Azolyacetones as precursors to indoles and naphthofurans facilitated by microwave irradiation with simultaneous cooling

Article abstract of DOI:10.3390/molecules14082976

Phthalimide reacted with phenacyl bromide under microwave irradiation to yield phenacyl isoindolidene-1,3-dione (3b), while 3a reacted with phenylhydrazine to yield the phenylhydrazone 4 that was readily converted into indoylphthalimide 8. Similarly N-benzotriazolylacetone (6a) reacted with phenyl hydrazine to yield the phenylhydrazone 7a that was converted into indoylbenzotriazole 9. Treatment of 8 with hydrazine hydrate afforded a mixture of phthalhydrazide 10 and 3-amino-2-methylindole (11). Reacting enaminone 13 with naphthoquinone (14) afforded the aryl naphthofuran 17. The possibility of the formation of the aldehyde 18 was excluded based on HMQC, which revealed that the carbonyl carbon is not linked to any hydrogen.

Full text of DOI:10.3390/molecules14082976

Molecules 2009, 14, 2976-2984; doi:10.3390/molecules14082976
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Azolyacetones as Precursors to Indoles and Naphthofurans
Facilitated by Microwave Irradiation with Simultaneous
Cooling
Saleh Mohammed Al-Mousawi * and Morsy Ahmed El-Apasery
Department of Chemistry, Faculty of Science; University of Kuwait, Safat, 13060, P.O. Box 12613,
Kuwait
* Author to whom correspondence should be addressed; E-mail: saleh.almousawi@yahoo.com;
Tel.: +965-24985547; Fax: +965-24816482
Received: 8 July 2009; in revised form: 30 July 2009 / Accepted: 5 August 2009 /
Published: 11 August 2009
Abstract: Phthalimide reacted with phenacyl bromide under microwave irradiation to
yield phenacyl isoindolidene-1,3-dione (3b), while 3a reacted with phenylhydrazine to
yield the phenylhydrazone 4 that was readily converted into indoylphthalimide 8. Similarly
N-benzotriazolylacetone (6a) reacted with phenyl hydrazine to yield the phenylhydrazone
7a that was converted into indoylbenzotriazole 9. Treatment of 8 with hydrazine hydrate
afforded a mixture of phthalhydrazide 10 and 3-amino-2-methylindole (11). Reacting
enaminone 13 with naphthoquinone (14) afforded the aryl naphthofuran 17. The possibility
of the formation of the aldehyde 18 was excluded based on HMQC, which revealed that
the carbonyl carbon is not linked to any hydrogen.
Keywords: microwave irradiation; aminoindole; naphthofuran; azolylacetone
Introduction
Azolylketones are versatile reagents and their chemistry has received considerable attention [1-4].
In previous work from our laboratories [5-9], we have investigated possible utility of 2-(2-
oxopropyl)isoindole-1,3-dione (3a) and 1-benzotriazol-1-yl-propan-2-one (6a) for synthesis of
polyfunctional heteroaromatics. In conjunction of this work we report here on utility of compounds 3
and 6 as precursors to substituted indoles and naphthofurans. However, we found that the reactions of
azolylketones were rather sluggish at room temperature, affording the final naphthofurans in moderate

Molecules 2009, 14
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yields. During the course of our explorations, we observed that the rate and the yield 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
Reacting potassium phthalimide (1) with phenacyl bromide (2b) either by refluxing in
dimethylformamide (DMF) for 30 minutes or in microwave oven (MW) at 55 °C for 10 minutes
afforded the phenacyl isoindolidinedione (3b) (cf. Scheme 1).
Scheme 1. Preparation of 2-(2-Oxo-2-phenylethyl)isoindole-1,3-dione.
O
O
O
O
X
N
Y
Y
NK
O
2a, X = Cl, Y = Me
b, X = Br, Y = Ph
MW
O
3a, Y = Me
b, Y = Ph
1
Compound 3a [6,7] reacted with phenylhydrazine under MW at 130 °C for 20 minutes to yield the
phenylhydrazone 4 [7] in 74% yield, while similar treatment of 3b [10-12] resulted in formation of
phthalimide (5) (cf. Scheme 2).
Scheme 2. Preparation of 2-[2-(Phenylhydrazono)propyl]isoindole-1,3-dione.
O
NHPh
N
N
MW
MW
CH3
O
O
4
O
PhNHNH2
Toluene
N
Y
O
O
NH
3a, Y = Me
b, Y = Ph
O
5
Similarly, N-benzotriazolylacetone (6a) reacted with phenylhydrazine under MW at 130 °C for 20
minutes to yield the phenylhydrazone 7a in 89% yield (cf. Scheme 3).

Molecules 2009, 14
Scheme 3. Preparation of N-(2-Benzotriazol-1-yl-1-methyl-ethylidene)-N'-phenylhydrazine.
2978
NHPh
Y
N
N
O
N
N
N
N
N
PhNHNH2
Y
EtOH
MW
6a, Y = Me
b, Y = Ph
7a, Y = Me
b, Y = Ph
Heating of 4 or 7a with zinc chloride and a few drops of acetic acid under microwave irradiation at
160 °C for 30 minutes afforded compounds 8 or 9 in 72% and 88% yields, respectively. Despite
Katritzky’s reports [13,14] that benzotriazole substituents are masked halides, we failed to replace the
benzotriazolyl moiety in the formed indole under a variety of conditions. It is of value to report that
compound 8 has been previously obtained via pyrolysis of 4,5-disubstituted 1-phthalimido-1,2,3-
triazoles [15]. Treatment of 8 with hydrazine hydrate under MW at 130 °C for 20 minutes afforded
phthalhydrazide (10) in 85% yield, along with a product which was identified as 3-amino-2-
methylindole (11). This amine 11 has been previously prepared in two steps via nitration of
2-methylindole and subsequent reduction [16] (cf. Scheme 4).
Scheme 4. Synthesis of 1-(2-Methyl-1H-indol-3-yl)-1H-benzotriazole.
4 or 7a
N
+
N
AcOH / ZnCl2
N
O
MW at 160 oC
for 30 min
N
O
H3C
N
H3C
H
N
H
9
O
8
H2N
NH
NH
NH2NH2. H2O
MW
+
H3C
N
H
O
10
11
In previous work we have shown that the methylene group in N-alkylazolylketones is activated
toward electrophiles and that this activity is enhanced by microwave heating [17]. In continuation of
this work we report on the synthesis of 2-(4-dimethylamino-2-oxo-3-butenyl)isoindole-1,3-dione as
precursor to the title compounds. Thus, condensation of 3a with dimethylformamide dimethyl acetal
(DMF-DMA, 12) has afforded enaminone 13 in 76% and 77% yields, either by refluxing in xylene for
8 h or by heating under MW without solvent at 180 °C for 20 min, respectively. We decided to
investigate the effect of microwave irradiation, keeping the temperature at 30 °C. This should also

Molecules 2009, 14
2979
allow us to maintain the maximum power input of 70 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 these for the reaction run at room temperature, we performed the reaction of enaminone
13 with naphthoquinone (14) under microwave irradiation with simultaneous cooling to 30 °C. The
reaction proceeded smoothly, furnishing the corresponding arylnaphthofuran product 17 in increased
yield (66%); this is 52% higher compared to the conventional reaction at room temperature. It is
noteworthy that the reactions could be performed using the irradiation power of 70 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 18 was excluded based on HMQC, which revealed that the carbonyl carbon is not linked
to any hydrogen (cf. Scheme 5).
Scheme 5. Synthesis of 2-[2-(5-Hydroxynaphtho[1,2-b]furan-3-yl)-2-oxoethyl]isoindole-1,3-dione.
CHO
O
O
N
HO
O
N
O
CH3
O
O
3a
18
DMFDMA
12
OH
OH
O
O
O
O
O
N
O
N
+
O
NMe2
O
NMe2
15
13
14
OH
O
OH
OH
O
O
O
O
N
N
O
O
CHO
16
17

Molecules 2009, 14
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Conclusions
In summary, we could extend Fisher’s indole reaction to enable the synthesis of 2-(2-methyl-1H-
indol-3-yl)isoindole-1,3-dione and 1-(2-methyl-1H-indol-3-yl)-1H-benzotriazole using microwave
irradiation. It is worthwhile to mention here that thermal and microwave assisted reactions were
conducted in different solvents, with the exception of 13, which was prepared by microwave heating
without solvent. We have also revealed that the reactions described have proceeded to completion in a
much shorter time when irradiated in a focused microwave oven. Moreover, the microwave assisted
reactions produced somewhat higher yields than those obtained by conventional heating.
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
spectrometer in CDCl3 or DMSO 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. Compounds 3a, 6a,b and 7b have been reported earlier and proven to be identical
with the products obtained here [1,6,7,13,18].
2-(2-Oxo-2-phenylethyl)isoindole-1,3-dione (3b)
Thermal method: A mixture of phthalimide potassium salt (1.85 g, 0.01 mol) and phenacyl bromide
(1.99 g, 0.01 mol) in dry DMF (20 mL) was mixed gently until the exothermic reaction ceased. The
mixture was heated for 30 min, filtered and washed with water. The solid product was collected and
crystallized from EtOH to give a yield of 95%, mp 160-164 °C (all data agreed with the published
values [11,12]).
Microwave method: A mixture of phthalimide potassium salt (1.85 g, 0.01 mol) and phenacyl bromide
(1.99 g, 0.01 mol) in dry DMF (2 mL) was irradiated in focused microwave at 55 °C for 10 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 a built-in system in the instrument until the

Molecules 2009, 14
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temperature had fallen below 50 °C. The crude product was poured onto water and the solid product,
so formed, was collected by filtration and crystallized from EtOH to give a 68% yield of the
target compound.
General method for preparation of compounds 4 and 7a
A dried heavy-walled Pyrex tube containing a small stir bar was charged with compounds 3a or 6a
(0.01 mol), phenylhydrazine (1.08 g, 0.01 mol)) and ethanol (2 mL) or toluene (2 mL). The tube
containing the reaction mixture was fitted with a PCS cap and then it was exposed to microwave
irradiation at 130 °C for 20 min. The solvent was removed and the residue, when cooled, deposited a
solid, which was crystallized from ethanol.
2-[2-(Phenylhydrazono)propyl]isoindole-1,3-dione (4): mp 158-160 °C; IR (KBr, cm-1): 3321 (NH),
1774 (CO); MS (EI) m/z: (%) 293 (M+, 100%);1H-NMR (DMSO-d6): δ = 1.90 (s, 3H, CH3), 4.37 (s,
2H, CH2), 6.85 (t, 1H, J = 7.2 Hz, phenyl-H), 6.72 (d, 2H, J = 7.8 Hz, phenyl-H), 6.94 (t, 2H, J = 7.8
Hz, phenyl-H), 7.87-7.88 (m, 2H, phthalmidyl-H), 7.92-7.93 (m, 2H, phthalmidyl-H) 8.90 (s, 1H, NH),
Anal. Calcd. for C17H15N3O2 (293.32): C, 69.61; H, 5.15; N, 14.33. Found: C, 69.24; H, 5.36; N,
13.94.
N-(2-Benzotriazol-1-yl-1-methyl-ethylidene)-N'-phenylhydrazine (7a): mp 128-130 °C; IR (KBr, cm-1):
3359 (NH), LC-MS 265 (M+, 58%);1H-NMR (DMSO-d6): δ = 1.84 (s, 3H, CH3), 5.53 (s, 2H, CH2),
6.68 (t, 1H, J = 7.2 Hz, arom-H), 6.96 (d, 2H, J = 8.4 Hz, arom-H), 7.11 (t, 2H, J = 7.6 Hz, arom-H),
7.39 (t, 1H, J = 7.2 Hz, arom-H), 7.53 (t, 1H, J = 7.2 Hz, arom-H), 7.79 (d, 1H, J = 8.4 Hz, arom-H),
13
8.07 (d, 1H, J = 8.4 Hz, arom-H), 9.10 (s, 1H, NH), C-NMR (DMSO-d6): δ = 13.61 (CH3), 54.24
(CH2), 110.81, 112.42, 118.80, 119.18, 123.94, 127.34, 128.79, 133.23, 138.61, 145.32, 145.65.
General method for preparation of compounds 8 and 9
A dried heavy-walled Pyrex tube containing a small stir bar was charged with compounds 4 or 7a
(0.01 mol), zinc chloride (1.36 g, 0.01 mol) and acetic acid (2 mL). The tube was exposed to MW at
160 °C for 30 min. The crude product was poured onto water, and the solid product, so formed, was
collected by filtration and crystallized from toluene.
2-(2-Methyl-1H-indol-3-yl)isoindole-1,3-dione (8): mp 222-224 °C; IR (KBr, cm-1): 3278 (NH), MS
(EI) m/z: (%) 276 (M+, 100%);1H-NMR (DMSO-d6): δ = 2.77 (s, 3H, CH3), 6.95 (t, 1H, J = 7.2 Hz,
indolyl -H), 7.07 (t, 1H, J = 7.2 Hz, indolyl -H), 7.23 (d, 1H, J = 8.0 Hz, indolyl -H), 7.36 (d, 1H,
J = 8.0 Hz, indolyl-H), 7.91-7.93 (m, 2H, phthalmidyl-H), 7.98-8.00 (m, 2H, phthalmidyl-H) 11.41 (s,
1H, NH), 13C-NMR (DMSO-d6): δ = 11.07 (CH3), 103.74, 111.13, 117.09, 119.28, 120.93, 123.43,
124.75, 125.36, 128.24, 128.93, 131.85, 133.27, 133.95, 134.65, 163.49. Anal. Calcd. for C17H12N2O2
(276.29): C, 73.90; H, 4.38; N, 10.14. Found: C, 73.83; H, 4.38; N, 10.05.
1-(2-Methyl-1H-indol-3-yl)-1H-benzotriazole (9): mp ›300 °C; IR (KBr, cm-1): 3280 (NH), MS (EI)
m/z: (%) 248 (M+, 30%);1H-NMR (DMSO-d6): δ = 2.30 (s, 3H, CH3), 7.03 (t, 1H, J = 7.2 Hz, arom-
H), 7.07 (d, 1H, J = 7.8 Hz, arom-H), 7.16 (t, 1H, J = 8.4 Hz, arom-H), 7.49-7.75 (m, 4H, arom-H),

Molecules 2009, 14
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13
7.56 (t, 1H, J = 7.8 Hz, arom-H), 8.16 (d, 1H, J = 8.4 Hz, arom-H), 11.75 (s, 1H, NH), C- NMR
(DMSO-d6: δ = 11.33 (CH3), 109.38, 111.05, 112.10, 116.33, 119.21, 120.02, 120.67, 122.20, 124.70,
128.20. 131.65, 134.10, 134.51, 145.49.
2-Methyl-1H-indol-3-ylamine (11)
A mixture of compound 8 (2.76 g, 0.01 mol) and hydrazine hydrate (1.43 g, 0.02 mol) in EtOH
(3 mL) was irradiated by focused microwave at 130 °C for 20 min. The solid product, so formed, was
collected by filtration to separate the side product [phthalhydrazide (10)]. The filtrate was evaporated
under vacuum to remove the solvent and the product 11 was isolated using column chromatography
(EtOAc – CHCl2) (all data were in agreement agreed with the published values [16]).
2-(4-Dimethylamino-2-oxobut-3-enyl)isoindole-1,3-dione (13)
Thermal method: A mixture of phthalimidoacetone (2.03 g, 0.01 mol) and DMF-DMA (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 crystals, yield (76%), mp 159-162 °C
1
(literature mp 155 °C [18]); IR (KBr) ν 1769 (CO), 1714 (CO), 1660 (CO) (cm-1); 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); MS (EI) m/z (%): 258.1[M+, 20%],
160(20), 76(10); 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 DMF-DMA (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 a built-in 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 a 77%
yield of the target compound.
2-[2-(5-Hydroxynaphtho[1,2-b]furan-3-yl)-2-oxoethyl]isoindole-1,3-dione (17)
Thermal method: A mixture of compound 13 (2.58g, 0.01 mol) and naphthoquinone (1.54g, 0.01 mol)
was dissolved in glacial acetic acid (10 mL), then stirred over night at room temperature. The so
formed crystals were collected by filtration and crystallized from dioxane. This compound was
obtained in yield (52 %). mp 301-303 °C; IR (KBr)(cm-1): 3309 (OH), 1776 (CO), 1722 (CO), 1666
1
(CO); H-NMR (DMSO-d6): δ 5.17 (s, 2H, CH2), 7.45 (s, 1H, H-4), 7.58 (t, 1H, J=8.4Hz, H-7), 7.70
(t, 1H, J=8.4Hz, H-8), 7.91-7.92 (m, 1H, H-14), 7.97-7.98 (m, 1H, H-13), 8.23 (d, 1H, J=8.4Hz, H-9),
8.25 (d, 1H, J=8.4Hz, 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); MS (EI) m/z (%) = 371 [M+]; 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.

Molecules 2009, 14
2983
Microwave method: A mixture of compound 13 (2.58 g, 0.01 mol), naphthoquinone (1.54 g, 0.01 mol),
and glacial acetic acid (1 mL) was irradiated at 30 °C for 5 min, continuously at the maximum power
of 70 W. After completion of the reaction the solvent was evaporated. The crude product was then
collected by filtration and crystallized from dioxane to give a 66% yield of 17.
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.
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Sample Availability: Samples of the compounds 1-17 are available from the authors.
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