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Tesi etd-01182011-085054


Tipo di tesi
Tesi di dottorato di ricerca
Autore
RIBECAI, ARIANNA
URN
etd-01182011-085054
Titolo
New Microwave-Promoted Synthesis of Heterocyclic Derivatives without Added Metal Catalysts.
Settore scientifico disciplinare
CHIM/06
Corso di studi
SCIENZE CHIMICHE
Commissione
tutor Prof. Carpita, Adriano
Parole chiave
  • indoles
  • heterocycles
  • green chemistry
  • cycloisomerization of alkynes
  • microwaves
  • azaindoles
  • water
Data inizio appello
27/01/2011;
Disponibilità
completa
Riassunto analitico
The indole ring system is a structural component of a vast number of biologically active natural and unnatural compounds and it can be found in many pharmaceutical agents. The synthesis and functionalization of indoles have been a major area of focus for synthetic organic chemists and numerous methods have been developed. Among the many described approaches, the cyclization reaction of both N-substituted and N-unsubstituted-2-alkynylaniline derivatives is a major procedure for the construction 2,3-disubstituted and 2-substituted indoles.
In fact, there is the significant advantage of ready availability of the starting 2-alkynylanilines which can be prepared easily by Sonogashira-type alkynylation from a large variety of commercially available substrates. Typically, the cyclization is achieved using strong bases (like metal alkoxides, metal hydrides and metal amides) or transition metals. However, most of the cited methods require the use of moisture sensitive bases, harsh or strongly basic conditions which are incompatible with a wide range of functional groups. As regards the use of transition metals, the cyclization of 2-alkynylanilines and 2-alkynylanilides typically takes place in the presence of catalytic amounts of Pd(II) salts or Pd(0) complexes, stoichiometric or catalytic Cu(I) and Cu(II) salts or complexes, and catalytic Au(III) salts. In addition, also the use of platinum, molybdenum, iridium, rhodium, zinc, mercury, iron and indium have been recently described for preparing substituted indoles. Nonetheless, only a small number of these methods deal with N-un-protected 2-alkynylanilines, which cyclize in the presence of expensive metal-sources and/or with high catalyst loadings, with the additional drawback of potential metal-contamination of the products.
Curiously, a very few examples describe the application of microwave irradiation in this type of cyclization. On the other hand, the need for cleaner and more benign processes is becoming ever more urgent. In this novel perception, reactions conducted in aqueous media as well as the application of microwaves for reaction mixtures heating have been receiving increasing attention. Recently, microwave irradiation was applied with significant advantages in heterocyclic synthesis, allowing to reach quickly higher temperatures and to obtain faster reactions than by conventional heating. Particularly worthy of note are synthetic organic reactions run in water and under superheated conditions. An interesting example is represented by the hydration of terminal alkynes in superheated water at 200 °C under microwave irradiation described by Vasudevan et al. In 2006 Alami and coworkers expanded the scope of hydration of alkynes and demonstrated the positive effect of microwave heating toward the hydration of arylalkynes, diarylalkynes as well as arylpropargylic alcohols performed in ethanol with p-toluenesulfonic acid. Recently, the same authors showed that this methodology can successfully afford 2-arylsubstituted benzofurans and benzothiophenes from diarylalkynes.
Bearing in mind all these considerations, we put forward the idea that a microwave-assisted cycloisomerization of 2-alkynylanilines, taking place via an intramolecular hydroamination, might be a feasible way to prepare substituted indoles. In particular, we wanted to explore the use of water as solvent and apply microwave irradiation to reach the water "near critical" region. Our investigations demonstrated that 1H-indole and 2-substituted indoles can be obtained by a straightforward methodology which involved a microwave-promoted cycloisomerization in water, taking place via intramolecular hydroamination of the corresponding 2-alkynylanilines. The cyclization proceeded without any additive, either acid or basic, and without any added metal catalyst.
For the preparation of the required alkyne substrates without significant metal-contamination, we developed during this Doctorate Thesis an ad hoc efficient copper-free Sonogashira protocol with Pd EnCat(TM) catalysts. The products were obtained with Pd contents lower than 0.1 ppm by AAS. In order to avoid potential metal contaminants during the cyclization, we used ACS UltraTrace water, where most common transition and non transition metals are present at a 10-5 ppm level.
Moderate to good yields were achieved for a variety of substrates, however, the methodology presented clear limitations especially in terms of applicability. In fact, if high yields were obtained for compounds bearing electron-donating substituents, the introduction of electron-withdrawing groups caused a significant decrease in yields. Moreover, when we tried to increase the concentration of the substrates above 0.1 mmol/ml, the yield dropped in most cases, and, after significant efforts, it appeared clear that a further improvement of these conditions was not straightforward.
In the search for more efficient cyclization conditions, with the aim of developing a more general method suitable for higher substrate loadings and for diversified starting materials, we tried to find species that, if added to water, could help the cyclization, enhance the interaction of the substrates with microwaves and/or possibly increase the solubility in water of the less reactive substrates.
Our first intent was to explore the effect of the addition of inorganic salts. Our idea arose from the well known principle that microwave absorbance of water is improved by the addition of inorganic salts. Thus, we screened neutral, basic and acid salts as additives, and eventually demonstrated that even catalytic amounts facilitated the cycloisomerization. Moreover, the use of aqueous salt solutions proved extremely effective to overcome limitation encountered in terms of low substrate loading.
However, the presence of the salt, even if beneficial for the yield, was accompanied by a significant increase of the pressure which was developed during the heating to 200 °C inside the reaction vials. In our equipment, this caused leakages from the reaction caps with loss of water and compounds, especially at the higher substrate concentrations. The application of short cycles of microwave-heating circumvented the problem and provided the same irradiation times in conditions less stressful for the equipment (reaction vials are cooled and de-pressurized between one cycle of heating and the other).
The reactivity of different substrates was studied and we were able to show that differently substituted indoles and azaindoles could be prepared by microwave-promoted cycloisomerization of 2-alkynylanilines and alkynylpyridinamines in water, expedited by the use of catalytic amounts of inorganic salts such as KCl and NaHCO3.
We obtained good to very good yields for a variety of both electron-rich and electron-poor substrates, even bearing labile functional groups. In some instances, also the addition of 1 or 2 equiv of pyrrolidine instead of the salt gave good yields.
In conclusion, the ambitious objectives we fixed at the beginning of this work were thus reached, since we developed efficient procedures for the cycloisomerization to (aza)indole derivatives. We even collected data obtained under thermal heating conditions, to show that microwave heating was necessary to obtain significant yields in short reaction times.
As a natural extension of our studies, we were interested in verifying the behaviour of N-protected anilines and pyridinamines in the cycloisomerization to (aza)indoles, since these substrates are described as being more reactive in such reactions. Moreover, a further expansion would be represented by the inclusion of oxygen- or sulfur-bearing substrates, and, in particular, (2-methoxyaryl)alkynes and/or (2-carboxylaryl)alkynes. Unfortunately, our work program could not be extended enough to include in-depth experimental data sets acquisition within the deadlines established for this Doctorate Thesis. As a consequence, only preliminary results could be collected.
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