Synthesis of 3-arylquinazolin-4(3H)-imines from 2-amino-N&#39;-arylbenzamidines and triethyl orthoformate

Nikodem Kuźnik; Wojciech Szczepankiewicz

Synthesis of 3-arylquinazolin-4(3H)-imines from 2-amino-N'-arylbenzamidines and triethyl orthoformate

By Wojciech Szczepankiewicz and Nikodem Kuźnik

The synthesis of several 3-arylquinazolin-4(3H)-imines by the simple heating of 2-amino-N'-arylbenzamidines in triethyl orthoformate solution at 100 °C is described....Read more

Synthesis of 3-arylquinazolin-4(3H)-imines from 2-amino-N 0 -arylbenzamidines and triethyl orthoformate Wojciech Szczepankiewicz ⇑ , Nikodem Kuz ´ nik Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, 44-100 Gliwice, Poland article info Article history: Received 20 October 2014 Revised 30 December 2014 Accepted 20 January 2015 Available online 24 January 2015 Keywords: Amidines Unsubstituted imines Cyclization Triethyl orthoformate Quinazoline-imines abstract The synthesis of several 3-arylquinazolin-4(3H)-imines by the simple heating of 2-amino-N 0 -arylbenz- amidines in triethyl orthoformate solution at 100 °C is described. Ó 2015 Elsevier Ltd. All rights reserved. Quinazolin-4(3H)-imines unsubstituted at the 4a position are relatively less known compared to their 4(3H)-oxo analogues. These quinazoline-4(3H)-imines are typically obtained via the two-step reaction of anthranilonitrile with diethylthiocarbamoyl chloride, followed by cyclization of the resulting intermediate with N,N-dimethylformamide. 1 In a similar two-step reaction of anthra- nilonitrile with triethyl orthoformate and then with aliphatic amines, products with aliphatic substituents at the 3 position were obtained in moderate yields. 2 Several derivatives with an aromatic substituent at the same position have been obtained by the cycli- zation reaction of (2-cyanophenyl)chloromethanimidoyl chloride with anilines, 3 via the annulation of anthranilonitrile with triethyl orthoformate, 4 by intramolecular cyclization of o-cyanophenylcar- bodiimides in the presence of Lewis acids as catalysts, 5,6 or by the reaction of 2-amino-N 0 -arylbenzamidines 7,8 with 2,3-dichloro- 1,2,3-dithiazolium chloride. 9 Additionally, these imines have been postulated as intermediates in the reaction of 2-amino-N 0 -aryl- benzamidines with butanedione. 10 In these last two reactions the nitrogen atom of the @NAAr fragment of the amidine substrate was located at the 3 position of the newly created heterocyclic ring. On the other hand, reactions of 2-amino-N 0 -arylbenzamidines with formic acid, 7 aromatic aldehydes, 11 tetracyanoethylene, 12 isa- toic anhydride, 13 2-dicyanomethyleneindane-1,3-dione, 14 or with 2,3-dichloronaphtho-1,4-quinone 15 lead to the corresponding 4-arylamino or 4-aryliminoquinazoline derivatives. These examples show that the NAAr fragment of the amidine substrate was located at the exocyclic position of the quinazoline products. The above cited results indicate that the amidine group of 2-amino-N 0 -arylbenzamidine can act as an ambident nucleophilic reagent toward some electrophilic carbon synthons. However, the acidity of the nitrogen atom of the @NAAr fragment 11 and its nucleophilicity, calculated by semi-empirical 10 and DFT 16 meth- ods, is much higher than that of the NH 2 group of the amidine frag- ment. Thus, the higher reactivity of the N 0 -amidine atom suggests its predomination over the NH 2 fragment in cyclization reactions with carbon electrophiles. Hence, formation of the cyclic NAAr fragment should be preferred. Thus, products containing an exocy- clic NAAr fragment should be created in the subsequent process, for example, the Dimroth rearrangement of quinazoline-4(3H)- imine intermediates (Scheme 1). If our hypothesis were correct it should be possible to capture quinazoline-4(3H)-imine intermediates during the reaction of 2-amino-N 0 -arylbenzamidines 1a–g with an appropriate carbon electrophilic reagent. http://dx.doi.org/10.1016/j.tetlet.2015.01.133 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +48 32 2372635; fax: +48 32 2372094. E-mail address: wojciech.szczepankiewicz@polsl.pl (W. Szczepankiewicz). NH 2 N Ar NH 2 RCX 3 -3HX N N NH Ar N N HN Ar R R Scheme 1. Proposed sequence of the reaction of 2-amino-N 0 -arylbenzamidines with carbon electrophiles. Tetrahedron Letters 56 (2015) 1198–1199 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet

Triethyl orthoformate was the reagent of choice. It has weak acid–base properties and it would not be expected to participate in the possible subsequent Dimroth rearrangement of the postu- lated 4(3H)-imines. Initial attempts to perform the reaction of the amidines with triethyl orthoformate at its boiling point (146 °C) failed and complicated mixtures of products were obtained. However, reducing the temperature to 100 °C allowed 3-arylquinazolin-4(3H)-imines 2a–g to be obtained after two hours in moderate to good yields 17 (Scheme 2, Table 1). The distinction between imines 2a–g and the known isomeric 4-arylaminoquinazolines is relatively simple. The corresponding isomers differ in melting points. Additionally, the NMR and MS spectra differ signiﬁcantly. However, the most clear differences are visible on TLC plates (Merck Kieselgel 60 F 254). The imines 2a–g show R f values in the range of 0.4–0.5, while those of the iso- meric 4-arylaminoquinazolines 7 are located in the range of 0.8–0.9 (acetone/dichloromethane = 1:1). In conclusion, we have described a convenient, one-step method for the synthesis of several new 3-arylquinazolin-4(3H)- imines by heating 2-amino-N 0 -arylbenzamidines with triethyl orthoformate without any additional solvent or catalyst. The expected Dimroth rearrangement of the quinazoline-imines obtained into products with an exocyclic NAAr group is being studied. Acknowledgements The authors would like to thank Anna Pawlik for her intensive laboratory work. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.01. 133. References and notes 1. Ogata, M.; Matsumoto, H. Heterocycles 1978, 11, 139–144. 2. Nomoto, Y.; Takai, H.; Ohno, T.; Kubo, K. Chem. Pharm. Bull. 1991, 39, 900–910. 3. Divišová, H.; Havlišová, H.; Borek, P.; Pazdera, P. Molecules 2000, 5, 1166–1174. 4. Marinho, E.; Araújo, R.; Proença, F. Tetrahedron 2010, 66, 8681–8689. 5. Naganaboina, V. K.; Chandra, K. L.; Desper, J.; Rayat, S. Org. Lett. 2011, 13, 3718– 3721. 6. Alawode, O. E.; Naganaboina, V. K.; Liyanage, T.; Desper, J.; Rayat, S. Org. Lett. 2014, 16, 1494–1497. 7. Szczepankiewicz, W.; Suwin ´ ski, J. Tetrahedron Lett. 1998, 39, 1785–1786. 8. Koutentis, P. A.; Mirallai, S. I. Tetrahedron 2010, 66, 5134–5139. 9. Mirallai, S. I.; Manos, M. J.; Koutentis, P. A. J. Org. Chem. 2013, 78, 9906–9913. 10. Szczepankiewicz, W.; Kuz ´ nik, N.; Boncel, S.; Siewniak, A. Chem. Heterocycl. Compd. 2014, 50, 1291–1297. 11. Szczepankiewicz, W.; Suwin ´ ski, J.; Bujok, R. Tetrahedron 2000, 56, 9343–9349. 12. El-Shaieb, K. M.; Hopf, H.; Jones, P. G. Z. Naturforsch., B 2009, 64, 858–864. 13. El-Shaieb, K. M.; Hopf, H.; Jones, P. G. Z. Naturforsch., B 2009, 64, 945–951. 14. Abdel-Latif, F. F.; El-Shaieb, K. M.; El-Deen, A. G. J. Chem. Res. 2010, 699–701 15. El-Shaieb, K. M. J. Chem. Res. 2010, 137–139 16. Suwin ´ ski, J.; Szczepankiewicz, W.; Basso, E. A.; Tormena, C. F.; Freitas, M. P.; Rittner, R. Spectrochim. Acta, Part A 2003, 59, 3139–3145. 17. General procedure for the synthesis of 3-arylquinazolin-4(3H)-imines 2a–g:a mixture of amidine 1 (0.04 mol) and triethyl orthoformate (20 ml) was heated at 100 °C for 2 h. After completion of the reaction, the volatiles were removed under reduced pressure and the solid residue was recrystallized from EtOAc to give product 2. 3-(4-Bromophenyl)quinazolin-4(3H)-imine (2g): Colorless solid, mp 183–184 °C. 1 H NMR (400 MHz, CDCl 3 ): d H = 8.16 (d, 1H, H-5, J 8.0 Hz), 7.68–7.71 (m, 3H, H- 3 0 +H-5 0 +H-2), 7.63 (td, 1H, H-7, J 1 1.4 Hz and J 2 8.0 Hz), 7.57 (dd, 1H, H-8, J 1 1.4 Hz and J 2 8.0 Hz), 7.43 (dd, 1H, H-6, J 1 1.4 Hz and J 2 8.0 Hz), 7.27 (d, 2H, H- 2 0 +H-6 0 , J 8.6 Hz), 5.85 (br s, 1H, NH). 13 C NMR (100 MHz, CDCl 3 ): d C = 121.18 (C4 0 ), 123.57 (C4a), 124.85 (C2 0 +C6 0 ), 127.42 (C8), 127.55 (C6), 129.43 (C3 0 +C5 0 ), 132.95 (C7), 133.50 (C4), 136.81 (C1 0 ), 144.49 (C8a), 145.07 (C2), 154.97 (C4). EI-MS: m/z (%) 298 ([MÀH] + , 100), 300 ([MÀH+2] + , 96), 219 ([MÀHÀBr] + , 22), 171 ([C 6 H 6 79 BrN] + , 9), 173 ([C 6 H 6 81 BrN] + , 8), 155 ([C 6 H 4 79 BrN] + , 9), 157 ([C 6 H 4 81 BrN] + , 7), 102 ([C 7 H 4 N] + , 11), 76 ([C 6 H 4 ] + , 13). HRMS (ESI): calcd for [M+H] + : 300.0136; observed 300.0136. NH 2 N Ar NH 2 HC(OEt) 3 100 °C, 2 h N N NH Ar 2a-g 1a-g Scheme 2. Synthesis of 3-arylquinazolin-4(3H)-imines 2a–g. Table 1 3-Arylquinazolin-4(3H)-imines 2a–g obtained via the reaction of 2-amino-N 0 -aryl- benzamidines 1a–g with triethyl orthoformate Product Ar Yield (%) Mp (°C) 2a C 6 H 5 49 148–150 2b 2-MeC 6 H 4 81 100–101 2c 2,4-Me 2 C 6 H 3 94 105–107 2d 2-ClC 6 H 4 84 173–174 2e 3-ClC 6 H 4 67 156–158 2f 4-ClC 6 H 4 69 182–183 2g 4-BrC 6 H 4 65 183–184 W. Szczepankiewicz, N. Kuz ´nik / Tetrahedron Letters 56 (2015) 1198–1199 1199

Tetrahedron Letters 56 (2015) 1198–1199 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet Synthesis of 3-arylquinazolin-4(3H)-imines from 2-amino-N0 -arylbenzamidines and triethyl orthoformate Wojciech Szczepankiewicz ⇑, Nikodem Kuźnik Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, 44-100 Gliwice, Poland a r t i c l e i n f o Article history: Received 20 October 2014 Revised 30 December 2014 Accepted 20 January 2015 Available online 24 January 2015 a b s t r a c t The synthesis of several 3-arylquinazolin-4(3H)-imines by the simple heating of 2-amino-N0 -arylbenzamidines in triethyl orthoformate solution at 100 °C is described. Ó 2015 Elsevier Ltd. All rights reserved. Keywords: Amidines Unsubstituted imines Cyclization Triethyl orthoformate Quinazoline-imines Quinazolin-4(3H)-imines unsubstituted at the 4a position are relatively less known compared to their 4(3H)-oxo analogues. These quinazoline-4(3H)-imines are typically obtained via the two-step reaction of anthranilonitrile with diethylthiocarbamoyl chloride, followed by cyclization of the resulting intermediate with N,N-dimethylformamide.1 In a similar two-step reaction of anthranilonitrile with triethyl orthoformate and then with aliphatic amines, products with aliphatic substituents at the 3 position were obtained in moderate yields.2 Several derivatives with an aromatic substituent at the same position have been obtained by the cyclization reaction of (2-cyanophenyl)chloromethanimidoyl chloride with anilines,3 via the annulation of anthranilonitrile with triethyl orthoformate,4 by intramolecular cyclization of o-cyanophenylcarbodiimides in the presence of Lewis acids as catalysts,5,6 or by the reaction of 2-amino-N0 -arylbenzamidines7,8 with 2,3-dichloro1,2,3-dithiazolium chloride.9 Additionally, these imines have been postulated as intermediates in the reaction of 2-amino-N0 -arylbenzamidines with butanedione.10 In these last two reactions the nitrogen atom of the @NAAr fragment of the amidine substrate was located at the 3 position of the newly created heterocyclic ring. On the other hand, reactions of 2-amino-N0 -arylbenzamidines with formic acid,7 aromatic aldehydes,11 tetracyanoethylene,12 isatoic anhydride,13 2-dicyanomethyleneindane-1,3-dione,14 or with 2,3-dichloronaphtho-1,4-quinone15 lead to the corresponding 4-arylamino or 4-aryliminoquinazoline derivatives. These ⇑ Corresponding author. Tel.: +48 32 2372635; fax: +48 32 2372094. E-mail address: wojciech.szczepankiewicz@polsl.pl (W. Szczepankiewicz). http://dx.doi.org/10.1016/j.tetlet.2015.01.133 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved. examples show that the NAAr fragment of the amidine substrate was located at the exocyclic position of the quinazoline products. The above cited results indicate that the amidine group of 2-amino-N0 -arylbenzamidine can act as an ambident nucleophilic reagent toward some electrophilic carbon synthons. However, the acidity of the nitrogen atom of the @NAAr fragment11 and its nucleophilicity, calculated by semi-empirical10 and DFT16 methods, is much higher than that of the NH2 group of the amidine fragment. Thus, the higher reactivity of the N0 -amidine atom suggests its predomination over the NH2 fragment in cyclization reactions with carbon electrophiles. Hence, formation of the cyclic NAAr fragment should be preferred. Thus, products containing an exocyclic NAAr fragment should be created in the subsequent process, for example, the Dimroth rearrangement of quinazoline-4(3H)imine intermediates (Scheme 1). If our hypothesis were correct it should be possible to capture quinazoline-4(3H)-imine intermediates during the reaction of 2-amino-N0 -arylbenzamidines 1a–g with an appropriate carbon electrophilic reagent. N Ar NH2 NH2 NH RCX3 -3HX N N HN Ar R Ar N N R Scheme 1. Proposed sequence of the reaction of 2-amino-N0 -arylbenzamidines with carbon electrophiles. W. Szczepankiewicz, N. Kuźnik / Tetrahedron Letters 56 (2015) 1198–1199 N Ar NH2 NH2 obtained into products with an exocyclic NAAr group is being studied. NH HC(OEt) 3 N Ar Acknowledgements N 100 °C, 2 h 1a-g 1199 2a-g Scheme 2. Synthesis of 3-arylquinazolin-4(3H)-imines 2a–g. The authors would like to thank Anna Pawlik for her intensive laboratory work. Supplementary data Table 1 3-Arylquinazolin-4(3H)-imines 2a–g obtained via the reaction of 2-amino-N0 -arylbenzamidines 1a–g with triethyl orthoformate Product Ar Yield (%) Mp (°C) 2a 2b 2c 2d 2e 2f 2g C6H5 2-MeC6H4 2,4-Me2C6H3 2-ClC6H4 3-ClC6H4 4-ClC6H4 4-BrC6H4 49 81 94 84 67 69 65 148–150 100–101 105–107 173–174 156–158 182–183 183–184 Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.01. 133. References and notes 1. 2. 3. 4. 5. 6. Triethyl orthoformate was the reagent of choice. It has weak acid–base properties and it would not be expected to participate in the possible subsequent Dimroth rearrangement of the postulated 4(3H)-imines. Initial attempts to perform the reaction of the amidines with triethyl orthoformate at its boiling point (146 °C) failed and complicated mixtures of products were obtained. However, reducing the temperature to 100 °C allowed 3-arylquinazolin-4(3H)-imines 2a–g to be obtained after two hours in moderate to good yields17 (Scheme 2, Table 1). The distinction between imines 2a–g and the known isomeric 4-arylaminoquinazolines is relatively simple. The corresponding isomers differ in melting points. Additionally, the NMR and MS spectra differ significantly. However, the most clear differences are visible on TLC plates (Merck Kieselgel 60 F 254). The imines 2a–g show Rf values in the range of 0.4–0.5, while those of the isomeric 4-arylaminoquinazolines7 are located in the range of 0.8–0.9 (acetone/dichloromethane = 1:1). In conclusion, we have described a convenient, one-step method for the synthesis of several new 3-arylquinazolin-4(3H)imines by heating 2-amino-N0 -arylbenzamidines with triethyl orthoformate without any additional solvent or catalyst. The expected Dimroth rearrangement of the quinazoline-imines 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. Ogata, M.; Matsumoto, H. Heterocycles 1978, 11, 139–144. Nomoto, Y.; Takai, H.; Ohno, T.; Kubo, K. Chem. Pharm. Bull. 1991, 39, 900–910. Divišová, H.; Havlišová, H.; Borek, P.; Pazdera, P. Molecules 2000, 5, 1166–1174. Marinho, E.; Araújo, R.; Proença, F. Tetrahedron 2010, 66, 8681–8689. Naganaboina, V. K.; Chandra, K. L.; Desper, J.; Rayat, S. Org. Lett. 2011, 13, 3718– 3721. Alawode, O. E.; Naganaboina, V. K.; Liyanage, T.; Desper, J.; Rayat, S. Org. Lett. 2014, 16, 1494–1497. Szczepankiewicz, W.; Suwiński, J. Tetrahedron Lett. 1998, 39, 1785–1786. Koutentis, P. A.; Mirallai, S. I. Tetrahedron 2010, 66, 5134–5139. Mirallai, S. I.; Manos, M. J.; Koutentis, P. A. J. Org. Chem. 2013, 78, 9906–9913. Szczepankiewicz, W.; Kuźnik, N.; Boncel, S.; Siewniak, A. Chem. Heterocycl. Compd. 2014, 50, 1291–1297. Szczepankiewicz, W.; Suwiński, J.; Bujok, R. Tetrahedron 2000, 56, 9343–9349. El-Shaieb, K. M.; Hopf, H.; Jones, P. G. Z. Naturforsch., B 2009, 64, 858–864. El-Shaieb, K. M.; Hopf, H.; Jones, P. G. Z. Naturforsch., B 2009, 64, 945–951. Abdel-Latif, F. F.; El-Shaieb, K. M.; El-Deen, A. G. J. Chem. Res. 2010, 699–701 El-Shaieb, K. M. J. Chem. Res. 2010, 137–139 Suwiński, J.; Szczepankiewicz, W.; Basso, E. A.; Tormena, C. F.; Freitas, M. P.; Rittner, R. Spectrochim. Acta, Part A 2003, 59, 3139–3145. General procedure for the synthesis of 3-arylquinazolin-4(3H)-imines 2a–g: a mixture of amidine 1 (0.04 mol) and triethyl orthoformate (20 ml) was heated at 100 °C for 2 h. After completion of the reaction, the volatiles were removed under reduced pressure and the solid residue was recrystallized from EtOAc to give product 2. 3-(4-Bromophenyl)quinazolin-4(3H)-imine (2g): Colorless solid, mp 183–184 °C. 1 H NMR (400 MHz, CDCl3): dH = 8.16 (d, 1H, H-5, J 8.0 Hz), 7.68–7.71 (m, 3H, H30 +H-50 +H-2), 7.63 (td, 1H, H-7, J1 1.4 Hz and J2 8.0 Hz), 7.57 (dd, 1H, H-8, J1 1.4 Hz and J2 8.0 Hz), 7.43 (dd, 1H, H-6, J1 1.4 Hz and J2 8.0 Hz), 7.27 (d, 2H, H20 +H-60 , J 8.6 Hz), 5.85 (br s, 1H, NH). 13C NMR (100 MHz, CDCl3): dC = 121.18 (C40 ), 123.57 (C4a), 124.85 (C20 +C60 ), 127.42 (C8), 127.55 (C6), 129.43 (C30 +C50 ), 132.95 (C7), 133.50 (C4), 136.81 (C10 ), 144.49 (C8a), 145.07 (C2), 154.97 (C4). EI-MS: m/z (%) 298 ([M H]+, 100), 300 ([M H+2]+, 96), 219 ([M H Br]+, 22), 171 ([C6H679BrN]+, 9), 173 ([C6H681BrN]+, 8), 155 ([C6H479BrN]+, 9), 157 ([C6H481BrN]+, 7), 102 ([C7H4N]+, 11), 76 ([C6H4]+, 13). HRMS (ESI): calcd for [M+H]+: 300.0136; observed 300.0136.

Log In

Synthesis of 3-arylquinazolin-4(3H)-imines from 2-amino-N'-arylbenzamidines and triethyl orthoformate