The Journal of Organic Chemistry
3248 MANNING AN:D COLEMAN 25-8; 4, x = H, 707-98-2; 4, x = CN, 21708-27-0; 6, n = 2, 21708-28-1; 6, n = 3, 21708-29-2; 6, n = 6, 21708-30-5; 7, n = 3, 21708-31-6; 7, = 6, 21708-327; 10, n = 2, 21708-33-8; 10, n = 3, 21708-34-9; 10, n = 6,21708-35-0; Ad-C3-NAn, 21708-36-1; DMNAnC3, 21708-37-2; NA.n-C3-NAn1 21708-38-3; DMNAnC1-TMB, 21708-39-4; DMNAn-C2-TMB, 21708-40-7 ; DMNAn-C2-Ind, 21708-41-8; DMNAn-Cs-Ind, 2170842-9; 9-benzylisoalloxazine1 21708-43-0; 9-(3-bromopropyl)adenine, 21.708-44-1 ; 9-[3-(3,4-dimethylanilino)propyl]adenine, 21766-51-8; 9-[3-(3,5-dimethoxy-
anilino) propylladenine, 21708-45-2; 9- [3-(aden-9-yl)propyl]isoalloxazine, 21708-46-3. Acknowledgment.-We are pleased to acknowledge the support of this work by a research grant (USPHSGM-05829) from the National Institutes of Health, U. S. Public Health Service. We wish to thank Professor G. Weber of this department for his many helpful suggestions and for his guidance in the attendant spectroscopic investigation of the compounds in the series la-d.
Reaction of Hydroxylamine with 3,3-Disubstituted 2,4=Pentanediones. Formation of Novel Isoxazole Derivatives DAVID T. MANNING AND HAROLD A. COLEMAN Research and Denelopment Department, Union Carbide Corporation, Chemicals and Plastics, South Charleston, West Virginia Received April 4, 1969 3,3-Disubstituted 2,4pentanediones reacted with hydroxylamine to give good yields of novel 2-isoxazolin-5-ols. 3,4,4,5-Tetramethyl-2-isoxazolin-5-ol ( 5 ) , prepared in this manner, underwent ring opening on treatment with excess hydroxylamine, forming 3,3-dimethyl-2,4-pentanedionedioxime (3). By contrast, all efforts to isolate a dioxime by hydroxylamine treatment of the 4,4-dipropargyl analog (7) of 5 failed. 3,5-Dimethyl-4,4-di(2propynyl)-2-isoxazolind-ol (7) reacted with alcohols, in the presence of acids, to form the corresponding 5-alkoxy derivatives. Dehydration of 7 by treatment with thionyl chloride and pyridine gave a 5-methylen~2-isoxazoline (15) whose high stability contrasts markedly with analogous ezo-methylene enamines of the related pyrazole series. Upon heating to 145", 15 underwent exothermic isomerization to an allene, 5-(2,3-butadienyl)-3-methyl-4-(2propyny1)isoxazole (16); a novel Claisen-Cope-type rearrangement is evidently involved. Attempted purification of 16 by alumina column chromatography caused an unexpected isomerization to a new, highly crossconjugated sllene, 5-( l13-butadienyl)-3-methyl-4-( 1,2-propadienyl)isoxazole(18), in near-quantitative yield.
Our interest in simple derivatives of 3,3-disubstituted 2,bpentanediones led to a study of their reaction products with hydroxylamine. Gnichtel and Schonherr have reported' that 3,3-dimethyl-2,4-pentanedione (1) and 3,3-diethyl-2,4-pentanedione(2) react with hydroxylamine to give the expected dioximes 3 and 4. This contrasted with our observation of cyclic (pyrazole) products resulting from reaction of 3,3-disubstituted 2,4-pentanediones with methylhydrazine, an isostere of hydro~ylamine.~. At the same time, we employed approximately equimolar amounts of diketones and methylhydrazine whereas Gnichtel and Schonherr used a substantial excess of hydroxylamine. Some other standard carbonyl derivatives of 3,3-disubstituted 2,4-pentanediones have been r e p ~ r t e d ~although -~ it is not evident, in all cases, whether cyclic or acyclic derivatives were obtained. Results Reaction of a 1: 1 mol ratio of hydroxylamine with 3,3-dimethyl-2,4-pentanedione(1) afforded the novel 3,4,4,5-tetramethy1-2-isoxazolin-5-01 ( 5 ) in 61% yield. Treatment of 5 with excess hydroxylamine then gave Gnichtel and Schonherr's dioxime 3 in a yield of 48% (1) H. Gnichtel and H. Schonherr, Chem. Ber., 99, 618 (1966). (2) D. T. Manning, H. A . Coleman, and R. A. Langdale-Smith, J . Org. Ckem., Sa, 4413 (1968). (3) A. E. Favorskii and A. S. Onisohenko, J. Gen. Chem. USSR,11, 1111 (1941). (4) M . F. Ansell, W. J. Hickinbottom, and A. A. Hyatt, J . Ckem. Soc., 1592 (1955). ( 5 ) R. B. Davis and P. Hurd, J. Amer. Chem. Soc., 17, 3284 (1955). ( 6 ) E. Detilleux and J. Jadot, Bull. SOC.Roy. Sei. Liege. 24, 366 (1955). (7) T. A. Favorskaya, A. V. Marshueva, and Ting-Yli Hsu, J . Gen. Chem. C S S R , 80, 2499 (1960). (8) J. J. Bloomfield, J . Ore. Chem., 26, 4112 (1961).
SCHEME I
/CHJ
/ excess NH,OH
(CHjC0)C 'CH,
CHJ 3
1
1
5
(Scheme I). The reaction of 3,3-di(2-propynyl)-2,4pentanedione (6) with hydroxylamine was then studied under various conditions. Treatment of 6 with a 4: 1 mol ratio of hydroxylamine in refluxing aqueous ethanol produced only the 2-isoxazolin-5-01 (7) in yields as high as 85%. Examination of 7 showed it to be an acid, soluble in aqueous NaOH, and recoverable as an insoluble precipitate on adjustment to pH 6. Use of Gnichtel and Schonherr's conditions (2.88 mol of hydroxylamine hydrochloride in ethanol-pyridine) gave 7 (29%) along with its ethoxy derivative 8 (32%) (Scheme 11) but not the dioxime. On the other hand, reaction of 6 with a high (1O:l) excess of hydroxylamine gave 7 along with a minor unidentified impurity appearing, in the nmr spectrum, as a singlet at 6 1.8 ppm. Such a resonance is about what would be expected for a methyl group of the unknown dioxime of 6.
Vol. $4, No. 1 1 , November 1969
FORMATION O F NOVELISOXAZOLE DERIVATIVES 3249
Nevertheless there is a clear divergence here between the behavior of 1 (and 2) and 6 which has no ready explanation. While one would expect bulky R substituents to shift the equilibrium, below, to the right (the
isoxazole ring and, along with the nmr data, are also in accord with the spectral features of the conventionally prepared model isoxazole 20. Except for lack of an CHaN signal the nmr spectrum of 16 is almost identical with that of the pyrazole analog 19.2 The energetics of the 15 + 16 conversion, presumably a novel type of Claisen-Cope rearrangement, differ markedly from those of the pyrazole series, however. By contrast, rearrangements of 4-propargyl-5-methylene-2-pyrazolines (14, R or R’ = CH2C=CH) occur fairly rapidly even at O o , hampering isolation of these enamine intermediates. 2, l1 Further characterization of 16 was obtained by catalytic hydrogenation into 5-butyl-3-methyl-4-propylisoxazole (17) and by an unexpected isomerization into the cross-conjugated allene 18 (Scheme 111). This SCHEME I11 YH3
9
CHZC-CH
10
“gem” effectg) it is not evident, assuming that such an equilibrium is important, why R = propargyl should stabilize the heterocycle 10, with respect to 9 (or the corresponding dioxime) more than would methyl or ethyl groups. Formation of 5-alkoxy derivatives of 2-isoxazolin-5ols, such as 8, is facilitated by the expected ability of the C-5 ring position to accommodate a positive charge. Compound 7 reacted with alcohols, in the presence of HC1, giving 5-alkoxy-2-isoxazolines, exemplified by 11 and 12, in fair to good yields.
-n,
CH,C=CH
CH3
I
\
\
CHZ CH=C=CHz
CH2CH=C=CHz
16
19
4 y
CH3
CH3
I
I
11, R = n-C4HS
13
14
12, R = - C H , C H , N ~
Preparation of 2-isoxazolin-5-01s from 3,3-disubstituted 2,4-pentanediones and hydroxylamine contrasts sharply with the behavior of these diketones with methylhydrazine. The latter reactions did not give isolable 5-hydroxypyrazolines (13) but, instead, either 5-methylene enamines (14) or pyrazoles were formed, depending upon the C-4 substituents.2 It was of interest then to note that 7 can be dehydrated by treatment with thionyl chloride in pyridine to give the stable exomethylene-2-isoxazoline 15. The methylene protons of this compound lie in nonequivalent magnetic environments and appear as an AB pattern of doublets (nmr in CDCP), J = 3.5 Hz, centered at 6 4.30 and 4.72. Compound 15 proved relatively inert toward water at pH 7 and 25” but addition of acid to an aqueous slurry caused rehydration to 7. Although 15 is stable and can be stored at room temperature, heating to ca. 145’ caused exothermic rearrangement to the air-sensitive allene 16 in 77% yield. The ir and uv spectra of 16, 6.11 and 6.28 p and ,A 220 (E 6680), are characteristic’o of the (9) G . Hammond, “Sterio Effeots in Organio Chemistry,” M . 8. Newman, Ed.. John Wiley & Sons. Ino., New York, N. Y., 1958. (10) W. L. Meyer, R . W. Huffman and P. G. Schroeder, Tetrahedron, 34 (18), 5959 (1968).
step occurred in nearly quantitative yield upon attempted purification of 16 by alumina column chromatography at 25”. The polyene 18 is a white crystalline solid which undergoes fairly rapid polymerization on storage, at temperatures as low as -25”, with relatively little change in appearance. The nmr spectrum of 18 shows the eight protons lining the conjugated chains as a series of lines at 6 5.05-7.10 (Figure 1). CH3
I
t a ~ CH-CH = b
I
c
=CH,d
‘ 3 3
20
18 ~
~~
(11) The less facile rearrangement of 16, compared with the 2-pyrasoline analoga. probably reflects a decreased capacity for electron donation from the more electronegative oxygen (as in 16A) cornpared with donation from nitrogen in the corresponding pyrasoline enamines.
I+
I%*
CH,mCH CH,CZCH 6-
15A
3250 MANNING AND COLEMAN
The Journal of Organic Chemist~y
39
7
H :=
c:
CH2 f
0 CH- CH-CH=CH2 a b c d
I
I
8
I
I
5
6
7
I
I
4
I
I
3
I
2
e-8 Figure 1.-The
100-Mc spectrum of 5 4 1,3-butadienyl)-3-methyl-4-(1,2-propdienyl)isoxazole(18)in CDCls solution. V
9 1. o
5V
I
v
