Microwave-assisted synthesis of 4H-benzo[f]imidazo[1,4]diazepin-6-ones via a post-Ugi copper-catalyzed intramolecular Ullmann coupling

Article abstract of DOI:10.1016/j.tetlet.2014.02.023

An efficient post-Ugi copper-catalyzed intramolecular Ullmann coupling strategy has been elaborated for the diversity-oriented synthesis of 4H-benzo[f]imidazo[1,4]diazepin-6-ones and the scope and limitations of this protocol are investigated.

Full text of DOI:10.1016/j.tetlet.2014.02.023

Tetrahedron Letters 55 (2014) 2070–2074
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted synthesis of 4H-benzo[f]imidazo[1,4]diazepin-6-
ones via a post-Ugi copper-catalyzed intramolecular Ullmann
coupling
Zhenghua Li a, Laetitia Legras a, Amit Kumar a,b, Dipak D. Vachhani a, Sunil K. Sharma b,
Virinder S. Parmar b, Erik V. Van der Eycken a,
⇑
a Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001 Leuven, Belgium
b Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient post-Ugi copper-catalyzed intramolecular Ullmann coupling strategy has been elaborated for
the diversity-oriented synthesis of 4H-benzo[f]imidazo[1,4]diazepin-6-ones and the scope and limita-
tions of this protocol are investigated.
Received 13 January 2014
Revised 6 February 2014
Accepted 10 February 2014
Available online 21 February 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Synthetic methods
Multicomponent reactions
Microwave-assisted synthesis
Imidazobenzodiazepinones
Copper
Introduction
In recent years, the combination of multicomponent reactions9
with transition metal-catalysis10 has become one of the most
The 4H-benzo[f]imidazo[1,4]diazepin-6-one scaffold is widely
important tools for diversity-oriented synthesis of complex mole-
cules in few steps.11 Interested in improving the synthetic method-
ology for 4H-benzo[f]imidazo[1,4]diazepin-6-ones, we recently
developed a novel efficient diversity-oriented post-Ugi/gold(I)-cat-
alyzed heteroannulation process for the synthesis of imi-
dazo[1,4]diazepin-7-ones12 (Scheme 1). However, the absence of
a fused aryl ring system in the imidazo[1,4]diazepin-7-one scaffold
decreases the structural resemblance with commercially available
imidazobenzodiazepinone drugs (Fig. 1), and the employment of
an expensive gold catalyst restricts its industrial scope.
present in various natural products and pharmaceuticals1 (Fig. 1)
exhibiting potent biological activities on the c-aminobutyric acid
type A (GABAA) receptors.2 The commercially available flumazenil,
a high-affinity GABAA-BZ site antagonist, has been used to treat
benzodiazepine intoxication,3 as well as to improve cognitive func-
tion in Alzheimer’s patients.4 On the other hand, sarmazenil and
bretazenil have been served as the partial agonist for GABAA recep-
tors to rapidly re-awaken anaethetized animals5 and treat organo-
phosphate poisoning,6 respectively.
The classically used strategy7 for the synthesis of 4H-
benzo[f]imidazo[1,4]diazepin-6-one derivatives starts from the
reaction of isatoic anhydride with a suitable amino acid, generating
benzo[e][1,4]diazepine-2,5-diones, which upon treatment with
ethyl isocyanoacetate, under strongly basic conditions, produces
the corresponding 4H-benzo[f]imidazo[1,4]diazepin-6-ones. Some
improvements of this approach have been reported.8 However,
these methods suffer from harsh reaction conditions and are
restricted in the scope of the substitution pattern.
Therefore, the development of a powerful and efficient strategy
to prepare 4H-benzo[f]imidazo[1,4]diazepin-6-ones is still
desirable. Due to unique advantages like dramatical acceleration
of transformations, increased yields, and cleaner reactions,
O
O
Cl
Br
O
F
N
N
N
N
O
N
O
H
N
O
N
N
O
N
O
O
Flumazenil
Bretazenil
Sarmazenil
⇑
Corresponding author. Tel.: +32 16 327406.
E-mail address: erik.vandereycken@chem.kuleuven.be (E.V. Van der Eycken).
Figure 1. Drugs possessing the 4H-benzo[f]imidazo[1,4]diazepin-6-one scaffold.
http://dx.doi.org/10.1016/j.tetlet.2014.02.023
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

Z. Li et al. / Tetrahedron Letters 55 (2014) 2070–2074
2071
(Table 1, entries 1 and 2). When changing the solvent to DMSO,
the yield was increased to 78% (Table 1, entry 3). Reduction of
the reaction temperature to 80 °C led to a lower yield of 40%
(Table 1, entry 4). Employing various copper salts such as CuBr,
CuCl, Cu(OAc)2, and Cu(OTf)2, no improvement of the yield was ob-
served (Table 1, entries 5–8). Moreover, using another base such as
potassium carbonate or sodium carbonate did not increase the
yield (Table 1, entries 9 and 10). The application of L-proline and
(R,R)-(ꢀ)-N,N0-dimethyl-1,2-cyclohexanediamine as ligand deliv-
ered the desired product in lower yields of 65% and 60%, respec-
tively (Table 1, entries 11 and 12). Diminishing the catalyst
loading to 5 mol % resulted in a decreased yield of 45% (Table 1,
entry 13). Using 20 mol % of CuI, a slightly lower yield of 6a was
observed (Table 1, entry 14).
To investigate the scope and limitations of our optimized proto-
col (Table 1, entry 3), diversely substituted Ugi-adducts 5b–r were
prepared and subjected to these conditions. Mostly the intramolec-
ular Ullmann coupling proceeded smoothly giving 4H-benzo[f]imi-
dazo[1,4]diazepin-6-ones 6 in moderate to good yields. Various
substituents on the aromatic ring of the acid and the amine are
well tolerated. Surprisingly, in the case of C-2 or C-5 substituted
imidazole-4-carbaldehyde, decomposition of the starting material
was observed (Table 2, entries 14 and 15). Moreover, the
imidazole-2-carbaldehyde was employed for the formation of
Ugi-adducts 5p, 5q, and 5r, which were subjected to intramolecu-
lar Ullmann coupling delivering the corresponding products 6p, 6q,
and 6r in 85%, 76%, and 69% yields, respectively (Table 2, entries
16–18).
Scheme 1. Comparison of this work with our previous work.
microwave-assisted organic synthesis has served as a powerful
tool for the generation of medium-sized heterocycles.13 In contin-
uation of our efforts to synthesize bioactive important heterocyclic
compounds, we developed a microwave-assisted post-Ugi copper-
catalyzed intramolecular Ullmann coupling approach for the syn-
thesis of 4H-benzo[f]imidazo[1,4]diazepin-6-ones (Scheme 1).
Results and discussion
Based on previous investigations of Ullmann coupling,14
a
The Ugi-adduct 5a was synthesized via the Ugi-4CR (Ugi four-
component reaction)9 of imidazole-4-carbaldehyde (1a), p-
methoxybenzylamine (2a), 2-iodobenzoic acid (3a), and tert-butyl
isonitrile (4a) in 69% yield. This was chosen as a model substrate to
optimize the reaction for the intramolecular Ullmann coupling un-
der microwave irradiation. The reaction produced 4H-benzo[f]imi-
dazo[1,4]diazepin-6-one 6a in 26% and 34% yields employing
10 mol % of CuI at 100 °C for 30 min in DMF or DMA, respectively
plausible mechanism for this copper(I)-catalyzed intramolecular
reaction is depicted in Scheme 2. The coordination of copper(I) io-
dine with the amine of the Ugi-adduct 5a produces the intermedi-
ate A. The Cu(I) inserts into the aryl iodine bond delivering
intermediate B. Finally, reductive elimination leads to the regener-
ation of the copper(I) catalyst and the formation of the
4H-benzo[f]imidazo[1,4]diazepin-6-one 6a.
Table 1
Optimization of the intramolecular Ullmann coupling reactiona
O
N
N
PMB
O
O
PMB
O
O
PMB
H2N
I
N
Conditions
Microwave
N
N
H
MeOH, r.t
48h, 69%
2a
1a
3a
+
I
NC
HN
HN
N
5a
N
6a
COOH
N
H
4a
Entry
Catalyst (mol %)
Base
Solvent
Temp (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuBr (10)
CuCl (10)
Cu(OAc)2 (10)
Cu(OTf)2 (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (5)
Cs2CO3
DMF
DMA
100
100
100
80
26
34
78
40
50
42
60
52
61
55
65c
60d
45
73
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
100
100
100
100
100
100
100
100
100
100
CuI (20)
a
All the reactions were run on 0.10 mmol scale of Ugi adduct 5a with base (2 equiv), solvent (1 mL) under microwave irradiation at 100 or 80 °C and 100 W maximum
power for 30 min.
b
Yields are isolated yields.
20 mol % of L-proline was used.
c
d
20 mol % of (R,R)-(ꢀ)-N,N0-dimethyl-1,2-cyclohexanediamine was used; Tf = trifluoromethanesulfonyl, PMB = p-methoxybenzyl.

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Z. Li et al. / Tetrahedron Letters 55 (2014) 2070–2074
Table 2
Scope and limitations of the intramolecular Ullmann couplinga
Entry Ugi adduct 5 (% yieldb)
4H-Benzo[f]imidazo[1,4]diazepin-6-ones Entry Ugi adduct 5 (% yieldb)
6 (% yieldb)
4H-Benzo[f]imidazo[1,4]diazepin-6-ones
6 (% yieldb)
O
O
O
O
O
O
O
O
I
I
1
2
3
4
5
7
N
O
HN
N
N
O
N
HN
N
N
HN
HN
O
O
N
N
N
N
5g, 46%
6g, 60%
6a
, 78%
5a, 69%
N
H
N
H
O
O
O
O
O
I
O
O
O
O
O
I
8
N
N
O
N
O
N
N
O
N
O
HN
HN
HN
HN
N
N
N
N
6h, 56%
6b
, 64%
5h
N
H
N
H
, 53%
5b, 75%
O
O
O
O
O
O
I
O
I
O
O
O
O
O
N
N
O
N
O
9
N
O
N
N
O
F
HN
HN
HN
HN
N
N
N
N
F
6i, 70%
N
H
5c, 86%
5i, 86%
N
H
6c, 65%
O
O
O
O
I
O
N
N
O
N
O
O
I
N
O
10
N
O
F
HN
HN
N
N
HN
HN
N
N
6d, 66%
N
H
5d
, 34%
F
6j
N
, 70%
N
H
O
5j
, 69%
O
O
O
O
I
O
O
O
O
O
I
N
N
O
11
N
O
N
O
N
O
HN
HN
HN
HN
N
N
N
N
Cl
Cl
6k
, 74%
N
6e
, 68%
N 5k
N
H
, 30%
5e, 55%
H
O
O
O
O
O
O
I
O
O
O
O
I
N
N
O
N
O
6
12
N
HN
N
HN
O
HN
HN
O
N
N
Cl
N
Cl
N
6f
, 72%
5l, 67%
6l
, 74%
N
H
5f
, 58%
N
H
N
O
O
O
O
O
O
O
O
O
O
I
I
N
N
O
13
16
N
O
N
O
N
O
HN
N
Cl
HN
HN
HN
N
Cl
HN
N
N
N
6m, 60%
6p
, 85%
5p
N
H
, 36%
5m, 58%

Z. Li et al. / Tetrahedron Letters 55 (2014) 2070–2074
2073
Table 2 (continued)
Entry Ugi adduct 5 (% yieldb)
4H-Benzo[f]imidazo[1,4]diazepin-6-ones Entry Ugi adduct 5 (% yieldb)
6 (% yieldb)
4H-Benzo[f]imidazo[1,4]diazepin-6-ones
6 (% yieldb)
O
O
O
O
O
O
O
I
O
O
O
O
I
O
14
17
N
O
N
N
O
HN
6nc
N
O
N
O
HN
HN
HN
N
N
HN
N
N
N
5q
, 71%
6q
N
, 76%
5n,69%
H
O
O
O
O
O
O
O
I
O
I
15
18
N
N
O
N
O
N
HN
O
N
HN
O
HN
HN
N
N
HN
N
N
6oc
N
5o, 47%
5r, 59%
N
H
6r, 69%
a
b
c
Reactions were run on a 0.30 mmol scale under the optimized conditions (Table 1, entry 3).
Isolated yields.
The starting material was decomposed.
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.02.023.
O
I
PMB
PMB
O
N
O
N
N
O
HN
5a
N
References and notes
HN
N
N
H
6a
CuI
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O
O
PMB
O
PMB
N
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N
O
I
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HN
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CuN
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I
A
B
N
Scheme 2. Plausible mechanism for the intramolecular Ullmann coupling.
Conclusion
In conclusion, we have developed an expedient copper-cata-
lyzed, diversity-oriented intramolecular Ullmann coupling strategy
to prepare 4H-benzo[f]imidazo[1,4]diazepin-6-ones from commer-
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Acknowledgments
The authors are thankful to the Research Fund of the University of
Leuven (K.U. Leuven) for financial support. Z.L. appreciates the CSC
(China Scholarship Council) for providing a doctoral scholarship.
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