An Efficient Scalable Synthesis of 2,3-epoxypropyl Phenylhydrazones

A series of mono and diN -2,3-epoxypropyl N-phenylhydrazones have been prepared on a large scale by reaction of the corresponding N-phenylhydrazones of 9-ethyl-3-carbazolecarbaldehyde, 9-ethyl-3,6-carbazoledicarbaldehyde, 4-dimethyl-amino-, 4-diethylamino-, 4-benzylethylamino-, 4-(diphenylamino)-, 4-(4,4‫-ۥ‬dimethyl-diphenylamino)-, 4-(4-formyldiphenylamino)-and


Introduction
Epoxides are versatile intermediates in organic synthesis; and a large variety of reagents are known for the ring opening of these compounds to yield products with important biological activities and pharmacological properties [1,2].On the other hand, hydrazine derivatives are nowadays of considerable technical and commercial importance [3].Particularly hydrazones are often mentioned among the most effective charge transporting low-molecular-weight materials used in electrophotography, due to their excellent hole-transporting properties and relatively simple synthesis [4][5][6][7].
Recently, we have reported the synthesis and properties of new hole transporting materials consisting of two hydrazone branches.These materials were synthesized by connecting two N-2,3-epoxypropyl N-phenylhydrazones with various difunctional nucleophilic compounds.The molecular structure of these transporting materials makes crystallization in the solid state difficult, so these materials are able to form glasses. Another peculiarity of the branched hydrazones is the presence of two hydroxyl groups in the molecule that improves their adhesion to some substrates and compatibility with some polymers, such as polyvinylbutyraldehyde.A variety of these branched hydrazones, involving N-ethylcarbazole, N,N-diethylaniline, N,N-benzylethylaniline and triphenylamine moieties have been generated [8,9].Moreover, a new class of polymeric hydrazones was reported [10].They ensure rapid charge transporting ability, high photosensitivity and durability of EPL, however until now there was no data concerning the synthesis of the epoxypropyl phenylhydrazones of arylaldehydes, which are the starting materials for preparation of above described novel electronactive molecules.

Results and Discussion
At first the reaction of phenylhydrazones with epichlorohydrin was carried out at room temperature in the presence of potassium hydroxide and anhydrous K 2 CO 3 and lasted for 3 days.More attractive seemed the alkylation at 55-60 ο C which allows to obtain various N-2,3-epoxypropylated hydrazones.At the elevated temperature the reaction time was reduced to 1.5-2 h, and high yields (57-81 %) were observed.
The experiments carried out revealed that this method was not suitable for bigger than preparative scale synthesis.At 55-60 ο C in the presence of KOH and anhydrous K 2 CO 3 the reaction often slipped out of control due to the polymerization of epichlorohydrin.Some changes to this method were made: the reaction was carried out at 35-40˚°C by adding KOH and dewatering material in three portions with prior cooling of the reaction mixture to 20-25°C, the anhydrous K 2 CO 3 was replaced by anhydrous Na 2 SO 4 .These changes enabled to decrease the amount of the water adsorbent used, reduce the amount of poly(epichlorohydrin) formed and ensure better reaction control.
The structures of 1a-i were confirmed by their 1 H-NMR spectra and elemental analysis data.A typical set of lines for the epoxypropyl group appears in the 4.40-2.50ppm region of the 1 H-NMR spectra of 1a-f and 2a-c.In the 1 H-NMR spectrum of 1e (shown in Figure 1) we observed the most clearly defined ABX systems of the non-equivalent geminal protons of NCH 2 and CH 2 O. Thus the CH 2 O appeared as a doublet of doublets at 2.62 ppm (H A with J AB =4.8 Hz, J AX =2.7 Hz) and as a doublet of doublets at 2.84 ppm (H B with J BX =4.1 Hz) due to the coupling with CH, while protons of NCH 2 respectively gave dd at 4.35 ppm (H A′ with J A′B′ =16.4 Hz, J A′X =2.4 Hz) and dd at 3.99 ppm (H B′ with J B′X =4.1 Hz).

Hb' Hx
General method for the preparation of aldehyde mono-and diphenylhydrazones Phenylhydrazine (0.1 mol for monohydrazones or 0.25 mol in case of dihydrazones) and the corresponding aldehyde (0.1 mol) were dissolved in 2-propanol (100 mL) in case of hydrazones or THF (100 mL) in the case of dihydrazones.The mixture was refluxed until the aldehyde disappeared (10 min).At the end of the reaction, the mixture was cooled to room temperature.The crystals formed upon standing were filtered off and washed with 2-propanol to give corresponding phenylhydrazones, which were subjected to the reaction with epichlorohydrin without further purification.

General method of the preparation of N-2,3-epoxypropylated phenylhydrazones 1a-f
To the mixture of phenylhydrazone of the corresponding aldehyde (1 mol) and epichlorohydrin (1.5˚mol), powdered 85 % potassium hydroxide (3 mol) and anhydrous Na 2 SO 4 (0.4 mol) were added in three portions with prior cooling of the reaction mixture to 20-25˚°C (1 st portion -1/2 of Na 2 SO 4 and 1/3 of KOH; 2 nd portion -1/4 of Na 2 SO 4 and 1/3 of KOH after 1h from the beginning of the reaction; 3 rd -1/4 of Na 2 SO 4 and 1/3 of KOH after 2h from the beginning of the reaction).The reaction mixture was stirred vigorously at 35-40˚°C until the starting hydrazone disappeared (3-4 h).After termination of the reaction, the mixture was cooled to RT and filtered off.The organic layer was washed with distilled water until the wash water was neutral.The organic layer was dried over anhydrous magnesium sulfate, treated with activated charcoal, filtered and excess of epiclorohydrin was removed.In the case of 1a-d the obtained residue was dissolved in a 1:1 mixture of toluene and 2propanol.The crystals formed upon standing were filtered off and washed with 2-propanol.Compounds 1e,f were purified by column chromatography.

General synthetic method of bis(N-2,3-epoxypropyl-N-phenyl)hydrazones 2a-c
To the mixture of the diphenylhydrazone of the corresponding dialdehyde (1 mol) and epichlorohydrin (22.5˚mol), powdered 85 % potassium hydroxide (4.5 mol) and anhydrous Na 2 SO 4 (0.6 mol) were added in three portions with prior cooling of the reaction mixture to 20-25˚°C (1 st portion -1/2 of Na 2 SO 4 and 1/3 of KOH; 2 nd portion -1/4 of Na 2 SO 4 and 1/3 of KOH after 1h from the beginning of the reaction; 3 rd -1/4 of Na 2 SO 4 and 1/3 of KOH after 2h from the beginning of the reaction).The reaction mixture was stirred vigorously at 35-40˚°C until the starting dihydrazone disappeared (7-8 h).After completion of the reaction, the mixture was cooled to RT and filtered off.The organic part was washed with distilled water until the wash water was neutral.The organic layer was dried over anhydrous magnesium sulfate, treated with activated charcoal, filtered and the excess of epiclorohydrin was removed.In the case of 2a,b the residues obtained were recrystallized from toluene and the crystals formed upon standing were filtered off and washed with 2-propanol.Compound 2c was purified by column chromatography.