The condensation of active methylene reagents with salicylaldehyde: Novel synthesis of chromene, azaanthracene, pyrano[3,4-c]chromene and chromeno[3,4-c]pyridine derivatives

Article abstract of DOI:10.1002/jhet.5570410502

On heating of the cyanoacetic acid cyclopentylidene hydrazide 1 with salicylaldehyde in the presence of bases the azaanthracene derivative 6 was formed. Also, reaction of 3 with malononitrile and ketones 10a,b afforded the pyrano[3,4-c]chromene 9 and chromeno[3,4-c]pyridine 11 respectively. A mechanism for these reactions is proposed.

Full text of DOI:10.1002/jhet.5570410502

Sep-Oct 2004
655
The Condensation of Active Methylene Reagents with
Salicylaldehyde: Novel Synthesis of Chromene, Azaanthracene,
Pyrano[3,4-c]chromene and Chromeno[3,4-c]pyridine Derivatives
a*Tarek M. Abu Elmaati
a
Faculty of Applied Arts, Damietta,, Egypt
bFathi M. El-Taweel, bShymaa M. Elmougi and bAbdelghani Elagamey
b
Chemistry Department, Faculty of Science, New Damietta, Egypt
Received March 2, 2004
On heating of the cyanoacetic acid cyclopentylidene hydrazide 1 with salicylaldehyde in the presence of
bases the azaanthracene derivative 6 was formed. Also, reaction of 3 with malononitrile and ketones 10a,b
afforded the pyrano[3,4-c]chromene 9 and chromeno[3,4-c]pyridine 11 respectively. A mechanism for these
reactions is proposed.
J. Heterocyclic Chem., 41, 655 (2004).
The condensation of acid derivatives containing an
In the course of our investigation on the chemistry of
heteroaromatic acetonitriles [5,6], and as a part of our pro-
gram directed for development of new simple and efficient
procedures for the synthesis of fused heterocyclic nitrogen
compounds utilizing readily obtainable nitriles intermedi-
ates [7,8] we carried out the reaction of the nitrile 1 with
salicylaldehyde 2 in the presence of bases such as piperi-
dine in boiling ethanol. In contrast to Sheurmann's results
[4] we have not obtained coumarine imine but the azaan-
thracene derivative 6 in quantitative yield. Apparently, the
coumarine imine 3 initially formed, spontaneously under-
active methylene group with salicylaldehyde in the pres-
ence of a base is a well-known reaction that leads to the
formation of coumarine imines [1,2] or coumarines [2,3].
Sheurmann et al. [4] noted that the reaction of 5-(phenyl-
methyl)-4H-1,2,4-triazol-3-acetonitrile with 5-(diethy-
lamino)-2-hydroxybenzaldehyde in the presence of pyrro-
lidine gives coumarine imine which reacts with diphenyl-
carbonate affording 9-(diethylamino)-3-(phenylmethyl)-
5H-[1]benzopyrano[3, 2-e]1,2,4-triazolo[4,3-c]pyrimidine-
5-one.

656
T. M. Abu Elmaati, F. M. El-Taweel, S. M. Elmougi and A. Elagamey
Vol. 41
went cyclization with a second molecule of salicylalde-
hyde (2). The reaction could be stopped, however, at the
stage of coumarine imine 3 by using 15% alcoholic
sodium hydroxide as a catalyst. Compound of type 6
proved to be stable under acidic and basic conditions. The
structure assignment of 6 is based mainly on spectroscopic
evidences. The molecular mass of the product 6 is 373.
The IR spectrum is consistent with the assigned structure,
showing absorption at 3160 (OH) and 1620 cm-1 (C=N).
The first step of the reaction leading to 6 is the
Knoevenagel condensation between salicylaldehyde (2)
and the nitrile 1 with the formation of the coumarine imine
3. Attack of a second molecule of 2 on the coumarine
imine 3 leads to the formation of compound 4 with simul-
tanous elimination of a water molecule. Base-catalysed
rearrangment of 3 gives product 6.
We isolated intermediates 3 and 4 and thus confirmed
the proposed mechanism. Compound 3 was isolated when
substrates 1 and 2 were heated without any catalyst, or the
reaction was performed in the presence of ammonium
acetate. As expected, the intermediate coumarine 3 upon
treatment with 2 and piperidine in boiling ethanol gave the
final product 6. Hydrolysis of 4 gave the chromene 5. The
same product obtained from the hydrolysis of the couma-
rine imine 3. Also, compound 3 was subjected to reaction
with malononitrile in refluxing ethanol containing a cat-
alytic amount of piperidine. Two structures 7 and 8 have
been assigned as reaction products. The pyran structure 8
was preferred over the pyridine 7 based on 1H NMR spec-
trum which revealed the presence of H-4 pyran signal at δ
= 5.4 ppm. Compound 8 when heated with hydrochloric
acid in ethanol, was converted to 5-oxo derivative 9.

Sep-Oct 2004
The Condensation of Active Methylene Reagents with Salicylaldehyde
657
-1
(CO), 1690 (CO amide), 1620 (C=N) cm ; H nmr: δ 1.40-1.80
(m, 8H, cyclopentane), 7.10 -7.70 (m, 4H, aromat.), 8.8 (s, 1H,
13
coumarin 4-H); C nmr: δ 168.0 (CO), 162.0 (CO amide), 155.6
(imine carbon), 151.4, 124.4 (vinyl carbons), 150.8, 128.1, 127.8,
125.6, 125.2, 121.3 (aromatic carbons), 34.9, 28.9, 28.5, 28.5
1
Similarly, the coumarine imine 3 reacted with the
ketones 10a, b to afford the chromene[3,4-c]pyridine
derivatives 11a,b which then hydrolyzed to the corre-
sponding ketones 12a,b upon refluxing in EtOH/HCl.
In conclusion, this work demonstrates a very simple and
e fficient method for the synthesis of the targeted com-
pounds in excellent yields.
+
(aliphatic carbons); ms: m/z (M ).
Anal. Calcd. for C H N O : C, 66.66; H, 5.22; N, 10.36.
15 14
Found C, 66.43; H, 5.00; N, 10.30.
2 3
Formation of Compound 6.
EXPERIMENTAL
To a solution of the nitrile 1 (0.01 mol) and compound 2 (0.02
mol) in anhydrous ethanol (0.01 mol) was added 2 drops of
piperidine and the solution refluxed for 1 h. The solid formed was
collected by filtration and crystallized from DMF as yellow crys-
tals, yield 71%, m.p. 290 °C; ir: 3160 (OH), 1710 (CO), 1620
All melting points are uncorrected. IR spectra were recorded in
KBr disks using a Shimadzu IR-740 spectrometer. Only the most
1
13
significant IR absorption bands are listed. H and C NMR spec-
tra were recorded at 300 MHz on a Brucker 300 spectometer.
Chemical shifts are reported in δ units (ppm). Mass spectra were
measured on GC/MS INCOS XL Finnigan MAT. Elemental
analysis were performed on a Earlo Ebra 1106 analyzer; for C, H,
N, the results agreed within + or – 0.4 % of the theoretical values.
-1
1
(C=N) cm ; H nmr: δ 1.40-1.80 (m, 8H, cyclopentane), 4.2 (s,
2H, CH ), 6.75-7.55 (m, 7H, aromat.), 9.10 (d, 1H, J = 8Hz, 6`
2
H); ms: m/z 373 (M ).
Anal. Calcd. for C H N O : C, 70.76; H, 5.13; N, 11.25.
+
22 19
Found C, 70.70; H, 5.22; N, 11.23.
3 3
2-Imino-2-H-chromene-3-carboxylic Acid Cyclopentylidene
Hydrazide (3).
Reaction of 3 with Active Methylene Reagents: Formation of
Compounds 8 and 11a,b.
To a solution of the nitrile 1 (0.01 mol) and salicylaldehyde (2)
(0.01 mol) in anhydrous ethanol (5 ml) 1-2 drops of 15% ethano-
lic sodium hydroxide was added. The solution was heated under
reflux for 2 h and then allowed to stand at room temp. for ca. 12
h. The product was collected by filtration and purified by crystal-
lization from ethanol as orange crystals, yield 80%; m.p. 154 °C;
ir: 3300 (NH), 1690 (CO-amide), 1620 (C=N) cm ; H nmr: δ
1.40-1.80 (m, 8H, cyclopentane), 7.05 -7.60 (m, 4H, aromat.),
13
8.35 (s, 1H, coumarin imine 4-H).- C nmr: δ 168 (CO amide),
A mixture of compound 3 (0.01 mol) and the appropriate
active methylene reagent (0.01 mol) in an anhydrous ethanol (20
ml) was refluxed for 3 h. The solid products that deposited upon
cooling were collected by filtration and crystallized form the
proper solvent to give compounds 8 and 11a,b respectively.
-1
1
2-Amino-4-(N-cyclopentylidenehydrazino)-5-imino-5 H, 1 0 bH-
pyrano[3,4-c]chromene-1-carbonitrile (8).
Compound 8 was obtained as yellow crystals from ethanol,
yield 78 %; m.p. 245 °C; ir: 3320, 3315 (NH ), 2210 (CN), 1620
164, 155.7 (imine carbons), 142, 120 (vinyl carbons), 155.1,
129.2, 127.5, 122.1, 121.0, 115.6 (aromatic carbons), 34.9, 28.9,
2
(C=N) cm ; H nmr: δ 1.40-1.85 (m, 8H, cyclopentane), 5.4 (s,
1H, pyran 4H), 6.88-7.90 (m, 4H, aromat.), 9.4, 9.54 (2s, 2H,
-1
1
+
28.6, 28.6 (aliphatic carbons); ms: m/z 269 (M ).
Anal. Calcd. for C H N O : C, 66.90; H, 5.61; N, 15.60.
15 15
Found: C, 66.92; H, 5.58; N, 15.63.
3 2
13
2NH); C nmr: δ 164, 155.6 (imine carbons), 176, 162.0, 74.1,
57.3 (vinyl carbons), 158.0, 130.7, 126.8, 124.9, 115.6, 121.0
(aromatic carbons), 117.3 (CN), 35.3, 29.3, 28.6, 28.6, 14.5
2-Cyclopentylideneamino-3-(2-hydroxyphenyl)-2,3-dihydro-10-
oxa-2-azaanthracene-1-one (4).
+
(aliphatic carbons); ms: m/z (M ).
Anal. Calcd. for C H N O : C, 64.47; H, 5.11; N, 20.88.
To a solution of the nitrile 1 (0.01 mol) and salicylaldehyde (2)
(0.02 mol) in anhydrous ethanol (5 ml) was added ammonium
acetate (50 mg) and the mixture refluxed for 0.5 h. The precipi-
tate formed was separated by filtration and crystallized from
dioxane as yellow crystals, yield 70%, m.p. 220 °C; ir: 3360
18 17
5 2
Found C, 64.40; H, 5.21; N, 20.91.
3 - C y c l o p e n t y l i d e n e a m i n o - 5 - i m i n o - 2 - m e t h y l - 3 , 5 - d i h y d r o -
chromeno[3,4-c]pyridine-4-one (11a).
-1 1
Compound 11a was obtained as yellow crystals from ethanol,
yield 71 %; m.p. 235 °C; ir: 3218 (NH), 1690 (CO), 1620 (C=N)
(OH), 1700 (CO), 1650 (C=N) cm ; H nmr: δ 1.40-1.80 (m, 8H,
cyclopentane), 6.80-7.55 (m, 9H, aromat. and 5-H), 8.00 (s, 1H,
-1
cm ; H nmr: δ 1.35 (s, 3H, CH ), 1.4-1.8 (m, 8H, cyclopen-
1
13
12-H), 9.4 (s, 1H, OH); C nmr: δ167.0 (CO amide), 155.6
3
tane), 5.55 (s, 1H, CH), 7.15-8.0 (m, 4H, aromat.), 9.4 (s, 1H,
(imine carbon), 154.5, 134.6, 133.4, 98.9 (vinyl carbons), 155.9,
154.4, 129.6, 128.5, 128.4, 127.9, 126.9, 123.4, 122.6, 120.9,
115.6, 115.5 (aromatic carbons) 35.2, 29.2, 28.6, 28.6 (aliphatic
13
NH);
C nmr: δ 164.0, 155.6 (imine carbons), 163.0 (CO),
155.1, 133.7, 113.2, 103.7 (vinyl carbons), 155.2, 129.1, 127.6,
122.1, 121.0, 115.6 (aromatic carbons), 35.3, 29.3, 28.6, 28.6,
+
carbons); ms: m/z 373 (M ).
A n a l. Calcd. for C H N O : C, 70.76; H, 5.13; N, 11.25.
+
20.3 (aliphatic carbons); ms: m/z 307 (M ).
Anal. Calcd. for C H N O : C, 70.34; H, 5.58; N, 13.67.
22 19 3 3
Found: C, 70.50; H, 5.02; N, 11.11.
18 17
Found: C, 70.30; H, 5.41; N, 13.91.
3 2
2-Oxo-2H-chromene-3-carboxylic Acid Cyclopentylidene
Hydrazide (5).
3 - C y c l o p e n t y l i d e n e a m i n o - 5 - i m i n o - 2 - p h e n y l - 3 , 5 - d i h y -
drochromeno[3,4-c]pyridine-4-one (11b).
A solution of compound 4 (0.01 mol) in hydrochloric acid (10
ml) was refluxed for 5 min. The solution was made alkaline with
aqueous 20% sodium hydroxide. The compound 5 which precip-
itated, was collected by filtration and crystallized from methanol
as brown crystals, yield 75%, m.p. 210 °C; ir: 3280 (NH), 1710
Compound 11b was obtained as brown crystals from DMF,
yield 70%; m.p. >300 °C; ir: 3218 (NH), 1690 (CO), 1620
-1
(C=N) cm ; H nmr: δ 1.35 (s, 3H, CH ), 1.4-1.8 (m, 8H,
1
3
cyclopentane), 6.13 (s, 1H, CH), 7.0-8.2 (m, 9H, aromat.), 9.35

658
T. M. Abu Elmaati, F. M. El-Taweel, S. M. Elmougi and A. Elagamey
Vol. 41
+
(s, 1H, NH); ms: m/z 369 (M ).
Anal. Calcd. for C H N O : C, 74.78; H, 5.18; N, 11.37.
+
5.55 (s, 1H, CH), 7.15-8.0 (m, 4H, aromat.); ms: m/z 308 (M ).
Anal. Calcd. for C H N O : C, 70.12; H, 5.23; N, 9.09.
18 16 2 3
Found C, 70.30; H, 5.31; N, 9.11.
23 19
Found C, 74.50; H, 5.41; N, 11.61.
3
2
Reaction of Compounds 8 and 11a,b with Hydrochloric Acid:
Formatiom of Compounds 9 and 12a,b.
3-Cyclopentylideneamino-2-phenyl-3,5-dihydrochromeno[3,4-c]-
pyridine-4,5-dione (12b).
A solution of 8 or 11a,b (0.01 mol) in ethanol (30 ml) was
treated with concentrated (37%) hydrochloric acid (10 ml). The
reaction mixture was heated under reflux for 2 h. and then evapo-
rated under reduced pressure. The remaining product was tritu-
rated with water and neutralized by addition of aqueous ammo-
nia. The solid products that deposited were collected by filtration
and crystallized from the proper solvent.
Compound 12b was obtained as colorless crystals from
ethanol, yield 63 %; mp. 281 °C; ir: 1710,1690 (CO), 1620
H nmr: δ 1.4 (s, 3H, CH ), 1.45-1.8 (m, 8H,
3
cyclopentane), 6.15 (s, 1H, CH), 7.0-8.2 (m, 9H, aromat.); ms:
+
m/z 370 (M ).
-1
(C=N) cm ;
1
Anal. Calcd. for C H N O : C, 74.58; H, 4.90; N, 7.56.
23 18 2 3
Found: C, 74.30; H, 5.00; N, 7.63.
2 - A m i n o - 4 - (N-cyclopentylidenehydrazino)-5-oxo-5H, 10b H-
pyrano[3,4-c]chromene-1-carbonitrile (9).
REFERENCES AND NOTES
Compound 9 was obtained as colorless crystals from ethanol,
yield 68 %; m.p. >300 °C; ir: 3320, 3315 (NH ), 1705 (CO),
[1] E. Profft, K. Stuhmer, Arch Pharm., 300, 1 (1967).
[2] P. Czerney, H. Hartmann, Z. Chem., 21, 408 (1981).
[3] S. Matei, J. Russu, P. Coltea, Rev. Chim. (Bucharest) 33
2
2210 (CN), 1625 (C=N) cm ; H nmr: δ 1.40-1.85 (m, 8H,
cyclopentane), 5.4 (s, 1H, pyran 4H), 6.88-7.90 (m, 4H, aromat.),
-1
1
(1982).
+
9.4 (s, 2H, NH); ms: m/z 336 (M ).
Anal. Calcd. for C H N O : C, 64.28; H, 4.79; N, 16.66.
[4] BASF AG (H. Sheurmann, W. Mach, D. Augart, Inv.),
D.O.S. 2415661 (Oct. 23, 1975); Chem. Abstr. 84 61197a (1976).
[5] S. N. Ayad, F. M. El-Taweel, M. A. Sofan, T. M. Abu
Elmaati, A. A. Elagamey, An. De Chim., 91, 711 (1995).
[6] T. M. Abu Elmaati, Acta Chim. Slov., 49, 721 (2002).
[7] F. M. El-Taweel, M. H. Elnagdi, J. Heterocyclic Chem., 38,
981 (2001).
18 16
Found C, 64.00; H, 4.53; N, 16.50.
4 3
3-Cyclopentylideneamino-2-methyl-3,5-dihydrochromeno[3,4-c]-
pyridine-4,5-dione (1 2 a) .
Compound 12a was obtained as colorless crystals from
ethanol, yield 60 %; mp. 275 °C; ir: 1710,1690 (CO), 1620
[8] T. M. Abu Elmaati, S. B. Sais, N. S. Abu Elenein, M. N.
Khodeir and M. A. Sofan, J. Heterocyclic Chem., 40, 481 (2003).
-1
(C=N) cm ; 1.40 (s, 3H, CH ), 1.45-1.8 (m, 8H, cyclopentane),
3