Direct and Enantioselective Synthesis of N?H-Free 1,5-Benzodiazepin-2-ones by an N-Heterocyclic Carbene Catalyzed [3+4] Annulation Reaction

Article abstract of DOI:10.1002/chem.201705050

An NHC-catalyzed formal [3+4] annulation of α,β-unsaturated acylazoliums with protecting-group-free aryl 1,2-diamines was developed for a direct and highly enantioselective synthesis of 4-aryl N?H-free 1,5-benzodiazepin-2-ones. This methodology offers an efficient and rapid access to a wide range of enantioenriched target compounds from easily accessible starting materials. The protocol is also scalable and the desired products can easily undergo subsequent N-functionalization to afford diverse N-substituted derivatives. Additionally, a mechanism was proposed to explain the high enantioselectivity in this process.

Full text of DOI:10.1002/chem.201705050

A Journal of
Accepted Article
Title: Direct and Enantioselective Synthesis of N-H-Free 1,5-
Benzodiazepin-2-ones via NHC-Catalyzed [3+4] Annulation
Reaction
Authors: Ding Du, Jing Cao, Chao Fang, Kewen Sun, Jindong Zhu,
and Tao Lu
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201705050
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10.1002/chem.201705050
Chemistry - A European Journal
Direct and Enantioselective Synthesis of N-H-Free 1,5-
Benzodiazepin-2-ones via NHC-Catalyzed [3+4] Annulation
Reaction
Chao Fang, Jing Cao, Kewen Sun, Jindong Zhu, Tao Lu,* and Ding Du*
a) Representative bioactive 1,5-benzodiazepin-2-ones
Abstract: An NHC-catalyzed formal [3+4] annulation of -
R
H
N
unsaturated acylazoliums with protecting group-free aryl 1,2-
diamines was developed for a direct and highly enantioselective
synthesis of 4-aryl N-H-free 1,5-benzodiazepin-2-ones. This
methodology offers an efficient and rapid access to a wide range of
enantioenriched target compounds from easily accessible starting
materials. The protocol is also scalable and the desired products can
easily undergo subsequent N-functionalization to afford diverse N-
substituted derivatives. Additionally, a mechanism was proposed to
explain the high enantioselectivity in this process.
N
N
H
Cl
N
O
O
Ph
1,5-benzodiazepin-2-one
1a
R = H, Iofendazam,
R = CO2Et, Arfendazam, 1b
O
EtO
Ph
H
N
Ar
N
H3C
F3C
N
N
H
H
O
O
1c
1d
treatment of CNS disorder
treatment of disorder
caused by Shiga toxins
Introduction
b) Direct and asymmetric synthesis via NHC-catalyzed [3+4]
annulation
(this work)
R2
H
N
R2
O
O
The 1,5-benzodiazepin-2-one heterocyclic motif is a privileged
structure frequently found in numerous natural products and
synthetic compounds with diverse biological activities (Scheme
1a).[1] Among these 1,5-benzodiazepin-2-ones, 4-aryl-
substituted derivatives have evoked considerable interest owing
to their pronounced pharmacological activities, and great
attention has been laid on their synthesis[2] and biological
study.[3] However, enantioselective synthesis of 4-substituted
R
R2
H
HN
R

a
O
3
Br
N
H
NHC*
4
NHC*
NH2
desired products
with high ee
II
desired
intermediates
O
challenge!
R2
NHC*
I
R2
a
b
H
N
R2
R
NH2
R
NH2
H2N
R
1,5-benzodiazepinones
investigated. So far, there are only three documented synthetic
methods that utilized asymmetric hydrogenation or
remains
challenging
and
less
b
N
H
O
4'
N
H
O
III
undesired products
without ee
2
undesired products
or intermediates
hydrosilylation of cyclic imine precursors to generate N-
protected derivatives reported by Rueping[4] and Zhang[5]
respectively. There are more or less some limitations for these
methods such as preparation of the cyclic imines in advance,
use of a transition metal catalyst or stoichiometric amount of a
reductant, and the formation of N-protected products which
inevitably require N-deprotection process for further N-
functionalization. Thus, the development of direct and efficient
synthetic strategies to access enantioenriched N-H free 1,5-
benzodiazepin-2-ones from easily accessible starting materials
is highly desirable.
Over the last decade, N-heterocyclic carbene (NHC)
catalysis has emerged as a powerful tool to enable a variety of
unconventional chemical transformations.[6] Among these
transformations, the architecture of seven-membered ring
systems via the formal [3+4] annulation of diverse NHC-bound
intermediates is most intriguing and more challenging since it
usually requires specific substrates and design strategies. On
one hand, the groups of Ye,[7] Scheidt[8] and Zhao[9] developed
NHC-catalyzed a3-d3 umpolung [3+4] annulations of enals with
diverse electrophiles for the synthesis of functionalized -
lactones, while Glorius[10] and Enders[11] recently developed
Scheme 1. Representative bioactive 1,5-benzodiazepin-2-ones and their
asymmetric synthesis
three strategies for the asymmetric synthesis of N-containing
seven-membered rings via NHC-catalyzed a3-d3 umpolung [3+4]
annulation of enals or isatin-derived enals. On the other hand,
Chi[12] reported an elegant work concerning NHC-catalyzed
formal [3+4] annulation of enals with azomethine imines via an
oxidative -activation strategy. ,-Unsaturated acylazolium I[6] is
an important class of NHC-bound intermediate that has been
intensively studied
Notwithstanding, the formal [3+4] annulations of ,-unsaturated
acylazoliums with 1,4-bisnucleophiles were less investigated.
There are only two [3+4] annulation examples
sulfur-centered and carbon-centered nucleophiles respectively
for the -functionalization of ,-unsaturated acylazoliums. To
date, the employment of nitrogen-centered nucleophiles for -
functionalization of ,-unsaturated acylazoliums in [3+4]
annulations has not yet been explored, although N-protected
hydrazides have been previously used as nitrogen-centered
nucleophiles for the -functionalization of ,-unsaturated
in
recent
years
(Scheme
1b).
[13]
that utilized
acylazoliums in
a
[3+2] annulation by Chi‘s group.[14] In
continuation of our studies on the exploration of NHC-catalyzed
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10.1002/chem.201705050
Chemistry - A European Journal
15]
[3+m] annulations,[13b,
we hypothesized that it might be
substituents like OMe and Br at 2-position of phenyl ring
afforded the desired products 4c, 4d and 4i in lower yields but
still with high ee values. Additionally, 1-or 2-naphthyl- and 2-
heteroaromatic-substituted 2-bromoenals were also suitable for
this transformation, affording the desired products 4q-u in 48-
96% yields with 90-98.6% ee. Unfortunately, this protocol was
not applicable for the synthesis of 4-alkyl-substituted 1,5-
benzodiazepin-2-one like 4v. Subsequently, the generality of this
protocol was evaluated by employing diversely substituted
symmetric aryl 1,2-diamines. 4,5-Dihalogen- and 4,5-dimethyl-
substituted benzene 1,2-diamines were first examined through
their reactions with bromoenal 3a. These reactions worked
equally well to afford products 4aa-ad in high yields with high
enantioselectivity. The reaction of naphthalene-2,3-diamine also
gave the desired product 4ae in 87% yield with 98.2% ee.
Unfortunately, when we tested the reactions of alkyl 1,2-
diamines such as cis-cyclohexane-1,2-diamine and ethane-1,2-
diamine, the desired products 4w and 4x were not obtained.
possible to realize a formal [3+4] annulation of ,-unsaturated
acylazoliums with readily accessible substituted aryl 1,2-
diamines for the direct synthesis of enantioenriched N-H free
1,5-benzodiazepin-2-ones 4 that can easily undergo subsequent
N-functionalization (Scheme 1b). However, there are two
competing reaction pathways when 2-bromoenals 3[15e, 16] and
aryl 1,2-diamines 2 are used as the substrates with NHC
catalysis. Besides the desired pathway (path a) via intermediate
II, another pathway (path b) could also take place to form III as
the final products or as the intermediates that may further
undergo intramolecular conjugate addition to afford the
undesired racemic products 4’. Therefore, it is a challenge to
achieve a highly chemoselective and enantioselective [3+4]
annulation in this process. Fortunately, the desired 1,5-
benzodiazepin-2-ones 4 were obtained in moderate to high
yields with high chemoselectivity and enantioselectivity when the
reactions were carried out in the presence of a chrial NHC
precursor. Herein, we report an unprecedented asymmetric
formal [3+4] annulation of aryl 1,2-diamines with -unsaturated
acylazoliums derived from 2-bromoenals. In this reaction,
protecting group-free aryl amines that were rarely used as
nucleophiles in C(sp3)-N bond formation[17] with NHC catalysis
were successfully installed at the -carbon of 2-bromoenals in a
highly enantioselective manner.Therefore, the obtained products
avoid the N-deprotection process and thus can be used directly
for subsequently diverse N-functionalization.
Table 1. Optimization of the reaction conditionsa
H
N
Ph
cat. (10 mol%)
base (2.0 equiv)
O
NH2
NH2
+
Ph
H
o
solvent, 4 A MS
rt, N2, overnight
N
H
Br
3a
O
2a
4a
O
O
N
N
N
N
N
Cl
N
N
N
N
N
Bn
N
N
Ar
Results and Discussion
Mes
Mes
Mes
BF4
Cl
Cl
D
Ar = Ph,
= Mes, E
A
B
C
We started our investigations on the model reaction of
commercially available benzene-1,2-diamine 2a with (Z)-2-
bromoenal 3a (Table 1). Initially, the efficiency of three
commonly chiral NHC precursors A-C was examined using
NaOAc as the base and PhMe as the solvent (entries 1-3). All
these catalysts especially B and C show high catalytic efficiency
that the desired 1,5-benzodiazepin-2-one product 4a was
obtained in high yields and enantioselectivity. Further screening
of the solvents and bases in the presence of catalyst C (entries
4-8) reveals that NaOAc and 1,2-dichloromethane (DCM) are
the optimal base and solvent, respectively, affording product 4a
in 96% yield with 97% ee (entry 5). However, lowering the
catalyst loading to 5 mol% led to a decreased yield but with a
maintained ee value (entry 9). Therefore, the conditions shown
in entry 5 were selected as the optimal one used for further
scope exploration. Additionally, this transformation still works in
the presence of achiral NHC precursor D or E but resulting in
relatively lower yields (entries 10 and 11).
With the optimized conditions in hand, we moved our
attention to explore the reaction scope initially through variation
of the (Z)-2-bromoenals 3 (Table 2). It was found that a variety
of 2-bromoenals with diverse substituents at different positions
of the phenyl ring were well tolerated to this protocol and the
corresponding products 4b-p were obtained in moderate to high
yields and excellent enantioselectivity. It seems that the steric
effect of the substituents on the phenyl ring has certain influence
on the reaction yields since 2-bromoenals with bigger
entry
1
cat.
A
B
C
C
C
C
C
C
C
D
E
base
solvent
yield (%)b
92
ee (%)c
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
K2CO3
PhMe
PhMe
PhMe
THF
79
96
97
98
97
-
2
91
3
90
4
41
5
DCM
DCM
DCM
DCM
DCM
DCM
DCM
96
6
<10
65
7
Cs2CO3
DIPEA
NaOAc
NaOAc
NaOAc
95
-
8
<10
74
9d
10
11
95
-
41
44
-
a Unless otherwise noted, all reactions were carried out with 2a (0.2 mmol), 3a
(0.3 mmol), a base (0.4 mmol) and 200 mg of 4Å molecular sieves (MS) in an
anhydrous solvent (3 mL) under N2 at room temperature (rt). Isolated yields
based on 2a. Ee values were determined via HPLC analysis. 5 mol% of C
was used. Mes = 2,4,6-(CH3)3C6H2; DIPEA = N,N-diisopropylethylamine
b
c
d
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10.1002/chem.201705050
Chemistry - A European Journal
that the reactions of 3-chloro and 3-methyl benzene-1,2-
diamines gave the desired products 5d and 5e both in excellent
regioselectivity. However, product 5e was obtained with lower
enantioselectivity. The structures of these regioisomers were
established by analysis of their NOESY spectra since the
hydrogen of N-H has interaction in space with the hydrogen or
the methyl group on the benzene ring.
Subsequently, a control study of the stereochemistry of the
2-bromoenal substrate and further reaction scope exploration
were carried out (Scheme 2). First, the reactivity of (E)-2-
bromoenal 3a under standard conditions was tested. The
stereochemistry of 2-bromoenals proved to have great impact on
the reaction yield since the reaction between (E)-3a and 2a
afforded product 4a in a significantly decreased yield but with
maintained enantioselectivity compared to that of (Z)-3a
(Scheme 2a). Since ,-unsaturated acylazolium I can be also
generated from enals with NHCs under oxidative conditions,[6]
the reaction of 2a with cinnamaldehyde under NHC/oxidative
conditions was test, but failed to afford the target product 4a
(Scheme 2b). Then, the reactivity of N-protected bis-secondary
amine 6a and mono-secondary amine 6b were examined under
the standard conditions, however, both substrates were not
suitable to this protocol (Scheme 2c). Last, the reaction of ,-
disubstituted 2-bromoenal 3w was examined but did not work
(Scheme 2d).
To further explore the synthetic utility of this protocol, a
scale-up synthesis of this protocol and derivatization of the
products were carried out (Scheme 3). With a 1.5 mmol scale
under standard conditions, product 4a was obtained in a slightly
decreased yield with maintained enantioselectivity (Scheme 3a).
As the N-H free 1,5-benzodiazepin-2-ones can easily undergo
N-functionalization, we then carried out some typical acylation
reactions of 4a and 4ab (Scheme 3b). The N-acylation of 4a and
4ab afforded compounds 7a and 7b respectively in high yields
and maintained ee values. Since the (S)-enantiomers of 7a and
7b are known compounds, the absolute configuration of 7a and
7b was assigned as (R) by comparing the optical rotation with
the literature value of their (S)-enantiomers.[4] Therefore, the
absolute configuration of products 4 and 5 was established as
Furthermore, the reactivity of several unsymmetrical
benzene-1,2-diamines were also tested (Table 3). The reaction
of 4-chlorobenzene-1,2-diamine afforded two regioisomers 5aa
and 5ab in 47% and 29% yields, respectively. Both regioisomers
were obtained in excellent enantioselectivity. The reaction of 4-
methyl and 4-methoxy benzene-1,2-diamines both afforded two
regioisomers with 1.2:1 rr and 2.4:1 rr, respectively, which
cannot be separated by column chromatography. Although the
regioselectivity of these cases is poor, the combined yields are
high and ee values are excellent for each isomer. It is interesting
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10.1002/chem.201705050
Chemistry - A European Journal
(R). The reaction between 4a and ethyl carbonochloridate with
different bases gave different N-substituted products. The
reaction using K2CO3 as a base afforded product 7c as the
enantiomeric variant of compound 1c in a high yield with
maintained enantioselectivity, while the reaction using NaH as a
base afforded product 7d in a moderate yield with somewhat
decreased enantioselectivity. Last, the reduction of the amide
group of 4a with LiAlH4 was carried out to give desired product 8
in 87% yield with 94.3% ee.
A plausible mechanism for this transformation is proposed in
Scheme 4. The reaction is initiated by a combination of (Z)-2-
bromoenal 3a with NHC C’ generated upon deprotonation of
carbene precursor
C with NaOAc affording the Breslow
intermediate IV. The a3-d3 umpolung of IV induces the formation
of intermediate V that is tautomerized to 2-bromoacylazolium VI.
The subsequent loss of the bromide produces the more stable
(E)--unsaturated acylazolium VII. Possible H-bonding
between amino group of 2a and the carbonyl group of VII gives
the favored transition state (TS) VIII that may play a significant
role in controlling the enantioselectivity. TS VIII’ is disfavored
due to the steric conflict between the benzene ring of 2a and the
big chiral group of VII. The subsequent Si-face attack of the
amino group to the -carbon affords intermediate IX that
undergoes sequential tautomerization and lactam formation to
produce product (R)-4a in a highly enantioselective manner.
3a
2a
a) The reaction of (E)-bromoenal
with
H
N
Ph
standard
NH2
NH2
Br
conditions
CHO 51%, 97.5% ee
3a
+
Ph
N
H
O
2a
4a
(E)-
2a
b) The reaction of cinnamaldehyde with
under oxidative conditions
tBu tBu
O
H
N
O
standard
CHO
N
N
conditions
3a
O
O
N
OH
4a
2a
+
(R)
Mes
O
Ph
N
[O]
N
N
Ph
4a H
Ph
C'
[O]
tBu
tBu
lactam
formation
N
Br
Mes
c) The reaction of N-protected benzene-1,2-diamines
IV
NaOAc
O
NH2
NHR4
C
standard conditions
HN
Ph
H
OH
NR
+
O
H
O
NHR5
O
N
N
N
Br
3a
Ph
Ph
(R)
4
5
6a
N
R = R = Ts,
Br
Mes
N
N
X
V
6b
R
4 = H, R5 = Ts,
Mes
steric
hindered
3w
d) The reaction of .-disubstituted 2-bromoenal
N
H2
O
O
H2N
Re-face
H3C
Ph
H
standard conditions
H
NH2
2a
NR
+
O
N
H2N
O
Ph
H
O
attack
Br
3w
O
N
N
N
O
VIII'
N
Ph
Ph
(R)
Mes
N
N
Br
N
IX
disf avored TS
N
Scheme 2. Further reaction scope exploration.
Mes
1,4-addition
VI
Mes
-Br-
a) A scale-up synthesis
standard conditions
NH2
H
2a
H
O
4a
2a
82%, 97.3% ee
+
3a
NH2
O
O
1.5 mmol
N
N
O
Si-face
Ph
N
b) N-functionalization of the products
Ph

attack
N
N
N
Mes
Ac
Ph
Ac
VIII
favored TS
VII
Mes
Ph
N
N
Cl
(R)
AcCl
(R)
AcCl
4a
4ab
DMAP
DCM, rt
Pyridine
Scheme 4. Proposed mechanism.
97% ee
N
96.4% ee
Cl
N
DMF, rt
H
O
H
O
7a, 85%, 96% ee
7b, 88%, 98.9% ee
O
H
N
Ph
EtO2C
O
Conclusions
H
N
Ph
Ph
O
N
Cl
OEt
K2CO3
THF, rt
Cl
OEt
In conclusion, we have demonstrated an NHC-catalyzed formal
[3+4] annulation of -unsaturated acylazoliums with aryl 1,2-
diamines. This protocol offers a direct and rapid access to a
wide range of enantioenriched N-H-free 4-aryl-substituted 1,5-
benzodiazepin-2-ones from easily accessible starting materials.
Moreover, this protocol is scalable for the synthesis of the target
compounds that can easily undergo subsequent N-
functionalization to give diverse N-substituted derivatives such
as the enantiomeric variant of compound 1c used for treating
disorder caused by Shiga toxins.[1c] Further investigation and
application of -unsaturated acylazoliums in the construction
NaH
THF, rt
N
N
H
N
H
O
EtO2C
O
7c
, 88%, 97% ee
4a
7d
, 52%, 86.7% ee
, 97% ee
c) Reduction of the amide group
H
N
Ph
O
H
N
Ph
LiAlH4
THF, 70oC
N
H
N
H
4a 97% ee
8, 87%, 94.3% ee
Scheme 3. A scale-up synthesis and derivatization of the products.
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10.1002/chem.201705050
Chemistry - A European Journal
[3]
[4]
a) S. Miyanaga, H. Sakurai, I. Saiki, H. Onaka, Y. Igarashi, Bioorg. Med.
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laboratory.
Experimental Section
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X. Chen, Y. Zheng, C. Shu, W. Yuan, B. Liu, X. Zhang, J. Org. Chem.
2011, 76, 9109.
General experimental procedure for the
synthesis of products 4 and 5
For selected reviews, see: a) C.-H. Zhang, J. F. Hooper, D. W. Lupton,
ACS Catal. 2017, 7, 2583; b) M. H. Wang, K. A. Scheidt, Angew. Chem.
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To an oven-dried 25 mL two-neck bound-bottom flask was
charged with substituted aryl-1,2-diamines 2 (0.2 mmol), -
bromoenals 3 (0.3 mmol), carbene precursor C (8.4 mg, 0.02
mmol), NaOAc (33 mg. 0.4 mmol), and 200 mg of 4 Å MS under
N2 atmosphere. Then anhydrous DCM (3 mL) was added and
the resulting mixture was stirred overnight at rt under N2. Then,
the mixture was filtered, and the filtrate was evaporated under
reduced pressure. The residue was purified by chromatography
on silica gel using hexane/EtOAc (3:1) as eluent to afford the
products 4 or 5.
Typical characterization of 4b: Semi-solid, 46 mg, 89% yield,
96% ee. []D = +11.8 (c = 0.144 in CH2Cl2). HPLC DAICEL
CHIRALCEL IF, n-hexane/2-propanol = 80/20, flow rate = 2.0
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2013, 52, 8607; Angew. Chem. 2013, 125, 8769; c) Z.-Q. Liang, L. Yi,
K.-Q. Chen, S. Ye, J. Org. Chem. 2016, 81, 4841.
RT
mL/min, λ = 254 nm, retention time: 8.55 min (major), 12.44 min
[8]
[9]
J. Izquierdo, A. Orue, K. A. Scheidt, J. Am. Chem. Soc. 2013, 135,
10634.
1
(minor). H NMR (300 MHz, CDCl3) δ 8.60 (brs, 1H), 7.59 (td, J
= 7.6, 1.7 Hz, 1H), 7.30-7.22 (m, 1H), 7.15-7.00 (m, 3H), 6.97-
6.88 (m, 2H), 6.83 (d, J = 7.5 Hz, 1H), 5.40 (dd, J = 7.0, 5.5 Hz,
1H), 3.82 (brs, 1H), 2.94-2.78 (m, 2H). 13C NMR (125 MHz,
CDCl3) δ 172.1, 159.5 (d, J = 245 Hz), 138.4, 130.5 (d, J = 12.8
Hz), 129.4 (d, J = 8.1 Hz), 128.1, 127.6 (d, J = 4.0 Hz), 125.9,
124.4 (d, J = 3.3 Hz), 122.4, 121.6, 121.1, 115.6 (d, J = 21.5 Hz),
56.3 (d, J = 3.0 Hz), 39.8. HRMS (ESI) calcd for C15H13FN2O:
256.1012, found: 256.1016.
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Acknowledgements
This work is funded by the National Natural Science Foundation
of China (No. 21572270), the Qing Lan Project of Jiangsu
Province, and the Priority Academic Program Development of
Jiangsu Higher Education Institutions.
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Keywords: benzodiazepinone •carbene • [3+4] annulation •
asymmetric synthesis • -unsaturated acylazolium
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[2]
[17] To the best of our knowledge, there is only one example that used
protecting group-free aryl amines as substrates in NHC-catalyzed sp3C-
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N bond formation reaction. H.-R. Zhang, Z.-W. Dong, Y.-J. Yang, P.-L.
Wang, X.-P. Hui, Org. Lett. 2013, 15, 4750.
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