Zhang et al.
was stirred at rt for 2 h. The reaction mixture was precipitated
by addition to Et2O followed by filtration. The resulting ether
solution was washed with water to eliminate DMAP, concen-
trated under reduced pressure, and filtered through silica gel
(EtOAc) to produce the corresponding ester in good to excellent
yield and purity.
reagent in the area of combinatorial library development
is underway and will be reported shortly.
Experimental Section
Synthesis of Mono-endo-amine 2.20 cis-5-Norbornene-
endo-2,3-dicarboxylic anhydride (10 g, 60.9 mmol) was refluxed
with 1,2-diaminoethane (16.3 mL, 243.7 mmol) in toluene (80
mL) overnight to give 10.5 g (83%) of product as a pale yellow
solid. 1H NMR and 13C NMR spectra are consistent with
literature examples.
Preparation of Urea 3. Cyclohexyl isocyanate (0.95 g, 7.6
mmol) was added dropwise to a solution of mono-endo-amine
2 (1.42 g, 6.9 mmol) at 0 °C in CH2Cl2 (30 mL). After
completion of the addition, the ice bath was removed, and the
reaction solution was stirred at rt for 1.5 h. CH2Cl2 was
evaporated under reduced pressure, and the residue was
recrystallized using ethanol to give 2.14 g of urea 3 as a slightly
yellow solid (94%): 1H NMR δ 6.08 (s, 2H), 4.87 (br s, 1H),),
4.63 (br s, 1H), 3.49-3.23 (m, 9H), 1.88 (d, J ) 9.9, 2H), 1.73-
1.66 (m, 3H), 1.60-1.50 (m, 2H), 1.37-1.27 (m, 2H), 1.15-
1.04 (m, 3H); 13C NMR δ 178.0, 157.3, 134.3, 52.1, 49.0, 45.8,
44.8, 39.0, 38.1, 33.8, 25.5, 24.9; HRMS (FAB) calcd for M +
H (C18H26N3O3) required 332.1974, found 332.1948.
General Procedure for Amidation Using 2GOACCn.
Method A. To a stirring solution of acid (0.1 mmol) and amine
(0.1 mmol) in CH2Cl2 (0.5 mL) at 0 °C was added dropwise a
solution of 2GOACC50 (43 mg, 0.13 mmol) in CH2Cl2 (0.5 mL).
After addition, the ice bath was removed, and the reaction
solution was stirred at rt for 2-7 h. The reaction mixture was
precipitated by addition to EtOAc (or Et2O or MeOH) followed
by filtration. The resulting filtrate was concentrated under
reduced pressure and filtered through a silica gel (EtOAc) to
produce the corresponding amide in good to excellent yield and
purity.
Method B. To a suspension of 5-bromo-2-furoic acid (0.52
mmol), amine (1.0-1.5 equiv), and DMAP (10 mol %) in CH2-
Cl2 (0.3 mL) at rt was added dropwise a solution of 2GOACC100
(1.5-2.0 equiv) in CH2Cl2 (2 mL). After addition, the reaction
mixture was stirred at rt for 7-12 h. After completion of
reaction (TLC), the DMAP and excess amine were scavenged
using Amberlyst A-15 ion-exchange resin (purchased from
Aldrich, load ) 4 mmol/g). The reaction mixture was precipi-
tated by addition to EtOAc (or MeOH), filtered through a short
SPE (SiO2), and concentrated under reduced pressure to
produce the corresponding amide in good to excellent yield and
purity.
General Procedure for Anhydride Formation Using
2GOACC50. To a stirring solution of acid (0.2 mmol) in CH2Cl2
(0.5 mL) at 0 °C was added dropwise a solution of 2GOACC50
(43 mg, 0.13 mmol) in CH2Cl2 (0.5 mL). After addition, the
reaction solution was stirred at 0 °C for 1.5-2.0 h. The reaction
mixture was precipitated by addition to an Et2O followed by
filtration. The resulting filtrate was concentrated under
reduced pressure and filtered through silica gel (EtOAc) to
produce the corresponding anhydride in good to excellent yield
and purity.
Dehydration of Urea 3 To Form Monomer Carbodi-
imide 4. Using the same procedure as shown in ref 21, to a
suspension of urea 3 (1.15 g, 3.47 mmol) in triethylamine (2.4
mL, 17.3 mmol) was added phenylsulfonyl chloride (1.02 mL,
6.9 mmol) at rt. After the addition was completed, the resulting
suspension was stirred and heated to 70 °C for 1.5 h. The
reaction was quenched with ice-water and partitioned be-
tween water and ether. The organic portion was separated,
washed with water and brine, dried (MgSO4), and concentrated
under reduced pressure. The residue was purified by column
chromatograph (40% EtOAc in hexanes) to obtain 793 mg of
required carbodiimide 4 (73%): 1H NMR δ 6.05 (t, J ) 1.7,
2H), 3.41 (t, J ) 6.6, 2H), 3.34-3.28 (m, 2H), 3.24-3.19 (m,
5H), 1.83-1.77 (m, 2H), 1.67-1.60 (m, 3H), 1.47 (d, J ) 8.7,
2H), 1.29-1.10 (m, 5H); 13C NMR δ 177.2, 139.1, 134.2, 55.3,
51.9, 45.5, 44.7, 43.5, 38.8, 34.5, 25.1, 24.2; HRMS (FAB) calcd
for M + H (C18H24N3O2) required 314.1869, found 314.1868.
ROM Polymerization Procedure for the Generation
of the Oligomeric Alkyl Cyclohexylcarbodiimide
Acknowledgment. This investigation was gener-
ously supported by partial funds provided by the
National Science Foundation (NSF Career 9984926), the
University of Kansas Research Development Fund, and
the NIH Combinatorial Methodology and Library De-
velopment Center of Excellence (KU-CMLD, NIH 1P50
GM069663-01) with additional funds from the State of
Kansas and the National Institutes of Health Center
for Cancer Experimental Therapeutics (NIH-COBRE
P20 RR15563, Core-D). We thank Neogenesis Pharma-
ceuticals, Inc., for providing generous postdoctoral sup-
port (M.Z.) and Materia, Inc., for supplying the catalyst
and helpful discussions. We thank Professor Gwendolyn
L. Macpherson, Director of the Plasma Analytical
Laboratory at the University of Kansas, for carrying out
ICP-MS measurements. We also thank the reviewers
for many kind suggestions.
(
2GOACC50). In a 100 mL round-bottom flask, N-cyclohexyl-
N′-(2-succinimidoethyl)carbodiimide (4) (0.80 g, 2.55 mmol)
was dissolved in degassed (argon) CH2Cl2 (30 mL). To this
solution was added the second-generation Grubbs’ metathesis
catalyst 5 (43 mg, 0.051 mmol) in one portion. The reaction
was refluxed under argon and monitored by TLC analysis.
Once the polymerization was complete (∼3.5 h), the reaction
was quenched by ethyl vinyl ether (approximately 1.0 mL) over
a 10 min period. The mixture was reduced to 1/3 of the original
volume and dripped into 60 mL of dry Et2O to induce
precipitation. Subsequent filtration produced 0.78 g (98%)
of 2GOACC50 as a light-brown free-flowing solid: 1H NMR δ
7.83-6.99 (m, terminal Ph), 5.72-5.60 (m, 2H, olefin), 3.94-
2.92 (m, 9H), 2.12-0.80 (m, 12H); 13C NMR δ 176.5, 139.4,
129.5 55.5, 48.8, 45.2, 43.6, 40.2, 39.4, 34.7, 25.3, 24.4; FTIR
(film) 2122 (NdCdN), 1703 cm-1. Anal. Calcd for CH2d
(C18H25N3O2)50dCHC6H5: C, 69.14; H, 7.40; N, 13.32. Found:
C, 69.48; H, 7.28; N, 13.01.
Supporting Information Available: Tabulated 1H NMR,
13C NMR, and mass data of crude products 6-9 obtained by
2GOACCn coupling reactions; 1H NMR spectra of 3, 4,
2GOACC50, and 6-9. This material is available free of charge
General Procedure for Esterification Using 2GOACC50.
To a stirring solution of acid (0.1 mmol), alcohol [or phenol or
thiol (0.1 mmol)], and DMAP (1.2 mg, 10 mmol %) in CH2Cl2
(0.5 mL) at 0 °C was added dropwise a solution of 2GOACC50
(47 mg, 0.15 mmol) in CH2Cl2 (0.5 mL). After complete
addition, the ice bath was removed, and the reaction solution
JO048870C
8344 J. Org. Chem., Vol. 69, No. 24, 2004