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I am confused with the last step of clozapine synthesis: enter image description here

How can the amine group attack the amide group to form the amidine in such acidic environment? Is the intermolecular reaction between an amine and amide group feasible under not too extreme conditions?

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There reaction environment would have to be acidic to protonate the amide, the amide is not natively electrophilic enough to be attacked by the amine.

A possible point of concern is 'won't the nuclophilic amine be protonated?' And the answer is absolutely. But the protonation is a reversible reaction, and at equilbrium with a catalytic amount of acid (almost always TSA is used in catalytic quantities), the proton will be exchanged with various, some of which will lead to the condensation resulting in product.

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  • $\begingroup$ The reaction goes well because it is intramolecular I guess. Would an intermolecular reaction give a decent yield to be considered useful? $\endgroup$
    – EJC
    Mar 6, 2015 at 10:52
  • $\begingroup$ Intramolecular reactions are more favorable than similar intermolecular reactions for entropic reasons as long as the ring is small-- in this case 7 atoms works great. Once you start making 9 or 10-member rings, the entropy gain becomes much smaller. In this case the resulting conjugation might also be a enthalpic driving force. $\endgroup$
    – Lighthart
    Mar 6, 2015 at 15:15
  • $\begingroup$ I know that but Would an intermolecular reaction give a decent yield? $\endgroup$
    – EJC
    Mar 6, 2015 at 18:43
  • $\begingroup$ I'm skeptical this would work well intermolecularly, but I no longer have access to literature searching to verify $\endgroup$
    – Lighthart
    Mar 6, 2015 at 19:41
  • $\begingroup$ Seems like the acetals of amides are used: organic-chemistry.org/synthesis/C2N/amidines.shtm $\endgroup$
    – EJC
    Mar 7, 2015 at 9:18

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