Benzophenone hydrazone

The Buchwald-Hartwig amination reaction has gained great interest in the last decade in both academic and industrial environments. In the work presented herein, we discuss a very interesting effect in the competitive reaction of two amines (benzophenone hydrazone and n-hexylamine) with 3-bromobenzotrifluoride. 

The reactions involving either benzophenone hydrazone or w-hexylamine have been studied by reaction calorimetry. The benzophenone hydrazone reaction presents zero order kinetics, while the hexylamine reaction is first order in the aryl halide and zero order in the amine. Under synthetically relevant conditions, at 90°C, the rate of the hexylamine reaction is about 30-fold higher than the rate of the benzophenone reaction. 

Figure 26.1 represents the heat profile of the benzophenone hydrazone and hexylamine reactions. At the same conditions, at 90°C, the reaction involving hexylamine is considerably faster. The heat profile of the hexylamine reaction at 70°C shows how the reaction has positive order kinetics, while the benzophenone reaction shows overall zero order kinetics. 

Scheme 26.3 Competitive reaction of benzophenone hydrazone and w-hexylamine.

When reacting alone, the hexylamine is evidently more reactive on the other hand, the benzophenone hydrazone forms a more stable intermediate (the BINAP(Pd)Ar(amine) complex that we observed by NMR). The interesting question was which amine will react first ... 

Figure 26.2 Heat profile and conversion of the benzophenone hydrazone and of the hexylamine for a competitive amination reaction involving 3-bromobenzotrifluoride (0.5 M), benzophenone hydrazone (0.25 M) and hexylamine (0.25 M). Temperature 90°C.

The heat profile shows that the reaction has zero order kinetics at first, and then switches to positive order kinetics. The benzophenone hydrazone reacts first only when it is completely consumed, the reaction involving hexylamine begins. Samples were taken and analyzed by and NMR. One sample was taken when the aryl halide conversion was low, at about 5%, and the profile was overall zero order the second when the profile had switched to positive order and the conversion of the halide was greater than 50%. 

The following scheme represents the possible paths which can be followed during a competitive experiment. Path a refers to the hexylamine, path b to the benzophenone hydrazone. 

We studied the competitive amination of two amines (benzophenone hydrazone and -hexylamine) and one aryl halide (3-bromobenzotrifluoride), catalyzed by Pd(BlNAP). We showed that, when reacting alone at the same conditions, n-hexylamine is considerably more reactive and shows positive order kinetics benzophenone hydrazone shows zero order kinetics and forms a very stable intermediate, the BlNAP(Pd)Ar(amine) we also observed by NMR. During the competitive reaction of the two amines, the benzophenone hydrazone reacts first and only when it is completely consumed, the hexylamine starts to react. In this case it is the stability of the major intermediate, and not the relative reactivity, which dictates the selectivity. 

B. Benzophenone hydrazone. A hydrogenation bomb is charged with 25.2 g. (0.138 mole) of benzophenone, 7.46 g. (0.23 mole) of anhydrous hydrazine, and 14 ml. of absolute alcohol. The bomb is closed with a safety head instead of the usual pressure gauge assembly and is then heated for 4 hours at 150°. After the bomb has cooled, it is opened and the benzophenone hydrazone is removed from the mixture. It weighs 26.4 g. and melts at 94-99°. After recrystallization from 75 ml. of 95% alcohol, the hydrazone forms long white needles which melt at 97-98° and weigh 21.5-22.0 g. (80-82%). 

C. Diphenyldiazomethane. In a pressure bottle are placed 19.6 g. (0.1 mole) of benzophenone hydrazone, 22 g. (0.1 mole) of yellow oxide of mercury, and 100 ml. of petroleum ether (b.p. 30-60°). The bottle is closed, wrapped in a wet towel, and shaken mechanically at room temperature for 6 hours. The mixture is then filtered to remove mercury and any benzophenone azine (Note 5), and the filtrate is evaporated to dryness under reduced pressure at room temperature. The crystalline residue of diphenyldiazomethane melts when its temperature reaches that of the room (Note 6), but it is difficult to purify and this product is pure enough for all practical purposes. The material weighs 17.3-18.6 g. (89-96%). The product should be used immediately (Note 7). 

Benzonitrile, 2,6-dimethoxy-, 22, 35 Benzophenone, 23, 99 Benzophenone azine, 24, 55 Benzophenone hydrazone, 24, 54 Benzopyrrole, 23, 42 Benzothiazole, I-amino-5-methyl-,... 

Diphenyldiazomethane has been prepared only by oxidation of benzophenone hydrazone.3 The procedure given above is that of Staudinger, Anthes, and Pfenninger, with minor changes. The method of preparation of benzophenone hydrazone given above is a modification of the procedure of Curtius and Rauter-berg.4... 

Benzophenone hydrazone is a particularly active substrate for palladium-catalyzed reactions, as summarized in (Equation (24)), 99 and these products can serve as precursors to A-aryl hydra-... 

The reaction of diphenykoethy) radical with benzophenone azine or benzophenone hydrazone gives 2,2,3,3-tetrapbenylaziridme384 (Eq, 23a). 

Most solid-phase syntheses of pyrazoles are based on the cyclocondensation of hydrazines with suitable 1,3-dielectrophiles. The reported examples include the reaction of hydrazines with support-bound a,(3-unsaturated ketones, 1,3-diketones, 3-keto esters, a-(cyano)carbonyl compounds, and a, 3-unsaturated nitriles (Table 15.19). Pyrazoles have also been prepared from polystyrene-bound 3-(hydrazino)esters, which are generated by the addition of ester enolates to hydrazones (Entry 7, Table 15.19 see also Section 10.3). Benzopyrazoles can be prepared from support-bound hydra-zones using the reaction sequence outlined in Figure 15.11. Oxidation of a polystyrene-bound benzophenone hydrazone yields an a-(acyloxy)azo compound. Upon treatment with a Lewis acid, this intermediate is converted into a 1,2-diazaallyl cation,... 

A mixture of benzophenone (1.84 g, 10 mmol) and 80% hydrazine hydrate (1 g, 20 mmol) in toluene (15 mL) was taken in an Erlenmeyer flask and placed in a commercial microwave oven operating at 2450 MHz frequency. After irradiation of the mixture for 20 min, (monitored by TLC) it was cooled to room temperature, extracted with chloroform and dried over anhydrous Na2S04. Removal of solvent gave the benzophenone hydrazone in 95% yield. For the Wolff-Kishner reductions, a mixture of hydrazone 3a (5 mmol) and KOH (2 g) were taken in an Erlenmeyer flask and placed in a microwave oven. Irradiation for 30 min and usual workup gave the corresponding diphenylmethane in 95% yield. 

Curini, M. Rosati, O. Pisani, E. Preparation of diphenylmethyl esters by oxone oxidation of benzophenone hydrazone. Tetrahedron Lett. 1997, 38, 1239-1240. 

This proposal was based on speculation that the work of Homer, L., andFemekess, H. Chem.Ber., 1961, 94, 712 (in which they showed that moderate yields of esters and ethers could be obtained by adding peracetic acid to benzophenone hydrazone in the presence of excesses of carboxylic acids and phenols) may provide a basis for a commercial process to DPM esters. 

The oxidation is carried out by refluxing the benzhydryl waste in aqueous 30% nitric acid (see footnote 17, example 37). The benzophenone produced is easily converted to benzophenone hydrazone for recycle to the DDM process. See also Rivkin, S. M. J. Appl. Chem. (USSR), 1938, 11, 83 (Chem. Abstr., 1938, 32, 4566). The nitric acid oxidation process was adopted by Albright and Wilson, our benzophenone hydrazone supplier. 

The second project was to determine whether the anodic oxidation of benzophe-none hydrazone could be manipulated to produce diphenyldiazomethane (DDM) as the end product in high yield. Literature evidence95 indicated that the anodic oxidation of benzophenone hydrazone using either a platinum or graphite anode under various conditions with a variety of electrolytes gave a number of products that were... 

Chiba and co-workers gave no indication that the anodic oxidation of benzophenone hydrazone could be stopped at the DDM stage. Professor Martin and Dr. John Hulteen, Colorado State University, were, however, able to devise conditions, based... 

FIGURE 2. Electrochemical oxidation of Benzophenone Hydrazone to Diphenyldia-zomethane. 

Benzophenone hydrazone (5.88 g, 20 mM) was dissolved in methylene chloride (20 ml) and over-layered with 1 M sodium hydroxide (40 ml) containing, as phase transfer catalyst, tetrabutylammonium sulfate (0.68 g) and sodium iodide (300 mg). The cathode half cell contained 1 M sodium hydroxide (60ml). The whole cell was cooled to 0°C, the anode compartment stirred and electrolysed at a current of 50 mA. Formation of DDM was followed using the DDM absorption peak at 525 nm. The chart obtained was as shown in Figure 2. 

Azoles can be produced from products of palladium-catalyzed hydrazone arylation and can serve as substrates for arylation reactions to produce N-aryl azoles. The Fischer indole synthesis uses N-ary I hydrazones, and these hydrazones can be generated by palladium-catalyzed chemistry. Benzophenone hydrazone was found by both the Yale and MIT groups to be a particularly effective substrate for palladium-catalyzed reactions, as summarized in Eq. (24) [140,141]. Reactions of benzophenone hydrazone with either aryl bromides or iodides occur in high yields using either DPPF- or BINAP-ligated palladium. These reactions are general and occur with electron-rich, electron-poor, hindered or unhindered aryl halides. The products of these reactions can be converted to hydrazones that bear enolizable hydrogens and are suitable for indole synthesis in the presence of acid and ketone [140]. 

Hydrazinopyridines are important in the preparation of triazines and as intermediates in the production of agrochemicals and pharmaceuticals. Thus, Arterburn et al. investigated the reaction between hydrazine derivatives and pyridyl halides and triflates [124]. These workers found that 2-bromo- and 2-chloropyridine reacted with benzophenone hydrazone... 

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