Application of Baylis-Hillman methodology in the direct construction of chromone derivatives

Article abstract of DOI:10.1016/j.tet.2015.11.039

Pyridinium chlorochromate oxidation of Baylis-Hillman-derived tert-butyl 2H-chromene-3-carboxylates affords chromone-3-carboxylate esters, providing the first application of Baylis-Hillman methodology in a direct and convenient three-step synthesis of chr

Full text of DOI:10.1016/j.tet.2015.11.039

Accepted Manuscript
Application of Baylis-Hillman Methodology in the Direct Construction of Chromone
Derivatives
Faridoon, Temitope.O. Olomola, Rosalyn Klein, Prof Perry.T. Kaye
PII:
S0040-4020(15)30224-6
10.1016/j.tet.2015.11.039
TET 27296
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 22 September 2015
Revised Date: 6 November 2015
Accepted Date: 17 November 2015
Please cite this article as: Faridoon Olomola TO, Klein R, Kaye PT, Application of Baylis-Hillman
Methodology in the Direct Construction of Chromone Derivatives, Tetrahedron (2015), doi: 10.1016/
j.tet.2015.11.039.
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ACCEPTED MANUSCRIPT
Application of Baylis-Hillman Methodology in the Direct
Construction of Chromone Derivatives
Faridoon,a Temitope.O. Olomola,a,b Rosalyn Kleina and Perry.T. Kayea*
aDepartment of Chemistry and Centre for Chemico- and Biomedicinal Research, Rhodes University, Grahamstown, 6140,
South Africa. bDepartment of Chemistry, Obafemi Awolowo University, Ile-Ife, 220005, Nigeria.
ABSTRACT. Pyridinium chlorochromate oxidation of Baylis-Hillman-derived tert-butyl
2H-chromene-3-carboxylates affords chromone-3-carboxylate esters, providing the first
application of Baylis-Hillman methodology in a direct and convenient three-step synthesis of
chromone derivatives.
Key Words:
Chromones
Benzopyran-4-ones
chromone-3-carboxylate esters
Baylis-Hillman
________________________
* Corresponding author:
Prof Perry Kaye. Tel. +27 46 6037030;
Fax. +27 466225109. E-mail. P.Kaye@ru.ac.za
Dept. of Chemistry, Rhodes University,
Grahamstown, 6140, South Africa.
1

ACCEPTED MANUSCRIPT
1. Introduction.
Chromone (benzopyran-4-one) derivatives are widely distributed in nature, and many of them
exhibit interesting biological activity.1 For example, the furanochromone khellin 1, isolated
from Amni visnaga has long been used in the treatment of asthma,2 while the synthetic
chromone derivative, disodium cromoglycate, now finds clinical use as an anti-asthmatic.3
Gaspar et al.4 have shown that chromone-3-carboxamides, such as compound 2 prepared
from chromone-2-carboxylic acid, exhibit selective inhibition of monoamine oxidase-B
(MAO-B) with IC50 values in the nano- and low micromolar range, and have, even more
recently, published a comprehensive review on the chromone nucleus as a “valid scaffold in
medicinal chemistry”.5
OMe O
Cl
O
O
N
H
O
O
Me
O
OMe
1
2
We have previously reported seminal contributions to the application of Baylis-Hillman
methodology in the construction of benzannulated heterocyclic systems,6 including
indolizines,7 quinolines8 and coumarins.9,10 However, attempts to extend this methodology to
access 4-oxygenated derivatives has proved frustrating since cyclisation of appropriate
Baylis-Hillman adducts is typically effected under acidic or neutral conditions and is
accompanied by loss of the 4-hydroxyl group in a dehydration step. We have recently
shown11 how base-catalysed cyclisation of the salicylaldehyde-derived Baylis-Hillman
adducts 4a-e (Scheme 1) not only permits chemoselective access to the 2H-chromene-3-
carboxylic acids 5a-e, but that the overall transformation proceeds through three discrete
steps, viz., base-catalysed intramolecular conjugate addition, base-catalysed dehydration and,
finally, base-catalysed ester hydrolysis. The intermediates (6) and (7) are isolable in some
cases and, in this communication, we discuss their use as chromone precursors−to our
knowledge, the first reported application of Baylis-Hillman methodology in the direct
construction of the chromone nucleus.
Scheme 1.
2

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2. Results and Discussion.
Oxidation (including aromatization) of the 2,3-dihydro-4-hydroxybenzopyran-2-carboxylate
esters 6a-e (as diastereomeric pairs) appeared to present the most obvious approach to
chromone derivatives. However, only the 6-chloro- (6b) and 6-bromo- (6c) analogues could
be isolated in practicable yields using Na2CO3 in DMF-H2O rather than KOH in THF-H2O as
reported previously.11 Of the various bases (KOH, pyridine, Na2CO3, and NaHCO3)
examined, Na2CO3 (0.25 eq.) in DMF-H2O proved most efficient, affording, in each case,
combined yields of both diastereomers of ≥ 85%. Even after 15 days, the remaining adducts
(6a, d-f) failed to exhibit useful transformation to the corresponding 4-hydroxychroman-3-
carboxylate esters. In our hands, the reaction of 5-chlorosalicylaldehyde 3b with tert-butyl
acrylate in the presence of K2CO3, following the method reported by Satoh et al.,12 gave
compound 6b in only 20% yield.
Following various unsatisfactory attempts to effect oxidation (including the use of: MnO2 in
dry acetone; acidified KMnO4; and H2CrO4), use of pyridinium chlorochromate (PCC)
supported on charcoal, as reported by Al-Hamdany and Jihad,13 finally provided practicable
access to the 4-oxo derivatives 8b,c. Thus, PCC oxidation of diastereomeric mixtures of both
analogues afforded the corresponding 4-oxo derivatives 8b (44%) and 8c (50%) (Scheme 2),
the NMR spectra of which appear to be complicated by tautomerism of the β-keto ester
moiety. Subsequent treatment of the 6-chloro derivative 8b with DMSO-I2 led, with
concomitant elimination of the carboxylate ester moiety, to 6-chlorochromone 9b in 44%
yield. Given the apparent lack of generality in using this strategy, attention was turned to the
2H-chromene-3-carboxylate esters 7a-f as possible chromone precursors.
Scheme 2.
3

ACCEPTED MANUSCRIPT
Refluxing mixtures of the Baylis-Hillman adducts 4a-f and KOH in THF–H2O for 8 h
afforded the corresponding 2H-chromene-3-carboxylate esters 7a-f in yields of up to 48%. In
attempts to improve the yield, the 5-chloro adduct 4b was refluxed with KOH (1 eq.) in tert-
butyl alchohol for 8 hours, but the cyclised product was collected in 46% yield which
represented no improvement on the yield obtained in THF-H2O. [Use of ButOK (in different
molar ratios) in tert-butyl alchohol, also failed to improve the yield.] Oxidation of the 6-
chloro analogue 7b with KMnO4 gave the α-hydroxy ketone 10b, dehydration of which was
achieved using molecular iodine (20 mol%) in DMSO at 100 ºC to afford the desired
chromone-2-carboxylate ester 11b in 41% yield.
It was found, however, that the target compounds 11a-f could be obtained more efficiently in
a single step (and in up to 88% yield!) from the corresponding 2H-chromene-3-carboxylate
esters 7a-f, using PCC in CH2Cl2 − a reagent system used by Kim et al.14 to generate 3-
benzoylchromone from a 3-benzylidenylchromone precursor in the final step of a five-step
sequence. The chromone derivatives 11a-f, five of which are new, were thus obtained in only
three steps from the Baylis-Hillman substrates 3a-f.
While further optimisation of individual steps may well be expected, it is clear that the
methodology developed here offers a new, viable and convenient approach to important
chromone scaffolds.
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 on a Waters API Q-TOF Ultima spectrometer with an ESI source (Central
Analytical Facility, University of Stellenbosch).
Preparation of the Baylis-Hillman adducts 4a-f,10 the diastereomeric 4-hydroxychroman-3-
carboxylate esters 6c11 and the tert-butyl 2H-chromene-3-carboxylate esters 7a-c11 has been
described previously.
3.1. General procedure for synthesis of the tert-butyl 4-hydroxychroman-3-carboxylates
6b,c.
A solution of Na2CO3 (0.186 g, 1.75 mmol) in water (3 mL) was added to a solution of 4b
(2.0 g, 7.02 mmol) in DMF (15 mL) and the mixture was stirred for 4 days. Addition of ice
gave a creamy solid which was filtered off, dried and flash chromatographed [on silica gel;
elution with hexane–Et2O (4:1)] to afford the following two diastereomers.
tert-Butyl (3S*,4S*)-6-chloro-4-hydroxychroman-3-carboxylate 6b1 as a white solid (0.38 g,
19%), m.p. 126-127 °C; ν/cm-1 3436 (OH) and 1706 (C=O); (Found: MH+ - ButOH, m/z
35
211.0167. C14H18O3 Cl - ButOH requires 211.0162.); δH (600 MHz; CDCl3) 1.49 (9H, s,
But), 2.93 (1H, dd, J = 6.1, 3.9 Hz, CHCHCH2), 3.26 (1H, d, J = 5.5 Hz, CHCHO), 4.40-4.27
(2H, m, CHCH2O), 4.94 (1H, s, OH), 6.77 (1H, d, J = 8.8 Hz, ArH), 7.14 (1H, dd, J = 8.7,
1.9 Hz, ArH) and 7.32 (1H, d, J = 1.7 Hz, ArH); δC (150 MHz; CDCl3) 28.2, 44.9, 62.8, 64.1,
82.8, 118.3, 124.7, 125.7, 129.7, 129.9, 152.9 and 170.2.
4

ACCEPTED MANUSCRIPT
tert-Butyl (3S*,4R*)-6-chloro-4-hydroxychroman-3-carboxylate 6b2 as a white solid (1.30
g, 65%), m.p. 92-93 °C; ν/cm-1 3470 (OH) and 1700 (C=O); (Found: MH+ - ButOH, m/z
35
211.0152. C10H8O3 Cl requires 211.0162.); δH (600 MHz; CDCl3) 1.46 (9H, s, But), 2.87
(1H, td, J = 8.6, 3.6 Hz, CHCHCH2), 3.04 (1H, d, J = 4.4 Hz, CHOH), 4.16 (1H, dd, J = 11.2,
9.1 Hz, CHCHaHbO), 4.40 (1H, dd, J = 11.3, 3.6 Hz, CHCHaHbO), 5.01 (1H, dd, J = 7.6, 4.4
Hz, CHOH), 6.74 (1H, d, J = 8.8 Hz, ArH), 7.12 (1H, dd, J = 8.7, 2.4 Hz, ArH) and 7.44 (1H,
d, J = 2.2 Hz, ArH); δC (150 MHz; CDCl3) 28.1, 46.9, 64.6, 65.5, 82.7, 118.0, 125.2, 126.1,
128.1, 129.3, 152.5 and 170.3.
3.2. General procedure for synthesis of the tert-butyl 4-chromanone-3-carboxylates 8b,c.
A mixture of PCC supported on charcoal (1.7 g) was suspended in DCM (15 mL) and stirred
for 2 min. A solution of (3S*,4R*)-tert-butyl 6-bromo-4-hydroxychroman-3-carboxylate 6b
(0.5 g, 1.5 mmol) in DCM (2 mL) was then added in one portion, and the mixture stirred for
ca. 24 h. After being left to stand for 3 h, the resulting mixture was shaken with dry Et2O and
filtered. The filtrate was concentrated in vacuo and flash chromatographed [on silica gel;
elution with hexane–Et2O (4:1)] to afford tert-butyl 6-chloro-4-chromanone-3-carboxylate 8b
as a red solid (0.25 g, 50.3%), comprising a 2:1 mixture of keto and enol tautomers, m.p. 72-
35
74 °C; [Found: MH+, m/z 281.0567. C14H15O4 Cl requires 281.0581]; ν/cm-1 1746 and 1712
(C=O); δH (600 MHz; CDCl3; data cited for major, keto tautomer) 1.47 (9H, s, But), 3.61
(1H, dd, J = 7.5, 4.2 Hz, CHCH2O), 4.60 (1H, dd, J = 11.7, 4.2 Hz, CHaHbO), 4.78 (1H, dd, J
= 11.7, 7.5 Hz, CHaHbO), 6.96 (1H, d, J = 8.8 Hz, ArH), 7.45 (1H, dd, J = 8.8, 2.6 Hz, ArH)
and 7.88 (1 H, d, J = 2.6 Hz, ArH).
3.2.1. tert-Butyl 6-bromo-4-chromanone-3-carboxylate 8c, a red solid (0.22 g, 44.3%)
comprising a 2:1.4 mixture of the keto and enol tautomers, m.p. 86-88 °C (Found: MH+, m/z
79
325.0062. C14H15O4 Br requires 325.0075.); δH (600 MHz; CDCl3; data cited for major, keto
tautomer) 1.46 (9 H, s, But), 3.60 (1H, dd, J = 7.5, 4.3 Hz, CHCH2O), 4.59 (1H, dd, J = 11.7,
4.2 Hz, CHaHbO), 4.77 (1H, dd, J = 11.7, 7.5 Hz, CHaHbO), 6.90 (1H, d, J = 8.8 Hz, ArH),
7.56 (1H, dd, J = 8.8, 2.5 Hz, ArH) and 8.02 (1H, d, J = 2.5 Hz, ArH).
3.3. Preparation of 6-chlorochromone 9b
A mixture of compound 8b (25 mg, 0.09 mmol) and molecular iodine (25 mol%) in DMSO
was stirred at 100 ºC for 12 h. The cool reaction mixture was poured into sat. aq. sodium
thiosulphate and extracted with EtOAc. The organic fraction was washed with H2O and dried
using anhydr. MgSO4. Concentration in vacuo and column chromatography [on silica gel;
elution with hexane–EtOAc (8:1)] gave 6-chlorochromone 9b as a white solid (7 mg, 44 %),
m.p. 129-132 °C (Lit.15 137 °C).
3.4. Preparation of tert-butyl 6-chloro-3-hydroxychroman-4-one-3-carboxylate 10b
A solution of KMnO4 (250 mg, 1.7 mmol) in acetone (3 mL) and H2O (1 mL) was added
drop-wise to a solution of compound 7b (284.7 mg, 1 mmol) in acetone (8 mL), H2O (2 mL)
and acetic acid (0.4 mL). After stirring at r.t. for 30 min, the mixture was filtered through a
pad of Celite, which was washed several times with CH2Cl2. The filtrate and washings were
washed with aq. NaHCO3 and dried (anhydr. MgSO4). The solvent was evaporated in vacuo,
and the crude product chromatographed [on silica gel; elution with CHCl3–petroleum ether
(3:2)] to give tert-butyl 6-chloro-2-hydroxy-chroman-4-one-3-carboxylate 10b as a white
solid (251 mg, 84%), m.p. 78-80 °C; [Found: M-1, m/z 299.0676. C14H16O5Cl requires
299.0686]; ν/cm-1 ca. 2400-3200 (OH), 1653 and 1633 (C=O); δH (600 MHz; CDCl3) 1.39
5

ACCEPTED MANUSCRIPT
(9H, s, But), 4.09 (1H, s, OH), 4.34 (1H, d, J = 11.8 Hz, CHaHbO), 4.67 (1 H, d, J = 11.8 Hz,
CHaHbO), 6.97 (1H, d, J = 8.9 Hz, ArH), 7.46 (1H, dd, J = 8.9, 2.7 Hz, ArH), 7.87 (1H, d, J =
2.7 Hz, ArH); δC (150 MHz; CDCl3) 27.9, 72.1, 74.7, 85.1, 119.7, 120.3, 126.9, 127.6, 136.6,
160.0, 168.1 and 188.3.
3.5. Synthesis of the tert-butyl 2H-chromene-3-carboxylates 7a-f was effected following
the reported method,11 but increasing the reaction time from 5 h to 8 h.
3.5.1. tert-Butyl 8-methoxy-2H-chromene-3-carboxylate 7d, a yellow oil (176 mg, 39%);
[Found: M-1, m/z 261.1128. C15H17O4 requires 261.1127]; ν/cm-1 1696 (C=O); δH (600 MHz;
CDCl3) 1.52 (9 H, s, But), 3.87 (3H, s, CH3O), 5.01 (2H, s, CH2O), 6.76 (1H, t, J = 6 Hz,
ArH), 6.86 (2H, 2 x overlapping d, J = 6 Hz, ArH) and 7.31 (1H, s, CH=C); δC (150MHz;
CDCl3): δC 28.3, 56.2, 65.1, 81.4, 114.4, 120.9, 121.5, 121.9, 124.5, 132.6, 144.1, 148.0 and
164.0.
3.5.2. tert-Butyl 8-ethoxy-2H-chromene-3-carboxylate 7e, a yellow oil (204 mg, 37%);
[Found: M-1, m/z 275.1287. C16H19O4 requires 275.1283]; ν/cm-1 1694 (C=O); δH (600 MHz;
CDCl3) 1.44 (3H, t, J = 7.0 Hz, CH3CH2), 1.52 (9H, s, But), 4.09 (2H, q, J = 7.0 Hz,
CH3CH2O), 5.00 (2H, s, CH2O), 6.75 (1H, dd, J = 7.2 and 1.8 Hz, ArH), 6.82-6.87 (2H, 2 x
overlapping m, ArH) and 7.31 (1H, s, CH=C); δC (150 MHz; CDCl3) 15.0, 28.3, 64.7, 65.0,
81.3, 115.9, 121.0, 121.4, 122.1, 124.4, 132.7, 144.4, 147.3, 164.0.
3.5.3. tert-Butyl 6,8-dibromo-2H-chromene-3-carboxylate 7f, a white solid (351 mg, 45%),
79
m.p. 122-124 °C; [Found: M-1, m/z 388.9386. C14H15O3 Br2 requires 388.9388]; ν/cm-1 1717
(C=O); δH (600 MHz; CDCl3) 1.52 (9H, s, But), 5.07 (2H, s, CH2O), 7.19 (1H, d, J = 2.2 Hz,
ArH), 7.20 (1H, s, CH=C), 7.54 (1 H, d, J = 2.2 Hz, ArH); δC (150 MHz; CDCl3) 28.2, 65.8,
82.1, 111.0, 113.6, 123.7, 126.2, 130.2, 130.6, 136.8, 151.0 and 163.1.
3.6. tert-Butyl 6-chlorochromone-3-carboxylate 11b (Method A). A mixture of compound
10b (0.25 mmol, 75 mg) and molecular iodine (20 mol%) in DMSO was stirred overnight at
100 ºC. On cooling, the reaction mixture was poured into a saturated aqueous solution of
sodium thiosulphate. The resulting mixture was extracted with EtOAc and the organic
fraction was washed with water and dried (anhydr. MgSO4). Concentration in vacuo followed
by column chromatography [on silica gel; elution with CHCl3–petroleum ether (2:3)]
afforded compound 11b as a white solid (29 mg, 41%).
3.7. General procedure (Method B) for the synthesis of the tert-butyl chromone-3-
carboxylates 11a-f.
PCC (2 mmol) was added to a stirred solution of the chromene ester (7) (0.5 mmol) in
CH2Cl2 (10 mL). After refluxing for 48 h, the reaction mixture was cooled to r.t., filtered
through a silica pad, which was thoroughly washed with CH2Cl2. Evaporation of the filtrate
in vacuo and column chromatography of the residue [on silica gel; elution with CHCl3–
petroleum ether (2:3) for 11a-c,f and CHCl3 for 11d,e] gave the target compounds.
3.7.1. tert-Butyl chromone-3-carboxylate 11a, a white solid (86 mg, 70%), m.p. 103-105 °C
(Lit.16 101-105 °C); ν/cm-1 1736 and 1706 (C=O); δH (600 MHz; CDCl3) 1.60 (9H, s, But),
7.30-7.34 (2H, m, ArH), 7.58-7.63 (2H, m, ArH) and 8.39 (1 H, s, C=CHO); δC (150 MHz;
CDCl3) 28.2, 83.0, 116.8, 118.1, 119.7, 124.8, 129.4, 134.1, 147.7, 155.1, 157.0 and 162.0.
3.7.2. tert-Butyl 6-chlorochromone-3-carboxylate 11b, a white solid (109 mg, 77%), m.p.
35
152-154 °C; [Found: M-1, m/z 281.0569. C14H14O4 Cl requires 281.0561]; ν/cm-1 1730 and
1698 (C=O); δH (600 MHz; CDCl3) 1.60 (9H, s, But ), 7.30 (1H, d, J = 8.8 Hz, ArH), 7.56
(1H, dd, J = 8.8, 2.4 Hz, ArH), 7.58 (1H, d, J = 2.4 Hz, ArH) and 8.31 (1H, s, C=CH-O); δC
6

ACCEPTED MANUSCRIPT
(150 MHz; CDCl3) 28.1, 83.3, 118.2, 119.0, 120.9, 128.3, 130.0, 133.8, 146.0, 153.4, 156.2
and 161.6.
3.7.3. tert-Butyl 6-bromochromone-3-carboxylate 11c, a white solid (120 mg, 74%), m.p.
79
169-170 °C; [Found: MH+- C4H9, m/z 268.9434. C10H4O4 Br requires 268.9449]; ν/cm-1
1749 and 1705 (C=O); δH (600 MHz; CDCl3) 1.60 (9H, s, But), 7.24 (1H, d, J = 8.8 Hz,
ArH), 7.70 (1H, dd, J = 8.8, 2.3 Hz, ArH), 7.74 (1H, d, J = 2.3 Hz, ArH) and 8.30 (1H, s,
C=CH-O); δC (150 MHz; CDCl3) 28.1, 83.3, 117.2, 118.5, 119.5, 120.9, 131.4, 136.6, 145.9,
153.8, 156.4 and 161.5.
3.7.4. tert-Butyl 8-methoxychromone-3-carboxylate 11d, a yellow solid (87 mg, 63%), m.p.
70-71 °C; [Found: M-1, m/z 277.1070. C15H17O5 requires 277.1076] ν/cm-11697 and 1696
(C=O); δH (600 MHz; CDCl3) 1.59 (9H, s, But), 3.96 (3H, s, OCH3), 7.15 (2H, d, J = 8.0 Hz,
ArH), 7.22-7.25 (1H, m, ArH) and 8.36 (1H, s, C=CHO); δC (150 MHz; CDCl3) 28.2, 56.4,
82.9, 115.6, 118.7, 119.9, 120.6, 124.6, 144.9, 147.2, 147.8, 156.4 and 162.0.
3.7.5. tert-Butyl 8-ethoxychromone-3-carboxylate 11e, a yellow solid (96 mg, 66%), m.p.
64-65 °C; [Found: M-1, m/z 291.1218. C16H19O5 requires 291.1232]; ν/cm-1 1757 and 1704
(C=O); δH (600 MHz; CDCl3) 1.47 (3H, t, J = 6.7 Hz, CH2CH3), 1.58 (9H, s, But), 4.16 (2H,
q, J = 6.8 Hz, CH3CH2O), 7.12 (2H, 2 x overlapping d, ArH), 7.19 (1H, t, J = 6.7 Hz, ArH)
and 8.32 (1H, s, C=CHO); δC (150 MHz; CDCl3) 14.8, 28.2, 65.2, 82.8, 117.0, 118.7, 119.8,
120.5, 124.6, 145.1, 146.5, 147.7, 156.6 and 162.0.
3.7.6. tert-Butyl 6,8-dibromochromone-3-carboxylate 11f, a white solid (178 mg, 88%),
m.p. 142-144 °C; [Found: M-1, m/z 402.9162. C14H13O4 Br2 requires 402.9161]; ν/cm-1 1742
79
and 1700 (C=O); δH (600 MHz; CDCl3) 1.60 (9H, s, But), 7.68 (1H, d, J = 2.2 Hz, ArH), 7.95
(1H, d, J = 2.1 Hz, ArH) and 8.24 (1H, s, C=CHO); δC (150 MHz; CDCl3) 28.2, 83.7, 111.4,
117.2, 120.3, 121.8, 130.7, 139.3, 145.6, 151.0, 155.1 and 161.3.
4. Acknowledgements
The authors thank the National Research Foundation (IFR 2011032500034) and Rhodes
University for generous financial support and for a bursary (to Faridoon). T.O.O. also
gratefully acknowledges the Organisation for Prohibition of Chemical Weapons (OPCW) for
a travel grant. This work is based on research supported by the National Research
Foundation, and any opinion, findings and conclusions or recommendations expressed in this
material are those of the authors and therefore the NRF do not accept any liability in regard
thereto.
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