Hydroformylation/Fischer indole synthesi

General Procedure for the Hydroformylation/Fischer Indole Synthesis. Synthesis of Tryptamine Derivatives in Water. Aminoolefin (1 eq), aromatic hydrazine (1 eq), Rh(acac)(CO)2 (0.3 mol %) and TPPTS (1.5 mol %) are dissolved in H2SO4 (4wt% in H2O, 2.5 wt % olefin), filled in an autoclave and pressurized with lObar H2 and 50 bar CO. After stirring for 3 days at 100 °C ammonia (30 wt% in water) is added and the mixture is extracted with EtOAc. The solvent is evaporated to give the product which purified by column chromatography (silica, CH2C12, PrOH, NEt3) if necessary. 

Scheme 39 Rearrangement involved in hydroformylation/Fischer indole synthesis - Access to 2-aryl tryptamines.

Relying on a tandem hydroformylation/Fischer indole synthesis, a number of indoles possessing various substituents at C-3 and/or C-5 were prepared in moderate yields. Thus for example, the tryptamines 98 were produced from hydrazines 99 and the methallylic phthalimide 100 <03OL3213>. 

This hydroformylation Fischer indole synthesis was extended and developed by Eilbracht and his research group [88-93]. A small selection of this elegant chemistry is shown in Scheme 10 (equations 1-5). This chemistry has been adapted to the synthesis of tetrahydro-p-carbolines, a process that uses 2,5-dihydropyrroles and arylhydrazines and features spiroindoleninium cation intermediates (equation 5) [92]. 

A novel rhodium-catalyzed one-pot synthesis of indole systems via tandem hydroformylation-Fischer indole synthesis starting from olefins and arylhydrazines was described. The procedure leads directly to 3-substituted indoles if unsubstituted phenylhydrazine is used. Using para- or ortho-substituted arylhydrazines, the corresponding 3,5- and 3,7-disubstituted indoles are formed, respectively [160]. 

The same group also developed an efficient entry to indoles using a combination of a hydroformylation and a Fischer indole synthesis [212]. Under optimized condi-... 

After copper and palladium, rhodium is the third most important transition metal for the synthesis of the indole ring. For a 2007 review on this reaction, see Patil and Paiil [1], Some early examples (Scheme 1) are Alper s rhodium reaction of 2-aryl-2/7-azirines to give 2-styiylindoles (equation 1) [2], Watanabe s Rh-catalyzed Fischer indole synthesis (equation 2) [3], Ucciani s 3-methylindole synthesis via the hydroformylation of o-nitrostyrene (equation 3) [4], and Burst s preparation of 3-acetyl-2-hydrox-yindoles from the Rh-catalyzed decomposition and carbenoid aromatic C-H bond insertion (equation 4) [5]. Narasaka extended Alper s 2-aryl-2//-azirine reaction to a Rh(II)-catalyzed synthesis of 2,3-disubstituted indoles [6], and both Cenini [7] and Alper [8] stretched the deoxygenation of o-nitrostyrenes to give indoles. Burst s Rh-catalyzed decomposition of a-diazo carbonyl compounds was used by Bauban [9] and Jha [10] in the synthesis of substituted oxindoles. 

As Eilbracht and coworkers [38] showed in numerous examples, the reaction cascade hydroformylation—(Fischer indolization) is a useful protocol for the synthesis of three-substituted indoles, including the essential amino acid tryptophan, the tissue hormone melatonin, and the neutrotransmitter serotonin (Figure 5.25). In addition, pharmacologically active tryptamine or homotryptamine derivatives, such as the marketed serotonin agonists sumatriptan, naratriptan, or zolmitriptan, or compounds that show a platelet aggregation inhibitory and antithrombotic effect (vintoperol) can be synthesized by such a protocol. Also active drug components for the treatment of schizophrenia (sertindole) can probably be produced by this approach [39]. It is estimated that the worldwide demand for such indole derivatives is about 20 000 mt/a [40]. 

The tandem hydroformylation-Fischer indolization protocol was used in the synthesis of 2,3-disubstituted indoles. Several olefins, bearing substituents with various functional groups, as well as cyclic olefinic systems were investigated (Equations 7.20 and 7.21)... 

Maeda and Yoshida 238, 239) by hydroformylation of acrolein obtained l,l-diacetoxy-4,4-dialkoxybutane (17), which by Buecherer s reaction gave (3-(hydanto-5-yl-)propionaldehyde acetal (18). The phenyl-hydrazone of (18), by the Fischer indole synthesis, gave tryptophan hydantoin (20). Attempts to obtain crystalline (20) were unsuccessful,... 

With this tandem hydroformylation/hydrazone formation/Fischer indolization 3-substituted indoles such as valuable intermediates for the synthesis of pharmaceuticals as well as pharmaceuticals can be obtained in a very... 

In addition, a number of reports on the indole synthesis utilizing a similar concept of the in sUu generation of the key reactive arylhydrazones, similar to 284, with the aid of transition metal catalysts recently appeared in the literature. Among them, the domino Rh-catalyzed hydroformylation [263] of alkenes leading to aldehydes followed by a subsequent hydrazone formation and Fischer indolization process, which was introduced by Eilbracht [264—267] and later investigated by Beller [268], represents an attractive and efficient 3 + 1 + 1 approach for a one-pot construction of complex indoles. 

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