3050 J . Org. Chem., Vol. 67, No. 9, 2002
Spanka et al.
(231 µL, 3 mmol) in CH2Cl2 (5 mL) was slowly added. After
completion of the addition the reaction was warmed to room
temperature overnight with stirring. The clear yellow solution
was concentrated to 5 mL and added to cold, stirred methanol
(200 mL). The precipitated polymer was filtered off, washed
with cold methanol (2 × 10 mL), and vacuum-dried to afford
a pale yellow fine powder (1.08 g, quant. polymer recovery).
IR: 1740 (CdO, ester), 1710 (CdO, ketone). 1H NMR (500
MHz, CDCl3): δ 2.25 (3H, COCH3), 2.56 (2H, CH2Ar), 3.45
(2H, CH2COCH3), 4.04 (4H, CH2OAr), 4.16 (2H, CH2O2C). (6b,
R ) Ph) A solution of 4′-hydroxybutyl microgel 5 (1.5 g, ca.
1.5 mmol) and 5-(hydroxy-phenylmethylene)-2,2-dimethyl-[1,3]-
dioxane-4,6-dione (930 mg, 3.75 mmol) in THF (35 mL) was
heated to reflux for 18 h. After cooling, the mixture was
concentrated under reduced pressure to yield a yellow oil. The
crude product was dissolved in chloroform (5 mL) and pre-
cipitated as above, affording a pale yellow powder (1.41 g, 85%
polymer recovery). IR: 1737 (CdO, ester), 1687 (CdO, ketone).
1H NMR (500 MHz, CDCl3): δ 2.48 (2H CH2Ar), 3.98 (2H, CH2-
COPh), 4.03 (4H, CH2OAr), 4.17 (2H, CH2O2C), 7.34 (2H, PhH-
3,5), 7.53 (1H, PhH-4), 7.93 (2H, PhH-2,6).
Gen er a l P r oced u r e for t h e Dia zot r a n sfer R ea ct ion ,
P r ep a r a tion of Micr ogel-Bou n d r-Dia zo-â-k etoester s 6.
A solution of a â-ketoester 6 (1 g, ca. 1 mmol), triethylamine
(0.76 mL, 5.5 mmol), and 4-dodecylbenzenesulfonyl azide (1.68
mL, 5 mmol) in toluene (12 mL, 10 wt %) was protected from
light and stirred for 48 h. The clear dark solution was
concentrated to a volume of 5 mL and added to cold stirred
methanol (100 mL). The precipitated polymer was filtered off,
washed with cold methanol (2 × 5 mL), and dried by suction.
The precipitation was repeated a second time in order to
remove traces of unreacted sulfonyl azide. Drying under
vacuum afforded the products as yellow powders.
â-k etoester s 9 w ith Dibr om otr ip h en ylp h osp h or a n e. To
a solution of microgel 9 (105 mg, ca. 68 µmol) and triethy-
lamine (38 µL, 0.27 mmol) in CH2Cl2 (3 mL) was added
dibromotriphenylphosphorane (59 mg, 0.14 mmol) in one
portion at 0 °C with stirring. The clear yellow solution was
stirred for 3 h at room temperature under argon. Then, the
reaction mixture was added to stirred cold methanol (30 mL),
and the precipitated polymer was filtered off, washed with cold
methanol (2 × 5 mL), and air-dried. High vacuum drying at
room temperature for 5 h gave the polymer-bound oxazoles
10 as tan colored powders (polymer recovery, 78-95%).
Selected Da ta . 10f (R1 ) Ph, R2 ) H): 95 mg, 90%. IR:
1730(CdO, ester). 1H NMR (500 MHz, CDCl3): δ 2.50 (2H,
CH2Ar), 4.03 (very broad, 4H, CH2OAr), 4.53 (2H, CH2O2C);
7.48 (6H, ArH), 8.17 (2H, ArH), 8.24 (2H, ArH).
Gen er a l P r oced u r e for th e P r ep a r a tion of Micr ogel-
Bou n d Oxa zoles 10 by Cyclyza tion of r-(Ben zoyla m in o)-
â-k etoester s 9 w ith Bu r gess Rea gen t. A solution of micro-
gel 9 (150 mg, ca. 0.15 mmol) and Burgess reagent (174 mg,
0.75 mmol) in 1,2-dichloroethane (3 mL) was heated overnight
at 70 °C (oil bath) in a sealed 10 mL reaction vial. After cooling
to room temperature the clear brown colored solution was
added to cold stirred methanol (25 mL). The precipitated
polymer was filtered off, washed with cold methanol (2 × 5
mL), and dried under vacuum (rt, 6 h) to afford a beige colored
powder (polymer recovery. 90% to quant.).
Selected Da ta . 10c (R1 ) Me,R2 ) 4-CF3): 138 mg, 92%.
IR: 1716(CdO, ester), 1321 (CF3). 1H NMR (500 MHz,
CDCl3): δ 2.55 (2H, CH2Ar), 2.69 (3H, 5-CH3), 4.03 (very
broad, 4H, CH2OAr), 4.38 (2H, CH2O2C), 7.70 (2H, ArH-2,6),
8.18 (2H, ArH-3,5).
Gen er a l P r oced u r e for Clea va ge w ith Dieth yla m in e/
Alu m in u m Ch lor id e. 5-Met h yl-2-p h en yloxa zole-4-ca r -
boxylic a cid d ieth yla m id e (11a ). A 0.25 M AlCl3/1 M Et2NH
stock solution was prepared by dropwise addition of freshly
distilled diethylamine (1 mL, 10 mmol) to a stirred suspension
of anhydrous aluminum chloride (333 mg, 2.5 mmol) in CH2-
Cl2 (9 mL) at 0 °C. After all aluminum chloride had dissolved,
the solution was ready for use and stored under argon.
An aliquot of the above solution (0.92 mL, 2 equiv of AlCl3,
8 equiv of Et2NH) was added by syringe to a solution of
polymer-bound oxazole (120 mg, 115 µmol, loading, 0.96 mmol
g-1) in CH2Cl2 (3 mL). After stirring at room temperature
overnight the dark orange reaction mixture was added to
vigorously stirred methanol (25 mL). Precipitated polymer and
aluminum salts were removed by filtration, and the filtrate
was concentrated to 5 mL, passed through a mixed bed ion-
exchange resin, and evaporated to dryness to give the crude
product. HPLC: tR ) 12.52 min (purity 90%). Purification by
preparative TLC (ethyl acetate/hexanes 1:3) afforded 11a as
an off white crystalline solid (10.8 mg, 36%); TLC: Rf ) 0.35);
IR: 2968, 2931, 1626 (CdO amide-I), 1561, 1478, 1449, 1379,
1337, 1260, 1195, 1095, 1074, 863, 778, 710, 691; 1H NMR (400
MHz, CDCl3) δ 1.24 (br t, J ) 7.3 Hz, 3H), 1.32 (br t, J ) 7.0
Hz, 3H), 2.63 (s, 3H), 3.52 (br q, J ) 6.6 Hz, 2H), 3.77 (br q, J
) 7.0 Hz, 2H), 7.43-7.48 (m, 3H), 7.99-8.02 (m, 2H). HRMS:
calcd for C15H18N2O2 259.1441, found 259.1448.
7a (R ) Me): 913 mg, 92%. IR: 2138 (CdN2), 1718 (CdO,
ester), 1658 (CdO, ketone). 1H NMR (500 MHz, CDCl3): δ 2.48
(3H, COCH3); 2.56 (2H, CH2Ar), 4.04 (4H, CH2OAr), 4.25 (2H,
CH2O2C). Elemental analysis: N, 2.88% (loading, 1.03 mmol
g-1 CdN2).
7b (R ) Ph): 1.34 g, 96%. IR: 2140 (CdN2), 1722 (CdO,
ester), 1689 (CdO, ketone). 1H NMR (500 MHz, CDCl3): δ 2.48
(2H, CH2Ar), 4.03 (4H, CH2OAr), 4.19 (2H, CH2O2C), 7.34 (2H,
PhH-3,5), 7.52 (1H, PhH-4), 7.62 (2H, PhH-2,6). Elemental
analysis: N, 1.82% (loading, 0.65 mmol g-1 CdN2).
Gen er a l P r oced u r e for th e Rh od iu m -Ca ta lyzed In ser -
tion Rea ction . To a solution of R-diazo-â-ketoester 7 (150 mg,
0.15 mmol) in toluene (5 mL) was added benzamide 8 (0.75
mmol). The reaction vial was sealed with a rubber septum,
purged with argon, and placed in a preheated oil bath (60 °C).
Then, a 12 mM solution of rhodium(II) acetate dimer in toluene
(0.25 mL, 3 µmol, 2 mol %) was injected in one portion to the
vigorously stirred reaction mixture. After an induction period
of a few minutes effervescence of nitrogen was observed. After
30 min no further nitrogen was liberated, and stirring was
continued overnight. The mixture cooled to room temperature,
and unreacted benzamide was filtered off. The filtrate was
concentrated to a volume of ca. 1 mL and added to stirred cold
methanol (25 mL). The precipitated polymer was filtered off,
washed with cold methanol (2 × 5 mL), and dried by suction.
Further drying in a high vacuum overnight at room temper-
ature afforded the polymer bound R-(benzoylamino)-â-ke-
toesters 9 as finely divided tan powders (polymer recovery, 79-
99%).
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support from the National Institutes of Health
(GM-56154), The Scripps Research Institute, The Sk-
aggs Institute for Chemical Biology and Novartis Phar-
ma AG, Basel, Switzerland. B.C. is a Skaggs postdoc-
toral fellow. We thank Erica Strable for assistance in
conducting the light scattering experiments.
Selected Da ta for 9. 9c (R1 ) Me, R2 ) 4-F3C): 155 mg,
97%. IR: 3419 (N-H), 1747 (CdO, ester), 1726 (CdO, ketone),
1
1672 (CdO, amide), 1324 (CF3). H NMR (500 MHz, CDCl3):
δ 2.43 (3H, COCH3), 2.55 (2H, CH2Ar), 4.02 (4H, CH2OAr),
4.25 (2H, CH2O2C), 5.43 (1H, CH), 7.70 (2H, ArH-2,6), 7.94
(2H, ArH-3,5). 9h (R1 ) Ph, R2 ) 4-F3C): 132 mg, 83%. IR:
3402 (N-H), 1739 (CdO, ester), 1689 (CdO, ketone), 1677 (Cd
O, amide), 1324 (CF3). 1H NMR (500 MHz, CDCl3): δ 2.40 (2H
CH2Ar), 3.99 (4H, CH2OAr), 4.20 (2H, CH2O2C), 5.34 (1H, CH),
7.43 (3H, PhH-2,4,6), 7.70 (2H, ArH-2,6), 7.91 (2H, PhH-3,5),
8.16 (2H, ArH-3,5).
Su p p or tin g In for m a tion Ava ila ble: Procedures for the
synthesis of monomer 4 and analytical data for compounds
11a -k . This material is available free of charge via the
Internet at http://pubs.acs.org. 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.
Gen er a l P r oced u r e for th e P r ep a r a tion of Micr ogel-
Bou n d Oxa zoles 10 by Cyclyza tion of r-(Ben zoyla m in o)-
J O016362M