2- pyrroles, synthesis preparation

Tracey, M. R., Hsung, R. P., Lambeth, R. H. Allylated 3-keto esters as precursors in Paal-Knorr-type pyrrole synthesis Preparations of chiral and bispyrroles. Synthesis 2004, 918-922. 

The Barton-Zard (BZ) pyrrole synthesis is similar both to the van Leusen pyrrole synthesis that uses Michael acceptors and TosMlC (Section 6.7) and the Montforts pyrrole synthesis using a,P-unsaturated sulfones and alkyl a-isocyanoacetates." An alternative to the use of the reactive nitroalkenes 1 is their in situ generation from P-acetoxy nitroalkanes, which are readily prepared via the Henry reaction between an aldehyde and a nitroalkane followed by acetylation. Examples are shown later. 

A zinc-free alternative to the Knorr pyrrole synthesis employs catalytic hydrogenation, as for 17 + 18 to 19. Oximes such as 17 are readily prepared by nitrosation (NaNOa, HO Ac) of the active methylene group. 

The simplicity of the PK pyrrole synthesis often makes it the method of choice. The preparation of 2,5-dimethyl-1-phenylpyrrole from 2,5-hexanedione and aniline is an undergraduate laboratory experiment," and applications of the PK reaction in research... 

Mainly C-substituted pyrroles have been synthesized by application of the Knorr pyrrole synthesis however N-substituted pyrroles can also be prepared, when starting with secondary aminoketones, e.g. bearing an N-methyl or N-phenyl substituent. 

The Barton-Zard pyrrole synthesis has now been extensively applied to synthesis of naniral and unnaniral products containing pyrrole units Methyl 4-methylpyrrole-3-carboxylate is the trail-maker pheromone of the Texas leaf-aitting ant Arm lexaiia It is readily prepared by the Barton Zard method in 60% yield fEq 10 33 ... 

Py rrolostatin is a novel lipid peroxidation inhibitor, which is isolated from Sirepinmyces diresinmyceiiois. Its stnicnire consists of a pyrrole-3-carboxyiic acid v/ith a geranyl group at the 4-posidon. It is readily prepared by applying the Barton-Zard pyrrole synthesis, as shown inEq. 10.33. ... 

Barton-Zard pyrrole synthesis is ffso applied to synthesis of pyrroles with a variety of subsdtuents Pyrroles subsdtuted with long ilkylsubsdtuents at the 3 and 4 posidons, pyrroles with fi-CF3 fEq 10 26, 3,4-diarypyrroles fEq 10 27i, and pyrrole-2-phophonates fEq 10 28are prepared in a sirtular matmer based on isonitnle cyclizadon... 

Nitroalkenes can be replaced by ct,fi-iinsatiirated siilfones in the Barron-Zard pyrrole synthesis Each method has its own merit Nitroalkenes are more reactive than a,fi-iinsatiirated siilfones therefore, nitroalkenes should be used in less reactive cases. On the other hand, cychc a,fi-nnsanirated siilfones are more easily prepared than cychc nitroalkenes pyrrole synthesis using siilfones is the method of choice in such cases, as shovm in Eq. 10.41. 

Barton-Zard pyrrole synthesis is also applied to synthesis of pyrroles with a variety of substituents. Pyrroles substituted with long alkyl substituents at the 3 and 4 positions,30 pyrroles with P-CF3 (Eq. 10.26),31 3,4-diarypyrroles (Eq. 10.27),32 and pyrrole-2-phophonates (Eq. 10.28)33 are prepared in a similar manner based on isonitrile cyclization. 

In 1988, Ono and Maruyama reported a very simple synthesis of octaethylporphyrin (OEP) from 3,4-diethylpyrrole-2-carboxylate, as shown in Eq. 10.44 49 Reduction of this pyrrole with LiAlH4 gives 2-hydroxyethylpyrrole, which is converted into OEP on treatment with acid and an oxidizing agent. This route is very convenient for synthesis of porphyrins. This method is now used extensively for synthesis of P-substituted porphyrins.50 For example, a highly conjugated porphyrin, shown in Eq. 10.45, has been prepared by this route.51 The requisite pyrroles are prepared from nitro compounds or sulfones thus, various substituents are readily introduced into porphyrins. 

A Knorr-type pyrrole synthesis involving the condensation between a-amino-P-ketoesters and P-ketonitriles provided P-cyanopyrroles <06OPRD899>. The former amine substrates were prepared by reduction of the corresponding a-isonitroso-P-ketoesters with Zn/HOAc. 

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>. 

The large scale preparation of orthogonally protected pyrrole tricarboxylic acid derivatives (i.e., 92) was reported. A key step was the selective a-chlorination of a 2,4-dimethylpyrrole intermediate that was derived from the Knorr pyrrole synthesis. 

Benzofuranyl)pyrroles, 2-(2-thienyl)pyrroles , 2,2 -dipyrroles, 3-(2-pyr-rolyl)indoles , 2-(2-benzimidazolyl)pyrroles and2-(2-, 3- and4-pyridyl)pyrroles were prepared using this method. Reaction of alkynes (for example, propyne) or allene with ketoximes in a superbase system (MOH/DMSO) leads to 2,5-di- or 2,3,5-trisubstituted pyrroles Pyrroles and dipyrroles were synthesized also from corresponding dioximes and acetylene in a KOH/DMSO system It has also been shown that 1,2-dichloroeth-ane can serve as a source of acetylene in pyrrole synthesis. Oxime 52 in the system acetylene/RbOH/DMSO at 70 °C afforded a mixture of three pyrroles 53-55 in low yields (equation 23). The formation of product 53 occurred through recyclization of pyrrolopy-ridine intermediate. ... 

Dimethylaminonitroethylene is prepared from the anion of nitromethane and the salt prepaffed from dimethylformamide and dimethyl sulfate. The condensation step is general for other types of active methylene compounds, indicating further potential for pyrrole synthesis. A related process involves the condensation of ketones with the moao-N,N-dimethylhydrazone of glyoxal base-catalyzed condensation affords the hydrazones of a conjugated 1,4-dicarbonyl system, and sodium thiosulfate reduction then affords 2,3-disubstituted pyrroles (equation 85) (77CB491). 

Various approaches have been used to prepare pyrroles on insoluble supports (Figure 15.1). These include the condensation of a-halo ketones or nitroalkenes with enamines (Hantzsch pyrrole synthesis) and the decarboxylative condensation of N-acyl a-amino acids with alkynes (Table 15.3). The enamines required for the Hanztsch pyrrole synthesis are obtained by treating support-bound acetoacetamides with primary aliphatic amines. Unfortunately, 3-keto amides other than acetoacetamides are not readily accessible this imposes some limitations on the range of substituents that may be incorporated into the products. Pyrroles have also been prepared by the treatment of polystyrene-bound vinylsulfones with isonitriles such as Tosmic [28] and by the reaction of resin-bound sulfonic esters of a-hydroxy ketones with enamines [29]. 

Huisgen and coworkers have also described the cycloaddition behavior of the munchnones , unstable mesoionic A2-oxazolium 5-oxides with azomethine ylide character.166 Their reactions closely parallel those of the related sydnones. These mesoionic dipoles are readily prepared by cyclodehydration of N-acyl amino acids (216) with reagents such as acetic anhydride. The reaction of munchnones with alkynic dipolarophiles constitutes a pyrrole synthesis of broad scope.158-160 1,3-Dipolar cycloaddition of alkynes to the A2-oxazolium 5-oxide (217), followed by cycloreversion of carbon dioxide from the initially formed adduct (218), gives pyrrole derivative (219 Scheme 51) in good yield. Cycloaddition studies of munchnones with other dipolarophiles have resulted in practical, unique syntheses of numerous functionalized monocyclic and ring-annulated heterocycles.167-169... 

Pyrrole synthesis. A new route to pyrroles1,2 is based on a base-catalyzed Michael addition of an alkyl isocyanoacetate to a nitroalkene to give an intermediate that cyclizes to a pyrrole. The nitroalkene is generally obtained from a P-acetoxy nitroalkane (1), prepared by a nitro aldol reaction of an aldehyde with a nitroalkane. The synthesis of ethyl 3,4-diethylpyrrole-2-carboxylate (2) is typical. 

Several new examples of the Barton-Zard pyrrole synthesis from nitroalkenes and isocyanoacetate esters demonstrate the broad utility of this procedure. An excellent yield of ethyl 3-(9-anthryl)-4-ethylpyrrole-2-carboxylate was obtained starting with the nitroalkene from anthracene-9-carboxaldehyde and 1-nitropropane. <95TL8457> Bums et.al. reported an improved synthesis of benzyl isocyanoacetate which facilitates the synthesis of benzyl pyrrole-2-carboxylate esters by this method. <95SC379> 3-(l-Arylpyrrol-2-yl)pyrrole-2-carboxylates were prepared from l-aryl-2-(nitrovinyl)pyrroles. <95JHC 1703>... 

Returning again to pyrroles, probably the most widely-used method for their preparation is the Knorr pyrrole synthesis, which is the condensation of a ketone 2.22 with an a-aminoketone 2.23 to give pyrrole 2.13, via enamine 2.24. A reasonable mechanism is shown below, although none of the intermediates is isolated. 

Tricyclic pyrrole derivative 2.43 is a drug currently under development for the treatment of schizophrenia. It is prepared by a Knorr pyrrole synthesis. What are the structures of the two starting materials required, and that of the intermediate enamine ... 

Bromination of ketone 3.17 gives 3.18 which can be converted to azide 3.19. Hydrogenation of 3.19 in the presence of hydrochloric acid affords aminoketone hydrochloride salt 3.20. Such aminoketones are often isolated as the corresponding salts because the free aminoketones are prone to dimerisation, having both nucleophilic and electrophilic centres. (For a common alternative preparation of aminoketones, see the Knorr pyrrole synthesis, Chapter 2.) Liberation of the free base of 3.20 in the presence of the acid chloride affords amide 3.21 which is cyclised to oxazole 3.22. Ester hydrolysis then affords the biologically-active carboxylic acid 3.23. 

A pyrrole synthesis leading to 20 has been achieved by a CuBr catalyzed cyclization of the intermediate imine 21, which was prepared over several steps from 1,3-hexadiyne (22) in a one-pot operation <02CHE748>. Aminomethyl substituted allenes have also been used for the synthesis of pyrroles by a palladium catalyzed annulation with aryl iodides <02H(57)2261>. 

The versatile Knorr pyrrole synthesis is an important route to pyrroles 169 it involves the condensation of a -keto ester 167 with an -amino ketone 168 (Scheme 95). The -keto ester can be replaced by a -diketone simple ketones give poor yields. The amino ketone is frequently prepared in situ by nitrosation and reduction (e.g., with Zn—AcOH) of a second molecule of the -keto ester. 

The versatile van Leusen pyrrole synthesis (Section 4.2.3.3.4) is also useful for the preparation of fused pyrrole derivatives, for example, 165, which is obtained in good yield upon treatment of the lactam 164 with >-toluenesulfo-nylmethyl isocyanide (TosMIG) in the presence of DBU (Scheme 98) <2003BML1939>. This method has also been used in the construction of isoindole derivatives <1997H(45)1989, CHEC-III(3.03.9)327>. 

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