:Hantzsch pyrrole synthesis
{{Short description|Chemical reaction}}
The Hantzsch Pyrrole Synthesis, named for Arthur Rudolf Hantzsch, is the chemical reaction of β-ketoesters (1) with ammonia (or primary amines) and α-haloketones (2) to give substituted pyrroles (3).Hantzsch, A. Ber. 1890, 23, 1474.Feist, F. Ber. 1902, 35, 1538.
Pyrroles are found in a variety of natural products with biological activity, so the synthesis of substituted pyrroles has important applications in medicinal chemistry.Furstner, A. Angew. Chem. Int. Ed. 2003, 42¸ 3582-3603.{{Cite journal|last1=Leonardi|first1=Marco|last2=Estévez|first2=Verónica|last3=Villacampa|first3=Mercedes|last4=Menéndez|first4=J.|date=February 2019|title=The Hantzsch Pyrrole Synthesis: Non-conventional Variations and Applications of a Neglected Classical Reaction|url=http://www.thieme-connect.de/DOI/DOI?10.1055/s-0037-1610320|journal=Synthesis|volume=51|issue=4|pages=816–828|doi=10.1055/s-0037-1610320|s2cid=104444238|issn=0039-7881|url-access=subscription}} Alternative methods for synthesizing pyrroles exist, such as the Knorr Pyrrole Synthesis and Paal-Knorr Synthesis.
Mechanism
Below is one published mechanism for the reaction:Li, J.J. Name Reactions; 4th ed.; Springer-Verlag: Berlin, Germany, 2009; p. 276.
The mechanism starts with the amine (1) attacking the β carbon of the β-ketoesters (2), and eventually forming an enamine (3). The enamine then attacks the carbonyl carbon of the α-haloketone (4). This is followed by the loss of H2O, giving an imine (5). This intermediate undergoes an intramolecular nucleophilic attack, forming a 5-membered ring (6). Finally, a hydrogen is eliminated and the pi-bonds are rearranged in the ring, yielding the final product (7).
An alternative mechanism has been proposed in which the enamine (3) attacks the α-carbon of the α-haloketone (4) as part of a nucleophilic substitution, instead of attacking the carbonyl carbon.Wang, Zerong. Comprehensive Organic Name Reactions and Reagents, 3 Volume Set; John Wiley & Sons, Hoboken, New Jersey, 2009; pp. 1326-1327.
Generalized reaction under mechanochemical conditions
A generalization of the Hantzsch pyrrole synthesis was developed by Estevez, et al.Estevez, V.; Villacampa, M.; Menendez, J.C. Chem. Commun. 2012, 49, 591-593. In this reaction highly substituted pyrroles can be synthesized in a one-pot reaction, with relatively high yields (60% - 97%). This reaction involves the high-speed vibration milling (HSVM) of ketones with N-iodosuccinimide (NIS) and p-toluenesulfonic acid, to form an α-iodoketone in situ. This is followed by addition of a primary amine, a β-dicarbonyl compound, cerium(IV) ammonium nitrate (CAN) and silver nitrate, as shown in the scheme below:
Applications
=2,3-dicarbonylated pyrroles=
2,3-dicarbonylated pyrroles can be synthesized by a version of the Hantzsch Pyrrole Synthesis.Moss, T.A.; Nowak, T. Tetrahedron Lett. 2012, 53, 3056-3060. These pyrroles are particularly useful for total synthesis because the carbonyl groups can be converted into a variety of other functional groups.
=Substituted indoles=
The reaction can also occur between an enamine and an α-haloketone to synthesize substituted indoles, which also have biological significance.Jones, C.D; Suarez, T. J. Org. Chem. 1972, 37, 3622-3623.
=Continuous flow chemistry=
A library of substituted pyrrole analogs can be quickly produced by using continuous flow chemistry (reaction times of around 8 min.).Herath, A.; Cosford, N.D.P. Org. Lett. 2010, 12, 5182-5185. The advantage of using this method, as opposed to the in-flask synthesis, is that this one does not require the work-up and purification of several intermediates, and could therefore lead to a higher percent yield.
