Bohlmann-Rahtz reactions

The Bohlmann-Rahtz reaction has also been improved by the use of microwave... 

Scheme 54 Application of the three-component Bohlmann-Rahtz reaction to the synthesis of dimethyl sulfomycinamate...

Steroidal, alicyclic or aromatic annulated pyridines were prepared via a microwave-assisted, base-catalyzed Henry reaction of /1-formyl enamides and nitromethane on an alumina support [97]. Highly substituted tri- and tetrasubstituted pyridines were synthesized in a Bohlmann-Rahtz reaction from ethyl /3-amino crotonate and various alkynones. The reaction involved a Michael addition-cyclodehydration sequence and was effected in a single synthetic step under microwave heating conditions [98]. An alternative approach towards polysubstituted pyridines was based on a reaction sequence involving an inverse electron-demand Diels-Alder reaction between various enamines 45 and 1,2,4-triazines 44 (Sect. 3.6), followed by loss of nitrogen and subsequent elimination-aromatization. Enamines 45 were formed in situ from various ketones and piperidine under one-pot microwave dielectric heating conditions [99]. Furthermore, a remarkable acceleration of the reaction speed (from hours and days to minutes) was observed in a microwave-assisted cycloaddition. Unsymmetrically substituted enamines 45 afforded mixtures of regioisomers (Scheme 35). 

The Bohlmann-Rahtz reaction is a classic pyridine synthesis that has been studied and modified in many ways. Bagley et al. has elaborated on his previous work and reported an iodine-mediated catalytic Bohlmann-Rahtz reaction of aminodienone intermediates <05SL649>. This modified process is reported to be rapid at ambient temperatures resulting in good yields. Moreover, Bagley and co-workers presented a one-pot, three-component Bohhnann-Rahtz reaction to synthesize 2,3,6-trisubstituted and 2,3,4,6-tetrasubstituted pyridines 8 and 9 from P-ketoesters 10 and alkynes 11 as shown in Seheme 3 <05JOC1389>. 

The reaction of yne-ones (also synthons for 1,3-dicarbonyl compounds) with 3-amino-enones or 3-amino-acrylates (the Bohlmann-Rahtz reaction) is regioselective, since conjugate addition of the ketone enamine is the first step the intermediates thus produced can be isolated from reactions in ethanol and converted on to the aromatic pyridine Acetic acid or ytterbium triflate give good results. 

Bagley MC, Chapaneri K, Dale JW, Xiong X, Bower J (2005) One-pot multistep Bohlmann-Rahtz heteroannulation reactions synthesis of dimethyl sulfomycinamate. J Org Chem 70 1389-1399... 

Tri- or tetra-substituted pyridines were prepared in a one-pot Bohlmann-Rahtz het-eroannulation of ethyl (3-aminocrotonate and an alkynone, which involved a Michael addition-cyclodehydration sequence. The reaction proceeded within just 20 min under single-mode microwave heating conditions (Scheme 3.28)48. 

Promothiocin A was initially synthesised by a three-component coupling approach <1998CC2049>. A Bohlmann-Rahtz pyridine synthesis established the oxazoyl-thiazole-pyridine heterocyclic centerpiece. The thiazole building blocks were obtained by the Hantzsch reaction. Two different strategies for macrocylization were successfully employed, with the dedroalanine side-chain being introduced in the last steps of the synthesis <2000JA3301>. 

The reaction proceeds through initial Diels-Alder reaction of 2-pyrazinones 4 with an acetylene forming bicyclic intermediate 5. This is followed by spontaneous elimination of cyanogen chloride or an isocyanate to obtain 2-pyridone 6 and pyridine 7, respectively. Additionally, continuous flow reactors have been designed for microwave reactions, which improve the energy efficiency. The eontinuous flow microwave reaction was illustrated using a mierowave assisted Bohlmann-Rahtz pyridine synthesis <05JOC7003>. 

There are many ingenious sophisticated variations on the reactor cells, but a simple, though not very versatile, flow cell has been described for use in a microwave heater, where the reaction solution was percolated through sand in a test tube as the equivalent of multiple microchannels. This set-up was used to carry out a Bohlmann-Rahtz pyridine synthesis and a Fischer indolisation. ... 

Bischler-Napieralski synthesis (isoquinoline) 413 Bltimlein-Lewy synthesis (oxazole) 172 B oekelheide reaction 362 Bonnemann synthesis (pyridine) 373 Bohlmann-Rahtz synthesis (pyridine) 369 Borsche synthesis (cinnoline) 494 von Braun degradation 432 Brederek synthesis... 

Alkynes bearing electron-withdrawing substituents are more suitable for this reaction as was shown earlier by Bohlmann and Rahtz. Pyridines are formed from intermediate Michael adducts in the reaction of a-oxoalkynes having a j8-hydrogen and several primary enaminones in high yield. If, however, jS-substituted propargylaldehyde derivatives are used, a normal Hantzsch-type reaction without attack of the alkyne bond leads to 1,4-dihydropyridines (equation 79). This method was used later for converting cyclic enaminones to pyridine derivatives, however in low yield, and to quinolines in a better yield (equation 80). 

It is also impossible here to go into detail about the numerous syntheses of heterocycles that include formation of C—N bonds as well as new C—C bonds only rarely does the C—N bonding occur as an isolated partial step in the reaction. A recent example of such separation is the unusually smooth synthesis of pyridine derivatives discovered by Bohlmann and Rahtz 896 in this, an activated enamine, e.g., ethyl 3-aminocrotonate, adds to an acyl acetylene, and the resulting amino carbonyl compound is then converted into the pyridine derivative by heat. 

---