Experimental and theoretical studies on the effect of the oxo group in 1,4-benzodiazepines

Article abstract of DOI:10.1039/c4ob00444b

Two families of regioisomeric 1,4-benzodiazepines, 4-benzyl-3H-benzo[e][1, 4]diazepin-5-ones and 4-benzoyl-4,5-dihydro-3H-benzo[e][1,4]diazepines, have been synthesized through a similar Ugi/reduction cyclization sequence. Their conformation and stability depend on the position of the tautomeric imine/enamine equilibrium present in the diazepine nucleus, which in turn depends on the relative position of the carbonyl group adjacent to the nitrogen at the 4-position in the benzodiazepine system. Moreover, the electrophilic center on the imine tautomer is essential for the antitumor activity of some benzodiazepines as a DNA binding position. The mechanism of tautomerization in the presence or absence of the oxo group has been studied computationally using DFT methods (B3LYP/6-31G** level). This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00444b

Organic &
Biomolecular Chemistry
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PAPER
Experimental and theoretical studies on the effect
of the oxo group in 1,4-benzodiazepines†
Cite this: Org. Biomol. Chem., 2014,
12, 4905
Pablo Pertejo,a María García-Valverde,*a Pablo Peña,a Nicolás A. Cordero,b
Tomás Torrobaa and Alfonso González-Ortegac
Two families of regioisomeric 1,4-benzodiazepines, 4-benzyl-3H-benzo[e][1,4]diazepin-5-ones and
4-benzoyl-4,5-dihydro-3H-benzo[e][1,4]diazepines, have been synthesized through
a similar Ugi/
reduction cyclization sequence. Their conformation and stability depend on the position of the tauto-
meric imine/enamine equilibrium present in the diazepine nucleus, which in turn depends on the relative
position of the carbonyl group adjacent to the nitrogen at the 4-position in the benzodiazepine system.
Moreover, the electrophilic center on the imine tautomer is essential for the antitumor activity of some
benzodiazepines as a DNA binding position. The mechanism of tautomerization in the presence or
absence of the oxo group has been studied computationally using DFT methods (B3LYP/6-31G** level).
Received 26th February 2014,
Accepted 9th May 2014
DOI: 10.1039/c4ob00444b
www.rsc.org/obc
intermediates in the synthesis of fused hydantoin–benzo-
Introduction
diazepines.6 The synthesis of these intermediates was carried
The Ugi reaction followed by post-condensation transform- out by a sequential Ugi reaction–deprotection cyclization
ations constitutes a powerful synthetic tool for the preparation employing an Ugi-5-component CO2 mediated condensation.
of pseudopeptidic structures.1 The synthesis of peptidomi- We thought that the similitude of intermediates B with benzo-
metics capable of mimicking β-turn structures has gained diazepines A would be a good starting point in the design of
interest for the discovery of new therapeutic agents, since the new pseudopeptidic structures.
interaction between the peptide ligands and their receptor
Following this idea, we planned the synthesis of two
targets usually implies these structures.2 An approach to con- different families of regioisomeric benzodiazepines, 4-benzyl-
struct peptidomimetics involves the design of conformation- 3H-benzo[e][1,4]diazepin-5(4H)-ones type A and 4-benzoyl-4,5-
ally restricted analogs by incorporation of heterocycles to dihydro-3H-benzo[e][1,4]diazepines analogous to intermediate
improve the characteristics of the receptor-bound confor- B, following a similar strategy. In the course of this work, we
mation of the endogenous peptide.3
have observed that the position of the carbonyl group is
Following this strategy, we recently described the synthesis crucial in the evolution of the imine–enamine tautomeric equi-
of a new group of pseudopeptidic 3H-benzo[e][1,4]diazepin- librium present in the diazepine nucleus, which in turn is
5(4H)-ones A (Fig. 1) by a sequential Ugi reaction–Staudinger/ crucial for the conformation and stability of these systems and
aza-Wittig cyclization.4 Interestingly, the backbone of these therefore for the development of new drugs. On the basis of
heterocycles superimposes well with β-turn motifs, such as the experimental results, we have carried out computational
those in the δ antigen, LDL receptor module, acetyl-CoA
carboxylase and erabutoxin B,5 which makes them useful
candidates for designing new drugs.
Additionally a new series of 4-methoxycarbonyl-4,5-dihydro-
3H-benzo[e][1,4]diazepines B (Fig. 1) has been described as
aChemistry Department, Faculty of Science, University of Burgos, 09001-Burgos,
Spain. E-mail: magaval@ubu.es
bPhysics Department, Higher Polytechnic School, University of Burgos, 09001-Burgos,
Spain
cOrganic Chemistry Department, Faculty of Science, University of Valladolid,
47011-Valladolid, Spain
†Electronic supplementary information (ESI) available: Spectra of all new
compounds and computational data. See DOI: 10.1039/c4ob00444b
Fig. 1 1,4-Benzodiazepines synthesized using the Ugi reaction.
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studies to explain the different behaviors of these
regioisomers.
These drawbacks prompted us to attempt a new sequence
to overcome them, looking for a more ecofriendly, simple and
scalable methodology, and basically a methodology easily
applicable to the synthesis of both families of benzodiazepines
under study in order to be able to compare the results
obtained from their syntheses.
Results and discussion
In this way we decided to use the Ugi reaction followed by a
reduction cyclization sequence, choosing the nitro group as a
masked amino group for subsequent cyclizations. Therefore,
in the synthesis of benzo[e][1,4]diazepine-5-ones A, we selected
the commercially available 2-nitrobenzoic acid in place of
2-azidobenzoic acid as the carboxylic acid component in the
Ugi reaction. Following the most common procedure,11 the
corresponding imine was pre-formed by mixing substituted
benzylamine 2a–e (1 equiv.) with a solution of arylglyoxal 1a–b
(1 equiv.) in methanol. Alkyl isocyanide 4a–b (1 equiv.) and
2-nitrobenzoic acid 3 (1 equiv.) were then added to the imine
solution and the mixture was stirred at room temperature for
one day until precipitation of Ugi products 5. Filtration and
recrystallization of the solid afforded the Ugi adduct exclu-
sively as an enol tautomer on the basis of NMR spectra
(Table 1).4
Looking for a general method for the synthesis of both
families of benzodiazepines we thought that the method-
ologies previously developed for the synthesis of benzo[e][1,4]-
diazepine-5-ones A4 or 4,5-dihydro-3H-benzo[e][1,4]diazepines
B had several drawbacks. On the one hand, the Ugi–Staudin-
ger/aza-Wittig methodology described in the synthesis of A
used 2-azidobenzoic acid as the starting material for the Ugi
reaction. This reagent had to be synthesized from anthranilic
acid and sodium azide7 and the potential explosion hazard of
azides discourages the use of this process.8 Moreover the Stau-
dinger/aza-Wittig sequence requires anhydrous conditions, an
inert atmosphere and generates large quantities of triphenyl-
phosphine oxide which had to be eliminated by chromato-
graphy.9 On the other hand, the sequence Ugi/deprotection
cyclization described in the synthesis of 4,5-dihydro-3H-benzo-
[e][1,4]diazepines B6 used ortho-N-Boc-benzylamine as the
starting amine in the Ugi reaction, an amine that had to be
The conversion of Ugi adducts 5 to 5-oxobenzo[e][1,4]diaze-
pin-3-carboxamides 6 was accomplished by reduction of the
nitro group with subsequent cyclization. The key factor in the
choice of the reduction methodology was the tolerance toward
synthesized from 2-aminobenzylamine in
a
three-step
sequence resulting in a global process with a poor atom
economy.10
Table 1 Synthesis of benzo[e][1,4]diazepine-5-ones from 2-nitrobenzoic acid
Entry
1 (R1)
2 (R2)
4 (R3)
5a (%)
5a (65)
Metal/acid
6a (%)
1
2
3
4
5
6
7
8
1a (H)
2a (H)
4a (cC6H11
)
Fe/AcOHb
6a (41)
6a (89)e
6a (85)
6b (84)
6c (91)
6d (84)
6e (87)
6f (82)
6g (83)
6h (81)
6i (83)
6j (87)
Fe/HClc
SnCl2/HCld
SnCl2/HCld
SnCl2/HCld
SnCl2/HCld
SnCl2/HCld
SnCl2/HCld
SnCl2/HCld
SnCl2/HCld
SnCl2/HCld
SnCl2/HCld
1a (H)
1a (H)
1a (H)
1a (H)
1b (F)
1a (H)
1a (H)
1a (H)
1a (H)
2b (CH3)
2c (OCH3)
2d (F)
2e (Cl)
2a (H)
4a (cC6H11
4a (cC6H11
4a (cC6H11
4a (cC6H11
4a (cC6H11
4b (CH2C6H5)
4b (CH2C6H5)
4b (CH2C6H5)
4b (CH2C6H5)
)
)
)
)
)
5b (64)
5c (66)
5d (65)
5e (65)
5f (57)
5g (66)
5h (63)
5i (69)
5j (61)
9
2a (H)
10
11
12
2b (CH3)
2c (OCH3)
2e (Cl)
a Isolated yields. b Fe (10 equiv.), acetic acid, 70 °C, 3 h. c Fe (10 equiv.), HCl (3 equiv.), ethanol, reflux, 45 min. d SnCl2 (10 equiv.), HCl (3 equiv.),
ethanol, reflux, 45 min. e Isolated yield of benzodiazepine 6a when the reduction was quantitative.
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Table 2 Synthesis of 4-benzoyl-4,5-dihydro-3H-benzo[e][1,4]diazepines from 2-nitrobenzylamine
Entry
4 (R3)
8 (R4)
9a (%)
10a (%)
1
2
3
4b (CH2C6H5)
8a (H)
8b (Br)
8b (Br)
9a (46)
9b (38)
9d (41)
10a (59)
10b (61)
10c (62)
4a (cC6H11
)
4b (CH2C6H5)
a Isolated yields.
.
other functional groups present in reactants and/or products cation of products by recrystallization, the lack of need for an
such as ketones, imines, benzyl amides or aryl halides. inert atmosphere or dry solvents as that required for the Stau-
Initially we investigated the use of iron in acetic acid,12 but dinger/aza-Wittig reaction, the high efficiency of the reaction,
the reduction took place with poor conversion (Table 1, relatively insensitive to small changes in reagents concen-
entry 1). We then tried the reduction with iron and hydro- tration or time, and the relatively easy disposal of the non-
chloric acid in hot ethanol,13 and although the initial results toxic residues. Additionally, this methodology was readily
were promising (Table 1, entry 2), conversions were not applicable to the synthesis of other series of benzodiazepines
consistent from run to run, depending on several factors such we were interested in.
as temperature, concentration or stirring efficiency.14
In this way, the second family of benzodiazepines, the
Looking for a more robust method, we studied the reducing 4-benzoyl-4,5-dihydro-3H-benzo[e][1,4]diazepines, was syn-
ability of stannous chloride in the presence of hydrochloric thesized by applying a similar methodology to that described
acid.15 Fortunately the reduction using this system took place above, in only two steps from the commercial products. We
with high reproducibility and high yield for many different started from commercial 2-nitrobenzylamine 7 as the amine
substituents (Table 1). The typical procedure followed was component containing the nitro group for further cyclization.
treatment of the suspension of the Ugi adducts 5 in ethanol Its reaction with phenylglyoxal 1a, alkyl isocyanide 4a–b and
with stannous chloride (10 equiv.) and hydrochloric acid solu- carboxylic acid 8a–c in the typical procedure10 yielded the Ugi
tion 0.6 M (3 equiv.). These reactions were performed at reflux adducts 9. The similar characteristics of Ugi adducts 5 and 9
with full conversion within 45 minutes.
allowed us to apply the optimized reduction conditions for the
We found several advantages in the reduction methodology former, yielding benzodiazepines 10 (Table 2). When the ter-
chosen, such as the cost and ready availability of the reducing ephthalic acid was used as the carboxylic component, double
agent which can tolerate a variety of reducible functionalities, Ugi adduct 9d and double benzodiazepine 10d were obtained
the high yields and short reaction times, the simple purifi- with higher yields than simple Ugi adducts 9a–c and benzo-
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Then, the experimental results should be explained as a
consequence of the acidic method employed in the reduction
process; otherwise, both benzodiazepines should be obtained
as the same tautomer due to the high barrier of interconver-
sion which prevents the tautomerization from the initial tauto-
mer formed in the cyclization. Under these acidic conditions
in ethanol, the benzo[e][1,4]diazepine-5-one 6g is again more
stable as imine than as enamine (11.7 kcal mol−1), whereas
the 4,5-dihydrobenzo[e][1,4]diazepine 10a is again more stable
as enamine (9.6 kcal mol−1). However, the free energies of acti-
vation calculated for each stage of the tautomerization in acid
medium, protonation of imine and formation of enamine, are
significantly lower in both families of compounds than the
interconversion barrier under neutral conditions (Fig. 2).
For the benzo[e][1,4]diazepine-5-one 6g the activation
energy decreases from 58.7 kcal mol−1 under neutral con-
ditions to 26.5 and 29.0 kcal mol−1 in acidic medium for the
protonation of imine and the enamine formation respectively
(Fig. 2). These values allow us to calculate the reaction rate at
each stage from the Eyring–Polanyi equation indicating that
tautomerization is not possible at room temperature (k1 = 2.45
Scheme 1 Oxidative cleavage
diazepines.
of
4,5-dihydro-1H-benzo[e][1,4]-
diazepines 10a–c due to their lower solubility. The high sym-
metry of compounds 9d and 10d simplifies their NMR spectra
(see ESI†).
Interestingly, the tautomer observed by NMR spectra of 10
was not the 4,5-dihydro-3H-benzo[e][1,4]diazepine as has been
proposed for compounds of type B (Fig. 1)6 but the 4,5-
dihydro-1H-benzo[e][1,4]diazepine 10. Moreover, this tautomer
underwent an oxidative cleavage on standing in CDCl3 in the
presence of air (Scheme 1) as has been described for fused
hydantoinbenzodiazepines,6 probably through the formation
of unstable 1,2-dioxetanes generated in a [2 + 2] singlet oxygen
addition over the double bond in the enamine.16 This means
that the tautomerism is important not only for the confor-
mation but also for the stability of these systems. Moreover,
the electrophilic center on the imine tautomer is essential for
the antitumor activity of some benzodiazepines as a DNA
binding position.17 For these reasons it is very important to
understand the effect of the presence of a carbonyl group on
the benzodiazepine system.
Comparing the structure of benzodiazepines 6 and 10 we
could establish that the presence of the oxo group at the
5-position in the benzodiazepine nucleus is critical in the
tautomeric equilibrium imine/enamine. In order to under-
stand the observed results DFT quantum chemical calculations
were carried out using Gaussian 0918 on two models, benzo-
diazepines 6g and 10a. The geometries of all species were fully
optimized at the B3LYP/6-31G** level.
First, we studied the stability of these benzodiazepines
under neutral conditions; the calculations showed the
different stability of tautomers depending on the relative posi-
tion of the carbonyl group adjacent to the nitrogen at the
4-position in the benzodiazepine system. The imine tautomer
in the benzo[e][1,4]diazepine-5-one 6g is 7.0 kcal mol−1 more
stable than the enamine component in ethanol, whereas in
the 4,5-dihydrobenzo[e][1,4]diazepine 10a the enamine is
2.3 kcal mol−1 more stable than the imine tautomer. However,
our calculations demonstrate that the interconversion between
tautomers is not possible at moderate temperatures under
neutral conditions because the free energy of activation calcu-
lated for the tautomerization in both cases is too high (58.7
and 49.0 kcal mol−1 for 6g and 10a respectively for the tauto-
merization in a water-assisted process).19
× 10−7 −1, k2 = 3.35 × 10−9 −1) and it is a very slow process in
s s
boiling ethanol (k1 = 3.26 × 10−3 s−1, k2 = 1.09 × 10−4 s−1).
Additionally, the conversion of imine to enamine is thermo-
dynamically unfavorable, especially in the second stage with
an equilibrium constant of 1.57 × 10−8. Although we have con-
sidered only one water molecule as a proton shuttle molecule
and the real tautomerization barriers for 6 (as for the tauto-
merization in 10) could be much smaller, this would not influ-
ence the conclusions, since only the thermodynamic product
6im would be obtained. With these results in hand it is inter-
esting to note that these benzodiazepines are then potential
drug candidates, not only because of their conformation4 but
also due to their stability at high temperature and under acidic
conditions.20
The behavior of 4-benzoyl-4,5-dihydrobenzo[e][1,4]diaze-
pines 10 is quite different. For the benzodiazepine 10a the
enamine is the most stable tautomer under acidic conditions
in ethanol (thermodynamically favorable) with equilibrium
constants for the conversion of imine to enamine of 1.87 × 103
and 6.23 × 103 (calculated using the Arrhenius equation), for
protonation and generation of enamine respectively, and
besides, the tautomeric interconversion under acidic con-
ditions is fast at room temperature (kinetically favorable) with
reaction rates of k1 = 6.51 × 102 s−1 and k2 = 5.50 × 102 s−1 for
each stage, calculated from the free energies of activation in
both stages (about 13.7 kcal mol−1, Fig. 2). The higher stability
of the enamine tautomer is a problem, as these regioisomers
undergo an oxidative cleavage of the double bond in the pres-
ence of oxygen (Scheme 1). Thus, in contrast with benzo[e][1,4]-
diazepine-5-one, these regioisomers would have several pro-
blems as pharmaceutical products due to their low stability in
air.
The process of tautomerization is similar for both families
of regioisomeric benzodiazepines. It starts with the protona-
tion on the nitrogen atom of the imine groups (Scheme 2). The
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Fig. 2 Energy diagrams for the imine–enamine interconversion of 6g (left) and 10a (right) in acidic medium. The energy values reported in the
diagram are in kcal mol−1 and refer to calculations performed in ethanol.
Scheme 2 Process of tautomerization for benzodiazepines 6g and 10a.
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Fig. 3 Frontier molecular orbitals surfaces of the imine (left) and enamine tautomers (right) of 6 which have been constructed by using the B3LYP/
6-31G** level of theory.
Fig. 4 Frontier molecular orbital surfaces of the imine (left) and enamine tautomers (right) of 10 which have been constructed by using the B3LYP/
6-31G** level of theory.
similar charge distribution calculated for structures 6im and the benzodiazepine system from the amide group to the
10im by NBO analysis explains the similarity between the acti- benzene ring and the CvN π-bonding, whereas in 10im it is
vation complexes (TS16 and TS110, Fig. 2) found in the first mainly localized on CvN π-bonding and the benzene ring.
stage.
The HOMO surfaces for the enamine tautomers 6en and 10en
However the second stage seems to be dependent on the are similarly delocalized over the CvC π-bonding and the
regioisomer under study. This is supported by the fact that the benzene ring. The HOMO–LUMO gap is similar for all the tau-
NBO analysis of 10imH reveals a more negative charge in the tomers (Fig. 3 and 4).
oxygen of the carbonyl group adjacent to the nitrogen at the
The calculated bond lengths reveal some differences
4-position in the 1,4-diazepine ring (−0.66e) than in the between tautomers of benzo[e][1,4]diazepine-5-ones 6 and 4,5-
oxygen of the 3-aminocarbonyl substituent (−0.63e). This dihydrobenzo[e][1,4]diazepines 10. The C2vN1 bonds in the
difference favors the participation of the former group in a imine tautomers 6im and 10im have similar lengths and the
seven-member ring transition state TS210 in which a molecule N1–C7 and C5–C6 bonds are slightly shorter in 6im. This differ-
of water acts as a “hydrogen bridge”.
ence can be explained by the conjugation between the imine
The electronic distribution of the HOMO of the imine tau- and the amide group through the benzene ring only possible
tomers depends on the presence of the oxo group in the in benzodiazepines 6. In the enamine forms, the C2–N1 bond
benzodiazepine ring, the HOMO in 6im is delocalized along is much shorter in 10en than in 6en due in this case to the
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General procedure for the synthesis of Ugi adducts 5a–j
A solution of arylglyoxal 1a–b (1 mmol) and substituted ben-
zylamine 2a–e (1 mmol) in methanol was stirred for 15 min at
room temperature. Then, 2-nitrobenzoic acid 3 (0.167 g,
1 mmol) and isocyanide 4a–b (1 mmol) were added and the
mixture was stirred for 1 day until a solid precipitated. The
solid was filtered and recrystallized from i-PrOH–i-Pr2O.
(E)-N-Cyclohexyl-2-[N-benzyl-N-(2-nitrobenzoyl)amino]-3-
hydroxy-3-phenylacrylamide 5a. White solid, m.p. 192–193 °C.
(conformational isomers E1/E2: 77/23).4 IR (KBr, cm−1): 3418
(OH), 2937, 2855, 1651 (CvO), 1538, 1350. 1H NMR (300 MHz,
CDCl3) δ: 15.97 (s, 0.23H, OH E2), 15.36 (s, 0.77H, OH E1),
8.35–6.80 (m, 13H, HAr E1/E2), 6.36 (d, J = 8.1 Hz, 0.77H, NH
E1), 5.87 (d, J = 8.1 Hz, 0.23H, NH E2), 5.86 (d, J = 13.6 Hz,
0.23H, CH2 benz E2), 4.12 (d, J = 13.8 Hz, 0.77H, CH2 benz E1),
3.77 (d, J = 13.8 Hz, 0.77H, CH2 benz E1), 3.62 (d, J = 13.6 Hz,
023H, CH2 benz E2), 3.70–3.55 (m, 0.77H, CH E1), 3.25–3.10
(m, 0.23H, CH E2), 2.05–0.30 (m, 10H, E1/E2). 13C NMR
(75 MHz, CDCl3) δ: 171.4, 169.0, 168.5, 168.4, 145.5 (Cq E1/E2),
135.0 (CHAr), 133.7 (Cq E1/E2), 133.5 (CHAr), 132.0 (Cq), 131.6,
130.6, 130.5, 130.4, 130.2, 130.1, 129.4, 129.3, 128.8, 128.7,
128.1, 127.9, 127.7, 127.6, 125.6, 125.1 (CHAr E1/E2), 105.1
(Cq), 56.2 (CH2), 54.0 (CH2), 49.0 (CH), 48.7 (CH), 32.8 (CH2),
32.7 (CH2), 32.0 (CH2), 31.8 (CH2), 25.6 (CH2), 25.4 (CH2), 25.2
(CH2), 25.2 (CH2). MS (EI) m/z (relative intensity): 499 (M+, 5);
349 (20); 224 (10); 150 (53); 105 (49); 91 (100); 77 (19). HRMS
(EI): calcd for C29H29N3O5 [M+] 499.2107 found 499.2094.
(E)-N-Cyclohexyl-2-[N-(4-methylbenzyl)-N-(2-nitrobenzoyl)-
amino]-3-hydroxy-3-phenylacrylamide 5b. White solid, m.p.
Fig. 5 Relevant bond lengths in the diazepine system calculated at the
B3LYP/6-31G** level of theory.
more favored conjugation with the carboxamide group in
3-position through the double bond C2vC3 of the enamine
(Fig. 5).
Conclusions
In summary, we have developed a simple and scalable method- 185–186 °C (conformational isomers E1/E2: 63/37). IR (KBr,
ology for the synthesis of regioisomeric pseudopeptidic benzo- cm−1): 3425 (OH), 2928, 2856, 1651 (CvO), 1538, 1349. 1H
diazepines from economical and available reagents in only two NMR (300 MHz, CDCl3) δ: 15.96 (s, 0.37H, OH E2), 15.37 (s,
steps. The tautomerism present in the 1,4-benzodiazepines is 0.63H, OH E1), 8.33–6.66 (m, 13H, HAr E1/E2), 6.33 (d, J = 8.3
crucial to understand the different behaviors of 4-benzyl-3H- Hz, 0.63H, NH E1), 5.89 (d, J = 13.9 Hz, 0.37H, CH2 benz E2),
benzo[e][1,4]diazepin-5(4H)-ones and 4-benzoyl-4,5-dihydro- 5.82 (d, J = 8.3 Hz, 0.37H, NH E1), 4.08 (d, J = 13.9 Hz, 0.63H,
3H-benzo[e][1,4]diazepines in acidic medium, their confor- CH2 benz E1), 3.73 (d, J = 13.9 Hz, 0.63H, CH2 benz E1), 3.58
mation and stability as well as to evaluate their potential use (d, J = 13.9 Hz, 0.37H, CH2 benz E2), 3.70–3.60 (m, 0.63H, CH
as drug candidates. The experimental results have been con- E1), 3.30–3.06 (m, 0.37H, CH E2), 2.33 (s, 1.11H, CH3 E2), 2.28
firmed by DFT quantum calculations at the B3LYP/6-31G** (s, 1.89H, CH3 E1), 2.02–0.21 (m, 10H, E1/E2). 13C NMR
level of theory.
(75 MHz, CDCl3) δ: 171.3, 169.0, 168.3, 145.4, 138.5 (Cq E1/E2),
135.1 (CHAr), 134.5 (Cq), 133.5 (CHAr), 133.4 (Cq), 131.6, 130.6,
130.5, 130.4, 130.1, 130.0, 129.4, 128.6, 128.1, 127.9, 127.7,
127.6, 125.6, 125.1 (CHAr E1/E2), 105.0 (Cq), 55.9 (CH2), 53.7
(CH2), 48.9 (CH), 48.7 (CH), 32.8 (CH2), 32.7 (CH2), 31.9 (CH2),
31.8 (CH2), 25.6 (CH2), 25.5 (CH2), 25.4 (CH2), 25.3 (CH2), 25.2
(CH2), 21.4 (CH3). MS (EI) m/z (relative intensity): 513 (M+, 4);
Experimental section
General information
Melting points are not corrected. Infrared spectra were regis- 363 (16); 269 (9); 150 (71); 105 (100); 77 (13). HRMS (EI): calcd
1
tered in potassium bromide tablets. H and 13C NMR spectra for C30H31N3O5 [M+] 513.2264 found 513.2258.
were recorded in CDCl3 and DMSO-d6 at 400 and 100 MHz or
(E)-N-Cyclohexyl-2-[N-(4-methoxylbenzyl)-N-(2-nitrobenzoyl)-
at 300 and 75 MHz on a Varian Inova 400 or a Varian Mercury amino]-3-hydroxy-3-phenylacrylamide 5c. White solid, m.p.
300, respectively. Chemical shifts are reported in parts per 192–193 °C (conformational isomers E1/E2: 57/43). IR (KBr,
million with respect to residual solvent protons, and coupling cm−1): 3425 (NH), 2937, 2855, 1651 (CvO), 1538, 1351. 1H
constants are reported in hertz. Low resolution mass spectra NMR (300 MHz, CDCl3) δ: 15.95 (s, 0.43H, OH E2), 15.37 (s,
and HRMS were recorded in the positive ion mode by elec- 0.57H, OH E1), 8.33–6.63 (m, 13H, HAr E1/E2), 6.36 (d, J = 7.9
tronic impact at 70 eV.
Hz, 0.57H, NH E1), 5.86 (d, J = 7.9 Hz, 0.43H, NH E2), 5.80 (d,
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J = 13.7 Hz, 0.43H, CH2 benz E2), 4.07 (d, J = 13.9 Hz, 0.57H, 408 (16), 410 (13), 383 (100), 288 (39), 245 (44), 150 (83), 125
CH2 benz E1), 3.79 (s, 1.3 H, CH3 E2), 3.76 (s, 1.7 H, CH3 E1), (74), 105 (51). HRMS (EI): calcd for C29H28ClN3O5 [M+]
3.73 (d, J = 13.9 Hz, 0.57H, CH2 benz E1), 3.69–3.62 (m, 0.43H, 533.1717 found 533.1717.
CH E2), 3.58 (d, J = 13.7 Hz, 0.43H, CH2 benz E2), 3.31–3.16
(E)-N-Cyclohexyl-2-[N-benzyl-N-(2-nitrobenzoyl)amino]-3-
(m, 0.57H, CH E1), 2.10–0.27 (m, 10H, E1/E2). 13C NMR hydroxy-3-(4-fluoro)phenylacrylamide 5f. White solid, m.p.
(75 MHz, CDCl3) δ: 171.3, 169.5, 169.0, 168.4, 168.3, 168.1, 154–155 °C (conformational isomers E1/E2: 63/37). IR (KBr,
160.0, 159.8, 146.7, 145.4 (Cq E1/E2), 135.1, 135.0, 133.8, cm−1): 3422 (OH), 2928, 2855, 1651 (CvO), 1538, 1403, 1349.
133.6, 133.5, 132.0, 131.6, 131.4, 131.3, 130.6, 130.5, 130.4, 1H NMR (300 MHz, CDCl3) δ: 16.08 (s, 0.37H, OH E2), 15.42 (s,
129.4, 128.8, 128.7, 128.5, 128.1, 127.9, 127.7, 127.6, 125.7, 0.63H, OH E1), 8.42–6.75 (m, 13H, HAr E1/E2), 6.46 (d, J = 7.9
125.6, 125.1, 114.7, 114.1 (CHAr E1/E2), 107.9, 104.9 (Cq E1/ Hz, 0.63H, NH E1), 5.88 (d, J = 7.9 Hz, 0.37H, NH E2), 5.85 (d,
E2), 55.5 (CH2), 53.3 (CH3), 49.3, 48.9, 48.7 (CH E1/E2), 32.8, J = 13.9 Hz, 0.37H, CH2 benz E2), 4.13 (d, J = 13.9 Hz, 0.63H,
32.0, 32.0, 25.7, 25.6, 25.4, 25.2 (CH2 E1/E2). MS (EI) m/z (rela- CH2 benz E1), 3.87 (d, J = 13.9 Hz, 0.63H, CH2 benz E1),
tive intensity): 529 (M+, 4.4), 408 (9), 285 (14), 150 (45), 121 3.76–3.65 (m, 0.63H, CH E2), 3.62 (d, J = 13.9 Hz, 0.37H, CH2
(100), 105 (22). HRMS (EI): calcd for C30H31N3O6 [M+] 529.2213 benz E2), 3.27–3.09 (m, 0.37H, CH E2), 2.05–0.26 (m, 10H, E1/
found 529.2208.
E2). 13C NMR(75 MHz, CDCl3) δ: 170.7, 169.4, 168.8, 168.6,
1
(E)-N-Cyclohexyl-2-[N-(4-fluorobenzyl)-N-(2-nitrobenzoyl)- 167.4 (Cq E1/E2), 164.0 (d, J = 250.4 Hz, Cq E1/E2), 145.4 (Cq
amino]-3-hydroxy-3-phenylacrylamide 5d. White solid, m.p. E1/E2), 135.2, 133.6, 133.5, 133.5, 133.4, 130.7, 130.5, 130.2,
182–183 °C (conformational isomers E1/E2: 56/44). IR (KBr, 130.0, 129.8, 129.7, 129.4, 128.8, 128.7, 127.7, 127.6, 116.3 (d,
cm−1): 3419 (OH), 2927, 2855, 1651 (CvO), 1530,1347. 1H 2J = 21.5 Hz), 116.0 (d, J = 21.5 Hz, CHAr E1/E2), 107.6, 104.7
2
NMR (400 MHz, CDCl3) δ: 15.98 (s, 0.44H, OH E2), 15.37 (s, (Cq E1/E2), 56.0, 53.9 (CH2 E1/E2), 49.1, 48.7 (CH E1/E2), 32.8,
0.56H, OH E1), 8.30–6.71 (m, 13H, HAr, E1/E2), 6.36 (d, J = 7.9 32.8, 32.0, 31.8, 25.6, 25.4, 25.4, 25.3, 25.2, 25.2 (CH2 E1/E2).
Hz, 0.56H, NH E1), 5.89 (d, J = 7.9 Hz, 0.44H, NH E2), 5.76 (d, MS (EI) m/z (relative intensity): 517 (M+, 4); 367 (20); 278 (22);
J = 13.9 Hz, 0.44H, CH2 benz E2), 4.08 (d, J = 13.9 Hz, 0.56H, 277 (31); 150 (53); 123 (50); 98 (25); 91 (100). HRMS (EI): calcd
CH2 benz E1), 3.77 (d, J = 13.9 Hz, 0.56H, CH2 benz E1), for C29H28N3O5F [M+] 517.2013 found 517.2009.
3.74–3.63 (m, 0.44H, CH E2), 3.58 (d, J = 13.9 Hz, 0.44H, CH2
(E)-N-Benzyl-2-[N-benzyl-N-(2-nitrobenzoyl)amino]-3-
benz E2), 3.30–3.19 (m, 0.56H, CH E1), 2.05–0.26 (m, 10H, E1/ hydroxy-3-phenylacrylamide 5g. White solid, m.p. 148–149 °C
E2). 13C NMR (100 MHz, CDCl3) δ: 171.7, 171.6, 169.4, 169.0, (conformational isomers E1/E2: 58/42). IR (KBr, cm−1): 3427
1
1
168.6, 168.3 (Cq E1/E2), 163.1 (d, J = 247.8 Hz), 162.9 (d, J = (OH), 3064 (CAr), 3032, 2923, 1651 (CvO), 1529, 1402, 1346. 1H
247.8 Hz, E1/E2), 146.9, 145.5, 135.2 (Cq E1/E2), 135.1 (CHAr), NMR (300 MHz, CDCl3) δ: 15.76 (s, 0.42H, OH E2), 15.13 (s,
134.9, 134.8, 133.7 (Cq E1/E2), 133.5 (CHAr), 133.4, 133.4, 132.6 0.58H, OH E1), 8.31–6.70 (m, 19H, HAr, E1/E2), 7.02–6.94 (m,
(Cq E1/E2), 132.0, 131.8, 131.7, 131.3, 130.6, 130.5, 129.6, 0.58H, NH E1), 6.51–6.39 (m, 0.42H, NH E2), 5.80 (d, J = 13.6
128.9, 128.6, 128.2, 127.9, 127.7, 127.6, 125.6, 125.1 (CHAr E1/ Hz, 0.42H, CH2 benz E2), 4.49 (dd, J = 15.0, 6.0 Hz, 0.58H, CH2
2
2
E2), 116.0 (d, J = 21.5 Hz), 115.8 (d, J = 21.5 Hz, CHAr E1/E2), benz E1), 4.39 (dd, J = 15.0, 6.0 Hz, 0.58H, CH2 benz E1), 4.11
107.8, 104.7 (Cq E1/E2), 55.2, 53.2 (CH2 E1/E2), 49.0, 48.7 (CH (d, J = 13.8 Hz, 0.58H, CH2 benz E1), 4.07 (dd, J = 14.5, 5.5 Hz,
E1/E2), 32.8, 32.1, 32.0, 25.7, 25.6, 25.4, 25.3, 25.2, 24.9, 24.9 0.42H, CH2 benz E2), 3.81(d, J = 13.8 Hz, 0.58H, CH2 benz E1),
(CH2 E1/E2). MS (EI) m/z (relative intensity): 517 (M+, 4.6), 367 3.62 (d, J = 13.6 Hz, 0.42H, CH2 benz E2), 3.55 (dd, J = 14.5, 5.5
(13), 150 (87), 109 (100), 105 (54). HRMS (EI): calcd for Hz, 0.42H, CH2 benz E2). 13C NMR (75 MHz, CDCl3) δ: 171.6,
C29H28FN3O5 [M+] 517.2013 found 517.2002.
170.2, 170.0, 168.5, 146.8, 145.5, 137.9, 137.2, 136.1 (Cq E1/
(E)-N-Cyclohexyl-2-[N-(4-chlorobenzyl)-N-(2-nitrobenzoyl)- E2), 135.1, 134.8, 133.4, 133.3, 131.8, 130.7, 130.6, 130.2, 130.1,
amino]-3-hydroxy-3-phenylacrylamide 5e. White solid, m.p. 129.9, 129.5, 128.8, 128.7, 128.2, 128.1, 128.0, 127.6, 127.4,
197–198 °C (conformational isomers E1/E2: 55/45). IR (KBr, 125.6, 125.4 (CHAr E1/E2), 107.6, 105.0 (Cq E1/E2), 56.1, 53.6,
cm−1): 3424 (OH), 2930, 2857, 1651 (CvO), 1538, 1350. 43.4, 43.1 (CH2 E1/E2). MS (EI) m/z (relative intensity): 507 (M+,
1H NMR (300 MHz, CDCl3) δ: 16.00 (s, 0.45H, OH E2), 15.40 (s, 6.6), 357 (17), 150 (43), 91 (100). HRMS (EI): calcd for
0.55H, OH E1), 8.30–6.71 (m, 13H, HAr, E1/E2), 6.38 (d, J = 8.3 C30H25N3O5 [M+] 507.1794 found 507.1796.
Hz, 0.55H, NH E1), 5.92 (d, J = 8.3 Hz, 0.45H, NH E2), 5.81 (d,
J = 13.9 Hz, 0.45H, CH2 benz E2), 4.09 (d, J = 13.9 Hz, 0.55H, 3-hydroxy-3-phenylacrylamide
(E)-N-Benzyl-2-[N-(4-methylbenzyl)-N-(2-nitrobenzoyl) amino]-
5h. White solid, m.p.
CH2 benz E1), 3.79 (d, J = 13.9 Hz, 0.55H, CH2 benz E1), 144–145 °C (conformational isomers E1/E2: 64/36). IR (KBr,
3.75–3.72 (m, 0.45H, CH E2), 3.57 (d, J = 13.9 Hz, 0.45H, CH2 cm−1): 3441 (OH), 3065 (CAr), 3031, 2934, 2859, 1651 (CvO),
1
benz E2), 3.34–3.14 (m, 0.55H, CH E1), 2.10–0.90 (m, 10 H). 1393, 1348. H NMR (300 MHz, CDCl3) δ: 15.71 (s, 0.36H, OH
13C NMR (75 MHz, CDCl3) δ: 171.2, 169.4, 168.9, 168.6, 168.4, E2), 15.09 (s, 0.64H, OH E1), 8.29–6.52 (m, 18H, HAr, E1/E2),
168.1, 146.8, 145.5 (Cq E1/E2), 135.2, 134.8, 133.6, 133.3, 7.03–6.95 (m, 0.64H, NH E1), 6.51–6.39 (m, 0.36H, NH E2),
132.1, 131.7, 131.6, 131, 3, 130.7, 130.6, 130.5, 129.5, 129.4, 5.77 (d, J = 13.5 Hz, 0.36H, CH2 benz E2), 4.49 (dd, J = 15.0, 6.2
128.9, 128.6, 128.1, 127.9, 127.7, 127.5, 125.7, 125.2 (CHAr), Hz, 0.64H, CH2 benz E1), 4.37 (dd, J = 15.0, 6.2 Hz, 0.64H, CH2
107.7, 104.5 (Cq E1/E2), 55,3, 53.3 (CH2 E1/E2), 49.0, 48.7 (CH benz E1), 4.07 (d, J = 13.8 Hz, 0.64H, CH2 benz E1), 4.04 (dd,
E1/E2), 32,9, 32.1, 32.0, 25.6, 25.4, 25.3, 25.3, 25.2 (CH2 E1/E2). J = 14.0, 6.0 Hz, 0.36H, CH2 benz E2), 3.76 (d, J = 13.8 Hz,
MS (EI) m/z (relative intensity): 533 (M+, 27), 535 (M+ + 2, 10), 0.64H, CH2 benz E1), 3.61 (dd, J = 14.0, 6.0 Hz, 0.36H, CH2
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benz E2), 3.60 (d, J = 13.5 Hz, 0.36H, CH2 benz E2), 2.30 (s, General procedure for the synthesis of Ugi adducts 9a–c
1.08H, CH3 E2), 2.28 (s, 1.92H, CH3 E1). 13C NMR (75 MHz,
CDCl3) δ: 171.5, 170.0, 169.9, 168.5, 145.5, 138.4, 138.4, 137.9, The o-nitrobenzylamine hydrochloride 7 (0.207 g, 1.1 mmol)
137.2 (Cq E1/E2), 135.1 (CHAr), 134.8, 133.6, 133.4, 131.1 (Cq was treated with a solution of KOH (1.0 mmol) in ethanol for
E1/E2), 131.7, 130.7, 130.5 (CHAr E1/E2), 130.4 (Cq), 130.2, 10 min, after which the phenylglyoxal hydrate 1a (0.152 g,
130.0 (CHAr E1/E2), 129.8, 129.8 (Cq E1/E2), 129.5, 129.4, 1 mmol) was added. The mixture was stirred for 15 min at
128.7, 128.7, 128.6, 128.2, 128.0, 128.0, 127.6, 127.5, 127.4, room temperature. Then, the corresponding carboxylic acid
125.6, 125.3 (CHAr E1/E2), 107.7, 105.0 (Cq E1/E2), 55.8, 53.4, 8a–b (1 mmol) and isocyanide 4a–b (1 mmol) were added and
43.5, 43.2 (CH2 E1/E2), 21.5, 21.4 (CH3 E1/E2). MS (EI) m/z the mixture was stirred for 2 days until a solid precipitated.
(relative intensity): 521 (M+, 6.4), 371 (14), 269 (10), 150 (73), The solid was filtered and recrystallized from i-PrOH–i-Pr2O.
105 (100), 91 (26). HRMS (EI): calcd for C31H27N3O5 [M+]
521.1951 found 521.1937.
(E)-N-Benzyl-2-[N-(2-nitrobenzyl)-N-benzoylamino]-3-hydroxy-
3-phenylacrylamide 9a. White solid, m.p. 177–178 °C. IR
(E)-N-Benzyl-2-[N-(4-methoxybenzyl)-N-(2-nitrobenzoyl) amino]- (KBr, cm−1): 3483 (OH), 1670 (CvO), 1543, 1393. 1H NMR
3-hydroxy-3-phenylacrylamide
5i. White
solid,
m.p. (300 MHz, DMSO-d6) (as a mixture of tautomers and confor-
142–143 °C (conformational isomers E1/E2: 57/43). IR (KBr, mers) δ: 15.38 (s, 0.50H, OH enol E1), 15.34 (s, 0.13H, OH enol
cm−1): 3440 (OH), 1658 (CvO), 1526, 1398, 1348. 1H NMR E2), 9.46 (t, J = 5.3 Hz, 0.50H, NH E1), 9.24 (t, J = 5.0 Hz, 0.37H,
(400 MHz, CDCl3) δ: 15.71 (s, 0.43H, OH E2), 15.09 (s, 0.57H, NH keto), 9.06 (t, J = 5.1 Hz, 0.13H, NH enol E2), 8.00–6.63 (m,
OH E1), 8.29–6.52 (m, 18H, HAr E1/E2), 7.07–6.94 (m, 0.57H, 19H, HAr), 6.08 (s, 0.37H, CH keto), 5.39–4.78 (m, 2H),
NH E1), 6.51–6.43 (m, 0.43H, NH E2), 5.72 (d, J = 13.6 Hz, 4.58–3.65 (m, 2H). 13C NMR (75 MHz, DMSO-d6) δ: 194.7,
0.43H, CH2 benz E2), 4.50 (dd, J = 14.9, 6.3 Hz, 0.57H, CH2 193.2, 173.1, 172.9, 171.6, 170.6, 165.4, 148.5, 147.9, 138.6,
benz E1), 4.39 (dd, J = 14.9, 6.3 Hz, 0.57H, CH2 benz E1), 4.06 138.4, 135.8, 135.5, 135.1, 134.5, 134.3, 134.0, 133.9, 133.7,
(dd, J = 14.2, 6.0 Hz, 0.43H, CH2 benz E2), 4.04 (d, J = 13.9 Hz, 130.7, 129.6, 129.4, 129.3, 129.1, 129.0, 128.9, 128.6, 128.5,
0.57H, CH2 benz E1), 3.76 (d, J = 13.9 Hz, 0.57H, CH2 benz E1), 128.4, 128.1, 128.0, 127.7, 127.1, 126.6, 125.5, 125.0, 109.2,
3.75 (s, 1.32H, CH3 E2), 3.72 (dd, J = 14.2, 6.0 Hz, 0.43H, CH2 68.0, 64.8, 49.6, 46.0, 43.1. MS (EI) m/z (relative intensity): 400
benz E2), 3.72 (s, 1.68H, CH3 E1), 3.67 (dd, J = 14.2, 6.0 Hz, (18), 104 (100), 90 (36).
0.43H, CH2 benz E2), 3.60 (d, J = 13.6 Hz, 0.43H, CH2 benz E2).
(E)-N-Cyclohexyl-2-[N-(2-nitrobenzyl)-N-(2-bromobenzoyl)-
13C NMR (100 MHz, CDCl3) δ: 171.5, 170.3, 170.0, 168.5, 168.5, amino]-3-hydroxy-3-phenylacrylamide 9b. White solid. M.p.
167.8, 159.8, 159.7, 146.8, 145.5, 137.9, 137.1, 135.2, 134.9 (Cq dec. (>180 °C). (E1/E2: 61/39). IR (KBr, cm−1): 3393 (OH), 1651
E1/E2), 133.6 (CHAr), 133.5, 133.2 (Cq) 131.7, 131.4, 131.1, (CO), 1632 (CO), 1537, 1524, 1381, 1344. 1H NMR (300 MHz,
130.6, 130.2, 129.4, 128.8, 128.7, 128.7, 128.6, 128.1, 128.0, CDCl3) δ: 15.68 (s, 0.39H, OH enol E2), 15.13 (s, 0.61H, OH
127.9, 127.6, 127.6, 127.5, 127.4, 125.6, 125.5, 125.3, 114.3, enol E1), 7.91–6.99 (m, 13H, HAr), 6.11 (d, J = 8.1 Hz, 0.61H,
114.0 (CHAr E1/E2), 107.7, 104.9 (Cq E1/E2), 55.5 (CH3), 55.4 NH enol E1), 5.91 (d, J = 8.1 Hz, 0.39H, NH enol E2), 5.85 (d,
(CH2), 55.3 (CH3), 53.1, 44.2, 43.5, 43.3 (CH2 E1/E2). MS (EI) J = 14.1 Hz, 0.61H, enol E1), 4.73 (d, J = 14.1 Hz, 0.39H, enol
m/z (relative intensity): 537 (M+, 0.6), 121 (32), 105 (100), 91 (48). E2), 4.19 (d, J = 14.1 Hz, 0.39H, enol E2), 4.05 (d, J = 14.1 Hz,
(E)-N-Benzyl-2-[N-(4-chlorobenzyl)-N-(2-nitrobenzoyl)amino]- 0.61H, enol E1), 3.71–3.62 (m, 0.61H, enol E1), 3.33–3.22 (m,
3-hydroxy-3-phenylacrylamide
5j. White
solid,
m.p. 0.39H, enol E2), 2.01–0.56 (m, 10H). 13C NMR (75 MHz, CDCl3)
152–153 °C (conformational isomers E1/E2: 58/42). IR (KBr, δ: 171.3, 170.4, 170.0, 169.4, 168.4, 168.9, 168.5 (Cq enol E1/
cm−1): 3427 (OH), 1651 (CvO), 1538, 1393, 1353. 1H NMR E2), 133.6, 133.5, 133.1, 131.0, 130.8, 127.7, 129.6, 129.5, 128.8,
(300 MHz, CDCl3) δ: 15.76 (s, 0.42H, OH E2), 15.13 (s, 0.58H, 128.6, 128.1, 128.0, 127.8, 127.7, 127.6, 126.8, 125.1, 124.9
OH E1), 8.31–6.60 (m, 18H, HAr, E1/E2), 7.01 (t, J = 5.9 Hz, (CHAr enol E1/E2), 109.9 (Cq), 50.7 (CH2), 48.9 (CH), 46.9
0.58H, NH E1), 6.45 (t, J = 5.9 Hz, 0.42H, NH E2), 5.72 (d, J = (CH2), 33.3, 32.7, 32.2, 31.9, 25.6, 25.4, 25.3, 25.2, 24.7 (CH2
13.6 Hz, 0.42H, CH2 benz E2), 4.56 (dd, J = 14.8, 6.5 Hz, 0.58H, enol E1/E2). MS (EI) m/z (relative intensity): 577 (M+, 0.07), 579
CH2 benz E1), 4.37 (dd, J = 14.8, 6.5 Hz, 0.58H, CH2 benz E1), (M + 2, 0.09), 269 (28), 183 (92), 185 (88), 105 (100), 77 (28).
4.07 (d, J = 13.8 Hz, 0.58H, CH2 benz E1), 4.04 (dd, J = 14.3, 6.5 HRMS (EI): calcd for C29H28BrN3O5 577.1212 found 577.1202.
Hz, 0.42H, CH2 benz E2), 3.79 (d, J = 13.8 Hz, 0.58H, CH2 benz
E1), 3.72 (dd, J = 14.3, 6.5 Hz, 0.42H, CH2 benz E2) 3.60 (d, J = 3-hydroxy-3-phenylacrylamide
(E)-N-Benzyl-2-[N-(2-nitrobenzyl)-N-(2-bromobenzoyl)amino]-
9c. White solid, m.p.
13.6 Hz, 0.42H, CH2 benz E2). 13C NMR (75 MHz, CDCl3) δ: 157–158 °C (E1/E2: 60/40). IR (KBr, cm−1): 3273 (OH), 1699
171.8, 170.1, 169.9, 168.7, 168.6, 167.9, 145.5, 137.8, 137.0 (Cq (CO), 1677 (CO), 1449, 1343, 1288, 1258. 1H NMR (300 MHz,
E1/E2), 135.2 (CHAr), 134.7 (Cq), 133.4 (CHAr), 133.2 (Cq), 131.9 CDCl3) δ: 15.41 (s, 0.4H, OH enol E2), 14.91 (s, 0.6H, OH enol
(CHAr), 131.8 (Cq), 131.5, 131.2, 130.8, 130.7, 130.4, 129.5, E1), 7.94–6.85 (m, 18.4H, HAr + NH E2), 6.51 (t, J = 5.2 Hz,
129.3, 128.9, 128.7, 128.2, 128.1, 127.8, 127.6, 127.6, 125.7, 0.6H, NH E1), 5.79 (d, J = 13.9 Hz, 0.4H, enol E2), 4.66 (d, J =
125.4 (CHAr E1/E2), 107.7, 104.6 (Cq E1/E2), 55.2, 53.2, 43.5, 14.1 Hz, 0.6H, enol E1), 4.45–4.24 (m, 2H), 4.26 (d, J = 14.1 Hz,
43.4 (CH2 E1/E2). MS (EI) m/z (relative intensity): 541 (M+, 24), 0.6H, enol E1), 4.08 (d, J = 13.9 Hz, 0.4H, enol E2). 13C NMR
543 (M+ + 2, 10), 391 (65), 393 (23), 253 (26), 150 (100), 125(98), (75 MHz, CDCl3) δ: 171.7, 170.7, 170.1, 170.0, 169.4, 168.3,
105 (63), 91 (57), 77 (30). HRMS (EI): calcd for C30H24ClN3O5 149.6, 149.4, 137.2, 137.0, 136.5, 134.1 (Cq E1/E2), 133.8, 133.7
[M+] 541.1404 found 541.1412.
(CHAr E1/E2), 133.5 (Cq) 133.4, 133.3, 133.1, 132.9, 131.7,
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131.3, 131.0, 130.9 (CHAr E1/E2), 130.0 (Cq), 129.7, 129.6, 21.7 Hz, CHAr), 59.2 (CH), 52.9 (CH2), 48.1 (CH), 32.3 (CH2),
129.5, 129.0, 128.9, 128.8, 128.6 (CHAr E1/E2), 128.5 (Cq), 32.2 (CH2), 25.2 (CH2), 24.7 (CH2), 24.5 (CH2). MS (EI) m/z
128.4, 128.2, 128.1, 128.0, 127.9, 127.7, 127.6, 126.9, 125.1, (relative intensity) 469 (M+, 6.9), 344 (100), 253 (48), 227 (15),
125.0 (CHAr E1/E2), 120.5, 120.0, 106.9, 104.0 (Cq E1/E2), 50.6, 197 (16), 91 (45). HRMS (EI): calcd for C29H28FN3O2 [M+]
46.6, 44.1, 43.0 (CH2 E1/E2). MS (EI) m/z (relative intensity): 469.2166 found 469.2168.
585 (M+, 0.3), 587 (M + 2, 0.28), 185 (100), 105 (86), 91 (53), 77
N,4-Dibenzyl-5-oxo-2-phenyl-4,5-dihydro-3H-benzo[e][1,4]di-
(29). HRMS (EI): calcd for C30H24BrN3O5 585.0899 found azepino-3-carboxamide (6g). White solid, m.p. 180–181 °C. IR
585.0903.
(KBr, cm−1): 3327 (NH), 3027, 1682 (CvO), 1633. 1H NMR
(300 MHz, CDCl3) δ: 8.03–6.67 (m, 19H, HAr), 5.67–5.48 (m,
1H, NH), 5.34 (s, 1H), 5.08 (d, J = 14.6 Hz, 1H, CH2 benz), 4.70
Procedure for the synthesis of Ugi adduct 9d
The o-nitrobenzylamine hydrochloride 7 (0.207 g, 1.1 mmol) (d, J = 14.6 Hz, 1H, CH2 benz), 3.95–3.79 (m, 2H, CH2 benz).
was treated with a solution of KOH (1.0 mmol) in ethanol for 13C NMR (75 MHz, CDCl3) δ: 167.5 (Cq), 165.6 (Cq), 164.2 (Cq),
10 min, after which the phenylglyoxal hydrate 1a (0.152 g, 146.0 (Cq), 137.7 (Cq), 136.7 (Cq), 136.3 (Cq), 132.3 (CHAr),
1 mmol) was added. The mixture was stirred for 15 min at 131.2 (CHAr), 130.7 (CHAr), 129.2 (CHAr), 128.9 (CHAr), 128.8
room temperature. Then, the terephthalic acid 8c (0.083 g, (CHAr), 128.6 (CHAr), 128.5 (CHAr) 127.8 (CHAr), 127.6 (CHAr),
0.5 mmol) and the cyclohexylisocyanide 4a (0.109 g, 1 mmol) 127.4 (CHAr), 126.6 (CHAr), 125.8 (Cq), 59.1 (CH), 52.9 (CH2),
were added and the mixture was stirred for 2 days until a solid 43.8 (CH2). MS (EI) m/z (relative intensity) 459 (M+, 11), 326
precipitated. The solid was filtered and recrystallized from (24), 325 (16), 235 (11), 91 (100). HRMS (EI): calcd for
MeOH–DMF.
C30H25N3O2 [M+] 459.1947 found 459.1943.
N-Benzyl-4-(4-methylbenzyl)-5-oxo-2-phenyl-4,5-dihydro-3H-
N1,N4-Bis((E)-1-cyclohexylaminocarbonyl-2-hydroxy-2-phenyl-
ethenyl)-N1,N4-bis(2-nitrobenzyl)terephthalamide 9d. White benzo[e][1,4]diazepino-3-carboxamide (6h). White solid, m.p.
solid, m.p. 214–216 °C. IR (KBr, cm−1): 3333 (OH), 1650 (CO), 139–140 °C. IR (KBr, cm−1): 3327 (NH), 3027, 1682 (CvO),
1609, 1377, 1530, 1314. H NMR (400 MHz, CDCl3) δ: (princi- 1633. 1H NMR (300 MHz, CDCl3) δ: 8.02–6.65 (m, 18H, HAr),
1
pal conformer) 15.32 (s, 2H, OH enol), 8.42–6.70 (m, 22H, 5.65–5.54 (m, 1H, NH), 5.33 (s, 1H), 5.01 (d, J = 14.6 Hz, 1H,
HAr), 5.88–5.78 (m, 3H), 4.16 (d, J = 15 Hz, 2H), 3.62–3.40 (m, CH2 benz), 4.67 (d, J = 14.6 Hz, 1H, CH2 benz), 3.94–3.84 (m,
2H), 1.62–0.72 (m, 20H). 13C NMR (100 MHz, CDCl3) δ: (princi- 2H, CH2 benz), 2.22 (s, 3H). 13C NMR (75 MHz, CDCl3) δ: 167.4
pal conformer) 171.2 (Cq), 169.7 (Cq), 169.5 (Cq), 137.3 (Cq), (Cq), 165.7 (Cq), 164.3 (Cq), 146.0 (Cq), 138.3 (Cq), 137.7 (Cq),
133.8 (CHAr), 132.2 (CHAr), 131.2 (CHAr), 131.0 (CHAr), 129.5 136.7 (Cq), 133.2 (Cq), 132.2 (CHAr), 131.0 (Cq), 130.7 (CHAr),
(CHAr), 129.1 (CHAr), 129.0 (CHAr), 127.7 (CHAr), 127.7 (CHAr), 129.9 (CHAr), 128.9 (CHAr), 128.7 (CHAr), 128.6 (CHAr), 128.4
126.9 (CHAr), 125.1 (CHAr), 108.5 (Cq), 49.0 (CH2), 48.4 (CH2), (CHAr), 127.8 (CHAr), 127.6 (CHAr), 127.5 (CHAr), 127.4 (CHAr),
48.3 (CH), 33.0 (CH2), 32.5 (CH2), 32.3 (CH2), 25.3 (CH2), 25.0 126.5 (Cq), 58.9 (CH), 52.5 (CH2), 43.8 (CH2), 21.2 (CH3). MS
(CH2), 24.8 (CH2). MS (FAB+) m/z (relative intensity): 921 (M+ + (EI) m/z (relative intensity) 473 (M+, 27), 340 (33), 235 (31), 105
1, 32), 922 (M+ + 2, 23), 822 (100), 823 (49), 526 (54).
(100), 91 (36). HRMS (EI): calcd for C31H27N3O2 [M+] 473.2103
found 473.2108.
General procedure for the synthesis of benzodiazepines 6a–j
N-Benzyl-4-(4-methoxybenzyl)-5-oxo-2-phenyl-4,5-dihydro-
To a suspension of enol 5a–j (0.5 mmol) in ethanol (10 mL) 3H-benzo[e][1,4]diazepino-3-carboxamide (6i). White solid,
and hydrochloric acid solution 0.6 M (1.5 mmol) was added m.p. 144–145 °C. IR (KBr, cm−1): 3333 (NH), 3027; 1673 (CvO),
1
stannous chloride (5 mmol). The reaction was refluxed for 1514, 1455, 1248. H NMR (300 MHz, CDCl3) δ: 8.08–6.48 (m,
45 min, cooled and concentrated under reduced pressure. The 18H, HAr), 5.66–5.53 (m, 1H, NH), 5.35 (s, 1H), 4.94 (d, J = 14.7
residue was dissolved in dichloromethane and washed with a Hz, 1H, CH2 benz), 4.70 (d, J = 14.7 Hz, 1H, CH2 benz),
diluted KOH solution and then with water. The organic extract 3.96–3.83 (m, 2H, CH2 benz), 3.72 (s, 3H). 13C NMR (75 MHz,
was dried with Na2SO4 and concentrated. The crude residue CDCl3) δ: 167.6 (Cq), 165.9 (Cq), 164.5 (Cq), 159.8 (Cq), 146.2
was recrystallized from methanol.
(Cq), 138.0 (Cq), 136.9 (Cq), 132.4 (CHAr), 131.2 (CHAr), 130.8
(CHAr), 130.5 (CHAr), 128.9 (CHAr), 128.8 (CHAr), 128.4 (Cq),
Compounds 6a–e have been previously described.4
N-Cyclohexyl-4-benzyl-5-oxo-2-(4-fluorophenyl)-4,5-dihydro- 128.2 (CHAr), 127.9 (CHAr), 127.8 (CHAr), 127.5 (CHAr), 126.7
3H-benzo[e][1,4]diazepino-3-carboxamide (6f). White solid, (CHAr), 126.0 (Cq), 114.7 (CHAr), 59.1 (CH), 55.4 (CH3), 52.3
m.p. 176–177 °C. IR (KBr, cm−1): 3323 (NH), 3065 (CAr), 2931, (CH2), 44.0 (CH2). MS (EI) m/z (relative intensity) 489 (M+, 13),
2855, 1681 (CvO), 1622 (CvO), 1515, 1454. 1H NMR 356 (12), 235 (19), 121 (100), 91 (22). HRMS (EI): calcd for
(300 MHz, CDCl3) δ: 8.01–7.04 (m, 13H, HAr), 5.22 (s, 1H), 5.14 C31H27N3O3 [M+] 489.2052; found 489.2042.
(d, J = 14.3 Hz, 1H, CH2 benz), 5.11 (d, J = 8.1 Hz, 1H, NH),
N-Benzyl-4-(4-chlorobenzyl)-5-oxo-2-phenyl-4,5-dihydro-3H-
4.60 (d, J = 14.3 Hz, 1H, CH2 benz), 3.26–3.13 (m, 1H, CH), benzo[e][1,4]diazepino-3-carboxamide (6j). White solid, m.p.
1.95–0.95 (m, 8H), 0.61–0.40 (m, 2H). 13C NMR (75 MHz, 177–178 °C. IR (KBr, cm−1): 3272 (NH), 1682 (CvO), 1633,
1
1
CDCl3) δ: 167.5 (Cq), 164.6 (d, J = 252.5 Hz, Cq), 164.4 (Cq), 1538, 1455. H NMR (300 MHz, CDCl3) δ: 8.14–6.59 (m, 18H,
163.6 (Cq), 146.1 (Cq), 136.4 (Cq), 132.3 (CHAr), 130.7 (CHAr), HAr),5.78–5.61 (m, 1H, NH), 5.27 (s, 1H), 5.06 (d, J = 14.5 Hz,
129.9 (CHAr), 129.8 (CHAr), 129.4 (CHAr), 129.0 (CHAr), 128.7 1H, CH2 benz), 4.65 (d, J = 14.5 Hz, 1H, CH2 benz), 3.99 (dd,
(CHAr), 127.2 (CHAr), 126.4 (CHAr), 125.8 (Cq), 115.8 (d, 2J = J = 14.5, 5.6 Hz, 1H, CH2 benz), 3.90 (dd, J = 14.5, 5.6 Hz, 1H,
4914 | Org. Biomol. Chem., 2014, 12, 4905–4916
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CH2 benz). 13C NMR (75 MHz, CDCl3) δ: 167.7 (Cq), 165.7 (Cq), Henam2), 5.93 (s, 0.2 Henam1), 5.66 (d, J = 14.1 Hz, 0.8 Henam2),
164.3 (Cq), 146.0 (Cq), 137.6 (Cq), 136.9, 134.9, 134.5, 132.5, 4.71 (d, J = 15.6 Hz, 0.2 Henam1), 4.50 (d, J = 15.6 Hz, 0.2
131.4, 130.9, 130.4, 129.3, 128.9, 128.9, 128.0, 127.8, 127.7,
H
enam1), 4.42–3.86 (m, 2.8H). 13C NMR (100 MHz, CDCl3) δ:
127.6, 126.9, 125.9, 59.6 (CH), 52.5 (CH2), 44.1 (CH2). MS (EI) 182.8, 182.1, 169.3, 137.8, 137.4, 132.7, 130.7, 130.4, 129.99,
m/z (relative intensity): 493 (M+, 30), 360 (72), 235 (57), 179 129.2, 128.9, 128.6, 128.5, 128.1, 127.5, 127.0, 122.4, 119.8,
(31), 150 (31), 127 (32), 125 (100), 121(90), 91 (68). HRMS (EI): 119.2, 112.9, 57.0, 53.4, 43.9. MS (EI) m/z (relative intensity):
calcd for C30H24N3O2Cl [M+] 493.1548; found 493.1557.
537 (M+, 19), 539 (M + 2, 19), 407 (18), 405 (18), 246 (30), 219
(42), 183 (61), 185 (60), 105 (100), 91 (75). HRMS (EI): calcd for
C30H24BrN3O2 537.1052, found 537.1047.
General procedure for the synthesis of benzodiazepines 10a–c
To a suspension of enol 9a–c (0.5 mmol) in ethanol (10 mL)
and hydrochloric acid solution 0.6 M (1.5 mmol) was added
stannous chloride (5 mmol). The reaction was refluxed for
45 min, cooled and concentrated under reduced pressure. The
residue was dissolved in dichloromethane and washed with a
diluted KOH solution and then with water. The organic extract
was dried with Na2SO4 and concentrated. The crude residue
was purified by chromatography (hexane–AcOEt).
4-(Benzoyl)-N-benzyl-2-phenyl-4,5-dihydro-1H-benzo[e][1,4]-
diazepino-3-carboxamide (10a). Yellow oil (enam1/enam2: 69/
31). IR (KBr, cm−1): 3423 (NH), 3280 (NH), 1653, 1628. 1H
NMR (300 MHz, CDCl3) δ: 8.37–8.34 (m, 1H, HAr), 7.99 (s, 0.69
Procedure for the synthesis of benzodiazepine 10d
To a suspension of enol 9d (0.5 mmol) in ethanol (10 mL) and
hydrochloric acid solution 0.6 M (3.0 mmol) was added stan-
nous chloride (10 mmol). The reaction was refluxed for
45 min, cooled and concentrated under reduced pressure. The
residue was dissolved in dichloromethane and washed with a
diluted KOH solution and then with water. The organic extract
was dried with Na2SO4 and concentrated. The crude residue
was recrystallized from diisopropyl ether.
4,4′-Terephthaloylbis(N-cyclohexyl-2-phenyl-4,5-dihydro-1H-
benzo[e][1,4]diazepine-3-carboxamide) (10d). White solid,
m.p. 176–177 °C (enam1/enam2: 85/15). IR (KBr, cm−1): 3324
H
enam1) 7.86 (t, J = 5.3 Hz, 0.69H, NHenam1), 7.55–6.77 (m, 18H,
1
HAr), 6.00 (s, 0.31 Henam2), 5.71 (d, J = 14.2 Hz, 0.31 Henam2),
5.62 (t, J = 5.4 Hz, 0.31 H, NHenam2), 4.71 (d, J = 14.6 Hz, 0.69
(NH), 1693, 1681, 1651. H NMR (300 MHz, CDCl3) (principal
conformer) δ: 8.33–6.89 (m, 23H, HAr + NH), 4.56 (d, J = 14.8
Hz, 2H), 4.35 (d, J = 14.8 Hz, 2H), 3.71–3.61 (m, 2H), 1.79–0.85
(m, 20H). 13C NMR (75 MHz, CDCl3) (principal conformer) δ:
190.2 (Cq), 171.8 (Cq), 136.8 (Cq), 135.9 (Cq), 133.1 (CHAr),
129.2 (CHAr), 129.0 (CHAr), 128.5 (CHAr), 127.4 (CHAr), 125.5
(CHAr), 123.3 (Cq), 84.8 (Cq), 48.8 (CH), 32.5 (CH2), 32.1 (CH2),
25.6 (CH2), 24.5 (CH2), 24.4 (CH2). MS (EI) m/z (relative inten-
sity): 388 (25), 361 (26), 256 (78), 235 (87), 149 (100), 105 (93).
H
enam1), 4.51–3.96 (m, 3H). 13C NMR (75 MHz, CDCl3) δ: 190.6,
172.9, 171.5, 169.1, 164.2, 146.2, 145.4, 139, 138.2, 137.7,
137.1, 136.6, 136.0, 134.2 (Cq), 132.9, 131.3, 130.6, 130.2,
130.1, 129.4, 129.2, 129.1, 129.0, 128.9, 128.8, 128.7, 128.4,
128.1, 128.0, 127.5, 127.4, 127.3, 127.1, 127.0, 125.5, 122.8,
122.3, 119.6 (CHAr), 115.3, 114.4, 85.0 (Cq), 53.6, 48.8, 43.8,
43.8 (CH2). MS (EI) m/z (relative intensity): 459 (M+, 7), 460
(M + 1, 4), 370 (22), 264 (24), 105 (100), 91 (24), 77 (40). HRMS
(EI): calcd for C30H25N3O2 459.1947, found 459.1943.
Computational methods
N-Benzyl-4-(bromobenzoyl)-2-phenyl-4,5-dihydro-1H-benzo-
[e][1,4]diazepino-3-carboxamide (10b).. Yellow solid, m.p.
96–97 °C (enam1/enam2: 20/80). IR (KBr, cm−1): 3404 (NH),
The geometries of all species were fully optimized at the
B3LYP/6-31G** level. The environmental effects were taken
into account by the Polarizable Continuum Mode (PCM) using
the integral equation formalism variant (IEFPCM).21 The
nature of all optimized structures was determined using har-
monic frequency analysis as true minima with no imaginary
frequencies or transition states with only one imaginary fre-
quency. All transition state structures and reaction paths were
further validated by intrinsic reaction coordinate (IRC) calcu-
lations in both forward and reverse directions. All reported
energy differences correspond to Gibbs’ free energies. All cal-
culations were performed using the Gaussian 09 program.18
3198, 1703 (CO), 1677 (CO), 771, 753, 694 cm−1 1H NMR
.
(300 MHz, CDCl3) δ: 7.70–6.65 (m, 13.8H, HAr + NHenam2), 6.23
(d, J = 7.3 Hz, 0.2H, NHenam1), 6.00 (s, 0.8 Henam2), 5.88 (s, 0.2
H
enam1), 5.67 (d, J = 14.0 Hz, 0.8 Henam2), 4.71 (d, J = 15.1 Hz,
0.2 Henam1), 4.56 (d, J = 15.1 Hz, 0.2 Henam1), 4.23 (d, J = 14.0
Hz, 0.8 Henam2), 3.67–3.56 (m, 0.2 Henam1), 3.26–3.161 (m, 0.8
H
enam2), 1.93–0.29 (m, 10H). 13C NMR (75 MHz, CDCl3) δ:
168.8, 164.1, 140.5, 138.8, 137.8, 137.6, 133.5, 132.4, 131.5,
131.0, 130.4, 130.2, 129.9, 129.6, 129.4, 129.1, 128.9, 128.6,
128.5, 128.4, 127.7, 127.6, 127.3, 127.2, 122.1, 119.9, 119.2,
113.6, 53.8, 53.4, 47.9, 33.0, 32.2, 25.8, 25.5, 25.0, 24.8. MS (EI)
m/z (relative intensity): 529 (M+, 4), 531 (M + 2, 4), 456 (5), 458
(5), 378 (34), 183 (39), 185 (39), 105 (100), 77 (27). HRMS (EI):
calcd for C29H28BrN3O2 529.1365, found 529.1362.
Acknowledgements
We gratefully acknowledge financial support from Ministerio
de Economía y Competitividad, Spain (project CTQ2012-
4-(Bromobenzoyl)-N-cyclohexyl-2-phenyl-4,5-dihydro-1H-
benzo[e][1,4]diazepino-3-carboxamide (10c). Yellow solid, m. 31611), from Ministerio de Ciencia e Innovación, Spain and
p. 124–125 °C (enam1/enam2: 20/80). IR (KBr, cm−1): 3434 Fondo de Desarrollo Regional (project MAT2011-22781), as
(NH), 3296 (NH), 1650, 1644, 1633, 1606, 1591, 753, 699. 1H well as from Junta de Castilla y León, Consejería de Educación
NMR (400 MHz, CDCl3) δ: 7.60–6.66 (m, 18.8H, HAr
+
y Cultura y Fondo Social Europeo (project ref. BU246A12-1 and
NHenam2), 6.22 (d, J = 7.3 Hz, 0.2H, NHenam1), 6.04 (s, 0.8 BU327A11-2).
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