Synthesis of 1,5-benzodiazepines with unusual substitution pattern from chalcones under solvent-free microwave irradiation conditions

Article abstract of DOI:10.1080/00397910802372517

1,5-Benzodiazepines have been synthesized from the corresponding 2'-hydroxychalcones [1-(2-hydroxyphenyl)-3-aryl-2-propen-1-ones] and o-phenylenediamine, both in methanol, under reflux and under solvent-free microwave irradiation conditions on alumina. Th

Full text of DOI:10.1080/00397910802372517

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Synthesis of 1,5-
Benzodiazepines with Unusual
Substitution Pattern from
Chalcones Under Solvent-
Free Microwave Irradiation
Conditions
Carlos A. Escobar a , Oscar Donoso-Tauda a , Ramiro
Araya-Maturana b & Dieter Sicker c
a Laboratorio de Recursos Naturales, Departamento
de Ciencias Químicas, Universidad Andres Bello,
Santiago, Chile
b Departament of Organic and Physical Chemistry,
Faculty of Chemical and Pharmaceutical Sciences,
University of Chile, Santiago, Chile
c Institute of Organic Chemistry, University of
Leipzig, Leipzig, Germany
Version of record first published: 15 Feb 2011.
To cite this article: Carlos A. Escobar , Oscar Donoso-Tauda , Ramiro Araya-Maturana
& Dieter Sicker (2008): Synthesis of 1,5-Benzodiazepines with Unusual Substitution
Pattern from Chalcones Under Solvent-Free Microwave Irradiation Conditions,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:1, 166-174
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Synthetic Communications1, 39: 166–174, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802372517
Synthesis of 1,5-Benzodiazepines with Unusual
Substitution Pattern from Chalcones
Under Solvent-Free Microwave Irradiation
Conditions
Carlos A. Escobar,1 Oscar Donoso-Tauda,1
Ramiro Araya-Maturana,2 and Dieter Sicker3
Laboratorio de Recursos Naturales, Departamento de Ciencias Quımicas,
1
´
Universidad Andres Bello, Santiago, Chile
2Departament of Organic and Physical Chemistry, Faculty of Chemical
and Pharmaceutical Sciences, University of Chile, Santiago, Chile
3Institute of Organic Chemistry, University of Leipzig, Leipzig, Germany
Abstract: 1,5-Benzodiazepines have been synthesized from the corresponding
20-hydroxychalcones [1-(2-hydroxyphenyl)-3-aryl-2-propen-1-ones] and o-phenylene-
diamine, both in methanol, under reflux and under solvent-free microwave
irradiation conditions on alumina. The latter method proved to be advantageous.
Keywords: Alumina, benzodiazepine, chalcone, microwave irradiation, solvent-
free synthesis
INTRODUCTION
The synthesis of 2,3-dihydro-1H -1,5-benzodiazepines from chalcones has
generally been carried out by condensation reactions using o -phenylene-
diamine as binucleophile. A variety of reaction conditions have been
described. Heating to reflux in solvents such as toluene[1,2] or ethanol[3,4]
are representative examples. Additionally, solvent-free oil bath heating of
Received April 2, 2008.
Address correspondence to Carlos A. Escobar, Laboratorio de Recursos
´
Naturales, Departamento de Ciencias Quımicas, Universidad Andres Bello,
AV. Repu´blica 275, Santiago, Chile. E-mail: cescobar@unab.cl
166

Benzodiazepine Synthesis
167
the reacting compounds adsorbed over different inorganic supports such
as alumina, silica gel, and molecular sieves has been reported,[5] and
depending on the substitution pattern, yields rang from moderate to
good. However, if the substitution pattern is unfavorable to the cycliza-
tion reaction, yields are lower (40 to 60%), and decrease to 16% if the
chalcone substrate is sterically hindered.[1]
The microwave-assisted synthesis of 1,5-benzodiazepines has been
restricted to symmetrical ketones,[6] which act both as reagent and
solvent, under acidic catalysis.[5] At ambient temperature with sulfated
zirconia[7] or magnesia[8] as catalysts, other 1,5-benzodiazepines have
been obtained.
Electronic and=or steric factors are the reasons for the low yield in
the cyclization reaction involving chalcones and binucleophiles. In fact,
Kudar et al.[4] found that the enhanced electron-donating effect of a
ferrocenyl substituent can influence the yield obtained in the reaction
of both 1-aryl–3-ferrocenyl–2-propen–1-ones or 3-aryl–1-ferrocenyl–2-
propen–1-ones with asymmetric hydrazine binucleophiles. Meanwhile,
Cox and coworker[9] found that b-alkyl substituted chalcones tend to
react slower with hydrazine hydrate to form dihydropyrazoles than with
the corresponding unsubstituted ones, showing the effect of both the
steric and the donor inductive ability of the alkyl substituent over the
condensation reaction to form heterocycles.
To study the effect of microwave irradiation on the yield, the synthe-
sis of dimethoxylated analogs of the 4-(2-hydroxyphenyl)–2-phenyl–2,
3-dihydro–1H–1,5-benzodiazepines 2, obtained via the reaction of
o-phenylenediamine and a dimethoxylated chalcone, was investigated.
RESULTS AND DISCUSSION
Thus, we report on two alternative methods to prepare dimethoxy analogs
of the 4-(2-hydroxyphenyl)-2-phenyl-2,3-dihydro-1H-1,5-benzodiazepine.
In the first one, the reaction mixture was only refluxed in methanol, in the
second, the reactants were adsorbed over alumina, and the solvent-free
mixture was exposed to a 900-W microwave irradiation.
The yields for the reaction in refluxing toluene for compounds 2a,b
were previously reported by Srivastava and Verma to be 60 and 59%,
respectively.[2] For compound 2a, we obtained the best result, 78% yield
after a reaction free of solvent over alumina, exposed for 5 min to 900-W
microwave irradiation. In contrast, compound 2b led to a lower yield in
both procedures, with maximum 51% yield after 5 min of microwave irra-
diation over alumina, which is a short time when compared with the 4–6 h
of overall reaction time given previously by Srivastava and Verma.

168
C. A. Escobar et al.
Microwave syntheses of compounds 2c–e are reported for the first
time. The yield obtained for 2c ranged between 40 and 42% under
microwave conditions. For compound 2d, the best yields were obtained
also under microwave irradiation, ranging from 36 to 54% depending
on the irradiation exposure time. Compound 2e was obtained in 26%
yield after 5 min of microwave exposure. Because the substitution pattern
in compound 2e is the most unfavorable for a cyclization, due to the 2-
(2,4-dimethoxyphenyl) substitution pattern, the yields obtained are the
lowest with either method.
In general, yields obtained by 900-W microwave irradiation were
higher than those obtained by the reflux method. However, long expo-
sure time (30 min) to the microwave irradiation caused compounds
2a,b and e to decompose to dark tarry mixtures. In contrast, compounds
2c and 2d were obtained in higher yields by long exposure to microwave
conditions without decomposition.
In summary, this work demonstrates a rapid and efficient method of
synthesis of 4-(2-hydroxyphenyl)-2-dimethoxyphenyl-2,3-dihydro-1H-
1,5-benzodiazepines (2) under microwave heating, and the results
obtained confirm the superiority of the microwave irradiation method
over the classical reflux heating.
EXPERIMENTAL
Aluminium oxide puriss. (ꢀ 98% Al2O3 basis; cat. no. 11028), from
Riedel-de Hae¨n was used as a solid support without any further treat-
ment. Melting points were determined using a Stuart Scientific SMP3
melting-point apparatus. Microwave experiments were performed at a
Milestone Ethos D microwave labstation. IR spectra were recorded on a
Fourier transform infrared (FTIR) spectrometer (Genesis Series from
1
ATI=Mattison) in KBr. H and 13C NMR were recorded on a Bruker
Avance DRX-400. Mass spectra were recorded in the EI mode on a
VG12–250 mass spectrometer from FG Masslab Manchester. The peak
matching was carried out on a MAT 95XP Thermo Finnigan, in the EI
mode, using perfluorokerosene as a reference.
General Procedure for the Synthesis of 1,5-Benzodiazepines
´
2-Hydroxychalcone (2-Hydroxy-benzylideneacetophenone) 1a was pur-
chased from Merck. The other chalcones were prepared as previously
described.[10]
A solution of the corresponding dimethoxy substituted benzaldehyde
(7.34 mmol in ethanol, 20 mL) was added dropwise to a stirred mixture of

Benzodiazepine Synthesis
169
2-hydroxyacetophenone solution (7.34 mmol, in ethanol, 20 mL) and
potassium hydroxide solution (2 g in 10 mL distilled water). The mixture
was allowed to react overnight, then diluted with distilled water (200 mL),
neutralized with hydrochloric acid, and extracted with ethyl acetate
(4 ꢁ 50 mL). The combined organic phases were concentrated in a
vacuum, redissolved in ethanol, and allowed to crystallize to yield the
following compounds.
[11]
3,4-Dimethoxy-2-hydroxychalcone 1b
´
Yellow crystals (43%); mp 113.5–113.8 C. IR (KBr) cmꢃ1: 3461 (OH),
1554 (C¼O). 1H NMR (DMSO-d6, 200 MHz): d 3.85 (3H, s, OCH3), 3.90
(3H, s, OCH3), 7.03 (3H, m, Harom), 7.45 (1H, dd, H6, J6,2 ¼ 1.6 Hz
J6,5 ¼ 8.4 Hz), 7.6 (2H, m, Harom), 7.84 (1H, d, Ha, Jab ¼ 15.3 Hz), 7.96
(1H, d, Hb, Jab ¼ 15.3 Hz), 8.32 (1H, d, Harom, J ¼ 7.3), 12.82 (1H, s,
OH). 13C NMR (DMSO-d6,200 MHz): d 93.2, 93.4, 148.6, 149.2, 155.3,
156.4, 156.5, 158.1, 162.2, 164.8, 168.3, 173.8, 183.3, 186.7, 189.3,
199.7, 231.2. EI MS, m=z (%) 283.9 (M þ, 100), 266.9 (12), 252.9 (25),
190.9 (9); 163.9 (80); 150.9 (85).
ꢂ
´
2,3-Dimethoxy-2-hydroxychalcone 1c
Yellow crystals (59%); mp 102–103 ꢂC (lit. 99–100 ꢂC[12]; 102–103 ꢂC[10]).
´
2,5-Dimethoxy-2-hydroxychalcone 1d
Yellow crystals (72%); mp 95–96 C (lit. 95–96 C[10]).
ꢂ
ꢂ
´
2,4-Dimethoxy-2-hydroxychalcone 1e
Yellow crystals (58%); mp 107–109 C (lit. 107–109 C[10]).
ꢂ
ꢂ
1,5-Benzodiazepines
These were prepared according to two different procedures (see also
Table 1).
Method A (reflux, general procedure). A solution of o-phenylenediamine,
(1.056 mmol, in 20 mL methanol) was added to a stirred solution of the

170
C. A. Escobar et al.
corresponding dimethoxy substituted 2-hydroxychalcone 1 (0.704 mmol,
in 20 mL methanol). The reaction mixture was heated under reflux as
described in Table 1. In the following step, the reaction mixture was con-
centrated to dryness in a rotatory evaporator and submitted to column
chromatography (silica gel 60, ethyl acetate–hexane ¼ 1:10). The fractions
containing the benzodiazepine 2 were combined and concentrated in a
rotatory evaporator to obtain a yellow solid, which was redissolved in
methanol and allowed to crystallize. Compounds were obtained as a yel-
low crystals. Crystalline structures of compounds 2a–d[13] have been
recently reported by us. Melting points are given in Table 1.
Method B (microwave irradiation, general procedure). The corresponding
dimethoxy substituted 20-hydroxychalcone 1 (0.704 mmol) was dissolved
in the minimum amount of dichloromethane (ca. 10 mL ), and the solid
support, alumina (1.2 g), was added. After mixing well, the solvent was
removed in a rotatory evaporator to give a light yellow solid mixture
(chalcone-impregnated support). A solution of o-phenylenediamine
(1.056 mmol, in 10 mL dichloromethane) was poured over the chalcone-
impregnated support and allowed to mix well, and then the dichloro-
methane was removed in a rotatory evaporator to obtain a light yellow
solid mixture. This mixture was then exposed to 900-W irradiation in
the microwave for 5 min. to obtain the benzodiazepine 2 bound to the
solid support. The benzodiazepine was separated from the solid support
by column chromatography: the benzodiazepine’s impregnated solid sup-
port was placed at the top of a preparative chromatographic column
(silica gel 60), and a mixture of ethyl acetate and hexane (1:10 v=v) was
used as eluent to obtain the benzodiazepine. Removal of the eluent’s sol-
vent mixture in a rotatory evaporator gave a yellow solid. Recrystalliza-
tion in methanol afforded yellow crystals. Melting points are given in
Table 1.
4-(2-Hydroxyphenyl)-2-phenyl-2,3-dihydro-1H-1,5-benzodiazepine, 2a
[2,13]
ꢂ
Yellow crystals (163 mg, 61.2%); mp 106.0–109.0 C (methanol) (lit.
118 C, methanol; 106–109 ꢂC, methanol). IR (KBr) cmꢃ1: 3356 (NH),
ꢂ
1
3054 (CHarom), 1595 (C¼C), 1561 (NH), 1505, 1477, 1448 (C¼C). H
NMR (CDCl3, 300 MHz): d 3.07 (1H, dd, J ¼ 3.6 Hz; J ¼ 13.8 Hz, H-
3a), 3.32 (1H, dd, J ¼ 8.4 Hz, J ¼ 13.8 Hz, H-3b), 5.19 (1H, dd, J ¼ 3.6 Hz,
J ¼ 8.4 Hz, H-2), 6.7–6.8 (1H, m, Harom), 6.85 (1H, dd, J ¼ 8.1 Hz,
J ¼ 1.5 Hz, Harom), 7.0–7.1 (2H, m, Harom), 7.1–7.2 (1H, m, Harom),
7.3–7.4 (8H, m, Harom). 13C NMR (CDCl3, 300 MHz): d 36.7 (C-3),
69.9 (C-2), 118.2, 118.5, 119.0, 120.9, 121.6, 125.9, 127.7, 128.3, 128.36,

171

172
C. A. Escobar et al.
128.42, 129.1, 133.2, 134.8, 139.3 (C-N ¼), 144.2 (C-NH-), 162.7 (C-OH),
171.3 (C-4). EI MS, m=z (%) 314.1 (Mþ, 67), 299.2 (100), 210.1 (86).
HRMS calc. for C23H22N2O3 314.14191; found 314.14048.
4-(2-Hydroxyphenyl)-2-(3,4-dimethoxyphenyl)-2,3-dihydro-1H-1,
5-benzodiazepine, 2b
Yellow crystals (76 mg, 42%), mp 166.3–167.5 C, methanol (lit.[2,13]166
ꢂ
ꢂC, benzene; 166.3–167.5 ꢂC, methanol). IR (KBr) cmꢃ1: 3498 (OH),
3324 (NH), 3075 (CHarom), 1609, 1591 (C¼C), 1580 (NH), 1515, 1497
(C¼C). 1H NMR (CDCl3,400 MHz): d 5.04 (1H, dd, J ¼ 7.6 Hz;
J ¼ 13.6 Hz, H-3a), 5.28 (1H, dd, J ¼ 4 Hz, J ¼ 13.6 Hz, H-3b), 5.73
(3H, s, OCH3), 5.86 (3H, s, OCH3), 7.16 (1H, dd, J ¼ 4 Hz, J ¼ 8 Hz,
H-2), 8.71 (1H, dd, J ¼ 8, Hz, J ¼ 7.2, Harom), 8.8–8.9 (2H, m, Harom),
8.9–9.0 (3H, m, Harom), 9.04 (1H, d, J ¼ 8 Hz, Harom), 9.12 (1H, dd,
J ¼ 6.8 Hz, J ¼ 7.6 Hz, Harom), 9.21 (1H, d, J ¼ 8 Hz, Harom), 9.2–9.3
(2H, m, Harom). 13C NMR (CDCl3,400 MHz): d 36.6 (C-3), 55.9
(OCH3) 56.1 (OCH3), 70.3 (C-2), 109.3, 111.3, 118.1, 118.2, 118.3,
119.2, 120.8, 121.7, 127.5, 128.2, 128.4, 133.0, 135.5, 136.9 (CꢃN ¼),
139.2 (CꢃNHꢃ), 149.0 (C-OMe), 149.3 (C-OMe), 162.6 (CꢃOH),
171.7 (C-4). EI MS, m=z (%) 374.2 (M+, 42), 359.1 (84), 281.2 (22),
210.1 (100). HRMS calc. for C23H22N2O3 374.16304; found 374.16125.
4-(2-Hydroxyphenyl)-2-(2,3-dimethoxyphenyl)-2,3-dihydro-1H-1,5-
benzodiazepine, 2c
Yellow crystals (56 mg, 42.5%); mp 154–155 ꢂC, methanol (lit.[13]154–
155 ꢂC, methanol). IR (KBr) cmꢃ1: 3500 (OH), 3394 (NH), 3053
(CHarom), 1612 (C¼C), 1569 (NH), 1504, 1490 (C¼C). 1H NMR
(CDCl3,400 MHz): d 3.02 (1H, dd, J ¼ 9.2 Hz; J ¼ 13.6 Hz, H-3a), 3.36
(1H, dd, J ¼ 3.2 Hz, J ¼ 13.6 Hz, H-3b), 3.90 (3H, s, OCH3), 3.93 (3H,
s, OCH3), 5.63 (1H, dd, J ¼ 3.2 Hz, J ¼ 9.2 Hz, H2), 6.79 (1H, dd,
J ¼ 7.6 Hz. J ¼ 7.6 Hz, Harom), 6.86 (1H, d, J ¼ 7.6 Hz, Harom), 6.92
(1H, d, J ¼ 8 Hz), 6.9–7.0 (3H, m, Harom), 7.1–7.2 (2H, m, Harom), 7.2–
7.3 (2H, m, Harom), 7.53 (1H, d, J ¼ 8 Hz, Harom). 13C NMR (CDCl3,
400 MHz): d 35.3 (C-3), 56.1 (C-2), 61.2 (OCH3), 63.5 (OCH3), 112.1,
118.0, 118.33, 118.35, 119.0, 120.9, 121.3, 124.7, 127.7, 128.3, 128.5,
133.3, 134.8, 138.2 (CꢃN ¼), 139.5 (CꢃNHꢃ), 145.2 (C-OMe), 152.8
(C-OMe), 162.8 (CꢃOH), 172.0 (C-4). EI MS, m=z (%) 374.2 (M+,
42), 359.2 (42), 281.2 (16), 210.1 (100). HRMS calc. for C23H22N2O3
374.16304, found 374.16115.

Benzodiazepine Synthesis
173
4-(2-Hydroxyphenyl)-2-(2,5-dimethoxyphenyl)-2,3-dihydro-1H -1,5-ben-
zodiazepine, 2d
Yellow crystals (118 mg, 54.1%), mp 156.0–157.4 ꢀC, methanol
(lit.[13]156–157 C, methanol). IR (KBr) cmꢁ1: 3450 (OH), 3354 (NH),
ꢀ
2998, 2957 (CHarom), 1601 (C¼C), 1565 (NH), 1493, 1476 (C¼C).1H
NMR (CDCl3, 300 MHz): d 5.10 (1H, dd, J ¼ 8.4 Hz, J ¼ 13.6 Hz, H-
3a), 5.29 (1H, dd, J ¼ 3.6 Hz, J ¼ 13.6 Hz, H-3b), 5.66 (3H, s, OCH3),
5.87 (3H, s, OCH3), 7.64 (1H, dd, J ¼ 3.6 Hz, J ¼ 8.4 Hz, H-2), 8.7–8.8
(2H, m, Harom), 8.82 (1H, dd, J ¼ 8.8 Hz, Harom), 8.92 (1H, dd, J ¼ 1.2 Hz,
J ¼ 7.6 Hz, Harom), 8.9– 9.0 (2H, m, Harom), 9.1–9.2 (2H, m, Harom), 9.2–
9.3 (2H, m, Harom), 9.39 (1H, dd, J ¼ 1.2 Hz, J ¼ 7.6 Hz, Harom). 13C
NMR (CDCl3,400 MHz): d: 34.2, 56.0, 56.1, 63.8, 111.5, 112.9, 113.3,
118.2, 118.3, 119.2, 120.9, 121.3, 127.6, 128.3, 128.5, 133.1, 133.4,
134.8, 139.7, 149.9, 154.0, 162.7, 172.3. EI MS, m=z (%) 374.1 (M+,
78), 359.1 (70), 343.1 (47), 281.2 (20), 210.1 (100). HRMS calc. for
C23H22N2O3 374.16304, found 374.16121.
4-(2-Hydroxyphenyl)-2-(2,4-dimethoxyphenyl)-2,3-dihydro-1H-1,5-ben-
zodiazepine, 2e
Yellow crystals (18 mg, 13.9%), mp 177–179 ꢀC, methanol. IR (KBr),
cmꢁ1: 3500 (OH), 3394 (NH), 2993 (CHarom), 1607, 1585 (C¼C), 1561
1
(NH), 1497, 1481 (C¼C). H NMR (CDCl3, 300 MHz): d 3.13 (1H,
dd, J ¼ 8.1 Hz; J ¼ 13.8 Hz, H-3a), 3.28 (1H, dd, J ¼ 3.6 Hz, J ¼ 13.8 Hz,
Hz, H-3b), 3.78 (3H, s, OCH3), 3.86 (3H, s, OCH3), 5.55 (1H, dd,
J ¼ 3.6 Hz, J ¼ 8.1 Hz, H-2), 6.41 (1H, dd, J ¼ 2.1 Hz, J ¼ 8.7 Hz, Harom),
6.47 (1H, d, J ¼ 2.1 Hz, Harom), 6.77 (1H, dd, J ¼ 7.2 Hz, J ¼ 7.2 Hz,
H
arom); 6.89 (1H, d, J ¼ 7.8 Hz, Harom), 6.99 (1H, ddd, J ¼ 0.9 Hz,
J ¼ 7.5 Hz, J ¼ 7.5 Hz, Harom), 7.0–7.1 (2H, m, Harom), 7.3–7.4 (4H, m,
H arom). 13C NMR (CDCl3,400 MHz): d: 34.6, 55.53, 55.56, 63.2,
98.7, 104.3, 118.3, 118.4, 119.0, 120.2, 121.2, 124.7, 127.2, 127.8, 128.2,
128.6, 133.4, 133.9, 139.7, 156.8, 160.6, 162.6, 172.2. EI MS, m=z (%)
374 (M+, 64), 359 (52), 281 (10), 210 (100). HRMS calc. for
C23H22N2O3 374.16304, found 374.16085.
ACKNOWLEDGMENTS
This work was supported by Fondecyt through Grant 1080147, awarded
to C. A. E. O. D. T. is grateful to Universidad Andres Bello (UNAB) for
´
a graduate fellowship. We are also grateful to Dr. Alvaro Canete M. and
~

174
C. A. Escobar et al.
to MECESUP UCH0116, the ‘‘Red Nacional de Doctorado en
´
Quımica,’’ for the peak matching experiments.
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