1.2.3.4- Tetrasubstituted pyrroles synthesis

Scheme 14.15 Ullman coupling conditions for the preparation of divinylhydrazines and application to tetrasubstituted pyrrole synthesis. ...

Scheme 12 Synthesis of tetrasubstituted pyrroles by coupled domino processes...

One of the most common approaches to pyrrole synthesis is the Paal-Knorr reaction, in which 1,4-dicarbonyl compounds are converted to pyrroles by acid-mediated dehydrative cyclization in the presence of a primary amine. The group of Taddei has reported a microwave-assisted variation of the Paal-Knorr procedure, whereby a small array of tetrasubstituted pyrroles was obtained (Scheme 6.181) [342], The pyrroles were effectively synthesized by heating a solution of the appropriate 1,4-dicarbonyl compound in the presence of 5 equivalents of the primary amine in acetic acid at 180 °C for 3 min. The same result was obtained by heating an identical mixture under open-vessel microwave conditions (reflux) for 5 min. Interestingly, the authors were unable to achieve meaningful product yields when attempting to carry out the same transformation by oil-bath heating. 

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-... 

Boger and his research group [10] have also developed a very efficient and flexible synthesis of lukianol A as depicted in Scheme 3. The key transformation for the formation of the tetrasubstituted pyrrole precursor (15) involves formation of a symmetrically substituted diazine (14) by a Diels-... 

Alder/retrograde Diels-Alder reaction sequence of a diaryl alkyne with a 3,6-dicarbomethoxy tetrazine. The resulting diazine (14) is then reduced, cleaved and cyclized with Zn/acetic acid to the 2,3,4,5-tetrasubstituted pyrrole (15), which is then N-alkylated with a-bromo-4-methoxyacetophenone to give a pentasubstituted pyrrole (16). The synthesis of lukianol A is completed by ester hydrolysis, decarboxylation, ring closure and deprotection. 

In this method, Furstner converts N-BOC protected pyrrole to the 2,5-dibromo compound (122) with NBS and this is followed by metalation and carbomethoxylation with t-butyl lithium in THF and subsequent trapping of the metalated species with methyl chloroformate to yield a pyrrole diester (123). Bromination of this diester at positions 3 and 4 with bromine in water followed by Suzuki cross-coupling with 3,4,5-trimethoxyphenyl boronic acid yields the symmetrical tetrasubstituted pyrrole (125). Base-mediated N-alkylation of this pyrrole with 4-methoxyphenethyl bromide produces the key Boger diester (126) and thereby constitutes a relay synthesis of permethyl storniamide A (120). 

Chiral rra s-2,5-dialkylpyrrolidines, which were used for the synthesis of ant-venom pyrrolizidines, were prepared in the following manner, d-Alanine was transformed into an pentenylamine which, upon intramolecular amidomercuration, yielded 15 (90TA561 92JOC4401). From a protected AA amide, after a Grignard reaction and treatment of the aminoketone with ethyl acetoacetate, the tetrasubstituted pyrrole 16 was obtained [93H(35)843],... 

Another example of reaction-rate enhancement was reported for the microwave-assisted Paal-Knorr synthesis of a series of tetrasubstituted pyrroles [18]. Following the standard procedure, 1,4-dicarbonyl compounds were converted to pyrrole rings via acid-mediated dehydrative cyclization in presence of primary amines. The main limitation of the standard protocol is the harsh reaction conditions (reflux in acetic acid for extended times). The use of microwaves slashes the reaction times to few minutes, giving good isolated yields of the desired products (Scheme 15.5). 

Scheme 15.5 Synthesis of tetrasubstituted pyrroles by microwave-assisted Paal-Knorr reaction.

Polysubstituted 1,3-oxazolidines were prepared in a one-pot diversity oriented four-component reaction (4-MCR), comprising two linked domino processes. Thus, domino synthesis of enol ethers 9 was followed by a sequential amine addition-cyclization sequence [74]. While strong microwave irradiation (900 W) of silica-gel absorbed conjugated alkynoates 9 and amines afforded tetrasubstituted pyrroles (via the skeletal rearrangement of 1,3-oxazolidines, see Sect. 2.1 and Scheme 5) [24], the use of milder microwave conditions (160 W power, 90 min) furnished 1,3-oxazolidines. Under these mild conditions the 1,3-oxazolidines did not rearrange to pyrroles and with respect to diastereoselectivity, the 1,3-oxazolidines were obtained as mixtures of syn/anti isomers. Overall, the formation of one C-C bond, one C-0 bond, two C - N bonds and a ring in this MCR required less than 3 hours and utilized simple and commercially available reagents (Scheme 26). 

A route involving annulation of ketene-AiA-acetals has been developed, as illustrated by the transformation of the substrate 143 into the tetrasubstituted pyrrole 144 (Equation 41). This methodology was used for the synthesis of some key pyrrole intermediates toward the alkaloids lukianol A and lamellarin Q <2005TL475>. 

A Comprehensive Example Synthesis and Purification of Libraries of Tri- and Tetrasubstituted Pyrroles... 

The synthesis of pyrrole 17 is performed by a reductive ring-contraction reaction effected by treatment of 1,2-diazine 16 with Zn/TFA. First, the 1,2-diazine 16 is reduced to the corresponding 1,4-dihydro-1,2-diazine 10, which is subsequently reduced to 11. Then, 11 undergoes an intramolecular cyclization providing the tetrasubstituted pyrrole 17 (see Key Chemistry). 

A useful modification of the Knorr pyrrole synthesis was developed in the laboratory of J.M. Hamby for the construction of tetrasubstituted pyrroles. The necessary a-amino ketones were prepared from A/-methoxy-A/-methylamides of amino acids (Weinreb amides). These Weinreb amides were prepared by the mixed anhydride method and treated with excess methylmagnesium bromide in ether to afford the corresponding Cbz-protected a-amino ketones in excellent yield. The Cbz group is removed by catalytic hydrogenation in the presence of the active methylene compound (e.g., acetoacetic ester), the catalyst is then filtered and the resulting solution is heated to reflux to bring about the condensation. 

In the laboratory of D.F. Taber, the large-scale preparation of a tetrasubstituted pyrrole, a key precursor for the preparation of hemes and porphyrins, was achieved. The 1,4-dicarbonyl substrate was generated from a ketal via hydrolysis and was immediately subjected to the Paal-Knorr pyrrole synthesis by heating it with ammonium carbonate in DMF. The resulting 1/-/-pyrrole was formylated with trimethyl orthoformate in trifluoroacetic acid. 

In the laboratory of A. Millar, the convergent enantloselective synthesis of CI-981, a potent and tissue-selective Inhibitor of HMG-CoA reductase was achieved. The central tetrasubstituted pyrrole ring was prepared via the Paal-Knorr pyrrole synthesis. The required 1,4-diketone precursor was efficiently prepared by the Stetter reaction between p-fluorobenzaldehyde and an unsaturated amide. Interestingly, the A/-benzyl thiazolium chloride catalyst afforded only the benzoin condensation product and none of the desired diketone. However, when the A/-ethyl thiazolium bromide catalyst was employed, under anhydrous and concentrated reaction conditions, the 1,4-diketone was formed in good yield. The authors also noted that the simple dilution of the reaction mixture resulted in a dramatic increase in the formation of the undesired benzoin condensation product. 

Yavari I, Kowsari E (2009) Efficient and green synthesis of tetrasubstituted pyrroles promoted by task-specific basic ionic hquids as catalyst in aqueous media. Mol Divers 13 519-528... 

Pyrrole is one of the most prominent heterocycles in several natural products and synthetic pharmaceuticals. The most common approach to pyrroles is the Paal-Knorr reaction. Taddei and coworkers have investigated a rapid and versatile synthesis of tetrasubstituted pyrroles in few highly efficient steps ... 

The synthesis of dictyodendrins A and F was realized through a sequential C—H functionahzation strategy inclusive of an initial C3 arylation, a site-selective double C—H alkylation with an aryldiazoacetate derivative and a subsequent Suzuki-Miyaura cross-coupHng with indole-3-boronic acid pinacol ester 107 (2015JAC644). A formal 67r-electrocyc-lization of the resultant tetrasubstituted pyrrole 108 fashioned the required pyrrolo-[2,3-c]carbazole core (109) which was further elaborated to the targets. 

A pyrrole ring is the core structure found in the skeletons of many naturally occurring biomolecules such as globins, porphyrins, vitamins, and so on and constitutes a unit of pharmaceuticals. Most commonly, pyrroles are synthesized by multistep synthetic methods. A one-pot three-component synthesis of 2,3,4,5-tetrasubstituted pyrroles from benzoin, 1,3-dicarbonyls, and ammonium acetate was carried out using SSA under solvent-free conditions (Tamaddon and Farahi, 2012) (Scheme 5.21). Veisi (2010) reported a room temperature synthesis of N-substituted... 

Tamaddon, F. and Farahi, M. 2012. A new three-component reaction catalyzed by silica sulfuric acid Synthesis of tetrasubstituted pyrroles. Synlett 23 1379-1383. 

SCHEME 6.50 A-Methylimidazole-catalyzed synthesis of tetrasubstituted pyrroles 343 in water. 

Jeong and Atar were the first who recently developed the synthesis of tetrasubstituted pyrroles 356 sustained by silica gel-supported tungstic acid (STA) 355 [114]. The reactions proceed in high yields (60-88%), and the catalyst could be reused in several reactions without losing its catalytic activity (Scheme 6.52). 

A new three-component reaction catalyzed by silica sulfuric acid synthesis of tetrasubstituted pyrroles. 

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