• Nem Talált Eredményt

NITROGEN CONTAINING BASES

III. NEW SCIENTIFIC RESULTS

1. Hydrazine derivatives as nucleophylic reagents have been applied for the first time in homogeneous catalytic aminocarbonylation reaction.

It has been proved, that carbonylation of steroids (bearing 17-iodo-, 17-bromo-alkenyl- 3-trifiloxy-17-bromo-alkenyl- and 3-trifiloxy-aryl-functionalities) can be carried out with good selectivity and without any side products in the presence of mono- and disubstituted hydrazines and a Pd-phosphine catalyst system.

Novel, presumably biologically active steroidal hydrazides were isolated as products.

They were characterised by analytical measurements (1H, 13C-NMR, IR and MS).

2. The reactivities of hydrazines were compared and the influence of reagents on the regioselectivity was investigated. These factors highly depended on the number and the electronic and steric parameters of the functional groups attached to the nitrogens.

(a) N,N-disubstituted hydrazines (N,N-diphenyl-, N,N-dimethyl-hydrazine) could be acylated exclusively on the unsubstituted nitrogen with lower reactivity then in the case of monosubstituted-derivatives. It should be mentioned, that according to the literature tertiary amines can take part in the catalytic carbonylation as nucleophylic reagents. No such phenomenon was observed under the conditions applied here.

(b) Functional groups possessing negative resonance effect (phenyl-, acetyl-, benzoyl-group) decrease the nucleophilicity, so only the unsubstituted nitrogen is able to take part in the acylation reaction. The bulky groups decrease the reactivity of connected nitrogen also because of their steric effect.

(c) Nucleophilicity of the substituted nitrogen is increased by the less bulky methyl group with +I feature. In this case both excellent selectivity and reactivity were observed.

3. It has been shown that the reactivity of the steroidal substrates is determined by the nature of the leaving group and it can be only slightly influenced by other functional groups of the steroidal skeleton.

4. Using monoalkyl-, or monoarylhydrazines as reagents, no diacylation was observed. Diacyl derivatives containing two steroidal skeletons could be synthesised only in two steps, via carbonylation of a steroidal alkenyl iodide in the presence of an isolated monoacyl derivative in fivefold excess.

5. Some 17-(N-acetamido-carbamoyl)- and (N-benzamido-carbamoyl) steroids synthesised by hydrazinocarbonylation can be transformed with good conversion into oxadiazole derivatives via intramolecular ring closure reaction in the presence of POCl3. The 2'-methyl- and 2'-phenyl-1',3',4'-oxadiazole derivatives have been isolated and identified by analytical methods (NMR, IR, MS).

N

6. Conversion of a (N-acetamido-carbamoyl)-derivative into the corresponding 17-(2’-methyl-1’,3’,4’-thiadiazole) was also attempted. However, beside the required product, a considerable amount of the 1’,3’,4’-oxadiazole derivative was obtained in competitive side reaction. Results obtained using various sulphur-containing reagents are as follows:

(a) Oxadiazole was the main product in the presence of P2S5. The selectivity can be improved by using 1-ethyl-2-pyrrolidone, xylene as solvents and acetic acid, or toluene-4-sulfonic acid as additive (product distribution of thiadiazole: 25%, 30 %, respectively).

(b) Better results ( 54 %) could be obtained with the use of Lawesson’s reagent. In this case the two products could be found in almost equal amounts in the reaction mixture.

(c) The most promising reaction was that of the substrate with Lawesson’s reagent under microwave irradiation (product distribution of thiadiazole: 65 %).

or Lawesson's reagent

7. Steroidal substrates used in hydrazinocarbonylation were reacted with O-substituted hydroxylamines (O-trimethylsilyl-, O-benzyl-, O-methyl-hydroxylamine) via homogeneous carbonylation reaction. The method is suitable for effective and selective synthesis of novel, presumably pharmacologically active steroidal hydroxamates. The derivatives obtained have been characterised by NMR, IR and MS measurements.

8. Reactivities of various substrates and reagents were compared in the catalytic reactions.

(a) According to the results obtained, the reactivities of O-substituted hydroxylamines are determined by both the steric and electronic parameters of the substituents.

(b) In the case of the steroidal substrates the reactivities depend on the nature of the leaving group.

9. Reactions of N-substituted hydroxylamines (N-acetyl, N-t-butyl, N-methyl-hydroxylamine) and steroidal substrates have also been investigated under the reaction conditions mentioned above. Both N- and O-acylated derivatives of hydroxylamines have been formed. Separation of the products has been achieved by column chromatography. The new compounds were identified by spectroscopic methods (NMR, IR, MS).

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10. As in the hydrazinocarbonylation, here also, both the steric and electronic effects of the substituent determine the selectivity of the reaction and the reactivity of the reagent.

(a) In the case of N-substituted hydroxylamines having a less bulky, electron-donating group (methyl-group), the formation of hydroxamic acid has been favoured.

(b) O-acylated derivatives were the main products in the presence of reagents with negative resonance (N-acetyl-hydroxylamine) and ⁄ or considerable steric (N-t-butyl-hydroxylamine) effects.

11. The same order of substrate reactivity was observed as before. Steroidal alkenyl iodides were found to be the most reactive. Enol triflates have smaller reactivity while the bromo-derivative was completely unreactive.

12. When N-methyl-hydroxylamine was used as the nucleophile, the regioselectivity of the reaction has been strongly influenced by the structure of the substrate.

(a) Selectivities of reactions of steroidal derivatives with a lactame-structure in the A-ring essentially differ from the selectivities of the reactions of other steroids.

(b) It has been proved, that the reason of the marked difference in the regioselectivity can not be the coordination of the lactame ring to the palladium. The difference can probably be explained by the ‘long-range effect’ of steroids, which means electronic interaction between the functional groups of the steroid skeleton.

13. The use of an appropriate solvent is also a crucial point regarding the selectivity of the reaction. In DMF the N-acylated or O-acylated products formed with good selectivity depending on the structure of the steroid substrate. In the case of toluene the two products

could be found in almost equal amounts in the reaction mixture. Both of the products could be produced in good yields by using the appropriate solvent.

14. The selectivity of the reaction in the presence of N-methyl-hydroxylamine was further investigated. According to the results, the O-acylated derivatives can not spontaneously transform to the N-acylated compounds under the conditions of the catalytic carbonylation reaction.