Indole double bond

An excellent synthesis of 5-bromo- (18) and 5-iodoindole (19) involves protecting the indole double bond as sulfonate 16, acetylation to 17, and halogenation [27]. Indoline itself undergoes bromination at C-4 and C-7 [28]. 

Snieckus described short syntheses of ungerimine (121) and hippadine by Suzuki couplings of boronic acid 118 with 7-bromo-5-(methylsulfonyloxy)indoline (116) and 7-iodoindoline (117), respectively [130]. Cyclization and aerial oxidation also occur. Treatment of 119 with Red-Al gave ungerimine (121) in 54% yield, and oxidation of 120 with DDQ afforded hippadine in 90% yield. Indoline 116 was readily synthesized from 5-hydroxyindole in 65% overall yield by mesylation, reduction of the indole double bond, and bromination. Indoline 117 was prepared in 67% yield from N-acetylindoline by thallation-iodination and basic hydrolysis. 

The partial synthesis70 of macroline (136) from normacusine B (140) was inspired by its postulated biosynthesis from a sarpagine-type precursor. Normacusine B (140), prepared by a previously published route from perivine, was protected at the primary alcohol group and then methylated on Na. Direct epoxidation of the product (141) failed however, osmylation gave the desired diol together with the related oxindole obtained by simultaneous oxidation of the indole double-bond, followed by rearrangement. Conversion of these diols into the related epoxides gave a mixture of (142) and (143), from which the desired epoxide (142) could be separated satisfactorily by fractional crystallization. 

Our group has also encountered success in cycloadding an isomiinchnone dipole across an indole double bond [28]. Cycloadduct 91 was generated in high yield as a single diastereomer from the Rh2(OAc)4-catalyzed reaction of diazoimide 90. The assignment was unequivocally established by an X-ray crystal structure. The ready construction of these poly-heterocycles in one step and in... 

In an analogous manner the indole double bond in VIII/203 was opened oxidatively (02, rose Bengal, 200 W halogen lamp, CH3OH/CH2Cl2, 25, 5 h) and the desired eight-membered lactam VIII/204 was isolated in 82% yield [118]. Compound VIII/204 is an intermediate in a synthetic approach to the potent antitumor antibiotic mitomycin A (see Chapter VIII.2). 

However, Sauer and coworkers have been able to reduce selectively the styrene double bond in ergoline derivative (17) without affecting the indole double bond (equation 50). ... 

A related procedure utilizes zinc dust amalgam and HCl. Thus, several indoles are reduced to indolines in excellent yield (equation Somewhat similarly, the facile reduction of the indole double bond... 

As will be seen in this section, mixed boron hydrides and complexes of boron probably represent the most general and efficient reagents for the reduction of the indole double bond. 

Only those indoles that are sufficiently basic to be protonated by acetic acid are reduced under these conditions. Thus, 5-nitroindole and 2,3-diphenylindole are recovered unchanged,whereas 5,6-dimeth-oxyindole is cleanly reduced to 5,6-dimethoxyindoline in 86% yield with NaBHsCN/HOAc. " This differential reactivity has been exploited by Cava and Rawal in their synthesis of CC-1065 analogs in which only the more basic double bond in (23) is reduced (equation 61).Indeed, this same tactic has since been utilized by Boger," Moodyand Sundberg, and their coworkers, in their respective synthetic efforts towards CC-1065 and the related phosphodiesterase inhibitors PDE-I and PDE-II. Likewise, Joule and coworkers have utilized NaBHsCN/HOAc in a chemoselective reduction of the more basic indole double bond in benzodipyrrole (24 equation 62). ... 

Zagorevskii et al. have observed the same stereoselective trans reduction with several tetrahydro-T-carbolines by generating the diborane from NaBIlt in situ (equation 79).As expected, treatment of these carbolines with pyridine-borane and acid gives the cw-fused isomers (equation 80).Bosch and coworkers have also utilized an in situ generation of diborane to effect the chemoselective reduction of the indole double bond during the synthesis of a new indolomorphan. 

Chu and coworkers observed that the indole ester (26) can be reduced selectively using pyridine-bo-rane/HCl (equation 81), but Fritz and coworkers found that the same conditions reduce both the indole double bond and the carbonyl group in ketone (27 equation 82) but only the indole double bond in amide (28 equation 83). ... 

Madindoline A and (-)-madindoline B are potent and selective inhibitors of interleukin 6. The relative and absolute configuration of these natural products was determined by means of their total synthesis by A.B. Smith and S. Omura." The key step was the SAE of the indole double bond, which led to the formation of the hydroxyfuroindole ring of both compounds. 

Alkylation of aromatic amines. Reduction of indole (1) with sodium borohydride in acetic acid results in reduction of the indole double bond and alkylation of the nitrogen atom to give N-ethylindoline. The reaction can be carried out in two steps (1) (3) (2). 

Although Maier achieved the first intramolecular 1,3-dipolar cycloaddition reaction of an isomunchnone, it was Padwa who unleashed the synthetic utility of this reaction. Thus Padwa and co-workers also found that isolated 7t-bonds can successfully and efficiently capture the in situ-generated isomunchnones, as shown by the examples 518 519 (Fig. 4.156). The alkene can also be tethered adjacent to the nitrogen atom (not shown). The indole double bond in 520 intercepts an isomunchnone 1,3-dipole to give the single diastereomer 521, the stmcture of which is supported by X-ray crystallography. 

As indicated previously, in similar fashion, indole analog 520 undergoes a smooth cycloaddition, via an isomunchnone intermediate, to adduct 521 (Fig. 4.156). Unfortunately, attempts to apply this chemistry to a synthesis of the alkaloid vallesamidine 534 were not successful (Fig. 4.161). Thus diazo imides 533 failed to cyclize onto the indole double bond via the corresponding isomunchnone. 

Indole Derivatives , wherein the versatile indole double bond can serve as either dienophile or part of a diene. 

Boronic acid 225 and alkenylindole 226 underwent a domino 1,4-addition/intramolecular Diels—Alder cycloaddition/protodeboronation sequence to furnish indole twistenedione 227 in 40% yield. The boronic acid moiety is critical to promote the regioselective 1,4-addition, which generates an appropriately reactive dienolate. The indole double bond of... 

Reduction of the indole double bond using sodium cyanoborohydride in glacial acetic acid. The use of sodium borohydride leads to reduction and N-alkylation. 

All doubts as to the correctness of the structure of lysergic acid were removed by a synthesis first of all of rac-6,8-dimethylergoline and then rac-dihydrolysergic acid but the comparisons were made difficult because of the production of isomers (three asymmetric centres are involved). The early approaches to the synthesis of lysergic acid itself were frustrated by its tendency under acidic conditions to isomerize irreversibly into the isomeric naphthalene . A synthesis was finally accomplished in a simple elegant manner in which the key concept was the introduction of the indolic double bond as the last step (Chart 4.7). 

The indole double bond does not initiate the cascade and serves only as the dipolarophile. However, under certain conditions, usually when the alkene dienophile is bulky, the indole does react with the oxadiazole first (Scheme 16.105) [201]. This reaction takes a different course and the intermediate does not react with the remaining alkene. Nevertheless, this example illustrates that the indole may be able to initiate a cascade [4 + 2]/[3 + 2] cycloaddition. 

Reduction of indole double bond of Trp Use Fmoc-Trp(Boc)-OH, and avoid use of triethyl silane (TES)... 

The reduction of several indolo[2,3-a]quinolizidines by BY gave novel products resulting from reduction of the indole double bond, cleavage of the C-D ring junction, or reduction of a lactame to a carbinol amine [371]. The known reduction of aromatic nitro compounds has been used as a key step in the synthesis of 2-aryl-2/f-benzotriazoles. Thus, treatment of the o-nitrophenylazo dye 342 gave the 2-aryl-2/7-benzotriazole-l-oxides 343 in good yields [513]. 

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