2-Silyl-3-substituted indoles

The reaction can be regioselective with unsymmetrical alkynes, and this is particularly tme with sUylated alkynes wherein the silyl group always resides at the C-2 indole position in the product. This is noteworthy because silyl-substituted indoles are valuable substrates for other chemistry (halogenation, Heck coupling). Gronowitz used the appropriate silylated alkynes with o-iodoanilines to fashion substituted tryptophans following desilylation with AICI3 [26]. Similarly, a series of 5-, 6-, and 7-azaindoles was prepared by UjjainwaUa and Warner from o-aminoiodopyridines... 

Another route to synthesize heteroaromatic silyl-bridged cyclic systems is the use of 1,2- and l,3-bis(silyl)indoles [6,10]. N-silyl-substituted indoles react with lithium alkyls via two pathways ... 

Direct 3-silylation of A -substituted indoles has been ellected by reaction of the indoles with trimethylsilyl triflate in the presence of triethylamine[12]. The trimethylsilyl group has also been introduced via 3-lithio-l-(phenylsulfonyl)-indole[13]. 

The N-silylated brominated o-toluidine 1504 reacts with Zn and subsequently with CuCN/LiCl to give the intermediate 1505 which reacts with a variety of acid chlorides to give, via 1506, 2-substituted indoles 1507 [47] (Scheme 9.28). 

Compared to the cyclic ketones, the coupling of aliphatic aldehydes to prepare 3-substituted indoles was less successful, except for phenyl acetaldehyde, which afforded 3-phenyl indole 83 in 76% yield (Scheme 4.22). The lack of imine formation or the instability of the aliphatic aldehyde towards the reaction conditions may be responsible for the inefficiency of these reactions. Therefore, a suitable aldehyde equivalent was considered. With the facile removal of a 2-trialkylsilyl group from an indole, an acyl silane was tested as a means of preparing 3-substituted indoles. Indeed, coupling of acetyl trimethylsilane with the iodoaniline 24 gave a 2 1 mixture of 2-TMS-indole 84 and indole (85) in a combined 64% yield. Evidently, the reaction conditions did lead to some desilylation. Regardless, the silyl group of 84 was quantitatively removed upon treatment with HC1 to afford indole (85). 

Recendy, we found that A -allyl-o-vii rlaniline 44 gave 1,2-dihydroquinoline 45 by normal RCM and developed silyl enol ether-ene metathesis for the novel synthesis of 4-siloxy-1,2-dihydroquinoline and demonstrated a convenient entry to quinolines and 1,2,3,4-tetrahydroquinoline [13], We also have found a novel selective isomerization of terminal olefin to give the corresponding enamide 46 using rathenium carbene catalyst [Ru] and silyl enol ether [14], which represented a new synthetic route to a series of substituted indoles 47 [12], We also succeeded an unambiguous characterization of mthenium hydride complex [RuH] with ACheterocyclic carbene... 

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]. 

Indol-3-yl)-2,3-dihydro-l,2,4-triazine-3-thione was prepared, its X-ray structure determined, and used for the preparation of fused triazolo- and tetrazolotriazines <05RJO875>. Silyl substituted l,2,4-triazin-5-ones have been obtained from a-silyl-a-keto esters and thiosemicarbazide <05TL4049>. 

The silyl groups can be removed to give the C-7 substituted indole. Electrophiles which were successful include Mel (95%), DMF (70%), and allyl bromide (69%). 

Larock modified the annulation process to access 3-substituted indoles by employing silyl-substituted alkynes. In this case, the bulky silyl group dominates the regioselectivity of the annulation and thus serves as a phantomdirecting group in the heteroannulation step. Silylated alkynes provide 2-silyl-3-substituted indoles with excellent regioselectivity. Subsequent desilylation affords 3-substituted indoles in good yield. 

As mentioned early in the chapter, one of the general features of Larock indole synthesis is that the reaction gave exclusively 2-silyl indoles when a silyl-substituted alkyne was present, and the corresponding 2-silyl indoles can be further functionalized. In this respect, Denmark and Baird recently reported a sequential Larock heteroannulation and silicon-based... 

Radical anions from aromatics which are intermediates in Birch-type reductions were prepared sonochemically. Pyridine, quinoline, and indole sonicated with lithium in THF in the presence of trimethylsilyl chloride yield the bis-TMS dihydroaromatics, which can be reoxidized, by air or benzoquinone, in a rapid and easy method to prepare silyl-substituted aromatics. The procedure was extrapolated to phenols (Eq. 6). ... 

These annulations can be extended bqrond indole syntheses. For example, the analogous reaction with ortho-iodophenols can provide an effective method to build up benzofurans (Scheme 6.50) [67]. Presumably due to the lower nudeophilicity of the phenolic oxygen, these reactions generally require higher reaction temperatures. Nevertheless, similar regioselectivity was found here as with the indole synthesis, and, in particular, 2 -silyl-substituted benzofuran is often obtained with high selectivity. This same approach can be applied to the construction of pyrroles and furans [68]. 

Silylated diynes are used in the synthesis of methylene cyclopentanes, notably acyl derivatives of Oppoizer s camphor sultam, enediyne antibiotics, and CpCo omplexed dihydrocarbazoles, and ( )-Lysergene and (+)-LSD from a substituted indole and Me3SiC=CR through a [2+2+2]cycloaddition. Monosilylated hexatriyne and octatetrayne are used in the synthesis of the caryoynencin polyyne antibiotics, while triflate substituted disilyl polyynes result from the corresponding allyl derivative with The hydropyrolysis of bis-... 

D. Hong, Z. Chen, X. Lin, Y. Wang, Synthesis of substituted indoles from 2-azidoacrylates and orfto-silyl aryltriflates, Org. Lett. 12 (2010) 4608 611. 

Hie activating effect of n-complexation of a Cr(CO)3 complex allows for selective nucleophilic substitution in indoles, such as OTptophan, providing intermediates for the synthesis of clavicipitic acid. Indole was readily transformed into the corresponding tricarbonylchromium complex and silylated to the orange-colored complex 17. The addition of 17 to a solution of the lilhiated sulfone followed by oxidative quenching with iodine and desilyladon furnished the C-4 substituted indole 18 in 90% yield. The conversion of 18 to the enone 19 was achieved in 78% yield by sequential acid and base treatment. 

Iwao et d. introduced an efficient methodology ftH the synthesis of 3,4-disubstituted indoles 113 (57). Their strategy comprises two sequential steps 1) selective functionalization of l-silyl-3-dimethylaminomethylindole (111) at the 4-position by directed lithiation, followed by quenching with electrophiles, for the preparation of 4-dimethylamino-substituted indole 112 (58) 2) substitution of the dimethylamino group of 112 for various nucleophiles giving 113 upon desilylation through quatemization followed by a fluoride ion-induced elimination-addition reaction (Scheme 17) (59). 

Since it was first reported in 1991, the Larock indole synthesis has become one of the most attractive and practical methods for the preparation of 2,3-disubstituted indoles (Scheme 24.46, disconnection D-1). In the seminal publication, Larock and Yum described the palladium-catalyzed heteroannulation of internal alkynes such as 71 with o-iodoanilines to generate substituted indoles such as 73 in excellent yield (Scheme 24.47) [149]. Unsymmetrical alkynes could be regioselectively incorporated, with the more sterically hindered group of the alkyne resulting at the 2-position of the indole. Trimethylsilyl-substituted alkynes were found to be particularly effective, affording the corresponding 2-silylated products such as 73 in exemplary yields. 

Since the publication of these works, the concept of LUMO-lowering activation of a,P-unsaturated aldehydes has been extended to a broad number of transformations. As examples we can cite the utilization of a-branched aldehydes [7], intramolecular reactions [44-46], and the use of anilines derivatives as nucle-ophihc aromatic systems [47, 48]. Diarylprolinol silyl ether analogs were also successfully used in such approaches. An example with 4,7-dihydroindoles, which after oxidation afford 2-substituted indole derivatives, is illustrated in Scheme 35.2 [11]. 

Substituting the benzene ring with a double bond, Pd-catalyzed intramolecular alkoxylation of alkyne 122 also proceeded via an alkenyl palladium complex to form furan 123 instead of a benzofurans [99, 100]. In addition, 3-hydroxyalkylbenzo[fc]furans was prepared by Bishop et al via a Pd-catalyzed heteroannulation of silyl-protected alkynols with 2-iodophenol in a fashion akin to the Larock indole synthesis, [101]. 

The silylation of heteroarenes was also reported [96]. Silylation of thiophene or furan with 11 occurs selectively at the ot-position in the presence of [Ir(COD) (OMe)]2/2-ferf-butyl-l,10-phenanthroline (tbphen, 17). Silylation of pyrrole or indole under the same conditions was unsuccessful presumably due to the presence of the acidic N-H bond. Accordingly, N-substituted pyrrole and indole undergo silylation with 11, to selectively give 3-substituted products (Scheme 7). 

Wang et al. investigated the catalytic behavior of cation exchange resin supported lanthanide(III) salts of the general structure (31) (Scheme 4.15), prepared from Dowex, Amberlite, Amberlyst and other resins [99]. It turned out that Am-berlyst XN-1010 and Amberlyst 15 complexed best with lanthanides(III). Thus, among others, electrophilic substitution of indole with hexanal and Mukayiama-type aldol reaction of benzaldehyde with ketene silyl acetal proceeded in excellent yields under catalytic conditions (Scheme 4.16). 

The reactive indolo-2,3-quinodimethanes are generated in situ generally from N-protected 2,3-disubstituted indoles (514,515). Generation of reactive indolo-2,3-quinodimethanes was achieved by fluoride-induced, 1,4-elimination of silylated indolyl ammonium salts, and was applied in the synthesis of substituted tetrahydrocarbazoles (516). Subsequently, the iodide-induced 1,4-elimination of ]V-benzoyl-2,3-bis(bromomethyl)indole (534) methodology was developed for the synthesis of reactive indolo-2,3-quinodimethanes and was applied for the first time in the synthesis of substituted carbazoles (e.g., 536) (517) (Scheme 5.14). 

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