The Journal of Organic Chemistry
Note
rac-1,4-Benzodioxane-2-carboxaldehyde (rac-6). Obtained
(R)-1,4-Benzodioxane-2-carboxaldehyde Bisulfite Adduct.
Sodium metabisulfite (600 mg, 3.16 mmol), (R)-6 (950 mg, 5.78
mmol), ethyl acetate (5 mL), ethanol (4 mL), and water (1 mL) were
mixed and stirred at 40 °C overnight. After ethyl acetate (3 mL) was
added and the mixture was cooled to 0 °C, the precipitated sodium α-
hydroxymethanesulfonate (1.18 g, 4.40 mmol) was isolated by
filtration as a white solid. The filtrate was concentrated, and the
residue was triturated in hot ethyl acetate and collected by filtration to
give an additional amount (238 mg, 0.89 mmol) of the desired
product. The overall yield was 91%. The bisulfite adduct, which
decomposed about 160 °C, was a nearly equimolar mixture of two
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from rac-5 in 92−96% yield as described for (R)-6. The H NMR
and 13C NMR data were identical to those of (R)-6.
(R)-1,4-Benzodioxane-2-carboxamide [(R)-7]. Pd(PPh3)4 (214
mg, 0.18 mmol) was added to a solution of (S)-5 (1.00 g, 6.20 mmol)
in formic acid (9 mL). After 1 h of stirring, ethyl acetate and NaHCO3
saturated aqueous solution were added. The layers were separated, and
the organic phase was repeatedly washed with NaHCO3 saturated
solution until neutral pH was reached. The organic phase was dried
with Na2SO4 and concentrated under vacuum to give the crude amide.
Purification on silica gel (cyclohexane/AcOEt 6:4) gave (R)-7 as a
white solid. The yields ranged between 92% (1.03 g) and 95% (1.06
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diastereomers epimeric at the newly formed stereocenter. H NMR
g). TLC (cyclohexane/EtOAc 9:1) Rf = 0.56; mp = 138.88 °C; [α]D25
=
(300 MHz, DMSO-d6) δ 3.90−4.09 (m, 2H), 4.30 (dd, J1 = 1.92 Hz, J2
= 5.8 Hz, ∼0.5H), 4.39 (pseudo d, J1 = 8.8 Hz, ∼0.5H), 4.55 (m,
∼0.5H), 4.67 (dd, J1 = 2.2 Hz, J2 = 11.6 Hz, ∼0.5H), 5.72 (d, J1 = 5.8
Hz, ∼0.5 H, exchanges with D2O), 6.05 (d, J1 = 5.5 Hz, ∼0.5 H,
exchanges with D2O), 6.75−6.85 (m, 4H); 13C NMR (75 MHz,
DMSO-d6) δ 65.1, 66.2, 74.5, 75.0, 82.0, 83.8, 117.3, 117.5, 117.7,
117.8, 121.6, 121.8, 143.7, 143.9, 144.0, 144.5; HRMS (ESI) m/z calcd
for C9H9O6S− (M − Na+) 245.01253, found 245.01329.
+102.85 (c 1, MeOH); 98.0−98.1% ee (determined by HPLC analysis
on a Kromasyl AmyCoat column, 250 mm × 4.6 mm i.d.; hexane/
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MeOH/2-propanol 78:20:2; 0.3 mL/min; 280 nm; tR ≈ 30 min); H
NMR (300 MHz, CDCl3) δ 4.23 (dd, J = 7.15 Hz, 11.55 Hz, 1H), 4.53
(dd, J = 2.75 Hz, 11.55 Hz, 1H), 4.70 (dd, J = 2.75 Hz, 7.15 Hz, 1H),
6.12 (br s, 1H), 6.54 (br s, 1H), 6.86−6.95 (m, 4H); 13C NMR (75
MHz, DMSO-d6) δ 65.4, 73.2, 117.7, 118.0, 122.1, 122.2, 142.9, 143.7,
169.7. Anal. Calcd for C9H9NO3 (179.18): C, 60.33; H, 5.06; N, 7.82.
Found: C, 60.11; H, 5.09; N, 7.79.
(S)-1,4-Benzodioxane-2-carboxaldehyde Bisulfite Adduct.
Obtained from (S)-6 in 93% yield as a nearly equimolar mixture of
two diastereomers with the S configuration at the dioxane stereocenter
and epimeric at the newly formed stereocenter, as described for the
(S)-1,4-Benzodioxane-2-carboxamide [(S)-7]. Obtained from
(R)-5 in 90−93% yield as described for (R)-7. Mp = 140.35 °C; [α]D25
= −103.61 (c 1 MeOH); ee 98.0−98.3% (determined by HPLC
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bisulfite adduct of (R)-6. The H NMR and 13C NMR data were
identical to those of the bisulfite adduct of (R)-6.
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analysis as described for (R)-7; tR ≈ 36 min); the H NMR and 13C
Regeneration of (R)-6 and (S)-6 from the Respective Bisulfite
Adducts. Both of the bisulfite adducts (1.10 g, 4.10 mmol) were
combined with CH3CN (20 mL) and TMS-Cl (1.3 mL, 10.25 mmol)
and heated at 40 °C for 2 h. The mixtures were allowed to cool to
room temperature. Ethyl acetate and water were added, and the layers
were separated. The organic phases were dried with Na2SO4 and
concentrated under vacuum to give (R)-6 and (S)-6 as clear oils (94%
NMR data were identical to those of (R)-7.
rac-1,4-Benzodioxane-2-carboxamide (rac-7). Obtained from
rac-5 in 89−93% yield as described for (R)-7. Mp = 141.04 °C; the 1H
NMR and 13C NMR data were identical to those of (R)-7.
(R)-Methyl 1,4-Benzodioxane-2-carboxylate [(R)-2b]. KOH
solution in methanol (1 M, 12.0 mL, 12.00 mmol) was added
dropwise to a solution of (S)-4 (1.40 g, 5.98 mmol) in MeOH (10
mL) at −15 °C. The mixture was allowed to reach room temperature
and stirred for 1 h. TLC analysis (cyclohexane/ethyl acetate 8:2)
showed complete conversion into (R)-methyl 1,4-benzodioxane-2-
imidate [(R)-8] (Rf = 0.18). The mixture was cooled to −15 °C and
filtered to remove precipitated KCl. Amberlyst-15 ion-exchange resin
(1.53 g, 7.20 mequiv) was added to the filtrate, and the mixture was
stirred for 30 min. After the resin was filtered off, the filtrate was
concentrated under vacuum to give the crude methyl ester, which was
purified by chromatography on silica gel (cyclohexane/ethyl acetate
8:2), yielding (R)-2b as a white solid. The yields ranged between 76%
(885 mg) and 78% (908 mg). TLC (cyclohexane/EtOAc 8:2) Rf =
0.43; mp = 77.6 °C;16 [α]D25 = +55.8 (c 1, CHCl3); 98.1−98.3% ee
(determined by HPLC analysis on a Kromasyl AmyCoat column, 250
mm × 4.6 mm i.d.; hexane/MeOH/2-propanol 78:18:4; 0.4 mL/min;
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and 93% yield, respectively). The H NMR and 13C NMR data were
identical to those of (R)-6 and (S)-6 obtained from (S)-4 and (R)-4,
respectively.
(S)-2-Hydroxymethyl-1,4-benzodioxane [(S)-1]. NaBH4 (141
mg, 3.73 mmol) was added to a solution of the bisulfite adduct of (R)-
6 (1.00 g, 3.73 mmol) in methanol (8 mL), and the suspension was
stirred for 3 h at room temperature. The solvent was evaporated under
vacuum, and the residue was partitioned between water and DCM.
The layers were separated, and the organic phase was dried with
Na2SO4 and concentrated to give (S)-1 as a white solid. The yields
ranged between 75% (464 mg) and 76% (471 mg). Mp = 75.82 °C;16
[α]2D5 = −36.8 (c 0.1, EtOH); 97.8−98.0% ee (determined by HPLC
analysis on a Kromasyl AmyCoat column, 250 mm × 4.6 mm i.d.;
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hexane/EtOH 95:5; 1.2 mL/min; 280 nm; tR ≈ 14 min); H NMR
(300 MHz, CDCl3) δ 2.03 (br s, 1H, exchange with D2O), 3.82−3.93
(m, 2H), 4.07−4.14 (m, 1H), 4.24−4.32 (m, 2H), 6.83−6.98 (m, 4H);
13C NMR (75 MHz, CDCl3) δ 62.0, 65.4, 73.7, 117.5, 117.5, 121.8,
121.9, 143.2, 143.3.
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280 nm; tR ≈ 16 min); H NMR (300 MHz, CDCl3) δ 3.82 (s, 3H),
4.37 (d, J = 3.85 Hz, 2H), 4.84 (t, J = 3.85 Hz, 1H), 6.86−6.98 (m,
3H), 7.00 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 53.0, 65.1, 71.2,
117.5, 117.6, 122.1, 122.4, 142.5, 143.2, 168.8. (R)-8: oil resulting from
the concentration of an aliquot of the methanolic solution after
(R)-2-Hydroxymethyl-1,4-benzodioxane [(R)-1]. Obtained
from the bisulfite adduct of (S)-6 in 72−75% yield as described for
(S)-1. Mp = 74.82 °C;16 [α]D25 = +35.9 (c 0.1, EtOH); 97.6−97.7% ee
(determined by HPLC analysis as described for (S)-1; tR ≈ 17 min);
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removal of KCl; H NMR (300 MHz, CDCl3) δ 3.84 (s, 3H), 4.04
(dd, J = 7.15 Hz, 11.55 Hz, 1H), 4.43 (dd, J = 2.75 Hz, 11.55 Hz, 1H),
4.61 (dd, J = 2.75 Hz, 7.15 Hz, 1H), 6.87 (m, 3H), 7.00 (m, 1H), 7.92
(br s, 1H, exchanges with D2O); 13C NMR (75 MHz, CDCl3) δ 53.8,
65.7, 71.2, 117.6, 117.6, 122.2, 122.4, 142.2, 143.2, 167.8; MS (ESI)
m/z calcd for C10H12NO3 (MH+) 194.08, found 194.1. Anal. Calcd for
C10H11NO3 (193.20): C, 62.17; H, 5.74; N, 7.25. Found: C, 62.02; H,
5.78; N, 7.23.
(S)-Methyl 1,4-Benzodioxane-2-carboxylate [(S)-2b]. Ob-
tained from (R)-4 in 74−75% yield as described for (R)-2b. Mp =
76.91 °C;16 [α]D25 = −55.5 (c 1, CHCl3), ee 98.0−98.1% (determined
by HPLC analysis as described for (R)-2b; tR ≈ 14 min); the 1H NMR
and 13C NMR data were identical to those of (R)-2b.
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the H NMR and 13C NMR data were identical to those of (S)-1.
ASSOCIATED CONTENT
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* Supporting Information
1H NMR and 13C NMR spectra, HRMS spectra, DSC curves,
and HPLC chromatograms. This material is available free of
AUTHOR INFORMATION
Corresponding Author
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rac-Methyl 1,4-Benzodioxane-2-carboxylate (rac-2b). Ob-
tained from rac-4 in 72−76% yield as described for (R)-2b. Mp =
50.09 °C;16 the 1H NMR and 13C NMR data were identical to those of
(R)-2b.
Notes
The authors declare no competing financial interest.
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dx.doi.org/10.1021/jo500964y | J. Org. Chem. XXXX, XXX, XXX−XXX