M. V. Madhubabua,
R. Shankara,
Satish. S. Morea,
Mandava V. Basaveswara Raob,
U. K. Syam Kumar*a and
A. Raghunadh*a
aTechnology Development Centre, Custom Pharmaceutical Services, Dr. Reddy's Laboratories Ltd, Hyderabad 500049, India. E-mail: raghunadha@drreddys.com
bDepartment of Chemistry, Krishna University, Machilipatnam, Andhra Pradesh, India
First published on 5th April 2016
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.
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
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).
Entry | Lewis acid (eq./vol) | Yieldb (%) |
---|---|---|
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·Et2Oa (3.0 eq.) | 62 |
2 | BF3·Et2Oa (1.5 eq.) | 49 |
3 | BF3·Et2Oa (2.0 eq.) | 61 |
4 | BF3·Et2Oc (3.0 eq.) | 49 |
5 | BF3·Et2Od (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 |
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 |
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.
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.
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.
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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