2,3-functionalized indoles

The Ti coordination via the carbocycle prevails for indole and carbazole, although the species were also found in organomanganese and -iridium chemistry. Osmium carbonyls tend to produce the species with the bridging indole function. Some illustrations of the ti N) coordination exist. 

Using derivatized glycine usually lowers the yields compared with sarcosin -nevertheless various functionalized glycine derivatives have been used. Amine 245, obtained by reaction of a trimethoxy-indole functionalized amino acid with an aliphatic co-amino-aldehyde, has been coupled with an oligonucleotide to increase the affinity of Cjq conjugates to certain nucleic acids (Figure 4.13) [288]. 

Figure 4.13 Amine 245 was obtained by reaction of a trimethoxy-indole functionalized amino-acid with an a-aminoaldehyde.

If Trp residues are present in the molecule, it is advisable to protect the indole function in order to suppress possible side reactions. For this purpose usually the A "-formyl derivative is used which is removed by rapid base treatment without affecting the disulfide bonds already formed 118 ... 

Indoles (functionalized with a phos-phoylide group) (Table 2) are other N-coordinated ligands and behave as the most effective neutral electron-releasers with reported Pi values (—0.92 to -1.0 V) [28]. 

Some research groups have exploited the intrinsic reactivity of the bicycloadducts formed in the pyran-2-one Diels-Alder reactions. An example of this strategy is shown in Scheme 33, where the pyran-2-one decorated with indole functionality 255 was reacted with an assortment of electron-rich and electron-poor dienes <2000T5205>. The richly functionalized bicyclo[2.2.2]adduct 256 was then subjected to mild aminolysis to produce tetrasubstituted hexene 257 as single diastereoisomers. 

In the course of the reactions, the other functional groups are also derivatized. Hydroxyamino acids and Tyr react with alkyl chloroformate with the formation of carbonate esters, Cys and CysH provide thiocarbonates, and the imidazole nitrogen of His is also protected. The indole functional group of Try does not change, Pro forms a stable carbalkoxydithiocarbamate and Arg does not provide any volatile product. The derivatives were separated successfully (except the pair Leu-De) on 5% of QF-1 with temperature programming (94-235°C). The reproducibility of the method was stated to be 5%. Using an FID and ECD, 10-10 and 10-13 mol of amino acids, respectively, can be determined. 

Indole and several indoles functionalized at C-2 were condensed with aziridines, vinylaziridines, oxiranes, and vinyloxiranes in the solid state on the surface of silica (Equations 134 and 135) <2005JOC3490>. 

The formyl group is routinely used for the protection of the tryptophan indole function in Boc/Bzl chemistry in solution and on solid support (see Section 2.6.3), and cleavage of the A -formyl derivative with HF/ethane-l,2-dithiob ° l or TFA/2-sulfanylethanoh ° l as well as by exposure to alkaline conditions (pH is well established. Less detailed information... 

Davies has further exploiled his previously reporied approach to (he tropanc skeleton related to cocaine based on the rhodium catalyzed decomposition of the vinyidiazomethane 81 in the presence of A/-Boc-pyrroIe (82) <01BMCL487>. Reduction of the non-conjugated double bond followed by A -deprotection and N-alkylation provided substrate 83 which was susceptible to conjugate addition of nucleophiles such as 84 in the presence of CuBr to afford 3-p-aryl tropanes which exhibited potent binding affinity for both the dopamine and serotonin transporters. Additionally, this author described the synthesis of various methyl heteroaryldiazoacetate analogues of 81, (me of which possessed an indole function, for use in catalytic asymmetric cyclopropanations . 

Unconventional activation techniques could also be used for indole functionalization. Within 10 min, including reaction and purification time, 3-p3rranyl indole derivatives could be obtained with good yields, through one-pot microwave-assisted reactions, with InCls as catalyst (Figure 18) [37]. Indolyl chalcones could be prepared from indole-3-carboxaldehyde and heteroaryl active methyl compounds under conventional heating, but the yield was much improved and reaction time was drastically reduced (from more than 9 h to less than 15 min) when microwave irradiation was introduced [38]. Ultrasounds aid the selective formation of... 

Scheme 4.71 General overview of the indol-functionalization of iV-vinyl pyrrolidone...

Scheme 4.73 Heck conditions for the indol-functionalization of vinyl pyrrolidone III-92...

Scheme 4.75 Larhed conditions fen the indol-functionalization of enamide ni-92...

It was carried out some conversions of 5-acetyl-2-ethoxycarbonyl-3-p-nitrophenyl indole functional groups, particularly by reduction of nitrogroup was obtained corresponding amine and its condensation products with catbortyl compounds, mono and diacetyl derivatives. 

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 nucleophilicity of the nitrogen atom survives in many different functional groups, although its basicity may be lost. Reactions of non-basic, but nucleophilic urea nitrogens provide, for example, an easy entry to sleeping-pills (barbiturates) as well as to stimulants (caffeine). The nitrogen atoms of imidazoles and indole anions are also nucleophilic and the NH protons can be easily substituted. 

One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

Fischer indole cyclizations incorporating functionalized substituents... 

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