A convenient one-pot preparative method for 4,5-diarylisoxazoles involving amine exchange reactions

Article abstract of DOI:10.1021/jo960024h

4,5-Diarylisoxazoles 1 are efficiently prepared by submitting enaminones 2, readily obtained from deoxybenzoins 3, to oximation conditions. This conversion implies an uncommon amine group exchange reaction. Preparation of 4-isoxazolines 5 and ring-opening transformations to β-keto nitriles 4 and 1,3-amino alcohol derivatives 7 are also described.

Full text of DOI:10.1021/jo960024h

J . Org. Chem. 1996, 61, 5435-5439
5435
A Con ven ien t On e-P ot P r ep a r a tive Meth od for
4,5-Dia r ylisoxa zoles In volvin g Am in e Exch a n ge Rea ction s
Esther Dom´ınguez,* Est´ıbaliz Ibeas, Eduardo Mart´ınez de Marigorta, J on Kepa Palacios, and
Raul SanMart´ın
Kimika Organikoa Saila, Euskal Herriko Unibertsitatea, Posta kutxatila 644, 48080 Bilbo, Spain
Received J anuary 2, 1996X
4,5-Diarylisoxazoles 1 are efficiently prepared by submitting enaminones 2, readily obtained from
deoxybenzoins 3, to oximation conditions. This conversion implies an uncommon amine group
exchange reaction. Preparation of 4-isoxazolines 5 and ring-opening transformations to â-keto
nitriles 4 and 1,3-amino alcohol derivatives 7 are also described.
Sch em e 1
In the context of our ongoing interest in the synthetic
potential of enamino ketones 2,1 we set out to study the
synthesis and reactivity of 4,5-diarylisoxazoles 12 using
compounds 2 as key intermediates (Scheme 1).
Enamino ketones,3 â-diketones,4 and â-chlorovinyl
ketones5 have been used inter alia as starting materials
for the preparation of isoxazoles.6 In every case, the
cyclization reaction can be typified as a C-C-C + N-O
ring closure process. However, only the use of enamino
ketone provides a single isomer,7 which is the result of
an unusual amine exchange reaction.1b,8 Nevertheless,
in all cases the cyclization reaction may proceed by two
possible mechanisms,9 which differ in their sequential
nucleophilic attack/amine exchange reactions (Scheme 2).
As such, the identification of the reaction products
provides unequivocal proof4a,9 of the mechanism involved
in the transformation.
Sch em e 2
The isoxazole ring has wide synthetic applications.10
Particularly, a 4,5-diaryl substituted heterocycle ad-
equately functionalized can be used as a substrate for
Ullmann or Suzuki diaryl coupling reactions,11-13 leading
to tetracyclic planar systems of great interest. Therefore,
and taking into account the few examples of this type of
heterocycle in the literature,14 it appeared worthwhile to
find a simple high-yielding method for the synthesis of
4,5-diaryl-substituted isoxazoles.
Resu lts a n d Discu ssion
* To whom correspondence should be addressed. Phone: +34-4-
4647700 (ext 2622). Fax: +34-4-4648500.
Enamino ketones 2a -g, readily obtained from the
corresponding deoxybenzoins 3,1 were submitted to reac-
tion with hydroxylamine hydrochloride under standard
oximation conditions,15 yielding 4,5-diarylisoxazoles 1a -g
in a “one-pot” reaction, as shown in Table 1 and Scheme
3.
X Abstract published in Advance ACS Abstracts, J uly 15, 1996.
(1) (a) Dom´ınguez, E.; Mart´ınez de Marigorta, E.; San Mart´ın, R.
Tetrahedron 1994, 50, 2255-2264. (b) Dom´ınguez, E.; Mart´ınez de
Marigorta, E.; San Mart´ın, R.; Olivera, R. Synlett 1995, 955-956.
(2) For
a review see: Lang, S. A.; Lin, Y. in Comprehensive
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon
Press: Exeter, 1984; Vol. 6, pp 1-130.
(3) (a) Lin, Y.; Lang, S. A J . Org. Chem. 1980, 45, 4857-4860. (b)
An example using enamino aldehydes: De, D.; Mague, J . T.; Byers, L.
D.; Krogstad, D. J . Tetrahedron Lett. 1995, 36, 205-208.
(4) (a) Beam, C. F.; Dyer, M. C. D.; Schwarz, R. A.; Hauser, C. R. J .
Org. Chem. 1970, 35, 1806-1810. (b) Newkome, G. R.; Paudler, W.
W. Contemporary Heterocyclic Chemistry. Synthesis, Reactions and
Applications; Wiley-Interscience: New York, 1982; pp 40-41.
(5) Kochetkov, N. K.; Sokolov, S. D. In Advances in Heterocyclic
Chemistry; Katritzky, A. R., Ed.; Academic Press: New York, 1963;
vol. 2, pp 365-422.
The results allowed us to propose a mechanism for the
formation of the target isoxazoles in which the first step
is an amine exchange reaction (Scheme 4). Subsequent
nucleophilic attack of the so-obtained hydroxylamine
derivative to the carbonyl group, followed by elimination,
yields the target heterocycle.
(6) Wakefield, B. J .; Wright, D. J . in Advances in Heterocyclic
Chemistry; Katritzky, A. R., Ed.; Academic Press: New York, 1979;
Vol. 25, pp 147-165.
(12) Other examples of the Ullmann reaction: (a) Lindsten, G.;
Wennerstrom, O.; Isaksson, R. J . Org. Chem. 1987, 52, 547-554. (b)
Matsumoto, H.; Inaba, S.; Rieke, R. D. J . Org. Chem. 1983, 48, 840-
843. (c) Tsou, T. T.; Kochi, J . K. J . Am. Chem. Soc. 1979, 101, 7547-
7560. (d) Takagi, K.; Hayama, M.; Inokawa, S. Chem. Lett. 1979, 917-
918. (e) Bamfield, P.; Quan, P. M. Synthesis 1978, 537-538.
(13) A very recent diaryl synthesis through Suzuki methodology:
(a) Anderson J . C.; Namli, H. Synlett 1995, 765-766. Other papers on
Suzuki reaction: (b) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett
1992, 207-210. (c) Suzuki, A. Pure Appl. Chem. 1994, 213-222.
(14) (a) Raju, G. V.; Rao, K. S. Curr. Sci. 1987, 56, 1280-1281;
Chem. Abstr. 1988, 109; 128873y. (b) Rao, V. K.; Ghary, T. J .; Murthy,
A. K. Proc. Indian Acad. Sci., Chem. Sci. 1992, 104, 569-576; Chem.
Abstr. 1993, 118, 6902x.
(7) Quilico, A. Adv. Heterocycl. Chem. 1962, 17, 1.
(8) (a) Martin, J . C.; Barton, K. R.; Gott, P. G.; Meen, R. M. J . Org.
Chem. 1966, 31, 943-946. (b) Cecchetti, V.; Fravolini, A.; Schiaffella,
F. Synth. Commun. 1991, 21, 2301-2308.
(9) (a) Abu-Shanab, F. A.; Redhouse, A. D.; Thompson, J . R.;
Wakefield, B. J . Synthesis 1995, 557-560. (b) Lin, Y.; Lang, S. A. J .
Heterocycl. Chem. 1977, 14, 345-347.
(10) (a) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Simoni,
D. Synthesis 1987, 857-869. (b) De Bernardo, S.; Weigele, M. J . Org.
Chem. 1977, 42, 109-112. (c) Mitkidou, S.; Stephanidou-Stephanatou,
J . Tetrahedron Lett. 1991, 32, 4603-4604.
(11) (a) A review on the Ullmann reaction: Fanta, P. E. Synthesis
1974, 9-21.
(15) Goda, H.; Sato, M.; Ihara, H.; Hirayama, C. Synthesis 1992,
849-851.
S0022-3263(96)00024-2 CCC: $12.00 © 1996 American Chemical Society

5436 J . Org. Chem., Vol. 61, No. 16, 1996
Dom´ınguez et al.
Ta ble 1. 4,5-Dia r ylisoxa zoles 1 P r ep a r ed
Sch em e 5
yielda
(%)
mpb
(°C)
isoxazoles
Ar1
Ar2
1a
1b
1c
1d
1e
1f
Ph
Ph
90
99
91
96
97
95
88
68-7014
126-128
62-63
52-54
69-71
82-84
oil
3,4-(MeO)2Ph
3,4-(MeO)2Ph
2,3,4-(MeO)3Ph 3,4-(MeO)2Ph
2,3,4-(MeO)3Ph Ph
3,4-(MeO)2Ph
2,3,4-(MeO)3Ph 3,4,5-(MeO)3Ph
3,4-(MeO)2Ph
Ph
In the light of these results, we propose that the
observed ring-opening reaction not only represents a
practical synthesis of the mentioned ketonitriles, but also
a valuable method for checking the position of the
substituents in the parent heterocycle,3,9a thus establish-
ing unambiguously the mechanism previously proposed
for the construction of isoxazoles 1. In fact, only the 4,5-
substituted isoxazole, and not the 3,4-disubstituted isox-
azole, would be able to react with base to directly produce
a cyanoketone.
3,4,5-(MeO)3Ph
1g
Yield of pure crystallized compound. b Crystallized from metha-
a
nol.
Sch em e 3
Similar to isoxazoles,18 isoxazolines also have phar-
macological,19 industrial,20 and synthetic applications.21
Among these compounds, 4-isoxazolines 52,22 are quite
rare, and as far as we know, no general method for their
preparation has been reported to date. In order to
perform the selective reduction of isoxazoles 1 to 4-isox-
azolines 5, we first carried out N-methylation17a,23 reac-
tions with trimethyloxonium tetrafluoroborate (Meerwein
salt).24 The so-obtained N-methylisoxazolinium salts 6
were then submitted to reduction with both LiAlH4 and
NaBH4,22 affording quite different results. In fact, while
low yields of 4-isoxazolines 5 were obtained with the
former, the use of NaBH4 considerably improved the
outcome (Table 3, Scheme 6).
Sch em e 4
Ta ble 2. â-Keton itr iles 4 P r ep a r ed
On the other hand, although 2-isoxazolines are known
to be good precursors22,25,26 of 1,3-amino alcohols, versatile
building blocks for natural product synthesis27 as well
as useful chiral inductors,28 no examples of reductive
cleavage of 4-isoxazolines of type 5 to 1,2-diaryl-substi-
tuted 1,3-amino alcohols 7 are known. Toward this goal,
we attempted the tandem reduction of the stilbenic C-C
double bond/cleavage of the N-O bond of isoxazolines 5,
yielda
(%)
mpb
(°C)
â-ketonitriles
Ar1
Ar2
4a
4b
4c
4d
Ph
Ph
70
91
81
88
81-82
3,4-(MeO)2Ph
3,4-(MeO)2Ph
3,4-(MeO)2Ph
Ph
103-105
113-114
114-115
2,3,4-(MeO)3Ph 3,4-(MeO)2Ph
a
b
Yield of pure crystallized compound. Crystallized from hex-
ane-diethyl ether (1:1).
(19) (a) Neil, G. L; Berger, A. L.; McPartland, R. P.; Grindey, G. B.;
Bloch, A. Cancer Res. 1979, 39, 852-856. (b) Martin, D. G.; Duchamp,
D. J . Tetrahedron Lett. 1973, 2549-2552. (c) Tso, J . Y.; Bower, S. G.;
Zalkin, H. J . Biol. Chem. 1980, 255, 6734-6738.
Routinely, basic treatment of C-3-unsubstituted isox-
azoles induces ring opening to give â-keto nitriles,6,16
useful difunctionalized compounds.17 In our case, treat-
ment of heterocycles 1 with EtONa/EtOH17b under vari-
ous reaction conditions provided the expected â-keto
nitriles 4 in 30-36% yield. Low yields (20-28%) also
resulted as well by using LDA as a base, although it has
been reported that this reagent has been successfully
applied to 5-substituted isoxazoles.16b Furthermore,
though LiAlH4 has been reported to selectively reduce
isoxazoles,18c in our hands â-keto nitriles 4 were obtained
via a ring-opening process, only with low yields (19-
25%). Finally, â-keto nitriles 4 were prepared in high
yield using NaH (Table 2, Scheme 5).
(20) (a) Tomita, K.; Mizugai, M. J pn. Kokai 1979, 7952074; Chem.
Abstr. 1980, 92, 41921. (b) Hong, S. J . Kwajak. Konghak. 1973, 11,
404; Chem. Abstr. 1974, 81; 7293.
(21) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410-416.
(22) (a) Alberola, A.; Gonza´lez, A. M.; Laguna, M. A.; Pulido, F. J .
Synthesis 1982, 1067-1068; (b) 1983, 413-414; (c) 1984, 510-512.
(d) J eon, H. B.; Kim, K. Tetrahedron Lett. 1993, 34, 1939-1940.
(23) (a) Woodman, D. J . J . Org. Chem. 1968, 33, 2397-2399. (b)
Woodward, R. B; Woodman, D. J . J . Org. Chem. 1966, 31, 2039-2040.
(c) Woodward, R. B; Olofson, R. A. Tetrahedron Suppl. 1966, 7, 415-
440.
(24) (a) Becker, D. A.; Anderson, F. E., III; McKibben, B. P.; Merola,
J . S.; Glass, T. E. Synlett 1993, 866-868. (b) LeBel, N. A.; Balasubra-
manian, N. Tetrahedron Lett. 1985, 26, 4331-4334. (c) Kevill, D. N.;
Lin, G. N. L. Tetrahedron Lett. 1978, 949-952. (d) Borch, R. F. J . Org.
Chem. 1969, 34, 627-629. (e) House, H. O.; Richey, F. A. J . Org. Chem.
1969, 1430-1439.
(25) Yamaguchi, S.; Mosher, H. S. J . Org. Chem. 1973, 38, 1870-
1877.
(26) (a) J a¨ger, V.; Schwab, W.; Buss, V. Angew. Chem., Int. Ed. Engl.
1981, 20, 601-603. (b) Burri, K. F.; Cardone, R. A.; Chen, W. Y.; Rosen,
P. J . Am. Chem. Soc. 1978, 100, 7069-7071.
(27) (a) J a¨ger, V.; Grund, H.; Buss, V.; Schwab, W.; Mu¨ller, I.;
Schohe, R.; Franz, R.; Ehrler, R. Bull. Soc. Chim. Belg. 1983, 92, 1039-
1053. (b) Mu¨ller, I.; J a¨ger. V. Tetrahedron Lett. 1982, 23, 4777-4780.
(c) Kozikowski, A. P.; Ghosh, A. K. J . Am. Chem. Soc. 1982, 104, 5788-
5789. (d) Caramella, P.; Cellerno, G.; Corsico-Coda, A. J . Org. Chem.
1976, 41, 3349-3356.
(28) (a) Didier, E.; Loubinoux, B.; Ramos Tombo, G. M.; Rihs, G.
Tetrahedron 1991, 47, 4941-4958. (b) Meyers, A. I.; Brich, Z.; Erickson,
G. W.; Traynor, S. G. J Chem. Soc., Chem. Commun. 1979, 556-567.
(16) (a) Ho, T.-L. Tandem Organic Reactions; Wiley-Interscience:
New York, 1992; pp 288. (b) Alberola, A.; Gonza´lez, A. M.; Laguna, M.
A.; Pulido, F. J . Tetrahedron Lett. 1986, 27, 2027-2030.
(17) (a) Alberola, A.; Antol´ın, L. F.; Cuadrado, P.; Gonza´lez, A. M.;
Laguna, M. A.; Pulido, F. J . Synthesis 1988, 203-207. (b) Ciller, J . A.;
Mart´ın, N.; Seoane, C.; Soto, J . L. J . Chem. Soc., Perkin Trans. 1 1985,
2581-2584.
(18) (a) Welter, T. R.; Delany, J . J . Eur. Pat. Appl. EP 476.760, 1992.
(b) Polo, C.; Ramos, V.; Torroba, T.; Antequera, T. An. Quim. 1990,
84C, 329-332. (c) Tatee, T.; Kurashige, S.; Shiozawa, A.; Narita, K.;
Takei, M.; Ito, S.; Miyazaki, H.; Yamanaka, H.; Mizugaki, M.; Saka-
modo, T.; Fukada, H. Chem. Pharm. Bull. 1986, 34, 1634-1642 and
1643-1655.

One-Pot Preparative Method for 4,5-Diarylisoxazoles
J . Org. Chem., Vol. 61, No. 16, 1996 5437
Ta ble 3. Isoxa zolin iu m Sa lts 6 a n d 4-Isoxa zolin es 5 P r ep a r ed
6
5
Ar1
Ar2
yielda (%)
mpb (°C)
yielda (%)
mp (°C)
a
b
c
d
Ph
Ph
85
94
96
99
139-141
161-163
158-160
152-153
84
64
90
93
oil
3,4-(MeO)2Ph
3,4-(MeO)2Ph
2,3,4-(MeO)3Ph
3,4-(MeO)2Ph
Ph
3,4-(MeO)2Ph
109-111c
oil
oil
a
b
Yield of pure compound. Crystallized from ethyl acetate. c Crystallized from methanol.
using UV light (254 nm) and Dragendorff’s reagent32 as
developing agents. Flash column chromatography33 was per-
formed on Merck Kieselgel 60 (230-400 mesh ASTM); air-
pressure chromatography was carried out on Kieselgel 60 (70-
230 mesh ASTM) or on neutral alumina 90 (activity I, 70-
230 mesh ASTM). Evaporation of solvents under reduced
pressure was performed in a rotatory evaporator. Melting
points are uncorrected. Infrared spectra were recorded as KBr
plates, as a neat liquid, or in CHCl3, and peaks are reported
in cm-1. NMR spectra were recorded at 250 MHz for 1H and
62.83 MHz for 13C. Chemical shifts (δ) were measured in ppm
relative to tetramethylsilane (δ 0.00) or chloroform (δ 7.26 for
1H or 77.00 for 13C) as internal standards; dimethyl sulfoxide-
Sch em e 6
Ta ble 4. 1,3-Am in o Alcoh ols 7 P r ep a r ed
1,3-amino
alcohols
yielda
(%)
Ar1
Ar2
mp (°C)
oil
117-119b
7a
7b
Ph
Ph
47
55
3,4-(MeO)2Ph 3,4-(MeO)2Ph
1
d6 (δ 2.49 for H or 39.5 for 13C) has been used when indicated.
a
b
Yield of pure compound. Crystallized from methanol.
Multiplicities are indicated by s (singlet), b s (broad singlet),
d (doublet), t (triplet), q (quartet), m (multiplet), or dd (doublet
Sch em e 7
of doublets). Coupling constants, J , are reported in hertz. 13
C
DEPT experiments were used to assist with the assignment
of the signals. Data for mass spectra (EI) are reported in the
form m/z (intensity relative to base ) 100).
Enamino ketones 2e and 2g were prepared in accordance
with our previous reports,1 and the following results were
obtained.
but neither BBN29 nor DIBAL-H,26b,30 under a wide range
of conditions, induced reaction.
Nevertheless, while Pd-C catalytic hydrogenation only
produced 1,2-diarylpropanones 8, the use of the Adams
3-(N ,N -Dim e t h yla m in o)-2-p h e n yl-1-(2,3,4-t r im e t h -
oxyp h en yl)p r op en on e (2e) (77%): pale yellow powder; mp
137-138 °C (diethyl ether); Rf (hexane-EtOAc, 2:8) 0.4; νmax
1640 (CdO), δH 2.60 (6H, s, NMe2), 3.78 (6H, s, OMe), 3.83
(3H, s, OMe), 6.64 (1H, d, J ) 8.5, H-5′arom), 6.87 (1H, d, J )
8.5, H-6′arom), 7.11 (1H, s, dCHN), 7.1-7.2 (5H, m, Harom); δC
43.1 (NMe), 55.7, 60.6, and 61.6 (OMe), 106.6, 113.1 (CaromH),
123.1 (dCCO), 126.0, 127.2, and 131.8 (CaromH), 129.5, 136.4
(CaromC), 141.5, 150.5, and 153.5 (CaromO), 153.9 (dCHN), 192.6
(CO). Anal. Calcd for C20H23O4N: C, 70.36; H, 6.79; N, 4.10.
Found: C, 70.45; H, 6.85; N, 4.20.
3-(N,N-Dim eth yla m in o)-1-(2,3,4-tr im eth oxyp h en yl)-2-
(3,4,5-tr im eth oxyp h en yl)p r op en on e (2g) (88%): pale yel-
low powder; mp 139-141 °C (diethyl ether); Rf (hexane-
EtOAc, 2:8) 0.1; νmax 1635 (CdO); δH 2.67 (6H, s, NMe2), 3.77
(9H, s, OMe), 3.81 (6H, s, OMe), 3.85 (3H, s, OMe), 6.39 (2H,
s, H-2′′arom and H-6′′arom), 6.58 (1H, d, J ) 8.5, H-5′arom), 6.87
(1H, d, J ) 8.5, H-6′arom), 7.07 (1H, s, dCHN); δC 43.3 (NMe),
55.9, 60.6, 60.7, and 61.8 (OMe), 106.7, 109.1 (CaromH), 113.3
(dCCO), 123.1 (CaromH), 129.5, 131.9 (CaromC), 136.4, 141.8,
150.7, 152.2, and 153.7 (CaromO), 154.1 (dCHN), 192.9 (CO).
Anal. Calcd for C23H29O7N: C, 64.02; H, 6.77; N, 3.25.
Found: C, 63.96; H, 6.87; N, 3.58.
4,5-Dip h en ylisoxa zole (1a ). Typ ica l P r oced u r e. NH2-
OH‚HCl (210 mg, 3.15 mmol) and Na2CO3 (170 mg, 1.6 mmol)
were added to a stirred solution of enamino ketone 2a 1 (720
mg, 2.86 mmol) in methanol (30 mL) and water (15 mL) at
room temperature. The reaction mixture was acidified with
glacial acetic acid up to pH 4-5 and refluxed for 2 h. After
cooling, the reaction mixture was basified to pH 8 with
ammonium hydroxide solution and extracted with dichlo-
romethane (4 × 30 mL). The organic extracts were dried over
anhydrous sodium sulfate and evaporated in vacuo to afford
a yellow oil, which was crystallized in methanol, providing
isoxazole 1a (570 mg, 90%) as a white powder: mp 68-70 °C
(methanol); Rf (CH2Cl2-EtOAc, 9:1) 0.8; νmax 1630 (CdN); δH
7.3-7.4 (8H, m, Harom), 7.6-7.7 (2H, m, Harom), 8.34 (1H, s,
catalyst furnished the expected 1,3-amino alcohols 7
though in moderate yields (47% and 55%) (Table 4,
Scheme 7).
To summarize, we have accomplished an efficient
conversion of deoxybenzoins to 4,5-diarylisoxazoles and
we have studied their behaviour under ring opening
reaction conditions in basic medium, thus isolating the
corresponding â-ketonitriles, which represents a proof of
the structure of the original heterocycles. We have also
prepared a series of 4,5-diaryl-4-isoxazolines by submit-
ting the parent heterocycles to tandem N-quaternization/
reduction conditions. Apart from that, the so-obtained
isoxazolines were regioselectively converted to the cor-
responding 1,2-diaryl-substituted 1,3-aminoalcohols.
Exp er im en ta l Section
Gen er a l P r oced u r es. Solvents were either purified ac-
cording to methods described by Perrin et al.31 or used as
received from the manufacturers, depending on their purity.
Thin layer chromatography (TLC) was performed on plates
coated to a thickness of 0.2 mm with Merck Kieselgel 60 F254
(29) For the use of BBN see: Brown, H. C.; Kulkarni, S. U. J . Org.
Chem. 1977, 42, 4169-4170.
(30) For some uses of DIBAL-H see: (a) Carren˜o, M. C.; Garc´ıa-
Ruano, J . L.; Garrido, M.; Ruiz, H. P.; Solladie´, G. Tetrahedron Lett.
1990, 31, 6653-6656. (b) Alexakis, A.; Duffault, J . M. Tetrahedron Lett.
1988, 29, 6243-6246.
(31) Perrin, D. D.; Armarego, W. L. Purification of Laboratory
Chemicals; Pergamon Press: Oxford, 1988.
(32) Krebs, K. G.; Heusser, D.; Winner, H. Thin Layer Chromatog-
raphy, 2nd ed.; Stahl, E., Ed.; Springer-Verlag: Berlin, Heidelberg,
New York, 1969; pp 873-874.
(33) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.

5438 J . Org. Chem., Vol. 61, No. 16, 1996
Dom´ınguez et al.
H-3); δC 116.1 (C-4), 127.2 (CaromH), 127.5 (CaromC), 127.9,
128.5, 128.7, and 128.9 (CaromH), 129.9 (CaromC), 151.7 (C-3),
163.9 (C-5); m/z 221 (M+, 23), 193 (22), 165 (60), 143 (11), 116
(15), 105 (55), 77 (32). Anal. Calcd for C15H11ON: C, 81.42;
H, 5.01; N, 6.33. Found: C, 81.39; H, 4.98; N, 6.40.
By use of the same procedure the following isoxazoles were
prepared:
4,5-Bis(3,4-d im eth oxyp h en yl)isoxa zole (1b) (99%): mp
126-128 °C (methanol); Rf (CH2Cl2-EtOAc, 9:1) 0.8; νmax 1630
(CdN); δH 3.76 (3H, s, OMe), 3.79 (3H, s, OMe), 3.89 (3H, s,
OMe), 3.91 (3H, s, OMe), 6.8-7.0 (4H, m, Harom), 7.2-7.3 (2H,
m, Harom), 8.29 (1H, s, H-3); δC 55.8, 55.9 (OMe), 109.9, 110.9,
111.5, and 111.9 (CaromH), 114.9 (C-4), 119.3, 121.3 (CaromH),
122.8 (CaromC), 148.8, 149.1, and 150.3 (CaromO), 151.9 (C-3),
163.5 (C-5); m/z 341 (M+, 34), 298 (10), 165 (100), 137 (8), 77
(3). Anal. Calcd for C19H19O5N: C, 66.85; H, 5.61; N, 4.10.
Found: C, 66.70; H, 5.52; N, 4.01.
5-(3,4-Dim eth oxyp h en yl)-4-p h en ylisoxa zole (1c) (91%):
mp 62-64 °C (methanol); Rf (CH2Cl2-EtOAc, 9:1) 0.7; νmax
1620 (CdN); δH 3.58 (3H, s, OMe), 3.75 (3H, s, OMe), 6.71 (1H,
d, J ) 8.4, H-5′arom), 7.02 (1H, d, J ) 1.9, H-2′arom), 7.12 (1H,
dd, J ) 8.4, 1.9, H-6′arom), 7.2-7.3 (5H, m, Harom), 8.21 (1H, s,
H-3); δC 55.1, 55.3 (OMe), 109.5, 110.7 (CaromH), 114.6 (C-4),
119.7, 119.8, 127.5 and 128.3 (CaromH), 128.4, 129.9 (CaromC),
148.4, 149.9 (CaromO), 151.3 (C-3), 163.4 (C-5); m/z 281 (M+,
100), 238 (10), 195 (4), 166 (8), 165 (55), 116 (5). Anal. Calcd
for C17H15O3N: C, 72.58; H, 5.37; N, 4.98. Found: C, 71.98;
H, 5.33; N, 5.13.
4-(3,4-Dim et h oxyp h en yl)-5-(2,3,4-t r im et h oxyp h en yl)-
isoxa zole (1d ) (96%): mp 98-100 °C (methanol); Rf (CH2-
Cl2-EtOAc, 9:1) 0.6; νmax 1620 (CdN); δH 3.51 (6H, s, 2 ×
OMe), 3.70 (9H, s, OMe), 6.5-6.9 (5H, m, Harom), 8.34 (1H, s,
H-3); δC 55.0, 55.2, 55.5, 60.3, and 60.7 (OMe), 106.8, 110.0,
110.8 (CaromH), 114.2 (C-4), 116.7 (CaromC), 119.2 (CaromH), 122.1
(CaromC), 125.0 (CaromH), 141.8, 147.9, and 148.4 (CaromO), 149.7
(C-3), 151.7, 155.1 (CaromO), 161.4 (C-5); m/z 371 (M+, 32), 238
(10), 340 (5), 195 (100), 152 (7), 77 (3). Anal. Calcd for
C20H21O6N: C, 64.68; H, 5.70; N, 3.77. Found: C, 64.58; H,
5.73; N, 4.02.
4-P h en yl-5-(2,3,4-tr im eth oxyph en yl)isoxazole (1e) (97%):
mp 69-71 °C (methanol); Rf (CH2Cl2-EtOAc, 9:1) 0.8; νmax
1620 (CdN); δH 3.57 (3H, s, OMe), 3.79 (3H, s, OMe), 3.81 (3H,
s, OMe), 6.64 (1H, d, J ) 8.7, H-5′arom), 7.02 (1H, d, J ) 8.7,
H-6′arom), 7.1-7.2 (5H, m, Harom), 8.43 (1H, s, H-3); δC 55.6,
60.4, 60.7 (OMe), 107.0 (CaromH), 114.2 (C-4), 116.9 (CaromC),
125.1, 126.9, 127.1, and 128.3 (CaromH), 129.8 (CaromC), 140.0,
150.0, and 151.8 (CaromO), 155.3 (C-3), 162.3 (C-5); m/z 311 (M+,
4), 208 (42), 196 (45), 105 (100), 77 (33). Anal. Calcd for
C18H17O4N: C, 69.44; H, 5.50; N, 4.50. Found: C, 69.40; H,
5.43; N, 4.84.
5-(3,4-Dim et h oxyp h en yl)-4-(3,4,5-t r im et h oxyp h en yl)-
isoxa zole (1f) (95%): mp 52-54 °C (methanol); Rf (CH2Cl2-
EtOAc, 9:1) 0.8; νmax 1620 (CdN); δH 3.76 (6H, s, 2 × OMe),
3.79 (3H, s, OMe), 3.87 (3H, s, OMe), 3.89 (3H, s, OMe), 6.59
(2H, s, H-2′′arom and H-6′′arom), 6.85 (1H, d, J ) 8.5, H-5′arom),
7.19 (1H, d, J ) 2.0, H-2′arom), 7.26 (1H, dd, J ) 8.5, J 2.0,
H-6′arom), 8.30 (1H, s, H-3); δC 55.6, 55.7, 55.9, 60.8, and 61.2
(OMe), 107.2, 110.5, and 111.2 (CaromH), 114.8 (C-4), 117.1
(CaromC), 119.7 (CaromH), 122.7 (CaromC), 125.5 (CaromH), 142.3,
148.4, and 148.8 (CaromO), 150.2 (C-3), 152.2, 155.5 (CaromO),
161.9 (C-5). Anal. Calcd for C20H21O6N: C, 64.68; H, 5.70;
N, 3.77. Found: C, 64.62; H, 5.72; N, 4.01.
4-(3,4,5-Tr im et h oxyp h en yl)-5-(2,3,4-t r im et h oxyp h en -
yl)isoxa zole (1g) (88%): colorless oil; Rf (CH2Cl2-EtOAc, 9:1)
0.9; νmax 1610 (CdN); δH 3.69 (3H, s, OMe), 3.71 (6H, s, 2 ×
OMe), 3.82 (3H, s, OMe), 3.85 (3H, s, OMe), 3.89 (3H, s, OMe),
6.49 (2H, s, H-2′′arom and H-6′′arom), 6.72 (1H, d, J ) 8.6,
H-5′arom), 7.08 (1H, d, J ) 8.6, H-6′arom), 8.47 (1H, s, H-3); δC
55.9, 56.1, 55.9, 60.8, 60.9, 61.4 (OMe), 104.6, 107.3 (CaromH),
114.7 (C-4),117.1, 121.8 (CaromC), 125.6 (CaromH), 137.5, 142.4
(CaromO), 150 (CaromH), 142.3, 148.4, and 148.8 (CaromO), 150.2
(C-3), 152.3, 153.3, 155.6 (CaromO), 162.6 (C-5). Anal. Calcd
for C21H23O7N: C, 62.83; H, 5.77; N, 3.49. Found: C, 62.90;
H, 5.72; N, 3.41.
a solution of isoxazole 1a (114 mg, 0.52 mmol) in dry THF (25
mL) under argon at room temperature. The resulting slurry
was refluxed for 10 h, cooled, quenched with saturated aqueous
NH4Cl (20 mL), and extracted with dichloromethane (3 × 20
mL). The combined organic layers were dried over anhydrous
sodium sulfate and evaporated to give a yellow oil. Flash
column chromatography (hexane/EtOAc 2:8) afforded a color-
less oil, which was crystallized from hexane-diethyl ether,
providing â-ketonitrile 4a (80 mg, 70%) as a white solid: mp
91-92 °C (hexane-diethyl ether, 1:1) (lit.34 mp 93-94 °C); Rf
(hexane/EtOAc 2:8) 0.8; νmax 2245 (CN), 1695 (CdO); δH 5.61
(3H, s, CHCN), 7.4-7.5 (8H, m, Harom), 7.9-8.0 (2H, m, Harom);
δC 46.6 (CHCN), 116.5 (CN), 128.2, 129.1, 129.2, 129.6, 130.3
(CaromH), 133.6, 134.4 (CaromC), 188.8 (CdO). Anal. Calcd for
C15H11ON: C, 81.43; H, 5.01; N, 6.33. Found: C, 81.20; H,
5.10; N, 6.40.
By use of the same procedure the following compounds were
prepared:
2,3-Bis-(3,4-dim eth oxyph en yl)-3-oxopr opan on itr ile (4b)
(91%): mp 103-105 °C (hexane/diethyl ether, 1:1); Rf (hexane/
EtOAc 2:8) 0.8; νmax 2240 (CN), 1685(CdO); δH 3.84 (3H, s,
OMe), 3.86 (3H, s, OMe), 3.89 (3H, s, OMe), 3.92 (3H, s, OMe),
5.51 (1H, s, CHCN), 6.83 (1H, d, J ) 8.2, H-5′′arom), 6.85 (1H,
d, J ) 8.4, H-5′arom), 6.91 (1H, d, J ) 2.2, H-2′′arom), 6.97 (1H,
dd, J ) 8.2, 2.2, H-6′′arom), 7.49 (1H, d, J ) 2.1, H-2′arom), 7.57
(1H, dd, J ) 8.2,J 2.1, H-6′arom); δC 45.9 (CHCN), 55.9, 56.0,
56.2 (OMe), 110.1, 111.2, 111.6 (CaromH), 116.9 (CN), 120.7
(CaromH), 123.0 (CaromC), 124.1 (CaromH), 126.5 (CaromC), 149.3,
149.6, 149.8, 154.3 (CaromO), 187.5 (CdO). Anal. C19H19O5N:
C, 66.85; H, 5.61; N, 4.10. Found: C, 66.81; H, 5.50; N, 4.19.
3-(3,4-Dim et h oxyp h en yl)-2-p h en yl-3-oxop r op a n on i-
tr ile (4c) (91%): mp 113-114 °C (hexane/diethyl ether, 1:1);
Rf (hexane/EtOAc 2:8) 0.5; νmax 2245 (CN), 1685(CdO); δH 3.77
(3H, s, 2 × OMe), 3.81 (3H, s, OMe), 5.62 (1H, s, CHCN), 6.77
(1H, d, J ) 8.4, H-5′arom), 7.2-7.3 (5H, m, Harom), 7.40 (1H, d,
J ) 1.8, H-2′arom), 7.52 (1H, dd, J ) 8.4, 1.8, H-6′arom); δC 46.0
(CHCN), 55.7, 55.9 (OMe), 110.0, 110.9, (CaromH), 116.9 (CN),
126.6, (CaromC), 127.9, 128.8, 129.3 (CaromH), 130.8 (CaromC),
149.1, 154.2 (CaromO), 187.4 (CdO). Anal. Calcd for
C17H15O3N: C, 72.58; H, 5.37; N, 4.98. Found: C, 72.66; H,
5.30; N, 5.01.
2-(3,4-Dim et h oxyp h en yl)-3-(2,3,4-t r im et h oxyp h en yl)-
3-oxop r op a n on itr ile (4d ) (88%): mp 114-115 °C (hexane/
diethyl ether, 1:1); Rf (hexane/EtOAc 2:8) 0.3; νmax 2245 (CN),
1695 (CdO); δH 3.69 (3H, s, OMe), 3.70 (3H, s, OMe), 3.71 (3H,
s, OMe), 3.74 (3H, s, OMe), 3.86 (3H, s, OMe), 5.74 (1H, s,
CHCN), 6.54 (1H, d, J ) 8.9, H-5′arom), 6.66 (1H, d, J ) 8.1,
H-5"arom), 6.74 (1H, d, J ) 2.0, H-2"arom), 6.77 (1H, dd, J ) 8.1,
2.0, H-6"arom), 7.28 (1H, d, J ) 8.9, H-6′arom); δC 48.5 (CHCN),
55.6, 55.7, 55.9, 60.6, 61,7 (OMe), 107.2, 110.9, 111.1 (CaromH),
117.2 (CN), 120.8 (CaromC), 121.8 (CaromH), 122.9 (CaromC), 126.7
(CaromH), 141.2, 149.1, 153.1, 158.3 (CaromO), 189.5 (CdO). Anal.
Calcd for C20H21O6N: C, 64.68; H, 5.70; N, 3.77. Found: C,
64.40; H, 5.61; N, 3.89.
N-Meth yl-4,5-d ip h en ylisoxa zoliu m Tetr a flu or obor a te
(6a ). Typ ica l P r oced u r e. Isoxazole 1a (500 mg, 2.2 mmol)
was dissolved in freshly distilled dichloromethane and added
dropwise into a stirred suspension of trimethyloxonium tet-
rafluoroborate (500 mg, 3.3 mmol) in dichloromethane under
argon at room temperature. After being stirred overnight, the
reaction mixture was evaporated in vacuo and the resulting
oil was treated with diethyl ether (2 mL) to give a yellow
powder, which was filtered and crystallized in ethyl acetate,
affording 6a (600 mg, 85%) as white needles:35 mp 139-141
°C (ethyl acetate); Rf (CH2Cl2) 0.5; νmax 1645 (CdN+); δH
(DMSO-d6) 4.63 (3H, s, NMe), 7.4-7.7 (10H, m, Harom), 9.76
(1H, s, H-3); δC (DMSO-d6) 45.1 (NMe), 125.3(C4), 128.7, 130.9,
127.7, and 134.7 (CaromH), 154.1 (C-3), 172.8 (C-5). Anal.
Calcd for C16H14ONBF4: C, 59.48; H, 4.37; N, 4.33. Found:
C, 59.40; H, 4.41; N, 4.39.
(34) Kascheres,A.; Marchi, D. J . Org. Chem. 1975, 40, 2985-2987.
(35) Similarly to some other isoxazolium salts of the literature (see
ref 23), 6a turned yellow and decomposed in 1-2 months at room
temperature.
2,3-Dip h en yl-3-oxop r op a n on itr ile 4a . Typ ica l P r oce-
d u r e. NaH (106 mg, 4.4 mmol) was added in one portion to

One-Pot Preparative Method for 4,5-Diarylisoxazoles
J . Org. Chem., Vol. 61, No. 16, 1996 5439
By use of the same procedure the following compounds were
prepared:
and 148.3 (CaromO), 149.3 (C-5). Anal. Calcd for C20H23O5N:
C, 67.21; H, 6.49; N, 3.92. Found: C, 67.29; H, 6.44; N, 3.92.
N-Meth yl-5-(3,4-d im eth oxyp h en yl)-4-p h en yl-4-isoxa zo-
lin e (5c) (90%): colorless oil; Rf (CH2Cl2) 0.4; νmax 1660 (CdC);
δH 2.85 (3H, s, NMe), 3.65 (3H, s, OMe), 3.80 (3H, s, OMe),
3.99 (1H, m, CHaHbN), 4.65 (1H, m, CHaHbN), 6.74 (1H, d, J
) 8.3, H-5′arom), 6.95 (1H, d, J ) 1.9, H-2′arom), 7.05 (1H, dd, J
) 8.3, 1.9, H-6′arom), 7.1-7.2 (5H, m, Harom); δC 47.1 (NMe),
55.3, 55.4 (OMe), 65.5 (C3), 104.4 (C4), 110.5, 110.7 (CaromH),
120.8 (CaromC), 121.4, 125.9, 126.6, and 127.9 (CaromH), 133.5
(CaromC), 146.7, 148.2 (CaromO), 149.4 (C-5). Anal. Calcd for
C18H19O3N: C, 72.71; H, 6.44; N, 4.71. Found: C, 72.79; H,
6.36; N, 4.80.
N-Met h yl-4-(3,4-d im et h oxyp h en yl)-5-(2,3,4-t r im et h -
oxyp h en yl)-4-isoxa zolin e (5d ) (93%): colorless oil; Rf (CH2-
Cl2) 0.3; νmax 1645 (CdC); δH 2.84 (3H, s, NMe), 3.47 (3H, s,
OMe), 3.72 (3H, s, OMe), 3.76 (3H, s, OMe), 3.78 (3H, s, OMe),
3.79 (3H, s, OMe), 3.82 (1H, m, CHaHbN), 4.64 (1H, m,
CHaHbN), 6.50 (1H, d, J ) 8.3, H-5′arom), 6.52 (1H, s, H-2′′arom),
6.61 (1H, d, J ) 5.7, H-6′′arom), 6.65 (1H, d, J ) 5.7, H-5′′arom),
6.93 (1H, d, J ) 8.3, H-6′arom); δC 47.4 (NMe), 54.8, 55.4, 55.7,
60.6, and 61.1 (OMe), 63.8 (C3), 106.5, 107.3, 108.5, and 110.7
(CaromH), 116.5 (C4), 117.7 (CaromC), 125.7 (CaromH), 125.8
(CaromC), 142.4, 145.1, 146.9, 148.1, 152.6 (CaromO), 154.7 (C-
5). Anal. Calcd for C21H25O6N: C, 65.10; H, 6.50; N, 3.61.
Found: C, 65.04; H, 6.58; N, 3.60.
N-Meth yl-4,5-bis(3,4-dim eth oxyph en yl)isoxazoliu m tet-
r a flu or obor a te (6b) (94%): white powder; mp 161-163 °C
(ethyl acetate); Rf (CH2Cl2) 0.5; νmax 1650 (CdN+); δH (DMSO-
d6) 3.71 (3H, s, OMe), 3.77 (3H, s, OMe), 3.87 (3H, s, OMe),
3.91 (3H, s, OMe), 4.60 (3H, s, NMe), 7.10 (1H, d, J ) 8.3,
H-5′arom), 7.12 (1H, s, H-2′′arom), 7.16 (2H, dd, J ) 7.5, 1.5,
H-5′′arom and H-6′′arom), 7.33 (1H, d, J ) 2.1, H-2′arom), 7.43 (1H,
dd, J ) 8.3, J 2.1, H-6′arom), 9.61 (1H, s, H-3); δC 40.9 (NMe),
55.6, 55.9 (OMe), 110.3, 112.2 (CaromH), 115.2 (C-4), 117.3,
117.9 (CaromH), 121.5 (CaromC), 149.0, 149.2, and 150.0 (CaromO),
152.9 (C-3), 165.6 (C-5). Anal. Calcd for C20H22O5NBF4: C,
54.20; H, 5.00; N, 3.16. Found: C, 54.29; H, 5.08; N, 3.20.
N-Met h yl-5-(3,4-d im et h oxyp h en yl)-4-p h en ylisoxa zo-
liu m tetr a flu or obor a te (6c) (96%): white powder; mp 158-
160 °C (ethyl acetate); Rf (CH2Cl2) 0.2; νmax 1650 (CdN+); δH
(DMSO-d6) 3.66 (3H, s, OMe), 3.90 (3H, s, OMe), 4.60 (3H, s,
NMe), 7.12 (1H, d, J ) 8.6, H-5′arom), 7.25 (1H, d, J ) 2.1,
H-2′arom), 7.38 (1H, dd, J ) 8.6, 2.1, H-6′arom), 7.59 (5H, m,
Harom), 7.04 (1H, s, H-2′arom), 7.15 (1H, dd, J ) 8.4, 1.9,
H-6′′arom), 7.21 (1H, d, J ) 1.9, H-2′′arom), 9.60 (1H, s, H-3); δC
(DMSO-d6) 41.5 (NMe), 56.0, 56.3 (OMe), 111.4, 112.8 (CaromH),
116.2 (C-4), 119.3, 123.4 (CaromH), 127.1, 130.3 (CaromC), 150.5
(CaromO), 154.6 (C-3), 186.3 (C-5). Anal. Calcd for C18H18O3-
NBF4: C, 56.43; H, 4.73; N, 3.65. Found: C, 56.39; H, 4.70;
N, 3.70.
3-(N-Meth yla m in o)-1,2-d ip h en ylp r op a n ol (7a ). Typ i-
ca l P r oced u r e. A mixture of 4-isoxazoline 5a (95 mg, 0.4
mmol), prereduced Adams catalyst (from 10 mg of platinum
oxide), and HCl (0.5 mL of a 3 mol L-1 solution in water) in
dry methanol (20 mL) was hydrogenated for 7 h (PH2 ) 2.5
atm). The mixture was filtered, and the filtrate was evapo-
rated to give a brown oil that was dissolved in diethyl ether
and treated with 3 drops of concentrated HCl solution. The
resulting solid hydrochloride was filtered, washed with dichlo-
romethane, and redissolved in a mixture of methanol-water
(9:1). This solution was basified to pH 9 with ammonium
hydroxide solution to produce the free amino alcohol and
extracted with dichloromethane (4 × 15 mL). The combined
organic extracts were dried over anhydrous sodium sulfate and
evaporated in vacuo to afford 1,3-amino alcohol 7a (45 mg,
47%): colorless oil; Rf (CH2Cl2/MeOH 9.5:0.5) 0.7; νmax 3500
(OH), 3300 (NH); δH 2.33 (3H, s, NMe), 2.51 (1H, bs, NH or
OH), 2.83 (2H, d, J ) 6.5, CH2N), 3.29 (1H, q, J ) 6.5,
CHCH2N), 4.93 (1H, d, J ) 6.5, CHOH), 7.1-7.2 (10H, m,
Harom); δC 36.1 (NMe), 51.5 (CHCH2N), 53.0 (CH2N), 77.9
(CHOH), 126.6 126.8, 127.1, 127.8, 128.3, 128.4, and 129.4
(CaromH), 139.7, 141.9 (CaromC). Anal. Calcd for C16H19ON: C,
79.63; H, 7.93; N, 5.80. Found: C, 79.66; H, 7.98; N, 5.72.
By use of the same procedure 3-(N-methylamino)-1,2-bis-
(3,4-dimethoxyphenyl)propanol (7b) was prepared (55%): pale
yellow powder; mp 118-119 °C (dichloromethane); Rf (CH2-
Cl2/MeOH 9.5:0.5) 0.4; νmax 3510 (OH), 3310 (NH); δH 2.33 (3H,
s, NMe), 2.61 (1H, bs, NH or OH), 2.78 (2H, d, J ) 6.7, CH2N),
3.22 (1H, q, J ) 6.7, CHCH2N), 3.74 (3H, s, OMe), 3.78 (3H, s,
OMe), 3.84 (6H, s, OMe), 4.85 (1H, d, J ) 6.7, CHOH), 6.6-
6.8 (6H, m, Harom); δC 36.3 (NMe), 51.4 (CHCH2N), 54.3 (CH2N),
55.6, 55.8 (OMe), 78.1 (CHOH), 109.9, 110.3, 111.1, 111.9,
119.1, and 120.6 (CaromH), 132.2, 134.4 (CaromC), 147.8, 148.2,
148.3, and 148.7 (CaromO). Anal. Calcd for C20H27O5N: C,
66.46; H, 7.53; N, 3.87. Found: C, 66.50; H, 7.55; N, 3.91.
N-Met h yl-4-(3,4-d im et h oxyp h en yl)-5-(2,3,4-t r im et h -
oxyp h en yl)isoxa zoliu m t et r a flu or ob or a t e (6d ) (99%):
white powder; mp 152-153 °C (ethyl acetate); Rf (CH2Cl2) 0.6;
νmax 1670 (CdN+); δH (DMSO-d6) 3.34 (3H, s, OMe), 3.60 (3H,
s, OMe), 3.67 (3H, s, OMe), 3.77 (3H, s, OMe), 3.90 (3H, s,
OMe), 4.45 (3H, s, NMe), 6.92 (1H, dd, J ) 8.4, 1.9, H-6′′arom),
7.00 (1H, d, J ) 1.9, H-2′′arom), 7.05 (1H, d, J ) 8.4, H-5′′arom),
7.06 (1H, d, J ) 8.9, H-5′arom), 7.31 (1H, d, J ) 8.9, H-6′arom),
10.09 (1H, s, H-3); δC (DMSO-d6) 41.2 (NMe), 55.5, 56.3, 60.7,
and 61.3 (OMe), 109.2, 111.0 (CaromH), 118.1 (C-4), 120.5
(CaromH), 126.2, 141.6 (CaromC), 148.9, 149.8, and 151.9 (CaromO),
157.7 (C-3), 164.1 (C-5). Anal. Calcd for C21H24O6NBF4: C,
53.30; H, 5.11; N, 2.96. Found: C, 53.24; H, 5.12; N, 2.99.
N-Meth yl-4,5-diph en yl-4-isoxazolin e (5a). Typical P r o-
ced u r e. A stirred suspension of NaBH4 (110 mg, 2.9 mmol)
in dry ethanol (15 mL) was added via cannula to a stirred
suspension of isoxazolium salt 6a (108 mg, 0.33 mmol) in the
same solvent (5 mL) under argon at room temperature. After
being stirred for 6 h the reaction was quenched by adding
saturated aqueous NH4Cl solution (10 mL) and extracted with
dichloromethane (5 × 20 mL). The aqueous layer was acidified
to pH 8 with diluted hydrochloric acid and extracted again
with dichloromethane (5 × 20 mL). The combined organic
layers were washed with water, dried over anhydrous sodium
sulfate, and evaporated under reduced pressure to give a
brown oil that was purified by flash chromatography using
CH2Cl2 as eluent. Isoxazoline 5a was obtained (66 mg, 84%)
as a colorless oil; Rf (CH2Cl2) 0.5; νmax 1661 (CdC); δH 2.92
(3H, s, NMe), 3.99 (1H, m, CHaHbN), 4.75 (1H, m, CHaHbN),
7.1-7.3 (8H, m, Harom), 7.51 (2H, m, Harom); δC 47.5 (NMe), 65.7
(CH2), 105.8 (C4), 126.4, 126.9, and 128.3 (CaromH), 128.4
(CaromC), 128.4, 129.2 (CaromH), 133.6 (CaromC), 147.3 (C-5).
Anal. Calcd for C16H15ON: C, 80.98; H, 6.37; N, 5.90.
Found: C, 81.06; H, 6.36; N, 5.92.
By use of the same procedure the following compounds were
prepared:
Ack n ow led gm en t. The authors gratefully acknowl-
edge PETRONOR, S.A. (Muskiz, Bizkaia) for the gener-
ous gift of solvents. Financial support of the University
of the Basque Country (Project UPV 170.310-EA188/
94) and the Basque Government (Project PGV 9213 and
fellowship to R.S.M) is gratefully acknowledged.
N -Me t h yl-4,5-b is(3,4-d im e t h oxyp h e n yl)-4-isoxa zo-
lin e (5b) (64%): white powder; mp 109-111 °C (methanol);
Rf (CH2Cl2) 0.3; νmax 1655 (CdC); δH 2.82 (3H, s, NMe), 3.59
(3H, s, OMe), 3.67 (3H, s, OMe), 3.77 (3H, s, OMe), 3.78 (3H,
s, OMe), 3.96 (1H, m, CHaHbN), 4.59 (1H, m, CHaHbN), 6.6-
6.7 (4H, m, Harom), 7.51 (2H, m, Harom); δC 47.2 (NMe), 55.3,
55.5, 55.6 (OMe), 65.5 (C3), 105.8 (C4), 109.9, 110.5, 110.8, 119.1
and 120.9 (CaromH), 121.7, 126.1 (CaromC), 145.7, 147.4, 148.2,
J O960024H