1,2-Disubstituted Benzimidazoles by the Iron Catalyzed Cross-Dehydrogenative Coupling of Isomeric o-Phenylenediamine Substrates

Article abstract of DOI:10.1021/acs.joc.9b02714

Benzimidazoles are common in nature, medicines, and materials. Numerous strategies for preparing 2-arylbenzimidazoles exist. In this work, 1,2-disubstituted benzimidazoles were prepared from various mono- and disubstituted ortho-phenylenediamines (OPD) by iron-catalyzed oxidative coupling. Specifically, O₂ and FeCl₃·6H₂O catalyzed the cross-dehydrogenative coupling and aromatization of diarylmethyl and dialkyl benzimidazole precursors. N,N′-Disubstituted-OPD substrates were significantly more reactive than their N,N-disubstituted isomers, which appears to be relative to their propensity for complexation and charge transfer with Fe³⁺. The reaction also converted N-monosubstituted OPD substrates to 2-substituted benzimidazoles; however, electron-poor substrates produce 1,2-disubstituted benzimidazoles by intermolecular imino-transfer. Kinetic, reagent, and spectroscopic (UV-vis and EPR) studies suggest a mechanism involving metal-substrate complexation, charge transfer, and aerobic turnover, involving high-valent Fe(IV) intermediates. Overall, comparative strategies for the relatively sustainable and efficient synthesis of 1,2-disubstituted benzimidazoles are demonstrated.

Full text of DOI:10.1021/acs.joc.9b02714

Subscriber access provided by UNIV OF NEBRASKA - LINCOLN
Article
1,2-Disubstituted Benzimidazoles by the Iron Catalyzed Cross-
Dehydrogenative-Coupling of Isomeric o-Phenylenediamine Substrates
Pawan Thapa, Philip M. Palacios, Tam Tran, Brad S. Pierce, and Frank W. Foss
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 13 Jan 2020
Downloaded from pubs.acs.org on January 14, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
,2-Disubstituted Benzimidazoles by the Iron Catalyzed Cross-
Dehydrogenative-Coupling of Isomeric o-Phenylenediamine Substrates
1
1
1
2
1*
Pawan Thapa, Philip M. Palacios, Tam Tran, Brad S. Pierce, Frank W. Foss, Jr.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
Department of Chemistry and Biochemistry, The University of Texas Arlington, Arlington,
Texas, USA 76019-0065
2
Department of Chemistry and Biochemistry, The University of Alabama, Tuscaloosa, Alabama,
USA 35487
*
ffoss@uta.edu
Abstract: Benzimidazoles are common in nature, medicines, and materials. Numerous
strategies for preparing 2-arylbenzimidazoles exist. In this work, 1,2-disubstituted
benzimidazoles were prepared from various mono- and di-substituted ortho-phenylenediamines
(OPD) by iron-catalyzed oxidative coupling. Specifically, O
2
and FeCl36H O catalyzed the
2
cross dehydrogenative coupling and aromatization of diarylmethyl- and dialkyl- benzimidazole
precursors. N,N’-disubstituted-OPD substrates were significantly more reactive than their N,N-
disubstituted isomers, which appears to be relative to their propensity for complexation and
3
+
charge transfer with Fe . The reaction also converted N-monosubstituted OPD substrates to 2-
substituted-benzimidazoles; however, electron-poor substrates produce 1,2-disubstituted
benzimidazoles by intermolecular imino-transfer. Kinetic, reagent, and spectroscopic (UV-Vis
and EPR) studies suggest a mechanism involving metal-substrate complexation, charge transfer,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
and aerobic turn over, involving high-valent Fe(IV) intermediates. Overall, comparative
strategies for the relatively sustainable and efficient synthesis of 1,2-disubstituted
benzimidazoles are demonstrated.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Introduction: Benzimidazoles are heteroaromatic compounds well known for their
medicinal use and material applications as dyes, polymers, metal ligands, and organocatalysts.2-5
Specifically, 1,2-disubstituted benzimidazoles have significant pharmacological utility (Figure
6
7
1
), such as antihypertensive telmisartan (1), non-sedating antihistamine drug mizolastine (2),
agonist (3).8
and GABA
A
Figure 1: A Few Medicinally Important 1,2-Disubstituted Benzimidazoles
By our count, over 400 individual publications describe new methods to prepare
benzimidazoles. Classically, 2-substituted-benzimidazoles are prepared by cyclocondensation
reactions between ortho-phenylenediamines (OPDs) and highly-oxidized functional groups
(carboxylic acids, nitriles, ortho esters) in the presence of strong acids and heat or microwave
conditions.9-10 More mild cyclocondensations were achieved by a variety of reagents, including:
1
1
,12 Sc(OTf)
,13 Cu(OTf)
,14 and CeCl37H
O/CuI. Oxidative cyclizations from
15
DDQ, KHSO
4
3
2
2
alcohols , aldehydes, or amines are known, including our previously reported flavin-catalyzed
as a terminal oxidant.16
oxidative cyclizations with O
2
Benzimidazoles were also synthesized by cross coupling methods through direct C-H
functionalization and C-N bond formation.17-19 A number of methods have been developed that
involve direct C-N bond construction via intramolecular or intermolecular approaches, known as
ACS Paragon Plus Environment

Page 3 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
cross dehydrogenative coupling (CDC) approaches.20-32 CDC reactions formally remove the α-
hydride from amines, ethers, and thiols to generate reactive electrophilic carbon centers,33-45
reminiscent of dehydrogenations performed by metal- or flavin-dependent oxygenases. In this
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
work, relatively inexpensive and safe FeCl36H O is shown to catalyze oxidative intramolecular
2
CDC alpha to the 2º or 3º amines of N-substituted OPDs, to efficiently prepare many 1,2-
disubstituted benzimidazoles (Scheme 1C). While synthetic methods for 1,2-disubstituted
benzimidazoles construction have been developed (1A, 1B),46-55 the oxidative CDC methods
leading to the construction of 1,2-disubstituted benzimidazoles are relatively underexplored.56-58
5
6
These more recent methods involve Cu(II)-mediated aerobic CDC to linear triazoles and tris(o-
phenylenediamine) macrocycles57 The methods describe good yields only for select N,N’-
diarylmethyl-OPDs, and do not investigate other OPD isomers or alkyl-OPD substrates.
Iron trichloride is a valuable catalyst in organic synthesis—available and applicable to a
growing number of transformations.59-61 With relevance to this work, FeCl
is a one electron
oxidant with a Fe /Fe couple (0.771 V vs. standard hydrogen electrode) that can be re-
oxidized by molecular oxygen. Because FeCl is appealing for sustainable chemical
3
3+
2+
3
6
2
methodologies, it is often evaluated for oxidation reactions. This publication describes Fe(III)-
catalyzed aerobic oxidations of various isomers of OPDs, from both mono- and di-substituted
substrates. Furthermore, dialkyl-OPD substrates are demonstrated and reactivity and
spectroscopic comparisons are made to other metal (Fe, Cu, Ag) catalysts.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 1: Dehydrogenative Construction of 2-Substituted and 1,2-Disubstituted Benzimidazoles: (A) Strategy with
aerobic TEMPO catalyst, (B) Strategies with anaerobic H -transfer by Ir and Ru catalysts, and (C) an aerobic Fe
2
catalyst, presented here, comparing various o-phenylenediamines.
Results and Discussion: During the synthesis of N,N-disubstituted OPDs, isomeric N,N’-
OPDs were occasionally prepared and isolated. As described below, these N,N’-isomers became
more efficient substrates for cross-dehydrogenative coupling by aerobic Fe(III) catalysis. Our
efforts began with a comparative study of 1,2-disubstituted benzimidazole formations from N,N’-
disubstituted-OPD (1) and N,N-disubstituted-OPD (3, Scheme 2). Whether investigating
dibenzyl-OPDs (1a vs. 3a) or dioctyl-OPDs (1o vs. 3l), the N,N’-system, bearing two 2º amines,
reacted faster and reached greater yields compared to the N,N-disubstituted-OPDs. To rule out an
autocatalytic process, dependent on assembly of a ligand dependent catalyst that could act on either
substrate, a competitive experiment (Scheme 2C) was performed, producing corresponding 1,2-
disubstituted benzimidazole 2u in excellent yield along with 89% of recovered N,N-OPD 3o
ACS Paragon Plus Environment

Page 5 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
starting material. Time dependent NMR experiments of a 1o and 3m mixture showed similar
selectivity (Figure SI-9). Reaction conditions were then improved for N,N’-disubstituted
substrates.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 2: Comparative studies performed on isomeric substrates: (A) N,N-dibenzyl-OPD and N,N’-dibenzyl-OPD
each 0.5 mmol in separate vessels; (B) N,N-dioctyl-OPD and N,N’-dioctyl-OPD each 0.5 mmol in separate vessels;
(
C) Competitive mixture of N,N-dibenzyl-5-fluoro-OPD and N,N’-dibenzyl-4-OPD in the same vessel.
A univariate investigation of reaction catalysts, solvents, oxidants, and additives was
undertaken. FeCl36H
Polar aprotic solvents were preferred to non-polar solvents (see Table S2). Various O
containing atmospheres were investigated (Table 1). Interestingly, open-air vessels appear
2
O performed best among the investigated metal sources (see Table S1).
2
-
superior to higher concentrations of O
2
(balloon or closed vessel, entries 9 and 11). Oxidant t-
; 3 however, this
BuOOH is known to perform benzylic oxidations in the presence of FeCl 6
3
additive diminished yields (25% yield) and led to many byproducts (entry 12). Additives such as
butylated hydroxytoluene (BHT), K CO3, and TEMPO either diminished (K CO , BHT) or had
no effect (TEMPO) on yields (entries 6, 7 and 8).
2
2
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 1: Select reaction optimization conditionsa
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Cat. (mol%),
atmosphere
Additive
(Equiv.)
% NMR
yield
Entry
FeCl
3
•6H
air
none,
air
2
O (5),
1
2
-
-
-
-
-
90
ND
86
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
3
3
3
3
3
3
3
•6H
air
•6H
Ar
•6H
air
•6H
air
•6H
air
•6H
air
2
2
2
2
2
2
2
O (5)
O (5)
O (5)
O (5)
O (5)
O (5)
O (5)
3b
4
ND
78
5c
6
2 3
K CO
ND
(1 equiv.)
TEMPO
(1 equiv.)
BHT
72d
7
8
61
25
57
58e
25
60
(1 equiv.)
•6H
9
-
-
-
capped vial
FeCl •6H O (2. 5)
3
2
1
1
1
0
1
2
air
FeCl
3
3
3
2
•6H O (5)
balloon
•6H
air
•6H
air
O
2
FeCl
2
O (5)
tBuOOH
(2 eq)
FeCl
2
O (1)
13f
-
a
All reactions performed on 1a (20 mg, 0.5 M) scale for 3 h, with
b
c
o
d
2 2
CH Br as an internal standard; dark; 60 C; isolated yield performed
on 100 mg scale; 12% unreacted material and 5-10% imine; 24 h ND =
not detected
e
f
Various substrates were tested with consistent reaction conditions from these investigations
(
Table 2). In most cases, good yields were obtained in three hours. Control reactions seemed to
provide trace products, which were not detected by NMR but appeared visible by TLC analysis.
Electronic effects appear to play a minor role in N,N’-dibenzyl-OPDs (2b-2i) substrate
reactivity. Steric effects were observed for the ortho-substituted series (2c, 2e) and the isomeric
series (2b, 2c, 2d); however, these changes were relatively small based on end point analysis of
the reactions. Two grams of substrate 1c gave 2c in 79% isolated yield. π-deficient OPD 1k
ACS Paragon Plus Environment

Page 7 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
provided lower yields. The naphthylenyl substrate (1j) offered lower yields, and though the
reaction mixture was fully soluble, starting material remained unreacted. To our delight, N,N’-
diallylic (1l) and N,N’-dialkayl substrates (1m-1q) provided useful yields revealing the
versatility of this method. 1p showed no detectable ring opened products, suggesting that α-C-
H’s in this system are not removed by H-atom abstraction. Non-symmetrical disubstituted
substrate 1r and 1s yielded only one detectible benzimidazole isomer, 2r and 2s respectively;
the selectivity matched relative C-H bond dissociation energies. Non-symmetric dibenzyl
substituted 1t, however, gave two isomeric benzimidazole product in 3:1 mixture, again
favoring cyclization with the more labile benzylic C-H position. In most cases, no starting
materials were detected under the reported reaction times.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 2: Substrate scope for N,N’-disubstituted-o-phenylenediaminea
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
b
c
Reaction conditions:1b-1r (0.3 mmol), DMF (0.5 M). isolated yield on 2-gram scale reaction at 10 h. 16 h
d
e
reaction. 14 h reaction. 0.5 mmol scale
With these results in hand, isomeric substrates N,N-disubstituted-OPDs, including
tetrahydroisoquinoline (THIQ) derivatives, were investigated (Table 3). THIQ derived
benzimidazoles find utility as functional molecules in a variety of fields.64-66 Comparatively,
N,N-disubstituted substrates in Table 3 reacted more slowly than the N,N'-disubstituted
substrates above. Nonetheless, the substrates showed a fair scope, especially those associated
with THIQ moieties.
In this series of substrates, an apparent electronic effect was consistent with increasing
positive charge in critical high energy transition states, likely during an oxidation step described
ACS Paragon Plus Environment

Page 9 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
below. Electron deficient OPDs (3b and 3c) were poor substrates compared to electron rich
OPDs (3d-3h). A silyl protecting group was well tolerated under the condition as depicted in
entry 4g. Isoindoline substrate (3i) gave an over-oxidation cyclic amide product, albeit with
reduced yield. The production of 4i, however, occurred faster than the THIQ substrate, with full
conversion of starting materials. A plausible explanation for further oxidation involves trapping
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
an iminium ion intermediate with H
2
O
2
(or H
O), followed by oxidation and tautomerization.67-68
2
N,N-disubstituted-OPDs with benzylic substituent, 3l, provided good yields. However, only
trace amounts of product were seen for non-THIQ heterocycle containing substrates (3k, 3m and
3
n). On the contrary, 3j converted to the corresponding product 4j. Overall, poly-substituted
benzimidazoles were synthesized in useful yields from aerobic iron trichloride catalyst system
for the substrates represented in Table 3. However, the vast difference in isomer reactivity, such
as 3m compared to 1o helped to inform our understanding of potential mechanisms, as discussed
below.
Table 3: Substrate scope for N,N-disubstituted-o-phenylenediaminea
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
b
Reaction conditions: 3 (0.3 mmol), DMF (0.5 M solution). 24-hour reaction
The synthesis of 2-substituted benzimidazoles was considered (Table 4). Mono-substituted
OPDs containing benzyl groups (5a-5f) were effective substrates under the general condition.
However, the 4-fluorobenzyl substrate, 5g, experienced intermolecular group transfer, leading to
a mixture of mono and di-substituted products and suggesting an imine intermediate for at least
these substrates. The major product was a 1,2-disubstituted benzimidazole, 6g’. Substrates with
aliphatic substituents (5i-5k) or electron poor substrates (5h) also provided 1,2-disubstituted
benzimidazoles presumably through an imino group transfer. These observations suggest that
electron withdrawing groups and alkyl substituents have greater tendency for imine hydrolysis or
transfer—occurring after formation of the oxidized, but acyclic imine intermediate.
Interestingly, allylic substituted substrate 5l afforded 1-allylbenzimidazole, presumably due to
cleavage of the 2-vinyl group after formation of 1,2-diallyl-OPD. A control reaction with DMF-
d gave the same non-deuterated product 6l in 26% yield with no deuterated product observed,
7
which rules out DMF solvent as a C2 source for 6l. The imino transfer observed by mono-
ACS Paragon Plus Environment

Page 11 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
substituted OPDs is supportive of an imine’s intermediacy in the mechanism, though no imines
were observed during the standard transformation conditions.
Table 4: Substrate scope for N-substituted-o-phenylenediaminea
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
b
c
d
e
Reaction conditions: 0.3 mmol, 0.5 M. Yields in parenthesis represent NMR yield. 48 h, 16 h, 24 h reaction.
To investigate the mechanism and relative rates of the various OPD isomers further, the
progression of reactions was initially followed by UV-visible spectroscopy under aerobic and
anaerobic conditions. N,N’-diethyl-OPD 1m was investigated because it reacts on a useful
timescale. At low temperature, -78 ºC, two peaks are observed ca. 505 nm and 535 nm, the
energy and intensity of these features were consistent with charge transfer bands between the
ligand and metal, LMCT having been previously observed by OPD ligands (Figure 2, orange
trace).69-70 Equivalent reactions performed at ambient temperature exhibited an additional
absorption feature at ca. 800 nm (light blue trace). Similar charge transfer spectra have been
III
reported for a variety of high valent metal-oxo species [Fe -O-O-R (where R = H or Fe) or
IV
Fe =O] generated upon addition of molecular oxygen to reduced non-heme mono- and dinuclear
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
iron synthetic model complexes and metalloenzymes.71-76 At increased temperature, peaks at
5
00 nm and 800 nm became more pronounced (grey trace). Additional UV-visible
measurements were made with degassed solvent to clarify the origin of the 800 nm charge
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
transfer feature. As illustrated in Figure 2, the 800 nm absorbance was not observed under
anaerobic conditions (blue trace). However, addition of H
2
2
O (10 mol equivalents) to an
anaerobic reaction restored the 800 nm peak (yellow trace); thus, supporting the conclusion that
this feature may be attributed to an iron-oxo species.
aerobic at -78
2
aerobic at RT
aerobic at 60 °C
1
0
.5
1
anaerobic at RT
H₂O₂ + anaerobic at RT
.5
0
4
00
600
800
1000
Wavelength (nm)
Figure 2: Absorbance spectra of crude reaction sample containing N,N’-diethyl-o-phenylenediamine (1m) (7.5
mM) (w/FeCl
3
(0.75mM) at different condition at 5-minute reaction time
o
A time course study performed at elevated temperature (60 C) under aerobic condition
initially showed three bands (500 nm, 535 nm, and 800 nm), which later decreased and an
appearance of a new band around 370-375 nm was observed (Figure 3A). The new peaks
correspond to product as confirmed by mixture of the pure product and FeCl under similar
3
reaction concentrations (Figure S8). Interestingly, no clear electronic bands were observed in
the case of isomeric substrate N,N-diethyl-o-phenylenediamine 3m. A small shoulder around
5
00 nm was observed but ruled out as being a charge transfer band with the substrate, because
ACS Paragon Plus Environment

Page 13 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
the spectrum of FeCl
3
and DMF showed the appearance of an identical curve (blue trace in
Figure 3B).
before heat
A
B
B
10 min
30 min
Abs (1 min)
2
2
1
0
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Abs (30 min)
Abs (240 min)
3
hour
1
0
16 hour
350
550
750
950
3
50
550
750
950
Wavelength (nm)
wavelength (nm)
Figure 3: (A) Spectral time course for N,N’-diethyl-o-phenylenediamine (1m) (7.5 mM) ( w/FeCl
aerobic conditions; (B) Spectral time course for N,N-diethyl-o-phenylenediamine (3m) (7.5 mM) w/FeCl
aerobic condition (Curve matches FeCl + solvent spectrum with blue curve trace in graph B as Abs, 1 min)
3
(0.75 mM) at 60 °C and
3
(0.75 mM) at RT and
3
Comparative studies at elevated temperature (60 °C) were performed with three different
metal salts, FeCl36H O, CuCl , and AgCl (Figure S4-S6). In all cases, we saw similar
2
2
characteristic charge transfer bands ~ 500 nm for the N,N’-OPD substrate 1m. However, the
broad 800 nm feature was absent in reactions performed using copper and silver, suggesting the
importance of iron/O
2
reactions in the overall catalytic oxidation of OPDs. Of note, in CuCl
2
reactions, lower energy features (λmax ~ 750 nm) were observed after 24-hours (Figure S5). In
these experiments, the concentration of transient absorption features was not determined and thus
their molar extinction coefficients were unknown.
EPR spectroscopy was used to follow the speciation of iron at selected points in the reaction.
Pre-oxidative samples were made by preparing samples of 0.1 M 1m and 0.1 mol. equivalent FeCl
3
o
in degassed DMF under strict anaerobic conditions. Samples were heated to 60 C and allowed to
react for one- and 10-minutes prior to transferring into an EPR tube and quenching in liquid
nitrogen (77K). As shown in Figure 4 (trace A), the transverse mode EPR spectra of samples
collected anaerobically at one-minute shows two distinct paramagnetic species. The observed
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
isotropic feature at g ~ 4.3 signal originates from a transition within the middle doublet of the S =
5
/2 spin system with a large rhombic zero field splitting (E/D ~ 0.29). In the good quantum number
= |±3/2>” doublet.75, 77 These
regime, this would be designated as a transition within the “m
s
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
features are consistent with a mononuclear high spin ferric site similar to hexaquaFe(III). For
clarity, this species will be referred to as (1a) henceforth. An additional isotropic S = 1/2 signal is
observed at g = 2.005 in Fig.4 (trace A). The line width, g-values, and microwave power saturation
behavior of this species is consistent with those observed for organic radicals (R•); this signal
likely originates from the one-electron oxidized substrate cation-radical, presumably the
semiquinone form of OPDs.
Fig.4 (spectrum B) shows the EPR spectra for the same one-minute (anaerobic) sample in
which the applied microwave field (B
1
) is polarized parallel to the static magnetic field (B ). Under
0
such conditions, the EPR selection rules are altered to favor observation of transitions with an
integer-spin.78-79 At 4.2 K, the broad signal observed with a valley at g ~ 8.8 is indicative of high
spin ferrous iron (S = 2).73, 80-81
o
As indicated in Fig. 4 C, anaerobic samples allowed to react for a longer time at 60 C (10-
minutes) showed further speciation of high spin ferric species. In this sample, the amount of (1a)
associated with the isotropic g ~ 4.3 signal is significantly attenuated. However, a new (S = 5/2)
species [designated (1b)] is identified with observable g-values at 8.7 and 5.2. These new signals
7
7
are also associated with a mononuclear high spin iron complex; however, the rhombicity of (1b)
is more axial than (1a) [E/D = 0.18 versus 0.29, respectively]. This suggests a ligand exchange
occurs at the mononuclear Fe(III) site at increased time points under these anaerobic conditions.
ACS Paragon Plus Environment

Page 15 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 4: Dual mode X-band EPR spectra of reactions prepared anaerobically (spectra A-C) as compared to aerobic (D). Spectra
1
were collected for both transverse (A, C, and D) and parallel B -field polarization (B). Spectroscopic simulations (dashed blue
lines) were calculated and overlaid on data for all S > 1/2 species. Sample conditions: anaerobic samples contain 0.1 M 1m and
o
(
3
0.1 equiv.) FeCl prepared in degassed DMF and heated to 60 C. At selected time points, 1- (A and B) and 10-minutes (C),
aliquots were transferred into an EPR tube and frozen in liquid nitrogen. Equivalent aerobic samples (D) were prepared for
comparison. Instrumental conditions: temperature, (A, C, and D) 10 K, (B) 4 K; microwave frequency, [transverse] 9.65 GHz (A,
C, and D), [parallel] 9.38 GHz (B); microwave power, 40µW (A, C, and D), 0.32 mW (B); modulation amplitude, 0.9 mT.
By contrast, nearly all ferrous iron is absent in aerobic reactions quenching at one- and 10-
minutes. While still present, the amount of the g ~ 2.005 radical species is decreased in aerobic
reactions quenched at one-min as compared to anaerobic samples. However, in addition to the
aforementioned radical and ferric species observed anaerobically, an entirely new EPR signal (Int)
with g value at 3.85 is observed in samples where oxygen was introduced. For clarity, the signal
associated with this signal is isolated and scaled 2x below trace D. The contribution from (Int) is
easy to miss as its intensity is much lower than the adjacent (1a) high spin Fe(III) site [shown in
Fig. 4A]. However, unlike the isotropic g ~ 4.3 signal, (Int) g-values span 4.14 to 2.0 and thus its
integrated contribution is half that of (1a).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Collectively, these observations are in good agreement with the general mechanistic model
proposed below. Specifically, rapid electron transfer between the organic substrate and FeIII-
catalyst are supported by the direct observation of an organic radical (S = 1/2) and high spin ferrous
iron (S = 2) by EPR spectroscopy. Further, the subsequent loss of Fe(II) and formation of the of
the (Int) S = 3/2 Fe-species is consistent with formation of a high valent iron-oxo species upon
addition of molecular oxygen.72, 82-83 While additional spectroscopic experiments are needed for
corroboration, the observed S = 3/2 species produced following addition of molecular oxygen is
reminiscent of the so-called Compound I intermediate identified in horse radish peroxidase (HRP),
catalase (Cat), and lignin peroxidase (LiP).74, 76 In these enzymes, the S = 3/2 spin state originates
from a ferromagnetic coupling between a low-spin Fe(IV)-oxo (S = 1) and the coordinating
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
IV
porphyrin radical cation (P•, S = 1/2) [Fe O/P•]. While such studies are beyond the scope of this
report, ongoing experiments are in progress to evaluate the kinetic mechanism and
spectroscopically characterize iron-oxo intermediates produced in this reaction.
Though not specifically observed in the reactions, the reactivity of potential oxidized imine
intermediates was investigated, by subjecting various species to there action conditions (Scheme
3
). Mono-imine substrates 5ai and 5hi gave the corresponding 2-phenylbenzimidazole products
(entry 1 and 2). A 2:3 mixture of mono-imine 1ei and substrate 1e (obtained by partial preparation
of 1e) gave 1,2-disubstituted product 2e in ~80% yield (entry 3). By contrast, diimine
intermediates demonstrate hydrolysis products in excess of trace products(entry 4) and supports
the generation of a mono-imine intermediate during the transformation. An imine intermediate was
only observed when reactions containing sub-stoichiometric or excess base (K
2
CO ) provided no
3
desired benzimidazole product along with the accumulation of trace mono-imine species (entry 5).
ACS Paragon Plus Environment

Page 17 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3: Evidence of potential intermediates.
Interestingly, we found that the hydrogen atom alpha to our amines, which must be lost as H+ or
H• to generate an imine such as 5ai, were not part of the rate determining step by kinetic isotope
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
effect studies. Deuterated and non-deuterated substrate (1m) revealed k
H
/k = 1.0 ± 0.13. So, for
D
these substrates, we believe the loss (or rearrangement) of this α-H+/H• must be relatively
8
6
rapid. Considering these results, early Fe/OPD research, and more recent literature related to
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
87
non-innocent PDA ligands on metal centers, we considered the intermediacy of a
benzoquinone diimide, which could be expected to rapidly rearrange to mono-imine
intermediates. Oxidation of 1v (eq. 5) by the reaction system cannot rearrange to mono-imines.
Though a benzoquinone diimide (1v-di) was not isolated as complexed to Fe or trapped by
dienophile or thiol additives, aposafrinone 7a was isolated in 15% as a red solid. The production
of 7a can be imagined to proceed through the proposed benzoquinone diimide 1v-di by
electrocyclization or electrophilic aromatic substitution.
A possible reaction mechanism based on the collective information is proposed for further
consideration (Figure 5). As suggested by anaerobic UV-Vis and EPR study, the OPD substrate
exchanges ligands with Fe(III) to form a new complex (I). This complex likely experiences
initial charge transfer from the ligand to the metal to produce a Fe(II)-bound radical cation (II).
As the isolated radical and Fe(II) are observed by EPR, it is possible that these species are in
equilibrium with the Fe(II)-bound radical.84 Oxidation of species II in the presence of oxygen
appears to give a high valent iron(IV)-oxo complex (III), as suggested by UV-vis studies and
-
from s=3/2 spin state in EPR data for the aerobic sample. Additional e transfer from ligand to
the Iron species III generates iron(III)-oxo complex (IV) as well as the two electron oxidized
8
5
O
, generating OPD2+.
ligand intermediate. Electrophilic iminium species IV, can eliminate H
2
2
2
+
The structure of OPD has not been observed directly, but may be the imine VII. However, the
data also allow for the benzoquinone diimide form, VI, based on previous reports of metal/OPD
redox transformations,86-87 supported by the KIE experiments, and the unexpected generation of
ACS Paragon Plus Environment

Page 19 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
aposafrinone. If generated as a complex or in its free state, VI would expectedly rearrange to the
imine intermediate VII, restoring aromaticity. Nucleophilic attack by the proximal nitrogen
provides the cyclized benzimidazoline species VIII. Dehydrogenation of the benzimidazoline
species is rapidly achieved by aerobic or acid-catalyzed conditions to give the desired
benzimidazole product P.16, 22, 24, 88 The coordination of N,N’-disubstituted OPD substrate to
Fe(III) is strongly suggested by UV-Vis and EPR experiments. Whether oxidation of N,N-
disubstituted or mono-substituted OPD species occur after ligation to Fe, or in an outer-sphere
fashion is less certain. These substrates react more slowly and do not demonstrate charge transfer
bands in UV experiments. Certainly, if a benzoquinone diimide structure is required for all
substrate classes, the tertiary amine of the N,N-disubstituted substrates 3 would require a higher
energy iminium intermediate than the N,N’-disubstituted 1 substrates. Further kinetic studies and
structural evidence is required to further elucidate the mechanisms for these interesting redox
active substrates/ligands.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 5: Plausible mechanistic details for the synthesis of 1,2-disubstuted benzimidazole products. V
may lead to literature proposed structures VI or VII directly.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Conclusion: Here, 1,2-disubstituted benzimidazoles are accessed from readily prepared N,N-
and N,N’-disubstituted o-phenylenediamines. Both alkyl and arylmethyl substrates undergo the
transformation with surprising ease considering the difference in bond dissociation energies for
alpha-protons of each substituent class. An interesting difference was observed for isomeric
substrates; with N,N’-disubstituted OPD’s converging to 1,2-disubstituted benzimidazoles more
efficiently than their N,N-disubstituted OPD isomers. This difference in isomeric substrate
selectivity appears to be directly related to the coordination of Fe(III) species based on
spectroscopic investigation, and the ease of oxidation of N,N-OPDs as non-innocent ligands,
allowing for enhanced SET. Group transfer was observed in mono-substituted OPDs, for
electron deficient substrates, also leading to 1,2-benzimidazoles. This relatively mild and
sustainable protocol also prepares polycyclic benzimidazoles. With convenient access to various
substrates, through orthogonal chemistries, we believe this work provides alternative approaches
to 1,2-disubstited benzimidazoles and potential guidance for future catalyst design.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
EXPERIMENTAL SECTION:
General Comments:
Chemicals were purchased from Alfa Aesar, Sigma Aldrich and Acros Organics and were used
without further purification. Unless otherwise specified, all reactions were performed under
1
atmospheric conditions and all reagents were weighed and handled in air at room temperature. H
NMR spectroscopic data were recorded on 300 MHz and 500 MHz spectrometers and referenced
to the internal solvent signals (7.26 ppm in CDCl
3
or 3.33 ppm in CD OD or 2.5 ppm in DMSO-
3
d
6
). 13C NMR spectroscopic data were recorded on 75 MHz and 125 MHz spectrometers
referenced to the internal solvent signals (central peak 77.00 ppm in CDCl
3
or 45.00 ppm in
CD OD or 39.5 in DMSO-d ). Dibromomethane and anisole were used as internal standards during
3
6
optimization of reaction conditions and kinetic studies. NMR data are reported as follows:
ACS Paragon Plus Environment

Page 21 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
chemical shift (in ppm, δ), integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, br = broad), coupling constant (in Hz). Thin layer chromatography experiments
were done on silica gel coated aluminum plates (EMD Merck F254, 250 mm thickness). 254 nm
ultraviolet light, Ninhydrin and Iodine stain were used to visualize spots. Flash column
chromatography was performed with Silicycle Siliaflash P60 silica gel (mesh 230-400). IR spectra
were obtained in Bruker Alpha-P FT-IR Spectrometer using attenuated total reflectance on a
diamond sample plate. Melting points were recorded in capillary tubes on a Mel-Temp II apparatus
and were uncorrected. Electron Paramagnetic Spectroscopy (EPR) experiments were recorded on
a Bruker (Billerica, MA) EMX Plus spectrometer equipped with a bimodal resonator (Bruker
model 4116DM). HRMS data were obtained in Shimadzu TOF spectrometer in the Shimadzu
Center for Advanced Analytical Chemistry at UT Arlington.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
General Procedures for synthesis of Starting Materials:
A. General procedure for synthesis of starting materials N,N’-dialkyl-o-phenylenediamine
(1a-1e, 1g-1j, 1l, 1n, 1o and 1q) N,N-dibenzyl-o-phenylenediamine (3a) and N-alkyl-o-
phenylenediamine (5a-5g and 5i-5l):
8
9
Following a known procedure , o-phenylenediamine (4.32 g, 40 mmol) and K
2
CO (5.52 g, 40
3
mmol) were added with 40 mL methanol in a flame dried round bottom flask. Alkyl or Aryl
bromide (30 mmol, 1 equiv.) was added drop-wise into the reaction vessel. The resulting mixture
was stirred for 4 hours at room temperature. When most of the starting materials were consumed
as indicated by TLC, 15 mL of water was added, and the solution was extracted with
dichloromethane (3×20 mL). The organic phase was dried in anhydrous Na
2
SO . The solution was
4
concentrated under reduced pressure and the crude products were purified with column
chromatography in silica gel using hexanes and ethyl acetate as eluents.
Starting material 3a, 5a-5g and 5i-5l were obtained as byproducts during the preparation of
respective N,N’-dialkyl-o-phenylenediamine derivatives.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
B. Procedure for synthesis of starting material 1f:
9
0
Following a known procedure , o-phenylenediamine (1.08 g, 10 mmol) and salicylaldehyde (2.44
g, 20 mmol) were added in 25 mL of Methanol. The resulting mixture was refluxed until orange
coloured precipitates were observed. The solution was cooled to room temperature and sodium
borohydride (1.45 g, 50 mmol) was added in portion wise until yellow transparent solution was
obtained. The reaction mixture was poured into 50 mL of distilled water and allowed to stand until
white precipitates were formed. The resulting solid was filtered and was successively washed with
cold water and cold diethyl ether (5 mL) to obtain 81% (2.59 g) of desired product 1f.
C. Procedure for synthesis of starting material 1k, 5h and 5hi:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
91
Following a known procedure , 2,3-diaminopyridine (0.82 g, 7.5 mmol), dried molecular sieves
(2.5 g, 4 Å), and benzaldehyde (0.9 mL, 9 mmol) were added in benzene (50 mL). The resulting
mixture was refluxed for 3 h, after which the mixture was brought to room temperature and
continued stirring for another 20 h. The solid was filtered and washed with cold ether (5 mL). The
filtrate was concentrated under reduced pressure and the crude product was dissolved in 50 mL of
ethanol followed by portion wise addition of sodium borohydride (2 g). The mixture was refluxed
in oil bath for another 18 h. The reaction mixture was then cooled to room temperature and
quenched with water (50 mL). The aqueous solution was extracted with methylene chloride (20
mL×2), dried with anhydrous Na
2
SO and concentrated under reduced pressure. The crude product
4
was purified with flash column chromatography using ethyl acetate and acetone in 1:1 ratio as
eluents to obtain 54% (1.17 g) of desired product 1k as brown solid.
Starting material 5h was synthesized in 67% as brown liquid by following similar procedure as
described above except the benzaldehyde was used in 4.5 mmol scale. Starting material 5hi was
obtained as intermediate during preparation of 5h in 88% yield as yellow solid.
ACS Paragon Plus Environment

Page 23 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
D. Procedure for synthesis of starting material 1m, 1p and 1m-D :
4
9
2
Following a known procedure , a mixture of ortho-phenylenediamine (1 g, 9.2 mmol) and acetic
anhydride (1.9 g, 18.5 mmol) or cyclopropanecarbonyl chloride (1.93 g, 18.5 mmol) in 2 mL
acetic acid was added with LiCl (20 mg, 0.46 mmol) at room temperature. The solution was
stirred for 1 hour. A white solid immediately formed. The solution was diluted with 5 mL water
and the solid was filtered off, washed with 10 mL water and dried under vacuum to afford 75-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
0% of diamide intermediate. This intermediate (2.0 mmol) was dissolved in 15 mL dry THF
solvent and cooled in ice-water bath. LiAlH (380 mg, 10 mmol) was added in small portion.
The mixture was removed from the ice water bath and refluxed for 4 hours after which it was
carefully quenched with water and saturated Na CO solution under ice cold condition. The
4
2
3
white precipitates were filtered, and the filtrate was concentrated under reduced pressure. The
crude product was purified with column chromatography in silica gel using hexanes and ethyl
acetate in 10:1 as eluents to obtain 1m in 66% (216 mg) as pale pink liquid and 1p in 68% (292
mg) as clear liquid.
Synthesis of substrate 1m-D4 was performed like synthesis of substrate 1m except LiAlD
4
was
used as a reducing agent and 0.8 mmol scale of diamide intermediate was used.
E. Procedure for synthesis of starting material N-benzyl-N’-methylbenzene-1,2-diamine
(1r),
N-benzyl-N’-butylbenzene-1,2-diamine
(1s)
and
methyl
4-(((2-
((benzylamino)phenyl)amino)methyl)benzoate (1t):
N-methyl-o-phenylenediamine (122 mg, 1.0 mmol) or N-butyl-o-phenylenediamine (164 mg, 1.0
mmol), benzyl bromide (115 µL, 0.9 mmol) and potassium carbonate (138 mg, 1.0 mmol) were
mixed in 5 mL Methanol. The mixture was stirred for 4 hours at room temperature. The solution
was directly concentrated under reduced pressure and purified in column chromatography using
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
hexanes and ethyl acetate in 5:1 ratio as eluents to obtain 1r in 39% as brown liquid and 1s in
4
6% as pale brown liquid.
1t was synthesized as follows: solution of methyl 4-(bromomethyl)benzoate (1.0 mmol, 229 mg)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
in acetonitrile was added dropwise into the mixture of N-benzyl-o-phenylenediamine (1.0 mmol,
1
98 mg), potassium carbonate (1.0 mmol, 138 mg) and 5 mL acetonitrile. The resulting mixture
was stirred at room temperature for 4 hours. After that the solution was filtered and the solid was
washed with 2 mL acetonitrile. The combined filtrate solution was concentrated in rotary
evaporator before isolating the desired product in column chromatography using hexanes and
ethyl acetate in 10:1 ratio as eluents. 1t was obtained as pale-yellow liquid in 51% yield.
F. General procedure for synthesis of starting materials 3b-3n:
27
Following a known procedure , amine (10 mmol, 1 equiv.) and 2-fluoronitrobenzene (1.41 g, 10
mmol) were added to a solution of potassium carbonate (1.65 g, 12 mmol) in DMF (15 mL). The
reaction mixture was stirred at 100 °C in oil bath until the reaction was complete as indicated by
TLC. The solution was cooled at room temperature and diluted with distilled water (50 mL). The
mixture was extracted with ethyl acetate (30 mL×3). The combined organic layer was dried over
anhydrous Na
2
SO and concentrated under reduced pressure. The crude residue was dissolved in
4
methanol (40 mL) followed by careful addition of Pd/C (10 % by weight). The resulting mixture
was hydrogenated (4 atm.) at room temperature for 4 h. The mixture was filtered through celite
pad and washed with methanol (10 mL). The crude product was concentrated under reduced
pressure. The crude product was purified by flash column chromatography over silica gel using
hexanes and ethyl acetate as eluants to obtain 66% -87% of desired products.
Substrate 3c was synthesized following SnCl
2
.2H O reduction of corresponding crude nitro
2
intermediate. In a typical experiment, crude nitro intermediate was added with 4 equivalents of
ACS Paragon Plus Environment

Page 25 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
SnCl
2
.2H
2
O in 30 mL ethanol. The resulting solution was refluxed until the starting material was
consumed as indicated by TLC. The solution was cooled first at ice-water condition and carefully
added with 10% sodium bicarbonate solution until the solution became slightly basic. The solution
was extracted with ethyl acetate (30 mL×3), dried under anhydrous magnesium sulphate and
concentrated under reduced pressure. The crude amine product was purified by column
chromatography using 4:1 hexanes and ethyl acetate as eluents to obtain 3c in 76% (2.3 g) as white
solid.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Substrate 3g was synthesized by tert-butyldimethyl silyl chloride (TBDMS-Cl) protection of
substrate 3f. In a typical procedure, 3f (100 mg, 0.41 mmol) and imidazole (54 mg, 0.8 mmol)
were mixed with distilled THF (5 mL) and stirred under Nitrogen at room temperature. TBDMS-
Cl (94 mg, 0.625 mmol) was then added dropwise over 5 minutes. The mixture was stirred for 14
hours. After the reaction was quenched with 5 mL water, the crude product was extracted with
diethyl ether (5 mL × 3). The combined organic phase was dried under anhydrous Magnesium
sulfate. The crude product was purified with column chromatography using hexanes and ethyl
acetate in 5:1 ratio as eluant to obtain white solid 3g in 55% (79.8 mg) yield.
G. General Procedure for synthesis of benzimidazole products:
N-alkyl-o-phenylenediamine
phenylenediamine (0.3 mmol, 1 equiv.) was added in an oven dried 1.5-dram vial fitted with
magnetic stirrer followed by addition of FeCl36H O (0.015 mmol, 0.05 equiv.) and DMF (0.6
or
N,N-dialkyl-o-phenylenediamine
or
N,N’-dialkyl-o-
2
mL solution). The reaction mixture was stirred at a given temperature in heating mantle with open
cap until most of the starting material was consumed as indicated by TLC experiment. The reaction
mixture was first cooled down to room temperature and then was diluted with 3 mL of H O and
2
extracted with ethyl acetate (5 mL×3). The combined organic layer was dried with anhydrous
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
MgSO
4
and was concentrated under reduced pressure. The crude product was purified by column
chromatography using hexanes and ethyl acetate or dichloromethane and methanol as eluents.
H. Spectroscopic and Analytical data for 1,2-disubstituted benzimidazole products:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-benzyl-2-phenyl-1H-benzo[d]imidazole (2a)20:
1
Purified by column chromatography using hexanes and ethyl acetate in 2:1 ratio as eluants; Yield
1
61% (52 mg), White solid; mp 121-123 °C; H NMR (500 MHz, CDCl
3
) δ 7.88 (d, J = 8.0 Hz,
1
H), 7.73 – 7.67 (m, 2H), 7.51 – 7.43 (m, 3H), 7.37 – 7.29 (m, 4H), 7.26 – 7.19 (m, 2H), 7.11 (d,
1
3
1
J = 7.0 Hz, 2H), 5.47 (s, 2H); C{ H} NMR (125 MHz, CDCl ) δ 154.2, 143.2, 136.5, 136.1,
3
-1
-1
1
30.0, 129.4, 129.2, 128.9, 127.9, 126.1, 123.1, 122.8, 120.1, 110.6, 48.5; IR (neat, cm ) γ/cm :
+
3011, 2899, 1520; HRMS (ESI) calcd for C20
H
17
N [M+H] , 285.1386 found, 285.1387
2
-(2-methylbenzyl)-2-(o-tolyl)-1H-benzo[d]imidazole (2b)20:
1
Purified by column chromatography using hexanes and ethyl acetate in 2:1 ratio as eluants; Yield
1
76% (71 mg), White solid; mp 137-139 °C; H NMR (500 MHz, CDCl
3
) δ7.89 (dd, J = 8.0,
0
2
1
1
.6Hz, 1H), 7.39 – 7.11 (m, 10H), 7.05 – 7.00 (m, 1H), 6.64 (d, J = 7.7 Hz, 1H), 5.19 (s, 2H),
13
1
.25 (s, 3H), 2.15 (s, 3H); C{ H} NMR (125 MHz, CDCl
3
) δ 153.9, 142.9, 138.4, 135.0,
34.9, 134.0, 130.7, 130.4, 129.9, 129.9, 129.7, 127.6, 126.4, 126.1, 125.7, 123.0, 122.5, 120.0,
-1
10.6, 45.8, 19.9, 19.1; IR (neat, cm ): 3061, 3023, 2976, 2944, 2923, 2856, 1454; HRMS (ESI)
+
calcd for C22
H
21
N
2
[M+H] , 313.1699 found, 313.1690
2
0
1
-(3-methylbenzyl)-2-(m-tolyl)-1H-benzo[d]imidazole (2c) :
Purified by column chromatography using hexanes and ethyl acetate in 2:1 ratio as eluants; Yield
1
7
1
7% (72 mg), White solid; mp 136-138 °C; H NMR (300 MHz, CD
3
OD) δ 7.75 (d, J = 7.9 Hz,
H), 7.48 – 7.17 (m, 8H), 7.09 (d, J = 4.0 Hz, 2H), 6.95 (dd, J = 7.6, 3.8 Hz, 1H), 6.51 (d, J = 7.6
1
3
1
Hz, 1H), 5.27 (s, 2H), 2.09 (s, 3H), 2.05 (s, 3H); C{ H} NMR (75 MHz, CD OD) δ 155.1, 143.1,
3
ACS Paragon Plus Environment

Page 27 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
39.5, 136.4, 136.2, 135.4, 131.6, 131.4, 130.9, 130.7, 128.6, 127.1, 126.8, 124.4, 123.9, 119.8,
-1
12.1, 46.5, 19.7, 19.0; IR (neat, cm ): 3080, 2980, 1454; HRMS (ESI) calcd for C22
H
21
N
2
+
[M+H] , 313.1699 found, 313.1693
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-(4-methylbenzyl)-2-(p-tolyl)-1H-benzo[d]imidazole (2d)20:
1
Purified by column chromatography using hexanes and ethyl acetate in 2:1 ratio as eluants; Yield
1
8
1
1% (76 mg), Brown solid; mp 116-118 °C; H NMR (500 MHz, CDCl
3
) δ 7.91 (d, J = 8.1 Hz,
H), 7.63 (d, J = 8.1 Hz, 2H), 7.35 – 7.31 (m, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.23 (dt, J = 8.5, 3.8
Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 5.43 (s, 2H), 2.42 (s, 3H), 2.35 (s, 3H);
1
3
1
C{ H} NMR (125 MHz, CDCl ) δ 154.1, 142.4, 140.4, 137.6, 135.9, 133.3, 129.8, 129.5, 129.2,
3
-1
126.6, 125.9, 123.1, 122.8, 119.6, 110.6, 48.3, 21.5, 21.1; IR (neat, cm ): 3025, 2947, 1611;
+
HRMS (ESI) calcd for C22
H
21
N
2
[M+H] , 313.1699 found, 313.1700
2
-([1,1'-biphenyl]-3-yl)-1-([1,1'-biphenyl]-3-ylmethyl)-1H-benzo[d]imidazole (2e):
Purified by column chromatography using hexanes and ethyl acetate in 2:1 ratio as eluants; Yield
1
7
1% (93 mg), White solid; mp 160-162 °C; H NMR (300 MHz, CD
3
OD ) δ 7.72 (d, J = 8.0 Hz,
1
H), 7.57 (dd, J = 7.6, 1.1 Hz, 1H), 7.47 – 6.90 (m, 18H), 6.80 (d, J = 7.1 Hz, 2H), 6.33 (d, J = 7.7
1
3
1
Hz, 1H), 4.68 (s, 2H); C{ H} NMR (75 MHz, CD
3
OD) δ 155.2, 143.0, 142.8, 142.1, 141.3,
1
1
40.9, 136.3, 134.8, 132.4, 131.7, 131.1, 130.8, 130.2, 129.6, 129.5, 129.5, 129.4, 128.6, 128.5,
-1
28.3, 127.1, 124.3, 123.8, 119.7, 111.6, 46.1; IR (neat, cm ): 3061, 2956, 1448; HRMS (ESI)
+
calcd for C32
H
25
N
2
[M+H] , 437.2012 found, 437.2011
2
0
2-(1-(2-hydroxybenzyl)-1H-benzo[d]imidazol-2-yl)phenol (2f) :
Purified by column chromatography using hexanes and ethyl acetate in 2:1 ratio as eluants; Yield
1
8
0% (76 mg), White solid; mp 203-205 °C; H NMR (300 MHz, DMSO-d
6
) δ 11.05 (s, 1H), 9.92
(s, 1H), 7.71 (dd, J = 6.3, 1.7 Hz, 1H), 7.48 – 7.30 (m, 4H), 7.28 – 7.15 (m, 2H), 7.03 (t, J = 5.8
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 63
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Hz, 2H), 6.89 (t, J = 7.5 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.58 (t, J = 7.4 Hz, 1H), 6.38 (d, J =
1
3
1
7
.5 Hz, 1H), 5.40 (s, 2H); C{ H} NMR (75 MHz, DMSO-d ) δ 156.3, 154.4, 152.1, 141.8, 135.2,
6
131.4, 130.3, 128.3, 126.7, 122.6, 122.5, 122.0, 119.0, 119.0, 118.7, 116.4, 116.2, 115.0, 110.8,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
[M+H]+,
4
3
1
3.2; IR (neat, cm ): 3250 (br), 3072, 2929, 1594; HRMS (ESI) calcd for C20
H
17
N
2
O
2
17.1285 found, 317.1285
-(4-fluorobenzyl)-2-(4-fluorophenyl)-1H-benzo[d]imidazole (2g):
Purified by column chromatography using hexanes and ethyl acetate in 1:1 ratio as eluants; Yield
1
8
2% (79 mg), White solid; mp 106-108 °C; H NMR (500 MHz, CDCl
3
) δ 7.88 – 7.84 (m, 1H),
7
.64 (dd, J = 8.9, 5.3 Hz, 2H), 7.33 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 7.26 (ddd, J = 8.2, 7.1, 1.1
1
3
1
Hz, 2H), 7.22 – 7.19 (m, 1H), 7.15 (t, J = 8.7 Hz, 2H), 7.08 – 6.99 (m, 4H), 5.40 (s, 2H); C{ H}
NMR (125 MHz, CDCl ) δ 164.1 (d, J = 188.2 Hz), 162.1 (d, J = 184.2 Hz), 153.2, 143.2, 136.0,
32.0 (d, J = 3.1 Hz), 131.3 (d, J = 8.5 Hz), 127.7 (d, J = 8.2 Hz), 126.3 (d, J = 3.3 Hz), 123.4,
3
1
1
9
123.0, 120.2, 116.3 (d, J = 14.2 Hz), 116.1 (d, J = 14.4 Hz), 110.4, 47.8; F NMR (471 MHz,
-1
CDCl
3
) δ -109.9, -113.9; IR (neat, cm ): 2921, 1604, 1508; HRMS (ESI) calcd for C20
H
15
F
2
N
2
+
[
M+H] , 321.1198 found, 321.1196
1
-benzyl-5,6-dimethyl-2-phenyl-1H-benzo[d]imidazole (2h):
Purified by column chromatography using hexanes and ethyl acetate in 2:1 ratio as eluants; Yield
1
9
1
3% (87 mg), White solid; mp 190-192 °C; H NMR (500 MHz, CDCl
3
) δ 7.66 (d, J = 6.5 Hz,
H), 7.51 – 7.39 (m, 1H), 7.33 (d, J = 6.1 Hz, 1H), 7.18 – 7.06 (m, 1H), 6.98 (s, 1H), 5.41 (s, 1H),
13
1
2.39 (s, 1H), 2.33 (s, 1H); C{ H} NMR(125 MHz, CDCl
3
) δ 153.3, 141.5, 136.7, 134.6, 132.5,
1
31.8, 130.1, 129.8, 129.2, 129.1, 128.8, 127.7, 125.9, 119.9, 110.7, 48.3, 20.7, 20.43; IR (neat,
-1
+
cm ): 3052, 2945, 1455; HRMS (ESI) calcd for C22
H
21
N [M+H] , 313.1699 found, 313.1690
2
1-benzyl-5,6-difluoro-2-phenyl-1H-benzo[d]imidazole (2i):
ACS Paragon Plus Environment

Page 29 of 63
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Purified by column chromatography using hexanes and ethyl acetate in 1:1 ratio as eluants; Yield
1
8
8% (85 mg), White solid; mp 132-134 °C; H NMR (500 MHz, CD
3
OD) δ 7.65 (d, J = 7.0 Hz,
1
3
1
2H), 7.60 – 7.48 (m, 4H), 7.35 – 7.23 (m, 4H), 7.01 (d, J = 7.4 Hz, 2H), 5.50 (s, 2H); C{ H}
NMR (125 MHz, CD OD) δ 157.2, 150.5 (dd, J = 15.3, 11.5 Hz), 148.5 (dd, J = 15.4, 9.5 Hz),
38.7 (d, J = 9.6 Hz), 137.2, 132.5 (d, J = 11.0 Hz), 131.6 (s), 130.4 (s), 130.3, 130.1, 130.0,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
1
1
-1
29.0, 127.2, 107.1 (d, J = 20.2 Hz), 100.5 (d, J = 23.5 Hz); IR (neat, cm ): 3031, 1522, 1481;
+
HRMS (ESI) calcd for C20
H
15
F
2
N
2
[M+H] , 321.1198 found, 321.1190
1
-benzyl-2-phenyl-1H-naphtho[2,3-d]imidazole (2j):
Purified by column chromatography using hexanes and ethyl acetate in 1:1 ratio as eluants; Yield
1
68% (68 mg), Brown solid; mp 196-198 °C; H NMR (500 MHz, CDCl
3
) δ 8.56 (s, 1H), 8.04
(dd, J = 6.3, 3.4 Hz, 1H), 7.87 (dd, J = 13.1, 5.9 Hz, 4H), 7.71 (s, 1H), 7.62 (t, J = 7.4 Hz, 1H),
7
.56 (t, J = 7.6 Hz, 3H), 7.51 – 7.45 (m, 3H), 7.39 (tt, J = 7.8, 3.7 Hz, 4H), 7.16 (dd, J = 7.8, 1.3
1
3
1
Hz, 2H), 5.65 (s, 2H); C{ H} NMR (125 MHz, CDCl
3
) δ 156.7, 135.3, 131.8, 131.2, 131.1,
1
29.7, 129.5, 129.4, 128.9, 128.7, 128.3, 127.7, 126.0, 125.3, 124.7, 116.1, 107.4, 49.1; IR (neat,
-1
+
cm ): 3056, 3031, 2922, 1493; HRMS (ESI) calcd for C24
H
19
N [M+H] , 335.1543 found,
2
3
35.1546
-benzyl-2-phenyl-3H-imidazo[4,5-b]pyridine (2k) :
9
3
3
Purified by column chromatography using hexanes and ethyl acetate in 1:2 ratio as eluants; Yield
1
4
1% (35 mg), Brown solid; mp 115-117 °C; H NMR (300 MHz, CD
3
OD) δ 8.44 (dd, J = 4.9,
1.4 Hz, 1H), 8.16 (dd, J = 8.1, 1.4 Hz, 1H), 7.68 (dd, J = 8.1, 1.6 Hz, 2H), 7.60 – 7.50 (m, 3H),
7
.43 (dd, J = 8.0, 4.9 Hz, 1H), 7.25 (dd, J = 5.1, 1.9 Hz, 3H), 7.04 – 6.98 (m, 2H), 5.68 (s, 2H);
1
3
1
C{ H} NMR (75 MHz, CD
3
OD) δ 156.6, 149.6, 145.5, 138.1, 135.8, 131.9, 130.7, 130.3,
ACS Paragon Plus Environment