| Oct
1, 2005 |
| By:
Panagiotis
Ioannidis, Ronny
Lundin, Pino
Pilotti |
| Pharmaceutical
Discovery |
|
Pyrimidines constitute a prominent class of heterocyclic compounds;
their derivatives show interesting pharmacological properties. One
synthesis approach that has attracted attention is the reaction of
alkynones and amidinium salts (1).
Alkynones can be prepared by a Sonogashira-type reaction from acid
chlorides and terminal alkynes. Recently, a copper-free method was
reported (2) in which the formation of undesired 1,3-butadiyne derivatives
are avoided. These authors found that cross-coupling reactions could be
performed with a palladium(II)-acetate catalyst and no ligand, giving good
to excellent yields.
These findings encouraged us to try a pyrimidine-synthesis reaction
from acid chlorides via in situ-formed alkynones under microwave
conditions. For the cross-coupling reaction catalyst, we chose
palladium(II) acetate that was microencapsulated in a polyurea matrix (3),
Pd(II)EnCat™. This reagent had certain handling benefits, especially
when in microwave conditions: the risk of hot spot overheating due to
metal attachment to the glass vial wall was eliminated. The
catalyst-filtering procedure was easier as well.
Results and Discussion
The cross-coupling reaction between benzoyl chloride and 4-ethynyltoluene
was used as a model for the optimization of the alkynone formation, and
was performed on a 0.2-mmol scale. The reaction was heated by microwaves
in an Emrys™ Optimizer in the presence of TEA using Pd(II)EnCat™ as
catalyst and THF as solvent. Purity of the reaction mixture, as assessed
by LC-MS, was greater than 80% within 15 min at 90 °C when reacting
equimolar amounts of acid chloride and alkyne in 3 equiv. TEA and 2 mol%
catalyst. The encapsulated catalyst was subsequently filtered easily using
an ordinary filter frit.
In the following pyrimidine-forming step, the reaction with
benzamidinium chloride was used as a model for the optimization.
When 1.2 equiv. amidine hydrochloride and 2.4 equiv. Na2CO3
x H2O were added to the filtered alkynone solution and the
resulting mixture was heated by microwaves at 160 °C for 10 min, the
LC-MS purity of the reaction mixture obtained was greater than 90%
(Scheme).
In subsequent syntheses, some modifications of the optimized protocol were
necessary (entries 13-18, see Table). The alkynone formation in entries 13
and 14 required 1.5 equiv. of acid chlorides and a prolonged reaction time
(30 min) at a slightly higher temperature (100 °C). In entries 15-18,
excess acid chlorides was increased to 3 equiv. and 3 equiv. of amidinium
chlorides were required as well.
The formed pyrimidines were purified by chromatography on a Horizon™
HPFC™ System, using a FLASH 12+M prepacked silica cartridge.
One of the synthesis reactions was uniformly scaled up 16-fold (3.2
mmol, entry 8), with microwave heating in an Emrys™ Optimizer EXP. The
result after purification was comparable with the 0.2 mmol synthesis
(entry 7). The resulting isolated overall yields are summarized in the
Table.
General experimental procedure
A 2-mL reaction vial, loaded with a
mixture of 0.2 mmol acid chloride, 0.2 mmol alkyne, 0.004 mmol Pd(II)EnCat™
(0.4 mmol Pd/g), 0.6 mmol TEA, and 1.0 mL THF was capped and heated to 90
°C in an Emrys Optimizer™ for 15 min. After cooling, the vial was
uncapped and the catalyst was filtered. To the resulting solution, 0.24
mmol amidinium hydrochloride and 0.48 mmol Na2CO3 x
H2O were added. The mixture was heated to 160 °C in an Emrys™
Optimizer for 10 min. After cooling, the vial was uncapped, the solid was
filtered, and the solution was concentrated. The residue was purified as
described above. The products were analyzed by LC-MS and characterized by 1H-NMR.
The purities of the isolated pyrimidines were all found to be greater than
95%.
Conclusions
In this article, we describe a
two-step, microwave-assisted synthesis method for the preparation of
2,4,6-trisubstituted pyrimidines. In the first step, the intermediate
alkynone was synthesized by reacting an acid chloride with a terminal
alkyne in a Sonogashira type cross-coupling reaction. The cross-coupling,
however, was performed without addition of copper salts or ligand, and
used palladium as a catalyst, microencapsulated in a polyurea matrix,
which facilitated handling. In the second step, the formed alkynone was
reacted without purification with amidinium chloride, yielding the desired
pyrimidine. The total reaction times ranged between 25-40 minutes and the
isolated overall yields after chromatography purification were between
49-83%.
References:
1. A.S. Karpov and T.J. Mü J. Synthesis
18, 2815 (2003).
2. D.A. Alonso, C. Nájera and M.C.
Pacheco. J. Org. Chem. 69, 1615 (2004).
3. The microencapsulated Pd catalyst,
Pd(II)EnCat™, is available from Avecia Ltd.
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