Exploiting the acylating nature of the imide-ugi intermediate: A straightforward synthesis of tetrahydro-1,4-benzodiazepin-2-ones

Article abstract of DOI:10.1021/jo2015054

We describe a simple and novel protocol for the synthesis of tetrahydro-1,4-benzodiazepin-2-ones with three points of diversity, exploiting the acylating properties of the recently rediscovered Ugi-imide. The final compounds can be easily prepared in thre

Full text of DOI:10.1021/jo2015054

Note
pubs.acs.org/joc
Exploiting the Acylating Nature of the Imide-Ugi Intermediate: A
Straightforward Synthesis of Tetrahydro-1,4-benzodiazepin-2-ones
Riccardo Mossetti, Desiree Saggiorato, and Gian Cesare Tron*
̀
̀
̀
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Universita degli Studi del Piemonte Orientale “A.
Avogadro”, Via Bovio 6, 28100 Novara, Italy
S
* Supporting Information
ABSTRACT: We describe a simple and novel protocol for the
synthesis of tetrahydro-1,4-benzodiazepin-2-ones with three
points of diversity, exploiting the acylating properties of the
recently rediscovered Ugi-imide. The final compounds can be
easily prepared in three synthetic steps using a multi-
component reaction, a Staudinger reduction, and an acylative
protocol, with good to excellent yields for each synthetic step.
enzodiazepines can be considered privileged structures in
medicinal chemistry1 because of their capability to bind
tetrahydro-1,4-benzodiazepin-2-ones by using a multicompo-
nent reaction as a key step.
B
specific domains of proteins. Over the last few decades, this
scaffold has become an important structural unit in many
pharmacologically relevant agents with biological activities not
only restricted to CNS treatment.2 For example, benzodiaze-
pines endowed with antitumor3 and anti-HIV4 properties have
been reported. Several synthetic approaches to benzodiazepines
using the classical two-component chemistry have been
described,5 and several benzodiazepines (both 1,4- and 1,5-)
have been synthesized using a multicomponent reaction,
usually coupled with a postcondensation modification.6 The
search for different synthetic routes to benzodiazepines is a
topic of continuous interest for both organic and medicinal
chemists, as starting material availability and functional group
tolerance can dictate which particular benzodiazepine-synthetic
plan is best suited.
Among the different benzodiazepines, tetrahydro-1,4-benzo-
diazepin-2-ones7 appear to be more difficult to prepare than the
corresponding 1,4-benzodiazepine-2,5-ones, with only three
synthetic strategies reported to date.8 In 2000 and 2003, this
scaffold was prepared by solid-phase synthesis using a multistep
approach.9 A drawback for this reaction is that the final product
always contains a carboxamide group deriving from the release
of the resin. In 2005, a patent was disclosed10 in which this
scaffold was prepared in six synthetic steps starting from 2-
aminobenzylamine analogues, involving, among other things, an
ozonolysis reaction and a Pd-catalyzed Suzuki reaction. Finally,
a synthesis of 1,4-benzodiazepin-2-ones unsubstituted at the
two nitrogen atoms by coupling the 2-nitrobenzyl bromide with
a series of amino acids has been reported.11 Because it is now
well-understood that multicomponent reactions12 offer a
distinct advantage over the classical two-component chemistry
favoring the preparation of libraries of compounds by simply
varying each component and allowing the construction of
molecules not easily accessible with the two component
chemistry, herein we wish to report a novel synthesis of
Very recently, we focused attention on the under-exploited
imide-Ugi backbone (5), which can be easily prepared by a
four-component reaction among a secondary amine (1), an
aldehyde (2), a carboxylic acid (3), and an isocyanide (4) in
dichloromethane in the presence of 4 Å molecular sieves.13 We
have also demonstrated that the presence of an imide compared
with the unreactive bis-amide of the classical Ugi adduct
expands the repertoire of the postcondensation reactions that
can be used. For instance, because of their increased reactivity,
imides can easily give an aza-Wittig reaction with the formation
of quinazolinones (6) or 2,3-diaminoindoles (7) according to
the position of the azide group. Furthermore, fully substituted
pyrimidinones (8) were prepared by trapping, intramolecularly,
the electrophilic carbonyl of the imide with an aliphatic amine
(Figure 1).13
As it is well-known that imides have acylating properties,14
we thought we might exploit this propensity by placing a
nucleophilic group at the right position to be acylated
generating the 1,4-benzodiazepine-2-one molecular scaffold
(Figure 2).
Azido substituted dibenzylamines (9−14), which can be
easily prepared by reductive amination between the amines and
the corresponding azido benzaldehydes, were used as the amine
component. In Figure 3, the secondary amines employed for
this project are reported.
Using different aldehydes (both aliphatic and aromatic), the
secondary amine described above, butyl isocyanide, and acetic
acid in dichloromethane in the presence of 4 Å molecular
sieves, the corresponding imides were obtained.15 After column
chromatography, the purified imides, which have not been
characterized, were subjected to a Staudinger reduction16 in
order to reduce the aromatic azide group to aniline. The use of
Received: July 22, 2011
Published: November 9, 2011
© 2011 American Chemical Society
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Note
In Figure 4 are represented the tetrahydro-1,4-benzodiaze-
pine-2-ones (17−29) prepared with this procedure with yields
ranging from 14 to 46%. Yields are referred over three synthetic
steps (a multicomponent reaction, a Staudinger reaction, and
an acylative protocol), indicating an average yield of 71−82%
for each synthetic step.
Aliphatic as well as aromatic aldehydes were well-tolerated,
and the presence of an electron-withdrawing group in the same
aromatic ring of the amine was not detrimental for the ring
closure. When aromatic aldehydes were used, the correspond-
ing benzodiazepinones precipitate, and the final compounds
can be easily obtained by filtration.
In conclusion, we disclosed a new postcondensation
transformation of the so-called imide Ugi-adduct exploiting
the strong acylating properties of the imide group, which led to
the facile and rapid synthesis of 1,4-benzodiazepin-2-ones with
three points of diversity. Compared with the synthesis of
tetrahydro-1,4-benzodiazepin-2-ones reported to date, this
procedure does not require the use of advanced intermediates
and transition metals, but only the use of cheap commercially
available aldehydes, butyl isocyanide, and acetic acid and easily
accessible secondary amines with an azide group. The biological
investigation of the synthesized compounds is under evaluation
and the results will be reported in due course.
Figure 1. Different molecular scaffolds generated by postcondensation
strategies of the imide-Ugi adduct.
Figure 2. Proposed generation of tetrahydro-1,4-benzodiazepin-2-
ones.
EXPERIMENTAL SECTION
■
Chemistry. Commercially available reagents and solvents were
used without further purification. Dichloromethane was purified by
distillation on P2O5 and stored on activated molecular sieves (4 Å).
When needed, the reactions were performed in flame- or oven-dried
glassware under a positive pressure of dry N2 or in a Schlenk tube.
Melting points were determined in open glass capillary and are
uncorrected. Chemical shifts are reported in parts per million (ppm).
Column chromatography was performed on silica gel 70−230 mesh
ASTM or silica gel 230−400 ASTM. Thin layer chromatography
(TLC) was carried out on 5 × 20 cm plates with a layer thickness of
0.25 mm (silica gel 60 F254). When necessary, they were developed
with KMnO4 or Dragendorff reagent. The purity of the target
compounds (>95%) was analyzed via elemental analysis and was
within ±0.4% of the calculated value.
General Procedure for the Preparation of the Amines 9−
14. To a solution of the corresponding azidoaldehyde (1 equiv) and
the corresponding amine (1 equiv) in dry dichloromethane, sodium
sulfate (4 equiv) was added. The reaction was vigorously stirred at
room temperature for 3 h. Sodium sulfate was filtered off, and the
filtrate was evaporated. The crude residue was dissolved in MeOH and
acetic acid (5 equiv) and cooled at 0 °C, and NaBH3CN (1 equiv) was
added portionwise. The reaction was then stirred at room temperature
for 2 h. The reaction was worked up by addition of 2 N HCl and
extracted with EtOAc (× 2). The aqueous phase was basified with 6 N
NaOH (pH > 12) and extracted with EtOAc (× 3). The collected
organic layers were washed with brine (× 1). Drying over sodium
Figure 3. Secondary amine building blocks.
trimethyl phosphine was compulsory for the success of the
reduction step, as using triphenyl phosphine or even
tributylphosphine, the corresponding iminophosphorane was
very stable and reluctant to react with water even at reflux
conditions. After the Staudinger reduction, the solvent was
evaporated, and the residue was dissolved in xylene and heated
at reflux, bringing the formation of the desired 1,4-
benzodiazepin-2-ones. The use of butyl isocyanide (15) and
acetic acid (16), which are lost during the formation of the
benzodiazepine scaffold, was the best compromise between
reactivity and atom economy. (Scheme 1)
Scheme 1. Synthetic Scheme for the Generation of the Tetrahydro-1,4-benzodiazepin-2-ones
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Note
Figure 4. Tetrahydro-1,4-benzodiazepin-2-ones synthesized. Yields are referred over three steps.
sulfate and evaporation of the solvent gave the corresponding amine as
a yellow oil.
Caution: Trimethylphosphine has pyrophoric tendencies and is very
2H), 7.02 (br t, 2H), 3.74 (br s, 4H); 13C NMR (300 MHz, CDCl3) δ
162,0 (d, J = 242 Hz), 138.3, 136.0 (d, J = 2 Hz), 131.4, 129.8 (d, J =
8.0 Hz), 128.6, 124.8, 115.1 (d, J = 21.18 Hz), 52.4, 48.9; νmax(neat)/
cm−1 3100, 2100, 1310; MS (ESI) m/z 216 (M + H)+. Yellow oil.
General Procedure for the Preparation of the Tetrahydro-
1,4-benzodiazepin-2-ones (17−29). Aldehyde (1 equiv), acetic
acid (1 equiv), and butyl isocyanide (1 equiv) were added sequentially
to a solution of amine (1 equiv) in dry dichloromethane with
molecular sieves 4 Å. The reaction was stirred at room temperature for
2 h (when aromatic aldehyde was used, the reaction was stirred at 40
°C for 3 days). The solvent was evaporated, and the imide was purified
by column chromatography (the unreacted aromatic aldehydes were
eliminated via Bertagnini reaction). The imide was then dissolved with
THF/water 1:1 and cooled at 0 °C. Trimethylphosphine (1.7 equiv)
(1.0 M solution in toluene) was added, and the reaction was stirred at
room temperature for 30 min. The reaction was diluted with EtOAc
and washed with water (× 1). After evaporation of the organic solvent,
the crude residue was dissolved in xylene, and the reaction was heated
at reflux for 3−4 h. Evaporation of the solvent, followed by column
chromatography, yielded the desired tetrahydro-1,4-benzodiazepin-2-
one.
volatile (bp 38−39 °C).
N-(2-Azidobenzyl)-1-phenylmethanamine (9): 1H NMR (300
MHz, CDCl3) δ 7.50−7.28 (m, 8H), 7.23−7.10 (m, 2H), 3.84 (s, 2H),
3.82 (s, 2H); 13C NMR (300 MHz, CDCl3) δ 140.8, 138.7, 132.0,
130.9, 128.9, 128.7, 127.5, 125.3, 118.7, 53.7, 49.4; νmax(neat)/cm−1
3026, 2119, 1487, 1451, 1281; MS (ESI) m/z 239 (M + H)+. Yellow
oil.
N-(2-Azido-5-bromobenzyl)-1-phenylmethanamine (10): 1H
NMR (300 MHz, CDCl3) δ 7.51 (d, J = 2.3 Hz, 1H), 7.41 (dd, J =
8.4 Hz, 2.3 Hz, 1H), 7.38−7.25 (m, 6H), 7.00 (d, J = 8.4 Hz), 3.79 (s,
2H), 3.72 (s, 2H); 13C NMR (300 MHz, CDCl3) δ 140.5, 137.8,
134.2, 133.5, 131.6, 129.0, 128.7, 127.6, 120.1, 118.3 53.7, 48.8;
νmax(neat)/cm−1 3110, 2121, 1480, 1275; MS (ESI) m/z 317/319 (M
+ H)+. Yellow oil.
N-(2-Azido-4,5-dimethoxybenzyl)butan-1-amine (11): 1H NMR
(300 MHz, CDCl3) δ 6.80 (s, 1H), 6.58 (s, 1H), 3.83 (s, 3H), 3.81 (s,
3H), 2.54 (t, J = 6.9 Hz, 2H), 1.73 (broad s, 1H), 1.44 (quint, J = 7.1
Hz, 2H), 1.30 (sext, J = 7.1 Hz, 2H), 0.85 (t, J = 7.1 Hz, 3H); 13C
NMR (300 MHz, CDCl3) δ 149.3, 146.7, 130.2, 123.9, 113.8, 102.3,
56.5, 56.4, 49.4 (2C), 32.4, 20.8, 14.3; νmax(neat)/cm−1 3361, 2108,
1736, 1259; MS (ESI) m/z 265 (M + H)+. Yellow oil.
N-(2-Azidobenzyl)cyclopropanamine (12): 1H NMR (300 MHz,
CDCl3) δ 7.27−7.13 (m, 2H), 7.08−6.93 (m, 2H), 3.71 (s, 2H), 2.25
(s, 1H), 2.06−1.94 (m, 1H), 0.42−0.29 (m, 4H); 13C NMR (300
MHz, CDCl3) δ 138.5, 132.2, 130.9, 128.7, 125.0, 118.4, 49.7, 30.2,
6.9, 6.8; νmax(neat)/cm−1 3108, 2106, 1275; MS (ESI) m/z 189 (M +
H)+. Yellow oil.
4-Benzyl-7-bromo-3-hexyl-4,5-dihydro-1H-benzo[e][1,4]-
diazepin-2(3H)-one (17): 1H NMR (300 MHz, CDCl3) δ 8.41
(broad s, 1H), 7.41−7.10 (m, 7H), 6.86 (d, J = 8.3 Hz, 1H), 3.88 (d, J
= 15.4 Hz, 1H), 3.81 (d, J = 13.5 Hz, 1H), 3.69 (d, J = 15.4 Hz, 1H),
3.59 (d, J = 13.5 Hz, 1H), 3.53 (t, J = 7.7 Hz, 1H), 1.97−1.81 (m, 1H),
1.77−1.58 (m, 1H), 1.53−1.12 (m, 8H), 0.87 (t, J = 6.3 Hz, 3H); 13
C
NMR (300 MHz, CDCl3) δ 172.0, 136.0, 133.7, 130.6, 129.0, 128.9,
126.6, 126.5, 125.1, 119.4, 114.6, 63.0, 54.0, 50.3, 29.6, 28.2, 26.7, 24.1,
20.3, 11.8; νmax(KBr)/cm−1 1653, 1490, 1223, 958; MS (ESI) m/z
415/417 (M + H)+. White solid: mp 86.3−86.6 °C. Anal. Calcd for
C22H27BrN2O: C, 63.61; H, 6.55; N, 6.74. Found C, 64.34; H, 6.20; N,
6.32.
1-(3-Azidonaphthalen-2-yl)-N-(4-chlorobenzyl)methanamine
(13): 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J = 9.1 Hz, 1H), 7.73
(d, J = 4.4 Hz, 2H), 7.54−7.40 (m, 3H), 7.36−7.24 (m, 5H), 3.88 (s,
2H), 3.78 (s, 2H); 13C NMR (300 MHz, CDCl3) δ 139.2, 137.6,
133.8, 131.5, 131.0, 130.1, 129.8, 129.1, 128.2, 127.2, 126.9, 126.2,
116.1, 52.8, 49.7; νmax(neat)/cm−1 3106, 2120, 1264; MS (ESI) m/z
323/325 (M + H)+. Yellow oil.
4-Benzyl-3-cyclohexyl-4,5-dihydro-1H-benzo[e][1,4]diazepin-
2(3H)-one (18): 1H NMR (300 MHz, CDCl3) δ 8.75 (broad s, 1H),
7.44−7.21 (m, 6H), 7.16−6.97 (m, 3H), 3.98 (d, J = 13.1 Hz, 1H),
3.71 (s, 2H), 3.66 (d, J = 13.1 Hz, 1H), 3.27 (d, J = 10.4 Hz, 1H), 2.12
(d, J = 12.9 Hz, 1H), 1.80−1.37 (m, 5H), 1.20−0.78 (m, 5H); 13C
NMR (300 MHz, CDCl3) δ 174.2, 139.3, 138.0, 130.4, 130.3, 129.2,
N-(2-Azidobenzyl)-1-(4-fluorophenyl)methanamine (14): 1H
NMR (300 MHz, CDCl3) δ 7.34−7.25 (m, 4H), 7.16−7.10 (m,
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Note
128.9, 128.8, 127.6, 125.1, 120.6, 71.8, 59.8, 54.6, 37.8, 30.9, 30.4, 27.0,
26.3 (2C); νmax(KBr)/cm−1 1659, 1589, 1494, 760; MS (ESI) m/z 335
(M + H)+. White solid: mp 182.5−182.8 °C. Anal. Calcd for
C22H26N2O: C, 79.00; H, 7.84; N, 8.38. Found C, 79.34; H,8.20; N,
8.00.
4-Benzyl-3-isopropyl-4,5-dihydro-1H-benzo[e][1,4]diazepin-
2(3H)-one (19): 1H NMR (300 MHz, CDCl3) δ 8.70 (broad s, 1H),
7.45−7.21 (m, 6H), 7.16−7.04 (m, 2H), 7.01 (d, J = 8.0 Hz, 1H), 3.99
(d, J = 13.2 Hz, 1H), 3.77−3.61 (m, 3H), 3.13 (d, J = 10.4 Hz, 1H),
1.80−1.64 (m, 1H), 0.98 (d, J = 6.0 Hz, 3H), 0.89 (d, J = 6.0 Hz, 3H);
13C NMR (300 MHz, CDCl3) δ 174.2, 139.3, 138.0, 130.5, 130.4,
C22H19ClN2O: C, 72.82; H, 5.28; N, 7.72. Found C, 72.65; H, 5.26; N,
7.60.
4-Benzyl-3-(4-methoxyphenyl)-4,5-dihydro-1H-benzo[e][1,4]-
diazepin-2(3H)-one (25): 1H NMR (300 MHz, DMSO-d6) δ 10.08
(s, 1H), 7.41−7.23 (m, 8H), 7.18−7.04 (m, 3H), 6.87 (d, J = 8.8 Hz,
2H), 4.05 (s, 1H), 3.86 (d, J = 14.3 Hz, 1H), 3.72 (s, 3H), 3.46 (t, J =
14.3 Hz, 2H), 3.30 (d, J = 14.3 Hz, 1H); 13C NMR (300 MHz,
DMSO-d6) δ 169.0, 156.9, 136.8, 136.6, 128.7, 128.5, 128.3, 126.8
(2C), 126.6, 125.4, 125.3, 122.4, 118.9, 111.5, 67.7, 53.7, 53.2, 49.3;
νmax(KBr)/cm−1 1672, 1516, 1492, 1249, 744; MS (ESI) m/z 359 (M
+ H)+. White solid: mp 219−219.3 °C. Anal. Calcd for C23H22N2O2:
C, 77.07; H, 6.19; N, 7.82. Found C, 77.00; H, 6.40; N, 7.69.
4-Benzyl-3-phenyl-4,5-dihydro-1H-benzo[e][1,4]diazepin-2(3H)-
one (26): 1H NMR (300 MHz, DMSO-d6) δ 10.12 (broad s, 1H),
7.48−7.19 (m, 11H), 7.17−7.03 (m, 3H), 4.13 (s, 1H), 3.88 (d, J =
14.3 Hz, 1H), 3.57−3.27 (m, 3H); 13C NMR (300 MHz, DMSO-d6) δ
169.3, 137.2, 136.9, 136.4, 128.1, 126.8, 126.6, 126.5 (2C), 125.9,
125.3 (2C), 122.0, 118.7, 69.3, 55.3, 50.3; νmax(KBr)/cm−1 1670, 1492,
1340, 1269, 746; MS (ESI) m/z 329 (M + H)+. White solid: mp
270.4−270.8 °C. Anal. Calcd for C22H20N2O: C, 80.46; H, 6.14; N,
8.53. Found C, 80.40; H, 6.15; N, 8.32.
3,4-Dibenzyl-7-bromo-4,5-dihydro-1H-benzo[e][1,4]diazepin-
2(3H)-one (27): 1H NMR (300 MHz, CDCl3) δ 7.50−7.08 (m,
13H), 6.88 (d, J = 8.5 Hz, 1H), 4.04−3.79 (m, 3H), 3.66 (d, J = 10.4
Hz, 1H), 3.61 (d, J = 8.8 Hz, 1H), 3.32 (dd, J = 14.0 Hz, 6.9 Hz, 1H),
2.96 (dd, J = 14.0 Hz, 7.4 Hz, 1H); 13C NMR (300 MHz, CDCl3) δ
172.0, 136.2, 135.8, 133.9, 130.6, 129.2, 128.9, 127.1, 126.5, 126.2,
126.0, 125.1, 124.1, 119.7, 114.9, 64.8, 54.4, 50.7, 34.6; νmax(KBr)/
cm−1 1643, 1480, 1399, 867; MS (ESI) m/z 421/423 (M + H)+. White
solid: mp 128.3−128.7 °C. Anal. Calcd for C23H21BrN2O: C, 65.57; H,
5.02; N, 6.65. Found C, 65.40; H, 4.82; N, 6.87.
4-Benzyl-3-(4-fluorophenyl)-4,5-dihydro-1H-benzo[e][1,4]-
diazepin-2(3H)-one (28): 1H NMR (300 MHz, DMSO-d6) δ 7.43−
7.30 (m, 6H), 7.29−7.21 (m, 2H), 7.13−6.97 (m, 5H), 4.34 (s, 1H),
3.95 (d, J = 14.3 Hz, 1H), 3.64 (d, J = 14.3 Hz, 1H), 3.59 (d, J = 2.8
Hz, 2H); 13C NMR (300 MHz, DMSO-d6) δ 171.2, 160.0 (d, J = 242
Hz), 139.1, 138.8, 135.6, 130.7 (d, J = 7.4 Hz), 130.5, 129.1 (2C),
128.8 (2C), 128.5, 127.6, 124.5, 121.1, 114.9 (d, J = 21,2 Hz), 70.7,
57.5, 52.5; νmax(KBr)/cm−1 1633, 1530, 1290, 980, 867; MS (ESI) m/
z 347 (M + H)+. White solid: mp 250−251 °C. Anal. Calcd for
C22H19FN2O: C, 76.28; H, 5.53; N, 8.09. Found C, 76.50; H, 5.82; N,
7.80.
4-(4-Fluorobenzyl)-3-hexyl-4,5-dihydro-1H-benzo[e][1,4]-
diazepin-2(3H)-one (29): 1H NMR (300 MHz, DMSO-d6) δ 8.90
(br s, 1H), 7.34−7.20 (m, 3H), 7.10−6.96 (m, 5H), 3.89 (d, J = 15.1
Hz, 1H), 3.78 (t, J = 13.5 Hz, 1H), 3.70 (d, J = 15.1 Hz, 1H), 3.63−
3.47 (m, 2H), 2.01−1.83 (m, 1H), 1.78−1.62 (m, 1H), 1.52−1.18 (m,
8H), 0.87 (t, J = 6.6 Hz, 1H); 13C NMR (300 MHz, DMSO-d6) δ
175.7, 162.1 (d, J = 243,3 Hz), 137.1, 134.5, 130.3 (d, J = 11.4 Hz),
128.7, 128.5, 124.3, 120.3, 115.2 (d, J = 21,2 Hz), 65.3, 55.9, 53.0, 31.9,
30.7, 29.1, 26.4, 22.7, 14.2; νmax(KBr)/cm−1 1630, 1450, 1250, 870;
MS (ESI) m/z 355 (M + H)+. Amorphous solid. Anal. Calcd for
C22H27FN2O: C, 74.55; H, 7.68; N, 7.90. Found C, 74.50; H, 7.72; N,
8.05.
129.3, 129.0, 128.8, 127.6, 125.2, 120.7, 73.2, 59.9, 54.8, 28.6, 20.4,
20.1; νmax(KBr)/cm−1 1673, 1489, 1266, 761; MS (ESI) m/z 295 (M
+ H)+. White solid: mp 120.1−120.5 °C. Anal. Calcd for C19H22N2O:
C, 77.52; H, 7.53; N, 9.52. Found C, 77.50; H,7.40; N, 9.50
4-Butyl-7,8-dimethoxy-3-(thiophen-2-yl)-4,5-dihydro-1H-benzo-
[e][1,4]diazepin-2(3H)-one (20): 1H NMR (300 MHz, CDCl3) δ
8.78 (broad s, 1H), 7.20 (d, J = 5.0 Hz, 1H), 6.98−6.83 (m, 2H), 6.64
(s, 1H), 6.54 (s, 1H), 4.58 (s, 1H), 4.01 (d, J = 14.6 Hz, 1H), 3.86 (s,
3H), 3.81 (s, 3H), 3.72 (d, J = 14.6 Hz, 1H), 2.52 (t, J = 6.9 Hz, 2H),
1.78−1.19 (m, 4H), 0.87 (t, J = 7.4 Hz, 3H); 13C NMR (300 MHz,
CDCl3) δ 173.1, 149.5, 146.7, 143.7, 130.6, 126.7, 126.5, 126.2, 121.2,
113.5, 105.3, 67.1, 56.8, 56.6, 53.1, 52.6, 30.4, 20.8, 14.5; νmax(KBr)/
cm−1 1662, 1512, 1251, 1133, 704; MS (ESI) m/z 361 (M + H)+.
Brownish solid: mp 164.0−164.4 °C. Anal. Calcd for C19H24N2O3S: C,
63.31; H, 6.71; N, 7.77. Found C, 63.60; H, 6.92; N, 8.12.
4-Benzyl-3-hexyl-4,5-dihydro-1H-benzo[e][1,4]diazepin-2(3H)-
one (21): 1H NMR (300 MHz, CDCl3) δ 8.38 (broad s, 1H), 7.43−
7.21 (m, 6H), 7.06 (d, J = 5.2 Hz, 2H), 6.98 (d, J = 8.0 Hz, 1H), 3.88
(d, J = 14.8 Hz, 1H), 3.84 (d, J = 13.5 Hz, 1H), 3.73 (d, J = 14.8 Hz,
1H), 3.60 (d, J = 13.5 Hz, 1H), 3.54 (t, J = 7.1 Hz, 1H), 2.0−1.84 (m,
1H), 1.81−1.64 (m, 1H), 1.53−1.14 (m, 8H), 0.87 (t, J = 6.6 Hz, 3H);
13C NMR (300 MHz, CDCl3) δ 176.2, 139.2, 137.4, 131.0, 130.7,
129.3, 128.8 (2C), 127.6, 124.7, 120.5, 65.5, 56.9, 53.5, 32.2, 30.9, 29.5,
26.7, 23.0, 14.5; νmax(KBr)/cm−1 1672, 1589, 1492, 1290, 769; MS
(ESI) m/z 337 (M + H)+. White solid: mp 83.3−83.8 °C. Anal. Calcd
for C22H28N2O: C, 78.53; H, 8.39; N, 8.33. Found C, 78.05; H,8.12;
N, 8.78.
4-Cyclopropyl-3-hexyl-4,5-dihydro-1H-benzo[e][1,4]diazepin-
2(3H)-one (22): 1H NMR (300 MHz, CDCl3) δ 8.86 (br s, 1H),
7.27−7.16 (m, 2H), 7.09−6.97 (m, 2H), 4.01 (d, J = 14.9 Hz, 1H),
3.87 (d, J = 14.9 Hz, 1H), 3.59 (t, J = 7.7 Hz, 1H), 2.08−1.99 (m, 1H),
1.79 (quint, J = 7.1 Hz, 1H), 1.65−1.50 (m, 1H), 1.48−0.98 (m, 8H),
0.84 (t, J = 6.6 Hz, 3H), 0.57−0.36 (m, 4H); 13C NMR (300 MHz,
CDCl3) δ 176.6, 137.5, 130.5, 129.8, 128.7, 124.6, 120.5, 67.1, 54.2,
35.3, 32.1, 31.3, 29.5, 26.9, 23.0, 14.5, 8.2, 7.3; νmax(KBr)/cm−1 1653,
1592, 1440, 1048, 884; MS (ESI) m/z 287 (M + H)+. White solid: mp
87.1−87.6 °C. Anal. Calcd for C18H26N2O: C, 75.48; H, 9.15; N, 9.78.
Found C, 75.78; H, 9.43; N, 9.46.
4-(4-Chlorobenzyl)-3-isopropyl-4,5-dihydro-1H-naphtho[2,3-e]-
[1,4]diazepin-2(3H)-one (23): 1H NMR (300 MHz, CDCl3) δ 8.18
(broad s, 1H), 7.76 (d, J = 9.1 Hz, 2H), 7.64 (s, 1H), 7.52−7.22 (m,
7H), 4.01 (d, J = 13.2 Hz, 1H), 3.79 (d, J = 12.1 Hz, 1H), 3.65 (d, J =
12.1 Hz, 1H), 3.58 (d, J = 13.2 Hz, 1H), 1.80−1.51 (m, 1H), 0.89 (d, J
= 6.6 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H); 13C NMR (300 MHz, CDCl3)
δ 172.6, 137.8, 136.5, 134.0, 133.2, 131.8, 130.8, 130.3, 129.8, 129.1,
128.1, 127.6, 127.4, 126.2, 117.6, 72.2, 59.5, 56.1, 28.4, 20.4, 19.9;
νmax(KBr)/cm−1 1670, 1490, 1258, 1074, 750; MS (ESI) m/z 379/381
(M + H)+. White solid: mp 194.2−194.3 °C. Anal. Calcd for
C23H23ClN2O: C, 72.91; H, 6.12; N, 7.39. Found C, 73.05; H, 6.30; N,
7.12.
ASSOCIATED CONTENT
■
S
* Supporting Information
Characterization data and copies of H and 13C NMR spectra
1
4-Benzyl-3-(4-chlorophenyl)-4,5-dihydro-1H-benzo[e][1,4]-
diazepin-2(3H)-one (24): 1H NMR (300 MHz, DMSO-d6) δ 10.00
(broad s, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.38−7.25 (m, 8H), 7.13 (d, J
= 8.5 Hz, 2H), 7.05 (d, J = 7.7 Hz, 1H), 4.19 (s, 1H), 3.91 (d, J = 14.3
Hz, 1H), 3.55 (d, J = 14.3 Hz, 1H), 3.47 (d, J = 4.1 Hz, 1H); 13C
NMR (300 MHz, DMSO-d6) δ 168.3, 136.6 (2C), 136.0, 130.1, 128.9,
128.5, 126.9 (2C), 126.7, 126.0, 125.5, 125.4, 122.7, 119.1, 67.6, 54.2,
49.6; νmax(KBr)/cm−1 1670, 1492, 1263, 743; MS (ESI) m/z 363/365
(M + H)+. White solid: mp 242.5−242.7 °C. Anal. Calcd for
for all compounds synthesized. This information is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Tel.: +39-0321-375857. Fax: +39-0321-375821. E-mail: tron@
pharm.unipmn.it.
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dx.doi.org/10.1021/jo2015054 | J. Org. Chem. 2011, 76, 10258−10262

The Journal of Organic Chemistry
Note
ACKNOWLEDGMENTS
Financial support from Universita
is gratefully acknowledged.
■
̀
del Piemonte Orientale, Italy
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