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Hantzsch Dihydropyridine Synthesis
Synthesis of pyridines

Bohlmann-Rahtz Pyridine Synthesis

The Bohlmann-Rahtz Pyridine Synthesis allows the generation of substituted pyridines in two steps. Condensation of enamines with ethynylketones leads to an aminodiene intermediate that, after heat-induced E/Z isomerization, undergoes a cyclodehydration to yield 2,3,6-trisubstituted pyridines.

Mechanism of the Bohlmann-Rahtz Pyridine Synthesis

The reaction is related to the well-known Hantzsch Dihydropyridine Synthesis, in which in situ-generated enone and enamine species give dihydropyridines. The direct use of ynones instead of enones obviates the need for an aromatizing oxidation step to get the target pyridines. Although the Bohlmann-Rahtz Synthesis is more versatile, purification of the intermediate and the high temperatures required for the cyclodehydration are significant drawbacks that have limited its synthetic utility. Some of the drawbacks have been overcome recently, making the Bohlmann-Rahtz Synthesis more valuable for the generation of pyridines.

Although no mechanistic studies have been conducted, intermediates can be characterized by 1H-NMR, which clearly shows that the main product of the initial Michael Addition and subsequent proton transfer is a 2Z-4E-heptadien-6-one, which is isolated and purified by column chromatography.

High cyclodehydration temperatures are therefore required to facilitate Z/E isomerizations that are a prerequisite for heteroannelation.

Some methods that allow the synthesis of tri- and tetrasubstituted pyridines in a one-step procedure have recently been developed. Instead of using butynone as the substrate, Bagley screened different solvents for the conversion of the less volatile and cheaper 4-(trimethylsilyl)but-3-yn-2-one. It was shown that only EtOH and DMSO are suitable solvents, with EtOH clearly favored as being protic and polar solvent vs. DMSO as a polar aprotic solvent. In both solvents, spontaneous protodesilylation took place. Bagley has also shown that acid catalysis allowed the cyclodehydration to proceed at a significantly lower temperature.

As Brønstedt acid catalysis also promotes the conjugate addition, a range of enamines were then reacted with ethynyl ketones in a (5:1) mixture of toluene and acetic acid to afford functionalized pyridines in a single step in good to excellent yields.

M. C. Bagley, J. W. Dale, J. Bower, Synlett, 2001, 1149-1151.

Following the success of Brønstedt acid catalysis, Bagley investigated the potential of Lewis acid catalysts. The best conditions utilized either 20 mol% ytterbium triflate or 15 mol% zinc bromide in refluxing toluene. Although mechanistic studies were not undertaken, it is assumed that coordination by the catalyst accelerates the Michael Addition, isomerization and cyclodehydration steps. A drawback is the limited compatibility with acid-sensitive substrates. For example, acid-catalyzed decomposition of the starting enamines occurs with tert-butylester and cyano as electron withdrawing groups. A mild alternative is the use of Amberlyst-15 ion exchange reagent that allows a simple work up and tolerates tert-butylesters.

As the enamines are not readily available, and to improve the facility of the process, a three-component reaction was developed using ammonium acetate as the amino group source. In this efficient procedure, the enamine is generated in situ and then reacts with the alkynone present.

In a first attempt, AcOH and ZnBr2 were used as additional catalysts with toluene as solvent, but it has been shown more recently that acid-sensitive substrates react under milder (acid-free) conditions with EtOH as solvent.

X. Xiong, M. C. Bagley, K. Chapaneri, Tetrahedron Lett., 2004, 45, 6121-6124.

A review of the Bohlmann-Rahtz Pyridine Synthesis can be found in a recent report by Bagley (Synthesis, 2007, 2459. DOI). Here, some additional synthetic alternatives are described, such as the use of microwaves, and recent applications such as the synthesis of fused heterocycles and natural products are covered.

Recent Literature

A new mild method for the one-pot synthesis of pyridines
X. Xiong, M. C. Bagley, K. Chapaneri, Tetrahedron Lett., 2004, 45, 6121-6124.

A new one-step synthesis of pyridines under microwave-assisted conditions
M. C. Bagley, R. Lunn, X. Xiong, Tetrahedron Lett., 2002, 43, 8331-8334.

A New Modification of the Bohlmann-Rahtz Pyridine Synthesis
M. C. Bagley, J. W. Dale, J. Bower, Synlett, 2001, 1149-1151.