4-Alkoxycarbonyl- and aminocarbonyl-substituted isoxazoles as masked acrylates and acrylamides in the asymmetric synthesis of Δ2- isoxazolines

Article abstract of DOI:10.1021/jo0602569

4-Alkoxycarbonyl and aminocarbonyl-substituted isoxazoles undergo conjugate reduction to give Δ²-isoxazolines on treatment with sodium borohydride and sodium trifluoroacetoxyborohydride, respectively. They are also alkylated at C5 through sonication with secondary and tertiary alkyl iodides in the presence of zinc dust and copper(I) iodide. These reactions are analogous to those observed with acrylates and acrylamides. The behavior is characteristic of the 4-substituted isoxazoles but not the 5-substituted regioisomers. The reductions of 4,5-disubstituted isoxazoles and the C5 alkylations of 4-substituted isoxazoles generally afford trans-4,5-disubstituted isoxazolines. Incorporating chiral auxiliaries into the alkoxycarbonyl group maintains this relative stereoselectivity. It does not provide significant levels of asymmetric induction in the reductions, but the alkylations occur with good levels of stereocontrol at both C4 and C5. Because both enantiomers of the auxiliaries are available, this provides access to either enantiomer of the products, in 93 to ≥98% de. The methodology, therefore, provides a complementary approach to nitrile oxide cycloadditions to alkenes for the asymmetric synthesis of Δ²-isoxazolines.

Full text of DOI:10.1021/jo0602569

4-Alkoxycarbonyl- and Aminocarbonyl-Substituted Isoxazoles as
Masked Acrylates and Acrylamides in the Asymmetric Synthesis of
∆2-Isoxazolines
Connie K. Y. Lee,†,‡ Anthony J. Herlt,† Gregory W. Simpson,§ Anthony C. Willis,† and
Christopher J. Easton*,†
Research School of Chemistry, Australian National UniVersity, Canberra, ACT 0200, Australia
easton@rsc.anu.edu.au
ReceiVed February 7, 2006
4-Alkoxycarbonyl and aminocarbonyl-substituted isoxazoles undergo conjugate reduction to give ∆2-
isoxazolines on treatment with sodium borohydride and sodium trifluoroacetoxyborohydride, respectively.
They are also alkylated at C5 through sonication with secondary and tertiary alkyl iodides in the presence
of zinc dust and copper(I) iodide. These reactions are analogous to those observed with acrylates and
acrylamides. The behavior is characteristic of the 4-substituted isoxazoles but not the 5-substituted
regioisomers. The reductions of 4,5-disubstituted isoxazoles and the C5 alkylations of 4-substituted
isoxazoles generally afford trans-4,5-disubstituted isoxazolines. Incorporating chiral auxiliaries into the
alkoxycarbonyl group maintains this relative stereoselectivity. It does not provide significant levels of
asymmetric induction in the reductions, but the alkylations occur with good levels of stereocontrol at
both C4 and C5. Because both enantiomers of the auxiliaries are available, this provides access to either
enantiomer of the products, in 93 to g98% de. The methodology, therefore, provides a complementary
approach to nitrile oxide cycloadditions to alkenes for the asymmetric synthesis of ∆2-isoxazolines.
SCHEME 1
Introduction
∆2-Isoxazolines are of interest as precursors of 1,3-diols,
â-hydroxy ketones, R,â-unsaturated ketones, γ-amino alcohols,
â-hydroxy nitriles, and related compounds,1 and in this context,
they have been employed in numerous natural product synthe-
ses.2 The conventional method for their synthesis is via
cycloaddition of nitrile oxides and alkenes (Scheme 1). These
reactions are generally highly regioselective, and the configu-
ration of the alkenes is retained in the cycloadducts; however,
developing stereoselective syntheses of isoxazolines continues
to be a challenge.3 The asymmetric induction observed in the
cycloadditions of optically active nitrile oxides with alkenes is
typically poor.4 More promising results have been obtained using
chiral alkenes, such as allylic ethers,5 allylic amines,6 allyl
(2) (a) Kozikowski, A. P.; Chen, Y. Y.; Wang, B. C.; Xu, Z. B.
Tetrahedron 1984, 40, 2345. (b) Martin, S. F.; Colapret, J. A.; Dappen, M.
S.; Dupre, B.; Murphy, C. J. J. Org. Chem. 1989, 54, 2209. (c) Smith, A.
L.; Pitsinos, E. N.; Hwang, C. K.; Mizuno, Y.; Saimoto, H.; Scarlato, G.
R.; Suzuki, T.; Nicolaou, K. C. J. Am. Chem. Soc. 1993, 115, 7612. (d)
Bode, J. W.; Carreira, E. M. J. Org. Chem. 2001, 66, 6410. (e) Kim, D.;
Lee, J.; Shim, P. J.; Lim, J. I.; Jo, H.; Kim, S. J. Org. Chem. 2002, 67,
764.
† Australian National University.
‡ Current address: School of Chemistry, University of Sydney, Sydney, NSW
2006, Australia.
§ CSIRO Molecular & Health Technologies, Clayton, VIC 3169, Australia.
(1) (a) Caramella, P.; Gru¨nanger, P. In 1,3-Dipolar Cycloaddition
Chemistry; Padwa, A., Ed.; Wiley-Interscience: New York, 1984; Vol. 1,
p 291. (b) Easton, C. J.; Hughes, C. M. M.; Savage, G. P.; Simpson, G. W.
AdV. Heterocycl. Chem. 1994, 60, 261.
(3) (a) Tamai, T.; Asano, S.; Totani, K.; Takao, K.-I.; Tadano, K.-I.
Synlett 2003, 1865. (b) Zhang, H.; Chan, W. H.; Lee, A. W. M.; Xia, P.-F.;
Wong, W. Y. Lett. Org. Chem. 2004, 1, 63.
10.1021/jo0602569 CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/23/2006
J. Org. Chem. 2006, 71, 3221-3231
3221

Lee et al.
silanes,7 vinyl sulfoxides,8 vinyl phosphine oxides,9 vinyl
ethers,10 acrylates,11,12 and acrylamides.11,13 With compounds
of these types, the stereoselectivity varies widely, but of
particular note, reactions of acrylamide derivatives of Oppolzer’s
chiral sultam,13 a novel camphor derivative,14 and Kemp’s
diacid15 have afforded isoxazolines with 98% de. Chiral metal
chelates have also been exploited to accomplish highly asym-
metric cycloadditions of nitrile oxides with allylic alcohols16
and acrylamides.17
FIGURE 1. Resonance contributors illustrating the acrylate-type
polarization of a 4-alkoxycarbonyl-substituted isoxazole.
SCHEME 2
Recently, we reported some unusual substituent effects in
reactions of acyl- and alkoxycarbonyl-substituted isoxazoles.18,19
Isoxazoles substituted at the 4-position underwent efficient
electrochemical and yeast-catalyzed ring opening via cleavage
of the N-O bond. By contrast, the regioisomers substituted at
the 5-position did not. The basis of these substituent effects
was investigated through X-ray crystallographic and theoretical
structural analyses.19 These showed that the 4-substituted
isoxazoles are conjugated and polarized like Michael acceptors,
with C5 being more electropositive than C4, in a manner
analogous to the â- and R-carbons of an acrylate, respectively
(Figure 1). The 5-substituted isoxazoles lack this type of
conjugation and polarization. Accordingly, the 4-methoxycar-
bonyl-substituted isoxazole 1a was found to react by conjugate
reduction with sodium borohydride, to form the 4-hydroxy-
(4) (a) Kozikowski, A. P.; Kitagawa, Y.; Springer, J. P. J. Chem. Soc.,
Chem. Commun. 1983, 1460. (b) Kozikowski, A. P.; Ghosh, A. K. J. Org.
Chem. 1984, 49, 2762. (c) Boyd, E. C.; Paton, R. M. Tetrahedron Lett.
1993, 34, 3169.
(5) (a) Kozikowski, A. P.; Ghosh, A. K. J. Am. Chem. Soc. 1982, 104,
5788. (b) Houk, K. N.; Moses, S. R.; Wu, Y. D.; Rondan, N. G.; Ja¨ger, V.;
Schohe, R.; Fronczek, F. R. J. Am. Chem. Soc. 1984, 106, 3880. (c)
Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L. Tetrahedron 1988,
44, 4645.
SCHEME 3
(6) Wade, P. A.; Singh, S. M.; Pillay, M. K. Tetrahedron 1984, 40, 601.
(7) Curran, D. P.; Kim, B. H. Synthesis 1986, 312.
(8) Bravo, P.; Bruche´, L.; Crucianelli, M.; Farina, A.; Meille, S. V.; Merli,
A.; Seresini, P. J. Chem. Res., Synop. 1996, 348.
(9) Brandi, A.; Cannavo`, P.; Pietrusiewicz, K. M.; Zablocka, M.;
Wieczorek, M. J. Org. Chem. 1989, 54, 3073.
(10) Boa, A. N.; Dawkins, D. A.; Hergueta, A. R.; Jenkins, P. R. J. Chem.
Soc., Perkin Trans. 1 1994, 953.
(11) Curran, D. P.; Kim, B. H.; Piyasena, H. P.; Loncharich, R. J.; Houk,
K. N. J. Org. Chem. 1987, 52, 2137.
(12) (a) Kametani, T.; Nagahara, T.; Ihara, M. J. Chem. Soc., Perkin
Trans. 1 1981, 3048. (b) Olsson, T.; Stern, K.; Sundell, S. J. Org. Chem.
1988, 53, 2468. (c) Olsson, T.; Stern, K.; Westman, G.; Sundell, S.
Tetrahedron 1990, 46, 2473. (d) Akiyama, T.; Okada, K.; Ozaki, S.
Tetrahedron Lett. 1992, 33, 5763.
(13) (a) Curran, D. P.; Kim, B. H.; Daugherty, J.; Heffner, T. A.
Tetrahedron Lett. 1988, 29, 3555. (b) Curran, D. P.; Heffner, T. A. J. Org.
Chem. 1990, 55, 4585. (c) Zhang, J.; Curran, D. P. J. Chem. Soc., Perkin
Trans. 1 1991, 2627.
(14) Yang, K.-S.; Lain, J.-C.; Lin, C.-H.; Chen, K. Tetrahedron Lett.
2000, 41, 1453.
methylisoxazoline 2a (Scheme 2), while the 5-substituted
isoxazole 4a gave only the 5-hydroxymethylisoxazole 5a under
analogous conditions (Scheme 3).19 A similar pattern of reactiv-
ity was seen with the isoxazoles 1b and 4b.
We have now examined the scope and limitations of the use
of 4-alkoxycarbonylisoxazoles and the corresponding amides,
as masked acrylates and acrylamides, in alkylations as well as
reductions. Of particular significance, we have found that, by
incorporating chiral auxiliaries into the alkoxycarbonyl group,
alkylation affords isoxazolines with a high degree of stereo-
control at both C4 and C5, providing an efficient and comple-
mentary method to nitrile oxide cycloadditions to alkenes for
the asymmetric synthesis of these compounds.
(15) Curran, D. P.; Jeong, K.-S.; Heffner, T. A.; Rebek, J., Jr. J. Am.
Chem. Soc. 1989, 111, 9238.
(16) (a) Kanemasa, S.; Tsuge, O. Heterocycles 1990, 30, 719. (b) Ukaji,
Y.; Sada, K.; Inomata, K. Chem. Lett. 1993, 1847. (c) Shimizu, M.; Ukaji,
Y.; Inomata, K. Chem. Lett. 1996, 455. (d) Yoshida, Y.; Ukaji, Y.; Fujinami,
S.; Inomata, K. Chem. Lett. 1998, 1023. (e) Yamamoto, H.; Watanabe, S.;
Kadotani, K.; Hasegawa, M.; Noguchi, M.; Kanemasa, S. Tetrahedron Lett.
2000, 41, 3131. (f) Tsuji, M.; Ukaji, Y.; Inomata, K. Chem. Lett. 2002,
1112. (g) Ukaji, Y.; Inomata, K. Synlett 2003, 1075.
(17) Sibi, M. P.; Itoh, K.; Jasperse, C. P. J. Am. Chem. Soc. 2004, 126,
5366.
(18) (a) Easton, C. J.; Hughes, C. M.; Kirby, K. D.; Savage, G. P.;
Simpson, G. W.; Tiekink, E. R. T. J. Chem. Soc., Chem. Commun. 1994,
2035. (b) Easton, C. J.; Heath, G. A.; Hughes, C. M. M.; Lee, C. K. Y.;
Savage, G. P.; Simpson, G. W.; Tiekink, E. R. T.; Vuckovic, G. J.; Webster,
R. D. J. Chem. Soc., Perkin Trans. 1 2001, 1168.
Results and Discussion
A variety of 4- and 5-substituted isoxazoles were required
for this study. The syntheses of the 4-methoxycarbonylisox-
azoles 1a,b and their corresponding 5-substituted regioisomers
4a,b were carried out as reported recently.19 The isoxazoles 1c
and 1d20 were prepared via cycloaddition of mesitonitrile oxide
(7) with methyl tetrolate (6d) and dimethyl acetylenedicarboxy-
(19) Lee, C. K. Y.; Easton, C. J.; Gebara-Coghlan, M.; Radom, L.; Scott,
A. P.; Simpson, G. W.; Willis, A. C. J. Chem. Soc., Perkin Trans. 2 2002,
2031.
(20) (a) Franz, J. E.; Pearl, H. K. J. Org. Chem. 1976, 41, 1296. (b)
Abu-Orabi, S. T. J. Chem. Eng. Data 1986, 31, 505.
3222 J. Org. Chem., Vol. 71, No. 8, 2006

Isoxazoles as Masked Acrylates and Acrylamides
SCHEME 4a
a Reagents and conditions: (i) THF, reflux, 6a gave 8a and 9 (quantitative), 6b gave 8b (quantitative). (ii) DCC/DMAP, Et2O, 18 °C, 6b and (-)-8-
phenylmenthol gave 10b (86%). (iii) Me3Al, toluene, reflux, 6c and (+)-10-dicyclohexylsulfamoyl-L-isoborneol gave 10a (95%), 6d and (+)-10-
dicyclohexylsulfamoyl-L-isoborneol gave 10c (95%). (iv) THF, reflux, 10a gave 11c (19%) and 12c (56%), 10b gave 11e (93%), 10c gave 11f (13%) and
12f (81%). (v) DCC/DMAP, Et2O, 18 °C, 8a and 9 and Whitesell’s auxiliary gave 11a (50%) and 12a (38%), 8a and 9 and (-)-8-phenylmenthol gave 11b
(48%) and 12b (37%), 8b and Whitesell’s auxiliary gave 11d (87%).
late, respectively. The isoxazoles 13a-c and 15 were synthe-
sized through the reaction of mesitonitrile oxide (7) with
propiolamide, tetrolamide, and 3-phenylpropiolamide. The latter
two reactions were completely regioselective, while that of
propiolamide afforded a 1:2 mixture of the 4- and 5-substituted
regioisomers 13a and 15.
4-Alkoxycarbonylisoxazoles esterified with the chiral auxil-
iaries (-)-(1R,2S)-2-phenylcyclohexanol (Whitesell’s auxil-
iary),21 (-)-8-phenylmenthol [(-)-(1R,2S,5R)-5-methyl-2-(1-
methyl-1-phenylethyl)cyclohexanol], and (+)-10-dicyclohexylsul-
famoyl-L-isoborneol [(+)-(1R,2S,4S)-N,N-dicyclohexyl-7,7-
dimethyl-2-hydroxybicyclo[2.2.1]heptane-1-methanesulfon-
amide]22 were also prepared (Scheme 4). The reaction of
mesitonitrile oxide (7) and propiolic acid (6a) gave a 1.3:1
mixture of the acids 8a and 9, which were coupled with
Whitesell’s auxiliary and (-)-8-phenylmenthol, using DCC/
DMAP,23 to produce mixtures of 11a,b and 12a,b that were
separated using chromatography. For the sterically more en-
cumbered isobornyl auxiliary, a trimethylaluminum-catalyzed
transesterification24 of methyl propiolate (6c), followed by the
cycloaddition of the resulting chiral alkyne 10a with mesito-
nitrile oxide (7), gave rise to the chiral acylisoxazoles 11c and
12c, which were separated by chromatography. The 5-methyl-
substituted isoxazole 11d bearing Whitesell’s auxiliary was
synthesized in two steps by the cycloaddition of mesitonitrile
oxide (7) and tetrolic acid (6b), followed by a DCC/DMAP-
mediated esterification of the resulting cycloadduct 8b. The other
5-methyl-substituted isoxazoles 11e,f were formed, as a sepa-
rable mixture, with the regioisomer 12f in the case of 11f by
the reaction of mesitonitrile oxide (7) with the corresponding
chiral dipolarophiles 10b,c. The dipolarophiles 10b and 10c25
(21) Whitesell, J. K.; Chen, H.-H.; Lawrence, R. M. J. Org. Chem. 1985,
50, 4663.
(22) (a) Oppolzer, W.; Chapuis, C.; Bernardinelli, G. Tetrahedron Lett.
1984, 67, 1397. (b) Oppolzer, W.; Dudfield, P. Tetrahedron Lett. 1985,
26, 5037. (c) Oppolzer, W.; Marco-Contelles, J. HelV. Chim. Acta 1986,
69, 1699. (d) Oppolzer, W. Tetrahedron 1987, 43, 1969.
(23) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17,
522.
(24) Oppolzer, W.; Barras, J.-P. HelV. Chim. Acta 1987, 70, 1666.
(25) Fonquerna, S.; Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron
1995, 51, 4239.
J. Org. Chem, Vol. 71, No. 8, 2006 3223

Lee et al.
SCHEME 5
SCHEME 6
SCHEME 7
had been prepared by esterification of tetrolic acid (6b),
mediated with DCC/DMAP, and by transesterification of methyl
tetrolate (6d) with trimethylaluminum, respectively.
In a fashion similar to the reactions of the 4-methoxycarbonyl-
substituted isoxazoles 1a,b,19 treatment of 1c with excess sodium
borohydride in ethanol at reflux afforded the trans isomer of
the isoxazoline 2c26 and the isoxazole 3c26 in yields of 61 and
30%, respectively (Scheme 2). Under identical conditions, the
diester 1d gave only the trans and cis isomers of the isoxazoline
2d in yields of 70 and 20%, respectively. The aminocarbonyl-
isoxazoles 13a-c and 15 were unreactive toward sodium
borohydride. However, with sodium trifluoroacetoxyborohy-
dride,27 which was prepared in situ by the treatment of sodium
borohydride with trifluoroacetic acid, the 4-aminocarbonylisox-
azoles 13a-c were efficiently converted to the corresponding
isoxazolines (()-14a, (()-14b,28 and (()-14c,28 while the
5-aminocarbonylisoxazole 15 remained inert (Scheme 5). Thus,
conjugate reduction is the major reaction pathway for the
4-alkoxycarbonyl- and aminocarbonyl-substituted isoxazoles
1a-d and 13a-c. The isoxazole 1a was also efficiently
converted to the isoxazoline 2a through a reaction with lithium
borohydride in THF at reflux, although it was unreactive toward
either sodium cyanoborohydride, potassium borohydride, sodium
borohydride/15-crown-5, or lithium borohydride/12-crown-4.
The isoxazole 1c also reacted with lithium borohydride to give
the cis and trans isomers of the isoxazoline 2c, in a 1:2 ratio.
Having observed conjugate reduction in the reactions of the
4-alkoxycarbonyl- and aminocarbonyl-substituted isoxazoles
1a-d and 13a-c, we next investigated the possibility of
alkylations of compounds of these types. Treatment of the
4-methoxycarbonylisoxazole 1a with lithium dimethylcopper,
a reagent commonly used for conjugate additions to R,â-
unsaturated carbonyl compounds,29 was not successful. Instead,
mesitonitrile was produced, presumably via anionic cleavage
of the isoxazole ring.30 Likewise, no alkylation of the 4-meth-
oxycarbonylisoxazole 1a was observed on treatment with
nitroalkanes under basic conditions,31 no free radical addition
occurred using either alkyl iodides, tributyltin hydride, and 2,2′-
azobisisobutyronitrile32 or alkylmercuric iodides and sodium
borohydride,33 and no Diels-Alder cycloaddition resulted from
treatment with either cyclopentadiene or Danishefsky’s diene.34
Success was eventually realized with the methodology of
Luche et al.,35 whereby conjugate additions of alkyl halides to
R,â-unsaturated carbonyl compounds are effected via a radical
mechanism, in the presence of zinc dust and cuprous iodide,
with sonication. The C5 alkylations of the 4-alkoxycarbonyl-
and aminocarbonyl-substituted isoxazoles 1a,b and 13a with a
range of alkyl iodides that were performed using this procedure
are summarized in Schemes 6 and 7. Those involving tert-butyl
iodide, 1-iodoadamantane, and isopropyl iodide were highly
stereoselective and afforded good to excellent yields of the trans-
isoxazolines (()-16a-c, (()-16f,g, and (()-17. The relative
configuration of these compounds was confirmed through their
lack of epimerization at C4 on treatment with base (cis isomers
would be expected to convert to their thermodynamically more
stable trans forms)36 and by X-ray crystallographic analysis in
the case of (()-16b. The corresponding cis-isoxazolines were
(31) Kadas, I.; Morvai-Kadas, V.; Toke, L. Acta Chim. Hung. 1983, 113,
303.
(32) (a) Burke, S. D.; Forbare, W. F.; Armistead, D. M. J. Org. Chem.
1982, 47, 3348. (b) Giese, B.; Dupuis, J. Angew. Chem., Int. Ed. Engl.
1983, 22, 622. (c) Adlington, R. M.; Baldwin, J. E.; Basak, A.; Kozyrod,
R. P. J. Chem. Soc., Chem. Commun. 1983, 944. (d) Giese, B.; Gonza´lez-
Go´mez, J. A.; Witzel, T. Angew. Chem., Int. Ed. Engl. 1984, 23, 69. (e)
Giese, B. Angew. Chem., Int. Ed. Engl. 1985, 24, 553. (f) Curran, D. P.
Synthesis 1988, 417. (g) Ohno, M.; Ishizaki, K.; Eguchi, S. J. Org. Chem.
1988, 53, 1285. (h) Beckwith, A. L. J.; Chai, C. L. L. J. Chem. Soc., Chem.
Commun. 1990, 1087.
(33) (a) Giese, B.; Kretzschmar, G. Chem. Ber. 1982, 115, 2012. (b)
Larock, R. C. Organomercury Compounds in Organic Synthesis; Springer-
Verlag: Berlin, 1985. (c) Crich, D.; Davies, J. W.; Negro´n, G.; Quintero,
L. J. Chem. Res., Synop. 1988, 140.
(26) Toma, L.; Quadrelli, P.; Perrini, G.; Grandolfi, R.; Di Valentin, C.;
Corsaro, A.; Caramella, P. Tetradedron 2000, 56, 4299.
(27) (a) Umino, N.; Iwakuma, T.; Itoh, N. Tetrahedron Lett. 1976, 763.
(b) Sundaramoorthi, R.; Marazano, C.; Fourrey, J.-L.; Das, B. C. Tetrahe-
dron Lett. 1984, 25, 3191.
(28) Caramella, P.; Reami, D.; Falzoni, M.; Quadrelli, P. Tetrahedron
1999, 55, 7027.
(29) (a) Alderdice, M.; Sum, F. W.; Weiler, L. Org. Synth. 1984, 62,
14. (b) Oppolzer, W.; Dudfield, P.; Stevenson, T.; Godel, T. HelV. Chim.
Acta 1985, 68, 212. (c) Oppolzer, W.; Moretti, R.; Bernardinelli, G.
Tetrahedron Lett. 1986, 27, 4713.
(30) (a) Botteghi, C.; Guetti, E.; Ceccarelli, G.; Lardicci, L. Gazz. Chim.
Ital. 1972, 102, 945. (b) Logemann, W.; Almirante, L.; Caprio, L. Chem.
Ber. 1954, 87, 1175.
(34) Nesi, R.; Giomi, D.; Papaleo, S.; Corti, M. J. Org. Chem. 1990,
55, 1227.
(35) (a) Petrier, C.; Dupuy, C.; Luche, J. L. Tetrahedron Lett. 1986, 27,
3149. (b) Luche, J. L.; Allavena, C.; Petrier, C.; Dupuy, C. Tetrahedron
Lett. 1988, 29, 5373. (c) Luche, J. L.; Allavena, C. Tetrahedron Lett. 1988,
29, 5369. (d) Dupuy, C.; Petrier, C.; Sarandeses, L. A.; Luche, J. L. Synth.
Commun. 1991, 21, 643.
3224 J. Org. Chem., Vol. 71, No. 8, 2006

Isoxazoles as Masked Acrylates and Acrylamides
not detected, except in the reaction of 1a with cyclohexyl iodide
that afforded a 5:4 mixture of (()-16e and the corresponding
cis isomer. In contrast to the facile reactions of tertiary and
secondary alkyl iodides, treatment of the isoxazole 1a with ethyl
iodide as a representative primary iodide gave only a 32% yield
of the trans-isoxazoline (()-16d, and the starting material was
recovered in a 63% yield, even after extended periods of reaction
and repeated additions of the alkyl iodide, zinc powder, and
cuprous iodide. Under similar conditions, no reaction was
observed between the isoxazole 1a and methyl iodide. This is
consistent with the pattern of reactivity reported by Luche et
al.,35 for the utility of various classes of alkyl halides in
alkylations of this type. The 5-methoxycarbonyl-substituted
isoxazole 4a was inert to a reaction with isopropyl iodide under
the conditions used to alkylate the 4-substituted regioisomer 1a,
confirming that the reactivity of isoxazoles as masked acrylates
and acrylamides is characteristic of those substituted at C4 with
alkoxycarbonyl and aminocarbonyl groups.
The reductions of the isoxazoles 1c,d and 13b,c and the
alkylations of 1a,b and 13a generally showed a strong preference
for the formation of trans-4,5-disubstituted isoxazolines, but the
products are racemic. To determine whether chiral auxiliaries
attached to isoxazoles could be exploited to control the absolute
as well as the relative stereochemistry in 4,5-disubstituted
isoxazolines, reductions of 11d-f and alkylations of 11a-c
were also investigated. The reactions of 11d-f with sodium
borohydride were impractically slow. After extended reaction
times, in each case the trans isomer of the isoxazoline 2c26 and
the corresponding 4-hydroxymethylisoxazole 3c were produced
but in yields of only about 10-15 and 5-10%, respectively.
There was no evidence of formation of the cis isomer of the
isoxazoline 2c. The lack of enantioselectivity in the reactions
to give the isoxazoline 2c was determined by DCC/DMAP-
mediated coupling with (S)-2-phenylpropionic acid and analysis
kylations to give ∆2-isoxazolines and, as such, they may be
regarded as masked acrylates and acrylamides. This behavior
is not observed with the regioisomeric 5-substituted isoxazoles.
The reductions of 4,5-disubstituted isoxazoles generally show
a strong preference for the formation of trans-4,5-disubstituted
isoxazolines, but this stereocontrol was not augmented by the
chiral auxiliaries of 11d-f, which failed to provide significant
levels of asymmetric induction. By contrast, the C5 alkylations
of 4-substituted isoxazoles gave good yields of trans-4,5-
disubstituted isoxazolines and, in the cases of the chiral
isoxazoles 11a-c, with control of the absolute stereochemistry
at both C4 and C5. This methodology, therefore, provides an
alternative and complementary approach to nitrile oxide cy-
cloadditions to alkenes for the asymmetric synthesis of ∆2-
isoxazolines. It is versatile in that the auxiliaries of 11a-c are
each available in either enantiomeric form and the alkylations
of 11a,b and 11c give the opposite stereoselectivity. This method
is likely to be particularly useful for accessing isoxazoles
substituted at C5 with secondary and tertiary alkyl groups, which
are well-suited to incorporation, using the alkylation procedure,
and where the alkenes required for the corresponding cycload-
dition method are not readily available.
1
of the product diastereomeric esters using H NMR spectros-
copy. In each case, this showed a de of approximately 10%,
indicating that the conjugate reductions of 11d-f were not only
inefficient, but also that they occurred with little asymmetric
induction. The alkylations of 11a-c with tert-butyl iodide and
of 11a with isopropyl iodide gave the trans-isoxazolines 18a,b,
19, and 20 in variable yields up to 86-88% and with de values
of 95, 93, 94, and g98%, respectively. The relative and absolute
stereochemistries of 18a and 20 were determined through X-ray
crystallographic analysis. That of 18b and 19 was assigned by
analogy with 18a and 20 on the basis of MM2 calculations and
the examination of models that show the re face of the isoxazoles
11a,b and the si face of 11c to be hindered such that alkylation
from the opposite face is favored. The de values were calculated
Experimental Section
Methyl 5-Methyl-3-(2,4,6-trimethylphenyl)isoxazole-4-car-
boxylate (1c). A mixture of mesitonitrile oxide (7; 0.50 g, 3.1
mmol) and methyl tetrolate (6d; 0.30 g, 3.1 mmol) in THF (25
mL) was heated at reflux for 4 days, then cooled, and concentrated
under reduced pressure. Chromatography of the residue afforded
the isoxazole 1c (0.79 g, 98%) as colorless blocks after recrystal-
lization through vapor diffusion of hexanes into Et2O at room
temperature: mp 76-78 °C; IR 2952, 2923, 2858, 1730, 1719,
1603, 1441, 1409, 1311, 1297, 1250, 1191, 1096, 1035, 994, 980,
1
on the basis of analysis of H NMR spectra of crude samples
of 18a,b, 19, and 20. Minor resonances attributable to the other
trans-4,5-disubstituted isoxazoline diastereomers were observed
with 18a,b and 19, but there was no evidence of this with 20.
However, small amounts of the cis isomer of 20 were sometimes
observed in the alkylations of 11c.
1
851, 806, 770 cm-1; H NMR (300 MHz) δ 2.05 (s, 6H), 2.31 (s,
3H), 2.77 (s, 3H), 3.67 (s, 3H), 6.91 (s, 2H); 13C NMR (75.4 MHz)
δ 13.6, 19.9, 21.2, 51.6, 109.1, 124.2, 128.0, 136.8, 138.6, 161.9,
162.2, 175.4; LRMS (%) m/z 259 (M+, 100), 244 (28), 228 (42),
212 (65), 200 (24), 185 (92), 171 (57), 157 (59), 144 (17), 130
(22), 115 (30), 103 (20), 91 (28), 77 (31). HRMS (m/z): (M+) calcd
for C15H17NO3, 259.1208; found, 259.1213.. Anal. Calcd for C15H17-
NO3: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.40; H, 6.41; N,
5.68. The structure of the isoxazole 1c was confirmed using X-ray
crystallographic analysis (CCDC-261167).
Conclusion
Thus, all of the results discussed above show that isoxazoles
substituted at the 4-position with alkoxycarbonyl and aminocar-
bonyl groups undergo unusual conjugate reductions and al-
Dimethyl 3-(2,4,6-Trimethylphenyl)isoxazole-4,5-dicarboxy-
late (1d). A mixture of mesitonitrile oxide (7; 0.50 g, 3.1 mmol)
(36) Alberola, A.; Gonzalez, A. M.; Laguna, M. A.; Pulido, F. J. Synthesis
1983, 413.
J. Org. Chem, Vol. 71, No. 8, 2006 3225

Lee et al.
and dimethyl acetylenedicarboxylate (0.44 g, 3.1 mmol) in THF
(40 mL) was heated at reflux for 2 days, then cooled, and
concentrated under reduced pressure. Chromatography of the residue
afforded the isoxazole 1d (0.91 g, quantitative) as a colorless solid,
mp 56-57 °C, with physical and spectral data consistent with
reported values.20
tetrolic acid (6b; 0.42 g, 5.0 mmol) in THF (55 mL) was heated at
reflux for 2 days, then cooled, and concentrated under reduced
pressure. The residue was recrystallized from a mixture of hexanes
and Et2O to afford 8b (1.2 g, quantitative) as a colorless solid: mp
205-207 °C; IR 2922, 1688, 1595, 1453, 1313, 1145, 1093, 1035,
1
979, 944, 849, 796, 772, 735 cm-1; H NMR (300 MHz) δ 2.02
(br s, 1H), 2.08 (s, 6H), 2.34 (s, 3H), 2.80 (s, 3H), 6.91 (s, 2H);
13C NMR (75.4 MHz) δ 13.8, 19.9, 21.2, 108.5, 124.8, 128.1, 136.9,
138.8, 161.8, 166.8, 177.5; LRMS (%) m/z 245 (M+, 100), 228
(9), 212 (32), 201 (17), 186 (52), 170 (15), 158 (77), 142 (10), 128
(10), 115 (19), 103 (11), 91 (27), 77 (21), 65 (9). HRMS (m/z):
(M+) calcd for C14H15NO3, 245.1052; found, 245.1051. Anal. Calcd
for C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.31; H,
6.21; N, 5.69.
trans-4-Hydroxymethyl-5-methyl-3-(2,4,6-trimethylphenyl)-
∆2-isoxazoline (trans-2c) and 4-Hydroxymethyl-5-methyl-3-
(2,4,6-trimethylphenyl)isoxazole (3c). Sodium borohydride (0.22
g, 5.8 mmol) was added slowly to a solution of the isoxazole 1c
(0.10 g, 0.39 mmol) in EtOH (10 mL) at 0-5 °C. The mixture
was then heated at reflux for 24 h before it was cooled to 0-5 °C
and adjusted to pH 2 through the dropwise addition of 1 M aq
HCl. The resultant solution was concentrated under reduced
pressure, and the residue was taken up in Et2O and washed with
H2O. The aqueous washings were extracted with Et2O. The organic
solutions were combined, washed with H2O and saturated brine,
dried (anhyd MgSO4), and concentrated under reduced pressure.
Chromatography of the residue afforded the isoxazoline 2c (55 mg,
61%) and the isoxazole 3c (27 mg, 30%) as colorless oils with
physical and spectral data consistent with reported values.26
trans-4,5-Di(hydroxymethyl)-3-(2,4,6-trimethylphenyl)-∆2-
isoxazoline (trans-2d) and cis-4,5-Di(hydroxymethyl)-3-(2,4,6-
trimethylphenyl)-∆2-isoxazoline (cis-2d). The procedure described
above for the reaction of the isoxazole 1c with sodium borohydride
was followed in the treatment of the isoxazole 1d (0.10 g, 0.33
mmol) with sodium borohydride (0.19 g, 5.0 mmol), which afforded
the trans-disubstituted isoxazoline trans-2d (57 mg, 70%) as a
colorless solid: mp 102-103 °C; IR 3332, 2953, 2925, 1612, 1438,
1118, 1031 cm-1; 1H NMR (500 MHz) δ 1.60 (br s, 2H), 2.27 (s,
6H), 2.29 (s, 3H), 3.65 (m, 1H), 3.90 (m, 2H), 4.05 (m, 1H), 4.13
(m, 1H), 4.89 (ddd, J ) 10.0, 6.0, 3.5 Hz, 1H), 6.90 (s, 2H); 13C
NMR (75.4 MHz) δ 20.0, 21.0, 55.4, 57.8, 59.8, 81.7, 124.8, 128.2,
136.8, 139.1, 159.0; LRMS (%) m/z 249 (M+, 48), 229 (14), 218
(77), 188 (100), 172 (61), 158 (52), 146 (42), 130 (38), 119 (53),
103 (20), 91 (58), 77 (31), 65 (13). HRMS (m/z): (M+) calcd for
C14H19NO3, 249.1365; found, 249.1360. Anal. Calcd for C14H19-
NO3: C, 67.45; H, 7.68; N, 5.62. Found: C, 67.42; H, 7.62; N,
5.60. The cis isomer, cis-2d (16 mg, 20%), was obtained as a
colorless solid: mp 85-86 °C; IR 3369, 2921, 2874, 1611, 1453,
(+)-(1R,2S,4S)-N,N-Dicyclohexyl-7,7-dimethyl-2-propyno-
yloxybicyclo[2.2.1]heptane-1-methanesulfonamide (10a). Tri-
methylaluminum (2 M in hexanes, 0.35 mL, 0.70 mmol) was added
dropwise to a solution of methyl propiolate (6c; 65 µL, 0.73 mmol)
in dry toluene (3 mL) at 18 °C, and the mixture was stirred at that
temperature for 20 min. A solution of (+)-(1R,2S,4S)-N,N-dicy-
clohexyl-7,7-dimethyl-2-hydroxybicyclo[2.2.1]heptane-1-methane-
sulfonamide (0.25 g, 0.63 mmol) in dry toluene (0.5 mL) was then
added, and the mixture was heated at reflux for 72 h. After cooling
to 0-5 °C (ice bath), the reaction was quenched by the addition of
aq NH4Cl. The solvent was then evaporated under reduced pressure,
and the residue was taken up in EtOAc (50 mL). The organic
solution was washed with H2O (30 mL). The aq washings were
extracted with EtOAc (3 × 30 mL). The combined organic solutions
were washed with brine (30 mL), dried (anhyd Na2SO4), and then
concentrated under reduced pressure. Chromatography of the residue
afforded the ester 10a (0.27 g, 95%) as a colorless solid: mp 225-
230 °C; [R]D +45.4 (c 0.5); IR 3233, 2935, 2856, 2115, 1713, 1452,
1321, 1165, 1141, 1123, 1109, 1049, 982, 894, 858, 733, 641 cm-1
;
1H NMR (300 MHz) δ 0.89 (s, 3H), 1.00 (s, 3H), 1.01-1.40 (m,
9H), 1.50-1.66 (m, 2H), 1.67-1.88 (m, 16H), 1.90-2.08 (m, 2H),
2.67 (d, J ) 13.5 Hz, 1H), 2.80 (s, 1H), 3.20-3.34 (m, 2H), 3.27
(d, J ) 13.5 Hz, 1H), 5.10 (dd, J ) 7.6, 2.7 Hz, 1H); 13C NMR
(75.4 MHz) δ 19.9, 20.3, 25.1, 26.4, 26.8, 29.8, 32.6, 32.7, 39.0,
44.4, 49.0, 49.4, 53.3, 57.4, 73.7, 80.4, 151.3; LRMS (%) m/z 449
(M+, 30), 406 (19), 298 (87), 272 (9), 259 (6), 244 (80), 205 (17),
180 (64), 162 (13), 135 (100), 121 (16), 107 (42), 83 (49). HRMS
(m/z): (M+) calcd for C25H39NO4S, 449.2600; found, 449.2601.
Anal. Calcd for C25H39NO4S: C, 66.78; H, 8.74; N, 3.12. Found:
C, 66.08; H, 8.02; N, 2.93.
1
1081, 1042, 851 cm-1; H NMR (500 MHz) δ 1.61 (br s, 2H),
2.26 (s, 6H), 2.28 (s, 3H), 3.62-3.77 (m, 3H), 3.81 (m, 1H), 3.97
(m, 1H), 4.72 (dt, J ) 7.5, 3.5 Hz), 6.91 (s, 2H); 13C NMR (75.4
MHz) δ 20.2, 21.2, 56.1, 61.4, 63.5, 84.4, 124.7, 128.7, 136.8,
138.9, 158.4; LRMS (%) m/z 249 (M+, 45), 218 (100), 205 (21),
188 (80), 172 (54), 158 (47), 145 (42), 130 (44), 119 (34), 103
(17), 91 (41), 77 (29), 57 (48). HRMS (m/z): (M+) calcd for C14H19-
NO3, 249.1365; found, 249.1366. Anal. Calcd for C14H19NO3: C,
67.45; H, 7.68; N, 5.62. Found: C, 67.40; H, 7.65; N, 5.61.
3-(2,4,6-Trimethylphenyl)isoxazole-4-carboxylic Acid (8a) and
3-(2,4,6-Trimethylphenyl)isoxazole-5-carboxylic Acid (9). A
mixture of mesitonitrile oxide (7;37 1.0 g, 6.2 mmol) and propiolic
acid (6a; 0.44 g, 6.3 mmol) in THF (60 mL) was heated at reflux
for 2 days, then cooled, and concentrated under reduced pressure.
Chromatography of the residue afforded an inseparable mixture of
8a and 9 in a 1.3:1 ratio (colorless oil, 1.4 g, quantitative): IR
2924, 2361, 2338, 1700, 1652, 1576, 1506, 1457, 1295, 1140, 910,
851, 732, 667 cm-1. 8a: 1H NMR (300 MHz) δ 2.06 (s, 6H), 2.33
(s, 3H), 6.94 (s, 2H), 8.40-9.10 (br s, 1H), 9.16 (s, 1H). 9: 1H
NMR (300 MHz) δ 2.13 (s, 6H), 2.33 (s, 3H), 6.96 (s, 2H), 6.98
(s, 1H), 8.40-9.10 (br s, 1H). LRMS (%) m/z 231 (M+, 100), 213
(5), 203 (10), 186 (84), 170 (31), 158 (100), 144 (34), 130 (27),
115 (40), 103 (23), 91 (53), 77 (44), 65 (22). HRMS (m/z): (M+)
calcd for C13H13NO3, 231.0895; found, 231.0898.
(-)-(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclohex-
yl Tetrolate (10b). DMAP (21 mg, 0.17 mmol) was added to a
stirred mixture of (-)-(1R,2S,5R)-5-methyl-2-(1-methyl-1-phenyl-
ethyl)cyclohexanol (0.46 g, 2.0 mmol) and tetrolic acid (6b; 0.15
g, 1.8 mmol) in Et2O (15 mL) at 0-5 °C (ice bath). After 10 min,
DCC (0.40 g, 1.9 mmol) was added and stirring was continued at
18 °C for an additional 48 h. The mixture was then diluted with
Et2O (50 mL) and filtered through a pad of Celite. The filter cake
was washed with Et2O (6 × 100 mL), and the combined filtrates
were evaporated under reduced pressure to about 50 mL. The
residual solution was washed with 1 M aq HCl (3 × 30 mL), aq
NaHCO3 (2 × 30 mL), H2O (1 × 30 mL), and brine (1 × 30 mL),
and then it was dried (anhyd MgSO4) and concentrated under
reduced pressure. Chromatography of the residue afforded the ester
10b (0.46 g, 86%) as a colorless solid with physical and spectral
data consistent with reported values.25
(+)-(1R,2S,4S)-N,N-Dicyclohexyl-7,7-dimethyl-2-tetrolyloxy-
bicyclo[2.2.1]heptane-1-methanesulfonamide (10c). The proce-
dure described above for the synthesis of the propiolate 10a was
followed for the reaction of trimethylaluminum (2 M in hexanes,
0.35 mL, 0.70 mmol), methyl tetrolate (6d; 56 mg, 0.57 mmol),
and (+)-(1R,2S,4S)-N,N-dicyclohexyl-7,7-dimethyl-2-hydroxybicyclo-
[2.2.1]heptane-1-methanesulfonamide (0.25 g, 0.63 mmol), which
afforded 10c (0.25 g, 95%) as a colorless solid: mp 132-134 °C;
[R]D +51.7 (c 0.12); IR 2929, 2854, 1708, 1452, 1325, 1258, 1165,
5-Methyl-3-(2,4,6-trimethylphenyl)isoxazole-4-carboxylic Acid
(8b). A mixture of mesitonitrile oxide (7; 0.81 g, 5.0 mmol) and
(37) Liu, K.-C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45,
3916.
3226 J. Org. Chem., Vol. 71, No. 8, 2006

Isoxazoles as Masked Acrylates and Acrylamides
1
1143, 1110, 1048, 982, 854, 824 cm-1; H NMR (300 MHz) δ
Calcd for C29H35NO3: C, 78.17; H, 7.92; N, 3.14. Found: C, 78.01;
H, 7.88; N, 3.10. The regioisomer, 12b (0.19 g, 37%), was obtained
as a colorless oil: [R]D +0.20 (c 0.6); IR 2956, 2923, 2869, 1733,
1613, 1583, 1495, 1456, 1388, 1378, 1296, 1218, 1173, 1121, 1050,
994, 850, 763, 700 cm-1; 1H NMR (300 MHz) δ 0.91 (d, J ) 6.5
Hz, 3H), 0.91-1.02 (m, 1H), 1.10-1.38 (m, 2H), 1.25 (s, 3H),
1.38 (s, 3H), 1.48-1.60 (m, 1H), 1.66-1.78 (m, 1H), 1.79-1.92
(m, 1H), 1.93-2.05 (m, 1H), 2.11 (s, 6H), 2.21 (td, J ) 10.5, 4.0
Hz, 1H), 2.33 (s, 3H), 5.12 (td, J ) 10.5, 4.0 Hz, 1H), 6.29 (s,
1H), 6.91-6.94 (m, 3H), 7.15-7.18 (m, 2H), 7.26-7.32 (m, 2H);
13C NMR (75.4 MHz) δ 20.2, 21.1, 21.7, 24.0, 26.4, 28.8, 31.3,
34.3, 39.5, 41.4, 50.2, 65.8, 110.2, 124.9, 125.1, 125.2, 127.9, 128.4,
137.0, 139.1, 151.1, 156.0, 160.1, 162.3; LRMS (%) m/z 445 (M+,
10), 326 (10), 283 (33), 232 (92), 214 (8), 186 (20), 158 (18), 143
(8), 119 (100), 105 (17), 91 (38). HRMS (m/z): (M+) calcd for
C29H35NO3, 445.2617; found, 445.2617. Anal. Calcd for C29H35-
NO3: C, 78.17; H, 7.92; N, 3.14. Found: C, 78.28; H, 7.87; N,
3.11.
0.87 (s, 3H), 0.99 (s, 3H), 1.01-1.40 (m, 7H), 1.50-1.62 (m, 2H),
1.65-1.84 (m, 16H), 1.85-2.04 (m, 2H), 1.92 (s, 3H), 2.64 (d, J
) 13.5 Hz, 1H), 3.15-3.35 (m, 2H), 3.27 (d, J ) 13.5 Hz, 1H),
5.04 (dd, J ) 8.0, 3.0 Hz, 1H); 13C NMR (75.4 MHz) δ 3.7, 20.0,
20.4, 25.0, 26.3, 26.4, 26.8, 29.8, 32.5, 32.7, 39.2, 44.4, 49.0, 49.3,
53.3, 57.6, 73.1, 79.8, 84.1, 151.3; LRMS (%) m/z 463 (M+, 11),
420 (3), 315 (3), 298 (32), 272 (7), 244 (27), 216 (5), 180 (36),
153 (8), 135 (44), 110 (6), 93 (24). HRMS (m/z): (M+) calcd for
C26H41NO4S, 463.2756; found, 463.2746. Anal. Calcd for C26H41-
NO4S: C, 67.35; H, 8.91; N, 3.02. Found: C, 67.17; H, 8.94; N,
2.90.
(-)-(1R,2S)-2-Phenylcyclohexyl 3-(2,4,6-Trimethylphenyl)-
isoxazole-4-carboxylate (11a) and (-)-(1R,2S)-2-Phenylcyclo-
hexyl 3-(2,4,6-Trimethylphenyl)isoxazole-5-carboxylate (12a).
The procedure described above was followed for the synthesis of
the tetrolate 10b. A reaction of DMAP (16 mg, 0.13 mmol), DCC
(0.30 g, 1.4 mmol), (-)-(1R,2S)-2-phenylcyclohexanol (0.25 g, 1.4
mmol), and a 1.3:1 mixture of the acids 8a and 9 (0.30 g, 1.3 mmol)
afforded the ester 11a (0.25 g, 50%) as colorless plates after
chromatography and recrystallization from hexanes/Et2O: mp 119-
121 °C; [R]D -22.6 (c 0.5); IR 2930, 2858, 1717, 1583, 1449, 1390,
1288, 1172, 1134, 1120, 1015, 851, 776, 699, 531 cm-1; 1H NMR
(300 MHz) δ 1.10-1.66 (m, 4H), 1.80 (s, 3H), 1.68-2.00 (m, 2H),
1.91 (s, 3H), 2.04-2.16 (m, 2H), 2.26-2.38 (m, 1H), 2.37 (s, 3H),
5.06 (td, J ) 10.5, 4.5 Hz, 1H), 6.89 (s, 1H), 6.92 (s, 1H), 6.98 (s,
1H), 7.01 (s, 1H), 7.10-7.25 (m, 3H), 8.87 (s, 1H); 13C NMR (75.4
MHz) δ 19.6, 19.7, 21.2, 24.2, 25.5, 32.0, 33.9, 49.4, 76.6, 114.3,
124.2, 126.3, 127.2, 127.7, 128.1, 128.6, 136.9, 138.6, 142.5, 159.9,
160.4, 163.3; LRMS (%) m/z 389 (M+, 5), 279 (1), 231 (12), 186
(9), 130 (17), 91 (93). HRMS (m/z): (M+) calcd for C25H27NO3,
389.1991; found, 389.2003. Anal. Calcd for C25H27NO3: C, 77.09;
H, 6.99; N, 3.60. Found: C, 76.90; H, 6.89; N, 3.51. The
regioisomer, 12a (0.19 g, 38%), was obtained as a colorless oil:
[R]D -116.1 (c 0.3); IR 2930, 2856, 2118, 1739, 1450, 1294, 1280,
(+)-(1R,2S,4S)-N,N-Dicyclohexyl-7,7-dimethyl-2-(3-(2,4,6-tri-
methylphenyl)isoxazole-4-carboxy)bicyclo[2.2.1]heptane-1-meth-
anesulfonamide (11c) and (+)-(1R,2S,4S)-N,N-Dicyclohexyl-7,7-
dimethyl-2-(3-(2,4,6-trimethylphenyl)isoxazole-5-carboxy)bi-
cyclo[2.2.1]heptane-1-methanesulfonamide (12c). A mixture of
the propiolate 10a (0.27 g, 0.60 mmol) and mesitonitrile oxide (7;
97 mg, 0.60 mmol) in THF (15 mL) was heated at reflux for 7
days, then cooled, and concentrated under reduced pressure.
Chromatography of the residue afforded the cycloadduct 11c (70
mg, 19%) as a colorless oil: [R]D +34.0 (c 0.48); IR 2931, 2855,
1731, 1612, 1454, 1324, 1282, 1236, 1166, 1143, 1111, 1048, 982,
1
910, 894, 853, 770, 732, 654, 515 cm-1; H NMR (300 MHz) δ
0.88 (s, 3H), 0.90 (s, 3H), 1.14-1.39 (m, 7H), 1.50-1.84 (m, 18H),
1.86-2.00 (m, 2H), 2.06 (s, 3H), 2.09 (s, 3H), 2.30 (s, 3H), 2.68
(d, J ) 13.5 Hz, 1H), 3.08-3.30 (m, 2H), 3.17 (d, J ) 13.5 Hz,
1H), 5.14 (dd, J ) 8.0, 3.0 Hz, 1H), 6.92 (s, 2H), 8.90 (s, 1H); 13
C
NMR (75.4 MHz) δ 19.7, 19.9, 20.0, 20.3, 21.1, 25.0, 26.2, 26.3,
26.9, 30.3, 32.6, 32.7, 39.2, 44.3, 48.9, 49.4, 53.8, 57.4, 78.7, 114.6,
123.5, 128.2, 136.6, 137.0, 139.0, 158.8, 161.0, 161.7; LRMS (%)
m/z 610 (M+, 23), 439 (7), 421 (2), 380 (100), 316 (7), 298 (12),
246 (14), 214 (43), 180 (21), 158 (18), 135 (76), 107 (20), 83 (35).
HRMS (m/z): (M+) calcd for C35H50N2O5S, 610.3440; found,
610.3435. Anal. Calcd for C35H50N2O5S: C, 68.82; H, 8.25; N,
4.59. Found: C, 69.07; H, 8.12; N, 4.11. The regioisomer, 12c
(0.21 g, 56%), was obtained as a colorless solid: mp 200-202
°C; [R]D +36.1 (c 0.48); IR 3769, 2929, 2855, 1731, 1612, 1453,
1325, 1282, 1165, 1143, 1111, 1048, 1029, 982, 894, 853, 769,
732 cm-1; 1H NMR (300 MHz) δ 0.94 (s, 3H), 1.13 (s, 3H), 1.20-
1.39 (m, 7H), 1.46-1.58 (m, 2H), 1.62-2.20 (m, 18H), 2.12 (s,
6H), 2.33 (s, 3H), 2.73 (d, J ) 13.5 Hz, 1H), 3.22 (m, 2H), 3.49
(d, J ) 13.5 Hz, 1H), 5.31 (dd, J ) 7.5, 3.0 Hz, 1H), 6.95 (s, 2H),
6.97 (s, 1H); 13C NMR (75.4 MHz) δ 19.9, 20.1, 20.2, 20.9, 24.9,
26.0, 26.1, 26.8, 29.9, 32.4, 32.7, 39.1, 44.3, 49.0, 49.4, 53.2, 57.3,
80.1, 111.3, 124.7, 128.3, 136.8, 139.1, 155.2, 160.8, 162.4; LRMS
(%) m/z 610 (M+, 9), 380 (22), 323 (11), 298 (14), 259 (11), 232
(23), 214 (14), 180 (100), 158 (23), 135 (89), 107 (42), 83 (70).
HRMS (m/z): (M+) calcd for C35H50N2O5S, 610.3440; found,
610.3433. Anal. Calcd for C35H50N2O5S: C, 68.82; H, 8.25; N,
4.59. Found: C, 68.57; H, 8.03; N, 4.92.
1216, 1119, 1007, 851, 768, 755, 699, 532 cm-1; H NMR (300
1
MHz) δ 1.11-1.78 (m, 4H), 1.78-2.13 (m, 2H), 2.07 (s, 6H),
2.25-2.38 (m, 2H), 2.31 (s, 3H), 2.85 (td, J ) 11.5, 4.0 Hz, 1H),
5.20 (td, J ) 10.5, 4.0 Hz, 1H), 6.63 (s, 1H), 6.92 (s, 2H), 7.12-
7.28 (m, 5H); 13C NMR (75.4 MHz) δ 20.2, 21.1, 24.7, 25.6, 32.1,
33.3, 49.5, 78.7, 110.5, 124.8, 126.6, 127.5, 128.3, 128.4, 137.1,
139.2, 142.3, 156.1, 160.2, 162.4; LRMS (%) m/z 389 (M+, 6),
224 (4), 206 (2), 186 (20), 158 (100), 130 (14), 91 (44). HRMS
(m/z): (M+) calcd for C25H27NO3, 389.1991; found, 389.1999. Anal.
Calcd for C25H27NO3: C, 77.09; H, 6.99; N, 3.60. Found: C, 76.93;
H, 6.92; N, 3.52. The structure of the isoxazole 11a was confirmed
using X-ray crystallographic analysis (CCDC-261168).
(-)-(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclohex-
yl 3-(2,4,6-Trimethylphenyl)isoxazole-4-carboxylate (11b) and
(+)-(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclohex-
yl 3-(2,4,6-Trimethylphenyl)isoxazole-5-carboxylate (12b). The
procedure described above was used for the synthesis of the tetrolate
10b. A reaction of DMAP (14 mg, 0.12 mmol), DCC (0.27 g, 1.3
mmol), (-)-(1R,2S,5R)-5-methyl-2-(1-methyl-1-phenylethyl)cyclo-
hexanol (0.30 g, 1.3 mmol), and a 1.3:1 mixture of the isoxazoles
8a and 9 (0.27 g, 1.2 mmol) afforded the ester 11b (0.25 g, 48%)
as a colorless oil: [R]D -77.3 (c 0.8); IR 2954, 2922, 1723, 1573,
1457, 1392, 1304, 1295, 1172, 1129, 1012, 849, 778, 700 cm-1
;
(-)-(1R,2S)-2-Phenylcyclohexyl 5-Methyl-3-(2,4,6-trimeth-
ylphenyl)isoxazole-4-carboxylate (11d). The procedure described
above was followed for the synthesis of the tetrolate 10b. A reaction
of DMAP (12 mg, 96 µmol), DCC (0.22 g, 1.1 mmol), (-)-(1R,2S)-
2-phenylcyclohexanol (0.19 g, 1.1 mmol), and the isoxazole 8b
(0.24 g, 0.96 mmol) afforded the ester 11d (0.34 g, 87%) as a
colorless oil: [R]D -53.3 (c 0.9); IR 2929, 1716, 1611, 1434, 1308,
1296, 1285, 1181, 1134, 1096, 1070, 1033, 1016, 980, 851, 790
1H NMR (300 MHz) δ 0.86 (d, J ) 6.5 Hz, 3H), 0.90-1.10 (m,
1H), 1.14 (s, 3H), 1.20 (s, 3H), 1.24-1.54 (m, 3H), 1.61-1.74
(m, 1H), 1.78-1.92 (m, 2H), 1.97 (s, 3H), 2.10 (s, 3H), 2.28 (m,
1H), 2.32 (s, 3H), 4.86 (td, J ) 11.0, 4.5 Hz, 1H), 6.91 (s, 1H),
6.95 (s, 1H), 7.08-7.18 (m, 1H), 7.19-7.25 (m, 4H), 7.74 (s, 1H);
13C NMR (75.4 MHz) δ 19.8, 21.1, 21.5, 22.7, 26.3, 29.5, 31.1,
34.3, 39.2, 41.1, 49.7, 74.5, 113.1, 123.9, 124.8, 125.0, 127.8, 127.9,
128.0, 136.6, 136.7, 138.7, 152.2, 159.4, 160.4, 162.8; LRMS (%)
m/z 445 (M+, 9), 327 (17), 232 (60), 214 (31), 199 (6), 186 (9),
158 (18), 143 (8), 119 (100), 105 (38), 91 (42), 77 (11). HRMS
(m/z): (M+) calcd for C29H35NO3, 445.2617; found, 445.2619. Anal.
1
cm-1; H NMR (300 MHz) δ 1.10-2.60 (m, 9H), 1.73 (s, 3H),
1.95 (s, 3H), 2.37 (s, 3H), 2.59 (s, 3H), 5.05 (td, J ) 10.5, 4.5 Hz,
1H), 6.86-6.97 (m, 4H), 7.10-7.23 (m, 3H); 13C NMR (75.4 MHz)
δ 13.3, 19.8, 19.9, 21.3, 24.6, 25.7, 32.1, 34.5, 49.3, 75.5, 109.1,
J. Org. Chem, Vol. 71, No. 8, 2006 3227

Lee et al.
125.6, 126.3, 127.2, 127.4, 127.6, 128.1, 128.2, 128.3, 136.7, 136.8,
138.3, 142.5, 153.0, 161.1, 161.6; LRMS (%) m/z 403 (M+, 13),
273 (1), 246 (37), 228 (21), 212 (17), 201 (13), 186 (59), 171 (6),
158 (100), 129 (13), 117 (20), 104 (8), 91 (85), 67 (9). HRMS
(m/z): (M+) calcd for C26H29NO3, 403.2147; found, 403.2151. Anal.
Calcd for C26H29NO3: C, 77.39; H, 7.24; N, 3.47. Found: C, 77.16;
H, 7.28; N, 3.46.
(0.21 g, 3.1 mmol) in THF (25 mL) was heated at reflux for 3
days, then cooled, and concentrated under reduced pressure.
Chromatography of the residue afforded the isoxazole 13a (0.23
g, 32%) as colorless rods after recrystallization from acetone/
hexanes: mp 195-200 °C; IR 3422, 3324, 2922, 2392, 1662, 1583,
1401, 1378, 1136, 1034, 855, 775, 739 cm-1; 1H NMR (300 MHz)
δ 2.10 (s, 6H), 2.35 (s, 3H), 5.28 (br s, 1H), 5.44 (br s, 1H), 7.02
(s, 2H), 9.16 (s, 1H); 13C NMR (75.4 MHz) δ 19.9, 21.3, 116.5,
122.7, 129.1, 137.5, 140.5, 158.2, 158.3, 163.8; LRMS (%) m/z
230 (M+, 37), 213 (49), 186 (27), 170 (13), 157 (100), 142 (16),
130 (14), 115 (18), 103 (10), 91 (24), 77 (21), 65 (11). HRMS
(m/z): (M+) calcd for C13H14N2O2, 230.1055; found, 230.1057.
Anal. Calcd for C13H14N2O2: C, 67.81; H, 6.13; N, 12.17. Found:
C, 67.65; H, 6.15; N, 12.09. The regioisomer, 15 (0.45 g, 64%),
was obtained as colorless plates after recrystallization from acetone/
hexanes: mp 135-137 °C; IR 3391, 3185, 2923, 1672, 1613, 1460,
(-)-(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclohex-
yl 5-Methyl-3-(2,4,6-trimethylphenyl)isoxazole-4-carboxylate (11e).
The procedure described above for the synthesis of the isoxazoles
11c and 12c was followed for the reaction of mesitonitrile oxide
(7; 0.25 g, 1.5 mmol) and the alkyne 10b (0.46 g, 1.5 mmol), which
afforded the isoxazole 11e (0.65 g, 93%) as a colorless oil: [R]D
-40.4 (c 0.6); IR 2953, 2922, 2869, 1712, 1599, 1436, 1307, 1136,
1089, 986, 849, 700 cm-1; 1H NMR (300 MHz) δ 0.85 (d, J ) 6.5
Hz, 3H), 1.06 (m, 1H), 1.08 (s, 3H), 1.17 (s, 3H), 1.24-1.60 (m,
4H), 1.72 (td, J ) 11.0, 4.0 Hz, 1H), 1.77-1.88 (m, 2H), 2.04 (s,
3H), 2.11 (s, 3H), 2.36 (s, 3H), 2.43 (s, 3H), 4.98 (td, J ) 11.0,
4.0 Hz, 1H), 6.94 (s, 1H), 6.96 (s, 1H), 7.07-7.17 (m, 3H), 7.19-
7.24 (m, 2H); 13C NMR (75.4 MHz) δ 13.2, 19.9, 20.0, 21.1, 21.6,
25.6, 26.6, 26.8, 31.1, 34.1, 39.7, 41.9, 50.2, 74.3, 109.3, 125.1,
125.3, 127.8, 128.0, 136.6, 136.7, 138.7, 151.1, 160.8, 161.7, 175.3;
LRMS (%) m/z 459 (M+, 7), 341 (9), 246 (74), 228 (8), 214 (2),
201 (6), 186 (31), 158 (22), 119 (100), 105 (38), 91 (48). HRMS
(m/z): (M+) calcd for C30H37NO3, 459.2773; found, 459.2779. Anal.
Calcd for C30H37NO3: C, 78.40; H, 8.11; N, 3.05. Found: C, 78.58;
H, 8.05; N, 3.01.
1
1364, 1244, 1118, 1033, 851 cm-1; H NMR (300 MHz) δ 2.14
(s, 6H), 2.33 (s, 3H), 5.27 (br s, 1H), 6.55 (br s, 1H), 6.91 (s, 1H),
6.96 (s, 2H); 13C NMR (75.4 MHz) δ 20.3, 21.2, 109.3, 124.6,
128.4, 136.9, 139.3, 157.8, 162.5, 163.1; LRMS (%) m/z 230 (M+,
70), 186 (100), 171 (6), 158 (60), 143 (16), 130 (9), 115 (16), 103
(9), 91 (24), 77 (18), 65 (8). HRMS (m/z): (M+) calcd for
C13H14N2O2, 230.1055; found, 230.1054. Anal. Calcd for
C13H14N2O2: C, 67.81; H, 6.13; N, 12.17. Found: C, 67.72; H,
6.09; N, 12.21. The structures of the isoxazoles 13a and 15 were
confirmed using X-ray crystallographic analysis (CCDC-261169
for 13a and CCDC-261172 for 15).
5-Methyl-3-(2,4,6-trimethylphenyl)isoxazole-4-carboxamide
(13b). A mixture of mesitonitrile oxide (7; 0.50 g, 3.1 mmol) and
tetrolamide (0.26 g, 3.1 mmol) in THF (25 mL) was heated at reflux
for 6 days, then cooled, and concentrated under reduced pressure.
Chromatography of the residue afforded the isoxazole 13b (0.72
g, 95%) as colorless needles after recrystallization from acetone/
hexanes: mp 214-215 °C; IR 3439, 1683, 1601, 1449, 1353, 1183,
1155, 902, 873, 767, 750, 711, 689, 502 cm-1; 1H NMR (300 MHz)
δ 2.11 (s, 6H), 2.34 (s, 3H), 2.83 (s, 3H), 5.02 (br s, 1H), 5.21 (br
s, 1H), 7.00 (s, 2H); 13C NMR (75.4 MHz) δ 13.6, 19.8, 21.2, 109.9,
124.1, 129.1, 137.5, 140.3, 159.3, 163.5, 176.0; LRMS (%) m/z
244 (M+, 89), 227 (49), 212 (42), 202 (5), 185 (100), 171 (50),
157 (100), 142 (15), 130 (19), 115 (31), 103 (18), 91 (45), 77 (35),
63 (7). HRMS (m/z): (M+) calcd for C14H16N2O2, 244.1212; found,
244.1216. Anal. Calcd for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47.
Found: C, 68.78; H, 6.55; N, 11.41. The structure of the isoxazole
13b was confirmed using X-ray crystallographic analysis (CCDC-
261170).
5-Phenyl-3-(2,4,6-trimethylphenyl)isoxazole-4-carboxamide
(13c). A mixture of mesitonitrile oxide (7; 0.10 g, 0.62 mmol) and
phenylpropiolamide (90 mg, 0.62 mmol) in THF (6 mL) was heated
at reflux for 6 days, then cooled, and concentrated under reduced
pressure. Chromatography of the residue afforded the isoxazole 13c
(0.18 g, 93%) as colorless blocks after recrystallization from
acetone/hexanes: mp 192-193 °C; IR 3304, 2921, 2853, 1677,
1611, 1422, 1363, 1131, 1035, 853, 691 cm-1; 1H NMR (300 MHz)
δ 2.18 (s, 6H), 2.36 (s, 3H), 5.15 (br s, 1H), 5.35 (br s, 1H), 7.02
(s, 2H), 7.51-7.56 (m, 3H), 8.10-8.14 (m, 2H); 13C NMR (75.4
MHz) δ 19.8, 21.1, 110.3, 124.1, 126.8, 128.2, 128.3, 128.9, 131.1,
137.4, 140.0, 160.6, 163.1, 172.2; LRMS (%) m/z 306 (M+, 50),
289 (30), 277 (2), 262 (5), 233 (100), 218 (4), 184 (2), 158 (4),
130 (3), 105 (100), 91 (7), 77 (41), 65 (2). HRMS (m/z): (M+)
calcd for C19H18N2O2, 306.1369; found, 306.1368. Anal. Calcd for
C19H18N2O2: C, 74.49; H, 5.92; N, 9.14. Found: C, 74.38; H, 5.86;
N, 9.16. The structure of the isoxazole 13c was confirmed using
X-ray crystallographic analysis (CCDC-261171).
(+)-(1R,2S,4S)-N,N-Dicyclohexyl-7,7-dimethyl-2-(5-methyl-3-
(2,4,6-trimethylphenyl)isoxazole-4-carboxy)bicyclo[2.2.1]heptane-
1-methanesulfonamide (11f) and (+)-(1R,2S,4S)-N,N-Dicyclohexyl-
7,7-dimethyl-2-(5-methyl-3-(2,4,6-trimethylphenyl)isoxazole-5-
carboxy)bicyclo[2.2.1]heptane-1-methanesulfonamide (12f). The
procedure described above for the synthesis of the isoxazoles 11c
and 12c was followed for the reaction of mesitonitrile oxide (7;
0.12 g, 0.72 mmol) and the alkyne 10c (0.22 g, 0.48 mmol), which
afforded the isoxazole 11f (40 mg, 13%) as a colorless solid: mp
200-202 °C; [R]D +32.2 (c 0.35); IR 2929, 2855, 1723, 1614,
1454, 1326, 1291, 1165, 1144, 1048, 982, 854, 776 cm-1; 1H NMR
(300 MHz) δ 0.95 (s, 3H), 1.13 (s, 3H), 1.00-1.40 (m, 7H), 1.48-
2.01 (m, 20H), 2.01 (s, 3H), 2.03 (s, 3H), 2.08 (s, 3H), 2.33 (s,
3H), 2.72 (d, J ) 13.5 Hz, 1H), 3.22 (m, 2H), 3.53 (d, J ) 13.5
Hz, 1H), 5.27 (dd, J ) 8.0, 3.0 Hz, 1H), 6.95 (s, 2H); 13C NMR
(75.4 MHz) δ 7.9, 19.8, 19.9, 20.2, 20.4, 21.1, 25.2, 26.2, 26.3,
27.0, 29.6, 30.1, 32.5, 33.0, 39.4, 44.5, 49.2, 49.5, 53.3, 57.4, 79.8,
122.2, 124.2, 128.3, 128.4, 137.1, 137.3, 139.3, 155.6, 156.4, 164.3;
LRMS (%) m/z 624 (M+, 15), 337 (25), 298 (12), 272 (7), 246
(42), 200 (34), 180 (100), 136 (37), 107 (15), 83 (22). HRMS (m/
z): (M+) calcd for C36H52N2O5S, 624.3597; found, 624.3595. Anal.
Calcd for C36H52N2O5S: C, 69.20; H, 8.39; N, 4.48. Found: C,
69.23; H, 8.21; N, 4.06. The regioisomer, 12f (0.24 g, 81%), was
obtained as a colorless solid: mp 205-208 °C; [R]D +33.3 (c 0.60);
IR 2931, 2856, 1725, 1613, 1452, 1326, 1255, 1165, 1143, 1144,
1
1048, 982, 853, 774, 643 cm-1; H NMR (300 MHz) δ 0.61 (s,
3H), 0.82 (s, 3H), 1.05-1.40 (m, 7H), 1.50-1.84 (m, 18H), 1.85-
2.00 (m, 2H), 2.04 (s, 3H), 2.12 (s, 3H), 2.29 (s, 3H), 2.63 (d, J )
13.5 Hz, 1H), 2.74 (s, 3H), 3.05 (d, J ) 13.5 Hz, 1H), 3.09-3.21
(m, 2H), 5.22 (dd, J ) 8.0, 3.5 Hz, 1H), 6.87 (s, 2H); 13C NMR
(75.4 MHz) δ 13.2, 19.6, 19.7, 19.9, 20.0, 20.9, 24.7, 24.9, 26.1,
26.3, 26.7, 30.5, 32.6, 32.7, 39.0, 44.1, 48.6, 49.3, 53.6, 57.2, 57.3,
78.2, 110.1, 124.8, 127.9, 128.0, 136.4, 136.5, 138.4, 160.4, 161.7,
173.1; LRMS (%) m/z 624 (M+, 2), 380 (100), 316 (16), 298 (22),
246 (36), 228 (96), 186 (72), 158 (24), 146 (12), 135 (100), 119
(6), 107 (22), 93 (28), 83 (32), 67 (10). HRMS (m/z): (M+) calcd
for C36H52N2O5S, 624.3597; found, 624.3595. Anal. Calcd for
C36H52N2O5S: C, 69.20; H, 8.39; N, 4.48. Found: C, 69.47; H,
8.37; N, 4.38.
3-(2,4,6-Trimethylphenyl)-∆2-isoxazoline-4-carboxamide [(()-
14a]. Trifluoroacetic acid (0.17 mL, 2.2 mmol) was added dropwise
to a stirred solution of sodium borohydride (82 mg, 2.2 mmol) in
dry THF (2.5 mL), and the mixture was stirred at room temperature
for 0.5 h. A solution of the isoxazole 13a (33 mg, 0.14 mmol) in
dry THF (2.5 mL) was then added, and the mixture was stirred at
3-(2,4,6-Trimethylphenyl)isoxazole-4-carboxamide (13a) and
3-(2,4,6-Trimethylphenyl)isoxazole-5-carboxamide (15). A mix-
ture of mesitonitrile oxide (7; 0.50 g, 3.1 mmol) and propiolamide
3228 J. Org. Chem., Vol. 71, No. 8, 2006

Isoxazoles as Masked Acrylates and Acrylamides
room temperature for 30 h before it was cooled to 0-5 °C and
adjusted to pH 2 through the dropwise addition of 1 M aq HCl.
The resultant solution was concentrated under reduced pressure,
and the residue was taken up in EtOAc and washed with H2O. The
aq washings were extracted with EtOAc. The organic solutions were
combined, washed with saturated brine, dried (anhyd MgSO4), and
concentrated under reduced pressure. Chromatography of the residue
afforded the isoxazoline (()-14a (31 mg, 92%) as a colorless
solid: mp 175-176 °C; IR 3334, 3194, 2923, 1677, 1611, 1455,
1394, 1337, 1306, 1289, 1195, 1118, 1035, 943, 908, 852, 730
cm-1; 1H NMR (300 MHz) δ 2.27 (s, 6H), 2.30 (s, 3H), 4.25 (dd,
J ) 11.0, 8.0 Hz, 1H), 4.64 (m, 1H), 5.01 (m, 1H), 5.10 (br s, 1H),
5.29 (br s, 1H), 6.92 (s, 2H); 13C NMR (125 MHz, CD3OD) δ
19.9, 21.2, 58.6, 73.2, 125.8, 129.5, 138.6, 140.3, 157.1, 172.1;
LRMS (%) m/z 232 (M+, 67), 214 (26), 201 (33), 185 (90), 171
(31), 158 (83), 144 (100), 130 (55), 121 (5), 115 (48), 103 (27), 91
(63), 77 (45), 71 (32), 65 (20), 59 (5). HRMS (m/z): (M+) calcd
for C13H16N2O2, 232.1212; found, 232.1210. Anal. Calcd for
C13H16N2O2: C, 67.22; H, 6.94; N, 12.06. Found: C, 67.28; H,
6.97; N, 12.07.
trans-5-Methyl-3-(2,4,6-trimethylphenyl)-∆2-isoxazoline-4-
carboxamide [(()-14b]. The procedure described above for the
reaction of the isoxazole 13a with sodium trifluoroacetoxyboro-
hydride was followed for the treatment of the isoxazole 13b (0.10
g, 0.41 mmol) with sodium borohydride (0.23 g, 6.1 mmol) that
had been pretreated with trifluoroacetic acid (0.46 mL, 6.1 mmol),
which afforded the isoxazoline (()-14b (90 mg, 90%) as a colorless
solid, with physical and spectral data consistent with reported
values.28
reaction of zinc dust (70 mg, 1.08 mmol), cuprous iodide (62 mg,
0.32 mmol), the isoxazole 1a (50 mg, 0.20 mmol), and 1-iodoada-
mantane (0.32 g, 1.20 mmol), which afforded the isoxazoline (()-
16b (74 mg, quantitative) as colorless plates after recrystallization
from hexanes/Et2O: mp 82-84 °C; IR 2904, 2849, 1743, 1612,
1434, 1306, 1289, 1198, 1168, 1003, 897, 867, 850 cm-1; 1H NMR
(300 MHz) δ 1.18-1.37 (m, 6H), 1.51-1.62 (m, 6H), 2.00-2.09
(m, 3H), 2.22 (s, 6H), 2.27 (s, 3H), 3.53 (s, 3H), 4.27 (d, J ) 11.0
Hz, 1H), 4.69 (d, J ) 11.0 Hz, 1H), 6.85 (s, 2H); 13C NMR (75.4
MHz) δ 20.4, 21.5, 28.3, 30.8, 35.3, 36.5, 36.7, 36.9, 37.8, 38.4,
41.0, 53.0, 56.0, 93.1, 125.1, 128.8, 137.2, 139.0, 153.3, 170.0;
LRMS (%) m/z 381 (M+, 18), 246 (100), 218 (9), 186 (34), 158
(12), 135 (69), 108 (7), 93 (13), 79 (19), 66 (10). HRMS (m/z):
(M+) calcd for C24H31NO3, 381.2304; found, 381.2303. Anal. Calcd
for C24H31NO3: C, 75.56; H, 8.19; N, 3.67. Found: C, 75.49; H,
8.14; N, 3.63. The structure of the isoxazoline (()-16b was
confirmed using X-ray crystallographic analysis (CCDC-261173).
Methyl trans-5-(Prop-2-yl)-3-(2,4,6-trimethylphenyl)-∆2-isox-
azoline-4-carboxylate [(()-16c]. The procedure described above
for the synthesis of the isoxazoline (()-16a was followed, except
that the reagents were added in aliquots over 60 h, in the reaction
of zinc dust (245 mg, 3.78 mmol), cuprous iodide (217 mg, 1.12
mmol), the isoxazole 1a (50 mg, 0.20 mmol), and 2-iodopropane
(420 µL, 4.20 mmol), which afforded the isoxazoline (()-16c (48
mg, 82%) as a colorless oil: IR 2960, 2926, 2875, 1742, 1611,
1595, 1435, 1266, 1198, 1168, 1031, 897, 851 cm-1; 1H NMR (300
MHz) δ 1.00 (d, J ) 6.5 Hz, 3H), 1.09 (d, J ) 6.5 Hz, 3H), 2.05
(m, 1H), 2.24 (s, 6H), 2.28 (s, 3H), 3.56 (s, 3H), 4.16 (d, J ) 10.0
Hz, 1H), 4.86 (dd, J ) 10.0, 7.0 Hz, 1H), 6.87 (s, 2H); 13C NMR
(75.4 MHz) δ 17.6, 18.1, 19.7, 20.9, 31.6, 52.4, 58.8, 89.6, 124.6,
128.4, 136.8, 138.6, 153.6, 169.0; LRMS (%) m/z 289 (M+, 34),
246 (100), 218 (17), 186 (95), 158 (52), 146 (24), 119 (12), 101
(7), 91 (12). HRMS (m/z): (M+) calcd for C17H23NO3, 289.1678;
found, 289.1678. Anal. Calcd for C17H23NO3: C, 70.56; H, 8.01;
N, 4.84. Found: C, 70.36; H, 8.06; N, 4.80.
trans-5-Phenyl-3-(2,4,6-trimethylphenyl)-∆2-isoxazoline-4-car-
boxamide [(()-14c]. The procedure described above for the
reaction of the isoxazole 13a with sodium trifluoroacetoxyboro-
hydride was followed for the treatment of the isoxazole 13c (0.10
g, 0.33 mmol) with sodium borohydride (0.19 g, 4.9 mmol) that
had been pretreated with trifluoroacetic acid (0.38 mL, 4.9 mmol),
which afforded the isoxazoline (()-14c (93 mg, 92%) as a colorless
solid, with physical and spectral data consistent with reported
values.28
Methyl trans-5-Ethyl-3-(2,4,6-trimethylphenyl)-∆2-isoxazo-
line-4-carboxylate [(()-16d]. The procedure described above for
the synthesis of the isoxazoline (()-16a was followed, except that
the reagents were added in aliquots over 8 days, in the reaction of
zinc dust (840 mg, 13.0 mmol), cuprous iodide (744 mg, 3.84
mmol), the isoxazole 1a (50 mg, 0.20 mmol), and iodoethane (1.15
mL, 14.4 mmol), which afforded the isoxazoline (()-16d (18 mg,
32%) as a colorless oil: IR 1741, 1611, 1434, 1378, 1309, 1151,
Methyl trans-5-tert-Butyl-3-(2,4,6-trimethylphenyl)-∆2-isox-
azoline-4-carboxylate [(()-16a]. A suspension of zinc dust (35
mg, 0.54 mmol) and cuprous iodide (31 mg, 0.16 mmol) in 65%
aq MeOH (3 mL) was sonicated at 5 °C for 5-10 min until it
turned black. The isoxazole 1a (50 mg, 0.20 mmol) was then added,
followed by the slow addition of a solution of tert-butyl iodide (70
µL, 0.60 mmol) in 65% aq MeOH (3 mL) over 2 h, while the
solution was maintained at 5 °C and sonication was continued. After
an additional 9 h, saturated aq NH4Cl (1 mL) was added, and the
mixture was filtered through a pad of Celite. The filter cake was
washed with EtOAc, and the filtrate was concentrated under reduced
pressure. The residue was taken up in Et2O, and the solution was
washed with H2O. The aq layer was extracted with Et2O. The
organic solutions were combined, washed with saturated aq
Na2S2O4, H2O, and brine, dried (anhyd MgSO4), and concentrated
under reduced pressure. Chromatography of the residue afforded
the isoxazoline (()-16a (59 mg, quantitative) as a colorless solid:
mp 59-62 °C; IR 2956, 2871, 1743, 1610, 1434, 1398, 1367, 1306,
1292, 1199, 1026, 1000, 906, 851, 781 cm-1; 1H NMR (300 MHz)
δ 1.02 (s, 9H), 2.23 (s, 6H), 2.27 (s, 3H), 3.54 (s, 3H), 4.20 (d, J
) 11.0 Hz, 1H), 4.85 (d, J ) 11.0 Hz, 1H), 6.86 (s, 2H); 13C NMR
(75.4 MHz) δ 20.0, 21.2, 25.3, 33.7, 52.7, 57.4, 92.7, 124.7, 128.4,
136.9, 138.7, 153.4, 169.3; LRMS (%) m/z 303 (M+, 31), 246 (100),
218 (59), 186 (68), 158 (54), 146 (24), 119 (10), 91 (10), 77 (6).
HRMS (m/z): (M+) calcd for C18H25NO3, 303.1834; found,
303.1835. Anal. Calcd for C18H25NO3: C, 71.26; H, 8.31; N, 4.62.
Found: C, 71.14; H, 8.28; N, 4.66.
1
1033, 893, 852 cm-1; H NMR (300 MHz) δ 1.08 (t, J ) 7.5 Hz,
3H), 1.79 (m, 1H), 1.92 (m, 1H), 2.24 (s, 6H), 2.29 (s, 3H), 3.58
(s, 3H), 4.08 (d, J ) 9.0 Hz, 1H), 5.02 (dt, J ) 9.0, 6.5 Hz, 1H),
6.88 (s, 2H); 13C NMR (75.4 MHz) δ 9.3, 20.0, 21.2, 27.4, 52.6,
60.9, 85.7, 124.6, 128.5, 136.9, 138.8, 153.7, 168.8; LRMS (%)
m/z 275 (M+, 49), 256 (27), 246 (95), 230 (7), 214 (19), 202 (7),
186 (100), 170 (12), 158 (65), 144 (20), 130 (27), 115 (24), 103
(14), 91 (38), 77 (23), 65 (10), 57 (14). HRMS (m/z): (M+) calcd
for C16H21NO3, 275.1521; found, 275.1518. Anal. Calcd for C16H21-
NO3: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.71; H, 7.63; N,
5.04.
Methyl cis-5-Cyclohexyl-3-(2,4,6-trimethylphenyl)-∆2-isox-
azoline-4-carboxylate and Methyl trans-5-Cyclohexyl-3-(2,4,6-
trimethylphenyl)-∆2-isoxazoline-4-carboxylate [(()-16e]. The
procedure described above for the synthesis of the isoxazoline (()-
16a was followed, except that the reagents were added in aliquots
over 6 days, in the reaction of zinc dust (630 mg, 9.72 mmol),
cuprous iodide (558 mg, 2.88 mmol), the isoxazole 1a (50 mg,
0.20 mmol), and cyclohexyl iodide (1.40 mL, 10.8 mmol), which
afforded methyl cis-5-cyclohexyl-3-(2,4,6-trimethylphenyl)-∆2-isox-
azoline-4-carboxylate (13 mg, 20%) as a colorless oil: IR 2925,
2853, 1742, 1611, 1449, 1378, 1309, 1275, 1208, 1171, 1032, 999,
1
Methyl trans-5-(Adamantan-1-yl)-3-(2,4,6-trimethylphenyl)-
∆2-isoxazoline-4-carboxylate [(()-16b]. The procedure described
above for the synthesis of the isoxazoline (()-16a was followed,
except that the reagents were added in aliquots over 14 h, in the
906, 886, 851, 782, 576 cm-1; H NMR (300 MHz) δ 1.00-1.50
(m, 6H), 1.60-1.94 (m, 4H), 1.97-2.09 (m, 1H), 2.22 (s, 6H),
2.27 (s, 3H), 3.53 (s, 3H), 4.18 (d, J ) 10.5 Hz, 1H), 4.83 (dd, J
) 10.5, 7.5 Hz, 1H), 6.86 (s, 2H); 13C NMR (75.4 MHz) δ 20.0,
J. Org. Chem, Vol. 71, No. 8, 2006 3229

Lee et al.
21.1, 25.6, 25.8, 26.3, 28.4, 29.0, 41.6, 52.6, 59.1, 89.1, 124.6,
128.5, 136.9, 138.7, 153.8, 169.1; LRMS (%) m/z 329 (M+, 45),
270 (2), 246 (100), 218 (31), 202 (4), 186 (67), 158 (34), 145 (20),
130 (25), 119 (24), 101 (12), 91 (25), 67 (8). HRMS (m/z): (M+)
calcd for C20H27NO3, 329.1991; found, 329.1994. Anal. Calcd for
C20H27NO3: C, 72.92; H, 8.26; N, 4.25. Found: C, 72.73; H, 8.24;
N, 4.23. The trans isomer, (()-16e (16 mg, 25%), was obtained as
a colorless oil: IR 2925, 2853, 1740, 1611, 1450, 1434, 1311, 1245,
10.0 Hz, 1H), 6.00 (br s, 1H), 6.89 (s, 2H); 13C NMR (75.4 MHz)
δ 20.1, 21.2, 25.4, 33.7, 58.0, 91.6, 124.9, 128.8, 137.2, 139.1,
152.9, 168.7; LRMS (%) m/z 288 (M+, 14), 255 (2), 231 (24), 214
(14), 203 (17), 185 (39), 146 (30), 130 (20), 119 (16), 103 (8), 86
(100), 77 (12), 65 (5), 57 (37). HRMS (m/z): (M+) calcd for
C17H24N2O2, 288.1838; found, 288.1843. Anal. Calcd for
C17H24N2O2: C, 70.80; H, 8.39; N, 9.71. Found: C, 70.76; H, 8.32;
N, 9.70.
1
1202, 1173, 1152, 1034, 888, 850 cm-1; H NMR (300 MHz) δ
(-)-(1R,2S)-2-Phenylcyclohexyl (4R,5R)-5-tert-Butyl-3-(2,4,6-
trimethylphenyl)-∆2-isoxazoline-4-carboxylate (18a). The pro-
cedure described above for the synthesis of the isoxazoline (()-
16a was followed, except that the reagents were added in aliquots
over 8 days, in the reaction of zinc dust (384 mg, 5.76 mmol),
cuprous iodide (336 mg, 1.73 mmol), the isoxazole 11a (35 mg,
90 µmol), and tert-butyl iodide (768 µL, 6.48 mmol), which
afforded the isoxazoline 18a (35 mg, 88%) as colorless blocks after
recrystallization from hexanes/Et2O: mp 92-93 °C; [R]D -116.5
(c 0.2); IR 2934, 2860, 1734, 1611, 1448, 1398, 1367, 1293, 1191,
1.00-1.40 (m, 6H), 1.58-1.87 (m, 4H), 1.88-2.09 (m, 1H), 2.27
(s, 6H), 2.31 (s, 3H), 3.64 (s, 3H), 4.15 (d, J ) 9.5 Hz, 1H), 4.43
(app. t, J ) 9.5 Hz, 1H), 6.88 (s, 2H); 13C NMR (75.4 MHz) δ
20.1, 21.1, 25.4, 25.7, 26.2, 30.1, 30.3, 37.9, 52.1, 58.2, 88.5, 124.9,
128.7, 137.0, 138.9, 155.7, 167.7; LRMS (%) m/z 329 (M+, 51),
312 (2), 270 (6), 246 (100), 201 (5), 186 (79), 168 (10), 158 (66),
145 (25), 130 (30), 119 (22), 103 (11), 91 (30), 67 (10). HRMS
(m/z): (M+) calcd for C20H27NO3, 329.1991; found, 329.1990. Anal.
Calcd for C20H27NO3: C, 72.92; H, 8.26; N, 4.25. Found: C, 72.75;
H, 8.30; N, 4.21.
1
1170, 1124, 1026, 960, 899, 851 cm-1; H NMR (300 MHz) δ
Methyl trans-5-tert-Butyl-3-nonyl-∆2-isoxazoline-4-carboxy-
late [(()-16f]. The procedure described above for the synthesis of
the isoxazoline (()-16a was followed in the reaction of zinc dust
(35 mg, 0.54 mmol), cuprous iodide (31 mg, 0.16 mmol), the
isoxazole 1b (52 mg, 0.20 mmol), and tert-butyl iodide (72 µL,
0.60 mmol), which afforded the isoxazoline (()-16f (60 mg,
quantitative) as a colorless oil: IR 2955, 2926, 2855, 1743, 1466,
0.68 (s, 9H), 1.10-1.91 (m, 8H), 2.20 (s, 6H), 2.29 (s, 3H), 2.42
(m, 1H), 3.96 (d, J ) 11.5, 1H), 4.57 (d, J ) 11.5 Hz, 1H), 4.85
(td, J ) 11.0, 4.5 Hz, 1H), 6.86 (s, 2H), 6.90-7.27 (m, 5H); 13C
NMR (75.4 MHz) δ 20.1, 20.7, 24.6, 25.1, 25.6, 31.0, 33.1, 33.2,
49.6, 56.9, 76.9, 92.1, 124.9, 126.4, 127.2, 128.2, 128.3, 128.4,
128.7, 137.0, 138.6, 142.5, 153.7, 168.0; LRMS (%) m/z 447 (M+,
46), 424 (3), 390 (72), 346 (3), 290 (16), 270 (2), 232 (43), 204
(28), 188 (55), 159 (66), 130 (19), 117 (25), 91 (100). HRMS (m/
z): (M+) calcd for C29H37NO3, 447.2773; found, 447.2770. Anal.
Calcd for C29H37NO3: C, 77.82; H, 8.33; N, 3.13. Found: C, 77.76;
H, 8.30; N, 3.18. The structure of the isoxazoline 18a was confirmed
using X-ray crystallographic analysis (CCDC-261174). Analysis
1
1435, 1366, 1292, 1164, 1026, 907 cm-1; H NMR (300 MHz) δ
0.88 (t, J ) 7.0 Hz, 3H), 0.91 (s, 9H), 1.20-1.38 (m, 12H), 1.42-
1.68 (m, 2H), 2.18-2.32 (m, 1H), 2.33-2.48 (m, 1H), 3.76 (s,
3H), 3.77 (d, J ) 8.5 Hz, 1H), 4.54 (d, J ) 8.5 Hz, 1H); 13C NMR
(75.4 MHz) δ 14.2, 22.7, 25.0, 26.1, 26.9, 29.1, 29.2, 29.3, 29.5,
31.9, 34.1, 52.8, 56.0, 91.8, 154.8, 169.8; LRMS (%) m/z 311 (M+,
34), 282 (3), 268 (7), 254 (40), 236 (3), 226 (23), 212 (34), 199
(66), 182 (7), 167 (5), 154 (25), 141 (22), 128 (13), 110 (8), 100
(24), 85 (31), 72 (42), 57 (100). HRMS (m/z): (M+) calcd for
C18H33NO3, 311.2460; found, 311.2462. Anal. Calcd for C18H33-
NO3: C, 69.41; H, 10.68; N, 4.50. Found: C, 69.26; H, 10.61; N,
4.56.
1
of the crude product mixture by H NMR spectroscopy showed
that 18a was produced in 95% de. Separate resonances of a minor
diastereomer were observed as follows: 1H NMR (300 MHz) δ
0.73 (s, 9H), 3.77 (d, J ) 11.0 Hz, 1H), 4.59 (d, J ) 11.0 Hz, 1H),
5.05 (td, J ) 10.5, 4.0 Hz, 1H).
(-)-(1R,2S)-2-Phenylcyclohexyl (4R,5S)-5-(Prop-2-yl)-3-(2,4,6-
trimethylphenyl)-∆2-isoxazoline-4-carboxylate (18b). The pro-
cedure described above for the synthesis of the isoxazoline (()-
16a was followed, except that the reagents were added in aliquots
over 12 days, in the reaction of zinc dust (576 mg, 8.64 mmol),
cuprous iodide (504 mg, 2.59 mmol), the isoxazole 11a (35 mg,
90 µmol), and 2-iodopropane (936 µL, 9.72 mmol), which afforded
the isoxazoline 18b (34 mg, 86%) as a colorless oil: [R]D -110.2
(c 0.1); IR 2930, 2858, 1734, 1611, 1492, 1448, 1378, 1271, 1123,
Methyl trans-3-Nonyl-5-(prop-2-yl)-∆2-isoxazoline-4-carboxy-
late [(()-16g]. The procedure described above for the synthesis of
the isoxazoline (()-16a was followed, except that the time allowed
for alkylation was 2.5 days, in the reaction of zinc dust (35 mg,
0.54 mmol), cuprous iodide (31 mg, 0.16 mmol), the isoxazole 1b
(52 mg, 0.20 mmol), and 2-iodopropane (60 µL, 0.60 mmol), which
afforded the isoxazoline (()-16g (44 mg, 74%) as a colorless oil:
IR 2956, 2926, 2855, 1743, 1466, 1435, 1369, 1267, 1201, 1167,
1027, 905 cm-1; 1H NMR (300 MHz) δ 0.88 (t, J ) 7.0 Hz, 3H),
0.91 (d, J ) 7.0 Hz, 3H), 0.97 (d, J ) 7.0 Hz, 3H), 1.18-1.38 (m,
12H), 1.42-1.64 (m, 2H), 1.87 (m, 1H), 2.26 (m, 1H), 2.42 (m,
1H), 3.74 (d, J ) 8.0 Hz, 1H), 3.77 (s, 3H), 4.59 (dd, J ) 8.0, 6.5
Hz, 1H); 13C NMR (75.4 MHz) δ 14.2, 17.7, 17.9, 22.7, 26.2, 27.0,
29.1, 29.2, 29.3, 29.5, 31.9, 32.9, 52.8, 57.6, 88.9, 155.1, 169.6;
LRMS (%) m/z 297 (M+, 19), 268 (3), 254 (65), 240 (5), 226 (10),
210 (3), 198 (53), 185 (100), 168 (11), 154 (13), 141 (11), 126
(19), 110 (9), 101 (30), 85 (21), 71 (37), 57 (42). HRMS (m/z):
(M+) calcd for C17H31NO3, 297.2304; found, 297.2311. Anal. Calcd
for C17H31NO3: C, 68.65; H, 10.51; N, 4.68. Found: C, 68.43; H,
10.48; N, 4.73.
1
1032, 894, 851, 756, 699 cm-1; H NMR (300 MHz) δ 0.80 (d, J
) 6.5 Hz, 3H), 0.82 (d, J ) 6.5 Hz, 3H), 1.05-2.10 (m, 9H), 2.19
(s, 6H), 2.29 (s, 3H), 2.42 (m, 1H), 3.90 (d, J ) 11.0 Hz, 1H),
4.49 (dd, J ) 11.0, 7.5 Hz, 1H), 4.85 (td, J ) 11.0, 4.5 Hz, 1H),
6.85 (s, 2H), 7.02-7.30 (m, 5H); 13C NMR (125 MHz) δ 17.3,
18.4, 20.1, 21.1, 24.5, 25.5, 31.0, 31.5, 33.8, 49.6, 58.5, 77.9, 89.6,
125.0, 126.6, 128.4, 128.5, 128.8, 137.1, 138.7, 142.6, 154.4, 167.9;
LRMS (%) m/z 433 (M+, 31), 390 (60), 274 (10), 232 (33), 203
(11), 188 (27), 158 (53), 171 (16), 91 (100). HRMS (m/z): (M+)
calcd for C28H35NO3, 433.2617; found, 433.2621. Anal. Calcd for
C28H35NO3: C, 77.56; H, 8.14; N, 3.23. Found: C, 77.48; H, 8.17;
N, 3.25. Analysis of the crude product mixture by 1H NMR
spectroscopy showed that 18b was produced in 93% de. Separate
resonances of a minor diastereomer were observed as follows: 1H
NMR (300 MHz) δ 3.65 (d, J ) 11.0 Hz, 1H), 5.06 (td, J ) 11.0,
4.0 Hz, 1H).
Methyl trans-5-tert-Butyl-3-(2,4,6-trimethylphenyl)-∆2-isox-
azoline-4-carboxamide [(()-17]. The procedure described above
for the synthesis of the isoxazoline (()-16a was followed, except
that the reagents were added in aliquots over 48 h, in the reaction
of zinc dust (228 mg, 3.54 mmol), cuprous iodide (198 mg, 1.02
mmol), the isoxazole 13a (50 mg, 0.22 mmol), and tert-butyl iodide
(450 µL, 3.9 mmol), which afforded the isoxazoline (()-17 (61
mg, quantitative) as a colorless solid: mp 143-146 °C; IR 3369,
3175, 1693, 1601, 1400, 1365, 1349, 1307, 1247, 1039, 895, 845,
(-)-(1R,2S,5R)-5-Methyl-2-(1-methyl-1-phenylethyl)cyclohex-
yl (4R,5R)-5-tert-Butyl-3-(2,4,6-trimethylphenyl)-∆2-isoxazoline-
4-carboxylate (19). The procedure described above for the synthesis
of the isoxazoline (()-16a was followed, except that the reagents
were added in aliquots over 8 days, in the reaction of zinc dust
(384 mg, 5.76 mmol), cuprous iodide (336 mg, 1.73 mmol), the
isoxazole 11b (40 mg, 90 µmol), and tert-butyl iodide (744 µL,
6.48 mmol), which afforded the isoxazoline 19 (39 mg, 87%) as a
1
728 cm-1; H NMR (300 MHz) δ 1.02 (s, 9H), 2.24 (s, 6H), 2.28
(s, 3H), 3.96 (d, J ) 10.0 Hz, 1H), 4.20 (br s, 1H), 5.02 (d, J )
3230 J. Org. Chem., Vol. 71, No. 8, 2006

Isoxazoles as Masked Acrylates and Acrylamides
colorless oil: [R]D -53.8 (c 1.7); IR 2954, 2919, 1730, 1611, 1455,
1367, 1294, 1191, 1170, 1031, 850, 764, 700 cm-1; 1H NMR (300
MHz) δ 0.65 (d, J ) 6.5 Hz, 3H), 0.70-1.85 (m, 6H), 1.00 (s,
9H), 1.14 (s, 3H), 1.22 (s, 3H), 1.44 (m, 1H), 1.73 (m, 1H), 2.13
(s, 6H), 2.27 (s, 3H), 3.78 (d, J ) 11.5 Hz, 1H), 4.59 (td, J ) 10.5,
4.5 Hz, 1H), 4.83 (d, J ) 11.5 Hz, 1H), 6.82 (s, 2H), 7.08-7.32
(m, 5H); 13C NMR (75.4 MHz) δ 15.4, 18.0, 20.3, 21.1, 21.6, 25.6,
26.6, 26.8, 29.8, 30.8, 33.2, 34.2, 39.8, 49.7, 56.6, 76.4, 91.8, 124.9,
125.1, 125.3, 125.5, 127.9, 128.0, 128.4, 128.7, 137.3, 138.7, 151.0,
153.7, 167.9; LRMS (%) m/z 503 (M+, 34), 446 (27), 385 (4), 328
(4), 290 (47), 232 (46), 214 (12), 188 (89), 158 (19), 119 (100).
HRMS (m/z): (M+) calcd for C33H45NO3, 503.3399; found,
503.3404. Anal. Calcd for C33H45NO3: C, 78.69; H, 9.00; N, 2.78.
Found: C, 78.59; H, 8.97; N, 2.81. Analysis of the crude product
48.7, 49.1, 53.9, 56.6, 57.6, 80.3, 92.4, 125.4, 128.7, 136.9, 139.0,
153.2, 167.7; LRMS (%) m/z 668 (M+, 0.2), 611 (4), 425 (2), 414
(0.4), 397 (2), 380 (56), 316 (8), 298 (20), 259 (6), 246 (18), 228
(34), 203 (10), 180 (32), 158.1 (12), 146 (18), 135 (100), 107 (30),
93 (36), 83 (46), 67 (16). HRMS (m/z): (M+) calcd for C39H60N2O5S,
668.4223; found, 668.4219. Anal. Calcd for C39H60N2O5S: C,
70.02; H, 9.04; N, 4.19. Found: C, 70.02; H, 8.92; N, 3.86. The
structure of the isoxazoline 20 was confirmed using X-ray crystal-
lographic analysis (CCDC-261175). Analysis of the crude product
mixture by 1H NMR spectroscopy showed no separate resonances
attributable to the other trans-4,5-disubstituted diastereomer of the
isoxazoline 20 and, on this basis, it was calculated that 20 was
produced in g98% de. However, the yields from repeated alkyla-
tions of the isoxazole 11c were variable, and small amounts of one
of the cis-diastereomers of 20 were sometimes formed. For this
1
mixture by H NMR spectroscopy showed that 19 was produced
1
in 94% de. Separate resonances of a minor diastereomer were
observed as follows: 1H NMR (300 MHz) δ 4.19 (d, J ) 11.5 Hz,
1H), δ 4.69 (d, J ) 11.5 Hz, 1H).
compound, [R]D -69.3 (c 0.15); H NMR (300 MHz) δ 0.72 (s,
3H), 0.82 (s, 3H), 1.11-1.96 (m, 27H), 1.06 (s, 9H), 2.25 (s, 6H),
2.35 (s, 3H), 2.62 (d, J ) 13.0 Hz, 1H), 3.17 (d, J ) 13.0 Hz, 1H),
3.25 (p, J ) 7.5 Hz, 1H), 4.47 (d, J ) 11.0 Hz, 1H), 4.69 (dd, J )
3.5, 8.0 Hz, 1H), 4.76 (d, J ) 9.0 Hz, 1H), 6.83 (s, 2H); LRMS
(%) m/z 668 (M+, 5), 611 (15), 425 (3), 380 (45), 316 (5), 298
(13), 259 (2), 246 (18), 228 (28), 203 (5), 180 (24), 158 (11), 146
(12), 135 (100), 107 (23).
(+)-(1R,2S,4S)-N,N-Dicyclohexyl-7,7-dimethyl-2-((4S,5S)-5-
tert-butyl-3-(2,4,6-trimethylphenyl)-∆2-isoxazoline-4-carboxy)-
bicyclo[2.2.1]heptane-1-methanesulfonamide (20). The procedure
described above for the synthesis of the isoxazoline (()-16a was
followed, except that the reagents were added in aliquots over 13
days, in the reaction of zinc dust (576 mg, 8.64 mmol), cuprous
iodide (504 mg, 2.59 mmol), the isoxazole 11c (55 mg, 90 µmol),
and tert-butyl iodide (1.12 mL, 9.72 mmol), which afforded the
isoxazoline 20 (52 mg, 87%) as colorless plates after recrystalli-
zation from hexanes/Et2O: mp 245-246 °C; [R]D +141.9 (c 0.69);
IR 2929, 2856, 1737, 1613, 1372, 1327, 1280, 1190, 1166, 1144,
Acknowledgment. The authors acknowledge the receipt of
an Australian Postgraduate Award (Industry) for C.K.Y.L and
are grateful for financial support provided by CSIRO Molecular
& Health Technologies, Dunlena Pty., Ltd., and the Australian
Research Council.
1
1109, 1049, 1028, 981, 908, 853, 775, 741, 643 cm-1; H NMR
(300 MHz) δ 0.02 (s, 3H), 0.72 (s, 3H), 0.80-1.90 (m, 27H), 1.06
(s, 9H), 2.20 (s, 6H), 2.25 (s, 3H), 2.51 (d, J ) 13.5 Hz, 1H), 3.00
(d, J ) 13.5 Hz, 1H), 3.21 (p, J ) 7.5 Hz, 2H), 4.19 (d, J ) 11.0
Hz, 1H), 4.75 (dd, J ) 8.0, 3.5 Hz, 1H), 5.03 (d, J ) 11.0 Hz,
1H), 6.81 (s, 2H); 13C NMR (150 MHz) δ 18.6, 19.8, 20.2, 21.0,
25.0, 25.5, 26.4, 26.5, 26.8, 29.7, 31.2, 32.5, 32.9, 33.4, 38.9, 44.2,
Supporting Information Available: General experimental
details as well as atomic displacement plots and cifs for compounds
1c, 11a, 13a-c, 15, (()-16b, 18a, and 20. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO0602569
J. Org. Chem, Vol. 71, No. 8, 2006 3231