SYNTHESIS 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...

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. 

Larock and co-workers described the one-step Pd-catalyzed reaction of o-haloanilines with internal alkynes to give indoles [385, 386]. This excellent reaction, which is shown for the synthesis of indoles 303, involves oxidative addition of the aryl halide (usually iodide) to Pd(0),. vyw-insertion of the alkyne into the ArPd bond, nitrogen displacement of the Pd in the resulting vinyl-Pd intermediate, and final reductive elimination of Pd(0). 

Even more attractive is the prospect of preparing phenazines in a single synthetic operation by sequential inter-Zintramolecular AT-arylation. This would require the transformation of either two o-haloanilines 122 and 135 or of an o-phenylenediamine 82 with an o-dihalobenzene 136. Until recently, not even a single example could be found for this one-step synthesis of heterocycles via double Pd-catalyzed AT-arylation. Numerous experiments conducted in a variety of different combinations of various Pd catalysts, bases, and phosphine ligands in our laboratory failed to realize this novel synthetic principle. 

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. 

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>. 

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

The dehydrohalogenation approach outlined in Scheme 1 reduces problems of selectivity in the synthesis of carbazoles. The method can be improved further by producing the N-aryl-2-haloaniline starting materials in the same pot as the subsequent carbazole product. This is achieved by Buchwald-Hartwig amination of 2-chloroanilines with aryl bromides [13], An illustrative example of this one-pot procedure is shown in Scheme 4. 

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]. 

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>. 

ORTON Haloaniline rearrangement 282 OSTROMISLENSKY Butadiene synthesis 282 OVERMAN Pyrrolidine synthesis 263... 

Pyridopyrimidines and pyrimidines fused with five- or six-membered heterocycles can be prepared via the ring closure of intermediate ethynylpyrimidines, which are themselves obtained by the Pd-catalyzed cross-coupling of halopyrimidines with alkynic compounds (Scheme 34). ° ""° o-Alkynylanilines such as (51), which are made by Pd-catalyzed coupling reactions of alkynes with o-haloaniline precursors, are easily cyclized to the indoles in the presence of base (Scheme 35). " " Similar meth( s can be employed in the synthesis of isocoumarins," thienopyridines," furopy-ridines" and the marine alkaloid asptamine." ... 

The indole nucleus is a common and important feature of a variety of natural products and medicinal agents.2 The traditional approach for preparing the indole nucleus is the Fischer indole reaction.3 As this reaction has shortcomings, the palladium-catalyzed coupling of ortho-haloanilines is becoming an excellent alternative.4 Recently, the submitters disclosed a new and efficient method for indole synthesis using a palladium-catalyzed annulation between o-iodoanilines and ketones (Scheme I).5... 

It is now possible to couple chlorophenols, haloanilines, and halovinyl alcohols with organozinc reagents without concern that protic groups found in R -X will react with the transmetalating agent. Equation 12.83 outlines this procedure, which also shows another variation in the synthesis of organozinc compounds— direct insertion of Zn into a C-X bond in the presence of LiCl.171... 

The aforementioned heteroannulation of o-haloanilines has been adapted by various means to the synthesis of carbazoles by several groups [458-462], and Larock has extended this to a carboline ring construction as shown for 400 to 401 [462]. 

A convenient synthesis of 2-mercaptobenzothiazoles 44 features an exclusive ortho-selective nucleophilic aromatic substitution reaction of or//zo-haloanilines 41 and subsequent intramolecular cyclization of the intermediate O-ethyl carbonodithioates 43 <05JHC727>. 2-Mercaptobenzothiazoles 44 are readily converted to the corresponding 2-chlorobenzothiazoles 45 upon treatment with sulfuryl chloride. 

Cyclizations. Synthesis of substituted indoles from o-haloanilines by condensation with ketones or nitriles is promoted by r-BuOK in DMSO. 

Indole synthesis. Lalloz and Caubere have reported a new synthesis of indoles from a halogenated aryl anil of type (1), prepared by condensation of a haloaniline with a ketone. Treatment of the anils with this complex base... 

Another recent copper-mediated approach for the construction of benzimidazole drugs uses a somewhat different strategy than those previously described. Inspired in part by Driver and Shen s iron(II)-catalyzed synthesis of benzimidazoles from aryl azides,Lee and co-workers have described a copper-catalyzed three-component synthesis of benzimidazoles from an o-haloaniline, an aldehyde, and sodium azide. Under the optimized conditions, the reaction proceeds with CuCl (5 mol%), TMEDA (5 mol%) in DMSO at 120 to afford benzimidazoles in moderate to high yields. The mechanism for this reaction has not been fully explored, but may involve the intermediacy of a 2-iminoaryl azide. This approach has been applied toward the one-pot synthesis of tiabendazole, a fungicide, and parasiticide sold under the trade names Mintezol and Tesederm. 

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