Advancements in the synthesis of fused tetracyclic quinoline derivatives

Abstract

Fused tetracyclic systems containing a quinoline nucleus represent an important class of heterocyclic bioactive natural products and pharmaceuticals because of their significant and wide-spectrum biological properties. Several of these compounds have been obtained with diverse pharmacological and biological activities, such as antiplasmodial, antifungal, antibacterial, potent antiparasitic, antiproliferative, anti-tumor and anti-inflammatory activities. This information will be beneficial for medicinal chemists in the field of drug discovery to design and synthesize new fused tetracyclic quinolines as potent therapeutical agents. This review article provides a comprehensive report regarding the methods developed for the synthesis of fused tetracyclic quinolines reported so far (till October 2019). The article includes synthesis by one-pot domino reaction, microwave synthesis using a catalyst, using ionic liquids, photocatalytic synthesis (UV radiation), Pfitzinger reaction, I₂-catalyzed cyclization reaction, Wittig reaction, cascade reaction, imino Diels-Alder reaction, Friedel-Crafts reaction, CDC reaction, solvent-free reactions and using small chiral organic molecules as catalysts. To the best of our knowledge, this is the first review focused on the synthesis of fused tetracyclic quinolines along with mechanistic aspects.

Fig. 1. Structures of natural products containing quinoline ring.

Scheme 1. Synthesis of isoindolo[2,1-a]quinoline-5,11-diones 3.

Scheme 2. The synthetic route to tetracyclic isoindolo[2,1-a]quinolines 10.

Scheme 3. An efficient synthesis of isoindolo[2,1-a]quinolines 16 from 11.

Scheme 4. Synthesis of isoindolo[2,1-a]quinolines 16 from 17.

Scheme 5. Synthesis of isoindolo[2,1-a]quinolines 22 from phthalimides 20.

Scheme 6. Synthesis of 5,11-dihydroisoindolo[2,1-a]quinoline-5,11-diones 25 and 26.

Scheme 7. Synthesis of 11-benzoyl-8,10-dinitroisoindolo[2,1-a]quinoline (30).

Scheme 8. Synthesis of 6-azido-isoindolo[2,1-a]quinoline-5,11-diones 34.

Scheme 9. One-pot synthesis of isoindolo[2,1-a]quinolin-11-ones 36 by reacting 7 with 35.

Scheme 10. A plausible mechanism for the formation of isoindolo[2,1-a]quinolin-11-ones 36.

Scheme 11. Synthesis of isoindolo[2,1-a]quinoline-5,11-dione (16).

Scheme 12. Microwave-assisted synthesis of isoindolo[2,1-a]quinoline-5,11-diones 45.

Scheme 13. Synthesis of 2-chloro-isoindolo[2,1-a]quinoline-5(11H)-one (47) via intramolecular Heck coupling cyclization of 46.

Scheme 14. Synthesis of indeno[1,2-b]quinolin-11-ones 49via intramolecular CDC reaction.

Scheme 15. Proposed mechanism for the formation of indeno[1,2-b]quinolin-11-ones 49via intramolecular CDC reaction.

Scheme 16. Synthesis of 11-oxo-11H-indeno[1,2-b]quinoline-6-carboxamides 56.

Scheme 17. Synthesis of indeno[1,2-c]quinolines 61.

Scheme 18. Synthesis of 6-amino-9-chloro-11H-indeno[1,2-c]quinoline-11-ones 65.

Scheme 19. Synthesis of indolo[2,3-b]quinoline derivatives 70a–c.

Scheme 20. Chemoselective Suzuki reaction of 2,3-dihaloquinsolines 71 and 73.

Scheme 21. Synthesis of 10H-indolo[3,2-b]quinolines 75 and 6H-indolo[2,3-b]quinolines 76.

Scheme 22. Synthesis of 6H-indolo[2,3-b]quinolines 79.

Scheme 23. Synthesis of 6H-indolo[2,3-b]quinolines 84.

Scheme 24. Synthesis of 11-chloroneocryptolepines 89.

Scheme 25. Molecular iodine catalyzed synthesis of polyfunctionalized indolo[2,3-b]-quinolines 92.

Scheme 26. Pd-mediated synthesis of 11-carboxymethyl substituted 6H-indolo[2,3-b]-quinolines 95.

Scheme 27. Proposed reaction mechanism for the formation of 11-carboxymethyl substituted 6H-indolo[2,3-b]quinolines 95.

Scheme 28. NBS catalyzed synthesis of novel indolo[2,3-b]quinolines 98.

Scheme 29. Synthesis of 6H-indolo[2,3-b]quinolines 103via thermolysis of N-[2-(1-alkynyl)-phenyl]-N-phenylcarbodiimides 100.

Scheme 30. Synthesis of 6-methyl-indolo[2,3-b]quinolines 105 by Pd-catalyzed annulation of unsaturated isothioureas.

Scheme 31. A suggested mechanism for the Pd-catalyzed formation of 6-methyl-indolo[2,3-b]quinolines 105.

Scheme 32. A green method for the synthesis of 11-aryl-6H-indolo[2,3-b]quinolines 108 under microwave heating.

Scheme 33. Proposed mechanistic pathway.

Scheme 34. Synthesis of indolo[2,3-b]quinolines 111via Heck–Suzuki coupling and DDQ-mediated C–H amination.

Scheme 35. A suggested mechanism for the DDQ-mediated oxidative C–H cycloamination.

Scheme 36. A novel approach for the synthesis of 5-methyl-5H-indolo[2,3-b]quinoline (127).

Scheme 37. A four-step formal synthesis of 5-methsyl-5H-indolo[2,3-b]quinoline (127).

Scheme 38. Synthesis of 6-methyl-6H-indolo[2,3-b]quinolines 139via one-pot reduction–cyclization–dehydration reactions of α-hydroxy lactams 136.

Scheme 39. A short and convenient method for the synthesis of 6H-indolo[2,3-b]quinoline (145).

Scheme 40. A new synthesis of 6H-indolo[2,3-b]quinolines 145.

Scheme 41. A novel and one-pot synthesis of different 6H-indolo[2,3-b]quinolines 150 using I₂ as a catalyst.

Scheme 42. Postulated mechanism for the formation of 150.

Scheme 43. Route toward the synthesis of 162.

Scheme 44. RuY catalyzed synthesis of 6H-indolo[2,3-b]quinolines 150.

Scheme 45. Proposed mechanistic pathway for the RuY catalyzed formation of 6H-indolo- [2,3-b]quinoline 150.

Scheme 46. One-step synthesis of 5-methyls-5H-indolo[2,3-b]quinolines 165.

Scheme 47. Proposed synthesis of 5-methyl-5H-indolo[2,3-b]quinolines 165.

Scheme 48. A concise synthesis of 6H-indolo[2,3-b]quinolines 171.

Scheme 49. Proposed mechanism for the formation of 6H-indolo[2,3-b]quinolines 171.

Scheme 50. A pivalic-acid assisted one-pot alkylation–dehydration–cyclization–aromatization method for the synthesis of 6H-indolo[2,3-b]quinolines 173.

Scheme 51. A plausible mechanism for the synthesis of 6H-indolo[2,3-b]quinolines 173.

Scheme 52. Iron-promoted synthesis of 6H-indolo[2,3-b]quinolines 180 from the reaction of 179 with different indoles 90.

Scheme 53. Postulated mechanism for the construction of indolo[2,3-b]quinolines 180 from 179 and 90.

Scheme 54. Rh(iii)-catalyzed C–H amination/annulation of substituted indole derivatives 90 with 181.

Scheme 55. Plausible catalytic cycle.

Scheme 56. Synthesis of 6-substituted-6H-indolo[2,3-b]quinolines 185 from isoindigo derivatives 184 in the presence of SnCl₂ in acidic media.

Scheme 57. A possible reaction mechanism for the formation of 6-substituted-6H-indolo-[2,3-b]quinolines 185.

Scheme 58. Scope of DDQ-mediated intramolecular C2–N bond formation for the synthesis of indolo[2,3-b]quinolines 190.

Scheme 59. Microwave-mediated Bi(NO₃)₃-catalyzed synthesis of indolo[2,3-b]quinolines 98.

Scheme 60. Plausible reaction mechanism for Bi(iii)-catalyzed synthesis of indolo[2,3-b]-quinolines 98 through activation of the in situ formed imine.

Scheme 61. Synthesis of 5,11-dihydro-6H-indolo[3,2-c]quinolin-6-ones 193.

Scheme 62. A new methodology for the synthesis of indolo[3,2-c]quinolines 197–199.

Scheme 63. A one-pot procedure for the synthesis of 6-aryl-11H-indolo[3,2-c]quinolines 203.

Scheme 64. A plausible reaction mechanism for the formation of 203.

Scheme 65. A convenient synthesis of 6-substituted-11-methyl-11H-indolo[3,2-c]quinolines 205, 206 and 208.

Scheme 66. Synthesis of D-ring substituted 11H-indolo[3,2-c]quinolines 212via auto-tandem Pd-catalyzed intermolecular C–N and intramolecular C–C bond formation.

Scheme 67. Reductive cyclization of 2-(2-nitrophenyl)indoles 213 to indolo[3,2-c]quinolines 214.

Scheme 68. The proposed mechanism of indolo[3,2-c]quinoline 214 formation.

Scheme 69. Synthesis of 11H-indolo[3,2-c]quinolines 218 with amino group substituted at the C-6 position.

Scheme 70. One-pot two-step synthesis of 221 from 219, 220 and aq. NH₃.

Scheme 71. Plausible mechanism for the formation of 221.

Scheme 72. A new and convenient synthesis of 11-aryl-11H-indolo[3,2-c]quinolines 224.

Scheme 73. Synthesis of indolo[3,2-c]quinolines 227 from 2-(2-nitrophenyl)indole (225).

Scheme 74. A plausible mechanism for the formation of 227 from 225 and 226.

Scheme 75. Synthesis of indolo[3,2-c]quinolines 230via PPA-mediated cyclization reaction between 228 and 229.

Scheme 76. A plausible mechanism for the formation of 230.

Scheme 77. Pd-catalyzed synthesis of benzofuro[3,2-c]quinolin-6(5H)-ones 233.

Scheme 78. Synthesis of 6H-chromeno[4,3-b]quinoline-6-ones 236.

Scheme 79. Synthesis of CFQ 237 and CFDQ 238.

Scheme 80. Possible mechanism for the formation CFDQ 238.

Scheme 81. Plausible mechanism for the formation CFQ 237 from CFDQ 238.

Scheme 82. TMSCl-mediated synthesis of 240 from 239.

Scheme 83. Three steps synthesis of 3,9-dimethoxy-6,12-dihydro-6H-chromeno[4,3-b]-quinoline-7-one (245).

Scheme 84. Synthesis of 7-halogenated-6H-chromeno[4,3-b]quinolines 247via Cu-catalyzed cascade reaction.

Scheme 85. A suggested mechanism for the formation of 247 from 246.

Scheme 86. Highly modular synthesis of chromeno[4,3-b]quinolines 250via arylation-ring closure.

Scheme 87. A plausible mechanism for the formation of chromeno[4,3-b]quinolines 250via arylation–cyclization reaction.

Scheme 88. Cyclization of 2-[(3-substituted-phenoxy)methyl]quinolines 251 to chromeno-[3,4-b]quinolines 252.

Scheme 89. Proposed mechanism for the formation of tetracyclic 252 from 251.

Scheme 90. One-pot synthesis of cyclopenta[b]pyrrolo[3,2-f]quinolins 255 and pyrrolo-[3,2-a]acridines 258 under catalyst-free conditions.

Scheme 91. Synthesis of benzopyrano[4,3-c]quinoline (262) from N-methylformanilide (259) and homophthalic acid (260).

Scheme 92. Synthesis of benzopyrano[4,3-b]quinoline derivatives 266 and 267.

Scheme 93. A regioselective synthesis of new benzothiopyrano[2,3-b]quinolines 270.

Scheme 94. A one-pot synthesis of benzothieno[3,2-b]quinoline-4,11-dicarboxylic acid (275).

Scheme 95. A new method for the synthesis of benzothieno[3,2-b]quinoline-11(5H)-one (280).

Scheme 96. Synthesis of benzothieno[2,3-b]quinolines 284via reaction of 2-ethynylaryl radicals 282 with aryl isothiocyanates 283.

Scheme 97. Reaction mechanism for the formation of benzothieno[2,3-b]quinolines 284.

Scheme 98. Synthesis of benzothieno[3,2-b]quinolines 292 from 265 and 288.

Scheme 99. A highly efficient synthesis of new benzothieno[3,2-b]quinolines 296via the Pd-catalyzed reaction of 293 with 97.

Scheme 100. One-pot synthesis of benzothieno[3,2-b]quinoline (300).

Scheme 101. Molecular iodine catalyzed synthesis of fused tetracyclic quinolines 305–307.

Scheme 102. A plausible mechanism for the synthesis of products 305–307.

Scheme 103. Synthesis of furothiopyrano[2,3-b]quinolines 312via iodocyclization of 3-homoallylquinolin-2-thiones 311.

Scheme 104. Plausible mechanism for the formation of furothiopyrano[2,3-b]quinolines 312.

Scheme 105. Synthesis of quinolino[3,2-b]quinoxalines 319 in one-pot process.

Scheme 106. Synthesis of pyrido[2′,1′:2,3]imidazo[4,5-c]quinolines 322.

Scheme 107. Plausible mechanism for the formation of pyrido[2′,1′:2,3]imidazo[4,5-c]-quinolines 322.

Scheme 108. Synthesis of new fluorescent tetracyclic compounds 326.

Scheme 109. Proposed mechanism for the formation of pyrido[2′,1′:2,3]imidazo[4,5-b]-quinolines 326.

Scheme 110. Synthesis of pyrido[2′,1′:2,3]imidazo[4,5-b]quinoline (328) via auto-tandem amination on 327 with 320.

Scheme 111. DBU-catalyzed synthesis of pyrido[2′,1′:2,3]imidazo[4,5-b]quinolines 330.

Scheme 112. Acetic acid catalyzed synthesis of imidazo[1′,2′:1,2]pyrrolo[3,4-c]quinolin-11-ones 334via cascade of reactions.

Scheme 113. Molecular I2 catalyzed synthesis of cyclopenta[c]pyrazolo[4,3-f]quinolines 336.

Scheme 114. Synthesis of benzo[h]pyrimido[4,5-b]quinoline-8,10-diones 339 in ionic liquid.

Scheme 115. l-Proline mediated synthesis of benzo[g]pyrazolo[3,4-b]quinoline-5,10-diones 342.

Scheme 116. Proposed mechanism for the formation of benzo[g]pyrazolo[3,4-b]quinoline-5,10-diones 342.

Scheme 117. A multistep synthesis of thieno[3′,2′:4,5]thieno[2,3-c]quinolones 347.

Scheme 118. Synthesis of ethyl 5-alkyl-5H-1-thia-3,5,6-triazaaceanthrylenes 352–354, 357 and ethyl 5-alkyl-5H-1-thia-3,4,5,6-tetraazaaceanthrylenes 355.

Scheme 119. Synthesis of 1,2,3,5,6-pentaazaaceanthrylenes 359 and 361.

Scheme 120. Synthesis of 1,2,3,4,5,6-hexaazaaceanthrylenes 366 from 363.

Scheme 121. Synthesis of 5,7,8,10a,11-pentaazabenzo[a]fluorenes 372.

Scheme 122. Synthesis of novel 1H-5-thia-1,2,3,6-tetraazaacephenanthrylenes 376, 1H-5-thia-1,3,6-triazaacephenanthrylenes 377 and linear pyrimidothienoquinolines 380.

Scheme 123. Synthesis of methyl 3-amino-1,4,5,6,6a-pentaazabenzo[a]indacene-2-carboxylate (387).

Scheme 124. Synthesis of new 1,4,5,6,6a-pentaazabenzo[a]indacenes 389 and 391.

Scheme 125. Synthesis of methyl 1-ethyl-4-thioxo-3(4H)-1,3,5,6-tetraazaaceanthrylene-2-carboxylates 392 and 5,7,9,11-tetraazabenzo[a]fluorenes 394.

Scheme 126. Synthesis of methyl 5-butyl-1-ethyl-4-oxo-3(4H)-1,3,5,6-tetraazaaceanthrylene-2-carboxylate (395) and methyl 5-butyl-1-ethyl-1,3,5,6-tetraazaaceanthrylene-2-carboxylate (396).

Scheme 127. Synthesis of 1-aryl-1,2,3,4,5,6-hexaazaacephenanthrylenes 399 from 348.

Scheme 128. Synthesis of isoxazolo[3′,4′:4,5]pyrrolo(or thieno)[3,2-c]quinolines 403.

Scheme 129. Synthesis of 3-amino-1H-pyrazolo[4,3-c]quinoline derivatives 405.

Scheme 130. Reaction mechanism for the formation of 3-amino-4-chloro-1H-pyrazolo-[4,3-c]quinoline (363).

Scheme 131. Coupling reaction of 411 with active methylenes 412.

Scheme 132. Reaction mechanism for the formation of 9-substituted-[1,2,4]triazino[4′,3′:1,5]-pyrazolo[4,3-c]quinolines 413.

Scheme 133. Synthesis of 3-alkyl-4-amino-5-chloro-2-oxo-2,3-dihydrobenzo[c][2,7]naphthy-ridine-1-carbonitriles 418.

Scheme 134. Synthesis of 3-alkyl-2-oxo-6-phenyl-5-thioxo-3,4,5,6-tetrahydro-2H-benzo[c]-pyrimido[4,5,6-ij][2,7]naphthyridine-1-carbonitriles 420.

Scheme 135. Synthesis of 3,6-dialkyl-5-methyl-2-oxo-3,6-dihydro-2H-benzo[c]pyrimido-[4,5,6-ij][2,7]naphthyridine-1-carbonitriles 424.

Scheme 136. Synthesis of benzo[c]pyrimido[4,5,6-ij][2,7]naphthyridine-1-carbonitriles 425 and benzo[c][1,2,3]triazino[4,5,6-ij][2,7]naphthyridine-1-carbonitriles 427.

Scheme 137. Synthesis of 8-amino-6-substituted-pyrimido[1′,2′:1,5]pyrazolo[4,3-c]quinoline-9,10-dicarbonitriles 428.

Ramadan A. Mekheimer

Mariam A. Al-Sheikh