Organocatalyzed one-pot synthesis of substituted 1,5-benzodiazepine and benzimidazole derivatives

Article abstract of DOI:10.1080/00397910903161686

An efficient synthesis of some heterocycles is described by condensation between o-phenylenediamine and 1,3-dicarbonyl compounds catalyzed by L-proline. The reaction is carried out either at room temperature or reflux depending on the substrates. Copyright

Full text of DOI:10.1080/00397910903161686

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Organocatalyzed One-Pot Synthesis of
Substituted 1,5-Benzodiazepine and
Benzimidazole Derivatives
Papori Goswami a & Babulal Das a
a Department of Chemistry , Indian Institute of Technology
Guwahati , Guwahati, Assam, India
Published online: 06 May 2010.
To cite this article: Papori Goswami & Babulal Das (2010) Organocatalyzed One-Pot Synthesis of
Substituted 1,5-Benzodiazepine and Benzimidazole Derivatives, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:11, 1685-1693,
DOI: 10.1080/00397910903161686
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Synthetic Communications1, 40: 1685–1693, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903161686
ORGANOCATALYZED ONE-POT SYNTHESIS
OF SUBSTITUTED 1,5-BENZODIAZEPINE
AND BENZIMIDAZOLE DERIVATIVES
Papori Goswami and Babulal Das
Department of Chemistry, Indian Institute of Technology Guwahati,
Guwahati, Assam, India
An efficient synthesis of some heterocycles is described by condensation between
o-phenylenediamine and 1,3-dicarbonyl compounds catalyzed by L-proline. The reaction
is carried out either at room temperature or reflux depending on the substrates.
Keywords: Diazepines; b-diketones; b-ketoesters; L-proline; o-phenylenediamine; organocatalysis
INTRODUCTION
The 1,5-benzodiazepines occupy an important place in the arena of heterocyclic
chemistry because they are important precursors of a variety of fused ring
compounds[1–3] and also possess significant pharmaceutical properties.[4–6] Likewise,
they are commercially important for their use as dyes for acrylic fibers.[7] These pharma-
cological and industrial applications have made their synthesis considerably important
in the field of synthetic organic chemistry and have activated the research in this area.
These heterocycles are generally synthesized by condensation of o-phenylene-
diamines with a,b-unsaturated carbonyl compounds, b-haloketones, or ketones.
The condensations are carried out in presence of BF3-OEt2,[8] NaBH4,[9] polypho-
sphoric acid–SiO2,[10] metal triflates,[11,12] and MgO=POCl3
and also under
[13]
microwave irradiation.[14,15] Fewer recently reported reagents for the synthesis are
bromo dimethyl sulfonium bromide,[16] organic acids,[17] and POCl3.[18]
In this line, the two heterocycles, namely, 2-alkyl and 2-aryl benzimidazole
derivatives, are medicinally important as antihistamines[19] and antiulcer drugs,[20]
and they also have other biological activities.[21–23] The reported methods use Lewis
acids in liquid[24] as well as solid phases[25] for their synthesis. However, because
some procedures previously described suffer from several drawbacks,[26] the scope
of investigation in this field is broadened up. Until now, no report of organocatalytic
synthesis[27] of these heterocycles has been reported to the best of our knowledge.
In this article, we report the synthesis of substituted 1,5-benzodiazepines,
benzimidazoles by condensation of o-phenylenediamine, and 1,3-dicarbonyl
Received March 26, 2009.
Address correspondence to Papori Goswami, Department of Chemistry, Indian Institute of
Technology Guwahati, Guwahati-781039, Assam, India. E-mail: papori@iitg.ernet.in
1685

1686
P. GOSWAMI AND B. DAS
Scheme 1. Synthesis of substituted heterocycles.
compounds at room temperature or under reflux in the presence of catalytic amount
of L-proline as shown in Scheme 1.
RESULTS AND DISCUSSION
To start with, a set of reactions was carried out with acetyl acetone 2a and
o-phenylenediamine 1 in ethanol at room temperature without any catalyst. The
reaction formed the enamine A with one amino group of 1 in 25% yields without
giving the desired heterocyclic product as shown in Scheme 2.
Hence, the reaction was carried out with a varying amount of L-proline at
room temperature, of which 20 mol% was appropriate to form the desired product
3a at ambient temperature as shown in Table 1.
Next, acetyl acetone 2a and o-phenylenediamine 1 were chosen as model
substrates with the aim of screening and finding the appropriate amino catalyst
Scheme 2. Synthesis of substituted heterocycles.

1,5-BENZODIAZEPINE AND BENZIMIDAZOLE DERIVATIVES
1687
Table 1. Optimization of the amount of catalyst at room temperature
Entry
Catalyst (mol%)
Time (h)
Yield (%)a
1
2
3
4
5
6
—
5
24
24
24
24
12
12
—
25
40
75
60
92
10
15
15
20
aIsolated yield.
for obtaining the maximum yield at room temperature. Among the screened
catalysts, L-proline was the most effective in completing the reaction with good yield
and less reaction time, as shown in Table 2.
Thus, the set of reactions with acetyl acetone 2a and o-phenylenediamine 1 in
ethanol in presence of 20 mol% of proline at room temperature furnished 2,4-
dimethyl-1,5-benzodiazepine 3a in 92% yield. Similarly, 3b was obtained in good
yield. Next, we tried to explore the reaction with a variety of structurally diverse
b-ketoesters to study their reactivity. Initially, a reaction of methyl acetoacetate 6a
and 1 in ethanol was stirred at room temperature in the presence of 20 mol% of
L-proline, which did not furnish any products even after 24 h. Consequently, the
reaction was carried out under reflux, and the product obtained was 2-methyl ben-
zoimidazole 7 instead of the expected 1,5-benzodiazepine derivative. Interestingly,
all the reactions with any alkyl acetoacetate 6a–e gave product 7 in moderate to good
yields. With this result in hand, we next tried to explore the reaction with ethyl
benzoyl acetate 4 in which the methyl is substituted by a phenyl group. Remarkably,
this reaction took a different course, leading to the formation of 4-phenyl-1,5-
benzediazepin-2-one 5. The results are shown in Table 3.
The structures of compound 5 and 7 (Tables 4 and 5) were further confirmed
by single-crystal x-ray diffraction (XRD) as shown in Fig. 1.
The probable sequence of steps for the formation of 1,5-benzodiazepin-2-one 5
and imidazole 7 is depicted in Scheme 3. Initially the imine derivative is formed under
the catalytic activity of L-proline. The key to the formation of two different products
can be ascribed to the formation of two different kinds of imine intermediates.
Table 2. Screening of catalyst for optimal yield
Entry
Catalyst (20 mol%)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
D-Norvaline
D-Tyrosine
24
24
24
24
24
24
12
40
57
50
65
70
45
92
L-Cysteine
L-Histidine
Pyridine dicarboxylic acid
Adenine
L-proline
aIsolated yield.

1688
P. GOSWAMI AND B. DAS
Table 3. Synthesis of substituted benzodiazepines and benzimidazoles
Entry
Substrate
Product
Time (h)
Yield (%)a,b
1
2
3
4
5
6
7
8
2a
2b
4
3a
3b
5
12
12
6
92
90
80
85
87
75
72
69
6a
6b
6c
6d
6e
7
4
7
4
7
7
7
5
7
5
aIsolated yield.
bThe products were analyzed by IH NMR, 13C NMR, mass, and elemental
analyses.
Interestingly, in the case of ethyl benzoylacetate (4), the phenyl group stabilizes the
imine B as a result of resonance, leading to the formation of 1,5-benzodiazepin-2-
one (5) as shown in Scheme 3a.
Table 4. CIF for 5
Parameter
Value
Identification code
Empirical formula
Formula weight
Temperature
pg-ph_0 m
C15 H12 N2 O
508.61
293(2) K
˚
0.71073 A
Wavelength
Crystal system
Space group
Unit cell dimensions
Monoclinic
C2=c
ꢀ
˚
a ¼ 31.5696(16) A a ¼ 90
ꢀ
˚
b ¼ 4.7337(2) A b ¼ 17.972(4)
ꢀ
˚
c ¼ 19.3029(12) A c ¼ 90
3
˚
Volume
Z
2547.7(2) A
4
Density (calculated)
Absorption coefficient
F(000)
1.326 Mg=m3
0.087 mmꢁ1
1080
Crystal size
Theta range for data collection
Index ranges
0.45 ꢂ 0.15 ꢂ 0.10 mm3
1.46 to 28.40ꢀ.
–41 ꢃ h ꢃ 42, ꢁ6 ꢃ k ꢃ 6, ꢁ25 ꢃ l ꢃ 25
Reflections collected
Independent reflections
Completeness to theta ¼ 28.40ꢀ
Absorption correction
Refinement method
Data=restraints=parameters
Goodness of fit on F2
Final R indices [I > 2sigma(I)]
R indices (all data)
Extinction coefficient
Largest diff. peak and hole
19631
3104 [R(int) ¼ 0.0462]
96.9%
None
Full-matrix least-squares on F2
3104=0=174
1.043
R1 ¼ 0.0698, wR2 ¼ 0.2008
R1 ¼ 0.1263, wR2 ¼ 0.2308
0.0057(15)
ꢁ3
˚
0.432 and ꢁ0.545 e.A

1,5-BENZODIAZEPINE AND BENZIMIDAZOLE DERIVATIVES
1689
Table 5. Crystal data and structure refinement for 7
Paramenter
Value
Identification code
Empirical formula
Formula weight
Temperature
pg-05
C8 H8 N2
132.16
293(2) K
˚
Wavelength
0.71073 A
Tetragonal
P42=n
Crystal system
Space group
Unit cell dimensions
ꢀ
ꢀ
˚
a ¼ 13.9764(12) A a ¼ 90
˚
b ¼ 13.9764(12) A b ¼ 90
ꢀ
˚
c ¼ 7.1848(6) A c ¼ 90
3
˚
Volume
Z
1403.5(2) A
8
Density (calculated)
Absorption coefficient
F(000)
1.251 Mg=m3
0.078 mmꢁ1
560
Crystal size
Theta range for data collection
Index ranges
0.45 ꢂ 0.32 ꢂ 0.12 mm3
2.06 to 27.45ꢀ.
–18 ꢃ h ꢃ 18, ꢁ18 ꢃ k ꢃ 0, ꢁ9 ꢃ l ꢃ 9
6153
Reflections collected
Independent reflections
Completeness to theta ¼ 27.45ꢀ
Refinement method
Data=restraints=parameters
Goodness of fit on F2
Final R indices [I > 2sigma(I)]
R indices (all data)
Extinction coefficient
Largest diff. peak and hole
1609 [R(int) ¼ 0.0281]
99.9%
Full-matrix least-squares on F2
1609=0=93
1.185
R1 ¼ 0.0287, wR2 ¼ 0.1197
R1 ¼ 0.0307, wR2 ¼ 0.1319
0.0000(15)
ꢁ3
˚
0.234 and ꢁ0.484 e.A
In the case of 6, the intermediate imine C is relatively unstable and easily reacts
with the other amino group to form the aminal intermediate D, which retards the
reaction rate of the amino group over the ester functionality. L-Proline attacks the
carbonyl group of the ester moiety in the later stage, leading to the formation of 7.
Figure 1. ORTEP plot of 5 and 7.

1690
P. GOSWAMI AND B. DAS
Scheme 3. Probable mechanism for the formation of 4-phenyl-1,5-benzediazepin-2-one (5) and substituted
benzoimidazole (7): (a) formation of 4-phenyl-1,5-benzediazepin-2-one and (b) formation of substituted
benzoimidazole.
Similarly, the formation of benzodiazepine 5 probably proceeds through the
initial formation of an enamine influenced by L-proline with the elimination of water
by the reaction of one amino group and the hydroxyl group of the enol form of the
1,3-diketones. The enamine so formed again intramolecularly condenses with the
other amino group to form the benzodiazepine derivative.

1,5-BENZODIAZEPINE AND BENZIMIDAZOLE DERIVATIVES
1691
EXPERIMENTAL
Synthesis of 1,5-Benzodiazepines
A mixture of benzoyl acetone 2b (1 mmol) or acetyl acetone 2a (1 mmol) and
o-phenylene diamine 1 (1 mmol) was dissolved in ethanol and stirred at room
temperature, to which was added L-proline (20 mol%). The reaction mixture was
allowed to stir at room temperature for 12 h. After completion of the reaction as
monitored by thin-layer chromatography (TLC), the reaction mixture was poured
in water and extracted with dichloromethane (3 ꢂ 15 mL). The extracted layer was
dried over anhydrous Na2SO4 and evaporated under reduced pressure to give the
crude reaction mixture. The crude reaction mixture was purified through column
1
chromatography (1:9: EtOAc=hexane) in 90% yield and analyzed directly by H
NMR, 13C NMR, IR, mass, and elemental analyses.
Synthesis of 1,3-Dihydro-1,5-benzodiazepin-2-one
A mixture of ethyl benzoyl acetate 4 (1 mmol) and o-phenylene diamine 1
(1 mmol) was dissolved in ethanol, to which was added L-proline (20 mol%). The
reaction mixture was allowed to reflux for 6 h. After completion of the reaction as
monitored by TLC, the reaction mixture was poured in water and extracted with
dichloromethane (3 ꢂ 15 mL). The extracted layer was dried over anhydrous Na2SO4
and evaporated under reduced pressure to give the crude reaction mixture. The crude
reaction mixture was recrystallized from ethanol in 80% yield and analyzed directly
1
by H NMR, 13C NMR, IR, mass, and elemental analyses.
Synthesis of 2-Methyl Benzimidazole
A mixture of methyl acetoacetate 6a (1 mmol) and o-phenylene diamine 1
(1 mmol) was dissolved in ethanol, to which was added L-proline (20 mol%). The
reaction mixture was allowed to reflux for 4 h. After completion of the reaction
(monitored by TLC), the reaction mixture was poured in water and extracted with
dichloromethane (3 ꢂ 15 mL). The extracted layer was dried over anhydrous Na2SO4
and evaporated under reduced pressure to give the crude reaction mixture. The crude
reaction mixture was recrystallized from ethanol in 85% yield and analyzed directly
1
by H NMR, 13C NMR, IR, mass, and elemental analyses.
Spectral Data of Some Compounds
Compound 3b. 1H NMR (400 MHz, CDCl3): 2.32 (s, 3H), 7.27 (s, 1H),
7.28–7.29 (m, 2H), 7.43–7.45 (m, 2H), 7.48–7.49 (m, 2H), 7.53–7.55 (m, 2H),
8.04–8.06 (m, 2H); 13C NMR (100 MHz): 38.84, 125.34, 125.50, 127.42, 127.84,
128.42(2C), 128.69, 129.05(2C), 131.04, 137.25, 140.46, 140.90, 153.66, 158.28. Anal.
calcd. for C16H14N2: C, 82.02%; H, 6.02%. Found: C, 81.92%; H, 6.21%. TOF
MS: 234.
Compound 5. 1H NMR (400 MHz, CDCl3): 2.65 (s, 3H), 7.21–7.24 (m, 2H),
7.27 (bs, 1H), 7.53–7.56 (m, 2H); 13C NMR (100 MHz): 15.15, 114.72 (2C), 122.37

1692
P. GOSWAMI AND B. DAS
(2C), 138.93 (2C), 151.71. Anal. calcd. for C8H8N2: C, 72.70%; H, 6.10%. Found: C,
72.85%; H, 6.01%. TOF MS: 132.
CONCLUSION
In conclusion, we have devised a simple method for the synthesis of a variety of
substituted heterocycles using L-proline as the catalyst. The operational simplicity,
lack of chromatographic separation for most of the compounds, and good to
excellent yields are the advantages of the procedure. We believe that this protocol
will contribute to the realm of synthetic heterocyclic chemistry.
ACKNOWLEDGMENTS
The work was carried out with under Grant No. SR=FTP=CS-15=2007 of the
Department of Science and Technology, New Delhi, India. The director of the
Indian Institute of Technology, Guwahati, is given special thanks for providing
the required research facility to carry out the work.
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