Synthesis, characterization, and X-ray analysis of new N,N′- disubstituted-1,4-diazepanes

Article abstract of DOI:10.1016/j.tetlet.2012.08.094

The synthesis and structural characterization of six 1,4-diazepanes prepared by condensation of 2,2′-(1,3-propanediyldiimino)diphenols with glyoxal or 2,3-butanedione to give bisbenzoxazolidines and subsequent reduction with BH₃-DMS is reported. The new 1,4-diazepanes were obtained in yields between 75% and 83% and characterized by NMR, IR, and HRMS. In addition, the crystal structure analysis showed that the seven-membered ring in 1,4-diazepanes (12a, 12e, and 12d) and bisbenzoxazolidines (11a, 11c, 11f) adopt in all cases twisted chair conformation. Compounds 12a and 12e show disorder in the seven member ring, as a result of the conformational flexibility of the seven-membered ring.

Full text of DOI:10.1016/j.tetlet.2012.08.094

Tetrahedron Letters 53 (2012) 5887–5890
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis, characterization, and X-ray analysis of new
N,N0-disubstituted-1,4-diazepanes
Pedro I. Ramirez-Montes a, María Eugenia Ochoa a, Vianey Rodríguez a, Rosa Santillan a,
,
⇑
Héctor García-Ortega b, Patricia Rodríguez c, Norberto Farfán b
a Departamento de Química, Centro de Investigación y de Estudios Avanzados del IPN, Apdo. Postal 14-740, 07000 México, D.F., Mexico
b Facultad de Química, Departamento de Química Orgánica, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 México, D.F., Mexico
c Universidad Politécnica de Tlaxcala, Av. Universidad Politécnica No. 1, San Pedro Xalcaltzinco, Tepeyanco, Tlax. 90180, Mexico
a r t i c l e i n f o
a b s t r a c t
The synthesis and structural characterization of six 1,4-diazepanes prepared by condensation of 2,20-(1,3-
propanediyldiimino)diphenols with glyoxal or 2,3-butanedione to give bisbenzoxazolidines and subse-
quent reduction with BH3–DMS is reported. The new 1,4-diazepanes were obtained in yields between
75% and 83% and characterized by NMR, IR, and HRMS. In addition, the crystal structure analysis showed
that the seven-membered ring in 1,4-diazepanes (12a, 12e, and 12d) and bisbenzoxazolidines (11a, 11c,
11f) adopt in all cases twisted chair conformation. Compounds 12a and 12e show disorder in the seven
member ring, as a result of the conformational flexibility of the seven-membered ring.
Ó 2012 Elsevier Ltd. All rights reserved.
Article history:
Received 8 August 2012
Revised 20 August 2012
Accepted 21 August 2012
Available online 31 August 2012
Keywords:
Diazepane
(Propanediyldiimino)diphenols
Bisbenzoxazolidine
X-ray
Introduction
piperazines15 (7), bisoxazolidines16 (8), oxazino-oxazines17 (9) and
oxadiazepines18 (10) (Fig. 2).
In the last years the interest in the synthesis of 1,4-diazepanes
has increased due to the fact that they exhibit important
pharmacological activities. In particular, 1,4-diazepane is a build-
ing block used for the construction of fasudil1 (1), tetrazepam2
(2), antibacterial3 (3) and antiamyloidogenic4 (4) agents, dilazep5
(5), and suvorexant6 (6), a potent dual orexin receptor antagonist
(Fig. 1).
In continuation with our studies on condensation reactions, we
describe herein a three step synthesis of 1,4-disubstituted diaze-
panes (13a–f) through the condensation between ethylenediami-
nealcohols (11a–c) and dicarbonylic compounds followed by
stereoselective reduction of the bisbenzoxazolidines to afford
N,N0-disubstituted-1,4-dizepanes.
The wide range of biological activities7 and applications of 1,
4-diazepanes as calcium channel blockers,8 marketed drugs2,3
and herbicides,9 as well as their selectivity for trapping toxic metal
ions10 is responsible for the current interest in the synthesis of
these derivatives. For this reason, different pathways have been
reported, for example, reductive cyclization of N-b-hydroxyethyl-
N-methyl-1,3-propanediamine,11 from diarylpiperidones via
a Schmidt reaction and subsequent reduction,7a aminolysis of
Results and discussion
The reaction between 2 equiv of the o-aminophenol and 1
equivalent of 1,3-dibromopropane was carried out in a sealed tube,
heating in an oil bath at 130 °C for 14 h, to give the corresponding
2,20-(1,3-propanediyldiimino)diphenols 11a–c (Scheme 1), as de-
scribed in the literature.15,19
The bisbenzoxazolidines (12a–f) were obtained in moderate
yields (50–72%), when the reaction between diphenols (11a–c)
and glyoxal or 2,3-butanedione was carried out in a 1:1 molar ratio
under reflux of toluene for 6–8 h (Scheme 1). The structures of
these compounds were confirmed using two-dimensional HETCOR
and COSY NMR experiments and those of 12a, 12c, and 12f were
further established by X-ray analysis.
aziridines with
x-aminoalcohols and subsequent Fukuyama–
Mitsunobu cyclization,12 by microwave-assisted cyclization and
LiAlH4 reduction of cyclic lactams13 and by alkylation of the
nitrogens of homopiperazine,14 among other methodologies.
Using the condensation reaction of aminoalcohols with a-dicar-
bonyl compounds, our research group has reported the synthesis of
Stereoselective reduction of 12a–f with BH3–DMS under reflux
of anhydrous THF for 6 h followed by hydrolysis afforded the
corresponding 1,4-diazepanes 13a–f in yields from 76% to 84%.
⇑
Corresponding author. Tel.: +52 55 57 47 37 25.
E-mail address: rsantill@cinvestav.mx (R. Santillan).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.094

5888
P. I. Ramirez-Montes et al. / Tetrahedron Letters 53 (2012) 5887–5890
Figure 1. 1,4-Diazepane derivatives with important pharmacological activities.
This reaction occurs from the less hindered side to give trans
substituted derivatives 13d–f, as confirmed by X-ray analysis. It
is worth noting that analogous 1,4-diazepanes possess pharmaco-
logical activities.20
12d, 174 for 12e and 12f. The IR spectra showed bands at
m
= ꢀ3056–3000 cmꢁ1 for the aromatic moiety, at
m
= ꢀ1481–
1495 cmꢁ1 and at
m
= ꢀ1244–1222 cmꢁ1 for the C–N–C and the
C–O–C moiety respectively. The structures of bisbenzoxazolidines
12a, 12c and 12f were further confirmed by X-ray analyses (see
Fig. 1 Supplementary data), The structures of compounds 12a,
12c, and 12f consist of two benzoxazolidine cores fused to the se-
ven-membered ring, corresponding to the 1,4-diazepane motif,
showing slightly distorted twisted chair conformations in the solid
The 1H and 13C NMR spectra of the N,N0-propylen-2,20-bisbenz-
oxazolidines (12a–f) show one half of the total number of expected
signals due to the fact that they exhibit C2 symmetry; for these
compounds, the assignment of the aromatic signals was attained
using two dimensional experiments and by comparison with the
data for the analogous N,N0-ethylene-2,20-bisbenzoxazolidines pre-
viously described,15,18 since the chemical shifts remained nearly
unchanged. Evidence for the formation of these bicycles was the
characteristic shift of C2 (CH and C) in the range from 98.1 and
104.9 ppm. The 1H NMR spectra show the signals for the methine
protons at the ring fusion between 5.49 and 5.54 ppm and the dis-
appearance of the signals corresponding to both the amino and hy-
droxyl groups. Formation of the seven-membered ring heterocycle
was confirmed by the doublet of triplets corresponding to the dia-
stereotopic protons of the methylene from 3.52 to 3.67 ppm and
3.16 to 3.24 ppm. In turn, the methylene at position 9 gives a quin-
tuplet at ꢀ2.00 ppm while the methyl signal from the 2,3-butane-
dione fragment (12d–f) appears at ꢀ1.60 ppm. The COSY spectrum
confirmed correlations for the aromatic protons and between the
H-8 and H-9 hydrogens from the seven-membered ring. The
assignment of the aromatic region in the 13C NMR spectrum was
also confirmed by two-dimensional HETCOR experiments.
The mass spectra of 12a–f show peaks for the corresponding
molecular ion at m/z = 280 for 12a, 308 for 12c, 147 for 12b and
3
30
-C2–C20-R
state (Fig. 2 Supplementary data). The dihedral angles sR
= 178.49/172.84/169.71 (12a, 12c, 12f) between the substituents
(Me or H) in positions 2 and 20 of the 1,4-diazepane ring show a
trans arrangement, derived from the stereoselective nature of the
condensation reaction. The N(3)–C(2), N(30)–C(20), N(3)–C(8), and
N(30)–C(80) distances, are not significantly different from the mean
value of Csp3–Nsp3 (1.469(14)) bond distance.21 The N(3)–C(3A)
and N(30)–C(3A0) distances are significantly shorter (1.396(3) for
12a, 1.400(2) for 12c and 1.403(6) for 12f) than the mean value
for a typical Car-Nsp3 (1.426(11)) bond distance. The C(7A)–O(1),
C(7A0)–O(10), O(1)–C(2), O(1)–C(10) distances are not significantly
different from typical Car–O (1.370(11)) y Csp3–O (1.424(12))
values.
As in the case of the precursors, the diazepanes exhibit C2
symmetry and the X-ray structure of 13d and 13e provided evi-
dence for the trans arrangement of the methyl groups at posi-
tions 2 and 3. The structures of the 1,4-diazepanes (13a–f)
were assigned by 1H NMR in comparison with the data described
for analogous derivatives.19 The 1H NMR spectra of 13a–c show a
singlet for the N–CH2–2 group at ꢀ3.21 ppm in comparison with
12a-c which appears around ꢀ5.49–5.57 ppm due to the oxygen
effect in the five-membered ring. The CH2CH2CH2 fragment
shows a quintet for the central methylene in the seven-mem-
bered ring which resonates at 2.10 ppm and the triplet for the
N–CH2-5 group shifted to a higher frequency (ꢀ3.24 ppm), in
comparison with diphenols 11a–c which appears around
ꢀ3.10 ppm. Further evidence for the cleavage of the five-mem-
bered heterocycle is the characteristic low frequency shift of
the methine carbon C-2 (ꢀ64.5 ppm) of 1,4-diazepane 13d–f.
The 1H NMR spectra of 13d–f show the characteristic methine
protons for the AX3 resonating system at ꢀ3.04 ppm and a dou-
blet signal for methyl protons at ꢀ1.17 ppm. The aromatic signals
of the 13C spectra of compounds 13a–f were assigned by compar-
ison with the starting materials and by the use of two-dimen-
sional experiments.
Ph
R
N
OH
N
H
O
H3C
Ph
N
CH3
N
R
O
H
HO
8a: R = -CH2Ph
8b: R = -CH3
7
R1
R1
H
N
R
R
R2
R2
O
N
N
H
H
N
H
O
O
O
O
HO
OH
9
10
The IR spectra for compounds 13a–f show bands at 3000 cmꢁ1
for the aromatic moiety and a broad band at 3300 cmꢁ1 for the
Figure 2. Heterocyclic compounds from aminoalcohols.

P. I. Ramirez-Montes et al. / Tetrahedron Letters 53 (2012) 5887–5890
5889
6
1
R1
OH
R1
2
R2
OH
HO
HN
R1
R2
1) Br-(CH2)3-Br
2) KOH/H2O
5
2
R2
NH
NH2
4
3
11a-c
R1
R2
H
a: H
O
b: CH3
c: H
H
R3
CH3
R3
O
HO
OH R3
3´
7
10
3
6
4´
2´
7a
3a
2
R1
R1
R2
R3
R3
9
R1
O
2
O
R1
1
4 BH3-DMS
4
N
N
R3
6
5
1´
5´
R2
N
N
6´
R2
R2
5
7
4
8
13a-c
13d f
-
12a-c
12d f
-
R1
R2 R3
R3 = CH3
R1
H
R2 R3
R3 = H
a:
b: CH3
c:
H
H
H
H
H
H
d:
H
H
CH3
CH3
e: CH3
H
CH3
f:
H
CH3 CH3
Scheme 1. Synthetic route for the preparation of N,N0-disubstituted-1,4-diazepanes (13).
Figure 3. ORTEP diagram of compounds (a) 13a, (b) 13d and (c) 13e thermal ellipsoids are drawn at 30% probability level for all atoms other than H. Only the principal
position for disordered atoms is shown.
alcohol group. In all cases the mass spectra showed the molecular
ion peaks.
main position, 40% refined occupancy). The structure of compound
13d presented a twist chair conformation as expected.
The crystal structure for 1,4-diazepane derivatives 13a, 13d,
and 13e (Fig. 3), confirmed the formation of a seven-membered
ring with a twist chair conformation, and the trans disposition of
Conclusions
3
30
In this contribution we report a new simple three steps route
for the synthesis of six new 1,4-diazepanes from the reduction of
the corresponding bisbenzoxazolidine with BH3–DMS. Reduction
of the bisbenzoxazolidines proceeds with diastereoselectivity lead-
ing to the trans diastereoisomers. All compounds were character-
ized by spectroscopic methods and in some cases by X-ray
diffraction. The crystal structure analysis of compounds 12f, 13d,
and 13e confirmed the trans arrangement between the
the methyl groups (sR
ꢂ 85.0) in 13d and 13e. The struc-
-C2–C3-R
ture of compound 13a presented disorder in atoms C(2), C(3) and
N(1) with a 70% refined occupancy. The other disordered compo-
nent is a pseudorotation related twist chair in which the pseudo
C2 axis goes through N(4) and crosses N(1A) C(7) bond. The struc-
ture of compound 13e presented disorder in the entire seven mem-
ber ring (the disordered position corresponds to a twist boat
conformation also pseudorotationally related with the twist chair

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P. I. Ramirez-Montes et al. / Tetrahedron Letters 53 (2012) 5887–5890
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seven-membered ring in 1,4-diazepanes and bisbenzoxazolidines
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Acknowledgments
The authors acknowledge financial support from Consejo
Nacional de Ciencia y Tecnología (CONACyT) and PAPIIT IN-
214010. P. I. Ramirez and P. Rodríguez thank CONACyT for granting
scholarships. Thanks are given to I.Q. Geiser Cuéllar for mass
spectra, Q. Teresa Cortés for NMR spectra, and Marco A. Leyva for
determination of X-ray structures.
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Supplementary data
Crystallographic data for the structures reported in this paper
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication nos. CCDC 876686 (12a),
876685 (12c), 876687 (12f), 876936 (13a), 891939 (13d) and
894560 (13e). These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
Supplementary data (general procedures and spectral data)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.08.094. These data include
MOL files and InChiKeys of the most important compounds
described in this article.
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