Malonates reaction with indole

Rainier devised a variant of the 5-exo-dig radical cyclization of 2-alkynylisocyanides 122 wherein thiols were utilized to both initiate the radical cascade as well as act as nucleophiles in the reaction with the indolenine intermediate 123 yielding the indoles 124 . When R = TMS, elimination of the C-10 thioether can be effected in a gramine-like fashion so as to add nucleophiles (e.g., malonate anion) in the presence of Bu3P allowing for the preparation of more highly functionalized indoles. 

The previously described lanthanide triflate promoted ring opening of indoles 115 with 1,1-cyclopropanediesters 116 has been extended to provide an annulation reaction of indoles, wherein nucleophilic ring opening by the indole C-3 followed by attack of the intermediate malonic enolate 117 on the iminium moiety to afford the annulated products 118 <99TL5671>. 

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonate[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7]. Deformylation and reduction leads to 2-sub-stituted indoles. 

HF calculations with the 6-31G(d) basis set were used to study the mechanism of the Michael addition (or Friedel-Crafts alkylation) reaction of indole with dimethyl alkylidenemalonate. This reaction proceeds through two transition states, TSi and TS2 in the first step, assumed to be rate determining, the new C-C bond is formed, whereas in the second step, proton transfer from indole to malonate occurs with the formation of the new C-H bond. The calculations show that the transfer and interaction of the 7r-electrons in the reactant molecules may play an important role in the cleavage of the original C=C bond and the formation of the new bonds (C-C and C-H) the electron transfer is believed to be the driving force for the reaction to occur. 

Gramme is a common precursor for indol-3-ylmethylation of enolates and other nucleophiles. Such reactions normally occur by an elimination-addition mechanism. Following development of procedures for 4-substitution via directed lithiation with l-(tri-/w-propylsilyl)-gramine, Iwao and Motoi have developed conditions for tandem nucleophilic substitution of the dimethylamino group. Quatemization followed by reaction with a nucleophile in the presence of TBAF leads to alkylation. <95TL5929> The carbon nucleophiles which were successfully used include nitromethane, methyl acetoacetate, diethyl malonate and diethyl 2-(acetamido)malonate. Phthalimide, thiophenol, TMS-CN and TMS-Nj were also used as sources of nucleophiles. 

The enantioselective reactions of indoles using alkylidene malonates gave the alkylation products 92 in excellent yield and with moderate ee. 

Nitro-l-(phenylsulfonyl)indole undergoes nucleophilic substitution reactions with enolates, for example, of diethyl malonate and cyclohexanone (Scheme 77), to afford the corresponding 3-substituted 2-nitroindoles <1997TL5603, 1999TL7615>. Similar S -type displacements of phenylsulfinate work very efficiently in an intramolecular sense (e.g., Scheme 78) <1999PHC45>. 

Radicals such as benzyl and hydroxyl are unselective in their interaction with indoles, resulting in mixtures of products, so such reactions are of little synthetic use. On the other hand, benzoyloxylation of N-substituted indoles gives benzoates of indoxyl, i.e. it effectively oxidises the indole heterocyclic ring, via p-attack by the strongly electrophilic benzoyloxy-radical. In contrast, the weakly electrophilic radical derived from malonate reacts selectively at C-2, via an atom-transfer mechanism." "... 

Subsequently, Fu and co-workers synthesized a series of easily accessible heteroarylidene malonate-derived bis(oxazoline) ligands 71 and 72 and their Cu complexes were found highly efficient for the catalytic AFC reaction of indoles with diethyl alkylidene malonates (Scheme 6.28). The corresponding addition products were obtained in good to excellent yields (70-99%) with up to 99.5% ee. 

Scheme 6.29 Cu"-bis(oxazoline) complex catalyzed AFC reaction of indoles with trifluoroethylidene malonates 78 reported by Lu.

The following results are not shown in the schemes but will be discussed. The reaction of unsubstituted indole 128 with benzylidene ethyl malonate 184b (where Ar = Ph) afforded a 50% yield and 85% ee of (< -186b (where Ar = Ph) at 0 °C, but with coaddition of 2 equiv (CF3)2CHOH, a clearly faster reaction with a higher yield (99%) and improved enantiocontrol (85% ee) was observed. The lower reaction temperature, however, appeared to be responsible for the improved stereocontrol. When the same reaction... 

Friedel-Crafts Alkylation. The Pr-bisoxazoline-Cu(OTf)2 system is an efficient catalyst in Friedel-Crafts alkylation of indole (eq 17) with arylidene malonates. Using 10 mol of Cu(OTf)2 in FBuOH, the 5-enantiomer was obtained in yields ranging from 50 to 94% and with 97% ee (eq 17, R = H, Ri = Et). The opposite enantiomer was obtained at 0°C by using CH2CI2 or 1,1,2,2-tetrachloroethane as solvent, in up to 78% ee. The Cu(OTf)2-Pr-bisoxazoline system also proved to be efficient for the asymmetric Friedel-Crafts reaction of indole derivatives with arylidene mal-onates. 

Pyrrole- and indole-carboxylic acid chlorides react with dialkyl- and diaryl-cadmium to yield the ketones and it is noteworthy that the reaction of the anhydride of indole-2,3-dicarboxylic acid with diphenylcadmium produces 3-benzoylindole-2-carboxylic acid and not its isomer (53JCS1889). The ability of l-methylindole-2-carboxylic acid to react with nucleophiles is enhanced by conversion into the mixed anhydride with methanesulfonic acid. The mixed anhydride reacts with carbanions derived from diethyl malonate and from methyl acetate to yield the indolyl (3- keto esters (80TL1957). 

Methyl-2-diphenylphosphino-3-(l -isoquinolyl)indole with pallada-cycle derived from dimethyl-1-naphthyl ethylamine and potassium hexa-fluorophosphate yields chelate 310 (97T4035). With [(r)3-PhCH = CH = CHPh)Pd( j.-Cl)]2, allyl 311 follows in the presence of silver tetrafluor-oborate. Addition of ligands 312 (R = R1 = H, Me) to [(r 3-PhCHCHCHPh)Pd (Cl) ]2 under conditions of allylic alkylation of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate leads to the formation of P,N-chelates 313 (R = R1 = H, Me), the active species of the catalytic reaction (00T(A)4753). 

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