Solid-phase combinatorial synthesis of polyisoxazolines: A two-reaction iterative protocol

Article abstract of DOI:10.1021/jo961730l

Starting from a polymer-bound olefin, iterative application of nitrile oxide 1,3-dipolar cycloaddition and selenide oxidation/elimination steps were employed to deliver a polymer-bound triisoxazoline that can be liberated from the resin by transesterification. When four nitroseleno ethers (2-5) and four capping nitroalkanes (6-9) were employed, a triisoxazoline library (V) of 64 positional isomers was obtained by three iterative applications of these two reactions. The tactical flexibility of this strategy for preparing small polyfunctional oligomers is particularly attractive in that each subunit addition proceeds via a C-C bond-forming step.

Full text of DOI:10.1021/jo961730l

J . Org. Chem. 1996, 61, 8755-8761
8755
Solid -P h a se Com bin a tor ia l Syn th esis of P olyisoxa zolin es: A
Tw o-Rea ction Iter a tive P r otocol
Mark J . Kurth,* Lisa A. Ahlberg Randall, and Kazuya Takenouchi1
Department of Chemistry, University of California, Davis, California 95616
Received September 10, 1996X
Starting from a polymer-bound olefin, iterative application of nitrile oxide 1,3-dipolar cycloaddition
and selenide oxidation/elimination steps were employed to deliver a polymer-bound triisoxazoline
that can be liberated from the resin by transesterification. When four nitroseleno ethers (2-5)
and four capping nitroalkanes (6-9) were employed, a triisoxazoline library (V) of 64 positional
isomers was obtained by three iterative applications of these two reactions. The tactical flexibility
of this strategy for preparing small polyfunctional oligomers is particularly attractive in that each
subunit addition proceeds via a C-C bond-forming step.
In tr od u ction
The first reports of combinatorial chemistry focused on
creation of peptide libraries utilizing iterative amide
bond-forming protocols.2 Thus, starting with suitably
protected amino acid building blocks, large array and
split-mix peptide libraries can be prepared by the itera-
tive application of deprotection and activation/coupling
steps. The resulting peptides are of utility, but their
pharmaceutical applications are limited because of dif-
ficulties encountered in biodistribution3,4 (e.g., crossing
the blood-brain barrier) and in vivo stability (e.g.,
F igu r e 1. Iterative strategy for the solid-phase synthesis of
proteases in the stomach and bloodstream effectively
degrade these biopolymers).5 The combinatorial synthe-
sis of peptoid libraries from readily available starting
materials has been exploited to address these issues.6,7
For example, the Chiron peptoid approach6 employed
iterative synthetic steps of N-acylation and CR-N-substi-
tution to deliver oligomers of N-substituted glycines.
polyisoxazolines.
synthetic strategies,10 the importance of C-C bond-
forming reactions in organic chemistry, and our interest
in small molecule library synthesis,11 led us to explore
the isoxazoline-based iterative strategy outlined in Figure
1. In addition, isoxazolines are often biological active12
suggesting that the targeted polyisoxazolines may prove
useful in addressing some of the biochemical issues
mentioned above.
These results, coupled with the importance of meth-
odological developments in solid-phase8 and combinato-
rial strategies,9 the general advantages of iterative
Starting from a polymer-bound olefin, iterative ap-
plication of nitrile oxide 1,3-dipolar cycloaddition13 and
selenide oxidation/elimination14 steps were envisioned to
deliver polymer-bound polyisoxazoline I. This strategy
could be adopted to library preparations by one of three
methods: (i) polyisoxazoline libraries with the same
repeating unit but variable length (variable “n” in I) could
be prepared, (ii) polyisoxazoline libraries of fixed length
(fixed “n” in I) but incorporating variable “subunits” (i.e.,
prepared from various nitroseleno ethers of general
structure III) could be prepared, and (iii) polyisoxazoline
libraries of variable length and composed of variable
X Abstract published in Advance ACS Abstracts, November 15, 1996.
(1) Permanent address: Institute for Biomedical Research, Teijin
Ltd., 4-3-2 Asahigaoka Hino, Tokyo 191, J apan.
(2) (a) Lam, K. S.; Salmon, S. E.; Hersh, E. M.; Hruby, V. J .;
Kazmierski, W. M.; Knapp, R. J . Nature 1991, 354, 82-4. (b) Zuck-
ermann, R. N.; Kerr, J . M.; Siani, M. A.; Banville, S. C. Int. J . Pept.
Protein Res. 1992, 40, 497-506.
(3) Kim, B. H.; Chung, Y. J .; Keum, G.; Kim, J .; Kim, K. Tetrahedron
Lett. 1992, 33, 6811-14.
(4) Spatola, A. F. In Chemistry and Biochemistry of Amino Acids,
Peptides, and Proteins; Weinstein, B., Ed.; Marcel Dekker: New York,
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M.; Moos, W. H. Drug Dev. Res. 1995, 35, 20-32.
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G. B.; Shoemaker, K. R.; Kerr, J . M.; Figliozzi, G. M.; Goff, D. A.; Siani,
M. A.; Simon, R. J .; Banville, S. C.; Brown, E. G.; Wang, L.; Richter,
L. S.; Moos, W. H. J . Med. Chem. 1994, 37, 2678-85.
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1995, 8, 250-7.
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44. (b) Leznoff, C. C. Chem. Soc. Rev. 1974, 3, 65-85. (c) Leznoff, C.
C. Acc. Chem. Res. 1978, 11, 327-33.
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E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29, 144-54.
(c) Thompson, L. A.; Ellman, J . A. Chem. Rev. (Washington, D.C.), 1996,
96, 555-600. (d) Eichler, J .; Appel, J . R.; Blondelle, S. E.; Dooley, C.
T.; Doerner, B.; Ostresh, J . M.; Perez-Paya, E.; Pinilla, C.; Houghten,
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Kurth, M. J . J . Am. Chem. Soc. 1994, 116, 2661-2. (b) Kurth, M. J .;
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59, 5862-4.
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S0022-3263(96)01730-6 CCC: $12.00 © 1996 American Chemical Society

8756 J . Org. Chem., Vol. 61, No. 25, 1996
Kurth et al.
Sch em e 1a
“subunits” could be prepared. In addition to this tactical
flexibility, the strategy outlined in Figure 1 is appealing
in that each subunit addition proceeds via a C-C-bond-
forming step. Here, we report iterative application of the
two-step process outlined in Figure 1 to prepare a small
library of fixed length (three isoxazoline units) composed
of variable subunits (four nitroseleno ethers plus four
“capping” nitroalkanes).
Resu lts a n d Discu ssion
Our initial plan was to employ nitrotrityl ether IV as
the generic precursor to each isoxazoline subunit. The
idea was that 1,3-dipolar cycloaddition followed by trityl
deprotection, -CH2OH f -CHO oxidation, and Wittig
methenylation would deliver homologated resin II. More-
over, condensation of the aldehyde intermediate with
(MeO)2P(O)CHN2 would deliver the alkyne analog of II15
and set the stage for isoxazole formation in the second
iteration. However, since this approach requires four
steps per iteration versus the two steps required using
nitroseleno ether III, the former was abandoned.16
To validate the nitroseleno ether iterative strategy
outlined in Figure 1, we set out to prepare triisoxazolines
1226 and 1227 (Scheme 1).17 Our starting resin, polymer-
bound 3-butenyl benzoate [®1; ® ) resin (styrene/2%
divinylbenzene copolymer)], was prepared from polysty-
rene/2%-divinylbenzene copolymer by lithiation/CO2
quench,18 -CO2H f -COCl activation,19 and esterifica-
tion with 3-buten-1-ol in pyridine. Dehydrative 1,3-
dipolar cycloaddition of 1-nitro-4-(phenylseleno)butane
(2) with resin ®1 was accomplished by treatment of the
benzene swollen resin with phenyl isocyanate (4 equiv),
triethylamine, and 2 (2 equiv) at reflux for 4 d under
nitrogen. Subsequent transesterification of resin ®12
with sodium methoxide (THF:MeOH4:1)20 delivered isox-
azoline 12 [44% yield and ≈95% crude purity (see Figure
3) from ®CO2H; yield based on a titrated ®CO2H loading
of 2.1 mequiv/g], establishing that the crucial C-C bond-
forming 1,3-dipolar cycloaddition step was successful.
Sodium periodate selenide to selenoxide oxidation with
concomitant elimination regenerated the requisite olefin
functional group. The success of this transformation was
again established by NaOMe transesterification, but the
product obtained proved to be the conjugated olefin (a
consequence of olefin isomerization during the transes-
terification step as no isoxazoline products arising from
the conjugated olefin were observed in subsequent itera-
tions). Having thus established the efficacy of both the
1,3-dipolar cycloaddition step and the olefin regeneration
a
Note: see ref 17 for a comment regarding compound number-
ing.
step, we applied a second iteration converting ®12 to
diisoxazoline ®122 (again employing nitroseleno ether 2)
and a third iteration converting ®122 to triisoxazoline
®1226 [using nitrobutane (6) as a “capping” unit]. Both
steps of solid-phase iterations two (®12 f ®122) and
three (®122 f ®1226) were effected at room temperature
(instead of reflux for the 1,3-dipolar cycloaddition steps
as optimized in corresponding solution-phase reactions)
and validated by sodium methoxide transesterification
of ®1226, yielding the targeted “trimer” 1226. This fully
characterized triisoxazoline was obtained in 18% overall
yield and ≈95% purity (see the supporting information)
from ®C6H4CO2H; an average yield of 81% per step for
this eight step solid-phase synthesis. In a similar
fashion, “trimer” 1227 was obtained from ®1 by two
iterations with nitroseleno ether 2 and a capping itera-
tion with nitroalkane 7 (overall yield of 17%; 80% per
step).
With these results in hand, attention was turned to
the construction of a library of triisoxazolines of general-
ized structure V. By employing four different nitroseleno
ethers (2-5) in iterations one and two plus four different
capping nitroalkanes (6-9) in iteration three, a library
of 64 (4 × 4 × 4) positionally isomeric triisoxazolines
would be obtained. We anticipated using mass spec-
trometry to verify that each21 targeted triisoxazoline was
in fact obtained in this split-mix22 protocol. However,
since numerous of these analogs would have the same
(15) Brown, D. G.; Velthuisen, E. J .; Commerford, J . R.; Brisbois,
R. G.; Hoye, T. R. J . Org. Chem. 1996, 61, 2540-1.
(16) A polyisoxazole version of this approach is currently under
investigation and will be reported in due course.
(17) Note: a systematic numbering system is employed where the
product number is derived from the compound numbers of its compo-
nent precursors. Thus, refering to Scheme 1, combinatorial components
1, 2, 2, and 6 are employed to construct triisoxazoline 1226 (®1226
when polymer-bound) by the sequence 1 f ®1 + 2 f ®12 + 2 f ®122
+ 6 f ®1226 f 1226. Solution libraries (see Table 1) are lettered A-U;
when polymer-bound, these same libraries are referred to as ®A-®U.
Finally, oxidative elimination of selenium from ®12 gives olefin ®12a ;
likewise, oxidative elimination of selenium from library ®A gives
library ®Aa. The symbol ® denotes the resin (styrene/2% divinyl
benzene copolymer).
(18) Fyles, T. M.; Leznoff, C. C. Can. J . Chem. 1976, 54, 935-42.
(19) Fyles, T. M.; Leznoff, C. C., Weatherston, J . Can. J . Chem. 1978,
56, 1031-41.
(20) Meyers, H. V.; Dilley, G. J .; Durgin, T. L.; Powers, T. S.;
Winssinger, N. A.; Zhu, H.; Pavia, M. R. Mol. Diversity 1995, 1, 13-
20.
(21) In a large library, it is quite probable that not all of the targets
would be present [see: (a) Lowe, G. Chem. Soc. Rev. 1995, 24, 309-
317. (b) Zhao, P.-L.; Zambias, R.; Bolognese, J . A.; Boulton, D.;
Chapman, K. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 10212-6]. We
have used mass spectrometry to verify that each targeted positional
isomer is present in our library.

Synthesis of Polyisoxazolines
J . Org. Chem., Vol. 61, No. 25, 1996 8757
a
b
F igu r e 3. (a) 1H-NMR spectrum of 12. (b) 13C-NMR spectrum
of 12.
hydride24 (-I f -SePh). Nitroseleno ethers 4 and 5 were
prepared by Michael addition of the potassium alkoxide
of HO(CH2)3SePh [in turn prepared from HO(CH2)3Br +
(PhSe)2/NaBH4] to O2NCHdCHC6H5 and O2NCHdCHCH-
(CH3)2, respectively. Nitrobutane (6) is commercially
available, and nitroalkanes 7-9 were prepared by treat-
ment of the appropriate benzyl bromide with sodium
nitrite.25
Several observations regarding this combinatorial
synthesis are pertinent. For example, both the -CHdCH2
f isoxazoline and -CH2CH2SePh f -CHdCH2 trans-
formations are reliable solid-phase reactions. Figure 3
shows the crude 1H- and 13C-NMR spectra for 12, the
product obtained by sequential treatment of resin ®1
with nitroseleno ether 2 + PhNCO/Et3N and sodium
F igu r e 2. Combinatorial targets, precursors, and modified
split-mix protocol.
1
methoxide. These spectra, as well as the H- and 13C-
NMR spectra obtained from 13 (®1 + 3), 14 (®1 + 4),
and 15 (®1 + 5), show essentially pure monoisoxazoline
product.
We find that both solution- and solid-phase 1,3-dipolar
cycloaddition reactions deliver mixtures of diastereomers
in iterations two and three. While this can present
reaction management problems in solution, these issues
are minimized in our solid-phase protocol where product
diastereomers are as easily manipulated as are subunit
positional isomers.
Mass spectrometry has proven to be an ideal tool for
verifying the split-mix ensemble of products formed by
this iterative strategy (see Table 1). Using the modified
split-mix protocol outlined in Figure 2, 21 four-component
libraries were obtained where library A is a monoisox-
azoline mixture, libraries B-E are diisoxazoline mix-
tures, and libraries F-U are triisoxazoline mixtures. All
of these libraries were analyzed by low-resolution FAB+
mass spectrometry to verify that each targeted isoxazo-
line derivative was indeed present in the relevant library
(our modified split-mix protocol ensured that no library
contained positional isomers with identical formulas). For
example, library D contains four phenylseleno-containing
diisoxazolines (124, 134, 144, and 154), and unit mass
FAB+ data provides clear evidence that each anticipated
molecular formula, we adapted the modified split-mix
procedure outlined in Figure 2. Treating resin ®1 with
each of the four nitroseleno ethers 2-5 in separate flasks
followed by admixture gave the four-component resin
mixture ®A ([R] is defined in Figure 2; ®A ) ®12 + ®13
+ ®14 + ®15). Phenylseleno ether to olefin conversion
(®A f ®Aa) followed by performing iteration two in four
flasks, again using nitroseleno ethers 2-5, delivered four
unique positionally isomeric mixtures designated ®B, ®C,
®D, and ®E. Submitting each of these mixtures to
oxidative elimination and iteration three (required four
flasks for each diisoxazoline mixture ®Ba-®Ea, one for
each “capping” subunit 6-9) produced a total of 16
unique positionally isomeric mixtures; for example, ®B
f ®Ba and subsequent reaction with O2N(CH2)3CH3 (6)
gives ®F, with O2NCH2C6H5 (7) gives ®G, with O2-
NCH2C6H4(p)-CH3 (8) gives ®H, and with O2NCH2C6H4-
(p)-Br (9) gives ®I.
The combinatorial players required for this modified
split-mix procedure were all readily available. Nitrose-
leno ethers 2 and 3 were prepared from bromochlorobu-
tane and bromochloropentane, respectively, by sequential
treatment with sodium nitrite23 (-Br f -NO2), sodium
iodide (-Cl f -I), and diphenyl diselenide/sodium boro-
(22) (a) Furka, AÄ .; Sebestye´n, F.; Asgedom, M.; Dibo´, G. Int. J . Pept.
Protein Res. 1991, 37, 487-93. (b) J anda, K. D. Proc. Natl. Acad. Sci.
U.S.A. 1994, 91, 10779-85.
(23) Brewster, K.; Harrison, J . M.; Inch, T. M.; Williams, N. J . Chem.
Soc., Perkin Trans. 1 1987, 21-26.
(24) Clive, D. L., Bergstra, R. J . J . Org. Chem. 1990, 55, 1786-92.
(25) (a) Kornblum, N.; Larson, H. O.; Blackwood, R. K.; Mooberry,
D. D.; Oliveto, E. P.; Graham, G. E. J . Am. Chem. Soc. 1956, 78, 1497-
1501. (b) Kornblum, N.; Smiley, R. A.; Blackwood, R. K.; Iffland, D. C.
J . Am. Chem. Soc. 1955, 77, 6269-80.

8758 J . Org. Chem., Vol. 61, No. 25, 1996
Kurth et al.
Ta ble 1. F AB+ Ma ss Sp ectr om etr y Da ta for
Com bin a tor ia l P r od u cts
Exp er im en ta l Section
Gen er al P r ocedu r es. Polystyrene/2%-divinylbenzene (200-
400 mesh) was purchased from Acros Organics and used
directly. Solvents were purified as follows: dimethyl sulfoxide
(DMSO) and ethanol were dried over 4 Å molecular sieves;
pyridine was distilled from sodium; benzene was distilled from
potassium; tetrahydrofuran (THF) was distilled from sodium/
benzophenone. All reactions were conducted under an inert
atmosphere. 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. Mass spectra were obtained with a Fisons/
VG ZAB-VSE double focus sector instrument with BE geom-
etry [fast-atom bombardment (FAB); sample dissolved in
CH2Cl2 or MeOH; probe tip contained NBA/Na matrix; ioniza-
tion by Cs+ and accelerated to 8000 eV]. Elemental analyses
were performed at the MidWest Microlab, Indianapolis, IN.
1-Nitr o-4-(p h en ylselen o)bu ta n e (2). To a solution of
NaNO2 (6.90 g, 100.0 mmol) in DMSO (120 mL) was added
1-bromo-4-chlorobutane (8.57 g, 50.0 mmol), and the reaction
was stirred at room temperature for 3 h. Water (50 mL) was
added, and the resulting mixture was extracted with ether (3
× 100 mL). The combined extracts were washed with brine,
dried (Na2SO4), and evaporated under atmospheric pressure
at 50 °C to give 6.58 g (96%) of crude 1-chloro-4-nitrobutane
as a pale yellow oil: 1H NMR δ 1.84-1.95 (m, 2 H), 2.15-2.24
(m, 2 H), 3.59 (t, 2 H, J ) 6 Hz), 4.44 (t, 2 H, J ) 6 Hz).
To a solution of crude 1-chloro-4-nitrobutane (6.58 g, 48
mmol) in acetone (250 mL) was added NaI (10.8 g, 71.8 mmol),
and the solution was refluxed overnight. The reaction was
quenched by the addition of aqueous NaHSO3 (50 mL), and
the resulting solution was extracted with ether (3 × 100 mL).
The combined extracts were washed with brine, dried (Na2-
SO4), and evaporated under atmospheric pressure at 50 °C to
give 4.37 g (40%) of crude 1-iodo-4-nitrobutane as a brown oil:
1H NMR δ 1.92 (quintet, 2 H, J ) 6 Hz), 2.15 (quintet, 2 H, J
) 6 Hz), 3.22 (t, 2 H, J ) 6 Hz), 4.42 (t, 2 H, J ) 6 Hz).
To a solution of diphenyl diselenide (3.57 g, 11 mmol) in
absolute EtOH (120 mL) was added NaBH4 (0.87 g, 22 mmol),
and the reaction mixture was stirred at room temperature for
0.5 h. A solution of crude 1-iodo-4-nitrobutane (4.37 g, 19
mmol) in absolute EtOH (25 mL) was added to the reaction
and stirring continued for 2 h at room temperature. After
concentration of the solution in vacuo, water (100 mL) was
added, and the solution was extracted with ether (3 × 100 mL).
The combined extracts were washed with brine, dried (Na2-
SO4), and evaporated in vacuo. The residue was purified by
silica gel chromatography (1:99 f 2:98 f 4:96 ethyl acetate/
hexane) to give 2 (3.23 g, 25% from 1-bromo-4-chlorobutane)
compd [MH]+ [MNa]+ library compd [MH]+ [MNa]+ library
12 314
13 328
14 420
336
350
442
408
419
433
525
491
433
447
539
505
525
539
631
597
491
505
597
563
346
360
452
418
380
na
A
A
A
A
B
B
B
B
C
C
C
C
D
D
D
D
E
E
E
E
F
1437 478
1537 444
1238 386
1338 400
1438 492
1538 458
1239 450/452 472/474
1339 464/466 486/488
1439 556/558 578/580
1539 522/524 544/546
1246 430
1346 444
1446 536
1546 502
1247 464
1347 478
1447 570
1547 536
1248 478
1348 492
1448 584
1548 550
500
466
408
422
514
480
K
K
L
L
L
15 386
122 397
132 411
142 503
152 469
123 411
133 425
143 517
153 483
124 503
134 517
144 609
154 575
125 469
135 483
145 575
155 541
1226 324
1326 338
1426 430
1526 396
1227 358
1327 372
1427 464
1527 430
1228 372
1328 386
1428 478
1528 444
L
M
M
M
M
N
N
N
N
O
O
O
O
P
452
466
558
524
486
500
592
558
500
514
606
572
P
P
P
F
F
F
1249 542/544 564/566
1349 556/558 578/580
1449 648/650 670/672
1549 614/616 636/638
Q
Q
Q
Q
R
R
R
R
S
S
S
S
T
T
T
T
U
U
U
U
G
G
G
G
H
H
H
H
I
I
I
I
J
486
452
394
408
500
466
1256 396
1356 410
1456 502
1556 468
1257 430
1357 444
1457 536
1557 502
1258 444
1358 458
1458 550
1558 516
418
na
524
490
452
na
558
524
466
480
572
538
1229 436/438 458/460
1329 450/452 472/474
1429 542/544 564/566
1529 508/510 530/532
1236 338
1336 352
1436 444
1536 410
1237 372
1337 386
360
374
466
432
394
408
J
J
J
K
K
1259 508/510 530/532
1359 522/524 na
1459 614/616 na
1559 580/582 602/604
positional isomer is present in the mixture; selenium
isotope fingerprints for both the [MH]+ and the [MNa]+
molecular ions in libraries B-E are particularly un-
equivocal. Likewise, library M contains four bromine-
containing triisoxazolines (1239, 1339, 1439, and 1539),
and again, unit mass FAB+ data provide definitive
evidence that each anticipated positional isomer is
present in the mixture. Exact mass FAB+ analysis of
these mixtures also proved useful. For example, HRMS
FAB+ data for library N gave ([triisoxazoline‚H]+/
calculated g/mol/observed g/mol) 1246/430.2342/430.2355,
1346/444.2498/444.2510, 1446/536.2761/536.2778, and
1546/502.2917/502.2933. Electrospray mass analysis
was also investigated and corroborated the FAB+ data
presented in Table 1.
as a colorless oil: FTIR (neat) 1556 (NO2), 1383 (NO2) cm-1
;
1H NMR δ 1.74 (quintet, 2 H, J ) 6 Hz), 2.10 (quintet, 2 H, J
) 6 Hz), 2.90 (t, 2 H, J ) 6 Hz), 4.33 (t, 2 H, J ) 6 Hz), 7.22-
7.29 (m, 3 H), 7.44-7.49 (m, 2 H); 13C NMR δ 26.54, 26.96,
27.02, 74.81, 127.01, 129.04, 129.44, 132.72. Anal. Calcd for
C10H13NO2Se: C, 46.52; H, 5.08; N, 5.43. Found: C, 46.53;
H, 5.14; N, 5.39.
5-Nitr o-1-(p h en ylselen o)bu ta n e (3). Following the pro-
cedure described for the synthesis of 2, 1-bromo-5-chloropen-
tane was converted to 3 (50% from 1-bromo-5-chloropentane)
as a colorless oil: FTIR (neat) 1550 (NO2), 1383 (NO2) cm-1
;
1H NMR δ 1.47-1.55 (m, 2 H), 1.73 (quintet, 2 H, J ) 6 Hz),
1.99 (quintet, 2 H, J ) 6 Hz), 2.89 (t, 2 H, J ) 6 Hz), 4.34 (t,
2 H, J ) 6 Hz), 7.23-7.29 (m, 3 H), 7.46-7.49 (m, 2 H); 13C
NMR δ 26.25, 26.76, 27.18, 29.29, 75.35, 126.89, 129.04,
129.96, 132.66. Anal. Calcd for C11H15NO2Se: C, 48.54; H,
5.55; N, 5.15. Found: C, 48.61; H, 5.64; N, 5.13.
2-P h e n yl-2-[[3-(p h e n ylse le n o)p r op yl]oxy]n it r oe t h -
a n e (4). To a solution of diphenyl diselenide (26.95 g, 86
mmol) in absolute EtOH (900 mL) was slowly added NaBH4
(6.53 g, 173 mmol) and the solution stirred at room temper-
ature for 0.5 h. 3-Bromoethanol (20.0 g, 144 mmol) was added
with stirring for 3 h at room temperature. After concentration
in vacuo, water (200 mL) was added and the mixture extracted
with ether (3 × 200 mL). The combined extracts were washed
Su m m a r y
A tactically flexible strategy for the preparation of
oligomeric isoxazolines has been reported. In addition
to the subunit versatility of this approach to combinato-
rial synthesis, the method benefits from the fact that each
subunit addition proceeds via a C-C-bond forming step.
A “traceless attachment”26 and isoxazole variants of this
strategy will be reported in due course.
(26) See, for example: Plunkett, M. J .; Ellman, J . A. J . Org. Chem.
1995, 60, 6006-7.

Synthesis of Polyisoxazolines
J . Org. Chem., Vol. 61, No. 25, 1996 8759
with brine, dried (Na2SO4), and evaporated in vacuo to give
crude 3-(phenylseleno)propanol quantitatively (35.92 g) as an
orange oil: IR (neat) 3351 (br), 1579, 1478, 1437, 1247, 1065,
1022 cm-1; 1H NMR δ 1.85 (quintet, 2 H, J ) 7 Hz), 2.45 (t, 1
H J ) 7 Hz), 2.96 (t, 2 H, J ) 7 Hz), 3.67 (q, 2 H, J ) 7 Hz),
7.22 (m, 3 H), 7.49 (m, 2 H)]; 13C NMR δ 23.95, 32.48, 61.79,
126.66, 128.90, 129.91, 132.33.
The polymer was rinsed with anhydrous THF (2 × 50 mL),
additional THF (200 mL) was added, and CO2 was bubbled
into the mixture for 5 h at room temperature. The reaction
mixture was filtered, washed sequentially with THF (2 × 50
mL), water (4 × 50 mL), and EtOH (1 × 50 mL), and
suspended in 20% HCl in THF (200 mL). The mixture was
stirred at room temperature for 0.5 h and filtered and the
polymer washed with THF/water (1:1, 2 × 50 mL), water (6 ×
50 mL), EtOH (4 × 50 mL), and Et2O (4 × 50 mL). Drying
under vacuum overnight gave polymer-bound benzoic acid as
a light brown solid. The average acid content of the polymer
was found to be 2.1 mmol H+/g-polymer by acid-base titration
[the resin (0.2 g) was swollen in THF/water (1/1) with excess
standard aqueous NaOH and back-titrated with standard
aqueous HCl]: FTIR (KBr) 1687 (shoulder at 1727) (CdO),
Potassium hydride (10.66 g, 93.0 mmol, 35 wt % KH in
mineral oil) was washed with hexane (6 × 10 mL), dried in a
stream of N2, and suspended in dry THF (50 mL). A solution
of crude 3-(phenylseleno)propanol (17.11 g, 79 mmol) in THF
(50 mL) was added dropwise at room temperature. The
mixture was cooled to -40 °C, and a solution of trans-â-
nitrostyrene (6.22 g, 41.7 mmol) in THF (50 mL) was added
dropwise over 15 min and stirred for an additional 0.5 h. The
reaction was quenched by the addition of 1 M acetic acid (120
mL) followed by water (150 mL), the mixture separated, and
the aqueous extracted with ether (3 × 200 mL). The combined
extracts were washed with saturated aqueous NaHCO3 and
brine, dried (Na2SO4), and evaporated in vacuo. The residue
was purified by silica gel chromatography (2: 98 ethyl acetate/
hexane) to give 4 (5.80 g, 38% from trans-â-nitrostyrene) as a
pale yellow oil: FTIR (neat) 1554 (NO2), 1379 (NO2) cm-1; 1H
NMR δ 1.89 (quintet, 2 H, J ) 6 Hz), 2.91 (t, 2 H, J ) 6 Hz),
3.40 (dt, 1 H, J ) 6, 12 Hz), 3.47 (dt, 1 H, J ) 6, 12 Hz), 4.36
(dd, 1 H, J ) 3, 12 Hz), 4.58 (dd, 1 H, J ) 9, 12 Hz), 5.02 (dd,
2500-3600 (OH) cm-1. Anal. Calcd for [(C9H8O2‚H2O)0.20
+
(C8H8)0.80]: C, 84.50; H, 7.26. Found: C, 84.75; H, 7.07.
P olym er -Bou n d Ben zoyl Ch lor id e.19 To a solution of
polymer-bound benzoic acid (5.00 g) in SOCl2 (75 mL, 1.03 mol)
was added 10 drops of DMF, and the resulting mixture was
refluxed for 2 h. The reaction mixture was filtered and the
polymer washed (3 × 25 mL each) with CHCl3, THF, and Et2O
and dried under vacuum overnight to give polymer-bound
benzoyl chloride as a pale yellow solid: FTIR (KBr) 1755
(CdO) cm-1
.
P olym er -Bou n d 3-Bu ten yl Ben zoa te (®1). Polymer-
bound benzoyl chloride (4.98 g) was swollen in pyridine (100
mL) with stirring at room temperature for 3.5 h and treated
with 3-buten-1-ol (1; 1.39 g, 19.2 mmol). Stirring was contin-
ued at room temperature for 7 d. The mixture was filtered,
and the polymer was washed with THF (2 × 20 mL), THF/
water (1:1; 2 × 20 mL), THF (3 × 20 mL), water (2 × 20 mL),
THF (4 × 20 mL), and Et2O (3 × 20 mL) and dried under
vacuum overnight to give ®1 as a yellowish brown solid: FTIR
1 H, J ) 3, 9 Hz), 7.19-7.26 (m, 3 H), 7.30-7.46 (m, 7 H); 13
C
NMR δ 24.02, 29.97, 68.43, 78.50, 80.29, 126.67, 126.70,
128.98, 129.01, 129.98, 132.40, 132.47, 136.30. Anal. Calcd
for C17H19NO3Se: C, 56.05; H, 5.26; N, 3.84. Found: C, 56.18;
H, 5.28; N, 3.94.
3-Meth yl-2[[3-(p h en ylselen o)p r op yl]oxy]n itr obu ta n e
(5). Nitromethane (48.8 g, 0.80 mol) and isobutyl aldehyde
(28.8 g, 0.40 mol) were stirred together in a room temperature
water bath. Potassium hydroxide in MeOH (1.5 mL, 3 M) was
added dropwise, and the reaction was stirred for 30 min and
quenched by the addition of concd H2SO4 (20 drops, to pH )
1). The layers were separated, and the organic was washed
with saturated aqueous NaHCO3 and brine, dried (Na2SO4),
and concentrated in vacuo to give 1-nitro-3-methyl-2-butanol
(44.0 g, 83%) as a pale yellow liquid: 1H NMR δ 0.97 (d, 3 H,
J ) 7 Hz), 0.99 (d, 3 H, J ) 7 Hz), 1.79 (octet, 1 H, J ) 7 Hz),
2.92 (d, 2 H, J ) 6 Hz), 4.07-4.13 (m, 1 H), 4.33-4.51 (m, 2
H); 13C NMR δ 17.20, 18.12, 31.62, 73.30, 79.24.
1-Nitro-3-methyl-2-butanol (38.2 g, 0.29 mol) and acetic
anhydride (43.97 g, 0.431 mol) were refluxed together for 5 h
before quenching with aqueous NaHCO3. The resulting
mixture was heated for 1 h at 80 °C while NaHCO3 powder
was added. The layers were separated, and the aqueous was
extracted with ether (3 × 75 mL). The combined organics were
dried (Na2SO4) and concentrated in vacuo to give a light brown
oil (32.76 g, 99%). The 1-nitro-3-methyl-1-butene oil was
distilled to a yellow oil prior to use: 1H NMR δ 1.13(s, 6 H),
1.16 (s, 6 H), 2.56-2.64 (m, 1 H), 6.95 (dd, 1 H, J ) 1, 13 Hz),
7.25 (dd, 1 H, J ) 7, 13 Hz); 13C NMR δ 20.79, 28.17, 137.96,
148.33.
(KBr) 1724 (CdO) cm-1
(C8H8)0.80]: C, 87.34; H, 7.49. Found: C, 87.75; H, 7.48.
. Anal. Calcd for [(C13H14O2)0.20 +
P olym er -Bou n d 2-[4,5-Dih yd r o-3-[3-(p h en ylselen o)-
p r op yl]-5-isoxa zolyl]eth yl Ben zoa te (®12). Resin ®1 (1.00
g) was swollen in benzene (15 mL) with stirring for 0.5 h.
Sequential addition of 2 (997 mg, 3.86 mmol; in 5 mL of
benzene), phenyl isocyanate (920 mg, 7.72 mmol), and triethyl-
amine (10 drops) gave a mixture that was refluxed for 4 d.
Upon cooling to room temperature, water (2 mL) was added
and stirring continued for 1 h. The resulting mixture was
filtered and the polymer washed (3 × 5 mL each) with THF,
THF/water (1:1), THF, CH2Cl2, THF, and Et2O. Drying under
vacuum overnight gave ®12 as a brown solid: FTIR (KBr)
1715 (CdO) cm-1
(C8H8)0.80]: C, 76.90; H, 6.69; N, 1.63. Found: C, 78.03; H,
6.74; N, 1.80.
. Anal. Calcd for [(C23H25NO3Se)0.20 +
P olym er -Bou n d 2-[4,5-Dih yd r o-3-(2-p r op en yl)-5-isox-
a zolyl]eth yl Ben zoa te (®12a ). Resin ®12 (320 mg) was
swollen in THF (6 mL) with stirring at room temperature for
1.5 h and treated with NaIO4 (396 mg, 1.85 mmol) in a mixture
of water/MeOH (2 mL/2 mL). After being refluxed for 15 h,
the reaction mixture was filtered and the polymer was washed
(3 × 5 mL each) with THF, THF/water (1/1), saturated aqueous
NaHCO3, water, THF/water (1/1), THF, CH2Cl2, THF, and
Et2O. Drying under vacuum overnight gave resin ®12a as a
Following the procedure described for the synthesis of 4,
3-methyl-1-nitro-1-butene was converted to 5, purifying by
silica gel chromatography (5:95 EtOAc/Hex) to give 5 as a
colorless oil (72% from 3-methyl-1-nitro-1-butene): FTIR (neat)
pale brown solid: FTIR (KBr) 1717 (CdO) cm-1
.
1
1558 (NO2), 1385 (NO2) cm-1; H NMR δ 0.91 (d, 3 H, J ) 6
P olym er -Bou n d 2-[4,5-Dih yd r o-3-[[4,5-d ih yd r o-3-[3-
(ph en ylselen o)pr opyl]-5-isoxazolyl]m eth yl]-5-isoxazolyl]-
eth yl Ben zoa te (®122). Resin ®12a (559 mg) was swollen
in benzene (10 mL) with stirring at room temperature for 0.5
h. Sequential addition of 2 (836 mg, 3.24 mmol; in 5 mL
benzene), phenyl isocyanate (771 mg, 6.47 mmol), and triethyl-
amine (10 drops) gave a mixture that was stirred at room
temperature for 4 d. The reaction mixture was quenched with
water (1 mL), allowed to stir for 1 h, and filtered. The polymer
was washed (3 × 3 mL each) with THF, THF/water (1:1), THF,
CH2Cl2, THF, and Et2O and dried under vacuum overnight to
give ®122 as a yellowish brown solid: FTIR (KBr) 1717 (CdO)
Hz), 0.93 (d, J ) 6 Hz, 3 H), 1.83-1.97 (m, 3 H), 1.92 (t, 2 H,
J ) 6 Hz), 3.51 (dt, 1 H, J ) 6, 9 Hz), 3.61 (dt, 1 H, J ) 6, 9
Hz), 3.82 (dt, 1 H, J ) 3, 6 Hz), 4.34-4.43 (m, 2 H), 7.20-7.27
(m, 3 H), 7.44-7.48 (m, 2 H); 13C NMR δ 17.62, 17.86, 24.13,
30.06, 30.33, 70.01, 77.00, 81.49, 126.70, 128.98, 130.06,
132.45. Anal. Calcd for C14H21NO3Se: C, 50.91; H, 6.41; N,
4.24. Found: C, 50.86; H, 6.38; N, 4.17.
P olym er -Bou n d Ben zoic Acid . With adaptation of the
Fyles and Leznoff procedure,18 polystyrene/2% divinylbenzene
(20.0 g) was swollen in cyclohexane (200 mL) with stirring at
room temperature for 0.5 h and treated sequentially with
n-butyllithium (150 mL, 0.24 mol, 1.6 M in n-hexane) and
TMEDA (30.8 g, 0.265 mol). The mixture was heated to 65
°C for 15 h and cooled to room temperature, the polymer
allowed to settle, and the supernatant was removed via canula.
cm-1
. Anal. Calcd for [(C27H30N2O4Se)0.20 + (C8H8)0.80]: C,
75.22; H, 6.63; N, 2.97. Found: C, 75.71; H, 6.75; N, 2.93.
P olym er -Bou n d 2-[4,5-Dih yd r o-3-[[4,5-d ih yd r o-3-(2-
p r op en yl)-5-isoxa zolyl]m et h yl]-5-isoxa zolyl]et h yl Ben -

8760 J . Org. Chem., Vol. 61, No. 25, 1996
Kurth et al.
zoa te (®122a ). Following the procedure described for the
preparation of ®12a , ®122 (600 mg) gave ®122a as a pale
Mon oisoxa zolin es 13-15. As described for 12, resins
®13-®15 gave 13-15 as brown oils. 13: FTIR (neat) 3437
yellow solid: FTIR (KBr) 1717 (CdO) cm-1
.
(OH), 1579, 1478, 1438, 1073, 1023 cm-1
;
1H NMR δ 1.62-
1.91 (m, 6 H), 2.31-2.44 (m, 3 H), 2.57 (dd, 1 H, J ) 8 Hz),
2.89-3.03 (m, 3 H), 3.75 (t, 2 H, J ) 6 Hz), 4.62-4.72 (m, 1
H), 7.21-7.28 (m, 3 H), 7.44-7.48 (m, 2 H); 13C NMR δ 26.11,
27.10, 29.36, 37.52, 42.35, 59.54, 77.77, 78.28, 126.68, 128.94,
130.02, 132.35, 158.85. 14 (≈1:1 mixture of diastereomers):
P olym er -Bou n d 2-[4,5-Dih yd r o-3-[[4,5-d ih yd r o-3-[(4,5-
dih ydr o-3-pr opyl-5-isoxazolyl]m eth yl]-5-isoxazolyl]m eth -
yl)-5-isoxa zolyl]eth yl Ben zoa te (®1226). Following the
procedure described for the preparation of ®12, ®122a (100
mg) and nitrobutane (60 mg, 0.58 mmol) gave ®1226 as a pale
yellow solid: FTIR (KBr) 1718 (CdO) cm-1. Anal. Calcd for
[(C25H31N3O5Se‚H2O)0.20 + (C8H8)0.80]: C, 77.08; H, 7.38; N,
4.73. Found: C, 77.26; H, 7.27; N, 4.27.
FTIR (neat) 3426 (OH), 1578, 1478, 1437, 1073, 1022 cm-1
;
1H NMR δ 1.62-2.06 (m, 4 H), 2.22 (br s, 1 H), 2.30-2.82 (m,
2 H), 3.02 (t, 2 H, J ) 8 Hz), 3.54-3.76 (m, 4 H), 4.62-4.74
(m, 1 H), 5.24 (s, 1 H), 7.19-7.25 (m, 3 H), 7.26-7.43 (m, 5
H), 7.43-7.53 (m, 2 H); 13C NMR δ 24.19, 29.94, 29.97, 30.20,
37.30, 37.70, 38.01, 38.06, 59.34, 59.42, 68.08, 76.41, 76.46,
77.42, 78.71, 78.78, 125.34, 125.81, 125.94, 126.05, 126.68,
128.01, 128.48, 128.93, 129.97, 132.31, 132.34, 136.68, 137.63,
159.32, 159.50. 15 (≈1:1 mixture of diastereomers): FTIR
4,5-Dih yd r o-3-[[4,5-d ih yd r o-3-[(4,5-d ih yd r o-3-p r op yl-5-
isoxa zolyl)m et h yl]-5-isoxa zolyl]m et h yl]-5-(2-h yd r oxy-
eth yl)isoxa zole (1226). Resin ®1226 (86 mg) was swollen
in a mixture of THF/MeOH (2 mL:0.5 mL) with stirring at
room temperature for 0.5 h. Sodium methoxide (72 mg, 25
wt % in MeOH, 0.33 mmol) was added, and the mixture was
stirred at room temperature for 2 h. Saturated aqueous NH4-
Cl (1 mL) was added and stirring continued for 1 h. The
resulting mixture was filtered, and the polymer was washed
(3 × 2 mL each) with CH2Cl2, water, and CH2Cl2. The filtrate
was separated into two layers, and the aqueous layer was
extracted with CH2Cl2 (2 × 5 mL). The combined organics
were dried (Na2SO4), and the solvent was removed in vacuo
to give 22.8 mg of crude product. The crude material was
purified by silica gel chromatography (EtOAc/Hex (1/1) f
EtOAc) to give 1226 (7.3 mg, 18.1% from the polymer-bound
acid) as a white waxy solid: FTIR (neat) 3300 (br), 2922, 1427,
(neat) 3433 (OH), 1579, 1478, 1438, 1266, 1095, 1023 cm-1
;
1H NMR δ 0.82 (d, 3 H, J ) 7 Hz), 1.01 (d, 3 H, J ) 7 Hz),
1.74-1.97 (m, 5 H), 2.52-2.71 (m, 2 H), 2.93-3.10 (m, 3 H),
3.36-3.53 (m, 2 H), 3.67 (d, 1 H, J ) 9 Hz), 3.77 (t, 2 H, J )
6 Hz), 4.72-4.77 (m, 1 H), 7.21-7.27 (m, 3 H), 7.45-7.49 (m,
2 H); 13C NMR δ 18.25, 18.29, 19.01, 19.05, 24.22, 29.88, 30.20,
30.96, 31.00, 37.73, 38.43, 38.56, 59.41, 68.27, 78.21, 78.24,
80.65, 80.73, 126.69, 128.94, 129.91, 132.37, 132.41, 159.22.
See Table 1 for FAB MS data (m/ e [M + H]+ and [M + Na]+)
for these monoisoxazolines.
P olym er -Bou n d Mon oisoxa zolin e Alk en e ®12a . Resin
®12 (4.82 g) was swollen in THF (45 mL) with stirring at room
temperature for 1 h. A solution of sodium periodate (6.48 g,
30.3 mmol) in H2O/MeOH (15 mL/15 mL) was added, and the
mixture was heated at reflux for 14.5 h. Upon cooling, the
mixture was filtered and the polymer was washed (5 × 15 mL
each) with THF, THF/water (1:1), saturated aqueous NaHCO3,
water, THF/water (1:1), THF, CH2Cl2, THF, and Et2O. The
resin was dried under vacuum overnight to give ®12a as a
1
1051, 870, 810 cm-1; H NMR δ 0.97 (dt, 3 H, J ) 3, 6 Hz),
1.55-1.67 (m, 2 H), 1.77-2.20 (m, 3 H), 2.32 (dt, 2 H, J ) 3,
6 Hz), 2.64 (d, 4 H, J ) 6 Hz), 2.67-2.91 (m, 3 H), 3.05-3.25
(m, 3 H), 3.74-3.82 (m, 2 H), 4.71-4.88 (m, 3 H); 13C NMR δ
13.72, 13.75, 19.69, 29.55, 29.67, 33.00, 33.04, 33.09, 33.14,
33.22, 37.52, 37.57, 37.59, 42.07, 42.14, 42.22, 42.87, 42.94,
42.99, 43.34, 43.39, 59.74, 59.77, 59.83, 76.71, 76.81, 76.86,
77.16, 77.20, 77.30, 77.52, 77.60, 77.62, 77.72, 78.65, 78.67,
78.73, 155.76, 155.96, 155.98, 159.17. Anal. Calcd for
brown solid: FTIR (KBr) 1716 (CdO) cm-1
.
P olym er -Bou n d Mon oisoxa zolin e Alk en es ®13a , ®14a ,
a n d ®15a . As described for ®12a , ®13 (4.70 g) and NaIO4
(6.33 g, 29.6 mmol) gave ®13a [FTIR (KBr) 1716 (CdO) cm-1],
®14 (5.45 g) and NaIO4 (7.34 g, 34.3 mmol) gave ®14a [FTIR
(KBr) 1716 (CdO) cm-1], and ®15 (5.11 g) and NaIO4 (6.89 g,
32.2 mmol) gave ®15a [FTIR (KBr) 1716 (CdO) cm-1].
P olym er -Bou n d Diisoxa zolin es ®B, ®C, ®D, and ®E.
Resins ®12a , ®13a , ®14a , and ®15a were mixed together
(3.20 g each) to give mixed resin ®Aa. This mixed resin was
partitioned into four flasks (3.10 g each) and swollen in
benzene (50 mL) with stirring at room temperature for 0.5 h.
Nitroseleno ether 2 (5.04 g, 19.5 mmol, in 20 mL benzene) was
added to flask one, nitroseleno ether 3 (5.32 g, 19.5 mmol, in
20 mL benzene) was added to flask two, nitroseleno ether 4
(7.11 g, 19.5 mmol, in 20 mL benzene) was added to flask three,
and nitroseleno ether 5 (6.45 g, 19.5 mmol, in 20 mL benzene)
was added to flask four. Phenyl isocyanate (4.65 g, 39.1 mmol)
and triethylamine (50 drops) were added to each flask, and
the mixtures were stirred at room temperature for 4 d. The
reactions were quenched with water (20 mL) and allowed to
stir for 1 h. Each mixture was filtered, and the polymer was
washed (5 × 15 mL each) with THF, THF/water (1:1), THF,
CH2Cl2, THF, and Et2O and dried under vacuum overnight to
give ®B, ®C, ®D, and ®E as a brown solid: FTIR (KBr) ®B,
1712 (CdO); ®C, 1716 (CdO); ®D, 1716 (CdO); ®E, 1716
C
16H25N3O4: C, 59.43; H, 7.79; N, 12.99. Found: C, 59.39; H,
7.96; N, 12.77. The recovered polymer was washed (3 × 3 mL
each) with THF and Et2O and dried under vacuum overnight
to give polymer-bound methyl benzoate as a pale yellow solid:
FTIR (KBr) 1722 (CdO) cm-1
.
Libr a r y Syn th esis. P olym er -Bou n d Mon oisoxa zolin es
(®12, ®13, ®14, ®15). Resin ®1 (2.1 mmol H+/g polymer, 4.00
g each) was placed into four flasks and swollen in benzene (50
mL) with stirring at room temperature for 0.5 h. Sequential
addition of each of the four nitro compounds [16.8 mmol: 2
(4.34 g in 20 mL benzene) to flask one; 3 (4.57 g in 20 mL
benzene) to flask two; 4 (6.12 g in 20 mL benzene) to flask
three; 5 (5.55 g in 20 mL benzene)], phenyl isocyanate (4.00
g, 33.6 mmol), and triethylamine (50 drops) at room temper-
ature gave mixtures that were refluxed for 4 d. The reactions
were cooled, quenched with water (20 mL), and allowed to stir
for 1 h. Each mixture was filtered and the polymer washed
(5 × 15 mL each) with THF, THF/water (1:1), THF, CH2Cl2,
THF, and Et2O, and dried under vacuum overnight to give
®12, ®13, ®14, and ®15 as brown solids: FTIR (KBr) ®12,
1716 (CdO); ®13, 1714 (CdO); ®14, 1716 (CdO); ®15, 1716
(CdO) cm-1. These resins were mixed to form library ®A.
Mon oisoxa zolin e 12. Resin ®12 (0.20 g) was suspended
in THF (3 mL) and allowed to swell for 15 min. Sodium
methoxide was added (0.2 mL, 25 wt % solution in MeOH),
and the reaction was stirred for 2 h, quenched with H2O (1
mL), and filtered. The polymer was washed with THF/H2O
(1:1, 8 × 1 mL), THF (3 × 1 mL), MeOH (3 × 1 mL), THF (6
× 1 mL), and ether (3 × 1 mL). The filtrate was concentrated
in vacuo and extracted with ether (3 × 4 mL). The organic
was washed with brine, dried (MgSO4), and concentrated to
give 0.065 g of 12 as a brown solid: FTIR (neat) 3419 (OH),
(CdO) cm-1
.
Solu tion Diisoxa zolin e Libr a r ies B, C, D, a n d E. The
procedure described for transesterification of ®12 to liberate
monoisoxazoline 12 was followed except 0.40 g of resin (®B,
®C, ®D, or ®E), THF (6 mL), NaOMe/MeOH (0.4 mL), and
water (2 mL) were used, giving ≈110 mg each of solution
libraries B, C, D, and E. See Table 1 for FAB MS data (m/ e
[M + H]+ and [M + Na]+) for these diisoxazolines.
1579, 1478, 1438, 1065, 1022 cm-1; H NMR δ 1.73-1.91 (m,
1
P olym er -Bou n d Olefin ®Ba , ®Ca , ®Da , a n d ®Ea . The
procedure described for conversion of ®12 to olefin ®12a was
followed except resin ®B (3.02 g), ®C, (3.07 g) ®D (2.94 g), or
®E (2.93 g) was used in place of ®12 to give ®Ba, ®Ca, ®Da,
and ®Ea as light brown solids: FTIR (KBr) ®Ba, 1718 (CdO);
2 H), 1.95 (quintet, 2 H, J ) 7 Hz), 2.45 (br t, 3 H, J ) 7 Hz),
2.55 (dd, 1 H, J ) 8 Hz), 2.91-3.01 (m, 3 H), 3.76 (t, 2 H, J )
6 Hz), 4.63-4.73 (m, 1 H), 7.24-7.27 (m, 3 H), 7.47-7.50 (m,
2 H); 13C NMR δ 26.53, 26.92, 27.67, 37.50, 42.62, 59.61, 78.09,
126.89, 128.99, 132.65, 134.73, 158.27.
®Ca, 1716 (CdO); ®Da, 1716 (CdO); ®Ea, 1716 (CdO) cm-1
.

Synthesis of Polyisoxazolines
J . Org. Chem., Vol. 61, No. 25, 1996 8761
P olym er -Bou n d Tr iisoxa zolin es ®F , ®G, ®H, a n d ®I.
Resin ®Ba was partitioned into four flasks (600 mg each) and
swollen in benzene (15 mL) with stirring at room temperature
for 1 h. To these flasks were added a nitroalkane [nitrobutane
(390 mg) to flask one, phenylnitromethane25a (518 mg, 3.8
mmol) to flask two, (4-methylphenyl)nitromethane25b (571 mg)
to flask three, and (4-bromophenyl)nitromethane25b (817 mg)
to flask four], phenyl isocyanate (0.90 g, 7.6 mmol), and
triethylamine (20 drops). Each mixture was stirred for 4 d at
room temperature, quenched with water (3 mL), and allowed
to stir for 1 h. The mixtures were filtered, and each polymer
was washed (5 × 5 mL each) with THF, THF/water (1/1), THF,
CH2Cl2, THF, and Et2O and dried under vacuum overnight to
give ®F, ®G, ®H, and ®I as a yellow solids: FTIR (KBr) ®F,
1718 (CdO); ®G, 1718 (CdO); ®H, 1718 (CdO); ®I, 1718
Solu tion Tr iisoxa zolin e Libr a r ies F -U. The procedure
described for transesterification of ®12 to liberate monoisox-
azoline 12 was followed except 0.40 g of resin (®F, ®G, ®H,
®I, ®J , ®K, ®L, ®M, ®N, ®O, ®P, ®Q, ®R, ®S, ®T, or ®U),
THF (6 mL), NaOMe/MeOH (0.4 mL), and water (2 mL) were
used, giving 90-230 mg each of solution libraries F, G, H, I,
J , K, L, M, N, O, P, Q, R, S, T, or U. See Table 1 for FAB MS
data (m/ e [M + H]+ and [M + Na]+) for these triisoxazolines.
Ack n ow led gm en t. We are grateful to the National
Science Foundation (Grant CHE-9406891) and Teijin
Ltd. for financial support of this work.
(CdO) cm-1
.
Su p p or tin g In for m a tion Ava ila ble: 1H- and 13C-NMR
spectra for 122 and 1226 (5 pages). This material is contained
in libraries on microfiche, immediately 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.
P olym er -Bou n d Tr iisoxa zolin es ®J , ®K, ®L, ®M, ®N,
®O, ®P , ®Q, ®R, ®S, ®T, a n d ®U. The same procedure
described for the conversion of ®Ba to ®F, ®G, ®H, and ®I
was followed: FTIR (KBr) ®J , 1718 (CdO); ®K, 1718 (CdO);
®L, 1718 (CdO); ®M, 1718 (CdO); ®N, 1718 (CdO); ®O, 1718
(CdO); ®P, 1716 (CdO); ®Q, 1718 (CdO); ®R, 1718 (CdO);
®S, 1718 (CdO); ®T, 1718 (CdO); ®U, 1718 (CdO) cm-1
.
J O961730L