Synthesis of some novel annulated pyrido[2,3-d] pyrimidines via stereoselective intramolecular hetero Diels-Alder reactions of 1-oxa-1,3-butadienes

Article abstract of DOI:10.3762/bjoc.6.11

Some novel annulated pyrido[2,3-d]pyrimidines 6 and 7 were synthesized stereoselectively by intramolecular hetero Diels-Alder reactions involving 1-oxa-1,3-butadienes.

Full text of DOI:10.3762/bjoc.6.11

Synthesis of some novel annulated pyrido[2,3-d]
pyrimidines via stereoselective intramolecular hetero
Diels–Alder reactions of 1-oxa-1,3-butadienes
Mohit L. Deb and Pulak J. Bhuyan*
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2010, 6, No. 11.
Medicinal Chemistry Division, North East Institute of Science &
Technology, Jorhat 785006, Assam, India, Fax: 0376 2370011
doi:10.3762/bjoc.6.11
Received: 12 November 2009
Accepted: 28 January 2010
Published: 04 February 2010
Email:
Pulak J. Bhuyan* - pulak_jyoti@yahoo.com
* Corresponding author
Associate Editor: J. Aubé
Keywords:
© 2010 Deb and Bhuyan; licensee Beilstein-Institut.
License and terms: see end of document.
β-halo aldehydes; hetero Diels–Alder reaction; 1-oxa-1,3-butadiene;
pyrido[2,3-d]pyrimidines; uracil
Abstract
Some novel annulated pyrido[2,3-d]pyrimidines 6 and 7 were synthesized stereoselectively by intramolecular hetero Diels–Alder
reactions involving 1-oxa-1,3-butadienes.
Introduction
The importance of uracil and its annulated derivatives is well Hetero Diels–Alder reactions [32-35] are becoming a mainstay
recognized by synthetic as well as biological chemists [1-8]. of heterocyclic and natural product synthesis. This powerful
Pyrido[2,3-d]pyrimidines represent a broad class of annelated reaction method does not only allow the efficient synthesis of
uracils which have received considerable attention over the past complex compounds starting from simple substrates but also
years due to their wide range of biological activities such as permits the preparation of highly diversified molecules. One
antibacterial [9,10], antitumor [11,12], cardiotonic [13,14], such reaction type, the oxabutadiene Diels–Alder reaction is a
hepatoprotective [13], antihypertensive [13], bronchiodilator very useful method for the synthesis of dihydropyrans [36-38].
[15] and vasodilator [16] properties. Additionally, some com-
pounds of this type exhibit antialergic [17], antimalarial [18], Heterocyclic β-halo aldehydes are very interesting compounds
analgesic [19,20] and antifungal [21] activity. Consequently, which can be transformed in a number of ways to fused hetero-
much effort has been directed towards the synthetic manipula- cycles [39,40] by using the reactivity of halide for nucleophilic
tion of uracil for the preparation of these complex molecules. substitution in combination with a multitude of transformation
However, there still remains many challenges in the synthesis of possibilities from the aldehyde function.
these naturally occurring complex molecules [22-31].
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Beilstein Journal of Organic Chemistry 2010, 6, No. 11.
Results and Discussion
of a cyclic compound and two carbon atoms to which the dieno-
As part of our continued interest in uracils [41-45] and the phile is attached are part of a ring system, the endo-transition
development of highly expedient methods for the synthesis of state is energetically more favorable than the exo-transition
diverse heterocyclic compounds of biological importance state, and thus the cis-cycloadducts were formed predominantly
[46-50], we now report the stereoselective synthesis of some (entries 1–5). In case of entries 6–8, the bulky ethyl group
new complex annulated pyrido[2,3-d]pyrimidines by further favors the endo-transition and in these cases cis-
intramolecular hetero Diels–Alder reactions involving 1-oxa- annelated products were formed exclusively. In some of our
1,3-butadienes (Scheme 1).
previous efforts, we also obtained either cis-isomers or the
mixtures of both the cis- and trans-isomers [52,53].
The key intermediate, the 2-chloro-3-formyl uracil derivative 1
(β-halo aldehyde), was prepared by the reaction of N,N-di- When N-methylallylamine (2b) or N-benzylallylamine (2c) was
methyl barbituric acid with Vielsmeier reagent (DMF + POCl3) used for the reaction as shown in Scheme 1, the Knoevenagel
using excess phosphorous oxychloride as solvent following our condensation did not occur even after refluxing in the presence
published method [51]. The nucleophilic substitution of the of piperidine. The reason might be the delocalization of the lone
chloro group of 1 by allyl amines 2 afforded the 6-N-allyl-1,3- pair on the allyl nitrogen through the formyl group which makes
dimethyl-5-formyl uracils 3. Compounds 3 were then reacted it less electrophilic towards the active methylene compounds.
with cyclic β-diamides/β-diketones 4 in presence of a base cata- However, the use of a stronger base, e.g. N,N-diisopropylethyl-
lyst (usually piperidine) to produce the 1-oxa-1,3-butadienes 5 amine (DIPEA) under refluxing conditions in ethanol for 3 h
which underwent intramolecular Diels–Alder reaction under gave quite satisfactory results in all cases. In the case of
reflux conditions in toluene (12 to 15 h) to give the cycload- N-phenylallylamine substituted uracils the condensation reac-
ducts. In most of cases the formation of two compounds was tions proceeded normally in the presence of either of the bases.
observed. The compounds were separated by column chromato-
graphy and their structures were determined from their spectro- Conclusion
scopic data as the cis-(6) and trans-(7) isomers of the cycload- In summary, we report the stereoselective preparation of some
duct. The generality of the reaction was established by synthes- new complex tetracyclic annulated uracil derivatives by
izing a series of tetracyclic annulated uracil derivatives 6a–h intramolecular hetero Diels–Alder reactions involving 1-oxa-
and 7a–e. Our results are recorded in Table 1.
1,3-butadiene. This reaction, which can also be investigated for
the synthesis of many other heyterocyclic compounds of biolo-
In all of the reactions the cis-annelated products were formed gical importance, is a valuable addition to the chemistry of
either predominantly or exclusively. As the oxabutadiene is part uracils.
Scheme 1: Stereoselective synthesis of some new complex annulated pyrido[2,3-d]pyrimidines by intramolecular hetero Diels–Alder reactions
involving 1-oxa-1,3-butadienes.
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Beilstein Journal of Organic Chemistry 2010, 6, No. 11.
Table 1: Synthesis of some novel annulated pyrido[2,3-d]pyrimidines 6/7.a
Entry
Allyl amines (2)
Compound (4)
Product yieldb
Reaction time (h)
cis : trans
6 : 7
1
6a + 7a (64%)
15
78 : 22
84 : 16
78 : 22
88 : 12
76 : 24
100 : 0
100 : 0
100 : 0
2
3
4
5
6
7
8
6b + 7b (55%)
6c + 7c (62%)
6d + 7d (50%)
6e + 7e (60%)
6f (62%)
12
16
12
16
15
16
16
6g (60%)
6h (57%)
aAll the reactions were carried out under reflux conditions.
bIsolated yields.
Experimental
LC ESI ion trap mass spectrometer and HRMS were obtained
All reagents and solvents were of reagent grade and were used with a MALDI-TOF instrument. Elemental analyses were
without drying. The IR spectra were recorded on a Perkin Elmer performed on a Perkin Elmer-2400 spectrometer. Analytical
system-2000 FTIR spectrometer. 1H NMR and 13C NMR TLC and column chromatography were performed using E.
spectra were recorded on Bruker Avance-DPX 300 MHz and 75 Merck aluminum-backed silica gel plates coated with silica gel
MHz FT NMR in CDCl3 using TMS as the internal standard. G and E. Merck silica gel (100–200 Mesh); melting points
LR-MS were recorded on a Bruker Daltonics ESQUIRE 3000 (uncorrected) were determined on a Büchi B-540 apparatus.
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Beilstein Journal of Organic Chemistry 2010, 6, No. 11.
Preparation of 1,3-dimethyl-6-chloro-5-formyluracil (1): (280 mg). The other hetero Diels–Alder products 6b–h and
DMF (12 ml) in a 100 ml round bottomed flask was very slowly 7b–e were synthesized similarly.
treated with phosphorous oxychloride (46 ml) with cooling after
the addition of every 1 ml portion of POCl3. 1,3-Dimethylbar- cis-isomer 6a: mp 312–314 °C. IR (KBr); 3033, 2954, 1698,
bituric acid (4 g) was added and the mixture heated under reflux 1687, 1165, 744 cm−1. 1H NMR (300 MHz, CDCl3); δ, 2.96 (s,
for 1 h. Excess POCl3 was removed under reduced pressure. 3H), 2.98 (s, 3H), 3.21 (s, 3H), 3.47 (s, 3H), 3.59–3.68 (m, 3H),
The viscous mixture was poured into ice-cold water and then 4.23 (d, J = 5.28 Hz, 2H), 4.39 (d, J = 6.39 Hz, 1H), 7.0 (t, 2H,
extracted with dichloromethane (two to three times). After J = 7.41 Hz), 7.17–7.27 (m, 3H). 13C NMR (75 MHz, CDCl3);
drying with sodium sulfate, the dichloromethane was removed δ, 163.21, 156.35, 153.37, 149.54, 136.91, 129.95, 123.86,
under reduced pressure. The brown compound obtained 118.69, 104.32, 89.61, 51.52, 37.05, 32.05, 29.0, 28.78, 28.31,
contained some impurities and was used without further purific- 26.18. m/z 438.2 (M + H)+. Anal. Calcd for C22H23N5O5; C,
ation.
60.41; H, 5.26; N, 16.01; found C, 60.68; H, 5.33; N, 15.87.
Reaction of 1,3-dimethyl-6-chloro-5-formyluracil (1) with trans-isomer 7a: mp 317–318 °C. IR (KBr); 3033, 2954, 1698,
N-allylanilines/N-allylamines (2) and preparation of 1687, 1165, 744 cm−1. 1H NMR (300 MHz, CDCl3); δ, 2.96 (s,
6-amino-5-formyluracils 3: Compound 1 (2 mmol, 404 mg) 3H), 2.98 (s, 3H), 3.21 (s, 3H), 3.45 (s, 3H), 3.53–3.67 (m, 3H),
dissolved in dichloromethane, was treated with an equivalent 4.24 (d, J = 5.8 Hz, 2H), 4.36 (d, J = 11.7 Hz, 1H), 7.08 (t, 2H,
amount of N-allylaniline (2a) (2 mmol, 266 mg) and triethyl- J = 7.36 Hz), 7.17–7.27 (m, 3H). 13C NMR (75 MHz, CDCl3);
amine (2 mmol), and the mixture stirred at room temperature δ, 163.26, 156.35, 153.30, 149.47, 136.91, 129.63, 123.86,
for 2 h. The solvent was evaporated and the residue was puri- 118.65, 105.47, 89.61, 51.31, 37.43, 32.05, 29.11, 28.78, 28.31,
fied by column chromatography (silica gel, 100–200 Mesh) 26.18. m/z 438.2 (M + H)+. Anal. Calcd for C22H23N5O5; C,
using dichloromethane to give 3a as a yellow solid 568 mg 60.41; H, 5.26; N, 16.01; found C, 60.65; H, 5.37; N, 15.82.
(95%). Similarly, 3b–c were prepared from the reaction of 1
with 2b–c.
Supporting Information
Knoevenagel condensation of 3 with cyclic β-diamide/β-
Supporting Information File 1
diketones 4 and synthesis of 5: Equimolar amounts of 3a (2
mmol, 598 mg) and 4a (2 mmol, 312 mg) were mixed thor-
oughly in a round-bottomed flask containing water (8 ml). Two
drops of piperidine (in case of Meldrum’s acid (4b), piperidine
acetate was used) were added and the mixture stirred for 4 h.
The solid was removed by filtration and recrystallized from
ethanol to afford a white solid (769 mg, 88%). The compound
was assigned structure 5a from a consideration of its spectro-
scopic data. In case of N-methylallylamine 2b and
N-benzylallylamine 2c, N,N-diisopropylethylamine (DIPEA)
was used as catalyst for the Knoevenagel condensation and
reactions were performed under reflux in ethanol for 3 h. The
method gave satisfactory yields of up to 90%. Compounds 5b–h
were synthesized similarly.
Spectroscopic and elemental analyses data of the
compounds 6b–h and 7b–e.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-6-11-S1.pdf]
Acknowledgements
We thank the DST, New Delhi, for financial support. M. L. Deb
thanks the CSIR (India) for the award of Senior Research
Fellowship and Director, NEIST, Jorhat for providing the facil-
ities to perform the work.
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