Catalytic effects in baylis-hillman reactions of chromone-3-carbaldehydes with acrylonitrile and methyl acrylate

Article abstract of DOI:10.1080/00397910902788166

The effects of various catalysts, the solvent system, and the temperature on the efficiency and chemoselectivity of reactions of a series of chromone-3-carbaldehydes with acrylonitrile and methyl acrylate are discussed.

Full text of DOI:10.1080/00397910902788166

Synthetic Communications1, 39: 3586–3600, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902788166
Catalytic Effects in Baylis–Hillman Reactions
of Chromone-3-carbaldehydes with Acrylonitrile
and Methyl Acrylate
Duduzile M. Molefe and Perry T. Kaye
Department of Chemistry and Centre for Chemico- and Biomedicinal
Research, Rhodes University, Grahamstown, South Africa
Abstract: The effects of various catalysts, the solvent system, and the temperature
on the efficiency and chemoselectivity of reactions of a series of chromone-3-
carbaldehydes with acrylonitrile and methyl acrylate are discussed.
Keywords: Baylis–Hillman catalysts, chromone-3-carbaldehydes, solvent systems
The Baylis–Hillman reaction between activated alkenes and aldehydes in
the presence of a tertiary amine catalyst often provides convenient access
to polyfunctional products containing a new stereogenic center.[1–5] In
our own laboratories, we have used this reaction to develop syntheses
of various heterocyclic systems[6] and have been exploring their potential
in the construction of medicinal compounds, including HIV-1 protease
inhibitors.[7] We also have an ongoing interest in chromone chemistry
and have reported Baylis–Hillman reactions between chromone-3-carbal-
dehydes and the activated alkenes, acrylonitrile,[1] methyl acrylate, and
methyl vinyl ketone,[8] using 1,4-diazabicyclo[2.2.2]octane as catalyst.
However, the choice of catalyst often has a significant effect on the
efficiency and rate of Baylis–Hillman reactions. In this communication,
we report the results of a comparative study of the relative efficacy of three
catalysts, 1,4-diazabicyclo[2.2.2]octane (DABCO), 3-hydroxyquinuclidine
Received November 5, 2008.
Chromone Studies, Part 16.
Address correspondence to Perry T. Kaye, Department of Chemistry, Rhodes
University, Grahamstown 6140, South Africa. E-mail: P.Kaye@ru.ac.za
3586

Chromone-3-carbaldehyde Reactions
3587
Scheme 1. Baylis–Hillman reactions of chromone-3-carbaldehydes.
(3-HQ), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), under various con-
ditions.
The series of chromone-3-carbaldehydes 2a–e, prepared by ‘‘double’’
Vilsmeier–Haack formylation[9] of the corresponding 2-hydroxyaceto-
phenones 1a–e, were reacted with acrylonitrile 3 using 3-hydroxyquinucli-
dine as catalyst in a minimal volume of chloroform at 25ꢀC for 24 h
(Scheme 1). Purification of the crude products using flash chromatogra-
phy afforded the desired Baylis–Hillman adducts 4a–e in yields ranging
from 57 to 73% (Table 1). The chromatographic separation was opti-
mized by adding a few drops of dichloromethane (DCM) immediately
after loading the sample onto the silica column. The yields are compar-
able to those obtained previously using 3-hydroxyquinuclidine (53–
67%)[1] and significantly better than those obtained after several weeks
using DABCO as catalyst (12–31%).[10]
Use of DBU as catalyst afforded the Baylis–Hillman adducts 4a–e in
yields ranging from 51 to 64% after 6 h, and 60 to 80% after 24 h (Table 1),
indicating that DBU is, in fact, a very acceptable catalyst, in terms of
both reaction rate and efficiency, when compared with the previously
favored catalyst, 3-hydroxyquinuclidine.[11] As already indicated, the
DABCO-catalyzed reactions have proved not only to be very slow but

3588
D. M. Molefe and P. T. Kaye
Table 1. Isolated yields (%) of Baylis–Hillman products 4a–e using various
catalysts
3-HQ in
CHCl3
(24 h)
DBU in
CHCl3
(6 h)
DBU in
CHCl3
(24 h)
DABCO in
NMP
(24 h)
R
Compound
H
Cl
Br
F
4a
4b
4c
4d
4e
57
66
73
60
71
64
57
52
51
55
80
71
64
60
77
60
50
50
50
45
MeO
also very inefficient.[10] However, both the rate and efficiency of the
reaction were found to increase markedly when DABCO was used as
the catalyst in the presence of the aprotic solvent 1-methyl-2-pyrrolidinone
(NMP)[12]; the Baylis–Hillman adducts were isolated in yields ranging from
45 to 60% after 24h (Table 1). Use of DABCO in the previous reactions
also afforded, in some cases, the bis(chromone)-acrylonitrile adducts 5 in
poor yield (5–24%), but these compounds were not isolated from reactions
using the improved catalytic systems described above.
The chromone-3-carbaldehydes 2a–e were also reacted with methyl
acrylate 6 using 3-HQ, DBU, and DABCO in the presence of 1-methyl-2-
pyrrolidinone. Thus, flash chromatography of the crude products
obtained after 24 h from reactions using 3-hydroxyquinuclidine as the
catalyst and chloroform as solvent (Scheme 1) gave the Baylis–Hillman
adducts 7a–e in moderate overall yields ranging from 52 to 63%
(Table 2), improving considerably on the efficiencies obtained previously
using DABCO (8–17%).[8] The corresponding Baylis–Hillman dimers 8a–
e were obtained as minor products in considerably lower yields (3–6%).
When DBU was used as the catalyst, only the Baylis–Hillman adducts
appeared to be formed (50–63% yield). Similar chemoselectivity appears
to occur when DABCO is used in the presence of 1-methyl-2-pyrrolidi-
none as solvent, because under these conditions, the Baylis–Hillman
adducts 7a–e were again isolated as the sole products.
Good yields of Baylis–Hillman adducts have been reported when
DABCO-catalyzed reactions were conducted at reduced temperature.[13]
Consequently, the chromone-3-carbaldehydes 7a–e were reacted with
methyl acrylate at 0ꢀC for 12 h, in the presence of DABCO using minimal

Chromone-3-carbaldehyde Reactions
3589
Table 2. Isolated yields (%) of the Baylis–Hillman products 7a–e and Baylis–
Hillman dimers 8a–ea obtained using various catalysts after 24 h
R
B-H product 3-HQa in CHCl3 DBU in CHCl3 DABCO in NMP
H
Cl
7a
7b
7c
7d
7e
52 (4)
60 (5)
63 (3)
63 (5)
50 (6)
62
63
57
50
61
50
47
38
30
44
Br
F
MeO
aYields in parentheses.
volumes of various solvents viz., CHCl3, CH2Cl2, tetrahydrafuran
(THF), and dimethylformamide (DMF). Purification of the crude pro-
ducts using flash chromatography appeared to afford the Baylis-Hillman
dimers 8a–e chemoselectively in yields ranging from 5 to 45% (Table 3).
Neither the Baylis-Hillman adducts 7a–e nor the expected[13] dioxanone
derivatives were observed after 12 h, and although these reactions were
not particularly efficient, the conditions employed clearly permit chemo-
selective formation of the Baylis–Hillman dimers 8.
In summary, it is apparent that the reaction conditions can be
controlled to permit efficient and selective formation of the primary
Baylis–Hillman adducts 7, but at low temperature the Baylis–Hillman
dimers 8 were the only products to be isolated.
EXPERIMENTAL
NMR spectra were recorded on Bruker AMX400 or Avance 400-MHz
spectrometers at 303 K in CDCl3 and calibrated using solvent signals.
Infrared (IR) spectra were recorded on a Perkin-Elmer Fourier
transform–infrared (FT-IR) Spectrum 2000 spectrometer. Low-resolution
mass spectra (LRMS) were obtained on Finnigan-Mat GCQ (EI) and

3590
D. M. Molefe and P. T. Kaye
Table 3. Yields (%) of the Baylis–Hillman dimers 8a–c isolated from
DABCO-catalyzed reactions with methyl acrylate in different solvents at 0 ꢀC
R
Dimer
THF
CH2Cl2
CHCl3
DMF
H
8a
8b
8c
5
12
17
22
35
37
45
25
30
15
20
27
Cl
Br
LCQ (ES) mass spectrometers, and high-resolution (EI) mass were
determined spectra on a VG70-SEQ Micromass double-focusing magnetic
sector spectrometer (Cape Technikon mass spectrometry unit). The
chromone-3-carbaldehydes 2a–e were prepared as described previously.[1]
3-(2-Cyano-1-hydroxy-2-propenyl)-4H-1-benzopyran-4-one 4a
Acrylonitrile (0.56 mL, 8.6 mmol) was added to a stirred solution of
chromone-3-carbaldehyde 2a (1.0 g, 5.7 mmol) and 3-hydroxyquinucli-
dine (3.7 g, 29 mmol) in CHCl3 (7.0 mL). The resulting mixture was
stirred vigorously at room temperature for 25 h. Evaporation of the
solvent in vacuo gave a brown oily residue which was purified by flash
chromatography [on silica; elution with hexane–EtOAc (2:3)] to afford
3-(2-cyano-1-hydroxy-2-propenyl)-4H-1-benzopyran-4-one 4a as a yel-
low crystalline solid (0.65 g, 57%), mp 68–70ꢀC (lit.[1] 69–71ꢀC). Found
Mþ: 227.0570. Calc. for C13H9NO3, M: 227.0582. nmax (KBr)=cmꢁ1
3430 (br, OH), 2225 (CN) and 1630 (C¼O); dH (400 MHz; CDCl3) 4.22
(1H, br s, 30-OH), 5.29 (1H, s, 30-H), 6.13 and 6.32 (2H, 2xs, 10-CH2),
7.44 (1H, t, J ¼ 7.6 Hz, 6-H), 7.50 (1H, d, J ¼ 8.5 Hz, 8-H), 7.72 (1H, t,
J ¼ 7.8 Hz, 7-H), 8.05 (1H, s, 2-H) and 8.18 (1H, d, J ¼ 8.0 Hz, 5-H);
dC (100 MHz; CDCl3) 69.3 (C-30), 116.7 and 124.3 (C-20 and CN),
118.3 (C-8), 121.3 (C-3), 123.8 (C-4a), 125.5 (C-5), 125.6 (C-6), 131.0
(C-10), 134.4 (C-7), 153.8 (C-2), 156.4 (C-8a) and 177.6 (C¼O); m=z
227 (Mþ, 46%) and 210 (100).
This reaction was repeated using DBU (2.2 mL, 15 mmol) as catalyst
for 6 h and 24 h. The reaction was then quenched, in each case, by

Chromone-3-carbaldehyde Reactions
3591
diluting with diethyl ether (20 mL), and the resulting mixture was washed
with aq. HCl (2 M, 20 mL) and then with water (20 mL) and dried over
Na2SO4. Evaporation of the solvent in vacuo gave a brown oily residue,
which was purified by flash chromatography [on silica; elution with
hexane–EtOAc (2:3)] to afford 3-(2-cyano-1-hydroxy-2-propenyl)-4H-
1-benzopyran-4-one 4a as a yellow crystalline solid (0.73 g, 64%, and
0.91 g, 80%).
The reaction was repeated for 24 h using DABCO (0.27 g, 2.4 mmol)
as catalyst and 1-methyl-2-pyrrolidinone (4 mL) as solvent. The reaction
was quenched by dilution with water (15 mL) followed by extraction with
EtOAc (3 ꢂ 10 mL). Evaporation of the organic solvent in vacuo gave a
brown oily residue, which was purified by flash chromatography [on
silica; elution with hexane–EtOAc (1:2)] to afford 3-(2-cyano-
1-hydroxy-2-propenyl)-4H-1-benzopyran-4-one 4a as a yellow crystalline
solid (0.68 g, 60%).
6-Chloro-3-(2-cyano-1-hydroxy-2-propenyl)-4H-1-benzopyran-4-one 4b
The experimental procedure employed for the synthesis of 3-(2-cyano-
1-hydroxy-2-propenyl)-4H-1-benzopyran-4-one 4a was followed, using
6-chlorochromone-3-carbaldehyde 2b (0.50 g, 2.40 mmol), acrylonitrile
(0.24 mL, 3.6 mmol), 3-hydroxyquinuclidine (1.53 g, 12.0 mmol), and
CHCl3 (7.0 mL). Workup afforded 6-chloro-3-(2-cyano-1-hydroxy-
2-propenyl)-4H-1-benzopyran-4-one 4b as a yellow crystalline solþid
(0.42 g, 66%), mp 132–133ꢀC (lit.[1] 133–134ꢀC). Found M :
261.0196. Calc. for C13H8O3N35Cl, M: 261.0193. nmax (KBr)=cmꢁ1
3440 (br, OH), 2300 (CN), and 1653 (C¼O); dH (400 MHz; CDCl3)
4.04 (1H, br s, 30-OH), 5.34 (1H, s, 30-H), 6.12 and 6.30 (2H, 2xs,
10-CH2), 7.45 (1H, dd, J ¼ 8.9 and 2.1 Hz, 7-H), 7.64 (1H, d,
J ¼ 8.9 Hz, 8-H), 8.08 (1H, s, 2-H) and 8.12 (1H, d, J ¼ 2.1 Hz, 5-H);
dC(100 MHz; CDCl3) 69.5 (C-30), 104.3 (C-5), 116.8 (C-3), 119.8
(C-8), 120.2 (C-4a), 124.2 and 124.3 (C-20 and CN), 124.7 (C-7),
131.0 (C-10), 151.2 (C-8a), 153.4 (C-2), 157.4 (C-6) and 177.6 (C¼O);
m=z 261 (Mþ, 52%) and 209 (100).
When DBU (0.91 g, 6.2 mmol) was used as catalyst, workup after 6 h
and 24 h afforded 6-chloro-3-(2-cyano-1-hydroxy-2-propenyl)-4H-
1-benzopyran-4-one 4b as a yellow crystalline solid (0.36 g, 57%, and
0.45 g, 71%).
When DABCO (0.14 g, 1.2 mmol) and 1-methyl-2-pyrrolidinone
(2 mL) were used as catalyst and solvent, respectively, workup afforded
6-chloro-3-(2-cyano-1-hydroxy-2-propenyl)-4H-1-benzopyran-4-one4bas
a yellow crystalline solid (0.32 g, 50%).

3592
D. M. Molefe and P. T. Kaye
6-Bromo-3-(2-cyano-1-hydroxy-2-propenyl)-4H-1-benzopyran-4-one 4c
The experimental procedure employed for the synthesis of 3-(2-cyano-
1-hydroxy-2-propenyl)-4H-1-benzopyran-4-one 4a was followed, using
6-bromochromone-3-carbaldehyde 2c (1.00 g, 3.95 mmol), acrylonitrile
(0.39 mL, 5.9 mmol), 3-hydroxyquinuclidine (2.5 g, 20 mmol), and CHCl3
(7.0 mL). Workup afforded 6-bromo-3-(2-cyano-1-hydroxy-2-propenyl)-
4H-1-benzopyran-4-one 4c as an orange-yellow crystalline solid (0.88 g,
73%), mp 124–125ꢀC (lit.,[1] 123–125ꢀC). Found Mþ: 304.9724. Calc.
for C13H8O3N79Br, M: 304.9688. nmax (KBr)=cmꢁ1 3420 (br, OH),
2225 (CN) and 1648 (C¼O); dH (400 MHz; CDCl3) 4.18 (1H, br s,
30-OH), 5.33 (1H, s, 30-H), 6.12 and 6.31 (2H, 2xs, 10-CH2), 7.40 (1H,
d, J ¼ 8.9 Hz, 8-H), 7.79 (1H, dd, J ¼ 8.9 and 2.40 Hz, 7-H), 8.09 (1H,
s, 2-H) and 8.28 (1H, d, J ¼ 2.4 Hz, 5-H); dC (100 MHz; CDCl3) 69.0
(C-30), 116.5 (CN), 119.3 (C-6), 120.3 (C-8), 121.6 (C-20), 123.9 (C-3),
124.9 (C-4a), 128.2 (C-5), 131.5 (C-10), 137.5 (C-7), 154.0 (C-2), 155.1
(C-8a) and 176.1 (C¼O); m=z 305 (Mþ, 44%) and 253 (100).
When DBU (2.2 g, 15 mmol) was used as catalyst, workup after 6 h
and 24 h afforded 6-bromo-3-(2-cyano-1-hydroxy-2-propenyl)-4H-
1-benzopyran-4-one 4c as a yellow crystalline solid (0.63 g, 52%, and
0.78 g, 64%, respectively).
When DABCO (0.14 g, 1.2 mmol) and 1-methyl-2-pyrrolidinone
(2 mL) were used as catalyst and solvent, respectively, workup afforded
6-bromo-3-(2-cyano-1-hydroxy-2-propenyl)-4H-1-benzopyran-4-one 4c
as a yellow crystalline solid (0.60 g, 50%).
3-(2-Cyano-1-hydroxy-2-propenyl)-6-fluoro-4H-1-benzopyran-4-one 4d
The experimental procedure employed for the synthesis of 3-(2-cyano-
1-hydroxy-2-propenyl)-4H-1-benzopyran-4-one 4a was followed, using
6-fluorochromone-3-carbaldehyde 2d (0.50 g, 2.6 mmol), acrylonitrile
(0.26 mL, 3.9 mmol), 3-hydroxyquinuclidine (1.6 g, 13 mmol), and
CHCl3 (7.0 mL). Workup afforded 3-(2-cyano-1-hydroxy-2-propenyl)-6-
fluoro-4H-1-benzopyran-4-one 4d as a yellowþcrystalline solid (0.39 g,
60%), mp 59–60ꢀC (lit.,[1] 60–62ꢀC). Found: M , 245.0490. C13H8O3NF
requires M, 245.0488. nmax (KBr)=cmꢁ1 3200 (br, OH), 2235 (CN) and
1640 (C¼O); dH (400 MHz; CDCl3) 4.08 (1H, br s, 30-OH), 5.31 (1H, s,
30-H), 6.15 and 6.33 (2H, 2xs, 10-CH2), 7.45 (1H, m, 7-H), 7.53 (1H, m,
8-H), 7.81 (1H, dd, J ¼ 8.1 and 3.1 Hz, 5-H) and 8.08 (1H, s, 2-H); dC
(100 MHz; CDCl3) 69.1 (C-30), 110.3 (JCF ¼ 23 Hz, C-5), 116.6 and
124.0 (C-20 or CN), 120.5 (JCF ¼ 8.1 Hz, C-8), 120.7 (C-3), 122.9
(JCF ¼ 25 Hz, C-7), 124.9 (JCF ¼ 7.6 Hz, C-4a), 131.4 (C-10), 152.5

Chromone-3-carbaldehyde Reactions
3593
(C-8a), 154.0 (C-2), 160.0 (C-6) and 176.5 (C¼O); m=z 245 (Mþ, 57%)
and 193 (100).
When DBU (1.0 g, 6.7 mmol) was used as catalyst, workup after 6 h
and 24 h afforded 3-(2-cyano-1-hydroxy-2-propenyl)-6-fluoro-4H-
1-benzopyran-4-one 4d as a yellow crystalline solid (0.32 g, 51%, and
0.39 g, 60%, respectively).
When DABCO (0.14 g, 1.2 mmol) and 1-methyl-2-pyrrolidinone
(2 mL) were used as catalyst and solvent, respectively, workup afforded
3-(2-cyano-1-hydroxy-2-propenyl)-6-fluoro-4H-1-benzopyran-4-one 4d
as a yellow crystalline solid (0.31 g, 50%).
3-(2-Cyano-1-hydroxy-2-propenyl)-6-methoxy-4H-1-benzopyran-4-one 4e
The experimental procedure employed for the synthesis of 3-(2-cyano-
1-hydroxy-2-propenyl)-4H-1-benzopyran-4-one 4a was followed, using
6-methoxychromone-3-carbaldehyde 2e (1.0 g, 4.9 mmol), acrylonitrile
(0.48 mL, 7.3 mmol), 3-hydroxyquinuclidine (3.1 g, 25 mmol), and
CHCl3 (10 mL). Workup afforded 3-(2-cyano-1-hydroxy-2-propenyl)-6-
methoxy-4H-1-benzopyran-4-one 4e as a yellow crystalline solid (0.89 g,
71%), mp 114–115ꢀC (lit.,[1] 114–117ꢀC). Found: Mþ: 257.0686. Calc. for
C14H11O4N, M: 257.0688. nmax (KBr)=cmꢁ1 3400 (br, OH), 2225 (CN),
and 1650 (C¼O); dH (400MHz; CDCl3) 3.89 (3H, s, OCH3), 4.41 (1H, br
s, 30-OH), 5.28 (1H, s, 30-H), 6.14 and 6.34 (2H, 2xs, 10-CH2), 7.32 (1H,
dd, J ¼ 9.2 and 3.1Hz, 7-H), 7.45 (1H, d, J ¼ 9.2Hz, 8-H), 7.52 (1H, d,
J¼ 3.1 Hz, 5-H) and 8.08 (1H, s, 2-H); dC (100 MHz; CDCl3) 55.9
(OCH3), 69.1 (C-30), 104.4 (C-5), 116.8 and 124.2 (C-20 or CN), 119.8
(C-8), 120.3 (C-3), 124.3 (C-7), 124.8 (C-4a), 131.0 (C-10), 151.3 (C-8a),
154.0 (C-2), 160.0 (C-6) and 176.5 (C¼O); m=z 257 (Mþ, 46%) and 205 (100).
When DBU (1.85 g, 12.6 mmol) was used as catalyst, workup after
6 h and 24 h afforded 3-(2-cyano-1-hydroxy-2-propenyl)-6-methoxy-4H-
1-benzopyran-4-one 4e as a yellow crystalline solid (0.69 g, 55%, and
0.97 g, 77%, respectively).
When DABCO (0.14 g, 1.2 mmol) and 1-methyl-2-pyrrolidinone
(2 mL) were used as catalyst and solvent, respectively, the workup
afforded 3-(2-cyano-1-hydroxy-2-propenyl)-6-methoxy-4H-1-benzopyran-
4-one 4e as a yellow crystalline solid (0.57 g, 45%).
3-[1-Hydroxy-2-(methoxycarbonyl)-2-propenyl]-4H-1-benzopyran-4-one
7a and the Corresponding Baylis–Hillman Dimer 8a
Methyl acrylate (0.56 mL, 8.6 mmol) was added to a stirred solution of
chromone-3-carbaldehyde 2a (1.0 g, 5.7 mmol) and 3-hydroxyquinuclidine

3594
D. M. Molefe and P. T. Kaye
(3.7g, 29mmol) in CHCl3 (7.0 mL). The resulting mixture was stirred
vigorously at room temperature for 24h. Evaporation of the solvent in
vacuo gave a brown oily residue, which was purified by flash chromatogra-
phy [on silica; elution with hexane–EtOAc (1:2)] and afforded two fractions:
3-[1-Hydroxy-2-(methoxycarbonyl)-2-propenyl]-4H-1-benzopyran-4-
one 7a as a yellow solid (0.78 g, 52%), mp 109–110ꢀC (lit.,[8] 109–112ꢀC).
Found Mþ: 260.0690. Calc. for C14H12O5, M: 260.0685. nmax (KBr)=cmꢁ1
3423 (br, OH), 1723 and 1655 (2x C¼O); dH (400MHz; CDCl3) 3.74 (3H,
s, OCH3), 4.57 (1H, br s, 30-OH), 5.59 (1H, s, 30-H), 6.14 and 6.43 (2H, 2xs,
10-CH2), 7.41 (1H, m, 6-H), 7.45 (1H, d, J ¼ 8.0 Hz, 8-H), 7.68 (1H, m,
7-H), 8.02 (1H, s, 2-H) and 8.18 (1H, dd, J ¼ 8.0 and 1.4 Hz, 5-H); dC
(100MHz; CDCl3) 52.0 (OCH3), 67.6 (C-30), 118.3 (C-8), 123.0 (C-3),
124.0 (C-4a), 125.4 (C-6), 125.6 (C-5), 126.8 (C-10), 134.0 (C-7), 139.5
(C-20), 154.3 (C-2), 156.3 (C-8a), 166.5 (CO.O) and 177.9 (C¼O); m=z
260 (Mþ, 7%) and 200 (100).
The Baylis–Hillman dimer 8a as a pale yellow solid (0.12 g, 4%), mp
193–195ꢀC (lit.,[8] 192–195ꢀC). Found: Mþ, 502.1250. Calc. for
C28H22O9, M: 502.1257. nmax (KBr)=cmꢁ1 1712, 1707, 1653 and 1631
(4x C¼O); dH (400 MHz; CDCl3) 3.12 and 3.37 (2H, 2x d, J ¼ 14.7 Hz,
13-CH2), 3.61 and 3.65 (6H, 2xs, 12-and 16-CH3), 4.50 (2H, dd, J ¼ 17
and 1.6 Hz, 2-CH2), 5.05 (1H, s, 9a-H), 6.90 (1H, t, J ¼ 7.8 Hz, 6-H),
6.97 (1H, d, J ¼ 8.4 Hz, 5-H), 7.30 (1H, s, 4-H), 7.35 (1H, t, J ¼ 8.4 Hz,
7-H) 7.40 (2H, m, 70-H and 80-H), 7.50 (1H, s, 17-H), 7.69 (1H, t,
J ¼ 7.2 Hz, 60-H), 7.72 (1H, dd, J ¼ 7.9 and 1.5 Hz, 8-H), 7.90 (1H, s,
20-H) and 8.16 (1H, d, J ¼ 7.2 Hz, 50-H); dC (100 MHz; CDCl3) 28.4
(C-13), 50.3 (C-4a), 51.8 (C-12), 52.1 (C-16), 65.8 (C-2), 99.9 (C-9a),
117.7 (C-8), 117.9 (C-80), 119.9 (C-10a), 120.5 (C-4a0), 122.7 (C-6),
123.9 (C-30), 125.5 (C-60), 126.2 (C-5), 127.7 (C-50), 129.1 (C-3), 130.8
(C-14), 133.1 (C-17), 133.8 (C-4), 136.0 (C-7), 136.1 (C-70), 154.9 (C-20),
157.1 (C-8a), 155.8 (C-8a0), 163.8 (C-11), 167.3 (C-15), 174.9 (C-40) and
191.4 (C-10); m=z 502 (Mþ, 24%) and 243 (100).
The reaction was repeated using DBU (2.19 mL, 15 mmol) as catalyst.
After 24 h, the reaction was quenched by diluting it with diethyl ether
(20 mL). The resulting solution was washed with aq. HCl (2 M; 20 mL),
followed by water (20 mL), and then dried over Na2SO4. Evaporation
of the solvent in vacuo gave a brown oily residue, which was purified by
flash chromatography [on silica; elution with hexane–EtOAc (2:3)] to
afford 3-[1-hydroxy-2-(methoxycarbonyl)-2-propenyl]-4H-1-benzopyran-
4-one 7a as a yellow solid (0.93 g, 62%).
The reaction was repeated using DABCO (0.27 g, 2.4 mmol) as
catalyst and 1-methyl-2-pyrrolidinone (4 mL) as solvent. After 24 h, the
reaction was quenched by dilution with water (15 mL), and the resulting
mixture was extracted with EtOAc (3 ꢂ 10 mL). Evaporation of the

Chromone-3-carbaldehyde Reactions
3595
organic solvent in vacuo gave a brown oily residue, which was purified by
flash chromatography [on silica gel and elution with hexane–EtOAc (1:2)]
to afford 3-[1-hydroxy-2-(methoxycarbonyl)-2-propenyl]-4H-1-benzo-
pyran-4-one 7a as a yellow crystalline solid (0.75 g, 50%).
6-Chloro-3-[1-hydroxy-2-(methoxycarbonyl)-2-propenyl]-4H-
1-benzopyran-4-one 7b and the Corresponding Baylis–Hillman Dimer 8b
The experimental procedure employed for the synthesis of 3-[1-hydroxy-
2-(methoxycarbonyl)-2-propenyl]-4H-1-benzopyran-4-one 7a and the
corresponding Baylis–Hillman dimer 8a was followed, using
6-chlorochromone-3-carbaldehyde 2b (1.0 g, 4.8 mmol), methyl acrylate
(0.48mL, 7.2 mmol), 3-hydroxyquinuclidine (3.1g, 24mmol), and
CHCl3 (7.0 mL). Workup and flash chromatography afforded two fractions.
6-Chloro-3-[1-hydroxy-2-(methoxycarbonyl)-2-propenyl]-4H-1-ben-
zopyran-4-one 7b as yellow solid (0.85 g, 60%), mp 108–110ꢀC (lit.,[8]
110–112ꢀC). Found MHþ: 295.0373. Calc. for C14H1135ClO5, M þ 1:
295.0373. nmax (KBr)=cmꢁ1 3423 (br, OH), 1718 and 1650 (2 ꢂ C¼O);
dH (400 MHz; CDCl3) 2.90 (1H, br s, 30-OH), 3.74 (3H, s, OCH3),
5.60 (1H, s, 30-H), 6.14 and 6.44 (2H, 2xs, 10-CH2), 7.42 (1H, d,
J ¼ 8.9 Hz, 8-H), 7.61 (1H, dd, J ¼ 8.9 and 2.5 Hz, 7-H), 8.04 (1H, s,
2-H) and 8.13 (1H, d, J ¼ 2.5 Hz, 5-H); dC (100 MHz; CDCl3) 52.0
(OCH3), 67.4 (C-30), 120.0 (C-8), 123.2 (C-3), 124.8 (C-6), 125.1
(C-4a), 125.6 (C-5), 127.0 (C-10), 131.4 (C-5), 134.2 (C-7), 154.5 (C-2),
154.6 (C-8a), 166.5 (CO.O), and 176.6 (C¼O); m=z 294 (Mþ, 33%)
and 234 (100).
The Baylis–Hillman dimer 8b as yellow solid (0.13 g, 5%), mp
210–212ꢀC (lit.,[8] 210–213ꢀC). Found Mþ: 572.0636. Calc. for
C28H20O935Cl2, M: 572.0641. nmax (KBr)=cmꢁ1, 1715, 1710, 1650, and
1646 (4x C¼O); dH (400 MHz; CDCl3) 3.10 and 3.35 (2H, 2xd,
J ¼ 14.7 Hz, 13-CH2), 3.67 and 3.69 (6H, 2xs, 12 and 16-OCH3), 4.52
(2H, dd, J ¼ 17 and 2.0 Hz, 2-CH2), 5.04 (1H, s, 9a-H), 6.93 (1H, d, J ¼
8.9 Hz, 8-H), 7.27 (1H, m, 4-H), 7.29 (1H, m, 7-H) 7.42 (1H, d,
J ¼ 9 Hz, 80-H), 7.48 (1H, s, 17-H), 7.61 (1H, m, 70-H), 7.65 (1H, d,
J ¼ 2.4 Hz, 5-H), 8.00 (1H, s, 20-H) and 8.10 (1H, d, J ¼ 2.5 Hz, 50-H);
dC (100 MHz; CDCl3) 28.4 (C-13), 50.3 (C-4a), 51.9 (C-12), 52.3
(C-16), 66.0 (C-2), 100.0 (C-9a), 119.5 (C-8), 119.8 (C-80), 120.5
(C-4a), 120.8 (C-30), 125.5 (C-50), 127.0 (C-5), 128.5 (C-10a), 129.4
(C-3), 131.2 (C-14), 131.7 (C-60), 132.3 (C-17), 134.4 (C-70), 135.4
(C-7), 136.0 (C-4), 154.0 (C-8a), 155.1 (C-20), 155.5 (C-8a0), 163.8
(C-6), 167.8 (C-11), 173.6 (C-15), 175.7 (C-40) and 190.3 (C-10); m=z
571 (Mþ, 38%) and 277 (100).

3596
D. M. Molefe and P. T. Kaye
When DBU (1.8 g, 12 mmol) was used as the catalyst, workup after
24 h afforded 6-chloro-3-[1-hydroxy-2-(methoxycarbonyl)-2-propenyl]-4-
H-1-benzopyran-4-one 7b as a yellow crystalline solid (0.89 g, 63%).
When DABCO (1.1 g, 9.6 mmol) was used as catalyst and
1-methyl-2-pyrrolidinone (5 mL) as solvent, workup after 24 h afforded
6-chloro-3-[1-hydroxy-2-(methoxycarbonyl)-2-propenyl]-4H-1-benzo-
pyran-4-one 7b as a yellow crystalline solid (0.66 g, 47%).
6-Bromo-3-[1-hydroxy-2-(methoxycarbonyl)-2-propenyl]-4H-
1-benzopyran-4-one 7c and the Corresponding Baylis–Hillman Dimer 8c
The experimental procedure employed for the synthesis of 3-[1-hydroxy-
2-(methoxycarbonyl)-2-propenyl]-4H-1-benzopyran-4-one 7a and the
corresponding Baylis–Hillman dimer 8a was followed, using 6-
bromochromone-3-carbaldehyde 2c (1.1 g, 4.3 mmol), methyl acrylate
(0.44 mL, 6.6 mmol), 3-hydroxyquinuclidine (2.8 g, 22 mmol), and CHCl3
(7.0 mL). Workup and flash chromatography afforded two fractions.
6-Bromo-3-[1-hydroxy-2-(methoxycarbonyl)-2-propenyl]-4H-1-ben-
zopyran-4-one 7c as a yeþllow solid (0.93 g, 63%), mp 114–116ꢀC (lit.,[8]
114–116ꢀC). Found M : 337.9790. Calc. for C14H1179BrO5, M:
337.9789. nmax (KBr)=cmꢁ1 3440 (br, OH), 1716 and 1642 (2x C¼O);
dH (400 MHz; CDCl3) 3.75 (3H, s, OCH3), 4.38 (1H, d, J ¼ 8.0 Hz,
30-OH), 5.59 (1H, d, J ¼ 8.0 Hz, 30-H), 6.11 and 6.42 (2H, 2xs, 10-
CH2), 7.37 (1H, d, J ¼ 8.9 Hz, 8-H), 7.75 (1H, dd, J ¼ 9.0 and 2.5 Hz,
7-H), 8.02 (1H, s, 2-H) and 8.28 (1H, d, J ¼ 2.5 Hz, 5-H); dC (100 MHz;
CDCl3) 52.0 (OCH3), 67.5 (C-30), 118.8 (C-8), 120.2 (C-6), 123.3 (C-3),
125.2 (C-4a), 125.6 (C-5), 127.0 (C-10), 128.3 (C-5), 137.0 (C-7), 154.5
(C-2), 155.0 (C-8a), 166.5 (CO2O), and 176.5 (C¼O); m=z 338 (Mþ,
17%) and 280 (100).
The corresponding Baylis–Hillman dimþer 8c (50 mg, 3%), mp
223–225ꢀC (lit.,[8] 223–225ꢀC). Found M : 657.9471. Calc. for
C28H2079Br2O5, M: 657.9474. nmax (KBr)=cmꢁ1 1715, 1705, 1650, and
1646 (4x C¼O); dH (400 MHz; CDCl3) 3.11 and 3.33 (2H, 2xd,
J ¼ 14.7 Hz, 13-CH2), 3.65 and 3.69 (3H, 2xs, 12 and 16-OCH3), 4.51
(2H, dd, J ¼ 17.0 and 2.0 Hz, 2-CH2), 5.02 (1H, s, 9a-H), 6.88 (1H, d,
J ¼ 8.8 Hz, 8-H), 7.27 (1H, m, 4-H), 7.35 (1H, d, J ¼ 8.9 Hz, 70-H), 7.41
(1H, dd, J ¼ 9.0 and 2.5 Hz, 7-H), 7.48 (1H, s, 17-H), 7.78 (1H, dd,
J ¼ 9.0 and 2.5 Hz, 80-H), 7.81 (1H, d, J ¼ 2.5 Hz, 5-H), 7.88 (1H, s,
20-H) and 8.26 (1H, d, J ¼ 2.5 Hz, 50-H); dC (100 MHz; CDCl3) 28.4
(C-13), 50.3 (C-4a), 52.0 (C-12), 52.3 (C-16), 66.0 (C-2), 100.0 (C-9a),
115.7 (C-8), 119.2 (C-4a0), 119.8 (C-80), 120.1 (C-10a), 120.6 (C-6),
121.3 (C-60), 125.0 (C-30), 128.8 (C-50), 129.3 (C-3), 130.1 (C-5), 131.2

Chromone-3-carbaldehyde Reactions
3597
(C-14), 132.8 (C-17), 135.4 (C-70), 137.0 (C-7), 138.8 (C-4), 154.4 (C-20),
155.0 (C-8a0), 156.0 (C-8a), 163.8 (C-11), 167.1 (C-15), 173.5 (C-40),
and 190.2 (C-10); m=z 658 (Mþ, 10%) and 323 (100).
When DBU (1.8 g, 12 mmol) was used as catalyst, workup after 24 h
afforded 6-bromo-3-[1-hydroxy-2-(methoxycarbonyl)-2-propenyl]-4H-
1-benzopyran-4-one 7c as a yellow solid (0.86 g, 57%).
When DABCO (0.99 g, 8.8 mmol) was used as the catalyst and
1-methyl-2-pyrrolidinone (5 mL) as solvent, workup after 24 h afforded
6-bromo-3-[1-hydroxy-2-(methoxy-carbonyl)-2-propenyl]-4H-1-benzopy-
ran-4-one 7c as a yellow solid (0.57 g, 38%).
6-Fluoro-3-[1-hydroxy-2-(methoxycarbonyl)-2-propenyl]-4H-
1-benzopyran-4-one 7d and the Baylis–Hillman Dimer 8d
The experimental procedure employed for the synthesis of 3-[1-hydroxy-
2-(methoxycarbonyl)-2-propenyl]-4H-1-benzopyran-4-one 7a and the
corresponding Baylis–Hillman dimer 8a was followed, using
6-fluorochromone-3-carbaldehyde 2d (0.50 g, 2.6 mmol), methyl acrylate
(0.20mL, 3.9 mmol), 3-hydroxyquinuclidine (1.7g, 13mmol), and
CHCl3 (7.0mL). Workup and flash chromatography afforded two fractions.
6-Fluoro-3-[1-hydroxy-2-(methoxycarbonyl)-2-propenyl]-4H-
1-benzopyran-4-one 7d as a yellow solid (0.46 g, 63%), mp 139–141ꢀC
(lit.,[8] 140–142ꢀC). Found Mþ: 278.0596. Calc. for C14H11FO5, M:
278.0591. nmax (KBr)=cmꢁ1 3423 (br, OH), 1716 and 1640 (2x C¼O);
dH (400 MHz; CDCl3), 3.75 (3H, s, OCH3), 4.43 (1H, d, J ¼ 7.8 Hz,
30-OH), 5.60 (1H, d, J ¼ 7.8 Hz, 30-H), 6.12 and 6.46 (2H, 2xs, 10-CH2),
7.40 (1H, m, 7-H), 7.48 (1H, dd, J ¼ 9.1 and 4.2 Hz, 8-H), 7.81 (1H,
dd, J ¼ 8.3 and 3.0 Hz, 5-H), and 8.05 (1H, s, 2-H); dC (100 MHz; CDCl3)
52.0 (OCH3), 67.6 (C-30), 110.5 (C-5), 120.4 (C-8), 122.3 (C-7), 122.5
(C-3), 125.8 (C-4a), 126.9 (C-10), 139.2 (C-20), 152.5 (C-8a), 154.6 (C-2),
159.6 (C-6), 166.5 (CO.O) and 177.1 (C¼O); m=z 278 (Mþ, 34%) and
193 (100).
The Baylis–Hillman dimer 8d as yellow solid (70 mg, 5%), mp
198–200ꢀC (lit.,[8] 200–202ꢀC). Found: Mþ: 538.1074. Calc. for
C28H20F2O5, M: 538.1075. nmax (KBr)=cmꢁ1 1727, 1713, 1650, and
1648 (4x C¼O); dH (400 MHz; CDCl3) 3.10 and 3.35 (2H, 2xd,
J ¼ 14.7 Hz, 13- CH2), 3.64 and 3.70 (3H, 2xs, 12 and 16-OCH3), 4.51
(2H, dd, J ¼ 17.0 and 2.0 Hz, 2-CH2), 5.01 (1H, s, 9a-H), 6.97 (1H, dd,
J ¼ 9.0 and 4.0 Hz, 5-H), 7.05 (1H, m, 7-H), 7.24 (1H, s, 4-H), 7.33
(1H, dd, J ¼ 8.3 and 2.8 Hz, 8-H), 7.38–7.48 (2H, m, 50-H and 70-H),
7.50 (1H, s, 17-H), 7.78 (1H, dd, J ¼ 8.3 and 2.8 Hz, 80-H) and 7.90
(1H, s, 20-H); dC (100 MHz; CDCl3) 28.4 (C-13), 50.2 (C-4a), 51.9

3598
D. M. Molefe and P. T. Kaye
(C-12), 52.2 (C-16), 65.9 (C-2), 100.1 (C-9a), 111.0 (C-80), 112.7 (C-8),
119.5 (C-5), 119.8 (C-30), 120.2 (C-50), 120.6 (C-10a), 122.3 (C-70), 123.6
(C-7), 124.9 (C-4a0), 129.4 (C-3), 131.1 (C-14), 132.8 (C-17), 135.4
(C-4), 151.9 (C-8a0), 153.3 and 157.8 (C-8a and C-60), 155.1 (C-20),
159.7 (C-6), 163.8 (C-11), 167.1 (C-15), 174.0 (C-140) and 190.6 (C-10);
m=z 538 (Mþ, 21%) and 261 (100).
When DBU (0.99 g, 6.7 mmol) was used as the catalyst, workup after
24 h afforded 6-fluoro-3-[1-hydroxy-2-(methoxycarbonyl)-2-propenyl]-4-
H-1-benzopyran-4-one 7d as a yellow solid (0.37 g, 50%).
When DABCO (0.585 g, 5.20 mmol) was used as the catalyst and
1-methyl-2-pyrrolidinone (5 mL) as solvent, workup after 24 h afforded
6-fluoro-3-[1-hydroxy-2-(methoxycarbonyl)-2-propenyl]-4H-1-benzopyr-
an-4-one 7d as a yellow solid (0.22 g, 30%).
3-[1-Hydroxy-2-(methoxycarbonyl)-2-propenyl]-6-methoxy-4H-
1-benzopyran-4-one 7e and the Corresponding Baylis–Hillman Dimer 8e
The experimental procedure employed for the synthesis of 3-[1-hydroxy-
2-(methoxycarbonyl)-2-propenyl]-4H-1-benzopyran-4-one 7a and the
corresponding Baylis–Hillman dimer 8a was followed, using
6-methoxychromone-3-carbaldehyde 2e (1.0 g, 4.9 mmol), methyl acrylate
(0.49 mL, 7.3 mmol), 3-hydroxyquinuclidine (3.1 g, 25 mmol), and
CHCl3 (7.0 mL). Workup and flash chromatography afforded two
fractions.
3-[1-Hydroxy-2-(methoxycarbonyl)-2-propenyl]-6-methoxy-4H-1-
benzopyran-4-one 7e as yellow oil (0.73 g, 50%). Found Mþ: 290.0780.
Calc for C15H14O6, M: 290.0790. nmax (KBr)=cmꢁ1 3426 (br, OH),
1723 and 1643 (2x C¼O); dH (400 MHz; CDCl3) 3.70 (3H, s, CO.OCH3),
3.81 (3H, s, 6-OCH3), 4.68 (1H, d, J ¼ 4.5 Hz, 30-OH), 5.60 (1H, d,
J ¼ 2.5 Hz, 30-H), 6.10 and 6.39 (2H, 2xs, 10-H), 7.18 (1H, dd, J ¼ 9.1
and 3.0 Hz, 7-H), 7.30 (1H, d, J ¼ 9.0 Hz, 8-H), 7.44 (1H, d, J ¼ 3.0 Hz,
5-H) and 7.98 (1H, s, 2-H); dC (100 MHz; CDCl3) 51.7 (CO.OCH3),
55.6 (6-OCH3), 67.1 (C-30), 104.3 (C-5), 119.4 (C-8), 122.2 (C-3), 123.9
(C-7), 124.3 (C-4a), 126.3 (C-10), 139.7 (C-20), 150.9 (C-8a), 154.0 (C-2),
156.8 (C-6), 166.3 (CO2O), and 177.4 (C¼O); m=z 290 (Mþ, 26%) and
151 (100).
The Baylis–Hillman dimer 8e (0.15 g, 6%) as a yellow viscous oil.
Found: Mþ, 562.1467. Calc. for C30H26O11, M: 562.1475. nmax
(KBr)=cmꢁ1, and 1722, 1715, 1650, and 1646 (4x C¼O); dH (400 MHz;
CDCl3) 3.10 and 3.35 (2H, 2xd, J ¼ 14.7 Hz, 13-CH2), 3.60 (3H, s,
12-H), 3.70 (3H, s, 6-OCH3), 3.78 (3H, s, 16-H), 3.89 (3H, s, 60-OCH3),
4.39–4.53 (2H, dd, J ¼ 17 and 2.0 Hz, 2-CH2), 5.45 (1H, s, 9a-H), 6.70

Chromone-3-carbaldehyde Reactions
3599
(1H, s, 4-H), 6.73 (1H, d, J ¼ 9.0 Hz, 9-H), 7.00 (1H, m, 7-H), 7.10 (1H, d,
J ¼ 3.0 Hz, 5-H), 7.26 (1H, dd, J ¼ 9.0 and 3.0 Hz, 70-H), 7.38 (1H, d,
J ¼ 9.1 Hz, 80-H), 7.50 (1H, d, J ¼ 3.2 Hz, 50-H), 7.55 (1H, s, 17-H) and
7.91 (1H, s, 20-H); dC (100 MHz; CDCl3) 31.2 (C-13), 51.0 (C-4a), 51.7
(C-12), 52.2 (C-16), 55.7 (6-OCH3), 55.9 (60-OCH3), 62.9 (C-2), 99.2
(C-9a), 105.3 (C-50), 107.6 (C-5), 119.0 (C-10a), 119.2 (C-8), 119.4
(C-80), 119.6 (C-30), 123.9(C-70), 124.5 (C-4a0), 125.6 (C-7), 129.9 (C-3),
130.6 (C-14), 133.3 (C-17), 135.0 (C-4), 150.7 (C-8a0), 151.8 (C-8a),
154.3 (C-20), 154.7 (C-6), 157.1 (C-60þ), 163.9 (C-11), 167.8 (C-15), 175.1
(C-40) and 192.4 (C-10); m=z 562 (M , 37%) and 289 (100).
When DBU (1.9 g, 13 mmol) was used as the catalyst, workup after
24 h afforded 3-[1-hydroxy-2-(methoxycarbonyl)-2-propenyl]-6-methoxy-
4H-1-benzopyran-4-one 7e as a yellow solid (0.86 g, 61%).
When DABCO (1.10 g, 9.78 mmol) was used as the catalyst and
1-methyl-2-pyrrolidinone (5 mL) as the solvent, workup after 24 h
afforded 3-[1-hydroxy-2-(methoxycarbonyl)-2-propenyl]-6-methoxy-4H-
1-benzopyran-4-one 7e as a yellow solid (0.62 g, 44%).
ACKNOWLEDGMENTS
The authors thank the Medical Research Council of South Africa (MRC)
for a bursary (to D. M. M.) and Rhodes University, the National
Research Foundation (NRF), and the MRC for generous financial
support.
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