DABCO bond cleavage for the synthesis of piperazine derivatives

Abstract

The applications of DABCO (1,4-diazabicyclo[2.2.2]octane) in the synthesis of piperazine derivatives including biologically active compounds via C-N bond cleavage are investigated in this review. Different reagents such as alkyl halides, aryl(heteroary) halides, carboxylic acids, diaryliodonium salts, tosyl halides, activated alkynes, benzynes etc. were applied for the preparation of the corresponding quaternary ammonium salts of DABCO, which are very good electrophiles for various nucleophiles such as phenols, thiophenols, thiols, alcohols, aliphatic and aromatic amines, sulfinates, phthalimide, indoles, NaN₃, triazole and terazoles, NaCN, enols and enolates, halides, carboxylic acid salts etc. Besides preactivated DABCO salts, the in situ activation of DABCO in multicomponent reactions is also an efficient tactic in synthetic organic chemistry for the diversity oriented synthesis of drug-like piperazine derivatives.

Fig. 1. Selected marketed drugs or drug candidates containing piperazine motif.

Fig. 2. General synthetic strategies toward piperazine scaffold.

Fig. 3. DABCO-quaternary salts.

Scheme 1. Synthesis of poly-1,4-ethylenepiperazine from DABCO.

Scheme 2. Synthesis of mono- or bisquaternary salts of DABCO and their ring opening with sodium benzoate.

Scheme 3. C–N bond cleavage of DABCO quaternary salts with various nucleophiles.

Scheme 4. Synthesis of ether isosteres of Vanoxerine via DABCO bon cleavage.

Scheme 5. DABCO bond cleavage via the reaction of DABCO with 1-methoxy-indole-3-carbaldehyde.

Scheme 6. Reaction of nitrochlorobenzenes with DABCO.

Scheme 7. Synthesis of piperazine derivatives containing aza crown ethers of various ring sizes.

Scheme 8. Synthesis of piperazines via the reaction of chlorotriazines with various equivalents of DABCO.

Scheme 9. Microwave-assisted DABCO bond cleavage using heteroaryl chlorides.

Scheme 10. Microwave assisted quinuclidine C–N bond cleavage.

Scheme 11. Microwave-assisted DABCO ring opening using p-substituted halobenzenes.

Scheme 12. Reaction of azaarene halides, DABCO, and Na₂S for synthesis of piperazine derivatives.

Scheme 13. One-pot four-component reaction for the synthesis of piperazine derivatives.

Scheme 14. Cs₂CO₃-catalyzed DABCO bond cleavage using 2-bromopyridine and phenols.

Scheme 15. Synthesis of ruzadolane via DABCO bond cleavage strategy.

Scheme 16. Carboxylic acids and anhydrides as nucleophile in DABCO bond cleavage.

Scheme 17. Synthesis of 4-(2-chloroethyl)piperazino derivatives of carbaphosphazenes.

Scheme 18. Synthesis of piperazine substituted nucleoside via DABCO bond cleavage.

Scheme 19. DABCO bond cleavage by in situ prepared benzyne and a nucleophile.

Scheme 20. Proposed mechanism for DABCO bond cleavage by in situ prepared benzyne.

Scheme 21. One-pot three-component reaction of polyynes, DABCO, and a protic nucleophile.

Scheme 22. Proposed mechanism for the synthesis of multiheterocyclic products from polyynes, DABCO and nucleophiles.

Scheme 23. Reaction of polyynes with DABCO in the present of trifilic acid and subsequent ring opening with a nucleophile.

Scheme 24. One-pot three component reaction of tetrayne, DABCO and benzotriazole.

Scheme 25. Utilization of phenolic natural products as nucleophiles in benzyne-activated DABCO bond cleavage.

Scheme 26. Transition-metal catalyzed piperazination of arenes.

Scheme 27. Cu(i)-catalyzed synthesis of N-alkyl-N′-aryl-piperazines.

Scheme 28. Proposed mechanism for Cu(i)-catalyzed synthesis of N-alkyl-N′-aryl-piperazines.

Scheme 29. Cu(i)-catalyzed synthesis of piperazines using aryl triflates or alkenyl iodides (triflates).

Scheme 30. DABCO bond cleavage using pyridine-N-oxides, TFAA and a nucleophile.

Scheme 31. Synthesis of functionalized Quinoxyfen–piperazine and MC2050 starting from pyridine-N-oxides.

Scheme 32. Proposed mechanisms for the synthesis of N-(2-pyridyl)-DABCO salt from pyridine-N-oxide.

Scheme 33. Synthesis of quinolones containing bis(ethylpiperazine) motif.

Scheme 34. Using bis-N-oxide in DABCO bond cleavage reaction.

Scheme 35. Aryl(mesityl)iodonium triflates as activating agents for DABCO bond cleavage.

Scheme 36. Synthesis of biologically active compounds from N-aryl-DABCO salts.

Scheme 37. Proposed mechanism for the reaction of DABCO with diaryliodonium triflate.

Scheme 38. Introducing 4-(2-chloroethyl)piperazinyl group on the C4 position of 1,2,3-dithiazoles and their postfuncionalization.

Scheme 39. Proposed mechanism for the reaction of 101 with DABCO.

Scheme 40. One-pot three-component reaction of DABCO, DMAD and carboxylic acids.

Scheme 41. One-pot pseudo three-component reaction of DABCO, DMAD and amino acids.

Scheme 42. Reaction of DABCO with tosyl chloride.

Scheme 43. A one-pot or two-pot strategy for the synthesis of 1-(2-substitued ethyl)-4-sulfonylpiperazines.

Scheme 44. Synthesis of piperazines via direct amidation of carboxylic acid with DABCO.

Scheme 45. Synthesis of 1,4-dinitrosopiperazine from DABCO and N₂O_4.

Scheme 46. Enzyme-mediated oxidation of DABCO by ethylhydroperoxide (EHP).

Scheme 47. Synthesis of piperazines using 3,4-dihalo-2(5H)-furanone.

Azim Ziyaei Halimehjani

Elham Badali