Medicinally Relevant Modification of the Isoquinoline-1,3-dione Scaffold via Metal-Free Arylation and Fluorination of Diazo Homophthalimides?-in Bronsted Acids

Article abstract of DOI:10.1055/s-0037-1611882

Protonation of 4-diazoisoquinoline-1,3(2 H,4 H)-diones in Bronsted acids gives rise to diazonium cations that can be trapped with arenes to give 4-arylisoquinoline-1,3(2 H,4 H)-diones (homophthalimides). This provides a new, metal-free approach to 4-aryltetrahydroisoquinolines (obtainable from respective homophthalimides by reduction). Similarly, a fluorine atom can be introduced by trapping the diazonium cation with HF. This led to the preparation of the first examples of 4-monofluoro-substituted isoquinoline-1,3-diones (as well as their 4-bromo-4-fluoro and 4-chloro-4-fluoro variants), important carboxylic acid isosteres on their own and precursors of useful 4-fluorotetrahydroisoquinoline building blocks.

Full text of DOI:10.1055/s-0037-1611882

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–J
paper
A
en
A. Golushko et al.
Paper
Synthesis
Medicinally Relevant Modification of the Isoquinoline-1,3-dione
Scaffold via Metal-Free Arylation and Fluorination of Diazo
Homophthalimides in Brønsted Acids
Andrei Golushkoa
Dmitry Dar’ina
Grigory Kantina
Natalia Guranovaa
Aleksander V. Vasilyev*a,b
Mikhail Krasavin*a
O
O
O
HF⋅Py
(NXS)
ArH
TfOH
R
O
R
O
R
O
N
N
N
F
X
Ar
N2
X = H, Br, Cl or F
44–86%
11 examples
23–89%
20 examples
a Saint Petersburg State University, Saint Petersburg
199034, Russian Federation
m.krasavin@spbu.ru
b Department of Chemistry, Saint Petersburg State Forest
Technical University, Institutsky per. 5, Saint Petersburg
194021, Russian Federation
с Immanuel Kant Baltic Federal University, Kaliningrad
236016, Russian Federation
Received: 16.05.2019
Accepted after revision: 13.06.2019
Published online: 08.07.2019
H
N
N
H
N
O
O
H
DOI: 10.1055/s-0037-1611882; Art ID: ss-2019-z0276-op
Ph
N
N
Ph
OH
Abstract Protonation of 4-diazoisoquinoline-1,3(2H,4H)-diones in
Brønsted acids gives rise to diazonium cations that can be trapped with
arenes to give 4-arylisoquinoline-1,3(2H,4H)-diones (homophthalimid-
es). This provides a new, metal-free approach to 4-aryltetrahydroiso-
quinolines (obtainable from respective homophthalimides by reduc-
tion). Similarly, a fluorine atom can be introduced by trapping the
diazonium cation with HF. This led to the preparation of the first exam-
ples of 4-monofluoro-substituted isoquinoline-1,3-diones (as well as
their 4-bromo-4-fluoro and 4-chloro-4-fluoro variants), important car-
boxylic acid isosteres on their own and precursors of useful 4-fluorotet-
rahydroisoquinoline building blocks.
O
O
MsHN
2
1
OH
H
N
O
O
O
N
Br
N
H
4
O
O
O
3
O
H
N
N
H
OMe
O
N
H
5
O
Key words homophthalimides, diazo compounds, arylation, Friedel–
Crafts reaction, monofluorination, fluorohalogenation, Brønsted acids,
isoquinoline-1,3(2H,4H)-dione
Figure 1 Examples of bioactive compounds incorporating isoquino-
line-1,3-dione (homophthalimide) scaffold
Isoquinoline-1,3-dione (often referred to as homoph-
thalimide) is frequently encountered as a substructure in
natural products and compounds endowed with various bi-
ological activities.1 Illustrative examples of bioactive com-
pounds incorporating this motif include insulin-like growth
factor receptor inhibitor 1,1b dual HIV reverse transcriptase-
associated RHase H/polymerase inhibitor 2,1e hepatitis C vi-
rus NS5B polymerase inhibitor 3,1f caspase-3 inhibitor 4,1g
and selective tyrosyl DNA phosphodiesterase II inhibitor 51h
(Figure 1).
Such a modification, however, mandates the use of a transi-
tion metal catalyst [Rh2(OAc)4], which is not a desirable fea-
ture from the standpoint of pharmaceutical process chem-
istry.5 Therefore, we turned our attention to possible ways
to replace the diazo function with other medicinally rele-
vant groups without involving a metal catalyst or an or-
ganometallic reagent. In particular, as reported recently, di-
azo compounds can be turned into competent electrophiles
for the Friedel–Crafts arylation of aromatic substrates in
Brønsted superacid CF3SO3H (triflic acid, TfOH).6 The intro-
duction of aryl groups at position 4 of the isoquinoline-1,3-
dione core (to give compounds 7) represents a particularly
sought after modification (hitherto achieved directly via
Cu-promoted7 or Pd-catalyzed8 arylation) as the resulting
compounds are precursors (obtainable via double carbonyl
reduction) for the important, central nervous system fo-
Considering the apparently privileged2 character of the
isoquinoline-1,3-dione scaffold, it is desirable that reliable
methods for its selective modification are in place. Recently,
we reported a facile introduction of the diazo group at posi-
tion 4 of homophthalimides (to give compounds 6)3 which
offered a way to convert this position into a spiro center.4
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
A. Golushko et al.
Paper
Synthesis
cused 4-aryltetrahydroisoquinolines represented by such
physiologically active substances as natural product cheryl-
line (8),9 high-affinity D1-selective dopamine receptor ago-
nist dihydrexidine (9),10 and triple monoamine reuptake in-
hibitor stimulant diclofensine (10).11 Another distinctly de-
sirable modification of the isoquinoline-1,3-dione core is
the introduction of fluorine atoms. Besides the widely ac-
cepted influence of fluorination on the lipophilicity and af-
finity profile of bioactive small molecules,12 it can signifi-
cantly alter the NH-acidity of the homophthalimide moiety,
a carboxylic acid isostere.13 While ,-difluorohomoph-
thalimides 11 have been reported as prepared via Cu-cata-
lyzed cross-coupling cyclization,14 their monofluoro coun-
terparts 12 have not been featured in the literature
(Scheme 1). Considering that diazo function can be effec-
tively replaced with fluorine (alone or in combination with
another halogen) via treatment of the diazo substrate with
hydrogen fluoride,6b,15 we investigated this transformation,
along with the preparation of compounds 7, in Brønsted
acid medium. Herein, we present the results of these stud-
ies.
vent).6 After brief experimentation involving variations in
the reaction temperature and time, we arrived at the opti-
mal conditions involving exposure of diazo compound 6 to
the ArH/TfOH mixture over 40 min at r.t. which led to the
full disappearance of the starting material and minimal tar
formation. Under these conditions, we screened a number
of aromatic substrates 13 in combination with exemplary
diazohomophthalimides 6a. Likewise, substrates 6b–i bear-
ing a range of substituents on the imide nitrogen atom were
arylated with benzene (Scheme 2).
As it is evident from the data presented in Scheme 2, the
scope of the Friedel–Crafts reaction of diazohomophthalim-
ides 6 with a range of aromatic substrates is rather broad
and, reassuringly, includes halogenated benzenes (7h–k)
and even (trifluoromethyl)benzene (7l). Notably, other
electron-poor substrates (nitrobenezene, ethyl benzoate)
failed to undergo the reaction and so did, somewhat sur-
prisingly, naphthalene and indole. In all these cases, a com-
plex mixture of products formed where the target product
was present in <10% amount according to the 1H NMR anal-
ysis of the crude reaction mixture. The reaction appears to
be rather sensitive to steric factors as illustrated by the for-
mation of only 2 out of 3 possible isomers of product 7f. In-
troduction of an unsubstituted phenyl group (7m–t) pro-
ceeded with markedly higher yields and tolerated a range of
substituents at the imide nitrogen atom. Notably, the pres-
ence of a basic nitrogen atom in substrate 6i did not inter-
fere with the formation of the desired product. The struc-
ture of a representative arylation product (7a) was con-
firmed by single-crystal X-ray analysis (ESI).
O
O
R
O
R
O
N
N
4
N2
O
Ar
6
7
HF (NBX)
O
R
O
R
O
N
N
Arylation of diazohomophthalimides 6 presents a supe-
rior alternative to their possible involvement in RhII-cata-
lyzed C–H insertion with aromatic substrates. While we
have earlier reported a single example of such reaction of
6a with dihydrobenzofuran occurring in moderate yield,4
the same reaction with unsubstituted benzene (employed
as a solvent) gave a disappointingly low yield of 7a (Scheme
3).
F
X
F
F
12
X = H or other Hal
11
HO
Me
NH
N
H
MeO
H
8
9
Replacement of the diazo functionality with a fluorine
atom was achieved (after brief experimentation with tem-
perature and time regimens) with HF·pyridine15 (12a–h) in
good to excellent yields. Addition of N-chlorosuccinimide
(NCS) or N-bromosuccinimide (NBS) to the reaction mix-
ture led to incorporation of an additional chlorine or bro-
mine atom, respectively (12i,j).15 Interestingly, Just as with
the arylation reactions (vide supra), the presence of a basic
nitrogen atom in 6i did not interfere with the Brønsted acid
promoted generation of the carbocation intermediate. It
should be noted that compounds 12a–j represent the first
examples of homophthalimides monofluorinated at posi-
tion 4. Attempts to replace the diazo functionality with
both a fluorine and an iodine atom by using HF·pyridine
mixture with N-iodosuccinimide (NIS) led to the formation
of ,-difluorohomophthalimide 12k (the structure of
HO
OH
OH
MeO
Me
N
10
Cl
Cl
Scheme 1 Evolution of isoquinoline-1,3-dione (homophthalimide)
core via arylation of diazo compounds 6 and its medicinal relevance;
structures of fluorinated homophthalimides 11 (reported earlier) and
12 (investigated in this work)
As the basic set of conditions for the Brønsted acid pro-
moted arylation of 6, we selected neat triflic acid in a mix-
ture with aromatic hydrocarbon 13 (employed as a co-sol-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

C
A. Golushko et al.
Paper
Synthesis
O
O
R
O
R
O
ArH (13)
N
N
TfOH
r.t., 40 min
N2
Ar
6a–i
7a–t
6a: R = Me; 6b: R = Et; 6c: R = i-Pr; 6d: R = Ph; 6e: R = p-Tol;
6f: R = 4-FC6H4; 6g: R = 4-MeOC6H4; 6h: R = Bn; 6i: R = Me2N
O
O
O
O
O
Me
Me
O
Me
O
N
Me
Me
O
N
N
N
N
O
O
Me
Me
Me
Me
4
4
2
3
Me
Me
Me
7b, 30%
7c, 43%
7a, 95%
(4-/2- = 1:0.7)
(4-/3- = 1:0.6)
7d, 55%
7e, 86%
O
O
N
O
N
O
O
Me
Me
O
Me
Me
Me
N
N
N
O
O
F
O
O
5
6
Me
OMe
Cl
Br
Me
4
4
4
4
2
2
2
2
Me
7f, 25%
7g, 72%
7h, 82%
7i, 67%
7j, 73%
(5-/6- = 1:0.3)
(4-/2- = 1:0.7)
(4-/2- = 1:0.8)
(4-/2- = 1:0.6)
(4-/2- = 1:0.5)
O
O
O
N
O
O
N
O
O
N
O
Me
Me
N
N
O
O
Cl
4
3
Cl
CF3
7k, 67%
(4-/3- = 1:0.2)
7l, 41%
7m, 81%
7n, 89%
7o, 84%
CH3
OMe
F
O
N
O
N
O
O
N
O
O
O
N
N
N
O
O
O
7p, 86%
7q, 74%
7r, 88%
7s, 43%
7t, 86%
Scheme 2 TfOH-promoted Friedel–Crafts arylation of homophthalimides 6a–i
O
which was confirmed by single-crystal X-ray analysis), pre-
sumably via nucleophilic displacement of a labile iodine in
the -iodo--fluoro intermediate (Scheme 4).
O
Me
O
Me
N
N
O
ref. 4
O
Mechanistically, the arylation (6 → 7) and fluorination
processes (6 → 12) described herein are likely related and
involve generation of a diazonium cation A in Brønsted acid
medium via protonation of 6 and (possibly concerted) trap-
ping of the resulting intermediate with either arene (to give
7) or fluoride anion (to give 12a–h). In case of additionally
employing N-halosuccinimides, compound 6 can undergo
electrophilic halogenation to give cation B which, in turn,
could react with the fluoride anion to give 12i,j and 12k′
(Scheme 5) as proposed by Olah and co-workers.16 As al-
N2
O
32%
6a
C6H6
Me
O
N
O
7a, 4%
Reaction conditions: 1 mol% Rh2(OAc)4, MW, 120 °C, 2 h
Scheme 3 Comparative examples of RhII-catalyzed arylation of 6a
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

D
A. Golushko et al.
Paper
Synthesis
O
O
HF.Py
(NXS)
R
O
R
O
N
N
CH2Cl2
0 °C to r.t.
F
X
N2
12
6
X = H, Br, Cl or F
O
O
O
F
O
F
Me
N
Ph
O
C6H4Me-p
N
N
N
O
O
O
F
F
12a, 67%
12b, 86%
12c, 76%
12d, 72%
O
N
O
N
O
O
Bn
O
C6H4OMe-p
N
O
C6H4F-p
N
N
O
O
F
F
F
F
12e, 69%
12f, 62%
12g, 79%
12h, 62%
O
O
N
O
O
Me
N
Me
O
Me
O
Me
O
N
N
via
O
F
Cl
F
Br
F
F
F
I
12i, 53%
12j, 58%
12k, 44%
12k'
Scheme 4 Preparation of 4-fluorohomophthalimides 12a–k; reactions were complete in 1.5 h for 12a–h,j,k and were carried out over 24 h for 12i
ready mentioned, ,-difluorohomophthalimide 12k likely
formed as a result of an I → F nucleophilic substitution in
12k′. The proposed lability of the iodine in 12k′ is also in
line with our observation that other monohalides (chlo-
rides and bromides) which we attempted to prepare by re-
action of compounds 6 with HCl and HBr, respectively, were
unstable to isolation.
4-aryltetrahydroisoquinolines,9–11,17 we synthesized com-
pound 7a on 500-mg scale and successfully reduced the
both carbonyl groups with LiAlH4 (Scheme 6).
O
Me
Me
O
N
N
LiAlH4
THF, reflux
5 h
Finally, in order to demonstrate the genesis of com-
pounds 7 developed in this work to the medicinally relevant
Ph
13a, 57%
Ph
7a
Scheme 6 Reduction of exemplary homophthalimide 7a
O
R
N
In summary, we have described a novel application of
arylation and fluorination of diazo compounds in Brønsted
acids. It provides a new approach to selectively modifying
the medicinally relevant position 4 of isoquinoline-1,3-di-
one nucleus in a simple, efficient, and metal-free fashion.
Monofluorinated isoquinoline-1,3-diones have been pre-
pared for the first time. Both sets of compounds can be con-
verted, via reduction of the carbonyl groups into com-
pounds of importance in drug design: 4-aryltetrahydroiso-
quinolines (a privileged, CNS-focused scaffold) and 4-
fluorotetrahydroisoquinolines (building blocks of emerging
prominence in drug design).
O
O
O
ArH
– N2
R
O
R
O
Ar
O
H+
N
N
– H+
7
N
HF
– N2
– H+
+N
R
O
N2
A
6
N
H+
NXS
– N2
O
X
O
F
R
O
R
F–
12a–h
N
N
O
B
F
X
12i–k'
Scheme 5 Plausible mechanism for the formation of compound 7 and
12
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

E
A. Golushko et al.
Paper
Synthesis
was evaporated under reduced pressure. In the case of 12i,k, the reac-
tion product was additionally purified by preparative TLC (silica gel,
petroleum ether/EtOAc, 9:1).
The NMR spectra of solutions of compounds in CDCl3 were recorded
at 400.13, 100.61, and 376.50 MHz for 1H, 13C, and 19F NMR spectra,
respectively, at 23 °C. The solvent residual signals of CDCl3 ( = 7.26)
for 1H NMR spectra and the carbon signals of CDCl3 ( = 77.0) for 13
C
Reduction of 7a to 13a
NMR spectra were used as references. 19F NMR spectra were indirect-
ly referred to the signal of CFCl3 ( = 0.0). Mass spectra were recorded
with a Bruker Maxis HRMS-ESI-qTOF spectrometer (electrospray ion-
ization mode). Purification by column chromatography was carried
out with silica gel 60 (0.040–0.063 mm). Preparative TLC was per-
formed on Silica gel LSL254 5–40 m with 13% of gypsum. Melting
points were determined with a Stuart SMP50 instrument in open
capillary tubes and are uncorrected.
To a suspension of LiAlH4 (0.304 g, 8.0 mmol) in THF (12 mL), a solu-
tion of 7a (0.252 g, 1.0 mmol) in THF (4 mL) was slowly added under
vigorous stirring. The mixture was heated at reflux for 5 h and cooled
to –10 °C. Water (4.0 mL) was slowly added, and stirring was contin-
ued for an additional 20 min. EtOAc (30 mL) was added, the suspen-
sion was transferred to a 50 mL centrifuge tube. The organic layer was
separated by centrifugation at 4700 rpm for 3 min, the residue was
additionally extracted with EtOAc (20 mL). The combined organic
phases were dried (Na2SO4) and the solvent was removed by reduced
pressure evaporation. The crude oily residue was subjected to flash
column chromatography (silica gel, 7 to 25% acetone/n-hexane) to af-
ford 13a as clear yellowish oil; yield: 127 mg (57%). Spectral data are
in agreement with the literature.19
X-ray Diffraction Study
A suitable crystal was selected and studied on the diffractometer. The
crystal was kept at 100(2) K during data collection. Using Olex2, the
structure was solved with the ShelXS structure solution program us-
ing Direct Methods and refined with the ShelXL refinement package
using least squares minimization.18
1Н NMR:  = 7.37–7.31 (m, 2 H), 7.30–7.22 (m, 3 H), 7.20–7.15 (m, 1
H), 7.14–7.08 (m, 2 H), 6.91 (d, J = 7.7 Hz, 1 H), 4.32 (dd, J = 8.3, 6.0 Hz,
1 H), 3.80 (d, J = 14.8 Hz, 1 H), 3.67 (d, J = 14.8 Hz, 1 H), 3.08 (ddd, J =
11.5, 5.7, 1.4 Hz, 1 H), 2.62 (dd, J = 11.5, 8.6 Hz, 1 H), 2.47 (s, 3 H).
Homophthalimides 7a–t; General Procedure
Diazohomophthalimide 6 (30 mg) in CH2Cl2 (0.4 mL) was added drop-
wise to a mixture of arene (0.2 mL) and TfOH (1.0 mL). The mixture
was stirred at r.t. for 40 min, then poured into water (20 mL) and ex-
tracted with CHCl3 (3 × 10 mL). The combined organic layers were
washed with sat. aq NaHCO3 (10 mL) and water (2 × 20 mL) and dried
(Na2SO4). The solvent was evaporated under reduced pressure. In
some cases, reaction products were additionally purified by prepara-
tive chromatography (silica gel, petroleum ether/EtOAc).
2-Methyl-4-phenylisoquinoline-1,3(2H,4H)-dione (7a)
Obtained from 6a (500 mg, 2.49 mmol) and benzene (2 mL, 22.5
mmol) as a yellowish solid; yield: 592 mg (95%); mp 107–108 °C.
1Н NMR:  = 3.35 (s, 3 H), 5.08 (s, 1 H), 7.11–7.14 (m, 3 H), 7.27–7.32
(m, 3 H), 7.47 (td, J = 7.6, 1.3 Hz, 1 H), 7.54 (td, J = 7.5, 1.5 Hz, 1 H),
8.29 (dd, J = 7.8, 1.5 Hz, 1 H).
13C NMR:  = 27.4, 52.6, 125.5, 128.1, 128.1, 128.5, 128.6, 128.9, 129.2,
134.0, 138.4, 139.2, 165.1, 172.1.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H13NNaO2: 274.0839;
found: 274.0841.
Large-Scale Preparation of Homophthalimide 7a
Diazohomophthalimide 6a (500 mg, 2.49 mmol) in CH2Cl2 (2 mL) was
added dropwise to a mixture of arene (1.5 mL, 17 mmol) and TfOH
(3.0 mL). The mixture was stirred at r.t. for 40 min, poured into water
(20 mL), and extracted with CHCl3 (3 × 20 mL). The combined organic
layers were washed with sat. aq NaHCO3 (10 mL) and water (2 × 20
mL) and dried (Na2SO4). Evaporation of the solvent under reduced
pressure gave the product; yield: 592 mg (95%).
2-Methyl-4-(2/4-methylphenyl)isoquinoline-1,3(2H,4H)-diones
7b, Mixture of Regioisomers
Obtained from 6a (30 mg, 0.15 mmol) and toluene (0.2 mL, 1.9
mmol). Purification by preparative TLC (petroleum ether/EtOAc, 9:1)
gave a yellow oil; yield: 12 mg (30%).
1H NMR:  (p-isomer, selected signals) = 2.31 (s, 3 H), 3.34 (s, 3 H),
5.05 (s, 1 H);  (o-isomer, selected signals) = 2.32 (s, 3 H), 3.40 (s, 3 H),
5.29 (s, 1 H);  (mixture) = 6.89–6.91 (m, 1 H), 6.95–6.97 (m, 1 H),
7.01 (d, J = 8.1 Hz, 1 H), 7.10–7.16 (m, 4 H), 7.42–7.56 (m, 5 H), 8.27–
8.30 (m, 2 H).
13C NMR:  (p-isomer, selected signals) = 21.2, 27.4, 52.3, 165.2, 172.3;
 (o-isomer, selected signals) = 20.1, 27.3, 52.6, 165.1, 172.1;  (mix-
ture) = 125.5, 125.7, 126.7, 127.89, 127.92, 128.0, 128.2, 128.5, 128.8,
129.3, 129.9, 131.5, 134.0, 134.1, 136.3, 136.8, 137.9, 138.6, 139.0.
4-Fluorohomophthalimides 12a–h; General Procedure
To a solution of HF·Py (0.4 mL, 14 mmol, HF ~70%, pyridine ~30%) in
CH2Cl2 (0.6 mL) in a Teflon vial at 0 °C was added dropwise a solution
of diazohomophthalimide 6 (0.7 mmol) in CH2Cl2 (0.4 mL). The mix-
ture was stirred at this temperature for 0.5 h, then for 1.5 h at r.t. (24
h for 12i) and poured into water (20 mL). Extraction was carried out
with CHCl3 (3 × 15 mL). The combined organic layers were washed
with aq H2SO4 (10 mL, pH ~ 3) and water (2 × 20 mL) and dried (Na2-
SO4). The solvent was evaporated under reduced pressure.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H15NNaO2: 288.0995;
found: 288.1007.
4-Fluoro-4-halohomophthalimides 12i–k; General Procedure
To a mixture of HF·Py (0.2 mL, 7 mmol, HF ~70%, pyridine ~30%) and
N-halosuccinimide (0.60 mmol, 4 equiv) in CH2Cl2 (0.6 mL) in a Teflon
vial at 0 °C, a solution of diazohomophthalimide 6a (30 mg, 0.15
mmol) in CH2Cl2 (0.3 mL) was added dropwise. The mixture was
stirred at this temperature for 0.5 h, then for 1.5 h at r.t. (24 h for 12i)
and poured into water (20 mL). Extraction was carried out with CHCl3
(3 × 15 mL). The combined organic layers were washed with aq H2SO4
(10 mL, pH ~ 3) and water (2 × 20 mL) and dried (Na2SO4). The solvent
4-(2,3/3,4-Dimethylphenyl)-2-methylisoquinoline-1,3(2H,4H)-di-
ones 7c Mixture of Regioisomers
Obtained from 6a (30 mg, 0.15 mmol) and o-xylene (0.2 mL, 1.66
mmol). Purification by preparative TLC (petroleum ether/EtOAc, 9:1)
gave a yellow oil; yield: 18 mg (43%).
1H NMR:  (3,4-isomer, selected signals) = 2.20 (s, 3 H), 2.21 (s, 3 H),
3.35 (s, 3 H), 5.01 (s, 1 H), 6.91 (d, J = 2.1 Hz, 1 H), 7.53 (td, J = 7.5, 1.5
Hz, 1 H);  (2,3-isomer, selected signals) = 2.15 (s, 3 H), 2.30 (s, 3 H),
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

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Synthesis
3.40 (s, 3 H), 5.31 (s, 1 H), 6.96 (d, J = 7.8 Hz, 1 H);  (mixture) = 6.78–
6.83 (m, 1 H), 6.82 (dd, J = 7.8, 2.1 Hz, 1 H), 7.03–7.06 (m, 2 H), 7.11–
7.15 (m, 2 H), 7.42–7.50 (m, 3 H), 8.27–8.30 (m, 2 H).
13C NMR:  (3,4-isomer, selected signals) = 19.5, 27.4, 52.3, 166.3,
172.4;  (2,3-isomer, selected signals) = 16.2, 20.0, 27.3, 166.1, 172.3;
 (mixture) = 125.3, 125.4, 125.9, 126.1, 127.80, 127.84, 128.0, 128.5,
128.8, 128.9, 129.8, 129.97, 130.01, 130.2, 130.4, 133.99, 134.0,
135.25, 136.6, 136.7, 137.6, 138.3, 138.8, 139.4.
4-(2/4-Methoxyphenyl)-2-methylisoquinoline-1,3(2H,4H)-diones
7g, Mixture of Regioisomers
Obtained from 6a (30 mg, 0.15 mmol) and anisole (0.2 mL, 1.84
mmol). Purification by preparative TLC (petroleum ether/EtOAc, 7:3)
gave a yellow oil; yield: 30 mg (72%).
1H NMR:  (p-isomer, selected signals) = 3.37 (s, 3 H), 3.79 (s, 3 H),
5.06 (s, 1 H), 6.85 (d, J = 8.9 Hz, 2 H), 7.06 (d, J = 8.8 Hz, 2 H), 7.17 (d,
J = 7.6 Hz, 1 H), 7.49–7.51 (m, 1 H), 7.57 (td, J = 7.5, 1.5 Hz, 1 H), 8.31
(dd, J = 7.9, 1.5 Hz, 1 H);  (o-isomer, selected signals) = 3.45 (s, 3 H),
3.63 (s, 3 H), 5.16 (s, 1 H), 6.83–6.86 (m, 1 H), 6.93–6.95 (m, 1 H), 7.00
(dd, J = 7.5, 1.1 Hz, 1 H), 7.05–7.07 (m, 1 H), 7.30–7.35 (m, 1 H), 7.41
(t, J = 7.3 Hz, 1 H), 7.46 (dd, J = 7.6, 1.5 Hz, 1 H), 8.27 (dd, J = 7.9, 1.5 Hz,
1 H).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H17NNaO2: 302.1152;
found: 302.1141.
4-(2,4-Dimethylphenyl)-2-methylisoquinoline-1,3(2H,4H)-dione
(7d)
13C NMR:  = (27.1, 27.3, 48.6, 51.8, 55.4, 55.7, 112.0, 114.6, 121.2,
125.2, 125.5, 127.4, 127.4, 128.0, 128.5, 128.5, 128.5, 128.9, 129.6,
129.7, 131.3, 131.3, 133.5, 134.0, 138.7, 139.0, 156.7, 159.4, 165.1,
165.4, 172.4.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H15NNaO3: 304.0945;
found: 304.0949.
Obtained from 6a (30 mg, 0.15 mmol) and m-xylene (0.2 mL, 1.66
mmol). Purification by preparative TLC (petroleum ether/EtOAc, 9:1)
gave a yellow oil; yield: 23 mg (55%).
1Н NMR:  = 2.28 (s, 3 H), 2.30 (s, 3 H), 3.39 (s, 3 H), 5.25 (s, 1 H), 6.78
(d, J = 7.8 Hz, 1 H), 6.94 (d, J = 7.8 Hz, 1 H), 6.98 (d, J = 7.7 Hz, 1 H), 7.05
(s, 1H), 7.43 (t, J = 7.2 Hz, 1 H), 7.49 (td, J = 7.5, 1.6 Hz, 1 H), 8.28 (dd,
J = 7.8, 1.6 Hz, 1 H).
4-(2/4-Fluorophenyl)-2-methylisoquinoline-1,3(2H,4H)-diones7h,
Mixture of Regioisomers
13C NMR:  = 20.1, 21.1, 27.3, 49.6, 125.4, 127.4, 127.8, 127.9, 128.8,
129.9, 132.3, 134.0, 134.8, 136.5, 137.9, 139.2, 165.1, 172.2.
Obtained from 6a (30 mg, 0.15 mmol) and fluorobenzene (0.2 mL,
2.12 mmol) as a yellow oil; yield: 33 mg (82%).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H17NNaO2: 302.1152;
found: 302.1149.
1H NMR:  (p-isomer, selected signals) = 3.34 (s, 3 H), 5.07 (s, 1 H),
7.42–7.46 (m, 1 H), 7.56 (td, J = 7.5, 1.4 Hz, 1 H);  (o-isomer, selected
signals) = 3.42 (s, 3 H), 5.28 (s, 1 H), 7.05 (d, J = 7.1 Hz, 1 H), 7.28–7.34
(m, 1 H);  (mixture) = 6.97–7.01 (m, 2 H), 7.08–7.16 (m, 6 H), 7.48–
7.52 (m, 2 H), 8.26–8.30 (m, 2 H).
4-(2,5-Dimethylphenyl)-2-methylisoquinoline-1,3(2H,4H)-dione
(7e)
Obtained from 6a (30 mg, 0.15 mmol) and p-xylene (0.2 mL, 1.66
mmol) as a reddish solid; yield: 36 mg (86%); mp 136–138 °C.
13C NMR:  (p-isomer, selected signals) = 27.4 (d, J = 2.9 Hz), 51.7,
116.1 (d, J = 21.6 Hz), 124.8 (d, J = 3.5 Hz), 125.5, 128.3, 128.4, 129.01,
133.9, 134.0 (d, J = 15.0 Hz), 138.1, 162.8 (d, J = 186.6 Hz), 164.91,
171.9 (d, J = 1.2 Hz);  (o-isomer, selected signals) = 46.8 (d, J = 2.3
Hz), 51.7, 116.4 (d, J = 21.2 Hz), 125.1 (d, J = 1.0 Hz), 126.7 (d, J = 14.6
Hz), 127.7, 128.0, 128.99, 130.1 (d, J = 8.1 Hz), 131.1 (d, J = 3.5 Hz),
134.1, 134.9 (d, J = 3.5 Hz), 137.7 (d, J = 0.6 Hz), 160.3 (d, J = 186.9 Hz),
164.85, 171.2 (d, J = 1.1 Hz).
1Н NMR:  = 2.23 (s, 6 H), 3.40 (s, 3 H), 6.24 (s, 1 H), 6.71 (s, 1 H), 6.97
(d, J = 7.8 Hz, 1 H), 7.02 (dd, J = 7.9, 1.8 Hz, 1 H), 7.11 (d, J = 7.7 Hz, 1
H), 7.43 (t, J = 7.3 Hz, 1 H), 7.49 (td, J = 7.5, 1.7 Hz, 1 H), 8.29 (dd, J =
7.7, 1.6 Hz, 1 H).
13C NMR:  = 19.6, 21.0, 27.3, 49.9, 125.3, 127.8, 127.9, 128.8, 128.9,
131.4, 133.5, 134.0, 136.2, 137.4, 139.1, 165.1, 172.1.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H17NNaO2: 302.1152;
19F{H} NMR:  (p-isomer, selected signal) = –114.2;  (o-isomer, se-
found: 302.1151.
lected signal) = –116.80.
2-Methyl-4-(2,4,5/2,3,5-trimethylphenyl)isoquinoline-1,3(2H,4H)-
diones 7f, Mixture of Regioisomers
HRMS (ESI-TOF): m/z [M – H]– calcd for C16H11FNO2: 268.0768; found:
268.0761.
Obtained from 6a (30 mg, 0.15 mmol) and 1,2,4-trimethylbenzene
(0.2 mL, 1.46 mmol). Purification by preparative TLC (petroleum
ether/EtOAc, 9:1) gave a yellow oil; yield: 11 mg (25%).
4-(2/4-Chlorophenyl)-2-methylisoquinoline-1,3(2H,4H)-diones 7i,
Mixture of Regioisomers
1H NMR:  (2,4,5-isomer, selected signals) = 2.13 (s, 3 H), 2.20 (s, 3 H),
2.22 (s, 3 H), 3.40 (s, 1 H), 6.64 (s, 1 H), 6.95–6.98 (m, 1 H), 7.00 (s, 1
H), 7.43 (t, J = 7.2 Hz, 1 H), 7.49 (td, J = 7.5, 1.5 Hz, 1 H), 8.27–8.30 (m,
1 H);  (2,3,5-isomer, selected signals) = 2.21 (s, 3 H), 2.26 (s, 3 H),
3.41 (s, 1 H), 6.60 (s, 1 H), 6.95–6.98 (m, 1 H), 7.00 (s, 1 H), 7.41–7.50
(m, 1 H), 7.47–7.51 (m, 1 H), 8.27–8.30 (m, 1 H).
13C NMR:  (2,4,5-isomer, selected signals) = 19.39, 19.42, 19.51,
27.29, 165.17, 172.36;  (2,3,5-isomer, selected signals) = 15.8, 20.96,
20.98, 27.30, 165.15, 172.39;  (mixture) = 49.61, 49.63, 125.2, 125.3,
127.7, 127.9, 128.0, 128.8, 128.9, 130.9, 131.2, 132.0, 132.9, 133.8,
134.0, 134.8, 135.0, 135.5, 136.5, 138.1, 139.3, 139.5.
Obtained from 6a (30 mg, 0.15 mmol) and chlorobenzene (0.2 mL,
1.98 mmol) as a yellow oil; yield: 29 mg (67%).
1H NMR:  (p-isomer, selected signals) = 3.34 (s, 3 H), 5.06 (s, 1 H),
7.06 (d, J = 8.4 Hz, 2 H), 7.10 (d, J = 7.7 Hz, 1 H), 7.56 (td, J = 7.5, 1.5 Hz,
1 H);  (o-isomer, selected signals) = 3.43 (s, 3 H), 5.43 (s, 1 H), 6.95 (d,
J = 7.6 Hz, 1 H);  (mixture) = 7.27–7.30 (m, 4 H), 7.41–7.44 (m, 3 H),
7.46–7.51 (m, 2 H), 8.27–8.30 (m, 2 H).
13C NMR:  (p-isomer, selected signals) = 27.4, 51.8, 164.86, 171.7; 
(o-isomer, selected signals) = 27.3, 50.6, 164.88, 171.1;  (mixture) =
125.3, 125.5, 127.4, 127.5, 127.6, 128.0, 128.4, 128.4, 129.0, 129.1,
129.2, 129.4, 129.6, 130.1, 130.6, 131.3, 132.0, 134.0, 134.1, 134.2,
134.3, 137.0, 137.6, 137.79, 137.83.
HRMS (ESI-TOF): m/z [M – H]– calcd for C19H18NO2: 292.1332; found:
292.1334.
HRMS (ESI-TOF): m/z [M – H]– calcd for C16H11ClNO2: 284.0473;
found: 284.0474.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

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Synthesis
4-(2/4-Bromophenyl)-2-methylisoquinoline-1,3(2H,4H)-diones 7j,
13C NMR:  = 13.2, 35.8, 52.7, 125.7, 128.0, 128.1, 128.4, 128.5, 128.9,
Mixture of Regioisomers
129.2, 133.9, 138.4, 139.3, 164.6, 171.7.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H15NNaO2: 288.0995;
Obtained from 6a (30 mg, 0.15 mmol) and bromobenzene (0.2 mL,
1.91 mmol) as a yellow oil; yield: 36 mg (73%).
found: 288.1001.
1H NMR:  (p-isomer, selected signals) = 3.34 (s, 3 H), 5.04 (s, 1 H),
7.00 (d, J = 8.5 Hz, 2 H), 7.10 (d, J = 7.7 Hz, 1 H), 7.43 (d, J = 8.5 Hz, 2 H),
7.55 (td, J = 7.5, 1.6 Hz, 1 H);  (o-isomer, selected signals) = 6.95 (d, J =
7.6 Hz, 1 H), 7.13–7.16 (m, 1 H), 7.21 (t, J = 7.6 Hz, 1 H), 7.31 (t, J = 7.3
Hz, 1 H), 7.62 (dd, J = 8.0, 1.4 Hz, 1 H);  (mixture) = 7.46–7.51 (m, 3
H), 8.27–8.29 (m, 2 H).
13C NMR:  (p-isomer, selected signals) = 27.4, 51.9, 122.3, 125.5,
138.4, 128.4, 129.04, 130.4, 132.3, 134.1, 137.7, 138.1, 164.8, 171.6; 
(o-isomer, selected signals) = 27.3, 52.6, 125.4, 127.4, 128.0, 128.2,
129.0, 129.8, 130.1, 131.6, 133.9, 134.0, 137.9, 138.8, 164.9, 171.0.
2-Isopropyl-4-phenylisoquinoline-1,3(2H,4H)-dione (7n)
Obtained from 6c (30 mg, 0.13 mmol) and benzene (0.2 mL, 2.25
mmol) as a yellow oil; yield: 32 mg (89%).
1Н NMR:  = 1.35 (d, J = 6.9 Hz, 3 H), 1.45 (d, J = 6.9 Hz, 3 H), 5.01 (s, 1
H), 5.11 (hept, J = 6.9 Hz, 1 H), 7.10–7.13 (m, 3 H), 7.26–7.32 (m, 3 H),
7.45 (td, J = 7.5, 1.4 Hz, 1 H), 7.52 (td, J = 7.5, 1.5 Hz, 1 H), 8.26 (dd, J =
7.7, 1.5 Hz, 1 H).
13C NMR:  = 19.1, 20.2, 45.7, 53.6, 126.2, 128.0, 128.0, 128.1, 128.3,
129.0, 129.2, 133.8, 138.2, 139.1, 165.1, 172.3.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H17Cl3NNaO2: 302.1151;
found: 302.1153.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H12BrNNaO2: 351.9944;
found: 351.9934.
4-(2,3/3,4-Dichlorophenyl)-2-methylisoquinoline-1,3(2H,4H)-di-
ones 7k, Mixture of Regioisomers
2,4-Diphenylisoquinoline-1,3(2H,4H)-dione (7o)
Obtained from 6d (30 mg, 0.11 mmol) and benzene (0.2 mL, 2.25
mmol) as a milky white solid; yield: 30 mg (84%); mp 174–175 °C.
1Н NMR:  = 5.25 (s, 1 H), 7.12 (d, J = 7.2 Hz, 2 H), 7.22–7.26 (m, 3 H),
7.31–7.36 (m, 3 H), 7.40–7.47 (m, 3 H), 7.52 (td, J = 7.6, 1.2 Hz, 1 H),
7.62 (td, J = 7.5, 1.5 Hz, 1 H), 8.34 (dd, J = 7.9, 1.4 Hz, 1 H).
13C NMR:  = 53.4, 125.8, 128.2, 128.3, 128.4, 128.5, 128.6, 128.7,
129.3, 129.3, 134.4, 135.2, 138.3, 138.9, 165.0, 171.9.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C21H15NNaO2: 336.0995;
found: 336.0987.
Obtained from 6a (30 mg, 0.15 mmol) and 1,2-dichlorobenzene (0.2
mL, 1.77 mmol) as a yellow oil; yield: 32 mg (67%).
1H NMR:  (3,4-isomer, selected signals) = 3.34 (s, 3 H), 5.04 (s, 1 H),
6.96 (dd, J = 8.3, 2.2 Hz, 1 H), 7.10 (d, J = 7.6 Hz, 1 H), 7.23 (d, J = 2.2 Hz,
1 H), 7.38 (d, J = 8.3 Hz, 1 H). 7.52 (dd, J = 7.5, 1.3 Hz, 1 H), 7.58 (td, J =
7.5, 1.5 Hz, 1 H), 8.30 (dd, J = 7.9, 1.5 Hz, 1 H);  (2,3-isomer, selected
signals) = 3.42 (s, 3 H), 5.45 (s, 1 H), 6.92 (d, J = 7.5 Hz, 1 H), 7.13–7.15
(m, 1 H), 7.22–7.24 (m, 1 H), 7.43–7.49 (m, 3 H), 8.28 (dd, J = 7.4, 1.8
Hz, 1 H).
13C NMR:  (3,4-isomer, selected signals) = 27.5, 51.4, 164.6, 171.1; 
(2,3-isomer, selected signals) = 27.4, 51.4, 164.7, 170.1;  (mixture) =
125.3, 125.5, 126.4, 127.1, 127.4, 127.9, 128.1, 128.2, 128.4, 128.6,
129.16, 129.22, 129.4, 130.5, 130.8, 131.0, 132.6, 133.3, 134.1, 134.3,
137.0, 137.2, 139.0, 139.1.
HRMS (ESI-TOF): m/z [M – H]– calcd for C16H10Cl2NO2: 318.0094;
found: 318.0095.
2-(4-Methylphenyl)-4-phenylisoquinoline-1,3(2H,4H)-dione (7p)
Obtained from 6e (30 mg, 0.11 mmol) and benzene (0.2 mL, 2.25
mmol) as yellow crystals; yield: 31 mg (86%); mp 143–145 °C.
1Н NMR:  = 2.38 (s, 3 H), 5.24 (s, 1 H), 6.99 (d, J = 7.8 Hz, 2 H), 7.22–
7.24 (m, 5 H), 7.30–7.36 (m, 3 H), 7.52 (td, J = 7.6, 1.3 Hz, 1 H), 7.61
(td, J = 7.5, 1.5 Hz, 1 H), 8.33 (dd, J = 7.9, 1.4 Hz, 1 H).
13C NMR:  = 21.3, 53.4, 125.9, 128.1, 128.2, 128.3, 128.4, 128.5, 129.3,
129.3, 130.1, 132.5, 134.3, 138.3, 138.7, 139.0, 165.1, 172.0.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C22H17NNaO2: 350.1152;
found: 350.1172.
2-Methyl-4-[3-(trifluoromethyl)phenyl]isoquinoline-1,3(2H,4H)-
dione (7l)
Obtained from 6a (30 mg, 0.15 mmol) and (trifluoromethyl)benzene
(0.2 mL, 1.64 mmol). Purification by preparative TLC (petroleum
ether/EtOAc, 8:2) gave a yellow oil; yield: 20 mg (41%).
1Н NMR:  = 3.36 (s, 3 H), 5.16 s (1 H), 7.09 (d, J = 8.0 Hz, 1 H), 7.28 (d,
J = 8.0 Hz, 1 H), 7.42–7.47 (m, 2 H), 7.51 (t, J = 7.6 Hz, 1 H), 7.56–7.59
(m, 2 H), 8.32 (dd, J = 7.6, 1.3 Hz, 1 H).
13C NMR:  = 27.5, 52.1, 123.9 q (CF3, J = 272.6 Hz), 125.1 q (J = 3.8 Hz),
125.6., 125.8 q (J = 3.8 Hz), 128.4, 128.6, 129.2, 129.3, 129.7, 131.6 q
(J = 32.5 Hz), 134.3, 137.3, 140.0, 167.8, 171.4.
2-(4-Fluorophenyl)-4-phenylisoquinoline-1,3(2H,4H)-dione (7q)
Obtained from 6f (30 mg, 0.11 mmol) and benzene (0.2 mL, 2.25
mmol) as a yellow oil; yield: 26 mg (74%).
1Н NMR:  = 5.24 (s, 1 H), 7.06–7.15 (m, 4 H), 7.20–7.25 (m, 3 H),
7.31–7.37 (m, 3 H), 7.53 (t, J = 7.5 Hz, 1 H), 7.62 (dd, J = 7.5, 1.5 Hz, 1
H), 8.33 (d, J = 7.5 Hz, 1 H).
13C NMR:  = 53.4, 116.4 (d, J = 22.9 Hz), 125.7, 128.3, 128.4, 128.6,
129.4, 130.3 (d, J = 8.8 Hz), 131.0 (d, J = 3.3 Hz), 134.5, 138.5 (d, J =
54.9 Hz), 162.5 (d, J = 248.0 Hz), 165.0, 171.9.
19F NMR:  = –62.62.
HRMS (ESI-TOF): m/z [M – H]– calcd for C17H11F3NO2: 318.0747;
found: 318.0747.
19F{H} NMR:  = –112.97.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C21H14FNNaO2: 354.0901;
found: 354.0897.
2-Ethyl-4-phenylisoquinoline-1,3(2H,4H)-dione (7m)
Obtained from 6b (30 mg, 0.14 mmol) and benzene (0.2 mL, 2.25
mmol) as a yellow oil; yield: 30 mg (81%).
2-(4-Methoxyphenyl)-4-phenylisoquinoline-1,3(2H,4H)-dione (7r)
1Н NMR:  = 1.17 (t, J = 7.1 Hz, 3 H), 3.93–4.01 (m, 1 H), 4.02–4.11 (m,
1 H), 5.06 (s, 1 H), 7.12–7.14 (m, 3 H), 7.27–7.33 (m, 3 H), 7.46 (td, J =
7.5, 1.3 Hz, 1 H), 7.54 (td, J = 7.5, 1.5 Hz, 1 H), 8.29 (dd, J = 7.8, 1.5 Hz,
1 H).
Obtained from 6g (30 mg, 0.10 mmol) and benzene (0.2 mL, 2.25
mmol) as a red oil; yield: 30 mg (88%).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

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A. Golushko et al.
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Synthesis
1Н NMR:  = 3.81 (s, 3 H), 5.24 (s, 1 H), 6.96 (d, J = 9.1 Hz, 2 H), 7.03 (d,
J = 8.7 Hz, 2 H), 7.21–7.24 (m, 3 H), 7.30–7.35 (m, 3 H), 7.51 (td, J = 7.6,
1.3 Hz, 1 H), 7.61 (td, J = 7.5, 1.5 Hz, 1 H), 8.33 (dd, J = 7.8, 1.5 Hz, 1 H).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H10FNNaO2: 278.0588;
found: 278.0590.
13C NMR:  = 53.4, 55.6, 117.7, 125.9, 127.7, 128.2, 128.3, 128.4, 128.5,
4-Fluoro-2-(4-methylphenyl)isoquinoline-1,3(2H,4H)-dione (12c)
129.28, 129.34, 129.4, 134.3, 138.3, 139.0, 159.6, 165.3, 172.1.
Obtained from 6e (30 mg, 0.11 mmol) as white crystals; yield: 22 mg
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C22H17NNaO3: 366.1101;
(76%); mp 200–203 °C.
1Н NMR:  = 2.43 (s, 3 H), 6.18 (d, J = 46.7 Hz, 1 H), 7.11 (d, J = 8.3 Hz, 2
H), 7.32 (d, J = 8.0 Hz, 2 H), 7.64 (t, J = 7.4 Hz, 1 H), 7.74 (d, J = 7.3 Hz, 1
H), 7.79 (td, J = 7.5, 1.3 Hz, 1 H), 8.25 (d, J = 7.9 Hz, 1 H).
found: 366.1109.
2-Benzyl-4-phenylisoquinoline-1,3(2H,4H)-dione (7s)
Obtained from 6h (30 mg, 0.11 mmol) and benzene (0.2 mL, 2.25
mmol). Purification by preparative TLC (petroleum ether/EtOAc, 8:2)
gave a transparent oil; yield: 15 mg (43%).
1Н NMR:  = 5.06 (d, J = 13.9 Hz, 1 H), 5.11 (s, 1 H), 5.24 (d, J = 13.9 Hz,
1 H), 7.08–7.14 (m, 3 H), 7.20–7.23 (m, 3 H), 7.27–7.30 (m, 3 H), 7.33–
7.36 (m, 2 H), 7.46 (td, J = 7.6, 1.3 Hz, 1 H), 7.54 (td, J = 7.5, 1.5 Hz, 1
H), 8.28 (dd, J = 7.9, 1.5 Hz, 1 H).
13C NMR:  = 21.4, 84.3 (d, J = 184.6 Hz), 124.8 (d, J = 4.3 Hz), 126.6 (d,
J = 5.1 Hz), 128.2, 129.6, 130.3, 130.4 (d, J = 2.4 Hz), 133.2 (d, J = 18.8
Hz), 134.6 (d, J = 1.1 Hz), 139.3, 163.6 (d, J = 1.5 Hz), 167.6 (d, J = 18.9
Hz).
19F NMR:  = –184.53 (d, J = 46.8 Hz, F).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H12FNNaO2: 292.0744;
found: 292.0749.
13C NMR:  = 43.8, 52.9, 125.6, 127.6, 128.10, 128.15, 128.47, 128.50,
128.6, 128.9, 129.1, 129.2, 134.1, 137.1, 138.4, 139.1, 164.8, 171.9.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C22H17NNaO2: 350.1151;
4-Fluoro-2-isopropylisoquinoline-1,3(2H,4H)-dione (12d)
Obtained from 6c (30 mg, 0.13 mmol) as a transparent oil; yield: 21
found: 350.1147.
mg (72%).
1Н NMR:  = 1.48 (d, J = 3.5 Hz, 3 H), 1.50 (d, J = 3.6 Hz, 3 H), 5.10
(hept, J = 6.9 Hz, 1 H), 5.95 (d, J = 47.0 Hz, 1 H), 7.58 (t, J = 7.6 Hz, 1 H),
7.63 (t, J = 7.6 Hz, 1 H), 7.70 (t, J = 7.4 Hz, 1 H), 8.19 (d, J = 7.8 Hz, 1 H).
2-(Dimethylamino)-4-phenylisoquinoline-1,3(2H,4H)-dione (7t)
Obtained from 6i (30 mg, 0.13 mmol) and benzene (0.2 mL, 2.25
mmol) as a yellow oil; yield: 31 mg (86%).
13C NMR:  = 19.3, 20.3, 46.3, 84.2 (d, J = 184.2 Hz), 125.2 (d, J = 4.4
Hz), 126.0 (d, J = 5.0 Hz), 129.2, 130.2 (d, J = 2.3 Hz), 133.1 (d, J = 18.9
Hz), 134.1 (d, J = 1.2 Hz), 163.6 (d, J = 1.5 Hz), 168.3 (d, J = 18.7 Hz).
19F NMR:  = –186.34 (d, J = 47.0 Hz, F).
HRMS (ESI-TOF): m/z [M – H]– calcd for C12H11FNO2: 220.0768; found:
1Н NMR:  = 2.87 (s, 6 H), 5.08 (s, 1 H), 7.10–7.13 (m, 3 H), 7.27–7.32
(m, 3 H), 7.47 (td, J = 7.6, 1.4 Hz, 1 H), 7.54 (td, J = 7.5, 1.5 Hz, 1 H),
8.28 (dd, J = 7.9, 1.5 Hz, 1 H).
13C NMR:  = 43.6, 54.5, 126.3, 128.2, 128.2, 128.2, 128.3, 129.2, 129.3,
134.1, 137.7, 138.6, 164.3, 171.1.
220.0775.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H16N2NaO2: 303.1104;
found: 303.1118.
4-Fluoro-2-(4-fluorophenyl)isoquinoline-1,3(2H,4H)-dione (12e)
Obtained from 6f (30 mg, 0.11 mmol) as a white solid; yield: 20 mg
(69%); mp 168–170 °C.
4-Fluoro-2-methylisoquinoline-1,3(2H,4H)-dione (12a)
Obtained from 6a (140 mg, 0.15 mmol) as yellowish crystals; yield:
90 mg (0.7 mmol); mp 144–146 °C.
1Н NMR:  = 3.38 (s, 3 H), 6.00 (d, J = 46.7 Hz, 1 H), 7.60 (t, J = 7.5 Hz, 1
1Н NMR:  = 6.18 (d, J = 46.7 Hz, 1 H), 7.19–7.21 (m, 4 H), 7.65 (t, J =
7.5 Hz, 1 H), 7.75 (d, J = 7.5 Hz, 1 H), 7.80 (t, J = 7.5 Hz, 1 H), 8.25 (d, J =
7.8 Hz, 1 H).
H), 7.67 (d, J = 7.5 Hz, 1 H), 7.73 (t, J = 7.5 Hz, 1 H), 8.21 (d, J = 7.9 Hz, 1
H).
13C NMR:  = 27.3, 83.7 (d, J = 183.5 Hz), 124.6 (d, J = 4.3 Hz), 126.5 (d,
J = 5.0 Hz), 129.2, 130.3 (d, J = 2.4 Hz), 133.2 (d, J = 18.8 Hz), 134.3 (d,
J = 1.5 Hz), 163.6 (d, J = 1.5 Hz), 168.0 (d, J = 18.9 Hz).
19F NMR:  = –185.12 (d, J = 46.7 Hz, F).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H8FNNaO2: 216.0432;
13C NMR:  = 84.2 (d, J = 184.9 Hz), 116.6 (d, J = 23.0 Hz), 124.6 (d, J =
4.3 Hz), 126.6 (d, J = 5.0 Hz), 129.6, 129.9 (d, J = 3.4 Hz), 130.4 (d, J =
8.8 Hz), 130.5 (d, J = 2.3 Hz), 133.2 (d, J = 18.8 Hz), 134.8 (d, J = 1.4 Hz),
161.5, 163.5 (d, J = 48.0 Hz), 167.5 (d, J = 19.1 Hz).
19F NMR:  = –184.47 (d, J = 46.6 Hz, F), –112.15 to –112.08 (m, Farom).
HRMS (ESI-TOF): m/z [M – H]– calcd for C15H8FNO2: 272.0518; found:
272.0520.
found: 216.0445.
4-Fluoro-2-(4-methoxyphenyl)isoquinoline-1,3(2H,4H)-dione
4-Fluoro-2-phenylisoquinoline-1,3(2H,4H)-dione (12b)
(12f)
Obtained from 6d (30 mg, 0.11 mmol) as a white solid; yield: 24 mg
Obtained from 6g (30 mg, 0.11 mmol) as a white solid; yield: 18 mg
(86%); mp 139–140 °C.
(62%); mp 220–223 °C.
1Н NMR:  = 6.19 (d, J = 76.7 Hz, 1 H), 7.22–7.24. (m, 2 H), 7.45–7.54
(m, 3 H), 7.64 (t, J = 7.5 Hz, 1 H), 7.75 (d, J = 7.3 Hz, 1 H), 7.79 (t, J = 7.4
Hz, 1 H), 8.25 (d, J = 7.9 Hz, 1 H).
1Н NMR:  = 3.86 (s, 3 H), 6.19 (d, J = 46.8 Hz, 1 H), 7.02 (d, J = 8.9 Hz, 2
H), 7.14 (d, J = 8.9 Hz, 2 H), 7.64 (t, J = 7.3 Hz, 1 H), 7.75 (d, J = 7.1 Hz, 1
H), 7.77–7.81 (m, 1 H), 8.26 (d, 7.8 Hz, 1 H).
13C NMR:  = 84.2 (d, J = 184.6 Hz), 124.8 (d, J = 4.5 Hz), 126.6 (d, J =
5.0 Hz), 128.6, 129.2, 129.5, 129.6, 130.5 (d, J = 2.4 Hz), 133.2 (d, J =
18.7 Hz), 134.1, 134.6 (d, J = 1.3 Hz), 163.5 (d, J = 1.6 Hz), 167.5 (d, J =
19.0 Hz).
13C NMR:  = 55.6, 84.3 (d, J = 184.8 Hz), 114.9, 124.8 (d, J = 4.4 Hz),
126.57, 126.62, 129.6, 129.7, 130.5 (d, J = 2.4 Hz), 133.2 (d, J = 18.8
Hz), 134.6 (d, J = 1.0 Hz), 160.0, 163.8 (J = 1.4 Hz), 167.8 (d, J = 18.8
Hz).
19F NMR:  = –184.6 (d, J = 46.7 Hz, F).
19F NMR:  = –184.4 (d, J = 46.6 Hz, F).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

I
A. Golushko et al.
Paper
Synthesis
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H12FNNaO3: 308.0693;
4,4-Difluoro-2-methylisoquinoline-1,3(2H,4H)-dione (12k)
found: 308.0684.
Obtained from 6a (30 mg, 0.15 mmol). Purification by preparative TLC
(petroleum ether/EtOAc, 9:1) gave a yellowish solid; yield: 14 mg
(44%); mp 85–87 °C.
2-Benzyl-4-fluoroisoquinoline-1,3(2H,4H)-dione (12g)
1Н NMR:  = 3.44 (s, 3 H), 7.75 (td, J = 7.6, 1.3 Hz, 1 H), 7.82 (td, J = 7.6,
1.3 Hz, 1 H), 7.89 (dd, J = 7.8, 0.9 Hz, 1 H), 8.28 (dd, J = 8.0, 0.9 Hz, 1 H).
Obtained from 6h (30 mg, 0.11 mmol) as a transparent oil; yield: 23
mg (79%).
1Н NMR:  = 3.86 (s, 2 H), 6.19 (d, J = 46.8 Hz, 1 H), 7.02 (d, J = 8.9 Hz, 2
H), 7.14 (d, J = 9.0 Hz, 2 H), 7.64 (t, J = 7.3 Hz, 1 H), 7.75 (d, J = 7.1 Hz, 1
H), 7.77–7.81 (m, 1 H), 8.26 (d, J = 7.8 Hz, 1 H).
13C NMR:  = 27.6, 105.8 (t, J = 241.1 Hz), 125.6 (t, J = 5.6 Hz), 125.9 (t,
J = 2.7 Hz), 129.4, 131.1 (t, J = 24.4 Hz), 132.6 (t, J = 1.9 Hz), 134.8 (t, J =
1.7 Hz), 162.1, 163.2 (t, J = 30.5 Hz).
13C NMR:  = 55.6, 84.3, 114.9, 124.8 (d, J = 4.4 Hz), 126.57, 126.2,
129.6, 129.7, 130.5 (d, J = 2.4 Hz), 133.2 (d, J = 18.8 Hz), 134.6 (d, J =
1.0 Hz), 160.0, 163.8 (J = 1.4 Hz), 167.7 (d, J = 18.8 Hz).
19F NMR:  = –91.73 (s).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H7F2NNaO2: 234.0337;
found: 234.0343.
19F NMR:  = –184.4 (d, J = 46.6 Hz, F).
HRMS (ESI-TOF): m/z [M – H]– calcd for C16H11FNO2: 268.0768; found:
268.0770.
Funding Information
Synthesis of diazo homophthalimides was supported by the Russian
Science Foundation Grant No. 19-75-30008. Electrophilic reactions of
diazo compounds with arenes and fluorination reactions were sup-
2-(Dimethylamino)-4-fluoroisoquinoline-1,3(2H,4H)-dione (12h)
Obtained from 6i (30 mg, 0.13 mmol) as a yellow oil; yield: 18 mg
(62%).
ported by the Russian Science Foundation Grant No. 18-13-00008.
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1Н NMR:  = 2.94 (s, 6 H), 6.00 (d, J = 46.9 Hz, 1 H), 7.60 (t, J = 7.5 Hz, 1
H), 7.64 (d, J = 7.6 Hz, 1 H), 7.72 (td, J = 7.5, 1.4 Hz, 1 H), 7.80 (d, J = 7.8
Hz, 1 H).
13C NMR:  = 44.0, 84.8 (d, J = 185.6 Hz), 124.8 (d, J = 4.6 Hz), 126.4 (d,
J = 5.0 Hz), 129.4, 130.4 (d, J = 2.3 Hz), 132.7 (d, J = 18.8 Hz), 134.4 (d,
J = 1.5 Hz), 163.0 (d, J = 1.6 Hz), 167.2 (d, J = 18.7 Hz).
Acknowledgement
We thank the Research Centre for Magnetic Resonance, the Center for
Chemical Analysis and Materials Research of Saint Petersburg State
University Research Park for obtaining the analytical data.
19F NMR:  = –184.5 (d, J = 47.0 Hz, F).
HRMS (ESI-TOF): m/z [M – H]– calcd for C11H10FN2O2: 221.0721;
found: 221.0715.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611882. Copies of 1H and 13C NMR
4-Chloro-4-fluoro-2-methylisoquinoline-1,3(2H,4H)-dione (12i)
Obtained from 6a (30 mg, 0.15 mmol). Purification by preparative TLC
(petroleum ether/EtOAc, 9:1) gave white crystals; yield: 18 mg (53%);
mp 104–105 °C.
spectra and crystallographic data are provided.
S
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p
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1Н NMR:  = 3.44 (s, 3 H), 7.67 (t, J = 7.6 Hz, 1 H), 7.80 (td, J = 7.6, 1.4
Hz, 1 H), 7.90 (dd, J = 7.8, 1.2 Hz, 1 H), 8.22 (d, J = 7.8 Hz, 1 H).
References
(1) (a) Chen, Y.-L.; Tang, J.; Kesler, M. J.; Sham, Y. Y.; Vince, R.;
Geraghty, R. J.; Wang, Z. Bioorg. Med. Chem. 2012, 20, 467.
(b) Mayer, S. C.; Banker, A. L.; Boschelli, F.; Di, L.; Johnson, M.;
Kenny, C. H.; Krishnamurthy, G.; Kutterer, K.; Moy, F.; Petusky,
S.; Ravi, M.; Tkach, D.; Tsou, H. R.; Xu, W. Bioorg. Med. Chem.
Lett. 2008, 18, 3641. (c) Billamboz, M.; Bailly, F.; Lion, C.; Touati,
N.; Vezin, H.; Calmels, C.; Andréola, M. L.; Christ, F.; Debyser, Z.;
Cotelle, P. J. Med. Chem. 2011, 54, 1812. (d) Billamboz, M.; Bailly,
F.; Barreca, M. L.; De Luca, L.; Mouscadet, J. F.; Calmels, C.;
Andréola, M. L.; Witvrouw, M.; Christ, F.; Debyser, Z.; Cotelle, P.
J. Med. Chem. 2008, 51, 7717. (e) Vernekar, S. K. V.; Liu, Z.; Nagy,
E.; Miller, L.; Kirby, K. A.; Wilson, D. J.; Kankanala, J.; Sarafianos,
S. T.; Parniak, M. A.; Wang, Z. J. Med. Chem. 2015, 58, 651.
(f) Ontoria, J. M.; Rydberg, E. H.; Marco, S. D.; Tomei, L.; Attenni,
B.; Malancona, S.; Hernando, J. I. M.; Gennari, N.; Koch, U.;
Narjes, F.; Rowley, M.; Summa, V.; Carroll, S. S.; Olsen, D. B.;
Francesco, R. D.; Altamura, S.; Migliaccio, G.; Carfì, A. J. Med.
Chem. 2009, 52, 5217. (g) Chen, Y.-H.; Zhang, Y.-H.; Zhang, H.-J.;
Liu, D.-Z.; Gu, M.; Li, J.-Y.; Wu, F.; Zhu, X.-Z.; Li, J.; Nan, F.-J.
J. Med. Chem. 2006, 49, 1613. (h) Kankanala, J.; Marchand, C.;
Abdelmalak, M.; Aihara, H.; Pommier, Y.; Wang, Z. J. Med. Chem.
2016, 59, 2734.
13C NMR:  = 28.06, 96.0 (d, J = 251.6 Hz), 123.4 (d, J = 5.0 Hz), 125.6
(d, J = 3.9 Hz), 129.3, 131.7 (d, J = 1.2 Hz), 135.0, 135.4 (d, J = 23.3 Hz),
162.1, 164.9 (d, J = 26.3 Hz).
19F NMR:  = –115.25.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C10H8ClFNO2: 228.0222;
found: 228.0214.
4-Bromo-4-fluoro-2-methylisoquinoline-1,3(2H,4H)-dione (12j)
Obtained from 6a (30 mg, 0.15 mmol) as a yellowish solid; yield: 24
mg (58%); mp 110–112 °C.
1Н NMR:  = 3.44 (s, 3 H), 7.65 (td, J = 7.8, 1.4 Hz, 1 H), 7.78 (td, J = 7.8,
1.4 Hz, 1 H), 7.91 (dd, J = 7.9, 1.2 Hz, 1 H), 8.19 (d, J = 7.9 Hz, 1 H).
13C NMR:  = 28.1, 88.1 (d, J = 263.3 Hz), 122.7 (d, J = 4.7 Hz), 125.4 (d,
J = 4.2 Hz), 129.3 (d, J = 1.0 Hz), 131.5 (d, J = 0.8 Hz), 134.9, 136.5 (d, J =
2.7 Hz), 162.1 (d, J = 1.1 Hz), 165.6 (d, J = 24.7 Hz).
19F NMR:  = –119.95.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C10H8BrFNO2: 293.9536;
found: 293.9539.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

J
A. Golushko et al.
Paper
Synthesis
(2) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger,
R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.;
Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.;
Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31,
2235.
(3) Kantin, G.; Dar’in, D.; Krasavin, M. Eur. J. Org. Chem. 2018, 4857.
(4) Guranova, N.; Dar’in, D.; Kantin, G.; Novikov, A.; Bakulina, O.;
Krasavin, M. J. Org. Chem. 2019, 84, 4534.
(12) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell,
N. A. J. Med. Chem. 2015, 58, 8315.
(13) Lassalas, P.; Gay, B.; Lasfargeas, C.; James, M. J.; Tran, V.;
Vijayendran, K. G.; Brunden, K. R.; Kozlowski, M. C.; Thomas, C.
J.; Smith, A. B.; Huryn, D. M.; Ballatore, C. J. Med. Chem. 2016, 59,
3183.
(14) Pan, Y.; Holmes, C. P.; Tumely, D. J. Org. Chem. 2005, 70, 4897.
(15) Emer, E.; Twilton, J.; Tredwell, M.; Calderwood, S.; Collier, T. L.;
Liegault, B.; Taillefer, M.; Gouverneur, V. Org. Lett. 2014, 16,
6004.
(5) Flahive, E.; Ewanicki, B.; Yu, S.; Higginson, P. D.; Sach, N. W.;
Morao, I. QSAR Comb. Sci. 2007, 26, 679.
(6) (a) Zhai, C.; Xing, D.; Jing, C.; Zhou, J.; Wang, C.; Wang, D.; Hu,
W. Org. Lett. 2014, 16, 2934. (b) Satumov, E. T.; Medvedev, J. J.;
Nilov, D. I.; Sandzhieva, M. A.; Boyarskaya, I. A.; Nikolaev, V. A.;
Vasilyev, A. V. Tetrahedron 2016, 72, 4835.
(7) Lowe, J. A.; Newman, M. E. Synth. Commun. 1987, 17, 803.
(8) Yang, Y.; Li, Y.; Cheng, C.; Yang, G.; Zhang, J.; Zhang, Y.; Zhao, Y.;
Zhang, L.; Li, C.; Tang, L. J. Org. Chem. 2018, 83, 3348.
(9) Brossi, A.; Grethe, G.; Teitel, S.; Wildman, W. C.; Bailey, D. T.
J. Org. Chem. 1970, 35, 1100.
(16) Olah, G. A.; Welch, J. T.; Vankar, Y. D.; Nojima, M.; Kerekes, I.;
Olah, J. A. J. Org. Chem. 1979, 44, 3872.
(17) (a) Fan, J.; Kalisiak, J.; Lui, R. M.; Mali, V. R.; Mcmahon, J. P.;
Powers, J. P.; Tanaka, H.; Zeng, Y.; Zhang, P. WO 2016187393
2016; Chem. Abstr. 2016, 166, 28225. (b) Roth, G. J.; Fleck, M.;
Haebel, P. W.; Heimann, A.; Heine, N. US 20160075657, 2016;
Chem. Abstr. 2016, 164, 416513.
(18) CCDC 1910818 – (7a) contains the supplementary crystallo-
graphic data for this paper. The data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
(10) Cueva, J. P.; Giorgioni, G.; Grubbs, R. A.; Chemel, B. R.; Watts, V.
J.; Nichols, D. E. J. Med. Chem. 2006, 49, 6848.
(11) Zara-Kaczian, E.; Gyorgy, L.; Deak, G.; Seregi, A.; Doda, M. J. Med.
Chem. 1986, 29, 1189.
(19) Singh, K. N.; Singh, P.; Singh, P.; Deol, Y. S. Org. Lett. 2012, 14,
2202.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J