Uses
5-Bromo-2-(dimethylamino)pyrimidine is a common pharmaceutical and chemical intermediate. Pyrimidines are important bioactive molecular structures, and their role as fundamental building blocks in new drug design and synthesis has long attracted attention. Studies have shown that different substitution modifications on the pyrimidine ring significantly affect its physiological activity. For example, 2,4-diaminopyrimidine derivatives exhibit good inhibitory activity against protein tyrosine phosphatase 1B; 2-amino-4-alkoxypyrimidine derivatives exhibit bioactivity against cyclin-dependent kinases; pyrimidine thiourea compounds exhibit neuraminidase inhibitory activity, and so on. All the bioactive compounds reported in the literature above contain a 2-substituted aminopyrimidine structure.
Synthesis
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.
References
[1] Patent: WO2012/162818, 2012, A1. Location in patent: Page/Page column 45-46
[2] Journal of Organic Chemistry, 2008, vol. 73, # 23, p. 9326 - 9333
