|
|
5
|
AcOH (20)
|
MeOH
|
60
|
94
|
|
6
|
AcOH (20)
|
MeCN
|
120
|
84
|
|
7
|
AcOH (20)
|
i-PrOH
|
120
|
79
|
|
8
|
AcOH (5)
|
MeOH
|
90
|
83
|
|
9
|
AcOH (10)
|
MeOH
|
60
|
93
|
|
10
|
AcOH (15)
|
MeOH
|
60
|
94
|
a Reaction conditions: isatoic anhydride (2; 3 mmol), aniline (1a; 3 mmol), cyclohexanone (3; 3 mmol), solvent (10 mL), catalyst, reflux.
b Isolated yield.
Spiroquinazolinones and their derivatives constitute a privileged class of fused heterocycles,
as they possess notable biological properties, especially antimicrobial activities.[4] Such scaffolds have been explored as core structures and have been extensively studied
in many bioactive natural and synthetic molecules.[5] Quinazolinones present numerous biological actions, such as antitumor,[6]
[7] antifibrillatory,[8] antidepressant,[9] analgesic,[10] diuretic,[11] antihistamine,[12] vasodilatory,[13] antihypertensive,[14] CNS-stimulant,[15] tranquilizing,[16] anxiolytic,[17] and plant-growth-regulating[18] activities. In addition, quinazolin-4(3H)-ones are useful synthetic precursors.[19]
[20]
[21]
[22]
[23] In continuation of our interest in the design and synthesis of heterocyclic candidates,[24] we describe an efficient and scalable cascade strategy for the synthesis of diversely
functionalized 1′H-spiro[cycloalkyl-1,2′-quinazolin]-4′(3′H)-one derivatives through a one-pot condensation of isatoic anhydride, an aryl or
aliphatic amine, and a cyclic ketone in the presence of a catalytic amount of acetic
acid.
We started our study by investigating the 4-toluenesulfonic acid (PTSA)-catalyzed
three-component reaction of aniline (1a), isatoic anhydride (2), and cyclohexanone (3) as model substrates in ethanol at reflux temperature. We found that the desired
product 4a was obtained in 51% yield after heating at reflux for two hours. In attempts to increase
the reaction efficiency, we studied sulfamic acid and acetic acid as catalysts (Table
[1], entries 2–4). From these observations, it was clear that acetic acid (20 mol%)
gave the best yield (91%) in the shortest reaction time (entry 4). Subsequently, we
screened a range of polar solvents (ethanol, methanol, acetonitrile, and propan-2-ol)
(entries 4–7) and we found that methanol was the most efficient solvent for this condensation,
affording the desired spiro product 4a in 94% yield (entry 5). Screening the quantity of the catalyst showed that a yield
of 93% was obtained by using 10 mol% of acetic acid (entry 9). We also attempted to
reduce the reaction temperature from reflux to ambient temperature, but the reaction
was sluggish and the yield decreased (not shown). Hence, the optimal conditions were
determined to be refluxing methanol containing 10 mol% of acetic acid as the catalyst.
After the optimization studies, the synthesis of a variety of functionalized 1′H-spiro[cyclohexane-1,2′-quinazolin]-4′(3′H)-ones[25]
[26] was performed to explore the efficiency and versatility of this method (Scheme [1]), and the results are presented in Table [2]. Various aromatic amines bearing either electron-withdrawing or electron-donating
substituents successfully afforded the corresponding products 4b–j in good to excellent yields (Table [2], entries 2–10). In contrast, aliphatic amines 1k and 1l (Table [2], entries 11 and 12) provided only moderate yields, presumably due to their higher
nucleophilicity compared with aryl amines. The products were characterized by means
of 1H and 13C NMR spectroscopy and by X-ray single-crystal analysis.
Scheme 1 Acetic acid-assisted three-component synthesis of 3′-aryl-1′H-spiro[cyclohexane-1,2′-quinazolin]-4′(3′H)-ones
In the 1H NMR spectrum of compound 4b, as a representative example, the aliphatic protons (–CH2–) of the cyclohexane moiety appeared as multiplets at δ = 0.91, 1.25, 1.55, and 2.04
ppm; the secondary amine (–NH–) proton appeared as a singlet at δ = 7.01 ppm; and
the aromatic protons were observed as multiplets at δ = 6.68–7.65 ppm. In the 13C NMR spectrum, the carbons in the cyclohexane ring appeared as resonances at δ = 21.1,
24.0 and 34.5 ppm, and the amide carbon (–CONX) exhibited as a peak at δ = 162.8 ppm.
Furthermore, the structures of compounds 4a (Figure [1]) and 4e (Figure [2]) were confirmed by single-crystal X-ray analysis.[27]
To extend the scope of the reaction, we applied the optimized protocol to the synthesis
of 1′H-spiro[cyclopentane-1,2′-quinazolin]-4′(3′H)-ones by reaction with cyclopentanone (5; Scheme [2]). Aromatic amines 1a–j bearing various functional groups at various positions reacted with isatoic anhydride
(2) smoothly in the presence of cyclopentanone (5), and the corresponding targets (6a–j) were obtained. The results are summarized in Table [3].
Table 2 Synthesis of 1′H-Spiro[cyclohexane-1,2′-quinazolin]-4′(3′H)-one Derivativesa
|
Entry
|
Amine
|
Product
|
Time (min)
|
Yieldb (%)
|
|
1
|
 
|
|
60
|
93
|
|
2
|
|
|
75
|
91
|
|
3
|
|
|
40
|
96
|
|
4
|
|
|
45
|
95
|
|
5
|
|
|
40
|
96
|
|
6
|
|
|
80
|
89
|
|
7
|
|
|
45
|
93
|
|
8
|
|
|
75
|
90
|
|
9
|
|
|
80
|
88
|
|
10
|
|
|
80
|
86
|
|
11
|
|
|
90
|
84
|
|
12
|
|
|
90
|
81
|
a Reaction conditions: isatoic anhydride (2; 3 mmol), amine 1 (3 mmol), cyclohexanone (3; 3 mmol), AcOH (10 mol%), MeOH (10 mL), reflux.
b Isolated yield.
Table 3 Synthesis of 1′H-Spiro[cyclopentane-1,2′-quinazolin]-4′(3′H)-one Derivativesa
|
Entry
|
Amine
|
Product
|
Time (min)
|
Yieldb (%)
|
|
1
|
|
|
60
|
91
|
|
2
|
|
|
80
|
94
|
|
3
|
|
|
45
|
97
|
|
4
|
|
|
45
|
94
|
|
5
|
|
|
45
|
95
|
|
6
|
|
|
85
|
90
|
|
7
|
|
|
50
|
92
|
|
8
|
|
|
80
|
89
|
|
9
|
|
|
90
|
86
|
|
10
|
|
|
90
|
85
|
|
11
|
|
|
95
|
86
|
|
12
|
|
|
110
|
81
|
a Reaction conditions: isatoic anhydride (2; 3 mmol), amine (1; 3 mmol), cyclopentanone (5; 3 mmol) AcOH (10 mol%), MeOH (10 mL), reflux.
b Isolated yields.
The 1H NMR spectrum of compound 6b showed multiplets at δ = 1.43, 1.71, and 1.89 ppm corresponding to the aliphatic
protons of the cyclopentane group. The secondary amine (–NH–) proton appeared as a
singlet at δ = 6.93 ppm, and the aromatic protons appeared as multiplets at δ = 6.69–7.67
ppm. In the 13C NMR spectrum, the amide carbon (–CONX) was evident as a resonance at δ = 163.0 ppm.[29] Moreover, the structure of 6e was confirmed by single-crystal X-ray analysis (Figure [3]).
Figure 1 ORTEP of compound 4a (CCDC 1543174)[28]
Scheme 2 Three-component synthesis of 3′-aryl-1′H-spiro[cyclopentane-1,2′-quinazolin]-4′(3′H)-ones
Figure 2 ORTEP of compound 4e (CCDC 1543282)[28]
Figure 3 ORTEP of compound 6e (CCDC 1543283)[28]
Finally, we examined the reaction with benzene-1,4-diamine (7) instead of an aromatic monoamine (Scheme [3]), and this pseudo-five-component reaction led to the novel bis{1′H-spiro[cycloalkane-1,2′-quinazolin]-4′(3′H)-ones} 8 and 9 in good yields. Their structures were confirmed by 1H and 13C NMR spectroscopic analyses.
Scheme 3 Pseudo-five-component synthesis of bis{1′H-spiro[1,2′-quinazolin]-4′(3′H)-ones}
In conclusion, we have disclosed an efficient and concise approach for the one-pot
synthesis of various 1′H-spiro[cycloalkyl-1,2′-quinazolin]-4′(3′H)-one derivatives through a three-component reaction in the presence of a catalytic
amount of acetic acid. The method tolerates an array of functional groups and has
the advantages of mild reaction conditions, short reaction times, experimental simplicity,
and excellent yields.
