Expedient Synthesis of 1,4-Benzodiazepines via a Tandem Condensation/[1,5]-Hydride Transfer/Cyclization Process

Article abstract of DOI:10.1002/adsc.201800781

An expedient approach to 1,4-benzodiazepines via a tandem condensation/[1,5]-hydride shift/cyclization process has been developed. This transformation started from readily available o-amino benzaldehyde and aminomalonate and was promoted by low-cost FeCl₃ with high step and atom economy. (Figure presented.).

Full text of DOI:10.1002/adsc.201800781

Title: Expedient Synthesis of 1,4-Benzodiazepines via a Tandem
Condensation/[1,5]-Hydride Transfer/Cyclization Process
Authors: Baomin Wang, Siyuan Liu, Tuan Zhao, and Jingping Qu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800781
Link to VoR: http://dx.doi.org/10.1002/adsc.201800781

10.1002/adsc.201800781
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Expedient Synthesis of 1,4-Benzodiazepines via a Tandem
Condensation/[1,5]-Hydride Transfer/Cyclization Process
Siyuan Liu,a Tuan Zhao,a Jingping Qu,a and Baomin Wanga,*
a
State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of
Technology, Dalian 116024, P. R. China
E-mail: bmwang@dlut.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: An expedient approach to 1,4-benzodiazepines
via a tandem condensation/[1,5]-hydride shift/cyclization
process has been developed. This transformation started
from readily available o-amino benzaldehyde and
aminomalonate and was promoted by low-cost FeCl3 with
high step and atom economy.
Keywords: [1,5]-hydride shift/cyclization; benzodiazepine;
tandem reaction; C(sp3)-H functionalization; N-heterocycle
Figure 1. Representative alkaloids and drug molecules
containing the benzodiazepine core.
Benzodiazepines
(BDZs),
particularly
1,4-
benzodiazepines, are present in many natural
alkaloids[1] and have long been the center of attention
because of their diverse array of pharmacological
activities (Figure 1),[2] which make them potential
candidates for use in anti-cancer,[2a] anti-
On the other hand, the direct functionalization of a
C(sp3)-H bond by an intramolecular 1,5-hydride
transfer/cyclization sequence, which is characterized
by an “internal redox” process, has drawn much
attention of the synthetic organic chemistry
community, as this method can accomlish rapid
increase of molecular complexity from simple
precursors with high efficiency and excellent
step/atom economy.[4] However, there are limited
reports[5] on seven-membered ring formation by such
C(sp3)-H bond functionalization, although six-
membered ring formation by this reaction sequence is
very common. In particular, the synthesis of
benzodiazepines with this strategy remains
unexplored.
infective,[2a,2b]
antihypertensive,
anxiolytic,
hypnotic,[2c] and anti-HIV[2d] drugs. Furthermore, the
application of benzodiazepines has been extended to
the treatment of bipolar disorder[2e-2g] and chronic
back pain.[2h] In addition, structurally many of these
drugs and bioactive compounds contain a fused
pyrrolidine or dihydropyrrole skeleton. Because of
the significance of benzodiazepines, much effort has
been devoted to accessing this class of compounds
via, for example, the Ugi condensation[3a], Friedel-
Crafts
reaction[3b]
,
click
chemistry,[3c,3d]
carboamination,[3e] ring expansion reactions,[3f,3g] and
aza-Michael cyclization.[3h] While each of these
methods affords a series of benzodiazepines and has
great potential utility in the new drug discovery,
preparative difficulties and complex operations have
restricted their extensive application.[2b] Thus, the
development of efficient methods for the construction
of the benzodiazepine skeleton still remains a highly
desirable yet challenging task.
1
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10.1002/adsc.201800781
Advanced Synthesis & Catalysis
spectrum of 4aa, a sharp singlet peak assigned to the
-C-H of the malonate moiety appeared at 4.41 ppm,
while for 3aa a diagnostic broad singlet signal
assigned to the N-H moiety appeared at 3.43 ppm. In
addition, the structure of 3aa was further confirmed
by the DEPT technique.
Table 1. Screening of optimal reaction conditionsa)
Entry
1
2
3
4
5
6
7
8
Catalyst
--
AcOH
TsOH
TFA
DPP
Bi(OTf)3
Cu(OTf)2
La(OTf)3
Zn(OTf)3
Yb(OTf)2
SnCl4
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
DCE
t (h)
5
5
4
3
4.5
10
10
10
4
Yieldb)
29
32
25
40
47
--
--
21
40
46
14
42
53
47
23
Scheme 1. Strategies for the synthesis of diazacycle via
condensation/[1,5]-hydride transfer/cyclization sequences.
In continuation of our interest in the 1,5-hydride
transfer/cyclization strategy[6] and as part of our
research program on the development of potentially
bioactive N-heterocyclic systems,[7] we envisioned a
one-pot
reaction
of
involving
aminomalonic
acid-catalyzed
acid ester
9
condensation
10
11
12
13
14
15
16
17
18
19
20
21c)
22d)
23e)
24f)
3
5
4
3
hydrochloride with o-amino-substituted benzaldehyde,
followed by an intramolecular 1,5-hydride transfer/7-
cyclization sequence, to afford multi-substituted
benzodiazepines (Scheme 1).
ZnCl2
FeCl3
.
BF3 Et2O
5
Our study began with the selection of the two-
component coupling of diethyl aminomalonate
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
--
20
10
10
10
6
4
5
3
6
toluene
THF
trace
trace
trace
23
48
38
hydrochloride
1a
and
2-(pyrrolidin-1-yl)-
benzaldehyde 2a as a model reaction to identify the
optimal reaction conditions (Table 1). Albeit with a
low yield of 29%, the initial experiment revealed that
substrates 1a and 2a could be converted into the
desired product 3aa in ethanol without any extra
catalyst (entry 1). In order to improve the product
yield, we then screened various catalysts for the
model reaction in refluxing ethanol. A brief survey of
Brønsted acid catalysts (entries 2-5) showed that 3aa
could be obtained in an acceptable yield of 47%, in
4.5 h, when using 10 mol% diphenyl phosphate (DPP)
(entry 5). Some Lewis acids were also tested as
catalysts to promote this process (entries 6-14). It was
encouraging to find that the reaction catalyzed by the
low-cost FeCl3 (10 mol%) proceeded to completion
in 3 h and afforded 3aa with an increased yield of
53% (entry 13). Further investigation was carried out
by screening various reaction media and the amounts
of solvent and catalyst (entries 15-24). However,
owing to the generation of complex, highly polar
compounds which are difficult to identify, higher
conversion was not obtained. Moreover, we expected
that neutralization of HCl in the reaction medium by
adding an equivalent amount of NaHCO3 would
furnish higher yield (entry 25). Surprisingly, instead
of the desired 3aa, six-membered ring product 4aa
was obtained in a high yield of 84% in this case. The
structures of 3aa and 4aa were confirmed by the
dioxane
MeCN
i-PrOH
EtOH
EtOH
EtOH
EtOH
EtOH
48
36
3
1.5
50
25g)
84h)
a)
All reactions were carried out with 1 (0.48 mmol), 2
(0.40 mmol) in solvent (4.0 mL) at room temperature.
After the catalyst (10 mol%) was added, the reaction was
heated to reflux until completion of the reaction. b) Isolated
yield of 3aa. c) Temperature 60 C. d) 20 mol% catalyst. e) 5
o
mol% catalyst. f) Solvent 2 mL. g) Addition of 0.48 mmol
NaHCO3. h) Isolated yield of 4aa.
With the optimal reaction conditions in hand, we
next focused on the generality of the 1,5-hydride
transfer/7-endo cyclization process. First, we carried
out the reaction of tertiary amino benzaldehydes 2
with diethyl aminomalonate hydrochloride 1a to
examine the substrate scope (Scheme 2). The reaction
outcome suggested that substrates bearing halogen,
alkyl, alkynyl, or aryl substituents at the 4-position of
the benzene ring successfully underwent the reaction
to form the desired products in 50%-61% yields
(Scheme 2, 3ab-3af). Moreover, substrates with
1
comparative analysis of their H NMR spectra. In the
2
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10.1002/adsc.201800781
Advanced Synthesis & Catalysis
substituents of halogen, alkyl, alkoxyl, and aryl at the
5-position could also be smoothly transformed into
the corresponding products in 30-64% yields (3ag-
3ak). The substrates with a halogen groups showed
high reaction efficiency probably because of the
electron-withdrawing effect in the condensation step.
Next, a methyl group was introduced to the 6-position
of the o-amino benzaldehyde, and the desired product
3al was successfully formed in 40% yield. To further
broaden the scope of this reaction, related larger-
membered azacyclic substrates were employed.
However, owing to the generation of some complex
by-products, the reaction of diethyl aminomalonate
hydrochloride 1a and 2-(piperidin-1-yl)benzaldehyde
2m could not afford the desired product 3am. But
excitedly, when the tertiary amino benzaldehyde was
were tolerated in the H-shift/7-endo ring closure with
2a, affording the corresponding 3ba and 3ca in 56%
and 31% yield, respectively. The slightly lower yield
of 3ca as compared to that of 3aa and 3ba was
probably due to steric hindrance from the isopropyl
group. Next, a phenyl group was introduced to the
amine moiety of the diethyl aminomalonate substrate.
Surprisingly, instead of seven-membered-ring
product 3da, the demalonate product 4da was
obtained in 42% yield.[8] And the structure of 4da
was verified by comparing to the reported 1H and 13C
NMR spectra.[8a]
To demonstrate the practical utility of the 1,5-
hydride shift/7-cyclization process, a gram-scale
changed to 2-(azepan-1-yl)benzaldehydes (2n and 2o), reaction of 1a (9.6 mmol) with 2a (8.0 mmol) was
the target products 3an and 3ao were obtained in
38% and 30% yield, respectively. In addition, eight-
membered azacyclic substrate 2p was also tried in
this reaction. Interestingly, instead of the seven-
membered ring product 3ap, the six-membered ring
product 4ap was obtained in 35% yield.
conducted, and the desired product 3aa (1.19 g, 3.6
mmol) was obtained with 45% yield in 4 h (Scheme
3).
Scheme 3 Gram scale synthesis of 3aa.
During the course of the reaction process, it was
observed that the six-membered aminal prodcut 4aa
was initially formed in large amount, which gradually
disappeared with the accumulation of diazepine 3aa.
In order to prove the possibility of the rearrangement
of 4aa to 3aa, the aminal 4aa was exposed to
equiequivalent hydrochloric acid and 10 mol% FeCl3
in refluxing EtOH. As a result, interestingly,
benzodiazepine 3aa was obtained in 43% yield
(Scheme 4). Based on this result, a plausible
mechanism for the formation of benzodiazepine 3aa
was proposed and depicted in Scheme 5. First, with
the activation by the acid promoter, diethyl
aminomalonate hydrochloride (1a) reacts with 2-
(pyrrolidin-1-yl)benzaldehyde (2a) to form the Schiff
base I by condensation. Then, with the activation of
the imine by ferric chloride, the key hydride transfer
occurs, followed by [1,6]-endo-cyclization to give the
six-membered ring product 4aa, which then
rearranged to the azepine product 3aa through
cleavage of the aminal moiety and the ensuing
Mannich procedure (Path A). On the other hand, the
direct 7-endo-cyclization from intermediate II might
also occur to give straightforwardly the diazepine
product 3aa (Path B).
Scheme 2. Substrate scope of aminomalonic acid esters
and o-amino-substituted benzaldehydesa, b) a) The reaction
was carried out on a 0.4 mmol scale with FeCl3 (10 mol %)
b)
in 4.0 mL EtOH, the ratio of 1/2 was 1.2/1. Isolated
c)
yields.
The reaction was carried out with 2-
(phenylamino)malonate (1d) and 2-(pyrrolidin-1-yl)-
benzaldehyde (2a) as the substrates.
Further extension of the substrate scope was then
attempted by focusing on amino malonic ester 1.
Both dimethyl and diisopropyl aminomalonic esters
Scheme 4. Transformation of 4aa to 3aa.
3
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10.1002/adsc.201800781
Advanced Synthesis & Catalysis
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Scheme 5. Proposed mechanism for the construction of
3aa.
In conclusion, we have developed a new strategy
for the direct synthesis of benzodiazepines via a
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sequential
condensation/[1,5]-hydride
shift/cyclization process by using an inexpensive
catalyst FeCl3, featuring high step and atom economy.
With this concise strategy, benzodiazepines of
potential pharmaceutical relevance with a novel
structure can be readily obtained in synthetically
useful yields (30%-64%). The reaction has an
extensive substrate scope and can afford the desired
product on a gram scale. Additional efforts to realize
similar versions of H-shift/7-endo-cyclization with a
diverse range of hydride acceptors are ongoing in our
laboratory, and the results will be reported in due
course.
Experimental Section
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General procedure for the synthesis of products 3
To a solution of 1 (0.48 mmol) and 2 (0.40 mmol) in
EtOH (4.0 mL), FeCl3 (10 mol%) was added, then the
reaction mixture was refluxed until completion (monitored
by TLC). After purification by column chromatography on
silica gel (ethyl acetate/petroleum ether = 1:5 as eluent),
benzodiazepine product 3 was obtained.
Acknowledgements
We thank the Fundamental Research Funds for the Central
Universities (DUT18LAB16) for support of this work.
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5
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Advanced Synthesis & Catalysis
COMMUNICATION
Expedient Synthesis of 1,4-Benzodiazepines via a
Tandem Condensation/[1,5]-Hydride Transfer/
Cyclization Process
Adv. Synth. Catal. Year, Volume, Page – Page
Siyuan Liu, Tuan Zhao, Jingping Qu, and Baomin
Wang*
6
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