Applications of Palladium-Catalyzed C-N Cross-Coupling Reactions

Abstract

Pd-catalyzed cross-coupling reactions that form C-N bonds have become useful methods to synthesize anilines and aniline derivatives, an important class of compounds throughout chemical research. A key factor in the widespread adoption of these methods has been the continued development of reliable and versatile catalysts that function under operationally simple, user-friendly conditions. This review provides an overview of Pd-catalyzed N-arylation reactions found in both basic and applied chemical research from 2008 to the present. Selected examples of C-N cross-coupling reactions between nine classes of nitrogen-based coupling partners and (pseudo)aryl halides are described for the synthesis of heterocycles, medicinally relevant compounds, natural products, organic materials, and catalysts.

Figure 1

Summary of supporting ligands and palladium precatalysts most frequently encountered in this review.

Figure 2

Main fields of application of Pd-catalyzed C–N cross-coupling reactions.

Scheme 1. Synthesis of Heterocycles via the Coupling of Primary Alkylamines

Scheme 2. Synthesis of Biologically Active Compounds via the Coupling of Primary Alkylamines

Scheme 3. Applications of the Coupling of Primary Alkylamines in Medicinal Chemistry

Scheme 4. N-Arylation of Primary Alkylamines in the Synthesis of Natural Products

Scheme 5. Synthesis of Organic Materials via the Coupling of Primary Alkylamines

Scheme 6. Synthesis of a Hydrocarbon Dendron via the Coupling of a Primary Alkylamine

Scheme 7. Synthesis of Diaminoanthraquinones via the Coupling of Alkyl Primary Amines

Scheme 8. Synthesis of NHCs via the Coupling of Primary Alkylamines

Scheme 9. Synthesis of Chiral Ligand via the Coupling of an Alkyl Primary Amine

Scheme 10. Applications of Substituted Piperidines in Drug Discovery

Scheme 11. Examples of Heterocyclic-Containing Piperidines in Medicinal Chemistry

Scheme 12. Use of Pyrrolidines in the Synthesis of Drug Candidates

Scheme 13. Examples of the Coupling of Secondary Cyclic Amines in the Pharmaceutical Industry

Scheme 14. Applications of Piperazine in Medicinal Chemistry

Scheme 15. N-Arylation of 4-Substituted Piperazines

Scheme 16. Piperazine Derivatives in C–N Cross-Coupling Reactions

Scheme 17. Examples of Morpholine Coupling in the Synthesis of Pharmaceutically Interesting Compounds

Scheme 18. C–N Cross-Coupling of Ortho-Substituted Piperazine 119 Using an L15-Based Catalyst

Scheme 19. Use of Secondary Amine N-Arylation in Total Synthesis

Scheme 20. Applications of Linear Dialkylamines in the Synthesis of Organic Materials

Scheme 21. Corrole Functionalization via Piperazine and Morpholine Coupling

Scheme 22. General Strategies for the Synthesis of Heterocycles via the Coupling of Primary Anilines

Scheme 23. Synthesis of Acridines and N-Aryl-4-quinolones via the Coupling of Primary Anilines

Scheme 24. Synthesis of Dibenzodiazepines via the Intramolecular Coupling of Primary Anilines

Scheme 25. General Strategies for the Synthesis of Carbazole Derivatives via the Coupling of Primary Anilines

Scheme 26. Synthesis of Carbazole-Based Heterocycles via the Sequential Intermolecular Coupling of Primary Anilines/C–H Activation Reactions

Scheme 27. Synthesis of Carbazoles via the Double N-Arylation of Primary Anilines

Scheme 28. Synthesis of Heterocycles via the Double N-Arylation of Primary Anilines

Scheme 29. Synthesis of Biscarbazoles via the Coupling of Primary Anilines

Scheme 30. Synthesis of N-Substituted Dibenzoazepines and Benzotriazoles via the Intermolecular Coupling of Primary Anilines

Scheme 31. Synthesis of N-Methylacridones and Dibenzoazepinones via the Coupling of Primary Anilines

Scheme 32. Synthesis of Bioactive Compounds Containing Diarylamines via the Coupling of Primary Anilines

Scheme 33. Synthesis of Biologically Active Diarylamines

Scheme 34. Synthesis of Bioactive Compounds Containing Pyrimidine(aryl)amines via the Coupling of Primary Anilines

Scheme 35. Synthesis of Biologically Active Compounds Containing Pyrazine(aryl)amines via the Coupling of Primary Anilines

Scheme 36. General Strategies for the Synthesis of N-Arylbenzimidazoles via the Coupling of Primary Anilines

Scheme 37. Synthesis of Bioactive Compounds Containing Benzo-Fused Azoles via the Coupling of Primary Anilines

Scheme 38. Synthesis of Carbazole Alkaloids via the Coupling of Primary Anilines

Scheme 39. Synthesis of Carbazole Alkaloids via a C–N/C–H Bond-Forming Sequence

Scheme 40. General Strategies for the Synthesis of Materials via the Coupling of Primary Anilines

Scheme 41. Synthesis of Materials via the Intramolecular Cyclization of Primary Anilines

Scheme 42. Synthesis of Materials via the Intermolecular Cyclization of Primary Anilines

Scheme 43. Synthesis of Materials via the Intermolecular Coupling of Primary Anilines

Scheme 44. Synthesis of Materials via the Intermolecular Coupling of Primary Anilines

Scheme 45. Synthesis of Materials via the Sequential Intermolecular/Intramolecular Coupling of Anilines

Scheme 46. Synthesis of Materials via the Sequential Intermolecular Couplings of Anilines

Scheme 47. Synthesis of Materials via Multiple N-Arylation Reactions

Scheme 48. Examples of Ligand Synthesis via the Coupling of Primary Anilines

Scheme 49. Examples of the Synthesis of BOPA-type Ligands via the Coupling of Primary Anilines

Scheme 50. Ferrocene-type Ligand Synthesis via the Coupling of Primary Anilines

Scheme 51. Synthesis of Phenanthridines via the Intramolecular Coupling of Secondary Anilines

Scheme 52. Synthesis of Drug Candidates via the Intermolecular Coupling of Secondary Anilines

Scheme 53. Synthesis of Natural Products via the Intramolecular Coupling of Secondary Anilines

Scheme 54. Use of N-Arylation of Secondary Anilines To Remove Protecting Groups Selectively

Scheme 55. Synthesis of Materials via the Intermolecular Cyclization with Secondary Anilines

Scheme 56. Synthesis of Double-Decker 272 via the Intermolecular Cyclization of Secondary Anilines

Scheme 57. Synthesis of Materials via the Coupling of Secondary Anilines

Scheme 58. Synthesis of Materials via Multiple Couplings of Secondary Anilines

Scheme 59. Synthesis of Materials via Multiple Couplings of Secondary Anilines

Scheme 60. Synthesis of Metal Complexes via the Coupling of Secondary Anilines

Scheme 61. Heterocycle Synthesis via Intermolecular 2-Aminopyridine Coupling

Scheme 62. Synthesis of Drug Candidates via 2-Aminopyridine Coupling

Scheme 63. Synthesis of Drug Candidate 301 via 3-Aminopyridine Coupling

Scheme 64. Scalable Synthesis of Biologically Active Compound 304 via 2-Aminopyridine Coupling

Scheme 65. Synthesis of N-Substituted Azacalix[6]aromatics via 2-Aminopyridine Coupling

Scheme 66. Synthesis of Interesting Materials via the Coupling of 3-Amino- or 4-Aminopyridines

Scheme 67. Synthesis of Ligands via 2-Aminopyridine Coupling

Scheme 68. Synthesis of Drug Candidates via 2-Aminopyrimidine Coupling Reactions

Scheme 69. Synthesis of Drug Candidates via 2-Aminopyrimidine Coupling

Scheme 70. Nucleobase Functionalization via 2-Amino-4-pyrimidone

Scheme 71. Heterocycle Synthesis via Aminodiazine Coupling

DME = dimethoxyethane.

Scheme 72. Synthesis of Drug Candidates via Aminotriazine Coupling

Scheme 73. Examples of Aminopyrrole Coupling

Scheme 74. Synthesis of Bioactive Compounds via Aminothiopehene and Aminofuran Coupling

Scheme 75. Synthesis of Drug Candidates via Aminopyrazole, Aminoimidazole, and Aminothiazole Coupling

Scheme 76. Recent Methods for Selective Arylation of Unprotected Aminopyrazoles and Aminoimidazoles

Scheme 77. General Strategies for Heterocycle Synthesis via Amide Coupling

Scheme 78. Heterocycle Synthesis via Intramolecular Primary Amide Coupling

Scheme 79. Heterocycle Synthesis via Intermolecular Primary Amide Coupling

Scheme 80. Benzimidazole Synthesis via Intermolecular Primary Amide Coupling

Scheme 81. Synthesis of Drug Candidates via Primary Amide Coupling

Scheme 82. Continuous Flow Synthesis of TRPC Inhibitors

Scheme 83. Examples of Primary Amide Coupling in Synthesis of Natural Products

DMB = 2,4- dimethoxybenzyl.

Scheme 84. Synthesis of Optically Active Compounds via Primary Amide Coupling

Scheme 85. Ligand Synthesis via Primary Amide Coupling

Scheme 86. Heterocycle Synthesis via Lactam Coupling

Scheme 87. Heterocycle Synthesis via Intramolecular Secondary Amide Coupling

Scheme 88. Post-Ugi Functionalization via Intramolecular Secondary Amide Coupling

Scheme 89. Synthesis of Spiroindolinones

Scheme 90. Post-Ugi Functionalization via Intramolecular Secondary Amide Coupling

Scheme 91. Heterocycle Synthesis via Intermolecular Secondary Amide Coupling

Scheme 92. Synthesis of Drug Candidates via Coupling of Lactams or Intramolecular Coupling of Secondary Amides

Scheme 93. Scalable Synthesis of Bioactive Compound 30 via Lactam Coupling

Scheme 94. Examples of Lactam and Intramolecular Secondary Amide Coupling in Natural Products Synthesis

Scheme 95. Synthesis of Drug Candidates via Sulfonamide Coupling

Scheme 96. Large-Scale Synthesis of Biologically Active Compounds 411 and 413 via Sulfonamide Coupling

Scheme 97. Heterocycle Synthesis via Urea Coupling

Scheme 98. Synthesis of Biologically Active Compounds by the Coupling of Ureas

Methyl ester formation was due to the presence of MeOH in the DME.

Scheme 99. Synthesis of Omecamtiv Mecarbil via Urea Coupling

Scheme 100. Scalable Synthesis of Drug Candidate 419 via Urea Coupling

Scheme 101. Synthesis of Indoles via Carbamate Coupling

Scheme 102. Carbamate Coupling in Medicinal and Process Chemistry

Scheme 103. Synthesis of Optically Active Caged Glutamates via Carbamate Coupling

Scheme 104. Synthesis of Optically Active Materials via Carbamate Coupling

Scheme 105. Synthesis of Thiourea-Based Organocatalysts via Carbamate Coupling

Scheme 106. Synthesis of Benzimidazoles via Intramolecular and Intermolecular Amidine Coupling

Scheme 107. Heterocycle Synthesis via Intramolecular and Intermolecular Amidine Coupling

Scheme 108. Benzimidazole Synthesis, Large-Scale Preparation of Bioactive Compound 436, and Synthesis of Boron-Based Dyes

Scheme 109. General Reaction Scheme of the Use of Ammonia Equivalents

Scheme 110. N-Arylation of Benzophenone Imine in Medicinal Chemistry

Scheme 111. Large-Scale Coupling of Benzophenone Imine

Scheme 112. Applications of the Coupling of Benzophenone Imine in the Synthesis of Natural Products

Scheme 113. Coupling of Benzophenone Imine in the Synthesis of a Biological Probe

Scheme 114. Applications of the Coupling of Benzophenone Imine in the Synthesis of Organic Materials

Scheme 115. Applications of the Coupling of Benzophenone Imine in the Synthesis of Organocatalysts

Scheme 116. N-Arylation of LHMDS in Drug Discovery

Scheme 117. Large-Scale Coupling of LHMDS

Scheme 118. N-Arylation of LHMDS in the Synthesis of Natural Products

Scheme 119. Applications of LHMDS Coupling in Materials Chemistry

Scheme 120. LHMDS Coupling in Organic Materials

Scheme 121. Direct Coupling of Ammonia in the Synthesis of Heterocycles

Scheme 122. N-Arylation of Ammonia in the Synthesis of Natural Product 498

Scheme 123. Synthesis of Heterocycles via Direct Hydrazine Coupling Reactions

Scheme 124. Synthesis of Fused Quinazolinones via the Intramolecular Coupling of Hydrazine

Scheme 125. Synthesis of Heterocycles via the Intermolecular Coupling of Functionalized Hydrazines

Scheme 126. Hydrazine Coupling in Drug Discovery

Scheme 127. Syntheses of Photoswitches via Hydrazine Coupling

Scheme 128. Syntheses of Photoswitch 525 via Hydrazine Coupling

Scheme 129. Use of Hydrazones in the Synthesis of Heterocycles

Scheme 130. Medicinal and Process Synthetic Routes of Drug Candidate 529

Scheme 131. Application of Benzophenone Hydrazone Coupling to the Synthesis of Organocatalyst 531

Scheme 132. N-Arylation of Carbazoles Applied to the Synthesis of OLEDs

Scheme 133. Use of Carbazole Coupling in the Synthesis of Fluorescent Materials

Scheme 134. Carbazole Coupling in the Synthesis of High Molecular Weight Materials

Scheme 135. An Example of the N-Arylation of Indole in Medicinal Chemistry

Scheme 136. Synthesis of (−)-Aspergilazine a via Indole Cross-Coupling

Scheme 137. Alternative Methods for the Synthesis of Fused Phenantridines

Scheme 138. Two Synthetic Strategies To Access Nilotinib

Scheme 139. Imidazole-type N-Arylations for the Synthesis of Biologically Active Compounds

Scheme 140. Synthesis of Fused Heterocycles via the Coupling of Five-Membered Heteroaryl Halides

Scheme 141. N-Arylation of S-Based Heterocycles in Drug Discovery

Scheme 142. N-Arylation of Azoles in the Synthesis of Biologically Active Compounds

Scheme 143. Pd-Catalyzed C–N Coupling Reactions of Haloimidazole Derivatives

Scheme 144. Large-Scale Reactions of Five-Membered Heteroaryl Halides

Scheme 145. Thiophene Couplings in Materials Chemistry

Scheme 146. N-Arylation of Five-Membered Heteroaryl Halides in the Synthesis of Organic Materials

Scheme 147. Modification of Porphyrins via C–N Coupling

Scheme 148. Modification of Nucleosides via N-Arylation

Scheme 149. Synthesis of Hmpta Ligand via the Coupling of 2-Bromothiazole