Preparation of Heteroaromatics

Masahiro Yoshida of the University of Tokushima described Tetrahedron Lett. 2008, 49, 5021) the Pt-mediated rearrangement of alkynyl oxiranes such as 1 to the furan 2. Roman Dembinski of Oakland University reported J. Org. Chem. 2008, 73, 5881) a related zinc-mediated rearrangement of propargyl ketones to furans. The cychzation of aryloxy ketones such as 3 to the benzofuran 4 developed Tetrahedron Lett. 2008, 49, 6579) by Ikyon Kim of the Korea Research Institute of Chemical Technology is likely proceeding by a Friedel-Crafts mechanism. 

Sandro Cacchi and Giancarlo Fabrizi of Universita degli Studi La Sapienza , Roma, observed Organic Lett. 2008,10, 2629) that base converted the enamine 5 to the pyrrole 6. Alternatively, oxidation of 5 with CuBr led to a pyridine. Zhuang-ping Zhuan of Xiamen University prepared Adv. Synth. Cat 2008, 350,2778) pyrroles such as 9 by condensing an alkynyl carbinol 7 with a 1,3-dicarbonyl compoimd. Richard C. Larock of Iowa State University fotmd J. Org. Chem. 2008, 75, 6666) that combination of an alkynyl ketone 10 with 11 followed by oxidation with I-Cl led to the pyrazole 12. 

A variety of methods have been put forward for functionalizing pyridines. Sukbok Chang of KAIST described J. Am. Chem. Soc. 2008, 130, 9254) the direct oxidative homologation of a pyridine A-oxide 16 to give the unsaturated ester 18. Jonathan Clay den of the University of Manchester observed (Organic Lett. 2008,10, 3567) that metalation of 19 gave an anion that rearranged to 20 with complete retention of enantiomeric excess. 

Driver of the University of Illinois, Chicago found (Angew. Chem. Int. Ed. 2008, 47, 5056) that Rh octanoate catalyzed the well-known thermal conversion of an azide such as 28 to the indole 29. Valeriya S. Velezheva of the A. N. Nesmeyanov Institute of Organoelement Compormds uncovered (Tetrahedron Lett. 2008, 49, 7106) an improved protocol for the Nenitzescu s mthesis, combining 30 and 31 to give 32. For an overview of the nine t5 es of indole synthesis, see our upcoming review in Angewanrfie Chemie. 

It has been known for some time that an acid chloride 1 can be added to an alkyne 2 to give the P-chloro enone. Yasushi Tsnji of Kyoto University found J. Am. Chem. Soc. 2009,131, 6668) that with an Ir catalyst, the condensation of 1 with 2 could be directed to the litran 3. Huanfeng Jiang of the Sonth China University of Technology described Organic Lett. 2009, 77,1931)a complementary ronte to lurans, Cu-mediated condensation of a propaigyl alcohol 4 with the diester 5 to give 6. 

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Kiener, A. (1992) Enzymic oxidation of methyl groups in heteroarenes a versatile method for the preparation of heteroaromatic carborylic acids. Angewandte Chemie-International Edition, 31 (6), 774—775. 

The reaction sequence described herein enables the preparation of heteroaromatic stilbenes by direct condensation of methyl or methylene groups with anils derived from aromatic aldehydes, in the presence of strong base, and in certain dipolar aprotic solvents. 

The preparation of heteroaromatic olefinic electroluminescencing derivatives is described (3) and illustrated, (IV). 

General methods of preparation of heteroaromatic Ar-imines arc beginning to be recognized, but they have not yet been widely applied. In addition, several special methods exist which have been used only for one specific heterocycle. Given this situation, the methods of preparation are classified in this chapter according to the parent heterocycle. The four most general methods of preparation are discussed in detail under the pyridine Ar-imines since this is where the experimental material is most extensive. 

A common method of preparation of heteroaromatic A-imines is the deprotonation of the corresponding A-aminoimmonium salts (12). Most of the pyridine A-imines synthesized have been obtained by this method. The strength of base necessary for deprotonation depends on the substituent R in the salts (12) (see Section III,F). For instance, dilute aqueous alkali is sufficient for A-acyl-, Ar-sulfonyl-, and A-carbamoylimines, but concentrated alkali must be used for unsubstituted A-imines. Unsubstituted pyridine A-imines have only been detected by spectroscopic methods in solution (see Section III,B, and III,D). 

Bastug G, Eviolitte C, Mark6 IE (2012) Functionalized orthoesters as powerful building blocks for the efficient preparation of heteroaromatic bicycles. Organic Lett 14 3502-3507... 

A novel method for preparing amino heterocycles is illustrated by the preparation of 2-amino-5-methylthiophene (159). In this approach vinyl azides act as NH2 equivalents in reaction with aromatic or heteroaromatic lithium derivatives (82TL699). A further variant for the preparation of amino heterocycles is by azide reduction the latter compounds are obtained by reaction of lithio derivatives with p- toluenesulfonyl azide and decomposition of the resulting lithium salt with tetrasodium pyrophosphate (Scheme 66) (82JOC3177). 

Silylated cyanohydrins have also been prepared via silylation of cyanohydrins themselves and by the addition of hydrogen cyanide to silyl enol ethers. Silylated cyanohydrins have proved to be quite useful in a variety of synthetic transformations, including the regiospecific protection of p-quinones, as intermediates in an efficient synthesis of a-aminomethyl alcohols, and for the preparation of ketone cyanohydrins themselves.The silylated cyanohydrins of heteroaromatic aldehydes have found extensive use as... 

Silver(I) triflate is widely applied to the preparation of various derivatives of triflic acid, both covalent esters [66] and ionic salts For example, it can be used for the in situ generation of iodine([) triflate, a very effective lodinatmg reagent for aromatic and heteroaromatic compounds [130] (equations 65 and 66)... 

Van Leusen and co-workers also demonstrated the condensation of heteroaromatic aldehydes with TosMIC. Table 6.7.1 shows the 5-heteroaryloxazoles 6 prepared in 47-88% yield in the presence of equimolar amounts of potassium carbonate in refluxing methanol. 

Tlie interest in the preparation and use of dithiolium salts in connection with the synthesis of TTF derivatives led to the development of a new uses of heteroaromatic cations in organic synthesis. Based on that, a new carbonyl olefination for the synthesis of numerous heterofulvalenes was developed (77S861). For example, 2-dimethoxyphosphinyl-l,3-benzodithiole was deprotonated with butyllithium in THF at -78°C and the resulting phosphonate carbanion reacted with 9-alkyl-acridones to give the dithia-azafulvalenes of type 45 (78BCJ2674) (Scheme 15). 

Tliionyl halides and A-heteroaromatics are known to be in equilibrium with the corresponding A-(halosulhnyl)heteroarylium halides. N-(Chlorosulhnyl)pyridinium chloride (36), for example, readily reacts with a second molecule of pyridine to give the A-[l-chlorosulhnyl-l,4-dihydro-pyridine-4-yl]pyridinium chloride (37a). The intermediate 37a is probably involved in the preparation of A-(pyridine-4-yl)pyridinium chloride hydrochloride (37b). However, the authors could not detect either 37a or 37b in their experiments (91CB2013) (Scheme 10). 

Methods for the Preparation of Aromatic and Heteroaromatic Diazo Compounds... 

The dienone, which is prepared essentially as described by Benedikt7 and Calo,8 monobrominates a wide range of primary, secondary, and tertiary aromatic amines almost exclusively in the para-position. The procedure described is of general synthetic utility for the preparation of para-brominated aromatic and heteroaromatic amines in high yields and frequently in a high state of purity. The submitters have used this technique to para-brominate many compounds in quantities... 

Recently, the required heteroaromatic organozinc halides for the Negishi reaction have also been prepared using microwave irradiation [23]. Suna reported that a Zn - Cu couple (activated Zn), prepared using a slightly modified LeGoff procedure from Zn dust and cupric acetate monohydrate, allowed the smooth preparation of (3-pyridinyl)zinc iodide and (2-thienyl)zinc iodide... 

Until 1987, the (R)-PaHNL from almonds was the only HNL used as catalyst in the enantioselective preparation of cyanohydrins. Therefore, it was of great interest to get access to HNLs which catalyze the formation of (5 )-cyanohydrins. (5 )-SbHNL [EC 4.1.2.11], isolated from Sorghum bicolor, was the first HNL used for the preparation of (5 )-cyanohydrins. Since the substrate range of SbHNL is limited to aromatic and heteroaromatic aldehydes as substrates, other enzymes with (5 )-cyanoglycosides have been investigated as catalysts for the synthesis of (5 )-cyanohydrins. The (5 )-HNLs from cassava (Manihot esculenta, MeHNL) and from Hevea brasiliensis (HbHNL) proved to be highly promising candidates for the preparation of (5 )-cyanohydrins. Both MeHNL and HbHNL have been overexpressed successfully in Escherichia coli, Saccharomyces cerevisiae and Pichia pastoris. 

The aforementioned PEPPSI-IPr pre-catalyst 16 has also been used in the Suzuki-Miyaura reaction. This pre-catalyst allowed the easy preparation of hindered biaryls and drug-like heteroaromatic compounds in good to excellent yields (Scheme 6.27). 

The introduction of a formyl or acyl group can be achieved by transformation of VNS products. Hydrolysis of dichloromethylnitroarenes, VNS products between heteroaromatic nitro compounds and chloroform, is a method of choice for the preparation of heterocyclic aldehydes, as shown in Eq. 9.41, in which 4-nitroimidazole is converted into 5-formyl-4-nitroimidazole.69... 

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