Indoles, silyl derivatives

Pyrroles and indoles can be protected with the r-butyldimethylsilyl group by treatment with TBDMSCl and n-BuLi or NaH. Triisopropylsilyl chloride (NaH, DMF, 0°-rt, 73% yield) has been used to protect the pyrrole nitrogen in order to direct electrophilic attack to the 3-position.It has also been used to protect an indole.This derivative can be prepared from the silyl chloride and The silyl protective group is cleaved with Bu4N F , THF, rt or with CF3COOH. 

Both the silyl derivative (59) and the alcohol (60) may be used as sources of the iminium salt (61) in reactions with a wide variety of nucleophiles. In practice, it was found feasible to use Grignard reagents for reaction with the silyl derivative, while TiC was effective in promoting attack on the carbinol amine by weaker nucleophiles. The process is shown in Scheme 24 using the addition of indole as an example. 

Only a few papers on silyl derivatives of heteroaromatics, e.g. indoles and pyrroles, have been published [1-7], After the synthesis of mono-, bis-, tris-, and tetralds(indol-l-yl)silanes and (pyrrol-l-yl)silanes, this chemistry is extended to furan compounds [7, 8]. A further interest is to couple the heterocycles with bridging silyl groups to obtain chains and cyclic molecules. 

Iwasawa and co-workers developed a facile method for the construction of polycyclic indole derivatives 190a and 190b by the tungsten(0)-catalyzed reaction of A-(2-(l-alkynyl)phenyl)imine 188 with the electron-rich alkenes 189a and 189b (Scheme 32).42b Photoirradiation of a mixture of imine 188 and ketene silyl acetal 189a with 10mol% of... 

Recognizing that l-(phenylsulfonyl)-3-lithioindole tends to isomerize to the corresponding 2-lithioindole derivative, Bosch et al. used a silyl ether protection to solve the problem. They prepared 3-indolylzinc reagent 36 from 3-bromo-l-(terr-butyldimethylsilyI)indole (35) and then coupled 36 with 2-halopyridine 33 to form 3-(2-pyridyl)indole 37. Finally, the Negishi adduct 37 was further manipulated to a naturally occurring indole alkaloid, ( )-nordasycarpidone (38) [23,27]. 

Michael additions to quinones. In the presence of TrC104, enol silyl ethers undergo 1,4-addition to benzoquinone to give adducts that cyclize to benzofurans.1 A similar reaction with diimidoquinones produces indole derivatives. 

The procedure was proved to be general for the preparation of protected hydroxy acids from lactones (121). This apparently trivial process is often difficult to carry out, as the attempted derivatization of y or J-hydroxyacids frequently results in relactonization rather than hydroxyl protection. The method was applied to several aldonolactones to produce the corresponding intermediate hydroxyamides. Protection using [(2-trimethylsilyl)-ethoxy]methyl chloride, methoxymethyl chloride, ter/-butylchlorodimeth-ylsilane, or zm-butylchlorodiphenylsilane followed by ozonolysis gave the protected N-(y- or <5-hydroxyacyl)indole derivatives. Mild saponification gave indole and the acetal- or silyl-protected hydroxy acids. 

The aromatic silylation of five-membered heteroarenes under the same conditions (catalyst, temperature, solvent) also proceeded in regioselective fashion. Both, thiophene and furane derivatives are exclusively silylated at the a-position, but 1-triisopropylsily 1-pyrrole and -indole each produce selectively ]3-silyl products (Equations 14.9 and 14.10). 

Decarboxylation of 117 was effected by treatment of 117 with LiCl in hot, aqueous HMPA at 105 °C providing 118 as a mixture of diastereomers that were separated and carried forward individually. Protection of the secondary amide group as the corresponding methyl lactim ether was accomplished by treating 118 with trimethyloxonium tetrafluoroborate in dichloromethane that contained cesium carbonate. Next, the indole nitrogen atom was protected as the corresponding Boc derivative by treatment with dicarbonic acid bis(rm-butyl)ester in the presence of DMAP and the silyl ether was removed with tetrabutylammonium fluoride to provide diol 119 in 52-78% overall yield from 118. Selective conversion of the allylic alcohol to the corresponding... 

In a useful extension to this chemistry, the coupling of the starting iodoaniline with trimethylsilylalkynes was found to give the silylated species 5, which can bp a useful precursor to either 2-unsubstituted indoles or 2-halogenated derivatives as shown in Scheme 8. These could then be taken on further with standard organometallic coupling reactions. 

The l-(benzotriazol-l-yl)methyl derivatives of indole and carbazole were also used to effect < -silylation/alkylation. <950M734>... 

The reaction of zinc-copper reagents with acid chlorides has a remarkable generality [7,19] and has found many applications in synthesis (Scheme 9-30) [16,59-64]. The treatment of silyl-protected o-aminated benzylic zinc-copper derivatives such as 33 with an acid chloride leads to a 2-substituted indole 34. Aromatic and heterocyclic zinc compounds provide polyfunctional aromatic or heterocyclic ketones like 35 (see Section 9.6.8 Scheme 9-31) [60]. 

Addition and cyclization reactions. Chiral propargylic amines are obtained from aUcynylation of imines by catalysis of the silver salt of IB. The enantiomer of phosphate ID also finds use in the addition of indole to a-acetaminostyrenes. One more catalyst for intramolecular hydroamination to form pyrrolidine derivatives is the silylated 3. The... 

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