Synthesis of 1,4-diazepin-5-ones under microwave irradiation and their reduction products

Article abstract of DOI:10.1016/j.tetlet.2007.02.021

A new efficient access to 1,4-diazepane derivatives is described via a microwave assisted synthesis of 7-substituted-1,4-diazepin-5-ones, which proceeds rapidly in good yields. Catalytic reduction gave 1,4-diazepan-5-ones and 1,4-diazepanes whereas a ring

Full text of DOI:10.1016/j.tetlet.2007.02.021

Tetrahedron Letters 48 (2007) 2583–2586
Synthesis of 1,4-diazepin-5-ones under microwave irradiation
and their reduction products
´
Nicolas Wlodarczyk, Pauline Gilleron, Regis Millet, Raymond Houssin
*
´
and Jean-Pierre Henichart
Institut de Chimie Pharmaceutique Albert Lespagnol, EA 2692, IFR 114, Universite´ de Lille 2, BP 83,
3 rue du Professeur Laguesse, 59006 Lille, France
Received 22 December 2006; revised 1 February 2007; accepted 5 February 2007
Available online 9 February 2007
Abstract—A new efficient access to 1,4-diazepane derivatives is described via a microwave assisted synthesis of 7-substituted-1,4-di-
azepin-5-ones, which proceeds rapidly in good yields. Catalytic reduction gave 1,4-diazepan-5-ones and 1,4-diazepanes whereas a
ring opening was observed by hydride reduction when a phenyl group occupies the N-benzylic position.
Ó 2007 Elsevier Ltd. All rights reserved.
Small peptides often exhibit in vitro pharmacological
activity but their lack of oral bioavailability prevents
them from being used as drugs. Special attention has
been given to replace peptidic moieties by rigid residues,
such as heterocyclic rings or constrained peptidomimet-
ics, with the aim to mimic their bioactive conformation
and therefore to confer an in vivo activity. Seven-mem-
bered rings like benzodiazepine are very attractive com-
pounds and a large number of strategies have used this
heterocycle to develop original compounds. For exam-
ple, benzodiazepines were introduced in the design of
(i) anticonvulsant or anxiolytic hypnotic agents; (ii)
farnesyltransferase inhibitors or (iii) CCK2 ligands.1
R2
N
R2
N
R2
N
R2
7
R
R
R
O
H
HN
O
γ
R
N
N
N
N
O
O
R1
R1
R1
R1
A
B
C
Figure 1. Analogy between a hydrogen bond in a c-turn and the seven-
member rings such as 1,4-diazepane derivatives A–C.
ring. Here we report the synthesis of the substituted 1,4-
diazepanes C and of their precursors, 1,4-diazepin-5-
ones A and 1,4-diazepan-5-ones B.
We focussed our attention on particularly attractive
templates to develop new anticancer agents, that is,
the 7-substituted-2,3,4,5-tetrahydro-1,4-diazepin-5-ones
A, 7-substituted-1,4-diazepan-5-ones B and full-reduced
7-substituted-1,4-diazepanes C (Fig. 1). These hetero-
cycles can be considered as dipeptidomimetics by
rigidification of an intramolecular hydrogen bond in a
c-turn.2 Moreover, they represent an alternative to the
classical benzodiazepine scaffold.
In the course of our investigations in the diazepane
series, we wished to consider a versatile and efficient
approach leading easily to diazepanes bearing an aryl or
an alkyl substituent on C-7. According to these consider-
ations, we defined the synthetic route outlined in Scheme
1. The first step of the synthesis was the cyclization of
various b-ketoesters 1a–h (b-ketoesters 1e–h were pre-
pared according to a previously reported method,3
whereas b-ketoesters 1a–d were commercially available)
with ethylenediamine 2 to give 2,3,4,5-tetrahydro-1,4-di-
azepin-5-ones 3a–h, using a modification of a described
procedure:4 the two reactants were heated at reflux in
xylene for 8 h to achieve azeotropic removal of water and
ethanol. Yields and LC/MS analysis provided evidence
for the formation of various by-products, which resulted
from several side reactions depending on the reaction
conditions (Scheme 2). For example, condensation of
To the best of our knowledge, no efficient synthesis
describes the way to obtain the saturated 1,4-diazepane
Keywords: 1,4-Diazepin-5-one; 1,4-Diazepane; Ethanediamine; Micro-
wave irradiation.
*
Corresponding author. Tel.: +333 2096 4374; fax: +333 2096 4906;
e-mail: jean-pierre.henichart@univ-lille2.fr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.021

2584
N. Wlodarczyk et al. / Tetrahedron Letters 48 (2007) 2583–2586
R
N
N
H
3'a-h
O
X
H
H
R
O
R
R
N
N
H2N
7
a
b
90%
OEt
6
+
32-60%
N
N
H
O
H2N
H
O
O
1a-h
2
3a-h
4a-h
Boc
Boc
Boc
R
R
R
H
N
N
N
c
95%
d
+
when 5a-f
N
N
N
H
H
H
O
5a-h
6a-f
7a-c
a
b
R = C6H5
R = 4(MeO)-C6H4
c
d
R = 4(CF3)-C6H4
R = Me
g
h
R = 1-naphtyl
R = 4(Br)-C6H4
e
f
R =
R =
n
i-Bu
-Bu
Scheme 1. Reagents and conditions: (a) (1) xylene, reflux, 8 h or (2) xylene, microwave irradiation, 10 min; (b) H2, 50 bars, 10% Pd/C, MeOH, 60 °C,
24 h; (c) (Boc)2O, DIEA, dioxane/water (4:1), rt, 48 h; (d) LiAlH4, THF, rt, 24 h.
O
H
N
N
N
OEt
O
R
R
N
O
R
NH2
NH2
EtO
O
OEt
O
II
I
+
O
H
N
NH2
N
OEt
R
R
N
H
OEt
O
IV
III
Scheme 2. By-products observed after reaction of a b-ketoester with ethylenediamine.
ethylenediamine with ethyl benzoylacetate 1a gave
mainly 2,3,4,5-tetrahydro-1,4-diazepin-5-one 3a at 40%
yield whereas ethyl acetoacetate 1d gave 2,3,4,5-tetra-
hydro-1,4-diazepin-5-one 3d and bis(iminoester) I (R =
Me) at 32% and 30% yields, respectively. These results
illustrate the difficulty to establish the adequate
experimental conditions to selectively obtain the target
products.
the corresponding non-conjugated system of imino-
lactams (30a–h).
The application of microwave dielectric heating for con-
ducting organic reactions is an emerging technique
which constitutes a good technique for any reaction
where water and/or alcohol are formed7 and often leads
to better yields and cleaner products. In an attempt to
increase the rate of cyclization into diazepinones 3a–h,
the reaction was carried out in a flask equipped with a
Dean–Stark apparatus under microwave irradiation.8
Replacement of thermal heating by microwave irradia-
tion (Table 1, method B) significantly shortened reaction
time and improved the yields (47–60%) in each run of
experiments.
Other works5 on similar compounds stated that the rate
of formation of by-products depend on parameters such
as pH, reaction time and solvent.
We found xylene as the best solvent for limiting forma-
tion of imidazolidinone II, imidazolidine III and imine
IV. Basic conditions (pyridine, alcoholic potassium
hydroxide) have also been explored6 but did not allowed
here to upgrade the yield of 3a from 1a, whereas an
acidic medium increased the yield of imidazolidine III.
The better conditions to obtain 2,3,4,5-tetrahydro-1,4-
diazepin-5-ones 3a–h were azeotropic distillation in neu-
tral medium (Table 1, method A). In addition, analysis
1,4-Diazepan-5-ones 5a–h were next obtained accord-
ing to a two-step procedure by catalytic reduction
of the ethylenic bond of diazepinones 3a–h, followed
by protection of the amine group as carbamate (Scheme
1).
1
of the H NMR spectra assigned to 3a–h the structure
Conjugation of the ethylenic group with the lactam
function and/or without a 7-phenyl substituent de-
of conjugated enaminolactams rather than the one of

N. Wlodarczyk et al. / Tetrahedron Letters 48 (2007) 2583–2586
2585
Table 1. Comparative yields for synthesis of the 2,3,4,5-tetrahydro-
1,4-diazepin-5-ones 3a–h under thermal and microwave conditions
Table 2. Reduction of 1,4-diazepan-5-ones 5a–f with LiAlH4
Boc
N
Boc
N
Boc
HN
Compound
R
Method Aa
Yield (%)
Method Bb
Yield (%)
R
R
R
LiAlH4 (2 eq), THF
+
3a
3b
3c
40
39
36
60
58
55
N
H
N
N
H
H
O
5a-f
6a-f
7a-c
O
Entry
R
6
7
Yield (%)
Yield (%)
CF3
a
b
20
13
O
CH3
3d
3e
32
35
47
48
18
22
10
7
CF3
c
3f
38
41
54
57
CH3
d
e
f
55
51
57
0
0
0
3g
Br
3h
40
55
a Method A: xylene, thermal heating, azeotropic distillation, 8 h.
b Method B: xylene, microwave irradiation (300 W), azeotropic distil-
lation, 10 min.
rolidine,13 or may be compared with the classical cata-
lytic hydrogenolysis of N-benzylamines.
In conclusion, a straightforward method for the
synthesis of 2,3,4,5-tetrahydro-1,4-diazepin-5-ones was
optimized using microwave irradiation, which offers
several advantages including good yields, short reaction
time and limited formation of by-products. The corre-
sponding 1,4-diazepan-5-ones were easily obtained by
catalytic hydrogenation and their reduction with LiAlH4
gave 1,4-diazepanes. This reduction led to an unex-
pected ring opening when an aryl substituent is present
on the vicinal carbon of the carbamate-protected amine,
thus limiting the yields of diazepanes.
creased its reactivity towards reduction and required
harsher conditions than the ones usually adopted
(hydrogen pressure: 50 bars, 60 °C, 24 h, 10% Pd/C).
The N-protection reaction was carried out in almost
quantitative yields (>95%) by using di-tert-butyl
dicarbonate and N,N-diisopropylethylamine. Reduction
of 1,4-diazepan-5-ones 5a–f into 1,4-diazepanes, that
represent potential building units in peptidic drug
design, was thoroughly examined. Treatment with
metal hydrides such as boron derivatives (BH3–THF,
BH3ÆMe2S) or with a mixture of monochloroalane
(AlH2Cl) and dichloroalane (AlHCl2), prepared in situ
from LiAlH4 and AlCl3,9 resulted only in a decarbamo-
ylation of the starting materials.
Acknowledgements
We gratefully acknowledge the financial support of the
Ligue Nationale contre le Cancer (to J.-P.H.) and Dr.
Surprisingly, the reduction of compound 5a carried out
with LiAlH4 (2 equiv) was not chemoselective (Table 2)
and performed an unexpected ring opening10 that was
not observed on 1-tert-butoxycarbonyl-2-phenylpiperi-
din-3-one11 or on a 3-amino-1-tert-butoxycarbonyl-2-
phenylpiperidine (in CP-99,994, NaBH4 as hydride).12
Chromatographic and LC/MS analysis indicated that
reduction (into diazepane 6a) and hydrogenolysis (into
ethanediamine 7a) occurred simultaneously whereas a
complete conversion of lactams 5a–c into amines 7a–c
was effective when the stoichiometry of LiAlH4 rose to
4 equiv. Furthermore, a comparative study of this reac-
tion done with 7-aryl and 7-alkyl 1,4-diazepan-5-ones
(5b,c and 5d–f, respectively) showed the exclusive occur-
rence of a ring opening when a phenyl ring was present
(5a), whatever the electronic influence of its substituent
(4-methoxy for 5b, 4-trifluoromethyl for 5c); this reactiv-
ity is reminiscent of the lithium reductive opening of
nitrogen-containing heterocycles, such as 2-phenylpyr-
`
N. Lebegue for help with microwave experiments.
References and notes
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LiAlH4 (Table 2, entry a): 1,4-Diazepan-5-one 5a (5 g,
17 mmol) was diluted in anhydrous THF (200 mL) before
LiAlH4 (2.6 g, 34 mmol) was added slowly at 0 °C. After
stirring for 24 h at room temperature, the reaction was
quenched by adding water dropwise (15 mL) at 0 °C, then
10% aqueous sodium hydroxide (100 mL). The precipitate
was filtered off and the filtrate was concentrated. The
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´
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1-tert-Butoxycarbonyl-7-phenyl-1,4-diazepane (6a): Rf =
0.62 (CH2Cl2–MeOH 9/1). m = 0.95 g (20% yield). IR
(neat): 1697 (CO). 1H NMR (300 MHz, CDCl3): 1.50
(s, 9H, CH3), 1.85–1.89 (m, 1H, CHCH2CH2NH), 2.03–
2.12 (m, 1H, CHCH2CH2NH), 2.13 (m, 1H, NH), 2.82–
2.95 (m, 1H, CHCH2CH2NH), 3.13–3.19 (m, 1H,
CHCH2CH2NH), 3.36–3.75 (m, 5H, CH2CH2N(Boc)CH),
7.21–7.45 (m, 5H, ar). 13C NMR (75 MHz, CDCl3): 29.4
(CH3), 38.4 (CHCH2CH2NH), 44.8 (CH2NBoc), 49.6
(CH2NHCH2), 65.1 (CH), 125.8 (ar). MS (APCI+)
m/z = 277 (MH+).
1-tert-Butoxycarbonyl-2-(3-phenylpropyl)ethane-1,2-diamine
(7a): Rf = 0.40 (CH2Cl2–MeOH 9/1). m = 0.60 g (13%
yield). IR (neat): 1697 (CO). 1H NMR (300 MHz, CDCl3):
1.45 (s, 9H, CH3), 1.79–1.84 (m, 3H, CH2CH2CH2NH),
2.62–2.72 (m, 6H, CH2CH2CH2NHCH2), 3.21–3.23 (m,
2H, CH2NHBoc), 5.07 (m, 1H, NHBoc), 7.18–7.27 (m,
5H, ar). 13C NMR (75 MHz, CDCl3): 28.4 (CH3), 31.6
(CH2CH2CH2), 33.6 (CH2ar), 40.2 (CH2NHBoc), 49.0
(CH2NHCH2), 125.8 (ar), 128.4 (ar). MS (APCI+)
m/z = 279 (MH+).
8. General microwave irradiation procedure for the prepara-
tion of 1,4-diazepin-5-ones 3a–h (Table 1, Method B):
7-Phenyl-2,3,4,5-tetrahydro-1,4-diazepin-5-one (3a): The
reaction was carried out at atmospheric pressure in an
open microwave oven (CEM DiscoverÒ) along with a
built-in magnetic stirrer. A long-neck quartz vessel was
used equipped with an external azeotropic Dean–Stark
apparatus. Ethylenediamine (4.7 g, 78 mmol) was added
to ethyl benzoylacetate (15 g, 78 mmol) in dry xylene
(50 mL). The mixture was heated at 135 °C while stirring
under microwave irradiation (300 W) for 10 min. After
cooling to room temperature, the reaction mixture was
concentrated under vacuum. The product was washed
with diethyl ether and filtered (8.8 g, 60% yield). Rf = 0.25
(CH2Cl2–MeOH 9/1). Mp 206 °C [lit.4 mp 207–209 °C].
IR (neat): 1626 (CO), 1550 (CN). 1H NMR (300 MHz,
CDCl3): 3.49–3.53 (m, 2H, CH2NH), 3.64–3.68 (m,
2H, CH2NHCO), 4.91 (m, 1H, NH), 5.00 (s, 1H, CH),
11. Kise, N.; Ohya, K.; Arimoto, K.; Yamashita, Y.; Hirano,
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