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Reactions with Heterocyclic Enamines Synthesis of New Isoxazole Derivatives.

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Reactions with Heterocyclic Enamines
Teil XVII der Sene: Carbon-13Nuclear Magnetic Resonance Spectra; Teil XVI: H. Duddeck und
V. Wiskamp, Org. Magn. Reson. 15, 361 (1981).
A. Uvai und R. BognBr, Acta Chim. Acad. Sci. Hung. 97, 77 (1978) und dort zit. Lit.;
C.A. 90, 6376 g (1979).
S. Sternhell, Rev. Chem. SOC.23, 236 (1969).
R.R. Emst, J. Chem. Phys. 45, 3845 (1966).
J.B. Stothers in Carbon-13 NMR Spectroscopy, Academic Press, New York 1972.
E. Pretsch, T. Clerc, J. Seibl und W. Simon, Tabellen zur Strukturaufklarung organischer
Verbindungen mit spektroskopischen Methoden, Springer-Verlag, Berlin 1976.
L.F. Johnson in Spin-Decoupling Methods in 13CNMR Studies, in Topics in Carbon-13 NMR
Spectroscopy, Hrsg. G.C. Levy, Bd. 3, S. 2, John Wiley & Sons, New York 1979.
A.F. Cockerill, G.L.O. Davies, R.C. Harden und D.M. Rackham, Chem. Rev. 73, 553
0.Hofer in The Lanthanide Induced Shift Technique: Application in ConformationalAnalysis, in
Topics in Stereochemistry, Hrsg. N.L. Allinger und E.L. Eliel, Bd. 9, S. 111, John Wiley & Sons,
New York 1976.
10 O.A. Gansow, P.A. Loeffler, R.E. Davis, M.R. Willcott IIIund R.E. Lenkinski, J. Am. Chem.
SOC.95,3389 (1973); K. Tori, Y. Yoshimura, M. Kainosho und K. Ajisaka, Tetrahedron Lett.
1973, 3127.
11 H. Duddeck und M. Kaiser, unveroffentlichte Ergebnisse.
12 H. Duddeck, M.H.A. Elgamal, F.K.A. Elhady und N.M.M. Shalaby, Org. Magn. Reson. 14,256
[Ph 5501
Arch. Pharm. (Weinheim) 316,105-110 (1983)
Reactions with Heterocyclic Enamines
Synthesis of New Isoxazole Derivatives
Ezzat M. Zayed, Mohamed A.E. Khalifa, L i l a I. Ibraheim and Mohamed H.
Chemistry Department, Faculty of Science, Cairo University, Giza, A.R. Egypt
Eingegangen am 19. Januar 1982
Several new isoxazole derivatives were prepared from the 5-aminoisoxazole derivatives 1 and the
3-aminoisoxazole derivative 12 as starting materials.
Reaktionen mit heterozyklischen Enaminen: Darstellung verschiedener nener Isoxazol-Derivate
Verschiedene neue Isoxazol-Derivatewurden ausgehend von den 5-Aminoisoxazol-Derivaten1 und
dem 3-Aminoisoxazol-Derivat 12 synthetisiert.
S U2.50/0
Q Vcrlag Chemie GmbH, Weinheim 1983
Arch. Pharm.
Zayed, Khalifa, Ibraheim and Elnagdi
The considerable biological activities of isoxazole derivatives have stimulated enormous interest in
the synthesis and chemistry of this class of compounds'"). As part of a medicinal chemistry
program4." in our laboratories the synthesis of several substituted aminoisoxazole derivatives were
required. In the present paper we report the results of our work in this direction. Several new,
otherwise difficultaccessible, isoxazole derivatives have been prepared. More over the results offer a
new efficient route for the synthesis of azolo-pyridine and azolo-pyran derivatives.
It has been found that 5-amino-3-phenylisoxazole (1)reacts with acrylonitrile or with
ethyl acrylate to yield a product of molecular formula C1,&NO3. The IR spectrum of the
product revealed two carbonyl absorptions at 1800cm-' and 1830cm-' typical for a six
membered lactone carbonyl groups. Structure 2 was thus suggested for this product.
In contrast to the behaviour of 1 toward acrylonitrile, it reacted with benzalmalononitrile (3) to yield a mixture of two products of m.p. 222 "C and 133"C.The high melting
product afforded analytical data corresponding to a molecular formula C19H14N40.
isomeric structures seemed possible for this product (cf. structures 4 and 5). Structure 4
was established for this product based on 'HNMR which revealed a multiplet for two
pyridine CH protons at 6 4.66. If this compound is the isomeric 5, a signal for only one CH
should have appeared. The formation of 4 from 1and 3 might be assumed to proceed via
addition to the activated double bond in a manner similar to that observed here with
9a: R = COPh
b: R = COzCZHs
Reactions with Heterocyclic Enamines
acrylonitrile to yield an acyclic adduct which then cyclizes into the final product 4. The
analytical data of the low melting product indicated that this compound is the Schiffs base
6. This structure assignment was established via synthesis of 6 from 1and benzaldehyde.
The formation of ylidenes on reacting 3 with amines has been previously observed6).
Compound 1 also reacted with a-cyanochalcone 7 to yield the isoxazolo-pyridine
derivative 8. The formation of 8 from the re-tion of 1 with 7 affords a new efficient
procedure for the synthesis of isoxazolo[4,3-b]pyridines.Attempts to extend this reaction
however to synthesize isoxazolo[2,3-a]pyridines,via reaction of 7 with 5-amino-3-methylisoxazole 12 were unsuccessful.
Compound 1 and l2 reacted with benzoyl- and with ethoxycarbonylisothiocyanates to
yield the corresponding thiourea derivatives 9a,b and 13a,b, resp. Attempts to effect
cyclization of 9a,b into isoxazolo-pyrimidine derivatives were unsuccessful. Under mild
conditions compounds 9a,b were recovered unreacted, when more drastic conditions were
used the isoxazol-5-yl-thiourea derivative 10 was the only isolable product. With silver
nitrate 9s was converted into 11.Similarly attempts to effect cyclization of 13a,b resulted in
their decomposition.
138: R
b: R
17a: R = COCH,
b: R = COOCzH,
Zayed, Khalifa, Ibraheim and Elnagdi
Arch. Phann.
In a previous work from our laboratories it has been shown that 3- and 5-aminopyrazoles
can be readily diazotized to yield stable diazonium compounds which could be utilized for
synthesis of several pyrazoles and fused pyrazole derivatives'). Now we have investigated
the possible utility of diazotized 1 and 12. Although our efforts to isolate or trap diazonium
compound from 1 were unsuccessful, compound 12 could be readily diazotized. However
the diazo derivative could not be isolated in a pure form. Its formation could be indicated
via isolation of the diazoaminoisoxazolederivative 14 on treatment of the diazotized amine
solution with sodium acetate. Moreover several coupling products were also isolated.
Thus, the hydrazones lS17were isolated from reaction of the diazotized amine solution
with ethyl cyanoacetate, 2-amino-crotononitrile,a-chloroacetylacetone and ethyl a-chloroacetate. From the reaction of diazotized 12 with malononitrile, the amide 18 was
obtained. Beside the previously mentioned hydrazones, compound 14 was also isolated
with 15 and 18.
M P : uncorr. IR spectra: (KJ3r) Pye Unicum SP 1OOO. 'H-NMR spectra: Varian A-60 in DMSO. TMS
int. stand., chemical shifts: 6 (ppm).
A solution of 1.6g 1 in 30ml pyridine was treated with 0.01 mol acrylonitrile or ethyl acrylate. The
reaction mixture was refluxed for 3 h. The solvent was removed i.vac. The remaining solid product
was triturated with methanol, and crystallizedfrommethanol. Compound2 formed brownish crystals,
m.p. 145"C,yield75%. IR: 1800and1830cm-'(lactoneCO). C12HgNO3(215)Calcd.C67.OH4.2N
6.5; Found C 67.1 H 4.6 N 6.7.
Reaction of 1 with benzylidine malononitrile (3)
To a solution of 1.6 g 1 in ethanol was added 1.5 g benzylidine malononitrile (3) and 0.5 ml
triethylamine. The reaction mixture was refluxed for 4 h and then evaporated i. vac. The remaining
solid product was treated with hot methanol and filtered while hot. The solid product remained
undissolved was crystallized from dioxane and was identified as 4. Colourless crystals, m.p. 222"C,
yield35%. IR: 1645(6NH2),2200(conj. CN),3180and3380cm-'vNH2). 'H-NMR &(ppm)=4.66
(m, 2H, ring CH), 7.07 8.2 (m, 10 H,2 C6H5).Cl,H14N40 (314) Calcd. C 72.6 H 4.5 N 17.8;Found
C 72.6 H 4.2 N 17.4.
The methanol solution after the separation of compound 4 was conc. and cooled. The solid product so
formed was crystallized from methanol and was identified as 6. Pale yellow crystals, m.p. 133"C, yield
50 % . IR: 1610cm-' (C=N). C16H12N20(248) Calcd. C 77.4 H 4.8 N 11.3; Found C 77.8 H 4.6 N 11.2.
Compound 6 was found to be identical (m.p. and mixed m.p.) with the product obtained from the
reaction of 1 with benzaldehyde in ethanol-triethyl-amine.
1 reacted with benzylidene o-cyanoacetophenone (7) using the same procedure for the reaction of 1
with 3.The solid product was crystallized from dioxane and was identified as 8. Colourless crystals,
m.p. 202"C, yield 65 %. IR: 2210 cm-' (con]. CN). (&H&@ (373) Calcd. C 80.4 H 4.0 N 11.3;
Found C 80.3 H 4.0 N 10.9.
Reactions with Heterocyclic Enamines
Reaction of 1 and l2 with isothwcyanates: General procedure
A solution of 0.1 mol of 1 or 12 in 50 ml acetone was added to a solution of the isothiocyanate
derivative (prepared from 0.12 mol of NH4SCNand the appropriate quantity of benzoyl chloride or
ethyl chloroformate as has been previously described*))and was refluxed for 3 h then evaporated i.
vac. The remaining solid product was then triturated with water, and crystallized from ethanol.
Compound 9p formed yellow crystals, m.p. 173"C, yield 85 %. IR:1620 (C=N), 1675 (benzoyl CO),
3420 cm-l (NH). Cl,H13N302S (323) Calcd. C 63.2 H 4.0 S 9.9; Found C 63.2 H 4.0 S 10.1.
m.p. 150"C,yield70 %. IR:1620(C=N), 1720(C0),3200
cm-l (NH).C13H13N303S(291) Calcd. C 53.6 H 4.5; Found C 53.6 H 4.7.
Compound l3a formed pale yellow crystals, m.p. 150"C, yield 83 %. IR:1620 (C=N), 1675 (benzoyl
CO), 3220 cm-' (NH). C12HllN30zS (261) Calcd. C 55.2 H 4.2 S 12.2; Found C 55.6 H 4.2 S
Compound Ub formed yellow crystals, m.p. 158"C, yield 86 %. IR:1620 (C=N), 1725 (CO), 3180
cm-' (NH). C8HllN303S (229) Calcd. C 41.9 H 4.8 S 13.9; Found C 41.9 H 5.1 S 13.7.
To a solution of sodium ethoxide (prepared from 1g of sodium metal and 100mlof ethanol) was added
2g 9a. The reaction mixture was refluxed for 4 h and the solvent was then removed i. vac. The
remaining solid product was dissolved in water and acidified with HCl. The solid product, so
separated, was crystallizedfrom dilute ethanol. Compound 10formed colourlesscrystals, m.p. 179"C,
yield 70 %. IR:1610 (C=N), 1620 (6NH2), 3250 and 3290 cm-' (v NHJ. C1&$J3OS(219) Calcd. C
54.8 H 4.1 N 19.2; Found C 55.1 H 4.6 N 18.9.
A solution of 0.01 mol9p was treated with 100 ml IN-AgNO, and the reaction mixture was refluxed
for 1 h. The precipitated silver sulphide was filtered off and the filtrate was evaporated i. vac. The
remaining solid product was triturated with water, and crystallized from ethanol. Compound 11
formed yellow crystals, m.p. 221"C, yield 85 %. IR:1625 (6NH2), 1680 (benzoyl CO), 3190,3260
cm-' (v NHJ. C17H13N303(307) Calcd. C 66.4 H 4.2; Found C 66.4 H 4.4.
Formation of the diazoaminoisoxazole derivative 14
A solution of diazotized l2 (prepared from 0.1 mol of l2 and the appropriate quantities of sodium
nitrite and sulphuric acid as has been previouslydescribed')) was added to cold 150 mlethanol and 10g
sodium acetate. The reaction mixture was stirred at room temp. for 1 h and then ammonia solution
was added till pH 6. The solid product so formed was washed with water and crystallized from dilute
methanol. Compound 14 forms yellowish brown crystals, m.p. 148"C, yield 68 %. IR:1560 (N=N),
1620 (C=N), 3240 cm-' (NH). C8H9N50z(207) Calcd. C 46.4 H 4.3; Found C 46.6 H 4.6.
Coupling of diazotized l2 with active methylene reagents: General procedure
A solution of diazotized 12,prepared as previously described, was added to 0.1 mol of the appropriate
active methylene reagent in 150ml ethanol and 10g sodium acetate. The reaction mixture was stirred
at room temp. for 1h. The solid product, so formed, was washed with water and crystallized from the
proper solvent. In case of coupling of diazotized 12 with ethyl cyanoacetate and malononitrile the
mother liquor after the separation of 14 was left overnight and the solid product, so formed was
washed with water and crystallized from the proper solvent.
Compound 16 forms dark brown crystals from methanol, m.p. 223"C, yield 80 %. IR:1540 (N=N),
1640(C=N),2200(conj. CN),324Ocm-'(NH). C 8 ~ 5 0 ( 1 9 1 ) C a l c dC50.3H4.7;FoundC50.0H
Arch. Pharm.
Compound 17a forms colourless crystals from methanol, m.p. 197"C,yield 82 %. IR: 1550 (N=N),
1620 (C=N), 1680 cm-' (CO). C,H,N30,CI (201.5) Calcd. C 41.7 H 4.0; Found C 41.5 H 4.4.
Compound 1% forms colourless crystals from methanol, m.p. MOT, yield 83 %. IR: 1550 (N=N),
1640 (C=N), 1760 cm-' (CO). C,HloN,O,CI (231.5) Calcd. C 41.5 H 4.3; Found 42.0 H 4.4.
Compound 15 forms yellow crystals from methanol, m.p. 155"C, yield 53 %. IR: 1550 (N=N), 1620
(C=N), 1750 (CO), 2200 cm-l (conj. CN). c 9 H 1 & J 4 0 3 (222) Calcd. C 48.6 H 4.5; Found C 48.9 H
Compound 18 forms pale yellow crystals from methanol, m.p. 225"C, yield 50 %. IR: 1550 (N=N),
1620 (6 NH2), 1675 (amide CO), 2220 (conj. CN), 3190,3260 cm-' (v NH). C,H,N502 (193) Calcd. C
46.4 H 4.3; Found C 46.6 H 4.7.
F. Lambein, Y. H. Kuo and R. Van Parijs, Heterocycles 4, 567 (1976).
G. B. Carr, H. G. Durham and D. K. Hass, J. Med. Chem. 20, 934 (1977).
A. Corsaro, U. Chiacchio and G. Purrello, J. Chem. SOC.Perkin Trans. 1 1977, 2154.
M. H. Elnagdi, M. A. E. Khalifa, M. K. A. Ibraheim and M. R. €3. Elrnoghayar, J. Heterocycl.
Chem. 18, 877 (1981).
M. H. Elnagdi and H. Wamhoff, Chemistry Lett. 1981, 419.
M. R. H. Elrnoghayar, M. K. Ibraheim, A. H. Elghandour and M. H. Elnagdi, Synthesis 1981,
M. H. Elnagdi, E. M. Zayed and S. Abdou in Review on Heterocyclic Diazo Compounds,
Heterocycles, in press.
I. B. Douglass and F. B. Dains, J. Am. Chem. SOC.56, 1408 (1934).
M. H. Elnagdi, M. R. H. Elmoghayar, D. H. Fleita and S. M. Fahmy, J. Org. Chem. 42, 378
[Ph 5511
Arch. Pharm. (Weinheim) 316, 110-114 (1983)
Jurgen Dusemund+)
Institut fiir Pharmazie der Freien Universitat Berlin, Konigin-Luise-Str.2/4, lo00 Berlin 33
Eingegangen am 20. Januar 1982
Bei der Umsetzung des Isocumarins 2 mit Methylhydrazin entsteht als Hauptprodukt die
Spiro-Verbindung 3b, aus der die Titelverbindungen 8 und 9 dargestellt werden konnen.
Reaction of the isocoumarin 2 with methylhydrazine yields the spiro-compound 3b as the major
product. Compound 3b was converted to the title compounds 8 and 9.
Herrn Prof. Dr. Alfred Kreutzberger mit den besten Wiinschen zum 60. Geburtstag gewidmet.
0 3 6 ~ ~ 3 / ~ x n o u )s i02.50~1
0 Verlag Chemie GmbH, Weinheim 1983
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synthesis, reaction, heterocyclic, isoxazole, new, derivatives, enamine
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