2-Methyl-4-iodoaniline

This new impurity proved to be derived from the Pd-catalyzed oxidation of DIPA to the enamine via P-hydride elimination. In fact, mixing Pd(OAc)2 with DIPA in DMF-d7 readily formed Pd black along with two species, primary amine and acetone, presumably derived from the enamine through hydrolysis. The resulting enamine or acetone then underwent a coupling reaction with iodoaniline 28. Heterocyclization through the arylpalladium(II) species provided 2-methyl indole 71, as shown in Scheme 4.19. 

Palladium-catalyzed reactions of arylboronic acids have been utilized to craft precursors for constructing indole rings. Suzuki found that tris(2-ethoxyethenyl)borane (149) and catechol-derived boranes 150 readily couple with o-iodoanilines to yield 151, which easily cyclize to indoles 152 with acid [158]. Kumar and co-workers used this method to prepare 5-(4-pyridinyl)-7-azaindoles from 6-amino-5-iodo-2-methyl-3,4 -bipyridyl [159], A similar scheme with catechol-vinyl sulfide boranes also leads to indoles [160]. A Suzuki protocol has been employed by Sun and co-workers to synthesize a series of 6-aryloxindoles [161]. 

Gronowitz adapted this technology to one-pot syntheses of indole-3-acetic acids and indole-3-pyruvic acid oxime ethers from A-BOC protected o-iodoanilines [328, 329]. Rawal employed the Pd-catalyzed cyclization of A-(o-bromoallyl)anilines to afford 4- and 6-hydroxyindoles, and a 4,6-dihydroxyindole [330], and Yang and co-workers have used a similar cyclization to prepare 8-carbolines 287 and 288 as illustrated by the two examples shown [331]. The apparent extraneous methyl group in 288 is derived from triethylamine. 

Bowman et al. reported the total synthesis of ellipticine (228) involving an imidoyl radical cascade reaction (730). For this key step, the required imidoyl radical was generated from the imidoyl selanide 1290, which was obtained from ethyl 2-(4-pyridyl)acetate (1286). Reaction of 1286 with LDA, followed by addition of methyl iodide, led to the corresponding methyl derivative 1287. Treatment of 1287 with 2-iodoaniline (743) in the presence of trimethylaluminum (AlMes) afforded the amide 1288. Using Sonogashira conditions, propyne is coupled with the amide 1288 to afford the aryl acetylene 1289. The aryl acetylene 1289 was transformed to the... 

The synthetic utility of many of the substitution reactions described so far is limited because there are well-established thermal routes to the same products. However, a third group of photochemical nucleophilic substitutions involves aryl halides and nucleophiles based on sulfur, phosphorus or, of particular importance, carbon. Two examples are the reaction of bromobenzene with the anion of t-butyl methyl ketone 13.12), and the replacement of bromine by cyanomethyl in 2-bromopyridine (3.13). This type of reaction offers a clear advantage over lengthy thermal alternatives, and intramolecular versions have been used in the synthesis of indoles (e.g. 3.14) or benzofurans from o-iodoaniline or o-iodoanisole respectively. 

Cyclizations occur with secondary amine derivatives, also. N-Allyl-o-iodoaniline produces 3-methyl-indole, for example, in high yield at 25 C using sodium carbonate as the base with tetrabutylammonium chloride in DMF solution (equation 24).7S Similar procedures have been applied to the synthesis of in-... 

The reaction proceeds well with unhindered secondary amines as both nucleophiles and bases. The yield of allylic amine formed depends upon how easily palladium hydride elimination occurs from the intermediate. In cases such as the phenylation of 2,4-pentadienoic acid, elimination is very facile and no allylic amines are formed with secondary amine nucleophiles, while phenylation of isoprene in the presence of piperidine gives 29% phenylated diene and 69% phenylated allylic amine (equation 30).84 Arylation occurs at the least-substituted and least-hindered terminal diene carbon and the amine attacks the least-hindered terminal ir-allyl carbon. If one of the terminal ir-allyl carbons is substituted with two methyl groups, however, then amine substitution takes place at this carbon. The reasons for this unexpected result are not clear but perhaps the intermediate reacts in a a- rather than a ir-form and the tertiary center is more accessible to the nucleophile. Primary amines have been used in this reaction also, but yields are only low to moderate.85 A cyclic version occurs with o-iodoaniline and isoprene.85... 

T.F. Walsh and co-workers synthesized two (S)- 3-methyl-2-aryltryptamine based gonadotropin hormone antagonists via a consecutive Larock indole synthesis and Suzuki cross-coupling. The required (S)-P-methyltryptophol derivatives were prepared by coupling 4-substituted o-iodoanilines with optically active internal alkynes under standard conditions. The resulting 2-trialkylsilyl substituted indoles were then subjected to a silver-assisted iododesilylation reaction to afford the 2-iodo-substituted indoles that served as coupling partners for the Suzuki cross-coupling step. 

Ionized aniline possesses an isomeric stable species, the 4- (or 3-) dehydroanilinium distonic ions (m/z 93). It is thus expected that their identification could afford some additional pieces of information related to the localization of the initial site of protonation. The distonic ions can readily be prepared by protonation of iodoanilines followed by collisional deiodination. Such a protonation-deiodination sequence is also readily performed in the quadrupole-time of flight instrument and the CID spectra of all the m/z 93 ions are collected in Table 5. As a reference for aniline radical cations, AZ-methylaniline was used and was observed to intensively expel a methyl radical after protonation and excitation (high cone voltage). 

The synthesis of 2,3-disubstituted indoles 17 by the palladium-catalyzed coupling of 2-iodoanilines or its A-methyl, -acetyl and -tosyl derivatives with a wide variety of internal alkynes139 (equation 18) was reported. 

Fluoro-4-iodoaniline Aniline, 2-fluoro-4-iodo- (8,9) (29632-74-4) p-Toluenesulfonic acid monohydrate (8) Benzenesulfonic acid, 4-methyl-, monohydrate (9) (6192-52-5)... 

In the area of organometallic chemistry, we begin with a procedure for the palladium-catalyzed animation of aryl halides and aryl triflates, illustrated by syntheses of N-HEXYL-2-METHYL-4-METHOXYANIUNE and N-METHYL-N-<4-CHLOROPHENYL)-ANILINE. The next procedure describes the synthesis of 1,2,3,4-TETRAHYDROCARBAZOLE by the palladium-catalyzed annulation of ketones with o-iodoaniline. Next, a procedure for the synthesis of 2,7-DIMETHYLNAPHTHALENE via the nickel-catalyzed coupling of aryl O-carbamates with Grignard reagents is presented. The fourth procedure in this section describes the synthesis of 5-METHYL-2,2 -BIPYRIDINE by a Negishi cross-coupling reaction... 

Reaction of o-iodoaniline (33) with internal alkynes offers a good synthetic method of substituted indoles [13], A practical synthesis of psilocin was carried out by utilizing the reaction of the iodoaniline derivative 34 with internal alkyne to form an indole derivative as a key reaction [14], The thieno[3.2- ]pyrrole 37 was obtained by the reaction of 2-iodo-3-aminothiophene (35) with the alkyne 36 [15], These reactions of aryl iodides proceed in the absence of phosphine ligands. The isocoumarin 39 was obtained by the reaction of methyl o-iodobenzoate (38). Poor yield was obtained when the free acid was used [11]. 

To a 2-L round-bottomed flask were added 102 g 2-iodo-6-methoxyaniline (0.41 mol), 179 g Schollkopf derivative (0.49 mol), 17.4 g LiCl (0.41 mol), 141.3 g K2CO3 (1.02 mol) 1.84 g Pd(OAc)2 (8.2 mmol), and 700 mL anhydrous DMF. The mixture was then degassed with a vacuum pump three times at room temperature (with argon). The suspension that resulted was heated for 36 h at 100°C under an atmosphere of argon. After the consumption of iodoaniline, as monitored by TLC, the reaction mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with H2O (5 x 20 mL) to remove DMF. The organic layer was washed with brine, dried over Na2S04, and concentrated under reduced pressure. Purification by flash chromatography over silica gel (2% EtOAc/hexane) provided 149 g (5/f,25 )-3,6-diethoxy-2-isopropyl-5-[7-methoxy-2-(triethylsilyl)-3-indolyl]methyl-2,5-dihydropyrazine as a yellow oil, in a yield of 75%. 

The synthesis of 11-methoxymacroline 350 (239) required 6-methoxy-D-tryptophan 359, which was prepared by Larock s Pd-catalyzed heteroannulation of iodoaniline 360 and the propargyl compound 361 (prepared in turn from the Schollkopf chiral auxiliary derived from L-valine), followed by removal of the chiral auxiliary, and N(l)-methylation (Scheme 28). The 6-methoxy-D-tryptophan 359 was then transformed into the pentacyclic sarpagine derivative 362, via the 11-methoxytetracyclic ketone 354, following the same protocol as that employed in the A -methylsarpagine synthesis (vide... 

A binaphthyl-based PTC (S)-21 was found to be an effective catalyst for the catalytic asymmetric synthesis of axially chiral o-iodoanilides. M-allevlation of achiral o-iodoanilines catalysed by (S)-21 gave axially chiral o-iodoanilides in high enantioselectivity (Scheme 17.27). In this reaction, the large steric difference between the ort/zo-substituents (methyl and iodo groups) on anilides was necessary to achieve high enantioselectivity. 

Two (5)-P-methyl-2-aryltryptamine-based gonadotropin-releasing hormone antagonists 95 and 96 were synthesized via a consecutive Larock indole synthesis and Suzuki cross-coupling reaction." The key transformation involved the Larock heteroannulation of o-iodoaniline 97 with chiral silyl alkyne 98 in the presence of Pd(OAc)2, PPha, 1 equiv of LiCl, and 2.5 equiv of K2CO3 in DMF at 100 °C to give 99 in 72% yield. 

A copper-catalyzed intermolecular cyclization of 2-iodoanilines with allenes was developed by Huang and co-workers in 2012. This new methodology allows for the synthesis of 2-methyl-lH-indole-3-carbo)ylates in moderate to good yields from readily available substrates (Scheme 2.89). 

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