J. Org. Chem.
1984, 49, 3423-3424 3423
2 H); IR (CC14) 3060 (m), 2950 (m), 1415 (vs) cm"1. Registry No. la, 100-52-7; lb, 98-01-1; lc, 91328-45-9; Id,
IV-Methyl-3-phenyl-5-(trimethylsilyl)isoxazolidine (3a): 111-71-7; le, 924-44-7; (Z)-2a, 7372-59-0; (Z)-2b, 91328-46-0; 2c,
NMR (CDC13) 0.1 (s, 9 ), 1.8-2.9 (m, 2 H), 2.7 (s, 3 H), 3.2-3.9 91328-47-1; (Z)-2d, 91328-48-2; (E)-2e, 81206-60-2; (Z)-2e,
(m, 2 H), 7.3 (m, 5 H); IR (neat) 3030 (m), 2960 (vs), 2840 (s), 81206-61-3; cis-3a, 91328-49-3; trans-Sa, 91328-56-2; cts-3b,
1245 (vs) cm'1. 91328-50-6; trans-3b, 91328-57-3; 3c, 91328-51-7; c¿s-3d, 91328-52-8;
-Fury 1-TV-methylnitrone (2b): NMR (CDC13) 3.6 (s, 3 H), trans-3d, 91328-58-4; cis-3e, 91328-53-9; trans-3e, 91328-59-5;
6.3 (m, 1 H), 7.2 (m, 2 H), 7.5 (m, 1 H); IR (CC14) 3020 (w), 2940 (£)-4a, 14371-10-9; (E)-4b, 39511-08-5; 4c, 91328-54-0; (£)-4d,
(w), 1590 (w), 1410 (vs), 1145 (vs) cm'1. 18829-56-6; (E)-4e, 2960-66-9; (J5)-4e (p-nitrophenylhydrazone),
JV-Methyl-3-furyl-5-(trimethylsilyl)isoxazolidine (3b): 91328-55-1; MeNHOH-HCl, 4229-44-1; CH^HSiMeg, 754-05-2.
NMR (CDC13) 0.1 (s, 9 ), 1.9-2.6 (m, 2 H), 2.6 (s, 3 ), 3.1-3.8
(m, 2 ), 6.1 (m, 2 H), 7.2 (m, 1 H); IR (CC14) 2970 (m), 1255 (m),
1170 (vs) cm'1; mass spectrum, m/z (relative intensity) 225 (M+,
62), 210 (10), 73 (100).
/8-Furylacrolein (4b): NMR (CDC13) 6.46 (dd, J = 1.8, 3.5,
1 H), 6.53 (dd, J = 7.9,15.8,1 ), 6.70 (d, J = 3.5,1 ), 7.17 (d, Reduction of 4-Cyanoisoxazoles with Lithium
J = 15.8, 1 H), 7.49 (d, J = 1.4, 1 H), 9.53 (d, J = 7.9, 1 H); IR Aluminum Hydride. Synthesis of
(CC14) 3120 (w), 2805 (s), 2715 (s), 1685 (vs), 1630 (vs) cm'1; mass 5-Aminoisoxazoles
spectrum, m/z (relative intensity) 122 (M+, 100), 94 (45), 65 (40),
39 (31).
Angel Alberola,* Ana María González, Miguel Angel Laguna,
-Methylnitrone 2c: NMR (CDClg) 1.77 (s, 3 ), 3.19 (s, and Francisco José Pulido
3 H), 4.85 (A of AB q, J = 11.7,1 ), 4.90 (B of AB q, J = 11.7,
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1 H), 4.96 (A of AB q, J = 11.4,1 ), 5.02 (B of AB q, J = 11.4,
1 H), 5.45 (d, J = 7.4, 1 ), 6.10 (s, 1 H), 6.74 (d, J = 7.4, 1 H),
Departamento de Química Orgánica, Facultad de Ciencias,
Universidad de Valladolid, Valladolid, Spain
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6.8 (m, 2 H), 7.3 (m, 16 H); IR (CC14) 3030 (w), 2995 (m), 2830
(w), 1585 (m), 1490 (s) cm'1; mass spectrum, m/z (relative in- Received January 18, 1984
tensity) 509 (M+, 0.1), 280 (8), 91 (100).
JV-Methyl-5-(trimethylsilyl)isoxazolidine 3c: NMR (CD-
Clg) 0.1 (s, 9 ), 1.8 (s, 3 ), 2.1-2.5 (m, 2 H), 2.3 (s, 3 ), 3.1
In the course of our investigations of the reduction of
(m, 1 H), 3.3 (m, 1 H), 4.3 (m, 1 ), 5.1 (s, 2 H), 5.2 (s, 2 H), 5.9 isoxazole derivatives with complex metal hydrides, 2-, 3-,
(s, 1 H), 6.9 (m, 2 H), 7.3 (m, 16 H); IR (CC14) 3050 (m), 2970 (s), and 4-isoxazolines have been selectively synthesized in
2880 (s), 1480 (vs), 1200 (vs) cm'1; mass spectrum, m/z (relative good yields;1'3 In order to obtain adequate reactivity of
intensity), 609 (M+, 0.1), 536 (2), 280 (14), 91 (100). the isoxazole ring toward reduction, activation of the nu-
,/9-Unsaturated aldehyde 4c: NMR (CDClg) 1.46 (s, 3 H), cleus by quaternization of the nitrogen1 or introduction
4.99 (dd, J = 1.1, 2.5, 1 ), 5.07 (s, 4 H), 5.74 (s, 1 H), 6.3 (m, of electron-accepting groups at C-42 is necessary. In
2 H), 6.9 (m, 2 H), 7.4 (m, 16 H), 8.86 (d, J = 7.5,1 H); IR (CC^)
3050 (w), 2880 (w), 2730 (w), 1695 (vs) cm'1; mass spectrum, m/z
particular, 3,5-dimethylisoxazoles with electron-with-
(relative intensity) 506 (M+, 0.1), 332 (7), 91 (100). Anal. Caled11 drawing groups at C-4 on reaction with sodium boro-
for C33Hgo05: C, 78.22; H, 5.97. Found: C, 78.03; , 6.12. hydride are reduced to 2-isoxazolines regiospecifically.2
a-a -Hexyl-JV-methylnitrone (2d): NMR (CDClg) 0.8-1.5 (m, Although the reduction of 4-cyano-3,5-dimethylisoxazole
11 H), 2,3-2.7 (m, 2 H), 3.6 (s, 3 H), 6.7 (t, =7 = 7,1 H); IR (neat) with sodium borohydride leads to the expected 4-cyano-
3050 (w), 2930 (vs), 1605 (s), 1410 (vs) cm'1; mass spectrum, m/z 2-isoxazoline,2 surprisingly, we found that reduction of
(relative intensity) 144 (M+ + 1, 25), 86 (50), 73 (100). 4-cyano-3,5-dimethylisoxazole with lithium aluminum
JV-Methyl-3-n -hexyl-5-(trimethylsilyl)isoxazolidine (3d): hydride leads to 5-amino-4-ethyl-3-methylisoxazole re-
NMR (CDClg) 0.1 (s, 9 ), 0.8-1.0 (m, 3 ), 1.2-1.6 (m, 10 H),
sulting from an unusual rearrangement.
1.8-2.4 (m, 3 H), 2.6 (s, 3 ), 3.1-3.9 (m, 1 H); IR (neat) 2960 (vs), The interest in 5-aminoisoxazoles as intermediates for
2860 (s), 1250 (s), 825 (vs), cm'1; mass spectrum, m/z (relative
the synthesis of derivatives with antihistaminic,4 analgesic,5
intensity) 243 (M+, 15) 227 (41), 170 (39), 158 (25), 140 (67), 73
GOO).
antibactericidal,6 and insecticidal7 activity led us to study
2-Nonenal (4d): NMR (CDC13) 0.89 (m, 3 ), 1.29-1.57 (m,
Table I. Reduction of 3,5-Disubstituted-4-cyanoisoxazoles
8 H), 2.36 (ddt, =7 = 1.5,6.8,5.0, 2 ), 6.12 (ddt, =7 = 1.5, 7.9,15.6, la-c with Lithium Aluminum Hydride (1 Equiv) at 0 °C in
1 H), 6.86 (dt, =7 = 6.8,15.6,1 ), 9.50 (d, =7 = 7.9,1 H); IR (neat) Ether for 6 h
2940 (vs), 2740 (w), 1690 (vs), 890 (vs), 715 (vs) cm'1; mass
spectrum, m/z (relative intensity) 140 (M+, 100). Metal Product Yield
NEC R
or-Carbethoxy-IV-benzylnitrone (2e) (E and Z mixture): Complex
RP‘wR ’/.
NMR (CDClg) 1.3 (t, 3 H), 4.3 (q, 2 H), 5.5 (m, 2 ), 7.1 (s, 1 H),
7.4 (m, 5 H); IR (CC14) 3030 (w), 2980 (m), 1745 (s), 1140 (vs) cm'1.
R-V Hydride
h2^VN
JV-Benzyl-3-carbethoxy-5-(trimethylsilyl)isoxazolidine A=H 55
1q 2a, R=R'=CH3
(3e): NMR (CDClg) 0.1 (s, 9 ), 1.1 (t, 3 ), 2.0-2.6 (m, 2 H), R=R'=CH3 LIAIHA
, ,
3.3-4.2 (m, 6 H), 7.2 (s, 5 H); IR (neat) 3040 (m), 2960 (s), 2840 la, R=R‘=CH3 LI AIDA 2b, R=R'=CH3 , A= D 55
(m), 1745 (vs), 1185 (vs) cm'1; mass spectrum, m/z (relative 1b, R=Ph , RkCH3 liaiha 2c, R=Ph, R'=CH3 A=H
, 75
intensity)'307 (M+, 15), 234 (22), 91 (100).
p -Nitrophenylhydrazone of 4e: mp 158-162 °C; NMR 1b, R=Ph ,R=CH3 LIAIDa 2d, R=Ph, R'=CH3 ,A=D 75
(Me2SO-d6) 1.23 (t, =7 = 7.1, 3 ), 4.15 (q, =7 = 7.1, 2 H), 6.35 (d, 1c ,R=R'=Ph liaiha 2e,R=R‘=Ph, A=H 45
J = 15.6,1 ), 7.15 (A of AB q, J = 9.2, 2 H), 7.25 (dd, <7 = 15.6,
9.7, 1 H), 7.84 (d, =7 = 9.7, 1 ), 8.14 (B of AB q, =7 = 9.2, 2 H);
IR (CC14) 3050 (w), 2940 (m), 1735 (m), 1610 (m), 1340 (vs) cm'1.
(1) Alberola, A.; Gonzalez, A. M.; Laguna, . A.; Pulido, F. J. Syn-
Acknowledgment. We acknowledge the generous fi- thesis 1982, 1067.
nancial support of the Public Health Service (GM (2) Alberola, A.; González, A. M.; Laguna, . A.; Pulido, F. J. Syn-
thesis 1983, 413.
30743-01). We thank Dr. Robert Minard and Mr. Greg (3) Alberola, A.; González, A. M.; Laguna, . A.; Pulido, F. J. Syn-
Hancock for help in obtaining mass spectra and Mr. Alan thesis, in press.
(4) Kano, H.; Makisumi, N. Japan Patent 9228, Oct 30, 1957.
Freyer and Dr. V. Elango for FT-NMR spectra. (5) Takahashi, T.; Fujimura, H.; Asai, A. Yakugaku Zasshi 1962, 82,
474.
(6) Pinzauti, S.; Dal Piaz, V.; Berdondini, I.; Lenzi, L. Boll. Chim.
(11) Elemental analyses were performed by Micro-Tech Laboratories, Farm. 1974, 773(1), 26.
Skokie IL. (7) Fancher, 0.; Llewellyn W. U.S. Patent 4104 375, Feb 24, 1977.
0022-3263/84/1949-3423$01.50/0 © 1984 American Chemical Society
3424 J. Org. Chem. 1984, 49, 3424-3426
Table II. Reduction of 4-Cyanoisoxazoles la-c with Lithium Aluminum Hydride
MS (70 eV),
m/e (M+, rel IR (Nujol) v
product mp, °C mol form0 intensity) (cm-1) NMR (CDClg, 60 Hz) 6, J (Hz)
2a6 84-85 (hexane-ether) 126 (88) 3400, 3250, 1640 1.05 (t, 3 H, J = 7.1, 4-CH2CH3e, 2.05 (s, 3 H,
3-CH3), 2.25 (q, 2 H, J 7.1, 4-CH2CH3), 5.60
=
(br s, 2 H, NH2)
2b 87-88 (hexane-ether) 128 (71) 3400, 3250, 2200, 1.05 (s, 3 H, 4-CD2CH3e, 2.10 (s, 3 H, 3-CH3),
2120, 1640 4.70 (br s, 2 H, NH2)
2c 58-59 (benzene) ^11^12^2^ 188 (18) 3350, 3200, 1650 1.00 (t, 3 H, J 7.6, 4-CH2CH3), 2.30 (q, 2 H,
=
J = 7.6, 4-CH2CH3), 5.20 (br s, 2 , NH2), 7.40
(m, 5 H, 3-C6H5)
2d 60-61 (benzene) 190 (10) 3450, 3200, 2250, 1.00 (s, 3 H, 4-CD2CH3), 5.10 (br s, 2 H, NH2),
2140, 1650 7.50 (m, 5 H, 3-C6H6)
2e 88-89 (hexane-benzene) ^16^14-^2^ 250 (42) 3350, 3200, 1630 3.60 (s, 2 H, 4-CH2C6H6), 7.20 (m, 5 H,
4-CH2C6H5), 7.50 (m, 5 H, 3-C6H5), 7.80
(br s, 2 H, NH2)
“Satisfactory analytical data (C ± 0.19%, ± 0.17%, N ± 0.18%). 13C NMR (CDC13)
b
9.07 (CH3 attached to methylene group), 12.65
(CH3 attached to C-3), 13.46 (CH2), 92.60 (C-4), 159.66 (C-3), 163.95 (C-5).
Scheme I Experimental Section
UN) All reactions were carried out under nitrogen atmosphere.
NEC r "c N=C Melting points are uncorrected. 4-Cyanoisoxazoles were prepared
by established procedures.9 *** NMR spectra were recorded on
r'£wn r'^K a Varían A-60 analytical spectrometer. 13C NMR spectra were
f Tf determined with a Varían FT-80 instrument. Chemical shifts are
@
AID¿, reported in part per million relative to Me4Si as the internal
éID3 aid2 standard by using CDC13 as solvent. Infrared spectra were re-
1
corded for Nujol mulls, using a Pye-Unicam SP-1100 spectro-
photometer. Solvents and reagents were purified by conventional
r'd2c R r'd^ methods. Electron ionization mass spectra were obtained on a
U
/in
n; y
Hewlett-Packard 5946-A.
5-Amino-4-ethyl-3-methylisoxazole (2a). General Proce-
dure. (4-Cyano-3,5-dimethylisoxazole9a (la; 6.1 g, 0.05 mol) in
aid2 ether (100 mL) is added to a suspension of lithium aluminum
hydride (2 g, 0.05 mol) in 50 mL of ether. The mixture is stirred
at 0 °C for 6 h and then hydrolyzed with a saturated solution of
ammonium chloride. The ethereal layer is separated and dried
with magnesium sulfate. Evaporation of the solvent leaves a solid,
the scope of this process. We report here an apparently which is chromatographed on silica gel with dichloromethane; yield
general method for the regiospecific synthesis of 5- 3.46 g (55%) of 2a; mp 84-85 °C (hexane-ether). Anal. Caled
aminoisoxazoles8 by reduction of 4-cyanoisoxazoles with for C6H10N2O: C, 57.12; H, 7.99; N, 22.20. Found: C, 56.99; H,
lithium aluminum hydride. Furthermore, the mechanism 7.94; N, 22.12.
of the reaction has been elucidated by incorporation of Physical constants and spectral and analytical data for com-
deuterium in the resulting 5-aminoisoxazoles when the pounds 2a-e are summarized in Table II.
reduction is carried out with lithium aluminum deuteride. Registry No. la, 31301-46-9; lb, 24400-67-7; lc, 54535-49-8;
2a, 91084-67-2; 2b, 91084-68-3; 2c, 91084-69-4; 2d, 91084-70-7; 2e,
Result and Discussion 91084-71-8; LiAlH4, 16853-85-3; LiAlD4, 14128-54-2.
3,5-Disubstituted-4-cyanoisoxazoles la-c react with
LiAlH4 or L1AID4 to give 3,4-disubstituted-5-amino- (9) (a) Kochetkov, N. K.; Sokolov, S. D.; Luboshnikova, V. M. Zh.
isoxazoles 2a-e in 45-75% yields (Table I). Incorporation Obshch. Khim. 1962, 32, 1778. (b) Renzi, G.; Dal Piaz, V.; Pinzauti, S.
Gazz. Chim. Ital. 1969, 98, 753. (c) Quilico, A.; Fusco, R. Rend. R, 1st.
of deuterium in the methylene group attached at C-4 of Lomb. Sci. Lett. 1936, 69, 439.
2b ,d clearly shows that the methylene carbon comes from
the original C-5 carbon atom of la,b.
From the deuteration experiments the mechanism of the
reaction appears to occur by initial attack of hydride at
C-5 and formation of the intermediate 3 (Scheme I) which NMR Studies of Geometric Isomers of
is common for all the reductions of 4-functionalized 3,5- S-Dehydro-jS-ionone1
disubstituted isoxazoles with complex metal hydride.2 The
second hydride attack at C-5 may occur with preliminary Agnes T. Nakayama, T. T. Bopp, and R. S. H. Liu*
Lewis acid catalyzed ring cleavage and formation of an
,/3-unsaturated nitrile intermediate 4 followed by intra- Department of Chemistry, 2545 The Mall, University of
molecular addition of the nitrile salt intermediate 5 which Hawaii, Honolulu, Hawaii 96822
cyclizes to the respective 5-aminoisoxazole.
Received February 8, 1984
Recently a considerable amount of effort has been di-
(8) For references of known methods for synthesis of 5-amino-
rected toward studies of structural properties of retinal and
isoxazoles, see: (a) Yamada, S.; Kowaki, C. J. Pharm. Soc. Jpn. 1951, 71,
1356. (b) Lopez, L.; Barrans, J. C. R. Hebd. Seances Akad. See., Ser. C.
1966,263(7), 557. (c) Harsanyi, K.; Takacs, K.; Horvath, K. Chem. Ber. 1
Taken from the Senior Honors Thesis of A.T.N., University of
1974, 207(8), 2563. (d) Colau, R; Viel, C. Bull. Soc. Chim. Fr. 1980,163. Hawaii.
0022-3263/84/1949-3424101.50/0 © 1984 American Chemical Society
