Cross-dehydrogenative coupling and oxidative-amination reactions of ethers and alcohols with aromatics and heteroaromatics

Abstract

Cross-dehydrogenative coupling (CDC) is a process in which, typically, a C-C bond is formed at the expense of two C-H bonds, either catalyzed by metals or other organic compounds, or via uncatalyzed processes. In this perspective, we present various modes of C-H bond-activation at sp³ centers adjacent to ether oxygen atoms, followed by C-C bond formation with aromatic systems as well as with heteroaromatic systems. C-N bond-formation with NH-containing heteroaromatics, leading to hemiaminal ethers, is also an event that can occur analogously to C-C bond formation, but at the expense of C-H and N-H bonds. A large variety of hemiaminal ether-forming reactions have recently appeared in the literature and this perspective also includes this complementary chemistry. In addition, the participation of C-H bonds in alcohols in such processes is also described. Facile access to a wide range of compounds can be attained through these processes, rendering such reactions useful for synthetic applications via C_sp³ bond activations.

Fig. 1. Pictorial representation of CDC and oxidative-amination reactions.

Scheme 1. CDC reactions of aromatic and heteroaromatic compounds with ethers (Ar = aryl, Het = heteroaryl). Metals and reagents used for these reactions are shown in the orange color.

Scheme 2. Reactions of isochroman with electron-rich aromatic systems.

Scheme 3. Reactions of isochroman with various methoxy arenes and those of various isochromans with anisole.

Scheme 4. A proposed mechanistic pathway for the arylation of isochroman by Cu^II.

Scheme 5. CDC reactions of resorcinol derivatives with THF.

Fig. 2. CDC reactions of naphthols, a 4-chromenone and two xanthones with THF.

Scheme 6. CDC and oxidation leading to 1,4-naphthoquinones.

Fig. 3. Reactions of alcohols with 1,4-dihydroxynaphthalene.

Scheme 7. The Pd-mediated portion of the reaction of resorcinol with THF.

Scheme 8. Reactions of aryl boronic acids with THF and THP, catalyzed by Ni(acac)₂.

Fig. 4. Products of the reactions of benzo[d]-1,3-dioxole, N,N-dimethylaniline, DMA and N-methylpyrrole with PhB(OH)₂.

Scheme 9. Four products obtained in radical trapping experiments with 1,1-DPE and a plausible mechanism.

Scheme 10. Oxidation of ethers by DDQ followed by reactions with aryl Grignard reagents.

Fig. 5. Products obtained via the use of PIFA and DDQ.

Fig. 6. Alkyl-, allyl-, vinyl- and nitrogen-substituted isochromans.

Fig. 7. Other products that can be produced with AZADOL/PIFA.

Scheme 11. A plausible reaction mechanism leading to an oxocarbenium ion for reaction with nucleophiles.

Scheme 12. Ir^III(ppy)₃-catalyzed benzylic arylation with p-dicyanobenzene. Ar = p-CN-Ph.

Fig. 8. Other aryl dinitriles and activated nitriles used in the arylation of PhCH₂OTBDMS, product yields as well as regioisomer ratios with unsymmetrical substrates are shown.

Scheme 13. Arylation of 2,5-dihydrofuran with p-dicyanobenzene.

Fig. 9. Products obtained with 0.2 wt% Pd on TiO₂ and yields.

Scheme 14. Reactions of 1,1-diarylethenes and styrenes with THF.

Fig. 10. Reactions of other ethers with 1,1-diarylethenes.

Scheme 15. Cu(OTf)₂/K₂S₂O₈ promoted CDC reactions of heterocycles with ethers.

Scheme 16. Two plausible reaction pathways.

Scheme 17. FeF₂/t-BuOOH promoted CDC reactions of heterocycles with ethers.

Scheme 18. A plausible mechanism for FeF₂/t-BuOOH mediated CDC reactions.

Scheme 19. Reactions of oxazoles and benzoxazoles with 1,4-dioxane, catalyzed by Co₂CO₃.

Fig. 11. Products formed from reactions of oxazoles and benzoxazoles with other ethers.

Scheme 20. Experiments involving monodeuterated benzoxazole.

Scheme 21. A mechanistic scheme for the Co-catalyzed CDC reactions of ethers with oxazoles (and benzoxazoles).

Fig. 12. Products formed in metal-free CDC reactions with ethers.

Scheme 22. CDC reactions of alcohols with benzothiazole.

Scheme 23. Photochemical α-heteroarylation of two ethers with benzothiazole.

Scheme 24. CDC products obtained from quinoline, isoquinoline and 2-phenylpyridine N-oxides.

Scheme 25. CDC reaction of 4-methylquinoline-N-oxide with EtOH.

Scheme 26. Plausible mechanism for the CDC reaction of quinoline N-oxides with ethers.

Scheme 27. Cu-Catalyzed CDC reactions of pyridine N-oxides with cyclic ethers.

Scheme 28. CDC reaction of pyridine-N-oxide with dioxane using (t-BuO)₂.

Fig. 13. Products from metal-free CDC reactions of pyridine N-oxides with THF.

Fig. 14. Expanding the scope of the metal-free CDC reactions of pyridine N-oxides.

Scheme 29. Reduction of some of the CDC products to the free pyridines.

Scheme 30. Photochemical Ir^III mediated Minisci-type process.

Fig. 15. Products from the photochemical Ir-mediated CDC reactions with THP.

Scheme 31. Photochemical CDC reactions of various ethers with isoquinoline (ratios of isomeric products are indicated with blue arrows).

Scheme 32. A possible mechanism for the CDC reaction of 4,7-dichloroquinoline with 1,4-dioxane, mediated by PIFA/NaN₃.

Scheme 33. Reactions of isoquinolines, quinolines, pyridines, benzothiazoles, benzimidazoles and a carboline with THF.

Scheme 34. Reactions of other ethers with isoquinoline, mediated by NHS (sites and ratios of regioisomeric products are indicated with blue arrows, diastereomeric ratios are indicated by dr and the yields indicated with an asterisk were obtained with 5 equiv. of the ether).

Scheme 35. A plausible mechanism for the (NH₄)₂S₂O₈/amine mediated CDC reaction of THF with isoquinoline.

Fig. 16. CDC reactions of alcohols with azaaromatics catalyzed by PdCl₂/(±)-BINAP.

Scheme 36. Reaction of 4-methylquinoline with EtOH using six Au catalysts.

Fig. 17. Gold-catalyzed acylation of heteroaromatics.

Scheme 37. Monitoring of the reaction of 4-methylquinoline and EtOH by ESI-MS.

Scheme 38. A possible mechanism for the Au-catalyzed acylation reaction.

Fig. 18. 1,1-Bis-indolylmethane derivatives prepared and their yields.

Fig. 19. Ratio of products as a function of the indole substituent (top) and unsymmetrical compounds synthesized (bottom).

Scheme 39. A plausible mechanism for the formation of 1,1-bis-indolylmethanes.

Scheme 40. Synthesis of oxindoles from N-methyl-N-phenylmethylacrylamide.

Fig. 20. Various oxindoles synthesized via the cascade CDC cyclization.

Scheme 41. Mechanism for the formation of oxindoles.

Fig. 21. C3 alkylation of indole with 1,4-dioxane using Ni(acac)₂/Zn(OTf)₂.

Fig. 22. C2 alkylation of indoles and a benzofuran with 1,4-dioxane using NiF₂/PPh₃.

Fig. 23. Two indoles used in competitive reactions with 1,4-dioxane/1,4-dioxane-d ₈.

Fig. 24. Uncatalyzed CDC reactions of indoles with isochroman.

Fig. 25. Other ethers tested in the metal-free CDC reactions with indoles.

Scheme 42. A plausible mechanism for the CDC reaction of indole with isochroman.

Fig. 26. Uncatalyzed CDC reactions of 3- and 2-substituted indoles with 1,4-dioxane.

Fig. 27. CDC reactions of indole carboxylic esters with other ethers and cycloalkanes.

Scheme 43. KIE measurement in the reaction of methyl 1H-indole-3-carboxylate with 1,4-dioxane and 1,4-dioxane-d ₈.

Fig. 28. Three products obtained from the reaction of indole with 1,2-DME.

Scheme 44. Rh-Mediated reaction of ethers with diisopropyl azodicarboxylate.

Fig. 29. Fe-Catalyzed reactions of imidazoles, benzimidazole, pyrazole and 1,2,4-triazole with THF. Conditions 1, 2 and 4 are shown in parentheses along with yields.

Fig. 30. Products from oxidative-amination reactions of benzimidazole and ethers. BIm = 1H-benzimidazol-1-yl.

Scheme 45. A potential reaction mechanism involving an Fe^III–Fe^II redox cycle.

Fig. 31. Reactions of benzimidazole, 2-methylbenzimidazole and benzotriazole with 1,4-dioxane and THF.

Fig. 32. FeCl₃·6H₂O/t-BuOOH mediated reactions of 5-aryltetrazoles with THF.

Fig. 33. Reactions of 5-phenyl-1H-tetrazole with other ethers (EtOAc was used as the reaction solvent except with 1,4-dioxane, where DCE was used).

Scheme 46. CuCl₂/(t-BuO)₂ mediated C–N bond formation of indoles and a benzimidazole.

Fig. 34. Reactions of carbazoles with THF.

Fig. 35. Oxidative-amination reactions of two indoles and two carbazoles with ethers.

Scheme 47. Synthesis of N-benzylisoquinolin-1(2H)-one from isoquinoline and toluene.

Scheme 48. The two products from the reaction of isoquinoline with p-methylanisole.

Fig. 36. Products from the reactions of other ethers with isoquinoline.

Scheme 49. Utility of the N-benzylation reaction for access to natural product structures.

Fig. 37. Cationic intermediates, identified using ESI-MS, in the reaction of isoquinoline with toluene.

Scheme 50. Plausible mechanism for the reaction of isoquinoline with anisole.

Scheme 51. Reactions of BtOTs and BtH with NMP.

Fig. 38. Reactions of other azoles with THF under the Ru-catalyzed conditions.

Fig. 39. Unusual products formed in the radical-trapping experiment with TEMPO.

Scheme 52. A plausible mechanism for the Ru-catalyzed reaction.

Scheme 53. Isomerization of the N2-alkylated benzotriazoles to the N1 isomers, and a possible mechanism.

Scheme 54. Reactions of THF with phthalimides, succinimide and benzotriazole.

Fig. 40. Products from the reactions of phthalimide with other ethers. Phthal = phthalimido.

Scheme 55. Hypoiodite or iodite intermediates formed in n-Bu₄N⁺I^–-catalyzed reactions of ethers with imides.

Fig. 41. Products derived from saccharin and other isothiazolone 1,1-dioxides.

Fig. 42. Products from the reactions of saccharin with other ethers and yields. Sacc = saccharin.

Fig. 43. A saccharin–BHT adduct obtained in a radical inhibition experiment.

Fig. 44. Products obtained in reactions of 5-aryl-2H-tetrazoles with 1,4-dioxane.

Fig. 45. Products from the reactions of 5-phenyl-2H-tetrazole with other ethers.

Fig. 46. Products from the reactions of 4-aryl-1,2,3-triazoles with 1,4-dioxane.

Scheme 56. Reactions of anisole and its derivatives with 5-phenyl-2H-tetrazole.

Fig. 47. Reactions of other ethers and an unusual reaction of 4-methylanisole.

Fig. 48. Reactions of other 5-aryl-2H-tetrazoles and 1H-benzotriazole.

Fig. 49. Products obtained from the reactions of benzimidazoles and purine.

Scheme 57. Reaction of 2,6-dichloro-9H-purine with THF.

Fig. 50. Products from the reactions of THF with various purine derivatives.

Fig. 51. Products from the reactions of 2,6-dichloro-9H-purine with other ethers.

Fig. 52. Products of the uncatalyzed oxidative-amination with phthalimide, imidazole, benzimidazole, indole, carbazole, 5-methyluracil and 5-fluorouracil.

Scheme 58. Possible reaction mechanisms for the uncatalyzed oxidative amination.

Scheme 59. Uncatalyzed reaction of BtH with EtOH.

Fig. 53. Products from the reactions of benzotriazoles with alcohols.

Fig. 54. Products obtained from the reactions of 5-aryl-1H-tetrazoles with ethers.

Scheme 60. A possible mechanism for the reaction of BtH with EtOH.

Scheme 61. Cascade cyclization reactions of N-methyl-N-phenylmethylacrylamide with alcohols.

Fig. 55. Various oxindoles synthesized through the cascade cyclization with iPrOH.

Scheme 62. Experiments to determine kinetic isotope effects.

Scheme 63. Proposed mechanism for the cascade reaction with alcohols leading to oxindoles.

Fig. 56. Products from the CDC reactions with TFE.

Scheme 64. A possible mechanism for the reaction of indole with TFE.

Scheme 65. Use of the CDC products for the synthesis of other CF₃-substituted compounds.