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. 2020 Sep 14;10(56):33937-33943.
doi: 10.1039/d0ra04345a. eCollection 2020 Sep 10.

Retro Diels Alder protocol for regioselective synthesis of novel [1,2,4]triazolo[4,3- a]pyrimidin-7(1 H)-ones

Awad I Said  1   2 , Márta Palkó  1 , Matti Haukka  3 , Ferenc Fülöp  1
Affiliations

Retro Diels Alder protocol for regioselective synthesis of novel [1,2,4]triazolo[4,3- a]pyrimidin-7(1 H)-ones

Awad I Said et al. RSC Adv. .

Abstract

Reactions of diastereochemically varied norbornene-condensed 2-thioxopyrimidin-4-ones 6 and 10 with variously functionalized hydrazonoyl chlorides 2a-h gave regioselectively angular norbornene-based [1,2,4]triazolo[4,3-a]pyrimidin-7(1H)-ones 7a-h and 11a,c-e, respectively. Thermal retro Diels-Alder (RDA) reaction of 7a-h and 11a,c-e resulted in the target compounds 4a-h as single products. On the other hand, reactions of thiouracil 1 and hydrozonoyl chlorides 2a-e gave regioselectively [1,2,4]triazolo[4,3-a]pyrimidinone-5(1H)-ones 3a-e. The opposite regioselectivity of thiouracil 1 and norbornene-condensed 2-thioxopyrimidin-4-ones 6 and 10 was attributed to electronic factors according to DFT calculations. The angular structure of norbornene based [1,2,4]triazolo[4,3-a]pyrimidin-7(1H)-ones was confirmed by single crystal X-ray crystallography.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Scheme 1
Scheme 1. Solvents and conditions: dioxane, TEA, reflux 4–6 h. The ratio of compounds 3 : 4 was calculated from the 1H-NMR spectrum of the crude reaction mixture using the signals at around 6.1 ppm and 6.5 ppm for H-6 of regioisomers 3 and 4, respectively. Separation of the regioisomers by column chromatography, eluent: EtOAc, Rf = 3: 0.4; 4 : 0.05.
Scheme 2
Scheme 2. Solvents and conditions: (i) CSCl2, NaHCO3, CHCl3; (ii) NH3, MeOH; (iii) dioxane, TEA, reflux, 4–6 h; (iv) MW: in 1,2-DCM, 200 °C, 30–120 min, 200 W.
Scheme 3
Scheme 3. Reaction pathways of thiouracil 1 and hydrazonoyl chlorides 2 to form regioisomers 3 and 4.
Scheme 4
Scheme 4. Isomerization of hydrazonoyl chlorides (2e as an example).
Fig. 1
Fig. 1. Optimized geometric structure and HOMO energy levels of tautomers A and B of compounds 1, 6 and 10.
Fig. 2
Fig. 2. TELP image of 7e at 50% probability level. There are two independent molecules in the asymmetric unit.
Fig. 3
Fig. 3. TELP image of 11d at 50% probability level.
See this image and copyright information in PMC

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