Pyrrole palladium chemistry

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]. 

N-Arylation. The development of palladium chemistry now allows relatively easy N-arylations of pyrroles and indoles, using aryl iodides and bromides <1998JA827, 20000L1403>. The combination of Pd(OAc)2 and DPPF catalyzes the formation of N-aryl azoles 45 in the presence of CS2CO3 or /-BuONa with electron-rich, electron-neutral, or electron-poor aryl halides (Scheme 12) <1998JA827>. The system Pd(OAc)2, SIPrnHCl, NaOH [where SIPr= 1,3-bis... 

Reactions of the species prodnced by the a-lithiation of A -substituted-pyrroles are widely nsed for the introdnction of gronps, either by reaction with electrophiles or by coupling processes based on palladium chemistry (4.2). Some examples where removable iV-blocking groups have been nsed in the synthesis of... 

In most cases, the oxidative addition process consumes stoichiometric amount of Pd(OAc>2. One of the earliest examples of the use of palladium in pyrrole chemistry was the Pd(0Ac)2 induced oxidative coupling of A-methylpyrrole with styrene to afford a mixture of olefins 18 and 19 in low yield based on palladium acetate [28]. 

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. 

In this new book, Jack Li and Gordon Gribble have compiled an impressive array of richly referenced examples of the use of palladium in heterocyclic chemistry. The book is organized by class of heterocycle (pyrroles, indoles, pyridines, etc.) and each chapter contains the syntheses of heterocyclic precursors as well as details of uses of palladium to both synthesize and functionalize these heterocyclic systems. This book will appeal to anybody involved in heterocyclic chemistry, and will provide an easy entry into the field for those unfamiliar with the area. 

The amination of aryl halides and triflates catalyzed by palladium complexes is suitable for use in complex synthetic problems. Many substrates will produce high yields of mixed arylamines with one of the existing catalyst systems. Nevertheless, there are many combinations of substrates for which the amination chemistry may be substantially improved. For the most part, these reactions involve nitrogen centers, such as those in pyrroles, indoles, amides, imidazoles and other heterocyclic groups that are less basic than those in standard alkylamines. Although mild reaction conditions have been developed for many substrates, the harsh conditions used in many of the applications indicate that continued studies on developing mild condi-... 

Several new routes involve formation of one carbon-carbon bond in pre-formed substrates. Palladium-catalyzed cyclization of /3-hydroxyenamine derivatives has been employed in a route to substituted pyrroles and 4,5,6,7-tetrahy-droindoles with multiple substituents by formation of the C-3-C-4 bond as the key feature, as illustrated by construction of the molecule 534 (Equation 146) <2006T8533>. Zinc perchlorate-catalyzed addition of alcohols to the nitrile functionality of a-cyanomethyl-/3-ketoesters, followed by annulation gave access to a series of substituted ethyl 5-alkoxypyrrole-3-carboxylates <2007T461>. Similar chemistry has also been used for synthesis of a related set of pyrrole-3-phosphonates <2007T4156>. A study on preparation of 3,5,7-functionalized indoles by Heck cyclization of suitable A-allyl substituted 2-haloanilines has also appeared <2006S3467>. In addition, indole-3-acetic acid derivatives have been prepared by base induced annulation of 2-aminocinnamic acid esters (available for instance from 2-iodoani-lines) <2006OL4473>. 

An A-vinylation of pyrrole utilized a palladium-catalyzed coupling of pyrrole with vinyl triflates <05JOC8638>. For example, treatment of pyrrole and triflate 53 in the presence of palladium and the XPhos ligand gave Al-vinylpyrrole 54. This chemistry was utilized in the preparation of the tricyclic mymicarin alkaloids <05OL4423>. 

Interestingly, this Heck-type palladium-catalyzed oxidative addition/insertion manifold can also be applied to the actual formation of the carbon-heteroatom bond. This was illustrated by Narasaka in the reaction of olefin-tethered oxime derivatives. This chemistry can be considered to arise from oxidative addition of the N—O bond to palladium (30) followed by the more classical olefin insertion and (3-hydride elimination, ultimately allowing the assembly of pyrroles (Scheme 6.58) [79]. The nature of the OR unit was found to be critical in pyrrole formation, with the pentafluorobenzoylimine leading to selective cyclization and rearrangement to the aromatic product. An analogous approach has also been applied to pyridines and imidazoles [80]. 

Gabriele, B., Salerno, G. and Cassoni, S. (2005) Heteroqfdic derivative syntheses by palladium-catalyzed oxidative cyclization-alkoxycarbonylation of substituted y-oxoalkynes. The Journal of Organic Chemistry, 70, 4971 979. no Gabriele, B., Salerno, G., Fazio, A. and Campana, F.B. (2002) Unprecedented carbon dioxide effect on a Pd-catalysed oxidative carbonylation reaction a new synthesis of pyrrole-2-acetic esters. Journal of the Chemical Society, Chemical Communications, 1408-1409. m Gabriele, B., Salerno, G., Fazio, A. and Veltri, L (2006) Versatile synthesis of pyrrole-2-acetic esters and (pyridine-... 

---