Nickel-Catalyzed C-F/N-H Annulation of 2-(2-Fluoroaryl) N-Heteroaromatic Compounds with Alkynes: Activation of C-F Bonds

Article abstract of DOI:10.1055/a-1337-5504

The reaction of 2-(2-fluoroaryl) N-heteroaromatic compounds, such as benzimidazole and indole derivatives, with internal alkynes in the presence of a catalytic amount of a nickel complex results in C-F/N-H annulation with alkynes. The reaction shows a high functional group compatibility. The presence of a strong base, such as KOBu- ^tor LiOBu ^t, is required for the reaction to proceed.

Full text of DOI:10.1055/a-1337-5504

SYNTHESIS
0
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1
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–F
special topic
A
Bond Activation – in Honor of Prof. Shinji
H. Kawakami et al.
Special Topic
Synthesis
Nickel-Catalyzed C–F/N–H Annulation of 2-(2-Fluoroaryl) N-Het-
eroaromatic Compounds with Alkynes: Activation of C–F Bonds
Haruka Kawakami
Ni(cod)2
Me4phen
KOBut
R
R
X
N
Itsuki Nohira
X
N
Naoto Chatani*
+
R'
R'
DMF
100 °C
F
H
R'
R'
Department of Applied Chemistry, Faculty of Engineering,
Osaka University, Suita, Osaka 565-0871, Japan
chatani@chem.eng.osaka-u.ac.jp
N
N
Me4phen
Dedicated to Professor Shinji Murai for his contribution to bond
activation
Published as part of the Special Topic
Bond Activation – in Honor of Prof. Shinji Murai
NDeMeapoataiColrotcCmrhhraeeatnstapatnnooi@infdAcihpnepgmliAe.eudnthCgoh.oresmakisat-ruy.,aFca.jcpulty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
Received: 01.12.2020
Accepted after revision: 15.12.2020
Published online: 15.12.2020
doloisoquinolines from the reaction of 2-iodo- or 2-bro-
moaryl N-heteroaromatic compounds with alkynes via C–C
and C–N bond formation (Scheme 1b).5 The reaction re-
quired higher reaction temperatures, frequently in the 130–
150 °C range, even when 2-iodoaryl N-heteroaromatic com-
pounds were used as the substrates. In contrast, we found
that a similar transformation using 2-fluoroaryl N-het-
eroaromatic compounds proceeds even at 100 °C, by taking
advantage of a base-promoted strategy (Scheme 1).
DOI: 10.1055/a-1337-5504; Art ID: ss-2020-f0614-st
Abstract The reaction of 2-(2-fluoroaryl) N-heteroaromatic com-
pounds, such as benzimidazole and indole derivatives, with internal
alkynes in the presence of a catalytic amount of a nickel complex results
in C–F/N–H annulation with alkynes. The reaction shows a high func-
tional group compatibility. The presence of a strong base, such as
KOBut or LiOBut, is required for the reaction to proceed.
Key words C–F bond activation, nickel, alkyne, annulation, N-het-
eroaromatic compounds
(a) Our previous work (2020)
O
O
Ni(cod)2
KOBut
Ar
R
Ar
N
N
H
+
R
R
DMF
40–60 °C
F
Transition-metal-catalyzed functionalization reactions
of aryl halides (Ar–X) have revolutionized the way chemists
approach the synthesis of a variety of molecules.1 Com-
pared with C–I, C–Br, and C–Cl bonds, the use of C–F bonds
in organic transformation is significantly more challenging
because of their inherent bond strength.2 Indeed, C–F bonds
are among the strongest bonds in organic compounds.
Nickel complexes are known to show a high catalytic reac-
tivity for activating C–F bonds.3 We recently reported on a
new Ni(0) system for the activation of C–F bonds using an
amidate-promoted strategy. The reaction involves the Ni-
catalyzed C–F/N–H annulation of ortho-fluoro-substituted
aromatic amides with alkynes, leading to the production of
isoquinolin-1(2H)-one derivatives (Scheme 1a).4 The reac-
tion proceeds under mild reaction conditions (most reac-
tions can be carried out at 40–60 °C) and even under li-
gand-free conditions. A key to the success of the reaction is
the use of a base, such as KOBut or even a weak base such as
Cs2CO3, which functions to abstract a proton from an amide
with the generation of an amidate anion. The amidate anion
functions as a directing group to activate a C–F bond.
R
(b) Parthasarathy (2020)
X
X
NiBr2(dppe)
Zn
+
N
R
R
R
N
toluene
130–150 °C
X
H
R
X = Br, I
Present work
Ni(cod)2
Me4phen
KOBut
X
N
X
N
+
R
R
DMF
100–120 °C
F
H
R
R
1
2
3
N
N
Me4phen
Scheme 1 Ni(0)-catalyzed C–X/N–H annulation with alkynes
The reaction of 2-(2-fluorophenyl)-1H-benzo[d]imidaz-
ole (1a) (0.25 mmol) with hex-3-yne (2a) (0.3 mmol) in the
presence of Ni(cod)2 (0.025 mmol) as the catalyst, PPh3
(0.05 mmol) as the ligand, and KOBut (0.25 mmol) as the
base in DMA (N,N-dimethylacetamide) (0.25 mL) at 120 °C
for 18 hours gave 5,6-diethylbenzo[4,5]imidazo[2,1-a]iso-
In 2020, Parthasarathy reported on the Ni-catalyzed
synthesis of pyrroloquinolines, indoloquinolines, and in-
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
H. Kawakami et al.
Special Topic
Synthesis
quinoline (3aa) in 18% NMR yield, along with 30% of 1a be-
ing recovered (Table 1, entry 1). The use of other phos-
phines, such as dppe, dfppe, and DPEphos {bis[(2-diphenyl-
phosphino)phenyl] ether} failed to improve the product
yield, and when NHC ligands were used, the reaction failed
to proceed. Gratifyingly, the use of 2,2′-dipyridine (bpy) and
1,10-phenanthroline (Phen) dramatically improved the
product yield to 92% and 87% NMR yields, respectively (en-
tries 2 and 3). Finally, 3,4,7,8-tetramethyl-1,10-phenanth-
roline (Me4Phen) was found to be the ligand of choice (en-
try 4). The use of strong bases, such as LiOBut, NaOBut, and
KOMe gave 3aa in good yields (entries 5–7), while weak
bases, such as NaOAc, KOAc, and K2CO3 gave only trace
amounts of 3aa. Although LiOBut gave a slightly higher
product yield, KOBut was used for further optimization be-
cause it is less expensive. The solvent effects were exam-
ined using dtbbpy [4,4′-bis(di-tert-butyl)-2,2′-bipyridine]
as a ligand. Polar solvents, such as DMF and DMSO gave
higher product yields (entries 10 and 11). Finally, the opti-
mal conditions for this reaction were established to be the
following: 1a (0.25 mmol) with hex-3-yne (2a; 0.3 mmol)
in the presence of Ni(cod)2 (0.025 mmol) as the catalyst,
Me4Phen (0.05 mmol) as the ligand, and KOBut (0.25 mmol)
as the base in DMF (0.25 mL) at 100 °C for 18 hours (entry
13). We previously reported on the Ni-catalyzed synthesis
of benzo[4,5]imidazo[2,1-a]isoquinoline derivatives via ox-
idative C–H/N–H coupling of 2-phenyl-1H-benzo[d]imidaz-
ole with alkynes, in which the ortho C–H bond participates
in the reaction.6 However, such a reaction did not proceed
and the C–F bond was selectively activated under the condi-
tions.
Table 1 Optimization of the Reaction Conditions
Ni(cod)2 10 mol%
N
N
ligand
base
20 mol%
1 equiv
N
N
+
Et
Et
solvent 0.25 mL
18 h
F
H
Et
Et
3aa
1a 0.25 mmol
2a 0.3 mmol
Entry Base
Ligand
Solvent
Temp
(°C)
NMR yield (%)a
3a 1a
1
2
KOBut
KOBut
KOBut
KOBut
LiOBut
NaOBut
KOMe
KOBut
KOBut
KOBut
KOBut
KOBut
KOBut
PPh3
DMA
120
18
30
bpy
DMA
120
120
120
120
120
120
120
120
120
120
100
100
92
0
0
3
Phen
DMA
87 (70)
93 (78)
4
Me4Phen
Me4Phen
Me4Phen
Me4Phen
dtbbpy
dtbbpy
dtbbpy
dtbbpy
Me4Phen
Me4Phen
DMA
0
5
DMA
>99 (84)
70
0
6
DMA
0
7
DMA
64
0
8
1,4-dioxaneb
toluene
DMF
3
32
38
0
9
33
10
11
12
13
77
DMSO
DMA
>99
53
0
45
0
DMF
99 (88)
a Numbers in parentheses refer to isolated yields.
b 1,4-Dioxane (0.5 mL).
N
N
N
N
N
N
The results for the reaction of 2-(2-fluorophenyl)-1H-
benzo[d]imidazole (1a) with various alkynes 2 are shown
in Figure 1. Both aliphatic and aromatic internal alkynes
were applicable to this annulation reaction. However, the
reaction of 1a with 1,2-bis[4-(trifluoromethyl)phe-
nyl]ethyne gave the expected product, but in low yield (data
not shown). Similar to our previous work,4 an electron-defi-
cient alkyne retarded the reaction. The reaction with 1-
phenylpent-1-yne (2f) gave 3af in a regioselective manner.
A single crystal of 3af was isolated and the structure was
confirmed by X-ray crystallographic analysis.
Et
Et
3aa 88%
Me
Me
3ab 71%
3ac 67%
N
N
N
N
N
N
Me
MeO
OMe
F
F
3af 55%a
3ad 70%
3ae 72%
CCDC 2046289
The scope for the reaction with respect to the N-het-
eroaromatic substrate 1 is shown in Figure 2. Similar to our
previous work,4 the presence of an electron-withdrawing
group on the phenyl ring retarded the reaction and a higher
reaction temperature was required, as in 3ca–ea. These re-
sults suggest that the activation of the C–F bond is not the
rate-determining step. The reaction of 1h which contains a
methyl group on the benzimidazole ring gave 3ha as a sin-
gle product and the other isomer was not formed. The reac-
tion was also applicable to 2-(2-fluorophenyl)-1H-indole
(1i) to give 5,6-diethylindolo[2,1-a]isoquinoline (3ia) in
70% yield when LiOBut was used as a base instead of KOBut.
Figure 1 Alkyne scope. Reagents and conditions: 1a (0.25 mmol),
alkyne 2 (0.3 mmol), Ni(cod)2 (0.025 mmol), Me4phen (0.05 mmol),
KOBut (0.25 mmol), DMF (0.25 mL), 100 °C, 18 h; yields shown are
isolated yields. a At 120 °C.
Gratifyingly, it was found that an inexpensive and
benchtop-stable Ni(OAc)2/Zn system also gave a good yield
of the corresponding product 3aa. The method was applica-
ble to a gram-scale reaction using the Ni(II)/Zn system
(Scheme 2).
A proposed mechanism for the above annulation reac-
tion is shown in Scheme 3. The base abstracts an NH proton
in 1a to generate the anion A, which is the actual substrate,
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, A–F

C
H. Kawakami et al.
Special Topic
Synthesis
MeO
F
N
N
N
N
N
N
N
N
N
H
1a
tBuOH
tBuO
N
F
F
N
N
A
Et
Et
Et
Et
Et
Et
Ni(0)Ln
3aa 88%
3ba 75%a
3ca 60%b
R
R
3
F3C
Cl
N
N
N
N
N
N
N
MeO
N
N
N
NiLn
Et
Et
F
K+
Et
Et
Et
Et
NiLn
B
R
3da 20%b
3ea 63%b,c
3fa 77%
R
D
Me
MeO
MeO
N
N
N
N
R
R
N
KF
N
N
Ni
Ln
C
Et
Et
Et
Et
Et
Et
Scheme 3 A proposed mechanism
3ga 87%a,b,c
3ha 84%
3ia 70%a
Figure 2 Substrate scope. Reagents and conditions: 1 (0.25 mmol), hex-
3-yne (2a; 0.3 mmol), Ni(cod)2 (0.025 mmol), Me4Phen (0.05 mmol),
KOBut (0.25 mmol), DMF, 100 °C, 18 h. a LiOBut was used as a base.
b The reaction was carried out at 120 °C. c Bpy (2,2′-dipyridine) was
used in place of Me4Phen.
1H and 13C NMR spectra were recorded on a JEOL ECZ-400 spectrome-
ter; samples were dissolved in CDCl3 with tetramethylsilane as an in-
ternal reference standard. IR spectra were recorded on a JASCO FT/IR-
4200 spectrometer using the ATR method. Mass spectra were ob-
tained using a SHIMDZU QP-2010 spectrometer with a quadrupole
mass analyzer operating at 70 eV. HRMS was carried out on a JEOL
JMS-T100LP spectrometer with a time-of-flight mass analyzer. Melt-
ing points were determined on a Stanford Research Systems MPA100
apparatus equipped with a digital thermometer. Column chromatog-
raphy was performed on silica gel (Silicycle Siliaflash F60; 230–400
mesh).
Ni(OAc)2 10 mol%
Me4Phen 20 mol%
N
N
Zn
1 equiv
1 equiv
N
N
KOBut
+
Et
Et
DMF 5 mL
F
H
100 °C, 18 h
Et
Et
1a 4.78 mmol
2a 6 mmol
3aa 83% (1.084 g)
(1.015 g)
Scheme 2 Use of inexpensive and benchtop-stable Ni(OAc)2/Zn as cat-
alytic system (gram scale)
2-(2-Fluoroaryl) N-Heteroaromatic Compounds 1a–i
2-Fluoroarylbenzimidazoles 1a–h are all known compounds and
were prepared by the reaction of 1,2-phenylenediamine derivatives
with aldehydes in the presence of MgCl2:9 2-(2-fluorophenyl)-1H-
benzo[d]imidazole (1a) [CAS Reg. No. 321-51-7], 2-(2-fluoro-5-me-
thoxyphenyl)-1H-benzimidazole (1b) [CAS Reg. No. 1508940-34-8],
2-(2,5-difluorophenyl)-1H-benzimidazole (1c) [CAS Reg. No.
1097793-36-6], 2-(5-chloro-2-fluorophenyl)-1H-benzimidazole (1d)
[CAS Reg. No. 1094668-22-0], 2-[2-fluoro-5-(trifluoromethyl)phe-
nyl]-1H-benzimidazole (1e) [CAS Reg. No. 1536220-29-7], 2-(2-fluo-
ro-4-methoxyphenyl)-1H-benzimidazole (1f) [CAS Reg. No. 2620-81-7],
2-(2-fluoro-4,5-dimethoxyphenyl)-1H-benzimidazole (1g) [CAS Reg.
No. 2443949-80-0], and 2-(2-fluorophenyl)-7-methyl-1H-benzimid-
azole (1h) [CAS Reg. No. 626606-16-4]. 2-(2-Fluorophenyl)-1H-indole
(1i) [CAS Reg. No. 52765-22-7] was prepared by the Fischer indole
synthesis by the reaction of 2-fluoroacetophenone and phenylhydra-
zine hydrochloride in the presence of polyphosphoric acid.10
because one equivalent of base was used. The reaction of A
with Ni(0) gives the nickelate complex B. Oxidative addition
of the C–F bond gives the nickelacycle C, which is assisted
by the coordination of the potassium cation to the F atom in
B.7 The coordination of an alkyne to complex C, followed by
the insertion of an alkyne into the C–Ni bond gives the sev-
en-membered nickalacycle D, which then undergoes reduc-
tive elimination to give the annulated product 3 with the
regeneration of Ni(0).
In summary, we reported on the Ni(0)-catalyzed C–F/N–H
annulation of 2-(2-fluoroaryl) N-heteroaromatic com-
pounds with alkynes. The use of KOBut or LiOBut was essen-
tial for the reaction to proceed. This strategy is a promising
method for the activation of C–F bonds4 as well as other un-
reactive bonds, such as C–O, C–S, and C–CN.8 Investigations
on the further use of this methodology for the activation of
unreactive bonds are currently underway and will be re-
ported in due course.
5,6-Diethylbenzo[4,5]imidazo[2,1-a]isoquinoline (3aa); Typical
Procedure
To an oven-dried 5 mL screw-capped vial in a glove box, KOBut (28.1
mg, 0.25 mmol), Me4Phen (11.8 mg, 0.05 mmol), Ni(cod)2 (6.9 mg,
0.025 mmol), 2-(2-fluorophenyl)-1H-indole (1a, 53.1 mg, 0.25
mmol), hex-3-yne (2a, 24.6 mg, 0.3 mmol), and DMF (0.25 mL) were
added in sequential order. The vial was then sealed and the mixture
was stirred for 5 min at room temperature. The vial was then placed
on a preheated aluminum heating block [Thermo Mighty Stirrer HHE-
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, A–F

D
H. Kawakami et al.
Special Topic
Synthesis
19G-USIII (KPI)] and stirred for 18 h at 100 °C and then allowed to
cool to room temperature. The resulting mixture was filtered through
a Celite pad and the filtrate concentrated to dryness in vacuo. The res-
idue was purified by column chromatography (silica gel, hexane/EtOAc,
10:1) to afford the desired product 3aa.
5,6-Bis(4-fluorophenyl)benzo[4,5]imidazo[2,1-a]isoquinoline
(3ae)
[CAS Reg. No. 2281949-54-8]
Yield: 72.0 mg (72%); pale yellow solid; Rf = 0.26 (hexane/EtOAc, 3:1).
1H NMR (400 MHz, CDCl3):  = 6.08 (d, J = 8.5 Hz, 1 H), 6.96–7.03 (m, 3
H), 7.09–7.19 (m, 4 H), 7.29–7.34 (m, 3 H), 7.39 (t, J = 7.7 Hz, 1 H), 7.59
(t, J = 7.7 Hz, 1 H), 7.70 (t, J = 7.5 Hz, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 8.98
(dd, J = 8.0, 0.9 Hz, 1 H).
Yield: 59.5 mg (88%); white solid; mp 123 °C; Rf = 0.26 (hexane/EtOAc,
3:1).
IR (ATR): 2970 m, 1630 w, 1523 m, 1450 s, 1368 s cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.31 (t, J = 7.6 Hz, 3 H), 1.48 (t, J = 7.6
Hz, 3 H), 2.99 (q, J = 7.6 Hz, 2 H), 3.40 (q, J = 7.6 Hz, 2 H), 7.33 (t, J = 7.6
Hz, 1 H), 7.47 (t, J = 7.6 Hz, 1 H), 7.60 (t, J = 7.2 Hz, 1 H), 7.66 (td, J =
8.4, 1.4 Hz, 1 H), 7.84 (d, J = 8.2 Hz, 1 H), 7.97 (d, J = 8.5 Hz, 1 H), 8.03
(d, J = 8.1 Hz, 1 H), 8.91 (d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 113.9, 115.4 (d, J = 22.2 Hz), 116.3 (d,
J = 22.2 Hz), 119.9, 121.6, 123.1, 124.4, 125.3, 126.3, 128.2, 129.8,
130.2, 131.2, 131.5, 132.5, 132.6 (d, J = 7.7 Hz), 133.2 (d, J = 7.6 Hz),
134.5, 144.4, 147.8, 162.1 (d, J = 247.6 Hz), 163.1 (d, J = 249.5 Hz).
13C NMR (100 MHz, CDCl3):  = 13.1, 15.1, 20.4, 22.3, 114.6, 119.6,
120.0, 121.6, 122.9, 123.4, 124.0, 125.6, 126.8, 130.0, 130.6, 131.3,
136.7, 144.4, 148.1.
MS (EI, 70 eV): m/z (%) = 275 (17), 274 [M+] (76), 260 (21), 259 (100),
257 (13), 243 (21), 128 (10), 122 (15), 115 (10).
5-Phenyl-6-propylbenzo[4,5]imidazo[2,1-a]isoquinoline (3af)11
Yield: 45.3 mg (55%); mp 181 °C; Rf = 0.38 (hexane/EtOAc, 3:1).
IR (ATR): 2959 m, 2930 w, 2871 w, 1630 w, 1608 w, 1595 w, 1525 m,
1479 m, 1445 s, 1373 m cm–1
.
1H NMR (400 MHz, CDCl3):  = 0.91 (t, J = 7.3 Hz, 3 H), 1.63–1.65 (m, 2
H), 2.65–2.69 (m, 2 H), 5.85 (d, J = 8.5 Hz, 1 H), 6.89 (t, J = 7.3 Hz, 1 H),
7.32 (t, J = 7.6 Hz, 1 H), 7.47–7.50 (dd, J = 8.0, 1.6 Hz, 2 H), 7.62–7.76
(m, 5 H), 7.93 (t, J = 7.3 Hz, 2 H), 8.97 (d, J = 7.2 Hz, 1 H).
HRMS-TOF: m/z [M + H]+ calcd for C19H19N2: 275.1543; found:
275.1544.
5,6-Diphenylbenzo[4,5]imidazo[2,1-a]isoquinoline (3ab)
[CAS Reg. No. 1037289-22-7]
13C NMR (100 MHz, CDCl3):  = 14.5, 24.1, 30.3, 113.9, 119.5, 120.3,
121.1, 123.6, 123.9, 124.2, 125.7, 127.6, 129.5, 129.9, 130.0, 130.3,
131.3, 131.6, 134.5, 134.5, 144.2, 147.6.
Yield: 65.5 mg (71%); white solid; Rf = 0.36 (hexane/EtOAc, 3:1).
MS (EI, 70 eV): m/z (%) = 337 (11), 336 [M+] (49), 308 (22), 307 (100),
306 (24), 305 (19), 153 (10).
HRMS-TOF: m/z [M + H]+ calcd for C24H21N2: 337.1700; found:
337.1693.
1H NMR (400 MHz, CDCl3):  = 6.00 (d, J = 8.5 Hz, 1 H), 6.92 (t, J = 7.8
Hz, 1 H), 7.20–7.30 (m, 5 H), 7.33–7.42 (m, 7 H), 7.56 (t, J = 7.7 Hz, 1
H), 7.68 (t, J = 7.5 Hz, 1 H), 7.98 (d, J = 8.2 Hz, 1 H), 8.99 (d, J = 8.0 Hz, 1
H).
13C NMR (100 MHz, CDCl3):  = 114.2, 119.7, 121.4, 123.0, 123.6,
124.2, 125.1, 126.5, 127.4, 127.9, 128.1, 128.9, 129.3, 130.0, 130.7,
131.3, 131.6, 132.7, 133.8, 135.2, 135.8, 144.4, 147.9.
5,6-Diethyl-2-methoxybenzo[4,5]imidazo[2,1-a]isoquinoline
(3ba)
Yield: 55.5 mg (75%); white solid; mp 118 °C; Rf = 0.20 (hexane/EtOAc,
3:1).
5,6-Bis(4-methylphenyl)benzo[4,5]imidazo[2,1-a]isoquinoline
(3ac)
IR (ATR): 2969 m, 2902 w, 2837 w, 1614 m, 1521 m, 1499 s, 1359 s,
1231 s cm–1
.
[CAS Reg. No. 2281949-52-6]
1H NMR (400 MHz, CDCl3):  = 1.28 (t, J = 7.6 Hz, 3 H), 1.46 (t, J = 7.6
Hz, 3 H), 2.94 (q, J = 7.6 Hz, 2 H), 3.36 (q, J = 7.6 Hz, 2 H), 4.02 (s, 3 H),
7.25–7.28 (m, 1 H), 7.32 (t, J = 7.8 Hz, 1 H), 7.47 (t, J = 7.7 Hz, 1 H), 7.74
(d, J = 8.9 Hz, 1 H), 7.97 (d, J = 8.5 Hz, 1 H), 8.03 (d, J = 8.2 Hz, 1 H), 8.27
(d, J = 2.7 Hz, 1 H).
Yield: 64.1 mg (67%); white solid; Rf = 0.37 (hexane/EtOAc, 3:1).
1H NMR (400 MHz, CDCl3):  = 2.33 (s, 3 H), 2.42 (s, 3 H), 6.03 (d, J =
8.5 Hz, 1 H), 6.94 (t, J = 7.8 Hz, 1 H), 7.09 (s, 4 H), 7.18–7.23 (m, 4 H),
7.33–7.38 (m, 2 H), 7.56 (t, J = 7.0 Hz, 1 H), 7.67 (t, J = 7.0 Hz, 1 H), 7.98
(d, J = 8.2 Hz, 1 H), 8.97 (d, J = 7.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 13.2, 15.2, 20.5, 22.1, 55.9, 105.6,
114.7, 119.6, 119.9, 120.7, 121.5, 124.0, 124.2, 125.2, 125.5, 130.8,
134.4, 144.4, 147.9, 158.5.
13C NMR (100 MHz, CDCl3):  = 21.4, 21.7, 114.4, 119.6, 121.2, 123.0,
123.6, 124.1, 125.1, 126.5, 127.7, 128.9, 129.6, 129.9, 130.6, 131.0,
131.4, 132.8, 133.1, 135.4, 136.8, 139.1, 144.4, 147.9.
MS (EI, 70 eV): m/z (%) = 305 (24), 304 [M+] (100), 290 (20), 274 (10),
5,6-Bis(4-methoxyphenyl)benzo[4,5]imidazo[2,1-a]isoquinoline
246 (16), 245 (10).
(3ad)
HRMS-TOF: m/z [M + H]+ calcd for C20H21N2O: 305.1648; found:
[CAS Reg. No. 2281949-53-7]
305.1650.
Yield: 79.3 mg (70%); white solid; Rf = 0.20 (hexane/EtOAc, 3:1).
5,6-Diethyl-2-fluorobenzo[4,5]imidazo[2,1-a]isoquinoline (3ca)
1H NMR (CDCl3, 399.78 MHz):  = 3.80 (s, 3 H), 3.85 (s, 3 H), 6.12 (d, J =
8.5 Hz, 1 H), 6.82 (d, J = 8.9 Hz, 2 H), 6.90 (d, J = 8.7 Hz, 2 H), 6.96 (t, J =
7.8 Hz, 1 H), 7.10 (d, J = 8.7 Hz, 2 H), 7.22 (d, J = 8.7 Hz, 2 H), 7.36 (t, J =
8.2 Hz, 2 H), 7.56 (t, J = 7.7 Hz, 1 H), 7.66 (t, J = 7.7 Hz, 1 H), 7.98 (d, J =
8.0 Hz, 1 H), 8.97 (dd, J = 8.0, 0.7 Hz, 1 H).
13C NMR (CDCl3, 100.53 MHz):  = 55.3, 55.4, 113.6, 114.3, 114.4,
119.6, 121.3, 123.0, 123.6, 124.1, 125.1, 126.3, 126.5, 127.7, 128.1,
129.9, 131.4, 131.9, 132.6, 133.2, 135.4, 144.4, 147.9, 158.6, 160.0.
Yield: 43.4 mg (60%); white solid; mp 225 °C; Rf = 0.43 (hexane/EtOAc,
3:1).
IR (ATR): 2970 m, 1631 w, 1526 w, 1450 m, 1367 m, 1289 w cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.31 (t, J = 7.6 Hz, 3 H), 1.48 (t, J = 7.6
Hz, 3 H), 2.98 (q, J = 7.6 Hz, 2 H), 3.39 (q, J = 7.6 Hz, 2 H), 7.35–7.37 (m,
2 H), 7.48 (td, J = 8.0, 0.9 Hz, 1 H), 7.79–7.82 (m, 1 H), 7.97 (d, J = 8.5
Hz, 1 H), 8.01 (d, J = 8.2 Hz, 1 H), 8.52 (dd, J = 9.2, 2.7 Hz, 1 H).
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, A–F

E
H. Kawakami et al.
Special Topic
Synthesis
13C NMR (100 MHz, CDCl3):  = 13.1, 15.1, 20.7, 22.3, 110.8 (d, J = 23.1
Hz), 114.7, 118.5 (d, J = 24.1 Hz), 119.2, 120.2, 122.1, 124.2, 124.5 (d,
J = 9.6 Hz), 125.9 (d, J = 8.7 Hz), 127.9, 130.7, 136.1, 144.4, 147.2,
161.3 (d, J = 247.6 Hz).
MS (EI, 70 eV): m/z (%) = 305 (24), 304 [M+] (100), 290 (20), 289 (88),
246 (15), 245 (10).
HRMS-TOF: m/z [M + H]+ calcd for C20H21N2O: 305.1648; found:
305.1667.
MS (EI, 70 eV): m/z (%) = 293 (17), 292 [M+] (72), 278 (21), 277 (100),
275 (13), 261 (20), 167 (17), 149 (47), 131 (14), 71 (19), 57 (25).
HRMS-TOF: m/z [M + H]+ calcd for C19H18N2F: 293.1449; found:
5,6-Diethyl-2,3-dimethoxybenzo[4,5]imidazo[2,1-a]isoquinoline
(3ga)
293.1451.
Yield: 70.0 mg (87%); yellow solid; mp 175–176 °C; Rf = 0.43 (hexane/
EtOAc, 1:10).
2-Chloro-5,6-diethylbenzo[4,5]imidazo[2,1-a]isoquinoline (3da)
IR (ATR): 2968 w, 2831 w, 1632 w, 1523 m, 1454 s, 1362 w, 1260 s,
Yield: 15.4 mg (20%); white solid; mp 190–191 °C; Rf = 0.50 (hexane/
1246 s cm–1
.
EtOAc, 3:1).
1H NMR (400 MHz, CDCl3):  = 1.36 (t, J = 7.4 Hz, 3 H), 1.51 (t, J = 7.4
Hz, 3 H), 3.01 (q, J = 7.6 Hz, 2 H), 3.44 (q, J = 7.6 Hz, 2 H), 4.05 (s, 3 H),
4.14 (s, 3 H), 7.22 (s, 1 H), 7.33 (t, J = 7.8 Hz, 1 H), 7.48 (t, J = 7.7 Hz, 1
H), 8.01 (d, J = 8.0 Hz, 2 H), 8.27 (s 1 H).
13C NMR (100 MHz, CDCl3):  = 13.2, 15.0, 20.8, 22.3, 56.1, 56.5, 104.3,
106.0, 114.6, 117.1, 119.2, 119.6, 121.1, 124.0, 126.5, 130.7, 135.4,
144.6, 147.9, 149.3, 151.8.
IR (ATR): 2970 m, 1629 w, 1525 m, 1452 m, 1368 s, 740 s cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.33 (t, J = 7.6 Hz, 3 H), 1.53 (t, J = 7.6
Hz, 3 H), 3.02 (q, J = 7.6 Hz, 2 H), 3.45 (q, J = 7.6 Hz, 2 H), 7.39 (t, J = 7.8
Hz, 1 H), 7.51 (t, J = 7.7 Hz, 1 H), 7.63 (dd, J = 8.9, 2.3 Hz, 1 H), 7.81 (d,
J = 8.7 Hz, 1 H), 8.01–8.04 (m, 2 H), 8.91 (d, J = 2.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 13.1, 15.2, 20.6, 22.4, 114.7, 119.3,
120.3, 122.2, 124.2, 124.4, 125.1, 125.2, 129.7, 130.5, 130.7, 133.0,
137.1, 144.4, 147.0.
MS (EI, 70 eV): m/z (%) = 335 (25), 334 [M+] (100), 320 (12), 319 (52),
303 (19).
MS (EI, 70 eV): m/z (%) = 310 (28), 309 (19), 308 [M+] (79), 295 (34),
HRMS-TOF: m/z [M + H]+ calcd for C21H23N2O2: 335.1754; found:
294 (22), 293 (100), 291 (10), 277 (10), 243 (10), 128 (11), 122 (13).
335.1754.
HRMS-TOF: m/z [M + H]+ calcd for C19H18N2Cl: 309.1153; found:
309.1152.
5,6-Diethyl-11-methylbenzo[4,5]imidazo[2,1-a]isoquinoline (3ha)
Yield 59.1 mg (84%); pale yellow solid; mp 123 °C; Rf = 0.59 (hexane/
EtOAc, 3:1).
5,6-Diethyl-2-(trifluoromethyl)benzo[4,5]imidazo[2,1-a]isoquin-
IR (ATR): 3022 w, 2970 m, 1629 m, 1525 s, 1451 s, 1367 m cm–1
.
oline (3ea)
Yield: 53.2 mg (63%); white solid; mp 179–180 °C; Rf = 0.51 (hexane/
EtOAc, 3:1).
1H NMR (400 MHz, CDCl3):  =1.32 (t, J = 7.6 Hz, 3 H), 1.48 (t, J = 7.6
Hz, 3 H), 2.86 (s, 3 H), 3.00 (q, J = 7.2 Hz, 2 H), 3.41 (q, J = 7.2 Hz, 2 H),
7.22–7.29 (m, 2 H), 7.59 (t, J = 7.5 Hz, 1 H), 7.66 (t, J = 7.5 Hz, 1 H),
7.82–7.85 (m, 2 H), 8.97 (d, J = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 13.1, 15.1, 17.3, 20.4, 22.2, 112.1,
119.5, 121.5, 123.2, 123.3, 124.1, 125.8, 126.7, 129.8, 129.9, 130.3,
131.2, 136.8, 143.8, 147.5.
IR (ATR): 2972 m, 1630 w, 1526 m, 1454 w, 1168 s cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.34 (t, J = 7.6 Hz, 3 H), 1.52 (t, J = 7.6
Hz, 3 H), 3.03 (q, J = 7.6 Hz, 2 H), 3.43 (q, J = 7.6 Hz, 2 H), 7.39 (t, J = 7.8
Hz, 1 H), 7.51 (t, J = 7.7 Hz, 1 H), 7.86 (d, J = 8.7 Hz, 1 H), 7.93–8.04 (m,
3 H), 9.20 (s, 1 H).
13C NMR (100 MHz, CDCl3):  = 12.9, 15.0, 20.5, 22.5, 114.7, 119.1,
120.2, 122.4, 122.7, 123.2 (q, J = 4.8 Hz), 124.2 (q, J = 272.6 Hz), 124.2,
124.5, 125.9 (q, J = 2.9 Hz), 128.6 (q, J = 33.7 Hz), 130.5, 133.5, 139.0,
144.3, 147.2.
MS (EI, 70 eV): m/z (%) = 289 (24), 288 [M+] (98), 274 (22), 273 (100),
271 (10), 258 (10), 257 (20), 128 (10), 122 (11).
HRMS-TOF: m/z [M + H]+ calcd for C20H21N2: 289.1699; found:
289.1701.
MS (EI, 70 eV): m/z (%) = 343 (20), 342 [M+] (89), 328 (22), 327 (100),
325 (12), 311 (16).
HRMS-TOF: m/z [M + H]+ calcd for C20H18N2F3: 343.1417; found:
5,6-Diethylindolo[2,1-a]isoquinoline (3ia)
Yield: 46.7 mg (70%); pale yellow solid; mp 106 °C; Rf = 0.22 (hexane/
343.1418.
Et2O, 400:1).
IR (ATR): 2968 m, 1616 w, 1651 w, 1452 m, 1370 m cm–1
.
5,6-Diethyl-3-methoxybenzo[4,5]imidazo[2,1-a]isoquinoline (3fa)
1H NMR (400 MHz, CDCl3):  = 1.31 (t, J = 7.6 Hz, 3 H), 1.54 (t, J = 7.8
Hz, 3 H), 2.97 (q, J = 7.6 Hz, 2 H), 3.45 (q, J = 7.6 Hz, 2 H), 7.25–7.34 (m,
3 H), 7.43–7.51 (m, 2 H), 7.74 (d, J = 7.6 Hz, 1 H), 7.83 (d, J = 7.6 Hz, 1
H), 8.07 (d, J = 8.7 Hz, 1 H), 8.23 (d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 13.3, 15.0, 20.5, 22.7, 94.0, 115.1,
117.3, 120.6, 120.6, 121.4, 123.3, 123.8, 125.5, 126.2, 127.5, 128.6,
129.9, 132.0, 136.2, 137.5.
MS (EI, 70 eV): m/z (%) = 274 (23), 273 [M+] (100), 272 (13), 259 (19),
258 (88), 257 (12), 243 (18), 242 (18), 241 (14), 121 (11), 121 (18).
HRMS-TOF: m/z [M + H]+ calcd for C20H20N: 274.1590; found:
274.15875.
Yield: 56.8 mg (77%); white solid; mp 150–151 °C; Rf = 0.29 (hexane/
EtOAc, 3:1).
IR (ATR): 2969 m, 2904 w, 2837 w, 1631 s, 1525 m, 1451 s, 1381 m,
1370 m, 1222 s cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.33 (t, J = 7.6 Hz, 3 H), 1.49 (t, J = 7.6
Hz, 3 H), 2.97 (q, J = 7.6 Hz, 2 H), 3.40 (q, J = 7.6 Hz, 2 H), 3.95 (s, 3 H),
7.21–7.26 (m, 2 H), 7.31 (t, J = 7.8 Hz, 1 H), 7.46 (t, J = 7.6 Hz, 1 H), 7.97
(t, J = 9.3 Hz, 2 H), 8.83 (d, J = 8.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 13.1, 14.9, 20.6, 22.4, 55.5, 106.1,
114.4, 115.2, 116.8, 119.2, 119.6, 121.2, 123.9, 127.5, 130.6, 133.2,
137.3, 144.6, 148.3, 161.2.
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, A–F

F
H. Kawakami et al.
Special Topic
Synthesis
Funding Information
J. Org. Chem. 2018, 83, 2993. (g) Ho, Y. A.; Leiendecker, M.; Liu,
X.; Wang, C.; Alandini, N.; Rueping, M. Org. Lett. 2018, 20, 5644.
(h) Zhao, X.; Wu, M.; Liu, Y.; Cao, S. Org. Lett. 2018, 20, 5564.
(i) Lim, S.; Song, D.; Jeon, S.; Kim, Y.; Kim, H.; Lee, S.; Cho, H.;
Lee, B. C.; Kim, S. E.; Kim, K.; Lee, E. Org. Lett. 2018, 20, 7249.
(j) Tian, Y.-M.; Guo, X.-N.; Kuntze-Fechner, M. W.;
Krummenacher, I.; Braunschweig, H.; Radius, U.; Steffen, A.;
Marder, T. B. J. Am. Chem. Soc. 2018, 140, 17612. (k) Yan, S.-S.;
Wu, D.-S.; Ye, J.-H.; Gong, L.; Zeng, X.; Ran, C.-K.; Gui, Y.-Y.; Li, J.;
Yu, D.-G. ACS Catal. 2019, 9, 6987. (l) Capdevila, L.; Meyer, T. H.;
Steven, R.-G.; Luis, J. M.; Ackermann, L.; Ribas, X. ACS Catal.
2019, 9, 11074. (m) Kang, Q.-K.; Lin, Y.; Li, Y.; Shi, H. Synlett
2020, 31, 1135. (n) Müller, V.; Ghorai, D.; Capdevila, L.;
Messinis, A. M.; Ribas, X.; Ackermann, L. Org. Lett. 2020, 22,
7034. (o) Wu, C.; McCollom, S. P.; Zheng, Z.; Zhang, J.; Sha, S.-C.;
Li, M.; Walsh, P. J.; Tomson, N. C. ACS Catal. 2020, 10, 7934.
(4) Nohira, I.; Liu, S.; Bai, R.; Lan, Y.; Chatani, N. J. Am. Chem. Soc.
2020, 142, 17306.
This work was supported by a Grant-in-Aid for Specially Promoted
Research by the Ministry of Education, Culture, Sports, Science and
Technology, Japan (MEXT) (No. 17H06091).
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1337-5504.
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References
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(11) A single crystal of 3af was isolated and the structure was con-
firmed by X-ray crystallographic analysis. CCDC 2046289 con-
tains the supplementary crystallographic data for 3af. These
data can be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/structures.
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, A–F