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Institut für Chemie

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    Selective transformations of substituted aryl compounds to fluorenes and phosphoramidates : synthetic and spectroscopic studies
    (2010) Haggam, Reda; Beifuss, Uwe
    Because of their diverse biological properties and their high potential for the development of new drugs the synthesis of fluorenes and related systems such as benzo[b]fluorenes is of great interest in the fields of organic and medicinal chemistry. The most relevant benzo[b]fluorenes include the naturally occurring kinamycins. Recently, two fluorene derivatives have been isolated from the sweat of hippopotamus (Hippopotamus amphibius). The biological function of the two dyes named hipposudoric acid (4) and norhipposudoric acid (5) is still unknown. For the synthesis of fluorenes a number of synthetic approaches have been developed. Among the most important methods there are the intramolecular electrophilic substitution, the Pschorr cyclization and palladium-mediated intramolecular cyclizations. The first part of the present study focusses on the construction of fluorenes carrying several methoxy groups by employing the Pschorr cyclization and the palladium-mediated intramolecular cyclization of suitable substrates. A comparison of the two methods is also presented. In addition, the cleavage of the methyl ethers 203 into the corresponding hydroxy-substituted fluoren-9-ones 206 is also included in the first part. To begin with, the synthesis of hydroxy- and alkoxy-substituted fluoren-9-ones through Pschorr cyclizations was studied. For the preparation of the substrates 233 the bromides 229 were first lithiated with t-butyllithium and then reacted with the aldehydes 231. Using this method it was possible to prepare the secondary alcohols 233a-e with excellent yields ranging from 87 to 98 % (Scheme 74). Treatment of the secondary alcohols 233a-e using K2Cr2O7 as an oxidant gave the corresponding ketones 234a-e with very good yields (85 to 92 %; Table 16). Reduction of the nitro group of the substituted ketones 234a-e using iron powder resulted in the formation of substituted 2-aminobenzophenones 235a-e with very good results (Table 17). The compounds 235a-e were cyclized to furnish the methoxy-substituted fluoren-9-ones by Pschorr cyclizations. For this purpose the substituted 2-aminobenzophenones 235a-e were oxidized to the corresponding diazonium salts with n-amylnitrite in glacial acetic acid at 0 °C which underwent cyclization to give the methoxy-substituted fluoren-9-ones 236a-e with yields ranging from 72 to 86 % (Table 18). Ether cleavage of the methoxy-substituted fluoren-9-ones 236a-e performed using boron tribromide resulted in the formation of the hydroxy-substituted fluoren-9-ones 242a-e with yields between 60 and 84 % (Table 19). These results show that the Pschorr cyclization allows for the preparation of substituted fluoren-9-ones in four steps from readily available starting materials. Palladium-mediated reactions play a very important role in current organic synthesis. Therefore, it was studied whether the palladium-mediated cyclizations of 2-iodo-substituted benzophenones 243 can be employed for the efficient synthesis of fluoren-9-ones. It was of great interest to learn whether this method is superior to the Pschorr cyclization approach. For this purpose, the 2-iodobenzophenone derivatives 243a-f were synthesized. They were obtained by reaction of the 2-amino-substituted benzophenones 235 with n-amylnitrite followed by treatment with KI. Following this procedure, the iodides 243a-e could be obtained with yields between 65 and 73 % (Table 20). Compound 243f was synthesized by intermolecular Friedel-Crafts acylation of 228 with 244 in 97 % yield (Scheme 75). It turned out that the best results for the palladium-mediated cyclization of the iodides 243a-c,e,f could be achieved when PdCl2(PPh3)2 was used as a palladium reagent in the presence of NaOAc as a base and DMA as a solvent. Heating at 130 °C afforded the fluoren-9-ones 236a-c,e,f with yields in the range between 31 and 86 % (Scheme 76). On the whole, it can be concluded that the palladium-catalyzed intramolecular arylations of 243 suffer from high palladium-loadings, high reaction temperatures and long reaction times. In addition, in a few cases the yields for the palladium-mediated cyclizations are not sufficient. Compared to the results of the Pschorr cyclizations the palladium-mediated cyclizations need an extra step; i.e. the transformation of the 2-aminobenzophenones 235 into the corresponding 2-iodobenzophenones 243. This is why the Pschorr cyclization is more efficient for the synthesis of fluoren-9-ones 236 than the palladium-mediated cyclization. In addition, attempts were undertaken to cyclize the substituted 2-nitrobenzophenones 234b,c to the corresponding acridinones 205. When the benzophenones were treated with triethyl phosphite (161) the unexpected formation of diethyl N-arylphosphoramidates 251b (59 % yield) and 251c (62 % yield) was observed. With these unexpected results in hand it was decided to develop a new synthetic protocol for the efficient conversion of nitroarenes into the corresponding phosporamidates. Phosporamidate oligonucleotides play an important role in medicinal chemistry because they have been considered for diagnostic as well as therapeutic applications within the antisense field. The preparation of phosphoramidate substituted nucleoside analogues is also of great interest as many of them exhibit anticancer, antiviral (anti-HIV) and spermicidal activities. Therefore, the second goal of this thesis was to develop a practical and efficient method for the synthesis of dialkyl N-arylphosphoramidates by reaction of readily available nitroarenes with tervalent phosphorous reagents such as triethyl phosphite or trimethyl phosphite under both thermal and microwave conditions. In order to evaluate the scope of this conversion it was necessary to study the effects of substitution on the aromatic ring at different positions. It was found that nitroarenes 255a-o can easily be transformed into the corresponding diethyl N-arylphosphoramidates 256a-o by treatment with an excess of triethyl phosphite (161) or trimethyl phosphite (257). Yields were in the range of 52 to 79 % (Table 21). The results obtained clearly indicate that ? in contrast to previous reports ? the reaction of nitroarenes with trialkyl phosphites is a practical and efficient method for the selective preparation of dialkyl N-arylphosphoramidates in one synthetic operation. The structures of all compounds prepared during this study have been elucidated unambiguously by analytical and spectroscopic methods including NMR spectroscopy, mass spectrometry, UV spectroscopy, IR spectroscopy and elemental analysis.