Tandem C–S Coupling and Debrominative Cyclization Enables an Easy Access to β‑Thiazole-Fused Porphyrins

A catalyst-free synthetic approach to β-thiazole-fused 5,10,15,20-tetraarylporphyrins via a cascade reaction of nickel(II) or copper(II) 2-amido-3-bromo-5,10,15,20-tetraarylporphyrins and Lawesson’s reagent is described. During the course of the reaction, 3-bromo-2-thioamido-5,10,15,20-tetraarylporphyrins formed in situ undergo debrominative cyclization in refluxing toluene to provide novel β-thiazole-fused porphyrin macrocycles in good yields. Furthermore, free-base and zinc(II) β-thiazole-fused porphyrins have also been constructed in excellent yields by using standard demetalation and zinc metal insertion procedures. The preliminary photophysical studies revealed a significant bathochromic shift in the electronic absorption and emission spectra of new porphyrins as compared to meso-tetraarylporphyrin precursors

Cascade Amination and Aza-6π-Annulation-Aromatization Strategy for the Synthesis of β‑Pyrimidine-Fused Porphyrins

Novel nickel(II) and copper(II) complexes of 2-(N,N-dimethylformamidine)-3-formyl-5,10,15,20-tetraarylporphyrins have been synthesized for the first time from 2-aminoporphyrins under Vilsmeier–Haack conditions. These porphyrins are utilized as new building blocks to construct diverse β-pyrimidine-fused 5,10,15,20-tetraarylporphyrins in good yields via a cascade ammonia-mediated condensation and intramolecular aza-6π-annulation/aromatization in 1,2-dichloroethane at 80 °C. Furthermore, copper(II) β-pyrimidine-fused porphyrins underwent demetallation in the presence of conc. H2SO4 to afford free-base porphyrins, which on zinc insertion using Zn(OAc)2 in CHCl3–MeOH provided zinc(II) β-pyrimidine-fused porphyrins in appreciable yields. Notably, these newly synthesized π-extended porphyrins displayed a modest bathochromic shift in their electronic absorption and emission spectra as compared to the traditional meso-tetraarylporphyrins. However, the protonated porphyrins (2a) and (3g) displayed a significant red-shifted absorption

Controlling Both Ground- and Excited-State Thermal Barriers to Bergman Cyclization with Alkyne Termini Substitution

The cross-coupling reaction of 2,3-dibromo-5,10,15,20-tetraphenylporphyrin with corresponding organostannanes in the presence of a Pd0 catalyst in THF at reflux temperature yields free base 2,3-dialkynylporphyrins 1a,c−e. The subsequent deprotection of trimethylsilyl group of 1a with TBAF in THF under aqueous conditions produces the 2,3-diethynyl-5,10,15,20-tetraphenylporphyrins 1b in 87% yield. Compounds 1a−d undergo zinc insertion upon treatment with Zn(OAc)2·2H2O in CHCl3/MeOH to give zinc(II) 2,3-dialkynyl-5,10,15,20-tetraphenylporphyrins (2a−d) in 70−92% yields. Thermal Bergman cyclization of 1a−e and 2a−d was studied in chlorobenzene and ∼35-fold 1,4-cyclohexadiene at 120−210 °C. Compounds 1b and 2b with R = H react at lower temperature (120 °C) and produce cyclized products 3b and 4b in higher yields (65−70%) than their propyl, isopropyl, and phenyl analogues, with R = Ph being the most stable. Continuing in this trend, the −TMS derivatives 1a and 2a exhibit no reactivity even after heating at 190 °C in chlorobenzene/CHD for 24 h. Photolysis (at λ ≥ 395 nm) of 1b and 2b at 10 °C leads the formation of isolable picenoporphyrin products in 15 and 35% yields, respectively, in 72 h, whereas these compounds are stable in solution under same reaction conditions at 25 °C in the dark. Unlike thermolysis at 125 °C, which did not yield Bergman cyclized product for R = Ph, photolysis generated very small amounts of picenoporphyrin products (3c:  5%; 4c:  8% based on 1H NMR) as well as a mixture of reduced porphyrin products that were not separable. Thus, trends in the barrier to Bergman cyclization in the excited state exhibit the same trend as those observed in the ground state as a function of R-group. Finally, photolysis of 2b at 10 °C with λ ≥ 515 or 590 nm in benzene/iPrOH (4:1, 72 h) produces 4b in 15 and 6% isolated yields, indicating that conjugation of the enediyne unit into the porphyrin electronic transitions leads to sufficient distortion to generate photoproduct even with long wavelength excitation

Controlling Both Ground- and Excited-State Thermal Barriers to Bergman Cyclization with Alkyne Termini Substitution

The cross-coupling reaction of 2,3-dibromo-5,10,15,20-tetraphenylporphyrin with corresponding organostannanes in the presence of a Pd0 catalyst in THF at reflux temperature yields free base 2,3-dialkynylporphyrins 1a,c−e. The subsequent deprotection of trimethylsilyl group of 1a with TBAF in THF under aqueous conditions produces the 2,3-diethynyl-5,10,15,20-tetraphenylporphyrins 1b in 87% yield. Compounds 1a−d undergo zinc insertion upon treatment with Zn(OAc)2·2H2O in CHCl3/MeOH to give zinc(II) 2,3-dialkynyl-5,10,15,20-tetraphenylporphyrins (2a−d) in 70−92% yields. Thermal Bergman cyclization of 1a−e and 2a−d was studied in chlorobenzene and ∼35-fold 1,4-cyclohexadiene at 120−210 °C. Compounds 1b and 2b with R = H react at lower temperature (120 °C) and produce cyclized products 3b and 4b in higher yields (65−70%) than their propyl, isopropyl, and phenyl analogues, with R = Ph being the most stable. Continuing in this trend, the −TMS derivatives 1a and 2a exhibit no reactivity even after heating at 190 °C in chlorobenzene/CHD for 24 h. Photolysis (at λ ≥ 395 nm) of 1b and 2b at 10 °C leads the formation of isolable picenoporphyrin products in 15 and 35% yields, respectively, in 72 h, whereas these compounds are stable in solution under same reaction conditions at 25 °C in the dark. Unlike thermolysis at 125 °C, which did not yield Bergman cyclized product for R = Ph, photolysis generated very small amounts of picenoporphyrin products (3c:  5%; 4c:  8% based on 1H NMR) as well as a mixture of reduced porphyrin products that were not separable. Thus, trends in the barrier to Bergman cyclization in the excited state exhibit the same trend as those observed in the ground state as a function of R-group. Finally, photolysis of 2b at 10 °C with λ ≥ 515 or 590 nm in benzene/iPrOH (4:1, 72 h) produces 4b in 15 and 6% isolated yields, indicating that conjugation of the enediyne unit into the porphyrin electronic transitions leads to sufficient distortion to generate photoproduct even with long wavelength excitation

Controlling Both Ground- and Excited-State Thermal Barriers to Bergman Cyclization with Alkyne Termini Substitution

The cross-coupling reaction of 2,3-dibromo-5,10,15,20-tetraphenylporphyrin with corresponding organostannanes in the presence of a Pd0 catalyst in THF at reflux temperature yields free base 2,3-dialkynylporphyrins 1a,c−e. The subsequent deprotection of trimethylsilyl group of 1a with TBAF in THF under aqueous conditions produces the 2,3-diethynyl-5,10,15,20-tetraphenylporphyrins 1b in 87% yield. Compounds 1a−d undergo zinc insertion upon treatment with Zn(OAc)2·2H2O in CHCl3/MeOH to give zinc(II) 2,3-dialkynyl-5,10,15,20-tetraphenylporphyrins (2a−d) in 70−92% yields. Thermal Bergman cyclization of 1a−e and 2a−d was studied in chlorobenzene and ∼35-fold 1,4-cyclohexadiene at 120−210 °C. Compounds 1b and 2b with R = H react at lower temperature (120 °C) and produce cyclized products 3b and 4b in higher yields (65−70%) than their propyl, isopropyl, and phenyl analogues, with R = Ph being the most stable. Continuing in this trend, the −TMS derivatives 1a and 2a exhibit no reactivity even after heating at 190 °C in chlorobenzene/CHD for 24 h. Photolysis (at λ ≥ 395 nm) of 1b and 2b at 10 °C leads the formation of isolable picenoporphyrin products in 15 and 35% yields, respectively, in 72 h, whereas these compounds are stable in solution under same reaction conditions at 25 °C in the dark. Unlike thermolysis at 125 °C, which did not yield Bergman cyclized product for R = Ph, photolysis generated very small amounts of picenoporphyrin products (3c:  5%; 4c:  8% based on 1H NMR) as well as a mixture of reduced porphyrin products that were not separable. Thus, trends in the barrier to Bergman cyclization in the excited state exhibit the same trend as those observed in the ground state as a function of R-group. Finally, photolysis of 2b at 10 °C with λ ≥ 515 or 590 nm in benzene/iPrOH (4:1, 72 h) produces 4b in 15 and 6% isolated yields, indicating that conjugation of the enediyne unit into the porphyrin electronic transitions leads to sufficient distortion to generate photoproduct even with long wavelength excitation

Controlling Both Ground- and Excited-State Thermal Barriers to Bergman Cyclization with Alkyne Termini Substitution

The cross-coupling reaction of 2,3-dibromo-5,10,15,20-tetraphenylporphyrin with corresponding organostannanes in the presence of a Pd0 catalyst in THF at reflux temperature yields free base 2,3-dialkynylporphyrins 1a,c−e. The subsequent deprotection of trimethylsilyl group of 1a with TBAF in THF under aqueous conditions produces the 2,3-diethynyl-5,10,15,20-tetraphenylporphyrins 1b in 87% yield. Compounds 1a−d undergo zinc insertion upon treatment with Zn(OAc)2·2H2O in CHCl3/MeOH to give zinc(II) 2,3-dialkynyl-5,10,15,20-tetraphenylporphyrins (2a−d) in 70−92% yields. Thermal Bergman cyclization of 1a−e and 2a−d was studied in chlorobenzene and ∼35-fold 1,4-cyclohexadiene at 120−210 °C. Compounds 1b and 2b with R = H react at lower temperature (120 °C) and produce cyclized products 3b and 4b in higher yields (65−70%) than their propyl, isopropyl, and phenyl analogues, with R = Ph being the most stable. Continuing in this trend, the −TMS derivatives 1a and 2a exhibit no reactivity even after heating at 190 °C in chlorobenzene/CHD for 24 h. Photolysis (at λ ≥ 395 nm) of 1b and 2b at 10 °C leads the formation of isolable picenoporphyrin products in 15 and 35% yields, respectively, in 72 h, whereas these compounds are stable in solution under same reaction conditions at 25 °C in the dark. Unlike thermolysis at 125 °C, which did not yield Bergman cyclized product for R = Ph, photolysis generated very small amounts of picenoporphyrin products (3c:  5%; 4c:  8% based on 1H NMR) as well as a mixture of reduced porphyrin products that were not separable. Thus, trends in the barrier to Bergman cyclization in the excited state exhibit the same trend as those observed in the ground state as a function of R-group. Finally, photolysis of 2b at 10 °C with λ ≥ 515 or 590 nm in benzene/iPrOH (4:1, 72 h) produces 4b in 15 and 6% isolated yields, indicating that conjugation of the enediyne unit into the porphyrin electronic transitions leads to sufficient distortion to generate photoproduct even with long wavelength excitation

Ambient Temperature Activation of Haloporphyrinic-Enediynes: Electronic Contributions to Bergman Cycloaromatization

We have synthesized the nickel(II) 2,3-bis(haloethynyl)-5,10,15,20-tetraphenylporphyrins with −Br (2a) or −I (2b) at the alkyne termini position from the corresponding 2,3-diethynyl analogue (1). The cross coupling of nickel(II) 2,3-dibromo-5,10,15,20-tetraphenylporphyrin with trimethyl(trimethylstannanylethynyl)silane in the presence of a Pd0 catalyst and subsequent deprotection with base under aqueous conditions yields the nickel(II) 2,3-diethynyl-5,10,15,20-tetraphenylporphyrin (1). Subsequent reaction of 1 with N-bromo- or N-iodosuccinimide in dry acetone in the presence of AgNO3 yields 2,3-bis(haloethynyl)-5,10,15,20-tetraphenylporphyrins in 70% (2a) and 68% (2b) yields. The X-ray crystal structures of 2a,b show that the porphyrin backbone deviates significantly from planarity due to a Ni(II)-induced mixture of the classic ruffle and saddle distortions. Thermolysis of 2a at 190 °C for 6 h in chlorobenzene and 30-fold 1,4-cyclohexadiene (CHD) generates the Bergman cyclized nickel(II) dibromopicenoporphyrin product (3) in 65% yield, which derives from diradical addition across the adjacent meso-phenyl substituents. Similarly, nickel(II) 2,3-bis(iodoethynyl)-5,10,15,20-tetraphenylporphyrin, 2b, cyclizes at 190 °C in chlorobenzene/CHD via high-temperature substitution of iodine by hydrogen (from CHD) or chlorine (from solvent) to afford a mixture of 4 (15%) and 5 (45%). Remarkably, ambient temperature incubation of 2a in MeOH/CHCl3 (1:3, 22 h) or chlorobenzene/CHD (3:1, 24 h) leads to generation of 3 in 15% and 22% isolated yields, respectively. Addition of 1.2 equiv of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in CHCl3/MeOH dramatically accelerates the rate of reaction, producing 3 in 30% yield within 0.5 h. The origin of the ambient temperature activation of 2a derives from the ability of electron-withdrawing functionalities at the alkyne termini to decrease the activation barrier to the Bergman product

Ambient Temperature Activation of Haloporphyrinic-Enediynes: Electronic Contributions to Bergman Cycloaromatization

We have synthesized the nickel(II) 2,3-bis(haloethynyl)-5,10,15,20-tetraphenylporphyrins with −Br (2a) or −I (2b) at the alkyne termini position from the corresponding 2,3-diethynyl analogue (1). The cross coupling of nickel(II) 2,3-dibromo-5,10,15,20-tetraphenylporphyrin with trimethyl(trimethylstannanylethynyl)silane in the presence of a Pd0 catalyst and subsequent deprotection with base under aqueous conditions yields the nickel(II) 2,3-diethynyl-5,10,15,20-tetraphenylporphyrin (1). Subsequent reaction of 1 with N-bromo- or N-iodosuccinimide in dry acetone in the presence of AgNO3 yields 2,3-bis(haloethynyl)-5,10,15,20-tetraphenylporphyrins in 70% (2a) and 68% (2b) yields. The X-ray crystal structures of 2a,b show that the porphyrin backbone deviates significantly from planarity due to a Ni(II)-induced mixture of the classic ruffle and saddle distortions. Thermolysis of 2a at 190 °C for 6 h in chlorobenzene and 30-fold 1,4-cyclohexadiene (CHD) generates the Bergman cyclized nickel(II) dibromopicenoporphyrin product (3) in 65% yield, which derives from diradical addition across the adjacent meso-phenyl substituents. Similarly, nickel(II) 2,3-bis(iodoethynyl)-5,10,15,20-tetraphenylporphyrin, 2b, cyclizes at 190 °C in chlorobenzene/CHD via high-temperature substitution of iodine by hydrogen (from CHD) or chlorine (from solvent) to afford a mixture of 4 (15%) and 5 (45%). Remarkably, ambient temperature incubation of 2a in MeOH/CHCl3 (1:3, 22 h) or chlorobenzene/CHD (3:1, 24 h) leads to generation of 3 in 15% and 22% isolated yields, respectively. Addition of 1.2 equiv of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in CHCl3/MeOH dramatically accelerates the rate of reaction, producing 3 in 30% yield within 0.5 h. The origin of the ambient temperature activation of 2a derives from the ability of electron-withdrawing functionalities at the alkyne termini to decrease the activation barrier to the Bergman product

Ambient Temperature Activation of Haloporphyrinic-Enediynes: Electronic Contributions to Bergman Cycloaromatization

We have synthesized the nickel(II) 2,3-bis(haloethynyl)-5,10,15,20-tetraphenylporphyrins with −Br (2a) or −I (2b) at the alkyne termini position from the corresponding 2,3-diethynyl analogue (1). The cross coupling of nickel(II) 2,3-dibromo-5,10,15,20-tetraphenylporphyrin with trimethyl(trimethylstannanylethynyl)silane in the presence of a Pd0 catalyst and subsequent deprotection with base under aqueous conditions yields the nickel(II) 2,3-diethynyl-5,10,15,20-tetraphenylporphyrin (1). Subsequent reaction of 1 with N-bromo- or N-iodosuccinimide in dry acetone in the presence of AgNO3 yields 2,3-bis(haloethynyl)-5,10,15,20-tetraphenylporphyrins in 70% (2a) and 68% (2b) yields. The X-ray crystal structures of 2a,b show that the porphyrin backbone deviates significantly from planarity due to a Ni(II)-induced mixture of the classic ruffle and saddle distortions. Thermolysis of 2a at 190 °C for 6 h in chlorobenzene and 30-fold 1,4-cyclohexadiene (CHD) generates the Bergman cyclized nickel(II) dibromopicenoporphyrin product (3) in 65% yield, which derives from diradical addition across the adjacent meso-phenyl substituents. Similarly, nickel(II) 2,3-bis(iodoethynyl)-5,10,15,20-tetraphenylporphyrin, 2b, cyclizes at 190 °C in chlorobenzene/CHD via high-temperature substitution of iodine by hydrogen (from CHD) or chlorine (from solvent) to afford a mixture of 4 (15%) and 5 (45%). Remarkably, ambient temperature incubation of 2a in MeOH/CHCl3 (1:3, 22 h) or chlorobenzene/CHD (3:1, 24 h) leads to generation of 3 in 15% and 22% isolated yields, respectively. Addition of 1.2 equiv of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in CHCl3/MeOH dramatically accelerates the rate of reaction, producing 3 in 30% yield within 0.5 h. The origin of the ambient temperature activation of 2a derives from the ability of electron-withdrawing functionalities at the alkyne termini to decrease the activation barrier to the Bergman product

Synthesis and Antiviral Activity of Novel Acyclic Nucleoside Analogues of 5-(1-Azido-2-haloethyl)uracils

We present the discovery of a novel category of 5-substituted acyclic pyrimidine nucleosides as potent antiviral agents. A series of 1-[(2-hydroxyethoxy)methyl] (5−7), 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl] (8−10), and 1-[4-hydroxy-3-(hydroxymethyl)-1-butyl] (11−13) derivatives of 5-(1-azido-2-haloethyl)uracil were synthesized and evaluated for their biological activity in cell culture. 1-[4-Hydroxy-3-(hydroxymethyl)-1-butyl]-5-(1-azido-2-chloroethyl)uracil (12) was the most effective antiviral agent in the in vitro assays against DHBV (EC50 = 0.31−1.55 μM) and HCMV (EC50 = 3.1 μM). None of the compounds investigated showed any detectable toxicity to several stationary and proliferating host cells