[(L)proline]2Zn catalysed synthesis of 1,5-benzodiazepine derivatives under solvent-free condition

Article abstract of DOI:10.1081/SCC-200034752

This communication demonstrates that a novel Lewis acid complex, Zn[(L)proline]₂, catalysed one pot synthesis of 1,5-benzodiazepine derivatives under solvent-free conditions. The efficiency of the catalyst has been examined by conventional meth

Full text of DOI:10.1081/SCC-200034752

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[(L)Proline]2Zn
Catalysed Synthesis of
1,5‐Benzodiazepine
Derivatives Under
Solvent‐Free Condition
V. Sivamurugan a , K. Deepa a , M. Palanichamy a
V. Murugesan a
&
a Department of Chemistry, Anna University,
Chennai, 600 025, India
Published online: 10 Jan 2011.
To cite this article: V. Sivamurugan , K. Deepa , M. Palanichamy & V. Murugesan
(2004): [(L)Proline]2Zn Catalysed Synthesis of 1,5‐Benzodiazepine Derivatives Under
Solvent‐Free Condition, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 34:21, 3833-3846
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 21, pp. 3833–3846, 2004
[(L)Proline]2Zn Catalysed Synthesis of
1,5-Benzodiazepine Derivatives Under
Solvent-Free Condition
V. Sivamurugan, K. Deepa, M. Palanichamy,
*
and V. Murugesan
Department of Chemistry, Anna University, Chennai, India
ABSTRACT
This communication demonstrates that a novel Lewis acid complex,
Zn[(L)proline]2, catalysed one pot synthesis of 1,5-benzodiazepine
derivatives under solvent-free conditions. The efficiency of the catalyst
has been examined by conventional method and microwave irradiation
technique. 1,5-Benzodiazepine is obtained in moderate to good yield
(up to 93%) in all the reactions within a shorter reaction time under
microwave irradiation. The recycling ability of the catalyst has also
been evaluated. The catalyst is reusable up to five times without
appreciable loss of its catalytic activity.
Key Words: 1,5-Benzodiazepine; Lewis acid; Multi component
reaction; One-pot condensation; Solvent-free; Zn-proline.
*
Correspondence: V. Murugesan, Department of Chemistry, Anna University, Chennai
600 025, India; Fax: þ91-44-22200660; E-mail: v_murugu@hotmail.com.
3833
DOI: 10.1081/SCC-200034752
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Sivamurugan et al.
INTRODUCTION
Benzodiazepines are pharmacologically active compounds finding
application as antiinflammatory,[1] antianxiety, anticonvulsant, and
hypnotic agents.[2,3] The synthesis of 1,5-benzodiazepines is associated
with a condensation of o-phenylene diamine with aryl/alkyl ketone or
a, b-unsaturated carbonyl compounds,[4] or b-haloketones[5] in the
presence of conventional acid catalyst, Lewis acid catalysts like BF3-
etherate,[6] NaBH4,[7]and polyphosphoric acid.[8] Furthermore, the synthe-
sis of 1,5-benzodiazepine derivatives catalysed by MgO/POCl3,[9]
Yb(OTf)3,[10] ionic liquid,[11] and sulfated zirconia[12] has been reported
recently.
In recent years, organic synthesis under solvent-free conditions is of
great interest in view of a flowering environmental awareness.[13a,b]
Among the solvent-free techniques, microwave accelerated organic synthesis
is an effective route proposed during the last decade due to drastic reduc-
tion of reaction time, minimize cumbersome workup, and improved
[15]
yields.[14a,b] After a few initial attempts with Al2O3/P2O5
or AcOH,[16]
we investigated the possibility of Zn[(L)proline]2, a recyclable and
inexpensive Lewis acid complex, in the synthesis of 1,5-benzodiazepine
derivatives under solvent-free conditions assisted with microwave
irradiation.
Symmetrical and asymmetrical alkyl ketones, alicyclic ketones, and sub-
stituted aryl ketones have been used for the synthesis of 1,5-benzodiazepine
derivatives employing Zn[(L)proline]2 complex. However, aryl-1,2-diamine
is the unchanged substrate in all the reactions. In all the reactions 5 mmol of
o-phenylene diamine have been condensed with 11 mmol of ketone in the
presence of 0.2 mmol of the catalyst. In order to evaluate the catalytic activity
of the catalyst, the reactions were carried out by conventional heating
and microwave irradiation. The progress of the reactions was monitored by
TLC analysis. After completion of reaction, the reaction mixture was
diluted with 100 mL of CH2Cl2 and the product was separated by simple
filtration. The excess solvent was removed by evaporation and purified
through column chromatography, and the product was obtained with
acceptable purity.
The catalyst is soluble in water, sparingly soluble in methanol,
ethanol, and THF, and insoluble in dichloromethane and other nonpolar
solvents. Thus, the solubility nature of the catalyst can facilitate the separation
of products from the catalyst. The used catalyst can be recycled and used for
the next reaction without any further purification.
From Table 1, it is observed that microwave-irradiated reactions have
afforded good yield within shorter reaction time than conventional method.

Synthesis of 1,5-Benzodiazepine Under Solvent-Free Condition
3835

3836
Sivamurugan et al.

Synthesis of 1,5-Benzodiazepine Under Solvent-Free Condition
3837

3838
Sivamurugan et al.

Synthesis of 1,5-Benzodiazepine Under Solvent-Free Condition
3839
For all the reactions, 325 w (ꢁ50% of MW power), which is 50% less than the
literature reported values, has been used to obtain moderate to good yield.[16]
This demonstrates clearly that [(L)proline]2Zn complex effectively catalyses
1,5-benzodiazepine synthesis.
The catalytic efficiency has been evaluated from the recycling ability
of the catalyst. The reaction of o-phenylene diamine with acetone in the
presence of 0.2 mmol of the catalyst has been taken as a model reaction
for recycling studies. The reaction has been carried out by conventional
heating and microwave irradiation. The progress of the reaction was moni-
tored by TLC. After completion of the reaction, the mixture was washed
with CH2Cl2 (5 ꢂ 20 mL) until complete removal of organic components.
The catalyst was dried in vacuum for 2 hr at 608C and used for the next
cycle. Thus, the same catalyst was reused for six cycles. It is found that
the catalyst does not lose its activity up to five cycles. The reduction of
yield in the sixth cycle is due to the decomposition of the metal complex.
The reaction time and yield of the product for different cycles are listed in
Table 2.
The present investigation revealed that Zn[(L)proline]2 complex is found
to be a viable catalyst for the synthesis of 1,5-benzodiazepine derivatives.
This catalyst can be used for a wide range of ketones. Zn[(L)proline]2
complex assisted microwave-irradiated reactions afford moderate to good
yield. This complex exhibits good catalytic activity even in low MW power
(ꢁ325 w) and can be used up to five cycles without appreciable loss of
catalytic activity.
Table 2. The catalyst recycling studies.a
Conventional
Microwave irradiation
Catalyst
recycle
Time (hr)b
Yield (%)c
Time (min)b
Yield (%)c
92
I
2
2
2
2
2
2
90
90
85
83
80
75
3
II
3
3
3
3
3
90
90
88
85
76
III
IV
V
VI
aModel reaction: o-phenylene diamine with acetone in the presence of 0.2 mmol of
catalyst.
bReaction progress monitored by TLC analysis.
cIsolated yield.

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Sivamurugan et al.
EXPERIMENTAL
Materials and Methods
All the materials used in this study were of pure quality and purchased
from E-merck (Germany). The melting point of the products was determined
on Raga hot stage apparatus and were uncorrected. The UV-visible spectra of
the products were recorded in a Shimadzu (model: UV-1601) UV-Visible
spectrophotometer. The FTIR spectra of the products were recorded on a
Nicolet 360 FTIR using KBr pellet technique. 1H NMR spectra were recorded
on a JEOL GSX-400 spectrometer at ambient temperature using TMS as
internal standard and CDCl3 as solvent. The data were recorded as chemical
shift in ppm from the internal standard. The elemental analysis of the
derivatives was carried out in a Heraeus CHNO rapid analyzer. The mass
spectra of all the products were recorded on a Finnigan Mat 8230MS
spectrometer.
Synthesis of Bis[(L)Prolinato-N, O]Zn Complex
Twenty mmol of (L)proline was dissolved in 50 mL absolute ethanol con-
taining 20 mmol potassium hydroxide and stirred well for 15 min. In order
.
to maintain the metal to ligand ratio 1 : 2, 10 mmol of Zn(NO3)2 6H2O
was dissolved in a small quantity of double distilled water and this solu-
tion was added in drops to the solution of (L)proline. The contents were
vigorously stirred at room temperature for 6 hr. Zn[(L)proline]2 complex
was obtained as a white solid. It was filtered and dried at 708C in
vacuum for 6 hr. Yield: 94%. FT IR (n cm21): 3206, 2995, 1605, 1516,
1403, 1239, 825, and 533. Elemental composition (C10H16N2O4Zn). Calc:
C, 40.91; H, 5.49; N, 9.54; O, 21.80%. Found: C, 40.74; H, 5.60; N, 9.30;
O, 21.70%.
Synthesis of 1,5-Benzodiazepine Derivatives
Conventional Method
A mixture of 5 mmol of o-phenylene diamine and 11 mmol of acetone was
thoroughly mixed with 0.2 mmol of the catalyst and adsorbed on alumina
(neutral). The alumina supported mixture was taken in a 15 mL clean stainless
steel autoclave and thermostated at 1008C for 2 hr. After completion of the
reaction the mixture was diluted with CH2Cl2 and the product was separated

Synthesis of 1,5-Benzodiazepine Under Solvent-Free Condition
3841
Scheme 1.
by simple filtration. The alumina-supported catalyst was washed thoroughly
until complete removal of the product. The catalyst was dried in vacuum at
708C for 6 hr and reused for the next reaction without any further purification.
The excess solvent from the product was removed by rotary evaporator.
The product was purified by column chromatography (n-hexane to ethyl
acetate ratio ¼ 80 : 20) and recrystallized from ethanol. The product was
obtained as a yellow crystalline solid. The same procedure was followed for
other reactions (Sch. 1). The reaction time and yield for all the reactions are
presented in Table 1.
Microwave Irradiation
A mixture of 5 mmol of o-phenylene diamine and 11 mmol of ethyl
methyl ketone was thoroughly mixed with 0.2 mmol of catalyst and adsorbed
on alumina (neutral). The alumina-supported mixture was taken in an open
Erlenmeyer flask (100 mL) and irradiated using a household microwave
oven (model: IFB 17PM 1S) with a power range of 325 w and a pulse of 15
seconds. The progress of the reaction was monitored by TLC (silica gel

3842
Sivamurugan et al.
precoated plate; n-hexane to ethyl acetate ratio ¼ 75 : 25). After completion of
the reaction, the mixture was diluted with CH2Cl2 and the product was
separated by column chromatography (n-hexane to ethyl acetate
ratio ¼ 80 : 20) and recrystallized from ethanol. The same procedure was
adopted for all the reactions (Sch. 1). The reaction time and yield are presented
in Table 1.
Spectral Characterization of the Products (a–k)
2,2,4-Trimethyl-2,3-dihydro-1H-1,5-benzodiazepine (a). Yellow solid.
M.p.: 137–1398C (from ethanol/hexane ¼ 9 : 1). UV-Visible (lmax, nm):
458, 313, 260. FTIR spectrum (KBr, cm21): 3350 (N-Hstr), 2980 (alkyl
1
C-Hstr), 1625 (C55Nstr), 1520(aromatic C55C). HNMR spectrum (CDCl3,
400 MHz): 7–7.25 (m, 4H, Ar-H), 3.5 (br, s, 1H, N-H), 3 (s, 2H, N55C–
CH2), 2.5 (m, 3H, N55C–CH3), 1.50–1.75 (s, 6H, 2CH3). C12H16N2
(188.13) Calcd.: C, 76.56; H, 8.57; N, 14.88. Found: C, 76.25; H, 8.40; N,
14.5. MS: m/z Mþ ¼ 188.
2-Ethyl-2,3,4-trimethyl-2,3-dihydro-1H-1,5-benzodiazepine (b). Yellow
solid. M.p.: 139–1418C (from ethanol/hexane ¼ 9 : 1). UV-Visible
(lmax, nm): 486, 458, 304, 263. FTIR spectrum (KBr, cm21): 3340
(N-Hstr), 2975 (alkyl C-Hstr), 1635 (C55Nstr), 1530 (aromatic C55C).
1HNMR spectrum (CDCl3, 400 MHz): 7–7.25 (m, 4H, Ar-H), 3.75
(br, s, 1H, N-H), 2.85 (q, 1H, N55C–CH–CH3), 2.5 (s, 3H, N55C–CH3),
1.75 (d, 3H, N55C–CH-CH3), 1.50 (s, 3H, N–C–CH3), 1.25 (q, 2H,
.
CH2–CH3), 0.98 (t, 3H, CH2–CH3) C14H20N2 (216.33) Calcd.: C,
77.73; H, 9.32; N, 12.95. Found: C, 77.50; H, 9.50; N, 12.75. MS: m/z
Mþ ¼ 216.
2,2,4-Triethyl-3-methyl-2,3-dihydro-1H-1,5-benzodiazepine
(c).
Yellow solid. M.p.: 1458C (from ethanol). UV-Visible (lmax, nm): 354,
304, 279, 260. FTIR spectrum (KBr, cm21): 3330 (N-Hstr), 2980
1
(alkyl C-Hstr), 1640 (C55Nstr), 1535 (aromatic C55C). HNMR spectrum
(CDCl3, 400 MHz): 6.9–7.25 (m, 4H, Ar-H), 3.8 (br, s, 1H, N-H), 2.85
(q, 1H, N55C–CH–CH3), 2 (d, 3H, N55C–CH–CH3), 1.6–1.3 (m, 6H,
CH2–CH3), 1.2-0.95 (m, 9H, CH2–CH3). C16H24N2 (244.38) Calcd.: C,
78.64; H, 9.90; N, 11.46. Found: C, 78.50; H, 10.10; N, 11.35. MS: m/z
Mþ ¼ 244.
3-Ethyl-2,2,4-tri-n-propyl-2,3-dihydro-1H-1,5-benzodiazepine
(d).
Yellow solid. M.p.: 146–1488C (from ethanol). UV-Visible (lmax, nm):
355, 304, 260. FTIR spectrum (KBr, cm21): 3335 (N-Hstr), 2980
1
(alkyl C-Hstr), 1635 (C55Nstr), 1530 (aromatic C55C). HNMR spectrum
(CDCl3, 400 MHz): 6.8–7.2 (m, 4H, Ar-H), 4.2 (br, s, 1H, N-H), 2.4 (t, 1H,

Synthesis of 1,5-Benzodiazepine Under Solvent-Free Condition
3843
N55C–CH–CH2CH3), 1.6–1.4 (m, 8H, CH2–CH2), 1.25–0.85(m, 18H,
CH2–CH2–CH3). C20H32N2 (300.49) Calcd.: C, 79.94; H, 10.73; N, 9.32.
Found: C, 79.75; H, 10.65; N, 9.40. MS: m/z Mþ ¼ 300.
3-Ethyl-2,4-dimethyl-2-n-propyl–2,3-dihydro-1H-1,5-benzodiazepine
(e). Yellow solid. M.p.: 1438C (from ethanol/hexane). UV-Visible (lmax
,
nm): 458, 305, 255. FTIR spectrum (KBr, cm21): 3360 (N-Hstr), 2980
1
(alkyl C-Hstr), 1630 (C55Nstr), 1525 (aromatic C55C). HNMR spectrum
(CDCl3, 400 MHz): 7–7.25 (m, 4H, Ar-H), 3.9 (br, s, 1H, N-H), 2.4 (t, 1H,
N55C–CH–CH2CH3), 2.2 (S, 3H, N-C-CH3) 1.85 (s, 3H, N55C–CH3),
1.50–1.75 (m, 2H, CH2CH3), 1.3–0.8 (m, 10H, CH2–CH2CH3). C16H24N2
(244.38) Calcd.: C, 78.64; H, 9.90; N, 11.46. Found: C, 78.55; H, 9.75; N,
11.55. MS: m/z Mþ ¼ 244.
Spirocyclohexan-2,3,4,10,11,11a-hexahydro-1H-dibenzo[b,e][1,4]dia-
zepine (f). Yellow solid. M.p.: 1378C (from ethanol/hexane). UV-Visible
(lmax, nm): 458, 304, 275, 261. FTIR spectrum (KBr, cm21): 3350
(N-Hstr), 2980 (alkyl C-Hstr), 1625 (C55Nstr), 1520 (aromatic C55C).
1HNMR spectrum (CDCl3, 400 MHz): 7–7.3 (m, 4H, Ar-H), 3.8 (br, s, 1H,
N-H), 2.85–3.15 (m, 3H, N55C–CH and N55C–CH2), 1.96–2.75
(m, 8 ꢂ CH2, 16H). C18H24N2 (268.41) Calcd.: C, 80.55; H, 9.01; N, 10.44.
Found: C, 80.45; H, 8.95; N, 10.35. MS: m/z Mþ ¼ 268.
Spirocycloheptan-6,7,8,9,10,10a,11,12-octahydrobenzo[b]cyclo hepta
[e][1,4]diazepine (g). Dark yellow solid. M.p.: 1358C (from ethanol/
hexane). UV-Visible (lmax, nm): 489, 440, 299, 260. FTIR spectrum
(KBr, cm21): 3350 (N-Hstr), 2980 (alkyl C-Hstr), 1625 (C55Nstr), 1520
(aromatic C55C). 1HNMR spectrum (CDCl3, 400 MHz): 7–7.3 (m, 4H,
Ar-H), 3.8 (br, s, 1H, N-H), 2.9–3.2 (m, 3H, N55C–CH and N55C–
CH2), 1.5–2.75 (m, 10 ꢂ CH2, 20H). C20H28N2 (296.46) Calcd.: C,
81.03; H, 9.52; N, 9.45. Found: C, 81.25; H, 9.45; N, 9.40. MS: m/z
Mþ ¼ 296.
2-Methyl-2,4-diphenyl-2,3-dihydro-1H-1,5-benzodiazepine (h). Dark
yellow solid. M.p.: 150–1528C (from ethanol). UV-Visible (lmax, nm): 485,
300, 265. FTIR spectrum (KBr, cm21): 3325 (N-Hstr), 3010 (aromatic C-H
1
str), 2975 (alkyl C-Hstr), 1630 (C55Nstr), 1535(aromatic C55C). HNMR
spectrum (CDCl3, 400 MHz): 6.8-7.55 (m, 14H, Ar-H), 4.1 (br, s, 1H, N-H),
3.1 (s, 2H, N55C-CH2), 1.75 (s, 3H, CH3). C22H20N2 (312.42) Calcd.: C,
84.58; H, 6.45; N, 8.97. Found: C, 84.45; H, 6.53; N, 8.75. MS: m/z
Mþ ¼ 312.
2-Methyl-2,4-di(4-chlorophenyl)-2,3-dihydro-1H-1,5-benzodiazepine
(i). Dark yellow solid. M.p.: 160–1638C (from ethanol). UV-Visible (lmax
,
nm): 475, 310, 260. FTIR spectrum (KBr, cm21): 3330 (N-Hstr), 3010
(aromatic C-Hstr), 2950 (alkyl C-H str), 1625 (C55Nstr), 1520 (aromatic
1
C55C). HNMR spectrum (CDCl3, 400 MHz): 6.85–7.45 (m, 12H, Ar-H),

3844
Sivamurugan et al.
4 (br, s, 1H, N-H), 2.95 (s, 2H, N55C–CH2), 1.65 (s, 3H, CH3). C22H18N2Cl2
(381.31) Calcd.: C, 69.30; H, 4.76; N, 8.97. Found: C, 69.10; H, 4.55; N, 8.85.
MS: m/z Mþ ¼ 381.
2-Methyl-2,4-di(4-bromophenyl)-2,3-dihydro-1H-1,5-benzodiazepine
(j). Dark yellow solid. M.p.: 1718C (from ethanol/hexane). UV-Visible
(lmax, nm): 480, 299, 260. FTIR spectrum (KBr, cm21): 3335 (N-Hstr),
3015 (aromatic C-Hstr), 2960 (alkyl C-H str), 1635 (C55Nstr), 1515 (aromatic
C55C). 1HNMR spectrum (CDCl3, 400 MHz): 6.8–7.40 (m, 12H, Ar-H), 4.2
(br, s, 1H, N-H), 3.2 (s, 2H, N55C–CH2), 1.65 (s, 3H, CH3). C22H18N2Br2
(470.21) Calcd.: C, 56.20; H, 3.86; N, 5.96. Found: C, 56.25; H, 3.75; N,
5.80. MS: m/z Mþ ¼ 470.
2-Methyl-2,4-di(4-hydroxyphenyl)-2,3-dihydro-1H-1,5-benzodiazepine
(k). Yellow solid. M.p.: 137–1398C (from ethanol/hexane). UV-Visible
(lmax, nm): 490, 312, 276, 246. FTIR spectrum (KBr, cm21): 3340
(N-Hstr), 3010 (aromatic C-Hstr), 2970 (alkyl C-H str), 1635 (C55Nstr),
1515(aromatic C55C). 1HNMR spectrum (CDCl3, 400 MHz): 6.95–7.50
(m, 12H, Ar-H), 3.9 (br, s, 1H, N-H), 2.9 (s, 2H, N55C-CH2), 1.60 (s, 3H,
CH3). C22H20N2O2 (344.42) Calcd.: C, 76.72; H, 5.85; N, 9.29. Found: C,
76.65; H, 5.70; N, 9.40. MS: m/z Mþ ¼ 344.
ACKNOWLEDGMENT
The authors are grateful to University Grants Commission (UGC),
New Delhi for financial support in the form of a major sponsored project.
One of the authors (V. Sivamurugan) thanks the Council of Scientific and
Industrial Research (CSIR), New Delhi for the award of senior research
fellow.
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Received in India June 14, 2004