Disconnections guidelines

We really would prefer to keep the two OH groups and start from catechol(guideline 7), This forces us to disconnection (3a). We require a reagent for synthon (6) and the obvious choice is the dlaiionium salt (7). 

We would rather leave the OMe group alone (guideline 6), the amino group will be added via nitration and reduction which gives us some flexibility of orientation (guideline 3), and the chlorine can be added by direct chlorination or by diazoniura displacement. The most obvious disconnection is to remove the chlorine. Unfortunately chlorination of the very electron-rich amine (16) oxidises it to black tars it would in any case give a mixture of isomers as all positions in the ring in (16) are activated. 

The chlorine can be disconnected with the alternative polarity via the diazonium salt to amine (19) (guideline 4), The amino group is more powerfully electron-donating than OMe so we can disconnect the NO group. The amino group is itself derived from another nitro group. 

Answer The nitro groups must be put in by nitration but the orientation is wrong. The methyl group cannot be disconnected as a Friedel-Crafts alkylation would never work on the available but extremely unreactive m-dinitro benzene. The solution (guideline 5) is to introduce a dummy amino group in such a position that it can activali... 

The synthesis of the natural product citronellol (1) (used in perfumery) shows guidelines 1 and 4 in action. Disconnection at the branchpoint is possible (la) and the required alcohol (2) comes from available ketone (3) (p Tl) by reduction. 

Guideline 1 Consider the effects of each functional group on the others. Add first (that is disconnect last) the one that will increase reactivity in a helpful way. So, for aromatic compounds, introduce first that group that helps, by reactivity or direction, the introduction of the others. 

Our next example emphasises one aspect of guideline 1. Some functional groups are so deactivating that it is difficult to do any further chemistry once they have been inserted. In other contexts it may be that they are so unstable that we would not wish to risk any further reactions. Musk ambrette 6 is a synthetic musk, essential in perfumes to enhance and retain the fragrance. It has five substituents round a benzene ring. Two of these, the nitro groups, are so deactivating that we want to add them last. So we disconnect them first. 

Compound 33 was needed to make some antimalarial drugs.12 We prefer not to disconnect the OEt group (Guideline 3) and there are good reactions-nitration and chloromethylation-that would go in the right position (ortho or para) to the activating OEt group. Either disconnection a or b could be tried first. 

We can extend these guidelines when we realise that a junction between a ring and a chain and, even more, a junction between two rings, is always at a branchpoint. The series of drugs based on bicyclic structure 5 has an excellent disconnection between the two rings. 

The hardest task in designing a retrosynthetic analysis is spotting where to make the disconnections. We shall offer some guidelines to help you, but the best way to learn is through experience and practice, The overall aim of retrosynthetic analysis is to get back to starting materials that are available from chemical suppliers, and to do this as efficiently as possible,... 

In all the retrosynthetic analyses you ve seen so far there is a heteroatom (N or O) joining the rest of the molecule together, and in each case we made the disconnection next to that N or O, This guideline works for esters, amides, ethers, amines, acetals, sulfides, and so on, because these compounds are often made by a substitution reaction,... 

Chlorbenside is used to kill ticks and mites. Using Guideline 2 we can suggest a disconnection next to the sulfur atom using Guideline 1 we know that we must disconnect on the alkyl and not on the aryl side. 

Both (a) and (b) pose problems of chemoselectivity as it would be hard to alkylate the phenol in the presence of the basic nitrogen atom. Between (c) and (d), (c) appears to be the better choice because the next disconnection after (d) will have to be an alkylation of O in the presence of an NH2 group. To avoid chemoselectivity problems like this, we want to try and introduce reactive groups late in the synthesis. In terms of retrosynthetic analysis, then, we can formulate another guideline. 

This guideline helps us in the next retrosynthetic step for the ICI-D7114 intermediate. Disconnection (c) gave us a compound with two ethers that might be disconnected further by disconnection (e) or (/). 

Disconnection (e) requires alkylation of a compound that is itself an alkylating agent. Disconnection (/) is much more satisfactory, and leads to a compound that is easily disconnected to 4-hydroxyphenol (pdra-cresol) and 1,2-dibromoethane. Using Guideline 3, we can say that it s best to disconnect the bromoethyl group (J) before the benzyl group because the bromoethyl group is more reactive and more likely to cause problems of chemoselectivity. 

Before we leave C-X disconnections and go on to look at OC disconnections we should just review some important points. We suggested three guidelines for choosing disconnections and now that you have met the principle of two-group disconnections, we can add a fourth ... 

Using guideline 5 (p. 787) we want to convert the halide to an oxygen-based group, and a sensible solution is to choose the ketone. 1,3-Disconnection of this compound corresponds to a Mannich reaction. This is another case where FGI of the amine to an alcohol is not desirable, because the Mannich reaction will produce the amine directly. 

Below are summarized some important guidelines for choosing disconnections of bonds. Thus, the initial stage of the retrosynthetic analysis key fragments are recognized, which then can be recombined in the forward synthetic step in an efficient way. ... 

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