Intramolecular inverse electron demand Diels-Alder reactions of pyrimidines

Research output: Thesisinternal PhD, WU


<p>This thesis deals with the intramolecular inverse electron demand Diels-Alder reaction of pyrimidines. The main objective of the study was to investigate the synthetic applicability of this reaction and to get more insight in the electronic and steric effects which determine the reactivity of compounds that undergo this intramolecular cycloaddition reaction.<p>After a general introduction about the Diels-Alder reaction, in Chapter 1 a global historical overview is given of the inverse electron demand Diels-Alder reaction of heteroaromatic azadienes with emphasis on the intramolecular version, which has been developed in the recent past.<p>Pyrimidines carrying an ω-alkyne side-chain -XCH <sub><font size="-1">2</font></sub> CH <sub><font size="-1">2</font></sub> C <u>=</u> CH (X = O, N, S, SO, SO <sub><font size="-1">2</font></sub> ) at the 2- or 5-position undergo intramolecular inverse electron demand Diels-Alder reactions across the C-2 and C-5 positions: elimination of hydrogen (or alkyl) cyanide from the intermediate adducts leads to fused pyridines (Chapter 2). The influence of the heteroatom (X) in the dienophilic side-chain on the reactivity is discussed. It is found that the reactivity increases in the order NH &lt; O &lt; S &lt; N C(O)CH <sub><font size="-1">3</font></sub> , reflecting the decrease of electron- donation into the π-electron system of the pyrimidine ring. Substituents on the pyrimidine ring also influence the reactivity due to a combination of electronic and steric factors. In general electron-withdrawing groups increase the rate of reaction although this effect may be partly negated by steric hindrance.<p>Pyrimidines carrying an ω-alkynyl side-chain -CR <sub><font size="-1">2</font></sub> (CH <sub><font size="-1">2</font></sub> )nCH <sub><font size="-1">2</font></sub> C <u>=</u> CH (R = H, CN; n = 1, 2) at the 2-position also undergo intramolecular inverse electron demand Diels- Alder reactions across the C-2 and C-5 positions (Chapter 3). Loss of hydrogen cyanide, caused by a retro-Diels-Alder reaction, from the intermediate cycloadducts leads to 6,7-dihydropyrindines (n = 1) and 5,6,7,8-tetrahydroquinolines (n = 2), respectively. The dicyano compounds (R = CN) are found to be more reactive than the compounds in which R = H. This rate enhancement is ascribed to a combination of the so-called "Thorpe-Ingold" ("scissoring") effect and an increase in the relative population of reactive <em>syn</em> rotamers.<p>2-(1,1-Dicyanohex-5-yn-l-yl)pyrimidines, having an extra methylene group in the tether between diene and dienophile, react much slower than the corresponding 2-(1,1-dicyanopent-4-yn-l-yl)pyrimidines due to decreased entropic assistance.<p>Even 2-(1,1-dicyanopent-4-yn-l-yl)nitropyridines are found to undergo intramolecular Diels-Alder reactions into the corresponding 2,3-dihydronitro-1 <em>H</em> -indenes.<p>In Chapter 4, the synthesis of 2- and 5-propynyloxymethylpyrimidines and their intramolecular Diels-Alder reaction is studied. The products of the reaction are 5,7-dihydrofuro[3,4- <u>b</u> ]pyridines and 1,3-dihydrofuro[3,4- <u>c</u> ]pyridines, respectively. Introduction of one or two alkyl (aryl) groups at the α- or γ-position of the side-chain of the 5-propynyloxymethylpyrimidines results in an increased reaction rate. This phenomenon is discussed in terms of relative rotamer population.<p>A Hammett plot for the intramolecular Diels-Alder reaction of some psubstituted 5-phenyl-2-(1,1-dicyanopent-4-yn-1-yl) pyrimidines into the corresponding 3-aryl-7,7-dicyano-6,7-dihydro-5H-1-pyrindines reveals a linear relationship with a positive slope ρ= 0.061 (Chapter 5), which is in agreement with the inverse electron demand character of this reaction. The low value of p and the small effect of solvent polarity indicates that there is little or no charge separation in the rate determining transition state.<p>N-Alkylpyrimidinium cations carrying a dienophilic side-chain at the 2- or 5- position undergo intramolecular inverse electron demand Diels-Alder reactions into the corresponding annelated pyridine derivatives under considerably milder conditions than the corresponding neutral pyrimidines as a result of a lower HOMO <sub><font size="-1">dienophile</font></sub> /LUM0 <sub><font size="-1">diene</font></sub> energy separation (Chapter 6). Protonation of the pyrimidine ring also facilitates the intramolecular Diels-Alder reaction. Protonation of less activated pyrimidines leads, however, to annelated pyrimidinium cations posessing an exocyclic methylene group in the annelated ring at the carbon atom αto the quaternary nitrogen atom. These products result from an intramolecular coplanar cycloamination reaction.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • van der Plas, H.C., Promotor
  • Marcelis, A.T.M., Promotor
Award date18 Oct 1990
Place of PublicationS.l.
Publication statusPublished - 1990


  • pyrimidines
  • synthesis
  • organic compounds

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