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

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

Received 5th January 2016 , Accepted 4th April 2016

First published on 5th April 2016


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.


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.
image file: c5ra28097d-f1.tif
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


image file: c5ra28097d-s1.tif
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 acidse
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


Table 2 Screening of solventsa
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.

Table 3 Synthesis of various isoindoloquinazolinones derivatives

image file: c5ra28097d-u1.tif

Entry R1 R2 R3 R4 R5 R6 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


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.


image file: c5ra28097d-s2.tif
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

  1. Bioactive Heterocyclic Compound Classes: Pharmaceuticals and Agrochemicals, ed. C. Lamberth and J. Dinges, Wiley-VCH, New York, 2012 Search PubMed.
  2. (a) S. S. Jew, H. J. Kim, M. G. Kim, E. Y. Roh, Y. S. Cho, J. K. Kim, K. H. Cha, K. K. Lee, H. J. Han, J. Y. Choi and H. Lee, Bioorg. Med. Chem. Lett., 1996, 6, 845 CrossRef CAS; (b) J. H. Lee, J. M. Lee, J. K. Kim, S. K. Ahn, S. J. Lee, M. Y. Kim, S. S. Jew, J. G. Park and C. Hong, Arch. Pharmacal Res., 1998, 21, 581 CrossRef CAS.
  3. (a) K. Dzierzbicka, P. Trzonkowski, P. L. Sewerynek and A. Mysliwski, J. Med. Chem., 2003, 46, 978 CrossRef CAS PubMed; (b) J. Guillaumel, S. Leonce, A. Pierre, P. Renard, B. Pfeiffer, P. B. Arimondo and C. Monneret, Eur. J. Med. Chem., 2006, 41, 379 CrossRef CAS PubMed; (c) R. Yilin, C. Yun Feng, C. Ting, A. Y. Chen, C. Yu, L. F. Liu and C. C. Cheng, Pharm. Res., 1993, 10, 918 CrossRef.
  4. P. Friedländer and N. Roschdestwensky, Chem. Ber., 1915, 48, 1841 CrossRef.
  5. N. K. Utkina and S. A. Fedoreev, Tetrahedron Lett., 2007, 48, 4445–4447 CrossRef CAS.
  6. (a) V. Ziaee, H. Jalalizadeh, M. Iranshahi and A. Shafiee, Iran. J. Chem. Chem. Eng., 2004, 23, 33 CAS; (b) A. Kamal, V. K. Ramana and M. V. Rao, J. Org. Chem., 2001, 66, 997 CrossRef CAS PubMed.
  7. (a) T. Harayama, Y. Morikami, Y. Shigeta, H. Abe and Y. Takeuchi, Synlett, 2003, 847–848 CrossRef CAS; (b) Z. Ma, Y. Hano, T. Nomura and Y. Chen, Bioorg. Med. Chem. Lett., 2004, 14, 1193–1196 CrossRef CAS PubMed; (c) M. C. Tseng, Y. W. Chu, H. P. Tsai, C. M. Lin, J. Hwang and Y. H. Chu, Org. Lett., 2011, 13, 920–923 CrossRef CAS PubMed; (d) S. B. Mhaske and N. P. Argade, J. Org. Chem., 2004, 69, 4563–4566 CrossRef CAS PubMed; (e) S. P. Chavan and R. Sivappa, Tetrahedron, 2004, 60, 9931–9935 CrossRef CAS; (f) M. B. Wagh, R. Shankar, U. K. S. Kumar and C. H. Gill, Synlett, 2011, 84–88 CAS; (g) L. Nagarapu, H. K. Gaikwad and R. Bantu, Synlett, 2012, 23, 1775–1778 CrossRef CAS; (h) M.-C. Tseng, P.-Y. Lai, L. Shi, H.-Y. Li, M.-J. Tseng and Y.-H. Chu, Tetrahydron, 2014, 70, 2629 CrossRef CAS; (i) R. Shankar, M. B. Wagh, M. V. Madhubabu, N. Vembu and U. K. S. Kumar, Synlett, 2011, 844–848 CAS.
  8. S. E. Yeulet, P. G. Mantle, J. N. Bilton, H. S. Rzepa and R. N. Sheppard, J. Chem. Soc., Perkin Trans. 1, 1986, 1891–1894 RSC.
  9. W. W. Li, X. Y. Wang, R. L. Zheng, H. X. Yan, Z. X. Cao, L. Zhong, Z. R. Wang, P. Ji, L. L. Yang, L. J. Wang, Y. Xu, J. J. Liu, J. Yang, C. H. Zhang, S. Ma, S. Feng, Q. Z. Sun, Y. Q. Wei and S. Y. Yang, J. Med. Chem., 2012, 55, 3852 CrossRef CAS PubMed.
  10. L. A. Mitscher, W. C. Wong, T. De Meulenere, J. Sulko and S. Drake, Heterocycles, 1981, 15, 1017–1019 CrossRef CAS.
  11. W. R. Bowman, M. R. J. Elsegood, T. Stein and G. W. Weaver, Org. Biomol. Chem., 2007, 5, 103–113 CAS.
  12. (a) R. K. Raghavendra, M. Ramamohan, A. Raghunadh, M. Suresh Babu, S. Praveen Kumar, D. Kalita, E. Laxminarayana, B. Prasad and M. Pal, RSC Adv., 2015, 5, 61575 RSC; (b) N. V. Murthy, S. P. Nikumbh, S. Praveen Kumar, L. Vaikunta Rao and A. Raghunadh, Tetrahedron Lett., 2015, 56, 5767–5770 CrossRef.
  13. J. MinQiang and L. Y. Shu, ACS Catal., 2013, 3, 622 CrossRef.
  14. (a) H. Yan, Z. Xinying and F. Xuesen, Chem. Commun., 2014, 50, 5641 RSC; (b) X. Pu, H. Li and T. J. Colacot, J. Org. Chem., 2013, 78, 568 CrossRef CAS PubMed.

Footnote

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

This journal is © The Royal Society of Chemistry 2016
Click here to see how this site uses Cookies. View our privacy policy here.