Incorporating Morpholine and Oxetane into Benzimidazolequinone Antitumor Agents: The Discovery of 1,4,6,9-Tetramethoxyphenazine from Hydrogen Peroxide and Hydroiodic Acid-Mediated Oxidative Cyclizations

Article abstract of DOI:10.1021/acs.joc.9b01427

The reactivity of hydrogen peroxide and catalytic hydroiodic acid toward 3,6-dimethoxy-2-(cycloamino)anilines is tunable to give ring-fused benzimidazoles or 1,4,6,9-tetramethoxyphenazine in high yield. Mechanisms via a detected nitroso-intermediate are p

Full text of DOI:10.1021/acs.joc.9b01427

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Note
Incorporating Morpholine and Oxetane into Benzimidazolequinone Anti-
Tumour Agents: The Discovery of 1,4,6,9-Tetramethoxyphenazine from
Hydrogen Peroxide and Hydroiodic Acid-Mediated Oxidative Cyclizations
Darren Conboy, Styliana I. Mirallai, Austin Craig, Patrick McArdle,
Ali A. Al-Kinani, Stephen J. Barton, and Fawaz Aldabbagh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01427 • Publication Date (Web): 11 Jul 2019
Downloaded from pubs.acs.org on July 11, 2019
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The Journal of Organic Chemistry
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Incorporating Morpholine and Oxetane into Benzimidazolequinone
Anti-Tumour Agents: The Discovery of 1,4,6,9-Tetramethoxyphenazine
from Hydrogen Peroxide and Hydroiodic Acid-Mediated Oxidative
Cyclizations
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Darren Conboy,† Styliana I. Mirallai,‡ Austin Craig,‡ Patrick McArdle,‡ Ali A. Al-Kinani,† Stephen
Barton,† and Fawaz Aldabbagh*†,‡,§
†Department of Pharmacy, School of Life Sciences, Pharmacy and Chemistry, Kingston University, Penrhyn Road,
Kingston upon Thames, KT1 2EE, UK.
‡School of Chemistry, National University of Ireland Galway, University Road, Galway, H91 TK33, Ireland.
ABSTRACT: The reactivity of hydrogen peroxide and catalytic hydroiodic acid towards 3,6-dimethoxy-2-
(cycloamino)anilines is tunable to give ring-fused benzimidazoles or 1,4,6,9-tetramethoxyphenazine in high yield.
Mechanisms via a detected nitroso-intermediate are proposed for oxidative cyclization and the unexpected intermolecular
displacement of the oxazine. An aqueous solution of molecular iodine is capable of the same transformations. Oxidative
demethylation gave targeted benzimidazolequinones, including without cleavage of the incorporated oxetane.
Morpholine is prevalent in marketed drugs.1 The
replacement of functional groups with morpholine can
increase metabolic stability and hydrophilicity.2,3 Oxetane
is a cyclic ether with similar hydrogen bonding avidity to
morpholine, which has emerged as a polar alternative to the
(cycloamino)anilines, a tunable one-pot transformation
was established (Scheme 1(b)).15
Scheme 1. H2O2 and HX-Mediated Transformations.
(a) The combination of H2O2 and HX:
(1)
(2)
H2O2 + HX
HOX + HX
HOX + H2O
X2 + H2O
gem-dimethyl
NAD(P)H:quinone oxidoreductase 1 (NQO1) is a reductase
over-expressed in many solid
tumours.6,7
group
in
medicinal
chemistry.4,5
(b) Previous work (X = Cl, Br):15
O
Benzimidazolequinones are reported excellent substrates
for NQO1, which was demonstrated using recombinant
human NQO1.8 Computational docking has shown that a
polar group (e.g. cyclic ether) four or five bonds away from
the quinone functional group can lead to more efficient
NQO1 binding.9 This led us to target morpholine and
spirocyclic oxetane ring-fused benzimidazolequinones 1
and 2 (Figure 1).
H2O2, HX,
X
X
where [HX] > [H2O2]
N
N
OMe
OMe
or X2, H2O
NH2
N
Y
n
O
51-95% yield
Y
n
OMe
N
H2O2, HX,
X
X
where [H2O2] > [HX]
N
Y
O
O
OMe
n
N
N
N
N
54-92% yield
O
O
(c) This work:
OMe
O
O
OMe
N
1
2
H2O2, HI (0.2 equiv.),
EtOAc (25 mM), reflux
Figure 1. Synthetic targets.
N
Y
NH2
O
Hydrogen peroxide is a cheap, low molar mass, odorless,
and eco-friendly oxidant with high atom economy. H2O2 is
an established mediator for the oxidative cyclization of o-
cyclic amine substituted anilines to give ring-fused
benzimidazoles.10-15 We have shown that when H2O2 is
combined with HX (where X = Cl or Br), the oxidative
cyclization can be accompanied by a selective aromatic
halogenation in one-pot.13 When the same H2O2 and HX
OMe
69-91% yield
n
N
OMe
Y
O
n
OMe
OMe
N
N
H2O2, HI (0.2 equiv.),
EtOAc (100 mM), rt
OMe
OMe
82% yield
A higher molar ratio of H2O2 relative to HX resulted in
halogenation and oxidative cyclization, while lower relative
system
was
applied
to
3,6-dimethoxy-2-
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amounts of H2O2 to HX mediated one-pot halogenation, 19% yield. Using these conditions on substrate 4b gave
1
2
3
4
5
6
7
8
cyclization and quinone formation, generating halogenated
ring-fused benzimidazolequinones. A larger proportion of
the hydrohalic acid relative to hydrogen peroxide favors
halogen (X2) formation (Scheme 1(a)), and molecular
chlorine and bromine in water were shown to
independently mediate the six-electron oxidative
transformation to give the halogenated ring-fused
benzimidazolequinones. The use of hydroiodic acid (HI) is
preferred over the other hydrohalic acids for the synthesis
of targets 1 and 2, since the oxidative cyclization is more
likely to occur without halogenation, as the electrophilicity
of the halogens decreases from Cl2>Br2>I2.16 Herein, the
reactivity of 3,6-dimethoxy-2-(cycloamino)anilines using
H2O2 and a catalytic amount of HI in ethyl acetate is shown
to be tunable to favor either the intramolecular reaction to
give ring-fused benzimidazoles or the unexpected
spirocyclic oxetane ring-fused benzimidazole 5b in 74%
yield with 11% phenazine 6 formed. The amount of
phenazine 6 (12% yield) was consistent for other six-
membered cyclizations, as demonstrated by conversion of
3,6-dimethoxy-2-(piperidin-1-yl)aniline (4c) to give 6,9-
dimethoxy-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazole
(5c) in 72% yield. Variation of ring-sizes was investigated,
with the five- and seven-membered cyclizations of 3,6-
dimethoxy-(2-pyrrolidin-1-yl)aniline (4d) and 2-(azepan-
1-yl)-3,6-dimethoxyaniline (4e) proceeding in high yield to
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respectively
give
5,8-dimethoxy-2,3-dihydro-1H-
pyrrolo[1,2-a]benzimidazole (5d) and 1,4-dimethoxy-
7,8,9,10-tetrahydro-6H-azepino[1,2-a]benzimidazole (5e)
in 89% and 91% yield. The absence of phenazine 6 from the
latter reactions is consistent with previous observations of
six-membered oxidative cyclizations being more difficult
than those forming five and expanded ring-fused
intermolecular
tetramethoxyphenazine (Scheme 1 (c)).
The four-step synthesis
reaction
to
give
1,4,6,9-
benzimidazole
analogues.14
For
all
reactions,
chromatography was not required, with residues triturated
in diethyl ether to afford benzimidazoles 5a-5e.
of
ring-fused
benzimidazolequinones 1 and 2 began with nucleophilic
aromatic substitution (SNAr) of morpholine and 2-oxa-7-
Phenazine is the scaffold of secondary metabolites from
Pseudomonas and Streptomyces with many natural and
unnatural examples having potent biological activity,
notably anti-cancer.19,20 The oldest synthesis is the Wohl-
Aue reaction,21 which is known to be low-yielding, and
reported to give 1,4,6,9-tetramethoxyphenazine (6) in 10%
yield using potassium hydroxide in benzene (Scheme 3).22
We attempted to improve this condensation of the aniline
with nitrobenzene by using potassium tert-butoxide as base
in toluene,23 but the yield of 6 remained low, at 34%. We set
about establishing a more facile route to 6 through
manipulation of the optimized H2O2 and HI-mediated
oxidative cyclization conditions for morpholine 4a (Table
1). Given that phenazine 6 formation is an intermolecular
reaction, it seemed plausible that the use of more
concentrated conditions (less ethyl acetate) would lead to
increased yields of 6. This was indeed the case when
reducing the amount of solvent by 4-fold, phenazine 6
became the major product in 47% yield with benzimidazole
5a formed in 28% yield. The H2O2 and HI-mediated
cyclization seemed to give the thermodynamic product,
since the yield of cyclized benzimidazole 5a became
increasingly insignificant (4% then 2%), when reducing the
reaction temperature from reflux to 40 °C to room
temperature with phenazine 6 isolated in excellent yield of
82%. The requirement for higher temperatures for the
cyclization may also be due to the nature of the oxidizing
system, although hypoiodous acid (HOI) is formed, the
mediating oxidant is unknown.24,25
azaspiro[3.5]nonane17
onto
1,4-dimethoxy-2,3-
dinitrobenzene. The substitution using bis(2-oxa-7-
azaspiro[3.5]nonan-7-ium) ethanedioate gave 7-(3,6-
dimethoxy-2-nitrophenyl)-2-oxa-7-azaspiro[3.5]nonane
(3) in 68% yield, when using K2CO3 (4 equiv) in a 5:1
acetonitrile:water mixture (Scheme 2). Reduction of
nitrobenzenes with iron powder gave the aniline oxidative
cyclization precursors in high yields with 3,6-dimethoxy-2-
(2-oxa-7-azaspiro[3.5]nonan-7-yl)aniline (4b) formed in
80% yield.
Scheme 2. Preparation of 3,6-Dimethoxy-2-(2-oxa-7-
azaspiro[3.5]nonan-7-yl)aniline (4b).
O
OMe
OMe
NO2
N
NO2
NO2
O
K2CO3, MeCN, H2O
reflux, 40 h
+
O
O
N
O
OMe
H
H
OMe
2
O
3
(68%)
OMe
NH2
N
Fe, NH4Cl, EtOH, H2O
reflux, 18 h
3
OMe
O
4b
(80%)
With 3,6-dimethoxy-2-(morpholin-4-yl)aniline (4a)15 and
spirocyclic oxetane analogue 4b in hand, the oxidative
cyclization using H2O2 and HI was investigated (Table 1). In
keeping with the principles of green chemistry, ethyl
acetate was chosen as the reaction solvent.14,18 Morpholine
4a did not undergo any transformation in EtOAc at reflux in
the presence of H2O2 (20 equiv) alone. Addition of one
stoichiometric equivalent of HI gave after 1 hour, 6,9-
dimethoxy-3,4-dihydro-1H-[1,4]oxazino[4,3-
a]benzimidazole (5a) in 56% yield along with an
unexpected orange precipitate. Spectroscopic data
identified the precipitate as 1,4,6,9-tetramethoxyphenazine
(6), formed in 25% yield. Using less than stoichiometric
amounts of HI (0.2 equiv), increased the yield of the desired
benzimidazole 5a to 69%, and less phenazine 6 formed in
Phenazine 6 was not formed when replacing HI (0.2 equiv)
with HCl (0.2 equiv) (Scheme 4(a)). Under these conditions
mainly recovered 4a was observed with 4-chloro-3,6-
dimethoxy-2-(morpholin-4-yl)aniline (4f) formed in 17%
yield. The regioselectivity of the chlorination was confirmed
by X-ray crystallography (Scheme 4(b) and Figure S1). The
yield of chlorinated aniline 4f increased to 76% through use
of a stoichiometric equivalent of HCl with H2O2. The greater
reactivity of catalytic amounts of HI relative to HCl, reflects
the lower pKa of HI,26 and relative ease of oxidation of
iodine,27 which allows facile breakdown of H2O2.24,25
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Table 1. Yields Obtained from H2O2 and HI-Mediated Reactions.a
2
3
4
5
6
OMe
OMe
OMe
OMe
OMe
OMe
NH2
N
N
N
N
H2O2, HI
+
N
EtOAc, reflux
Y
O
OMe
Y
OMe
5a-5e
n
O
n
7
4a-4e
6
8
9
Entry
Aniline
Y
n
1
1
1
1
HI (mmol)
Time (h)
Yield of 5a-5e (%)b
5a, 0
Yield of 6 (%)b, c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2
3
4
4a
4a
4a
4b
O
O
O
0.0
1.0
0.2
0.2
16
1
0
25
19
11
5a, 56
1
5a, 69
1
5b, 74
5
6
4c
4d
4e
4a
4a
4a
CH2
CH2
CH2
O
1
0
2
1
1
1
0.2
1
1
5c, 72
5d, 89
5e, 91
5a, 28
5a, 4
12
0
0.2
7
0.2
1
0
8
0.2d
0.2d, e
0.2d, f
1
47
79
82
9
O
16
24
10
O
5a, 2
aConditions: Aniline (1.0 mmol), H2O2 (20.0 mmol), EtOAc (40 mL). bIsolated. cPrecipitate. dEtOAc (10 mL). e40 °C. frt.
Scheme 3. Wohl-Aue Reaction.a
Scheme 4. Alternative Oxidative Conditions and X-ray
Crystal Structure with Cyclization of 4-Chloro-3,6-
dimethoxy-2-(morpholin-4-yl)aniline (4f) (Thermal
Ellipsoids Set at 40% Probability).
OMe
OMe
OMe
OMe
OMe
NH2
NO2
N
N
(i) or (ii)
+
(a)
OMe
OMe
OMe
OMe
OMe
OMe
H2O2 (20 equiv)
HCl (X equiv)
6
NH2
N
NH2
N
10 mmol
30 mmol
N
N
unreacted
4a
(i) 10%
(ii) 34%
yields:
+
+
EtOAc
Cl
O
reflux, 1 h
OMe
O
OMe
O
aConditions: (i) KOH (90 mmol), benzene (50 mL), reflux, 5 h.22
OMe
(ii) t-BuOK (40 mmol), toluene (50 mL), reflux, 16 h.
4a
4f
5a
X = 0.2: 17%
X = 1.0: 76%
yields:
6%
4%
64%
0%
Recently, chlorine (50 equiv) and bromine (50 equiv) with
water (100 equiv) have been established as mediators for
six-electron oxidation, converting 3,6-dimethoxy-2-
(cycloamino)anilines into cyclized benzimidazolequinones
(Scheme 1(b)).15 Molecular iodine is however, a less
powerful oxidizing agent,27 and using the latter conditions
did not give benzimidazolequinones, but mixtures of
difficult to separate iodinated aromatics. In the iodine-
mediated reactions, ethyl acetate was replaced by
acetonitrile, since the former solvent is immiscible with
water. Using iodine (10 equiv) in 20% aqueous acetonitrile,
a 4-electron oxidation occurred in 10 minutes to give
cyclized non-iodinated benzimidazoles (Scheme 4(c)).
Morpholine 4a and pyrrole 4d were converted to 6,9-
dimethoxy[1,4]oxazino[4,3-a]benzimidazole (5a) and 5,8-
dimethoxypyrrolo[1,2-a]benzimidazole (5d) in 48% and
92% yield respectively. Similar to the H2O2 and HI-mediated
reaction, the five-membered cyclization was regioselective,
and did not give phenazine, however the less favored
morpholine cyclization gave side-products, including 6 in
6% yield. Presumably for iodine in water, the concentration
of HOI is greater than in the H2O2 and HI-mediated reactions
(in Table 1) resulting in intractable iodinated side-products.
(b)
OMe
H2O2 (20 equiv)
Hl (1 equiv)
N
N
EtOAc
Cl
O
reflux, 1 h
OMe
5f
(79%)
4f
X-ray crystal structure of
OMe
OMe
OMe
OMe
(c)
OMe
OMe
OMe
N
NH2
N
N
N
2 (10 equiv)
+
H2O, MeCN (1:5)
reflux, 10 min
N
Y
Y
OMe
n
6
n
4a 4d
,
5a
5d
(6%)a
(48%)
(92%)
(0%)
a& an intractable mixture of iodinated benzimidazoles.
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Scheme 5. Proposed Mechanisms for the H2O2 and HI (Catalyst) Mediated Transformations Using 3,6-Dimethoxy-2-
(morpholin-4-yl)aniline (4a).
1
2
3
4
5
6
OMe OH
NH
OMe
OMe
OMe
OH
N
OH
N
N
N
- HI
[O]
- HOI

N
N
N
O
O
O
7
8
OMe
O
OMe
OMe
OMe

8
9
5a
9


10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
OMe
OMe
OMe
OMe O
N
OMe O
N
OMe
OMe
OMe
OMe
X
4a
N
NH2
N
N
N
X
[O]
HI
- HOI

H
N
N
SNAr
HN
N
-
HN
O
OMe H
OMe
OMe
O
OMe
O
OMe
OMe
H
MeO
-
O
4a
7
6
10
11
X =
N
O
- HI
Common to the oxidative cyclization of o-cyclic amine
substituted anilines to give benzimidazoles,10,28 and the
Wohl-Aue and other phenazine syntheses,19,20,29 is the
likelihood of a nitroso-intermediate. Transformations via
the N-oxide of the tert-amine of 4a are unlikely, with amine
N-oxides isolated intermediates only when the primary NH2
is deactivated to an acetamide.30,31 We were however
phenazine 1436 not observed. The presence of appropriately
positioned OMe groups does not however guarantee
phenazine formation. Surprisingly chloride 4f exclusively
cyclized to give 7-chloro-6,9-dimethoxy-3,4-dihydro-1H-
[1,4]oxazino[4,3-a]benzimidazole (5f) in 79% isolated
yield (Scheme 4(b)), using the H2O2 and HI reaction
conditions (in Table 1), which favored formation of 6.
Presumably electronic effects of the Cl substituent
circumvent the SNAr step (in Scheme 5).
unable to isolate
a
nitroso-intermediate, although
encouragingly GC-MS of the reaction mixture (entry 10,
Table 1) after 1 hour revealed an EI-MS fragmentation
pattern supporting the formation of intermediate 7 (Figure
S2, Scheme 5). The existence of highly reactive nitroso-
intermediate 7 is supported by Meth-Cohn, who also
refuted claims of isolations of o-nitroso-tert-anilines,
including the nitrosation of p-benzyldimethylaniline, which
gave only the nitro-compound.32 Nitroso 7 should undergo
a formal 1,5-hydride shift to the likely hydroxylamine 8,28,32-
Scheme
6.
Preparation
of
2-(2-Oxa-7-
azaspiro[3.5]nonan-7-yl)aniline (12b) and Oxidative
Cyclizations.
O
O
(i)
O
O
N
O
34
NH2
N
NO2
F
H
H
which subsequently cyclizes and is oxidized to give
, K2CO3
2
benzimidazole
5a.
The
unexpected
1,4,6,9-
MeCN, H2O, reflux, 5 h
tetramethoxyphenazine (6) formation via nitroso
intermediate 7 would involve intermolecular reaction of 7
with starting aniline 4a resulting in nucleophilic aromatic
substitution adduct 10. The proposed formation of iodide
11 is reminiscent of the Bamberger-Ham reaction for
making phenazine-N-oxides,35 where two nitrosobenzenes
(ii)
Fe, NH4Cl, EtOH, H2O, reflux, 16 h
O
12b
(83% for 2 steps)
H2O2 (20 equiv)
NH2
N
N
N
N
HI (1 equiv)
+
EtOAc, reflux, 1 h
Y
O
N
Y
n
substituted
with
para-electron-donating
(through
O
n
14
resonance) groups condense under acidic conditions.19,20 It
is known that HOI reacts with H2O2 via a reduction to
generate additional HI,24,25 which would favor conversion of
10 to 11. Further the yield of phenazine 6 is increased when
using a full equivalent of HI (entry 2, Table 1). Similar to the
conversion of hydroxylamine salts 9 and 11 into products
5a and 6 respectively, Nguyen et al. also proposed iodide as
a direct reductant for removal of oxygen in iodine-catalyzed
reductive cyclizations of o-nitro-tert-anilines to give
benzimidazoles.33 The necessity for the electron-donating
(OMe) group in our H2O2 and HI-mediated synthesis of
phenazine was investigated using 2-(morpholin-4-
yl)aniline (12a)13 and 2-(2-oxa-7-azaspiro[3.5]nonan-7-
yl)aniline (12b), prepared from 1-fluoro-2-nitrobenzene
(Scheme 6). In both cases, oxidative cyclization adducts
(13a33 and 13b) were exclusively isolated in moderate
yields (67 and 70%) after column chromatography with
12a 12b
),
Y = O (
(0%)
(0%)
13a
13b
(67%)
(70%)
The structure of 6’,9’-dimethoxy-1’,2’-dihydro-4’H-
spiro[oxetane-3,3’-pyrido[1,2-a]benzimidazole] (5b) was
confirmed by X-ray crystallography prior to being subjected
to oxidative demethylation (Scheme 7 and Figure S3). The
hypervalent
iodine
reagent
[bis(trifluoroacetoxy)iodo]benzene (PIFA) in water at room
temperature is reported to convert p-dimethoxybenzenes
to quinones.37 This mild procedure was used to give target
ether-containing ring-fused benzimidazolequinones 1 and
2 in 74% and 78% yield from 6,9-dimethoxy-3,4-dihydro-
1H-[1,4]oxazino[4,3-a]benzimidazole (5a) and spirocyclic
oxetane ring-fused benzimidazole (5b) respectively.
Importantly, PIFA unlike other oxidants,38,39 had no
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apparent adverse effect on the integrity of the oxetane onto 1-fluoro-2-nitrobenzene (Fluorochem, 99%), followed
1
2
3
4
5
6
7
8
motif.
by reduction with iron powder. H2O2 (Honeywell Fluka,
50% w/v in water, stabilized), HI (Sigma Aldrich, 57% w/v
in water), HCl (Sigma Aldrich, 37% w/v in water), I2 (VWR,
≥99%, resublimed), and PIFA (Sigma Aldrich, 97%) were
used as received. Thin layer chromatography (TLC) was
performed on TLC silica gel 60 F254 plates. Flash column
chromatography was carried out on silica gel (Apollo
Scientific 60/40–63 µm).
In summary, H2O2 and HI-mediated oxidative cyclization of
3,6-dimethoxy-2-(cycloamino)anilines to give the ring-
fused benzimidazoles can be tuned to alternatively give
1,4,6,9-tetramethoxyphenazine (6) in high yield. Phenazine
formation is however not ubiquitous and competes with the
six-membered cyclization only when the 3,6-dimethoxy-2-
(cycloamino)anilines are suitably activated. The detection
of nitroso-intermediate 7, has led to a proposed mechanism
for this new HI-catalyzed reaction. Future work will
establish the anti-tumor activity and NQO1 specificity of the
synthesized benzimidazolequinones.
Measurements
9
Melting points: Melting points were measured on a Stuart
Scientific melting point apparatus SMP1, except for 1,4,6,9-
tetramethoxyphenazine (6) recorded using differential
scanning calorimetry (DSC) performed on a Mettler Toledo
DSC822 differential scanning calorimeter, using standard
aluminum pans.
10
11
12
13
14
15
16
17
18
19
20
21
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23
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25
26
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46
47
48
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50
51
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54
55
56
57
58
59
60
Scheme 7. Oxidative Demethylation and X-ray Crystal
Structure
spiro[oxetane-3,3’-pyrido[1,2-a]benzimidazole] (5b)
(Thermal Ellipsoids Set at 40% Probability).
Gas chromatography: GC-MS used to detect the formation
of nitrosoarene 7 was performed on an Agilent 6890N
Series GC system equipped with an Agilent 5973 Inert Mass
Selective Detector (EI) and an SGE, 25 m, ID 0.25 mm, FD
0.25 μm column. The carrier gas used was He at a flow rate
of 1.3 mL/min. The injector heated to 80 °C and the oven
temperature increased from 80 to 280 °C at the rate of 10
°C/min and increased to 320 °C at 40 °C/min.
of
6’,9’-Dimethoxy-1’,2’-dihydro-4’H-
OMe
O
O
O
O
N
N
N
N
PIFA, H2O, MeOH
rt, 2 h
O
O
OMe
Infrared (IR) spectroscopy: IR spectra were recorded
using a Perkin-Elmer Spec 1 with ATR attached.
1
5a
(74%)
Nuclear Magnetic Resonance (NMR) spectroscopy: NMR
spectra for compounds 2, 3, 4b and 5b were recorded using
a Jeol ECX 400 MHz instrument equipped with a DEC AXP
300 computer workstation. NMR Spectra for all other
compounds were recorded using a Bruker Avance II 400
MHz spectrometer. The chemical shifts are in ppm relative
to tetramethylsilane. 13C-NMR spectra at 100 MHz are with
complete proton decoupling. NMR assignments are
supported by Distortionless Enhancement by Polarization
Transfer (DEPT) and 1H-1H and 1H-13C correlation.
OMe
N
N
PIFA, H2O, MeOH
rt, 2 h
N
N
O
O
OMe
2
(78%)
5b
High resolution mass spectrometry (HRMS): HRMS
spectra were obtained using ESI time-of-flight mass
spectrometer (TOFMS) on a Waters LCT Mass Spectrometry
instrument. The precision of all accurate mass
measurements was better than 5 ppm.
5b
X-ray crystal structure of
Experimental Section
Materials
X-ray crystallography: A single crystal of 4f was grown
from CH2Cl2 at 2 °C, and a single crystal of 5b was grown by
slow evaporation from CH2Cl2. Single crystal data was
collected using an Oxford Diffraction Xcalibur system
operated using the CrysAlisPro software and the data
collection temperature was controlled at 298 K using a
Cryojet system from Rigaku Oxford Diffraction. The crystal
structures were solved using ShelxT version 2014/55,42 and
refined using ShelxL version 2017/1,43 both of which were
operated within the Oscail software package.44
Crystallographic data for compounds 4f and 5b was
deposited with the Cambridge Crystallographic Data Centre
with deposit number of CCDC 1917886 and CCDC 1917885
respectively. This data is available free of charge via
www.ccdc.cam.ac.uk/data_request/cif (or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax +44 1223 336033; or e-mail
deposit@ccdc.cam.ac.uk).
All chemicals were obtained from commercial sources and
used without further purification. 1,4-Dimethoxy-2,3-
dinitrobenzene was prepared from 1,4-dimethoxybenzene
(Sigma Aldrich, 99% (GC)) and nitric acid (Honeywell Fluka,
64-66%).40
Bis(2-oxa-7-azaspiro[3.5]nonan-7-ium)
ethanedioate was prepared using the procedure described
by our group.17 The preparations of 3,6-dimethoxy-2-
(morpholin-4-yl)aniline (4a), 3,6-dimethoxy-2-(piperidin-
1-yl)aniline (4c), 3,6-dimethoxy-2-(pyrrolidin-1-yl)aniline
(4d) and 2-(azepan-1-yl)-3,6-dimethoxyaniline (4e) were
previously reported using the SNAr of morpholine (Alfa
Aesar, 99%), piperidine (Sigma Aldrich, 99%), pyrrolidine
(Acros, +99%), and azepane (Fluorochem, >98%)
respectively
onto
1,4-dimethoxy-2,3-dinitrobenzene,
followed by reduction with iron powder (Alfa Aesar,
reduced, 99%).14,15 2,5-Dimethoxyaniline was prepared by
the reduction of 1,4-dimethoxy-2-nitrobenzene (TCI,
>99.0% (GC)) using iron powder.41 2-(Morpholin-4-
yl)aniline (12a)13 was prepared by the SNAr of morpholine
Experimental Procedures
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The Journal of Organic Chemistry
Page 6 of 10
Synthesis of 3,6-Dimethoxy-2-(2-oxa-7-azaspiro[3.5]nonan-
38.3 (C), 34.9 (CH2); HRMS (ESI) m/z [M + H]+ Calcd for
C13H17N2O3 249.1239; Found 249.1245.
1
2
3
4
5
6
7
8
7-yl)aniline (4b). 1,4-Dimethoxy-2,3-dinitrobenzene (0.680
g, 2.98 mmol), bis(2-oxa-7-azaspiro[3.5]nonan-7-ium)
ethanedioate (2.053 g, 5.96 mmol) and K2CO3 (1.647 g,
11.92 mmol) in MeCN (30 mL) and H2O (6 mL) were heated
at reflux for 40 h. The mixture was evaporated, dissolved in
EtOAc (30 mL) and washed with brine (3 x 20 mL). The
organic extract was dried (MgSO4), evaporated, and purified
by column chromatography using gradient elution of
petroleum ether/EtOAc to give 7-(3,6-dimethoxy-2-
nitrophenyl)-2-oxa-7-azaspiro[3.5]nonane (3) (0.624 g,
68%) as a yellow solid; Rf 0.44 (1:1 pet. ether/EtOAc); m.p.
125-127 °C; νmax (neat, cm-1) 2931, 2861, 2841, 1539 (NO2),
The above nitrobenzene (0.480 g, 1.94 mmol), iron powder
(0.347 g, 6.21 mmol) and NH4Cl (52 mg, 0.97 mmol) in EtOH
(30 mL) and H2O (10 mL) were heated at reflux for 16 h. The
mixture was filtered through Celite®, evaporated, dissolved
in EtOAc (60 mL) and washed with brine (2 x 40 mL). The
organic extract was dried (MgSO4), evaporated, and purified
by column chromatography using gradient elution of
petroleum ether/EtOAc to give 12b (0.372 g, 88%) as a pale
brown solid; Rf 0.35 (3:2 pet. ether/ EtOAc); m.p. 137-139
°C; νmax (neat, cm-1) 3408, 3325, 3032, 2914, 2856, 2806,
2740, 2677, 1617, 1501, 1461, 1438, 1425, 1383, 1289,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
1495, 1381 (NO2), 1256, 1094, 1057; H NMR (400 MHz,
1
1211, 1135, 1125; H NMR (400 MHz, CDCl3) δ: 6.94-6.86
CDCl3) δ: 6.83 (d, J = 9.2 Hz, 1H), 6.74 (d, J = 9.2 Hz, 1H), 4.42
(s, 4H, OCH2), 3.80 (s, 3H, Me), 3.78 (s, 3H, Me), 2.97-2.90
(br.s, 4H), 1.88-1.80 (br.s, 4H); 13C{1H} NMR (100 MHz,
CDCl3) δ: 152.7, 144.5, 141.9, 133.9 (all C), 112.9, 109.4
(both CH), 82.1 (OCH2), 56.8, 56.2 (both Me), 47.8 (CH2),
38.4 (C), 35.6 (CH2); HRMS (ESI) m/z [M + H]+ Calcd for
C15H21N2O5 309.1449; Found 309.1450.
(m, 2H), 6.74-6.65 (m, 2H), 4.46 (s, 4H, OCH2), 4.02-3.87
(br.s, disappears with D2O, 2H, NH2), 2.89-2.60 (br.s, 4H),
2.06-1.86 (br.s, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ: 141.6,
139.6 (both C), 124.6, 119.8, 118.5, 115.1 (all CH), 81.9
(OCH2), 48.7 (CH2), 38.6 (C), 35.9 (CH2); HRMS (ESI) m/z [M
+ H]+ Calcd for C13H19N2O 219.1497; Found 219.1487.
H2O2 and HX-Mediated Transformations
Nitrobenzene 3 (0.616 g, 2.00 mmol), iron powder (0.357 g,
6.40 mmol) and NH4Cl (55 mg, 1.00 mmol) in EtOH (40 mL)
and H2O (12 mL) were heated at reflux for 18 h. The mixture
was filtered through Celite®, evaporated, dissolved in EtOAc
(80 mL) and washed with brine (2 x 60 mL). The organic
extract was dried (MgSO4), evaporated, and purified by
column chromatography using gradient elution of
petroleum ether/EtOAc to give 4b (0.445 g, 80%) as an off-
white solid; Rf 0.33 (3:1 pet. ether/ EtOAc); m.p. 138-140 °C;
νmax (neat, cm-1) 3444, 3338, 2989, 2917, 2856, 2830, 1605,
Reaction conditions are given in Table 1 and Schemes 4(b),
and 6 for H2O2 and HI, and in Scheme 4(a) for H2O2 and HCl.
H2O2 and HX were sequentially added dropwise to a stirred
solution of the anilines (1 mmol) in EtOAc (10 or 40 mL) at
the indicated reaction temperatures. For the room
temperature reaction of aniline 4a, the addition of H2O2 and
HI were done over ice, and the mixture was then allowed to
warm to room temperature. At the end of the reaction, the
solution was filtered, and the orange precipitate washed
with EtOAc (30 mL) to give 1,4,6,9-tetramethoxyphenazine
(6). The filtrate was washed with Na2CO3 (satd., 60 mL), and
dried (MgSO4). The organic extract was evaporated, and the
residue triturated from Et2O to give benzimidazoles 5a-5d.
Azepane 5e did not require purification. The residues of 4f,
5f, 13a and 13b were purified by column chromatography
using gradient elution of petroleum ether/EtOAc.
1
1556, 1490, 1258, 1107; H NMR (400 MHz, CDCl3) δ: 6.54
(d, J = 8.8 Hz, 1H), 6.13 (d, J = 8.8 Hz, 1H), 4.56 (s, 2H, OCH2),
4.40 (s, 2H, OCH2), 4.37-4.27 (br.s, disappears with D2O, 2H,
NH2), 3.78 (s, 3H, Me), 3.71 (s, 3H, Me), 3.14 (t, J = 12.1 Hz,
2H), 2.75 (d, J = 11.4 Hz, 2H), 2.13 (d, J = 12.4 Hz, 2H), 1.79-
1.66 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ: 153.6, 142.1,
135.4, 126.3 (all C), 107.5, 99.0 (both CH), 82.8, 81.7 (both
OCH2), 56.1, 55.5 (both Me), 47.3 (CH2), 38.6 (C), 36.7 (CH2);
HRMS (ESI) m/z [M + H]+ Calcd for C15H23N2O3 279.1709;
Found 279.1701.
6,9-Dimethoxy-3,4-dihydro-1H-[1,4]oxazino[4,3-
a]benzimidazole (5a) (0.161 g, 69%, Table 1, entry 3); pale
brown solid; m.p. 109-111 °C; vmax (neat, cm-1) 2929, 2827,
1523, 1475, 1440, 1426, 1402, 1316, 1259, 1227, 1193,
Synthesis of 2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)aniline
(12b). 1-Fluoro-2-nitrobenzene (0.296 g, 2.10 mmol), bis(2-
oxa-7-azaspiro[3.5]nonan-7-ium) ethanedioate (0.722 g,
2.10 mmol) and K2CO3 (1.161 g, 8.40 mmol) in MeCN (20
mL) and H2O (4 mL) were heated at reflux for 5 h. The
mixture was evaporated, dissolved in EtOAc (20 mL) and
washed with brine (3 x 20 mL). The organic extract was
dried (MgSO4), evaporated, and purified by column
chromatography using gradient elution of petroleum
1
1165, 1119, 1103, 1084; H NMR (400 MHz, CDCl3) δ: 6.45
(ABq, J = 8.6 Hz, 2H), 4.92 (s, 2H, 1-CH2), 4.41 (t, J = 5.2 Hz,
2H), 4.03 (t, J = 5.2 Hz, 2H), 3.87 (s, 3H, Me), 3.79 (s, 3H, Me);
13C{1H} NMR (100 MHz, CDCl3) δ: 146.3, 145.8, 141.8, 134.4,
125.0 (all C), 102.8, 102.0 (both CH), 65.5 (1-CH2), 64.3
(CH2), 55.9, 55.8 (both Me), 44.9 (CH2); HRMS (ESI) m/z
[M+H]+ Calcd for C12H15N2O3 235.1083; Found 235.1081,
and 1,4,6,9-tetramethoxyphenazine (6) (29 mg, 19%);
orange solid; m.p. (DSC) onset 351.2 °C, peak max 355.9 °C
(lit m.p.26 >360 °C); νmax (neat, cm-1) 3075, 3010, 2900, 2833,
1177, 1622, 1492, 1456, 1445, 1437, 1322, 1266, 1248,
ether/EtOAc
to
give
7-(2-nitrophenyl)-2-oxa-7-
azaspiro[3.5]nonane (0.489 g, 94%) as an orange solid; Rf
0.38 (3:2 pet. ether/EtOAc); m.p. 95-96 °C; νmax (neat, cm-1)
2931, 2859, 2814, 1603, 1567, 1519 (NO2), 1488, 1463,
1
1197, 1157, 1127, 1109; H NMR (400 MHz, CDCl3) δ: 6.97
(s, 4H), 4.09 (s, 12H, Me); 13C{1H} NMR (100 MHz, CDCl3) δ:
148.8, 135.6 (both C), 106.0 (CH), 56.1 (Me); HRMS (ESI)
m/z [M + H]+ Calcd for C16H17N2O4 301.1188; Found
301.1179.
1
1444, 1384, 1343 (NO2), 1298, 1234, 1167, 1129; H NMR
(400 MHz, CDCl3) δ: 7.76 (dd, J = 8.1, 1.6 Hz, 1H), 7.48-7.43
(m, 1H), 7.11 (dd, J = 8.3, 1.1 Hz, 1H), 7.05-7.00 (m, 1H), 4.48
(s, 4H, OCH2), 2.95 (t, J = 5.5 Hz, 4H), 2.02 (t, J = 5.5 Hz, 4H);
13C{1H} NMR (100 MHz, CDCl3) δ: 146.3, 143.3 (both C),
133.4, 125.9, 121.7, 121.2 (all CH), 81.6 (OCH2), 49.2 (CH2),
6’,9’-Dimethoxy-1’,2’-dihydro-4’H-spiro[oxetane-3,3’-pyrido-
[1,2-a]benzimidazole] (5b) (0.203 g, 74%); off-white solid;
m.p. 166-167 °C; νmax (neat, cm-1) 3004, 2931, 2865, 2837,
1
1810, 1606, 1523, 1441, 1260, 1223, 1100, 1082; H NMR
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Page 7 of 10
The Journal of Organic Chemistry
(400 MHz, CDCl3) δ: 6.47 (s, 2H), 4.53 (ABq, J = 6.1 Hz, 4H, Reaction conditions are given in Scheme 3. At the end of the
1
2
3
4
5
6
7
8
OCH2), 4.45 (t, J = 6.3 Hz, 2H, 1´-CH2), 3.92 (s, 3H, Me), 3.83
(s, 3H, Me), 3.32 (s, 2H, 4´-CH2), 2.34 (t, J = 6.3 Hz, 2H, 2´-
CH2); 13C{1H} NMR (100 MHz, CDCl3) δ: 148.2, 145.6, 141.8,
135.0, 125.3 (all C), 102.6, 101.8 (both CH), 80.8 (OCH2),
55.93, 55.89 (both Me), 41.7 (1´-CH2), 37.7 (C), 35.0 (4´-
CH2), 31.3 (2´-CH2); HRMS (ESI) m/z [M + H]+ Calcd for
C15H19N2O3 275.1396; Found 275.1380, and 1,4,6,9-
tetramethoxyphenazine (6) (17 mg, 11%).
reaction, the mixture was filtered, and the precipitate
washed with water (30 mL) to give 6 (1.02 g, 34%) as an
orange solid. Spectral data and melting point of phenazine
6 is consistent with the above.
Aqueous I2-mediated transformations
Anilines (1.00 mmol) in MeCN (10 mL) and H2O (2 mL) were
heated to reflux. I2 (10.00 mmol) was added, and the
mixture was stirred at reflux for 10 min. The mixture was
filtered, and the precipitate washed with water (20 mL) to
give phenazine 6. The filtrate was washed with Na2CO3
(satd., 20 mL) and Na2S2O3 (1 M, 20 mL), and the organic
extract was dried (MgSO4) and evaporated to dryness.
Benzimidazole 5d did not require purification. The residue
of benzimidazole 5a was purified by column
chromatography using gradient elution of petroleum
ether/EtOAc.
6,9-Dimethoxy-1,2,3,4-tetrahydropyrido[1,2-
9
a]benzimidazole (5c) (0.167 g, 72%); brown solid; spectral
data and melting point consistent with the literature,14 and
1,4,6,9-tetramethoxyphenazine (6) (18 mg, 12%).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5,8-Dimethoxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole
(5d) (0.194 g, 89%); off-white solid; spectral data and
melting point consistent with the literature.14
1,4-Dimethoxy-7,8,9,10-tetrahydro-6H-azepino[1,2-
a]benzimidazole (5e) (0.224 g, 91%); brown oil; spectral
data consistent with the literature.14
6,9-Dimethoxy-3,4-dihydro-1H-[1,4]oxazino[4,3-
a]benzimidazole (5a) (0.112 g, 48%), Rf 0.35 (EtOAc); and
1,4,6,9-tetramethoxyphenazine (6) (9 mg, 6%). Spectral data
and melting points for 5a and 6 were consistent with the
above.
4-Chloro-3,6-dimethoxy-2-(morpholin-4-yl)aniline
(4f)
(0.207 g, 76%); Rf 0.51 (1:1 pet. ether/EtOAc); pale brown
solid; m.p. 149-151 °C; νmax (neat, cm-1) 3434, 3335, 2960,
2909, 2881, 2843, 1596, 1549, 1480, 1456, 1445, 1419,
5,8-Dimethoxy-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole
(5d) (0.201 g, 92%); off-white solid; spectral data and
melting point consistent with the literature.14
1
1261, 1177, 1153, 1041; H NMR (400 MHz, CDCl3) δ: 6.65
(s, 1H), 3.98-3.88 (br.s, 2H), 3.87 (s, 3H, Me), 3.81 (s, 3H,
Me), 3.78-3.63 (br.s, 2H), 3.52-3.35 (br.s, 2H), 2.87-2.68
(br.s, 2H), NH2 is absent; 13C{1H} NMR (100 MHz, CDCl3) δ:
148.9, 143.6, 133.7, 130.5, 114.8 (all C), 109.3 (CH), 68.4 (2
x CH2), 61.8, 56.0, (both Me), 51.0 (2 x CH2); HRMS (ESI) m/z
[M + H]+ Calcd for C12H18N2O3Cl 273.1006; Found 273.1012;
General Procedure for the Synthesis of Quinones 1 and 2.
Benzimidazole (0.26 mmol) and PIFA (0.447 g, 1.04 mmol)
in H2O (29 mL) and MeOH (0.75 mL) were stirred at room
temperature for 2 h. The mixture was extracted with CH2Cl2
(3 x 40 mL). The organic extracts were dried (MgSO4),
evaporated, and purified by column chromatography using
gradient elution of petroleum ether/EtOAc and
EtOAc/MeOH.
and
6,9-dimethoxy-3,4-dihydro-1H-[1,4]oxazino[4,3-
a]benzimidazole (5a) (9 mg, 4%); Rf 0.35 (EtOAc).
7-Chloro-6,9-dimethoxy-3,4-dihydro-1H-[1,4]oxazino[4,3-
a]benzimidazole (5f) (0.212 g, 79%); Rf 0.43 (EtOAc); brown
solid; m.p. 144-146 °C; νmax (neat, cm-1) 2931, 2836, 2359,
1605, 1508, 1473, 1428, 1399, 1309, 1212, 1153, 1111,
1070; 1H NMR (400 MHz, CDCl3) δ: 6.64 (s, 1H), 5.00 (s, 2H,
1-CH2), 4.44 (t, J = 5.2 Hz, 2H), 4.17 (t, J = 5.2 Hz, 2H), 3.96
(s, 3H, Me), 3.94 (s, 3H, Me); 13C{1H} NMR (100 MHz, CDCl3)
δ: 147.7, 147.0, 136.7, 133.4, 128.5, 120.5 (all C), 104.8 (CH),
65.5, 64.1 (CH2), 62.5, 56.1 (both Me), 44.2 (CH2); HRMS
(ESI) m/z: [M + H]+ Calcd for C12H14N2O3Cl 269.0693; Found
269.0685.
3,4-Dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-6,9-dione
(1) (39 mg, 74%); yellow solid; Rf 0.41 (EtOAc); m.p.
(decomp. >165 °C); νmax (neat, cm-1) 2924, 1664 (C=O),
1584, 1531, 1475, 1436, 1379, 1345, 1317, 1289, 1225,
1
1202, 1112, 1095, 1066; H NMR (400 MHz, CDCl3) δ: 6.68
(ABq, J = 10.4 Hz, 2H), 4.99 (s, 2H, 1-CH2), 4.44 (t, J = 5.2 Hz,
2H), 4.14 (t, J = 5.2 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)
δ: 180.9, 178.1 (both C=O), 148.0, 141.2 (both C), 136.6,
135.8 (both CH), 130.1 (C), 65.0 (1-CH2), 63.3, 44.7 (both
CH2); HRMS (ESI) m/z [M + H]+ C10H9N2O3 Calcd for
205.0613; Found 205.0623.
3,4-Dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole
(13a)
(0.117 g, 67%); pale brown solid; Rf 0.21 (EtOAc); spectral
1’,2’-Dihydro-4’H-spiro[oxetane-3,3’-pyrido[1,2-
data and melting point consistent with the literature.33
a]benzimidazole]-6’,9’-dione (2) (49 mg, 78%); yellow oil; Rf
0.44 (1:10 MeOH/EtOAc); νmax (neat, cm-1) 2929, 1661
(C=O), 1510, 1487, 1446, 1350, 1270, 1202, 1132; 1H NMR
(400 MHz, CDCl3) δ: 6.62 (ABq, J = 10.4 Hz, 2H), 4.56 (ABq, J
= 6.2 Hz, 4H, OCH2), 4.38 (t, J = 6.2 Hz, 2H, 1´-CH2), 3.32 (s,
2H, 4´-CH2), 2.38 (t, J = 6.2 Hz, 2H, 2´-CH2); 13C{1H} NMR (100
MHz, CDCl3) δ: 181.1, 178.2 (both C=O), 151.9, 149.9 (both
C), 136.5, 136.0 (both CH), 130.2 (C), 80.5 (OCH2), 41.7 (1´-
CH2), 37.2 (C), 34.4 (4´-CH2), 30.4 (2´-CH2); HRMS (ESI) m/z
[M + H]+ C13H13N2O3 Calcd for 245.0926; Found 245.0923.
1',2'-dihydro-4'H-spiro[oxetane-3,3'-pyrido[1,2-
a]benzimidazole] (13b) (0.149 g, 70%); off-white solid; Rf
0.23 (1:10 MeOH/EtOAc) m.p. 141-143 °C; νmax (neat, cm-1)
3052, 2936, 2864, 1668, 1616, 1516, 1485, 1457, 1417,
1
1371, 1344, 1319, 1283, 1228, 1161; H NMR (400 MHz,
CDCl3) δ: 7.73-7.67 (m, 1H), 7.33-7.28 (m, 1H), 7.28-7.22 (m,
2H), 4.59 (ABq, J = 6.2 Hz, 4H, OCH2), 4.14 (t, J = 6.3 Hz, 2H,
1’-CH2), 3.40 (s, 2H, 4’-CH2), 2.47 (t, J = 6.3 Hz, 2H, 2’-CH2);
13C{1H} NMR (100 MHz, CDCl3) δ: 149.5, 143.2, 134.3 (all C),
122.4, 122.2, 119.2, 108.9 (all CH), 80.6 (OCH2), 38.8 (1’-
CH2), 38.0 (C), 34.9 (4’-CH2), 30.7 (2’-CH2); HRMS (ESI) m/z
[M + H]+ C13H15N2O Calcd for 215.1184; Found 215.1180.
ASSOCIATED CONTENT
Modified Wohl-Aue Reaction
Supporting Information. The supporting information is
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Quinones: Excellent Substrates for NAD(P)H:Quinone
Oxidoreductase 1. Org. Biomol. Chem. 2007, 5, 3665-
3673.
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2
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5
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8
XXXXXXX.
GC-MS, 1H and 13C NMR spectra, and crystallographic data
(PDF).
(9) Fagan, V.; Bonham, S.; Carty, M. P.; Saenz-Méndez, P.;
Eriksson, L. A.; Aldabbagh, F. COMPARE Analysis of the
Toxicity of an Iminoquinone Derivative of the
Imidazo[5,4-f]benzimidazoles with NAD(P)H:Quinone
Oxidoreductase 1 (NQO1) Activity and Computational
Docking of Quinones as NQO1 Substrates. Bioorg. Med.
Chem. 2012, 20, 3223–3232.
AUTHOR INFORMATION
Corresponding Author
* E-mail: f.aldabbagh@kingston.ac.uk
Present Addresses
9
§ Department of Pharmacy, School of Life Sciences, Pharmacy
and Chemistry, Kingston University, Penrhyn Road, Kingston
upon Thames, KT1 2EE, UK.
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Oxidative Cyclization with Peroxytrifluoroacetic Acid. J.
Am. Chem. Soc. 1961, 83, 3518–3521.
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Syntheses of Heterocyclic Compounds. Part III. Pyrolytic
Cyclisation of Aromatic Azides. J. Chem. Soc. 1963, 1666–
1669.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Kingston University for a PhD studentship for Darren
Conboy, and the Irish Research Council (IRC) for a Government
of Ireland Postdoctoral Fellowship for Styliana I. Mirallai.
(12) Fahey, K.; Aldabbagh, F. Synthesis of Seven- and
Eight-Membered
Benzimidazoles
[1,2-a]
and
Alicyclic
3-Aziridinylazepino[1,2-
Ring-Fused
a]benzimidazolequinone as a Potential Antitumour
Agent. Tetrahedron Lett. 2008, 49, 5235–5237.
(13) Gurry, M.; Sweeney, M.; McArdle, P.; Aldabbagh, F.
One-Pot Hydrogen Peroxide and Hydrohalic Acid
Induced Ring Closure and Selective Aromatic
Halogenation To Give New Ring-Fused Benzimidazoles.
Org. Lett. 2015, 17, 2856–2859.
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Table of Contents artwork
OMe
OMe
N
N
EtOAc, Diluted
or I2, H2O
Y
O
OMe
OMe
n
NH2
N
H2O2
HI (cat.)
69-92% yield
OMe
OMe
Y
N
N
O
n
EtOAc, Concentrated
room temperature
OMe
OMe
82% yield
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