Formation of benzimidazoisoquinolinium and benzimidazoisoindolinum cyclic systems by the reaction of 2-(2-alkynylphenyl)benzimidazoles with iodine and iodine-iodine interaction including halogen bonding in their crystal structures

Article abstract of DOI:10.1021/acs.joc.6b00607

The reaction of 2-(2-alkynylphenyl)benz[d]imidazoles with molecular iodine constructed 5- and 6-membered rings as novel organic salts in high yield. The constituted number of ring systems was influenced by the substituent at the triple bond: 6-membered rings were formed from compounds bearing aryl substituents, whereas 5-membered ones were obtained from compounds with hydrogen or alkyl substituents. The products were obtained with triiodide as a counteranion; however, compounds with iodide were also obtainable under certain conditions. We also revealed that they had an iodine-iodine interaction included in halogen bonding between an iodo moiety of the cation and a triiodide or iodide of the counteranion. The iodine-iodine interaction was formed with greater preference than the electrostatic interaction between the cationic atom and triiodide or iodide.

Full text of DOI:10.1021/acs.joc.6b00607

Article
pubs.acs.org/joc
Formation of Benzimidazoisoquinolinium and
Benzimidazoisoindolinum Cyclic Systems by the Reaction of 2‑(2-
Alkynylphenyl)benzimidazoles with Iodine and Iodine−Iodine
Interaction Including Halogen Bonding in Their Crystal Structures
Shoji Matsumoto,*,† Shu Kikuchi,† Naoto Norita,† Hyuma Masu,†,‡ and Motohiro Akazome†
†Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33 Yayoicho, Inageku,
Chiba, 263-8522, Japan
‡Center for Analytical Instrumentation, Chiba University, 1-33 Yayoicho, Inageku, Chiba, 263-8522, Japan
S
* Supporting Information
ABSTRACT: The reaction of 2-(2-alkynylphenyl)benz[d]imidazoles with
molecular iodine constructed 5- and 6-membered rings as novel organic salts
in high yield. The constituted number of ring systems was influenced by the
substituent at the triple bond: 6-membered rings were formed from
compounds bearing aryl substituents, whereas 5-membered ones were
obtained from compounds with hydrogen or alkyl substituents. The products
were obtained with triiodide as a counteranion; however, compounds with
iodide were also obtainable under certain conditions. We also revealed that
they had an iodine−iodine interaction included in halogen bonding between
an iodo moiety of the cation and a triiodide or iodide of the counteranion.
The iodine−iodine interaction was formed with greater preference than the
electrostatic interaction between the cationic atom and triiodide or iodide.
construction of crystal structures,15 application as an organic
INTRODUCTION
■
catalyst,16 molecular recognition,17 etc.18
Ring formation is one of the most important reactions to utilize
the synthesis of various cyclic compounds including natural
RESULTS AND DISCUSSION
■
products, biologically active compounds, functional materials,
Ionic Heterocycle Formation with I2. We tried to
and so on.1−3 Intramolecular nucleophilic cyclization reaction
synthesize the reactants (1a−e) using the Sonogashira coupling
reaction (Scheme 2). The compounds (1a, 1b, and 1e) were
prepared by the condensation reaction of 2-aminodiphenyl-
amine and 2-bromobenzaldehyde, followed by the Sonogashira
coupling with ethynylene derivatives. The removal of a
hydroxylisopropyl group of 1e was utilized to obtain 1d. It
was possible to form 1c by reaction with p-bromoanisole and
1d prepared in situ from 1e even in low yield, because 1c was
yielded heterocyclic compounds when a heteroatom was used
as a nucleophile. Iodine-induced cyclization reactions4,5 were
reported to form heterocycles such as (benzo)furans,6
pyrroles,7 indoles,8 (benzo)thiophenes,9 and (benzo)-
selenophenes.10 Those reactions yielded compounds in neutral
form because the reaction was completed by the removal of a
proton or alkyl substituent on a heteroatom. Recently, we
reported that the ionic heterocycle, benzo[c]thiophen-1-
aminium iodide, was obtained by the reaction of 2-alkynyl-
benzothioamide with iodine (Scheme 1).11 On the basis of our
result, we suppose that cyclization reactions yield ionic
heterocycles even if there is no leaving group on the
heteroatom. However, there were few reports about salt
formation by the reaction of halo-cyclization.12 We herein
report the reaction of 2-(2-alkynylphenyl)benz[d]imidazoles
(1) with molecular iodine to give the corresponding ionic
heterocycles, benz[4,5]imidazo[2,1-a]isoquinolin-7-ium (2+)
and benz[4,5]imidazo[2,1-a]isoindol-10-ium (3+). Further-
more, we revealed an interaction including halogen bonding
between iodine atoms on the cation and the counteranion
(triiodide or iodide) by single-crystal X-ray analysis. The
halogen bond13,14 has the potential to be utilized in the
not obtained by the coupling reaction with p-methoxypheny-
lacetylene.
We first examined the reaction of 1a (R = Ph) with 1 mol
equiv of I2 in CHCl3 at ambient temperature. During the
reaction progress, the precipitate was obtained. However, we
found that 1a remained even after a period of 67 h by TLC
analysis. From 1H NMR analysis of the precipitate, we observed
two discrete peaks at 9.26 and 8.54 ppm with a ratio of 22:78,
and no other byproduct was observed (see Figure S1). Such a
downfield shift of the proton peak was also observed in the case
of benzo[c]thiophen-1-aminium iodides (ca. 9.4 ppm), which
have 5-membered cationic cyclic system.11 Therefore, we
Received: March 22, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b00607
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The Journal of Organic Chemistry
Article
would also exist. The yield of the cation part could be
calculated from the integration of 1H NMR with dibenzyl as an
internal standard. Because there was no method to determine
the ratio of I3− and I− directly, we estimated it from the yield of
the cation part and the weight of the product using
simultaneous equations as follows
Scheme 1. Formation of Various Heterocyclic Systems by
Iodocyclization Reaction
+
+
+
+
From material balance: W = (Y2 × M2 + Y3 × M3 )
−
−
−
−
+ (Y × MI + Y × MI )
I3
I
3
+
+
−
−
From charge balance: Y2 + Y3 = Y + Y
I3
I
+
+
−
3
where W is the weight of the obtained precipitate; Y2 , Y3 , YI ,
−
and YI correspond to the number of moles (ions) of the
+
+
−
obtained compounds; and M2 , M3 , MI (=380.7), and
3
−
MI (=126.9) are molecular (ion) weights. In the case of 1a,
+
+
+
+
both of M2 and M3 are 498.4. Y2 and Y3 were obtained from
1
the H NMR analysis using an internal standard (dibenzyl or
terepthalaldehyde). Finally, we could determine the yield of
each component both in cations and in anions within 1%
error (Table 1, entry 1). Although 1 mol equiv of I2 was treated,
I3− was a major component in the reaction in CHCl3. The total
yield of the cyclized product was 51%, and the recovery of 1a
was obtained in 49%. On the basis of the consumption of
molecular iodine, this cyclization reaction proceeded efficiently.
To examine the influence of the solvent, the reaction was
conducted in various solvents. In EtOAc and CH3CN, the
Scheme 2. Preparation of 1
−
products with I3 were obtained as a major anion with the
precipitate formation in medium yields (entries 2 and 3). When
the reaction was treated in DMF, the ratio of I− was increased
(entry 4). By raising the reaction temperature, the reaction
yielded no precipitate after the reaction, and the products
bearing I− were obtained in 74% yield, although the reaction
period for 72 h was required to disappear 1a on TLC (entry 5).
When 1a was treated with 2 mol equiv of I2, which is an
−
efficient amount to give the compound with I3 counteranion,
−
the products with I3 were obtained in excellent yield within 1
h (entry 7). We also found that the complete conversion to the
−
products with I3 based on molecular iodine was achieved
within 1 h in the case of 1 mol equiv of I2 in CHCl3 when the
reaction was stopped for 1 h even in remaining 1a (entry 6). All
of the reactions with 1a gave the benz[4,5]imidazo[2,1-
a]isoquinolin-7-ium structure (2a+) as major products. A sole
countercation (2a+) was obtained from the reaction with a
raised temperature (entry 5).
The reaction mechanism was proposed as follows (Scheme
3). The triple bond on 1a was activated by coordination of I2 to
yield an iodonium cation (A). An intramolecular nucleophilic
attack at the sp2 nitrogen atom in intermediate A occurred,
creating the cyclic structure (2a+ and 3a+). The cyclized cation
part will possess I− as a counteranion at first, but equilibrium
between I− and I3− should exist at the beginning of the reaction
because there is an excess amount of I2. The triiodide
compound is excluded as a precipitate from the reaction
solution except for warming DMF solution. As a result, the
thought that two types of the cyclization product (2a+ and 3a+)
would be obtained, and the minor peak with 9.26 ppm would
have a 5-membered cyclic cation (3a+). We could obtain a good
crystal for measuring by single-crystal X-ray analysis (vide
infra), and revealed that the major product was benz[4,5]-
−
cyclized product with I3 was obtained as a major product.
imidazo[2,1-a]isoquinolin-7-ium triiodide (2a+·I3 ). Further-
Where there is no precipitate formation (entry 5), the
−
−
more, from the elemental analysis of the precipitate, the wt % of
C (obtained with C, 38.67%; H, 2.02%; N, 3.13%) were larger
equilibrium between I− and I3 serves I2 in the reaction
conditions. Therefore, all of I2 can react with the substrate to
−
values compared to the product with triiodide (I3 ) as a
yield the cyclized product with I− as a major product.
counteranion (calculated with C, 36.93%; H, 2.07%; N, 3.19%).
We tried to examine the reaction of compounds with
aromatic substituents with electron-donating groups and
Therefore, other compounds with iodide (I−) as a counteranion
B
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Article
a
Table 1. Reaction of 1 with Iodine
b
c
yield of cation (%)
yield of anion (%)
recovery of 1 (%)
2+
3+
I3
I−
−
entry
R
solvent
mol equiv of I2
time (h)
1
2
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1e
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CHCl3
EtOAc
CH3CN
DMF
1.0
1.0
1.0
1.0
1.0
1.0
2.0
1.0
2.0
1.0
2.0
1.0
2.0
1.0
1.0
2.0
67
67
67
67
72
1
40
31
40
44
84
38
75
90
83
92
11
14
8
45
6
0
49
46
44
43
0
45
48
27
10
50
93
6
3
0
4
13
0
30
74
0
d
5
DMF
6
CHCl3
CHCl3
12
18
0
50
0
7
1
0
d
8
p-MeC6H4
p-MeC6H4
p-MeOC6H4
p-MeOC6H4
H
DMF
72
1.5
72
1
84
21
85
0
0
9
CHCl3
9
71
7
0
d
10
11
12
13
14
15
16
DMF
0
0
CHCl3
100
e
0
100
0
d
DMF
72
1
0
H
CHCl3
0
92
92
0
0
d
e
C(CH3)2OH
C(CH3)2OH
C(CH3)2OH
DMF
72
72
29
39
0
CHCl3
CHCl3
0
0
51
49
2
0
24
100
100
a
b
1
Reaction conditions: 1 (0.3 mmol), solvent (3 mL), room temperature. Determined by the integration of H NMR with an internal standard
c
d
e
(dibenzyl or terephthalaldehyde). Determined by the relation of material and charge balance. See the text. Reacted at 100 °C. A complex mixture.
membered cyclization was achieved by the compound bearing a
p-anisyl substituent (1c) (entry 11). The electron-donating
substituent stabilizes the positive charge at the benzyl position.
Thus, reaction path a in Scheme 3 was enhanced to yield the 6-
membered cyclization product (2c+). When no substituted
compound at the triple bond (1d) was treated with iodine in
CHCl3, 5-membered cyclization products (3d+) determined by
single-crystal X-ray analysis (vide infra) were obtained as the
sole cation part via path b (entry 13), although a complex
mixture was obtained in DMF (entry 12). In the case of the
reaction of 1e bearing a bulkier substituent, −C(CH3)2OH, 3e+
was also obtained as the sole cation part, although a prolonged
reaction time was required (entries 15 and 16). Therefore, the
preference of the cyclic system was determined by the
stabilization of positive charge in intermediate A, especially
when stabilized with a benzylic position.
Scheme 3. Plausible Mechanism of the Reaction and the
Formation of the Products
In the case of the reactions of 1a, 1b, and 1c, the ratio of
counteranion could be switched to inhibit the precipitate
formation by raising the reaction temperature (entries 5, 8, and
10). The reaction of 1d and 1e yielded a complex mixture
under those conditions (entries 12 and 14). However,
surprisingly, the reaction of 1e in CHCl3 yielded a product
−
with I3 as a counteranion, even in the presence of 1.0 mol
equiv of I2 without the precipitate formation after the reaction
(entry 15). There is no clear explanation for this result, but it
suggested that the reaction was restricted toward the less
−
reactive 1e with I2 by the equilibrium between I− and I3 in
CHCl3 under ambient temperature.
Crystal Structure of Cyclic Compounds. We were
interested in the crystal structure of products because the
compounds may possess the possibility of a halogen bonding
between the iodine atom on the cationic and anionic parts.
Good crystals could be obtained to measure the single-crystal
X-ray structure of 2a+·I3 , 2b+·I3 , 2c+·I3 , and 3d+·I3 by
recrystallization from CHCl3 by diffusion of hexane vapor. The
structures are summarized in Figure 1. All fused rings were
aligned in the same plane, and phenyl rings on nitrogen were
oriented perpendicularly. Distances and angles around
imidazolium and iodovinyl moieties are listed in Table 2.
Focusing on the benzimidazolium structure, little difference
−
−
−
−
aliphatic substituents at the triple bond because the electron-
withdrawing substituent would decrease the reaction ratio to
inhibit the coordination of I2 at the triple bond. A p-tolyl
substituted compound (1b) increased the ratio of 6-membered
products (2b+) (entries 7 vs 9), and complete control of the 6-
C
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C2−C3 bond was shorter than that of the resonance C−C bond
(1.38 Å). Thus, it was revealed that there was little resonance
between imidazolium and C−C bonds derived from the triple
bond in 1.
−
As I3 possesses a negative charge, the interaction with the
cationic imidazolium moiety should be attractive. However, the
−
−
two crystal structures (2b+·I3 and 3d+·I3 ) showed no
−
interaction between I3 and the cationic carbon (C1) on the
imidazolium moiety with longer distances between C1 and I3
−
(Figure 1b,c), whereas the distance between C1 and iodine of
I3 in 2a+·I3 and 2c+·I3 was observed within the sum of van
der Waals radii [3.75 Å = 1.98 Å (I) + 1.77 Å (C)] (Figure
1a,c).
−
−
−
Focused on the halogen−halogen interaction, the edge of the
iodine atom on I3− was situated in close contact with the iodine
atom on the iodovinyl moiety of the cation structure. The
distance between two iodine atoms was shortened about 10%
compared to the sum of van der Waals radii of iodine [3.96 Å =
1.98 Å (I) + 1.98 Å (I)].22 Bartashevich and co-workers report
that the halogen bonding in the compounds of heterocyclic
−
cations and I3 was mainly observed in the range of 3.7−3.8
Å.23 Such a halogen bond was reported in terms of “charge-
assisted halogen bond”, which gave significant contraction of
halogen−halogen distance.17b,24 Mentioned above, there was
little conjugation between iodovinyl and benzimidazolium
moieties in 2a−c+·I3 and 3d+·I3 . Therefore, the driving
force to make the interaction between two iodine atoms would
be the inductive electron-withdrawing ability of the benzimi-
dazolium cation. The three atoms (C3, I1, and I2) were almost
in linear alignment. It is reasonable for halogen bonding,
although the C−I···I angle was slightly tilted from the ideal
angle (180°).13,25 On the basis of the difference in the two
angles (C3−I1···I2 and I1···I2−I3) reported by Desiraju et al.,15b
−
−
−
−
−
Figure 1. Molecular structures of (a) 2a+·I3 , (b) 2b+·I3 , (c) 2c+·I3 ,
−
−
and (d) 3d+·I3 with the situation of I3 around the cation part
obtained by single-crystal X-ray crystallographic analysis.
between two C−N bonds was observed within 0.03 Å. To the
best of our knowledge, the smallest difference between C−N
bond lengths of N-arylimidazole was 0.043 Å,19 and the largest
one of benzimidazolium was 0.028 Å.20 Therefore, the
imidazole moiety of the products possesses a resonance
character such as imidazolium cation. On the contrary, the
C−N bond formed by the cyclization reaction (N2−C2) was
observed at around 1.40 Å. It is longer than the general
C(sp2)−N(planar) and C(aromatic)−N(planar) single bond
lengths (1.36 and 1.37 Å, respectively).21 The distance of the
the compounds were categorized in 2a+·I3 as type I contact
−
and in 2b+·I3 , 2c+·I3 , and 3d+·I3− as type II contact, which are
−
−
actually halogen bondings.26 Furthermore, it was found that I3
−
was located on various positions in crystalline structures in
keeping with that interaction (Figure 1). These results
suggested that the I···I interaction in those compounds has
the ability to overwhelm both the electrostatic interaction
between cationic and anionic atoms and the requirement of
crystal packing.
Table 2. Selected Distances and Angles of Products in Single-Crystal X-ray Structure
distance (Å)
angle (deg)
a
compound
N1−C1
C1−N2
N2−C2
C2−C3
I1···I2
C3−I1···I2
I1···I2−I3
2a+·I3
1.355
1.344
1.350
1.337
1.353
1.354
1.372
1.363
1.353
1.360
1.399
1.403
1.403
1.433
1.401
1.363
1.342
1.352
1.332
1.342
3.703 [93.5]
3.647 [92.1]
3.556 [89.8]
3.638 [91.9]
3.496 [88.3]
154.36
170.75
169.01
174.16
165.87
148.33
106.73
130.70
79.05
−
2b+·I3
−
2c+·I3
−
3d+·I3
−
2a+·I−
a
Value in parentheses was percentage of the contraction against the sum of van der Waals (vdW) radii (distance I1···I2/3.96 (sum of vdW of iodine)
× 100).
D
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Article
10.0 mmol). The mixture was stirred for 22 h under refluxing
conditions. The reaction mixture was extracted with EtOAc (5 mL ×
3), and the organic layer was dried with MgSO4. After filtration and
evaporation, the residue was subject to column chromatography on
SiO2 (hexane:EtOAc = 4:1) to give 2-(2-bromophenyl)-1-phenyl-1H-
benz[d]imidazole (1.02 g, 2.92 mmol, 58%) as a colorless solid: mp =
After trying different recrystallization conditions, a single
crystal included in pyridine was obtained by recrystallization of
2a+·I− from pyridine solution with diffusion of hexane vapor.
An almost identical structure of the benzimidazolium part was
present in 2a+·I3− and 2a+·I− (Figure 2 and Figure S3). Contact
between cationic carbon (C1) and iodine atom was observed.
An I···I halogen bond also existed with a 3.496 Å distance and
with a nearly linear angle (165.87°). Therefore, the preference
of I···I interaction would also be affected in the case of I− as a
counteranion.
1
158−159 °C; H NMR (CDCl3, 300 MHz) δ 7.22−7.39 (m, 10H),
7.46 (dd, J = 1.8 and 7.4 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.92
(diffused d, J = 7.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 110.6,
120.3, 122.9, 123.6, 123.7, 126.7, 127.0, 128.1, 129.3, 131.0, 132.3,
132.5, 132.8, 135.6, 135.9, 142.8, 151.5; IR (KBr disk) 3057, 1597,
1496, 1455, 1428, 1384, 1324, 1272, 1261, 1251, 1073, 1030, 1002,
772, 758, 742, 729, 709, 698 cm−1. HRMS (ESI, orbitrap) m/z: [M +
H]+ Calcd for C19H14N2Br 349.0335; Found 349.0321.
CONCLUSION
■
The reaction of 2-(2-alkynylphenyl)benz[d]imidazoles (1) with
I2 gave novel 5- and 6-membered ring structures bearing iodine
substituents as organic salts. The cyclization with activation of
the triple bond by iodine occurred through a nucleophilic attack
by a nitrogen atom at the benz[d]imidazolyl group toward the
carbon atom in a benzylic position with the electron-donating
substituents. The compounds with I3− were selectively obtained
by the precipitate formation or by reaction with 2 mol equiv of
I2. Furthermore, by investigation of their crystal structures, it
was revealed that the I···I interaction such as halogen bonding
between iodine atoms in the iodovinyl moiety of the cation part
and anion part was formed with greater preference than the
electrostatic interaction between the cationic atom and triiodide
or iodide.
1-Phenyl-2-(2-(phenylethynyl)phenyl)-1H-benz[d]imidazole (1a).
To a solution of 2-(2-bromophenyl)-1-phenyl-1H-benz[d]imidazole
(0.268 g, 0.767 mmol) in THF (0.8 mL) and NEt3 (1.1 mL) were
added ethynylbenzene (87.8 mg, 0.860 mmol), Pd(PPh3)2Cl2 (12.6
mg, 0.018 mmol), CuI (6.3 mg, 0.033 mmol), and PPh3 (9.3 mg, 0.035
mmol). The mixture was stirred for 24 h under refluxing conditions.
After filtration with pads of Celite and Florizil and evaporation, the
residue was subject to column chromatography on SiO2 (hexane:E-
tOAc = 4:1) to give 1-phenyl-2-(2-(phenylethynyl)phenyl)-1H-
benz[d]imidazole (1a) (0.256 g, 0.692 mmol, 90%) as a yellow oil:
1H NMR (CDCl3, 300 MHz) δ 7.14−7.40 (m, 15H), 7.50 (diffused
dd, J = 2.0 and 7.1 Hz, 1H), 7.55 (diffused dd, J = 2.5 and 6.5 Hz, 1H),
7.94 (diffused d, J = 8.6 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 87.7,
93.1, 110.3, 120.0, 122.8, 123.3, 123.9, 126.6, 127.7, 127.9, 128.1,
128.2, 129.0, 129.2 (broadened), 129.3, 130.8, 131.4, 132.2, 133.0,
125.8, 136.2, 143.0, 151.9; IR (NaCl plate) 3061, 2957, 2218, 1597,
1495, 1455, 1380, 1327, 1264, 1216, 1191, 1085, 1071, 1027, 1009,
979, 906, 825, 753, 691 cm−1. HRMS (ESI, orbitrap) m/z: [M + H]+
Calcd for C27H19N2 371.1543; Found 371.1525.
EXPERIMENTAL SECTION
General Information. Melting points were uncorrected. NMR
■
1
measurements were recorded with a 300 MHz spectrometer for H
2-((2-(4-Methylphenyl)ethynyl)phenyl)-1-phenyl-1H-benz[d]-
imidazole (1b). This compound was prepared in 32% isolated yield
(0.125 g, 0.325 mmol) for 1 day under refluxing conditions according
to a procedure similar to that mentioned in 1a: Colorless solid; mp =
NMR and with a 75 MHz spectrometer for 13C NMR. Chemical shifts
1
(δ) of H NMR were expressed in parts per million downfield or
upfield from tetramethylsilane in CDCl3 (δ = 0) or DMSO-d5 (δ =
2.49) as an internal standard. Multiplicities are indicated as s (singlet),
d (doublet), t (triplet), m (multiplet), and bs (broadened singlet), and
coupling constants (J) are reported in hertz units. Chemical shifts (δ)
of 13C NMR are expressed in parts per million downfield or upfield
from CDCl3 (δ = 77.0) or DMSO-d6 (δ = 39.6) as an internal
standard. Analytical thin-layer chromatography (TLC) was performed
on glass plates that had been precoated with SiO2 (0.25 mm layer
thickness). Column chromatography was performed on 70−230 mesh
SiO2. Anhydrous CHCl3 was distilled from CaCl2 after washing with
aq. NaOH and was stored with MS 4 Å. Anhydrous CH3CN was
distilled from sodium hydride and was stored with MS 3 Å. Anhydrous
DMF was distilled from P2O5 under reduced pressure and was stored
with MS 4 Å. All other materials were used without further
purification. The reactions were performed under a nitrogen
atmosphere.
1
53−54 °C; H NMR (CDCl3, 300 MHz) δ 2.26 (s, 3H), 6.99 (d, J =
8.2 Hz, 2H), 7.04 (d, J = 8.2 Hz, 2H), 7.18−7.23 (m, 2H), 7.27−7.38
(m, 8H), 7.45 (diffused dd, J = 2.6 and 6.3 Hz, 1H), 7.55 (diffused dd,
J = 2.9 and 6.0 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H); 13C NMR (CDCl3,
75 MHz) δ 21.4, 87.1, 93.4, 110.4, 119.8, 120.1, 122.8, 123.3, 124.1,
126.7, 127.7, 127.8, 128.9, 129.1, 129.4, 130.9, 131.4, 132.2, 132.9,
135.8, 136.3, 138.5, 143.1, 152.1; IR (KBr disk) 3059, 2922, 2216,
1597, 1499, 1452, 1380, 1326, 818, 752, 696 cm−1. HRMS (ESI,
orbitrap) m/z: [M + H]+ Calcd for C28H21N2 385.1699; Found
385.1689.
2-Methyl-4-(2-(1-phenyl-1H-benz[d]imidazol-2-yl)phenyl)but-3-
yn-2-ol (1e). This compound was prepared in 86% isolated yield
(0.861 g, 2.44 mmol) for 1 day under refluxing conditions according to
a procedure similar to that mentioned in 1a: Colorless solid; mp =
1
143−144 °C; H NMR (CDCl3, 300 MHz) δ 1.31 (s, 6H), 3.15 (bs,
Preparation of 1. 2-(2-Bromophenyl)-1-phenyl-1H-benz[d]-
imidazole.27 To a solution of 2-aminodiphenylamine (0.923 g, 5.01
mmol) in H2O (10 mL) was added 2-bromobenzaldehyde (1.85 g,
1H), 7.20−7.40 (m, 12H), 7.89 (dd, J = 1.4 and 6.7 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) δ 31.0, 65.0, 80.2, 98.3, 110.4, 119.9, 122.9,
123.4, 123.8, 126.8, 127.7, 128.0, 129.3 (large intensity), 130.5, 132.3,
132.8, 135.6, 136.1, 142.6, 151.6; IR (KBr disk) 3232, 2976,
2224,1733, 1597, 1499, 1452, 1389, 1330, 1172, 1137, 968, 764,
750, 698 cm−1. HRMS (ESI, orbitrap) m/z: [M + H]+ Calcd for
C24H21N2O 353.1648; Found 353.1640.
2-((2-(4-Methoxylphenyl)ethynyl)phenyl)-1-phenyl-1H-benz[d]-
imidazole (1c). To a solution of 1e (0.856 g, 2.43 mmol) in toluene (4
mL) were added 4-bromoanisole (0.466 g, 2.53 mmol), CuI (49.7 mg,
0.261 mmol), Pd(PPh3)2Cl2 (0.172 g, 0.244 mmol), nBu4NI (89.7 mg,
0.2463 mmol), and a 5 M aqueous solution of NaOH (1.6 mL, 8.0
mmol). The mixture was stirred at 80 °C for 14 h. After filtration with
pads of Celite and Florisil and evaporation, the residue was subject to
column chromatography on SiO2 (hexane:EtOAc = 4:1) to give 2-((2-
(4-methoxylphenyl)ethynyl)phenyl)-1-phenyl-1H-benz[d]imidazole
(1c) (92.7 mg, 0.232 mmol, 10%) as a yellow solid; mp = 48−50 °C;
1H NMR (CDCl3, 300 MHz) δ 3.76 (s, 3H), 6.74 (d, J = 8.9 Hz, 2H),
Figure 2. Interactions of 2a+·I−·(pyridine)0.75 obtained by single-
crystal X-ray crystallographic analysis. Pyridines were omitted for
clarity.
E
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The Journal of Organic Chemistry
Article
7.09 (d, J = 8.9 Hz, 2H), 7.21 (d, J = 6.3 Hz, 1H), 7.22 (d, J = 7.6 Hz,
1H), 7.28−7.40 (m, 8H), 7.47 (diffused dd, J = 2.2 and 6.9 Hz, 1H),
7.55 (diffused dd, J = 1.9 and 7.1 Hz, 1H), 7.95 (d, J = 7.2 Hz, 1H);
13C NMR (CDCl3, 75 MHz) δ 55.2, 86.5, 93.3, 110.4, 113.8, 115.0,
120.1, 122.8, 123.3, 124.3, 126.6, 127.6, 127.8, 129.1, 129.4, 130.8,
132.1, 132.7, 132.9, 135.8, 136.3, 143.1, 152.1, 159.6; IR (KBr disk)
3059, 2934, 2836, 2215, 1600, 1511, 1500, 1452, 1380, 1288, 1250,
1175, 1028, 833, 752, 696 cm−1. HRMS (ESI, orbitrap) m/z: [M +
H]+ Calcd for C28H21ON2 401.1648; Found 401.1642.
Calcd for C28H20I4N2: C, 37.70; H, 2.26; N, 3.14%. Found: C, 37.53;
H, 2.15; N, 2.96%. 2b+·I−: 0.184 g of collected precipitate (entry 7 in
Table 1); yellow solid; mp = 327−329 °C; IR (KBr disk) 3027, 1618,
1522, 1508, 1482, 1466, 1448, 1322, 1025, 823, 744, 702 cm−1. Anal.
Calcd for (C28H20I2N2)0.93(C28H20I4N2)0.07: C, 51.26; H, 3.07; N,
4.27%. Found: C, 51.00; H, 3.07; N, 4.14%.
5-Iodo-6-(4-methoxylphenyl)-12-diphenyl-12H-benz[4,5]-
−
imidazo[2,1-a]isoquinolin-7-ium Triiodide (2c+·I3 (X = I3)) and
−
Iodide (2c+·I− (X = I)). Same NMR spectra were obtained from 2c+·I3
and 2c+·I−: 1H NMR (DMSO-d6, 300 MHz) δ 3.99, (s, 3H), 6.09 (d, J
= 8.7 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.41 (d, J = 8.7 Hz, 2H),
7.45−7.48 (m, 2H), 7.58 (d, J = 8.7 Hz, 2H), 7.68 (t, J = 7.7 Hz, 1H),
7.75 (t, J = 7.4 Hz, 1H), 7.61−7.90 (m, 2H), 7.95−7.97 (m, 3H), 8.15
(t, J = 7.5 Hz, 1H), 8.53 (d, J = 8.2 Hz, 1H); 13C NMR (DMSO-d6, 75
MHz) δ 55.7, 96.9, 112.8, 115.6, 116.1, 116.2, 124.9, 125.9, 127.5,
127.9, 128.9, 129.2, 130.2, 131.6, 131.9, 132.3, 134.1, 134.2, 134.5,
2-(2-Ethynylphenyl)-1-phenyl-1H-benz[d]imidazole (1d). To a
solution of 1e (0.115 g, 0.326 mmol) in 2-propanol (1.5 mL) was
added KOH (5.81 mg, 0.103 mmol). The mixture was stirred for 3 h
under refluxing conditions. To the reaction mixture was added H2O
(20 mL), and was extracted with EtOAc (10 mL × 3). The organic
layer was dried with MgSO4. After filtration and evaporation, the
residue was subject to column chromatography on SiO2 (hexane:E-
tOAc = 2:1) to give 2-(2-ethynylphenyl)-1-phenyl-1H-benz[d]-
imidazole (1d) (40.2 mg, 0.136 mmol, 42%) as a yellow solid; mp
−
135.4, 135.6, 139.3, 141.9, 161.3. 2c+·I3 : 0.156 g of collected
precipitate (entry 10 in Table 1). Further purification was achieved by
the recrystallization from CHCl3 and hexane; brown solid; mp = 255
°C (decomp.); IR (KBr disk) 3118, 3052, 2927, 1616, 1507, 1481,
1448, 1294, 1255, 1175, 1025, 835, 744, 699 cm−1. Anal. Calcd for
C28H20I4N2O: C, 37.03; H, 2.22; N, 3.08%. Found: C, 37.24; H, 2.06;
N, 2.97%. 2c+·I−: 0.186 g of collected precipitate (entry 9 in Table 1);
light brown solid; mp = 278−280 °C; IR (KBr disk) 3118, 3026, 2932,
2835, 1616, 1523, 1507, 1482, 1448, 1324, 1293, 1253, 1175, 1024,
835, 744, 701 cm−1. Anal. Calcd for (C28H20I2N2O)0.88(C28H20-
I4N2O)0.12: C, 49.11; H, 2.94; N, 4.09%. Found: C, 48.94; H, 2.82; N,
4.05%.
(E)-11-(Iodomethylene)-5-phenyl-5,11-dihydrobenz[4,5]imidazo-
[2,1-a]isoindol-10-ium Triiodide (3d+·I3−). 0.185 g of collected
precipitate (entry 12 in Table 1); brown solid; mp = 213-214 °C;
1H NMR (DMSO-d6, 300 MHz) δ 7.25 (d, J = 7.7 Hz, 1H), 7.60 (d, J
= 8.0 Hz, 1H), 7.68 (t, J = 7.3 Hz, 1H), 7.73 (t, J = 7.5 Hz, 1H), 7.80
(t, J = 7.4 Hz, 1H), 7.85−7.94 (m, 5H), 7.98 (t, J = 8.0 Hz, 1H), 8.71
(d, J = 8.4 Hz, 1H), 8.95 (s, 1H), 8.98 (d, J = 8.1 Hz, 1H); 13C NMR
(DMSO-d6, 75 MHz) δ 65.4, 82.3, 114.0, 122.8, 123.5, 125.4, 126.8,
126.9, 127.5, 127.9, 131.0, 131.3, 131.79, 131.83, 134.2, 135.3, 136.8,
138.1, 149.3; IR (KBr disk) 3067, 1559, 1497, 1478, 1458, 1439, 1143,
743, 711, 693 cm−1. Anal. Calcd for C21H14I4N2: C, 31.45; H, 1.76; N,
3.49%. Found: C, 31.32; H, 1.69; N, 3.21%.
(E)-11-(2-Hydroxy-1-iodo-2-methylpropylidene)-5-phenyl-5,1−1-
dihydrobenz[4,5]imidazo[2,1-a]isoindol-10-ium Triiodide (3e+·I3 ).
0.228 g of collected precipitate (entry 15 in Table 1); brown solid; mp
= 74−76 °C; 1H NMR (DMSO-d6, 300 MHz) δ 1.92 (s, 6H), 5.90 (s,
1H), 7.07 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.57 (t, J = 7.3
Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.67 (t, J = 7.4 Hz, 1H), 7.86−7.94
(m, 6H), 8.30 (d, J = 8.5 Hz, 1H), 9.29 (d, J = 8.4 Hz, 1H); 13C NMR
(DMSO-d6, 75 MHz) δ 32.5, 79.6, 112.5, 119.9, 121.1, 122.8, 123.4,
125.8, 125.9, 126.7, 127.3, 130.6, 130.7, 131.1, 131.5, 131.9, 132.0,
133.7, 136.6, 143.3, 150.7; IR (KBr disk) 3420, 2993, 1622, 1569,
1498, 1478, 1456, 1331, 1172, 755, 696 cm−1. Anal. Calcd for
C24H20I4N2O: C, 33.52; H, 2.34; N, 3.26%. Found: C, 33.53; H, 2.34;
N, 2.98%.
X-ray Crystallography. Data collections were carried out on a
commercial X-ray diffractometer with Mo Kα or Cu Kα radiations. All
structures were solved by a direct method using SHELXS-97,28 and
the non-hydrogen atoms were refined anisotropically against F2, with
full-matrix least-squares methods using SHELXL-97.29 All hydrogen
atoms were positioned geometrically and refined as riding.
1
= 141−142 °C; H NMR (CDCl3, 300 MHz) δ 2.95 (s, 1H), 7.24−
7.51 (m, 12H), 7.93 (d, J = 8.0 Hz, 1H); 13C NMR (CDCl3, 75 MHz)
δ 81.3, 81.5, 110.5, 120.3, 122.8, 122.9, 123.4, 126.9, 127.9, 128.5,
129.2, 129.3, 130.9, 133.1, 133.6, 135.9, 136.2, 143.0, 151.6; IR (KBr
disk) 3288, 3066, 2107, 1597, 1495, 1472, 1456, 1432, 1386, 1323,
1254, 1087, 762, 753, 742, 700 cm−1. HRMS (ESI, orbitrap) m/z: [M
+ H]+ Calcd for C21H15N2 295.1230; Found 295.1216.
Procedure for the Cyclization of 1 with Molecular Iodine. To
a solution of 1 (0.3 mmol) in solvent (3 mL) was added I2 (1.0 or 2.0
mmol) at the appropriate temperature (see Table 1). After being
stirred at that temperature, the precipitate was obtained. If no
precipitate was obtained, n-hexane (30 mL) was added to give the
precipitate. After collection of the solid and drying in vacuo, the
corresponding cyclic compounds (2 and/or 3) were obtained. The
yield of the cation part was estimated from the integration of 1H NMR
by dissolving the cyclic compound (5.0−10.0 mg) and terepthal-
aldehyde or dibenzyl (ca. 10 wt % of the cyclic compound), as an
internal standard, in DMSO-d6. The method for the estimation of
counteranion was described in the text.
5-Iodo-6,12-diphenyl-12H-benz[4,5]imidazo[2,1-a]isoquinolin-7-
−
ium Triiodide (2a+·I3 (X = I3)) and Iodide (2a+·I− (X = I)): Same
−
1
NMR Spectra Were Obtained from 2a+·I3 and 2a+·I−. H NMR
(DMSO-d6, 300 MHz) δ 5.87 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 8.4 Hz,
1H), 7.40 (t, J = 7.6 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.65−7.74 (m,
3H), 7.77 (t, J = 7.4 Hz, 1H), 7.86−7.89 (m, 5H), 7.96 (m, 3H), 8.16
(t, J = 7.4 Hz, 1H), 8.54 (d, J = 8.3 Hz, 1H); 13C NMR (DMSO-d6, 75
MHz) δ 96.1, 113.0, 116.0, 116.2, 125.0, 125.8, 127.4, 127.9, 129.0,
130.1, 130.3, 130.4, 131.8, 132.0, 132.3, 134.1, 134.2, 134.6, 135.48,
−
135.54, 137.0, 139.3, 141.9. 2a+·I3 : 0.340 g of collected precipitate
(entry 6 in Table 1); brown solid; mp = 244 °C (decomp.); IR (KBr
disk) 3118, 3051, 2356, 2337, 1616, 1587, 1516, 1446, 756, 747, 715,
700 cm−1. Anal. Calcd for C27H18I4N2: C, 36.93; H, 2.07; N, 3.19%.
Found: C, 36.83; H, 1.97; N, 3.00%. 2a+·I−: 0.165 g of collected
precipitate (entry 5 in Table 1). Further purification was achieved by
the recrystallization from CHCl3 and hexane; yellow solid; mp = 329−
330 °C; IR (KBr disk) 3120, 3051, 3026, 1617, 1518, 1482, 1466,
1448, 1325, 1025, 759, 716, 701 cm−1. Anal. Calcd for C27H18I2N2: C,
51.95; H, 2.91; N, 4.49%. Found: C, 51.75; H, 2.97; N, 4.48%.
5-Iodo-6-(4-methylphenyl)-12-diphenyl-12H-benz[4,5]imidazo-
[2,1-a]isoquinolin-7-ium Triiodide (2b+·I3− (X = I3)) and Iodide (2b+·
I− (X = I)). Same NMR spectra were obtained from 2b+·I3− and 2b+·I−:
1H NMR (DMSO-d6, 300 MHz) δ 2.59 (s, 3H), 5.98 (d, J = 8.6 Hz,
ASSOCIATED CONTENT
* Supporting Information
■
1H), 7.34 (d, J = 8.3 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1H), 7.46 (d, J = 8.1
Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.67 (m, 3H), 7.76 (t, J = 7.7 Hz,
1H), 7.88−7.97 (m, 5H), 8.15 (t, J = 7.9 Hz, 1H), 8.54 (d, J = 8.3 Hz,
1H); 13C NMR (DMSO-d6, 75 MHz) δ 21.5, 96.9, 112.9, 116.1, 116.2,
125.0, 125.8, 127.5, 128.0, 129.0, 130.0, 130.2, 130.8, 131.9, 132.3,
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b00607.
1H and 13C NMR spectra of the products, list of X-ray
−
134.1, 134.2, 134.3, 134.6, 135.4, 135.6, 139.4, 141.5, 141.9. 2b+·I3 :
1
crystallographic data, H NMR spectrum of precipitate
0.242 g of collected precipitate (entry 8 in Table 1). Further
purification was achieved by the recrystallization from CHCl3 and
hexane; brown solid; mp = 267 °C (decomp.); IR (KBr disk) 3121,
3049, 1616, 1521, 1506, 1481, 1448, 1324, 824, 743, 698 cm−1. Anal.
(Figure S1), ORTEP drawing of crystal structure (Figure
−
S2), and single crystal structures of 3e+·I3 (Figure S3)
and 2a+·I−·(pyridine)0.75 (Figure S4) (PDF)
F
DOI: 10.1021/acs.joc.6b00607
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The Journal of Organic Chemistry
Article
−
X-ray crystallographic data of 2a+·I3− (CIF)
X-ray crystallographic data of 2b+·I3− (CIF)
X-ray crystallographic data of 2c+·I3− (CIF)
X-ray crystallographic data of 3d+·I3− (CIF)
X-ray crystallographic data of 3e+·I3 (CIF)
X-ray crystallographic data of 2a+·I−·(pyridine)0.75 (CIF)
(10) (a) Speranca
G. Tetrahedron Lett. 2011, 52, 388−391. (b) Rosario, A. R.;
́
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, A.; Godoi, B.; Costa, M. D.; Menezes, P. H.; Zeni,
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AUTHOR INFORMATION
Corresponding Author
*Tel.: +81-43-290-3369. Fax: +81-43-290-3401. E-mail:
smatsumo@faculty.chiba-u.jp.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from Research Promotion
on SIS (the Society of Iodine Science).
■
(14) (a) Cavallo, G.; Metrangolo, P.; Milani, R.; Pilati, T.; Priimagi,
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(b) Gilday, L. C.; Robinson, S. W.; Barendt, T. A.; Langton, M. J.;
Mullaney, B. R.; Beer, P. D. Chem. Rev. 2015, 115, 7118−7195.
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DOI: 10.1021/acs.joc.6b00607
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