Metalation of Triazines, Ii (1) Synthesis of Bi-1,2,4-Triazines and 1,2,4-Triazine-6-Carbaldehydes

Abstract

5-Methoxy-6H-l,2,4-triazines la-c, 5H-l,2,4-triazine-6-diethylcarboxamides 7a, b and 3,6diphenyl-l,2,4-triazine 4-oxide 10 were lithiated with lithium 2,2,6,6-tetramethylpiperidide and the formed lithio-1,2,4-triazines 2a -c, 8a, b, 1J, reacted with chlorotrimethylsilane and other reagents to give the bi-1,2,4triazines 3a -c, 4a, b, 12, 13. 6-Lithio-l,2,4-triazines 2a, b afforded 3a, b and 5-methoxy-l,2,4-triazine-6carbaldehydes 5a, b when reacted with N-formylpiperidine or ethyl formate. Treatment of the 3-aryl-5-methoxy-l,2,4-triazines la-c with four equivalents lithium 2,2,6,6tetramethylpiperidide (LiTMP) in tetrahydrofurane (THF) at -100 °C and reaction of the formed 6-lithio derivatives 2a -c with chlorotrimethylsilane by the equilibrium shift procedure (8) afforded unexpectedly not the 6-trimethylsilyl-l,2,4-triazines but the 5,5'-dimethoxy-6,6'-bi-l,2,4-triazines 3a -c and the l,6-dihydro-6,6'bi-l,2,4-triazines 4a, b. As described earlier (1), to shift the equilibrium i + LiTMP 2 + TMPH to the right side, getting the highest yield of 2, one has to use a three-to fourfold excess of LiTMP. 513Brought to you by | Purdue University Libraries Authenticated Download Date | 6/7/15 1:38 AM

Metalated Heterocycles and Their Applications in Synthetic Organic Chemistry

“…However, LiTMP has been used for the lithiation of 5-methoxy-1,2,4-triazine to give the corresponding 6-lithio-1,2,4-triazine derivative using a DoM to give triazine-derived aldehydes when reacted with N-formylpiperidine or ethyl formate. 163 In addition, 5,6-disubstituted-1,2,4-triazines such as 107 have been lithiated at C-2 to give in this case intermediate 108, for the reaction with different aldehydes such as o-bromobenzaldehyde to give the alcohol 109, in a methodology useful for the preparation of 1-azafluorenones (Scheme 26). 164 Furthermore, 3-aryl-1,2,4,5-tetrazines have been lithiated with LiTMP and react with aldehydes and benzophenone to give the corresponding alcohols.…”

Carbon‐metalated triazines and tetrazines: Synthesis and reactivity

“…−100 C led to formation of bi-1,2,4-triazines 30 and 31 through the intermediate lithio compounds 26 (Scheme 5). [15] Note that when no additive or other chlorosilanes were used, almost negligible yields were observed (down to 0% for Ph 3 SiCl) and significant recovery of the starting . [15] Lithiotriazines 26 could be successfully trapped with elemental iodine, and iodotriazine 32 formed was further coupled with TMS-protected acetylene in the presence of Pd catalyst to give product 33 (Scheme 5).…”

“…[15] Note that when no additive or other chlorosilanes were used, almost negligible yields were observed (down to 0% for Ph 3 SiCl) and significant recovery of the starting . [15] Lithiotriazines 26 could be successfully trapped with elemental iodine, and iodotriazine 32 formed was further coupled with TMS-protected acetylene in the presence of Pd catalyst to give product 33 (Scheme 5). [8] Despite the fact that electrophile trapping with ethyl formate, N-formyl piperidine, [15] PhCHO, MeCHO [8] or 3-phenyl-1,2,4,5-tetrazine [16] were possible (to furnish the expected products 27 to 29, Scheme 5), the attempted reactions of the related 3-aryl-5-lithio-1,2,4-triazine-6-diethylcarboxamide 36 (generated from the precursor 34, Scheme 6) with benzaldehyde were unsuccessful [15] and led only to the formation of dimers 38.…”

“…[15] Lithiotriazines 26 could be successfully trapped with elemental iodine, and iodotriazine 32 formed was further coupled with TMS-protected acetylene in the presence of Pd catalyst to give product 33 (Scheme 5). [8] Despite the fact that electrophile trapping with ethyl formate, N-formyl piperidine, [15] PhCHO, MeCHO [8] or 3-phenyl-1,2,4,5-tetrazine [16] were possible (to furnish the expected products 27 to 29, Scheme 5), the attempted reactions of the related 3-aryl-5-lithio-1,2,4-triazine-6-diethylcarboxamide 36 (generated from the precursor 34, Scheme 6) with benzaldehyde were unsuccessful [15] and led only to the formation of dimers 38. Metalation of 3,6-diphenyl-1,2,4-triazine-1-N-oxide 35 gave lithiotriazine 37, which rapidly underwent self-dimerization into both the bi-1,2,4-triazine-bi-N-oxide 40 and its deoxygenated derivative 39 (Scheme 6).…”

“…Metalation of 3,6-diphenyl-1,2,4-triazine-1-N-oxide 35 gave lithiotriazine 37, which rapidly underwent self-dimerization into both the bi-1,2,4-triazine-bi-N-oxide 40 and its deoxygenated derivative 39 (Scheme 6). [15] In a related reaction, which probably involves the intermediate formation of C-magnesiated triazines, interaction of 6-phenyl-1,2,4-triazine-3,5(2H,4H)-dione 41, 3,5,6-triphenyl-1,2,4-triazine 42 or 3-chloro-5,-6-diphenyl-1,2,4-triazine 43 with PhMgBr afforded a complex mixture, among which 2,4,6-triphenyl-1,3,5-triazine 44, 2,4,4,5-tetraphenyl-4H-imidazole 45 and bi-1,2,4-triazine 46 were identified (Scheme 7). [17] sp 2 -Metalation of 3-methylthio-1,2,4-triazine with LiTMP proceeded at the C(6) ring position in THF media at −78 C, [18] and further trapping with n-Bu 3 SnCl was possible (see Section 2.2.1).…”