Reduction of indoles to indolines

While catalytic reduction of the indole ring is feasible, it is slow because of the aromatic character of the C2-C3 double bond. The relative basicity of the indole ring, however, opens an acid-catalysed pathway through 3if-indoleninm intermediates. 

A traditional method for such reductions involves the use of a reducing metal such as zinc or tin in acidic solution. Examples are the procedures for preparing l,2,3,4-tetrahydrocarbazole[l] or ethyl 2,3-dihydroindole-2-carbox-ylate[2] (Entry 3, Table 15.1), Reduction can also be carried out with acid-stable hydride donors such as acetoxyborane[4] or NaBHjCN in TFA[5] or HOAc[6]. Borane is an effective reductant of the indole ring when it can complex with a dialkylamino substituent in such a way that it can be delivered intramolecularly[7]. Both NaBH -HOAc and NaBHjCN-HOAc can lead to N-ethylation as well as reduction[8]. This reaction can be prevented by the use of NaBHjCN with temperature control. At 20 C only reduction occurs, but if the temperature is raised to 50°C N-ethylation occurs[9]. Silanes cun also be used as hydride donors under acidic conditions[10]. Even indoles with EW substituents, such as ethyl indole-2-carboxylate, can be reduced[ll,l2]. 

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The structure of the piperidine moiety and the presence of an unsubstituted tryptamine bridge in alkaloids of the mavacurine-pleiocarpamine class can be proved by a catalytic reduction to the corresponding indolines, which show very different spectra because now the main fragments contain ring D,los (212)- -(216)- -[2I7]-> [218]->[219]. The reduction of indole to indoline alkaloids seems an attractive route for the structure determination of those alkaloids.25... 

The reduction of indoles to indolines (2,3-dihydroindoles) has been intensively studied since the turn of the century and several reviews to the early literature are available. Nevertheless, over the past decade, a number of new and exciting methods for effecting this important reduction have been discovered. 

In summary, myriad boron hydride and silicon hydride reduction methods are available for the reduction of indoles to indolines. It is interesting to compare the various methods for the stereoselective reduction of 2,3-dimethylindole to cis- and trfl/is-2,3-dimethylindoline (Table 1). While most methods show a preference for the more stable trans isomer, only with Zn(BH4>2 is this preference pronounced. 

The reduction of indole to indoline alkaloids seems an attractive route for the structure determination of those alkaloids. ... 

B. E. MaryanofF and D. F. McComsey. Borane complexes in trifluoroacetic acid. Reduction of indoles to indolines and generation of bis(trifluoroacetoxy)borane. J. Org. Ghem., 1978, 43, 2733. 

Alkali metal borohydrides are frequently used for the reduction of rc-electron-deficient heteroaromatic systems, but reduction of jt-electron-excessive arenes is generally possible only after protonation of the systems [e.g. 35-37]. The use of tetra-n-butylammonium borohydride under neutral conditions for the conversion of alkylindoles into indolines [38] is therefore somewhat unusual. Reduction of indoles by diborane under strongly alkaline conditions involves the initial interaction of the indolyl anion with the diborane to form an amino-borane which, under the basic conditions, reacts with a second molecule of diborane to produce the indoline [39]. The reaction of tetra-n-butylammonium borohydride with indoles could also proceed via the intermediate formation of diborane. 

Therefore better methods for the chiral reduction of indole-2-carboxylic acid derivatives would provide an elegant synthesis of this intermediate. A study by Kuwano and Kashiwabara of the reduction of indole derivatives into the corresponding indohnes found that a range of the more common ligand systems gave almost no enantioselectivity but the TRAP ligand gave the chiral indolines in up to 95 % ee for reduction of the methyl ester (B, R=Me, R =H). Further developments are awaited. 

Chemical reduction of pyrroles by hydriodic acid and phosphorus leads to the formation of pyrrolidines (B-77MI30507) except when the 2-position is substituted by electron-withdrawing groups, which reduce the ease of protonation at the 3-position and, consequently, promote the formation of 2-substituted A3-pyrrolines (cf. Scheme 54) (B-74MI30500, 79MI30504). The analogous reduction of indole-2-carboxamide yields indoline-2-carboxamide (72HC(25-l)l). 

Indole Volume hbf4 Volume EtOH Reaction Time (h) Extent of Reduction (by GC) to Indoline... 

Watanabe and coworkers have reported that the mthenium-catalyzed reduction of indoles using formic acid as the hydrogen source leads to indolines (equation 44). It seems likely that acid is required in these reductions (equation 42-44) in order to protonate the indole C-3 position, since, in at least one report using only ammonium formate and palladium, the indole ring is not reduced (equation 45). Admittedly, these conditions are much milder than those that use formic acid. 

Although the early attempts to reduce indole to indoline with metals (Sn and Zn) and mineral acid e.g. hydrochloric acid) invariably led to polymerization, Dolby and Cribble found that 85% phosphoric acid is a suitable medium in combination with Zn for a successful indole to indoline reduction (69%). However, the reactions of 2,3-dimethylindole and 1,2,3,4-tetrahydrocarbazole with Z11/H3PO4 give much lower yields of reduction product. ... 

The reduction of indole (198) has also been achieved with sodium borohydride-aluminum chloride mixtures (5 3) in pyridine at room temperature." The pyridine serves to moderate the reducing agent and a 68% yield of indoline (201) was obtained along with unchanged starting material. When 2-methylpyridine replaced pyridine, no reduction was observed. 

The reduction of the indolinones 209 with NBH in methanol leads readily to the indoles 210 in 56-96% yield. Intermediacy of the corresponding alcohols has been proposed." The reduction of indoles and related compounds has been the subject of a previous review." Oxindoles (211) are reduced with LAH to indoles (212) but in low yields. Small amounts of the indolines 213 are also obtained. Dimerization on hydride reduction has also been recorded." ... 

Based on the early studies of radical generation from organotin hydrides and their addition to multiple bonds [1-3], particnlarly in cyclization [4-7], several groups applied this chemistry to the synthesis of indoles and indolines. For example, in 1975 Beckwith and colleagues found that < -(A -allyl-Af-methylamino)iodobenzene was converted to 1,3-dimethylindoline (78% yield) upon treatment with tri-n-butylstannane (prepared by the reduction of tri-n-butyltin chloride with LiAlH ) in the presence of AIBN (azobisisobutyronitrile) and benzene at 130°C in a sealed tube [4],... 

Recently, the methodology was successfully employed for the enantioselective reduction of indoles 137 into indolines 138 using catalysts 113c and 118b (Scheme 15.28) [98gj. To faciUtate the enamine/imine tautomeric equiUbrium, the required Br0nsted acid was generated by a controlled hydrolysis of excess trichlorosilane with water. 

Enantioenriched indolines are very important compounds, which exist extensively in natural alkaloids or unnatural bioactive compounds. The development of facile methods toward chiral indolines continues to be a challenge for organic chemists. Unprotected indole 106 could be considered as a special enamine in an aromatic system. Inspired by the possible shift between enamine and imine of indole in the presence of strong acid. Sun and Chen et al. envisioned that a direct reduction of indole 106 to indoline 107 by a combined catalysis of Lewis base and Br0nsted acid would be highly possible (Scheme 32.24). Indeed, using the strategy... 

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