Nonorganometallic Pathway of the Passerini Reaction Assisted by Titanium Tetrachloride

The Passerini reaction assisted by TiCl4 is a three component reaction (RNC, R′2CO, TiCl4) leading to CC bond formation between the carbonyl and the isonitrile groups, and the formation of α-hydroxy amides. In order to clarify the mechanism of the reaction, we have isolated TiCl4-RNC and TiCl4R2CO adducts, {2,6-Me2C6H3NC)TiCl3]2(μ-Cl)2}2, 2, [TiCl4{μ2-COC(OEt)CH2-NC}]2,3, [TiCl4{μ2-OP(OEt)2CH2NC}]2, 4, and [TiCl4{PhCCO)C(O)Ph}], 5. Spectroscopic and X-ray analysis on 2 and 3 ruled out any insertion of the isocyanide into TiCl bonds, as required by the accepted mechanism of this reaction. The reaction on the ketone- or isocyanide–TiCl4 adducts with the third component of the Passerini reaction led us to the isolation and full characterization of [mer-TiCl3(η3-OC(Mes)(H)C(Cl)NCH2C(OEt)O], 6, [mer-TiCl3-(η3-OC(Ph)(Me)C(Cl)NCH2C(OEt)O], 7, [mer-TiCl3(η3-OC(Ph)(Me)C(Cl)NCH2P-(OEt)2O], 10, and [mer-TiCl3(η3-OC(Ph)(OCPh)C(Cl)NCH2C(OEt)O], 12, derived from the reaction of MesCHO and PhCOMe with EtOOCCH2NC, of PhCOCH3 with OP(OEt)2-CH2NC, and PhCOCOPh with EtOOCH2NC, respectively. These are high yield reactions and form, as imposed by the planar assembled ligand, the mer-isomer only. The hydrolysis of 6, 7, 10, and 12 gave the expected α-hydroxy amide derivatives, 8, 9, 11, and 13, respectively. The overall mechanism of the TiCl4-assisted Passerini reaction can be described as the electrophilic activation of a carbonyl group by TiCl4 followed by the nucleophilic attack on the carbonylic carbon by the RNC nucleophile. Crystallographic details: 2 is monoclinic, space group P21/n, a = 13.943(1) Å, b = 8.045(1) Å, c = 12.141(1) Å, α = γ = 90°,β = 104.76(1)°, Z = 2, R = 0.048; 4 is monoclinic, space group P21/c, a = 12.961(1) Å, b = 11.770(1) Å, c = 10.917(1) Å, α = γ = 90°, β = 114.13(1)°, Z = 2, R = 0.049; 5 is triclinic, space group P1̄, a = 10.549(1) Å, b = 10.668(1) Å, c = 9.533(1) Å, α = 115.08(1)°, β = 115.47(1)°, β = 95.01(1)°, Z = 2, R = 0.035; 7 is triclinic, space group P1̄, a = 9.731(2) Å,b = 10.552(3) Å, c = 8.978(2) Å, α = 96.66(2)°, β = 101.86(2)°, γ = 95.30(2)°, Z = 2, R = 0.042; 10 is monoclinic, space group P21/c, a = 11.503(2) Å, b = 14.095(2) Å, c = 15.110(2) Å, α = γ = 90°, β = 96.79(2)°, Z = 4, R = 0.116; 12 is triclinic, space group P1̄, a = 9.272(4) Å, ft = 9.965(4) Å, c = 15.029(6) Å, α = 101.84(3)°, β = 104.12(3)°, γ = 99.53(3)°, Z = 2, R = 0.092.