From 2-Haloanilines

In the cases of 2-iodo- and 2-chloroaniUnes the yields of desired 3-substituted dihydroquinoxalin-2-ones were, at best, 63 and 65 %, respectively, and unlike 2-bromoanilines did not depend on the reaction conditions (Tanimori et al. 2009). 

At mild room temperature, ligand-ffee copper-catalyzed coupling of a-amino acids 312a, c, e, 328, including heretofore-unexplored arylglycines 312a, with N-Boc-2-iodoanilines 327 to deliver A-arylated a-amino acids 329 has been developed 

In 2006, Kalinski and coworkers reported a new strategy employing an Ugi four-component reaction (4CR) and a Pd-assisted intramolecular iV-aryl amidation reaction (Kalinski et al. 2006). The Ugi(4CR) reaction of 2-bromoanilines 308, ketones/aldehydes 198e, 2531, carboxylic acid 331, and an isocyanide 254a, h, i in polar protic solvents (methanol, trifluoroethanol) generally resulted from good to 

Similarly, the Ugi four-component reaction of aldehydes 252a, 253a, b, m, n, 2-iodoaniline 334, indole-2-carboxylic acid 309e, isocyanides 254a-c, and 

When bicyclic iV-tosylcyclohexene and cyclopentene aziridines were used with various 2-bromoanilines flie process easily provided cyclohexa- and cyclopenta-annulated tetrahydroquinoxalines with up to 80 % yields (Ghorai et al. 2011). 

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The related cyclization of 2-ethynylanilines 67 also represents one of the usefiil methods for the synthesis of 2-substituted indoles since the precursors are easily prepared from 2-haloanilines 66 by Pd-catalyzed cross-coupling with terminal alkynes. Althou cyclizations of such alkynes are normally effected using Cu(I) or Pd(II) species, Sakamoto showed that in the absence of such metals, base catalysis (e.g., NaOEt) alone can accomplish the same goal. This author now reports that tetrabutylammonium fluoride (TBAF) is capable of inducing cyclization to the indoles 68 without affecting functionalities such as bromo, cyano, ethoxycarbonyl, and ethynyl <99JCS(P1)529>. 

P-carbohnes [29] (Schane 3, equation 1). A variety of secondary amines were employed, and the method was adapted to the preparation of pyrrolo[3,2-/lindoles and dipyrrolo[3,2-h 2, 3 -c]pyridines [30]. Cacchi and colleagues synthesized 3-aroylindoles from the copper-catalyzed cyclization of lV-(2-iodoaryl)enaminones (equation 2) [31]. The latter were prepared from 2-haloanilines and a,p-ynones, which can react directly with 2-iodoaniline under the copper protocol to give 3-benzoyl-2-phenylindole (76%), thus bypassing the enaminone. Patel described a copper-catalyzed 3-aroylindole synthesis from 2-alkynylated... 

Scheme 9 Copper-Catalyzed Indole Synthesis from 2-Haloanilines and p-Dicarbonyl Compounds...

Scheme 3.26 Pd-catafyzed synthesis of quinolines from 2-haloanilines.

As early as 1985, a palladium-catalyzed carbonylative procedure for the synthesis of 1,4-benzodiazepines was reported. Starting from 2-haloanilines and amino acids, the desired seven-membered heterocycles were formed in moderate yields. More recently, an efficient, one-pot method for the synthesis of dibenzodiazepinone derivatives involving copper-catalyzed tandem C-N bond formation was reported. Using various halo amide and 2-iodoaniline derivatives as substrates, an array of dibenzcxliazepinone... 

Scheme 4.9 Cu-catalyzed synthesis of dibenzodiazepinones from 2-haloanilines.

The von Richter cinnoline process was further extended to solid-phase synthesis. The route began from benzylaminomethyl polystyrene and the required diverse o-haloaryl resins represented by 21 were prepared from substituted o-haloanilines. A Pd-mediated cross-coupling reaction with 21 and the alkynes provided the alkynylaryl derivatives represented by alkyne 22. The von Richter cyclization reaction with hydrobromic or hydrochloric acid in acetone/HaO and cleavage from the resin occurred in the same step to furnish the cinnoline derivatives 23 in 47-95% yield and 60-90% purity (no yield reported for each entry). 

Scheme 6 Indoles from o-haloanilines synthesis of tryptamines and tryptophols via re-gioselective hydroformylation of functionalized anilines...

A few additional Pd-catalyzed schemes have been employed for Ilac type cyclization chemistry. Palladium-phenanthroline complexes were used by the Ragaini group to prepare indoles via the intermolecular cyclization of nitroarenes and alkynes in the presence of carbon monoxide <06JOC3748>. Jia and Zhu employed Pd-catalysis for the annulation of o-haloanilines with aldehydes <06JOC7826>. A one-pot Ugi/Heck reaction was employed in the preparation of polysubstituted indoles from a four-component reaction system of acrylic aldehydes, bromoanilines, acids, and isocyanides <06TL4683>. 

The cyclization of IV-allyl-o-haloanilines was adapted to the solid phase for both indoles [332, 333] and oxindoles [334]. For example, as illustrated below, a library of l-acyl-3-aIkyl-6-hydroxyindoles is readily assembled from acid chlorides, allylic bromides, and 4-bromo-3-nitroanisole [332], Zhang and Maryanoff used the Rink amide resin to prepare Af-benzylindole-3-acetamides and related indoles via Heck cyclization [333], and Balasubramanian employed this technology to the synthesis of oxindoles via the palladium cyclization of o-iodo-N-acryloylanilines [334], This latter cyclization route to oxindoles is presented later in this section. 

Whereas Hegedus [335] and Danishefsky [336] were the first to discover a tandem Heck reaction from o-allyl-A -acryloylanilines leading to tricyclic pyrrolo[l,2-a]indoles or pyridino[l,2-a]indoles [336], it has been the fantastic work of Grigg to unleash the enormous potential of this chemistry. Grigg and his co-workers parlayed their Pd-catalyzed tandem polycyclization-anion capture sequence into a treasure trove of syntheses starting with IV-allyl-o-haloanilines [337-345], Diels-Alder and olefin metathesis reactions can be interwoven into the sequence or can serve as the culmination step, as can a wide variety of nucleophiles. An example of the transformation of 289 to 290 is shown below in which indole is the terminating nucleophile [340],... 

Spiro-2-oxindoles, such as 331, are readily crafted from the Pd-catalyzed reactions of o-haloanilines with vinyl halides and triflates in the presence of CO [428]. The o-iodo enamide is presumed to form initially, followed by Heck cyclization. 

With conventional methods, the formation of indole derivatives from anilines proceeds at the expense of both unsubstituted ortho positions in the phenyl ring. This leads to undesirable by-products. Particularly, the formation of by-products takes place during Fischer s synthesis of benzohet-erocycles. In the previously described ion-radical variant of the synthesis, only one indole isomer is formed—the isomer that corresponds strictly to the structure of the starting haloaniline. 

In the second, >100 DBFs were identified in indoor chlorinated and brominated pools, including many nitrogenous DBFs (haloamides, halonitriles, haloanilines, haloamines, haloanisoles, and halonitro-compounds), likely due to the nitrogen-containing precursors from swimmers (urine, sweat, etc.) [143]. Trichloramine and THMs were also measured in the pool air [143]. Nitrosamines have been measured in chlorinated pools and hot tubs, up to a maximum of429 ng/L... 

Astatohalobenzenes have also been prepared from the corresponding haloaniline isomers by decomposition of their diazoniiun salts under conditions similarly described for astatotoluenes vide supra). Here again, relatively low radiochemical yields (10-26%) were obtained. Again, this has been attributed to the competing reaction of hydroxyl ions present in the aqueous solution in a much higher concentration than At , leading to the by-product formation of phenols 99,100,105). 

Ilac Gassman method for synthesis of indoles from /V-haloanilines 3.06.3.4.3... 

Amidine derivatives are effective dehalogenation inhibitors for the chemoselective hydrogenation of aromatic halonitro compounds with Raney nickel catalysts. The best modifiers are unsubstituted or N-alkyl substituted formamidine acetates and dicyandiamide which are able to prevent dehalogenation even of very sensitive substrates. Our results indicate that the dehalogenation occurs after the nitro group has been completely reduced i.e. as a consecutive reaction from the halogenated aniline. A possible explanation for these observations is the competitive adsorption between haloaniline, nitro compound, reaction intermediates and/or modifier. The measurement of the catalyst potential can be used to determine the endpoint of the desired nitro reduction very accurately. 

The synthesis of indoles by the photoinduced substitution reaction of o-haloanilines (22) with carbanions derived from aliphatic ketones in liquid ammonia is an important example of the SRN1 reaction followed by a spontaneous ring closure in the reaction media in moderate to excellent yield (53%-100%) [1]. Although the enolate anions of aromatic ketones do not react in liquid ammonia with 22, they will cyclize to indoles in DM SO under photoinitiation (Scheme 10.44) [60, 61]. 

The absorption spectra of the carbenes produced from the 2-halophenols are shown in Fig. 1 along with those obtained from the 4-halophenols and 4-haloanilines (see below). 

These results were interpreted with reference to an intramolecular heavy atom effect the authors concluded the carbene is formed from the excited singlet state of the molecule, in competition to intersystem crossing. A direct proof of this statement could, however not be obtained [24], It should be noted here that alternative explanations for the effect of halogen substitution on photolysis quantum yields have been put forward for the 4-haloanilines (see below). 

In the discussion of the mechanism of product formation from the 2-haloanilines, a strong similarity to the behavior of the 2-halophenols was noted. The two major monomeric products correspond to the processes of photohydrolysis and ring contraction which are also characteristic for this group of compounds (see above). The photohydrolysis reaction was proposed to be a concerted process of halide elimination and H20 attack. Two possibilities were noted for the ring contraction process, the first one similar to the mechanism observed for 2-chlorophenol, possibly via a singlet car-bene, the other one involving the intermediate formation of phenylnitrene. No direct proof could be obtained for either mechanism, not least because it was impossible to observe any transients by nanosecond spectroscopy. The... 

The first two derivatives in the series, monuron and metobromuron, are related to the 4-haloanilines. Their primary photochemistry has been studied by Boulkamh and Richard by means of nanosecond absorption spectroscopy [80]. The transients detected from both compounds in aqueous solution could be assigned to the N-substituted 4-iminocarbene, imino-p-benzoquinone-O-oxide and anilino radical from a complete analogy of their spectral and reactive behavior with that of the species obtained from 4-chloroaniline [55,57]. The quantum yields of carbene formation were determined to be = 0.051 for monuron and

halogen-substituted phenylurea derivatives underwent the same heterolytic dehalogenation process as the 4-haloanilines, which could be understood with reference to the protonability of the amine nitrogen, as in the case of 4-chloro-N,N-dimethylanilinc [55]. 

Several new routes involve formation of one carbon-carbon bond in pre-formed substrates. Palladium-catalyzed cyclization of /3-hydroxyenamine derivatives has been employed in a route to substituted pyrroles and 4,5,6,7-tetrahy-droindoles with multiple substituents by formation of the C-3-C-4 bond as the key feature, as illustrated by construction of the molecule 534 (Equation 146) <2006T8533>. Zinc perchlorate-catalyzed addition of alcohols to the nitrile functionality of a-cyanomethyl-/3-ketoesters, followed by annulation gave access to a series of substituted ethyl 5-alkoxypyrrole-3-carboxylates <2007T461>. Similar chemistry has also been used for synthesis of a related set of pyrrole-3-phosphonates <2007T4156>. A study on preparation of 3,5,7-functionalized indoles by Heck cyclization of suitable A-allyl substituted 2-haloanilines has also appeared <2006S3467>. In addition, indole-3-acetic acid derivatives have been prepared by base induced annulation of 2-aminocinnamic acid esters (available for instance from 2-iodoani-lines) <2006OL4473>. 

Many of the known examples involve base-promoted carbanion formation from aromatic amides. For example, indol-2-one derivatives 161 have been made by treatment of N-acyl-o-haloanilines 160 with LDA in THF, or KNH2 in liquid ammonia [132-134] (Scheme 35). Similarly, a,P-unsaturated anilides 162 afford the ring-closed 3-alkylideneoxindoles 163 on irradiation and treat-... 

Haloanilines are obtained from halonitrobenzenes preferably by the iron-acid reduction procedure. Nuclear halogenation occurs during the reduction of nitrobenzene by stannous chloride in the presence of acetic anhydride a quantitative yield of p-chloroacetanilide is obtained. Hydrogenation of halonitrobenzenes over Raney nickel catalyst is possible provided that the temperature is kept below 150°, at which point... 

By combining the advantages of known ort o-selective nucleophilic substitution of 2-haloanilines with potassium (or sodium) ethyl xanthate, followed by facile intramolecular cyclization step, a possible reaction pathway implies the formation of 2-thioxothio-chromen-4-one anionic intermediate la from o-bromoacetophenone and the xanthate. This intermediate can thereafter be transformed into the final products with yet another key intermediate, viz. thioalde-hyde, obtained apparently in situ from an appropriate aldehyde and potassium ethyl xanthate. 

Photophysical and flash photolysis experiments in various solvents showed that the resulting reactions of haloanilines proceed from the triplet state. The latter is involved in the photochemical processes resulting in C—X bond cleavages in which both homolytic and heterolytic pathways are rather competitive with each other152. There is also a certain correlation between the BDE(C—N) and activation energy for the C—N bond cleavage in the T state with the BDE(C—N) of the ground So state. 

In Ai-protonated 4-haloanilines, the C—X bond energies rapidly decrease in going from X = F to X = I. With a bonding energy of just around 224 kJ mol-1, cleavage of a C—I bond in (V-protonated iodoanilines readily takes place upon collisional activation giving the distonic isomers b, c or d. 

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