1,3-Dipolar Cycloadditions

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Chapter: Organic Chemistry : Planning Organic Syntheses

The essential features of the Diels–Alder reaction are a four-electron π system and a two-electron π system which interact by a HOMO–LUMO interaction.


1,3-DIPOLAR CYCLOADDITIONS

The essential features of the Diels–Alder reaction are a four-electron π system and a two-electron π system which interact by a HOMO–LUMO interaction. The Diels–Alder reaction uses a conjugated diene as the four-electron π system and a π bond between two elements as the two-electron component. However, other four-electron π systems could potentially interact with olefins in a similar fashion to give cycloaddition products. For example, an allyl anion is a four-electron π system whose orbital diagram is shown below. The symmetry of the allyl anion nonbonding HOMO matches that of the olefin LUMO (as does the olefin HOMO and the allyl anion LUMO); thus effective overlap is possible and cycloaddition is allowed. The HOMO–LUMO energy gap determines the rate of reaction, which happens to be relatively slow in this case.


Molecules isoelectronic with the allyl anion but which are neutral and have at least one resonance form with formal positive and negative changes in a 1,3 relationship are called 1,3 dipoles.


All have an orbital diagram analogous to the allyl anion in which three inter-acting p orbitals give rise to three molecular orbitals containing a total of four π electrons. For example, a nitrone is seen to have a C–N π bond interacting with a filled orbital on the oxygen atom to define a new π system containing four π electrons.


Interaction of the HOMO of the 1,3 dipole with the LUMO of a simple π bond (called a dipolarophile in this process) leads to bond formation between the ends of the 1,3 dipole and the olefin, producing a new five-membered ring.


The process is a concerted 4π + 2π cycloaddition and is related electroni-cally to the Diels–Alder reaction. The formal charges are destroyed during the cyclization and a wide variety of heteroatom components are possible in the 1,3 dipole. Moreover other π bonds besides alkenes and alkynes can be used as dipolarophiles. As a result, 1,3 dipolar cycloadditions have been used to make a large number of heterocyclic compounds.

Since the 1,3 dipolar cycloaddition is concerted, the reaction is stereospecific and the geometry of the olefin is maintained in the cyclic product.


If a symmetric dipolarophile is used, then no regioisomers are possible. If, however, the dipolarophile is unsymmetric, then regioisomers are possible.


As in the case of the Diels–Alder reaction, the regioselectivity can be understood in terms of the electron distribution in the 1,3 dipole and the dipolarophile. For example, a nitrile oxide should have a relatively electron deficient carbon and a relatively electron rich oxygen. Reaction with propene, which has greatest elec-tron density at C-2 because of the inductive effect of the methyl group, gives the regioisomer C. Matching the polarity of the dipole and the dipolarophile predicts this product. Conversely reaction with methyl acrylate, which because of conju-gation has electron deficiency at C-3, gives regioisomer D as the major product.


Polarity matching to predict the major product of 1,3 dipolar cycloadditions is qualitative only and frequently fails to predict the major product correctly. This is because each 1,3 dipole tends to exhibit a characteristic regioselectivity toward particular dipolarophiles that may be modified by steric and/or strain effects. In fact there is still some uncertainty as to just what factors do influence the regioselectivity in these systems.

Nevertheless 1,3 dipolar cycloadditions are an important method for the syn-thesis of a wide variety of heterocyclic compounds. Furthermore they illustrate the generality of 4 + 2 cycloaddition reactions as a means to prepare cyclic products efficiently from acyclic precursors.

To use 1,3 dipolar cycloadditions in a retrosynthetic sense, it is necessary to know what 1,3 dipoles are available. The list on pages 319–320 is repre-sentative of the more common and useful examples, although many others have been reported. Azides, diazo compounds, and nitrones are normally isolable com-pounds which can be added to a solution of an olefin. Other 1,3 dipolar species such as nitrile oxides and azomethine ylides are not stable molecules; they must be generated in the reaction mixture in the presence of the olefin. As might be expected, many different ways to generate 1,3 dipoles have been developed.


Nitrile oxides are often generated by the dehydration of nitro compounds by reagents such as phenyl isocyanate. Azomethine ylides can be generated by the pyrolysis of aziridines or by the prototopic isomerization of imines upon heating.

The next step is to identify the five-membered ring which could be assembled by a 1,3 dipolar cycloaddition and then identify the π system and 1,3 dipole needed to give the proper array of heteroatoms. Thus if the pyrrolidine H is needed, it is clear the alcohol could be made by reducing the ester function of E. Also important is the issue of the all-cis stereochemistry. One way to ensure the all-cis stereochemistry is to do a catalytic hydrogenation of the olefin O. The delivery of hydrogen would come from the less hindered face of O and would give the all-cis product. The needed olefin O could be made by a 1,3 dipolar addition between an azomethine ylide and diphenyl acetylene.


The only concern is the cis stereochemistry of the cycloadduct O. If the planar azomethine ylide adopts the least sterically hindered “W” geometry, then the cis isomer will be produced as a pair of enantiomers. The use of cis-stilbene as the dipolarophile to obtain the all-cis geometry in one step would require that only the endo transition state produces product. Although endo transitions are favored in 1,3 dipolar cycloadditions, mixtures of diastereomers from the exo and endo transition states are usually formed. Catalytic hydrogenation has a higher facial selectivity and is much more likely to give a single diastereomer.


These are but a few examples of how retrosynthetic analysis can be used to develop one or more synthetic routes to a target. Developing synthetic strategies is one of the most creative activities that organic chemists perform. It requires that many different inputs and conditions be cohesively merged into a single thematic development that contains elements of texture and beauty, proportion and balance, and risk and reward. The process is every bit as creative as painting, sculpting, or writing the great American novel!

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