Pyrrole synthesis from primary amine

Pyrroles are the core unit of a wide variety of natural products [76]. Although many methods are available for the synthesis of these species, most are multi-step procedures resulting in low yields [77, 78]. However, Hantzsch made another important contribution to the progress of multicomponent chemistry. In his procedure pyrroles were successfully prepared from primary amines, j8-ketoesters, and a-halo-genated j5-ketoesters [79]. Only a few other one-step procedures have been reported for pyrroles but, because of to long reaction times and insufficient scope of substitution at the ring, these are not very satisfactory [80, 81]. 

The Hantzsch pyrrole synthesis remains useful for the preparation of A/-substituted pyrroles from primary amines for materials chemistry and medicine. However, for pyrroles where N is unsubstituted, the Hantzsch pyrrole synthesis has largely been replaced by the Knorr pyrrole synthesis because the latter generally leads to higher product yields. 

Z. Hossaini, F. Rostami-Charati, S. Z. Sayyed-Alangi, Chin. Chem. Lett. 2012, 23, 1119-1121. Synthesis of highly functionalized pyrroles from primary amines and activated acetylenes in water. 

A milder Clauson-Kaas pyrrole synthesis was reported that alleviated the need for acid or heat <06TL799>. The innovation involved the hydrolysis of 2,5-dimethoxytetrahydrofuran giving 2,5-dihydroxytetrahydrofuran. The latter was converted into pyrroles by treatment with primary amines in an acetate buffer. The Clauson-Kaas pyrrole synthesis was studied utilizing a K-10 montmorillonite acid catalyst and microwave irradiation <06OPP495>. Mild reaction conditions (cat. p-TsOH) allowed for the preparation of pyrrole-3-carboxaldehydes from 2,5-dimethoxytetrahydrofuran-3-carboxaldehydes <06S1494>. 

Treatment of Baylis-Hillman (BH) derivatives 10, obtained from 3-(2-bromophenyl)-5-methyl-4-isoxazolecarbaldehyde, with tributyltin hydride allowed a straightforward synthesis of isoxazolo-benzazulene systems 11 along with minor amounts of the debrominated products 12 <06TL7043>. BH adducts made from 5-isoxazolecarbaldehydes were converted in moderate yields into pyrrole derivatives by reaction with primary amines and then DBU <06S1021>. 

Tejedor and coworkers have utilized a combination of two domino processes for a microwave-promoted synthesis of tetrasubstituted pyrroles [344]. The protocol combines two coupled domino processes the triethylamine-catalyzed synthesis of enol-protected propargylic alcohols and their sequential transformation into pyrroles through a spontaneous rearrangement from 1,3-oxazolidines (Scheme 6.183). Overall, these two linked and coupled domino processes build up two carbon-carbon bonds, two carbon-nitrogen bonds, and an aromatic ring in a regioselective and efficient manner. The tetrasubstituted pyrroles could be directly synthesized from the enol-protected propargylic alcohols and the primary amines by microwave irradia-... 

An early example of this strategy is the palladium black catalyzed conversion of (Z)-2-buten-l,4-diol with primary amines (cyclohexyl amine, 2-aminoethanol, -hexyl amine, aniline) at 120 °C to give A-substituted pyrroles in 46-93% yield [119]. Trost extended this animation to the synthesis of a series of AT-benzyl amines 169 from the readily available a-acetoxy-a-vinylketones 168 [120]. This methodology allowed for the facile preparation of pyrrolo-fused steroids. 

Disubstituted thiophenes 96 and 1,2,5-tri- and 2,5-disubstituted pyrrole derivatives 97 are available readily from m-3,6-disubstituted-3,6-dihydro-l,2-dioxins in a one-pot synthesis. The reaction proceeds by an initial Kornblum-de la Mare rearrangement of the 3,6-dihydro-l,2-dioxin to its isomeric 1,4-diketone followed by the condensation with Lawesson s reagent, ammonium carbonate, or a primary amine (Scheme 21) <2002TL3199>. 

The 1,4-dicarbonyl compounds resulting from Stetter reactions have been used by Muller and colleagues [52] and by Bharadwaj and Scheidt [53] in efficient one-pot Stetter-Paal-Knorr protocols for the synthesis of highly substituted pyrroles. In an analogous fashion, Frantz et al. converted their a-ketoamides into the corresponding imidazoles by treatment with a primary amine [54]. 

Dake s group84 published an interesting report in which AgOTf and cationic gold (I) complexes were compared for their use in the synthesis of the pyrrole scaffold. From (3-alkynyl ketones 66 (Scheme 5.29) and various primary amines 67, the imine intermediates JJ were formed in situ and the intramolecular cyclization produced various pyrroles 68. Both catalysts AgOTf (5 mol%) or Au(PPh3)OTf (5 mol%) were efficient, but the reaction proceeded more rapidly with silver catalysis. 

In an application of the Paal-Knorr pyrrole synthesis, the synthetic equivalents 3 of 1,4-ketoaldehydes were prepared by the radical addition of ketones 4 to vinyl pivalate. Treatment of the intermediates 3 with amines gave pyrroles 5 <03SL75>. Other new extensions of this popular pyrrole synthesis include the preparation of a number of pyrroles from hexane-2,5-dione and amines under solvent-free conditions in the presence of layered zirconium phosphate or phosphonate catalysts <03TL3923>, and the development of a solid-phase variant of this reaction <03SL711>. Likewise, the preparation of iV-acylpyrroles from primary amides and 2,5-dimethoxytetrahydrofuran in the presence of one equivalent of thionyl chloride has also been reported <03S1959>. 

From a retrosynfhetic viewpoint, N-aryl-l,2-diimine Ni precatalysts are synthesized by (i) reaction of 1,2 diimines with nickel halides from (ii) 1,2-diimine ligands which in turn are obtained by (iii) condensing 1,2-dicarbonyl substrates with two equivalents of primary aromatic amines, usually under acidic conditions [11]. In analogy, the synthesis of N-hetaryl 1,2 diimine catalysts starts from the corresponding substituted N-heterocyclic primary amines as the amine building blocks. The synthesis of three types of such heterocycles, N-amino-pyrroles, -indoles and -carbazoles, and their corresponding diimine derivatives is presented in the following sections. 

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. 

An interesting variant is the multicomponent synthesis of pyrroles from carbonyl compounds, primary amines, and nitroalkanes first described by Ishii et al. 

A domino Mannich/aza-Michael reaction was applied to the synthesis of 2,5-cis-configured polysubstituted pyrrolidines from y-malonate-substituted a,P-unsaturated esters with N-protected arylaldimines [117]. In this report, bifunctional thioureas were trialed with the Takemoto catalyst, being the most efficient with respect to yield as well as enantiomeric and diastereomeric excess. In a separate approach, the Garcia-Tellado group approached the pyrrole ring system 234, beginning with a tertiary skipped diyne 233 and a primary amine (Scheme 7.50). 

The Hantzsch synthesis has been used to generate pyrroles, thiazoles and dihydropyridine derivatives. Pyrroles (3) are generated from the reaction of P-ketoesters with ammonia, ammonia derivatives or primary amines, and a-haloketones (path A). Thiazoles (5) are generated from the reaction between a-haloketones and thiourea or thioamide derivatives (path B). Dihydropyridines (7) are generated from the reaction of aldehydes with p-ketoesters and ammonia or ammonia derivatives, or enamines derived from the reaction of ketones or P-ketoesters with amines (path C). Dihydropyridines can be readily converted to the corresponding pyridine derivatives and so this reaction is often termed the Hantzsch pyridine synthesis. 

The traditional Hantzsch pyrrole synthesis consists of a one-pot reaction between P-ketoesters with ammonia, ammonia derivatives or primary amines, and a-haloketones. This process, known as the three-component (3CP) Hantzsch pyrrole synthesis, has been largely replaced by a two component (2CP) Hantzsch synthesis using preformed enamines. Preformed enamines help provide better control over the regioselectivity of the reaction. In addition, the use of preformed enamines helps reduce the side products produced from the self condensation of P-ketoesters. 

Schulte [285, 286] and later Chalk [287] described the Cu(I)-catalyzed synthesis of symmetrical 2,5-diarylpyrroles 261 from conjugated diynes 257 and primary amines 258. The reaction is believed to proceed via the transition metal-catalyzed hydroamination [33, 288-291] leading to tautomeric aminoenyne 259 or homopro-pargylic imine 260 intermediates, which further undergo 5-endo-dig cyclization to furnish pyrrole product 261 (Scheme 8.95). 

A number of 4-1-1 protocols for the synthesis of pyrrole cores featuring the Cu (I)primary amine derivatives as the key carbon-heteroatom bond forming reaction have been reported recently. Thus, Buchwald described an efficient Cu(I)-catalyzed synthesis of tri-, tetra-, and penta-substituted pyrroles 302 from 1,4-dihalo-l,3-dienes 300 and carbamates 281 (Scheme 8.107) [305]. This methodology displayed excellent functional group compatibility, providing good to... 

---