Facile synthesis of 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones: Via cyclization of N -alkoxy α-halogenoacetamides with N -(2-chloromethyl)aryl amides

Article abstract of DOI:10.1039/c9ob02260k

A facile and efficient cyclization of N-alkoxy α-halogenoacetamides with N-(2-chloromethyl)aryl amides has been achieved for rapid access to 1,2,4,5-tetrahydro-1,4-benzodiazepine-3-one derivatives (up to 95% yield). The intriguing features of this intermolecular cyclization include its mild reaction conditions and easy handling for scalable synthesis.

Full text of DOI:10.1039/c9ob02260k

Organic &
Biomolecular Chemistry
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COMMUNICATION
Facile synthesis of 1,2,4,5-tetrahydro-
1,4-benzodiazepin-3-ones via cyclization
of N-alkoxy α-halogenoacetamides with
N-(2-chloromethyl)aryl amides†
a,b
Cite this: Org. Biomol. Chem., 2019,
17, 9708
Received 18th October 2019,
Accepted 1st November 2019
DOI: 10.1039/c9ob02260k
Qiaomei Jin,
*
a,b Dongjian Zhanga,b and Jian Zhang
*
rsc.li/obc
A facile and efficient cyclization of N-alkoxy α-halogenoacet- considerable attention due to their highly diverse activities,
amides with N-(2-chloromethyl)aryl amides has been achieved such as being a potent inhibitor of the vitamin D receptor in
for rapid access to 1,2,4,5-tetrahydro-1,4-benzodiazepine-3-one Paget’s disease of bone,3 PARP inhibitor4 and protein kinase C
derivatives (up to 95% yield). The intriguing features of this inter- modulator5 for anticancer drugs.
molecular cyclization include its mild reaction conditions and easy
Consequently, during the past decades, various syntheti-
cally feasible protocols have been developed to construct this
coveted moiety through intramolecular cyclization pathways.
The existing methods for the synthesis of 1,2,4,5-tetrahydro-
1,4-benzodiazepine-3-ones typically are intramolecular nucleo-
philic aromatic substitution,6 intramolecular cycloaddition,7
palladium-catalyzed N-arylation8 and Ullmann’s aryl amin-
ation (Scheme 1a).9 Although these methods provide con-
venient access to 1,2,4,5-tetrahydro-1,4-benzodiazepine-3-one
derivatives, the reported applications suffer from drawbacks
such as multistep reactions and harsh reaction conditions
(transition metal catalyzed cyclization and/or high tempera-
ture). In light of the above-mentioned limitations, the explora-
handling for scalable synthesis.
Benzodiazepines, a member of the family of core structural
subunits, occupy a significant place among pharmaceutical
ingredients.1 These compounds have been extensively studied
for their manifold bioactivities. Some representative examples
are shown in Fig. 1: diazepam is used to treat anxiety;1a abbe-
mycin, isolated from Streptomyces sp. AB-999F-52, is an anti-
biotic.2 Although 1,4-benzodiazepine-2-ones have been widely
studied, their analogues 1,2,4,5-tetrahydro-1,4-benzodiazepine-
3-ones have been less investigated. They have recently attracted
Fig. 1 Representative biologically active compounds containing the
benzodiazepine skeleton.
aAffiliated Hospital of Integrated Traditional Chinese and Western Medicine,
Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu, China.
E-mail: jqmxy@163.com, zjwonderful@hotmail.com
bLaboratories of Translational Medicine, Jiangsu Province Academy of Traditional
Chinese Medicine, Nanjing 210028, Jiangsu, China
†Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic data. See DOI: 10.1039/c9ob02260k
Scheme 1 Previous reports on and our approach for the synthesis of
1,2,4,5-tetrahydro-1,4-benzodiazepine-3-ones.
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Table 1 Optimization of the reaction conditionsa
tion of newer and sustainable methods under benign con-
ditions to access diverse 1,2,4,5-tetrahydro-1,4-benzodiazepine-
3-ones is still in high demand.
In recent years, azaoxyallyl cations, generated in situ from
N-alkoxy α-halogenoacetamides in the presence of a base, con-
stitute a class of versatile building blocks useful for the rapid
construction of biologically important molecules. In their pio-
neering work, Jeffrey’s group reported inter- and intra-
molecular [4 + 3] cycloadditions of azaoxyallyl cations with
furans for heterocycle synthesis.10 After that, azaoxyallyl
cations, such as 1,3-dipoles, have been widely applied in
[3 + 1]-,11 [3 + 2]-,12 and [3 + 3]-13 cycloaddition reactions.
Recent investigations also revealed that aza-o-quinone
methides (aza-oQMs), generated in situ through the base-
mediated elimination of N-(2-chloromethyl)aryl amides, have
been widely used as the new reactive synthons in [4 + m] cyclo-
addition reactions.14 Because of their high reactivity profiles,
we firstly envisioned a direct pathway to assemble 1,2,4,5-tetra-
hydro-1,4-benzodiazepine-3-ones via [3 + 4] annulation of
N-alkoxy α-halogenoacetamides with aza-oQMs (Scheme 1b).
Unexpectedly, a cyclization reaction proceeded via [2 + 4]
annulation when we started to investigate the model reaction
of 3-(((2-bromo-2-methylpropanamido)oxy)methyl)benzene-
1-ylium with methyl(2-(chloromethyl)phenyl)carbamate
(Scheme 1b).15 Inspired by this result, we observed that the
[2 + 4] annulation of dialkyl substituted haloamides proceeded
efficiently with aza-oQMs. As part of our efforts in developing
the [3 + 4] annulation of N-alkoxy α-halogenoacetamides with
aza-oQMs, we describe here our work on the aforementioned
reaction of unsubstituted haloamides with aza-oQMs.
Base
Entry (equiv.)
Temp. Time Yield
X
Solvent
(°C)
(h)
of 3a b (%)
1
2
3
4
5
6
7
8
Cs2CO3 (2.0) Cl DMF
K2CO3 (2.0) Cl DMF
Na2CO3 (2.0) Cl DMF
t-BuOK (2.0) Cl DMF
NaOH (2.0)
KOH (2.0)
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
4
4
4
4
4
4
4
4
4
4
4
3
3
3
3
3
3
3
3
3
3
3
3
58
47
42
<10
—
Trace
27
—
—
—
17
75
73
43
35
55
37
45
65
Cl DMF
Cl DMF
NaOMe (2.0) Cl DMF
NEt3 (2.0)
DIPEA (2.0)
DMAP (2.0)
DBU (2.0)
Cs2CO3 (2.5) Cl DMF
Cs2CO3 (3.0) Cl DMF
Cl DMF
Cl DMF
Cl DMF
Cl DMF
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Cs2CO3 (2.5) Cl 1,4-Dioxane rt
Cs2CO3 (2.5) Cl Toluene
Cs2CO3 (2.5) Cl THF
Cs2CO3 (2.5) Cl DCM
Cs2CO3 (2.5) Cl DCE
Cs2CO3 (2.5) Cl CH3CN
Cs2CO3 (2.5) Cl HFIP
Cs2CO3 (2.5) Cl DMAc
Cs2CO3 (2.5) Br DMF
Cs2CO3 (2.5) Cl DMF
rt
rt
rt
rt
rt
rt
rt
rt
45
Trace
62
73
68
a Unless noted otherwise, reaction of 1a (0.2 mmol), 2a (0.24 mmol)
and base was performed in 2.0 mL of solvent under Ar. b Isolated yield
based on 1a.
Our work commenced with the screening of various para-
meters in order to search for the ideal reaction conditions for temperature resulted in slightly decreased yields (entry 23,
an efficient and successful annulation of N-OBn substituted Table 1). An N-OBn substituted bromoacetamide derivative was
chloroacetamide derivative 1a with benzyl (2-(chloromethyl) also used for the preparation of 3a during the exploration of
phenyl)carbamate 2a (Table 1). Initially, it was found that the reaction scope (entry 22, Table 1).
Cs2CO3 (2.0 equiv.) was effective in promoting this transform-
Having identified the optimal reaction parameters, we then
ation, affording our desired [3 + 4] product in 58% yield in focused on the exploration of the reaction scope (Scheme 2).
DMF at room temperature in 4 h (entry 1, Table 1). Then, sys- Initially, a variety of N-(ortho-chloromethyl)aryl amides 2 were
tematic optimization of the reaction conditions was per- examined. N-(ortho-Chloromethyl)aryl amides 2 with electron-
formed. A series of bases were explored. Inorganic bases, such withdrawing or electron-donating groups at different positions
as t-BuOK, NaOH and KOH, failed to produce the expected were well tolerated in this reaction (3c: 54%, 3d: 43%, 3e: 50%,
product (entries 4–6, Table 1), and the other bases such as and 3f: 63%). In addition, the reaction of the N-protecting
K2CO3, Na2CO3 and NaOMe exhibited comparable activity group of 2 either resulted in moderate yields or did not work
(entries 2, 3 and 7, Table 1). As is shown, among the several at all. The N-Cbz group, N-COOMe group, N-COOi-Pr group
commonly used inorganic bases, Cs2CO3 was proven to be the and N-COOi-Bu group afforded the corresponding products
most effective choice. Organic bases such as Et3N, DIPEA, in moderate yields. Nevertheless, the N-Ts group was not suit-
DMAP and DBU were found to be ineffective for this reaction able and the expected product was not formed. Finally, we
(entries 8–11, Table 1). Next, the amount of Cs2CO3 was varied moved toward investigating the reactivity of the N-alkoxy
(entries 12 and 13, Table 1). By performing the reaction with α-halogenoacetamide partner. As expected, the reactions of
Cs2CO3 (2.5 equiv.), the reaction proceeded smoothly and the these unsubstituted N-alkoxy α-halogenoacetamides worked
yield of 3a increased to 75% (entry 12, Table 1). Further, the equally smoothly to give the desired products in good yields.
effect of solvent was examined (entries 14–21, Table 1). A Hydroxamates with variation in their protecting groups on the
survey was conducted on alternative solvents such as 1,4- nitrogen atom such as methoxy, ethoxy, allyloxy, isopropoxy
dioxane, toluene, THF, DCM, DCE, CH3CN, HFIP and DMAc, and tert-butoxy tend to provide 1,2,4,5-tetrahydro-1,4-benzo-
which revealed that DMF was the optimal solvent of choice. diazepine-3-one derivatives in 85–95% yields (3k–3o). The reac-
Finally, temperature has a little effect on the reaction. High tion was also efficient when N-(benzyloxy)-2-bromopropana-
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Scheme 3 Follow-up chemistry.
Scheme 4 Plausible reaction mechanism.
dehydes (Scheme 3b).16a To further investigate the reaction
scope, N-(benzyloxy)-2,2-dichloroacetamide was tested. Curiously,
the unexpected product 5 was obtained in 85% yield (Scheme 3c).
On the basis of our results and the previous studies,17
a
plausible mechanism was proposed as illustrated in
Scheme 4. First, N-(ortho-chloromethyl)aryl amide 2a reacts
with Cs2CO3 to form the in situ generated aza-oQM intermedi-
ates. Then, deprotonation on the nitrogen atom of N-alkoxy
α-halogenoacetamide 1a occurred under the promotion of a
base. Finally, the reaction might occur through a cascade aza-
Mannich addition/intramolecular SN2 pathway to generate the
final domino product 3a.
Scheme 2 The reaction scope. Typical conditions: Cs2CO3 (2.5 equiv.)
was added to a stirred solution of 1 (0.2 mmol) and 2 (0.24 mmol) in
DMF (2.0 mL) at room temperature for 3 h under an Ar atmosphere.
Isolated yield based on 1.
In summary, N-alkoxy α-halogenoacetamides and aza-oQMs
formed in situ undergo a cascade aza-Mannich addition/
intramolecular SN2 domino reaction to provide synthetically
useful 1,2,4,5-tetrahydro-1,4-benzodiazepine-3-ones in average
to good yields (up to 95% yield). The present methodology is a
concise, mild, practical and one-pot method. Further studies
on the application of 1,2,4,5-tetrahydro-1,4-benzodiazepine-3-
ones are underway in our laboratory.
mide was used, leading to the desired product 3p in 74% yield.
However, N-benzyl-2-chloroacetamide was found to be not suit-
able for this reaction, and no desired product was observed.
In order to address the viability and potential synthetic
application of this reaction, gram-scale scale-up reactions and
several applications were carried out (Scheme 3). Product 3a was
obtained in a sustained yield (78%) on an 8 mmol scale under
the standard conditions (Scheme 3a). Next, the deprotection of
the benzyloxy group of 3a was performed. We found that both
the C–N bond and the benzyloxy group of 3a were readily trans-
formed through hydrogenation with Pd/C in methanol solvent.
The glycinamide product 4 is an important intermediate that
Conflicts of interest
was used to afford 1-alkyl(aryl)-4-chloro-1H-imidazole-5-carbal- There are no conflicts to declare.
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