Furans, Paal-Knorr synthesis

Acid-catalyzed cyclization of 1,4-ketones to form furans. 

Recent Advances in Furan Chemistry. Part 1. In Advances in Heterocyclic Chemistry, Katritzky, A. R., Ed. Academic Press New York, 1982 Vol. 30, 167-238. (Review). 

Mohamed-Hachi, A. About-Jaudet, E. Collignon, N. Synth. Commun. 1997, 27, 1165. 

Friedrichsen, W. Furans and Their Benzo Derivatives Synthesis. In Comprehensive Heterocyclic Chemistry // Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds. Per-gamon New York, 1996 Vol. 2, 351—393. (Review). 

Gilchrist, T. L. Heterocyclic Chemistry, 3rd ed. Longman Singapore, 1997 211. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 188, Springer-Verlag Berlin Heidelberg 2009 

Heterocyclic Chemistry, Springer New York, 1999 Vol. 2, 83-84. (Review). 

Heterocyclic Chemistry, 4th ed. Blackwell Science Cambridge, 

Heterocyclic Chemistry, 4th ed. Blackwell Science Cambridge, 2000 308-309. (Review). 

In 1884, C. Paal and L. Knorr almost simultaneously reported that 1,4-diketones upon treatment with strong mineral acids underwent dehydration to form substituted furans. This transformation soon became widely used and now it is referred to as the Paal-Knorr furan synthesis. The general features of the method are 1) virtually any 1,4-dicarbonyl compound (mainly aldehydes and ketones) or their surrogates are suitable substrates 2) the dehydration is affected by strong mineral acids such as hydrochloric acid or sulfuric acid, but often Lewis acids and dehydrating agents (e.g., phosphorous pentoxide, acetic anhydride, etc.) can be used and 3) the yields are usually moderate to good. The two major drawbacks of the reaction are the relative difficulty to obtain the 1,4-dicarbonyl substrates, and the sensitivity of many functionalities to acidic conditions. 

The synthesis of a soluble nonacenetriquinone based on the well-known Diels-Alder reaction of 1,3-diarylisoben-zofurans was developed by L.L. Miller and co-workers. The preparation of the 1,3-diarylisobenzofuran commenced with the Paai-Knorr furan synthesis. The substrate was an aromatic 1,4-diketone, which was treated with excess neat boron trifluoride etherate for almost two days to afford the desired 2,5-diarylfuran in almost quantitative yield. Interestingly, this cyclization could not be achieved efficiently by using the more traditional acid catalysts such as H2SO4 or PPA. 

The first furan-isoannelated [14]annulene was prepared by Y.-H. Lai et al. The furan moiety was installed by the Paai-Knorr furan synthesis. The 1,4-diketone substrate was synthesized via an oxidative coupling using Mn02/AcOH. The dehydration to the furan was effected by phosphorous pentoxide in ethanol. 

Cooper and co-workers synthesized several quinolones containing five- and six-membered heterocyclic substituents at the 7-position and tested their antibacterial activities. The 1,4-diketone substrate was prepared via the oxidative coupling of isopropenyl acetate and an acetophenone derivative. The Paai-Knorr furan synthesis was conducted in the presence of p-TsOH. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 201, Springer International Publishing Switzerland 2014 

Example 5, Concurrent debromination along with furan formation 

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Treatment of 1,4-dicarbonyls (1) with catalytic acid yields substituted furans (2) and is called the Paal-Knorr furan synthesis. This method is used extensively to produce a variety of mono-, di-, tri-, and tetrasubstituted furans. ... 

Ibers used the Paal-Knorr furan synthesis to prepare a key intermediate for the synthesis of novel porphyrin-like aromatic macrocycles. Bis yrolyljfuran 27 was available in good yield via the acid catalyzed condensation of diketone 26. ... 

The Paal-Knorr furan synthesis can also be used to prepare 2,5-arylalkylfurans, as illustrated in the following example. Salimbeni produced furan 29 from dione 28 and subsequently used the furan as an intermediate for the production of angiotensin II receptor antagonists. ... 

Shea, K. M. Paal—Knorr Furan Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 168—181. (Review). 

The widely applicable acid-catalyzed cyclization of 1,4-dicarbonyl compounds and their surrogates, known as the Paal-Knorr furan synthesis, is frequently used in the synthesis of furan-containing compounds (Equation 1). 

The reaction conditions of the classical Paal-Knorr furan synthesis can be too harsh, when labile functionality has to be preserved. In the synthesis of the 3-oxa guaianolide 4, a five-step detour proved to be more efficient than direct cyclization (Scheme 4) <2000T6331>. Cyclic carbinol amides yield a-trifluoromethyl-sulfonamido furans upon treatment with triflic anhydride (Equation 7) <20030L189>. 

Butene-l,4-diones and 2-butyne-l,4-diones were converted into 2,5-diaryl- and 2,3,5-triarylfurans in high yields in the presence of HCOOH and a catalytic anaount of Pd on carbon under microwave-irradiation conditions <03JOC5392>. This procedure provides a new approach to the starting material used in the Paal-Knorr furan synthesis, as unsaturated diones are reduced to saturated diones in situ by formic acid and palladium. The solid-phase synthesis of 2,3,5-trisubstituted furans from 1,4-diketones was also reported <03SL711>. 

Related reactions Paal-Knorr furan synthesis ... 

Acetic anhydride and aluminum chloride in caibon disulfide gives a high yield of the para-acylated product with thioanisole, and in dichloromethane the same reagents give an almost quantitative yield of 3-acetyl-1-benzenesulfonylindole. Acylation of more nucleophilic heterocycles can be achieved using milder catalysts, such as zinc chloride. It has been known for some time that furan can be acylated very efficiently using acetic anhydride and zinc chloride. The Paal-Knorr furan synthesis (1,4-diketone, acetic anhydride and zinc chloride) can sometimes result in acylation as well as cyclization (equation 40). - Equations (41) and (42) further exemplify the acylation of furan derivatives that have been used in the synthesis of cytotoxic furanonaphthoquinones. 

The Paal-Knorr furan synthesis involves the treatment of a 1,4-dicarbonyl with catalytic acid to generate the corresponding furan. A variety of differentially substituted 1,4-dicarbonyls have been used in the Paal-Knorr reaction to synthesize the corresponding mono-, di-, tri-, and tetrasubstituted flirans. Commonly employed acids include sulfuric, hydrochloric, and p-toluenesulfonic acid. The reaction generally takes place at room temperature or under thermal conditions. 

Other references related to the Paal-Knorr furan synthesis are cited in the literature. ... 

Furans are prepared by modification of the chemistry used to make pyrrole derivatives. Because furans have an oxygen atom rather than a nitrogen atom, a modification of the reactive partners is required. When 2,5-hexanedione (115) is treated with acid, the product is a furan, 124. This is called the Paal-Knorr furan synthesis, and it begins with protonation of one carbonyl and attack of the oxygen atom of the second carbonyl to close the ring. Elimination of water leads to the furan because it generates an aromatic system. The reaction of protonated ketones and aldehydes with oxygen nucleophiles was discussed in Chapter 18 (Section 18.6). The mechanism for formation of 124 is therefore related to the chemistry presented in Chapter 18. 

Concentrated H2SO4 or HCIO4 induce polymerization of furans via cations 42. Dilute acids, hke HCIO4 in aqueous dimethyl sulfoxide (DMSO), cause hydrolysis to 1,4-dicarbonyl compounds 44, probably via nucleophilic attack of H2O at the 2-position of 42 and ring-opening of the thus obtained 2-hydroxy-2,3-dihydrofuran (43). The transformation 41 -> 44 is the reversal of the ring-closing steps in the Paal-Knorr furan synthesis (cf. p. 71). 

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