SYNTHESIS OF HETEROCYCLES BY INTRAMOLECULAR CYCLATION

The application of several intramolecular and intermolecular reactions for the formation of carbocyclic systems have been studied in sufficient detail, such as intramolecular condensation reactions of the aldol type, intramolecular acylation, alkylation, and the Diels-Alder cyclization reaction. , electrocyclic, sigmatropic reactions, etc. etc

The construction of heterocyclic systems also uses these same reactions, with the particularity that the heterocyclic system must be present or contain at least one atom other than carbon. The most common are nitrogen, oxygen, sulfur and phosphorus.

The cyclic system of the molecule to be synthesized can come from the modification of a cyclic system present in one of the reagents involved in the synthesis or be the result of cyclization of non-cyclic antecedents and that has been built in the development of the synthesis by intramolecular cyclization or by methods based on intermolecular cyclizations (cycloadditions).

1. Intramolecular cyclization

The general rules for the disconnection of heterocycles originating from an intramolecular cyclization, were adequately systematized by JI Borrell , the same as those assumed in this section (Het = N, O, S)

1.        In the synthesis of a monocyclic compound, ring closure generally involves the formation of a carbon-heteroatom bond.

Model:

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Example:

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2.        If the system contains two adjacent heteroatoms, it is unusual for ring closure to result in the formation of a bond between them. Exceptions are cyclizations on nitro, nitroso or diazonium groups.

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Example :

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3.        If the target molecule is bicyclic, with the heterocyclic ring fused to a benzene ring, it is common for the starting compound to always be a suitably ortho-disubstituted benzene derivative.

Model:

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Example:

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BORRELL JI   "Introduction to Retrosynthetic Analysis" . Chap. 8. Laboratori de Sintesi. Molecular Engineering Group (GEM). Sarriá Chemical Institute, Ramon Llull University. Spain. (Support Slides for Classes)

1.1. Models for intramolecular cyclization

In order to understand the formation of heterocycles through intramolecular cyclization, it is necessary to take into account that both the substrates and the intermediate and final products that are formed, usually present various tautomeric forms, from which it is necessary to select the most useful tautomer to carry out. disconnection or to identify the corresponding syntons.

Three models for intramolecular cyclization and the corresponding disconnections can be mentioned:

Saturated model:

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α-unsaturated model

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α-carbonyl model

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1.1.1.      saturated model

The direct disconnection C-Het, occurs only in some particular cases, it is more common, previously transform it into   an α-unsaturated or α-carbonyl model, as can be seen in the following scheme:

modelsatu2.png

Propose a synthesis design, from simple and affordable materials, for the following molecules:

MOb 65

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MOb 66

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mob 67

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MOb 65 . Retrosynthetic analysis .   the MOb , can be previously functionalized, towards an α -carbonyl model or an unsaturated model, to find precursor molecules, which can be more easily disconnected. The path that is proposed the AGF , according to (b), is the most appropriate, as it requires fewer steps, for the synthesis.

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Synthesis. It begins with the Friedel-Crafts acylation of benzene on the one hand and on the other with the bromination of ethyl acetate, according to HVZ. The following stages require work in a basic medium and at the end we proceed to the hydrogenation of unsaturated centers to reach the mob 65.

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MOb. 66. Retrosynthetic Analysis . The attack of the nucleophilic N on the β carbon, in relation to the ester group, (MOb 66) is orienting to think that it was formed by an intramolecular conjugated Michael addition of an amine on an α, β unsaturated ester. The C-N disconnection gives rise to other common disconnections, until reaching simple starting materials.  

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synthesis . The o-methyl benzaldehyde can be prepared, if necessary, by the Gattermann-Koch reaction on para-methyl sulfonic acid. The rest of reactions, for the synthesis of the MOb. 66, allow us to think that they will be produced with an acceptable yield in the synthesis.

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MOb 67. Retrosynthetic analysis. As in the previous example, the CO bond at the β position to the ester group, in the mob 67, suggests disconnecting by said link, which would have to have been formed by a reaction   intramolecular Michael of an alcohol on the α,β unsaturated CO.

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Synthesis. The synthesis of the Mob 67, requires that it be addressed in two ways, so it turns out to be convergent and in the last stage, in the formation of the cyclic ether, a base is required, which transforms the alcohol into its alkoxide, which is more nucleophilic.

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1.1.2.      α-unsaturated model

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Propose a synthesis design from simple and affordable materials, for the following molecules:

MOb: 68

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MOb: 69

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MOb: 70

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MOb: 71

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MOb 68. Retrosynthetic analysis . The disconnection process the mob , can be faced by two alternatives. (a) requires the preparation of a 1,4-dicarbonyl intermediate and (b) a γ-hydroxyketone intermediate.

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Synthesis. The ways of disconnection, of the mob 68, generate two synthesis routes, equally valid. A design based on the disconnection alternative (b) is proposed, which requires the temporary protection of the ketone group in one of its stages.

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MOb 69 . Retrosynthetic analysis. The disconnection of the furanic ring leads to a synthon   or synthetic equivalent 1,4-diCO, which is disconnected according to this model to produce an illogical electrophilic synthon.

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synthesis .   The use of LDA is sufficient to guarantee the enolate of acetophenone, as a nucleophile, to replace the halogen of the halogenated ketone, so it is not necessary to exercise control over this molecule. The formation of furan requires acid catalysis.

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MOb. 70 . Retrosynthetic analysis .   This MOb is a pyridine derivative, the structure it presents is characteristic of the products formed in the Hansch pyridine synthesis, that is, the pyridine cycle must be formed from an aldehyde and two moles of 1,3-diCO compound and oxidize the intermediate dihydroquinone formed .

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Synthesis : The necessary ketoester to react with benzaldehyde is previously prepared by the Claisen condensation of ethyl acetate. And as an oxidant in the last step, to form the Mob 70, DDQ can be used

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MOb 71 . Retrosynthetic analysis.   the MOb It has a pyridine ring as a substituent on the benzene ring of a quinoline. In such a way that it is preferable, to think first about the formation of this structure, so that the retroanalysis begins with the pyridine structure of the quinoline.

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The simultaneous disconnection, on the ketone and the amine, shows the aniline and the carbonyl compound to have condensed. Since the introduction of the benzene ring into a pyridine is unlikely, the strategy of constructing the pyridine ring from appropriate acetylide derivatives is taken.

synthesis .   Nitrile esters, together with m-nitrobenzaldehyde, allow intermolecular cyclization to form a hydropyridine derivative that is oxidized to pyridine with conc HNO 3 .

Then he   nitro group, allows to build the quinoline pyridine ring, by condensation reactions with a suitable diCO compound. ethylation of the amino group, allows to form   the mob 71.

mobsolb_70.png

1.1.3.      α-carbonyl model

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Propose a synthesis plan, from simple materials, for the following molecules:

MOb: 72

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MOb: 73

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MOb: 74

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MOb 72. Retrosynthetic analysis . This MOb is a tetrahydropyranone, it is disconnected by the S-CO bond. The following IGFs allow the formation of a 1,5-diCO precursor, which, when disconnected, provides the starting materials.

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Synthesis.   The Michael condensation between the α, β-unsaturated ester and the acetaldehyde in a basic medium, forms the 1,5-aldehyde ester, which after reducing the CHO group to alcohol with thiourea it is possible to have the precursor molecule that will act on the group ester, to form the mob 72.

mobsolb_72.png

MOb 73. Retrosynthetic analysis . Disconnection of the lactam amido bond generates the first precursor molecule, which is a γ. amino ester, which is formed between a primary amine and the γ-bromoester and consequently γ-hydroxyester, which is reacted between ethyl acetate enolate and an epoxide as simple and affordable starting materials.

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Synthesis : The epoxide and acetate   ethyl are the reactants that react to form the γ -hydroester. The OH is replaced by bromine with PBr 3   and this reacts with methylamine. to form the precursor molecule that closes in a lactam ring, to form the mob 73.

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MOb 74. Retrosynthetic analysis .   the MOb in question, is the chemotherapeutic drug, Gram (-) ROSOXACIN, which by an IGF, forms a lactam with a five-link cycle, which when disconnected, forms a precursor molecule   amino ester derivative   of a nitroester. The nitroester is an adduct that can be formed from a nitro dienophile and a diene. The diene requires a Wittig reaction for its formation.

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synthesis .   Initially, the condensation of an aromatic aldehyde with nitromethane is used; to reduce the nitro group, the OH groups are protected.

The preparation of the intermediate aminoester proceeds by simple reactions, as well as the formation of the five-membered lactam. The lactam is subjected to selective reduction with LiAlH 4 , and then the double bond is hydrogenated, to produce the mob 74.

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