For pyrrole synthesis

The condensation of nitro ilkenes with enamino- ketones or enamino-esters CGrob-Camenisch reacdoni has been v/idely used for pyrrole synthesis fEq. 10.4. This process is now carried out v/ith resin-boiind enamino-ketones for combinatoriM syntheses of pyrroles. ... 

Isonitnle cyclizadon provides a useful altemadve method of the Knorr type cyclizadon for pyrrole synthesis. In 1972, Lensen and coworkers reported pyrrole synthesis based on the reacdon of tosylmeJhyl isocyanide (TosMICi with electron-deficient alkenes FEq. 10.12. ... 

The condensation of nitroalkenes with enamino- ketones or enamino-esters (Grob-Camenisch reaction) has been widely used for pyrrole synthesis (Eq. 10.4).6a This process is now carried out with resin-bound enamino-ketones for combinatorial syntheses of pyrroles.6b... 

Various variants of this process are presented for pyrrole synthesis. For example, reactions of 1,3-dicarbonyl compounds with P-nitrostyrene followed by treatment with amines give 3-acylpyrroles (Eq. 10.5).7... 

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). 

Scheme 8 Proposed mechanism for pyrrole synthesis from an amine, alkyne, and CO via zirconaaziridine...

Two methods have been developed recently for pyrrole synthesis a twofold coupling reaction of (Z,Z)-1,4-dihalo-1,3-dienes (bromides and iodides) with BocNH2, and stepwise coupling of alkenyl iodides with A,A -diBoc hydrazine/ ... 

One of the weaknesses of the Trofimov reaction is the requirement for using acetylene under high pressure. To obviate this requirement, acetylene analogs (vinyl halides and 1,2-dihaloethanes) were examined for the utility as components in the Trofimov reaction. The results are promising and indicated that further development of this variation in the Trofimov reaction could lead to a more practical and attractive method for pyrrole synthesis. 

Route II leads (after H2O addition and enamine hydrolysis e/f) to the y-amino aldol intermediate 36. Retro-aldol reaction may follow (retroanalysis step g) resulting in the formation of a-amino carbonyl compounds 38 and methylene ketones 37 as possible starting materials for pyrrole synthesis. 

Dipolar components are frequently utilized for pyrrole synthesis (c also p. 175), as shown by some characteristic examples. 

In recent years, synthesis of pyrroles has drawn the attention of chemists. Traditional methods used for pyrrole synthesis include the Hantzsch reaction [45] and the Paal-Knorr condensation reaction [46,47], The latter is the most widely used method, which involves the cyclocondensation reaction of 1,4-dicarbonyl compounds with primary amines to produce substituted pyrroles. In addition, there are several methods such as 1,3-dipolar cydoaddition reaction, aza-Wittig reaction, reductive coupling, and titanium-catalyzed hydroamination of diynes. Scheme 1 shows several catalysts used in this type of reaction [44]. 

Paulson, M. 2010. Novel Methods for Pyrrole Synthesis. Saarbriicken, Germany Lambert Academic Pnbhshing. 

Knorr Synthesis. Condensation of an a-aminoketone with a carbonyl compound was first reported by Knott (20). This reaction and its modifications are among the most important and widely used methods for the synthesis of pyrroles. 

The exploration of the chemistry of azirines has led to the discovery of several pyrrole syntheses. From a mechanistic viewpoint the simplest is based upon their ability to behave as a-amino ketone equivalents in reactions analogous to the Knorr pyrrole synthesis cf. Section 3.03.3.2.2), as illustrated in Schemes 91a and 91b for reactions with carbanions. Parallel reactions with enamines or a-keto phosphorus ylides can be effected with electron-deficient 2//-azirines (Scheme 91c). Conversely, electron-rich azirines react with electron deficient alkynes (Scheme 91d). 

In 1985, in the course of their interest in nitroalkane chemistry, Barton and Zard reported the base-catalyzed reaction of nitroalkenes with a-isocyanoacetates leading to pyrrole esters having an ideal substitution pattern for the synthesis of porphyrins and bile... 

The mechanism of the original Knorr pyrrole synthesis entails in situ reduction of the oxime moiety to an amine, condensation with the second carbonyl compound, and cyclization with loss of a second molecule of water to give a pyrrole for example, 10 + 11 to 12. Several studies have demonstrated that different pathways and pyrrole products obtain depending on the substrates. 

Despite its apparent simplicity, the PK pyrrole synthesis has retained its mystique since being discovered. Several investigations into the PK mechanism have been reported, including a gas phase study. Current evidence (intermediate isolation, kinetics, isotope effects) suggests the following (abbreviated) mechanism for the formation of pyrrole 13. However, the specific PK mechanism is often dependent on pH, solvent, and amine and dicarbonyl structure, especially with regard to the ringclosing step. 

The major development in the Knorr pyrrole synthesis has been access to the amine component. For example, use of preformed diethyl aminomalonate with 1,3-diketones affords much higher yields of pyrroles 14. Reaction of 6-dicarbonyl compounds with hydroxylamine 0-sulfonic acid gives pyrroles 15 in one step. Weinreb a-aminoamides have found use in the Knorr pyrrole synthesis of a wide variety of pyrroles 16. °... 

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 use of 2,5-dimethoxytetrahydrofuran (20) as a succinaldehyde equivalent has expanded the PK synthesis to include unsubstituted pyrroles, for example, 21. A novel synthesis of monosubstituted succinaldehydes is also available for the PK pyrrole synthesis. ... 

In 1972, van Leusen, Hoogenboom and Siderius introduced the utility of TosMIC for the synthesis of azoles (pyrroles, oxazoles, imidazoles, thiazoles, etc.) by delivering a C-N-C fragment to polarized double bonds. In addition to the synthesis of 5-phenyloxazole, they also described reaction of TosMIC with /7-nitro- and /7-chloro-benzaldehyde (3) to provide analogous oxazoles 4 in 91% and 57% yield, respectively. Reaction of TosMIC with acid chlorides, anhydrides, or esters leads to oxazoles in which the tosyl group is retained. For example, reaction of acetic anhydride and TosMIC furnish oxazole 5 in 73% yield. ... 

Methods for the synthesis of pyrroles are of importance, since the pyrrole unit is found in natural products widespread in nature. For example a pyrrole unit is the building block of the porphyrin skeleton, which in turn is the essential structural subunit of chlorophyll and hemoglobin. 

The foregoing examples show that the nucleophilic attack to nitroarenes at theorr/io-posidcn followed by cyclizadon is a generid method for the synthesis of various heterocycles. When nucleophiles have an electrophilic center, heterocyclic compounds are obtained in one step. Ono and coworkers have used the anion dedved from ethyl isocyanoacetate as the reacdve anion for the preparadon of heterocyclic compounds. The carbanion reacts with various nitroarenes to give isoindoles or pyriirddines depending on the stnicture of nitroarenes fEqs. 9.56 and9.57. The synthesis of pyrroles is discussed in detail in Chapter 10. 

The Michael addidon to nitroalkenes followed by cyclizadoti provides a getieriil method for the synthesis of various pyrroles. The reacdoti of nitroalkenes v/iih acetoacetate followed by reducdoti v/ith Znin acedc acid provides another route to 3-methyl-3-pyrrolecarboxylates fEq. 10.8. °... 

Barton and Zard found that the base-catalyzed reacdon of nitroalkenes or fi-n v/ith alkyl isocyanoacetate or TosMIC gives pyrrole-3-carboxylates or 3-suifonylpyrroles, respecdvely fsee Eqs 10 18 and 10 19) This reacdon is very convenient for the synthesis of... 

Battersby and coworkers have developed selective methods for total synthesis of chlorins on a model system, as shown in Scheme 10.15, in which the Michael addition of 5-f3-nittoethyl pyrrole to enone and reductive cyclizadon are used as key steps. "... 

The enzymatic conversion of a-(aminomethyl)pyrroles is also used by nature to produce porphyrinogens like uroporphyrinogen III (see introduction, compound 8), which is the key building block in the biosynthesis of all known porphinoid natural products. This biomimetic method is a powerful tool for the synthesis of different porphyrins, e.g. for the preparation of JV,Af, V ,Ar"-tetramethylporphyrin-2,3,7,8,12,13,17,18-octaacetic acid dibromide 12.36... 

The important biological role of the isobacteriochlorins has decisively influenced the development of synthetic approaches leading to the isobacteriochlorin class of compounds. All of the naturally occurring isobacteriochlorins contain geminally dialkylated structural parts in the saturated pyrrole rings, which require special approaches for their synthesis. Until the discovery of siroheme and sirohydrochlorin, this structural element could only be found in vitamin B,2. Using the synthetic potential, which was invented during numerous syntheses of... 

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