Heck reaction pyrroles

Methyl-l,2,3,9-tetrahydro-4H-carbazol-4-one, the key building block of the neuroactive compound alosetron, was easily obtained from 3-[(2-halophenyl)(methyl)amino]cyclohex-2-en-l-one by pyrrole ring formation via Heck reaction under microwave irradiation [94], While the iodo substrate gave an excellent yield in only 30 min at 100 °C the corresponding bromo derivative converted only poorly under the same reaction conditions (Scheme 88). 

An interesting approach to the pyrrolizidine skeleton was devised wherein pyrrole-2-carboxaldehyde (70) underwent A-allylation under basic conditions and subsequent olefmation with ethyl p-tolylsulfinylmethanephosphonate to produce the pyrrolyl alkene 71 <00TL1983>. Intramolecular Heck reaction of the iodo species then produced the 1 -p-tolylsulfinyl-1,3-diene 72. 

Palladium chemistry involving heterocycles has its unique characteristics stemming from the heterocycles inherently different structural and electronic properties in comparison to the corresponding carbocyclic aryl compounds. One example illustrating the striking difference in reactivity between a heteroarene and a carbocyclic arene is the heteroaryl Heck reaction (vide infra, see Section 1.4). We define a heteroaryl Heck reaction as an intermolecular or an intramolecular Heck reaction occurring onto a heteroaryl recipient. Intermolecular Heck reactions of carbocyclic arenes as the recipients are rare [12a-d], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles, pyrroles and indoles, etc. are excellent substrates. For instance, the heteroaryl Heck reaction of 2-chloro-3,6-diethylpyrazine (1) and benzoxazole occurred at the C(2) position of benzoxazole to elaborate pyrazinylbenzoxazole 2 [12e]. 

As will be seen in this chapter and in the rest of the book, the Heck reaction and its numerous variations represent a fantastically powerful set of tools available to the heterocyclic chemist. Although most Heck chemistry that involves pyrroles is intramolecular or entails synthesis of the pyrrole ring, a few intermolecular Heck reactions of pyrroles are known. Simple pyrroles (pyrrole, A-methylpyrrole, A-(phenylsulfonyl)pyrrole) react with 2-chloro-3,6-dialkylpyrazines under Heck conditions to give mixtures of C-2 and C-3 pyrrole-substituted pyrazines in low... 

Pyrrole fails to undergo a Heck reaction with 1-bromoadamantane [90], However, dihydropyrroles such as 131 and 132 undergo Heck reactions with ease, although the yields are variable [91-93]. Some examples are illustrated below. Since dihydropyrroles can be oxidized to pyrroles with a variety of reagents [94, 95], these Heck reactions of dihydropyrroles should constitute viable routes to pyrroles. 

Grigg has utilized the Heck reaction in several ways, from the simple cyclization of N-(2-iodobenzoyl)pyrrole (139) to afford tricyclic lactam (140) [100] to the complex cascade... 

A related tandem Heck reaction is seen in the conversion of 145 to 146, wherein the pyrrole ring is the site of termination [102],... 

Several pyrrole-ring syntheses have been developed that utilize an intramolecular Heck reaction, but, since these transformations involve C-N bond formation, they are covered in Section 2.7. Grigg has employed the intramolecular Heck reaction to craft a series of spiro-pyrrolidines (147)... 

Since Heck reactions on metalated substrates are known (e.g., with organomercurials [105]), applications of these transformations to pyrrole chemistry have been reported. For example, mercuration of pyrrole 149 followed by exposure to methyl acrylate under Heck reaction conditions leads to 150 [106]. This Heck variation has been extended by Smith to mercurated porphyrins [107]. Pyrrolylacrylates like 150 have also been made using conventional Heck reactions on 3-iodopyrroles [108,109]. 

Under mercuration conditions, pyrrole itself reacts with a mixture of Hg(OAc)2, PdCh, LiBr, CO, EtOH, and Cu(OAc)2 to give 2-(ethoxycarbonyl)pyrrole, but in only 4% yield [115]. In contrast, using the thallation-palladium modification of the Heck reaction, Monti and Sleiter have prepared pyrrole ester 159 in high yield [111]. 

In conclusion, the already rich chemistry of pyrroles is greatly expanded by the palladium reactions presented in this chapter. The abundance of both 2- and 3-pyrrolyl halides and triflates has led to many examples of high-yielding Negishi, Suzuki, Stille, Sonogashira, and Heck reactions. Noteworthy are the excellent approaches to alkynyl pyrroles and porphyrins using Sonogashira, Stille, and Suzuki reactions. 

Similar to the Pd-catalyzed pyrrole and thiophene annulations, an intramolecular Heck reaction of substrate 91 resulted in benzofuran 92 [80], Such an approach has become a popular means of synthesizing fused furans. Muratake et al. exploited the intramolecular Heck cyclization to establish the tricyclic core structure en route to the synthesis of a furan analog of duocarmycin SA, a potent cytotoxic antibiotic [81]. Under Jeffery s phase-transfer catalysis conditions, substrate 93 was converted to tricyclic derivatives 94 and 95 as an inseparable mixture (ca. 4 1) of two double bond isomers. 

Oxazoles and benzoxazoles are viable participants in the heteroaryl Heck reactions. In their monumental work published in 1992, Ohta and colleagues demonstrated that oxazoles and benzoxazoles, along with other rc-sufficient aromatic heterocycles such as furans, benzofurans, thiophenes, benzothiophenes, pyrroles, thiazole and imidazoles, are acceptable recipient partners for the heteroaryl Heck reactions of chloropyrazines [22b]. Therefore, treatment of 2-chloro-3,6-diethylpyrazine (27) with oxazole led to regioselective addition at C(5), giving rise to adduct 28. By contrast, a similar reaction between 2-chloro-3,6-diisobutylpyrazine (29) and benz[fc]oxazole took place at C(2) exclusively to afford pyrazinylbezoxazole 30. 

Furthermore, Ohta s group successfully conducted heteroaryl Heck reactions of chloropyrazines with many rt-electron-rich heteroaryls including furan, thiophene, benzo[ ]furan and benzo[6] thiophene [42, 43]. In reactions of chloropyrazines with furan, thiophene and pyrrole, disubstituted heterocycles were also isolated albeit in low yields. 

Although the heteroaryl Heck reactions of chloropyrazines with pyrrole itself were low-yielding for both mono- and bis-arylation products, better yields were obtained for N-phenylsulfonylpyrrole. Bulkier alkyl substituents on the pyrazine ring promoted the formation of C(3)-substituted pyrroles. The C(3)-substituted pyrrole 64 was the major product (62%) for the coupling of 1 and Al-phenylsulfonylpyrrole, while C(2)-substituted pyrrole 63- was a minor product (15%). 

Benzo-annulated pyrrolizin-3-ones 129 were synthesized in good yields from A-o-benzoylated pyrroles 128 by an intramolecular Heck reaction (Scheme 22) <2001JME4615>. 

The participation of halopyrroles in Heck coupling is mostly limited to intramolecular transformations. In a recent example of intermolecular Heck reaction different A-protcctcd 3-iodo-4-trimethylsilyl-pyrroles were coupled... 

A palladium-mediated annulation of Y-( o-bromoary l)pyrroles across strained alkenes led to the formation of pyrrolo[l,2-a]quinolines <07OL1761>. An intramolecular Heck reaction involving tethered iodoarenes produced an entry to pyrrolo[2,3-t/][2]benzazepin-7-ones, analogues of the pyrrole natural product latonduines <07T867>. A Heck reaction of a 3-iodopyrrole with a 2,3-dihydrofuran provided pyrrole deoxyribonucleosides <07T12747>. 

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