Protecting-Group-Free Total Synthesis and Biological Evaluation of 3-Methylkealiiquinone and Structural Analogues

Article abstract of DOI:10.1021/acs.joc.8b01436

The modular protecting-group-free total synthesis of 3-methylkealiiquinone, an analogue of the marine alkaloid kealiiquinone, was accomplished in seven steps. A regioselectively constructed functionalized arylbenzimidazolone moiety and dimethyl squarate were used as the only two building blocks. A thermal ring expansion via 6π-conrotatory ring closure to build the quinone fragment gave rise to the desired linear analogue of the natural compound along with a nondescribed structurally attractive angular naphtho[1,2-d]imidazole regioisomer. The IC₅₀ values for the compounds were determined on three cancer cell lines.

Full text of DOI:10.1021/acs.joc.8b01436

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Note
Protecting-Group-Free Total Synthesis and Biological
Evaluation of 3-Methylkealiiquinone and Structural Analogues
Velayudham Ramadoss, Angel Josabad Alonso-Castro,
Nimsi Campos-Xolalpa, and César R. Solorio-Alvarado
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01436 • Publication Date (Web): 09 Aug 2018
Downloaded from http://pubs.acs.org on August 10, 2018
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The Journal of Organic Chemistry
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Protecting-Group-Free Total Synthesis and Biological Evaluation of
3-Methylkealiiquinone and Structural Analogues
Velayudham Ramadoss†, Angel Josabad Alonso-Castro‡, Nimsi Campos-Xolalpa,¶ and César R.
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Solorio-Alvarado*†
† Universidad de Guanajuato, Departamento de Química, División de Ciencias Naturales y Exactas, Campus Guanajuato.
Cerro de la Venada S/N, 36040, Guanajuato, Gto. México.
‡ Universidad de Guanajuato, Departamento de Farmacia, División de Ciencias Naturales y Exactas, Campus Guanajuato.
Noria Alta S/N, 36050, Guanajuato, Gto. México.
¶ Universidad Autónoma Metropolitana, Unidad Xochimilco, Calzada del Hueso 1100, Coyoacan 04960, México, D.F.
Supporting Information Placeholder
OMe
O
O
MeO
O
O
Me
Me
Me
1) n-BuLi, -78 ºC
MeO
MeO
N
Br
N
N
O
√
√
√
√
Protecting-group-free
7 steps
MeO
O
O
O
N
2)
3)
N
N
+
Me
Me
Me
8 analogues synthesized
two building blocks
(gram and multigram scales
MeO
O
)
160 ºC
OMe
OMe
OMe
linear
angular
3-methylkealiiquinone
3-methylkealiiquinone
ABSTRACT: The modular protecting-group-free total synthesis of 3-methylkealiiquinone, an analogue of the marine alkaloid
kealiiquinone, was accomplished in seven steps. A regioselectively-constructed functionalized arylbenzimidazolone moiety and
dimethyl squarate were used as the only two building blocks. A thermal ring expansion via 6p-conrotatory ring closure to build the
quinone fragment gave rise to the desired linear analogue of the natural compound along with a non-described structurally attractive
angular naphtho[1,2-d]imidazole regioisomer. The IC50 values for the compounds were determined on three cancer cell lines.
Naturally occurring compounds1 represent an excellent plat-
form in the initial search for efficient and active anticarcino-
gens. These secondary metabolites isolated from marine
sources have been a major contributor to the development of
new drugs.2 Recently, some imidazole alkaloids have been
isolated from the Micronesian marine sponges of the genera
Leucetta and Clathrina.3 Kealiiquinone 1 (Figure 1) is the
most complex naphtho[2,3-d]imidazole derivative obtained
therefrom, and showed modest cytotoxicity against MCF7
cancer cells.4
To date only two approaches5 toward the fully functionalized
kealiiquinone core, which eventually concluded in its total
synthesis, have been reported (Scheme 1).
Ohta5a-b described the total synthesis of kealiiquinone by us-
ing an intramolecular Friedel-Carfts alkylation/oxidation se-
quence as key step, to form the naphtho[2,3-d]imidazole core.
Even tough this route showed in general good yields, the syn-
thesis is based upon the imidazole chemistry; this strongly
limits the orthogonality in different stages of the process. In
consequence the use of at least two protecting groups was
necessary. This implied several organic redox fluctuations,
which were reflected in the fifteen total synthetic steps.
O
Me
MeO
N
O
On the other hand the total synthesis of the 7´-
desmethylkealiiquinone was recently reported by Lovely.5c-d In
the route a [4+2] cycloaddition/ oxidation sequence was used
to build the central rings of the natural product. For this syn-
thetic protocol, moderate to good yields are observed in gen-
eral. However the procedure also uses the imidazole core as
base, to construct the natural product. Additionally, it was
necessary the use of at least one protecting group which finally
impact on the thirteen steps to complete the route.
N
MeO
3
R
O
OMe
Kealiiquinone (1, R= -H)
3-methylkealiiquinone (2, R= -Me)
Figure 1. Structures of kealiiquinone and 3-methylkealiiquinone.
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Scheme 1. Approaches for the synthesis of the kealiiqui-
none core.
Scheme 3. Multigram scale synthesis of the benzimidazo-
lone 8 and the building blocks 3 and 9.
1
2
3
4
5
6
7
8
Otha (15 steps)5a-b
OCOMe
Me
Br
NO2
Br
NH2
MeOCO
OMe
Br
NO2
NH2
Me
MeO
MeO
SnCl2·2H2O
NIS
N
MeO
N
SPh
SPh
N
1
NH2
EtOH
70 ºC, 3 h
AcOH
80 ºC, 2 h
NH2
N
MeO
Br
I
I
+
regioselective
methylation.
Big challeng
4
6 (94%)
20 g scale
5 (86%)
20 g scale
OHC
OMe
step 1
step 2
step 3
OMe
Cl
Lovely (13 steps) 5c-d
O
O
Me
Me
DCE
rt, 1 h
CHO
CHO
O
MeO
MeO
N
N
O
N
H
O
Bn
N
Cl
N
N
O
Me
RO
RO
O
O
9
H
N
Br
Br
N
MeI, KOH
MeO
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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31
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
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57
58
59
60
7´O
OMe
DMSO
rt, 0.7 h
N
Me
N
H
H
7´-desmethylkealiiquinone
3 (R= Me, 43%)7
9 (R= iPr, 60%)8
I
I
This work (7 steps)
8 (96%)
12 g scale
O
7 (92%)
16.4 g scale
Me
Me
step 4
MeO
O
MeO
MeO
Br
N
N
symmetrically
methylated
O
O
+
3 N
Me
N
MeO
O
Me
O
The dimethylbenzimidazolone 8, bearing bromo and iodo
groups at appropriate positions for further orthogonal Suzuki
cross-coupling, was constructed regioselectively. Thus, its
preparation started with the iodination of 49 in acidic media to
obtain 510 in a good yield (86%). Then, the reduction of the
nitro group gave rise to 6 in an excellent 94% yield. The reac-
tion with phosgene subsequently afforded the benzimidazo-
lone core, providing 7 in 92% yield. The final methylation
furnished the chemo differentiated benzimidazolone 8. This
four-step and high yielding sequence was performed on a
multigram scale without the use of any chromatography for
purification. On the other side of the convergent synthetic
process, the isopropyl and methyl squarates 98 and 3,7 were
synthesized according literature procedures, also on gram
scales. The starting material 8 was used for the synthesis of the
fully functionalized arylbenzimidazolone core 10 via orthogo-
nal Suzuki cross-coupling. We also took the opportunity to
prepare two further analogues, 11 and 12, in a modular fashion
and on gram scales by using different arylboronic acids. In this
reaction we also observed few amounts of the bis-coupled
product (scheme 4).11
OMe
3-methylkealiiquinone
OMe
Inspired by the molecular architecture and preliminary bio-
logical activity of 1,4 it was decided to apply our protecting-
group-free synthetic approach for the symmetrized 3-
methylkealiiquinone analogue,6 which is outlined in Scheme 2.
Scheme 2. Retrosynthesis of 3-methylkealiiquinone (2).
metal-halogen
quinone
exchange and
formation
1,2-addition
methylation
Me
benzimidazolone
formation
O
Me
Me
MeO
O
O
MeO
MeO
Br
N
N
N
Br
N
+
O
O
O
N
N
MeO
B(OH)2
Me
O
Me
3
Me
methylation
I
Regioselective
Suzuki
8
OMe
cross-coupling
OMe
3-methylkealiiquinone (2)
OMe
10
Br
NH2
NH2
Cl
+
O
Cl
I
6
This convergent protecting-group-free strategy involves the
synthesis of two main building blocks, the dimethyl squarate 3
and the arylbenzimidazolone 10. From 3 the 1,4-quinoid ring
was constructed trough a thermal ring expansion via 6p-
conrotatory ring closure. Prior to this transformation, 3 partic-
ipates as electrophile in the 1,2-addition of the anion formed
Scheme 4. Synthesis of arybenzimidazolones 10-12.
Me
B(OH)2
Br
N
Pd(PPh3)4 (8 mol %)
O
8
+
N
Me
from
10 by metal-halogen exchange.
The
3-
K2CO3, 90 ºC, 8 h
dioxane/H2O (5:1)
R
methylkealiiquinone arylbenzimidazolone fragment 10 was
envisioned as the remaining building block. This compound
was synthesized by two-step sequence, the first step consisting
step 5
R
Me
Me
Me
Br
Br
Br
of
a
regioselective Suzuki cross-coupling between 4-
N
N
N
O
O
O
anisylboronic acid and the benzimidazolone 8, the second step
was the N-bismethylation. Finally, compound 8 is formed by
the reaction of phosgene with the corresponding 3,5-
dihalogenated o-phenylenediamine 6.
N
N
N
Me
Me
Me
11 (72%)
12 (80%)
10 (79%)
2 g scale
2.5 scale
5 g scale
OMe
Cl
This convergent, modular and straightforward strategy uses
the central ring of the natural compound as key building block,
allowing an excellent scalability of the arylbenzimidazolone
moiety, since this does not depend on the imidazole chemistry
used in the last two reports.5 Thus, this approach inserts the
appropriate functional groups at initial stages of the synthesis,
avoiding redox-fluctuations such as add-remove-add groups as
employed in the routes of Ohta5a-b and Lovely.5c-d
Our synthesis started with preparation of the two main build-
ing blocks 10 and 3. In such a way, the synthesis of the dime-
thylbenzimidazolone 8 was necessary to prepare 10 (Scheme
3).
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Once the building blocks 10 and 3 were obtained, the fifth
Scheme 6. Synthesis of the fully functionalized kealiiqui-
none core model systems 17-22.
1
2
3
4
5
6
7
step of the synthetic proposal was completed. Thus, everything
was ready to complete the synthesis of 2 by metal-halogen
exchange and 1,2-addition to the squarate esters. However, it
has been described that dimethyl squarate 3 is sensitive and
prone to hydrolysis.12 Thus, prior to attempting the proposed
route it was decided to test a model system by using the more
stable diisopropyl squarate 9 (Scheme 5).
Me
Br
N
O
O
O
O
1) n-BuLi (1.2 equiv)
-78 ºC, 0.75 h
Me
N
Me
N
2) 9 (0.6 equiv)
O
OH
N
Me
THF
3) NH4Cl
R
13 (R= OMe, 41%)
15 (R= Cl, 41%)
16 (R= H, 43%)
10 - 12
(500 mg)
R
160 ºC, 1 h
neat or 1,4-dioxane
8
9
Scheme 5. Model system for the 1,2-addition of the aryl-
benzimidazolone 10 to squarate 9.
From 16
From 13
From 15
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
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
1) n-BuLi (1.2 equiv)
-78 ºC, 0.75 h
Me
Me
Me
Me
Me
in
NMR
tube
N
N
O
N
N
N
N
O
O
2) 9 (0.6 equiv)
O
O
OH
O
N
Me
N
Me
H
H
H
H
H
H
10
(100 mg)
N
Me
N
Me
NOE
NOE
NOE
Me
THF
3) NH4Cl
13 (33%)
14 (99%)
angular
OMe
Cl
H
17 (18%)a
19 (20%)a
OMe
OMe
18 (21%)a
+
+
+
NOE
NOE
Me
NOE
Me
H
H
H
O
O
O
O
O
O
Me
Metal-halogen (M-H) exchange on a hundred-milligram
scale of 10 by using 1.2 equiv of n-butyllithium, followed by
the addition of 0.6 equiv of diisopropyl squarate 9, gave 13 in
33% yield. After a number of assays, the optimal reaction
stoichiometry was determined to be that mentioned above. The
fast isolation and characterization allowed us to identify this
tertiary alcohol. However, within a short period of time (less
than 2 hours) the sample in the NMR tube exhibited carbonyl
regeneration via acidic solvolysis promoted by the deuterated
solvent (CDCl3). Thereby, 14 was obtained in almost quantita-
tive yield. The same transformation was observed for the rest
of the synthesized sample of 13 once in slightly acidic solu-
tion.
O
O
O
O
O
N
N
N
O
O
O
N
Me
N
Me
N
Me
O
linear
OMe
Cl
21 (20%)a
H
20 (24%)a
22 (21%)a
ayields of two steps
(6π-conrotatory ring closure-oxidation)
accepted
intermediates
O
O
OH
O
Me
N
Me
N
O
O
HO
O
O
or
N
Me
N
Me
Ar= Ph,
4-Cl-Ph or
4-OMe-Ph
O
Ar
AI-2
Ar
AI-1
for lineal isomers
20 to 22
for angular isomers
17 to 19
The previously optimized conditions for the M-H ex-
change/1,2-addition sequence were used for generating the
lithiated arylbenzimidazolones form 10-12 which were subse-
quently reacted with the diisopropyl squarate 9. In this way, on
500-milligram scales of each arylbenzimidazolone, the corre-
sponding tertiary alcohols 13, 15 and 16 were obtained in
modest yields (41% to 43%). As previously mentioned, their
rapid isolation prevented decomposition and allowed full
characterization of these compounds, followed immediately by
heating to 160 ºC. Depending on whether or not the compound
melted at this temperature, this heating step was carried out
either neat or in dioxane. After one hour of reaction, a perfect-
ly separable mixture of two compounds essentially in a 1:1
ratio was observed. These products were detected for each of
the three thermolysis reactions. To our delight, both of the
observed compounds are the products of a thermal ring expan-
sion, which proceed via 6p-conrotatory ring closure. From this
transformation it was possible to directly access to the 1,4-
quinoid ring without the need for an additional oxidation reac-
tion. One set of products corresponds to the desired kealiiqui-
none model system with all of the fused rings organized in
linear fashion (20-22). The second group of products showed a
novel naphtho[1,2-d]imidazole architecture (17-19), which for
simplicity we refer to them as angular isomers. This modular
route allowed the synthesis of electron-donating (17 and 20),
electron-withdrawing (18 and 21) as well as electron-neutral
(19 and 22) model systems at the pendant phenyl ring of the
molecule, also isopropoxy groups at the 1,4-quinoid ring. The
known chemistry of squaric acid can be inferred to explain the
formation of these two regioisomers. In agreement with the
This short study provided several important pieces of infor-
mation about our synthetic route: 1) the M-H exchange and
1,2-addition over squarate 9 was possible, but an acid-
sensitive tertiary alcohol was obtained, 2) we found no 1,2-
addition with the benzimidazolone carbonyl, 3) as compared
with literature,7 here, much milder acidic conditions gave rise
to the solvolysis of the tertiary alcohol and concomitant car-
bonyl regeneration, and 4) as soon as prepared, the 1,2-
addition products should be immediately subjected to ther-
molysis in order to obtain the 1,4-quinoid ring.8, 13
Considering all the aforementioned learned aspects, it was
decided to complete our route to obtain model systems of the
fully functionalized kealiiquinone core (Scheme 6).
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previously described mechanism for this chemistry,8,13 the
cell lines of cervix (HeLa), lung (A549) and colon (SW620) as
accepted formation of a ketene intermediate14 such as AI-1
explains the formation of the linear regioisomers (20-22),
while the accepted formation of a ketene intermediate14 such
as AI-2 explains the formation of the angular regioisomers
(17-19). Both regioisomers were unequivocally assigned by
NOESY experimentation (see SI).
well as non-carcinogenic human keratinocytes cell line (Ha-
CaT) were examined and compared versus cis-platin (CDDP)
as control of activity (Table 1).
1
2
3
4
5
6
Table 1. Determination of IC50 values for the synthesized
compounds in different cancer cell lines.
It is important to mention here that after the thermolysis of
13, 15 and 16 a hydroquinone was formed8,13 that spontane-
ously oxidized to the corresponding quinoid form. This is a
two-step one-pot reaction, in consequence the final yields for
17-22 are the result of these two steps and are higher overall.
Thereby, the yields are ca. 45% to 49% for each single step
calculated in a linear manner. Moreover, the synthesis was
carried out in a protecting-group-free manner.
7
8
9
Comp.
2
Helaa
> 100
A549a
> 100
SW620a
> 100
Ha-Cata
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
> 100
2.6 ± 0.3
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
24
> 100
> 100
> 100
20
76.9 ± 8.2
> 100
57.2± 5.6
> 100
57.3 ± 6.9
> 100
17
21
> 100
> 100
> 100
18
> 100
> 100
> 100
Based on the understanding gained from our model systems,
the protecting group-free total synthesis of 3-
methylkealiiquinone (2) was then attempted (Scheme 7).
22
76.5 ± 7.6
> 100
64.3 ±4.3
> 100
61.3 ± 3.7
> 100
19
10
57.4 ± 3.8
76.3 ± 4.9
> 100
63.7 ±5.2
76.1 ±6.2
> 100
68 ± 7.1
> 100
11
Scheme 7. Protecting-group-free total synthesis of the 3-
methylkeliiquinone (2) and its angular analogue (24).
12
> 100
CDDP
1.6 ± 0.1
2.4 ± 0.1
2.7 ± 0.2
Me
1) n-BuLi, -78 ºC, 0.6 h
MeO
MeO
O
a The IC50 values are in µM units.
Br
N
Me
MeO
O
O
N
2)
N
OH
O
Me
N
MeO
O
3
The electron-rich analogue of naturally occurring kealiiqui-
none 20 as well as its electronic-neutral congener 22 showed
modest cytotoxicity in the three cancer cell lines but low cyto-
toxicity in the non-carcinogenic HaCaT. Surprisingly, very
similar biological activity was observed for the benzimidazo-
lones 10 and 11, which no contain the 1,4-quinone moiety.
Several others computational studies surrounding these results
are currently been carrying out in our group to describe a
functional group pattern of activity.
Me
THF
23 (54%)
OMe
3) NH4Cl
OMe
160 ºC neat
10
step 6
step 7
OMe
O
O
O
MeO
Me
Me
MeO
MeO
N
N
O
O
O
N
+
N
Me
Me
In summary, a modular, original and straightforward route to
the total synthesis of the 3-methylkealiiquinone 2 was devel-
oped, which is a closely related analogue of the natural com-
pound 1. The synthetic strategy was carried out in a protect-
ing-group-free manner and in seven steps, allowing the prepa-
ration of the fully functionalized kealiiquinone core. The syn-
thesis of eight structurally-analogous derivatives was also
achieved. Additionally, the described procedure allowed the
discovery of a novel naphtho[1,2-d]imidazole architecture.
Finally, it is worth mentioning the short synthetic route (seven
steps), the use of only two building blocks (10 and 3) for the
full synthesis, their multigram scalability, the avoidance of
protecting groups and redox fluctuation, and the non-
dependent imidazole chemistry of the process. These features
represent significant improvements over the last two described
syntheses. While the compounds displayed only modest cyto-
toxic activity, the modular developed route described herein
opens the possibility to synthesize a range of derivatives that
could potentially increase the observed biological activity.
OMe
OMe
2 (18%)
24 (13%)
linear
angular
3-methylkealiiquinone
3-methylkealiiquinone
The arylbenzimidazolone 10 was subjected to M-H ex-
change using 1.2 equiv of n-butyllithium. The generated anion
was reacted with 0.6 equiv of dimethyl squarate 3 yielding the
alcohol 23 in 54% yield. This represents the sixth step in the
overall route. Thereafter, neat thermolysis at 160 ºC for one
hour, gratifyingly afforded the desired 3-methylkealiiquinone
2 (18%) in a separable mixture with its angular isomer 24
(13%).15 We were unable to achieve significant improvement
of the yield even after several attempts at optimization.16 This
final reaction marks the seventh and final step of our synthe-
sis, none of which involved the use of protecting groups.
This was a consisting result that gave the expected linear and
angular compounds according to the model systems observa-
tions in Scheme 6. Additionally, although the final yield ap-
pears to be low, it should be reiterated that this is the result of
two steps, both of which are protecting-group-free. This means
that it was possible to obtain good amounts of the methylated
natural compound kealiiquinone 2, as well as its novel angular
isomer 24, after just a single column purification.
EXPERIMENTAL SECTION
General Information. All moisture and oxygen sensitive
reactions were carried out in flame-dried round bottom flasks
under an inert atmosphere of nitrogen. Unless otherwise speci-
fied, all commercial materials were used as received without
further purification. Anhydrous solvents were purchased from
Sigma Aldrich in SureSeal® bottles. Column chromatography
Finally to complete this work, the biological assays of activi-
ty by testing the synthesized compounds in three cancer cell
lines and one non-carcinogenic line were carried out. Thereby
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was performed using silica gel of size 100-200 and 230-400 (200 mL) and dried under vacuo. The aqueous portion was
1
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3
4
5
6
7
8
mesh (Sigma Aldrich). Thin layer chromatography was per-
formed with TLC Silica gel 60 F256 plates, and visualization
was effected with short wavelength UV light (254 nm). Com-
pounds were characterized using 1H-NMR, 13C-NMR. (Copies
neutralized with saturated NaHCO3 (200 mL) solution, fol-
lowed by extraction with EtOAc (3 x 50 mL). The combined
organic fractions were washed with brine (100 mL), dried with
Na2SO4, and concentrated under reduced pressure to afford
additional amount of such solid. The orange solid obtained
from filtration and extraction process was collected to furnish
5 (22 g, 86%) that was used without further purification for
next step. m.p. = 135-137 °C. Rf = 0.5 (20% EtOAc/Hexane).
IR (neat) ν/cm-1 = 3572, 3453, 3101, 1541, 1435, 1346, 1241,
1
of H-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
1
given. H 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 shift, multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet), coupling constant (Hz), and inte-
gration. Chemical shifts of the 13C NMR spectra were meas-
ured relative to CDCl3 (δ = 77.16 ppm). All the starting mate-
rials were synthesized according to reported procedures in the
literature. High-resolution masses (HRMS) analysis were
obtained under the following procedure: samples were intro-
duced by direct infusion at 3 µl min-1 to the electrospray ioni-
zation source of a quadrupole time-of-flight mass spectrometer
(Bruker Daltonics ESI-QTOF-MS maXis impact), equipped
with Data Analysis 4.1. ESI was operated in positive mode
with ion spray voltage 4 500 V, nitrogen dry gas 4 L min-1,
drying temperature 180 ºC and gas pressure 0.4 Bar. Mass
calibration was accomplished based based on sodium formate
clusters. 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 appa-
ratus.
1
9
1070, 872, 671. H NMR (500 MHz, CDCl3): δ 8.31 (d, J =
2.3 Hz, 1H), 8.01 (d, J = 2.3 Hz, 1H), 6.67 (bs, 2H). 13C NMR
(126 MHz, CDCl3): δ 147.5, 143.3, 131.9, 129.4, 108.1, 88.0.
HRMS (EI): m/z calculated for C6H4BrIN2O2 [M]+= 341.8501,
found 341.8504.
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5-bromo-3-iodobenzene-1,2-diamine (6):17 4-bromo-2-iodo-6-
nitroaniline 5 (20 g, 58.65 mmol, 1 equiv) was charged in a
500 mL two-necked round-bottom flask, dissolved in EtOH
(300 mL) and heated to 70 °C. To the resulting solution was
added SnCl2·2H2O (66 g, 307.91 mmol, 5 equiv) portion wise
within 5 minutes and continued to be stirred at 70 °C for 3
hours. The reaction mixture was poured into ice-cold water.
The resulting solid was filtered-off and dried in vacuo to give
5-bromo-3-iodobenzene-1,2-diamine 6 (18.1 g, 94%) as an
off-white solid which was used without further purification.
m.p. = 136-138 °C. Rf = 0.4 (40% EtOAc/Hexane). IR (neat)
ν/cm-1 = 3493, 3396, 3064, 1640, 1567, 1458, 1080, 765, 705.
1H NMR (500 MHz, CDCl3): δ 7.30 (d, J = 2.1 Hz, 1H), 6.80
(d, J = 2.1 Hz, 1H), 3.63 (bs, 4H). 13C NMR (126 MHz,
CDCl3): δ 135.3, 135.1, 131.1, 119.1, 111.9, 86.2. HRMS
(ESI): m/z calculated for C6H7BrIN2 [M+H]+= 312.8863,
found 312.8837.
Sequence followed in Scheme 3. 4-bromo-2-nitroaniline (4):9
The synthesis of compound 4 was reported in literature. How-
ever, we synthesized the compound based on our developed
procedure. To a 500 mL round-bottom flask charged with 2-
nitroaniline (20 g, 144.9 mmol) in 1,4-dioxane (100 mL) was
added NBS (25.6 g, 144.9 mmol, 1.0 equiv) portion wise over
5 minutes. The solution was stirred at room temperature for 1
hour. The reaction mixture was poured into H2O (200 mL) and
extracted with EtOAc (4 x 100 mL). The combined organic
layers were washed with saturated solution of Na2CO3 (500
mL) followed by brine (100 mL) and dried over Na2SO4, con-
centrated under reduced pressure to afford the regioselective
mono brominated compound 4 (28 g, 90%) as light brownish
solid. m.p.=100-102 °C. Rf = 0.35 (20% EtOAc/Hexane). IR
(neat) ν/cm-1 = 3470, 3345, 2916, 2850, 1730, 1622, 1557,
1496, 1336, 1242, 1097, 813. 1H NMR (500 MHz, CDCl3): δ
8.26 (d, J = 2.3 Hz, 1H), 7.42 (dd, J = 8.9, 2.3 Hz, 1H), 6.73
(d, J = 8.9 Hz, 1H), 6.10 (bs, 2H). 13C NMR (126 MHz,
CDCl3): δ 143.7, 138.6, 132.5, 127.9, 120.4, 107.9. HRMS
(ESI): m/z calculated for C6H6BrN2O2 [M+H]+ = 216.9613,
found 216.9632.
4-bromo-2-iodo-6-nitroaniline (5): Synthesis of compound 510
was reported in literature. However, we synthesized the com-
pound 5 based on our developed procedure. To a 500 mL two-
necked round-bottom flask, was charged with a solution of 4-
bromo-2-nitroaniline 4 (20 g, 92.16 mmol, 1 equiv) in glacial
AcOH (120 mL) and heated to 80 °C. N-iodosuccinimide (40
g, 184.16 mmol, 2 equiv) was added portion wise and stirred
for 2 hours. The reaction mixture was poured into ice-cooled
water (300 mL) and immediately an orange color solid was
formed. The resulted solid was filtered-off, washed with DCM
6-bromo-4-iodo-1,3-dihydro-2H-benzo[d]imidazol-2-one (7):
In a 500 mL two-neck round-bottom flask, was added 5-
bromo-3-iodobenzene-1,2-diamine 6 (16.4 g, 52.73 mmol, 1.0
equiv) and dissolved in 200 mL of DCE at room temperature.
Then, a solution of phosgene 15 wt. % in toluene (40 mL,
319.13 mmol, 7 equiv) was added drop wise to the reaction
mixture and stirred for 1 hour. The reaction mixture was
poured into ice-cooled water (300 mL) and immediately a
white solid was formed. The resulting solid was filtered-off
and dried under vacuum to give 7 (92%, 16.3 g) as an off-
white solid. The compound was used without purification for
next step. m.p. = 212-214 °C. Rf = 0.4 (60% EtOAc/Hexane).
IR (neat) ν/cm-1 = 3064, 2944, 1703, 1605, 1572, 1481, 1444,
1
1247, 1023, 954, 825. H NMR (500 MHz, DMSO-d6): δ
11.06 (s, 1H), 10.99 (s, 1H), 7.42 (d, J = 1.7 Hz, 1H), 7.05 (d,
J = 1.7 Hz, 1H). 13C NMR (126 MHz, DMSO-d6): δ 155.0,
132.9, 131.0, 130.7, 113.3, 111.3, 73.9. HRMS (ESI): m/z
calculated for C7H5BrIN2O [M+H]+= 338.8661, found
338.8630.
6-bromo-4-iodo-1,3-dimethyl-1,3-dihydro-2H-
benzo[d]imidazol-2-one (8):A dried 500 mL two-neck flask
was charged with dry DMSO (180 mL), powdered KOH (14 g,
249.25 mmol, 7 equiv) and was stirred for 30 minutes at room
temperature. 6-bromo-4-iodo-1,3-dihydro-2H-benzo[d]imida-
zol-2-one 7 (12 g, 35.60 mmol, 1 equiv) was added in portions
to the reaction mixture followed by the drop wise addition of
MeI (22 mL, 356.08 mmol, 10 equiv) over a period of 5
minutes. The mixture was stirred at room temperature for 1
hour and quenched by the addition of H2O (200 mL). A white
solid was formed. This resulted solid was filtered-off, washed
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The Journal of Organic Chemistry
Page 6 of 10
with water (100 mL) and dried under vacuo. The aqueous phenyl boronic acid. The crude material was purified by flash
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3
4
5
6
7
8
portion was extracted with EtOAc (4 x 25 mL). The combined
organic layers were washed with brine (100 mL), dried over
Na2SO4 and finally concentrated under reduced pressure to
obtain additional amount of such solid. The withe solid ob-
tained from extraction and filtration stages were collected to
furnish 8 (12.5 g, 96%), which was used for next step without
purification. m.p.=163-165 °C. Rf = 0.6 (40% EtOAc/Hexane).
IR (neat) ν/cm-1 = 3066, 2940, 1699, 1572, 1481, 1444, 1384,
1247, 1097, 1023, 825, 735, 692. 1H NMR (500 MHz, CDCl3):
δ 7.58 (d, J = 1.5 Hz, 1H), 7.03 (d, J = 1.5 Hz, 1H), 3.71 (s,
3H), 3.36 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 154.8,
134.4, 132.3, 129.9, 114.6, 110.5, 70.6, 30.0, 27.4. HRMS
(ESI): m/z calculated for C9H9BrIN2O [M+H]+= 366.8943,
found 366.8933.
column chromatography over silica gel with the system (25%
EtOAc/Hexane) to afford the cross-coupled product 10 (3.7 g,
79%) as white solid and the bis-coupled product 10a (600 mg,
12%) as an off-white solid. m.p.=154-156 °C. Rf = 0.55 (40%
EtOAc/Hexane). IR (neat) ν/cm-1 = 3071, 2945, 1696,1607,
1
1481, 1450, 1388, 1241, 1176,1122, 1025, 832, 741, 692. H
NMR (500 MHz, CDCl3): δ 7.27 (d, J = 8.6 Hz, 2H), 7.09 (d,
J = 1.9 Hz, 1H), 7.08 (d, J = 1.9 Hz, 1H), 6.96 (d, J = 8.6 Hz,
2H), 3.87 (s, 3H)(OMe), 3.42 (s, 3H) (NMe1), 2.97 (s, 3H)
(NMe3). 13C NMR (126 MHz, CDCl3): δ 159.6, 155.1, 131.8,
130.9, 129.2, 126.6, 126.5, 126.1, 113.5, 113.2, 109.4, 55.4
(OMe), 30.4 (NMe1), 27.4 (NMe3). HRMS (ESI): m/z calcu-
lated for C16H16BrN2O2 [M+H]+= 347.0395, found 347.0396.
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Data for bis-coupled product. 4,6-bis(4-methoxyphenyl)-1,3-
3,4-dimethoxycyclobut-3-ene-1,2-dione (3):6 In a 500 mL two-
neck round bottom flask connected to a Dean-Stark reflux
condenser, was added squaric acid (2.5 g, 21.93 mmol, 1
equiv) and dissolved in MeOH (50 mL) at 70 °C. To the reac-
tion mixture was added trimethyl orthoformate (5.4 mL, 46.05
mmol, 2.1 equiv) and refluxed for 48 h. The reaction mixture
was evaporated under reduced pressure. The crude of reaction
was washed with EtOAc (2x50 mL) and extracted with H2O (2
x 100 mL). The collected organic fractions were dried with
Na2SO4, filtered, and concentered under reduced pressure. The
resulting crude was purified by column chromatography (30%
EtOAc/Hexane) to provide the compound 3 (1.35 g, 43%) as
white solid. The spectroscopic data match with those previous-
ly described. m.p. = 38-40 °C. Rf = 0.35 (40% EtOAc/Hexane).
IR (neat) ν/cm-1 = 2988, 1806, 1736, 1724, 1582, 1417, 1339,
dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one
(10a):
m.p.=134-136 °C. Rf = 0.5 (40% EtOAc/Hexane). IR (neat)
ν/cm-1 = 3030, 2894, 1728, 1604,1465, 1246, 1144, 937, 804,
1
636. H NMR (500 MHz, CDCl3): δ 7.54 (d, J = 8.8 Hz, 2H),
7.34 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 1.7 Hz, 1H), 7.12 (d, J =
1.7 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H),
3.88 (s, 3H), 3.85 (s, 3H), 3.50 (s, 3H), 3.03 (s, 3H). 13C NMR
(126 MHz, CDCl3): δ 159.4, 159.1, 155.6, 134.2, 133.8, 131.3,
131.1, 130.6, 128.2, 126.5, 124.9, 123.1, 114.4, 113.5, 104.7,
55.53, 55.50, 30.5, 27.5. HRMS (ESI): m/z calculated for
C23H23N2O3 [M+H] + = 375.1709, found 375.1716.
6-bromo-4-(4-chlorophenyl)-1,3-dimethyl-1,3-dihydro-2H-
benzo[d]imidazol-2-one (11): The following reaction (2.0 g
scale of 8) was carried out according to above mentioned
general procedure for Suzuki-Miyaura cross-coupling reaction
using 4-chlorophenyl boronic acid. The crude material was
purified by flash column chromatography over silica gel with
the system (15% EtOAc/Hexane) to afford cross-coupled
product 11 (1.83 g, 72%) as yellowish solid and bis-coupled
product 11a (220 mg, 10%) as white solid. m.p.=170-172 °C.
Rf = 0.5 (30% EtOAc/Hexane). IR (neat) ν/cm-1 = 2999, 2912,
1
1072, 1011, 900,782. H NMR (500 MHz, CDCl3): δ 4.37 (s,
6H). 13C NMR (126 MHz, CDCl3): δ 189.2, 184.6, 61.1.
3,4-diisopropoxycyclobut-3-ene-1,2-dione (9):7a To a solution
of squaric acid (5.0 g, 43.86 mmol, 1 equiv) in isopropanol
(100 mL) was added H2SO4 (3 mL) and stirred at 80 °C for 48
hours. The reaction mixture was cooled and evaporated under
reduced pressure. The crude was washed with EtOAc (100
mL) and extracted with 200 mL water. The combined organic
fractions were evaporated, and the crude was purified by col-
umn chromatography (20% EtOAc/Hexane) to afford the 3,4-
diisopropoxycyclobut-3-ene-1,2-dione 9 (5.2 g, 60%) as white
solid. m.p. = 39-41 °C. Rf = 0.6 (40% EtOAc/Hexane). IR
(neat) ν/cm-1 = 2965, 2393, 1870, 1811, 1720, 1582, 1479,
1
1797, 1617, 1433, 1256, 1073, 735. H NMR (500 MHz,
CDCl3): δ 7.41 (d, J = 7.7 Hz, 2H), 7.29 (d, J = 7.7 Hz, 2H),
7.11 (s, 1H), 7.05 (s, 1H), 3.42 (s, 3H), 2.96 (s, 3H). 13C NMR
(126 MHz, CDCl3): δ 155.1, 135.5, 134.6, 132.0, 131.1, 128.5,
126.4, 126.3, 124.9, 113.4, 109.9, 30.6, 27.5. HRMS (ESI):
m/z calculated for C15H13BrClN2O [M+H]+ = 350.9900, found
350.9917.
1
1413, 1352, 1034, 922, 829. H NMR (500 MHz, CDCl3): δ
Data for bis-coupled product. 4,6-bis(4-chlorophenyl)-1,3-
dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (11a): m.p.
= 132-134 °C. Rf = 0.45 (30% EtOAc/Hexane). IR (neat) ν/cm-
5.34 (hept, J = 6.2 Hz, 2H), 1.45 (d, J = 6.2 Hz, 12 H). 13C
NMR (126 MHz, CDCl3): δ 189.3, 184.1, 78.9, 22.8.
1
Reactions in Scheme 4. General Procedure for Suzuki-
Miyaura cross-coupling reaction. To a solution of 6-bromo-
4-iodo-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one
8 (1.0 equiv) in 1,4-dioxane (50 mL) and water (3 mL) were
added boronic acid (2.0 equiv), potassium carbonate (2.5
equiv) and Pd(PPh3)4 (8 mol%). The reaction mixture was
purged with N2 and stirred at 90 °C for 8 hours. The reaction
was quenched by addition of water and extracted with EtOAc.
The organic layers were washed with brine (100 mL), dried
with Na2SO4, and concentrated under reduced pressure. After
column chromatography purification it was obtained the corre-
sponding arylbenzimidazolones 10-12.
= 2954, 1714, 1682, 1611, 1591, 1453, 1338, 1248, 1084,
1013, 790, 753, 727. HRMS (ESI): m/z calculated for
C21H17Cl2N2O [M+H]+= 383.0718, found 383.0736.
6-bromo-1,3-dimethyl-4-phenyl-1,3-dihydro-2H-
benzo[d]imidazol-2-one (12): The following reaction (2.5 g
scale of 8) was carried out according to above mentioned
general procedure for Suzuki-Miyaura cross-coupling reaction
using phenyl boronic acid. The crude material was purified by
flash column chromatography over silica gel with the system
(15% EtOAc/Hexane) to afford cross-coupled product 12
(1.68 g, 81%) as an off-white solid and the bis-coupled prod-
uct 12a (280 mg, 13%) as white solid. m.p.= 124-126 °C. Rf =
0.5 (40% EtOAc/Hexane). IR (neat) ν/cm-1 = 3055, 2917,
1737, 1599, 1469, 1107, 1061, 827, 569. 1H NMR (500 MHz,
CDCl3) δ 7.45 – 7.40 (m, 3H), 7.35 (dd, J = 6.6, 2.9 Hz, 2H),
7.10 (d, J = 3.2 Hz, 2H), 3.43 (s, 3H), 2.94 (s, 3H). 13C NMR
6-bromo-4-(4-methoxyphenyl)-1,3-dimethyl-1,3-dihydro-2H-
benzo[d]imidazol-2-one (10): The following reaction (5 g
scale of 8) was carried out based upon the general procedure
for Suzuki-Miyaura cross coupling reaction using 4-methoxy
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The Journal of Organic Chemistry
(126 MHz, CDCl3) δ 155.2, 137.1, 131.9, 129.9, 129.6, 128.3,
30.6, 27.7, 23.2. HRMS (ESI): m/z calculated for C23H23N2O5
[M+H]+= 407.1607, found 407.1605.
1
2
3
4
5
6
7
8
128.2, 126.5, 126.4, 113.3, 109.6, 30.5, 27.5. HRMS (ESI):
m/z calculated for C15H14BrN2O [M+H]+= 317.0290, found
317.0301.
Sequence in Scheme 6: 1) Metal-Halogen exchange/1,2-
addition. General procedure for metal-halogen exchange
reaction and 1,2-addition: A flame-dried 250 mL two-neck
round-bottom flask was charged with benzimidazolones 10-12
(500 mg, 1 equiv) dissolved in dry THF (30 mL) and stirred at
-78 °C (acetone/dry ice bath). Afterwards it was added 1.6 M
solution of n-BuLi in hexane (1.2 equiv) drop wise. The clear
solution was stirred at that temperature for additional 15
minutes, then a solution of isopropyl squarate 9 (0.6 equiv) in
dry THF (1 mL) was added dropwise to the reaction mixture,
and the stirring was continued at -78 °C for 30 minutes. The
reaction was quenched by addition of saturated NH4Cl solu-
tion (10 mL) and stirred for 10 minutes and allowed to reach
room temperature. The layers were separated, and the aqueous
layer was extracted with EtOAc (3 x 20 mL). The combined
organic layers were dried over Na2SO4 and concentrated under
reduced pressure to give crude material.
Data for bis-coupled product. 1,3-dimethyl-4,6-diphenyl-1,3-
dihydro-2H-benzo[d]imidazol-2-one (12a): m.p.=134-136 °C.
Rf = 0.5 (40% EtOAc/Hexane). IR (neat) ν/cm-1 = 2956, 1697,
1
1622, 1472, 1439, 1389, 1252, 1125, 768, 701, 667. H NMR
(500 MHz, CDCl3): δ 7.62 (d, J = 7.8 Hz, 2H), 7.48 – 7.40 (m,
7H), 7.34 (t, J = 7.4 Hz, 1H), 7.21 (dd, J = 8.3 Hz, 2H), 3.51
(s, 3H), 3.01 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 155.6,
141.1, 138.4, 134.6, 131.4, 130.0, 128.9, 128.1, 128.0, 127.25,
127.20, 126.8, 125.2, 123.3, 105.3, 30.5, 27.5. HRMS (ESI):
m/z calculated for C21H19N2O [M+H]+= 315.1497, found
315.1511.
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10
11
12
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Sequence in Scheme 5. 6-(1-hydroxy-2,3-diisopropoxy-4-
oxocyclobut-2-en-1-yl)-4-(4-methoxyphenyl)-1,3-dimethyl-1,3-
dihydro-2H-benzo[d]imidazol-2-one (13): A flame-dried 100
mL two-neck round-bottom flask was charged with compound
10 (100 mg, 1 equiv) dissolved in dry THF (10 mL) and
stirred at -78 °C (acetone/dry ice bath). Afterwards it was
added 1.6 M solution of n-BuLi in hexane (0.2 mL, 0.0691
mmol, 1.2 equiv) drop wise. The clear solution was stirred at
that temperature for additional 15 minutes, then a solution of
isopropyl squarate 9 (35 mg, 0.1734 mmol, 0.6 equiv) in dry
THF (2 mL) was added dropwise to the reaction mixture, and
the stirring was continued at -78 °C for 30 minutes. The reac-
tion was quenched by addition of saturated NH4Cl solution (10
mL), stirred for 10 minutes and allowed to reach room tem-
perature. The layers were separated, and the aqueous layer was
extracted with EtOAc (3 x 20 mL). The combined organic
layers were dried over Na2SO4 and concentrated under reduced
pressure to give crude material, which was purified by basic
column chromatography (60% EtOAc/Hexane- 1% Et3N) to
yield 13 (45 mg, 33%) as colorless sponge like solid. m.p.=
208-210 °C. Rf = 0.2 (60% EtOAc/Hexane). IR (neat) ν/cm-1 =
3288, 2980, 2800, 1619, 1609, 1420, 1328, 1286, 985, 838,
763, 690. 1H NMR (500 MHz, CDCl3): δ 7.70 (d, J = 1.4 Hz,
1H), 7.61 (d, J = 1.4 Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 6.98
(d, J = 8.6 Hz, 2H), 5.62 (hept, J = 6.2 Hz, 1H), 4.01 (hept, J =
6.2 Hz, 1H), 3.88 (s, 3H), 3.50 (s, 3H), 3.00 (s, 3H), 1.54 (d, J
= 6.2 Hz, 6H), 1.20 (d, J = 6.2 Hz, 6H). 13C NMR (126 MHz,
CDCl3): δ 193.3, 193.2, 191.6, 173.9, 159.8, 155.3, 131.1,
131.05, 131.02, 129.2, 125.2, 124.7, 120.8, 113.7, 105.0, 80.1,
64.5, 55.5, 30.6, 27.7, 25.5, 23.1. HRMS (ESI): m/z calculated
for C26H31N2O6 [M+H]+= 467.2182, found 467.2169.
6-(1-hydroxy-2,3-diisopropoxy-4-oxocyclobut-2-en-1-yl)-4-(4-
methoxyphenyl)-1,3-dimethyl-1,3-dihydro-2H-
benzo[d]imidazol-2-one (13): After basic column chromatog-
raphy (60% EtOAc/Hexane- 1% Et3N), compound 13 (280
mg, 41%) was obtained as colorless sponge like solid.
4-(4-chlorophenyl)-6-(1-hydroxy-2,3-diisopropoxy-4-
oxocyclobut-2-en-1-yl)-1,3-dimethyl-1,3-dihydro-2H-
benzo[d]imidazol-2-one (15): After basic column chromatog-
raphy (60% EtOAc/Hexane- 1% Et3N), compound 15 (280
mg, 41%) was obtained as colorless sponge like solid. m.p.=
100-102 °C. Rf = 0.2 (60% EtOAc/Hexane). IR (neat) ν/cm-1 =
3287, 2978, 2900, 1768, 1682, 1620,1464, 1383, 1313, 1156,
1
1047, 1014, 942, 828, 743. H NMR (500 MHz, CDCl3): δ
7.41 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.22 (d, J =
1.7 Hz, 1H), 7.03 (d, J = 1.7 Hz, 1H), 4.93 (hept, J = 6.1 Hz,
2H), 3.45 (s, 3H), 2.98 (s, 3H), 2.63 (s, 1H), 1.39 (d, J = 6.2
Hz, 3H), 1.37 (d, J = 6.2 Hz, 3H), 1.34 (d, J = 6.2 Hz, 3H),
1.29 (d, J = 6.2 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ
183.6, 178.4, 165.4, 155.5, 136.6, 134.2, 133.7, 131.2, 130.6,
128.3, 127.3, 123.5, 121.4, 104.8, 87.3, 77.7, 74.1, 30.6, 27.6,
22.93, 22.90, 22.7, 22.5. HRMS (ESI): m/z calculated for
C25H28ClN2O5 [M+H]+= 471.1687, found 471.1661.
6-(1-hydroxy-2,3-diisopropoxy-4-oxocyclobut-2-en-1-yl)-1,3-
dimethyl-4-phenyl-1,3-dihydro-2H-benzo[d]imidazol-2-one
(16): The crude 16 (500 mg scale) was purified by basic col-
umn chromatography (60% EtOAc/Hexane–1% Et3N) to yield
pure 16 (300 mg, 43%) of white sponge like solid. m.p.= 180-
182 °C. Rf = 0.2 (60% EtOAc/Hexane). IR (neat) ν/cm-1
=
3-isopropoxy-4-(7-(4-methoxyphenyl)-1,3-dimethyl-2-oxo-2,3-
dihydro-1H-benzo[d]imidazole -5-yl) cyclobut-3-ene-1,2-
dione (14): This compound was formed inside the NMR tube,
after c.a. 2 hours of carried out the NMR experiment acquisi-
tion for compound 13. It was obtained (40 mg, 99%) of a light
yellowish solid corresponding to pure 14 formed due to acidic
conditions of deuterated chloroform. m.p.= 280-230 ºC. Rf=
0.5 (40% EtOAc/Hexane). IR (neat) ν/cm-1 = 3300, 3159,
1865, 1708, 1423, 1344, 1244, 1071, 745. 1H NMR (500 MHz,
CDCl3): δ 7.71 (d, J = 1.5 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H),
7.29 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 5.63 (hept,
d, J = 6.2 Hz, 1H), 3.89 (s, 3H), 3.51 (s, 3H), 3.01 (s, 3H),
1.55 (d, J = 6.2 Hz, 6H). 13C NMR (126 MHz, CDCl3): δ
193.3, 193.2, 191.6, 173.9, 159.8, 155.3, 131.2, 131.08,
131.05, 129.2, 125.2, 124.7, 120.8, 113.7, 105.1, 80.2, 55.5,
3287, 2981, 1766, 1683, 1622, 1469, 1384, 1371, 1311, 1251,
1
1093, 1044, 945, 864, 704. H NMR (500 MHz, CDCl3): δ
7.43-7.41 (m, 3H), 7.37 – 7.34 (m, 2H), 7.23 (d, J = 1.7 Hz,
1H), 7.07 (d, J = 1.7 Hz, 1H), 4.93 (hept, J = 6.2 Hz, 2H), 3.45
(s, 3H), 2.96 (s, 3H), 2.74 (s, 1H), 1.39 (d, J = 6.2 Hz, 3H),
1.37 (d, J = 6.2 Hz, 3H), 1.34 (d, J = 6.2 Hz, 3H), 1.29 (d, J =
6.2 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 183.7, 165.5,
155.5, 138.1, 133.7, 131.0, 130.4, 130.0, 128.1, 128.0, 127.3,
124.9, 121.5, 104.5, 87.4, 77.6, 74.0, 30.5, 27.5, 22.9, 22.9,
22.7, 22.5. HRMS (ESI): m/z calculated for C25H29N2O5
[M+H]+= 437.2076, found 437.2056.
Sequence in Scheme 6: 2) Thermolysis reactions. General
procedure for thermolysis: A 20 mL glass vial was charged
with the tertiary alcohol (13 or 15 or 16). The vial was placed
during 1 hour in a preheated oil bath which temperature was
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previously adjusted and fixed at 160 °C. Depending on wheth- 4-(4-chlorophenyl)-6,7-diisopropoxy-1,3-dimethyl-1H-
Page 8 of 10
1
2
3
4
5
6
7
8
er or not the compound melted at this temperature, this heating
step was carried out either neat or in dioxane (1 mL). After
this period of time the reaction mixture was removed form the
oil bath allowing to reaching room temperature and dissolve in
DCM (20 mL). The DCM was evaporated under reduced
pressure and the crude of reaction such obtained was purified
by column chromatography (20% EtOAc/Hexane) to afford
the two regioisomer as linear (20-22) and angular (17-19)
compounds.
naphtho[2,3-d]imidazole-2,5,8(3H)-trione(21): m.p.= 146-148
°C. Rf= 0.55 (40% EtOAc/Hex). IR (neat) ν/cm-1 = 2971, 2926,
2870, 1720, 1650, 1613, 1484, 1348, 1259, 1179, 1088, 1034,
950, 735. 1H NMR (500 MHz, CDCl3): δ 7.76 (s, 1H), 7.40 (d,
J = 8.2 Hz, 2H), 7.19 (d, J = 8.2 Hz, 2H), 4.86 (hept, J = 6.2
Hz, 1H), 4.82 (hept, J = 6.2 Hz, 1H), 3.51(s, 3H), 2.73 (s, 3H),
1.33 (d, J = 6.2 Hz, 6H), 1.24 (d, J = 6.2 Hz, 6H). 13C NMR
(126 MHz, CDCl3): δ 182.4, 182.3, 155.2, 148.6, 145.7, 134.8,
134.1, 133.6, 132.1, 130.8, 128.5, 127.5, 123.8, 123.5, 105.4,
76.1, 75.9, 30.0, 27.8, 22.8, 22.7. HRMS (ESI): m/z calculated
for C25H26ClN2O5 [M+H]+= 469.1530, found 469.1561.
9
Thermolysis of 13. The tertiary alcohol 13 (280 mg) was sub-
jected to the general procedure for thermolysis. The column
chromatography purification (18% EtOAc /Hexane system)
affords the angular compound 17 (49 mg, 18%) as yellow
solid and the linear compound 20 (68 mg, 24%) as yellowish
solid (20% EtOAc/Hexane system).
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
Thermolysis of 16. The tertiary alcohol 16 (300 mg) was sub-
jected to the general procedure for thermolysis. The column
chromatography purification (18% EtOAc /Hexane system)
affords the angular compound 19 (55 mg, 20%) as yellow
solid and the linear compound 22 (56 mg, 21%) as yellowish
solid (19% EtOAc/Hex system).
7,8-diisopropoxy-4-(4-methoxyphenyl)-1,3-dimethyl-1H-
naphtho[1,2-d]imidazole-2,6,9(3H)-trione (17): m.p.= 192-
194 °C. Rf= 0.55 (40% EtOAc/Hexane). IR (neat) ν/cm-1
=
7,8-diisopropoxy-1,3-dimethyl-4-phenyl-1H-naphtho[1,2-d]-
imidazole-2,6,9(3H)-trione(19): m.p.= 141-143 °C. Rf = 0.6
(40% EtOAc/Hexane). IR (neat) ν/cm-1 = 2953, 2919, 2838,
1725, 1651, 1593, 1473, 1376, 1288, 1196, 1129, 1101, 1059,
2955, 2924, 2851, 1711, 1655, 1608, 1466, 1379, 1245, 1200,
1129, 1059, 939, 750. 1H NMR (400 MHz, CDCl3): δ 7.76 (s,
1H), 7.25 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 8.5 Hz, 2H), 4.96
(hept, J = 6.3 Hz, 1H), 4.89 (hept, J = 6.3 Hz, 1H), 3.87 (s,
3H), 3.72 (s, 3H), 2.99 (s, 3H), 1.36 (d, J = 6.3 Hz, 6H), 1.34
(d, J = 6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3): δ 182.0,
181.9, 160.0, 156.9, 148.8, 146.8, 133.7, 130.7, 128.9, 128.0,
125.1, 124.5, 114.7, 113.9, 113.8, 76.1 76.0, 55.5, 34.2, 31.3,
22.9, 22.8. HRMS (ESI): m/z calculated for C26H29N2O6
[M+H]+= 465.2026, found 465.2048.
1
944, 708. H NMR (500 MHz, CDCl3): δ 7.78 (s, 1H), 7.45
(bs, 3H), 7.34 (bs, 2H), 4.96 (hept, J = 6.2 Hz, 1H), 4.90 (hept,
J = 6.2 Hz, 1H), 3.73 (s, 3H), 2.96 (s, 3H), 1.37 (d, J = 6.2 Hz,
6H), 1.35 (d, J = 6.2 Hz, 6H). 13C NMR (126 MHz, CDCl3):
181.93, 181.90, 156.9, 148.7, 146.8, 136.9, 133.5, 130.7,
129.6, 128.8, 128.4, 128.1, 125.1, 124.2, 114.8, 76.1, 76.0,
34.2, 31.2, 22.9, 22.8. HRMS (ESI): m/z calculated for
C25H27N2O5 [M+H]+= 435.1920, found 435.1947.
6,7-diisopropoxy-4-(4-methoxyphenyl)-1,3-dimethyl-1H-
naphtho[2,3-d]imidazole-2,5,8(3H)-trione (20): m.p.= 186-
6,7-diisopropoxy-1,3-dimethyl-4-phenyl-1H-naphtho[2,3-d]-
imidazole-2,5,8(3H)-trione(22): m.p.= 154-156 °C. Rf = 0.55
(40% EtOAc/Hexane). IR (neat) ν/cm-1 = 2977, 2934, 2247,
1713, 1652, 1595, 1479, 1444, 1346, 1267, 1178, 1095, 1036,
188 °C. Rf = 0.5 (40% EtOAc/Hexane). IR (neat) ν/cm-1
=
2960, 2924, 2853, 1720, 1611, 1514, 1344, 1245, 1185, 1031,
949, 747. 1H NMR (400 MHz, CDCl3): δ 7.75 (s, 1H), 7.15 (d,
J = 8.6 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 4.89 (hept, J = 6.2
Hz, 1H), 4.82 (hept, J = 6.2 Hz, 1H), 3.88 (s, 3H), 3.52 (s,
3H), 2.74 (s, 3H), 1.34 (d, J = 6.2 Hz, 6H), 1.25 (d, J = 6.1 Hz,
6H). 13C NMR (101 MHz, CDCl3): δ 182.7, 182.4, 159.4,
155.3, 148.7, 145.6, 133.4, 132.5, 130.5, 128.1, 127.5, 124.9,
124.1, 113.6, 105.2, 76.0, 75.7, 55.3, 30.0, 27.7, 22.8, 22.7.
HRMS (ESI): m/z calculated for C26H29N2O6 [M+H]+=
465.2026, found 465.2042.
1
949, 743. H NMR (500 MHz, CDCl3): δ 7.77 (s, 1H), 7.47-
7.40 (m, 3H), 7.28-7.22 (m, 2H), 4.88 (hept, J = 6.2 Hz, 1H),
4.82 (hept, J = 6.2 Hz, 1H), 3.53 (s, 3H), 2.69 (s, 3H), 1.34 (d,
J = 6.2 Hz, 6H), 1.24 (d, J = 6.2 Hz, 6H). 13C NMR (126
MHz, CDCl3): δ 182.6, 182.3, 155.3, 148.6, 145.7, 136.3,
133.5, 132.1, 129.4, 128.1, 128.0, 127.4, 125.0, 123.9, 105.3,
76.0, 75.7, 29.8, 27.8, 22.8, 22.7. HRMS (ESI): m/z calculated
for C25H27N2O5 [M+H]+= 435.1920, found 435.1948.
Thermolysis of 15. The tertiary alcohol 15 (280 mg) was sub-
jected to the general procedure for thermolysis. The column
chromatography purification (17% EtOAc /Hexane system)
affords the angular compound 18 (58 mg, 21%) as yellow
solid and the linear compound 21 (55 mg, 20%) as yellowish
solid (19% EtOAc/Hex system).
Sequence in Scheme 7. 6-(1-hydroxy-2,3-dimethoxy-4-
oxocyclobut-2-en-1-yl)-4-(4-methoxyphenyl)-1,3-dimethyl-1,3-
dihydro-2H-benzo[d]imidazol-2-one (23): A flame-dried 250
mL two-neck round-bottom flask was charged with benzimid-
azolone 10 (500 mg, 1 equiv) dissolved in dry THF (30 mL)
and stirred at -78 °C (acetone/dry ice bath). Afterwards it was
added drop wise a solution of n-BuLi 1.6 M in hexane (1.0
mL, 1.734 mmol, 1.2 equiv). The clear solution was stirred at
that temperature for additional 15 minutes. Then a solution of
methyl squarate 3 (123 mg, 0.867 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 reac-
tion was quenched by addition of saturated NH4Cl solution (20
mL) and stirred for 10 minutes allowing reaching room tem-
perature. The layers were separated, and the aqueous layer was
extracted with EtOAc (3 x 20 mL). The combined organic
layers were dried over Na2SO4 and concentrated under reduced
pressure to give crude material. The crude material was puri-
fied by column chromatography (60% EtOAc/Hexane-1%
Et3N) to yield 23 (200 mg, 54%) as colorless floppy solid.
4-(4-chlorophenyl)-7,8-diisopropoxy-1,3-dimethyl-1H-
naphtho[1,2-d]imidazole-2,6,9(3H)-trione (18): m.p.= 185-
187 °C. Rf = 0.6 (40% EtOAc/Hexane). IR (neat) ν/cm-1
=
2957, 2925, 1714, 1646, 1588, 1470, 1378, 1197, 1127, 1056,
945, 748. 1H NMR (500 MHz, CDCl3): δ 7.74 (s, 1H), 7.45 (d,
J = 8.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 4.96 (hept, J = 6.2
Hz, 1H), 4.90 (hept, J = 6.2 Hz, 1H), 3.74 (s, 3H), 2.99 (s,
3H), 1.37 (d, J = 6.2 Hz, 6H), 1.35 (d, J = 6.2 Hz, 6H). 13C
NMR (126 MHz, CDCl3): δ 181.82, 181.81, 156.8, 148.8,
146.8, 135.3, 135.1, 133.5, 130.9, 130.8, 128.7, 126.6, 125.2,
124.0, 115.0, 76.2, 76.1, 34.3, 31.4, 22.9, 22.8. HRMS (ESI):
m/z calculated for C25H26ClN2O5 [M+H]+= 469.1530, found
469.1567.
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The Journal of Organic Chemistry
m.p.= 220-222 °C. Rf = 0.3 (60% EtOAc/Hexane). IR (neat)
ASSOCIATED CONTENT
ν/cm-1 = 3304, 2950, 1755, 1703,1673,1622, 1514, 1462,
1
2
3
4
5
6
7
8
1
Supporting Information
1329, 1243, 1178, 1124, 1027, 838, 735, 693. H NMR (500
The Supporting Information is available free of charge on the
ACS Publications website.
MHz, CDCl3): δ 7.28 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 1.5 Hz,
1H), 7.03 (d, J = 1.5 Hz, 1H), 6.96 (d, J = 8.6 Hz, 2H), 4.10 (s,
3H), 4.01 (s, 3H), 3.87 (s, 3H), 3.45 (s, 3H), 2.98 (s, 3H), 2.04
(s, 1H). 13C NMR (126 MHz, CDCl3): δ 184.0, 166.1, 159.5,
155.5, 135.6, 131.1, 131.0, 130.2, 130.0, 127.6, 124.7, 121.7,
113.5, 104.3, 87.7, 60.5, 58.9, 55.5, 30.5, 27.6. HRMS (ESI):
m/z calculated for C22H23N2O6 [M+H]+= 411.1556, found
411.1528.
Biological essays of activity for compounds 2, 24, 20,
17, 21, 18, 22, 19, 10, 11, 12 and CDDP as well as
Copies of 1H and 13C for all of compounds
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10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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34
35
36
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47
48
49
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55
56
57
58
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60
AUTHOR INFORMATION
Thermolysis reaction. Procedure for thermolysis of (23): A
20 mL glass vial was charged with the tertiary alcohol 23 (200
mg). Without the addition of solvent, the vial was placed dur-
ing 1 hour in a preheated oil bath which temperature was
previously adjusted and fixed at 160 °C. After this period, the
reaction mixture was removed from the hot bath allowing
reaching room temperature and dissolved in DCM (20 mL).
The DCM was evaporated under reduced pressure and the
crude of reaction such obtained was purified by column chro-
matography (34% EtOAc/Hexane) affording the angular com-
pound 24 (13%, 25 mg) as a yellow solid and the linear 3-
methylkealiiquinone 2 (18%, 33 mg) as a yellow solid. In this
reaction we also identified the compound 25 (35 mg, 18%) as
a yellowish solid, which is the product of the carbonyl regen-
eration via solvolysis.
Corresponding Author
* E-mail: csolorio@ugto.mx
ORCID
César R. Solorio-Alvarado: 0000-0001-6082-988X
Velayudham Ramadoss: 0000-0002-7600-3406
Ángel J. Alonso-Castro: 0000-0003-2660-8156
Nimsi Campos-Xolalpa: 0000-0002-5499-5432
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Linear
3-methylkealiiquinone:
6,7-dimethoxy-4-(4-
We are grateful to CONACyT (CB-2013/220836) for financial
support. We acknowledge the facilities of DCNyE, the Chemistry
Department, and the National Laboratory UG-CONACyT
(LACAPFEM) of the University of Guanajuato for full character-
ization. We thank CONACyT for fellowship to V. Ramadoss.
methoxyphenyl)-1,3-dimethyl-1H-naphtho[2,3-d]imidazole-
2,5,8(3H)-trione (2). m.p.= 201-203 °C. Rf= 0.5 (60%
EtOAc/Hexane). IR (neat) ν/cm-1 = 2919, 2849, 1714, 1655,
1
1621, 1514, 1454, 1347, 1281, 1176, 1028, 909, 832, 776. H
NMR (500 MHz, CDCl3): δ 7.76 (s, 1H), 7.14 (d, J = 8.5 Hz,
2H), 6.97 (d, J = 8.5 Hz, 2H), 4.05 (s, 3H), 3.96 (s, 3H), 3.88
(s, 3H), 3.53 (s, 3H), 2.77 (s, 3H). 13C NMR (126 MHz,
CDCl3): 182.0, 181.7, 159.5, 155.3, 148.0, 145.5, 133.5,
132.6, 130.4, 127.9, 127.1, 125.0, 123.7, 113.7, 105.2, 61.37,
61.36, 55.4, 29.9, 27.6. HRMS (ESI): m/z calculated for
C22H21N2O6 [M+H]+= 409.1403, found 409.1433.
REFERENCES
(1) For recent reviews on marine natural products, see: (a) Blunt, J.
W.; Carroll, A. R.; Copp, B. R.; Davis, R. A.; Keyzers, R. A.; Prinsep,
M. R. Marine Natural Products. Nat. Prod. Rep. 2018, 35, 8-53. (b)
Blunt, J. W.; Copp, B. R.; Keyzers, R. A.; Munro, M. H. G.; Prinsep,
M. R. Marine Natural Products. Nat. Prod. Rep. 2016, 33, 382-431.
(c) Newman, D. J.; Cragg, G. M. Natural Products as Sources of New
Drugs from 1981 to 2014. J. Nat. Prod. 2016, 79, 629-661. For a
review on marine natural products for China, see: (d) Fu, X.-M.;
Zhang, M.-Q.; Shao, C.-L.; Li, G.-Q.; Bai, H.; Dai, G.-L.; Chen, Q.-
W.; Kong, W.; Fu, X.-J.; Wang, C.-Y. Chinese Marina Materia Medi-
ca Resources: Status and Potential. Mar. Drugs. 2016, 14, 46.
(2) For recent reviews on natural occurring compounds see: (a)
Clardy, J.; Walsh, C. Lessons from Natural Molecules. Nature 2004,
432, 829-837. (b) Paterson, I.; Anderson, E. A. The Renaissance of
Natural Products as Drug Candidates. Science 2005, 310, 451-453. (c)
Nicolaou, K. C.; Chen, J. S.; Edmons, D. J.; Estrada, A. A. Recent
Advances in the Chemistry and Biology of Naturally Occurring Anti-
biotics. Angew. Chem. Int. Ed. 2009, 48, 660-719.
(3) (a) Akee, R. K.; Carroll, T. R.; Yoshida, W. Y.; Scheuer, P. J.
Two Imidazole Alkaloids from a Sponge. J. Org. Chem. 1990, 55,
1944-1946. (b) Plubrukarn, A.; Smith, D. W.; Cramer, R. E.; Dvison,
B. S. (2E,9E)-Pyronaamidine 9-(N-Methylimine), a New Imidazole
Alkaloid from the Northern Mariana Islands Sponge Leucetta sp. cf.
Chagosensis. J. Nat. Prod. 1997, 60, 712-715.
(4) Koswatta, P. B.; Kasiri, S.; Das, J. K.; Bhan, A.; Lima, H. M.;
García-Barbosa, B.; Khatibi, N. N.; Yusufuddin, M.; Mandal, S. S.;
Lovely, C. J. Total Synthesis and cytotoxicity of Leucetta Alkaloids.
Bioorg. Med. Chem. 2017, 25, 1608-1621.
Angular
3-methylkealiiquinone:
7,8-dimethoxy-4-(4-
methoxyphenyl)-1,3-dimethyl-1H-naphtho[1,2-d]imidazole-
2,6,9(3H)-trione (24): m.p.= 165-167 °C. Rf = 0.55 (60%
EtOAc/Hexane). IR (neat) ν/cm-1 = 2926, 1714, 1662, 1621,
1
1514, 1454, 1382, 1347, 1230, 1176, 1028, 909, 832, 747. H
NMR (500 MHz,): δ 7.78 (s, 1H), 7.26 (d, J = 8.6 Hz, 2H),
6.98 (d, J = 8.6 Hz, 2H), 4.12 (s, 3H), 4.09 (s, 3H), 3.88 (s,
3H), 3.73 (s, 3H), 3.01 (s, 3H). 13C NMR (126 MHz, CDCl3):
δ 181.5, 181.1, 160.1, 156.9, 148.1, 146.3, 133.8, 130.9, 130.7,
128.8, 128.2, 124.7, 124.6, 114.3, 113.8, 61.5, 61.4, 55.5,
34.2, 31.3. HRMS (ESI): m/z calculated for C22H21N2O6
[M+H]+= 409.1403, found 409.1431.
3-methoxy-4-(7-(4-methoxyphenyl)-1,3-dimethyl-2-oxo-2,3-
dihydro-1H-benzo[d]imidazol-5-yl) cyclobut-3-ene-1,2-dione
(25): m.p.= 225-227 °C. Rf = 0.4 (60% EtOAc/Hexane). IR
(neat) ν/cm-1 = 2965, 2251, 1781, 1737, 1703, 1591, 1515,
1
1439, 1248, 1180, 1098, 1026, 915, 838, 727. H NMR (500
MHz, CDCl3): δ 7.67 (d, J = 1.2 Hz, 1H), 7.60 (d, J = 1.2 Hz,
1H), 7.28 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 4.58 (s,
3H), 3.87 (s, 3H), 3.50 (s, 3H), 3.00 (s, 3H). 13C NMR (126
MHz, CDCl3): δ 193.7, 193.2, 191.5, 173.7, 159.8, 155.2,
131.2, 131.0, 130.8, 129.1, 125.2, 124.9, 120.5, 113.7, 105.1,
61.8, 55.5, 30.6, 27.7. HRMS (ESI): m/z calculated for
C21H19N2O5 [M+H]+= 379.1294, found 379.1278.
(5) For the Ohta total synthesis approach, see: (a) Kawasaki, I.;
Taguchi, N.; Yamamoto, T.; Yamashita, M.; Ohta, S. Total Synthesis
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Kawasaki, I.; Ohta, S.; Ohishi, Y. Synthesis of a regio-isomer of
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Desmethoxykealiiquinone, and 2´-Deoxykealiiquinone. J. Org. Chem.
2014, 79, 2481-2490. Another related approach: (e) Das, J.; Mukher-
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(6) The financial support for this project (CONACyT CB-
2013/220836) is focused to the discovery of new anti-cancer drug
candidates. Thus, inspired by the described regulatory-protective
effect of the methylation of natural compounds to prevent or modulate
the epigenetic DNA-methylation, we envisioned the synthesis of the
3-methylkealiiquinone as model system to further study the molecular
target of action in the biological activity against cancer cell lines: (a)
Mirza, S.; Sharma, G.; Parshad R.; Gupta, S. D.; Pandya, P.; Ralhan,
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Green Tea Catechins. Pharmacology, 2015, 95, 111-116. (c) Wu, W-
Y.; Wu, Y-Y.; Huang, H.; He, C.; Li, W-Z.; Wang, H-L.; Chen, H-Q.;
Yin, Y-Y. Biochanin A attenuates LPS-induced pro-inflamatory
responses and inhibits the activation of the MAPK pathway in BV2
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Ngollo, M.; Lebert, A.; Dagdemir, A.; Penault-Llorca, F.; Boiteux, J-
P.; Bignon, Y-J.; Guy, L.; Bernard-Gallon, D. Comparative effects of
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Brominating Agent in the Presence of Solvents and Under Solvent-
Free Conditions. J. Iran. Chem. Soc. 2016, 13, 2019-2028.
(10) Zhang, X.; Zheng X.; Chupack, L. S. Aryl substituted bicyclic
heteroaryl compounds. WO 2017019828, February 2, 2017.
(11) Less than 13% of biscoupled product was observed in
1
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3
4
5
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8
each case. See SI for details.
9
(12) Liebeskind, L. S.; Wirtz, K. R. Regioespecific Preparation of
Cyclobutenedione Monoacetals. J. Org. Chem. 1990, 55, 5350-5358.
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(c) Enhsen, A.; Karabelas, K.; Heerding, J. M.; Moore, H. W. Synthe-
sis of Hydroxyquinones and Related Compounds: Semisquaric Acids,
(±)-Terreic Acid, (±)-Perezone, and (±)-Isoperezone. J. Org.
Chem. 1990, 55, 1177-1185. (d) Moore, H. W.; Perri, S. T. General
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(15) It was identified the formation of the carbonyl regeneration
product 25 via solvolysis, see supporting information for details.
(16) Different conditions such as heating at 200 ºC and 180 ºC as
well as the use of sealed tubes or microwave-assisted reactions give
very complex mixtures and lower yields. The use of heating at reflux-
ing conditions in xylenes or the use of Lewis acids only showed the
starting material decomposition.
(17) Zhang, X.; Zheng, X.; Chupak, L. S. Aryl-substituted bicyclic
compounds as PAR4 inhibitors and their preparation. PCT Int. Appl.
WO2017019828, 2017.
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(7) Liu, H.; Gayo, L. M.; Sullivan, R. W.; Choi, A. Y. H.; Moore,
H. W. Synthetic Utility of Alkenylcyclobutenedione Monoketals.
Michael Additions and the Synthesis of a Natural Benzofuranosesqui-
terpenequinone. J. Org. Chem. 1994, 59, 3284-3288.
(8) (a) Liebeskind, L. S.; Fengl, R. W.; Wirtz, K. R.; Shawe, T. T.
An improved Method for the Synthesis of Substituted Cyclobutene-
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O. R.; Tsui, H-C. Total Synthesis of Furaquinocin A, B, and E. J. Am.
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T. P.; Whitby, R. J.; Sneddon, H. F.; Harrowen, D. C. New Insights
into Cyclobutenone Rearrangements: A Total Synthesis of the Natural
ROS-Generating Anti-Cancer Agent Cribrostatin 6. Chem. Eur. J.
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