Synthesis of heterocycles by intermolecular cyclization
1. 1,3-dipolar cyclizations
These reactions normally form five-membered heterocyclic rings, for which the reaction between a dipolar n1,3 compound and an alkene is necessary. The reaction is a [3-2] cycloaddition.   The 1,3-dipolar compounds that have had the most use to form pentagonal heterocycles are: Azides, diazoalkanes, nitrous oxide, nitrile imines, nitrile oxides, azomethylene imines, azoxy compounds, azomethane ylides, nitrones, carbonyl oxides, and ozone. The following cyclizations and disconnections are quite common, showing the wide range of 1,3-dipolar reactants and their resonance structures or tautomers used for the purpose of forming pentagonal heterocycles. The generally accepted mechanism of the 1,3-dipolar reaction responds to a concerted reaction.

Propose a synthesis plan for the following molecules: MOb 86 . Retrosynthetic analysis . the MOb , is a derivative of isoxazole. Its disconnection can be oriented to the use of a nitrile oxide and a   acetylenic derivative.
Synthesis.   Nitrile oxide can be prepared from nitromethane by the Mukaiyama reaction. The acetylenic derivative, from benzaldehyde, making the chain grow with unsaturation, previously, with the Wittig reaction. The polar diene and the dienophile formed combine according to Diels-Alder to form the mob 86.

MOb 87 . Retrosynthetic analysis. the MOb it is a derivative of triazole, and it can be disconnected according to the Diels-Alder reaction, which allows to propose simple starting molecules

Synthesis. Sodium azide and acetylene are good starting materials for preparing the mob 87.

MOb 88. Retrosynthetic analysis : The tetrazole derivative MOb 88, is disconnected to generate azide and nitrile precursors that combine in a heteromolecular cycloaddition to form a heterocyclic adduct

Synthesis: The required benzonitrile, a strong dienophile, is formed from benzene by the basic reactions shown. The cycloaddition reaction, to form the MOb 88 adduct, is carried out with sodium azide, as a polar dienophile, catalyzed with a little heat.

2. Heteronuclear Diels-Alder reaction.
When in the Diels-Alder reaction, a   carbon atom by a heteroatom on the diene or dienophile of the reaction, a six-membered heterocyclic adduct is formed, with at least one heteroatom in the ring. All theoretical and reactivity considerations, studied for the Diels-Alder reaction for the formation of carbocyclic adducts, apply.
heterodienes:
They are good heterodienes, aldehydes and conjugated ketones, 1-azadienes and 2-azadienes. Conjugated aldehydes and ketones produce pyranic rings, the reaction is facilitated by Lewis acids or increased pressure, as well as the presence of an electron group. attractive to the alkene.
Most common heterodienophiles in the Diels-Alder reaction: Heterodienophiles:
Aldehydes, ketones and aldehydes, if they are deficient in electrons, react under mild conditions, otherwise they require high pressure and temperature conditions or Lewis acid type catalysts. These heterodienophiles allow the formation of pyranic systems, useful in the preparation of acyclic precursors of various drugs, as is the case of macrocyclic antibiotics. Due to the instability of imines, they are prepared in situ despite being less used as heterodienophiles than ketones and aldehydes. Acceptor groups on imines make them more stable.   and allow the formation of hydropyridines. Most common heterodienes in the Diels-Alder reaction: Propose a synthesis design for the following molecules: MOb 89 , Retrosynthetic analysis. the MOb It presents the structure of a typical adduct, formed by the Diels-Alder reaction, which is why a retro-Diels-Alder disconnection is proposed, with which a diene and a heterodienophile are produced as suitable precursors to face the synthesis.

synthesis . The Wittig reaction on benzaldehyde allows the formation of the diene. The heterodienophile is formed by a Friedel-Crafts acylation reaction on benzene. Diene and dienophile combine with gentle heating to form the mob 89

MOb 90 . Retrosynthetic analysis . the MOb It has the structure of a Diels-Alder heteroadduct, for which a retro Diels-Alder disconnection is performed. Then the precursor molecules are already easy to synthesize directly
synthesis . The Wittig and Reilly oxidation reactions are combined, taking care to activate the heterodienophile to carry out the Diels-Alder reaction and arrive at the mob 90.

MOb 91 . Retrosynthetic analysis . The initial disconnection the mob , can follow the path of a retro-Diels-Alder, giving rise to a common diene and a heterodiene, which are then unconnected to arrive at simple precursors

synthesis . Heterodiene is formed by condensation between ketone and formaldehyde. The dienophile is formed by aldol condensation of the   acetaldehyde, which then forms the mob 91.

MOb 92. Retrosynthetic analysis. . the MOb a pyridine derivative, it is functionalized towards an adduct, where it disconnects according to rDA. The disconnection of the heterodiene produces simple starting molecules,   the dienophile is an acetylenic derivative.
synthesis . The heterodiene is prepared by condensation between amidine and glyoxylic acid, to then combine the product with the dienophile. The formed adduct is aromatized with DDQ, to form the mob 92
MOb 93. Retrosynthetic analysis . the MOb , it is disconnected by rDA. The diene is cyclopentadiene and the heterodienophile is an imine, which by disconnection leads to benzonitrile, as starting material.

synthesis . The imine formed acts as a dienophile and combines with cyclopentadiene to form the mob 93

MOb 94. Retrosynthetic analysis . In the tautomer of the mob , it proceeds to disconnect according to rDA. The diene formed tautomerizes to quench as α,β-insat.CO and then continues to quench as 1,5-diCO.

synthesis . The aniline imine combines with the diene that is an α tautomer, β-insat.CO, to form an adduct, which turns out to be a tautomer of the mob 94

cycloadditions
The most studied cycloadditions are those that occur between pentagonal heterocyclic compounds such as oxazoles and some dienophiles, which can be combined with them by electrocyclic addition and subsequent elimination of a small molecule, to produce pyridine rings. Examples:

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