4
Faridoon et al. / Tetrahedron xxx (2015) 1e6
Scheme 5. Preliminary computational studies of cyclisation pathways.
with the apparent absence of experimental evidence for the for-
mation of coumarin derivatives under these basic conditions.
Acid-catalysed transformation of the Baylis-Hillman adducts 7
to the coumarin derivatives 6 (Scheme 4), on the other hand, is
considered to favour a very different pathway, involving a series of
tandem steps, viz., i) O-alkyl cleavage of the ester to afford iso-
butylene and the corresponding carboxylic acid; ii) conjugate ad-
gel; elution with hexane-EtOAc-diethyl ether (8:1:1)] to afford two
fractions.
Fraction 1: tert-Butyl 4-hydroxychroman-3-carboxylate 8a as
a white solid comprising a single diastereomer (0.16 g, 32%); mp
75e76 ꢂC; (Found: C, 66.96; H, 7.09. C14H18O4 requires: C, 67.18; H,
7.25%); 1H NMR (400 MHz; CDCl3):
d
1.45 (9H, s), 2.86 (1H, dt, J¼7.6
and 3.3 Hz), 3.07 (1H, br s), 4.2e4.4 (2H, 2ꢃm), 5.04 (1H, d,
J¼7.6 Hz), 6.81 (1H, d, J¼8.0 Hz), 6.94 (1H, t, J¼7.4 Hz), 7.17 (1H, t,
J¼7.6 Hz) and 7.43 (1H, d, J¼7.6 Hz); 13C NMR (100 MHz; CDCl3):
dition of HCl to the
a,b-unsaturated moiety; iii) dehydration to
a (Z)- -(chloromethyl)cinnamic acid; iv) isomerisation to the (E)-
a
diastereomer; and, finally, cyclisation to the 3-(chloromethyl)-
d 28.4, 47.6, 64.7, 66.0, 82.6, 116.9, 121.5, 124.1, 128.8, 130.0, 154.2
coumarin.24
and 170.9.
Fraction 2: tert-butyl 2H-chromene-3-carboxylate 9a as a pale
yellow solid (0.11 g, 24%), mp 25e26 ꢂC (lit.21 reported as an oil); 1H
NMR (400 MHz; CDCl3): 1.54 (9H, s), 4.95 (2H, s), 6.83 (1H, d,
In conclusion, these results clearly demonstrate that changing
the catalyst from acidic (HCl/AcOH) to basic (KOH/H2O) changes the
regioselectivity of the cyclisation step completely. Chemoselective
synthesis of either coumarin (6) or 2H-chromene-3-carboxylic acid
derivatives (10) may thus be achieved readily from the same sub-
strates (7) in a single reaction (Path IV or Path V; Scheme 4). The
latter products (10) may be obtained directly without the need to
isolate the conjugate addition- or dehydration intermediates (8)
and (9), respectively.
d
J¼8.1 Hz), 6.90 (1H, t, J¼7.4 Hz), 7.11 (1H, d, J¼7.4 Hz), 7.20 (1H, t,
J¼7.7 Hz) and 7.33 (1H, s); 13C NMR (100 MHz; CDCl3):
d 28.6, 65.1,
81.6, 116.5, 121.6, 122.1, 124.7, 129.2, 132.0, 133.0, 155.5 and 164.3.
3.2. Preparation of the diastereomeric tert-butyl 6-bromo-4-
hydroxychroman-3-carboxylate esters 8b1 and 8b2 and tert-
butyl 6-bromo-2H-chromene-3-carboxylate 9b
3. Experimental
1H and 13C NMR spectra were recorded on Bruker Avance 400 or
600 MHz spectrometers at 303 K, and were calibrated using the
solvent signals; coupling constants are given in Hertz (Hz). High
resolution electrospray ionisation accurate mass measurements
(HRMS) were recorded in positive or negative mode on a Waters
API Q-TOF Ultima spectrometer with an ESI source (Central Ana-
lytical Facility, University of Stellenbosch).
A solution of KOH (56 mg, 1.0 mmol) in water (1.0 mL)
was added to a solution of tert-butyl 3-hydroxy-3-(5-bromo-2-
hydroxyphenyl)-2-methylenepropanoate 7b (0.329 g, 1.0 mmol)
in CH3CN (2.5 mL) and the mixture was heated under reflux for 5 h.
On cooling, the crude product was precipitated as pale yellow solid.
Column chromatography [on silica gel; elution with hexane-EtOAc
(8:1)] of the crude product afforded three fractions.
Fraction 1: tert-Butyl 6-bromo-2H-chromene-3-carboxylate 9b
The Baylis-Hillman adducts 7aee required for the preparation of
as a yellow solid (86 mg, 27.7%), mp 97e98 ꢂC (lit.25 96e97 ꢂC); 1H
compounds 10aee were prepared as described previously.21
NMR (600 MHz; CDCl3):
d 1.55 (9H, s), 4.97 (2H, s), 6.74 (1H, d,
J¼9 Hz), 7.26 (2H, s) and 7.30 (1H, d, J¼9 Hz); 13C NMR (150 MHz;
3.1. Preparation of tert-butyl 4-hydroxychroman-3-
carboxylate 8a and tert-butyl 2H-chromene-3-carboxylate 9a
CDCl3):
154.2 and 163.6.
Fraction 2:
d 28.3, 65.0, 81.7, 113.7, 117.9, 123.1, 125.6, 131.0, 131.1, 134.1,
tert-Butyl
6-bromo-4-hydroxychroman-3-
A solution of KOH (0.11 g, 2.0 mmol) in water (1 mL) was added
carboxylate 8b1, the syn-diastereomer, as a white solid (10 mg,
to
a
solution of tert-butyl 3-hydroxy-3-(2-hydroxyphenyl)-2-
3%), mp 124e125 ꢂC;
(600 MHz; CDCl3):
n
d
/cmꢄ1 3433 (OH) and 1706 (C]O); 1H NMR
1.49 (s, 9H), 2.98 (dt, 1H, J¼9.8, 3.8 Hz),
methylenepropanoate 7a (0.5 g, 2 mmol) in CH3CN (5 mL) and
the mixture was heated under reflux for 5 h. After cooling, the
crude product was extracted with EtOAc, dried with anhydrous
MgSO4, concentrated in vacuo and flash chromatographed [on silica
4.32e4.39 (2H, m), 4.96 (1H, d, J¼3.6 Hz), 6.73 (d, 1H, 8.4 Hz), 7.29
(d,1H, J¼8.4 Hz) and 7.49 (s, 1H); 13C NMR (150 MHz; CDCl3):
d 28.2,
44.9, 62.9, 64.1, 82.9, 113.0, 118.8, 125.2, 132.7, 132.8, 153.5 and