7558 J. Am. Chem. Soc., Vol. 121, No. 33, 1999
Anderson et al.
aqueous solution of sodium chloride. Compounds 6, 6-d1, and 6-d2,4e
7, 8,23 10,24 11,25 2-bromo-N,N-diiospropylbenzamide,26 2-bromo-N,N-
isopropylbenzamide,27 and N-isopropylphthalimide (12)28 were prepared
according to previously published procedures.
(mp 100-103 °C, lit. mp 99-103 °C28), which was spectroscopically
and chromatographically analogous to 8. FI/MS analysis revealed 99.6%
d2, 0.4% d1.
Synthesis of 1,3-Dimethyl-5-phenylimidazolidine-2,4-dione (9).
A solution of 6 (327 mg, 1.83 mmol) and TMEDA (5.50 mmol, 0.83
mL, 3.0 equiv) in 20 mL of THF was treated with sec-BuLi (5.50 mmol,
3.0 equiv) at -78 °C. After 1 h, CO2 was bubbled through the solution.
Water was added to the solution after 15 min and allowed to warm to
room temperature. The solution was extracted with CH2Cl2 and dried
over MgSO4. After filtration and evaporation, the residue was chro-
matagraphed on silica (50% EtOAc/petroleum ether) to provide 333
mg (82%) of 9 as a white solid (mp 100-101 °C): 1H NMR (CDCl3,
500 MHz) δ 2.89 (s, 3H), 3.06 (s, 3H), 4.79 (s, 1H), 7.23-7.27 (m,
2H), 7.40-7.42 (m, 3H); 13C (CDCl3, 125 MHz) δ 25.2, 28.1, 65.9,
127.2, 129.3, 132.5, 156.9, 171.3; FI/MS (M+) 204. Anal. Calcd for
C11H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C, 64.38; H, 5.97;
N, 13.83.
Procedure for Determination of Intramolecular Isotope Effects.
A ca. 0.05 M solution of 6-d1, 7-d1, or 8-d1 in THF was treated with
a solution of TMEDA (2.2, 1.1, and 2.2 equiv, respectively) and sec-
BuLi (2.2, 1.1, and 2.2 equiv, respectively) in THF at -78 °C in a
cold transfer flask. After 15 min, anhydrous CO2 was bubbled through
the solution for at least 15 min. After warming to room temperature,
the solution was treated with 2 N HCl, extracted with CH2Cl2, and
dried over MgSO4. Filtration and evaporation gave the corresponding
products 9, 10, or 11, which were separated from the starting materials
chromatographically on silica (EtOAc, 3% MeOH/CH2Cl2, and 5%
MeOH/CH2Cl2, respectively) Mass recoveries were typically better than
80%. Carboxylic acids 10 and 11 were converted to N-isopropylphthal-
imide (12) prior to characterization.24 Mass spectrometry was performed
on the recovered 6, 7, and 8 as well as the products 9 and 12, and the
ratios of 9-11-d1 to 9-11-d0 were calculated.
Procedure for Determination of Intermolecular Isotope Effects.
A ca. 0.05 M solution of known mixtures of 6-d0/6-d2, 7-d0/7-d2, or
8-d0/8-d2 in THF was treated with a solution of TMEDA (1.2-1.8,
0.25-0.9, and 1.2-1.8 equiv, respectively) and sec-BuLi (1.2-1.8,
0.25-0.9, and 1.2-1.8 equiv, respectively) in THF at -78 °C in a
cold transfer flask. After 15 min, anhydrous CO2 was bubbled through
the solution for at least 15 min. After warming to room temperature,
the solution was treated with 2 N HCl, extracted with CH2Cl2, and
dried over MgSO4. Filtration and evaporation gave the corresponding
products 9, 10, or 11, along with starting materials, which were
separated chromatographically on silica (EtOAc, 3% MeOH/CH2Cl2,
and 5% MeOH/CH2Cl2 respectively). Yields and mass balances were
calculated from isolated materials. Mass recoveries were typically better
than 80%. Carboxylic acids 10 and 11 were converted to 12 prior to
characterization. Mass spectrometry was performed on the recovered
6, 7, and 8, as well as the products 9 and 12, and the extents of
conversion of 6-8-d0 to 9-11-d0 and 6-8-d2 to 9-11-d1 were
calculated.
Synthesis of N,N-Diisopropylbenzamide-d1 (7-d1). A solution of
2-bromo-N,N-diisopropylbenzamide (1.35 g, 4.75 mmol) in 12 mL of
THF was treated with n-BuLi (7.13 mmol, 1.5 equiv) at -78 °C. After
1 h, MeOD (1 mL) was added. After the solution warmed to room
temperature, the THF was removed in vacuo and the residue extracted
with Et2O (3 × 15 mL), washed with brine, and dried over MgSO4.
After filtration and removal of solvent, the residue was purified by
chromatography on silica (20% EtOAc/petroleum ether) to provide 993
mg (95%) of 7-d1 as a white solid (mp 70-71 °C, lit. mp 69.5-72
°C22), which was spectroscopically and chromatographically analogous
to 7. FI/MS analysis revealed 99.3% d1, 0.7% d0.
Synthesis of N,N-Diisopropylbenzamide-d2 (7-d2). A solution of
7 (1.00 g, 4.88 mmol) in 15 mL of THF was added to a solution of
sec-BuLi (10.74 mmol, 2.2 equiv) and TMEDA (10.74 mmol, 1.62
mL, 2.2 equiv) in 30 mL of THF at -78 °C. After 15 min, MeOD (1
mL) was added. After the solution warmed to room temperature, the
THF was removed in vacuo and the residue extracted with Et2O (3 ×
15 mL), washed with brine, dried over MgSO4, filtered, and evaporated.
The above procedure was repeated twice. The product was purified by
chromatography on silica (20% EtOAc/petroleum ether) to provide 857
mg (85%) of 7-d2 as a white solid (mp 70-71 °C, lit. mp 69.5-72
°C22), which was spectroscopically and chromatographically analogous
to 7. FI/MS gave 99.4% d2, 0.6% d1.
Synthesis of N-Isopropylbenzamide-d1 (8-d1). A solution of
2-bromo-N-isopropylbenzamide (1.15 g, 4.76 mmol) in 10 mL of D2O
and 10 mL of CDCl3 was stirred vigorously for 48 h. The layers were
separated, and the organic layer was dried over MgSO4, filtered, and
evaporated to give the corresponding N-D analogue. This material
was dissolved in 30 mL of THF, treated with NaH (572 mg, 3.0 equiv),
and heated to reflux for 16 h. The solution was treated with n-BuLi
(14.3 mmol, 3.0 equiv) at -78 °C. After 1 h, MeOD (2.9 mL) was
added. After warming to room temperature, the solution was treated
with 2 N HCl and extracted with CH2Cl2. After the solution was dried
over MgSO4 and filtered and the solvent removed, the residue was
purified by chromatography on silica (30% EtOAc/petroleum ether) to
provide 605 mg (77%) of 8-d1 as a white solid (mp 101-103 °C, lit.
mp 99-103 °C29), which was spectroscopically and chromatographi-
cally analogous to 8. FI/MS analysis revealed 97.0% d1, 3.0% d0.
Synthesis of N-Isopropylbenzamide-d2 (8-d2). A solution of 8 (1.04
g, 6.39 mmol) in 5 mL of THF was added to a solution of tert-BuLi
(19.2 mmol, 3.0 equiv) and TMEDA (19.2 mmol, 2.89 mL, 3.0 equiv)
in 20 mL of THF at -78 °C. After 15 min, MeOD (2.6 mL) was added.
After warming to room temperature, the solution was treated with 2 N
HCl, extracted with CH2Cl2, dried over MgSO4, and filtered, and the
solvent was removed in vacuo. The procedure was repeated twice. The
residue was purified by chromatography on silica (30% EtOAc/
petroleum ether) to provide 605 mg (77%) of 8-d2 as a white solid
Acknowledgment. We thank the National Institutes of
Health (GM-18874) and the National Science Foundation (NSF
CHE 95-26355) for financial support for this work.
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Supporting Information Available: Sample calculations for
isotope effects and evaluation of error propagation (PDF). This
material is available free of charge via the Internet at
JA991043M