Pyridyl indoles from

Recently, Wu group synthesized a series of novel iV-(2-pyridyl)indoles from alkynes and aniline derivatives via a heterogeneous Pd-catalyzed oxidative C-H activation reaction [10]. In the presence of Pd/Ce02 catalyst, only catalytic amounts of Cu(II) and air as co-oxidant were required, delivering the desired indoles in moderate to excellent isolated yields (Scheme 14.8). As shown, both... 

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]. 

The preparation and study of tautomers derived from 2-(2 -pyridyl)indole, 2-(2 -pyrrolo)[l,8]naphthyridine, and related heterocycles has been undertaken using ultraviolet (UV) and nuclear magnetic resonance (NMR) spectroscopy and also by molecular orbital (MO) calculations <1998JOC4055>. 

The reaction of l-methyl-2-(2 -pyridyl)indole (274) with bromoacetone in acetone gave the dimethyl derivative (275) of indoloquinolizinium salt (42%). The cyclization product from 2-(2 -pyridyl)indole (276), however, was not 7-methyl-12//-indolo[2,3-a]quinolizinium salt (277), but 11-meth-ylindolo[2,1 -a]-2-azoniaquinolizinium salt (278) (34%) (64JOC3584). 

Examples of migratory insertion to aromatic rings also include the total syntheses of anhydrolycorine-7-one (217) [102] and the f-azaebutnane series [103]. As illustrated in Scheme 38, an intramolecular Heck reaction of Af-acylindoline 216 installed the six-membered lactam in anhydrolycorine-7-one (217). In a similar process, the tetracyclic pyrido-[2 ,3 -prepared from bromopyridine 218 under phase-transfer catalysis conditions. Pyridyl indole 219 is a precursor of the pentacyclic skeleton of the E-azaeburnane series. 

Highly nucleophilic aromatic compounds are capable of arylating acyl-pyridinium salts. The first example of this striking reaction was described by Koenigs and Ruppelt s ho observed the formation of 4-(/>-dimethyl-aminophenyl) pyridine from pyridine, benzoyl chloride and dimethyl-aniline in the presence of copper. Benzaldehyde is also formed s, 736 and the copper is not necessaryThe dihydropyridine (105) is probably an intermediate. Other examples of the reaction are known s, 493 but attempts to isolate the intermediates have failed , though that from dimethyl-m-toluidine may have been obtained. In contrast, the dihydropyridines (106) were isolated when indole was the nucleophile. Skatole reacted similarly, at the 2-position of the indole nucleus, giving the fully aromatic 3-methyl-2-(4 -pyridyl)indole. These reactions failed with 2- and 4-picoline . Similar reactions occur between acylpyridinium salts and pyrroles (p. 71). 

Both vinyl- and aryl triflates have been cross-coupled with 2-furylzinc chloride [26-28]. Since vinyl triflates are easily obtained from the corresponding ketones, they are useful substrates in Pd-catalyzed reactions. In the following example, a Negishi coupling of 2-furylzinc chloride and indol-5-yl triflate (22) provided an expeditious entry to 2-(5 -indolyl)furan (23). Protection of the NH in the indole ring was not required. A similar reaction was successful with pyridyl- and quinolinyl triflates. 

Aqueous NaOH (40%, 3 ml) is added dropwise to the indole (5.2 mmol), TosN, (1.02 g, 5.2 mmol) and TEBA-CI (30 mg, 0.13 mmol) in PhH (40 ml). The mixture is stirred at room temperature for 18 h in the dark and the organic phase is then separated, washed with H20 (3 x 30 ml), dried (Na2S04), and evaporated to yield the diazoindole, which can be purified by chromatography from silica [e.g. 3-diazo-2-phenyl-3//-indole, 75% 3-diazo-2-(2-pyridyl)-3//-indole, 87% 3-diazo-2-(2-thienyl)-3W-indole, 83%]. 

Structural information on aromatic donor molecule binding was obtained initially by using H NMR relaxation measurements to give distances from the heme iron atom to protons of the bound molecule. For example, indole-3-propionic acid, a structural homologue of the plant hormone indole-3-acetic acid, was found to bind approximately 9-10 A from the heme iron atom and at a particular angle to the heme plane (234). The disadvantage of this method is that the orientation with respect to the polypeptide chain cannot be defined. Other donor molecules examined include 4-methylphenol (p-cresol) (235), 3-hydroxyphenol (resorcinol), 2-methoxy-4-methylphenol and benzhydroxamic acid (236), methyl 2-pyridyl sulfide and methylp-tolyl sulfide (237), and L-tyrosine and D-tyrosine (238). Distance constraints of between 8.4 and 12.0 A have been reported (235-238). Aromatic donor proton to heme iron distances of 6 A reported earlier for aminotriazole and 3-hydroxyphenol (resorcinol) are too short because of an inappropriate estimate of the molecular correlation time (239), a parameter required for the calculations. Distance information for a series of aromatic phenols and amines bound to Mn(III)-substituted HRP C has been published (240). 

Benzofuranyl)pyrroles, 2-(2-thienyl)pyrroles , 2,2 -dipyrroles, 3-(2-pyr-rolyl)indoles , 2-(2-benzimidazolyl)pyrroles and2-(2-, 3- and4-pyridyl)pyrroles were prepared using this method. Reaction of alkynes (for example, propyne) or allene with ketoximes in a superbase system (MOH/DMSO) leads to 2,5-di- or 2,3,5-trisubstituted pyrroles Pyrroles and dipyrroles were synthesized also from corresponding dioximes and acetylene in a KOH/DMSO system It has also been shown that 1,2-dichloroeth-ane can serve as a source of acetylene in pyrrole synthesis. Oxime 52 in the system acetylene/RbOH/DMSO at 70 °C afforded a mixture of three pyrroles 53-55 in low yields (equation 23). The formation of product 53 occurred through recyclization of pyrrolopy-ridine intermediate. ... 

Attention was centered on radical precursors in which the 3-pyridyl moiety was attached at the indole-3-position with the aim of directly producing the pyrido[4,3-b]carbazole skeleton of ellipticine by regioselective cyclization upon the 4-position of the pyridine ring. Satisfactorily, A-methyl and A-benzyl selenoesters 52a and 52b led to the ellipticine quinones 53a and 53b in acceptable yields (60 and 42% yield, respectively), after the radical cyclization and the in situ oxidation at the interannular methylene group. The cyclization was clearly less efficient from A-(methoxymethyl) selenoester 52c and no reaction was observed... 

As base. Many reactions that are promoted by a base can be effected with KF/AljO, for example, in deprotonating malononitrile for Michael reaction, in N-pyridylation of indole which is based on the S,.jAr mechanism, and in the preparation of a-heterosubstituted Weinreb amides from 7V-methoxy-A(-methyl chloroacetamide. ... 

Direct 3-lithiation can be accomplished with ortfto-assistance from a 2-(2-pyridyl)- or a 2-carboxyl group. Direct 3-lithiation even without a snbstitnent at C-2 can be achieved with an iV-di(f-butyl) flnorosilyl-, iV-tri-i-propylsilyl- or iV-(2,2-diethylbntanoyl)-snbstitnent in place, the latter nsing sec-bntyllithium in the presence of iV,iV,iV, iV iV -pentamethyldiethylenetriamine. Other directed metallation processes in the hetero-ring include 2-lithiation of 1-substituted indole-3-carboxylic acids and amides, and of 3-hydroxymethyl-l-phenylsulfonylindole. ... 

Most syntheses of aza-indoles start from pyridines and parallel the standard indole syntheses discussed above. However, the Fischer reaction using pyridyl-hydrazones is much less consistent and useful than for arylhydrazones the Madelung reaction is also not as useful, however the Bartoli route" (20.16.1.9) and the Gassman approach" (20.16.1.12) can be used to effect. The most successful methods involve palladium-catalysed coupling of acetylenes with amino-halo-pyridines either as one-" or two-step " processes. The starting amino-halo-pyridines are generally available via directed metaUations. 

With the additive 2-oxazoUdinone in DMSO to assist Cul at 120°, A-arylation of amides (lactams) is readily performed. A more commonly used ligand is 1,10-phenanthroline, as it is applied also to form iV-(aryl)alkoxyamines from RNHOR. In A-arylation of iV-heterocycles (indole, pyrrole, imidazole, pyrazole,...), l,3-di(2-pyridyl)-l,3-propane-dione appears to be a useful ligand for Cul. ... 

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