1,5-Benzoheteroazepines through eco-friendly general condensation reactions

Article abstract of DOI:10.1016/j.tetlet.2011.06.029

Condensation reactions of o-phenylenediamine and 2 equiv of acetone produce biaryl-substituted 1,5-benzodiazepines. The synthetic protocol shows general applicability since similar reaction of o-phenylenediamines, o-aminophenol, and o-aminothiophenol with

Full text of DOI:10.1016/j.tetlet.2011.06.029

Tetrahedron Letters 52 (2011) 4827–4834
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Tetrahedron Letters
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1,5-Benzoheteroazepines through eco-friendly general condensation reactions
Monica Nardi a, , Annalisa Cozza a, Loredana Maiuolo a, Manuela Oliverio b, Antonio Procopio b
⇑
a Dipartimento di Chimica, Università della Calabria, ponte Bucci cubo 12/c, 87030 Arcavacata di Rende (Cs), Italy
b Dipartimento di Scienze Farmacobiologico, Università Magna Græcia di Catanzaro, Complesso Ninì Barbieri, 88021 Roccelletta di Borgia (CZ), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Condensation reactions of o-phenylenediamine and 2 equiv of acetone produce biaryl-substituted 1,
5-benzodiazepines. The synthetic protocol shows general applicability since similar reaction of o-pheny-
lenediamines, o-aminophenol, and o-aminothiophenol with ketones or chalcones leads to formation of
functionalized 1,5-benzoheteroazepines in good to excellent yields. The synthetic protocol fulfills many
green-chemical requirements using simple MW-assistance to promote the activation of ketones and the
eco-compatible Er(III) triflate as activator of chalcones.
Received 28 April 2011
Revised 31 May 2011
Accepted 7 June 2011
Available online 15 June 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Benzodiazepine
Benzooxazepine
Benzothiazepine
Erbium(III) triflate
Microwave
The clinical importance and commercial success associated
with pharmacologically active benzodiazepines have led to their
recognition by the medicinal community as structures of particular
significance.1 1,5-Benzodiazepines exert a biological activity simi-
lar to well known 1,4-derivatives and their ring system has demon-
strated considerable utility not only in central nervous system
(CNS)-drug design, but also as peptidomimetic scaffolds2 and key
intermediates for the preparation of other fused ring compounds.3
Consequently, the development of new synthetic approaches to the
1,5-benzodiazepine ring system and their further elaboration have
provided access to a broad range of functionalized derivatives that
have contributed to advance in understanding the underlying prin-
ciples of structure and reactivity. The commonly employed meth-
ods to construct the ring skeletons involve the cyclocondensation
of 1,2-diamines with ketones,4 enones,5 b-haloketones,2 using
ytterbium triflate,6 BF3-etherate,2 polyphosphoric acid,2b MgO
and POCl3,4 ionic liquids,7 microwave assistance,8 SbCl3–Al2O3,9
demand. Nonetheless, the search for a better methodology to syn-
thesize benzodiazepines and analogs continues, whereby general
applicability, simplicity, reusability, ecological safety, and eco-
nomic viability could be achieved.
In the last decade, our research group has been making consid-
erable efforts, designing and carrying out innovative synthetic pro-
tocols in organic synthesis adopting
a more eco-sustainable
approach.20–22 As a part of this research, we found that lantha-
nide(III) derivatives such as MW-irradiation can promote reactive
pathways in very convenient way from green chemical point of
view. Thus, we report herein a new utility of erbium(III) triflate cat-
alyst for MW-assisted condensation reactions of o-phenylenedi-
amine a, o-aminophenol b or o-aminothiophenol c with carbonyl
compounds to form functionalized 1,5-benzodiazepines, 1,5-ben-
zoxazepines and 1,5-benzothiazepines.
In an attempt to identify the most optimal experimental condi-
tions, a detailed study was performed on o-phenylenediamine a
and acetone (Scheme 1). Table 1 presents the results obtained
using different reaction solvents under the conditions of 5 mol %
catalyst and 3–7 h at room temperature. As can be seen from the
data, acetonitrile was found to be a good solvent (Table 1, entry
1) giving 1,5-benzodiazepine in 82% yield (Table 1, entry 1).
Increasing the amount of Er(OTf)3 to 10 mol % did not significantly
improve the yield (Table 1, entry 2). Lower yield of product 1a was
registered when the reaction was performed in some other little
polar solvents (Table 1, entries 3–5), whilst only traces of the prod-
uct were collected carrying out the process in water (Table 1, en-
tries 6). Surprisingly, the reaction of o-phenylenediamine a and
and zinc montmorillonite heterogeneous catalysts,10 sulfated zir-
12
conia,11 Ag3PW12O40
,
CH3COOH,13 MCM-41 zeolite,14 piperi-
dine-AcOH,15 Ga(OTf)3,16 PPA/SiO2,2b dodecylsulfonic acid in
water,17 La(NO3)3,18 sulfamic acid,19 etc. Although development
of non-hazardous synthetic methodologies for organic reactions
is one of the latest challenge to the organic chemists, only few of
the known benzodiazepine synthesis methods tried to answer this
⇑
Corresponding author.
E-mail address: nardi@unical.it (M. Nardi).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.029

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M. Nardi et al. / Tetrahedron Letters 52 (2011) 4827–4834
favorable cases) were obtained from this reaction (Table 2, entry 10).
NH2
NH2
N
However, only in the case of 4-nitrobenzene-1,2-diamine f accept-
able yield of 1,5-benzodiazepine derivative was collected (Table 2,
entry 11) and no product was detected in the case of 6-nitroben-
zene-1,2-diamine g (Table 2, entry 12) most likely due to the H-
bonding between imine N–H and o-nitro group.
acetone, Er(OTf)3
solvent
N
a
1a
In the case of o-aminophenol b, the increased nucleophilicity of
the oxygen atom made the evolution of the imine intermediate to-
ward the 1,5-benzoxazepine derivative more difficult. Nonetheless,
o-aminophenol b reacted with acetone, providing modest yield of
products 13b (Table 2, entry 13), whereas electron-rich or –poor
systems did not furnish any cyclic product (Table 2, entry 14). Even
more, the highly nucleophilic sulfur atom made unreactive the imi-
nic reaction intermediate, so that no 1,5-benzothiazepine deriva-
tives were collected in any reported examples of reaction
between ketones and o-aminothiophenol c (Table 2, entry 15).
These reactions (Table 2, entries 14 and 15), in, fact lead to the for-
mation of the corresponding Schiff bases without further cycliza-
tion to form of 1,5-benzoheteroazepine as observed by GC–MS
analysis of the crude reaction mixture.
Taking into account the benign effects that the microwave
assistance exerts on the synthesis of 1,5-benzodiazepines cata-
lyzed by mesoporous MCM-41,8 the developed protocol was also
performed using MW. In such cases, significant improvements in
yield were observed for all reported examples (Table 2).23 Sur-
prisingly, good results were also obtained when the same
MW-assisted reactions were performed in the absence of any
catalyst (Table 2).
Scheme 1. Er(OTf)3 catalyzed reaction of o-phenylendiamine and acetone.
Table 1
Er(OTf)3-catalyzed (5 mol %) reactions of o-phenylenediamine and acetone
Entry
Solvent
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
CH3CN
CH3CNb
AcOEt
CH2Cl2
CHCl3
H2O
3
7
7
7
7
7
3
3
82
84
56
39
30
Trace
98
98
0
Neat
Neatc
Neatd
12
a
b
c
Isolated yield.
10 mol % of catalyst were used.
3 mol % of catalyst were used.
No catalyst was used.
d
acetone catalyzed by Er(OTf)3 (5 mol %) in solvent free conditions
gave the corresponding 2,2,4-trimethyl-2,3-dihydro-1H-1,5-ben-
zodiazepine 1a in almost quantitative yield (Table 1 entry 8),
whereas 98% of product was obtained performing the reaction in
presence of 3 mol % of catalyst only. Finally, in a control reaction
without using the catalyst, no desired product was observed, even
after prolonged reaction time (Table 1, entry 9).
Thus, stir a mixture of o-phenylenediamine a (2 mmol), acetone
(4.5 mmol), and Er(OTf)3 (0.1 mmol) at room temperature for 3 h
was found to be the best condition for the synthesis of 1,5-benzo-
diazepine 1a.23 This general procedure was used for reactions of
o-phenylenediamine a, o-aminophenol b and o-aminothiophenol
c with different aryl- and alkylketones (Scheme 2, Table 2). Reac-
tions of o-phenylenediamine a with acetophenones bearing weak
electron-donating and electron-withdrawing substitution groups
gave products in good to excellent yields (94–98%) (Table 2, entries
22–4). In contrast, only modest yield of the product was registered
when the reaction was performed on the highly electron rich p-
methoxy acetophenone (Table 2, entries 5).
In the attempt to explore the wide applicability of the proposed
method, the experiments involving reaction of a,b-unsaturated ke-
tones (chalcones) and o-anilino derivatives a, b and c were also
carried out (Scheme 3).24,25 However, only modest yield of conden-
sation product 20h was detected from the reaction conducted at
room temperature with 5 mol % of Er(OTf)3 between o-phenylene-
diamine a and (E)-chalcone h, (Table 3, entry 1), probably due to
the low nucleophilicity of the amino group, as described in previ-
ous reports.16 However, the reaction between 2-hydroxylchalcon
i and o-phenylendiamine a gave good yield of 1,5-benzodiazepine
derivative 21i (Table 3, entry 2), thus confirming the crucial posi-
tive effect of the hydroxyl group at 2-position of chalcone.16 Even
better, almost quantitative yield of product 21j was collected when
the reaction was performed on the more electron-rich (E)-1-(2-
hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one j (Table 3,
entry 3).
We have also explored the reactions of o-aminophenol b and
o-aminothiophenol c with chalcone using Er(OTf)3 as a catalyst.
Unfortunately, the reaction of o-aminophenol b with the chalcons
h did not afford any product and the same unsatisfying result was
obtained in the case of more reactive 20-hydroxychalcone deriva-
tives i and j (Table 3, entry 4–6). In contrast, the reaction of simple
chalcone h with o-aminothiophenol c generated fair yield of prod-
uct 26h, whereas, very good results were registered for the more
reactive substrates i and j (Table 3, entries 8 and 9). Confirming
the trend reported for the 1,5-benzodiazepine derivatives. All the
Reactions of alkylketones such as acetone, 2-butanone, 3-penta-
none, and 2,4-pentandione, also produced benzodiazapines(Table 2,
entries 1, 6–8), however, slightly lower yields were obtained from
the more hindered alkylketones (Table 2, entries 6 and 7). Moreover,
4-and 6-methylbenzene-1,2-diamine (d and e) were used as the
substrates to evaluate the substituent effect on o-phenylenedi-
amine. Good product yield (99%) and regioselectivity (85:15 in more
R3
R2
X
N
XH
O
Er(OTf)3
5 mol%
R3
+
CH3CN
R1
R1
R2
CH2 R3
NH2
R2
1-19 a-g
a-g
Scheme 2. 1,5-benzoheteroazipenes from o-phenylendiamines a, d-g, o-aminophenol b and o-aminothiophenol c.

M. Nardi et al. / Tetrahedron Letters 52 (2011) 4827–4834
4829
Table 2
Synthesis of 1,5-benzodiazepines, oxazepines and thiazepine from ketones catalyzed by 5 mol % of Er(III) triflate
Entry
Substrate
Ketone
Producta
Yieldb
H
N
95
1
a
Acetone
99c
99d
N
1a
H
N
98
2
a
Acetophenone
99c
80d
N
2a
H
N
94
3
a
p-Methyl acetophenone
98c
82d
N
3a
NO2
H
N
95
4
a
p-Nitro acetophenone
99c
85d
N
NO2
4a
OMe
H
N
45
5
a
p-Methoxy acetophenone
80c
73d
N
OMe
5a
6a
7a
H
N
80
6
7
a
a
2-Butanone
3-Pentanone
95c
70d
N
H
N
76
83c
65d
N
(continued on next page)

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M. Nardi et al. / Tetrahedron Letters 52 (2011) 4827–4834
Table 2 (continued)
Entry
8
Substrate
Ketone
Producta
Yieldb
H
N
98
a
2,4-Pentandione
99c
99d
N
8a
9d
H
N
99
N
(5.5/4.5)e
99c
9
p-Methyl phenylenediamine (d)
Acetone
(6.5/3.5)e,c
99c(5.9/4.1)e
H
N
N
9dd
10e
H
N
99c
(1.5/8.5)e,c
99c
N
10
o-Methyl phenylenediamine (e)
Acetone
(2.0/8.0)e,c
99d
H
N
(2.5/7.5)e
N
10ee
H
N
O2N
75c
(4.0/6.0c)
75c
N
11f
11
p-Nitro phenylenediamine (f)
Acetone
(3.0/7.0)e,c
75d
H
N
(4.2/5.8)e
O2N
N
11ff
NO2
H
N
0e,c
0c,e
0d,e
N
12g
12
o-Nitro phenylenediamine(g)
Acetone
H
N
N
NO2
12gg
13b
O
45c
55c
46d
13
b
Acetone
N

M. Nardi et al. / Tetrahedron Letters 52 (2011) 4827–4834
4831
Table 2 (continued)
Entry Substrate
Ketone
Producta
Yieldb
X
O
Acetophenone
p-Nitro acetophenone
p-Methoxy acetophenone
0f
14
b
c
c
0c,f
0d,f
N
X
14b: X=H; 15b: X=NO2, 16b: X=OCH3;
S
0f
15
Acetone
0c,f
0d,f
N
17c
X
S
Acetophenone
p-Nitro acetophenone
p-Methoxy acetophenone
0f
16
0c,f
0d,f
N
X
18b: X=H; 19b: X=NO2, 20b: X=OCH3;
All products were characterized by 1H and 13C NMR spectra.26
All products were purified by flash column chromatography.
MW-assisted reaction.
a
b
c
d
e
f
MW-assisted reaction without catalyst.
Product ratio was determined by 1H NMR.
The intermediate Shiff’s base was the only product detected by GC–MS and 1H NMR.
O
R1
X
XH
R2
Er(OTf)
R1
3 5 mol %
CH3CN
+
R2
N
NH2
c
X=O; : X=S.
h-j
a:
b:
X=NH;
20-26 h-j
Scheme 3. Synthesis of benzoheterodiazepines from o-phenylendiamine a, o-aminophenol b and o-aminothiophenol c and chalcones.
attempts to improve the reported results by employing the micro-
wave activation failed and only inextricable mixture of products
was collected.
is proposed to obtain the synthesis of 1,5-benzodiazepines and 1,5-
benzoxazepines through a previously unreported solvent-free
microwave-assisted condensation process.
In summary, Er(OTf)3 was found to be an effective catalyst for
the synthesis of 2,2,4-trisubstituted-1,5-benzoheteroazepines un-
der very mild reaction conditions promoting the reactions of o-
phenylenediamine a and o-aminophenol b with several ketones
and the reaction of chalcone derivatives with o-phenylenediamine
a and o-aminothiophenol c. Moreover, a very eco-friendly protocol
Acknowledgment
Financial support from MIUR PRIN 2008 ‘A Green Approach to
Process Intensification in Organic Synthesis’ is gratefully
acknowledged.

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M. Nardi et al. / Tetrahedron Letters 52 (2011) 4827–4834
Table 3
Synthesis of 1,5-benzodiazepines, oxazepines and thiazepine from chalcones catalyzed by 5 mol % of Er(III) triflate at room temperature
Entry
Substrate
Chalcone
Producta
Yieldb
O
H
N
1
a
20
h
N
20h
OH
O
H
N
2
a
88
i
N
HO
21i
OH
O
OMe
H
N
OMe
3
a
98
j
N
HO
22j
O
4
b
h
0
N
23h
O
5
b
i
0
N
HO
24h

M. Nardi et al. / Tetrahedron Letters 52 (2011) 4827–4834
4833
Table 3 (continued)
Entry
Substrate
Chalcone
Producta
Yieldb
OMe
O
6
b
j
0
N
HO
25j
S
7
c
h
45
N
26h
S
8
c
i
83
N
HO
27i
OMe
S
9
c
j
98
N
28j
HO
a
All products were characterized by 1H and 13C NMR spectra.
All products were purified by flash column chromatography.
b
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NH), 6.88–8.08 (m, 12H, ArH); 13C NMR10; 2-Methyl-2,4-di(4-methoxyphenyl)-
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86–94.
23. General procedure for synthesis of 1,5-benzodiazepines from ketones by
Er(OTf)3: a mixture of o-phenylenediamine (2 mmol) and ketone (4 mmol) was
stirred at room temperature in the presence of Er(OTf)3 (0–5 mol %), adding in
5 ml of MeCN in the case of solid reagents only, for 3 h. After completion of the
reaction (TLC analysis), the reaction mixture was diluted with water, and
extracted with dichloromethane. The combined organic layer was dried
(Na2SO4), and concentrated in vacuo. The crude product was purified by
silica gel column chromatography (15% ethyl acetate in hexane) to afford the
pure product. All reactions were completed within 3 h. All products were
characterized by comparison of their 1H NMR spectra with those of authentic
samples.
24. General procedure for synthesis of 1,5-benzodiazepines from ketones and from
chalcones by microwave: a mixture of o-phenylenediamine (2 mmol), ketone
(2.2 mmol) and 0–5 mol % of Er(OTf)3, suspended in 6.0 ml of MeCN (6.0 ml) in
the case of solid reagents only, was put in the teflon reaction vessel of a
Synthos 3000 microwave synthesizer and the teflon tube tapped and stirred at
120 °C for 30 min under MW radiation (1000 W). The reaction mixture was
diluted with water, and extracted with dichloromethane. The combined
organic layer was dried (Na2SO4), and concentrated in vacuo.
25. General procedure for synthesis of 2,4-disubstituted-1,5-benzoheteroazepine
from calchones: a mixture of o-phenylenediamine (2 mmol) and calchone
2,3-dihydro-1H-1,5-benzodiazepine (7a): green oil2b
; 2,4-Dimethyl-1H-1,5-
benzodiazepine (8a): orange oil; 1H NMR (300 MHz, CDCl3) d 1.83 (s, 3H, CH3),
d 2.10 (s, 3H, CH3), d 3.82 (s br, 1H, NH), d 5.23 (s, 1H), d 6.69–7.36 (m, 4H, ArH);
13C NMR2c; GC/MS: M+ = 172; 2,2,4,8-Tetramethyl-2,3-dihydro-1H-1,5-benzo
diazepine (9dd); 2,2,4,7-Tetramethyl-2,3-dihydro-1H-1,5-benzodi azepine
(9d): brown oil2d
; 2,2,4,9-Tetramethyl-2,3-dihydro-1H-1,5-benz odiazepine
(10e); 2,2,4,6-Tetramethyl-2,3-dihydro-1H-1,5-benzodiazepine (10ee): green
oil, 1H NMR (300 MHz, CDCl3): d 0.93 (t, 3H, CH3), 1.31 (s, 6H, 2CH3), 1.32 (t, 3H,
CH3), 1.33 (s, 6H, 2CH3), 1.81 (d, 1H, CH2), 1.91 (d, 1H, CH2), 2.23 (d, 1H, CH2),
2.29 (d, 1H, CH2), 2.37 (s, 3H, CH3ar), 2.57 (s, 3H, CH3ar), 6.58–6.51 (m, 3H, CHar),
6.87–6.91 (m, 3H, CHar).10C NMR10 GC/MS: M+ = 202; 2,2,4-Trimethyl-8-nitro-
2,3-dihydro-1H-1,5-benzodiazepine (11f); 2,2,4-Trimethyl-7-nitro-2,3-dihy
dro-1H-1,5-benzodiazepine (11ff): orange oil2e; 2,2,4-Trimethyl-2,3-dihydro-
1H-1,4-benzooxazepine (13b): yellow solid; 1H NMR (300 MHz, CDCl3): d 1.65
(s, 3H, CH3), 1.88 (d, 1H, CH2), 2.14 (d, 1H, CH2), 2.64 (s, 6H, 2CH3), 6.08–6.11
(m, 2H, CHar), 6.72–6.80 (m, 2H, CHar).2f 13C NMR2f GC/MS: M+ = 189; 2,4-
diphenyl-2,3-dihydro-1H-1,4-benzodiazepine (20h): yellow solid2n 2-phenyl-
4-(2-hydroxy phenyl)-2,3-dihydro-1H-1,4-benzodiazepine (21i): yellow
solid2e 4-(2-hydroxy phenyl), 2-(4-methoxy phenyl)-2,3-dihydro-1H-1,4-
benzodiazepine (22j): yellow solid2e 2,4-Diphenyl-2,3-dihydro-1H-1,4-
benzothiazepine (26h): yellow solid.2e 2-phenyl-4-(2-hydroxy phenyl)-2,3-
dihydro-1H-1,4-benzothiazepine (27i):2e 4-(2-hydroxy phenyl), 2-(4-methoxy
phenyl)-2,3-dihydro-1H-1,4-benzothiazepine (28j): yellow solid2e