Indole derivatives bond activation

Investigation of a related indole template, however, yielded potent compounds, as exemplified by the sulphonamide derivative (33). Activity was improved further by introducing steric constraints to the sidechain and introduction of a 7-methyl substituent on the indole ring, leading to compound (34) [82]. Derivatives generally possessed only moderate pharmacokinetic properties however (clearance 25-45 ml/min/kg in dog), which was attributed to metabolic vulnerability of the indole (C2-C3) double bond. Attempts to block metabolism by C2, C3 di-methyl substitution resulted in the loss of oxytocin activity. 

An unusually facile hydroxydemethoxylation reaction has been reported for 1-benzoyl-4-methoxynaphthalene. The use of 0-enriched hydroxide confirmed that reaction occurs by the NAr pathway rather than by cleavage of the oxygen to methyl bond. A related reaction is observed in 3-(4-methoxy-l-naphthoyl)indole derivatives. These results indicate the possibility of SnAt activation by a 4-carbonyl group the reaction is facilitated by use of a naphthyl ketone as substrate and DMSO as solvent. ... 

Triple bonds are in general more reactive than double bonds as is exemplified in the following process (1.2.).13 The active catalyst is HPdOAc, which is formed by the oxidative addition of acetic acid onto Pd(0). The organic substrate is attached to the palladium in a regio- and stereospecific step that is followed by an oxidative addition (N.B. Pd(II)-Pd(IV) transition) and reductive elimination, or alternatively carbopalladation and reductive elimination, to give the indole derivative. 

Although not fitting exactly into the scope of this book, the iridium catalyzed borylation of five membered heterocycles through C-H bond activation also deserves mentioning. A recent report by Miyaura disclosed the reaction of bis(pinacolato)diboron with heteroaromatic systems, where thiophene, fiirane and pyrrole were converted to their 2-boryl derivatives with good selectivity (6.86.), The yields presented refer to the diboron compound since the heterocycles were used in excess in all cases. Indole, benzofurane and benzothiophene were monoborylated with similar efficiency.116... 

Corey et al. recently revived this useful transformation in the syntheses of several tryptophan-derived natural products [134]. For eiample, an unusual paUadium(II)-catalyzed ring closure under an atmosphere of dioxygen followed by ring enlargement (cf Scheme 7.54) is the key step in the total synthesis of okaramrne N (217) (215 216 Scheme 7.52). This transformation is particularly remarkable because C—H bond activation is chemoselective the unprotected indole unit reacted whereas the N-protected indole remained untouched during the catalysis. 

Reaction of the cyclometallated derivative of phenyl-2-pyridylketone 73 leads to indenol-chelated, palladium-containing derivatives 74. Here, incorporating an electrophilic (CO) function in the starting palladacycle signifies that, following alkyne insertion in the Pd-C bond, an intramolecular attack of the vinyl palladated unit on the metal-bound, activated CO function occurs. This is in sharp contrast to the reaction described in Scheme 9 whereby incorporating a nucleophilic, masked, secondary amine function leads to indole derivatives 40 and to the azepinium synthesis from the metallated benzylpyridine complex 34. Therefore, these reactions are rather sensitive to the nature of other potentially reactive functions within the metallacyclic framework. 

The reaction relies on the fast oxidative addition of the N-O bond onto Pd(0) providing an electrophilic Pd(ll) metal center, which subsequently undergoes aromatic C-H activation. Final reductive ehmination provides the indole derivatives in good yields. 

A novel three-component coupling reaction for the synthesis of 2-(aminomethyl) indoles and polycyclic indole derivatives from readily available N-protected ethynylanilines, amines, and aldehydes was reported by Ohno, Fujii, and coworkers. This is the first copper catalytic multicomponent construction of an indole ring that produces water as the only by-product. Two C-N bonds and one C-C bond are formed, whereas C(sp)-H bonds of alkynes and C(sp )-H bonds of aldehydes were activated in this reaction [45-48] (Scheme 8.19). 

Zou, Zhang et cd. developed an efficient Cu(OAc)2-catalyzed synthesis of indolo[l,2-c]quinazoline derivatives using environmentally friendly air as the oxidant (Scheme 8.104). Various indolo[l,2-c]quinazoline derivatives could be generated from readily available 2-(2-halophenyl)-LW-indoles and (aryl)methanamines in moderate to good yields via C(sp )-H bond activation [178]. 

Driver and coworkers reported on iridium-catalyzed Af-heterocyclization by benzylic C-H bond activation [154]. In this case, treatment of an ort/ro-substituted aryl azide with a catalytic amount of [lr(OMe)(cod)]2 (2mol%) at 25 C gave a mixture of the corresponding aniline, indole, and indoline in 19, 13, and 58% yield, respectively, for a total yield of 90% (Scheme 11.6). The introduction of the electron-withdrawing CF3 group on the aryl substituent led to indoline derivatives in high yield with high selectivity. 

SOMO catalysis, which has been the subject of considerable attention in recent years, is a unique and versatile activation mode that can participate in bond construction with various n-rich nucleophiles. The first asymmetric intramolecular a-arylation of aldehydes was reported by Nicolaou in 2009 using organo-SOMO catalysis [17a]. The authors applied imidazolidinone 23 as catalyst and cerium ammonium nitrate (CAN) as the oxidant Various 5-oxopentylbenzenes 36, or indole derivatives 38, could furnish the cyclic products 37 or 39, respectively, in good yields and with excellent ees (Scheme 36.11). Later, MacMillan disclosed similar research [17b], and a theoretical study of the intramolecular a-arylation of aldehydes was also reported by the same group via density functional theory [17c],... 

A tandem radical addition/cyclization process has been described for the formation of benzindolizidine systems from l-(2-iodoethyl)indoles and methyl acrylate <00TL10181>. In this process, sun-lamp irradiation of a solution of the l-(2-iodoethyl)ethylindoles 149 in refluxing benzene containing hexamethylditin and methyl acrylate effects intermolecular radical addition to the activated double bond leading to the stabilized radical 150. Intramolecular cyclization to the C-2 position of the indole nucleus then affords the benzindolzidine derivatives 151 after rearomatization of the tricyclic radical. 

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