Synthesis of pyrroles

Pyrrole syntheses have been organized systematically into intramolecular (type I) and intermolecular (type II) approaches and classified by the location of the new bonds that describe the pyrrole ring forming step (two examples illustrated below). 

Highly substituted pyrroles are important A/ -heterocyclic compounds found in a number of natural and synthetic bioactive compounds. In 2010, Glorius and coworkers reported a new method for the synthesis of pyrroles from enamines and alkynes by Rh-catalyzed sp C-H bond activation (Eq. (5.22)) [16]. Several AT-substituents on the enamides were examined, and the acetyl group was found to be critical for the reaction. Internal alkynes with aromatic substituents were successfully coupled. It is noteworthy that the reaction appears to proceed by an sp C-H activation at the y-position, which leads to a sbc-membered rhodacycle D2 or D3. The resulting intermediate undergoes alkyne insertion and subsequent reductive elimination to afford 23. 

Interestingly, a similar method can be used for the synthesis of 3-borylated pyrroles 24 from enamides and internal alkyne AT-methyliminodiacetic acid (MIDA) boronates (Eq, (5.23)) [17]. Product 24a undergoes Suzuki-Miyaura coupling with bromobenzene to give 24c in good yield, with a concomitant removal of the acetyl group. 

Similarly, Huestis and Fagnou reported a cationic Rh-catalyzed preparation of unsymmetrically substituted pyrroles from the coupling of enamides with enynes in good yield (Eq. (5.24)) [5c]. In this reaction, alkenes were selectively introduced at the C2 position of the corresponding pyrroles by using a Rh-catalyzed vinylic 

Equations (5.25)-(5.27) illustrate some other Rh(lll)-catalyzed vinylic sp C-H activation and annulation reactions with various coupling partners to give pyrrole derivatives. For example, ( )-3-phenylbut-3-en-2-one 0-methyl oxime reacted with the Af-tosyl imine of ethyl glyoxylate in DCE (1,2-dichloroethane) to afford pyrrole 26 in 78% yield [18a]. Similar reactions that involve vinylic sp C-H and allylic C-H activation have also been reported [18b,cj. 

Glorias developed a Rh(III)-catalyzed oxidative ortAo-olefination and exo-cyclization reaction for the synthesis of y-butyrolactam derivatives [19a]. The resulting data showed that only products with a Z-configured exocyclic C=C bond are formed. A representative transformation, in which benzamide and n-butyl acrylate generate 29 in 62% yield, is shown in the following (Eq. (5.28)). Similarly, Zhou and Li developed a Rh(lll)-catalyzed C-H bond activation and annulation of 0-methyl oximes with isocyanates for the synthesis of 3-methyleneisoindolin-l-ones 30 (Eq. (5.29)) [19b]. 

From 1,4-dicarbonyl compounds and ammonia or primary amines  

4-Dicarbonyl compounds react with ammonia or primary amines to give pyrroles. 

Pyrroles are formed by the reaction of ammonia or a primary amine with a 1,4-dicarbonyl compound(see also 15.14.1.1). An alternative to the use of ammonia for the synthesis of A-unsubstituted pyrroles by this method employs hexamethyldi-silazide with alumina.Successive nucleophilic additions of the amine nitrogen to the two carbonyl carbon atoms and the loss of two mol equivalents of water represent the net course of the synthesis a reasonable sequencefor this is shown below using the synthesis of 2,5-dimethylpyrrole as an example. 

The best synthon for unstable succindialdehyde, for the ring synthesis of C-unsubstituted pyrroles, is 2,5-dimethoxytetrahydrofuran (section 15.1.4), or 1,4-dichloro-1,4-dimethoxybutane obtainable from it. 2,5-Dimethoxytetrahydrofuran will react with aliphatic and aromatic amines, amino esters, arylsulfonamides, trimethylsilylethoxycarbonylhydrazine, or primary amides to give the corresponding A-substituted pyrroles. 

A Still useful synthesis of A-substituted pyrroles, which consists of dry distillation 

1 From 1,4-Dicarbonyl Compounds and Ammonia or Primary Ammex  

Several variations have been shown to improve the efficiency microwave irradiation makes the process very rapid and the use of iodine on a clay support are just two of these. An alternative to the use of ammoifia for the synthesis of A-unsubstituted-pyrroles employs hexamethyldisilazide with alumina, or a solution of ammonia can be generated in situ conveniently, using the reaction of magnesium nitride, MgsNa, with methanol.  

The best synthon for unstable succindialdehyde, for the ring synthesis of C-unsubstituted pyrroles, is 

A still-useful synthesis of A-substituted pyrroles, which consists of dry distillation of the alkylammonium salt of mucic or saccharic acid, probably also proceeds by way of a 1,4-dicarbonyl intermediate. The overall process involves loss of four mol equivalents of water and two of carbon dioxide, and may proceed as shown. 

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The preparation of 2 4-dimethyl-3 5-dicarbethoxypyrrole (II) is an example of the Knorr synthesis of pyrrole derivatives, involving the reaction of an -aminoketone (or a derivative thereof) with a reactive methylene ketone (or a derivative thereof). The stages In the present synthesis from ethyl acetoacetate (I) may be represented as follows ... 

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. 

Hantzsch and Feist Syntheses. The Hant2sch synthesis of pyrroles iavolves condensation of an a-haloketone (10) with a p-keto ester (6) ia the presence of ammonia or an amine (22). 

The use of a vinylphosphonium salt as the source of the QQ fragment instead of the more commonly employed 1,2-dicarbonyl substrate is illustrated by the pyrrole synthesis in Scheme 79b (8UOC2570). A particularly interesting feature is the intramolecular Wittig reaction with an amide carbonyl group. A very useful synthesis of pyrroles depends upon the addition of the anion of p-toluenesulfonylmethyl isocyanide (TOSMIC) to a,/3-unsatur-... 

Ono and Lash have been the two pioneers in applying the BZ reaction to the synthesis of pyrroles and, particularly, with applications to the synthesis of novel fused and other porphyrins. Although the concept was recognized by Barton and Zard, Ono and Lash independently discovered the conversion of 2-pyrrolecarbo ylates, prepared by the BZ reaction, into porphyrins by what is now a standard protocol (1. LiAlfL 2. 3. 

Other PK variations include microwave conditions, solid-phase synthesis, and the fixation of atmospheric nitrogen as the nitrogen source (27—>28). Hexamethyldisilazane (HMDS) is also an excellent ammonia equivalent in the PK synthesis. For example, 2,5-hexanedione and HMDS on alumina gives 2,5-dimethylpyrrole in 81% yield at room temperature. Ammonium formate can be used as a nitrogen source in the PK synthesis of pyrroles from l,4-diaryl-2-butene-l,4-diones under Pd-catalyzed transfer hydrogenation conditions. 

The wide applicability of the PK reaction is apparent in the synthesis of pyrroles, for example, 45, en route to novel chiral guanidine bases, levuglandin-derived pyrrole 46, lipoxygenase inhibitor precursors such as 47, pyrrole-containing zirconium complexesand iV-aminopyrroles 48 from 1,4-dicarbonyl compounds and hydrazine derivatives. The latter study also utilized Yb(OTf)3 and acetic acid as pyrrole-forming catalysts, in addition to pyridinium p-toluenesulfonate (PPTS). 

A useful and possibly more general alternative to the Lwowski synthesis- of 1,3-diphenylisoindoles involves condensation of a l,2-dibenzoyl-l,4-cyclohexadiene (e.g., 55) with ammonia or a primary amine. Cyclohexadiene derivatives of this type are easily prepared by Riels-Alder addition of a 1,3-diene to dibenzoylacetylene, and these adducts lead directly, and in high yield, to the corresponding isoindoles (56). The reaction is closely related to the well-known synthesis of pyrroles by condensation of 1,4-diketones with ammonia. 4,7-Dihydro- and 4,5,6,7-tetrahydroisoindoles (57 and 58) have been... 

Synthesis of pyrrole, pyrazole, and thiazole derivatives using conjugated azoal-kenes and related compounds 97SL1128. 

Because diacetylene is unstable, a stable diacetylene derivative, 1-methoxybut-l-en-3-yne (65CB98), is often employed in the synthesis of pyrroles. The reaction with ammonia proceeds under conditions of heterogeneous catalysis (a mixture of reagent vapors is passed through a catalyst-containing reactor heated to 150°C), approaching a yield of 50-70% but with primary aromatic amines, the yield drops to 20%. 

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. 

As a new and practical synthesis of pyrroles, Zard and coworkers have presented the reduction of Y-nitroketones v/ith formamidinesiilfinic acid fEq. IC.Bi/... 

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... 

The combination of the Diels-Alder reaction of fi-sulfonylnitroethylene and the Barton-Zard reaction provides a new synthesis of pyrroles fused with polycyclic skeletons fEq 10 31 Pyrroles fused with bicycle [3 3 3 Qctodiene are important precursors for synthesis of isoindoles via the retro Diels-Alder reaction fEq 10 33 ... 

Scheme 28 Synthesis of pyrrole and furan derivatives 134 from the 1-methoxyethyli-denechromium complex 6a and enyneketimines or -ketones 131 [92,93]. For further details see Table 6...

Table 6 Synthesis of pyrrole and furan derivatives 134 (see Scheme 28)...

The same procedure used for the synthesis of pyrroles 16 was applied to prepare furans, namely heating 1,4-diketones 15 in AcOH under microwave... 

Some advances have been made in the Paal-Knorr synthesis of pyrroles by the condensation of primary amines with 1,4-dicarbonyl species. For instance, a new synthetic route to monosubstituted succinaldehydes allows for the facile preparation of 3-substituted pyrroles <96TL4099>. Additionally, a general method for the synthesis of 1-aminopyiroles has been devised by the condensation of commercially available 2,2,2-trichloroethyl- or 2-(tri-methylsilyl)ethylhydrazine with 1,4-dicarbonyl compounds <96JOCl 180>. A related route to such compounds involves the reaction of a-halohydrazones with p-dicarbonyl compounds <96H(43)1447>. Finally, hexamethyldisilazane (HMDS) can be utilized as the amine component in the Paal-Knorr synthesis in the presence of alumina, and this modification has been employed in the synthesis of tm azaprostacyclin analog <96S1336>. 

Pagenkopf s group developed a novel domino process for the synthesis of pyrroles 4-183, which allows for the control over the installation of substituents at three positions and seems to be very suitable for combinatorial chemistry [62]. The process consists of a 1,3-dipolar cycloaddition of an intermediate 1,3-dipole formed from the cyclopropane derivative 4-181 with a nitrile to give 4-182 followed by dehydration and isomerization (Scheme 4.39). The yield ranges from 25 to 93 %, and the procedure also works well with condensed cyclopropanes. 

Scheme 10.15. Solid-state domino synthesis of pyrrole derivatives.

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. 

The ring cleavage of 3-aryl-2-substituted-2//-azirines by molybdenum hexacarbonyl has been described earlier in regard to the synthesis of pyrroles, pyrazoles and isoxazoles. In contrast to this behavior, analogous reactions of 2-unsubstituted derivatives lead to the formation of mixtures of 2,5-diarylpyrazines (139) and isomeric 3,6- and 1,6-dihydropyrazine derivatives (140,141) (Scheme 163).47,53 It is possible that the pyrazine products are formed by an intermolecular nitrene mechanism akin to the intramolecular processes described earlier (see Scheme 22 in Section IV,A,1). 

A similar strategy has been used for the Biginelli condensation reaction to synthesize a set of pyrimidinones (65-95%) in a household MW oven [152]. This MW approach has been successfully applied to combinatorial synthesis [153]. Yet another example is the convenient synthesis of pyrroles (60-72 %) on silica gel using readily available enones, amines and nitro compounds [154]. 

Ferreira developed a novel method for the preparation of masked 1,4-dicarbonyl derivatives for utilization in the Paal-Knorr synthesis of pyrroles <00SC3215>. In this process, the reaction between diazocompound 3 and n-butyl vinyl ether using dirhodium tetraacetate as catalyst provides dihydrofurans 4 which are easily converted into substituted... 

Ohta has developed a facile and efficient synthesis of pyrroles 42 that involves the Pd-catalyzed oxidative cyclization of hydroxy enamines such as 41 [41]. Fused pyrroles 43 and 44 were also synthesized in similar fashion. 

Stille couplings on W-protected derivatives of 85 proceed well, as shown below for the synthesis of pyrroles 86 [70]. 

Scheme 6. Multi-step synthesis of pyrroles employing support-bound reagents and scavengers.

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