General procedure for the synthesis of 5-bromo-2-(dimethylamino)pyrimidines from 2-amino-5-bromopyrimidines and iodomethane:
1. preparation of the related pyran(mi)dihalides A-H. Key steps include:
(a) 85-90% yield of pyridine; quantitative yield of pyrimidine using NBS and NH4OAc in MeCN at room temperature for 5 min;
(b) Pyridine: refluxed with RCHO and Na(CN)BH3 in MeCN for 1-12 hr (82%, R=C5Hn); pyrimidine: using NaH and R1 in THF, overnight at room temperature (85%, R=Me);
(c) Pyridine yield 77-83%; pyrimidine yield 30-40% using Me3(Bn)NBr and f-BuONO in CH2Br2, overnight at room temperature;
(d) Pyrimidine: reaction using HI in CH2Cl2 at 0°C, 80-85% yield;
(e) Steps included: i. reaction using NaOH and Br2 in aqueous solution, room temperature, 50-60% yield; ii. refluxing using POCl3 and PhNEt2 for 4 hrs, 75-85% yield; iii. reaction using HI in CH2Cl2, 0 °C, 80-85% yield;
(f) Reaction using ROH and Na at room temperature for 1-12 hr in quantitative yield;
(g) Use of RZnI and Cl2Pd(PPh3)2 in DMF/THF overnight at room temperature in 72% (R=C6H13) yield for pyridine (Br) and 81% (R=C6H13) yield for pyrimidine (I);
(h) Quantitative yields using alkynes, Cul, Cl2Pd(PPh3)2, and Et3N in MeCN, reacted for 1-12 h at room temperature.
Pyrimidinyl bromides were prepared in a similar manner starting from the bromination of 2-aminopyrimidine. N-alkylation could not be achieved by reductive amination (probably due to the reduced nucleophilicity of the amine), but N-(B) was achieved using NaH and the appropriate alkyl halide. Non-aqueous diazotization/halogenated deoxidation was used to prepare 5-bromo-2-halogenated pyrimidines, but in reduced yield relative to a similar reaction with 2-aminopyridine (again, possibly due to reduced nucleophilicity of the amine group). Alternatively, 2-pyrimidinone can be used as a precursor to 5-bromo-2-halopyrimidines (Lutz, F.; Kawasaki, T.; Soai, K. Tetrahedron-Asymmetry 2006,17,486) or as a substrate for alkylation. Generation of 5-bromo-2-alkoxypyrimidines (D) (Kokatla, HP; Lakshman, MK Org. Lett. 2010,12,4478.) was obtained by introduction of an alkynyl substituent at the 2-position (which was carried out satisfactorily under Sonogoshira conditions, but alkylation using Negishi conditions was non-selective. Since 2-alkynylpyrimidinyl bromides (F) were competitively removed due to the reduction of 2-alkynylpyrimidinyl bromides (H) to the corresponding 2-alkylpyrimidinyl bromides (H), we turned to 5-bromo-2-iodopyrimidines as precursors for the cross-coupling reaction, with a significant increase in selectivity and yield.
