Metal-Free Ring Opening Cyclization of Cyclopropane Carbaldehydes and N-Benzyl Anilines: An Eco-Friendly Access to Functionalized Benzo[b]azepine Derivatives

Article abstract of DOI:10.1002/adsc.201801714

Herein, we report a p-toluenesulfonic acid (PTSA) initiated mild and user-friendly ring opening/domino ring opening cyclization reaction (depends on substituent present in N-benzyl aniline) of cyclopropane carbaldehyde and N-benzyl aniline towards the formation of substituted 4-amino butanal/2,3-dihydro-1H-benzo[b]azepine. The product dihydro-1H-benzo[b]azepine was also converted into the corresponding tetrahydro-1H-benzo[b]azepine. (Figure presented.).

Full text of DOI:10.1002/adsc.201801714

Title: Metal Free Ring Opening Cyclization of Cyclopropane
Carbaldehydes and N-benzyl Anilines: An Eco-friendly Access to
Functionalized Benzo[b]azepine Derivatives
Authors: Raghunath Dey and Prabal Banerjee
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801714
Link to VoR: http://dx.doi.org/10.1002/adsc.201801714

10.1002/adsc.201801714
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Metal-Free Ring Opening Cyclization of Cyclopropane
Carbaldehydes and N-benzyl Anilines: An Eco-friendly Access to
Functionalized Benzo[b]azepine Derivatives
Raghunath Dey a and Prabal Banerjee a,*
a
Department of Chemistry, Indian Institute of Technology Ropar, Nangal Road, Rupnagar, Punjab-140001, India.
Fax: (+91)-1881-223395, E-mail: prabal@iitrpr.ac.in.
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))
(namely transition metal halides and triflates) or other
transition metal catalyst, cyclopropane undergoes
various cycloaddition, ring opening, rearrangement
and ring expansion reactions towards the formation of
Abstract. Herein, we report a p-toluenesulfonic acid
(PTSA) initiated mild and user-friendly ring
opening/domino ring opening cyclization reaction (depends
on substituent present in N-benzyl aniline) of cyclopropane
carbaldehyde and N-benzyl aniline towards the formation of
diverse
high-value
open-chain
and
cyclic
compounds.[3] For example, Chan et al. synthesized
2,3-dihydro-1H-benzo[b]azepine via a gold-catalyzed
rearrangement of 2-tosylaminophenyl cyclopropyl
methanol.[4a] Whereas, Wender et al. employed
cyclopropyl imine and alkyne in rhodium catalyzed
(5+2) cycloaddition reaction for the construction of
azepine derivatives (Scheme 1).[4b] In the last decade,
the practitioners of organic chemistry have extensively
explored varieties of metal catalyzed reactions of
cyclopropane. Many of them have been successively
utilized in the total synthesis as well. [5]
substituted
4-amino
butanal/2,3-dihydro-1H-
benzo[b]azepine. The product dihydro-1H-benzo[b]azepine
was also converted into the corresponding tetrahydro-1H-
benzo[b]azepine.
Keywords: cyclopropane carbaldehyde; N-benzyl aniline;
metal-free ring opening cyclization; benzo[b]azepine
Nitrogen heterocycles are the unique class of cyclic
structural frameworks present in various natural and
non-natural products. In particular, benzo[b]azepine,
a distinct class of seven-member N-heterocycles,
exists as a pivotal structural segment in many
molecules of biological and pharmaceutical
importance.[1] For instance, clomipramine, an
antidepressant agent,[1a] OPC-41061, a highly potent
human vasopressin V2-receptor antagonist,[1b] and
benazepril, an ACE inhibitor[1c] are the representative
examples of the drugs containing benzo[b]azepine as
a
cyclic core (Figure 1). Consequently, the
construction of such heterocycles from simple
precursors is always a major interest.
Scheme 1. Synthesis of azepine derivatives from
cyclopropane.
Figure 1. Drugs with benzo[b]azepine skeleton.
Despite of the exciting explorations of various
reactivities and their utilization, very often some
Lewis acid catalyzed reactions of cyclopropane
associated with many disadvantages like toxicity,
Over the years, cyclopropane has emerged as an
inimitable three carbon building block in the arena of
organic synthesis.[2] Owing to their inherent ring strain,
upon activation with an external agent like Lewis acid
1
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10.1002/adsc.201801714
Advanced Synthesis & Catalysis
hazardous handling, high cost and a trace amount of
metal contamination in the final product.[6] In
pharmaceutical and biological grounds, the latter issue
is a serious practical problem and thereby requires an
additional time consuming and expansive metal
removing step.[6b] Moreover, their extreme moisture
sensitivity often necessities the use of 4 Å molecular
sieves as an additive. Hence, it is necessary to develop
the discussed reactions of cyclopropane in mild and
metal-free conditions.
PTSA in monohydrate form allowed us to perform all
the designed reactions in open flask.
In the beginning, cyclopropanecarbaldehyde (1a)
and N-benzyl dimethoxy aniline (2a) were chosen as
model substrates to obtain the optimal condition for
the ring opening reaction (Table 1). In the presence of
PTSA, 1a and 2a were exposed in various solvents.
Alcoholic solvents like methanol and ethanol gave a
complex reaction mixture. Formation of the complex
mixture was also found in acetonitrile (ACN) and
tetrahydrofuran (THF). A good yield was acquired in
benzene, toluene, dichloromethane (DCM), and
dichloroethane (DCE) solvent. Among them for the
short reaction time, DCM was adopted as the solvent
of choice. To probe the equitable mol% of PTSA, we
carried out the described reaction with various mol%
of PTSA. On increasing the PTSA loading from 20
mol% to 50 mol% lead to decrease the reaction time
and yield as well. Consequently, these results drive us
to choose 20 mol% PTSA in DCM solvent as an
optimal reaction condition.
Table 1. Optimization of the reaction conditions for the ring
opening reactiona)
entry PTSA
(mol%)
solvent time (h) yield (%)b)
01
02
03
04
05
06
07
08
09
10
11
-
toluene
toluene
benzene
ACN
MeOH
EtOH
THF
24
24
24
15
07
07
12
18
15
15
12
22
58
56
20
20
20
20
20
20
20
20
30
50
c.m.c)
c.m.c)
c.m.c)
c.m.c)
55
DCE
DCM
DCM
DCM
64
60
48
a)Reactions were carried out with 1 equiv of 1a and 1 equiv
of 2a. b)Isolated yield. c)c.m. = complex mixture.
In the contemporary metal-free reactions of
cyclopropane, one of the impressively achieved ways
is Bronsted acid catalytic activation.[7] Where the
hydrogen bonding of acceptor functionality with the
Bronsted acid results the vicinal C-C bond polarization
and therefore, makes the cyclopropane susceptible
towards nucleophilic ring opening reaction. With the
Bronsted acid catalytic activation, in a recent seminal
report, Moran et al. have displayed a cyclopropane
ring opening reaction by trimethoxybenzene,
catalyzed by triflic acid in hexafluoroisopropanol.[7b]
Very recently, Kerr et al. reported a ring opening
reaction of cyclopropane-1,1-dicarboxylate with
indole via hydrogen bonding activation.[7c]
On the other hand, commercially inexpensiveness,
strong hydrogen bonding ability, ease of handling, and
the existence of a rich body of literature on Bronsted
acid catalysis,[8] drive us to test the ability of PTSA on
the activation of cyclopropane carbaldehyde. Thereby,
on the basis of discussed literature reports, and our
previous works on metal-catalyzed reactions of
cyclopropane,[9] we anticipated that the cyclopropane
carbaldehyde can be activated by PTSA and would
undergo ring opening reaction with a strong
nucleophile like N-benzyl aniline. Afterwards, the
formed open chain compound may undergo a Friedel-
Crafts type reaction to form 2,3-dihydro-1H-
benzo[b]azepine. More importantly, the presence of
Scheme 2. Substrate scope evaluation for the ring opening
reaction: Unless otherwise specified, all reactions were
carried out in DCM at rt with 1 equiv of 1 and 1 equiv of 2
in presence of PTSA (20 mol %). Isolated yields are
reported.
Having the optimized condition in hand, we
explored the substrate scope and limitation of the ring
opening reaction (Scheme 2). To evaluate the substrate
scope with respect to N-benzyl aniline, a range of N-
benzyl anilines bearing different aromatic rings were
employed in the ring opening reaction. A good yield
2
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10.1002/adsc.201801714
Advanced Synthesis & Catalysis
was provided by N-benzyl aniline bearing 3,4-
dimethoxy phenyl (2a), 4-methoxyphenyl (2b), and 3-
methoxyphenyl (2c) group. N-benzyl aniline
containing phenyl ring (2d) engendered the desired
product 3ad with longer reaction time. Whereas, N-
benzyl aniline (2e) having 4-nitrophenyl group did not
participate in the reaction. This may be due to the
lowering of nucleophilicity by very high electron
withdrawing ability of the nitro group. However, N-
benzyl aniline with 4-fluorophenyl (2l), 4-
bromophenyl (2m) and 4-iodophenyl (2n) ring were
comfortably converted to their corresponding ring
opened product with a good yield.
Having synthesized a range of ring-opened product,
we conceived the possibility of an intramolecular
Friedel-Crafts type reaction between the N-aryl and
aldehyde functionality in 3 towards the formation of
benzo[b]azepine moiety (Scheme 3A). Our initial trial
with ring opened compound 3ab bearing 4-
methoxyphenyl ring was not accomplished (Scheme
3A). However, we could attain the intended compound
with the ring-opened product 3aa bearing 3,4-
dimethoxy phenyl ring. Eventually, the efficient
conversion of 3ac into the homologous
benzo[b]azepine 4ac manifested that the presence of a
methoxy substituent at 3-position of phenyl ring is
essential for the cyclization to happen. After this
successful cyclization, to achieve the domino ring
opening-cyclization reaction, we carried out both steps
in one pot. Gratifyingly, with this domino decorum,
the desired 4aa was synthesized in a satisfactory yield
(Scheme 3B). It is important to note that the addition
of 1.2 equivalent of PTSA at a time resulted the
To check the effect of benzyl group on the said
reaction, we employed two different N-benzyl anilines
(2f, 2g) containing 4-bromo benzyl and 2,3-dimethoxy
benzyl group. However, in both cases, reaction rate,
and yield were similar. Therefore, these results
revealed that the substitution on the benzyl group has
no such considerable effect on the titled reaction. In
order to examine the effect of aryl substituent on
cyclopropane, we executed a series of reactions of N-
benzyl-4-methoxyaniline (2b) with a range of
cyclopropane carbaldehydes (1a-1h). Cyclopropane
bearing more electron donating group like
methylenedioxyphenyl (1b) furnished the desired
product with a lower yield. Perhaps this is due to the
presence of highly electron donating substituent which
makes the cyclopropane carbaldehyde vulnerable to
decomposition. The same outcome was also noticed
for cyclopropane carbaldehyde bearing a 2-naphthyl
substituent (1c). Cyclopropane (1d) bearing 4-
(benzyloxy)phenyl group gave a satisfactory yield.
The best yield was accomplished with the
cyclopropane (1e) containing the tolyl group.
Cyclopropane with simple phenyl ring (1f) and
cinnamyl group (1h) also gave good yield whereas,
cyclopropane (1g) with 4-chlorophenyl ring furnished
the product in longer reaction time. This is because of
the electron withdrawing ability of choro substituent;
making the respective cyclopropane carbaldehyde less
reactive towards nucleophilic ring opening.
decomposition of
a
considerable amount of
cyclopropane carbaldehyde. Therefore, firstly 0.2
equivalent of PTSA was added to complete the ring
opening process followed by addition of the remained
amount of PTSA (1 equivalent) to fulfill the
cyclization process.
Scheme 3. Towards cyclization of the ring-opened product.
Scheme 4. Evaluation of the substrate scope for domino ring
opening-cyclization reaction: Unless otherwise specified,
3
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10.1002/adsc.201801714
Advanced Synthesis & Catalysis
all reactions were carried out in DCM at rt with 1 equiv of
1 and 1 equiv of 2 in presence of PTSA (120 mol %).
Isolated yields are reported.
nucleophilic ring opening with N-benzyl aniline 2 to
form the open chain compound 3. Afterward, the
aldehyde functionality of 3 get activated by PTSA to
form intermediate
B
which underwent an
intramolecular Friedel-Crafts type reaction to produce
the alcohol D via formation of C. Finally, D converted
into the desired compound 4 by dehydration. To
investigate the stereospecificity of the ring opening
Having established the domino protocol, we
evaluated the scope and limitation of other substrates
in this process, and the outcomes are depicted in
scheme 4. Among the various cyclopropanes,
cyclopropanes (1a and 1f) bearing 4-methoxyphenyl
and phenyl group gave the good yield, as obtained in
the ring opening reaction. However, cyclopropane
having methylenedioxyphenyl (1b) and 4-benzyloxy
phenyl ring (1d) afforded their respective cyclic
process,
an
enantioenriched
cyclopropane
carbaldehyde 1f was employed in the mentioned
reaction (Scheme 6). Formation of the enantioenriched
product 3fb established that the reaction proceeds in
an almost stereospecific manner.
product in
a
lower yield. Tolyl substituted
cyclopropane (1e) provided a very clean reaction
towards the formation of the desired product 4ea in a
better yield. Prolonged reaction time was noticed for
the cyclopropane bearing 4-chlorophenyl ring (1g). To
check the scope for N-benzyl anilines, a range of N-
benzyl anilines (2h-2k) bearing 3,4-dimethoxy
substituted phenyl ring were engaged in the domino
reaction. But no such pronounced effect was noticed.
Starting with a fused cyclopropane carbaldehyde (1i),
benzo[b]azepines 4ia containing a fused [6-7-6]
tricyclic framework was constructed in a good yield.
Scheme 7. Plausible mechanism
Scheme 5. Reduction of 4aa.
In conclusion, we displayed a metal-free ring
opening and cyclization reaction of cyclopropane
carbaldehyde and N-benzyl aniline, mediated by
commercially inexpensive PTSA. Depends on the
substituent present in aryl ring of N-benzyl aniline, the
process provides substituted 4-amino butanal or 2,3-
dihydro-1H-benzo[b]azepine via ring opening or
domino ring opening-cyclization pathway. Happening
of the reaction in an open-flask exhibit the user-
friendliness of the process. Furthermore, the product
2,3-dihydro-1H-benzo[b]azepine was also converted
to a high-value structural scaffold, like 2,3,4,5-
Scheme 6. Stereospecificity of the ring opening reaction.
tetrahydro-1H-benzo[b]azepine
derivative.
Development of the asymmetric version of this
protocol and application in the total synthesis of the
natural product are underway in our laboratory.
After the successful preparation of a range of 2,3-
dihydro-1H-benzo[b]azepines, the 2,3-dihydro-1H-
benzo[b]azepine 4aa was converted into the
corresponding 2,3,4,5-tetrahydro-1H-benzo[b]azepine
derivative 5aa through the reduction with LAH/FeCl2
mixture (Scheme 5).[10]
Experimental Section
Representative procedure for ring opening reaction of
cyclopropane carbaldehyde (1) and N-benzyl aniline (2)
On the basis of other literature reports and our
observations, we sketched a plausible mechanism as
shown in scheme 7. Initially, PTSA interacts with the
cyclopropane carbaldehyde 1 to form an activated
To a round-bottom flask equipped with a magnetic stir bar
was charged with PTSA (0.05 mmol, 0.2 equiv). A DCM
(2.8 mL) solution of cyclopropane carbaldehyde (0.28 mmol,
1 equiv) and N-benzyl aniline (0.28 mmol, 1 equiv) was
added and stirred at room temperature until completion of
intermediate A.
Intermediate A encountered a
4
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10.1002/adsc.201801714
Advanced Synthesis & Catalysis
the reaction (as monitored by TLC). The solvent was
evaporated on a rotary evaporator. The crude mixture was
further purified by column chromatography on silica gel
with ethyl acetate/hexane as eluent.
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Zhou, W. Pan, J. Ren, Z. Wang, Org. Lett. 2018, 20,
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Representative procedure for domino ring opening-
cyclization reaction of cyclopropane carbaldehyde (1)
and N-benzyl aniline (2):
To a round-bottom flask equipped with a magnetic stir bar
was charged with PTSA (0.05 mmol, 0.2 equiv). A DCM
(2.8 mL) solution of cyclopropane carbaldehyde (0.28 mmol,
1 equiv) and N-benzyl aniline (0.28 mmol, 1 equiv) was
added and stirred at room temperature. After consumption
of the starting materials, (as monitored by TLC) PTSA (0.28
mmol, 1 equiv) was added and stirred at room temperature.
After completion of the reaction, the organic layer was
diluted with DCM and washed with aqueous NaHCO3
solution. The organic layer was dried over Na2SO4 and
concentrated on a rotary evaporator. The crude mixture was
further purified by column chromatography on silica gel
with ethyl acetate/hexane as eluent.
[6] a) C.-L. Sun, Z.-J. Shi, Chem. Rev. 2014, 114,
9219−9280; b) H. Miyamoto, C. Sakumoto, E.
Takekoshi, Y. Maeda, N. Hiramoto, T. Itoh, Y. Kato,
Org. Process Res. Dev. 2015, 19, 1054−1061; c) C. E.
Garrett, K. Prasad, Adv. Synth. Catal. 2004, 346, 889–
900.
Acknowledgments
We are thankful to the Department of Science and Technology,
New Delhi and CSIR, India for the financial support. RD thanks
IIT Ropar for his research fellowship.
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5
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10.1002/adsc.201801714
Advanced Synthesis & Catalysis
COMMUNICATION
Metal-Free Ring Opening Cyclization of
Cyclopropane Carbaldehydes and N-benzyl
Anilines: An Eco-friendly Access to Functionalized
Benzo[b]azepine Derivatives
Adv. Synth. Catal. Year, Volume, Page – Page
Raghunath Dey, Prabal Banerjee*
6
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