1,3-dipolar cycloadditions of heterocycles xvi.* reduction ... tion of n + 1-memhered heterocycles...

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  • 1,3-Dipolar cycloadditions of heterocycles XVI.* Reduction of isoxazolines — a pathway to condensed



    Department of Organic Chemistry, Slovak Technical University, CS-812 37 Bratislava

    Received 4 July 1986

    Dedicated to Professor Ing. J. Kováč, DrSc, in honour of his 60th birthday

    1,3-Dipolar cycloaddition of acetonitrile oxide at substituted 1,3-dioxep- -5-enes produces a diastereomeric pair of endo and exo adducts. A prepara­ tion of n + 1-memhered heterocycles from л-membered ones via a simple sequence of 1,3-dipolar cycloaddition, reduction, and cyclization is de­ scribed. Reduction of isoxazolines with lithium-aluminium hydride fur­ nishes a mixture of heterocyclic erythro and threo /-amino alcohols VI, VII, IX, X which upon cyclization with 4-nitrobenzaldehyde produce condensed tetrahydro-l,3-oxazine derivatives XI, XII.

    В результате 1,3-диполярного циклоприсоединения окиси ацетони- трила к замещенным 1,3-диоксеп-5-енам образуется диастереомерная пара эндо- и экзо-адцуктов. Описано получение n + 1-членных гетеро- циклов из л-членных посредством простой последовательности 1,3-ди­ полярного циклоприсоединения, восстановления и циклизации. Вос­ становление изоксазолинов алюмогидридом лития приводит к обра­ зованию смеси гетероциклических эритро- и т/?ео-/-аминоспиртов VI, VII, IX, X, которые в результате циклизации с 4-нитробензальдегидом дают конденсированные тетрагидро-1,3-оксазиновые производные XI, XII.

    Isoxazoline derivatives proved to be useful intermediates in the synthesis of y-amino alcohols [1—3], /?-hydroxycarbonyl compounds [4—6] and their de­ rivatives. In our previous papers we have shown [7—16] that aryl-substituted isoxazolines can be photochemically converted to heterocyclic [7—14] or acyclic [15, 16] enamino aldehydes. This paper deals with 1,3-dioxepane skeleton in order to assess the role of the methyl group in the rearrangement and in the synthesis of heterocyclic y-amino alcohols.

    * For Part XV see Ref. [26].

    Chem. Papers 41 (5) 609-622 (1987) g Q 9



    H b i , R h R2 R̂

    Я Ш

    J /Г. Ti R1—CH NH R - q H A J n 2








    R1 =

    R1 =

    R1 =

    R1 =


    H, R 2 = C 6 H 5

    H, R2 = CH3

    6 ^ 5 ' R = ^ ^ 3

    R2 - CH 3


    the reaction of/with the benzonitrile oxide [9, 10, 13]. Structures of exo and endo adducts were assigned based on different chemical shifts of C-2 and C-6 triplets in 13C NMR spectra due to the bent structure of the bicyclic adducts. Exo adducts He—He with equatorial R displayed for C-2 {8 = 70.25 ppm) and C-6 (8 = 65.23 ppm) values, almost identical with those of the unsubstituted derivative lib (8 = 71.66 ppm and 66.59 ppm). In the 13C NMR spectra of endo derivatives on the other hand /-effect could be observed, shifting all correspond- ing triplets upfields due to the influence of the axial 4-R substituent, e.g. for I He 8 = 64.97 ppm (C-2) and 62.89 ppm (C-6). Other chemical shift values found in 'H and 13C NMR spectra of adducts support the suggested structure of / /and / / / (see Experimental), being in fact very similar to the spectra of the corre- sponding 8-phenyl-substituted derivatives [10, 13]. Referring to 8-phenyl deriva- tives the UV spectral maxima of 8-methyl-substituted derivatives are blue-shif- ted by about 10 nm.

    Although the photochemistry of isoxazolines is still rather intensively studied [7—16] and [19—22], nobody has so far studied the photochemistry of isoxazoli- nes substituted by nonaromatic chromophore. Adducts / / and / / / were irra- diated by the nearly monochromatic light with Amax = 253.7 nm in methanol. The quantum yield for lib, measured from the diminishing concentration of the starting compound was by 0.11 higher than that of the corresponding phenyl

    250 300 350 Vnm

    Fig. L Spectral changes during the irradiation of lib in methanol by monochromatic light (A = 253 nm).

    //min: /. 0; 2. 15; 3. 20; 4. 25; 5. 30; 6. 35.

    Chem. Papers 41 (5) 609—622 (1987) (y \ J


    derivative Па (Ф= 0.016). The irradiation of IIb was monitored by periodic scans of UV spectra of the reaction mixture, where the gradual disappearance of the peak at Amax = 254 nm, belonging to the starting lib could be observed together with the new peak being formed at Amax % 300 nm. The latter peak was much less intensive than that of IIa (Fig. 1). Preparative experiments failed to produce isolable product. In analogy with the aryl derivatives we assume that


    methyl derivatives rearrange to heterocyclic enamino aldehydes 77 -• IV, hv

    III-> IV, which are photochemically unstable. Even stopping the irradiation at low conversion of the starting material could not produce anything but uniden­ tifiable material. Similar results were obained with isoxazolines containing carbonyl groups, amino groups, and two-valent sulfur [23—26].

    , As has already been mentioned isoxazolines are precursors of /-amino alco­ hols, which are extensively studied due to their pharmacological activity. Espe­ cially important are therefore synthetic procedures leading stereoselectively to /-amino alcohols possessing a free amino group, e.g. amino acids and aminogly­ coside antibiotics [27, 28]. Consequently our aim has been to utilize condensed isoxazolines for the preparation of /-amino alcohols having tetrahydrofuran and 1,3-dioxepane structure. There has been reported so far only one synthesis of 3-hydroxy-4-(l-aminoethyl)tetrahydrofuran (IXc, Xc) by the reduction of isoxazoline VIIIc. The reduction produced the corresponding /-amino alcohols with three chiral centres; erythro-IXc and threo-Xc were formed in the ratio mc: mt = 70: 30 in favour of the erythro derivative [29]. Jäger et al. have shown [30—33] that 3,5-disubstituted and 3,4,5-trisubstituted isoxazolines, prepared from alkenes or cycloalkenes and nitrile oxides, could be reduced by lithium- -aluminium hydride (LAH) in ether stereoselectively to /-amino alcohols pos- sessing mostly erythro configuration (we:mt = 85:15), only in case of 2,5-di- hydrofuran derivative the ratio me: mx was only 70: 30 [29].

    Several reducing agents are capable of producing /-amino alcohols, the outcoming ratio of diastereomers being dependent on the reducing agent [33]. For the reduction of isoxazolines V and VIII (Scheme 2) we have tested Zn/CH3COOH and NaBH4/NiCl2. Yields fell in the range of 47—56%, but diastereoselectivity was rather low, only the ratio w e :w t%55:45 could be achieved. After consulting the literature we have finally opted for the system LAH—ether. With equimolar amount of LAH in refluxing ether the reaction took more than 10 days. With twofold mole excess of LAH the reduction still took 5—9 days till the maximum conversion (50—80%) was reached (GLC control). Higher boiling point solvents (tetrahydrofuran or methyl terr-butyl eth^r) pushed the conversion to 100 % in 2 days. /-Amino alcohols were formed as diastereomeric pairs erythro (VI), (IX) and threo (VII, X) which could not be separated. The separation also failed in already reported cases [29—33]. Struc-

    612 Chem. Papers 41 (5) 609—622 (1987)


    tures of the prepared alcohols were determined from spectral data, based on the finding [30—33] that in solution intramolecular hydrogen bonds enforced a chair conformation with the concomitant quasi-equatorial position of sub- stituents in erythro configuration and one axial substituent in threo configura­ tion. Infrared spectra of all y-amino alcohols Via—Vic, Vila—VIIc, IXa—IXc, Xa—Xd, Xf, Xg displayed a broad band in the region of v = 3280—3360 cm"1, indicating a strong intramolecular OH ••• NH 2 hydrogen bond. ' H N M R spec­ tra showed signals of OH and NH 2 protons in a multiplet at S = 3.0—4.5 ppm.

    H R


    Ф ^ H R





    a C 6 H 5 b 4-Вг-С 6 Н 4

    с СН3

    d 4-СН 3 -С б Н 4

    e 4-Снз°~СбН4

    / * - С 1 - С б Н 4 g 2-furyl

    _ ^ H

    H R



    H R



    Scheme 2

    _ ^ H

    H H



    г + C U H H J Й H

    Xa-Xd, Xf, Xg

    гН^ 2 ЙГ

    ХПа, ХЩ

    H R


    Chem. Papers 41 (5) 609—622 (1987) /-1 3


    The assignment was confirmed by the addition of 2 H 2 0 to the sample of diastereomeric pair Via—Vila, which showed a three-proton broad singlet at 3.38ppm. 'H NMR spectra showed further H-3 multiplet of 3-hydroxy-4- -aminoarylalkyl tetrahydrofurans (IX, X) as well as that of H-5 of 5-hydroxy-4- -aminoarylalkyl-l,3-dioxepanes (VI, VI


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