Strategy XIII Introduction to Ring Synthesis Saturated Heterocycles

Background Needed for this Chapter Reference to Clayden, Organic Chemistry Chapter 42 Saturated Heterocycles and Stereoelectronics. 

This chapter is about intramolecular reactions and, in particular, about making heterocycles by cyclisation reactions. At the end of the last chapter we mentioned that the synthesis of 76 by reaction of the primary alkyl chloride 74 with MeNH2 was likely to give a poor yield (numbers from chapter 28). The problem is that the product 75 is also a nucleophile and will react at a similar rate with 74 as does MeNH2- The reaction is mtermolecular and so bimolecular. 

We hope you would not be surprised that the very similar reaction of 2 gives exclusively the pyrrolidine 3. The reaction 4 is now intramolecular—a unimolecular cyclisation in fact—and is greatly preferred to any bimolecular processes. In fact 2 cannot be prepared as the free amine its salts, e.g. the hydrochloride, are stable but neutralisation with base liberates 2 which promptly cyclises to 3. 

This chapter is about the advantage that cyclisations have over intermolecular reactions and therefore about the simplicity of heterocyclic synthesis. We need to look first at some details. It is not true that all cyclisations are favourable. A general cyclic amine synthesis shows that there is a large difference in the rates of formation of rings of different sizes.1 Five-membered rings 

Organic Synthesis The Disconnection Approach. Second Edition Stuart Warren and Paul Wyatt 2008 John Wiley Sons, Ltd 

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Strategy XIII Introduction to Ring Synthesis Saturated Heterocycles... 

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