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3. Opening the nitrogen- and oxygen-containing three-membered heterocycles.
A further expansion of possibilities of practical using hydrogen fluoride in organic synthesis is the opening of small oxygen- and nitrogen-containing cycles under the influence of HF. Hydrogen fluoride may be used either directly in a solution of ionizing base solvent or as a complex with bases. 3.1. Opening the epoxy-ring by anhydrous hydrogen fluoride or by its complexes with bases. Successful using anhydrous hydrogen fluoride and its complexes with bases for opening the epoxy cycle is caused by the fact that this is one of the most successful and perspective methods to produce b-fluoroalcohols [330,331]. As the starting materials are available and the procedure of carrying out the reaction is easy, this approach has expanded considerably the sphere of practical use of hydrogen fluoride for introduction of a fluorine atom into organic molecules. Regioselective synthesis of fluoroalcohols from various epoxides has been intensively developed due to the increasing importance in the synthesis of biologically active substances in series of steroids, amino-acids, sugars (table 22). But it is not recommended to use anhydrous hydrogen fluoride itself due to low nucleophilicity of the fluoride ion for the opening of the epoxy-cycle because this process is followed by polymerization, rearrangements and different side-reactions. The yield of a desired fluoro-hydrate considerably depends on the substrate nature [40,332]. So, the opening of 1,2-epoxycyclohexene and 2,2-dimethyloxirane by anhydrous hydrogen fluoride results in formation of 2-fluorocyclohexanol and 2-fluoro-2-methylpropanol-1 in the yields of only 14 and 20% accordingly. Better results are obtained when organic solvents are used. Thus, solutions of hydrogen fluoride in the following substances as diethyl ether [331,334], tetrahydrofurane [335,336], dioxane [337], dimethylformamide [338] and acetonitrile [339,340] were used. To reduce the system acidity and to increase the concentration of fluoride-ions, usually the reaction is carried out in an ether medium and complexes of hydrogen fluoride with amines (tertiary amines[341,342], pyridine [342-346a]) or KHF2 are used. Table 22. Effect of anhydrous HF upon epoxides
Opening the epoxy-ring may be realized in the following two ways due to the change of hydrogen fluoride ionization by a base or by a solvent.
Way a is realized in diethyl ether , whereas with R3N* nHF most probably way b takes place due to the fluoride-ion attack. Trans-addition occurs in the second option. The reaction of opening the epoxy-ring under the effect of anhydrous
hydrogen fluoride was used for synthesis of fluorine-containing steroids,
9 When there is one alkyl substituent at the epoxy-ring, then only one fluoroalcohol is formed.
Epoxides of olefins with perfluoroalkyl substituents or with electron-acceptor groups require the presence of Lewis' acids (SbF5 or BF3 *Et2O) for opening their cycle. Thus, perfluoro(2,2-dimethyloxirane) gives perfluoro(2-methylpropan)-2-ol in 56% yield. The use of KHF2 salt in the reaction with 2(chloromethyl)oxirane (epichlorohydrin) gives a mixture of 1,3-difluoropropan-2-ol and 1-chloro-3-fluoro-propan-2-ol [321]. The yield of reaction products increases up to 67% with increase of the KF content. Similarly 2-(hydroxymethyl)-oxirane under the effect of KHF2 in dimethylformamide gives 3-fluoropropan-1,2-diol in low yield [346b] and 1,2-epoxycyclohexane gives 2-fluoro-cyclohexanol accordingly [328].
For cyclic epoxides the nature of base plays an important role for transformation direction, that may be shown on an example of hydrofluorination of 9-oxabicyclo[6.1.0.]-non-4-ene: the effect of Et3N/3HF system results in formation of trans-2-fluorocyclooct-5-en-1-ol in a quantitative yield with preservation of the cyclic system whereas the effect of 70% HF/Py results in formation of a fluoro-alcohol with transformation the monocyclic system into the bicyclic one, thus exo/endo-fluorobicyclo-[3.3.0]octan-2-ol and its C-6 epimer are obtained. The formation of the latter runs at the expense of transannular cyclization of the intermediate carbcation [344].
Substituents at the epoxy-ring influences the process of the opening of the ring also considerably. That is due to their effect on stabilization of the intermediate carbcation. For example, in case of electron-acceptor substituents at the epoxy ring the forming alcohol group OH was found at the carbon atom connected with the substituent that denotes regioselectivity of opening the epoxy ring (table 23) [347-349]. When one alkyl substituent is at the epoxy cycle the opening of the epoxy cycle under influence of 70% HF/Py runs regioselectively. Table 23. Epoxy ring opening under the effect of 70% HF/Py in H2Cl2.
* - used MeCN Table 24. Epoxy ring opening under the effect of 70% HF/Py
Table 25. Epoxy ring opening under the effect of HF/Py complex [343]
But ,as a rule, a second fluoro-alcohol is formed in small quantities. The result of such a process depends on the reaction conditions, on a solvent used in particular. (table 24)[350-353] HF/Py complex is an available commercial product and is well known as a reagent for opening an epoxy cycle (table 25) [333]. For the first time it was used for synthesis of fluoro-steroids [354]. In this complex the hydrogen fluoride content is especially high (9:1 relative to pyridine). In this relation it differs from complexes of hydrogen fluoride with alkyl amines. Consequently the reactivity of this complex is considerably higher. Formation of fluoro-alcohols in opening epoxy cycles was used in a
method to obtain
Regioselective hydrofluorination of terminal epoxides with Olah's reagent
(Py/9HF) results in formation appropriate fluoro-alcohols with High regioselectivity is achieved in using (Et)(Pr2i)N/HF complex also [350]. So, 2(benzyloxymethyl)oxirane gives 3-benzyloxy-1-fluoro-2-propanol in 97% regioselectivity and trans-2,3-epoxy-1-hexanol gives 3-fluoro-1,2-hexandiol [350].
Cis-6,7-epoxydodecane (R1=R2=C5H11) under the effect of anhydrous hydrogen fluoride gives threo-fluoro-alcohol and trans-isomer gives erythro-fluoro-alcohol [350]. Reactions of 1,3,3-trihalo-7-oxabicyclo[4.1.0]-heptanes with HF/Py complex gives appropriate cis-fluoro-alcohols in a good yield with high regio- and stereoselectivity [346].
Specific influence of a system on opening the epoxy cycle was shown by
the authors of paper [356]. Thus. epoxide, formed from a terminal olefin,
in hydrofluorination under the effect of KHF2 in the presence of
18-crown-6 forms methyl ether of
An epoxide, formed from an internal olefin and containing carboxylic
group at the
The opening-addition of epoxy cycles under the effect of hydrogen fluoride in nucleosides and sugars is a convenient method for synthesis of monofluoronucleosides and monofluoro-sugars for biological purposes. Addition of hydrogen fluoride to epoxy-substances, particularly to oxides of steroids, brought to development of a method to synthesize a great number of potentially useful fluoro-steroids and showed prospects of the method. In active derivatives of sugars a normal opening of the epoxy ring takes place [357].
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-fluorocortizol [325] for example.
Anti-inflammatory activity was
increased almost 10 times when fluorine atom was introduced in comparison
with cortizol. The importance of this medicine is obvious because no
medicines exceeded fluorinated corticosteroids regarding their
anti-inflammatory activity have been found up to now.
-fluoroamino acids [339]. Epoxynitriles and esters in a
reaction with adduct (HF)n-pyridine undergo stereoselective opening the
ring to form a-hydroxy-
-fluoro(
