Tandem one pot synthesis of 1,5-benzodiazocine-2-one by isocyanide based Ugi multicomponent reaction

Article abstract of DOI:10.1016/j.tetlet.2012.05.013

We have developed an efficient one-pot, two-step reaction protocol for the synthesis of eight-membered 1,5-benzodiazocine-2-ones by Ugi four-center three-component coupling reaction (U-4C-3CR) and subsequent reductive cyclization using Fe/NH₄Cl

Full text of DOI:10.1016/j.tetlet.2012.05.013

Tetrahedron Letters 53 (2012) 3619–3622
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Tetrahedron Letters
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Tandem one pot synthesis of 1,5-benzodiazocine-2-one by isocyanide based
Ugi multicomponent reaction
⇑
Goutam Kulsi, Abhijit Ghorai, Partha Chattopadhyay
Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed an efficient one-pot, two-step reaction protocol for the synthesis of eight-membered
1,5-benzodiazocine-2-ones by Ugi four-center three-component coupling reaction (U-4C-3CR) and sub-
sequent reductive cyclization using Fe/NH4Cl in protic solvent.
Received 29 February 2012
Revised 30 April 2012
Accepted 3 May 2012
Available online 11 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Ugi reaction
IMCR
Benzodiazocine
Fe/NH4Cl
Heterocycles
Benzofused cyclic molecules play important roles in both drug
discovery and chemical biology.1 In particular, seven and eight
membered heterocycles like azocines and diazocines are constitu-
ents of a number of compounds with interesting pharmacological
properties.2,3 Benzodiazocines containing two nitrogen atoms are
present in various biologically active molecules possessing
antihypertensive,4a herbicidal,4b anti-depressant,4c analgesic,4d
antitussive,4e and anthelmintic4e activities. Moreover, 1,5-ben-
zodiazocines have attracted much interest as homologs of 1,4-ben-
zodiazepine drugs5 and inhibitors of 17-b hydroxysteroid
dehydrogenase type 3.6 However, medium sized heterocycles, that
is eight or higher membered rings are difficult to prepare due to
enthalpic and entropic reasons and transannular interaction.7 In
continuation of our interest in developing expeditious routes to
various heterocyclic molecules, we therefore undertook a study to
establish a convenient synthetic route to such molecules Scheme 1.
Generating a remarkably high degree of molecular complexity
in just one step is among the most challenging objectives in mod-
ern organic synthesis. In this context, multicomponent reactions
(MCRs)8 are very relevant because they are extremely convergent,
leading to the formation of multiple bonds with a high bond form-
ing efficiency (BFE).9 While the classical versions of Ugi10 and
Passerini11 reactions lead to acyclic adducts, we realized that inter-
esting heterocyclic structures may be accessed by their intramolec-
ular variants or by coupling the isocyanide based multi component
reaction (IMCR)12 with a subsequent secondary transformation,
taking advantage of additional functionalities suitably placed on
one or two of the components.
Transition metals have also been used for catalyzing transforma-
tions in tandem9,13 processes in an attempt to construct biologically
active heterocyclic compounds and significant progress has been
made in this regard. Cropper et al.14 tried to construct the eight-
membered benzolactam ring using intramolecular Pd-catalyzed
aryl amidation reaction, but tandem C–N/C–O bond forming reac-
tion occurred instead, furnishing novel spiro benzofuran lactams.
Recently we reported15 the synthesis of chiral 1,5-benzodiazocine
derivatives by Pd catalyzed intramolecular aryl amination reaction
using different sugar derived amines. Buchwald and co-workers16
have reported an interesting approach toward the synthesis of
benzofused medium ring heterocycles by aryl amidation followed
by b-lactam ring opening reaction. However, the possibility of an
easy access to b-lactams17 via Ugi four-center three-component
coupling reaction (U-4C-3CR) encouraged us to construct an inter-
mediate that can provide the 1,5-benzodiazocine skeleton by
reductive cyclization accompanied by nucleophilic substitution to
open the b-lactam ring. We noted that Andreana and co-workers18
have synthesized 1,4-benzodiazepinone derivatives employing Ugi
reaction and aza-Michael cyclization using Fe/NH4Cl in ethanol as
reducing agent under microwave condition. In this Letter we report
an efficient one-pot two-step reaction protocol utilizing Ugi three-
component reaction and reductive cyclization using Fe/NH4Cl, an
environmentally benign reagent, to furnish the highly substituted
benzofused eight-membered heterocycles Table 1.
In this tandem reaction, the first step is a Ugi multicomponent
reaction carried out using different isocyanides, aromatic nitro
⇑
Corresponding author. Tel.: +91 33 2499 5834; fax: +91 33 24735197.
E-mail address: partha@iicb.res.in (P. Chattopadhyay).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.013

3620
G. Kulsi et al. / Tetrahedron Letters 53 (2012) 3619–3622
R2
R2
O
HN
O
HN
H
NH2
N
CHO
NO2
N
(i)
(ii)
R1
R2 N C
R1
R1
O
NO2
N
H
5 a-h
COOH
O
1
(
)
2
3
(
)
4
a-h
4e/5e, R1 = H,
R2 = tert-Butyl
4a/5a, R1 = 4, 5-OMe, R2 = Cyclohexyl
4b/5b, R1 = 4, 5-OMe, R2 = tert-Butyl
4c/5c, R1 = 4, 5-OMe, R2 = iso-Propyl
4f/5f, R1 = H,
R2 = iso-Propyl
4g/5g, R1 = 5-Cl, R2 = Cyclohexyl
4h/5h, R1 = 4-CF3, R2 = Cyclohexyl
4d/5d R1 = H,
R2 = Cyclohexyl
Scheme 1. Reagents and conditions, (i) EtOH/H2O (2:1), rt; (ii) Fe/NH4Cl, EtOH/H2O (2:1), 85–100 °C.
Table 1
Optimization experiments for b-lactam ring opening reaction
Entry
Substrate
Reagent
Solvent
Temperature (°C)
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
4a
4a
4a
4a
4b
4d
4h
Fe/NH4Cl
Fe/NH4Cl
Fe/NH4Cl
In/NH4Cl
In/NH4Cl
Fe/NH4Cl
In/NH4Cl
CH3CN/H2O
EtOH/H2O
MeOH/H2O
EtOH/H2O
MeOH/H2O
CH3CN/H2O
EtOH/H2O
90
100
85
100
85
16
15
16
18
20
20
18
5a
5a
5a
5a
5b
5d
5h
70
81
71
68
62
58
74
90
100
Table 2
Synthesis of 1,5-benzodiazocine-2-one using b-alanine as amino acid
Entry
Nitro aldehyde
Isocyanide
Product
Overall yield (%)
O
O
HN
O
O
H
1
81
N
C
NH
O
O
NO2
HN
(5a)
O
O
HN
O
NH
O
O
2
75
O
O
H
N
C
NO2
HN
HN
(5b)
O
O
HN
O
O
O
NH
O
O
3
72
H
N
C
NO2
(5c)
O
O
O
HN
H
4
76
N
C
NH
NO2
HN
(5d)
O

G. Kulsi et al. / Tetrahedron Letters 53 (2012) 3619–3622
3621
Table 2 (continued)
Entry Nitro aldehyde
Isocyanide
Product
Overall yield (%)
O
O
HN
N
C
H
NH
5
66
NO2
HN
(5e)
O
O
HN
O
NH
N
C
H
6
61
NO2
HN
O
(5f)
O
O
HN
Cl
H
H
7
73
N
N
C
C
N
Cl
NO2
HN
(5g)
O
O
O
HN
H
H
8
88
N
F3C
NO2
F3C
HN
(5h)
O
aldehydes, and b-alanine to furnish well established b-lactam
products. Among the isocyanides tested o-tolyl and 2-naphthyl
isocyanides gave only poor yield and were excluded from further
studies which were carried out using the three aliphatic isocyanides
(i.e., cyclohexyl, tert-butyl, and iso-propyl). We further planned to
reduce the nitro group in the lactam products to aromatic amine
in the hope that this group would make a nucleophilic attack on
the lactam carbonyl to open the lactam ring. Although p-nitro aro-
matic aldehydes have been employed for the synthesis of b-lactams
by Ugi reaction, we used the o-nitro isomers to access the eight-
membered heterocyclic ring. Among various reagents and solvents
tried to reduce the aromatic nitro group, Zn, or Sn in CH3COOH
afforded the aromatic amine but cyclization did not occur. We then
came across a publication wherein a six-membered heterocycle
(an oxazine) has been synthesized19 employing In/NH4Cl in etha-
nol–water medium for reduction and subsequent b-lactam ring
opening reaction. We therefore decided to use this and also the re-
lated two-electron reducing agent Fe(0) with NH4Cl in aqueous
medium due to its mild acidic nature and also high functional group
tolerance.20 To our satisfaction, reduction and also cyclization took
place rapidly, furnishing medium ring heterocycles. An electron
withdrawing group present in the aromatic nitro aldehyde was
expected to enhance the rate of both the steps of the reaction. In-
deed, the trifluoro methyl substituted nitro aldehyde produced
1,5-benzodiazocine-2-one 5h in very good yield (88%).21 The some
what higher yield obtained using cyclohexyl isocyanide (Table 2,
entry 1 vs 2, 3; 4 vs 5, 6) may be ascribed to the smaller steric size.
In conclusion, we have developed an efficient one-pot, two-step
reaction protocol for the synthesis of eight-membered 1,5-ben-
zodiazocine-2-one from readily available aromatic nitro aldehydes
1, b-alanine 2 and isocyanides 3 by Ugi MCR. Using protic solvent
and the two electron reducing agent Fe(0)/NH4Cl for the reductive
cyclization step, these biologically relevant small molecules can be
prepared efficiently. Experiments are in progress in our laboratory
to effect aryl amination followed by b-lactam ring opening reaction
using bromo lactams instead of nitro lactams 4 to get 1,5-ben-
zodiazocine-2-one derivatives.
Acknowledgments
We thank the CSIR (New Delhi) for funding research project
(NWP 0005) and providing research fellowship to G.K. and A.G.
We thank Dr. B. Achari, formerly of IICB, and Professor B. Dinda
of Tripura Central University for their helpful suggestion and
support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
05.013.
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room temperature for half an hour. The isocyanide (1.0 mmol, 1.0 equiv) was
added to the previous solution and the resulting mixture was stirred at room
temperature for 20 h, when the reaction appeared complete by TLC (CH2Cl2/
MeOH 98:2), Fe powder (1 mmol) and solid NH4Cl (8–10 equiv.) were added.
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a crude product. This was purified by column
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an eluent, when 5a was isolated as a light yellow solid. Compound 5a: Yield:
81%, mp 202–204 °C, IR (KBr) m ;
max = 1517, 1666, 2928, 3073, 3349, 3443 cmÀ1
1H NMR (CDCl3, 600 MHz): dH = 0.08–0.16 (m, 3H), 1.25 (s, 1H), 1.31–1.37 (m,
2H), 1.57–1.59 (m, 1H), 1.65–1.70 (m, 2H), 1.85–1.89 (m, 2H), 2.81–2.85 (m,
1H), 2.98–3.02 (m, 1H), 3.16–3.19 (m, 1H), 3.68–3.70 (m, 1H), 3.77 (s, 3H), 3.83
(s, 3H), 5.40 (s, 1H), 6.07–6.15 (m, 1H), 6.30 (s, 1H), 6.70 (s, 1H) ppm; 13C NMR
(CDCl3, 150 MHz) dC = 22.6 (2CH2), 24.6 (CH2), 32.6 (CH2), 32.7 (CH2), 36.1
(CH2), 38.9 (CH2), 48.6 (CH), 55.0 (CH), 55.7 (CH3), 56.5 (CH3), 101.1 (CH), 111.1
(C), 112.0 (CH), 139.3 (C), 142.0 (C), 150.1 (C), 168.0 (C), 168.8 (C) ppm; MS
(ESI): m/z = 384 [M+Na]+. Anal. Calcd for C19H27N3O4: C, 63.14; H, 7.53; N,
11.63. Found: C, 63.27; H, 7.61; N, 11.52.
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