N-Protected indole

Methylthiophene is metallated in the 5-position whereas 3-methoxy-, 3-methylthio-, 3-carboxy- and 3-bromo-thiophenes are metallated in the 2-position (80TL5051). Lithiation of tricarbonyl(i7 -N-protected indole)chromium complexes occurs initially at C-2. If this position is trimethylsilylated, subsequent lithiation is at C-7 with minor amounts at C-4 (81CC1260). Tricarbonyl(Tj -l-triisopropylsilylindole)chromium(0) is selectively lithiated at C-4 by n-butyllithium-TMEDA. This offers an attractive intermediate for the preparation of 4-substituted indoles by reaction with electrophiles and deprotection by irradiation (82CC467). 

Comins and Killpack have also investigated the lithiation of a small number of N-protected indole-3-carboxaldehydes, using lithium N-methyl-piperazide to form the a-amino alkoxide, and found that decomposition occurred with the A -benzenesulfonyl, N-ter/-butoxycarbonyl, and A -di-methylcarbamyl derivatives (87JOC104). Success was achieved with the N-methoxymethyl derivative 19, although no attempt was made to subsequently remove the normally difficult to hydrolyze methoxymethyl protecting group. Therefore the real viability of this method as a route to... 

In a sequence that proceeds by tandem directed ortho metalation steps (Scheme 133) the N,N-diethyl isonicotinamide (447a) has been converted into the chemotherapeutic alkaloid ellipticine (589) (Scheme 182) (80JA1457). Thus, in a rapid, one-pot procedure, metalation of 447a followed by condensation with N-protected indole-3-carboxaldehyde derivatives leads to the intermediates 615 which, upon second metalation and aerial oxidation affords the quinones 616 in modest to good yields. Established steps were used to convert 616, R = CH2OMe into ellipticine (589), concluding a route which complements that based on the oxazolino DMG (Scheme 175). 

The use of indole salts is frequently required to achieve selective attack at the 3-position in the acylation reaction. However, this approach is not applicable to indoles bearing functional groups labile under basic conditions, and consequently, Grignard reagents or alkylzinc compounds cannot be used for the preparation of the indole salts as shown in Scheme 2.2. A second approach involves the use of N-protected indoles and requires protection-deprotection steps. 

It is possible to lithiate the 2-position of N-protected indoles exploiting the ortho effect employing LDA, as shown by Wenkert and co-workers, who obtained l-benzenesulfonyl-2-prenylindole in 76% yield [56], which could be deprotected by reduction with sodium amalgam. 

Several N-protected indol-2-yltributylstannanes were examined in Pd-catalyzed cross-coupling with aryl halides and triflates, acyl chlorides and benzylic and allylic bromides. <94J0C4250> The 1-methyl and l-(2-trimethylsilylethoxymethyl) (SEM) derivatives reacted readily whereas the 1-t-butoxycarbonyl derivative was somewhat less reactive. The SEM group is removable with BU4N F , providing acces to the deprotected 2-substituted indoles. 

Scheme 56 Zhang and Li s oxidative coupling of N-protected indoles with pyridine N-oxides.

Subsequently, Luo and co-workers further applied the binary-acid strategy to the regioselective AFC alkylation of N-protected indoles with p,y-unsatu-rated a-keto esters. Interestingly, the reaction of an Af-methyl indole with a p,y-unsaturated a-keto ester led to predominantly the 1,2-adduct 89a with high regioselectivity (>30 1) and 90% ee (Scheme 6.32). 

Scheme 6.33 Enantioselective 1,2- and 1,4-addition of N-protected indoles with a-keto esters catalyzed by binary-acid catalysis reported by Luo.

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. 

An interesting selectivity was uncovered in the direct cross-dehydrogenative coupUng between N-protected indoles and arenes (Scheme 11.40) [151]. Thus, whereas 2-arylated indoles 67a were preferentially obtained from N-acetyhndole in the presence of Cu(OAc)2, the reaction of N-pivalolyUndole with AgOAc led to 67b, with excellent selectivities. The reason for this C-2/C-3 selectivity is most likely due to the formation of higher-order palladium clusters or paUadium/copper clusters under the different reaction conditions. A related reaction between aryl-boronic acids and arenes or heteroarenes also proceeds under oxidative conditions with Pd(OAc)2 as catalyst [76]. A catalytic cycle initiated by an electrophihc attack of Pd(II) on the arene, followed by transmetallation with the aryl boronic acid and reductive elimination, was suggested. In this transformation, Cu(OAc)2 as stoichiometric oxidant could be replaced by O2, and for indoles, arylation at C-2 was observed. 

In 2005, Sames [50] developed a C-H arylation of N-alkyl indoles (indoles with a free NH can also be used) and pyrroles with aryl iodides using a rhodium catalyst. They demonstrated that CsOPiv activates the rhodium catalyst to form Rh(OPiv)2(Ph)L2 (L = P[p-(CF3)CgH4]j). In 2006, Sames [51] also developed a palladium NHC catalyst 53 for the C-H arylation of N-protected indoles, pyrroles, imidazoles, and imidazo[l,2-a]pyridines (Section 17.2.4.5) with aryl iodides. 

Baeza, A. Pfaltz, A. Iridium-catalyzed asymmetric hydrogenation of N-protected indoles. Chem. - Eur.. 2010,16,2036-2039. 

In order to extend this chemistry for the synthesis of other types of indoles besides 2-alkylindoles, the same group disclosed an efficient synthesis of N-protected indoles 48 fromiV-arylhydroxamic acidsW-aryl-Af-hydroxycarbamates 47 and a variety of alkynes via gold and zinc cooperative catalysis (Scheme 12.23) [27]. They found that catalytic Zn(OTf)2 enhances the nucleophilicity of these hydroxylamine derivatives via the formation of deprotonated chelates, which is similar to the metal ion catalysis in metalloenzymes. This chemistry is a rare example of cooperative dual catalysis involving gold catalyst. 

Platinum(II) chloride-catalysed reaction of allenes R R C=C=CHR with N-protected indoles (In) in THF with added MeOH proceeds at 70 C over 20 h and affords products of geminal bisindolylation, that is, R R CH-CH2C(3-In)2R. By contrast, gold(I) complexes catalyse monoindolylation, giving rise to allyl indoles... 

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