Science of Synthesis

von Angerer, S., Science of Synthesis Knowledge Updates, (2011) 1, 331.

Halogenation of pyrimidines is an important reaction to render this heterocycle susceptible to the attack of various nucleophiles. Some of these halogenation reactions have been the subject of several reviews.[‌733‌,‌781‌] Fluorine,[‌782‌–‌787‌] chlorine,[‌788‌–‌795‌] bromine,[‌281‌,‌411‌,‌746‌,‌789‌,‌795‌–‌804‌] and iodine[‌788‌,‌805‌–‌809‌] can be introduced into this heterocyclic system under appropriate conditions. In general the 5-position is attacked, e.g. to give ‌578‌, due to the nucleophilic character of this carbon. Activation of the heterocycle by oxygen and amino functions in the 2-, 4-, and/or 6-positions is generally required for successful halogenation reactions. ‌Table 4‌ gives an overview of the numerous reagents used for the halogenation of pyrimidines.

‌Meeee 8‌ Meeeeeee eee Meeeeeeeeeee ee Meeeeeeeeee[‌888‌,‌888‌,‌888‌,‌888‌,‌888‌,‌888‌–‌888‌,‌888‌,‌888‌–‌888‌,‌888‌–‌888‌,‌888‌–‌888‌]

e e.e. = eee eeeeeeee.

e Mee ee MMM, MMMMM, eee MMMe8 eeeeeeee ee eeeeeeeeee eeee-eeeee eeeeeeeeeee (M8 = MMMeMe).

Meeeeeeeee ee eeeeeeee eee eeeeeeeeeeeeee eeeeeeeee ee eeeee eeeeeee eee ee eeeee eeeeeeeee eeeeee eeeeeeee eeee e eeeeee eeeeeeeee eeeee ee eeeee ee eeeeeeee e eeeeee eeeeeeeeeeee. M eeeeeeee eeeeee ee eeeee eeeee eeeeee ee eeeeeeeeee eeeeeeeee ee eee eeeeeeeeeee ee eeeeeeeee eeeeeeeeeee. Meeeeeeee ee eeeeeeeeeee eeeeeeeee-8(8M)-eeee eeee M-eeeeeeeeee­eeeee eeeee eeeeeeeee eeeeeeeeeee eeeee eee eeeeeeeeeeeee 8-eeeeeeeeeeeee-8(8M)-eeee ‌888‌ ee eeeeeeeee eeeee (‌Meeeee 888‌).[‌888‌] Meeeeeee (‌8‌) eeeeee ee eee eeee eee eeee e eeeeeeee eeeee eeeee (88%), eeeeeee 8-eeeeeeeeeeeeeeeee-8(8M)-eee eeeeeee eeeeeeeeee. Meee eeeeeeee eee eeee ee eeeeeeeee ee eeeee eeeeeee.[‌888‌]

‌Meeeee 888‌ 8-Meeeeeeeeeeee-8(8M)-eeee ee Meeeeeeee-Meeeeeee Meeeeeeeee ee Meeeeeeee-8(8M)-eeee[‌888‌]

‌Meeeeeeeeee 888‌

Meeeee eee eeee ee eeeeeeeeee eeee eeeeeeeeeee eee eeeeeeeee ee eeeee eeeeeeeee eeeeeeeeeeeee ee eeeee ee Meeeeee ‌88.88.8.8.8.8‌.[‌888‌,‌888‌,‌888‌,‌888‌,‌888‌] Meee eeeeeeee eee eeeeeeeee eeee eeee ee eeee eee eeeeeeeeeeeeee eeeeeeeeeeee ee eeeee ee eeeeeeee eee eeee ee eeeeeeeeee. Meee eeeeeeee eeee eeeeeeee eee eeee eeeeeeee ee eeee ee eeeeeeeeeee eee eee eeeeeeeeeee ee eeeeeeeeeeeeeee eee eeeee eeeeeeeee eeeeeeeee. Meeeeeeeee eeeeee eeee e eeeeeee ee eeeeeee 8,8,8,8-eeeeeeeeeeeeeeeeeeeee, eeeeeeeee ee eeee eeee eeeeeeeeeeee eee eee eeeee, eee eeee(MM) eeeeeeee/M,M,M′,M′-eeeeeeeeeeeeeeeeeeeeeeeeee eeeeeee ee eeee 8-eeeeeeeeeeeeee (‌888‌) ee 88% eeeee eeeeeeee eeee eeeeee ee eee 8-eeeeee eee 8,8′-eeeeeeeeeeee (‌Meeeee 888‌).[‌888‌,‌888‌] Mee ee eee eeeeeee eeeeeeeeee eeee eee eeeeeeeee ee 8-eeee eeeeeeeeeee, eeeee eee eeeeeeeee ee eeeeeee ee eeeeee eeeeeeeeee, ee eeeeeeee.

‌Meeeee 888‌ 8-Meeeeeeeeeeeee ee Meeeeeee ee Meeeeeeee Meeeeeeeee eeee Meeeee[‌888‌,‌888‌]

Meeeeee eeeeee ee eeeeeeeee eeeeee eeee eeeeeeeeeee ee eee eeeeeeee ee 8-eeeeeeeeeeeeeeee-8(8M)-eee eeee eeeeeeeeeeeeee, eeeee eeeeee 8-eee-8-(eeeeeeeeeeeee)-8,8-eeeeeeeeeeeeeeee-8-eeeee (‌888‌), e eeeeeeeee eeeeeeeeeeee ee eee eeeeeeeee ee eeeeeeeeeeee eeeeee, eeeee ee eeeeeee eeeeeeeee eeee 8-eeeeeee-8-eeeeeeeeeeeee-8(8M)-eee (‌888‌) (‌Meeeee 888‌).[‌888‌]

‌Meeeee 888‌ 8-Meeeeee-8-eeeeeeeeeeeee-8(8M)-eee eee Meeeeeee ee 8-Meeeeeeeeeeeeeee-8(8M)-eee eeee Meeeeeeeeeeeee[‌888‌]

Meeeeeeeeeee Meeeeeeee

8-Meeeeeeeeeeee (‌888‌, M8 = MM; M8 = MM8; M8 = M; M = Me); Meeeeee Meeeeeeee:[‌888‌]

MMMMMMM: Meeeeee ee e eeeeee eeeeeeee ee eee eeee, eeeeee eeeeeeeee, eeeee, eee eeee. Meeeee eeeeeee eeeeee eeeeee eee eeeeeee eeeee ee eeeeeee eeee eeee eee eeee.

Me8 (8.8 eM, 8.8 eeee) eee eeeee ee e eeeeeeeeee ee eeeeeeeeee eeeeeeee (‌8‌; 8.88 e, 8.8 eeee) ee M8M (88 eM). Mee eeeeeee eee eeeeeee ee ee eee 8 e eee eeee eeeeeeeeeeee eeeeeeeee. Mee eeeeeeeeeee eeeeeeeeeee eee eeeeeeeee ee eeeeeeeeee eee eeeeee eeee eeee M8M ee eeee 8-eeeeeeeeeeeee eeeeeeeeeeee; eeeee: 8.88 e (88%); ee 888–888°M. Me eeeeeeeeee 888 ee ee eee eeeeeee eeeee ee eeeeeeee eeee eee eeeeeeee ee eeeeeeeeeeeeee; eeeee eeeee: 8.88 e (88%). Mee eeee eeee eeeee ee eeeeeeee ee eeeeeeeee ee e eeeeeeeeee ee eee eeeeeeeeeeee (8.88 e, 8.8 eeee) ee M8M (88 eM) eeee eeeee MM8MM (8.8 eM, 88 eeee). Mee eeeeeeeeeee eee eeeeeeeee, eeeeee eeee M8M, eee eeeeeeeeeeeeee (M8M); eeeee: 8.88 e (88%); ee 888–888°M.

8-Meeee-8,8-ee-eeee-eeeeeeeeeeeeee-8(8M)-eee (‌888‌, M8 = M8 = e-Me; M8 = MM; M = Me); Meeeeee Meeeeeeee:[‌888‌]

8,8-Me-eeee-eeeeeeeeeeeeee-8(8M)-eee (8 e, 88.8 eeee) eee MMM (8.8 e, 88.8 eeee) ee MMMe8 (88 eM) eeee eeeeeeee eee 8 e eeee eeeeeeee. Mee eeeeeeeeee eee eeeeeeee. Mee eeeeeeee eee eeeeeeeeeeee, eee eee eeeeeee eee eeeeeee eeee eeeeeee M8M (88 eM). Mee eeeee eee eeeeeeeee ee eeeeeeeeee, eeeee, eee eeeeeeeeeeeeee (MeMM); eeeee: 8.8 e (88%); ee 888–888°M.

8-Meeeeee-8-eeeeeeeeeeeeee (‌888‌, M8 = MM; M8 = M8 = M; M = M):[‌888‌]

M 8-M eeeee eee eeeeeee eeeeeeeeeeee eeee 8-eeeeeeeeeeeeeeeee eeeeeeeeeeeee (888 e, 8.88 eee), M8M (888 eM), eee MeMM (88 eM). Mee eeeeeee eee eeeeee ee 88°M, eee 88% ee MMe (888 eM, 8.88 eee) eee eeeee eeee 88 eee. Mee eeeeeee eee eeeeeee eee eeeeeee 8 e ee 88°M, eee eeee eeeeee ee ~8°M. Mee eeeeeeeeeee eee eeeeeeeee ee eeeeeeeeee eee eeeeee eeee M8M (8 × 888 eM). Mee eee eeeeeee eee eeeeeeeee ee eeeeeee (888 eM) eee eee eeeeeee eee eeeeeee eee 88 eee. Mee eeeeeeeeeee eee eeeeeeeee ee eeeeeeeeee eee eeeee eeeee eeeeeee eeeeeeee ee 88°M; eeeee: 888 e (88%).

8-Meeeeeeeeeeeee (‌888‌):[‌888‌]

Me e eeeeeee, eeeeee (8°M) eeee ee MMM (8.88 eM, 8.8 eeee) ee MMM (8 eM) eeee eeeeeeeeeeee eeeee e 8.8 M eeee ee MeMe (8.8 eeee) ee eeeeeee eee MeMe8•MMMMM (8.88 e, 8.8 eeee). Mee eeeeeee eee eeeeeee eee 88 eee ee 8°M eeeeee eeeeeeee ee eeeeeeeeee (8.88 e, 8.8 eeee). Meeee 8 e ee 88°M, e eeee ee M8 (8.88 e, 8.8 eeee) ee MMM (8 eM) eee eeeee. Mee eeeeeee eee eeeeeee eeeeeeeee eeeeee eeeeeeee ee eee. ee Me8M8M8 (8 eM) eee eeeeeeeeee eeee MeMMe (8 × 88 eM). Mee eeeeeeee eeeeeee eeeeee eeee eeeee (MeMM8), eeeeeeee, eee eeeeeeeeeeee eeeee eeeeeee eeeeeeee. Mee eeeeeee eee eeeeeeee eeeee eeeeeeeeeeee ee eeeee eeeeeeeeeeeeee (eeeeee eee, MM8Me8/MeMMe 888:8 ee 88:88) ee e eeeeee eeeeee; eeeee: 8.88 e (88%); ee 888°M (eee).

References