Indoles highly functionalized

Waldmann used (R) and (5>aminoacid methyl esters and chiral amines as chiral auxiliaries in analogous aza-Diels-Alder reactions with cyclodienes.111 The diastereoselectivity of these reactions ranged from moderate to excellent and the open-chain dienes reacted similarly. Recently, the aza-Diels-Alder reaction was used by Waldmann in the asymmetric synthesis of highly functionalized tetracyclic indole derivatives (Eq. 12.45), which is useful for the synthesis of yohimbine- and reserpine-type alkaloids.112... 

The occurrence of the indole subunit is well established within the class of natural products and pharmaceutically active compounds. Recently, the Reissig group developed an impressive procedure for the assembly of highly functionalized in-dolizidine derivatives, highlighting again the versatility of domino reactions [8]. The approach is based on a samarium(II) iodide-mediated radical cydization terminated by a subsequent alkylation which can be carried out in an intermolecular - as well as in an intramolecular - fashion. Reaction of ketone 3-11 with samarium(ll) iodide induced a 6-exo-trig cydization, furnishing a samarium enolate intermediate... 

Rainier devised a variant of the 5-exo-dig radical cyclization of 2-alkynylisocyanides 122 wherein thiols were utilized to both initiate the radical cascade as well as act as nucleophiles in the reaction with the indolenine intermediate 123 yielding the indoles 124 . When R = TMS, elimination of the C-10 thioether can be effected in a gramine-like fashion so as to add nucleophiles (e.g., malonate anion) in the presence of Bu3P allowing for the preparation of more highly functionalized indoles. 

A different variation on this theme has been developed by Ito, where the TRAP ligands (37) form a nine-membered metallocycle [157-162]. The ruthenium catalysts seem to function best at low pressures, but highly functionalized dehydroamino esters can be reduced with high degrees of asymmetric induction [157, 159-164], as well as indoles [165]. 

Masked o-benzoquinones, as the most accessible type of cyclohexa-2,4-dienones, are of immense synthetic potential [187-193]. At both room temperature and reflux, the dienones 263 generated in situ from commercially available 2-methoxyphenols 262 by adding (diacetoxyiodo)benzene (DAIB, 1 equiv.) at 0 °C in MeOH underwent unusual Michael addition to indoles (2, 19, 264) followed by aromatization of the adducts to give highly functionalized 2-arylindoles 265a-c in excellent yields (Scheme 57) [193]. 

The synthesis and chemistry of pyrroles, indoles, and fused pyrrole and indole compounds reported during the past year (2007) are the subjects of this monograph. Pyrroles and indoles continue to draw a lot of attention from the scientific community due to their prevalence in natural products, diverse biological activity, and materials science applications. Pyrroles and indoles are treated separately. A review article describing the synthesis of highly functionalized pyrroles has appeared <07S3095>. Specialized review articles will be mentioned in the relevant sections. 

The uncoordinated 3-vinylpyrrole complexes (e.g., 1133) resemble an electron-rich diene and, as such, undergo a facile Diels-Alder reaction with electron-deficient alkenes and alkynes under mild conditions, for example T-phenylmaleimide 1134 to generate, after decomplexation and oxidation, a highly functionalized indole 1135 in ca. 60% overall isolated yield (from pyrrole) (Scheme 221) <1996JA7117>. 

The aza-Diels-Alder reaction of substituted lf/-indole-2-carbaldehydes 1323 with Danishevsky s diene 1324 proceeds with a high degree of diastereoselectivity providing highly functionalized l-R -2-(Tmethyl-lf/-indol-2-yl)-2,3-dihydro-4(l//)-pyridinones 1325 which were further elaborated into novel polycyclic heterocycles (Equation 289) <2002TL29>. Attempts to form the imine of 12/-indole-2-carbaldehyde 1326 in situ in the presence of diene 1324 and zinc chloride or zinc triflate at 0 °C or at room temperature did not afford the expected cycloadduct 1327. Instead, 2-(177-indol-2-yl)-2,3-dihydro-477-pyran-4-one 1328 and the 5-hydroxy-l-methoxy-5-(l/7-indol-2-yl)-Tpenten-3-one 1329 were isolated in 45% and 25% yields, respectively (Equation 290). 

Ji and co-workers [73] have elaborated a simple and efficient approach for the synthesis of highly functionalized pyridines 24 via a one-pot, three-component reaction under microwave irradiation. This method enables the incorporation of a pyrazolo[3,4-h]pyridine and an indole moiety into the same molecule. The synthesis was achieved by reaction of a suitable aldehyde and 3-cyanoacetyl indole with 5-aminopyrazol. Particularly valuable features of this method include high yields, broad substrate scope, and short reaction times. It has been observed that when there are electron-withdrawing groups on the aryl aldehyde this results in a faster and higher yielding reaction (Scheme 21). 

Radical centers can also be generated on the aziridine ring itself, which can then take part in further reaction with preservation of the heterocyclic entity. This process is demonstrated by the radical cyclization of the highly functionalized indole 289 to give the tetracyclic aziridine 290 in fair overall yield (Scheme 75) <1998TL2455>. 

Gross S, Reissig H-U (2003) Novel stereoselective syntheses of highly functionalized benzannulated pyrrolizidines and indolizidines by samarium diiodide induced cyclizations of indole derivatives. Org Lett 5 4305 307... 

As previously noted, the typical high temperatures and long reaction times required for the normal electron demand Diels-Alder reactions with electron-poor indoles have rendered such approaches less attractive for the synthesis of more sensitive and highly functionalized substrates in total synthesis. Recently, there have been a few reports on attempts to accelerate these cycloaddition processes. For example, Piettre and coworkers investigated the activation of the dienophilic indoles under high pressure [33]. Thermal Diels-Alder reactions of lV-tosyl-indole-3-car-boxaldehyde (65) with dienes 66a and 66b (195°C, sealed tube, 72 h) resulted in conversions of 67% and 25%, respectively (Scheme 18). By increasing the pressure for the above reactions to 16 kbar (48 h, 50°C), the corresponding cycloadditions with dienes 66a and 66b resulted in conversions of 93% and 86%, respectively. 

A novel indole [5 + 2] cycloaddition reaction involving an oxidopyry-lium ylide resulted in an efficient and diastereoselective construction of highly fonctionalized and stereochemically challenging oxa-cyclohepta[l ] indoles with high functional-group tolerance and unique endo selectivity under very mild reaction conditions. (14AGE11051). 

The synthesis of highly functionalized cyclohepta[l)]indoles was achieved through an efficient sequence of [4 + 3]-cycloaddition-cydization-elimination. The cycloaddition features nitrogen-stabilized oxyallyl cations derived from epoxidations of N-aryl-N-sulfonyl-substituted allenamides, while the cyclization and elimination employed an intramolecular Grignard addition and a useful one-step Chugaev process, respectively (14OL2180). 

C. G. Neochoritis, A. Domling, Org. Biomol. Chem. 2014,12, 1649-1651. Towards a facile and convenient synthesis of highly functionalized indole derivatives based on mnlti-com-ponent reactions. 

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