Synthesis of pyrido[2,3-d]pyrimidines via palladium-catalyzed reaction of iodouracil with acetylenes

Article abstract of DOI:10.1016/S0040-4039(00)00964-3

The reactions of iodouracils having a formamidine or acetamidine moiety 1 with various acetylenes 2 in DMF at 120°C using potassium carbonate and a catalytic amount of palladium acetate gave a mixture of pyrido[2,3- d]pyrimidine derivatives in good to high yields. Addition of lithium chloride to the reaction solution resulted in a change of reaction selectivity. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00964-3

Tetrahedron Letters 41 (2000) 5899±5902
Synthesis of pyrido[2,3-d]pyrimidines via palladium-catalyzed
reaction of iodouracil with acetylenes
Jong Woo Bae, Seung Hwan Lee, Young Jin Cho, Yeon Joo Jung, Han-June Hwang
and Cheol Min Yoon*
Department of Life Science & Biotechnology, Graduate School of Biotechnology, Korea University, 1, 5-Ka,
Anam-Dong, Sungbuk-Ku, Seoul 136-701, South Korea
Received 13 March 2000; revised 5 June 2000; accepted 9 June 2000
Abstract
The reactions of iodouracils having a formamidine or acetamidine moiety 1 with various acetylenes 2 in
DMF at 120ꢀC using potassium carbonate and a catalytic amount of palladium acetate gave a mixture of
pyrido[2,3-d]pyrimidine derivatives in good to high yields. Addition of lithium chloride to the reaction
solution resulted in a change of reaction selectivity. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: iodouracil; acetylene; palladium acetate; LiCl; pyridopyrimidine.
Palladium-catalyzed reactions have attracted the attention of synthetic organic chemists, since
they are known to be an alternative to classical organic reactions. In particular, palladium-
catalyzed annulation methodology has been e€ectively employed for the preparation of new
aromatic systems.1
The pyridopyrimidines have received attention due to their potential biological activities.2
Recently, we reported an ecient method for the syntheses of pyrido[2,3-d]pyrimidines by the
reactions of iodouracil, having a formamidine or acetamidine moiety, with various ole®ns in
DMF using a catalytic amount of palladium acetate.3,4
As a continuation of this work, the reactions of iodouracils having a formamidine or
acetamidine moiety 1 with various acetylenes 2 were studied in the presence or absence of lithium
chloride, which might play a crucial role in the reaction selectivity (Scheme 1).
The reaction of iodouracil 1a with diphenylacetylene 2a in DMF in the presence of palladium
acetate as catalyst and potassium carbonate as base at 120ꢀC gave two pyridopyrimidines 3a
(dehydrogenated one) and 4a (deaminated one) in 67 and 27% yields, respectively (Table 1, entry
1). The selectivity was increased when the same reaction was tried in the presence of 1 equiv. of
lithium chloride.5 Pyridopyrimidine 3a was obtained in 93% yield and only a trace amount of
* Corresponding author. Tel: +82-415-860-1335; fax: +82-415-867-5396; e-mail: cmyoon@tiger.korea.ac.kr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00964-3

5900
Scheme 1.
Table 1
Synthesis of pyrido[2,3-d]pyrimidines via palladium-catalyzed reaction

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pyridopyrimidine 4a was observed by TLC.8 A similar selectivity was observed using 1 equiv. of
lithium bromide instead of 1 equiv. of lithium chloride. However, selectivity was not observed at
all when tetra-n-butylammonium bromide or tetra-n-butylammonium chloride was used instead
of lithium bromide or lithium chloride. On the basis of these experimental results, the selectivity
seems to be due to the lithium cation. Lithium cations in this reaction might prevent the insertion
of palladium of intermediate I (X=H) into the C±N(Me)2 bond to form intermediate II (X=H),
which is necessary for the formation of pyridopyridmidine 4a (Scheme 2). However, the exact
mechanism to prevent the formation of the intermediate II (X=H) by a lithium cation is not clear.
Scheme 2.
The reactions of iodouracil 1a with asymmetric acetylenes were tried in the presence of 1 equiv.
of lithium chloride.6 The reactions gave pyridopyrimidines with some regioselectivity (Table 1,
entries 3±5). In these cases, the other product (the deaminated one) was not observed. The
tendency of regioselectivity for these reactions is similar to that reported previously on the basis
of electronic and steric e€ects.1b
The reaction of iodouracil having an acetamidine moiety 1b with diphenylacetylene was tried
under the same conditions in DMF (Table 1, entry 7). The reaction in the presence of lithium
chloride did not give any coupling product and gave only deiodinated starting material. This
might be explained by considering the role of the lithium cation. The palladium ion of inter-
mediate I (X=Me) in the presence of lithium cation cannot insert into the C±N(Me)2 bond to
form intermediate II (X=Me), and also the insertion of palladium ion of intermediate I into the
C±CH3 bond to form intermediate III (X=Me) is dicult (Scheme 2).
However, the reactions of iodouracil 1b with acetylenes in the absence of lithium chloride gave
the pyridopyrimidines in high yields with regioselectivity (Table 1, entries 7±10).7 However, the
reaction of 1b with phenylacetylene gave decomposition products with none of the desired cyclic
compounds.
In conclusion, the reaction of iodouracils having a formamidine moiety 1a with acetylenes
using palladium acetate in DMF in the presence of lithium chloride at 120ꢀC gave pyrido-
pyrimidines with regioselectivity. The reaction of iodouracil having an acetamidine moiety 1b
with acetylenes without lithium chloride also gave pyridopyrimidines. Further work to determine
the role of lithium cations in the palladium-catalyzed reaction of iodouracils with alkynes is in
progress.
Acknowledgements
We wish to acknowledge the ®nancial support of the Korea Science and Engineering Foundation
(KOSEF) made in the program year of 1999.

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References
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2. (a) Grivsky, E. M.; Lee, S.; Siegel, C. W.; Nichol, C. A. J. Med. Chem. 1980, 23, 327. (b) Rahman, L. K. A.;
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5. One equivalent of lithium chloride in the reaction was identi®ed to be the optimal amount for the selectivity. When
2 equiv. of lithium chloride was used, several other side products were observed by TLC. When 0.5 equiv. of
lithium chloride was used, the selectivity was decreased. In this case, 14% of deaminated product 3a was obtained.
6. The reaction of iodouracil 1a with 1-phenyl-1-propyne 2b in the absence of lithium chloride resulted in less
selectivity, as shown below.
7. Insertion of palladium ion of the intermediate I into the C±N(Me)2 bond in the absence of lithium chloride is
possible to form intermediate II (Scheme 2).
8. Representative experimental procedure. To
a solution of 5-iodo-6-(dimethylaminomethylene)amino-1,3-
dimethyluracil 1a (100 mg, 0.297 mmol) in DMF (10 ml) was added Pd(OAc)2 (3.3 mg, 0.014 mmol), anhydrous
K2CO3 (82 mg, 0.595 mmol), lithium chloride (12.6 mg, 0.297 mmol) and diphenylacetylene (80 mg, 0.446 mmol).
The resulting solution was stirred at 120ꢀC for 1.5 h under nitrogen, concentrated under reduced pressure and
chromatographed on silica gel using a solution of ethyl acetate:hexane (1:10). Eluent concentration gave two
pyrido[2,3-d]pyrimidines as a white solid.