Regio- and chemoselective multiple functionalization of pyrimidine derivatives by selective magnesiations using TMPMgCl·LiCl

Article abstract of DOI:10.1021/ol800790g

(Chemical Equation Presented) Successive regio- and chemoselective magnesiations of pyrimidines using TMPMgCl·LiCl furnish, after trapping with various electrophiles, highly functionalized derivatives in good to excellent yields. Applications to the synth

Full text of DOI:10.1021/ol800790g

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2497-2500
Regio- and Chemoselective Multiple
Functionalization of Pyrimidine
Derivatives by Selective Magnesiations
using TMPMgCl·LiCl
Marc Mosrin and Paul Knochel*
Department Chemie and Biochemie, Ludwig-Maximilians-UniVersita¨t,
Butenandtstrasse 5-13, 81377 Mu¨nchen, Germany
Paul.Knochel@cup.uni-muenchen.de
Received April 7, 2008
ABSTRACT
Successive regio- and chemoselective magnesiations of pyrimidines using TMPMgCl·LiCl furnish, after trapping with various electrophiles,
highly functionalized derivatives in good to excellent yields. Applications to the synthesis of antiviral and anti-inflammatory agents such as
p38 and sPLA2 kinase inhibitors are reported.
Pyrimidines are important scaffolds for the preparation of
various biologically active compounds.1 The direct func-
tionalization of these heterocycles by lithiation is difficult
due to the electrophilic character of the ring, which readily
undergoes the addition of various organometallics in posi-
tions 4 and 6.2 This implies that low temperatures are often
required for the metalation of pyrimidines.3 Recently, we
have reported the new powerful base TMPMgCl·LiCl (1;
TMP ) 2,2,6,6-tetramethylpiperidyl), which allows direct
magnesiation of a number of arenes and heteroarenes.4
Herein, we report a procedure allowing selectiVe function-
alization of all positions of the pyrimidine ring starting from
simple compounds such as 2-bromopyrimidine5 (2) by
performing successive magnesiations using TMPMgCl·LiCl
(1; Scheme 1).
Thus, the treatment of 2-bromopyrimidine (2) with
TMPMgCl·LiCl (1; 1.1 equiv, -55 °C, 1.5 h) leads to the
4-magnesiated pyrimidine (3), which can be trapped by
various electrophiles such as MeSO2SMe, PhSO2SPh, I2,
BrCCl2CCl2Br, and TMSCN leading to the expected products
of type 4a-e in 67-85% (Scheme 1). The formation of a
new carbon-carbon bond is readily performed by a Negishi6
cross-coupling or a Sonogashira7 reaction of in situ generated
2-bromo-4-iodopyrimidine (4c) providing the 4-substituted
heterocycles 4f-h in 71-81% (Scheme 1).
* Corresponding author. E-mail:
(1) (a) Hurst, D. T. An Introduction to the Chemistry and Biochemistry
of Pyrimidines, Purines and Pteridines; Wiley: Chichester, 1980. (b) Brown,
D. J. The Pyrimidines; Wiley: New York, 1994. (c) Katrizky, A. R.; Rees,
C. W.; Scriven, E. F. V. ComprehensiVe Heterocyclic Chemistry II;
Pergamon: Oxford, 1996. (d) Gribble, G.; Joule, J. Progress in Heterocyclic
Chemistry; Elsevier: Oxford, 2007; Vol. 18.
A subsequent magnesiation is readily achieved at position
6 by the addition of TMPMgCl·LiCl (1) to various 4-sub-
(2) (a) Eicher, T.; Hauptmann, S.; Speicher, A. The Chemistry of
Heterocycles; Wiley: Weinheim, 2003. (b) Ple´, N.; Turck, A.; Couture, K.;
Que´guiner, G. Synthesis 1996, 838. (c) Ple´, N.; Turck, A.; Heynderickx,
A.; Que´guiner, G. Tetrahedron 1998, 54, 9701. (d) Ple´, N.; Turck, A.;
Heynderickx, A.; Que´guiner, G. J. Heterocycl. Chem. 1997, 34, 551.
(3) (a) Turck, A.; Ple´, N.; Mongin, F.; Que´guiner, G. Tetrahedron Lett.
2001, 57, 4489. (b) Schlosser, M.; Lefebvre, O.; Ondi, L. Eur. J. Org. Chem.
2006, 6, 1593.
(4) (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem.,
Int. Ed. 2006, 45, 2958. (b) Lin, W.; Baron, O.; Knochel, P. Org. Lett.
2006, 8, 5673.
(5) 2-Bromopyrimidine is commercially available from Acros, Aldrich,
Fluka ($15 for 1 g).
10.1021/ol800790g CCC: $40.75
Published on Web 05/29/2008
2008 American Chemical Society

Scheme 1
.
Magnesiation of 2-Bromopyrimidine (2) at Positions
Scheme 2. Negishi and Sonogashira Cross-Coupling Reactions
at Position 2 Leading to Fully Substituted Pyrimidines 7a-c
4, 6, and 5 using TMPMgCl·LiCl (1; 1.1 equiv)
pyrimidines 6a-f in 67-92% yield (entries 9-14). The
bromine attached at position 2 can be readily substituted
using a Negishi6 or a Sonogashira7 reaction giving the
2-substituted pyrimidines 7a-c in 85-91% yield (Scheme
2).
This method is of great utility for the preparation of
pharmaceutically active heterocycles such as pyrazolopy-
rimidines.11 Thus, the treatment of tetrasubstituted pyri-
midine 6d with NH2NH2·H2O in THF (rt, 10 min) leads
to the pyrazolopyrimidine 8 in 70% yield (Scheme 3). As
stituted 2-bromopyrimidines. Thus, the 2-bromo-4-(meth-
ylthio)pyrimidine8 4a is converted within 5 min at 20 °C to
the 6-magnesiated species, which is chlorinated by reaction
with FCl2CCF2Cl9 leading to the chloropyrimidine 5a in 76%
yield (entry 1 of Table 1). Reaction with BrCl2CCCl2Br
furnishes the bromo-pyrimidine 5b in 81% yield (entry 2).
An iodolysis using I2 leads to the 2-bromo-4-iodopyrimidine
derivative 5c in 78% yield (entry 3). Similarly, the 4-arylated-
2-bromopyrimidine 4f is magnesiated quantitatively with
TMPMgCl·LiCl (1; 1.1 equiv, -40 °C, 45 min) and reacted
with FCl2CCF2Cl, TMSCN, or MeSO2SMe affording the
expected 4,6-disubstituted 2-bromopyrimidines 5d-f in
72-91% yield (entries 4-6).
Scheme 3. Application to the Synthesis of Pyrazolopyrimidines
and Synthesis of a p38 Kinase Inhibitor (11)
Other 2-bromopyrimidines substituted at position 4 with
an alkynyl group or an iodine (4c, 4h) are magnesiated
under mild conditions. Quenching with typical electro-
philes furnishes the polyfunctional pyrimidines 5g and 5h
in 84-93% yield (entries 7 and 8). The last position
(position 5) can be magnesiated as well between -5 and
20 °C within 20-30 min with TMPMgCl·LiCl (1; 1.1
equiv). Trapping with iodine, PhCOCl (after transmeta-
lation with CuCN·2LiCl10 (1.1 equiv)), allyl bromide,
PhCHO, or MeSO2SMe provides the fully substituted
an application, we have prepared a p38 kinase inhibitor12
(useful as an anti-inflammatory and antiviral agent)
starting from 4,6-dichloro- 2-(methylthio)pyrimidine13 (9).
(6) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc.
1980, 102, 3298. (b) Negishi, E.; Kobayashi, M. J. Org. Chem. 1980, 45,
5223. (c) Negishi, E. Acc. Chem. Res. 1982, 15, 340. (d) Milne, J. E.;
Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028.
(10) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
(11) (a) Gomtsyan, A.; Didomenico, S.; Lee, C.; Stewart, A. O.;
Bhagwat, S. S.; Kowaluk, E. A.; Jarvis, M. F. Bioorg. Med. Chem. Lett.
2004, 14, 4165. (b) Revesz, L.; Blum, E.; Di Padova, F. E.; Buhl, T.; Feifel,
R.; Gram, H.; Hiestand, P.; Manning, U.; Neumann, U.; Rucklin, G. Bioorg.
Med. Chem. Lett. 2006, 16, 262.
(7) (a) Benderitter, P.; de Araujo, J. X., Jr.; Schmitt, M.; Bourguignon,
J. J. Tetrahedron 2007, 63, 12465. (b) Kim, J. T.; Gevorgyan, V. Org.
Lett. 2002, 4, 4697. (c) Sonogashira, K.; Tohda, Y.; Hagihara, N.
Tetrahedron Lett. 1975, 50, 4467. (d) Sonogashira, K. ComprehensiVe
Organic Synthesis; Pergamon Press: New York, 1991; Vol. 3.
(8) The thiomethyl group can serve as a leaving group in cross-coupling
reactions: Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979.
(9) Marzi, E.; Bobbio, C.; Cottet, F.; Schlosser, M. Eur. J. Org. Chem.
2005, 10, 2116.
(12) (a) Dewdney, N. J.; Gabriel, T.; McCaleb, K. L. WO 2007023115,
2007. (b) Arora, N.; Billedeau, R. J.; Dewdney, N. J.; Gabriel, T.; Goldstein,
D. M.; O’Yang, C.; Soth, M.; Trejo-Martin, T. A. WO 2007023105, 2007.
(c) Arora, N.; Billedeau, R. J.; Dewdney, N. J.; Gabriel, T.; Goldstein, D. M.;
O’Yang, C.; Soth, M. U.S. 2005197340, 2005.
(13) 4,6-Dichloro-2-(methylthio)pyrimidine is commercially available.
2498
Org. Lett., Vol. 10, No. 12, 2008

The magnesiation of 9 with TMPMgCl·LiCl is complete
within 20 min at 25 °C. Transmetalation with
CuCN·2LiCl10 (1.1 equiv) and acylation with 2-chloroben-
zoyl chloride (2 equiv, rt, 1 h) provides the tetrasubstituted
pyrimidine 10 in 90% yield. Subsequent treatment with
NH2NH2·H2O furnished the p38 kinase inhibitor 11 in 79%
yield (Scheme 4).
Table 1. Products Obtained by Regioselective Magnesiation of
Pyrimidines of Type 4 and 5 with TMPMgCl·LiCl (1) and
Quenching with Electrophiles
Scheme 4
.
Synthesis of an sPLA2 Inhibitor (15) by
Chemoselective Magnesiation
Similarly, we performed the synthesis of an sPLA2
inhibitor 15 having anti-inflammatory properties.14 Thus,
the iodination of the dichloropyrimidine 9 is leading to
the iodopyrimidine derivative 12 in 90% yield. The
substitution of the chlorine at position 6 with benzyl-
amine15 (1.7 equiv, THF, 25 °C, 20 min) leads to the
aminopyrimidine 13 in 91% yield. The Sonogashira7 cross-
coupling of the pyrimidine 13 with 1-butyne affords the
5-alkynyl-6-aminopyrimidine 14 in 98% yield. Smooth
cyclization with KOtBu16 (2 equiv, NMP, 25 °C, 1 h)
finally provides the sPLA2 inhibitor 15 in 45% yield
(Scheme 4).
In summary, we have reported the multiple function-
alization17 of the pyrimidine scaffold using TMPMgCl·LiCl
as an effective magnesium base. This method displays a
large scope and allows functionalization of all positions
of a pyrimidine unit. It should find broad applications to
(14) Hutchison, D. R.; Martinelli, M. J.; Wilson, T. M. WO 2000000201,
2000.
(15) Baindur, N.; Chadha, N.; Player, M. R. J. Comb. Chem. 2003, 5,
653.
(16) (a) Rodriguez, A. L.; Koradin, C.; Dohle, W.; Knochel, P. Angew.
Chem., Int. Ed. 2000, 39, 2488. (b) Koradin, C.; Dohle, W.; Rodriguez,
A. L.; Schmid, B.; Knochel, P. Tetrahedron 2003, 59, 1571.
(17) Procedure for Synthesis of (2-bromo-4-chloro-6-(methylthio)-
pyrimidin-5-yl)(phenyl)methanone (6a). A dry and argon-flushed 25 mL
Schlenk flask, equipped with a magnetic stirrer and a septum, was charged
with freshly titrated TMPMgCl·LiCl (1) (0.89 M in THF, 1.24 mL, 1.1
mmol, 1.1 equiv). 2-Bromo-4-chloro-6-(methylthio)pyrimidine (5a) (240
mg, 1.0 mmol) dissolved in THF (2 mL) was dropwise added at 25 °C,
and the resulting mixture was stirred for 20 min. The reaction mixture was
cooled to -30 °C and after addition of CuCN·2LiCl (1.00 M solution in
THF, 1.1 mL, 1.1 mmol) was stirred for 30 min. Then, benzoyl chloride
(281 mg, 2.0 mmol) was slowly added at -30 °C, and the resulting mixture
was stirred at room temperature for 45 min. The reaction mixture was
quenched with a saturated aqueous NH4Cl solution (10 mL), extracted with
diethyl ether (5 × 20 mL), and dried (Na2SO4). After filtration, the solvent
was evaporated in Vacuo. Purification by flash chromatography (CH2Cl2/
pentane 1:4) furnished (2-bromo-4-chloro-6-(methylthio)-pyrimidin-5-yl)-
(phenyl)methanone (6a) as a white solid (276 mg, 81% yield).
a Isolated, analytically pure product. b Transmetalation with 1.1 equiv
of CuCN·2LiCl. c Transmetalation with 5 mol % of CuCN·2LiCl.
Org. Lett., Vol. 10, No. 12, 2008
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the synthesis of pharmaceutically relevant molecules.
Extensions to the preparation of new materials are
currently under investigation in our laboratories.
shafen), Evonik Degussa AG (Hanau), and Chemetall GmbH
(Frankfurt) for the generous gift of chemicals.
Supporting Information Available: Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the Fonds der Chemischen
Industrie and the Deutsche Forschungsgemeinschaft (DFG)
for financial support. We also thank BASF AG (Ludwig-
OL800790G
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Org. Lett., Vol. 10, No. 12, 2008