Intramolecular Diels-Alder reactions of 2-(alkynyl)pyrimidines and 2-(alkynyl)pyridines

doi:10.1016/S0040-4020(01)81093-0

Tetrahedron

Volume 45, Issue 16, 1989, Pages 5151-5162

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Abstract

Pyrimidines 3, 7 and 13 carrying an ω-alkynyl side-chain -CR₂(CH₂)_nCH₂CCH (R = H, CN; n = 1, 2) at the 2-position undergo intramolecular inverse electron demand Diels-Alder reactions across the C-2 and C-5 positions. Loss of hydrogen cyanide, caused by a retro-Diels-Alder reaction, from the intermediate cycloadducts leads to annelated pyridines 5, 9 and 15, respectively. Similarly, from the nitropyridines 16 the 2,3-dihydronitro-1H-indenes 18 are obtained. The influence of electronic and steric effects on the rate of cycloaddition is discussed. Gem-disubstitution on the chain connecting the reaction centers leads to a considerable rate enhancement for compounds 3 vs 13. Compounds 7, having an extra methylene group in the tether between diene and dienophile, react much slower than compounds 3 due to decreased entropic assistance.

Abstract

Intramolecular Diels-Alder reactions of pyrimidines and pyridines carrying an ω-alkynyl side-chain are described. The influence of electronic and steric effects on the rate of above cyclization reactions is discussed.

References (26)

D.L. Boger
Tetrahedron
(1983)
D.L. Boger
Chem. Rev.
(1986)
D.L. Boger et al.
T. Jojima et al.
Heterocycles
(1979)
L.B. Davies et al.
J. Chem. Soc.
(1981)
L.S. Trifonov et al.
Helv. Chim. Acta
(1987)
G.D. Davies et al.
J. Heterocyclic Chem.
(1964)
D.J. Brown et al.
J. Chem. Soc. (C)
(1971)
E. Rougeout et al.
J. Heterocyclic Chem.
(1983)
H.C. van der Plas et al.
J. Heterocyclic Chem.
(1978)
A.E. Chichibabin et al.
J. Russ. Phys.-Chem. Soc.
(1920)
Chem. Abstr.
(1924)
R.P. Thummel et al.
J. Org. Chem.
(1977)
H. Neunhoeffer et al.
Ann. Chem.
(1985)
H. Neunhoeffer et al.
Ann. Chem.
(1974)
A.T.M. Marcelis et al.
J. Org. Chem.
(1986)

V.N. Charushin et al.

Tetrahedron Lett.

(1982)

bA.T.M. Marcelis and H.C. van der Plas, Tetrahedron, in...

T. Jojima et al.

Chem. Pharm. Bull.

(1972)

T. Jojima et al.

Chem. Pharm. Bull.

(1976)

T. Jojima et al.

Chem. Pharm. Bull.

(1976)

T. Jojima et al.

Chem. Pharm. Bull.

(1980)

D.L. Boger et al.

J. Org. Chem.

(1984)

D.L. Boger et al.

J. Org. Chem.

(1986)

D.L. Boger et al.

J. Am. Chem. Soc.

(1987)

D.A. de Bie et al.

Tetrahedron

(1988)

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Three representative 6,7-dihydro-5H-cyclopenta[b]pyridin-4-amines were synthesized using an intramolecular inverse electron demand hetero–Diels–Alder/retro–Diels–Alder sequence between pyrimidines (acting as azadienes) and ynamides (acting as dienophiles). Two solvents of this reaction, sulfolane and trifluorotoluene, were compared at 210 °C and the former consistently led to higher yields. In addition, these studies confirmed the importance of the steric bulk of the C5-position of the pyrimidinyl cycloaddition precursor.
Trois 6,7-dihydro-5H-cyclopenta[b]pyridin-4-amines representatives ont été synthétisées par une réaction d'hétérocycloaddition [4+2] intramoléculaire à demande électronique inverse (ihDA)/rétro-Diels–Alder (rDA) entre des pyrimidines (jouant le rôle d'azadiènes) et des ynamides (jouant le rôle de diénophiles). Deux solvants de cette transformation, le sulfolane et le trifluorotoluène, ont été comparés à 210 °C; le premier des deux a conduit systématiquement à de meilleurs rendements. De plus, ces études confirment l'importance de l'encombrement stérique de la position C5 du précurseur de cycloaddition de type pyrimidinyl.
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They react with more difficulty, due to the longer tether between diene ad dienophile leading to a decreased entropic assistance. At a considerable higher temperature than observed for the (1,1-dicyanopentynyl)pyrimidines (210 °C instead of 130 °C and 8,8-dicyano-5,6,7,8-tetrahydroquinolines are formed (89T5151) (Scheme 33). These intramolecular IHDA pyrimidine-to-pyridine ring transformations are also successfully applied to synthesize bicyclic heterocycles, containing a five-membered heterocyclic ring which is b- or c-annelated to the pyridine ring.
This chapter discusses the pyrimidine-to-pyridine ring transformation and pyridine-to-pyrimidine ring transformation. In nucleophile-induced pyrimidine-to-pyridine rearrangements, two types of reactions can be distinguished depending on the structure of the nucleophile: (1) reactions in which the nitrogen in the pyridine ring originates from the nitrogen of the pyrimidine ring or (2) reactions in which the pyridine nitrogen is derived from a nitrogen-containing reagent. In addition to nucleophile-induced transformations, the hetero Diels–Alder (HDA) cycloaddition reactions are also very suitable ways to perform the pyrimidine-to-pyridine ring transformations. To investigate the influence of substituents on the scope of the pyridine-to-pyrimidine ring transformation, a large number of 6-R-2-bromopyridines were investigated in an experiment. It was found that the ring transformation only occurs in quite limited cases. Only the 2-bromo-6-Ph-, 6-OPh- and 6-(substituted-C6H4O)-pyridines could be converted into the corresponding pyrimidine derivatives in reasonable yields (40–50%).
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They react with more difficulty, due to the longer tether between diene ad dienophile leading to a decreased entropic assistance. At a considerable higher temperature than observed for the (1,1-dicyanopentynyl)pyrimidines (210 °C instead of 130 °C and 8,8-dicyano-5,6,7,8-tetrahydroquinolines are formed (89T5151) (Scheme 33). These intramolecular IHDA pyrimidine-to-pyridine ring transformations are also successfully applied to synthesize bicyclic heterocycles, containing a five-membered heterocyclic ring which is b- or c-annelated to the pyridine ring.
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2(1H)-Pyrazinones bearing a X-(o-C₆H₄)CC-R moiety (X=NH, NAc) are shown to undergo an intramolecular cycloaddition-elimination reaction on thermolysis in refluxing bromobenzene yielding α-carbolines or β-carbolinones. The product distribution depends strongly on the substitution pattern of the pyrazinone precursors and the solvent used for thermolysis. A high yield and selective formation of β-carbolinones is possible when heating in tetrahydronaphthalene at reflux. Use of acetic anhydride as solvent facilitated the reaction and made it possible to realise a carbolin(on)e unaccessible by thermolysis in the previously mentioned solvents.
Computational studies towards the selectivity and reactivity of 5-propynyloxyclycloalkanepyrimidines in intramolecular diels-alder reactions.
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Computational studies (MNDO/PM3 and MMX) were performed towards the selectivity and reactivity of the ringtransformation reactions of the 5-(1-propynyloxyethyl)pyrimidine derivatives A1 -8. Determination of the energy and dipole moments of the transition states of the different possible reaction pathways revealed that the ratio of the product formation was determined by the polarity of the transition states, as expressed by their dipole moments, in combination with the dipole moment of the reaction medium. Also the reactivity of the compounds under study appeared to depend on the polarity of the transition state of the initial Diels-Alder reaction. The differences in dipole moments of the different TS's are ascribed to the geometry of the molecules in the TS's. Furthermore, a comparison of the heats of activation of the initial Diels-Alder reaction and the subsequent retro Diels-Alder reaction showed that the first one is the rate determining step.
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Intramolecular Diels-Alder reactions of 2-(alkynyl)pyrimidines and 2-(alkynyl)pyridines

Abstract

Abstract

Tetrahedron

Chem. Rev.

Heterocycles

J. Chem. Soc.

Helv. Chim. Acta

J. Heterocyclic Chem.

J. Chem. Soc. (C)

J. Heterocyclic Chem.

J. Heterocyclic Chem.

J. Russ. Phys.-Chem. Soc.

Chem. Abstr.

J. Org. Chem.

Ann. Chem.

Ann. Chem.

J. Org. Chem.

Tetrahedron Lett.

Chem. Pharm. Bull.

Chem. Pharm. Bull.

Chem. Pharm. Bull.

Chem. Pharm. Bull.

J. Org. Chem.

J. Org. Chem.

J. Am. Chem. Soc.

Tetrahedron