Solid-Phase Synthesis of Isoxazoles and Isoxazolines: En Route to a New Class of Ionophores

Article abstract of DOI:10.1021/jo970712g

Solid-phase organic synthesis (SPOS) was employed in the construction of isoxazole and/or isoxazoline polyheterocyclic systems. The [3 + 2] cycloaddition reactions of nitrile oxides generated from the corresponding primary nitro compounds, with resin-bound alkynes or alkenes were highly efficient both chemically and with regard to purification. A parallel solution-phase synthesis was carried out which compared the synthetic efficiency in both media. SPOS of isoxazole/isoxazoline 11, employing a functionalized polystyrene resin, was found to be more efficient than the solution-phase approach. Three other oligoisoxazoles were prepared with average yields per step being 82, 84, and 89%.

Full text of DOI:10.1021/jo970712g

J . Org. Chem. 1997, 62, 6797-6803
6797
Solid -P h a se Syn th esis of Isoxa zoles a n d Isoxa zolin es: En Rou te to
a New Cla ss of Ion op h or es
Eric J . Kantorowski and Mark J . Kurth*
Department of Chemistry, University of California, Davis, California 95616
Received April 21, 1997X
Solid-phase organic synthesis (SPOS) was employed in the construction of isoxazole and/or
isoxazoline polyheterocyclic systems. The [3 + 2] cycloaddition reactions of nitrile oxides, generated
from the corresponding primary nitro compounds, with resin-bound alkynes or alkenes were highly
efficient both chemically and with regard to purification. A parallel solution-phase synthesis was
carried out which compared the synthetic efficiency in both media. SPOS of isoxazole/isoxazoline
11, employing a functionalized polystyrene resin, was found to be more efficient than the solution-
phase approach. Three other oligoisoxazoles were prepared with average yields per step being 82,
84, and 89%.
In tr od u ction
preparation on solid-support9 has led us to investigate
the preparation of these as polyheterocyclic systems. In
this report we disclose preliminary studies targeting
construction of potentially tunable ionophores which may
find application as polymer-bound or polymer-free ligands.
The impetus for such chelating polymers derives from
the interest in developing methods for ion-specific analysis/
removal of metals from aqueous environments.10
Herein, we report our design of polymers incorporating
repeating isoxazole and/or isoxazoline heterocycles sepa-
rated by a variable spacer group (X, Y, Z). With a
potentially-iterative sequence for the preparation of these
compounds, it seemed tactically efficient to append the
developing chain to a polymer-support. Solid-phase
organic synthesis (SPOS) of heterocycles derived from
1,3-dipole/dipolarophile coupling has been achieved with
high efficiency in both linear syntheses and library
preparation.11 Alcohol-protected 2-nitroethanol seemed
an ideal 1,3-dipole precursor as the latent alcohol could
be used for further chemical elaboration post-cycloaddi-
tion. In this way, the spacer groups between the het-
erocyclic moieties could be easily augmented to incorpo-
rate additional functionality which should lend itself to
fine-tuning the properties of these compounds.
Nitrogen-containing ring systems have been widely
used as ligands in organometallic chemistry and their
role as “tunable” ligands, as well as their application as
cryptands, cannot be overstated.1,2 An important class
of nitrogen-containing heterocycles includes both the
oxazole and oxazoline ring systems. The latter can be
readily prepared by condensation of a carboxylic acid and
an amino alcohol.3 This coupled with the availability of
chiral 1,2-amino alcohols allows access to a host of
asymmetric ligands which have been utilized in asym-
metric catalysis.4
The isoxazole and isoxazoline ring systems have been
less extensively used in ligand design. The construction
of these heterocycles is typically accomplished by [3 + 2]
cycloaddition of a nitrile oxide to an alkyne or alkene,
respectively.5 The 1,3-dipole intermediate is usually
generated in situ from the corresponding primary nitro
compound6 or hydroximoyl chloride.7
Interest in ionophoric compounds8 coupled with our
recent work in the area of isoxazoline and isoxazole
X Abstract published in Advance ACS Abstracts, September 15, 1997.
(1) Izatt, R. M.; Pawlak, K.; Bradshaw, J . S.; Bruening, R. L. Chem.
Rev. 1991, 91, 1721-2085.
(2) (a) Gokel, G. Crown Ethers and Cryptands; The Royal Society
of Chemistry: Cambridge, England, 1991. (b) Zhang, X. X.; Bordunov,
A. V.; Izatt, R. M.; Bradshaw, J . S. NATO ASI Ser., Ser. C 1996, 485
(Physical Supramolecular Chemistry), 413-431. (c) Chand, D. K.;
Ghosh, P.; Shukla, R.; Sengupta, S.; Das, G.; Bandyopadhyay, P.;
Bharadwaj, P. K. Proc. - Indian Acad. Sci., Chem. Sci. 1996, 108, 229-
233. (d) Khopkar, S. M.; Gandhi, M. N. J . Sci. Ind. Res. 1996, 55,
139-155.
Resu lts a n d Discu ssion
The strategy reported here was to affix an alkynyl
alcohol to a polymer support via a benzoyl ester. The
ester linkage was considered to be stable under the
conditions we anticipated utilizing, and the substrate
could then be liberated from the resin by transesterifi-
cation with NaOCH3 in THF. Additionally, we chose to
run a parallel solution-phase synthesis of one targeted
compound where, to mimic the polymer-bound substrate
to an approximate degree, the benzoyl ester was chosen
(3) (a) Meyers, A. I.; Temple, D. L.; Nolen, R. L.; Mihelich, E. D. J .
Org. Chem. 1974, 39, 2778-2783. (b) Wehrmeister, H. L. J . Org.
Chem. 1961, 26, 3821-3824.
(4) (a) Evans, D. A.; J ohnson, J . S. J . Org. Chem. 1997, 62, 786-
787. (b) Nishibayashi, Y.; Segawa, K.; Takada, H.; Ohe, K.; Uemura,
S. Chem. Commun. 1996, 847-848. (c) Nishibayashi, Y.; Segawa, K.;
Ohe, K.; Uemura, S. Organomet. 1995, 14, 5486-5487. (d) Nishiyama,
H.; Yamaguchi, S.; Park, S.-B.; Itoh, K. Tetrahedron: Asymmetry 1993,
4, 143-150.
(5) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410-416. Cara-
mella, P.; Grunanger, P. 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley: New York, 1984.
(6) Mukaiyama, T.; Hoshino, T. J . Am. Chem. Soc. 1960, 82, 5339-
(9) (a) Kurth, M. J .; Randall, L. A. A.; Takenouchi, K. J . Org. Chem.
1996, 61, 8755-8761. (b) Lorsbach, B. A.; Miller, R. B.; Kurth, M. J .
J . Org. Chem. 1996, 61, 8716-8717.
5342.
(7) Christl, M.; Huisgen, R. Chem. Ber. 1973, 106, 3345-3367.
(8) For example, see: (a) Shih, J . S. J . Chin. Chem. Soc. (Taipei)
1994, 41, 309-314. (b) Moss, R. E.; Sutherland, I. O. Anal. Proc.
(London) 1988, 25, 272-274. (c) Schneider, H. J .; Blatter, T.; Eliseev,
A.; Ruediger, V.; Raevsky, O. A. Pure Appl. Chem. 1993, 65, 2329-
2334. (d) Ungaro, R.; Arduini, A.; Casnati, A.; Pochini, A.; Ugozzoli,
F. Pure Appl. Chem. 1996, 68, 1213-1218.
(10) (a) Morishima, Y.; Sato, T; Kamachi, M. Macromolecules 1996,
29, 1633-1637. (b) Saxena, R.; Singh, A. K.; Sambi, S. S. Anal. Chim.
1994, 295, 199-204. (c) Tomida, T.; Inoue, T.; Tsuchiya, K; Masuda,
S. Ind. Eng. Chem. Res. 1994, 33, 904-906.
(11) Kantorowski, E. J .; Kurth, M. J . Mol. Diversity 1997, 2, 207-
216.
S0022-3263(97)00712-3 CCC: $14.00 © 1997 American Chemical Society

6798 J . Org. Chem., Vol. 62, No. 20, 1997
Kantorowski and Kurth
Sch em e 2a
Sch em e 1a
a
Reagents: (a) O2NCH2CH2OTHP, PhNCO, PhH; (b) PPTS,
THF, EtOH, reflux; (c) MsCl, Et3N, CH2Cl2.
with these tethered alkynes to provide isoxazoles 6a and
7a (Scheme 2). Loss of the tCsH stretch (3297 cm-1
for 2 and 3291 cm-1 for 3) in the IR spectrum (KBr)
indicated these reactions were complete after 30 h. When
the same cycloaddition was performed in solution on 5,
the resulting cycloadduct was difficult to isolate due to
the ubiquitous nature of the 1,3-diphenyl urea byproduct.
This urea’s moderate solubility in organic solvents and
low solubility in water made extraction troublesome and
made chromatography difficult for larger reaction scales.
Alternatively, polymer-bound cycloaddition reactions boast
a simplified workup and isolation as this urea is easily
removed with several washings of the polymer beads. A
commonly used justification for employing SPOS is the
ability to overwhelm the substrate with a large excess of
reagent to drive the reaction to completion. This is
generally performed without regard for the large quantity
(usually 5 to 10 equiv) of reagent or reagent byproducts
that necessarily remain as filtration and subsequent
washing of the polymer obviate the need for chromato-
graphic separation of the product. In contrast, addition
of a large reagent excess to the solution-phase approach
severely retards product isolation.
Deprotection of the THP ether (6a , 7a ) was effected
using PPTS in refluxing THF/H2O (14:1).17 No sign of
ester hydrolysis is observed under these conditions.
Alcohols 6b and 7b are easily discernible in their IR
spectra by appearance of a broad OH absorbance at 3426
cm-1. The spectra are also partially simplified between
1250 and 950 cm-1 due to loss of the tetrahydropyranyl
moiety. In an attempt to simplify purification of crude
isoxazole 8a 18 (solution-phase analogue), it was thought
that removal of the THP group might allow for recrys-
tallization or at least generate disparate Rf values
(product vs contaminating diphenyl urea) to expedite
chromatography. However, THP deprotection or, as was
also discovered, removal of the benzoyl group was prob-
lematic when any significant amount of diphenyl urea
was present. Deprotection of the ether proceeded smoothly
when the urea content was less than 10% (determined
by 1H-NMR), by employing Dowex 50W-X8 polymer-
bound acid as the acid catalyst.19 Alcohol 8b was isolated
in 65% overall yield from starting alkyne 5.
a
Reagents: (a) 3-Butyn-1-ol, Et3N, CH2Cl2; (b) 4, Et3N, CH2Cl2;
(c) HCtCCH2Br, NaOH, H2O; (d) PhCOCl, Et3N, CH2Cl2.
to protect the alcohol (i.e., solution-phase 5 vs solid-phase
3). This solution synthesis would serve several pur-
poses: (i) make possible comparisons with the IR spectra
for the corresponding resin-bound material, (ii) make
possible direct comparisons of the 1H- and 13C-NMR
spectra of the liberated material (i.e. ®C6H4CO2R f ROH
and BzOR f ROH),12 and (iii) establish which approach
was more efficient.
Alkynyl esters 2 and 3 were readily prepared from
polymer-bound benzoyl chloride13,14a,b (1) and the corre-
sponding alkynols (Scheme 1). Pyridine was initially
used as solvent, but extended reaction times (8 d at 23
°C or 3 d at 60 °C) were required. Methylene chloride
proved to be superior in these reactions as the esterifi-
cation is complete after 10-12 h at ambient temperature.
Thus, 3-butynol was added to 1 (swollen in CH2Cl2) along
with triethylamine to yield 2.15 Alkyne 3 was prepared
in a similar manner using alkynol 4 which is readily
accessible by propargylation of 3-hydroxybenzyl alcohol
in aqueous NaOH. The progress of these reactions can
be followed by IR spectroscopy, wherein the disappear-
ance of the acid chloride carbonyl stretch at 1760 cm-1
is accompanied by appearance of an ester carbonyl
stretch at 1720 cm-1
.
Polymer-bound alkynes 2 and 3 were reacted with the
tetrahydropyranyl ether of 2-nitroethanol16 in refluxing
benzene in the presence of PhNCO along with a catalytic
amount of Et3N. The intermediate nitrile oxide
(THPOCH2CtN+O-) underwent [3 + 2] cycloaddition
(12) The resin is represented by the symbol ® in the text or as a
ball in the schemes.
(13) (a) Fyles, T. M.; Leznoff, C. C. Can. J . Chem. 1976, 54, 935-
942. (b) Fyles, T. M.; Leznoff, C. C.; Weatherson, J . Can. J . Chem.
1978, 56, 1031-1041.
(14) (a) The solid support used was a 2% divinyl benzene cross-
linked/polystyrene copolymer which was lithiated, exposed to CO2, and
acidified. Two batches of this polymer were made, and their loading
capacities were determined by titration. The polymer indicated for
compound 2 (and all subsequent compounds) was determined to have
a loading of 2.01 mmol/g; compound 3 (and all subsequent compounds)
had a loading of 1.50 mmol/g. This material was refluxed in SOCl2 to
generate the benzoyl chloride. See reference 9a for a detailed prepara-
tion. (b) After determination of initial loading, the loading for each
polymer was assumed to be constant throughout the synthesis.
(15) A typical workup of the polymer reactions consisted of washing
with THF, THF/H2O (1:1), CH2Cl2, THF, and Et2O (ea. 2 × 10 mL)
and then overnight drying in a vacuum desiccator.
(17) PPTS or TsOH in refluxing THF/EtOH are ineffective even after
40 h.
(18) A further point of consternation was that compound 8a had
near-identical Rf values with diphenyl urea for all solvent systems
investigated.
(16) Kozikowski, A. P.; Adamczyk, M. J . Org. Chem. 1983, 48, 366-
372.
(19) Beier, R.; Mundy, B. P. Synth. Commum. 1979, 9, 271-273.

Solid-Phase Synthesis of Isoxazoles and Isoxazolines
J . Org. Chem., Vol. 62, No. 20, 1997 6799
Sch em e 3a
a
Reagents: (a) BnHNCH2CHdCH2, THF, K2CO3; (b) Ph3P,
NBS, CH2Cl2; (c) PhCH2NO2, PhNCO, PhH; (d) NaOCH3, THF.
F igu r e 1. Progress of mesylation of 6b by FTIR analysis. The
developing absorbance at 1369 cm-1 (SdO) was compared
Ta ble 1. Ch em ica l Sh ift Va lu es for In ter m ed ia tes in th e
Solu tion -P h a se P r ep a r a tion of Ter tia r y Am in e 9
against a static peak at 1176 cm-1
.
With the alcohol unmasked, the substrate was now
poised for elaboration to a number of heteroatom-based
isoxazole spacers. Our choice was to explore the use of
interspersing nitrogen which could (i) offer the ability to
make branched isoxazole/isoxazoline oligomers and (ii)
in itself act as a chelating locus. Hence, preparation of
the mesylate followed by N-alkylation of a primary or
secondary amine was the evolution planned for these
compounds.20 Solid-phase alcohol mesylation (6b f 6c)
proved to be slow at ambient temperature, and refluxing
the reaction (CH2Cl2) had a negligible effect on the rate.
The progress of the reaction was followed by comparing
the relative intensities of IR absorbances at 1369 cm-1
(SdO stretch) against what was considered a static
absorbance at 1176 cm-1 (Figure 1). The reaction was
deemed complete after 40 h.
X
δ H1 (ppm)
δ H3 (ppm)
δ C1 (ppm)
OH
Cl
Br
4.74
4.56
4.39
4.27
6.40
6.45
6.44
6.39
6.51
6.35
-
35.41
20.31
-10.93
-
I
OMs
5.27
NBn(C3H5)
3.59 or 3.65a
-
a
One singlet is from the methylene on the benzyl group; actual
assignment not made.
was ineffective in a variety of solvents.22 In solution,
sodium iodide with 8d in refluxing DMF provided only a
small amount of product after 2 d. Thus, the solution-
phase iodide 8e was prepared by Finkelstein conversion
which was rapid and quantitative. This material smoothly
alkylated benzylallyl amine in THF with K2CO3 to afford
the desired tertiary amine 9 in excellent yield (Scheme
3). In a separate preparation, starting alcohol 8b was
converted to the bromide 8f using NBS and triph-
enylphosphine in CH2Cl2.23 This bromide similarly pro-
vided amine 9 after approximately twice the reaction
time required for the iodide. The chemical shifts of the
methylene protons (CH2X) and the isoxazole ring proton
were useful in tracking these transformations (Table 1).
The isoxazoline ring was appended to 9 under standard
conditions which afforded 10. Removal of the benzoyl
ester (NaOCH3, THF) gave 11 in 35% overall yield
starting from alkynol 4.
The solution-phase analogue of the mesylation reaction
(8b f 8c) revealed a limitation in analyzing the extent
of the polymer-bound reaction by IR spectroscopy. It was
found that mesylate 8c was the minor product; the major
product isolated in this solution reaction was chloride 8d
1
as was indicated by a 16-proton integration in the H-
NMR spectrum and a positive Beilstein test. The chloride/
1
mesylate product ratio was 3.8:1 (as determined by H-
NMR analysis of the crude product mixture). Liberation
of the crude mesylation product from the resin by
transesterification using NaOCH3 in THF provided meth-
yl ether 21 which presumably can arise from either the
mesylate or the chloride. The Cl/OMs product ratio from
the solid-phase reaction was therefore not easily ascer-
tained.
Surprisingly, the mesylated/chlorinated polymers (6c/
6d and 7c/7d ) displayed a higher reactivity toward amine
alkylation (Scheme 4). When reacted in THF with either
a primary or secondary amine containing an N-propargyl
group in THF, evidence for a tC-H stretch was seen in
the FTIR spectrum within 1 h. This absorbance in-
creased to a maximum within 12-14 h. On the basis of
these results, we speculate that either (i) the mesylate
Not surprisingly, chloride 8d proved to be a poor
alkylating agent for N-benzyl-N-allylamine or N-allyla-
niline.21 Use of catalytic amounts tetrabutylammonium
iodide (TBAI) to generate the more reactive iodide in situ
(21) (a) Clinton, R. O.; Salvador, U. J .; Laskowski, S. C. J . Am.
Chem. Soc. 1949, 71, 3366-3370. (b) Gibson, M. S. The Introduction
of the Amino Group. In The Chemistry of the Amino Group; Patai, P.,
Ed.; Wiley: New York, 1968; pp 45-52. (c) Spialter, L.; Pappalardo,
J . A. The Acyclic Aliphatic Tertiary Amines; Macmillan Co.: New York,
1985.
(22) THF, EtOH, PhH, and PhMe were ineffective solvents for this
reaction.
(23) Torrado, A; Imperiali, B. J . Org. Chem. 1996, 61, 8940-48.
(20) Deprotonation/propargylation of the alcohol which could lead
to ether-linked heterocycles tended to cause autocleavage of the ester
from the resin. Some initial attempts to incorporate sulfide-linked
heterocycles by mesylation followed by alkylation of allylmercaptan
led to cleavage of the ester linkage.

6800 J . Org. Chem., Vol. 62, No. 20, 1997
Kantorowski and Kurth
Sch em e 6a
Sch em e 4a
a
Reagents: (a) H2NCH2CtCH, THF; (b) HN(CH2CtCH)2,
THF; (c) CH3CH2COCl, Et3N, CH2Cl2.
Sch em e 5a
a
Reagents: (a) H2NCH2CtCH, THF; (b) BnNHCH2CHdCH2,
THF; (c) PhCH2COCl, Et3N, CH2Cl2.
a
Reagents: (a) PhCH2NO2, PhNCO; (b) NaOCH3, THF; (c)
is the major product for the polymer-supported reaction
or (ii) the microenvironment of the resin provides some
additional stabilization for the alkylation which is not
realized in solution. We side with the former explanation
on the grounds that (i) the SN2 alkylation is Type II and
a toluene-like environment does not assist in this regard,
(ii) although generally not intense, the C-Cl stretch in
IR is not evident, and (iii) intense absorbances typical of
the SdO group are present in the reaction of 6b or 7b
with MsCl/Et3N. Alkylation of N-benzyl-N-allylamine
with 7c/7d was difficult to monitor as the CdC offered
no strong absorbances with which to track the reaction
(Scheme 5). Hence, this reaction was run for 14 h and
presumed to be complete. In the case of secondary amine
products 12a and 14a , the amide was prepared using the
corresponding acid chloride in CH2Cl2 with Et3N. Amide
formation was rapid (7 h) as was evidenced by the
appearance of absorbances at 1663 cm-1 and 1655 cm-1
for compounds 12b and 14b, respectively.
EtNO2, PhNCO; (d) n-PrNO2, PhNCO.
F igu r e 2. 1H-NMR spectrum (1 to 7 ppm) of 16.
These four alkene or alkyne polymer-bound isoxazoles
were then subjected to a second 1,3-dipolar cycloaddition
with a “chain-terminating” nitrile oxide (derived from
RCH2NO2) and subsequently cleaved from the resin with
NaOCH3 in THF (Scheme 6). In each case, the overall
yields were good to excellent. Diisoxazoles 16 and 18,
each requiring eight synthetic steps beginning from resin
1, were prepared in 39.4% (89.0% average yield per step)
and 20.1% (81.8% average yield per step), respectively.
Triisoxazole 17 was obtained in 30.3% overall yield (7
steps, 84.3% average yield) from resin 1. Figure 2 shows
the 1H-NMR spectrum of diisoxazole 16 which, due to the
possibility of two amide rotomers, displays two sets of
resonance signals. The two rotomers are present in a
ratio of 43:57.
At several stages in solid-phase synthesis of 11 (from
3), we chose to liberate the polymer-bound products and
compare the efficiency against the solution-phase chem-
istry (5 f 11). In these comparisons, synthetic efficien-
cies were based on the starting alkynol 4 (Table 2). The
solution-phase approach delivered 11 in 35% overall yield
(seven steps) via the bromide intermediate 8f. When the
route incorporating iodide 8e was used, a 36% yield was
realized (eight steps). Application of SPOS to construct-
ing 11 resulted in an overall yield of 43% (seven steps,
88.6% average yield per step). It should be noted that
Ta ble 2. Com p a r ison Betw een Solu tion -P h a se a n d
Solid -P h a se Efficien cy
R
yield (%)a
cmpd polym soln steps
no. of
®
Ph
8a
R′
OTHP
R′′
OTHP
7a
7c/7d 8c/8d OMs/Cl
20
21
22
85
54
43
66
48
40
41
35
36
3
5
OCH3
15
9
N(Bn)(allyl) N(Bn)(allyl)
6b
7c
7b
8c
19
10
N(Bn)(isox) N(Bn)(isox)
11
43
a
Yields were calculated with the esterification step (i.e. 1 f 3
b
or benzoylation of 4) being the first step. This is via bromide 8f.
c This is via iodide 8e.
in the case of liberation of alcohols 22 and 11 that the
yield remains the same (i.e. 43%). This does not neces-
sarily imply that the [3 + 2] cycloaddition which gener-
ates the polymer-bound isoxazoline 19 is quantitative,

Solid-Phase Synthesis of Isoxazoles and Isoxazolines
J . Org. Chem., Vol. 62, No. 20, 1997 6801
by FTIR to determine the progress of the reaction. When the
reaction was judged complete, the polymer was filtered and
subsequently washed with THF, THF/H2O, CH2Cl2, THF,
Et2O. The polymer was dried in a vacuum desiccator over-
but rather that liberation of the alcohol (NaOCH3/THF)
may have varying degrees of efficiency. On the assump-
tion that the transesterification step was efficient, how-
ever, then it may be reasonable to project that the
isoxazoline formation on the polymer-bound alkene was
more efficient than the solution-phase version (i.e. 9 f
10 vs 15 f 19). We believe the solid support accelerated
and improved the cycloaddition reactions and avoided
chloride formation in the mesylation step.
night. 6a : FTIR (KBr) 1718, 1118 cm-1
1718, 1114 cm-1
. 7a : FTIR (KBr)
.
P olym er -Bou n d Isoxa zole/Alcoh ol 6b. Pyridinium p-
toluenesulfonate (0.84 g, 3.36 mmol) was added to polymer-
bound alkyne 6a (2.65 g, 2.01 mmol/g14b) swollen in THF/H2O
(325 mL, 14:1 THF:H2O). After 12 h the reaction was filtered,
washed in the usual manner and dried in a vacuum desiccator.
6b: FTIR (KBr) 3426, 1720 cm-1
.
Exp er im en ta l Section
P olym er -Bou n d Isoxa zole/Alcoh ol 7b. In similar fash-
ion to 2 f 6b, 3 delivers 7b: FTIR (KBr) 3426, 1716 cm-1
.
Gen er al P r ocedu r es. Polystyrene/2%-divinylbenzene (200-
400 mesh) was purchased from Acros Organics and used as
received. Solvents were purified as follows: tetrahydrofuran
(THF) was distilled from sodium/benzophenone ketyl; meth-
ylene chloride (CH2Cl2) was distilled from CaH2; benzene was
distilled from potassium. All reactions, unless otherwise
stated, were conducted under an inert atmosphere (N2 or Ar).
Infrared spectra were determined on a Galaxy 3000 Series
Mattson FTIR. 1H and 13C NMR spectra were measured in
CDCl3 at 300 and 75 MHz, respectively, and chemical shifts
are reported in ppm downfield from internal tetramethylsilane.
Thin layer chromatography (TLC) was performed on silica gel
plates, and components were visualized by UV light, iodine,
or by heating the plates after treatment with a phosphomo-
lybdic acid reagent (1:1 in EtOH). CC, RC, and PC refer to
column, radial, and planar chromatography on silica gel,
respectively. For CC and RC the eluent indicated refers to
the starting mixture of stepwise elution. Elemental analyses
were performed at the MidWest Microlab, Indianapolis, IN.
Gen er a l P r oced u r e for An a lysis of P olym er Rea ction
P r ogr ession /Wor k u p s. A small sample (10 mg) of polymer
was collected, filtered, and washed with THF, THF/H2O (1:1),
CH2Cl2, THF, Et2O (2 × 1 mL each). FTIR spectroscopy was
used to analyze the extent of the reaction (KBr). When a
reaction was judged complete, it was filtered and washed as
described above. The polymer was then dried in a vacuum
desiccator overnight.
P olym er -Bou n d Mesyla te/Ch lor id e 6c/6d . To a 0 °C
suspension of polymer-bound alcohol 6b (1.79 g, 2.01 mmol/g)
in CH2Cl2 (175 mL) were added methanesulfonyl chloride (1.35
mL, 17.44 mmol) and triethylamine (2.68 mL, 19.23 mmol).
The cold bath was removed, and the reaction was stirred at
room temperature for 40 h. The reaction was filtered, washed
in the usual manner and dried in a vacuum desiccator. 6c/
6d : FTIR (KBr) 1719, 1369 cm-1
.
P olym er -Bou n d Mesyla te/Ch lor id e 7c/7d . In similar
fashion to 6b f 6c/6d , 7b delivers 7c/7d : FTIR (KBr) 1716,
1371 cm-1
.
P olym er -Bou n d Am in e 12a . To polymer-bound mesylate/
chloride 6c/6d (0.83 g, 2.01 mmol/g) in THF (40 mL) was added
propargylamine (1.10 mL, 16.01 mmol). After stirring at room
temperature for 14 h, the reaction was filtered, washed in the
usual manner, and dried in a vacuum desiccator. FTIR (KBr)
3292, 1717 cm-1
.
P olym er -Bou n d Am in e 13. In similar fashion to 6c/6d
f 12a , 6c/6d with dipropargylamine delivers 13: FTIR (KBr)
3296, 1718 cm-1
.
P olym er -Bou n d Am in e 14a . In similar fashion to 6c/6d
f 12a , 7c/7d with propargylamine delivers 14a : FTIR (KBr)
3295, 1717 cm-1
.
P olym er -Bou n d Am in e 15. In similar fashion to 6c/6d
f 12a , 7c/7d with N-benzyl-N-allylamine delivers 15: FTIR
(KBr) 1717 cm-1
.
P olym er -Bou n d Am id e 12b. To a 0 °C suspension of 12a
(0.27 g, 2.01 mmol/g) in CH2Cl2 (25 mL) were added propionyl
chloride (0.24 mL, 2.76 mmol) and triethylamine (0.40 mL,
2.86 mmol). After stirring 7 h at room temperature, the
reaction mixture was filtered, washed in the usual manner,
and dried in a vacuum desiccator. FTIR (KBr) 1720, 1663
P olym er -Bou n d 3-Bu tyn yl Ben zoa te 2. 3-Butyn-1-ol
(5.8 mL, 76.6 mmol) was added to polymer-bound benzoyl
chloride9a (5.2 g, 2.01 mmol/g) which was swollen in CH2Cl2
(150 mL). Triethylamine (2.7 mL, 19.4 mmol) was added, and
the reaction was stirred until the IR indicated the reaction
was complete (10-12 h). The polymer was filtered, washed,
and dried overnight in a vacuum desiccator. FTIR (KBr) 3297
cm-1
.
P olym er -Bou n d Am id e 14b. In similar fashion to 12a
f 12b, 14a with phenylacetyl chloride delivers 14b: FTIR
(tCsH), 1720 (CdO) cm-1
P olym er -Bou n d Ben zoa te 3. Prepared by the same
method as 2. FTIR (KBr) 3291 (tCsH), 1718 (CdO) cm-1
.
(KBr) 1718, 1655 cm-1
.
.
3-(2-P r op yn yloxy)ben zen em eth yl Ben zoa te (5). To a
0 °C solution of 4 (8.2 g, 50.6 mmol) and benzoyl chloride (7.8
g, 55.5 mmol) in CH2Cl2 (100 mL) were added Et3N (7.73 g,
76.4 mmol) and DMAP (0.31 g, 2.54 mmol). The reaction was
stirred for 1.5 h at 0 °C and then poured into crushed ice (150
g). When the ice had melted, the organic layer was removed
and the aqueous layer extracted with CH2Cl2 (3 × 50 mL). The
combined organics were washed with water and brine (2 ×
150 mL each), dried (Na2SO4), filtered, and rotoevaporated.
CC (10% EtOAc in hexanes) provided 12.5 g of the ester (93%).
3-(2-P r op yn yloxy)ben zen em eth a n ol (4).24 3-Hydroxy-
benzyl alcohol (8.67 g, 70 mmol) was added to aqueous NaOH
(150 mL, 1.5 M) producing a homogeneous orange solution.
Propargyl bromide (11.0 mL, 74 mmol) was added, and the
reaction was stirred for 24 h. The biphasic reaction was
extracted with Et2O (3 × 50 mL), and the combined organics
were washed with 1.5 M NaOH (2 × 50 mL) and brine (2 × 75
mL) and dried (MgSO4). Removal of solvent provided an
orange oil which, after passing through a short silica column,
afforded alkynol 4 as a colorless liquid (10.77 g, 95%). FTIR
FTIR (thin film) 3288, 2121, 1720 cm-1
1H, J ) 2.5 Hz), 4.70 (d, 2H, J ) 2.5 Hz), 5.34 (s, 2H), 6.90-
8.25 (m, 9H).
.
1H NMR δ 2.51 (t,
(thin film) 3356, 3289, 2121 cm-1 1H NMR δ 2.51 (t, 1H, J )
.
2.4 Hz), 2.72 (br s, 1H), 4.60 (d, 2H, J ) 4.4 Hz), 4.64 (d, 2H,
J ) 2.4 Hz), 6.84-6.95 (m, 3H), 7.22 (m, 1H).
Isoxa zole 8a . Alkyne 5 (7.11 g, 26.7 mmol), tetrahydro-
pyranyl-2-nitroethanol (5.19 g, 29.6 mmol), and PhNCO (7.0
mL, 64.4 mmol) in PhH (150 mL) were treated with a catalytic
amount of Et3N (5-10 drops from a pipette). After 15 min a
precipitate formed. The reaction was stirred at rt for 12 h
and then at reflux for 6 h. The reaction was filtered, washed
with benzene, and concentrated. The resulting red oil was
purified by CC (15% EtOAc in hexanes) to afford 8a contami-
nated with diphenyl urea (73%, yield determined by 1H NMR).
This material was used without further purification. 1H NMR
δ 1.50-1.86 (m, 6H), 3.54 (m, 1H), 3.86 (m, 1H), 4.61 (d, 1H,
J ) 12.9 Hz),4.72 (t, 1H, J ) 3.2 Hz), 4.77 (d, 1H, J ) 12.9
Hz), 5.16 (s, 2H), 5.34 (s, 2H), 6.42 (s, 1H), 6.91-8.09 (m, 9H).
Gen er a l P r oced u r e for [3 + 2] Cycloa d d ition Rea c-
tion s on P olym er -Bou n d Alk yn es or Alk en es. The poly-
mer (1-10 g) was swollen in benzene (10-100 mL) along with
the nitro compound (1.4-5.0 equiv) and phenyl isocyanate
(3.0-10.7 equiv). A catalytic amount of Et3N was added (5-
10 drops from a pipette), and the reaction was stirred at room
temperature. Within 20 min, precipitated diphenylurea was
observed, and the reaction was then heated at reflux overnight
(20-30 h). Samples of the polymer were taken and analyzed
(24) Miura, M.; Gabel, D.; Oenbrink, G.; Fairchild, R. Tetrahedron
Lett. 1990, 31, 2247-50.

6802 J . Org. Chem., Vol. 62, No. 20, 1997
Kantorowski and Kurth
Alcoh ol 8b. Dowex 50W-X8 resin (2 g) was added to a
solution of 8a (2.20 g, 5.2 mmol) in CH3OH (25 mL). After
stirring at room temperature for 2 h, the reaction was filtered
and concentrated. RC (20% EtOAc in hexanes) gave 8b as a
white solid (1.69 g, 96%). FTIR (KBr) 3431, 1718, 1282, 711
2H), 5.93 (m, 1H), 7.21-7.35 (m, 5H). 13C NMR δ 51.57, 53.05,
115.72, 126.70, 127.95, 128.17, 136.64, 140.11.
Ter tia r y Am in e 9. N-Benzyl-N-allylamine (72 mg, 0.49
mmol) was added to a mixture of iodide 8e (134 mg, 0.30 mmol)
and K2CO3 (58 mg) in THF (12 mL) at rt. When the reaction
was judged complete (TLC, approximately 12 h) it was diluted
with water (20 mL) and extracted with CH2Cl2 (3 × 20 mL).
The organics were washed with water and brine (2 × 50 mL
each), dried (Na2SO4), filtered, and rotoevaporated. RC (20%
EtOAc in hexanes) provided pure 9 as a colorless, highly
viscous oil (116 mg, 83%). Under similar conditions, bromide
8f provided 9 in 75% yield. FTIR (thin film) 1719, 1601, 1270,
1251, 1110, 713. 1H NMR δ 3.09 (d, 2H, J ) 6.3), 3.59 (s, 2H),
3.65 (s, 2H), 5.13 (s, 2H), 5.26 (m, 2H), 5.33 (s, 2H), 5.86 (ddd,
1H, J ) 6.3, 6.3, 13.7 Hz), 6.36 (s, 1H), 6.91-8.08 (m, 14H).
13C NMR δ 48.00, 56.48, 57.60, 61.32, 66.19, 103.48, 114.26,
114.50, 118.07, 121.31, 127.02, 128.22, 128.33, 128.77, 129.62,
129.76, 129.90, 133.02, 135.10, 137.83, 138.54, 157.93, 162.36,
166.23, 167.45.
cm-1 1H NMR δ 4.74 (s, 2H), 5.16 (s, 2H), 5.33 (s, 2H), 6.40
.
(s, 1H), 6.90-8.08 (m, 9H). 13C NMR δ 56.96, 61.27, 66.27,
102.24, 114.42, 114.49, 121.46, 128.40, 129.68, 129.87, 129.93,
133.12, 137.91, 157.86, 163.61, 166.37, 168.17.
Ch lor id e 8d . To a 0 °C solution of alcohol 8b (1.90 g, 5.6
mmol) and methanesulfonyl chloride (1.38 g, 12.0 mmol) in
CH2Cl2 (40 mL) was added Et3N (2.20 mL, 15.8 mmol). The
reaction was stirred for 12 h at 0 °C and then poured onto
crushed ice (100 g) and stirred until the ice had melted. The
mixture was extracted with CH2Cl2 (3 × 20 mL), and the
combined organics were washed with 2% Na2CO3 (1 × 50 mL),
water (2 × 50 mL), and brine (2 × 50 mL), and dried (Na2SO4).
After filtration and rotoevaporation, the material was passed
through a short silica plug to provide 1.58 g (79%) of chloride
8d as a beige solid which was used without further purifica-
Isoxa zole/Isoxa zolin e 10. Alkene 9 (205 mg, 0.44 mmol),
PhNCO (142 mg, 1.19 mmol), and phenylnitromethane (80 mg,
0.58 mmol) were dissolved in benzene (30 mL). A catalytic
amount (5-10 drops from a pipette) of Et3N was added and
within 20 min precipitated diphenylurea was observed. The
reaction was stirred at rt for 10-12 h at which time it was
refluxed if starting material was still present. The precipitate
was filtered and washed with benzene, and the filtrate was
concentrated. The yellow oil was diluted with water (50 mL)
and extracted with CH2Cl2 (3 × 25 mL). The combined
organics were washed with water and brine (2 × 50 mL each),
dried (Na2SO4), and rotoevaporated. RC (20% EtOAc in
hexanes) affords pure 10 (222 mg, 86%) as a highly viscous
tion. FTIR (KBr) 1716, 1272, 713 cm-1
.
1H NMR δ 4.56 (s,
2H), 5.16 (s, 2H), 5.34 (s, 2H), 6.45 (s, 1H), 6.90-8.05 (m, 9H).
13C NMR δ 35.41, 61.17, 66.19, 103.02, 114.29, 114.41, 121.51,
128.37, 129.64, 129.87, 129.90, 133.09, 137.94, 157.80, 160.88,
166.27, 168.75.
Iod id e 8e. Chloride 8d (296 mg, 0.79 mmol) and NaI (290
mg, 2.04 mmol) were dissolved in acetone (12 mL) and stirred
for 12 h at rt. The solvent was removed by rotoevaporation,
and the remaining solid was diluted with Et2O (10 mL) and
NaHSO3 (10 mL). The white insoluble solid that remained
was collected by filtration and found to be pure 8e (356 mg,
quantitative). Mp 105.0-106.0 °C. FTIR (KBr) 1714, 1705,
oil. FTIR (thin film) 1718, 1450, 1270, 1110 cm-1 1H NMR δ
.
1271, 709 cm-1 1H NMR δ 4.27 (s, 2H), 5.13 (s, 2H), 5.34 (s,
.
2H), 6.39 (s, 1H), 6.90-8.10 (m, 9H). 13C NMR δ -10.93,
61.26, 66.24, 103.75, 114.34, 114.46, 121.52, 128.41, 129.69,
129.88, 133.12, 134.83, 137.95, 157.85, 162.00, 166.31, 168.51.
Anal. Calcd for C19H16NO4I: C, 50.80; H, 3.59; N, 3.12.
Found: C, 50.78; H, 3.55; N, 3.12.
2.77 (d, 2H, J ) 5.3 Hz), 3.02 (dd, 1H, J ) 7.58, 16.6 Hz), 3.20
(dd, 1H, J ) 11.0, 16.6 Hz), 3.69 (s, 2H), 3.81 (s, 2H), 4.83 (m,
1H), 5.08 (s, 2H), 5.31 (s, 2H), 6.31 (s, 1H), 6.90-8.07 (m, 19H).
13C NMR δ 38.23, 49.63, 56.40, 59.19, 61.25, 66.17, 80.19,
103.6, 104.38, 114.21, 114.48, 121.30, 126.55, 127.21, 128.28,
128.33, 128.58, 128.97, 129.47, 129.60, 129.75, 129.93, 133.02,
137.82, 138.44, 156.57, 157.89, 161.97, 166.21, 167.59.
Br om id e 8f. Following the procedure of Imperiali,23 NBS
(216 mg, 1.21 mmol) was added in one portion to a 0 °C
solution of alcohol 8b (392 mg, 1.10 mmol) and Ph3P (431 mg,
1.64 mmol) in CH2Cl2 (20 mL). The reaction was stirred at rt
for 6 h and then concentrated and subjected directly to CC
(30% EtOAc in hexanes). Removal of the solvents afforded 8f
(382 mg, 86%) as a beige solid. Mp 90.5-91.5 °C. FTIR (KBr)
Gen er a l P r oced u r e for Tr a n sester ifica tion of Com -
p ou n d s 8a , 8b, 8c/8d , 9, a n d 10. A sodium methoxide
solution (5-10 equiv, 25 wt % in CH3OH, Aldrich) was added
to the ester (0.1-0.5 mmol) which was dissolved in THF (3
mL). When the reaction was judged complete (TLC, typically
15-45 min) it was quenched with NH4Cl (2mL), diluted with
water (3 mL), and extracted with CH2Cl2 (3 × 3 mL). The
organics were washed with water and brine (2 × 5 mL each),
dried (Na2SO4), filtered, and rotoevaporated. RC or PC
provided the pure alcohol.
Gen er a l P r oced u r e for Liber a tion of P olym er -Bou n d
Com p ou n d s. The polymer was swollen in THF for 30 min
followed by addition of NaOCH3 (5-10 equiv, 25 wt % in
CH3OH, Aldrich). After stirring at room temperature for 4 h
the reaction was quenched with saturated NH4Cl and allowed
to stir for an additional 1.5 h. The resin was removed by
filtration and subsequently washed with CH2Cl2 and H2O. The
filtrate was extracted with CH2Cl2 (4 × 5 mL), washed with
brine (2 × 10mL), dried (Na2SO4), and filtered, and the solvent
was removed. The crude material was then purified by RC or
PC.
1715, 1705, 1273, 709 cm-1 1H NMR δ 4.39 (s, 2H), 5.15 (s,
.
2H), 5.34 (s, 2H), 6.44 (s, 1H), 6.90-8.09 (m, 9H). 13C NMR δ
20.31, 61.21, 66.21, 103.47, 114.31, 114.42, 121.52, 128.39,
129.66, 129.89, 129.91, 133.10, 137.95, 157.81, 166.15, 167.15,
168.71. Anal. Calcd for C19H16NO4Br: C, 56.73; H, 4.01; N,
3.48. Found: C, 56.37; H, 3.89; N, 3.41.
N-(P h en ylm eth yl)-N-(2-P r op en yl)a m in e. Benzaldehyde
(10.7 mL, 10.53) was added to neat allylamine (6.05 g, 10.59
mmol).25 The exothermic reaction was cooled by means of an
ice/water bath (10-20 °C). After 2 h the biphasic reaction was
separated and the aqueous portion extracted with CH2Cl2 (2
× 10 mL). The combined organic portions were dried (Na2SO4),
filtered, concentrated, and dissolved in 100 mL of CH3OH. The
solution was cooled to -30 °C and NaBH4 (4.22 g, 111.5 mmol)
was added in portions.26 Once the gas evolution had subsided
the reaction was allowed to stir at 0 °C for 1.5 h. The reaction
was diluted with CH2Cl2 (100 mL), poured onto crushed ice
(350 g), and stirred until the ice had melted. The organic layer
was removed and the aqueous portion extracted with CH2Cl2
(2 × 75 mL). The combined organics were washed with water
and brine (2 × 150 each), dried (Na2SO4), filtered, and
concentrated to give a colorless liquid. Distillation (66.0 °C/
2.0 torr) gave the pure secondary amine (14.5 g, 90%). FTIR
Isoxa zole 20. Transesterification of 8a provided alcohol
20 as an oil (97%). Similarly, transesterification of 7a (110
mg, 1.50 mmol/g) provided alcohol 20 (44.8 mg, 85% from 1).
FTIR (thin film) 3428, 1603, 1451, 1259, 1037 cm-1 1H NMR
.
δ 1.50-1.86 (m, 6H), 2.63 (br s, 1H), 3.52 (m, 1H), 3.85 (m,
1H), 4.58 (d, 1H, J ) 12.9 Hz), 4.63 (s, 2H), 4.69 (t, 1H, J )
3.2 Hz), 4.75 (d, 1H, J ) 12.9 Hz), 5.12 (s, 2H), 6.40 (s, 1H),
6.83-7.28 (m, 4H). 13C NMR δ 19.02, 25.15, 30.18, 60.16,
61.13, 62.12, 64.62, 98.23, 102.83, 112.93, 113.71, 120.03,
129.58, 142.94, 157.88, 161.58, 167.99.
(thin film) 3313, 1643, 1495, 1453 cm-1 1H NMR δ 1.38 (br,
.
1H), 3.27 (ddd, 2H, J ) 1.3, 1.4, 3.1 Hz), 3.78 (s, 2H), 5.15 (m,
Isoxa zole 21. Transesterification of 8c/8d provided alcohol
21 as a colorless liquid (93%). Similarly, transesterification
of 7c/7d (102 mg, 1.50 mmol/g) provided alcohol 21 (15.4 mg,
(25) Georg, G. I.; Kant, J .; He, P.; Ly, A. M.; Lampe, L. Tetrahedron
Lett. 1988, 29, 2409-2412.
(26) Godleski, S. A.; Villhauer, E. B. J . Org. Chem. 1986, 51, 486-
491.
54.2% from 1). FTIR (thin film) 3404, 1258, 1104 cm-1 1H
.

Solid-Phase Synthesis of Isoxazoles and Isoxazolines
J . Org. Chem., Vol. 62, No. 20, 1997 6803
NMR δ 2.40 (br s, 1H), 3.37 (s, 3H), 4.50 (s, 2H), 4.65 (s, 2H),
5.14 (s, 2H), 6.38 (s, 1H), 6.84-6.98 (m, 3H), 7.24-7.30 (m,
1H). 13C NMR δ 58.51, 61.19, 64.79, 65.58, 102.54, 113.03,
113.82, 120.13, 129.69, 142.89, 157.93, 161.41, 168.24.
Isoxa zole 22. Transesterification of 9 affords 22 as a
colorless, highly viscous oil (96%). Similarly, transesterifica-
tion of 15 (147 mg, 1.50 mmol/g) affords 22 (34.5 mg, 42.9%
Diisoxa zole 18. Transesterification of resin 14b′ (14b +
EtCtN+sO- f 14b′) (106 mg, 1.50 mmol/g) provided, after
PC (70% EtOAc in hexanes), diisoxazole 18 (14.8 mg, 20.1%
overall yield from 1) as a viscous oil. FTIR (thin film) 3419,
3128 (w), 1654, 1604, 1455, 1257, 1156, 1042, 1107 cm-1 1H
.
NMR (two amide rotomers) δ 1.23 (m, 3H), 2.10, (br s, 1H),
2.62 (m, 2H), 3.81 (s, 0.4H), 3.85 (s, 0.6H), 4.53 (s, 1.2H), 4.58
(s, 0.8H), 4.63 (s, 1.2H), 4.64 (s, 0.8H), 4.66 (s, 1.2H), 4.67 (s,
0.8H), 5.09 (s, 2H), 5.81 (s, 0.4H), 5.89 (s, 0.6H), 6.03 (s, 0.4H),
6.32 (s, 0.6H), 6.83-6.99 (m, 3H), 7.20-7.32 (m, 6H). 13C NMR
(two amide rotomers) δ 12.48, 12.51, 19.43, 40.67, 40.93, 40.99,
41.24, 43.39, 44.07, 61.13, 61.19, 64.75, 64.80, 64.84, 101.87,
102.53, 102.78, 103.41, 112.75, 112.90, 112.94, 113.96, 120.19,
120.25, 127.15, 127.18, 128.73, 128.84, 128.87, 129.72, 129.76,
133.98, 143.00, 143.13, 157.83, 157.91, 158.41, 158.75, 159.72,
159.99, 165.35, 165.42, 166.53, 167.38, 168.51, 169.28, 171.11,
171.31.
from 1). FTIR (thin film) 3400, 1450, 1258, 698 cm-1 1H NMR
.
δ 2.16 (br s, 1H), 3.09 (d, 2H, J ) 6.3 Hz), 3.58 (s, 2H), 3.65 (s,
2H), 4.64 (s, 2H), 5.11 (s, 2H), 5.20 (m, 2H), 5.86 (m, 1H), 6.35
(s, 1H), 6.84-7.31 (m, 9H). 13C NMR δ 48.02, 56.50, 57.62,
61.31, 64.80, 103.46, 113.07, 113.88, 118.20, 120.08, 127.07,
128.25, 128.83, 129.66, 135.02, 138.46, 142.87, 157.98, 162.36,
167.67.
Isoxa zole/Isoxa zolin e 11. Transesterification of 10 af-
fords 11 as a colorless, highly viscous oil (97%). Similarly,
transesterification of polymer-bound isoxazoline 19 (114 mg,
1.50 mmol/g) also provides alcohol 11 (35.2 mg, 42.5% from
Tr iisoxa zole 17. Transesterification of resin 13′ (13 +
MeCtN+sO- f 13′) (67 mg, 2.01 mmol/g) provided, after PC
(60% EtOAc in hexanes), triisoxazole 17 (13.5 mg, 30.3%
overall yield from 1) as a viscous oil. FTIR (thin film) 3400,
1). FTIR (thin film) 3405, 1447, 1358, 1258, 692 cm-1
.
1H
NMR δ 2.08 (br s, 1H), 2.77 (d, 2H, J ) 5.3 Hz), 3.01 (dd, 1H,
J ) 7.6, 16.6 Hz), 3.21 (dd, 1H, J ) 10.5, 16.6 Hz), 3.70 (s,
2H), 3.81 (s, 2H), 4.65 (s, 2H), 4.82 (m, 1H), 5.09 (s, 2H), 6.31
(s, 1H), 6.82-7.61 (m, 14H). 13C NMR δ 38.31, 49.69, 56.50,
59.29, 61.27, 64.83, 80.19, 103.62, 113.02, 113.94, 120.09,
126.61, 127.29, 128.34, 128.65, 129.02, 129.43, 129.66, 130.03,
138.47, 142.92, 156.70, 157.92, 162.03, 167.83.
3125 (w), 1603, 1419 cm-1
.
1H NMR δ 2.29 (s, 6H), 3.01 (t,
2H, J ) 6.2), 3.05 (br s, 1H), 3.74 (s, 2H), 3.82 (s, 4H), 3.95 (t,
2H, J ) 6.2), 6.10 (s, 2H), 6.18 (s, 1H). 13C NMR δ 11.37, 30.35,
48.64, 48.72, 59.93, 104.46, 104.69, 159.87, 161.11, 168.28,
171.08.
Diisoxa zole 16. Transesterification of resin 12b′ (12b +
PhCtN+sO- f 12b′) (97 mg, 2.01 mmol/g) provided, after PC
(70% EtOAc in hexanes), diisoxazole 16 (27.2 mg, 39.4% overall
yield from 1) as a viscous oil. FTIR (thin film) 3419, 3124 (w),
Ack n ow led gm en t. We would like to thank Dr.
Kazuya Takenouchi and Dr. Lisa A. Ahlberg-Randall
for many helpful discussions. This work has been
supported by a grant from the National Science Foun-
dation.
1656, 1602, 1470, 1442, 1212, 1056 cm-1 1H NMR (two amide
.
rotomers) δ 1.19 (t, 0.43H, J ) 7.3 Hz), 1.21 (t, 0.57H, J ) 7.3
Hz), 2.04 (t, 0.57H, J ) 5.8 Hz, disappears w/D2O), 2.30 (t,
0.43H, J ) 5.8 Hz, disappears w/D2O), 2.35 (br s, 0.43H), 2.50
(q, 0.43H, J ) 7.3 Hz), 2.55 (q, 0.57H, J ) 7.3 Hz), 2.94 (t,
0.57H, J ) 6.1 Hz), 2.97 (t, 0.43H, J ) 5.9 Hz), 3.87 (t, 0.57H,
J ) 6.1 Hz), 3.89 (t, 0.43H, J ) 5.9 Hz), 4.65 (s, 0.43H), 4.67
(s, 0.57H), 4.68 (s, 0.57H), 4.75 (s, 0.43H), 6.00 (s, 0.43H), 6.10
(s, 0.57H), 6.47 (s, 0.57H), 6.54 (s, 0.43H), 7.45 (m, 3), 7.76
(m, 2H). 13C NMR δ (two amide rotomers) 9.13, 9.20, 26.36,
26.45, 26.51, 30.37, 41.14, 41.41, 43.31, 44.10, 59.87, 59.94,
100.93, 101.19, 101.66, 102.02, 126.75, 126.81, 128.31, 128.64,
128.90, 129.00, 130.11, 130.33, 159.85, 160.26, 162.60, 162.72,
167.86, 168.78, 171.34, 171.42, 173.79, 173.96.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 4, 8a , 8b, 8d , 8e, 8f, 9, 10, 11, 16, 17, 18, 20, 21,
and 22, 13C NMR spectra for compounds 8b, 8d , 8e, 8f, 9, 10,
11, 16, 17, 18, 20, 21, and 22, and FT-IR spectra for compounds
8b, 8e, 8f, 9, 10, 11, 16, 17, 18, 20, 21, and 22 (40 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O970712G