COMMUNICATION
Regio- and chemoselective magnesiation of protected uracils and thiouracils
using TMPMgCl·LiCl and TMP2Mg·2LiCl†
Marc Mosrin, Nade`ge Boudet and Paul Knochel*
Received 21st July 2008, Accepted 22nd July 2008
First published as an Advance Article on the web 31st July 2008
DOI: 10.1039/b812528g
Two successive regio- and chemoselective magnesiations
using TMPMgCl·LiCl and TMP2Mg·2LiCl enable the full
functionalization of protected uracils and thiouracils in good
to excellent yields.
with ZnCl2 followed by the addition of Pd(dba)2 and P(o-
furyl)3), t-BuCOCl (after transmetalation with CuCN·2LiCl)8 and
ethyl cyanoformate provides a range of polyfunctional uracil
derivatives (7a–e) in 70–75% yield (Scheme 1 and Table 1,
entries 1–5). Subsequent magnesiation of selected uracils 7 allows
a further functionalization in position 5 leading to the 5,6-
disubstituted uracils 8a–c in 78–87% yield (entries 6–8). We have
extended our approach to the thiouracil derivative,9 and have
treated 2,4-bis(methylthio)pyrimidine (4) with TMP2Mg·2LiCl (3,
1.1 equiv, THF, −20 ◦C, 60 min), which provides the 6-magnesiated
pyrimidine derivative 9 (Scheme 2). No trace of 5-magnesiated
thiouracil could be detected. Thus, trapping of 9 with typical
electrophiles furnishes the new 6-substituted thiouracils 10a–c in
76–81% yield (Scheme 2 and Table 1, entries 9–11). The formation
of a new carbon–carbon bond is also readily performed by a
Negishi7 cross-coupling providing the 6-arylpyrimidines 10d and
10e in 71 and 80% (Table 1, entries 12–13). A◦further metalation
with TMP2Mg·2LiCl (3, 1.1 equiv, THF, −5 C, 45 min) can be
performed at position 5. Quenching with electrophiles such as I2,
PhCOCl (after transmetalation with CuCN·2LiCl)8 or PhCHO
provides the fully substituted pyrimidines 10a–c in 61–66% yield
(entries 14–16).
The functionalization of heterocycles like uracils is of great
importance for the preparation of bio-relevant molecules, es-
pecially with antiviral properties.1 Wada2 and Que´guiner3 have
reported the regioselective lithiation of 2,4-dimethoxypyrimidine
(2) using TMPLi. Recently, we have shown that TMPMgCl·LiCl
(1; TMP = 2,2,6,6-tetramethylpiperidyl)4 allows a full functional-
ization of the pyrimidine scaffold under mild conditions.5 Herein,
we wish to report a complementary metalation procedure of
the uracil derivative (2) as well as of the thio-analogue of 2
(2,4-bis(methylthio)pyrimidine 4) using TMPMgCl·LiCl (1)5 or
TMP2Mg·2LiCl (3).6 Whereas the lithiation of dimethoxyuracil
(2) with TMPLi3 (ether, 0 ◦C, 10 min) produces exclusively the
5-lithiated pyrimidine 5, we have found that the treatment of 2
with TMPMgCl·LiCl (1; 1.1 equiv, THF, 25 ◦C, 15 min) furnishes
exclusively the 6-magnesiated uracil derivative 6 (Scheme 1).
No trace of 5-magnesiated uracil could be detected after 1 h
at 25 ◦C.
Scheme 1
Scheme 2
Thus, the quenching of 6 with various electrophiles such
as I2, Me3SiCN, 4-ethyl iodobenzoate7 (after transmetalation
In summary, we have reported a new successive regioselective
functionalization of protected uracils and thiouracils. This method
should find broad applications in the synthesis of pharmaceuti-
cally relevant molecules. Further investigations are under way in
our laboratories.
Department Chemie, Ludwig-Maximilians-Universita¨t Mu¨nchen, Butenand-
str. 5-13, Haus F, 81377, Mu¨nchen, Germany. E-mail: Paul.Knochel@
cup.uni-muenchen.de; Fax: (+49)-89-2180-77680; Tel: (+49)-2180-77681
† Electronic supplementary information (ESI) available: Experimental
section and spectroscopic data. See DOI: 10.1039/b812528g
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3237–3239 | 3237
©
Mosrin, Marc
