Cyclisation of 3-alkenylpyrido[1,2-a]pyrimidines to furo[2,3-d]pyrido[1,2-a]pyrimidines

Article abstract of DOI:10.1016/S0040-4039(03)00087-X

3-Alkenylpyrido[1,2-a]pyrimidines react under mild conditions to give novel tricyclic furo[2,3-d]pyrido[1,2-a]pyrimidines in high yields. The cyclisation takes place in the presence of an acid catalyst. The product yield is affected by the type and the st

Full text of DOI:10.1016/S0040-4039(03)00087-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1939–1941
Cyclisation of 3-alkenylpyrido[1,2-a]pyrimidines to
furo[2,3-d]pyrido[1,2-a]pyrimidines
Mustafa Gu¨llu¨,* Sibel Uzun and Serkan Yalc¸in
Department of Chemistry, Faculty of Science, Ankara University, 06100, Tandog˘an, Ankara, Turkey
Received 4 November 2002; revised 19 December 2002; accepted 3 January 2003
Abstract—3-Alkenylpyrido[1,2-a]pyrimidines react under mild conditions to give novel tricyclic furo[2,3-d]pyrido[1,2-
a]pyrimidines in high yields. The cyclisation takes place in the presence of an acid catalyst. The product yield is affected by the
type and the strength of the acid used. Exceptionally high yields were obtained when an organic acid like trifluoromethanesulfonic
acid and trifluoroacetic acid were used. On the other hand, sulfuric acid gave the best results of the inorganic acids examined.
© 2003 Elsevier Science Ltd. All rights reserved.
Furo[2,3-d]pyrido[1,2-a]pyrimidines are novel tricyclic
pyrimidine derivatives and were synthesised for the first
time from 3-alkenylpyrido[1,2-a]pyrimidines in our ear-
lier research work.1,2 The thermal reaction of alkyliden-
We now report that the type of acid reagent is very
important in order to obtain high yields. Two exam-
ples, 2-hydroxy-8-methyl-3-(2-methyl-1-propenyl)-4H-
pyrido[1,2-a]pyrimidin-4-one 3a and 2-hydroxy-
8-methyl-3-(2-phenyl-1-propenyl)-4H-pyrido[1,2-a]
pyrimidin-4-one 3b, were used in cyclisation experi-
ments.1,2,7 Several organic and inorganic acids were
used for the cyclisation reaction and the results are
given in Table 1. A stronger acid catalyst is required for
high yields of cyclic products. No cyclisation occured
when a carboxylic acid, such as acetic, malonic or
oxalic acid was used. In contrast, good yields of furopy-
ridopyrimidines were obtained in the presence of
stronger carboxylic acids, e.g. trifluoroacetic acid.1,2
Trifluoromethanesulfonic acid gave quantitative yields
(entries 1, 3, and 4), but p-toluenesulfonic acid did not
produce cyclic products in good yields.
emalonate esters
2
with 2-aminopyridines gave
3-(2-alkenyl)pyrido[1,2-a]pyrimidines 3 in good yields.1
An interesting outcome of our earlier work is the
cyclisation of the 3-(2-alkenyl)pyrido[1,2-a]pyrimidines
3 in trifluoroacetic acid/dichloromethane in which
formation of 4H-5,6-dihydrofuro[2,3-d]pyrido[1,2-a]-
pyrimidines 4, was observed in good yields (Fig. 1).
Because the cyclisation yield was sufficiently high in the
solvent system used, no further study was carried out.
However, this reaction is quite attractive for the synthe-
sis of novel tricyclic pyrido[1,2-a]pyrimidine derivatives
and of some biologically important bicyclic furans.3–6
Therefore, the effect of different parameters on the
formation of 4H-5,6-dihydrofuro[2,3-d]pyrido[1,2-a]-
pyrimidines 4 needed to be investigated, particularly the
type and the strength of the acid catalyst, preferably to
avoid the use of expensive and toxic trifluoroacetic
acid.
Aqueous inorganic acids, such as concentrated HCl and
HBr led to simultaneous cleavage of the pyrimidine
ring of the substrate and product during the cyclisa-
tion process, and did not give cyclic products in
Figure 1. Synthesis of furo[2,3-d]pyrido[1,2-a]pyrimidines 4.
Keywords: cyclisation; furopyridopyrimidines; pyridopyrimidines.
* Corresponding author. Tel.: 312-2126720/1028; fax: 312-2232395; e-mail: gullu@science.ankara.edu.tr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00087-X

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M. Gu¨llu¨ et al. / Tetrahedron Letters 44 (2003) 1939–1941
Table 1. Cyclisation of 3-(2-alkenyl)pyrido[1,2-a]pyrimidines 3 in the presence of acids
Entry
Substrate (mmol)
Acid catalyst (mL/mmol)
Solvent (mL)
Temp. (°C)
Time (h)
Yielda 48 (%)
1
2
3
4
5
6
7
8
3a (1)
3a (2)
3a (1)
3a (1)
3a (1)
3a (1)
3a (1)
3a (1)
3a (1)
3a (1)
3a (1)
3a (1)
3a (1)
3a (1)
3b (1)
3b (1)
3b (2)
CF3SO3H (1.0 mL)
CF3SO3H (0.7 mL)
CF3SO3H (0.7 mL)
CF3SO3H (0.5 mL)
CH3COOH (3 mL)
CF3COOH (2 mL)
35% HCl (3 mL)
HCl gas (10 mmol)
HCl gas (10 mmol)
HCl gas (10 mmol)
TosOH (10 mmol)
H2SO4 (0.4 mL)
CHCl3 (10)
CHCl3 (7)
CHCl3 (5)
CHCl3 (5)
CHCl3 (3)
CH2Cl2 (4)
CHCl3 (5)
CHCl3 (5)
CH3COOH (5)
DMF (7)
CHCl3 (5)
CHCl3 (5)
CHCl3 (5)
CHCl3 (5)
CHCl3 (5)
CHCl3 (6)
CHCl3 (10)
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
14
4
17
5
48
12
24
4
24
5
3
4
1
4
0.25
3.5
0.35
100
62
100
100
–
90
40
–
–
–
–
50
80
98
85
96
80
b
b
b
9
b
10
11
12
13
14
15
16
17
b
H2SO4 (1.0 mL)
H2SO4 (2.0 mL)
H2SO4 (0.8 mL)
H2SO4 (1.2 mL)
H2SO4 (2.0 mL)
a Isolated cyclic product yields.
b A mixture of cyclic product, starting material and decomposition products was obtained.
yields greater than 40%. Anhydrous HCl gas was dis-
solved in some polar solvents (CHCl3, MeCN, DMF,
CH3COOH) and used for cyclisation, however, only
low yields of the furopyridopyrimidine derivatives were
obtained.
solution was neutralised with saturated Na2CO3 and
the organic material was extracted with dichloro
methane (2×20 mL), dried over Na2SO4, passed
through a small silica gel column (5 g) and evaporated.
The remaining solid was pure furopyridopyrimidine.
In summary, the synthesis of novel tricyclic pyrimidine
derivatives can be achieved in two steps from alkylidene
malonates and aminopyridines. Cyclisation of 3-(2-
alkenyl)pyrido[1,2-a]pyrimidines was realised in quanti-
tative yields at room temperature using suitable organic
and inorganic acids, preferably concentrated sulfuric
acid. This successful cyclisation reaction may find
important applications in the synthesis of cyclic furan
derivatives. An extension of this work is currently
under investigation.
Excellent results were obtained with concentrated sulfu-
ric acid, which led to good to excellent yields of the
desired pyrimidine 4 from both 3a and 3b (entries
13–17). The presence of water in the system caused
hydrolysis of pyrimidine ring in both starting materials
and cyclic products. This resulted in formation of ring
cleaved by-products and reduced the yield of 4. The
amount of acid catalyst is also an important factor.
One or two equivalents of acid were insufficient for the
cyclisation, at least a 10-fold excess of acid was
required for high yields. The cyclisation process is also
affected by the reaction temperature. Most of the
experiments were carried out at ambient temperature,
which was found to be satisfactory for the cyclisation.
In a few cases, reactions at reflux (CH2Cl2 and CHCl3)
were attempted, but unfortunately pyrimidine ring
cleavage took place in the substrate and the cyclic
product.
Acknowledgements
The author wishes to thank Ankara University, Scien-
tific Research Projects (BAP) Commission, for financial
support of this project (BAP-2002.07.05.067).
Typical procedure: the substrate (200–300 mg, 1 mmol)
was dissolved in dichloromethane or chloroform (5 mL)
and 1.0–1.5 mL of conc. sulfuric acid was added. The
solution was stirred over a period of 3–5 h at room
temperature. The resulting dark red solution was evap-
orated under reduced pressure. The remaining oil was
mixed with 5 g of ice-water mixture. The aqueous
References
1. Gu¨llu¨, M. Ph.D. Thesis, QMWC, University of London,
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2. Utley, J. H. P.; Elinson, M.; Gu¨llu¨, M.; Ludwig, R.;
Motevalli, M. Acta Chem. Scand. 1999, 53, 901–909.

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1941
3. McGuigan, C.; Barucki, H.; Blewett, S.; Carangio, A.;
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Barucki, H.; Brancale, H.; Andrei, G.; Snoeck, R.; De
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7. 2-Hydroxy-8-methyl-3-(2-methyl-1-propenyl)-4H-pyrido-
[1,2-a]pyrimidin-4-one 4a and 2-hydroxy-8-methyl-3-(2-
phenyl-1-propenyl)-4H-pyrido[1,2-a] pyrimidin-4-one 4b
were prepared in about 90% yield as described in Refs. 1
and 2. Both compounds gave satisfactory spectroscopic
and analytical data similar to that described in Ref. 2.
8. Cyclic products were isolated by flash column chromatog-
raphy (silica gel 60 and chloroform as eluent). Both com-
pounds 4a–b gave satisfactory spectroscopic and analytical
data. Product 4a: mp 135–136°C. wmax (KBr)/cm−1 2969,
1717 (CꢀO), 1654, 1592, 1498, 1344. lH (400 MHz; CDCl3,
TMS) 1.56 (6H, s, two CH3), 2.48 (3H, s, CH3-Py), 3.06
(2H, s, CH2), 6.92 (1H, d, J 8, 7-H), 7.28 (1H, s, 9-H), 8.95
(1H, d, J 8, 6-H). m/z 230.1 (M+, 100%, C13H14N2O2
requires 230.1), 189.1 (21.4), 172.1 (20.6), 144.1 (26.1),
135.1 (42.5), 113.0 (18.1), 92.1 (46.4). Product 4b: mp
121–122°C. wmax (KBr)/cm−1 3069, 3037, 2986, 1708 (CꢀO),
1651, 1600, 1510, 1491, 1459, 1437, 1375, 1336, 1080, 1054.
lH (400 MHz; CDCl3, TMS) 1.8 (3H, s, CH3), 2.45 (3H, s,
CH3-Py), 3.35 (1H, d, J 15, 5-H), 3.45 (1H, d, J 15, 5-H),
6.9 (1H, d, J 8, 7-H), 7.2–7.45 (6H, m, 9-H and Ph), 8.9
(1H, d, J 8, 6-H). m/z 292.1, (M+, %100, C18H16N2O2,
requires 292), 189.1 (59), 135.1 (33), 108.1 (24), 92.1
(37).