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org/joc Article

Visible-Light-Induced Deaminative Alkylation/Cyclization of Alkyl

Amines with N‑Methacryloyl-2-phenylbenzoimidazoles in
Continuous-Flow Organo-Photocatalysis
Vankudoth Ramesh, Maram Gangadhar, Jagadeesh Babu Nanubolu, and Praveen Reddy Adiyala*
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ABSTRACT: Herein, we present a metal-free visible-light-induced

eosin-y-catalyzed deaminative strategy for the sequential alkyla-
tion/cyclization of N-methacryloyl-2-phenylbenzoimidazoles with
alkyl amine-derived Katritzky salts, which provides an efficient
avenue for the construction of various benzo[4,5]imidazo[2,1-
a]isoquinolin-6(5H)-one derivatives in moderate to excellent
yields under mild reaction conditions. The key enabling feature
of this novel reaction includes utilization of redox-active
pyridinium salts from abundant and inexpensive primary amine
feedstocks that were converted into alkyl radicals via C−N bond
scission and subsequent alkylation/cyclization with N-methacry-
loyl-2-phenylbenzoimidazoles by the formation of two new C−C
bonds. In addition, we implemented this protocol for a variety of amino acids, affording the products in moderate yields. Moreover,
the novel, environmentally benign batch protocol was further carried out in a continuous-flow regime by utilizing a perfluoroalkoxy
alkane tubing microreactor under optimized reaction conditions with a blue light-emitting diode light source, enabling excellent
yields and a shorter reaction time (19 min) versus the long reaction time (16 h) of the batch reaction. The reaction displays excellent
functional group tolerance, easy operation, scalability, mild reaction conditions, and broad synthetic utility.

■ INTRODUCTION
Alkyl amines are widely abundant, readily available, inex-
As a vital class of structurally diverse polycycles,
benzimidazole-fused isoquinoline core frameworks are im-
pensive, and versatile building blocks found in a large number portant surrogates of pharmacophores and have attracted a
great deal of attention from the synthetic organic chemistry
of organic molecules, biologically active pharmaceuticals, drug
community due to their prevalent biological and therapeutical
molecules, and natural products.1 Remarkable progress has
activities such as antimicrobial, antifungal, anticancer, and anti-
been made in activating the C−N bond of alkyl amine
HIV-1 properties as well as their potential as functional
derivatives for the creation of carbon−carbon and carbon−
materials.10 Some of the pharmaceutically important surrogates
heteroatom bonds through C−N bond scission.2 However,
and functional materials having benzimidazo-isoquinoline
methods for their activation are still very limited due to high
tetracyclic core skeletons are depicted in Figure 1.
stability and high bond dissociation energy of inactivated C−N
From the past decade, much synthetic effort has been
bonds of alkyl amine derivatives.3 In 2017, Watson and co-
devoted to the construction of structurally diverse benzo[4,5]-
workers demonstrated that Katritzky salts synthesized via a
imidazo[2,1-a]isoquinoline tetracyclic core skeletons, such as
condensation of the corresponding alkyl amines with a bench-
[4+2] annulation of 2-arylimidazoles and α-diazoketoesters via
stable, commercially available pyrylium salt, were used as Cp*RhIII catalysis,11 decarboxylative radical cascade cycliza-
significant surrogates for the generation of alkyl radical tions,12 palladium-catalyzed intramolecular cyclization of
precursors from inactivated C−N bonds.4 The exciting seminal benzimidazoles,13 radical relay functionalizations,14 dehydro-
reports have attracted a great deal of attention from organic genative coupling of 2-[3,4-dihydroisoquinolin-2(1H)-yl]-
chemists and demonstrated that these redox-activated amines
could be employed as efficient alkyl radical precursors via C−N
bond cleavage, including alkylation,5 alkenylation/alkynyla- Received: July 2, 2021
tion,6 allylation,7 borylation8 and carbonylation reactions.9 Published: September 3, 2021
There is rapidly growing interest in this research area, which
highlights the challenges associated with C−N bond activation
and presents new avenues for forging C(sp3)-hybridized
centers via a deaminative strategy.

© 2021 American Chemical Society https://doi.org/10.1021/acs.joc.1c01555

12908 J. Org. Chem. 2021, 86, 12908−12921
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Figure 1. Important surrogates of benzimidazo-isoquinoline-containing polyhetereocyclic compounds.
Scheme 1. Background and This Work
aniline derivatives,15 TEMPO-mediated C(sp3)−H amina-
tion,16 fac-Ir(ppy)3- and g-C3N4-catalyzed visible-light-induced
radical cascade cyclization,17 TMEDA-catalyzed visible-light-
induced synthesis of perfluoroalkyl-substituted indolo[2,1-
a]isoquinolin-6(5H)-ones,18 and Mn-catalyzed electrochemical
cascade cyclization of alkyl boronic acids with N-substituted 2-
arylbenzoimidazoles.19 However, the utility of all of these
protocols for large scale synthesis is still limited due to the use
of expensive metal catalysts such as Rh, Pd, Mn, and Ir and
stoichiometric acid/base additives, expensive starting materials,
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inevitable metal residue, harsh reaction conditions, longer
reaction times, and limited scale-up potential, which might
hinder its synthetic application especially in the fields of
pharmacy and biotechnology. From the viewpoint of environ-
mental impact, it is highly desirable to construct benzo[4,5]-
imidazo[2,1-a]isoquinolin-6(5H)-one frameworks using an
efficient, environmentally benign, and sustainable approach
(Scheme 1).
Recently, visible-light photoredox catalysis as a renewable
energy source has been recognized as a powerful activation
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Table 1. Optimization of the Reaction Conditions for the Radical Cascade Alkylation/Cyclization of Amine-Derived Katritzky
Salts with N-Methacryloyl-2-phenylbenzoimidazolesa

entry photocatalyst base (equiv) solvent yield (%)b

1 rose bengal K2CO3 (2.0) ACN 22
2 eosin-y K2CO3 (2.0) ACN 40
3 Acr-Mes+ClO4− K2CO3 (2.0) ACN ND
4 rhodamine B K2CO3 (2.0) ACN 34
5 Ru(bpy)3PF6 K2CO3 (2.0) ACN 16
6 Ir(ppy)3 K2CO3 (2.0) ACN 31
7 Ru(bpy)3Cl2·6H2O K2CO3 (2.0) ACN 26
8 eosin-y Cs2CO3 (2.0) ACN 60
9 eosin-y DABCO (2.0) ACN 81
10 eosin-y DBU (2.0) ACN 51
11 eosin-y Na2CO3 (2.0) ACN 56
12 eosin-y DIPEA (2.0) ACN 90
13 eosin-y Et3N (2.0) ACN 72
14 eosin-y DIPEA (3.0) ACN 90
15 eosin-y DIPEA (1.0) ACN 60
16 eosin-y DIPEA (2.0) MeOH ND
17 eosin-y DIPEA (2.0) DCM 40
18 eosin-y DIPEA (2.0) DMF 55
19 eosin-y DIPEA (2.0) DMSO 65
20 eosin-y DIPEA (2.0) THF 50
21 eosin-y DIPEA (2.0) 1,4-dioxane 45
22c eosin-y DIPEA (2.0) ACN 90
23d eosin-y DIPEA (2.0) ACN 74
24e − DIPEA (2.0) ACN ND
25f eosin-y DIPEA (2.0) ACN ND
26g eosin-y DIPEA (2.0) ACN 83
27h eosin-y DIPEA (2.0) ACN 36
a
Standard reaction conditions: 1 (0.3 mmol), 2a (0.36 mmol), catalyst (2 mol %), base (2.0 equiv), and solvent (3 mL), stirred for 16 h, blue LED
light kept 10 cm from the reaction flask. Abbreviations: ND, product 3a not detected via TLC; DABCO, 1,4-diazabicyclo[2.2.2]octane; DIPEA,
N,N-diisopropylethylamine; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene. All of the reactions were performed under a nitrogen atmosphere. bIsolated
yields. cWith 3 mol % catalyst. dWith 1 mol % catalyst. eCatalyst not used. fNo light. gThe reaction was carried out with a green LED light source.
h
Under an open air atmosphere.

protocol in several highly synthetically efficient chemical
transformations.20 As a part of our continuing study of
visible-light-induced photocatalyzed reactions21 for the syn-
thesis of biologically active heterocycles,22 we report herein the
use of alkyl amine/amino acid-derived Katritzky salts as alkyl
radical precursors for the construction of benzimidazole-fused
isoquinoline core frameworks under continuous-flow visible-
light photocatalysis. Despite the significant advances in this
field, to the best of our knowledge, there has been no report of
the construction of benzo[4,5]imidazo[2,1-a]isoquinolin-
6(5H)-ones via a metal-free strategy via C−N bond cleavage
of alkyl amine/amino acid-derived Katritzky salts with N-
methacryloyl-2-phenylbenzoimidazoles under a continuous
flow.
nitrogen atmosphere and visible-light irradiation with 5 W blue
LED light in a batch process. As shown in Table 1, the reaction
was screened using 2 mol % rose bengal as a photocatalyst and
2 equiv of K2CO3 as the base in an ACN solvent for 16 h
(Table 1, entry 1). To our delight, the desired product was
afforded in 22% yield after 16 h. The structure of 3a was
characterized by 1H, 13C, DEPT, and mass spectroscopy. In
addition, a series of photocatalysts such as eosin-y, Acr-
Mes+ClO4−, rhodamine B, Ru(bpy)3PF6, Ir(ppy)3, and Ru-
(bpy)3Cl2·6H2O were tested to check the reaction efficiency
using ACN as the solvent and K2CO3 as the base for 16 h
(Table 1, entries 2−7), and the corresponding product was
obtained in improved yield in the presence of eosin-y as a
photocatalyst (Table 1, entry 2). Furthermore, we investigated

■ RESULTS AND DISCUSSION

To test the hypothesis presented above, we commenced our
study to investigate the optimal reaction conditions, including
photocatalysts, bases, solvents, and reaction times under a
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different bases such as Cs2CO3, DABCO, DBU, Na2CO3,
DIPEA, and Et3N (Table 1, entries 8−13, respectively),
showing that the product was obtained in high yield when 2.0
equiv of DIPEA was used as a base (90%, Table 1, entry 12).
We also examined the amount of base for this transformation
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Scheme 2. Substrate Scope with Respect to N-Methacryloyl-2-phenylbenzoimidazoles in a Batch Reactor
(Table 1, entries 14 and 15). Then we further investigated the
reaction efficiency with other solvents, including MeOH,
DCM, DMF, DMSO, THF, and 1,4-dioxane (Table 1, entries
16−21, respectively). The different amounts of photocatalyst
showed no significant or weaker impact on the yield of the
desired product (Table 1, entries 22 and 23). It should be
noted that no formation of the desired product was observed
in the absence of a photocatalyst or light in ACN (Table 1,
entries 24 and 25).
Varying the light source from a blue LED to a green LED
decreases the yield of the desired product (Table 1, entry 26).
In addition, the level of formation of the desired product was
very low when we conducted the experiment under an air
atmosphere (Table 1, entry 27).
After determining the optimized reaction conditions, we
turned our attention to the evaluation of the substrate scope
and limitations of the developed cascade alkylation/cyclization
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protocol under batch conditions (see Figure S1) as shown in
Schemes 2−4. Various N-methacryloyl-2-phenylbenzoimida-
zoles and alkyl amine/amino acid-derived Katritzky salts were
synthesized by a reported procedure (see Scheme S1). The
reaction was found to work well with a wide variety of
benzimidazole derivatives with electron-withdrawing substitu-
ents (-CN and -NO2) or electron-donating substituents (-tBu
and -OMe) on the 2-phenyl ring, and the compounds were
transformed into the corresponding desired products in
satisfactory yields (Scheme 2, 3b−3e). In addition, the
structure of 3b was further confirmed by X-ray crystallography
analysis (see the Supporting Information for the details;
CCDC 2065408, Figure S5). The reactions proceeded
smoothly and produced the desired products in good yields
when the halogen substituents were introduced into the 2-
phenyl ring of benzimidazole (Scheme 2, 3f and 3g). This
transformation also proceeded well when the ortho-substituted
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Scheme 3. Substrate Scope with Respect to Substituted Benzylic and Amino Acid-Derived Katritzky Salts in a Batch Reactor
2-phenyl ring benzimidazole derivatives were employed as
starting materials and delivered the corresponding products in
moderate to good yields (Scheme 2, 3i and 3j), and this
indicates that steric hindrance also did not effect the reaction.
Additionally, an electron-donating meta substituent on the 2-
phenyl ring of the benzimidazole derivative also displayed good
compatibility to generate the desired product in 57% yield
(Scheme 2, 3h).
It was very difficult to accomplish this transformation in the
presence of a heteroaromatic ring on the 2-phenyl ring of
benzimidazole derivatives (Scheme 2, 3k). We also inves-
tigated the effect of substituents on the Ar2 ring of 2-
arylbenzoimidazoles. To our delight, N-substituted 2-arylben-
zoimidazoles derived from substituted 1,2 diamines displayed
good compatibility and delivered the desired products in good
yields (Scheme 2, 3l−3n).
In addition, we are unable to obtain the desired products
when 1-(2-phenyl-1H-benzo[d]imidazol-1-yl)prop-2-en-1-one,
3-phenyl-1-(2-phenyl-1H-benzo[d]imidazol-1-yl)prop-2-en-1-
one, and 2-phenyl-1-(2-phenyl-1H-benzo[d]imidazol-1-yl)-
prop-2-en-1-one were utilized as starting materials (Scheme
2, 3ab−3ad, respectively). Notably, no formation of product
was observed in the case of N-methacryloyl-2-phenylindoles
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(Scheme 2, 3ae). We next sought to explore the scope of this
radical cascade cyclization protocol with respect to substituted
benzylic Katritzky salts as depicted in Scheme 3. In this regard,
a variety of substituted benzylic Katritzky salts were
synthesized to explore the efficiency of this method. Both
electron-withdrawing and electron-donating groups attached at
any positions of the aromatic ring of benzylic Katritzky salts
were found to be well tolerated and to afford the
corresponding desired product in good yields (Scheme 3,
3o−3w). Notably, no formation of the desired product was
observed in the case of the heteroaromatically derived
Katritzky salt (Scheme 3, 3x). Subsequently, we probed the
generality of this radical cascade cyclization protocol with
respect to amino acid ester-derived Katritzky salts under the
optimized reaction conditions. As summarized in Scheme 3,
glycine ester-derived Katritzky salts underwent this trans-
formation and also delivered the corresponding products in
moderate yields (Scheme 3, 4a, 42% yield; 4b, 40% yield; 4c,
41% yield). Remarkably, phenyl alanine ester-derived Katritzky
salts derived from naturally abundant phenylalanine derivatives
can be applied in this transformation and lead to the formation
of the desired products (Scheme 3, 4d, 42% yield; 4e, 42%
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Scheme 4. Substrate Scope with Respect to Aliphatic Alkyl Amine-Derived Katritzky Salts in a Batch Reactor

Table 2. Optimization of the Reaction Conditions for the Radical Cascade Alkylation/Cyclization of Amine-Derived Katritzky
Salts with N-Methacryloyl-2-phenylbenzoimidazolesa

entry flow rate (μL min−1) retention time yieldb (%)

1 200 1.96 10
2 100 3.92 18
3 80 4.90 33
4 50 7.85 63
5 30 13.08 71
6 25 15 78
7 20 19 90
8 10 39.26 91
a
All reactions were carried out with 0.3 mmol of 1a, 0.36 mmol of 2a, 2.0 equiv of DIPEA, and 2 mol % eosin-y in 3 mL of CH3CN. bIsolated
yields of chromatographically pure products. PFA microreactor with a serpentine microchannel (1 m in length, 500 μm in width).

yield; 4f, 43% yield). As per the NMR data, we observed only
one diastereomer for compounds 4c−4f.
The generality of this novel process was next examined;
Katritzky salts derived from nonbenzylic alkyl groups such as
cyclohexyl amine, isopropyl amine, cyclopentyl amine,
tetrahydro-2H-pyran-4-amine, and 2,3-dihydro-1H-inden-2-
amine were successfully converted to the corresponding
desired products in moderate to good yields (5a−5e) as
shown in Scheme 4. Note that Katritzky salts derived from
primary aliphatic alkyl amines, such as methyl amine and n-
butyl amine, could not generate the desired product, likely due
to the low stability of the formed primary alkyl radical species
(Scheme 4, 5f and 5g). Tertiary alkyl groups such as tertiary
butyl amine were unable to synthesize Katritzky salts (Scheme
4, 5h).
Continuous-Flow Reaction. Compared to the traditional
batch reactions, continuous-flow microreactor technology has
received a great deal of attention in an attempt to overcome
12913
the problems associated with batch chemistry.23 In particular,
photochemical reactions in flow reactors often result in shorter
reaction times, superior mixing, increased yields, short path
lengths, and greater scale-up possibilities.24 Encouraged by
significant progress in flow photochemical reaction over batch
chemistry, we developed a continuous-flow protocol for
photoredox-catalyzed synthesis of benzimidazo[2,1-a]-
isoquinoline-6(5H)-ones via radical cascade alkylation and
cyclization of N-methacryloyl-2-phenylbenzoimidazoles with
alkyl amine/amino acid-derived Katritzky salts. Initially, the
mixture solution of N-methacryloyl-2-phenylbenzoimidazole
(1a) and amine/amino acid-derived Katritzky salt (2a),
DIPEA (2 equiv), and eosin-y (2 mol %) in acetonitrile was
taken up into a syringe and injected into perfluoroalkoxy
alkane (PFA) capillary tubing (500 μm in diameter, 2.5 m in
length, 0.98 mL in volume) under a nitrogen atmosphere. A
schematic illustration of the continuous-flow microreactor is
shown in Figure S2. We further monitored the efficiency of the
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Scheme 5. Scale-Up Experimenta

a
Standard reaction conditions: 1a (4.0 mmol), 2a (4.8 mmol), DIPEA (2.0 equiv), eosin-y (2.0 mol %), and CH3CN as the solvent (40.0 mL) in a
PFA tube (500 μm in inside diameter, 8 m in length) at a flow rate of 20 μL min−1 under 50 W blue LED irradiation at room temperature. The
isolated yield of the product was calculated on the basis of 1a.

Scheme 6. Control Experiments

Scheme 7. Plausible Mechanistic Pathway

reaction in a continuous-flow manner at various residence
times by employing different flow rates over a blue LED light
source. The results are summarized in Table 2. The short
length of the microreactor and the high illumination
homogeneity of the microreactor yielded a higher photon
flux that resulted in full conversion of 3a in a residence time of
only 19 min with a flow rate of 20 μL min−1. Moreover, there
was a significant improvement in the reaction time, i.e., 19 min,
and the yields were slightly better than those of the batch
12914
reaction. In addition, we conducted a scale-up experiment
based on standard reaction conditions using substrate 1a (4
mmol, 1.048 g) and 2a (4.8 mmol, 2.328 g) in an ACN solvent
via a PFA capillary tube microreactor as shown in Scheme 5.
As expected, the reaction proceeds well to deliver the
corresponding product 3a in 80% yield.
To illustrate the mechanistic interrogation of this photo-
catalytic protocol, we carried out a few control experiments
under batch conditions when 2.0 equiv of TEMPO (2,2,6,6-
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tetramethylpiperidine-1-oxyl) was introduced into the reaction
mixture under the optimal conditions, and a trace amount of
3a was observed. In addition, the reaction was completely
quenched and the corresponding product 3a was not detected
when 2 equiv of free radical inhibitor BHT (2,6-di-tert-butyl-4-
methylphenol) was added to the reaction mixture. Moreover, a
TEMPO-trapped product was also determined by MS analysis
(see Figure S3). These results imply that the reaction
proceeded through a radical intermediate pathway (Scheme
6). UV−vis data and fluorescence quenching experiments were
conducted with eosin-y to elucidate the reaction mechanism,
and the excited photocatalyst was quenched with a Katritzky
salt or DIPEA.
These results suggest that an increase in the concentration of
the Katritzky salt resulted in a significant decrease in the
fluorescence intensity of eosin-y. UV−vis data and fluorescence
quenching experiments were conducted with eosin-y to
elucidate the reaction mechanism, and the excited photo-
catalyst was quenched by the Katritzky salt or DIPEA. These
results suggest that an increase in the concentration of the
Katritzky salt resulted in a significant decrease in the
fluorescence intensity of eosin-y. As might be expected, the
results showed that the amine/amino acid-derived Katritzky
salt (B1) could quench the photoexcited eosin-y effectively
(see Figure S4).
On the basis of the control experiment observations
presented above and previous literature reports,25 the
proposed mechanistic details for the radical cascade
alkylation/cyclization of N-methacryloyl-2-phenylbenzoimida-
zoles with amine/amino acid-derived Katritzky salts are
depicted in Scheme 7. Under visible-light irradiation, the
photocatalyst eosin-y will be excited to generate the eosin-y*
species followed by the single-electron reduction of a redox-
active Katritzky salt 2a by excited eosin-y*, resulting in a
dihydropyridine radical I and a fragmentation driven by the re-
formation of an aromatic pyridine ring to give an alkyl radical
II. Subsequently, the alkyl radical adds to the CC bond of
N-methacryloyl-2-phenylbenzoimidazoles 1a to give a new
carbon radical intermediate III, which underwent an
intermolecular cyclization to give radical intermediate IV.
Meanwhile, single-electron reduction of the EY•+ intermediate
by i-Pr2NEt regenerates the ground state EY to close the
photoredox cycle. Finally, the deprotonation of carbocation IV
afforded cyclization product 3a.
In summary, we have discovered a novel metal-free
environmentally friendly protocol for constructing diverse
benzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one derivatives in
continuous-flow photoredox mode under mild reaction
conditions. The readily available redox-active Katritzky salts
derived from abundant alkyl amines/amino acid derivatives
were used as alkyl radical precursors via a deaminative
pathway. Moreover, the scope of this deaminative alkylation/
cyclization protocol was widely generalized by confirming the
functional group tolerance of compounds bearing electron-
donating or -withdrawing substituent and halogens at ortho,
meta, and para positions on N-methacryloyl-2-phenylbenzoi-
midazoles as well as on Katritzky salts, leading to the formation
of diverse benzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one
derivatives in moderate to excellent yields by the formation
of two new C−C bonds. In addition, the implementation of
flow chemistry instead of batch chemistry using a PFA capillary
tube microreactor led to enhanced irradiation of the reaction
mixture and probed its effectiveness with a slightly higher yield
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with a residence time of only 19 min. Related photocatalyzed
cascade reactions via a deaminative strategy are ongoing in our
laboratory.
■ EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all reagents were
used as received from commercial suppliers. The eosin-y photo-
catalyst and DIPEA were purchased from Sigma-Aldrich and used
without further purification. All reactions were performed under an
inert atmosphere and in flame-dried or oven-dried glassware with
magnetic stirring. All solvents were dried before use following the
standard procedures. Reactions were monitored using thin-layer
chromatography (SiO2). TLC plates were visualized with UV light
(254 nm) or iodine treatment or using p-anisaldehyde stain, or PMA
solution column chromatography was carried out using silica gel (60−
120 and 100−200 mesh) packed in glass columns. NMR spectra were
recorded at 300, 400, and 500 MHz (1H) and at 75, 100, and 125
MHz (13C{1H}). Splitting patterns are designated as follows: s,
singlet; d, doublet; t, triplet; dd, doublet of doublets; m, multiplet.
Chemical shifts (δ) are reported in parts per million, using the
residual solvent peak in CDCl3 (1H, δ 7.26; 13C, δ 77.00) as an
internal standard, and coupling constants (J) are given in hertz.
HRMS data were recorded using ESI-TOF techniques. Blue-light
LEDs (model no. Day.strp.blu.5m.nwt.01; manufacturer, Daylight
LED; LED, 5 W, λ = 450 nm) were used for our study. For all
compounds, we have recorded the 1H and 13C NMR spectra. For
unknown compounds, we have included HRMS data along with 1H
and 13C NMR data.
General Procedure for the Photochemical Synthesis of
Benzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-one Derivatives
under Batch Conditions. A dried screw-cap vial was charged with
N-methyacryoyl-2-phenylbenzoimidazole 1a (0.3 mmol, 1.0 equiv)
and amine/amino acid-derived Katritzky salt 2a (0.36 mmol, 1.2
equiv) in CH3CN (3 mL), and DIPEA (0.74 mg, 0.6 mmol, 2.0
equiv) and 2 mol % eosin-y (0.006 mmol, 4 mg) were added after
irradiation with nitrogen gas via the reaction under a blue LED light at
room temperature for 16 h (monitored by TLC) as shown in Figure
S1. Then 10 mL of water was added to the reaction mixture. It was
extracted with ethyl acetate (3 × 10 mL). Then, to the organic layer
was added Na2SO4, and the mixture was concentrated under reduced
pressure. The residue was directly subjected to flash chromatography
on silica gel (hexane/ethyl acetate) to afford desired product 3a.
General Procedure for Visible-Light-Induced Continuous-
Flow Synthesis of Benzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-
one Derivatives in a PFA Microreactor (P2). In an oven-dried
glass vial, eosin-y (2 mol %), N-methyacryoyl-2-phenylbenzoimida-
zole 1a (1 equiv), and amine/amino acid-derived Katritzky salt 2a
(1.2 equiv) were dissolved in 3 mL of CH3CN (0.20 M), and then
DIPEA (2 equiv) was slowly added to the reaction mixture. The vial
was fitted with a PTFE septum and purged with argon wherever
necessary. The solutions were transferred into a 5 mL NORM-JECT
plastic syringe and introduced into the PFA tubing microreactor
through a syringe pump (see the Supporting Information for details,
as shown in Figure S2). The flow rate was set to 20 μL min−1, thus
resulting in a residence time of 19 min. After the mixture had reached
a steady state, a product sample was collected at the end of the PFA
capillary tubing reactor in a vial. The collected volume was measured,
and the sample was then diluted with water and extracted with ethyl
acetate (3 × 10 mL). The organic layer was washed with brine, dried
with Na2SO4, and evaporated under reduced pressure. The resulting
crude compound was absorbed on silica gel and purified via column
chromatography (EtOAc/hexane). The isolated compound was
analyzed by NMR.
Characterization Data. 5-Methyl-5-phenethylbenzo[4,5]-
imidazo[2,1-a]isoquinolin-6(5H)-one (3a). The title compound was
prepared according to the general procedure as described above in
90% yield (95 mg). It was purified by flash chromatography (20%
EtOAc/hexane; Rf = 0.5) to afford 3a as a colorless oil: 1H NMR (500
MHz, CDCl3) δ 8.53 (d, J = 7.0 Hz, 1H), 8.33 (dd, J = 7.2, 1.5 Hz,
1H), 7.83 (dd, J = 7.0, 1.3 Hz, 1H), 7.65−7.60 (m, 1H), 7.55−7.51
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The Journal of Organic Chemistry
(m, 2H), 7.47−7.40 (m, 2H), 7.12−7.09 (m, 2H), 7.03−7.00 (m,
1H), 6.96−6.91 (m, 2H), 2.86−2.79 (m, 1H), 2.35−2.20 (m, 3H),
1.76 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.9, 149.7,
144.0, 141.3, 140.2, 131.9, 131.2, 128.2, 128.1, 127.8, 126.0, 125.9,
125.8, 125.5, 123.1, 119.7, 115.6, 49.2, 44.1, 31.5, 29.4; IR (neat) νmax
3025, 2935, 1950, 1715, 1453, 1357, 1166, 761; HRMS (ESI-TOF)
m/z calcd for C24H21ON2 [M + H]+ 353.1654, found 353.1655.
5-Methyl-6-oxo-5-phenethyl-5,6-dihydrobenzo[4,5]imidazo[2,1-
a]isoquinoline-3-carbonitrile (3b). The title compound was prepared
according to the general procedure as described above in 82% yield
(93 mg). It was purified by flash chromatography (20% EtOAc/
hexane; Rf = 0.5) to afford 3b as a white solid: mp 169.8−171.1 °C;
1
H NMR (500 MHz, CDCl3) δ 8.61 (d, J = 8.1 Hz, 1H), 8.34−8.27
(m, 1H), 7.87−7.82 (m, 1H), 7.81−7.73 (m, 2H), 7.51−7.44 (m,
2H), 7.11−7.04 (m, 2H), 7.01−6.96 (m, 1H), 6.90−6.84 (m, 2H),
2.90−2.83 (m, 1H), 2.35−2.23 (m, 3H), 1.77 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 171.5, 147.6, 143.9, 142.1, 139.3, 131.2, 131.0,
130.3, 128.3, 128.1, 127.1, 126.6, 126.5, 126.3, 126.2, 120.2, 118.0,
115.9, 115.1, 49.2, 43.9, 31.6, 29.3; IR (neat) νmax 3069, 2927, 2233,
1719, 1453, 1361, 760; HRMS (ESI-TOF) m/z calcd for C25H19ON3
[M]+ 377.1528, found 377.1529.
5-Methyl-3-nitro-5-phenethylbenzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (3c). The title compound was prepared
according to the general procedure as described above in 77% yield
(92 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 3c as a white solid: mp 182.3−184.6 °C;
1
H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 8.6 Hz, 1H), 8.39−8.30
(m, 3H), 7.89−7.83 (m, 1H), 7.52−7.47 (m, 2H), 7.07−7.03 (m,
2H), 6.98−6.94 (m, 1H), 6.87 (d, J = 7.4 Hz, 2H), 2.97−2.86 (m,
1H), 2.44−2.23 (m, 3H), 1.82 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 171.5, 149.6, 147.3, 143.9, 142.6, 139.2, 131.2, 128.6, 128.3,
128.1, 127.1, 126.7, 126.4, 126.2, 122.8, 121.8, 120.3, 115.9, 49.6,
43.8, 31.7, 29.4; IR (neat) νmax 3092, 2938, 2495, 1720, 1536, 1450,
1352, 1173, 761; HRMS (ESI-TOF) m/z calcd for C24H20O3N3 [M +
H]+ 398.1505, found 398.1511.
3-(tert-Butyl)-5-methyl-5-phenethylbenzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (3d). The title compound was prepared
according to the general procedure as described above in 81% yield
(99 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 3d as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 8.45 (d, J = 8.3 Hz, 1H), 8.35 (d, J = 8.3 Hz, 1H), 7.83 (d, J
= 7.5 Hz, 1H), 7.59−7.53 (m, 2H), 7.46−7.40 (m, 2H), 7.12 (t, J =
7.5 Hz, 2H), 7.03 (t, J = 7.4 Hz, 1H), 6.94 (d, J = 7.3 Hz, 2H), 2.88−
2.82 (m, 1H), 2.35−2.19 (m, 3H), 1.76 (s, 3H), 1.44 (s, 9H);
13
C{1H} NMR (100 MHz, CDCl3) δ 173.1, 155.5, 149.8, 144.0,
140.9, 140.4, 131.2, 128.2, 128.1, 125.9, 125.7, 125.2, 125.1, 122.5,
120.4, 119.5, 115.6, 49.4, 44.2, 35.2, 31.6, 31.1, 29.6; IR (neat) νmax
3063, 2960, 2925, 1715, 1614, 1454, 1357, 1174, 757; HRMS (ESI-
TOF) m/z calcd for C28H29ON2 [M + H]+ 409.2254, found
409.2274.
3-Methoxy-5-methyl-5-phenethylbenzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (3e). The title compound was prepared
according to the general procedure as described above in 60% yield
(69 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 3e as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 8.45 (d, J = 8.7 Hz, 1H), 8.29 (dd, J = 7.4, 1.0 Hz, 1H),
7.79−7.76 (m, 1H), 7.43−7.37 (m, 2H), 7.13−7.00 (m, 5H), 6.97−
6.94 (m, 2H), 3.94 (s, 3H), 2.83−2.77 (m, 1H), 2.30−2.24 (m, 3H),
1.74 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.0, 162.7,
149.9, 144.1, 143.4, 140.3, 131.2, 128.2, 128.2, 127.9, 126.0, 125.7,
125.0, 119.3, 116.1, 115.6, 113.5, 111.7, 55.6, 49.4, 44.3, 31.5, 29.6; IR
(neat) νmax 3059, 3013, 2952,, 1719, 1553, 1351, 1221, 769; HRMS
(ESI-TOF) m/z calcd for C25H23N2O2 [M + H]+ 383.1756, found
383.1766.
3-Chloro-5-methyl-5-phenethylbenzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (3f). The title compound was prepared
according to the general procedure as described above in 78% yield
(90 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 3f as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 8.45 (d, J = 8.9 Hz, 1H), 8.32−8.27 (m, 1H), 7.83−7.79
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(m, 1H), 7.51−7.49 (m, 2H), 7.47−7.40 (m, 2H), 7.12−7.07 (m,
2H), 7.03−6.98 (m, 1H), 6.94−6.91 (m, 2H), 2.85−2.79 (m, 1H),
2.30−1.23 (m, 3H), 1.75 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 172.2, 148.8, 143.9, 143.0, 139.8, 138.2, 131.2, 128.5, 128.3, 128.1,
127.4, 126.3, 126.1, 126.0, 125.7, 121.8, 119.8, 115.7, 49.3, 44.1, 31.6,
29.3; IR (neat) νmax 3072, 3010, 2925, 1718, 1595, 1457, 1361, 761;
HRMS (ESI-TOF) m/z calcd for C24H20N2OCl [M + H]+ 387.1247,
found 387.1258.
3-Bromo-5-methyl-5-phenethylbenzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (3g). The title compound was prepared
according to the general procedure as described above in 78% yield
(101 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 3g as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 8.38−8.36 (m, 1H), 8.31−8.28 (m, 1H), 7.83−7.79 (m,
1H), 7.67−7.63 (m, 2H), 7.47−7.40 (m, 2H), 7.11−7.08 (m, 2H),
7.02−6.98 (m, 1H), 6.94−6.91 (m, 2H), 2.85−2.79 (m, 1H), 2.29−
2.24 (m, 3H), 1.75 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
172.1, 148.8, 143.9, 143.1, 139.7, 131.3, 131.2, 129.3, 128.2, 128.1,
127.4, 126.6, 126.1, 126.0, 125.8, 122.1, 119.8, 115.7, 49.2, 44.0, 31.5,
29.4; IR (neat) νmax 3066, 3016, 2924, 1719, 1455, 1360, 1219, 767;
HRMS (ESI-TOF) m/z calcd for C24H20N2OBr [M + H]+ 431.0747,
found 431.0753.
2-Methoxy-5-methyl-5-phenethylbenzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (3h) (2:1). The title compound was prepared
according to the general procedure as described above in 57% yield
(66 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 3h as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 8.34−8.30 (m, 1H), 8.21 (dd, J = 7.9, 1.1 Hz, 1H), 7.97 (d,
J = 2.8 Hz, 1H), 7.84−7.81 (m, 1H), 7.52−7.39 (m, 3H), 7.19 (dd, J
= 8.8, 2.8 Hz, 1H), 7.13−6.99 (m, 3H), 6.94 (dd, J = 5.1, 3.3 Hz, 1H),
6.89−6.86 (m, 1H), 3.99 (s, 2H), 3.95 (s, 1H), 3.12−3.04 (m, 1H),
2.82−2.69 (m, 1H), 2.29−2.17 (m, 3H), 1.83 (s, 1H), 1.72 (s, 2H);
13
C{1H} NMR (100 MHz, CDCl3) δ 174.1, 173.2, 158.9, 157.4,
149.9, 149.8, 144.0, 143.9, 140.6, 140.3, 133.6, 131.3, 131.2, 129.0,
128.2, 128.2, 128.0, 127.4, 126.0, 125.8, 125.8, 125.7, 125.5, 125.3,
124.1, 120.7, 119.6, 119.6, 118.6, 115.8, 115.7, 114.1, 107.8, 55.8,
55.5, 49.5, 48.8, 44.3, 39.8, 32.5, 31.6, 29.5, 25.7; IR (neat) νmax 2939,
2849, 1714, 1451, 1356, 1065, 765; HRMS (ESI-TOF) m/z calcd for
C25H23N2O2 [M + H]+ 383.1750, found 383.1754.
1-Bromo-5-methyl-5-phenethylbenzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (3i). The title compound was prepared
according to the general procedure as described above in 75% yield
(97 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 3i as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 8.39−8.33 (m, 1H), 7.97−7.90 (m, 1H), 7.85 (dd, J = 7.9,
1.0 Hz, 1H), 7.54 (dd, J = 8.0, 1.0 Hz, 1H), 7.48−7.44 (m, 2H), 7.39
(t, J = 7.9 Hz, 1H), 7.13−7.10 (m, 2H), 7.03 (t, J = 7.4 Hz, 1H),
6.95−6.91 (m, 2H), 2.83−2.77 (m, 1H), 2.30−2.20 (m, 3H), 1.76 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.0, 147.1, 144.3, 143.5,
140.0, 135.2, 131.2, 130.6, 128.2, 128.1, 126.2, 126.1, 125.8, 125.5,
122.5, 121.4, 120.7, 115.6, 49.6, 44.5, 31.4, 29.6; IR (neat) νmax 3065,
2927, 1715, 1567, 1370, 1161, 756; HRMS (ESI-TOF) m/z calcd for
C24H20BrN2O [M + H]+ 431.0754, found 431.0759.
7-Methyl-7-phenethylbenzo[h]benzo[4,5]imidazo[2,1-a]-
isoquinolin-8(7H)-one (3j). The title compound was prepared
according to the general procedure as described above in 67% yield
(81 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 3j as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 10.55 (d, J = 8.7 Hz, 1H), 8.46−8.37 (m, 1H), 8.09 (d, J =
8.7 Hz, 1H), 7.97−7.92 (m, 2H), 7.86−7.83 (m, 1H), 7.69−7.63 (m,
2H), 7.50−7.44 (m, 2H), 7.09 (t, J = 7.5 Hz, 2H), 7.01 (t, J = 7.3 Hz,
1H), 6.92 (d, J = 7.3 Hz, 2H), 2.93−2.87 (m, 1H), 2.47−2.40 (m,
1H), 2.29−2.15 (m, 2H), 1.82 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 173.1, 149.9, 144.1, 141.9, 140.3, 132.9, 132.8, 130.3, 128.8,
128.4, 128.2, 128.1, 128.1, 126.9, 126.0, 125.8, 122.9, 120.1, 118.4,
115.8, 49.5, 44.0, 31.6, 29.5; IR (neat) νmax 3061, 2925, 1714, 1456,
1365, 759; HRMS (ESI-TOF) m/z calcd for C28H23N2O [M + H]+
403.1788, found 403.1804.
9-Chloro-5-methyl-5-phenethylbenzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (3l). The title compound was prepared
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The Journal of Organic Chemistry
according to the general procedure as described above in 78% yield
(92 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 3l as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 8.50−8.47 (m, 1H), 8.32 (d, J = 1.9 Hz, 1H), 7.71 (d, J =
8.5 Hz, 1H), 7.66−7.62 (m, 1H), 7.55−7.51 (m, 2H), 7.41 (dd, J =
8.5, 2.1 Hz, 1H), 7.10−7.07 (m, 2H), 7.00 (t, J = 7.4 Hz, 1H), 6.91
(d, J = 7.0 Hz, 2H), 2.85−2.79 (m, 1H), 2.35−2.29 (m, 1H), 2.25−
2.21 (m, 2H), 1.75 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
172.8, 150.3, 142.6, 141.2, 139.9, 132.2, 131.7, 131.0, 128.2, 128.1,
127.9, 126.3, 126.1, 126.0, 126.0, 122.9, 120.3, 116.0, 115.8, 49.2,
44.2, 31.6, 29.4; IR (neat) νmax 3098, 2952, 1721, 1447, 1360, 1219,
770; HRMS (ESI-TOF) m/z calcd for [M + H]+ 387.1273, found
387.1275.
5,9,10-Trimethyl-5-phenethylbenzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (3m). The title compound was prepared
according to the general procedure as described above in 83% yield
(95 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 3m as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 8.48 (dd, J = 7.8, 1.2 Hz, 1H), 8.13 (s, 1H), 7.62−7.55 (m,
2H), 7.52−7.47 (m, 2H), 7.14−7.11 (m, 2H), 7.06−7.01 (m, 1H),
6.96−6.92 (m, 2H), 2.81−2.75 (m, 1H), 2.42 (s, 3H), 2.41 (s, 3H),
2.23 (dt, J = 37.5, 10.0 Hz, 3H), 1.73 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 172.8, 149.0, 142.4, 141.1, 140.4, 134.8, 131.6, 129.6,
128.2, 128.1, 127.7, 125.9, 125.9, 125.7, 123.4, 119.9, 116.0, 49.1,
44.3, 31.5, 29.3, 20.5, 20.4; IR (neat) νmax 3069, 2926, 1712, 1461,
1365, 767; HRMS (ESI-TOF) m/z calcd for C26H25N2O [M + H]+
381.2048, found 381.2053.
5,10,11-Trimethyl-5-phenethylbenzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (3n). The title compound was prepared
according to the general procedure as described above in 80% yield
(91 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 3n as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 8.60−8.53 (m, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.61−7.58
(m, 1H), 7.53−7.49 (m, 2H), 7.22 (d, J = 8.2 Hz, 1H), 7.15−7.11 (m,
2H), 7.07−7.03 (m, 1H), 6.97−6.93 (m, 2H), 2.81−2.74 (m, 1H),
2.66 (s, 3H), 2.43 (s, 3H), 2.30−2.13 (m, 3H), 1.74 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 172.8, 148.9, 143.6, 141.1, 140.5, 133.9,
131.6, 129.2, 128.2, 128.1, 127.6, 127.2, 126.0, 125.9, 123.5, 112.3,
49.2, 44.4, 31.5, 29.2, 19.5, 13.3; IR (neat) νmax 3016, 2925, 2852,
1713, 1459, 1354, 1221, 770; HRMS (ESI-TOF) m/z calcd for
C26H25N2O [M + H]+ 381.1949, found 381.1961.
5-Methyl-5-(2-methylphenethyl)benzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (3o). The title compound was prepared
according to the general procedure as described above in 85% yield
(93 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 3o as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 8.54 (dd, J = 7.8, 1.1 Hz, 1H), 8.40−8.36 (m, 1H), 7.86−
7.81 (m, 1H), 7.67−7.61 (m, 1H), 7.57−7.52 (m, 2H), 7.47−7.42
(m, 2H), 7.04−6.96 (m, 3H), 6.89−6.84 (m, 1H), 2.76−2.69 (m,
1H), 2.26−2.13 (m, 3H), 2.08 (s, 3H), 1.75 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 172.9, 149.8, 144.0, 141.4, 138.6, 135.7, 131.9,
131.3, 130.2, 128.8, 127.9, 126.2, 126.0, 126.0, 125.9, 125.5, 123.2,
119.7, 115.7, 49.3, 43.1, 29.3, 29.0, 18.8; IR (neat) νmax 3060, 3029,
2962, 1714, 1455, 1356, 1166, 757; HRMS (ESI-TOF) m/z calcd for
C25H23N2O [M + H]+ 367.1810, found 367.1811.
5-(3-Chlorophenethyl)-5-methylbenzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (3p). The title compound was prepared
according to the general procedure as described above in 72% yield
(84 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 3p as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 8.52 (dd, J = 8.1, 1.4 Hz, 1H), 8.34−8.30 (m, 1H), 7.84−
7.81 (m, 1H), 7.65−7.60 (m, 1H), 7.54−7.50 (m, 2H), 7.46−7.40
(m, 2H), 7.02−6.96 (m, 2H), 6.93 (t, J = 1.6 Hz, 1H), 6.81−6.77 (m,
1H), 2.83−2.77 (m, 1H), 2.32−2.18 (m, 3H), 1.75 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 172.8, 149.6, 144.0, 142.1, 141.0, 134.0,
132.0, 131.2, 129.4, 128.3, 127.9, 126.4, 126.2, 126.0, 125.9, 125.9,
125.5, 123.1, 119.8, 115.7, 49.1, 43.7, 31.3, 29.5; IR (neat) νmax 3062,
2925, 2854, 1717, 1456, 1363, 767; HRMS (ESI-TOF) m/z calcd for
C24H20N2OCl [M + H]+ 387.1246, found 387.1258.
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5-(4-Chlorophenethyl)-5-methylbenzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (3q). The title compound was prepared
according to the general procedure as described above in 75% yield
(87 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 3q as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 8.52 (d, J = 8.0 Hz, 1H), 8.31−8.25 (m, 1H), 7.85−7.80
(m, 1H), 7.64−7.61 (m, 1H), 7.54−7.51 (m, 2H), 7.47−7.41 (m,
2H), 7.05−7.01 (m, 2H), 6.86−6.82 (m, 2H), 2.83−2.76 (m, 1H),
2.32−2.19 (m, 3H), 1.75 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 172.8, 149.6, 143.9, 141.1, 138.5, 132.0, 131.2, 129.5, 128.3, 127.9,
126.0, 125.6, 123.2, 119.8, 115.6, 49.1, 44.0, 31.0, 29.5; IR (neat) νmax
3053, 3021, 2943, 1716, 1441, 1352, 754; HRMS (ESI-TOF) m/z
calcd for C24H20N2OCl [M + H]+ 387.1247, found 387.1258.
5-(3,4-Dichlorophenethyl)-5-methylbenzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (3r). The title compound was prepared
according to the general procedure as described above in 62% yield
(78 mg). It was purified by flash chromatography (20% EtOAc/
hexane; Rf = 0.5) to afford 3r as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 8.52 (dd, J = 7.8, 1.2 Hz, 1H), 8.31−8.25 (m, 1H), 7.85−
7.80 (m, 1H), 7.65−7.60 (m, 1H), 7.55−7.49 (m, 2H), 7.46−7.41
(m, 2H), 7.11 (d, J = 8.2 Hz, 1H), 6.99 (d, J = 2.1 Hz, 1H), 6.72 (dd,
J = 8.2, 2.1 Hz, 1H), 2.83−2.77 (m, 1H), 2.32−2.18 (m, 3H), 1.75 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.7, 149.4, 143.9, 140.8,
140.2, 132.0, 131.1, 130.1, 130.0, 128.0, 127.7, 126.0, 126.0, 125.9,
125.7, 123.1, 119.8, 115.6, 49.0, 43.5, 30.8, 29.6; IR (neat) νmax 3062,
2927, 2858, 1710, 1551, 1349, 1161, 752; HRMS (ESI-TOF) m/z
calcd for C24H19N2OCl2 [M + H]+ 421.0874, found 421.0880.
5-(2,5-Difluorophenethyl)-5-methylbenzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (3s). The title compound was prepared
according to the general procedure as described above in 70% yield
(82 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 3s as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 8.51 (dd, J = 7.7, 0.7 Hz, 1H), 8.34 (dd, J = 7.1, 1.6 Hz,
1H), 7.87−7.79 (m, 1H), 7.64−7.59 (m, 1H), 7.55−7.49 (m, 2H),
7.47−7.40 (m, 2H), 6.82−6.79 (m, 1H), 6.72−6.60 (m, 2H), 2.82−
2.77 (m, 1H), 2.36−2.22 (m, 3H), 1.74 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 172.7, 159.5, 157.9, 157.1, 155.6, 149.6, 144.0, 140.8,
132.0, 131.2, 129.0, 128.8, 127.9, 126.0, 126.0, 125.9, 125.5, 123.1,
119.8, 116.7, 116.7, 116.5, 116.4, 116.1, 116.1, 115.9, 115.8, 115.7,
114.2, 114.1, 114.0, 113.9, 49.2, 41.7, 29.8, 25.3; IR (neat) νmax 3063,
2972, 2854, 1716, 1497, 1362, 1201, 756; HRMS (ESI-TOF) m/z
calcd for C24H19N2OF2 [M + H]+ 389.1442, found 389.1460.
5-Methyl-5-[2-(naphthalen-1-yl)ethyl]benzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (3t). The title compound was prepared
according to the general procedure as described above in 74% yield
(89 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 3t as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 8.57 (dd, J = 7.8, 1.2 Hz, 1H), 8.40−8.35 (m, 1H), 7.88−
7.82 (m, 1H), 7.78−7.74 (m, 1H), 7.70−7.65 (m, 2H), 7.61−7.55
(m, 3H), 7.48−7.42 (m, 4H), 7.20 (dd, J = 8.1, 7.1 Hz, 1H), 7.04 (d,
J = 6.9 Hz, 1H), 2.98−2.91 (m, 1H), 2.78−2.71 (m, 1H), 2.68−2.61
(m, 1H), 2.42−2.37 (m, 1H), 1.75 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 172.9, 149.8, 144.0, 141.3, 136.6, 133.7, 132.0, 131.5,
131.3, 128.7, 128.0, 127.0, 126.1, 125.9, 125.6, 125.5, 125.3, 123.3,
119.8, 115.8, 49.4, 43.4, 29.5, 28.9; IR (neat) νmax 2958, 2867, 1715,
1454, 1358, 1171, 761; HRMS (ESI-TOF) m/z calcd for C28H23N2O
[M + H]+ 403.1786, found 403.1804.
5-Methyl-5-(4-phenoxyphenethyl)benzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (3u). The title compound was prepared
according to the general procedure as described above in 57% yield
(76 mg). It was purified by flash chromatography (20% EtOAc/
hexane; Rf = 0.5) to afford 3u as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 8.52 (dd, J = 7.7, 0.9 Hz, 1H), 8.35−8.30 (m, 1H), 7.85−
7.78 (m, 1H), 7.65−7.60 (m, 1H), 7.55−7.50 (m, 2H), 7.47−7.41
(m, 2H), 7.30−7.26 (m, 3H), 7.09−7.02 (m, 1H), 6.89−6.83 (m,
4H), 6.76−6.71 (m, 2H), 2.86−2.79 (m, 1H), 2.36−2.28 (m, 1H),
2.25−2.18 (m, 2H), 1.76 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 172.9, 155.4, 149.7, 144.0, 134.9, 132.0, 129.6, 129.4, 127.8, 126.1,
126.0, 125.9, 125.6, 123.2, 123.0, 119.8, 118.7, 118.6, 115.7, 49.2,
44.1, 30.9, 29.6; IR (neat) νmax 3099, 2952, 2848, 1720, 1493, 1231,
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770; HRMS (ESI-TOF) m/z calcd for C30H24N2O2 [M]+ 444.1837,
found 444.1842.
5-[4-(tert-Butyl)phenethyl]-5-methylbenzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (3v). The title compound was prepared
according to the general procedure as described above in 73% yield
(89 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 3v as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 8.52 (d, J = 7.9 Hz, 1H), 8.28 (d, J = 7.4 Hz, 1H), 7.82 (d, J
= 7.3 Hz, 1H), 7.65−7.59 (m, 1H), 7.54−7.51 (m, 2H), 7.45−7.37
(m, 2H), 7.11−7.07 (m, 2H), 6.83 (d, J = 8.3 Hz, 2H), 2.90−2.83 (m,
1H), 2.36−2.22 (m, 3H), 1.74 (s, 3H), 1.16 (s, 9H); 13C{1H} NMR
(100 MHz, CDCl3) δ 172.9, 149.7, 148.8, 143.9, 141.3, 136.8, 131.9,
131.3, 127.9, 127.8, 126.1, 125.9, 125.7, 125.5, 125.0, 123.2, 119.7,
115.7, 49.0, 43.8, 34.2, 31.2, 31.0, 29.8; IR (neat) νmax 3067, 2963,
2925, 1716, 1454, 1357, 757; HRMS (ESI-TOF) m/z calcd for
C28H29N2O [M + H]+ 409.2254, found 409.2274.
5-Methyl-5-(4-nitrophenethyl)benzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (3w). The title compound was prepared
according to the general procedure as described above in 75% yield
(89 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 3w as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 8.53 (dd, J = 7.8, 1.1 Hz, 1H), 8.25−8.19 (m, 1H), 7.92−
7.88 (m, 2H), 7.84−7.80 (m, 1H), 7.67−7.62 (m, 1H), 7.57−7.52
(m, 2H), 7.45−7.37 (m, 2H), 7.07−7.04 (m, 2H), 2.91−2.83 (m,
1H), 2.39−2.31 (m, 3H), 1.77 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 172.6, 149.4, 147.6, 146.2, 143.9, 140.7, 132.1, 131.0, 129.0,
128.1, 126.1, 125.9, 125.7, 123.4, 119.8, 115.5, 49.0, 43.3, 31.7, 29.6;
IR (neat) νmax 3097, 2932, 2473, 1718, 1537, 1455, 1351, 1163, 762;
HRMS (ESI-TOF) m/z calcd for C24H20N3O3 [M + H]+ 398.1491,
found 398.1499.
Methyl 3-(5-Methyl-6-oxo-5,6-dihydrobenzo[4,5]imidazo[2,1-a]-
isoquinolin-yl)propanoate (4a). The title compound was prepared
according to the general procedure as described above in 42% yield
(42 mg). It was purified by flash chromatography (50% EtOAc/
hexanes; Rf = 0.5) to afford 4a as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 8.49 (dd, J = 8.1, 1.4 Hz, 1H), 8.36−8.33 (m, 1H), 7.85−
7.80 (m, 1H), 7.61−7.57 (m, 1H), 7.52−7.48 (m, 2H), 7.45−7.43
(m, 2H), 3.47 (s, 3H), 2.78−2.72 (m, 1H), 2.43−2.37 (m, 1H),
2.09−2.02 (m, 1H), 1.94−1.87 (m, 1H), 1.76 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 172.5, 149.5, 144.0, 140.5, 132.1, 131.2, 128.0,
126.0, 125.7, 123.0, 119.9, 115.7, 51.6, 48.6, 36.9, 30.0, 29.2; IR
(neat) νmax 2953, 2852, 1730, 1361, 1212, 768; HRMS (ESI-TOF)
m/z calcd for C20H19N2O3 [M + H]+ 335.1377, found 335.1390.
Methyl 3-(3-Chloro-5-methyl-6-oxo-5,6-dihydrobenzo[4,5]-
imidazo[2,1-a]isoquinolin-5-yl)propanoate (4b). The title com-
pound was prepared according to the general procedure as described
above in 40% yield (44 mg). It was purified by flash chromatography
(50% EtOAc/hexanes; Rf = 0.5) to afford 4b as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 8.42 (dd, J = 8.1, 0.7 Hz, 1H), 8.35−8.31
(m, 1H), 7.83−7.80 (m, 1H), 7.50−7.43 (m, 4H), 3.49 (s, 3H),
2.79−2.71 (m, 1H), 2.38−2.30 (m, 1H), 2.10−2.03 (m, 1H), 1.95−
1.89 (m, 1H), 1.76 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
172.3, 171.7, 148.6, 143.9, 142.2, 138.3, 131.1, 128.7, 127.4, 126.3,
126.2, 125.9, 121.6, 119.9, 115.6, 51.7, 48.7, 36.9, 29.9, 28.9; IR
(neat) νmax 2953, 2852, 1730, 1361, 1212, 768; HRMS (ESI-TOF)
m/z calcd for C20H18N2O3Cl [M + H]+ 369.1003, found 369.1005.
Ethyl 3-(5-Methyl-6-oxo-5,6-dihydrobenzo[4,5]imidazo[2,1-a]-
isoquinolin-5-yl)propanoate (4c). The title compound was prepared
according to the general procedure as described above in 41% yield
(43 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 4c as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 8.51−8.47 (m, 1H), 8.37−8.33 (m, 1H), 7.85−7.79 (m,
1H), 7.62−7.57 (m, 1H), 7.52−7.43 (m, 4H), 3.97−3.91 (m, 2H),
2.79−2.70 (m, 1H), 2.43−2.33 (m, 1H), 2.09−2.00 (m, 1H), 1.92−
1.85 (m, 1H), 1.76 (s, 3H), 1.10 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 172.6, 172.1, 149.6, 144.0, 140.6, 132.1, 131.3,
128.0, 126.1, 126.0, 126.0, 125.7, 123.0, 119.9, 115.7, 60.6, 48.7, 36.9,
30.2, 29.1, 14.0; IR (neat) νmax 3099, 3061, 2972, 1729, 1455, 1215,
770; HRMS (ESI-TOF) m/z calcd for C21H21N2O3 [M + H]+
349.1530, found 349.1546.
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pubs.acs.org/joc Article
Methyl 2-Benzyl-3-(5-methyl-6-oxo-5,6-dihydrobenzo[4,5]-
imidazo[2,1-a]isoquinolin-5-yl)propanoate (4d). The title com-
pound was prepared according to the general procedure as described
above in 42% yield (60 mg). It was purified by flash chromatography
(30% EtOAc/hexanes; Rf = 0.5) to afford 4d as a colorless oil: 1H
NMR (500 MHz, CDCl3) δ 8.45 (dd, J = 7.8, 1.0 Hz, 1H), 8.37−8.34
(m, 1H), 7.85−7.79 (m, 1H), 7.57−7.53 (m, 1H), 7.48−7.44 (m,
4H), 7.17−7.13 (m, 3H), 6.97−6.94 (m, 2H), 2.86 (s, 3H), 2.84−
2.79 (m, 1H), 2.67−2.60 (m, 3H), 2.47−2.41 (m, 1H), 1.69 (s, 3H);
13
C{1H} NMR (126 MHz, CDCl3) δ 174.5, 172.5, 149.7, 144.1,
140.0, 137.8, 131.5, 131.3, 128.7, 128.3, 127.9, 127.2, 126.5, 126.0,
125.7, 125.6, 122.9, 119.8, 115.8, 51.2, 48.7, 44.7, 43.5, 39.8, 30.5; IR
(neat) νmax 3091, 2983, 1725, 1463, 1217, 771; HRMS (ESI-TOF)
m/z calcd for C27H25N2O3 [M + H]+ 425.1840, found 425.1859.
Methyl 2-Benzyl-3-(5,8,9-trimethyl-6-oxo-5,6-dihydrobenzo[4,5]-
imidazo[2,1-a]isoquinolin-5-yl)propanoate (4e). The title com-
pound was prepared according to the general procedure as described
above in 42% yield (60 mg). It was purified by flash chromatography
(30% EtOAc/hexanes; Rf = 0.5) to afford 4e as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 8.50−8.46 (m, 1H), 8.05 (d, J = 8.2 Hz,
1H), 7.52 (ddd, J = 8.0, 6.9, 1.5 Hz, 1H), 7.43 (dd, J = 11.4, 4.3 Hz,
2H), 7.23 (d, J = 8.2 Hz, 1H), 7.17−7.11 (m, 3H), 6.94 (dd, J = 7.7,
1.6 Hz, 2H), 2.86 (s, 3H), 2.79 (dd, J = 13.5, 9.2 Hz, 1H), 2.66 (d, J =
5.6 Hz, 4H), 2.63−2.58 (m, 3H), 2.43 (s, 3H), 1.66 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 174.6, 172.4, 148.8, 143.7, 139.8, 137.9,
134.0, 131.1, 129.2, 128.7, 128.3, 127.7, 127.2, 127.1, 126.5, 125.7,
123.3, 112.4, 51.1, 48.6, 44.7, 43.5, 39.7, 30.5, 19.5, 13.4; IR (neat)
νmax 3094, 2988, 1725, 1443, 1214, 773; HRMS (ESI-TOF) m/z
calcd for C29H29N2O3 [M + H]+ 453.2152, found 453.2172.
Ethyl 2-Benzyl-3-(6-oxo-5,6-dihydrobenzo[4,5]imidazo[2,1-a]-
isoquinolin-5-yl)propanoate (4f). The title compound was prepared
according to the general procedure as described above in 43% yield
(56 mg). It was purified by flash chromatography (50% EtOAc/
hexanes; Rf = 0.5) to afford 4f as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 8.44 (dd, J = 7.8, 1.2 Hz, 1H), 8.37−8.35 (m, 1H), 7.84−
7.82 (m, 1H), 7.57−7.52 (m, 1H), 7.48−7.43 (m, 4H), 7.18−7.10
(m, 3H), 6.97−6.94 (m, 2H), 3.44−3.77 (m, 1H), 3.12−3.06 (m,
1H), 2.81−2.77 (m, 1H), 2.68−2.60 (m, 3H), 1.69 (s, 3H), 0.66 (t, J
= 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 174.2, 172.6,
149.7, 144.1, 140.0, 137.8, 131.5, 131.3, 128.8, 128.2, 127.9, 127.3,
126.5, 125.9, 125.6, 125.5, 122.9, 119.8, 115.8, 60.2, 48.8, 44.8, 43.5,
39.9, 30.5, 13.5; IR (neat) νmax 3099, 2998, 1725, 1453, 1216, 770;
HRMS (ESI-TOF) m/z calcd for C28H27N2O3 [M + H]+ 439.2022,
found 439.2036.
5-(Cyclohexylmethyl)-5-methylbenzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (5a).13 The title compound was prepared
according to the general procedure as described above in 70% yield
(72 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 5a as a colorless oil: 1H NMR (400 MHz,
CDCl3) δ 8.49 (dd, J = 7.7, 1.1 Hz, 1H), 8.40−8.36 (m, 1H), 7.86−
7.81 (m, 1H), 7.84−7.82 (m, 1H), 7.50−7.42 (m, 4H), 2.48 (dd, J =
14.2, 8.0 Hz, 1H), 2.09−2.03 (m, 1H), 1.66 (s, 3H), 1.48−1.36 (m,
3H), 1.28−1.16 (m, 2H), 0.99−0.77 (m, 6H); 13C{1H} NMR (100
MHz, CDCl3) δ 173.5, 149.8, 144.0, 141.9, 131.6, 131.4, 127.5, 126.6,
125.9, 125.8, 125.5, 122.6, 119.7, 115.8, 48.8, 48.3, 34.9, 34.2, 32.9,
31.8, 25.9, 25.9; IR (neat) νmax 3061, 2928, 2852, 1717, 1452, 1356,
1173, 763; HRMS (ESI-TOF) m/z calcd for C23H25N2O [M + H]+
345.1966, found 345.1977.
5-Isobutyl-5-methylbenzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-
one (5b).13 The title compound was prepared according to the
general procedure as described above in 56% yield (56 mg). It was
purified by flash chromatography (20% EtOAc/hexanes; Rf = 0.5) to
afford 5b as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 8.51−8.48
(m, 1H), 8.40−8.37 (m, 1H), 7.86−7.81 (m, 1H), 7.57 (td, J = 7.6,
1.4 Hz, 1H), 7.49−7.42 (m, 4H), 2.46 (dd, J = 14.1, 8.3 Hz, 1H), 2.08
(dd, J = 14.1, 5.2 Hz, 1H), 1.69 (s, 3H), 1.34−1.27 (m, 1H), 0.63 (d,
J = 6.7 Hz, 3H), 0.57 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 173.5, 149.8, 144.0, 141.8, 131.6, 131.4, 127.5, 126.6, 125.9,
125.5, 122.6, 119.7, 115.7, 50.5, 48.5, 31.4, 25.6, 23.8, 22.3; IR (neat)
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J. Org. Chem. 2021, 86, 12908−12921
The Journal of Organic Chemistry
νmax 3065, 2960, 2874, 1715, 1355, 1157, 761; HRMS (ESI-TOF) m/
z calcd for C20H21N2O [M + H]+ 305.1653, found 305.1666.
5-Methyl-5-[(tetrahydro-2H-pyran-4-yl)methyl]benzo[4,5]-
imidazo[2,1-a]isoquinolin-6(5H)-one (5c).13 The title compound
was prepared according to the general procedure as described above
in 66% yield (69 mg). It was purified by flash chromatography (20%
EtOAc/hexanes; Rf = 0.5) to afford 5c as a colorless oil: 1H NMR
(500 MHz, CDCl3) δ 8.49 (dd, J = 7.8, 1.1 Hz, 1H), 8.39−8.36 (m,
1H), 7.85−7.81 (m, 1H), 7.61−7.56 (m, 1H), 7.51−7.43 (m, 4H),
3.70−3.62 (m, 2H), 3.05−2.93 (m, 2H), 2.53 (dd, J = 14.3, 6.9 Hz,
1H), 2.10 (dd, J = 14.3, 4.8 Hz, 1H), 1.69 (s, 3H), 1.25−1.19 (m,
2H), 1.15−1.03 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.1,
149.6, 144.0, 141.4, 131.7, 131.3, 127.7, 126.4, 126.0, 125.9, 125.6,
122.5, 119.7, 115.7, 67.4, 48.3, 48.1, 33.7, 32.8, 32.4, 31.6; IR (neat)
νmax 3020, 2936, 2842, 1714, 1451, 1215, 751; HRMS (ESI-TOF) m/
z calcd for C22H23N2O2 [M + H]+ 347.1756, found 347.1776.
5-[(2,3-Dihydro-1H-inden-2-yl)methyl]-5-methylbenzo[4,5]-
imidazo[2,1-a]isoquinolin-6(5H)-one (5d). The title compound was
prepared according to the general procedure as described above in
58% yield (66 mg). It was purified by flash chromatography (20%
EtOAc/hexanes; Rf = 0.5) to afford 5d as a colorless oil: 1H NMR
(400 MHz, CDCl3) δ 8.56−8.50 (m, 1H), 8.45−8.36 (m, 1H), 7.89−
7.82 (m, 1H), 7.64−7.56 (m, 1H), 7.55−7.44 (m, 4H), 7.00−6.90
(m, 4H), 2.81 (dd, J = 13.9, 7.3 Hz, 1H), 2.51 (dd, J = 8.8, 2.5 Hz,
2H), 2.46−2.36 (m, 2H), 2.27 (dd, J = 15.4, 9.9 Hz, 1H), 2.12−2.01
(m, 1H), 1.79 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.3,
149.7, 143.7, 142.5, 141.7, 131.8, 131.2, 127.9, 126.6, 126.0, 125.7,
124.0, 123.9, 122.6, 119.7, 115.8, 49.1, 48.1, 39.6, 39.0, 38.2, 30.2; IR
(neat) νmax 3023, 2931, 2842, 1715, 1453, 1359, 1165, 759; HRMS
(ESI-TOF) m/z calcd for C26H23N2O [M + H]+ 379.1810, found
379.1824.
5-(Cyclopentylmethyl)-5-methylbenzo[4,5]imidazo[2,1-a]-
isoquinolin-6(5H)-one (5e).13 The title compound was prepared
according to the general procedure as described above in 65% yield
(64 mg). It was purified by flash chromatography (20% EtOAc/
hexanes; Rf = 0.5) to afford 5e as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 8.49 (dd, J = 8.1, 1.3 Hz, 1H), 8.42−8.37 (m, 1H), 7.86−
7.81 (m, 1H), 7.60−7.54 (m, 1H), 7.51−7.41 (m, 4H), 2.53 (dd, J =
13.8, 7.6 Hz, 1H), 2.18 (dd, J = 13.8, 5.6 Hz, 1H), 1.73 (s, 3H), 1.41−
1.15 (m, 7H), 0.99−0.90 (m, 1H), 0.85−0.75 (m, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 173.5, 149.9, 143.9, 142.0, 131.6, 131.3,
127.6, 126.6, 125.8, 125.5, 122.7, 119.7, 115.7, 49.1, 37.4, 33.5, 32.4,
30.0, 24.8, 24.5; IR (neat) νmax 3064, 2948, 2867, 1714, 1450, 1355,
1182, 761; HRMS (ESI-TOF) m/z calcd for C22H23N2O [M + H]+
331.1810, found 331.1825.
■
ASSOCIATED CONTENT
* Supporting Information
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01555.
Copies of 1H and 13C NMR spectra for all new
compounds and X-ray structure of 3b (PDF)
Accession Codes
CCDC 2065408 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
■ AUTHOR INFORMATION
Corresponding Author
Praveen Reddy Adiyala − Department of Organic Synthesis
and Process Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500007 Telangana, India; Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad
12919
pubs.acs.org/joc Article
201002, India; orcid.org/0000-0003-1587-8265;
Email: praveenreddy@iict.res.in
Authors
Vankudoth Ramesh − Department of Organic Synthesis and
Process Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500007 Telangana, India; Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad
201002, India
Maram Gangadhar − Department of Organic Synthesis and
Process Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500007 Telangana, India; Academy
of Scientific and Innovative Research (AcSIR), Ghaziabad
201002, India
Jagadeesh Babu Nanubolu − Academy of Scientific and
Innovative Research (AcSIR), Ghaziabad 201002, India;
Centre for NMR and Structural Chemistry, CSIR-Indian
Institute of Chemical Technology, Hyderabad 500007
Telangana, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01555
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
V.R. thanks CSIR for a fellowship, and M.G. thanks UGC for a
fellowship. The authors thank CSIR for financial support (34/
1/TD-CLP/NCP-FBR 2020-RPPBDD-TMD-Se-MI). The
authors thank the Laboratory of X-ray Crystallography,
CSIR-IICT, for X-ray analysis. The authors thank the Director
of CSIR-IICT for the generous support (IICT/Pubs./2021/
097).
■
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