Redox condensation of o-halonitrobenzene with 1,2,3,4-tetrahydroisoquinoline: Involvement of an unexpected auto-catalyzed redox cascade

Article abstract of DOI:10.1039/c6cc01436d

A practical synthesis of fused benzimidazoles 5 has been developed by simply heating o-halonitrobenzenes 1 with tetrahydroisoquinolines 2. In this transformation, 2 played multiple roles as a building block, base and a double hydride donor in a cascade of uncatalyzed aromatic substitution, reduction of the nitro group, oxidation of the α-methylene group and condensation.

Full text of DOI:10.1039/c6cc01436d

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Redox condensation of o-Halonitrobenzene with 1,2,3,4-
Tetrahydroisoquinoline: Involvement of an Unexpected Auto-
catalyzed Redox Cascade
Received 00th January 20xx,
Accepted 00th January 20xx
*
DOI: 10.1039/x0xx00000x
T. B. Nguyen, L. Ermolenko and A. Al-Mourabit*
www.rsc.org/
Abstract. A practical synthesis of fused benzimidazoles 5 has been phenyl)ethylbenzimidazoles have been studied based on the
developed by simply heating o-halonitrobenzenes
1 with nature of R' groups. When R' = H (A1), Pd-catalyzed cyclization
8
7
tetrahydroisoquinolines 2. In this transformation,
2
2 played required excess AgOAc or Cu(OAc) as oxidants. Alternatively,
multiple roles: building block, base and double hydride donor in a the 2-iodo derivatives A2 (R' = I) can be cyclized under
9
cascade of uncatalyzed aromatic substitution, reduction of the photochemical activation.
nitro group, oxidation of the α-methylene group and
condensation.
H
2
N
N
N
O
O
N
N
N
N
(MeO)
2
The synthesis of benzimidazoles is of great interest because of
their wide occurrence in bioactive compounds and functional
materials. Polycyclic fused 5,6-dihydrobenzo[4,5]imidazo[2,1-
OMe
5b
Me
n-Bu
Me
N
5
a
5c
a]isoquinoline
5
,
a
subclass of benzimidazole family,
N
N
N
N
N
5
constitutes the structural centrepiece of a wide range of
R
bioactive products such as quinone 5a with specific
1
H N
CO H
2
2
N
O
Cl
O
cytotoxicity towards two cancer cell lines (HeLa and DU145),
R'
NR
5d, R = n-Hex, n-Pr
2
N
amine 5b capable of modulating potassium ion flux through
5f
O
voltage-dependent and effective in treating diseases via this
2
Cl
5e
mode of action (Scheme 1). Moreover, oligomethoxy 5c
displayed cytotoxicity against human cancer cell lines MCF-7, Scheme 1 Bioactive 5,6-dihydrobenzo[4,5]imidazo[2,1-a]isoquinolines
3
MDA-MB-231, and amides 5d with different alkyl chains
4
exhibit high affinities for peripheral benzodiazepine receptor.
Additionally, amino acid derivative 5e can inhibit L-type amino substitution for sulfur derivatives (R' = SAr) with Bu
Cyclization can also be accomplished via homolytic aromatic
GeH/AIBN
3
1
0
acid transporter 1 (LAT1) of essential amino acid that is one of initiator. Such methods suffer from difficulties in the
main nutrition for cancer cells and accordingly cause drain of preparation of benzimidazole derivatives and from complex
the essential amino acid on the cancer cells and finally can reaction conditions. An alternative approach starts from
5
11
12
prohibit the multiplication of cancer cells. Pentacyclic lactams anilines
B by Ir-catalyzed dehydrogenative or Fe-catalyzed
3
1
5f
may be used to treat hemoglobinopathies such as
β
-
oxidative or TEMPO-promoted cyclization. In both cases,
expensive catalysts/ligands were employed and the starting
6
thalassemia and sickle cell anaemia.
Although a number of synthetic methods for the preparation aniline
of 5,6-dihydrobenzo[4,5]imidazo[2,1-a]isoquinolines
have nitro compounds
B
are generally obtained by the reduction of the parent
rendering the methods redox
5
3,
been developed, they all consist in multi-step transformations uneconomical. This drawback can be overcome by using
with maximum one bond created in each operation and directly 3 as starting material with an external reducing agent.
require expensive catalysts, substrates, and/or reagents Such approach has been developed by Söderberg using a Pd-
(
Scheme 2).
catalyzed reductive cyclization involving carbon monoxide (6
N-(2- atm) as reductant. Substrates are readily synthesized from
and . The disadvantage of this method lies in the hazard
related to toxic CO under high pressure and the low yield of
44%) along with the formation of a by-product (6%) resulted
from dehydrogenation of the ethylene moiety of
Different
conditions
of
cyclization
of
3
1
2
5
(
5
.
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It becomes immediately clear that simple, one-step obtained in excellent yield and only traces of 3aa and 4aa were
approaches to such derivatives of from readily available detected in the crude mixture (Table 1 entry 1). Lower the
starting materials o-halonitrobenzenes and reaction temperature resulted in incomplete transformation of
5
1
tetrahydroisoquinolines (THIQ)
desirable.
2
are obviously highly both 3aa and 4aa in to 5aa (entry 2).
Table 1 Optimization of the reaction conditions
our approach
N
N
R'
N
radical or
R
N
R
A
metal catalyzed
5
NO
2
R' = H, I, SAr
not readily obtained
oxidative
HN
[Pd], CO (6 atm)
Halo
cyclization
R
1
2
reductive cyclization
readily available
NH
N
2
NO
2
reduction
a
b
c
entry
X
T (°C)
130
120
130
130
130
5aa:3aa:4aa
yield of 5aa (%)
N
R
R
N
S Ar
1
2
3
4
5
Cl
100:0:0
89
-
B
3
classical approaches
Cl
F
53:20:27
100:0:0
Scheme 2 Approaches to 5,6-dihydrobenzo[4,5]imidazo[2,1-a]isoquinoline
85
83
91
Br
I
95:0:5
In the course of our studies on new methods for the synthesis
of 5aa via reductive cyclization of o-nitroaniline 3aa, we
attempted to use uncatalyzed aromatic nucleophilic
100:0:0
a
Reaction conditions: 1a (1 mmol), 2a (2.5 mmol) under an
b
1
substitution reaction between 1a and 2a in the presence of argon atmosphere. Determined by H NMR analysis of the
c
K
2
CO
3
as a base in DMF (Scheme 3). We observed the reaction mixture.
formation of various unexpected side products in non- chromatography.
Isolated yield after column
negligible quantities along with the expected o-nitroaniline
3
aa in moderate yield (55%). N-oxide 4aa was readily isolated The optimized reaction conditions were next applied to other
as a white solid (12%) upon simple filtration of the reaction halogen derivatives 1aF
1aBr and 1aI. While intermediates
mixture diluted in CH Cl and water. Further chromatographic 3aa and 4aa were fully converted into 5aa in case of fluorine
analysis of the CH Cl filtrate allowed us to identify 5aa (8%) as (entry 3) and iodine (entry 5) derivatives, the reaction of the
a redox condensed product of 1a with 2a and as oxidized bromide analogue 1aBr resulted in 5% of unchanged 4aa
Because we were interested in obtaining (entry 4) for unknown reasons. Nevertheless, the desired
,
2
2
2
2
;
6
7
1
4
products of 2a
.
fused benzimidazole 5aa, this first observation prompted us to product 5aa was obtained in excellent yields in all cases.
perform further studies to maximize the yield of 5aa. We
reasoned that among the condensed products 3aa
aa, only the formation of 5aa required an additional reducing
agent, which should be THIQ 2a in the present case. The by-
, 4aa and
5
product of this redox transformation would be
6 and 7.
Consequently, much more 2a should be used.
Scheme 3 Formation of unusual products from 1a and THIQ 2a
Further optimization by changing solvents (DMSO, ethylene
glycol, n-butanol, 2-methoxyethanol) and bases (Na CO ,
2
3
Cs CO , NaOAc, Na PO , NEt , N-methylmorpholine...) did not
3
2
3
3
4
Scheme 4 Scope of o-halonitrobenzenes
1
lead to any significant improvement. Indeed, all the condensed
products 3aa 4aa and 5aa were yielded in comparable
,
A subsequent evaluation of the scope and limitation of the
uncatalyzed redox condensation proved the reaction to be
quantities along with the formation of unidentified products.
Finally, to our surprise, when the reaction was performed in
the absence of both solvent and additional base, 5aa was
broadly applicable to a range of o-halonitrobenzenes
1 with
2
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THIQ 2a (Scheme 4). Readily available o-chloro derivatives were trapped by strong alkaline bases such as Na
were used and led to various substituted fused benzimidazole or Cs CO to provide neutral alkaline halide salts, low yields of
derivatives in good to excellent yields. Alkyl (5ba), alkoxy (5ca), 5aa were obtained (vide supra).
trifluoromethyl (5da), halogen (5ea 5ja), and ester (5ka
groups as well as pyridine heterocycles (5la 5ma) were
2 3 2 3
CO , K CO
2
3
-
)
-
tolerated. Substitution effects were insignificant in the
investigated examples.
In case of polychlorinated substrates 1e-1h, only o-chloro
atoms were involved in the cascade process, leading to the
corresponding condensed products in high yields. Although the
p-chloro atoms of 1f and 1h are also activated by the nitro
group, they remain intact.
Because the present conditions can be equally effective to
other o-halo substrates
1 other than chlorinated one, the
method is highly economic as the most readily available
substrates could be used as exemplified by the access to 3ai
and 3aj starting from homohalogen substrates.
Scheme 6 Investigation of the reaction pathway
As shown in Scheme 5, 1,2,3,4-THIQ substrates 2b-2e with a
variety of substitution patterns the aromatic ring effectively
undergo the redox cascade to provide the corresponding fused
benzimidazoles in moderate to good yields. It is noteworthy
that the redox condensation works well also with
polyheterocyclic system such as natural tryptoline 2e, also
known as tetrahydro-β-carboline. The formation of fused
benzimidazole 5de demonstrated an easy incorporation of
fluorine containing motifs into a natural product to provide
From these observations, we tentatively propose a plausible
1
5
mechanism (Scheme 7). The first step is an uncatalyzed
aromatic nucleophilic substitution reaction between o-
chloronitrobenzene 1a and THIQ 2a, giving rise to 3aa along
with one hydrogen chloride molecule trapped as salt with 2a
17,18
.
1
This acid is necessary for subsequent redox cyclization
6
of
1
9
3
aa into 4aa
.
Furthermore, this acid facilitates the hydride
2
0
transfer step 4aa
→ 8.
unnatural
bioactive
candidates
bearing
different
pharmacophores in an extremely simple operation of heating.
Scheme 5 Scope of 1,2,3,4-tetrahydroisoquinoline substrates
2
Scheme 7 Mechanistic proposal
To probe the mechanism of these we submitted some
intermediates under standard conditions of temperature and
time (Scheme 6). First, we hypothesized fused benzimidazole
The present redox condensation was not effective for other
oxidizable amines such as benzylamine, dibenzylamine, N-
methylbenzylamine that tend to give only the expected
nitroanilines products (Scheme 6, eq. 3). This suggests that
rigid bicyclic structures of tetrahydroisoquinoline 3aa and
dihydroisoquinoline 4aa are required for an effective hydride
transfer.
5aa could be obtained directly by a reductive cyclization of
nitroaniline 3aa with 2a as reductant. A control experiment
resulted in low yields of 5aa and its oxygenated precursor 4aa
along with untransformed starting nitro 3aa and unidentified
side products (eq. 1).
In summary, we have developed an uncatalyzed redox
At this stage, we reasoned that the hydrohalide generated in
the first step of nucleophilic aromatic substitution was
responsible for both redox neutral cyclization of 3aa into 4aa
and reduction of 4aa into 5aa by 2a. As part of the further
support of this proposed mechanism, we conducted a
stoichiometric reaction using 3aa, THIQ (0.5 equiv) and
condensation of o-halonitrobenzenes
1 with 1,2,3,4-THIQ 2
under solvent-free conditions. Considering the easy availability
of these substrates, most of them are commercially available,
this method provides a novel and convenient way of
constructing fused polyheteroaromatic benzimidazoles. In
addition, by the mechanistic investigations using different
intermediate substrates, we have disclosed that the reaction
goes through an acid catalyzed hydrogen transfer. This acid
was autogenerated during the course of the reaction.
.
THIQ HCl (1 equiv) and which gave cleanly 5aa in 91% yield,
indicating the feasibility of the acid catalyst for hydrogen
transfer. Indeed, when hydrohalides generated from the
aromatic nucleophilic substitution reaction between 1a and 2a
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Moreover, THIQ acts as polyvalent substrates: nucleophile,
Journal Name
2
building block, base and four-electron reducing agent.
Notes and references
1
E. Moriarty, M. Carr, S. Bonham, M. P. Carty and F.
Aldabbagh, Eur. J. Med. Chem. 2010, 45, 3762.
2
3
4
A. B. Fulp and X. Wang, WO2005002503 A2, 2005.
L. W. Deady and T. Rodemann, Aust. J. Chem. 2001, 54, 529.
(a) A. Nakazato, T. Okubo, T. Kumagai, S. Chaki, K. Tomisawa,
M. Nagamine, M. Gotoh, K. Kondoh and M. Yoshida,
EP1481965 A1, 2004; (b) T. Okubo, R. Yoshikawa, S. Chaki, S.
Okuyama and A. Nakazato, Bioorg. Med. Chem. 2004, 12,
3
H. Endo, EP1481965 A1, 2004.
C. K. J. Shun and Y. C. Chou, WO2005002503 A2, 2005.
G. Meng, H. Y. Niu, G. R. Qu, J. S. Fossey, J. P. Li and H. M.
Guo, Chem. Commun. 2012, 48, 9601.
569.
5
6
7
8
(a) V. O. Iaroshenko, D. Ostrovskyi, M. Miliutina, A. Maalik, A.
Villinger, A. Tolmachev, D. M. Volochnyuk and P. Langer,
Adv. Synth. Catal. 2012, 354, 2495; (b) K. C. Pereira, A. L.
Porter and B. Deboef, Tetrahedron Lett. 2014, 55, 1729.
J. M. Oconnell, E. Moriarty and F. Aldabbagh, Synthesis,
9
1
1
2012, 44, 3371.
0 S. M. Allin, W. R. Bowman, R. Karim and S. S. Rahman,
Tetrahedron, 2006, 62, 4306.
1 (a) X. Sun, Y. Hu, S. Z. Nie, Y. Y. Yan, X. J. Zhang and M. Yan,
Adv. Synth. Catal. 2013, 355, 2179; (b) X. Sun, X. H. Lv, L. M.
Ye, Y. Hu, Y. Y. Chen, X. J. Zhang and M. Yan, Org. Biomol.
Chem. 2015, 13, 7381.
1
2 Y. Liu, G. Q. Chen, C. W. Tse, X. Guan, Z. J. Xu, J. S. Huang and
C. M. Che, Chem. Asian J. 2015, 10, 100.
1
1
1
1
3 D. Xue and Y. Q. Long, J. Org. Chem. 2014, 79, 4727.
4 All reactions were performed under an argon atmosphere.
5 For the pioneer reaction, see: J. Pinnow, Ber. 1895, 28, 3039.
6 Transformation of 3aa to 4aa is known to occur in the
presence of an organic acid: K. A. Hedley and S. P. Stanforth,
J. Heterocycl. Chem. 1995, 32, 529.
1
7 The transformation of 3aa to 4aa likely involves an
intramolecular hydride transfer or related sigmatropic event.
For recent reviews on this topic, see: (a) B. Peng ans N.
Maulide, Chem. Eur. J. 2013, 19, 13274; (b) M. C. Haibach
and D. Seidel, Angew. Chem. Int. Ed. 2014, 53, 5010.
8 For related examples of condensations of amines that lead to
the formation of aromatic rings, including fused rings see: (a)
I. Deb and D. Seidel, Tetrahedron Lett. 2010, 51, 2945; (b) A.
Y. Platonova and D. Seidel, Tetrahedron Lett. 2015, 56, 3147.
1
1
9 For related examples of amine
(
α
a) O. Meth-Cohn and M. A. Naqui Chem. Commun. 1967
-amination reactions, see:
,
157; (b) W. Verboom, M. R. J. Hamzink, D. N. Reinhoudt and
1
R. Visser, Tetrahedron Lett. 1984, 25, 4309; (c) S. V.
Ryabukhin, A. S. Plaskon, D. M. Volochnyuk, A. N. Shivanyuk
and A. A. Tolmachev, J. Org. Chem. 2007, 72, 7417; (d) C.
Zhang, S. Murarka and D. Seidel, J. Org. Chem. 2009, 74, 419;
(
e) K. Mori, Y. Ohshima, E. Ehara and T. Akiyama, Chem.
Lett. 2009, 38, 524; (f) M. T. Richers, I. Deb, A. Y. Platonova,
C. Zhang and D. Seidel, Synthesis 2013, 45, 1730.
2
0 (a) I. Deb, D. Das and D. Seidel, Org. Lett. 2011, 13, 812; (b) K.
Saito and T. Akiyama, Angew. Chem. Int. Ed. 2016, 55, 3148.
4
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