Integrated Ugi-Based Assembly of Functionally, Skeletally, and Stereochemically Diverse 1,4-Benzodiazepin-2-ones

Article abstract of DOI:10.1021/jo502382q

A practical, integrated and versatile U-4CR-based assembly of 1,4-benzodiazepin-2-ones exhibiting functionally, skeletally, and stereochemically diverse substitution patterns is described. By virtue of its convergence, atom economy, and bond-forming efficiency, the methodology documented herein exemplifies the reconciliation of structural complexity and experimental simplicity in the context of medicinal chemistry projects.

Full text of DOI:10.1021/jo502382q

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Article
Integrated Ugi-Based Assembly of Functional, Skeletal
and Stereochemically Diverse 1,4-Benzodiazepin-2-ones
Jhonny Azuaje, Jose M Perez-Rubio, Vicente Yaziji, Abdelaziz El
Maatougui, José C. González-Gómez, Víctor Sánchez-Pedregal, Armando
Navarro-Vázquez, Chistian F. Masaguer, Marta Teijeira, and Eddy Sotelo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502382q • Publication Date (Web): 05 Jan 2015
Downloaded from http://pubs.acs.org on January 7, 2015
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The Journal of Organic Chemistry is published by the American Chemical Society.
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Integrated Ugi-Based Assembly of Functional, Skeletal and
Stereochemically Diverse 1,4-Benzodiazepin-2-ones
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Jhonny Azuaje,1,2 José M. Pérez-Rubio,1,2 Vicente Yaziji,1,2 Abdelaziz El Maatougui,1,2
José Carlos González-Gomez,3 Víctor Sánchez-Pedregal,1 Armando Navarro-Vázquez,4
Christian F. Masaguer,2 Marta Teijeira4 and Eddy Sotelo1,2*
1Centro Singular de Investigación en Química Biológica y Materiales Moleculares
(CIQUS) and 2Departamento de Química Orgánica, Facultad de Farmacia.
Universidad de Santiago de Compostela. E-15782. Santiago de Compostela (Spain).
3Instituto de Síntesis Orgánica, Facultad de Ciencias. Universidad de Alicante. E-
03080-Alicante (Spain). 4Departamento de Química Orgánica, Facultad de Química.
Universidad de Vigo. E-36310-Vigo (Spain).
Key words: Benzodiazepines, Ugi Reaction, Isocyanides, Multicomponent Reaction.
Abstract: A practical, integrated and versatile U-4CR-based assembly of 1,4-
benzodiazepin-2-ones exhibiting functional, skeletal and stereochemically diverse
substitution patterns is described. By virtue of its convergence, atom economy and bond-
forming efficiency; the herein documented methodology exemplify the reconciliation of
structural complexity and experimental simplicity in the context of medicinal chemistry
projects.
*Corresponding author: Prof. Eddy Sotelo.
tel.: ++34-881-815732, Fax.: ++34-981-528093, e-mail: e.sotelo@usc.es
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Graphical Abstract:
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NH2
O
R3 R2
R6
N
R4
1) U-4CR
2) TFA
Twelve 1,4-Benzodiazepin-2-one
Chemotypes
+
HO
+
O
+
N
O
O
R5
O
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O
H
R1
H
H
O
O
O
O
N
R6
R6
N
Me
N
N
R6
R6
R6
R6
H
R4
R4
Me
N
N
N
O
O
O
H
H
H
O
O
O
O
N
N
N
N
N
Me
Me
Me
Me
N
O
N
O
N
N
N
N
R1
R1
R4
R1
R1
R1
R1
H
H
H
H
H
O
R6
R6
R6
R6
R6
N
N
N
N
N
R6
Me
Me
R4
N
O
O
H
O
O
O
O
O
O
O
N
N
N
N
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R3
R2
R3
R2
R3
R2
R3
R2
N
N
N
N
N
N
R1
R1
R1
R1
R1
R1
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Introduction
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Extensively employed as therapeutics since the early 1960s 1,4-benzodiazepin-2-
ones (BZDs)1 embody the archetypical privileged structure,2 a concept coined by Evans
in the late 1980s and that constitute a fruitful strategy to improve the low hit rates usually
experienced during high-throughput screening campaigns. Whereas BZD scaffolds are
recurrent templates in the context of CNS therapies (being extensively prescribed as
sedatives, anxiolytics, anticonvulsants or muscle relaxants),3 the continuous appearance
of reports describing novel pharmacological activities (e.g. antagonists of platelet
activating factor,4a anti-HIV,4b antitumor,4c,4d antimalarial,4e) unequivocally corroborate
the ability of BZDs to modulate relevant biomolecules go beyond CNS targets (Figure 1).
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Et
Et
N
Me
F3
C
N
Me
Me
H
H
O
O
O
O
O
N
F
N
N
N
N
N
N
O
F
N
OH
N
N
N
N
Cl
O2
N
N
Cl
Cl
N
Cl
Cl
N
Cl
Cl
Cl
F
Diazepam
Flunitrazepam
Halazepam
Flurazepam
Clonazepam
Lorazepam
Midazolam
S
SO2
R
H
N
H2
N
Me
F
Me
N
O
O
N
O
F3
C
H
O
O
H
O
O
O
N
H
N
F
N
Me
N
N
N
Cl
NH
O
N
N
O
O
Me
N
N
O
O
H
CCK-A Receptor Antagonist
Falcipain-2 Inhibitor
γ-Secretase Inhibitor
Peptide Antagonist
Figure 1. Representative drugs and bioactive compounds derived from the 1,4-
benzodiazepin-2-one scaffold.
The BZD´s pharmacogenicity profile heavily relies on its constrained peptide
mimic nature,3 which dictates the geometry of the heterocyclic core and its appended
functional groups, thus modulating the structural parameters ultimately governing
ligand/receptor interactions. It should be emphasized that BZDs exist in a boat
conformation, which confers intrinsic chirality to the heterocyclic core even in the
absence of stereogenic carbons.5 The barrier for racemization between (M)- and (P)-
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enantiomers (Figure 2) is known to be low,5,6 unless they exhibit a single substituent at
C3 -which is stabilized at the pseudoequatorial position- or a relatively large substituent
at position 1.7 Consequently, the stereochemical diversity in BZD´s collections can be
expanded by combining the chirality of the heterocyclic core with stereocenters at C3 or
by introduction of side-chains at position 1 of the framework.
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Figure 2. (P) and (M) conformational enantiomers of 1,4-benzodiazepin-2-ones.
In addition to the bioactivity issues, the versatility of a privileged scaffold is
heavily dependent on two key factors: it’s synthetic feasibility and its ability to be
decorated and/or reinterpreted according the specific requirements of distinct biological
targets. Therefore, the implementation of concise and efficient synthetic methodologies
providing integrated access to privileged molecular frameworks eliciting functional,
skeletal as well as stereochemical diversity, while enabling the reconciliation of the
molecular complexity with experimental simplicity, constitutes a highly appreciated goal
within the competitive environment of drug discovery. Notwithstanding the plethora of
synthetic methods targeting BZDs,8 established approaches consists in multistep linear
pathways; where diversity elements are usually early introduced. Epimerization is often
an issue; particularly during the subsequent functionalization of the heterocycle.9 A
valuable incorporation to the compendium of preparative methods targeting BZDs
includes multicomponent reactions (MCR);10 which have emerged as a tailored synthetic
paradigm in drug discovery. The most powerful MCR-assisted method for generating
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BZD libraries11 involves the Ugi four-component reaction (U–4CR).12 Whereas this
strategy has provided examples of elegant access to diverse BZD scaffolds,11,12 most
described protocols still require several synthetic steps and/or structurally elaborate
precursors; thereby hampering its extensive application in medicinal chemistry programs.
Additionally, the development of modular MCR-based approaches providing collections
of privileged molecular frameworks in enantio- or diastero- pure fashion remains a highly
elusive challenge.11 We herein document a conceptually simple and modular U–4CR–
based approach that provides an integrated access to functional, skeletal and
stereochemically diverse chemotypes derived of the pharmacologically useful 1,4-
bezodiazepin-2-one framework.
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Results and Discussion
In the frame of a medicinal chemistry program series of 1,4-benzodiazepin-2-
ones, simultaneously incorporating functionalized alkyl chains at N1 and concise
chemical and stereochemical substitution patterns at position 3 of the heterocyclic core,
were required. Being aware of the limitations of classical synthetic approaches to access
the targeted chemotypes, we decided to assess the feasibility of a MCR-based approach.
It was envisioned (Scheme 1) that the U-4CR reaction employing 2-aminophenylketones
(1) as amine input, in combination with N-Boc protected aminoacids (2), isocyanides (3)
and a carbonyl partner (4), would afford Ugi adducts (5), which upon removal of the
protecting group would undergo an intramolecular cyclization to provide the targeted
BZDs (Scheme 1). The feasibility of the proposed approach relies heavily on the
reactivity of the carbonyl moiety of the starting 2-aminophenylketone (1) when
coexisting with alternative carbonyl compounds during the U–4CR.
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O
H
R3 R2
N
R6
N
O
R4
HO
R
R6
4 R5
N
O
O
R3
R5
R2
O
N
O
O
O
H
NH2
H
O
N
H
2
N
R4
R3
R2
O
+
R5
O
O
N
R1
R6
N
R1
6-9
R1
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Scheme 1. Retrosynthetic analysis to BZD derivatives 6–9 through U–4CR.
While a few reports have exemplified the use of aminoketones (1) toward U-
4CR,13 to the best of our knowledge, these works have employed aldehydes as carbonyl
components; remaining unexplored the reaction outcome of this transformation with
ketones. Two recent papers have described Ugi-based benzodiazepine synthesis
conceptually related to herein document approach. The first study, published by Torroba
et al. in 2010,14 documents an U-4CR that employs 2-aminobenzophenone and (S)-2-
azido-3-phenylpropanoic acid as key components (in combination with
cyclohexylisocyanide and three substituted benzaldehydes); thus generating Ugi adducts
that were subsequently cyclized under the Staudinger/aza-Wittig reaction conditions. This
elegant approach is, notwithstanding, strongly limited by the scarce availability of
functional and stereochemical diverse 2-azidopropanoic acids and its atom economy. This
paper inspired the design of the herein documented pathway (Scheme 1). As observed, it
follows the Ugi-deprotect-Cyclize (UDC) strategy and capitalizes the availability
functional and stereochemical diversity of N-Boc protected aminoacids (2). During the
practical implementation of our study a communication15 described several novel U-4CR
approaches to 1,4-benzodiazepine scaffolds; one of them briefly exploring herein
documented approach. Since our exhaustive examination of the transformation reveals
novel reactivity facets and expand method´s scope, but also provides 1,4-benzodiazepin-
2-ones chemotypes featuring unexplored functional, skeletal and stereochemical
substitution patterns (Figure 3), we decided to present our results.
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H
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R6
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R4
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R5
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O
O
N
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R3
R2
3
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N
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6
R1
O
O
O
O
Me
N
R6
R6
R6
H
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R4
Me
N
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O
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H
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H
N
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R1
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R1
R1
H
H
H
O
R6
R6
R6
N
N
N
R6
N
H
Me
R4
Me
O
O
O
O
O
O
O
N
N
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R3
R2
R3
R2
R3
R2
R3
R2
N
N
N
N
R1
R1
R1
R1
H
H
H
H
R6
R6
R6
R6
N
N
N
N
R4
R4
O
O
O
O
O
O
O
O
N
N
N
N
Me
Me
Me
Me
N
N
N
N
R1
R1
R1
R1
Figure 3. Structure and numbering of 1,4-benzodiazepin-2-one chemotypes (6-9)
assembled through the Ugi–based approach herein described.
As a proof of concept (Scheme 2) 2-aminobenzophenone (1a) and 2-
aminoacetophenone (1b) were selected as model amine substrates for the Ugi reaction, in
combination with glycine Boc (2a) and benzyl isocyanide (3a). Whith the aim to
exhaustively evaluate the chemoselectivity profile of the transformation, and
consequentially its robustness and potential contribution in terms of chemical diversity,
aldehydes [e.g. formaldehyde (4a), butyraldehyde (4b) and benzaldehyde (4c)] but also
ketones [e.g. propanone (4d) and cyclohexanone (4e)] were employed as reactive inputs
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(Scheme 2). The selected substrates were submitted to the standard conditions of the Ugi
condensation in methanol (Scheme 2). Analysis of reaction behaviour for model
substrates revealed that transformations are successful regardless of the steric hindering
present at either the amine (1) or the carbonylic partners (4); with more than 85% of 1
consumed after 36 h in most experiments (independently of the use of aldehyde or
ketone). The intermediancy of the α-acylamino amides 5 was unequivocally confirmed
by the spectroscopic methods. It was gratifying to find that, upon reaction quenching and
subsequent cleavage of the protecting group, Ugi adducts are readily transformed;
triggering BZDs 6 in a two-step one-pot fashion with overall yields ranging 46-77%
(Scheme 2). Among a variety of tested reagents to remove the Boc group, 20% TFA in
DCE at 60ºC provided an efficient cleavage while simultaneously promoting mild
cyclization in short reaction times (0.5-1 h). With the aim to evaluate the robustness of
the method, the reactivity of other isocyanides [e.g. cyclohexyl (3b) or tert-butyl (3c)]
was preliminarily tested; thus generating the 1,4-benzodiazepin-2-ones 6k-t. In
concordance with previous observations,16 the use of polystyrene supported p-
toluenesulfonic acid once finished the U-4CR, in addition to remove traces of the
remaining isocyanide, simultaneously scavenges the unreacted amine (1); thus
simplifying the purification stage.
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Scheme 2. Ugi-Based Assembly of 1,4-benzodiazepin-2-ones 6.
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9
O
H
O
HO
R6
N
H
O
N
R6
R
4 R5
N
R
4 R
N
5 O
N
H
O
NH2
O
O
O
2a
H
O
N
R4
U-4CR
TFA
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+
O
MeOH
DCE
R5
O
N
O
R1
N
R1
R1
R6
1a-b
3a-c
4a-e
5
6a-t
NH
NH
Me
Me
NH
NH
NH
O
O
O
O
N
O
O
O
O
N
O
O
N
N
N
N
N
N
N
N
Me
Me
Me
Me
Me
6e (59%)
6a (60%)
6b (52%)
6c (67%)
6d (44%)
NH
NH
Me
NH
NH
NH
O
Me
O
O
O
O
O
N
O
O
N
O
O
N
N
N
N
N
N
N
N
6j (47%)
6i (45%)
6h (62%)
6g (63%)
6f (70%)
NH
NH
Me
Me
NH
NH
NH
O
O
O
O
N
O
O
O
N
O
O
O
N
N
N
N
N
N
N
N
Me
Me
Me
Me
Me
6l (54%)
6o (60%)
6n (49%)
6k (62%)
6m (65%)
NH
NH
Me
NH
NH
NH
O
Me
O
O
O
O
O
O
O
N
O
O
N
N
N
N
N
N
N
N
N
6t (44%)
6s (46%)
6r (56%)
6q (67%)
6p (52%)
As observed (Scheme 2), both aldehydes (aliphatic or aromatic) and ketones
(acyclic and cyclic) were found to be good substrates, with the transformation exhibiting
complete chemoselectivity. It should be highlighted that herein documented strategy
enables the straightforward introduction of challenging residues on the exocyclic
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acetamide linkage under neutral conditions, as represented for 2,2-dimethyl derivatives
(6d, 6i, 6n and 6s) and particularly for the cyclohexyl analogues (6e, 6j and 6t). In
addition to validate the feasibility of the proposed pathway, the results included in
scheme 2 provide a preliminary assessment of the exploratory power of this conceptual
and experimentally simple strategy. It should be noticed that the herein documented
strategy assemble BZDs 6 in a one-pot procedure that involves the formation of six new
bonds; thus exhibiting outstanding bond-forming efficiency and step economy.
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Analysis of the NMR spectra of compounds 6a-t enables to observe that exchange
between the two boat enantiomeric conformations P and M is slow in the NMR chemical
shift time scale, as previously observed for BZDs with bulky substituents on N1.7 This is
1
assessed by observing the H3 protons resonances in the H-NMR spectrum. At room
temperature the H3 protons are observed as two well separated doublets (δ Hax ~3.5 ppm
vs. δ Heq ~4.5 ppm, |2JHH| = 10.5 - 12.5 Hz). The strong shielding of the pseudoaxial
proton Hax is caused by the phenyl ring of the BZDs skeleton. When prochiral aldehydes
were used in the Ugi reaction (e.g. 4b and 4c), a new stereocenter is introduced in the
side chain at position 1’ and the (P) and (M) boat conformations become diastereomeric
1
(Figure 4). In the H-NMR spectra of these compounds (6b, 6c, 6g, 6h, 6l, 6m, 6o, 6q,
6r), resonances corresponding to each diastereomeric pair of enantiomers —(P,S)/(M,R)
vs (P,R)/(M,S)— can be seen, with diastereomeric ratios ranging from 1:2 to 1:5.
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Figure 4. Diastereomeric 1,4-benzodiazepin-2-one chemotypes assembled.
Once the feasibility of the proposed method was established for glycine Boc
(Scheme 2), and having identified optimal experimental conditions to perform the Ugi–
deprotect–cyclize (UDC) sequence, the robustness and scope of the developed
methodology was assessed substituting glycine-Boc (2a) by a set of assorted protected
aminoacids (2b-g) as key reactive precursors (Scheme 3). The study capitalizes the
excellent commercial availability of enantiopure Boc protected aminoacids (2) to
introduce functional and stereochemical diversity at position 3 of the heterocyclic
framework. Firstly we focused on the generation of collections of BZDs bearing a
stereocenter at C3 (Compounds 7, Scheme 3). With this aim amines 1a-b, assorted
isocyanides (3) and either formaldehyde (4a) or a symmetric ketone (4d-e) were
combined in the Ugi reaction with a set of structural and stereochemically diverse
enantiopure Boc-protected aminoacids (2b-g). We were pleased to observe that only
slight modifications of the previously optimized experimental protocol (Scheme 3) were
required to verify the transformation of reactive partners of the U-4CR in the α-
acylamino amides 5. A slight excess (1.3 equivalents) of the amine input (1) and longer
reaction times (48-72 h) were required to achieve similar conversion ratios during the U–
4CR, while maintaining mild experimental conditions.
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Scheme 3. U-4CR-based assembly of enantiopure BZDs incorporating functional and
5
6
stereochemically diverse groups at position 3.
7
8
9
O
R3 R2
N
HO
H
O
H
R6
R6
N
N
R
4R5
R4
O
H
10
11
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R
H
5O
NH2
O
O
2b-g
O
O
O
N
N
N
R4
U-4CR
TFA
R3
R2
+
O
MeOH
R2
DCE
R5
O
O
N
R1
N
R6
R1
R1
3a-c
1a-b
4a-e
7a-y
5
H
H
H
H
N
O
H
N
N
N
N
O
N
O
O
O
O
N
O
O
O
O
N
N
N
N
N
N
S
OH
N
N
N
H
7a (63%)
7b (63%)
7c (51%)
7d (70%)
7e (44%)
H
H
H
H
HN
O
N
N
N
N
O
O
O
O
N
O
O
O
O
O
N
N
N
N
N
N
S
OH
N
N
N
N
H
7f (70%)
7g (60%)
7j (45%)
7h (50%)
7i (59%)
H
H
H
H
H
N
N
N
N
N
O
O
N
O
O
O
O
O
O
O
O
N
N
N
N
S
OH
N
N
N
N
N
N
H
7l (63%)
7o (51%)
7m (69%)
7n (56%)
7k (70%)
H
H
H
H
H
N
N
N
N
N
O
O
O
O
O
O
O
O
N
O
O
N
N
N
N
N
OH
S
N
N
N
N
N
H
7p (66%)
7q (58%)
NH
7r (62%)
7s (63%)
NH
7t (67%)
NH
N
NH
O
HN
O
O
N
O
O
O
N
O
O
O
N
O
N
OH
N
N
S
N
N
S
N
H3C
H3C
H3C
7u (56%)
7v (47%)
7w (43%)
7x (46%)
7y (47%)
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7
8
9
As for the model systems, smooth cleavage of the protecting group on the Ugi
adducts (5) employing TFA (DCE/60ºC) afforded BZDs 7 in satisfactory overall yields
(44-71%). Chiral-stationary HPLC analysis enabled to verify that during the synthesis no
racemization occurs at the stereocenter (ee > 99%, see supporting information).
Inspection of scheme 3 provides a preliminary assessment of reaction´s scope, which
generates 1,4-benzodiazepin-2-one collections incorporating four points of diversity. As
observed, it encompasses the use of aliphatic as well as aromatic inputs of all variable
components, being not influenced by the electronic and steric variations of the reacting
substrates. Significant structural and stereochemical diversity is successfully provided by
the aminoacid partner (2), as exemplified by a range of diverse aminoacids (including
proteinogenic or synthetic ones); some of them bearing challenging residues (e.g.
compounds 7i and 7j). The NMR data of this series reveals that, for steric reasons, the
substituent at C3 is placed preferentially at the pseudoequatorial position (Figure 5).
Hence, the 3-S and 3-R enantiomers will be locked in the M and P conformations
respectively. Indeed, the 1H-NMR of all compounds 7 showed the resonances of a single
diastereoisomer, with the H3 resonance around 3.5 ppm, that is a clear indication of its
pseudoaxial position. Since a single set of signals is observed in the 1H-NMR spectrum, it
means that only (M,3S) or (P,3R) isomers were obtained.
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Figure 5. Preferred conformations of (P,3R) and (M,3S) enantiomers of 3-substituted
benzodiazepines.
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8
The structural assignment within the series was complemented by X-ray crystallography
data obtained on monocrystals of two representative compounds (Compound 7p and 7u, see
supporting information).17
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The success achieved on previous series led us to evaluate the utilization of prochiral
carbonyl components (4b-c), which will engender the exocyclic stereocenter formed during the
U–4CR (Scheme 4). Butyraldehyde (4b) and benzaldehyde (4c) were employed in combination
with enantiopure N-Boc protected aminoacids (2b-g) and the other reactive partners (Scheme
4). These substrates were submitted to stirring at room temperature in methanol affording the
corresponding diastereomeric Ugi adducts (5) that were directly transformed into BZDs 8
following the Boc-cleavage-cyclization sequence induced by TFA (Scheme 4). The obtained
compounds were purified (by either recrystallization or chromatography) and characterized by
spectroscopic and analytical techniques; thus verifying the isolation of desired BZDs (8) as 1:1
diastereomeric mixtures. Gratifyingly, the exhaustive scrutiny of solvent mixtures enabled to
separate a set of representative diastereomeric pairs (8a-g), employing conventional
chromatographic methods. Comparative chiral HPLC analysis of pure samples of the
diastereomeric mixture and the optically pure diastereoisomers confirmed the optical purity of
both pairs.
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Scheme 4. Ugi–Based Assembly of diastereoisomeric BZDs 8
5
R2
O
6
7
8
9
HO
H
H
N
H
O
R6
R6
N
N
R4
R4
N
O
H
O
NH2
O
O
2b-h
O
O
O
N
N
U-4CR
TFA
O
+
O
R2
MeOH
R2
DCE
R4
H
10
11
12
13
14
15
16
17
18
19
20
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22
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42
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46
47
48
49
50
51
52
53
O
N
R1
N
R6
R1
R1
3a-c
4b-c
1a-b
5
8a-g
H
H
H
H
N
N
N
N
O
O
O
O
O
O
O
O
N
N
N
N
N
N
N
N
8a1 (44%)
8a2 (40%)
8b1 (39%)
8b2 (43%)
H
H
N
N
H
H
N
N
O
O
O
N
O
N
O
N
O
N
O
O
N
N
N
N
N
N
H
H
8c1 (40%)
8c2 (36%)
8d1 (44%)
8d2 (32%)
H
H
N
N
H
H
N
N
O
N
O
N
O
O
O
O
O
O
N
N
OH
OH
N
N
N
N
S
S
8e1 (41%)
8e2 (38%)
8f1 (44%)
8f2 (36%)
NH
NH
O
O
O
O
N
N
N
N
8g1 (37%)
8g2 (31%)
Due to the difficulties to assign the configuration of the BZDs of the series 8, and taking
into account that important changes in chemical shifts were observed between the
diasteroisomeric pairs, we decided to resort to DFT computations as a procedure for the
assignment of the relative configurations of the obtained diasteroisomers 8. In the last decade
DFT ab initio chemical shift computations18 have gradually gained importance among the
54
55
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toolbox used by organic chemists for configurational and conformational analysis through
NMR in solution. These studies can be carried out at very affordable computer times, and with
enough accuracy, can be successfully employed to distinguish diastereoisomeric structures;
even in the presence of conformational flexibility.19 In the case of flexible molecules, like the
ones treated herein, the determination of the configuration is commonly coupled to the
determination of the preferred conformational state. We have therefore explored the
conformational space of four representative stereoisomers (8b1, 8b2 and 8d1, 8d2) by means
of molecular mechanics Monte Carlo calculations. The obtained molecular mechanics
structures were refined at the DFT RI-OPBE level (See experimental section for detailed
computational procedures). In accordance with NMR observations the BZD ring is
conformationally locked into the boat conformation where the alkyl group at C3 is placed into
the equatorial position. Computations show that the conformation of the N1-side chain is
dictated by the formation of an intramolecular hydrogen bond between the azepine carbonyl
group at C2 and the NH group, which build a new seven membered ring. The two rings adopt a
convex-concave disposition as the lowest energy form. Thus, the basal conformation for the
(3S,10R) isomer corresponds to a pseudo-axial disposition of the side-chain phenyl group, but a
pseudo-equatorial disposition in the case of the (3S,10S) form (Figure 6). The presence of an
intramolecular hydrogen bond between the NH and carbonyl C2 was confirmed experimentally
by variable temperature 1H-NMR in CDCl3 solution, that yielded temperature coefficients of –
1.4 ppb/K for compounds 8d1 and 8d2. Typically, values more positive than –4.5 ppb/K are
considered to support intramolecular H bond.20
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Figure 6. Top: DFT-computed lowest energy conformations for (P,3R,10S) -8b1 and
(P,3S,10R)-8b2. Bottom: Selected experimental (bold) vs. computed 1H chemical shifts
of compounds 8b (middle) and 8d (bottom).
1H Chemical shieldings were computed at the DFT/IGLO OPBE/pcS-1 level for the
lowest energy DFT optimized conformation of each diastereoisomer. The computed shieldings
were transformed into chemical shifts by computing shieldings for the tetramethysilane
molecule at the same level of theory. The most remarkable difference between the
diastereoisomers is a strong change of the H10 resonance (Δδ = 0.38 ppm and 0.88 ppm in 8b
1
and 8d, respectively) in the H NMR spectra. This agrees with the DFT computations, that
predicted deshielding values Δδ = 0.39 ppm for (P,3R10S)-8b1 vs (P,3R,10R)-8b2, and
Δδ=1.00 ppm for (M,3S,10R)-8d2 vs. (M,3S,10S)-8d1. The NMR structural assignment within
the series was corroborated by X-ray crystallography data obtained on a monocrystal of the
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diastereoisomer 8d2.21 Note that in the crystal the intramolecular hydrogen bond is no longer
present and intermolecular H-bond contacts appear instead. As previously mentioned, the
6
7
8
substituent at C3 is preferentially located on the pseudoequatorial position, fixing the BZD core
9
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either at the (M,3S) or at the (P,3R) conformation. The isopropyl group adopts an antiperiplanar
conformation around the H–C–C–H torsion angle. This is also the case in solution as evidenced
by a vicinal coupling between H3 and the isopropyl methine proton of ~10 Hz in both isomers
8d1 and 8d2.
As significant differences in the deshielding of the H10 resonance is a common
feature of all herein synthesized diastereomeric pairs, we used this diagnostic signal to
assign the configuration at C10 for compounds 8. Supported by the DFT calculations
performed (for 8b1, 8b2, 8d1, 8d2), as well as by the X-ray diffraction analysis of 8d2, we
assumed that the signal for H10 is more deshielded for (P,3R,10R) or (M,3S,10S)
compound than for the corresponding (P,3R,10S) or (M,3S,10R) diastereoisomer. The
assignment of the relative configuration at C10 of compounds 8 is presented in Table 1.
Table 1: Assignment of C10 configuration on compounds 8 based on chemical shifts of
H10.
δ H10 in ppm / (Configuration)
Diastereoisomer 1
5.68 / (P,3R,10S)-8a1
5.58 / (P,3R,10S)-8b1a
4.16 / (P,3R,10S)-8c1
Diastereoisomer 2
6.12 / (P,3R,10R)-8a2
6.00/ (P,3R,10R)-8b2a
5.09 / (P,3R,10R)-8c2
5.05 / (M,3S,10S)-8d1a 4.17 / (M,3S,10R)-8d2a,b
4.18 / (P,3R,10S)-8e1
5.80 / (P,3R,10S)-8f1
6.27 / (M,3S,10S)-8g1
4.99 / (P,3R,10R)-8e2
6.16/ (P,3R,10R)-8f2
5.79 / (M,3S,10R)-8g2
aPredicted by DFT calculations. bConfirmed by DRX
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To further challenge the robustness and versatility of the herein documented U-
4CR–based strategy, the assembly of BZDs exhibiting challenging substitution patterns at
position 3 of the heterocyclic backbone was briefly explored (Scheme 5). It should be
noted that, although large and diverse BZD libraries are available; 1,4-benzodiazepin-2-
ones featuring quaternary centres at position 3, and particularly spiranic compounds
derived of this heterocyclic core, have been only rarely described.5,6 To the best of our
knowledge, there are not precedents of 1,4-Benzodiazepin-2-ones featuring the substitution
patterns herein documented (e.g. 3,3-disubstituted and functionalized at position 1,
compounds 9); with its close analogues requiring lineal multistep synthetic strategies that
require harsh experimental conditions not compatible with functionalized frameworks.5,6
Since the introduction of these substitution patterns is expected to profoundly modify the
structural features of the heterocyclic core, and accordingly its pharmacological profile,
novel methods providing a rapid and experimentally simple entry to these chemotypes
remains a highly pursued methodological challenge.
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Two sterically hindering N-Boc protected carboxylic acids [e.g. 2-((tert-
butoxycarbonyl)amino)-2-methylpropanoic acid (2i) and 1-((tert-butoxycarbonyl)ami-
no)cyclopentanecarboxylic acid (2j)] were selected as model substrates to study the
proposed U–4CR sequence (Scheme 5); in combination with the precursors employed
along this study [e.g. amines 1a-b, tertbutyl isocyanide (3c) and the four carbonyl
components (4a-d)]. The information contained in scheme 5 reveals novel reactivity facets
of herein described Ugi–based BZDs assembly, while exemplify its contribution in terms
of rapid access to complex and hitherto unexplored diversity spaces. The preliminary
screening of the transformation revealed a significant decreasing on the reactivity profile
and scope respect previous series (Schemes 2-4), with reaction behaviour being highly
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dependent of the starting carbonyl compound (Scheme 5). Thus, aldehydes evaluated
(formaldehyde, butyraldehyde and benzaldehyde) smoothly underwent the U–4CR, albeit
with a reduced efficiency respect previous series, affording the corresponding Ugi adducts
that were subsequently cyclized (Scheme 5). It should be noted that isolated yields of
BZDs 9 range from moderate to satisfactory (35-52%), clearly correlating with the steric
hindering within the starting aldehyde (Scheme 5). In a clear contrast, the U–4CR
employing ketones (propanone and cyclohexanone) failed to provide the desired Ugi
adducts (Scheme 5); exclusively affording keto aminoacetamides 10 (43-66%) and variable
amounts of the unreacted precursors. All attempts to improve these results, by varying
reagents ratio, solvents (EtOH, CF3CH2OH, toluene, DCM) temperatures (45, 60ºC) did
not modify the reaction outcome. With the exception of U–4CR that employ formaldehyde
as carbonyl component, all transformations employing 2i and 2j afforded variable amounts
of substituted keto aminoacetamides 10; which becomes the only isolated reaction product
when employing ketones. Such an experimental outcome, not observed for the less
congested aminoacids (Schemes 2-5), clearly reflects the impossibility of the substituted
carboxylic acid (carboxylate to be more precise) to attack the steric hindered nitrilium ion
intermediates. It should also be noted that the steric factors at the starting amine (R1 = Me
or Ph) do not affect significantly the reaction´s viability (Scheme 5).
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Scheme 5. Ugi–Based Assembly of 1,4-benzodiazepin-2-ones featuring quaternary centres
5
6
at C3.
7
8
9
H
H
N
N
H
O
O
O
O
O
O
N
10
11
12
13
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N
N
TFA, DCE
H
H
R3
R2
R2
O
O
R3
MeOH, rt
NH2
O
N
R1
R1
5
9a-b, 9e-f
R1
1a-b
H
H
H
H
N
N
N
N
R4
R4
NH
R4
N
O
R4
NH
H
O
O
O
O
R2 R3
N
O
O
O
N
O
TFA, DCE
N
R4
H
HO
R3
R2
O
R2
O
O
MeOH, rt
R3
O
H
N
O
O
2a-f
R1
9c-d, 9g-h
R1
R1
R1
5
10a-d
+
H
N
N
R4
R5
O
O
3a-c
NH
R4
R5
MeOH, rt
O
R1
10a-d
H
H
N
N
H
H
H
N
N
N
O
O
O
O
N
N
O
O
O
O
O
O
N
N
N
N
N
N
N
N
Me
Me
Me
9a (42%)
9b (48%)
9c (53%)
9d (47%)
9e (31%)
NH
H
H
N
N
H
NH
N
O
O
O
O
O
N
N
NH
O
O
O
NH
N
N
N
O
O
N
Me
Me
9f (33%)
9g (33%)
9h (27%)
10a (48%)
10b (46%)
Although it is premature to propose a detailed mechanism at this stage; a plausible
mechanistic proposal, consistent with the above-described experimental results, is
presented in Scheme 6. The overall transformation would start with imine formation (11)
and its subsequent protonation, thus generating the iminium ion 12; which rapidly
undergoes nucleophilic addition of the isocyanide to generate the highly reactive nitrilium
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13. At this point of the transformation the steric hindering on the nitrilium ion intermediate
(13) govern the reaction outcome. Thus, less congested nitrilium adducts (R4 = R5 = H)
follow the normal course of the U–4CR [e.g. carboxylate insertion to give 14 and then
Mumm rearrangement] affording the expected Ugi adducts (15), that upon acid-mediated
cleavage generate the targeted BZDs (9). In contrast, for nitrilium ions 13 derived of
butyraldehyde, benzaldehyde or ketones the reaction behaviour heavily depends of its
substitution pattern at the acetamide linkage. The superior steric hindering in these
intermediates prevents the nucleophilc addition of the carboxylate ion (mainly in those
derived from ketones); accordingly a molecule of water could intercept the reactive
nitrilium intermediate (17) to afford the isolated keto aminoacetamides 10.
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R6
O
H
R6
O
H
H
R6
N
N
H
N
R4
O
R4
N
R4
N
R4
N
R6
O
O
O
O
N
R2
R3
NH2
R2
R3
NHBoc
N
R3
R2
O
R
2R3
R1
O
O
N
O
R1
16
R1
15
R1
NHBoc
9
14
O
R3 R2
O
R2 R3
N
O
HO
O
N
H
O
O
O
H
H
R
R4
R5
H
N
R4
R5
NH2
4R5
2
O
N
N
+H2O
-H2O
H
N
R6
O
+
R4
R5
O
O
O
R1
N
4
N
R6
R1
R1
R1
R6
13
1
3
11
12
H2O
H
R6
N
R4
H
R
4R5
R5
N
O
R6
NH
N
O
HO
O
R1
R1
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Scheme 6. Mechanistic proposal for the Ugi–Based Assembly of 3,3-substituted 1,4-
benzodiazepin-2-ones
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In summary, we have documented a convergent approach that enables the
straightforward assembly of 1,4-benzodiazepin-2-ones exhibiting high skeletal, functional
and stereochemical diversity. This versatile integrated U–4CR-based strategy, that exhibits
high bond-forming efficiency as well as structure and step economies, does not requires
advanced intermediates, anhydrous solvents or transition metal catalysts; thus
exemplifying the reconciliation of molecular complexity and functional diversity with
experimental simplicity. Further work is in progress in our laboratories to apply this
method to the synthesis of novel BZD derivatives and complete the pharmacological
evaluation of the herein documented library.
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Experimental Section
Commercially available starting materials and reagents were purchased and used
without further purification from freshly opened containers. All solvents were purified and
dried by standard methods. Organic extracts were dried with anhydrous sodium sulphate.
The reactions were monitored by TLC, and unless stated otherwise, UV light and/or iodine
vapour were used for the detection of compounds. The synthesis and purification of all
compounds were accomplished using the equipment routinely available in organic
chemistry laboratories. Most of the preparative experiments were performed in coated vials
on an organic synthesiser with orbital stirring. Purification of isolated products were
carried out by recrystallization or chromatographic methods. Reported yields correspond to
the mean of two synthetic experiments. Compounds were routinely characterized by
spectroscopic and analytical methods. Melting points were determined on a melting point
apparatus and are uncorrected. The chemical structures of the obtained compounds were
characterized by nuclear magnetic resonance spectroscopy (1H and 13C) and high-
resolution mass spectra (ESI-TOF). Unless otherwise quoted, NMR spectra were recorded
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in CDCl3. Chemical shifts are given as δ values against tetramethylsilane as internal
standard and J values are given in Hz. All NMR experiments were carried out at 298 K on
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a spectrometer operating at 600.13 MHz for H, 150.90 MHz for C and 90.56 MHz for
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2H, equipped with a triple resonance inverse (TXI) room temperature probe with Z-only
1
gradients. H and 13C resonances of (SR)-8b1 and (SS)-8b2 in CDCl3 solutions were
assigned from ge-HSQC, ge-HMBC and ge-COSY experiments. Shifts were referenced to
the corresponding CDCl3 (7.26) and CDCl3 peaks (77.0) ppm. The enantiomeric (or
diastereomeric) excesses were determined by chiral-stationary phase HPLC, employing
variable mixtures (90-10, 80-20 or 70-30) of n-hexane-isopropanol. The temperature of the
column was maintained at 20ºC with flow rates of 0.5-0.8 mL min-1. The eluent was
monitored at a wavelength of 200 to 300 nm. The conformational spaces of the
diastereoiosomers were explored using the Monte Carlo torsional procedure as
implemented in the Macromodel 9.1 software package using the MMFF94 force field. The
lowest MMFF94 energy structures were refined at the RI22-DFT BP86 level using the
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defbas-1 basis set
(QuickOpt option in ORCA package) and the def2-TZV auxiliary
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basis set.24 Chemical shifts were computed at the IGLO RI-OPBE /pcS-1 level for
the lowest energy DFT optimized conformation of each diastereoisomer. The SV/J
auxiliary basis set was employed for density fitting. Solvation was taken into account using
the COSMO model.28 The computed shieldings were transformed into chemical shifts by
computing shieldings for the tetramethysilane and benzene molecules at the same level of
theory. The benzodiazepine aromatic protons were reference according to benzene
shielding whereas the rest of protons were reference to TMS. The shifts were computed
according to the relationship:
σref −σcalc
1−σref
δcalc
=
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where σref and σcalc are the shieldings computed for the reference proton nuclei and the
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proton of interest in the benzodiazepine. All computations were performed using the Orca
2.9 software package.29
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General procedure for the one-pot synthesis of 1,4-benzodiazepin-2-ones 6-9. A
mixture of the carbonyl compound (1.0 mmol), the amine (1.3 mmol), the isocyanide (1.0
mmol) and the protected aminoacid (1.0 mmol) in MeOH (3 mL) was submitted to orbital
stirring at room temperature for 48–72 h. After completion of the reaction, CH2Cl2 (3 mL)
and PS-p-TsOH (2.0 mmol) were added. The reaction mixture was submitted to orbital
stirring at room temperature until complete consumption of the unreacted isocyanide (30–
60 min). The polymeric reagent was filtered off and successively washed [2 times (4 mL)]
with MeOH, AcOEt and CH2Cl2. Evaporation of the solvents from the filtrate afforded a
residue, which was treated with 20% TFA in DCE (and heated to 60ºC for 1h). The
obtained solution was then treated with saturated NaHCO3. After extraction with ethyl
acetate, the organic phase was dried (Na2SO4) and evaporated under reduced pressure to
afford an oily residue that was purified by chromatographic methods on silica gel using
hexane/AcOEt mixtures.
N-Benzyl-2-(5-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)acetamide
1
(6a): 193 mg, 60% yield, mp: 159 – 161ºC; H NMR (300 MHz, CDCl3) δ (ppm): 7.63 –
7.54 (m, 1H), 7.54 – 7.45 (m, 2H), 7.41 – 7.10 (m, 7H), 6.77 (d, J = 6.1 Hz, 1H), 4.64 (d, J
= 15.5 Hz, 1H), 4.57 – 4.43 (m, 2H), 4.36 (dd, J = 14.8, 5.4 Hz, 1H), 4.15 (d, J = 15.5 Hz,
1H), 3.66 (d, J = 12.0 Hz, 1H), 2.39 (s, 3H);13C NMR (75 MHz, CDCl3) δ (ppm): 170.2,
170.1, 168.4, 141.1, 137.8, 131.6, 130.2, 128.7, 127.6, 127.6, 127.5, 125.3, 122.3, 55.9,
52.4, 43.6, 25.5; HRMS (ESI) m/z calcd. for C19H20N3O2 [M+H]+: 322.1550, found:
322.1552.
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(±)N-Benzyl-2-(5-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-il)pentana-
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mide (6b): 189 mg, 52% yield, mp: 127 – 129 ºC; H NMR (300 MHz, CDCl3) δ (ppm):
7.71 – 7.09 (m, 9H), 5.02 (dd, J = 9.2, 6.4 Hz, 1H), 4.70 – 4.29 (m, 4H), 3.63 (dd, J = 11.2
Hz, 1H), 2.44 (d, J = 1.5 Hz, 3H), 1.80 (ddt, J = 14.2, 9.8, 6.3 Hz, 1H), 1.35 (dtd, J = 14.2,
9.4, 4.9 Hz, 1H), 1.15 – 0.78 (m, 2H), 0.71 (q, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ (ppm): 172.6, 171.4, 170.2, 138.1, 137.5, 130.6, 128.6, 127.5, 127.4, 127.2,
125.9, 124.4, 57.5, 56.3, 43.6, 29.5, 25.2, 18.9, 13.5; HRMS (ESI) m/z calcd. for
C22H26N3O2 [M+H]+: 364.2020, found: 364.2020.
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(±)N-Benzyl-2-(5-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)-2-phe-
1
nylacetamide (6c): 266 mg, 67% yield, mp: 167 – 168ºC; H NMR (300 MHz, CDCl3,
conformers are present) δ (ppm): 7.82 – 6.91 (m, 14H), 6.84 (t, J = 5.8 Hz, 0.38H), 6.56 (t,
J = 5.7 Hz, 0.74H), 6.03 (s, 0.54H), 5.67 (s, 0.35 H), 4.70 – 4.36 (m, 3H), 3.72 (d, J = 11.0,
1H), 2.42 (dd, J = 7.4, 1.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm): 170.78, 170.47,
170.41, 170.12, 169.40, 169.17, 141.65, 139.01, 137.79, 134.39, 134.10, 131.88, 131.32,
130.20, 129.10, 128.77, 128.69, 128.62, 128.55, 128.45, 128.22, 128.16, 127.66, 127.60,
127.56, 127.53, 127.46, 127.34, 127.26, 126.95, 126.58, 126.52, 125.77, 125.48, 125.43,
123.81, 69.52, 65.26, 56.65, 56.30, 43.94, 43.86, 25.20; HRMS (ESI) m/z calcd. for
C25H24N3O2 [M+H]+: 398.1863, found: 398.1855.
N-Benzyl-2-methyl-2-(5-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)-
propanamide (6d): 154 mg, 44 % yield; 1H NMR (300 MHz, CDCl3) δ (ppm): 7.59 – 7.11
(m, 9H), 6.73 – 6.32 (m, 1H), 4.64 – 4.16 (m, 3H), 3.56 (d, J = 11.6, 1.6 Hz, 1H), 2.37 (d, J
= 1.6 Hz, 3H), 1.54 (s, 3H), 1.44 (s, 3H); 13C NMR (75 MHz, CDCl3) δ (ppm):174.2,
173.2, 169.9, 138.5, 138.2, 133.3, 129.8, 128.6, 127.8, 127.4, 126.6, 126.4, 126.2, 63.9,
57.5, 44.1, 26.8, 25.9, 24.8; HRMS (ESI) m/z calcd. for C21H24N3O2 [M+H]+: 350.1863,
found: 350.1863.
N-Benzyl-1-(5-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)cyclohexa-
1
necarboxamide (6e): 230 mg, 59 % yield; H NMR (300 MHz, CDCl3) δ (ppm): 8.24 –
7.79 (m, 1H), 7.58 – 7.09 (m, 9H), 4.4.56 (dd, J= 14.9, 6.1 Hz, 1H), 4.45 (dd J= 14.9, 5.4
Hz, 1H), 4.37 (d, J= 12.8 Hz, 1H), 3.64 (d, J = 12.8 Hz, 1H), 3.32 – 2.93 (m, 1H), 2.48 (s,
3H), 1.85 – 0.99 (m, 8H), 0.82 – 0.49 (m, 1H); 13C NMR (75 MHz, CDCl3) δ (ppm): 177.3,
175.2, 170.3, 139.2, 138.4, 133.3, 129.9, 128.6, 127.5, 127.2, 126.5, 126.4, 126.0, 66.9,
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58.2, 43.7, 32.7, 32.4, 25.0, 24.8, 21.7, 20.7; HRMS (ESI) m/z calcd. for C24H28N3O2
[M+H]+: 390.2176, found: 390.2170.
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N-Benzyl-2-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)acetamide
(6f): 268 mg, 70% yield, mp: 217 – 219ºC; 1H NMR (300 MHz, CDCl3) δ (ppm): 7.69 (dd,
J = 8.4, 1.1 Hz, 1H), 7.63 – 7.48 (m, 3H), 7.49 – 7.03 (m, 10H), 6.82 – 6.57 (m, 1H), 4.82
(d, J = 10.7 Hz, 1H), 4.64 (d, J = 15.5 Hz, 1H), 4.55 – 4.21 (m, 3H), 3.85 (d, J = 10.6 Hz,
1H);13C NMR (75 MHz, CDCl3) δ (ppm): 170.7, 170.3, 168.4, 142.8, 138.6, 137.7, 131.9,
130.5, 130.5, 129.5, 128.9, 128.6, 128.3, 127.5, 127.4, 124.8, 122.1, 56.6, 52.2, 43.5;
HRMS (ESI) m/z calcd. for C24H22N3O2 [M+H]+: 384.1707, found: 384.1713.
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(±)N-Benzyl-2-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)penta-
namide (6g): 268 mg, 63 % yield; 1H NMR (300 MHz, CDCl3) δ (ppm): 7.85 – 7.05 (m,
14H), 5.04 (dd, J = 9.2, 6.3 Hz, 1H), 4.78 (dd, J = 10.9, 0.6 Hz, 1H), 4.71 – 4.27 (m, 3H),
3.80 (dd, J = 10.9, 7.5 Hz, 1H), 2.02 – 1.72 (m, 1H), 1.63 – 1.27 (m, 1H), 1.17 – 0.82 (m,
13
2H), 0.67 (t, J = 7.2 Hz, 3H); C NMR (75 MHz, CDCl3) δ (ppm): 172.7, 171.5, 170.4,
139.5, 138.2, 138.1, 131.0, 130.7, 130.7, 130.1, 129.4, 129.3, 128.6, 128.4, 128.3, 127.5,
127.4, 127.3, 125.4, 124.4, 57.7, 57.0, 43.6, 29.8, 19.1, 13.6; HRMS (ESI) m/z calcd. for
C27H28N3O2 [M+H]+: 426.2176, found: 426.2165.
(±)N-Benzyl-2-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)-2-phe-
1
nylacetamide (6h): 285 mg, 62% yield, mp: 203 – 204ºC; H NMR (300 MHz, CDCl3,
conformers are present) δ (ppm): 7.75 (dd, J = 8.3, 1.2 Hz, 1H), 7.42 – 6.74 (m, 18H),
6.68 (t, J = 5.9 Hz, 0.25 H), 6.61 – 6.42 (m, 0.81H), 6.02 (d, J = 2.1 Hz, 0.74H), 5.60 (d, J
= 2.0 Hz, 0.22 H), 4.61 (dd, J = 10.7, 6.4 Hz, 1H), 4.53 – 4.15 (m, 2H), 3.71 (dd, J = 10.7,
13
1.9 Hz, 1H); C NMR (300 MHz, CDCl3) δ (ppm): 171.0, 170.5, 169.3, 140.0, 138.4,
137.6, 134.1, 130.3, 130.2, 129.4, 129.4, 129.2, 129.1, 128.7, 128.6, 128.5, 128.2, 128.2,
128.1, 128.0, 127.6, 127.4, 127.3, 127.2, 127.0, 125.9, 124.8, 64.1, 56.9, 43.8; HRMS (EI)
m/z calcd. for C30H25N3O2 [M]+: 459.1947, found: 459.1950.
N-Benzyl-2-methyl-2-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-
yl)propanamide (6i): 185 mg, 45% yield, mp: 213 – 215ºC; 1H NMR (300 MHz, CDCl3)
δ (ppm): 7.81 – 7.57 (m, 2H), 7.56 – 7.00 (m, 12H), 6.84 – 6.54 (m, 1H), 4.66 (d, J = 11.4
Hz, 1H), 4.44 (dd, J = 14.7, 6.1 Hz, 1H), 4.28 (dd, J = 14.7, 5.1 Hz, 1H), 3.76 (d, J = 11.5
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Hz, 1H), 1.56 (s, 3H), 1.50 (s, 3H); 13C NMR (75 MHz, cdcl3) δ (ppm): 174.2, 173.6,
167.0, 140.6, 138.0, 137.8, 132.0, 130.7, 130.1, 129.0, 128.5, 127.6, 127.2, 126.2, 63.9,
58.4, 43.9, 26.8, 26.2; HRMS (ESI) m/z calcd. for C26H26N3O2 [M+H]+: 412.2020, found:
412.2031.
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necarboxamide (6j): 212 mg, 47% yield, mp: 225-226ºC; H NMR (300 MHz, CDCl3) δ
(ppm): 7.81 (t, J = 6.0 Hz, 1H), 7.77 – 7.66 (m, 2H), 7.65 – 7.38 (m, 5H), 7.38 – 7.17 (m,
7H), 4.77 – 4.53 (m, 2H), 4.46 (dd, J = 14.9, 5.5 Hz, 1H), 3.80 (d, J = 12.3 Hz, 1H), 2.96
(d, J = 13.1 Hz, 1H), 2.14 – 1.04 (m, 8H), 1.00 – 0.65 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ (ppm): 176.72, 175.09, 169.94, 141.23, 138.44, 137.38, 131.74, 130.74, 130.11,
129.20, 128.95, 128.64, 128.42, 127.54, 127.27, 126.72, 125.94, 66.85, 58.84, 43.73,
32.43, 29.69, 24.85, 21.85, 21.14; HRMS (CI) m/z calcd. for C29H30N3O2 [M+H]+:
452.2338, found: 452.2344.
N-Cyclohexyl-2-(5-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)aceta-
1
mide (6k): 194 mg, 62% yield, mp: 202 – 203ºC; H NMR (300 MHz, CDCl3) δ (ppm):
7.97 – 7.36 (m, 3H), 7.26 (t, J = 7.5 Hz, 1H), 6.30 (d, J = 8.3 Hz, 1H), 4.76 – 4.35 (m, 2H),
13
4.07 (d, J = 15.3 Hz, 1H), 3.90 – 3.53 (m, 2H), 2.48 (s, 3H), 2.20 – 0.82 (m, 10H); C
NMR (75 MHz, CDCl3) δ (ppm): 170.1, 170.1, 167.5, 141.2, 131.6, 130.2, 127.5, 125.3,
122.4, 56.0, 52.7, 48.4, 32.8, 25.6, 25.4, 24.7; HRMS (CI) m/z calcd. for C18H24N3O2
[M+H]+: 314.1869, found: 314.1864.
(±)N-Cyclohexyl-2-(5-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-
yl)pentanamide (6l): 192 mg, 54% yield, mp: 128 – 129ºC; 1H NMR (300 MHz, CDCl3) δ
(ppm): 7.69 – 7.52 (m, 1H), 7.53 – 7.38 (m, 2H), 7.34 – 7.23 (m, 1H), 6.85 (d, J = 8.1 Hz,
1H), 4.92 (dd, J = 9.2, 6.4 Hz, 1H), 4.52 (d, J= 11.2 Hz, 1H), 3.78 (m, 1H), 3.64 (d, J =
11.2, 1H), 2.44 (s, 3H), 2.07 – 1.46 (m, 5H), 1.46 – 0.81 (m, 9H), 0.70 (q, J = 7.7, 6.8 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ (ppm): 172.9, 170.7, 170.3, 137.9, 132.3, 130.8, 127.3,
126.0, 124.6, 57.8, 56.6, 48.4, 32.9, 29.6, 25.7, 25.5, 24.8, 19.1, 13.7; HRMS (CI) m/z
calcd. for C21H30N3O2 [M+H]+: 356.2338, found: 356.2337.
(±)N-(Cyclohexyl)-2-(5-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)-2-
1
phenylacetamide (6m): 248 mg, 65% yield, mp: 187 – 189ºC, H NMR (300 MHz,
CDCl3, conformers are present) δ (ppm): 7.80 – 7.52 (m, 1H), 7.53 – 7.37 (m, 1H), 7.37 –
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6.94 (m, 7H), 6.47 (d, J = 8.1 Hz, 0.34 H), 6.10 (d, J = 8.0 Hz, 0.61H), 5.95 (s, 0.56H),
5.58 (s, 0.37H), 4.49 (t, J = 11.3 Hz, 1H), 4.12 – 3.52 (m, 2H), 2.44 (dd, J = 25.4, 1.5 Hz,
3H), 2.04 – 1.46 (m, 5H), 1.47 – 0.89 (m, 5H); 13C NMR (75 MHz, CDCl3) δ (ppm):
170.72, 170.51, 170.39, 170.10, 168.43, 168.14, 141.80, 139.04, 134.69, 134.45, 131.85,
131.27, 130.16, 129.01, 128.86, 128.65, 128.54, 128.37, 128.20, 128.03, 128.00, 127.05,
126.89, 126.44, 125.71, 125.54, 125.39, 123.81, 69.65, 65.23, 56.69, 56.32, 48.91, 48.66,
32.79, 32.70, 32.55, 32.48, 25.47, 25.25, 25.18, 24.74, 24.63; HRMS (CI) m/z calcd. for
C24H28N3O2 [M+H]+: 390.2182, found: 390.2186.
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N-(Tert-butyl)-2-methyl-2-(5-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-
yl)propanamide (6n): 154 mg, 49% yield, mp: 166 – 168ºC; 1HNMR (300 MHz, CDCl3)
δ (ppm): 7.56 – 7.38 (m, 2H), 7.36 – 7.29 (m, 2H), 5.99 (brs, 1H), 4.42 (d, J = 11.7 Hz,
1H), 3.58 (d, J = 11.7, 1H), 2.52 (s, 3H), 1.54 (s, 3H), 1.36 (s, 3H), 1.31 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ (ppm): 173.43, 173.17, 169.87, 138.79, 133.09, 129.95, 126.43,
126.40, 125.83, 64.31, 57.77, 51.01, 28.39, 27.33, 25.24, 25.13; HRMS (CI) m/z calcd. for
C18H26N3O2 [M+H]+: 316.2025, found: 316.2036.
(±)N-(Tert-butyl)-2-(5-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)-2-
phenylacetamide (6o): 218 mg, 60% yield, mp: 196 – 198ºC; 1H NMR (300 MHz, CDCl3,
conformers are present) δ(ppm): 1H NMR (300 MHz, ) δ (ppm): 7.66 (dd, J = 8.1, 1.2 Hz,
1H), 7.51 – 7.42 (m, 1H), 7.33 – 7.26 (m, 2H), 7.22 – 7.02 (m, 7H), 6.41 – 6.29 (m,
0.38H), 5.94 (s, 0.69H), 5.90 (s, 0.69H), 5.51 (s, 0.38H), 4.53 (dd, J = 11.0, 8.9 Hz, 1H),
3.73 (ddd, J = 10.9, 3.0, 1.6 Hz, 1H), 2.49 (d, J = 1.5 Hz, 1H), 2.41 (d, J = 1.5 Hz, 2H),
13
1.42 (s, 6H), 1.31 (s, 3H); C NMR (75 MHz, CDCl3,conformers are present) δ (ppm):
170.81, 170.46, 170.34, 170.09, 168.49, 141.82, 138.76, 134.75, 134.52, 131.87, 131.31,
131.21, 130.09, 129.04, 128.63, 128.45, 128.33, 127.94, 126.99, 126.87, 126.34, 125.85,
125.69, 125.34, 123.85, 70.24, 65.84, 65.54, 56.75, 56.39, 51.90, 51.54, 28.61, 28.44,
25.28, 25.23, 15.26; HRMS (CI) m/z calcd. for C22H26N3O2 [M+H]+: 364.2025, found:
364.2021.
N-Cyclohexyl-2-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)aceta-
1
mide (6p): 195 mg, 52% yield, mp: 228 – 230ºC; H NMR (300 MHz, CDCl3) δ (ppm):
7.66 – 6.89 (m, 9H), 6.07 (d, J = 8.2 Hz, 1H), 4.64 (d, J = 10.6 Hz, 1H), 4.37 (d, J = 15.5
Hz, 1H), 4.08 (d, J = 15.4 Hz, 1H), 3.67 (d, J = 10.6 Hz, 1H), 3.61 – 3.36 (m, 1H), 1.80 –
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