β-Dimethylphenylsilylethyl esters: A linker for solid-phase chemistry

Article abstract of DOI:10.1016/S0040-4039(00)00909-6

Preparation of a β-dimethylphenylsilylethyl (BMPSE) ester linker from 2% divinylbenzene-styrene copolymer by lithiation, chlorodimethylvinylsilane silylation, hydroboration/oxidation (giving 9), and O-acylation is reported. The resulting polymer-bound BMPSE esters were employed in a reaction sequence consisting of RCHO→RCH=NOH→isoxazoline/isoxazole (giving 12). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00909-6

Tetrahedron Letters 41 (2000) 5617±5622
b-Dimethylphenylsilylethyl esters: a linker for solid-phase
chemistry
Concepcion Alonso, Michael H. Nantz and Mark J. Kurth*
Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616-5295, USA
Received 18 April 2000; accepted 1 June 2000
Abstract
Preparation of a b-dimethylphenylsilylethyl (BMPSE) ester linker from 2% divinylbenzene±styrene
copolymer by lithiation, chlorodimethylvinylsilane silylation, hydroboration/oxidation (giving 9), and O-
acylation is reported. The resulting polymer-bound BMPSE esters were employed in a reaction sequence
consisting of RCHO!RCHˆNOH!isoxazoline/isoxazole (giving 12). # 2000 Elsevier Science Ltd. All
rights reserved.
Choosing the correct linker is a crucial step in solid-phase organic synthesis. Alternative
methods1 for attachment/detachment of substrates from solid-supports have resulted in the
construction of an impressive range of compound classes.2 A survey of the literature indicates an
increasing popularity of trialkylsilyl groups in solid-phase linker applications.3 This application
breadth re¯ects solution-phase developments where silyl-based linkers are: (1) readily introduced
at many functional groups; (2) compatible with many organic transformations; (3) compatible
with other protecting group strategies; and (4) easily and chemoselectively cleaved. That said,
trialkylsilyl protection of carboxylic acids is rare owing to hydrolytic lability. With TMSE
[2-(trimethylsilyl)ethyl] esters, independently introduced by Sieber4a and Gerlach4b for the pro-
tection of the carboxyl functionality, requisite stability is achieved by positioning the silicon atom
b to the carboxylate giving TMSE-esters that are broadly applied, uniquely stable, and can be
readily deprotected with tri¯uoroacetic acid.
The focus of the present report is the development of a polymer-anchored b-dimethyl-
phenylsilylethyl (BMPSE) ester protecting group and its application in the synthesis of carboxylic
acid and ester substituted isoxazolines. An early report of the solid-phase synthesis of this type of
isoxazoline by Cheng and Mjalli5 used Wang resin. We report here that the BMPSE ester linker is
readily introduced, compatible with all synthetic steps required for this isoxazoline synthesis, and
labile under both TFA and TBAF cleavage conditions.
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00909-6

5618
To determine the feasibility of a solid-phase BMPSE linker, we ®rst established resin-compatible
conditions for the derivatization of a vinyl silane moiety for ester formation as well as conditions
under which the silicon±carbon bond could be cleaved under mild conditions. Toward this end, a
solution-phase model study beginning with dimethylphenylvinylsilane was initiated for the
synthesis of aryl-substituted isoxazolines.6 The results of this solution-phase study are outlined in
Scheme 1. Hydroboration/oxidation of commercially available dimethylphenylvinylsilane was
carried out using dicyclohexylborane as the hydroborating agent. This generally regioselective
reagent7 added with complete selectivity to vinyl silane 1 giving alcohol 2 upon oxidative work-up.
Esteri®cation of 2 with 4-tbutylbenzoyl chloride gave silyl ethyl ester 3. Tetrabutylammonium
¯uoride (TBAF) treatment in THF (rt) delivered 4-tbutylbenzoic acid in 43% yield (unoptimized).
Likewise, treating 3 with 20% tri¯uoroacetic acid (TFA) in CH2Cl2 delivered 4-tbutylbenzoic acid
in 56% yield (unoptimized).
Scheme 1.
With these protocols in hand, treatment of silyl ethanol 2 with 4-formyl benzoyl chloride under
neutral conditions a€orded the expected silyl ethyl ester 4 (Scheme 2). Reaction of 4 with
hydroxylamine and sodium acetate in EtOH at room temperature a€orded 5 in quantitative
yield.8 This aldoxime was added dropwise over 15 min to a mixture of methyl acrylate (1 equiv.)
and catalytic Et3N in CH2Cl2 plus an aqueous sodium hypochlorite9 solution. As demonstrated
by Martin and Dupre,10 sterically hindered nitrile oxides undergo highly regioselective cycload-
dition with cis-disubstituted ole®ns. This bias is based on the size of the ole®n substituents with
the nitrile betaine oxygen adding to the more hindered site and, in the present example, gave only
6 (1H NMR of crude reaction). Selective cleavage of the silyl ethyl ester in the presence of the
methyl ester in 6 with either TBAF in THF or 20% TFA in CH2Cl2 gave the desired desilylated
product in 75 and 72% yield, respectively.
Scheme 2.
Attention was next focused on development of the polymer-supported analog of this
strategy (Scheme 3). Following the method developed by Chalk,11 commercial 2% cross-linked
polystyrene-divinylbenzene copolymer ( ) was lithiated at 65ꢀC with the complex formed from
nbutyllithium and TMEDA (1:1) in cyclohexane. The resulting polymer-bound aryllithium12 was
quenched in situ with chlorodimethyl±vinylsilane in benzene (FTIR: 1250 and 835 cm^1 for

5619
Scheme 3. See Reference 13
SiMe). The extent of polymer lithiation was determined by CO2 quench and subsequent acid-base
titration; loading generally falls in the range of 0.9±1.02 mmol/g resin. The most reliable method
for monitoring the progress of this and all subsequent solid-phase transformations was by
recording FTIR spectra of the crushed resin.
Hydroboration of resin 8 and oxidative work-up with basic peroxide provided the silyl ethanol
resin 9 which was esteri®ed with 4-formylbenzoyl chloride to a€ord polymer 10 as evidenced by
both aldehyde and ester group absorptions in the IR spectrum (1690 and 1736 cm^1, respectively).
Reaction of 10 with hydroxylamine in the presence of sodium acetate in EtOH at room tem-
perature a€orded the aldoxime resin 11 which was suspended in THF and treated with excess
bleach (Clorox, 10 equiv.) and methyl acrylate to form the corresponding nitrile oxide.
Concomitant 1,3-dipolar cycloaddition gave resin-bound Á2-isoxazoline 12.
An important advantage of the solid-phase 11!12 process over the solution-phase 5!6
reaction is the ease of separation and isolation of the targeted cyclic isoxazoline; resin washing in
the former versus aqueous work-up and chromatography in the latter. Again, protodesilylation
Table 1
Library application of the solid-phase BMPSE ester linker14

5620
was smoothly accomplished by treatment of resin 12 with CF3COOH/CH2Cl2 to give isoxazoline
7 in ꢁ95% purity and 60% overall yield from lithiated PS-DVB.
Reaction rates for the solid- and solution-phase reactions were comparable. Moreover, both
1,3-dipolar cycloaddition protocols were highly regioselective. Encouraged by these observa-
tions, we applied this solid-phase DMPSE ester technology to the preparation of a library of
aryl-substituted isoxazolines. By employing three di€erent formyl carboxylic acid chlorides and
four di€erent dipolarophiles, a library of 12 isoxazolines was obtained (see Table 1).
In conclusion, a b-dimethylphenylsilylethyl (DMPSE) ester linker has been developed for solid-
phase organic synthesis and used in the preparation of a library of aryl-substituted isoxazolines.
Protolytic cleavage of the coupled products from the resin proceeds under mild conditions and
generally in high yield.
Acknowledgements
We thank the National Science Foundation for ®nancial support of this research and the
National Science Foundation CRIF program (CHE-9808183) for Varian Inova 400 MHz and
Mercury 300 MHz NMR instrument purchases. C.A. thanks the Departamento de Educacion,
Universidades e Investigacion del Gobierno Vasco (Spain) for a postdoctoral fellowship.
References
1. Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555.
2. For reviews, see: (a) Lorsbach, B. A.; Kurth, M. J. Chem. Rev. 1999, 99. (b) Booth, S.; Hermkens, P. H. H.;
Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron 1998, 54, 15385. (c) Fruchtel, J. S.; Jung, G. Angew. Chem., Int. Ed.
Engl. 1996, 35, 17. (d) Balkenhohl, F.; Von dem Bussche-Hunnefeld, C.; Lansky, A.; Zechel, C. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2289. (e) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J. Tetrahedron
1995, 51, 8135. (f) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem.
1994, 37, 1385.
3. (a) Boehm, T. L.; Showalter, H. D. H. J. Org. Chem. 1996, 61, 6498. (b) Han, Y.; Walker, S. D.; Young, R. N.
Tetrahedron Lett. 1996, 37, 2703. (c) Plunkett, M. J.; Ellman, J. A. J. Org. Chem. 1995, 60, 6006. (d) Chenera, B.;
Finkelstein, J. A.; Veber, D. F. J. Am. Chem. Soc. 1995, 117, 11999. (e) Fotouhi, N.; Kemp, D. S. Int. J. Peptide
Protein Res. 1993, 41, 153. (f) Chan, T.-H.; Huang, W.-Q. J. Chem. Soc., Chem. Commun. 1985, 909.
4. (a) Sieber, P. Helv. Chim. Acta 1977, 60, 2711. (b) Gerlach, H. Helv. Chim. Acta 1977, 60, 3039. (c) For a review,
see: Kocienski, P. J. Protecting Groups; Thieme Medical Inc.: New York, 1994.
5. Cheng, J. F.; Mjalli, A. M. M. Tetrahedron Lett. 1998, 39, 939.
6. (a) Zhang, L.-H.; Costello, T. D.; Valvis, I.; Ma, P.; Kau€man, S.; Ward, R. J. Org. Chem. 1997, 62, 2466. (b)
Zhang, L.-H.; Anzalone, L.; Ma, P.; Kau€man, S.; Storace, L.; Ward, R. Tetrahedron Lett. 1996, 37, 4455 (c)
Wityak, J.; Sielecki, T. M.; Pinto, D. J.; Emmett, G.; Sze, Y. Y.; Liu, J.; Tobin, A.; Wang, S.; Jiang, B.; Ma, P.;
Mousa, S. A.; Olson, R. E.; Wexler, R. R. J. Med.Chem. 1997, 40, 1292.
7. (a) Soderquist, J. A.; Shiau, F.-Y.; Lemesh, R. A. J. Org. Chem. 1984, 49, 2565. (b) Fleming, I.; Lawrence, N.
J. Chem. Soc., Perkin Trans. 1 1992, 3309.
8. Hydroxylamine hydrochloride (0.090 g, 1.3 mmol) and sodium acetate (0.14 g, 1.7 mmol) were added to ethanolic
(10 mL) 4 (0.31 g, 1 mmol) and the solution was stirred at room temperature overnight. The solvent was removed
(rotoevaporation) and the crude product was triturated into CH2Cl2. Puri®cation by ®ltration a€orded an almost
pure oxime (99% yield) which was used in the next reaction without further puri®cation. For analytical purposes,
1
the oxime was puri®ed by column chromatography to give 5 as a colorless oil in 86% yield (0.28 g): H NMR
(CDCl3) ꢀ 8.18 (s, 1H), 7.96 (d, 2H, J=6.0 Hz), 7.61 (d, 2H, J=6.0 Hz), 7.56±7.35 (m, 5H), 4.44 (t, 2H, J=8.0
Hz), 2.70 (s, 1H), 1.41 (t, 2H, J=8.0 Hz), 0.37 (s, 6H); 13C NMR (CDCl3) ꢀ 166.2, 149.3, 136.1±126.5 (m), 63.2,

5621
16.6, ^2.9; IR 3383, 1704, 1679, 1112, 768 cm^1. Anal. calcd for C18H21NSiO3: C, 66.02; H, 6.46; N, 4.28. Found:
C, 65.65; H, 6.50; N, 4.15.
9. Lee, G. A. Synthesis 1982, 508.
10. Martin, S. F.; Dupre, B. Tetrahedron Lett. 1983, 24, 1337.
11. Chalk, A. J. J. Polym. Sci., Part B 1968, 6, 649.
12. Farrall, M. J.; Frechet, J. M. J. J. Org. Chem. 1976, 41, 3877.
13. Solid-phase preparation of isoxazolines (7; via 10!11!12). A solution of acid chloride (1.0 mmol) in dry CH2Cl2
(2.0 mL) was added dropwise to a cold mixture (0ꢀC) of polymeric alcohol 9 (0.200 g) swollen in CH2Cl2 (7.0 mL)
and containing triethylamine (0.28 mL, 2.0 mmol) and DMAP (0.0012 g, 0.01 mmol). The mixture was shaken at
room temperature overnight, ®ltered and washed with CH2Cl2, water, THF and MeOH to a€ord the
corresponding polymeric ester aldehyde 10. To this resin was added EtOH (5.0 mL), hydroxylamine
hydrochloride (0.069 g, 1.0 mmol) and sodium acetate (0.106 g, 1.3 mmol) and the mixture was shaken at room
temperature for 2 days. The polymer was ®ltered and washed with EtOH, water, THF and MeOH a€ording
polymeric oxime 11. This oxime was swollen in CH2Cl2 (5.0 mL) and treated dropwise over 15 min with a cold
solution (0ꢀC) of dipolarophile (1.0 mmol), triethylamine (0.001 g, 0.01 mmol), 5.25% aqueous sodium
hypochlorite (2.64 mL, 0.140 g NaOCl, 1.8 mmol) and dichloromethane (2.0 mL). The mixture was shaken at
room temperature overnight and the resin ®ltered and washed with CH2Cl2, water, THF:water (3:1), THF and
MeOH to give 12. Substrate cleavage was accomplished by treating 12 with a freshly prepared TFA:CH2Cl2 (1:4)
solution (3 h at re¯ux temperature; ethylene release is observed). Filtration, resin washing with MeOH (3Â), and
solvent removed gave the targeted isoxazolines or isoxazoles in 50±75% yield which were puri®ed by
crystallization a€ording the expected isoxazolines 7 (spectroscopic data given below).
14. Compound 7a: 72% yield (0.159 g); m.p. 196±197ꢀC; H NMR (CDCl3/CD3OD) ꢀ 8.05 (d, 2H, J=9.0 Hz), 7.69
1
(d, 2H, J=9.0 Hz), 5.18 (dd, 1H, J=10.5 Hz , J=8.0 Hz), 3.78 (s, 3H), 3.64 (d, 1H, J=8.0 Hz), 3.63 (d, 1H,
J=10.5 Hz); 13C NMR (CDCl3/CD3OD) ꢀ 177.6, 167.7, 155.4, 132.0, 131.9, 130.1, 126.6, 78.2, 52.8, 38.5; IR 2960,
1759, 1687, 1429, 1290 cm^1. Anal. calcd for C12H11NO5: C, 57.83; H, 4.45; N, 5.62. Found: C, 58.10; H, 4.76; N,
5.75. Compound 7b: 70% yield (37 mg); m.p. 207±208ꢀC; H NMR (CDCl3/CD3OD) ꢀ 8.02 (d, 2H, J=9.1 Hz),
1
7.75 (d, 2H, J=9.1 Hz), 5.02±4.94 (m, 1H), 4.90±4.16 (m, 2H), 3.46 (dd, 1H, J=16.8 Hz, J=10.9 Hz), 3.16 (d, 1H,
J=16.8 Hz, J=8.4 Hz), 2.14 (s, 3H); 13C NMR (CDCl3/CD3OD) ꢀ 171.3, 163.4, 155.7, 133.2, 130.3, 127.0, 126.6,
78.7, 64.8, 36.9, 20.7; IR 2936, 1738, 1680, 1426, 1232 cm^1. Anal. calcd for C13H13NO5: C, 59.31; H, 4.98; N, 5.32.
Found: C, 59.19; H, 4.90; N, 5.17. Compound 7c: 51% yield (27 mg); m.p. 159±160 (dec.)ꢀC; H NMR (CDCl3/
1
CD3OD) ꢀ 8.09 (d, 2H, J=1.5 Hz), 7.73 (d, 2H, J=1.5 Hz), 3.90 (d, 1H, J=16.9 Hz), 3.80 (s, 3H), 3.23 (d, 1H,
J=16.9 Hz), 1.72 (s, 3H); 13C NMR (CDCl3/CD3OD) ꢀ 172.3, 160.1, 155.6, 133.5, 133.4, 130.6, 126.7, 86.7, 53.1,
44.4, 23.5; IR 2954, 1738, 1680, 1427, 1290 cm^1. Anal. calcd for C13H13NO5: C, 59.31; H, 4.98; N, 5.32. Found: C,
59.01; H, 5.28; N, 4.97. Compound 7d: 69% yield (40 mg); m.p. 156±157ꢀC; 1H NMR (CDCl3/CD3OD) ꢀ 8.14 (d,
2H, J=6.0 Hz), 7.75 (d, 2H, J=6.0 Hz), 4.00 (s, 3H), 3.87 (s, 3H); 13C NMR (CDCl3/CD3OD) ꢀ 168.4, 160.6,
159.8, 159.5, 156.3, 132.0, 131.2, 130.3, 128.2, 115.8, 53.5, 53.2; IR 2960, 1724, 1687, 1430, 1265 cm^1. Anal. calcd
for C14H11NO7: C, 55.09; H, 3.63; N, 4.59. Found: C, 55.30; H, 4.01; N, 4.19. Compound 7e: 75% yield (40 mg);
m.p. 114±115ꢀC; 1H NMR (CDCl3/CD3OD) ꢀ 7.55 (d, 2H, J=9.0 Hz), 6.90 (d, 2H, J=9.0 Hz), 5.11 (t, 1H, J=8.9
Hz), 4.59 (s, 2H), 3.75 (s, 3H), 3.56 (d, 2H, J=8.9 Hz); 13C NMR (CDCl3/CD3OD) ꢀ 170.9, 170.8, 159.5, 155.5,
128.5, 121.7, 114.8, 77.6, 65.0, 52.8, 39.0; IR 2911, 1724, 1435, 1245 cm^1. Anal. calcd for C13H13NO6: C, 55.92; H,
4.69; N, 5.02. Found: C, 55.88; H, 4.69; N, 4.82. Compound 7f: 67% yield (39 mg); m.p. 134±135ꢀC; H NMR
1
(CDCl3/CD3OD) ꢀ 7.57 (d, 2H, J=9.0 Hz), 6.90 (d, 2H, J=9.0 Hz), 4.96±4.87 (m, 1H), 4.63 (s, 2H), 4.25±4.13 (m,
2H), 3.40 (dd, 1H, J=16.7 Hz, J=10.8 Hz), 3.10 (dd, 1H, J=16.7 Hz, J=7.21 Hz), 2.05 (s, 3H); 13C NMR
(CDCl3/CD3OD) ꢀ 171.1, 170.9, 159.2, 155.8, 128.2, 122.2, 114.7, 77.8, 64.8, 63.9, 37.2, 20.5; IR 2923, 1710, 1362,
1235 cm^1. Anal. calcd for C14H15NO6: C, 57.34; H, 5.16; N, 4.78. Found: C, 56.99; H, 5.08; N, 4.66. Compound
7g: 70% yield (41 mg); m.p. 119±120ꢀC; 1H NMR (CDCl3/CD3OD) ꢀ 7.60 (d, 2H, J=9.0 Hz), 6.93 (d, 2H, J=9.0
Hz), 4.67 (s, 2H), 3.80 (d, 1H, J=18.0 Hz), 3.79 (s, 3H), 3.18 (d, 1H, J=18.0 Hz), 1.70 (s, 3H); 13C NMR (CDCl3/
CD3OD) ꢀ 172.7, 170.1, 159.3, 155.9, 128.3, 122.3, 114.8, 85.9, 58.0, 53.0, 44.9, 23.5; IR 2969, 1732, 1709, 1426,
1247 cm^1. Anal. calcd for C14H15NO6: C, 57.34; H, 5.16; N, 4.78. Found: C, 57.52; H, 5.21; N, 4.58. Compound
7h: 69% yield (46 mg); m.p. 90±91ꢀC; H NMR (CDCl3/CD3OD) ꢀ 7.63 (d, 2H, J=9.0 Hz), 6.99 (d, 2H, J=9.0
1
Hz), 4.67 (s, 2H), 3.99 (s, 3H), 3.89 (s, 3H); 13C NMR (CDCl3/CD3OD) ꢀ 171.1, 169.7, 161.9, 160.6, 159.5, 156.5,
126.7, 120.2, 115.0, 114.9, 64.8, 53.4, 53.2; IR 2954, 1726, 1421, 1229 cm^1. Anal. calcd for C15H13NO8: C, 53.74;
H, 3.91; N, 4.18. Found: C, 54.05; H, 3.89; N, 3.82. Compound 7i: 50% yield (27 mg); m.p. 148±149ꢀC; 1H NMR
(CDCl3/CD3OD) ꢀ 7.36±6.80 (m, 4H), 5.10±5.03 (m, 1H), 4.60 (s, 2H), 3.75±3.61 (m, 5H); 13C NMR (CDCl3/

5622
CD3OD) ꢀ 171.1, 168.6, 155.5 (2), 131.7, 129.9, 122.0, 118.3, 112.0, 78.1, 65.4, 65.3, 41.5; IR 2917, 1711, 1235 cm^1.
Anal. calcd for C13H13NO6: C, 55.92; H, 4.69; N, 5.02. Found: C, 55.66; H, 4.34; N, 4.97. Compound 7j: 51%
yield (30 mg); m.p. 65±66ꢀC; H NMR (CDCl3/CD3OD) ꢀ 7.26±6.78 (m, 4H), 4.63±4.62 (m, 1H), 4.33 (s, 2H),
1
4.04-3.93 (m, 2H), 3.31 (dd, 1H, J=16.8 Hz, J=10.7 Hz), 3.02 (dd, 1H, J=16.8 Hz, J=7.1 Hz), 1.93 (s, 3H); 13
C
NMR (CDCl3/CD3OD) ꢀ 171.3, 156.4, 156.1, 155,5, 131.8, 130.1, 120.7, 119.1, 114.0, 77.4, 68.2, 63.1, 39.7, 20.8;
IR 2940, 1737, 1615, 1226 cm^1. Anal. calcd for C14H15NO6: C, 57.34; H, 5.16; N, 4.78. Found: C, 57.33; H, 5.07;
N, 4.70. Compound 7k: 57% yield (33 mg); 1H NMR (CDCl3/CD3OD) ꢀ 7.28±6.74 (m, 4H), 4.33 (s, 2H), 3.78 (d,
1H, J=17.6 Hz), 3.61 (s, 3H), 3.21 (d, 1H, J=17.6 Hz), 1.48 (s, 3H); 13C NMR (CDCl3/CD3OD) ꢀ 173.0, 156.4
(2), 156.0, 131.6, 131.0, 121.0, 120.9, 113.8, 85.0, 68.3, 52.8, 47.1, 23.2; IR 2967, 1731, 1709, 1246 cm^1. Anal.
calcd for C14H15NO6: C, 57.34; H, 5.16; N, 4.78. Found: C, 57.63; H, 5.10; N, 4.66. 7l: 51% yield (34 mg); m.p.
174±175ꢀC; 1H NMR (CDCl3/CD3OD) ꢀ 7.63±6.79 (m, 4H), 4.75 (s, 5H), 4.71 (s, 3H); 13C NMR (CDCl3/
CD3OD) ꢀ 169.7, 168.3, 159.4, 159.3, 156.0, 134.2, 133.9, 133.8, 121.6, 121.8, 115.9, 112.2, 91.5, 65.5, 65.3; IR
2912, 1737, 1709, 1248 cm^1. Anal. calcd for C15H13NO8: C, 53.74; H, 3.91; N, 4.18. Found: C, 54.01; H, 3.70; N,
4.29.