Sequential 1,3-dipolar cycloadditions in the synthesis of bis-isoxazolo substituted piperidinones

Article abstract of DOI:10.1021/jo991418m

A strategy for the efficient synthesis of novel bis-isoxazolo substituted piperidinones has been developed. The protocol consists of the Michael addition of an unsaturated alkoxide to β-nitrostyrene followed by an intramolecular nitrile oxide cycloaddition (INOC) or an intramolecular silyl nitronate olefin cycloaddition (ISOC) to give III. Grignard addition to this isoxazoline intermediate followed by DCC coupling of the resulting isoxazolidine with nitroacetic acid gave II, and a second intramolecular cycloaddition via 1,3-dipoles result in the formation of the targeted novel tetracycles (I). A solid-supported scavenger was employed to increase the efficiency and yield of the Michael addition step.

Full text of DOI:10.1021/jo991418m

J . Org. Chem. 2000, 65, 499-503
499
Sequ en tia l 1,3-Dip ola r Cycloa d d ition s in th e Syn th esis of
Bis-Isoxa zolo Su bstitu ted P ip er id in on es
Kevin Sheng-Lin Huang, Edwin H. Lee, Marilyn M. Olmstead, and Mark J . Kurth*
Department of Chemistry, One Shields Avenue, University of California, Davis, California 95616
Received September 8, 1999
A strategy for the efficient synthesis of novel bis-isoxazolo substituted piperidinones has been
developed. The protocol consists of the Michael addition of an unsaturated alkoxide to â-nitrostyrene
followed by an intramolecular nitrile oxide cycloaddition (INOC) or an intramolecular silyl nitronate
olefin cycloaddition (ISOC) to give III. Grignard addition to this isoxazoline intermediate followed
by DCC coupling of the resulting isoxazolidine with nitroacetic acid gave II, and a second
intramolecular cycloaddition via 1,3-dipoles result in the formation of the targeted novel tetracycles
(I). A solid-supported scavenger was employed to increase the efficiency and yield of the Michael
addition step.
Sch em e 1. Retr osyn th etic Ap p r oa ch to
In tr od u ction
Isoxa zoloisoxa zolin e-Con ta in in g Tetr a cycle I
Isoxazolidine and isoxazoline heterocycles are com-
monly found in polycyclic compounds with biological
activity. Some examples include the immuno-suppressive
cyclolignans1 and steroidal antiflammatory drugs.2 There
are also numerous examples of these N,O-heterocycles
being used as key building blocks in the total synthesis
of natural and unnatural compounds such as â-lactam
antibiotics,3 quinolizidine and indolizine tricycles,4 tes-
tosterone,5 sarkomycin,6 and biotin.7 The potential for
control of two (isoxazoline) or three (isoxazolidine) con-
tiguous stereocenters in these heterocycles affords ad-
ditional synthetic opportunities.
Sch em e 2. Nitr oeth er F or m a tion
The biological and synthetic utility apparent for isox-
azolidine and isoxazoline heterocycles has prompted us
to develop a synthetic route to novel polycyclic compounds
which incorporate these subfragments. Herein we report
the results of that investigation which constitutes a
strategic route for the synthesis of isoxazoloisoxazoline-
containing tetracyclic targets of general structure I
(Scheme 1). Enroute, we compare the diastereoselectivity
of an intramolecular nitrile oxide olefin cycloaddition
(INOC) with a silyl nitronate olefin cycloaddition (ISOC).
Resu lts a n d Discu ssion
The first step in the preparation of furano- or pyra-
noisoxazoline III (n ) 1 or 2, respectively) is depicted in
Scheme 2. Michael addition of excess sodio allyl (1),
cinnamyl (2), or 3-butenyl (3) alkoxide to â-nitrostyrene
in dry THF at -78 °C affords nitroethers 4-6. We have
found that excess sodio or potassio (but not litho) alkoxide
effectively avoids the competing Michael addition of the
nitronate intermediate to â-nitrostyrene.8 By employing
a polymer-supported acyl chloride as a polymer sponge,
this excess alkoxide can be easily removed from the
reaction mixture9 [-C(dO)Cl at 1760 cm-1 f -C(dO)OR
at 1721 cm-1] to deliver the targeted nitroethers in 75-
93% yield.
Our retrosynthetic approach to I engaged furano- or
pyranoisoxazolidine II (n ) 1 or 2, respectively) as the
key intermediate which in turn would be derived from
furano- or pyranoisoxazoline III. The commercial starting
points for this plan were trans-â-nitrostyrene and allyl
alcohols 1-3 which collectively deliver I with a phenyl
substituent on the furan/pyran ring (i.e., 1 and 2 f I with
a C1 phenyl substituent and n ) 1; 3 f I with C1 phenyl
substituent and n ) 2).
(1) Gordaliza, M.; Faircloth, G. T.; Castro, M. A.; Corral, J . M. M.;
Lopez-Vazquez, M. L.; Feliciano, A. S. J . Med. Chem. 1996, 39, 2865.
(2) Kwon, T.; Heiman, A. S.; Oriaku, E. T.; Yoon, K.; Lee, H. J . J .
Med. Chem. 1995, 38, 1048.
(3) J ung, M. E.; Vu, B. T. J . Org. Chem. 1996, 61, 4427.
(4) Werner, K. M.; De Los Santos, J .; Weinreb, S. M. J . Org. Chem.
1999, 64, 686.
With these nitroethers in hand, attention was turned
to the second step in the preparation of III (Scheme 3),
the intramolecular 1,3-dipolar cycloaddition reaction.
Both the ISOC (intermediacy of silyl nitronate 7 and
(5) Ihara, M.; Tokunaga, Y.; Fukumoto, K. J . Org. Chem. 1990, 15,
4497.
(6) Curran, D. P. J . Am. Chem. Soc. 1987, 109, 5280.
(7) Confalone, P. N.; Pizzolato, G.; Confalone, D. L.; Uskokovic, M.
R. J . Am. Chem. Soc. 1980, 102, 1954.
(8) Duffy, J . L.; Kurth, J . A.; Kurth, M. J . Tetrahedron Lett. 1993,
34, 1259.
(9) (a) Kaldor, S. W.; Siegel, M. G.; Fritz, J . E.; Dressman, B. A.;
Hahn, P. J . Tetrahedron Lett. 1996, 37, 7193. (b) Bunin, B. A. The
Combinatorial Index; Academic Press: San Diego; p 275.
10.1021/jo991418m CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/29/1999

500 J . Org. Chem., Vol. 65, No. 2, 2000
Huang et al.
Sch em e 3. ISOC vs INOC Ster eoselectivity
F igu r e 1. ISOC vs INOC for 6 f 12.
Sch em e 4. P r ep a r a tion of Isoxa zolid in es II
N-silyloxy isoxazolidine 8) and INOC (intermediacy of
nitrile oxide 9) reactions of nitroether 4 have been
reported.10 In our hands, the INOC of 4 delivers 10 as a
9:1 mixture of cis and trans furanoisoxazolines 10c and
10t, respectively, in 88% combined yield. This result was
obtained utilizing 1,4-phenylene diisocyanate as the
dehydrating agent as we have found that the resulting
urea polymer can be removed by simple filtration11
whereas the use of the more standard phenyl isocyanate
Mukayiyama dehydrating agent12 requires a difficult
chromatographic removal of the phenyl urea byproduct.13
We next investigated the ISOC and INOC reactions of
nitroether 5 and found that the stereoselectivity paral-
leled that of 4. That is, the ISOC on 5 gave 11c (and a
trace of 11t) in 82% combined, while the INOC on 5 gave
11c and 11t in a 6:1 ratio, respectively (75% combined
yield). Thus, with nitroether 5, the INOC requires a
longer reaction time and a higher temperature than the
corresponding ISOC. With these substrates 4 and 5, the
INOC is not as effective as the ISOC in the construction
of furanoisoxazolines. In contrast, the ISOC and INOC
stereoselectivities with nitroether 6, which now delivers
pyranoisoxazolines, were quite different. Here, the ISOC
on 6 gave 12c and 12t in a 1:1 ratio, respectively (40%
combined yield), while the INOC reaction on 6 gave
essentially only 12t (12c:12t ) 3:97) in 77% yield. Our
rationale for these results with 6 is summarized in
Figure 1. ISOC 6 f 12 is disfavored by a "TMSO || Ph"
nonbonding interaction in intermediate conformation 712t
or by “Ph axial interactions” in 712c. As a result, ISOC 6
f 12 is an ineffective (40% yield) and nonselective (1:1
product ratio) transformation. In contrast, the linear
nitrile oxide intermediate 912t which is operative in INOC
6 f 12 avoids both of these destabilizing interactions and
is both effective (77% yield) and stereoselective (94% de).
With routes to furanoisoxazolines and pyranoisoxazo-
lines in hand, attention was directed toward the conver-
sion of III to furano- and pyranoisoxazolidines II (Scheme
4). Not surprisingly, the isoxazoline ring of III is quite
unreactive toward carbon nucleophiles.14 Reports of
oxime activation by Lewis acid complexation15 led us to
pretreat a toluene solution of furanoisoxazoline 10c with
boron trifluoride etherate at -78 °C. Subsequent addition
of an ethereal solution of allylmagnesium bromide de-
livered furanoisoxazolidine 13 with no evidence of the
C6a-epimer in the crude reaction mixture (88% yield).
Likewise, furanoisoxazoline 11c and pyranoisoxazoline
12t gave only cis-fused allyl addition products 14 (80%
yield) and 15 (80% yield), respectively.
(10) (a) Beebe, X.; Schore, N. E.; Kurth, M. J . J . Am. Chem. Soc.
1962, 114, 10061. (b)Beebe, X.; Chiappari, C. L. Olmstead, M. M.;
Kurth, M. J .; Schore, N. E. J . Org. Chem. 1995, 60, 4204. (c)
Kozikowski, A. P.; Murgrage, B. B. J . Chem. Soc., Chem. Commun.
1988, 198. (d) Rai, K. M. L.; Hassner, A. Indian J . Chem., Sect. B:
Org. Chem. Incl. Med. Chem. 1997, 36, 242. (e) Hassner, A.; Friedman,
O.; Dehaen, W. Liebigs Ann.-Recueil. 1997, 587. (f) Namboothiri, I. N.
N.; Hassner A.; Gottlieb, H. E. J . Org. Chem. 1997, 62, 485. (g)
Hassner, A.; Rai, K. M. L.; Dehaen W. Synth. Commun. 1994, 24, 1669.
(h) Murthy, K. S. K.; Hassner A. Isr. J . Chem. 1991, 31, 239. (i) Rai K.
M. L.; Linganna N.; Hassner A.; Anjanamurthy, C. Org. Prep. Proced.
Int. 1992, 24, 91. (j) Dehaen W.; Hassner A. Tetrahedron Lett. 1990,
31, 743. (k) Chiacchio, U.; Corsaro, A.; Gumina, G.; Pistara, V.;
Rescifina, A.; Alessi, M.; Pipero, A.; Romeo, G.; Romeo, R. Tetrahedron
1997, 53, 13855. (l) Aurich, H. G.; Biesemeier, F. Synthesis 1995, 1171.
(m) Ihara, M.; Tokunaga, Y.; Taniguchi, N.; Fukumoto, K.; Kabuto, C.
J . Org. Chem. 1991, 56, 5281.
Next, the nitroacetamide moiety in isoxazolidines 16-
18 was introduced by a DCC-mediated N-acylation of 13-
15. Nitroacetic acid, which was generated by treatment
of nitromethane with potassium hydroxide (formation of
the dipotassium salt of nitroacetic acid) followed by
treatment with tartaric acid,16 and DCC were added to
an ice-cold, dry THF solution of isoxazolidines 13-15.
(14) Bastide, J .; Henri-Rousseau, O. Bull. Soc. Chim. Fr. 1973, 2294.
(15) Moody, C. J ., Lightfoot, A. P.; Gallagher, P. T. J . Org. Chem.
1997, 62, 746.
(11) Kantorowski, E. J .; Brown, S. P.; Kurth, M. J . J . Org. Chem.
1998, 63, 5272.
(12) Mukaiyama, T.; Hoshino, T. J . Am. Chem. Soc. 1960, 82, 5339.
(13) Basel, Y.; Hassner A. Synthesis 1997, 309.
(16) Shipchandler, M. T. Synthesis 1979, 666. (b) Feuer, H.; Hass,
H. B.; Warren, K. S. J . Am. Chem. Soc. 1949, 71, 3078. (c) Dear, R. E.
A.; Pattison, F. L. M. J . Am. Chem. Soc. 1963, 85, 616. (d) Armarego,
W. L. F. J . Chem. Soc. (C) 1969, 986.

Synthesis of Bis-Isoxazolo Substituted Piperidinones
J . Org. Chem., Vol. 65, No. 2, 2000 501
as received. All reactions were carried out under nitrogen
atmosphere. Tetrahydrofuran (THF) was distilled under ni-
trogen from potassium/benzophenone immediately prior to use.
Benzene and toluene were distilled under nitrogen from
sodium immediately prior to use. Triethylamine was distilled
under nitrogen from calcium hydride immediately prior to use.
Silica gel chromatography was performed according to the
method of Still.18 All melting points are uncorrected.
Sch em e 5. P r ep a r a tion of Bis-Isoxa zolo
Su bstitu ted P ip er id on on e I
1-(Allyloxy)-2-n itr op h en yleth a n e (4).19 A three-necked
50 mL round-bottom flask equipped with a magnetic stir bar
was charged with NaH (160 mg, 4 mmol, 60% in mineral oil),
and the oil was removed by washing with dry hexane (5 × 3
mL). The resulting solid NaH was dried under vacuum, and
the flask was flushed with nitrogen and charged with dry THF
(20 mL). Allyl alcohol (300 µL, 4 mmol) was added slowly via
syringe, and the mixture was allowed to stir for 1 h at room
temperature. The solution was cooled to -78 °C, and nitrosty-
rene (290 mg, 2 mmol) in dry THF (5 mL) was added via
syringe pump at a rate of 510 µL per minute. After an
additional 1 h at -78 °C, the mixture was warmed to 0 °C.
Polymer-supported acyl chloride (1.3 g, 2 mmol) was added in
portions, and the solution was stirred at for 2 h at 0 °C. The
mixture was quenched with 1 N HCl (20 mL) and filtered to
remove the polymer. The aqueous layer was separated and
extracted with ethyl ether (3 × 10 mL). The combined organic
washes were washed with saturated NaHCO3 and brine, dried
(MgSO4), filtered, and concentrated by rotatory evaporation
to give 4 (330 mg, 1.6 mmol, 80%) as a yellow oil which was
used in the next step without further purification: 1H NMR δ
3.81 (dd, J ) 13, 6 Hz, 1H), 3.98 (dd, J ) 13, 5 Hz, 1H), 3.98,
4.39 (dd, J ) 13, 3 Hz, 1H), 4.63 (dd, J ) 13, 10 Hz, 1H), 5.16
(m, 3H), 5.82 (m, 1H), 7.38 (m, 5H); 13C NMR δ 69.9, 76.7,
77.5, 80.3, 117.3, 126.8, 128.9, 133.8, 136.5; IR (neat) 3081,
Filtration and flash column chromatography removed the
DCU byproduct leading to crystalline nitroacetamides
16-18 in excellent yield (86-90%).
The phenylisocyanate-mediated dehydration of ni-
troacetates is known to deliver the corresponding nitrile
oxide [i.e., ROC(dO)CH2NO2 + PhNCO f ROC(dO)Ct
N+-O-].17 Drawing on this precedent, we were optimistic
that a similar dehydration of the nitroacetamide moiety
in isoxazolidines 16-18 would deliver the analogous
amido nitrile oxide. Indeed, we were pleased to find that
treatment of nitroacetamide 16 with our modified Mu-
kaiyama protocol of 1,4-phenylene diisocyanate instead
of phenyl isocyanate produced (furoisoxazolidino)isox-
azolopiperidinone 19 as the sole product in 65% yield.
Conformational biases clearly dictate complete facial
selectivity for this INOC reaction. In similar fashion, the
INOC of nitroacetamide 17 delivered (furoisoxazolidino)-
isoxazolopiperidinone 20, again as the sole product. Thus,
in the reaction sequence beginning with nitroether 5, the
lone stereocenter of this starting material played forward
by a highly stereoselective ISOC reaction on 5, a com-
pletely stereoselective Grignard addition to 11c, and a
completely stereoselective INOC reaction on 17, render-
ing heterocycle 20 as the sole product. INOC reactions
of 16 and 17 produced none of the C10a-epimeric cy-
cloaddition products of 19 and 20 (Scheme 5).
3031, 2923, 2865, 1558, 1380, 1100 cm-1
.
1-(Cin n a m yloxy)-2-n itr o-1-p h en yleth a n e (5).19 The pro-
cedure described for the preparation of 4 was employed with
the following reagents and quantities: NaH (5 g, 125 mmol;
60% in mineral oil), cinnamyl alcohol (18 g, 134 mmol), and
nitrostyrene (8.9 g, 59.4 mmol). Workup and column chroma-
tography (hexane/ethyl acetate 10:1) gave 5 (15 g, 55.4 mmol,
93%) as a yellow oil: 1H NMR δ 3.97 (ddd, J ) 13, 7, 1 Hz,
1H), 4.13 (ddd, J ) 13, 6, 1 Hz, 1H), 4.37 (dd, J ) 13, 3 Hz,
1H), 4.64 (dd, J ) 13, 10 Hz, 1H), 5.17 (dd, J ) 10, 3 Hz, 1H),
6.18 (m, 1H), 6.50 (d, 16 Hz, 1H), 7.33 (m, 10 H); 13C NMR δ
69.5, 76.8, 77.3, 80.3, 125.0, 126.6, 126.9, 127.8, 128.6, 129.1,
133.0, 136.3, 136.5; IR (thin film) 3030, 2920, 2860, 1556, 1381,
-1
1103 cm
.
1-(Bu t-3-en yloxy)-2-n itr o-1-p h en yleth a n e (6).19 The pro-
cedure described for the preparation of 4 was employed with
the following reagents and quantities: NaH (2 g, 50 mmol;
60% in mineral oil), 3-buten-1-ol (4 mL, 46.50 mmol), and
nitrostyrene (3 g, 19.80 mmol). Workup gave 6 (4 g, 18.10
mmol, 93%) as a yellow oil which was used in the next step
without further purification: 1H NMR δ 2.30 (m, 2H), 3.42
(m, 2H), 4.37 (dd, J ) 13, 3 Hz, 1H), 4.60 (dd, J ) 13, 10 Hz,
1H), 5.02 (m, 3H), 5.74 (m, 1H), 7.38 (m, 5H); 13C NMR δ 33.8,
68.9, 78.5, 80.4, 116.4, 126.6, 128.9, 128.9, 134.6, 136.8, IR
-1
(thin film) 3074, 3034, 2916, 2872, 1556, 1380, 1107 cm
.
In conclusion, we have reported an efficient and highly
stereoselective route to novel bis-isoxazolo substituted
pyridinone tetracycles of general structure I. The reaction
sequence consists of alkoxide Michael addition to â-ni-
trostyrene, INOC or ISOC to give furano- or pyranoisox-
azolines (III), facial-selective Grignard addition to the
oxime moiety in III, N-acylation of the resulting furano-
or pyranoisoxazolidines with nitroacetic acid to give II,
and INOC or ISOC to give I.
Gen er a l P r oced u r e for INOC. A 250 mL round-bottom
flask equipped with a magnetic stir bar was charged with
nitroether, dry benzene, 1,4-phenylene diisocyanate (3 equiv),
and a catalytic amount of triethylamine (3 drops). The result-
ing solution was stirred under a blanket of nitrogen at room
temperature for 3 d at which time additional 1,4-phenylene
diisocyanate (1 equiv) was added. The mixture was then
refluxed for 1 d, quenched with water (10 mL), and stirred at
70 °C for 3 h. Polymeric phenylurea was removed by filtration
and washed with diethyl ether. The combined organic washes
were washed with brine, dried (MgSO4), filtered, and concen-
trated by rotatory evaporation. Column chromatography af-
forded the desired isoxazoline.
Exp er im en ta l Section
Gen er a l Exp er im en ta l. Unless otherwise noted, starting
materials were obtained from commercial suppliers and used
(18) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 14, 2923.
(19) Duffy, J . Ph.D. Thesis, University of California, Davis, 1993.
(17) Garanti., L.; Zecchi, G. J . Heterocycl. Chem. 1980, 17, 609.

502 J . Org. Chem., Vol. 65, No. 2, 2000
Huang et al.
Gen er a l P r oced u r e for ISOC. A 100 mL round-bottom
flask equipped with a magnetic stir bar was charged with
nitroether, dry benzene, chlorotrimethylsilane (3 equiv), and
triethylamine (3 equiv). The resulting solution was stirred
under a blanket of nitrogen at room temperature for 2 d at
which time 1 N aq HCl was added. Rapid stirring was
continued for an additional 1 h at room temperature at which
time the layers were separated, and the aqueous layer was
extracted with diethyl ether (3 × 20 mL). The combined
organic washes were washed with brine, dried (MgSO4),
filtered, concentrated by rotatory evaporation, and purified by
column chromatography.
6, 1H), 3.62 (t, J ) 9 Hz, 1H), 3.98 (d, J ) 9 Hz, 1H), 4.64 (t,
J ) 9 Hz, 1H), 4.66 (s, 1H), 4.99 (dd, J ) 17, 1 Hz, 1H), 5.07
(s, 1H), 5.13 (dd, J ) 10, 1 Hz, 1H), 5.60 (m, 1H), 7.33 (m,
5H); 13C NMR δ 34.9, 51.7, 72.5, 77.0, 78.2, 86.5, 120.6, 125.9,
127.3, 127.8, 131.9, 137.6; IR (thin film) 3214, 3032, 2929,
2856, 1063 cm-1. Anal. Calcd for C14H17NO2: C, 72.70; H, 7.41;
N, 6.06. Found: C, 72.52; H, 7.39; N, 5.84.
6a -Allyl-3a ,6a -cis-3,6-d ip h en yl-3,3a -tr a n s-3a ,6-tr a n s-
3,3a -d ih yd r o-1H,4H,6H-fu r o[3,4-c]isoxa zole (14). The pro-
cedure described for the preparation of 13 was employed with
the following reagents and quantities: isoxazoline 11c (2.5 g,
9.50 mmol), dry toluene (100 mL), boron triflouride etherate
(3.60 mL, 29.27 mmol), and allylmagnesium bromide (1 M in
diethyl ether; 30 mL, 30 mmol). Column chromatography
(hexane/ethyl acetate 8:1) afforded 14 as a colorless oil (2.3 g,
7.60 mmol, 80%): Rf ) 0.30; 1H NMR δ 1.58 (dd, J ) 15, 9 Hz,
1H), 1.99 (dd, J ) 15, 6 Hz, 1H), 3.30 (t, J ) 8 Hz, 1H), 3.74
(t, J ) 8 Hz, 1H), 4.67 (m, 3H), 4.85 (s, 1H), 5.01 (m, 1H), 5.17
(s, 1H), 5.49 (m, 1H), 7.33, (m, 10H); 13C NMR δ 35.0, 58.2,
72.9, 79.4, 86.1, 88.4, 119.5, 125.3, 126.0, 127.4, 127.5, 127.9,
128.8, 131.8, 137.5, 139.2; IR (thin film) 3086, 3029, 2847,
6-P h en yl-3a ,6-tr a n s-3,3a -d ih yd r o-4H ,6H -fu r o[3,4-c]-
isoxa zole (10c).20 The INOC procedure described above was
employed with the following reagents and quantities: nitro-
ether 4 (3 g, 15 mmol), dry benzene (100 mL), 1,4-phenylene
diisocyanate (5.3 g, 33.10 mmol), catalytic amount of triethy-
lamine (3 drop), and additional 1,4-phenylene diisocyanate (2.4
g, 15 mmol T0 + 24 h). Column chromatography (hexane/ethyl
acetate 3:1) afforded 10c as a white solid (1.5 g, 7.98 mmol,
53%): Rf ) 0.31, mp 77-78 °C; 1H NMR δ 3.74 (m, 1 H), 4.00
(m, 1H), 4.17 (m, 1 H), 4.36 (m, 1 H), 4.52 (m, 1 H), 5.55 (s, 1
H), 7.35 (m, 5 H); 13C NMR δ 54.6, 69.9, 73.1, 73.6, 125.8, 128.4,
128.7, 137.8, 170.0; IR (CH2Cl2) 3006, 2914, 2862, 1458, 1009
1065, cm-1
.
7a -Allyl-3a ,7a -cis-7-p h en yl-3a ,7-cis-3,3a ,4,5-tetr a h yd r o-
1H,7H-p yr a n o[3,4-c]isoxa zole (15). The procedure described
for the preparation of 13 was employed with the following
reagents and quantities: isoxazoline 12t (2.4 g, 11.66 mmol),
dry toluene (100 mL), boron triflouride etherate (4.40 mL,
38.28 mmol), and allylmagnesium bromide (1 M in diethyl
ether; 35 mL, 35 mmol). Column chromatography (hexane/
ethyl acetate 2:1) afforded 15 as a colorless oil (2.3 g, 9.33
mmol, 80%): Rf ) 0.30; 1H NMR δ 1.84 (m, 2H), 2.49 (m, 2H),
2.78 (m, 1H), 3.69 (m, 2H), 4.09 (m, 2H), 4.66 (s, 1H), 5.13 (m,
2H), 5.90 (m, 2H), 7.31 (m, 5H); 13C NMR δ 27.0, 38.6, 41.9,
66.1, 66.9, 74.1, 79.7, 119.4, 127.8, 128.2, 133.0, 137.4; IR (thin
cm-1
.
3,6-Diph en yl-3,3a-tr a n s-3a,6-tr a n s-3,3a-dih ydr o-4H,6H-
fu r o[3,4-c]isoxa zole (11c).19 The ISOC procedure described
above was employed with the following reagents and quanti-
ties: nitroether 5 (2.7 g, 9.51 mmol), dry benzene (50 mL),
chlorotrimethylsilane (4.20 mL, 33.09 mmol), and triethyl-
amine (4.60 mL, 33 mmol). The resulting solution was stirred
under a blanket of nitrogen at room temperature for 2 d at
which time 1 N HCl (32 mL) was added. Column chromatog-
raphy (hexane/ethyl acetate 5:1) afforded 11c as a pale yellow
film) 3219, 3032, 2931, 2873, 1097 cm-1. Anal. Calcd for C15H19
-
1
oil (2.1 g, 7.91 mmol, 82%): Rf ) 0.30; H NMR δ 3.99 (dd, J
NO2: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.08; H, 7.82; N,
5.64.
) 9, 8 Hz, 1H); 4.22 (m, 1H), 4.43 (t, J ) 8, 1H), 5.52 (d, J )
12 Hz, 1H), 5.64 (s, 1H), 7.38, (m, 10H); 13C NMR δ 60.3, 69.4,
73.2, 89.0, 125.6, 126.6, 128.4, 128.7, 136.8, 137.3, 170.9; IR
6a -Allyl-3a ,6a -cis-1-(r-n itr oa cetyl)-6-p h en yl-3a ,6-tr a n s-
3,3a -d ih yd r o-4H,6H-fu r o[3,4-c]isoxa zole (16). A 500 mL
Erlenmeyer flask equipped with a magnetic stir bar was
charged with potassium hydroxide (226 g, 4.02 mol) and water
(300 mL). The solution was cooled to room temperature,
nitromethane (60 g, 983 mmol) was added dropwise over 1.5
h, and the solution was refluxed until crystals appeared. Upon
cooling to room temperature, the light yellow crystals were
collected by filtration and either used immediately or stored
in the refrigerator to prevent decomposition.
To the nitroacetic acid dipotassium salt (3 g, 71.37 mol) was
added ice cold water (10 mL), and the solution was then cooled
to -8 °C (dry ice/ethanol). Tartaric acid (21.43 g, 142.8 mmol
dissolved in 40 mL of water) was added over a period of 20
min at which time the mixture was filtered and the mother
liquor was extracted with ice cold diethyl ether (5 × 30 mL).
The combined organic washes were dried (Na2SO4) and
concentrated by rotatory evaporation (at room temperature)
to afford a yellow oil which was dissolved in chloroform (1 mL),
concentrated again, and dried under high vacuum at 0 °C for
6 h to afford pale yellow crystals (67-70% by mass) which was
used immediately without purification.
(thin film) 3062, 3032, 2873, 1456, 1022 cm-1
.
7-P h en yl-3a ,7-cis-3,3a ,4,5-tetr a h yd r o-7H-p yr a n [3,4-c]-
isoxa zole (12t).19 The INOC procedure described above was
employed with the following reagents and quantities: nitro-
ether 6 (3.6 g, 16.36 mmol), dry benzene (100 mL), 1,4-
phenylene diisocyanate (7.9 g, 49.08 mmol), catalytic amount
of triethylamine (3 drop), and additional 1,4-phenylene diiso-
cyanate (2.6 g, 16.36 mmol T0 + 24 h). Column chromatogra-
phy (hexane/ethyl acetate 3:1) afforded 12t as a white solid
1
[2.6 g, 12.59 mmol, 77%; Rf ) 0.25; mp 88-89 °C; H NMR δ
1.91 (m, 1H), 2.21 (m, 1H), 3.51 (m, 1H), 3.73 (m, 1H), 3.83
(dd, J ) 12, 8 Hz, 1H), 4.21 (m, 1H), 4.64 (dd, J ) 10, 8 Hz,
1H), 5.11 (s, 1H), 7.39 (m, 5H); 13C NMR δ 33.0, 46.6, 66.5,
73.8, 77.2, 127.6, 128.1, 128.4, 136.7, 158.2; IR (thin film) 3032,
2927, 2856, 1454, 1070 cm-1].
6a -Allyl-3a ,6a -cis-6-p h e n yl-3a ,6-tr a n s-3,3a -d ih yd r o-
1H,4H,6H-fu r o[3,4-c]isoxa zole (13). A toluene (100 mL)
solution of 10c (1.7 g, 8.83 mmol) was cooled to -78 °C under
a blanket of nitrogen, and boron triflouride etherate (3.40 mL,
27.6 mmol) was added over 10 min via syringe pump. Upon
complete addition, the solution was stirred for an additional
30 min at which time allylmagnesium bromide (1 M in diethyl
ether; 28.0 mL, 28.0 mmol) was added at -78 °C over 20 min
via syringe pump. The resulting mixture was stirred for 24 h
with gradual warming to room temperature. The reaction was
quenched by a slow addition of water (5 mL), and the aqueous
layer was separated and extracted with diethyl ether (3 × 50
mL). The combined organic extracts were washed with brine,
dried (MgSO4), filtered, and concentrated by rotatory evapora-
tion. Column chromatography (hexane/ethyl acetate 3:1) af-
forded isoxazolidine 13 as a colorless oil (1.8 g, 7.76 mmol,
A 250 mL round-bottom flask equipped with a magnetic stir
bar was charged with 13 (620 mg, 2.69 mmol) and dry cold
THF (100 mL). This solution was cooled to 0 °C, and DCC (700
mg, 3.39 mmol) and freshly prepared nitroacetic acid (340 mg,
3.24 mmol) were added. After 24 h at 0 °C, additional DCC
(1.2 g, 5.96 mmol) and nitroacetic acid (614 mg, 5.84 mmol)
were added and stirring was continued for an additional 24 h
from 0 °C to room temperature. The mixture was then filtered
to remove DCU. Column chromatography (hexane/ethyl ace-
tate 3:2) and subsequent recrystallization with hot ethyl
acetate/hexane afforded 16 as colorless crystals (730 mg, 2.30
1
88%): Rf ) 0.32; H NMR δ 1.64 (dd, J ) 15, 9 Hz, 1H), 2.07
1
mmol, 86%): Rf ) 0.25, mp 124-125 °C; H NMR δ 1.81 (dd,
(dd, J ) 15, 6, 1H), 3.01 (q, J ) 14, 8 Hz, 1H), 3.53 (dd, J ) 9,
J ) 15, 8 Hz, 1H), 2.80 (dd, J ) 15, 6 Hz, 1H), 3.24 (m, 1H),
3.75 (t, J ) 9 Hz, 1H), 3.90 (d, J ) 8 Hz, 1H), 4.00 (dd, J ) 9,
5 Hz, 1 H), 4.48 (t, J ) 8 Hz, 1H), 5.06 (d, J ) 17 Hz, 1H),
5.07 (s, 1 H), 5.12 (d, J ) 10 Hz, 1H), 5.25 (d, J ) 14 Hz, 1H),
(20) Hassner, A.; Murthy, K. S. K.; Padwa, A.; Chiacchio, U.; Dean,
D. C.; Schoffstall, A. M. J . Org. Chem. 1989, 54, 5277.

Synthesis of Bis-Isoxazolo Substituted Piperidinones
J . Org. Chem., Vol. 65, No. 2, 2000 503
5.33 (d, J ) 14 Hz, 1H), 5.63 (m, 1 H), 7.36 (m, 5 H); 13C NMR
δ 36.1, 54.2, 70.4, 71.6, 78.1, 82.8, 120.0, 127.1, 127.9, 128.0,
131.8, 136.5, 155.0; IR (CH2Cl2) 2360, 2336, 1671, 1559, 1375,
1066 cm-1. Anal. Calcd for C16H18N2O5: C, 60.37; H, 5.70; N,
8.80. Found: C, 60.12; H, 5.67; N, 8.70.
and quantities: nitroester 16 (567 mg, 1.78 mmol) dry benzene
(15 mL), 1,4-phenylene diisocyanate (600 mg, 3.75 mmol), a
catalytic amount of triethylamine (3 drops), and additional 1,4-
phenylene diisocyanate (T0 + 3 d; additional diisocyanate was
added; 285 mg, 1.78 mmol). Afterward, the mixture was
filtered and concentrated by rotatory evaporator. Column
chromatography (ethyl acetate) afforded 19 as a white solid
(348 mg, 1.16 mmol 65%): Rf ) 0.35; mp 265-266 °C; 1H NMR
δ 1.81 (dd, J ) 13, 13 Hz, 1H), 2.29 (m, 1H), 2.59 (dd, J ) 13,
5 Hz, 1H), 3.09 (m, 1H), 3.69 (dd, J ) 13, 8 Hz, 1H), 3.79 (dd,
J ) 9, 8 Hz, 1H), 4.17 (s, 1H), 4.18 (d, J ) 3 Hz, 1H), 4.25 (dd,
J ) 10, 9 Hz, 1H), 4.53 (t, J ) 9 Hz, 1H), 4.65 (s, 1H), 7.40 (m,
5 H); 13C NMR δ 33.2, 41.8, 56.1, 72.0, 76.0, 78.0, 85.4, 126.7,
128.7, 129.1, 135.3, 152.4, 154.0; IR (CH2Cl2) 2995, 2873, 1701,
1456 cm-1. Anal. Calcd for C16H16N2O4: C, 63.99; H, 5.37; N,
9.33. Found: C, 64.08; H, 5.49; N, 9.35.
6a -Allyl-3a ,6a -cis-1-(r-n it r oa cet yl)-3,6-d ip h en yl-3,3a -
t r a n s-3a ,6-t r a n s-3,3a -d ih yd r o-4H ,6H -fu r o[3,4-c]isox-
a zole (17). The procedure described for the preparation of 16
was employed with the following reagents and quantities:
isoxazolidine 14 (850 mg, 2.77 mmol), dry THF (35 mL), DCC
(900 mg, 4.32 mmol; T0 + 24 h 590 mg, 2.86 mmol), and
nitroacetic acid (420 mg, 3.99 mmol; T0 + 24 h 330 mg, 3.14
mmol). Column chromatography (hexane/methylene chloride
5:1) and subsequent recrystallization with hot ethyl acetate/
hexane afforded 17 as colorless crystals (1.2 g, 3.67 mmol,
90%): Rf ) 0.25; mp 129-130 °C; 1H NMR δ 1.76 (dd, J ) 15,
8 Hz, 1H), 2.87 (dd, J ) 15, 6 Hz, 1H), 3.31 (dd, J ) 9, 5 Hz,
1H), 4.13 (d, J ) 10 Hz, 1H), 4.29 (dd, J ) 10, 5 Hz, 1H), 5.11
(m, 3H), 5.31 (d, J ) 14 Hz, 1H), 5.40 (d, J ) 14 Hz, 1H), 5.69
(s, 1H), 5.72 (m, 1H), 7.40, (m, 10H); 13C NMR δ 36.8, 61.7,
68.5, 76.6, 80.1, 86.8, 87.8, 120.2, 126.8, 127.0, 127.7, 128.1,
129.0, 129.6, 132.6, 134.5, 137.8, 155.1; IR (CH2Cl2) 2850, 2837,
1672, 1560, 1374, 1037 cm-1. Anal. Calcd for C22H22N2O5: C,
66.99; H, 5.62; N, 7.10. Found: C, 66.82; H, 5.62; N, 7.11.
7a -Allyl-3a ,7a -cis-1-(r-n it r oa cet yl)-7-p h en yl-3a ,7-cis-
3,3a ,4,5-tetr a h yd r o-7H-p yr a n o[3,4-c]isoxa zole (18). The
procedure described for the preparation of 16 was employed
with the following reagents and quantities: isoxazolidine 15
(300 mg, 1.22 mmol), dry THF (50 mL), DCC (379 mg, 1.84
mmol; T0 + 24 h, additional DCC was added; 251 mg, 1.22
mmol), and nitroacetic acid (200 mg, 1.90 mmol; T0 + 24 h,
additional nitroacetic acid was added; 128 mg, 1.22 mmol).
Column chromatography (hexane/methylene chloride 3:1) and
subsequent recrystallization with hot ethyl acetate/hexane
afforded 18 as colorless crystals (365 mg, 1.09 mmol, 90%):
1,4-Dip h en yl-1,3a -tr a n s-3a ,4-tr a n s-3a ,10a -tr a n s-3a ,11a -
cis-3,3a-dihydro-1H-furo[3′,4′:3,4]isoxazolidino[3,2-f]-10,10a-
d ih yd r oisoxa zolo[3,4-c]p ip er id in -7-on e (20). The INOC
procedure described above was employed with the following
reagents and quantities: nitroester 17 (275 mg, 0.697 mmol)
dry benzene (10 mL), 1,4-phenylene diisocyanate (400 mg, 2.50
mmol), a catalytic amount of triethylamine (3 drops), and
additional 1,4-phenylene diisocyanate (T0 + 3 d; additional
diisocyanate was added; 112 mg, 0.697 mmol). Afterward, the
mixture was filtered, and concentrated by rotatory evaporator.
Column chromatography (ethyl acetate) afforded 20 as color-
less crystals (178 mg, 0.453 mmol 65%): Rf ) 0.30; mp 231-
232 °C; 1H NMR δ 1.58 (dd, J ) 13, 13 Hz, 1H), 2.18 (m, 1H),
2.57 (dd, J ) 13, 5 Hz, 1H), 3.13 (m, 1H), 3.58 (dd, J ) 13, 8
Hz, 1H), 4.14 (dd, J ) 10, 6 Hz, 1H), 4.23 (dd, J ) 10, 8 Hz,
1H), 4.69 (dd, J ) 9, 9 Hz, 1H), 4.89 (s, 1H), 5.48 (d, J ) 3 Hz,
1H), 7.40 (m, 10H); 13C NMR δ 45.9, 55.0, 75.7, 85.4, 89.5, 90.8,
97.8, 103.2, 138.6, 139.8, 141.9, 142.2, 142.4, 142.5, 142.8,
148.3, 164.4, 165.6; IR (CH2Cl2) 2922, 2884, 1680, 1457 cm-1
.
1
Rf ) 0.33; mp 120-121 °C; H NMR δ 1.88 (m, 1H), 2.11 (m,
Anal. Calcd for C22H20N2O4: C, 70.20; H, 5.36; N, 7.44.
Found: C, 70.32; H, 5.40; N, 7.38.
1H), 2.61 (dd, J ) 14, 9 Hz, 1H), 3.09 (m, 2H), 4.04 (m, 4H),
4.52 (s, 1H), 4.91 (d, J ) 14 Hz, 1H), 5.20 (d, J ) 14 Hz, 1H),
5.24 (m, 2H), 5.72 (m, 1H), 7.32, (s, 5H); 13C NMR δ 21.8, 36.7,
42.9, 62.6, 69.7, 72.2, 80.4, 120.8, 127.3, 128.0, 128.4, 132.0,
137.2, 144.1, 156.5; IR (CH2Cl2) 2873, 2844, 1673, 1549, 1377,
1055 cm-1. Anal. Calcd for C17H20N2O5: C, 61.43; H, 6.06; N,
8.43. Found: C, 61.29; H, 6.05; N, 8.41.
Ack n ow led gm en t. We are grateful to the Novartis
Crop Protection AG and National Science Foundation
for financial support of this research.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H NMR,
13C NMR, and IR spectra for compound 14 . This material is
available free of charge via the Internet at http://pubs.acs.org.
1-P h en yl-1,3a -tr a n s-3a ,10a -tr a n s-3a ,11a -cis-3,3a -d ih y-
d r o-1H -fu r o[3′,4′:3,4]isoxa zolid in o[3,2-f]-10,10a -d ih y-
d r oisoxa zolo[3,4-c]p ip er id in -7-on e (19). The INOC proce-
dure described above was employed with the following reagents
J O991418M