An efficient microwave-assisted synthesis of dihydropyrazinones and bis-benzoylketones

Article abstract of DOI:10.1016/j.tetlet.2009.12.057

Microwave-assisted modified Sandmeyer reactions of oximinoacetanilides, themselves obtained from substituted primary aromatic amines, in concentrated H₂SO₄ give isatins. N-Acetylisatins undergo ring cleavage and subsequent ring closing with alkanediamines in the presence of ethanol under MW irradiation to give the corresponding dihydropyrazinones in excellent yields. Modification of the reaction conditions affords bis-benzoylketones under MW irradiation.

Full text of DOI:10.1016/j.tetlet.2009.12.057

Tetrahedron Letters 51 (2010) 1155–1157
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Tetrahedron Letters
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An efficient microwave-assisted synthesis of dihydropyrazinones and
bis-benzoylketones
a
a
b
Mamun M. Hossain a, , Rabiul M. Islam , Sukanta K. Saha , Mohammad K. Islam
*
a Department of Chemistry, Faculty of Science, Jahangirnagar University, Savar, Dhaka 1342, Bangladesh
b Faculty of Life Science, Mawlana Bhashani Science and Technology University, Tangail 1902, Bangladesh
a r t i c l e i n f o
a b s t r a c t
Article history:
Microwave-assisted modified Sandmeyer reactions of oximinoacetanilides, themselves obtained from
substituted primary aromatic amines, in concentrated H2SO4 give isatins. N-Acetylisatins undergo ring
cleavage and subsequent ring closing with alkanediamines in the presence of ethanol under MW irradi-
ation to give the corresponding dihydropyrazinones in excellent yields. Modification of the reaction con-
ditions affords bis-benzoylketones under MW irradiation.
Received 2 September 2009
Revised 30 November 2009
Accepted 11 December 2009
Available online 21 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Since the publication of the first paper on organic synthesis un-
der microwave (MW) dielectric heating, the field has expanded
dramatically.1–4 The use of MW irradiation minimizes the forma-
tion of unwanted by-products and reduces the need for organic
solvents to a minimum, or even solvent-free.5,6 Isatins and related
compounds have beneficial biological effects, including antifungal,
antiviral, and antiproliferative activities.7,8 Hence, there is signifi-
cant interest in the design of various isatins and related com-
pounds as drugs in the field of medicinal organic chemistry.9–11
In addition, the reactions of carbonyl moieties at the b-position
of various isatins and N-acetylisatins, are important.12–14 Accord-
ingly, we report on the MW-assisted synthesis and the character-
ization of several N-acetylisatins and their transformations into
dihydropyrazinones and bis-benzoylketones using alkanediamines
in excellent yields.
yield 81%, conventional yield 66%, decomposed at 298 °C). The IR
(KBr, disc) spectrum of 2a showed absorptions at 1758 (s, C@O, lac-
tam), 1684 (s, C@O), and 1625 (s, C@O, amide) cmꢀ1 for the three
carbonyl groups, respectively. In addition, 2a showed signals in
the 1H NMR spectrum (DMSO-d6) at d 7.82 for the aromatic proton
(C4-H) as a doublet and the C6-H proton appeared at d 7.64 as a
doublet of doublets. The CH3 protons appeared as a singlet at d
2.41. The microanalysis data were consistent with the structures
of products 2a–c.
An important aspect of this work was the ring cleavage of
N-acetylisatins 2a–c with ethanol and their subsequent cycliza-
tion with alkanediamines (Scheme 1). The N-acetylisatin
2
(3.0 mmol) was dissolved in distilled ethanol and the appropriate
diamine (3.0 mmol) was added to the mixture. The reaction mix-
ture was irradiated under MW conditions for 40–50 s. The extent
of the reaction was monitored by TLC (EtOAc–MeOH–n-hexane,
2:1:5) after irradiation. Cooling, followed by neutralization of
the reaction mixture with 2% aq HCl solution gave a yellow solid
mass. Recrystallization of the crude solid from EtOAc afforded
compounds 1a–d (>80% yield, conventional yield was found to
be <70%). A few reactions of acetylisatins with alkanediamines
were studied previously using conventional heating.14–16 A plau-
sible mechanism involves nucleophilic attack by ethanol at the
lactam carbonyl carbon of N-acetylisatin and subsequent ring
cleavage to generate keto ester B (Scheme 2). Next, nucleophilic
attack of the alkanediamine on the ester carbonyl carbon fol-
lowed by elimination of ethanol and intramolecular cyclization
gives dihydropyrazinone C.
A microwave oven (Shikoku Instrumentation Co. Ltd, Japan,
power range: 0–650 W at 2.45 GHz) was used. The temperature
gradient of the reactor was 2–5 °C/s and each reaction was carried
out at least three times to ensure accuracy.
The ring closing reaction of oximinoacetanilides 4a–c with con-
centrated H2SO4 to give isatins 3a–c in 85–95% yields (conven-
tional yields below 80%) was carried out under MW conditions
for 10 s. It is worth noting that the interaction of H2SO4 with
MW irradiation was found to be problematic. In particular, pro-
longed exposure to MW irradiation resulted in decomposition of
the products. To prevent decomposition, a short pulse irradiation
technique was applied (5 s/irradiation). Two 5 s pulses were suffi-
cient to complete the cyclization to give isatins 3a–c. Acetylation of
3a–c in Ac2O/pyridine under MW irradiation for 50–70 s afforded
the corresponding N-acetylisatins 2a–c in excellent yields (2a:
The NMR spectra and microanalyses of pyrazinones 1a–d were
consistent with the structures shown.17 The melting point (190–
192 °C, lit.14 189–191 °C) and the spectral data of bromopyrazi-
none 1b corresponded well with that reported earlier for the same
compound obtained by conventional heating.
* Corresponding author. Tel.: +88 02 891 4393; fax: +88 02 779 1052.
E-mail address: chemmamun2@yahoo.com (M.M. Hossain).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.057

1156
M. M. Hossain et al. / Tetrahedron Letters 51 (2010) 1155–1157
O
4
7
R
5
O
3
R
R
MW, 10 s
2
50-70 sec
MW,
CH
NOH
O
O
conc. H2SO4
70 oC
1
pyridine
N
Ac2O,
6
O
N
N
H
125 oC
COCH3
2a R = 5-Cl (81%)
(93%)
H
3a R = 5-Cl
3b R = 5-Br (88%)
3c R = H (85%)
(86%)
4a R = 4-Cl
4b R = 4-Br
4c R = H
2b R = 5-Br
2c R = H (92%)
EtOH, 110oC
NH2(CH2)nNH2
2. dioxane
NH2(CH2)3NH2
0-5 oC, 90 min
1. EtOH
MW,
40-50 sec
O
40-50 s
MW,
90 oC
2
3'
1
2'
R
4'
CH3COHN
R
O
O
NHCOCH3
R
NH
1'
3
NH
HN
(CH2)3
N4
6'
n
O
O
n = 2,3
NHCOCH3
1eR = 5-Cl (62%)
1f R = 5-Br (66%)
1g R = H (58%)
n=2 (82%)
1a R = 5'-Cl,
1b R = 5'-Br, n=2 (85%)
1c R = H,
n=2
(80%)
1d R = H, n=3
(81%)
Scheme 1.
Scheme 2.
Alternatively the N-acetylisatin 2 (3.0 mmol) in distilled ethanol
(5.0 mL) was irradiated under MW conditions for 40–50 s followed
by cooling.18 Next, dioxane (8.0 mL) and 1,3-diaminopropane
(1.5 mmol) were added and reaction mixture was stirred at
0–5 °C for 90 min. The crude solid obtained after work-up was
chromatographed on silica gel (cyclohexane, ethyl acetate, and
methanol as eluents). Removal of the solvent under reduced pres-
sure gave a brown crystalline solid, which was recrystallized from
a mixture of CHCl3 and EtOAc. The above-mentioned reaction con-
ditions facilitated the addition of the intermediate ester B (Scheme
2) to the diamine in a 1:2 molar ratio and afforded the bis-ben-
zoylketones 1e–g in fairly good yields. The analytical data for com-
pounds 1e–g were consistent with the structures shown.
Typically, MW-dielectric heating plays an important role in the
rapid formation of molecules in higher yields compared to reac-
tions carried out using classical heating. In conclusion, we have
demonstrated that microwave irradiation could be employed effi-
ciently for the synthesis of biologically important isatins and their
related heterocyclic compounds. The MW-assisted synthesis was
more advantageous over classical heating with regard to reaction
time, solvent quantity, and product yield in almost every case. A
possible explanation for the formation of the products in short
reaction times lie in the fact that the MW provides elevated heat-
ing rates which shortens reaction times.
References and notes
1. Giguere, R. J.; Bray, T. L.; Duncan, S. M. Tetrahedron Lett. 1986, 27, 4945.
2. Kingstone, H. M.; Stephen, J. H. J. Am. Chem. Soc. 1997, 3, 5.
3. Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.; Laberge, L.; Rousell,
J. Tetrahedron Lett. 1986, 27, 279.
4. Strauss, C. Aust. J. Chem. 1999, 83.
5. Loupy, A.; Petit, A.; Hamelin, J.; Boullet, F. T.; Jacquault, P.; Mathé, D. Synthesis
1998, 1213.
6. Hossain, M. M.; Kawamura, Y.; Yamashita, K.; Tsukayama, M. Tetrahedron 2006,
62, 8625.
7. Giselle, C.; Ferreira, A. J. Braz. Chem. Soc. 2006, 17, 1.
8. Hossain, M. M.; Islam, N.; Khan, R.; Islam, M. R. Bangladesh J. Pharmacol. 2007, 2,
66.
9. Salvam, P.; Murugesh, N.; Chandramohan, M.; Clereq, D. E. Ind. J. Pharm. Sci.
2004, 66, 465.
10. Islam, M. R.; Mohsin, M. Bangladesh J. Pharmacol. 2007, 2, 7.
11. Solis, P. N.; Wright, C. W.; Anderson, M. M.; Gupta, M. P.; Phillipson, J. D. Planta
Med. 2007, 59, 250.
12. Islam, M. R.; Abedin, J.; Khayer, K. Indian J. Chem., Sect. B 2001, 40, 240.
13. Islam, M. R.; Abedin, J.; Hossain, M. M.; Duddeck, H. J. Bangladesh Chem. Soc.
1998, 11, 71.
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15. Franke, A. Liebigs Ann. Chem. 1982, 794.

M. M. Hossain et al. / Tetrahedron Letters 51 (2010) 1155–1157
1157
16. Joshi, B. S.; Likhate, M. A.; Viswanathan, N. Indian J. Chem., Sect. B 1984, 23, 114.
17. Compound 1a: 1H NMR (400 MHz, CD3OD): d 10.68 (br s, NH), 9.88 (br s, NH),
7.58 (d, 1H, J = 1.6 Hz, C20–H, ArH), 7.37 (dd, 1H, J = 7.6 Hz, J = 1.6 Hz, C40–H,
ArH), 7.15 (d, 1H, J = 7.6 Hz, C50-H, ArH), 4.12 (t, 2H, J = 8.1 Hz, C-5), 3.21 (br m,
2H, C-6), 2.50 (s, 3H, CH3). Compound 1e: 1H NMR (400 MHz, CD3OD): d 9.21 (s,
2H, 2 ꢁ NH), 7.76 (d, 2H, J = 1.9 Hz, C6–H, ArH ꢁ 2), 7.54 (dd, 2H, J = 8.1 Hz,
J = 1.9 Hz, C4–H, ArH ꢁ 2), 6.84 (d, 2H, J = 8.1 Hz, C3–H, ArH ꢁ 2), 3.52 (m, 4H,
2 ꢁ CH2), 2.55 (s, 6H, 2 ꢁ CH3), 1.38 (m, 2H, CH2).
Compounds 1a–d: N-Acetylisatin 2a (545.5 mg, 3.0 mmol) was dissolved in
distilled ethanol and the appropriate diamine (3.0 mmol) was added to the
mixture. The reaction mixture was irradiated using a microwave for 40–50 s.
Cooling followed by neutralization of the reaction mixture with 2% aqueous
HCl solution gave a yellow solid mass. Recrystallization of the crude solid from
EtOAc gave compound 1a.
Compounds 1e–g: N-Acetylisatin 2a (545.5 mg, 3.0 mmol) was dissolved in
distilled ethanol (5.0 mL) and the resulting reaction mixture was irradiated
using a microwave for 40–50 s. The mixture was cooled to rt and dioxane
(8.0 mL) was added followed by propan-1,3-diamine (1.5 mmol) and the
reaction mixture was stirred at 0–5 °C for 90 min. The obtained crude solid was
chromatographed on silica gel using cyclohexane, EtOAc and MeOH as eluent.
Removal of the solvent under reduced pressure gave a brown crystalline solid,
which was recrystallized from a mixture of CHCl3 and EtOAc to give 1e.
18. Representative procedures: Compounds 3a–c: Oximinoacetanilide 4a (0.99 g,
5.0 mmol) was mixed with concentrated sulfuric acid (5.0 mL) and the
resulting mixture was irradiated (20% radiation) using a microwave oven for
10 s (5 s ꢁ 2 irradiation). The extent of the reaction was monitored by TLC
(CH2Cl2–EtOAc, 5:1). Neutralization of the reaction mixture with 20% aq
Na2CO3 solution gave an orange solid mass. Recrystallization of crude solid
from methanol afforded compound 3a.