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The Hantzsch Pyrrole Synthesis, named for
The mechanism starts with the amine (1) attacking the β carbon of the β-ketoesters (2), and eventually forming an
Arthur Rudolf Hantzsch
Arthur Rudolf Hantzsch (7 March 1857 – 14 March 1935) was a German chemist.
Life and work
Hantzsch studied chemistry in Dresden and graduated at the University of Würzburg under Johannes Wislicenus. As a professor, he taught at the Universitie ...
, is the chemical reaction
A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...
of β-ketoesters (1) with ammonia
Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...
(or primary amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen
Hydrogen is the chemical element wi ...
s) and α-halo ketones (2) to give substituted pyrroles (3).
Pyrroles are found in a variety of natural products with biological activity, so the synthesis of substituted pyrroles has important applications in medicinal chemistry. Alternative methods for synthesizing pyrroles exist, such as the Knorr Pyrrole Synthesis
The Knorr pyrrole synthesis is a widely used chemical reaction that synthesizes substituted pyrroles (3). The method involves the reaction of an α-amino-ketone (1) and a compound containing an electron-withdrawing group (e.g. an ester as shown) Π...
and Paal-Knorr Synthesis.
Mechanism
Below is one published mechanism for the reaction:
The mechanism starts with the amine (1) attacking the β carbon of the β-ketoesters (2), and eventually forming an enamine
An enamine is an unsaturated compound derived by the condensation of an aldehyde or ketone with a secondary amine. Enamines are versatile intermediates.
:
The word "enamine" is derived from the affix ''en''-, used as the suffix of alkene, and t ...
(3). The enamine then attacks the carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containi ...
carbon of the α-haloketone (4). This is followed by the loss of H2O, giving an imine
In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bon ...
(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. 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
''In situ'' (; often not italicized in English) is a Latin phrase that translates literally to "on site" or "in position." It can mean "locally", "on site", "on the premises", or "in place" to describe where an event takes place and is used in ...
''. This is followed by addition of a primary amine, a β-dicarbonyl compound, cerium(IV) ammonium nitrate (CAN) and silver nitrate
Silver nitrate is an inorganic compound with chemical formula . It is a versatile precursor to many other silver compounds, such as those used in photography. It is far less sensitive to light than the halides. It was once called ''lunar causti ...
, 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. 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 substitutedindole
Indole is an aromatic heterocyclic organic compound
In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other c ...
s, which also have biological significance.
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.
See also
*Hantzsch pyridine synthesis
The Hantzsch pyridine synthesis or Hantzsch dihydropyridine synthesis is a multi-component organic reaction between an aldehyde such as formaldehyde, 2 equivalents of a β-keto ester such as ethyl acetoacetate and a nitrogen donor such as ammoni ...
References
{{Reflist Pyrroles Chemical synthesis Name reactions