Hydrazones reactions, review

The Fischer cyclization has proved to be a very versatile reaction which can tolerate a variety of substituents at the 2- and 3-positions and on the aromatic ring. An extensive review and compilation of examples was published several years ago[3]. From a practical point of view, the crucial reaction parameter is often the choice of the appropriate reaction medium. For hydrazones of unsymmetrical ketones, which can lead to two regioisomeric products, the choice of reaction conditions may determine the product composition. 

Preparation of thiadiazoles via the Hurd-Mori cyclization has led to the synthesis of a variety of biologically active and functionally useful compounds. Discussion of reactions prior to 1998 on the preparation of thiadiazoles have been compiled in a review by Stanetty et al Recent syntheses of thiadiazoles as intermediates for useful transformations to other heterocycles have appeared. For example, the thiadiazole intermediate 36 was prepared from the hydrazone 35 and converted to benzofuran upon treatment with base. Similarly, the thiadiazole acid chloride 38 was converted to the hydrazine 39 which, upon base treatment, provided the pyrazolone, which can be sequentially alkylated in situ to provide the product 40. ... 

Intramolecular addition of trialkylboranes to imines and related compounds have been reported and the main results are part of review articles [94, 95]. Addition of ethyl radicals generated from Et3B to aldimines affords the desired addition product in fair to good yield but low diaster control (Scheme 40, Eq. 40a) [96]. Similar reactions with aldoxime ethers [97], aldehyde hydrazones [97], and N-sulfonylaldimines [98] are reported. Radical addition to ketimines has been recently reported (Eq. 40b) [99]. Addition of triethylborane to 2H-azirine-3-carboxylate derivatives is reported [100]. Very recently, Somfai has extended this reaction to the addition of different alkyl radicals generated from trialkylboranes to a chiral ester of 2ff-azirine-3-carboxylate under Lewis acid activation with CuCl (Eq. 40c) [101]. 

Numerous methods to prepare individual classes of aliphatic diazo compounds have been extensively developed. The major strategies for their synthesis involve the alkaline cleavage of N-alkyl-N-nitroso-ureas, -carboxamides and -sulfonamides, dehydrogenation of hydrazones, as well as diazo group transfer from sulfonyl and related azides to active methylene compounds, and electrophilic diazoalkane substitution reactions. These synthetic methods have been comprehensively reviewed (15,16). Useful information on the preparation of selected diazo compounds can be found elsewhere (6,17). 

Heterogeneous hydrogenation of the C=N bond is a very widely used synthetic process with application to small and large-scale reactions. Many of the catalysts described in other sections may also be employed, for example those based on supported rhodium, palladium etc, and Raney Nickel. This area has been reviewed extensively recently192. Hydrogenation of oximes and hydrazones results in formation of amines. Milder conditions can be used for oxime reduction if the ethylaminocarbonyl derivative is prepared in situ prior to reduction276. 

The cyclization of the phosphorylated arylhydrazones, leading to compounds 168, presumably takes place through the initial formation of 3-phosphorylated indoles 69, which isomerize to compounds 168 in the course of the reaction. Such 3—>2 rearrangements are well-known [30, 180-182, 231]. The transposition of the phosphorus-containing substituent in indoles was first observed in [178, 179]. In the review [8] the data on the formation of 2-phosphorylindoles from the arylhydrazones of phosphorylpropionic aldehyde were considered proved, but the results on the cyclization of hydrazones of phosphorylacetaldehyde to the 2-isomers were placed under some doubt. 

The transition metal catalyzed synthesis of arylamines by the reaction of aryl halides or tri-flates with primary or secondary amines has become a valuable synthetic tool for many applications. This process forms monoalkyl or dialkyl anilines, mixed diarylamines or mixed triarylamines, as well as N-arylimines, carbamates, hydrazones, amides, and tosylamides. The mechanism of the process involves several new organometallic reactions. For example, the C-N bond is formed by reductive elimination of amine, and the metal amido complexes that undergo reductive elimination are formed in the catalytic cycle in some cases by N-H activation. Side products are formed by / -hydrogen elimination from amides, examples of which have recently been observed directly. An overview that covers the development of synthetic methods to form arylamines by this palladium-catalyzed chemistry is presented. In addition to the synthetic information, a description of the pertinent mechanistic data on the overall catalytic cycle, on each elementary reaction that comprises the catalytic cycle, and on competing side reactions is presented. The review covers manuscripts that appeared in press before June 1, 2001. This chapter is based on a review covering the literature up to September 1, 1999. However, roughly one-hundred papers on this topic have appeared since that time, requiring an updated review. 

In order to keep this review to a manageable size we do not discuss in detail related reactions, e.g. additions of diazonium ions to simple anions hke OH", CN", and Nj, or the so-called oxidative azo coupling reaction, discovered by Hunig in which electrophilic reagents comparable but not identical with diazonium ions are obtained by oxidation of heteroaromatic hydrazones. 

Reactions of this type were first studied by Curtius and co-workers . For example, diethyl malonate and /(-toluenesulphonyl azide reacted in the presence of cold sodium ethoxide to give the sodium salt of the 5-hydroxytrizizole (296) . Acidification gave the 5-triazolone (297) which isomerized to the diazo compound (298) (overall yield 90%). (The same product could be obtained in 85% yield without base by heating the azide and malonate at 100° and a pressure of 20 mm) . This reaction provided the basis for the so-called diazo-transfer reaction, an extremely useful method of synthesizing diazo compounds, which has been reviewed. The reaction has been formulated as shown in equation (134), and has been extended to the synthesis of azides by a diazo transfer to amine anions/i-Toluenesulphonyl azide reacts with hydrazone... 

For many organic photochromic compounds (e.g., spiropyrans, anils, and hydrazones) for which the color change is photochemically induced, the bleaching reaction is at least partly thermally controlled. Most of these systems are discussed in other chapters of this monograph or have been discussed elsewhere2 among these, we will only review those systems for which the thermal equilibrium between the colorless and colored forms has been studied. 

Amidine and amine groups may be joined together to form this triazepinone ring by heating the compound with methanolic sulphuric add for 3h. The reactant is obtained by stirring isatoic anhydride (review of reactions [3008]) with an amidrazone (formally, a hydrazone of a carboxamide). 

The quinonoid hydrazones (51.1) are readily cyclized to indazolediones at ambient temperature in dilute mineral acid. When the mixture is warmed, the Ts group is cleaved as it is also in the thermal cyclization of (51.1) at 180°C [2879]. This unexpected reaction provides a convenient synthesis of these ind-azoles and a mechanism involving displacement of the t-amino group by the tosyl-carrying nitrogen is proposed. The chemistry of heterocyclic quinones has been reviewed [2947, 3650). 

Nitrobenzaldehyde methylhydrazone undergoes oxidative cyclization to a betaine JV-oxide in high yield. Although the yield in this particular conversion is very high, it is worth considering the use of the phenyliodo diesters (review of the use of these and similar reagents [3714]). The reactions of hydrazones have been reviewed [2384]. 

Using a-acetyl-y-butyrolactone as the carbonyl component in the Fischer synthesis, decarboxylation occurs and it is thus possible to prepare a 1,2-disub-stituted indol-3-ylethanol [2637]. In a related reaction, a y-haloaldehyde or a y-haloketone reacts with an arylhydrazine to give a tryptamine in which the side-chain nitrogen is derived from the terminal nitrogen of the reacting phenylhydrazine this and related reactions were reviewed in 1974 and 1988 [2641,3461). The course of Fischer indolization of the preformed monophenyl-hydrazone of cyclohexane-1,3-dione changes when the reaction is allowed to proceed under conditions which encourage ketal formation [2565]. 

Oxidation of aryl hydrazones by thianthrene radical cation have also been suggested to occur via electron-transfer and such reactions have been reviewed previously [110]. Reaction of oximes with thianthrene radical cation produces cycloaddition products [56,57], nitriles, and carbonyl compounds. The cycloaddition products are believed to be formed via initial one-electron oxidation of the oxime. 

When reviewed in CHEC-I some examples of cyclization y to the heteroatom had been described for the synthesis of pyridazines, but the method was of most importance in the synthesis of cinnolines. Examples of pyridazine syntheses included cyclization of ketazines with EDA, and intramolecular Wittig reactions of phosphoranes derived from phosphacumuleneneylides and the hydrazones produced from 1,3-dicarbonyl compounds and aryldiazonium salts. Synthetically useful approaches to cinnolines given include the intramolecular Friedel-Crafts acylation of the diacid chlorides derived from the condensation products of aryldiazonium salts and diethyl malonate to give 4(l//)-cinnolinones, and thermal cyclization of iminium hydrazones obtained from enamine esters and aryldiazonium salts. 

The chemistry of 1,3,4-thiadiazole has been recently reviewed <04MI405>. The 2-substituted 1,3,4-thiadiazoles 258 are formed by the reactions of thiohydrazides 257 with DMF and diethyl chlorophosphate. This cyclodehydrating agent is superior to several commonly used ones such as ethyl orthoformate, ethyl formate or even phosphorus oxychloride for this type of cyclization <04817>. Reaction of/ -tolualdehyde hydrazone 259 with disulfur dichloride in the presence of DBU gives 2,5-di(p-tolyl)-1,3,4-thiadiazole 260 <04S1929>. 

Regitz diazo transfer reactions have been reviewed previously.1-3 The following two main routes have been known for the synthesis of diazo compounds (1) diazotization of amines, oximes, nitrosoamines, and hydrazones (2) transfer of the diazo function from tosyl or mesyl azides to active methylene compounds. 

---