Divergent regioselective synthesis of 2,5,6,7-tetrahydro-1 H -1,4-diazepin-2-ones and 5 H -1,4-benzodiazepines

Article abstract of DOI:10.1021/jo201497r

A novel and simple one-pot synthesis of 3-substituted 2,5,6,7-tetrahydro- 1H-1,4-diazepin-2-ones from 1,2-diaza-1,3-dienes (DDs) and N-unsubstituted aliphatic 1,3-diamines is described. Here we also report a procedure to selectively obtain alkyl 5H-1,4-be

Full text of DOI:10.1021/jo201497r

ARTICLE
pubs.acs.org/joc
Divergent Regioselective Synthesis of 2,5,6,7-Tetrahydro-1H-1,
4-diazepin-2-ones and 5H-1,4-Benzodiazepines
Orazio A. Attanasi, Lucia De Crescentini,* Gianfranco Favi, Fabio Mantellini, and Simona Nicolini
Istituto di Chimica Organica, Universitꢀa degli Studi di Urbino “Carlo Bo”, Via I Maggetti 24, 61029 Urbino, Italy
S Supporting Information
b
ABSTRACT: A novel and simple one-pot synthesis of 3-substituted 2,5,6,7-tetrahydro-
1H-1,4-diazepin-2-ones from 1,2-diaza-1,3-dienes (DDs) and N-unsubstituted aliphatic
1,3-diamines is described. Here we also report a procedure to selectively obtain alkyl 5H-
1,4-benzodiazepine-3-carboxylates from the DDs and 2-aminobenzylamine. Both
processes occur by means of sequential 1,4-conjugated addition followed by regiose-
lective 7-exo cyclization. The behavior of N-methyl- and N,N0-dimethyl-1,3-diamino-
propanes toward the DDs furnished pyrazol-3-ones and bis-α-aminohydrazones,
respectively.
’ INTRODUCTION
1,2-Diaza-1,3-dienes24 (DDs) are versatile intermediates and
react with a wide range of nucleophiles at its highly electrophilic
center (at C-4),25 leading to a wide variety of heterocyclic
rings.24,26In particular, we went back to our previous investiga-
tions on the reaction of DDs 1 with 1,2-diamines to obtain
1,2,5,6-tetrahydro-2-pyrazinones I27 or pyrazines II,27 depending
from the conditions used, and with 1,3-diamines (in the molar
ratio 2:1) that furnished the corresponding bis-α-aminohydra-
zones III,28 respectively (Scheme 1).
On the basis of these experiences, and in continuation of our
ongoing interest in the discovery of reactions for the synthesis of
new heterocycles from azo-ene systems, we have designed a novel
method for the preparation of 1,4-diazepin-2-ones A and/or 1,4-
diazepines B fromDDs 1 and 1,3-diamines 2 in the molar ratio 1:1
(Scheme 2). Our analysis of the seven-membered heterocyclic
core emphasizes strategic disconnections along the C(2)ꢀN(1)
and C(3)ꢀN(4) bonds. This reveals two subunits that trace the
lower-half to the pertinent diamines 2, and the upper half to the
α,β-dications C and D, that further can be correlated to the
4-alkoxycarbonyl azoene system of the DDs 1. The high electro-
philicity at the carbon terminus of the heterodiene system25
permits the formation of C(3)ꢀN(4) junction in A and in B,
by means of a 1,4-Michael-type addition with one of the nitrogens
in diamine 2.
The exploration of privileged structures in drug discovery has
gained increasing interest and relevance.1 Among the small
molecules employed in this field, molecular scaffolds that mimic
peptide secondary structures are particularly useful for the identi-
fication and development of therapeutic agents.1,2 For example,
1,4-benzodiazepine is a privileged scaffold or fragment that has
been studied extensively and frequently appeared in the biologi-
cally active molecules and drugs.3 In particular, a large number of
1,4-benzodiazepines act as anxiolytic, antidepressant, anticonvul-
sant, and antihypnotic agents4 and some of them exhibit antitumor
activity.5
The seven-membered 1,4-diazepin-2-one ring mimics β- and
γ-turn secondary structures6ꢀ8 and exhibits anticonvulsant
activity,9 antibacterial activity against multidrug-resistant Myco-
bacterium tubercolosis strains,10 antitumor properties,11 and lym-
phocytefunction-associated antigen-1 (LFA-1) antagonists.12 For
these reasons, the development of new strategies for the synthesis
of 1,4-diazepin-2-ones is ever evolving.
The most reported synthetic approaches to 1,4-benzodiaze-
pine skeletons include reaction of 2-aminobenzoic acids and their
derivatives or 2-aminobenzophenones with α-amino acids,13
cyclocondensation of 2-halobenzoic acid derivatives or 2-halo-
benzophenones with diamines,14 and PictetꢀSpengler reaction of
N,N0-dimethyl-N-phenyl-1,2-ethanediamine with aldehydes.15
The diazepinone ring is reported in the literature to be
prepared from linear precursors by intramolecular reductive
amination,8,16ꢀ18 lactam formation,19ꢀ21 and transamidation.22
Also, the preparation of 1,4-diazepin-2-ones involves iminopho-
sphorane intermediates by means of intramolecular aza-Wittig
reaction or hydrolysis of the iminophosphoranes to the corre-
sponding amino derivatives followed by intramolecular
cyclocondensation.23 The limit of these procedures is that they
involve some preparative difficulties and require several steps.
At this point, two different C(2)ꢀN(1) junctions can be
obtained by means of a subsequent intramolecular 7-exo cycliza-
tion of the second nitrogen of the diamine that can occur on the
carboxylic function of C, giving 1,4-diazepin-2-ones A, or on the
hydrazonic function of E, furnishing 1,2-diazepines B, respectively.
To the best of our knowledge, only one example29 for the
synthesis of 1,4-diazepin-2-ones was reported in literature, using
Received: July 19, 2011
Published: September 09, 2011
r
2011 American Chemical Society
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this disconnection approach. In 1969, in fact, McDougal and
Malik attempted to prepare simple 1,4-diazepine starting from
glyoxal sodium hydrogen sulfite and 2,4-diaminopentane; instead
they obtained cis-dimethylhexahydro-1,4-diazepin-2-one.29 The
authors tried unsuccessfully to enlarge the scope of this metho-
dology by using both 1,3-diamines and 1,2-dicarbonyl or α-
halogen carbonyl derivatives. The same method was then used
by Knapp et al.30 starting from the same glyoxal derivative with N,
N-dimethylpropane-1,3-diamine, obtaining the expected 1,4-di-
methyl-1,4-diazepan-2-one but in very poor yield while employing
harsh reaction conditions. Thus, the reaction had limited scope.
On the other hand, only relatively few methods are reported for
the synthesis of 1,4-diazepines, starting from diamine derivatives
and bis-electrophiles, and often they are unsatisfctory.29,31
in diethyl ether (Scheme 3). To avoid the formation of bis-α-
aminohydrazones,31 we carried out the reaction in equimolar
ratio and by adding reagents 1 to 2.
Under these conditions, the disappearance of the typical red
color of the starting DDs indicated the completion of the reaction
rapidly (1 min), and TLC revealed one as major spot. The
products were isolated as solids, simply by partial evaporation of
the reaction solvent, and identified to be the α-aminohydrazones
3aꢀd (Scheme 3, path a, Table 1). As compounds 3 are not very
stable in solution, their spectroscopic NMR analyses must be
done promptly. Their formation takes place by means of an aza-
Michael addition by one of the two nitrogens in 2aꢀc to the
terminus carbon of the azo-ene system of the DDs 1.
When DDs 1aꢀf were allowed to react with the same aliphatic
1,3-diamines 2aꢀc in 1:1 molar ratio, in ethanol rather than in
diethyl ether, we directly obtained the expected 3-substituted
2,5,6,7-tetrahydro-1H-1,4-diazepin-2-ones 4aꢀo, which precipi-
tated out from the reaction medium with satisfactory yields
(48ꢀ67%) (Scheme 3, path b, Table 2).
’ RESULTS AND DISCUSSION
Therefore, with the aim to synthesize 1,4-diazepin-2-ones
or 1,4-diazepines, initially we explored the reaction of DDs
1aꢀc32 with aliphatic 1,3-diamines 2aꢀc at room temperature
Scheme 3. Synthesis of α-Aminohydrazones 3aꢀd and of
3-Substituted 2,5,6,7-Tetrahydro-1H-1,4-diazepin-2-ones
4aꢀo
Scheme 1. Reactivity of 1,2-Diaza-1,3-dienes 1 with 1,2-
Diamines A and with 1,3-Diamines B (in the molar ratio 1:2)
Scheme 2. Retrosynthetic Strategy for the Preparation of 1,4-Diazepin-2-ones A or 1,4-Diazepines B
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Table 1. Synthesis of α-Aminohydrazones 3aꢀd
Scheme 4. Synthesis of α-Aminohydrazones 3eꢀh and of
Alkyl 5H-1,4-Benzodiazepine-3-carboxylates 5aꢀd
1,2-diaza-1,3-dienes 1
1,3-diamines 2
products 3
entry
1
R1
R2
R3
2
R4 R5
3
yield (%)a
1
2
3
4
1a
Et
Ot-Bu
Me 2a
H
H
3a 90
3b 100
3c 98
3d 90
1b Me NHPh Me 2a
H
H
1c
1c
Me Ot-Bu
Me Ot-Bu
Me 2b
Me 2c
H
Me
Me
Me
a Yield of pure isolated products 3 based on DDs 1.
Table 2. One-Pot Synthesis of 3-Substituted 2,5,6,7-Tetra-
hydro-1H-1,4-diazepin-2-ones 4aꢀo
1,2-diaza-1,3-dienes 1
1,3-diamines 2
products 4
entry
1
R1 R2 R3
2
R4 R5 4 time (h) yield (%)a
1
2
3
4
5
6
7
8
9
1a Et Ot-Bu Me 2a
1b Me NHPh Me 2a
H
H
H
H
H
H
4a 3.0
4b 2.5
4c 2.0
4d 2.0
4e 2.5
58
48
44
57
48
63
62
40
57
61
63
62
42
54
65
Table 3. Synthesis of α-Aminohydrazones 3eꢀh and Alkyl
5H-1,4-Benzodiazepine-3-carboxylates 5aꢀd
H
H
H
H
H
H
H
H
H
1d Me OBn
1e Me NH2
1f Me NH2
Me 2a
Me 2a
Et 2a
1,2-diaza-1,3-dienes 1
products 3
products 5
entry
1
R1
R3
3
yields (%)a
5
time (h) yields (%)b
1b Me NHPh Me 2b
1c Me Ot-Bu Me 2b
Me 4f 4.0
Me 4g 4.0
Me 4h 4.0
Me 4i 6.0
Me 4j 2.0
1
2
3
4
1a
1c
1g
1h
Et
Me 3e
Me 3f
72
96
95
66
5a
5b
5c
5d
4.0
5.0
4.0
3.0
47
53
62
71
1d Me OBn
1e Me NH2
Me 2b
Me 2b
Et 2b
Me
Me
i-Pr
Et
3g
10 1f Me NH2
Me 3h
11 1b Me NHPh Me 2c Me Me 4k 3.0
12 1c Me Ot-Bu Me 2c Me Me 4l 2.5
a Yield of pure isolated products 3 based on DDs 1. b Yield of pure
isolated products 5 based on α-aminohydrazones 3.
13 1d Me OBn
14 1e Me NH2
15 1f Me NH2
a Yield of isolated pure product 4 based on DD 1.
Me 2c Me Me 4m 8.0
Me 2c Me Me 4n 1.0
Et 2c Me Me 4o 4.0
from DDs and 1,2-diamines,27 there is a good agreement in the
diagnostic signals both at 1H and 13C NMR.
In order to obtain the 1,4-benzodiazepine core, we examined
the reaction of DDs 1a,c,g,h and 2-aminobenzylamine 2d, in 1:1
molar ratio. The best conditions we found involved the use of
1-tert-butoxycarbonyl-DDs in ethyl acetate at room temperature,
obtaining the corresponding α-aminohydrazones 3eꢀh in good
to excellent yields (66ꢀ96%) simply by precipitation from the
reaction medium (Scheme 4, Table 3).
Compounds 3 are formed by means of an aza-Michael
addition of the more nucleophilic benzylic nitrogen of the
diamine 2d at the terminus carbon of the azo-ene system of
DDs 1. Compounds 3eꢀh in toluene under reflux were con-
verted into the corresponding alkyl 5H-1,4-benzodiazepine-3-
carboxylates 5aꢀd in satisfactory yields (47ꢀ71%) (Scheme 4,
Table 3). Their formation involves a regioselective ring closure
by the anilinic nitrogen on the hydrazonic function and the
subsequent spontaneous loss of tert-butyl carbazate moiety.
The peculiar regioselectivity observed in the ring closure
process of these reactions depends on the differential nucleophi-
licity of the involved nitrogen atoms in aliphatic (2aꢀc) or
aromatic (2d) 1,3-diamines, respectively, together with the
diverse nucleophilic affinity of ester and hydrazone groups. Also
the different strain of monocyclic 1,4-diazepin-2-ones 4 com-
pared with that of bicyclic 1,4-benzodiazepines 5 could play an
important role.
In this case, the initial 1,4-addition of the amino group in 1,3-
diamines 2aꢀc takes place at the terminus carbon of the
heterodiene DDs 1aꢀf to form hydrazones 3, followed by
regioselective nucleophilic attack of the second amino group at
the ester function, with the loss of an alcohol molecule. Then
spontaneous oxidation of the CꢀN bond furnishes 2,5,6,7-
tetrahydro-1H-1,4-diazepin-2-ones 4aꢀo. The role of the air in
this process was confirmed, performing the same reaction under
inert atmosphere: in fact, under these conditions, no products 4
were detected, but we obtained complicated reaction mixtures.
Probably, the presence of three conjugated double bonds confers
stability to these compounds 4. It should be noted that synthesis
of these interesting molecules are limited in the literature.33 All
attempts to convert α-aminohydrazones 3aꢀd into the corre-
sponding 4 failed, giving complicated reaction mixtures, and this
is ascribed to the poor stability of compounds 3 in solution.
The 7-exo cyclization has been confirmed by comparing the 1H
chemical shifts of the hydrogens bound to the nitrogens involved
in this process. In particular, the amine NH2 in the 1,4-adducts 3
show a chemical shift at ∼2.20 ppm; on the contrary, the amide
NH in the diazepinone derivatives 4 is at 8.19ꢀ8.65 ppm. Also,
the multiplicity of this diagnosticsignal in the latter thatappears as
a triplet confirms unequivocally that the nitrogen responsible for
the ring closure process derives from the starting reagents 2. With
respect to the analogous six-membered compounds obtained
Then, we studied the behavior of N-monosubstituted 1,3-
diamine toward DDs. When the reactions between DDs 1a,b,g,i
and N-methyl-1,3-diaminopropane 2e were carried out in
dichloromethane at room temperature, in a 1:1 molar ratio,
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Scheme 5. Synthesis of 4-[(3-Aminopropyl)-
(methyl)amino]-1H-pyrazol-3-ones 6aꢀd and Bis-α-amino-
hydrazones 7a,b
Figure 1. NOE experiments on compound 6a.
often recur in organic, biological and medicinal chemistry and
they have been applied also in the analytical and agricultural
fields.34
Then we extended this study to the reactions of N,N0-
dimethyl-1,3-diaminopropane 2f with DDs 1a,b. We explored
several conditions without much success, except when carried
out in acetonitrile at room temperature, in a 2:1 molar ratio: bis-
α-aminohydrazones 7a,b were obtained in 5 min, in very good
yields (Scheme 5, Table 4).31
Under conditions employed for the formation of 2,5,6,7-
tetrahydro-1H-1,4-diazepin-2-ones 4, the reactions of DDs with
diamines 2e,f furnished complicated reaction mixtures.
Table 4. Synthesis of 4-[(3-Aminopropyl)(methyl)amino]-
1H-pyrazol-3-ones 6aꢀd and Bis-α-aminohydrazones 7a,b
’ CONCLUSION
1,2-diaza-1,3-dienes 1 1,3-diamines 2 products 6 products 7
In summary, we have reported novel regioselective syntheses
of 2,5,6,7-tetrahydro-1H-1,4-diazepin-2-ones and alkyl 5H-1,4-
benzodiazepine-3-carboxylates, starting from DDs and aliphatic
as well as aromatic 1,3-diamines, respectively. Also, the reactivity
of N-unsubstituted, N-mono-, or N,N0-disubstituted 1,3-dia-
mines were compared in the transformation process, that gave
2,5,6,7-tetrahydro-1H-1,4-diazepin-2-ones and 5H-1,4-benzo-
diazepines, 4-[(3-aminopropyl)(methyl)amino]-1H-pyrazol-3-
ones, and bis-α-aminohydrazones, respectively.
Therefore, the utility of the described syntheses to obtain
interesting heterocyclic scaffolds, together with mild and simple
reaction conditions (no dry solvents or inert atmosphere) makes
them well suitable for the generation of combinatorial libraries
that might be useful in the chemical biology research.
time yield
(h) (%)a
7
yield
(%)b
entry
1
R1
R2
R3
2
R6 R7
6
1
2
3
4
5
6
1a Et Ot-Bu Me 2e
1b Me NHPh Me 2e
1g Me Ot-Bu Et 2e
1i Et OMe Me 2e
H
H
H
H
Me 6a 0.1 54
Me 6b 0.2 50
Me 6c 0.1 91
Me 6d 0.1 60
1a Et Ot-Bu Me 2f Me Me
7a 98
7b 98
1b Me NHPh Me 2f Me Me
a Yield of pure isolated products 6 based on DDs 1. b Yield of pure
isolated products 7 based on DDs 1.
pyrazol-3-ones 6aꢀd were obtained as sole products in good to
excellent yields (Scheme 5, Table 4).
’ EXPERIMENTAL SECTION
The mechanism for the formation of pyrazol-3-one ring
provides the preliminary formation of nonisolable α-aminohy-
drazones that can occur by the 1,4-addition of the more
nucleophilic secondary nitrogen or of the less nucleophilic
NH2 of diamine 2e. The subsequent intramolecular nucleophilic
attack of the hydrazonic nitrogen atom on the ester group with
loss of an alcohol molecule and tautomerism can furnish
structures I or II of pyrazolone ring, respectively (Figure 1).24
The exact structure of pyrazol-3-ones 6 was determined by
NOE experiments on compound 6a, chosen as example, that
showed considerable NOE enhancement of NꢀCH3 at 2.52
ppm by irradiation of CH3 at 2.16 ppm and vice versa: this
evidence suggests the proximity of these two groups, in agree-
ment with 4-[(3-aminopropyl)(methyl)amino]-1H-pyrazol-3-
ones of structure I (Figure 1) obtained by the initial nucleophilic
attack of the secondary nitrogen. Hence, in this case, the lack of
the hydrogen bound to the tertiary nitrogen derived from the
diamine 2e probably drives the different regioselectivity of the
ring closure to pyrazol-3-ones, preventing the formation of the
CdN bond. Pyrazoles are molecules of interest because they
General Remarks. All the commercially available reagents and
solvents were used without further purification. 1,2-Diaza-1,3-dienes
1aꢀi were synthesized as a mixture of E/Z isomers as previously
reported.32 Chromatographic purification of compounds was carried
out on silica gel (60ꢀ200 μm). TLC analysis was performed on
preloaded (0.25 mm) glass-supported silica gel plates (Kieselgel 60);
compounds were visualized by exposure to UV light and by dipping the
plates in 1% Ce(SO4) 4H2O, 2.5% (NH4)6Mo7O24 4H2O in 10%
3
3
sulfuric acid followed by heating on a hot plate. All 1H NMR and 13
C
NMR spectra were recorded at 400 and 100.56 MHz, respectively.
Proton and carbon spectra were referenced internally to solvent signals,
using values of δ = 2.50 ppm for proton (middle peak) and δ = 39.50
ppm for carbon (middle peak) in DMSO-d6 and δ = 7.27 ppm for
proton and δ = 77.00 ppm for carbon (middle peak) in CDCl3. The
following abbreviations are used to describe peak patterns where
appropriate: s = singlet, d = doublet, t = triplet, dd = double doublet,
dt = double triplet, q = quartet, qi = quintet, sex = sextet, sept = septet, m
= multiplet, and br = broad signal. All coupling constants (J) are given in
hertz. FT-IR spectra were obtained as Nujol mulls. Mass spectra were
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The Journal of Organic Chemistry
ARTICLE
recorded in the EI (70 eV) or ESI mode. Melting points were
determined in open capillary tubes and are uncorrected.
3H), 1.52 (s, 9H), 1.78 (s, 3H), 2.27 (br s, 1H), 3.71 and 3.79
(AB-system, J = 12.0 Hz, 2H), 4.12 (s, 1H), 4.18ꢀ4.25 (m, 2H), 4.52
(br s, 2H), 6.64ꢀ6.69 (m, 2H), 7.01 (d, J = 7.2 Hz, 1H), 7.08 (t, J = 7.2
Hz, 1H), 7.51 (s, 1H). 13C NMR (CDCl3): δ = 12.3 (q), 14.1 (q), 20.2
(q), 50.4 (t), 61.4 (t), 67.0 (d), 81.2 (s), 115.6 (d), 117.7 (d), 123.0 (s),
General Procedure for the Synthesis of α-Aminohydrazones 3aꢀh.
To a solution of aliphatic 1,3-diamines 2aꢀc (1.0 mmol) in diethyl ether
(2 mL) or 2-aminobenzylamine 2d (1.0 mmol) in ethyl acetate (2 mL)
magnetically stirred at room temperature, a solution of 1,2-diaza-1,3-
dienes 1aꢀc,g,h (1.0 mmol) in diethyl ether (3 mL) in the case of
aliphatic 1,3-diamines 2aꢀc or ethyl acetate (3 mL) in the case of
2-aminobenzylamine 2d was added. At the disappearance of the red
color of 1aꢀc,g,h that occurred within 1 min, products 3aꢀd were
crystallized by partial evaporation of the solvent under reduced pressure,
while products 3eꢀh directly crystallized from the reaction solvent.
Compounds 3 are not very stable in solution, and in some cases, it is
difficult to record 13C NMR spectra. Spectroscopic data for α-aminohy-
drazones 3aꢀd are given below.
128.5 (d), 130.3 (d), 146.5 (s), 147.2 (s), 152.3 (s), 170.7 (s). IR: νmax
=
3475, 3378, 3138, 1749, 1726, 1618 cmꢀ1. MS: m/z (%) = 364 [M+] (1),
258 (3), 232 (19), 202 (12), 188 (8), 159 (40), 143 (17), 130 (50), 121
(65), 106 (100). Anal. calcd for C18H28N4O4: C, 59.32; H, 7.74; N,
15.37. Found: C, 59.28; H, 7.79; N, 15.19.
tert-Butyl 2-{2-[(2-Aminobenzyl)amino]-3-methoxy-1-methyl-3-
oxopropylidene}hydrazinecarboxylate (3f). White powder from ethyl
acetate; mp 120ꢀ2 °C. 1H NMR (DMSO-d6): δ = 1.44 (s, 9H), 1.78
(s, 3H), 2.59 (br s, 1H), 3.49 and 3.55 (AB-system, J = 12.4 Hz, 2H),
3.65 (s, 3H), 5.13 (s, 1H), 4.50 (br s, 2H), 6.48 (t, J = 7.6 Hz, 1H), 6.62
(d, J = 7.6 Hz, 1H), 6.92ꢀ6.98 (m, 2H), 9.65 (s, 1H). 13C NMR
(DMSO-d6): δ = 13.4 (q), 28.1 (q), 48.8 (t), 52.0 (q), 66.3 (d), 79.3 (s),
114.7 (d), 115.8. (d), 122.3 (s), 127.9 (d), 129.7 (d), 147.3 (s), 147.4
(s), 152.9 (s), 171.4 (s). IR: νmax = 3496, 3372, 3149, 1749, 1738,
1624 cmꢀ1. MS: m/z (%) = 350 [M+] (3), 322 (4), 256 (6), 218 (25),
188 (18), 174 (14), 159 (31), 144 (19), 130 (63), 121 (93), 106 (100).
Anal. calcd for C17H26N4O4: C, 58.27; H, 7.48; N, 15.99. Found: C,
58.33; H, 7.65; N, 15.73.
tert-Butyl 2-{2-[(3-Aminopropyl)amino]-3-ethoxy-1-methyl-3-oxo-
propylidene}hydrazinecarboxylate (3a). White powder from diethyl
ether; mp 140ꢀ2 °C. 1H NMR (DMSO-d6): δ = 1.15 (t, J = 7.2 Hz, 3H),
1.41 (s, 9H), 1.47ꢀ1.50 (m, 2H), 1.73 (s, 3H), 2.25 (br s, 2H),
2.31ꢀ2.48 (m, 4H), 3.30 (s, 1H), 3.81 (s, 1H), 4.09 (dq, J = 7.2 Hz, J
= 2.4 Hz, 2H), 9.56 (s, 1H). 13C NMR (DMSO-d6): δ = 12.8 (q), 14.0
(q), 28.1 (q), 29.6 (t), 45.3 (t), 45.4 (t), 60.5 (t), 67.5 (d), 79.2 (s), 149.7
(s), 152.9 (s), 170.9 (s). IR: νmax = 3229, 1744, 1732, 1712, 1678 cmꢀ1
.
MS: m/z (%) = 316 [M+] (12), 298 (12), 286 (6), 272 (16), 260 (49),
236 (45), 216 (100), 204 (84), 185 (54), 172 (60), 155 (76), 143 (52),
130 (70), 111 (52). Anal. calcd for C14H28N4O4: C, 53.15; H, 8.92; N,
17.71. Found: C, 53.28; H, 8.79; N, 17.91.
Methyl N-(2-Aminobenzyl)-3-[(tert-butoxycarbonyl)hydrazono]norvali-
1
nate (3g). White powder from ethyl acetate; mp 84ꢀ6 °C. H NMR
(CDCl3): δ = 1.02 (t, J = 7.6 Hz, 3H), 1.50 (s, 9H), 1.74 (br s, 1H),
2.18ꢀ2.24 (m, 2H), 3.64ꢀ3.78 (m 2H), 3.72 (s, 3H), 4.05 (s, 1H), 4.53
(br s, 2H), 6.60ꢀ6.66 (m, 2H), 6.97ꢀ7.06 (m, 2H), 7.90 (s, 1H). 13C
NMR (CDCl3): δ = 9.3 (q), 20.1 (t), 28.1 (q), 50.3 (t), 52.1 (q), 65.2
(d), 81.2 (s), 115.6 (d), 117.6 (d), 122.7 (s), 128.5 (d), 130.1 (d), 146.4
(s), 151.4 (s), 152.5 (s), 171.5 (s). IR: νmax = 3440, 3338, 3223, 1744,
1726, 1624 cmꢀ1. MS: m/z (%) = 364 [M+] (1), 233 (13), 202 (17), 188
(14), 173 (16), 158 (14), 144 (9), 130 (23), 121 (83), 106 (100). Anal.
calcd for C18H28N4O4: C, 59.32; H, 7.74; N, 15.37. Found: C, 59.42; H,
7.89; N, 15.23.
Methyl 2-[(3-Aminopropyl)amino]-3-[(anilinocarbonyl)hydrazono]-
butanoate (3b). White powder from diethyl ether; mp 110ꢀ2 °C. 1H
NMR (DMSO-d6): δ = 1.54ꢀ1.59 (m, 2H), 1.83 (s, 3H), 2.46ꢀ2.57
(m, 4H), 2.65ꢀ2.70 (m, 2H), 3.66 (s, 3H), 3.67 (s, 1H), 4.05 (s, 1H),
6.99 (t, J = 7.2 Hz, 1H), 7.28 (t, J = 7.6 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H),
8.73 (s, 1H), 9.68 (br s, 1H). 13C NMR (DMSO-d6): δ = 13.1 (q), 29.5
(t), 45.3 (t), 45.4 (t), 51.9 (q), 67.1 (d), 119.2 (d), 122.3 (d), 128.5 (d),
138.9 (s), 146.8 (s), 153.2 (s), 171.5 (s). IR: νmax = 3372, 3194, 1745,
1693 cmꢀ1. MS: m/z (%) = 321 [M+] (1), 264 (7), 185 (7), 176 (63),
165 (11), 149 (18), 136 (24), 119 (100), 111 (40). Anal. calcd for
C15H23N5O3: C, 56.06; H, 7.21; N, 21.79. Found: C, 56.28; H, 7.19;
N, 21.91.
tert-Butyl 2-{2-[(3-Amino-2-methylpropyl)amino]-3-methoxy-1-
methyl-3-oxopropylidene}hydrazinecarboxylate (3c). White powder
from diethyl ether; mp 111ꢀ3 °C. 1H NMR (DMSO-d6):
δ = 0.80ꢀ0.83 (m, 3H), 1.38ꢀ1.40 (m, 1H), 1.44 (s, 9H), 1.76 (s,
3H), 2.18ꢀ2.47 (m, 6H), 3.63 (s, 3H), 3.85 (br s, 1H), 3.86 (s, 1H), 9.62
(br s, 1H). 13C NMR (DMSO-d6): δ = 12.9 (q), 15.1 (q), 28.1 (q), 35.7
(d), 45.2 (t), 51.8 (9), 64.9 (t), 67.6 (d), 79.2 (s), 149.5 (s), 152.9 (s),
171.4 (s). IR: νmax = 3370, 3198, 1743, 1698 cmꢀ1. MS: m/z (%) = 316
[M+] (8), 286 (11), 263 (15), 251 (51), 216 (100), 184 (44), 171 (51),
158 (86), 130 (60), 110 (40). Anal. calcd for C14H28N4O4: C, 53.15; H,
8.92; N, 17.71. Found: C, 53.18; H, 8.81; N, 18.01.
tert-Butyl 2-{2-[(3-Amino-2,2-dimethylpropyl)amino]-3-methoxy-
1-methyl-3-oxopropylidene}hydrazinecarboxylate (3d). White pow-
der from diethyl ether; mp 116ꢀ8 °C. 1H NMR (DMSO-d6): δ = 0.88
(s, 6H), 1.51 (s, 9H), 1.81 (s, 3H), 2.20ꢀ2.27 (m, 4H), 2.47ꢀ2.49 (m,
2H), 2.63 (s, 1H), 3.73 (s, 3H), 4.01 (s, 1H), 7.57 (s, 1H). (It is
impossible to obtain a good 13C NMR spectrum, because of the poor
stability of the compound in solution.) IR: νmax = 3224, 1738, 1718,
1702, 1662 cmꢀ1. MS: m/z (%) = 330 [M+] (7), 312 (10), 295 (8), 269
(13), 258 (33), 238 (34), 202 (100), 185 (32), 167 (60), 142 (64), 130
(70), 111 (75). Anal. calcd for C15H30N4O4: C, 55.52; H, 9.15; N, 16.96.
Found: C, 55.47; H, 9.21; N, 17.01.
tert-Butyl 2-{2-[(2-Aminobenzyl)amino]-3-isopropoxy-1-methyl-3-
oxopropylidene}hydrazinecarboxylate (3h). White powder from ethyl
acetate; mp 144ꢀ6 °C. 1H NMR (CDCl3): δ = 1.23 and 1.25 (2d, J = 6.4
Hz, 6H), 1.50 (s, 9H), 1.75 (s, 3H), 2.12 (br s, 1H), 3.69 and 3.78 (AB-
system, J = 12.4 Hz, 2H), 4.05 (s, 1H), 4.38 (br s, 2H), 5.07 (sept, J = 6.4
Hz, 1H), 6.63ꢀ6.67 (m, 2H), 6.98ꢀ7.08 (m, 2H), 7.64 (2s, 1H). 13C
NMR (CDCl3): δ = 12.3 (q), 21.6 (q), 28.1 (q), 50.3 (t), 67.1 (d), 69.1
(d), 81.2 (s), 115.6 (d), 117.7 (d), 119.8 (s), 128.5 (d), 130.3 (d), 146.5
(s), 147.2 (s), 152.4 (s), 170.2 (s). IR: νmax = 3465, 3375, 3135, 1752,
1735, 1617 cmꢀ1. MS: m/z (%) = 378 [M+] (1), 289 (3), 247 (10), 233
(4), 216 (11), 202 (7), 189 (4), 174 (8), 159 (24), 142 (6), 130 (20),
121 (46), 106 (100). Anal. calcd for C19H30N4O4: C, 60.30; H, 7.99; N,
14.80. Found: C, 60.44; H, 7.85; N, 14.93.
General Procedure for the Synthesis of 2,5,6,7-Tetrahydro-1H-1,4-
diazepin-2-ones 4aꢀo. To a solution of diamines 2aꢀc (1.0 mmol) in
EtOH (2 mL) magnetically stirred at room temperature was added a
solution of 1,2-diaza-1,3-dienes 1aꢀf (1.0 mmol) in EtOH (3 mL). The
disappearance of the red color of 1aꢀf occurred within 1 min, and, at this
point of the reaction, the TLC analysis revealed the presence of α-
aminohydrazones 3 as major products. After 1.0ꢀ8.0 h, compounds 3
were converted into the corresponding 2,5,6,7-tetrahydro-1H-1,4-dia-
zepin-2-ones 4aꢀo that in part crystallized from the reaction medium,
while the remaining part was obtained by flash chromatography (silica,
10% methanolꢀ90% ethyl acetate as eluant). Spectroscopic data for
2,5,6,7-tetrahydro-1H-1,4-diazepin-2-ones 4aꢀo are given below.
tert-Butyl 2-[1-(2-Oxo-2,5,6,7-tetrahydro-1H-1,4-diazepin-3-yl)-
ethylidene]hydrazinecarboxylate (4a). White powder from ethanol;
mp 248ꢀ50 °C. 1H NMR (DMSO-d6): δ = 1.41 (s, 9H), 1.81 (qi, J = 6.8
Hz, 2H), 2.02 (s, 3H), 2.85 (q, J = 6.0 Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H),
tert-Butyl 2-{2-[(2-Aminobenzyl)amino]-3-ethoxy-1-methyl-3-oxo-
propylidene}hydrazinecarboxylate (3e). White powder from ethyl
1
acetate; mp 122ꢀ4 °C. H NMR (CDCl3): δ = 1.27 (t, J = 7.2 Hz,
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ARTICLE
8.19 (t, J = 6.0 Hz, 1H), 10.05 (s, 1H). 13C NMR (DMSO-d6): δ = 11.5
(q), 28.0 (q), 28.1 (t), 36.0 (t), 47.7 (t), 79.8 (s), 147.1 (s), 152.2 (s),
166.5 (s), 167.2 (s). IR: νmax = 3230, 1739, 1708, 1678, 1648 cmꢀ1. MS:
m/z (%) = 268 [M+] (1), 212 (29), 195 (24), 167 (49), 150 (13), 139
(100), 111 (94). Anal. calcd for C12H20N4O3: C, 53.72; H, 7.51; N,
20.88. Found: C, 53.88; H, 7.59; N, 20.61.
1-(2-Oxo-2,5,6,7-tetrahydro-1H-1,4-diazepin-3-yl)-1-ethanone N-
Phenylsemicarbazone (4b). White powder from ethanol; mp
182ꢀ4 °C. 1H NMR (DMSO-d6): δ = 1.85 (qi, J = 6.4 Hz, 2H), 2.07
(s, 3H), 2.91 (q, J = 6.0 Hz, 2H), 3.59 (t, J = 6.0 Hz, 2H), 7.03 (t, J = 7.6
Hz, 1H), 7.32 (t, J = 7.6 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 8.42 (t, J = 6.0
Hz, 1H), 8.57 (s, 1H), 10.28 (br s, 1H). 13C NMR (DMSO-d6): δ = 10.9
(q), 28.0 (t), 36.0 (t), 48.0 (t), 118.3 (d), 122.7 (d), 129.0 (d), 138.3 (s),
143.9 (s), 152.4 (s), 165.8 (s), 166.3 (s). IR: νmax = 3362, 3255, 3183,
1697, 1668, 1612 cmꢀ1. MS: m/z (%) = 287 [M+] (17), 195 (4), 167
(64), 140 (100), 111 (79). Anal. calcd for C14H17N5O2: C, 58.52; H,
5.96; N, 24.38. Found: C, 58.39; H, 6.09; N, 24.51.
Benzyl 2-[1-(2-Oxo-2,5,6,7-tetrahydro-1H-1,4-diazepin-3-yl)ethylidene]
hydrazinecarboxylate (4c). White powder from ethanol; mp 230ꢀ2. 1H
NMR (DMSO-d6): δ = 1.80 (qi, J = 6.4 Hz, 2H), 2.02 (s, 3H), 2.90 (q, J
= 6.0 Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H), 5.16 (s, 2H), 7.32ꢀ7.41 (m, 5H),
8.21 (t, J = 6.8 Hz, 1H), 10.43 (br s, 1H). 13C NMR (DMSO-d6): δ =
11.6 (q), 28.1 (t), 36.0 (t), 47.8 (t), 66.1 (t), 127.9 (d), 128.0 (d), 128.4
(d), 136.4 (s), 148.0 (s), 153.3 (s), 165.4 (s), 167.1 (s). IR: νmax = 3398,
3229, 1740, 1711, 1685, 1646 cmꢀ1. MS: m/z (%) = 302 [M+] (3), 225
(5), 211 (3), 196 (2), 167 (95), 152 (4), 139 (100), 111 (92). Anal. calcd
for C15H18N4O3: C, 59.59; H, 6.00; N, 18.53. Found: C, 59.61; H, 6.03;
N, 18.61.
1-(2-Oxo-2,5,6,7-tetrahydro-1H-1,4-diazepin-3-yl)-1-ethanone Semi-
carbazone (4d). White powder from ethanol; mp 233ꢀ5 °C. 1H NMR
(DMSO-d6): δ = 1.82 (qi, J = 6.8 Hz, 2H), 1.99 (s, 3H), 2.87 (q, J = 6.4
Hz, 2H), 3.54 (t, J = 6.4 Hz, 2H), 5.82 and 6.51 (2br s, 2H), 8.23 (t, J =
6.4 Hz, 1H), 9.89 (s, 1H). 13C NMR (DMSO-d6): δ = 10.8 (q), 28.0 (t),
Hz, 3H), 1.44 (s, 9H), 1.98 (s, 3H), 2.13 (sex., J = 5.6 Hz, 1H), 2.54 (dt, J
= 14.4 Hz, J = 4.8 Hz, 1H), 2.89 (dt, J = 14.4 Hz, J = 6.0 Hz, 1H), 3.11
(dd, J = 10.8 Hz, J = 7.2 Hz, 1H), 3.62 (dd, J = 10.4 Hz, J = 5.6 Hz, 1H),
8.32 (t, J = 6.0 Hz, 1H), 10.06 (s, 1H). 13C NMR (DMSO-d6): δ = 11.5
(q), 16.4 (q), 28.0 (q), 34.6 (d), 42.8 (t), 54.8 (t), 79.9 (s), 147.1 (s),
152.2 (s), 165.5 (s), 167.3 (s). IR: νmax = 3397, 3240, 1746, 1723,1685,
1651 cmꢀ1. MS: m/z (%) = 283 [M+] (1), 267 (3), 226 (25), 209 (20),
181 (45), 153 (100), 139 (19), 125 (49), 110 (35). Anal. calcd for
C13H22N4O3: C, 55.30; H, 7.85; N, 19.84. Found: C, 55.18; H, 7.99;
N, 19.66.
Benzyl 2-[1-(6-Methyl-2-oxo-2,5,6,7-tetrahydro-1H-1,4-diazepin-3-yl)-
ethylidene]hydrazinecarboxylate (4h). White powder from ethanol;
mp 110ꢀ2 °C. 1H NMR (DMSO-d6): δ = 0.89 (d, J = 6.8 Hz, 3H), 2.02
(s, 3H), 2.14 (sex., J = 5.6 Hz, 1H), 2.48ꢀ2.61 (m, 1H), 2.92 (dt, J = 14.4
Hz, J = 7.6 Hz, 1H), 3.15 (dd, J = 8.8 Hz, J = 8.0 Hz, 1H), 3.65 (dd, J =
10.6 Hz, J = 6.4 Hz, 1H), 5.18 (s, 2H), 7.33ꢀ7.40 (m, 5H), 8.36 (t, J =
6.8 Hz, 1H), 10.47 (br s, 1H). 13C NMR (DMSO-d6): δ = 11.6 (q), 16.4
(q), 34.6 (d), 42.8 (t), 54.8 (t), 66.1 (t), 127.9 (d), 128.0 (d), 128.4 (d),
136.4 (s), 148.1 (s), 153.3 (s), 165.4 (s), 167.1 (s). IR: νmax = 3390,
3221, 1744, 1717, 1682, 1645 cmꢀ1. MS: m/z (%) = 316 [M+] (1), 239
(9), 224 (20), 196 (56), 183 (12), 167 (75), 151 (19), 139 (31), 126
(35), 108 (100). Anal. calcd for C16H20N4O3: C, 60.75; H, 6.37; N,
17.71. Found: C, 60.64; H, 6.43; N, 17.65.
1-(6-Methyl-2-oxo-2,5,6,7-tetrahydro-1H-1,4-diazepin-3-yl)-1-etha-
none Semicarbazone (4i). Pink powder from ethanol; mp 148ꢀ50 °C.
1H NMR (DMSO-d6): δ = 0.89 (d, J = 6.8 Hz, 3H), 1.99 (s, 3H), 2.15
(sex., J = 5.2 Hz, 1H), 2.56 (dt, J = 14.8 Hz, J = 4.4 Hz, 1H), 2.92 (dt, J =
14.8 Hz, J = 8.0 Hz, 1H), 3.14 (dd, J = 8.4 Hz, J = 8.0 Hz, 1H), 3.65 (dd, J
= 10.6 Hz, J = 6.0 Hz, 1H), 5.92 and 6.66 (2br s, 2H), 8.35 (t, J = 6.0 Hz,
1H), 9.90 (s, 1H). 13C NMR (DMSO-d6): δ = 10.8 (q), 16.5 (q), 34.6
(d), 42.9 (t), 54.9 (t), 142.9 (s), 156.4 (s), 165.8 (s), 166.7 (s). IR: νmax
=
3451, 3193, 1725, 1705, 1694, 1655 cmꢀ1. MS: m/z (%) = 225 [M+] (1),
209 (2), 181 (68), 165 (4), 153 (100), 139 (6), 125 (43), 110 (14). Anal.
calcd for C9H15N5O2: C, 47.99; H, 6.71; N, 31.09. Found: C, 48.08; H,
6.79; N, 31.16.
36.0 (t), 47.8 (t), 142.8 (s), 156.3 (s), 165.8 (s), 166.6 (s). IR: νmax
=
3460, 3192, 1718, 1704, 1683, 1635 cmꢀ1. MS: m/z (%) = 211 [M+] (1),
167 (83), 151 (44), 139 (85), 111 (100). Anal. calcd for C8H13N5O2: C,
45.49; H, 6.20; N, 33.16. Found: C, 45.38; H, 6.39; N, 33.01.
1-(2-Oxo-2,5,6,7-tetrahydro-1H-1,4-diazepin-3-yl)-1-propanone
Semicarbazone (4e). White powder from ethanol; mp 196ꢀ8 °C. 1H
NMR (DMSO-d6): δ = 0.90 (t, J = 7.6 Hz, 3H), 1.80 (qi, J = 6.4 Hz, 2H),
2.58 (q, J = 7.6 Hz, 2H), 2.84 (q, J = 6.4 Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H),
5.86 and 6.56 (2br s, 2H), 8.20 (t, J = 6.4 Hz, 1H), 10.02 (s, 1H). 13C
NMR (DMSO-d6): δ = 10.0 (q), 16.8 (t), 28.0 (t), 36.1 (t), 47.8 (t),
146.9 (s), 156.4 (s), 165.8 (s), 165.9 (s). IR: νmax = 3463, 3201, 1708,
1687, 1654 cmꢀ1. MS: m/z (%) = 225 [M+] (1), 181 (81), 164 (21), 153
(45), 110 (100). Anal. calcd for C9H15N5O2: C, 47.99; H, 6.71; N, 31.09.
Found: C, 48.03; H, 6.79; N, 31.11.
1-(6-Methyl-2-oxo-2,5,6,7-tetrahydro-1H-1,4-diazepin-3-yl)-1-pro-
panone Semicarbazone (4j). Pink powder from ethanol; mp
190ꢀ2 °C. 1H NMR (DMSO-d6): δ = 0.89 (d, J = 8.4 Hz, 3H), 1.03
(t, J = 7.2 Hz, 3H), 2.16 (sex., J = 6.0 Hz, 1H), 2.48ꢀ2.61 (m, 3H), 2.92
(dt, J = 14.8 Hz, J = 7.2 Hz, 1H), 3.18 (dd, J = 9.0 Hz, J = 9.2 Hz, 1H),
3.62 (dd, J = 8.0 Hz, J = 6.0 Hz, 1H), 5.90 and 6.63 (2br s, 2H), 8.33 (t, J
= 5.6 Hz, 1H), 10.05 (s, 1H). 13C NMR (DMSO-d6): δ = 10.0 (q), 16.4
(q), 16.9 (t), 34.6 (d), 43.0 (t), 54.9 (t), 146.9 (s), 156.4 (s), 165.8 (s),
165.9 (s). IR: νmax = 3399, 3191, 1703, 1687 cmꢀ1. MS: m/z (%) = 240
[M+] (1), 224 (4), 195 (24), 179 (42), 164 (37), 149 (23), 138 (32), 126
(78), 111 (100). Anal. calcd for C10H17N5O2: C, 50.20; H, 7.16; N,
29.27. Found: C, 50.33; H, 7.09; N, 29.44.
1-(6-Methyl-2-oxo-2,5,6,7-tetrahydro-1H-1,4-diazepin-3-yl)-1-etha-
none N-Phenylsemicarbazone (4f). Pink powder from ethanol; mp
178ꢀ80 °C. 1H NMR (DMSO-d6): δ = 0.91 (d, J = 7.2 Hz, 3H), 2.06 (s,
3H), 2.15 (sex., J = 6.0 Hz, 1H), 2.61 (dt, J = 14.8 Hz, J = 5.6 Hz, 1H),
2.98 (dt, J = 14.8 Hz, J = 5.6 Hz, 1H), 3.20 (dd, J = 9.0 Hz, J = 8.4 Hz,
1H), 3.70 (dd, J = 10.2 Hz, J = 6.0 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 7.32
(t, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 8.53 (t, J = 6.0 Hz, 1H), 8.59
(s, 1H), 10.04 (br s, 1H). 13C NMR (DMSO-d6): δ = 11.0 (q), 16.5 (q),
34.6 (d), 42.9 (t), 55.0 (t), 118.3 (d), 122.7 (d), 129.0 (d), 138.4 (s),
144.0 (s), 152.4 (s), 165.8 (s), 169.3 (s). IR: νmax = 3451, 3327, 3195,
3066, 1705, 1654 cmꢀ1. MS: m/z (%) = 301 [M+] (23), 209 (6), 181
(63), 167 (11), 154 (100), 139 (22), 125 (69), 111 (57). Anal. calcd for
C15H19N5O2: C, 59.79; H, 6.36; N, 23.24. Found: C, 59.89; H, 6.49;
N, 23.11.
1-(6,6-Dimethyl-2-oxo-2,5,6,7-tetrahydro-1H-1,4-diazepin-3-yl)-1-
ethanone N-Phenylsemicarbazone (4k). Pink powder from ethanol;
mp 216ꢀ8 °C. 1H NMR (DMSO-d6): δ = 0.91 (s, 6H), 2.04 (s, 3H),
2.58 (d, J = 6.0 Hz, 2H), 3.28 (s, 2H), 7.01 (t, J = 7.2 Hz, 1H), 7.30 (t, J =
7.2 Hz, 2H), 7.40 (d, J = 7.6 Hz, 2H), 8.57 (s, 1H), 8.65 (t, J = 6.0 Hz,
1H), 10.38 (br s, 1H). 13C NMR (DMSO-d6): δ = 10.9 (q), 24.4 (q),
39.9 (s), 48.5 (t), 60.4 (t), 118.3 (d), 122.7 (d), 128.9 (d), 138.4 (s),
144.0 (s), 152.4 (s), 165.6 (s), 166.4 (s). IR: νmax = 3325, 3196, 3086,
1702, 1662, 1599 cmꢀ1. MS: m/z (%) = 315 [M+] (17), 285 (1), 223
(5), 195 (43), 176 (15), 167 (100), 153 (11), 139 (29), 119 (32), 110
(30). Anal. calcd for C16H21N5O2: C, 60.94; H, 6.71; N, 22.21. Found:
C, 61.02; H, 6.85; N, 22.43.
tert-Butyl 2-[1-(6,6-Dimethyl-2-oxo-2,5,6,7-tetrahydro-1H-1,4-dia-
zepin-3-yl)ethylidene]hydrazinecarboxylate (4l). Pink powder from
ethanol; mp 220ꢀ4 °C. 1H NMR (DMSO-d6): δ = 0.88 (s, 6H), 1.44
(s, 9H), 1.98 (s, 3H), 2.52 (d, J = 6.4 Hz, 2H), 3.22 (s, 2H), 8.45 (t, J =
6.0 Hz, 1H), 10.06 (s, 1H). 13C NMR (DMSO-d6): δ = 11.5 (q), 24.4
tert-Butyl 2-[1-(6-Methyl-2-oxo-2,5,6,7-tetrahydro-1H-1,4-diaze-
pin-3-yl)ethylidene]hydrazinecarboxylate (4g). Pink powder from
1
ethanol; mp 242ꢀ4 °C. H NMR (DMSO-d6): δ = 0.87 (d, J = 6.8
8325
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The Journal of Organic Chemistry
ARTICLE
(q), 28.0 (q), 39.9 (s), 48.5 (t), 60.1 (t), 79.8 (s), 147.2 (s), 152.2 (s),
165.4 (s), 167.3 (s). IR: νmax = 3255, 1746, 1720,1688, 1651 cmꢀ1. MS:
m/z (%) = 296 [M+] (1), 281 (2), 240 (19), 223 (18), 195 (31), 179 (6),
167 (100), 153 (18), 139 (35), 124 (20), 110 (45). Anal. calcd for
C14H24N4O3: C, 56.74; H, 8.16; N, 18.90. Found: C, 56.88; H, 8.23;
N, 18.66.
128.1 (d), 128.8 (s), 129.0 (d), 147.9 (s), 154.5 (s), 163.1 (s), 168.0 (s).
IR: νmax = 1752, 1738, 1640 cmꢀ1. MS: m/z (%) = 230 [M+] (34), 191
(4), 171 (6), 145 (30), 130 (100), 117 (33). Anal. calcd for
C13H14N2O2: C, 67.81; H, 6.13; N, 12.17. Found: C, 67.66; H, 6.28;
N, 12.31.
Isopropyl 2-Methyl-5H-1,4-benzodiazepine-3-carboxylate (5d).
1
Benzyl 2-[1-(6,6-Dimethyl-2-oxo-2,5,6,7-tetrahydro-1H-1,4-diaze-
pin-3-yl)ethylidene]hydrazinecarboxylate (4m). Pink powder from
Yellow powder from cyclohexaneꢀethyl acetate; mp 112ꢀ4 °C. H
NMR (CDCl3): δ = 1.28 (d, J = 6.0 Hz, 6H), 2.48 (s, 3H), 4.25 (br s,
2H), 5.1 (sept, J = 6.4 Hz, 1H), 7.20ꢀ7.36 (m, 4H). 13C NMR (CDCl3):
δ = 21.4 (q), 25.4 (q), 54.3 (t), 70.2 (d), 125.6 (d), 126.9 (d), 128.0 (d),
1
ethanol; mp 90ꢀ2 °C. H NMR (DMSO-d6): δ = 0.90 (s, 6H), 2.03
(s, 3H), 2.55 (d, J = 6.0 Hz, 2H), 3.25 (s, 2H), 5.19 (s, 2H), 7.33ꢀ7.42
(m, 5H), 8.51 (t, J = 6.0 Hz, 1H), 10.48 (br s, 1H). 13C NMR (DMSO-
d6): δ = 11.7 (q), 24.5 (q), 39.9 (s), 48.6 (t), 60.2 (t), 66.2 (t), 128.0 (d),
128.1 (d), 128.5 (d), 136.4 (s), 148.2 (s), 153.5 (s), 165.4 (s), 167.2 (s).
IR: νmax = 3399, 3223, 1749, 1717, 1690 cmꢀ1. MS: m/z (%) = 330 [M+]
(1), 239 (6), 206 (19), 191 (100), 128 (19), 108 (49). Anal. calcd for
C17H22N4O3: C, 61.80; H, 6.71; N, 16.96. Found: C, 61.69; H, 6.55;
N, 17.02.
128.7 (s), 128.8 (d), 146.7 (s), 155.2 (s), 162.1 (s), 163.1 (s). IR: νmax
=
1724, 1645, 1605 cmꢀ1. MS: m/z (%) = 244 [M+] (37), 229 (4), 202
(11), 186 (16), 157 (26), 130 (100), 116 (19), 103 (10). Anal. calcd for
C14H16N2O2: C, 68.83; H, 6.60; N, 11.47. Found: C, 68.99; H, 6.49;
N, 11.51.
General Procedure for the Synthesis of 4-[(3-Aminopropyl)-
(methyl)amino]-1H-pyrazol-3-ones 6aꢀd. To a solution of N-meth-
yl-1,3-diaminopropane 2e (1.0 mmol) in dichloromethane (2 mL)
magnetically stirred at room temperature was added a solution of 1,2-
diaza-1,3-dienes 1a,b,g,i (1.0 mmol) in dichloromethane (3 mL). The
disappearance of the red color of 1a,b,g,i occurred within 0.1ꢀ0.2 h and
products 6aꢀd directly crystallized from the reaction solvent. Spectro-
scopic data for 4-[(3-aminopropyl)(methyl)amino]-1H-pyrazol-3-ones
6aꢀd are given below.
1-(6,6-Dimethyl-2-oxo-2,5,6,7-tetrahydro-1H-1,4-diazepin-3-yl)-1-
ethanone Semicarbazone (4n). Scarlet powder from ethanol; mp
1
208ꢀ10 °C. H NMR (DMSO-d6): δ = 0.91 (s, 6H), 1.99 (s, 3H),
2.55 (d, J = 6.4 Hz, 2H), 3.25 (s, 2H), 5.92 and 6.67 (2br s, 2H), 8.49 (t, J
= 6.0 Hz, 1H), 9.88 (br s, 1H). 13C NMR (DMSO-d6): δ = 10.8 (q), 24.5
(q), 39.8 (s), 48.5 (t), 60.2 (t), 142.9 (s), 156.3 (s), 165.6 (s), 166.7 (s).
IR: νmax = 3450, 3294, 3204, 1690, 1655 cmꢀ1. MS: m/z (%) = 240 [M+]
(1), 224 (3), 209 (3), 195 (54), 178 (10), 167 (100), 153 (8), 139 (21),
124 (19), 113 (48). Anal. calcd for C10H17N5O2: C, 50.20; H, 7.16; N,
29.27. Found: C, 50.29; H, 7.19; N, 29.46.
tert-Butyl 4-[(3-Aminopropyl)(methyl)amino]-3-methyl-5-oxo-2,5-
dihydro-1H-pyrazole-1-carboxylate (6a). Pink powder from dichlor-
omethane; mp 95ꢀ7 °C. 1H NMR (CDCl3): δ = 1.49ꢀ1.57 (m, 4H),
1.61 (s, 9H), 2.16 (s, 3H), 2.52 (s, 3H), 2.77ꢀ2.83 (m, 2H), 2.85ꢀ2.92
(m, 2H), 8.94 (br s, 1H). 13C NMR (CDCl3): δ = 15.8 (q), 24.1 (t), 38.0
(t), 40.7 (t), 54.7 (q), 82.5 (s), 113.0 (s), 150.6 (s), 150.7 (s), 160.4 (s).
IR: νmax = 3443, 3219, 1732, 1648 cmꢀ1. MS: m/z (%) = 284 [M+] (1),
256 (4), 226 (6), 211 (8), 184 (32), 167 (15), 153 (18), 140 (100), 126
(64), 111 (29). Anal. calcd for C13H24N4O3: C, 54.91; H, 8.51; N, 19.70.
Found: C, 54.88; H, 8.59; N, 19.81.
4-[(3-Aminopropyl)(methyl)amino]-3-methyl-5-oxo-N-phenyl-2,5-
dihydro-1H-pyrazole-1-carboxamide (6b). Pink powder from dichlor-
omethane; mp 132ꢀ4 °C. 1H NMR (DMSO-d6): δ = 1.58ꢀ1.61 (m,
2H), 2.00 (s, 3H), 2.04 and 2.31 (2br s, 2H), 2.61 (s, 3H), 2.63ꢀ2.93 (m,
4H), 6.99 (t, J = 7.6 Hz, 1H), 7.28 (t, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz,
2H), 8.03 (br s, 1H), 12.66 (s, 1H). 13C NMR (DMSO-d6): δ = 16.3 (q),
25.1 (t), 38.3 (t), 43.1 (t), 54.5 (q), 108.4 (s), 118.8 (d), 122.2 (d), 128.9
(d), 139.2 (s), 148.3 (s), 149.8 (s), 160.1 (s). IR: νmax = 3338, 3184,
1725, 1690, 1662, 1599 cmꢀ1. MS: m/z (%) = 303 [M+] (2), 277 (9),
234 (7), 221 (14), 210 (26), 188 (53), 176 (37), 166 (23), 151 (22), 140
(70), 119 (100), 111 (62). Anal. calcd for C15H21N5O2: C, 59.39; H,
6.98; N, 23.09. Found: C, 59.48; H, 6.89; N, 23.01.
tert-Butyl 4-[(3-Aminopropyl)(methyl)amino]-3-ethyl-5-oxo-2,5-
dihydro-1H-pyrazole-1-carboxylate (6c). Pink powder from dichloro-
methane; mp 128ꢀ30 °C. 1H NMR (CDCl3): δ = 1.17 (t, J = 7.2 Hz,
3H), 1.42 (br s, 2H), 1.48ꢀ1.50 (m, 2H), 1.62 (s, 9H), 2.50ꢀ2.55 (m,
5H), 2.61ꢀ2.82 (m, 2H), 2.87ꢀ2.94 (m, 2H), 8.96 (br s, 1H). 13C NMR
(CDCl3): δ = 13.6 (q), 22.7 (t), 26.9 (t), 37.4 (t), 39.5 (t), 53.9 (q), 82.2
(s), 112.3 (s), 150.8 (s), 155.8 (s), 160.3 (s). IR: νmax = 3316, 3186,
1729, 1638 cmꢀ1. MS: m/z (%) = 298 [M+] (3), 267 (8), 235 (30), 197
(19), 180 (24), 168 (29), 134 (42), 128 (49), 115 (100). Anal. calcd for
C14H26N4O3: C, 56.35; H, 8.78; N, 18.78. Found: C, 56.42; H, 8.69;
N, 18.66.
Methyl 4-[(3-Aminopropyl)(methyl)amino]-3-methyl-5-oxo-2,5-di-
hydro-1H-pyrazole-1-carboxylate (6d). Pink powder from dichloro-
methane; mp 150ꢀ2 °C. 1H NMR (CDCl3): δ = 1.52ꢀ1.64 (m, 4H),
2.19 (s, 3H), 2.59 (s, 3H), 2.89ꢀ2.96 (m, 4H), 3.89 (s, 3H), 8.69 (br s,
1H). 13C NMR (CDCl3): δ = 15.2 (q), 24.2 (t), 38.9 (t), 41.5 (t), 53.0
(q), 55.7 (q), 112.3 (s), 151.5 (s), 151.6 (s), 160.4 (s). IR: νmax = 3450,
3282, 1739, 1648 cmꢀ1. MS: m/z (%) = 242 [M+] (21), 211 (29), 198
1-(6,6-Dimethyl-2-oxo-2,5,6,7-tetrahydro-1H-1,4-diazepin-3-yl)-1-
propanone Semicarbazone (4o). Scarlet powder from ethanol; mp
176ꢀ8 °C. 1H NMR (DMSO-d6): δ = 0.89 (s, 6H), 0.92 (t, J = 7.2 Hz,
3H), 2.45ꢀ2.59 (m, 4H), 3.23 (s, 2H), 5.88 and 6.62 (2br s, 2H), 8.45 (t,
J = 6.4 Hz, 1H), 10.05 (s, 1H). 13C NMR (DMSO-d6): δ = 10.1 (q), 16.9
(t), 24.4 (q), 39.8 (s), 48.5 (t), 60.2 (t), 146.9 (s), 156.4 (s), 165.9 (s),
166.1 (s). IR: νmax = 3432, 3203, 3159, 1711, 1664, 1596 cmꢀ1. MS: m/z
(%) = 253 [M+] (1), 209 (91), 181 (100), 167 (23), 153 (32), 139 (19),
110 (92). Anal. calcd for C11H19N5O2: C, 52.16; H, 7.56; N, 27.65.
Found: C, 52.27; H, 7.48; N, 27.49.
General Procedure for the Synthesis of Alkyl 5H-1,4-Benzodiaze-
pine-3-carboxylates 5aꢀd. A solution of α-aminohydrazones 3eꢀh
(1.0 mmol) in toluene (5 mL) was refluxed for 3.0ꢀ5.0 h, until the
corresponding alkyl 5H-1,4-benzodiazepine-3-carboxylates 5aꢀd were
formed. After flash chromatography (silica, 10% ethyl acetateꢀ 90%
cyclohexane as eluant), compounds 5aꢀc were obtained as oils, while 5d
was crystallized from cyclohexaneꢀethyl acetate. Spectroscopic data for
alkyl 5H-1,4-benzodiazepine-3-carboxylates 5aꢀd are given below.
Ethyl 2-Methyl-5H-1,4-benzodiazepine-3-carboxylate (5a). Red oil.
1H NMR (CDCl3): δ = 1.34 (t, J = 7.2 Hz, 3H), 2.54 (s, 3H), 4.30 (q, J =
7.2 Hz, 2H), 4.63 (br s, 2H), 7.22ꢀ7.39 (m, 4H). 13C NMR (CDCl3): δ
= 14.0 (q), 25.6 (q), 54.5 (t), 62.4 (t), 125.7 (d), 127.1 (d), 128.1 (d),
128.8 (s), 128.9 (d), 146.8 (s), 154.9 (s), 162.6 (s), 163.2 (s). IR: νmax
=
1731, 1633 cmꢀ1. ESI+: m/z = 231 [M + H]+. Anal. calcd for
C13H14N2O2: C, 67.81; H, 6.13; N, 12.17. Found: C, 67.98; H, 6.29;
N, 12.01.
Methyl 2-Methyl-5H-1,4-benzodiazepine-3-carboxylate (5b). Or-
1
ange oil. H NMR (CDCl3): δ = 2.43 (s, 3H), 3.72 (s, 3H), 4.62 (br
s, 2H), 7.12ꢀ7.27 (m, 4H). 13C NMR (CDCl3): δ = 25.6 (q), 53.0 (q),
54.5 (t), 125.6 (d), 127.1 (d), 128.0 (d), 128.6 (s), 128.9 (d), 146.7 (s),
154.3 (s), 162.9 (s), 163.1 (s). IR: νmax = 1749, 1729, 1640 cmꢀ1. ESI+:
m/z = 217 [M + H]+. Anal. calcd for C12H12N2O2: C, 66.65; H, 5.59; N,
12.96. Found: C, 66.88; H, 5.33; N, 13.02.
Methyl 2-Ethyl-5H-1,4-benzodiazepine-3-carboxylate (5c). Orange
oil. 1H NMR (CDCl3): δ = 1.27 (t, J = 7.2 Hz, 3H), 2.88 (q, J = 7.6 Hz,
2H), 3.85 (s, 3H), 4.82 (br s, 2H), 7.25ꢀ7.41 (m, 4H). 13C NMR
(CDCl3): δ = 11.1 (q), 31.5 (t), 53.1 (q), 54.6 (t), 125.7 (d), 127.0 (d),
8326
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ARTICLE
(36), 184 (10), 166 (21), 154 (7), 140 (100), 111 (19). Anal. calcd for
C10H18N4O3: C, 49.57; H, 7.49; N, 23.13. Found: C, 49.48; H, 7.53;
N, 23.25.
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General Procedure for the Synthesis of Bis-α-aminohydrazones 7a,
b. To a solution of 1,2-diaza-1,3-dienes 1a,b (2.0 mmol) in acetonitrile
(3 mL) magnetically stirred at room temperature, a solution of N,N0-
dimethyl-1,3-diaminopropane 2f (1 mmol) in acetonitrile (2 mL) was
added. At the disappearance of the red color of 1a,b that occurred within
5 min, products 7a,b were obtained simply by evaporation of the
reaction solvent; 7a was obtained as yellow oil, while 7b was crystallized
from diethyl etherꢀpetroleum ether (bp 40ꢀ60 °C). Spectroscopic
data for bis-α-aminohydrazones 7a,b are given below.
Di-tert-Butyl 5,11-Bis(ethoxycarbonyl)-4,6,10,12-tetramethyl-2,3,6,
10,13,14-hexaazapentadeca-3,12-diene-1,15-dioate (7a). Yellow oil.
1H NMR (CDCl3): δ = 1.24 (t, J = 7.2 Hz, 6H), 1.47 (s, 18H),
1.60ꢀ1.64 (m, 2H), 1.85 (s, 6H), 2.25 (s, 6H), 2.39ꢀ2.45 (m, 4H), 3.90
(s, 2H), 4.12ꢀ4.19 (m, 4H), 7.63 (br s, 2H). 13C NMR (CDCl3): δ =
12.2 (q), 13.8 (q), 27.8 (q), 38.4 (t), 51.8 (t), 53.2 (t), 60.2 (q), 73.7 (d),
80.5 (s), 148.0 (s), 152.3 (s), 169.8 (s). IR: νmax = 3390, 3205, 1740,
1685 cmꢀ1. MS: m/z (%) = 586 [M+] (6), 513 (3), 343 (12), 312 (24),
286 (40), 274 (32), 244 (13), 213 (100). Anal. calcd for C27H50N6O8:
C, 55.27; H, 8.59; N, 14.32. Found: C, 55.38; H, 8.69; N, 14.21.
Dimethyl 1,15-Dianilino-4,6,10,12-tetramethyl-1,15-dioxo-2,3,6,10,
13,14-hexaazapentadeca-3,12-diene-5,11-dicarboxylate (7b). Yellow
powder from diethyl etherꢀlight petroleum (bp 40ꢀ60 °C); mp
68ꢀ70 °C. 1H NMR (CDCl3): δ = 1.65ꢀ1.69 (m, 2H), 2.00 (s, 6H),
2.34 (s, 6H), 2.54ꢀ2.63 (m, 4H), 3.74 (s, 6H), 4.00 (s, 2H), 7.02ꢀ7.04
(m, 2H), 7.25ꢀ7.31 (m, 4H), 7.43ꢀ7.47 (m, 4H), 8.06 (s, 2H), 8.95 (br
s, 2H). 13C NMR (CDCl3): δ = 13.5 (q), 38.5 (t), 50.1 (t), 51.5 (t), 51.9
(q), 73.7 (d), 119.1 (d), 123.3 (d), 128.9 (d), 137.9 (s), 146.7 (s), 153.5
(s), 170.6 (s). IR: νmax = 3368, 3193, 1742, 1690, 1651 cmꢀ1. MS: m/z
(%) = 596 [M+] (1), 356 (4), 326 (3), 294 (100). Anal. calcd for
C29H40N8O6: C, 58.37; H, 6.76; N, 18.78. Found: C, 58.58; H, 6.89;
N, 18.95.
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’ ASSOCIATED CONTENT
1
S
Supporting Information. Figures giving H NMR and
b
13C NMR spectral data for compounds 3aꢀh, 4aꢀo, 5aꢀd,
6aꢀd, and 7a,b. This material is available free of charge via the
Internet at http://pubs.acs.org.
(20) Gravier-Pelletier, C.; Charvet, I.; Le Merrer, Y.; Depezay, J. C. J.
Carbohydr. Chem. 1997, 16, 129–141.
(21) Balsells, J.; Waters, M.; Hansen, K.; Kieczykowski, G. R.; Song,
Z. J. Synthesis 2007, 18, 2779–2781.
(22) Alajarín, M.; Vidal, A.; Tovar, F. Tetrahedron 2005,
61, 1531–1537.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: lucia.decrescentini@uniurb.it.
(23) Vokv, M. V.; Golovach, N. M.; Sukach, V. A.; Chernyuk, O. N.;
Manoilenko, O. V. Russ. J. Org. Chem. 2010, 46, 480–484.
(24) For reviews on the chemistry of 1,2-diaza-1,3-dienes, see: (a)
Attanasi, O. A.; De Crescentini, L.; Filippone, P.; Mantellini, F.;
Santeusanio, S. Arkivoc 2002, xi, 274–292. (b) Attanasi, O. A.; De
Crescentini, L.; Favi, G.; Filippone, P.; Mantellini, F.; Perrulli, F. R.;
Santeusanio, S. Eur. J. Org. Chem. 2009, 3109–3127.
’ ACKNOWLEDGMENT
This work was supported by the financial assistance from the
Ministero dell’Istruzione, dell’Universitꢀa
(MIUR)-Roma (PRIN 2007), and Universitꢀa degli Studi di
Urbino.
e della Ricerca
(25) For the electrophilicity parameters E of DDs, see: Kanzian, T.;
Nicolini, S.; De Crescentini, L.; Attanasi, O. A.; Ofial, A. R.; Mayr, H.
Chem.—Eur. J. 2010, 16, 12008ꢀ12016 and references cited therein.
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Lꢁopez, Y.; de los Santos, J. M. Tetrahedron 2005, 61, 2815–2830. (d)
Attanasi, O. A.; De Crescentini, L.; Favi, G.; Nicolini, S.; Perrulli, F. R.;
Santeusanio, S. Org. Lett. 2011, 13, 353–355. (e) Boga, C.; Zanna, N.;
Attanasi, O. A.; Baccolini, G.; De Crescentini, L.; Forlani, L.; Mantellini,
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