An efficient and convenient protocol for the synthesis of tetracyclic isoindolo[1,2-a]quinazoline derivatives

Abstract

A convenient and one-pot synthesis of tetracyclic isoindolo [1,2-a]quinazoline derivatives via Lewis acid mediated sequential C–N bond formation reactions is reported. This protocol provides a simple and rapid strategy for the synthesis of 12-benzylidene-10,12-dihydroisoindolo[1,2-b]quinazoline derivatives. However, a variety of tetracyclo indole fused quinazoline motifs were synthesized in good yields.

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Isoindoloquinazolinones symbolize the core structure in numerous biologically active molecules.¹ In addition, they are also important building blocks of potential drug molecules and natural products such as camptothecin 1, belotecan (CKD-602) 2,² batracylin 3,³ tryptanthrin 4,⁴ ophiuroidine 5,⁵ (−)-vasicine 6,⁶ luotonin 7a, 7b & 7c,⁷ and auranthine 8 (Fig. 1).⁸ Isoindolo quinazolinones have been reported with anti-cancer, anti-viral, anti-tubercular and anti-malarial activities. Recently Yang and co-workers⁹ reported that substituted quinazolines have novel potent and selective FLT3 inhibitory and anti-acute myeloid leukaemia (AML) activities.

Fig. 1 Examples of natural products containing quinazolinone skeletons.

Because of varied biological properties of quinazolinone derivatives, it is necessary to develop efficient and convenient methods to prepare isoindoloquinazolinone derivatives. Throughout the course of our literature survey we found minimum number of reports for the preparation of isoindoloquinazoline derivatives. Mitscher et al. have described intramolecular Aza-Wittig reaction using triethylamine,¹⁰ Weaver et al. have reported oxidative radical cyclization for synthesis of quinazolines from quinazolin-4(3H)-one.¹¹

The development of simple methodology for the preparation of isoindoloquinazolinone derivatives is always in demand. In the past, our group described numerous protocols for the preparation of quinazolinone based natural products and their derivatives.¹²

In this communication, we wish to report simple and straight forward synthesis of poly-substituted isoindoloquinazolinones derivatives.

The synthetic strategy employed for the synthesis of (Z)-12-benzylidene-10,12-dihydroisoindolo[1,2-b]quinazoline derivatives is depicted in Scheme 1. The (Z)-12-benzylidene-10,12-dihydroisoindolo[1,2-b]quinazolines derivatives 11a could be easily obtained by a reaction of (2-aminophenyl)methanol 9a¹³ with 2-(phenylethynyl) benzonitrile 10a.¹⁴

Scheme 1 Retrosynthesis of 11a.

The compound 11 was characterized by ¹H NMR, ¹³C NMR, HRMS and IR. Substituted (Z)-12-benzylidene-10,12-dihydroisoindolo [1,2-b]quinazoline derivatives were prepared from (2-aminophenyl)methanol 9 with 2-(phenylethynyl) benzonitrile 10.

In an effort to develop an optimal conditions, various reaction parameters were studied for the preparation of 11 via condensation of 2-(phenylethynyl)benzonitrile 10 (1.0 eq.) with (2-aminophenyl)methanol 9 (1.0 eq.) and BF₃·Et₂O (3.0 eq.). The acids have a strong effect on these reactions with respect to yield.

Among all the screened acids, optimum yields were obtained when the reaction was performed in the presence of BF₃·Et₂O (3.0 eq.) (Table 1). Solvents like DMSO, DMF, 1,4-dioxane, THF, acetonitrile and toluene were screened in presence of BF₃·Et₂O. BF₃·Et₂O alone had proven to be the best condition for this reaction instead of use of other solvents (Table 2).

Table 1 Screening of various acids^e

Entry	Lewis acid (eq./vol)	Yield^b (%)
a 48–50% solution of reagent was used.b Isolated yields after column chromatography.c Reaction at 45 °C.d Reaction with boron trifluoride acetic acid complex at 25 °C.e Reaction and conditions: (2-aminophenyl)methanol 9 (1.0 eq.), 2-(phenylethynyl)benzonitrile 10 (1.0 eq.) and BF3·Et2O (3.0 eq.) at 70 °C.
1	BF3·Et2O^a (3.0 eq.)	62
2	BF3·Et2O^a (1.5 eq.)	49
3	BF3·Et2O^a (2.0 eq.)	61
4	BF3·Et2O^c (3.0 eq.)	49
5	BF3·Et2O^d (3.0 eq.)	26
6	BF3·2AcOH (3.0 eq.)
7	Acetic acid (5.0 eq.)	8
8	TFA (5.0 eq.)	16
9	H2SO4 (2.0 eq.)	12
10	AlCl3 (3.0 eq.)	22
11	AlBr3 (3.0 eq.)	18
12	Hg(OAc)2 (3.0 eq.)	Traces
13	TiCl4 (3.0 eq.)	41

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Table 2 Screening of solvents^a

Entry	Solvents	Isolated yield (%)
a Reaction and conditions: (2-aminophenyl)methanol 9 (1.0 eq.), 2-(phenylethynyl)benzonitrile 10 (1.0 eq.) BF3·Et2O (3.0 eq.) at 70 °C.
1	DMSO	30
2	DMF	26
3	1,4-Dioxane	62
4	BF3·Et2O	68
5	Acetonitrile	42
6	THF	15
7	Toluene	20

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With the optimized reaction conditions in hand, we explored the applicability of our reaction. We employed a variety of substituted alcohols and substituted benzonitriles & the results were summarized in Table 3. Good yields were observed when the reaction was conducted with (2-aminophenyl)propan-2-ol and (2-aminophenyl)ethanol when compared to (2-aminophenyl)methanol due to the stability of the carbocation.

Table 3 Synthesis of various isoindoloquinazolinones derivatives

Entry	R^1	R^2	R^3	R^4	R^5	R^6	Product	Yield
1	H	H	H	H	H	H	11a	68
2	H	H	H	CH3	H	H	11b	72
3	H	H	H	H	H	Cl	11c	65
4	H	H	CH3	CH3	H	H	11d	71
5	H	H	CH3	H	H	H	11e	69
6	H	H	CH3	CH3	CH3	H	11f	74
7	H	H	H	CH3	CH3	H	11g	75
8	H	H	H	CH3	CH3	OCH3	11h	69
9	OCH3	OCH3	H	H	H	H	11i	67
10	OCH3	OCH3	H	CH3	H	H	11j	64

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The Scheme 2 represents a plausible mechanism for the three component reaction leading to the compound 11. The nucleophilic attack of primary amine on nitrile group of 10 yield imidamide intermediate 12, imidamide can attack on alkyne or alcohol leads to the formation of cyclized intermediate either 13 or 15 which on subsequent cyclization will yield the 11.

Scheme 2 Proposed reaction mechanism.

In conclusion, we have established a short and efficient methodology for the synthesis of isoindoloquinazolinone derivatives. The novel synthetic approach involves construction of two new rings via sequential C–N bond formation under Lewis acid condition. 4g-scale synthesis of compound 11a was performed with success. This methodology is operationally simple and amenable for scale-up.

Acknowledgements

The authors would like to thank Dr Vilas Dahanukar, Dr Rama Mohan and the analytical group of CPS-DRL for spectral data.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, spectral data for all new compounds, copies of spectra. See DOI: 10.1039/c5ra28097d

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