Synthesis of Five-Membered Cyclic Ethers
allowed the isolation of 2,5-di(methoxycarbonyloxy)hexane as
a light-colored oil in 64% yield.
product was purified by gradient elution chromatography on silica
gel using first CH2Cl2/cyclohexane (9:1) (for the isolation of the
cyclic ether), and then CH2Cl2/methanol (97:3) (for the isolation of
the carbonate derivative) as eluents.
2,5-Di(methoxycarbonyloxy)hexane (mixture of isomers): 1H NMR
(300 MHz, CDCl3): d=4.6–4.8 (m, 2H), 3.8 (s, 6H), 1.7–1.5 (m, 4H),
1.28 ppm (d, 6H); 13C NMR (75 MHz, CDCl3): d=155.2, 74.9, 75.6,
54.4, 31.6, 31.2, 19.8, 19.7 ppm; HRMS: m/z calcd for C10H18O6+Na+
: 257.1001 [M+Na+]; found: 257.1035.
Phthalan (transparent liquid, 30%): Characterization data were con-
sistent with those obtained for the commercially available com-
pound.
2,5-Dihydrofuran (example from Table 2, entry 7): In a round-bot-
tomed flask equipped with a dephlegmator, cis-but-2-ene-1,4-diol
(1.0 g, 11.3 mmol, 1 equiv), DMC (4.1 g, 45.45 mmol, 4 equiv), and
NaOMe (0.03 g, 0.56 mmol, 0.05 equiv) were heated at reflux while
stirring continuously under a nitrogen atmosphere. The reaction
was followed by NMR spectroscopy until complete disappearance
of the starting materials. The solution was then filtered and the sol-
vent removed by evaporation. Column chromatography using
CH2Cl2/methanol (98:2) as eluent allowed the isolation of (Z)-1-hy-
droxy 4-methoxycarbonyloxy-2-butene as a transparent oil in 24%
1,2-Bis[(methoxycarbonyloxy)methyl)]benzene (light yellow liquid,
41%): M.p.: 51–51.58C; 1H NMR (300 MHz, CDCl3): d=7.48–7.30 (m,
4H), 5.27 (s, 4H), 3.77 ppm (s, 6H); 13C NMR (75 MHz, CDCl3): d=
155.4, 133.8, 129.8, 128.9, 66.9, 54.8 ppm; HRMS: m/z calcd for
C12H14O6+Na+: 277.0688 [M+Na+]; found: 277.0722.
(À)-Norlabdane (ambroxan) (example from Table 4, entry 1): In
a round-bottomed flask equipped with a dephlegmator, amberlyn
diol (1.0 g, 3.93 mmol, 1 equiv), DMC (10.6 g, 118.0 mmol,
30 equiv), and potassium tert-butoxide (0,88 g, 7.87 mmol, 2 equiv)
were heated at reflux while stirring continuously under a nitrogen
atmosphere. The reaction was followed by TLC until complete dis-
appearance of the starting materials. The solution was then filtered
and DMC removed by evaporation to afford ambroxan as a color-
less crystalline powder in 95% yield. Purer samples of ambroxan
could be obtained either by crystallisation from 2-propanol or by
column chromatography using CH2Cl2/methanol (98:2) as eluent.
yield and (Z)- 1,4-di(methoxycarbonyloxy)-2-butene as
a light
yellow oil in 31% yield.
(Z)-1-Hydroxy 4-methoxycarbonyloxy-2-butene:[26] 1H NMR (300 MHz,
CDCl3): d=5.93–5.50 (m, 2H), 4.67 (d, 2H), 4.21 (d, 2H), 3.69 (s,
3H), 2.88 ppm (brs, 1H, OH); 13C NMR (75 MHz, CDCl3): d=156.9,
133.9, 124.5, 63.3, 58.0, 54.7 ppm; GC-MS for C6H10O4: M=
146.06 gmolÀ1
.
(À)-Norlabdane:[17,22] M.p.: 69.1–708C; 1H NMR (300 MHz, CDCl3):
d=0.84 (s, 3H), 0.85 (s, 3H), 0.89 (s, 3H), 0.91–1.09 (m, 2H), 1.12 (s,
3H), 1.36–1.51 (m, 7H), 6.92–6.80 (m, 2H), 5.95 (s, 1H, OH), 4.37 (t,
2H), 3.81 (s, 3H), 3.05 ppm (t, 2H); 13C NMR (75 MHz, CDCl3): d=
79.8, 64.8, 60.0, 57.1, 42.3, 39.8, 39.6, 36.0, 33.5, 32.9, 22.5, 21.0,
(Z)- 1,4-di(methoxycarbonyloxy)-2-butene:[27] 1H NMR (300 MHz,
CDCl3): d=5.83 (t, 2H), 4.73 (d, 2H), 3.81 ppm (s, 6H); 13C NMR
(75 MHz, CDCl3): d=156.7, 127.8, 63.0, 58.0, 54.7 ppm; GC-MS for
C8H12O6: M=204.06 gmolÀ1
.
20.5, 18.3, 14.9 ppm; GC-MS for C16H28O: M=236.21 gmolÀ1
.
2,3-Dihydrobenzofuran (example from Table 3, entry 1): In
a round-bottomed flask equipped with a dephlegmator, 2-(2-hy-
droxyethyl)phenol (1.0 g, 7.24 mmol, 1 equiv), DMC (6.5 g,
72.4 mmol, 10 equiv), and NaOMe (0.19 g, 3.6 mmol, 0.5 equiv)
were heated at reflux while stirring continuously under a nitrogen
atmosphere. After 7 h the reaction was stopped, cooled at room
temperature, and diethyl ether was added to the mixture. The re-
action mixture was then filtered and the solvent evaporated. The
solvent was distilled under vacuum to give the crude product that
was then analysed by 1H NMR spectroscopy to determine the prod-
uct ratio. Finally, the product was purified by gradient elution chro-
matography on silica gel using first CH2Cl2/cyclohexane (9:1) (for
the isolation of the cyclic ether), and then CH2Cl2/methanol (97:3)
(for the isolation of the carbonate derivative) as eluents.
Monomethoxycarbonyloxy derivative of Amberlyn diol (Table 4,
entry 7):[22] The compound was purified by column chromatography
(CH2Cl2/EtOAc, 92:8), and was isolated as a yellow oil in 90% yield.
Isosorbide (example from Table 5, entry 4): A mixture of d-sorbi-
tol (2.0 g, 10.98 mmol, 1 equiv), DMC (8 g, 87.88 mmol, 8 equiv),
NaOMe 2.4 g, 43.42 mmol, 4 equiv), and methanol (30 mL) was
placed in a round-bottomed flask, and heated at reflux while stir-
ring continuously under a nitrogen atmosphere. After 8 h the reac-
tion was stopped, cooled at room temperature, and diethyl ether
was added to the mixture. The reaction mixture was then filtered
and the solvent evaporated. The solvent was distilled under
vacuum to afford the crude product. Finally, the product was puri-
fied by gradient elution chromatography on silica gel using CH2Cl2/
methanol (9:1) as eluent.
1
2,3-Dihydrobenzofuran (transparent liquid, 55%): H NMR (300 MHz,
CDCl3): d=7.20 (d, 1H), 7.15 (t, 1H), 6.90–6.77 (m, 2H), 4.6 (t, 2H),
3.25 ppm (t, 2H); 13C NMR (75 MHz, CDCl3): d=159.9, 127.8, 126.7,
Isosorbide (light yellow crystals, 75%): Characterization data were
consistent with those obtained for the commercially available com-
pound.
124.8, 120.2, 70.9, 29.6 ppm; GC-MS for C8H8O: M=120.06 gmolÀ1
.
[28]
2-(2-methoxycarbonyloxy)phenol (light yellow oil, 29%):
M.p.:
68.5–68.88C; 1H NMR (300 MHz, CDCl3): d=7.20–7.08 (m, 2H),
6.92–6.80 (m, 2H), 5.95 (s, 1H, OH), 4.37 (t, 2H), 3.81 (s, 3H),
3.05 ppm (t, 2H); 13C NMR (75 MHz, CDCl3): d=156.9, 153.4, 130.9,
128.2, 120.6, 67.6, 54.8, 30.0 ppm; GC-MS for C10H12O4: M=
Ab initio calculations
The potential energy surface (PES) was studied by DFT calculations
making use of the B3LYP functional.[29] The 6-311G(d) polarized
basis set[30] was used in geometry optimizations. The nature of
each critical point (reactant, product, intermediate, or transition
structure) was determined by harmonic vibrational analysis. To
obtain an estimate of energy barriers, single-point energy calcula-
tions were carried out by using Dunning’s correlation-consistent
basis set (aug-cc-pVTZ).[31] Final free energy values were calculated
by combining 6-311G(d) thermochemical corrections with single-
point DFT/aug-cc-pVTZ energy values.
196.07 gmolÀ1
.
Phthalan (example from Table 3, entry 5): In a round-bottomed
flask equipped with a dephlegmator, dihydroxymethylbenzene
(1.0 g, 7.24 mmol, 1 equiv), DMC (6.5 g, 72.4 mmol, 10 equiv), and
NaOMe (0.19 g, 3.6 mmol, 0.5 equiv) were heated at reflux while
stirring continuously under a nitrogen atmosphere. After 7 h the
reaction was stopped, cooled at room temperature, and diethyl
ether was added to the mixture. The reaction mixture was then fil-
tered and the solvent evaporated. The solvent was distilled under
vacuum to give the crude product that was then analysed by
1H NMR spectroscopy to determine the product ratio. Finally, the
Solvent effects were taken into account by the self-consistent reac-
tion field method using the integral equation formalism for the po-
ChemSusChem 0000, 00, 1 – 10
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
7
&
ÞÞ
These are not the final page numbers!