Tandem hydroformylation-Fischer indole

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>. 

Figure 5.25 Some naturally occurring or pharmacologically relevant 3-substituted indol derivatives accessible by tandem hydroformylation-(Fischer indolization) reaction.

Scheme 5.148 Tandem hydroformylation-(Fischer indolization) reaction.

Interestingly, the protocol discussed above provides a clever analytical method for fast determination of the ratio of regioisomers obtained by tandem hydroformylation-Fischer indolization of olefins (Scheme 5.153 and Figure 5.26)... 

Scheme 5.153 Tandem hydroformylation-(Fischer indolization)-(Wagner-Meerwan-type rearrangement) reaction for the determination of the regiochemistry.

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 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)... 

An interesting one-pot hydroformylation/Fischer indole sequence can be achieved by running the hydroformylation in the presence of a phenylhy-drazine. This protocol gave access to the methyl ester of the plant growth regulator 3-indole butanoic acid (IBA) (Scheme 16) [61-63]. A review on related tandem processes involving the hydroformylation as a key step has appeared recently [9]. 

Scheme 5.149 Access to 3-indolyl based a- and p-amino acids using a hydroformylation-(Fischer indolization) tandem reaction as a key step.

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... 

---