N Boc indoles

Ishikura et al. reported the total synthesis of ellipticine (228) starting from N-Boc indole (1256) and the vinyl bromide 1258 (719-721). This methodology involves a palladium-catalyzed, tandem cyclization-cross-coupling reaction of the indolyl borate 1257 with the vinyl bromide 1258 as the key step. Using a literature procedure, the vinyl bromide 1258 was prepared as an E/Z mixture starting from CIS- and trans-crotyl alcohol. The indolyl borate 1257 was generated in situ from... 

Bennasar et al. reported a new radical-based route for the synthesis of calothrixin B (378) (869). This synthesis starts from the 2,3-disubstituted N-Boc indole 1558 and uses a regioselective intramolecular acylation of a quinoline ring as the key step for the construction of the calothrixin pentacyclic framework. Chemoselective reaction of in s/fM-generated 3-lithio-2-bromoquinoline [from 2-bromoquinoline 1559 with LDA] with the 3-formylindole 1558 followed by triethylsilane reduction of the... 

Kuwano, R. and Kashiwahara, M. Ruthenium-catalyzed Asymmetric Hydrogenation of N-Boc-Indoles. Org. Lett. 2006, 8, 2653-2655. 

Whilst carbamate derivatives of indoles and pyrroles are easily prepared, they have limited synthetic utility because they are easily attacked by nucleophiles. For example, A -Aloc525 and A -Cbz526 derivatives of tryptophan are known, but they are destroyed by piperidine. Boc derivatives of indoles, pyrroles and imidazoles are sufficiently hindered to be synthetically useful For example, N-Boc indole is stable towards piperidine and it can be metallated in the 2-position with ferf-butyllithium.527 Nevertheless, they are still more easily cleaved by nucleophiles than Boc-derivatives of secondary amines as illustrated by the fact that Boc-derivatives of pyrrole are cleaved with sodium methoxide, ammonia or hydrazine in methanol527 In tryptophan derivatives, the Ar>w-Boc group is less susceptible to aridolysis than an Na-Boc group with trifluoroacetic acid. However, the M"-Boc group can be cleaved selectively by thermolysis as illustrated by a step in a synthesis of Asperazine [Scheme 8,271 ].52 ... 

Fortunately, this Ru catalyst was also effective for 3 substituted N Boc indoles, and the 3 methyl and 3 phenyl indoles 28a and 28b were hydrogenated to the correspond ing indolines with 87 and 94% ee, respectively [39]. This catalyst system was also extended to hydrogenation of 2,3 disubstituted indoles, and only the cis 2,3 dimethy lindoline ( ) 31 was observed with 59% yield and 72% ee (Scheme 10.29). 

Dixneuf, Bruneau and coworkers have reported an interesting reduction of the unsaturated acyl oxazolidinone (2.90). The reduction works with high yield and asymmetric induction, and the product (2.91) is effectively propionic acid with a chiral auxiliary attached. The chiral auxiliary was then used to induce asymmetry in a subsequent step. 2,3-Substituted N-Boc indoles imdergo hydrogenation to... 

In order to improve the nucleophilicity of the lactam, we decided to pre-form the potassium salt of pyrrolidin-2-one III-69 [172]. Unfortunately, no alkylated product was detected in the reaction of III-69 with N-Boc indole III-67 in DMF (Scheme 4.42) [173]. When the reaction was carried of using toluene as the solvent, only spiro[cyclopropane-l,3 -indole] (III-66) was detected. Futhermore, spiro[cyclopropane-l,3 -indole] (III-66) was the only product observed in the reaction of the potassium salt III-69 with 3-(2-bromoethyl)-l//-indole in toluene. 

The N " -BOC group can be removed under the usual conditions for removing the BOC group CF3COOH and HF. It can also be removed with hydrazine and NH3/ MeOH. NaOMe/MeOH/THF has been used to remove the BOC group from pyrroles in 66-99% yield. Thermolysis at 180° cleaves the BOC group from indoles and pyrroles in 92-99% yield. 

The indolyltributylstannanes, which are more robust than their trimethylstannyl counterparts, are prepared similarly [166, 167]. Labadie and Teng synthesized the IV-Me, N-Boc, and jV-SEM (indol-2-yl)tributylstannanes [167], and Beak prepared the A-Boc trimethyl- and tributyltin derivatives in high yield [166]. Caddick and Joshi found that tributylstannyl radical reacts with 2-tosylindoles to give the corresponding indole tin compounds as illustrated [168]. 

A mixture of l-(t-Boc)indol-2-yl-tri-n-butylstannanc (1.2 mmol) and 4-bromo-benzonitrile (1.0 mmol) and Pd(PPh3)2Cl2 (0.02 mmol) in dry dioxane (5 ml) was heated at 100°C overnight under nitrogen. The reaction mixture was cooled, diluted with EtOAc and stirred for 15 min with 15% aq. KF. The precipitate was removed by filtration and washed with EtOAc. The EtOAc layer was separated, washed with brine, dried (Na2S04) and concentrated. The residue was purified by chromatography on silica. The yield was 66%. 

Gronowitz adapted this technology to one-pot syntheses of indole-3-acetic acids and indole-3-pyruvic acid oxime ethers from N-BOC protected o-iodoanilines [328, 329]. Rawal employed the Pd-catalyzed cyclization of A (o-bromoahyl)anilines to afford 4- and 6-hydroxyindoles, and a 4,6-dihydroxyindole [330], and Yang and co-workers have used a similar cyclization to prepare 8-carbolines 287 and 288 as illustrated by the two examples shown [331]. The apparent extraneous methyl group in 288 is derived from triethylamine. 

Protection of tryptophan. The Boc group can also be used to protect the indole in tryptophan. The mt thyl ester of di-Boc-Trp can be prepared in almost quantitative yield and used for peptide synthesis. Both Boc groups are cleaved with TFA in a reasonable yield. The N -Boc group can be cleaved selectively with 2.7 M HCl in dioxane at 25". 

TV-Substituted pyrroles and indoles normally undergo lithiation at the 2-position (a-metaladon), so when there is an ortho director on the nitrogen, metalation is facilitated. For example, the lithiation of TV-t-BOC pyrrole and its addition to benzaldehyde occurs in 7S% yield. SimUar lithiations of N-t-BOC indole and TV-benzenesulfonylindole > have also been reported. Exanqiles of these reactions are illustrated in Scheme 25. 

N-Boc-hexahydro-iso-indole-5,6-dicarboxylic acid monoamide primary, secondary aliphatic amines acid/ EDC cyano [13,15]... 

Indole synthesis. This Michael acceptor reacts with o-lithio-N-Boc-aniline. The product undergoes a sila-Pummerer rearrangement to induce ring closure. Indoles are obtained on elimination of the [PhSH] element. 

Jones conditions), aqueous acid, and mild Lewis acids.The Boc group is usually removed by treatment with aqueous HCll or with anhydrous trifluoroacetic acid. In Lai s synthesis of indole analogs of mycophenolic acid, indole derivative 143 was converted to the N-Boc compound (144) using Boc anhydride. Elaboration of the side chain in three steps was followed by deprotection with HCl in dioxane, giving 145 in 72% yield. Trifluoroacetic acid in dichloromethane converted 145 to 146 in 60% yield. 

N-acyl imines [144]. A slightly modified chiral Br0nsted acid 185 was found to catalytically induce addition of indoles to N-Boc-protected enecarbamates ISK) in high yields and enantioselectivities (Scheme 8.51) [145]. In a related study, Zhou demonstrated the use of a-aryl enamides to obtain optically enriched tertiary amine products [146]. 

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