Green protocol for synthesis of 1,5-benzodiazepines and 1,5-benzothiazepines in the presence of nanocrystalline aluminum oxide

Article abstract of DOI:10.1080/00397910802657925

An efficient protocol associated with readily available starting materials, mild conditions, excellent yields, and a broad range of the products in synthetic chemistry was established for synthesis of 1,5-benzodiazepine and 1,5-benzothiazepine derivatives

Full text of DOI:10.1080/00397910802657925

Synthetic Communications1, 39: 2549–2559, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802657925
Green Protocol for Synthesis
of 1,5-Benzodiazepines and 1,5-Benzothiazepines
in the Presence of Nanocrystalline
Aluminum Oxide
Rahim Hekmatshoar, Sodeh Sadjadi, Soudeh Shiri,
Majid M. Heravi, and Yahya S. Beheshtiha
Department of Chemistry, School of Science, Alzahra University,
Vanak, Tehran, Iran
Abstract: An efficient protocol associated with readily available starting materials,
mild conditions, excellent yields, and a broad range of the products in synthetic
chemistry was established for synthesis of 1,5-benzodiazepine and 1,5-benzothiaze-
pine derivatives in the presence of a catalytic amount of nanocrystalline aluminum
oxide in water.
Keywords: o-Aminothiophenol,
nanocrystalline aluminum oxide, o-phenylenediamines, reusable catalyst
1,5-benzodiazepine,
1,5-benzothiazepine,
INTRODUCTION
Both 1,5-benzothiazepine and 1,5-benzothiazine ring systems have deriva-
tives of biological importance. Many functionalized benzodiazepines have
been used as analgesic, sedative, anticonvulsant, antianxiety, antidepressive,
and hypnotic agents.[1] Because of its well-known bioactivities, 1,5-
benzothiazepine is especially important in nitrogen- and sulfur-containing
heterocyclic compounds in drug research. Thiazesim and diltiazem are
well-known drugs that have 1,5-benzothiazepine skeletons.[2]
Received November 5, 2008.
Address correspondence to Rahim Hekmatshoar, Department of Chemistry,
School of Science, Alzahra University, Vanak, Tehran, Iran. E-mail: rhekmatus@
yahoo.com
2549

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R. Hekmatshoar et al.
A general way to construct the ring skeletons of 1,5-benzodiazepine
and 1,5-benzothiazepine is via reactions of o-phenylenediamines (o-PDA)
or o-aminothiophenol (o-ATP) with ketones, a,b-unsaturated carbonyl
compounds, or b-haloketones. Catalysts such as BF3 ꢀ Et2O, NaBH4, poly-
phosphoric acid (PPA)=SiO2, MgO=POCl3, amberlyst-15, Yb(OTf)3,
Al2O3=P2O5, AcOH=MW, sulfated zirconia, N-bromosuccinimide (NBS),
Ga(OTf)3,[3] sodium dodecyl sulfate (SDS),[4] and ionic liquids[5–9] have
been used to improve reaction efficiency.
There remains the necessity of developing a more effective and
convenient synthetic procedure because the reported methods have one
or more disadvantages such as the use of a high-boiling solvent (e.g.,
dimethylformamide, DMF) that is difficult to recover, excess amounts
of acid or base, special apparatus, corrosive (e.g., HCl gas; trifluoroacetic
acid TFA) and hazardous (e.g., pyridine, piperidine, halogenated hydro-
carbon) reagents=solvents, and special efforts to prepare the catalysts and
adsorb the reactants onto a solid support.
In continuation of our interest in exploring catalytic methodology in
organic transformations,[10–12] we report herein recyclable Al2O3 nano-
particles as the catalyst for an efficient synthesis of 1,5-benzodiazepine
and 1,5-benzothiazepine diaryl ethers.
Nanocrystalline metal oxides find excellent applications as active
adsorbents for gases and destruction of hazardous chemicals.[13] They
Figure 1. Scanning electron micrograph of nanosized Al2O3 particles.

Synthesis of 1,5-Benzodiazepines
2551
Table 1. 1,5-Benzodiazepines from o-phenylenediamine and ketones
Entry
1
Ketone
Product
Yield (%)
95
2
90
3
4
93
87
5
91
6
7
93
71

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R. Hekmatshoar et al.
are also gaining tremendous importance because of their distinct catalytic
activities for various organic transformations. Recently, researchers have
reported various[14] organic transformations using different nanocrystal-
line metal oxides. These high reactivities are due to the large surface areas
combined with unusually reactive morphologies.
Al2O3 nanosized particles were synthesized by a wet chemical proce-
dure. The morphology and size distribution of Al2O3 nanoparticles were
determined by scanning electron micrography (SEM) (Fig. 1).
Tandem reactions involve one-pot, multistep transformations and
avoid the isolation and purification of intermediates, thereby minimizing
cost, time, labor, and waste. Hence, they are convergent, elegant, and
ecofriendly procedures for the rapid construction of complex molecules
and are attractive from the viewpoint of green chemistry.[15]
o-Phenylenediamine and acetophenone were chosen as the substrates
for method development reactions. The reactions were carried out by tak-
ing a 1:2.5 molar ratio mixture of o-phenylenediamine and the ketone
along with a catalytic amount of nano-Al2O3 with stirring at room tem-
perature for the appropriate time. Cyclic ketones such as cyclohexanone
also reacted effectively to produce the corresponding fused ring benzodia-
zepines. The results are summarized in Table 1.
No reaction was observed when o-PDA was reacted with acetone
under similar conditions in the absence of the catalyst, thus highlighting
the role of nano-Al2O3 as a promoter.
Reactions of o-PDA with acetophenones bearing electron-donating and
electron-withdrawing substitution groups gave products in good to excellent
yields (71–95%) (Table 1, entries 1–7). Reactions of alkylketones such as acet-
one and cyclohexanone also gave benzodiazapines (Table 1, entries 6 and 7).
Scheme 1. A plausible mechanism for 1,5-benzodiazepines.

Synthesis of 1,5-Benzodiazepines
2553
Table 2. Synthesis of 1,5-benzothiazepines from o-aminothiophenol and
chalcones
Entry
1
Ketone
Product
Yield (%)
71
2
79
3
85
4
5
6
81
86
90
(Continued )

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R. Hekmatshoar et al.
Table 2. Continued
Entry
7
Ketone
Product
Yield (%)
84
8
75
The mechanism of the reactions 1–7 probably involves an intramole-
cular imine–enamine cyclization promoted by nano-Al2O3 as shown in
Scheme 1. The amine of o-PDA attacks the carbonyl group of ketone,
giving the intermediate diimine A. A 1,3-shift of the hydrogen-attached
methyl group then occurs to form isomeric enamine B, which cyclizes
to afford a seven-membered ring.[16]
To analyze the scope of the reaction, we tested chalcones as carbonylic
sources to afford the 1,5-benzodiazepines. Our initial efforts to react chal-
cones with o-aminothiophenol under reflux (oil-bath temperature 110ꢁC)
for 12 h did not produce any significant amount of 1,5-benzodiazepines
in the presence of nanosized Al2O3. Thus, o-aminothiophenol was used
to replace o-PDA for the reaction. When the reaction was carried out in
water under the same condition, 1,3-diphenyl-2,3-dihydro-1,5-benzothiaze-
pine was formed in 71% yield (Table 2, entry 1).
To establish the generality of this method, we investigated the
cyclocondensation of various substituted 1,3-diarylpropenones. The
reaction of various 1,3-diarylpropenones with 2-aminothiophenol
afforded the corresponding 1,3-diaryl-2,3-dihydro-1,5-benzothiazepines
in 71–90% yields (Table 2). The reaction was compatible with various
electron-donating (Me and OMe) and electron-withdrawing (Cl and NO2)
substituents.
The reaction of o-aminothiophenol (o-ATP) with an a,b-unsaturated
carbonyl functionality leads to benzodiazepines and benzothiazepines,
respectively, via [4 þ 3]-annulation. Although in all reactions between a
dinucleophile (hydrazines, hydroxylamine, o-phenylenediamine, etc.)
with a dielectrophile of the type mentioned, two compounds can be

Synthesis of 1,5-Benzodiazepines
2555
Scheme 2. A plausible mechanism for 1,5-benzothiazepines.
formed; because only benzothiazepines were isolated, it was assumed that
the reaction starts by 1,4-Michael addition of the SH on the CC double
bond followed by the condensation of the NH2 on the carbonyl group
(Scheme 2).[17]
The efficiency of bulk Al2O3 and basic Al2O3 as catalysts was also stu-
died for this reaction, but the model reaction (of 1,3-diphenylpropenone
and 2-aminothiophenol) did not complete in the presence of these cata-
lysts, even after long reaction times (48 h) and with more catalyst (Table 3).
The increased catalytic activity of nano-Al2O3 over commercially
available bulk Al2O3 and basic Al2O3 may be attributed to the larger sur-
face area of nano-Al2O3 than bulk Al2O3 as well as the greater surface
concentration of the reactive sites. As seen with other metal oxides, once
they are made into nanoparticles, their reactivity is greatly enhanced.
This is thought to be due to the morphological differences: whereas larger
crystallites have only a small percentage of the reactive sites on the
surface, smaller crystallites possess a much greater surface concentration
of such sites.[18]
The nano-Al2O3 catalyst could be reused for four cycles without loss
of activity and selectivity. Infrared (IR) spectra of fresh and used nano-
Al2O3 catalyst confirmed the fact that the structure and morphology of
the catalyst remained the same during the course of the reaction
(Figure 2).
Table 3. Comparison between nano-Al2O3 and commercially available bulk
Al2O3 and basic Al2O3 catalysts in the reaction of 1,3-diphenylpropenone and
2-aminothiophenol
Entry
Catalyst
Time (h)
Amount of catalyst (mmol)
Yield (%)
1
2
3
Nano-Al2O3
Bulk Al2O3
Basic Al2O3
12
48
48
0.03 mmol
0.1 mmol
0.1 mmol
71
27
34

2556
R. Hekmatshoar et al.
Figure 2. IR spectrum of nanosized Al2O3 before (a) and after (b) use.
In summary, nanosized Al2O3 was an effective catalyst for the
synthesis of 2,2,4-trisubstituted-1,5-benzodiazepines under mild reaction
conditions. We also report nanosized Al2O3 as a highly efficient heteroge-
neous reusable catalyst for chemoselective thia-Michael addition to a,b-
unsaturated carbonyl compounds. The methodology finds application
in a one-pot synthesis of 2,3-dihydro-1,5-benzothiazepines.
EXPERIMENTAL
Synthesis of Nanosized Al2O3
The Al2O3 nanoparticles were synthesized by precipitation of the alumi-
num hydroxide gels in aqueous solution using Al(NO3)3 as salt and
aqueous ammonia as the precipitating agent. Initially, the pH of 200 ml
of distilled water was adjusted to 5 by addition of aqueous ammonia.
To this solution, 0.1 M aluminum nitrate solution was added dropwise
with continuous stirring. The rate of addition of the salt solution was
kept at 20 ml=h during the addition; the pH was maintained at 7 by con-
trolled addition of aqueous ammonia solution. After completion of the
precipitation procedure, the mixture was stirred at room temperature
for 12 h, filtered, repeatedly washed with distilled water, dried at
120ꢁC, and calcined at 500ꢁC for 2 h. The temperature of the furnace

Synthesis of 1,5-Benzodiazepines
2557
was linearly raised from room temperature to 500ꢁC with an increment of
10ꢁC=min. At 500ꢁC, the temperature was maintained for 2 h to yield the
final material.
General Procedure for Synthesis of 2,2,4-Trisubstituted-
1,5-benzodiazepines (Table 1)
A mixture of o-PDA (0.21 g, 2 mmol), acetophenone (0.54 g, 4.5 mmol),
and nano-Al2O3 (0.003 g, 0.03 mmol) in 10 mL of water was refluxed
(oil-bath temp. 110ꢁC) for 6 h. After completion of the reaction [thin-layer
chromatographic (TLC) analysis], the catalyst was filtered, and the
reaction mixture was extracted with dichloromethane (2 ꢂ 10 mL). The
combined organic layer was dried over Na2SO4 and concentrated to dry-
ness in vacuo, and the residue was purified by column chromatography
(eluted with 2:8 EtOAc–petroleum ether) to afford pure diazepine.
Synthesis of 2,3-Dihydro-2,4-diphenyl-1,5-benzothiazepine
(Table 2, Entry 1)
A mixture of 1,3-diphenylpropenone (0.21 g, 1 mmol) in water (5 mL) was
heated under reflux (oil-bath temp 110ꢁC) under magnetic stirring until it
formed a melt and mixed with water as tiny droplets. 2-Aminothiophenol
(0.13 g, 1.1mmol, 1.1 equiv) was added, followed by nano-Al2O3 (0.003 g,
0.03 mmol), and the mixture was stirred at 110ꢁC for 12h. The cooled (rt)
reaction mixture was extracted with EtOAc (3ꢂ 5mL), the catalyst was
filtered, and the combined EtOAc extracts were washed with brine, dried
(Na2SO4), and concentrated under rotary vacuum evaporation. The crude
product was subjected to column chromatography using EtOAc=hexane
(2:98) as eluent to afford 2,3-dihydro-2,4-diphenyl-1,5-benzothiazepine
(71%) as a yellow solid, identical (spectral data and mp) with an authentic
compound.[3–4] The remaining reactions were carried out following this gen-
eral procedure. All the product structures were in full agreement with the
spectral data (IR, NMR, and MS) and gave satisfactory elemental analyses.
Reusing the Catalyst
After completing the model reaction, the catalyst was filtered and washed
three times with 10-ml portions of methanol, dried at 150ꢁC overnight,
and subjected to a second run of the reaction process with the same
substrate.

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R. Hekmatshoar et al.
ACKNOWLEDGMENT
The authors are thankful to the Alzahra Research Council for partial
financial support.
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