Science of Synthesis

Black, D. StC., Science of Synthesis, (2001) 9, 444.

The most important example of the [C2 + C2 + N] classification is the Hantzsch synthesis, which combines a β-dicarbonyl compound, an α-halo ketone, and ammonia or an amine (‌Scheme 5‌).[‌26‌] Commonly, the β-dicarbonyl compound is a β-oxo ester, such as ‌16‌, ‌17‌, and ‌30‌, and this leads to pyrroles such as ‌18‌–‌21‌, ‌26‌, ‌29‌, ‌31‌, and ‌34‌, substituted with an ester in the C3 position. The α-halo carbonyl compound can be either an aldehyde, such as compounds ‌13‌, ‌14‌, and ‌24‌, or a ketone, such as compounds ‌15‌ and ‌25‌, and protected forms of the aldehyde such as geminal halo acetates, e.g. ‌27‌, or halo ethers, e.g. ‌28‌, can also be used.[‌27‌–‌29‌] Only primary amines and ammonia are applicable to this synthesis. It is generally understood that the amine reacts initially with the β-dicarbonyl compound to form an enamino carbonyl ‌22‌, which then reacts with the α-halo carbonyl compound to give an intermediate ‌23‌. The regiochemistry usually involves formation of a C—C bond by electrophilic attack of the α-halo carbonyl compound at the enamine group, followed by cyclizative condensation of the amine on to the carbonyl group. Thus the combination of 2-bromobutanal (‌13‌), ethyl 3-oxobutanoate (‌16‌), and ammonia gives the pyrrole ‌18‌ in 45% yield. The yield is only 30% when 2-chlorobutanal (‌24‌) is used. The use of 2-bromohexanal (‌14‌) gives yields of pyrroles ‌19‌ and ‌20‌ of approximately 50%. In general, α-halo aldehydes perform much better than α-halo ketones. α-Chloroacetone (‌25‌) is something of an exception, giving a 50% yield of pyrrole ‌26‌, whilst 2-bromopentan-3-one (‌15‌) only gives a 7% yield of pyrrole ‌21‌.[‌27‌] The replacement of an aldehyde group by a halo acetate or halo ether is a useful alternative, especially where the aldehydes are very sensitive compounds, and does not require a change of reaction conditions or workup.[‌27‌]

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References

Meeeeee Meeeeeeeeee

• 8.Meeeee-Meee, (8888) M 8e, 888.
• 8.Meeeee-Meee, (8888) M 88e8, 888.