One-Pot Synthesis of Dihalogenated Ring-Fused Benzimidazolequinones from 3,6-Dimethoxy-2-(cycloamino)anilines Using Hydrogen Peroxide and Hydrohalic Acid

Article abstract of DOI:10.1021/acs.orglett.8b03135

3,6-Dimethoxy-2-(cycloamino)anilines undergo 4- or 6-electron oxidations to afford novel ring-fused halogenated benzimidazoles or benzimidazolequinones using H₂O₂/HCl or H₂O₂/HBr. Cl₂ and Br₂

Full text of DOI:10.1021/acs.orglett.8b03135

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
One-Pot Synthesis of Dihalogenated Ring-Fused
Benzimidazolequinones from 3,6-Dimethoxy-2-(cycloamino)anilines
Using Hydrogen Peroxide and Hydrohalic Acid
Martin Sweeney,† Lee-Ann J. Keane,† Michael Gurry,† Patrick McArdle,† and Fawaz Aldabbagh*,†,‡
†School of Chemistry, National University of Ireland Galway, University Road, Galway, H91 TK33, Ireland
‡Department of Pharmacy, School of Life Sciences, Pharmacy & Chemistry, Kingston University, Penrhyn Road, Kingston upon
Thames, KT1 2EE, United Kingdom
S
* Supporting Information
ABSTRACT: 3,6-Dimethoxy-2-(cycloamino)anilines undergo 4- or 6-electron
oxidations to afford novel ring-fused halogenated benzimidazoles or benzimidazole-
quinones using H2O2/HCl or H2O2/HBr. Cl2 and Br2 are capable of the same
oxidative transformation to the benzimidazolequinones. Labeling experiments
indicate that water is necessary for oxidation of the para-dimethoxybenzenes to
the corresponding quinones.
Scheme 2. H2O2/HX in the Preparation of Benzimidazoles
and Benzimidazolequinones
he cleanest method of generating elemental chlorine and
Tbromine in situ is to mix hydrogen peroxide with excess
hydrochloric and hydrobromic acid respectively, since the only
byproduct is water (Scheme 1).1,2 The intermediate is
hypohalous acid (HOX), which is commonly used to disinfect
water. The molecular halogen (X2) in water is in equilibrium
with an acidic (HX) solution of HOX.3,4
Scheme 1. Generation of X2 from H2O2/HX
The HOX solution has been used in the electrophilic
halogenation of many aromatics.2,5−8 On the other hand, H2O2
in trifluoroacetic acid (TFA) has traditionally been used to give
ring-fused benzimidazoles from o-cyclic amine substituted
anilines.9 Recently, methanesulfonic acid (0.5−1 equiv) has
replaced TFA in H2O2-mediated cyclizations to give alicyclic
ring-fused benzimidazoles.10 In comparison, the H2O2/HX
system is relatively underutilized in the synthesis of hetero-
cycles with H2O2/HBr used to catalyze the aziridination of
alkenes with chloramine-T.11 One-pot H2O2/HX-mediated
oxidative cyclization of o-cyclic amine substituted anilines with
selective dichlorination and dibromination gave a series of five-
to eight-membered ring-fused benzimidazoles, generally in
>80% yield (Scheme 2a).8
Skibo and co-workers popularized aziridinyl-substituted
pyrrolo[1,2-a]benzimidazolequinones as bioreductive antitu-
mor alternatives to the mitomycins,12 and other groups
reported benzimidazolequinones with useful cytotoxicity,13−21
including specificity toward hypoxic tumor cells,18 NAD(P)-
H:quinone oxidoreductase 1 (NQO1)19 and Fanconi anemia
cells.20,21
When para-dimethoxybenzenes are precursors, a two-step
HBr-mediated demethylation to the hydroquinone followed by
FeCl3-mediated oxidation is used to give the benzimidazole-
Received: October 1, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03135
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
quinone.10,14,18,19 One-step conversion of para-dimethoxyben-
zenes to the desired quinones has been effected with AgO,22
Ce(NH4)2(NO3)6 (CAN),13,23−25 CoF3,26 NBS with a
catalytic amount of H2SO4,20,27 and PhI(OCOCF3)2
(PIFA).28 For one-step formation of quinones, H2O2/HX
has advantages of high atom economy29 and low cost. The
simultaneous halogenation on the aromatic or the quinone can
be useful for further nucleophilic aromatic substitution14,15,30,31
and transition-metal-catalyzed cross-couplings,32,33 with the
resultant functionalization significantly altering biological
activity.14,15,21,30,31,33 There are reports of low to moderate
yields of oxidative demethylation with dihalogenation giving
5,6-dichloro- and 5,6-dibromobenzimidazolequinones using
aqua regia (HNO3/HCl (1:3))15,16 and HBr/NaBrO3,
respectively.16 However, the combination of 2-electron
oxidation to the quinone with 4-electron oxidative cyclization
in one pot is unknown. Herein, we utilize H2O2/HX to carry
out oxidative cyclization, aromatic halogenation, and oxidative
demethylation to give a new series of ring-fused dihalogenated
benzimidazolequinones in mostly high yields (Scheme 2b). In
all but one system, the protocol is tunable by adjusting the
[H2O2] to [HX] ratio with high yields of the dihalogenated
ring-fused dimethoxybenzimidazoles obtained when the
[H2O2] is higher. Furthermore, the halogenation is selective
to the activated aromatic or quinone moiety when an
additional fused aromatic ring is in place.
Scheme 3. Synthesis of Dihalogenated Benzimidazoles
Using H2O2/HX
a,b
Initially, 3,6-dimethoxy-2-(cycloamino)anilines 1a−1e were
treated with higher amounts of H2O2 (10 equiv) relative to HX
(5 equiv) to give, in mostly high yields and without the need
for chromatography, novel ring-fused dimethoxy-substituted
benzimidazoles via a 4-electron oxidative cyclization and
dihalogenation (Scheme 3). 2-(Pyrrolidin-1-yl)aniline 1a and
2-(piperidin-1-yl)aniline 1b were found to be consumed within
20 min in MeCN under reflux to give dichlorinated and
dibrominated pyrrolo[1,2-a]benzimidazoles (2a, 3a) and
pyrido[1,2-a]benzimidazoles (2b, 3b) in yields of 80−92%.
For cyclizations of morpholine 1c, azepane 1d, and azocane 1e
using H2O2/HCl, some oxidation to the benzimidazolequinone
was detected at reflux. [1,4]Oxazino[4,3-a]benzimidazole 2c,
azepino[1,2-a]benzimidazole 2d, and azocino[1,2-a]-
benzimidazole 2e were selectively formed in good to high
yields (67−95%) by lowering the reaction temperature (from
reflux to 40 °C or rt) and increasing the reaction time (from 20
min to 2−24 h). Benzimidazolequinone formation was not
detected in the HBr-mediated cyclizations of 1c−1e at reflux,
with 3c obtained in 89% yield, while a 6 h reaction time
afforded complete dibromination to give 3d and 3e in excellent
yield (92% and 95%, respectively). X-ray crystal structures for
the eight-membered dichlorinated and dibrominated adducts
2e and 3e were obtained due to similarities of respective NMR
spectra.
a
Conditions: 1a−1f (1.0 mmol), H2O2 (10 mmol), HX (5 mmol),
b
c
d
e
f
MeCN (10 mL). Isolated yields. 2 h, 40 °C. 24 h, rt. 5 h, 40 °C. 6
g
h
i
h. MeCN (15 mL), 24 h, rt. MeCN (15 mL). MeCN (15 mL), 4.5
h, rt. X-ray crystal structures showing one of the two molecules in the
asymmetric unit cell for 2e and 3e with thermal ellipsoids set at 40%
probability (Figures S1 and S2), and for 4f thermal ellipsoids set at
40% probability.
monochlorination was observed, affording 4f in 60% yield,
while reaction for 24 h afforded the dichlorinated product 2f in
51% yield. The site of monochlorination was confirmed by X-
ray crystallography on 4f.
The room temperature reaction allowed reaction profiling by
HPLC (Figure 1) with mass spectrometry detection of
chlorinated aniline intermediate 1g, suggesting that chlorina-
tion of 1f occurs prior to oxidative cyclization. This
observation may explain the selectivity of other one-pot
oxidative cyclizations to benzimidazoles with aromatic
halogenations,8 which can now be assumed to be a
consequence of the NH2 of the substrate strongly directing
the initial electrophilic aromatic substitution.
The utility of the H2O2/HX-mediated system was
investigated using the more challenging 2-(3,4-dihydro-
isoquinolin-2(1H)-yl)-3,6-dimethoxyaniline (THIQ substrate)
1f with potential for halogenation on the additional aromatic
ring (Scheme 3). Upon treatment of 1f (0.07 M in MeCN)
with H2O2 (10 equiv) and HBr (5 equiv) at reflux for 20 min,
oxidative cyclization was observed at the benzylic position to
afford 3f in 73% yield. The isolation of dichlorinated analogue
2f proved challenging under the same conditions due to the
greater reactivity of the H2O2/HCl system. The H2O2/HCl
system could be tuned to deliver mono- or dichlorination. At
room temperature and a 4.5 h reaction time, only
To carry out the one-pot overall 6-electron oxidation, to
afford dihalogenated quinones, conditions which favor X2
formation were employed (Schemes 1 and 4). H2O2 (50
equiv) and HCl (180 equiv) converted anilines 1a−1e into
dichlorinated ring-fused benzimidazolequinones 5a−5d in
moderate to high yields (62−80%) after 4 h in MeCN at 80
°C, while 5e was isolated in 54% yield. For the H2O2/HBr-
mediated transformations, the high concentrations of HBr
required for quinone formation made it desirable to perform
brominations under solvent-free conditions (except for 6f,
which necessitated the use of MeCN due to the lower
solubility of 1f in HBr). Dibrominated analogues 6a−6e were
B
DOI: 10.1021/acs.orglett.8b03135
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Synthesis of Dihalogenated
Benzimidazolequinones Using H2O2/HX
a,b
Figure 1. HPLC chromatograms as a function of time (t) for the
reaction of 2-(3,4-dihydroisoquinolin-2(1H)-yl)-3,6-dimethoxyaniline
(1f) with H2O2 (10 equiv) and HCl (5 equiv) in MeCN (15 mL) at
rt. ESI HRMS (Figure S3) was used to detect 4-chloro-2-(3,4-
dihydroisoquinolin-2(1H)-yl)-3,6-dimethoxyaniline (1g).
obtained in high yield (67−92%) using H2O2 (60 equiv) in
neat HBr (30 mL) under reflux for 12 h. Ring-fused
dihalogenated benzimidazolequinones (Scheme 4) were
purified by flash column chromatography with the exception
of dibrominated pyrrolo[1,2-a]benzimidazolequinone 6a,
which was isolated cleanly without purification. X-ray crystal
structures of 7,8-dichloro-3,4-dihydro-1H-[1,4]oxazino[4,3-a]-
benzimidazole-6,9-dione (5c), dichlorinated and dibrominated
pyrrolo[1,2-a]benzimidazolequinones 5a and 6a, and azepino-
[1,2-a]benzimidazolequinones 5d and 6d were obtained.
Isolation of significant amounts of 9,10-dichloro-5,6-dihydro-
benzimidazo[2,1-a]isoquinoline-8,11-dione (5f) was however
not possible by treatment of THIQ 1f with a high molar ratio
of HCl relative to H2O2 at reflux. The reaction gave mainly
inseparable products with ESI HRMS (m/z 388.9−392.9)
indicative of tetrachlorination (Figure S4). This led us to
employ the relatively mild conditions of H2O2 (10 equiv) and
HCl (5 equiv) at rt, which allowed aromatic monochloride and
dichloride 4f and 2f to be isolated in good yields after 4.5 and
24 h, respectively (Scheme 3, Figure 1), with extension to 72 h
giving benzimidazolequinone 5f in 56% isolated yield (Scheme
4, Figure S5 for the HPLC chromatograms). The structure of
5f was confirmed by X-ray crystallography. In contrast the
dibrominated analogue 6f was isolated in 68% yield from a 7 h
reflux in the presence of a large excess of HBr; over-
bromination adducts were not detected. This is in line with
the greater reactivity of Cl2 relative to Br2 in electrophilic
halogenation reactions.34
Due to the suspected high concentration of Cl2 or Br2 in the
one-pot 6-electron oxidative cyclizations with dihalogenation,
we decided to investigate if the formation of ring-fused
dihalogenated benzimidazolequinones could be effected by
elemental X2, with or without water. Chlorine gas was bubbled
into a solution of anilines 1b−1e in MeCN containing added
H2O (Table 1). Dichlorinated benzimidazolequinones 5b−5d
were isolated, but in lower yields in comparison to the H2O2/
HCl method, although 5e was given in a comparable yield of
58% in this 10 min reflux reaction. A comparative study, using
1c and Cl2, was carried out in an equivalent amount of water
(10.75 mL) to the H2O2/HCl protocol; however, the yield of
5c was decreased further from 54% to 47%. Thus, water is
a
Conditions: For the synthesis of dichlorides 5a−5e: 1a−1e (1.0
mmol), H2O2 (50 mmol), HCl (180 mmol), MeCN (10 mL), 4 h, 80
°C. For the synthesis of dibromides 6a−6f: 1a−1f (1.0 mmol), H2O2
b
c
(60 mmol), HBr (30 mL), 12 h, reflux. Isolated yields. H2O2 (10
mmol), HCl (5 mmol), MeCN (15 mL), 72 h, rt. HBr (135 mmol),
MeCN (15 mL), 7 h. X-ray crystal structures shown of 5a, 5c, 5d, 5f,
6a, and 6d have thermal ellipsoids set at 40% probability. Crystal
structure of 6a is one of the six molecules in the asymmetric unit cell
(Figure S6).
d
required but not to the extent of the H2O2/HCl method.
Moreover, yields deteriorated when the Cl2 reaction was
performed under anhydrous conditions with inseparable
products given. Overchlorination of 1-methylnaphthalene was
observed by Johnson et al. when Cl2 was used under aprotic
conditions.35 Higher yields (71−90%) were achieved for the
analogous one-pot transformation giving dibrominated benzi-
midazolequinones 6b, 6d, and 6e using Br2 and H2O at 40 °C
for 4 h, which is indicative of the greater control achieved with
less reactive Br2 (that is not susceptible to further
bromination).
Finally we investigated the role of water in the quinone
formation step. 7,8-Dihalo-6,9-dimethoxybenzimidazoles 2c
and 3b were respectively treated with Cl2 and Br2 (both 50
equiv), and H218O (100 equiv) in MeCN (Scheme 5). The
formation of the doubly 18O-labeled dihalogenated
benzimidazolequinones 7c and 8b was confirmed by EI-MS
C
DOI: 10.1021/acs.orglett.8b03135
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
is not accompanied by oxidation to the quinone, allowing the
selective formation of a new series of ring-fused dihalogenated
benzimidazoles.
Table 1. Synthesis of Dihalogenated
Benzimidazolequinones Using Elemental Chlorine and
a b
,
Bromine
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03135.
aniline
X
Y
n
yield (%)
Detailed experimental and synthetic procedures, charac-
terization data, NMR spectra, and crystallographic data
for all new compounds (PDF)
1b
1c
1c
1d
1e
1b
1d
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
CH2
O
O
CH2
CH2
CH2
CH2
CH2
1
1
1
2
3
1
2
3
5b, 41
5c, 54
c
5c, 47
Accession Codes
5d, 71
5e, 58
6b, 71
6d, 90
6e, 90
CCDC 1863022−1863030 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
1e
a
Conditions: For synthesis of dichlorides: 1b−1e (1.0 mmol), Cl2 (50
mmol), H2O (1.8 mL), MeCN (10 mL), reflux, 10 min. For synthesis
of dibromides: 1b, 1d−1e (1.0 mmol), Br2 (50 mmol), H2O (1.8
b
c
mL), MeCN (10 mL), 40 °C, 4 h. Isolated yields. H2O (10.75 mL).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: f.aldabbagh@kingston.ac.uk.
ORCID
Scheme 5. Detecting the Role of Water in Quinone
Formation with Proposed Mechanism
a
Michael Gurry: 0000-0001-8161-6912
Fawaz Aldabbagh: 0000-0001-8356-5258
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Irish Research Council (IRC) for a Government
of Ireland Postgraduate Scholarship for M.S. and the College
of Science, National University of Ireland Galway (NUI
Galway) for a Postgraduate Scholarships for L.-A.J.K. and M.G.
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