Palladium-Catalyzed Indole Synthesis

The discussion of process development will focus on the following  

2) Optimization of the Pd-catalyzed coupling reaction between iodoaniline 28 and bis-trialkylsily 1 butynol ether 29. 

The ICl-CaC03 procedure required a filtration to remove insoluble, inorganic by-products prior to biphasic extraction. In an effort to develop a homogeneous process for the iodination step, a pH control protocol was later implemented in the manufacturing process. The pH-controlled iodination was run in a single phase in a MeOH-water system by simultaneous addition of the aqueous IC1 solution and 1M NaOH. Citric acid was added to increase the buffer capacity to the optimal pH (5-5.5) for robust operation. Under these conditions, the iodoaniline 28 was typically obtained in 99 A% with 1% of diiodoaniline 32. Residual 

IC1 was quenched with sodium thiosulfate. A solvent switch from MeOH to EtOAc followed by water wash allowed isolation of the crude iodoaniline 28 in solution in EtOAc. Subsequent crystallization from EtOAc-heptane afforded iodoaniline 28 in 95% yield in 99A% purity. The procedure was quite robust and produced high quality 28 that could readily be used in the coupling step. 

2 Optimization of the Pd-Catalyzed Coupling Reaction Between Iodoaniline 28 and Bis-TES Butynol Ether 

---

Rizatriptan (Maxalt ) A 5-HTm Receptor Agonist 4.1.2.2 Palladium-Catalyzed Indole Synthesis... 

Knochel demonstrated the effectiveness of soluble potassium or cesium alkoxides such as KO Bu or CsO Bu as well as KH in iV-methylpyrrolidinone (NMP) for promoting the 5-endo-dig cyclizations of 2-alkynylanilines to 2-substituted indoles in solution or the solid-phase <00AG(E)2488>. Alternatively, Cacchi coupled a palladium-catalyzed cyclization of o-alkynyltrifluoroacetanilides with the addition of benzyl bromide or ethyl iodoacetate to afford 2-substituted-3-benzyl or 3-indolylcarboxylate esters, respectively <00SL394>. Yamamoto reported a new palladium catalyzed indole synthesis in which 2-(l-alkynyl)-Ar-alkylideneanilines 117 give 2-substituted-3-(l-alkenyl)indoles 118 directly from the imine by the in situ coupling of an aldehyde with the alkynylaniline <00JA5662>. 

Later on, the pre-formation of enolates was found to be unnecessary. In 1997, Chen and co-workers reported a palladium-catalyzed indole synthesis... 

Thus far, we have discovered and demonstrated a new and effident method for the synthesis of indoles from various carbonyl compounds. This, in conjunction with the use of alkyries in the palladium-catalyzed indolization, widens the spectrum of indoles that can be prepared by these means. The simple procedure, mild reaction conditions, and ready availability of the starting materials render these methods valuable additions to indole chemistry. We next extended this method to the synthesis of the indole core of a PGD2 receptor antagonist, laropiprant 3. 

A one-step palladium-catalyzed oxidative synthesis of 5- and h-SFs-in-doles from SFs-anfrines was developed by Chen, Xu, and Mi (15TL4204). In a representative example, d-SFs-aniline (39) or 4-SF5-aniline (11) reacted with acetone in the presence of a catalytic amount of Pd(OAc)2 and Cu(0Ac)2 H20 as an oxidant in dimethyl sulfoxide (DMSO) to directly provide the corresponding 2-methyl-6-SF5-indole (40) in 50% yield or 2-methyl-5-SF5-indole (41) in 56% yield (Scheme 9). 

Palladium-Catalyzed Indole Ring Synthesis Hegedus... 

Given the truly voluminous literature on palladium-catalyzed indole ring synthesis and the large number of recent reviews on this topic [1-11], coverage in this chapter and in succeeding ones is strictly limited. Additional reviews are cited in Chapter 1. 

The first reported Au-catalyzed indole synthesis was that of Utimoto and coworkers (Scheme 1, equation 1) [5], Like copper, palladium, and rhodium, gold effects the cycliza-tion of o-alkynylanilines to indoles with ease. This basic electrophilic cyclization was improved upon by MarineUi [6, 7], was adapted to the synthesis of indole libraries [8, 9], was used with supported gold nanoparticles and o-alky-nylnitroarenes under hydrogenation conditions in a one-pot indole synthesis [10], and was employed in total syntheses of the alkaloids (-)-mersicarpine [11] and voacangalactone [12]. There have been an abundance of extensions to the Au-catalyzed cyclization of o-aUcynylanilines to afford 2,3-disubstituted indoles. Arcadi and colleagnes introduced both a,p-enones [13] and 1,3-dicarbonyl compounds... 

---