Unprotected indoles

Yoshino reports a novel and general method for the C-3 acylation of indoles with acyl chlorides in the presence of dialkylaluminium chloride which obviates the need for prior N-protection . Interestingly, as described in this preliminary communication, the unprotected indoles 147 are first treated with the Lewis acids prior to addition of the acid chlorides, yielding the desired 3-acyl derivatives 148. In reactions more typical of indoles under acidic conditions, Nakatsuka determined the structures of the dimers and trimers of 1-trimethylacetylindole produced in the presence of aluminium chloride . 

Iridium-catalyzed borylation has also proved to develop the first general approach to functionalized unprotected indoles at the 7-position [67]. This selectivity can be explained by the nitrogen-directed aromatic borylation pathway in the mechanistic steps (Scheme 7.34). 

Two years after the discovery of the first asymmetric Br0nsted acid-catalyzed Friedel-Crafts alkylation, the You group extended this transformation to the use of indoles as heteroaromatic nucleophiles (Scheme 11). iV-Sulfonylated aldimines 28 are activated with the help of catalytic amounts of BINOL phosphate (5)-3k (10 mol%, R = 1-naphthyl) for the reaction with unprotected indoles 29 to provide 3-indolyl amines 30 in good yields (56-94%) together with excellent enantioselec-tivities (58 to >99% ee) [21], Antilla and coworkers demonstrated that A-benzoyl-protected aldimines can be employed as electrophiles for the addition of iV-benzylated indoles with similar efficiencies [22]. Both protocols tolerate several aryl imines and a variety of substituents at the indole moiety. In addition, one example of the use of an aliphatic imine (56%, 58% ee) was presented. 

Later, the same group reported the Friedel-Crafts addition of unprotected indoles to enecarbamates containing aliphatic substituents (Scheme 5.6) [13]. Use... 

Protected and unprotected indole derivatives dissolved in hydrogen fluoride are also fluorinated by 18F-F. The relatively stable melatonin (10), a neurohormone responsible for the biological clock and other brain functions, gave only the 6-[l8F]fluoro derivative 11, but even the more fragile 5-hydroxytryptophan (12) could be fluorinated under these conditions resulting in a mixture of 4- and 6-[l8F]fluorohydroxytryptophan 13.54... 

The fert-butyloxycarbonyl (BOC) group is cleaved using TFA in an aprotic solvent like CH2C12. The cleavage proceeds via protonation of the carbonyl group of carbamate 16, subsequent elimination of carbenium ion 58 and liberation of unstable free carbaminic acid 60 which breaks down yielding the unprotected indole 61 with loss of C02. Cation 58 is deprotonated giving 2-methyl propene 59. 

The reaction of pyrrole with iodobenzene proceeds selectively at the 2-position when MgO is used as base, even without N-protection (Eq. 2) [7, 8]. The strong N-Mg interaction has been proposed as the key to the effective coupling. As expected, N-unprotected indoles are arylated selectively at the 2-position in the presence of MgO (Eq. 3). The arylation of indolidines occurs under conditions similar to those in Eq. (1) (Eq. 4) [9]. 

A second, more versatile, method involves the O-acyl thiohydroxamates. These compounds are generally prepared by reaction of acyl chlorides with the commercial sodium salt (1) of 2-mercapto-pyridine A(-oxide (equation 6 X = Cl). Use of mixed anhydrides formed by reaction of the carboxylic acid with isobutyl chloroformate (equation 6 X = OCC>2CH2CHMe2) renders the procedure compatible with unprotected indoles, phenols, secondary and, presumably, tertiary alcohols. An alternative mode of preparation of the 0-acyl thlohydroxamates involves the s t (2) in reaction with the carboxylic acid (equation 7). 

The aluminum chloride-promoted Friedel-Crafts acylation can also be successfully performed in ionic media. An easy-to-handle ionic liquid is that prepared from a mixture of one to two equivalents of aluminum chloride and l-ethyl-3-methylimidazolium chloride or iodide (EtMeimCl-AlCl3 and EtMeiml-AlCls, respectively). These solvent-catalysfs can be utilized in the easy and efficient acylation of unprotected indoles with a variety of acyl chlorides to give C-selective acylation at the 3-position in 38%-87% yield. ... 

Strong N-Mg interaction has been proposed to be the key for the effective coupling. As expected, N-unprotected indole is arylated selectively at the 2 position in the presence of MgO. The arylation of indolidines has also been reported [133]. 

The regiochemical course of the above reactions was similar to what was observed in Pindur s work. However, the diastereoselectivity for the Diels-Alder reactions involving A-acylated indoles 139 was quite different than that previously reported. When the unprotected indole derivatives 135 were subjected to Diels-Alder cycloadditions, the endo products were formed almost exclusively. In contrast, the cycloadditions with A-protected indoles in the presence of magnesium perchlorate as the Lewis acid provided a wide range of endo/exo product ratios (143 144, Scheme 36). 

Carbonylation of a 2-iodoindole in the presence of an amine provides a method for the preparation of indole-2-carboxamides 76 (Scheme 35). Unprotected indole was a better substrate than its Boc-protected derivative in this reaction. The methodology can also be used to construct more complex carbamates 77. " ... 

Alford and Davies reported the aminoacylation of indoles and pyrroles via a three-component reaction with ynol ethers and sulfonyl azides. In the presence of copper(I) thiophene-2-carboxylate (CuTC), alkyne 221 and azide 222 react to form an intermediate Al-sulfonyltriazole. N-Methylin-dole (220) adds into this species, which after quench, affords acylated indole 223 in good yield. Various substitution patterns on the indole are tolerated unprotected indole also works and delivers the expected product in 57% yield (14JA10266). 

Corey et al. recently revived this useful transformation in the syntheses of several tryptophan-derived natural products [134]. For eiample, an unusual paUadium(II)-catalyzed ring closure under an atmosphere of dioxygen followed by ring enlargement (cf Scheme 7.54) is the key step in the total synthesis of okaramrne N (217) (215 216 Scheme 7.52). This transformation is particularly remarkable because C—H bond activation is chemoselective the unprotected indole unit reacted whereas the N-protected indole remained untouched during the catalysis. 

Boron Conjugate addition of alkenylboronic acids PhCH=CHB(OH)2 and alkynylboronic esters to ArCH=CHCOMe (Ar = unprotected indoles), carried... 

The aminoquinolinamide auxiliary was also shown to mediate the construction of 1,1,2-trisubstimted arylcyclopropanes [43]. Substrate 78, bearing a cis-substituted cyclopropyl moiety, reacted smoothly with a variety of (hetero)aryl iodides in a Pd-catalyzed, Ag-mediated transformation (Scheme 21). Notably, substituents such as an aldehyde, a hydroxyl, or an unprotected indole were tolerated under the reaction conditions. Additionally, the reactivity of trans-cyclopropyl substrate 79 was investigated (Scheme 21). The challenge here was... 

The optimization of the PKR for forming the bridged bicyclic core of (-)-alstonerine was discussed above. The eneyne 88 employed in the successful synthesis was available in enantiopure form from trytophan in four steps. Neither the unprotected indole nitrogen nor the additional sp centers in the piperidine ring adversely affected the PKR. Under the optimized conditions, the desired compound 89 was isolated in 92% yield as a single diastereomer. 

Chiral indolines represent useful building blocks in pharmaceuticals, herbicides and insecticides. Asymmetric hydrogenation of unprotected indoles with molecular hydrogen represents the most straightforward and atom-economy method to produce these compounds.Although the asymmetric (up to 98% ee) hydrogenation of N-protected or N-Ts indoles with is known since 2000 (R. Kuwano, Kyushu... 

The enantioselective hydrogenation of V-unprotected indoles with H2 in CH2CI2 and TFE (1 1) is catalysed by Pd(OCOCF3)2/(5)-Cio-BridgePHOS (33) in the presence of D-camphorsulfonic acid (additive) to indolines in quantitative yield and up to 98% ee. The methodology is suitable for the hydrogenation of indoles substituted at the... 

An intermolecular asymmetric addition of heteroarenes (indoles, thiophenes, pyrroles, and furans) to bicycloalkenes has been developed (with <99% ee). The reaction is catalysed by the complex generated from [(COD)lrCl]2 (1.5mol%) and (5)-TDBM-SEGPHOS (3 mol%) and proceeds in THF at 100 °C over 24 h via the initial activation of the C-H bond vicinal to the heteroatom (even with unprotected indoles, which typically undergo alkylation at the C(3) position), followed by a iy -addition across the C=C bond.128... 

Triarylphosphines could be utilized as coupling partners in biaryl couplings with oxazoles, thiazoles, benzothiazole, and unprotected indole (eq 43). ... 

The classical Fischer indole synthesis has persisted as a commonly used procedure due to its working simplicity. However, this method suffers some drawbacks, such as the need for strong acids, poor selectivity with unsymmetrical ketones, and poor functional group tolerance. Huang et al. developed an alternative synthetic strategy for the synthesis of unprotected indoles a tandem ortho-C-H activation and annulation by using triazenyl arenes and alkynes. This reaction involves a ring contraction by a 1,2-Rh shift and an N=N insertion (Eq. (5.12))... 

Enantioenriched indolines are very important compounds, which exist extensively in natural alkaloids or unnatural bioactive compounds. The development of facile methods toward chiral indolines continues to be a challenge for organic chemists. Unprotected indole 106 could be considered as a special enamine in an aromatic system. Inspired by the possible shift between enamine and imine of indole in the presence of strong acid. Sun and Chen et al. envisioned that a direct reduction of indole 106 to indoline 107 by a combined catalysis of Lewis base and Br0nsted acid would be highly possible (Scheme 32.24). Indeed, using the strategy... 

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