Part3.1. - Continuation.

3.2.Opening nitrogen-containing three-membered heterocycles

As it is seen from the data review [408] the opening of the aziridine cycle under the influence of different nucleophilic reagents has drawn great attention. The effect of anhydrous hydrogen fluoride on aziridines became an important method to produce interesting 1-amino-2-fluorocompounds i.e. -fluoroamines, -amino- and -fluoro-acids and b-fluoroazaalkanes [38, 407-418]. The process runs through an intermediate formation of quaternary ammonium salt B in which fluoride-ion attacks carbon -atom of the three-membered cycle.

N-Aryl-2,2-difluoro-3,3-bis(trifluoromethyl)aziridines were obtained in a reaction of imines with difluorocarbenes by the effect of anhydrous hydrogen fluoride in the presence of BF₃ as a catalyst, the three-membered cycle was open to form secondary amines [419]. But there was observed formation of cyclic compounds also in dependence on the nature of the substituent in the benzene ring. Opening the aziridine cycle runs at the account of initial protonation of the nitrogen atom, whereas opening cyclic compound takes place at the account of the attack of carbcation generated in the opening of the protonated cycle. The presence of BF₃ in the system increases the Hammett acidity constant sharply and makes the cyclization process easier ( anhydrous HF(99.5%) has Ho = -11 and Ho of a 7% HF solution has a value of -16.6) [419].

Opening the cycle of 1-phenyl-1-allylaziridine under the effect of Et3N 3HF runs regioselectively to form -fluoroamines. Regioselectivity in this case also is determined by the nature of the substituent at the aziridine cycle.

a-Hydroxyaziridines by the effect of HF/Py complex depending on the reaction conditions are converted into appropriate fluoroalcohols and in very many cases the OH group is replaced with fluorine while the structure of the aziridine ring is not changed ( table 32)[234].

Aziridines containing alkyl groups under the effect of hydrogen fluoride and its complexes with amines open the cycle to form 2- fluoroalkylamines [395, 413,416,420-424]. The effect of the mole ratio of HF/pyridine on regio- and stereo-selectivity can be explained as the effect of solvation of intermediate carbene ions.

Table 32. Effect of HF/Py on -hydroxyaziridines

R¹	R²	R³	R⁴	T, ^oC	Time, h	Yield, %
H	Ph	H	H	20	1	78
H	Me	Me	Et	70	24	90
Et	Ph	H	H	70	1	47
cis-H	Ph	H	Me	20	6 days	69
trans-H	Ph	H	Me	20	5	71

Opening the aziridine cycle with a 70% HF/Py system makes possible to obtain iso-butyl-3-fluoroalanine, methyl-3-fluorophenylalanine [407]. Stereochemistry of the reaction depends both on the fluorinations agent and on the aziridine structure. As a rule there is formed a mixture of diastereomeres [407, 411, 420] For example, two regioisomers of 2-fluorocyclohexylamine are formed in hydrofluorination of cis- and trans-eriminocyclohexane with 70% HF/Py [412].

Great attention of researchers has been drawn to regioselectivity and stereochemistry of the cycle opening [413, 421]. In case of non-symmetrically substituted aziridines the both isomeric fluoroalkylamines are formed.

Phenylvinylaziridine reacts with HF/Py to form ,-fluoroallylamine along with ,-fluoroamine, but in this case the total yield of the reaction products is very small [421].

Bicyclic aziridines such as derivatives of pyranosidines and furanosidines are hydrofluorinated to form fluoroamine derivatives. So, aziridine derivative 36 under the effect of tetrabutylammonium fluoride gives (benzoyloamino) fluoropyranoside 37 [425,426].

The availability of such substituents at the aziridine cycle as phenyl and nitrile brings to formation of only one isomeric product under the effect of 70%HF/Py system [420].

The HF/Py complex hydrofluorinates aziridines containing cyclic fragments 38 to form a mixture of fluorocycloamines 39 and 40 with cis-isomers 40 prevalence. Probably , isomerization of trans-isomer 39 into cis-isomer 40 takes place in this process due to thermodynamic control [38].


R= Ph	0	100
Et	22	78
H	33	66

Bicyclic aziridines 41 react with 1-azabicyclo[n.1.0.]alkane under the effect of hydrogen fluoride in diethylether or with HF/Py to give 3-fluoro-1-azacycloalkanes 42 [416,417].

Stereochemistry in case of bicyclic aziridines also depends on the fluorinating agent used and on the reaction conditions. For example, interaction of bicyclic aziridine 43 with HF/Py results in formation of cis-3-fluoro-2,3-diphenylazetidine 44 at a short reaction time whereas an increase in the reaction time or using anhydrous hydrogen fluoride results in formation of trans-isomer 45 more thermodynamically stable [417].

Aziridines containing alkyl group at the nitrogen are less reactive in comparison with the same containing carbonyl group. Heating N-activated aziridines ( COR ¹ as the substituent at nitrogen) 46 with HF/Py gives oxazoline derivative 47 mainly and a small amount of fluoroamine 48, whereas the effect of Et₃N*3HF complex results in the opposite picture [38, 411, 413]. That points to the importance of steric effects at the nitrogen atom and to the influence of effectiveness of the nucleophilic agent.

Interaction of cis-cyano-2- and cis-amido-2-aziridines with HF/Py complex results in formation of -fluoro--amino acid and esters in good yield. Cis-2-cyanoaziridine gives a mixture of threo- and erythro-2-amino-3-fluoronitrile ( ratio of 57:43)[410,414,415].

Phenyl-substituted azirine under the effect of HF/Py complex converts either into -fluoroketone or into ,-difluoroamine [2,38,410,415,420,422,423,427].

In a number of cases there was observed formation of pyrazine derivatives (table 33)[220, 221a, b, 416, 422].

It is supposed that interaction of azirine with hydrogen fluoride runs via initial protonation of the nitrogen atom of the azirine derivative with generation of cation A.

Further there are several ways to realize conversions of the cation:

1.conversion into intermediate B from which either -fluoroketones are formed or pyrazine at the expense of condensation of two molecules of intermediate B.

2. Conversion into intermediate B from which ,-difluoroamines are formed via further conversions under the effect of the system proton .

Formation of compound 51 can be explained by the following scheme:

The substituents at the aziridine cycle plays the key role in realization of either direction. So, azirines ,containing alkyl substituents only, form ,-difluoroamines ( way 2 is realized) whereas those containing electron-acceptor groups form pyrazine derivatives and -fluoroketones ( way 1 is realized) [427]. For example, interaction of 1-phenyl-3-hydroxyaziridine with HF/Py results in formation of the appropriate pyrazine derivative and -fluoropropiophenone [427] . A temperature increase to 20-50^oC gives the pyrazine derivative only.

In this case cationoid intermediate B is not stabilized by one alkyl substituent and electron-acceptor groups and the reaction runs via intermediate B. When two alkyl substituents or one phenylgroup in position 2 are present, intemediate B is stabilized by these groups that results in formation of -fluoroketone as the main product.

Steroids containing the azirine cycle under the effect of HF/Py in tetrahydrofurane give fluoroketones, not amines [38].

Table 33. Fluorination of 2H-azirine derivatives under the effect of HF/Py

Conclusion

The examples of using hydrogen fluoride in organic synthesis given in the review have shown that the old time-proved fluorinating agent has been used actively. The new process conditions and new view on the potential of anhydrous hydrogen fluoride and its complexes allow to hope for their wide practical application not in laboratory practice only but in technology of industry of little-fluorinated organic compounds. Anhydrous hydrogen fluoride is an important Lewis acid used not only as fluorinating agent but as a component of catalytic systems also, which wide application predetermines progress in general organic synthesis of little-fluorinated compounds. The author does hope that the review will help investigators to enter this interesting and perspective part of organic chemistry as well as will stimulate and provide development and improvement of methods of direct fluorination that will clear horizons of wide practical application of very many perspective substances.