Enaminones in heterocyclic synthesis: A novel route to tetrahydropyrimidines, dihydropyridines, triacylbenzenes and naphthofurans under microwave irradiation

Article abstract of DOI:10.3390/molecules15010058

Condensation of phthalimidoacetone (1) with DMFDMA (N,NDimethylformamide dimethyl acetal) has afforded enaminone 2. Refluxing 2 with equimolecular amounts of benzaldehyde and urea in acetic acid afforded a mixture of tetrahydropyrimidine 5 and the dihydropyridine 6. Compound 2 undergoes selfcondensation on heating in acetic acid or under microwave irradiation in presence of acidic zeolite to give 1,3,5-triacylbenzene 9. Reacting enaminone 11a with naphthoquinone 15 afforded the naphthofuran 18. The possible formation of the aldehyde 19 was excluded based on an HMQC experiment, which revealed that the carbonyl carbon is not linked to any hydrogen.

Full text of DOI:10.3390/molecules15010058

Molecules 2010, 15, 58-67; doi:10.3390/molecules15010058
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Enaminones in Heterocyclic Synthesis: A Novel Route to
Tetrahydropyrimidines, Dihydropyridines, Triacylbenzenes and
Naphthofurans under Microwave Irradiation
Saleh Mohammed Al-Mousawi *, Morsy Ahmed El-Apasery and Mohamed H. Elnagdi
Department of Chemistry, Faculty of Science; Kuwait University, P.O. Box 5969 Safat, 13060, Kuwait
* Author to whom correspondence should be addressed; E-Mail: saleh.almousawi@yahoo.com;
Tel.: +965-24985547; Fax: +965-24816482.
Received: 27 October 2009; in revised form: 18 December 2009 / Accepted: 23 December 2009 /
Published: 25 December 2009
Abstract: Condensation of phthalimidoacetone (1) with DMFDMA (N,N-
Dimethylformamide dimethyl acetal) has afforded enaminone 2. Refluxing 2 with
equimolecular amounts of benzaldehyde and urea in acetic acid afforded a mixture of
tetrahydropyrimidine 5 and the dihydropyridine 6. Compound 2 undergoes self-
condensation on heating in acetic acid or under microwave irradiation in presence of acidic
zeolite to give 1,3,5-triacylbenzene 9. Reacting enaminone 11a with naphthoquinone 15
afforded the naphthofuran 18. The possible formation of the aldehyde 19 was excluded
based on an HMQC experiment, which revealed that the carbonyl carbon is not linked to
any hydrogen.
Keywords: enaminones; Biginelli's condensation; naphthofuran; zeolites; microwave
irradiation with simultaneous cooling
Introduction
Enaminones are valuable intermediates in synthetic organic chemistry [1–4]. In the last few years
we and others have reported a variety of syntheses of heteroaromatics that have been developed using
functionally substituted enamines as readily obtainable building blocks possessing multi electrophilic
and nucleophilic moieties [5–9]. In conjunction to this work we report here an efficient microwave
assisted synthesis of 2-(4-dimethylamino-2-oxo-but-3-enyl)isoindole-1,3-dione (2) and the results of

Molecules 2010, 15
59
our investigations devoted to exploring its synthetic potential. The work has enabled new synthetic
approaches to the title compounds. We report here on the utility of 2 as precursor to substituted
naphthofurans. In the course of this research we observed that the enaminone reactions were rather
sluggish at room temperature, affording the final naphthofuran in moderate yield., but during the
course of our explorations, we observed that the rate and the yields of these reactions could be greatly
improved when performed under microwave irradiation in combination with simultaneous cooling at
30 °C. In this contribution, we would like to disclose the preliminary results of our investigations.
Results and Discussion
Condensation of phthalimidoacetone (1) with dimethylformamide dimethyl acetal (DMFDMA) has
afforded enaminone 2 in 76% and 77 % yields, respectively, either by refluxing in xylene for 8 h or by
heating in MW without solvent at 180 °C for 20 min. The same condensation product had been
obtained earlier by Al-Mousawi et al. [10,11]. Fischer et al. [12] have used coupling of carbonyl
carbons with protons to establish relative geometry extensively, but using 13C-NMR to identify the
long range coupling of C-H as an indication of the stereochemistry from the CO group is very difficult
because of the appearance of carbonyl carbons as broad signals. This is expected theoretically because
this carbonyl carbon has three different 2J, 2J and 3J couplings with nearby protons. We have run
NOE difference experimentx to establish the stereo-orientation of either E or Z-forms for enaminone 2.
The NOE showed that irradiating the alkene CH at δ 5.04 ppm enhanced the dimethylamino protons at δ
2.79 and 3.08 ppm, confirming that they are proximal in space as required by the E-form (cf. Scheme 1).
Scheme 1. Preparation of 2-(4-dimethylamino-2-oxo-but-3-enyl)isoindole-1,3-dione (2).
O
O
N
Me
O
1
DMFDMA
MW
O
O
O
O
NMe2
N
N
NMe2
O
O
2
3
Compound 2, thus formed, has proven to be a versatile starting material for a variety of otherwise
not readily obtainable functionally substituted aromatics and heteroaromatics. Thus, refluxing 2 with
equimolecular amounts of benzaldehyde and urea in acetic acid afforded a 3:1 mixture of
tetrahydropyrimidine 5 and the dihydropyridine 6, which was readily separated by fractional
crystallization (cf. Scheme 2).

Molecules 2010, 15
Scheme 2. Preparation of tetrahydropyrimidine 5 and dihydropyridine 6.
60
O
O
O
Ph
O
O
..
N
PhCHO / Urea
AcOH
N
NH2
N
H
O
NMe2
NMe2
O
2
4
O
O
O
O
Ph
NH
O
Ph
O
N
+
N
N
O
O
N
H
O
O
N
H
5
6
Compound 2 undergoes self-condensation upon heating in acetic acid for 10 hours or upon
irradiation at 150 ºC for 1 hour in a focused microwave oven in the presence of an acidic zeolite
(Montmorillonite K-10) to give 1,3,5-triacylbenzene 9. We believe that compound 2 is initially
converted to the open chain intermediate 7 that further adds to one molecule of enaminone 2 to yield
the intermediate 8, which aromatize under these reaction conditions to give the final isolable product 9
(cf. Scheme 3).
Scheme 3. Synthesis of 2-(2-3,5-di[2-(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)acetyl]-
phenyl-2-oxoethyl)-1,3-isoindolinedione (9).
R
O
O
O
NMe2
R
2
R
R
NMe2
R
NMe2
2
O
O
COR
8
7
-HNMe2
O
O
O
N
O
R=
N
CH2
O
O
N
O
O
O
N
O
O
9

Molecules 2010, 15
61
Compound 2 reacted with anilines 10a-c to yield the aniline derivatives 11a-c. Compound 11a
when heated with zeolite in an attempt to effect an intramolecular Friedel Craft’s cyclization reaction
under MW in the absence of solvent at 160 °C for 30 min afforded N-phenylphthalimide (12) that was
readily obtained from the MW assisted reaction of phthalic anhydride (14) with aniline without solvent
at 180 °C for 60 min. It is most likely that in the initial step in this transformation the nitrogen atom
lone pair attacks the phthalimidocarbonyl moiety. Similarly, heating (2) by MW in Zeolite without
solvent at 160 °C for 30 min. afforded N-methylphthalimide (13) (cf. Scheme 4).
Scheme 4. Synthesis of 2-(2-oxo-4-phenylamino-but-3-enyl)isoindole-1,3-dione, 2-[4-(4-
methoxyphenylamino)-2-oxo-but-3-enyl]isoindole-1,3-dione, and 2-[4-(4-nitrophenyl-
amino)- 2-oxo-but-3-enyl]isoindole-1,3-dione.
NH2
O
O
N
2
+
NH
O
X
10-11 a, X= H
11
b, X= OMe
X
c, X= NO2
Zeolites
MW
Zeolites
MW
O
O
O
10a
O
N
Me
N Ph
MW
O
O
O
14
13
12
We decided to investigate the reaction utilizing microwave irradiation, while keeping the
temperature at 30 °C. This should also allow maintaining the maximum power input of 80 W during
the full run of the irradiation. To ensure a correct temperature measurement, a fiber optic sensor was
used. Using the same reagent ratios and solvent as those for the reaction run at room temperature
(~25 °C), we performed the reaction of enaminone 11a with naphthoquinone 15 under microwave
irradiation with simultaneous cooling at 30 °C.
The reaction proceeded smoothly, furnishing the corresponding naphthofuran 18. The yield of the
product was increased to 76%; The conventional method reaction at room temperature yielded only
68%. It is noteworthy that the reactions could be performed using an irradiation power of 80 W
continuously during the whole run, as the high power level was needed to maintain the temperature at
30 °C because of the efficient external cooling. The differences in yield could be attributed to a lower
rate of decomposition of the compounds when using simultaneous cooling.
The possibility of the formation of the aldehyde 19 was excluded based on the HMQC data which
revealed that the carbonyl carbon is not linked to any hydrogen.

Molecules 2010, 15
62
From H,H-COSY, H-8 at δ 7.70 correlates with H-9 at δ 8.23 and H-7 at δ 7.58 correlates with H-8
and with H-6 at δ 8.25 ppm. From HMBC, H-9 was detected at δ 8.23 ppm because it correlates with
C-9b at δ 145.0, which also correlates with H-2 at δ 9.31 ppm. CO-12 correlated at δ 167.99 with CH2-
11 at δ 5.70 ppm and CH-13 at δ 7.98 ppm (cf. Scheme 5).
Scheme 5. Synthesis of 2-[2-(5-hydroxynaphtho[1,2-b]furan-3-yl)-2-oxoethyl]isoindole-1,3-dione.
O
O
O
OH
N
O
O
MW
N
NH
+
O
O
O
OH
16
11a
NHPh
15
10.34
8.25
OH
H
151.65
123.80
123.9
7.98
7.58
7.45
100.12
H
H
OH
7.92
H
125.61
O
123.89
O
H
O
O
128.01
N
120.2
135.28
7.70
H
167.99
188.71
121.1
145.02
119.80
8.23
120.0
153.74
N
H
O
5.17
O
45.23
OH
132.02
H
CHO
9.31
O
18
17
CHO
O
N
O
HO
O
19
Experimental
General
Melting points are uncorrected. All the reactions were conducted under microwave irradiation in
heavy-walled Pyrex tubes (capacity 10 mL) fitted with PCS caps. Microwave heating was carried out
with a single mode cavity Explorer Microwave Synthesizer (CEM Corporation, NC, USA), producing
continuous irradiation and equipped with simultaneous external air-cooling system. Compound 17 was
prepared in a microwave irradiation experiment which was carried out in a dedicated CEM-Discover-
Coolmate monomode microwave apparatus operating at a frequency of 2.45 GHz with continuous
irradiation power from 0 to 300 W. The reaction was carried out in an open 10 mL double walled glass
vial, which was cooled to 10 °C using a microwave transparent cooling liquid. The temperature was
measured with a fiber-optic device inserted into the reaction vessel. IR spectra were recorded in KBr
1
disks using a Perkin-Elmer System 2000 FT-IR spectrophotometer. H-NMR (400 MHz) and
13C-NMR (100 MHz) spectra were recorded on a Bruker DPX 400, super-conducting NMR

Molecules 2010, 15
63
spectrometer in CDCl3 or DMSO-d6 as solvent and TMS as internal standard; chemical shifts were
reported in δ units (ppm). Mass spectra were measured on a VG Autospec-Q (high resolution, high
performance, tri-sector GC/MS/MS). Microanalyses were performed on a LECO CHNS-932
Elemental Analyzer.
2-(4-Dimethylamino-2-oxo-but-3-enyl)isoindole-1,3-dione (2)
Thermal method: A mixture of phthalimidoacetone (2.03 g, 0.01 mol) and DMFDMA (1.19 g,
0.01 mol) in xylene (5 mL) was heated under reflux for 8 h. The solid product was collected by
filtration and crystallized from EtOH. The reaction gave yellow crystal, yield (76%); mp 162 °C (lit.
[11] mp 159–162 °C ); IR (KBr) ν 1,769, 1,714, 1,660 (CO) (cm-1); MS (EI) m/z (%): 258 [M+, 20%],
1
160(20), 76(10); H-NMR (DMSO-d6): δ(ppm) 2.72 (s, 3H, CH3), 3.05 (s, 3H, CH3), 4.40 (s, 2H,
CH2), 5.04 (d,1H, J = 12 Hz, CH), 7.61 (d,1H, J = 12 Hz, CH), 7.85-7.91 (m, 4H, phthalimidyl-H);
Anal. Calcd. for C14H14N2O3: C, 65.11; H, 5.46; N, 10.85; Found: C, 65.18; H, 5.44; N, 10.76.
Microwave method: A mixture of phthalimidoacetone (2.03 g, 0.01 mol) and DMFDMA (1.19 g,
0.01 mol) was irradiated by focused microwave at 180 °C for 20 min. The build-up of pressure in the
closed reaction vessel was carefully monitored. After the irradiation, the reaction tube was cooled with
high-pressure air through an inbuilt system in the instrument until the temperature had fallen below
50 °C. The solid product, so formed, was collected by filtration and crystallized from EtOH to give
compound 2 in 77% yield.
General procedure for the synthesis of compounds 5 and 6
A solution of compound 2 (2.58 g 0.01 mol), benzaldehyde (1.06 g 0.01 mol), urea (0.76 g
0.01 mol), and acetic acid (10 mL) was heated under reflux for 3 h (completion of reaction was
monitored by TLC). The precipitate thus formed was then collected by filtration, washed with water
and crystallized from acetic acid to give (61%) of tetrahydropyrimidine 5. The filtrate was then
washed thoroughly with water the solid product, so formed, was collected by filtration and crystallized
from ethanol to afford dihydropyridine 6.
2-[2-Oxo-2-(2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidin-5-yl)ethyl]isoindole-1,3-dione (5): Yellow
crystals, yield 61%; mp 280–282 °C; IR (KBr, cm-1): 3,236, 3,101 (NH), 1,714, 1,655 (CO); MS (EI)
m/z: (%) 361 [M+, 15%]; 342 (100), 316 (22), 200 (86), 172 (25). 157 (100), 131 (76), 103 (38), 77
(52); 1H-NMR (DMSO-d6): The diasterotopic protons NCH2 appear as two doublets 4.81, 4.91 (d, 1H,
J = 13.6 Hz, d, 1H, J = 13.6 Hz, NCH2), 5.15 (s, 1H, CH), 7.23 (t, 3H, J = 8.0 Hz, arom-H), 7.31 (t,
13
2H, J = 7.2 Hz, arom-H), 7.83-7.90 (m, 6H, arom-H, NH), 9.74 (s, 1H, NH); C-NMR (DMSO-d6):
δ = 187.41, 168.08, 152.09 (CO), 144.41, 140.92, 135.19, 132.80, 128.88, 127.84, 126.72, 123.70,
110.84, 53.20, 42.85 (CH2); Anal. Calcd. for C20H15N3O4 (361.35): C, 66.48; H, 4.18; N, 11.63.
Found: C, 66.49; H, 4.40; N, 11.54.
2-[2-(5-(2-(1,3-Dioxoisoindolin-2-yl)acetyl)-4-phenyl-1,4-dihydropyridin-3-yl)-2-
oxoethyl]isoindoline-1,3-dione (6): Orange crystals, yield 20%; mp 274–276 °C; IR (KBr, cm-1):
3,236, 3,101 (NH), 1,714, 1,655 (CO); MS (EI) m/z: (%) 531 [M+, 14%]; 513 (100), 454 (32), 369

Molecules 2010, 15
64
1
(55), 343 (22). 284 (18), 182 (26), 160 (100), 147 (72), 104 (74), 76 (61); H-NMR (DMSO-d6):
4.76-4.90 (m, 4H, 2NCH2), 5.16 (s, 1H, CH), 7.10 (t, 3H, J = 7.6 Hz, arom-H), 7.16 (d, 2H, J = 7.2 Hz,
arom-H), 7.21-7.37 (m, 2H, arom-H), 7.87-7.97 (m, 8H, arom-H), 10.14 (s, 1H, NH); 13C-NMR
(DMSO-d6): δ = 188.41, 167.62 (CO), 146.11, 138.00, 134.68, 131.58, 128.80, 128.44, 126.28, 126.09,
123.26, 114.01, 27.24, 42.80 (CH2); Anal. Calcd. for C31H21N3O6 (531.51): C, 70.05; H, 3.98; N, 7.91.
Found: C, 70.21; H, 4.20; N, 8.13.
2-(2-3,5-Di[2-(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)acetyl]phenyl-2-oxoethyl)-1,3-isoindolinedione (9)
Thermal method: A mixture of compound 2 (2.58 g, 0.01 mol) and acetic acid (10 mL) was refluxed
for 10 h, upon completion of the reaction, as checked by TLC, the product was extracted with EtOH.
After evaporation of the solvent under reduced pressure, the product was recrystallized from toluene.
This compound was obtained as light brown crystals, yield (84 %); mp. 300–301 °C; IR (KBr, cm-1):
1
1,776 , 1,721, (CO); MS (EI) m/z (%) = 639 [M+]; H-NMR (DMSO-d6): δ (ppm) 5.57 (s, 6H, CH2),
13
7.93-7.99 (m-12H, phthalimidyl-H), 8.98 (s, 3H, benzyl-H); C-NMR (DMSO-d6): δ 192.23, 167.98
(2 CO), 135.33, 135.20, 133.39, 132.02, 123.93, 45.50 (CH2); Anal. Calcd. for C36H21N3O9 (639.56);
C, 67.61; H, 3.31; N, 6.57. Found 67.46; H, 3.33; N, 6.81.
Microwave method: A mixture of compound 2 (2.58 g, 0.01 mol), zeolite (Montmorillonite k-10
clay, 1 g) and acetic acid (1 mL) was irradiated in microwave at 150 ºC for 60 min. The crude product
was poured onto water, the solid product, so formed, was collected by filtration and crystallized from
toluene. This gave compound 9 in 57% yield.
General procedure for the synthesis of compounds 11a-c
A solution of compound 2 (2.58 g 0.01 mol), compounds 10a-c (0.01 mol), and EtOH (20 mL) was
heated under reflux for 5 h (completion of reaction was monitored by TLC). The reaction mixture was
poured into cold water, filtered and crystallized from ethanol to afford compounds 11a-c.
2-(2-Oxo-4-phenylamino-but-3-enyl)isoindole-1,3-dione (11a): Yellow-orange crystals, yield 88%; mp
167–169 °C; IR (KBr, cm-1): 3,457 (NH), 1,773, 1,706, 1,640 (CO); MS (EI) m/z: (%) 306 [M+, 20%];
160 (25), 146 (100), 117 (8), 104 (14), 77 (12); 1H-NMR (DMSO-d6): 4.50 (s, 2H, NCH2), 5.45 (d, 1H,
J = 8.0 Hz, CH), 7.03 (t, 1H, J = 7.2 Hz, phenyl-H), 7.25 (d, 2H, J = 8.0 Hz, phenyl-H), 7.30 (t, 2H, J
= 7.2 Hz, phenyl-H), 7.77 (dd, 1H, J = 8.0 Hz, J = 8.0 Hz CH), 7.87-7.90 (m, 2H, phthalimidyl-H),
7.91-7.95 (m, 2H, phthalimidyl-H), 11.15 (d, 1H, J = 12.6 Hz, NH); 13C-NMR (DMSO-d6):
δ = 191.47, 168.22 (CO), 145.75, 140.38, 135.16, 132.14, 130.06, 123.96, 123.69, 116.66, 93.58, 45.79
(NCH2); Anal. Calcd. for C18H14N2O3 (306.31): C, 70.58; H, 4.61, N, 9.15. Found: 70.55; H, 4.61, N,
9.27.
2-[4-(4-Methoxyphenylamino)-2-oxo-but-3-enyl]isoindole-1,3-dione (11b): Yellow crystals, yield
83%; mp 204–206 °C; IR (KBr, cm-1): 3,455 (NH), 1,772, 1,706, 1,632 (CO); MS (EI) m/z: (%) 336
1
[M+, 82%]; 175 (100), 160 (42), 132 (65), 103 (22), 76 (21); H-NMR (DMSO-d6): 3.71 (s, 3H,
OCH3), 4.46 (s, 2H, NCH2), 5.37 (d, 1H, J = 7.8 Hz, CH), 6.88 (d, 2H, J = 8.4 Hz, arom-H), 7.19 (d,
2H, J = 8.4 Hz, arom-H), 7.64 (dd, 1H, J = 7.8 Hz, J = 7.8 Hz CH), 7.86-7.89 (m, 2H, phthalimidyl-

Molecules 2010, 15
65
H), 7.91-7.93 (m, 2H, phthalimidyl-H), 11.18 (d, 1H, J = 12.6 Hz, NH); 13C-NMR (DMSO-d6):
δ = 190.27, 167.70 (CO), 155.80, 145.99, 134.62, 133.30, 131.65, 123.18, 117.65, 114.77, 92.08, 55.99
(NCH2), 44.34 (OCH3); Anal. Calcd. for C19H16N2O4 (336.34): C, 67.85; H, 4.79, N, 8.33. Found: C,
67.73; H, 4.85, N, 8.30.
2-[4-(4-Nitrophenylamino)-2-oxo-but-3-enyl]isoindole-1,3-dione (11c): Yellow crystals, yield 79%;
mp 234–236 °C; IR (KBr, cm-1): 3,460 (NH), 1,768, 1,715, 1,653 (CO); MS (EI) m/z: (%) 351 [M+,
1
84%]; 306 (53), 261 (28), 191 (60), 159 (41), 145 (43), 116 (45), 104 (70). 76 (100); H-NMR
(DMSO-d6): 4.57 (s, 2H, NCH2), 5.65 (d, 1H, J = 8.4 Hz, CH), 7.49 (d, 2H, J = 9.0 Hz, arom-H), 7.82
(dd, 1H, J = 8.4 Hz, J = 8.4 Hz CH), 7.85-7.89 (m, 2H, phthalimidyl-H), 7.90-7.94 (m, 2H,
phthalimidyl-H), 8.15 (d, 2H, J = 9.0 Hz, arom-H), 11.18 (d, 1H, J = 12.6 Hz, NH); 13C-NMR
(DMSO-d6): δ = 190.26, 167.32 (CO), 155.72, 145.42, 141.53, 134.57, 131.69, 125.63, 123.32, 116.14,
108.33, 36.55 (NCH2); Anal. Calcd. for C18H13N3O5 (351.31): C, 61.54; H, 3.73, N, 11.96. Found: C,
61.53; H, 3.82, N, 11.96.
General procedure for the synthesis of 12 and 13
Equimolar quantities (0.01 mol) of either compound 2 or 11a and corresponding zeolite were heated
under solvent-free conditions for 30 min in a focused microwave oven at 160 °C. Upon completion of
the reaction, as checked by TLC, the product was extracted with EtOH (3 × 10 mL). After evaporation
of the solvent under reduced pressure, the product was recrystallized from toluene.
2-Phenylisoindole-1,3-dione (12): Buff crystals, yield 96% ; mp 206-208 °C (lit. [13] mp 205–207 °C
1
yield 95%); MS (EI) m/z: (%) 223 [M+, 100%]; 179 (78), 152 (10), 104 (16), 76 (40). H-NMR
(DMSO-d6): 7.44 (d, 3H, J = 7.2 Hz, phenyl-H), 7.53 (t, 2H, J = 7.2 Hz, phenyl-H), 7.91-7.94 (m, 2H,
phthalimidyl-H), 7.96-7.99 (m, 2H, phthalimidyl-H); 13C-NMR (DMSO-d6): δ = 167.49 (CO), 135.17,
132.37, 132.02, 129.31, 128.53, 127.89, 123.89; Anal. Calcd. for C14H9NO2 (223.23): C, 75.33; H,
4.06, N, 6.27. Found: C, 75.57; H, 4.12, N, 6.36.
2-Methyl-isoindole-1,3-dione (13): Buff crystals, yield 87%, mp 131–133 °C (lit. [14] mp 134 °C and
yield 68%); MS (EI) m/z: (%) 161 [M+, 100%]; 132 (50), 117 (74), 104 (82), 76 (81), 66 (44);
1H-NMR (DMSO-d6): 3.36 (s, 3H, CH3), 7.81-7.83 (m, 2H, phthalimidyl-H), 7.84-7.88 (m, 2H,
phthalimidyl-H); 13C-NMR (DMSO-d6): δ = 168.53 (CO), 134.72, 132.30, 123.36, 24.20 (CH3); Anal.
Calcd. for C9H7NO2 (161.16): C, 67.07; H, 4.38, N, 8.69. Found: C, 67.01; H, 4.39, N, 9.19.
Reaction of phthalic anhydride with aniline
Equimolar quantities (1.48 g, 0.01 mol) of phathalic anhydride and aniline (0.93 g, 0.01 mol) were
heated for 60 min in a focused microwave oven at 180 °C under solvent-free conditions. Upon
completion of the reaction, as checked by TLC, the product was extracted with EtOH. After
evaporation of the solvent under reduced pressure, the product was recrystallized from toluene to
afford compound 12, yield 94%.

Molecules 2010, 15
66
2-[2-(5-Hydroxynaphtho[1,2-b]furan-3-yl)-2-oxoethyl]isoindole-1,3-dione (18)
Thermal method: A mixture of compound 11a (3.06 g, 0.01 mol) and naphthoquinone (1.54 g,
0.01 mol) was dissolved in glacial acetic acid (10 mL), then stirred overnight at room temperature. The
so formed crystals were collected by filtration and crystallized from dioxane. This compound was
obtained in 68 % yield, mp 303 °C (lit. [15] mp 301–303 °C); IR (KBr, cm-1): 3,309 (OH), 1,776,
1
1,722, 1,666 (CO); MS (EI) m/z (%) = 371 [M+]; H-NMR (DMSO-d6): δ 5.17 (s, 2H, CH2), 7.45 (s,
1H, H-4), 7.58 (dt, 1H, J = 7.8, 1.2 Hz, H-7), 7.70 (dt, 1H, J = 7.8, 1.2 Hz, H-8), 7.91-7.92 (m, 1H, H-
14), 7.97-7.98 (m, 1H, H-13), 8.23 (d, 1H, J = 8.4 Hz, H-9), 8.25 (d, 1H, J = 8.4 Hz, H-6), 9.31 (s, 1H,
H-2), 10.34 (s, 1H, OH); 13C-NMR (DMSO-d6): δ 188.71 (C-10), 167.99 (C-12), 153.74 (C-2), 151.65
(C-5), 145.02 (C-9b), 135.28 (C-14), 132.02 (C-12a), 128.01 (C-8), 125.61 (C-7), 123.97 (C-5a),
123.89 (C-13), 123.80 (C-6), 121.19 (C-9a), 120.28 (C-3a), 120.08 (C-3), 119.85 (C-9), 100.12 (C-4),
45.23 (CH2, C-11); Anal. Calcd. for C22H13NO5 (371.35); C, 71.16; H, 3.53; N, 3.77. Found C, 71.14;
H, 3.65; N, 3.95.
Microwave method: A mixture of compound 11a (3.06 g, 0.01 mol), naphthoquinone (1.54 g,
0.01 mol), and glacial acetic acid (1 mL) was irradiated at 30 °C for 30 min, continuously at the
maximum power of 80 W. After completion of the reaction the solvent was evaporated. The crude
product was then collected by filtration and crystallized from dioxane to give the title compound in
76% yield.
Conclusions
In summary, we could show that the enaminone 2 is a valuable precursor to the
tetrahydropyrimidine, dihydropyridine, triacylbenzene and naphthofuran moieties. It is worthwhile to
mention here that thermal and microwave assisted reactions were conducted in different solvents with
exception of 2, 12 and 13, which were prepared by microwave heating without solvent. We have also
revealed that the reactions described proceeded to completion in a much shorter time when irradiated
in a focused microwave oven. Moreover, microwave irradiation in combination with simultaneous
cooling assisted the reactions and produced somewhat higher yield than those obtained by
conventional heating.
Acknowledgments
The authors are grateful to Kuwait University, Research Administration for financial support
through project SC 05/06. Analytical facilities provided by SAF projects # GS 01/01 & GS 03/01 are
greatly appreciated.
References
1. Riyadh, S.M.; Abdelhamid, I.A.; Al-Matar, H.M.; Hilmy, N.H.; Elnagdi, M.H. Enamines as
precursors to polyfunctional heteroaromatic compounds; a decade of development. Heterocycles
2008, 75, 1849–1905.
2. Stanovnik, B.; Svete, synthesis of heterocycles from alkyl 3-(dimethylamino) propenoates and
related enaminones. Chem. Rev. 2004, 104, 2433–2480.

Molecules 2010, 15
67
3. Zhu, S.; Zhao, K.; Su, X.; Ji, S. Microwave-assisted synthesis of new spiro[indoline-3,4'-
quinoline] derivatives via a one-pot multicomponent reaction. Synth. Commun. 2009, 39,
1355–1366.
4. Loghmani-Khouzani, H. Sabzyan, H, Rezaei-Pooranari, A. Synthesis and structure of α-azo-2-
ketomethylquinolines. Dye. Pigment. 2008, 76, 447–454.
5. Al-Omran, F.; Abdel Khalik, M.M.; ElKhair, A.A.; Elnagdi, M.H. Studies with functionally
substituted heteroaromatics: A novel route for the synthesis of 1-aryl-6-oxopyridazinones, 1-
arylpyridazine-6-imines and 1-aryl-6-imino-4-pyridazinals. Synthesis 1997, 91–94.
6. Al-Mousawi, S.; Moustafa, M.S.; Elnagdi, M.H. Studies with enamines: Functionally substituted
enamines as aldehyde equivalents in Gewald reaction ARKIVOC, 2008, 10, 17–25.
7. Elassar, A.A.; El-Khair, A.A. Recent developments in the chemistry of enaminones. Tetrahedron
2003, 59, 8463–8480.
8. De Koning, C.B.; Michael, J.P.; Riley, D.L. Formal Synthesis of (5R,8R,8aS)-indolizidine 209I
via enaminones incorporating weinreb amides. Heterocycles 2009, 79, 935–953.
9. Svete, J. Utilisation of chiral enaminones and azomethine imines in the synthesis of
functionalised pyrazoles. ARKIVOC 2006, 7, 35–56.
10. Al-Mousawi, S.; John, E.; Al-Kandery, N. Studies with enaminones: Synthesis and chemical
reactivity of 2-(4-dimethylamino-2-oxobut-3-enyl)-isoindole-1,3-dione and of 4-(4-
dimethylamino-2-oxobut-3-enyloxy)-2h-phthalazin-l-one. J. Heterocycl. Chem. 2004, 41,
381–385.
11. Al-Mousawi, S.M.; El-Apasery, M.A.; Al-Kanderi, N.H. Microwave-assisted organic synthesis:
the Gabriel approach as a route to new pyrazolylhydrazonoazoles. ARKIVOC 2008, 16, 268–278.
13
12. Fischer, P.; Schweizer, E.; Langner, J.; Schmidt, U. C, 1H Long - range coupling constants in
configuration assignment of some trisubstituted alkenes. Magn. Reson. Chem. 1994, 32, 567–568
13. Nikpour, F.; Mogaddam, B.M. An expedient method to the synthesis of n-substituted 1h-
isoindole-1,3(2h)-diones. Heterocycles 2008, 75, 2289–2292.
14. Hekmatshoar, R.; Heravi, M.M.; Baghernejad, B.; Asadolah, K. Microwave-assisted N-alkylation
of potassium phthalimide and potassium succinimide onto silica gel in dry media. Phos. Sulf. Silic.
2004, 179, 1611–1614.
15. Al-Mousawi, S.M.; El-Apasery, M.A.; Al-Kanderi, N.H. Azolylacetones as precursors to indoles
and naphthofurans facilitated by microwave irradiation with simultaneous cooling. Molecules
2009, 14, 2976–2984.
Sample Availability: Samples of compounds 1-18 are available from the authors.
© 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).