Indoles 3-olefinic

SCHEME 13.14. A paUadium-catalyzed intramolecular indole olefination in the total synthesis of the toxic metabolites (+)-austamide 62 and (-l-)-deoxyisoaustamide 61. 

The reaction conditions applied are usually heating the amine with a slight excess of aldehyde and a considerable.excess of 2d-30hydrochloric acid at 100 °C for a few hours, but much milder ( physiological ) conditions can be used with good success. Diols, olefinic double bonds, enol ethers, and glycosidic bonds survive a Pictet-Spengler reaction very well, since phenol and indole systems are much more reactive than any of these acid sensitive functional groups (W.M. Whaley, 1951 J.E.D. Barton, 1965 A.R. Battersby, 1969). 

The reactions of enamines with positively activated olefins have been extended to arylations with />-quinones (350,362-369) and quinone sulfoni-mides (365-368,370). Thus a new pathway for the facile formation of benzofurans and indoles became available. 

The Hegedus indole synthesis involves one of the earlier (formal) examples of olefin hydroamination. An ortho-vinyl or ortho-nllyl aniline derivative 1 is treated with palladium(II) to deliver an intermediate resulting from alkene aminopalladation. Subsequent reduction and/or isomerization steps then provide the indoline or indole unit 2, respectively. 

Pyrano[3,4-i]indol-3-one (329) enters the Diels-Alder reaetion with methoxy-butenone as an eleetron-rieh olefin [92JCS(P1)415]. After deearboxylation of the primary adduet330,2-aeetyl-3-methoxy-l, 9-dimethyl-2,3-dihydroearbazole (331) eliminates methanol to form 2-aeetyl-l,9-dimethylearbazole (332) [92JCS (Pl)415]. 

The high enantioselectivity again can be rationalized by enantioface-selective alkene coordination in 63 (Fig. 35). The olefin moiety is expected to bind trans to the upper imidazoline moiety [70,73] thereby releasing the catalyst strain. Coordination at this position may, in principal, afford four different isomers assuming the stereoelectronically preferred perpendicular orientation of the alkene and the Pt(II) square plane. In the coordination mode shown, steric repulsion between both olefin substituents and the ferrocene moiety is minimized. Outer-sphere attack of the indole core results in the formation of the product s stereocenter. 

Huang H, Peters R (2009) A highly strained planar chiral platinacycle for catalytic activation of internal olefins in the Eriedel-Crafts alkylation of indoles. Angew Chem Int Ed 48 604-606... 

Diels-Alder reaction of the 1,3,4-oxadiazole with the pendant olefin and loss of N2, the C2-C3 7t bond participates in a subsequent 1,3-dipolar cycloaddition with the carbonyl ylide to generate complex polycycles such as 45 as single diastereomers with up to six new stereocenters. That the cascade reaction is initiated by a Diels-Alder reaction with the alkene rather than with the indole is supported by the lack of reaction even under forcing conditions with substrate 46, in which a Diels-Alder reaction with the indole C2-C3 n bond would be required [26a]. 

The Fukuyama indole synthesis involving radical cyclization of 2-alkenylisocyanides was extended by the author to allow preparation of2,3-disubstituted derivatives <00S429>. In this process, radical cyclization of 2-isocyanocinnamate (119) yields the 2-stannylindole 120, which upon treatment with iodine is converted into the 2-iodoindole 121. These N-unprotected 2-iodoindoles can then undergo a variety of palladium-catalyzed coupling reactions such as reaction with terminal acetylenes, terminal olefins, carbonylation and Suzuki coupling with phenyl borate to furnish the corresponding 2,3-disubstituted indoles. 

This is opposed to attack of the indole onto the Pd-coordinated, hence activated, olefin (Equation (164)). 

A closely related dicationic platinum complex has been shown to transform efficiently /3-citronellene into cis-thujane in a highly diastereoselective manner, which mimics terpene biosynthesis.362 Also, using platinum(n) catalysis, Widenhoefer has reported an intramolecular alkylation of indoles with unactivated olefins, which can be carried out in an enantioselective fashion (Scheme 99).363... 

Indole from the Union Carbide Olefins Company, Institute, West Virginia, is satisfactory. 

Among early reported Pd-catalyzed reactions, the Mori-Ban indole synthesis has proven to be very useful for pyrrole annulation. In 1977, based on their success of nickel-catalyzed indole synthesis from 2-chloro-fV-allylaniline, the group led by Mori and Ban disclosed Pd-catalyzed intramolecular reactions of aryl halides with pendant olefins [122]. Compound 102, easily prepared from 2-bromo-lV-acetylaniline and methyl bromocrotonate, was adopted as the cyclization precursor. Treatment of 102 with Pd(OAc)2 (2 mol%), Ph3P (4 mol%) and NaHCQ3... 

With Pd(0) generated in situ, the oxidative addition of aryl bromide 102 to Pd(0) proceeds to form Pd(II) intermediate 104. Migratory insertion of 104 then occurs to furnish the cyclized indoline intermediate 105. Subsequent reductive elimination of 105 takes place in a cis fashion, giving rise to exo-cyclic olefin 107, which then tautomerizes spontaneously to the thermodynamically more stable indole 103. The reductive elimination by-product as a palladium hydride species 106 reacts with base, regenerating Pd(0) to close the catalytic cycle. 

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],... 

Abstract Aldehydes obtained from olefins under hydroformylation conditions can be converted to more complex reaction products in one-pot reaction sequences. These involve heterofunctionalization of aldehydes to form acetals, aminals, imines and enamines, including reduction products of the latter in an overall hydroaminomethylation. Furthermore, numerous conversions of oxo aldehydes with additional C.C-bond formation are conceivable such as aldol reactions, allylations, carbonyl olefinations, ene reactions and electrophilic aromatic substitutions, including Fischer indole syntheses. 

If the hydroformylation of olefins is conducted in the presence of aromatic hydrazines and Bronsted or Lewis acids indoles can be obtained directly in one pot [91-93,95]. Hydroformylation of the olefin gives an intermediate aldehyde, which is trapped immediately by the present aromatic hydrazine as an aromatic hydrazones similar to the formation of imines under hydroformylation conditions. Under acid mediation these aromatic hydrazones undergo a Fischer indolization, consisting of a [3,3]-sigmatropic rearrangement followed by a cyclization and elimination of ammonia (Scheme 38). 

General Procedure for the Hydroformylation/Fischer Indole Synthesis. Synthesis of Tryptamine Derivatives in Water. Aminoolefin (1 eq), aromatic hydrazine (1 eq), Rh(acac)(CO)2 (0.3 mol %) and TPPTS (1.5 mol %) are dissolved in H2SO4 (4wt% in H2O, 2.5 wt % olefin), filled in an autoclave and pressurized with lObar H2 and 50 bar CO. After stirring for 3 days at 100 °C ammonia (30 wt% in water) is added and the mixture is extracted with EtOAc. The solvent is evaporated to give the product which purified by column chromatography (silica, CH2C12, PrOH, NEt3) if necessary. 

Even 2,3-disubstituted indoles can be achieved if internal olefins are used. Regioselective hydroformylation of a styrene-type olefin and subsequent hy-drazone formation and Fischer indolization gives an intermediate indole with a quaternary center in 3-position. The regained aromaticity is the driving force for the rearrangement of one substituent into the 2-position of the indole core (Scheme 39). 

Recendy, we found that A -allyl-o-vii rlaniline 44 gave 1,2-dihydroquinoline 45 by normal RCM and developed silyl enol ether-ene metathesis for the novel synthesis of 4-siloxy-1,2-dihydroquinoline and demonstrated a convenient entry to quinolines and 1,2,3,4-tetrahydroquinoline [13], We also have found a novel selective isomerization of terminal olefin to give the corresponding enamide 46 using rathenium carbene catalyst [Ru] and silyl enol ether [14], which represented a new synthetic route to a series of substituted indoles 47 [12], We also succeeded an unambiguous characterization of mthenium hydride complex [RuH] with ACheterocyclic carbene... 

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

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