S. Nemouchi et al. / C. R. Chimie 15 (2012) 394–397
395
O
R1
O
O
R3
R3
H
PhB(OH)2 5mol %
+
R2
R2
+
R1
1a-w
O
EtOH/H2O
Reflux
CN
3a-b
R2
R2
2a-b
O
4a-w
NH2
Scheme 1.
[31], [3+2] dipolar cycloaddition [32] and amidation of
carboxylic acids [33–35].
2-furaldehyde and give the corresponding product in high
yield (entry 13). The scope of this one-pot reaction was
further extended by replacing dimedone 2a with cyclo-
hexane-1,3-dione 2b and various highly functionalized
4H-benzo[b]pyrans were produced in good yields (entries
14–16). However, aliphatic aldehydes such as acetalde-
hyde, propionaldehyde and isobutyraldehyde needed
longer reaction times to provide moderate yields of the
corresponding products (entries 17–19).
To assess the generality and versatility of the catalyst,
the same reaction conditions as described above were
applied for the synthesis of ethyl 2-amino-4H-benzo[b]-
pyrans-3-carboxylate by replacing malonitrile 3a with
ethyl cyanoacetate 3b. The expected compounds were
then obtained in good yields (entries 20–21).
Phenylboronic acid, a commercially available material,
has been exploited previously by us in Biginelli and
Hantzsch three-component reactions [36,37] as a nontoxic,
inexpensive, easy handling and mild catalyst. Now we wish
to report here the catalytic activity of PhB(OH)2 in the one-
pot synthesis of tetrahydrobenzo[b]pyrans 4 between
aromatic aldehydes 1, dimedone or 1,3-cyclohexanedione
2 and malonitrile (or ethyl cyanoacetate) 3 in refluxing
H2O/EtOH (Scheme 1).
2. Results and discussion
In order to optimize the conditions, we studied the
reaction of benzaldehyde 1a with dimedone 2a, maloni-
trile 3, and 20 mol % of phenylboronic acid as a simple
model substrate in various conditions. First, we tested the
effect of various solvents at different temperatures. When
using aprotic polar solvent such as CH3CN, the reaction
afforded the corresponding 4H-benzopyran 4a with a
modest yield of after 6 h at reflux (Table 1, entry 1).
However, the reactions in refluxing protic solvents such as
In all cases, the final products were isolated by simple
filtration, washed with cold water and purified by
recrystallization from ethanol1.
We propose the following mechanism to account for
the reaction. We checked that, at reflux for 30 min in EtOH/
H2O (1/1) without phenylboronic acid, malonitrile reacts
quite quantitatively with aromatic aldehyde
1 in a
Knoevenagel transformation, while only small amounts
of 4 was produced in such conditions. 1,3-Dicarbonyl
compound would be therefore first activated by phenyl-
boronic acid to give a boron enolate 2’. Addition to
H2O or EtOH gave better yields (entries
2 and 3);
nevertheless, it was not completed even after 3 days at
ambient temperature (entry 4). Similarly, the reaction
without any solvent at 80 8C was not very successful (entry
5). The 50% aqueous ethanol is proven to be the most
suitable solvent for this condensation in terms of yield and
reaction time (entry 6).
1
General procedure to synthesis of tetrahydrobenzo[b]pyran derivatives 4
using PhB(OH)2 as catalyst: a mixture of aldehyde (1 mmol), cyclohexane-
1,3-dione or dimedone (1 mmol), malonitrile or ethyl cyanoacetate
(1 mmol) and phenylboronic acid (5 mol%) in 6 ml of EtOH/H2O (v:v:1:1)
was refluxed for 30 min (the reaction was monitored by TLC). After
completion of the reaction, the mixture was cooled to room temperature
and cold water was added and stirring was continued for 10 min. The
crude products were filtered, washed with water and recrystallized from
ethanol (95%) to afford pure products which were identified by IR, 1H
NMR, 13C NMR and melting points. Spectral data for:
We also evaluated the amount of phenylboronic acid
required for the reaction. It was found that when
decreasing the amount of the catalyst from 20 to 10 mol
%, the yield increased from 85 to 88% (entry 7). The use of 5
mol% of PhB(OH)2 maintaining the yield at 88%, so this
amount is sufficient to promote the reaction. In the
presence of more than this amount of the catalyst, neither
the yield nor the reaction time were improved (entries 9
and 10). Thus, the best result was obtained with 5 mol % of
catalyst in 50% aqueous ethanol at reflux (entry 8).
In comparison with PhB(OH)2, the use of Ph-CH=CH-
B(OH)2 as catalyst in the model reaction under refluxing
condition showed good catalytic effects and afforded
comparable yield of the desired product (entry 11).
In contrast, other Lewis acid catalysts such as
CeCl3.7H2O gave lower yield (entry 12).
2-Amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-
benzopyran-3-carbonitrile (4a). IR (KBr, cmÀ1
)
n
: 3402, 2966, 2195,
1651, 1369; 1H NMR (250 MHz, DMSO-d6)
d: 7.37–7.24 (m, 2H), 7.21–7.13
(m, 3H), 7.03 (s, 2H, NH2), 4.18 (s, 1H), 3.37 (s, 2H), 2.23 (d, J = 16.1HZ, 1H),
2.13 (d, J = 16.1 Hz, 1H), 1.05 (s,3H), 0.96 (s, 3H); 13C NMR (62.9 MHz,
DMSO-d6) d: 195.6, 162.5, 158.5, 144.7, 128.3, 127.1, 126.5, 119.7, 112.7,
58.2, 50.0, 38.7, 35.6, 31.4, 28.4, 26.8. 2-Amino-4-(4-nitrophenyl)-5-
oxo-5,6,7,8-tetrahydro-4H-benzopyran-3-carbonitrile (4o). IR (KBr,
cmÀ1
DMSO-d6)
NH2), 4.37 (s, 1H), 3.28 (s, 2H), 2.60–2.51 (m, 2H), 2.27–2.24 (m, 2H),
2.05–1.85 (m, 2H); 13C NMR (62.9 MHz, DMSO-d6)
: 196.0, 164.8, 158.9,
) n
: 3384, 2982, 2195, 1690, 1516, 1346; 1H NMR (250 MHz,
d
: 8.10 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 6.63 (s, 2H,
d
All reactions delivered good to excellent products yields
and accommodated a wide range of aromatic aldehydes
containing electron-donating and electron-withdrawing
groups (entries 1–12) without any significant substituent
effect. This three-component condensation reaction also
proceeded with heteroaromatic aldehyde, such as
152.0, 146. 6, 128.7, 123.6, 119.54, 113.6, 57.8, 39.6, 36.6, 35.9, 27.1, 20.1.
2-Amino-7,7-dimethyl-4-ethyl-5-oxo-5,6,7,8-tetrahydro-4H-ben-
) n H
zopyran-3-carbonitrile (4s). IR (KBr, cmÀ1 : 3417, 2191, 1654, 1380; 1
NMR (250 MHz, DMSO-d6)
2H), 2.17 (s, 2H), 1.53–1.38 (m, 2H), 1.03 (s, 3H), 1.01 (s, 3H), 0.69 (t, J =
7.2 Hz, 3H); 13C NMR (62.9 MHz, DMSO-d6)
: 201.30, 168.06, 164.90,
125.05, 117.63, 61.31, 55.50, 36.70, 35.08, 33.87, 32.71, 32.09, 31.77.
d: 6.16 (s, 2H), 3.20 (t, J = 4.4 Hz, 1H), 2.31 (s,
d