Indoles catalyst systems

The bis-indole diphosphine delivers the best ee and as the heterocyclic units are also electron rich aromatics this also gives the added advantage of the highest activity of the catalyst system. This overcomes one drawback often encountered, that high hydrogen pressures are frequently needed for ruthenium-based catalysts. 

Iodo-lV-(methanesulfonyl)anilines can be converted to 2-subslituted indoles by reaction with terminal acetylenes in a one-pot process involving Cul, EtjN and Pd(PPh3)2Cl2 as the catalyst system[2]. Yields ranged from 40% to 70% for alkyl, aryl and several oxygenated alkyl substituents. 

The direct alkenylation of arylamines at the ortho position has been reported in reactions of o -chloroalkenylmagnesium chloride with N-lithioarylamines.22 Use of the CuI-L-proline catalyst system in DMSO has been found to be successful in promoting reactions of aryl iodides and bromides with activated methylene compounds, such as ethyl acetoacetate and diethyl malonate.23 The same catalyst in dioxane has been used in intramolecular cyclization of ene-carbamates leading to indoles or pyrrolo[2,3-cjpyridines.24... 

As a parallel to the rapid growth of asymmetric catalysis, chiral imida-zolidinon-HX salts 124a-c were used as catalysts for Michael-type alkylations between indoles and a,(3-unsaturated aldehydes with high levels of enan-tioselectivity and reaction efficiency. This chiral catalyst system is the first reported nonchelating catalyst for indole alkylation. It was assumed that the catalyst reacts with the unsaturated aldehydes to yield the chiral and highly reactive imimum intermediate, which influences both the LUMO-lowering... 

Aluminum salen complexes have been identified as effective catalysts for asymmetric conjugate addition reactions of indoles [113-115]. The chiral Al(salen)Cl complex 128, which is commercially available, in the presence of additives such as aniline, pyridine and 2,6-lutidine, effectively catalyzed the enantioselective Michael-type addition of indoles to ( )-arylcrolyl ketones [115]. Interestingly, this catalyst system was used for the stereoselective Michael addition of indoles to aromatic nitroolefins in moderate enantiose-lectivity (Scheme 36). The Michael addition product 130 was easily reduced to the optically active tryptamine 131 with lithium aluminum hydride and without racemization during the process. This process provides a valuable protocol for the production of potential biologically active, enantiomerically enriched tryptamine precursors [116]. 

The indole and pyrrole rings are incorporated into many biologically active molecules. Therefore, the functionalization of indole and pyrrole cores via Michael-type additions has been discussed. This chapter especially focuses on studies of the last 10 years on catalyst systems, enantioselective synthesis and the design of natural products or biological active molecules as related to Michael additions of indole and pyrrole. 

Indoles, pyrroles and carbazoles themselves are suitable substrates for palladium-catalyzed amination. An initial study of this reaction using DPPF-ligated palladium as catalyst showed that these reactions occurred readily with electron-poor aryl halides. With unactivated aryl bromides, the reaction with pyrrole or indole resulted in good yield, but reaction times were long and the temperature was 120 °C. Thus, an improved catalyst system was necessary for reactions to occur in a more general fashion and with temperature- or base-sensitive substrates. 

The sterically hindered alkylmonophosphines provide an improved catalyst system (Table 7.5) [132]. In this case, reactions occur at 100 °C over 8 h for activated or deactivated aryl bromides and with electron-poor or electron-neutral aryl chlorides. Reactions of ortho-substituted aryl halides were surprising, providing a mixture of 1-and 3-substituted indoles. However these aryl halides were suitable substrates when the 3-position of the indole was substituted. The origin of this C- versus N-arylation is unknown. 

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-... 

Furthermore, a one-pot indole synthesis starting from o-chloroiodoben-zenze was also achieved using a single catalyst system consisting of Pd(OAc)2, Cul, IPr HC1 and CS2CO3. 

Also, the pyridazino-fused ring system 124 containing an indole core can be readily synthesized upon using a Pd(OAc)2-BINAP catalyst system for the amination-CH activation sequence, as recently demonstrated by Matyus and coworkers [100,101] (Scheme 44). 

As an excellent complement to the Pd-catalyzed methodology that has been utilized in a number of applications, in general experimentally simple and inexpensive catalyst system for the N-arylation of a wide variety of azoles (pyrrole, indoles, 7-azaindole, carbazole) has been developed (Equation 37) <2001JA7727>. In particular, it was shown that the combination of air stable Cul and racemic ( )-l,2-cyclohexanediamine 186a in the presence of K3PO4 is an extremely efficient and general catalyst system for the N-arylation of a number of azoles. Competitive C-arylation under these conditions is not observed. 

The combination of palladium dibenzylidenacetone and 2-dicyclohexylphosphino-2, 4, 6 -triisopropyl-l,T-biphenyl (XPhos) in the presence of potassium phosphate (toluene or toluene/dioxane, 3 1) provides a highly active catalyst system for the efficient and selective synthesis of the A -vinylpyrroles 213 (A -vinylindoles 214) from pyrroles (indoles) and cyclic and acyclic vinyl triflates (Equations 50 and 51) <2005JOC8638>. 

In the phase-transfer catalyst system (ClCH2CH2Br/KOH/18-crown-6, toluene) indoles 218 form A -vinylindoles 219 in 42-68% yields (Equation 53) via intermediate chloroethyl derivatives. In a similar reaction the substituted oxime 220 was obtained as the only product (Equation 54) <2002CHE682>. 

Metal enolate complexes have also been used to catalyze the allylation of carbonyl compounds ° °, addition of aldehydes to l,3-dienes ° and alkynes as well as the addition of alkenes to alkynes " and indoles ". In the latter study, 5 mol% of Pd(acac)2 (29) and 10 mol% of PPhs were found to be an effective catalyst system for the coupling of Ai-methylindole (93) with a variety of 2-acetoxymethyl-substituted electron-deficient alkenes, including methyl 2-(acetoxymethyl)acrylate (94) (equation 26). Substituted indoles (95) constitute an important class of biologically active natural products and synthetic routes to these valuable compounds have therefore attracted considerable attention. 

Fortunately, this Ru catalyst was also effective for 3 substituted N Boc indoles, and the 3 methyl and 3 phenyl indoles 28a and 28b were hydrogenated to the correspond ing indolines with 87 and 94% ee, respectively [39]. This catalyst system was also extended to hydrogenation of 2,3 disubstituted indoles, and only the cis 2,3 dimethy lindoline ( ) 31 was observed with 59% yield and 72% ee (Scheme 10.29). 

A gold(I)-catalyzed tand [3,3]-rearrangement/[2+2]-cycloaddition provided cyclobutane-fused indoUnes <05JA16804>. For example, treatment of indole 163 with a gold/sUvo- catalyst system gave tetracyclic indoline 164. 

The above approach of an intermolecular ortho-alkylation followed by an intermolecular Mizoroki-Heck coupling was later extended to heteroaryl iodides by Lautens [48], Using a Pd(OAc)2/triarylphosphine catalyst system, 3-iodothiophene, -benzothiophene, and -indole were transformed to the o/t/zo-alkylation/Mizoroki-Heck coupling products in good to excellent yields (Scheme 17). Unfortunately, 2-iodoheteroaryls were found to be poor substrates for the reaction. 

Coupling reactions. A catalyst system for coupling of indoles (at C-2) with Arl is made up of Pd(OAc)2, Ag20 and the ArCOOH additive, no phosphine hgand is needed. Cinnamyl esters are s3fnthesized from Arl and allylic esters hy the Heck reaction, the... 

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