Pyridine Bohlmann synthesis

Moody s synthesis of promothiocin 43 provided evidence that the Bohlmann-Rahtz method can be used for the rapid synthesis of complex pyridines. Oxazaole 44 was treated with alkynyl ketone 45 to afford 46 in 83% yield. The ester moiety of 46 was elaborated into a thiazole substituent providing entry into the northeast quadrant of 43. 

The Bohlmann-Rahtz synthesis of trisubstituted pyridines from /3-aminocrotonates and an ethynyl ketone has found application in the preparation of a variety of heterocycles based on the substituted pyridine motif. Bagley and coworkers have developed a microwave-assisted modification of this one-pot heteroannulation method that is best conducted in dimethyl sulfoxide at 170 °C for 20 min, providing the desired pyridines in 24—94% yield (Scheme 6.227) [406, 407]. Typically, 2 equivalents of the /3-aminocrotonates were employed. 

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>. 

W. Bohlmann, K. Schandert, A. Poppl, and H.-C. Semmelhack, Synthesis and Electron Spin Resonance Studies of MCM-41 Doped with Copper Pyridine Complexes. Zeolites, 1997,19, 297-304. 

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>. 

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>. 

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. ... 

The Bohlmann-Rahtz pyridine synthesis from discovery to applications , Bagley, M. C., Glover, C. and Merritt, E.A., Synlett, 2007, 2459. 

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. 

The Bohlmann-Rahtz synthesis is viable for the construction of di- or tri-substituted pyridines and has been applied in the synthesis of complex target molecules. The Baldwin group was one of the first to employ this method for the construction of pyridine substituted a-amino acids. Exposure of alkynyl ketone 182 to 3-aminocrotoyl ester 183 or ketone 184 in ethanol at reflux gave rise to the desired pyridyl-P-alanines 185 and 186, respectively, which were subsequently deprotected to afford the a-amino acid L-azatyrosine analogues 187 and 188, respectively. 

Thiopeptide antibiotics are a class of highly modified macrocyclic sulfur-containing peptides, and nearly all the thiopeptide antibioties identified to date inhibit protein synthesis in bacteria. The Bohlmann-Rahtz pyridine synthesis is a useful methodology in the synthetic approach for thiopeptide antibiotics.For example, one-step Bohlmann-Rahtz assembly of 189 and 190 in the presence of ammonium acetate in acetic acid at reflux afforded the corresponding pyridine-thiazole cores of thiopeptide antibiotics 191 in 63% yield.The TBS protecting group was also replaced by an acetate, probably as a consequence of acid-promoted cleavage and consequent Fischer-type esterification of the liberated alcohol. 

Bohlmann-Rahtz method has also been applied in the solution-phase synthesis of a library of functionalized pyridine scaffold as well as the preparation of a 2,3 6 3"-terpyridine scaffold as an a-helix mimetic. ... 

Later on, the Rueping group reported an organocatalytic enantioselective reduction of pyridine 180 (Scheme 17.30) [74], according to the procedure described by Bohlmann and Rahtz [75]. The key step in the synthesis of decahydroquinolines from the pumiliotoxin family involved Hantzsch dUiydropyridine 172 as the hydride source and involved BINOL-phosphoric acid 181 as a chiral Br0nsted acid catalyst... 

The applicability of this new method was demonstrated in the formal synthesis of i /cpi-pumihotoxin C 31 from the pumiliotoxin family (Scheme 9) [91]. Hence, the reduction of pyridine 29a, which can be readily prepared according to Bohlmann and Rahtz s procediue starting from 27 and 28 [92,93], gives the corresponding (5)-2-propylhexahydroquinolinone 30a as a key intermediate for the subsequent transformation (Scheme 9) [94]. 

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... 

Thiocillin I (158, Figure 8.8) is a member of thiopeptide antibiotics isolated from Bacillus cereus [172]. The seminal work of Walsh et al. [173] has established the significance of this 26-membered macrocycle. Recently, total synthesis of thiocillin I along with its structural assignment has been described (Scheme 8.14) [174]. The synthesis is notable for two reasons use of new methods in the retrosynthetic scheme and chemoselectivity in the macrolactonization step. The synthesis of precursor 159 involved a key step of modified Bohlmann-Rahtz pathway to the pyridine nucleus [175]. This polar carboxylic acid 159 was coupled in crude form with 162 to yield 160. Global deprotection followed by macrocyclization gave thiocillin I 158 that was identical to the natural product. The carboxyl group at... 

Guareschi-Thorpe pyridine synthesis Chichibabin (Tschitschibabin) pyridine synthesis Bohlmann-Rahtz pyridine synthesis Krohnke pyridine synthesis... 

A novel protocol for the synthesis of highly substituted pyridines in a single synthesis step by the microwave-assisted Michael addition-cyclodehydration of ethyl p-aminocrotonate, an alky none, has been developed by Bagley et al. (2002). This new one-pot Bohlmann-Rahtz procedure was conducted at 170°C in a self tunable microwave synthesizer giving high yield with total control of regiochemistry. 

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