Total synthesis of kealiiquinone: the regio-controlled strategy for accessing its 1-methyl-4-arylbenzimidazolone core

Article abstract of DOI:10.1039/C8RA06676K

A practical, concise and straightforward total synthesis of kealiiquinone 1, a naphtho[2,3-d]imidazole alkaloid obtained from the Micronesian marine sponge Leucetta sp. was accomplished. The squaric acid chemistry to construct the 1,4-quinoid ring and the regioselective N-methylation through a benzo[c][1,2,5]selenadiazolium heterocycle are the key features in this report. The full details of the representative approaches involving the different attempted synthetic strategies are also presented. Finally a successful total synthesis of this complex secondary metabolite is described.

Full text of DOI:10.1039/C8RA06676K

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Total synthesis of kealiiquinone: the regio-
controlled strategy for accessing its 1-methyl-4-
Cite this: RSC Adv., 2018, 8, 30761
arylbenzimidazolone core†
a
b
c
Velayudham Ramadoss,
Angel J. Alonso-Castro,
Berenice Yahuaca-Juarez
Nimsi Campos-Xolalpa,
and Cesar R. Solorio-
´
d
d
Rafael Ortiz-Alvarado,
´
a
*
Alvarado
A practical, concise and straightforward total synthesis of kealiiquinone 1, a naphtho[2,3-d]imidazole
alkaloid obtained from the Micronesian marine sponge Leucetta sp. was accomplished. The squaric acid
chemistry to construct the 1,4-quinoid ring and the regioselective N-methylation through a benzo[c]
[1,2,5]selenadiazolium heterocycle are the key features in this report. The full details of the representative
approaches involving the different attempted synthetic strategies are also presented. Finally a successful
total synthesis of this complex secondary metabolite is described.
Received 8th August 2018
Accepted 24th August 2018
DOI: 10.1039/c8ra06676k
rsc.li/rsc-advances
of several protecting groups (four of them) could be pointed as
limitants to scale up the process. The second total synthesis of
kealiiquinone was described by Lovely.6 In this approach, the
Introduction
Natural secondary metabolites obtained from marine sponges
have been an extensive source of pharmacologically active new
drugs.1 Representative examples obtained from the sponge
Leucetta chagosensis include clathridine, naamidines A, G, H,2
and (ꢀ)-spiroleucettadine.3 In 1990 Scheuer and Clardy isolated
two new imidazole alkaloids from the Leucetta sp. sponge, the
pyronaamidine and kealiiquinone 1 (Fig. 1).4
same two main features about the use of a functionalized
imidazole, as well as the Friedel–Cras-type condensation also
in acidic media for equally constructing the central B ring of the
alkaloid are found. Notwithstanding great similarities can be
identied, the synthesis was completed but several (four of
them) organic redox uctuations (oxidation–reduction–oxida-
tion) are found. Additionally the biological assays of activity
were carried out in a successful way.7
Kealiiquinone 1, is a complex natural compound, which
contains
a 1,4-quinoid ring (A ring), fused to a regio-
A particular and well-identied synthetic challenge in the
total synthesis of keliiquinone is the regioselective N-methyla-
tion at the rst position nitrogen of the imidazolone ring (see
differentiated N-methyl-4-arylbenzimidazolone with the aryl
and the methyl groups at opposite hemispheres of the alkaloid.
Due to its attractive molecular architecture and to its modest
biological activity, two total syntheses have been developed to
date (Scheme 1).
The rst total synthesis of kealiiquinone was described by
Ohta.5 This strategy was mainly based upon the central ring (B
ring, Scheme 1) formation in acid media via a Friedel–Cras-
type condensation. The procedure is overall efficient, however
a functionalized imidazole as building block as well as the use
aUniversidad de Guanajuato, Departamento de Quımica, Division de Ciencias
Naturales Exactas, Campus Guanajuato, Cerro de la Venada S/N, 36040,
Guanajuato, Gto., Mexico. E-mail: csolorio@ugto.mx
´
´
y
bUniversidad de Guanajuato, Departamento de Farmacia, Division de Ciencias
´
Naturales y Exactas, Noria Alta S/N, 36050, Guanajuato, Gto., Mexico
c
´
Universidad Metropolitana, Unidad Xochimilco, Calzada del Hueso 1100, Coyoacan
´
04960, Mexico D.F., Mexico
dUniversidad Michoacana de San Nicolas de Hidalgo, Facultad de Quımico
´
´
´
´
Farmacobiologıa, Tzintzuntzan 173, col. Matamoros 58240, Morelia, Michoacan,
Mexico
† Electronic supplementary information (ESI) available. See DOI:
Fig. 1 Representative imidazole alkaloids isolated from the Leucetta
10.1039/c8ra06676k
sp. sponge.
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Also we present our developed route, which was totally focused
in the regioselective N-methylation of the imidazole ring and
nally allowed us to accomplish the total synthesis of kealii-
quinone 1 by late stage construction of the 1,4-quinoid ring (A
ring).
Results
The rst attempted strategy to prepare 1 is following outlined
(Scheme 2).
In this route, kealiiquinone 1 can be obtained from the
iodoquinone 1a by MOM removal and cross-coupling reaction
with the p-anisyl boronic acid. The 1,4-quinone 1a could be
obtained by oxidation of the Diels–Alder adduct 1b, where the
MOM group may act as protecting-directing group for the
directed ortho-metalation (DoM)/iodination.10 The compound
1b is the result of the Diels–Alder reaction between diene 1d and
benzyne 1c, which comes from 9. Thus, different routes inten-
ded to prepare 9 are following summarized (Scheme 3).
We prepared the known symmetric aniline 2,11 that reacted
ꢁ
with CDI in toluene at 80 C affording the benzimidazolone 3.
Then, by using dimethylsulfate, the single methylation for
accessing to the non-symmetric benzimidazolone 4 was not
observed. Instead a mixture of 4 and 5 in almost (1 : 1) ratio was
obtained (Scheme 3A). Accordingly to the required nitrogens
differentiation in 4, a different route was attempted (Scheme
3B). Therein the mono-tosylation of 2, was achieved giving rise
to 6 in 93% of yield. The subsequent benzimidazolone forma-
tion by using CDI in DCE yielded 7 in 66%, which was meth-
ylated in presence of methyliodide to furnish 8 in 90% of yield.
Finally the treatment with sulphuric acid lead to 4 in 61%. This
derivative shows the desired non-symmetric mono-methylated
benzimidazolone.
Several other trials (Scheme 3C) to obtain 4 such as the use of
N-methylsuccinimide or methyltosylate as methylating reagent
on 3 resulted in no reaction. On the other hand accordingly with
the 1b structure (see Scheme 2), a MOM group is necessary as
protecting-directing group for the DoM/iodination sequence.
Thereby the incorporation of MOM was tried in 4, unfortunately
the decomposition of starting material was found aer different
attempts. Upon the failure to attach a single MOM group in 4, it
was decided to install the iodine atom of the iodoquinone 1a.
Different trials by using NIS/TFA in 3 or 4 to get 3a/4a
Scheme 1 Described total synthesis of kealiiquinone to date.
Fig. 1), this is the key objective of our work to complete the total
synthesis of 1. To highlight the importance of the aforemen-
tioned molecular regio-differentiation, is worth to mention the
efforts to address this problem, mainly by Lovely group.8 In the
same context, our group recently described the total synthesis of
the 3-methylkealiiquinone,9 in route to the total synthesis of the
natural alkaloid 1.
In regards to previous reports, our procedure overcomes the
necessity for using imidazole as building block as described by
Ohta and Lovely. This is an advantage in our strategy since it
allowed us to scale up in a straightforward fashion the starting
materials.
Also
a
metallation–sulphinilation–oxidation
sequence at the rst imidazole carbon was necessary for the
nal imidazolone construction in the Ohta route, which did not
occur in ours. On the other hand, at least four sequences
implying REDOX uctuations were presented in the Lovely
kealiiquinone synthesis, while in our route only two of them
were used and correspond to the protecting groups used.
Additionally as we described9 our strategy is modular and is
possible to introduce different functional groups in the 1,4-
quinone as well as in the aryl pendant rings. Finally is impor-
tant to mention that the regiodifferentiation to get selective
methylation in nal natural alkaloid include several steps. In
our synthesis the use of protecting groups is necessary. However
we use only two protecting groups instead of four as in the Ohta
protocol.
Considering all of these reports, herein we describe the full
details about representative strategies attempted to prepare 1.
Scheme 2 First strategy towards the total synthesis of kealiiquinone 1.
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Scheme 4 Second strategy towards the total synthesis of kealiiqui-
none 1.
synthesized by a Suzuki cross-coupling reaction within p-ani-
sylboronic acid and the regio-differentiated bromoiodoacetyl-
nitroaniline 13. The most relevant aspect in this alternative is
the regioselective proposal for introducing the desired methyl
group at rst position nitrogen of the natural compound. This
Scheme 3 Synthesis of benzimidazolones 4 and 5 for preparing 9.
respectively only showed the low reactivity of the starting regiochemistry is based upon the different oxidation states at
material and as consequence no reaction was observed. Even the adjacent nitrogens (Scheme 5).
tough we did not succeed in the compound 9 synthesis, it was
The synthesis of the arylbenzimidazolone 20 was developed
tested the benzyne formation since is the key step in the by two convergent routes (route A and B), which merged in 13.
proposed route. Thus, compound 5 was mixed with n-BuLi at In the route A, two commercially available compounds were
ꢀ78 ꢁC in presence of furane. Several conditions changing base used for starting. In one side para-bromoaniline was iodinated
equivalents, time and temperatures were assayed, however we and on the other side the ortho-iodoaniline was brominated in
were unable to get any Diels–Alder adduct 5a (see ESI†). 88% and 92% of yield respectively, to get 11. Aer an extensive
Presumably due to an electron-rich dienophile formation in experimental analysis, we determined this as a good point for
a direct electron demand Diels–Alder reaction.
the acetyl group introduction, which produced 12 almost
In this point, we decided to change substantially the general quantitatively. Next, the sulfonitric mixture gave rise to a low-
strategy towards the total synthesis of 1. A very important aspect yielding and non-selective nitration that produced the
was not to complete the total synthesis by using a Friedel–Cras regioisomers 13 (20%) and 14 (11%). Other attempts such as
strategy as key step, since Ohta and Lovely previously described nitration of 11 to get 1613 for the regioselective introduction of
it. Based upon our expertise,9 we focused in the construction of the nitro group ortho to the amino, resulted in no reaction.
the quinone ring as the last step of the route, we planned the Regarding the non-selective nitration, although the regioiso-
use of the squaric acid chemistry12 for building up it. Accord- meric mixture of 13 and 14 is chromatographically separable,
ingly, the new synthetic strategy is described (Scheme 4).
the strong acid medium promoted the deacetylation of 12
In this approach, kealiiquinone 1 comes from the tertiary giving poor yields for each compound, thus resulting in a no
alcohol 1e via the thermally-promoted electrocyclic sequence viable alternative. In consequence, another route (route B)
4p-conrotatory ring opening/6p-conrotatory ring closure. The with the initially adjacent installed nitrogens but in different
alcohol 1e can be the result of the 1,2-addition between the oxidation states was envisioned. Thereby the known
dimethylsquarate 10 and the organolithium generated form 20 compound 15,14 was synthesized from o-nitroaniline. The
by metal–halogen (M–H) exchange. Compound 20 is obtained iodination of 15 gave rise to 16 in 85% of yield, which was
by the methylation of the bromobenzimidazolone 19 which can acetylated in a modest 45% to furnish the convergence
be prepared by the nitro group reduction concomitant phos- compound 13. This moderate yield is more evident if the
gene treatment of 17. Finally this ortho-nitroarylaniline can be acetylation reactions of 16 to 13 with 11 to 12 are compared.
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acetyl group to basic conditions17 and strongly limits the
scalability. Therefore the M–H exchange over 20 (see Scheme
4) was not carried out.
Aer this set of reactions we preliminarily concluded two
relevant points: (1) the haloaniline 16 was identied as a very
important building block due to the properly functionalization
for further orthogonal reactions. In 16, there is a nitro group,
which was reduced and regioselective methylated, an iodine
atom for the chemoselective Suzuki cross-coupling and
a bromine for organolithium generation via M–H exchange. (2)
Even tough this second strategy failed, it could be useful with
a more basic-resistant group instead of an acetyl. However was
not possible by this route.
Thus, an alternative procedure based on 16 to introduce
regioselectively a basic-resistant group was started (Scheme 6).
In this strategy the aniline 16 participated in a Suzuki cross-
coupling reaction with p-anisylboronic acid, giving rise to the
arylnitroaniline 23 in 78% of yield. Next, aer too many
attempts to functionalized the amino group with basic-resistant
groups such as TIPS, MOM or Piv (see ESI†), we systematically
failed. Presumably due to the aforementioned bis-ortho-substi-
tution steric effect.
Previous to rule out this sequence, an additional alternative
was considered. For instance, 16 was reduced in presence of
tin(II) chloride affording 24 in 80%. The following reaction with
phosgene allowed the formation of 25 in excellent 90%. In this
stage the regioselective methylation was rationalized by using
a bulky methylating reagent, in order to direct the reaction at
rst position nitrogen. Different quaternary ammonium salts
such as triphenylanilinium, methyltriphenylphosphonium, N-
methylcollidine or the N-methylnitrocollidine were tested. All of
them did not show any reaction to yield the regioselective-
methylated derivative 26.
Frustratingly we can preliminarily summarize that aer
three different strategies and more than three hundred experi-
ments, we were unable to establish a successful route for the
total synthesis of kealiiquinone 1. Therefore a deep analysis of
the developed work revealed potential compounds such as 25
Scheme 5 Synthesis of the regio-differentiated arylbenzimidazolone
20.
The bulkiness of the iodine atom in 16 as well as of the nitro
group, severely restricted the functionalization of the amino
group due to a bis-ortho-substitution effect.15 This steric effect
was observed during all of our work development including
the fails for some basic-resistant groups (TIPS, MOM, Piv) we
tried to introduce. Nevertheless a moderate overall yield at this
stage was obtained, we decided to continue with the route to
validate it. The following Suzuki cross-coupling reaction
between 13 and the p-anisyl boronic acid afforded the arylni-
troaniline 17 in 62% of yield. The non-acidic Hassanloie16
conditions for chemoselective nickel-catalyzed nitro group
reduction, gave rise to 18 in 80% without acetyl removal. This
compound was subjected to benzimidazolone formation by
phosgene treatment to furnish 19 in 70% of yield. Finally, the
methylation of 19 in basic medium was carried out, unfortu-
nately a very complex reaction mixture was observed. Several
optimization assays were done, however in the best of our
results a very low-yielding mixture consisting of the desired
compound 20 (13%), methyl-deacetylated benzimidazolone 21
(7%) and the bismethylated derivative 22 (9%) were isolated.
This result evidenced the extremely poor resistance of the
Scheme 6 Attempts to synthesize the aniline 23a and benzimidazo-
lone 26.
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Scheme 7 Successful retrosynthetic analysis of the kealiiquinone 1.
(Scheme 6), which is an excellent chemo-differentiated building
block for orthogonal Suzuki cross-coupling and M–H exchange
reactions. Also we identied the compound 21 (Scheme 5). This
resulted a very attractive derivative, since it contains the desired
methyl group regioselectively installed, the p-anisyl group in the
correct position, the third-position nitrogen available for a pro-
tecting group introduction and nally a bromine atom for the
organolithium generation by M–H exchange.
On the other side aer an extensive bibliographic search18 it
was found an excellent opportunity in the selenium chemistry
described by Milata19 for the regioselective methylation of 2-
aminoanilines that can give the desired regiodifferentiated
methylbenzimidazolone aer the reaction with phosgene. The
compounds 16, 25 and 21 were considered in this approach that
nally allowed us the total synthesis of kealiiquinone 1. The
overall strategy is illustrated in the following retrosynthetic
analysis (Scheme 7).
In this strategy the naturally occurring kealiiquinone 1, was
obtained from 38 aer MOM-deprotection in acidic medium.
This protected 1,4-quinone is the result of the electrocyclic 6p-
ring closure carried out in the thermal ring expansion of 36.
This tertiary alcohol comes from the 1,2-addition of the orga-
nolithium generated from 21 to the dimethylsquarate 10. The
mentioned arylbenzimidazolone was obtained from the slena-
diazolium 28 aer the regioselective methylation of the corre-
sponding selenadiazol 27 that is obtained form the
halonitroaniline 16.
From this analysis it was determined that compound 21 is key
to complete the total synthesis of kealiiquinone 1. Thereby two
routes (C and D) were developed allowing for accessing in good
yield as well as in a regio-controlled fashion to the 1-methyl-4-
arylbenzimidazolone core of kealiiquinone (Scheme 8).
Scheme 8 Synthetic route for accessing to the 1-methyl-4-arylben-
zimidazolone 21 of the kealiiquinone.
The route C started with the reaction between the 2-ami-
noaniline 24 and selenium dioxide, to produce the benzo[c]
[1,2,5]selenadiazol 27 in excellent 93% of yield. In agreement
with the Milata19 reports, these derivatives are methylated by
heating in dimethyl sulfate as solvent. Based upon our
previous strategies results (see Scheme 5), it was rationalized
that the steric hindrance provided by the iodine atom, would
direct the methylation to the nitrogen at the rst position. To
our delight we found the regioselective methylation in such
expected nitrogen, giving rise to the 1-methylbenzo[c]
selenadiazol-1-ium 28 nearly to quantitative yield. Is worth to
mention that these two last steps proceeded without any
purication. Next, the ring opening of 28 in basic-medium
yielded the aniline 29 in 69%. The NOESY experimentation
for this compound unequivocally conrmed the required
regioselective methylation (see ESI†). The route continued
with the benzimidazolone formation by phosgene treatment of
29 furnishing the 1-methyl-6-bromo-4-iodobenzimidazol-2-
one 26 in 91% of yield. This compound was used for the
MOM-group introduction trials, however it was found only
complex reaction mixtures aer exhaustive attempts (see
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ESI†). Therefore it was introduced in a different synthetic
Aer the successful preparation of the regio-differentiated 1-
stage. The route C concludes with the Suzuki cross-coupling methyl-4-p-anisylbromobenzimidazolone 21, the challenge to
within 26 and p-anisylboronic acid leading to 21 in 75%. On address is the introduction of a basic-resistant protecting
the other hand, the route D started with the reduction of group, which tolerates the M–H exchange reaction conditions.
nitroaniline 26 by using two reaction conditions. The rst are We focused our attention to the MOM group, since is a strong
the Hassanloie-reducing16 conditions using sodium borohy- basic-resistant group even used for DoM reactions,9 can be
dride in presence of nickel chloride to get 31 in 80%. As deprotected in relative milder acid medium and has moderate
alternative, the usage of tin(II) chloride in ethanol yielded the steric hindrance. This former aspect is very important because
nitro group reduction in 54%. Similarly the reaction with our previous experimentation (see Schemes 6 and 8) showed
selenium dioxide of this 2-aminoarylaniline furnished the great difficulties to introduce big groups in the third position of
structurally related 4-arylbenzo-[c][1,2,5]selenadiazol 32 in benzimidazolone. We assumed was due to the bis-ortho-
75% of yield. Under the same rationale, the regioselective substitution effect. Thus, aer the fail to introduce de MOM
methylation took place by heating 32 at 130 ꢁC in dimethyl group in 26 (see Scheme 8) such functionalization was
sulfate, giving rise to the 4-anisylbenzo[c][1,2,5]selenadiazo- attempted in 21. In this way, 35 was obtained in 72% of yield
lium 33 in excellent 98% of yield. The following ring opening with the desired MOM-protection at nitrogen. In view that
in basic medium provided 34 in 63%. The regioselective benzimidazolone is bidentated at nitrogen and oxygen, the
methylation of this route was unequivocally conrmed by regioselectivity in the nitrogen MOM-functionalization was
NOESY experimentation in this compound (see ESI†). Aer- conrmed by NOESY experiments (see ESI† and down of
wards the treatment of 34 with phosgene convergently Scheme 9). Then the M–H exchange generated in situ the
produced 21 in 75%.
organolithium 35a, which reacted with the dimethylsquarate 10
Aer carry out this group of experiments, gratifyingly we yielding 61% of the tertiary alcohol 36. The following heating of
ꢁ
were able to establish a regio-controlled strategy for accessing to 36 at 160 C along 1 h, promoted the thermal 4p-conrotatory
the 1-methyl-4-arylbenzimidazolone core of kealiiquinone.
ring opening/6p-conrotatory ring closure for the p-homologa-
Finally, the total synthesis of the natural alkaloid was tion system. This transformation take place through the
accomplished (Scheme 9).
accepted ketene intermediates,20 which have been described for
this chemistry.12 The reaction furnished a (1 : 1) regioisomeric
mixture of the 1,4-quinones 37 and 38 in 16% and 18.5% of
yield respectively. For simplicity we refer to them as angular and
linear compounds. This expected result showed the desired
linear 3-MOM-kealiiquinone 38 as well as an angular 3-MOM-
kealiiquinone 37 which posses a novel naphtho[1,2-d]imid-
azole nucleus. Is important to highlight that even though the
yields are moderately-low, they are the result of a two consec-
utives reactions (hydroquinone formation/oxidation to 1,4-
quinone). Therefore this two-step one-pot reaction represents
a ca. 40% and 43% of yield respectively for each transformation
calculated in linear manner. Finally the MOM group-removal by
heating at 50 ꢁC in triuoroacetic acid lead to the completion of
the total synthesis of kealiiquinone 1 in 87% of yield aer 12 h.
Table 1 Comparison of 1H MNR data of kealiiquinonea
Kealiiquinone (1)
1H NMR acquired in DMSO-d6
Naturala
Ohtab
Lovelyc
This work
3.58 (s, 3H)
3.78 (s, 3H)
3.83 (s, 3H)
3.92 (s, 3H)
6.88 (d, 2H)
7.12 (d, 2H)
7.69 (s, 1H)
—
3.39 (s, 3H)
3.82 (s, 3H)
3.85 (s, 3H)
3.94 (s, 3H)
6.98 (d, 2H)
7.13 (d, 2H)
7.68 (s, 1H)
11.03 (bs, 1H)
3.40 (s, 3H)
3.83 (s, 3H)
3.85 (s, 3H)
3.94 (s, 3H)
6.98 (d, 2H)
7.13 (d, 2H)
7.68 (s, 1H)
11.02 (bs, 1H)
3.39 (s, 3H)
3.82 (s, 3H)
3.85 (s, 3H)
3.94 (s, 3H)
6.98 (d, 2H)
7.13 (d, 2H)
7.68 (s, 1H)
11.03 (bs, 1H)
The spectroscopic data were obtained from ref. 4. b The spectroscopic
data were obtained from ref. 5. c The spectroscopic data were obtained
from ref. 6.
a
Scheme 9 Completion of the total synthesis of kealiiquinone 1.
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Table 2 Comparison of 13C MNR data of Kealiiquinone
successful strategy through which we were able to synthesized
in a regio-controlled manner the 1-methyl-4-(p-anisyl)benzimi-
dazolone fragment as key building block of 1. This was a big
Kealiiquinone (1)
13C NMR obtained in DMSO-d6
challenge addressed via
a selenadiazolium intermediate
formation. On the other hand unless of the thermal ring
expansion, which is the only step showing moderately-low yield,
the rest of this route proceeds in good to excellent yields. Our
strategy required only two protecting groups whose procedures
for introduction and removal took place under mild and effi-
cient conditions. The use of MOM as basic-resistant protecting
group resulted in an excellent choice since we demonstrated
that bulkier analogues such as TIPS or Piv were not possible to
introduce owing to a bis-ortho-substitution effect. Finally as
expected, in the thermal ring expansion result, it was found
Naturala
Ohtab
Lovelyc
This work
182.4
181.8
159.0
158.3
148.2
147.8
146.0
137.9
131.1
130.6
129.4
124.1
122.9
113.3
105.1
61.0
181.3
181.1
158.5
154.8
147.8
134.0
132.6
129.9
127.7
126.5
126.5
123.5
122.6
113.9
104.6
60.8
181.3
181.1
158.5
154.8
147.8
145.2
134.0
132.7
129.9
127.7
126.4
123.5
122.6
113.9
104.5
60.8
181.3
181.1
158.5
154.8
147.8
145.2
134.0
132.7
129.9
127.7
126.4
123.5
122.6
113.9
104.5
60.8
a
non-described angular analogue of kealiiquinone that
contains an attractive naphtho[1,2-d]imidazole moiety. The
complete characterization for the nal naturally occurring
alkaloid kealiiquinone 1, concisely matched with the previous
reports conrming the ketonic-form in its imidazolone ring.
61.0
60.8
60.8
60.8
55.4
29.2
55.0
26.8
55.0
26.8
55.0
26.8
Experimental section
General information
The spectroscopic data were obtained from ref. 4. b The spectroscopic
data were obtained from ref. 5. c The spectroscopic data were obtained
from ref. 6.
a
All moisture and oxygen sensitive reactions were carried out in
ame-dried round bottom asks under an inert atmosphere of
nitrogen. Unless otherwise specied, all commercial materials
were used as received without further purication. Anhydrous
solvents were purchased from Sigma Aldrich in SureSeal®
bottles. Column chromatography was performed using silica gel
of size 100–200 and 230–400 mesh (Sigma Aldrich). Thin layer
chromatography was performed with TLC Silica gel 60 F256
plates, and visualization was effected with short wavelength UV
light (254 nm). Compounds were characterized using 1H NMR,
13C NMR. (Copies of 1H NMR and 13C NMR spectra are provided
for all the compounds.) Data of known compounds were
compared with existing literature characterization data and the
references are given. 1H and 13C NMR spectra were recorded
with 500 MHz and Bruker advance 400 MHz instruments using
deuterated solvents purchased from Sigma Aldrich like CDCl3.
1H spectra were referenced with tetramethyl silane (TMS, 0.0
ppm) or chloroform (CDCl3, 7.26 ppm) and are reported as
follows: chemical shi, multiplicity (s ¼ singlet, d ¼ doublet, t
¼ triplet, q ¼ quartet, m ¼ multiplet), coupling constant (Hz),
and integration. Chemical shis of the 13C NMR spectra were
measured relative to CDCl3 (d ¼ 77.16 ppm). All the starting
materials were synthesized according to reported procedures in
the literature. High resolution mass (HRMS) analysis was ob-
tained using MAXIS IMPACT BRUKER. Chemical nomenclature
was generated using Chemdraw. Infrared (IR) spectra were
recorded using Perkin-Elmer system 2000 FT-IR spectrometer.
Melting points of solids were measured using Fisher-Johns
melting point apparatus.
From the angular derivative was also obtained in 82% of yield
along of 20 h of reaction.
The spectroscopic data were compared and they match with
those reported by Ohta and Lovely (Tables 1 and 2).
The Table 1 shows a very good correlation among the spec-
troscopic data for the 1H NMR of kealiiquinone reported by
Ohta and Lovely and our synthetic alkaloid. Certainly the
naturally occurring compound we obtained is in the carbonyl
tautomer form at the benzimidazolone ring more than an enol-
form such as was isolated by Scheuer and Clardy.4 Previously,
this observation has been pointed out.5,6
On the other hand the spectroscopic data obtained for the
13C NMR of our synthetic kealiiquinone also matched with the
reports of Ohta and Lovely (Table 2).
We found an excellent correlation in the comparison of the
13C NMR spectroscopic data. Also we found a better correlation
with Ohta and Lovely reports than form original isolation
report. Surely due to the thermodynamically more stable
ketonic-form of kealiiquinone instead to its enolic-form as
mentioned by Lovely.6
Therefore kealiiquinone 1, was successfully synthesized.
Conclusions
In summary, we have developed a new, convergent and modular
total synthesis of the naturally occurring marine alkaloid kea-
liiquinone 1. Our procedure was completely focused in the
regioselective methylation at the rst nitrogen position of its
arylbenzimidazolone core. Accordingly, several experimenta-
Scheme 1 to prepare 4,5-dibromobenzene-1,2-diamine (2)
N,N0-(1,2-Phenylene)bis(4-methylbenzenesulfonamide) (a). A
tions we described, progressively guided us to the nal 1000 mL round bottom ask charged with o-phenylenediamine
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(5.0 g, 46.296 mmol), was dissolved in pyridine (30 mL). To the dibromo-1,3-dihydro-2H-benzo[d]imidazol-2-one 3 (0.8 g, 87%)
ꢁ
reaction mixture was added p-toluenesulfonyl chloride (17.6 g, as white solid. Mp >300 C. Rf ¼ 0.3 (100% EtOAc). IR (neat, n/
92.592 mmol), and it was stirred at room temperature for 12 h. cmꢀ1): 3155, 3055, 2990, 2837, 2734, 1690, 1478, 1362, 1020,
The reaction mixture was evaporated under reduced pressure. 775. 1H NMR (500 MHz, CDCl3): d 10.8 (s, 2H), 7.22 (s, 2H). 13
C
The reaction mixture was washed with 200 mL of HCl (1 N), NMR (126 MHz, CDCl3): d 155.0, 130.7, 113.9, 112.7. HRMS
followed by extracted with EtOAc (200 mL). The organic layers (ESI+): m/z calcd for C7H5Br2N2O, [M + H]+ ¼ 290.8769, found
were dried with Na2SO4 and concentrated under reduced pres- 290.8742.
sure. The resulting crude was puried by column chromatog-
Methylation of 3. A dried 50 mL two-neck ask was
raphy (25% EtOAc/hexane) to provide the compound a (16.6 g, charged with 5,6-dibromo-1,3-dimethyl-1,3-dihydro-2H-
86%) as pale white solid. Rf ¼ 0.6 (50% EtOAc/hexane). 1H NMR benzo[d]imidazole-2-one 3 (0.2 g, 0.34 mmol, 1 equiv.) was
(500 MHz, CDCl3): d 7.57 (d, J ¼ 8.2 Hz, 4H), 7.21 (d, J ¼ 8.2 Hz, dissolved in 15 mL of dry THF. To the reaction mixture was
4H), 7.04–7.01 (m, 2H), 6.97–6.95 (m, 2H), 6.93 (bs, 2H), 2.39 (s, added NaH (0.1 g, 2.07 mmol, 7 equiv.) and was stirred for 10
6H). 13C NMR (126 MHz, CDCl3): d 144.3, 135.6, 130.9, 129.8, minutes at room temperature. Dimethyl sulphate (0.18 mL,
127.70, 127.5, 126.3, 21.7. HRMS (ESI+): (m/z) calcd for 2.76 mmol, 10 equiv.) was added dropwise to the reaction
C
20H20N2O4S2 [M]+ ¼ 416.0864 found 416.0860.
mixture over a period of 5 minutes. The mixture was stirred at
N,N0-(4,5-Dibromo-1,2-phenylene)bis(4-methylbenzenesulfonamide) room temperature for 1 hour and quenched by the addition
(b). Bis-tosylated phenylenediamine (15.0 g, 36.057 mmol) was of H2O (10 mL). The resulted reaction mixture was extracted
charged to a 500 mL two neck dried round ask and was dis- with EtOAc (4 ꢂ 25 mL) and water (50 mL). The combined
solved in dry dichloromethane (150 mL). To the reaction organic layers were washed with brine (100 mL), dried over
mixture was added Br2 (7.4 mL, 144.230 mmol, 4 equiv.) at Na2SO4 and nally concentrated under reduced pressure to
ꢁ
0 C, and then reuxed it for 12 h. The reaction mixture was obtain crude. The resulted crude was puried by column
poured into ice-cold water (200 mL) and solid was formed. The chromatography (30% EtOAc/hexane) to afford mono meth-
resulting solid was ltered-off and dried in vacuum to get N,N0- ylated compound 4 (0.021 g, 48%) as off white solid and bis-
(4,5-dibromo-1,2-phenylene)bis(4methylbenzenesulfonamide) methylated compound 5 (0.043 g, 40%) as an orange solid.
b (17.2 g, 86%) as pale solid. Mp 196–198 ꢁC. IR (neat, n/cmꢀ1):
Data for 5,6-dibromo-1-methyl-1,3-dihydro-2H-benzo[d]
1
3249, 3215, 1596, 1464, 1304, 1158, 706. H NMR (500 MHz, imidazol-2-one (4). Mp 292–294 ꢁC. Rf ¼ 0.3 (40% EtOAc/
CDCl3): d 7.60 (d, J ¼ 8.1 Hz, 4H), 7.28 (d, J ¼ 7.9 Hz, 4H), 7.20 hexane). IR (neat, n/cmꢀ1): 3069, 2991, 1690, 1625, 1596, 1496,
(s, 2H), 6.84 (s, 2H), 2.42 (s, 6H). 13C NMR (126 MHz, CDCl3): 1390, 1083, 827, 746, 709. 1H NMR (500 MHz, CDCl3): d 7.48 (1H,
d 145.0, 135.0, 130.9, 130.2, 130.1, 127.7, 122.7, 21.8. HRMS s), 7.25 (1H, s), 3.25 (3H, s). 13C NMR (126 MHz, CDCl3): d 154.4,
(ESI+): m/z calcd for C20H19Br2N2O4S2, [M + H]+ ¼ 572.9153, 131.8, 129.4, 113.9, 113.8, 112.6, 111.9, 26.5. HRMS (ESI+): m/z
found 572.9112.
calcd for C8H7Br2N2O [M + H] ¼ 304.8925, found 304.8915.
Data for 5,6-dibromo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]
4,5-Dibromobenzene-1,2-diamine21 (2). A 250 mL two necked
round bottom ask was charged with 4,5-dibromo-bistosylated imidazol-2-one (5). Mp: 218–220 ꢁC. Rf ¼ 0.5 (40% EtOAc/
compound c (10.0 g, 17.42 mmol) and concentrated sulphuric hexane). IR (neat, n/cmꢀ1): 3386, 3195, 3062, 2922, 1702, 1508,
acid (20 mL, 34.832 mmol) was added at room temperature. The 1140, 772. 1H-NMR (500 MHz, CDCl3): d 7.22 (2H, s), 3.39 (6H, s).
reaction mixture was stirred at 23 ꢁC for 1 h and then it was 13C-NMR (126 MHz, CDCl3): d 154.2, 130.4, 115.8, 111.8, 27.3.
poured into ice–cold water (100 mL). The reaction mixture was
N-(2-Amino-4,5-dibromophenyl)-4-methylbenzenesulfonamide (6).
neutralized with 50% NaOH solution until the colour of the A ame dried 100 mL round bottom ask was charged with 4,5-
solution is off-white and the solid was formed. The resulting dibromobenzene-1,2-diamine 2 (0.8 g, 4.90 mmol) and was
solid was ltered-off and dried in vacuo to afford 4,5- dissolved in 15 mL of dry DCM. To the reaction mixture was
dibromobenzene-1,2-diamine 2 (4.5 g, 97%) as an orange solid. added p-toluenesulphonyl chloride (0.59 g, 2.94 mmol, 0.6
Mp > 250 C. Rf ¼ 0.3 (100% EtOAc). IR (neat, n/cmꢀ1): 3385, equiv.). The reaction mixture was stirred at room temperature
ꢁ
3313, 1628, 1569, 1485, 1272, 860, 689. 1H NMR (500 MHz, for 12 h and then the solvent was evaporated under the reduced
CDCl3): d 6.93 (2H, s), 3.40 (4H, s). 13C-NMR (126 MHz, CDCl3): pressure. The resulted crude was puried by column chroma-
d 135.5, 120.6, 113.7. HRMS (ESI+): m/z calcd for C6H7Br2N2 [M + tography (30% EtOAC/hexane) to get the N-tosylated-4,5-
H]+ ¼ 264.8976, found 264.8971.
dibromo-phenylenediamine 6 (0.6 g, 93% yield) as white solid.
The yield was calculated based on starting material recovered.
Mp 142–145 ꢁC. Rf ¼ 0.5 (40% EtOAc/hexane). IR (neat, n/cmꢀ1):
3440, 3356, 3255, 1614, 1597, 1478, 1317, 1154, 812, 664. 1H
Sequence followed in Scheme 3
5,6-Dibromo-1,3-dihydro-2H-benzo[d]imidazol-2-one (3). 4,5- NMR (500 MHz, CDCl3): 7.64 (d, J ¼ 7.63 Hz, 2H), 7.31 (d, J ¼
dibromo phenylenediamine 2 (1.0 g, 3.80 mmol) was charged 7.78 Hz, 2H), 7.02 (s, 1H), 6.66 (s, 1H), 5.93 (bs, 1H), 4.16 (bs,
into a 100 mL two-necked round bottom ask and dissolved in 2H), 2.46 (s, 3H). 13C NMR (126 MHz, CDCl3): 144.8, 144.6,
30 mL of toluene. To the reaction mixture was added carbon- 135.1, 132.7, 129.8, 127.5, 124.7, 121.1, 121.0, 111.1, 21.6. HRMS
yldiimidazole (0.928 g, 5.7033 mmol, 1.5 equiv.) and stirred at (ESI+): m/z calcd for C13H13Br2N2O2S2 [M + H]+ ¼ 418.9064,
ꢁ
80 C for 2 h. The reaction mixture was poured into ice-cooled found 418.9055.
water (50 mL) and immediately a white solid was formed. The
5,6-Dibromo-1-tosyl-1,3-dihydro-2H-benzo[d]imidazol-2-one
solid was ltered-off and dried under vacuum to afford 5,6- (7). To a 50 mL round bottom ask was charged with N-tosylated
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4,5-dibromophenylenediamine 6 (0.1 g, 0.237 mmol) and was white solid. The spectroscopic data match with those previously
ꢁ
dissolved in 5 mL of dry dichloroethane. To the reaction described. Mp ¼ 38–40 C. Rf ¼ 0.35 (40% EtOAC/hexane). IR
mixture Et3N (0.05 mL, 0.3577 mmol, 1.5 equiv.) was added. (neat, n/cmꢀ1): 2988, 1806, 1736, 1724, 1582, 1417, 1339, 1072,
1
Then carbonyldiimidazole (0.046 g, 0.2877 mmol, 1.2 equiv.) 1011, 900, 782. H NMR (500 MHz, CDCl3): d 4.37 (s, 6H). 13C
was added at room temperature. The reaction mixture was NMR (126 MHz, CDCl3): d 189.2, 184.6, 61.1.22
ꢁ
stirred at 60 C for 3 h. The resulted solid was ltered-off and
washed with EtOAC (10 mL), dried in high vacuum, to afford
5,6-dibromo-1-tosyl-1,3-dihydro-2H-benzo[d]imidazol-2-one
Sequence followed in Scheme 5
7
Route A
4-Bromo-2-iodoaniline (11)
(0.097 g, 66%) as light yellowish solid. Mp 237–239 ꢁC. Rf ¼ 0.3
(100% EtOAc). IR (neat, n/cmꢀ1): 2923, 1749, 1613, 1485, 1177,
664. 1H NMR (500 MHz, CDCl3): 11.8 (s, 1H) 7.98 (s, 1H), 7.93 (d,
J ¼ 8.9 Hz, 2H), 7.47 (d, J ¼ 8.09 Hz, 2H), 7.36 (s, 1H), 2.40 (s,
3H). 13C NMR (126 MHz, CDCl3): 149.7, 146.0, 133.5, 129.8,
129.2, 127.3, 126.5, 118.3, 116.1, 115.3, 114.0, 20.8. HRMS
(ESI+): m/z calcd for C14H11Br2N2O3S, [M + H]+ ¼ 444.8857,
found 443.8833.
Procedure A. 4-Bromoaniline (0.5 g, 2.941 mmol) was charged
in 100 mL two necked round bottom ask and dissolved in
10 mL of glacial acetic acid. To the reaction mixture was added
N-iodosuccinimide (0.650 g, 2.941 mmol, 1 equiv.) portion-wise
ꢁ
and stirred at 23 C for 1 h. The reaction mixture was neutral-
ized by addition saturated NaHCO3 solution (50 mL) and
extracted with EtOAc (50 mL). The resulted crude was puried
by column chromatography (8% EtOAc/hexane) to furnish 11
(0.5 g, 88%) as light yellowish solid.
5,6-Dibromo-1-methyl-3-tosyl-1,3-dihydro-2H-benzo[d]imidazol-
2-one (8). To a solution of 5,6-dibromo-1-tosyl-1,3-dihydro-2H-
benzo[d]imidazol-2-one 7 (0.90 g, 0.3611 mmol, 1 equiv.) in
20 mL of dry THF, was added powdered KOH (0.041 g,
Procedure B. A 100 mL round bottom ask was charged with
0.7223 mmol, 2 equiv.) at room temperature. To the reaction 2-iodoaniline (4.5 g, 20.6422 mmol) and was dissolved in 25 mL
mixture was added MeI (0.15 mL, 0.7223 mmol, 2 equiv.) and of dry dimethylformamide. To this reaction mixture was added
stirred at 23 ꢁC for 10 h. The reaction mixture was quenched by N-bromosuccinimide (3.6 g, 20.6422 mmol, 1 equiv.) portion-
water and extracted with EtOAc (30 mL) and washed with brine wise and stirred at 23 ꢁC for 1 h. The resulted reaction
(10 mL). The organic layers were dried over Na2SO4, concen- mixture was evaporated and extracted with EtOAC (100 mL) and
trated in vacuum and the resulted crude was puried by column water (200 mL). The organic layers were evaporated under
chromatography (30% EtOAc/hexane) to afford compound 8 reduced pressure and the resulted crude was puried by column
(0.090 g, 90%) as white solid. Mp 200–202 ꢁC. Rf ¼ 0.4 (50% chromatography (10% EtOAc/hexane) to give 4-bromo-2-
EtOAc/hexane). IR (neat, n/cmꢀ1): 3213, 3115, 3092, 2916, 2851, iodoaniline 11 (5.6 g, 92%) as light yellowish solid. Mp 69–
1
1746, 1612, 1484, 1368, 1175, 663. H NMR (500 MHz, CDCl3): 71 ꢁC. Rf ¼ 0.6 (24% EtOAC/hexane). IR (neat, cmꢀ1): 3383, 3288,
d 8.20 (s, 1H), 8.01 (d, J ¼ 8.24 Hz, 2H), 7.35 (d, J ¼ 8.09 Hz, 2H), 3176, 2923, 2853, 1866, 1738, 1621, 1557, 1471, 1384, 1283,
7.18 (s, 1H), 3.26 (s, 3H), 2.44 (s, 2H). 13C NMR (126 MHz, 1251, 1081, 1020, 870, 830, 807. 1H NMR (CDCl3, 500 MHz): 7.73
CDCl3): d 150.2, 146.3, 134.3, 130.4, 129.9, 128.3, 125.9, 119.5, (d, J ¼ 2.2 Hz, 1H), 7.22 (dd, J ¼ 8.5, 2.2 Hz, 1H), 6.62 (d, J ¼
117.6, 117.5, 112.5, 27.3, 21.7. HRMS (ESI+): m/z calcd for C15- 8.5 Hz, 1H), 4.05 (s, 2H). 13C NMR (CDCl3, 126 MHz); d 146.1,
H13Br2N2O3S [M + H]+ ¼ 458.9014 found 458.9003.
140.5, 132.2, 115.7, 110.0, 84.2, 77.2. HRMS (ESI+): m/z calcd for
C6H6BrIN [M + H]+ ¼ 297.8728, found 297.8726.
5,6-Dibromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-
2-one (4). A 20 mL two-necked round bottom ask was
N-(4-Bromo-2-iodophenyl)acetamide (12). A ame dried 100 mL
charged with 5,6-dibromo-1-methyl-3-tosyl-1,3-dihydro-2H- round bottom ask was charged with 4-bromo-2-iodoaniline 11
benzo[d]imidazol-2-one 8 (0.090 g, 0.3478 mmol) and 1 mL of (5.5 g, 18.5810 mmol) and dissolved in 25 mL of dry dichloro-
concentrated sulfuric acid was added. The reaction mixture methane. To the reaction mixture was added triethylamine (2.6
was stirred at room temperature for 1 h. The reaction mixture mL, 18.581 mmol, 1 equiv.) at room temperature followed by the
was neutralized with saturated NaHCO3 solution (10 mL) and dropwise addition of acetyl chloride (1.3 mL 18.581 mmol, 1
resulted solid was ltrated-off to furnish 5,6-dibromo-1- equiv.). The reaction mixture was stirred at room temperature
methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 4 (0.037 g, for 5 h and then the solvent evaporated under the reduced
61%) as off-white solid.
pressure. The resulted crude was puried by column chroma-
3,4-Dimethoxycyclobut-3-ene-1,2-dione (10). In a 500 mL tography (15% EtOAC/hexane) to get the N-(4-bromo-2-
two-neck round bottom ask connected to a Dean–Stark reux iodophenyl)acetamide 12 (6.2 g, 98% yield) as pale white
condenser, was added squaric acid (2.5 g, 21.93 moles, 1 equiv.) solid. Mp 210–212 ꢁC. Rf ¼ 0.5 (40% EtOAC/hexane). IR (neat, n/
and dissolved in MeOH (50 mL) at 70 ꢁC. To the reaction cmꢀ1): 3275, 3068, 2928, 1892, 1737, 1656, 1562, 1514, 1459,
mixture was added trimethyl orthoformate (5.4 mL, 46.05 1368, 1282, 1245, 1086, 1031, 1006, 870, 816, 724. 1H NMR
moles, 2.1 equiv.) and reuxed for 48 h. The reaction mixture (CDCl3, 500 MHz): d 8.12 (d, J ¼ 8.3 Hz, 1H), 7.90 (d, J ¼ 1.9 Hz,
was evaporated under reduced pressure. The crude of reaction 1H), 7.45 (dd, J ¼ 8.8, 2.1 Hz, 1H), 7.38 (s, 1H), 2.23 (s, 3H). 13
C
was washed with EtOAc (2 ꢂ 50 mL) and extracted with H2O (2 NMR (CDCl3, 126 MHz): d 168.3, 140.6, 137.6, 132.4, 122.9,
ꢂ 100 mL). The collected organic fractions were dried with 117.5, 77.12, 24.9. HRMS (ESI+): m/z calcd for C8H8BrINO [M +
Na2SO4, ltered, and concentred under reduced pressure. The H]+ ¼ 339.8834, found 339.8817.
resulting crude was puried by column chromatography (30%
Nitration on N-(4-bromo-2-iodophenyl)acetamide (12). To
EtOAc/hexane) to provide the compound 3 (1.35 g, 43%) as a solution of N-(4-bromo-2-iodophenyl)acetamide 12 (4.0 g,
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11.8343 mmol, 1 equiv.) in 20 mL of concentrated sulfuric acid, under the reduced pressure. The resulted crude was puried by
was added sulfonitric mixture (4 mL) at 0 ꢁC. The reaction column chromatography (20% EtOAC/hexane) to get the N-(4-
ꢁ
mixture was stirred at 23 C for 3 h. The reaction mixture was bromo-2-iodo-6-nitrophenyl)acetamide 13 (0.380 g, 45% yield)
quenched by saturated NaHCO3 solution (100 mL) and extrac- as pale white solid.
ted with EtOAc (200 mL) and washed with brine (100 mL). The
organic layers were dried over Na2SO4, concentrated in vacuum (17). To
N-(5-Bromo-40-methoxy-3-nitro-[1,10-biphenyl]-2-yl)acetamide
solution of N-(4-bromo-2-iodo-6-nitrophenyl)
a
and the resulted crude was puried by column chromatography acetamide 13 (0.5 g, 1.305 mmol) in toluene (30 mL) and
to afford the two regioisomeric compounds 13 (0.6 g, 20%) as water (3 mL) was added 4-methoxyphenyl boronic acid (0.44 g,
light yellow solid and the compound 14 (0.5 g, 11%) as pale 2.872 mmol, 2.2 equiv.), sodium carbonate (0.34 g, 3.262 mmol,
white solid.
2.5 equiv.) and Pd(PPh3)4 (0.12 g, 0.1044 mmol, 8 mol%). The
Spectra data for N-(4-bromo-2-iodo-6-nitrophenyl)acetamide reaction mixture was purged with N2 and stirred at 80 ꢁC for 8 h.
(13). Mp 182–184 ꢁC. Rf ¼ 0.4 (40% EtOAC/hexane). IR (neat, The reaction was quenched by addition of water and extracted
n/cmꢀ1): 3264, 2923, 2853, 1666, 1560, 1522, 1506, 1446, 1366, with EtOAc. The organic layers were washed with brine (100
1325, 1281, 1123, 1062, 1014, 968, 887, 882. 1H NMR (CDCl3, 500 mL), dried with Na2SO4, and concentrated under reduced
MHz): d 8.87 (s, 1H), 8.15 (s, 1H), 7.52 (s, 1H), 2.28 (s, 3H). 13C pressure. The resulted crude was puried by column chroma-
NMR (CDCl3, 126 MHz): d 168.4, 150.3, 143.5, 138.6, 116.9, tography (25% EtOAc/hexane) to yield N-(5-bromo-40-methoxy-3-
108.6, 93.3, 25.0. HRMS (ESI+): m/z calcd for C8H7BrIN2O3 [M + nitro-[1,10-biphenyl]-2-yl)acetamide 17 (0.297 g, 62%) as
H]+ ¼ 384.8685, found 384.8679.
yellowish solid. Mp 172–174 ꢁC. Rf ¼ 0.4 (40% EtOAc/hexane). IR
Spectra data for N-(4-bromo-2-iodo-6-nitrophenyl)acetamide (neat, n/cmꢀ1): 3319, 3236, 3083, 2997, 2951, 2926, 2854, 2832,
ꢁ
(14). Mp 179–181 C. Rf ¼ 0.3 (40% EtOAC/hexane) IR (neat, n/ 1739, 1673, 1608, 1511, 1455, 1362, 1334, 1243, 1181, 1030, 966,
cmꢀ1): 3257, 3083, 3083, 2992, 1730, 1706, 1663, 1552, 1503, 883, 836, 814, 717. H NMR (500 MHz, CDCl3): d 8.69 (s, 1H),
1
1439, 1367, 1334, 1276, 1247, 1110, 1034, 1009, 870, 738. 1H 7.45 (s, 2H), 7.25 (d, J ¼ 10.2 Hz, 3H), 7.09 (s, 1H), 7.02 (d, J ¼
NMR (CDCl3, 500 MHz): d 8.61 (s, 1H), 7.99 (s, 1H), 7.35 (s, 1H), 11.3 Hz, 2H), 3.87 (s, 3H), 2.03 (s, 3H). 13C NMR (126 MHz,
2.25 (s, 3H).13C NMR (CDCl3, 126 MHz): d 168.4, 150.3, 143.5, CDCl3): d 168.2, 160.1, 135.1, 134.4, 132.2, 130.3, 127.9, 125.7,
138.8, 117.00, 108.5, 93.4, 25.0. HRMS (ESI+): m/z calcd for C8- 124.0, 119.1, 114.9, 55.6, 24.9. HRMS (ESI+): m/z calcd for
H7BrIN2O3 [M + H]+ ¼ 384.8685, found 384.8662.
C
15H14BrN2O4 [M + H]+ ¼ 365.0317, found 365.0119.
Route B
N-(3-Amino-5-bromo-40-methoxy-[1,10-biphenyl]-2yl)acetamide (18). N-
4-Bromo-2-iodo-6-nitroaniline (16). A 500 mL two-necked (5-Bromo-40-methoxy-3-nitro-[1,10-biphenyl]-2-yl)acetamide 17 (0.2 g,
round-bottom ask, was charged with a solution of 4-bromo- 0.5494 mmol, 1 equiv.) was charged in a 250 mL two-necked round-
2-nitroaniline 15 (2.0 g, 9.216 mmol, 1 equiv.) in glacial AcOH bottom ask and dissolved in MeOH (30 mL). To the resulting solu-
(25 mL) and heated to 80 ꢁC. N-iodosuccinimide (4.0 g, tion was added NaBH4 (0.208 g, 5.4945 mmol, 10 equiv.) portion wise
18.416 mol, 2 equiv.) was added portion-wise and stirred for 2 h. within 5 minutes at 0 ꢁC and followed by NiCl2$6H20 (0.021 g,
The reaction mixture was poured into ice-cooled water (50 mL) 0.1648 mmol, 0.3 equiv.). The reaction mixture was stirred at 23 ꢁC for
and immediately an orange colour solid was formed. The 0.5 h and was poured into ice-cold water. The resulting mixture was
resulted solid was ltered-off, washed with DCM (50 mL) and extracted with EtOAc (200 mL) and water (200 mL). The organic layers
dried under vacuo. The aqueous portion was neutralized with were dried over Na2SO4 and concentrated under reduced pressure.
saturated NaHCO3 (50 mL) solution, followed by extraction with The crude was puried by column chromatography (60% EtOAc/
EtOAc (100 mL). The combined organic fractions were washed hexane) to furnish N-(3-amino-5-bromo-40-methoxy-[1,10-biphenylꢁ]-2-
with brine (50 mL), dried with Na2SO4, and concentrated under yl)acetamide 18 (0.144 g, 80%) as yellowish solid. Mp 185–187 C.
reduced pressure to afford additional amount of such solid. The Rf ¼ 0.3 (100% EtOAc). IR (neat, n/cmꢀ1): 3481, 3360, 3320, 3233, 2950,
orange solid obtained from ltration and extraction process 2928, 2832, 1674, 1645, 1608, 1511, 1425, 1364, 1291, 1242, 1178,
were collected to furnish 16 (2.2 g, 85%) that was used without 1033, 928, 828, 815, 805, 735, 718. 1H NMR (500 MHz, CDCl3): d 7.21
further purication for next step. Mp 135–137 ꢁC. Rf ¼ 0.5 (20% (d, J ¼ 8.7 Hz, 2H), 6.95 (d, J ¼ 8.7 Hz, 2H), 6.92 (d, J ¼ 2.1 Hz, 1H),
EtOAc/hexane). IR (neat, n/cmꢀ1): 3572, 3453, 3101, 1541, 1435, 6.86 (d, J ¼ 2.1 Hz, 1H), 6.63 (s, 1H), 4.13 (s, 2H), 3.85 (s, 3H), 2.05 (s,
1346, 1241, 1070, 872, 671. 1H NMR (500 MHz, CDCl3): d 8.31 (d, 3H). 13C NMR (126 MHz, CDCl3): d 169.6, 159.6, 144.5, 140.1, 130.2,
J ¼ 2.3 Hz, 1H), 8.01 (d, J ¼ 2.3 Hz, 1H), 6.67 (bs, 2H). 13C NMR 123.2, 121.1, 120.5, 119.4, 114.2, 55.5, 23.3. HRMS (ESI+): m/z calcd for
(126 MHz, CDCl3): d 147.5, 143.3, 131.9, 129.4, 108.1, 88.0. C15H16BrN2O2 [M + H]+ ¼ 335.0395, found 335.0374.
HRMS (ESI): m/z calcd for C6H4BrIN2O2 [M + H]+ ¼ 342.8501,
1-Acetyl-5-bromo-7-(4-methoxyphenyl)-1,3-dihydro-2H-benzo[d]
imidazol-2-one (19). To a 100 mL two-neck round-bottom ask,
found 342.8504.
N-(4-Bromo-2-iodo-6-nitrophenyl)acetamide (13).
A
dried was added N-(3-amino-5-bromo-40-methoxy-[1,10-biphenyl]-2-yl)
100 mL round bottom ask was charged with 4-bromo-6-iodo-2- acetamide 18 (0.140 g, 0.4191 mmol) and dissolved in 15 mL
nitroaniline 16 (1.0 g, 2.9321 mmol) and dissolved in 25 mL of of DCE at room temperature. Then, a solution of phosgene
dry dimethylformamide. To the reaction mixture was added 15 wt% in toluene (0.8 mL, 3.3528 mmol, 8 equiv.) was added
sodium hydride (0.281 g, 11.7.30 mmol, 4 equiv.) at 0 ꢁC fol- drop wise to the reaction mixture and stirred for 1 h. The
lowed by the dropwise addition of acetyl chloride (4.1 mL, reaction mixture was poured into ice-cooled water (30 mL) and
58.642 mmol, 20 equiv.). The reaction mixture was stirred at immediately a white solid was formed. The resulting solid was
room temperature for 12 h and then the solvent evaporated ltered-off and dried under vacuum to give 19 (0.105 g, 70%) as
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an off-white solid. The compound was used without purication 7.09 (d, J ¼ 1.9 Hz, 1H), 7.08 (d, J ¼ 1.9 Hz, 1H), 6.96 (d, J ¼
for next step. Mp 194–196 ꢁC. Rf ¼ 0.3 (40% EtOAc/hexane). IR 8.6 Hz, 2H), 3.87 (s, 3H), 3.42 (s, 3H), 2.97 (s, 3H). 13C NMR (126
(neat) n/cmꢀ1 ¼ 2938, 2837, 2274, 1714, 1667, 1611, 1515, 1466, MHz, CDCl3): d 159.6, 155.1, 131.8, 130.9, 129.2, 126.6, 126.5,
1442, 1367, 1383, 1388,1309, 1287, 1246, 1143, 1045, 1020, 995, 126.1, 113.5, 113.2, 109.4, 55.4, 30.4, 27.4. HRMS (ESI+): m/z
840, 762. 1H NMR (500 MHz, DMSO-d6): d 11.57 (s, 1H), 7.24 (d, J calcd for C16H16BrN2O2 [M + H]+ ¼ 347.0395, found 347.0396.
¼ 7.5 Hz, 2H), 7.13 (s, 1H), 7.12 (s, 1H), 6.92 (d, J ¼ 8.8 Hz, 2H),
3.78 (s, 3H), 2.50 (s, 3H).13C NMR (126 MHz, DMSO-d6): d 168.6,
158.5, 152.9, 132.3, 131.2, 130.3, 128.1, 125.5, 123.22, 116.4,
Sequence followed in Scheme 6
113.6, 110.1, 55.0, 39.5, 25.5. HRMS (ESI+): m/z calcd for
5-Bromo-3-iodobenzene-1,2-diamine (24). 4-Bromo-2-iodo-6-
nitroaniline 16 (6.4 g, 18.768 mmol, 1 equiv.) was charged in
C
16H14.BrN2O3 [M + H]+ ¼ 361.0188, found 361.0176.
Methylation of N-(3-amino-5-bromo-40-methoxy-[1,10-biphenyl]- a 500 mL two-necked round-bottom ask, dissolved in EtOH
2-yl)acetamide (19). A dried 50 mL two-neck ask was charged (300 mL) and heated to 70 ꢁC. To the resulting solution was
with dry DMSO (10 mL), powdered KOH (0.14 g, 2.55 mol, 4 added SnCl2$2H2O (21.2 g, 93.841 mmol, 5 equiv.) portion wise
ꢁ
equiv.) and was stirred for 10 minutes at room temperature. within 5 minutes and continued to be stirred at 70 C for 3 h.
Then 6-bromo-4-iodo-1,3-dihydro-2H-benzo[d]imidazol-2-one The reaction mixture was poured into ice-cold water. The
19 (0.230 g, 0.638 mol, 1 equiv.) was added in portions to the resulting solid was ltered-off and dried in vacuo to give 5-
reaction mixture followed by the drop wise addition of MeI (0.25 bromo-3-iodobenzene-1,2-diamine 24 (4.65 g, 80%) as an off-
mL, 3.833 mmol, 6 equiv.) over a period of 5 minutes. The white solid which was used without further purication. Mp
mixture was stirred at room temperature for 1 h and quenched 136–138 ꢁC. Rf ¼ 0.4 (40% EtOAc/hexane). IR (neat, n/cmꢀ1):
by the addition of H2O (20 mL). The crude was extracted with 3493, 3396, 3064, 1640, 1567, 1458, 1080, 765, 705. 1H NMR (500
EtOAc (2 ꢂ 25 mL). The combined organic layers were washed MHz, CDCl3): d 7.30 (d, J ¼ 2.1 Hz, 1H), 6.80 (d, J ¼ 2.1 Hz, 1H),
with brine (100 mL), dried over Na2SO4 and nally concentrated 3.63 (bs, 4H). 13C NMR (126 MHz, CDCl3): d 135.3, 135.1, 131.1,
under reduced pressure. The resulted crude was puried by 119.1, 111.9, 86.2. HRMS (ESI+): m/z calcd for C6H7BrIN2 [M +
column chromatography (20% EtOAc/hexane) to furnish 20 H]+ ¼ 312.8837, found 312.8863.
(32 mg, 13%) as pale solid, 21 (16 mg, 7%) as white solid and 22
6-Bromo-4-iodo-1,3-dihydro-2H-benzo[d]imidazol-2-one
(20 mg, 9%) as white solid.
(25). To a 500 mL two-neck round-bottom ask, was added 5-
Spectral data for 3-acetyl-6-bromo-4-(4-methoxyphenyl)-1-methyl-1,3- bromo-3-iodobenzene-1,2-diamine 24 (4.5 g, 14.469 mmol, 1.0
dihydro-2H-benzo[d]imidazol-2-one (20). The following compound equiv.) and was dissolved in 100 mL of DCE at room tempera-
was obtained by column chromatography purication with a 20% ture. Then, a solution of phosgene 15 wt% in toluene (11.0 mL,
EtOAc/hexane gradient. Mp 229–231 ꢁC. Rf ¼ 0.6 (40% EtOAc/ 101.286 mmol, 7 equiv.) was added drop-wise to the reaction
hexane). IR (neat, n/cmꢀ1): 3035, 2976, 2939, 2832, 1738, 1722, mixture and stirred for 1 h. The reaction mixture was poured
1605, 1595, 1517, 1450, 1364, 1272, 1251, 1185, 1174, 1024, 994, 827. into ice-cooled water (100 mL) and immediately a white solid
1H NMR (500 MHz, CDCl3): d 7.47 (d, J ¼ 1.8 Hz, 1H), 7.25 (d, J ¼ was formed. The resulting solid was ltered-off and dried under
8.6 Hz, 2H), 7.19 (d, J ¼ 1.8 Hz, 1H), 6.93 (d, J ¼ 8.7 Hz, 2H), 3.78 (s, vacuum to give 25 (4.55 g, 90%) as an off-white solid. The
3H), 3.35 (s, 3H), 2.49 (s, 3H). 13C NMR (126 MHz, CDCl3): d 168.4, compound was used without purication for next step. Mp 212–
158.5, 152.4, 133.8, 131.2, 130.2, 128.2, 125.9, 121.9, 116.8, 113.7, 214 C. Rf ¼ 0.4 (60% EtOAc/hexane). IR (neat, n/cmꢀ1): 3064,
ꢁ
109.7, 55.1, 27.3, 25.5. HRMS (ESI+): m/z calcd for C17H16BrN2O3 [M 2944, 1703, 1605, 1572, 1481, 1444, 1247, 1023, 954, 825. 1H
+ H]+ ¼ 375.0344, found 375.0341.
NMR (500 MHz, DMSO-d6): d 11.06 (s, 1H), 10.99 (s, 1H), 7.42 (d,
Spectral data for 6-bromo-4-(4-methoxyphenyl)-1-methyl-1,3- J ¼ 1.7 Hz, 1H), 7.05 (d, J ¼ 1.7 Hz, 1H). 13C NMR (126 MHz,
dihydro-2H-benzo[d]imidazol-2-one (21). The following compound DMSO-d6): d 155.0, 132.9, 131.0, 130.7, 113.3, 111.3, 73.9. HRMS
was obtained by column chromatography purication with a 30% (ESI+): m/z calcd for C7H5BrIN2O [M + H]+ ¼ 338.8630, found
ꢁ
EtOAc/hexane gradient as white solid. Mp 225–227 C. Rf ¼ 0.4 338.8661.
(40% EtOAc/hexane). IR (neat, n/cmꢀ1): 3137, 3048, 2953, 2927,
5-Bromo-40-methoxy-3-nitro-[1,10-biphenyl]-2-amine (23). To
a solution of 4-bromo-2-iodo-6-nitroaniline 16 (2.5 g,
2833, 1703, 1608, 1578, 1517, 1450, 1380, 1339, 1291, 1247, 1178,
962, 823, 767. 1H NMR (500 MHz, CDCl3): d 8.72 (s, 1H), 7.43 (d, J 7.3099 mmol, 1.0 equiv.) in 1,4-dioxane (30 mL) and water (2
¼ 8.7 Hz, 2H), 7.24 (d, J ¼ 1.8 Hz, 1H), 7.06 (d, J ¼ 1.4 Hz, 1H), mL) were added p-anisyl boronic acid (1.76 g, 12.6315 mmol, 1.6
7.02 (d, J ¼ 8.7 Hz, 2H), 3.87 (s, 3H), 3.40 (s, 3H). 13C NMR (126 equiv.), potassium carbonate (2.0 g, 14.6198 mmol, 2.0 equiv.)
MHz, CDCl3): d 159.9, 155.0, 132.7, 129.2, 128.5, 125.1, 124.3, and Pd(PPh3)4 (0.675 g, 0.6315 mmol, 8 mol%). The reaction
ꢁ
124.2, 114.9, 114.7, 109.5, 55.5, 27.2. HRMS (ESI+): m/z calcd for mixture was purged with N2 and stirred at 90 C for 6 h. The
C15H14BrN2O2 [M + H]+ ¼ 333.0239, found 333.0218.
reaction was quenched by addition of water and extracted with
Spectral data for 6-bromo-4-(4-methoxyphenyl)-1,3-dimethyl- EtOAc. The organic layers were washed with brine (100 mL),
1,3-dihydro-2H-benzo[d]imidazol-2-one (22). The following dried with Na2SO4, and concentrated under reduced pressure.
compound was obtained by column chromatography purica- The resulted crude was puried by column chromatography
tion with a 25% EtOAc/hexane gradient as white solid. Mp 154– (20% EtOAc/hexane) to afford 5-bromo-40-methoxy-3-nitro-[1,10-
156 ꢁC. Rf ¼ 0.55 (40% EtOAc/hexane). IR (neat, n/cmꢀ1) ¼ 3071, biphenyl]-2-amine 23 (1.84 g, 78%) as yellow solid. Mp 117–
2945, 1696,1607, 1481, 1450, 1388, 1241, 1176, 1122, 1025, 832, 119 C. Rf ¼ 0.5 (40% EtOAc/hexane). IR (neat, n/cmꢀ1): 3469,
ꢁ
741, 692. 1H NMR (500 MHz, CDCl3): d 7.27 (d, J ¼ 8.6 Hz, 2H), 3356, 3097, 3010, 2954, 2928, 2904, 2834, 2532, 1607, 1578,
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1496, 1461, 1388, 1358, 1321, 1287, 1241, 1174, 1028, 876, 819, 1505, 1470, 1445, 1430, 1399, 1274, 1224, 1058, 833, 822, 774,
696. 1H NMR (500 MHz, CDCl3): d 8.26 (d, J ¼ 2.4 Hz, 1H), 7.36 674. 1H NMR (500 MHz, CDCl3): d 7.25 (d, J ¼ 2.1 Hz, 1H), 6.69
(d, J ¼ 2.4 Hz, 1H), 7.29 (d, J ¼ 8.7 Hz, 2H), 7.02 (d, J ¼ 8.7 Hz, (d, J ¼ 2.1 Hz, 1H), 3.57 (bs, 3H), 2.82 (s, 3H). 13C NMR (126
2H), 6.27 (s, 2H), 3.86 (s, 3H). 13C NMR (126 MHz, CDCl3): MHz, CDCl3): d 139.7, 134.3, 129.0, 113.7, 113.3, 86.4, 31.1.
d 160.2, 142.2, 138.9, 132.9, 132.8, 130.4, 127.6, 127.4, 115.1, HRMS (ESI+): m/z calcd for C7H9BrN2 [M + H]+ ¼ 326.8994,
107.4, 55.5. HRMS (ESI+): m/z calcd for C13H12BrN2O3 [M + H]+ found 326.8998. The regioselectivity of this methylation reac-
¼ 323.0031, found 323.0009.
tion was conrmed by NOESY experiments (see spectra le).
6-Bromo-4-iodo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-
one (26). In a 250 mL two-neck round-bottom ask, was added
5-bromo-3-iodo-N1-methylbenzene-1,2-diamine 29 (3.2 g,
9.815 mmol) and dissolved in 50 mL of DCE at room temper-
Sequence followed in Scheme 8
Route C
6-Bromo-4-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-benzo-6- ature. Then, a solution of phosgene 15 wt% in toluene (8.5 mL,
bromo-4-iodo-benzo[c][1,2,5]selenadiazole (27). To a solution of 5- 78.527 mmol, 8 equiv.) was added drop-wise to the reaction
bromo-3-iodobenzene-1,2-diamine 24 (3.8 g, 12.218 mmol) in mixture and stirred for 1 h. The reaction mixture was poured
60 mL of dry ethanol, was added SeO2 (1.9 g, 18.3279 mmol, 1.5 into ice-cooled water (200 mL) and immediately a white solid
ꢁ
equiv.) in water. The reaction mixture was stirred at 70 C for was formed. The resulting solid was ltered-off and dried
1 h, then the resulted solid was ltered-off and dried under under vacuum to give 26 (2.7 g, 91%) as an off-white solid. The
vacuum. The yellowish solid was obtained from ltration compound was used without purication for next step. Mp
process was collected to furnish 6-bromo-4-iodobenzo[c][1,2,5] 136–138 ꢁC. Rf ¼ 0.5 (60% EtOAc/hexane). IR (neat, n/cmꢀ1):
selenadiazole 27 (4.4 g, 93%) that was used without further 3376, 3113, 3032, 2919, 2850, 2258, 1687, 1616, 1586, 1485,
purication for next step. Mp 168–170 ꢁC. Rf ¼ 0.8 (40% EtOAc/ 1440, 1376, 1307, 1240, 1178, 1105, 1074, 959, 879, 826, 736,
hexane). IR (neat) n/cmꢀ1: 3295, 3229, 2955, 2915, 2850, 1738, 718, 670. 1H NMR (500 MHz, CDCl3): d 8.42 (s, 1H), 7.51 (d, J ¼
1729, 1571, 1469, 1392, 1245, 1195, 1178, 1048, 991, 940, 850, 1.6 Hz, 1H), 7.07 (d, J ¼ 1.0 Hz, 1H), 3.37 (s, 3H). 13C NMR (126
740, 719. 1H NMR (500 MHz, CDCl3): d 8.11 (d, J ¼ 1.7 Hz, 1H), MHz, CDCl3): d 153.9, 131.7, 131.6, 130.2, 114.8, 110.9, 73.0,
8.03 (d, J ¼ 1.6 Hz, 1H). 13C NMR (126 MHz, CDCl3): d 158.8, 27.5. HRMS (ESI+): m/z calcd for C8H7BrIN2O [M + H]+
157.6, 141.9, 125.7, 125.5, 91.1. HRMS (ESI+): m/z calcd for C6- 352.8786, found 352.8784.
¼
H3BrIN2Se [M + H]+ ¼ 388.7690, found 388.7676.
6-Bromo-4-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-benzo
6-Bromo-4-iodo-1-methylbenzo[c][1,2,5]selenadiazol-1-ium (28). [d]imidazol-2-one (21). To a solution of 6-bromo-4-iodo-1-
A 100 mL two-necked round bottom ask was charged 6-bromo- methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 26 (2.5 g, 7.207
4-iodobenzo[c][1,2,5]selenadiazole 27 (4.3 g, 0.011 mmol, 1 mmol) in 1,4-dioxane (60 mL) and water (5 mL) were added p-
equiv.) and dimethyl sulphate (22.0 mL, 0.2216 mmol, 20 anisyl boronic acid (1.35 g, 8.649 mmol, 1.2 equiv.), potassium
ꢁ
equiv.). The reaction mixture was heated at 130 C for 1 h. To carbonate (2.48 g, 18.019 mmol, 2.5 equiv.) and Pd2(dba)3
the resulted reaction mixture was added diethyl ether at room (0.68 g, 0.7207 mmol, 1 mol%). The reaction mixture was
ꢁ
temperature to get an orange solid. This solid was ltered-off purged with N2 and stirred at 90 C for 6 h. The reaction was
and dried well. The orange solid obtained from ltration quenched by addition of water and extracted with EtOAc (200
process was collected to furnish 6-bromo-4-iodo-1-methylbenzo mL). The organic layers were washed with brine (100 mL),
[c][1,2,5]selenadiazol-1-ium 28 (4.5 g, 97%) as orange solid. Mp: dried with Na2SO4, and concentrated under reduced pressure.
224–226 ꢁC. Rf ¼ 0.8 (40% EtOAc/hexane). IR (neat) n/cmꢀ1
:
The resulted crude was puried by column chromatography
3071, 3002, 2863, 2573, 2230, 1572, 1510, 1478, 1441, 1478, (30% EtOAc/hexane) to afford 6-bromo-4-(4-methoxyphenyl)-1-
1392, 1311, 1284, 1202, 1157, 1013, 845, 749. 1H NMR (500 MHz, methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 21 (1.8 g, 75%)
DMSO-d6): d 8.55 (d, J ¼ 1.6 Hz, 1H), 8.39 (d, J ¼ 1.6 Hz, 1H), 4.46 as white solid. Mp 225–227 ꢁC. Rf ¼ 0.55 (60% EtOAc/hexane).
(s, 3H). 13C NMR (126 MHz, DMSO-d6): d 154.6, 150.2, 141.3, IR (neat, n/cmꢀ1): 3137, 3048, 2953, 2927, 2833, 1703, 1608,
132.5, 119.1, 97.8, 52.7, HRMS (ESI+): m/z calcd for C7H5- 1578, 1517, 1450, 1380, 1339, 1291, 1247, 1178, 962, 823, 767.
BrIN2Se+ [M + H]+ ¼ 402.7841, found 402.7837.
1H NMR (500 MHz, CDCl3): d 8.72 (s, 1H), 7.43 (d, J ¼ 8.7 Hz,
5-Bromo-3-iodo-N1-methylbenzene-1,2-diamine (29). A 50 mL 2H), 7.24 (d, J ¼ 1.8 Hz, 1H), 7.06 (d, J ¼ 1.4 Hz, 1H), 7.02 (d, J ¼
two-necked round bottom ask was charged with 25 mL of 2 M 8.7 Hz, 2H), 3.87 (s, 3H), 3.80 (s, 3H). 13C NMR (126 MHz,
NaOH solution. To this solution was added 6-bromo-4-iodo-1- CDCl3): d 159.9, 155.0, 132.7, 129.2, 128.5, 125.1, 124.2, 114.9,
methylbenzo[c][1,2,5]selenadiazol-1-ium 28 (4.5 g, 11.1940 114.7, 109.5, 55.5, 27.2. HRMS (ESI+): m/z calcd for
mmol) portion wise at room temperature. The reaction mixture
was stirred at 23 ꢁC vigorously for 1 h. The reaction mixture was
extracted with EtOAc (100 mL) and the organic layers were
collected, dried over Na2SO4, concentrated under reduced
pressure. The resulted crude was puried by column chroma-
tography (15% EtOAc/hexane) to afford 5-bromo-3-iodo-N1-
methylbenzene-1,2-diamine 29 (3.2 g, 69%) as red solid. Mp 61–
C
15H14BrN2O2 [M + H]+ ¼ 333.0239, found 333.0218.
Sequence followed in Scheme 8
Route D
Synthesis of 5-bromo-40-methoxy-[1,10-biphenyl]-2,3-diamine (31)
Conditions A. To a 100 mL two-necked round bottom ask was
63 ꢁC. Rf ¼ 0.6 (40% EtOAc/hexane). IR (neat, n/cmꢀ1): 3363, added 5-bromo-40-methoxy-3-nitro-[1,10-biphenyl]-2-amine 23
3346, 3079, 2975, 2931, 2883, 2847, 2794, 2553, 2457, 1578, (0.300 g, 0.9345 mmol, 1 equiv.) and dissolved in 15 mL of dry
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ꢁ
ethanol at 70 C. To the reaction mixture SnCl2$2H2O (1.05 g, ether to get a yellowish solid. This solid was ltrated-off and dried
4.6728 mmol, 5 equiv.) was added portion wise and the reaction in vacuum to furnish 6-bromo-4-(4-methoxyphenyl)-1-methylbenzo
mixture was stirred at 70 ꢁC for 5 h. Then the reaction mixture [c][1,2,5]selenadiazol-1-ium 33 (1.8 g, 98%) that was used without
ꢁ
was poured into 50 mL of ice-cold water and extracted with further purication for next step. Mp 208–210 C. Rf ¼ 0.8 (40%
EtOAc (100 mL) followed by washing with brine (20 mL). The EtOAc/hexane). IR (neat) n/cmꢀ1: 3059, 2941, 2841, 2540, 1605,
resulted organic layers were dried over Na2SO4 and concen- 1585, 1492, 1443, 1375, 1287, 1246, 1143, 1045, 1020, 995, 840, 827,
trated under reduced pressure. The resulted crude was puried 762. 1H NMR (500 MHz, DMSO-d6): d 8.31 (d, J ¼ 1.4 Hz, 1H), 7.95
by column chromatography (30% EtOAc/hexane) to afford 5- (d, J ¼ 1.4 Hz, 1H), 7.89 (d, J ¼ 8.7 Hz, 1H), 7.15 (d, J ¼ 8.7 Hz, 1H),
bromo-40-methoxy-[1,10-biphenyl]-2,3-diamine 31 (0.160 g, 50%) 4.52 (s, 3H), 3.85 (s, 3H). 13C NMR (126 MHz, DMSO-d6): d 160.5,
as orange solid.
153.5, 151.8, 136.9, 133.3, 131.7, 130.1, 126.4, 117.1, 114.2, 55.4,
38.6. HRMS (ESI+): m/z calcd for C13H10BrN2OSe [M]+ ¼ 382.9298,
found 382.9296.
Conditions B. 5-Bromo-40-methoxy-3-nitro-[1,10-biphenyl]-2-
amine 23 (3.2 g, 9.9688 mmol, 1 equiv.) was charged in
a 500 mL two-necked round-bottom ask and was dissolved in
MeOH (100 mL). To the reaction mixture was added NaBH4
(3.8 g, 99.688 mmol, 10 equiv.) portion-wise within 5 minutes at
0 ꢁC followed by NiCl2$6H20 (0.720 g, 2.9906 mmol, 0.3 equiv.).
5-Bromo-40-methoxy-N3-methyl-[1,10-biphenyl]-2,3-diamine (34).
A
250 mL two-necked round bottom ask was charged with
50 mL of 2 M NaOH solution. To this solution was added 6-
bromo-4-(4-methoxyphenyl)-1-methylbenzo[c][1,2,5]
selenadiazol-1-ium 33 (1.7 g, 4.691ꢁmmol) portion wise. The
reaction mixture was stirred at 23 C vigorously for 1 h. The
reaction mixture was extracted with EtOAc (100 mL) and the
organic layers were collected, dried over Na2SO4 and concen-
trated under reduced pressure. The resulted crude was puri-
ed by column chromatography (15% EtOAc/hexane) to afford
5-bromo-40-methoxy-N3-methyl-[1,10-biphenyl]-2,3-diamine 34
(0.9 g, 63%) as red solid. Mp 120–122 ꢁC. Rf ¼ 0.4 (20% EtOAc/
hexane). IR (neat, n/cmꢀ1): 3384, 3310, 3039, 2098, 2934, 2854,
2834, 1608, 1596, 1565, 1513, 1501, 1460, 1472, 1288, 1241,
ꢁ
The reaction mixture was stirred at 23 C for 1 h. The reaction
mixture was poured into ice-cold water and the resulting
mixture was extracted with EtOAc (200 mL) and water (200 mL).
The organic layers were dried over Na2SO4 and concentrated
under reduced pressure. The crude such obtained was puried
by column chromatography (30% EtOAc/hexane) to furnish 5-
bromo-40-methoxy-[1,10-biphenyl]-2,3-diamine 31 (1.78 g, 54%)
as yellowish solid. Mp 137–139 ꢁC. Rf ¼ 0.3 (40% EtOAc/hexane).
IR (neat, n/cmꢀ1): 3407, 3394, 3310, 3224, 3054, 3009, 2961,
2922, 2840, 1607, 1557, 1510, 1463, 1241, 1174, 1024, 830, 778,
699. 1H NMR (500 MHz, CDCl3): d 7.32 (d, J ¼ 8.7 Hz, 1H), 6.98
(d, J ¼ 8.7 Hz, 1H), 6.83 (d, J ¼ 2.1 Hz, 1H), 6.82 (d, J ¼ 2.1 Hz,
1H), 3.85 (s, 3H), 3.45 (s, 2H). 13C NMR (126 MHz, CDCl3):
d 159.3, 136.3, 131.7, 130.7, 130.6, 130.3, 124.1, 118.1, 114.5,
111.4, 55.5. HRMS (ESI+): m/z calcd for C13H14BrN2O [M + H]+ ¼
293.0290 found 293.0286.
1
1176, 1025, 821, 776, 709. H NMR (500 MHz, CDCl3): d 7.33–
7.28 (m, 1H), 7.00–6.96 (m, 1H), 6.80 (d, J ¼ 1.5 Hz, 1H), 6.74
(d, J ¼ 2.1 Hz, 1H), 3.86 (d, J ¼ 7.4 Hz, 2H), 3.41 (bs, 3H), 2.84
(s, 3H). 13C NMR (126 MHz, CDCl3): d 159.2, 140.4, 130.9,
130.7, 130.4, 130.1, 122.4, 114.5, 112.7, 112.7, 55.5, 31.2.
HRMS (ESI+): m/z calcd for C14H16BrN2O [M]+ ¼ 307.0446,
found 307.0455. The regioselectivity of this methylation reac-
tion was conrmed by NOESY experiments (see spectra le).
6-Bromo-4-(4-methoxyphenyl)-1-methyl-1,3-dihydro-2H-benzo
[d]imidazol-2-one (21). In a 250 mL two-neck round-bottom
6-Bromo-4-(4-methoxyphenyl)benzo[c][1,2,5]selenadiazole (32).
To
a
solution of 5-bromo-40-methoxy-[1,10-biphenyl]-2,3-
diamine 31 (1.75 g, 5.9931 mmol) in 10 mL of dry ethanol,
was added SeO2 (0.98 g, 8.9897 mmol, 1.5 equiv.) in water. The
reaction mixture was stirred at 70 C for 1 h, and the resulted
ask,
was
added
5-bromo-40-methoxy-N3-methyl-[1,10-
ꢁ
biphenyl]-2,3-diamine 34 (0.9 g, 2.931 mmol, 1.0 equiv.) and
dissolved in 20 mL of DCE at room temperature. Then,
a solution of phosgene 15 wt% in toluene (3.2 mL, 29.31 mmol,
10 equiv.) was added drop wise to the reaction mixture and
stirred for 1 h. The reaction mixture was poured into ice-
cooled water (300 mL) and extracted with EtOAc (100 mL).
The organic layers were dried over Na2SO4 and concentrated
under reduced pressure. The crude was puried by column
chromatography (30% EtOAc/hexane) to afford 6-bromo-4-(4-
methoxyphenyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-
one 21 (0.82 g, 86%) as a pale white solid. Mp 225–227 ꢁC. Rf ¼
0.55 (60% EtOAc/hexane). IR (neat, n/cmꢀ1): 3137, 3048, 2953,
2927, 2833, 1703, 1608, 1578, 1517, 1450, 1380, 1339, 1291,
1247, 1178, 962, 823, 767. 1H NMR (500 MHz, CDCl3): d 8.72 (s,
1H), 7.43 (d, J ¼ 8.7 Hz, 2H), 7.24 (d, J ¼ 1.8 Hz, 1H), 7.06 (d, J ¼
1.4 Hz, 1H), 7.02 (d, J ¼ 8.7 Hz, 2H), 3.87 (s, 3H), 3.80 (s, 3H).
13C NMR (126 MHz, CDCl3): d 159.9, 155.0, 132.7, 129.2, 128.5,
125.1, 124.2, 114.9, 114.7, 109.5, 55.5, 27.2. HRMS (ESI+): m/z
calcd for C15H14BrN2O2 [M + H]+ ¼ 333.0239, found 333.0218.
solid was ltered-off and dried under vacuum. The yellowish
solid was obtained from ltration process and collected to
furnish 6-bromo-4-(4-methoxyphenyl)benzo[c][1,2,5]selenadia-
zole 32 (1.7 g, 75%) which was used without further purication
for next step. Mp 188–190 ꢁC. Rf ¼ 0.8 (40% EtOAc/hexane). IR
(neat) n/cmꢀ1: 3072, 2986, 2955, 2930, 2907, 2832, 1877, 1718,
1665, 1606, 1585, 1501, 1463, 1316, 1289, 1235, 1185, 1060,
1
1035, 952, 884, 829, 797, 763, 745. H NMR (500 MHz, CDCl3):
d 8.01 (d, J ¼ 1.8 Hz, 1H), 7.79 (d, J ¼ 8.8 Hz, 2H), 7.57 (d, J ¼
1.8 Hz, 1H), 7.05 (d, J ¼ 8.8 Hz, 2H), 3.89 (s, 3H). 13C NMR (126
MHz, CDCl3): d 161.2, 160.2, 158.0, 136.1, 130.81, 130.6, 128.9,
125.9, 123.7, 114.0, 55.4. HRMS (ESI+): m/z calcd for C13H10
BrN2OSe [M + H]+ ¼ 368.9142, found 368.9147.
-
6-Bromo-4-(4-methoxyphenyl)-1-methylbenzo[c][1,2,5]selenadiazol-
1-ium (33). A 100 mL two-necked round bottom ask was charged
with 6-bromo-4-(4-methoxyphenyl)benzo[c][1,2,5]selenadiazole 32
(1.62 g, 4.4277 mmol) and dimethyl sulphate (5.0 mL,
44.2779 mmol, 10 equiv.). The reaction mixture was heated at
130 ꢁC for 1 h. To the resulted reaction mixture was added diethyl
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mL). The DCM was evaporated under reduced pressure and the
crude of reaction such obtained was puried by column chro-
matography (28% EtOAc/hexane) to afford the angular
compound 37 (22 mg, 18.5%) as a yellow solid and the linear
isomer 38 (19 mg, 16%) as a yellow solid.
7,8-Dimethoxy-3-(methoxymethyl)-4-(4-methoxyphenyl)-1-
methyl-1H-naphtho[1,2-d]imidazole-2,6,9(3H)-trione (37). Mp
145–147 ꢁC. Rf ¼ 0.5 (28% EtOAc/hexane). IR (neat, n/cmꢀ1):
2922, 2852, 1720, 1664, 1623, 1611, 1514, 1455, 1379, 1342,
1284, 1242, 1242, 1081, 1047, 1028, 964, 811, 756, 698. 1H NMR
(500 MHz, CDCl3) d 7.75 (s, 1H), 7.30 (d, J ¼ 8.6 Hz, 2H), 6.98 (d, J
¼ 8.6 Hz, 2H), 4.84 (s, 2H), 4.12 (s, 3H), 4.09 (s, 3H), 3.87 (s, 3H),
3.72 (s, 3H), 3.03 (s, 3H). 13C NMR (126 MHz, CDCl3): d 181.4,
181.0, 160.1, 156.9, 148.3, 146.3, 132.3, 131.3, 130.5, 129.3,
128.8, 125.5, 125.1, 114.5, 113.8, 72.5, 61.5, 61.4, 56.2, 55.5, 34.3.
HRMS (ESI+): m/z calcd for C23H23N2O7 [M + H]+ ¼ 439.1505,
found 439.1487.
6,7-Dimethoxy-3-(methoxymethyl)-4-(4-methoxyphenyl)-1-
methyl-1H-naphtho[2,3-d]imidazole-2,5,8(3H)-trione (38). Mp
191–193 ꢁC. Rf ¼ 0.5 (60% EtOAc/hexane). IR (neat, n/cmꢀ1):
2939, 2836, 1707, 1664, 1654, 1611, 1600, 1514, 1469, 1454,
1382, 1340, 1282, 1241, 1178, 1123, 1080, 1045, 1027, 958, 908,
828, 812, 755. 1H NMR (500 MHz, CDCl3): d 7.77 (s, 1H), 7.15 (d,
J ¼ 8.6 Hz, 2H), 6.98 (d, J ¼ 8.6 Hz, 2H), 4.46 (s, 2H), 4.05 (s, 3H),
3.96 (s, 3H), 3.88 (s, 3H), 3.53 (s, 3H), 3.02 (s, 3H). 13C NMR (126
MHz, CDCl3): d 182.0, 181.6, 159.5, 155.4, 148.3, 145.4, 134.2,
131.4, 130.0, 128.2, 127.4, 126.0, 124.1, 113.8, 105.4, 72.0, 61.4,
61.4, 55.9, 55.4, 27.8. HRMS (ESI+): m/z calcd for C23H23N2O7 [M
+ H]+ ¼ 439.1505, found 439.1501.
Sequence followed in Scheme 9
6-Bromo-3-(methoxymethyl)-4-(4-methoxyphenyl)-1-methyl-
1,3-dihydro-2H-benzo[d]imidazol-2-one (35). A dried 100 mL
two-necked round bottom was charged with 6-bromo-4-(4-
methoxyphenyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-
one 21 (1.76 g, 5.3162 mmol) and 50 mL dry dimethylacetamide.
To the reaction mixture was added Cs2CO3 (8.6 g, 26.581 mmol,
5.0 equiv.), followed by addition of MOM-Cl (2.0 mL,
26.581 mmol, 5.0 equiv.) dropwise at room temperature and
ꢁ
stirred at 50 C for 12 h. The reaction mixture was quenched
with H2O and extracted with EtOAc (200 mL). The organic layers
were collected and dried over Na2SO4, concentrated under
reduced pressure. The resulted crude was puried by column
chromatography (27% EtOAc/hexane) to afford the MOM-
protected compound 35 (1.44 g, 72%) as pale white solid. Mp
144–146 ꢁC. Rf ¼ 0.5 (50% EtOAc/hexane). IR (neat, n/cmꢀ1):
3056, 2996, 2938, 2855, 1700, 1604, 1515, 1449, 1372, 1289,
1
1246, 1172, 1087, 1066, 1021, 955, 910, 826, 753, 696. H NMR
(500 MHz, CDCl3): d 7.30 (d, J ¼ 8.6 Hz, 1H), 7.09 (d, J ¼ 1.8 Hz,
1H), 7.05 (d, J ¼ 1.8 Hz, 1H), 6.95 (d, J ¼ 8.6 Hz, 1H), 4.80 (s, 1H),
3.85 (s, 2H), 3.42 (s, 2H), 3.03 (s, 2H). 13C NMR (126 MHz,
CDCl3): d 159.7, 155.2, 132.2, 130.7, 129.2, 127.3, 127.1, 125.1,
114.3, 113.6, 109.7, 72.2, 55.9, 55.5, 27.5. HRMS (ESI+): m/z calcd
for C17H18BrN2O3 [M + H]+ ¼ 377.0501, found 377.0496.
Metal–halogen exchange and 1,2 addition of compound (36).
A ame-dried 250 mL two-neck round-bottom ask was charged
with MOM-protected benzimidazolone 35 (0.33 g, 0.8776 mmol)
dissolved in dry THF (30 mL) and stirred at ꢀ78 ꢁC (acetone/dry
ice bath). Aerwards it was added 1.6 M solution of n-BuLi in
hexane (1.4 mL, 2.1941 mmol, 2.5 equiv.) drop wise. The clear
solution was stirred at ꢀ78 ꢁC temperature for additional 15
Removal of MOM-group from kealiiquinone analogous
minutes, then
a solution of dimethylsquarate (0.1 g,
7,8-Dimethoxy-4-(4-methoxyphenyl)-1-methyl-1H-naphtho
[1,2-d]imidazole-2,6,9(3H)-trione (39). To a 25 mL of two-necked
round bottom ask was charged with 7,8-dimethoxy-3-
(methoxymethyl)-4-(4-methoxyphenyl)-1-methyl-1H-naphtho
[1,2-d]imidazole-2,6,9(3H)-trione 37 (9 mg, 0.0205 mmol) and
was dissolved in triuoroacetic acid (3 mL). The reaction
mixture was stirred at 60 ꢁC for 20 h and it was neutralized with
20 mL of sat. NaHCO3 solution followed by extracted with EtOAc
(30 mL). The organic layer was dried over Na2SO4, concentrated
under reduced pressure. The crude was puried by crystalliza-
tion method (EtOAc/hexane 1 : 2) to afford angular isomer of
kealiiquinone 39 (6 mg, 82%) as light red solid. Mp > 300 ꢁC. Rf
¼ 0.4 (50% EtOAc/hexane). IR (neat, n/cmꢀ1): 3159, 2953, 2921,
2851, 1708, 1665, 1646, 1623, 1515, 1460, 1377, 1330, 1249,
0.7021 mmol, 0.6 equiv.) in dry THF (3 mL) was added drop-wise
to the reaction mixture, and the stirring was continued at
ꢀ78 ꢁC for 30 minutes. The reaction was quenched by addition
of saturated NH4Cl solution (10 mL) and stirred for 10 minutes
allowing to reach room temperature. The layers were separated,
and the aqueous layer was extracted with EtOAc (100 mL). The
combined organic layers were dried over Na2SO4 and concen-
trated under reduced pressure to give crude material. The
resulted crude was puried by column chromatography (75%
EtOAc/hexane) to furnish the intermediate 36 (0.15 g, 61%) as
white sponge like solid. Mp 60–62 ꢁC. Rf ¼ 0.3 (75% EtOAc/
hexane). IR (neat, n/cmꢀ1): 3308, 2932, 2838, 1771, 1687, 1611,
1514, 1459, 1338, 1242, 1175, 1087, 1053, 1056, 982, 833, 758,
690. 1H NMR (500 MHz, CDCl3): d 7.32 (d, J ¼ 8.6 Hz, 2H), 7.22
(d, J ¼ 1.7 Hz, 1H), 7.01 (d, J ¼ 1.7 Hz, 1H), 6.96 (d, J ¼ 8.7 Hz,
2H), 4.82 (s, 2H), 4.10 (s, 3H), 4.02 (s, 3H), 3.86 (s, 3H), 3.46 (s,
3H), 3.39 (s, 1H), 3.03 (s, 3H). HRMS (ESI+): m/z calcd for
1
1195, 1104, 1059, 1031, 962, 908, 829, 735. H NMR (500 MHz,
CDCl3): d 8.16 (s, 1H), 7.93 (s, 1H), 7.46 (d, J ¼ 8.6 Hz, 2H), 7.06
(d, J ¼ 8.6 Hz, 2H), 4.13 (s, 3H), 4.10 (s, 3H), 3.89 (s, 3H), 3.75 (s,
3H). HRMS (ESI): m/z calcd for C21H19N2O6 [M + H]+ ¼ 395.1243,
found 395.1238.
C
23H25N2O7 [M + H]+ ¼ 441.1662, found 441.1658.
Thermolysis of 36. A ame dried 20 mL glass vial was charged
with the intermediate 36 (0.14 g). Without the addition of
solvent, the vial was placed in a preheated oil bath for 1 hour in
which temperature was previously adjusted and xed at 160 ꢁC.
Aer this period, the vial was removed from the hot bath
allowed to reach room temperature and dissolved in DCM (20
Kealiiquinone
6,7-Dimethoxy-4-(4-methoxyphenyl)-1-methyl-1H-naphtho
[2,3-d]imidazole-2,5,8(3H)-trione (1). To a 25 mL two-necked
round bottom ask was charged with 7,8-dimethoxy-3-
(methoxymethyl)-4-(4-methoxyphenyl)-1-methyl-1H-naphtho
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[1,2-d]imidazole-2,6,9-(3H)-trione 37 (9 mg, 0.0205 mmol) and
was dissolved in triuoroacetic acid (3 mL). The reaction
mixture was stirred at 60 ꢁC for 12 h and it was neutralized with
20 mL of sat. NaHCO3 solution followed by extracted with EtOAc
(30 mL). The organic layer was dried over Na2SO4, concentrated
under reduced pressure. The crude was puried by crystalliza-
isokealiiquinone (methylation at the position 3)
S. Nakamura, N. Tsuno, M. Yamashita, I. Kawasaki, S. Ohta
and Y. Ohishi, J. Chem. Soc., Perkin Trans. 1, 2001, 429–436.
9 V. Ramados, A. J. Alonso-Castro, N. Xolalpa and C. R. Solorio-
Alvarado, J. Org. Chem., 2018, DOI: 10.1021/acs.joc.8b01436,
ASAP.
tion method (EtOAc/hexane 1 : 2) to afford kealiiquinone 1 10 (a) For excellent revision on DoM reactions see: V. Sniekus,
(6.5 mg, 87%) as red solid. Mp 291–293 ꢁC. Rf ¼ 0.4 (50% EtOAc/
hexane). IR (neat, n/cmꢀ1): 3183, 2954, 2921, 2852, 1712, 1665,
1648, 1625, 1611, 1516, 1460, 1333, 1288, 1253, 1198, 1186,
Chem. Rev., 1990, 90, 879–933; (b) For use of the MOM
group in DoM reactions see: M. R. Winkle and
R. C. Ronald, J. Org. Chem., 1982, 47, 2102–2108; (c) For
the sequence DoM/iodination see: C. A. Townsend and
L. M. Bloom, Tetrahedron Lett., 1981, 22, 3923–3924.
1
1107, 1060, 1031, 961, 830, 747, 724, 670. H NMR (400 MHz,
DMSO-d6) d 11.02 (s, 1H), 7.68 (s, 1H), 7.12 (d, J ¼ 8.0 Hz, 2H),
6.97 (d, J ¼ 7.9 Hz, 2H), 3.93 (s, 3H), 3.85 (s, 3H), 3.82 (s, 3H), 11 J. Shao, J. Chang and C. Chi, Org. Biomol. Chem., 2012, 10,
3.39 (s, 3H). 13C NMR (101 MHz, DMSO-d6) d 181.3, 181.2, 158.6,
154.8, 147.8, 145.2, 134.0, 132.6, 129.9, 127.7, 126.5, 123.5, 12 (a) L. S. Liebeskind, R. W. Fengl, K. R. Wirtz and T. T. Shawe,
7045–7052.
122.8, 113.9, 104.6, 60.8, 60.8, 55.1, 26.8. HRMS (ESI+): m/z calcd
for C21H19N2O6 [M + H]+ ¼ 395.1243, found 395.1242. The
spectroscopic data match for those reported by Ohta5 and
Lovely.6
J. Org. Chem., 1988, 53, 2482–2488; (b) B. M. Trost, O. R. Thiel
and H.-C. Tsui, J. Am. Chem. Soc., 2003, 125, 13155–13164; (c)
M. Mohamed, T. P. Goncalves, R. J. Whitby, H. F. Sneddon
and D. C. Harrowen, Chem.–Eur. J., 2011, 17, 13698–13705;
(d) B. Yucel, B. Sanil, H. Akbulut, S. Ozbey and
A. B. Benniston, Org. Biomol. Chem., 2012, 10, 1775–1784;
(e) L. S. Liebeskind, S. Iyer and C. F. Jewell Jr, J. Org.
Chem., 1986, 51, 3065–3067; (f) S. T. Perri and
H. W. Moore, J. Am. Chem. Soc., 1990, 112, 1897–1905; (g)
A. Enhsen, K. Karabelas, J. M. Heerding and H. W. Moore,
J. Org. Chem., 1990, 55, 1177–1185; (h) H. W. Moore and
S. T. Perri, J. Org. Chem., 1988, 53, 996–1003; (i) S. T. Perri
and H. W. Moore, Tetrahedron Lett., 1987, 28, 4507–4510.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
We are grateful to CONACyT (CB-2013/220836) for nancial
support. We acknowledge the facilities of the DCNyE, the
Chemistry Department, and the National Laboratory UG- 13 X. Zhang and X. Zheng and L. S. Chupack, Aryl substituted
CONACyT (LACAPFEM) of the University of Guanajuato for
full characterization. We also thank to CONACyT for fellowships
to V. Ramadoss.
bicyclic heteroaryl compounds, WO 2017019828, February
2, 2017.
14 R. Salmasi, M. Gholizadeh, A. Salimi and J. Garrison, J. Iran.
Chem. Soc., 2016, 13, 2019–2028.
15 (a) E. Lindstedt, E. Stridfeldt and B. Oloffson, Org. Lett.,
2016, 18, 4234–4237; (b) D. Liu, L. P. Sanow and C. Zhang,
Tetrahedron Lett., 2014, 55, 3090–3092; (c) T. F. Woiwode,
C. Rose and T. J. Wandless, J. Org. Chem., 1998, 63, 9594–
9596.
Notes and references
1 N. M. Shady, E. M. El-Hossary, M. A. Fouad, T. A. M. Gulder,
M. S. Kamel and U. R. Abdelmohsen, Molecules, 2017, 22,
781.
2 A. R. Carrol, B. F. Bowden and J. C. Coll, Aust. J. Chem., 1993, 16 The NiCl2-NaBH4 system has been used for different organic
46, 1229–1234.
transformations: (a) For selective carbonyl reduction in
presence of acetyl group see: N. Hassanloie, B. Zeynizadeh,
S. Ashuri and F. Hassanloie, Open Cancer Immunol. J.,
2014, 59–62; (b) For desulfurization reactions see:
T. G. Back, D. L. Baron and K. Yang, J. Org. Chem., 1992,
58, 2407–2413.
3 R. A. Lamb, N. S. Aberle, N. T. Lucas, G. Lessen and
B. C. Hawkins, Angew. Chem., Int. Ed., 2017, 56, 14663–14666.
4 R. K. Akee, T. R. Carrol, W. Y. Yoshida, P. J. Scheuer,
T. J. Stout and J. Clardy, J. Org. Chem., 1990, 55, 1944–1946.
5 I. Kawasaki, N. Taguchi, T. Yamamoto, M. Yamashita and
S. Ohta, Tetrahedron Lett., 1995, 36, 8251–8254.
6 J. Das, A. Bhan, S. S. Mandal and C. J. Lovely, Bioorg. Med.
Chem. Lett., 2013, 23, 6183–6187.
17 Is well known the poor basic- or acid-resistance of the acetyl
group, however when is bonded to nitrogen its liability
decreases substantially.
7 P. B. Koswatta, S. Kasiri, J. K. Das, A. Bhan, H. M. Lima, 18 (a) E. V. D. Brge and R. Robiette, J. Org. Chem., 2013, 78,
´
B. Garcıa-Barboza, N. N. Khatibi, M. Yousufuddin,
12220–12223;
(b)
R.
Soundararajan
and
S. S. Mandal and C. J. Lovely, Bioorg. Med. Chem. Lett.,
2017, 25, 1608–1621.
T. R. Balasubramanian, Tetrahedron Lett., 1984, 25, 5555–
5558; (c) Y. Ono, Y. Izawa and Z.-I. Fu, J. Chem. Soc., Chem.
Commun., 1995, 9; (d) E. Boredon, B. Chabaud, A. Gaset,
S. Thiebaud-Roux and S. Ouk, Monomethylation of
Nitrogenous Heterocycles, US 2004/0024205 A1, February 5,
2004.
8 (a) H. M. Lima, R. Sivappa, M. Yousufuddin and C. J. Lovely,
Org. Lett., 2012, 14, 2274–2277; (b) H. M. Lima, R. Sivappa,
M. Yousufuddin and C. J. Lovely, J. Org. Chem., 2014, 79,
2481–2490; (c) J. Das, R. Mukherjee and A. Basak, J. Org.
Chem., 2014, 79, 3789–3798; (d) For the synthesis of
This journal is © The Royal Society of Chemistry 2018
RSC Adv., 2018, 8, 30761–30776 | 30775

View Article Online
RSC Advances
Paper
19 M. Bella and V. Milata, J. Heterocycl. Chem., 2008, 45, 425–
G. Cerioni, R. Janoshchek, Z. Rappaport and T. T. Tidwell,
427.
J. Org. Chem., 1996, 61, 6212–6217.
20 (a) A. D. Allen, J. D. Colomvakos, I. Egle, J. Lusztyk, 21 J. Shao, J. Chang and C. Chi, Org. Biomol. Chem., 2012, 10,
M. A. McAllister, T. T. Tidwell, B. D. Wagner and 7045–7052.
D.-C. Zhao, J. Am. Chem. Soc., 1995, 117, 7552–7553; (b) 22 L. S. Liebeskind, R. W. Fengl, K. R. Wirtz and T. T. Shawe, J.
Org. Chem., 1988, 53, 2482–2488.
30776 | RSC Adv., 2018, 8, 30761–30776
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