The Journal of Organic Chemistry
Note
diethyl ether afforded 4 (0.037 g, 37%)19 as a white solid; mp = 127−
1
131 °C; H NMR (CDCl3) δ 7.43 (m, 5H), 5.71 (m, 1H), 3.69 (dd,
J = 19.23, 7.44 Hz, 1H), 3.52 (ddd, J = 18.96, 6.03, 1.65 Hz, 1H),
2.96 (ddd J = 132.7, 4.1, 6.3 Hz, 1H), 2.14 (ddd J = 130.2, 6.0, 9.9 Hz,
1H); 13C NMR (CDCl3, 50 scans) δ 199.5, 45.3; IR (ATR) 3037,
2921, 2899, 1731, 1682, 1280, 1238, 1049, 1000, 944, 892, 754, 694,
659 cm−1; HRMS (EI) calcd for C9H10O313C2 192.06971, found
192.06978.
Figure 3. Possible enol intermediates.
6-Phenyldihydro-2H-pyran-2,4(3H)-dione-2,3,4,5-13C4 (5).
Using the standard procedure (0.60 mmol scale, 45 °C) and tritura-
tion with diethyl ether afforded 5 (0.046 g, 39%)19 as a white solid;
mp = 130−133 °C; 1H NMR (CDCl3) δ 7.43 (m, 5H), 5.71 (m, 1H),
3.81 (m, 1H), 3.32 (m, 2H), 2.71 ppm (m, 1H); 13C NMR (CDCl3,
50 scans) δ 199.5, 167.0, 47.1, 45.2 ppm: IR (ATR) 3037, 2964, 2890,
1702, 1671, 1260, 1247, 1047, 997, 935, 888, 752, 694, 652 cm−1;
HRMS (EI) calcd for C7H10O313C4 194.07642, found 194.07647.
Methyl 3-(Hydroxy(phenyl)methyl)-2-oxocyclopentanecar-
boxylate (13). Using the standard procedure (2.0 mmol scale, 70 °C)
and flash chromatography on silica gel (16−20% EtOAc/hexanes)
afforded 13 (0.395g, 81%) as a yellow oil. A pale yellow solid (0.342 g,
70%) was obtained after trituration with Et2O; mp = 90−93 °C; 1H NMR
(CDCl3) δ 10.27 (s, 1H), 7.40 (m, 4H), 6.92 (t, J = 2.46, 2.46 Hz, 1H),
4.29 (q, J = 7.14, 0.14, 7.14 Hz, 2H), 2.90 (m, 2H), 2.67 (m, 2H), 1.34 (t,
J = 7.14, 7.14 Hz, 3H); 13C (CDCl3) (Mixture of keto and enol forms) δ
201.0, 170.0, 169.7, 169.5, 138.3, 136.7. 135.1, 134.7, 134.6, 130.7, 129.8,
129.2, 128.8, 128.6, 128.3, 127.5, 124.0, 106.1, 61.5, 60.2, 54.3, 26.3, 25.2,
24.4, 14.4, 14.2; IR (ATR) 3020, 2978, 2921, 1638, 1600, 1234, 1169,
1094, 770, 751, 723, 686, 634 cm−1; HRMS (EI) calcd for C15H16O3
244.10995, found 244.10911.
General Procedure for NMR Monitoring Studies. To a flame-
dried 5 mm screw-capped NMR tube under nitrogen were added
benzaldehyde (0.10 mmol), 1.0 mL of methanol-D4 with TMS, the
acetoacetate ester (0.10 mmol), and potassium carbonate (0.20 mmol).
The septa and the nitrogen filled balloon were replaced with the NMR
cap. A timer was started immediately after the potassium carbonate was
added. The sample was warmed to 45 °C in the NMR probe, and then
the magnetic field was shimmed and locked on the sample. Eight scans
of the heterogeneous mixture were collected every 60 min for 16 h. The
reaction was worked up using the procedure described above.
Procedure for Microwave Experiment. To a small test tube
were added benzaldehyde (0.10 mL, 0.99 mmol), 1.0 mL of ethanol,
ethyl acetoacetate (0.13 mL, 1.03 mmol), and potassium carbonate
(0.279 g, 2.02 mmol). The mixture was irradiated in a 1080 W
household microwave at 50% power for 3 min. After the tube was
cooled to room temperature, the reaction mixture was transferred to
a separatory funnel using 15 mL of ethyl acetate and then 10 mL of
1 M HCl(aq) were slowly added. The aqueous layer was extracted with
two additional portions (2 × 15 mL) of ethyl acetate. The combined
organic extracts were dried over Na2SO4, filtered, concentrated, and
purified by flash chromatography (30%−60% EtOAc/hexanes) yielding
compounds 6 (0.019g, 8.6%) and 3 (0.027g, 14%). Compound 6 Rf =
0.25 (30% EtOAc/hexanes); Compound 3 Rf = 0.27 (67% EtOAc/
hexanes).
react with benzaldehyde, but compound 3 does not. Proton
transfer could readily occur with enol 15 (from compound 12),
and enol 16 (from an acetoacetate ester), but it could not occur
with enol 17 (from 3) because the distance is too great.
Based upon our findings, our proposed mechanism for the
potassium carbonate induced condensation between benzalde-
hyde and an acetoacetate ester involves (1) deprotonation at the
α-carbon, (2) rearrangement of the α-anion to form a γ-anion,
(3) addition of the resulting γ-anion to the carbonyl carbon
forming a hydroxyketoester, and then (4) intramolecular
transesterification (see Scheme 2).
EXPERIMENTAL SECTION
■
General Experimental. Acetoacetic acid15 and compound 611b
were synthesized using known methods, and the 1H NMR spectra for
these compounds were compared to previously published H NMR
1
spectra (acetoacetic acid16 and 617). Benzaldehyde, ethyl acetoacetate,
methyl acetoacetate sodium salt, ethyl acetoacetate-3,4-13C2, ethyl
acetoacetate-1,2,3,4-13C4, ethyl 2-oxocyclopentane-carboxylate, potas-
sium carbonate, potassium ethoxide, and methanol-D4 were purchased
and used without further purification. Ethanol and methanol were
distilled under nitrogen from sodium. NMR spectra were collected
on a 300 MHz spectrometer. IR spectra were collected using ATR
(diamond crystal). Mass spectra were collected on a double-focusing
sector mass spectrometer (70 eV). Distance calculations were
performed using Parallel Quantum Solutions (PQS) software, version
4.0 (Parallel Quantum Solutions, Fayetteville, AR, USA).
General Procedure for the Preparation of Compounds 3,3 4,
5, and 13. To a flame-dried screw-capped test tube18 under nitrogen
was added benzaldehyde (1.0 equiv), the alcohol solvent (1.0 mL per
mmol of benzaldehyde) (distilled from sodium and stored over
activated 3 Å sieves), the acetoacetate ester (1.0 equiv), and the base
(2.0 equiv of potassium carbonate or 1.0 equiv of potassium ethoxide).
The septa and the nitrogen filled balloon were replaced with a screw
cap, and the mixture (heterogeneous with K2CO3 and homogeneous
with alkoxide bases) was stirred overnight (16−24 h) at the described
temperature. The reaction mixture was then transferred to a separatory
funnel using diethyl ether, and the product was extracted with water
(2 times). The organic layer was discarded, and the combined aqueous
layers were acidified with 6 M HCl and extracted with three portions
of ethyl acetate. The combined organic extracts were dried over
Na2SO4, filtered, concentrated, and purified by flash chromatography
or trituration with diethyl ether.10a
6-Phenyldihydro-2H-pyran-2,4(3H)-dione-4,5-13C2 (4). Using
the standard procedure (0.52 mmol scale, 45 °C) and trituration with
Scheme 2. Proposed Mechanism for the Potassium Carbonate Promoted Condensation between Benzaldehyde and an
Acetoacetate Ester
D
dx.doi.org/10.1021/jo400213s | J. Org. Chem. XXXX, XXX, XXX−XXX