11.3. Some common sequences in synthesis

Many reactions are used as part of a common sequence to achieve a specific synthetic goal.  We saw that in the example synthesis in the previous section, where it was necessary to convert an alcohol into an ether using the Williamson ether synthesis.  Below are given some of these common sequences:

The alkene shuffle

Want to move a functional group from one carbon over to the neighboring carbon?  Try this!  Use Markovnikov’s Rule to guide you.  (Note: The HBr/ROOR reaction is covered later, in section 18.4., but it’s included here for completeness.)

A set of reactions for adding or removing groups to/from an alkene

Extending a chain via an SN2 reaction

There are three common examples of this, and all three processes involve a key step.  In each case, the starting material is converted into its conjugate base in the first step, and that conjugate base is used as an SN2 nucleophile for the second step.  Usually you would use the same solvent for both steps.  These reactions were all introduced in section 9.2.  In these reaction schemes, the added carbons are shown in orange.  Since all three processes involve attachment of an alkyl group (to the conjugate base), they would all be classed as “alkylation” reactions.

(a) Converting an alcohol to an ether via the Williamson ether synthesis

See section 9.5. for more details.  The conjugate base of an alcohol is called an alkoxide.  Here you may have a choice of which alkyl group comes from the alcohol, and which one comes from the alkyl halide; you should always try to use the less substituted alkyl group (ideally methyl or 1o alkyl) in the alkyl halide, as that will lead to a cleaner SN2 reaction.  This example is the one used in the previous section in the synthesis example:

An example of a Williamson ether synthesis starting from an alcohol

(In practice, the first step of the reaction can be done on a small scale in DMSO, but on a larger scale NaH can catch fire when added to DMSO.)  With liquid alcohols, sometimes Na metal is used instead of NaH for making the alkoxide.

(b) Converting a terminal alkyne into an internal alkyne

See section 9.8 for more details.  The conjugate base of a terminal alkyne is called an acetylide, and it is made using a strong base: Either NaH (possibly in DMSO on a small scale) or NaNH2 (in liquid ammonia).

Example of acetylide alkylation

(c) Extending the alkyl chain of a ketone.

See section 9.7 for more details.  The conjugate base of a ketone is called an enolate.  It is usually made using the strong lithium base LDA, which forms the conjugate base on the less substituted alpha carbon.  The alpha carbons are the carbons either side of the carbonyl (C=O) group.  The reaction is done as a two-step sequence in cold THF (often at -78 oC) as the polar aprotic solvent.

Example of alkylation of an enolate