One-Pot Synthesis of Imidazolyl Isoquinolines under a Palladium-Catalyzed C-H Activation/Annulation (CHAA) Reaction

Article abstract of DOI:10.1055/s-0036-1588101

A microwave-assisted Pd-catalyzed one-pot C-H activation/annulation (CHAA) protocol has been developed for the synthesis of imidazo[2,1-a]isoquinolines and benzo[4,5]imidazo[2,1-a]isoquinolines. Further N-alkylation for the preparation of a series of the

Full text of DOI:10.1055/s-0036-1588101

SYNTHESIS
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2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
A
R. Zhu et al.
Paper
Synthesis
One-Pot Synthesis of Imidazolyl Isoquinolines under a Palladium-
Catalyzed C–H Activation/Annulation (CHAA) Reaction
Ranran Zhua,b,c
R2
Yuntao Wanga,b,c
Jialin Liua,b,c
Qing Wanga,b,c
Jianhui Huang*a,b,c
R1
N
N
Pd(OAc)2
Cu(OAc)2
K3PO4
NMP
Ar
Ar
N
NH
R2
R1
microwave
a School of Pharmaceutical Science and Technology, Tianjin University,
92 Weijin Road, Nankai District, Tianjin 300072, P. R. of China
b Collaborative Innovation Center of Chemical Science and Engineering
(Tianjin), Tianjin 300072, P. R. of China
c Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency,
School of Pharmaceutical Science and Technology, Tianjin University,
Tianjin 300072, P. R. of China
R1 = H, aryl
2 = H, Me, OMe, Cl, F
11 examples
35–72%
R
jhuang@tju.edu.cn
Received: 22.07.2016
Accepted after revision: 27.10.2016
Published online: 01.12.2016
demonstrated in Scheme 1, the construction of heteroaro-
matics has been realized via C–H activation/annulation re-
actions starting from readily available precursors. Previous-
ly we have utilized alkynes as coupling partners for the
preparation of a number of heterocycles under Pd-cata-
lyzed conditions. Under directed C–H activation processes,
the new C–C bond was initially formed (marked in pink),
followed by C–N bond formation (marked in green). Hetero-
cycles, such as isoquinolone,6 isoquinoline N-oxide,7 as well
as the seven-membered benzoazepine,8 have been pre-
pared by a single-step reaction. In this communication, we
report our latest discovery on the synthesis of a new class of
isoquinoline derivative via a one-pot protocol via initial C–
N bond formation followed by double C–H bond activation
(Scheme 1).
As proposed, the imidazo[2,1-a]isoquinoline ring sys-
tem could be formed via hydroamination an alkyne with
imidazole followed by double C–H activation of both ring
systems to make the third ring. The hydroamination reac-
tion of imidazole and a terminal alkyne was first studied.
The reaction of commercially available 1H-imidazole (1a)
and phenylacetylene (2a) in DMSO gave an 80:20 mixture
of Z-alkene 3a and E-alkene 3a′ with a full reaction conver-
sion (Table 1, entry 1). Further screening of the reaction
conditions, such as the solvent, base, and heating mode,
was fruitful; inorganic bases such as K3PO4 and Cs2CO3 ei-
ther in DMSO or NMP gave good Z/E selectivity (Table 1, en-
tries 2, 3, 5, and 6). It is noteworthy that the use of base is
crucial for the stereoselectivity, particularly for Z selectivity.
This empirical observation had been previously reported in
the literature, unfortunately, the mechanism is still not
quite understood.9 We envisaged that after the hydroami-
nation of phenylacetylene, the cation–π-interaction be-
DOI: 10.1055/s-0036-1588101; Art ID: ss-2016-h0516-op
Abstract A microwave-assisted Pd-catalyzed one-pot C–H activa-
tion/annulation (CHAA) protocol has been developed for the synthesis
of imidazo[2,1-a]isoquinolines and benzo[4,5]imidazo[2,1-a]isoquino-
lines. Further N-alkylation for the preparation of a series of the corre-
sponding isoquinolium salts has also been demonstrated. The fluores-
cent properties of these isoquinolines have been studied.
Key words C–H activation/annulation, microwave, fluorophore, het-
erocycle, fluorescent
Fluorophores are a useful tool in biology for staining
large molecules, such as enzymes and proteins, and they
can be also used as molecular probes and indicators.1 The
search and fine tuning of glowing molecules has left chal-
lenges for chemists from a synthetic perspective. Many flu-
orophores have been found and discovered in the past;2 as
key fluorophores, quinoline, quinolone, isoquinoline, and
isoquinolone and their salts have shown unique fluorescent
properties.3 The preparation and functionalization of these
core structures by an easily accessible route has attracted
reasonable attention for the discovery of new fluorophores.
Molecules having these quinolone cores have also been
shown to have good biological activities against tumor cells
as well as possessing DNA binding ability.4 The construction
of these heteroarene skeletons has become more conve-
nient using recently developed C–H direct functionalization
approaches using transition-metal catalysts, such as rhodi-
um, ruthenium, palladium, and iridium.5 We, together with
other pioneers in the field, have developed ways of making
these nitrogen-containing heterocycles in an atom- and
step-economical fashion by using palladium catalysts. As
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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R. Zhu et al.
Paper
Synthesis
Table 1 Screening of the Reaction Conditions for the Hydroamination
Pd-catalyzed C–H activation/annulation reactions: (C–C/C–N order)
of Phenylacetylenea
O
O
R1
R1
R3
R3
N
Ph
N
N
Pd cat.
N
N
N
H
our group: 2012
R2
base
N
NH
H
R2
R1
R1
3a'
3a
1a
2a
R3
OH
O
N
Pd cat.
Pd cat.
N
our group: 2013
R2
Entry
Solvent Base
Time
Conv. (%)
Ratiob Z/E
R3
1
DMSO
DMSO
DMSO
DMSO
NMP
KOHc
25 min
25 min
25 min
24 h
99
99
99
99
99
99
80:20
95:5
R2
O
O
2
3
K3PO4
Cs2CO3
K3PO4
K3PO4
Cs2CO3
R4
90:10
98:2
O
O
R4
Jiang/Wang: 2013
N
4d
5
6
N
H
R4
R4
25 min
25 min
97:3
R4
Ar
R4
NMP
85:15
This work: (C–N/C–C order)
a Reaction conditions: phenylacetylene (2a, 30.6 mg, 0.3 mmol), imidazole
(1a, 31 mg, 0.45 mmol), solvent (1.0 mL), base (2.0 equiv), microwave
conditions (120 °C, 300 W) unless otherwise stated.
b Ratio based on GC measurements.
N
N
Ar
Pd cat.
N
c KOH (0.5 equiv).
N
d Under standard thermal conditions without microwave irradiation.
H
R
R
Scheme 1 C–H Activation/annulation reaction using an alkyne as the
coupling partner
tween the aromatic ring and the potassium cation gives rise
to the Z-isomer as the most stable isomer. The Z-alkene
would be the sole isomer that could be converted into the
ring system without further rotation of the C=C bond. Un-
der conventional thermal conditions, the hydroamination
reaction also went smoothly to provide the desired alkene
3a with excellent selectivity, which agreed with results pre-
viously described in the literature.10 When reaction was al-
lowed to stir for 4 hours, it led to the conversion of the ki-
netically stable Z-isomer into the thermodynamically sta-
ble E-isomer. So the ratio of Z/E depends on the reaction
time. It seemed that both DMSO and NMP were also poten-
tial solvents for the further ring-closing reaction. Solvents
such as toluene, DCE, and BuOH did not provide any of the
desired product 3a or 3a′.
With optimal conditions for the Z-selective hydroami-
nation reaction in hand, we attempted to find conditions to
combine both processes into a single chemical step. In the
presence of base and Pd catalyst, the reaction did not give
us any of the desired imidazolyl isoquinoline 4a. With lon-
ger reaction times, E-alkene 3a′ was isolated as the sole
product in near quantitative yield. Our focus then moved to
screening the reaction conditions for an alternative one-pot
reaction that combined the hydroamination and Pd-cata-
lyzed double C–H activation as two separate steps.
Table 2 Reaction Condition Screening on Double C–H Activation Ring
Closurea
N
N
Pd(OAc)2, oxidant
base
N
N
H
solvent 1
microwave
solvent 2
microwave
H
1a
2a
4a
Entry Step 1
Solvent 1 Base
Step 2
Solvent 2
Oxidant
Yieldb
(%)
1
DMSO
DMSO
NMP
Cs2CO3
K3PO4
–
AgOAc
0
2
mesitylene
AgOAc
0
3
Cs2CO3 mesitylene
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
<5
11
15
50
72
24
52
45
4
NMP
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
mesitylene
1,4-dioxane
5
NMP
6
NMP
1,4-dioxane/HOAc (10:1) Cu(OAc)2
7
NMP
NMP
1,4-dioxane/HOAc (5:1)
1,4-dioxane/HOAc (5:1)
1,4-dioxane/HOAc (5:1)
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
8c
9
DMSO
NMP
10
Cs2CO3 1,4-dioxane/HOAc (5:1)
a Reaction conditions: 1. phenylacetylene (2a, 30.6 mg, 0.3 mmol), imidaz-
ole (1a, 30.6 mg, 0.45 mmol), base (2.0 equiv), solvent 1 (1.0 mL), micro-
wave conditions (120 °C, 300 W), 25 min; 2. Pd(OAc)2 (10 mol%), Cu(OAc)2
(2.0 equiv), solvent 2 (1 mL), microwave conditions (120 °C, 300 W), 6 h,
unless otherwise stated.
As shown in Table 2, entry 4, after hydroamination in
NMP, when mesitylene was used as the second solvent un-
der Pd-catalyzed conditions in the presence of Cu(OAc)2 as
the oxidant, our desired imidazolyl isoquinoline 4a was ob-
tained in 11% yield.11 The double C–H activation reaction is
b Isolated yield.
c Under standard thermal conditions without microwave irradiation. Reac-
tion time (step 1: 24 h; step 2: 48 h).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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R. Zhu et al.
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Synthesis
favored under acid conditions (Table 2, entry 6), the addi-
tion of acetic acid as the co-solvent provide the desired
product in 50% yield over two steps and no work-up or pu-
rification was needed in between. Increasing the amount of
acid led to the desired product 4a in 72% overall yield. In
contrast, under conventional thermal conditions, the de-
sired product was obtained in 24% yield. Comparing to the
reaction under microwave conditions, the reaction under
thermal conditions was slower and E-alkene was formed
from Z-alkene during C–H activation processes (Table 2, en-
try 8).
With the optimal conditions in hand, we examined the
scope and limitations of this reaction (Scheme 2). To our
delight, a range of imidazolyl isoquinolines 4a–e and ben-
zoimidazolyl isoquinolines 4f–k were synthesized. When
1H-imidazole (1a) and terminal arylacetylenes 2 were uti-
lized, arylacetylenes 2 bearing electron-rich or electron-de-
ficient substituents at the para-position were converted
into the corresponding 9-substituted imidazolyl isoquino-
lines 4b–d in 40–64% yields. As this synthesis begins from
cheap and readily available substrates, the efficiency of the
molecular growth is very promising. An internal alkyne was
also tolerated and isoquinoline 4e was successfully pre-
pared in 50% yield from diphenylacetylene. A range of ben-
zoimidazolyl isoquinolines 4f–k were prepared from 1H-
benzimidazole (1b) and 5,6-dimethyl-1H-benzimidazole
(1c) and aryl- and diarylacetylenes 2 under identical condi-
tions.
The direct alkylation of imidazolyl isoquinoline deriva-
tives 4 is straightforward; the corresponding isoquinolium
salts 5 were prepared in good yields. As demonstrated in
Scheme 3, the alkylation of imidazolyl isoquinoline 4a with
MeI, BuI, or BnBr gave the corresponding isoquinolium salts
5a–c in good yields. Similar reactivity was also observed on
benzoimidazolyl derivatives. The reactions with substituted
imidazolyl isoquinolines with alkyl halide also gave the de-
sired products 5g–i in good yields.
R3
N
N
reflux
R3
X
R1
R1
toluene
N
N
X
R2
R2
5
4
N
N
N
I
N
Br
N
I
N
5b (65%)
5c (88%)
5a (71%)
Ar
N
N
Ar
N
N
N
1. K3PO4, NMP, 120 °C, MW
N
N
Br
I
I
N
N
N
H
R
2. Pd(OAc)2, Cu(OAc)2
1,4-dioxane/AcOH (5:1)
R
1a
2a
4a
5f (87%)
5e (62%)
5d (83%)
N
N
N
N
F
Cl
N
N
N
N
N
N
N
N
F
Cl
I
N
I
I
N
4a (72%)
4b (45%)
4c (40%)
4d (64%)
5h (70%)
5i (75%)
5g (80%)
N
N
N
N
N
N
N
Scheme 3 Synthesis of imidazolyl and benzoimidazolyl isoquinolium
salts. Reagents and conditions: imidazolyl and benzoimidazolyl isoquino-
line 4 (0.2 mmol), RX (2–4 mmol), toluene (0.2 M), 24 h.
F
Cl
N
Ph
4e (50%)
4f (52%)
4g (44%)
4h (35%)
The fluorescent properties of these imidazolyl isoquino-
lines 4 and the corresponding isoquinolium salts 5 are giv-
en in the Supporting Information and selected examples are
illustrated in Table 3. As shown in the Supporting Informa-
tion, most of the isoquinolium salts 5 are fluorescent with a
wavelength of maximum absorbance between 253–313
nm, while emission intensities range from 347–410 nm,
they have relative large Stokes shifts12 from 88–147 nm;
they show a useful to good quantum yield generally of
about 40%. In particular, as compared in Table 3, benzoimid-
azolyl isoquinoline 4f and its 12-methyl isoquinolium salt
5d show stronger fluorescence than the corresponding im-
idazolyl derivatives 4a and its 1-methyl salt 5a due to the
extended aromatic system with more delocalization possi-
N
N
N
N
OMe
N
N
Ph
4j (45%)
4i (39%)
4k (40%)
Scheme 2 Microwave-assisted one-pot reaction for the synthesis of
imidazolyl and benzoimidazolyl isoquinolines. Reagents and conditions:
1. aryl- or diarylacetylene 2 (0.3 mmol), 1H-imidazole (1a) or 1H-benz-
imidazole (1b) (0.45 mmol), K3PO4 (2.0 equiv), NMP (1.0 mL), micro-
wave conditions (120 °C, 300 W), 10–120 min; 2. Pd(OAc)2 (10 mol%),
Cu(OAc)2 (2.0 equiv), 1,4-dioxane/HOAc (5:1, 1.0 mL), microwave con-
ditions (120 °C, 300 W), 5–9 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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R. Zhu et al.
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Synthesis
bilities. The para-chloro substituent on the acetylene af-
fected the fluorescence, as 2-chloro product 4g had a low
quantum yield (13%) compared to the unsubstituted iso-
quinoline 4f. While as the quantum efficiency of the elec-
tron-donating group containing 2-methoxy product 4j is al-
most the same as 4f. It is worth noting that the 12-benzyl-
substituted benzoimidazolyl isoquinolium salt 5f gave a rel-
ative high quantum yield of 57%. In order to further increase
the quantum efficiency, the future direction would be the
late-stage functional group introduction via ortho-C–H ac-
tivation protocols as well as the meta-selective C–H activa-
tions developed within our group13 or the Ackermann and
Frost groups.14
Reagents and solvents were commercially available and were used
without further purification. Phenylacetylene and imidazole were
purchased from Heowns. Diarylacetylenes were prepared via
Sonogashira coupling reactions of the corresponding arylacetylene
and iodoarene using the literature procedures. The analytical data of
products are in agreement with previously reported data.
Imidazo[2,1-a]isoquinolines 4a–k; General Procedure
Into a 10-mL microwave vial was weighed arylacetylene (0.3 mmol),
imidazole (2.0 equiv), and K3PO4 (2.0 equiv). The vial was charged
with a magnetic stir bar and subsequently NMP (1.0 mL) was added as
the solvent. The microwave vial cap was affixed onto the vial and the
mixture was heated in the microwave at 120 °C (300 W) for 10–120
min (t1). After the first step was complete, without purification, to the
mixture was added Pd(OAc)2 (10 mol%), Cu(OAc)2 (2 equiv), HOAc
(200 μL), and dioxane (1.0 mL). Then the mixture was heated at 120 °C
(300 W) in the microwave for 5–9 h (t2). The reaction course was
monitored by GC-MS or TLC. The vessel was cooled to r.t., the mixture
was diluted with EtOAc (20 mL), and it was transferred to a separatory
funnel, and washed with water (3 × 30 mL) and brine (45 mL). The
organic phase was dried (Na2SO4) and filtered and the solvent was re-
moved under reduced pressure to provide the crude product. The pu-
rification was performed by flash column chromatography (silica gel).
Table 3 Fluorescent Properties of Imidazolyl Isoquinoline and Isoquin-
olium Salts
Compound
λabs (nm)a
λem (nm)a
Stokes shift (nm) ϕb (%)
4a
4f
254
277
279
277
281
249
262
269
377
378
378
385
390
347
409
378
123
101
99
9
43
13
50
38
33
43
57
4g
4i
Imidazo[2,1-a]isoquinoline (4a)
108
109
98
t1 = 25 min; t2 = 6 h. Yellow solid; yield: 36 mg (72%); mp 69–70 °C.
4j
1H NMR (400 MHz, CDCl3): δ = 8.63 (d, J = 8.0 Hz, 1 H), 7.91 (d, J = 7.0
Hz, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.67–7.53 (m, 4 H), 7.03 (d, J = 7.0 Hz,
1 H).
5a
5d
5f
147
109
13C NMR (101 MHz, CDCl3): δ = 143.2, 131.4, 129.4, 128.2, 128.2,
126.9, 124.0, 123.2, 123.1, 114.2, 113.2.
HRMS (ESI): m/z [M]+ calcd for C11H8N2: 168.0687; found: 168.0688.
a Wavelengths of maximum absorbance (λabs) or emission intensity (λem).
b Quantum yield determined by using Rhodamine B as a standard
(ϕ = 0.71).
9-Chloroimidazo[2,1-a]isoquinoline (4b)
t1 = 10 min; t2 = 6 h. Yellow solid; yield: 27 mg (45%); mp 70–72 °C.
In conclusion, we have reported a novel approach for
the synthesis of a series of imidazolyl isoquinoline and the
corresponding isoquinolium salts via a one-pot Pd-cata-
lyzed CHAA reaction. The preliminary fluorescent property
studies have provided potentially good fluorophores for fu-
ture investigations of structure–function relationships.
1H NMR (400 MHz, CDCl3): δ = 8.60 (d, J = 2.0 Hz, 1 H), 7.89 (d, J = 7.0
Hz, 1 H), 7.60 (m, 3 H), 7.49 (dd, J = 9.0, 2.0 Hz, 1 H), 7.00 (d, J = 7.5 Hz,
1 H).
13C NMR (100 MHz, CDCl3): δ = 142.0, 134.1, 131.8, 128.6, 128.4,
127.6, 125.0, 123.3, 122.8, 114.6, 112.5.
HRMS (ESI): m/z [M]+ calcd for C11H735ClN2: 202.0298; found:
202.0299.
Flash chromatography was performed on silica gel 100–200 μm. The
solvent system used was a gradient of petroleum ether/EtOAc, in-
creasing in polarity to EtOAc. TLC was performed on glass backed
plates pre-coated with silica (GF254), which were developed using
standard visualizing agents. 1H and 13C NMR spectra were recorded
on a 600 MHz or 400 MHz Bruker Avance spectrometer at 25 °C with
the solvent resonance as the internal standard (1H: CHCl3: δ = 7.26;
DMSO: δ = 2.50).13C NMR spectra were recorded with complete pro-
ton decoupling with the solvent resonance as the internal standard.
LR-MS were recorded on Micromass Autospec, operating in Agilent
GC-MS operating in either EI or CI mode. HRMS recorded for accurate
mass analysis, were performed on either a Q-TOF micro (Bruker Com-
pass Data Analysis 4.0) spectrometer. The UV-vis and fluorescence
spectra were performed on Hitachi (U-3900) and Edinburgh (FLS
980).
9-Fluoroimidazo[2,1-a]isoquinoline (4c)
t1 = 10 min; t2 = 6 h. Yellow solid; yield: 22 mg (40%); mp 65–66 °C.
1H NMR (400 MHz, CDCl3): δ = 8.27 (dd, J = 9.5, 2.5 Hz, 1 H), 7.90 (d,
J = 7.5 Hz, 1 H), 7.70 (dd, J = 9.0, 5.5 Hz, 1 H), 7.62 (s, 1 H), 7.59 (s, 1 H),
7.30 (td, J = 9.0, 2.5 Hz, 1 H), 7.04 (d, J = 7.5 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 162.3 (d, J = 248.5 Hz), 131.7, 129.3 (d,
J = 8.8 Hz), 125.9 (d, J = 2.1 Hz), 125.5, 122.4 (d, J = 2.1 Hz), 116.9 (d,
J = 24.0 Hz), 114.6, 112.6, 110.8, 108.6 (d, J = 23.8 Hz).
HRMS (ESI): m/z [M]+ calcd for C11H719FN2: 186.0593; found:
186.0597.
9-Methylimidazo[2,1-a]isoquinoline (4d)
t1 = 30 min; t2 = 6 h. Yellow solid; yield: 35 mg (64%); mp 78–79 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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R. Zhu et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 8.45 (s, 1 H), 7.86 (d, J = 7.5 Hz, 1 H),
7.55–7.61 (m, 3 H), 7.39 (d, J = 8.0 Hz, 1 H), 7.02 (d, J = 7.5 Hz, 1 H),
2.56 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 8.59 (s, 1 H), 8.00 (d, J = 7.0 Hz, 1 H),
7.74 (s, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.53 (s, 1 H), 7.45 (d, J = 8.0 Hz, 1
H), 6.96 (d, J = 7.5 Hz, 1 H), 2.57 (s, 3 H), 2.45 (s, 6 H).
13C NMR (101 MHz, CDCl3): δ = 138.4, 131.3, 129.7, 129.4, 127.2,
126.8, 124.0, 123.0, 122.3, 114.2, 113.0, 21.8.
HRMS (ESI): m/z [M]+ calcd for C12H10N2: 182.0844; found: 182.0846.
13C NMR (101 MHz, CDCl3): δ = 146.7, 142.4, 138.3, 133.7, 131.1,
129.1, 128.6, 126.9, 124.5, 123.7, 120.6, 119.7, 110.8, 109.9, 21.6,
20.70, 20.68.
HRMS (ESI): m/z [M]+ calcd for C18H16N2: 260.1313; found: 260.1314.
5-Phenylimidazo[2,1-a]isoquinoline (4e)
2-Methoxybenzo[4,5]imidazo[2,1-a]isoquinoline (4j)
t1 = 120 min; t2 = 9 h. Yellow solid; yield: 36 mg (50%); mp 120–
122 °C.
t1 = 40 min; t2 = 6 h. White solid; yield: 33 mg (45%); mp 124–125 °C.
IR (KBr): 3552, 2989, 2413, 1720, 1617, 1449, 1324, 766 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.67 (d, J = 5.5 Hz, 1 H), 7.72 (d, J = 5.5
Hz, 1 H), 7.67–7.63 (m, 3 H), 7.61–7.50 (m, 6 H), 7.02 (s, 1 H).
13C NMR (151 MHz, CDCl3): δ = 143.7, 135.9, 134.4, 131.0, 129.9,
129.7, 129.1, 128.6, 128.4, 128.0, 126.9, 123.3, 123.1, 113.1, 99.9.
HRMS (ESI): m/z [M]+ calcd for C17H12N2: 244.1000; found: 244.1000.
.
1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 2.5 Hz, 1 H), 8.09 (d, J = 7.5
Hz, 1 H), 8.03 (d, J = 8.0 Hz 1 H), 7.84 (d, J = 8.0 Hz, 1 H), 7.67 (d, J = 8.5
Hz, 1 H), 7.52 (td, J = 8.0, 1.5 Hz, 1 H), 7.41 (td, J = 8.0, 1.5 Hz, 1 H),
7.28 (dd, J = 9.0, 3.0 Hz, 1 H), 7.04 (d, J = 7.5 Hz, 1 H), 4.04 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 159.7, 147.2, 143.8, 130.2, 128.7,
125.7, 124.9, 124.7, 121.8, 120.8, 119.8, 119.2, 111.2, 110.0, 105.1,
55.9.
HRMS (ESI): m/z [M]+ calcd for C16H12N2O: 248.0950; found:
248.0953.
Benzo[4,5]imidazo[2,1-a]isoquinoline (4f)
t1 = 25 min; t2 = 6 h. Yellow solid; yield: 34 mg (52%); mp 111–112 °C.
1H NMR (400 MHz, CDCl3): δ = 8.83 (m, 1 H), 8.16 (d, J = 8.0 Hz, 1 H),
8.02 (d, J = 8.5 Hz, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.74 (m, 1 H), 7.68 (m,
2 H), 7.52 (td, J = 7.5, 1.0 Hz, 1 H), 7.42 (td, J = 8.0, 1.0 Hz, 1 H), 7.07 (d,
J = 7.0 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 146.3, 142.8, 130.6, 129.1, 129.0,
127.2, 126.0, 124.0, 123.7, 122.6, 120.8, 120.4, 118.9, 110.3, 108.8.
6-Phenylbenzo[4,5]imidazo[2,1-a]isoquinoline (4k)
t1 = 120 min; t2 = 9 h. Yellow solid; yield: 35 mg (40%); mp 171–
173 °C.
IR (KBr): 3552, 3235, 2027, 1617, 1527, 1394, 1311, 1274, 878 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.89 (m, 1 H), 7.99 (d, J = 8.0 Hz, 1 H),
7.77–7.54 (m, 8 H), 7.40 (td, J = 8.0, 1.0 Hz, 1 H), 7.00 (td, J = 8.0, 1.0
Hz, 1 H), 6.91 (s, 1 H), 6.49 (d, J = 9.0 Hz, 1 H).
.
HRMS (ESI): m/z [M]+ calcd for C15H10N2: 218.0844; found: 218.0842.
13C NMR (101 MHz, CDCl3): δ = 148.3, 144.3, 137.5, 134.7, 131.6,
130.7, 130.1, 129.9, 129.4, 129.0, 127.9, 126.7, 125.1, 124.2, 122.9,
121.3, 119.7, 114.1, 112.6.
2-Chlorobenzo[4,5]imidazo[2,1-a]isoquinoline (4g)
t1 = 10 min; t2 = 6 h. Yellow solid; yield: 33 mg (44%); mp 152–155 °C.
1H NMR (400 MHz, CDCl3): δ = 8.74 (d, J = 2.0 Hz, 1 H), 8.05 (d, J = 7.0
Hz, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.76 (d, J = 8.5 Hz, 1 H), 7.59 (d,
J = 8.5 Hz, 1 H), 7.51 (m, 2 H), 7.39 (t, J = 8.0 Hz, 1 H), 6.95 (d, J = 7.0
Hz, 1 H).
HRMS (ESI): m/z [M]+ calcd for C21H14N2: 294.1157; found: 294.1158.
1-Alkylimidazo[2,1-a]isoquinolium Salts 5a–i; General Procedure
Freshly made imidazo[2,1-a]isoquinoline 4 (0.2 mmol) was dissolved
in toluene (1 ml) and the electrophilic agent (10–20 equiv) was add-
ed. The reaction was stirred for 24 h under reflux. The final product
precipitated from the solution and it was recovered by filtration. The
residue was washed extensively with Et2O and dried to yield the cor-
responding 1-alkylimidazo[2,1-a]isoquinolium salt framework 5a–i.
13C NMR (101 MHz, CDCl3): δ = 145.9, 143.6, 134.1, 130.3, 129.9,
129.7, 128.4, 125.0, 124.5, 124.4 122.3, 121.5, 120.0, 110.5, 109.9.
HRMS (ESI): m/z [M]+ calcd for C15H935ClN2: 252.0454; found:
252.0455.
2-Fluorobenzo[4,5]imidazo[2,1-a]isoquinoline (4h)
1-Methyl-1H-imidazo[2,1-a]isoquinolin-4-ium Iodide (5a)
t1 = 10 min; t2 = 6 h. Brown solid; yield: 24 mg (35%); mp 172–174 °C.
1H NMR (400 MHz, CDCl3): δ = 8.47 (dd, J = 9.5, 2.5 Hz, 1 H), 8.15 (d,
J = 7.5 Hz, 1 H), 8.02 (d, J = 8.5 Hz, 1 H), 7.85 (d, J = 8.0 Hz, 1 H), 7.75
(dd, J = 8.5, 5.5 Hz, 1 H), 7.53 (t, J = 8.0 Hz, 1 H), 7.47–7.37 (m, 2 H),
7.07 (d, J = 7.5 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 162.2 (d, J = 249.0 Hz), 143.6 (s), 129.4
(d, J = 8.5 Hz), 128.1, 128.1, 125.1 (d, J = 9.5 Hz), 125.0, 122.3, 120.7 (d,
J = 2.5 Hz), 120.0, 118.7 (d, J = 24.0 Hz), 110.8, 110.8, 110.5 (d, J = 24.0
Hz), 110.0.
White solid; yield: 44 mg (71%); mp 251–254 °C.
IR (KBr): 3549, 3236, 2024, 1618, 1548, 1483, 1455, 803, 746 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 8.79 (d, J = 8.0 Hz, 1 H), 8.67 (d,
J = 7.5 Hz, 1 H), 8.45 (d, J = 2.0 Hz, 1 H), 8.26 (d, J = 2.0 Hz, 1 H), 8.24
(d, J = 8.0 Hz, 1 H), 8.00 (m, 2 H), 7.90 (d, J = 7.2 Hz, 1 H), 4.48 (s, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 136.9, 132.4, 132.2, 130.2, 129.0,
127.5, 125.1, 124.8, 118.4, 117.9, 116.5, 39.1.
HRMS (ESI): m/z [M – I]+ calcd for C12H11IN2: 183.0922; found:
183.0924.
.
HRMS (ESI): m/z [M]+ calcd for C15H9FN2: 236.0750; found: 236.0751.
2,9,10-Trimethylbenzo[4,5]imidazo[2,1-a]isoquinoline (4i)
1-Butyl-1H-imidazo[2,1-a]isoquinolin-4-ium Iodide (5b)
t1 = 25 min; t2 = 6 h. Yellow solid; yield: 30.5 mg (39%); mp 197–
199 °C.
IR (KBr): 3020, 2920, 2853, 1732, 1518, 1458, 1363, 1003, 824 cm–1
Yellow solid; yield: 46 mg (65%); mp 138–141 °C.
IR (KBr): 3550, 3065, 2953, 1726, 1545, 1521, 1214, 1070, 815 cm–1
.
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

F
R. Zhu et al.
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Synthesis
1H NMR (400 MHz, DMSO-d6): δ = 8.67 (d, J = 7.0 Hz, 1 H), 8.64 (dd,
J = 7.5, 2.0 Hz, 1 H), 8.49 (d, J = 2.0 Hz, 1 H), 8.31 (d, J = 2.0 Hz, 1 H),
8.27–8.22 (m, 1 H), 8.06–7.96 (m, 2 H), 7.91 (d, J = 7.5 Hz, 1 H), 4.87 (t,
J = 7.5 Hz, 2 H), 2.04–1.85 (m, 2 H), 1.46 (m, 2 H), 0.95 (t, J = 7.5 Hz, 3
H).
13C NMR (101 MHz, DMSO-d6): δ = 136.2, 132.7, 132.2, 130.5, 129.3,
126.8, 125.3, 124.4, 118.1, 117.9, 116.93, 50.60, 31.11, 19.47, 14.01.
IR (KBr):3550, 3413, 2995, 1617, 1525, 1472, 1327, 803, 752 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 9.44 (d, J = 7.5 Hz, 1 H), 8.77 (dd,
J = 7.5 Hz, J = 2.0 Hz, 1 H), 8.61 (d, J = 8.5 Hz, 1 H), 8.33 (d, J = 8.0 Hz, 1
H), 8.27 (dd, J = 8.0 Hz, J = 2.0 Hz, 1 H), 8.16 (d, J = 7.5 Hz, 1 H), 8.08 (t,
J = 8.0 Hz, 1 H), 7.93–7.83 (m, 3 H), 7.44–7.30 (m, 5 H), 6.48 (s, 2 H).
13C NMR (101 MHz, DMSO-d6): δ = 141.4, 135.3, 134.6, 134.0, 133.8,
130.4, 129.6, 129.4, 129.3, 128.6, 127.6, 126.6, 126.5, 125.9, 123.8,
117.6, 117.3, 114.2, 113.3, 50.2.
HRMS (ESI): m/z [M – I]+ calcd for C15H17IN2: 225.1392; found:
225.1392.
HRMS (ESI): m/z [M – Br]+ calcd for C22H1779BrN2: 309.1386; found:
309.1387.
1-Benzyl-1H-imidazo[2,1-a]isoquinolin-4-ium Bromide (5c)
White solid; yield: 68 mg (88%); mp 245–247 °C.
2,12-Dimethyl-12H-benzo[4,5]imidazo[2,1-a]isoquinolin-7-ium
IR (KBr): 3551, 3148, 3065, 1617, 1546, 1463, 1359, 1181, 806 cm–1
.
Iodide (5g)
White solid; yield: 59 mg (80%); mp 287–290 °C.
IR (KBr): 3550, 3413, 3019, 1619, 1532, 1500, 1448, 1035, 770 cm–1
1H NMR (600 MHz, DMSO-d6): δ = 8.78 (d, J = 7.5 Hz, 1 H), 8.63 (s, 1
H), 8.43 (d, J = 8.5 Hz, 1 H), 8.38 (s, 1 H), 8.22 (d, J = 8.0 Hz, 1 H), 7.95
(m, 2 H), 7.81 (t, J = 8.0 Hz, 1 H), 7.40 (t, J = 7.5 Hz, 2 H), 7.34 (t, J = 7.5
Hz, 1 H), 7.29 (d, J = 7.5 Hz, 2 H), 6.22 (s, 2 H).
13C NMR (151 MHz, DMSO-d6): δ = 136.3, 134.2, 132.3, 131.9, 129.7,
129.1, 128.6, 128.2, 126.8, 126.4, 125.0, 124.0, 117.9, 117.1, 117.0,
53.1.
.
1H NMR (400 MHz, DMSO-d6): δ = 9.27 (d, J = 7.5 Hz, 1 H), 8.84 (s, 1
H), 8.67 (d, J = 8.5 Hz, 1 H), 8.35 (d, J = 8.5 Hz, 1 H), 8.22 (d, J = 8.5 Hz,
1 H), 8.03 (d, J = 7.0 Hz, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 7.91 (t, J = 7.5 Hz,
1 H), 7.82 (t, J = 7.5 Hz, 1 H), 4.66 (s, 3 H), 2.71 (s, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 141.2, 140.7, 135.4, 133.6, 132.8,
129.0, 128.9, 127.1, 126.1, 125.6, 122.5, 118.2, 117.1, 113.9, 113.4,
35.5, 22.0.
HRMS (ESI): m/z [M – Br]+ calcd for C18H1579BrN2: 259.1235; found:
259.1236.
HRMS (ESI): m/z [M – I]+ calcd for C17H15IN2: 247.1235; found:
247.1235.
12-Methyl-12H-benzo[4,5]imidazo[2,1-a]isoquinolin-7-ium Io-
dide (5d)
White solid; yield: 60 mg (83%); mp 280–283 °C.
2-Chloro-12-methyl-12H-benzo[4,5]imidazo[2,1-a]isoquinolin-7-
IR (KBr): 3549, 3018, 1617, 1528, 1478, 1419, 1252, 1001, 755 cm–1
.
ium Iodide (5h)
White solid; yield: 55 mg (70%); mp 238–241 °C.
IR (KBr): 3529, 3030, 1950, 1534, 1446, 1413, 1318, 879, 764 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 9.34 (d, J = 7.5 Hz, 1 H), 9.10 (d,
J = 8.5 Hz, 1 H), 8.69 (d, J = 8.5 Hz, 1 H), 8.35 (m, 2 H), 8.16 (t, J = 8.0
Hz, 1 H), 8.11–8.02 (m, 2 H), 7.93 (t, J = 8.5 Hz, 1 H), 7.84 (t, J = 8.5 Hz,
1 H), 4.65 (s, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 141.5, 134.9, 133.9, 133.6, 130.3,
129.2, 129.0, 127.1, 126.7, 126.2, 123.3, 118.12, 117.2, 113.9, 113.4,
35.4.
.
1H NMR (400 MHz, DMSO-d6): δ = 9.38 (d, J = 6.5 Hz, 1 H), 9.00 (s, 1
H), 8.70 (d, J = 8.0 Hz, 1 H), 8.38 (t, J = 8.0 Hz, 2 H), 8.22 (d, J = 8.0 Hz, 1
H), 8.12 (d, J = 6.0 Hz, 1 H), 7.94 (t, J = 7.0 Hz, 1 H), 7.87 (t, J = 7.0 Hz, 1
H), 4.68 (s, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 140.5, 134.9, 134.1, 133.6, 133.5,
131.2, 129.3, 127.0, 126.5, 125.5, 123.9, 119.3, 116.7, 114.0, 113.6,
35.2.
HRMS (ESI): m/z [M – I]+ calcd for C16H13IN2: 233.1079; found:
233.1078.
HRMS (ESI): m/z [M – I]+ calcd for C16H1235ClIN2: 267.0689; found:
267.0688.
12-Butyl-12H-benzo[4,5]imidazo[2,1-a]isoquinolin-7-ium Iodide
(5e)
White solid; yield: 50 mg (62%); mp 252–254 °C.
2-Fluoro-12-methyl-12H-benzo[4,5]imidazo[2,1-a]isoquinolin-7-
IR (KBr): 3550, 3037, 1920, 1617, 1526, 1472, 1455, 1367, 750 cm–1
.
ium Iodide (5i)
Yellow solid; yield: 56 mg (75%); mp 255–259 °C.
IR (KBr): 3013, 1648, 1620, 1503, 1412, 1287, 1213, 1036, 714 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 9.35 (d, J = 7.5 Hz, 1 H), 8.87 (d,
J = 8.5 Hz, 1 H), 8.70 (d, J = 8.5 Hz, 1 H), 8.35 (m, 2 H), 8.20–8.04 (m, 3
H), 7.92 (t, J = 7.5 Hz, 1 H), 7.84 (t, J = 8.0 Hz, 1 H), 5.16 (t, J = 7.5 Hz, 2
H), 2.01 (dt, J = 15.0, 7.5 Hz, 2 H), 1.55 (dq, J = 15.0, 7.5 Hz, 2 H), 0.95
(t, J = 7.3 Hz, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 140.6, 135.1, 133.8, 133.4, 130.8,
129.5, 129.1, 127.3, 126.3, 126.0, 123.6, 117.7, 117.3, 114.0, 113.5,
46.9, 31.1, 19.8, 14.2.
.
1H NMR (400 MHz, DMSO-d6): δ = 9.35 (d, J = 7.5 Hz, 1 H), 8.84 (dd,
J = 10.5, 2.5 Hz, 1 H), 8.70 (d, J = 8.0 Hz, 1 H), 8.44 (dd, J = 9.0, 6.0 Hz, 1
H), 8.38 (d, J = 8.5 Hz, 1 H), 8.16–8.06 (m, 2 H), 7.94 (t, J = 8.0 Hz, 1 H),
7.85 (t, J = 7.5 Hz, 1 H), 4.66 (s, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 162.1 (d, J = 248.5 Hz), 140.8 (d,
J = 4.5 Hz), 133.6, 132.2 (d, J = 9.5 Hz), 131.8, 129.2, 127.0, 126.4,
122.96 (d, J = 23.7 Hz), 122.92 (d, J = 2.5 Hz), 119.3 (d, J = 10.5 Hz),
116.7, 114.0, 113.5, 112.1 (d, J = 26.0 Hz), 35.1.
HRMS (ESI): m/z [M – I]+ calcd for C21H19IN2: 275.1548; found:
275.1550.
HRMS (ESI): m/z [M – I]+ calcd for C16H12FIN2: 251.0985; found:
251.0986.
12-Benzyl-12H-benzo[4,5]imidazo[2,1-a]isoquinolin-7-ium Bro-
mide (5f)
White solid; yield: 75 mg (87%); mp 253–255 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

G
R. Zhu et al.
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Synthesis
Acknowledgment
(4) Parenty, A. D. C.; Smith, L. V.; Guthrie, K. M.; Long, D. L.; Plumb,
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The financial supports from ‘National Basic Research Program of
China’ (No. 2015CB856500), National Natural Science Foundation of
China (Grant No. 21672159, 21302136), Tianjin Natural Science Foun-
dation (Grant No. 13JCQNJC04800) are gratefully acknowledged.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588101.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G