Verbeeck et al.
JOCArticle
2-Benzofuran-1,3-dione (5). The title compound was obtained
following a literature procedure as a white solid in quantitative
yield.21 1H NMR (CDCl3/DMSO-d6 1:1): δ 12.77 (m, 2H), 12.71
(m, 2H). 13C NMR (CDCl 3/DMSO-d6 1:1): δ 167.9, 141.2,
Quinazoline-d6 (30). In a 20-mL pressure tube equipped with a
septum and cap were placed brought quinazoline-d4 (300) (0.175 g,
1.305 mmol) and Pd/C (0.075 g, 0.0705 mmol) in 10 mL of D2O
under Ar atmosphere. A H2 balloon was put on the tube via a
needle through the septum. The mixture was flushed with H2 via a
second needle through the septum. After flushing for 30 min the
balloon and the extra needle were removed, and the mixture was
heated at 55 °C for 48h and then to 90 °C for 6 h. The mixture was
filtered through a paper filter and extracted with 3 ꢀ 100 mL of
EtOAc, and the organic phase was dried over MgSO4. The sol-
vent was evaporated to near dryness. The residue was brought
onto a silica gel column and separated using DCM/EtOAc (6:4)
asthe eluent. The title compoundwasobtainedasa creamcolored
solid in 50% yield (0.088 g). 13C NMR (CDCl3): δ 159.8 (t, J =
26.97 Hz), 154.9 (t, J = 30.29 Hz), 150.0, 133.7 (t, J = 24.55 Hz),
128.0 (t, J = 24.85 Hz), 127.4 (t, J = 24.66 Hz), 126.7 (t, J =
25.65 Hz), 124.9. HRMS (ESI) for C8D6HN2þ [M þ H]þ, calcd
137.0986, found 137.1001.
Procedures Followed for the Determination of KIEs for Dif-
ferent Substrate/Alkylamine Combinations Using KMnO4 or
AgPy2MnO4 as Oxidant. 3-Nitropyridine (1): To a stirred solu-
tion of equimolar amounts of 3-nitropyridine (1 mmol, 124 mg)
and 3-nitropyridine-d4 (1 mmol, 128 mg) in alkylamine (10 mL) at
8 - 10 °C was added 0.8 mmol of oxidant (KMnO4 or AgPy2-
MnO4) in small portions over 30 min. After a stirring time of 1.5 h,
the alkylamine was removed under reduced pressure. The residue
was dissolved in DCM and filtered over Celite. The PH/PD ratio
was measured via high resolution mass spectrometry.
136.1, 130.50. HRMS (ESI) for C8H5O3 [M þ H]þ, calcd
þ
149.0233, found 149.0235.
Phthalimide (6). The title compound was obtained as a white
solid following a literature procedure in 95% yield.11b 1H NMR,
13C NMR, and MS data are in agreement with literature.22
1H NMR (CDCl3): δ 7.87 (m, 2H), 7.76 (m, 2H), 7.52 (br s, 1H,
NH). 13C NMR (CDCl3): δ 167.7, 134.4, 132.7, 123.7. HRMS
(ESI) for C8H6NO2þ [M þ H]þ, calcd 148.0399, found 148.0385.
Phthalamide (7). The title compound was obtained as a white
solid following a literature procedure in 81% yield.11c 1H NMR
(DMSO-d6): δ 7.69 (s, 2H), 7.43-7.49 (m, 4H), 7.31 (s, 2H). 13
C
NMR (DMSO-d6) δ: 170.7, 136.7, 129.7, 128.1. HRMS (ESI)
for C8H9N2O2þ [M þ H]þ, calcd 165.0659, found 165.0645.
Quinazoline-2,4(1H,3H)-dione (8). The title compound was
obtained as a white solid following a literature procedure in 95%
yield.11d 1H NMR and 13C NMR data are in agreement with
literature.23 1H NMR (DMSO-d6): δ 11.20 (s, 1H), 11.10 (s,1H),
7.87 (dd, 1H, J = 8.11 Hz, 1.46 Hz), 7.61 (ddd, 1H, J = 8.21 Hz,
7.61 Hz, 1.52 Hz), 7.13-7.17 (m, 2H). 13C NMR (DMSO-d6): δ
163.3, 150.8, 141.3, 135.4, 127.4, 122.8, 115.8, 114.8. HRMS (ESI)
for C8H7N2O2þ [M þ H]þ, calcd 163.0508, found 163.0515.
2,4-Dichloroquinazoline (9). In a 50-mL three-necked round-
bottomed flask equipped with a reflux condenser and septum was
placed quinazoline-2,4(1H,3H)-dione (8) (1.420 g, 8.76 mmol) in
toluene (10 mL). The solution was flushed with Ar, stirred, and then
heated up to 50 °C. Phosphoryl trichloride (9 mL, 8.76 mmol) was
added, and the temperature was increased to 105 °C. DBU (2.6 mL,
17.25 mmol) was added in small portions with a syringe through the
septum. The mixture was refluxed for 24 h (oil bath temperature
120 °C) under magnetic stirring, then allow to cool to room tempera-
ture, and poured on ice. The water layer was extracted with EtOAc
(2 ꢀ 100 mL). The organic layer was dried on MgSO4, and the
solvent was evaporated. Purification by flash column chromatogra-
phy with DCM as the eluent provided the title compound as a white
solid in 75% yield (1.334 g). 1H NMR data are in agreement with
literature.24 1H NMR (CDCl3): δ 8.27 (d, 1H, J = 8.38 Hz), 8.01
(d, 1H, J = 3.64 Hz), 7.74-7.78 (m, 2H). 13C NMR (CDCl3): δ
163.0, 154.1, 151.4, 135.1, 128.2, 127.0, 125.0, 121.3. HRMS (ESI)
for C8H5N2Cl2þ [M þ H]þ, calcd 198.9824, found 198.9822.
Quinazoline (3). In a 50-mL round-bottomed flask equipped
with a septum were added 2,4-dichloroquinazoline (9) (1.393 g,
7 mmol), Pd/C (0.112 g, 0.105 mmol), and flame-dried Cs2CO3
(6.84 g, 21.00 mmol) in 15 mL of EtOAc. Air was replaced by Ar
atmosphere. A hydrogen balloon was put on the flask via a
needle through the septum under magnetic stirring. The mixture
was flushed with hydrogen via a second needle through the
septum, then the extra needle was removed. When all starting
material had reacted, the mixture was poured over Celite and
rinsed with EtOAc. The solvent was evaporated to dryness, and
the crude product was purified by flash column chromatogra-
phy over silica gel with DCM/EtOAc (6:4) as the eluent. The title
compound was obtained as a pale white solid in 50% yield (0.455
g). 1H NMR (CDCl3): δ 9.39 (s, 1H), 9.35 (s, 1H), 8.04 (d, 1H,
J = 8.86 Hz), 7.89-7.93 (m, 2H), 7.65 (ddd, 1H, J = 8.43 Hz,
6.91 Hz, 1.05 Hz). 13C NMR (CDCl3): δ 160.1, 155.2, 149.9,
1,3-Dinitrobenzene (2): 1,3-Dinitrobenzene (0.5 mmol, 0.084
g) and 1,3-dinitrobenzene-d4 (0.5 mmol, 0.086 g) were dissolved
in n-butylamine (10 mL) at room temperature. The oxidant
(KMnO4 or AgPy2MnO4) (0.4 mmol) was added in small
portions over 30 min under magnetic stirring. After overnight
stirring, the alkylamine was removed under reduced pressure. The
residue was dissolved in DCM and silica gel was added. The DCM
was evaporated, and the residue was brought onto a silica gel
column and subsequently eluted using DCM and DCM/heptane
(7:3). The PH/PD ratio was measured via 1H NMR on the isolated
mixture of deuterated and undeuterated reaction product.
Quinazoline (3): Quinazoline (0.5 mmol, 65 mg) and quinazo-
line-d6 (0.5 mmol, 68 mg) were dissolved in alkylamine (10 mL)
at 8-10 °C. The oxidant (KMnO4 or AgPy2MnO4) (0.4 mmol)
was added in small portions over 30 min under magnetic stirring.
After overnight stirring, the alkylamine was removed under
reduced pressure. The residue was dissolved in DCM, and silica
gel was added. The DCM was evaporated, and the residue was
brought onto a silica gel column and subsequently eluted with
1
DCM/MeOH (98: 2). The PH/PD ratio was measured via H
NMR on the isolated mixture of deuterated and undeuterated
reaction product.
General Procedure for the Preparation of Samples for the 1H
NMR Studies. A 0.4 M solution of substrate in alkylamine was
added to a small NMR tube. This small tube was placed in a
broader NMR tube, filled with CDCl3. In the case where
AgNO3 or TBACl were added as an additive, the sample
preparation procedure was identical, with 2 equiv of additive
relative to the substrate. The mixtures obtained were allowed to
achieve equilibrium for 15 min at the set temperature before
each measurement.
þ
134.0, 128.3, 127.8, 127.1, 125.00. HRMS (ESI) for C8H7N2
[M þ H]þ, calcd 131.0609, found 131.0605.
van’t Hoff equation
- ΔHr°
RT
ΔSr°
lnðKeq,T Þ ¼
þ
R
(21) Brown, R. F. C.; Coulston, K. J.; Eastwood, F. W.; Vogel, C. Aust.
J. Chem. 1988, 41, 1687.
(22) Lasri, J.; Kopylovich, M. N.; Guedes da Silva, M. F. C.; Charmier,
M. A. J.; Pombeiro, A. J. L. Chem.;Eur. J. 2008, 14, 9312.
(23) Mizuno, T.; Mihara, M.; Nakai, T.; Iwai, T.; Ito, T. Synthesis 2007,
16, 2524.
with
½σH-adductꢁ
½substrateꢁ
Keq,T
¼
(24) Kanuma, K.; et al. Bioorg. Med. Chem. 2006, 14, 3307.
5132 J. Org. Chem. Vol. 75, No. 15, 2010