1-Tosyl-6-vinyl-4,5,6,7-tetrahydro-1 H -benzo[ d ]imidazole-2-amine H imidazole-2-amine

: The alkene functionalised 2-aminobenzimidazole ring found in terrazoanthine natural products was synthesized in 3 steps from 1,2-epoxy-4-vinylcyclohexane via epoxide ring opening with toluenesulphonamide yielding 2 regioisomeric, separable amino alcohols. One isomer was oxidized to the corresponding ketone and subsequently condensed with cyanamide to furnish the title compound, which was characterized by 1 H-NMR and 13 C-NMR spectroscopy. Abstract: The alkene functionalised 2-aminobenzimidazole ring found in terrazoanthine natural products was synthesized in 3 steps from 1,2-epoxy-4-vinylcyclohexane via epoxide ring opening with toluenesulphonamide yielding 2 regioisomeric, separable amino alcohols. One isomer was oxidized to the corresponding ketone and subsequently condensed with cyanamide to furnish the title compound, which was characterized by 1 H-NMR and 13 C-NMR spectroscopy.


Introduction
The terrazoanthines (A-C) are a family of 2-aminoimidazole alkaloids isolated from the marine invertebrate group, the zoantharians, off the coast of Ecuador by Thomas et al. [1] These compounds give an insight into the chemical content of Terrazoanthus onoi. Terrazoanthine A and B both contain a previously unknown 6-(imidazol-5-yl)benzo[d]imidazole skeleton ( Figure 1).

Introduction
The terrazoanthines (A-C) are a family of 2-aminoimidazole alkaloids isolated from the marine invertebrate group, the zoantharians, off the coast of Ecuador by Thomas et al. The 2-aminoimidazole ring is an interesting structural moiety in medicinal chemistry. Biological targets containing glutamate and aspartate residues can interact with the 2-aminoimidazole ring via four hydrogen bonds. [2] It has also been utilized as a bioisostere for the replacement of guanidine, benzamidine and triazole groups in biologically active compounds [3][4][5]. There have been several 2-aminoimidazole natural products that have been the synthesized including sceptrin [6,7], ageliferin [7,8] and dragmacidins D and F [9,10]. We envisaged that the 2-aminoimidazole ring could be installed via a condensation strategy using an α-amino ketone. Alternative strategies have been reported for 2-aminoimidazole synthesis, including reaction of α-halo ketones with guanidine salts [11], or lithiation of imidazoles and subsequent quenching with an electrophilic source of azide and subsequent hydrogenolysis to yield the 2-aminoimidazole functionality [12].   The 2-aminoimidazole ring is an interesting structural moiety in medicinal chemistry. Biological targets containing glutamate and aspartate residues can interact with the 2aminoimidazole ring via four hydrogen bonds. [2] It has also been utilized as a bioisostere for the replacement of guanidine, benzamidine and triazole groups in biologically active compounds [3][4][5]. There have been several 2-aminoimidazole natural products that have been the synthesized including sceptrin [6,7], ageliferin [7,8] and dragmacidins D and F [9,10]. We envisaged that the 2-aminoimidazole ring could be installed via a condensation strategy using an α-amino ketone. Alternative strategies have been reported for 2-aminoimidazole synthesis, including reaction of α-halo ketones with guanidine salts [11], or lithiation of imidazoles and subsequent quenching with an electrophilic source of azide and subsequent hydrogenolysis to yield the 2-aminoimidazole functionality [12].

Results and Discussion
The synthesis was commenced from commercially available 4-vinyl-1-cyclohexene 1,2epoxide, mixture of isomers 1. The epoxide underwent aminolysis with p-toluenesulfonamide 2 of 5 under microwave irradiation, using conditions similar to those reported by Yang and Murray [13], giving two separable, regioisomeric amino alcohols 2 and 3. The more polar isomer 3 (R f 0.22, EtOAc-cyclohexane, silica plates) was isolated and then oxidised with PCC in dichloromethane and the resulting ketone 4 was condensed with cyanamide by heating at reflux in H 2 O to give the 2-aminoimidazole 5 containing the fused ring of terrazoanthine A/B (Scheme 1). Efforts to transform the alkene 5 into functional groups that would enable a second 2-aminoimidazole ring to be incorporated have not been successful to date in our hands. Reactions investigated have included aziridination with chloramine-t hydratetrimethylphenyl ammonium bromide (decomposition); dihydroxylation with OsO 4 (recovered reactant), RuCl 3 -NaIO 4 -CeCl 3 (decomposition), I 2 -AgOAc (decomposition), epoxidation with mCPBA (recovered reactant) and halohydrin formation with NBS/NIS/NCS (recovered reactant). The structural assignment is supported by gHMBCAD experiments combined with gHSQCAD in 4. The CH 2 signals between the CHs with the vinyl and Ts groups appear as 2 multiplets at δ 2.63 and δ 1.78 ppm. In the gHMBCAD this CH 2 signal (ms at δ 2.63 (weak) and δ 1.78 (strong)) ppm show crosspeaks to the 13 C signal for the CH bonded to the NHTs group (δ 56.95 ppm). The signal at δ 1.78 ppm also showed strong crosspeaks with the signal for the C = O (δ 205.86 ppm) and the alkene CH (δ 138.5 ppm) indicating this proton is located on the CH 2 between the NHTs and vinyl groups. In addition, the NMR assignments for 5 determined by 2D gCOSY, gHSQCAD and gHMBCAD and 2D-NOESY are shown in Figure 2. In the NOESY a cross peak between the multiplet at δ 2.76-2.84 ppm and the Ts protons supported the placement of the Ts group on the nitrogen atom closest to this proton.

Results and Discussion
The synthesis was commenced from commercially available 4-vinyl-1-cyclohexene 1,2-epoxide, mixture of isomers 1. The epoxide underwent aminolysis with p-toluenesulfonamide under microwave irradiation, using conditions similar to those reported by Yang and Murray [13], giving two separable, regioisomeric amino alcohols 2 and 3. The more polar isomer 3 (Rf 0.22, EtOAc-cyclohexane, silica plates) was isolated and then oxidised with PCC in dichloromethane and the resulting ketone 4 was condensed with cyanamide by heating at reflux in H2O to give the 2-aminoimidazole 5 containing the fused ring of terrazoanthine A/B (Scheme 1). Efforts to transform the alkene 5 into functional groups that would enable a second 2-aminoimidazole ring to be incorporated have not been successful to date in our hands. Reactions investigated have included aziridination with chloramine-t hydrate-trimethylphenyl ammonium bromide (decomposition); dihydroxylation with OsO4 (recovered reactant), RuCl3-NaIO4-CeCl3 (decomposition), I2-AgOAc (decomposition), epoxidation with mCPBA (recovered reactant) and halohydrin formation with NBS/NIS/NCS (recovered reactant). The structural assignment is supported by gHMBCAD experiments combined with gHSQCAD in 4. The CH2 signals between the CHs with the vinyl and Ts groups appear as 2 multiplets at δ 2.63 and δ 1.78 ppm. In the gHMBCAD this CH2 signal (ms at δ 2.63 (weak) and δ 1.78 (strong)) ppm show crosspeaks to the 13 C signal for the CH bonded to the NHTs group (δ 56.95 ppm). The signal at δ 1.78 ppm also showed strong crosspeaks with the signal for the C = O (δ 205.86 ppm) and the alkene CH (δ 138.5 ppm) indicating this proton is located on the CH2 between the NHTs and vinyl groups. In addition, the NMR assignments for 5 determined by 2D gCOSY, gHSQCAD and gHMBCAD and 2D-NOESY are shown in Figure 2. In the NOESY a cross peak between the multiplet at δ 2.76-2.84 ppm and the Ts protons supported the placement of the Ts group on the nitrogen atom closest to this proton.

Results and Discussion
The synthesis was commenced from commercially available 4-vinyl-1-cyclohexene 1,2-epoxide, mixture of isomers 1. The epoxide underwent aminolysis with p-toluenesulfonamide under microwave irradiation, using conditions similar to those reported by Yang and Murray [13], giving two separable, regioisomeric amino alcohols 2 and 3. The more polar isomer 3 (Rf 0.22, EtOAc-cyclohexane, silica plates) was isolated and then oxidised with PCC in dichloromethane and the resulting ketone 4 was condensed with cyanamide by heating at reflux in H2O to give the 2-aminoimidazole 5 containing the fused ring of terrazoanthine A/B (Scheme 1). Efforts to transform the alkene 5 into functional groups that would enable a second 2-aminoimidazole ring to be incorporated have not been successful to date in our hands. Reactions investigated have included aziridination with chloramine-t hydrate-trimethylphenyl ammonium bromide (decomposition); dihydroxylation with OsO4 (recovered reactant), RuCl3-NaIO4-CeCl3 (decomposition), I2-AgOAc (decomposition), epoxidation with mCPBA (recovered reactant) and halohydrin formation with NBS/NIS/NCS (recovered reactant). The structural assignment is supported by gHMBCAD experiments combined with gHSQCAD in 4. The CH2 signals between the CHs with the vinyl and Ts groups appear as 2 multiplets at δ 2.63 and δ 1.78 ppm. In the gHMBCAD this CH2 signal (ms at δ 2.63 (weak) and δ 1.78 (strong)) ppm show crosspeaks to the 13 C signal for the CH bonded to the NHTs group (δ 56.95 ppm). The signal at δ 1.78 ppm also showed strong crosspeaks with the signal for the C = O (δ 205.86 ppm) and the alkene CH (δ 138.5 ppm) indicating this proton is located on the CH2 between the NHTs and vinyl groups. In addition, the NMR assignments for 5 determined by 2D gCOSY, gHSQCAD and gHMBCAD and 2D-NOESY are shown in Figure 2. In the NOESY a cross peak between the multiplet at δ 2.76-2.84 ppm and the Ts protons supported the placement of the Ts group on the nitrogen atom closest to this proton.

Conclusions
The fused core of terrazoanthines A/B natural products were synthesized in 3 steps via epoxide aminolysis, oxidation and condensation strategy to yield the fused 2-aminoimidazole heterocycle, with the structure determined by a combination of 1D and 2D NMR spectroscopic techniques (Supplementary Materials).

General Information
All reagents used were from commercial sources and used without further purification. TLC experiments were performed using aluminum sheets pre-coated with silica gel 60 (HF254, E. Merck, Darmstadt, Germany). NMR experiments were carried out in CDCl 3 using a 500 MHz spectrometer (Varian Ltd (Agilent), CA, Palo Alto, USA), with the chemical shifts reported relative to internal Me 4 Si (δ 0.00). NMR spectra were processed and analysed using MestReNova software. Signals from 1 H and 13 C spectra were assigned using 2D gCOSY, gHSQCAD & gHMBCAD spectroscopy and 2D-NOESY. J values are reported as observed. CDCl 3 (δ 77.16) and signals were used for assignment of 13 C signals. HRMS data were obtained using a Waters LCT Premier XE Spectrometer. Chromatography was performed with silica gel 60 (Sigma Aldrich, Wicklow, Ireland). IR spectra were measured for films on KBr plates.