Efficient and green method for the synthesis of 1,5-benzodiazepine and quinoxaline derivatives in water

Article abstract of DOI:10.1080/00397910701489388

Various 1,5-benzodiazepine and quinoxaline derivatives have been synthesized in water with excellent yields using a catalytic amount of indium chloride at room temperature. This synthetic protocol is nontoxic, safe, and environmentally benign. Copyright T

Full text of DOI:10.1080/00397910701489388

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Efficient and Green Method for the Synthesis
of 1,5‐Benzodiazepine and Quinoxaline
Derivatives in Water
Parasa Hazarika a , Pranjal Gogoi a & Dilip Konwar a
a Synthetic Organic Chemistry Division, Regional Research Laboratory ,
Jorhat, Assam, India
Published online: 05 Oct 2007.
To cite this article: Parasa Hazarika , Pranjal Gogoi & Dilip Konwar (2007) Efficient and Green Method for
the Synthesis of 1,5‐Benzodiazepine and Quinoxaline Derivatives in Water, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:19, 3447-3454, DOI:
10.1080/00397910701489388
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Synthetic Communicationsw, 37: 3447–3454, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701489388
Efficient and Green Method for the
Synthesis of 1,5-Benzodiazepine and
Quinoxaline Derivatives in Water
Parasa Hazarika, Pranjal Gogoi, and Dilip Konwar
Synthetic Organic Chemistry Division, Regional Research Laboratory,
Jorhat, Assam, India
Abstract: Various 1,5-benzodiazepine and quinoxaline derivatives have been
synthesized in water with excellent yields using a catalytic amount of indium
chloride at room temperature. This synthetic protocol is nontoxic, safe, and environ-
mentally benign.
Keywords: 1,5-benzodiazepine, indium chloride, Lewis acid, quinoxaline, water
media
The development of simple and efficient chemical processes or methodologies
for the synthesis of biologically active compounds in water is one of the major
challenges for chemists, because water is a safe, readily available, and
environmentally benign solvent.[1] 1,5-Benzodiazepine and quinoxaline units
are important because they are found in many biologically active
compounds.[2] In clinical practice, 1,5-benzodiazepine derivatives are used as
anticonvulsant, antianxiety, and hypnotic agents.[2] In organic synthesis, they
are used as valuable synthons for the preparation of fused ring compounds
such as triazolo-, oxadiazolo-, oxazino, and furano-benzodiazepines.[3] On the
other hand, functionalized quinoxalines are useful intermediates in organic
Received February 2, 2007
Address correspondence to Pranjal Gogoi, Synthetic Organic Chemistry Division,
Regional Research Laboratory, Jorhat 785006, Assam, India. E-mail: gogoipranj@
yahoo.co.uk
3447

3448
P. Hazarika, P. Gogoi, and D. Konwar
synthesis; they are found in various synthetic pharmaceuticals displaying a
broad spectrum of biological activity including antiviral, antibacterial, and
anti-inflammatory properties and as kinase inhibitors.[2] Quinoxaline and 1,5-
benzodiazepine derivatives are also used for the preparation of various dyes.[4]
The condensation of 1,2-diamine with ketones or 1,2-dicarbonyl
compounds gives 1,5-benzodiazepine and quinoxaline derivatives, respect-
ively. A number of synthetic strategies have been reported for the synthesis
of these two derivatives in the literature. For the synthesis of 1,5-benzo-
diazepine, BF3-OEt2,[5] NaBH4,[6] polyphosphoric acid,[7] SiO2,[7] MgO and
POCl3,[8] Sc(OTf)3,[9] Yb(OTf)3,[10] AcOH under microwave irradiation,[11]
and ionic liquid[12] may be mentioned. On the other hand, ceric(IV)
ammonium nitrate,[13] iodine,[14] zeolite,[15] microwave,[16] and solid-phase
synthesis[17] are used for the synthesis of quinoxaline; other reagents
such as Pd(OAc)2 or RuCl2-(PPh3)3-2,6,6-tetramethyl-1-peperidinyloxyl
(TEMPO)[18] and MnO2
[19]
are used for the synthesis of quinoxaline via a
tandem oxidation process. However, many of the synthetic protocols
reported so far suffer from disadvantages such as anhydrous conditions, use
of organic solvents, drastic reaction conditions, prolonged reaction time,
and use of transition metals. Therefore, development of an efficient, safe,
and environmentally friendly reagent system is desirable.
Lewis acid–catalyzed reactions are currently of great interest because of
their unique reactivity, selectivity, and use of mild conditions, but they have
been believed to be unusable in water.[20] Mostly lanthanide triflates such as
Sc(OTf)3 and Yb(OTf)3 are used as water-tolerant Lewis acids for various
organic transformations.[21] On the other hand, indium salts are extensively
used in organic synthesis because of their low toxicity and stability in air
and water.[22] Very recently, we have synthesized biologically active imidazo-
line and benzimidazole units from aldehyde and diamine via a condensation
followed by oxidation process in water.[23] Now, we report here a green
method for the synthesis of 1,5-benzodiazepine and quinoxaline derivatives
from aldehyde and ketone/1,2-diketone using indium(III) chloride as a
water-tolerant Lewis acid catalyst.
In a typical procedure, O-phenylenediamine (1.0 mmol), acetone
(2 mmol) or 1,2-diketone (1 mmol), and indium chloride (10 mol%) were
stirred in water (10 ml). After workup, the corresponding 1,5-benzodiazepine
and quinoxaline were obtained with excellent yields (Scheme 1).
The formation of these two derivatives were not observed without any
catalyst; the addition of indium chloride as a catalyst smoothly formed the
desired products with excellent yields in water. The catalytic amount of
indium chloride was optimized, and it was found that 10 mol% is sufficient for
both the condensations. As shown in Table 1, both aliphatic (cyclic and
acyclic) and aromatic ketones react with diamine to give their corresponding
1,5-benzodiazepines with excellent yields. The reaction of cyclic ketones with
O-phenylinediamine gave fused-ring 1,5-benzodiazepine derivatives. When
the 2-butanone was used as a substrate (entry 3), the cyclization occured

1,5-Benzodiazepine and Quinoxaline Derivatives
3449
Scheme 1. Synthesis of 1,5-benzodiazepine and quinoxaline derivativeds.
Table 1. InCl3-catalyzed syntheses of dihydro-1H-1,5-benzodiazepines and quinoxz-
line derivatives
Yield
(%)a
Entry
1
Diamine
Ketone/1,2-diketone
Product
CH3COCH3
97
2
CH3CH2COCH2CH3
90
3
4
CH3COCH2CH3
PhCOCH3
92
90
5
6
85
85
CH3COCH3
(continued)

3450
P. Hazarika, P. Gogoi, and D. Konwar
Table 1. Continued
Yield
(%)a
Entry
7
Diamine
Ketone/1,2-diketone
Product
PhCOCH3
80
8
9
79
98
10
11
95
94
12
13
91
88
aYields are isolated pure products and were characterized by NMR and MS
spectra.[10,13]
selectively from one side of the carbon skeleton to a single product. The conden-
sation of diamine with an equimolar amount of 1,2-diketone gave quinoxaline
with excellent yields. The products were separated by a simple filtration from
the reaction mixture. These condensations occurred in water at room tempera-
ture, and the undesired products were not obtained in the reaction mixture.
Regarding the mechanism of the reaction, it is proposed that O-phenyle-
nediamine forms diimine, A, with 2 equivalents of ketones. In the presence of
indium(III) chloride, diimine undergoes a 1,3-shift of hydrogen to enamine, B,
which undergoes intramolecular cyclazation to form a seven-membered ring
(Scheme 2).

1,5-Benzodiazepine and Quinoxaline Derivatives
3451
Scheme 2. Proposed mechanism and tentative intermediates.
We have demonstrated a simple, efficient, and green synthesis of
biologically active 1,5-benzodiazepine and quinoxaline derivatives in the
presence of a catalytic amount of indium(III) chloride in water. The advan-
tages of the present reaction are the elimination of transition metals, organic
solvents, and toxic reagents; operational simplicity; and high yield of the
products.
EXPERIMENTAL
Typical Experimental Procedure for the Synthesis of
1,5-Benzodiazepine
A mixture of 1,2-diamine (1.0 mmol), ketone (2.0 mmol), and indium chloride
(0.1 mmol) in water (5 ml) was stirred at room temperature for 3 h (monitored
by thin-layer chromatography, TLC). After completion of the reaction, a
solution of sodium bicarbonate (10 ml; 5% w/v) was added, and the
product was extracted with ethyl acetate (15 ml ꢀ 3). The combined ethyl
acetate layers dried over anhydrous sodium sulfate and were concentrated
under reduced pressure to give the crude product, then purified by crystalliza-
tion using a solvent mixture of hexane and ethyl acetate.
2,2,4-Trimethyl-2,3-dihydro-1H-1,5-benzodiazepine (1): Yellow solid; mp
1
122–1248C; H NMR (CDCl3, 300 MHz): d 1.34 (s, 6H), 2.22 (s, 2H), 2.36
(s, 3H), 2.97 (s, 1H), 6.71–7.27 (m, 4H); 13C NMR (CDCl3, 75 MHz): d
30.75, 31.37, 45.96, 69.30, 122.62, 122.99, 126.57, 126.76, 127.70, 138.77,
141.67, 173.31; FTIR (KBr): 3295.8 (NH), 2963.8 and 2911 (CH), 1637.2
(C55N) cm21; HRMS calcd. for C12H16N2 (Mþ) 188.131, found 188.25.

3452
P. Hazarika, P. Gogoi, and D. Konwar
Typical Experimental Procedure for the Synthesis of Quinoxaline
To a mixture of 1,2-diamine (1.0 mmol), 1,2-diketone (1.0 mmol) and indium
chloride (0.1 mmol) in water (5 ml) were stirred at room temperature for
30 min (monitored by TLC). After completion of the reaction, the crude
product was filtered, washed with water (3 ꢀ 10 ml), and recrystallized
from ethanol.
2,3-Diphenyl-quinoxaline (9): White solid; mp 125–1288C; 1H NMR
(CDCl3, 300 MHz): d 6.24–8.19 (m, 14H); 13C NMR (CDCl3, 75 MHz): d
129.14, 129.67, 130.08, 130.71, 130.83, 139.95, 142.10, 154.34; FTIR
(KBr): 1682.7 and 1672.0 (C55N) cm21; HRMS calcd. for C20H14N2 (Mþ)
282.116; found 182.4.
ACKNOWLEDGMENT
The authors acknowledge the director, P. G. Rao, and N. Borthakur, Head of
Division (HOD), Synthetic Organic Chemistry Division, the Analytical
Division of Regional Research Laboratory (RRL), Jorhat, Assam, India, for
their help. Also, P. G. and P. H. are grateful to the Council of Scientific and
Industrial Research (CSIR) for its grant of junior research fellowships.
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