1530
Z. Wang et al.
SHORT PAPER
action mixture was purified by flash silica gel chromatography elut-
ing with EtOAc–MeOH (12:1) to give 60 g (63%) of 7 as a pale
yellow solid; mp 143.6–144.3 °C.
IR (KBr): 2600 (br), 1682, 1403, 1320, 983 cm–1.
1H NMR (400 MHz, CDCl3): d = 13.1 (s, 1 H), 8.11 (s, 1 H), 6.33
(s, 1 H), 2.35 (s, 3 H).
MeNH2
93%
NaOMe, MeOH
80%
N
N
N
N
6
OMe
NHMe
Br
Br
KCN, 18-crown-6
THF, r.t., 32%
2
3
13C NMR (100 MHz, CDCl3): d = 166.7, 164.5, 147.8, 113.4, 24.0.
N
N
CN
HRMS (+ESI): m/z [M + H] calcd for C5H7N2O: 111.0558; found:
Br
111.0563.
4
5-Bromo-6-methylpyrimidin-4-ol (1)
Scheme 4
N-Bromosuccinimide (71 g, 400 mmol) was added to a solution of
6-methylpyrimidin-4-ol (7; 40 g, 360 mmol) in anhyd MeCN (1.2
L) under N2 at r.t. After 1 h, the reaction mixture was concentrated
under reduced pressure. The crude residue was purified by flash sil-
ica gel chromatography eluting with CH2Cl2–MeOH (98:2 to 95:5)
to give 65 g (94%) of 1 as a white solid; mp 184.1–185.2 °C.
IR (KBr): 2961 (br), 1652, 1399, 1015 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.17 (s, 1 H), 3.43 (br, 1 H),
2.44 (s, 3 H).
Studies focused on directly conjugating carbon nucleo-
philes in a chemoselective fashion with 6 are currently
underway. Related analogue 5-bromo-4,6-dimethylpyri-
midine (5) was synthesized in bulk by treating 4,6-di-
methylpyrimidine (13) with bromine in ethanol
(Scheme 5), whereupon after several hours at room tem-
perature, the desired 5-bromopyrimidine 5 precipitated
from solution in high purity (>98%) as its HBr salt, thus
negating the need for further purification.10 This one-step
route is an appreciable improvement to the previously re-
ported three-step11 route.12
13C NMR (100 MHz, DMSO-d6): d = 161.9, 157.8, 147.6, 111.9,
24.1.
HRMS (+ESI): m/z [M + H] calcd for C5H6BrN2O: 188.9664 and
190.9643; found: 188.9662 and 190.9643.
5-Bromo-4-chloro-6-methylpyrimidine (6)
N
N
N
N
Br2, EtOH
43%
A solution of 5-bromo-6-methylpyrimidin-4-ol (1; 20 g, 100 mmol)
in POCl3 (200 mL) was stirred at reflux for 2 h, and then at r.t. for
an additional 1 h under N2. The reaction mixture was concentrated
under reduced pressure. The residue was partitioned between
EtOAc (200 mL) and sat. aq NaHCO3 (300 mL). The layers were
separated and the aqueous layer was further extracted with EtOAc
(3 × 200 mL). The combined organic extracts were washed with
brine (2 × 200 mL), dried (Na2SO4), filtered, and concentrated un-
der reduced pressure to give 19 g (91%) of 6 as a light yellow solid;
mp 58.8–59.4 °C.
IR (KBr): 1541, 1423, 1330, 1039, 748 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.74 (s, 1 H), 2.71 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.8, 160.6, 155.6, 120.9, 25.8.
Br
5
13
Scheme 5
In summary, we have described a scalable synthesis of 4-
substituted 5-bromo-6-methylpyrimidines 1–5 using reli-
able classical chemistry. Although all key intermediates
exemplified in this communication were previously
known in the literature, the published routes towards them
were not fully amenable to scale-up. Pyrimidines 1, 2, and
6 are of particular utility because their pendant function-
ality can be used as a handle for further elaboration. We
have presented this convenient route to facilitate access to
these monomers.
HRMS (+ESI): m/z [M + H] calcd for C5H5BrClN2: 206.9325 and
208.9304; found: 206.9324 and 208.9301.
5-Bromo-4-methoxy-6-methylpyrimidine (2)
NaOMe (160 mg, 2.90 mmol) was added to a solution of 5-bromo-
4-chloro-6-methylpyrimidine (6; 300 mg, 1.45 mmol) in anhyd
MeOH (10.0 mL) and the mixture was stirred at r.t. for 3 h. The pre-
cipitate formed was filtered and the solution concentrated under re-
duced pressure. The residue was purified by flash silica gel
chromatography eluting with PE–EtOAc (5:1) to give 240 mg
(81%) of 2 as a white solid; mp 80.4–81.6 °C.
IR (KBr): 2959, 1569, 1387, 1080, 771 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.39 (s, 1 H), 3.91 (s, 3 H), 2.46
(s, 3 H).
NMR spectra were recorded on a Bruker Avance II spectrometer
(1H: 400 MHz, 13C: 100 MHz) at 25 °C, using CDCl3, CD3OD or
DMSO-d6 as the solvent. Chemical shifts are reported in parts per
million (ppm) relative to solvent (CDCl3: 7.27 and 77.0 ppm;
DMSO-d6: 2.50 and 39.51 ppm; CD3OD: 3.31 and 49.2 ppm in 1H
and 13C NMR, respectively). IR spectra were recorded on a FT-IR
type Nicolet 380 spectrometer and are reported in cm–1. Mass spec-
tra were recorded using the +ESI method on an Agilent
G1969A LC/MSD TOF mass spectrometer. Melting points were
measured on a WRS-2A apparatus and are uncorrected. Petroleum
ether (PE) used refers to the fraction boiling in the range 30–60 °C.
13C NMR (100 MHz, CDCl3): d = 166.2, 165.6, 155.4, 106.8, 55.1,
24.3.
6-Methylpyrimidin-4-ol (7)
HRMS (+ESI): m/z [M + H] calcd for C6H7BrN2O: 202.9820 and
A solution of formamidine acetate (11; 150 g, 1,400 mmol), methyl
acetoacetate (12; 100 g, 860 mmol) and NaOMe (93 g, 1.7 mol) in
anhyd MeOH (1.5 L) was stirred under N2 at r.t. for 18 h. The pH of
the reaction mixture was adjusted to pH 7 by the addition of glacial
AcOH, and then concentrated under reduced pressure. The crude re-
204.9800; found: 202.9810 and 204.9788.
5-Bromo-N,6-dimethylpyrimidin-4-amine (3)
5-Bromo-4-chloro-6-methylpyrimidine (6; 90 mg, 0.43 mmol) was
added to a solution of MeNH2 (2.0 mL, 4.0 mmol, 2 M in THF). Af-
Synthesis 2011, No. 10, 1529–1531 © Thieme Stuttgart · New York