Highly efficient synthesis of pyrimidines under microwave-assisted conditions

Article abstract of DOI:10.1055/s-2003-36781

Microwave irradiation of an amidine and alkynone in acetonitrile at 120°C gives 2,4-disubstituted and 2,4,6-trisubstituted pyrimidines in very high yield.

Full text of DOI:10.1055/s-2003-36781

LETTER
259
Highly Efficient Synthesis of Pyrimidines under Microwave-assisted
Conditions
Efficient
Synthesis of
P
a
yrimidinesrk C. Bagley,* David D. Hughes, Paul H. Taylor
Department of Chemistry, Cardiff University, PO Box 912, Cardiff, CF10 3TB, UK
Fax +44(29)20874030; E-mail: bagleymc@cf.ac.uk
Received 27 November 2002
R'
O
R4
N
Abstract: Microwave irradiation of an amidine and alkynone in
acetonitrile at 120 °C gives 2,4-disubstituted and 2,4,6-trisubsti-
tuted pyrimidines in very high yield.
R3
R2
R3
R
N
Key words: pyrimidines, microwave synthesis, heterocycles
N
R6
ref. 3
ref. 5
Microwave dielectric heating has emerged as a valuable
R5
R3
alternative to conventional conductive heating methods in
O
recent years.1 With no direct contact between the chemi-
ref. 8,9
ref. 6-9
R
N
N
R3
R5
NR2
O
R
cal reactants and the energy source, microwave-assisted
R'
1
chemistry can be more efficient, in terms of the energy
used, provide faster heating rates and enable rapid optimi-
sation of synthetic procedures, often with an increase in
reaction rate and efficiency. Recent advances in instru-
mentation, with the introduction of dedicated ovens for
organic synthesis that focus microwaves in a monomodal
cavity, have increased the popularity and reproducibility
of microwave chemistry, increasing the methodology
available for the development of new synthetic reactions
and optimisation of existing procedures.2
ref. 14,15
O
ref. 7,
8,10
ref. 4,
8,9,11-14,
16a
R
N
HN
R
N
R2
N
R'
N
N
R'
H2N
R3
R2
R'
Scheme 1 Ethynyl ketones as synthetic intermediates
Ethynyl ketones 1 are valuable synthetic intermediates
for the preparation of a wide range of simple nitrogen-
containing heteroaromatic molecules. Pyridazines,3 py-
ridines,4 quinolines,5 pyrazoles,6–9 isoxazoles,8,9 triazoles9
and pyrimidines7,8,10 have all been prepared from these in-
termediates (Scheme 1), the latter used in the facile syn-
thesis of heterocyclic building blocks, biologically active
targets and non-proteinogenic amino acids.10
R
MeCN-H2O
base, heat
O
NH⋅HCI
N
R
+
R2
NH2
(55-90%)7
R'
R2
N
R'
1
2⋅HCl
3
Scheme 2 Synthesis of pyrimidines 3 using traditional heating
methods
We have developed a number of new methods for the syn-
thesis of pyridines11–14 and pyrido[2,3-d]pyrimidines14,15
using ethynyl ketones. As part of our interest in the devel-
opment of new procedures in microwave chemistry for the
facile synthesis of simple nitrogen-containing heterocy-
cles,16 we set out to to extend these findings to the prepa-
ration of pyrimidines from ethynyl ketones under
microwave-assisted conditions. Using traditional heating
methods this conversion is effected by heating a solution
of an ethynyl ketone 1 and the hydrochloride salt of an
amidine 2 in wet acetonitrile in the presence of base to
give pyrimidines 3 in good yield (Scheme 2).7,8,10
In a new microwave-assisted procedure, a range of readily
available alkynones 1a–e12 and an excess of the hydro-
chloride salt of either benzamidine 2a, acetamidine 2b or
guanidine 2c, was stirred at 120 °C for 40 min in acetoni-
trile in the presence of sodium carbonate using microwave
irradiation at an initial power of 90 W in a self-tunable mi-
crowave synthesizer (Scheme 3).17 After cooling and fil-
tering, pyrimidines 3a–g were obtained in excellent yield,
R
MeCN, Na2CO3
120 °C (90 W)
O
NH⋅HCI
N
R
+
R2
NH2
µwave, 40 min
(82%-quant)
R'
R2
N
R'
1a-e
2a-c⋅HCl
3a-g
Synlett 2003, No. 2, Print: 31 01 2003.
Art Id.1437-2096,E;2002,0,02,0259,0261,ftx,en;D21402ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
Scheme 3 Synthesis of pyrimidines 3a–g under microwave-assisted
conditions

260
M. C. Bagley et al.
LETTER
often without any need for further purification.18 The re- In conclusion, microwave irradiation of an amidine and
sults from this study were compared with experiments alkynone using a self-tunable microwave synthesizer pro-
conducted using more traditional heating methods vides a facile and extremely efficient method for the rapid
(Table 1). In all cases the microwave-assisted conditions synthesis of pyrimidines, often without any need for fur-
were found to be superior, often generating the pyrimidine ther purification. This new procedure is much more effi-
product in near quantitative yield. Traditional heating cient than other reported conditions using traditional
methods not only took longer but also gave a lower yield heating methods and so should find application in the syn-
of product and usually required further purification by thesis of these heterocyclic building blocks in the future.
column chromatography.
Table 1 Comparison of Microwave and Traditional Heating Methods
Entry
1
Alkynone 1a–d
Amidine 2a–c·HCl
Product 3a–g
Thermal
Yield%a
Microwave
Yield%b
95
>98
>98
>98
>98
NH
O
N
Ph
NH2
NH2
NH2
NH2
Ph
Ph
N
N
Ph
Ph
Me
2a
1a
3a
2
3
4
78c
88c
98c
O
NH
NH
NH
N
N
Ph
Ph
H
Ph
1b
2a
3a
O
TMS
Ph
Me
Ph
N
2a
1c
3b
O
Me
Ph
N
Ph
Me
1d
2a
Ph
N
Ph
3c
5
91
>98
O
NH
Et
Et
Ph
NH2
N
N
N
Me
2a
1e
Ph
N
N
Me
Ph
Ph
3d
6
7
8
91c
97c
NH
NH
NH
O
Me
NH2
NH2
NH2
Ph
Me
2b
1a
Ph
1b
3e
79c
91c
O
H
Me
Me
N
2b
3e
60c,d
82c,d
O
Me
Ph
Me
N
Me
2b
1d
Me
N
Ph
3f
9
71
90
NH
O
N
TMS
H2N
NH2
Me
H2N
N
Me
2c
1c
3g
a Reaction complete after heating at reflux for 2 h in the presence of Na2CO3.
b Reaction complete after irradiation for 40 min.
c Purification by column chromatography on silica, eluting with light petroleum-ether (1:1), was required.
d Unreacted alkynone 1 was still present in the crude reaction mixture.
Synlett 2003, No. 2, 259–261 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Highly Efficient Synthesis of Pyrimidines under Microwave-assisted Conditions
261
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Acknowledgement
We thank the B.B.S.R.C., Royal Society and Pfizer Ltd. for support
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Synlett 2003, No. 2, 259–261 ISSN 0936-5214 © Thieme Stuttgart · New York