Hydrogenation of indoles

Table 2.5 Asymmetric hydrogenation of indoles using (S,S)-(I ,I )-PhTRAP-rhodium complex as catalyst...

With Raney Ni in ethanol the hydrogenation of indole to 2,3-dihydroindole occurs quantitatively at 100-110°C and a maximum pressure of 9-10 MPa H2, and further hydrogenation at 150-160°C gives 1-ethyloctahydroindole quantitatively. Similarly,... 

Scheme 12.4 Hydrogenation of indole and 2,3-dihydroindole over Pd-BaSC>4 catalyst.

Hydrogenation to Indolines. Adkins and Coonradt observed that the hydrogenation of indole to indoline (2,3-dihydroindole) proceeded to the extent of only 70-80% over copper-chromium oxide at 170-190°C and 25 MPa H2 and suggested that indole (I) and indoline (II) were in equilibrium under the conditions... 

Hydrogenation of indole with Raney Ni in ethanol at 100-110°C and 9-10 MPa H2 has been reported to lead to the quantitative formation of indoline.10 Hydrogenation of indole over reduced Pd(0H)2-BaS04 in acetic acid-hydrochloric acid also gives indoline in high yield (eq. 12.11).12... 

TABLE 12.3 Hydrogenation of Indoles to Indolines over Platinum Oxide in EtOH - HBF/1... 

In accord with the propensity for indoles to protonate at the C-3 position, - Smith and Utley found that the catalytic hydrogenation of indoles in the presence of fluoboric acid proceeds smoothly to the indoline stage (equation 36). It seems that these acidic conditions are strong enough to protonate the in-... 

The ionic hydrogenation of indoles to indolines using EtsSiH/TFA has been described by Fames et al. and utilized by McKenzie, Magnus,Hlasta and Ward, and their coworkers in several different situations (equations 85-89). For the most part, the chemoselectivity and stereoselectivity that are observed with this reagent combination parallel that which was observed with NaBH4/TFA vide supra). 

The mechanism of function of pyridoxal phosphate in tryptophan biosynthesis is considered in more detail later in discussing other pyridoxine-dependent enzymes. An activated form of serine is formed which reacts with indole. Dehydration can take place in two ways intermolecularly, involving loss of water between the jS-hydroxyl of activated serine and the d-hydrogen of indole, or intramolecularly, involving loss of water from activated serine to give activated aminoacrylic acid, which then adds on to the i8-position of indole. Tatum and Shemin (858) in ingenious experiments... 

The pyridoxal phosphate complex of aminoacrylic acid can also be formed from serine by loss of an OH radical in a manner analogous to loss of the. 4.r" radical depicted above. This complex contains a reactive double bond to which the reactive /3-hydrogen of indole can add, giving a complex which on hydrolysis yields tryptophan. Such a mechanism is in accord with the known facts on tryptophan biosynthesis (cf. 858, and previous discussion, p. 41). 

Asymmetric Hydrogenation of Indoles 325 Table 10.12 Asymmetric hydrogenation of N tosylindoles (24a 24f). 

Based on the above results, asymmetric hydrogenation of indoles provides a... 

Scheme 10.31 Pathway of asymmetric hydrogenation of indoles (34a 34i) by Kuwano.

The hydrogenation of indoles is rather difficult and is normally achieved by use of Raney nickel at high temperatures and pressures. Either of the two rings may be saturated, depending on the conditions employed, and on the substitution pattern of the indole. The presence of a substituent on one of the two rings promotes reduction of the other ring. Stereochemical control of this type of reaction is not observed except for tricyclic systems [37]. 

Figure 8 Catalytic data for the hydrogenation of indole (I) as a function of the solvent and pressure [T = 373 K 0.45g of 5 wt.% Rh/AljOa 0.13 moles of indole in 135.0 mL of solvent].

Catalytic hydrogenation of indoles under pressure and at elevated temperature leads to 2,3-dihydro-indoles (indolines). These compounds are also formed by the action of reducing agents (zinc and phosphoric acid or tin and hydrochloric acid) on indoles. 

Bianchini reported several studies of ruthenium phosphine catalysts under hydrogen pressure using HP-NMR with sapphire tubes. These catalysts were investigated for the hydrogenation of indole, benzothiophene, and acetylacetone. The ruthenium tris(acetonitrile) complex [Ru(MeCN)3(triphos)]BPh4 was employed for the benzothiophene study.At elevated hydrogen pressures (>5 bar), the acetonitrile ligands were converted to a... 

Kuwano, R. Kashiwabara, M. Sato, K. Ito, T. Kaneda, K. Ito, Y. Catalytic asymmetric hydrogenation of indoles using a rhodium complex with a chiral bisphosphine ligand PhTRAP. Tetrahedron Asymmetry 2006,17,521-535. 

The enantioselective hydrogenation of V-unprotected indoles with H2 in CH2CI2 and TFE (1 1) is catalysed by Pd(OCOCF3)2/(5)-Cio-BridgePHOS (33) in the presence of D-camphorsulfonic acid (additive) to indolines in quantitative yield and up to 98% ee. The methodology is suitable for the hydrogenation of indoles substituted at the... 

The scope of the method was later extended to indoHnes [121] however, as the previous optimized conditions failed to afford any acylated product, a fine-tuning of both the nucleophilic catalyst and the acyl donor appeared to be necessary. After intensive screening, the use of a bulkier cyclopentadienyl-derived catalyst such as 113 in conjunction with 0-acetylated azlactone 111 led to a more effective catalytic system, allowing the resolution of various indo lines with useful levels of selectivity ranging from s = 9.5 to 31 (Scheme 41.45). Most importantly, 2,3-disubstituted indolines, which are usually difficult to obtain in high ee by other methods such as the asymmetric hydrogenation of indoles, were also shown to be suitable substrates. 

Kuwano R, Kaneda K, Ito T, Sato K, Kurokawa T, Ito Y (2004) Highly enantioselective synthesis of chiral 3-substituted indolines by catalytic asymmetric hydrogenation of indoles. Org Lett 6 2213-2215... 

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