Heck reaction indoles

Asymmetric cyclization using chiral ligands has been studied. After early attempts[142-144], satisfactory optical yields have been obtained. The hexahy-dropyrrolo[2,3-6]indole 176 has been constructed by the intramolecular Heck reaction and hydroaryiation[145]. The asymmetric cyclization of the enamide 174 using (S j-BINAP affords predominantly (98 2) the ( )-enoxysilane stereoisomer of the oxindole product, hydrolysis of which provides the ( l-oxindole aldehyde 175 in 84% yield and 95% ec. and total synthesis of (-)-physostig-mine (176) has been achieved[146]. 

The development of methods for aromatic substitution based on catalysis by transition metals, especially palladium, has led to several new methods for indole synthesis. One is based on an intramolecular Heck reaction in which an... 

The best procedures for 3-vinylation or 3-arylation of the indole ring involve palladium intermediates. Vinylations can be done by Heck reactions starting with 3-halo or 3-sulfonyloxyindoles. Under the standard conditions the active catalyst is a Pd(0) species which reacts with the indole by oxidative addition. A major con.sideration is the stability of the 3-halo or 3-sulfonyloxyindoles and usually an EW substituent is required on nitrogen. The range of alkenes which have been used successfully is quite broad and includes examples with both ER and EW substituents. Examples are given in Table 11.3. An alkene which has received special attention is methyl a-acetamidoacrylate which is useful for introduction of the tryptophan side-chain. This reaction will be discussed further in Chapter 13. 

Employing Jefferey s ligandless conditions, Larock and Babu (87TL5291) synthesized quinolines and other nitrogen-containing heterocycles via the intramolcular Heck reaction strategy as exemplified by reaction 144 145. This reaction is similar to the Mori-Ban indole... 

The intramolecular Heck reaction of polymer bound aryl halides such as 84 affords indole analogs 85 after cleavage of the final product from the resin with TFA <96TL4189>, Other notable uses of the Heck cyclization include a synthesis of an antimigraine agent <96TL4289>, and thia-tryptophans <96T14975>. 

A novel route to indoles and quinolines has been developed by sequential Wiltig and Heck reactions <96CC2253>. Thus, treatment of o-bromo- or iodo-lV-lrifluoroaceiylanilines (86) with a stabilized phosphorane affords the corresponding enamines 87 as a mixture of isomers. Cyclization to 88 is effected by heating with palladium acetate, tri phenyl phosphine, and bu.se. 

Yamazaki, Kondo and coworkers [78] reported on a combination of a Heck reaction and an animation on solid phase for the synthesis of indole carboxylate 6/1-148, employing an acetylated immobilized enamide 6/1-145 and a bifunctionalized... 

In domino Sonogashira processes, the second step is usually an amination or a hy-droxylation to give y-lactones, furans, or indoles however, there is also the possibility of performing a Heck reaction as a second step. 

The Yao group has made use of a Ic type intramolecular Heck reaction to prepare the C2-symmetric dimeric indole core of chloptosin <06OL4919>. A solvent-free variation of the Bischler indole synthesis, electrophilic cyclization of a-arylamino imine tautomers prepared from aniline derived a-arylamino ketones, has been used by Menendez and co-workers for the preparation of 2-arylindoles <06SL91>. 

A few additional Pd-catalyzed schemes have been employed for Ilac type cyclization chemistry. Palladium-phenanthroline complexes were used by the Ragaini group to prepare indoles via the intermolecular cyclization of nitroarenes and alkynes in the presence of carbon monoxide <06JOC3748>. Jia and Zhu employed Pd-catalysis for the annulation of o-haloanilines with aldehydes <06JOC7826>. A one-pot Ugi/Heck reaction was employed in the preparation of polysubstituted indoles from a four-component reaction system of acrylic aldehydes, bromoanilines, acids, and isocyanides <06TL4683>. 

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]. 

The intramolecular version of the Heck reaction has been extremely fruitful, enabling elegant synthesis of many complex molecules [68, 69]. The Mori-Ban indole synthesis (Section 1.10, vide infra) is a good example of such method. In addition, Rawal et al. carried out an intramolecular Heck cyclization of pentacyclic lactam 55 with a pendant vinyl iodide moiety [70]. Employing Jeffery s ligand-free conditions, 55 was converted to a hexacyclic strychnan alkaloid precursor 56 with complete stereochemical control... 

Both inter- and intramolecular Heck reactions of indoles have been pursued and these will be considered in turn. Appropriately, Heck and co-workers were the first to use Pd-catalyzed vinyl substitution reactions with haloindoles [239]. Thus, l-acetyl-3-bromoindole (217) gave a 50% yield of 3-indolylacrylate 218. A similar reaction with 5-bromoindole yielded ( )-methyl 3-(5-indolyl)acrylate (53% yield), but 3-bromoindole gave no identifiable product. 

Somei and co-workers made extensive use of the Heck reaction with haloindoles in their synthetic approaches to ergot and other alkaloids [26, 40, 41, 240-249]. Thus, 4-bromo-l-carbomethoxyindole (69%) [26], 7-iodoindole (91%) (but not 7-iodoindoline or l-acetyl-7-iodoindoline) [40, 41], and l-acetyl-5-iodoindoline (96%) [41] underwent coupling with methyl acrylate under standard conditions (PdlOAc /PhsP/EtjN/DMF/100 °C) to give the corresponding (E)-indolylacrylates in the yields indicated. The Heck coupling of methyl acrylate with thallated indoles and indolines is productive in some cases [41, 241, 246]. For example, reaction of (3-formylindol-4-yl)thallium bis-trifluoroacetate (186) affords acrylate 219 in excellent yield [241], Similarly, this one-pot thallation-palladation operation from 3-formylindole and methyl vinyl ketone was used to synthesize 4-(3-formylindol-4-yl)-3-buten-2-one (86% yield). 

Somei adapted this chemistry to syntheses of (+)-norchanoclavine-I, ( )-chanoclavine-I, ( )-isochanoclavine-I, ( )-agroclavine, and related indoles [243-245, 248]. Extension of this Heck reaction to 7-iodoindoline and 2-methyl-3-buten-2-ol led to a synthesis of the alkaloid annonidine A [247]. In contrast to the uneventful Heck chemistry of allylic alcohols with 4-haloindoles, reaction of thallated indole 186 with 2-methyl-4-trimethylsilyl-3-butyn-2-ol affords an unusual l-oxa-2-sila-3-cyclopentene indole product [249]. Hegedus was also an early pioneer in exploring Heck reactions of haloindoles [250-252], Thus, reaction of 4-bromo-l-(4-toluenesulfonyl)indole (11) under Heck conditions affords 4-substituted indoles 222 [250], Murakami described the same reaction with ethyl acrylate [83], and 2-iodo-5-(and 7-) azaindoles undergo a Heck reaction with methyl acrylate [19]. 

Triflates also undergo Heck reactions and Gribble and Conway reported several such couplings of l-(phenylsulfonyl)indol-3-yl triflate (34) to afford 3-vinylindoles 224 [183]. Cyclohexene, allyl bromide, and methyl propiolate failed to react under these conditions, but triphenylphosphine afforded 225 in excellent yield (93%), and divinyl carbinol yielded the rearranged enal 226 (82% yield). 

The vinyl triflate of Komfeld s ketone has been subjected to Heck reactions with methyl acrylate, methyl methacrylate, and methyl 3-(Af-rerf-butoxycarbonyl-lV-methyl)amino-2-methylenepropionate leading to a formal synthesis of lysergic acid [259]. A similar Heck reaction between l-(phenylsulfonyl)indol-5-yl triflate and dehydroalanine methyl ester was described by this research group [260]. Chloropyrazines undergo Heck couplings with both indole and 1-tosylindole, and these reactions are discussed in the pyrazine Chapter [261], Rajeswaran and Srinivasan described an interesting arylation of bromomethyl indole 229 with arenes [262]. Subsequent desulfurization and hydrolysis furnishes 2-arylmethylindoles 230. Bis-indole 231 was also prepared in this study. 

Several intramolecular Heck reactions involve aryl halides cyclizing onto indole rings. Grigg first described the simple Heck cyclizations of 254 and 255 [270], and this was followed by similar Heck reactions reported by Kozikowski and Ma on the bromide corresponding to 254 and the IV-benzylindole 256 [271,272]. These investigators also observed cyclization to the C-3 position in a Heck reaction of indole 257, and they prepared a series of peripheral-type benzodiazepine receptors 258 using this chemistry. For example, 258 (n = 3, R = n-Pr) is obtained in 81% yield. 

Whereas Hegedus [335] and Danishefsky [336] were the first to discover a tandem Heck reaction from o-allyl-A -acryloylanilines leading to tricyclic pyrrolo[l,2-a]indoles or pyridino[l,2-a]indoles [336], it has been the fantastic work of Grigg to unleash the enormous potential of this chemistry. Grigg and his co-workers parlayed their Pd-catalyzed tandem polycyclization-anion capture sequence into a treasure trove of syntheses starting with IV-allyl-o-haloanilines [337-345], Diels-Alder and olefin metathesis reactions can be interwoven into the sequence or can serve as the culmination step, as can a wide variety of nucleophiles. An example of the transformation of 289 to 290 is shown below in which indole is the terminating nucleophile [340],... 

A related Heck reaction of substituted o-bromoacetanilides with styrenes followed by selenium-induced cyclization of the resulting o-styiylacetanilides gives 2-arylindoles [378], Substituted o-bromonitrobenzenes react with ethyl vinyl ether under the influence of Pd(OAc)2 to give the corresponding o-ethoxyethenylnitrobenzenes. Zinc reduction then yields indoles [379]. The one-step Pd-catalyzed conversion of o-bromoanilines to indoles 302 with enamines (or with A/-vinyl-2-pyrrolidone) has been reported [380]. 

Ogasawara employed a Heck reaction of o-iodoaniline derivatives with dihydrodimethoxyfuran and vinylene carbonate to give intermediates that are readily cyclized to indoles with acid [381-383]. An example is shown below [381]. 

Several groups intercepted the indole-palladium complex that is initially obtained on cyclization by a subsequent Heck reaction. As will be seen, this can be a powerful elaboration of indoles. In the first example of this concept, Utimoto and co-workers ambushed intermediate 354 with a series of allylic chlorides to give 355. Normal acid workup yields the corresponding C-3 unsubstituted indoles (52-83%) [310]. 

The research group of Cacchi made extensive use of these tandem cyclization-Heck reactions to prepare a wide variety of indoles [311-314], For example, vinyl triflates react with o-aminophenylacetylene to afford an array of 2-substituted indoles in excellent yield, e.g., 356 to 357 [312], and a similar reaction of 358 with aryl iodides leads to an excellent synthesis of 3-arylindoles 359 [313],... 

In a synthetic route to the E-azaebumane series, an intramolecular heteroaryl Heck reaction was the major cyclization strategy [140], Under Jeffery s ligand-free conditions, E-azaebumane skeleton 182 was prepared from bromopyridine 181. The migratory insertion occurred at C(2) of the indole ring. 

While the intramolecular Heck reaction has been widely used to synthesize indoles and benzofurans, not many applications have been found in the preparation of benzothiophenes because of the thiophilicity of the Pd(II) species. Pleixats and coworkers treated iodophenylsulfide 151, obtained from o-iodoaniline and crotyl bromide in two steps, with... 

An intramolecular Heck cyclization strategy was developed for the construction of indole and benzofuran rings on solid support [82], enabling rapid generation of small-molecular libraries by simultaneous parallel or combinatorial synthesis. Sn2 displacement of resin-bound y-bromocrotonyl amide 97 with o-iodophenol 96 afforded the cyclization precursor 98. A subsequent intramolecular Heck reaction using Jeffery s ligand-free conditions furnished, after double bond tautomerization, the resin-bound benzofurans, which were then cleaved with 30% TFA in CH2CI2 to deliver the desired benzofuran derivatives 99 in excellent yields and purity. 

The Heck reaction on polymer-bound iodoarenes is assisted by the addition of a catalytic amount of tetra-n-butylammonium bromide and has been employed in the synthesis of 4-carboxycinnamic esters and amides [33], and 4-aminosulphonyl-cinnamic esters [34], It has also been reported that the presence of an equimolar equivalent of benzyltriethylammonium chloride aids the Pd(II)-mediated reaction of A -acyl-2-iodoanilines with vinylidene carbonate, which leads to A -acyl-2-hydroxy-indolines providing a convenient route to the indoles (80-90%) [35], The catalysed reaction of 2-hydroxy- and 2-tosylaminoiodobenzene with 1,2-dienes produces 1,2-dihydrobenzofurans and 1,2-dihydroindoles, respectively [36]. 

The intramolecular Heck reaction is useful for the construction of complex natural products [241] and for the synthesis of indoles [242] benzofurans [243] quinolines [244] and benzazepines [245]. 

Intramolecular Heck reaction of o-halo-aniline with pendant olefin to prepare indole. 

Kalinski C, Umkehrer M, Schmidt J, Ross G, Kolb J, Buidack C, Hiller W, Hoffmann SD (2006) A novel one-pot synthesis of highly diverse indole scaffolds by the Ugi/Heck reaction. Tetrahedron Lett 47 4683 686... 

Umkehrer M, Kalinski C, Kolb E, Burdack C (2006) A new and versatile one-pot synthesis of indol-2-ones by a novel Ugi-four-component-Heck reaction. Tetrahedron Lett 47 2391-2393... 

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