Formic acid as a sustainable and complementary reductant: An approach to fused benzimidazoles by molecular iodine-catalyzed reductive redox cyclization of: O -nitro- t -anilines

Article abstract of DOI:10.1039/c6gc00902f

Molecular iodine was found to be an excellent catalyst for reductive redox cyclization of o-nitro-t-anilines 1 into fused tricyclic or 1,2-disubtituted benzimidazoles 2. A range of functional groups such as halides (F, Cl, Br), methoxy, ester, trifluoromethyl, cyano, pyridine and even nitro groups were tolerated using formic acid as a clean, safe, user-friendly and complementary reductant. When iodine was used in a stoichiometric amount (50 mol%), the methodology allowed the direct synthesis of benzimidazole hydroiodides 2·HI in high yields by simple precipitation from the reaction mixture.

Full text of DOI:10.1039/c6gc00902f

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ARTICLE
Formic Acid as a Sustainable and Complementary Reductant:
Approach to Fused Benzimidazoles by Molecular Iodine-Catalyzed
Reductive Redox Cyclization of o-Nitro-t-Anilines
Received 00th January 20xx,
Accepted 00th January 20xx
T. B. Nguyen,* L. Ermolenko and A. Al-Mourabit*
DOI: 10.1039/x0xx00000x
Molecular iodine was found to be an excellent catalyst for reductive redox cyclization of o-nitro-t-anilines 1 into fused
tricyclic or 1,2-disubtituted benzimidazoles 2. A range of functions such as halides (F, Cl, Br), methoxy, ester,
trifluoromethyl, cyano, pyridine and even nitro groups were tolerated using formic acid as a clean, safe, user-friendly and
complementary reductant. When iodine was used in stoichiometric amount (50 mol %), the methodology allowed direct
synthesis of benzimidazole hydroiodides 2.HI in high yields by simple precipitation from reaction mixture.
www.rsc.org/
Fused tricyclic and 1,2-disubstituted benzimidazole different oxidative11-14 and dehydrogenative10 cyclization
heterocycles are of great interest in medicinal chemistry.1 conditions H2O2/acid,11
were developed, notably
Representative recent examples include the anticancer agent oxone/HCO2H,12 CF3CO3H,13 TEMPO (pathway 3).14. These
bendamustine hydrochloride
,2 poly(ADP-ribose) polymerase- pathways have some clear limitations, such as the availability
1 (PARP-1) inhibitor which are obtained by a 6-
,3 modulators of tumour necrosis factor of the starting materials 3 15
(TNF) activity C 4 anti-obesity drug D 5
anti-hepatitis B virus electron reduction of the parent nitroanilines , and the
(HBV) agent
,6 and histamine H3 receptor ligand F 7
A
B
,
,
,
1
E
.
formation of side-products directly linked to the oxidizing
conditions. For examples, when H2O2 was used in hydrochloric
or hydrobromic acid, halogenated fused benzimidazoles were
obtained as the main products.16
In this context, an alternative method by 2e– reductive redox
cyclization of o-nitro-t-anilines 1,
17 the parent compounds of o-
NH2-t-anilines 2 (pathway 4), would be more straightforward
with better atom-, step- and redox- efficiencies. Indeed, in a
single operation, a cascade of reaction occurs including: a
reduction of the nitro group, an oxidation of the
group and a cyclization. Evidently, this 2e– reductive redox
cyclization of
is more advantageous than its 6e– reductive
cyclization of the corresponding o-nitroanilides (pathway
α-methylene
1
Scheme 1. Representative fused tricyclic or 1,2-disubstituted benzimidazoles.
8
5),18 generally not practically available, which limits their
application.19
Methods of synthesis of such important scaffolds can be
roughly classified into two categories (Scheme 2). In the first
For the cyclization of
1 via pathway 4, although the global
reaction is a two-electron reduction, both oxidation and
reduction processes occur in the same molecule, the nitro
group is reduced partially by the methylene moiety of the t-
amino group and two other electrons are furnished by an
external reductant. An ideal or complementary reductant for
this purpose should provide only two required electrons and
should not act as a competitive reductant. Compared to
reported 2e- reductive redox cyclization conditions such as
H2/Pd,20 CO/Pd,21 Na2SO3,22 TiCl3,23 or pyrolytic,24 and
photolytic25 one, transfer hydrogenation provides a more
beneficial and practical alternative.
category, the reactions proceed via non-redox cyclization
8
(pathway 1) of anilines
4
or amidines
of o-phenylenediamines
7 without external reductant or oxidant.
5 or redox neutral
condensation (pathway 2)9
with -dialdehydes
6
α
,
ω
This strategy requires usually several steps to obtain the
starting materials, and harsh reaction conditions, thus limited
in the substrate range. The second strategy needs a reductant
or oxidant to promote the cyclization. When o-NH2-t-anilines
3
were used as low oxidation state o-dinitrogen precursors,
Formic acid has emerged as a safe, user-friendly surrogate for
hydrogen in the frame of synthetic chemistry and renewable
energies.26 Indeed, by applying formic acid as reductant, no
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high-pressure vessels are necessary and the only by-product is molecules, we are particularly interested in using molecular
gaseous CO2 spontaneously removed from the reaction media. iodine as well as its derivatives for redox transformations. We
20
Compared to previous methods using H2 or CO,21 the initiated our study with the reaction of o-(dibutylamino)
manipulation of flammable and/or highly toxic gases is nitrobenzene 1a in formic acid in the presence of different
avoided.
iodide sources as catalysts (10 mol %) (Table 1, entries 1-5).
Among these iodine sources (KI, NaI, TBAI, CuI, I2), molecular
iodine was shown to be the most efficient catalyst, leading to
the desired benzimidazole in good conversion (entry 5, 70%)
even when only a 5 mol % catalyst loading was used (entry 6,
48%). A background control experiment in the absence of any
iodine source resulted in the formation of the expected
product 2a but only in a trace quantity (entry 7).
NH2
NH2
4e- oxidative
R'
N
redox neutral
OHC
cyclization (3)
R
condensation (2)
OHC
R'
6
7
NH2
N
R
3
N
non-redox cyclization (1)
2e- reductive redox
cyclization (4)
2
6e-
6e- reductive
+ known methods:
- CO/Pd, H2/Pd
- TiCl3
reduction
R'
N
cyclization (5)
R
or
R
N
R'
N
R'
N
- photolysis
NH
R
X
R
- pyrolysis (230 °C)
6e-
R
The reaction conditions were further optimized by varying the
quantity of HCO2H. Indeed, lowering (entry 8) or increasing
(entry 9) the HCO2H amount resulted in lower conversions,
possibly due to the dilution effect for the latter case.30 Finally,
the reaction achieved almost total conversion after 24 h of
heating (entry 10). The same catalytic activity was observed
when aqueous HI was used as the iodine source (entry 11). HI
salt of the starting nitroaniline 1a.HI could also conveniently
employed as a solid and water-free HI source (entry 12). When
acetic was used in stead of formic acid, the desired
benzimidazole was also formed but in a negligible quantity
(entry 13). To confirm the redox catalytic role of I2/HI couple,
other non redox acids were also evaluated at the catalysts
(HCl, trifluoroacetic acid, H2SO4, CH3SO3H...). In all these cases,
2a was yielded only in trace quantities, suggesting redox
activity of iodide is critical for the reaction.
5
O
+ this work:
reduction
O
NH2
NO2
NO2
HCO2H/I2 (cat.)
1
8
4
Scheme 2. Cyclization methods of synthesis of fused tricyclic and 1,2-
disubstituted benzimidazoles
Additionally, the use of readily available and inexpensive
elements as reagents, building blocks and catalysts has drawn
our attention because of its simplicity and feasibility for large-
scale synthesis. In light of our interest in using molecular
iodine as a versatile catalyst for redox transformations, we
described here such a practical synthesis of diverse fused
benzimidazoles27 Compared to classical metal-catalyzed
reduction with formic acid, this approach is even more
attractive in the context where no expensive metal catalysts28
and/or ligands29 are required.
Table 1. Reaction condition screening
entrya
1
iodine source (mol %)
KI (10)
t (h)
12
12
12
12
12
12
12
12
12
24
24
24
24
V (mL)
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.5
0.2
0.2
0.2
0f
conversion (%)b
43
32
2
NaI (10)
TBAI (10)
CuI (10)
I2 (10)
3
38
4
27
5
70
6
I2 (5)
48
7
-
trace
56
8
I2 (10)
9
I2 (10)
65
10
11
12
13
I2 (10)
>95 (85)c
>95
>95
trace
HI (20)d
HI (20)e
I2 (10)
a
Reaction conditions: 1a (0.25 mmol), iodine source (10 mol %), HCO2H (V mL)
under an argon in a 17 mL test tube closed with a rubber septum unless
otherwise noted. b Determined by 1H NMR analysis of the crude reaction mixture.
Scheme 3. Scope of the formation of fused tricyclic and 1,2-disubstituted
benzimidazoles.
c
d
e
Isolated yield of 2a by chromatography. Aqueous 55% HI. HI as 1a.HI salt
Having developed a reliable protocol, we evaluated the
reaction scope. We first tested a range of nitrobenzenes o-
substituted by different secondary amines. Gratifyingly, all
tested substrates underwent clean transformation into the
desired fused benzimidazoles in moderate to excellent yields.
f
(20%) and 1a (0.20 mmol, 80%) were used as starting material and catalyst.
HOAc (0.2 mL) was used in place of HCO2H.
In continuing our effort to develop practical and simple
methods for the synthesis of bioactive nitrogen-containing
2 | J. Name., 2012, 00, 1-3
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While the reactions with piperidine derivatives 1b
ARTICLE
,c provided used, the reaction resulted in total recovery of unchanged
the corresponding products in high yields under similar starting substrates, suggesting that (i) t-aniline scaffold is
conditions, the reactions with morpholine 1d resulted in lower necessary; (ii) the nitro group must be in the o-position to the
yield, possibly due to a complexation between the oxygen t-amino group; (iii) the first step would not be the reduction of
atom of the morpholine moiety and iodine. Azepane 1e and the nitro group by formic acid.
pyrrolidine 1f were less reactive than piperidine 1c. In case of
pyrrolidine 1f, a higher molecular iodine catalyst loading (20%)
was required to attain high yield (70% instead of 45%). The
reaction displayed good functional group tolerance on the
benzene ring, either electron donating (2g) or withdrawing (2i
2m) substituents reacted well under the optimized conditions.
Halogens in different positions were also compatible (2h 2j ),
particularly bromide (2o). Furthermore, the reaction extensible
to heteroaromatic nitro compounds (2n ) is particularly
,
,
-l
,
o
interesting in view of obtaining fused polyaromatic
heterocycles.
Scheme 5. Direct formation of iodide salts.
The substrate scope of reductive processes is often limited if
other reducible substituents are present in the molecule. The
important feature of the present methodology is the ability to
Based on these observations, we proposed
a plausible
mechanism shown in Scheme 6. It was assumed that HI,
generated in situ from the reaction between iodine and formic
acid (eq. 1),31 which acts as both strong Brønsted acid and
reductant, was the active catalytic species.
tolerate such functional groups (ester 2m
bromopyridine 2o, nitrile 2p).
, pyridine 2n,
Interestingly, when dinitroanilines 1q,r was submitted to the
We suggested the involvement of the corresponding
benzimidazole N-oxide iv 32
.
The first step of this sequence
leading to . With a conjugating
underwent an intramolecular hydride transfer from
-methylene of the amino moiety to the nitro group to
standard reaction conditions, only the o-nitro group reacted
and cyclized to the expected nitrobenzimidazole, leaving the p-
nitro untouched. This p-nitro group can act as a masked 5-
amino group of the benzimidazole ring, readily released with a
reductant for further functionalization into useful products
began with a protonation of
structure,
the
1
i
i
α
provide iminium ii. Subsequent cyclization of ii into iii followed
by a dehydration would provide iv. It should be noted that the
(compounds
A and D, Scheme 1).
In case of fused benzimdazole 2r, we observed a formation of
formation of iv is easier when the
α
acidic (tetrahydroisoquinolines 1c
-methylene group is more
1r and 1s), and is
a pale yellow precipitate in non-negligible quantities (up to
1
,
18% as 2r.HI) during the course of the reaction. H, 13C NMR
observable in an unachieved reaction mixture. An alternative
mechanism of formation of iv involving a sequence of
elimination/addition may also be envisaged. Deoxygenation of
and HRMS analyses associated with elemental microanalysis of
this solid obtained by simple filtration showed that it was a
hydroiodide salt 2r.HI
.
iv leading to benzimidazole
2 could proceed via formate v and
subsequent fragmentation. It is possible that unstable formyl
iodide, generated in situ from formic acid and hydroiodic acid
or iodide, is the active formylating agent for the formation of
N-formate v. The formation of this intermediate is possible
thank to exceptionally strong nucleophilicity of iodide even in
acidic media.
Scheme 4. Formation of fused tricyclic and 1,2-disubstituted benzimidazoles in
the presence of reducible substituent.
On the basis of these observations, we undertook an
experiment to fully transformed o-nitro-t-anilines 1c
directly into 2c 2r-2s hydroiodide salts (Scheme 5). To achieve
this goal, 1c 1r-1s were heated with I2 (50 mol %) under the
, 1r-1s
,
,
standard conditions. In all cases tested, we were able to obtain
the corresponding salts 2c.HI, 2r.HI-2s.HI in high yields and
purities by simple dilution of the reaction mixture with diethyl
ether to induce their crystallization from the reaction mixture.
Overall, this approach provided a convenient method to
synthesize benzimidazoles as their iodide salts using I2 as both
catalyst and iodide source, avoiding the use of volatile, more
expensive and extremely corrosive HI as a traditional reagent
for this purpose.
To gain a better insight into the reaction mechanism, we
initially carried out some control experiments. When N-butyl-
o-nitroaniline, p-piperidinonitrobenzene or nitrobenzene was
Scheme 6. Proposed mechanism for the formation of benzimidazole
2
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Alternatively, iodide can act as direct reductant by removing
the oxygen atom of iv via vi with the formation of hypoiodide, 15 o-NH2-t-anilines were obtained by a reduction of their
parents o-nitro t-anilines.
which could be regenerated by reaction with formic acid. In
both cases, the catalytic role could be understood in view of
the unique redox and nucleophilic properties of I2/HI.
16 M. Gurry, M. Sweeney, P. McArdle and F. Aldabbagh, Org.
Lett. 2015, 17, 2856.
17 It should be noted that all the o-nitro-t-anilines 1 in this work
were readily obtained quantitatively by simply mixing
inexpensive parent o-chloronitrobenzenes with secondary
amines at different temperatures (rt to 110 °C), followed by
simple filtration of the reaction mixture through a pad of
silica gel with CH2Cl2 as a solvent.
Conclusions
In summary, we have demonstrated that N-substituted and
fused benzimidazole heterocycles could be conveniently
synthesized via reductive cyclization of o-nitro-t-anilines with
formic acid as reductant. More importantly, we have described the
first example of molecular iodine-catalyzed reduction using formic
acid as hydrogen source. It is anticipated that this study will set
the stage for a variety of other catalytic unbalanced redox
condensation processes involving an external redox reagent with
better atom-, step- and redox- efficiencies.
18 Representative examples: (a) Fe/H+: J. Alonso, N. Halland, M.
Nazaré, O. R'kyek, M. Urmann and A. Lindenschmidt, Eur. J.
Org. Chem. 2011, 234; (b) triethyl phosphite: J. Duchek and
A. Vasella, Helv. Chim. Acta. 2011, 94, 977.
19 While almost o-nitro-t-anilines
1
were obtained
quantitatively by simply heating a mixture of inexpensive o-
chloronitrobenzenes with the corresponding secondary
amines followed by simple filtration purification (see
Supporting Information), the synthesis of o-nitroanilides
8
requires copper- or palladium-catalyzed coupling reactions
between more expensive o-iodo- or o-bromonitrobenzenes
with the corresponding secondary amides: references 4, 7,
and 17.
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4
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9
Redox neutral condensation of o-phenylenediamines bearing
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as a specific method to provide benzimidazoles fused with an
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31 D. L. Hammick and M. Zvegintzov, J. Chem. Soc., 1926, 129,
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32 R. Fielden, O. Meth-Cohn and H. Suschitzky, J. Chem. Soc.,
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