Heterocyclizations acid catalysed

The carbon in the isothiocyanate grouping is highly susceptible to nucleophilic attack by the peptide s free amino group. Overall addition to the C=N creates a thiourea derivative. Making the conditions strongly acidic then promotes nucleophilic attack by the sulfur of the thiourea on to the carbonyl of the first peptide bond, producing a five-membered thiazoline heterocycle. Proton loss occurs from the nitrogen, and this creates an intermediate that is equivalent to the addition product in simple acid-catalysed amide... 

A highly regio- and stereo-selective Brpnsted acid-catalysed addition of aromatic heterocycles, such as pyrroles, furans, and indoles, to ynamides RC=CN(R)(EWG), catalysed by Tf2NH at —35 °C, has been developed as an equivalent of hydroarylation of ynamides.41... 

There are many syntheses of the major heterocycles and they are often complementary in that they afford different substitution patterns on the ring. Most of the synthetic methods we shall examine are fairly classical (indeed some are decidedly ancient ) although many of the specific examples are quite modern. Many classical syntheses of heterocycles revolve around the condensation reaction in its various guises. Let us consider the mechanism of a simple acid-catalysed condensation, that of generalised ketone 1.10 and amine 1.11 to give imine 1.12. 

A feature of the acid-catalysed nitrosation of some heterocyclic secondary amines and their 1-oxide derivatives is the reversibility of nitrosamine formation as shown in (10). Apparently these nitrosamines readily undergo denitro-sation (for a discussion of nitrosamine reactions see Section 7). In some cases... 

Hydrazones and oximes are oi value in itie synthesis of heterocycles. For example, the acid-catalysed cydization of phenylhydrazones gives indoles. 

The acid-catalysed intramolecular 1,5-nucleophilic O-heterocyclization of (p -dienyl)tricarbonyliron diols (82) occurs with 1,2-migration of the side chain. This cyclization has been shown to be a key stereoselective step towards racemic and optically active conformationally locked phosphocholins (83) and (84) as potential anticancer agents (Scheme 12). ... 

Thioketones (6) can be obtained by the acid-catalysed reaction of ketones with hydrogen sulfide (Scheme 2). The course of the reaction is dependent on the reaction temperature, the nature of the solvent, the concentration of the ketone and the stability of the thioketone (6), especially in relation to enolisation. This appears to be the most generally useful preparative route to thioketones, and many simple aliphatic derivatives are obtained by performing the reaction in ethanol at low temperature (-80°C to -55°C). The gem-dithiol (9) may also be converted into the thioketone (6) by heating it at approximately 200°C in the presence of a basic catalyst (Scheme 2). Reasonably stable thioketones, e.g. aromatic and heterocyclic derivatives like (10) and (11), can be prepared by heating the corresponding ketones with phosphorus pentasulfide in boiling toluene, pyridine or xylene (see Chapter 2, p. 21) (Scheme 3). 

Suzuki, I. Shigenaga, A. Nemoto, El. Shibuya, M. Acid-catalysed cycloaromatization of enediyne model compounds via enyne-allene intermediates. Heterocycles 2001, 54, 571-576. 

Heteroatom directed aromatic lithiation reaction is now widely used for the synthesis of condensed heterocyclic compounds. New synthesis of condensed heterocyclic compounds are now known which can provide compounds not readily available by the usual acid catalysed methods. In this chapter these newer methods and their applications to several natural products are presented. Also presented, in some cases, are other non-lithiation methods which can provide comparison with the lithiation method and especially to bring about the latter s superiority in specific cases. 

Carbonyls. Several papers have appeared this year from Issleib s group describing the synthesis of heterocyclic phosphorus compounds by acid-catalysed condensations of phosphines with carbonyl compounds. (Mercapto-alkyl)phenylphosphines (31) react with aldehydes or ketones to form 1,3-thiaphospholans or 1,3-thiaphosphorinans. The intermediate compound (32) can be isolated from a similar reaction with phenylisothiocyanate and is converted into a thiaphospholan by intramolecular loss of hydrogen sulphide. 

Scheme 193). On heating the mixture, preferably in the absence of triethylamine, the hexahydro-a-quinolone 185 was obtained directly, together with the enamide 184 and amide 186. Since the enamide could not be cyclized to the hexahydro-a-quinalone under thermal or acid-catalysed conditions, then clearly the enamide is not an intermediate in the formation of the heterocycle which must therefore arise by. /V-acylation of the enamine tautomer, followed by a [3,3]sigmatropic rearrangement and cyclization of the ketene intermediate (Scheme 194). Significantly vide infra), when the imine of 2-methylcyclohexanone was used, the rearrangement to the ketene occurred at the more substituted Cj position. 

This ring may be formed in an acid-catalysed cyclization of a 2-/ -cyanoethyl-thioaniline the use of this type of reaction for the synthesis of heterocycles has been reviewed [2547]. 

The ring synthesis of five-membered heterocycles has been extensively investigated, and many and subtle methods have been devised. Each of these three heterocyclic systems can be prepared from 1,4-dicarbonyl-compounds, for furans by acid-catalysed cyclising dehydration, and for pyrroles and thiophenes by interaction with ammonia or a primary amine, or a source of sulfur, respectively. 

The mineral-acid-catalysed polymerisation of pyrrole involves a series of Mannich reactions, but under controlled conditions, pyrrole can be converted into an isolable trimer, which is probably an intermediate in the polymerisation. The key to understanding the formation of the observed trimer is that the less stable, therefore more reactive, P-protonated pyrrolium cation is the electrophile that initiates the sequence, attacking a second mole equivalent of the heterocycle. The dimer , an enamine, is too reactive to be isolable, however pyrrole trimer , relatively protected as its salt, reacts further only slowly. ... 

The acid-catalysed polymerisation of pyrroles and indoles . Smith, G. F, Adv. Heterocycl. Chem., 1963, 2, 287. 

Comparable acid- (or Lewis acid) -catalysed ring closures of 2-arylthio- and 2-aryloxy- -ketones, and -2-arylthio- and 2-aryloxyacetyl- chlorides lead to 3-substituted heterocycles and 3-oxygenated heterocycles, respectively. It is possible to combine the preparation of the arylthio-ketone and the ring closure steps utilising two solid-supported reagents in a one-pot procedure, as illustrated. Formation of 3-aryl-benzothiophenes by this route can be complicated by partial or complete isomerisation to the 2-aryl-heterocycle,however using boron trifluoride as the Lewis acid produces only the 3-aryl-isomer. 3-Tosylamino-benzofurans can be prepared from aryl glyoxal hydrates. ... 

Rings containing One Heteroatom.—Oxygen Heterocycles. Base-catalysed addition of 17j8-hydroxy-5a-androstan-3-one to glyoxylic acid, to afford either the hydroxy-keto-acid (197) when the reaction is performed at room temperature, or the rra 5-ayS-unsaturated acid (199) in high yield when done under reflux, provides an entry to both cis-lactone (198) and trans-lactone (201). 

Oxygen-containing Heterocycles Three-membered Rings. - The addition of oxygen to double bonds remains the most common method for epoxide synthesis, and several new variations on that theme have appeared this year. Thus, alkenes are converted into epoxides using a solution of elemental fluorine in an acetonitrile/water mixture with complete retention of olefin stereochemistry.1 Prat and Lett have re-examined the use of tungstic acid catalysed epoxidation in an attempt to define the scope and synthetic utility of the process. They have shown that reactivity increases with the nucleophilicity of the double bond and... 

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