Cyclodehydration

Furfural is commercially produced in batch or continuous digesters (37) where the pentosans are first hydroly2ed to pentoses (primarily xylose (12), which are then subsequendy cyclodehydrated to furfural ... 

Synthesis and Properties. Several methods have been suggested to synthesize polyimides. The predominant one involves a two-step condensation reaction between aromatic diamines and aromatic dianhydrides in polar aprotic solvents (2,3). In the first step, a soluble, linear poly(amic acid) results, which in the second step undergoes cyclodehydration, leading to an insoluble and infusible PL Overall yields are generally only 70—80%. 

The synthesis of phenoxaphosphine-containing PODs by the cyclodehydration of polyhydra2ides obtained from 2,8-dichloroformyl-lO-phenylphenoxaphosphine-lO-oxide and aUphatic and aromatic dihydra2ides has been described (60). All polymers are soluble in formic acid, y -cresol, and cone H2SO4, but insoluble or partially soluble in ben2ene, chloroform, and hexamethylphosphoric triamide. 

Bischler-ISlapieralski Reaction. This synthetic method involves the cyclodehydration of N-acyl derivatives of p-phenethjlamines (26) to... 

Pyridazines with an appropriate side chain attached to the sulfur atom at position 3 can be transformed into bicyclic systems. For example, pyridazinyl /3-ketoalkyl sulfides are cyclodehydrated in sulfuric acid to give thiazolopyridazinium salts, and 3-carboxymethyl-thiopyridazines are transformed by acetic anhydride in pyridine into 3-hydroxythiazolo[3,2-6]pyridazinium anhydro salts (Scheme 52). 

Ring closures considered under this heading are essentially intramolecular cyclodehydrations (or their equivalent) and bear many resemblances to the intermolecular processes discussed in Section 4.03.3. They are more suited to the synthesis of ring-fused systems because of the ease of access to the requisite precursors. 

Substitution of the nitrogen atom in (289) and subsequent ring closure of (293) under acid cyclodehydration conditions gave the mesoionic system anhydro-5-hydroxythiazoIium hydroxide (294). These reactions are analogous to the cyclodehydration of the A-nitrosogly-cines (295) with acetic anhydride to give the sydnones (296) (see Chapter 4.21). 

Use of mesoionic ring systems for the synthesis of five-membered heterocycles with two or more heteroatoms is relatively restricted because of the few readily accessible systems containing two heteroatoms in the 1,3-dipole. They are particularly suited for the unambiguous synthesis of pyrazoles as the azomethine imine is contained as a masked 1,3-dipole in the sydnone system. An attractive feature of their use is that the precursor to the mesoionic system may be used in the presence of the cyclodehydration agent and the dipolarophile, avoiding the necessity for isolating the mesoionic system. 

Benzisothiazoles are best prepared by oxidative cyclization of o-aminothiobenz-amides (see Section 4.17.9.1.1), reaction of o-toluidines with thionyl chloride (see Section 4.17.9.2.1) or by sulfuration of 2,1-benzisoxazoles (see Section 4.17.10.2). 1,2-Benzisothiazoles can also be prepared from o-disubstituted benzene compounds, cyclodehydration of o-mercaptobenzaldoximes or oxidative cyclization of p-mercaptobenzylamines (see Section 4.17.9.1.1) being the most convenient. Both series of benzo compounds are readily substituted at the 5- and 7-positions by electrophilic reagents. 

A -Nitroso derivatives, prepared from secondary amines and nitrous acid, are cleaved by reduction (H2/Raney Ni, EtOH, 28°, 3.5 h CuCl/concd. HCl"). Since many V-nitroso compounds are carcinogens, and because some racemization and cyclodehydration of V-nitroso derivatives of V-alkyl amino acids occur during peptide syntheses, V-nitroso derivatives are of limited value as protective groups. 

The Robinson-Gabriel cyclodehydration of 2-acylamidoketones 1 is one of the oldest yet most versatile synthesis of 2,5-di- and 2,4,5-trialkyl, aryl, heteroaryl-, and aralkyloxazoles 2. ... 

Wipf and Miller have reported side-chain oxidation of 3-hydroxy amides with the Dess-Martin periodinane, followed by immediate cyclodehydration with triphenylphosphine-iodine, which provides a versatile extension of the Robinson-Gabriel method to substituted oxazoles. Application of this method was used to prepare the oxazole fragment 10 in 55% overall yield from 3-hydroxy amide 8. 

Nicolaou and co-workers established the severely strained A-ring oxazole (21) in their total synthesis of antitumor agent diazonamide A through initial oxidation of the hindered alcohol of intermediate 20 with TPAP and subsequent Robinson-Gabriel cyclodehydration of the resultant ketoamide with a mixture of POCI3 and pyridine (1 2) at 70°C. ... 

Workers at Lilly prepared the oxazole-containing, dual PPAR ot/y agonist 23, through Robinson-Gabriel cyclodehydration of ketone 22 with acetic anhydride and sulfuric acid in refluxing ethyl acetate. ... 

Bohlmann and Rahtz, in 1957, reported the preparation of 2,3,6-trisubstituted pyridines. Their method employed the Michael addition of acetylenic ketones 35 with enamines 36. The 5-aminoketones 37 are typically isolated and subsequently heated at temperatures greater than 120°C to facilitate the cyclodehydration to afford 38. Again one can see the parallels in this mechanism with that for the Hantzsch protocol. However, in this case the pyridine is formed directly removing the need for the oxidation step in the Hantzsch procedure. 

Further improvements to this method have been reported by Bagley. The requirement of harsh thermal conditions to facilitate the cyclodehydration can be minimized by simply adding acetic acid or Amberlyst 15. Alternatively, one could use Lewis acids such as ZnBr2 or Yb(OTf>3 in catalytic amounts. 

The Combes reaction is a sequence of the following reactions (a) condensation of an arylamine 1 with a 1,3-diketone, keto-aldehyde or dialdehyde 2 providing enamine 3, and (b) cyclodehydration to provide quinoline 4. 

Many acids other than sulfuric acid have been used for the challenging cyclodehydration step. It is important to note that when the concentration of sulfuric acid is below 70%, hydrolysis of the imine or enamine occurs. As previously mentioned, HCl/AcOH, ZnCla, PPA, POCI3, and lactic acid have been successfully applied to promote the cyclization. Chloroacetic acid was found to perform similar to lactic acid. Concentrated HCl, p-TsOH, and have proven beneficial in generating linear... 

Imine formation by reaction of aniline 58 and dione 49 under thermal conditions gave a mixture of imines. Cyclodehydration using PPA gave nearly a 1 1 mixture of isomers 59 and 60. These authors attempted thermal cyclization conditions (similar to Gould-Jacobs type conditions) to affect cyclization of this mixture and failed. Also, these authors reported difficulty in the clean formation of the imine. They observed large amounts of the A -acetyl compound presumably coming from fragmentation of the imine at the reported temperature... 

The mechanism was then reexamined 25 years later in 1997 by Kappe. Kappe used H and C spectroscopy to support the argument that the key intermediate in the Biginelli reaction was iminium species 16. In the event, 5 reacted with 3a to form an intermediate hemiaminal 17 which subsequently dehydrated to deliver 16. Iminium cation 16 then reacted with 6 to give 14, which underwent facile cyclodehydration to give 15. Kappe also noted that in the absence of 6, bisureide 8 was afforded as a consequence of nueleophilic attack of 16 by urea (3a). This discovery confirmed the conclusion of Folkers and Johnson in 1933. As far as the proposal from 25 years earlier by Sweet and Fissekis, Kappe saw no evidenee by H and NMR spectroscopy that a carbenium ion was a required species in the Biginelli reaetion. When benzaldehyde (5) and ethyl... 

Thenyl bromide and 2-pyridinealdehyde reacted to form a quaternary salt (182) which was cyclodehydrated to thieno(2,3-b)quin-azolinium bromide (183). ... 

The same oximino acid (49) underwent a cyclodehydration on treatment with dicyclohexyl carbodiimide to form the unsaturated hydroxamic acid (52) in almost quantitative yield. 

Under the conditions of the attempted conversion of the indolenine 17 into the quinoline 18 most of the indolenine was recovered, but there was also formed a small amount of a hydrolysis product, o-acetamido-jS-chloro-a-methylstyrene (22), obtainable in good yield with aqueous ethanolic potassium hydroxide. By analogy with a similar sequence of reactions in the carbocyclic series the hydrolysis product 22 might possibly undergo acid-catalyzed cyclodehydration to the quinoline... 

Application of the Bischler-Napieralski reaction to amides of tryptophan has been investigated. The cyclodehydration of acetyltrypto-phan under conventional conditions proved unsuccessful. Attempted ring closure of acetyltryptophan or its ethyl ester was accompanied by decarboxylation and aromatization, yielding... 

Treatment of 3-amino-4-oxoquinazolines (9) with cyanamide gave the 2-amino-l,2,4-triazolo [l,5-c]quinazolines 11 as a result of cyclodehydration of the intermediate 3-guanidino-4-oxoquinazolines 10 (68CB2106) (Scheme 9). Similarly, reaction of the 3-amino-4-thioxoquinazoline 12 with alkyl or aryl isothiocyanates yielded the mesoionic l,2,4-triazolo[l,5-cjquinazolines 14 (84S881) (Scheme 10). 

Reduction of the imine with sodium borohydride leads to an intermediate amino-ester that cyclizes spontaneously to the <5-lactam function. Solvolysis of the acetyl group with methoxide followed by acylation of the hydroxyl group thus liberated with trimethoxybenzoyl chloride leads to 38. Bischler-Napieralski cyclodehydration (phosphorus oxychloride) effects closure of the remaining ring. Reduction of the imine thus formed with sodium borohydride gives 39. This, it should be noted, leads to the... 

---