Neat reaction technology for the synthesis of novel 1,5-benzodiazepines

Article abstract of DOI:10.1080/00397910500451571

A convenient, solvent-free, green approach is described for the synthesis of novel 1,5-benzodiazepines by the reaction of ethylacetoacetate, aldehyde, and o-phenylenediamine without any catalyst at pH 7. Copyright Taylor & Francis Group, LLC.

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Neat Reaction Technology for the Synthesis of
Novel 1,5‐Benzodiazepines
Mazaahir Kidwai a & Poonam Mothsra a
a Department of Chemistry, University of Delhi, Delhi, India
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Synthetic Communicationsw, 36: 817–824, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500451571
Neat Reaction Technology for the Synthesis
of Novel 1,5-Benzodiazepines
Mazaahir Kidwai and Poonam Mothsra
Department of Chemistry, University of Delhi, Delhi, India
Abstract: A convenient, solvent-free, green approach is described for the synthesis
of novel 1,5-benzodiazepines by the reaction of ethylacetoacetate, aldehyde, and
o-phenylenediamine without any catalyst at pH 7.
Keywords: 1,5-Benzodiazepines, microwave irradiation, neat reaction technology,
o-phenylenediamine, solvent-free reaction
Among the large number of benzodiazepines that have been synthesized,
1,5-benzodiazepines form the most extensively explored group. The 1,5-
benzodiazepines have been studied over decades, largely because they show
sufficient pharmacological[1] and clinical activity to warrant introduction as
new drugs. 1,5-Benzodiazepines are widely used as anticonvulsant, antianxiety,
antiinflammatory, antidepressive, sedative, and hypnotic agents. They also act
as a valuable synthon[2] for fused-ring compounds. The fusion of a heterocyclic
system to the benzodiazepine ring appears, in fact, especially promising for the
synthesis of new derivatives with a higher activity and specificity.
Because of the pharmacological utility of benzodiazepines, several
protocols have been reported for their synthesis. 1,5-Benzodiazlpines are syn-
thesized by the condensation of diamine with a,b-unsaturated carbonyl
compound,[3] b-haloketone, or ketones.[4] A drawback to this reaction is the
requirement of Lewis acids as well as protic acids as promoters. To
improve the efficiency of synthesis, many catalysts have been tried such as
BF3-OEt2,[5] NaBH4,[6] polyphosphoric acid,[7] SiO2, MgO/POCl3,[8] and
Received in India May 9, 2005
Address correspondence to Mazaahir Kidwai, Department of Chemistry, University
of Delhi, Delhi 110007, India. Fax: 91 11 27666235; E-mail: kidwai_chemistry@
yahoo.co.uk
817

818
M. Kidwai and P. Mothsra
Yb(Of)3.[9] Most of these processes suffer from major or minor limitations
such as drastic reaction conditions, tedious workup procedures, expensive
and hazardous catalysts, stoichiometric amounts of catalyst, and strong
acidic conditions, thus rendering the procedures uneconomical and
polluting. Reduction in chemical pollution is the pressing need of all
nations. The challenge for the institution and industry is to come together
and pursue development in the field of green chemistry[10] by reducing or
eliminating the use and generation of hazardous substances, and elimination
of hazardous solvents is one of the prime concerns. One of the areas
wherein substantial progress has been seen in our laboratory[11] is the
microwave-assisted solid-support reaction. Recently solventless synthesis[12]
of 1,5-benzodiazepines has attracted much attention but these reactions still
require hazardous and expensive catalytic reagents, and moreover solid-
phase synthesis cannot be accepted as green methodology because an appreci-
able amount of solvent is required for adsorption of reactants and elution of
products. According to our earlier work on neat reaction technology,[13] it
not only eliminates the solvent from pre- and postworkup but also offers the
benefits of shorter reaction time along with enhanced yield when coupled
with microwaves.
This article describes a facile synthesis of 4a–g in microwave-assisted
neat reaction technology, eradicating the use of any acid or catalyst. Neutral
conditions were tried in light of our earlier[14] work on 1,5-benzodiazepines
where o-phenylenediamine condenses with a,b-unsaturated carbonyls under
neutral conditions, whereas the rest of the reactions require acidic conditions.
This is the first report on the synthesis of new series of 1,5-benzodiazepine
(4a–g) using ethylacetoacetate (1), aromatic aldehydes (2a–g), and
o-phenylenediamine (3) without the use of any catalytic reagent at pH 7.
One-step synthesis was conducted for novel 2,3-dihydro-1H-1,5-benzo-
diazepines (4a–g) as shown in Scheme 1.
During the work, we obtained 5 as a side product in addition to the desired
product. The formation of side product can be avoided by following the
Scheme 1. One-step synthesis.

Synthesis of 1,5-Benzodiazepines
819
two-step synthesis rather than one-step condensation. Initially ethylacetoace-
tate (1) and aldehyde (2a–g) were added in equimolar ratio in an Erlenmeyer
flask and irradiated for a sufficient interval of time. Then o-phenylinediamine
(3) was added, which condenses with the intermediate and afforded the desired
product exclusively Scheme 2.
Benzodiazepines were obtained in good yields within few minutes of
irradiation. The results are summarized in Table 1.
Completion of the reaction was monitored by TLC. The sticky solid
obtained on irradiation was triturated to isolate 4a–g and was characterized
by IR, 1H NMR, and elemental analyses. The product was purified by
silica-gel chromatography (60–120 mesh) eluted by benzene and ethylacetate
(8 : 2 v/v) mixture.
In conclusion, we have generated novel 3-ethylcarboxylate-4-methyl-2,3-
dihydro-1H-1,5-benzodiazepines (4a–g) in the absence of any toxic and
corrosive mineral acids or organic solvents. Interestingly, the two-step synthesis
leads to the formation of the desired product only whereas the single step
results in other side reactions also. The remarkable features of the new
procedure are high conversion, shorter reaction times, eliminations of hazardous
reagents, cleaner reaction profile, solvent-free conditions, and simple experimen-
tal and workup procedure. Considering the advantages of this new methodology
we can synthesize various useful heterocyclic compounds. As a result we have
developed a simple, economical, and environmentally benign synthesis.
EXPERIMENTAL
Melting points were determined using a Thomas Hoover melting-point
apparatus and are uncorrected. IR spectra (nmax in cm21) were obtained on
Perkin-Elmer FTIR-1710 spectrophotometer using KBr discs. 1H NMR
Scheme 2. Two-step synthesis.

820
M. Kidwai and P. Mothsra
Table 1. Microwave synthesis of 1,5-benzodiazepines (4a–g) using two-step
condensation
Yield
(%)
Time of
irradiation (min)
Entry
Aldehyde
Product
4a
97
2.5
4b
94
3
4c
93
3
4d
86
2
4e
91
3.5
(continued)

Synthesis of 1,5-Benzodiazepines
821
Table 1. Continued
Yield
(%)
Time of
irradiation (min)
Entry
Aldehyde
Product
4f
87
92
2.5
4g
2.5
spectra were recorded in CDCl3 on Brucker Avance spectrometer operating
at 300 MHz using TMS as internal standard (chemical shift in d, ppm).
Elemental analyses were performed on a Heraeus CHN Rapid Analyser.
A Kenstar (model no. OM-9925E) microwave oven (2450 MHz, 800 W)
was used for all experiments. The purity of compounds was checked on
silica-gel-coated aluminium plates (Merck). The approximate temperature,
as measured by AZ, Mini Non-contact Infrared Thermometer model no.
8868, was 1308C to 1508C.
General Procedure for the Synthesis of 3-Ethylcarboxylate-4-
methyl-2,3-dihydro-1H-1,5-benzodiazepines (4a–g)
One-Step Synthesis
Appropriate aromatic aldehyde (2a–g) (10 mmol), ethylacetoacetate (1), and
o-phenylenediamine (3) were introduced in an Erlenmeyer flask. This was
subjected to microwave irradiation for a sufficient interval of time using
resting intervals of 1 min after every 30 s of irradiation. Reaction progress
was monitored by TLC. After cooling, the reaction mixture became sticky;
the sticky solid was then triturated to afford the product. The product was
purified using silica-gel chromatography.
Two-Step Synthesis
Equimolar amount of aromatic aldehyde (2a–g) (10 mmol) and ethylaceto-
acetate (1) were taken in an Erlenmeyer flask and irradiated in a microwave

822
M. Kidwai and P. Mothsra
oven. On formation of adduct as monitored by TLC examination, o-phenylene-
diamine (3) was added for further reaction. Reaction mixture was then mixed
using a glass rod and again irradiated for the formation of pure desired
product. The reaction mixture was worked up in the same way as in the first
method.
Conventional Heating
The synthesis of 3-ethylcarboxylate 4-methyl-2,3-dihydro-1H-1,5-benzo-
diazepine (4a–g) using conventional heating with stirring in ethanol
showed only trace amounts of product even after 4 to 5 h of heating.
Selected Data for New Compounds
4a: White powder; mp 123–1258C; IR (cm21) 3306 (NH), 1720 (C55O), 1611
(C55N); H NMR (300 MHz, CDCl3) d 1.2 (t, 3H, CH3), 2.50 (s, 3H, CH3),
1
2.62 (d, 1H, H-3), 3.4 (q, 2H, OCH2), 3.19 (s, 1H, NH), 5.5 (d, 1H, H-2),
6.9-7.7 (m, 9H, H arom); found: C, 74.31; H, 6.42; N, 9.47; C19H20O2N2
requires C, 74.02; H, 6.49; N, 9.09%.
4b: Yellow powder; mp 128–1308C; IR (cm21) 3308 (NH), 1723 (C55O),
1604 (C55N); 1H NMR (CDCl3 TMS) d 1.27 (t, 3H, CH3), 2.5 (s, 3H,
CH3), 2.69 (d, 1H, H-3), 3.29 (s, 1H, NH), 4.0 (q, 2H, OCH2), 5.48 (d, 1H,
H-2), 6.9–8.0 (m, 8H, H arom); found: C, 66.37; H, 5.17; N, 8.12;
C19H19O2N2Cl requires C, 66.66; H, 5.55; N, 8.18.
4c: Yellow crystalline powder; mp 120–1238C; IR (cm21) 3310 (NH), 1727
(C55O), 1608 (C55N); 1H NMR (300 MHz, CDCl3) d 1.27 (t, 3H, CH3), 2.47
(s, 3H, CH3), 2.56 (d, 1H, H-3), 3.3 (s, 1H, NH), 3.8 (q, 2H, OCH2), 4.58
(s, 3H, OCH3), 5.43 (d, 1H, H-2), 6.6–7.9 (m, 8H, H arom); found: C,
69.96; H, 6.42; N, 8.27; C20H22N2O3 requires C, 71.01; H, 6.51; N, 8.28.
4d: Light yellow; mp 118–1208C; IR (cm21) 3303 (NH), 1713 (C55O), 1600
(C55N); 1H NMR (300 MHz, CDCl3) d 1.23 (t, 3H, CH3), 2.45 (s, 3H, CH3),
2.68 (d, 1H, H-3), 3.36 (s, 1H, NH), 3.98 (q, 2H, OCH2), 5.48 (d, 1H, H-2),
6.6–7.8 (m, 8H, H arom), 8.2 (s, 1H, OH); found: C, 70.53; H, 6.29; N,
8.52; C19H20N2O3 requires C, 70.37; H, 6.17; N, 8.64.
4e: Brown crystals; mp 124–1268C; IR (cm21) 3317 (NH), 1728 (C55O),
1601 (C55N); H NMR (300 MHz, CDCl3) d 1.29 (t, 3H, CH3), 2.36 (s, 3H,
1
CH3), 2.64 (d, 1H, H-3), 3.24 (s, 1H, NH), 4.03 (q, 2H, OCH2), 5.5 (d, 1H,
H-2), 6.09–7.75 (m, 7H, H arom and H furyl); found: C, 68.53; H, 6.07; N,
9.46; C17H18N2O3 requires C, 68.46; H, 6.04; N, 9.40.

Synthesis of 1,5-Benzodiazepines
823
4f: Light yellow; mp 115–1188C; IR (cm21) 3301 (NH), 1730 (C55O), 1617
(C55N); 1H NMR (300 MHz, CDCl3) d 1.26 (t, 3H, CH3), 2.52 (s, 3H, CH3),
2.62 (d, 1H, H-3), 3.20 (s, 1H, NH), 4.01 (q, 2H, OCH2), 5.42 (d, 1H, H-2),
6.54–7.6 (m, 10H, H arom and NH indole). Found: C, 72.26; H, 6.23; N,
12.19; C21H21N3O2 requires C, 72.62; H, 6.05; N, 12.10.
4g: Brown crystals; mp 117–1198C; IR (cm21) 3319 (NH), 1725 (C55O),
1613 (C55N); H NMR (300 MHz, CDCl3) d 1.25 (t, 3H, CH3), 2.47 (s, 3H,
1
CH3), 2.70 (d, 1H, H-3), 3.40 (1H, s, NH), 3.95 (q, 2H, OCH2), 5.49
(d, 1H, H-2), 5.94 (s, 2H, CH2), 6.9–7.4 (m, 7H, H arom); found: C, 67.97;
H, 5.63; N, 8.07; C20H20N2O4 requires C, 68.18; H, 5.68; N, 7.95.
ACKNOWLEDGMENTS
One of the authors, P. Mothsra, is thankful to the Council of Scientific and
Industrial Research, New Delhi, for financial assistance.
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